2016 ASCO EDUCATIONAL BOOK

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Amgen
Merck & Co., Inc.

AMERICAN SOCIETY OF CLINICAL ONCOLOGY

2016 EDUCATIONAL BOOK

Support for this program is funded through

Collective Wisdom: The Future of Patient-Centered Care and Research

A PEER-REVIEWED, INDEXED PUBLICATION

52nd Annual Meeting | June 37, 2016 | Chicago, Illinois | Volume 36

Vol. 36
American Society of Clinical Oncology Educational Book
The 2016 ASCO Educational Book (Print ISSN: 1548-8748; Electronic ISSN: 1548-8756) is published by American Society of Clinical Oncology,
Inc. (ASCO).

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American Society of
Clinical Oncology
Educational Book
Editor in Chief: Don S. Dizon, MD

Associate Editor: Nathan Pennell, MD, PhD

Managing Editor: Lindsay Pickell, MFA
Production Manager: Donna Dottellis

2016 American Society of Clinical Oncology, Alexandria, VA

Contents
2016 ASCO Annual Meeting Disclosure xiii

20152016 Cancer Education Committee xiv

2016 Educational Book Expert Panel xvi

2016 Annual Meeting Supporters xx

Letter From the Editor 1

INVITED ARTICLES
Collaborative Practice in an Era of Multidisciplinary Care
Michael P. Kosty, Todd Pickard, and Pamela Viale 3
Value in Oncology: Balance Between Quality and Cost
Derek Raghavan and Mark W. Legnini 9
Womens Health Issues for BRCA Mutation Carriers
Mary E. Sabatini and Leif W. Ellisen 14
Collective Wisdom: Lobular Carcinoma of the Breast
George W. Sledge, Anees Chagpar, and Charles Perou 18

POINTS OF VIEW
Compassionate Use: A Modest Proposal
Arthur L. Caplan, Alison Bateman-House, and Joanne Waldstreicher e2
Less Is More: The Evolving Surgical Approach to Breast Cancer
Laura Esserman, Etienne Gallant, and Michael Alvarado e5
Strategies for Sustainable Cancer Care
David J. Kerr, Anant Jani, and Sir Muir Gray e11
The Role of Nephrectomy for Kidney Cancer in the Era of Targeted and Immune Therapies
Ulka N. Vaishampayan e16

BREAST CANCER
Breast Cancer Survivorship: Strategies for Optimal Care
Issues in Breast Cancer Survivorship: Optimal Care, Bone Health, and Lifestyle Modifications
Michelle E. Melisko, William J. Gradishar, and Beverly Moy e22

The 2016 ASCO Educational Book is published online at asco.org/edbook. Articles can also be accessed
from the Attendee Resource Center at am.asco.org/ARC. Articles that are only available online are
denoted with an e ahead of the page number.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK iii

Less Is More: A Multidisciplinary Conversation on Treatment Options
Tailoring Chemotherapy in Early-Stage Breast Cancer: Based on Tumor Biology or Tumor Burden?
Domen Ribnikar and Fatima Cardoso e31

Targeted Therapies in Hormone ReceptorPositive Breast Cancer

Improving Response to Hormone Therapy in Breast Cancer: New Targets, New Therapeutic Options
Hope S. Rugo, Neelima Vidula, and Cynthia Ma e40

Treatment of Premenopausal Women With Endocrine-Sensitive Breast Cancer

Challenges in Treating Premenopausal Women with Endocrine-Sensitive Breast Cancer
Hatem A. Azim Jr., Nancy E. Davidson, and Kathryn J. Ruddy 23

Triple-Negative Breast Cancer: Is Change on the Horizon?

The Evolution of Triple-Negative Breast Cancer: From Biology to Novel Therapeutics
Carey K. Anders, Vandana Abramson, Tira Tan, and Rebecca Dent 34

Updates and Controversies in HER2-Positive Breast Cancer

A Value-Based Approach to Treatment of HER2-Positive Breast Cancer: Examining the Evidence
Nancy Nixon and Sunil Verma e56
Emerging Therapeutic Options for HER2-Positive Breast Cancer
Miguel Martin and Sara Lopez-Tarruella
e64

CANCER PREVENTION, HEREDITARY GENETICS, AND EPIDEMIOLOGY

Controversies in Genetic Evaluation
How Far Do We Go With Genetic Evaluation? Gene, Panel, and Tumor Testing
Filipa Lynce and Claudine Isaacs e72

Evolving Recommendations on Prostate Cancer Screening

Evolving Recommendations on Prostate Cancer Screening
Otis W. Brawley, Ian M. Thompson Jr., and Henrik Gronberg e80

Refining Breast Cancer Risk Assessment: Additional Genes, Additional Screening

Refining Breast Cancer Risk Stratification: Additional Genes, Additional Information
Allison W. Kurian, Antonis C. Antoniou, and Susan M. Domchek 44

CARE DELIVERY AND PRACTICE MANAGEMENT

Access to Cancer Therapeutics in Low- and Middle-Income Countries
Access to Cancer Therapeutics in Low- and Middle-Income Countries
Sana Al-Sukhun, Charmaine Blanchard, Lawrence N. Shulman, and Paul Ruff 58

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Integrating Patient-Reported Outcomes Into Real-Life Medical Decisions
Patient-Reported Outcomes in Cancer Clinical Trials: Measuring Symptomatic Adverse Events With
the National Cancer Institutes Patient-Reported Outcomes Version of the Common Terminology
Criteria for Adverse Events (PRO-CTCAE)
Paul G. Kluetz, Diana T. Chingos, Ethan M. Basch, and Sandra A. Mitchell 67

Optimizing Team-Based Oncology Care: Building the Village

Electronic Patient-Reported Outcomes: The Time Is Ripe for Integration Into Patient Care and
Clinical Research
Lee Schwartzberg e89
Oncology Advanced Practitioners Bring Advanced Community Oncology Care
Wendy H. Vogel e97

Quality and Value: Measuring and Utilizing Both in Your Practice

Why the Quality Oncology Practice Initiative Matters: Its Not Just About Cost
Anne C. Chiang e102

The Oncology Care Model: The Man Behind the Curtain

The Oncology Care Model: A Critique
Christian A. Thomas and Jeffrey C. Ward e109

CENTRAL NERVOUS SYSTEM TUMORS

Multidisciplinary Management of Brain Metastases
Immune Checkpoint Inhibitors in Brain Metastases: From Biology to Treatment
Anna S. Berghoff, Vyshak A. Venur, Matthias Preusser, and Manmeet S. Ahluwalia e116
Targeted Therapy in Brain Metastases: Ready for Primetime?
Vyshak A. Venur and Manmeet S. Ahluwalia e123

The Future of Immunotherapy in Glioblastoma

Current State of Immune-Based Therapies for Glioblastoma
Michael Lim, Michael Weller, and E. Antonio Chiocca e132

Treatment of Low-Grade Gliomas in the Era of Genomic Medicine

Treatment of Adult Lower-Grade Glioma in the Era of Genomic Medicine
Susan M. Chang, Daniel P. Cahill, Kenneth D. Aldape, and Minesh P. Mehta 75

DEVELOPMENTAL THERAPEUTICS AND TRANSLATIONAL RESEARCH

Biomarkers, Blood-Based Testing, and the Heterogeneous Tumor
Tumor Evolutionary Principles: How Intratumor Heterogeneity Influences Cancer Treatment
and Outcome
Subramanian Venkatesan and Charles Swanton e141

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Biosimilars: Here and Now
Biosimilars: Here and Now
Steven J. Lemery, Francisco J. Esteva, and Martina Weise e151

Clinical Trial Eligibility Criteria: Tradition Versus Reality

Transforming Clinical Trial Eligibility Criteria to Reflect Practical Clinical Application
Edward S. Kim, Jennifer Atlas, Gwynn Ison, and Jennifer L. Ersek 83

Immunotherapy: Beyond Checkpoint Inhibitors

Arming the Immune System Through Vaccination to Prevent Cancer Recurrence
Diane F. Hale, Timothy J. Vreeland, and George E. Peoples e159
Overcoming Therapeutic Resistance by Targeting Cancer Inflammation
Gregory L. Beatty e168

Pharmacokinetics, Dynamics, and Genomics in the Era of Immunotherapy and Small Molecules
Pharmacogenomics, Pharmacokinetics, and Pharmacodynamics in the Era of Targeted Therapies
Emiliano Calvo, Christine Walko, E. Claire Dees, and Belen Valenzuela e175

GASTROINTESTINAL (COLORECTAL) CANCER

Potentially Resectable Metastatic Colorectal Cancer: A Multidisciplinary Discussion
Liver Metastases in Colorectal Cancer
Gunnar Folprecht e186

Questions on Treatment of Locally Advanced Rectal Cancer

Multimodal Rectal Cancer Treatment: In Some Cases, Less May Be More
Julio Garcia-Aguilar, Rob Glynne-Jones, and Deborah Schrag 92

GASTROINTESTINAL (NONCOLORECTAL) CANCER

Biliary Tract Cancer: The New and the Old
Biliary Tract Cancer: Epidemiology, Radiotherapy, and Molecular Profiling
John A. Bridgewater, Karyn A. Goodman, Aparna Kalyan, and Mary F. Mulcahy e194

Designing Clinical Trials to Achieve Breakthrough Results in Upper Gastrointestinal Malignancies

The Past, Present, and Future of Pancreatic Cancer Clinical Trials
Lynn M. Matrisian and Jordan D. Berlin e205

HER2, VEGFR, and Beyond: Genomic Profiling of Upper Gastrointestinal Tract Cancers and the Future of
Personalized Treatment
Gastric Adenocarcinoma: An Update on Genomics, Immune System Modulations, and Targeted Therapy
Jeeyun Lee, Adam J. Bass, and Jaffer A. Ajani 104

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Localized Pancreatic Cancer: Multidisciplinary Management With Incorporation of ASCO Guidelines
Localized Pancreatic Cancer: Multidisciplinary Management
Andrew L. Coveler, Joseph M. Herman, Diane M. Simeone, and E. Gabriela Chiorean e217

GENITOURINARY (NONPROSTATE) CANCER

Elderly Patients With Bladder Cancer: Perspectives From a Surgeon, Medical, and Radiation Oncologist
Treatment of Muscle-Invasive Bladder Cancer in Older Patients
Eila C. Skinner e228

Renal Cell Carcinoma: Systemic Treatment, Evolving TKIs, and Immuno-Oncology

The Evolution of Systemic Therapy in Metastatic Renal Cell Carcinoma
Thomas E. Hutson, Gregory R. Thoreson, Robert A. Figlin, and Brian I. Rini 113

GENITOURINARY (PROSTATE) CANCER

Contemporary Active Surveillance for Prostate Cancer: Do We Need Better Imaging and Molecular Testing?
Active Surveillance of Prostate Cancer: Use, Outcomes, Imaging, and Diagnostic Tools
Jeffrey J. Tosoian, Stacy Loeb, Jonathan I. Epstein, Baris Turkbey, Peter L. Choyke,
and Edward M. Schaeffer e235

Oligometastatic Disease in Prostate Cancer: Treating the Patient or the Scan?

Approach to Oligometastatic Prostate Cancer
Brandon Bernard, Boris Gershman, R. Jeffrey Karnes, Christopher J. Sweeney, and Neha Vapiwala 119

Precision Medicine in Advanced Prostate Cancer: Understanding Genomics, Androgen Receptor Splice
Variants, and Imaging Biomarkers
Emerging Molecular Biomarkers in Advanced Prostate Cancer: Translation to the Clinic
Himisha Beltran, Emmanuel S. Antonarakis, Michael J. Morris, and Gerhardt Attard 131

GYNECOLOGIC CANCER
Paradigm Shift in the Management Strategy for Epithelial Ovarian Cancer
Paradigm Shift in the Management Strategy for Epithelial Ovarian Cancer
Keiichi Fujiwara, Jessica N. McAlpine, Stephanie Lheureux, Noriomi Matsumura, and Amit M. Oza e247

Divide and Conquer: Epithelial Gynecologic Cancers Beyond BRCA

Gynecologic Cancers: Emerging Novel Strategies for Targeting DNA Repair Deficiency
Rebecca S. Kristeleit, Rowan E. Miller, and Elise C. Kohn e259

Intraperitoneal Chemotherapy for Ovarian Cancer: Trials and Tribulations

Update on Intraperitoneal Chemotherapy for the Treatment of Epithelial Ovarian Cancer
Charlie Gourley, Joan L. Walker, and Helen J. Mackay 143

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Neoadjuvant Chemotherapy: Location, Location, Location
Primary Surgery or Neoadjuvant Chemotherapy in Advanced Ovarian Cancer: The Debate
Continues
Alexandra Leary, Renee Cowan, Dennis Chi, Sean Kehoe, and Matthew Nankivell 153

Practical Challenges in Endometrial Cancer

Treatment of Older Women With Endometrial Cancer: Improving Outcomes With Personalized Care
Linda Duska, Armin Shahrokni, and Melanie Powell 164

Symptom Management for the Patient with Gynecologic Cancer

Enhancing Care of the Survivor of Gynecologic Cancer: Managing the Menopause and Radiation
Toxicity
Linda Van Le and Mary McCormack e270

HEAD AND NECK CANCER

Best of the Rest: Top Abstracts on Head and Neck Cancer From 20152016 Oncology Meetings
Whats New in Head and Neck Cancer: Key Findings in 20152016 From ECCO/ESMO, ASTRO,
and the Multidisciplinary Head and Neck Cancer Symposium
Sue S. Yom, Apar K. Ganti, and Andreas Dietz 176

Integrating Immune Checkpoint Inhibitors and Targeted Agents With Surgery and Radiotherapy for Patients
With Head and Neck Cancer
Immunotherapy and Checkpoint Inhibitors in Recurrent and Metastatic Head and Neck Cancer
Nooshin Hashemi Sadraei, Andrew G. Sikora, and David M. Brizel e277

Multimodality Management of Locoregionally Recurrent or Second Primary Head and Neck Cancer
Locoregional Recurrent or Second Primary Head and Neck Cancer: Management Strategies
and Challenges
Stuart J. Wong, Dwight E. Heron, Kerstin Stenson, Diane C. Ling, and John A. Vargo e284

HEALTH SERVICES RESEARCH AND QUALITY OF CARE

Defining and Measuring Quality
Challenges and Opportunities in Delivering High-Quality Cancer Care: A 2016 Update
Patricia A. Ganz, Michael J. Hassett, and David C. Miller e294

Removing Barriers to Clinical Trial Participation

The Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies
Joseph M. Unger, Elise Cook, Eric Tai, and Archie Bleyer 185

Using Social Media, Wearables, and Electronic Medical Records to Improve Quality of Cancer Care
Using Technology to Improve Cancer Care: Social Media, Wearables, and Electronic Health Records
Michael J. Fisch, Arlene E. Chung, and Melissa K. Accordino 200

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HEMATOLOGIC MALIGNANCIESLEUKEMIA, MYELODYSPLASTIC SYNDROMES,
AND ALLOTRANSPLANT
Evolving Therapies in Acute Myeloid Leukemia: Progress at Last?
Evolving Therapies in Acute Myeloid Leukemia: Progress at Last?
Daniel J. DeAngelo, Eytan M. Stein, and Farhad Ravandi e302

Molecularly and Phenotypically Defined Subtypes of Acute Lymphoblastic Leukemia: Implications

for Management
Advances in the Genetics and Therapy of Acute Lymphoblastic Leukemia
Sabina Chiaretti, Valentina Gianfelici, Susan M. OBrien, and Charles G. Mullighan e314

Progress in Myeloproliferative Neoplasms: Are We Ready?

Individualizing Care for Patients With Myeloproliferative Neoplasms: Integrating Genetics, Evolving
Therapies, and Patient-Specific Disease Burden
Ruben A. Mesa and Francesco Passamonti e324

Why Are Myelodysplastic Syndromes So Difficult to Cure?

Integrating Frailty, Comorbidity, and Quality of Life in the Management of Myelodysplastic
Syndromes
Gregory A. Abel and Rena Buckstein e337
Searching for a Light at the End of the Tunnel? Beyond Hypomethylating Agents in Myelodysplastic
Syndromes
Rami S. Komrokji e345

HEMATOLOGIC MALIGNANCIESLYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA

Current Management Concepts: Primary Central Nervous System Lymphoma, Natural Killer T-Cell Lymphoma
Nasal Type, Post-transplant Lymphoproliferative Disorder
Current Management Concepts: Primary Central Nervous System Lymphoma, Natural Killer T-Cell
Lymphoma Nasal Type, and Post-transplant Lymphoproliferative Disorder
Tracy T. Batchelor, Lim Soon Thye, and Thomas M. Habermann e354

PET-Directed Strategies in Lymphoma

Functional Imaging Using 18-Fluorodeoxyglucose PET in the Management of Primary Mediastinal
Large B-Cell Lymphoma: The Contributions of the International Extranodal Lymphoma Study Group
Franco Cavalli, Luca Ceriani, and Emanuele Zucca e368
Risk-Adapted Treatment of Advanced Hodgkin Lymphoma With PET-CT
Ryan C. Lynch and Ranjana H. Advani e376

Chemoimmunotherapy Versus Targeted Treatment in Chronic Lymphocytic Leukemia: When, How Long,
How Much, and in Which Combination?
Chemoimmunotherapy Versus Targeted Treatment in Chronic Lymphocytic Leukemia: When,
How Long, How Much, and in Which Combination?
Jennifer R. Brown, Michael J. Hallek, and John M. Pagel e387

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HEMATOLOGIC MALIGNANCIESPLASMA CELL DYSCRASIA
Consolidation and Maintenance: Moving Beyond Autotransplant
Moving Beyond Autologous Transplantation in Multiple Myeloma: Consolidation, Maintenance,
Allogeneic Transplant, and Immune Therapy
Amrita Krishnan, Ravi Vij, Jesse Keller, Binod Dhakal, and Parameswaran Hari 210

Defining and Redefining Myeloma

Future Directions in the Evaluation and Treatment of Precursor Plasma Cell Disorders
Salomon Manier, Karma Z. Salem, David Liu, and Irene M. Ghobrial e400
The Role of Imaging in the Treatment of Patients With Multiple Myeloma in 2016
Evangelos Terpos, Meletios A. Dimopoulos, and Lia A. Moulopoulos e407
Updated Diagnostic Criteria and Staging System for Multiple Myeloma
S. Vincent Rajkumar e418

Multiple Myeloma: Are We Ready for Personalized Therapy?

Minimal Residual Disease by Next-Generation Sequencing: Pros and Cons
Herve Avet-Loiseau e425
New Targets and New Agents in High-Risk Multiple Myeloma
Ajay K. Nooka and Sagar Lonial e431
Next-Generation Sequencing Informing Therapeutic Decisions and Personalized Approaches
Raphael Szalat and Nikhil C. Munshi e442

LUNG CANCER
Immunotherapy: Beyond AntiPD-1 and AntiPD-L1 Therapies
Immunotherapy: Beyond AntiPD-1 and AntiPD-L1 Therapies
Scott J. Antonia, Johan F. Vansteenkiste, and Edmund Moon e450

Local Therapies in the Management of Oligometastatic and Metastatic NonSmall Cell Lung Cancer
Local Therapy for Limited Metastatic NonSmall Cell Lung Cancer: What Are the Options and Is
There a Benefit?
Puneeth Iyengar, Steven Lau, Jessica S. Donington, and Robert D. Suh e460

Lung Cancer Screening and Prevention

Lung Cancer Screening With Low-Dose CT: Implementation Amid Changing Public Policy at One
Health Care System
Abbie Begnaud, Thomas Hall, and Tadashi Allen e468
Lung Cancer Screening, Cancer Treatment, and Addressing the Continuum of Health Risks Caused
by Tobacco
Graham W. Warren, Jamie S. Ostroff, and John R. Goffin 223

Lung Cancer, Small Cell Lung Cancer: On the Move (Again?)

Seeking New Approaches to Patients With Small Cell Lung Cancer
Marie Catherine Pietanza, Stefan Zimmerman, Solange Peters, and Walter J. Curran Jr. e477

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Treatment of Lung Cancer in Medically Compromised Patients
Treatment of Lung Cancer in Medically Compromised Patients
Jeffrey Crawford, Paul Wheatley-Price, and Josephine Louella Feliciano e484

MELANOMA/SKIN CANCERS
Clinical Conundrums in Melanoma Therapy
Biomarkers for Immunotherapy: Current Developments and Challenges
Kristen R. Spencer, Jianfeng Wang, Ann W. Silk, Shridar Ganesan, Howard L. Kaufman,
and Janice M. Mehnert e493

Curing High-Risk Melanoma: Are We There Yet?

Surgical Management and Adjuvant Therapy for High-Risk and Metastatic Melanoma
Alexander C.J. van Akkooi, Michael B. Atkins, Sanjiv S. Agarwala, and Paul Lorigan e505

PATIENT AND SURVIVOR CARE

Cancer Survivorship: Is Every Patients Journey the Same?
The Cancer Survivorship Journey: Models of Care, Disparities, Barriers, and Future Directions
Michael T. Halpern, Mary S. McCabe, and Mary Ann Burg 231

Cancer Treatment as an Accelerated Aging Process

Cancer Treatment as an Accelerated Aging Process: Assessment, Biomarkers, and Interventions
Arti Hurria, Lee Jones, and Hyman B. Muss e516

New and Improved? Use of White Blood Cell Growth Factors in Oncology Practice
Real-World Conundrums and Biases in the Use of White Cell Growth Factors
Thomas J. Smith and Bruce E. Hillner e524
Issues on the Use of White Blood Cell Growth Factors in Oncology Practice
Gary H. Lyman e528

Optimizing Palliative and End-of-Life Care: Evidence-Based Practice Improvement

Discussing the Evidence for Upstream Palliative Care in Improving Outcomes in Advanced Cancer
Myles S. Nickolich, Areej El-Jawahri, Jennifer S. Temel, and Thomas W. LeBlanc e534

Rehabilitation of Patients and Survivors: Seizing the Opportunity

Developing High-Quality Cancer Rehabilitation Programs: A Timely Need
Catherine M. Alfano, Andrea L. Cheville, and Karen Mustian 241

PEDIATRIC ONCOLOGY
Controversies in Germline Genetic Testing and Disclosure in Pediatric Oncology
The Advantages and Challenges of Testing Children for Heritable Predisposition to Cancer
Chimene Kesserwan, Lainie Friedman Ross, Angela R. Bradbury, and Kim E. Nichols 251

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Exploiting Laboratory Insights to Improve Outcomes of Pediatric Central Nervous System Tumors
Exploiting Laboratory Insights to Improve Outcomes of Pediatric Central Nervous System Tumors
Giles W. Robinson, Hendrik Witt, and Adam Resnick e540

The State of the Art in Neuroblastoma: From Biology to Survivorship

Neuroblastoma: A Tough Nut to Crack
Frank Speleman, Julie R. Park, and Tara O. Henderson e548

PROFESSIONAL DEVELOPMENT
Curing Burnout in Oncology: Mindful Self-Compassion, Communication, and Practice
Addressing Burnout in Oncology: Why Cancer Care Clinicians Are At Risk, What Individuals Can Do,
and How Organizations Can Respond
Fay J. Hlubocky, Anthony L. Back, and Tait D. Shanafelt 271

SARCOMA
Is There a Future for Immunotherapy in Sarcoma?
Immunotherapy for Soft Tissue Sarcoma: Tomorrow Is Only a Day Away
Alex Lee, Paul Huang, Ronald P. DeMatteo, and Seth M. Pollack 281
Manipulating the Immune System With Checkpoint Inhibitors for Patients With Metastatic Sarcoma
Sandra P. DAngelo e558

Noncytotoxic Approaches to the Treatment of Metastatic Soft Tissue Sarcoma

Local Ablative Therapies to Metastatic Soft Tissue Sarcoma
Alessandro Gronchi, B. Ashleigh Guadagnolo, and Joseph Patrick Erinjeri e566

TUMOR BIOLOGY
Expanding the Clinically Actionable Cancer Genome
Interrogating the Cancer Genome to Deliver More Precise Cancer Care
Joaquin Mateo and Johann S. de Bono e577

Molecular Diagnostics in Cancer

Considerations for Implementation of Cancer Molecular Diagnostics Into Clinical Care
Daniel F. Hayes 292

Tumor Heterogeneity and Therapeutic Resistance

Tumor Heterogeneity and Therapeutic Resistance
Christine M. Lovly, April K.S. Salama, and Ravi Salgia e585

Whats Next in Cancer Immunotherapy?

Basic Overview of Current Immunotherapy Approaches in Cancer
Vamsidhar Velcheti and Kurt Schalper 298

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2016 ASCO Annual Meeting Disclosure
As the CME provider for the 2016 Annual Meeting, ASCO is committed to balance, objectivity, and scientific rigor in the management of
financial interactions with for-profit health care companies that could create real or perceived conflicts of interest. Participants in the
Meeting have disclosed their financial relationships in accordance with ASCOs Policy for Relationships with Companies; review the policy at
asco.org/rwc.

ASCO offers a comprehensive disclosure management system, using one disclosure for all ASCO activities. Members and participants in
activities use coi.asco.org to disclose all interactions with companies. Their disclosure is kept on file and can be confirmed or updated with
each new activity.

Please email coi@asco.org with specific questions or concerns.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK xiii

20152016 Cancer Education Committee
The Cancer Education Committee assesses the need for, plans, develops, and initiates the education programs for the Annual Meeting.

Apar Kishor Ganti, MD, MBBSChair GASTROINTESTINAL (NONCOLORECTAL) CANCER

Michael A. Thompson, MD, PhDChair-Elect Vincent J. Picozzi, MDTrack Leader
John Vernon Cox, DO, FACP, FASCO, MBAImmediate Past Chair Tanios S. Bekaii-Saab, MD
Lillian L. Siu, MDBoard Liaison Jimmy J. Hwang, MD
Se Hoon Park, MD
BREAST CANCER Manish A. Shah, MD
Hope S. Rugo, MDTrack Leader William Small, MD
Judy Caroline Boughey, MD
Jennifer A. Brown, MD
Raquel Nunes, MD GENITOURINARY (NONPROSTATE) CANCER
Debra A. Patt, MD, MPH, MBA Stephen Boyd Riggs, MDTrack Leader
Rinaa S. Punglia, MD Thomas E. Hutson, DO, PharmD
Elizabeth C. Reed, MD Jose A. Karam, MD
Tallal Younis, MBBCh, FRCP Ulka N. Vaishampayan, MD

CANCER PREVENTION, HEREDITARY GENETICS, GENITOURINARY (PROSTATE)

AND EPIDEMIOLOGY CANCER
P. Kelly Marcom, MDTrack Leader Himisha Beltran, MDTrack Leader
Margreet Ausems, MD, PhD Chris Parker, BA, BM Bchir, MD, FRCR, FRCP
Monique A. De Bruin, MD Edward M. Schaeffer, MD, PhD
Jeri Kim, MD Nicholas J. Vogelzang, MD, FASCO
Howard L. McLeod, PharmD
Electra D. Paskett, PhD GERIATRIC ONCOLOGY
Surendra Srinivas Shastri, MD, MBBS
Andrew S. Artz, MD, MSTrack Leader
William P. Tew, MD
CARE DELIVERY AND PRACTICE MANAGEMENT William Tse, MD
Jeffery C. Ward, MDTrack Leader
Aditya Bardia, MBBS, MPH
GYNECOLOGIC CANCER
Kelly Bugos, RN, ANP, MS
Helen Mackay, MDTrack Leader
Moshe C. Chasky, MD
Elise C. Kohn, MD
John Emmett Hennessy, CMPE, MBA
Linda Duska, MD
Lee Steven Schwartzberg, MD, FACP
Linda Van Le, MD

CENTRAL NERVOUS SYSTEM TUMORS

Manmeet Singh Ahluwalia, MDTrack Leader HEAD AND NECK CANCER
Eric L. Chang, MD Joseph Kamel Salama, MDTrack Leader
Nicole A. Shonka, MD John Truelson, MD
Roger Stupp, MD John A. Ridge, MD, PhD
Irina Veytsman, MD
CLINICAL TRIALS
Sumithra J. Mandrekar, PhDTrack Leader HEALTH SERVICES RESEARCH AND QUALITY OF CARE
Janet Dancey, MD Bruce Lee Jacobs, MDTrack Leader
Ethan M. Basch, MD
DEVELOPMENTAL THERAPEUTICS AND TRANSLATIONAL Daniel Jacob Becker, MD
RESEARCH Dawn L. Hershman, MD
Howard A. Burris, MD, FASCOTrack Leader Nicole Maria Kuderer, MD
Julia A. Beaver, MD Jennifer W. Mack, MD
Francisco J. Esteva, MD, PhD
John Charles Morris, MD HEMATOLOGIC MALIGNANCIESLEUKEMIA,
MYELODYSPLASTIC SYNDROMES,
GASTROINTESTINAL (COLORECTAL) CANCER AND ALLOTRANSPLANT
Donald A. Richards, MD, PhDTrack Leader Jorge E. Cortes, MDTrack Leader
Chris R. Garrett, MD Steven M. Devine, MD
Chi Lin, MD, PhD Jonathan Michael Gerber, MD
Ashwin Reddy Sama, MD Hanna Khoury, MD
Henry Q. Xiong, MD David Leibowitz, MD

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HEMATOLOGIC MALIGNANCIESLYMPHOMA PEDIATRIC ONCOLOGY
AND CHRONIC LYMPHOCYTIC LYMPHOMA Tara O. Henderson, MD, MPHTrack Leader
Grzegorz S. Nowakowski, MDTrack Leader Gregory T. Armstrong, MD, MSCE
Matthew Alexander Lunning, DO Stewart Goldman, MD
Jeffrey Matous, MD Joel A. Weinthal, MD
John M. Pagel, MD, PhD
Michael A. Thompson, MD, PhD PROFESSIONAL DEVELOPMENT
Anne S. Tsao, MDTrack Leader
HEMATOLOGIC MALIGNANCIESPLASMA Kristin Anderson, MD, MPH
Kelly J. Cooke, DO
CELL DYSCRASIA Jill Gilbert, MD
Sagar Lonial, MDTrack Leader Laura Goff, MD
Asher Alban Chanan-Khan, MD Roberto Leon-Ferre, MD
Parameswaran Hari, MD
Irene M. Ghobrial, MD SARCOMA
Ravi Vij, MD Gary K. Schwartz, MDTrack Leader
L. Johnetta Blakely, MD
LUNG CANCER Robin Lewis Jones, MD, BSc, MBBS, MRCP
Martin J. Edelman, MDTrack Leader Min S. Park, MD, MS
Arkadiusz Z. Dudek, MD, PhD
Shirish M. Gadgeel, MD TUMOR BIOLOGY
Puneeth Iyengar, MD, PhD Kimryn Rathmell, MD, PhDTrack Leader
Craig H. Reynolds, MD Ravi Salgia, MD, PhD
David R. Spigel, MD Eliezer Mendel Van Allen, MD
Vamsidhar Velcheti, MD
MELANOMA/SKIN CANCERS
Sanjiv S. Agarwala, MDTrack Leader LIAISONS
Jason John Luke, MD, FACP Sana Al-Sukhun, MD, MScInternational Affairs Committee
Janice M. Mehnert, MD Howard Bailey, MDCancer Prevention Committee
Ahmad A. Tarhini, MD, PhD Gregg Franklin, MD, PhDClinical Practice Committee
Alexander Christopher Jonathan Van Akkooi, MD, PhD Melissa Johnson, MDCancer Research Committee
Thomas Leblanc, MD, MAEthics Committee
PATIENT AND SURVIVOR CARE Leonard Saltz, MDValue Task Force
Nagendra Tirumali, MDTrack Leader Manish Shah, MDClinical Practice Guidelines Committee
Deborah Mayer, PhD, RN, AOCN, FAAN Charles Shapiro, MDCancer Survivorship Committee
Kathi Mooney, PhD, RN William Tew, MDGeriatrics Special Interest Group
Maria Alma Rodriguez, MD Gina Villani, MDClinical Practice Guidelines Committee
Louise Christie Walter, BS, MD Ann Von Gehr, MDClinical Practice Guidelines Committee

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK xv

2016 Educational Book Expert Panel
The Expert Panel is a group of well-recognized physicians and researchers in oncology and related fields who have served as peer
reviewers of the ASCO Educational Book articles.

Ghassan K. Abou-Alfa, MD Emily K. Bergsland, MD Franco Cavalli, MD

Memorial Sloan Kettering Cancer Center, University of California, San Francisco University of Bellinzona
Weill Cornell Medical College
Axel Bex, MD, PhD Andrea Cercek, MD
Donald I. Abrams, MD The Netherlands Cancer Institute Memorial Sloan Kettering Cancer Center
San Francisco General Hospital
William Blum, MD Anthony Chan, MBBS, MD, FRCP, FHKCP,
Manmeet S. Ahluwalia, MD The Ohio State University FHKAM
Cleveland Clinic Sir YK Pao Centre for Cancer, Prince of Wales
Sharon Bober, PhD Hospital
Fabrice Andre, MD, PhD Dana-Farber Cancer Institute
Institut Gustave Roussy Alice Chen, MD
Diane Bodurka, MD, MPH National Cancer Institute at the National
Christina Annunziata, MD, PhD The University of Texas MD Anderson Institutes of Health
National Cancer Institute at the National Cancer Center
Allen M. Chen, MD
Insitutes of Health
Joann Bodurtha, MD, MPH University of California, Los Angeles
Stephen Maxted Ansell, MD Johns Hopkins University School of Medicine Stephen K.L. Chia, MD
Mayo Clinic BC Cancer Agency
George J. Bosl, MD
Frederick Appelbaum, MD Memorial Sloan Kettering Cancer Center Laura Quan Man Chow, MD
Fred Hutchinson Cancer Research Center University of Washington
Alba Brandes, MD
Saro Armenian, DO, MPH Bellaria Hospital Jessica Clement, MD
City of Hope University of Connecticut Health Center
Eduardo Bruera, MD
Gregory Armstrong, MD, MSCE The University of Texas MD Anderson Cancer Anthony Cmelak, MD
St. Jude Childrens Research Hospital Center Vanderbilt-Ingram Cancer Center

Christina Baik, MD, MPH Alan Haruo Bryce, MD Ezra Cohen, MD

Seattle Cancer Care Alliance Mayo Clinic University of California, San Diego

Lodovico Balducci, MD Jan C. Buckner, MD Robert Coleman, MD

Moffitt Cancer Center
Carlos H. Barrios, MD
Pontifical Catholic University of Rio Grande
do Sul School of Medicine
Brigitta G. Baumert, MD, PhD, MBA
University of Bonn Medical Center
Tanios S. Bekaii-Saab, MD
The Ohio State University Comprehensive
Cancer Center
Himisha Beltran, MD
Weill Cornell Medical College
Robert S. Benjamin, MD
The University of Texas MD Anderson
Cancer Center
Michael F. Berger, PhD
Memorial Sloan Kettering Cancer Center
P. Leif Bergsagel, MD, FASCO
Mayo Clinic
Mayo Clinic
Howard A. Burris, MD, FASCO
Sarah Cannon Research Institute, Tennessee
Oncology
Harold Burstein, MD, PhD, FASCO
Dana-Farber Cancer Institute
Toby Christopher Campbell, MD
University of Wisconsin Carbone Cancer
Center
Beverly E. Canin
Breast Cancer Options
Lisa Carey, MD
The University of North Carolina at
Chapel Hill
William L. Carroll, MD
NYU Langone Medical Center
Richard Carvajal, MD
Columbia University Medical Center
The University of Texas MD Anderson Cancer
Center
Frances Collichio, MD
The University of North Carolina at Chapel
Hill
Roisin Connolly, MBBCh
The Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins
Rena M. Conti, PhD
The University of Chicago
Daniel Costa, MD, PhD
Beth Israel Deaconess Medical Center
Carien L. Creutzberg, MD, PhD
Leiden University Medical Center
Sia Daneshmand, MD
University of Southern California
Molly S. Daniels, MS, CGC
The University of Texas MD Anderson Cancer
Center

xvi 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook

Jonas De Souza, MD
The University of Chicago
H. Joachim Deeg, MD
Fred Hutchinson Cancer Research Center
Egidio Del Fabbro, MD
VCU Massey Cancer Center
Pierre-Yves Dietrich, MD
Hopitaux Universitaires de Geneve
` University of Rochester
Mary L. Disis, MD
University of Washington
Tanya B. Dorff, MD
USC Norris Comprehensive Cancer Center
Mitchell Dowsett, PhD
The Royal Marsden NHS Foundation Trust
Martin Dreyling, MD
University Hospital Grosshadern
Dan Duda, DMD, PhD
Massachusetts General Hospital
Reinhard Dummer, MD
University Hospital Zurich
Linda R. Duska, MD
University of Virginia Health System
Grace K. Dy, MD
Roswell Park Cancer Institute
Craig Earle, MD, MSc
Institute for Clinical Evaluative Sciences
Martin J. Edelman, MD
University of Maryland School of Medicine
Lawrence H. Einhorn, MD
Indiana University Melvin and Bren Simon
Cancer Center
James M. Foran, MD
Mayo Clinic
James Ford, MD
Stanford University Medical Center
William Foulkes, MBBS, PhD
Jewish General Hospital
Jonathan Freidberg, MD, MMSc
Richard R. Furman, MD
Weill Cornell Medical College, New York-
Presbyterian Hospital
Leena Gandhi, MD, PhD
Dana-Farber Cancer Institute
David E. Gerber, MD
The University of Texas Southwestern
Medical Center
Peter Gibbs, MBBS, FRACP, MD
The Royal Melbourne Hospital
Sharon Hermes Giordano, MD, MPH
The University of Texas MD Anderson Cancer
Center
Robert G. Gish, MD
Stanford Medicine
Bernardo H.L. Goulart, MD, MS
Fred Hutchinson Cancer Research Center
Ramaswamy Govindan, MD
Washington University School of Medicine in
St. Louis
Timothy Graubert, MD
Massachusetts General Hospital
Gordon Hafner, MD, FACS
Inova Health System
Neil N. Hayes, MD, MPH
The University of North Carolina at Chapel
Hill
Bryan Hennessy, MD
The University of Texas MD Anderson Cancer
Center
John Emmett Hennessy, MBA, CMPE
Sarah Cannon Research Institute
Norah Henry, MD, PhD
University of Michigan
Peter Hillmen, PhD
Leed University
Jeffrey Hoch, PhD
Cancer Care Ontario
Christine Holmberg, DPhil, MPH
Charite Universitatsmedizin Berlin
Gabriel Hortobagyi, MD, FACP
The University of Texas MD Anderson Cancer
Center
Clifford A. Hudis, MD, FACP
Memorial Sloan Kettering Cancer Center
Kevin S. Hughes, MD, FACS
Harvard Medical School, Massachusetts
General Hospital
Kelly Hunt, MD
The University of Texas MD Anderson Cancer
Center
Maha Hussain, MD, FACP, FASCO
University of Michigan
Thomas Hutson, DO, PharmD, FACP
Texas Oncology, Baylor Charles A. Sammons
Cancer Center

Hatem El Halabi, MD Peter Hammerman, MD, PhD David H. Ilson, MD, PhD
Cancer Treatment Centers of America Dana-Farber Cancer Institute Memorial Sloan Kettering Cancer Center,
Weill Cornell Medical College
Marwan Fakih, MD Hans Hammers, MD, PhD
City of Hope Johns Hopkins University School of Medicine Syma Iqbal, MD
University of Southern California
Lesley Fallowfield, DPhil, BSc Nasser H. Hanna, MD
Sussex Health Outcomes Research and Indiana University Melvin and Bren Simon David Jablons, MD
Education in Cancer Cancer Center University of California, San Francisco
Michelle A. Fanale, MD Michelle Harvie, PhD Sekwon Jang, MD
The University of Texas MD Anderson Cancer Nightingale and Genesis Prevention Centre, Inova Comprehensive Cancer and Research
Center Wythenshawe Hospital Institute
Adele K. Fielding, MBBS, PhD Hege Haugnes, MD, PhD Michalina Janiszewska, PhD
University College London University Hospital of North Norway Dana-Farber Cancer Institute
Paul Graham Fisher, MD Axel Hauschild, MD Connie Jimenez,
PhD
Stanford University University of Kiel Vanderbilt University Medical Center
Gini F. Fleming, MD Gillian Haworth, MBBS Maxine S. Jochelson, MD
University of Chicago Medical Center Great Ormond Street Hospital for Children Memorial Sloan Kettering Cancer Center

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK xvii

Joseph Jurcic, MD
Columbia University Medical Center
Matthew Katz, MD, FACS
The University of Texas MD Anderson Cancer
Center
Steven Katz, MD, MPH
University of Michigan Medical School
Stanley B. Kaye, MBBS, MRCP, MD, FRCP,
FRCPS, FRSE, FMedSci
The Institute of Cancer Research, The Royal
Marsden NHS Foundation Trust
Andrew Kennedy, MD, FACRO
Sarah Cannon Research Institute
Gretchen Kimmick, MD
Duke University Medical Center
Hedy Kindler, MD
The University of Chicago
Heidi D. Klepin, MD, MS
Wake Forest University School of Medicine
Theresa Koppie, MD
Oregon Health & Science University
Thomas Krivak, MD
Magee-Womens Hospital of UMPC
Ian Krop, MD, PhD
Dana-Farber Cancer Institute
Geoff Ku, MD, MBA
Memorial Sloan Kettering Cancer Center
Shaji Kumar, MD
Mayo Clinic
Stephen Yenzen Lai, MD, PhD
The University of Texas MD Anderson Cancer
Center
James M.G. Larkin, MD, PhD
The Royal Marsden NHS Foundation Trust
Jonathan Ledermann, MD, FRCP
University College London Cancer Institute
Stuart M. Lichtman, MD
Memorial Sloan Kettering Cancer Center
Nancy Lin, MD
Dana-Farber Cancer Institute
Tracy Lively, PhD
National Cancer Institute at the National
Institutes of Health
Ravi Madan, MD
National Cancer Institute at the National
Institutes of Health
xviii 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Rami Manochakian, MD Ray D. Page, DO, PhD
Case Western Reserve University, Louis The Center for Cancer and Blood Disorders
Stokes Cleveland VA Medical Center
Sumanta Pal, MD
Mara-Victoria Mateos, MD, PhD City of Hope
University Hospital of Salamanca-IBSAL
Alberto Pappo, MD
Rana McKay, MD St. Jude Childrens Research Hospital
Dana-Farber Cancer Institute
Chris Parker, FRCR, BA, MBBCh, MD
Usha Menon, MD The Royal Marsden NHS Foundation Trust
University College London
Donald Williams Parsons, MD, PhD
Paul A. Meyers, MD Texas Childrens Cancer Center, Baylor
Memorial Sloan Kettering Cancer Center College of Medicine
Lynne Penberthy, MD, MPH
Linda R. Mileshkin, MBBS, MD, MBioeth
National Cancer Institute at the National
Peter MacCallum Cancer Centre
Institutes of Health
Matthew Milowsky, MD
Vincent J. Picozzi, MD
The University of North Carolina at Chapel
Hill Virginia Mason Medical Center
Blase N. Polite, MD, MPP
Shanu Modi, MD
Memorial Sloan Kettering Cancer Center The University of Chicago
Sandro V. Porceddu, MD
Ana Molina, MD
Weill Cornell Medical College Princess Alexandra Hospital
Michael Andrew Postow, MD
Alison Moliterno, MD
Johns Hopkins University Memorial Sloan Kettering Cancer Center
Thomas Powles, MD
Silvio Monfardini, MD
Barts Health
Istituto Palazzolo Fondazione Don Gnocchi
Kumar Prabhash, MD, DM
Halle C.F. Moore, MD
Tata Memorial Centre
Cleveland Clinic
Amanda Psyrri, MD, PhD
Kathleen N. Moore, MD
Attikon Hospital National Kapodistrian
The University of Oklahoma Health Sciences
University of Athens
Center
Cornelis J.A. Punt, MD, PhD
Philippe Moreau, MD University of Amsterdam
CHU de Nantes, Hotel DieuHME
Mark J. Ratain, MD
Lindsay Morton, PhD The University of Chicago
National Cancer Institute at the National
Institutes of Health John Ridge, MD, PhD
Fox Chase Cancer Center
Michael Neuss, MD
Vanderbilt-Ingram Cancer Center Danny Rischin, MBBS, MD, FRACP
Peter MacCallum Cancer Centre
Lee Nisley Newcomer, MD
United Health Group Miriam B. Rodin, MD, PhD
Saint Louis University School of Medicine
Grzegorz S. Nowakowski, MD
Mayo Clinic Julia Rowland, PhD
National Cancer Institute at the National
Olatoyosi Odenike, MD Institutes of Health
The University of Chicago
David P. Ryan, MD
Francesco Onida, MD Massachusetts General Hospital
University of Milan
Gilles A. Salles, MD, PhD
Eric Padron, MD Hospices Civils de Lyon, Universite Claude
Moffitt Cancer Center Bernard
Hanna Kelly Sanoff, MD, MPH
University of North Carolina at Chapel Hill
School of Medicine
Gary K. Schwartz, MD
Columbia University Medical Center
David W. Scott, MBCHB, PhD
BC Cancer Agency
Tanguy Y. Seiwert, MD
The University of Chicago
Charles L. Shapiro, MD
Ichan School of Medicine at Mount Sinai
Liran Shlush, MD, PhD
Princess Margaret Cancer Centre
Marc Shuman, MD
USCF Helen Diller Comprehensive Cancer
Center
Sonali Smith, MD
The University of Chicago
John David Sprandio, MD
Consultants in Medical Oncology and
Hematology
Zsofia K. Stadler, MD Catherine H. Van Poznak, MD
Memorial Sloan Kettering Cancer Center University of Michigan Comprehensive
Cancer Center
Stephan Stilgenbauer, MD
University Hospital Ulm Brian Van Tine, MD, PhD
Washington University School of Medicine in
Richard Sullivan, PhD St. Louis
Kings Health Partners Integrated Cancer
Anna Varghese, MD
Centre
Memorial Sloan Kettering Cancer Center
Joel Tepper, MD Dian Wang, MD, PhD
The University of North Carolina at Chapel Rush University Medical Center
Hill
Lari B. Wenzel, PhD
William P. Tew, MD University of California, Irvine
Memorial Sloan Kettering Cancer Center,
Weill Cornell Medical College William Wierda, MD, PhD
The University of Texas MD Anderson Cancer
Center
Mike Thompson, MD, PhD
Aurora Clinic
Peter Yu, MD
Palo Alto Medical Foundation
Andreas Ullrich, MD, MPH
World Health Organization Andrew Zelenetz, MD, PhD
Memorial Sloan Kettering Cancer Center
Saad Zafar Usmani, MD
Levine Cancer Institute/Carolinas Healthcare Clive Zent, MD
System University of Rochester
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK xix
2016 Annual Meeting Supporters*
MISSION ENDOWMENT FOUNDING DONORS
Genentech BioOncology
GlaxoSmithKline Oncology
Novartis Oncology
Sanofi Oncology

MISSION ENDOWMENT SUSTAINING DONORS

AbbVie, Inc.
Amgen
Astellas
AstraZeneca
Celgene Corporation
Eisai Inc.
Gilead Sciences, Inc.
HELSINN
Incyte Corporation
Lilly
Onyx Pharmaceuticals
Sanofi Oncology
Takeda Oncology

ENDOWED FUND DONORS

Anonymous
Sally Gordon YIA Endowment Fund
Conquer Cancer Foundation of ASCO Young Investigator Award, in memory of Sally Gordon
American Society of Clinical Oncology
Jane C. Wright, MD, YIA Endowment Fund
Jane C. Wright, MD, Young Investigator Award
Friends, Family, and Colleagues of Dr. Ronald Beller and Mrs. Judith Beller
Bradley Stuart Beller Endowment Fund
Bradley Stuart Beller Merit Award
Breast Cancer Research Foundation
Evelyn H. Lauder YIA Endowment Fund
Conquer Cancer Foundation of ASCO Young Investigator Award, in memory of Evelyn H. Lauder
Celgene Corporation
John R. Durant, MD, YIA Endowment Fund
Conquer Cancer Foundation of ASCO Young Investigator Award, in memory of John R. Durant, MD
GlaxoSmithKline Oncology
Gianni Bonadonna Award and Lecture Endowment Fund
Gianni Bonadonna Breast Cancer Award and Fellowship
HELSINN
Anna Braglia YIA Endowment Fund
Anna Braglia Young Investigator Award in Cancer Supportive Care, supported by HELSINN
Friends, Family, and Colleagues of Dr. James B. Nachman
James B. Nachman Pediatric Oncology Fund
James B. Nachman ASCO Junior Faculty Award in Pediatric Oncology
Aaron and Barbro Sasson
Bertil Eriksson YIA Endowment Fund
Ake
Bertil Eriksson Endowed Young Investigator Award
Ake

* This list reflects commitments as of April 18, 2016.

xx 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook

CANCERLINQ MAJOR SUPPORTERS Bayer HealthCare Pharmaceuticals Inc. Merck & Co., Inc.
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK xxi

Adenoid Cystic Carcinoma Research
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xxii 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK xxiii

Letter From the Editor
O n behalf of my Associate Editor, Dr. Nate Pennell, I welcome you to the 2016 American Society of Clinical Oncology (ASCO)
Annual Meeting. It is also my distinct honor to present the 36th volume of the NLM-indexed ASCO Educational Book. This
years theme, Collective Wisdom: The Future of Patient-Centered Care and Research, sits at the heart of what we aim to do as
oncologists: improve the lives of patients with cancer. Harnessing our combined knowledge, not just the expertise of one, is how
we must deliver the highest quality of personalized care to meet the diverse needs of our patients.

Dr. Julie Vose, 20152016 ASCO President, challenged us to bring our readers a volume that reflected the multidisciplinary
aspects of cancer care, representing not only the roles of the many different types of health care providers and their specialties,
but also topics such as quality, cost, and survivorship. We answered by requesting articles authored with this interdisciplinary
view in mind, and I am pleased to say that we have more co-authored articles than ever before represented in this years
volume. To be sure, the level of effort required for this impressive collaboration of minds was no small feat, and I humbly thank
the more than 100 authors who generously took the time to write and, in some cases, revise the articles in this volume.

In the same vein, the Invited Articles in this volume illustrate how, as our knowledge of cancer evolves, we must include
various areas of expertise to transform how we deliver care to our patients, such as enlisting genetic counselors and enhancing
the role of advanced practitioners. Beyond that, applying our collective wisdom into practice also means expanding com-
munication; we must incorporate results of molecular biology into treatment plans and converse honestly with patients about
treatment costs and care expectations, among other strategies. I graciously thank the authors of these articles for their
contributions to this volume.

This year, our readers will also find a new type of article that we are calling Points of View. Articles published under this
banner describe emerging and/or controversial topics in oncology care. I believe these articles are a most valuable addition to
the volume and highlight important care considerations for our patients as well as for the field of oncology.

Lastly, I want to recognize and thank our truly remarkable expert panel who dedicated their time and effort to careful,
thorough, and thoughtful reviews. Your commitment to education and ASCOs mission cannot be highlighted enough and is
tremendously underscored by this years theme.

It is my honor to invite you to read through the exceptional contributions that comprise the 2016 volume, only a selection of
which are found in the print edition. The print edition includes a curated selection of articles that most embody the power our
collective wisdom. For access to all of the 2016 ASCO Educational Book articles, as well as access to past volumes, please visit
www.asco.org/edbook.

Nate and I welcome your feedback and suggestions on how we can improve the content, so please contact us at edbook@
asco.org with your comments.

Sincerely,

Don S. Dizon, MD
Editor in Chief

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 1

INVITED ARTICLES
This years invited articles represent the 2016 ASCO Annual Meeting theme, Collective Wisdom: The Future
of Patient-Centered Care and Research. These important contributions to the 36th volume of the ASCO
Educational Book focus on the significance of a collaborative approach to how we provide care for our
patients. The authors represent a diverse, multidisciplinary set of expertise and backgrounds.

AUTHORS
Michael P. Kosty, MD, FACO, FASCO
Scripps Clinic
La Jolla, CA

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO

Levine Cancer Institute, Carolinas HealthCare System
Charlotte, NC

Mary E. Sabatini, MD, PhD

Massachusetts General Hospital
Boston, MA

George W. Sledge, MD, FASCO

Stanford University School of Medicine
Stanford, CA
 INVITED ARTICLES
Collaborative Practice in an Era of Multidisciplinary Care
Michael P. Kosty, MD, FACP, FASCO, Todd Pickard, MMSc, PA-C, and Pamela Viale, RN, MS, CNS, ANP
T he clinical practice of oncology has become increasingly
complex. An explosion of medical knowledge, increased
demands on provider time, and involved patients have
necessitated changes in the way many oncologists practice.
What was an acceptable practice model in the past may
now be relatively inefficient. The American Society of Clinical
Oncologys (ASCOs) annual National Oncology Census dem-
onstrates that with each successive year there is a shift
away from small independent group practice to larger in-
dependent groups or hospital-based affiliations.1-3 It is
unclear whether there will be further consolidation and/or
shift, or whether the rate of change will accelerate or
continue at its current pace. Ultimately, understanding the
practice environment surrounding providers who care for
patients with cancer is important to ensure that increasingly
complex therapies are delivered in an efficient, value-based
setting and that all patients have access to high-quality
cancer care.
The 2015 ASCO State of Cancer Care in America report
emphasized practice trends: workforce composition, health
systems innovation, regulatory compliance, and the financial
realities of cancer care today.4 Among the most pressing
issues the report highlighted was a growing population of
patients with cancer, increased complexity of care provided,
and an oncology workforce projected to fall short of the
expected demand (Fig. 1). In a recent survey of 22,000
oncologists, 11,700 medical oncologists were estimated to
provide direct care, managing the majority of patients with
cancer over extended periods of time.5 Factors contributing
to this predicted shortfall of providers and increasing
complexity of cancer care delivery are shown in Sidebar 1.6
Efficient multimodality therapy requires coordinated care
delivery among many diverse groups of clinical providers as
patients move along the continuum of cancer carefrom
risk assessment, prevention, diagnosis, treatment, and sur-
veillance to survivorship and care of advanced cancer.
Within any given clinic, increasingly complex therapies
require clinicians with advanced, specialized training.
From the Scripps Green Cancer Center, Scripps Clinic, La Jolla, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Physiological Nursing, University of
California, San Francisco, San Francisco, CA.
Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.
Corresponding author: Michael P. Kosty, MD, FACP, FASCO, Scripps Green Cancer Center, Scripps Clinic, 10666 North Torrey Pines Rd., MS217, La Jolla, CA 92037; email: mkosty@
scripps.edu.
2016 by American Society of Clinical Oncology.
COLLECTIVE WISDOM
Clear communication and transparent, defined roles and
responsibilities help ensure that care needs are addressed
and timely decisions are made. Lasting change can only come
from explicitly helping to transform individual clinicians and
separate groups into a team that works together.
Teams are defined as two or more people who interact
dynamically, interdependently, and adaptively to accom-
plish a shared goal.7 The field of primary care has actively
engaged in reinventing care to form a patient-centered
medical home.8-10 Experiments are underway to apply the
same concepts to specialty care delivery.11-16 At the same
time, public and private payers and ASCO are proposing
payment models that would move away from payment
based on specific procedures and physician contributions
toward an approach that provides bundled payments for
comprehensive care and allows greater flexibility in how
care is organized and delivered.17 A team-based approach
can potentially leverage these changes, provide an oppor-
tunity to reexamine clinician roles and responsibilities, and
may enable the most efficient delivery of high-quality health
care services. Ongoing education, training, mentorship,
networking, and communication are necessary to cultivate
and maintain a collaborative team-based practice model.
Integration of resources from each practice setting, com-
munity organizations, e-health technologies, and advocacy
groups is essential. Human factors, health system factors,
situational factors, and socioeconomic factors are constantly
changing within the continuum of care, and they must be
considered in designing tailored patient and caregiver
support (Fig. 2).6 The National Cancer Institute (NCI) and
ASCO have collaborated to bring clinicians, patient advo-
cates, and researchers together to explore application of the
evidence of team effectiveness to clinical practice. This
project fits into the larger context of the transformation of
health care delivery and payment models. The NCI-ASCO
Teams in Cancer Care Delivery project was presented at
the NCI-ASCO Teams in Cancer Care Delivery Workshop
in February 2016. Their findings will be published in the
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 3
KOSTY, PICKARD, AND VIALE

FIGURE 1. Baseline Projected Supply of and Demand
for Oncologist Visits, 2005 to 20205
Journal of Oncology Practice. In the context of increasingly
complex care requirements, increasing demand, and de-
creasing physician and economic resources, how do we create a
collaborative team-based practice model that allows for the
provision of high-quality, value-based oncology care?
INTEGRATING ADVANCED PRACTICE PROVIDERS
INTO ONCOLOGY PRACTICE
The cost of care is a primary concern in oncology today.
Collaborative practice models that provide mecha-
nisms for revenue generation and reduce unnecessary
costs to patients through application of clinical practice
guidelines will promote patient and provider satisfaction.
Shulman18 suggested several goals for integrating advanced
practice providers (APPs) into collaborative practice
in oncology: (1) improved patient care, (2) increased
clinical productivity, (3) improved access for patients,
(4) urgent care patient treatment, (5) long-term care of
patients with cancer, and (6) coverage for the academic
physician. 6 The oncology APP is a licensed health care
professional who has completed advanced training in
nursing or pharmacy or has completed training as a physician
assistant.
The use of APPs to help meet the workforce demands and
improve the quality and coordination of care has been one of
the proposed solutions since the ASCO board of directors
approved the initial workforce strategic plan in 2008. The
utilization of APPs in oncology practices can increase
practice efficiency, productivity, and professional satisfac-
tion of collaborating oncologists.19 The APPs role is diverse
and includes both inpatient and outpatient settings. Recent
publications have highlighted the practice of physician as-
sistants who provide intensive palliative care on inpatient
units through an interdisciplinary team model.20 Similarly,
nurse practitioners have published their experiences as an
inpatient malignant hematology nurse practitioner service
working within a collaborative and multidisciplinary model.21
The utilization of APPs on an allogeneic stem cell transplant unit
resulted in decreased length of stay and reduced hospital
charges with similar patient outcomes.22 Towle and col-
leagues23 suggested similar roles for the APP in a collaborative
practice model. These included (1) assisting patients during
treatment visits; (2) pain and symptom management; (3)
follow-up care for patients in remission (survivorship care); (4)
patient education and counseling; (5) end-of-life care; and (6)

SIDEBAR 1. Factors Affecting the Demand and Complexity of Cancer Care6

1. Implementation of the Affordable Care Act has resulted in an increasing number of individuals gaining access to health care.
2. An aging population has Medicare as their primary insurance.
3. The number of cancer survivors is growing related to improvements in cancer detection, risk-adapted treatment strategies,
supportive care, and palliative care.
4. Increasing costs of care are resulting in a shift in practice models and the integration of formalized programs for preauthorization
and reimbursement.
5. The oncology workforce is aging (50% over the age of 50), with a shift toward group practices in urban settings (. 90%).
6. Cancer care initiatives are being set as standards of care or required for certification necessary to achieve designation or improve
revenue.
7. Meaningful Use benchmarks are being developed for the use of electronic health records and patient-reported outcomes and their
impact on physician productivity.
8. The American College of Surgeons Commission on Cancer published Cancer Program Standards 2012: Ensuring Patient-Centered
Care, which established new requirements around patient-centered needs and is expanding the focus on improving the quality of
care and patient outcomes. More recently, the Commission on Cancer has set a standard for distress screening for every patient
with cancer and their caregivers across the continuum of care.
9. Survivorship care: The Institute of Medicine, ASCO, and the Commission on Cancer have set guidelines for survivorship care. Cancer
survivors are projected to exceed 19 million by 2024.
10. Palliative care: The Institute of Medicine released its report, Improving Palliative Care for Cancer, in 2000. ASCO published
a provisional clinical opinion in 2012, recommending that palliative care be integrated into the care of every patient with cancer at
the time of diagnosis. The National Consensus Project put forth its Clinical Practice Guidelines for Palliative Care, a set of nationally
recognized guidelines that include quality measures and the eight domains of palliative care. The National Comprehensive Cancer
Network published the first clinical practice guidelines for palliative care in 2013.

4 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


FIGURE 2. Collaborative Practice Relationships
Collaborative practice in oncology is a dynamic process focused on
interdisciplinary support of patients and their caregivers with a broad range of
health care providers. The AP in oncology plays a critical role in the collaborative
treatment of patients and their caregivers. Ongoing education, training,
mentorship, networking, and communication are necessary to cultivate and
maintain a collaborative practice model. Integration of resources from each
practice setting, community organizations, e-health technologies, and advocacy
groups is essential. Human factors, health system factors, situational factors, and
socioeconomic factors are ever-changing within the continuum of care and must
be considered in designing tailored patient and caregiver support.6
Abbreviations: AP, advanced practice provider.
Reprinted with permission from the Advanced Practitioner Society for
Hematology and Oncology.
ordering chemotherapy. The underlying theme in these
publications is that a collaborative practice model, with on-
cologists and APPs in oncology working together to the extent
of their training and licensure, can improve patient and pro-
vider satisfaction and safety and increase productivity and
revenue.24,25 However, the degree to which the use of APPs
FIGURE 3. Collaborative Practice Models Represented by the APSHO Practice Survey (192 patients)6,27
Abbreviation: APSHO, Advanced Practitioner Society for Hematology and Oncology.
COLLABORATIVE PRACTICE IN AN ERA OF MULTIDISCIPLINARY CARE
can help meet future demand is unclear because the current
and projected workforce of APPs in oncology has been
challenging to determine. Based on census data from 2013,
the American Academy of Physician Assistants (AAPA) re-
ported that there were an estimated 2,140 practicing
physician assistants in adult medical, surgical, and radiation
oncology subspecialties.2 This represented a 25% increase
compared with 2010 census data.3 However, important
characteristics such as age, geographic distribution, education,
years of experience, and years to expected retirement are un-
known. Similar challenges are faced when trying to describe
the nurse practitioner workforce in oncology. The American
Association of Nurse Practitioners (AANP) publically reports
survey data for licensed nurse practitioners. In 2013, of the
more than 205,000 licensed nurse practitioners, approxi-
mately 2,050 worked in oncology and had been in practice for
an average of 7.7 years and had a median age of 48.25
Varied collaborative practice models are currently in use
based on the needs of the practice, patient volume, skills, and
training of the physician and the APP. Each has implications for
billing and productivity. The key to efficient integration of an
APP in oncology into a collaborative practice model is a careful
assessment of skills and knowledge about oncology practice.
At a high level, potential roles of an APP include enabling
physicians to focus on more complex and higher acuity
patient needs; extending the range of high-level services for
patients without using additional physician time; and pro-
viding follow-up, symptom management, and survivorship
care to patients. To accomplish this, three models of care
utilize APPs in the team-based care setting: (1) the auton-
omous or independent visit model, in which APPs pre-
dominantly see patients independently in a clinic but under a
collaborative practice agreement with their physicians; (2)
the shared visit model, in which patients are seen by both
the APP and the physician during the same clinical en-
counter; and (3) the mixed visit model, in which both the
independent and shared visit models are used to manage the
clinical volume but neither is the predominant encounter
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 5
KOSTY, PICKARD, AND VIALE
used.26 The independent visit practice model goal is not to
supplant or replace physician involvement but to allow
physicians to delegate these tasks and medically direct
without a required physical presence at the time of service.
The shared visit model goal is to allow for combining
the individual efforts of the APPs and physicians into a
comanaged service that allows physicians to increase patient
volumes and the medical services they provide. This model
allows physicians to be continuously involved and to dele-
gate aspects of the services provided to the APP. The col-
laborative practice models represented by the Advanced
Practitioner Society for Hematology and Oncology (APSHO)
practice survey are shown in Figure 3.
To examine the differences between the different models,
Buswell et al26 reported the effect of these practice models
on productivity, fees, and provider and patient satisfaction
in an academic cancer center. They found that productivity
for the independent, mixed, and shared visit models, as
measured by the number of new and established patients,
was similar for all models (6.8, 6.7, and 7.0 patients seen
per 4-hour session, respectively). Both physician and APPs
were very satisfied with the independent visit model and
reported patient-centered and productivity-based reasons
influencing the decision to use their chosen model. The
shared visit model physicians were still very satisfied with
the model whereas APPs were only moderately satisfied.
Reasons for utilizing the shared visit model were more
physician-centered, focusing on physician preferences and
perceptions. Importantly, there were extremely high levels
of patient satisfaction for both models (100% satisfaction
with care received from either model).
In a much larger study in the private practice setting, the
results of the ASCO study of collaborative practice arrange-
ments similarly noted high levels of patient and provider
satisfaction with the different APP models.23 The most com-
mon model in the survey was the independent visit model. The
independent visit model was 19% more productive (based on
relative value units, RVUs) when the APP worked with the
entire group of physicians as compared with an independent
visit model when the APP worked exclusively with a limited
number of physicians. However, it may not be correct to
conclude that the most productive RVU model is the ideal
model in which to use APPs. Further insight into measures of
quality and continuity of care of the two models would be
important to distinguish. In addition, using RVUs as the sole
productivity measure is a limited assessment of the value an
APP might add to a practice. This study did not take into ac-
count the nonrevenue-generating activity performed for each
model, which could be important in defining the preferred
practice model. Value is not only about revenue generation;
quality of care and clinical productivity also are important and
might enhance physician quality of life.6,27
BARRIERS TO INTEGRATION
Provider and Patient
ASCOs study of the collaborative practice arrangements of
APPs identified physicians lack of interest in working with
6 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
APPs as the most common reason not to use them in their
practice.23 Exploring potential reasons for this lack of in-
terest is important to determine how to best motivate at-
titudinal change. Because the ASCO report was primarily
physician-owned private practices (73%) with only 8% sur-
veyed in academic practice, it is possible this lack of interest
was based on the fear of decreased physician compensation.
It has been shown that the private practice model has
significantly more oncologists compensated on an incentive-
based model compared with academic models (39.3% vs.
3.1%). 28 Therefore, it may be important to focus on the
increased practice productivity when using APPs to
encourage utilization in private practice. Furthermore,
because a pure incentive-based model is associated with the
highest rate of burnout, increased professional satisfaction
when working with APPs can be another educational point to
change perceptions.
Other challenges to incorporating APPs into clinical
practice are largely historical or based more on personal bias
than fact.29 For example, data do not substantiate the belief
that utilizing APPs will negatively affect the physician-
provider relationship or that patients will not accept APPs
as part of the care team. Studies have demonstrated high
levels of patient and provider satisfaction with the collab-
orative practice model with increased utilization nation-
ally.23 It is likely that the portion of the workforce nearing
retirement is also the same group that has less experience
and understanding of the physician assistant and nurse
practitioner professions and, therefore, more perceived
bias. This attitude is changing as new oncologists entering
the workforce come with experience working with APPs
during their fellowship. In a survey of fellowship program
directors in 2011, 90% of medical directors reported that
their fellows work with physician assistants and nurse
practitioners.30 What is unclear is how well prepared these
oncologists are to lead a medical team that incorporates
APPs. It will be important moving forward for oncologists to
understand the different models for APP utilization, as well
as the regulatory and reimbursement requirements to lead
the medical team effectively. Ideally, this educational need
will be incorporated into fellowship training programs be-
fore new oncologists enter the workforce and then will be
further refined at the practice level based on state laws and
institutional policies.
Productivity and Reimbursement
It is generally accepted that practices that incorporate APPs
are more productive and efficient in providing quality care to
patients than practices that do not. However, as practices
work to integrate APPs into clinical practice, they have been
challenged with accurately assessing the productivity and
value of individual APPs. Practices that use a system strictly
based on RVUs will likely underestimate the productivity and
value of APPs because of the inability to accurately measure
RVUs. For example, global surgical visits and the shared visit
model will render the time and effort of the APP invisible.31

Even in the independent visit model, all incident-to visits and
visits for many commercial payers are billed under the
physicians national provider identifier, despite all care being
provided by the APP. In addition, numerous clinical care
activities that APPs provide are not billable encounters, but
they bring quality and value to the practice. Importantly, if
the APP does not complete these nonrevenue-generating
activities, the physician would have to complete them. The
challenges in assessing the productivity of APPs and the
limited benchmarking data available affect the ability to not
only improve productivity of the APPs, but it also will hinder
increased utilization. Practices will struggle to determine
when to hire new APPs and decide how their time should be
allocated to support the clinical enterprise. Also, practice
managers inherently will be unable to determine equitable
compensation, comparison, and accountability of APPs
within a practice.
As to reimbursement, several common myths and
misconceptions can stymie the expansion of APPs in
oncology. Impressions such as APPs cant see new pa-
tients or APPs cant bill above a certain level are easily Although barriers remain, many are perceptual and rel-
debunked with a little education and, if needed, support
from national advocacy organizations. However, one of
the more challenging misconceptions is the over-
estimation that the 85% reimbursement rate of the APPs
compared with the physician rate will have on the cost-
effectiveness of APPs. Numerous studies on physician
assistants and nurse practitioners have demonstrated
that APPs are cost-effective health care providers. This
can be explained by physician salaries being consistently
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30% to 50% higher than APPs, incident-to billing reimbursed
at 100%, and the savings on APP reduced recruitment and
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Currently, ASCO is exploring a project to assess the con-
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services and other work that APPs conduct in oncology
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CONCLUSION
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8 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
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 INVITED ARTICLES
Value in Oncology: Balance Between Quality and Cost
Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, and Mark W. Legnini, DrPH
I t is a disturbing fact that the costs of health care are
spiraling upwards and that an exemplar of this troubling
trend is the domain of oncology treatment and research. By
2020, it is projected that cancer care will cost more than
$150 billion annually in the United States. Although this re-
presents only a relatively small fraction of total health care
cost, cancer care is escalating more rapidly than most other
specialties. Many factors contribute to this unhappy situa-
tion, including the aging of the population, persistence of
risk-taking by the community at large (smoking, excessive
sun exposure, and lack of attention to industrial pollution,
to name a few), increasingly expensive research, diagnostic
tests, surgical approaches, radiotherapy techniques, and
novel systemic therapies as well as some unrealistic expec-
tations of patients, families, and the community at large (often
predicated on false claims from our profession and/or hype
from the Fourth Estate). Of clear relevance is the consid-
eration that another political declaration of war on cancer,
the third in 40 years, this time an amalgam of the State of the
Union address and some opportunism from the biomedical
community, is unlikely to fix the problem. Although this type
of hyperbole might increase focus, and even funding, it will
create a renewed sense that death is optional and will en-
courage patients and their physicians to continue futile at-
tempts at active treatment of truly resistant disease, rather
than considering palliative care with its associated improve-
ment in quality of life and reduction in cost.
A more sensible approach is to weave the concept of
value-based medical care into the equation, thus leveraging
resource expenditure in a more productive and sensible way
than has characterized much of modern medicine. However,
one of the more substantial challenges in modern oncology
practice is to provide true increase in value when so many
new parameters of success are being introduced into the
equation. Health care spending to treat cancer rose 55% in
the decade from 2001 to 2011, and annual retail prescription
drug expenditures for cancer quintupled over the same
period.1 Almost 40% of expenditures for cancer care in 2011
From the Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC; University of Michigan Medical School, Institute for Healthcare Policy & Innovation, Ann Arbor, MI.
Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.
Corresponding author: Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Dr., Charlotte, NC 28204;
email: derek.raghavan@carolinas.org.
2016 by American Society of Clinical Oncology.
COLLECTIVE WISDOM
were publicly funded (34.1% Medicare and 5.3% Medicaid);
resulting federal scrutiny of health care spending meant
Washington policy makers measures of success often
became political and ideological footballs. Lobbying by the
health care industry to protect economic interests has
produced self-serving success stories, some from the
pharmaceutical and device industries and others from
providers of care locked in competition for patients and
revenues. The advocacy research behind these success
stories is frequently cited but often unvalidated and diverts
attention from a proper focus on the patient. Thus, oncol-
ogists must address the challenges of responding to the
communitys evolving requirements for greater value, with-
out loss of innovation, in a more proactive, creative, and
structured fashion to preserve quality while attempting to
contain expense.
At its simplest, the value proposition in health care has
been defined by Porter and Teisberg2,3 with the following
equation:
Value Outcomes=Cost
This equation makes sense and is routinely used in planning
the strategy of cancer care for our health care systems in the
Carolinas and Michigan, as it helps us to consider what is
contributing to poor value in cancer care and allows reso-
lution of those elements that are accessible. Of key impor-
tance is to critically consider the true benefits of the use of
our diagnostic and treatment modalities, defining whether
they contribute to prolongation of survival, increased quality
of life, or reduced morbidity of disease or its treatment, and
also whether the most cost-efficient options are chosen.
In addition, Porter and Teisburg2,3 have emphasized the
important principles of transparency, provision of com-
prehensive disease management and prevention services,
organization around medical conditions, and redefinition of
the health plan/subscriber relationship (with an end to cost-
shifting practices) as potential solutions to the current
dysfunction in the provision of health care.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 9
RAGHAVAN AND LEGNINI
The prospect of cancer treatment is daunting for most
patients when one considers the nature of the treatment
being offered and its potential consequences. In addition,
asymmetry of medical information, potential fiscal toxicity,
and dislocation of patients and their families for treatment
far from their homes mean patients lose control over their
lives, compounding their anxiety over a cancer diagnosis and
the treatment that follows. The provision of symmetrical
(i.e., evenly distributed) access to high-quality care, by
overcoming barriers of poverty, language, geographical
isolation, and information while providing the key advances
in modern oncology, with a greater emphasis on palliative
care optimization, should improve national cancer survival
and morbidity figures without continuing to increase the
strain on federal and state budgets.4,5 A focus on universally
distributed access contrasts with the continued reluc-
tance of some medical institutions to accept indigent, un-
derinsured, Medicaid, or even Medicare patients, thus
protecting their bottom lines from loss, an approach that is
unfair to the community.3 In addition to creating maldis-
tribution of the costs of providing care, cherry-picking of the
wealthiest, most educated, and robust patients (who also
usually have the strongest health insurance coverage) may
lead to biased representation of outcomes. These centers
publish data drawn from treatment of star patients, who
have fewer of the adverse prognosticators and comorbid-
ities of unselected patient populations, leading to inflated
survival figures and artificially reduced morbidity and tox-
icity data. Sadly, many politicians and community leaders
may fail to understand this nuance when they translate the
resulting highly selected data into expectations for the
population at large, thus distorting the concept of true value.
Successful provision of symmetrical, high-quality out-
comes also requires easily accessible tertiary and quaternary
level cancer care close to home, with access to clinical trials,
extensive patient support and navigation, optimal palliative
and supportive care, and the benefits of the genomic rev-
olution as elements of routine cancer care.1,5 It also has to be
refined by the establishment of an evidence-based, system-
wide set of standards for diagnosis and treatment, which are
routinely used by physicians.
In many major centers, following the innovative approach
of Fox Chase Cancer Center in the Delaware Valley, outreach
clinics have been established as a mechanism to provide
easier intake to attract new patients and provide access to
cancer trials. However, many of these ventures have not
been designed to provide all of the key resources, such as
access to translational trials with laboratory and bio-
repository support, genetic counseling, and patient-family
support, for these geographically isolated patients.
In the United States in recent times, less than 5% of pa-
tients have been enrolled in cancer clinical trials,6,7 and it is
clear that there are noteworthy disparities of access to high-
level cancer programs.4 We are now attempting to address
these challenging issues in the Carolinas8 and in Michigan,
two areas challenged by considerable geographical and
demographic constraints.
10 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
EXPERIMENTS IN THE DELIVERY OF
VALUE-BASED CANCER CARE
Toward Symmetry of Care in the Carolinas
Charlotte, the largest city in North Carolina, with a pop-
ulation approaching 1 million (and a referral base of around
2 million people) has not had local access to a comprehensive
cancer center. Specifically, there has been paucity of locally
available bone marrow transplant facilities and of phase I
and investigator-initiated clinical trials, although the latter
have been intermittently available on a small scale. Qua-
ternary cancer services have been provided by outstanding
cancer centers at Emory, Duke, Wake Forest, and The
University of North Carolina at Chapel Hill, but have often
required travel of more than 3 to 4 hours for geographically
isolated patients and for those living in Charlotte who
have needed more specialized cancer services. Carolinas
HealthCare System, an amalgam of more than 40 hospitals
and medical centers spanning North Carolina and South
Carolina, employs more than 2,000 physicians and 50,000
staff and sees more than 15,000 new cancer cases per year.
As the system has expanded to be one of the largest
nonprofit health systems in North America, it made sense
to establish a tertiary and quaternary referral cancer
center that would serve its network of smaller centers
throughout the Carolinas, but which would attempt to
provide a system of cancer care closer to the patients
home, contrary to some of the more conventional models.
In design, several criteria were deemed crucial and in-
corporated into the creation of this multisite institute, as
summarized in the Sidebar.
Our strategy for the system throughout the Carolinas has
been to link with selected hospitals and their staffs,
establishing contractual relationships with the hospital
leadership and personal and professional relationships with
their physicians, which includes the provision of centrally
controlled Levine Cancer Institute clinical trial units. Where
needed, additional faculty members have been recruited
from a range of other academic cancer centers. Academic
and programmatic leadership has been drawn from National
Cancer Institutedesignated comprehensive cancer centers,
and trained clinical investigators have been placed at out-
reach centers to ensure symmetry of access to trials. We
have thus created a hybrid academic-practice model, and
this has led to dramatic increments in cancer trial accrual and
maintenance of patient care in distant geographic sites, with
improved access to tertiary and quaternary facilities, often
via telemedicine.
Strategies in Play in Michigan
The Michigan Value Collaborative provides 65 hospitals
statewide with data and tools to help them control costs for
episodes of care, including colorectal cancer resection,
esophagectomy, lung cancer resection, and prostatectomy,
up to 90 days postdischarge. This includes the initial
hospitalization plus skilled nursing, rehabilitation, home
health, transfers/readmissions, etc. The Michigan Value
 VALUE IN ONCOLOGY: BALANCE BETWEEN QUALITY AND COST

SIDEBAR. Criteria for a Symmetrical System of Cancer Care

Multidisciplinary clinics with standard operating procedures and protocols of management, embedded in electronically linked,
evidence-based clinical pathways
System-wide interdisciplinary tumor boards and conferences, augmented by electronic two-way video conferencing to connect
geographically isolated oncology teams
Easy availability of clinical trials, with access close to home throughout North Carolina and South Carolina
A single, central institutional review board for cancer trials covering the whole system, facilitating swift and synchronous, system-
wide activation of studies
Central protocol review and monitoring system, with initial protocol submissions via tumor-specific teams
Central oversight of a tightly controlled clinical trials unit, with central training and monitoring of staff
Centralized connections and data capture for each hospital tumor registry with ability to measure outcomes and costs of care
Extensive patient support services, including patient navigation linked throughout the system, standard operating procedures for
emergency departments throughout the system, palliative care and pain management services, cancer-focused pastoral care, and live
or video-linked genetic counseling and financial counseling
Availability of subspecialty services, such as bone marrow transplantation, phase I clinical trial units, and sophisticated radiation
techniques and equipment in as accessible a fashion as possible
A focus on translational bench research that is focused specifically on the clinical emphases of the instituteearly programs have
focused on cancer pharmacology, stem cell biology of hematologic disorders, and molecular prognostication with availability of a
cost-effective, molecular testing platform where appropriate
Optimal informatics technology support and electronic and video linkage for conferencing, tumor boards, and creation of electronic
pathways in tumor-specific team meetings

Collaborative creates a unique window for hospitals to see
charges generated for a patients care outside their four
walls, an essential tool for cost-effective care coordination.
In addition, Collaborative Quality Improvement initia-
tives around the state share clinical process and outcomes
data to improve outcomes for patients receiving surgical,
radiation, and medical oncology services. Together, these
programs provide clinical and claims-based registries (price-
standardized and risk-adjusted), web-based analytic tools,
and forums across the state for practicing physicians and
hospital quality improvement staff to work on individ-
ual improvement and collectively to make Michigan a
better place for patients with cancer to receive treatment.
Combining episode costs (the value equations denominator)
with clinical outcomes data from collaborative quality im-
provements (the numerator) gives Michigans hospitals one
of the countrys best opportunities to improve the value of
cancer care.
CHOOSING WISELY
One of the most important aspects to reduction of un-
necessary expenditure in oncology is the consideration of
what is gained by the use of the available management
approaches. The Institute of Medicine has encouraged
physicians to carefully consider the benefits and drawbacks
associated, in particular, with expensive management op-
tions in the so-called Choosing Wisely campaign. In line
with this philosophy, the American Society of Clinical On-
cology (ASCO) created the Value Task Force and developed
two consensus documents,9,10 based on the best available
evidence, that proposed discontinuation of standard
clinical practices that provided no patient benefit (Table 1).
In each instance, level 1 to 2 evidence clearly showed that
discontinuation of these diagnostic or management ap-
proaches would not result in reduced outcomes and in some
cases (e.g., screening for prostate cancer in elderly men with
intercurrent diseases and limited life expectancy) could
actually improve survival and/or morbidity. As can easily be
appreciated from Table 1, nationwide implementation of
these recommendations has achieved dramatic cost savings,
without measurable loss of quality or outcomes.
These items were chosen because they reflected clinical
practice among most oncologists and thus would avoid
partisan subspecialty rivalries and concerns, were broadly
applicable to large numbers of patients, and also clearly
reflected the absence of a robust evidence base un-
derpinning patterns of standard clinical practice.
With the growing evidence on producing high value for
health expenditure, we will increasingly need to consider
clinical practices that have evolved without evidence to
support a survival or quality-of-life benefit and must focus on
whether the treatments selected have equi-active but less
costly alternatives (e.g., use of generic drugs, biosimilars,
and lower doses of cytotoxics, reduced treatment duration
of radiotherapy, and elimination of heroic but unproven
surgical procedures). In each case, the driver is cost con-
tainment or avoidance of profligate expenditure without
loss of quality or outcomes.
MEASUREMENT OF VALUE
In 2015, the ASCO Value Task Force published the Conceptual
Framework for Assessing Value in Cancer Care.11 The basic
construct is as follows:
Two major contextual categories are created, advanced
disease (e.g., treatment of metastases) and curative
intent (e.g., adjuvant therapy).

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 11

RAGHAVAN AND LEGNINI
Clinical benefit is given a score of 1 to 5, and then
numerical weightings are added to reflect the impact of
treatment on overall survival, progression-free survival,
or response rate. The weightings reflect the thought
that overall survival is more important than progression-
free survival, which is more important than response
rate when attempting to attribute value for the patient.
Negative scores are added to reflect the extent of
toxicity. In the advanced disease setting, bonus points
are awarded for palliation of symptoms and for longer
treatment-free intervals. Finally, the cost of treatment is
listed to broaden the context.
In the adjuvant setting, instead of the response-survival
parameters above, hazard ratio is incorporated into the
algorithm, and disease-free interval is substituted, but
with a slightly lower weighting.
The overall construct of net health benefit is incorpo-
rated to allow the patient to attribute likely value to the
treatment, balancing benefit(s) and toxicities.
Unbeknownst to the ASCO Task Force, the European
Society for Medical Oncology (ESMO) had also created a
similar task force, which produced the Magnitude of Clinical
Benefit Scale. Led by Dr. Nathan Cherny, the ESMO position
paper was published at about the same time as the ASCO
TABLE 1. ASCO Choosing Wisely List
Topic
Do not use cancer Rx if PS 3 to 4, no prior benefit,
ineligible for trial, and no evidence to support
more Rx
No extensive staging for low-risk early prostate
cancer
No extensive staging for low-risk early breast
cancer
No surveillance via biomarkers or imaging for
breast cancer after curative Rx (excludes
mammography)
No white cell stimulatory prophylaxis for
patients with < 20% risk of febrile
neutropenia
Avoid starting antinausea prophylaxis with most
expensive high-risk drugs for low-risk
emetogenic regimens
Avoid combination chemotherapy for salvage
Rx of metastatic breast cancer unless urgent
response is required
Avoid post-Rx routine surveillance with PET or
CT-PET scanning after completion of Rx unless
evidence shows survival benefit
Avoid screening asymptomatic men with PSA
for prostate cancer if < 10 years of life
expectancy
Do not use targeted therapy against specific
gene aberration unless biomarker predicts
likely response
Abbreviation: Rx, prescription; PS, pain scale; QOL, quality of life; PSA, prostate-specific antigen.
*Individual reflects potential for substantial copays or expensive self-pay. National reflects costs associated with specific service delivery as well as incidence/frequency figures at
national level.
12 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
position paper.12 What is quite remarkable is the extraor-
dinary similarity in concept and execution, achieved by two
committees working in the United States and in Europe, both
without knowledge of the work in progress of the other
team. The ESMO team also has focused on separate domains
of curative and palliative settings and attributed levels of
benefit predicated on absolute or relative increments in
survival and levels of toxicity. Of importance, they have set
time-dependent criteria, such that the value points allocated
for absolute survival increments differ for those with sus-
tained increases versus the less fortunate patients with only
short-term increments in survival.
Interestingly, both committees used similar sets of level 1
data to develop their models and came to quite similar
interpretations of value, notwithstanding different com-
munity pressures, health care costs, and medical traditions
on different sides of the Atlantic.
These efforts are important and represent crucial first
steps by members of our profession in attempting to in-
crease the level of self-discipline and value-based self-
criticism of what we do and increased transparency in
what we tell our patients about the benefits of treatment.
We would have preferred a higher bar with regard to at-
tribution of value pointsit is obvious that a patient with a
prognosis of only 3 to 6 months will sustain greater relative
Rationale Level of Cost Savings*
Logical, maximizes QOL, no loss of proven survival Extensive at individual and national level
benefit
Overview of published data shows extremely low Extensive at national level
positive yield within false-positive rate.
Overview of published data shows extremely low Extensive at national level
positive yield within false-positive rate.
No survival benefit from early diagnosis of metastatic Extensive at individual and national level
relapse
Risk of febrile neutropenia is predictable for low-risk Extensive at national level
patients; in high-risk patients, prophylaxis should
be considered
Effective options are available for control of regimens Extensive at national level
at low-risk of emesis; crossover can easily be
affected if vomiting occurs
Single-agent Rx is an effective salvage option and Extensive at individual and national level
usually associated with less toxicity
No data to support survival benefit of this approach Extensive at individual and national level
for most clinical settings
Randomized data do not support survival benefit Extensive at national level
from screening for prostate cancer and may cause
harm in elderly
Very low response rate to most targeted Rx unless Extensive at individual and national level
specific target is expressed by tumor

benefit from a 2-month increment than someone treated
with curative or aggressive palliative intent; that said, a
2-month survival increment, offset by considerable physical
or fiscal toxicity, needs to be taken into context. This is
complex, paradigm-shifting work and will require careful
and critical attention and feedback.
TRAINING THE NEXT GENERATION OF
PHYSICIANS TO INCORPORATE THE VALUE
PROPOSITION
Training oncology residents to provide high-value care is key
to transforming the practice of oncology in the United
States.13 Current policies to improve the performance of
health care practitioners and the institutions in which they
practice depend primarily on financial incentives aimed at
changing the behavior of fully-trained physicians. This is
much less effective than intervening earlier in the workforce
pipeline to influence physicians during their training and
professional socialization.
Expressed simply, residents who do not train in high-value
care settings are less likely to become high-value physi-
cians.13 Residency faculty must be skilled in the organization
and delivery of high-value care and in how to teach those
skills.
Exhortations without systems transformation will not
break the cycle of teaching each generation of oncologists
outmoded ways of thinking about safety, quality, and cost-
effectiveness during residency, when their decision making
habits, professional values, ways of interacting with pa-
tients and colleagues, etc., are shaped for the rest of their
References
1. Soni A. Trends in Use and Expenditures for Cancer Treatment among
Adults 18 and Older, U.S. Civilian Noninstitutionalized Population, 2001
and 2011. Medical Expenditure Panel Survey, Statistical Brief #443.
http://meps.ahrq.gov/mepsweb/data_files/publications/st443/
stat443.pdf. Accessed February 23, 2016.
2. Porter ME, Teisberg EO. How physicians can change the future of health
care. JAMA. 2007;297:1103-1111.
3. Porter ME, Teisberg EO. Redefining Health Care. Boston, MA: Harvard
Business School Press; 2006;97-283.
4. Raghavan D. Slow progress in cancer care disparities: HIPAA, PPACA,
and CHEWBACCA... but were still not there! Oncologist. 2011;16:
917-919.
5. Goss E, Lopez AM, Brown CL, et al. American Society of Clinical Oncology
policy statement: disparities in cancer care. J Clin Oncol. 2009;27:
2881-2885.
6. Lara PN Jr, Higdon R, Lim N, et al. Prospective evaluation of cancer
clinical trial accrual patterns: identifying potential barriers to enroll-
ment. J Clin Oncol. 2001;19:1728-1733.
7. Raghavan D. An essay on rearranging the deck chairs: whats wrong with
the cancer trials system? Clin Cancer Res. 2006;12:1949-1950.
VALUE IN ONCOLOGY: BALANCE BETWEEN QUALITY AND COST
professional lives. One way to transform training is to ensure
that teaching programs are located in care settings in which
residents see high-value care delivered every day. This will
require that funding for graduate medical education be
value-based to provide incentives for training programs to
change. Together, the federal Medicare program and a
majority of state Medicaid programs contribute approxi-
mately $14 billion annually to fund graduate medical edu-
cation, based primarily on counts of trainees and residency
program accreditation. If these payments were value-based,
that would be a strong incentive for programs to ensure that
succeeding cohorts of oncologists emerge from training
imbued with the concept of value in health care and
equipped with the tools to provide safe, high-quality, cost-
effective cancer care.
SUMMARY
The exponential increase in costs of health care is un-
necessary and reflects many avoidable factors at a com-
munity level, including poor health practices, unrealistic
expectations, corporate profiteering, and a poor medical
decision process (which often contravenes level 1 to 2 ev-
idence). Physicians must increasingly consider true value
(outcome/cost ratio) when creating management plans and
include these considerations in transparent and realistic
conversations with patients. Attention to these issues will
dramatically reduce the burgeoning costs of cancer care in
our community while improving the quality and value of
care.
8. Raghavan D. Costs of cancer care: rhetoric, value, and steps forward.
Semin Oncol. 2013;40:659-661.
9. Schnipper L, Smith TJ, Raghavan D, et al. American Society of Clinical
Oncology identifies five key opportunities to improve care and reduce
costs: the top five list for oncology: ASCOs top five list. J Clin Oncol.
2012;30:1715-1724.
10. Schnipper LE, Lyman GH, Blayney DW, et al. American Society of Clinical
Oncology 2013 top five list in oncology. J Clin Oncol. 2013;31:
4362-4370.
11. Schnipper LE, Davidson NE, Wollins DS, et al; American Society of
Clinical Oncology. American Society of Clinical Oncology statement:
a conceptual framework to assess the value of cancer treatment op-
tions. J Clin Oncol. 2015;33:2563-2577.
12. Cherny NI, Sullivan R, Dafni U, et al. A standardised, generic, validated
approach to stratify the magnitude of clinical benefit that can be an-
ticipated from anti-cancer therapies: the European Society for Medical
Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol.
2015;26:1547-1573.
13. Legnini, MW. Can low-performing hospitals train high-performing
residents? Am J Med Qual. 2011;26:408-410.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 13
 INVITED ARTICLES
Womens Health Issues for BRCA Mutation Carriers
Mary E. Sabatini, MD, PhD, and Leif W. Ellisen, MD, PhD
I n 2015, it was estimated that there were 1.6 million new
cases of cancer diagnosed in the United States.1 Remarkably,
more than 86,000 were diagnosed in women under the age
of 45. The majority of cancers are thought to be a result of
bad luck; that is, random mutations arising during DNA
replication in normal stem cells,2 whereas inherited muta-
tions are thought to be causal in 5%10% of cancers. Thus,
the number of cancer cases that are attributable to inherited
mutations may seem small, however, they are clinically
important. Cancers in patients with hereditary cancer syn-
dromes tend to occur at a younger age, and most hereditary
cancer syndromes are also associated with more than one
type of cancer.3
Approximately 20% of women with inherited breast and/
or ovarian cancers harbor a harmful mutation of one of the
breast cancer susceptibility genes 1 or 2, known as BRCA1 and
BRCA2.3,4 Mutations in BRCA1/2 are inherited in an autosomal
dominant fashion. Families that carry germline mutations may
have several women affected by breast and possibly ovarian
cancer and men with breast cancer and prostate cancer. These
mutations also predispose carriers to cancers such as fallopian
tube cancer, peritoneal cancer, endometrial cancer, pancreatic
cancer, colon cancer, and cancers in other sites. Although there
are many issues for BRCA mutation carriers who have been
diagnosed with cancer, this article will focus on the care of
women who are known carriers but who have not been di-
agnosed with cancer.
For BRCA1 mutation carriers, cumulative estimates of
developing cancer by age 70 vary by population, ranging
from 40% to 85% for breast cancer and 10% to 59% for
ovarian cancer. For BRCA2 mutation carriers, cumulative
estimates of developing cancer are 45% to 57% for breast
cancer and 11% to 18% for ovarian cancer.5-7 Because of
these risks, the National Comprehensive Cancer Network
(NCCN) has established guidelines for women with BRCA
mutations to reduce the risk of cancer.8 This includes breast
awareness and breast self-examinations starting at age 18,
with annual to biannual clinical examinations starting at age
From the Department of Obstetrics and Gynecology, Harvard Medical School, Massachusetts General Hospital, Boston, MA; Breast Medical Oncology, Harvard Medical School,
Massachusetts General Hospital Cancer Center, Boston, MA.
Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.
Corresponding author: Mary E. Sabatini, MD, PhD, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114; email: msabatini@mgh.harvard.edu.
2016 by American Society of Clinical Oncology.
14 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
COLLECTIVE WISDOM
25. Breast screening should begin by age 25 with MRI.
Earlier MRIs are also considered if any family member
was diagnosed with breast cancer before age 25. Annual
mammography and MRI starts at age 30. Risk-reducing
mastectomy should be offered as an option to all BRCA
mutation carriers, as it has been shown to reduce the risk
of cancer by as much as 90%, although definitive studies
showing either an overall or breast cancerspecific sur-
vival advantage are lacking. In contrast, risk-reducing bi-
lateral salpingo-oophorectomy (rrBSO) at age 35 to 40
or whenever childbearing is completed is associated with a
lower risk of breast cancer and reduces all-cause, ovarian
cancerspecific, and breast cancerspecific mortality.9
rrBSO results in an 80% risk reduction for ovarian, fallopian
tube, and peritoneal cancers. There has been recent interest
in the possibility of performing salpingectomy only, as it
seems that some ovarian cancers may arise primarily in the
fallopian tube, but this is not recommended other than in
the setting of a clinical trial. Hysterectomy is not routinely
recommended given that the absolute risk of endometrial
cancer is low enough that the benefits do not outweigh the
risks of surgery. For those who do not elect for rrBSO,
ovarian cancer screening with transvaginal ultrasound and
carbohydrate antigen 125 (CA-125) is suggested every
6 months starting at age 30. Notably, however, there are no
data to support the efficacy of this practice.
The NCCN guidelines are established by incorporating
the best evidence available to date. However, in caring for
women who do carry a deleterious BRCA mutation, one of
the major challenges is trying to help an individual patient to
make decisions using data obtained from studying pop-
ulations. Like most autosomal-dominant mutations, pene-
trance of a BRCA mutation is not 100%. The probability of
developing cancer for carriers is alarmingly high, yet the
morbidity associated with surveillance and/or prevention
is also not negligible. Furthermore, taking steps toward
prevention does not absolutely eliminate the risk of
cancer development. Decision making can be empowering,

as indicated by the New York Times opinion article written
by Angelina Jolie.10 Nonetheless, decisions can be anxiety
provoking, particularly when the consequences of the
wrong decision are so large and life altering.
Unfortunately, knowledge of ones mutation and the NCCN
guidelines does not necessarily enable an individual to plan
ones life accordingly. In an ideal world, perhaps every woman
who carried a BRCA mutation would have completed child-
birth prior to age 35. Indeed, younger age at first birth and
breast-feeding are protective for development of breast and
ovarian cancers overall. Additionally, in an ideal world, there
would be no repercussions to mastectomy and early surgical
menopause. However, these ideals run counter to the realities
of life for many. In high-income countries, the median age of
first birth is rising,11 with many women not starting a family
until after their 35th birthday. Surgery and surgical menopause
can cause morbidity and can be life altering.
A retrospective study including 305 BRCA mutation carriers
seen in a California integrated health system between 1995
and 2012 showed that the uptake of options for BRCA mu-
tation carriers who were informed of the NCCN guidelines was
lacking in some areas. The median follow-up during the
study was 41 months. The median time from diagnosis to risk-
reducing surgery was 6 months, with 74% of patients choosing
to undergo rrBSO and 44% of patients choosing to undergo
risk-reducing mastectomy. Of those choosing surveillance,
compliance was 45% in the first year but decreased to
approximately 10% at 3 years and 2% at 5 years.12
Decisions about prophylactic surgery are complicated
by concerns about appearance, sexuality, control of re-
production, and relationships. A retrospective study by
Stukey et al13 highlights that these decisions among carriers
are not, as might be anticipated, based on risk alone. Ninety
women, all of whom were carriers of BRCA mutation, were
offered prophylactic surgery. Fifty-one percent of the
women underwent surgery, 85% underwent BSO, and 28%
underwent mastectomy. Women who elected to have
surgery were more likely to be parous, married, employed,
and had a prior history of breast cancer. This implies that
those who did not elect for prophylactic surgery may be
interested in future fertility. BRCA2 mutation carriers were
more likely than BRCA1 carriers to pursue surgery. If
avoidance of developing disease were the only factor in-
volved in decision making, BRCA1 carriers should be more
likely to undergo surgery.
Hoskins et al14 described 11 cases of unmarried women
age 26 to 35 who carry a BRCA mutation. These women
relayed challenges regarding their perception of their own
desirability and anxiety about partners reactions to dis-
closure of mutation status. Another web-based survey of 44
women with a BRCA mutation included 13 women who were
unmarried, and all of them expressed concerns about how
and when to disclose their status to future partners. Most of
them expressed a sense of urgency to have children.15
Considering the anxiety expressed about the effect of their
own BRCA mutation on their relationships, very little data
exist regarding the attitudes of the sexual partners of
WOMENS HEALTH ISSUES FOR BRCA MUTATION CARRIERS
women with BRCA mutations. One recent survey study
described the reaction of 25 male partners about their fe-
male partners mutation status.16 Twenty of the men were
married or engaged at the time of the survey, and 19 had
been in the relationship at least 5 years. Nine participants
reported changes regarding intimacy levels, and two re-
spondents reported changes in their level of attraction.
Almost all participants noted changes in their commu-
nication after mutation disclosure, with changes in the
topics discussed and more discussions about the future.
Interestingly, of the 14 men whose partners had not un-
dergone a risk-reducing mastectomy, five expressed concerns
about their level of attraction to their partner, but of the 11
men whose partner had had a mastectomy, all said that they
were as attracted to their partner after surgery as they were
before surgery. It is difficult to generalize the results of this
study broadly, as most of these men were in long-term or
committed relationships at the time of the survey.
In general, reproductive options for all women have vastly
expanded in the past several years, and this may also benefit
those who carry a BRCA mutation. For women who are not
yet ready to have children, in vitro fertilization (IVF) can be
used to freeze either oocytes or embryos for future use.
Embryo cryopreservation has been available since the 1980s,
and outcomes have improved dramatically in the last several
years. For couples with infertility and a female partner
younger than age 35, expected pregnancy rates after a single
IVF are upwards of 50%.17 For couples with unknown fertility
interested in banking embryos for future use, there are no
numbers to guide us, but presumably the success rate would
be at least as good if not higher. Oocyte freezing is available
to women who are unpartnered, unwilling to use donor
sperm, or who wish to maintain complete autonomy of their
reproductive potential. Historically, oocyte freezing has been
technically more challenging. Although embryo freezing
remains the gold standard, this will likely change in the near
future as success rates with frozen oocytes are approaching
those of frozen embryos.17
Although embryo and oocyte preservation provide op-
tions, IVF is expensive, arduous, and time consuming. It
comes with risks including hemorrhagic cysts, ovarian tor-
sion, ovarian hyperstimulation syndrome, blood clots, in-
fections, medication reactions, and surgical risks associated
with oocyte extraction. For these reasons, it is not univer-
sally available or used. Overall, IVF has not been associated
with an increased risk of development of breast or ovarian
cancer18-22 in the general population or in BRCA mutation
carriers.23,24 The data for the general population are quite
robust as a result of the length of availability of IVF and the
number of people who have used IVF. For those with BRCA
mutations, however, the numbers are smaller and not as
robust, so the conclusions are not as definitive.
One of the most challenging issues for women who carry
a BRCA mutation surrounds the choice about the potential
to eliminate this mutation from future offspring. Pre-
implantation genetic diagnosis (PGD) is a procedure in which
a cell or cells from a human embryo are removed and tested
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 15
SABATINI AND ELLISEN
for diseases and/or mutations that can result in disease (for
example, cystic fibrosis, Huntington disease, BRCA mutation).
PGD requires IVF. The resulting embryos are allowed to grow
for 3 to 5 days so there are enough cells to be biopsied for PGD.
Embryos found by biopsy to be unaffected (on average ap-
proximately 50%) can be transferred into the womans uterus
with the hope that a normal pregnancy will be established.
Affected embryos generally are not transferred and can be
disposed per a couples wishes.
The topic of PGD can raise a number of social and ethical
debates. A recent large survey study of the general population
showed that approximately 70% of respondents were sup-
portive of PGD for diseases that were lethal in early childhood or
caused lifelong disability (e.g., cystic fibrosis), yet only 48%
supported it for screening embryos for diseases that strike later
in life (e.g., BRCA-associated cancers or Huntington disease).25
Another survey assessed the attitudes about PGD among
women with BRCA mutations and/or hereditary cancer syn-
dromes. Of the 52 respondents, 75% thought that PGD was an
acceptable option for those with BRCA mutation.26 Interestingly,
though, of the respondents who had completed family building,
only 37.5% would have used this option for themselves, and for
those who did not yet have children, only 14% stated they would
consider using PGD. Thirty-five percent of the respondents
stated they worried about the use of PGD because they assume
that the effectiveness of screening and prevention for women
with BRCA mutation will improve with time.
Choices about the use of birth control and/or any other
hormone treatments can also be complicated for BRCA
carriers. Oral birth control pills (OCPs; containing either
estrogen and progestin or just progestin) are the most
common form of reversible contraception used world-
wide.27 A very large cohort study showed that in the general
population OCPs are not associated with an increased risk
overall for cancer, and OCP users had a reduced risk of
ovarian, endometrial, and colorectal cancers.28 OCP use has,
however, also been linked to a trend toward increased risk of
breast cancer, but studies are conflicting.29-32 The literature
regarding OCP use for BRCA carriers is similar.33,34 Therefore,
the choice about use of OCPs must be individualized and
account not only for BRCA status but also other health issues
and reproductive goals.
Surgical menopause causes a more dramatic drop in
systemic levels of ovarian hormones than the gradual de-
cline that occurs with natural menopause. Additionally, for
BRCA carriers who undergo rrBSO per NCCN guidelines,
References
1. American Cancer Society. Cancer Facts & Figures 2015. www.cancer.org/
research/cancerfactsstatistics/cancerfactsfigures2015. Accessed Novem-
ber 12, 2015.
2. Tomasetti C, Vogelstein B. Cancer etiology. Variation in cancer risk
among tissues can be explained by the number of stem cell divisions.
Science. 2015;347:78-81.
16 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
surgical menopause happens at an earlier age than does
natural menopause. As such, menopausal symptoms, the
effects of hormonal changes, and their treatment should be
discussed with women prior to surgery. Menopause is as-
sociated with hot flashes, sleep disturbances, and changes in
mood. Women often have a decline in libido and sexual
satisfaction and have vaginal changes that result in difficulty
with intercourse; early menopause may also dramatically
impact bone and cardiovascular health.35,36
There are several medical and alternative treatments that
can be used to mitigate the effects of menopause; the most
effective of these is hormone replacement therapy (HRT)
containing estrogen. The use of HRT in women with BRCA
mutation can be somewhat of a contentious subject. Currently,
most of the literature does not show an increased risk of breast
cancer following rrBSO for BRCA carriers who use HRT.37,38
Women who use HRT report less discomfort with intercourse
and a higher quality of life than nonusers.39 Again, because of
the absence of long-term studies, the lack of randomization,
and the variations in treatments used, it is still difficult to
counsel patients about the safety of HRT. Any woman who
has a uterus should also be counseled about the use of pro-
gestin for endometrial protection. This also may impart a higher
risk of breast cancer based on previous data,40,41 but how this
applies to those with BRCA mutations is unclear.
In a recent article about her BRCA status and medical
decisions, Angelina Jolie said, Life comes with many chal-
lenges. The ones that should not scare us are the ones we can
take on and take control of.10 In that article, Jolie speaks
much about her family, her partner, and her children, which
no doubt gave her clarity on her health decisions. She did not
mention anything about PGD, so we are unclear about her
determination regarding this issue. Jolie also has vast access
to medical care and, thus, has many treatment options. For
many women, lifes circumstances do not make decisions so
clear. Decisions can be empowering, but they can also bring
about stress and anxiety. Fortunately, most of the studies
show that women who undergo risk-reducing surgery are
satisfied with their decision.42,43 Unfortunately, there are
very few studies that assess womens satisfaction with their
choices about nonintervention or appraise womens feelings
over long periods of time. Much additional work is needed to
help patients and the medical community deal effectively
with these complex issues. Even with strong data, decision
making can be complicated; but without data, it is all the
more difficult.
3. American Cancer Society. Family Cancer Syndromes. www.cancer.org/
cancer/cancercauses/geneticsandcancer/heredity-and-cancer. Accessed
January 8, 2016.
4. Couch FJ, Nathanson KL, Offit K. Two decades after BRCA: setting
paradigms in personalized cancer care and prevention. Science. 2014;
343:1466-1470.

5. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and
ovarian cancer associated with BRCA1 or BRCA2 mutations detected in
case series unselected for family history: a combined analysis of 22
studies. Am J Hum Genet. 2003;72:1117-1130.
6. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance.
J Clin Oncol. 2007;25:1329-1333.
7. Mavaddat N, Peock S, Frost D, et al; EMBRACE. Cancer risks for BRCA1
and BRCA2 mutation carriers: results from prospective analysis of
EMBRACE. J Natl Cancer Inst. 2013;105:812-822.
8. National Comprehensive Cancer Network Clinical Practice Guidelines in
Oncology. Genetic/Familial High-Risk Assessment. Version 2. 2015.
www.nccn.org/professionals/physician_gls/pdf/genetics_screening.
pdf. Accessed January 8, 2016.
9. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing
surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and
mortality. JAMA. 2010;304:967-975.
10. Jolie A. My Medical Choice. www.nytimes.com/2013/05/14/opinion/
my-medical-choice.html. Accessed February 6, 2016.
11. Finer LB, Philbin JM. Trends in ages at key reproductive transitions in
the United States, 1951-2010. Womens Health Issues. 2014;24:
e271-e279.
12. Garcia C, Wendt J, Lyon L, et al. Risk management options elected by
women after testing positive for a BRCA mutation. Gynecol Oncol. 2014;
132:428-433.
13. Stuckey A, Dizon D, Scalia Wilbur J, et al. Clinical characteristics and
choices regarding risk-reducing surgery in BRCA mutation carriers.
Gynecol Obstet Invest. 2010;69:270-273.
14. Hoskins LM, Roy K, Peters JA, et al. Disclosure of positive BRCA1/2-
mutation status in young couples: the journey from uncertainty
to bonding through partner support. Fam Syst Health. 2008;26:
296-316.
15. Hamilton R. Being young, female, and BRCA positive. Am J Nurs. 2012;
112:26-31, quiz 46, 32.
16. Mauer C, Spencer S, Dungan J, et al. Exploration of male attitudes on
partnerships and sexuality with female BRCA1/2 mutation carriers.
J Genet Couns. Epub 2015 Aug 8.
17. SART CORS. Clinic Summary Report 2013. www.sartcorsonline.com/
rptCSR_PublicMultYear.aspx?ClinicPKID=0. Accessed January 21,
2016.
18. Rizzuto I, Behrens RF, Smith LA. Risk of ovarian cancer in women treated
with ovarian stimulating drugs for infertility. Cochrane Database Syst
Rev. 2013;8:CD008215.
19. Sergentanis TN, Diamantaras AA, Perlepe C, et al. IVF and breast cancer:
a systematic review and meta-analysis. Hum Reprod Update. 2014;20:
106-123.
20. Gennari A, Costa M, Puntoni M, et al. Breast cancer incidence after
hormonal treatments for infertility: systematic review and meta-
analysis of population-based studies. Breast Cancer Res Treat. 2015;
150:405-413.
21. Zhao J, Li Y, Zhang Q, et al. Does ovarian stimulation for IVF increase
gynaecological cancer risk? A systematic review and meta-analysis.
Reprod Biomed Online. 2015;31:20-29.
22. Kessous R, Davidson E, Meirovitz M, et al. The risk of female malig-
nancies after fertility treatments: a cohort study with 25-year follow-up.
J Cancer Res Clin Oncol. 2016;142:287-293.
23. Gronwald J, Glass K, Rosen B, et al; Hereditary Breast Cancer Clinical
Study Group. Treatment of infertility does not increase the risk of
ovarian cancer among women with a BRCA1 or BRCA2 mutation. Fertil
Steril. Epub 2015 Dec 14.
24. Perri T, Lifshitz D, Sadetzki S, et al. Fertility treatments and invasive
epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation
carriers. Fertil Steril. 2015;103:1305-1312.
WOMENS HEALTH ISSUES FOR BRCA MUTATION CARRIERS
25. Winkelman WD, Missmer SA, Myers D, et al. Public perspectives on the
use of preimplantation genetic diagnosis. J Assist Reprod Genet. 2015;
32:665-675.
26. Menon U, Harper J, Sharma A, et al. Views of BRCA gene mutation
carriers on preimplantation genetic diagnosis as a reproductive option
for hereditary breast and ovarian cancer. Hum Reprod. 2007;22:
1573-1577.
27. United Nations. Population Facts. www.un.org/en/development/desa/
population/publications/pdf/popfacts/popfacts_2013-9.pdf. Accessed
January 14, 2016.
28. Hannaford PC, Selvaraj S, Elliott AM, et al. Cancer risk among users of
oral contraceptives: cohort data from the Royal College of General
Practitioners oral contraception study. BMJ. 2007;335:651.
29. Oral-contraceptive use and the risk of breast cancer. The Cancer and
Steroid Hormone Study of the Centers for Disease Control and the
National Institute of Child Health and Human Development. N Engl J
Med. 1986;315:405-411.
30. Hankinson SE, Colditz GA, Manson JE, et al. A prospective study of oral
contraceptive use and risk of breast cancer (Nurses Health Study,
United States). Cancer Causes Control. 1997;8:65-72.
31. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and
the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.
32. Vessey M, Yeates D. Oral contraceptive use and cancer: final report from
the Oxford-Family Planning Association contraceptive study. Contra-
ception. 2013;88:678-683.
33. McLaughlin JR, Risch HA, Lubinski J, et al; Hereditary Ovarian Cancer
Clinical Study Group. Reproductive risk factors for ovarian cancer in
carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet
Oncol. 2007;8:26-34.
34. Iodice S, Barile M, Rotmensz N, et al. Oral contraceptive use and breast
or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J Cancer.
2010;46:2275-2284.
35. Mercuro G, Zoncu S, Saiu F, et al. Menopause induced by oophorectomy
reveals a role of ovarian estrogen on the maintenance of pressure
homeostasis. Maturitas. 2004;47:131-138.
36. Lobo RA. Surgical menopause and cardiovascular risks. Menopause.
2007;14:562-566.
37. Madalinska JB, Hollenstein J, Bleiker E, et al. Quality-of-life effects of
prophylactic salpingo-oophorectomy versus gynecologic screening
among women at increased risk of hereditary ovarian cancer. J Clin
Oncol. 2005;23:6890-6898.
38. Kotsopoulos J, Huzarski T, Gronwald J, et al. Hormone replacement
therapy after menopause and risk of breast cancer in BRCA1 mutation
carriers: a case-control study. Breast Cancer Res Treat. 2016;155:
365-373.
39. Johansen N, Liavaag AH, Tanbo TG, et al. Sexual activity and functioning
after risk-reducing salpingo-oophorectomy: impact of hormone re-
placement therapy. Gynecol Oncol. 2016;140:101-106.
40. Chlebowski RT, Hendrix SL, Langer RD, et al; WHI Investigators. Influ-
ence of estrogen plus progestin on breast cancer and mammography in
healthy postmenopausal women: the Womens Health Initiative Ran-
domized Trial. JAMA. 2003;289:3243-3253.
41. Chlebowski RT, Rohan TE, Manson JE, et al. Breast cancer after use of
estrogen plus progestin and estrogen alone: analyses of data from 2
Womens Health Initiative Randomized Clinical Trials. JAMA Oncol.
2015;1:296-305.
42. Borreani C, Manoukian S, Bianchi E, et al. The psychological impact of
breast and ovarian cancer preventive options in BRCA1 and BRCA2
mutation carriers. Clin Genet. 2014;85:7-15.
43. Finch A, Narod SA. Quality of life and health status after prophylactic
salpingo-oophorectomy in women who carry a BRCA mutation: a re-
view. Maturitas. 2011;70:261-265.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 17
 INVITED ARTICLES
Collective Wisdom: Lobular Carcinoma of the Breast
George W. Sledge, MD, FASCO, Anees Chagpar, MD, and Charles Perou, PhD
B reast cancer researchers have a longstanding fascination
for infiltrating lobular carcinomas. Second in frequency
only to ductal adenocarcinomas, these tumors are charac-
terized by unique histopathology and (among breast can-
cers) distinctive clinical biology, both in the primary and
metastatic settings. Early hints regarding the underlying
sources of this peculiar cancer, in particular the important
role of E-cadherin loss, have now been confirmed through
comprehensive molecular portraits of the disease. These
molecular observations, in turn, go far to explain how lobular
carcinomas play out in the clinic, both as regards local
control and therapeutic response to systemic therapy. To-
gether, the collective wisdom of the laboratory and the
clinic paint an interesting portrait of this fascinating disease.
MOLECULAR BIOLOGY OF LOBULAR
CARCINOMAS
Invasive lobular breast carcinoma (ILC) is the second most
prominent histologic form of breast cancer and accounts for
10%15% of invasive breast tumors. On a molecular level,
lobular breast cancers are a distinct disease type and should
be considered as a unique disease. These molecular un-
derpinnings were recently intensely studied as part of The
Cancer Genome Atlas (TCGA) effort on breast cancer,
including a recent publication focused on lobular breast
cancers.1 In this publication, 817 breast tumors from the
TCGA project, including 490 invasive ductal cancers (IDCs),
127 ILCs, and 88 samples with a mixed IDC-ILC histology,
were molecularly profiled on six genomic platforms to de-
velop a comprehensive portrait of the genetic, epigenetic,
transcriptional, and proteomic landscape of lobular breast
cancers. Comprehensive multiplatform analyses, both su-
pervised and unsupervised, of ILC tumors and across his-
tologic subtypes were performed to identify genomic
drivers of ILC oncogenesis.
As expected, low expression of E-cadherin protein, as
determined by reverse-phase protein array (RPPA), and
From the Division of Oncology, Stanford University School of Medicine, Stanford, CA; Yale University, New Haven, CT; The University of North Carolina at Chapel Hill, Chapel
Hill, NC.
Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.
Corresponding author: George W. Sledge, MD, Stanford University School of Medicine, 269 Campus Dr., CCSR-1115, Stanford, CA 94305; email: gsledge@stanford.edu.
2016 by American Society of Clinical Oncology.
18 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
COLLECTIVE WISDOM
decreased E-cadherin mRNA levels were uniformly observed
in ILC cases. In total, 63% of ILC cases had an E-cadherin
mutation, and 95% of ILC cases had loss when mutation, DNA
copy number, and low gene and/or protein expression were
summed together. It is reassuring that this modern study
reaffirmed the primacy of E-cadherin loss in lobular breast
cancer, and if a biomarker were to be chosen to identify ILC
on a molecular level, it would likely be low E-cadherin
protein expression and/or DNA mutation of CDH1. Lobu-
lar carcinomas unique histopathologic features and its
metastatic patterns undoubtedly have their origins in their
impoverished E-cadherin status.
Beyond previously reported CDH1 and PIK3CA mutations
(which occur at a 48% frequency in ILC), the TCGA study
identified a number of novel ILC-enriched recurrent muta-
tions targeting FOXA1, PTEN, RUNX1, and TBX3. FOXA1
function is particularly intriguing, as it works with the es-
trogen receptor (ER) to drive the transcriptional output of
ER. Interestingly, FOXA1 also plays a similar role in prostate
cancer, but in these cancers its cofactor is the androgen
receptor.2 In ILC, we find an increased incidence (9% in ILC vs.
2% in IDC) of FOXA1 mutations, whereas in IDC, we find that
GATA3 mutations are considerably enriched in IDC luminal
tumors (19% IDC vs. 5% ILC). Within ILC tumors, FOXA1
mutations were found to cluster into a specific region of the
forkhead (FK) domain. A broader analysis of FOXA1 muta-
tions in breast and prostate cancer, in which it is also re-
currently mutated, confirms two specific hotspots in the FK
domain and the C-terminal transactivation domain. In-
terestingly, these mutational classes were associated with
higher FOXA1 messenger RNA and protein expression, and
with unique transcriptional changes suggesting different
functional effects.3 More work into why FOXA1 is mutated in
ILC, but GATA3 is mutated in IDC, is needed and could
possibly reveal some important underlying biology.
Another important finding concerning ILC was the in-
creased incidence of phosphatase and tensin homologue
(PTEN)-inactivating events. When including both mutations

and DNA copy number changes, ILC-luminal A showed a 13%
PTEN altered phenotype compared with 3% in IDC-luminal A
tumors. This increased mutation frequency of PTEN loss in
ILC correspond with decreased PTEN protein expression and
was largely mutually exclusive with PIK3CA mutations. Anal-
yses of RPPA protein and phosphor-protein expression data
demonstrated increased phosphoinositide-3 kinase/Akt signal-
ing as evident by increased levels of phosphorylated Akt (pS473
and pT308) and downstream Akt substrates including p-p27 and
p-p70S6 kinase in ILC tumors; these findings may represent a
potential therapeutic opportunity for patients with ILC.
In terms of gene-expression patterns, ILC was found to be
of the luminal A subtype in 83% of the cases. Within this ILC-
luminal A subset, additional expression subtypes were also
identified. These included a subset enriched for stromal and
extracellular matrix features, often referred to as the re-
active subtype.4 Another ILC expression subtype was en-
riched for immune cell features/infiltrates, whereas the
third group showed a more proliferative expression signa-
ture and a concomitant worse patient outcome. Finally, a
multiplatform analysis of the mixed histology tumors
showed that approximately 80% of these samples could
clearly be molecularly classified as either ILC or IDC, with
only a few showing a possibly hybrid phenotype. This could
have important implications for treatment of patients with
mixed ILC-IDC histology, as it suggests they are not a unique
group, but instead that their molecular features could be
used to classify them as either ILC or IDC.
SURGICAL ASPECTS OF LOBULAR CARCINOMA
ILC is a distinct subtype of breast cancer that is deserving of
particular attention by surgeons. ILCs tend to be insidious
as a result of their lack of E-cadherin, causing noncohesive
neoplastic cells that permeate through tissue in a single-file
pattern. Given its biology, a few areas are of particular
concern for surgeons.
Preoperative Imaging
It is clear that the extent of ILCs tend to be underestimated
by conventional imaging (Table 1). Some have suggested
that MRI may be useful in this context5; however, a recent
meta-analysis found that MRI did not significantly reduce
positive margin rates in patients with ILC undergoing breast
conservation.6 The concept that MRI could also find occult
contralateral disease has also been raised; however, ILCs are
no more likely to have a synchronous contralateral cancer
than are IDCs.7 MRI is therefore not routinely recommended
in the presurgical workup of patients with ILCs.8
Breast-Conserving Surgery Versus Mastectomy
Regardless of whether neoadjuvant chemotherapy is used or
not, ILCs are more often associated with positive margins
after breast-conserving surgery.911 Patients with this his-
tologic subtype are more likely to require re-excision, and
potentially mastectomy, for margin clearance.12 Some have
suggested that invasive lobular cancers treated with breast
LOBULAR CARCINOMA OF THE BREAST
TABLE 1. Imaging Concordance With Pathologic
Tumor Size (Correlation Coefficient)
Study MRI Mammography Ultrasound Clinical Exam
Boetes et al25 0.81 0.34 0.24
Francis et al 26
0.87 0.79 0.56 0.89
Kepple et al27 0.88 0.71
Kneeshaw et al28 0.86 0.47
29
Munot et al 0.97 0.66 0.67
conservation are more likely to result in local recurrences13;
however, this has not been borne out in other studies,9,10,14
and long-term survival rates are no different between breast
conservation and mastectomy.15 Hence, both are consid-
ered appropriate in terms of surgical management for this
disease. Of note, invasive lobular histology falls into the
American Society for Radiation Oncologys cautionary
subgroup for the use of accelerated partial breast irradia-
tion,16 given concerns regarding higher ipsilateral breast
tumor recurrences in this population.
Lymph Node Evaluation
Besides tumor extirpation from the breast, the other key task
of the breast surgeon is lymph node evaluation. Although it is
clear that sentinel node biopsy is feasible and accurate in
patients with ILC, the ability to find micrometastatic deposits
particularly on intraoperative evaluation with hematoxylin and
eosin staining alone may be challenging given the discohesive
nature of the neoplastic cells. Some pathologists have not
found this to be problematic.17 Others, however, may rec-
ommend deferral of final diagnosis to permanent sections, at
which time immunohistochemistry can be used to draw at-
tention to deposits that otherwise could be missed.18
SYSTEMIC THERAPY FOR LOBULAR CARCINOMA:
CHEMOTHERAPY
Response to Neoadjuvant Therapy
Increasingly, neoadjuvant chemotherapy is part of the mul-
tidisciplinary approach to breast cancer, as more novel ther-
apeutics are being evaluated in this setting. However,
physicians and patients should be aware that response rates to
neoadjuvant chemotherapy are lower for ILC than for its ductal
counterpart, as illustrated by the lower rates of pathologic
complete response and breast conservation (Table 2).
Why is neoadjuvant chemotherapy relatively ineffective for
lobular carcinomas? Is it something intrinsic to the biology of
lobular carcinomas per se? Mathieu et al19 have argued that
this relative futility is predictable, in that histologic and bi-
ologic factors predicting a poor response to chemotherapy
(low histologic grade, high ER content and bcl-2 expression,
and low proliferative rates as measured by Ki67 and negative
p53 staining) are all more frequent in lobular rather than
ductal carcinomas. These, in turn, reflect the luminal A
nature of most lobular carcinomas, discussed above.
There is a much smaller body of data evaluating neoadju-
vant hormonal therapy for lobular carcinoma. Dixon et al20
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 19
SLEDGE, CHAGPAR, AND PEROU
TABLE 2. Response to Neoadjuvant Chemotherapy
Study No. Patients
Truin et al30 IDC: 3,622
ILC: 466
Loibl et al31 Non-ILC: 7,969
ILC: 1,051
Lips et al32 IDC: 601
ILC: 75
Wenzel et al33 IDC: 124
ILC: 37
Tubiana-Hulin et al34 IDC: 742
ILC: 118
Cocquyt et al35 IDC: 101
ILC: 26
Abbreviations: pCR, pathologic complete response; BCS, breast-conserving surgery; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; NS, not significant.
evaluated the responsiveness of lobular carcinomas to neo-
adjuvant letrozole in 61 patients treated for 3 months. Mean
tumor volume reduction was 66%, with a high rate of breast
conservation (81%). Although we lack any head-to-head com-
parisons of neoadjuvant endocrine therapy with neoadjuvant
chemotherapy (and may never see such a comparison), a pri-
mary endocrine approach does not seem unreasonable.
RESPONSE TO HORMONAL THERAPY
If lobular carcinoma is relatively resistant to standard chemo-
therapeutic agents, and if this is largely as a result of predictable
biology (i.e., higher ER and lower proliferative rates), then what
about adjuvant hormonal therapy? Recent data suggest that
not all hormonal therapies are equal where lobular cancer is
concerned. In particular, tamoxifen appears to be considerably
less effective than aromatase inhibition for lobular cancers.
Metzger Filho et al21 compared the relative efficacies of
tamoxifen and letrozole for lobular and ductal carcinomas in
the BIG 1-98 trial. This trial was among the first randomized
controlled trials of aromatase inhibitor therapy in the ad-
juvant setting and now has relatively long follow-up (median
8.1 years). Comparing patients by histologic subtype, patients
with ILC were far more likely to benefit from letrozole than
tamoxifen, regardless of whether patients were luminal A
or luminal B like. The 8-year disease-free survival estimate
was 66% for tamoxifen compared with 82% for letrozole in
the ILC subset (hazard ratio [HR] 0.48) and was 75% for
tamoxifen and 82% for letrozole in the IDC subset (HR 0.80).
The test for interaction was significantly positive (p = .006).
These seem, on the face of it, to represent a clinically sig-
nificant difference and are paralleled by overall survival
differences (74% for tamoxifen compared with 89% for
letrozole in the ILC subset [HR 0.40]; 84% for tamoxifen and
88% for letrozole in the IDC subset [HR 0.73]).
In contrast, van de Water et al22 have examined the ad-
juvant TEAM (Tamoxifen and Exemestane Adjuvant Multi-
national) trial. This analysis differed considerably in that the
20 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
pCR (%) p Value BCS (%) p Value
20.2 , .0001 39.4 , .0001
4.9 24.4
17.4 , .001 71.1 , .0001
6.2 59.1
25 .01 46 .037
11 33
20 .009 79 .001
3 51
9 .002 48 .0004
1 30
15 .0066 50 NS
0 38
TEAM trial design in that early switch (2 to 3 years of ta-
moxifen followed by 2 to 3 years with an aromatase inhibitor)
and up-front (5 years with an aromatase inhibitor) strategies
were compared for relative benefit in lobular and invasive
ductal cancers. The TEAM analysis suggested that endocrine
therapy efficacy was similar for IDC and ILC once one had
adjusted for ER content. The early switch strategy arm might
well muzzle the treatment interactions seen in the BIG 1-98 trial.
If, as suggested by the BIG 1-98 analysis, lobular carci-
nomas are relatively less sensitive to tamoxifen than ductal
carcinomas, what molecular changes might underlie these
findings? Sikora et al23 have recently evaluated the response
of lobular carcinoma cell lines in vitro. Their work suggests
that the ER drives a unique program of gene expression in
lobular cancers when compared with ductal carcinomas.
Indeed, tamoxifen appears to drive the growth of these cell
lines, rather than inhibiting them, although this limited cell
line work cannot be safely extrapolated to the clinic.
In contrast to the preclinical results seen with tamoxifen,
Arthur et al24 have recently demonstrated in the neo-
adjuvant hormonal therapy setting that changes in gene
expression in response to letrozole were highly similar be-
tween responding ILC and IDC tumors.
CONCLUSION
Infiltrating lobular carcinoma of the breast represents a bi-
ologically distinct subset of breast cancer, a biology defined
by specific genetic aberrations in E-cadherin, the high
prevalence of ER-positive disease, the relatively low fre-
quency of HER2-positive disease, and specific mutational
events revealed by deep sequencing of ILC genomes. This
distinctive biology, in turn, affects the presentation, treat-
ment, andpotentiallythe prognosis of ILC. Biology af-
fects surgery and preoperative chemotherapy results, and,
as recent data suggest, it also affects adjuvant hormonal
therapy benefits. Ultimately, an improved understanding of
ILC biology should also lead to novel targeted approaches to
the conquest of the disease.

References
1. Ciriello G, Gatza ML, Beck AH, et al; TCGA Research Network. Comprehensive
molecular portraits of invasive lobular breast cancer. Cell. 2015;163:506-519.
2. Jozwik KM, Carroll JS. Pioneer factors in hormone-dependent cancers.
Nat Rev Cancer. 2012;12:381-385.
3. Cancer Genome Atlas Research Network. The molecular taxonomy of
primary prostate cancer. Cell. 2015;163:1011-1025.
4. Cancer Genome Atlas Network. Comprehensive molecular portraits of
human breast tumours. Nature. 2012;490:61-70.
5. Mann RM, Hoogeveen YL, Blickman JG, et al. MRI compared to con-
ventional diagnostic work-up in the detection and evaluation of invasive
lobular carcinoma of the breast: a review of existing literature. Breast
Cancer Res Treat. 2008;107:1-14.
6. Houssami N, Turner R, Morrow M. Preoperative magnetic resonance
imaging in breast cancer: meta-analysis of surgical outcomes. Ann Surg.
2013;257:249-255.
7. Langlands F, White J, Kearins O, et al. Contralateral breast cancer:
incidence according to ductal or lobular phenotype of the primary. Clin
Radiol. 2016;71:159-163.
8. Pilewskie M, King TA. Magnetic resonance imaging in patients with
newly diagnosed breast cancer: a review of the literature. Cancer. 2014;
120:2080-2089.
9. Fortunato L, Mascaro A, Poccia I, et al. Lobular breast cancer: same
survival and local control compared with ductal cancer, but should both
be treated the same way? analysis of an institutional database over a
10-year period. Ann Surg Oncol. 2012;19:1107-1114.
10. Molland JG, Donnellan M, Janu NC, et al. Infiltrating lobular carcinoma
a comparison of diagnosis, management and outcome with infiltrating
duct carcinoma. Breast. 2004;13:389-396.
11. Moore MM, Borossa G, Imbrie JZ, et al. Association of infiltrating lobular
carcinoma with positive surgical margins after breast-conservation
therapy. Ann Surg. 2000;231:877-882.
12. Kryh CG, Pietersen CA, Rahr HB, et al. Re-resection rates and risk
characteristics following breast conserving surgery for breast cancer
and carcinoma in situ: a single-centre study of 1575 consecutive cases.
Breast. 2014;23:784-789.
13. Hussien M, Lioe TF, Finnegan J, et al. Surgical treatment for invasive
lobular carcinoma of the breast. Breast. 2003;12:23-35.
14. Ott OJ, Hildebrandt G, Potter R, et al. Accelerated partial breast
irradiation with interstitial implants: risk factors associated with
increased local recurrence. Int J Radiat Oncol Biol Phys. 2011;80:
1458-1463.
15. Fodor J, Major T, Toth
J, et al. Comparison of mastectomy with breast-
conserving surgery in invasive lobular carcinoma: 15-year results. Rep
Pract Oncol Radiother. 2011;16:227-231.
16. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast
irradiation consensus statement from the American Society for Radi-
ation Oncology (ASTRO). Int J Radiat Oncol Biol Phys. 2009;74:987-1001.
17. Horvath JW, Barnett GE, Jimenez RE, et al. Comparison of intraoperative
frozen section analysis for sentinel lymph node biopsy during breast
cancer surgery for invasive lobular carcinoma and invasive ductal
carcinoma. World J Surg Oncol. 2009;7:34.
18. Cserni G, Bianchi S, Vezzosi V, et al. The value of cytokeratin immu-
nohistochemistry in the evaluation of axillary sentinel lymph nodes in
patients with lobular breast carcinoma. J Clin Pathol. 2006;59:518-522.
LOBULAR CARCINOMA OF THE BREAST
19. Mathieu MC, Rouzier R, Llombart-Cussac A, et al. The poor re-
sponsiveness of infiltrating lobular breast carcinomas to neoadjuvant
chemotherapy can be explained by their biological profile. Eur J Cancer.
2004;40:342-351.
20. Dixon JM, Renshaw L, Dixon J, et al. Invasive lobular carcinoma: re-
sponse to neoadjuvant letrozole therapy. Breast Cancer Res Treat. 2011;
130:871-877.
21. Metzger Filho O, Giobbie-Hurder A, Mallon E, et al. Relative effec-
tiveness of letrozole compared with tamoxifen for patients with lobular
carcinoma in the BIG 1-98 trial. J Clin Oncol. 2015;33:2772-2779.
22. van de Water W, Fontein DB, van Nes JG, et al. Influence of semi-
quantitative oestrogen receptor expression on adjuvant endocrine
therapy efficacy in ductal and lobular breast cancer - a TEAM study
analysis. Eur J Cancer. 2013;49:297-304.
23. Sikora MJ, Cooper KL, Bahreini A, et al. Invasive lobular carcinoma cell
lines are characterized by unique estrogen-mediated gene expression
patterns and altered tamoxifen response. Cancer Res. 2014;74:
1463-1474.
24. Arthur LM, Turnbull AK, Webber VL, et al. Molecular changes in lobular
breast cancers in response to endocrine therapy. Cancer Res. 2014;74:
5371-5376.
25. Boetes C, Veltman J, van Die L, et al. The role of MRI in invasive lobular
carcinoma. Breast Cancer Res Treat. 2004;86:31-37.
26. Francis A, England DW, Rowlands DC, et al. The diagnosis of invasive
lobular breast carcinoma. Does MRI have a role? Breast. 2001;10:38-40.
27. Kepple J, Layeeque R, Klimberg VS, et al. Correlation of magnetic
resonance imaging and pathologic size of infiltrating lobular carcinoma
of the breast. Am J Surg. 2005;190:623-627.
28. Kneeshaw PJ, Turnbull LW, Smith A, et al. Dynamic contrast enhanced
magnetic resonance imaging aids the surgical management of invasive
lobular breast cancer. Eur J Surg Oncol. 2003;29:32-37.
29. Munot K, Dall B, Achuthan R, et al. Role of magnetic resonance imaging
in the diagnosis and single-stage surgical resection of invasive lobular
carcinoma of the breast. Br J Surg. 2002;89:1296-1301.
30. Truin W, Vugts G, Roumen RM, et al. Differences in response and
surgical management with neoadjuvant chemotherapy in invasive
lobular versus ductal breast cancer. Ann Surg Oncol. 2016;23:51-57.
31. Loibl S, Volz C, Mau C, et al. Response and prognosis after neoadjuvant
chemotherapy in 1,051 patients with infiltrating lobular breast carci-
noma. Breast Cancer Res Treat. 2014;144:153-162.
32. Lips EH, Mukhtar RA, Yau C, et al; I-SPY TRIAL Investigators. Lobular
histology and response to neoadjuvant chemotherapy in invasive breast
cancer. Breast Cancer Res Treat. 2012;136:35-43.
33. Wenzel C, Bartsch R, Hussian D, et al. Invasive ductal carcinoma and
invasive lobular carcinoma of breast differ in response following
neoadjuvant therapy with epidoxorubicin and docetaxel + G-CSF. Breast
Cancer Res Treat. 2007;104:109-114.
34. Tubiana-Hulin M, Stevens D, Lasry S, et al. Response to neoadjuvant
chemotherapy in lobular and ductal breast carcinomas: a retrospective
study on 860 patients from one institution. Ann Oncol. 2006;17:
1228-1233.
35. Cocquyt VF, Blondeel PN, Depypere HT, et al. Different responses to
preoperative chemotherapy for invasive lobular and invasive ductal
breast carcinoma. Eur J Surg Oncol. 2003;29:361-367.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 21
POINTS OF VIEW
The section, new for 2016, contains articles describing emerging, highly debated, or controversial topics
in cancer research, treatment, and care to benefit patients and the field of oncology.

AUTHORS
Arthur L. Caplan, PhD
NYU Langone Medical Center
New York, NY

Laura Esserman, MD, MBA

University of California, San Francisco
San Francisco, CA

David J. Kerr, MD, PhD

University of Oxford
Oxford, United Kingdom

Ulka N. Vaishampayan, MD
Karmanos Cancer Institute
Detroit, MI
CAPLAN, BATEMAN-HOUSE, AND WALDSTREICHER

Compassionate Use: A Modest Proposal

Arthur L. Caplan, PhD, Alison Bateman-House, PhD, MPH, MA, and Joanne Waldstreicher, MD

Editors Note: The following article is based on the 2016 ASCO Annual Meeting Education Session Expanded Access and the
Right to Try: Navigating the Intersection of Drug Development and Patient Access to Investigational Agents. The authors
present the approach to compassionate use through use of an independent committee to vet and review requests for one
pharmaceutical company.

P atient requests for rapid access to agents that are still in

the research pipeline fall into two categories: requests
from groups of persons with the same malady and requests
by individuals. The former are often described as requests
for expanded access, the latter as requests for compas-
sionate use. Regulatory bodies in many countries have
created programs for providing greater access to requests
from groups including the creation of expanded access
programs and emergency use waivers for patients who do
not qualify for clinical trials. Compassionate use requests for
individuals have proven to be more difficult to resolve.
Compassionate use requests can come at any time during
the research processfrom when a drug is being tested in
animals, to its first-in-human studies, to dose-finding trials,
to when the agent under investigation nears the end of
clinical trials. Requests can come from patients nearing the
end of life, but they may also come from those facing serious
disability and pain for which no approved agent has been
proven effective. Requests can come from around the world
and from parents for their children, patients on their
deathbeds, those in the midst of lethal disease outbreaks,
those newly infected as well as the chronically ill, the very
poor, and those for whom money is no object.
Until very recently, the main strategy for patients seeking
compassionate use was to try to locate a possible treatment,
frequently online, and often, though not always, with the
help (or approval) of their physician. Once a possible treat-
ment was found, patients and/or their physicians seeking
compassionate use would try to contact the researcher or
leader of a group involved with testing the agentalmost
always at a company. Some are able to use personal con-
nections to initiate a request, whereas others reach out
to their elected officials, shareholders in the company, or
others thought to wield influence. Sometimes patients try to
interest the traditional media in their plight. Alternatively,
they may launch campaigns using social media with the hope
that public pressure might be brought to bear on the parties
who own the drug or agent. Regardless of the approach, this
process is, at best, hit or miss and one that favors patients
with a compelling personal interest story or who are oth-
erwise well-connected.
Many have claimed that the key obstacle for patients
seeking compassionate use access is the U.S. Food and Drug
Administration (FDA). However, estimates are that the FDA
approves over 99% of the compassionate use protocols it
receives.1 Furthermore, the FDA plays no role in responding
to requests for compassionate use until the company de-
veloping the agent has indicated its willingness to provide
the product. In contrast, companies encounter multiple
issues when faced with compassionate use requests. These
include the fact that they have no legal duty to offer access
and that they must balance requests with ongoing clinical
development programs. In addition, even if the company
wanted to respond, there may be uncertainty as to what the
response should be and how best to respond to all requests
fairly, particularly when there are those who are well-
connected and/or using social media campaigns.
In this article, we review the approach taken by one of
many companies (Janssen) that receives such requests,
which involved the formation of a third party. Internal
discussions at Janssen had focused on how to best handle
compassionate use requests consistent with its commit-
ment to obtain regulatory approval for investigational
agents, thereby making products available to the greatest
number of persons. Ultimately, Janssen decided to un-
dertake a first-of-its-kind partnership that enlisted a third
party to review requests made to the company for com-
passionate use. This novel approach was initiated as a pilot
program focused on a single investigational medicine,
daratumumab, which was being evaluated in late-stage
phase III trials at the time and had shown evidence of
efficacy in patients with refractory multiple myeloma.
Janssen approached the director of the Division of Medical
Ethics at NYU Langone Medical Center, Arthur Caplan, PhD,

From the New York University School of Medicine, New York, NY; NYU Langone Medical Center, New York, NY; Johnson & Johnson, New Brunswick, NJ.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Arthur L. Caplan, PhD, New York University School of Medicine, 227 East 30th St., New York, NY 10016; email: arthur.caplan@nyumc.org.

2016 by American Society of Clinical Oncology.

e2 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


to propose a method for reviewing compassionate use re-
quests that would be transparent, fair, beneficent, evidence-
based, and patient-focused. Drawing upon his prior work
involving the allocation of cadaver organs for transplan-
tation, Caplan formed a 10-person committee, the Com-
passionate Use Advisory Committee (CompAC), that consists
of physicians, bioethicists, patients, and patient advocates
from around the world to advise Janssen on compassionate
use requests for daratumumab. The CompAC was created
and staffed by the New York University School of Medicine
(NYUSOM) and was independent of Janssen. CompAC
members contracted with NYUSOM to remain indepen-
dent and reduce the risk of conflicts of interest. Some
CompAC members accepted payment for their time;
the chair and deputy chair, however, received no direct
compensation.
HOW THE COMPAC WORKS
Compassionate use requests for daratumumab are received
directly at Janssen through a standardized patient intake
form on the companys website. Janssen physicians screen
the intake forms for medical appropriateness, and, if the
patient is eligible for a clinical trial, expanded access pro-
gram, or has not yet tried an available drug or program,
Janssen informs the submitting physician of this and
does not route the request to CompAC. For all other
cases, CompAC receives requests on a weekly basis and
returns its recommendation to Janssen within 5 business
days of receiving each request. CompAC is an advisory
committee, and, legally, Janssen must remain in control
of the ultimate decision to provide access; however,
Janssen made a good faith commitment to follow CompAC
recommendations.
Although CompAC spent a good deal of time discussing
what, if any, criteria it would use in deciding who to rec-
ommend to receive access, it quickly became evident that
the key ethical requirement that the CompAC had to achieve
was fairness. The existing pathways for making requests of
Janssen and other companies were not always fair, some-
times favoring the rich, celebrities, and those who could
command attention. To work, CompAC had to ensure that it
would strengthen the fairness of compassionate use de-
cisions to better meet the needs of patients, doctors, re-
searchers, and the public. To do so, the CompAC:
KEY POINTS
This article describes the creation of a dedicated
committee to respond to compassionate use requests
for an investigational drug for multiple myeloma.
This article describes the importance of creating
principles of fair opportunity for those making requests
for compassionate use.
This article suggests that this model may have
application to other agents and settings.
COMPASSIONATE USE REQUESTS
1. worked to improve navigation of Janssens worldwide
websites so that those seeking compassionate use for
multiple myeloma would be able to more easily find
clear information on how to request daratumumab,
2. insisted that requests came from physicians and be
standardized so that all requests would have the same
information, unadorned by letters of support from
prominent individuals,
3. decided to rotate voting on requests among three of
its 10 members weekly to minimize any effort to lobby
the committee members,
4. directed Janssen to redact information pertaining to
the requesters name, location, nationality, and gen-
der to prevent these factors from being taken into
consideration by voting members,
5. created an appeal process by which a physician whose
request was denied could reintroduce further stan-
dardized information about his or her patient (i.e., new
laboratory values), and
6. committed to respond to all requests within 5 business
days, thereby ensuring that appropriate concern was
shown to all patients and that no one would be left
without an expeditious answerthe opposite of which
is commonly a source of great patient and physician
frustration about compassionate use requests.
Soon after the creation of the CompAC in May 2015, these
policies were implemented. Further discussion among
CompAC members led to an agreement on a set of principles
that would be used to guide the committees recommen-
dations in response to requests. These included: preventing
harm to patients, requiring that patients had exhausted all
available approved treatments before trying unapproved
agents, estimating the likelihood of obtaining an efficacious
response, and assessing patient functionality, and, at a lower
order of priority, prior participation in a clinical trial, direct
support for dependents, suffering from the disease, and age.
Decision making in response to requests commenced in July
2015, with an average of four to five requests per week.
Supply varied from week to week including some weeks in
which there was none.
LESSONS TO DATE
Although there is obvious interest both in who was se-
lected, who was rejected, and on what basis, the major
lesson learned from this pilot program is that it is fairness,
rather than justice, that is the key to the success of the
CompAC. By having a committee with broad expertise that
is insulated from what ought to be morally irrelevant
considerations of wealth, privilege, and media interest,
the CompAC has been able to institute strategies that
minimize the ability of any patient, family, advocacy
group, or advantaged party to sway decisions. Patients,
their doctors, and Janssen officials report that they be-
lieve that the pilot approach is more equitable than what
existed beforehand.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e3
CAPLAN, BATEMAN-HOUSE, AND WALDSTREICHER

The CompAC model may be applied to other novel agents
across Johnson & Johnson. Other companies, both large and
small, patient advocacy organizations, and government of-
ficials have all expressed interest in learning about or
extending the CompAC model to other settings.
The CompAC pilot program has been resource intensive,
involving many different groups to support its activities, and is
certainly not beyond criticism as to its composition, prin-
ciples, and decisions. However, the CompAC has identified
ways to make very hard decisions more equitable. Those
deserve close attention and debate in a world with many
more unapproved agents that will be sought by the des-
perate who face constraints upon the resources available
to them.

References

1. Silverman E. The FDA Says Its More Compassionate Than You Think.
Healthcare Blog, The Wall Street Journal. 2014. http://blogs.wsj.com/
corporate-intelligence/2014/05/05/the-fda-says-its-more-compassionate-than-
you-think/. Accessed February 24, 2016.

e4 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook

 THE EVOLVING SURGICAL APPROACH TO BREAST CANCER

Less Is More: The Evolving Surgical Approach to Breast Cancer

Laura Esserman, MD, MBA, Etienne Gallant, and Michael Alvarado, MD

Editors Note: The following article is based on the 2016 ASCO Annual Meeting Education Session Less Is More: A Multi-
disciplinary Conversation on Treatment Options. The authors review the indications for reducing the treatment burden for
women with breast cancer by capitalizing on the emerging opportunity to identify and recognize more indolent forms of the
disease using advanced tools, therapies, and screening methods.

OVERVIEW

Personalized medicine is emerging as an important guiding principle in diagnosis and treatment. This means not just doing
more for some, but safely doing less for others. The lessons learned about the biology of breast cancer over the last 2 decades
have enabled us to understand the incredible heterogeneity of breast cancer and its associated behavior. Although much
work remains, there is an emerging opportunity to identify and recognize more indolent forms of breast cancer, made more
prevalent through the widespread adoption of screening. With our improving systemic therapies and improved molecular
tools, we now have the opportunity to reduce the burden of treatment in women with lower-risk tumors. Our surgical
treatments have evolved, with less morbid and more cosmetic procedures. In this article, we review the indications for
further reducing local therapy, including adjuvant radiation.

T he history of breast surgery is one in which we have gone

from more to less. Radical mastectomies, when first
introduced by Halsted, were an improvement over leaving
women with fungating masses. However, the field evolved
through a series of randomized trials to minimize the
morbidity of our surgical procedures. Modified radical
mastectomies have replaced radical mastectomies. Imme-
diate reconstruction and skin-sparing mastectomy, and now
total skinsparing mastectomies, have been shown to be
oncologically safe and cosmetically better.1,2 We have re-
duced extended axillary procedures, and sentinel node
dissections have fortunately successfully reduced the
complications of lymphedema. Even in the setting of stage II
and III disease, with axillary disease, surgeons are finding
safe ways to reduce the burden of axillary surgery in the
setting of excellent responses to neoadjuvant chemother-
apy. Especially because we are increasingly more successful
in preventing recurrence and death from breast cancer and
as women lead longer lives, we must pay more attention to
identifying the opportunities to reduce the burden of
treatment. We now have the opportunity to focus on the
advances in molecular biology to help us to identify tumors
with indolent behavior and to adjust our local therapy
accordingly.3,4
Decision making for patients with low-risk disease is often
more complicated than for those with high-risk disease. The
reason is that the benefit from an intervention and its side
effects may not outweigh the risk of the disease. Thus, a
postmenopausal woman with favorable-risk hormone
receptorpositive breast cancer has several options after
breast conservation. In addition to what has been the gold
standard, standard dose external beam radiation therapy
(EBRT), there are several alternatives including hypo-
fractionated EBRT, intraoperative radiation therapy (IORT),
or no radiation, which are all supported by the literature as
at least equivalent, if not superior, strategies to EBRT.5,6 And
yet, trial results have not significantly influenced practice in
the United States.
Over time, the local recurrence rates have been decreasing
from the original reported risk of 10% EBRT. Recent studies
show rates largely less than 5% and even lower when en-
docrine therapy is used. Data from four trials with pop-
ulations of similar biology (postmenopausal women with
node-negative, hormone receptorpositive, early-stage breast
cancer) are shown in Table 1. Local recurrence rates are very
low in the EBRT arms or in the complete absence of radiation.
Fyles et al found that women over age 50 in the low-risk
groupimmunohistochemistry subtype luminal Ahad a
local recurrence of 4.9% at 10 years with or without EBRT.7
Intraoperative radiation therapy results, which also show a
very low locoregional recurrence, are consistent with other
modern trial results. It should be noted that there was no

From the University of California, San Francisco, San Francisco, CA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Laura Esserman, MD, MBA, University of California, San Francisco, 1600 Divisadero St., 2nd Floor, Box 1710, San Francisco, CA; email: laura.esserman@ucsf.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e5

ESSERMAN, GALLANT, AND ALVARADO
difference in metastatic rates or overall survival for any of
the trial arms.
The question of how to approach patients with early-
stage, favorable-risk breast cancer illustrates the complexity
of forces influencing decision making in regard to adoption
of new approaches. Whole-breast EBRT remains the stan-
dard of care following breast-conserving surgery. However,
multidose partial breast radiation is increasingly offered as
an alternative for eligible women. Emerging technologies
have provided impetus for shifts in radiation approaches
despite lack of randomized clinical trial data for these de-
vices. The frequency of brachytherapy use increased from
approximately 1% in 2001 to 10% in 2006, despite concerns
about long-term efficacy.8 In fact, over 30,000 women had
been treated with accelerated partial breast irradiation
(APBI) by the time the American Society for Radiation On-
cology published its first consensus statement.9
The finding from a randomized trial (CALGB 9343) that
older women with hormone receptorpositive breast cancer
could be effectively treated with tamoxifen without radia-
tion therapy has yet to be adopted into clinical practice.10
The results demonstrated that with or without radiation,
distant recurrence, breast cancer mortality, and mastectomy
rates are the same and very low in the two arms.11 Despite
these results with more than 10 years of follow-up and
corroborating evidence from a similar Canadian trial in all
postmenopausal women,12 as well as the PRIME 2 trial,13
radiation is rarely omitted and postlumpectomy radiation is
considered a quality measure by the American College of
Surgeons for older women. Fear of omitting therapy and
being less aggressive often makes both physicians and pa-
tients uncomfortable, even in the face of supporting evi-
dence to the contrary. The cultural bias that more aggressive
treatment of cancer is better, fear of malpractice, and fi-
nancial rewards all conspire to encourage intervention.
KEY POINTS
Surgery for breast cancer has dramatically changed in
recent years, moving away from extensive surgical
resections for all patients to more individualized, limited
surgery for early stages of disease.
Treatment decisions for patients with early-stage
disease are complex because decision making typically
involves multiple options that likely have little effect on
overall survival.
The widespread use of screening has resulted in
identification of a higher fraction of low-risk cancers.
Women undergoing breast-conserving therapy have
numerous options that include surgery alone or surgery
and limited fractionated radiation and IORT.
Molecular classifiers of indolent tumors can guide a less
aggressive initial strategy and should inform treatment
of both invasive disease and help to reclassify some
types of DCIS.
e6 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
When the CALGB 9343 results were presented in 2002,
they met a similar reaction to the results of the TARGIT-A
results in 2010. Many demanded 10 years of data prior to
adoption. However, even with 10 years of data demon-
strating that mortality is not impacted by radiation in women
over age 70, or even with the publication of the PRIME 2 trial
results,13 the standard of care after breast-conserving sur-
gery has remained EBRT.
Partial breast radiation as an alternative to EBRT has been
on the market for 10 years with variable uptake. There was
a large international randomized trial comparing single
intraoperative radiation using low-energy photons delivered
by the TARGIT device. The results of the TARGIT A trial were
first published in 2010, followed by a second publication in
2014.14 The results showed noninferiority, specifically for
the prepathology stratum (TARGIT given at time of lump-
ectomy). There was a great deal of criticism and arguments
that it was too early to adopt the findings,15 with bias from
many radiation oncologists not expecting that a treatment
with low-energy photons would work. Indeed, early adop-
tion of technology that turns out to be inferior to the status
quo can be harmful, but late adoption of technology that
turns out to be equivalent or superior to the status quo can
be a missed opportunity that also harms individuals and
society. Using a framework to evaluate the risks and benefits
of early versus late adoption, this technology is one where
early adoption would be preferable to EBRT for all eligible
cases.16
Breast cancer is now recognized as being comprised of
several distinct diseases. One of the reasons that the
locoregional recurrence appears to be so much lower is likely
due to the impact of mammography screening and the
identification of tumors that are biologically more
indolent.17-19 The results from older trials in which there
was a 40% locoregional recurrence in the absence of radi-
ation applied to younger women with tumors with more
aggressive biology.20 Thus, reframing risk and options must
occur as we have the ability to better characterize the bi-
ology of newly diagnosed breast cancers21 and offer better
options for women with low-risk disease. This is even more
important where local recurrence is not life threatening.
The risk for distant breast cancer recurrence for women
with hormone receptorpositive disease does extend over a
20-year period.22 This well-known fact leads to an erroneous
conclusion that long-term follow-up for 10 or more years is
needed to assess outcomes. However, the peak hazard rate
for local recurrence is early, and then is low and stable, thus,
the overall conclusions are extremely unlikely to change.
This has been demonstrated by the overview analyses as
well as many trials,23,24 the Canadian trial, the CALGB trial,
and the TARGIT A trial, which showed that early results
predicted the later results.12,25-27
The demonstration that less-aggressive interventions are
equally effective for women with lower-risk tumors is a
critical breakthrough for women and a major advance in our
ability to tailor treatments for women according to the
biology of their tumors. If we can safely accomplish the same
 THE EVOLVING SURGICAL APPROACH TO BREAST CANCER

TABLE 1. Recent Studies of Breast Conservation, Radiation, and Local Therapy Outcomes
Study Accrual Dates No. of Patients Study Arms 5-Year LRR 10-Year LRR 12.6-Year LRR
TARGIT-A14 20002012 2,298 prepathology IORT 2.1% NA NA
EBRT 1.1%
Studies Comparing XRT With No XRT
CALGB C934311 19941999 636 Tam 4% 7% 10%
Tam + RT 1% 1% 2%
Luminal A7 19922000 611 (all T1 patients) Tam 5.5% 13.8% NA
Tam + RT 0.4% 5.3%
114 (subset of G1/2, Tam 2% 4.9% NA
luminal A patients)
Tam + RT 5.5%
PRIME II13 20032009 1,326 No RT 4.1% NA NA
RT 1.3%
Studies Comparing Hypofractionated 3-Week EBRT With 5-Week EBRT
Hypofractionated 19931996 1,234 3-week EBRT 2.33% 6.2% NA
Radiation5
5-week EBRT 2.17% 6.7%
START-B6 19992001 2,215 3-week EBRT 1.9% 5.2% NA
5-week EBRT 3.3% 3.8%
Abbreviations: LRR, locoregional recurrence; NA, not available; IORT, intraoperative radiation therapy; EBRT, external beam radiation therapy; Tam, tamoxifen; RT, radiation therapy.

goal (preventing cancer recurrence) in a much more effi-
cient, less invasive, and less personally time-consuming
manner for women, the physician community should be
the first to embrace this therapy. The complaint about IORT
seems to be that the data are immature; however, clinical
practitioners can switch to IORT and watch the data mature.
The chance that the results will change has a very small
probability, and practitioners could switch back to EBRT or
switch to another treatment that has been shown to be
more effective than EBRT in the interim. As our analysis
indicates, little will have been lost for any patient who re-
ceives IORT, as many are also eligible for hormone therapy
alone.
Daily radiation treatments over many weeks are bur-
densome to patients, especially those that live far from an
adequate radiation treatment center. It is reasonable to
assume that patients would prefer no radiation, IORT, or
shorter courses of EBRT, even simply on the basis of con-
venience. Women concerned only about distant recurrence
should be advised about the options of no radiation for
node-negative disease. If a 5% to 10% difference in local
recurrence is important to avoid, IORT is an excellent al-
ternative to no radiation.
The difficulty in adoption of less-aggressive therapy may
best be approached by using biomarkers that characterize
tumors as indolent. One biomarker, specifically adapted for
the express purpose of identifying indolent disease in the
absence of all treatment, could have the potential to provide
reassurance to providers and patients alike that a less-
aggressive initial treatment is appropriate.
The widespread prevalence of screening has resulted in a
shift in the kinds of cancers detected. The objective of
screening is to identify cancers at a lower stage, however, a
consequence of screening is the identification of a higher
fraction of tumors with low-risk biology.28 An important way
to mitigate that risk is to recognize that lower-risk biology
tumors are more likely to be detected with screening and to
have tools to identify them at the time of diagnosis and
enable less-aggressive treatment. Using a data set from a
randomized trial of no treatment compared with treatment
with tamoxifen for 2 years, we sought to leverage a validated
molecular classifier to determine if we could define a group
of women whose prognosis was excellent even 20 years after
diagnosis.29 We used a test that was originally designed to
identify a population of patients with breast cancer, in the
absence of systemic therapy, with a good prognosis at
5 years. The 70-gene test (MammaPrint) has been used to
identify women who do not benefit from adjuvant che-
motherapy and is currently being evaluated in the MINDACT
clinical trial (6,600 patients; results expected late spring
2016). We created a new threshold with the purpose of
specifically evaluating long-term (. 20 years) breast can-
cerspecific mortality, which we have designated indolent
threshold.
The women in the STO1 study presented with palpable
tumors, so by definition, they had tumors that had come to
clinical attention. These are not cancers detected by
screening. When the indolent threshold is applied to the STO
study in which women presented with palpable, clinically
detected tumors, we were able to identify women whose
tumors, after surgery and a short course (2 to 5 years) of
tamoxifen, posed no risk for breast cancerspecific death for
15 years.29
An indolent tumor should signal that a more minimal
treatment approach would be sufficient. Although there
may be a small fraction of patients who progress, that
progression is many years later, and early treatments are
unlikely to impact that progression. The critical distinction is

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ESSERMAN, GALLANT, AND ALVARADO
FIGURE 1. Indolent Threshold of the 70-Gene Assay
An indolent threshold of the 70-gene assay has been validated in a randomized
trial of postmenopausal women with node-negative palpable tumors.29 These
tumors are essentially curable at the time of presentation. Thus, there would be no
value to identifying the precursors of such tumors. Such precursors would therefore
fit the definition of IDLE conditions18 and should not be called cancer nor be the target
of screening. The most likely candidates for these precursors are low-grade ductal
carcinoma in situ lesions. Studies are ongoing to investigate the relationship of
low-grade ductal carcinoma in situ and indolent invasive breast cancer.
Abbreviations: IDLE, indolent lesions of epithelial origin; DCIS, ductal carcinoma in
situ; Dx, diagnosis; TAM, tamoxifen.
that additional treatment should be reserved for when and
if that disease progresses, and additional treatment should
be administered at the time of progression (Fig. 1).
We can reflect on the three randomized studies that
demonstrate that women with relatively low-risk biology
have a low risk of recurrence in the setting of hormone
therapy alone and without radiation.11-13 The risk of local
recurrence, as stated earlier, has dropped over the years
likely because of the dramatic increase in the number of
women diagnosed who have indolent cancers.16 In the
CALGB 9343 trial of women treated with lumpectomy alone
and 5 years of tamoxifen, local recurrence was uncommon
and successfully treated at the time of diagnosis without an
impact on mortality or the mastectomy rate. Recurrence
rates in the absence of radiation are low,11-13 and, in par-
ticular, the event of recurrence appears to be salvageable
without an adverse impact on mastectomy rates or mor-
tality. In particular, the Canadian trial of radiation compared
with no radiation demonstrates that luminal A tumors have
only a 5% risk of local therapy with 5 years of tamoxifen
therapy and absence of radiation. The indolent threshold
described here is more stringent than the luminal A cate-
gory, with only 31% of luminal A tumors meeting the in-
dolent designation. Importantly, in all of the radiation versus
no radiation studies, the chance of dying of other causes is
considerably higher than the chance of dying of breast
cancer. The analysis of the Stockholm 1 study confirms the
existence of a tumor type that has an indolent course, which
can be treated less aggressively at the time of diagnosis. In
this population of women, the indolent threshold did not
identify women who had zero risk absent therapy, but al-
most no risk with a minimal course of tamoxifen.
e8 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
The indolent threshold could therefore be used to identify
women for whom lumpectomy alone and a short course
of adjuvant endocrine therapy is sufficient. Many women
are unable to tolerate 5 years of endocrine therapy, and as
many as 60% have discontinued aromatase inhibitors by
3 years.30,31 The ability to identify a population of women
with little benefit of extended endocrine risk-reducing
therapy would be of huge benefit. The indolent threshold
does not allow us to say that women would never experience
recurrence over their lifetime (we have not found the
classification for truly IDLE [indolent lesions of epithelial
origin] conditions), but we can say that the chance of any
recurrence is low and that more aggressive therapy can
be administered at the time of recurrence, sparing many
women treatments that will not be of benefit.
It is estimated that over a 10-year period, five to seven
cancers per 1,000 might be diagnosed that might not oth-
erwise come to clinical attention.32 These represent ap-
proximately 17% of the patients diagnosed with breast
cancer. Interestingly, approximately 15% of the STO1 trial
population had tumors that met the indolent threshold. In
the MINDACT study, a modern cohort of patients in which
over 80% of women are screened, the fraction of women
with screen-detected tumors with indolent cancers may be
in the range of 37%, or about 20% more than what was
observed in the STO trial, which was conducted prior to the
widespread use of screening. This is consistent with the
additional low-risk cancers diagnosed with screening. Over a
10-year period in the United States, where 50 million women
are screened for 10 years, this might amount to 300,000
cancers with extremely low-risk of recurrence. Character-
ization of all screen-detected cancers could provide critical
information about how to further personalize treatment.
Even in the setting of presentation of palpable disease,
about 10% of tumors fit the molecular definition of indolent
FIGURE 2. Identification and Therapy of the Indolent
Spectrum of Breast Cancers
Identification of the indolent spectrum of breast cancers and tailoring therapy
accordingly (local and systemic) should be considered part of the evolution
toward personalized breast cancer treatment.

disease. In the setting of screening, that number is more
likely to be in the range of 35% or higher33 in keeping with
observations from screening trials.34 If the biology of these
tumors can be recognized at the time of diagnosis, and
women can be reassured that their prognosis is excellent,
simpler interventions can be used such as excision alone,
sentinel node, and hormone therapy for 2 to 5 years.
Registry studies for using less intervention for post-
menopausal women with lower-risk tumors are under
development. The University of Michigan is leading a multi-
institutional study of surgical excision alone for women age
50 to 69 with T1NO tumors with Oncotype Dx results lower
than 18. LUMINA is a Canadian Ontario Cancer Group study
of lumpectomy alone for women older than age 55 with
T1NO tumors that are luminal A. There are several ductal
carcinoma in situ (DCIS) trials starting, two in Europe, in-
cluding the LORD trial and the LORIS trial, and three in the
United States (a registry trial through the ATHENA network,
the COMET trial recently funded by PCORI, and the ECOG-
ACRIN MRI and Oncotype prospective study) exploring op-
tions of using less intervention.
Overdiagnosis is much less of a problem if we accept and
recognize that we will identify indolent disease with
screening and if we have tools to characterize it and be less
aggressive with our interventions. To do so, we have to have
confidence in the tools that we use to identify such indolent
conditions.
These data should also make us reflect on the dilemma of
DCIS. If there are indolent cancers that can be successfully
treated upon diagnosis, then certainly there would not be
any value to finding the precursors of these indolent cancers.
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THE EVOLVING SURGICAL APPROACH TO BREAST CANCER
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All treatments have side effects. Mastectomy, even with
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can also be challenging to take for women, and it has been
reported that over 40% of women stop taking their medicine
after 3 years.30,31 The STO data suggest that 2 years of ta-
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11. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen
with or without irradiation in women age 70 years or older with early
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31:2382-2387.
12. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without
breast irradiation in women 50 years of age or older with early breast
cancer. N Engl J Med. 2004;351:963-970.
13. Kunkler IH, Williams LJ, Jack WJ, et al; PRIME II investigators. Breast-
conserving surgery with or without irradiation in women aged 65 years
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ESSERMAN, GALLANT, AND ALVARADO
or older with early breast cancer (PRIME II): a randomised controlled
trial. Lancet Oncol. 2015;16:266-273.
14. Vaidya J, Wenz F, Bulsara M, et al; TARGIT trialists group. Risk-
adapted targeted intraoperative radiotherapy versus whole-breast
radiotherapy for breast cancer: 5-year results for local control and
overall survival from the TARGIT-A randomised trial. Lancet. 2014;383:
603-613.
15. Woloshin S, Schwartz LM. Whats the rush? The dissemination and adoption
of preliminary research results. J Natl Cancer Inst. 2006;98:372-373.
16. Esserman LJ, Alvarado MD, Howe RJ, et al. Application of a decision
analytic framework for adoption of clinical trial results: are the data
regarding TARGIT-A IORT ready for prime time? Breast Cancer Res Treat.
2014;144:371-378.
17. Esserman LJ, Shieh Y, Rutgers EJ, et al. Impact of mammographic
screening on the detection of good and poor prognosis breast cancers.
Breast Cancer Res Treat. 2011;130:725-734.
18. Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer
and prostate cancer. JAMA. 2009;302:1685-1692.
19. Bleyer A, Welch HG. Effect of three decades of screening mammography
on breast-cancer incidence. N Engl J Med. 2012;367:1998-2005.
20. Fisher B, Montague E, Redmond C, et al. Findings from NSABP Protocol
No. B-04-comparison of radical mastectomy with alternative treat-
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26. Vaidya JS, Wenz F, Bulsara M, et al. Targeted intraoperative radio-
therapy for early breast cancer: TARGIT-A trial- updated analysis of local
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women 70 years of age or older with early breast cancer. N Engl J Med.
2004;351:971-977.
28. Esserman LJ, Thompson IM, Reid B, et al. Addressing overdiagnosis and
overtreatment in cancer: a prescription for change. Lancet Oncol. 2014;
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30. Cuzick JF, Sestak I, Howell A, et al. Anastrozole versus tamoxifen for the
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 STRATEGIES FOR SUSTAINABLE CANCER CARE

Strategies for Sustainable Cancer Care

David J. Kerr, MD, Anant Jani, PhD, and Sir Muir Gray, CBE, FRCPSGlas, FCLIP

Editors Note: The following article is based on the 2016 ASCO Annual Meeting Education Session NICE or Not? Evaluating
Global Strategies for Sustainable Cancer Care. The authors review strategies for sustainable cancer care and the National
Institute for Health and Care Excellences role in the assessment of clinical and cost-effectiveness of new pharmaceutical and
biopharmaceutical products in the United Kingdom.

OVERVIEW

There is an increasing focus on the relative cost-effectiveness and sustainability of delivering high-quality cancer care,1 with
most emphasis, debatably, given to cost control of innovative treatments. It is difficult to calculate all the direct and indirect
contributors to the total cost of cancer treatment, but it is estimated that cancer drugs constitute 10% to 30% of the total cost
of cancer care. A 2007 study in France2 showed the contribution of drug costs was less than 20%, with approximately 70% of
the total expenditure on cancer accounted for by health care resource use, such as hospitalization. The U.K. government
established the National Institute for Health and Care Excellence (NICE)the dominant function of which is technology
appraisalto assess the clinical and cost-effectiveness of new pharmaceutical and biopharmaceutical products. This is to
ensure that all National Health Service (NHS) patients have equitable access to the most clinically effective and cost-effective
treatments that are viable. NICE has developed a transparent, public process to judge incremental cost-effectiveness using
the quality-adjusted life year (QALY), which allows comparisons of cost-effectiveness across medical specialties. NICE has
been both lauded and criticizedespecially when it passes judgment on marginally effective but expensive anticancer
drugsbut it provides a route to rational rationing and, therefore, may contribute to sustainable cancer care by
highlighting the issue of affordable medicine. This implies a challenge to the wider oncology community as to how we might
cooperate to introduce the concept of value-driven cancer care.

M ichael Porter, a leading professor at the Harvard

Business Institute, has developed the following defi-
nition of value:
and the resources used. In turn, the outcome is determined
by the quality and safety of the intervention or service.

Value in any field must be defined around the customer, not
the supplier. Value must also be measured by outputs, not
inputs. Hence it is patient health results that matter, not the
volume of services delivered. But results are achieved at some
cost. Therefore, the proper objective is patient health
outcomes relative to the total cost (inputs). Efficiency, then,
is subsumed in the concept of value.3(p. 12)
Porter and Teisberg put this another way: Achieving high
value for patients must become the overarching goal of
health care delivery, with value defined as the health out-
comes achieved per dollar spent.4 Value, therefore, de-
pends on results, not input, and so value in health care is
measured by the outcomes achieved, not the volumes de-
livered, and the relative costs of achieving those outcomes.5
Put simply, value is the relationship between the outcome
STRATEGIES FOR SUSTAINABLE CANCER CARE:
VALUE
Value Versus Quality
Services become high quality for several reasons, many of
which are factors that have been shown to reduce the in-
cidence of errors, notably: (1) good leadership, (2) devel-
opment of systems, and (3) the creation of a strong culture.
To maximize the probability of benefit and minimize the
probability of harm and errors, professionals need standard
operating procedures (SOPs), commonly defined as a pro-
cedure, or set of procedures, to perform a given operation
or evolution in reaction to a specific event. To improve
quality and safety, it is necessary to have a style of gen-
eral management that will increase effectiveness and re-
duce harmfor example, promotion of safety culture; use
of systems, including clinical guidelines; clear lines of

From the Nuffield Division of Clinical and Laboratory Science, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: David J. Kerr, MD, Nuffield Division of Clinical and Laboratory Sciences, Level 4, Academic Block, John Radcliffe Infirmary, Headington, Oxford, OX3 9DU
United Kingdom; email: david.kerr@ndcls.ox.ac.uk.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e11

KERR, JANI, AND GRAY
accountability for risk management and safety; and data
collection about risk factors, errors, and near misses.
Certainly there is concern about low-value, low-quality
cancer care, and the Institute of Medicine report, Crossing
the Quality Chasm, on improving the quality of health care
has been welcome, but high-quality health care need not be
synonymous with high-value health care. Low-quality health
care is certainly of lower value, but there are many examples
of health care providing high quality that is of low value. The
semantics of this are important because consumers often
associate value (e.g., in supermarkets) at the lower end of
the market (e.g., Attention Kmart shoppers, as Beetlejuice
once said!).
The assessment of cost-effectiveness by organizations
such as NICE is of vital importance, but cost-effectiveness
refers to an intervention, whereas value refers to a pop-
ulations services. Perhaps populations will have to make
decisions between different degrees of cost-effectiveness,
worrying not about the financial cost of one particular in-
tervention but about its opportunity costnamely what else
can be done with resources within a finite health budget. If
there is an investment in cancer drugs, there may have to be
disinvestment elsewhere within the cancer program or the
wider health service.
Choosing Wisely
There is increasing recognition of unwarranted variation not
only in investment in cancer care but also in quality, cost, and
outcome. This variation highlights two other problems that
should be addressed not only by policy makers but also by
every clinician providing cancer services.
The first of these is overuse, highlighted in the Choosing
Wisely Campaign in the United States and in the Too Much
Medicine campaign of the British Medical Journal. Overuse
always wastes resources and sometimes does harm (e.g.,
prescribing chemotherapy to patients when palliative care
would be more appropriate, where the concern is not to save
costs, but that the prescription of chemotherapy can be
classified as inappropriate or futile).
KEY POINTS
There is a need to balance cost-effectiveness and
sustainability of delivering high-quality cancer care.
It is estimated that cancer drugs constitute 10% to 30%
of the total cost of cancer care.
The U.K. government established NICE to assess the
clinical effectiveness and cost-effectiveness of new
pharmaceutical and biopharmaceutical products.
NICE has been praised as well as criticized, but it
contributes to sustainable cancer care by highlighting
the issue of affordable medicine.
The worldwide oncology community must cooperate to
introduce the concept of value-driven cancer care for
patients.
e12 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
The second problem is underuse of effective and cost-
effective interventions for cancer, principally because of poor
organization in the management of cancer services. One other
aspect of underuse that should be considered is inequity, where
certain subgroups of the populationfor example, distin-
guished by age, ethnic background, or classreceive lower
levels of high-value treatment than the general population.
Therefore, a focus on value is needed. Three aspects of
value are:
allocative value, determined by how the assets are
distributed to different subgroups in the population;
technical value, determined by how well resources are
used for all the people in need in the population; and
personalized value, determined by how well the de-
cisions relate to the values of each individual.
Triple-Value Health Care
Practitioners providing cancer care should continue to cam-
paign for more resources for cancer, but they should also be
prepared to defend the allocative value of everything they are
currently doing. There are ways in which reallocation can be
facilitated. For example, in Spain, there was a bid for immu-
notherapy resources for malignant melanoma, the total cost
being about V2 million for the population served. The payers
said they were unable to find this resource, but actually, in that
same population, the annual expenditure on skin disease was
approximately V170 million per year. Practitioners in cancer
care should learn to argue that consideration should be given
to shifting V2 million from lower-value care for other skin
diseases to malignant melanoma.
The main challenge for people providing cancer services is
to consider the allocation of resources between different
cancer groups or between different modalities. The balance
of investment in different patient groups is often a matter of
historical accident, with one particular clinical group having
been more successful than others, but this should be
reviewed to see if the balance is optimal between the dif-
ferent types of common cancer, not excluding rare cancers.
As the path becomes more difficult, providers of cancer care
and patient representatives should consider whether the
balance is right; for example, should the interval between
breast cancer screening be increased to free up resources
that can be switched to chemotherapy for women with
breast cancer?
Technical value is different from efficiency. Technical value
has to take into account not only the use of resources for
the patients seen, but also the possibility of overuse and
underuse. Every cancer service should conduct a review of
inappropriate or futile care, which relates to the third type of
value, personalized value
In making decisions about personalized value, the model
of decision making at the Centre of Evidence-Based Medi-
cine is useful (Fig. 1). Cancer services should ensure that
every patient is fully informed about not only the benefits of
treatment, but also the risks, and help them reflect on how
these odds reflect on values.
 STRATEGIES FOR SUSTAINABLE CANCER CARE

FIGURE 1. Center of Evidence-Based Medicines of course plays to the current model of precision med-
Personalized Value Model of Decision Making icine, selecting the right drug for the right patient.
Payers also should be explicit about health care condi-
tions that will or will not be given treatment from
publicly/insurance-funded health services.
In addition, services must make explicit decisions and
publish the decisions to not provide interventions they
deem to be of low value, such as expensive but mar-
ginally effective cancer therapeutics.
Management of demand may not be possible if left
solely to individual clinicians faced with the distress of
the individual patient. Funders should make decisions
at a population level. This is the implicit tension be-
tween the practice of population and clinical medicine
should practicing clinicians always stand outside of
decisions on drug rationing to maintain the integrity of
Managing Clinical Demand their relationship with the patients entrusted to their
There is a fashion in operations, as there is in sleeves and care?
skirts: the triumph of some surgeon who has at last found out
how to make a once desperate operation fairly safe is usually
followed by a rage for that operation not only among the National Institute for Health and Care Excellence
doctors, but actually among their patients. Since 1999, NICE has provided the United Kingdoms NHS
and those who rely on it for their care, with an increasing
George Bernard Shaw, preface to The Doctors Dilemma, 1906 range of advice on effective, good-value health care, and
Enthusiastic medical professionals, altruistic as we are and it has gained a reputation for rigor, independence, and
keen to do good, are armed with information provided by objectivity (Fig. 3). This has been described by some as
enthusiastic promoters of new technology, expressed in terms rational rationing. Available guidance takes several forms:
of relative benefit rather than absolute benefit, and are, not
surprisingly, the people who may fuel the growth in demand.
NICE guidelines make evidence-based recommenda-
tions that aim to promote integrated care.
Clinical demand may be overtly expressedfor example by
clinicians leading a campaign for a new drug or a new facility
Technology appraisal guidance to assess the clinical and
cost-effectiveness of health technologies, such as new
such as a PET scanneror demand can arise through what pharmaceutical and biopharmaceutical products, but
is called creep (i.e., an inexorable increase in testing and
treatment). Innovation should decrease cost as well as increase
it, and there is now a drive to innovate for better value, FIGURE 2. Causes of Cost Inflation
harnessing the power of new technology and improved ways
of organizing services. A classic study by Eddy6 in the United
States showed that, in a health care system in which ex-
penditure is not finite, changes in the volume and intensity
of clinical practice are the main factors driving increases
in the cost of care that can be controlled by those who
pay for or manage health care. The other causes of in-
creasing costsaging population, medical and general price
inflationare beyond the power of health service managers
to control (Fig. 2).
Managing innovation usually focuses on a small number of
potentially high-cost interventions; however, the conclusion
from the work of Eddy,6 which is as true today as when it was
published, is that every innovation, no matter how small, should
have its introduction to, or removal from, the health care system
carefully managed, particularly if it is for a common disease.
Managing demand is not easy, but some steps can be
taken; for example:
Be very clear and explicit about the subgroups of cancer
patients most likely to benefit from an intervention and,
as a corollary, those who are least likely to benefit. This

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e13

KERR, JANI, AND GRAY

FIGURE 3. Kerr Led a Review of Scotlands Health care. These are derived from the best available evi-
ServiceThe Resemblance Is Evident! dence, particularly NICEs own guidance.

Technology Appraisals
NICE recommendations review clinical and economic evi-
dence, balancing the clinical data in relation to how much it
costs the NHSdoes it represent value for money? This advice
ends the uncertainty and helps to standardize access to health
care across the country. This is reflected in the NHS Consti-
tution, which states that patients have the right to drugs and
treatments that have been recommended by NICE for use in
the NHS, if their doctor believes they are clinically appropriate.
Sir Andrew Dillon, Chief Executive of NICE, said:
also include procedures, devices, and diagnostic agents. We support the general principle that the NHS should pay a
This is to ensure that all NHS patients have equitable price which reflects the additional therapeutic benefit of new
drugs. We also share the Governments ambition to ensure
access to the most clinically effective and cost-effective
that the option exists for all new licensed drugs to be offered
treatments that are viable. to those patients who can benefit from them, provided the
Quality standards are concise sets of statements with
accompanying metrics designed to drive and measure
price is a fair reflection of their value. We are confident that
the Government will want to take advantage of NICEs
priority quality improvements within a particular area of expertise and experience as it develops value-based pricing.

FIGURE 4. Estimating Cost and Cost-effectiveness

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The dominant drivers of NICEs approach are incremental
cost-effectiveness and the QALY, which allows comparisons
of cost-effectiveness across all of medicine. How else would
we compare the relative benefits of cataract or hip surgery
with cancer therapy? The following hypothetical example
gives a clear idea of how the arithmetic is worked out.
As is described in Fig. 4, the model is dependent on inputs.
If drug A had an incremental QALY of only 0.2 with an in-
cremental cost of 6,500, then the incremental cost-
effectiveness would be 32,500 and possibly outside the
value range.
Operationalizing Strategies for Sustainable Cancer
Care: Affordable Drugs
Almost every time that NICE makes a negative pro-
nouncement on a new cancer drug, there is a volubly
negative press reaction, often driven, understandably, by
disease-oriented interest groups. The NICE leadership has
pushed back on this somewhat and has set a series of
challenges for the wider oncology community,7 namely: (1)
the industry must operate in a much more efficient manner,
(2) the costs of drug development should be slashed, and (3)
oncologists and patient advocacy groups must ask tough
questions of regulators and the pharmaceutical industry.
They also made suggestions for practical implementation
of effective solutions:
They suggest that clinical trial costs could be decreased
by 40%60% without detriment to their quality using
measures such as electronic data capture, reduction in
the length of case management forms, and modified
site management practices.
References
1. Sullivan R, Peppercorn J, Sikora K, et al. Delivering affordable cancer care
in high-income countries. Lancet Oncol. 2011;12:933-980.
2. Amalric F. Analyse e conomique des Couts de Cancer en France. Impact Sur
la Qualite de Vie, Prevention, Depistage, Soin, Recherche. Paris: Institut
National Du Cancer; 2007.
3. Porter ME. Defining and introducing value in health care. In Evidence-
based Medicine and the Changing Nature of Health Care: 2007 Institute
of Medicine (IOM) Annual Meeting Summary. Washington, DC: Institute
of Medicine; 2008.
STRATEGIES FOR SUSTAINABLE CANCER CARE
The use of information technology to seamlessly in-
tegrate clinical and translational research and patient
care.
Greater use of adaptive (Bayesian) design techniques in
the design and analysis of randomized controlled trials
could reduce trial duration and the number of patients
needed.
Oncologists and patient advocacy organizations should
challenge regulatory authority data requirements.
Rather than criticize organizations such as NICE for de-
clining reimbursement on grounds of cost-effectiveness,
clinicians and patient advocates should start challenging
pharmaceutical companies about the high prices they
seek for products with modest benefits.
Address the difficulties facing low- and middle-income
countries in accessing affordable cancer care, rather
than only focusing on problems facing high-income
countries.
CONCLUSION
Research and technologic innovation continue to produce
novel therapies, but these are often of marginal clinical
value, while managing to be very costly. Similarly, there is
increasing dependence on expensive new imaging modali-
ties to assess tumor burden throughout treatment, despite
the seeming paradox that patients in the United Kingdom, at
least, present with later-stage disease. There is no doubt
that a programmatic approach to budgeting the totality of
cancer care for a specific population will highlight areas that
represent low value and that, therefore, could be targets for
disinvestment to make way for more effective treatment.
4. Porter ME, Teisberg EO. Redefining Health Care. Creating value-based
competition on results. Boston, MA: Harvard Business School Press;
2006.
5. Porter ME. What is value in health care? N Engl J Med. 2010;363:
2477-2481.
6. Eddy DM. Clinical decision making: from theory to practice. Three battles
to watch in the 1990s. JAMA. 1993;270:520-526.
7. Rawlins MD, Chalkidou K. The opportunity cost of cancer care: a state-
ment from NICE. Lancet Oncol. 2011;12:931-932.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e15
ULKA VAISHAMPAYAN

The Role of Nephrectomy for Kidney Cancer in the Era of

Targeted and Immune Therapies
Ulka N. Vaishampayan, MD

Editors Note: The following article is based on the 2016 ASCO Annual Meeting Education Session Cytoreductive Nephrectomy in
Renal Cell Carcinoma: A Debate. The author reviews the pros and cons of cytoreductive nephrectomy and whether recent
advances in systemic therapy warrant physicians to proceed directly to systemic therapy as in other metastatic solid tumors,
without the integral step of cytoreductive nephrectomy.

OVERVIEW

Although two phase III trials support the recommendation of nephrectomy followed by interferon alpha in metastatic renal
cell carcinoma (RCC), this procedure cannot be applied to every patient with this condition. Systemic therapy has changed
from interferon alpha to antiangiogenic-targeted therapy, and the clinical impact of nephrectomy in the era of targeted
therapy has not been proven. The SEER database shows that only 35% of patients with advanced RCC undergo nephrectomy
as their initial treatment. Retrospective studies showed improved overall survival (OS) outcomes with nephrectomy and
interleukin-2 (IL-2) therapy; however, the inherent selection bias of younger and healthier patients receiving IL-2 likely
accounts for this finding. Neoadjuvant therapy has demonstrated only modest efficacy in unresectable disease, and if
remission is obtained with systemic therapy, it is unclear whether nephrectomy has any incremental benefit. In the absence
of proven benefit of nephrectomy in the setting of targeted therapy, it seems advisable for patients with RCC with severely
symptomatic disease, competing comorbidities, poor performance status, or unresectable disease to avoid nephrectomy
and proceed directly to systemic therapy. The clinical implications of deferred cytoreductive nephrectomy for patients with
metastatic RCC are poorly understood, and patient cohorts that do not undergo this procedure are likely to be comprised of
patients with unfavorable disease characteristics. Unfortunately, the completed trials of targeted therapy were 90%
comprised of patients with prior nephrectomy (the majority of trials incorporate prior nephrectomy as an eligibility re-
quirement) and hence may not reflect the outcomes of the majority of the patients with advanced RCC who have not
undergone nephrectomy. Newer therapies such as nivolumab and cabozantinib have also been evaluated for a population in
which 90% of the patients underwent nephrectomy. Future clinical trials and registry studies must focus on the therapeutic
treatment and overall outcome of patients without nephrectomy and treated with contemporary systemic therapy.

K idney cancer is one of the few malignancies in which

surgical resection of the primary disease, or cytore-
ductive nephrectomy, has held tremendous importance.
Historically, systemic therapy was underdeveloped and in-
effective, and surgical resection was considered the only
hope of remission. However, an analysis of the Surveillance,
Epidemiology, and End Results Program (SEER) database
revealed that only 539 of the 1,537 (35%) cases diagnosed
with advanced RCC between 2000 and 2013 had nephrec-
tomy as their initial therapy.1
The major advances in systemic therapy of RCC in recent
years beg the fundamental question whether a large enough
impact has been made to consider proceeding directly to
systemic therapy as in other metastatic solid tumors,
without the integral step of cytoreductive nephrectomy.
The pros and cons of this procedure are summarized in
Table 1.
NEPHRECTOMY IN THE CONTEXT OF IMMUNE
THERAPY
Renal cell carcinoma is unique in the fact that randomized
trials have actually been conducted to establish the role of
nephrectomy in metastatic disease.24 The results revealed
that patients subjected to nephrectomy followed by in-
terferon alpha in the presence of metastatic disease ex-
perienced OS benefit (Table 2). The reasons for this
benefit remain unclear. It does not appear that nephrectomy

From the Karmanos Cancer Institute, Wayne State University, Detroit, MI.

Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook.

Corresponding author: Ulka N. Vaishampayan, MD, Karmanos Cancer Institute 4100 John R St., 4233 HWRC, Detroit, MI 48201; email: vaishamu@karmanos.org.

2016 by American Society of Clinical Oncology.

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TABLE 1. Pros and Cons of Nephrectomy in Metastatic
Renal Cell Carcinoma
Pros of Nephrectomy in Cons of Nephrectomy in
Metastatic RCC Metastatic RCC
Control of symptoms from Complications of surgery
primary tumor
Phase III trials showing OS benefit No benefit proven with targeted
therapy
No change in response to systemic
therapy
Resection of resistant clones Delay of systemic therapy
Long-term remissions noted with Impaired creatinine clearance,
surgical resection of metastatic increased risk of hypertension
RCC
Nephrectomy patients comprise Unlikely to benefit patients with
90% of clinical trial patient comorbidities and impaired
population performance status
Abbreviations: RCC, renal cell carcinoma; OS, overall survival
boosted the response rates to interferon therapy, as the
response rate remained at a dismal 3.3% and 3.6% in the
cytoreductive nephrectomy and interferon-alone arms,
respectively, regardless of whether the patients were
randomly selected to undergo nephrectomy or not. Retro-
spective case series have been reported favoring cytore-
ductive nephrectomy prior to immune therapy, such as IL-2,
because of OS benefit.5 However, the inherent biases of a
retrospective study are prominently prevalent in the IL-2
population, as this is a stringently selected group of patients
with excellent cardiopulmonary status and no brain me-
tastases, which predicts a better OS regardless of choice or
sequence of therapy. In fact, even the patients with a
performance status of 1 within the IL-2treated patient co-
hort had a minimal benefit in OS favoring cytoreductive
KEY POINTS
Two phase III trials support the recommendation of
nephrectomy in metastatic renal cancer when
compared with interferon therapy alone; however, the
clinical applicability of this finding is not clear in the era
of targeted therapy.
A delay in systemic therapy (because of nephrectomy)
can have deleterious effects on the survival of patients
with metastatic renal cancer.
Patients with poor-risk disease or predicted survival less
than 12 months are unlikely to benefit from
nephrectomy. The clinical implications of deferred
nephrectomy for patients with metastatic renal cancer
are not well understood.
Surveillance, Epidemiology, and End Results Program
database analysis revealed that 65% of patients with
advanced renal cancer do not undergo nephrectomy as
their initial treatment. This patient population warrants
further study, especially as it is not included in current
clinical trials.
ROLE OF NEPHRECTOMY IN THE TARGETED THERAPY ERA
nephrectomy; median OS was 6.9 months in the cytore-
ductive nephrectomy arm and 4.8 months in the interferon-
alone arm.5
There are numerous reports indicating that cytoreductive
nephrectomy improves host immune reaction to the
metastases and is likely to decrease the levels of immu-
nosuppressive factors. It also normalized the nuclear factor-
kappa B and various other immune defects.6,7 Clinically
spontaneous regressions have been observed. A peri-
operative (neoadjuvant) checkpoint inhibitor trial has
been proposed based on the finding that peripheral
blood PD-1 expression is reduced significantly after cyto-
reductive nephrectomy.8 Expression of PD-1 in tumor-
infiltrating lymphocytes was associated with a more
aggressive phenotype of RCC (larger tumors, higher nu-
clear grade, and sarcomatoid differentiation) and increased
risk of cancer-specific death, as reported in a study led
by the Mayo Clinic (risk ratio of 2.24; p = .004).9 However,
a recent report evaluating tumor PD-L1 expression in
417 cases of clear cell RCC from The Cancer Genome
Atlas database reported a lack of association between
PD-L1 expression and unfavorable tumor characteristics
and an improved OS outcome (hazard ratio [HR] 0.59;
p = .006).10
Unfortunately, modern immunotherapy trials cannot in-
form the benefits of treatment for patients who have not
undergone nephrectomy. For immune checkpoint inhibitors,
the recently reported randomized trial of nivolumab versus
everolimus mainly included patients who had undergone
nephrectomy.11 Similarly for patients on antiangiogenic or
mTOR inhibitor therapies, approximately 90% of the patients
included had nephrectomy prior to study enrollment.1216
Studies are ongoing to evaluate the impact of PD-1 inhibition
on biomarkers of immune response pre- and post-nephrectomy.
Phase II trials such as ADAPTeR (NCT02446860) are assessing
the response and changes in immune-related markers after
the neoadjuvant administration of nivolumab for 8 weeks
followed by nephrectomy.
NEPHRECTOMY IN THE CONTEXT OF VEGF
INHIBITOR THERAPY
The clinical implications of deferred nephrectomy for pa-
tients with metastatic renal cancer are not well understood.
As in the case of immunotherapy trials, the percentage of
patients who had undergone nephrectomy in a majority of
clinical trials evaluating VEGF inhibitors is greater than 90%.
The report by Choueiri et al,17 which suggested that patients
treated with targeted therapy had a Karnofsky performance
status less than 80% or poor-risk disease as gauged by the
Memorial Sloan Kettering Cancer Center criteria, experi-
enced no benefit from cytoreductive nephrectomy (p = .08
and .06, respectively; Table 2). A separate report used data
from the International Metastatic Renal Cell Carcinoma
Database Consortium database, which included 982 patients
treated with nephrectomy and targeted therapy and 676
patients treated with targeted therapy alone.18 Although
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ULKA VAISHAMPAYAN
TABLE 2. Summary of Study Data on Nephrectomy and Systemic Therapy
First Author, Reference Type of Study
Flanigan and Yonover2 Phase III
Mickisch et al3 Phase III
4
Flanigan et al Meta-analysis
Pantuck et al5 Retrospective
Choueiri et al17 Retrospective
targeted-therapy era
Heng et al18 Retrospective
targeted-therapy era
Abbreviation: CN, cytoreductive nephrectomy; OS, overall survival; IFN, interferon; PFS, progression-free survival; N/A, not applicable.
patients treated with cytoreductive nephrectomy had sig-
nificantly better OS compared with those treated with
targeted agents (median OS, 20.6 vs. 9.5 months, re-
spectively; HR 0.60; 95% CI, 0.520.69), it is important to
recognize that selection bias is at play; patients with poor-
risk disease comprised only 28% of those treated with
cytoreductive nephrectomy versus 54% of the group who did
not undergo the procedure. In addition, only 1% of patients
who did not undergo cytoreductive nephrectomy had fa-
vorable risk characteristics.
Several trials are seeking to prospectively evaluate the role
of cytoreductive nephrectomy for patients being treated
with targeted therapy. The CARMENA trial studying ne-
phrectomy followed by sunitinib versus sunitinib alone
will likely shed light on the question of whether cyto-
reductive nephrectomy remains relevant in the context
of anti-VEGF therapy for metastatic renal cancer. The
primary endpoint is OS, and secondary endpoints are
progression-free survival and operative complication rates.
The study has completed accrual, and results are awai-
ted. The SURTIME study is randomly selecting patients
with metastatic RCC to receive sunitinib followed by
nephrectomy versus sunitinib alone. The study will ad-
dress whether patients with adequate response to sys-
temic therapy should receive surgical consolidation with
nephrectomy.
SYNERGY BETWEEN NEPHRECTOMY AND
SYSTEMIC THERAPY: REALITY OR PERCEPTION?
Despite a hypothesized synergy between systemic therapy
and nephrectomy, it has not been borne out in clinical
practice. For example, the randomized trials of nephrectomy
and interferon versus interferon alone reported identical
response rates of approximately 3% in both arms. An ad-
juvant trial of sunitnib versus sorafenib versus placebo
(ASSURE/ECOG 2805) reported lack of benefit for either of
the agents postnephrectomy.18 The only data that suggest
potential synergy come from retrospective trials of patients
treated with IL-2 showing an improved outcome achieved
for patients who underwent nephrectomy as compared with
e18 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
No. of Patients Results
241 Median OS: CN + IFN: 11.1 months; IFN: 8.1 months; PFS 0; p = .05;
Median OS: CN + IFN: 17.4 months; IFN: 11.7 months; PFS 1; p = .08;
Median OS: CN + IFN: 6.9 months; IFN: 4.8 months
84 Median OS: CN + IFN: 17 months; IFN: 7 months (HR 0.54; 95% CI, 0.310.94)
331 Median OS: CN + IFN: 13.6 months; IFN: 7.8 months (HR 0.69; p = .002)
89 CN + IL-2: median OS, 16.7 months; 5-year OS, 19.6%
314 (CN: 201; Median OS: 19.8 months (CN) vs. 9.4 months (no CN); HR 0.44; p , .01;
no CN: 113) multivariate analysis: no benefit; p = .08; poor risk: no benefit; p = .06
1,658 (CN: 982; Median OS: 20.6 months (CN) vs. 9.5 months (no CN); p , .0001
no CN: 676)
those without nephrectomy.5 Neoadjuvant therapy has also
shown only modest benefit in advanced RCC.19 In summary,
until the results of randomized trials are available, no
synergy has been proven to date between targeted
antiangiogenic therapy and cytoreductive nephrectomy
in RCC.
THE IMPORTANCE OF MULTIDISCIPLINARY
TEAM INPUT: COLLECTIVE WISDOM AND THE
FUTURE OF PATIENT-CENTERED CARE AND
RESEARCH
Typically, patients who are not offered cytoreductive ne-
phrectomy have poor performance status, major comor-
bidities, and limited access to care. Racial disparity in rates of
nephrectomy has also been shown to have an impact on
patient outcomes. In a SEER database analysis of advanced
RCC, patients of African-American origin were noted to
have a worse OS outcome as compared with white patients
with metastatic RCC, and an interaction effect was noted
with the disparity in rates of nephrectomy.20 However,
whether this finding reflects other inherent biases noted
above is unknown. This observation highlights the need for
data collection regarding the factors commonly considered
toward the decision-making process of nephrectomy.
In addition, cytoreductive nephrectomy carries a certain
risk that has to be factored into the decision. The major
complication rates of cytoreductive nephrectomy have been
reported to be about 5%, and 11% of the patients did not
start systemic therapy within 60 days after nephrectomy
because of surgical complications. Overall, 61% of patients
did not start systemic therapy in a timely fashion. The
presence of liver metastases, intraoperative transfusion, and
pathologic nodal involvement were noted to be predictors of
delay of systemic therapy more than 60 days after cytore-
ductive nephrectomy.21
It is not advisable to reflexively send the patient for ne-
phrectomy upon diagnosis of advanced kidney cancer.
Multidisciplinary evaluation to carefully weigh the risk and
benefit ratio factoring in whether the bulk of the patients
symptoms are related to the cancer or to other comorbidities

would be important. Renal cancer is a heterogeneous dis-
ease,22 and to date, the resection of resistant clones is still
considered an ideal way to manage the problem. Stage IV
disease within RCC spans a wide spectrum of outcomes, and
risk prognostication is critically important before nephrec-
tomy is considered.
The reported efficacy of targeted therapy for patients with
metastatic renal cancer is mainly known only in the setting of
cytoreductive nephrectomy. This means that current clinical
trialbased data regarding efficacy of systemic therapy in
RCC do not apply to a large magnitude of the patient
population treated. As systemic therapy options and effi-
cacies evolve, the role of nephrectomy requires re-evaluation.
It does not seem appropriate to subject every patient with
metastatic renal cancer to the morbidity, adverse events,
cost, and potential delay of systemic therapy that result
from the nephrectomy procedure. In addition, special
efforts must be made to collect information regarding the
efficacy of specific systemic therapies for the patients who
are not candidates for nephrectomy. It is likely that the
presence of nephrectomy is an objective measure that
reflects a subgroup within RCC that has a distinctly favorable
outcome.
FACTORS TO BE CONSIDERED PRIOR TO
CYTOREDUCTIVE NEPHRECTOMY
Histology (Clear Cell or Non-clear Cell)
Non-clear cell histology has suboptimal systemic therapy
options, and hence cytoreductive nephrectomy maybe a
more important component of the management. However,
poor prognostic characteristics such as liver metastases,
impaired performance status, and the unresectable nature
of the disease should be considered as relative contrain-
dications to cytoreductive nephrectomy.
Patient Performance Status
Retrospective studies show that patients with impaired
performance status failed to benefit from cytoreductive
nephrectomy.
Current/Impending Symptoms From Disease
Delay in systemic therapy because of cytoreductive ne-
phrectomy is a concern for symptomatic patients with RCC.
Burden of Metastatic Disease
Patients with liver metastases or nodal involvement were
likely to have a higher complication rate with cytoreductive
nephrectomy that resulted in more than a 60-day delay in
systemic therapy.
Memorial Sloan Kettering Cancer Center Risk Criteria
Multivariate analysis revealed no benefit from cytoreduc-
tive nephrectomy for patients with poor risk characteristics
per the Memorial Sloan Kettering Cancer Centers risk
classification.
ROLE OF NEPHRECTOMY IN THE TARGETED THERAPY ERA
Risk of Surgical Complications
Patients with impaired performance status and comorbid-
ities are likely to have a higher complication rate from
cytoreductive nephrectomy.
CASE ILLUSTRATIONS
Deferral of Nephrectomy as a Result of Disease
Symptoms and Burden
Case 1. A 68-year-old man presented with malena, anemia
(hemoglobin of 4.0 g/dL), and hip pain. Imaging revealed
a large renal mass, hip metastases, and lung metastases.
Colonoscopy showed large mucosal lesions, the biopsy of
which revealed clear cell RCC. This patient, given the life-
threatening nature of his metastatic disease, would not be a
candidate for nephrectomy. The patient was started on an
oral anti-VEGF tyrosine kinase inhibitor. His hemoglobin
improved within 2 weeks of starting therapy, and his lesions
were clinically responding. Clearly, this case needed to
proceed to systemic therapy rapidly, and attempting cyto-
reductive nephrectomy for this patient was likely to have
a deleterious effect. This case also raises the dilemma of
whether to consider a nephrectomy at a later date after initial
response to targeted therapy. There is no evidence to support
that cytoreductive nephrectomy would be beneficial at this
time in this case. The concerns comprise discontinuing VEGF
inhibitor therapy, the regrowth potential of his disease, and
patient safety during surgery. In a clinical trial of preoperative
sunitinib followed by cytoreductive nephrectomy, about 36%
(17 of 47) of patients had disease progression during the
break from systemic therapy, confirming the concerns re-
garding this approach.19 The patient continues to be treated
without nephrectomy and with systemic therapy alone.
Case 2. A 58-year-old man presented with severe dyspnea,
noted to be related to pleural effusion. A 6-cm left-sided
renal mass was noted. Thoracentesis was performed, and
lung and pleural metastases were noted. Cytology revealed
malignant cells, and biopsy of kidney revealed clear cell
cancer. The patient was treated with targeted therapy and
demonstrated a response with complete resolution of the
pleural effusion and stable renal mass. In this case, ne-
phrectomy was considered advisable to render the patient in
clinical complete remission. However, there were valid
concerns of holding systemic therapy and risking progres-
sion of disease during cytoreductive nephrectomy and the
healing period after the procedure.
Case 3. A 52-year-old man was hospitalized with hyper-
calcemia; his corrected calcium was 15 mg/dL, and workup
revealed a renal mass and bilateral lung and bone lesions,
including one in the sacrum. Biopsy of bone showed clear cell
cancer consistent with renal primary. This patient needs to
proceed directly to systemic therapy, as attempting a ne-
phrectomy in the presence of uncontrolled metastatic dis-
ease would result in worsening patient condition and
compromise survival outcome.
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ULKA VAISHAMPAYAN
Deferral of Nephrectomy as a Result of Comorbid
Conditions
Case. An 85-year-old woman with coronary artery dis-
ease and angioplasty with stent placement 4 months
ago presented with microscopic hematuria. Workup
revealed a 7-cm right renal mass and bilateral lung
masses. Biopsy of the lung lesion demonstrated clear
cell carcinoma consistent with renal primary. Cytore-
ductive nephrectomy was considered risky because of
the patients cardiac condition, and, hence, systemic
therapy was started with clinical response. Currently,
the patient remains free of progression for the last
10 months.
References
1. National Cancer Institute. SEER*Stat Databases: November 2014 Submission.
http://seer.cancer.gov/data/seerstat/nov2014/. Accessed March 21, 2016.
2. Flanigan RC, Yonover PM. The role of radical nephrectomy in metastatic
renal cell carcinoma. Semin Urol Oncol. 2001;19:98-102.
3. Mickisch GH, Garin A, van Poppel H, et al; European Organisation for
Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical
nephrectomy plus interferon-alfa-based immunotherapy compared with
interferon alfa alone in metastatic renal-cell carcinoma: a randomised
trial. Lancet. 2001;358:966-970.
4. Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy
in patients with metastatic renal cancer: a combined analysis. J Urol.
2004;171:1071-1076.
5. Pantuck AJ, Belldegrun AS, Figlin RA. Nephrectomy and interleukin-2 for
metastatic renal-cell carcinoma. N Engl J Med. 2001;345:1711-1712.
6. Dadian G, Riches PG, Henderson DC, et al. Immunological parameters in
peripheral blood of patients with renal cell carcinoma before and after
nephrectomy. Br J Urol. 1994;74:15-22.
7. Uzzo RG, Clark PE, Rayman P, et al. Alterations in NFkappaB activation in
T lymphocytes of patients with renal cell carcinoma. J Natl Cancer Inst.
1999;91:718-721.
8. MacFarlane AW IV, Jillab M, Plimack ER, et al. PD-1 expression on
peripheral blood cells increases with stage in renal cell carcinoma
patients and is rapidly reduced after surgical tumor resection. Cancer
Immunol Res. 2014;2:320-331.
9. Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-
infiltrating immune cells and is associated with poor outcome for
patients with renal cell carcinoma. Clin Cancer Res. 2007;13:1757-1761.
10. Peters I, Tezval H, Kramer MW, et al. Implications of TCGA network data
on 2nd generation immunotherapy concepts based on PD-L1 and PD-1
target structures. Aktuelle Urol. 2015;46:481-485.
11. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 In-
vestigators. Nivolumab versus everolimus in advanced renal-cell car-
cinoma. N Engl J Med. 2015;373:1803-1813.
12. Escudier B, Eisen T, Stadler WM, et al; TARGET Study Group. Sorafenib in
advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134.
e20 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
CONCLUSION
Absence of cytoreductive nephrectomy is a very common oc-
currence in advanced RCC (65% of cases) and warrants further
clinical and research investigation. The efficacy and toxicity
reports from clinical trials of targeted and immune therapy
predominantly represent the patient population that has had
cytoreductive nephrectomy and need to be interpreted and
applied in the appropriate context. The complication rates of
nephrectomy range from 7% to 21%19 and may have impli-
cations in the delay of or inability to administer systemic therapy.
Outcome-based research and interventional trials focusing on
the clinical treatment of patients with metastatic RCC not un-
dergoing nephrectomy represent a critical unmet need.
13. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon
alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:
115-124.
14. Hudes G, Carducci M, Tomczak P, et al; Global ARCC Trial. Temsirolimus,
interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med.
2007;356:2271-2281.
15. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or
metastatic renal cell carcinoma: results of a randomized phase III trial.
J Clin Oncol. 2010;28:1061-1068.
16. Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial of bevacizumab plus
interferon alfa versus interferon alfa monotherapy in patients with
metastatic renal cell carcinoma: final results of CALGB 90206. J Clin
Oncol. 2010;28:2137-2143.
17. Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytore-
ductive nephrectomy on survival of patients with metastatic renal cell
carcinoma receiving vascular endothelial growth factor targeted
therapy. J Urol. 2011;185:60-66.
18. Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients
with synchronous metastases from renal cell carcinoma: results from
the International Metastatic Renal Cell Carcinoma Database Consor-
tium. Eur Urol. 2014;66:704-710.
19. Haas NB, Manola J, Uzzo R, et al. Initial results from ASSURE (E2805):
adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an
ECOG-ACRIN-led, NCTN phase III trial. J Clin Oncol. 2015;33;(suppl; abstr
403).
20. Vaishampayan U, Vankayala H, Vigneau FD, et al. The effect of targeted
therapy on overall survival in advanced renal cancer: a study of the
national surveillance epidemiology and end results registry database.
Clin Genitourin Cancer. 2014;12:124-129.
21. Gershman B, Moreira DM, Boorjian SA, et al. Comprehensive charac-
terization of the perioperative morbidity of cytoreductive nephrec-
tomy. Eur Urol. 2016;69:84-91.
22. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and
branched evolution revealed by multiregion sequencing. N Engl J Med.
2012;366:883-892.
BREAST CANCER

Breast Cancer Survivorship:

Strategies for Optimal Care

CHAIR
Beverly Moy, MD, MPH
Massachusetts General Hospital Cancer Center
Boston, MA

SPEAKERS
Debra L. Barton, PhD, AOCN, RN
University of Michigan
Ann Arbor, MI

William J. Gradishar, MD
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chicago, IL

Michelle E. Melisko, MD
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, CA
MELISKO, GRADISHAR, AND MOY

Issues in Breast Cancer Survivorship: Optimal Care, Bone

Health, and Lifestyle Modifications
Michelle E. Melisko, MD, William J. Gradishar, MD, and Beverly Moy, MD, MPH

OVERVIEW

There are an estimated 3.1 million survivors of breast cancer in the United States. The predominant reasons for this
substantially large population are that breast cancer is the most common noncutaneous malignancy among women and that
5-year survival rates after breast cancer treatment are approximately 90%. These patients have many medical consid-
erations, including the need to monitor for disease recurrence and to manage complications of their previous cancer
treatments. Most patients remain at risk indefinitely for local and systemic recurrences of their breast cancers and have an
increased risk of developing contralateral new primary breast cancers. Therefore, optimizing care for this patient population
is critical to the overall health care landscape in the United States. Here, we summarize survivorship care delivery and its
challenges, the optimization of bone health in breast cancer survivors, and opportunities for risk reduction through lifestyle
modifications.

T here are an estimated 3.1 million survivors of breast

cancer in the United States.1 The predominant reasons
for this substantially large population are that breast cancer
is the most common noncutaneous malignancy among
women and that 5-year survival rates after breast cancer
treatment are approximately 90%.2 In recognition of the
importance of breast cancer survivorship care, multiple
medical organizations, including the Institute of Medicine,
American Society of Clinical Oncology (ASCO), American
Cancer Society, and the Commission on Cancer, have high-
lighted the importance of addressing the many issues and
concerns of breast cancer survivors following treatment. The
medical community recognizes the multiple challenges for
breast cancer survivors that follow-up care creates. In addi-
tion to the significant logistics required to care for a large
population of breast cancer survivors, reasons for these
challenges include the long course of disease, a relentless risk
of recurrence even 15 to 20 years after the original diagnosis,
the need for endocrine therapy for 5 to 10 years in most
patients, and the need to continue screening because of a 1%
risk per year of new contralateral primary breast cancers.
Clinicians must address the physical, emotional, social, and
long-term effects faced by many breast cancer survivors after
they complete active treatment. These long-term effects
include anxiety and depression, vasomotor symptoms, cog-
nitive dysfunction, fatigue, pain, sexual dysfunction, loss of
bone density, infertility, neuropathy, and cardiac toxicity.
From an economic perspective, breast cancer is the
costliest of all cancers, with an estimated $18.1 billion of
national expenditures in the United States in 2014. Almost
$8 billion of these expenditures are for the costs of survi-
vorship care.3 This proportional cost of breast cancer care
exceeds the annual expenditures for the entire treatment of
other types of cancer, such as leukemia and ovarian, brain,
head and neck, or pancreatic cancer.
Despite the calls for action from multiple prestigious
medical societies and the reality of the various medical and
economic challenges, to date, there is no universally agreed
upon standardized follow-up model for patients with early-
stage breast cancer who have completed active cancer therapy.
Barriers to survivorship care implementation are well docu-
mented and include challenges with staffing and resources.4,5
Many societies have recommended that every patient receive a
survivorship care plan that details follow-up care plans, a sur-
veillance plan, and general health recommendations.6 However,
survivorship care plan adoption in oncology clinics is highly
variable, and there is insufficient evidence that the plans
improve outcomes for patients.4,7
There are three models of comprehensive survivorship
care delivery found in academic medical centers.8 The first
model consists of consultative clinics that offer a one-time
survivorship visit for patients when active therapy is com-
plete. The second model consists of advanced care
practitionerled survivorship clinics, during which patients

From the UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Mas-
sachusetts General Hospital Cancer Center, Boston, MA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Beverly Moy, MD, Massachusetts General Hospital Cancer Center, 55 Fruit St., Boston, MA 02114; email: bmoy@partners.org.

2016 by American Society of Clinical Oncology.

e22 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


meet with nurse practitioners or physician assistants either
in a stand-alone clinic or embedded within the oncology
practice. The patient is then transitioned back to primary care
as appropriate. The third model is a multidisciplinary survivor
program that relies on collaboration between oncologists,
advanced care practitioners, social workers, and psychologists
to provide comprehensive care.
Some policymakers would argue that follow-up care of these
patients can be transitioned to primary care physicians on the
basis of randomized trial results that show equivalent out-
comes with follow-up by either the oncologist or primary care
physician.9-12 The most compelling data are from a study in
which 968 women with early-stage breast cancer were ran-
domly assigned to follow-up care with either a family physician
or an oncologist.9 Recurrence rates, mortality rates, and rates
of serious clinical events, such as spinal cord compression,
pathologic fractures, brachial plexopathy, or hypercalcemia,
were equivalent in both the family physician and the oncol-
ogist groups. Health-related quality of life was also similar in
both groups. Lending additional support to simplifying follow-
up for breast cancer survivors, a British study revealed that
twice as many patients preferred simpler, less frequent follow-
up by telephone.13 Finally, patients are less likely to demand
medically inappropriate testing, such as imaging or tumor
markers, if they are educated about the specificity, sensitivity,
and usefulness of the available tests.14
These studies beg the question: Are we providing exces-
sively redundant care to breast cancer survivors? In the current
health care climate with finite resources, are oncology pro-
viders obligated to be more discriminating about the
amount of care we provide?15,16 There are myriad reasons
why oncology providers are not prepared to relinquish the
care of breast cancer survivors. Providers and patients often
feel emotionally attached to each other. It is not uncommon
for patients to want to see their oncologists more often for
KEY POINTS
Care for the estimated 3.1 million survivors of breast
cancer is logistically and medically complex, given the
long course of disease, continued risk of recurrence, and
treatment-related side effects.
Additional research to provide evidence about the
optimal way to deliver survivorship care to this large and
growing population is needed.
To date, there is no uniform consensus about the role of
bone-modifying agents in the treatment of early-stage
breast cancer.
Data on breast cancer risk reduction are based on
multiple epidemiologic studies.
Independent of the potential for reducing risk of breast
cancer recurrence, strong evidence exists that lifestyle
factors, such as modification of diet, increasing physical
activity, weight management, and smoking cessation,
influence other medical comorbidities that ultimately
impact overall survival.
ISSUES IN BREAST CANCER SURVIVORSHIP
reassurance, and, oncologists, driven by a sense of duty to
their patients, may be unwilling to relinquish control of their
patients medical care after developing close relationships
during active cancer treatment. Furthermore, primary care
physicians may be uncomfortable taking the lead in caring for
these patients because they may feel ill-prepared to manage
the many issues faced by breast cancer survivors. Regarding
specific guidance for medical care, we lack evidence about
whether certain types of breast cancer, such as locally ad-
vanced or hormone receptornegative disease, would benefit
from more intensive follow-up and imaging. Finally, with the
lack of interinstitutional standards, providers may worry about
the risk of being sued if they decrease their follow-up visits or
imaging studies.
There have been multiple efforts to provide clinical
guidance on how best to care for breast cancer survivors.
The National Comprehensive Cancer Network (NCCN) issued
guidelines for the treatment of breast cancer, which in-
cluded information on recommended surveillance for cancer
recurrence or new cancers.17 Both ASCO and NCCN have
symptom-specific survivorship care guidelines to address
issues such as cardiac toxicity and neuropathy.18,19 Recently,
ASCO and the American Cancer Society jointly issued a
breast cancer survivorship care guideline to provide con-
crete recommendations to assist clinicians, both oncologists
and primary care physicians, in the care of these patients.20
Among the concrete recommendations, there is a recom-
mendation patients receive a history and physical every 3 to
6 months for the first 3 years after primary therapy, every 6
to 12 months for the next 2 years, and annually thereafter.
Supported by the recommendations made by the ASCO
Choosing Wisely campaign, clinicians should not offer rou-
tine laboratory tests or imaging, except mammography if
indicated, for the detection of disease recurrence in the
absence of symptoms.21 The guideline also recommends that
the cancer treatment team provides a treatment summary
and survivorship care plan to primary care clinicians.
These and other similar guidelines are helpful. However,
they still provide ambiguity about the ideal models for care
and the appropriate intervals between follow-up exami-
nations. A history and physical every 3 to 6 months amounts
to a difference of two to four clinician visits per year. Can
these visits be shared between primary care physicians,
medical oncologists, surgical oncologists, and radiation
oncologists? Would patients benefit more from increased
care coordination? From a purely economical point of view,
one could argue that biannual visits by any oncology pro-
vider or by a primary care physician in an otherwise healthy
asymptomatic patient would be supported by the evidence
and may provide the most value in terms of containing
medical costs. However, certain higher-risk patient pop-
ulations may benefit from more intensive follow-up care.
Unfortunately, we lack clear evidence to be able to identify
these patient subgroups. There is a pressing need for ad-
ditional research to provide evidence about the optimal way
to deliver care to a large and growing breast cancer survi-
vorship population.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e23
MELISKO, GRADISHAR, AND MOY
BONE HEALTH AGENTS IN BREAST CANCER
The role of bone agents in the treatment of patients with
early-stage breast cancer has fallen under two broad cate-
gories: the established role of preventing loss of bone density
and the more contentious role of reducing the risk of re-
currence of breast cancer.22-25 The two classes of bone agents
used are bisphosphonates, of which several agents currently
are in use, and RANK ligand inhibitors, of which there is one,
denosumab. Cancer treatmentinduced bone loss is an iat-
rogenic disease, a condition created by breast cancer treat-
ments. It is well known that various cancer therapies (e.g.,
aromatase inhibitors, chemotherapy, and surgery) decrease
bone mineral density and increase the risk of fracture.26
Treatment-related fractures lead to decreased quality of life
and shorter survival times, which translate into clinical, social,
and economic consequences.27,28
The ABCSG-12,26,29,30 Z-FAST,31,32 and ZO-FAST33,34 trials
have shown that bone-targeted agents can prevent cancer
treatmentinduced bone loss in early breast cancer. In the
ZO-FAST trial,29,33,34 up-front zoledronic acid increased bone
mineral density in both the lumbar spine and hip. Gnant
et al26,29,30 reported that the addition of zoledronic acid to
both tamoxifen and anastrozole yielded no treatment-
induced bone loss compared with treatment without the
bone-strengthening agent. Additionally, denosumab pro-
duced similar results, with increases in bone mineral density
seen over 24 months in trabecular and cortical bone in women
with nonmetastatic breast cancer and low bone mass who
were receiving adjuvant aromatase inhibitor therapy.35
The issue of adjuvant bisphosphonate therapy in breast
cancer has been an area controversy. The results from several
long-term, large clinical trials have added to the confusion.
Improvements in disease-free survival (DFS) were reported
in postmenopausal women who were treated with letrozole
and zoledronic acid compared with letrozole alone (ZO-
FAST).29,33,35 In contrast, the findings of the AZURE trial35 did
not support the routine use of zoledronic acid in the ad-
juvant management of breast cancer; no significant benefits
in DFS and overall survival (OS) were reported. In both the
ABCSG-1226,30 and AZURE35 trials, adjuvant bisphosphonates
offered an advantage to postmenopausal women, regardless of
whether their postmenopausal status occurred naturally or was
drug induced. In the results of the 9-year update of the ABCSG-
12 trial, there was a persistent benefit in DFS with zoledronic
acid in a low-estrogen environment (e.g., a postmenopausal
state). The meta-analysis of 36 trials by Coleman et al,36 which
evaluated nearly 23,000 women, focused on the use of
bisphosphonates in the adjuvant setting. Although no effects on
disease outcomes in premenopausal women were observed,
adjuvant bisphosphonates reduced bone metastases and im-
proved survival in women who had low levels of reproductive
hormones (which included women older than age 55 if men-
opausal status was unknown). There was a 34% reduction in the
risk of bone recurrence (p = .00001) and a 17% reduction in the
risk of breast cancer death (p = .004). No significant reduction
was reported in first distant tumor recurrence outside of bone.
e24 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
The phase III ABSCG-18 trial was presented by Gnant et al at
the 2015 San Antonio Breast Cancer Symposium, in which
postmenopausal women with nonmetastatic breast cancer
were randomly assigned to receive the RANK ligand inhibitor,
denosumab, or placebo in addition to aromatase inhibitor
therapy. 37 Previous results from the ABCSG-18 trial de-
monstrated a reduced fracture rate with adjuvant denosumab
compared with placebo in postmenopausal women with
hormone receptorpositive breast cancer who were treated
with aromatase inhibitors.16 In the most recent presentation,
the primary outcomes were related to bone health, and the
secondary outcomes included DFS. In an intention-to-treat
analysis, the impact of denosumab on DFS reached borderline
significance (hazard ratio [HR] 0.82; 95% CI, 0.661.00). The
benefit was approximately 1% after 3 years, 2% after 5 years,
and 3% after 7 years of follow-up. Exploratory subgroup an-
alyses suggested that the benefit increases when denosumab
is started early, along with aromatase inhibitor therapy, and
that the benefit is greater in patients who have larger tumors
and ductal histology. Overall, the DFS benefit seen with
denosumab was comparable to that reported in the meta-
analysis of bisphosphonates.16
The debate about these data largely revolves around how
to translate the apparent benefit into day-to-day manage-
ment decisions. Different bone agents were used in the
trials, the trial designs were meant to evaluate primarily
bone health endpoints with DFS as a secondary endpoint,
duration of therapy is an open question, and which post-
menopausal patients should be considered for this type of
adjuvant therapy remains unclear. To date, though the data
are compelling, the NCCN guideline panel could not reach
consensus for supporting these bone agents as a compo-
nent of adjuvant therapy of breast cancer. That said, indi-
vidual patients who have any issues with bone density or
increased risks of fracture may reap the benefits on bone
health as well as some additional reduction in the risk of
disease recurrence.
RISK REDUCTION THROUGH LIFESTYLE
MODIFICATIONS
After a breast cancer diagnosis, most patients have great
interest in adoption of lifestyle changes that might reduce
their risk of cancer recurrence. Despite significant advances
in breast cancer therapies that are supported by randomized
clinical trials demonstrating benefits in DFS and OS, the data
on risk reduction through lifestyle modifications are more
limited and are primarily based on epidemiologic studies.
Patients, the lay press, and physicians alike often confuse the
data about which lifestyle factors may impact risk of de-
veloping breast cancer compared with those factors that
have an influence on recurrence after diagnosis. Strong
evidence exists that, independent of the potential for re-
ducing risk of breast cancer recurrence, lifestyle factors that
include modification of diet, increasing physical activity,
weight management, and smoking cessation influence other
medical comorbidities that ultimately impact OS. Similarly,

lifestyle and treatment factors also contribute to an in-
creased risk of second primary malignancies seen among
breast survivors.38
Management of Comorbidities
Cancer survivors face many health challenges, including
morbidity from residual treatment toxicity and increased
mortality from cardiovascular and respiratory diseases. The
impact of comorbidities on survival after a diagnosis of
breast cancer cannot be underestimated. Among 63,566
women diagnosed with breast cancer who were older than
age 66 and identified through the Surveillance, Epidemiol-
ogy, and End Results database, age and comorbidities at the
time of diagnosis had the largest effects on mortality from
causes other than breast cancer.39 The presence of car-
diovascular disease, chronic obstructive pulmonary disease,
or diabetes increased breast cancerspecific mortality by
between 10% and 24%. Among this study population, car-
diovascular disease was the primary cause of death in 15.9%
of women, followed closely by breast cancer in 15.1%. Al-
though this study focused on an older population with breast
cancer, exposure to radiation, anthracyclines, and trastu-
zumab are all associated with a small risk of cardiac toxicity
that may subsequently result in excess morbidity and, in
some cases, mortality.39 In addition, the long-term impacts
of inducing premature menopause and of treatment with
an aromatase inhibitor on cardiovascular health in younger
breast cancer survivors are still unknown. Studies to in-
vestigate beta blockers, angiotensin-converting enzyme
inhibitors, and statins to reduce the risk of cardiac toxicity
during and after treatment with anthracyclines and tras-
tuzumab have shown some promise, but none of these
pharmacologic interventions have become standard of
care.40-42 Attention to reducing the risk of subsequent
cardiovascular disease should be a priority after the di-
agnosis and treatment of breast cancer.
Weight Gain
Weight gain is common during and after treatment of breast
cancer and may be even more pronounced in patients who
are overweight or obese prior to diagnosis.43 Factors con-
tributing to weight gain include use of corticosteroid pre-
medications with chemotherapy, decreased physical activity
during treatment, transition into menopause, and ongoing
hormonal therapy.44 Weight gain after diagnosis has been
associated with a higher rate of breast cancer recurrences
and with worse OS. In an analysis of a cohort of 3,993 women
identified through state registries who were diagnosed with
stage I to III breast cancer, each 5-kg gain was associated
with a 12% increase in all-cause mortality, a 13% increase in
breast cancerspecific mortality, and a 19% increase in
cardiovascular disease mortality.45 A systematic review and
meta-analysis that included a total of 12 cohort studies and
clinical trials with a total of 23,832 patients measured weight
change after breast cancer diagnosis and investigated breast
cancerspecific mortality, all-cause mortality, and recur-
rence outcomes.46 Weight gain ($ 5.0%) compared with
ISSUES IN BREAST CANCER SURVIVORSHIP
maintenance (# 5.0% weight change) was associated with
increased all-cause mortality (HR 1.12). In a secondary
analysis to evaluate effects of the amount of weight gain,
moderate-level weight gain (5%10% compared with main-
tenance of baseline weight) was not associated with a hazard
of overall mortality (HR 0.97; 95% CI, 0.861.11; p = .70), but
higher weight gain (. 10% from baseline compared with
maintenance) was associated with increased mortality (HR
1.23; 95% CI, 1.091.39; p , .001). Among studies for which
data were available, weight gain among patients who were
already overweight at baseline (body mass index [BMI] .
25.0 kg/m2) did not result in worse mortality. In terms of breast
cancer outcomes, moderate weight gain (5%10%) was not
associated with breast cancerspecific mortality, whereas
there was a suggestion that weight gain of greater than 10%
was associated with breast cancerspecific mortality (HR 1.17;
95% CI, 1.001.38; p = .05). Interestingly, in the studies within
this meta-analysis that included data, no amount of weight
gain was associated with an increase in breast cancer recur-
rences.47,48 The reason for this may be that a larger number of
patients would be required to demonstrate a relatively small
contribution of weight gain on breast cancer recurrences.
Alternatively, the negative impact of weight gain on mortality
and possibly breast cancerspecific mortality after diagnosis of
breast cancer may not be due to increased rate of recurrence
but, rather, to the overall health, comorbidities, treatment
patterns, and responses to treatment after recurrence among
patients with significant weight gain.
Weight Loss Interventions
No matter what the underlying cause, avoidance of signif-
icant weight gain after a diagnosis of breast cancer is a de-
sirable goal to improve OS. The challenge of avoiding weight
gain is substantial for breast cancer survivors, many of whom
enter menopause abruptly as a result of chemotherapy and
some of whom remain on hormonal therapy as long as 10
years. Additionally, many patients suffer ongoing toxicities
from their treatment, including fatigue, sleep disturbance,
neuropathy, and arthralgias, all which may interfere with the
ability to initiate and maintain an exercise program supportive
of weight control.
There have been numerous weight loss intervention
studies among breast cancer survivors. A recent systematic
review included 15 studies, among which were eight ran-
domized controlled trials, four single-cohort experimental
intervention studies, two randomized parallel-intervention
trials, one randomized crossover trial, and one controlled
nonrandomized trial.49 The primary objective of each of
these studies was weight loss intervention with a focus on
changing body weight (measured as change in weight, BMI,
percentage body fat, or percent overweight). Studies de-
signs included multicomponent interventions that in-
corporated diet, physical activity, and behavior modification,
whereas other studies combined personalized lifestyle
telephone counseling with face-to-face group-based edu-
cation. Several studies used a commercial weight loss
programs, such as Weight Watchers and/or Curves,50,51 and
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e25
MELISKO, GRADISHAR, AND MOY
one study incorporated group teleconferencing for breast
cancer survivors in rural locations.52
Of the 15 studies included in this systematic review, 14
resulted in significant weight loss; weight loss of 5% or greater
from baseline was reported in 10 of the studies (p , .001).
Unfortunately, weight regain was observed in some
studies that included longer follow-up. For example, in the
Exercise and Nutrition to Enhance Recovery and Good
Health for You (ENERGY) study, 692 overweight or obese
breast cancer survivors were randomly assigned to either a
group-based behavioral intervention, supplemented with
telephone counseling and tailored newsletters, or to a less-
intensive control intervention to encourage weight loss.
Greater weight loss was observed in the intervention than in
the control group at 12 months (6% vs. 1.5%) and was still
maintained but was less pronounced at 24 months (3.7% vs.
1.3%). Improvements in blood pressure control and physical
activity were also observed in the intervention arm.53
Dietary Interventions
The evidence to support specific dietary recommendations
after a diagnosis of breast cancer is surprisingly limited and is
backed by only a handful of randomized clinical trials, few of
which achieved the desired endpoints of either reduction in
breast cancer recurrences or improvement in DFS or OS.
The Womens Intervention Nutrition Study (WINS) was a
randomized prospective multicenter clinical trial that
included a total of 2,437 patients with early-stage breast
cancer to test the effect of a dietary intervention designed to
reduce fat intake.54 The goal of the dietary intervention was
to reduce percentage of calories from fat to 15%, such that
there would actually be a sustained reduction in fat intake to
approximately 20% of calories in the intervention arm. The
low-fat eating plan included self-monitoring (fat gram
counting and recording), goal setting, modeling, and relapse
support and involved multiple in-person counseling sessions
initially and then subsequent contact with a dietician every
3 months. The patients in the control group had a baseline
dietician visit and then visits every 3 months, during which
general dietary guidelines were reviewed. At a median
follow-up time of 60 months, an interim analysis demon-
strated that dietary fat intake was significantly lower in the
intervention than in the control group (p , .001), and the
effect was maintained out to 60 months. Additionally, there
was a 6-pound lower mean body weight in the intervention
group. The hazard of relapse events (local, regional, distant,
or ipsilateral breast cancer recurrence or new contralateral
breast cancer) in the intervention group compared with the
control group was 0.76 (95% CI, 0.600.98). Subgroup an-
alyses were conducted on the basis of BMI, hormone re-
ceptor status, and nodal status, and the dietary intervention
had a greater effect on relapse-free survival in women with
estrogen receptornegative cancer (HR 0.58; 95% CI,
0.370.91) than in women with estrogen receptorpositive
disease (HR 0.85; 95% CI, 0.631.14). In this analysis, with a
60-month median follow-up time, there was no difference in
OS between the dietary intervention and control groups.
e26 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
The Womens Healthy Eating and Living (WHEL) randomized
trial tested whether increasing vegetable, fruit, and fiber intake
and decreasing dietary fat intake could reduce the risk of re-
currence or new primary breast cancer and impact mortality in
patients with early-stage breast cancer.55 A total of 3,088
women were randomly assigned to an intervention arm to
receive telephone counseling, cooking classes, and newsletters
promoting high fruit and vegetable intake, increasing fiber, and
reducing energy intake from fat, or to a comparison group that
was provided only with print materials. Analysis validated by
plasma carotenoid concentrations indicated that the inter-
vention group maintained significant differences compared
with the control group for increased fruit, vegetable, and fiber
intake and reduction in fat through 4 years of follow-up. After a
mean follow-up time of 7.3 years, there were no differences
between the intervention and control groups for recurrence of
invasive or noninvasive breast cancer or death. Explanations of
this lack of treatment effect included the fact that many WHEL
participants had already changed their dietary patterns after
diagnosis of breast cancer, so 75% of patients were already
consuming at least five servings of vegetables and fruit a day at
baseline; results suggest that intake of fruits and vegetables
beyond that amount may not be beneficial. Multiple sub-
sequent endocrinologic and behavioral findings and subset
analyses have been reported from the data collected from this
very well-conducted trial, which demonstrates the importance
of this study despite its negative results.
Exercise
Physical activity has been shown to improve quality of life
after a breast cancer diagnosis.56 Multiple cohort studies
have investigated the impact of physical activity after di-
agnosis on breast cancerspecific and overall mortalities.
Most of these studies describe exercise frequency and in-
tensity in metabolic equivalent (MET) hours, for which 3 MET
hours is equivalent to walking at average pace of 2 to 2.9 mph
for 1 hour. Among 2,987 patients with early-stage breast cancer
in the Nurses Health Study, the relative risk of death from
breast cancer, compared with women who engaged in fewer
than 3 MET hours per week of physical activity, for patients with
9 to 14.9 MET hours per week of exercise was 0.50 (95% CI,
0.310.82); for patients with 15 to 23.9 MET hours per week
was 0.56 (95% CI, 0.380.84); and for patients with 24 or more
MET hours per week was 0.60 (95% CI, 0.400.89). Absolute
mortality risk was also reduced by 6% at 10 years for women
who engaged in 9 or more MET hours per week.57
In the Collaborative Womens Longevity Study (CWLS),
4,482 women completed questionnaires on postdiagnosis
physical activity and other lifestyle factors. Compared
with women engaging in fewer than 2.8 MET hours per
week of physical activity, women who engaged in greater
levels of activity ($ 21 MET hours per week) had a sig-
nificantly lower risk of dying as a result of breast cancer
(HR 0.51; 95% CI, 0.290.89; p = .05) and had improved OS
(HR 0.44; 95% CI, 0.320.60; p , .001). These results were
consistent independent of age, stage of disease, and
BMI.58

In two smaller-sized cohorts (1,970 women in The Life After
Cancer Epidemiology [LACE] study and 933 women in the
Health, Eating, Activity and Lifestyle [HEAL] study), greater
physical activity after diagnosis was associated with a de-
crease in overall mortality but not in breast cancerspecific
mortality.59,60
A longitudinal study of 4,643 women diagnosed with in-
vasive breast cancer after entry into the Womens Health
Initiative study evaluated the association between change in
physical activity from before diagnosis to after diagnosis with
all-cause and breast cancerspecific mortalities. Physical ac-
tivity was reported at baseline (before breast cancer diagnosis)
and after diagnosis (3 or 6 years after baseline visit). Women
who engaged in moderate levels of physical activity (fast walking
for 3 hours/week) before diagnosis had lower all-cause mortality
(HR 0.61; 95% CI, 0.440.87; p = .01) than inactive women.
Women engaging in similar moderate physical activity levels
after diagnosis had both lower breast cancer mortality (HR 0.61;
95% CI, 0.350.99; p = .049) and lower all-cause mortality (HR
0.54; 95% CI, 0.380.79; p , .01). Women who increased or
maintained physical activity of 9 or more MET hours per week
after diagnosis had lower all-cause mortality (HR 0.67; 95% CI,
0.460.96) even if they were inactive before diagnosis.59
With the abundance of epidemiologic data demonstrating
the benefit of exercise after diagnosis of breast cancer, nu-
merous randomized prospective trials are ongoing to better
understand which interventions are most effective to increase
physical activity, what levels and types of physical activity are
optimal, and if associated lifestyle factors have an interaction
with the benefit of exercise.
Alcohol Consumption
There is reasonably strong evidence that moderate alcohol
consumption increases the risk of developing breast cancer,
but the effect of ongoing alcohol intake after diagnosis is
less clear. In the LACE cohort consisting of 1,897 patients
with early-stage breast cancer who enrolled on average 2
years after diagnosis, self-reported drinking of 6 g/day or
more of alcohol (approximately 2.5 ounces of wine, 6
ounces of beer, or 1.5 ounces of hard liquor) compared
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28. Gnant M, Eidtmann H. The anti-tumor effect of bisphosphonates ABCSG-
12, ZO-FAST and more. Crit Rev Oncol Hematol. 2010;74:S2-S6 (suppl 1).
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Cancer Study Group, Vienna, Austria. Adjuvant endocrine therapy plus
zoledronic acid in premenopausal women with early-stage breast
cancer: 62-month follow-up from the ABCSG-12 randomised trial.
Lancet Oncol. 2011;12:631-641.
30. Brufsky AM, Bosserman LD, Caradonna RR, et al. Zoledronic acid ef-
fectively prevents aromatase inhibitor-associated bone loss in post-
menopausal women with early breast cancer receiving adjuvant
letrozole: Z-FAST study 36-month follow-up results. Clin Breast Cancer.
2009;9:77-85.
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31. Brufsky AM, Harker WG, Beck JT, et al. Final 5-year results of Z-FAST trial:
adjuvant zoledronic acid maintains bone mass in postmenopausal
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1192-1201.
32. Coleman R, de Boer R, Eidtmann H, et al. Zoledronic acid (zoledronate)
for postmenopausal women with early breast cancer receiving adjuvant
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398-405.
33. Eidtmann H, de Boer R, Bundred N, et al. Efficacy of zoledronic acid in
postmenopausal women with early breast cancer receiving adjuvant
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2188-2194.
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35. Coleman R, Cameron D, Dodwell D, et al; AZURE investigators. Adjuvant
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37. Gnant M, Pfeiler G, Dubsky PC, et al; Austrian Breast and Colorectal
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41. Seicean S, Seicean A, Plana JC, et al. Effect of statin therapy on the risk
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42. Pituskin E, Mackey JR, Koshman S, et al. Prophylactic beta blockade
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43. Chlebowski RT, Aiello E, McTiernan A. Weight loss in breast cancer
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44. Goodwin PJ, Ennis M, Pritchard KI, et al. Adjuvant treatment and onset
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45. Nichols HB, Trentham-Dietz A, Egan KM, et al. Body mass index before
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markers Prev. 2009;18:1403-1409.
46. Playdon MC, Bracken MB, Sanft TB, et al. Weight gain after breast
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48. Jeon YW, Lim ST, Choi HJ, et al. Weight change and its impact on prognosis
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tervention among rural breast cancer survivors. Breast Cancer Res
Treat. 2012;132:631-639.
53. Rock CL, Flatt SW, Byers TE, et al. Results of the Exercise and Nutrition to
Enhance Recovery and Good Health for You (ENERGY) trial: a behavioral
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J Clin Oncol. 2015;33:3169-3176.
54. Chlebowski RT, Blackburn GL, Thomson CA, et al. Dietary fat reduction
and breast cancer outcome: interim efficacy results from the Womens
Intervention Nutrition Study. J Natl Cancer Inst. 2006;98:1767-1776.
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55. Pierce JP, Natarajan L, Caan BJ, et al. Influence of a diet very high in
vegetables, fruit, and fiber and low in fat on prognosis following
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(WHEL) randomized trial. JAMA. 2007;298:289-298.
56. Daley AJ, Crank H, Saxton JM, et al. Randomized trial of exercise therapy
in women treated for breast cancer. J Clin Oncol. 2007;25:1713-1721.
57. Holmes MD, Chen WY, Feskanich D, et al. Physical activity and survival
after breast cancer diagnosis. JAMA. 2005;293:2479-2486.
58. Holick CN, Newcomb PA, Trentham-Dietz A, et al. Physical activity and
survival after diagnosis of invasive breast cancer. Cancer Epidemiol
Biomarkers Prev. 2008;17:379-386.
59. Irwin ML, McTiernan A, Manson JE, et al. Physical activity and survival in
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60. Sternfeld B, Weltzien E, Quesenberry CP Jr, et al. Physical activity and
risk of recurrence and mortality in breast cancer survivors: findings from
the LACE study. Cancer Epidemiol Biomarkers Prev. 2009;18:87-95.
61. Kwan ML, Chen WY, Flatt SW, et al. Postdiagnosis alcohol consumption
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Cancer Epidemiol Biomarkers Prev. 2013;22:32-41.
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Epidemiol Biomarkers Prev. 2010;19:681-688.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e29
BREAST CANCER

Less Is More: A Multidisciplinary

Conversation on Treatment
Options

CHAIR
Fatima Cardoso, MD
Champalimaud Cancer Centre
Lisbon, Portugal

SPEAKERS
Eun-Sil Shelley Hwang, MD, MPH
Duke University
Durham, NC

Laura Esserman, MD, MBA

University of California, San Francisco
San Francisco, CA
 TAILORING CHEMOTHERAPY IN EARLY-STAGE BREAST CANCER

Tailoring Chemotherapy in Early-Stage Breast Cancer: Based

on Tumor Biology or Tumor Burden?
Domen Ribnikar, MD, and Fatima Cardoso, MD

OVERVIEW

The question of whether to offer adjuvant chemotherapy to patients with early-stage breast cancer has always been
challenging to answer. It is well known that a substantial proportion of patients with early-stage breast cancer are over
treated, especially when staging and hormonal and HER2 receptors are solely taken into consideration. The advances in our
knowledge of breast cancer biology and its clinical implications were the basis for the discovery of additional reliable
prognostic markers to aid decision making for adjuvant treatment. Gene expression profiling is a molecular tool that more
precisely defines the intrinsic characteristics of each individual tumor. The application of this technology has led to the
development of gene signatures/profiles with relevant prognosticand some predictivevalue that have become im-
portant tools in defining which patients with early-stage breast cancer can be safely spared from chemotherapy. However,
the exact clinical utility of these tools will only be determined after the results of two large prospective randomized trials,
MINDACT and TailorX, evaluating their role become available. Notwithstanding the existence of these genomic tools, tumor
burden (defined as tumor size and nodal status) still has independent prognostic value and must be incorporated in decision
making. In addition, these gene signatures have limited predictive value, and new biomarkers and new targets are needed.
Therefore close collaboration between clinicians and scientists is crucial. Lastly, issues of cost-effectiveness, reimbursement,
and availability are crucial and widely variable around the globe.

H istorically, breast cancer was viewed as one disease with

different histopathological characteristics and responses
to systemic treatment. The choice of treatment was solely
based on clinicopathologic parameters that are prognostic,
such as tumor size, nodal status, and histologic grade, and the
three predictive markers of response to either endocrine
therapy and/or trastuzumab therapy (estrogen and pro-
gesterone receptor expression for endocrine therapy and
HER2 for trastuzumab). These factors are combined with
different algorithms for treatment decision making, such as
those used by Adjuvant! Online1 and the Nottingham
Prognostic Index, and represent the basis of international
treatment guidelines, including those from the National
Comprehensive Cancer Network,2 National Cancer Institute,
and European Society for Medical Oncology 3 as well as
St. Gallens consensus statements.4 The major disadvantage of
this approach is that nearly 60% of all patients with early-stage
breast cancer receive adjuvant chemotherapy, but only 2% to
15% of these patients derive an important benefit and others
only experience its toxic effects.5
Fortunately, breast cancer was one of the first cancers with
advances in molecular profiling technologies, leading to a
deeper understanding of its biology and molecular subtypes.
The advent of genomic signatures allowed us to better
understand the heterogeneity of breast cancer and led to
more individualized systemic treatment approaches. In this
article, we describe traditional clinicopathologic factors and
new molecular tools that may be used to more accurately
tailor adjuvant treatment decisions for patients with early-
stage breast cancer. Additionally, we discuss some studies
showing that response to a specific type of treatment is
mainly determined by the intrinsic molecular characteristics
of each individual tumor rather than by anatomic prognostic
parameters. However, these anatomic parameters have
important risk implications and effects on the relative
magnitude of benefit of treatment.
TRADITIONAL FACTORS FOR ADJUVANT
CHEMOTHERAPY DECISION MAKING
The Early Breast Cancer Trialists Collaborative Group (EBCTCG)
meta-analyses (also called Oxford Overview) have demon-
strated substantial evidence of the efficacy of adjuvant
chemotherapy in early-stage breast cancer.6,7 The last pub-
lished results in 2005 report on data from 60 randomized
trials initiated before 1995 comparing polychemotherapy to
no chemotherapy (29,000 patients of whom 10,000 died).7

From the Department of Medical Oncology, Institute of Oncology, Ljubljana, Slovenia; Breast Unit, Champalimaud Cancer Center, Champalimaud Foundation, Lisbon, Portugal.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Fatima Cardoso, MD, Champalimaud Cancer Center, Av. De Brasilia, Doca De Pedroucos, 1400-048, Lisbon, Portugal; email: fatimacardoso@fundacaochampalimaud.pt.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e31

RIBNIKAR AND CARDOSO
At 15-year follow-up, there was a substantial reduction in
the absolute risk of recurrence and death from breast cancer
for polychemotherapy compared with no chemotherapy.
Among women younger than age 50, polychemotherapy
reduced the annual risk of relapse and death by 37% and
30%, respectively, and the absolute gain in survival was twice
as great at 15 years as it was at 5 years (10% vs. 4.7%). Among
older women (age 5069), at 15-year follow-up, the annual
risk of relapse and breast cancer mortality were reduced by
19% and 12%, respectively, and translated into an absolute
gain of 4.1% and 3%, respectively.7,8 The proportional re-
ductions in both recurrence and breast cancer mortality
were similar in node-negative and node-positive patients,
although the absolute benefit was greater in those with
node-positive disease. Furthermore, it was demonstrated
that the greatest effect of adjuvant chemotherapy occurs in
the initial few years after therapy.
Additional subgroup analyses showed that adjuvant che-
motherapy was effective in both estrogen receptornegative
and estrogen receptorpositive disease, albeit the magnitude
of the absolute benefit was larger in estrogen receptor
negative disease. Data from multiple Cancer and Leukemia
Group B (CALGB) trials among women with node-positive
breast cancer reveal greater chemotherapy benefit in es-
trogen receptornegative disease compared with estrogen
receptorpositive disease.7,9 Substantial reductions were
observed in the absolute risk of recurrence and cancer-
specific mortality of 12.3% and 9.2% for patients younger
than age 50 and 8.6% and 6.1% for patients age 5069,
respectively.
KEY POINTS
In the past, breast cancer was perceived to be one
disease with different anatomical extents and different
expressions of estrogen and progesterone receptors and
HER2.
Gene expression analysis has revealed distinct intrinsic
subtypes of breast cancer with different natural
behaviors and responses to treatment.
First-generation gene signatures have the common
ability to further subdivide estrogen receptorpositive
HER2-negative breast cancers into subgroups that differ
in regards to their expression of proliferation-related
genes. Additional biomarkers, particularly those with
predictive value, are urgently needed.
Classic clinicopathologic tools and new molecular
tools should be integrated in and complementary to
adjuvant treatment decision making for individual
patients with breast cancer, in particular for cases where
the benefit of chemotherapy is uncertain.
Treatment of patients with low-risk tumor biology
and high tumor burden is challenging since, despite
being at considerable high risk for distant relapse, the
expected benefit of chemotherapy might not be enough
in terms of the low proliferative biology.
e32 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Generally, decisions regarding adjuvant chemotherapy are
based on prognosis, that is, risk of disease recurrence, and on
the likelihood of benefit from the treatment. The threshold
of 10% risk for distant relapse is often used to make rec-
ommendation for adjuvant chemotherapy.10
Clinicopathological prognostic factors for survival of early-
stage breast cancer include tumor size, nodal status, his-
tologic grade, and estrogen receptor, progesterone re-
ceptor, and HER2 expression as well as the presence of
lymphovascular invasion. Several consensus and evidence-
based guidelines3,4,11,12 provide recommendations on the
use of adjuvant chemotherapy in early-stage breast cancer.
The St. Gallen guidelines,4 for instance, suggest that patients
with early-stage breast cancer at low enough risk to avoid
adjuvant chemotherapy are characterized by node-negative
disease with all of the following features: pathologic tumor
size of 2 cm or smaller, grade 1, estrogen receptor and pro-
gesterone receptor positive, HER2 negative, age older than
35, and no vascular invasion. All other patients who do not
meet these criteria are considered to derive sufficient benefit
from adjuvant chemotherapy because their risk of distant
relapse is considered higher than 10%.
Adjuvant! Online is an independently validated, widely
used web-based tool for assessment of the risk of recurrence
and mortality. It combines multiple clinical and pathologic
factors and produces estimates for recurrence and death
from early-stage breast cancer. It incorporates the effect of
comorbidities in the determination of prognosis and benefit
from different therapeutic strategies.13 However, there are
data suggesting that it generally overestimates prognosis
and it lacks some crucial elements such as HER2 status.
The guidelines described above and Adjuvant! Online can-
not reveal the substantial heterogeneity that exists between
patients with similar stages and grades of disease. Several
independent groups have conducted comprehensive gene
expression profiling studies using microarray technology to
develop new tools that are more effective at an individual
level and that can assess risk of relapse to improve decision
making for adjuvant treatment.
INTRINSIC MOLECULAR SUBTYPING
Over 10 years ago, Perou et al14 and Sorlie et al15 dem-
onstrated that estrogen receptorpositive and estrogen
receptornegative breast cancers are completely distinct
diseases on a molecular level. In addition, hierarchical
cluster analyses of genes that vary more between tumors
than between repeated samples of the same tumor, the so-
called intrinsic genes, revealed at least four molecular
subtypes of breast cancer, namely, luminal, HER2-enriched,
basal-like, and normal breastlike.14 Multiple independent
datasets have shown the prognostic effect of intrinsic sub-
typing of breast cancer with luminal A cases (high expression of
estrogen receptor and estrogen receptorregulated genes) to
be at low risk of early recurrence. Apart from its prognostic
implication, the intrinsic molecular subclassification seems to
predict responsiveness to chemotherapy.16 Studies evaluating

the association between molecular subtype and path-
ologic complete response (pCR) rate to preoperative
(neoadjuvant) chemotherapy have reported the highest
rate of pCR in basal-like (30%45%) and HER2-enriched
(33%55%) subtypes, while pCR rates for luminal B
(1%15%) and luminal A disease (0%7%) were substantially
lower.
It is important to highlight that molecular classifica-
tion is not without its inherent limitations because up
to 30% of breast cancers do not fit into any of the four
molecular categories. 17 The exact number of true mo-
lecular subclasses of breast cancer is currently unknown,
and it is expected that the molecular classification will
further evolve with new technological platforms and
improved understanding of tumor biology. In particular,
the immunohistochemistry-defined triple-negative sub-
type is currently being subdivided into several molecularly
distinct subtypes with potential future clinical and thera-
peutic implications.18
PROGNOSTIC GENE EXPRESSION SIGNATURES
Concomitant to the discovery of heterogeneity of breast
cancers, microarray-based gene expression profiling was
used to predict the outcomes of individual patients with
breast cancer and aimed to identify those patients who
could be safely omitted from adjuvant chemotherapy.19 First
attempts were empirical, whereby tumors from patients
with good and poor outcomes were profiled, and collections
of candidate genes that could discriminate between patients
with disease of good and poor prognosis were identified.19,20
Later, studies in which a multigene predictor was generated
on the basis of a hypothesis derived from in vivo or in vitro
experiments and then applied to breast cancer samples were
conducted.21
There are many gene-expression prognostic signatures
that were used during the past decade.22 The so-called first-
generation signatures have several common features. De-
spite the different gene sets that compose each of the
signatures, they characterize a unique population with a high
expression of proliferation-related genes associated with
poor prognosis.23 Because the levels of expression of
proliferation-related genes are usually high in estrogen
receptornegative disease, these signatures almost always
classify estrogen receptornegative cancers as being a poor
prognosis disease. In estrogen receptorpositive breast can-
cer, the strongest prognostic factor is the degree of ex-
pression of proliferation-related genes. Based on these
features, it seems that most of these signatures generally
correlate with response to conventional chemotherapy
regimens,24 that is, high proliferative tumors respond better
to chemotherapy; however, they are not predictive of one
type of chemotherapy agent over another and cannot be
used to define the best chemotherapy agent/regimen for
each individual patient.
In the early years of their development, some defended
that these signatures would be a more objective replacement
TAILORING CHEMOTHERAPY IN EARLY-STAGE BREAST CANCER
of common clinicopathologic features traditionally used
for determining prognosis of early-stage breast cancer;
important meta-analyses have shown that they com-
plement but do not replace traditional factors since both
tumor size and nodal status provide independent prog-
nostic information in multivariate analyses.25 In addition,
the accuracy of the outcome prediction of all first-
generation prognostic signatures is time-dependent,
with more accurate prediction during the first 5 years
after diagnosis and less accurate predictions for late
relapses.26 Finally, there is some evidence that the
prognostic information provided by first-generation
signatures may be comparable with that offered by
semiquantitative and centralized (high-quality) assess-
ment of estrogen and progesterone receptors, HER2, and
Ki-67.27
70-Gene Profile
The 70-gene profile, also known as MammaPrint, was the
first microarray-based prognostic signature to be approved
by the U.S. Food and Drug Administration. The 70-gene
profile may be used for determining the prognosis of pa-
tients with stage I and/or II, node-negative, invasive breast
cancer28 as well as for nodes 1 to 3 positive disease.29 This
gene profile was first established using RNA from fresh,
frozen tumor tissues; however, from 2012 onward, it is also
evaluable in formalin-fixed, paraffin-embedded tumor
tissue.28 The assay was based on an empirical microarray
analysis of 78 patients who did not receive adjuvant systemic
therapy for their breast cancer. They were younger than age
55, had tumors up to 5 cm, and were node-negative. If these
patients developed distant metastases within the first 5
years after primary diagnosis, they were classified as poor
prognosis or good prognosis in the event there were no
distant metastases during this timeframe. A list of 70 genes
that could accurately predict poor versus good prognosis for
these patients was identified by a supervised analysis of
25,000 genes included in the microarrays. Subsequent studies
in breast cancer cohorts that were retrospectively accrued
demonstrated the potential of the MammaPrint assay to
determine prognosis of both node-negative and node-
positive disease29 and also for patients with HER2-positive
disease.30 The prognostic subgroups, which were identified
by the MammaPrint assay, correlate sensitivity to che-
motherapy in general: patients with high-risk signatures
derive the greatest absolute benefit from adjuvant chemo-
therapy.31 However, it has no ability to differentiate sensi-
tivity to different types of chemotherapy regimens. One of
main disadvantages of the MammaPrint assay is its small
discriminatory power for patients with estrogen receptor
negative disease (only up to 5% of patients with estrogen
receptornegative disease are classified as having good
prognosis disease).32 The true clinical utility of MammaPrint is
being tested in a randomized prospective phase III trial EORTC
10041/BIG 3-04 MINDACT,33 the results of which will be
presented in April 2016.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e33
RIBNIKAR AND CARDOSO
Recurrence Score or Oncotype DX
In parallel with the development of microarray-based prog-
nostic signatures, Paik and et al34 developed Oncotype DX, a
quantitative reverse transcription polymerase chain reaction
based signature that measures the expression of 21 genes
(16 cancer-related genes and five reference genes). It can
be performed with RNA extracted from formalin-fixed,
paraffin-embedded tissue samples. Oncotype DX calcu-
lates the recurrence score (RS) to predict the risk of distant
relapse within 10 years for patients with estrogen receptor
positive, lymph nodenegative breast cancers. It was de-
veloped on the basis of analysis of clinical samples from the
National Surgical Adjuvant Breast and Bowel Project (NSABP)
B-20 clinical trial. Later, it was validated with material from
the B-14 trial. The RS is a continuous variable, ranging
from 0 to 100, and is an independent prognostic factor for
patients with estrogen receptorpositive, node-negative
breast cancer treated with adjuvant tamoxifen. Patients
are classified into three categories, including low risk
(RS , 18), intermediate risk (RS 18-31), and high risk (RS . 31),
which correlate with 10-year relapse rates of 7%, 14%,
and 30%, respectively. The optimal management of the
intermediate-risk group is uncertain and is being studied
in the TailorX trial, in which patients with estrogen
receptorpositive, node-negative breast cancer were assessed
for risk of distant relapse after surgery and assigned
to low-risk (RS , 11), intermediate-risk (RS 11-25), and
high-risk groups (RS . 25). Patients with intermediate-risk
disease were randomly assigned to either endocrine
therapy alone or in combination with chemotherapy. In
2015, the results of the low-risk patients (RS , 11) were
presented and demonstrated excellent outcome at
5 years with endocrine therapy alone, irrespective of age,
tumor size, and grade. The authors concluded that these
patients can be safely treated without chemotherapy.35
The main results of the intermediate-risk score group are
eagerly awaited.
Further analyses also demonstrated that RS generally
correlates with benefit from chemotherapy in estrogen
receptorpositive disease.36 However, it does not provide
predictive value to differentiate between different che-
motherapy agents/regimens. It is also not useful to dis-
criminate between subgroups of HER2-positive breast
cancer because HER2 is one of the 21 genes that constitute
the test.
During the last few years, the Oncotype DX assay was
validated among patients who had up to three positive
lymph nodes37 and for those who are supposed to be treated
with an aromatase inhibitors.38
Although the prognostic effect of the Oncotype DX assay
has been extensively validated, there is some evidence
that RS correlates with some clinicopathologic parame-
ters, and, some of them, such as tumor size, nodal status,
and even histologic grade, remain independent of RS.39,40
Hence, a model that combines RS with traditional ana-
tomic pathologic factors may be more prognostic than
RS alone.41
e34 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
76-Gene Signature
The 76-gene signature, also known as the Veridex signature,
was developed on the basis of a supervised analysis of
microarray data in a set of 115 breast cancers, of which 80%
were estrogen receptorpositive. Contrary to MammaPrint,
estrogen receptorpositive and estrogen receptornegative
cancers were analyzed separately, and this enabled the
identification of 60 genes that could predict the develop-
ment of distant metastases within 5 years among patients
with estrogen receptorpositive disease and 16 genes that
could predict distant dissemination in estrogen receptor
negative disease.42 All 76 genes together were applied to an
independent test set of 171 patients with node-negative
disease only. The 76-gene predictor was a strong prognostic
factor for development of metastases within the first 5 years
after diagnosis. The main disadvantages of this signature are
time dependency, requirement of fresh or frozen samples,
prognostic power supported by level III evidence only, and,
last but not the least, that the 16-gene signature developed
for estrogen receptornegative disease might not predict
the outcome of patients with triple-negative breast
cancer.23
Genomic Grade Index
In 2006, Sotiriou et al developed the Genomic Grade Index
(GGI). It was based on the expression of 97 genes that were
selected by comparing the gene expression of histologic
grade 2 tumors with that of grade 1 tumors by means of a
DNA microarray.43 Importantly, this signature was able to
divide estrogen receptorpositive grade 2 cancers into grade
1-like with a low frequency of distant relapse and grade
3-like with an aggressive clinical behavior that is similar to
that of histologic grade 3 tumors. Similar to MammaPrint,
GGI also correlates with the benefit from chemotherapy in
general: GGI grade 3 cancers seem to derive higher absolute
benefit from conventional chemotherapy versus GGI grade 1
tumors.44 The main common limitations of first generation
prognostic signatures also apply to GGI.22
PAM 50
PAM 50, also known as Prosigna, was originally developed
for intrinsic subtyping of breast cancer,45 but later it started
to be used to predict recurrence.46 It was developed for
patients receiving adjuvant tamoxifen. Its score, PAM 50
ROR (PAM 50 risk of recurrence), is calculated by using the
expression profile of 50 selected genes from four intrin-
sic subtypes, a proliferation score (18-gene subset), and
pathologic tumor size47; it classifies patients into those at
low, intermediate, and high risk of recurrence, but it also
provides the score as a continuous variable. It can be used
with formalin-fixed, paraffin-embedded tissue samples and
was approved by the U.S. Food and Drug Administration in
2013. An important finding was the ability of the PAM 50
ROR score to effectively divide patients into the three risk
groups according to risk for recurrence between 5 and 15
years after the primary diagnosis, using the samples from the

Austrian Breast and Colorectal Cancer Study Group 8 trial
(ABCSG-8). It is, therefore, a more useful signature to
predict late distant relapses compared with Oncotype DX
or MammaPrint.
Breast Cancer Index
The Breast Cancer Index (BCI) is another second-generation
gene signature that was found to be a prognostic marker for
patients with early-stage estrogen receptorpositive breast
cancer who have or who have not received tamoxifen. It
is a quantitative reverse transcription polymerase chain
reactionbased method that measures the expression of
two genes, HOXB13 and IL17BR (H/I), and classifies patients
into three recurrence risk categories (low, intermediate, and
high).48 The BCI was found to be useful for the assessment of
both early and late distant recurrence, according to the
Stockholm study. This study included 317 patients with
estrogen receptorpositive node-negative disease, treated
with adjuvant tamoxifen only, and showed that recurrence
rates for the low-risk group based on the BCI were very low,
not only in the first 5 years after the surgery, but also in years
5 to 10.
EndoPredict
The most recently developed second-generation gene sig-
nature is EndoPredict. Just like the majority of first- and
second-generation signatures, it is also used for estrogen
receptorpositive and HER2-negative breast cancers. It was
developed based on the analysis of 964 breast cancer
samples, from which eight genes and four control genes
were selected. The expression of these 12 genes is analyzed
with the quantitative reverse transcription polymerase chain
reactionbased method for the classification of patients into
two recurrence risk groups.49 The assay was validated in the
ABCSG-6 and ABCSG-8 trials that included patients with
estrogen receptorpositive, HER2-negative, lymph node
positive or negative breast cancers who were treated with
adjuvant tamoxifen only.50 Additionally, EndoPredictClin,
which combines the EndoPredict score with tumor size and
nodal status in a linear model, identified a subgroup of
patients with an excellent long-term prognosis after a
standard 5 years of endocrine therapy,51 thus making it
useful for evaluating risk of late relapse.
CONCORDANCE AMONG GENE
EXPRESSIONBASED PREDICTORS FOR BREAST
CANCER
Fan et al analyzed a single data set of 295 tumor samples and
applied five gene expressionbased models including in-
trinsic subtypes, MammaPrint assay, wound response,
Oncotype DX, and the two-gene ratio (BCI) for patients who
had been treated with tamoxifen.52 Four of these models
were similar in prediction for particular risk groups. For
instance, tumors classified as HER2-enriched, basal-like, and
luminal Blike by intrinsic subtyping were almost all clas-
sified as having a poor outcome by MammaPrint, Oncotype
TAILORING CHEMOTHERAPY IN EARLY-STAGE BREAST CANCER
DX, and wound response models. Of the five models that Fan
et al analyzed in their study, only the two-gene ratio (H/I)
failed to identify substantial differences in outcome within
that data set.
There are two additional reports evaluating the accu-
racy of prediction of BCI among patients with estrogen
receptorpositive, node-negative breast cancer. One report
by Reid et al showed that the two-gene model failed to
detect differences in outcome,53 and the other study,
conducted by Goetz et al, showed that the H/I ratio was a
substantial predictor of relapse-free survival and disease-
free survival.54 The possible explanation for these contra-
dictory findings is that a model based on the analysis of only
two genes is much more likely to be sensitive to technical
differences in analysis platforms than one based on many
genes.
Findings from multiple analyses incorporating first- and
second-generation gene signatures among patients with
early-stage breast cancer suggest that even though there is
very little gene overlap and different algorithms are used,
the prediction of outcome for the majority of patients is
similar. One may therefore conclude that, even though
different gene sets are being used as predictors of outcome,
the signatures identify a common set of biologic charac-
teristics that allow for a good distinction between different
subgroups of patients with breast cancer who have distinct
prognoses.
GENE EXPRESSION SIGNATURES AND RESPONSE
TO CHEMOTHERAPY
The predictive value of genomic signatures has been eval-
uated mostly in the neoadjuvant setting. Several small
studies suggested that the gene expression profiles of
cancers that are highly sensitive to chemotherapy differ
from those of less responsive tumors. For example, Ayers
et al conducted a prospectively designed study in which
needle-biopsy samples from 133 patients with stage I, II, and
III breast cancers were collected before systemic therapy.55
Patients were then treated with preoperative chemotherapy
with weekly paclitaxel and a combination of fluorouracil,
doxorubicin, and cyclophosphamide. A 30-gene predictor
was developed from the data from the first 82 patients, and
it was shown to have a higher sensitivity for prediction of
pCR than a clinical predictor that included age, nuclear
grade, and estrogen receptor status (92% vs. 61%). These
results need further validation and confirmation in in-
dependent and larger studies.
Currently no multigene predictor is ready to be used in
clinical practice with the aim of predicting response to
specific chemotherapy agents or regimens.
CONCLUSION
Undoubtedly, the era of molecular oncology has brought a
deeper insight into the complex biology of breast cancer
and its crucial clinical and therapeutic implications. A new
molecular-based classification of breast cancer exists, going
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RIBNIKAR AND CARDOSO

TABLE 1. Most Common Commercially Available Prognostic Gene Signatures for Breast Cancer
MammaPrint Oncotype DX Breast Cancer Index Mapquant DX PAM 50 ROR EndoPredict
Provider Agendia Genomic Health Biotheranostics Ipsogen NanoString Sividon
Type of 70-gene assay 21-gene 2-gene ratio (H/I) Genomic grade 50-gene assay 12-gene assay
Assay recurrence score and molecular
grade index
Type of Fresh or frozen FFPE FFPE Fresh or frozen FFPE FFPE
Sample or FFPE or FFPE
Technique DNA microarray qRT-PCR qRT-PCR DNA microarray qRT-PCR qRT-PCR
or qRT-PCR or qRT-PCR
Clinical Prognosis of Prediction of Prognostic in ER+, Molecular Originally for Recurrence
Application N0, , 5 cm, recurrence risk prediction of grading for intrinsic subtyping, prediction for
stage I/II, in ER+ and N0 response to TAM ER+, histologic recurrence prediction ER+ HER2
age , 61 treated with TAM grade II disease
Results Dichotomous, Continuous variable Continuous variable Dichotomous, Continuous variable Dichotomous, low
Presentation good or poor GGI I or GGI III or high risk
prognosis
Level of II I III III I I
Evidence
FDA Approval YES NO NO NO YES NO
Abbreviations: ER+, estrogen receptorpositive; FDA, U.S. Food and Drug Administration; FFPE, formalin-fixed, paraffin-embedded; GGI, Genomic Grade Index; qRT-PCR, quantitative
reverse transcription polymerase chain reaction; TAM, tamoxifen.

beyond traditional morphologic oncology. It is, however,
indispensable to use the new molecular tools in conjunction
with classic clinicopathologic parameters because the latter
retain their independent prognostic value for early-stage
breast cancer in multivariate models.
All available tools have advantages and limitations, both of
which must be discussed with patients. First-generation
prognostic gene signatures consistently demonstrate that
about half of the patients with estrogen receptorpositive,
HER2-negative disease are at low risk for early distant re-
lapse and are likely to obtain minimal, if any, benefit from
adjuvant chemotherapy, but do not provide information
about late relapses. Novel second-generation multigene
prognosticators have some additional advantages, such as a
better prediction of late distant relapses, a common situation
in estrogen receptorpositive, HER2-negative breast cancer.
Combination tools, such as EndoPredictClin and Prosigna, may
be even more accurate in determining short- and long-term
prognoses for this subgroup of breast cancer. Therefore,
tumor biology and tumor burden must be complementary
and not mutually exclusive, so that more individualized ad-
juvant treatment decision making can occur (Table 1).
While we wait for the results of the large prospective ran-
domized trials, MINDACT, TailorX, RxPONDER, and OPTIMA,
all major international guidelines recommend the use of
genomic tools in cases for which the potential benefit of
adjuvant chemotherapy is difficult to estimate based only
using on clinicopathologic factors.
Currently, one of the greatest challenges for the medical
oncologist is determining the treatment strategy for patients
with favorable tumor biology and high tumor burden. These
patients are at substantial risk for distant relapse with en-
docrine therapy alone.37,56 However, they do not seem to
derive a substantial benefit from adjuvant chemotherapy
and are at risk for the acute and long-term toxicities of this
therapy.
In summary, adjuvant treatment decision making in
breast cancer involves an integration of the available
clinicopathologic factors and new genomic tools, when-
ever appropriate, as well as a detailed and compre-
hensible discussion with each individual patient regarding
risk of recurrence, risk of adverse events, comorbidities,
performance status, and, very importantly, patient
preferences.

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cancer: understanding the molecular basis of histologic grade to im-
prove prognosis. J Natl Cancer Inst. 2006;98:262-272.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e37
RIBNIKAR AND CARDOSO
44. Liedtke C, Hatzis C, Symmans WF, et al. Genomic grade index is as-
sociated with response to chemotherapy in patients with breast cancer.
J Clin Oncol. 2009;27:3185-3191.
45. Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of breast
cancer based on intrinsic subtypes. J Clin Oncol. 2009;27:1160-1167.
46. Gnant M, Filipits M, Greil R, et al; Austrian Breast and Colorectal Cancer
Study Group. Predicting distant recurrence in receptor-positive breast
cancer patients with limited clinicopathological risk: using the PAM50
Risk of Recurrence score in 1478 postmenopausal patients of the
ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann
Oncol. 2014;25:339-345.
47. Filipits M, Nielsen TO, Rudas M, et al; Austrian Breast and Colorectal
Cancer Study Group. The PAM50 risk-of-recurrence score predicts risk
for late distant recurrence after endocrine therapy in postmenopausal
women with endocrine-responsive early breast cancer. Clin Cancer Res.
2014;20:1298-1305.
48. Zhang Y, Schnabel CA, Schroeder BE, et al. Breast cancer index identifies
early-stage estrogen receptor-positive breast cancer patients at risk for
early- and late-distant recurrence. Clin Cancer Res. 2013;19:4196-4205.
49. Filipits M, Rudas M, Jakesz R, et al; EP Investigators. A new molecular
predictor of distant recurrence in ER-positive, HER2-negative breast
cancer adds independent information to conventional clinical risk
factors. Clin Cancer Res. 2011;17:6012-6020.
50. Dubsky PC, Jakesz R, Mlineritsch B, et al. Tamoxifen and anastrozole as a
sequencing strategy: a randomized controlled trial in postmenopausal
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patients with endocrine-responsive early breast cancer from the
Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2012;
30:722-728.
51. Dubsky P, Brase JC, Jakesz R, et al; Austrian Breast and Colorectal Cancer
Study Group (ABCSG). The EndoPredict score provides prognostic in-
formation on late distant metastases in ER+/HER2- breast cancer pa-
tients. Br J Cancer. 2013;109:2959-2964.
52. Fan C, Oh DS, Wessels L, et al. Concordance among gene-expression-
based predictors for breast cancer. N Engl J Med. 2006;355:560-569.
53. Reid JF, Lusa L, De Cecco L, et al. Limits of predictive models using
microarray data for breast cancer clinical treatment outcome. J Natl
Cancer Inst. 2005;97:927-930.
54. Goetz MP, Suman VJ, Ingle JN, et al. A two-gene expression ratio of
homeobox 13 and interleukin-17B receptor for prediction of recurrence
and survival in women receiving adjuvant tamoxifen. Clin Cancer Res.
2006;12:2080-2087.
55. Ayers M, Symmans WF, Stec J, et al. Gene expression profiles predict
complete pathologic response to neoadjuvant paclitaxel and fluoro-
uracil, doxorubicin, and cyclophosphamide chemotherapy in breast
cancer. J Clin Oncol. 2004;22:2284-2293.
56. Saghatchian M, Mook S, Pruneri G, et al. Combining genomic profiling
(70-gene MammaPrint) with nodal status allows to classify patients
with primary breast cancer and positive lymph nodes (1-9) into very
distinct prognostic subgroups that could help tailor treatment strate-
gies. Cancer Res. 2009;69:a102.
BREAST CANCER

Targeted Therapies in Hormone

ReceptorPositive Breast Cancer

CHAIR
Hope S. Rugo, MD
University of California, San Francisco
San Francisco, CA

SPEAKERS
Cynthia Ma, MD, PhD
Washington University School of Medicine
St. Louis, MO

Dejan Juric, MD
Massachusetts General Hospital Cancer Center
Boston, MA
RUGO, VIDULA, AND MA

Improving Response to Hormone Therapy in Breast Cancer:

New Targets, New Therapeutic Options
Hope S. Rugo, MD, Neelima Vidula, MD, and Cynthia Ma, MD, PhD

OVERVIEW

The majority of breast cancer expresses the estrogen and or progesterone receptors (ER and PR). In tumors without
concomitant HER2 amplification, hormone therapy is a major treatment option for all disease stages. Resistance to
hormonal therapy is associated with disease recurrence and progression. Recent studies have identified a number of
resistance mechanisms leading to estrogen-independent growth of hormone receptorpositive (HR+) breast cancer as a
result of genetic and epigenetic alterations, which could be exploited as novel therapeutic targets. These include acquired
mutations in ER-alpha (ESR1) in response to endocrine deprivation; constitutive activation of cyclin-dependent kinases (CDK)
4 and 6; cross talk between ER and growth factor receptor signaling such as HER family members, fibroblast growth factor
receptor (FGFR) pathways, intracellular growth, and survival signals PI3K/Akt/mTOR; and epigenetic modifications by
histone deacetylase (HDAC) as well as interactions with tumor microenvironment and host immune response. Inhibitors of
these pathways are being developed to improve efficacy of hormonal therapy for treatment of both metastatic and early-
stage disease. Two agents are currently approved in the United States for the treatment of metastatic HR+ breast cancer,
including the mTOR inhibitor everolimus and the CDK4/6 inhibitor palbociclib. Management of toxicity is a critical aspect of
treatment; the primary toxicity of everolimus is stomatitis (treated with topical steroids) and of palbociclib is neutropenia
(treated with dose reduction/delay). Many agents are in clinical trials, primarily in combination with hormone therapy; novel
combinations are under active investigation.

T he estrogen-dependent nature of breast cancer has been

well established since the historical observation that
removal of the ovaries was effective in treating breast tumors.1
A number of pharmacological agents, referred to as endocrine
therapy, are now available in the clinic. These include aro-
matase inhibitors (AI) and gonadotropin-releasing hormone
(GnRH) agonists that reduce estrogen biosynthesis, the
selective estrogen receptor modulators (SERM) tamoxifen,
and the selective ER down regulator (SERD) fulvestrant. The
clinical application of these agents has led to substantial
improvements in survival outcomes for patients with ER+
breast cancer.2 However, despite standard therapy, over
20% of patients with early-stage disease experience relapse,
and, essentially, all patients with metastatic disease suc-
cumb to their illness.2,3 Although the mechanisms of en-
docrine resistance are not fully understood, significant
progress has been made in recent years in uncovering
several key molecular pathways that promote ligand-
independent activation of ER and tumor growth. In this
article, we will focus on evidence for ER-alpha (ESR1) mu-
tation, growth factor receptor signaling, PI3K/Akt/mTOR,
CDK4/6, and epigenetic and immune checkpoints as resis-
tance mechanisms and therapeutic targets in ER+ breast
cancer (Fig. 1).
UNDERSTANDING THE BIOLOGY OF HORMONE
RECEPTORS AND POTENTIAL MECHANISMS OF
RESISTANCE
Mechanisms of Action of Estrogen Receptors
Estrogen receptors belong to the family of steroid hormone
receptors and its main mechanism of action is a transcription
factor (Fig. 2). There are two different forms of ER, ER-alpha
and ER-beta, encoded by ESR1 and ESR2, respectively. There
is substantial sequence homology between ER-alpha and
ER-beta, although the function of ER-beta is less known.
Upon activation by estrogen, the cytosolic ER forms dimers
and translocates to the nucleus where ER binds directly to
the estrogen response elements (ERE) or is tethered to
the promoter regions of target genes via its interaction
with SP1. 4 Additional coregulators are then recruited
to the complex to regulate the transcription levels of
target genes, including cyclin D, to promote cell cycle

From the UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of San Francisco School of Medicine, San Francisco, CA; Department of Medicine,
Washington University School of Medicine in St. Louis, St. Louis, MO.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero St., San Francisco, CA 94115; email: hope.rugo@ucsf.edu.

2016 by American Society of Clinical Oncology.

e40 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


FIGURE 1. Key Pathways of Endocrine Resistance
Pink and blue color code activating and suppression signals, respectively, for pathway activation.
Abbreviations: HDAC, histone deacetylase; RTK, receptor tyrosine kinase.
progression.4,5 In addition to this classic genomic action of
ER, growth factor receptor tyrosine kinases and a variety of
proximal signaling molecules, such as G protein, Ras, Src,
PI3K, and Shc, could activate ER in the absence of estrogen,
KEY POINTS
Resistance to endocrine therapy in HR+ breast cancer is
associated with diverse molecular mechanisms,
including acquired mutations in ESR1 in response to
endocrine deprivation, constitutive activation of CDK4/6,
cross talk between the ER and growth factor receptor
signaling, epigenetic modifications by HDAC, and
interactions with tumor microenvironment and host
immune response.
Increased understanding of endocrine resistance
mechanisms has led to the development of targeted
agents, including two agents which are approved for
clinical use in the United States, that have improved
progression-free survival in combination with standard
hormone agents.
PI3K is the most commonly altered pathway in HR+
breast cancer; multiple agents that target this pathway
or related growth factor receptors are being studied. To
date, markers of PI3K pathway activation have not
identified a specific population most likely to benefit
from this therapy.
Toxicities of targeted therapies and impact on quality of
life must be taken into account and managed
expectantly when treating patients; common toxicities
are stomatitis (everolimus) and neutropenia
(palbociclib).
Ongoing trials are evaluating inhibitors of the PI3K
pathway, CDK4/6, and HDAC, primarily in combination
with hormone therapy in the metastatic, adjuvant, and
neoadjuvant settings; combination therapy targeting
two or more pathways is also under investigation.
IMPROVING RESPONSE TO HORMONE THERAPY
leading to estrogen-independent cell proliferation and resistance
to endocrine therapy.6-10
ESR1 Mutation
Although initially discovered in the 1990s, the ESR1 mutation
was largely overlooked until recent years when recurrent,
rather than primary, breast cancers were studied. In contrast
to the extremely low incidence in treatment-naive primary
breast cancers, mutations in ESR1 have been reported in
11%55% of recurrent or metastatic cancers that progressed
after long-term endocrine therapy (Fig. 3).11-14 The hot-spot
mutations cluster in the ligand-binding-domain of ER, which
induce a constitutive agonist conformation. Compared with
the wild-type ER, mutant ER is resistant to estrogen dep-
rivation and much less responsive to tamoxifen or fulves-
trant. Successful treatment of ESR1-mutant breast cancer
therefore requires the development of newer generation
SERMs or SERDs, or other strategies, that are effective in
targeting the mutated ER.
HER2 Gene Amplification
HER family members, including HER1 (EGFR), HER2, HER3,
and HER4, are tyrosine kinase receptors important in
promoting cell growth and survival.15 Cross talk between
ER and HER family members has been well recognized in
preclinical and clinical studies. HER2 amplification occurs
in about 10% of ER+ breast cancers and is an established
mechanism of endocrine resistance.16 Compared with ER+
HER2- disease, ER+ HER2+ breast cancer is associated with a
higher risk of relapse on adjuvant endocrine therapy17 and
incomplete cell cycle arrest to neoadjuvant endocrine
therapy.18 Adjuvant trastuzumab reduces relapse in ER+
HER2+ breast cancer and is the standard of care.19 In the
metastatic setting, hormonal therapy in combination with
HER2-targeted agents provides an alternative to chemo-
therapy regimens.20-22
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RUGO, VIDULA, AND MA

FIGURE 2. Estrogen Receptor Pathway and Cross Talk With Growth Factor Receptor, PI3K/AKT/mTOR, and
CDK4/6 Pathways

Estrogen-bound estrogen receptor (ER), in complex with coactivators (CoA) or corepressors (CoR), regulates target gene expression via the estrogen response element (ERE)
or the AP1 binding sites via its interaction with other transcription factors. Additionally, ER can interact with receptor tyrosine kinases (FGFR, EGFR/HER), which promote
estrogen-independent ER phosphorylation through pathways such as PI3K/Akt/mTOR and MAPK (a and b). The G1 to S phase transition is controlled by CDK4/6, which is
activated by the ER downstream target cyclin D. Constitutive activation of CDK4/6 is associated with endocrine resistance.

HER2 Mutation interaction with other HER family members. In preclinical

Somatic mutations in HER2 in otherwise HER2-negative
breast cancer have attracted much attention in recent years.
Although the overall HER2 mutation rate is approximately
2% in primary breast cancers,23 it reaches over 20% in in-
vasive lobular cancers.24 These mutations cluster in the
kinase domain and the extracellular domain important for its
models, many of these mutations have shown to be on-
cogenic and are sensitive to treatment with the irreversible
tyrosine kinase inhibitor of HER1/HER2, neratinib.23 Results
of the breast cancer cohort of the SUMMIT study, a mul-
ticenter, open-label, multihistology phase II basket trial of
neratinib for patients with HER2-mutant, nonamplified,

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FIGURE 3. ESR1 Mutation as an Acquired Mechanism
of Endocrine Resistance
The incidence of ESR1 mutations increases dramatically after treatment with long-
term endocrine therapy for recurrent or metastatic ER+ disease. The hot-spot ligand-
binding domain mutations induce a constitutive agonist conformation of ER, leading
to estrogen independence.
Abbreviations: AF1, activation function 1; DBD, DNA-binding domain; ER, estrogen
receptor; LBD, ligand-binding domain.
advanced solid tumors (NCT01953926), was recently re-
ported in an abstract form.25 Among the 19 evaluable pa-
tients, objective response was observed in six (overall
response rate 32%). As a majority of breast cancers with
HER2 mutation are ER+, the combination of fulvestrant and
neratinib is being studied among this patient population
(NCT01670877).
Fibroblast Growth Factor Receptors and Ligands
Amplification
The fibroblast growth factor (FGF) signaling is composed
of 18 ligands that exert their function through four highly
conserved transmembrane tyrosine kinase receptors
(FGFR1, FGFR2, FGFR3, and FGFR4) to control a wide range
of biologic functions and regulating cellular proliferation,
survival, migration, and differentiation.26 FGFR1 ampli-
fication has been identified in 16%27% of luminal B ER+
breast cancers and associated with increased Ki67, early
relapse, and poor survival.27 Less frequently, the pathway
could be activated by amplification of FGFR2 or different
ligands including FGF3 and FGF4.26 In preclinical studies,
FGFR1 amplification enhanced PI3K and MAPK pathway
signaling and rendered cancer cells resistance to endocrine
therapy, which was reversed by RNAi silencing of FGFR1.27
Dovitinib (TKI258), a first-generation oral tyrosine kinase in-
hibitor of FGFR1-3, VEGFR, and PDGFR, inhibited proliferation
of FGFR1/2-amplifiedbut not FGFRnormalbreast cancer
cell lines, and demonstrated promising antitumor activity for
patients with FGFR1/2/3-amplified breast cancers in a phase II
trial.28 Several FGFR inhibitors are currently being in-
vestigated in advanced HR+ breast cancer to overcome
endocrine resistance.
PI3K/Akt/mTOR Pathway
The PI3K/Akt/mTOR pathway is a cardinal nodal point in the
transduction of extracellular and intracellular growth and
IMPROVING RESPONSE TO HORMONE THERAPY
survival signals, and acquired endocrine resistance is often
accompanied by upregulation of PI3K pathway signaling.29-32
Gain of function mutations in the alpha catalytic subunit of PI3
kinase (PIK3CA) occurs at a frequency of 30%40% and is the
most frequent genetic abnormality in ER+ breast cancer.33,34
A majority of the mutations, including the three hot-spot
mutations E542K, E545K, and H1047R, are missense acti-
vating mutations that cluster in the evolutionarily conserved
accessary domain and the kinase domain.35 In preclinical
models, ER+ breast cancer carrying PIK3CA mutations was
highly dependent on p110 alpha for cell survival.31,36
Rapalogs are among the first agents introduced in the
clinic that indirectly inhibit the activity of mTOR complex 1
(mTOC1) through its interaction with FKBP12.37 Everolimus
is now approved for AI-resistant metastatic breast cancer.
However, inhibition of mTORC1 has the potential to upre-
gulate Akt activity due to the negative feedback loop be-
tween the downstream S6K and the upstream PI3K.38,39
Direct kinase inhibitors against both mTORC1 and mTORC2,
as well as inhibitors against Akt and PI3K, are in clinical trials
for more effective pathway inhibition. Promising activity has
been observed in some studies.40-43 However, it has become
evident that the efficacy of pan-PI3K inhibitors is limited by
dose-limiting toxicities that include rash, diarrhea, and el-
evated transaminases.43,44 Alpha-specific inhibitors are
likely advantageous in improving the therapeutic window,
but resistance mechanisms through acquiring mutations in
PTEN, leading to growth dependence on PI3K-beta, have
been reported in clinical trials of alpelisib, an alpha-specific
inhibitor.45 Preclinical modeling also indicated that effective
inhibition of mTOR remains important for upstream in-
hibitors,46 but combined PI3K and mTOR inhibition may not
be feasible due to overlapping toxicities. There has been
significant interest in developing biomarkers of treatment
efficacy, in particular PIK3CA mutation status. However, no
clear association has been identified even with the direct
PI3K inhibitors.40-43,47
Cyclin D/CDK4/6/Rb Pathway
The G1 to S phase transition is controlled by CDK4/6, which
are activated upon binding to D-type cyclins,48-51 leading to
phosphorylation of retinoblastoma susceptibility (RB1) gene
product (Rb) and the release of the E2F transcription fac-
tors.51 There is a strong link between the action of estrogen
and CDK4/6 activity.52-56 Persistent cyclin D1 expression and
Rb phosphorylation has been associated with resistance to
endocrine therapy in ER+ breast cancer.57 The poorer prog-
nosis, luminal B ER+ diseases are preferentially enriched with
gains of CCND1 (cyclin D1; 58% in luminal B vs. 29% in luminal
A) and CDK4 (25% in luminal B vs. 14% in luminal A) and loss of
CDKN2A (p16) and CDKN2C (p18), which are negative regu-
lators of CDK4/6.34
In preclinical studies, the CDK4/6 inhibitor palbociclib was
preferentially effective in inhibiting the cell proliferation of
ER+ cancer cells, including those resistant to anti-estro-
gens.58 Synergism was observed when combining palbociclib
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RUGO, VIDULA, AND MA
with various anti-estrogens,58,59 and efficacy was demon-
strated in patient-derived xenograft models of ER+ breast
cancer carrying ESR1 mutations.59 Cells lacking Rb (and
hence not dependent on cyclin D1/CDK4/6 for proliferation)
were resistant to palbociclib. Therefore lack of Rb may serve
as a biomarker of resistance to this class of agents. Palbo-
ciclib in combination with letrozole is now approved as first-
line treatment of postmenopausal women with metastatic
ER+ HER2 breast cancer. Several other CDK4/6 inhibitors
are in various stages of clinical development.
Combining PI3K and CDK4/6 Inhibitors in PIK3CA-
Mutant Breast Cancer
A drug screen of 42 agents identified the CDK4/6 inhibitor
ribociclib as a strong sensitizer to PI3K inhibition in three ER+
breast cancer cell lines with acquired resistance to PI3K
inhibitors.60 In this study, acquired resistance to PI3K in-
hibition was associated with maintained phosphorylation of
S6 and Rb. Addition of ribociclib reduced Rb phosphorylation
and induced synergist antitumor effect of the PI3K inhibitor,
particularly in those with PIK3CA mutation and intact Rb. The
synergism was also observed in the parental cell lines and those
with de novo resistance to PI3K inhibitors. The impressive an-
titumor activity and the nonoverlapping toxicities of these two
classes of agents has led to clinical evaluation of triplet regimens
composed of letrozole, ribociclib, and alpelisib.
Epigenetic Pathways
Preclinical studies indicated that epigenetic silencing of
ER and deregulation of growth factor receptorpathway
components play an important role in the development of
endocrine resistance.61-64 In addition, an array of mutations
have been identified in genes that regulate histone and DNA
modification.34 An example is the MLL3 (myeloid/lymphoid
or mixed-lineage leukemia gene) mutation, which occurred
in 8% of luminal A and 6% of luminal B breast cancers.34
Insulin-Like Growth Factor/Type 1 Insulin-Like
Growth Factor Signaling
The insulin-like growth factor (IGF)/type 1 insulin-like
growth factor receptor (IGF1R) signaling has a critical role
in cell growth, survival, and migration and is required for
mammary gland development.65 The IGF ligands, IGF1 and
IGF2, stimulate cell growth and survival signaling primar-
ily via binding to IGF1R and the subsequent activation of
the PI3K/Akt and RAS/MAPK pathways.65,66 Extensive bi-
directional regulation exists between ER and the IGF1R
pathway.67 ER-alpha is a major regulator of IGF signaling as
IGF1R and other IGF signaling components are its direct
transcription target,68-70 while IGF1R upregulates the tran-
scription level of ER-alpha and increases ER phosphorylation via
activation of mTOR/S6K signaling.71 Hyperactivation of IGF1R
and downstream signaling has been associated with the de-
velopment of endocrine resistance in ER+ breast cancer
preclinical models and patient specimens.65,72-74 However
targeting IGF1R in the endocrine-resistant setting has been
e44 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
complicated because of its functional redundancy with the
insulin receptor.75 In addition to mediating endocrine therapy
resistance, data also support the importance of IGF1R in
mediating treatment resistance to inhibitors against mTOR or
Akt in endocrine-resistant ER+ breast cancer because of the
negative feedback loop between the downstream target S6K
and the upstream IGF1R/IRSs/PI3K signaling.38,76 Preclinical
data support the clinical investigation for the combined in-
hibition of IGF1R/IR and Akt, along with ER targeting.76
Vascular Endothelial Growth Factor
In addition to contributing to neoangiogenesis, VEGF has
been shown to induce breast cancer cell proliferation and
resistance to endocrine therapy via an autocrine mecha-
nism.77,78 VEGF and the VEGF receptor have shown to be
overexpressed in breast cancers, and high levels of VEGF
have been linked to early recurrence and resistance to
hormonal therapy.79,80 These provided the preclinical ra-
tional for investigating the addition of VEGF inhibitors to
hormonal therapy for the treatment of ER+ breast cancer.
The challenge so far has been the difficulty in identifying a
target patient population who would derive the most benefit
from these agents.
Microenvironment and Immune Checkpoint Pathway
The immune checkpoint pathway, PD-1, and the PD-L1 path-
way has been implicated in tumor immune invasion.81 In-
hibitors against PD-1 and PD-L1, which disrupt the interaction
between PD-1 on T cells and its ligands PD-L1, have shown
antitumor activity in a variety of tumor types. Approximately
4%20% of ER+ breast cancers, perhaps more frequently in the
more proliferative luminal B versus luminal A subtypes, have
been reported to overexpress PD-L1 in cancer and stroma
cells.82-84 PD-1 and PD-L1 antibodies are being tested in HR+
breast cancer, with preliminary results available.
REVERSING HORMONE RESISTANCE IN THE
CLINIC
With a greater understanding of the mechanisms of re-
sistance to hormone therapy, new therapies have emerged
that hold the potential to overcome hormone resistance and
improve response, duration of response, and, hopefully,
survival. Targeted therapies that are being actively in-
vestigated in the clinic include mTOR inhibitors (ever-
olimus), PI3K inhibitors (buparlisib, alpelisib, and taselisib),
CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib),
HDAC inhibitors (entinostat), FGFR inhibitors (dovitinib and
lucitinib), and IGFR inhibitors. Altering the host immune re-
sponse with checkpoint inhibition is also being investigated in
advanced disease. Table 1 summarizes the major ongoing
phase II and III trials with the most-promising novel targeted
agents. Table 2 provides a summary of these agents, their
mechanisms of action, developmental status, and toxicity
profile. This section provides a more detailed review of these
emerging therapies, focusing on non-HER2 amplified disease.

Of note, two randomized trials have demonstrated im-
proved progression-free survival (PFS) with the addition of
HER2-targeted agents to AIs in the treatment of metastatic,
HR, and HER2+ disease.22,85 However, given the demonstrated
improvement in overall survival (OS) with chemotherapy,
trastuzumab, and pertuzumab in the first-line metastatic set-
ting, this is generally the preferred treatment approach, with
hormone therapy reserved for maintenance in combination
with HER2-targeted therapy following response.
Inhibition of mTOR
Several randomized trials have demonstrated that inhibition
of the mTOR pathway can improve duration of response to
hormone therapy, despite an initial rocky start. The first
randomized trial evaluated the efficacy of temsirolimus in
combination with the AI letrozole as first-line therapy for
metastatic HR+ breast cancer.86 There was no difference in PFS
between the two arms. It may be that the dose and schedule of
temsirolimus were not optimal, as stomatitis (a marker of drug
exposure) was seen at a lower rate than expected.
Greater success leading to the first approval of a targeted
therapy in combination with hormone therapy in HER2
disease was seen with everolimus. A phase II neoadjuvant
trial was conducted to evaluate efficacy and biomarkers,
with the primary endpoint of clinical response.87 Two
hundred-seventy postmenopausal women with HR+ early-
stage breast cancer were randomly selected to receive
letrozole plus everolimus or placebo for 4 months prior to
surgery. Clinical response was higher in the combination arm
compared with placebo (68.1% vs. 59.1%; p = .062). More
importantly, a significant decrease in cell proliferation on
repeat biopsy performed 2 weeks after treatment was noted
in the combination therapy arm compared with placebo
(57% vs. 30% decrease; p , .01). These data encouraged
further investigation of everolimus in combination with
hormone therapy.
Two subsequent trials tested everolimus in the metastatic
setting. The TAMRAD trial was a phase II open-label trial that
randomly selected 111 postmenopausal women whose
disease had progressed on an AI to receive tamoxifen and
everolimus or tamoxifen alone.88 The primary endpoint,
clinical benefit rate at 6 months, was improved with com-
bination therapy compared with tamoxifen alone (61% vs.
42%; p = .045). Progression-free survival in the combination
therapy arm was significantly longer at 8.6 months versus
4.5 months (p = .002).
Finally, regulatory approval of everolimus in combination
with exemestane for the treatment of metastatic breast
cancer progressing on nonsteroidal AIs was based on data
from the BOLERO-2 trial, a double-blind phase III trial that
randomly selected 724 postmenopausal women in a 2:1 ratio
to receive exemestane with everolimus at 10 mg a day or
placebo.89 At a median follow-up of 18 months, investigator-
assessed PFS (the primary endpoint) was more than doubled
with the addition of everolimus (7.8 months for everolimus
compared with 3.2 months for placebo; hazard ratio [HR]
IMPROVING RESPONSE TO HORMONE THERAPY
0.45; 95% CI, 0.380.54). Median OS was not significantly
improved at 31 months with everolimus compared with
26.6 months with placebo (HR 0.89; 95% CI, 0.731.10;
p = .14).90 A subset analysis of BOLERO-2 demonstrated
efficacy of combination therapy among patients with visceral
metastases and those with nonvisceral disease.91 Based on
the PFS data, everolimus is now being used clinically in
combination with exemestane in the metastatic setting.
Toxicity is a substantial issue with everolimus, but data
from subsequent trials suggest that physician and patient
education and expectant management reduces common
toxicity and increases tolerability.
The most common toxicity in BOLERO-2 was stomatitis
(56% all grade, aphthous-type ulcers), although the in-
cidence of grade 3 stomatitis was low (8%), and no grade 4
events were oberved.92 Stomatitis occurs early, with 80% of
cases occurring in the first 6 weeks of therapy.93 A meta-
analysis of seven phase III studies of everolimus in different
cancer types evaluated whether the incidence of stomatitis
correlated with clinical efficacy.94 There was commonality of
everolimus-induced stomatitis across solid tumors (66.9% all
grades of all patients), with 8.6% grade 3/4 stomatitis, and
the incidence of stomatitis correlated with at least as good if
not better PFS compared with the control population. This
suggests that stomatitis may be a marker of drug exposure
for everolimus and that dose reductions and delays for this
toxicity do not impact efficacy. A phase II trial evaluated a
commercially available steroid-based mouthwash among
patients taking prophylactic exemestane and everolimus to
determine if the incidence and severity of stomatitis might
be reduced with this approach.95 Data will be presented at
the 2016 American Society of Clinical Oncology (ASCO)
Annual Meeting.
Other commonly noted side effects with everolimus in-
clude fatigue, diarrhea, rash, hyperglycemia, pneumonitis,
weight loss, anemia, and thrombocytopenia. The risk of
pneumonitis persists over the course of therapy at a low
rate, with a 3% rate of grade 3 pneumonitis observed in
BOLERO-2. Additional clinical trials with everolimus are on-
going, summarized in Table 1. These include studies in the
neoadjuvant, adjuvant, and metastatic settings. Results from
BOLERO-6, comparing everolimus plus exemestane with
capecitabine, are expected this year.
Inhibition of PI3K
Two classes of PI3K inhibitors are being studied in HR+ breast
cancer, the pan-class I inhibitors (buparlisib [BKM120] and
pictilisib [GDC0941]) and the alpha-specific inhibitors
(alpelisib [BYL719] and taselisib [GDC0032]).
Results with the pan-PI3K inhibitors have been compli-
cated by toxicity and disappointing efficacy. The FERGI trial
was a phase II trial that randomly selected 168 women with
HR+ postmenopausal metastatic breast cancer previously
treated with an AI to receive fulvestrant with pictilisib or
placebo.44 Toxicity was increased in the pictilisib arm; 17% of
patients had at least grade 3 rash and 7% had at least grade 3
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e45
RUGO, VIDULA, AND MA

TABLE 1. Phase II/III Trials of the Novel Targeted Agents Under Development for Hormone ReceptorPositive
Breast Cancer

No.
Trial Novel Agent Primary Endpoint Patients Trial Status
Everolimus: mTOR Inhibitor
Baselga et al87 Everolimus Clinical examination response 270 Completed; response rate of 68.1% in
everolimus/letrozole arm compared with
59.1% in placebo/letrozole arm (p = .062)
GINECO88 Everolimus Clinical benefit rate at 6 months 111 Completed; clinical benefit rate of 61% in
everolimus/tamoxifen arm compared with
42% in tamoxifen arm (p = .045)
BOLERO-289 Everolimus PFS 724 Completed; median PFS of 7.8 months in
everolimus/exemestane arm compared
with 3.2 months in exemestane/placebo
(HR 0.45; 95% CI, 0.380.54)
UNIRAD127 Everolimus Disease-free survival 1,984 Ongoing
SWOG 1207128 Everolimus Invasive disease-free survival using 1,900 Ongoing, recruiting patients
a stratified log-rank test, assessed
up to 10 years
NCT02088684130 Everolimus PFS 46 Ongoing, recruiting patients
BOLERO-4143 Everolimus Percentage of patients progression- 202 Ongoing
free after completion of first-line
treatment
BOLERO-6144 Everolimus PFS 297 Ongoing, recruitment completed
BRE-43145 Everolimus Time to progression 33 Completed
LEO146 Everolimus PFS 137 Ongoing, active recruitment
147
FEVEX Everolimus PFS 745 Not yet open
PrE0102148 Everolimus PFS 130 Ongoing
NCT02236572113 Everolimus Achievement of a PEPI score of 0 66 Ongoing, recruiting patients
following neoadjuvant treatment
with everolimus and an aromatase
inhibitor at 26 weeks
NCT02123823149 BI 836845 (monoclonal antibody PFS 174 Ongoing, recruiting patients
to insulin like growth factor)
and everolimus
Taselisib (GDC0032): Alpha-Specific PI3K Inhibitor
LORELEI150 Taselisib Objective response rate and 330 Ongoing, recruiting patients
pathologic complete response
rate at 16 weeks of treatment
SANDPIPER98 Taselisib PFS 600 Ongoing, recruiting patients
Buparlisib (BKM120) Pan-Class I PI3K Inhibitor
BELLE-296 Buparlisib PFS 1147 Completed; PFS was slightly improved with
buparlisib vs. placebo (6.9 vs. 5 months; HR
0.78; 95% CI, 0.670.89)
BELLE-3151 Buparlisib PFS 420 Ongoing, recruiting patients
Pictlisib (GDC0941): Pan-Class I PI3K Inhibitor
FERGI44 Pictlisib PFS 168 PFS of 6.6 months for pictilisib/fulvestrant
arm compared with 5.1 months in
fulvestrant/placebo arm (HR 0.7; 95% CI,
0.521.06)
Palbociclib: CDK4/6 Inhibitor
PALOMA-1/TRIO- Palbociclib PFS 165 Completed; PFS for palbociclib/letrozole was
1899 20.2 months compared with 10.2 months
in letrozole arm (HR 0.49; 95% CI,
0.3190.748)
PALOMA-2100 Palbociclib PFS 650 Ongoing, closed to accrual
Continued

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 IMPROVING RESPONSE TO HORMONE THERAPY

TABLE 1. Phase II/III Trials of the Novel Targeted Agents Under Development for Hormone ReceptorPositive
Breast Cancer (Contd)
No.
Trial Novel Agent Primary Endpoint Patients Trial Status
PALOMA-3101 Palbociclib PFS 417 Completed; PFS of 9.2 months in palbociclib/
fulvestrant arm vs. 3.8 months in fulves-
trant/placebo arm (HR 0.42; 95% CI,
0.320.56)
PEARL104 Palbociclib PFS 348 Ongoing, recruiting patients
PENELOPEB103 Palbociclib Invasive disease-free survival 800 Ongoing, recruiting patients
PALOMA-4152 Palbociclib PFS 330 Ongoing, recruiting patients
PALOMA-2139 Palbociclib Treatment discontinuation rate 160 Ongoing, not recruiting patients
PALLET153 Palbociclib Change in proliferation rate (Ki67) 306 Ongoing, recruiting patients
at 2 weeks
FLIPPER154 Palbociclib PFS 190 Ongoing, recruiting participants
PARSIFAL155 Palbociclib PFS 304 Ongoing, currently recruiting patients
NCT02384239156 Palbociclib Tumor Progression as measured by 70 Ongoing, currently recruiting patients
RECIST 1.1
NCT02592746157 Palbociclib PFS 122 Ongoing, not yet recruiting patients
Abemaciclib: CDK4/6 Inhibitor
neoMONARCH134 Abemaciclib Change in proliferation rate (Ki67) 220 Ongoing, recruiting patients
at 2 weeks
monarcHER158 Abemaciclib PFS 225 Ongoing, not yet recruiting patients
MONARCH-1110 Abemaciclib Objective response rate 128 Closed to accrual
MONARCH-2112 Abemaciclib PFS 550 Ongoing
MONARCH-3113 Abemaciclib PFS 450 Ongoing
NCT02308020114 Abemaciclib Percentage of participants achieving 247 Recruiting
complete response or partial
response: objective intracranial
response rate
Ribociclib: CDK4/6 Inhibitor
MONALEESA-2141 Ribociclib PFS 667 Ongoing
159
MONALEESA-3 Ribociclib PFS 660 Ongoing, recruiting participants
Entinostat: HDAC Inhibitor
Yardley et al117 Entinostat PFS 130 Completed; PFS was 4.3 months in
exemestane/entinostat arm compared
with PFS of 2.3 months with exemestane
alone arm (p = .055); overall survival was
28.1 months in exemestane/entinostat
arm compared with 19.8 months in
exemestane alone arm (HR 0.59; 95% CI,
0.360.97)
E2112118 Entinostat PFS 600 Ongoing
Azacitidine: DNA Methylation Inhibitor
NCT01349959120 Azacitidine and entinostat Confirmed response rate 40 Ongoing
NCT02374099119 Azacitidine Time period of PFS 92 Ongoing, recruiting patients
Abbreviations: HR, hazard ratio; PFS, progression-free survival.

diarrhea, and 18% of patients discontinued due to adverse
events. Progression-free survival was similar between the
two treatment arms at 6.6 months for pictilisib and
5.1 months for placebo (HR 0.7; 95% CI, 0.521.06; p = .096),
and among patients with PI3KCA-mutant tumors. In an
exploratory analysis, there was a suggestion of benefit for
patients with PR+ disease.
The pan-PI3K inhibitor buparlisib was evaluated in the
phase III BELLE-2 trial.96 Patients with prior AI therapy were
randomly selected to fulvestrant with either buparlisib or
placebo, with a primary endpoint of PFS in the full pop-
ulation and in those with PI3K pathwayactivated tumors. In
the 1,147 women who received study therapy, PFS was
slightly improved with buparlisib compared with placebo
(6.9 vs. 5 months; HR 0.78; 95% CI, 0.670.89; p , .001).
Progression-free survival was not significantly improved for
patients with PI3K activation (6.8 vs. 4 months). In an ex-
ploratory analysis of PIK3CA mutations in circulating tumor

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RUGO, VIDULA, AND MA

TABLE 2. Summary of the Most-Promising Targeted Agents Under Development in the Treatment of Hormone
ReceptorPositive Breast Cancer

Agent Mechanism of Action Developmental Status Toxicity Profile

Everolimus mTOR inhibition FDA approval for everolimus plus exemestane as at Main toxicities include stomatitis, hyperglycemia,
least second-line therapy for HR+ advanced fatigue, pneumonitis
breast cancer
Palbociclib, Ribociclib, CDK4/6 inhibition FDA approval for palbociclib plus letrozole as first- Main toxicities include neutropenia without
Abemaciclib line therapy, and palbociclib plus fulvestrant as an increase in febrile neutropenia, QTc
at least second-line therapy for advanced breast prolongation, and fatigue; diarrhea most
cancer; ongoing trials with all 3 agents in the common with abemaciclib
metastatic, adjuvant, and neoadjuvant settings
Alpha-Specific
Alpelisib, Taselisib PI3K inhibition Ongoing trials Main toxicities include hyperglycemia, rash, and
liver dysfunction
Pan-PI3K
Buparlisib, Pictilisib PI3K inhibition Ongoing trials Main toxicities include hyperglycemia, rash, and
liver dysfunction
Entinostat HDAC inhibition FDA breakthrough status; ongoing phase III trial Main toxicities include fatigue, myelosuppression,
with exemestane diarrhea, nausea, and vomiting
Dovitinib, Lucitinib FGFR inhibition Pre-clinical and preliminary clinical efficacy with Main toxicities include diarrhea, nausea, and
FGFR/VEGF inhibition dovitinib and lucitinib hypertension, proteinuria, and liver dysfunction
(lucitinib)
Abbreviation: FDA, U.S. Food and Drug Administration.

DNA (ctDNA; 87 patients for buparlisib and 113 for placebo),
PFS was improved for those with PIK3CA mutations receiving
buparlisib compared with placebo (7.0 vs. 3.2 months; HR
0.56), with no difference in the wild-type population.
Toxicity was increased in the buparlisib arm, with grade
3/4 transaminitis (. 20%; approximately 0% grade 4), hy-
perglycemia (15.4%), rash (7.9%), anxiety (5.4%), and de-
pression (4.4%); 13% of patients discontinued treatment due
to adverse events.
The data from BELLE-2, although disappointing in the
overall population, provide the first data suggesting that
ctDNA could be a potential marker to select patients who
might benefit from specific targeted therapies. Ongoing
trials are evaluating the use of PIK3CA mutations in ctDNA as
predictive markers for response to alpha-specific PI3K in-
hibitors, such as alpelisib and taselisib.
The alpha-specific PI3K inhibitors alpelisib and taselisib
have demonstrated encouraging efficacy in early-phase
trials, with modest toxicity. Two ongoing placebo-controlled
phase III trials are evaluating the potential improvement in
PFS with the addition of alpelisib (SOLAR-197) or taselisib
(SANDPIPER98) to fulvestrant among patients with HR+
metastatic breast cancer, and neoadjuvant trials in combi-
nation with AIs are also ongoing (the buparlisib arm of the
NeoORB study was recently closed based on results from
BELLE-2). More details regarding ongoing studies are pro-
vided in Table 1. Results are eagerly awaited.
Inhibition of CDK4/6
Three CDK4/6 inhibitors (palbociclib, ribociclib, and abe-
maciclib) are in advanced clinical testing, and palbociclib has
regulatory approval for treatment of metastatic breast
cancer. Palbociclib and ribociclib are given on a 3-week-on,
1-week-off schedule, and abemaciclib is given continuously.
A number of studies are evaluating CDK4/6 inhibitors in the
neoadjuvant, adjuvant, and metastatic settings, as sum-
marized in Table 1. The results of pivotal trials and key
planned trials are summarized here.
PALOMA-1 was a phase II trial that randomly selected 165
postmenopausal women with untreated HR metastatic
breast cancer to receive letrozole with or without palbociclib.99
Progression-free survival with combination therapy was
20.2 months vs. 10.2 months in the control arm (HR 0.49;
95% CI 0.3190.748; p = .0004). The trial was not powered
to evaluate OS, which was similar between the two arms.
The primary toxicity was at least grade 3 neutropenia,
occurring in 54% of patients, with no cases of febrile
neutropenia; 13% of patients in the study arm dis-
continued therapy due to adverse events.
Based on this data, in 2015, the U.S. Food and Drug Ad-
ministration (FDA) granted accelerated approval for pal-
bociclib and letrozole for the first-line treatment of
postmenopausal patients with HR+ metastatic breast can-
cer. PALOMA-2 is a phase III trial designed to validate these
findings; data are expected to be presented at the 2016
ASCO Annual Meeting.100
PALOMA-3, a phase III trial, randomly selected 521 women
with advanced pretreated breast cancer 2:1 to treatment
with palbociclib and fulvestrant versus fulvestrant and
placebo.101 Progression-free survival was significantly im-
proved in the combination arm versus placebo (9.2 months vs.
3.8 months; HR 0.42; 95% CI, 0.320.56; p , .001). Pre-
menopausal women with ovarian suppression and pa-
tients with one line of prior chemotherapy appeared to

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have similar benefit. Toxicity was similar to PALOMA-1, al-
though only 2.6% of patients discontinued treatment due to
adverse events. Fulvestrant and palbociclib were approved
by the FDA in early 2016.
An international adjuvant trial of 4,600 patients is compar-
ing 2 years of treatment with palbociclib versus placebo
(PALLAS),102 and PENELOPE-B103 is studying 1 year of palbo-
ciclib as postneoadjuvant therapy for high-risk patients. Nu-
merous other trials are evaluating palbociclib as neoadjuvant
therapy compared with capecitabine in metastatic disease
(PEARL)104 and following chemotherapy, among others.
Ribociclib is a similar CDK4/6 inhibitor that is being studied
in the metastatic and neoadjuvant settings in the ongoing
MONALEESA trials.105,106 In addition, ongoing studies are
evaluating ribociclib combined with exemestane and ever-
olimus,107 and letrozole and the PI3K inhibitor alpelisib.108
Abemaciclib is a potent inhibitor of CDK4, more than CDK6,
and is the only agent in this class that can be given con-
tinuously. A phase IB trial including 47 patients demon-
strated single-agent activity with a clinical benefit rate of
61.1%,109 leading to the single agent MONARCH-1 trial of
patients with heavily pretreated HR+ metastatic breast
cancer; data are expected to be presented at the 2016 ASCO
Annual Meeting.110 An expansion cohort of the phase IB trial
evaluated abemaciclib plus fulvestrant; the clinical benefit
rate was 72.2%.111 The most common toxicity from abe-
maciclib is diarrhea, with a lower incidence of neutropenia.
Additional ongoing MONARCH trials are evaluating abe-
maciclib in the neoadjuvant setting,105 in metastatic disease
in combination with fulvestrant,112 or nonsteroidal AIs113 in
brain metastases114 and in HER2+ disease.112
Inhibition of FGFR
Dovitinib, an oral tyrosine kinase inhibitor of FGFR, has been
shown to have both preclinical and clinical efficacy.28 In a
study of 81 patients, five patients with tumor FGFR ampli-
fication experienced clinical benefit at 6 months. These
results prompted further trials with dovitinib and hormonal
therapy combinations, although toxicity is a limiting fac-
tor.115 Lucitanib is a FGFR/VEGFR tyrosine kinase inhibitor
with encouraging phase IB response data under evaluation
in a phase II single-agent trial.116 Toxicity is again limiting,
including hypertension, proteinuria, and transaminitis.
Inhibition of HDAC
A randomized phase II trial evaluated the addition of enti-
nostat or placebo to exemestane for 130 women with ad-
vanced breast cancer.117 Progression-free survival was
slightly improved in those receiving entinostat compared
with placebo (4.3 vs. 2.3 months; p = .055), but the ex-
ploratory endpoint of OS was significantly improved (28.1 vs.
19.8 months; HR 0.59; 95% CI, 0.360.97; p = .036), leading
to breakthrough drug status by the FDA. Interestingly,
protein lysine hyperacetylation in the entinostat biomarker
subset was associated with prolonged PFS. Fatigue and
neutropenia were the most common grade 3 or worse
IMPROVING RESPONSE TO HORMONE THERAPY
toxicities; 11% of patients discontinued due to adverse
events. A phase III trial, E2112, with a similar design is
ongoing (Table 1).118
Azacitidine, a DNA methylation inhibitor, is also being
investigated in breast cancer with hormonal therapy119 and
entinostat.120
Inhibition of IGFR
A number of IGFR inhibitors have been studied in the clinic, with
generally disappointing results to date. A randomized phase II
trial evaluated the benefit of adding ganitumab to either ful-
vestrant or exemestane as second-line therapy for 156 patients
with metastatic HR+ breast cancer.121 There was no difference
in PFS (3.9 months for the ganitumab arm vs. 5.7 months for
placebo). New agents that do not cause hyperglycemia may
offer advantages; the monoclonal antibody BI 836845 is being
studied in combination with everolimus and exemestane in a
randomized phase II trial based on promising phase I results.107
Inhibition of Angiogenesis
Although not currently in the clinical arena, a discussion of
this approach is important. Two randomized phase III trials
evaluated the potential efficacy from adding bevacizumab,
the VEGF antibody, to first-line hormone therapy with
letrozole or fulvestrant.122,123 Both trials demonstrated im-
provement in PFS comparing letrozole or fulvestrant plus
bevacizumab with hormone therapy alone, although only the
CALGB trial found this difference to be statistically significant
(LEA trial: 19.3 vs. 14.4 months; HR 0.83; 95% CI, 0.651.06;
p = .126; CALGB 40503: 20 vs. 16 months; HR 0.75; 95% CI,
0.590.96; p = .016); no difference was seen in OS. Adverse
events included at least grade 3 hypertension and proteinuria.
Further combined biomarkers analysis is ongoing.
Immune Checkpoint Inhibition
Based on the expression of PD-L1 in HR+ breast cancer, there
has been interest in evaluating the efficacy of this approach
in the advanced disease setting. Pembrolizumab, a PD-1
antibody, was tested in a number of solid malignancies in the
phase IB KEYNOTE-28 trial.124 Out of 248 patients who had
tissue available for screening, 48 (19.4%) had at least 1%
staining for PD-L1. The overall response rate among 25
treated patients was 12%, with a clinical benefit rate of 20%.
The median time to response was 8 weeks, and the median
duration of response had not yet been reached.
The phase IB Javelin trial evaluated the efficacy of the anti-
PD-L1 antibody avelumab for patients with metastatic solid
tumors, including breast cancer.125 Out of the 72 patients
with HR+ disease, an objective response was seen in only
2.8%, but 54% were found to have PD-L1 expression. This
brings into question the antibodies used for PD-L1 testing as
well as potential differences in efficacy between different
checkpoint inhibitors.
Overall, therapy was well tolerated in both trials, with
the primary toxicity reversible and immune related (e.g.,
thyroid disorders, hepatitis). Further studies will evaluate
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RUGO, VIDULA, AND MA
combination therapy with agents that could increase
expression of neo-antigens (such as HDAC inhibitors), and
therefore enhance immunogenicity.
CONCLUSION
Progress in the understanding of endocrine resistance
mechanisms has led to the development of a number of
agentssome approved and many in clinical trialsto
target growth factor receptor signaling, PI3K/Akt/mTOR,
CDK4/6, HDAC, and immune checkpoints, among others.
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152. NCT02297438. A study of palbociclib (PD-0332991) 1 letrozole vs.
placebo1 letrozole for 1st line treatment of Asian postmeno-
pausal women with ER1/HER2- advanced breast cancer [PALOMA-4].
https://clinicaltrials.gov/ct2/show/NCT02297438. Accessed March
26, 2016.
153. NCT02296801. A phase II randomized study evaluating the biological
and clinical effects of the combination of palbociclib with letrozole
as neoadjuvant therapy in post-menopausal women with estrogen-
receptor positive primary breast cancer (PALLET). https://clinicaltrials.
gov/ct2/show/NCT02296801. Accessed March 26, 2016.
154. NCT02690480. Comparison of efficacy and tolerability of fulvestrant1
placebo vs fulvestrant1palbociclib as first line therapy for post-
menopausal women with HR1 metastatic BC treated with 5 years of
hormonal therapy remaining disease free more than 12 months after
completion or have de novo metastatic disease (FLIPPER). https://
clinicaltrials.gov/ct2/show/NCT02690480. Accessed March 26, 2016.
155. NCT02491983. Study to evaluate the efficacy and safety of palbociclib
in combination with fulvestrant or letrozole in patients with ER1,
HER2- locally advanced or metastatic breast cancer (PARSIFAL). https://
clinicaltrials.gov/ct2/show/NCT02491983. Accessed March 26, 2016.
156. NCT02384239. A study of palbociclib in combination with fulvestrant
or tamoxifen as treatment for metastatic breast cancer. https://
clinicaltrials.gov/ct2/show/NCT02384239. Accessed March 26, 2016.
157. NCT02592746. A study of palbociclib with exemestane plus goserelin
versus capecitabine in premenopausal women with HR1 MBC. https://
clinicaltrials.gov/ct2/show/NCT02592746. Accessed March 26, 2016.
158. NCT02675231. A study of abemaciclib (LY2835219) in women with
HR1, HER21 locally advanced or metastatic breast cancer (monarcHER).
https://clinicaltrials.gov/ct2/show/NCT02675231. Accessed March
26, 2016.
159. NCT02422615. Study of efficacy and safety of LEE011 in postmenopausal
women with advanced breast cancer (MONALEESA-3). https://clinicaltrials.
gov/ct2/show/NCT02422615. Accessed March 26, 2016.
BREAST CANCER

Treatment of Premenopausal
Women With Endocrine-Sensitive
Breast Cancer

CHAIR
Nancy E. Davidson, MD
University of Pittsburgh Cancer Institute
Pittsburgh, PA

SPEAKERS
Hatem A. Azim Jr., MD, PhD
Institut Jules Bordet
Brussels, Belgium

Kathryn J. Ruddy, MD, MPH

Mayo Clinic
Rochester, MN
 TREATING PREMENOPAUSAL ENDOCRINE-SENSITIVE BREAST CANCER

Challenges in Treating Premenopausal Women with

Endocrine-Sensitive Breast Cancer
Hatem A. Azim Jr., MD, PhD, Nancy E. Davidson, MD, and Kathryn J. Ruddy, MD, MPH

OVERVIEW

For the hundreds of thousands of premenopausal women who are diagnosed annually with endocrine-sensitive breast
cancer, treatment strategies are complex. For many, chemotherapy may not be necessary, and endocrine therapy decision
making is paramount. Options for adjuvant endocrine regimens include tamoxifen for 5 years, tamoxifen for 10 years,
ovarian function suppression (OFS) plus tamoxifen for 5 years, and OFS plus an aromatase inhibitor for 5 years. There are
modest differences in efficacy between these regimens, with a benefit from OFS most obvious among patients with higher-risk
disease; therefore, choosing which should be used for a given patient requires consideration of expected toxicities and
patient preferences. An aromatase inhibitor cannot be safely prescribed without OFS in this setting. Additional research is
needed to determine whether genomic tests such as Prosigna and Endopredict can help with decision making about
optimal duration of endocrine therapy for premenopausal patients. Endocrine therapy side effects can include hot flashes,
sexual dysfunction, osteoporosis, and infertility, all of which may impair quality of life and can encourage nonadherence
with treatment. Ovarian function suppression worsens menopausal side effects. Hot flashes tend to be worse with
tamoxifen/OFS, whereas sexual dysfunction and osteoporosis tend to be worse with aromatase inhibitors/OFS. Preg-
nancy is safe after endocrine therapy, and some survivors can conceive naturally. Still, embryo or oocyte cryopreservation
should be considered at the time of diagnosis for patients with endocrine-sensitive disease who desire future childbearing,
particularly if they will undergo chemotherapy.

I n the United States, approximately 20% of patients with

breast cancer are diagnosed before age 50.1 This translates
into almost 50,000 new patients per year, which well ex-
ceeds the total number of women diagnosed with acute
leukemia and brain and stomach cancers in all ages com-
bined.1 A higher proportion of patients with breast cancer
are diagnosed at a younger age in other parts of the world,
such as Africa and the Middle East, where the average age of
developing breast cancer hardly exceeds 50.2
Over the past decade, several studies have indicated
that diagnosis at a younger age is associated with poorer
prognosis,3-5 especially for women with endocrine-sensitive
disease.3,5 Compared with patients with breast cancer who
are postmenopausal, younger patients are more commonly
diagnosed with highly proliferative estrogen receptor
positive tumors (i.e., luminal-B breast cancer).6 Further-
more, these tumors are enriched for molecular aberrations
that could render them more aggressive, including high
expression of stem cell markers and high prevalence of
GATA3 mutations,3,7 the latter of which has been implicated
in endocrine resistance. In addition, younger patients often
have unique challenges, most notably fertility-related issues,
poorer perceived quality of life, and difficulties adhering
to prescribed endocrine therapy. Therefore, treating pre-
menopausal women with early breast cancer, particularly
those with endocrine-sensitive disease, is rather complex.
HOW TO CHOOSE ENDOCRINE THERAPY FOR
PREMENOPAUSAL PATIENTS?
In recent years, several trials have evaluated different
strategies of adjuvant endocrine therapy for premenopausal
patients. These include tamoxifen for 5 years, tamoxifen for
10 years, OFS plus tamoxifen for 5 years, and OFS plus an
aromatase inhibitor for 5 years. As reviewed below, modest
differences between these options in terms of long-term
outcome have been reported. These approaches have different
toxicity profiles. Deciding which approach should be used for
a given patient requires consideration of risk of recurrence,
fertility considerations, and patient preferences regarding
expected toxicities.8 Unfortunately, premenopausal patients
with breast cancer have been found to have poor persistence

From the Department of Medicine, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium; University of Pittsburgh Cancer Institute and UPMC Cancer Center, Pittsburgh,
PA; Department of Oncology, Mayo Clinic, Rochester, MN.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Hatem A. Azim Jr., MD, PhD, Institut Jules Bordet, Boulevard de Waterloo, 121, 1000 Brussels, Belgium; email: hatemazim@icloud.com.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 23

AZIM, DAVIDSON, AND RUDDY
with endocrine therapy.9,10 Some studies have shown that only
50% of women complete the 5 years of scheduled tamoxifen.9
Therefore, it is very important for clinicians to engage young
patients in therapeutic decision making and to discuss toxicities
and expectations. Salient points pertaining to the use of the
different endocrine therapy options are discussed in this article.
Figure 1 summarizes a schema to help optimize treatment
decisions in daily practice.
Value of Ovarian Function Syndrome
Induction of amenorrhea for premenopausal patients with
endocrine-sensitive breast cancer has consistently been
shown to reduce risk of recurrence.11,12 This is true for OFS
by luteinizing hormone-releasing hormones (LHRH) agonists
or surgical or radiation ablation. However, because adjuvant
tamoxifen was not routinely administered to patients who
were premenopausal until the early 2000s, uncertainty
remained regarding the benefit of amenorrhea induction in
the presence of tamoxifen. Within the last several years, two
studies have provided important insights on this issue. The
first is the E-3193, INT-0142 trial, which randomly assigned
node-negative, estrogen receptorpositive patients to ta-
moxifen or OFS plus tamoxifen, both given for 5 years.13 This
KEY POINTS
Several adjuvant endocrine therapy options are
currently available for premenopausal patients with
endocrine-responsive early-stage breast cancer, and it
can be challenging to decide which is best for a given
patient.
Recent evidence from randomized trials indicates that a
substantial proportion of premenopausal women with
early-stage breast cancer can achieve excellent
outcomes with endocrine therapy only, in the absence
of chemotherapy, challenging the notion that adjuvant
chemotherapy should be considered in all young
patients with breast cancer.
Careful attention must be paid to the toxicities of
endocrine therapies including hot flushes, sexual
dysfunction, osteoporosis, and infertility, which could all
reduce adherence to endocrine therapy and
detrimentally impact patients quality of life.
Pregnancy following endocrine-responsive breast
cancer is safe, although challenges exist in the era of
extended adjuvant therapy. A prospective trial currently
is addressing the feasibility of temporary interruption of
endocrine treatment to allow pregnancy.
Embryo or oocyte cryopreservation prior to
chemotherapy is the best option to preserve fertility for
premenopausal patients with breast cancer, even those
who have endocrine-sensitive disease. Evolving data
suggest that LHRH agonists could reduce risk of
chemotherapy-induced amenorrhea and, thus, may
serve as a valid alternative to embryo or oocyte
cryopreservation if these are not feasible.
24 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
study did not accrue as planned, and it closed early with only
345 patients. Notably, 85% of patients had T1 disease and,
per protocol, none were treated with adjuvant chemo-
therapy. This underpowered study showed no difference in
10-year disease-free survival (DFS; 85.9% vs. 87.1%; p = .62)
or overall survival (OS; 92.5% vs. 92.4%; p = .67) between
both arms. The Suppression of Ovarian Function Trial (SOFT)
was a larger, properly powered trial that included 2,033
patients who were randomly assigned to either tamoxifen
with OFS or tamoxifen alone.14 In this trial, the main analysis
indicated no significant difference in 5-year DFS between the
OFS plus tamoxifen and tamoxifen alone arms (84.7% vs.
86.6%; p = .10). Subgroup analyses suggested a benefit with
the addition of OFS in women who had received chemo-
therapy (who were more likely to have node-positive dis-
ease) and those younger than age 35 at diagnosis. Of those
diagnosed with breast cancer younger than age 35 (94% of
whom received chemotherapy), the proportion who were
free of breast cancer for at least 5 years was 67.7% with
tamoxifen alone and 78.9% with tamoxifen with OFS, sug-
gesting that OFS cut the risk of recurrence by approximately
one-third in this group.
These results underscore several important points. First,
endocrine therapy alone, without chemotherapy, is a very
effective option for selected premenopausal women with
early-stage breast cancer. Second, in older premenopausal
women with low-risk early-stage breast cancer, OFS adds
little if any benefit to 5 years of tamoxifen. Finally, induction
of amenorrhea is therapeutic for younger premenopausal
patients with higher-risk disease.
Tamoxifen Versus Aromatase Inhibitors
In the postmenopausal setting, aromatase inhibitors have
largely replaced tamoxifen as the standard endocrine adju-
vant therapy.15 Among premenopausal patients, the final
results of the ABCSG-12 trial did not show a difference in DFS
between tamoxifen and anastrozole when administered for
3 years in combination with LHRH agonists, but OS was inferior
in the aromatase inhibitor arm.16 This raised concerns about
the use of aromatase inhibitors with OFS among pre-
menopausal patients. Recently, the results of a joint analysis
of the long-awaited SOFT and TEXT trials were published.17 In
total, 4,690 women were randomly assigned to receive either
tamoxifen or exemestane in addition to OFS for 5 years.
Approximately 40% of patients had node-positive disease and
nearly 50% received adjuvant chemotherapy. The results
demonstrated a 28% reduction in DFS hazard ratio (HR) at
5 years with exemestane compared to tamoxifen (91.1% vs.
87.3%, p , .001), with no difference in OS.
Although in line with the hypothesis and results observed
in the postmenopausal setting, the results of this pooled
analysis contrasted with those observed in the ABCSG-12
trial. However, it is important to note that the ABCSG-12 trial
was smaller in size and administered therapy for only
3 years, which does not reflect todays standard practice. An
unplanned analysis of ABCSG-12 suggested that the worse

FIGURE 1. Schema to Guide Decision Making of Primary Systemic Therapy of Premenopausal Women With
Endocrine ReceptorPositive (HER-Negative) Breast Cancer
Abbreviations: AI, aromatase inhibitor; ER, estrogen receptor; LHRH, luteinizing hormone-releasing hormone; OFS, ovarian function suppression; PR, progesterone receptor; y, years.
*No evidence on extended adjuvant therapy in women treated with adjuvant OFS/AI during first 5 years.
**Clinical utility of genomic tests to guide extended endocrine therapy is yet to be proven.
outcome observed in the aromatase inhibitor arm was re-
stricted to patients who were overweight or obese18; these
patients constituted nearly one-third of the study population.
This was hypothesized to reflect incomplete estrogen level
suppression by aromatase inhibitor for these women, which
has been seen among postmenopausal patients who were
obese,19 or incomplete ovarian suppression by LHRH agonists
in larger patients. Research is limited regarding the impact of
body weight on the efficacy of OFS, but it is possible that
surgical or radiation ablation would be more effective than
LHRH agonists in women who are overweight and obese.20
Alternatively, cross talk between estrogen signaling and in-
sulin growth factor signaling may play a role in the impact of
weight on the efficacy of OFS and AI.21 A randomized pro-
spective study from Japan in the neoadjuvant setting showed
superiority of aromatase inhibitor plus OFS over tamoxifen
plus OFS with a near doubling of clinical response rate on
MRI.22 However, in this study, only 17% of patients were
overweight or obese. Correlation between body mass index
(BMI) and outcome in the joint analysis of SOFT and TEXT is yet
to be published, but high BMI was shown to be associated
with high on-treatment estradiol levels in SOFT patients
randomly assigned to exemestane and OFS.23 Although most
SOFT patients maintained a low estradiol level on treatment,
34% of patients on OFS and aromatase inhibitor had high
estradiol levels at some point during the 12 months after
study initiation. No correlation with long-term outcome was
seen, perhaps because of the small number of patients in this
analysis (86 patients on LHRH agonist plus exemestane).
TREATING PREMENOPAUSAL ENDOCRINE-SENSITIVE BREAST CANCER
Thus, although the combination of OFS and exemestane
may be the most effective 5-year endocrine therapy regi-
men, adequate suppression of estradiol levels appears to be
more challenging for patients who are overweight or obese,
in whom ABCSG-12 suggests that OFS with tamoxifen may
produce equal if not better outcomes. Yet it is unclear
whether measurement of estradiol levels during LHRH ag-
onists therapy will be clinically useful in guiding the choice of
adjuvant endocrine therapy in daily practice.24
One final point that should be underscored is the very
favorable outcome of the 50% of women in the joint analysis
who did not receive adjuvant chemotherapy. Although these
patients were mostly low risk by virtue of stage, their 5-year
DFS was greater than 93%. Because the benefit of adjuvant
chemotherapy is largely a reduction in risk of recurrence
during the first few years after diagnosis, it is likely that
chemotherapy would not have been beneficial in the ma-
jority of these patients. These results strongly challenge the
notion that young premenopausal women should be offered
more chemotherapy, and they indicate that endocrine
therapy alone remains a very effective option for a large
fraction of young patients with endocrine-sensitive breast
cancer.
10-Year Versus 5-Year Schedule
Unlike estrogen receptornegative tumors, endocrine-
sensitive cancers have a propensity for late relapse. 25
Therefore, extending treatment beyond 5 years seems
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 25
AZIM, DAVIDSON, AND RUDDY

logical to improve the outcomes of these patients. In the
ATLAS and aTTom trials,26,27 taking tamoxifen for 10 years
was shown to be superior to the standard 5-year schedule,
and benefit was observed independent of menopausal
status. Given the established role of aromatase inhibitors in
treating postmenopausal women during the first 5 years,
these results appear to be most relevant for the treatment
of premenopausal women for whom tamoxifen is still
considered a mainstay treatment. Another study, MA17,
which previously showed the added benefit of extended
therapy with letrozole after 5 years of tamoxifen, demon-
strated that this benefit is mostly observed in women who
were premenopausal at the time they initiated tamoxifen
but became postmenopausal during its administration.28
These results in aggregate underscore the value of con-
sidering extending endocrine therapy to 10 years for pre-
menopausal women. However, the question remains as to
whether all women need this approach. This question is
relevant as prolonged treatment increases toxicity and could
impair quality of life. Acknowledging the adherence issues
highlighted earlier, it is important to define tools that can
identify the subsets of patients who will benefit the most
from this approach and spare others the burden of long-term
treatment.
Recently, several genomic tests, particularly Prosigna and
Endopredict, have been evaluated for their ability to predict
long-term recurrence in women who were treated with
5 years of adjuvant endocrine therapy in the context of
randomized phase III trials.29-31 Notably, these trials were
conducted among postmenopausal women and genomic
testing was not part of the initial study plan. In the ABCSG-8
trial, which randomly assigned postmenopausal patients to
receive either tamoxifen or anastrozole, approximately
1,300 patients were free of relapse at completion of 5 years
of endocrine therapy and were analyzed by Prosigna test-
ing.29 None of these patients received adjuvant chemo-
therapy and 30% were node-positive. Thirty-seven percent
of patients were classified as low risk by the genomic test, of
whom only 2.4% developed distant recurrence. In contrast,
17.5% of the 30% of patients classified as high risk developed
distant recurrence between years 5 and 15. Similar results
were observed in a combined analysis of the ABCSG-8 and
ATAC datasets.30 Endopredict showed comparable findings
when tested on the ABCSG-6 and ABCSG-8 trial. In 1,702
patients free of relapse after 5 years of endocrine therapy,
Endopredict identified 64% as low risk, with an absolute risk
of recurrence of 1.8% at 10 years.31
Thus, it appears that extending endocrine therapy beyond
5 years for women in the low-risk group category is very
unlikely to add any benefit because their risk of recurrence is
negligible. On the other hand, extended therapy could be more
useful for patients classified as high risk. Of note, none of these
studies included premenopausal patients, yet data with other
genomic tests such as Oncotype Dx32 and an in silico analysis3
indicated that the prognostic performance of genomic tests
is largely comparable irrespective of age. Currently, several
studies investigating extended endocrine therapy have yet to
report, and thus validation of the role of genomic tests to
inform on the benefit of this approach is warranted. Until then,
no solid statements could be made regarding their role in
guiding the use of extended endocrine therapy.
TOXICITIES OF ENDOCRINE THERAPY FOR
PREMENOPAUSAL WOMEN
Premenopausal women with breast cancer who require
endocrine therapy are vulnerable to a variety of treatment
toxicities. Although excess tamoxifen-associated uterine
cancer diagnoses and thromboembolic events have not been
observed among patients younger than age 50, some side
effects of endocrine therapy are more severe for young
patients, particularly if OFS is used. These side effects are
discussed below.
Hot Flashes
Hot flashes are problematic for the majority of young re-
cipients of adjuvant endocrine therapy,33 especially with the
addition of OFS,34 and perhaps more substantially with
tamoxifen than aromatase inhibitors. These hot flashes
often are accompanied by night sweats, which can interrupt
sleep and impair quality of life. In 345 young women enrolled
in the E-3193, INT-0142 phase III trial, grade 3 hot flashes
occurred in 4.7% of those receiving tamoxifen monotherapy
compared with 16.1% of those receiving tamoxifen with
OFS.13 In SOFT, grade 3 or 4 hot flashes occurred in 7.6% of
patients assigned to receive tamoxifen, compared with
13.2% of those assigned to OFS and tamoxifen.14 However,
the use of an aromatase inhibitor instead of tamoxifen with
OFS was associated with less sweating (reported by 54.5%
vs. 59%, respectively).17
Sexual Dysfunction
In contrast, sexual dysfunction is most severe for patients
who received an aromatase inhibitor with OFS.17 In the TEXT
trial, 52.4% of 2,318 women who received exemestane with
OFS and 47.4% of 2,325 women who received tamoxifen
with OFS had vaginal dryness. Forty-five percent of the
exemestane/OFS group and 40.9% of the tamoxifen/OFS
group had decreased libido, although dyspareunia was re-
ported in 30.5% and 25.8%, respectively. Of note, ovarian
dysfunction secondary to chemotherapy can cause similar
vaginal symptoms and sexual dysfunction.35 Tamoxifen
alone is less problematic,13 and it may even improve vaginal
dryness in some survivors by causing vaginal discharge.34
Sexual dysfunction in survivors of breast cancer can be
compounded by body image issues associated with local
therapies and the weight gain that many experience during
systemic chemotherapy.
Depression and Cognitive Dysfunction
SOFT results showed a nonstatistically significant trend
toward more mood impairment in those who received ta-
moxifen with OFS than in those who received tamoxifen

26 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


monotherapy, with depressive symptoms identified in
51.9% and 46.6%, respectively.14 An aromatase inhibitor
does not appear to cause more depression than tamoxifen.17
Treatment of depression can be complex for patients re-
ceiving tamoxifen because of concerns that certain anti-
depressants (e.g., fluoxetine, paroxetine, and sertraline)
may reduce the efficacy of tamoxifen by inhibiting
CYP2D6.36,37 One study found that survivors of breast cancer
who took paroxetine with tamoxifen had increased breast
cancer mortality, although another study identified no im-
pact of CYP2D6 inhibitor use on recurrence risk for patients
taking tamoxifen. Possibly, the CYP2D6 genotype is partic-
ularly relevant for tamoxifen efficacy for premenopausal
patients,38 but definitive studies of this issue are needed.
Cognitive dysfunction related to endocrine therapy is
understudied among premenopausal patients. However, in
the ZIPP trial, patient self-evaluation of memory and con-
centration was similar for patients with breast cancer who
received chemotherapy with or without goserelin, goserelin
plus tamoxifen, or tamoxifen alone.34 In addition, pre-
liminary results at 1 year from 86 of a planned 321 par-
ticipants in the cognitive function substudy of SOFT
demonstrated no worse objective cognitive function in
those who received tamoxifen plus OFS compared with
tamoxifen monotherapy.39
Bone Health
Tamoxifen is known to improve bone mineral density for
postmenopausal women, but it can thin bones in pre-
menopausal women.40 This is likely because of its mixed
agonist/antagonist effect on estrogen receptor. Therefore,
bone loss is a concern in most young patients with breast
cancer, not just in those who experience chemotherapy-
related premature menopause or receive OFS. A recent
study of survivors of breast cancer who were premenopausal
at the time of breast cancer diagnoses and had no known
history of osteoporosis revealed a 12% fracture risk during a
median 3.1-year follow-up after the completion of 56 years
of endocrine therapy. This was similar to the 15% fracture
risk this study identified in survivors of postmenopausal
breast cancer.41 However, the fractures in survivors of
premenopausal breast cancer were more commonly toe/
finger fractures, although those in postmenopausal women
were more commonly hip fractures. The median time to
first fracture was shorter in premenopausal than in post-
menopausal women (1.4 vs. 2.4 years; p = .01). Zoledronic
acid has been proven an effective preventative agent against
bone loss in this population.42,43 The lifetime fracture risk of
young recipients of endocrine therapy deserves additional
study in the new era of increased use of OFS and prolonged
duration of treatment.
Cardiovascular Toxicity
Although it occurs at low frequency in young patients,
cardiovascular toxicity also must be considered. Hyperten-
sion developed more frequently in SOFT participants who
TREATING PREMENOPAUSAL ENDOCRINE-SENSITIVE BREAST CANCER
received OFS with tamoxifen compared with those who
received tamoxifen monotherapy,14 identified in 23.3%
versus 17.2% of patients, respectively. But among TEXT
and SOFT participants who received OFS, hypertension
was equally likely with tamoxifen versus exemestane.17
Thrombosis or embolism occurred in 2.2% (95% CI, 1.62.8)
of patients who received OFS plus tamoxifen and 1.0% (95%
CI, 0.71.5) of those who received OFS plus aromatase
inhibitors.17
PREGNANCY AFTER ESTROGEN
RECEPTORPOSITIVE BREAST CANCER: SAFETY
AND FEASIBILITY IN THE ERA OF EXTENDED
ADJUVANT THERAPY
Infertility remains a main concern for young patients with
breast cancer. A recent prospective study including more
than 600 patients demonstrated that up to 50% of young
patients with breast cancer are concerned about infertility,
and, in a substantial fraction, this has an impact on treat-
ment decisions.44
The safety of subsequent pregnancy in women with a
history of estrogen receptorpositive breast cancer con-
tinues to be an area of concern. In a recent survey, ap-
proximately 40% of oncologists believed that hormonal
changes secondary to pregnancy could increase risk of re-
currence particularly during the first 2 years after cancer
diagnosis.45 Although this question has been addressed in
several studies over the past 3 to 4 decades,46-48 definitive
answers were complicated by lack of information on es-
trogen receptor status in many of these studies and
methodological concerns about patient selection. In 2013, a
large multicenter study was published in which the long-
term outcome of 333 women who became pregnant after
breast cancer diagnosis was compared with 874 survivors of
breast cancer who did not become pregnant.49 Both groups
were matched according to relevant tumor characteristics
and use of adjuvant systemic therapy. The primary endpoint
was 5-year DFS of the estrogen receptorpositive cohort. In
this cohort, which comprised 194 pregnant and 492 non-
pregnant patients, no difference in 5-year DFS was observed
by pregnancy status (HR 0.91; 95% CI, 0.671.24; p = .55).
Secondary endpoints, which included DFS in estrogen
receptornegative patients and OS, also did not differ be-
tween the pregnant and nonpregnant groups. These results
underscore the safety of pregnancy following breast cancer
irrespective of the estrogen receptor status of the primary
tumor. Similar to other studies,47 approximately 30% of
patients underwent abortion in this study. A preplanned
subgroup analysis showed that abortion did not have any
impact on patient prognosis, indicating that abortion should
not be recommended for therapeutic purposes.
However, with the increasing use of long-term endocrine
therapy up to 10 years, the feasibility of becoming pregnant
after completion of 510 years of endocrine therapy is a
major challenge. This raises the question of whether tem-
porary interruption of endocrine therapy to allow pregnancy
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 27
AZIM, DAVIDSON, AND RUDDY
is safe. This approach is sometimes considered in selected
cases, particularly for patients with low risk of recurrence or
advanced age at the time of diagnosis. Presently, it is not
known whether this approach is detrimental because it was
not investigated in any of the reported studies. As such, the
first international prospective trial (POSITIVE) was recently
launched to address the safety of temporary interruption of
endocrine therapy to allow pregnancy in young women
with estrogen receptorpositive breast cancer who wish to
become pregnant.50 This trial allows patients to receive
1830 months of endocrine therapy. Patients with adequate
ovarian function can temporarily interrupt endocrine therapy
for up to 2 years to allow pregnancy with or without breast-
feeding. Afterward, they are encouraged to resume endocrine
therapy for a total course of 510 years according to local
practice. POSITIVE is sponsored by the International Breast
Cancer Study Group and is performed in collaboration with
ALLIANCE in the United States. This study is expected to recruit
approximately 500 patients, which would provide solid evi-
dence for the safety and feasibility of endocrine therapy in-
terruption to allow pregnancy.
ASSISTED REPRODUCTION TO BECOME
PREGNANT AFTER BREAST CANCER: TIMING
AND IMPACT ON OUTCOME
Given the progressive decline in ovarian function with age51
and the detrimental impact of chemotherapy on ovarian
function,52 fertility preservation must be considered and
offered soon after breast cancer diagnosis to improve the
chances of future conception. Ovarian stimulation for oocyte
or embryo cryopreservation is a standard procedure. It is
currently endorsed by several guidelines for patients who
are newly diagnosed with breast cancer and are also con-
sidering future pregnancy.53-55 However, several concerns
hinder the wide application of this approach.
Potential Delay of Adjuvant Systemic Therapy
Optimally, ovarian stimulation should be performed before
the initiation of adjuvant therapy to precede the de-
struction of oocytes by cytotoxic agents. Standard stimu-
lation protocols are classicaly applied during the first days
of the menstrual cycle, which can result in a delay in ini-
tiation of chemotherapy as some woman can have to wait
up to 3 weeks for stimulation. Such a delay could be po-
tentially detrimental to patient outcome because the in-
terval between surgery and initiation of chemotherapy is
crucial, particularly in treating young patients with breast
cancer.56 Over the past 5 years, several studies were
published on random stimulation protocols, in which ovarian
stimulation is performed at any time during the menstrual
cycle.57-59 The number of days required for ovarian stimu-
lation is slightly longer using the random protocol, on av-
erage 1 to 2 days more, yet the oocyte yield is almost
identical. This approach increases the feasibility of per-
forming ovarian stimulation prior to starting systemic
therapy without substantial delay.
28 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Potential Detrimental Impact on Breast Cancer
Outcome Particularly in Patients With Estrogen
ReceptorPositive Disease
This is perhaps the greatest concern when considering assisted
reproduction in young patients with breast cancer, as this
procedure is associated with significant rise in serum estradiol
levels. Despite the fact that estradiol peaks only last for a few
days, defining protocols that would reduce estradiol peaks
without majorly compromising oocyte yield is desirable. Oktay
et al have performed a series of studies investigating the
addition of letrozole to standard ovarian stimulation protocols
to reduce estradiol peaks.60,61 They showed that this strategy
was associated with a comparable oocyte yield and significantly
lower estradiol peaks. In one study, the mean estradiol level at
human chorionic gonadotropin (known as hCG) triggering was
483.4 pg/mL with letrozole compared with 1,464 pg/mL for
the standard protocol (p , .001), with similar numbers of
mature oocytes (8.7 vs. 9.7; p = .43) and fertilization rates
(74.1% vs. 73.2%; p = .71). In addition, there was no difference
in days needed for stimulation, which was approximately
12 days.61 Other studies have confirmed these results.62,63 In
terms of fertility and pregnancy outcome, recent results from
131 patients with breast cancer who underwent ovarian
stimulation with letrozole before initiating adjuvant chemo-
therapy showed that 40 patients attempted to transfer
embryos back at an average time of 5.2 years following initial
embryo cryopreservation. The overall live birth rate was 45%,
which is comparable to figures observed in the general pop-
ulation of women of the same age. Importantly, no congenital
malformations were observed in 25 children after a mean
follow-up of 40 months.64
To provide more robust evidence regarding the safety of
this approach, a prospective study was initiated to eval-
uate the association between using ovarian stimulation
with letrozole and long-term breast cancer outcome.62 In
this study, 337 young patients with breast cancer (median
age 35) were included, of whom 120 underwent ovarian
stimulation with letrozole. At a median follow-up of
5 years, there was no difference in DFS between patients
who underwent stimulation and those who did not.65 No-
tably, in this study, patients who underwent stimulation
initiated adjuvant chemotherapy later compared with the
control group (45 days vs. 33 days; p , .01). This is not
unexpected because this study did not offer random stimu-
lation protocols. A subsequent analysis investigating patient
outcome according to the number of ovarian stimulation
cycles (one vs. two cycles) showed no difference in patient
prognosis with better fertility preservation cycle outcome in
those undergoing two cycles in terms of number of mature
oocytes (10.3 vs. 6.2; p = .004), fertilized oocytes (7.4 vs. 4.4;
p = .04) and embryos (6.4 vs. 3.7; p =.019).66
Although more data on larger series of patients with
breast cancer are still needed to establish the safety and
effectiveness of using ovarian stimulation with letrozole
in newly diagnosed patients, this approach is currently
preferred.
 TREATING PREMENOPAUSAL ENDOCRINE-SENSITIVE BREAST CANCER

Feasibility and Safety of Ovarian Stimulation for
Patients Already Treated With Chemotherapy
The postchemotherapy setting is suboptimal for ovarian
stimulation because of the detrimental effects of adjuvant
systemic therapy on ovarian function.52 Nevertheless, often
we are confronted by situations in which a patient did not
freeze embryos or oocytes before chemotherapy initiation
and wants to become pregnant but requires assisted re-
production to conceive. In the one study reported in this
setting, 25 women underwent ovarian stimulation some
years after primary chemotherapy to conceive. Their
outcome was compared with more than 170 women
who had spontaneous pregnancy after breast cancer
diagnosis.67 Approximately 50% of patients had endocrine-
sensitive disease. At a median follow-up of 4.5 years after
conception, no difference in breast cancer outcome was
observed between the two groups. This small study sug-
gests that this approach may be considered in selected
patients who did not have fertility preservation at di-
agnosis, completed their adjuvant therapy, and cannot
conceive spontaneously.
USE OF CONCOMITANT ADMINISTRATION OF
LHRH AGONISTS WITH CHEMOTHERAPY TO
PRESERVE FERTILITY
Several randomized studies have addressed the role of LHRH
agonists as a mean of preserving fertility with conflicting
results.68-71 Table 1 summarizes results from the main trials,
the largest of which, PROMISE and POEMS, showed reduced
rates of chemotherapy-induced amenorrhea with the con-
current administration of LHRH agonists.70,71 A recent meta-
analysis of published data showed higher odds of achieving
pregnancy as well (odds ratio 1.83; 95% CI, 1.023.28;
p = .04), although absolute numbers remain low (33 vs. 19
pregnancies) in the combined results from five different
trials.72
Although these data suggest that giving LHRH agonists
before and during chemotherapy could improve chances of
future fertility for young patients with breast cancer,
several important considerations should be taken into
account. First, these trials evaluated chemotherapy-
induced amenorrhea, which is an imperfect surrogate for
adequate ovarian function. Previous studies have shown
that even women who resume menses after chemo-
therapy have reduced ovarian reserve73 and will most
likely develop early menopause.74 Chemotherapy has
been shown to induce structural changes in the ovary
including hyalinization of cortical vessels, collagen de-
position, and cortical fibrosis, even in women who
resume menses after chemotherapy.75 Whether the co-
administration of LHRH agonists avoids any of these phe-
nomena remains unclear. Second, long-term data are scant.
The PROMISE trial did report that the 5-year cumulative
incidence estimate of resumption of menses was 72.6% in
the LHRH agonist group versus 64% in the control group
(age-adjusted HR 1.48; 95% CI, 1.121.95; p = .006).76
Unfortunately, none of the published studies has ade-
quate evaluation of ovarian function parameters over
time.
An individual-patient meta-analysis including all ran-
domized trials of LHRH agonist in this setting currently is
underway. This will allow subgroup analyses according to
age and estrogen receptor status. Yet based on current data,
LHRH agonists can be considered during chemotherapy to
potentially preserve the fertility of women in whom ovarian
stimulation was not possible.

TABLE 1. Main Randomized Trials That Investigated the Role of LHRH Agonist to Reduce Chemotherapy-Induced
Amenorrhea

PROMISE71,76 GBG 37 ZORO68 NCT0009084469 POEMS70

Country Italy Germany United States International
Number of Patients 281 61 49 135
Median Age 39 36 39 38
Chemotherapy Any chemotherapy AC-T AC-T or FEC Any chemotherapy
LHRH Agonists/28d Triptorelin Goserelin Triptorelin Goserelin
ER Status Any Negative Any Negative
Median Follow-up 7.3 years NR 1.5 years 4.1 years
Primary Endpoint (POF defined as) Amenorrhea + postmenopausal Amenorrhea at 6 Amenorrhea at Amenorrhea + postmenopausal
FSH and E2 at 12 months months 12 months FSH at 24 months
Absence of POF (%) LHRH: 91% LHRH: 56% LHRH: 88% LHRH: 92%
No LHRH: 74% No LHRH: 70% No LHRH: 90% No LHRH: 78%
Positive Negative Negative Positive
Pregnancies Achieved (number) LHRH: 8 LHRH: 1 LHRH: 0 LHRH: 22
No LHRH: 3 No LHRH: 1 No LHRH: 2 No LHRH: 12
Abbreviations: AC, doxorubicin, cyclophosphamide; E2, estradiol; ER, estrogen receptor; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; FSH, follicle-stimulating hormone; LHRH,
luteinizing hormone-releasing hormone; POF, premature ovarian failure; T, taxane.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 29

AZIM, DAVIDSON, AND RUDDY
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BREAST CANCER

Triple-Negative Breast Cancer: Is

Change on the Horizon?

CHAIR
Carey K. Anders, MD
The University of North Carolina at Chapel Hill
Chapel Hill, NC

SPEAKERS
Rebecca Dent, MD
National Cancer Center Singapore
Singapore

Vandana Abramson, MD
Vanderbilt University Medical Center
Nashville, TN
ANDERS ET AL

The Evolution of Triple-Negative Breast Cancer: From Biology

to Novel Therapeutics
Carey K. Anders, MD, Vandana Abramson, MD, Tira Tan, MBBS, and Rebecca Dent, MD

OVERVIEW

Triple-negative breast cancer (TNBC) is clinically defined as lacking expression of the estrogen receptor (ER), progesterone receptor
(ER), and HER2. Historically, TNBC has been characterized by an aggressive natural history and worse disease-specific outcomes
compared with other breast cancer subtypes. The advent of next-generation sequencing (NGS) has allowed for the dissection of
TNBC into molecular subtypes (i.e., basal-like, claudin-low). Within TNBC, several subtypes have emerged as immune-activated,
consistently illustrating better disease outcome. In addition, NGS has revealed a host of molecular features characteristic
of TNBC, including high rates of TP53 mutations, PI3K and MEK pathway activation, and genetic similarities to serous ovarian
cancers, including inactivation of the BRCA pathway. Identified genetic vulnerabilities of TNBC have led to promising therapeutic
approaches, including DNA-damaging agents (i.e., platinum salts and PARP inhibitors), as well as immunotherapy. Platinum salts are
routinely incorporated into the treatment of metastatic TNBC; however, best outcomes are observed among those with deficiencies
in the BRCA pathway. Although the incorporation of platinum in the neoadjuvant care of patients with TNBC yields higher pathologic
complete response (pCR) rates, the impact on longer-term outcome is less clear. The presence of immune infiltrate in TNBC has
shown both a predictive and prognostic role. Checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, are under investigation in
the setting of metastatic TNBC and have shown responses in initial clinical trials. Finally, matching emerging therapeutic strategies to
optimal subtype of TNBC is of utmost importance as we design future research strategies to improve patient outcome.

T riple-negative breast cancer is a unique subset of breast

cancer that accounts for approximately 15%20% of all
breast cancer diagnoses.1 Clinically defined as lacking ex-
pression of ER/PR and HER2, TNBC is characterized by an
aggressive natural history and worse disease-specific out-
comes compared with other breast cancer subtypes.2 Despite
initial responses to chemotherapy, early and higher rates of
distant, typically visceral, recurrences are observed for TNBC.3
Anthracycline and taxane-based chemotherapy traditionally
has been the mainstay of therapy for TNBC, but with the
advent of NGS, molecular dissection of TNBC is revealing novel
targets currently under investigation.4-6 Herein, we will review
the natural history of TNBC, our current understanding of the
molecular characteristics of this unique subset of breast
cancer, and emerging clinical strategies in the modern era,
with a highlight on immunotherapy and DNA damaging agents.
DEFINITION OF TRIPLE-NEGATIVE BREAST
CANCER
The term triple-negative breast cancer is a pathologic
definition based on the protein expression of the three most
commonly targeted biomarkers in the treatment of breast
cancer: ER, PR, and HER2. The definition of TNBC has varied
throughout the decades, namely around the definition of
ER and/or PR positivity (i.e., 1%10% vs. $ 1% by immu-
nohistochemistry [IHC]). More recently, ER/PR positivity
has been more strictly defined as greater than or equal to 1% by
the American Society of Clinical Oncology guidelines.7 Endo-
crine therapy is generally recommended for breast cancers
exhibiting greater than or equal to 1% ER and/or PR positivity
across all stages of breast cancer. HER2-postivity also has been
strictly defined as protein expression of 3+, and/or HER2/neu
gene amplification greater than or equal to 2.0 by fluorescence
in situ hybridization (FISH).8 Thus, the pathologic definition of
TNBC is currently defined as ER and/or PR IHC expression of
0 and HER2 negativity defined as either IHC expression of 01+
or lack of gene amplification (FISH , 2.0). This universal
definition is being incorporated into the design of TNBC clinical
trials. Such an approach will help interpret results of individual
clinical trials in the context of others because the biology of
breast cancers expressing hormone receptors at 1%10% is
likely distinct from those without any expression.

From the Department of Medicine, Vanderbilt University, Vanderbilt-Ingram Cancer Center, Nashville, TN; Department of Medicine, National Cancer Center Singapore, Singapore;
Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Carey K. Anders, MD, Division of Hematology Oncology, University of North Carolina at Chapel Hill, 710 Oxfordshire Ln., Chapel Hill, NC 27517; email:
carey_anders@medunc.edu.

2016 by American Society of Clinical Oncology.

34 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook

 TRIPLE-NEGATIVE BREAST CANCER: EVOLUTION OF BIOLOGY AND NOVEL THERAPEUTICS
NATURAL HISTORY AND CLINICAL BEHAVIOR OF
TRIPLE-NEGATIVE BREAST CANCER
In addition to its distinct pathologic definition, TNBC is
characterized by a unique clinical history as compared with
other subsets of breast cancer. Smid and colleagues reported
among 344 primary lymph nodenegative breast cancers
that the site of distant recurrence differed by breast cancer
subtype.9 In this analysis, visceral relapses, including lung
(p = .01) and brain metastases (p = .0035), more commonly were
observed among patients with basal-like tumors. In contrast,
bone relapse was more commonly seen among the luminal
subtype (p = .0031), and those with HER2-enriched breast
cancer more commonly recurred in the liver (p = .17; Fig. 1).
Moreover, Harrell et al evaluated tumor gene expression
using a dataset of approximately 1,000 human breast tumors
and confirmed that HER2-enriched tumors more commonly
spread to the liver, whereas basal-like and claudin-low breast
tumors, both commonly triple-negative, spread to the brain
and lung.10 Among patients with advanced TNBC, brain re-
lapse has been observed in approximately 50% of patients.11
Response to chemotherapy also differs by breast cancer
subtype, with the high-grade TNBC subset typically more
responsive to preoperative chemotherapy (i.e., higher rates
of pCR) but with higher overall rates of relapse.3,12 This
phenomenon has been coined the triple-negative para-
dox.3 The higher rate of distant recurrence for patients with
TNBC following neoadjuvant chemotherapy is likely attrib-
uted to residual disease (i.e., inability to achieve pCR).
Multiple studies have shown superior survival for patients
who experience pCR compared with those who do not
experience pCR in this setting. Efforts to convert patients
with residual disease following neoadjuvant chemotherapy
KEY POINTS
Triple-negative breast cancer (TNBC) is a pathologic
classification defined as lack of estrogen and
progesterone receptors (0% by IHC) expression and
HER2 negativity (01+ by IHC or lack of HER2/neu gene
amplification).
Although TNBC comprises only 15% to 20% of all breast
cancer diagnoses, it is over-represented among
advanced disease as recurrences are early and typically
visceral (e.g., lung and brain).
Next-generation sequencing has provided a powerful
platform to dissect the biology of TNBC to provide novel
therapeutic targets under clinical investigation.
Checkpoint inhibitors, including PD-1 and PD-L1, are
showing responses in TNBC in initial clinical trials, and
several studies are underway to confirm activity and
understand biomarkers of response.
Platinum-based chemotherapy, with a DNA-damaging
mechanism of action, is active in TNBC and is routinely
incorporated into the neoadjuvant and metastatic
settings. Investigation of platinums in the adjuvant
setting is ongoing.
to a pCR with novel chemotherapy combinations (platinums)
and novel targeted therapies (inhibitors of PARP inhibitors)
have shown superior pCR rates on a trial-level basis.13-15 It is
unclear, however, if incremental increases in pCR rates ul-
timately will translate into improvement in recurrence-free
survival.16
Triple-negative breast cancer is characterized by recurrence
patterns and natural history that are distinct from other
subtypes of breast cancer. Dent et al compared the natural
history and clinical behavior of TNBC to non-TNBC subtypes
among 1,601 patients diagnosed with early-stage breast
cancer in Toronto between 1987 and 1997.2 At a median
follow-up of 8 years, this analysis illustrated that women with
TNBC were more likely to experience a distant recurrence
(hazard ratio [HR] 2.6; p , .0001); survival for patients with
TNBC was inferior compared with others (HR 3.2; p , .001)
within 5 years of diagnosis. Interestingly, and compared with
patients with non-TNBC breast cancer, the risk of recurrence
peaked at the 3-year mark and declined thereafter. This
observation is in contrast to non-TNBC, in which the risk of
recurrence is lower during the initial 3-year follow-up period,
but it remains constant over time. These important dis-
tinctions between the clinical behaviors of TNBC versus
non-TNBC must be considered when designing clinical
interventions to prevent recurrence for this subset of
aggressive breast cancer.
TRIPLE-NEGATIVE BREAST CANCER SUBTYPES
Breast cancer is a heterogeneous disease characterized by
distinct intrinsic subtypes, traditionally defined as luminal A
and B, normal-like, HER2-enriched, and basal-like, each with
corresponding unique clinical behavior.1,17,18 Over the past
decade, TNBC also has been recognized as a similarly het-
erogeneous disease. Several groups have sought to dissect
the biology of TNBC using IHC, gene expression, and se-
quencing tools. Perhaps the most well-known classification
of TNBC by gene expression, when compared with all breast
cancers, is the basal-like subtype. The basal-like subtype,
which represents 15%20% of all breast cancers, originally
was classified by a basal epithelial cell gene expression
cluster including keratin 5, keratin 17, integrin-b4, and
laminin.1 Basal-like breast cancer is approximately 80%
concordant with the IHC classification of TNBC.19 A more
rare subtype of breast cancer, termed the claudin-low
subtype, is also commonly triple-negative.20 The claudin-
low subtype is characterized by low to absent expression of
luminal differentiation markers, high enrichment for
epithelial-to-mesenchymal transition (EMT) markers, im-
mune response genes, and cancer stem celllike features.
This breast cancer subtype, with high frequency of meta-
plastic and medullary differentiation, illustrates a response
to therapy that is intermediate between the basal-like and
luminal breast cancer subtypes.
A different, yet complementary, approach has been taken
by other investigators in which only TNBCs have been
subtyped using gene expression and sequencing tools to
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 35
ANDERS ET AL
FIGURE 1. Subtype-Specific Patterns of Distant Recurrence From 344 Primary Breast Cancers
Copyright pending as of February 1, 2016.
reveal distinct biologic subtypes with unique therapeutic
implications.5,6 Lehmann and colleagues analyzed gene
expression from over 500 TNBC tumors and identified six
unique subtypes: basal-like (two subtypes, BL1 and BL2),
immunomodulatory (IM), mesenchymal (M), mesenchymal
stemlike (MSL), and luminal androgen receptor (LAR).5 Cell-
line models representative of each subtype were identified
and therapeutically targeted. Results indicated that cell lines
of the BL1 and BL2 subtypes, with higher expression of cell
cycle and DNA damage response genes, were sensitive to
cisplatin. Mesenchymal and MSL subtype cell lines, which
were enriched for EMT and growth factor pathways, illus-
trated sensitivity to dual PI3K/mTOR inhibition and Src in-
hibition. Finally, LAR subtype cell lines were sensitive to an
androgen receptor (AR) antagonist, a strategy that has shown
early success in the clinical arena.21 In parallel, Burnstein et al
performed DNA and RNA sequencing on approximately 200
TNBC tumors with confirmation in independent datasets and
identified four subtypes: LAR, mesenchymal (MES), basal-like
immunosuppressed (BLIS), and basal-like immune-activated
(BLIA).6 The BLIS subtype conferred the worst prognosis and
BLIA the best prognosis, for both disease-free and disease-
specific survival. In this analysis, subtype-specific targets were
identified (such as AR in the LAR and STAT signal transduction
molecules and cytokines in the BLIA) that are worthy of
continued exploration.
36 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
MOLECULAR DISSECTION OF TRIPLE-NEGATIVE
BREAST CANCER
As with other breast cancer subtypes, the biology of triple-
negative, specifically basal-like, breast cancer was a focus of
The Cancer Genome Atlas (TCGA) project.4 In this large-scale
analysis of primary human breast cancers, genomic DNA
copy number arrays, DNA methylation, exome sequencing,
messenger RNA arrays, microRNA sequencing, and reverse-
phase protein arrays were evaluated. Among the 81 basal-
like breast cancers, of which 65 were both triple-negative
and basal-like, several hallmark findings were reported: (1) a
high frequency of TP53 mutations (80%); (2) loss of RB1 and
BRCA1; (3) high activation of the PI3K pathway (either
through PIK3CA gene mutation of approximately 9% or loss of
the negative regulators INPP4B and/or PTEN); (4) an enhanced
proliferation signature with hyperactivated FOXM1 as a tran-
scriptional driver of this signature; and (5) genetic similarity
between basal-like breast cancer and serous ovarian cancers.
These similarities included high frequencies of ATM and TP53
mutations, high expression of AKT3 and MYC, inactivation of
BRCA1 and BRCA2, RB1 loss, and cyclin E1 amplification. From a
therapeutic targeting perspective, approximately 20% of basal-
like tumors harbored a germline or somatic BRCA mutation,
which may confer sensitivity to platinum and/or PARP in-
hibitors that will be discussed below. Finally, copy number
 TRIPLE-NEGATIVE BREAST CANCER: EVOLUTION OF BIOLOGY AND NOVEL THERAPEUTICS
analysis revealed several amplifications or deletions that may
be targetable in the clinical arena. Amplifications included
PIK3CA (49%), KRAS (32%), BRAF (30%), and EGFR (23%). Other
less common amplifications were seen in FGFR1, FGFR2, IGFR1,
KIT, MET, and PDGFRA. As cited above, deletions were seen in
PTEN and INPP4B, which confer activation of the PI3K pathway.
Results of this valuable analysis are summarized in Sidebar 1
and provide a wealth of knowledge pertaining to our un-
derstanding of the biology of TNBC and ways to target this
disease more effectively.
TRIPLE-NEGATIVE BREAST CANCER: IS CHANGE
ON THE HORIZON?
In addition to our evolving understanding of the biology of
TNBC over the decades, therapeutic strategies to treat TNBC
across different stages are maturing. Although many mo-
lecularly targeted strategies under investigation exist, for
the purposes of this review, we will focus on the use of
platinums and the incorporation of immunotherapy into the
treatment of TNBC.
Optimal Use of Platinum in Triple-Negative
Breast Cancer
A subset of TNBC has been postulated to be phenotypically
and molecularly similar to familial BRCA1-associated breast
cancers, so called BRCAness.22 It is estimated that more
than 75% of tumors arising in BRCA1 mutation carriers are
triple-negative and/or have a basal-like phenotype.23 These
tumors are characterized by their heightened sensitivity to
damage by DNA cross-linking.24-26 Double-stranded DNA
breaks caused by agents such as platinum salts are con-
sidered the most incisive form of DNA damage, and they are
repaired by homologous recombination, an error-free
process, and nonhomologous end-joining, which is error
SIDEBAR 1. The Cancer Genome Atlas Molecular
Characteristics of Basal-like Breast Cancer
Characteristics
High concordance with TNBC (approximately 80%)
High rates of TP53 pathway alterations (TP53 mutations in
84%; gain of MDM2 14%)
High rates of PI3K pathway alterations (PIK3CA mutation
7%; PTEN mutation or loss 35%; INPP4B loss 30%)
High rates of RB pathway alterations (RB1 mutation or loss
20%; cyclin E1 amplification 9%; high expression of
CDKN2A; low expression of RB1)
High genomic instability
Hypomethylation compared with other breast cancer
subtypes
Similarities with serous ovarian carcinomas, including
approximately 20% rate of germline or somatic BRCA
mutations
Abbreviation: TNBC, triple-negative breast cancer.
prone. BRCA1 and BRCA2 are well-described tumor sup-
pressor genes that participate directly in homologous
recombinationmediated repair of double-stranded breaks.27
In humans, mutation in one copy of either of these genes in the
germline results in hereditary breast and ovarian cancer syn-
drome; tumors that subsequently develop are defective in
homologous recombinationmediated DNA repair.27 Recent
reports have expanded the range of genes implicated in familial
breast cancers, many of which are involved in the homologous
recombination pathway.23,28-30 In addition, defective homol-
ogous recombination also can be found in sporadic breast
cancers as shown by comparative genome hybridization
studies.31 Finally, impairment of homologous recombination
deficiency can occur through epigenetic mechanisms, such as
methylation of BRCA1/2, which is also part of the BRCAness
spectrum.22
Incorporation of Platinums in the Neoadjuvant
Treatment of Triple-Negative Breast Cancer
Over the past few decades, there has been considerable
interest in the use of platinum salts in the treatment of TNBC
on the basis that dysfunction of homologous recombination
DNA repair sensitizes tumor cells to these agents and in-
duces cell death. As a proof of concept, a small neoadjuvant
study reported a strikingly high pCR of 90% to four cycles of
neoadjuvant cisplatin in a group of 10 patients from Poland
with BRCA1 mutation, the majority of whom were the TNBC
phenotype.32 Larger phase II studies involving patients with
predominantly sporadic TNBC have described conflicting
results. Alba and colleagues reported a randomized phase II
study of standard neoadjuvant epirubicin plus cyclophos-
phamide chemotherapy followed by docetaxel with or
without carboplatin AUC 6 given every 21 days.33 The
prespecified primary endpoint of improvement in pCR rates
(defined as pCR in breast) was not met, with pCR rates in
breast and axilla of 30% of patients in both treatment
arms.33 In contrast, the German Breast Cancer Group ad-
ministered neoadjuvant paclitaxel, liposomal doxorubicin,
and bevacizumab with or without weekly carboplatin AUC 1.5-2
in the GeparSixto trial. Of the 315 patients with TNBC, 53.2%
of those treated with the addition of weekly carboplatin, as
compared with 36.9% treated without the addition of carbo-
platin, achieved a pCR (p = .005).14 Similarly, CALGB 40603, a
two-by-two factorial randomized phase II trial evaluating
weekly paclitaxel with or without carboplatin (AUC 6) and/or
bevacizumab followed by dose dense doxorubicin plus cyclo-
phosphamide showed an increase in pCR rate (defined as
ypT0/is) from 46% to 60% (odds ratio 1.76; p = .0018).15
Furthermore, an important clinical question revolves
around these data: does the purported improvement in pCR
rates translate to improved survival outcomes? Early survival
analysis of GeparSixto and CALGB 40603 simultaneously
were reported at the San Antonio Breast Cancer Symposium
in December 2015. In the GeparSixto study, the improved
pCR rate translated into a significant increase in 3-year
disease-free survival (DFS) from 76.1% to 85.8% (HR 0.56;
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 37
ANDERS ET AL

95% CI, 0.330.96; p = .035).34 This contrasts with the CALGB
40603 study, which reported a numerical improvement, but
no statistical difference in 3-year event-free survival nor
overall survival (OS), with the caveat that this trial was
underpowered to determine a survival benefit.13 Of note,
GeparSixto used a nonstandard, more intensive regimen of
concurrent anthracycline-taxane chemotherapy with the
incorporation of bevacizumab in all arms. Pharmacologic
synergy, as well as potentially the weekly schedule of
carboplatin, may have contributed to the better overall
prognosis in the GeparSixto trial.
Incorporation of Platinums in the Metastatic
Treatment of Triple-Negative Breast Cancer
In the metastatic setting, retrospective studies have been
conflicting and largely focused on comparing TNBC with
other subtypes.35-38 In the largest randomized phase III trial,
the Triple Negative Breast Cancer Trial (TNT), 376 patients in
U.K. centers were randomly assigned to receive either
carboplatin or docetaxel monotherapy as first-line treat-
ment with cross-over on progression.39 In the unselected
TNBC population, there was no difference in the primary
outcome of objective response rates in both treatment arms
when treated up front (31.4% vs. 35.6%; p = .44) or following
cross-over (22.8% vs. 25.6%; p = .73).39 Similarly, the sec-
ondary endpoint of progression-free survival (PFS) did not
significantly differ in both arms.39 To add to the burgeoning
evidence in favor of a role for platinum-based chemother-
apy, two studies from China have been reported: (1) a
randomized phase II trial comparing docetaxel and cisplatin
versus docetaxel and capecitabine and (2) a multicenter
randomized phase III trial of gemcitabine and cisplatin versus
gemcitabine and paclitaxel.40,41 In the phase II study, 53
patients with metastatic TNBC were randomly selected to
receive docetaxel with cisplatin or capecitabine in the first-
line setting. Both overall response rates (63.0% vs. 15.4%;
p = .001) and PFS (10.9 vs. 4.8 months; p # .001) were
significantly better in the cisplatin group.40 CBCSG006 was a
phase III study in which 240 patients were randomly assigned
to receive a maximum of eight cycles of gemcitabine and
either cisplatin or paclitaxel dosed every 21 days.41 The trial
used a hybrid design and was powered for noninferiority by
allowing for a prespecified superiority hypothesis to be
tested. Gemcitabine plus cisplatin was both noninferior to and
superior to gemcitabine plus paclitaxel (PFS: HR 0.692; 95% CI,
0.5230.915; p , .0001 [noninferiority] and p , .009
[superiority]).41 Therefore, in both studies, the cisplatin-
containing regimen outperformed the comparator.
Challenges in Incorporating Platinums Into Standard
Practice: Toxicities and Dosing Strategies
Given this encouraging clinical data on the role of platinum
agents in TNBC, important clinical questions still remain on
how best to choose the dose and/or schedule of the plat-
inum agent. No trials to date have been powered adequately
to demonstrate an improvement in long-term survival
outcome. The addition of carboplatin enhances acute tox-
icities associated with chemotherapy with higher discon-
tinuation rates, more dose reductions, and higher grade 3/4
adverse events, which could potentially compromise the
current standard of care in an already high-risk population
of patients. It may be reasonable to consider off-trial use of
carboplatin in locally advanced TNBC for rapid control of
locoregional disease and in young, fit patients with a high
risk of relapse as we await definitive results from ongoing
phase III trials powered for survival outcomesPEARLY
(NCT02441933), Gerpar-Octo (NCT021253144), NRG-
BR003 (NCT02488967), and TPPC (NCT02455141).
BIOMARKER DISCOVERY IN TRIPLE-NEGATIVE
BREAST CANCER
Triple-negative breast cancer is a heterogeneous disease.
Given the trade-off of greater toxicities in the early setting
and mixed results in the metastatic setting, it would be ideal
to be better able to identify patients most likely to benefit
from this treatment strategy. TBCRC009, a phase II bio-
marker discovery trial, has reported an improved response
rate in patients who harbored deleterious germline BRCA
mutation(s) without durability of response nor improve-
ment in PFS or OS.42 The TNT trial lends support to BRCA
genotyping and gene expression profiling to improved
therapy selection in metastatic TNBC.39 Patients with BRCA1
or BRCA2 mutations treated with carboplatin fared better
with a greater response rate (68% vs. 33.3%; p = .03) and PFS
(6.8 vs. 3.1 months; p = .03) as compared with docetaxel,
whereas nonbasal-like tumors did better with docetaxel
(73.7% vs. 16.7%; p # .01).39 Lastly, DNA-based assays have
been developed based on whole genome tumor loss of
heterozygosity score (LOH),43 telomeric allelic imbalance
score (TAI),44 and large-scale state transitions score (LST).45
These assays measure patterns of genomic instability derived
through comparison of BRCA1/2 mutated and nonmutated
tumors. The unweighted sum of LOH, TAI, and LST together
form the homologous recombination deficiency score. This
has been evaluated in the translational component of the
TBCRC009 and TNT trials. Again, results are conflicting. In
TBCRC009, tumors from patients with platinum-responsive
disease exhibited higher values for LST and LOH assays.42 This
was not so in TNT, in which the homologous recombination
deficiency score did not select for sensitivity to carboplatin
over docetaxel.39 Therefore, further development of an assay
to identify homologous recombination defect in non-BRCA1/2
tumors is needed. Finally, the group from Memorial Sloan
Kettering Cancer Center reported a comparison of homologous
recombination deficiency scoring methodologies and con-
cluded that homologous recombination DNA repair gene
sequencing demonstrated good sensitivity and specificity,
providing a potential biomarker for clinical trials of homologous
recombination deficiencytargeted therapies.46
In summary, for the practicing oncologist, what would be
the current standard of care with respect to the use of
platinum salts? In the neoadjuvant setting, platinum is a

38 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook

 TRIPLE-NEGATIVE BREAST CANCER: EVOLUTION OF BIOLOGY AND NOVEL THERAPEUTICS
reasonable choice for selected patients, especially if those
who are BRCA positive. There are no data to support platinum
salts in the adjuvant setting; clinical trials are ongoing. In the
metastatic setting, where the goal of therapy is palliative,
platinum is one of the standard chemotherapies oncologists
include in their armamentarium of chemotherapies, although
with the caveat that the most convincing data are in the front-
line setting for BRCA-germline mutation carriers.
IMMUNOTHERAPY AND IMMUNOCONJUGATES
FOR TRIPLE-NEGATIVE BREAST CANCER:
PROMISE AND POTENTIAL
Modern immunotherapy, in the form of monoclonal anti-
bodies that act as checkpoint inhibitors, has revolutionized
the landscape of the treatment of metastatic melanoma in a
relatively short period of time. Antibodies to cytotoxic
T-lymphocyte antigen 4 (CTLA-4), PD-1, and PD-L1, all of which
increase the immune response against the tumor by blocking
immune regulating proteins that downregulate the immune
system, have increased response rates and OS.47-49 Perhaps
more interestingly, other solid tumor malignancies, such as lung
cancer, which traditionally are not considered immunogenic,
have shown clinical benefit to checkpoint inhibitors.50 The role
of immunotherapy in breast cancer has yet to be defined, but
increasing evidence points to TNBCs as possibly having unique
characteristics that may make them more responsive to
checkpoint inhibition. Given the lack of targeted treatment
options for TNBC, immunotherapy poses an exciting opportu-
nity for the treatment of this aggressive disease.
OVERVIEW OF TUMOR IMMUNE SURVEILLANCE
IN THE SETTING OF BREAST CANCER
In a process called tumor immune surveillance, tumor immune
cells, including CD8+ T cells, recognize tumor-associated an-
tigens presented by tumor cells and attack the tumor cells. The
PD-1 receptor pathway plays an important role in modulating
immune responses and provides an escape mechanism to
tumor immune surveillance. PD-1 is an inhibitory immune
checkpoint receptor expressed on activated T cells, B cells,
natural killer cells, and other lymphocytes that can remain
active in inflammatory states such as cancer.51,52 PD-L1 is a
ligand of PD-1 and acts to suppress antitumor immunity by
binding PD-1. Ligation of PD-L1 with PD-1 inhibits T-cell pro-
liferation, cytokine production, and cytolytic activity, which
leads to the functional inactivation or exhaustion of T cells.53
Through upregulation of PD-L1 and other adaptive immune
resistance mechanisms, tumors are able to use this pathway to
evade the antitumor immune response.
The balance of cells in the tumor microenvironment, which
includes tumor cells, stromal cells (i.e., fibroblasts and mi-
crovasculature), and immune cells (i.e., lymphocytes), ap-
pears to influence breast cancer outcome.54 An association
between greater tumor infiltrative lymphocytes (TILs) and
better prognosis in breast cancer has been recognized for
some time, but newer studies have shown the specific
relevance in TNBC, which has been shown to have
substantial infiltration with TILs.55-58 Higher levels of TILs
generally are associated with poor-prognostic clinicopath-
ologic features, including ER negativity, higher grade, higher
proliferative rate, and lymph node positivity.55,59-62 How-
ever, despite worse clinical features, higher levels of TILs are
associated with improved DFS and OS, independent of
systemic therapy.59,63,64 This apparent paradox highlights
the role that the immune system may play in a subset of
TNBCs and suggests that TILs may be a surrogate for an
adaptive immune response in these cancers.
ASSOCIATION OF TUMOR INFILITRATIVE
LYMPHOCYTES AND RESPONSE OF TRIPLE-
NEGATIVE BREAST CANCER TO CHEMOTHERAPY
Generally, TILs are divided into intratumoral TILs that have
direct contact with tumor cells, and stromal TILs, which are
found between tumor cells within the tumor stroma, but
they do not have direct contact with tumor cells. A study of
patients with breast cancer receiving neoadjuvant chemo-
therapy with an anthracycline/taxane combination showed
an independent association between percentage of intra-
tumoral TILs and pCR.64 Those with lymphocyte-predominant
breast cancer, defined as more than 60% of stromal or
tumoral infiltration, had a particularly high rate of pCR (41.7%)
compared with only a 2% pCR rate in those tumors without any
tumoral lymphocyte infiltration. In the GeparSixto study that
evaluated the addition of carboplatin to chemotherapy in TNBC
or HER2-positive cancers, the presence of stromal TILs was
predictive of response to the addition of carboplatin, although
this correlation reached statistical significance only in HER2-
positive tumors.65 Regardless, this association between re-
sponse to chemotherapy based on the presence of TILs suggests
that TILs not only are predictive markers of response in TNBC,
but that cell death induced by platinum agents may prime or
generate neoantigens to stimulate nearby lymphocytes.
PROGNOSTIC IMPLICATIONS OF IMMUNE GENE
SIGNATURES IN TRIPLE-NEGATIVE BREAST
CANCER
Several other studies promote the exploration of the PD-1
pathway and immunotherapy in TNBC. Data from TCGA4
have confirmed higher PD-L1 mRNA expression in TNBC
versus non-TNBC samples.66 This and other studies have
shown that PD-L1 is not detected in normal breast tissue but
is expressed in about half of all breast cancers, including
approximately 20% to 30% of TNBCs.67,68 PD-L1 expression
is associated with TILs,69 correlates with higher histologic
grade, greater tumor size, and higher expression of the
proliferation marker Ki-67.70
Further supporting the link between immunotherapy and
TNBC are gene expression profiling studies that demonstrate
an association between expression of IM genes and better
clinical outcomes in TNBC.71 Desmedt et al were among the
first to create gene modules and correlate them with out-
come in different subtypes of breast cancer. Of the seven
gene expression modules they described (tumor invasion,
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 39
ANDERS ET AL
immune response, angiogenesis, apoptosis, proliferation,
and ER and HER2 signaling), only the immune response
module correlated with prognosis in the ER-/HER2- sub-
group. Since that time, several groups have described the
prognostic value of immune gene signatures and TNBC.72-74
More recently, analysis of gene expression profiles of 587
TNBC samples identified six distinct subtypes, including an
IM subtype characterized by high expression of immune-
related genes.5 This subtype is composed of immune-
activated and associated signaling components contributed
from both the tumor and the infiltrating lymphocytes, and
it has been associated with improved relapse-free survival
compared with other subtypes.5 RNA sequencing showed
this subtype to have substantially higher expression of PD-L1,
PD-1, and CTLA-4. These and other data provide evidence that
there may be a subset of TNBC in which checkpoint inhibitors
may have particular efficacy.
CLINICAL EXPERIENCE AND OUTCOMES WITH
IMMUNOTHERAPY IN TRIPLE-NEGATIVE BREAST
CANCER
The first reported study of an immune checkpoint inhibitor in
TNBC was a single-arm phase IB study of single-agent
pembrolizumab, a PD-1 antibody (KEYNOTE-012).75 This study
showed that pembrolizumab 10 mg/kg given every 2 weeks was
not only well-tolerated; it also showed activity in heavily pre-
treated patients with metastatic PD-L1positive TNBC. In-
terestingly, of all patients with TNBC who were screened, 58%
tested positive for PD-L1 in greater than 1% of tumor stroma or
tumor cells. Over 45% of patients had received more than three
prior treatments in the metastatic setting, and 21.9% had
received five or more treatments. Of the 27 participants
with centrally confirmed measurable disease (32 patients
total enrolled), one participant (3.7%) had a complete
response (CR), four participants (14.8%) had a confirmed
partial response (PR), 25.9% had stable disease, and 44.4%
had progressive disease by central review. The median
time to response was 18 weeks (range, 732 weeks), and
the median duration of response had not been reached
(range, 15more than 40 weeks).
The PD-L1 antagonist atezolizumab (MPDL3280A) also is
being evaluated in TNBC. An ongoing phase I study of atezo-
lizumab has an expansion cohort in heavily pretreated patients
with PD-L1positive and negative TNBC.76 Initial data show
the overall response rate for evaluable patients with metastatic
TNBC is 19%, including 9.5% CR and 9.5% PR, with 75% of
responses ongoing (range, 18 to more than 56 weeks).
References
1. Perou CM, Srlie T, Eisen MB, et al. Molecular portraits of human breast
tumours. Nature. 2000;406:747-752.
2. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer:
clinical features and patterns of recurrence. Clin Cancer Res. 2007;
13:4429-4434.
40 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
FUTURE DIRECTIONS FOR IMMUNOTHERAPY IN
TRIPLE-NEGATIVE BREAST CANCER
A decade ago, very little was known about the make-up of
TNBC, and the only promising treatments on the horizon
involved cytotoxic chemotherapy. Now, with a better
understanding of the heterogeneity of TNBC and the
understanding that immune targets are relevant in this
disease, we are in a new era in which we are exploring
checkpoint inhibitors, vaccines, and immune antagonists.
Two large phase III randomized studies of atezolizumab
and pembrolizumab are now ongoing in metastatic TNBC;
the first is nab-paclitaxel with or without atezolizumab
and the other is pembrolizumab versus single agent
chemotherapy. Studies with both agents are also planned
in the neoadjuvant setting. Finally, two studies evaluating
carboplatin with atezolizumab are to begin accrual
through the TBCRC in upcoming months to capitalize on
data with platinums in TNBC. Tissue samples from these
studies will further clarify the relationship of response and
resistance to PD-1 and PD-L1 expression, and to the
presence of TILs. The reported studies to date that show
responses in heavily pretreated patients with TNBC are
notable, but more impressive is the duration of response
seen in a disease that usually has a PFS of 2 to 3 months
after the first or second line of treatment of metastatic
disease. Immunotherapy rapidly has become a great
contender in the treatment of TNBC. Our next challenges
will be to identify how to use it best, whether it is with
chemotherapy or in combination with other immune
modulators, and to identify biomarkers of response.
CONCLUSION
Triple-negative breast cancer is an established subset of
breast cancer with characteristic clinical behavior and
natural history. Until recently, the mainstay of therapy
against TNBC has been cytotoxic chemotherapy. The
advent of NGS has opened our eyes to the possibility of
targeted therapy in a subset of breast cancer that lacks the
classic biomarkers (ER, PR, and HER2) in breast cancer.
Despite this challenge, investigators spanning the re-
search spectrum from bench-to-bedside are tackling TNBC
head on. We are seeing an explosion of activity in basic,
translational, and clinical research that includes plati-
nums, immunotherapy, and others. Coordinated research
efforts such as this are the way forward to improve the
outcome for our thousands of patients with TNBC.
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BREAST CANCER

Updates and Controversies in

HER2-Positive Breast Cancer

CHAIR
Sunil Verma, MD, MSEd, FRCPC
Cumming School of Medicine, University of Calgary
Calgary, AB, Canada

SPEAKERS
Kimberly L. Blackwell, MD
Duke University Medical Center
Durham, NC

Speaker
Miguel Martin, MD, PhD
~
Hospital General Universitario Gregorio Maranon
Madrid, Spain
NIXON AND VERMA

A Value-Based Approach to Treatment of HER2-Positive

Breast Cancer: Examining the Evidence
Nancy Nixon, MD, FRCPC, and Sunil Verma, MD, MSEd, FRCPC

OVERVIEW

Over the past decade, treatment of HER2-positive breast cancer has been revolutionized with the introduction of targeted
therapies. Survival in both early and advanced HER2-positive breast cancer has improved significantly. With evidence for
major clinical benefit, it is imperative that health systems evaluate new treatments to maximize the value of health
expenditures. Physicians, funding agencies, and policy makers are tasked with analyzing available evidence to ensure that
each individual patient receives the optimal treatment in a resource-challenged environment.

A pproximately 15% to 20% of breast cancer patients

overexpress HER2 protein. 1 Over the past decade,
treatment of HER2-positive breast cancer has been revo-
lutionized. Although previously a poor prognostic marker,
HER2-positive breast cancer now gives patients an equiva-
lent, if not superior, survival to those patients that are HER2-
negative.2 In metastatic disease, the median overall survival
(OS) has dramatically increased over the course of 15 years,
from 20 months, 50 months, and beyond.3 For metastatic
patients, American Society of Clinical Oncology (ASCO)
guidelines4 now recommend HER2-targeted therapies in all
lines of treatment of metastatic disease.
TREATMENT OF METASTATIC HER2-POSITIVE
BREAST CANCER
First Line
Trastuzumab, a human monoclonal IgG antibody that se-
lectively targets HER2, was the first targeted drug to be
approved. It has since has been shown to be effective in
combination with multiple chemotherapy drugs including
docetaxel, paclitaxel, vinorelbine, and capecitabine. In the
landmark trial by Slamon et al,5 patients were randomly
assigned 1:1 to standard chemotherapy alone versus
standard chemotherapy plus trastuzumab. In this study,
there was a substantial improvement in time to pro-
gression (TTP, 7.4 vs. 4.6 months; p , .001). Median OS
increased from 20.3 to 25.1 months (p = .046), establishing
trastuzumab as a standard of care in combination with
taxanes (Table 1).
Pertuzumab, a recombinant humanized monoclonal an-
tibody, binds to a separate domain on the HER2 receptor,
preventing the dimerization of HER2 with other members of
the EGFR family. The rationale for the addition of pertu-
zumab to trastuzumab is to overcome resistance to tras-
tuzumab caused specifically by formation of HER2:HER3
heterodimers. It was evaluated for metastatic disease in the
CLEOPATRA trial,6 which studied patients with HER2-positive
disease with no prior treatment of metastatic disease and
randomly assigned them 1:1 to trastuzumab and docetaxel,
plus either pertuzumab or placebo. Ninety percent of the
patients in this trial had not been on prior trastuzumab
therapy in the adjuvant setting, meaning the majority of the
patients were naive to anti-HER2 therapies. The results of
this trial established a new first-line standard of metastatic
HER2-positive breast cancer, with an increase in progression-
free survival (PFS) of 6 months (18.6 vs. 12.4 months; p , .001)
and OS (56.5 vs. 40.8 months; p = .002; Table 1).7
Second Line
For patients progressing on an anti-HER2 therapy combined
with a cytotoxic or endocrine agent, additional anti-HER2
therapy should be offered based on evidence showing it is
beneficial to continue suppression of the HER2 pathway.8-12
Laptinib is an oral tyrosine kinase inhibitor that functions
downstream of HER2, inhibiting both EGFR and HER2 re-
ceptors. It was shown to be an effective option for second-
line treatment in 2006 by Geyer et al13 for patients who
had locally advanced or metastatic HER2-positive breast
cancer previously treated with regimens that included an
anthracycline, a taxane, and trastuzumab. The addition of
lapatinib resulted in a significant improvement in median
TTP of 8.4 versus 4.4 months at interim analysis, meeting
specified criteria for early reporting (hazard ratio [HR] 0.49;
p , .001). There was no noticeable improvement in OS

From the University of Calgary, Calgary, Alberta, Canada.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Sunil Verma, MD, MSEd, FRCPC, University of Calgary, 1331 29 St. NW, Calgary, Alberta, Canada; email: drsunil.verma@albertahealthservices.ca.

2016 by American Society of Clinical Oncology.

e56 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


TABLE 1. Clinical Benefit of Targeted Therapies for Early HER2-Positive Breast Cancer
Indication Regimen
NSABP-B31 and Adjuvant early breast AC T vs. AC TH
NCCTG N983120 cancer
10-Year Follow-up Adjuvant early breast AC T vs. AC TH vs. TCH
BCIRG 00621 cancer
10-Year Follow-up Adjuvant early breast Standard chemotherapy vs. standard
HERA cancer chemotherapy + 1-y trastuzumab
Abbreviations: T, taxane; H, trastuzumab, C, cyclophosphamide, c, carboplatin; AC, doxorubicin and cyclophosphamide; HR, hazard ratio.
observed in this trial, likely in part because of early crossover
(Table 1).
In 2012, the EMILIA study14 was published, establishing a
new standard of care for second-line treatment. This trial
looked at T-DM1, an antibody-drug conjugate of trastuzumab
and the cytotoxic agent emtansine (DM1). The antibody
trastuzumab binds to the HER2 on tumor cell surfaces and
upon internalization the emtansine moiety is released,
binding to tubules and disrupting microtubule dynamics.
EMILIA compared T-DM1 versus lapatinib plus capectiabine
in patients with locally advanced or metastatic HER2-positive
breast cancer who had previously received zero to more than
three prior regimens. All the patients on this trial had prior
exposure to trastuzumab and a taxane. T-DM1 showed a
significant improvement in median PFS (9.6 vs. 6.4 months, HR
0.65; p , .001) and median OS (30.9 vs. 25.1 months; HR 0.68;
p , .001; Table 1). In addition, rates of grade 3 or higher
adverse events were higher in the lapatinib plus capecitabine
group. This established T-DM1 as the new standard for second-
line treatment.
KEY POINTS
Treatment of HER2-positive breast cancer, and its
prognosis, has been revolutionized since the
introduction of targeted treatment.
Significant improvements in overall survival have been
observed in both metastatic and adjuvant settings over
the past decade.
Despite significant clinical benefit with introduction of
targeted treatments, there is a risk that cost on a
population level may become prohibitive for
widespread use.
Physicians, funding agencies, and policy makers are
tasked with finding a means to ensure that treatments
are cost-effective in an environment of limited
resources.
Careful evaluation of the evidence and consideration of
clinical benefit alongside the cost-effectiveness of novel
therapies will help to guide clinical practice.
HER2-POSITIVE BREAST CANCER: A VALUE-ORIENTED APPROACH TO TREATMENT
Overall Survival Disease-Free Survival
HR 0.63; 75.2% vs. 84.0% at HR 0.60; p , .001; 62.3% vs.
8.4 years follow-up 73.7% at 8.4 years follow-up
HR 0.63 (AC-TH p , .0001; 85.9% HR 0.72 (AC-TH p , .001; 74.6%
vs. 78.7%) vs. 67.9%)
HR 0.76 (TCH p = .0075; 83.8% vs. HR 0.77 (TCH p = .0011; 73.0%
78.7%) vs. 67.9%)
HR 0.74; p , .001; 79.4% vs. HR 0.75; p , .001; 69.3% vs.
72.9% at 10 years follow-up 62.5% at 10 years follow-up
Beyond Second Line
After progression on trasuzumab, pertuzumab, and treat-
ment with T-DM1, there remain multiple options of treat-
ment, still including anti-HER2targeted treatments. These
include capecitabine plus lapatinib, trastuzumab plus
lapatinib,15-17 or trastuzumab in combination with another
cytotoxic agent. There is insufficient evidence to recommend
one regimen over another. Alternatively, patients may be
considered for enrollment on clinical trial.
In 2015, the THERESA trial was presented at the San
Antonio Breast Cancer Symposium. Showing OS benefit for
T-DM1 for patients who have had prior therapy with taxane,
trastuzumab, and lapatinib. This confirms the efficacy for
T-DM1 in later lines of therapy for patients who may not
have had received T-DM1 in the second-line setting.
TREATMENT OF EARLY HER2-POSITIVE BREAST
CANCER
Adjuvant
With the success of anti-HER2 therapy in the metastatic
setting, trastuzumab was evaluated in the adjuvant setting
in a series of pivotal trials, first reported in 2005. In the HERA
trial,18 patients were randomly assigned 1:1:1 to observa-
tion, versus 1 or 2 years of trastuzumab given every 3 weeks.
When compared with observation, trastuzumab given after
primary therapy reduced the rate of recurrence, in particular
distant recurrence, by approximately 50% after interim ef-
ficacy analysis with median follow-up of 12 months. This
benefit was confirmed in a 2012 meta-analysis of eight trials
of chemotherapy plus trastuzumab versus trastuzumab
alone.19 The HR for recurrence was 0.60, also with an im-
provement in OS and HR for death of 0.66. The benefit in OS
was most strongly associated with concurrent administra-
tion of trastuzumab with chemotherapy, as opposed to with
sequential treatment. In 2014, Perez et al published the
results of a planned joint analysis on survival from NSABP-31
and NCCTG N9831, where patients were randomly assigned
to doxorubicin plus cyclophosphamide followed by pacli-
taxel plus trastuzumab for 1 year versus paclitaxel alone.20
Adding trastuzumab led to 37% relative improvement in OS
(HR 0.63; p , .001). An improvement in disease-free survival
(DFS) of 40% was observed (HR 0.60; p , .001) with increase
in 10-year DFS rate from 62.2% to 73.7% (Table 2).
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e57
NIXON AND VERMA
TABLE 2. Clinical Benefit of Targeted Therapies for Early and Advanced HER2-Positive Breast Cancer
Indication Regimen
Slamon et al, First-line advanced breast Standard chemotherapy vs. standard che-
20015 cancer motherapy + H
CLEOPATRA6 First-line advanced breast TH + placebo vs. THP
cancer
EMILIA14 Second-line advanced T-DM1 vs. capecitbine + lapatinib
breast cancer
Geyer et al, Second-line advanced Lapatinib + capecitabine vs. capecitabine
200613 breast cancer
Abbreviations: T, taxane; H, trastuzumab; P, pertuzumab; DM1, emtansine; HR, hazard ratio; TTP, time to progression.
The benefit of adjuvant trastuzumab has been maintained
with longer follow-up. An updated analysis of the HERA trial
showed continued significant DFS and OS benefit of tras-
tuzumab despite substantial crossover (Table 2). Ten-year
follow-up from the BCIRG 006 trial, which randomly assigned
patients to three arms (doxorubicin plus cyclophosphamide
followed by taxane plus or minus trastuzumab, vs. docetaxel
plus carboplatin plus trastuzumab) was presented in 2015
at the San Antonio Breast Cancer Symposium (Table 2).
With 10.3 years of follow-up, there was significant benefit
in OS for both trastuzumab-containing arms compared
with chemotherapy alone (p , .001 for doxorubicin plus
cyclophosphamide followed by docetaxel plus trastuzu-
mab, and p = .0018 for docetaxel plus carboplatin plus
trastuzumab).
Neoadjuvant
There is greater interest in evaluating HER2 therapies in the
neoadjuvant setting, given the correlation between path-
ologic complete response (pCR) and long-term outcomes
including event-free survival (EFS).22 The U.S. Food and Drug
Administration granted approval to the addition of neo-
adjuvant pertuzumb to trastuzumab based on two random-
ized phase II studies, in which higher pCR rates were seen
compared with trastuzumab arms. NeoSphere compared four
regimens preoperatively (docetaxel plus trastuzumab vs.
docetaxel plus trastuzumab plus pertuzumab vs. trastuzumab
plus pertuzumab. vs. docetaxel plus pertuzumab).23 After
surgery, patients in the docetaxel arms received three cycles
of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC)
and completed a year of trastuzumab, whereas patients
who had received only antibody treatment received both
docetaxel and FEC followed by trastuzumab for a full year.
pCR rates were 29%, 46%, 17%, and 24% in each group,
respectively. In the TRYPHA-ENA study, women were ran-
domly assigned to trastuzumab plus pertuzumab and con-
current FEC followed by concurrent docetaxel, FEC alone
followed by concurrent docetaxel, or concurrent docetaxel
and carboplatin.24 After surgery, patients completed 1 year
of trastuzumab. The pCR rate was equivalent across arms. In
both studies, patients with ER-negative disease were more
likely to achieve pCR.
e58 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Overall Survival Progression-Free Survival
25.1 vs. 20.3 months (p = .046) 7.4 vs. 4.6 months
(p , .001)
56.5 months vs. 40.8 months 7.7 vs. 6. 3 months
(HR 0.68; p , .001) (HR 0.68; p , .001)
20.9 vs. 25.1 months (HR 0.68; 9.6 vs. 6.4 months
p , .001) (HR 0.65; p , .001)
TTP 8.4 vs. 4.4 months
(HR 0.49; p , .001)
Several studies have been done to look at lapatinib in
neoadjuvant treatment, both in combination with or in place
of trastuzumab. Lapatinib has been consistently inferior to
trastuzumab when compared head to head.25-27 The com-
bination was looked at in the NeoALLTO study, which en-
rolled women with HER2-positive, early breast cancer and
randomly assigned them 1:1:1 to lapatinib, trastuzumab, or
trastuzumab plus laptinib for 6 weeks followed by the anti-
HER2 treatment combined with paclitaxel for 12 weeks.
After surgery, women received three cycles of FEC followed
by 34 weeks of the assigned anti-HER2 neoadjuvant therapy.
Although patients in the combination group had improve-
ment in pCR, this did not translate to improved DFS or OS in
the confirmatory phase III adjuvant ALTTO study.
Near Future Directions
There continues to be new data that will add to our
knowledge of how to optimize treatment of early disease.
The APHINITY trial evaluating adjuvant pertuzumab plus
trastuzumab versus trastuzumab after surgery is yet to be
reported but may provide evidence for adjuvant utilization
of pertuzumab. Similarly, the KATHERINE trial, which recently
completed accrual, is evaluating the addition of T-DM1 as ad-
juvant treatment of patients treated with neoadjuvant che-
motherapy and trastuzumab who do not achieve pCR. T-DM1 is
also being evaluated in direct comparison to paclitaxel and
trastuzumab in the adjuvant setting for patients with low-risk
HER2-positive disease (ATEMPT trial).
VALUE-BASED APPROACH
Over the past decade, there has been rapid growth in the
cost of cancer care as a whole. In the United States, it is
expected to increase from $125 billion in 2010 to $158 billion
in 2020.28 Although drug treatment costs account for as
much as 20% of total cost, it is imperative that health
systems evaluate new treatments strategically to maximize
value of health expenditures. In HER2 breast cancer, the
benefits gained by new treatments have been undeniably
important clinically. Physicians, policy makers, and funding
agencies are tasked with identifying economic trade-offs and
ensuring patients have access to treatments with mean-
ingful health benefits in a resource-limited environment.
 HER2-POSITIVE BREAST CANCER: A VALUE-ORIENTED APPROACH TO TREATMENT

Clinical Benefit Value Assessment

The definition of clinical benefit is variable. Ideally, it would
include all patient-important outcomes. In practice, the evi-
dence used to create treatment guidelines is the highest quality
available, such as the randomized controlled trials described. In
ASCOs 2015 value framework, clinical endpoints used to assess
benefit (OS, PFS, DFS) were selected based on their repre-
sentation of data collected in clinical trials.29 Based on this
framework, Table 1 summarizes the clinical benefit observed in
landmark trials in early breast cancer. Table 2 summarizes
clinical benefit in advanced disease.
Economists use a variety of methods to assess value.
Commonly used in evaluations of medical intervention are
quality-adjusted life-years (QALYs) and incremental cost
effectiveness ratios (ICERs; Table 3). QALY incorporates both
quality and quantity of life achieved with treatment. A
treatment with a low cost per QALY is more cost effective
than one with high cost per QALY. An ICER is simply the ratio
between the difference in cost and the difference in benefit
of two interventions. In cost-effectiveness analyses, ICER are
commonly expressed as incremental cost per QALY. Defining

TABLE 3. Summary of Key North American Cost-Effectiveness Analyses on Targeted HER2 Therapies in Various
Lines of Treatment
Study Country HER2 Test and Treatment ICER/QALY
33
Neoadjuvant Pertuzumab Attard et al Canada HER2 test: not included in analysis Neosphere: $25,388 per QALY
NeoSphere: neoadjuvant TRYPHAENA: $46,196 per
docetaxel + trastuzumab 6 QALY
pertuzumab surgery
fluorouracil + epirubicin +
cyclophosphamide (FEC)
TRYPHAENA: docetaxel + carbo-
platin + trastuzumab +
pertuzumab
Adjuvant Trastuzumab Kurian et al32 United States HER2 test: not included in analysis Anthracycline based: $39,98
per QALY
Treatment: anthracycline-based Nonanthracycline is more ex-
regimens in NSABP B-31 and pensive and less effective,
NCCTGN9831 trials; nonan- therefore both with and
thracycline regimen from without trastuzumab ex-
BCIRG 006 + trastuzumab for 52 ceed $100,000 per QALY
weeks vs. chemotherapy only compared with anthracy-
cline regimens
Garrison et al46 United States HER2 test: not included in analysis $26,417 per QALY over
a lifetime
Treatment: anyhtacycline-based
regimens from NSABP B-31 and
NCCTG N9831 trials plus
trastuzumab (at actual dose/
duration received in trial) vs.
chemotherapy alone
Metastatic trastuzumab Elkin et al34 United States HER2 test: IHC +3; IHC with FISH Initial IHC with FISH confir-
for IHC 2+ and 3+; IHC with FISH mation: $125,0000 per
for IHC 2+; FISH only QALY
Treatment: trastuzumab + Initial FISH: $145,000 per
paclitaxel vs. paclitaxel only QALY
Other strategies for HER2
testing less cost effective
First-line pertuzumab Durkee et al36 United States HER2 testing: not included in $713,219 per QALY
analysis
Treatment: docetaxel + trastuzu-
mab + pertuzumab vs. doce-
taxel and trastuzumab alone
Metastatic T-DM1 PCODR Canada HER2 testing: not included in $162,839 per QALY
analysis
Treatment: T-DM1 vs. lapatinib
capecitabine
Metastatic capecitabine + lapatinib Le et al35 United States HER2 testing: not included in $166,113 per QALY
analysis
Treatment: capecitabine + lapati-
nib vs. capecitabine alone
Abbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-years; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; DM1, emtansine.

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NIXON AND VERMA
the threshold for cost effectiveness is a focus for funding
sources worldwide and is variable depending on the funding
party and the basic structure of the health care system. In
most analysis from the United States using USD, a threshold
level of $100,000 per QALY is considered cost-effective
(range 50,000 to three times the United States per capita
gross domestic product, or $160,000 per QALY).30 This
method of assessment is fraught with variability that is
highly subjective to the approach used to estimate OS in the
control group when crossover is allowed in the trial, in-
clusion of treatment past progression, and the cost of HER2
testing as demonstrated in a systemic review by Parkinson
et al.31
In the adjuvant setting, trastuzumab was shown to be cost-
effective by Kurian et al, who estimated an ICER of $39,982
USD per QALY.32 Cost-effectiveness of pertuzumab in the
neoadjuvant setting was investigated by Attard et al based
on pCR data from both NeoSphere and TRYPHAENA.33
Published EFS and OS data for patients achieving and not
achieving pCR were used in combination with percentage
achieving pCR in trials to estimate survival. The incremental
cost per QALY ranged from $25,388 CAD (NeoSphere) to
$46,196 CAD (TRYPHAENA analysis), making the addition of
pertuzumab cost-effective with a threshold of $100,000.
For treatment of advanced disease, the cost of even a
single targeted agent increases significantly per QALY. For
HER2 testing and treatment with trastuzumab in the met-
astatic setting, Elkin et al determined an ICER of $125,000
USD per QALY.34 A similar method was used to determine
the ICER for lapatinib pus capecitabine to be $166,113 USD
per QALY, not including testing for HER2 positivity.35 The
pan-Canadian Oncology Drug Review (pCODR) calculated a
cost of $162,839 CAD for T-DM1 based on EMILIA trial re-
sults. The addition of pertuzumab to docetaxel and tras-
tuzumab according to the CLEOPATRA trial, was found to be,
again, incrementally higher in a recent publication, with an
estimated ICER of $713,219 USD per QALY gained.36 Despite
the high cost, most funding agencies have adopted these
therapies into clinical practice. This brings to question what
practical considerations can be made to maximize access to
highly effective, costly treatments in an environment of
limited resources.
PRACTICAL CONSIDERATIONS
Metastatic Disease
There are several limitations to QALY as a means of eval-
uation for treatment of advanced breast cancer patients. In
the metastatic setting, successful treatments are victims of
their own success, because longer PFS extrapolates to more
time accruing costs for expensive therapies. Additionally,
QALY does not capture an individual patients priorities. For
patients with metastatic disease, the balance between
quality versus quantity of life is a much more personal
determination than for early breast cancer, where the goal
is to cure. It also does not take into account the benefit of
time-off treatment or symptom improvement. Based on
these limitations, we pose questions for discussion that still
e60 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
focus on treatment according to best evidence, while finding
ways to minimize costs and avoid overtreatment.
Should dual anti-HER2 maintenance be continued after
maximal response? There is limited evidence to answer
whether maintenance with dual anti-HER2 blockade should
be continued once maximal response is achieved. There is,
however, evidence of continued efficacy of trastuzumab
after progression on a trastuzumab-based regimen. A trial
by Von Minckwitz et al looked at the combination of
capecitabine plus trastuzumab versus trastuzumab alone
as a second-line treatment.10 This showed a significant im-
provement in TTP (8.2 vs. 5.6 months; p = .03) and a non-
significant trend in OS (25.5 vs. 20.4 months; p = .257). In a
separate study, the combination of trastuzumab plus laptinib
versus lapatinib alone after progression on a trastuzumab-
based regimen was investigated.16 This showed a significant
improvement for PFS in the combination arm (12 weeks vs.
8.1 weeks; p = .008) and OS (14 vs. 9.5 months).
Currently, no trials have been done to address con-
tinuation of targeted therapy after maximal response is
achieved. In most trials, HER2-targeted therapy was ad-
ministered until disease progression or until significant
toxicity leading to discontinuation of therapy. Current
recommendations on duration from ASCO and the cost-
effectiveness analysis mentioned before are based on the
approach used in relevant clinical trials. Potential gains in
both quality of life and cost-effectiveness may be achieved
if we consider treatment breaks in patients who have
sustained a response with no evidence of progression. This
approach needs to evaluated and studied in the metastatic
setting and could be guided by utilization of functional
imaging/circulating tumor cells.
Do all patients need dual anti-HER2 blockade up front? If
we are able to identify a certain subgroup within the HER2
population that derives the greatest benefit from dual-
antibody treatment, it allows us to be selective in who re-
ceives the treatment, sparing others both toxicities and cost.
Baselga et al looked to answer this question by assessing a
protocol-prespecified panel of biomarkers in tumor and
serum samples from patients on the CLEOPATRA trial.17
Biomarkers were identified based on previous under-
standing of HER2-signaling pathways, or HER2-targeted
therapy resistance. Pertuzumab was found to have a con-
sistent benefit for PFS, independent of biomarker sub-
groups. This indicates that to our current knowledge, HER2 is
the only marker that should be used for patient selection for
the combination of trastuzumab plus pertuzumab. There is a
need for further studies that may help to elucidate tumor, or
patient-related factors that may ultimately help us de-
termine which patients are best candidates for dual anti-
bodies up front.
One of the key questions that must be asked when ap-
plying evidence to practice is whether the patient population
in the study matches the patient being treated in the real-
world setting. In the CLEOPATRA trial, 90% of patients were

nave to any HER2-targeted therapy. In practice, many of the
patients we treat in the first line for metastatic disease are
being treated for recurrence, and have already received
antibody treatment in the adjuvant setting. Swain et al
recently published the results that suggest incremental
improvement for patients who relapsed postadjuvant
trastuzumab; however, although the HR was similar, the
prognosis and overall results for this population were in-
ferior compared with de novo patients.37 Forty-one patients
in the control group and 47 patients in the treatment arm
were enrolled after 1 year of adjuvant trastuzumab. The OS
was 46.6 months and 53.8 months, respectively (HR 0.8;
95% CI, 0.441.47), with a large confidence interval owing
to relatively small numbers. The study authors point out,
however, that since the introduction of trastuzumab in the
adjuvant setting the proportion of patients who had re-
current disease had significantly decreased, as shown in the
SystHERs trial.38 This means that the results of the CLEO-
PATRA trial may reflect what is seen in practice today, with
increased proportion of patients being treated with HER2-
positive de novo presentation.
Early Breast Cancer
Treatment of early breast cancer is distinct from advanced
breast cancer because the treatment goals are more clearly
defined and uniform across patients. Treatment with the
goal of cure makes decreasing treatment intensity an un-
common target. However, because outcomes of HER2-
positive breast cancer exceed survival rates of 95%, it is
important to consider whether a subset of patients exists in
whom we can de-escalate therapy.
Is there a population who do not need HER2-targeted
treatment? For patients who are HER2-negative, chemo-
therapy is generally not recommended unless they are
lymph nodepositive, or high-risk lymph nodenegative. In
the HER2+ population, however, the threshold for treatment
is lower based on our knowledge that even earlier stage
tumors are more likely to recur. OSullivan et al performed a
meta-analysis of five trastuzumab randomized controlled
trials in early breast cancer and tumors 2 cm or smaller.39
They concluded that patients with HER2-positive and tumors
2 cm or smaller had major DFS and OS benefits from tras-
tuzumab as part of the treatment regimen.
For patients with T1a or T1b tumors that are node-
negative, prognosis is less well-defined, even in the set-
ting of HER2 positivity. Ferenbacher et al did a retrospective
analysis of 234 patients with HER2-positive, lymph node
negative, and T1a or T1b tumors.40 Distant invasive re-
currence was the primary endpoint. Five-year distant
relapse-free survival was 98.2% for T1a, 89.4% for T1b, and
84.5% for 1-cm tumors. A majority (74%) of these patients
had no adjuvant treatment, raising the possibility of not
requiring therapy for certain T1a patients. In contrast, a
study by Rodriguez et al41 looked at 276 patients with
node-negative, T1a-b HER2-positive breast cancer. Of these
HER2-POSITIVE BREAST CANCER: A VALUE-ORIENTED APPROACH TO TREATMENT
patients, 47% had been given adjuvant chemotherapy and
trastuzumab. Disease-free survival at 40 months was 93% for
patients who had not received chemotherapy versus 99% for
those who had. In multivariate analysis, tumor size was not
associated with clinical outcomes, leading the authors to
state adjuvant treatment should be discussed with all HER2-
positive T1a-b tumors. Based on the available data, one has
to weigh the potential benefit:risk of toxicity and cost im-
plications specifically for patients with T1a/T1b tumors.
Does everyone need neoadjuvant pertuzumab? In the
adjuvant setting similarly to advanced disease, there is
question of whether patients who are positive for both HER2
and hormone receptors should be treated the same. In the
NeoSphere study, patients were stratified according to
hormone receptor status at the time of randomization. They
subsequently compared pCR results across these groups.
Patients that were estrogen receptor (ER) and progesterone
receptor (PgR)negative showed a pCR rate of 63% when
pertuzumab was added to docetaxel and trastuzumab, com-
pared with 36.8% with trastuzumab and docetaxel alone. In
patients who were also ER-positive, PgR-positive, or both, the
three-drug regimen had a pCR of 26%, compared with 20% with
docetraxel and trastuzumab. The updated EFS data show a
nonsignificant trend for improvement in EFS. One requires
confirmatory adjuvant data to truly assess the benefit of adding
pertuzumab to standard trastuzumab-based therapy.42
Do patients need 1 year of trastuzumab? Duration of
trastuzumab has been looked at in multiple studies. In the
original HERA study, trastuzumab for 1 year plus chemo-
therapy was compared with chemotherapy alone, and in a
third arm trastuzumab for 2 years was given. At a median
follow-up of 8 years, there was no difference between 1 and
2 years with respect to DFS (HR 0.99; p = .86) or OS (HR 1.05;
p = .63). The other pivotal trials discussed before used the
duration of 1 year somewhat empirically. Shorter duration of
adjuvant trastuzumab was studied in the FinHER trial.43 This
study tested nine cycles of weekly trastuzumab with adju-
vant docetaxel or vinorelbine followed by FEC in a subset of
early breast cancer patients with HER2-positive, high-risk
disease (node-positive or node-negative with tumors at least
2 cm). The primary endpoint of recurrence-free survival
favored the trastuzumab arm (HR 0.41; p = .01), as did OS (HR
0.41; p = .07). Documented clinical improvement was similar
to standard of 1-year therapy seen in previous trials.
In a larger phase III study, PHARE randomly assigned 1,693
patients with HER2-positive high-risk (node-positive) disease
to chemotherapy plus 6 months versus 1 year of trastuzu-
mab.44 This study failed to achieve its primary outcome of
noninferiority at a median follow-up of 3.5 years. Addi-
tionally, more patients in the 6 months group had a distant
recurrence as the first DFS event.
There are a number of ongoing studies to evaluate
shorter treatments of adjuvant trastuzumab comparing 6 to
12 months (e.g., the Hellenic group trial, the Persephone
study) and 3 to 12 months (e.g., SOLD study, Short-HER
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NIXON AND VERMA
study). These studies will provide insight into possibly reducing
the duration of adjuvant treatment and, subsequently, costs.
While awaiting these results, 1 year continues to be the
standard of care.
Biosimilars
The most intuitive way to receive the benefit of targeted
treatments without the cost is to find a cheaper, equally
effective alternative. For this purpose, there has been great
interest in the production of biosimilar agents. Biosimilars
are distinct from generic formulations in that they are not
biochemically identical to the original. Biologic agents are
complex, with larger size and more intricate structure, such
that exact replication is impossible.45 Biosimilars, therefore,
must be tested to ensure noninferior biologic activity, safety,
and efficacy.46 At least 10 trastuzumab biosimilar mono-
clonal antibodies are in active development. The furthest
along in testing is CT-P6, produced by Celltrion. CT-P6 has
been through phase III testing and has demonstrated an
equivalent overall response rate (primary endpoint) to
trastuzumab in patients with metastatic disease. Based on
this trial, CT-P6 has already been approved as a biosimilar in
South Korea. As this becomes available, the cost of tras-
tuzumab may drop by as much as 40%.
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BCIRG-006 Trial comparing doxorubicin plus cyclophosphamide
followed by docetaxel (ACT) with doxorubicin plus cyclosphosphamide
followed by docetaxel and trastuzumab (ACTH) with docetaxel, carbo-
platin, and trastuzumab (TCH) in HER2+ early breast cancer. Presented at:
San Antonio Breast Cancer Symposium; December 2015; San Antonio,
TX. Abstract S5-S04.
22. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and
long-term clinical benefit in breast cancer: the CTNeoBC pooled
analysis. Lancet. 2014;384:164-172.
23. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant
pertuzumab and trastuzumab in women with locally advanced, in-
flammatory, or early HER2-positive breast cancer (NeoSphere):
a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;
13:25-32.
24. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in
combination with standard neoadjuvant anthracycline-containing and
anthracycline-free chemotherapy regimens in patients with HER2-
positive early breast cancer: a randomized phase II cardiac safety
study (TRYPHAENA). Ann Oncol. 2013;24:2278-2284.
25. Baselga J, Bradbury I, Eidtmann H, et al; NeoALTTO Study Team.
Lapatinib with trastuzumab for HER2-positive early breast cancer
(NeoALTTO): a randomised, open-label, multicentre, phase 3 trial.
Lancet. 2012;379:633-640.
26. Guarneri V, Frassoldati A, Bottini A, et al. Preoperative chemo-
therapy plus trastuzumab, lapatinib, or both in human epidermal
growth factor receptor 2-positive operable breast cancer: results of
the randomized phase II CHER-LOB study. J Clin Oncol. 2012;30:
1989-1995.
27. Robidoux A, Tang G, Rastogi P, et al. Lapatinib as a component of
neoadjuvant therapy for HER2-positive operable breast cancer (NSABP
protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol.
2013;14:1183-1192.
28. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer
care in the United States: 2010-2020. J Natl Cancer Inst. 2011;103:
117-128.
29. Schnipper LE, Davidson NE, Wollins DS, et al; American Society of
Clinical Oncology. American Society of Clinical Oncology Statement: A
Conceptual Framework to Assess the Value of Cancer Treatment Op-
tions. J Clin Oncol. 2015;33:2563-2577.
HER2-POSITIVE BREAST CANCER: A VALUE-ORIENTED APPROACH TO TREATMENT
30. Ubel PA, Loewenstein G, Jepson C. Whose quality of life? A commentary
exploring discrepancies between health state evaluations of patients
and the general public. Qual Life Res. 2003;12:599-607.
31. Parkinson B, Pearson SA, Viney R. Economic evaluations of trastuzumab
in HER2-positive metastatic breast cancer: a systematic review and
critique. Eur J Health Econ. 2014;15:93-112.
32. Kurian AW, Thompson RN, Gaw AF, et al. A cost-effectiveness analysis of
adjuvant trastuzumab regimens in early HER2/neu-positive breast
cancer. J Clin Oncol. 2007;25:634-641.
33. Attard CL, Pepper AN, Brown ST, et al. Cost-effectiveness analysis of
neoadjuvant pertuzumab and trastuzumab therapy for locally ad-
vanced, inflammatory, or early HER2-positive breast cancer in Canada.
J Med Econ. 2015;18:173-188.
34. Elkin EB, Weinstein MC, Winer EP, et al. HER-2 testing and trastuzumab
therapy for metastatic breast cancer: a cost-effectiveness analysis. J Clin
Oncol. 2004;22:854-863.
35. Le QA, Hay JW. Cost-effectiveness analysis of lapatinib in HER-2-positive
advanced breast cancer. Cancer. 2009;115:489-498.
36. Durkee BY, Qian Y, Pollom EL, et al. Cost-effectiveness of pertuzumab in
human epidermal growth factor receptor 2-positive metastatic breast
cancer. J Clin Oncol. 2015;63:1-12.
37. Swain S, Baselga, J. Treatment of HER2-positive metastatic breast
cancer. N Engl J Med. Correspondence. 2015;372:1964-1965.
38. Tripathy D, Brufsky A, Cobleigh M, et al. Increasing proportion of de
novo compared with recurrent HER2-positive metastatic breast cancer:
early results from the systemic therapies for HER2-positive metastatic
breast cancer registry study. Presented at the 37th Annual San Antonio
Breast Cancer Symposium; December 2014; San Antonio, TX.
39. OSullivan CC, Bradbury I, Campbell C, et al. Efficacy of adjuvant
trastuzumab for patients with human epidermal growth factor receptor
2-positive early breast cancer and tumors #2cm: A meta-analysis of the
randomized trastuzumab trials. J Clin Oncol. 2015;33:2600-2608.
40. Fehrenbacher L, Capra AM, Quesenberry CP Jr, et al. Distant invasive
breast cancer recurrence risk in human epidermal growth factor re-
ceptor 2-positive T1a and T1b node-negative localized breast cancer
diagnosed from 2000 to 2006: a cohort from an integrated health care
delivery system. J Clin Oncol. 2006;32:2151-2158.
41. Rodrigues JM, Wassermann J, Albiges L, et al. Trastuzumab treatment
in T1ab, node-negative human epidermal growth factor receptor
2-overexpressing breast carcinomas. J Clin Oncol. 2010;28:e541-e542.
42. Gianni L, Pienkowski T, Im Y, et al. Five-year analysis of the phase II
NeoSphere trial evaluating four cycles of neoadjuvant docetaxel (D)
and/or trastuzumab (T) and/or pertuzumab (P). J Clin Oncol. 2015;33:
15s (suppl; abstr 505).
43. Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin, and cy-
clophosphamide with either docetaxel or vinorelbine, with or without
trastuzumab, as adjuvant treatments of breast cancer: final results of
the FINHER trial. J Clin Oncol. 2009;27:5684-5692.
44. Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of
adjuvant trastuzumab for patients with HER2-positive early breast cancer
PHARE: a randomized phase 3 trial. Lancet Oncol. 2013;14:741-748.
45. Thill M. New frontiers in oncology: biosimilar monoclonal antibodies for
the treatment of breast cancer. Expert Rev Anticancer Ther. 2015;15:
331-338.
46. Garrison LP Jr, Lubeck D, Lalla D, et al. Cost-effectiveness analysis of
trastuzumab in the adjuvant setting for treatment of HER2-positive
breast cancer. Cancer. 2007;110:489-498.
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MARTIN AND LOPEZ-TARRUELLA

Emerging Therapeutic Options for HER2-Positive Breast

Cancer
Miguel Martin, MD, PhD, and Sara Lopez-Tarruella,
MD, PhD

OVERVIEW

The natural history of HER2-positive breast cancer has progressively improved since the introduction of the first anti-HER2
directed therapy (trastuzumab). Trastuzumab has significantly increased survival of patients with HER2-positive metastatic
breast cancer and, after the standardization of the use of this drug in the adjuvant setting in 2005, has also avoided many
disease recurrences and, consequently, saved many lives. Later on, the introduction of lapatinib offered new choices for
patients with advanced HER2-positive breast cancer, although the drug has failed to show a clear efficacy in the adjuvant
setting. New promising drugs have been approved to broaden the horizon of HER2-positive breast cancer such as per-
tuzumab or T-DM1, but we need new options to further improve the management of these diseases. In this review, we cover
new strategies that are currently under evaluation for the treatment of patients with HER2-positive breast cancer, including
new tyrosine kinase inhibitors (neratinib, ONT-380), new antibody-drug conjugates targeting HER2 (MM-302), and new
indications of already approved drugs (T-DM1), as well as the potential dual combinations of anti-HER2 therapy with
phosphoinositide 3-kinase/mTOR or cell cycle inhibitors (palbociclib, abemaciclib). Last but not least, we briefly review a new
paradigm of emerging approaches that involve the host immune response, HER2 breast cancer vaccines, and other immune
strategies, including immune checkpoint inhibition.

A dvances in the treatment of patients with HER2-positive

breast cancer have been made over the past few de-
cades, both in the metastatic setting and in the neo/adjuvant
treatment of earlier stages. In the neo/adjuvant setting, the
combination of chemotherapy, trastuzumab, and perhaps
pertuzumab (for high-risk patients) has significantly im-
proved patient outcomes. In the metastatic setting, the
outcome of patients with HER2-positive tumors has also
significantly improved, owing to the introduction of effective
anti-HER therapies, including trastuzumab, pertuzumab,
lapatinib, and T-DM1. The reported median survival time
using these modern combination therapies is now approx-
imately 5 years compared with approximately 1.5 years in
the pretrastuzumab era.1,2
Despite this, 15%20% of patients with HER2-positive local-
regional breast cancer still relapse after receiving the currently
available neo/adjuvant therapies. In addition, metastatic HER2-
positive breast cancer essentially remains an incurable disease,
despite the improvement in survival seen after the introduction
of the new anti-HER2 therapies. Newer therapies and newer
approaches are therefore necessary to further improve the
current results. Here, we review the most promising emerging
therapeutic options currently in development for the treat-
ment of HER2-positive breast cancer (Table 1).
ORAL, SMALL-MOLECULE INHIBITORS
Neratinib
Neratinib is an oral, small-molecule, anti-HER receptor ty-
rosine kinase inhibitor with a complex history. It was designed
in the early 1990s at Lederle Laboratories (Pearl River, NY) and
was later was developed by Wyeth-Ayerst (Quebec, Canada),
Pfizer (Quebec, Canada), and, finally, Puma Biotechnology
(Los Angeles, CA), the current owner of the drug.3,4 Neratinib
is a covalent drug that, differently from lapatinib, binds ir-
reversibly to the ATP active site of the tyrosine kinase domain
of HER2. A phase I study of neratinib among patients with
solid tumors showed that the maximum tolerated dose and
the recommended dose for phase II trials was 320 mg and
240 mg once daily, respectively. Grade 3 diarrhea was the
dose-limiting toxicity.5 The drug has good oral bioavailability
and, in the presence of food, the half-life elimination on day
1 after a single 240-mg administration is 14 hours, supporting
a once-daily dosing regimen.
Neratinib was initially tested in a phase II trial of patients
with breast cancer with HER2-positive metastatic tumors (66
patients with and 70 without prior trastuzumab therapy,
respectively) at a dose of 240 mg once daily. The study
showed that single-agent neratinib has relevant antitumor
activity among patients with HER2-positive breast cancer

From the Instituto de Investigacion ~on,

Sanitaria Gregorio Maran Universidad Complutense, Madrid, Spain.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Miguel Martin, MD, PhD, Servicio de Oncologa Medica,

Instituto de Investigacion ~on,
Sanitaria Gregorio Maran Universidad Complutense, Dr. Esquerdo 46,
28007 Madrid, Spain; email: mmartin@geicam.org.

2016 by American Society of Clinical Oncology.

e64 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook

 EMERGING THERAPEUTIC OPTIONS FOR HER2 BREAST CANCER

who were pretreated. Objective response rates (ORRs) were TABLE 1. Emerging Therapies for HER2-Positive Breast
24% for patients who received prior trastuzumab treatment Cancer
and 56% for trastuzumab-naive patients. Responses were of
long duration (9 months for patients pretreated with tras- Class Drug Mechanism of Action
tuzumab and 12 months for trastuzumab-naive patients). Oral, Anti-HER2, Neratinib Tyrosine kinase inhibitor (HER2
Median progression-free survival (PFS) was approximately Small and HER1)
Molecules
5 months for patients pretreated with trastuzumab and ONT-380 Tyrosine kinase inhibitor (HER2)
approximately 9 months for trastuzumab-naive patients. Anti-HER2 Anti- T-DM1 Trastuzumab-like effect
The downside of the treatment was the high incidence of Body-Drug
Intracellular release of emtan-
Conjugates
adverse events, particularly diarrhea and, to a much lesser sine-cytotoxic toxicity in HER2-
overexpressing cells
extent, nausea, vomiting, and fatigue. Diarrhea was reported
MM-302 Intracellular release of pegylated
for 85% of patients pretreated with trastuzumab (grade 3 to liposomal doxorubicin in
4 for 30% of patients). The incidence of diarrhea was greater HER2-overexpressing cells
in the first week of therapy (85%) but significantly declined mTOR/PI3K/Akt Everolimus mTOR inhibition
with loperamide therapy from that time onward (60% at Inhibitors
Buparlisib Pan-class I PI3K inhibitor
weeks 2 to 4, less than 40% at month 2, and approximately
Pictilisib Pan-class I PI3K inhibitor
15% at month 3).6
Taselisib Alpha-specific PI3K inhibitor
Based on these appealing phase II data, single-agent
Alpelisib Alpha-specific PI3K inhibitor
neratinib was compared with the combination of lapatinib
and capecitabine in a phase II noninferiority study. The CDK4/6 Palbociclib CDK4/6 inhibition, cell cycle arrest
Inhibitors
comparator was the standard therapy for trastuzumab- Abemaciclib CDK4/6 inhibition, cell cycle arrest
pretreated HER2-positive metastatic breast cancer at the Vaccines E75 Peptide-based vaccine
time the study was designed (capecitabine plus lapatinib). Of GP2 Peptide-based vaccine
the study patients, 117 were allocated to receive 240 mg Immune Pembrolizumab AntiPD-1
of neratinib daily and 116 patients received 1,250 mg of Checkpoint
lapatinib daily plus 2,000 mg/m2 of capecitabine daily on Inhibitors
days 1 to 14 of each 21-day cycle. The study failed to show Abbreviation: PI3K, phosphoinositide 3-kinase.

noninferiority of neratinib compared with lapatinib plus

KEY POINTS
The currently available anti-HER2 therapies have
changed the natural history of HER2-positive breast
cancer, but new therapeutic options are necessary
because the disease is essentially incurable in the
metastatic setting and a relevant proportion of patients
with early-stage disease still relapse in spite of the use of
currently available therapies.
Neratinib is one of the most promising new drugs for
HER2-positive breast cancer, although the management
of its main side effect, diarrhea, should be addressed
and resolved to allow safe use of the drug.
Other drugs, such as ONT-380 (an oral, small-molecule,
HER2-selective inhibitor) and MM-302 (an anti-HER2
antibody-drug conjugate carrying pegylated liposomal
doxorubicin) have shown initial promising activity and
good tolerance among patients with HER2-positive
breast cancer.
Interest in the inhibition of downstream signaling of the
HER2 pathway with mTOR/phosphoinositide 3-kinase/
Akt and CDK4/6 inhibitors is currently under clinical
evaluation.
Some immunologic approaches (vaccines, alone or in
combination with trastuzumab, inhibitors of
immunocheckpoints, and others) are also being tested
in HER2-positive breast cancer.
capecitabine. However, neratib showed indisputable single-agent
activity in the trial, with a response rate of 29% versus 41%
with the combination of lapatinib and capecitabine (p = .067).
Median PFS and overall survival (OS) times were 4.5 and
19.7 months (neratinib) versus 6.8 and 23.6 months for the
combination, respectively. Eighty-five percent of patients taking
neratinib experienced diarrhea (grade 3 or greater for 28% of
patients). Diarrhea was more frequent in the first cycle of therapy
and was properly managed with loperamide or dose modifica-
tions for most patients.7
In view of the lack of demonstration of noninferiority of
neratinib versus the standard lapatinib plus capecitabine and to
prepare the registration trial of neratinib for trastuzumab-
pretreated HER2-positive metastatic breast cancer, a phase
I/II study combining neratinib and capecitabine was con-
ducted.8 The study was carried out in two parts. The first part
was a dose-escalation trial among 33 patients with advanced
solid tumors; they received oral neratinib once a day contin-
uously plus capecitabine twice a day (days 1 to 14 every
3 weeks) at predefined dose levels, to define the recom-
mended dose/schedule for phase II/III trials. In part two, 72
patients with trastuzumab-pretreated HER2-positive meta-
static breast cancer received the combination at the recom-
mended dose for phase II trials (240 mg of neratinib per day
continuously plus 1,500 mg/m2 of capecitabine for 2 weeks
every 21 days).
In part two, the ORR was 64% for patients with no prior
lapatinib exposure and 57% for patients previously treated with
lapatinib. Median PFS was approximately 9 and 8 months,

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MARTIN AND LOPEZ-TARRUELLA
respectively. The most common side effects of the combination
were diarrhea (88%) and palmar-plantar erythrodysesthesia
syndrome (48%). This study showed that the combination of
neratinib and capecitabine possesses significant antitumor
activity in trastuzumab-pretreated metastatic HER2-positive
breast cancer. A randomized registration trial (NALA;
NCT01808573) comparing neratinib plus capecitabine with
lapatinib plus capecitabine is underway.
A randomized phase II trial (NEFERTT; NCT00915018),
which included 479 patients with HER2-positive breast
cancer without any therapy for metastatic disease, com-
pared paclitaxel plus trastuzumab with paclitaxel plus ner-
atinib. No statistically significant differences in PFS (the
primary endpoint) or ORR (one of the trials secondary
endpoints) were seen.9 Grade 3 diarrhea was reported for
approximately 30% of patients receiving neratinib plus
paclitaxel compared with approximately 4% of patients in
the paclitaxel plus trastuzumab arm. Central nervous system
(CNS) progression occurred in 8.3% of patients in the ner-
atinib arm versus 17.3% in the trastuzumab arm (RR 0.48;
p = .002). However, the proportion of patients with CNS
involvement at study initiation was superior in the paclitaxel
arm (12 patients; 5.1%) compared with the neratinib arm
(6 patients; 2.5%).
The significant activity of neratinib observed in metastatic
HER2-positive breast cancer has prompted the evaluation of
the drug in earlier stages. A phase II trial conducted by the
NSABP group (NSABP FG-7 Trial) compared weekly paclitaxel
plus neratinib or trastuzumab or the combination of ner-
atinib and trastuzumab followed by standard doxorubicin
and cyclophosphamide as neoadjuvant therapy among
126 patients with HER2-positive locally advanced, operable
breast cancer.10 The proportions of patients with inflam-
matory breast cancer (a bad prognostic feature) were 16.7%
(neratinib arm) and 9.5% (in both the trastuzumab and the
trastuzumab plus neratinib arms). The pCR rates (breast plus
axillary lymph nodes) were 38.1% (trastuzumab arm), 33.3%
(neratinib arm), and 50% (neratinib plus trastuzumab arm).
The apparent superiority of the combination arm was
mainly attributable to the effect on patients with hormone
receptor (HR)negative disease (pCR rates of 57.1%, 46.2%,
and 73.7%, in the trastuzumab, neratinib, and combination
arms, respectively). For patients with HR-positive disease,
the pCR rates were not significantly different among arms
(29.6%, 27.6%, and 30.4%, respectively). Grade 3 diarrhea
was the most relevant side effect of neratinib (31% in both
neratinib arms vs. 0% in the trastuzumab arm). Intensive
primary prophylaxis with loperamide in neratinib-treated
patients implemented at European sites apparently reduced
the incidence of grade 3 diarrhea (17% in the neratinib
arm and 24% in the neratinib plus trastuzumab arm across
all cycles).
Neratinib has also been evaluated in the I-SPY 2 program,
a multicenter neoadjuvant trial among women with oper-
able breast cancer using adaptive randomization within
biomarker subtypes to evaluate novel antitumor drugs added
to conventional therapy.11 I-SPY 2 intends to identify new drugs
e66 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
that, in combination with standard therapy, meet a high
Bayesian predictive probability of statistical significance in a
future phase III neoadjuvant trial performed among the same
population. Patients with HER2-positive breast cancer were
randomly assigned to receive 12 weekly administrations of
paclitaxel plus trastuzumab or paclitaxel plus neratinib, fol-
lowed by four cycles of doxorubicin hydrochloride plus cy-
clophosphamide (AC) before surgery. Neratinib met the
predictive probability criterion in the population with HR-
negative/HER2-positive tumors. A phase III confirmatory trial
with neratinib is planned for patients with HER2-positive breast
cancer (I-SPY 3, a phase III registration trial).
Neratinib has been evaluated in an adjuvant phase III trial,
the ExteNET study. Eligible patients had operable-stage
HER2-positive breast cancer with no relapse after surgery,
chemotherapy, and up to 2 years after the completion of
1 year of trastuzumab. Patients were randomly assigned to
receive neratinib or placebo for 1 year (together with
hormonal therapy for patients with HR-positive tumors). In
the initial design, the trial had a 90% power to detect a
hazard ratio of 0.7 for invasive disease-free survival (iDFS),
at a two-sided 5% significance level. The study design suf-
fered from some modifications over time because the drug
owner changed and three different sponsors assumed re-
sponsibility. In the initial design, patients who were T$1c
node negative were eligible, a sample size of 3,850 patients
was established, and iDFS was the main endpoint. In view of
the good outcome of node-negative patients with standard
trastuzumab-containing chemotherapy later reported in
other adjuvant trials (particularly the BCIRG 006 study), an
initial amendment restricted recruitment to patients with
node-positive disease with trastuzumab completion 1 year
or earlier before randomization. In October 2011, the new
sponsor introduced two key changes: cessation of enroll-
ment (only 2,842 patients of the initially planned of 3,850
had been enrolled at that time) and shortening of follow-up
to 2 years from randomization. In January 2014, a new
amendment re-established the extension of data collection
for disease events and deaths to 5 years postrandomization
for consenting patients and the primary endpoint of iDFS at
2 years of follow-up was resumed. Treatment allocation
remained blinded to the sponsor prior to the first analysis
and an independent statistical evaluation by a reputed
biostatistician who had access to all data was performed.
The detailed analyses showed that the results remained
consistent throughout the trial and were trustable. The
primary analysis was first reported in 201512 and published
in detail in 2016.13 At 2 years from randomization, the hazard
ratio for iDFS in the neratinib group compared with the
placebo group was 0.67 (p = .009), with 2-year iDFS rates of
93.9% and 91.6%, respectively. A preplanned subgroup
analysis according to HR status showed that patients
with HR-positive tumors (the majority of whom were re-
ceiving concurrent hormonal therapy) obtained the greatest
benefit with neratinib (hazard ratio for iDFS of 0.51, p = .001),
whereas patients with HR-negative tumors had little or
no benefit (hazard ratio for iDFS, 0.93; p = .735; interaction

p = .054). Another preplanned analysis of iDFS for 1,463
patients with centrally confirmed HER2-positive disease
showed a hazard ratio of 0.51 (95% CI, 0.330.77; p = .002).
The 3-year update of the ExteNET trial was recently reported
and confirmed the earlier findings.14 OS data were not
mature but will continue to be monitored.
Diarrhea was the most frequent side effect of neratinib in
the ExteNET trial and occurred among most patients (grade 2
in 32.5%, grade 3 in 39.8%, and grade 4 in 0.1%). Ustaris
et al15 recently reviewed the characteristics and treatment
of neratinib-induced diarrhea. This side effect usually starts
during the first month of therapy and resolves or decreases
later among most patients either spontaneously or with
loperamide or dose reductions. Diarrhea is a cause of dose
reduction for 10%15% of patients. Permanent discontin-
uation of neratinib because of diarrhea occurs in a minority
of patients (0%14% of patients in the reviewed trials) and
seems to be reduced by the introduction of early, intense
loperamide prophylaxis. A prospective clinical trial is eval-
uating the efficacy of prophylactic loperamide among pa-
tients with HER2-positive operable breast cancer receiving
extended adjuvant neratinib (NCT02400476). Loperamide is
administered at a dose of 4 mg three times a day for the first
2 weeks of neratinib and 4 mg twice a day until week 8.
ONT-380
ONT-380 is an oral, small-molecule, HER2-selective inhibitor in
clinical development. It is speculated that the lack of inhibition
of HER1 could translate into a lower frequency of skin and
gastrointestinal toxicity with respect to HER2/HER1 dual in-
hibitors (i.e., lapatinib, or neratinib). In fact, a phase I trial with
ONT-380 as a single agent showed no treatment-related grade
3 diarrhea and only minimal skin toxicity. In a phase Ib trial of
ONT-380 in combination with T-DM1 among patients who
received prior taxane and trastuzumab treatment, a 41% ORR
was reported.16 A second study reported the CNS activity of
ONT-380 in combination with either T-DM1 or trastuzumab or
capecitabine. Patients with brain metastases assessable for
response were included in the combined analysis. Responses
and clinical benefit in the CNS were reported with the three
combinations tested, supporting future development of the
drug for this particular indication.17
ANTIBODY-DRUG CONJUGATES
T-DM1
T-DM1 is the first antibody-drug conjugate (ADC) approved for
metastatic HER2-positive breast cancer for the indication of
patients pretreated with taxanes and trastuzumab.18 The role
of T-DM1 in earlier stages of the disease is currently under
evaluation. The KAITLIN trial (NCT01966471) is an adjuvant
study in operable HER2-positive breast cancer. After surgery,
patients are randomly assigned to receive four cycles of
anthracycline-containing chemotherapy followed by combi-
nation treatment with taxane, trastuzumab, and pertuzumab
or with T-DM1 and pertuzumab. The study enrollment has
stopped and the protocol was amended in view of the results of
EMERGING THERAPEUTIC OPTIONS FOR HER2 BREAST CANCER
the MARIANNE trial, in which T-DM1 plus pertuzumab was not
superior to taxane plus trastuzumab as a first-line treatment for
patients in the metastatic setting.
The ADAPT trial19 is a phase II trial that enrolled 375 patients
with HR-positive, operable, HER2-positive tumors and ran-
domly assigned them to receive neoadjuvant T-DM1, T-DM1
plus endocrine therapy, or trastuzumab plus endocrine therapy
for 12 weeks prior to surgery. The pathologic complete re-
sponse rates (breast plus axilla) were 41%, 41.5%, and 15.1%,
respectively.
The phase III KATHERINE trial (NCT01772472) compares
adjuvant trastuzumab versus adjuvant T-DM1 for patients with
HER2-positive tumors in which the tumor persisted in the
breast or axilla after neoadjuvant chemotherapy plus trastu-
zumab. The KRISTINE trial (TRIO-021; NCT02131064) is an
ongoing phase III trial in which patients are randomly assigned
to neoadjuvant standard docetaxel, carboplatin, trastuzumab,
and pertuzumab or to T-DM1 plus pertuzumab, with pCR as the
main endpoint.
MM-302
MM-302 is an ADC composed of a HER2-directed antibody
(lacking anti-HER2 activity) linked to pegylated liposomal
doxorubicin. The antibody acts as a carrier delivering pegylated
liposomal doxorubicin into HER2-positive breast cancer cells.
The drug has been tested in a phase I trial with 69 patients
with HER2-positive metastatic breast cancer after a median of
four prior regimens for metastatic disease. Patients were
treated with either MM-302 alone, MM-302 plus trastuzumab,
or MM-plus trastuzumab and cyclophosphamide. The most
frequent adverse events (. 20% of patients) were con-
stipation, cough, decreased appetite, diarrhea, dyspnea, fa-
tigue, nausea, neutropenia, stomatitis, and vomiting. As a
single agent, a maximum tolerated dose was not reached at
50 mg/m2. Cardiotoxicity was seen only among patients with
extensive prior exposure to regular anthracyclines. Antitumor
activity was observed for 49 patients treated with 30 mg/m2 of
MM-302 or greater, alone or in combination with trastuzumab,
with a response rate of 12% and median PFS of 7.6 months.
Responses were seen for patients pretreated with trastuzu-
mab, T-DM1, and pertuzumab. The median PFS among the 13
patients receiving MM-302 plus trastuzumab and cyclophos-
phamide was 10.6 months.20 In view of these data, a ran-
domized phase II study (the HERMIONE trial; NCT02213744) is
ongoing. The study includes patients with metastatic HER2-
positive breast cancer who received prior trastuzumab, T-DM1,
and pertuzumab treatment (but not anthracyclines in any
setting) and randomly assigns patients to receive MM-302 plus
trastuzumab or trastuzumab plus a single chemotherapy agent
at the physicians choice.
INHIBITORS OF DOWNSTREAM SIGNALING
PATHWAYS
mTOR/Phosphoinositide 3-Kinase/Akt Inhibitors
The mTOR/phosphoinositide 3-kinase (PI3K)/Akt pathway
plays an important role in the downstream signaling of
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MARTIN AND LOPEZ-TARRUELLA
the HER2 pathway and is a potential target for combined
therapies.21 The BOLERO 3 trial studied adding the mTOR
inhibitor everolimus to conventional chemotherapy
(vinorelbine-trastuzumab) among patients with metastatic
HER2-positive breast cancer who were pretreated with
trastuzumab and taxanes. The addition of everolimus sig-
nificantly improved PFS compared with vinorelbine-
trastuzumab alone.22 The BOLERO 3 trial provided the
proof of principle that the blockade of mTOR can play a role
in the management of HER2-positive breast cancer; how-
ever, the significant increase in toxicity associated with
everolimus administration makes this combination un-
attractive. The BOLERO 1 trial, a first-line study comparing
paclitaxel plus trastuzumab with or without everolimus,
failed to show any significant advantage in PFS with ever-
olimus in the overall group of 719 patients. However, the HR-
negative subpopulation obtained an apparent benefit with
the addition of everolimus (median PFS of 20.27 months vs.
13.08 months with placebo, p = .0049), although the pre-
planned protocol-specified significance threshold (p = .0044)
was not crossed.23 Slamon et al24 used next-generation
sequencing (NGS) and immunohistochemistry (IHC) to es-
tablish the status of the PI3K pathway in tumor samples
(mainly primary tumors) from patients from the BOLERO
1 and 3 trials. Exons of 282 cancer-related genes were an-
alyzed by NGS, whereas PTEN (phosphatase and tensin
homolog) levels were determined by IHC. Patients with low
PTEN or known PIK3CA or AKT1 E17K mutations were
considered to have PI3K pathway activation. Patients with
PI3K pathway hyperactivity showed a significantly better PFS
with exemestane, but the remaining patients did not.24 The
role of everolimus in the routine therapy of metastatic HER2-
positive breast cancer is therefore currently undefined.
Clinical trials of PI3K pathway inhibitors (both pan-class
I and alpha-specific inhibitors) for the treatment of meta-
static HER2-positive breast cancer are underway. In a phase
Ib trial of buparlisib plus trastuzumab for patients with HER2-
positive metastatic breast cancer that progressed while they
were taking trastuzumab, the combination was well toler-
ated and showed some activity; at the recommended dose
for phase II trials, there were two partial responses (17%)
and seven disease stabilizations of 6 weeks or longer
(58%).25 Several studies are testing the activity of other
PI3K inhibitors, including alpelisib (NCT02038010), taselisib
(NCT02390427), and pictilisib (NCT00960960).
CDK4/6 Inhibitors
CDK4/6 controls a key pathway downstream of HER2. The
activated cyclin DCDK4/6 heterodimer promotes cell cycle
progression. Deregulation of cell cycle control is not un-
common in estrogen receptorpositive and HER2-positive
breast cancer; therefore, inhibition of CDK4/6 could be a
way to augment the effectiveness of standard anti-HER2
therapies.
Palbociclib, a CDK4/6 inhibitor, is synergistic with trastuzumab
and T-DM1 in HER2-positive preclinical models.26,27 A phase Ib
e68 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
study is exploring the combination of palbociclib and T-DM1
in metastatic HER2-positive breast cancer after prior tras-
tuzumab or other HER2-directed therapies (NCT01976169).
The PATRICIA trial (NCT02448420) is a phase II study of
palbociclib and trastuzumab with or without letrozole among
patients with HER2-positive metastatic breast cancer who
have received chemotherapy and treatment with trastu-
zumab for their metastatic disease.
Abemaciclib, another CDK4/6, has been safely combined
with trastuzumab in a phase Ib study (NCT02057133). Di-
arrhea was a dose-limiting toxicity. The recommended dose
for further studies is 150 mg/12 hours.28
VACCINES AND OTHER FORMS OF
IMMUNOTHERAPY
Tumor Vaccines
This strategy aims to amplify the patients immune response
against HER2-positive breast cancer. The majority of breast
cancer vaccine trials were initially performed in advanced
stages of the disease and the results were somewhat dis-
appointing.29 The high genomic instability and the loss of
antigens,30 together with defects in the antitumor immune
response (T-cell activation/function and regulation) found in
metastatic breast cancer, can explain these negative results.
Afterward, the cornerstones of clinical development of
cancer vaccines were redefined,31 emphasizing the need for
selecting an appropriate clinical context; herein, early or
minimal residual disease stages were proposed as more
suitable scenarios to be explored. Several vaccine formu-
lations have been tested among patients with HER2-positive
breast cancer.32
Peptide-based vaccines use antigen epitopes of cancer
cells combined with different adjuvants to elicit immune
responses. The main advantages of this approach include
their easy manufacture at low cost, storage stability, safety,
and measurable antigen-specific immune response in the
blood (direct monitoring of T-cell response).33
E75 is an immunogenic peptide derived from the extra-
cellular domain of HER2. Small-size phase I trials tested E75
with different immune-adjuvants in metastatic breast and
ovarian cancer, demonstrating that the peptide was able to
induce specific cytotoxic T-lymphocyte responses with a
favorable safety profile. However, no meaningful antitumor
activity was seen. Because the metastatic studies showed
that this active immunization could last several years after
the vaccination process, the vaccine was later tested in the
adjuvant setting. E75, in combination with granulocyte-
macrophage colony-stimulating factor (GM-CSF), was eval-
uated in a small randomized trial of patients with high-risk
breast cancer with any level of HER2 and HLA-A2+, dem-
onstrating its safety and effectiveness in eliciting immune
response in vivo in node-positive breast cancer. Recurrence
rates were lower in the vaccination arm (21% in the ob-
servation group vs. 8% in the vaccine group at a median
22 months of follow-up).34 The final results of the phase I/II
clinical trial of E75 among 195 patients with early breast
cancer were recently reported with a 60-month follow-up

time. A nonstatistically significant difference in 5-year
disease-free survival (DFS) in favor of the vaccine group was
reported (89.7% vs. 80.2%, p = .08). A phase III clinical trial
with E75 is currently ongoing (NCT01479244).
GP2 is a peptide from the transmembrane HER2 protein
domain found to be able to stimulate CD8 lymphocytes to
destroy HER2-overexpressing cells. The preliminary results
of a phase II trial among patients with HLA-A2+ with any level
of expression of HER2 were recently reported.35 The com-
bination of GP2 plus GM-CSF was compared with GM-CSF
alone in patients with breast cancer whose tumors had
diverse expression of HER2. The treatment was well toler-
ated. In the subset of patients with HER2-overexpressing
tumors treated with trastuzumab, the combination of GP2
vaccine plus GM-CSF was associated with a numerically
superior DFS (94% vs. 89% in the GM-CSF group, p = .86).
Other immunogenic approaches are also under clinical
testing, including peptides derived from the HER2 intracellular
domain, DNA-based and whole tumor cell vaccines (either
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2. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a
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EMERGING THERAPEUTIC OPTIONS FOR HER2 BREAST CANCER
autologous or from cell-line cultures), and dendritic cell
vaccines.36,37
The synergy of trastuzumab and vaccines was explored in a
phase I/II trial obtaining prolonged and robust T-cell re-
sponses with very low toxicity.38 Ongoing trials are even
considering the addition of chemotherapy to vaccine/
antibody combinations (NCT00266110). A further step in
the HER2 vaccination field is the generation of HER2 vaccine-
primed autologous T cells for therapeutic infusion reported
to be feasible and well tolerated in early phase I trials.39
Immune Checkpoint Inhibitors
The clinical testing of immune checkpoint inhibitors in breast
cancer, initially focused on triple-negative breast cancer, has
recently been extended to the HER2-positive subtype.
PANACEA (NCT02129556) is a phase IB/II trial evaluating the
efficacy of pembrolizumab and trastuzumab in trastuzumab-
resistant metastatic breast cancer.
11. Park JW, Liu MC, Yee D, et al. Neratinib plus standard neoadjuvant
therapy for high-risk breast cancer: efficacy results from the I-SPY 2
TRIAL. Cancer Res. 2014;74 (abstr CT227).
12. Chan A, Delaloge S, Holmes FA, et al. Neratinib after adjuvant che-
motherapy and trastuzumab in HER2-positive early breast cancer:
primary analysis at 2 years of a phase 3 randomized, placebo-controlled
trial (ExteNET). J Clin Oncol. 2015;33 (suppl; abstr 508).
13. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based
adjuvant therapy in HER2-positive breast cancer (ExteNET): a ran-
domized, double-blind, phase 3 trial. Lancet Oncol. 2016;17:367-377.
14. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based
adjuvant therapy in early-stage HER2+ breast cancer: 3-year analysis
from a phase 3 randomized, placebo-controlled double-blind trial
(ExteNET). Presented at: San Antonio Breast Cancer Symposium. San
Antonio, TX; 2015. Abstract S5-02.
15. Ustaris F, Saura C, Di Palma J, et al. Effective management and pre-
vention of neratinib-induced diarrhea. Am J Hematol Oncol. 2015;11:
13-22.
16. Ferrario C, Hamilton E, Aucoin N, et al. A phase 1b study of ONT 380, an
oral HER2-specific inhibitor, combined with ado trastuzumab emtansine
(T-DM1), in HER2+ metastatic breast cancer (MBC). Presented at: San
Antonio Breast Cancer Symposium. San Antonio, TX; 2015. Abstract P4-
14-20.
17. Murthy RK, Hamilton E, Borges VF, et al. ONT-380 in the treatment of
HER2+ breast cancer central nervous system (CNS) metastases (mets).
Presented at: San Antonio Breast Cancer Symposium. San Antonio, TX;
2015. Abstract P4-14-19.
18. Krop IE, Kim SB, Gonza lez-Martn A, et al; TH3RESA Study Collab-
orators. Trastuzumab emtansine versus treatment of physicians
choice for pretreated HER2-positive advanced breast cancer
(TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol.
2014;15:689-699.
19. Harbeck N, Gluz O, Christgen M, et al. Final analysis of WSG-ADAPT HER2
+/HR+ phase II trial: Efficacy, safety, and predictive markers for 12-
weeks of neoadjuvant TDM1 with or without endocrine therapy versus
trastuzumab+endocrine therapy in HER2-positive hormone-receptor-
positive early breast cancer. Presented at: San Antonio Breast Cancer
Symposium. San Antonio, TX; 2015. Abstract S5-03.
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20. LoRusso P, Krop I, Miller K, et al. A phase I study of MM-302, a HER2-
targeted PEGylated liposomal doxorubicin, in patients with HER2+
metastatic breast cancer. Cancer Res. 2015;75 (abstr CT234).
21. Rexer BN, Arteaga CL. Optimal targeting of HER2-PI3K signaling in breast
cancer: mechanistic insights and clinical implications. Cancer Res. 2013;
73:3817-3820.
22. Andre F, ORegan R, Ozguroglu M, et al. Everolimus for women with
trastuzumab-resistant, HER2-positive, advanced breast cancer
(BOLERO-3): a randomised, double-blind, placebo-controlled phase 3
trial. Lancet Oncol. 2014;15:580-591.
23. Hurvitz SA, Andre F, Jiang Z, et al. Combination of everolimus with
trastuzumab plus paclitaxel as first-line treatment for patients with
HER2-positive advanced breast cancer (BOLERO-1): a phase 3, rando-
mised, double-blind, multicentre trial. Lancet Oncol. 2015;16:816-829.
24. Slamon DJ, Hurvitz SA, Chen D, et al. Predictive biomarkers of ever-
olimus efficacy in HER2+ advanced breast cancer: combined exploratory
analysis from BOLERO-1 and BOLERO-3. J Clin Oncol. 2015;33 (suppl;
abstr 512).
25. Saura C, Bendell J, Jerusalem G, et al. Phase Ib study of buparlisib plus
trastuzumab in patients with HER2-positive advanced or metastatic
breast cancer that has progressed on tsrastuzumab-based therapy. Clin
Cancer Res. 2014;20:1935-1945.
26. Cadoo KA, Gucalp A, Traina TA. Palbociclib: an evidence-based review of
its potential in the treatment of breast cancer. Breast Cancer (Dove Med
Press). 2014;6:123-122.
27. Knudsen E, Cox D, Franco J, et al. Targeting CDK4/6 in HER2 positive
breast cancer: therapeutic effect, markers, and combination strategies.
Ann Oncol. 2014;25(suppl 1):i21-i22.
28. Goetz MP, Beeram M, Beck T, et al. Abemaciclib, an inhibitor of CDK4
and CDK6, combined with endocrine and HER2-targeted therapies for
women with metastatic breast cancer. Presented at: San Antonio Breast
Cancer Symposium. San Antonio, TX; 2015. Abstract P4-13-25.
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29. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving
beyond current vaccines. Nat Med. 2004;10:909-915.
30. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating
immunitys roles in cancer suppression and promotion. Science. 2011;
331:1565-1570.
31. Hoos A, Parmiani G, Hege K, et al; Cancer Vaccine Clinical Trial Working
Group. A clinical development paradigm for cancer vaccines and related
biologics. J Immunother. 2007;30:1-15.
32. Milani A, Sangiolo D, Montemurro F, et al. Active immunotherapy in
HER2 overexpressing breast cancer: current status and future per-
spectives. Ann Oncol. 2013;24:1740-1748.
33. Clifton GT, Mittendorf EA, Peoples GE. Adjuvant HER2/neu peptide
cancer vaccines in breast cancer. Immunotherapy. 2015;7:1159-1168.
34. Peoples GE, Gurney JM, Hueman MT, et al. Clinical trial results of a
HER2/neu (E75) vaccine to prevent recurrence in high-risk breast cancer
patients. J Clin Oncol. 2005;23:7536-7545.
35. Schneble EJ, Perez SA, Murray JL, et al. Primary analysis of the pro-
spective, randomized, phase II trial of GP2+GMCSF vaccine versus GM-
CSF alone administered in the adjuvant setting to high-risk breast
cancer patients. J Clin Oncol. 2014;32 (suppl 26; abstr 134).
36. Disis ML, Schiffman K, Guthrie K, et al. Effect of dose on immune re-
sponse in patients vaccinated with an HER-2/neu intracellular domain
proteinbased vaccine. J Clin Oncol. 2004;22:1916-1925.
37. Morse MA, Hobeika A, Osada T, et al. Long term disease-free survival
and T cell and antibody responses in women with high-risk Her2+ breast
cancer following vaccination against Her2. J Transl Med. 2007;5:42.
38. Disis ML, Wallace DR, Gooley TA, et al. Concurrent trastuzumab and
HER2/neu-specific vaccination in patients with metastatic breast can-
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39. Disis ML, Dang Y, Coveler AL, et al. HER-2/neu vaccine-primed autol-
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expressing cancers. Cancer Immunol Immunother. 2014;63:101-109.
CANCER PREVENTION, HEREDITARY GENETICS,
AND EPIDEMIOLOGY

Controversies in Genetic
Evaluation

CHAIR
Noah D. Kauff, MD
Memorial Sloan Kettering Cancer Center
New York, NY

SPEAKERS
Claudine Isaacs, MD, FRCPC
Georgetown Lombardi Comprehensive Cancer Center
Washington, DC

Victoria Raymond, MS, CGC

University of Michigan Medical School
Ann Arbor, MI
LYNCE AND ISAACS

How Far Do We Go With Genetic Evaluation? Gene, Panel, and

Tumor Testing
Filipa Lynce, MD, and Claudine Isaacs, MD, FRCPC

OVERVIEW

The traditional model by which an individual was identified as harboring a hereditary susceptibility to cancer was to test for a mutation
in a single gene or a finite number of genes associated with a particular syndrome (e.g., BRCA1 and BRCA2 for hereditary breast and
ovarian cancer or mismatch repair genes for Lynch syndrome). The decision regarding which gene or genes to test for was based on
a review of the patients personal medical history and their family history. With advances in next-generation DNA sequencing
technology, offering simultaneous testing for multiple genes associated with a hereditary susceptibility to cancer is now possible.
These panels typically include high-penetrance genes, but they also often include moderate- and low-penetrance genes. A number of
the genes included in these panels have not been fully characterized either in terms of their cancer risks or their management options.
Another way some patients are unexpectedly identified as carrying a germline mutation in a cancer susceptibility gene is at the time
they undergo molecular profiling of their tumor, which typically has been carried out to guide treatment choices for their cancer. This
article first focuses on the issues that need to be considered when deciding between recommending more targeted testing of a single
or a small number of genes associated with a particular syndrome (single/limited gene testing) versus performing a multigene panel.
This article also reviews the issues regarding germline risk that occur within the setting of ordering molecular profiling of tumors.

T hroughout the past several decades, we have witnessed

tremendous advances in our knowledge of evaluating
and treating patients with germline mutations in hereditary
cancer syndromes, with studies clearly demonstrating the
feasibility and clinical utility of genetic testing. Perhaps most
importantly, studies have provided convincing evidence
that implementing prevention strategies in some instances
prolongs the survival of mutation carriers. For example, for
unaffected women who carry a BRCA1 or BRCA2 mutation,
risk-reducing salpingo-oophorectomy results in a significant
reduction in all-cause mortality (3% vs. 10%; hazard ratio
[HR] 0.40; 95% CI, 0.260.6), breast cancer-specific mor-
tality (2% vs. 6%; HR 0.44; 95% CI, 0.260.76) and ovarian
cancerspecific mortality (0.4 vs. 3%; HR 0.21; 95% CI,
0.060.8) when compared with carriers who chose not to
undergo this procedure.1 Additionally, Markov modeling sug-
gests that a 30-year old healthy BRCA1 mutation carrier
would gain 0.2 to 1.8 years in life expectancy with risk-
reducing salpingo-oophorectomy and 0.6 to 2.1 years from
risk-reducing mastectomies.2,3 Given these findings, genetic
testing for hereditary cancer syndromes has now become part
of standard practice.
As set forth in the Evaluation of Genomic Applications in
Practice and Prevention (known as EGAPP) initiative4 and further
supported by the recent American Society of Clinical Oncology
(ASCO) policy statement on testing for genetic and genomic
cancer susceptibility,5 a number of criteria must be considered
when evaluating existing or emerging genetic tests. These cri-
teria include analytical and clinical validity, clinical utility, and
the associated ethical, legal, and social issues. In the context of
genetic testing, analytic validity refers to the accuracy and re-
producibility by which the assay detects the presence or absence
of a mutation. Clinical validity focuses on whether the test ac-
curately and reproducibly predicts the clinically defined disorder.
Clinical utility can be defined as the evidence that a genetic test
results in improved health outcomes typically based on early
detection or prevention strategies, and the tests usefulness
and added value to patient management decision making. For
genetic testing, particularly for moderate-penetrance genes,
clinical utility remains the fundamental issue.5 The EGAPP
framework is key when evaluating the utility of genetic testing
for hereditary cancer syndromes. Failure to meet some of
these criteria forms the basis for many concerns regarding the
current clinical actionability of multigene panel testing.
SINGLE/LIMITED GENE TESTING
For well over a century, it has been recognized that some
families harbor a hereditary predisposition to a variety of

From the Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC; Lombardi Comprehensive Cancer Center, Georgetown University,
Washington, DC.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Claudine Isaacs, MD, Lombardi Comprehensive Cancer Center, 3800 Reservoir Rd. NW, Washington, DC 20057; email: isaacsc@georgetown.edu.

2016 by American Society of Clinical Oncology.

e72 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


malignancies. In 1913, Warthin described a kindred known
as Family G, in which he noted an aggregation of endometrial
carcinoma along with gastric and colorectal cancer.6 This
family, among others, formed the basis of the initial
descriptions of hereditary nonpolyposis colorectal cancer
syndrome, now more commonly known as Lynch syn-
drome. Similarly, astute clinicians recognized other hered-
itary cancer syndromes such as Li-Fraumeni and Cowden
syndromes and hereditary breast and ovarian cancer based
on the cancer phenotype of the family.7-12 By the mid-1990s,
linkage analyses and other studies resulted in the abil-
ity to pinpoint individual genes associated with some of
these hereditary cancer syndromes.13,14 These included the
identification of BRCA1 and BRCA2 associated with hered-
itary breast and ovarian cancer; MLH1, MSH2, MSH6, PMS2,
and more recently EPCAM associated with Lynch syndrome;
FAP with familial adenomatous polyposis; and TP53 with
Li-Fraumeni syndrome.
However, it became apparent that many families with
striking histories consistent with either a hereditary colo-
rectal or breast/ovarian cancer syndrome are not found to
carry a mutation in one of the mismatch repair genes as-
sociated with Lynch syndrome or in BRCA1/2. For example,
studies indicate that a mutation in a mismatch repair gene is
found in approximately 40% to 80% of families that meet
the Amsterdam I criteria and only about 5% to 50% of
families meeting the Amsterdam II criteria.15 Similarly, only
about 5% to 10% of unselected patients with breast cancer16
and 20% to 25% of patients with hereditary breast cancer17
are found to carry a deleterious BRCA1 or BRCA2 mutation.
Additionally, a number of other genes associated either
KEY POINTS
Advances in technology have resulted in the ability to
test for multiple genes associated with a hereditary
predisposition to cancer.
Multigene panel testing can allow for a more
comprehensive and efficient approach to testing, but
many of the genes included in multigene panels have
not been fully characterized either in terms of their
cancer risks or management strategies. In many cases,
single/limited gene testing remains a very appropriate
testing option.
The decision to pursue single or limited gene testing is
complex and referral to clinicians with expertise in
cancer genetics is critical. Testing must be carried out
with pre- and post-test genetic counseling.
In the tumor molecular profiling setting, secondary
incidental germline mutations may be detected. ASCO
recommends that the possibility of identifying
secondary incidental germline information and the
clinical relevance, benefits, risks, and limitations of such
findings be discussed with all patients before they
undergo tumor sequencing.
SINGLE GENE VERSUS MULTIGENE PANEL TESTING FOR HEREDITARY CANCER
with rare high-penetrance syndromes or a more moderate
penetrance were identified.
Based on these findings, the general paradigm of testing
evolved whereby the more common genes such as BRCA1
and BRCA2 were tested first, and, if negative, sequential
testing for additional gene(s) was performed if the patient
met criteria for testing for other syndromes. This process
had both advantages and disadvantages. In terms of ad-
vantages, the genes tested in this setting typically have
well-described cancer risks and often have established
management guidelines. Additionally, through the pretest
counseling process, patients undergoing this testing have
had the opportunity to fully consider the benefits, risks, and
limitations of testing in their particular situation. In terms
of disadvantages, such testing is less comprehensive than
multigene testing, and, if performed, sequential testing is
quite time-consuming and costly.
MULTIGENE PANELS
There has been a dramatic shift in the genetic testing
landscape over the past several years in large part because of
two major factors. The first is the development of next-
generation sequencing, a high-throughput approach to DNA
sequencing that allows for massively parallel sequencing of
multiple genes more efficiently and at a lower cost than the
traditional Sanger sequencing methods. The second is the
Supreme Court decision in 2013 for Association for Mol-
ecular Pathology v. Myriad Genetics, which invalidated many
patents restricting BRCA1/2 testing. Very shortly after the
ruling, many companies and some academic institutions
announced they would offer BRCA testing in addition to the
existing genes on their multigene panels.18,19 As a result of
these two factors, offering relatively rapid turnaround times
for multigene testing in a reasonably affordable manner
became feasible.
The panels differ from company to company. They may
be comprehensive, tumor-specific, and focus only on highly
penetrant genes, or be customizable (Table 1). The price of
testing also has dropped significantly. It now can range from
$249 to $6,040, with most costing $1,500 to $6,040. The cost
varies among laboratories and differs based on the number
of genes included. In most cases, the cost of multigene panel
testing does not significantly differ from the cost of more
single/limited gene testing. Furthermore, the cost of testing
likely will continue to diminish over time. Adding to the
complexity of testing choices is that insurance companies
have different policies and may cover some but not all
choices.
A number of studies have evaluated the utility and impact
of multigene testing in a variety of settings. The key ques-
tions that must be addressed revolve around the clinical
utility or actionability of the findings from such testing,
namely (1) the numbers of patients who are found to have a
deleterious mutation in a gene for which cancer risks are
known and management strategies exist, (2) patients who
are found to have a mutation with uncertain cancer risks
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e73
LYNCE AND ISAACS

TABLE 1. Examples of Genes Included on Some Next-Generation Sequencing Cancer Panels*

Number
Company Test of Genes Genes Included
20
Comprehensive Ambry Genetics CancerNext 32 APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, BMPR1A, CDH1, CDK4,
Panels CDKN2A, CHEK2, EPCAM, GREM1, MLH1, MRE11A, MSH2, MSH6,
MUTYH, NBN, NF1, PALB2, PMS2, POLD1, POLE, PTEN, RAD50,
RAD51C, RAD51D, SMAD4, SMARCA4, STK11, TP53
GeneDx OncoGene Dx Compre- 32 APC, ATM, AXIN2, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1,
hensive Cancer Panel21 CDK4, CDKN2A, CHEK2, EPCAM, FANCC, MLH1, MSH2, MSH6,
MUTYH, NBN, PALB2, PMS2, POLD1, POLE, PTEN, RAD51C, RAD51D,
SCG5/GREM1, SMAD4, STK11, TP53, VHL, XRCC2
Myriad Genetics MyRisk22 25 BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH,
CDKN2A, CDK4, TP53, PTEN, STK11, CDH1, BMPR1A, SMAD4, PALB2,
CHEK2, ATM, NBM, BARD1, BRIP1, RAD51C, RAD51D
Invitae Invitae Multi-Cancer 79 ALK, APC, ATM, AXIN2, BAP1, BARD1, BLM, BMPR1A, BRCA1, BRCA2,
Panel23 BRIP1, CASR,CDC73, CDH1, CDK4, CDKN1B, CDKN1C, CDKN2A,
CEBPA, CHEK2, DICER1, DIS3L2, EGFR, EPCAM, FH, FLCN, GATA2,
GPC3, GREM1, HOXB13, HRAS, KIT, MAX, MEN1, MET, MITF, MLH1,
MSH2, MSH6, MUTYH, NBN, NF1, NF2, PALB2,PDGFRA, PHOX2B,
PMS2, POLD1, POLE, PRKAR1A, PTCH1, PTEN, RAD50,RAD51C,
RAD51D, RB1, RECQL4, RET, RUNX1, SDHA, SDHAF2, SDHB, SDHC,
SDHD, SMAD4, SMARCA4, SMARCB1, SMARCE1, STK11, SUFU, TERC,
TERT, TMEM127, TP53, TSC1, TSC2, VHL, WRN, WT1
Breast/Ovarian Ambry Genetics BRCAplus24 6 BRCA1, BRCA2, CDH1, PALB2, PTEN, TP53
Panels
BreastNext25 17 ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MUTYH,
NBN, NF1, PALB2, PTEN, RAD50, RAD51C, RAD51D, TP53
OvaNext26 23 ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1,
MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN,
RAD50, RAD51C, RAD51D, SMARCA4, STK11, TP53
Invitae Breast and Gynecologic 14 ATM, BRCA1, BRCA2, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6,
Cancers Guidelines PALB2, PMS2,PTEN, STK11, TP53
Based Panel27
Breast Cancer Guidelines 9 ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53
Based Panel28
Color Color 19 ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MHL1,
Genomics29 MSH2, MSH6, NBM, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11,
TP53
GeneDx Breast Cancer High/Mod- 9 ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53
erate Risk Panel21
Breast/Ovarian Cancer 21 ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FANCC,
Panel21 MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D,
STK11, TP53, XRCC2
Gastrointestinal Ambry Genetics ColoNext30 17 APC, BMPR1A, CDH1, CHEK2, EPCAM, GREM1, MLH1, MSH2, MSH6,
Panels MUTYH, PMS2, POLD1, POLE, PTEN, SMAD4, STK11, TP53
Invitae Colorectal Cancer Guide- 12 APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN,
lines Based Panel31 SMAD4, STK11, TP53
Myriad Genetics COLARIS32 6 MLH1, MSH2, EPCAM, MSH6, PMS2, MUTYH
COLARIS AP33 APC, MUTYH
GeneDx Colorectal Cancer Panel21 19 APC, ATM, AXIN2, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2,
MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SCG5/GREM1, SMAD4,
STK11, TP53
Lynch/Colorectal High Risk 7 APC, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2
Panel21
Abbreviation: VUS, variants of uncertain significance.
*Current as of February 2, 2016.

and/or no evidence-based recommendations for manage-
ment, and (3) the rate detection of variants of uncertain
significance (VUS). As summarized in Tables 2 and 3, the rate
of VUS varies between 3.3% and 42%, and many patients
were reported to have two or more VUS. The VUS rate is still
high in some reports, but it is expected to fall in the near
future because of the rapid accumulation of data from
multigene panel testing.
Given the high rate of VUS and the detection of genes for
which the cancer risks are not well-defined, several regis-
tries have been created to catalog and curate these vari-
ants with the goal of advancing our knowledge about their

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 SINGLE GENE VERSUS MULTIGENE PANEL TESTING FOR HEREDITARY CANCER

TABLE 2. Rate of Deleterious Mutations and VUS Reported in Multigene Testing Associated with Hereditary Breast
Cancer

BRCA Mutations Non-BRCA Mutations

Publication No. of Participants Panel Tested Detected (%) Detected (%) VUS Rate (%)
38
Kapoor et al 337 Ambry Genetics; different 3.6% 3.9%; gene mutations more often 3.3% BRCA1/2 and
panel types and genes detected: PALB2, CHEK2, ATM 13.4% non-BRCA1/2
tested
Slavin et al39 348 Not provided 3.4% 16.4% 42%
40
Tung et al 2,158 Cohort 1: Referred for 9.3% 4.2% 41.7%
commercial BRCA1/2
gene testing and
Cohort 2: Previously 3.7% 41.6%
tested negative for
BRCA1/2 mutations
Chong et al41 3,000 BRCAPlus: 6-gene panel 4.6% 1% 7.6%
(BRCA1, BRCA2, TP53,
CDH1, PTEN, SKT11)
Kurian et al42 198 (57 BRCA1/2, Invitae 11.4% 2.1% VUS/average per
141 BRCA1/2 neg) participant
LaDuca et al43 2,079 (874 had Ambry Genetics All previously underwent 7.4% gene mutations detected: 19.8%
breast panel) BRCA sequencing and CHEK2 (19), ATM (18), PALB2
BART testing and were (15), TP53 (4), PTEN (3), RAD50
negative (3), RAD51C (2), BRIP1 (1),
MRE11A (1), NBN (1)
Abbreviation: VUS, variants of uncertain significance.

clinical utility. The Prospective Registry of Multiplex Testing
(PROMPT)34 is a multi-institutional online registry that en-
courages patients to self-enter information about their
genetic testing results and to complete questionnaires about
their personal medical and family histories. Others involved
in reclassifying variants include ENIGMA (Evidence-based
Network for the Interpretation of Germline Mutant Alleles)
Consortium35 and ClinVar, a peer-reviewed database funded
by the National Institutes of Health, which is a freely available
archive of reports of relationships among medically important
variants and phenotypes.36 Professional societies such as the
American Medical Association also have adopted positions in
favor of data sharing.37
SINGLE/LIMITED GENE VERSUS MULTIGENE
PANEL TESTING
Several factors guide the decision to pursue testing of a single
gene or a finite set of genes associated with a particular
syndrome versus multigene panel testing. These include
(1) the characteristics of the probands personal and family
history, (2) an individuals preferences and tolerance re-
garding the possibility of ambiguous results, (3) insurance-
related issues, and (4) the rapidity with which results are
needed. A publication in the New England Journal of Medicine
in 2015, authored by experts from the United States, United
Kingdom, the Netherlands, Germany, Australia, and Canada,
thoughtfully reviewed the issues that must be addressed
when considering multigene panels.45 Additionally, ASCO
released a policy statement on genetic and genomic testing
for cancer susceptibility to reflect the impact of advances in
this field.5
Single/limited gene testing remains an excellent option
when the clinical features, such as the patients personal and
family history, are strongly indicative of a particular syn-
drome associated with a single or finite set of genes. This
approach allows for a focused and comprehensive pretest
evaluation in which individuals have an opportunity to more

TABLE 3. Rate of Deleterious Mutations and VUS Reported in Multigene Testing Associated with Colorectal Cancer

LS Genes (MLH1, MSH2, MSH6,

PMS2, EPCAM) Mutations De- Non-LS Genes Mutations
Publication No. Patients Panel Tested tected (%) Detected (%) VUS Rate (%)
LaDuca et al43 557 Ambry Genetics 4.5%: MSH (7), MLH1 (7), 4.7% (26): APC (6), CHEK2 (6), MUTYH 15.1% (84)
PMS2 (6), MSH (5) biallelic (6), SMAD4 (4), PTEN (3),
CDH1 (1), STK11 (1), TP53 (1)
Yurgelun et al44 1,260 Myriad MyRisk Hereditary 9.5% 3.8% (48): BRCA1/2 (15), APC biallelic 44%
Cancer MUTYH, PTEN, STK11, ATM,
BARD1, BRIP1, CHEK2, NBN, PALB2,
and RAD51C
Abbreviations: LS, Lynch syndrome; VUS, variants of uncertain significance.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e75

LYNCE AND ISAACS
fully consider the impact of testing for a particular gene or
set of genes. Additionally, such testing minimizes the like-
lihood of detecting a VUS or a deleterious mutation in a gene
with limited clinical information.
Multigene panel testing is an appropriate option when
the family phenotype is not suggestive of a single specific
mutation and one or more hereditary cancer syndromes
are in the differential. Additionally, panel testing is often
considered if more focused initial testing is negative (e.g.,
BRCA1/2 testing followed by multigene breast/ovarian
panel). Multigene panel testing has a number of advan-
tages and potential disadvantages (Table 4). The advan-
tages include gains in efficiency both in terms of cost and
time. Such testing also would result in a more compre-
hensive assessment of the genes that could account for
the cancer phenotype in the family. Finally, pragmatically,
in this era of multigene panel testing, it is unclear if an
individual could obtain insurance coverage for repeat
testing if the initial, more limited testing results were
negative. In terms of disadvantages, as described pre-
viously, multigene panel testing has a higher rate of de-
tection of VUS. Individuals undergoing testing must be
fully informed of this possibility before testing and coun-
seled on the interpretation of such a result. Furthermore,
it is important that an individual undergoing panel test-
ing understands it is possible that a high-penetrance mutation
in an uncommon or rare gene may be identified, even in the
absence of a classic presentation of the associated syndrome.
Consequently, aggressive interventions may be recommended,
such as consideration of prophylactic gastrectomy if a CDH1
mutation was found, even in the absence of gastric cancer in
the family. At this moment, it is unclear if the cancer risks for
patients identified through panel testing without features of
the associated syndrome are the same as quoted in the lit-
erature because of ascertainment bias. Moreover, laboratories
have varying methods by which they assure the analytic and
clinical validity and the clinical utility of the variants they re-
port. Expertise in this area is required to ensure accurate in-
terpretation of the clinical significance of the findings reported.
Given the panoply of testing options, this expertise is also
TABLE 4. Pros and Cons of Single/Limited Gene Testing and Multigene Panels
Single/Limited Gene Testing
Advantages Phenotype-directed testing
Cancer risks and management
options often more established
Lower likelihood of detecting VUS
More rapid turnaround time
Disadvantages Higher risk of loss to follow-up during sequential testing multiple
single genes (test fatigue)
Less comprehensive
Abbreviation: VUS, variants of uncertain significance.
e76 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
critical to guide the choice of which test to order and from
which laboratory. These issues further underscore the im-
portance of ensuring that patients undergo pre- and post-test
genetic counseling by well-trained professionals, as endorsed
by ASCO and the National Comprehensive Cancer Network.46
GERMLINE FINDINGS ON MOLECULAR
PROFILING OF TUMORS
An important challenge when performing vast-scale se-
quencing is the potential for detecting incidental findings.
Incidental findings are defined as unexpected positive
findings. In this context, they refer to the detection of
deleterious or likely deleterious alterations in genes that
have clinical significance and are unrelated to the in-
dication for obtaining the sequencing test. Typically, these
are germline mutations. As such, the only way to truly
determine if an identified sequence variant is somatic or
inherited is to simultaneously analyze tumor and normal
DNA. This analysis allows for a determination on which
variants are unique to the cancer (i.e., somatic) and which
are germline. Determining whether, which, and how in-
cidental findings are returned to the patient is becoming
increasingly important and controversial. The American
College of Medical Genetics and Genomics published a
policy statement on clinical sequencing that included
exome and genome sequencing.47 The policy state-
ment recommended that constitutional mutations from a
panel of 56 disease-associated genes be reported to the
ordering clinician, regardless of the indication for which
the clinical sequencing was ordered (Table 5). These
genes were chosen because they result in disorders for
which preventive strategies and/or treatments are
available. About half are associated with syndromes that
increase the risk of cancer; the others are primarily as-
sociated with various cardiac diseases. The American
College of Medical Genetics and Genomics also states
that the ordering clinician/team is responsible for pro-
viding the patient with comprehensive pre- and post-test
counseling.
Multigene Panels
More cost effective (less expensive per gene cost)
More time efficient
Decrease in testing fatigue for patients and providers
Efficient use of single specimen
Higher mutation detection rate, genes individually rare but
collectively significant
Increased prevalence of VUS
Cancer risks and management options often not well-defined,
particularly for some moderate- and low-penetrance genes
Unexpected findings such as off-phenotypic-target gene
mutation
Longer turnaround time
Panels may include genes that patients dont wish to test for
 SINGLE GENE VERSUS MULTIGENE PANEL TESTING FOR HEREDITARY CANCER

TABLE 5. Conditions and Genes Recommended by the American College of Medical Genetics and Genomics for
Return of Incidental Findings in Clinical Sequencing47

Phenotype Gene
Hereditary breast and ovarian cancer BRCA1, BRCA2
Li-Fraumeni syndrome TP53
Peutz-Jeghers syndrome STK11
Lynch syndrome MLH1, MSH2, MSH6, PMS2
Familial adenomatous polyposis APC
MYH-associated polyposis; adenomas; multiple colorectal cancers; familial amyloid MUTYH
polyneuropathy type 2; colorectal adenomatous polyposis, autosomal recessive,
with pilomatricomas
Von Hippel-Lindau syndrome VHL
Multiple endocrine neoplasia type 1 MEN1
Multiple endocrine neoplasia type 2 RET
Familial medullary thyroid cancer RET
PTEN hamartoma tumor syndrome PTEN
Retinoblastoma RB1
Hereditary paraganglioma-pheochromocytoma syndrome SDHD, SDHAF2, SDHC, SDHB
Tuberous sclerosis complex TSC1, TSC2
WT1-related Wilm syndrome WT1
Neurofibromatosis type 2 NF2
Ehlers-Danlos syndrome (vascular type) COL3A1
Marfan syndrome, Loeys-Dietz syndrome, familial thoracic aortic aneurysms and FBN1, TGFBR1, TGFBR2, SMAD3, ACTA2, MYLK, MYH11
dissections
Hypertrophic cardiomyopathy, dilated cardiomyopathy MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL3, ACTC1, PRKAG2,
GLA, MYL2, LMNA
Catecholaminergic polymorphic ventricular tachycardia RYR2
Arrhythmogenic right-ventricular cardiomyopathy PKP2, DSP, DSC2, TMEM43, DSG2
Romano-Ward Long QT syndrome types 1, 2, and 3; Brugada syndrome KCNQ1, KCNH2, SCN5A
Familial hypercholesterolemia LDLR, APOB, PCSK9
Malignant hyperthermia susceptibility RYR1, CACNA1S

Several challenges are inherent in this process. They range
from analytic issues (e.g., determining if the variant is
germline and, if so, if it is deleterious/likely deleterious,
a VUS, or a benign polymorphism) to practical issues related
to obtaining informed consent and delivering traditional
pre- and post-testing genetic counseling. ASCO recently
published a policy statement on genetic and genomic testing
for cancer susceptibility that includes germline implications of
somatic mutation profiling.5 The policy statement recognizes
that standard pre- and post-test counseling may not be
feasible in this setting for all patients. It recommends that the
possibility of identifying secondary incidental germline in-
formation as well as the clinical relevance, benefits, risks, and
limitations of such incidental findings be discussed with all
patients before they undergo tumor sequencing. ASCO also
endorses that providers should honor patients decisions if
they elect not to receive information about such incidental
findings.
CONCLUSION
Next-generation sequencing has introduced substantial
complexity and promise in the field of cancer risk assessment.
Although multigene panel testing provides a more com-
prehensive and efficient approach to testing an individual
for a hereditary susceptibility to cancer, the informa-
tion obtained can be challenging to interpret. Further-
more, many of the genes included in multigene panels
have not been fully characterized either in terms of
their cancer risks or management strategies. In many
cases, single/limited gene testing remains a very ap-
propriate testing option. Presently, we live in an era in
which our technical capabilities have outstripped our
medical knowledge. A strong and continuous part-
nership among clinicians, individuals with genetics
expertise, and laboratory geneticists is critical to bridge
this gap.
As to the detection of incidental findings on tumor se-
quencing, more research is clearly necessary to better clarify
how to approach this complex area. Until such time, as
stated by ASCO, it is critical that individuals undergoing
tumor sequencing be fully apprised of the possibility,
benefits, risks, and limitations that such testing could
uncover unanticipated mutations in cancer susceptibility
genes.

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LYNCE AND ISAACS
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CANCER PREVENTION, HEREDITARY GENETICS,
AND EPIDEMIOLOGY

Evolving Recommendations on
Prostate Cancer Screening

CHAIR
Otis W. Brawley, MD, FASCO
American Cancer Society
Atlanta, GA

SPEAKERS
Henrik Gronberg, MD, PhD
Karolinska Institutet
Stockholm, Sweden

Ian M. Thompson Jr., MD

The University of Texas Health Science Center at San Antonio
San Antonio, TX

BRAWLEY, THOMPSON, AND GRONBERG

Evolving Recommendations on Prostate Cancer Screening

Otis W. Brawley, MD, FASCO, Ian M. Thompson Jr., MD, and Henrik Gronberg, MD, PhD

OVERVIEW

Results of a number of studies demonstrate that the serum prostate-specific antigen (PSA) in and of itself is an inadequate
screening test. Today, one of the most pressing questions in prostate cancer medicine is how can screening be honed to
identify those who have life-threatening disease and need aggressive treatment. A number of efforts are underway. One
such effort is the assessment of men in the landmark Prostate Cancer Prevention Trial that has led to a prostate cancer
risk calculator (PCPTRC), which is available online. PCPTRC version 2.0 predicts the probability of the diagnosis of no
cancer, low-grade cancer, or high-grade cancer when variables such as PSA, age, race, family history, and physical findings
are input. Modern biomarker development promises to provide tests with fewer false positives and improved ability to
find high-grade cancers. Stockholm III (STHLM3) is a prospective, population-based, paired, screen-positive, prostate
cancer diagnostic study assessing a combination of plasma protein biomarkers along with age, family history, previous
biopsy, and prostate examination for prediction of prostate cancer. Multiparametric MRI incorporates anatomic and
functional imaging to better characterize and predict future behavior of tumors within the prostate. After diagnosis of
cancer, several genomic tests promise to better distinguish the cancers that need treatment versus those that need
observation. Although the new technologies are promising, there is an urgent need for evaluation of these new tests in
high-quality, large population-based studies. Until these technologies are proven, most professional organizations have
evolved to a recommendation of informed or shared decision making in which there is a discussion between the doctor
and patient.

T he U.S. Food and Drug Administration (FDA) first ap-

proved sale and use of a serum PSA test in 1986. It was
approved for assessing response to prostate cancer therapy
and monitoring for relapse. Large-scale prostate cancer
screening began in the United States in 1991 after publica-
tions showing serum PSA useful in finding localized prostate
cancer. Use increased dramatically after the American Cancer
Society recommended it in 1992.1 The FDA approved it as a
diagnostic test in 1994.
In the United States, use of the PSA test was rampant
throughout the 1990s, despite the lack of conclusive data to
show that screening and aggressive treatment of localized
prostate cancer saved lives. Screening spread outside of the
physician-patient relationship. There was mass screening at
shopping malls, community centers, and even on the floor of
national political conventions. The effect was that prostate
cancer incidence rates soared, and a large number of men
were treated for localized prostate cancer with radical pros-
tatectomy, radiation therapy, or cryotherapy.2 Screening has
not been as popular in Europe, and prostate cancer incidence
rates have not risen as much.3
It is of note that the first definitive studies to show that
localized therapy reduces mortality were published in 1997.
They were studies of hormones and radiation therapy for
locally advanced disease.4,5 A prospective randomized study
demonstrating a positive effect for radical prostatectomy
was first published in 2002.6,7
Two large relatively well-designed randomized trials
assessing prostate cancer screening were published in
2009.8,9 Although relatively well designed, both have some
flaws. One suggests screening is ineffective, and one sug-
gests a regimented screening program does reduce risk of
prostate cancer death. Both studies documented the harms
of prostate cancer screening, especially overdiagnosis and
resultant overtreatment.
The fact that there is considerable overdiagnosis associ-
ated with prostate cancer screening was confirmed in as-
sessment of the placebo arm of the large multi-institutional
Prostate Cancer Prevention Trial (PCPT).10 This trial of men at
average risk of prostate cancer demonstrated that annual
screening could diagnose prostate cancer in upward of 14%
of men in their fifties, sixties, and seventies. Men underwent
biopsy for diagnosis when their PSA was 4 ng/mL or greater
or when their PSA changed by 1 ng/mL in 1 years time.
Planned biopsies for men who screened normal every year
for 7 years (median age 69) found 15% of these men had

From the American Cancer Society, Emory University, Atlanta, GA; The University of Texas Health Science Center at San Antonio, San Antonio, TX; Karolinska Institute, Stockholm, Sweden.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Otis W. Brawley, MD, American Cancer Society, 250 Williams St., Ste. 600, Atlanta, GA 30303-1002; email: otis.brawley@cancer.org.

2016 by American Society of Clinical Oncology.

e80 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


prostate cancer. This demonstrates that PSA screening missed
as much cancer as it found.
Radical prostatectomy was compared with conservative
therapy in the Prostate Intervention versus Observation Trial
(PIVOT).11 Mortality reductions were only found among
patients treated for intermediate- and high-risk disease. This
again demonstrates that a considerable portion of men with
screened diagnosed prostate cancer have disease that does
not need treatment.
By 2010, the data became very clear that PSA testing iden-
tifies a lot of cancer, and a lot of that cancer is of no risk to
the patients lives. Today some even go so far as to ask
whether low-grade disease (Gleason 6) should be consid-
ered cancer.12 Gleason score 6 and lower disease constitutes
about 50% of screen-detected prostate cancer in the United
States.
It took a number of years for the screening activity to
subside. It is estimated that more than a million American
men were diagnosed and received treatment because of PSA
screening.13 Although a significant proportion of screen-
diagnosed prostate cancers are of no clinical significance,
prostate cancer is a significant cause of death.
The U.S. prostate cancer mortality rate has declined by
53% since 1991.14 Although some of this decline may be due
to screening and aggressive treatment, some is certainly not
due to screening and aggressive treatment. The U.S. death
rate began declining the same year that widespread PSA
screening was introduced. One would expect screening to
reduce mortality 8 or more years after introduction. There
have been declines in prostate cancer mortality in more than
two dozen countries. PSA screening is uncommon in most of
these countries.3 There is also speculation that some of the
decline is an artifact.15 The decline in mortality also corre-
sponded with changes in coding causes of death and the use
of PSA for assessing progression of prostate cancer. In re-
ality, the U.S. decline may be due to all of the above,
including a screening benefit.15,16
The U.S. Preventive Services Task Force (USPSTF) is a
health advisory group for the U.S. government. In 2008,
KEY POINTS
Prostate cancer screening has clear documented harms
and some possible benefits.
Men with low-grade or Gleason 6 disease generally have
long-term survival with observation.
The benefit-risk ratio of prostate cancer screening
improves if screening finds high-grade disease.
The Prostate Cancer Prevention Trial risk calculator is
useful in predicting whether a man of a specific PSA has
no cancer, low-grade cancer, or high-grade cancer and
reduces the number of unnecessary prostate biopsies.
The Stockholm III model is a promising predictor of low-
grade versus high-grade disease that may further
decrease the number of unnecessary prostate biopsies.
EVOLVING RECOMMENDATIONS ON PROSTATE CANCER SCREENING
USPSTF recommended against PSA-based prostate cancer
screening for men age 75 and older.17 USPSTF recom-
mended against screening for all men in 2012.18 During this
period, other organizations moved toward informed de-
cision making in which the decision to screen or not to screen
is made within the physician-patient relationship, with the
patient taking into account the potential harms and po-
tential benefits (informed decision making) or the physician
and patient taking into account potential harms and po-
tential benefits (shared decision making).19
According to the 2008 National Health Interview Survey,
40.6% of American men age 50 and older reported having
PSA screening within the previous year. By 2013, it was
20.8%. From 2010 to 2013 the prostate cancer incidence
declined by 18% in the United States. Longer follow-up is
needed to see whether these decreases are associated with
trends in mortality.
NEXT-GENERATION PROSTATE CANCER
SCREENING AND TREATMENT
The historical approach to prostate cancer screening was
based in part on the historically poor outcomes of treat-
ment of metastatic prostate cancer and the realization that
PSA-detected tumors were often cured with radiation or
surgery. As noted in Fig. 1, all patients over a certain age
(often age 50) were recommended to undergo annual
screening. If a PSA was found to be greater than 4.0 ng/mL,
a biopsy was recommended. If biopsy found cancer,
treatment with radiation or surgery was generally rec-
ommended. This approach led to a remarkable spike
in prostate cancer detection, treatment, and the con-
duct of the PLCO and ERSPC studies.8,20 Recognizing the
questionable impact of such an approach when com-
paring the potential benefit and the known risks of
treatment, the USPSTF recommended against PSA test-
ing in 2012.20
Twenty years of experience with this initial approach to
screening began to change with several sets of observations.
First, it was recognized that many tumors detected via PSA
screening were small and low-grade; the possible extent of
overdetection was illustrated in the end-of-study biopsies of
the PCPT in which all men with a PSA , 4.0 ng/mL were
recommended to undergo biopsy. In this group of men, 15%
were found to have cancer, a stunning risk of cancer when it
is recognized that the lifetime risk of cancer death in all men
is between 2% and 3%.21 Concurrent with this observation,
the first reports of the outcomes of active surveillance for
low-risk prostate cancer detected through PSA testing began
to appear.9 With the maturation of these series, it became
clear that low-grade (Gleason 3 + 3) and low-volume
intermediate-grade (Gleason 3 + 4) prostate cancers will
achieve high prostate cancerspecific survival at periods up
to 15 years.22 In a cohort of 993 men with such tumors, of
whom 13% had Gleason 3 + 4 tumors, combined cause-
specific survival at 10 years was 98.1% and at 15 years was
94.3%.23
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BRAWLEY, THOMPSON, AND GRONBERG
FIGURE 1. Early Approach to Prostate Cancer
Screening and Treatment
Abbreviation: PSA, prostate-specific antigen.
By studying the biopsy outcomes of the European Ran-
domized Study of Prostate Cancer Screening and the PCPT,
it also has become apparent that using a single biomarker
(i.e., PSA) to determine a mans risk of prostate cancer was
naive; other measures of risk had a profound impact on
prostate cancer risk.8 Also phase III randomized clinical
trials have demonstrated very little (if any) benefit of
treatment of low-grade tumors but mortality benefit for
high-grade tumors, the clinical community recognized
that screening should seek to identify the man with high-
grade cancer in whom a biopsy may have net potential
benefit from detection (and, presumably, treatment). On
the other hand, if biopsy would preferentially detect a
FIGURE 2. Prostate Cancer Prevention Trial Risk Calculator Patient Displays for (A) Case 1 and (B) Case 2
e82 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
low-grade cancer, the benefit-risk ratio would more likely
argue against a biopsy. The first tool developed for this
was the PCPTRC (www.prostate-cancer-risk-calculator.
com).8
Two clinical scenarios illustrate how such a tool can be
used in next-generation screening.24
Case 1: a healthy 55-year-old white man who has a
normal examination. His current PSA is 3.0 (previous
year was 1.5). He has no family history of prostate
cancer and no prior biopsy.
Case 2: a 72-year-old black man who runs 5K races each
weekend, winning his age group times (i.e., in good
health). His father had prostate cancer, and on ex-
amination, he has a prostate nodule. He has heard
that PSA doesnt matter, but, because of his family
history, asked his physician to have one drawn. It is
3.0 ng/mL.
The risk calculator displays outcomes as green smiley faces
(no cancer), yellow uncertain faces (low-grade cancer), and
red frowny faces (high-grade cancer). As can be seen in these
two examples, whereas the patient in case 1 (Fig. 2A) has a
3% risk of a high-grade cancer (potential benefit), he also
has a 15% risk of a low-grade cancer (unlikely benefit, likely
harm) and 82% likelihood of a negative biopsy (unnecessary
with risk of pain, bleeding, and infection). In contrast, the
patient in case 2 (Fig. 2B), with precisely the same PSA
value, has an eightfold greater risk of a high-grade cancer
(24%). In clinical practice, when provided these data with the
accompanying information regarding what happens to you if
you have any of these three outcomes, most patients simi-
lar to that in case 1 opt to not undergo biopsy, whereas
most patients similar to that in case 2 opt for a biopsy. It is
also important to note that, again in clinical practice, two
patients with precisely the same risks will often reach
two different decisions, on the basis of their own personal
preferences and values that they place on the different

outcomes of each possible finding. As can be seen at the
PCPTRC website, other biomarkers (e.g., percent free PSA) or
biomeasures (e.g., body mass index) can be incorporated to
better estimate risk.
It has also been recognized that annual PSA testing is
unnecessary for many men. In most population-based studies,
the median PSA is about 1.0 ng/mL. We have found, in a large
community-dwelling cohort, if a mans PSA is 1.0 ng/mL or
lower, his risk of a prostate cancer diagnosis within 10 years
is 3.4% and 90% of the cancers are low-grade. Thus, con-
ceivably, half of the general population could have their PSA
performed concurrently with their colonoscopy, eliminating
an enormous burden on society.
Finally, information is now available to better help patients
decide on treatment options. As up to two-thirds of patients
will qualify for active surveillance, it is important that men
with low-risk cancers are aware of this option.18 Multiple
series now attest to the safety of this approach and the
low risk of prostate cancer mortality. Studies are ongoing
to examine how to reduce the current burden of surveil-
lance. By comparison, phase III clinical trials have been
completed that demonstrate the importance of multi-
modal therapy (e.g., androgen deprivation plus radiation
or adjuvant radiotherapy after prostatectomy) for high-
risk tumors to reduce cancer recurrence and to reduce
mortality.18,25 To help patients with decision making, con-
siderable data are also available regarding the impact of
these treatments on genitourinary, sexual, and gastro-
intestinal functions.
It is unequivocal that using the current body of knowl-
edge regarding whom to screen, how frequently to screen
them, what their risk is for different biopsy outcomes, in-
corporating active surveillance, and, as appropriate, multi-
modal therapies for high-risk cancers, that the harms of
screening and treatment can be dramatically reduced. It
remains to be determined whether such an intelligent
approach, summarized only briefly in Fig. 3, to screening
and treatment reduces prostate cancer mortality and
morbidity.
A NEW VIEW ON PROSTATE CANCER SCREENING
Prostate cancer mortality and morbidity is substantial in
many parts of the world, and it is the most common cancer
among males in most parts of Europe, North and South
America, Australia, and sub-Saharan Africa.26 The over-
arching goal of prostate cancer screening is to decrease the
morbidity and suffering from advanced prostate cancer
without causing harm to men who do not require treatment
for low-risk prostate cancer.
The first question to ask is, is there evidence that PSA
screening decreases prostate cancer mortality? The highest
scientific weight is carried by randomized trials, and two
large randomized PSA screening studies have been pub-
lished, ERSPC (Europe) and PLCO (United States), un-
fortunately with contradictory results.21,27 The European
ERSPC trial examined the role of PSA screening in a largely
EVOLVING RECOMMENDATIONS ON PROSTATE CANCER SCREENING
FIGURE 3. Next-Generation Approach to Prostate
Cancer Screening and Treatment
Abbreviations: HG, high grade; LG, low grade; PSA, prostate-specific antigen.
unscreened population from eight countries with different
screening and treatment strategies. After 13 years of follow-
up, a significant 21% reduction (rate ratio 0.79; 95% CI,
0.690.91) in death from prostate cancer is found in a
predefined subgroup of men age 5569. After adjustment
for nonparticipation, the rate ratio of prostate cancer
mortality among men screened was 0.73 (95% CI, 0.610.88).
After 13 years of follow-up, there was no evidence of a
mortality benefit for organized annual PSA screening in
the PLCO trial compared with opportunistic screening
used in normal care. Men randomly assigned to the annual
screening group had a higher incidence of prostate cancer
(relative rate [RR] 1.12; 95% CI, 1.071.17) but no reduction
in prostate cancer mortality (RR 1.09; 95% CI, 0.871.36).
Differences in follow-up protocols and screening intervals
exist between the two trials. The major differences can
mostly be explained by the high screening rates (52% after
6 years) in the control arm and low compliance to biopsies
in the PLCO trial.
An interesting observation from cancer registries shows
that in a majority of countries in northern Europe and North
America, the age-adjusted mortality rates for prostate
cancer have been decreasing substantially in the last 20
years. However, this trend is not global, as several countries
in Asia and Africa record increasing mortality during the
same period (Fig. 4). Lithuania is an outlier with a very rapid
increase in mortality in the last 20 years.26 The drop in
mortality in some countries can be explained by PSA testing,
better treatment, or changes in how prostate cancer deaths
are recorded. On the basis of SEER data modeling, 50% of the
observed decrease is estimated due to earlier detection with
PSA, and 50% can be accounted to better treatment.28 More
detailed analysis from the Swedish Cancer Registries during
1990 to 2009 shows a lower prostate cancer mortality in
counties with high PSA testing as compared with less-intense
opportunistic PSA testing areas.29 Data from cancer regis-
tries also show that the incidence of advanced and meta-
static prostate cancer is going down.
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BRAWLEY, THOMPSON, AND GRONBERG
FIGURE 4. Trends in Prostate Cancer Mortality Rates
in 10 Selected Countries (Age Adjusted to World
Standard)
In a recent review of early detection of prostate cancer, 16 of
26 (62%) key opinion leaders agree that PSA screening does
reduce death from prostate cancer; others thought that the
present evidence is not sufficiently conclusive.30 The consensus
was that the magnitude of the effect was uncertain and that
substantial overdiagnosis and overtreatment exists, which
needs to be reduced before recommendations for PSA
screening in the general population can be made.
With available data, guideline committees have come to
very different conclusions, ranging from not recommending
PSA testing (USPTF) to recommending population-based,
organized PSA testing (Lithuania).31 Most professional or-
ganizations are somewhere in between, recommending PSA
testing for men age 45 or age 50 to 70 years but in a context
of shared decision making.32
FIGURE 5. Scheme for Prostate Cancer Screening, Diagnostics, and Treatment: Today and Tomorrow
Abbreviations: PSA, prostate-specific antigen; STKHLM3, Stockholm3.
e84 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
So what is the way forward? Continuing to argue over the
use of the PSA test would result in polarized discussion
rather than promote development of new ideas. We suggest
an alternative route forward, getting away from the PSA test
into a more modern diagnostic pipeline using the rapidly
advancing technology in biomarkers, imaging, and geno-
mics. The goal of such a new diagnostic pipeline is to sub-
stantially reduce the harm of current PSA testing while
maintaining or increasing the sensitivity for diagnosing high-
risk cancers.
Blood-Based Biomarkers and Risk Calculators
The currently used biomarker PSA has low specificity
(only 20%30%), which leads to many men without can-
cer undergoing prostate biopsies. Biopsies are unpleas-
ant, and 2%5% of men will get septicemia after the
biopsies.
Use of PCPTRC has been previously discussed. These risk
calculators are important tools, but unfortunately not used
as much as they should be.
With the inefficient use of PSA in Stockholm,33 we initiated
the STHLM3 study in 2011 with the goal of developing a
better prostate cancer test than PSA (Fig. 5). This new pros-
tate cancer test should at least have the same sensitivity to
identify men with high-risk prostate cancer but with much
better specificity. This improved specificity should lead
to fewer unnecessary biopsies and fewer men diagnosed
with low-risk cancer. The STHLM3 study is a prospective,
population-based, paired, screen-positive, diagnostic study
of men without prostate cancer aged 50 to 69 randomly
invited by date of birth from the Swedish Population Reg-
ister. The predefined STHLM3 model included a combination
of six plasma protein biomarkers (PSA, free PSA, intact PSA,
hK2, MSMB, MIC1), genetic polymorphisms (232 SNPs) as-
sociated with prostate cancer susceptibility, and clinical
variables (age, family, history, previous prostate biopsy,

FIGURE 6. Variables Used in the Stockholm III Model
Abbreviations: DRE, digital rectal examination; PSA, prostate-specific antigen;
STHLM3, Stockholm III
and prostate examination) with the endpoint of Gleason
score 7+ cancers.
The STHLM3 model was predefined in a test cohort of
11,130 men and then prospectively validated in an in-
dependent cohort of 47,688 men. All variables used in the
STHLM3 model were significantly associated with prostate
cancers with a Gleason score 7+ (p , .05) in a multiple
logistic regression model (Fig. 6). At the same level of
FIGURE 7. Comparison of Number of Intermediate- and High-Grade Prostate Cancers Diagnosed with Serum PSA
Screening Versus Stockholm III
Abbreviation: PSA, prostate-specific antigen
EVOLVING RECOMMENDATIONS ON PROSTATE CANCER SCREENING
sensitivity as the PSA test using a cutoff of at least 3 ng/mL
to diagnose high-risk prostate cancer, use of the STHLM3
model could reduce the overall number of biopsies by 32%
(95% CI, 24%39%) and small Gleason score 6 cancers by
17% (95% CI, 7%26%) and could avoid 44% (95% CI,
35%54%) of biopsies for men without cancer. The STHLM3
model also identifies a significant number of men with high-
risk cancers in the PSA range of 1-3 ng/mL (Fig. 7).
We see the STHLM3 test as a first step in reducing the
harms of current ongoing PSA screening. The Institute of
Health Economy in Lund, Sweden, has conducted a detailed
health-economic evaluation of the STHLM3 test. Compared
with current clinical practice in Stockholm today, the new
test can save money for the health care provider and at the
same time increase the quality of life in the population.
Targeted Prostate Biopsies Using MRI With Fusion
Technology
Men at increased risk of prostate cancer are traditionally
assessed using systematic prostate biopsies. The procedure
is performed under local anesthesia using antibiotic pro-
phylaxis and includes 10 to 14 cores taken from predefined
areas of the peripheral zone of the gland as visualized by
endorectal ultrasound. While the biopsies systematically
cover the prostatic gland rather than targeting a lesion, and
as low-risk cancers are common, the risk of overdiagnosis
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BRAWLEY, THOMPSON, AND GRONBERG
(i.e., detection of nonsignificant tumors) is high. The risk
of nonrepresentative biopsy findings results in under-
estimation of Gleason grade compared with subsequent
prostatectomy in up to 40% of men undergoing surgery.
Multiparametric MRI incorporating anatomic and func-
tional imaging has now been validated as a means of de-
tecting and characterizing prostate tumors. In 2012, the
European Society of Urogenital Radiology established the
Prostate Imaging Reporting and Data System (PI-RADS)
guidelines aimed at standardizing the acquisition, inter-
pretation, and reporting of prostate multiparametric MRI.
Consensus on an updated version (PI-RADS v2) has recently
been published, outlining aspects of both interpretation and
technical execution.34
Targeted biopsies of the prostate consist of imaging (MRI)
detecting a lesion and a biopsy procedure where biopsies are
targeted to that area using various devices for guidance.
Cognitive fusion is based on a skilled physician interpreting
the MRI images and directing needles solely on the basis of
the ultrasound images. The disadvantages of cognitive fu-
sion lie in the potential for human error when attempting to
mentally fuse the MRI with ultrasound while aiming for
cancers that are often smaller than 1 cm and the inability to
track the location of each biopsy site. Hard fusion enables
proper fusion of MRI information with the ultrasound image,
increasing precision of the biopsy.
A number of studies have investigated the value of fusion
biopsies, using nonrandomized designs and nonscreening
populations. A recent meta-analysis of 16 studies compared
MRI-targeted biopsies (MRI-TBx) and ultrasound-targeted
biopsies (TRUS-Bx) for prostate cancer detection.35 MRI-TBx
and TRUS-Bx did not significantly differ in overall prostate
cancer detection (sensitivity, 0.85 and 0.81, respectively).
MRI-TBx had a higher rate of detection of significant prostate
cancer compared with TRUS-Bx (sensitivity, 0.91 vs. 0.76)
and a lower rate of detection of insignificant prostate cancer
(sensitivity, 0.44 vs. 0.83). Subgroup analysis revealed an
improvement in significant prostate cancer detection by
MRI-TBx among men with previous negative biopsy, rather
than among men with initial biopsy. The authors concluded
that, due to underlying methodological flaws of MRI-TBx, the
comparison must be regarded with caution.
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EVOLVING RECOMMENDATIONS ON PROSTATE CANCER SCREENING
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localized prostate cancer. BJU Int. 2002;89:703-709.
24. Thompson IM, Ankerst DP, Chi C, et al. Assessing prostate cancer risk:
results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst.
2006;98:529-534.
25. Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate
cancer among men with a prostate-specific antigen level , or =4.0 ng
per milliliter. N Engl J Med. 2004;350:2239-2246.
26. Torre LA, Siegel RL, Ward EM, et al. Global cancer incidence and
mortality rates and trends-an update. Cancer Epidemiol Biomarkers
Prev. 2016;25:16-27.
27. Andriole GL, Crawford ED, Grubb RL III, et al; PLCO Project Team.
Prostate cancer screening in the randomized Prostate, Lung, Colorectal,
and Ovarian Cancer Screening Trial: mortality results after 13 years of
follow-up. J Natl Cancer Inst. 2012;104:125-132.
28. Etzioni RD, Thompson IM. What do the screening trials really tell
us and where do we go from here? Urol Clin North Am. 2014;41:
223-228.
29. Stattin P, Carlsson S, Holmstrom B, et al. Prostate cancer mortality in
areas with high and low prostate cancer incidence. J Natl Cancer Inst.
2014;106:dju007.
30. Cuzick J, Thorat MA, Andriole G, et al. Prevention and early detection of
prostate cancer. Lancet Oncol. 2014;15:e484-e492.
31. Smailyte G, Aleknaviciene B. Incidence of prostate cancer in Lithuania
after introduction of the Early Prostate Cancer Detection Programme.
Public Health. 2012;126:1075-1077.
32. Heidenreich A, Bastian PJ, Bellmunt J, et al; European Association of
Urology. EAU guidelines on prostate cancer. part 1: screening, diag-
nosis, and local treatment with curative intent-update 2013. Eur Urol.
2014;65:124-137.
33. Gronberg H, Adolfsson J, Aly M, et al. Prostate cancer screening in men
aged 50-69 years (STHLM3): a prospective population-based diagnostic
study. Lancet Oncol. 2015;16:1667-1676.
34. Barentsz JO, Weinreb JC, Verma S, et al. Synopsis of the PI-RADS v2
guidelines for multiparametric prostate magnetic resonance imaging
and recommendations for use. Eur Urol. 2016;69:41-49.
35. Schoots IG, Roobol MJ, Nieboer D, et al. Magnetic resonance imaging-
targeted biopsy may enhance the diagnostic accuracy of significant
prostate cancer detection compared to standard transrectal
ultrasound-guided biopsy: a systematic review and meta-analysis. Eur
Urol. 2015;68:438-450.
36. Bostrom PJ, Bjartell AS, Catto JW, et al. Genomic predictors of outcome
in prostate cancer. Eur Urol. 2015;68:1033-1044.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e87
CANCER PREVENTION, HEREDITARY GENETICS,
AND EPIDEMIOLOGY

Refining Breast Cancer Risk

Assessment: Additional Genes,
Additional Screening

CHAIR
Allison W. Kurian, MD, MSc
Stanford University School of Medicine
Stanford, CA

SPEAKERS
Antonis C. Antoniou, PhD
University of Cambridge
Cambridge, United Kingdom

Susan M. Domchek, MD
University of Pennsylvania Perelman School of Medicine
Philadelphia, PA
KURIAN, ANTONIOU, AND DOMCHEK

Refining Breast Cancer Risk Stratification: Additional Genes,

Additional Information
Allison W. Kurian, MD, MSc, Antonis C. Antoniou, PhD, and Susan M. Domchek, MD

OVERVIEW

Recent advances in genomic technology have enabled far more rapid, less expensive sequencing of multiple genes than was
possible only a few years ago. Advances in bioinformatics also facilitate the interpretation of large amounts of genomic data.
New strategies for cancer genetic risk assessment include multiplex sequencing panels of 5 to more than 100 genes (in which
rare mutations are often associated with at least two times the average risk of developing breast cancer) and panels of
common single-nucleotide polymorphisms (SNPs), combinations of which are generally associated with more modest cancer
risks (more than twofold). Although these new multiple-gene panel tests are used in oncology practice, questions remain
about the clinical validity and the clinical utility of their results. To translate this increasingly complex genetic information for
clinical use, cancer risk prediction tools are under development that consider the joint effects of all susceptibility genes,
together with other established breast cancer risk factors. Risk-adapted screening and prevention protocols are underway,
with ongoing refinement as genetic knowledge grows. Priority areas for future research include the clinical validity and
clinical utility of emerging genetic tests; the accuracy of developing cancer risk prediction models; and the long-term
outcomes of risk-adapted screening and prevention protocols, in terms of patients experiences and survival.

R ecent advances in genomic technology have enabled

far more rapid, less expensive sequencing of multi-
ple genes than was possible only a few years ago. Ad-
vances in bioinformatics also facilitate the interpretation
of large amounts of genomic data.1 Massively parallel,
next-generation sequencing allows the simultaneous
analysis of many different genes, 2,3 and the emerging
clinical application of whole-genome sequencing.4-6 For
clinical cancer risk assessment, this next-generation
sequencing technology has been implemented primar-
ily as germline multiplex panels that analyze from 5 to
more than 100 cancer-implicated genes. In general,
pathogenic mutations in genes on these multiplex se-
quencing panels confer a twofold or greater risk of de-
veloping cancer (considered in some settings to be a
threshold value for intensified screening),7,8 and are rare
in the population (, 0.5% carrier frequency).9,10 These
genes are sometimes referred to as moderate to high
penetrance cancer susceptibility genes. Focusing on
breast cancer risk, multiplex sequencing panels (MSPs)
represent an intermediate stage between the past
practice of testing BRCA1 and BRCA2 (BRCA1/2) only, 11
and a possible future of routine whole-genome sequencing.
The genes included on most MSPs are displayed in
Table 1. 12-42
Another recent development are panels of several
SNPs that correlate with breast cancer risk. Identified
largely through genome-wide association studies (GWAS)
that compared breast cancer cases and controls,43-46 SNPs
most often have minor allele frequencies of greater than
1% and are associated with a lower magnitude of cancer
risk (e.g., odds ratios of 1.0-1.5). Recent studies have ex-
plored the effect of SNP combinations,47,48 and of SNP
interactions with BRCA1/2 mutations14,49-51 and other risk
factors.52,53 As described later, SNP panels are being used
to improve the accuracy of breast cancer risk prediction
models.
At this time, no single, clinically available panel combines
all established breast cancerassociated genes and SNPs.
Practice guidelines have begun to extend management
recommendations to carriers of mutations in the higher-risk
genes on MSPs,12 but no guidelines currently exist for cancer
screening or prevention on the basis of the combined effects
of the common genetic variants (SNPs). Significant questions
remain about these emerging approaches to genetic risk
assessment.

From the Departments of Medicine and of Health Research and Policy, Stanford University School of Medicine, Stanford, CA; Centre for Cancer Genetic Epidemiology, Department of
Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Basser Research Center and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Allison W. Kurian, MD, MSc, Divisions of Oncology and Epidemiology, Stanford University School of Medicine, 150 Governors Ln., Stanford, CA 94305-5405;
email: akurian@stanford.edu.

2016 by American Society of Clinical Oncology.

44 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


ADVANTAGES OF MULTIPLEX SEQUENCING
PANELS
Multiplex sequencing panels that analyze several breast
cancerrelated genes simultaneously offer several advan-
tages over the prior standard of testing only two genes
(BRCA1/2). In past years, the high cost of sequencing
more than two genes was prohibitive and thus limited
to patients with striking features of Cowden, Li Fraumeni, or
other rare syndromes. By contrast, MSPs of 5 to greater than
100 genes now cost approximately $1,500, less than half the
cost of sequencing two genes in past years. With a turn-
around time of 3 to 4 weeks, MSPs are far more efficient than
the previous standard of care.
Multiplex sequencing panels also provide an improved
diagnostic yield. Among clinic-based studies that collectively
assessed more than 10,000 patients who tested negative for
BRCA1/2 mutations, mutation prevalence in other MSP
genes ranged from 4% to 16%.54-64 Some mutations were
clinically unexpected (e.g., a patient with triple-negative
breast cancer who was found to have a MSH6 mutation,
consistent with Lynch syndrome),56 prompting a change in
cancer screening or prevention targeted to the identified
mutation. There is growing recognition that the striking
cancer phenotypes associated with certain high-risk mu-
tations may be too narrowly defined, and that muta-
tion penetrance may be more variable than previously
believed.65-67
MULTIPLEX SEQUENCING PANELS
Questions of Clinical Validity
The benefits of MSPs are accompanied by potential risks and
uncertainties. These concern questions of clinical validity
(such as whether the test result correctly predicts a clini-
cal phenotype [e.g., high cancer risk]) and clinical utility
KEY POINTS
Recent advances in genomic technology have enabled
far more rapid, less expensive sequencing of multiple
genes than was possible only a few years ago.
Although these new multiple-gene panel tests are used
in oncology practice, questions remain about the clinical
validity and the clinical utility of their results.
Cancer risk prediction tools that consider the joint
effects of all known susceptibility genes, together with
other established breast cancer risk factors, are under
development.
Risk-adapted screening and prevention protocols are
underway, with ongoing refinement as genetic
knowledge grows.
Priority research areas include the validity of emerging
genetic tests; the accuracy of developing cancer risk
prediction models; and the long-term outcomes of risk-
adapted screening and prevention protocols, in terms of
patients experiences and survival.
EXTENDING GERMLINE TESTING IN PATIENTS WITH BREAST CANCER
(whether the test result enables better patient care and
outcomes).
With regard to clinical validity, a major challenge lies in
the high rate of reported variants of uncertain significance
(VUS) with MSPs. Variants of uncertain significance are
genetic alterations (frequently missense) whose disease
association is unknown, and uncertainty about their clinical
relevance may frustrate patients and physicians. With
MSPs, the prevalence of at least one VUS (among all se-
quenced genes) is approximately 20% to 40%.54,57,59,64,68
By contrast, VUS are rare (2%5%) when only BRCA1/2 are
sequenced, because widespread BRCA1/2 testing in diverse
populations has better defined the spectrum of normal
variation for these genes.69 Another challenge arises when
two laboratories provide conflicting interpretations of the
same genetic alteration (e.g., VUS vs. deleterious).
Questions of clinical validity also concern apparently
pathogenic (often truncating) mutations in genes whose
cancer risks are not well understood, yet are included on
MSPsfor example, whether a mutation in MRE11A confers
clinically meaningful risk of breast cancer.9,66 There is no
transparent process for gene selection on many MSPs, and
the combination of genes may seem arbitrary. Emerging
MSP delivery models that empower ordering clinicians to
select genes for inclusion on a custom panel (and to ex-
clude other genes considered irrelevant to a patients care)
may help, although this may require a level of genetic
knowledge that is unrealistic for most clinicians. A recent
review article designated 11 well-established breast
cancer susceptibility genes (ATM, BRCA1, BRCA2, CDH1,
CHEK2, NBN, NF1, PALB2, PTEN, STK11, TP53) and ad-
vised that mutations in other genes not be used in clinical
breast cancer risk assessment.70
Questions of Clinical Utility
The most pressing question about MSPs is their clinical utility.
Rather than the more typical process for a new intervention,
in which proof of clinical utility precedes widespread
adoption, MSPs diffused into oncology practice ahead of
any supporting evidence base.9,66 Causative forces include
new genomic technology, a 2013 U.S. Supreme Court de-
cision against gene patenting that caused increased market
competition and reduced costs, and celebrity testing dis-
closures that raised public awareness.71-74 In recent years,
studies have evaluated the clinical experience of MSP
testing in various populations, 54-60,62-64 with some re-
porting subsequent changes in screening and prevention
protocols.56,64 Practice guidelines including those of the
National Comprehensive Cancer Network (NCCN) have added
management recommendations for genes with a better-
established risk profile (e.g., ATM, CHEK2, PALB2),12,26 and
in 2015 the American Society of Clinical Oncology (ASCO)
issued a position statement on extended germline testing.75,76
However, uncertainty remains about patients preferences and
experiences of MSPs; the optimal care delivery models; and
the effectiveness of risk-reducing interventions developed for
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 45
KURIAN, ANTONIOU, AND DOMCHEK

TABLE 1. Cancer Risks and Guidelines for Breast CancerAssociated Genes Often Included on Multiplex Panels
Established Breast Cancer Susceptibility Genes
Breast Cancer
Gene Relative Risk Other Cancer Risks and Syndromes Clinical Practice Guidelines Reference
ATM Two- to threefold Ataxia telangiectasia syndrome in National Comprehensive Cancer Network (NCCN): Screening 12,13
homozygotes; possibly with breast MRI
colon, pancreas
BRCA1 10-fold Ovarian American Cancer Society (ACS) and NCCN: Screening 8,12,14-16
breast MRI, recommend risk-reducing bilateral
salpingo-oophorectomy (RRBSO),
discuss risk-reducing mastectomy (RRM)
BRCA2 10-fold Ovarian, pancreatic, prostate; ACS and NCCN: Screening breast MRI, recommend RRBSO, 8,12,14-16
possibly melanoma discuss RRM
CDH1 Fivefold Gastric NCCN: Screening breast MRI, discuss RRM, discuss 12,17-19
risk-reducing gastrectomy
CHEK2 Two- to threefold Possibly colon, thyroid, lung NCCN: Screening breast MRI 12,20,21
NBN Two- to threefold Nijmegen breakage syndrome in None 22-24
homozygotes; possibly ovarian
NF1 Two- to threefold Central nervous system, No breast cancerrelated guidelines 25
peripheral nerve sheath
PALB2 Three- to fivefold Pancreas; possibly ovarian NCCN: Screening breast MRI, discuss RRM 12,26
PTEN At least fivefold Thyroid, endometrial NCCN: Screening breast MRI, discuss RRM 12,27,28
STK11 At least fivefold Pancreas, colon, ovarian sex NCCN: Screening breast MRI, discuss RRM 12,29
cord-stromal
TP53 At least 10-fold Multiple: sarcoma, leukemia, NCCN: Screening breast MRI, discuss RRM; 12,30
adrenocortical, brain, others whole-body MRI, colonoscopy, complete
blood count, and other tests

Genes With Undefined Risk of Breast Cancer Frequently Included on Multiplex Sequencing Panels
Breast Cancer
Gene Relative Risk Other Cancer Risks and Syndromes Clinical Practice Guidelines Reference
BARD1 Undefined Unknown None 31,32
BLM Undefined Blooms syndrome in homozygotes None 33
BRIP1 Undefined Ovarian NCCN: Consider RRBSO 12,34
FAM175A Undefined Fanconi anemia in homozygotes None 35
FANCC Undefined Fanconi anemia in homozygotes None 36
MRE11A Undefined Ataxia telangiectasialike disorder in None 22,23,37
homozygotes; possibly ovarian
RAD50 Undefined Possibly ovarian None 22,23
RAD51C Undefined Ovarian NCCN: Consider RRBSO 12,38
RAD51D Undefined Ovarian NCCN: Consider RRBSO 12,39-41
XRCC2 Undefined Unknown None 42

BRCA1/2 mutation carriers among carriers of other gene
mutations.
UNANSWERED QUESTIONS ABOUT MULTIPLEX
SEQUENCING
Genetic Epidemiology
Determining the clinical utility of MSPs requires research in two
major disciplines: epidemiology and health service research.66
First, we must understand the prevalence, penetrance, and
phenotype of mutations in genes beyond BRCA1/2; second, we
must understand how identifying such mutations affects pa-
tients outcomes, in terms of psychosocial symptoms, cancer
detection rate and stage shift, and, ultimately, survival.
As discussed previously, studies have reported estimates
of the prevalence of other gene mutations among patients
tested for BRCA1/2 mutations.12,54-60,62-64 Although in-
formative and clinically relevant, most existing studies have
focused exclusively on patients with striking personal and/or
family histories of early onset breast/ovarian cancer, and on
non-Hispanic whites. A key question is the prevalence of
mutations and VUS among patients at lower estimated risk,
including breast cancer patients unselected for age or family
history; such data are essential to learning which pa-
tients may benefit from MSPs. Of similar importance is
defining the prevalence of mutations and VUS across
racial/ethnic groups, as done for BRCA1/2.77,78 Studies in

46 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


population-based datasets are currently underway to
address these questions.
Understanding the variability in penetrance of mutations
in genes beyond BRCA1/2 is necessary to enable accurate
patient counseling. Large, collaborative studies will be re-
quired to obtain sufficient numbers of mutation carriers:
ongoing consortium efforts include the PROMPT, Breast
Cancer Risk after Diagnostic Gene Sequencing (BRIDGES),
and COMPLEXO studies (www.promptstudy.info; cordis.
europa.eu/project/rcn/193315_en.html).79 Other crucial
research questions include reclassifying clinically ambiguous
VUS to benign or deleterious, which is an aim of the ENIGMA
consortium80; identifying the pathologic and prognostic
features of tumors associated with mutations in specific
genes; and etiologic studies of cancer causation by muta-
tions, particularly those in genes whose association with
breast cancer is less well proven.
Health Services Research
There are several crucial topics for health services research on
MSPs. One important question is how best to deliver genetic
counseling and testing services, in the challenging environ-
ment of increasingly complex test results and a shortage of
licensed genetic counselors.81 New delivery models include a
tiered and binned approach to summarizing test options by
risk categories.82 Long-distance counseling methods such as
telemedicine are also under investigation.
Another essential question is the patient experience of
MSP testing. As described before, there is concern that the
volume, complexity, and uncertainty of results may over-
whelm patients. One study reported that some patients
decline MSPs because of such concerns.83 In the ongoing
Hereditary Cancer Panel prospective trial of MSPs at three
academic cancer centers, most patients reported little
distress or uncertainty after receiving their test results.84
A related question is the impact of extended germline
sequencing on patients uptake of interventions such as
preventive surgery or more intensive screening (e.g.,
magnetic resonance imaging), given the concern that VUS
might be misinterpreted as cause for unwarranted in-
terventions. Although early results of the Hereditary Cancer
Panel trial offer no evidence that patients overuse pro-
phylactic procedures based on test results,84 longer-term
follow-up is required. Answering these questions about the
delivery and outcomes of MSP testing will be required
to guide analyses of the incremental benefit of analyzing
more versus fewer genes, both in terms of efficacy and of
cost-effectiveness.
POLYMORPHIC BREAST CANCER RISK FACTORS
AND NEW MODELS
Despite the widespread availability of MSPs and SNP arrays,
their utility is limited by the lack of risk prediction models
that consider the multifactorial etiology of breast cancer
susceptibility. There is an urgent need for breast cancer risk
prediction models that consider the joint effects of all known
EXTENDING GERMLINE TESTING IN PATIENTS WITH BREAST CANCER
genetic susceptibility variants, together with other estab-
lished risk factors. However, to construct such multifactorial
cancer risk prediction models, it is important first to un-
derstand the underlying models of genetic susceptibility for
breast cancer.
Models of Genetic Susceptibility to Breast Cancer
Epidemiologic studies have estimated that breast cancer is
approximately twice as common among first-degree rela-
tives of breast cancer patients (defined as the familial
relative risk).85 The most important breast cancer sus-
ceptibility genes are BRCA1/2, mutations that account for
17% to 20% of the excess familial risk of breast cancer.86-88
Rare mutations in the established breast cancer suscepti-
bility genes included on MSPs, such as PALB2, CHEK2, ATM,
TP53, PTEN, CHD1, STK11, NF1, and NBN (Table 1), account
for approximately 5%,89 and more than 100 common SNPs
account for an additional 16% of familial breast cancer.90
Together, all known breast cancer susceptibility variants
account for 38% to 41%; thus more than 50% of familial
clustering remains unexplained. Both known genetic vari-
ants and residual familial aggregation must be considered in
calculating the risk of developing breast cancer.
Combined Single-Nucleotide Polymorphisms
Associations
Individual common alleles confer modest risks and their
individual predictive utility is poor. Recently, Mavaddat
et al91 investigated all pairwise interactions between 77
breast cancerassociated SNPs and found no evidence of
deviation from a model in which SNPs combine multipli-
catively. Common SNPs can thus be combined into a Poly-
genic Risk Score (PRS): considering 90 common susceptibility
loci, 5% of women have a greater than twofold increased risk
and 0.7% have a greater than threefold increased risk,
compared with the general populations risk of breast
cancer.90 In models that considered the joint effects of PRS
and family history, PRS stratifies risk in women without
family history and further refines genetic risk assessment in
women with family history.48,91-95 Ongoing large studies,
such as the OncoArray experiment, are expected to refine
these models.
Single-Nucleotide Polymorphisms and BRCA1/2
Mutations
The International Consortium of Investigators of Modifiers
of BRCA1/2 (CIMBA) studied the effects of common SNPs on
BRCA1/2-associated breast cancer risks,96 using different
approaches: GWAS of BRCA1/2 mutation carriers,49,97,98
meta-analysis of BRCA1/2-associated risks with other similar
phenotypes, fine-scale mapping of known risk-modifying
loci,43 and directly assessing the effects of established
breast cancer susceptibility alleles in mutation carriers.99-103
CIMBA identified 24 SNPs that modify BRCA1-associated risk
(which have stronger associations with estrogen receptor
[ER]negative breast cancer in the general population) and
20 SNPs that modify BRCA2-associated risk.104-106 A recent
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 47
KURIAN, ANTONIOU, AND DOMCHEK
study investigated the associations of common SNPs sub-
divided by the ER status of BRCA1- and BRCA2-associated
breast tumors,51,103 and found that differences in SNP as-
sociations between BRCA1 and BRCA2 carriers and non-
carriers are largely explained by differences in the
prevalence of ER-positive and ER-negative tumors in mu-
tation carriers and the heterogeneity of the associations
between common alleles and ER-positive or ER-negative
disease. These are in line with a general model of suscep-
tibility under which BRCA1/2 mutations and common alleles
combine multiplicatively once stratified by ER status. As a
result, jointly, common SNPs can result in large differences in
the absolute lifetime risks of breast cancer among BRCA1/2
mutation carriers.97,107 Risk stratification may improve as
enhanced PRS are developed that include a large number of
SNPs. Women with BRCA1/2 mutations may be among the
first to gain a clinically meaningful benefit from the use of
common SNPs for risk assessment; however, large studies
are required to assess prospectively the enhanced PRS that
are currently under development.
Single-Nucleotide Polymorphisms and Other Rare
Gene Mutations
Little is known about the combined effects of common SNPs
and other rare mutations beyond BRCA1/2, mainly because of
the lack of large-scale cohorts tested with MSPs. However,
breast cancer risks among PALB2 and CHEK2 mutation car-
riers appear to be modified by other familial factors, in-
creasing with family history and/or with bilateral breast
cancer.26,108-110 These findings suggest a multiplicative model
as with BRCA1/2, but confirmatory studies are needed.
Combined Effects of Rare Gene Mutations
Recent evidence suggests that gene-gene interactions
among CHEK2, ATM, BRCA1, and BRCA2 may not be mul-
tiplicative.111 Indeed, a multiplicative model would be im-
plausible for BRCA1 and BRCA2, because it would predict an
extremely high breast cancer risk at very young ages. Pro-
teins encoded by the majority of breast cancer genes play
roles in DNA repair pathways. If no elevated risks are ob-
served in the presence of two gene mutations, the data
would be consistent with a model in which, if the pathway is
disrupted by a mutation, further disruption by a lower
penetrance mutation would not increase risk.112
Combined Effects of Genetic, Lifestyle, and Hormonal
Factors
Studies of common SNPs and other risk factors suggest that
they combine in a multiplicative fashion.113-116 There is
currently no evidence on how the risks of rare gene muta-
tions (other than BRCA1/2) combine with lifestyle and
hormonal factors, but large ongoing studies (e.g., BRIDGES,
cordis.europa.eu/project/rcn/193315_en.html), will report
on this question soon. The evidence for pathogenic variants
in BRCA1 and BRCA2 is currently limited and conflicting, but
there are some suggestions that the relative risks of lifestyle/
hormonal factors may not necessarily be the same in both
48 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
BRCA1 and BRCA2 mutation carriers as in the general
population.117 For example, later age of first birth is asso-
ciated with lower breast cancer risk for BRCA1 mutation
carriers, yet with higher breast cancer risk in the general
population.117
Implications for Cancer Risk Stratification
Our growing understanding of the multifactorial etiology of
breast cancer suggests that much more powerful risk pre-
diction can be achieved by combining data on all genetic,
lifestyle, and hormonal risk factors,92,118 reaching stratifi-
cation levels that can guide individual decision making and
population risk-reduction programs.93,95,119 However, the
assumptions underlying these projections require testing in
empirical studies.
Breast Cancer Risk Assessment Tools
Several breast cancer risk prediction models are available
for unaffected women; they differ in the risk factors they
consider and in their underlying statistical modeling ap-
proaches (Table 2). The two broad categories of models
are empirical and genetic. Empirical models do not
assume a specific genetic model, but instead consider
summary measures of family history: an example is the
widely used Gail model120 in the Breast Cancer Risk As-
sessment Tool (www.cancer.gov/bcrisktool/). Genetic
models make explicit assumptions about known and
unknown genetic effects, considering the mode of in-
heritance, mutation frequency, and penetrance. A major
advantage of genetic models is that they can compute
risks for families of any disease structure; however, their
adequacy depends on modeling all genetic effects, which
can be approximate only because all breast cancer sus-
ceptibility genes have not yet been discovered.121
Examples of genetic models include Claus,122,123
BRCAPRO,124 IBIS,125 and BOADICEA (Table 2).112,126,127
BRCAPRO, IBIS, and BOADICEA all consider the explicit
effects of BRCA1/2 mutations but differ in their modeling
of residual familial aggregation: IBIS assumes a hypo-
thetical third dominant gene, whereas BOADICEA
assumes a polygenic component.
Single-Nucleotide Polymorphisms in Risk Assessment
Tools
Several studies have demonstrated improvement in the
performance of some models through consideration of
common SNPs.47,119,128,129 However, most such studies as-
sumed that the risks predicted by existing models (e.g., IBIS,
BOADICEA) are multiplicative with those conferred by SNPs,
without adjusting for the fact that SNPs account for ap-
proximately 15% of the familial aggregation of breast cancer.
This approach warrants further validation before routine
clinical use. More accurate implementations will require the
underlying algorithms to be modified to ensure that the fa-
milial risks predicted by the models on the basis of the known
and unknown genetic effects are correctly specified.
 EXTENDING GERMLINE TESTING IN PATIENTS WITH BREAST CANCER

TABLE 2. Breast Cancer Risk Assessment Tools Used in Clinical Practice: Components and Assumptions
Factor* Gail Claus BRCAPRO IBIS BOADICEA
Family history YES (descriptive) YES YES YES YES
BRCA1, BRCA2 mutations NO NO YES YES YES
Common low-risk alleles NO NO NO NO NO
Intermediate-high risk mutations (CHEK2, PALB2, ATM, etc.) NO NO NO NO YES**
Residual non-BRCA1/2 familial aggregation NO NO NO YES; dominant YES; polygenic
3rd gene
BRCA1/2 breast cancer pathology associations NO NO YES NO YES
BRCA1/2 risk modification by family history NO NO NO NO YES
Variants of uncertain significance NO NO NO NO NO
Predicting estrogen receptor (ER)-specific risks NO NO NO NO NO
Mammographic density NO NO NO NO NO
Hormonal, lifestyle, and reproductive risk factors YES NO NO YES; assumes same NO
effect on BRCA1/2
Other cancers (nonbreast or ovarian cancer) NO NO YES NO YES
Predicting second cancer risks (contralateral breast, ovarian cancer) NO NO NO NO YES
*Considered in the available tools for clinical use.
**Beta-version release.
Only pathology information for the proband.

Rare Gene Mutations in Risk Assessment Tools
Until recently, no model incorporated the effects of muta-
tions in genes beyond BRCA1/2. A major difficulty had been
the lack of precise cancer risk estimates; however, a recent
extension to the BOADICEA risk assessment model includes
the effects of truncating mutations in PALB2, CHEK2, and
ATM for which reliable risk estimates are now available.70,112
A beta-testing version of this tool is available for clinical use
(ccge.medschl.cam.ac.uk/boadicea/). This extended BOA-
DICEA model can be used to obtain cancer risks on the basis
of mutation screening in all five major breast cancer sus-
ceptibility genes (BRCA1, BRCA2, PALB2, CHEK2, ATM) of
explicit family history information and of other risk factors
(Table 2). Figure 1A demonstrates that risks for carriers of
rare mutations (e.g., an ATM truncating variant) depend on
family history. Although the average lifetime breast cancer
risk for a carrier of an ATM truncating variant is approxi-
mately 29%, the risk for an ATM carrier whose mother de-
veloped breast cancer at age 40 is estimated at
approximately 44%. These differences may have implications
for screening and preventive interventions. Figure 1B shows
predicted risks for a woman whose mother carried a BRCA1
or ATM mutation and had breast cancer, but who has herself
tested negative for the same mutation (known as a true
negative or noncarrier130). Compared to considering
family history alone, the reduction in breast cancer risk after
negative testing is greater when the mother carries a
BRCA1 mutation (predicted risk approximately 15%)
compared with an ATM mutation (predicted risk . 18%).
These results suggest that negative predictive testing for
ATM (or similarly moderate-risk mutations) may not imply
sufficient risk reduction to enable reclassification for
clinical management purposes, and emphasize the need for
further study of the breast cancer risks associated with such
newly identified mutations for both mutation carriers and
their relatives.
Unresolved Problems in Risk Modeling, Challenges,
and Future Directions
Along with BRCA1, BRCA2, PALB2, ATM, and CHEK2, there are
several other breast cancer susceptibility genes which could
be incorporated into risk prediction.70 However, more ac-
curate estimates are required for the breast cancer risks of
mutations in these genes. Similarly, little is known about the
joint effects of rare gene mutations, about the risks for carriers
of mutations in more than one breast cancer susceptibility
gene, or how these genetic risks combine with other lifestyle
and hormonal risk factors. A number of ongoing research
programs will address these issues in the near future, such as
the PROMPT, BRIDGES, and CARRIERS programs. As discussed
before, another problem is VUS reported in BRCA1/2 and
other genes. Several efforts are underway to reclassify these
VUS through consortia like ENIGMA80 and using approaches
such as the posterior probability of causality.131,132 Future
modeling efforts should aim to include such evidence in order
to provide an integrated approach for counseling VUS carriers.
Breast cancer is a heterogeneous disease that differs
based on tumor characteristics. Tumor characteristics vary
based on genetic background, and risk factors have different
associations with different tumor subtypes.133,134 A meta-
analysis of trials of selective estrogen receptor modulators
as breast cancer chemoprevention agents suggested a 38%
risk reduction135; however, a critical gap for clinical trans-
lation is how to identify which women will develop ER-
positive breast cancer, because selective estrogen receptor
modulators prevent only ER-positive disease.133,136 Thus
there is need of risk models to predict ER-specific risks. Data
generated through the large scale B-CAST (Breast CAncer

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 49

KURIAN, ANTONIOU, AND DOMCHEK

FIGURE 1. Predicted Breast Cancer Risks Using the BOADICEA Model, Beta-Version 4.0

(A) Predicted breast cancer risk by ATM mutation status and family history. BOADICEA-predicted risks by ATM mutation status for a female in the United Kingdom born in 1995 (age
20). The three curves show the breast cancer risk in the population, the risk for the average carrier of an ATM mutation (without taking family history into account), and the risk for
a carrier of an ATM mutation whose mother also developed breast cancer at age 40.
(B) Negative predictive testing and predicted breast cancer risk. The predicted risk of breast cancer for a 20-year-old female born in 1995 in the United Kingdom, whose
mother developed breast cancer at age 40, according to her mothers mutation status. Risk estimates were obtained using the BOADICEA model, beta-version 4.0.

Stratification, http://www.b-cast.eu) program will yield valu-
able data for modeling disease subtypespecific risks.
Finally, it will be essential to validate risk-prediction
models in large, well-designed prospective studies, and to
develop user-friendly tools that meet the needs of clinicians
at all care levels.
RISK REFINEMENT AND STRATIFYING
SCREENING APPROACHES
Mammography
Recent updates to guidelines have triggered ongoing con-
troversy regarding the age of initiation and interval timing
of screening mammography in women at average risk for
breast cancer.137-139 Although the specifics of guidelines
differ, the trend is for later initiation of routine mammo-
grams, with the possibility of spacing them to every other
year. Throughout this discussion, it has been recognized that
risk stratification is key to optimizing the clinical benefit of
breast cancer screening; that is, these new recommenda-
tions are for women at average risk, but women at higher risk
may need a more intensive approach. However, most
women who develop breast cancer are not considered to be
at elevated risk before their diagnosis. Thus, as guidelines
favor fewer mammograms, it becomes increasingly impor-
tant to improve risk stratification using factors such as re-
productive and hormonal exposures, breast density, and
genetics; and to understand the complex interactions be-
tween these risk factors. Optimizing risk stratification is
essential to inform individualized breast cancer screening
recommendations.
Breast MRI
At the current time for women at elevated risk, breast MRI is
often added to yearly screening mammogram. Breast MRI is
more sensitive than mammogram for detecting cancers in
BRCA1/2 mutation carriers and women with a family history
of breast cancer.140 Compared with historical controls,
breast cancers detected by MRI are diagnosed at an earlier
stage; historical comparisons and modeling analyses predict
that MRI screening may improve survival.141-145 No ran-
domized studies have been performed evaluating breast
MRI as an adjunct to screening mammography. Concerns
about yearly breast MRI include cost, inconvenience (the
test requires intravenous contrast) and specificity. Cost of
breast MRI is particularly high in the United States. Although
adding annual breast MRI from the ages of 35 to 54 to annual

50 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


mammograms in BRCA1 mutation carriers has been shown
to be cost-effective at $100,000 per quality-adjusted life-
year, the cost-effectiveness of MRI screening decreases at
lower levels of risk. For example, Plevritis et al calculated a
cost-effectiveness ratio (CER) of $266,344/quality-adjusted
life-year for annual MRI in addition to mammogram screen-
ing of BRCA2 mutation carriers from ages 35 to 54.146 CERs
in women with mutations conferring a lower risk of breast
cancer will be even less favorable.
Regardless of concerns about cost, multiple guidelines
recommend annual breast MRI in women at elevated risk
of breast cancer.7,12,147-149 Guidelines differ in the
stipulated level of risk that should trigger the addition of
breast MRI, but in the United States, the American
Cancer Society, and NCCN recommend adding annual
breast MRI to mammogram in women with a lifetime risk
of greater than 20% based on a family history model8,12;
this recommendation exists despite the absence of
empirical evidence that breast MRI screening improves
outcomes. Existing guidelines do not specify what is
meant by lifetime riskwhether cumulative lifetime risk
or remaining risk at a womans current age. Therefore,
depending on the models used, different recommen-
dations may be made for the same woman.150
Average lifetime breast cancer risks are estimated to
approach or exceed 30% with mutations in PALB2, ATM,
NBN, and CHEK2 (for CHEK2, excluding the p.I157T and p.
S428F mutations). Therefore, carriers of mutations in
these genes could be considered for breast MRI screening
on the basis of existing U.S. guidelines. Importantly, two
missense mutations in CHEK2, p.I157T and p.S428F, are
associated with lower levels of breast cancer risk (relative
risk [RR] , 2), and the corresponding lifetime risks are
unlikely to exceed 20% in the absence of a family history of
breast cancer.151,152 Likewise, there is insufficient evi-
dence at this time to recommend breast MRI screening in
carriers of mutations in BARD1, BRIP1, MRE11A, RAD51C,
and RAD51D in the absence of a family history.70 In those
women who do meet existing guidelines for MRI sur-
veillance, the appropriate age at which to initiate screen-
ing is currently unclear. Because of the lower risks and
later median onset of breast cancer associated with mu-
tations in moderate penetrance genes compared with
BRCA1/2, it seems reasonable to initiate breast MRI
screening in carriers of mutations in moderate penetrance
genes later than for BRCA1/2 mutation carriers, for whom
MRI screening begins at age 25; however, screening
recommendations for any individual patient will depend
on family cancer history.
Currently, breast MRI screening often begins 5 to
10 years before the earliest age at diagnosis of breast
cancer in the family; however, a more rational approach
may be to focus on the absolute risk of breast cancer over
the next 5 years. As evidence accumulates, the ages for
initiation of surveillance and the type of surveillance
must be re-examined. Because guidelines recommend
less for women at average risk, women identified as
EXTENDING GERMLINE TESTING IN PATIENTS WITH BREAST CANCER
carriers of mutations in moderate penetrance genes
should continue annual screening mammograms. Re-
cently, Mandelblatt et al examined eight different
mammographic screening strategies and determined
that for women with a two- to fourfold increase over the
average breast cancer risk, annual screening from age
40 years had similar harms and benefits as did screening
average-risk women biennially from age 50 to 74 years.153
Finally, emerging technologies such as breast tomosynthesis
and rapid breast MRI may alter screening approaches in
the future.
Prevention Options
Women at elevated risk for breast cancer also have
options for prevention. All women, regardless of esti-
mated risk level, should be counseled on the harmful
impact that obesity, lack of exercise, and alcohol use
have on breast cancer risk. In addition, pharmacologic
breast cancer risk reduction with tamoxifen, raloxifene,
or an aromatase inhibitor is available. In randomized
clinical trials, tamoxifen taken for 5 years confers a 30%
to 50% reduction in the risk of developing breast can-
cer, 136,154 with continued benefit at 16 years of follow-
up (albeit no documented survival benefit to date). 136
Raloxifene also confers a reduction in the risk of breast
cancer. When directly compared with tamoxifen in a
randomized clinical trial, in long-term follow-up ralox-
ifene had 76% of the effectiveness of tamoxifen in
preventing invasive breast cancer, yet far less toxicity in
terms of the risk of endometrial cancer.155 Exemestane
(an aromatase inhibitor) has also been shown to reduce
breast cancer risk in a randomized controlled trial, with a
hazard ratio of 0.35 (95% CI, 0.180.70; p = .002). 156
Although eligibility criteria differed somewhat for these
studies, most included women age 60 or older, those
with a Gail modelbased estimate of 5-year risk of de-
veloping breast cancer of greater than 1.66%, and/or
those with lobular carcinoma in situ. Data are not
available regarding the effectiveness of chemoprevention
among carriers of mutations in moderate penetrance
breast cancer susceptibility genes. CHEK2 mutations do
appear to be associated with ER-positive breast cancer,
but data regarding chemoprevention in this setting are
unavailable.
There is no threshold risk that mandates risk-reducing
mastectomy in any unaffected woman, regardless of her
mutation type. It is unlikely that mastectomy will provide a
survival advantage to women with moderate penetrance
mutations, given their level of risk and the effectiveness of
breast cancer screening and treatment. Elicitation of indi-
vidual preferences and communication about levels of risk
are critical in these conversations.
Ovarian Cancer
Unfortunately, ovarian cancer screening has been shown not
to reduce mortality.157 Therefore, risk-reducing salpingo-
oophorectomy (RRSO) is the standard recommendation for
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KURIAN, ANTONIOU, AND DOMCHEK
women with BRCA1/2 mutations. Large case-control studies
have demonstrated that women with mutations in BRIP1,
RAD51C, and RAD51D are at increased risk of ovarian cancer.
The absolute risks associated with mutations in these genes
are intermediate between those of a woman with a BRCA1/2-
negative first-degree relative with ovarian cancer (RR 2.2,
absolute lifetime risk 3%5%) and of a woman carrying
BRCA2 mutation (absolute lifetime risk approximately
17%).15,158 Studies have not proven increased ovarian
cancer risks in carriers of mutations in other moderate
penetrance genes including PALB2, ATM, CHEK2, BARD1,
MRE11A, NBN, and RAD51B, although mutations in these
genes have been observed in families with both breast and
ovarian cancers.
Risk-reducing salpingo-oophorectomy is not routinely
recommended for women whose only ovarian cancer risk
factor is an affected first-degree relative. A womans cu-
mulative risk should therefore at least be similar to the risk
of a woman with an affected BRCA1/2-negative first-degree
relative with ovarian cancer before RRSO is recommended. It
is unlikely that carriers of mutations in BRIP1, RAD51C, or
RAD51D would cross this risk threshold before age 50.
However, family history of ovarian cancer may influence this
risk and thus may alter decision making about RRSO timing.
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129. Darabi H, Czene K, Zhao W, et al. Breast cancer risk prediction and
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130. Kurian AW, Gong GD, John EM, et al. Breast cancer risk for noncarriers
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131. Easton DF, Deffenbaugh AM, Pruss D, et al. A systematic genetic
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132. Lindor NM, Guidugli L, Wang X, et al. A review of a multifactorial
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133. Rosner B, Glynn RJ, Tamimi RM, et al. Breast cancer risk prediction
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CARE DELIVERY AND PRACTICE MANAGEMENT

Access to Cancer Therapeutics

in Low- and Middle-Income
Countries

CHAIR
Paul Ruff, MBBCh, MMed, FCP(SA)
University of Witwatersrand Faculty of Health Sciences
Johannesburg, South Africa

SPEAKERS
Lawrence N. Shulman, MD
Abramson Cancer Center of the University of Pennsylvania
Philadelphia, PA

Sana Al-Sukhun, MD, MSc

The University of Jordan
Amman, Jordan
RUFF ET AL

Access to Cancer Therapeutics in Low- and Middle-Income

Countries
Paul Ruff, MBBCh, MMed, FCP(SA), Sana Al-Sukhun, MD, MSc, Charmaine Blanchard, MPhil, MBBCh, BSc,
and Lawrence N. Shulman, MD

OVERVIEW

Cancer is rapidly becoming a major health care problem, especially in developing countries, where 60% of the worlds total
new cases are diagnosed. The success of new antineoplastic medicines and modern radiation devices to cure a good
proportion of patients with cancer and to alleviate the suffering of many more has been achieved at a dramatic cost.
Therefore, it has become mandatory for health care authorities and pharmaceutical companies to cooperate to use and
develop resources in an efficient manner to improve health care delivery to patients with cancer worldwide. Regulatory
harmonization is an important key to overcome delays in the approval process, whether for antineoplastic and pain control
medicines or for essential medical devices. More emphasis on the significant role of opiates in pain control among patients
with cancer is needed to overcome the ingrained belief in their potential for addiction. The World Health Organization (WHO)
serves an important role in guiding priorities for health care and efficiently allocating resources by providing essential
medicine lists (EMLs) and device lists. However, the financial challenge for access to health care is multi-tiered and requires
collaboration between key stakeholders including pharmaceutical industry, local national health authorities, WHO, and
other nonprofit, patient-oriented organizations.

S ince the turn of the century, we have seen a paradigm

shift in the way we treat cancer, with the advent of
targeted therapies, especially monoclonal antibodies and
small-molecule kinase inhibitors. Indeed the development of
imatinib in chronic myeloid leukemia (CML) and rituximab in
B-cell lymphomas have been considered among the greatest
breakthroughs in cancer care in the past 50 years. Unfor-
tunately, these and many other therapies that have signif-
icantly improved outcomes in patients with cancer are not
available to everyone who needs them, especially in low-
and middle-income countries (LMICs). The cost of new
anticancer medicines is increasing, with the average monthly
cost of some newly released molecules being over $12,000
per month for oral kinase inhibitors and $150,000 for
a course of monoclonal antibodies. These costs have long
been out of the range of most LMICs and are now becoming
excessive even for European and North American patients.
The treatment of cancer has always been costly and dif-
ficult to access, be it surgery, radiation therapy, systemic
medicines, or palliative care. Radiation machines are costly
and limited in access in LMICs, whereas chemotherapy drugs
have always been difficult to procure since they first became
available in the 1950s. Surgical care is limited by lack of skills
and facilities, whereas access to palliative medicines, es-
pecially for pain control, is limited by regulatory and legal
restrictions, costs, and storage, as well as cultural attitudes
to end-of-life issues. Radiation machines should be procured
and maintained in LMICs at reasonable prices without
sacrificing safety and efficacy, whereas surgical skills should
be enhanced by improving local facilities and training cancer
surgeons on site or at international centers.
There are no easy solutions to drug costs because phar-
maceutical companies should make profits to be able to
develop new medicines, knowing that not all medicines
undergoing study come to market and that antineoplastic
agents, especially biologic medicines, are difficult and costly
to produce. The current model of oncology drug develop-
ment, distribution, and marketing must change before it is
too late. There must be collaboration between academia and
individual pharmaceutical companies, as well as with reg-
ulatory authorities and governments, to avoid the situation
being experienced in renal cancer, where we now have more
than 10 agents on the market from multiple pharmaceutical
companies. Collaboration with regulatory authorities can

From the University of Jordan, Amman, Jordan; University of Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa; Abramson Cancer Center, University of
Pennsylvania, Philadelphia, PA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Paul Ruff, MBBCh, MMed, FCP(SA), University of Witwatersrand Faculty of Health Sciences, 7 York Rd., Johannesburg, 2193, South Africa; email: pruff@
iafrica.com.

2016 by American Society of Clinical Oncology.

58 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


reduce research and development costs by streamlining the
regulatory burden on clinical research and expediting reg-
istration of medicines with significant benefits over those
with limited benefits. Development of medicines with
limited benefits should be halted as early as possible.
Evergreening (enhanced intellectual property protection)
must also be prevented; extended patents are detrimental
to underfunded patients in both high-income countries and
LMICs. International collaboration in the development of
good quality generics and biosimilars will help make these
molecules available more rapidly to patients around the
world. Development of EMLs, both in individual countries
and internationally by WHO, will make the use of cancer
medicines more cost effective and less wasteful.
Unless we all work together to find a solution, cancer care
will only be available to the very wealthy. Indeed, we are
seeing the development of more and more exciting treat-
ments for fewer and fewer people.1
DRUG ACCESS AND APPROVAL IN LOW- AND
MIDDLE-INCOME COUNTRIES
Cancer is rapidly becoming a major health care problem,
especially in LMICs. The success of antineoplastic medicines
to cure patients and alleviate their suffering has been achieved at
a dramatic cost. Therefore, it has become mandatory for health
care authorities to cooperate to use resources efficiently to
improve health care delivery to patients with cancer worldwide.
The initial step in the process of access to antineoplastic
medicines is a pharmaceutical companys application for
approval by the responsible local health regulatory au-
thorities. The expected revenues of a medicine depend on
the volume of drug sold and the average income of targeted
KEY POINTS
The majority of patients with cancer reside in LMICs with
limited access to essential medicines and services,
resulting in a disproportionate increase in cancer
mortality.
Obstacles to cancer care are numerous and include
costs, regulatory and cultural barriers, and limited
availability of health care practitioners.
The financial challenge for access to care is multi-tiered
and requires collaboration between all stakeholders
including the pharmaceutical industry, national and
local health authorities, nongovernmental
organizations, and the World Health Organization.
Regulatory, financial, and cultural barriers limit access to
chemotherapy agents, supportive care medicines,
radiation therapy, and complementary and alternative
medicines required for good cancer pain management in
LMICs.
Collaborative partnerships and regulatory
harmonization can overcome delays in treatment access
and approval and facilitate the development of quality
cancer care delivery.
CULTURAL AND REGULATORY BARRIERS TO TREATING CANCER PAIN
populations.2 For cancer, expected revenues in LMICs may
not justify investment because the target populations
average income is low. This lack of incentive compelling
regulation to register medicines results in excessive delays
in access to newer medicines.
Once an application for a new medicine is filed, the
complex regulatory approval process starts to ensure
availability of high-quality, safe, and effective medicines.3
Although some countries can assess a new drug themselves,
based on the scientific dossier provided by the manufacturer
(usually high-income countries), middle-income countries
with varying levels of development and drug regulatory
capabilities, or low-income countries with very limited or no
drug regulatory capability cannot undertake full assess-
ments of new pharmaceutical products. LMICs depend to
differing extents on assessment made by a foreign drug
regulatory authority, for example the U.S. Food and Drug
Administration (FDA) or European Medicines Agency (EMA).
Drug approval by one of these major authorities provides
a valid basis for marketing a product in these LMICs. In an
attempt to facilitate drug registration in LMICs, WHO has
developed a certification scheme to provide quality assur-
ance for imported medicines by means of standard forms
confirming the registration of the product in the country of
manufacture (Certificate of Pharmaceutical Product [CPP])
and approval of good manufacturing practice conditions
based on inspections and quality analysis of the product.4,5
However, even after 2 decades of existence, the WHO
certification scheme is not widely used. Regulatory pro-
cedures still vary significantly among nations, with certificate
format, conditions, and wording varying from one country to
another.6 Each country requires different documentation,
but almost all require at least one CPP from the manufacturing
site, the packaging and release site, or both. The process for
registering medicines remains complex and burdened with
inefficiencies, duplications, delay, and, in some instances,
corruption.7,8 For instance, the manufacturing process may
take place in several countries, complicating the process of
obtaining a satisfactory CPP for the regulatory authorities in
importing countries. This will potentially delay regulatory ap-
proval if the regulatory authority requests different CPPs than
what was already provided. Some products are manufac-
tured and approved in a certain country for export only,
leading to concern that the competent authorities in the
manufacturing country are less stringent with regard to
products not to be used in their own territory. It is logical for
some importing countrys regulatory authority to request
more reassuring documentation (e.g., formal declaration
signed by the manufacturers responsible good manufacturing
practice person in addition to the Export CPP), to ensure
follow-up on complaints from the importing countrys au-
thority regarding product defects or inaccuracy of the dec-
larations contents. Still, the regulatory authority could refuse
to register that product.9,10 To further illustrate the complexity
of implementing the WHO certification scheme, assess-
ment of quality of active pharmaceutical ingredients was
also recommended by the International Conference of
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 59
RUFF ET AL
Drug Regulatory Authorities.7,11 Such recommendations
added to the confusion and complexity of drug approval
processes in LMICs, especially because many do not yet
have the regulatory capacity required to fully implement
the WHO certification scheme, let alone comply with
those recommendations.12
After a medicines approval by EMA or FDA, it takes a year
or more to register that medicine in LMICs. Some countries
adopt fast-track for the registration of priority medicines
fulfilling an unmet medical need.13 Even in North America, it
was estimated that more than 250,000 life-years are lost per
year of delay in access to drugs that were shown to prolong
overall survival in phase III clinical trials.14 Even more life-
years are lost if we consider the possible estimate in LMICs
where the delay is more of a challenge and the disease
burden is escalating. Regulatory harmonization (i.e., either
allowing for one centralized approval for drug registration in
multiple countries, or mutual recognition once a drug has
been registered in certain countries) is the key to using
resources more efficiently and especially to speeding up the
process to facilitate access to patients.7
Once a medicine is registered, access varies from one
country to another. Rarely, registration entails availability
for patients treated in public health care systems. In some
countries, even if the medicine were to be available, it takes
an additional 1 to 2 years to obtain.13 In most countries,
medicines will only be available for those who can pay out of
pocket, creating a financial access obstacle, probably the
most challenging in the access process. In many LMICs, as
much as 90% of the population purchase medicines on an
out-of-pocket basis,15,16 with spending often dispropor-
tionate to personal or family income. The recently updated
WHO EML for cancer could potentially serve as a valuable
asset for advocacy to influence the local health authorities in
LMICs to provide those medicines free of charge or make
them available for patients at affordable cost.17
The financial access challenge creates another serious
concern of drug quality. Many reports have described pa-
tients receiving substandard or counterfeit drugs.18,19 This is
mainly the result of importing cheaper, poorly manufactured
rogue generics. Although some governments have begun
to promote the development of generic drug manufacturing
capacity within their own bordersas in India, Brazil, South
Africa, and, recently, Jordanmany countries rely solely on
importing drugs. In its effort to combat this challenge faced
in every field of medicine, WHO developed a prequalification
program for pharmaceuticals and active pharmaceutical
ingredients,20 initially developed to help international
procurement agencies, but lately used by LMICs to guide
bulk purchase of medicines. Drugs passing quality control
appear on the WHO prequalification website; however,
antineoplastic medicines are not there yet. Conversely,
delayed market entry of generics because of evergreening in
countries that joined the World Trade Organization further
increases cost.21 Such countries should consider increasing
spending on public health to offset the adverse impact on
patients of strengthening its intellectual property protection
60 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
relevant to medicines, in addition to long-term plans to control
the price increase as a result of that commitment. Compulsory
licensing allowing generic versions of medications to be
produced despite the existence of a patent to provide med-
icines of need in a society at affordable prices, is a plausible
policy already adopted in India, South Africa, and Thailand.22
Direct price control measures could help reduce the price
by an average of 20%.23 Control measures could be price
setting included in registration and procurement through
a central government agency. Because most of antineo-
plastic medicines are not procured centrally, they are only
available in the private sector for out-of-pocket purchase at
much higher prices.7 If price is adjusted for affordability,
LMICs pay a much higher price compared with high-income
countries.24 The prices set for the recently developed bi-
ologics are prohibitive not only for out-of-pocket purchase
but also for central procurement, creating the case for
differential international pricing. Concerns related to this
approach (e.g., parallel trading and use in reference pricing)
do seem legitimate, but the experience with HIV treatment
does not support those concerns.22 However, this differ-
ential pricing is beneficial if the different pricing levels in-
deed reflect the ability of the target population to pay. This is
amplified by The World Banks country income classifica-
tion; although it was designed for World Bank lending
decisions, its improper adoption to inform health-related
decisions increases the cost of medicines. It does not reflect
health system capacity of governments to invest more in
health, and it does not take into account income inequality
within a nation. Many countries have graduated to become
upper-middle income resulting from statistical recalcula-
tions, although 15% to 55% live at or below national poverty
lines.25 This graduation will further complicate drug pricing
policies and availability of expanded drug access programs
for patients. Regulatory harmonization is the key to over-
come delays in the approval process and efficiently use
resources. The financial challenge for access is multitiered
and requires collaboration between key stakeholders
including pharmaceutical industry, local national health
authorities, WHO, and other nonprofit, patient-oriented
organizations.
CULTURAL AND REGULATORY BARRIERS TO
PAIN MANAGEMENT INCLUDING ANTICANCER
DRUGS, RADIOTHERAPY, AND SUPPORTIVE
MEDICINES IN LOW- AND MIDDLE-INCOME
COUNTRIES
More than half of all patients with cancer and more than
three-quarters of patients with advanced disease will suffer
from pain at some time in the course of the illness. The pain is
usually moderate to severe, affecting the patients quality of
life, and it can become chronic in long-term cancer survivors.26
The management of cancer pain is a multidisciplinary
process that has many barriers confronting patients and
their families, as well as health care professionals. There are
many difficult aspects to the management of cancer pain in

both high-income countries and LMICs developing. Despite
the high prevalence of cancer pain, it is often poorly treated
for several reasons. To manage cancer pain effectively, it is
important to assess the type of pain and its effect on quality
of life and to decide on a management plan using appropriate
interventions, analgesics, and supportive care as required.
Interventions can include disease-modifying therapies such as
chemotherapy, radiotherapy, or surgery. Analgesics include
nonopioid and opioid drugs, as well as co-analgesic (adjuvant)
drugs for pain that is either not responsive or partially re-
sponsive to opioids. Interventions and analgesics have side
effects, which should be treated with further medications.
Many societies and cultures use traditional or comple-
mentary and alternative medications and nondrug mea-
sures to control pain.
ORTHODOX MEDICINES
Cancer chemotherapy plays a critical role in reducing pain in
patients with cancer by shrinking and, in certain malig-
nancies, curing the cancer. As mentioned before, access to
cancer chemotherapy has always been limited by costs and
by slow regulatory approval in many LMICs. In South Africa,
approval of a new chemical entity or generic medicine may
take as many as 3 years unless a fast-track status is obtained,
owing to an unmet medical need or public health require-
ment, which will reduce the time to about 18 months.
Dossiers for registration have to go through three to four
committees, including the Naming and Scheduling Commit-
tee, the Pharmaceutical and Analytic Committee, the Central
Clinical Committee, and, in some cases, the Biologic Com-
mittee, all of which are understaffed. Many doctors in LMICs
are reluctant to refer patients for chemotherapy because of
myths concerning the side effects, and patients themselves
have similar views often perpetuated by the media.
Opioid analgesics are the mainstay of cancer pain con-
trol but are frequently inadequately used because of
doctors and patients fears concerning addiction and abuse.
Longer-acting opioids including slow-release morphine and
fentanyl patches are limited by slow regulatory approval
of generics and high costs of the originator. Opiophobia
is a significant barrier to pain control with opioid analge-
sics in LMICs. 27 Patient-related factors include fear of
psychological dependence and stigma related to opioid
use, especially where opioids are associated with crim-
inal activity and gang violence.28,29 Health professional
related opiophobia, including beliefs that opioids cause
addiction, tolerance, or difficult-to-control side effects, is
also a significant barrier to adequate pain treatment with
opioids.30
Tricyclics, anticonvulsants, and particularly a2d ligands
gabapentin and pregabalin play an important role in the
treatment of neuropathic pain but are often not available in
LMICs because of slow regulation of generics and high costs
of originators.
Osteoclast inhibitors including bisphosphonates and RANK-
ligand inhibitors play an important role in the management
CULTURAL AND REGULATORY BARRIERS TO TREATING CANCER PAIN
SIDEBAR. Medicines Used for Management of
Cancer Pain
Disease-Modifying Agents
Chemotherapeutic agents
Analgesics
Paracetamol
Nonsteroidal anti-inflammatory drugs
Weak opioids: codeine, tramadol.
Strong opioids: morphine, fentanyl
Local anesthesia
Co-analgesics (Adjuvants)
Tricyclic antidepressants
Anticonvulsants
a2d ligands: gabapentin and pregabalin
Baclofen
Benzodiazepines
Other Essential Medications
Laxatives
Antiemetics
Proton-pump inhibitors
Corticosteroids
Bisphosphonates and RANK-ligand inhibitors
of bone pain. Unfortunately, their availability is also limited
by slow regulatory approvals and high costs (Sidebar).
RADIATION THERAPY FACILITIES: LINEAR
ACCELERATOR VERSUS COBALT 60
Linear accelerator access is limited by high up-front and
maintenance costs, with less effective but low maintenance
and cheaper cobalt 60 being supported in some LMICs by the
International Atomic Energy Agency. In addition, cultural
beliefs and use of traditional medicines likely affect the ac-
ceptability of radiation therapy for patients in LMICs. A study
in San Francisco found that Chinese and other Asian women
received less radiation or other adjuvant treatment of breast
cancer than Japanese or white women, most likely because of
cultural beliefs about disease and death, body image, med-
ical decision making, and use of alternative medicines.31
TRADITIONAL OR COMPLEMENTARY AND
ALTERNATIVE MEDICINES
The use of traditional or complementary and alternative medi-
cines (TCAMs) varies across the world from 7% to 64%.32 In LMICs,
TCAMs are a natural element of traditional health practice.
TCAMs are categorized by the National Centre for Comple-
mentary and Alternative Medicine in the United States (Table 1).33
There is limited evidence for the effectiveness of TCAMS in
treating cancer pain. Differing responses to multidisciplinary
pain programs have been noted where the mood symptoms
improved in all patient groups but improvement in pain
was culturally determined.34 The effectiveness of TCAMs in
managing cancer pain is dependent on cultural beliefs and
expectations. However, reliance on TCAMs and resistance to
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 61
RUFF ET AL
TABLE 1. Categories of Traditional or Complementary
and Alternative Medicines
Category Example
Alternative medical systems Traditional Chinese, Ayurvedic,
and African traditional
medicine
Mind-body (spirit) Meditation, prayer, faith healing,
interventions support groups, music therapy,
and hypnosis
Biologically based therapies Herbal medicines, dietary
supplements, vitamins
Manipulation and TENS, acupuncture massage,
body-based therapies chiropractic, osteopathy,
and reflexology
Energy therapies Qi Gong, Reiki, and magnetic field
therapy
conventional interventions and opioids may exacerbate pain
in LMICs.
CANNABINOIDS
Historically, the use of cannabis as medicine dates back to
before the Christian era in Asia and spread to the Middle East
in the 10th century, to Africa in the 15th century, to South
America in the 16th century, and to Europe and the United
States in the 19th century.35 A meta-analysis of several
controlled clinical trials supports the use of cannabinoids
(dronabinol and nabilone) for chemotherapy-induced nau-
sea and vomiting, but not for pain. There is no good evidence
supporting the use of inhaled or oral extracts of cannabis for
any cancer-related side effects.36 Country- and state-specific
barriers to legalizing cannabis for symptom control exist
largely because of lack of adequate controls and concerns
about abuse.
CULTURAL BARRIERS TO CANCER PAIN
MANAGEMENT IN LOW- AND MIDDLE-INCOME
COUNTRIES
Many studies on cultural barriers, reported in English, are
largely associated with pain management in Western
countries with cultural minorities, usually of ethnic groups
originating from LMICs. These minority groups are often
marginalized and from lower socioeconomic levels, which
may confound the results because these groups often do not
have equitable access to health care. In these countries,
language barriers may also play a role in inaccurate pain
assessment. It has been shown that nurses who share the
same language as Arabic patients when assessing pain
usually assigned similar ratings to the patients compared
with non-Arabicspeaking nurses.37 However, with this in
mind, these studies may provide a proxy for studying cultural
aspects of cancer pain management in LMICs.
Two reviews of ethnic and cultural differences in pain and
pain management by Kwok and Bhuvanakrishna38 and by
Campbell and Edwards34 reveal the following potential
62 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
cultural barriers to pain management: (1) differences in
perception of pain, health beliefs, and the meaning of pain
with normalizing of the cancer experience; (2) reluctance to
report pain because of negative stigma associated with
cancer progression and fatalism, and a belief in accepting
pain with stoicism; and (3) different coping practices with
belief in traditional remedies, faith healing, prayer, or
positive thinking.
There appear to be differences in the experience of
physical pain, in the reporting of pain, and in the emotional
response to pain, which may reflect differences in the
meaning of pain in different cultures. There are cultural
taboos and fears that limit access to pain-relieving medi-
cations, but there are also traditional practices that are used
to manage pain. Although it is important to ensure that pain
medications and modalities to treat pain are accessible to all,
it is important to consider different cultural attitudes toward
illness and pain and its management.
WORLD HEALTH ORGANIZATION LIST OF
ESSENTIAL MEDICINES AND DEVICES:
MAXIMIZING CANCER CARE VALUE AND
SUPPORTING THE DEVELOPMENT OF CANCER
DELIVERY PROGRAMS
Cancer is a group of very disparate malignant diseases, with
the diagnostics and treatment varying widely among them.
In addition, many patients require sophisticated surgery,
radiation, and systemic therapies. High-quality pathology is
required to make accurate diagnoses in almost all patients,
and imaging is frequently necessary for cancer staging and
assessment of treatment response and follow-up. There are
many essential cancer medications with different cancers
requiring different noninterchangeable agents. Many
countries and ministries of health face daunting obstacles in
establishing functional and quality services in all of these
areas. Toward this end, the WHO has several processes
aimed at aiding countries in the establishment and en-
hancement of cancer services.
The Essential Medicines List
In 1977 WHO published its first EML addressing medicines
felt to be critical to treating many diseases, including cancer.
In the intervening years, additional medicines were evalu-
ated and added to the EML. In the case of cancer medicines,
agents were added one at a time, without clear instruction
about where the benefit for the medication existed. In 2012,
the Union International for Cancer Control and the Dana-
Farber Cancer Institute filed applications with WHO to add
trastuzumab and imatinib to the EML for cancer. At that
time, there were no targeted therapies or on-patent drugs
on the EML for cancer. The applications argued that these
two medicines dramatically alter the outcomes and survival
rates for patients with HER2-positive breast cancer and CML,
respectively, and that there were no less-costly alternatives
having similar benefits. WHO deferred judgment and asked
Union International for Cancer Control and Dana-Farber

Cancer Institute to lead a comprehensive review of the
cancer EML.
In 2014, a process was undertaken to identify cancers
where systemic therapies had significant impact. Cancers
were chosen if they were of high burden, if systemic ther-
apies had at least some benefit (such as nonsmall cell lung
cancer) and if they had lower disease burden (such as CML),
and if systemic therapies (e.g., imatinib) had a major impact
on survival. In all, 27 diseases were evaluated, with separate
applications for early-stage and metastatic disease for breast
cancer and colorectal cancer. Nearly 100 oncologists from all
continents were recruited to help in the process. For each
disease, a document was created that included: (1) an exec-
utive summary; (2) public health relevance; (3) requirements
for diagnosis, treatment, and monitoring; (4) overview of
regimens; (5) review of benefits and harms (including refer-
ences and systematic reviews); and (6) recommendations for
additions to the EML.
Each disease-based document was initially written by
a cancer expert or team of experts and reviewed and cri-
tiqued by at least two other experts or teams. A central
committee then collated the work of all three groups to form
a consensus-based document. The central committee added
the section on public health relevance and references fo-
cusing on important phase III studies and systematic re-
views, and in some cases costing information. Importantly,
each document contained a section on diagnostics and
specific needs for treatment and monitoring of patients.
The documents were designed to provide critical in-
formation to governments and ministries to understand
better what was needed to treat the particular disease
and make administration of the listed medications safe
and effective.
The approach in each document was regimen-based,
rather than based on individual medications. For some
diseases, such as CML, the regimen was a single drug; in this
case imatinib, but for many diseases the regimen consisted
of multiple drugs such as doxorubicin, bleomycin, vinblas-
tine, and dacarbazine (ABVD) for Hodgkin lymphoma. In
addition, the incremental benefit of the medicines was
quantitated. As an example for diffuse large B-cell lym-
phoma, where surgery is required for biopsy and diagnosis
but does not add at all to remission or cure rates, the
medicines alone accounted for all benefits. In this case, the
administration of cyclophosphamide, doxorubicin, vincris-
tine, and prednisone (CHOP) would result in a 55% long-term
remission rate, whereas the addition of rituximab to this
regimen (R-CHOP) would provide an incremental benefit of
15%, bringing the long-term remission rate to 70%. In the
case of early-stage breast cancer, where surgery is required
and will result in cure for many patients, the medicines
would have incremental benefit above surgery. In a hypo-
thetical patient with node-negative, estrogen receptor
positive, HER2-negative breast cancer, surgery alone might
result in a long-term remission rate of 70%. The addition of
hormone therapy such as tamoxifen might give 15% in-
cremental benefit to the long-term remission rate, bringing
CULTURAL AND REGULATORY BARRIERS TO TREATING CANCER PAIN
it to 85%, and the addition of adjuvant chemotherapy might
add 5% more to the long-term remission rate, bringing it
to 90%.
The disease-based documents contained specific infor-
mation on dosing of each medication as well as schedule and
duration of therapy. With this information, ministries of
health could estimate annual drug needs by knowing the
number of patients with each disease and the dose of each
drug needed to treat a patient.
Drafts of the 29 disease-based documents were reviewed by
an expert committee at an in-person meeting at WHO in
November 2014, and finalized documents were submitted to
WHO in December 2014. They were posted on the WHO
website for public comment in January 2015. In April 2015,
a WHO Expert Committee reviewed all documents, and in May
2015 made public their decisions. The documents had pro-
vided support for the 30 existing medications on the EML and
recommended the addition of 22 medicines. WHO approved
the 30 existing medications and added 16 new medicines to
the list, whereas six were rejected. Approved medications
included, for the first time, patented, costly agents (i.e.,
trastuzumab and imatinib). The rejected medicines included
two second-generation tyrosine kinase inhibitors for CML
(insufficient data to support them as more essential than
imatinib), two EGFR antagonists for the treatment of non
small cell lung cancer (molecular testing frequently unavail-
able with modest incremental benefit), arsenic trioxide for the
treatment of acute promyelocytic leukemia (insufficient data
to support it as an essential medication), and diethylstilbestrol
for the treatment of metastatic prostate cancer (mostly un-
available and toxic).39
The final documents and the revised EML for cancer are
now available on the WHO website. Each medicine on the
EML can be referenced back to a disease-based document
supporting and delineating its contribution to treatment of
the disease, something not previously available on the EML.
Planning is underway to develop a mechanism for periodic
reviews of the EML for cancer as new scientific data become
available.
ESSENTIAL MEDICAL DEVICES FOR CANCER
In April 2015, WHO convened a group of experts with the
goal of detailing needs for services critical to the diagnosis,
evaluation, and treatment of patients with cancer. Based on
the advice of this group, a steering committee of experts was
formed and met at WHO in September 2015 to better outline
a plan to accomplish the work. Committees were formed to
delineate needs for pathology and laboratory services, ra-
diology services, surgical services, administration of systemic
therapies, and radiation therapy. Committee members
were recommended by the steering committee and met
via teleconference throughout 2015.
This work is also disease-based, using a subset of cancers
to complete lists of essential medical devices for each of the
categories listed before. The work is still underway, with
plans to complete the lists in the first half of 2016.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 63
RUFF ET AL
THE ROLE OF WHO IN DEVELOPMENT OF
CANCER TREATMENT PROGRAMS
WHO exists to serve its member states in the arena of health
care. In many LMICs, ministries of health struggle with health
care priorities as advances in control of infectious diseases
and other important areas such as maternal-child health,
noncommunicable diseases become increasing health bur-
dens. In acknowledgment of this, the United Nations con-
vened a high-level meeting in September 2011 to address
the needs of noncommunicable diseases. The work of WHO
flows from the recommendations of this meeting and follow-
up meetings.
THE ROLE OF COUNTRIES AND MINISTRIES
WHO is providing guidance to countries and ministries on
essential medicines and devices for the diagnosis and
treatment of cancer. It remains, though, for individual
countries to develop cancer plans specific to their needs and
environment. In some LMICs, this is well underway, and in
others, much remains to be done. Many countries have little
or no in-country cancer care expertisefew, if any, pa-
thologists, medical oncologists, radiation oncologists, and
skilled nurses. Many countries have very limited resources
and must prioritize their needs as best they can. Partnerships
between cancer specialists from high-income countries and
LMICs can help. External funding would help immensely to
move the global cancer agenda forward, funding such as was
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All of this work aims at bringing affordable and high-quality
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27. Krakauer EL, Wenk R, Buitrago R, et al. Opioid inaccessibility and its
human consequences: reports from the field. J Pain Palliat Care
Pharmacother. 2010;24:239-243.
CULTURAL AND REGULATORY BARRIERS TO TREATING CANCER PAIN
28. Bagivan G, Tosun N, Komurcu S, et al. Analysis of patient-related
barriers in cancer pain management in Turkish patients. J Pain Symptom
Manage. 2009;38:727-737.
29. Kim YC, Ahn JS, Calimag MM, et al; ACHEON Working Group. Current
practices in cancer pain management in Asia: a survey of patients and
physicians across 10 countries. Cancer Med. 2015;4:1196-1204.
30. Peker L, Celebi N, Canbay O, et al. Doctors opinions, knowledge and
attitudes towards cancer pain management in a university hospital.
Agri. 2008;20:20-30.
31. Prehn AW, Topol B, Stewart S, et al. Differences in treatment patterns
for localized breast carcinoma among Asian/Pacific islander women.
Cancer. 2002;95:2268-2275.
32. Cassileth BR. Complementary therapies: overview and state of the art.
Cancer Nurs. 1999;22:85-90.
33. Molassiotis A, Fernadez-Ortega P, Pud D, et al. Use of complementary
and alternative medicine in cancer patients: a European survey. Ann
Oncol. 2005;16:655-663.
34. Campbell CM, Edwards RR. Ethnic differences in pain and pain man-
agement. Pain Manag. 2012;2:219-230.
35. Zuardi AW. History of cannabis as a medicine: a review. Rev Bras
Psiquiatr. 2006;28:153-157.
36. National Cancer Institute. Cannabis and CannabinoidsHealth Pro-
fessional Version http://www.cancer.gov/about-cancer/treatment/
cam/hp/cannabis-pdq. Accessed January 23, 2016.
37. Al-Atiyyat N. Cultural diversity and cancer pain. J Hosp Palliat Nurs.
2009;11:154-164.
38. Kwok W, Bhuvanakrishna T. The relationship between ethnicity and the
pain experience of cancer patients: a systematic review. Indian J Palliat
Care. 2014;20:194-200.
39. Shulman LN, Wagner CM, Barr R, et al. Proposing essential medicines to
treat cancer: Methodologies, processes, and outcomes. J Clin Oncol.
2016;34:69-75.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 65
CARE DELIVERY AND PRACTICE MANAGEMENT

Integrating Patient-Reported
Outcomes Into Real-Life Medical
Decisions

CHAIR
Paul G. Kluetz, MD
U.S. Food and Drug Administration
Kensington, MD

SPEAKERS
Diana T. Chingos, MS, MFA
Patient Advocate
Studio City, CA

Ethan M. Basch, MD, MSc

The University of North Carolina at Chapel Hill
Chapel Hill, NC

Sandra A. Mitchell, PhD, CRNP, FAAN

National Cancer Institute
Rockville, MD
 MEASURING SYMPTOMATIC ADVERSE EVENTS WITH PRO-CTCAE

Patient-Reported Outcomes in Cancer Clinical Trials:

Measuring Symptomatic Adverse Events With the National
Cancer Institutes Patient-Reported Outcomes Version of
the Common Terminology Criteria for Adverse Events
(PRO-CTCAE)
Paul G. Kluetz, MD, Diana T. Chingos, MS, MFA, Ethan M. Basch, MD, MSc, and
Sandra A. Mitchell, PhD, CRNP, FAAN

OVERVIEW

Systematic capture of the patient perspective can inform the development of new cancer therapies. Patient-reported outcomes
(PROs) are commonly included in cancer clinical trials; however, there is heterogeneity in the constructs, measures, and analytic
approaches that have been used making these endpoints challenging to interpret. There is renewed effort to identify rigorous
methods to obtain high-quality and informative PRO data from cancer clinical trials. In this setting, PROs are used to address specific
research objectives, and an important objective that spans the product development life cycle is the assessment of safety and
tolerability. The U.S. Food and Drug Administrations (FDA) Office of Hematology and Oncology Products (OHOP) has identified
symptomatic adverse events (AEs) as a central PRO concept, and a systematic assessment of patient-reported symptomatic AEs can
provide data to complement clinician reporting. The National Cancer Institutes Patient-Reported Outcomes version of the Common
Terminology Criteria for Adverse Events (PRO-CTCAE) is being evaluated by multiple stakeholders, including the FDA, and is
considered a promising tool to provide a standard yet flexible method to assess symptomatic AEs from the patient perspective. In this
article, we briefly review the FDA OHOPs perspective on PROs in cancer trials submitted to the FDA and focus on the assessment of
symptomatic AEs using PRO-CTCAE. We conclude by discussing further work that must be done to broaden the use of PRO-CTCAE as a
method to provide patient-centered data that can complement existing safety and tolerability assessments across cancer clinical trials.

T he intent of this educational manuscript is to discuss the im-

portance of PRO assessments in cancer trials, identify strengths
and limitations of currently used PRO strategies, and focus on
the potential utility of a rigorous and systematic assessment of
symptomatic AEs as a component of a broader PRO strategy.
As part of this effort, we have been fortunate to have a patient
advocate included to introduce the manuscript by providing her
personal perspective on the inclusion of PROs in cancer trials.
Diana Chingos is a 20-year survivor of early onset breast cancer
whose advocacy work extends to membership on the National
Cancer Institutes (NCI) Investigational Drugs Steering Com-
mittee and the National Clinical Trials Networks Core Correl-
ative Sciences Committee, as well as participation on a data and
safety monitoring board for the California Cancer Consortium
(a phase I/II clinical trials group) and an institutional review
board. Her experience as a patient and caregiver coupled with
extensive work as an advisor to cancer studies brings a unique
combination of patient focus and understanding of the com-
plexities of clinical trial design and conduct.
THE PATIENT PERSPECTIVE ON PATIENT-
REPORTED OUTCOMES IN CANCER TRIALS
Patients, and human beings more generally, are accustomed
to providing our views in many aspects of our lives. Until
recently, the act of seeking out feedback from those who
use the health care system was rare. One can argue that the
health care user experience should reign supreme over all
other contexts, when the quality and quantity of our lives is
at stake, sometimes at great financial and logistical expense.
Gratefully, at least from this patients view, PRO ques-
tionnaires have been developed to bring our perspective

From the Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD; Independent Cancer Patient
Advocate, Los Angeles, CA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; Outcomes Research Branch, National Cancer Institute, Rockville, MD.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Sandra Mitchell, PhD, CRNP, FAAN, Division of Cancer Control and Population Sciences, Outcomes Research Branch, National Cancer Institute, 9609 Medical
Center Blvd., Rockville, MD 20850; email: mitchlls@mail.nih.gov.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 67

KLUETZ ET AL
into the research setting more systematically. In my opinion,
soliciting patient reports espouses equity and autonomy,
enabling patients to speak for themselves, without the filter
of health care providers. Capturing a patients self-report
using well-validated measures offers a direct indicator of
change in symptoms, function, or well-being during treat-
ment, providing additional information to supplement the
clinicians evaluation of tumor response and toxicity.
Many patients with cancer are willing to play their part in
research through answering questionnaires. Unless patients
are very ill and/or have cognitive deficits, many patients with
cancer like the opportunity to contribute to research, es-
pecially meaningful research that can improve care for
patients in the future. It can be difficult for some patients to
assess the value of specific research studies, but everyone
understands treatment toxicity and side effects. You live it
and usually have something to say about it.
From the informed patients perspective, the patients
voice has been a key missing element in the current system
of drug safety assessment. Assessing patient-reported
symptomatic AEs can fill this need. Published studies have
demonstrated discordance between physician and patient
reports, with underreporting of patients symptoms and
their severity being common.1,2 Something is getting lost
in the translation. PRO measures provide an opportunity
for the patient to directly report side effects and their in-
tensity from the perspective of the person experiencing it.
The PRO-CTCAE has generated considerable interest in the
broader stakeholder community as a PRO tool that could be
used across the therapeutic development process to address
important questions related to the tolerability profile of a
specific therapy.
KEY POINTS
There is a need to strengthen the rigor of PROs in cancer
trials.
The FDAs Office of Hematology and Oncology Products
has identified the systematic assessment of
symptomatic adverse events reported by patients as
an opportunity to better describe the safety and
tolerability of an investigational product across the
drug development life cycle.
The NCIs PRO-CTCAE is a PRO measurement system
that includes a library of questions that measure
symptomatic adverse events from the patient
perspective.
PRO-CTCAE holds promise as a rigorous and flexible
approach to the longitudinal assessment of
symptomatic adverse events in cancer clinical trials.
Challenges and knowledge gaps exist with respect to
trial designs, implementation, and interpretation of
PRO-CTCAE. Effort is ongoing to identify the best
approaches to make PRO-CTCAE scores available,
alongside CTCAE grading, in published reports and
FDA drug labels.
68 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
I welcome the ability to report the side effects I have
experienced, and I encourage others to do so. However, it is
important to mention that although most patients want to
describe their experiences, it can become tedious, depending
on the time required. Survey fatigue is real and is magnified by
medication-related fatigue, cancer-related fatigue, and the
unfortunate synergy of physical, emotional, psychologic, and
environmental strains involved with being a patient with cancer
undergoing therapy. Given this, it is important to consider the
length of the survey, the relevance of the questions, and the
time points for assessment, while trying to reduce the re-
dundancy of questions.
Some patients need encouragement and validation to
participate in this process, that their voice is valued and
integral to the clinical trial. Patient engagement helps the
systemit does not hinder it. Empowering patients to ar-
ticulate their experiences can provide value to those who
develop cancer therapies by more accurately charac-
terizing a drugs effect on the patient and also may enhance
research participation, a necessity if we are to speed up the
rate of knowledge generation.
Past Efforts at Collecting Patient-Reported Outcomes
in Cancer Trials
To date, the most common PRO strategy for oncology has
been to assess the broad multidomain concept of health-
related quality of life (HRQOL), utilizing instruments largely
developed in a different therapeutic era.35 These existing
HRQOL measures have strengths, including translations
across multiple languages and a familiarity with their use
among the cancer therapeutic development community.
Many instruments have also been expanded to include
disease-specific modules in an effort to better capture
disease- and treatment-related symptoms.6,7 Substantial
data have been accumulated using many of these measures,
and some offer the advantage of well-established cut scores,
minimally important difference thresholds, and normative
values that can aid in interpretation.
However, although the PRO measures commonly used in
oncology trials to date address a broad range of impor-
tant and common symptoms and functional domains, they
typically include the same questions irrespective of disease
stage or the therapy under study. This can lead to questions
that may be less relevant to the trial context and/or miss the
assessment of important symptoms (e.g., toxicities not
currently included in existing static instruments). This limi-
tation is becoming more evident in the current drug devel-
opment era of molecularly targeted agents with wide-ranging
side effect profiles. Investigators could benefit from a more
flexible toolbox of PRO measures that can adapt to differing
disease and treatment contexts.
From the FDA OHOP perspective, all PRO data will be taken
into consideration as part of the overall data package to
inform the benefits and risks of a therapy under review.
However, not all data reviewed in an application can be
included in the FDA drug label. The FDA is tasked with

providing information in the product label that is useful to
prescribers in treating their patients and must ensure that
the information is easily interpreted, unbiased, and not
misleading. Broad concepts such as HRQOL are more
challenging to define, with some domains such as social well-
being farther removed from a therapys direct effect on the
patient. Submitted HRQOL data can be further complicated
by trial design limitations, missing data, and lack of pre-
specified analyses. For this reason, PRO data have rarely
been included in FDA labeling of cancer therapies. When
PRO data have been included in the FDA product label for
cancer products, it has predominantly relied on well-defined
measures of specific symptoms or functional measures that
relate directly to the disease under study.8
There continues to be wide variability in the type and
quality of PRO data acquired from cancer trials. This lack
of standardization includes heterogeneity in the PRO in-
struments used, as well as the assessment frequencies, and
the approach to data analysis and reporting. High levels of
missing data have also been a common challenge that can
adversely affect the interpretability of PRO findings. Many
stakeholders, including the FDA OHOP, have actively en-
gaged the oncology drug development community to
evaluate existing instruments and identify emerging op-
portunities to improve the PRO strategy in cancer trials to
provide more rigorous patient-centered data to all those
who weigh the risks and benefits of cancer therapies.9
FOCUSING ANALYSES ON CORE
PATIENT-REPORTED OUTCOME CONCEPTS
INCLUDING SYMPTOMATIC ADVERSE EVENTS
In most late-phase randomized clinical trials, concepts
such as HRQOL and social, emotional, and cognitive do-
mains are expected by many stakeholders to provide a
reasonably comprehensive picture of the patients ex-
perience of their disease and treatment. These data will
be reviewed by FDAs OHOP as important supportive data.
However, in an effort to increase the amount of patient-
centered data in FDA labeling, OHOP has recently pro-
posed that our key PRO analyses focus on three core
symptom and functional concepts (Fig. 1).10 Symptomatic
AEs, physical function, and disease-related symptoms are
considered by OHOP to be more well-defined and closer to
the effect of a therapy on the patient and their disease.
The careful collection and analysis of these core concepts
can provide PRO data that may be more consistent with
FDA requirements for labeling.
It should be acknowledged that cancer trials are
designed for differing purposes along the therapeutic
development continuum from first in-human exploration
of dose and safety, to exploratory therapeutic trials, to
trials designed to demonstrate substantial evidence of
safety, tolerability, and efficacy to support a regulatory
submission. Whereas a comprehensive PRO strategy may
be expected to address the needs of multiple stakeholders
in the later phases of therapeutic development, a focused
MEASURING SYMPTOMATIC ADVERSE EVENTS WITH PRO-CTCAE
PRO strategy may be more appropriate and efficient in
early clinical development. This is an important distinction,
as the classic phases of drug development are blurring, and
precision medicine trials may have multiple study arms
designed to simultaneously gauge antitumor activity11
with some single-arm cohorts potentially demonstrating
notable antitumor activity suitable for accelerated ap-
proval.12 Safety is an important trial objective in all phases
of therapeutic product development. Inclusion of a PRO
measure of symptomatic AEs can improve our understanding
of safety, tolerability, and dose selection and thus is applicable
to a broad range of clinical trial contexts.
THE USE OF PATIENT-REPORTED OUTCOMES TO
INFORM TREATMENT TOLERABILITY
Safety assessment in cancer clinical trials has been stan-
dardized through the use of the CTCAE.13 Currently, in
version 4, the CTCAE provides a widely accepted lexicon
and associated criteria for grading AEs of cancer treatment.
CTCAE is routinely updated and used in conjunction with
the Medical Dictionary for Regulatory Activities by regu-
latory agencies. Using CTCAE, AEs are graded on a scale
from grade 1 to 5, in which, by convention, grade 5 is death,
and grade 4 reflects toxicities that are life-threatening and
warrant urgent intervention. Grades 13 represent pro-
gressive worsening in severity or frequency of the toxicity,
interference with self-care and the performance of daily
activities, and the need for clinical intervention. Although
this method of safety reporting provides for standardiza-
tion and efficiency in data collection and analysis, the
assessment of AEs using CTCAE is elicited by health care
providers, including symptomatic AEs such as nausea or
sensory neuropathy. It has been stated by the FDA and
others that the patient is best positioned to report his or
her own symptoms.14 Thus, the systematic assessment of
symptomatic AEs using a PRO provides additional in-
formation that is complementary to existing safety as-
sessments reported by clinicians using the CTCAE.
The assessment of symptomatic AEs may be of increasing
importance as we enter into a new therapeutic era in ma-
lignant hematology and oncology. An expanding number of
mechanistic drug classifications have produced a more di-
verse range of potential toxicities.15 Many of the molecularly
targeted agents are administered orally, often require
prolonged treatment duration, and may produce less severe
but more chronically bothersome side effects.16 A system-
atic longitudinal assessment of relevant symptomatic AEs
using a PRO measure may provide informative patient-
centered data on symptomatic side effects that may oth-
erwise have been considered low grade by standard clinician
report.17
Existing HRQOL measures and their disease modules
evaluate a more limited range of side effects, many of
which were selected based on therapies that were used at
the time they were developed (e.g., cytotoxic chemo-
therapies). Given the different therapeutic landscape
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 69
KLUETZ ET AL

FIGURE 1. U.S. Food and Drug Administration Core Concepts for Patient-Reported Outcomes Analysis in Cancer Trials

In an effort to increase the amount of informative patient-centered data in product labeling, FDA OHOP focuses its PRO analyses on the core concepts of symptomatic
AEs, physical function, and disease-related symptoms. Although these well-defined concepts are more in line with the regulatory framework of the FDA for labeling
considerations, all submitted PRO data will be taken into consideration as important supportive data. The three core concepts are not the only PRO measures to assess
in a trial to support drug approval, as broader domains and HRQOL remain important exploratory measures. Reprinted from Kluetz et al.10
Abbreviations: OHOP, Office of Hematology and Oncology Products; PRO, patient-reported outlets; AEs, adverse events; HRQOL, health-related quality of life.

today, this can lead to measurement of irrelevant symp-
toms not considered part of the toxicity profile of the
newer drug and/or potentially miss the assessment of
important unique side effects of contemporary therapies.
Furthermore, the limited assessment frequency used to
date in many PRO corollary studies may not be optimal to
adequately gauge tolerability.
Contemporary drug development requires a more flexible
PRO approach to ensure an unbiased assessment of the most
important symptomatic treatment side effects based on the
anticipated toxicity profile of the therapies under study.
Selection of symptomatic AEs from a large library of options
would therefore be desirable. Recently, the NCI has de-
veloped and tested a measurement system to capture
symptomatic toxicities directly from patients.18 Com-
prised of both a library of 124 questions reflecting 78
symptomatic toxicities drawn from the CTCAE and an
electronic system for survey administration, reminders,
central monitoring, and alerts, NCI PRO-CTCAE is designed
to provide a standard yet flexible tool to assess symp-
tomatic AEs.
Development of the NCI PRO-CTCAE Measurement
System
The PRO-CTCAE measurement system has been developed
by NCI as a companion to the CTCAE. It was designed to
improve the validity, reliability, and precision with which
symptomatic adverse effects of treatment are evaluated
in patients on cancer clinical trials. PRO-CTCAE was developed
by a multidisciplinary team of trialists, methodologists, cli-
nicians, informatics experts, patients, and regulators18 and
has been tested and refined in a consortium of aca-
demic and community-based cancer-treatment sites and
in the NCI-sponsored clinical trials network (NCI contracts
HHSN261200800043C and HHSN261200800063C) and by
more than 120 early adopters in 10 countries. The PRO-CTCAE
item library consists of 124 discrete items representing 78

70 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


symptomatic AEs that are common in oncology clinical trials
and included in the CTCAE. PRO-CTCAE items were created
with substantial input from patients, clinicians, and PRO
methodologists and underwent refinement through cognitive
interviews with patients to establish content validity.19 Sub-
sequently, the quantitative measurement properties, in-
cluding validity, reliability, and responsiveness, were evaluated
in a large and diverse sample of patients receiving cancer
treatment in six sites around the United States.20
Each of the 78 symptom terms included in the PRO-CTCAE
item library is assessed relative to one or more distinct
attributes, including presence/absence, frequency, severity,
and/or interference with usual or daily activities.18 Re-
sponses are provided on a five-point Likert scale. The generic
PRO-CTCAE item structures for the frequency, severity, and
interference attributes are listed below:
Frequency item: How OFTEN did you have __________?
(Never / Rarely / Occasionally / Frequently / Almost
constantly)
Severity item: What was the SEVERITY of your
__________ at its WORST?
(None / Mild / Moderate / Severe / Very severe)
Interference item: How much did __________ INTERFERE
with your usual or daily activities?
(Not at all / A little bit / Somewhat / Quite a bit / Very
much)
The standard PRO-CTCAE recall period is the past 7 days.
A recent study suggests that longer recall periods (2-, 3-,
or 4-week recall) are associated with small but succes-
sively increasing measurement error, which must be
considered if recall periods longer than 1 week are used
in a trial for logistical reasons (TR Mendoza, AV Bennett,
SA Mitchell et al, unpublished data, March 2016). Ad-
ministration of PRO-CTCAE via different modes including
web, interactive voice response, and paper offers flexi-
bility for patients and study operations personnel, and
there is psychometric evidence to justify comparison of
results and pooled analyses across studies that use dif-
ferent PRO-CTCAE modes of administration.21 A pediatric
version of PRO-CTCAE is also currently in development.22
For more information about PRO-CTCAE, visit http://
healthcaredelivery.cancer.gov/pro-ctcae.
Early Adoption of PRO-CTCAE and Lessons Learned
The PRO-CTCAE has been implemented in multiple cancer
clinical trials. Patients are generally willing and able to self-
report this information weekly via the web or automated
telephone systems though electronic reminders; central
monitoring and personnel for backup data collection were
also needed to optimize response rates. Clinicians note
finding this information to be meaningful and valuable for
clinical decision-making and AE reporting.23
Selecting which symptomatic AEs to assess and de-
termining the time points for measurement are critical
trial-design decisions. In trials developed to date, items
from the PRO-CTCAE and time points of measurement
MEASURING SYMPTOMATIC ADVERSE EVENTS WITH PRO-CTCAE
have generally been specified using an approach similar to
that used to define the AE surveillance plan for the trial
more broadly. That is, the study team reviews published
data, as well as data from earlier phase trials or animal
models, if available, and incorporates information about
the known or anticipated on- and off-target effects of
agents in a similar mechanistic class to identify those
symptomatic AEs likely to be associated with the regimens
in the trial.24 PRO-CTCAE items corresponding to these
symptomatic AEs are loaded into a software platform.
Patients are trained to use the software and are asked to
self-report either from home on a regular basis or at clinic
visits. After establishing a pretreatment baseline, more
frequent PRO-CTCAE administration is generally war-
ranted during the first few cycles of therapy (e.g., weekly
reporting during the initial several months of ther-
apy). Thereafter, the assessment intervals may be extended
(e.g., monthly or quarterly, depending on the regimen
under study), particularly in trial contexts in which the
duration of investigational treatment is prolonged. How-
ever, the time points of measurement should reflect the
anticipated pattern of toxicity and scientific objectives of
the trial.
Moving forward, several challenges and knowledge gaps
must be addressed. Although multiple translations are in
progress (for example, Italian, Korean, Chinese, and Swed-
ish), and linguistically validated language versions are
available in Spanish, German, Japanese, and Danish,25-27
translation and linguistic validation of the PRO-CTCAE item
library in other languages is needed. Second, as is the case
for the collection of PRO data in any trial, there are per-
sonnel and infrastructure requirements. Investments will
be required to develop and refine strategies that achieve
efficient PRO data collection and ensure data completeness
(e.g., central monitoring and backup data collection). Po-
tential concerns about workload for clinical research staff
will also need to be addressed, and analyses are in prog-
ress that will yield specific estimates of the resource re-
quirements associated with collecting and analyzing PRO-CTCAE
data in NCI-sponsored clinical trials. Third, there is limited ex-
perience with respect to how to optimally analyze and interpret
patient-reported symptomatic AE data. Efforts are underway to
determine how PRO-CTCAE scores should be interpreted to
assign a corresponding CTCAE grade. Additional work will
be required to identify the most informative ways to display
symptomatic toxicity scores descriptively alongside CTCAE
grades in both published reports as well as potential product
labels.
Notably, FDA OHOP is committed to working with the
NCI as well as commercial sponsors early in programs to
identify opportunities to include PRO-CTCAE in clinical
trials. Data generated using PRO-CTCAE offer comple-
mentary descriptive patient-reported information about
symptomatic side effects that may further inform patients
and providers. There is also interest in using PRO-CTCAE
as a component to support comparative tolerability
trial designs. More work must be done to explore this
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 71
KLUETZ ET AL
opportunity, including identifying an appropriate approach
to capture the overall side effect burden of treatment. In
addition, FDA OHOP, in collaboration with Clinical Outcome
Assessment staff and the Office of Biostatistics, has initiated
several internal working groups to explore different analysis
and data presentation methods.
There is a reasonable concern that stacking new in-
struments on top of existing lengthy HRQOL and disease
modules as well as utility measures could lead to duplication
and pose additional respondent burden. FDA OHOP is fos-
tering international collaboration to review existing HRQOL
instruments and their disease modules to identify a col-
lection of new and existing or modified existing instruments
to meet the needs of all those who will use these data to
make treatment, regulatory, and health policy decisions. The
goal remains to identify approaches that increase the rel-
evance and interpretability of PRO data while minimizing the
burden to patients to ensure that the patient can be queried
at an assessment frequency that provides the best picture of
the patient experience while on therapy.
There has been a call to improve the quality of PRO data
captured from cancer clinical trials and integrate more of
these data in the FDA product label.28 To realize this goal,
more attention must be paid to PRO measures in both trial
design and conduct to improve overall data quality, re-
gardless of the symptoms or domains being measured. The
assessment of symptomatic AEs using a rigorously de-
veloped item library such as the PRO-CTCAE can increase the
likelihood of inclusion of descriptive patient-centered data
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72 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
in product labels, complementing the standard safety as-
sessment of a therapy.
CONCLUSION
Patients and their clinicians would benefit from improved
data about the effects of anticancer therapy on how an in-
dividual feels and functions. Traditional PRO strategies are
being revisited as patient-focused drug development has
generated multistakeholder interest to optimize the collec-
tion and interpretation of PRO data to satisfy the needs of the
many end users of this information. As a key component of a
broader PRO strategy, the systematic longitudinal assessment
of patient-reported symptomatic AEs can provide additional
complementary tolerability data to inform dose selection and
the overall benefit: risk assessment of a cancer therapy. The
PRO-CTCAE has been developed as a standardized mea-
surement system that can provide a flexible fit-for-purpose
approach to assess relevant symptomatic AEs across a broad
range of cancer therapies. It is anticipated that the NCI PRO-
CTCAE item library will continue to be iteratively refined as
novel symptomatic toxicities are identified and a deeper
understanding of its measurement properties emerges. There
is vigorous and ongoing international collaboration among
trialists, methodologists, regulators, and patients to address
these and other challenges in study design, implementation,
and interpretation to evolve a standard method to obtain
well-defined, descriptive patient-centered data on the safety
and tolerability of cancer therapies.
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cancer drug development and US regulatory review: perspectives from
industry, the Food and Drug Administration, and the patient. JAMA
Oncol. 2015;1:375-379.
10. Kluetz PG, Slagle A, Papadopoulos E, et al. Focusing on core patient-
reported outcomes in cancer clinical trials: symptomatic adverse
events, physical function, and disease-related symptoms. Clin Cancer
Res. 2016;22:1553-1558.
11. Biankin AV, Piantadosi S, Hollingsworth SJ. Patient-centric trials for
therapeutic development in precision oncology. Nature. 2015;526:
361-370.
12. Theoret MR, Pai-Scherf LH, Chuk MK, et al. Expansion cohorts in first-in-
human solid tumor oncology trials. Clin Cancer Res. 2015;21:4545-4551.
13. U.S. Department of Health and Human Services NIH, National Cancer
Institute. Common Terminology Criteria for Adverse Events (CTCAE)
Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf. Accessed February 27, 2016.
14. U.S. Food and Drug Administration. Guidance for Industry Patient-
Reported Outcome Measures: Use in Medical Product Development to
Support Labeling Claims. http://www.fda.gov/downloads/Drugs/
Guidances/UCM193282.pdf. Accessed February 27, 2016.
15. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse
events with immune checkpoint blockade: a comprehensive review. Eur
J Cancer. 2016;54:139-148.

16. Klastersky JA. Adverse events of targeted therapies. Curr Opin Oncol.
2014;26:395-402.
17. Thanarajasingam G, Hubbard JM, Sloan JA, et al. The imperative for a
new approach to toxicity analysis in oncology clinical trials. J Natl Cancer
Inst. 2015;107:djv216.
18. Basch E, Reeve BB, Mitchell SA, et al. Development of the National
Cancer Institutes patient-reported outcomes version of the common
terminology criteria for adverse events (PRO-CTCAE). J Natl Cancer Inst.
2014;106:dju244.
19. Hay JL, Atkinson TM, Reeve BB, et al; NCI PRO-CTCAE Study Group.
Cognitive interviewing of the US National Cancer Institutes Patient-
Reported Outcomes version of the Common Terminology Criteria for
Adverse Events (PRO-CTCAE). Qual Life Res. 2014;23:257-269.
20. Dueck AC, Mendoza TR, Mitchell SA, et al; National Cancer Institute
PRO-CTCAE Study Group. Validity and reliability of the US National
Cancer Institutes Patient-Reported Outcomes version of the Common
Terminology Criteria for Adverse Events (PRO-CTCAE). JAMA Oncol.
2015;1:1051-1059.
21. Bennett AV, Dueck AC, Mitchell SA, et al; National Cancer Institute PRO-
CTCAE Study Group. Mode equivalence and acceptability of tablet
computer-, interactive voice response system-, and paper-based ad-
ministration of the U.S. National Cancer Institutes Patient-Reported
Outcomes version of the Common Terminology Criteria for Adverse
Events (PRO-CTCAE). Health Qual Life Outcomes. 2016;14:24.
22. Reeve BB, Withycombe JS, Baker JN, et al. The first step to integrating
the childs voice in adverse event reporting in oncology trials: a content
MEASURING SYMPTOMATIC ADVERSE EVENTS WITH PRO-CTCAE
validation study among pediatric oncology clinicians. Pediatr Blood
Cancer. 2013;60:1231-1236.
23. Bruner DW, Hanisch LJ, Reeve BB, et al. Stakeholder perspectives on
implementing the National Cancer Institutes patient-reported out-
comes version of the Common Terminology Criteria for Adverse Events
(PRO-CTCAE). Transl Behav Med. 2011;1:110-122.
24. Cella D, Wagner L. Re-personalizing precision medicine: is there a role
for patient-reported outcomes? J Community Support Oncol. 2015;13:
275-277.
25. Arnold B, Lent L, Mendoza T, et al; PRO-CTCAE Spanish Translation
and Linguistic Validation Study Group. Linguistic validation of
the Spanish version of the National Cancer Institutes Patient-
Reported Outcomes version of the Common Terminology Criteria
for Adverse Events (PRO-CTCAE). Support Care Cancer. Epub 2016
Feb 2.
26. Kirsch M, Mitchell SA, Dobbels F, et al. Linguistic and content validation
of a German-language PRO-CTCAE-based patient-reported outcomes
instrument to evaluate the late effect symptom experience after al-
logeneic hematopoietic stem cell transplantation. Eur J Oncol Nurs.
2015;19:66-74.
27. Baeksted C, Pappot H, Bidstrup PE, et al. Danish translation and lin-
guistic validation of the Patient-Reported Outcomes version of the
Common Terminology Criteria for Adverse Events (PRO-CTCAE). J Pain
Symptom Manage. In press.
28. Basch E. Toward patient-centered drug development in oncology.
N Engl J Med. 2013;369:397-400.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 73
CARE DELIVERY AND PRACTICE MANAGEMENT

Optimizing Team-Based Oncology

Care: Building the Village

CHAIR
Lee Schwartzberg, MD, FACP
The West Cancer Center
Memphis, TN

SPEAKERS
Lillie D. Shockney, RN, BS, MAS
Johns Hopkins Breast Center
Baltimore, MD

Wendy H. Vogel, MSN, FNP, AOCNP

Wellmont Cancer Institute
Kingsport, TN
 INFORMING THE TEAM WITH PATIENT-REPORTED OUTCOMES

Electronic Patient-Reported Outcomes: The Time Is Ripe for

Integration Into Patient Care and Clinical Research
Lee Schwartzberg, MD, FACP

OVERVIEW

In the emerging team-based approach to delivering cancer care, collecting patient-reported outcomes (PROs) provides
longitudinal monitoring of treatment adverse effects, disease complications, functional statuses, and psychological states
throughout the cancer continuum for all providers to use. Electronic systems offer added capabilities, including easy
quantitation of individual symptom items and aggregated scales, standardization, and longitudinal tracking of patient
surveys for trend analysis over time. An ideal electronic PRO (ePRO) platform is clinically relevant, validated, and reliable and
would offer patient usability. Additionally, it should allow for automated responses to and from patients, have scheduling
functionality, and send real-time alerts to site personnel and patients. Clinical interfaces should be easy to read and in-
tegrated into the electronic medical record. Multiple ePRO systems, often using electronic tablets, have been created and are
beginning to be widely deployed. The Patient Care Monitor is one example of a system that has evolved into a com-
prehensive patient engagement platform, with a complete review of systems survey and capabilities for mobile health
usage. Recent clinical trials have established ePRO systems as an effective method of providing information, which aids
improved patient outcomes, including reduced health resource utilization and longer time on therapy. ePROs are also
increasingly incorporated into clinical trials, where they can provide more thorough reporting of adverse events than can be
captured by alternative methods. Mobile devices have the potential to become the method by which all members of the
provider team communicate with patients both at the point-of-care and between clinic visits to optimize care delivery.

A chieving optimal patient-centered cancer care depends

in large part on the crucial clinician-patient interaction
at the point of care. In an era of increasing demands on the
physicians time, declining reimbursement, a surge in doc-
umentation requirements, and ever-increasing patient
volumes, the very nature of the patient-provider relation-
ship is threatened. One fundamental goal of the patient
interview is to obtain relevant information about the present
health status to guide treatment and symptom control. A
thorough review of systems and evaluation of psychosocial
status and physical and social functioning is ideally ac-
complished at the clinic visit.
The complexities of modern oncology care require a team
approach to deliver quality management of these multiple
dimensions. Having a record of PROs, which are quantitative,
validated, easily captured, standardized, and recorded in the
electronic health record, has the potential to add huge value.
All of these characteristics can be achieved by using a variety
of electronic systems that have been developed to enhance
the interaction between the clinical staff and the patient.
A patient-reported outcome is defined as a measurement
of the patients condition, reported directly by the patient
without interpretation by a clinician or any other individual.
Collecting PROs allows clinicians to longitudinally monitor a
patients tolerance of therapy, response to therapy, and
symptoms that result from the underlying disease or
treatment. Psychological and functional statuses can be
assessed in the same fashion, which allows examination of
the interplay between treatment and global quality of life
and identification of issues that require referral to other
members of the team. The importance of subjective mon-
itoring is firmly established; pain as the fifth vital sign is an
integral assessment measure for the Quality Oncology
Practice Initiative program, and the Commission on Cancer
now requires distress screening as the sixth vital sign to be
measured and addressed at every visit. A systematic ap-
proach to assess distress can be enhanced through the use of
an ePRO system, which allows self-identification of the
problem without prejudice.
In a distributed care model, a permanent, searchable
record of the longitudinal health status allows all members
of the care team to access, interpret, and act on the findings.
It is well documented that patients with cancer are often
reluctant to discuss important toxicities with providers for a

From The West Cancer Center, Memphis, TN.

Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook.

Corresponding author: Lee Schwartzberg, MD, FACP, 7945 Wolf River Blvd., Germantown, TN 38138; email: lschwartzberg@westclinic.com.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e89

LEE SCHWARTZBERG
variety of reasons.1 Completion of an electronic survey
appears to reduce that reluctance.2
Empowering patients to self-report provides the best in-
formation on subjective symptoms. Multiple investigations
have clearly documented under-reporting when information
is provided by clinicians, although nurses appear better at
eliciting symptoms than physicians.3,4 Reasons for under-
reporting of toxicities may include a judgment call by the
clinician when the symptom is detected but not reported.
This circumstance might occur when symptoms are pre-
existing, attributable to the disease, or mild and not re-
quiring intervention.5 Symptoms that are not reported
because of inadequate communication are potentially more
damaging. With the advent of many new drugs, some with
novel toxicities, the possibility of missing unusual but im-
portant adverse effects that are not familiar to the provider
looms large in the presence of poor symptom communi-
cation. Standardized routine assessment is recognized
among medical policymakers as a key component of en-
suring high-quality patient-centered care.6
USE OF ePRO SYSTEMS
A review of ePRO systems used in cancer clinical care was
recently published.7 Thirty-three systems were identified;
the majority are used in the United States, and one-third are
used in a single academic institution, with the majority used
at a single clinical entity. Most systems were developed to be
used in the clinic at the point of care, and most are web-
based. The focus of these systems is use predominantly
during treatment and follow-up care, to monitor chemo-
therapy and other cancer therapy. Only half of the systems
had greater than 500 users. The majority of systems sent
real-time alerts of the patients response to providers and
KEY POINTS
PROs provide the most thorough and reliable
information on subjective symptoms, overcoming the
well-documented under-reporting by clinicians.
ePRO systems, which are web-based and are typically
delivered on tablets, computers, or other mobile
devices, are now readily available.
One example of an ePRO system, the Patient Care
Monitor, is a full patient engagement system, which
includes a complete review of system survey and a
flexible architecture that allows deployment of custom
surveys and patient alerts to relevant clinical staff.
The use of an ePRO survey for patients with advanced
cancer has been shown in a randomized controlled trial
to improve health-related quality of life, reduce
emergency department visits, and improve 1-year
survival compared with usual clinical care.
A subset of the Common Terminology Criteria for
Adverse Events library is now available as an ePRO
platform and has been validated as an alternative
method of eliciting symptom reports in clinical trials.
e90 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
staff, typically by email or text message. Many of the newer
systems are designed for long-term monitoring across the
cancer care continuum. Flexibility of system reporting allows
ePROs to be used effectively by various stakeholders of the
care team, including clinicians, navigators, psychologists,
care support counselors, and financial aid associates. One
limitation of most ePRO systems to date is a lack of the ability
of patients to add self-identified concerns, which would
require the use of free text and patient input into selection of
the items of most importance to them at a given moment in
the cancer trajectory.
In order for an ePRO system to be widely disseminated and
routinely used, value to both the provider and the patient
must be demonstrated. Evidence exists to support in-
tegration of ePROs into clinical workflow in a manner that is
relatively unobtrusive and that provides the potential for
improved symptom control and patient-clinician in-
teraction.8 Table 1 displays a proposed feature set that
serves as a good framework for elements of optimal
platforms.
DEVELOPMENT OF AN ePRO SYSTEM
Our group began developing an electronic tablet-based
system and an instrument to routinely monitor patient
symptoms and health statuses more than 15 years ago.
Assessment of items pertaining to physical symptoms,
emotional reactions, and functional statuses were identified
by a team of medical oncologists, clinical psychologists
working in oncology, oncology nurses, and patients. Items
were assembled by reviewing previously developed quality-
of-life instruments from the research setting and by de-
termining the importance via face validity in routine patient
care. Each item was presented as a 0-to-10 Likert scale of
severity, in which 0 represented no severity and 10 repre-
sented the most severe, with a timeframe of the past 7 days.
The instrument, termed the Patient Care Monitor (PCM;
initially called Cancer Care Monitor) consisted of 38 items,
grouped into seven constructs of physical symptoms,
treatment adverse effects, distress, despair, impaired am-
bulation, impaired performance, and global quality of life.
Validation studies established psychometric validity, scale
consistency, and reliability.9 Alternative form reliability
that was based on comparisons with paper forms was high,
and patient preference was for the tablet-administered
version. In subsequent studies, item validity by PCM was
compared with a blinded structured interview conducted by
an experienced oncology nurse, and good concordance was
established between the structured interview and patient
self-report.10
An expanded version of the PCM, termed PCM 2.0, was
subsequently created to address clinicians desires to have a
complete review of systems provided by patient self-report.
The gender-specific survey consisted of 86 items (79 for
men) that encompassed 13 organ sitespecific systems (e.g.,
gastrointestinal, cardiovascular). A validation study was
performed for PCM 2.0 and showed good correlation be-
tween patient- and nurse-reported severities.11 The median

TABLE 1. Desirable Features of ePRO Systems in
Clinical Care
Elements Attributes
Symptom Questions/ Demonstrated validity and reliability
Items
Known clinical significance of score changes
Relevance in the selected patient population
and clinical context
Appropriate recall period (no longer than
1 week)
Patient Interface Demonstrated usability in patients
Web-based and available in multiple modes
for data entry via internet, handheld de-
vice, tablet app
Allowance for in-clinic and/or between-visit
reporting
Inclusion of a scheduling/calendar compo-
nent to specify when patients are expected
to report
Automated reminders to patients to report
(e.g., email, text message, automated
telephone call)
Allowance for use of simple usernames/
passwords that are not overly complex or
cumbersome to patients
Availability of staff to train and assist patients
Allows patients to request additional help
Clinician Interface Includes displays of longitudinal patient-
reported symptoms numerically and
graphically
Integrated with electronic health record
Allows clinicians to report symptoms/
comment on patient reports
Alerts/Notifications Sends real-time automated alerts (e.g., email,
text message) to clinicians when patients
report symptom severities above
predetermined thresholds or experience
symptom worsening that exceeds a
predetermined amount
Triggers automated notifications to site
personnel when patients do not report at
a scheduled time point
Provides automated messages to patients
and triggers automated patient education
when symptoms exceed predetermined
absolute thresholds or score-change
thresholds
Back-up Data Includes predetermined methods to contact
Collection patients who do not self-report on
schedule
Abbreviations: ePRO, electronic patient-reported outcome.
Adapted from Basch and Abernethy.8
time for patients to complete PCM 2.0 was 11 minutes. This
version of the platform, which included a wireless tablet
system linked to a central server, was eventually deployed in
more than 100 community practice sites for use in practice
performance improvement projects and as part of routine
clinical care.
PCM 2.0 results were available both in a paper format
and integrated into the electronic medical record (EMR)
of commercial oncology EMR products through an HL-7
INFORMING THE TEAM WITH PATIENT-REPORTED OUTCOMES
interface. In the EMR, the items formed part of the per-
manent record located on the flowsheet for a given out-
patient visit. The paper version displayed demographics,
columns of the last three surveys of each item, and visual
prompts to allow the clinician to quickly scan the report for
severe endorsements and potentially clinically significant
differences ($ 3-point change) from the last survey, signified
by up and down arrows. The surveys are transmitted to the
clinician immediately after completion and serve the
function of focusing the patient interview on the most
severe/changed item endorsements.
PCM 2.0 was installed in a major academic cancer center in
2006. A pilot trial established patient satisfaction with PCM
usage and acknowledgment that the system facilitated
symptom reporting to the clinicians.12 Validation was ac-
complished in a larger trial of 275 patients with breast,
gastrointestinal, or lung cancer.13 Good internal consistency
was demonstrated; Cronbachs a coefficients were similar to
those determined in the community oncology validation
study. Pearson correlatives for PCM subscales were good,
and there was good factor concordance with the Functional
Assessment of Cancer TherapyGeneral (FACT-G), Func-
tional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F),
and MD Anderson Symptom Inventory (MDASI) instruments
widely used in the research setting. PCM 2.0 thus served a dual
functionality as a clinical and a research tool, which allowed
individual clinicians to use the data to inform the patient visit
and became part of a longitudinal repository of standardized
PRO items well suited to research. A larger data set of 5,624
patients who completed the PCM survey was recently ana-
lyzed. The instrument exhibited high internal consistency, and
investigators were able to accurate distribute the items into
three constructs of emotional function, physical function, and
physical symptoms.14 This large-scale experience firmly
established the practicality of systematic collection of ePROs
as part of the standard of care.
The widespread adoption of smartphones, tablets, and
other portable computing devices led to the development
of a new architecture for the PCM system in 2014, when it
was redeployed as a cloud-based, web-enabled application
with an open architecture to meet the growing need for
additional surveys at the practice level. The core instrument
was condensed somewhat to 56 items on the basis of the
evaluation of rarely reported symptoms and those that did
not contribute meaningfully to the aggregate scale scores.
A complete 13-system review to meet Centers for Medicare
& Medicaid Services guidelines for the highest-level visit
was retained.
This revised PCM core version is backward compatible with
earlier versions and has concordance with several other
commonly used instruments for core symptoms. The new
system is delivered via standard commercial tablets pro-
vided by the oncology practice rather than as the previously
used self-contained dedicated system. Acceptance by pa-
tients and providers has been excellent. All told, greater than
100,000 patients have completed PCM surveys since its
inception. Additional modules that have been added to the
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e91
LEE SCHWARTZBERG

core survey include a radiation therapyspecific survey, a FIGURE 1. Cumulative Incidence of Emergency
falls risk assessment and learning needs assessment survey, Department Visits
and a tobacco use and readiness to quit module.

BENEFIT OF ePROS
Despite the value attributed to PROs in reporting and
addressing routine symptoms, the impact of collecting this
data has not been settled. Systematic reviews have largely
failed to demonstrate a clear benefit of collecting PROs,
largely because of methodologic issues with the ways
studies are structured, such as including of several sources of
bias or widely varying endpoints.15 A prospective random-
ized controlled trial conducted at two academic medical
centers met its primary endpoint of demonstrating that self-
reporting of ePROs available to the clinician at the clinic visit
resulted in more discussion of the problem with the patient
than usual care when the symptom intensity was higher
than a predefined threshold.16 Patient-provider visits were
not significantly longer in duration despite having the PROs
to address, and most clinicians surveyed as part of the study
felt that the PROs served a clinical utility function.
A recent multicenter randomized controlled trial reported
by Basch et al17 assigned patients who received chemo-
therapy to report a small number of symptoms via tablet-
computer with weekly email prompts or to receive usual
care. Symptom assessment was delivered either to providers
at the outpatient visit or to the nursing staff via email when
patients reported severe or worsening symptoms. The pri-
mary endpoint of the study was change in health-related
quality of life (QOL) at 6 months compared with baseline.
Secondary endpoints included emergency department visits,
hospitalizations, and overall survival. Patients were addi-
tionally separated into subgroups on the basis of their prior
experiences with computer systems.
The trial revealed that more patients in the ePRO group at
6 months had improvements in health-related QOL (34% vs.
18%), fewer had a decrease (38% vs. 53%, p , .001), and the
mean health-related QOL score declined less in the ePRO group
than in the routine care group (1.4 vs. 7.1, p , .001). Im-
portantly, significantly fewer patients who routinely reported
PROs had an emergency department visit during the period of
study (Fig. 1), and those who used the electronic system re-
ceived chemotherapy longer. Overall survival at 1 year was
better for the ePRO group than the usual care group (75% vs.
69%, p = .05). Interestingly, computer-inexperienced patients
appeared to derive more benefit from the system with regard
to reduction in emergency department visits, perhaps because
this subgroup was older, less educated, and may have been
under-reporting symptoms previously for cultural reasons.
This study highlights the power of ePRO reporting to in-
fluence tangible outcome measures for patients with ad-
vanced cancer, including reduced resource utilization, better
quality of life, and evenpossiblyimproved survival. Why
The incidence of patients visiting the emergency department is shown, with
would this be? Routine reporting of cancer symptoms and a death as a competing event: all patients (A); computer-experienced patients (B);
system of planned interactions to address them appear to and computer-inexperienced patients (C).
Abbreviation: STAR, Symptom Tracking and Reporting (a web-based self-reporting
improve patient well-being and allow patients to tolerate system as the study intervention).
treatment better, which might influence survival. In the trial Adapted and used with permission.17

e92 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook

 INFORMING THE TEAM WITH PATIENT-REPORTED OUTCOMES

conducted by Basch et al,17 time on therapy was approxi-
mately 2 months longer in the ePRO group, which supports
this assertion. The results also mirror those of patients with
lung cancer who were referred early to palliative care,18 in part
because patients symptoms in both instances were taken
seriously and addressed. The patient-centered medical home
model, endorsed by the Centers for Medicare & Medicaid
Services (via its Oncology Care Model), calls for improved
interactions between the clinic staff and patients, including
mechanisms for patients to report problems in a real-time way
without having to resort to hospitalization or emergency
department visits. An ePRO system is an excellent tool to assist
implementation of the Oncology Care Model program.
PROS IN CLINICAL RESEARCH
Inclusion of patients self-reported symptoms and adverse
events is fundamental to evaluating new drugs in oncology.
The use of PROs is endorsed by all major entities involved in
conducting clinical trials.19 A multidisciplinary group was
charged by the Center for Medical Technology Policy to
create an evidence guidance document with recommen-
dations for PRO use in comparative effectiveness research.20
The group devised 15 recommendations related to three
broad domains of PROs: measure selection, implementation
measures, and data analysis/reporting. Chief among these
were the importance of selecting a validated tool that is fit
for the purpose of the study. Twelve symptoms that share
commonality among PRO instruments were highlighted as
having particular value in assessing wellbeing and health-
related QOL (Table 2). Implementation recommendations
focused on obtaining information rapidly, preferably elec-
tronically, when this method had been adequately com-
pared with other standard methods such as paper forms,
and on collecting information as frequently as necessary
for the proposed research without overburdening patients.
In using PROs for comparative effectiveness research, the
evidence guidance document recommended a priori power
calculations of PRO endpoints, a plan for handling missing
data, and a plan for reporting individual measure changes
proportionally and as mean group measure changes. The
document also endorsed simultaneous publication of the
PRO data analysis with the other endpoints of the re-
search trial.
Standard adverse event reporting in clinical trials is assessed
by the Common Terminology Criteria for Adverse Events
(CTCAE), created by the National Cancer Institute. Adverse
events may reflect laboratory abnormalities, physical exami-
nation changes, functional status variations, and patient-
elicited toxicities. Traditionally, symptoms are prompted
from the patient by a clinical observer involved in the trial.
However, evidence suggests that adverse event symptoms are
often under-reported by clinical investigators.21,22 The Na-
tional Cancer Institute has developed a library of items, termed
the PRO-CTCAE, which consists of 124 PROs that reflect 78
different adverse events. Recently, a validity and reliability
assessment of the PRO-CTCAE tool has been published.23 The
study included 975 adult patients receiving chemotherapy or
radiation therapy who completed the instrument on tablets in
clinic waiting rooms at nine U.S. cancer centers and com-
munity oncology practices. PRO-CTCAE were compared with
the clinician-reported Eastern Cooperative Oncology Group
(ECOG) performance status and a reference instrument, the
European Organization for Research and Treatment of Cancer
Core Quality of Life Questionnaire (QLQ-C30).
A broad sample of patients was enrolled, including many
who had ECOG performance statuses of 2 to 4. Symptom

TABLE 2. Availability in Existing PRO Instruments of Common Cancer Symptoms

PRO Instrument*
Symptom ESAS FACT LASA MDASI MSAS PCM PRO-CTCAE PROMIS QLQ-C30 RSCL SDS
Anorexia X X X X X X X X X
Anxiety X X X X X X X X X
Constipation X X X X X X X
Depression X X X X X X X X X
Diarrhea X X X X X X X X
Dyspnea X X X X X X X X X
Fatigue X X X X X X X X X X X
Insomnia X X X X X X X X X X X
Nausea X X X X X X X X X
Pain X X X X X X X X X X X
Neuropathy X X X X X X
Vomiting X X X X X X
Abbreviations: CER, comparative effectiveness research; ESAS, Edmonton Symptom Assessment Scale; FACIT, Functional Assessment of Chronic Illness Therapy; FACT-G, Functional
Assessment of Cancer Therapy-General; LASA, Linear Analog Self-Assessment; MDASI, MD Anderson Symptom Inventory; MSAS, Memorial Symptom Assessment Scale; PCM, Patient
Care Monitor; PRO, patient-reported outcome; PRO-CTCAE, PRO version of the Common Terminology Criteria for Adverse Events; PROMIS, PRO Measurement Information System;
QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; RSCL, Rotterdam Symptom checklist; SDS, Symptom Distress Scale.
Adapted and used with permission.20
*Instruments are listed alphabetically. Dash signifies symptom not measured by that instrument; X, measured by that instrument. Most measurement systems include additional
symptom items beyond these 12 symptoms.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e93

LEE SCHWARTZBERG
endorsement was compared with several clinical anchors,
including performance status, type of therapy, supportive
care measures initiated, expert consensus, and patient in-
put. A median (range) of 23 (091) PROs were endorsed.
Ninety-six percent of patients reported five or more
symptoms at the first visit, and 768 (81.7%) of 940 patients
reported at least one symptom as frequent, severe, and/or
interfering quite a bit with daily activities. Validity of the
instrument was achieved; all 124 items were endorsed in the
same direction as the QLQ-C30 reference instrument, and
114 items demonstrated meaningful correlations, with a
Pearson coefficient r of 0.1 or greater. Of these 114 items,
111 were significant (p , .05).
Responsiveness of items to the patient-reported global
impression of change (GIC) from visit one to two was
evaluated in a core set of 20 symptomatic adverse events
with high face validity for relation to change in QOL, physical
condition, and/or emotional state. Thirteen items achieved
excellent correlation with GIC scores, which validated this
symptom set as critical in approximating patient-reported
health statuses. This trial represents the culmination of more
than a decade of study comparing patient assessment of
toxicity to clinician assessment in clinical trials. The challenge
now will be to incorporate these assessments into routine
adverse event reporting when new therapeutic entities are
evaluated.
Longitudinal collection of ePROs offers opportunities to
integrate symptom attribution into retrospective studies of
treatment patterns in the real-world setting. Such analyses
have been performed with the PCM to address the effect of
FIGURE 2. Workflow for Smoking Cessation Program
Tobacco Use Cessaon
PCM Screening
PCM
PCM will present NEW
paents with quesons
about tobacco use at the
rst visit following NCCN
guidelines for smoking
cessaon.
PCM will present all other
paents the tobacco use
quesons on a rolling basis
over the first year to create
a sustainable work ow.
Screen for Case Finding
Currently use Tobacco
Frequency and quanty
Of tobacco use
Ready to Quit
Request for Informaon
The workflow is based on patient engagement platforms to survey patients on tobacco use.
Abbreviation: PCM, Patient Care Monitor.
e94 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
disease progression or various chemotherapy regimens on
PROs in metastatic breast cancer, prostate cancer, and lung
cancer.24-27
EXPANDING ePROS TO FULL PATIENT
ENGAGEMENT PLATFORM
A 2013 Institute of Medicine report, Delivering High-Quality
Cancer Care: Charting a New Course for a System in Crisis,
stated that cancer care is often not as patient-centered,
accessible, coordinated, or evidence-based as it should be.28
Part of the solution is to actively engage patients to interact
with an adequately staffed and trained workforce. To meet
the needs of an increasing number of patients, cancer clinics
must embrace and expand nonphysician members of the
care team to deliver high-quality multidimensional care.
Enhancing the patient-clinician interaction is another aspect
of best practice cancer care organizations.
The electronic platforms that serve as the basis for ePRO
acquisitions are being expanded to address the growing
needs of the cancer patient. Flexible system design can begin
to deliver functionality beyond information gathering.
Configured with advanced scheduling functions, branching
question capabilities, easy loading of additional surveys, and
two-way communication loops between patient and prac-
tice, patient engagement platforms can facilitate patient
decision support and shared decision making. These plat-
forms can triage patients automatically to appropriate
members of the care delivery team with minimal in-
terruption of normal clinic processes.
May we contact you to
support your eorts to quit
A Psycho-oncology Behavioral
using tobacco? Health Iniave
If NO, quesons will be
Yes No presented again in 6
months and at 1 year.
If YES, paent will be contacted via
phone, or e-mail or mail and will be provided
with resources via phone, email ,or postal
mail
Invitaon to aend weekly informaon
sessions to receive informaon about
smoking, resources, and support
Individual assessments
The opportunity to have an individual
session where personalized quit plans
will be provided
Informaon on pharmacotherapy
Resources on Quit lines
A dedicated email and phone will for the
smoking cessaon team will be provided as
a way for those interested to contact for
addional informaon

Our institution has recently launched a smoking cessation
project that identifies patients through a series of questions
on the PCM about their current and past tobacco use sta-
tuses and their readiness to quit (Fig. 2). If the patient is
smoking but does not self-identify as ready to quit, they will
be scheduled to be automatically recontacted at 6-month
intervals. If ready to quit and requesting more information,
an email message is sent to members of the psychology
team, who then contact the patient and enroll them in an
evidence-based smoking cessation program. Tobacco use
habits can also be appropriately coded to trigger email alerts
to clinicians for consideration of low-dose CT screening for
early detection of lung cancer.
With the advent of mobile technology, studies have ad-
dressed postoperative symptom severity after cancer sur-
gery at home, and an automated system has shown
superiority in controlling symptom threshold events in a
randomized trial.29 Multiple pilot studies are underway to
address adherence to oral medications, such as aromatase
inhibitors in early-stage breast cancer and tyrosine kinase
use in advanced colorectal cancer, through frequent
mobile surveying of emerging symptoms with triggers of
References
1. Forcina JM. Re: National Institutes of Health State-of-the-Science
Conference Statement: Symptom Management in Cancer: Pain, De-
pression, and Fatigue, July 15-17, 2002. J Natl Cancer Inst. 2004;96:
1109-1110, author reply 1110.
2. Gwaltney CJ, Shields AL, Shiffman S. Equivalence of electronic and
paper-and-pencil administration of patient-reported outcome mea-
sures: a meta-analytic review. Value Health. 2008;11:322-333.
3. Basch E, Iasonos A, McDonough T, et al. Patient versus clinician
symptom reporting using the National Cancer Institute Common Ter-
minology Criteria for Adverse Events: results of a questionnaire-based
study. Lancet Oncol. 2006;7:903-909.
4. Cirillo M, Venturini M, Ciccarelli L, et al. Clinician versus nurse symptom
reporting using the National Cancer Institute Common Terminology
Criteria for Adverse Events during chemotherapy: results of a com-
parison based on patients self-reported questionnaire. Ann Oncol.
2009;20:1929-1935.
5. Di Maio M, Basch E, Bryce J, et al. Patient-reported outcomes in the
evaluation of toxicity of anticancer treatments. Nat Rev Clin Oncol.
Epub 2016 Jan 20.
6. Bergeson SC, Dean JD. A systems approach to patient-centered care.
JAMA. 2006;296:2848-2851.
7. Jensen RE, Snyder CF, Abernethy AP, et al. Review of electronic patient-
reported outcomes systems used in cancer clinical care. J Oncol Pract.
2014;10:e215-e222.
8. Basch E, Abernethy AP. Supporting clinical practice decisions with real-
time patient-reported outcomes. J Clin Oncol. 2011;29:954-956.
9. Fortner B, Okon T, Schwartzberg L, et al. The Cancer Care Monitor:
psychometric content evaluation and pilot testing of a computer ad-
ministered system for symptom screening and quality of life in adult
cancer patients. J Pain Symptom Manage. 2003;26:1077-1092.
10. Fortner B, Baldwin S, Schwartzberg L, et al. Validation of the Cancer Care
Monitor items for physical symptoms and treatment side effects using expert
oncology nurse evaluation. J Pain Symptom Manage. 2006;31:207-214.
INFORMING THE TEAM WITH PATIENT-REPORTED OUTCOMES
emails/texts to nursing or navigator staff, who then contact
the patient directly. The goal is to alleviate severe toxicities
that emerge between visits by using electronic communi-
cation with the platform.
CONCLUSION
ePROs have emerged as an effective method of capturing
patient symptoms that can lead to a more thorough and
consistent evaluation of patient physical and emotional
health status and QOL. Numerous studies have validated
multiple assessment instruments and platforms that can
now be used in routine clinical practice. New data support an
ePRO solution to collecting patient symptoms consistent
with regulatory criteria in the clinical trial assessment of new
therapies. The widespread use of mobile devices provides an
excellent opportunity to expand patient engagement be-
yond the point of care to routinely monitor patients for
emerging problems with minimal investment of time and
resources by the care delivery system, thus enhancing the
overarching goal of high-quality patient-centered cancer
care.
11. Schwartzberg L, Fortner B, Houts A. Use of technology to enhance
doctor-patient interactions. Am Soc Clin Oncol Educ Book. 2007;27:686-
691.
12. Abernethy AP, Herndon JE II, Wheeler JL, et al. Feasibility and
acceptability to patients of a longitudinal system for evaluating cancer-
related symptoms and quality of life: pilot study of an e/tablet data-
collection system in academic oncology. J Pain Symptom Manage. 2009;
37:1027-1038.
13. Abernethy AP, Zafar SY, Uronis H, et al. Validation of the Patient Care
Monitor (Version 2.0): a review of system assessment instrument for
cancer patients. J Pain Symptom Manage. 2010;40:545-558.
14. Samsa GP, Wolf S, LeBlanc TW, et al. An exploratory factor analysis of
the scale structure of the Patient Care Monitor Version 2.0. J Pain
Symptom Manage. 2016;51:776-783.
15. Kotronoulas G, Kearney N, Maguire R, et al. What is the value of the
routine use of patient-reported outcome measures toward improve-
ment of patient outcomes, processes of care, and health service
outcomes in cancer care? A systematic review of controlled trials. J Clin
Oncol. 2014;32:1480-1501.
16. Berry DL, Blumenstein BA, Halpenny B, et al. Enhancing patient-provider
communication with the electronic self-report assessment for cancer:
a randomized trial. J Clin Oncol. 2011;29:1029-1035.
17. Basch E, Deal AM, Kris MG, et al. Symptom monitoring with patient-
reported outcomes during routine cancer treatment: a randomized
controlled trial. J Clin Oncol. 2015;34:557-565.
18. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with
metastatic nonsmall-cell lung cancer. N Engl J Med. 2010;363:733-742.
19. Lipscomb J, Gotay CC, Snyder CF. Patient-reported outcomes in cancer:
a review of recent research and policy initiatives. CA Cancer J Clin. 2007;
57:278-300.
20. Basch E, Abernethy AP, Mullins CD, et al. Recommendations for in-
corporating patient-reported outcomes into clinical comparative ef-
fectiveness research in adult oncology. J Clin Oncol. 2012;30:4249-4255.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e95
LEE SCHWARTZBERG
21. Di Maio M, Gallo C, Leighl NB, et al. Symptomatic toxicities experienced
during anticancer treatment: agreement between patient and physician
reporting in three randomized trials. J Clin Oncol. 2015;33:910-915.
22. Fromme EK, Eilers KM, Mori M, et al. How accurate is clinician reporting
of chemotherapy adverse effects? A comparison with patient-reported
symptoms from the Quality-of-Life Questionnaire C30. J Clin Oncol.
2004;22:3485-3490.
23. Dueck AC, Mendoza TR, Mitchell SA, et al; National Cancer Institute
PRO-CTCAE Study Group. Validity and Reliability of the US National
Cancer Institutes patient-reported outcomes version of the Common
Terminology Criteria for Adverse Events (PRO-CTCAE). JAMA Oncol.
2015;1:1051-1059.
24. Schwartzberg LS, Cobb P, Walker MS, et al. Patient and practice impact
of capecitabine compared to taxanes in first-/second-line chemo-
therapy for metastatic breast cancer. Support Care Cancer. 2009;17:
1081-1088.
e96 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
25. Walker MS, Masaquel AS, Kerr J, et al. Early treatment discontinuation
and switching in first-line metastatic breast cancer: the role of patient-
reported symptom burden. Breast Cancer Res Treat. 2014;144:673-681.
26. Stepanski EJ, Houts AC, Schwartzberg LS, et al. Second- and third-line
treatment of patients with non-small-cell lung cancer with erlotinib in
the community setting: retrospective study of patient healthcare uti-
lization and symptom burden. Clin Lung Cancer. 2009;10:426-432.
27. Walker MS, Reyes C, Kerr J, et al. Treatment patterns and outcomes
among patients with metastatic melanoma treated in community
practice. Int J Dermatol. 2014;53:e499-e506.
28. Levit L, Balogh E, Nass S, et al. Delivering High-Quality Cancer Care:
Charting a New Course for a System in Crisis. Washington, DC, Institute
of Medicine, National Academies Press; 2013.
29. Cleeland CS, Wang XS, Shi Q, et al. Automated symptom alerts reduce
postoperative symptom severity after cancer surgery: a randomized
controlled clinical trial. J Clin Oncol. 2011;29:994-1000.
 ADVANCED PRACTITIONERS IN ONCOLOGY CARE

Oncology Advanced Practitioners Bring Advanced Community

Oncology Care
Wendy H. Vogel, MSN, FNP, AOCNP

OVERVIEW

Oncology care is becoming increasingly complex. The interprofessional team concept of care is necessary to meet projected
oncology professional shortages, as well as to provide superior oncology care. The oncology advanced practitioner (AP) is a
licensed health care professional who has completed advanced training in nursing or pharmacy or has completed training
as a physician assistant. Oncology APs increase practice productivity and efficiency. Proven to be cost effective, APs may
perform varied roles in an oncology practice. Integrating an AP into an oncology practice requires forethought given to the
type of collaborative model desired, role expectations, scheduling, training, and mentoring.

2,400 pharmacists who specialized in oncology.1 The Na-

S uperior oncology care requires a superior team. As on-
cology care becomes increasingly complex, the inter-
professional team concept and collaborative care is no
longer an option but a necessity. A team is a group of two or
more people who function interdependently to achieve a
shared goal. Oncology APs are an integral part of the on-
cology team.
DEFINITION OF ADVANCED PRACTITIONER
An AP is defined as a licensed health care professional who
has completed advanced training in nursing (such as a nurse
practitioner or clinical nurse specialist) or pharmacy or has
completed training as a physician assistant.1 Table 1 lists the
various APs and educational requirements.
STATISTICS
The American Society of Clinical Oncologys (ASCO) The State
of Cancer Care in America: 2015 notes that the numbers of
APs in oncology are increasing. This may assist in meeting the
growth in demand for oncologists despite the fact that the
number of oncologists remains static.2 However, it is difficult
to estimate the exact number of APs in oncology. The 28th
Annual Advanced Practice Registered Nurse Legislative
Update3 notes there are more than 306,000 advanced
practice nurses in the United States, across all medical fields.
ASCO2 estimates that there are about 3,000 APs working in
oncology and that this number is growing. The Oncology
Nursing Society counts 2,601 nurse practitioners (NPs) and
1,173 clinical nurse specialists in the membership.1 The
Hematology/Oncology Pharmacy Organization notes about
tional Commission on Certification of Physician Assistants4
Statistical Profile of Recently Certified Physician Assistants
noted over 102,000 certified physician assistants in the
United States, across all heath fields. Data extrapolated from
the American Academy of Physician Assistants Physician
Assistants Annual Survey Report estimate that about 2.4% of
physician assistants work in oncology (approximately 2,000).
Based on these data, there could be over 11,000 oncology
APs, but it is impossible to give an exact number because
some oncology APs may belong to multiple societies, not all
APs have certification in oncology, and not all APs are
members of one of the previously mentioned societies.
SCOPE OF PRACTICE
Advanced practitioners legal scope of practice varies from
state to state,3 as noted in Table 1. The scope of practice may
also differ because of the APs type, level of experience,
and facility.1,5 The majority of APs have prescriptive
privileges, with differing requirements/rules for controlled
substances.3
COLLABORATIVE CARE MODELS IN ONCOLOGY
The majority of oncology care (80%) is provided in the
community setting.6 With the expected shortfall of oncol-
ogists by 2020, collaborative practice will be required to
meet the demands of oncology care.7,8 Collaborative
practice requires the involvement of all interdisciplinary
team members to maximize positive patient outcomes.1
Advanced practitioners are an integral part of the oncology

From the Wellmont Cancer Institute, Kingsport, TN.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Wendy H. Vogel, MSN, FNP, AOCNP, WMA Hematology & Oncology at Kingsport, Wellmont Cancer Institute, 4485 West Stone Dr., Suite 200, Kingsport, TN
37660; email: wendyvogel55@gmail.com.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e97

WENDY H. VOGEL

TABLE 1. Education, Licensure, Professional Organizations, and Certification of Advanced Practitioners in Oncology
Advanced Entry-Level Board Certification Professional Prescriptive
Practice Role Degree Licensure and Certifying Body Organizations Authority Eligibility*
Nurse Doctorate (DNP or PhD) State Board of Nursing General certification: American AANP, ANA, Scope defined by
Practitioner preferred, previously NP: adult, pediatric, Nurses Association and State APSHO, ONS individual states
masters level or acute care, primary Board of Nursing Oncology
postmasters care, family practice Certification: AOCNP-ONCC
certificate AOCN-ONCC
Physician Masters degree State Board requires PA-C, NCCPA AAPA, APAO, Yes, requires
Assistant PA National Certifying APSHO supervising
Examination, physician
administered by NCCPA agreement
Clinical 4-year professional State Board The Board of Pharmacy Specialties ACCP, APSHO, Scope defined by
Pharmacist degree (Doctor of Pharmacy provides testing and maintains ASHP, HOPA individual states
of Pharmacy) the Board Certified Oncology
Pharmacist status
Clinical Nurse Masters degree State Board of Nursing State Board of APSHO, ONS Scope defined by
Specialist Advanced Practice Nurse Nursing: AOCNS-ONS individual states**
Abbreviations: DNP, Doctor of Nursing Practice; AOCNP, advanced oncology certified nurse practitioner; ONS, Oncology Nursing Society; AOCN, advanced oncology certified nurse;
AANP, American Academy of Nurse Practitioners; ANA, American Nurses Association; APSHO, Advanced Practitioner Society for Hematology and Oncology; NCCPA, National
Commission on Certification of Physician Assistants; APAO, Association of Physician Assistants in Oncology; AAPA, American Academy of Physician Assistants; ACCP, American College
of Clinical Pharmacy; ASHP, American Society of Health-System Pharmacists; HOPA, Hematology/Oncology Pharmacy Organization; AOCNS, advanced oncology clinical nurse
specialist.
*Variability by state.
**From the National Council of State Boards of Nursings APRN campaign for Consensus: Moving Toward Uniformity in State Laws (https://www.ncsbn.org/5410.htm).
Adapted from Vogel5 and from Kurtin SE et al.1

team. The ASCO Workforce Advisory Group suggested that
increasing the use of and maximizing the potential of APs
would improve practice efficiency.7 Since this 2007 publi-
cation, other studies and publications have examined var-
ious collaborative oncology practice models.8
Three collaborative practice models have been described in
oncology practices: the incident-to visit model, the shared
visit model, and the independent visit model (Table 2).8,9 The
ASCO study of collaborative practice arrangements8 noted
that more than 75% of practices use the incident-to visit
model. This is likely to maximize reimbursement. Most of the
practices in this study (73%) were physician-owned private
KEY POINTS
An advanced practitioner is defined as a licensed health
care professional who has completed advanced training
in nursing or pharmacy or has completed training as a
physician assistant.
Advanced practitioner legal scope of practice varies
from state to state, but most have prescriptive
privileges, with differing requirements/rules for
controlled substances.
Three collaborative care models are identified in
oncology practices: incident-to visit model, the shared
visit model, and the independent visit model.
Barriers to efficient collaborative practice include
disallowing the AP the full scope of practice and
inadequate training and mentoring.
Advanced practitioners are cost effective and an integral
part of the future of oncology care.
practices. The collaborative model and billing practices in
academic oncology practices are likely to be different.10 In
the ASCO study, both the incident-to model and the in-
dependent model consist of the physician and AP working
independently; however, the primary difference is billing, the
amount of consultation required, and the autonomy of the
AP. Other disciplines, such as primary care, describe practice
models of the AP (an NP) working completely independent
of a physician. Currently in 15 states, NPs are regulated by a
Board of Nursing and have full autonomous practice and
prescriptive authority without requirement for physician
supervision, delegation, consultation, or collaboration.3
In some oncology practices, the AP works exclusively with
one oncologist; in other practices, the AP works with all
practice oncologists.8 The ASCO Study of Collaborative
Practice agreements noted that about 60% of APs work with
all practice oncologists and not exclusively with one on-
cologist. Interestingly, the practices with APs working with
all practice oncologists had higher productivity.8
When choosing a collaborative practice model, the
practice needs and patient volume must be considered, as
well as both the physician and APs training, strengths, skills,
and expert knowledge. The ability to meet regulatory
constraints for AP billing must be carefully considered to
avoid fraud. If the AP is new to oncology, a thorough training
and mentoring program must be planned.1,5,11
Barriers to efficient practice must also be considered. A
recent survey of APs in oncology noted the most common
barrier to the AP role was time spent on tasks that could
be delegated to non-AP staff.1,12 Other common barriers
included insufficient support, mentoring, and insufficient
autonomy and training to meet role expectations. Most APs
are trained as generalists with limited time devoted to

e98 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook

 ADVANCED PRACTITIONERS IN ONCOLOGY CARE

TABLE 2. Collaborative Practice Models8-10,18

Model Description
Incident-To (Mixed) Visit Model AP sees patient independently, following physician plan of care; physician consult available if needed;
physician generally in office suite; billing is incident-to at full physician fee schedule; however,
must meet CMS regulations on alternate visit schedules
Shared Visit Model Both the AP and the physician see patient. The physician completes the visit note and bills for services.
Independent Visit Model AP sees patient independently, consulting at critical treatment decision points (such as initial treatment
plans, at progression, end-of-life decisions); billed under NPP own provider number, at 85% of
physician fee schedule
Abbreviations: AP, advanced practitioner; CMS, Center for Medicaid & Medicare Services; NPP, nonphysician provider.

oncology.1,13 In a survey of physician assistants in oncology practice and prescriptive authority in some states.5 Physi-
practices,13 the majority reported that it took 1 to 2 years of cians and APs must work together to change restrictive
practice to become fully competent in the practice of legislation.
oncology. PAs in this survey also described the most im-
portant mode of obtaining their oncology knowledge base
was direct physician mentoring. The second most important MYTHS DEBUNKED
mode was self-study. A similar study of oncology NPs re- There was a fear among physicians that patients might not
ported that the majority of NPs felt inadequately prepared to be aware that their care was provided by an AP. However,
provide cancer care.14 These barriers are substantial, noting the ASCO Study of Collaborative Practice Arrangements8
that most oncology practices use informal, on-the-job found that 98% of patients with cancer were aware that an
training for new APs.8 Sidebar 1 lists organizations that AP was providing their care. There was also a belief that
provide AP oncology education. patients would be unhappy with the care of the AP. In fact,
Adequate and thorough training and direct mentoring by
the oncologist would enable the oncology AP to become
much more efficient and productive. Ensuring that the AP is
functioning at their highest scope of practice will maximize
SIDEBAR 2. Oncology Advanced Practitioner
the skills of the AP, allowing maximum productivity. It is
Functions and Roles*1,5,8,13
important to understand that adequate AP productivity History taking
measurements are lacking. To only measure AP productivity Physical examination
by relative value units (RVUs) will underestimate the value Diagnostic testing: ordering, interpretation, discussion
the AP brings to a practice.15 Treatment selection
Prescribing (including chemotherapy)
Cancer risk assessment, screening, and management
ROLES OF ADVANCED PRACTITIONERS IN Symptom management
ONCOLOGY Medication management
Advanced practitioners in oncology perform a variety of
In-patient hospital rounds
On-call services
functions (Sidebar 2). Roles vary according to legal scope of Patient education
practice, practice policy, and experience/expertise of the Staff/peer education
AP. To maximize role productivity and efficiency, the AP Survivorship care
must be allowed to work at their full scope of practice as Palliative care
independently as possible. The biggest obstacle to the most Hospice care
effective and efficient utilization of the AP is the lack of full Pain management
Research (including roles as principal or subinvestigator)
Emergent care
Case management
SIDEBAR 1. Organizations Providing Oncology Cancer patient navigator
Education for the Advanced Practitioner Genetic services
Association of Physician Assistants in Oncology
Lung nodule clinic
(www.apao.org)
Community education
American Society of Clinical Oncology (www.asco.org)
Faculty positions outside institution of employment
Advanced Practitioner Society for Hematology and On-
Procedures including (but not limited to) bone marrow
cology (www.apsho.org) aspiration/biopsy, paracentesis, thoracentesis, central line
National Cancer Institute (www.cancer.gov) placement, lumbar puncture, intrathecal chemotherapy
Oncology Nursing Society (www.ons.org) administration, punch biopsy, suturing, surgical assist
*This list is not all inclusive.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e99

WENDY H. VOGEL
this same study found that 92.5% of patients were extremely
satisfied with AP services. Other disciplines have docu-
mented similar results.16,17
One of the most common reasons that oncology practices
have cited as reasons for not adding an AP to the practice is
physician lack of interest in working with an AP.8 However,
data show that not only is practice productivity increased
with the addition of an AP, professional satisfaction of the
collaborative oncologist increases as well.8,15
There is also misunderstanding about the cost effectiveness
of an AP, especially in terms of AP billing. APs can see and bill
for new patients and can bill all levels of services. Data
consistently show the cost effectiveness of the AP.16,17
INTEGRATING THE ADVANCED PRACTITIONER
INTO THE ONCOLOGY TEAM
Oncology team members have a shared goal of improving
patient outcomes. Other goals of collaboration might in-
clude increased productivity of the practice, improved pa-
tient access to timely care, among others.18 Successful
collaboration takes time and deliberate planning to fully
engage each members unique strengths and skills. Mea-
surement of productivity must include not only individual
RVUs, but also team-based RVUs (combined physician and
References
1. Kurtin SE, Peterson M, Goforth P, et al. White Paper: The Advanced
Practitioner and Collaborative Practice in Oncology. J Adv Pract Oncol.
2015;6:515-527.
2. American Society of Clinical Oncology. The State of Cancer Care
in America: 2015. http://www.asco.org/sites/www.asco.org/files/
2015ascostateofcancercare.pdf. Accessed January 16, 2016.
3. Phillips SJ. 28th annual APRN legislative update: advancements con-
tinue for APRN practice. Nurse Pract. 2016;41:21-48.
4. National Commission on Certification of Physician Assistants. 2014
Statistical Profile of Recently Certified Physician Assistants. https://
www.nccpa.net/Uploads/docs/RecentlyCertifiedReport2014.pdf.
Accessed January 16, 2016.
5. Vogel WH. Advanced practitioners in oncology: meeting the challenges.
J Adv Pract Oncol. 2010;1:13-18.
6. Levit L, Smith AP, Benz EJ, et al. Ensuring quality cancer care through the
oncology workforce. J Oncol Pract. 2010;6:7-11.
7. Erikson C, Salsberg E, Forte G, et al. Future supply and demand for
oncologists : challenges to assuring access to oncology services. J Oncol
Pract. 2007;3:79-86.
8. Towle EL, Barr TR, Hanley A, et al. Results of the ASCO Study of Col-
laborative Practice Arrangements. J Oncol Pract. 2011;7:278-282.
9. Buswell LA, Ponte PR, Shulman LN. Provider practice models in ambu-
latory oncology practice: analysis of productivity, revenue, and provider
and patient satisfaction. J Oncol Pract. 2009;5:188-192.
10. Hinkel JM, Vandergrift JL, Perkel SJ, et al. Practice and productivity of
physician assistants and nurse practitioners in outpatient oncology
e100 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
AP RVUs). Productivity measures should also include value-
added functions (that might be nonrevenue generating),
patient satisfaction, and professional satisfaction.
Proactive and thoughtful scheduling of patient visits will
enable the oncologist to offer new patients rapid access.18
Planning for urgent care time slots decreases the use of the
emergency department, thus increasing patient satisfaction.
Efficient scheduling takes planning in advance and thorough
training of scheduling staff and patient education, as well as
the flexibility of the AP and oncologist.
Adequate training and mentoring of the AP will enable the
highest level of productivity in the timeliest manner. This will
also lower burnout rates and increase professional satis-
faction. Thoughtful preplanning for this education and
mentoring is required. It is also important to plan for the
lengthy time period that could be required for license and
credentialing. Ongoing education is critical for the AP to stay
current in this rapidly changing field.
CONCLUSION
Collaborative care is required to meet the increasing de-
mands of oncology care. The oncology AP is a cost-effective,
integral part of the professional oncology team.
clinics at national comprehensive cancer network institutions. J Oncol
Pract. 2010;6:182-187.
11. Kurtin S, Viale P, Hylton H, et al. The APSHO practice survey. Paper
presented at: 3rd JADPRO LIVE at Advanced Practitioner Society for
Hematology and Oncology Annual Meeting; November 2015; Phoenix,
AZ Poster JL316.
12. McCorkle R, Engelking C, Knobf MT, et al. Transition to a new cancer
care delivery system: opportunity for empowerment of the role of the
advanced practice provider. J Adv Pract Oncol. 2012;3:34-42.
13. Ross AC, Polansky MN, Parker PA, et al. Understanding the role of
physician assistants in oncology. J Oncol Pract. 2010;6:26-30.
14. Nevidjon B, Rieger P, Miller Murphy C, et al. Filling the gap: devel-
opment of the oncology nurse practitioner workforce. J Oncol Pract.
2010;6:2-6.
15. Kosty M, Acheson AK, Tetzlaff ED. Clinical oncology practice 2015:
preparing for the future. Am Soc Clin Oncol Educ Book. 2015;35:e622-
e627.
16. Martin-Misener R, Harbman P, Donald F, et al. Cost-effectiveness of
nurse practitioners in primary and specialised ambulatory care: sys-
tematic review. BMJ Open. 2015;5:e007167.
17. Donald F, Kilpatrick K, Reid K, et al. A systematic review of the cost-
effectiveness of nurse practitioners and clinical nurse specialists: what is
the quality of the evidence? Nurs Res Pract. 2014;2014:896587.
18. Shulman LN. Efficient and effective models for integrating advanced
practice professionals into oncology practice. Am Soc Clin Oncol Educ
Book. 2013;33:e377-e379.
CARE DELIVERY AND PRACTICE MANAGEMENT

Quality and Value: Measuring and

Utilizing Both in Your Practice

CHAIR
Lowell E. Schnipper, MD
Beth Israel Deaconess Medical Center
Boston, MA

SPEAKERS
Anne C. Chiang, MD, PhD
Yale Cancer Center
New Haven, CT

Steven L. DAmato, BCOP, RPh

New England Cancer Specialists
Scarborough, ME
ANNE C. CHIANG

Why the Quality Oncology Practice Initiative Matters: Its Not

Just About Cost
Anne C. Chiang, MD, PhD

OVERVIEW

The nature and cost of cancer care is evolving, affecting more patients and often involving expensive treatment options. The
upward cost trends also coincide with a national landscape of increasing regulatory mandates that may demand improved
outcomes and value, but that often require significant up-front investment in infrastructure to achieve safety and quality.
Oncology practices participating in the American Society of Clinical Oncology (ASCO) Institute for Qualitys Quality Oncology
Practice Initiative (QOPI) and the QOPI Certification Program (QCP) continue to grow in number and reflect changing
demographics of the provision of cancer care. QOPI and QCP benchmarking can be used to achieve quality improvement and
to build collaborative quality communities. These programs may be useful tools for oncology practices to comply with new
legislation such as the Medicare Access and CHIP Reauthorization Act (MACRA).

T he cost of cancer in the United States has risen signifi-

cantly over the past decade. According to the Centers
for Disease Control and Prevention, 8.5% of the adult U.S.
population has been diagnosed with cancer, totaling over
20 million patients in 2012 and more than 29 million
ambulatory visits to physician offices, hospital outpatient
offices, and emergency departments.1 The estimated direct
medical costs for cancer care in the United States in 2011
were $88.7 billion, with 50% of that cost for physician or
hospital outpatient office visits, 35% for inpatient stays, and
11% for prescription drugs.2 Projections of growth from 2010
to 2020 based on 13.8 and 18.1 million cancer survivors, re-
spectively, estimated the costs associated with cancer care to
be $124.57 and $157.77 billion, respectively, reflecting a 27%
increase in medical costs.3
The increase in costs is likely multifactorial, involving
more patients, more expensive drugs, and changes in
cancer care delivery. The upward cost trends also coincide
with a national landscape of increasing government and
regulatory mandates that often require significant up-
front investment in equipment and infrastructure to
achieve. Such government mandates include the Ameri-
can Recovery and Reinvestment Act of 2009 enacted on
February 17, 2009, that established incentive payments to
promote the adoption and meaningful use of qualified
electronic health records (EHRs) and interoperable health
information technology.4 The U.S. Pharmacopeia Chapter
797 describes enforceable sterile compounding standards
that apply to chemotherapy preparation, with even more
comprehensive detail in the recently released Chapter 800
regarding not only storage and preparation but also the
administration of hazardous drugs.5 The American College
of Surgeons has recently mandated implementation of
distress screening and survivorship care plans for hospitals
to achieve and maintain accreditation of their cancer
programs.6
More recently, MACRA was passed to reform Medicare
payments. This act is intended to focus on payment for value
and better care by incentivizing providers to participate in
quality programs through either a Merit-Based Incentive Pay-
ment System (MIPS) or Alternative Payment Model (APM). The
MIPS program involves three components: the physician
quality reporting system (PQRS), the value modifier (value-
based payment modifier), and the Medicare EHR incentive
program. Alternative Payment Models include accountable
care organizations, patient-centered medical homes, and
bundled payment models.7
In such an evolving landscape, it is critical to foster a
culture of self-examination and quality improvement to
maintain a focus on achieving quality and patient-centered
care. To this end, the principles and evolution of ASCOs
quality programs, QOPI and QCP, make them attractive tools
for practices to comply with legislation, such as MACRA, that
require not only benchmarking of standards but also built-in
quality improvement mechanisms. QOPI is deemed by the
Centers for Medicare & Medicaid Services (CMS) as a
Qualified Clinical Data Registry (QCDR), with clinical mea-
sures that are highly relevant to contemporary ambulatory

From the Yale University School of Medicine, New Haven, CT.

Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook.

Corresponding author: Anne C. Chiang, MD, PhD, Yale University School of Medicine, 200 York St., New Haven, CT 06520; email: anne.chiang@yale.edu.

2016 by American Society of Clinical Oncology.

e102 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


practice.8 Participants abstract and submit data for a set of
core measures as well as additional modules (e.g., disease-
specific) that they select. They receive detailed reports of
their performance on quality metrics, which allows them to
compare with national benchmark data, to identify areas for
improvement and develop focused improvement plans.
While QOPI focuses on quality metrics, QCP validates a
practices processes, demonstrating to patients, payers, and
colleagues a commitment to quality. Through practice and
policy review, including an on-site survey, QCP verifies
practice standards for safe administration of chemotherapy.
Some health plans recognize QOPI certification. QCP uses
national benchmarking standards developed by ASCO, the
Oncology Nursing Society (ONS), and other organizations
that safeguard the practice and patients.
CURRENT STATE OF QOPI
QOPI has been ASCOs signature quality program for almost
10 years, and since 2006, over half of all U.S.-based medical
oncologists have participated, numbering over 1,000 prac-
tices representing 7,000 oncologists. In addition, international
practices within the European Union, Argentina, Brazil, India,
and Saudi Arabia were recently allowed to participate in QOPI,
with 16 practices participating since fall 2015. A total of 994
practices submitted over 32,000 charts for the three most
recent abstraction rounds (fall 2013, spring 2014, and spring
2015). These results were compared with data from 5 years
ago (fall 2009, spring 2009, and fall 2010) and demonstrate
notable changes in the demographics, the practice model of
employment, and the range of services provided (Table 1).
Of note, the QOPI fall 2014 round did not take place because
of a change in vendor.
Several interesting trends were noted when comparing
data from 2009 to 2010 with data from 2013 to 2015. First,
KEY POINTS
ASCOs quality programsQOPI and QOPI QCPare
attractive tools for practices to comply with new
legislation, such as MACRA, that require not only
benchmarking of standards but also built-in quality
improvement mechanisms.
Oncology practices participating in QOPI and QCP
continue to grow in number and reflect changing
demographics of the provision of cancer care.
QOPI and QCP benchmarking can be used to identify
areas for improvement, provide comparative metrics for
quality initiative projects, and build collaborative quality
communities.
QCP provides hands-on expert gap analysis assessment
of a practice and a road map toward quality through
ASCO certification status.
ASCO has multiple offerings as vehicles for diverse
practices to join a quality community working toward
improving cancer care.
WHY QOPI MATTERS: ITS NOT JUST ABOUT COST
the mean number of medical oncologists per practice in-
creased from 6.7 to 7.8. The participating practices had
similar geographic distribution across the United States, but
overall, there was an increase in the number of practices that
are high volume (e.g., with more than 1,500 new patients
seen per year). Interestingly, the number of QOPI practices
with employed physicians increased from 15% (82) to 28.7%
(273), and the number of private independent physician
practices decreased from 63.8% (344) to 47.9% (455). The
percentage of practices identifying as academic full time
increased slightly from 7.2% (39) to 10.5% (100), while the
percentage of practices with academic affiliation was stable
at 7%. Roughly 6% of practices have a fellowship program.
QOPI participation correlates with improvement in scores
over time.9 The expectations of the nature of cancer care is
constantly changing, as evidenced by new standards man-
dated by the American College of Surgeons regarding dis-
tress screening and use of survivorship care plans as well as
the CMS requirement that practices deliver care using an
electronic medical record (EMR). These mandates parallel
the shift from oncologists being self-employed to employed;
hospital-affiliated practices certainly may have increased ac-
cess to other services. In fact, patient access to these in-
terdisciplinary services such as social work increased from 45%
(188) to 55.5% (466), nutrition from 38.2% (159) to 52.3%
(324), and genetic counseling from 31.9% (132) to 38.7% (324).
Furthermore, 90.7% (564) of practices now have an EMR.
FUTURE STATE OF QOPI
QOPI continues to offer new opportunities and enhance-
ments in its services to aid practices in assessing quality and
to comply with new federal requirements. CMS has approved
QOPI as such a registry for oncologists to satisfy PQRS mea-
sures. Oncology practices registered with QOPI can fulfill CMS
PQRS requirements by manually or electronically submitting
data through QOPI for the oncology measures group or by
submitting data through QOPI via a QCDR reporting pathway,
which offers 20 measures chosen by ASCO.10 Since QOPI has
been deemed as a QCDR, it is anticipated that QOPI will
become the primary mechanism for ASCO members to report
their quality as required by MIPS and in APMs.
In fall 2015, ASCO began piloting eQOPI to decrease the
burden of manual chart abstraction by implementing
technology to automate data abstraction. The technology
enables the required data elements in the EHR to be mapped
and extracted (or in some cases, data can be pushed); this
allows the majority of the elements required for the clinical
quality measures to be captured automatically, leaving
only a small percentage for manual abstraction. The dif-
ferences in the scope and reporting pathways for classic
QOPI and eQOPI are highlighted in Table 2. Many of the
performance measures in QOPI are already based on ASCO
clinical practice guidelines, and as guideline scope and
volume increase, so will the available measures yet to be
incorporated into QOPI, with an increased emphasis on out-
comes measures and measures that reflect patient experience,
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e103
ANNE C. CHIANG

TABLE 1. ASCO 2015 QOPI Practice Demographic Data

Fall 2009Fall 2010 (609) Fall 2013Spring 2015 (994)

Mean (SD) or N (%) Mean (SD) or N (%)
Number of Medical Oncologists 6.7 (10.0) 7.8 (13.6)
Number of New Patients
< 500 96 (31.8) 251 (31.5)
501-1,500 136 (45.0) 326 (40.8)
> 1,500 70 (23.2) 221 (27.7)
Census Region
Midwest 198 (32.5) 302 (30.4)
Northeast 111 (18.2) 192 (19.3)
South 195 (32.0) 308 (31.0)
West 105 (17.3) 192 (19.3)
Site Affiliation
Academic Full Time 39 (7.2) 100 (10.5)
Private With Academic Affiliation 40 (7.4) 67 (7.1)
Employee 82 (15.2) 273 (28.7)
Private Independent 344 (63.8) 455 (47.9)
Fellowship Program 34 (6.4) 55 (5.8)
Social Work 188 (45.1) 466 (55.5)
Dietician/Nutritionist 159 (38.2) 442 (52.3)
Genetic Counselor 132 (31.9) 324 (38.7)
Quality Improvement Training 320 (52.5)
Electronic Medical Records 564 (90.7)

as well as patient-reported outcomes. For instance, QOPI began
pilot testing value measures in 2015, based on lists of tests
and procedures ASCO developed as part of its participation
in the Choosing Wisely campaign that are not evidence-based.
As the technology that powers QOPI becomes more sophis-
ticated to decrease the workload on practices required for
quality reporting, QOPI-based quality assessment will become
a key and value-added component of ASCOs rapid-learning
system, CancerLinQ, where abstraction of data elements from
the EHR will be fully automated.11,12
QOPI CERTIFICATION PROGRAM
Although QOPI focuses on data regarding individual patients
and providers only, certification of practices by ASCO
requires a minimum QOPI Quality Score, submission of
documentation for 20 standards, and an on-site survey.13
The certification process provides a comprehensive evalu-
ation of patient care including examination of documen-
tation, policies and procedures, and administration of
chemotherapy. A surveyor travels to multiple sites in the
practice and has the opportunity to observe and evaluate
processes directly. The surveyor and ASCO QCP staff have
the opportunity to share feedback and best practices be-
tween sites to help address standards that are initially not in
accordance. The benefits of participating in the QCP pro-
gram include identifying areas for quality improvement and
achieving QOPI certification status by ASCO, as well as payor
benefits in some cases.
A total of 298 practices have achieved QOPI certification,
out of 525 applicants representing 336 unique practices.
Subsequently, 189 practices have applied for recertifica-
tion, with 96% receiving certification. Most certified practices
are small to midsized with one to three full-time equivalents
(FTEs; 30%) or four to seven FTEs (35%). The rest of the
practices are larger with seven to 15 FTEs (23%), 25 to 50
FTEs (4%), and even 50 to 100 FTEs (1%). Only 25% of the
practices identify themselves as private independent and
17% as academic full-time practices. The largest group of
practices (35%) identify themselves as employed, and an
additional 14% are hospital-employed. The practices are
distributed across the United States, with 23.4% in the
South, 28.2% in the East, 33.1% in the Midwest, and
15.2% in the West (Fig. 1; unpublished data, T. Gilmore,
ASCO).
In general, most practices performed well, with an average
of 4.1 missed standards out of 20. Eight standards dem-
onstrated 100% concordance in the last round. In rounds 9,
10, and 11, the top six missed standards were qualifications,
chart documentation, double check in administration,
documentation for each visit, oral chemotherapy monitor-
ing, and patient education. The top six most commonly met
standards include both process and policy measures: con-
sent policy, double check of order, day of treatment as-
sessments, referrals, toxicity assessment available prior to
writing chemotherapy order, and cumulative dosing (un-
published data, T. Conti-Kalchik, ASCO).

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 WHY QOPI MATTERS: ITS NOT JUST ABOUT COST

TABLE 2. Differences in Scope and Reporting and a positive effect on practices. To understand the effect
Pathways for Classic QOPI and eQOPI on practices, a survey in 2013 was sent to 1,450 participants
at 850 practices to assess which measure modules/standards
Classic QOPI were selected by QOPI/QCP participants as the basis for local
191 Measures quality initiative efforts and to understand the nature of the
7 Modules (Existing) improvement initiatives.14
1 Module (New) Out of 89 respondents, 96% (85/89) reported that QOPI/
3 Palliative Care
QCP led to quality improvement efforts. Respondents were
asked to select module(s) that spurred subsequent quality
3 Reporting Pathways (New)
improvement activities: core measures (57%; 45), symptom/
3 QOPI Certification Program
toxicity management (48%; 38), end-of-life care (38%; 29),
3 PQRS Oncology Measures Group breast cancer (13%; 10), colorectal cancer (10%; 8), non-
3 Patient-Centered Oncology Practice Hodgkin lymphoma (6%; 5), and nonsmall cell lung cancer
eQOPI (4%; 3). Related to the QCP structural safety standards,
38 Measures participants reported quality improvement projects as fol-
6 Modules (Existing) lows: chemotherapy planning/chart documentation (39%;
2 Reporting Pathways (New) 31), general chemotherapy standards (30%; 24), monitoring
3 QOPI Certification Program and assessment (29%; 23), chemotherapy administration
(27%; 21), chemotherapy orders (23%; 18), staffing (16%;
3 Qualified Clinical Data Registry
13), and drug preparation (9%; 7).
Practices reported that QOPI measures improved in
ASCO continues to expand and improve the QCP program subsequent rounds as a result of specific projects (22/25;
by exploring medical liability insurance discounts and new 88%); 100% felt that these quality improvement projects
measures to respond to MACRA MIPS/APM requirements affected their practices for the better. Quality improvement
and a pilot program to allow international practices to apply project results were presented primarily in practice meet-
for QOPI certification for the first time in 2016. ings (74%; 26), hospital or community forums (17%; 6), ASCO
Quality Care Symposium, or other meetings (9%; 3). No
projects reached publication. Of note, 17 of 31 respondents
QOPI IN ACTION who reported practice status indicated achieving QOPI
QOPI and QCP have succeeded in spurring local quality certification. Specific quality improvement projects included
improvement efforts that have led to score improvements, building oral chemotherapy order sets and modified anti-
achievement of standards, increased discussion of quality, emetic regimens in chemotherapy protocols, improving

FIGURE 1. QOPI Certification Program Growth, December 2015

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e105

ANNE C. CHIANG
documentation of distress, pain, performance status, smoking
status and referrals, chemotherapy consent, and intent of
treatment. Practices also improved safety by initiating
semiannual review and gap analysis of adherence to ASCO/
ONS Chemotherapy Safety Standards, improving the medi-
cation reconciliation process, and training for oral chemotherapy.
ASCO continues to build quality improvement resources
and practical training, such as the Quality Training Program,
launched in 2013 as part of its Institute for Quality.15 The
Quality Training Program uses in-person training sessions
and coaching to teach quality improvement curriculum and
skills throughout an improvement project and to develop
quality leaders and champion quality improvement. Since
2013, 60 individuals have participated in this program
(unpublished data, E. Holton, ASCO).
A QUALITY IMPROVEMENT COMMUNITY
QOPI has served as a platform to create a quality community
in two published reports by the Michigan Oncology Quality
Consortium and the National Cancer Institute Community
Cancer Centers Program (NCCCP). In each case, a network of
diverse practices agreed to benchmark their aggregate QOPI
and collaborate on quality improvement initiatives to im-
prove quality of care and to identify best practices.16,17 The
NCCCP practices demonstrated a measurable increase in
each sites QOPI scores from fall 2010 to fall 2013, with the
exception of one parameter.
Another example illustrates how QOPI can be used to
achieve hospital integration of a network of community
practices. The Smilow Cancer Hospital provides cancer
services by Yale Cancer Center clinicians in New Haven,
Connecticut, or in one of nine Care Center community lo-
cations. Started in 2012 by the acquisition of community
practices, all Smilow Cancer Hospital Care Centers are fully
integrated practice sites using a provider-based model and
unified EMR baseline data across all centers. They created a
quality council to focus on clinical quality and patient safety
and to coordinate quality improvement activities. In spring
2012, 49% (217/445) of the patients at Smilow Cancer
Hospital Care Centers had documented emotional assess-
ments, with compliance in two sites below 12%. Distress
screening was implemented in these two clinics through a
Quality Training Program pilot by using quality improvement
tools and subsequently expanded in 2015 to 2016 to all
References
1. Centers for Disease Control and Prevention. Cancer. http://www.cdc.
gov/nchs/fastats/cancer.htm. Accessed February 10, 2016.
2. American Cancer Society. Economic Impact of Cancer. http://www.
cancer.org/cancer/cancerbasics/economic-impact-of-cancer. Accessed
February 10, 2016.
3. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care
in the United States: 2010-2020. J Natl Cancer Inst. 2011;103:117-128.
e106 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
ambulatory clinics throughout Smilow to comply with the
American College of Surgeons mandate for psychosocial
distress assessment.18 Other areas of noncompliance have
been identified and addressed. An oral chemotherapy ad-
herence program including specialty pharmacy and EMR
workflows was recently established and implemented
through all clinics (unpublished data, K. Adelson). QOPI
certification was achieved for the Smilow Cancer Hospital
network and continues to spur quality improvement pro-
jects (e.g., pain assessment and immunotherapy toxicity
education and management).
CONCLUSION
QOPI and QCP continue to be ASCOs signature quality
programs, with continuing growth in the number and extent
of participating practices. With the increasing emphasis on
value because of the rising costs of cancer care, it is essential
to have constant development and validation of quality
measures that reflect the changing nature of oncology (e.g.,
oral chemotherapy adherence, Choosing Wisely measures,
and response to the demands of MACRA). QOPI bench-
marking can be used to identify areas for improvement,
provide comparative metrics for quality improvement
projects, and build collaborative quality communities.
Widespread EMR adoption will allow eQOPI to help reduce
the time burden of abstraction, and delivery of the QOPI
quality assessments through CancerLinQ will take advantage
of the fully automated data abstraction capabilities of that
platform. QCP provides hands-on expert gap analysis as-
sessment of a practice and a road map toward quality
through ASCO certification status. The ASCO Institute for
Quality also offers the Quality Training Program to help train
and coach interdisciplinary teams in quality improvement
initiatives and develop leadership. In summary, ASCO has
multiple offerings as vehicles for diverse practices to join a
quality community working toward improving cancer care.
ACKNOWLEDGMENT
I would like to acknowledge ASCO staff members Terry
Gilmore, Tara Conti-Kalchik, Elaine Holton, Stephanie Crist,
and Robert S. Miller, MD, for their help in providing data and
in reviewing the manuscript. I would to acknowledge Joe
Jacobson, MD, for his help in reviewing the manuscript.
4. Centers for Medicare & Medicaid Services. Electronic Health Records
(EHR) Incentive Programs. https://www.cms.gov/Regulations-and-Guid-
ance/Legislation/EHRIncentivePrograms/index.html?redirect=/ehrincen-
tiveprograms. Accessed February 10, 2016.
5. U.S. Pharmacopeial Convention. USP Compounding Standards & Resources.
http://www.usp.org/usp-healthcare-professionals/compounding. Accessed
February 10, 2016.

6. American College of Surgeons. Cancer Program Standards (2016
Edition). https://www.facs.org/quality%20programs/cancer/coc/
standards. Accessed February 10, 2016.
7. Hahn J, Blom KB. H.R. 2: The Medicare Access and CHIP Reauthorization Act
of 2015. Congressional Research Service. http://democrats.waysandmeans.
house.gov/sites/democrats.waysandmeans.house.gov/files/documents/
CRS%20report%20on%20HR%202.pdf. Accessed February 10, 2016.
8. Centers for Medicare & Medicaid Services. Qualified Clinical Data
Registry Reporting. https://www.cms.gov/medicare/quality-initiatives-
patient-assessment-instruments/pqrs/qualified-clinical-data-registry-
reporting.html. Accessed February 10, 2016.
9. Neuss MN, Malin JL, Chan S, et al. Measuring the improving quality of
outpatient care in medical oncology practices in the United States. J Clin
Oncol. 2013;31:1471-1477.
10. ASCO Institute for Quality. QOPI Certification Standards. http://www.
instituteforquality.org/qopi/qopi-certification-standards. Accessed February
10, 2016.
11. Jacobson JO, Neuss MN, Hauser R. Measuring and improving value of care in
oncology practices: ASCO programs from Quality Oncology Practice Initiative
to the rapid learning system. Am Soc Clin Oncol Educ Book. 2012;e70-e76.
12. Shah A, Stewart AK, Kolacevski A, et al. Building a rapid learning health
care system for oncology: why CancerLinQ collects identifiable health
information to achieve its vision. J Clin Oncol. 2016;34:756-763.
WHY QOPI MATTERS: ITS NOT JUST ABOUT COST
13. Gilmore TR, Schulmeister L, Jacobson JO. Quality Oncology Practice
Initiative Certification Program: measuring implementation of che-
motherapy administration safety standards in the outpatient oncology
setting. J Oncol Pract. 2013;9(2 Suppl)14s-18s.
14. Chiang AC, McNiff K, Kadlubek P, et al. Assessment of quality im-
provement efforts by ASCOs Quality Oncology Practice Initiative
(QOPI) participants. J Clin Oncol. 2013;31:15s (suppl; abstr 55).
15. Kamal, AH, Quinn, D, Gilligan TD, et al. Feasibility and effectiveness of a
pilot program to facilitate quality improvement learning in oncology:
experience of the American Society of Clinical Oncology Quality Training
Program. J Oncol Pract. Epub 2015 Aug 18.
16. Blayney DW, Stella PJ, Ruane T, et al. Partnering with payers for success:
quality oncology practice initiative, blue cross blue shield of michigan,
and the michigan oncology quality consortium. J Oncol Pract. 2009;5:
281-284.
17. Siegel RD, Castro KM, Eisenstein J, et al. Quality improvement in the
national cancer institute community cancer centers program: the
quality oncology practice initiative experience. J Oncol Pract. 2015;11:
e247-e254.
18. Chiang AC, Buia Amport S, Corjulo D, et al. Incorporating patient-
reported outcomes to improve emotional distress screening and as-
sessment in an ambulatory oncology clinic. J Oncol Pract. 2015;11:
219-222.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e107
CARE DELIVERY AND PRACTICE MANAGEMENT

The Oncology Care Model: The

Man Behind the Curtain

CHAIR
Christian A. Thomas, MD
New England Cancer Specialists
Scarborough, ME

SPEAKERS
Jeffery C. Ward, MD
Swedish Cancer Institute Edmonds
Edmonds, WA

Ronald Michael Kline, MD

Center for Medicare & Medicaid Innovation
Washington, DC
 THE ONCOLOGY CARE MODEL: A CRITIQUE

The Oncology Care Model: A Critique

Christian A. Thomas, MD, and Jeffrey C. Ward, MD

OVERVIEW

Rapidly increasing national health care expenditures are a major area of concern as threats to the integrity of the health care
system. Significant increases in the cost of care for patients with cancer are driven by numerous factors, most importantly the
cost of hospital care and escalating pharmaceutical costs. The current fee-for-service system (FFS) has been identified as a
potential driver of the increasing cost of care, and multiple stakeholders are interested in replacing FFS with a system that
improves the quality of care while at the same time reducing cost. Several models have been piloted, including a Center for
Medicare & Medicaid Innovation (CMMI)sponsored medical home model (COME HOME) for patients with solid tumors
that was able to generate savings by integrating a phone triage system, pathways, and seamless patient care 7 days a week to
reduce overall cost of care, mostly by decreasing patient admissions to hospitals and referrals to emergency departments.
CMMI is now launching a new pilot model, the Oncology Care Model (OCM), which differs from COME HOME in several
important ways. It does not abolish FFS but provides an additional payment in 6-month increments for each patient on active
cancer treatment. It also allows practices to participate in savings if they can decrease the overall cost of care, to include all
chemotherapy and supportive care drugs, and fulfill certain quality metrics. A critical discussion of the proposed model,
which is scheduled to start in 2016, will be provided at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting
with practicing oncologists and a Centers for Medicare & Medicaid Services (CMS) representative.

N ational health care expenditures (HCEs) are a substantial

part of the national spending and currently account for
17.1% of the U.S. gross domestic product, significantly more
than other developed countries, which typically spend be-
tween 8% and 12% of their gross domestic product on health
care. Despite high spending, several important health out-
comes measuresfor example, infant mortalitydo not re-
flect the current level of health care spending, supporting the
notion that there is a disconnect between money spent and
the quality of care produced by the system. When national
health care systems are compared according to country, the
United States currently ranks 54th when factors such as effi-
ciency, life expectancy, and health care cost are considered.1
A major concern is the significant growth rate of HCEs that
outpace other national financial benchmarks and continue
to rise at annual levels of greater than 5%. The inflation of
health carerelated expenditures is mainly driven by two
major factors: hospital-related expenditures and drug prices.
U.S. expenditures on pharmaceuticals are more than twice
that of any other member country of the Organisation for
Economic Cooperation and Development.2
Almost no other area of medicine is affected more by the
steep increase in the cost of pharmaceuticals than cancer
care where drug prices can easily top $10,000 per month per
patient.3
There is broad consensus that this trend is not sustainable
at the current rate. Private and public stakeholders are
discussing mechanisms to curb spending while at the same
time maintaining high-quality care. Because physician be-
havior can be influenced by financial incentives,4 it has been
postulated that tying payment directly to the quantity of
performed services, the backbone of the FFS system, in-
centivizes physicians to perform more services to improve
financial gain. The flipside of the argument is the Health
Maintenance Organization experience of the early 1990s
where FFS was replaced by a fixed monthly payment for each
patient but not tied to patient encounters or specific ser-
vices. This led to inadequate access to care with poor patient
care and satisfaction.
So how is a rational system of providing the right health
care to the right patient at the right time to be designed?
If FFS is abandoned for an improved way to deliver and pay
for health care, the following elements have to be met:
1. A payment system that adequately covers the true
cost of carethe current Medicare fee schedule is
underfunding the cost of care by 20% to 30%, forcing
providers to use other resources to cover the cost of
care for Medicare beneficiaries such as increasing their
fees for private payers;

From the New England Cancer Specialists, Scarborough, ME; Swedish Cancer Institute, Edmonds, WA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Christian A. Thomas, MD, New England Cancer Specialists, 100 Campus Dr., Suite 108, Scarborough, ME 04074; email: thomac@newecs.org.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e109

THOMAS AND WARD
2. A system that allows providers and their staff to care
for patients in a variety of ways including phone calls,
emails, and other forms of contact in addition to
traditional face-to-face encounters;
3. A system that allows easy and unrestricted access for
patients;
4. A system that ties successful adherence to nationally
accepted quality standards and patient satisfaction
directly to physician reimbursement;
5. A system that provides a mechanism for controlling
the cost for drug and hospital spending.
THE ONCOLOGY CARE MODEL
Federal legislation now mandates CMS to fund alternate
payment models to deliver health care, and CMS has es-
tablished the Center for Medicare & Medicaid Innovation
(CMMI) to explore options. From 2013 to 2015, a $20 million
grant was provided to 12 medical oncology practices for
the COME HOME project, which used three novel mecha-
nisms to control the cost of care for patients with common
cancers:
1. The systematic use of a phone triage system to de-
termine the acuity of a patients complaint and offer
them one of three options: advise over phone for
minor complaints, a same-day appointment in the
medical oncology office for more urgent issues, or a
direct referral to the nearest emergency department
for the sickest patients;
2. Extended office hours on evenings and weekends so
that patients requiring an assessment or office services
such as antiemetics, hydration, antibiotics, or other
injections would not have to visit a hospital or emer-
gency department;
3. The use of treatment pathways that were created by
the participating practices to create predictable, cost-
effective, but high-quality care.
Although savings varied geographically, as a whole
participating COME HOME practices were able to show
substantial savings with lower costs largely attributable
to avoiding costly hospital admissions and emergency
KEY POINTS
The rapidly increasing cost of health care threatens to
destabilize the health care system.
New systems are needed, and CMS has proposed a new
pilot model, the Oncology Care Model, that provides
payments to practices in addition to the traditional FFS if
practices can decrease overall cost of care and fulfill
quality criteria.
This article and its corresponding Education Session at
the 2016 ASCO Annual Meeting are aimed at providing
a critical overview of the model by practicing
physicians and a CMS representative.
e110 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
department referrals for patients who could be ade-
quately cared for in the office.5 This example of increasing
the value of care by reducing cost while at the same time
improving the quality of care and leading to higher patient
satisfaction is an encouraging example of positive health
care reform.
Unfortunately, CMMI decided to discontinue further fund-
ing for COME HOME and has presented a new model aimed
at reducing cost of care for medical oncology patients while
at the same time attempting to improve the quality of care,
the Oncology Care Model (OCM). This model uses two types
of additional payments in addition to the usual FFS pay-
ments and other payments, for example, for chemotherapy
administration: a performance-based incentive as well as
bundled monthly payments for patients undergoing che-
motherapy. In exchange, oncology practices are obligated to
establish systems aimed at providing a higher level of care
with additional reporting requirements to CMMI. As detailed
further below, practices will receive an additional payment
of $160 per beneficiary per month (the bundle) for any 6-
month period during which a patient is undergoing active
chemotherapy treatment in a medical oncology practice.
In return, practices agree to strict reporting and quality
standards:
Provide patient navigation;
Document a care plan that contains the 13 components
as outlined by the Institute of Medicine;
Provide 24-hour-a-day, 7-day-a-week patient access to
an appropriate clinician who has real-time access to the
practices medical records;
Treat patients with therapies consistent with nationally
recognized clinical guidelines;
Use data to drive continuous quality improvement;
Use an ONC-certified electronic health record and attest
to stage 2 of meaningful use by the end of the third
model performance year.
In addition, private payers were invited to apply, extending
the potential reach of the project to patients not covered
by CMS.
The OCM is often characterized as an episode-of-care or
bundled reimbursement model but is in reality a FFS and
shared savings model. The shared savings are predicated
on a calculated bundle, but the reimbursement application
would more honestly be called an Oncology Accountable
Care Organization.
There are theoretical advantages to a true bundle for both
payers and providers. The payers costs are predictable for
an individual patient for a set period time and the economic
incentive toward high-cost, high-quantity care, inherent in
FFS medicine, is replaced by physician accountability for
costs and quality they can control. The provider has freedom
from payer micromanagement and, ideally, adequate and
predictable payments. Then, released from the constraints
of practicing to billing codes, practices have the flexibility
necessary to seek high-quality care with fewer resources
through innovative care redesign. But the key to these

advantages is that the bundle has replaced FFS reimburse-
ment.6 Unfortunately, OCM fails to do that.
The Accountable Care Organization model has yet to
deliver on its promise of high-quality, low-cost care,7 per-
haps because simply adding incentives to decrease costs on
top of the existing payment system that incents increased
costs does not solve the problem. At the best, it requires a
very complicated balancing act of incentives and quality
accountability. At its worst, it is the hope that two wrongs
make a right. Skeptics might suggest that participants,
constrained by continued dependence on FFS reimburse-
ment from capitalizing on a redesign of the way they deliver
services, will be best served financially by collecting their FFS
billings and management fee, go through the motions of
CMS dictates, but avoid real innovative efforts and hope that
health care inflation and a bit of luck will result in some
additional booty.
LOGISTICAL HURDLES OF THE ONCOLOGY CARE
MODEL BUNDLE
However, it is the bundle construct that makes OCM both
novel and controversial. Additionally, because one can easily
envision that the CMMI pilot model is the precursor of a real
bundled reimbursement model, it requires careful scrutiny.
The OCM takes a simple approachall spending on all care
provided to the patient with a particular cancer is in a bundle
that starts with the initiation of chemotherapy and lasts for
6 months. This construct has raised a number of concerns.
The OCM bundle reimbursement is constructed based on
an individual practices historical costs when available and
on regional or national data adjusted for geographic vari-
ation when historical costs are not available. The focus on
competing against your own data guarantees that over time
opportunities for new cost sharing diminishes. Although
CMMI may not choose to ratchet down the reimbursement
for a bundle during the pilot model, the history of Medicares
oldest bundle, dialysis reimbursement, strongly suggests
that is exactly what will happen.
The choice of 6 months is arbitrary. In other specialties,
CMS and commercial payers have defined an episode of
care to be a full course of treatment of a specified treat-
ment. In this scenario, adjuvant concurrent fluorouracil
(5-FU) and radiation for rectal cancer is a shorter episode and
FOLFOX (folinic acid, 5-FU, and oxaliplatin) for colon cancer
is a longer episode. In the OCM model, the first patient is
paid a 6-month bundle for 5 weeks of treatment and the
second patient is paid the same bundle for 24 weeks of
therapy. Unless, of course, the second patient has some
delays in treatment, then the practice may be paid two
6-month bundles for 27 weeks of therapy. A study com-
missioned by CMS and performed by the RAND Corporation
demonstrated that gaps of this sort in courses of the same
therapy are common. One can envision that the longer the
bundle the greater the variation of practice costs within a
bundle and greater the opportunity for selection bias, either
intentionally or inadvertently. Critiques have suggested a
THE ONCOLOGY CARE MODEL: A CRITIQUE
sequence of shorter repeating bundles. ASCO has put
forward a monthly bundle in its own payment reform
proposal.8
The all-inclusive nature of the bundle has also been
controversial. Conceptually, the aim of a bundle is to transfer
risks associated with high levels of spending from payers to
the providers doing the spending. Presumably, the provider
then decreases the spending. However, within an all-
inclusive bundle, there is spending, or risks, that the pro-
vider can control and risks that he cannot. Economists refer
to these two categories of financial risk as technical risk and
probability risk.
Technical risk is a function of the practices clinical skill and
efficiency in managing the diagnosis and treatment or other
aspects of care that are under the physicians control and
that he is able to impact either by controlling utilization or
cost, preferably both. Probability risks are random or un-
predictable events that we classically buy insurance to
mitigate. In theory, a bundle should only include technical
risks and the probability risks should remain with the payer.
Practically, this can be very difficult.
When ASCOs payment reform work group attempted to
split patient care into oncology related versus other medical
care, it quickly became apparent that adjudicating which CPT
and ICD-10 codes should be attributed to the oncologist
was simply impractical. Furthermore, several pilot projects
have now demonstrated that medical oncology homes
can dramatically lower emergency department and hospital
costs,9-11 broadly indicating that there is substantial tech-
nical risk within patient care. CMS has indicated that the
probability risk that does exista patient with higher than
average comorbidities or the patient who is in an auto-
mobile accident on the way to their chemotherapy ap-
pointment, for examplecan be mitigated through risk
adjustments based on patient and service characteristics
in the first example and through reinsurance or stop-loss
provisions in the latter case. Of course, the most important
mitigation of risk in the pilot model is the provision of one-
sided risk, clearly a carrot that will ultimately be replaced
with a stick.
THE ECONOMICS OF DRUGS IN A BUNDLE
The RAND Corporation estimated that 25% to 40% of the
OCM bundle is chemotherapy and supportive care drugs.12
Among key opinion leaders and policymakers, the inclusion
of drugs in the oncology bundle seems a foregone conclu-
sion. It is assumed that (1) physicians, not patients, control
demand; (2) practices generate substantial revenue from
drugs via the buy-and-bill system; (3) if oncologists are at
financial risk for the drugs, they will choose the least costly
regimens when efficacies are similar; and (4) because on-
cologists will become more price sensitive, they will seek out
better prices through negotiations with manufacturers
and group purchasing organizations. Although theoretically
compelling, there is reason to question the practical validity
of these claims.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e111
THOMAS AND WARD
If drugs are to be appropriately included in a bundle,
analysis should conclude that drug spending is a technical
risk. Empirical evidence of this is limited. One often-cited
example of drugs being a technical risk is the Zaltrap story.13
Zaltrap was launched in 2012 at twice the price of Avastin, a
drug with similar outcomes. Physicians at Memorial Sloan
Kettering Cancer Center announced in a New York Times
Op-Ed piece that they would not prescribe Zaltrap, and its
price was reduced by 50%. Although this may have em-
boldened oncologists who have increasingly decried high-
priced drugs, the average monthly launch prices of cancer
drugs since then suggest that the pharmaceutical industry
has been unfazed.
Another expectation if drugs are a technical risk is that
practices should have leverage over the acquisition prices of
pharmaceuticals. Although there are examples of volume
discounts for large purchasers and group purchasing orga-
nizations, this applies only to generic medications and the
infrequent circumstance in which there are multiple infus-
able competitors with similar efficacy within a therapeutic
class. Oncology practices have no control over the price of
novel agents, and oral drug prices are negotiated by payers.
For these reasons, the prices of new cancer drugs, those that
drive costs the most, should be considered a probability risk.
Proponents of drugs in the bundle will argue that the
inability to control price is outweighed by the oncologists
ability to impact utilization. They argue that the 20% to 30%
of annual spending on off-label drugs represents tremen-
dous waste in the system, driven by FFS medicine and buy-
and-bill drug reimbursement. The evidence for this is sparse.
Brooks et al14 reported in an analysis of FFS Medicare data
that only 10% of regional variation in spending was a result of
drug choice, and that drug costs were only 16% of the total
spend. This was dwarfed by the 67% of regional spending
variation related to acute hospital care, accounting for 48%
of the total spend.
A real-life example of the principles of probability and
technical risks as they pertain to oncology may be found in
the recently reported United Health Care (UHC) dem-
onstration project. Margins on drugs were replaced by a
management fee to remove profit via drug choice, and
practices were incentivized to decrease hospital and
emergency department services through shared savings
and a bundling of inpatient evaluation and management
services. Drug costs increased, but the demonstration was
determined a success because of impressive decreases in
acute-care costs.9 One interpretation of these data is that
the probability risks (drug costs) could not be controlled, but
the technical risks associated with hospital and emergency
department services were.
MANAGING A BUNDLE ON DRUGS
The risks of a bundle are dependent on its variability. There
are three ways to manage the variable risk. One way is
to define bundles with enough granularity to minimize
the variability between patients and their associated costs.
e112 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Today, that means developing bundles based on the genetic
profiles of cancers. In a fairly short time, nonsmall cell lung
cancer has evolved from one monolithic cancer and four
equally efficacious treatment regimens to at least four
different cancers with very different therapies and associ-
ated personalized costs. Unfortunately, it would be naive to
assume that any payment system will be able to keep up with
the personalized medicine revolution. It is little wonder that
UHC and The University of Texas MD Anderson Cancer
Center have chosen head and neck cancer as their first
effort at a bundled payment contract. It is a disease for
which drug therapy and treatment options are limited.
Even then, they have eight distinct treatment/payment
bundles.15 Due to the impracticality of managing granular
bundles, it is anticipated that the OCM bundles will be
fairly generic buckets.
In that circumstance, the other way to manage the risk
of the bundle will be for practices to get big. Large volumes
of patients can then mitigate the risks associated with any
one individual. This would be expected to further the con-
solidation of oncology into larger groups through mergers,
acquisitions, and affiliations both in independent and hospital-
based practices. This may prove acceptable to health policy
makers but could have important unintended consequences;
there is very limited evidence that consolidation improves
either quality or access to care.
The third way to mitigate the risk of drugs in the bundle is
to move beyond efficiency in drug choice and utilization to
the realm of stenting on care. OCM promises to monitor
quality of care and to hold practices accountable for it, but
the task is not a simple one. It is hypocritical to believe that
buy-and-bill drives overutilization and to ignore the in-
centive to underuse inherent in drugs in a bundle.
THE ALTERNATIVE: PATHWAYS
An alternative to drugs in the bundle, one that may still
assure payers that drugs are being used appropriately, are
value-based treatment pathways.16 Evidence-based with
the purpose of improving value, quality, and safety, path-
ways have been shown to reduce variance in drug regimens,
doses, schedules, and treatment duration. Several studies
have shown savings with the utilization of what must be
considered rudimentary pathways and less than stellar path-
way compliance.17,18 One project reduced the 12-month
average costs for chemotherapy and supportive care drugs
for patients with lung cancer by 37% or $9,747.18
Another advantage to pathways over bundles is that,
as opposed to bundles developed by payers, pathways can
be developed by oncologists through transparent, peer-
reviewed, committee-selected regimens that incorporate
efficacy, toxicity, and cost considerations. ASCO recently
published a policy statement providing direction and rec-
ommendations regarding the development and utilization of
pathways in clinical practice.19 As pathway development ma-
tures, they will incorporate more sophisticated value models
that will account not only for drug costs but also the total

costs of a treatment regimen to include toxicity, ancillary
support services, acute care, and patient productivity loss.
ONCOLOGY CARE MODEL II: A PATHWAY/BUNDLE
HYBRID
Criticisms of OCMs reliance on competition against oneself,
an arbitrary 6-month episode, and fuzzy details on estab-
lishing limits on financial risk are details that can most cer-
tainly be overcome if CMMI is introspective in its evaluation
and willing to make incremental improvements.
However, the model has two Achilles heels that it must
consider if OCM is to become a win-win-win for patients,
providers, and payers. First, it must divorce itself from the
reliance on FFS as its backbone of reimbursement. Only then
can it align incentives with innovative solutions that can
produce both high-quality and efficient cancer care.
Then it must consider that drugs in a bundle may mitigate
cost and variability for payers, but this is only accomplished
by putting patients and practices at unacceptable risks.
Bundled drugs are structured to require the doctor to run a
gauntlet between rational care and rationed care through
the use of hidden incentives. Pathways, alternatively, use
transparency, consensus, and evidence-based practice
benchmarks to assist the doctor.
OCM II should not wait 7 years for completion of the
current OCM pilot model. It should be a hybrid model that
References
1. Chen S, Wong S. Singapore Beats Hong Kong in Health Efficiency:
Southeast Asia. http://www.bloomberg.com/visual-data/best-and-
worst/most-efficient-health-care-2014-countries. Accessed March
29, 2016.
2. Organisation for Economic Cooperation and Development. OECD
Health Statistics 2014. How Does the United States Compare? http://
www.oecd.org/unitedstates/Briefing-Note-UNITED-STATES-2014.pdf.
Accessed March 29, 2016.
3. Light DW, Kantarjian H. Market spiral pricing of cancer drugs. Cancer.
2013;119:3900-3902.
4. Lungren MP, Amrhein TJ, Paxton BE, et al. Physician self-referral:
frequency of negative findings at MR imaging of the knee as a marker
of appropriate utilization. Radiology. 2013;269:810-815.
5. Burns J. COME HOME Program Set to Save $33.5M Over 3 Years. http://
www.onclive.com/publications/oncology-business-news/2014/August-
2014/COME-HOME-Program-Set-to-Save-335M-Over-3-Years. Accessed
March 29, 2016.
6. American Medical Association. Center for Healthcare Quality and
Payment Reform: A Guide to Physician Focused Alternative Payment
Models. http://www.chqpr.org/downloads/Physician-FocusedAlternative
PaymentModels.pdf?utm_source=Distribute+Physician-Focused+APM+
Report&utm_campaign=Bundling+Badly&utm_medium=email. Accessed
March 29, 2016.
7. Burns LR, Pauly MV. Accountable care organizations may have difficulty
avoiding the failures of integrated delivery networks of the 1990s.
Health Aff (Millwood). 2012;31:2407-2416. Accessed March 29, 2016.
8. American Society of Clinical Oncology. Patient-Centered Oncology
Payment. Payment Reform to Support Higher Quality, More Affordable
THE ONCOLOGY CARE MODEL: A CRITIQUE
brings together a true bundle without FFS to reimburse the
care that an attentive and skilled physician can control and a
robust pathways program that will negate a perceived need
to change the way we pay for drugs.
ASCO is to be commended to convene an Education
Session at its 2016 Annual Meeting during which CMMI will
be able to present its model and have an open discussion
with oncology practice representatives from various back-
grounds about the models feasibility. It is clear that any
practices participating in the CMS model will have to in-
stitute significant structural changes to fulfill these criteria
and only the future will tell if the investment of time and
resources will benefit patients while at the same time
bending the cost curve for oncology. In reality, the model is
not designed to achieve at least the second goal, reducing
the cost of care. This is because the main drivers of ex-
pensive care are not addressed in the model (i.e., the cost
of hospital care and the ever-increasing cost of cancer
drugs). In addition, other expensive cost centers for patients
with cancer such as biopsies, surgical procedures, or ra-
diation therapy are also not part of the model, making it
impossible for medical oncology practices to affect the
overall cost of care.
Unless CMS addresses all price centers contributing to the
escalating cost of cancer care, its reforms will fail to make
good on their promise.
Cancer Care. http://www.chqpr.org/downloads/ASCO_Patient-centered_
Oncology_Payment.pdf. Accessed March 29, 2016.
9. Newcomer LN, Gould B, Page RD, et al. Changing physician incentives for
affordable, quality cancer care: results of an episode payment model.
J Oncol Pract. 2014;10:322-326.
10. Association for Value-Based Cancer Care. Value-Based Cancer Care:
Oncology Medical Home Shows Significant Cost-Savings, Improved
Care Delivery. http://www.valuebasedcancer.com/vbcc-issues/2015/
december-2015-vol-6-no-11/26472-oncology-medical-home-shows-
significant-cost-savings-improved-care-delivery. Accessed March 29,
2016.
11. Sprandio JD. Oncology patient-centered medical home. J Oncol Pract.
2012;8:47s-49s (suppl 3).
12. CMS Alliance to Modernized Healthcare. Specialty Payment Model
Opportunities and Assessment: Oncology Design Report. Santa Monica,
CA: RAND Corporation; 2014.
13. Conti RM, Berndt ER. Winners and losers of the Zaltrap price discount.
Health Affairs weblog. February 22, 2013. http://healthaffairs.org/blog/
2013/02/20/winners-and-losers-from-the-zaltrap-price-discount-
unintended-consequences/. Accessed March 29, 2016.
14. Brooks GA, Li L, Uno H, et al. Acute hospital care is the chief driver of
regional spending variation in Medicare patients with advanced cancer.
Health Aff (Millwood). 2014;33:1793-1800.
15. The University of Texas MD Anderson Cancer Center. MD Anderson,
UnitedHealthcare Launch New Cancer Care Payment Model. MD
Anderson News Release December 16, 2014. http://www.mdanderson.
org/newsroom/news-releases/2014/md-anderson-unitedhealthcare-
new-cancer-payment.html. Accessed March 29, 2016.
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16. Conti R, Ward JC, Page R, et al. A pathway through the bundle jungle.
J Oncol Pract. In press.
17. Kreys ED, Koeller JM. Documenting the benefits and cost savings of a
large multistate cancer pathway program from a payers perspective.
J Oncol Pract. 2013;9:e241-e247.
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18. Neubauer MA, Hoverman JR, Kolodziej M, et al. Cost effectiveness of
evidence-based treatment guidelines for the treatment of non-small-
cell lung cancer in the community setting. J Oncol Pract. 2010;6:12-18.
19. Zon RT, Frame JN, Neuss MN, et al. American Society of Clinical Oncology Policy
Statement on Clinical Pathways in Oncology. J Oncol Pract. 2016;12:261-266.
CENTRAL NERVOUS SYSTEM TUMORS

Multidisciplinary Management of
Brain Metastases

CHAIR
Manmeet S. Ahluwalia, MD
Cleveland Clinic
Cleveland, OH

SPEAKERS
Anna S. Berghoff, MD, PhD
University of Vienna
Vienna, Austria

Jeffrey Scott Wefel, PhD

The University of Texas MD Anderson Cancer Center
Houston, TX

Morris D. Groves, MD
Texas Oncology/The US Oncology Network
Austin, TX

Paul D. Brown, MD
The University of Texas MD Anderson Cancer Center
Houston, TX

Riccardo Soffietti, MD
University and San Giovanni Battista Hospital
Torino, Italy
BERGHOFF ET AL

Immune Checkpoint Inhibitors in Brain Metastases: From

Biology to Treatment
Anna S. Berghoff, MD, PhD, Vyshak A. Venur, MBBS, Matthias Preusser, MD, and
Manmeet S. Ahluwalia, MD

OVERVIEW

Cancer immunotherapy has been a subject of intense research over the last several years, leading to new approaches for
modulation of the immune system to treat malignancies. Immune checkpoint inhibitors (antiCLTA-4 antibodies and
antiPD-1/PD-L1 antibodies) potentiate the hosts own antitumor immune response. These immune checkpoint inhibitors
have shown impressive clinical efficacy in advanced melanoma, metastatic kidney cancer, and metastatic nonsmall cell lung
cancer (NSCLC)all malignancies that frequently cause brain metastases. The immune response in the brain is highly
regulated, challenging the treatment of brain metastases with immune-modulatory therapies. The immune microenvi-
ronment in brain metastases is active with a high density of tumor-infiltrating lymphocytes in certain patients and, therefore,
may serve as a potential treatment target. However, clinical data of the efficacy of immune checkpoint inhibitors in brain
metastases compared with extracranial metastases are limited, as most clinical trials with these new agents excluded
patients with active brain metastases. In this article, we review the current scientific evidence of brain metastases biology
with specific emphasis on inflammatory tumor microenvironment and the evolving state of clinical application of immune
checkpoint inhibitors for patients with brain metastases.

B rain metastases are a long-known devastating compli-

cation of advanced malignancies that lead to substantial
morbidity. As patients with metastatic cancer are expected
to live longer with newer systemic therapeutic agents and
with better and more sensitive imaging studies, it is expected
that more patients will be diagnosed with brain metastases. In
the past, traditional treatment approaches included surgery
or radiation therapy, or a combination of the two. Chemo-
therapeutic agents were generally used for refractory disease.
However, in the last few years, several treatment advances in
targeted therapy and immunotherapy have changed the land-
scape of the management of brain metastases. Recently, the
American Society of Clinical Oncology (ASCO) announced cancer
immunotherapy as the advance of the year,1 and its role in
the management of brain metastases is undergoing active
investigation. There has been a paucity of research focused on
brain metastases; as a result, there are several unanswered
questions. In this article, we present the available evidence
regarding the interactions between the immune system and
brain parenchyma in brain metastases, the clinical application
of immune checkpoint inhibitors in the management of brain
metastases, and the potential of combining radiation with
immune checkpoint inhibitors.
THE INFLAMMATORY MICROENVIRONMENT OF
BRAIN METASTASES
Immune responses in the brain parenchyma are tightly reg-
ulated to prevent overwhelming and potentially destroying
immune reactions in this organ, which has little recovery
capacity.2 Importantly, the brain parenchyma is not an im-
mune privileged organ that actively suppresses any immune
response, but, rather, it initiates and regulates immune
responses. Therefore, targeting the inflammatory tumor
microenvironment of brain metastases as a therapeutic
target must consider several unique factors compared with
the inflammatory tumor microenvironment of extracranial
malignancies.3
Immune escape is an emerging hallmark of cancer.4 A brain
metastasisinitiating cell has to facilitate the process of
immune escape several times, first during initiation of the
primary tumor, then during travel through the bloodstream,
and, finally, during the extravasation and metastatic out-
growth process within the brain parenchyma. The process of
metastatic spread may actually be supported by the immune
system, as tumor-associated macrophages were shown to
facilitate intravasation as well as extravasation from the
vascular system.5,6 Further, cytokines promote site-specific

From the German Cancer Research Center, University of Heidelberg, Heidelberg, Germany; Department of Medicine I, Medical University of Vienna, Vienna, Austria; Comprehensive
Cancer Center Vienna CNS Unit, Vienna, Austria; Division of Hematology and Oncology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA; Burkhardt
Brain Tumor and Neuro-Oncology Center, Neurologic Institute, Cleveland Clinic, Cleveland, OH; Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Manmeet S. Ahluwalia, MD, Cleveland Clinic, 9500 Euclid Ave., S73, Cleveland, OH 44195; email: ahluwam@ccf.org.

2016 by American Society of Clinical Oncology.

e116 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


metastatic behavior as the chemokine pair CXCR4/CXCL12
was shown to promote adhesion of the brain metastasis
initiating cells to brain vessels and further facilitated the
migration through endothelial cells.7,8
In established brain macrometastases, the inflammatory
tumor microenvironment is composed of the innate
immune system, namely microglia and blood-derived myeloid
cells/macrophages, and the adaptive immune system, which
is mainly represented by T cells.9
The density of microglia in and around human and in vivo
brain metastases were shown to be highly heterogeneous.10,11
Importantly, the differences in microglia accumulation were
observed early during the process of extravasation in pre-
clinical models, indicating that microglia may be involved in
the process of extravasation and survival in the perivascular
niche.11 The functions of microglia within the brain metastasis
tumor microenvironment include antigen presentation, cyto-
toxicity via expression of nitric oxide (NO) and superoxide, and
phagocytic function.12 Expression of HMGB1 by microglia
cells, a factor involved in antigen presentation and activation
of the adaptive immune system, was widely observed, indi-
cating that in general the tumor microenvironment is able to
alter an adaptive immune response. However, microglia and
macrophages were also shown to express immunosuppres-
sive factors like PD-L1.13
Infiltration with T cells or tumor-infiltrating T-lymphocytes
(TILs) was shown to be highly heterogeneous, varying from
total absence to very dense infiltration.10,14 Therefore, the
inflammatory microenvironment of brain metastases differs
between patients, showing active tumor-directed function
in some, but not all, cases. Here, expression of the immune
suppressive factor PD-L1 could be one mechanism whereby
cancer cells facilitate an immune escape. PD-L1 tends to
have higher expression in NSCLC-derived brain metastases
KEY POINTS
The inflammatory tumor microenvironment of brain
metastases differs from extracranial metastases, as the
brain is a highly regulated organ in terms of immune
response, and is active in the majority of cases with
dense infiltration of tumor-infiltrating lymphocytes.
The blood-brain barrier presents different challenges
and unique opportunities for the treatment of patients
with brain metastases.
Immune checkpoint inhibitors have shown intracranial
activity in early clinical trials for patients with brain
metastases from melanoma and nonsmall cell lung
cancer.
Several retrospective case series suggest immune
checkpoint inhibitors can be safely combined with
radiation therapies.
As the prevalence of brain metastases increases,
concerted research in this field of limited knowledge is
of essence. Meanwhile, a multidisciplinary approach for
the management of brain metastases is recommended.
IMMUNE CHECKPOINT INHIBITIORS IN BRAIN METASTASES
compared with the matched primary tumor.15 Further, the
composition of TIL subtypes differs. Infiltration with immune
suppressive FOXP3+ TILs, as well as so-called exhausted
PD-1+ TILs, has been observed in a large portion of speci-
mens.14 Characteristics of the primary tumor probably in-
fluence the T cell response in brain metastases, as a denser
TIL infiltration was observed in melanoma-derived brain
metastases compared with those that are derived from
breast cancer.14 Importantly, patients with brain metas-
tases who present with dense infiltration with effector
CD3+, cytotoxic CD8+, or memory CD45RO+ TILs had an
improved survival prognosis from diagnosis compared
with patients with little or absent infiltration of TILs.14 This
finding is well in line with the effect of the inflammatory
tumor microenvironment on survival prognosis in extra-
cranial malignancies, as high density of TILs is associated
with improved survival prognosis in various malignancies
that frequently cause brain metastases, such as triple-negative
breast cancer, NSCLC, or melanoma.16-18
Importantly, patients with extracranial metastatic mela-
noma and an active inflammatory tumor microenvironment,
as defined by dense infiltration with TILs, have shown in-
creased response rates to CTLA-4 immune checkpoint in-
hibitors.19 Further, expression of PD-L1 on tumor cells may
be associated with a higher chance of response to a PD-
1axis modulating immune checkpoint inhibitor.20 There-
fore, the potential tumor microenvironment preconditions
for response to an immune checkpoint inhibitor are present
in brain metastases, underscoring the importance of further
clinical investigation of immune checkpointbased therapy
strategies in patients with brain metastases.
The inflammatory microenvironment is further influenced
by the vascular properties in the brain parenchyma. The
blood-brain barrier is composed of endothelial cells with
tight junctions and astrocytes. Here, astrocytes are known
to facilitate pro-inflammatory as well as anti-inflammatory
aspects.21 However, data of the interaction of astrocytes
and TILs in the inflammatory microenvironment of brain
metastases is yet not available. Further, the vascular endo-
thelium regulates the infiltration of T cells. Presence of so-
called high endothelial venules, which are specialized blood
vessels for lymphocyte extravasation, in melanoma spec-
imens were shown to be associated with dense infiltration
of TILs.22 Although neovascularization is a characteristic of
brain metastases, with differing extent between primary
tumor types, no functional studies have yet investigated the
interaction of the blood-tumor barrier or the blood-brain
barrier in the infiltration zone of a brain metastasis con-
cerning their restriction of T-cell infiltration.
CLINICAL EFFICACY OF IMMUNE THERAPY IN
CANCER
The clinical utility of immune-based therapies in the fight
against cancer has been a fascinating story with ebb and
flow. Historically, melanoma and kidney cancer were the two
major malignancies that were thought to be susceptible to
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e117
BERGHOFF ET AL
immune modulation. Indeed, melanoma has high muta-
tional burden, with production of several neoantigens,
making it an ideal candidate for immunotherapy. Interleukin
(IL)-2 was one of the first immunotherapeutic agents to be
used in melanoma. IL-2 is a cytokine that is produced by
human T-lymphocytes and plays a pivotal role in expansion
and activation of T cells.23 In the 1990s, high-dose IL-2 was
studied in advanced melanoma and renal cell carcinomas
with modest success.24 An extracranial complete response
rate of 5% was seen, and some patients experienced sub-
stantial adverse effects, including death.24 Two single in-
stitution retrospective experiences have shown intracranial
activity of IL-2; however, because of concerns of vascular
leak syndrome and potential life-threatening thrombocy-
topenia, prospective studies excluded patients with brain
metastases.25,26
AntiCTLA-4 Antibody: Ipilimumab
With the advent of immune checkpoint inhibitors, immu-
notherapy has made substantial inroads in the management
of advanced malignancies. Ipilimumab is a fully human
monoclonal antibody against CTLA-4, which plays a pivotal
role in downregulating the production of cytotoxic T cells.27
The intracranial activity of ipilimumab was first noted in the
post hoc analysis of a phase III trial of ipilimumab with or
without gp100 peptide vaccine compared with gp100 vac-
cine alone.28 This double-blinded randomized trial included
82 patients with asymptomatic central nervous system (CNS)
metastases, of whom, 73 had received prior treatment for
CNS metastases. Ipilimumab was administered to 61 of the
82 patients; 46 patients also received gp100 and 15 received
ipilimumab alone. The hazard ratio (HR) for death in patients
with brain metastases was 0.70 (95% CI, 0.411.20) in the
ipilimumab plus vaccine group compared with 0.76 (95% CI,
0.381.54) in the ipilimumab alone group. This led to a
single-agent, open-label phase II study of ipilimumab for
patients with melanoma-derived brain metastases.29 Ipili-
mumab was administered at a dose of 10 mg/kg given every
3 weeks as a 12-week induction phase, followed by main-
tenance therapy every 12 weeks. A total of 72 patients were
enrolled across 10 centers in the United States.30 The trials
comprised of two cohorts: cohort A included 51 asymp-
tomatic patients with active brain metastases who were not
on corticosteroids, and cohort B included 21 patients with
symptomatic melanoma-derived brain metastases taking a
corticosteroid. A response rate of 18% (nine out of 51 pa-
tients) in cohort A and 5% (one out of 21 patients) in cohort B
were reported using modified World Health Organization
(WHO) criteria, but, when immune-related response criteria
were used, the response rate improved to 25% (13 patients)
and 10% (two patients) in cohorts A and B, respectively. The
median overall survival (OS) was 7.0 months in cohort A and
3.7 months in cohort B. Ipilimumab was well tolerated and
no unexpected adverse events were noted. Fatigue, nausea,
vomiting, diarrhea, and rash were the common side effects
noted in the study. As a part of the expanded access program,
e118 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
CA 184-045, 165 patients with stable brain metastases were
treated with 10 mg/kg of ipilimumab. The preliminary results
from this study reported a 1-year OS rate of 20%, similar to that
reported in the open-label, phase II study.31
Another open-label, single-arm, phase II trial evaluated the
combination of ipilimumab and fotemustine in advanced
metastatic melanoma with and without brain metastases
(NIBIT-M1).32 This Italian study enrolled a total of 83 pa-
tients; 20 of whom had asymptomatic brain metastases.
Eleven of the 20 patients completed the induction phase
of ipilimumab (four doses of 10 mg/kg every 3 weeks).
Immune-related disease control was observed in 10 pa-
tients; five had undetectable brain lesions and five had
stable disease. The median progression-free survival (PFS) in
patients with brain metastases was 3.0 months (range, 0 to
10.9 months). Adverse reactions were reported in 18 out
of 20 patients with brain metastases. Central nervous
system events like intracranial hemorrhage, seizures, and
headaches were reported in five patients, all of whom had
intracranial disease progression. A 3-year follow-up of this
trial was presented at the European Society for Medical
Oncology (ESMO) Congress in 2015, and the group with brain
metastases had a median OS of 12.7 months (95% CI,
2.722.7 months) and a 3-year survival rate of 27.8%.33 With
the promising results from the phase II trial, a phase III trial
of patients with melanoma-derived brain metastases
(NIBIT-M2) is planned.34 The trial was initially designed with
two arms; arm A with single-agent fotemustine and arm B
with fotemustine and ipilimumab. However, with recent
reports of high clinical activity with a combination of ipi-
limumab and the antiPD-1 monoclonal antibody nivo-
lumab, the protocol was amended to include a third arm,
arm C, with a combination of nivolumab and ipilimumab.35
Table 1 reviews the published studies of immune check-
point inhibitors in brain metastases.
AntiPD-1/PD-L1 Antibodies
Another promising immune checkpoint target is the
PD-1/PD-L1 pathway. AntiPD-1/PD-L1 antibodies such as
nivolumab and pembrolizumab have been approved for
advanced melanoma, kidney cancer, and NSCLC. All of the
early trials of antiPD-1/PD-L1 agents excluded patients with
brain metastases. In 2015, interim results of a single-center,
phase II study of pembrolizumab of patients with melanoma
and NSCLC with brain metastases was presented at the 2015
ASCO Annual Meeting.36,37 Patients with newly diagnosed
asymptomatic or progressing brain metastases who did not
require immediate treatment with steroids are being en-
rolled in this study. By December 2014, 17 patients with
metastatic melanoma and 10 patients with NSCLC were
enrolled. These patients were treated with 10 mg/kg of
pembrolizumab administered every 2 weeks. Among the
12 evaluable patients in the melanoma arm, three were
observed to have partial response and two had stable disease
with a 6-month OS of 47%. In the NSCLC arm, nine patients
were evaluated for response and four had partial response.
 IMMUNE CHECKPOINT INHIBITIORS IN BRAIN METASTASES

TABLE 1. Studies With Immunotherapy in Melanoma Patients With Brain Metastases

Concurrent
Local Intracranial
Special Trial Therapy Radiation Response OS
Study Design Characteristics Tested Treatment No. of Patients Rate PFS (Months)
Margolin et al29 Phase II Cohort A: no Ipilimumab None Cohort A: 51 24% NR 7.0
steroids
Cohort B: Cohort B: 21 10% 3.7
steroids
Di Giacoma Phase II Asymptomatic Ipilimumab/ None 20 50% NR 12.7
et al32 fotemustine
Patel R et al49 Retrospective SRS vs. SRS/ Ipilimumab SRS (given SRS only: 34 NR 1-year 12-month:
comparative ipilimumab within LC: 38%
analysis 4 months of 92.3%
initiation of
SRS/ 1-year 12-month:
ipilimumab)
ipilimumab: LC: 37.1%
20 71.4%
Weber et al50 Retrospective Ipilimumab/ Ipilimumab None 12 41.6% NR 14.0
analysis of budesonide
phase II trial (asymptomatic
BM)
Knisely et al41 Retrospective SRS vs. SRS/ Ipilimumab SRS SRS: 17 NR NR 4.9
comparative ipilimumab
SRS/ 21.3
analysis
ipilimumab:
11
Silk et al40 Retrospective SRS vs. SRS/ Ipilimumab SRS/WBRT No NR 3.3 5.3
comparative ipilimumab ipilimumab:
analysis 37
Ipilimumab: 33 2.7 18.3
42
Mathew et al Retrospective SRS vs. SRS/ Ipilimumab SRS SRS: 33 NR NR 6-month: 56%
comparative ipilimumab
SRS/ 6-month:45%
analysis
ipilimumab:
25
Ahmed et al43 Retrospective SRS/nivolumab Nivolumab SRS 26 NR NR 11.8
analysis
Abbreviations: BM, brain metastases; PFS, progression-free survival; OS, overall survival; NR, not reported; SRS, stereotactic radiosurgery; LC, local control; WBRT, whole-brain
radiotherapy.

Only one patient in both arms experienced grade 3 adverse
events related to pembrolizumab (liver function abnormali-
ties). The investigators presented updated results at the
16th World Conference on Lung Cancer in September 2015;
18 patients had sufficient follow-up time for response eval-
uation. The median OS was 7.7 months (95% CI, 3.5 months
to not reached).38 These early results appear promising for
the utility of pembrolizumab in patients with asymptomatic
brain metastases. Another multicenter phase II clinical trial
of ipilimumab plus nivolumab for patients with advanced
melanoma with brain metastases (NCT02320058) is currently
accruing patients.39 This study is planned to treat patients
with asymptomatic brain metastases from melanoma with an
induction phase of four cycles of 1 mg/kg of nivolumab and
3 mg/kg of ipilimumab every 3 weeks, followed by mainte-
nance therapy of 3 mg/kg of nivolumab every 2 weeks. Table 2
provides a list of other important clinical trials in this setting.
Immunotherapy and Radiation
Radiation therapy has been the cornerstone of treat-
ment for brain metastases. Stereotactic radiosurgery and
whole-brain radiation therapy (WBRT) with or without sur-
gery plays a crucial role in the management of symptomatic
brain metastases.
Several retrospective single-center case series have shown
that stereotactic radiation and ipilimumab can be combined
safely in the management of brain metastases derived from
melanoma.40-42 The safety of combining nivolumab with
stereotactic radiation was reported in a recent single-center
study.43 This retrospective report included patients who
were treated in the context of a clinical trial of nivolumab
for advanced melanoma. Twenty-six patients with brain me-
tastases were treated with stereotactic radiation, with, prior to,
or after nivolumab. The combination of nivolumab and ste-
reotactic radiation was well tolerated. Distant intracranial
recurrence and OS were improved compared with historical
controls treated with radiation alone.
There are three important aspects to combining radiation
with immune checkpoint inhibitors:
1. Can immunotherapy potentiate radiation therapy
(radio-sensitizing effect) leading to better intracranial
disease control?

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BERGHOFF ET AL
TABLE 2. Select Clinical Trials Currently Accruing Patients
Study Design Therapy tested
NCT0246006839 Multicenter, randomized, phase III Fotemustine
vs. fotemustine/ipilimumab
vs. ipilimumab/nivolumab
NCT0262151551 Multicenter, phase II Nivolumab in symptomatic brain metastases
NCT0232005852 Multicenter, phase II Nivolumab/ipilimumab followed by nivolumab
NCT0237424253 Multicenter, phase II Nivolumab/ipilimumab for melanoma brain metastases
NCT0208507054 Single-center, phase II Pembrolizumab
2. Will the combination of radiation therapy and immu-
notherapy lead to better extracranial disease control
(abscopal effect) and, thus, improved OS?
3. If the radiation potentiates the immunotherapy, what
is the best fractionation schedule to achieve the most
benefit?
The first question is relatively straightforward, and several
clinical trials are currently underway to answer the potential
intracranial responses of combining immunotherapy and
radiation. The major confounder in this endeavor is the use
of steroids. Relatively high doses of steroids have been used
with radiation, especially WBRT, to reduce the intracranial
edema. The detrimental effect of the concomitant use of
steroids and immunotherapy was observed in the phase II
trial of ipilimumab for patients with asymptomatic,
melanoma-derived brain metastases.29 Since this study, the
required steroid dose used with stereotactic radiation
therapy has decreased, and they are used often for a shorter
duration. In addition, many centers are now moving away
from using steroids routinely for all patients with brain
metastases.44
This second aspect of combining radiation and immuno-
therapy, the abscopal effect, is interesting and more
challenging to evaluate in clinical trials. It has been well
established that radiation causes DNA damage that leads to
cell death. However, the interaction of radiation and the
immune system is not well understood. Several preclinical
data have reported that cancer cells release numerous
chemokines and cytokines in response to radiation. The
damaged cancer cells have also been shown to upregulate
MHC-1 expression, hence increasing the interaction with
CD8 T cells.45 In addition, radiation leads to the upregulation
of PD-L1 on cancer cells, limiting their interaction with CD8
T cells.46,47 Nevertheless, the activated CD8 T cells can elicit a
systemic antitumor effect, thereby leading to reduction in
the tumor burden. Methods to reliably produce and po-
tentiate this abscopal effect are a subject of intense re-
search. However, increasing the interaction of CD8 T cells
with radiated tumor cells by the use of immune checkpoint
inhibitors may enhance the abscopal effect. A retrospective
case series tried to evaluate this effect by following the
e120 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Estimated
Primary Cancer Enrollment
Melanoma 168
Melanoma 70
Melanoma 110
Melanoma 75
Melanoma, 64
nonsmall cell
lung cancer
single largest extracranial lesion after stereotactic radiation
to the brain metastases and ipilimumab.44
The third aspect of combining radiation and immuno-
therapy and choosing the preferred fractionation schedule
is being evaluated in preclinical models. Single session and
fractioned radiation schedules with and without immuno-
therapy have been tested in a preclinical mouse model.48
TSA breast carcinoma and MCA38 colon cancer mouse
models were used to test the various radiation fractionation
schemes with and without antiCTLA-4 antibody, 9H10. The
mice were injected with tumor cells at two sites; a primary
and a secondary site. They were then randomly assigned
to receive radiation to the primary site at three different
fractionation schedules (one cycle of 20 Gy, three cycles
of 8 Gy, or five cycles of 5 Gy on consecutive days), im-
munotherapy alone, or a combination of radiation and
immunotherapy. Only fractionated radiation with immu-
notherapy to the primary site produced abscopal effect at
the secondary site. However, strong clinical data to sup-
port this preclinical model are lacking. Innovative clinical
trials are needed to improve our understanding of the in-
teraction of radiation and immunotherapy and the abscopal
effect.
CONCLUSION
In summary, some brain metastases harbor an immune
active microenvironment that in theory can be targeted by
immune-modulating therapies like immune checkpoint in-
hibitors. However, a deeper insight of the specific mecha-
nisms in the highly regulated microenvironment of the brain
is needed to understand and overcome potential resistance
mechanisms. Early results of immune checkpoint inhibitors
in clinical trials have shown intracranial activity in brain
metastases from melanoma and NSCLC. There are several
ongoing clinical trials investigating the role of immune
checkpoint blockade in brain metastases. Numerous retro-
spective case series suggest immune checkpoint inhibitors
can be safely combined with radiation. Prospective studies
are needed to further confirm the safety of such approaches
and define the timing and the dose of the optimal radiation
modality.

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 TARGETED THERAPY IN BRAIN METASTASES

Targeted Therapy in Brain Metastases: Ready for Primetime?

Vyshak A. Venur, MD, and Manmeet S. Ahluwalia, MD

OVERVIEW

Brain metastasis is a serious complication of cancer that causes significant morbidity for patients. Over the last decade,
numerous new driver somatic mutations have been recognized and targeted therapies are changing the landscape of
treatment in lung cancer, breast cancer, and melanoma, which are also the three most common cancers that result in
brain metastases. The common actionable mutations include the EGFR mutation and anaplastic lymphoma kinase (ALK)
translocations in nonsmall cell lung cancer, the HER2 mutation in breast cancer, and the BRAF mutation in melanoma.
However, most of the early trials with targeted agents excluded patients with brain metastases. With a better understanding
of the biology, several recent trials of targeted therapy that focus on brain metastases have been reported and others are
ongoing. Novel agents with better penetration across the bloodbrain barrier are currently being investigated for patients
with brain metastases. In this review, we discuss the current state of use and future directions of targeted therapies in brain
metastases.

T he discovery of driver mutations and agents targeting these

mutations and pathways has revolutionized the treatment
of patients with advanced malignancies in the past decade. The
incidence of brain metastases has increased, although newer
targeted agents have improved the systemic control of malig-
nancy and hence survival. It is estimated that approximately 40%
of patients with metastatic cancer will develop a symptomatic
brain metastasis.1 Lung cancer, breast cancer, and melanoma are
the three common malignancies that lead to brain metastases. In
the past, the cornerstone for treatment of brain metastases in-
cluded whole-brain radiation therapy (WBRT), stereotactic radia-
tion (SRS), and surgery. The evolution of systemic therapy in the
management of brain metastases has been restricted by the
presence of the bloodbrain barrier and efflux pumps. Most initial
studies of drugs for the management of advanced cancer excluded
patients with brain metastases, further limiting progress. Hence,
chemotherapy has had a limited role in the management of brain
metastases. Several new targeted agents with bloodbrain barrier
penetration are being developed, with emphasis on treatment
patients with brain metastases.2 In this article, we review the
current evidence on the role of agents targeting the various driver
mutations and pathways in management of brain metastases from
lung cancer, breast cancer, and melanoma (Table 1).
TARGETED THERAPY FOR LUNG CANCER WITH
BRAIN METASTASES
Lung cancer is the most common cancer that results in brain
metastases. A high proportion of patients with small cell lung
cancer develop brain metastases fairly early in the course of
the disease. They are usually treated with WBRT. Patients
with nonsmall cell lung cancer (NSCLC) are a more hetero-
geneous group, and 25%40% of patients with NSCLC will
develop a brain metastasis during the course of the disease.3
The common actionable mutations in nonsquamous NSCLC
include EGFR mutation and ALK gene rearrangements.
The frequency of somatic EGFR mutations varies from 30% to
50% among East Asians to approximately 10% among Cauca-
sians.4 Exon 19 (in-frame) deletions and point mutations (L858R)
at exon 21 comprise 90% of all known EGFR mutations in
NSCLC.5 Studies suggest that patients with an EGFR mutation
develop brain metastases more frequently, have several small
lesions with minimal peritumoral edema, and may have better
overall survival (OS) compared with patients with lung cancer
brain metastases without any mutation.6 Erlotinib and gefi-
tinib are two first-generation tyrosine kinase inhibitors (TKIs)
that target EGFR mutations and are approved by the U.S. Food
and Drug Administration (FDA) for use in lung cancer treatment.7
Both erlotinib and gefitinib have distinct pharmacologic char-
acteristics in the central nervous system (CNS). [11C]erlotinib
was shown to have effective CNS distribution in the presence
of brain metastases but not in the normal brain.8 However,
OSI-420, an active metabolite of erlotinib, is a substrate of
P-glycoprotein (P-gp), a drug efflux protein of the ATP-binding
cassette transporter family at the brain endothelial cells of the
bloodbrain barrier.9 Gefitinib is known to inhibit P-gp activity,
and none of its known metabolites are substrates of P-gp.10

From the Division of Hematology and Oncology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA; Burkhardt Brain Tumor and Neuro-Oncology
Center, Department of Medicine, Neurologic Institute, Cleveland Clinic, Cleveland, OH; Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Manmeet. S. Ahluwalia, MD, Cleveland Clinic, 9500 Euclid Ave., S73, Cleveland, OH 44195; email: ahluwam@ccf.org.

2016 by American Society of Clinical Oncology.

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VENUR AND AHLUWALIA
However, both of these drugs have limited bloodbrain barrier
penetration, and limited cerebral spinal fluid concentrations of
erlotinib (approximately 5%) and gefitinib (approximately 2.5%)
have been reported.11,12
A Japanese phase II study evaluated the efficacy of gefi-
tinib among 41 patients with brain metastases.13 The overall
response rate was 87.8%, with a progression-free survival
(PFS) of 14.5 months (95% CI, 10.218.3 months) and a
median OS of 21.9 months (95% CI, 18.530.1 months).13
Patients with an EGFR exon 19 deletion had significantly
better PFS and OS compared with those with an exon 21
L858R mutation. In one study, 31 Korean patients who had
never smoked and had EGFR-mutant NSCLC and synchro-
nous asymptomatic brain metastases were treated with
gefitinib or erlotinib.14 The objective response rate was
96.9%, PFS was 7.1 months, and OS was 18.8 months.
Several preclinical studies with human cell lines have in-
dicated that EGFR TKIs enhance radiation therapy.15 Nu-
merous clinical trials and retrospective reports have shown
increased efficacy of combining TKIs with radiation therapy
in the context of brain metastases from EGFR-mutant NSCLC.
In a prospective phase II study, 40 patients with brain
metastases received erlotinib for 1 week prior to WBRT,
concurrently with WBRT followed by maintenance erloti-
nib.16 Nine of the 40 patients carried an EGFR mutation, and
an overall response rate of 89.9% with a median OS of
19.1 months was noted in that cohort. In a randomized
phase II study, 80 patients with brain metastases from NSCLC
received either erlotinib or placebo with WBRT.17 In the
erlotinib arm, 35 of 40 patients had wild-type EGFR; no
KEY POINTS
Brain metastases are a major cause of morbidity for
patients with advanced malignancies, and the incidence
of brain metastases is increasing.
For patients with nonsmall cell lung cancer with a EGFR
mutation and an anaplastic lymphoma kinase mutation
with brain metastases, several agents have shown
intracranial activity. Newer EGFR-targeting agents with
better central nervous system penetration are in
development.
Lapatinib in combination with capecitabine and
neratinib has been tested in clinical trials for patients
with brain metastases from breast cancer harboring a
HER2 mutation.
Approximately 50% of patients with metastatic
melanoma carry a BRAF mutation. Small
moleculetargeted therapies such as vemurafenib and
dabrafenib have shown efficacy in BRAFV600-positive
melanoma brain metastases.
Innovative drug development and clinical trials for brain
metastases are needed to improve treatment options
and consequently outcomes of patients with brain
metastases.
e124 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
significant difference in PFS and OS was noted between the
two groups.
The second-generation EGFR TKI afatinib is an irreversible
inhibitor of EGFR.18 It also inhibits HER2 and ERBB4 re-
ceptors and was initially designed to overcome T790M
mutation.18 One-hundred patients with brain metastases
from EGFR-mutant NSCLC received afatinib in a compas-
sionate use program.19 All of the patients had been treated
previously with either erlotinib or gefitinib. For the 35
evaluable patients, time to tumor progression of 3.6 months
with an overall cerebral response rate of 35% was reported.
However, the CNS efficacy of afatinib has not been com-
pared with either erlotinib or gefitinib.
A number of third-generation EGFR TKIs, including osi-
mertinib (AZD-9291), rociletinib (CO-1686), ASP-8273, and
HM-61713, are in various phases of clinical investigation.20-23
These agents spare wild-type EGFRs and target mutant EGFRs,
including T790M.24 The activity of these newer agents against
brain metastases is currently being investigated. Initial studies
with the third-generation EGFR TKIs included several patients
with brain metastases. For example, 162 of 411 patients in the
phase I/II trial of AZD-9291 had CNS metastases,25 and 186 of
450 patients (41%) enrolled in the phase I/II trial of rociletinib
had a history of CNS involvement.26 In a report of patients who
were treated with osimertinib after progression on rociletinib,
all three patients with brain metastases showed a response.27
AZD-3759 is a novel EGFR TKI designed to cross the blood
brain barrier; however, it lacks activity against T790M mu-
tation.2 Preclinical studies show that AZD-3759 is not a sub-
strate of P-gp efflux pumps and has significantly higher
penetration across the bloodbrain barrier. Preliminary
results of the ongoing phase I trial of AZD-3759 demon-
strated that the drug was well tolerated, with early evidence
of intracranial activity.28
Approximately 3%7% of patients with nonsquamous NSCLC
have ALK gene rearrangement, resulting in a novel fusion gene
containing portions of echinoderm microtubule-associated
protein like-4 and the ALK gene.29 This rearrangement leads
to constitutive activity of the kinase domain of the ALK, leading
to activation of the phosphoinositide 3-kinase and RAS path-
ways.30 Crizotinib is a first-generation ALK inhibitor that also
has activity against ROS1 and MET tyrosine kinases. Although
crizotinib does not have good bloodbrain barrier penetration,
CNS activity has been seen in several case reports and in
retrospective subanalyses of clinical trials. In a retrospective
pooled analysis of 388 patients enrolled in the PROFILE 1005-
1007 clinical trial of crizotinib, 275 patients had asymptomatic
brain metastases.31 Of the 275 patients with brain metastases,
166 had received prior treatment. The intracranial disease
control rate was similar among those with prior treatment
compared with treatment-naive patients. However, the me-
dian intracranial time to tumor progression was 7 months for
patients with previously untreated brain metastases compared
with 13.2 months for patients with previously treated brain
metastases. In addition, the patients who continued crizotinib
beyond progression had better OS compared with those
who discontinued therapy at progression. A multi-institutional
 TARGETED THERAPY IN BRAIN METASTASES

TABLE 1. Selected Studies With Targeted Therapy in Brain Metastases

Intracranial
Concurrent Intracranial Progression- Overall
Primary Specific Trial Therapy Local No. of Response Free Survival Survival
Study Malignancy Design Characteristics Tested Treatment Patients Rate (%) (Months) (Months)
16
Welsh et al NSCLC Phase II Erlotinib started Erlotinib WBRT 40 86 8 11.8
a week prior to
and continued
through and
after WBRT
Lee et al17 NSCLC Phase II A randomized trial Erlotinib WBRT Arm A: 40 1.6 2.9
predominantly
Arm B: 40 1.6 3.4
among patients
with the EGFR
wild type; arm A:
WBRT alone;
arm B: WBRT plus
erlotinib
Ceresoli et al81 NSCLC Phase II Single-arm study, Gefitinib None 41 27 3 5
included both
newly diagnosed
and old BMs
Sperduto et al82 NSCLC Phase 3-arm study; arm A: Erlotinib WBRT plus Arm A: 44 8.1 13.4
(RTOG-0320) III WBRT plus SRS; SRS
Arm B: 40 4.6 6.3
arm B: WBRT plus
SRS plus temo- Arm C: 41 4.8 6.1
zolomide; arm
C: WBRT plus SRS
plus erlotinib
Bachelot et al59 HER2- Phase II Newly diagnosed Lapatinib None 45 65.9 5.5 17
(LANDSCAPE) positive BMs plus
breast capecitabine
cancer
Corte s et al61 HER2- Phase II 3-arm study; arm A: Afatinib None Arm A: 40 30 (12 of 40
positive afatinib; arm B: patients)*
breast afatinib plus
Arm B: 38 34.2 (13 of 38
cancer vinorelbine;
patients)*
arm C: investiga-
tors choice Arm C: 43 41.9 (18 of 43
patients)*
Freedman et al63 HER2- Phase II Single-arm study Neratinib None 40 1.9 8.7
positive in previously
breast treated patients
cancer
Long et al71 BRAF- Phase II Cohort A: no prior Dabrafenib None Cohort A, 39.2 4 (16.1 weeks) 8.2 (33.1
positive treatment of V600E: 74 weeks)
melanoma BMs; cohort B:
Cohort A, 6.7 2 (8.1 weeks) 7.7 (31.4
previously
V600K: 15 weeks)
treated BMs
Cohort B, 30.8 4.1 (16.6 4 (16.3
V600E: 65 weeks) weeks)
Cohort B, 22.2 4 (15.9 weeks) 5.2 (21.9
V600K: 18 weeks)
Kefford et al73 BRAF- Phase II Cohort 1: previously Vemurafenib None Cohort 1: 90 18 3.7 7
positive untreated;
Cohort 2: 56 20 3.94 9.53
melanoma cohort 2: previ-
ously treated
Abbreviations: NSCLC, nonsmall cell lung cancer; WBRT, whole-brain radiation therapy; BM, brain metastasis; SRS, stereotactic radiation.
*Patient benefit (defined as intracranial or extracranial progression-free survival, new neurologic signs or symptoms related to tumor, or increased corticosteroid use) at
12 weeks.

retrospective study included 90 patients with brain metastases
from ALK-positive lung cancer.32 The majority of patients (84 of
90) received radiation therapy. Crizotinib was administered to
84 patients and a second-generation ALK inhibitor was given to
41 patients (21 received ceritinib, 16 were treated with bri-
gatinib, two received alectinib, and two were administered
X-396). A median OS of 49.5 months from the diagnosis of a
brain metastasis was reported. The investigators concluded
that absence of extracranial disease, a Karnofsky performance
score (KPS) of 90 or greater, and no prior ALK inhibitor therapy
were independent prognostic factors for patients with brain
metastases from ALK-positive lung cancer. Several recent
studies have suggested CNS treatment failure and CNS-
predominant progression among patients treated with

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VENUR AND AHLUWALIA
crizotinib.33-35 Aggressive tumor biology, poor CNS penetration
of crizotinib, and mutation in the binding domain of crizotinib
have been suggested as the likely reasons.36,37
Ceritinib and alectinib are second-generation ALK in-
hibitors that can be used to overcome drug resistance to
crizotinib.38,39 The phase I trial of ceritinib (ASCEND-1) ac-
crued 246 patients, 124 of which had brain metastases at
baseline.40 Ninety-eight patients had received ALK inhibitors
in the past, whereas 26 patients were ALK-inhibitor naive. Of
the 14 patients with measurable brain metastases, seven
patients showed an intracranial response and three patients
had stable disease. Unlike crizotinib and ceritinib, alectinib is
not a substrate for P-gp efflux pumps, which may result in
a higher brain to plasma concentration of alectinib.41 The
phase I/II study of alectinib enrolled 47 patients who pro-
gressed or were intolerant to crizotinib.42 Eleven of the 21
patients with asymptomatic brain metastases had an ob-
jective response (six complete responses, five partial re-
sponses). Brigatinib is another ALK inhibitor that has shown
intracranial activity in an early phase I/II trial.43 A phase I trial
of brigatinib included 46 patients with brain metastases.
Thirteen patients had evaluable brain metastases; nine
patients (69%) had regression of the intracranial lesions,
including four patients with a complete response and two
with a partial response.44 The median intracranial PFS was
97 weeks. The phase II trial of this agent is currently accruing
patients and includes a cohort of patients with brain
metastases.44
TARGETED THERAPY FOR BREAST CANCER WITH
BRAIN METASTASES
Breast cancer is the second leading cause of brain metas-
tases. The propensity of brain metastases varies with
subtypes of breast cancer. Patients with metastatic triple-
negative breast cancer typically have brain metastases early
in the course of their disease, and they frequently present
with simultaneous progression of intracranial and extra-
cranial disease.45,46 By contrast, patients with HER2 over-
expression are often treated with targeted therapies that
include monoclonal antibodies, and they develop CNS me-
tastases relatively later in the disease process, often with
stable extracranial disease. Approximately 30%55% of
patients with HER2-positive breast cancer develop brain
metastases.47,48 The increased incidence of brain metasta-
ses in this subtype of breast cancer is attributed to two main
reasons. First, anti-HER2 agents such as trastuzumab are
effective in controlling the systemic disease, prolonging
survival, and, in turn, unmasking otherwise asymptomatic
brain metastases. Second, the monoclonal antibodies di-
rected against HER2, like trastuzumab, have poor CNS
penetration, especially for patients with an intact blood
brain barrier, thereby leading to brain metastases without
systemic progression of the disease.49 In the absence of
brain metastases, the CNS concentration of trastuzumab is
low compared with systemic concentrations.50 However,
among patients with brain metastases, studies using
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radiolabeled trastuzumab have shown increased CNS bio-
availability.51,52 Although no prospective clinical trial has yet
reported on the intracranial activity of trastuzumab, several
retrospective studies have shown superior outcomes with
trastuzumab after radiation.53 In one such retrospective
study, the median OS of patients with HER2-overexpressing
breast cancer brain metastases was 21 months with WBRT
followed by trastuzumab, compared with 9 months with
WBRT followed by chemotherapy.53 Two-thirds of patients
with brain metastases still die of the systemic disease, and
better control of the primary cancer and extracranial me-
tastases may be the reason for this observed survival benefit
with the use of trastuzumab. Hence, for a patient with
isolated CNS progression, it is reasonable to continue anti-
HER2 therapy as long as the extracranial disease is well
controlled.
HER2 (ERBB2) is shown to enhance EGFR signaling and vice
versa.54,55 Therefore, it is postulated that dual inhibition
of HER2 and EGFR by agents such as lapatinib may confer
improved outcomes among this patient population.56
Lapatinib in combination with capecitabine is approved for
treatment of patients with HER2-overexpressing metastatic
breast cancer who have progressed while taking trastuzu-
mab. Lapatinib is a small molecule inhibitor; however, its
bioavailability in the CNS is limited by breast cancer re-
sistance protein and P-gp efflux pumps.57 Lapatinib was
evaluated in an initial phase II study of patients with pro-
gressive brain metastases from HER2-positive breast can-
cer.58 The trial accrued 242 patients and all had received
prior radiation therapy and trastuzumab. The median PFS
and OS were 2.4 months and 6.37 months, respectively. This
study was amended to allow 50 additional patients who
were treated with lapatinib and capecitabine after pro-
gression with lapatinib. In this cohort, the median PFS was
3.65 months and a response rate of 20% was seen. The
pivotal study for the utility of lapatinib for patients with
breast cancer with brain metastases was the LANDSCAPE
trial, which investigated the combination of lapatinib and
capecitabine as a first-line combination therapy prior to
radiation.59 An intracranial response of 66% was seen among
the 45 patients enrolled in this phase II trial. The WBRT was
delayed by 8.6 months for patients with oligometastatic
asymptomatic brain metastases treated with lapatinib and
capecitabine. A median OS of 17.0 months was reported
among 44 patients who had measurable intracranial disease.
There is an ongoing randomized cooperative group study
evaluating WBRT in combination with lapatinib for patients
with brain metastases from HER2-positive breast cancer
(NCT01622868).
The drug-antibody conjugate T-DM1 (trastuzumab plus
emtansine) is approved by the FDA for treatment of pa-
tients with HER2-positive breast cancer. In a recent ret-
rospective report, an intracranial response rate of 20% was
seen for 10 patients with asymptomatic or progressive
brain metastases.60 Prospective trials are needed to better
understand the clinical activity of T-DM1 among patients
with brain metastases.

Afatinib, a second-generation inhibitor of the ERBB family,
is approved by the FDA for treatment of patients with NSCLC
harboring an EGFR mutation.18 In a phase II study of 121
patients with HER2-overexpressing breast cancer with brain
metastases, 40 patients were treated with afatinib, 38 re-
ceived afatinib and vinorelbine, and another 43 were treated
with the regimen of the investigators choice.61 Trastuzumab
and vinorelbine (11 of 43 patients) and lapatinib plus cape-
citabine (eight patients) were the most common treatments
chosen by the treating investigator. The primary study end-
point (absence of CNS or extracranial disease progression,
new neurologic symptoms, or new corticosteroid use [termed
as patient benefit]) at 12 weeks was seen in 12 of 40 patients
(30%) in the afatinib arm, 13 of 38 patients (34%) in the
afatinib plus vinorelbine arm, and 18 of 43 patients (42%) in
the investigator choice arm.
Neratinib is a potent irreversible inhibitor of EGFR, HER2,
and ERBB4 transmembrane tyrosine kinase receptors.62 A
phase II single-arm study evaluated neratinib among pa-
tients with HER2-overexpressing breast cancer with brain
metastases.63 The primary trial endpoint was intracranial
response rate, which also included neurocognitive and quality-
of-life (QoL) assessments. The intracranial response rate among
patients enrolled in the study was 8% (3 of 40 patients failed to
meet the primary endpoint of success). The rapid accrual of
patients and the neurocognitive and QoL endpoints of the trial
were noteworthy.
Pertuzumab, an antibody against the extracellular di-
merization domain of the HER2 receptor, has been shown to
increase efficacy when used with trastuzumab and docetaxel
among patients with untreated HER2-overexpressing meta-
static breast cancer.64 A case report has shown intracranial
activity from the combination of pertuzumab, trastuzumab,
and docetaxel.65
Patients with luminal breast cancer have a lower fre-
quency of brain metastases.66 It has been suggested that
hormone receptors are lost or altered during the process of
acquiring brain metastases.67 Newer agents such as mTOR
inhibitors and CDK4/6 have shown extracranial activity in
advanced luminal breast cancer; however, their role in the
treatment of patients with brain metastases is yet to be
defined. There have been limited novel agents available for
the treatment of patients with triple-negative breast cancer
with brain metastases who have a dismal prognosis.
TARGETED THERAPY FOR BRAIN METASTASES
FROM MELANOMA
Targeted agents against driver oncogenic mutations among cell
signaling pathways have shown benefit in metastatic mela-
noma. BRAF, NRAS, and KIT are the mutually exclusive driver
mutations commonly seen in metastatic melanoma.68 The
presence of these mutations increases the risk of CNS metas-
tases at the diagnosis of stage IV melanoma. In a 2012 study, a
higher prevalence of melanoma brain metastases was observed
in BRAF- and NRAS-mutant melanoma (24% and 23%, re-
spectively) compared with wild type (12%).69 BRAF mutation is
TARGETED THERAPY IN BRAIN METASTASES
seen for approximately 50% of patients with metastatic mel-
anoma and plays an important role in the MAPK (RAS-RAF-MEK-
ERK) pathway. Dabrafenib and vemurafenib are agents active
against BRAF V600E or V600K mutation that are approved by
the FDA for treatment of advanced metastatic melanoma. In the
phase I trial with dabrafenib, 8 of 10 patients with untreated
asymptomatic brain metastases showed an intracranial
response (four had a complete response and four had a partial
response).70 This initial observation led to a phase II multi-
center open-label study of dabrafenib among 172 patients with
asymptomatic brain metastases with a BRAFV600E or BRAFV600K
mutation and at least one measurable brain metastasis (BREAK-
MB).71 Cohort A consisted of 89 patients who had never re-
ceived any local treatment and cohort B comprised 83 patients
with a history of prior radiation therapy for brain metastases.
A modified version of the RECIST criteria with up to five in-
tracranial and extracranial index lesions was used to measure
the response to treatment. In cohorts A and B, patients with a
BRAFV600E mutation had intracranial response rates of 39%
(29 of 74) and 31% (20 of 65), respectively. Progression-free
survival of 16.1 weeks and 16.6 weeks and OS of 33.1 and
31.4 weeks were noted in cohorts A and B, respectively. Pa-
tients with a BRAFV600K mutation had lower intracranial re-
sponse rates of 7% (1 of 15) and 22% (4 of 18) in cohorts A and B,
respectively. This trial demonstrated that dabrafenib is active in
BRAF-mutant melanoma brain metastases, specifically among
patients with a BRAFV600E mutation with acceptable toxicity.
Vemurafenib was noted to have intracranial activity in an open-
label pilot trial of 24 untreated patients with melanoma brain
metastases harboring a BRAFV600 mutation.72 Of 19 patients with
measurable intracranial disease, seven had tumor regression of
more than 30% and three achieved a partial response. Median
PFS and OS were 3.9 and 5.3 months, respectively. Initial results
of a phase II study of 146 patients with BRAFV600 melanoma brain
metastases treated with vemurafenib were reported at the 2013
Society of Melanoma Research Congress.73 Cohort 1 consisted of
90 patients with newly diagnosed melanoma brain metastases
and cohort 2 included 56 patients with melanoma brain me-
tastases who progressed after initial local therapy. Both cohorts
had similar intracranial response rates at 18% and 20%, re-
spectively. Median PFS and OS were 3.7 and 6.5 months in cohort
1 and 4.0 and 6.4 months in cohort 2, respectively.
The feasibility, safety profile, and effectiveness of com-
bining BRAF inhibitors and radiation have not yet been
tested in a prospective setting. There is concern regarding an
increased incidence of dermatitis with concurrent use of
radiation and BRAF inhibitors, specifically in the extracranial
setting.74 A retrospective analysis evaluated the effectiveness
of combining vemurafenib and radiation in BRAFV600 mela-
noma brain metastases.75 Six patients were treated with SRS:
two received WBRT, one received SRS and WBRT, and the
remaining three received surgery and radiation. All 12 patients
received vemurafenib. Of the 48 index lesions, 36 showed a
response, with 23 (48%) complete responses and 13 (27%)
partial responses. Several other small retrospective case series
have been reported on outcomes of the combination of tar-
geted agents with SRS/WBRT.76-78
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VENUR AND AHLUWALIA
CONCLUSION
Targeted therapies have improved survival in a subset of
patients with NSCLC, breast cancer, and melanoma with
actionable driver mutations. For patients with brain metas-
tases, these agents provide not only intracranial control of the
disease, but they also help manage systemic cancer. The
clinical and pathobiology of brain metastases for patients with
mutations such as EGFR may differ from other patients with
NSCLC without such mutations.79 Some of the newer targeted
agents have shown promising results in the treatment of brain
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metastases, despite limitations of the bloodbrain barrier and
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21. Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated
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hibitors. N Engl J Med. 2010;363:1734-1739.
38. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-
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39. Seto T, Kiura K, Nishio M, et al. CH5424802 (RO5424802) for patients
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14:590-598.
40. Shaw A, Mehra R, Tan DSW, et al. BM-32 Ceritinib (LDK378) for
treatment of patients with ALK-rearranged (ALK+) non-small cell lung
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42. Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib
against systemic disease and brain metastases in patients with crizotinib-
resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results
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15:1119-1128.
43. Camidge DR, Bazhenova L, Salgia R, et al. Safety and efficacy of brig-
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44. Kerstein D, Gettinger S, Gold K, et al. LBA4: evaluation of anaplastic
lymphoma kinase (ALK) inhibitor brigatinib [AP26113] in patients with
ALK+ non-small cell lung cancer (NSCLC) and brain metastases. Ann
Oncol. 2015;26:i60-i61.
45. Dawood S, Lei X, Litton JK, et al. Incidence of brain metastases as a first
site of recurrence among women with triple receptor-negative breast
cancer. Cancer. 2012;118:4652-4659.
46. Lin NU, Claus E, Sohl J, et al. Sites of distant recurrence and clinical
outcomes in patients with metastatic triple-negative breast cancer: high
incidence of central nervous system metastases. Cancer. 2008;113:
2638-2645.
47. Brufsky AM, Mayer M, Rugo HS, et al. Central nervous system me-
tastases in patients with HER2-positive metastatic breast cancer:
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incidence, treatment, and survival in patients from registHER. Clin
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48. Olson EM, Abdel-Rasoul M, Maly J, et al. Incidence and risk of central
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49. Pestalozzi BC, Holmes E, de Azambuja E, et al. CNS relapses in patients
with HER2-positive early breast cancer who have and have not received
adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG
1-01). Lancet Oncol. 2013;14:244-248.
50. Stemmler HJ, Kahlert S, Siekiera W, et al. Characteristics of patients with
brain metastases receiving trastuzumab for HER2 overexpressing
metastatic breast cancer. Breast. 2006;15:219-225.
51. Dijkers EC, Oude Munnink TH, Kosterink JG, et al. Biodistribution
of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in
patients with metastatic breast cancer. Clin Pharmacol Ther. 2010;
87:586-592.
52. Tamura K, Kurihara H, Yonemori K, et al. 64Cu-DOTA-trastuzumab PET
imaging in patients with HER2-positive breast cancer. J Nucl Med. 2013;
54:1869-1875.
53. Bartsch R, Rottenfusser A, Wenzel C, et al. Trastuzumab prolongs overall
survival in patients with brain metastases from Her2 positive breast
cancer. J Neurooncol. 2007;85:311-317.
54. Worthylake R, Opresko LK, Wiley HS. ErbB-2 amplification inhibits
down-regulation and induces constitutive activation of both ErbB-2 and
epidermal growth factor receptors. J Biol Chem. 1999;274:8865-8874.
55. Graus-Porta D, Beerli RR, Daly JM, et al. ErbB-2, the preferred hetero-
dimerization partner of all ErbB receptors, is a mediator of lateral sig-
naling. EMBO J. 1997;16:1647-1655.
56. Konecny GE, Pegram MD, Venkatesan N, et al. Activity of the dual
kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing
and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66:
1630-1639.
57. Polli JW, Olson KL, Chism JP, et al. An unexpected synergist role
of P-glycoprotein and breast cancer resistance protein on the
central nervous system penetration of the tyrosine kinase inhibitor
lapatinib (N-3-chloro-4-[(3-fluorobenzyl)oxy]phenyl-6-[5-([2-(methylsulfonyl)
ethyl]aminomethyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metab
Dispos. 2009;37:439-442.
58. Lin NU, Dieras V, Paul D, et al. Multicenter phase II study of lapatinib in
patients with brain metastases from HER2-positive breast cancer. Clin
Cancer Res. 2009;15:1452-1459.
59. Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in
patients with previously untreated brain metastases from HER2-positive
metastatic breast cancer (LANDSCAPE): a single-group phase 2 study.
Lancet Oncol. 2013;14:64-71.
60. Bartsch R, Berghoff AS, Vogl U, et al. Activity of T-DM1 in Her2-positive
breast cancer brain metastases. Clin Exp Metastasis. 2015;32:729-737.
61. Cortes J, Dieras V, Ro J, et al. Afatinib alone or afatinib plus vinorelbine
versus investigators choice of treatment for HER2-positive breast
cancer with progressive brain metastases after trastuzumab, lapatinib,
or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2
trial. Lancet Oncol. 2015;16:1700-1710.
62. Zhang X, Munster PN. New protein kinase inhibitors in breast cancer:
afatinib and neratinib. Expert Opin Pharmacother. 2014;15:1277-1288.
63. Freedman RA, Gelman RS, Wefel JS, et al. Translational Breast Cancer
Research Consortium (TBCRC) 022: a phase II trial of neratinib for
patients with human epidermal growth factor receptor 2-positive breast
cancer and brain metastases. J Clin Oncol. 2016;34:945-952.
64. Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertu-
zumab, trastuzumab, and docetaxel in HER2-positive metastatic breast
cancer. N Engl J Med. 2015;372:724-734.
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65. Senda N, Yamaguchi A, Nishimura H, et al. Pertuzumab, trastuzumab
and docetaxel reduced the recurrence of brain metastasis from breast
cancer: a case report. Breast Cancer. 2016;23:323-328.
66. Arvold ND, Oh KS, Niemierko A, et al. Brain metastases after breast-
conserving therapy and systemic therapy: incidence and characteristics
by biologic subtype. Breast Cancer Res Treat. 2012;136:153-160.
67. Duchnowska R, Dziadziuszko R, Trojanowski T, et al. Conversion of
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in breast cancer metastases to the brain. Breast Cancer Res. 2012;14:
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CENTRAL NERVOUS SYSTEM TUMORS

The Future of Immunotherapy in

Glioblastoma

CHAIR
E. Antonio Chiocca, MD, PhD
Brigham and Womens Hospital
Boston, MA

SPEAKERS
Michael Lim, MD
The Johns Hopkins Hospital
Baltimore, MD

Michael Weller, MD
University Hospital Zurich
Zurich, Switzerland
LIM, WELLER, AND CHIOCCA

Current State of Immune-Based Therapies for Glioblastoma

Michael Lim, MD, Michael Weller, MD, and E. Antonio Chiocca, MD, PhD

OVERVIEW

Glioblastoma is one of the most aggressive solid tumors, and, despite treatment options such as surgery, radiation, and che-
motherapy, its prognosis remains grim. Novel approaches are needed to improve survival. Immunotherapy has proven efficacy for
melanoma, lung cancer, and kidney cancer and is now a focus for glioblastoma. In this article, glioblastoma-mediated immu-
nosuppression will be discussed and two exciting immune approaches, checkpoint inhibitors and viral-based therapies, will be
reviewed.

G lioblastoma has been studied as a paradigmatic tumor

for cancer-associated immunosuppression for more
than 3 decades. Initial observations included the charac-
terization of decreased immune responsiveness of periph-
eral blood cells harvested from patients with glioblastoma.1
This remote effect of a locally growing neoplasm could only
be explained by soluble factors released by the tumor in
sufficient quantities to induce systemic immunosuppression
(Fig. 1). The search for soluble factors produced by cultured
glioblastoma cells resulted in the identification of, among
others, transforming growth factor (TGF)-b as a key im-
munosuppressive cytokine that has remained a therapeutic
target until today. Yet, local application of antisense oli-
gonucleotides failed presumably because of poor target
coverage, whereas systemic application of TGF-b receptor
antagonists has its limits in nonhematologic toxicity. TGF-b
is a member of a large family of cytokines that interacts with
heterodimeric receptors. There are three TGF-b isoforms in
humans that have nonoverlapping functions, at least in
development, as demonstrated in knockout mouse models.
In contrast, the three isoforms are coregulated in glioblas-
tomas, and no isotype-specific roles have been identified so
far in the biology of glioblastoma.2 Other soluble immu-
nosuppressive factor candidates attributed a role in shaping
the immunosuppressive microenvironment in glioblastoma
include interleukin 10 and prostaglandin E2.
Admittedly, it has not been clarified definitively that the
peripheral immunosuppression encountered among patients
with glioblastoma is caused exclusively or even mainly by el-
evated levels of soluble mediators systemically. Alternatively,
it is conceivable that immune modulatory cells that encoun-
ter the glioblastoma microenvironment are forced to de-
velop into an immunosuppressive immune cell population that
indirectly mediates systemic immunosuppression. In fact, it
has recently been recognized that glioblastoma cells are
capable of reshaping the phenotype of tumor-infiltrating
host cells, which comprise a large proportion of cells within
the microenvironment of glioblastoma, to support their
growth and maintain any immunosuppressive milieu.3
In addition to the soluble immunosuppressive molecule
candidates mentioned above, immune-relevant molecules
expressed at the cell surface of glioblastoma have attracted
interest because there is major infiltration of glioblastomas
by host cells, although the cells are mainly of macrophage-
monocyte lineage. These surface molecules include the CD95
ligand, which may induce apoptosis in susceptible cells that
express the receptor, CD95, previously referred to as Fas or
APO-1. In the context of glioblastoma, cellular targets for
CD95-mediated apoptosis are probably mainly T cells. Addi-
tional candidate cell surface molecules with immunosup-
pressive properties, but with uncertain significance in
glioblastoma, include regeneration and tolerance factor (RTF),
lectin-like transcript 1, and HLA-E and HLA-G.4
More recently, major emphasis has been placed on the
aberrant expression of PD-L1 by glioblastoma cells. PD-L1 is
the ligand for PD-1, a cell surface molecule expressed mainly
on T cells now referred to as an immune checkpoint, to-
gether with CTLA-4. These two molecules, PD-1 and CTLA-4,
mediate inactivation of T cells, and antibody-mediated
therapeutic neutralization of these molecules with agents
such as nivolumab or pembrolizumab that target PD-1, or
ipilimumab that targets CTLA-4, can be considered the
greatest innovation in medical oncology in the past decade.5
They are currently being explored as novel agents across the
full spectrum of human cancers and have already been in-
tegrated into the standard of care for malignant melanoma.

From The Johns Hopkins University, Baltimore, MD; University Hospital Zurich, Zurich, Switzerland; Institute for the Neurosciences at the Brigham and Womens/Faulkner Hospital,
Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA; The University of Chicago, Chicago, IL.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Michael Lim, MD, Johns Hopkins Hospital, Neurosurgery-Phipps 123, 600 North Wolfe St., Baltimore, MD 21287; email: mlim3@jhmi.edu.

2016 by American Society of Clinical Oncology.

e132 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


Furthermore, antibodies targeting the ligand PD-L1 rather
than the receptor, such as atezolizumab, also are being ex-
plored in various tumor entities. The extent that glioblastomas
express PD-L1 in vivo has remained controversial,6 but PD-1
and CTLA-4 inhibition are remarkably active in mouse glioma
models, both as single agents and in combination. Impor-
tantly, inhibition of immune checkpoints probably confers a
nonspecific state of immune activation that will be of benefit
to patients if their particular cancers carry a high mutational
load, rendering them potentially recognizable as altered.
Whether the observed benefit can be translated to glio-
blastoma remains to be clarified. Several clinical trial initiatives
to explore immune checkpoint inhibitors in glioblastoma are
now underway.
Because of disappointing results with traditional cancer
therapy (radiotherapy, chemotherapy, and angiogenesis
inhibition by promising agents, such as VEGF pathway in-
hibitors bevacizumab and cediranib) in this disease, various
approaches to immunotherapy have gained a lot of interest.
As of early 2016, several phase II and phase III clinical trials of
immunotherapy are underway or have already been com-
pleted, including but not limited to (1) the rindopepimut
vaccine that targets epidermal growth factor variant III,
with a completed phase III trial in the newly diagnosed
setting (ACT IV) and encouraging activity in phase II in the
recurrent setting (Re-ACT); (2) the six-candidate peptide
cocktail ICT-107, which is used to generate a vaccine by
ex vivo stimulation of patient-derived dendritic cells, with a
completed randomized phase II trial that indicated activity in
patients who were HLA-A2 positive and a phase III program
scheduled to start in early 2016; and (3) the DCVax phase III
program that is near completion, with high logistical
complexityit uses autologous tumor to stimulate autol-
ogous dendritic cells.
These treatments likely are most effective with minimal
residual tumor burden, which should be associated with
decreased levels of soluble immunosuppressive factors and
KEY POINTS
Immunotherapy has proven efficacy for other solid
tumors and is now a focus for glioblastoma.
An important component of glioblastoma-mediated
immunosuppression stems from soluble factors such as
TGF-b.
Checkpoint inhibition probably confers a nonspecific
state of immune activation that is a promising approach
to glioblastoma, given the success of checkpoint
inhibitors in melanoma, lung cancer, and renal cancers.
Current strategies for biomarkers have focused on
protein expression, immune cell characterization, and
mutational burden.
Tumor-selective viruses and viral-based vectors have
shown increasingly promising results as easy-to-use
immunostimulants.
CURRENT STATE OF IMMUNE-BASED THERAPIES FOR GLIOBLASTOMA
decreased potential for immune cell re-education by bulky
tumor. Accordingly, most recent immunotherapy trials have
been and are now being conducted in highly selected patient
populations in the newly diagnosed setting and among
patients with little or no residual tumor after concomi-
tant temozolomide chemoradiotherapy. Given these de-
velopments, it can be assumed that neurosurgery will be
attributed a larger role not only in newly diagnosed patients
but also in the setting of recurrent disease, if the first de-
finitively positive immunotherapy data become available.
Although removing the source of immunosuppression sur-
gically seems to be the most straightforward approach to
overcome immunosuppression, additional strategies include
neutralizing TGF-b, at least transiently, or employing im-
mune adjuvants, such as granulocyte macrophage colony-
stimulating factor or toll-like receptor 2 agonists. The most
powerful combinatorial strategy for tumor-specific vaccines,
however, is likely to be the checkpoint inhibitors, as outlined
above. Such additional efforts at boosting immune re-
sponses may be essential for a benefit from upcoming
strategies of immunotherapy in broader populations of
patients, including patients with bulky disease, heavily
pretreated patients, and older patients who are likely to
exhibit impaired immune responsiveness.
CHECKPOINT INHIBITORS
An important component of tumor-induced immunosup-
pression involves the costimulatory interaction. Normally,
when a T cell encounters an antigen-presenting cell (APC)
expressing the appropriate antigen, a second interaction
with a checkpoint molecule is required to either activate or
suppress the T cell (Fig. 2).7,8 This second interaction plays
an important role in modulating an immune response.
Furthermore, there are multiple costimulatory molecules,
which suggest that a hierarchy of activation status exists. In
addition, this interaction is not unique to APCs and T cells;
other immune cells, such as natural killer cells and regulatory
T cells (Tregs), also have costimulatory molecules.8 Hence,
this suggests a hierarchy of immune cell activation as well as
an ability to attenuate an immune response.
Checkpoint inhibitors are a class of antibodies that are
designed to interrupt or activate these costimulatory mol-
ecules. Intense investigation is underway for the utilization
of checkpoint inhibitors for the treatment of solid tumors.
CTLA-4 was one of the first molecules to be studied. Leach
et al9 found that they could induce an antitumor immune
response within a murine model for melanoma by using an
antiCTLA-4 antibody.9 The second checkpoint inhibitor that
has been intensely studied is antiPD-1. AntiPD-1 has been
shown to induce an antitumor immune response in multiple
solid tumors, including glioblastoma.10,11
Proven Efficacy of Checkpoint Inhibitors
Several large clinical trials in humans verified the observed
efficacy of checkpoint inhibitors in the preclinical models. In
2010, Hodi et al12 ran a large phase III trial that demonstrated
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e133
LIM, WELLER, AND CHIOCCA
improved survival among patients with melanoma who were
treated with antiCTLA-4. The investigators also found that a
subset of patients were long-term survivors.12 Topalian et al13
then published their experience in treating multiple solid
tumors with antiPD-1, in which they found that antiPD-1
improved survival for patients with melanoma, renal cell
carcinoma, and nonsmall cell lung cancer. These and other
important studies resulted in U.S. Food and Drug Adminis-
tration (FDA) approval of checkpoint inhibitors. Checkpoint
inhibitors first gained FDA approval for use in patients with
melanoma in 2011, with the approval of antiCTLA-4. The FDA
approved antiPD-1 in September 2014 for melanoma.
Shortly after, antiPD-1 was approved for lung cancer (both
adenocarcinoma and squamous cell carcinoma) and renal cell
cancer. Hence, the enthusiasm for the use of checkpoint
inhibitors in glioblastoma is high.
Checkpoint Inhibitors for Glioblastoma
There are promising preclinical data suggesting that
checkpoint inhibitors may promote an antitumor immune
response. Fecci et al14 demonstrated improved survival
mediated by a CD4+ T-cell immune response in a murine
glioma model treated with antiCTLA-4. Zeng et al and
others have shown that antiPD-1 monotherapy improved
survival in a murine model for glioblastoma. Interestingly,
antiPD-L1 alone did not result in much survival im-
provement. With antiPD-1 use, the CD8+ T cells appear to
be responsible for the antitumor immune response.10,11
CURRENT TRIALS FOR GLIOBLASTOMA
Because we observed improved survival with the use of
checkpoint inhibitors in the previously mentioned solid
tumors, these compounds are now being applied to glio-
blastoma. Several clinical trials are currently underway, with
encouraging preclinical results.
NCT02017717
NCT02017717 is a large, randomized, phase III open-label
trial sponsored by Bristol Myers Squibb for patients with a
first-time recurrence of glioblastoma that used antiPD-1 as
the treatment backbone to assess its safety and, ultimately,
its efficacy. The study began with a small safety run-in,
during which patients were treated with antiPD-1 alone
or antiPD-1 with antiCTLA-4. Interim safety data that were
presented at the 2015 American Society of Clinical Oncology
Annual Meeting showed that the rates of severe adverse
events were significantly higher among patients who re-
ceived the combination of antiPD-1 and antiCTLA-4; 40%
of patients had to discontinue therapy (10 patients per arm).
Thus, a decision was made to expand the antiPD-1 cohort
and to use bevacizumab as the comparator arm. Although
this was a study of safety, a partial response in one patient
who was treated with anti-PD-1 alone, and a few cases of
pseudoprogression, was observed. The trial has finished
accrual.
e134 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
NCT02337491
NCT02337491 is phase II trial based on the premise that anti-
VEGF therapy could be synergistic with immunotherapy.15
This trial is a single-institution study sponsored by Merck using
Mercks antiPD-1 drug. The study will measure progression-
free survival at 6 months. The trial has two arms: antiPD-1
alone and antiPD-1 with bevacizumab.
NCT02336166
NCT02336166 is a phase II trial sponsored by the Ludwig
Foundation to study the antiPD-1 therapy developed by
AstraZeneca. The trial has multiple objectives. The first
cohort (cohort A) will study the efficacy of antiPD-L1 for
patients with newly diagnosed glioblastoma that has
unmethylated O(6)-methylguanine DNA methyltransferase.
The remarkable factor in this arm is that temozolomide
(TMZ) will be withheld; patients will receive only antiPD-L1
and radiation. The rationale behind this design is that ra-
diation and antiPD-L1 are synergistic, so systemic che-
motherapy may be counterproductive. The second cohort
(cohort B) will assess the efficacy of antiPD-L1 alone for
patients who have recurrent glioblastoma. The third cohort
(cohort C) will administer antiPD-L1 to patients who have
recurrent glioblastoma that is progressing with bevacizumab
treatment.
NCT02617589
NCT02617589 is a phase III trial sponsored by Bristol Myers
Squibb to assess the efficacy of antiPD-1 with radiation
among patients who have newly diagnosed glioblastoma.
The comparator arm will enroll patients for treatment with
radiation and temozolomide (standard of care).
NCT02313272
NCT02313272 is a phase I trial to assess the safety of an
antiPD-1 drug developed by Merck with bevacizumab and
hypofractionated stereotactic irradiation for patients who
have recurrent high-grade gliomas.
NCT02530502
NCT02530502 is a phase I/II trial for patients with newly
diagnosed glioblastoma. Phase I will assess the safety of
combining an antiPD-1 drug developed by Merck with
radiation and temozolomide for patients with newly di-
agnosed glioblastoma. Phase II will compare the efficacy of
adding antiPD-1 to radiation and temozolomide for pa-
tients treated with radiation and temolozomide.
NCT02311582
NCT02311582 is a phase I, open-label, randomized safety
study to assess the addition of MK-3475, an antiPD-1
drug developed by Merck, for treatment among patients
who are being treated with laser ablation for recurrent
glioblastoma.

BIOMARKERS
What we have learned from checkpoint inhibitor trials in
other tumors is that the overall response rate is between
20% and 30%. Therefore, it is important to identify patients
who would not respond and to minimize toxicities and treat
them with other therapies. Current strategies for biomarkers
have focused on protein expression, immune cell charac-
terization, and mutational burden.
The melanoma and lung cancer trials have focused on the
expression of PD-L1 on tumor cells as a biomarker to predict
response. Investigators have found that tumors that express
PD-L1 were more likely than PD-L1negative tumors to
respond (overall response rate) to antiPD-1 therapy.16
Interestingly, the expression of PD-L1 was not important
in the trial of patients with melanoma who received the
concurrent combination of antiPD-1 and antiCTLA-4.
Some theorized that an adaptive immune response oc-
curred with the combination therapy and that combination
caused tumor cells to express PD-L1 as a defense mecha-
nism.17 In an interesting twist, when the therapies were
sequencedpatients received antiCTLA-4 first, followed by
antiPD-1the overall response rate again correlated to the
PD-L1 status of the tumor.18
Another approach has been to assess the activation status
of various immune cells as a predictor of response. As an
example, investigators assessed the activation status of CD8+
T cells by measuring eomesodermin for patients with mela-
noma after they received treatment with antiCTLA-4 and
found that the eomesodermin status predicted relapse-free
survival. Other markers of interest are interferon gamma
expression, Helios expression, and various other checkpoint
molecules.19
Last, investigators have assessed mutational burden as a
predictor of response. Chan et al20 correlated mutational
burden among patients with lung cancer to response rates
among patients who received antiPD-1 therapy. They
found that patients with lung cancer who had a history of
smoking had higher mutational burdens than patients with
lung cancer who did not smoke and that the higher number
of mutations correlated to improved survival.20 Le et al21
also studied patients with colon cancer and found that
patients who had a defective DNA repair gene had a higher
number of mutations in their tumor, and this again corre-
lated to improved survival. Some theorize that the reason for
the observed improved antitumor immune responses in
patients with tumors that had more mutations was that
the tumors expressed a higher number of target antigens for
the immune system.21,22
TOXICITY
Immune-related toxicities are an important issue for pa-
tients who receive immunotherapy. Most of the toxicities
are related to autoimmune reactions. The most common
toxicities include colitis, pneumonitis, hepatitis, pancreatitis,
dermatitis, hypophysitis, and thyroiditis. If the toxicities are
not recognized early, these reactions could become life
CURRENT STATE OF IMMUNE-BASED THERAPIES FOR GLIOBLASTOMA
threatening. Treatments often require stopping the treat-
ment, starting high-dose corticosteroids, and possibly ad-
ministering infliximab.12,13,23
IMAGING
Determining response to immunotherapy with imaging has
become an area of intense interest. In the trial reported by
Hodi et al,12 a large number of patients with melanoma who
received antiCTLA-4 experienced pseudoprogression.
Furthermore, the researchers found that pseudoprogression
could take months to resolve.24,25 As a result, many trials
have built in lag times for imaging to allow patients to
continue therapy and to avoid considering the treatment a
failure. In glioblastoma, Okada et al26 have developed an
iRANO protocol specifically tailored for immunotherapy.
COMBINATION THERAPY
As previously mentioned, the response rates for patients who
receive immunotherapy has ranged from 20% to 30%. Studies
are investigating ways to combine checkpoint inhibitors with
other modalities, such as radiation, bevacizumab, and de-
vices. Zeng et al10 demonstrated in a preclinical glioblastoma
model that the combination of focused radiation with
antiPD-1 is synergistic. Clinical trials (e.g., NCT02313272) are
looking at stereotactic radiation use in combination with
checkpoint inhibitors. Bevacizumab also may work syner-
gistically with immunotherapy.20 Preclinical data suggest
that this approach could be effective, and a phase II trial
(NCT02337491) is looking at the combination of bevacizumab
and antiPD-1 for patients with glioblastoma. Finally, another
interesting approach is the combination of laser ablation with
antiPD-1. A phase I trial (NCT02313272) is looking at the
combination of antiPD-1 with laser ablation.
In conclusion, checkpoint inhibitors have shown great
promise in other solid tumors. There is much excitement
about checkpoint inhibitors in the setting of glioblastoma.
Several large trials are underway to assess the efficacy of
checkpoint inhibitors in glioblastoma.
VIRAL- AND GENE-MEDIATED
IMMUNOTHERAPIES FOR GLIOBLASTOMA
We have discussed the various types of immunotherapy for
glioblastoma. Now, we discuss one additional mode that
involves the use of genetically engineered viruses to deliver
cytotoxic/immunostimulatory genes into tumors.27 Two
main types of viruses are used in this technology: replication-
defective vectors, in which viral genes have been removed so
there is no expression of viral genes or generation of progeny
viruses, but there is expression of an immunostimulatory
and/or cytotoxic gene, and tumor replicationselective vi-
ruses (oncolytic viruses), in which a viral pathogen is engi-
neered so that its pathogenicity is now targeted to tumor
cells and not normal cells.28 It is recognized now that the
presence of viral genes and viral proteins in both of these
technologies can elicit powerful anticancer immune re-
sponses, which are a major component of efficacy.29
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e135
LIM, WELLER, AND CHIOCCA
FIGURE 1. Immunosuppressive Properties of Glioma Stem Cells
Abbreviation: TGF-b, transforming growth factor-beta.
Modified from Hatiboglu et al.42
Characteristics that differentiate this immunotherapy
from others are the following: this immunotherapy in-
volves a neurosurgical component of direct injection into
glioblastoma, either by stereotaxy or free-hand injection
during a craniotomy; is off-the-shelf, in that manipulation of
cells from the patient before or after treatment is not in-
volved; and does not require a priori knowledge of the
identity of tumor-specific antigens that require targeting
and, at least in theory, the cytotoxic action of the viral
vector-delivered cytotoxic gene or of the replicating onco-
lytic viruses will expose the repertoire of all tumor-specific
antigens to the immune system.
There are more than 2 decades of clinical trial experiences
that used various types of replication-defective vectors to
deliver various types of cytotoxic/immunostimulatory genes,
but none have resulted in an FDA-approved clinical product,
and two phase III clinical trialsa retroviral vector to deliver the
cytotoxic/immunostimulatory herpes thymidine kinase (TK)
gene for recurrent glioblastoma30 and an adenoviral vector to
deliver TK in newly diagnosed glioblastoma (ASPECT)have
failed.31 However, we recently reported the results of a phase II
trial in which aglatimagene besadenovec (AdV-tk), a non-
replicating adenovirus expressing the herpesvirus TK gene,
was free-hand injected in a resected, newly diagnosed, ma-
lignant glioma cavity.32,33 The patient then received the oral
antiherpetic prodrug (valacyclovir) while undergoing standard-
of-care radiochemotherapy (gene-mediated cytotoxic immu-
notherapy [GMCI]). There are multiple modes of cytotoxic and
immunostimulatory anticancer action (Fig. 3):
e136 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
1. The delivered TK gene product phosphorylates the ad-
ministered valacyclovir drug, which becomes incorporated
at sites where DNA is becoming repaired or where DNA is
replicating. This leads to termination of DNA repair and/or
replication, leading to immunogenic cell death.
2. Standard of care also leads to cytotoxicity, and
radiation-induced DNA damage leads to additional
unsuccessful and cytotoxic attempts at DNA repair
using the phosphorylated valacyclovir pools.
3. The delivered TK antigen and viral vector proteins act
as superantigens, providing an immunostimulatory
stimulus in the glioblastoma microenvironment.
4. The cytotoxic death of glioblastoma cells is also im-
munogenic, releasing and exposing multiple glioma
antigens to the immune system.
Our published mature phase II data appear to show en-
couraging, albeit not definite, results in terms of possible
efficacy on the basis of the extent of residual tumor burden:
the median overall survival (OS) durations for patients who
underwent gross total resection were 25.0 and 16.9 months
(a difference of 8.1 months) for GMCI/standard of care
and standard of care, respectively (hazard ratio 0.59; 95%
CI, 0.350.998; p = .0492); for patients who underwent
subtotal resections, the difference was only 1 month (13.5
vs. 12.5 months for GMCI/standard of care vs. standard of
care; p = .4584).33 To further improve this therapy, we have
returned to the laboratory. The current theory is that to
be effective, an anticancer immune response by cytotoxic
 CURRENT STATE OF IMMUNE-BASED THERAPIES FOR GLIOBLASTOMA

FIGURE 2. Examples of Activating (CD28) and Inhibiting (PD-1) Immune Checkpoints

T cells requires removal of immune checkpoint signaling
mediated by PD-1/PD-L1,34-36 the CTLA-4/B7 family,37,38 and
other molecules. We thus hypothesize that a combination of
GMCI and checkpoint inhibitors may lead to more effective
immunotherapy.8 In fact, we are finding that the application
of GMCI in mouse gliomas does lead to increase signaling of
immune checkpoint networks and that inhibition of these
networks does lead to even more encouraging antigliomal
effects of GMCI.
For the second type of viral-mediated therapy, multiple
types of oncolytic viruses have been tested in clinical trials of
glioblastoma, all in the recurrent setting. No trial for glio-
blastoma has progressed to phase III, but there are two
oncolytic viruses (an oncolytic adenovirus from DNAtrix

FIGURE 3. Schematics of the Published Clinical Trials and Different Modes of Anticancer Action of Gene-Mediated
Cytotoxic Immunotherapy

(Top panel) Schematic of the published clinical trials of gene-mediated cytotoxic immunotherapy (GMCI). On the day of surgery, the adenoviral vector that delivers TK (AdV-
tk) is injected in the resected newly diagnosed glioblastoma tumor cavity. The oral agent (valacyclovir) is administered to the patient on days 1 to 14. Standard-of-care
radiation and temozolomide are also administered as per the Stupp regimen. (Lower panel) Schematic of the different modes of anticancer action of GMCI.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e137

LIM, WELLER, AND CHIOCCA
and an oncolytic retrovirus from Tocagen) that have
completed phase II evaluation and planning for advanced
phase III trials. Commercial interest in this area of
oncolytic virusbased immunotherapy has been resur-
rected recently by the FDA approval of a herpes simplex
virus (HSV) oncolytic virus for melanoma.29,39 Our group
has been involved in the preclinical and clinical devel-
opment of an oncolytic virus, based on HSV1, that
has been engineered to selectively replicate and de-
stroy gliomas on the basis of tumor deregulation of the
p16 tumor suppressor pathway and expression of the
glioma stem-cell marker, nestin.40,41 This oncolytic virus
(rQNestin34.5v.2) shows potency in animal models of
gliomas compared with older, clinical trialtested versions
of herpes oncolytic viruses. Extensive preclinical data
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11. Reardon DA, Freeman G, Wu C, et al. Immunotherapy advances for
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have been obtained to justify filing of an investigational
new drug application with the FDA for a planned first-
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In summary, the use of tumor-selective viruses and viral-
based vectors is increasingly delivering promising results as
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successful completion of phase III trials for several of these
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We thank Eileen Kim for her help with Fig. 2.
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18. Callahan MK, Postow MA, Wolchok JD. CTLA-4 and PD-1 pathway
blockade: combinations in the clinic. Front Oncol. 2014;4:385.
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T cells associated with ipilimumab treatment. J Transl Med. 2012;10:
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20. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology: mutational
landscape determines sensitivity to PD-1 blockade in nonsmall-cell
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21. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-
repair deficiency. N Engl J Med. 2015;372:2509-2520.
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24. Hodi FS, Ribas A, Daud A, et al. Patterns of response in patients with
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evaluation of immune-related response criteria (irRC). J Immunother
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25. Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor
remission, and long-term safety in patients with advanced melanoma
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26. Okada H, Weller M, Huang R, et al. Immunotherapy response assess-
ment in neuro-oncology: a report of the RANO working group. Lancet
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27. Kaufmann JK, Chiocca EA. Glioma virus therapies between bench and
bedside. Neuro Oncol. 2014;16:334-351.
28. Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer
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29. Lawler SE, Chiocca EA. Oncolytic virus-mediated immunotherapy:
a combinatorial approach for cancer treatment. J Clin Oncol. 2015;33:
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30. Rainov NG. A phase III clinical evaluation of herpes simplex virus type 1
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31. Westphal M, Yla-Herttuala S, Martin J, et al; ASPECT Study Group.
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2013;14:823-833.
32. Chiocca EA, Aguilar LK, Bell SD, et al. Phase IB study of gene-mediated
cytotoxic immunotherapy adjuvant to up-front surgery and intensive
timing radiation for malignant glioma. J Clin Oncol. 2011;29:3611-3619.
33. Wheeler LA, Manzanera AG, Bell SD, et al. Phase 2 multicenter study of
gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection
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34. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted
CD8 T cells during chronic viral infection. Nature. 2006;439:682-687.
35. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immu-
noinhibitory receptor by a novel B7 family member leads to negative
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36. Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immu-
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37. Lane P. Regulation of T and B cell responses by modulating interactions
between CD28/CTLA4 and their ligands, CD80 and CD86. Ann N Y Acad
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39. Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec
improves durable response rate in patients with advanced melanoma.
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40. Aghi M, Visted T, Depinho RA, et al. Oncolytic herpes virus
with defective ICP6 specifically replicates in quiescent cells with
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e139
CENTRAL NERVOUS SYSTEM TUMORS

Treatment of Low-Grade Gliomas

in the Era of Genomic Medicine

CHAIR
Minesh P. Mehta, MD, MBChB, FASTRO
University of Maryland Medical Center
Baltimore, MD

SPEAKERS
Kenneth D. Aldape, MD
The University of Texas MD Anderson Cancer Center
Houston, TX

Susan M. Chang, MD
University of California, San Francisco
San Francisco, CA
 LOWER-GRADE GLIOMAS, MOLECULAR MARKERS, AND THERAPEUTIC CHOICES

Treatment of Adult Lower-Grade Glioma in the Era of Genomic

Medicine
Susan M. Chang, MD, Daniel P. Cahill, MD, PhD, Kenneth D. Aldape, MD, and Minesh P. Mehta, MBChB, FASTRO

OVERVIEW

By convention, gliomas are histopathologically classified into four grades by the World Health Organization (WHO) legacy
criteria, in which increasing grade is associated with worse prognosis and grades also are subtyped by presumed cell of origin.
This classification has prognostic value but is limited by wide variability of outcome within each grade, so the classification is
rapidly undergoing dramatic re-evaluation in the context of a superior understanding of the biologic heterogeneity and
molecular make-up of these tumors, such that we now recognize that some low-grade gliomas behave almost like malignant
glioblastoma, whereas other anaplastic gliomas have outcomes comparable to favorable low-grade gliomas. This clinical
spectrum is partly accounted for by the dispersion of several molecular genetic alterations inherent to clinical tumor
behavior. These molecular biomarkers have become important not only as prognostic factors but also, more critically, as
predictive markers to drive therapeutic decision making. Some of these, in the near future, will likely also serve as potential
therapeutic targets. In this article, we summarize the key molecular features of clinical significance for WHO grades II and III
gliomas and underscore how the therapeutic landscape is changing.

S everal challenges limit the efficacy of surgery, radio-

therapy (RT), chemotherapy, and targeted agents for
WHO grades II and III glioma (categorized as lower-grade
glioma, or LrGG). These include the diffuse and imprecisely
defined boundaries of extension, proximity to, and growth
into critical cortical and subcortical structures, inability of
therapeutic agents to adequately cross the blood-brain
barrier, active transport mechanisms of drug efflux, high
plasma protein binding of most conventional agents, and
multiple and redundant drug and radiation resistance
mechanisms. Biologic tumor heterogeneity, with respect to
response to treatment and resistance mechanisms, despite
similar grade or histology, is another important challenge.
The era of genomic medicine holds the promise of gener-
ating personalized medicine treatment paradigms to im-
prove outcomes. The ability of isocitrate dehydrogenase
(IDH) mutations, loss of heterozygosity of 1p and 19q, and
methylation of methylguanine methyl transferase (MGMT)
status to serve as predictive biomarkers is of specific interest
in the treatment of LrGG.
MOLECULAR CHARACTERIZATION OF LOWER-
GRADE GLIOMA
Clinicopathologic assessment, valuable to distinguish
grades of glioma, does not address the distinct genetic
and biologically different subgroups that are nested within
each grade category. 1 In addition, the interevaluator
variability that has been demonstrated, especially for
mixed histologies, is a major limitation in provision of
uniform and reproducible pathologic diagnoses.2 Recent
molecular characterization has identified potential bio-
markers that can serve to define the framework of different
subtypes of these tumors with more uniform prognosis
and also potentially can serve as indicators for treatment
selection.3,4
Somatic mutations in the isocitrate dehydrogenase genes
IDH1 and IDH2 are of important prognostic value. These
mutations are present in 50% to 80% of WHO grades II and III
astrocytic and oligodendroglial tumors in adults and also
occur with similar frequency in secondary glioblastoma.
These mutant enzymes lead to conversion of a-ketoglutarate
into D-2-hydroxyglutarate, an oncometabolite that drives
the oncogenic activity of IDH mutations.5 Irrespective of
treatment choice, patients with IDH-mutated tumors ex-
perience superior survival compared with patients who
have IDH wild-type gliomas of the same histologic grade; this
difference clearly underscores the prognostic significance of
this marker. In tumors of oligodendroglial lineage, the most
common cytogenetic alteration consists of an unbalanced
t1,19(q10;p10) translocation that results in the fusion of the

From the University of California, San Francisco, San Francisco, CA; Harvard Medical School, Boston, MA; Toronto General Hospital/Research Institute, Toronto, Canada; University of
Maryland, Baltimore, MD.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Minesh P. Mehta, MD, FASTRO, Department of Radiation Oncology, University of Maryland, 22 South Greene St., Baltimore, MD 21201; email: mmehta@umm.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 75

CHANG ET AL
chromosomal arms of 1p and 19q, accompanied by the loss
of one hybrid chromosome, which thus results in the loss of
heterozygosity of 1p and 19q. These tumors have better
prognoses than histologically identical tumors of the same
grade that do not harbor this codeletion. Furthermore, this
biomarker has been proven to be a critical predictive bio-
marker of chemotherapy response, and improved survival
after chemoradiotherapy, compared with RT alone.
Recent reports also have reinforced the redefini-
tion of subgroups of LrGG by incorporating additional
biomarkersfor example, activating mutations of the tel-
omerase reverse transcription (TERT) promotor and muta-
tions and losses of alpha thalassemia/mental retardation
syndrome X linked (ATRX) and tumor protein P53 (TP53). By
using these genetic alterations, the vast majority of adult
diffuse gliomas fall into one of three distinct categories that
more reproducibly predict clinical outcome and guide
treatment by creating more homogeneous subsets.3,4 These
consist of (1) molecular glioblastomas, which are highly
aggressive tumors characterized by the TERT promoter
mutation and concomitant deletions of chromosome 10 and
gain of chromosome 7 with EGFR amplification, and they are
notable for the absence of IDH1/2 mutations (i.e., they
are IDH wild type); (2) molecular astrocytomas, which are
characterized by mutations in IDH1/2, TP53, and ATRX, and
the absence of promoter mutations or codeletion of 1p19q;
and (3) molecular oligodendrogliomas, which are char-
acterized by IDH mutation and TERT promoter mutation,
KEY POINTS
WHO grades II and III gliomas, conventionally
substratified as astrocytomas or oligodendrogliomas (or
mixed), are highly heterogeneous tumors with complex,
overlapping, and varied biological behavior.
In the past decade, significant new therapeutic strides
have been made to improve overall survival in almost all
of these entities, in large measure, as a consequence of
robust, international clinical trial collaborations with
parallel tissue collection for molecular analysis.
This tissue collection effort, with well-annotated
matching clinical outcomes, has secondarily identified
several key molecular markers that have crucial
prognostic significance, such as IDH1/2 mutations,
1p19q co-deletions, MGMT methylation, and more.
These markers are also increasingly identified as crucial
predictive markers, which thereby influence therapeutic
decision making.
Some of these molecular markers, such as the IDH1/2
mutation, are now also emerging as future therapeutic
targets. Multivariate analysis of clinical and molecular
markers is identifying subgroups that likely need to be
treated with greater therapeutic intensity and others for
which therapeutic de-intensification could potentially
be contemplated, posing novel challenges for clinical
trial design and conduct.
76 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
1p19q codeletion, and mutations in CIC and FUBP1, with an
absence of mutations in TP53 or ATRX.
WHO GRADE III ANAPLASTIC
OLIGODENDROGLIOMA: THE CASE FOR A
PREDICTIVE BIOMARKER FOR CHEMOTHERAPY
On the basis of several retrospective series and phase II
trials that demonstrated the chemosensitivity of oligoden-
drogliomas, two prospective randomized phase III trials
evaluated the role of postoperative chemoradiotherapy
compared with RT alone.6,7 In both studies, the experimental
arm was RT combined with procarbazine, lomustine, and
vincristine (PCV). In the Radiation Therapy Oncology Group
(RTOG) trial RTOG-9402, patients were randomly assigned
either to four cycles of intensified PCV followed by RT or to
immediate RT without chemotherapy. Mature data from this
study showed that the median survival of those with
codeleted tumors who were treated with PCV plus RT was
twice that of patients who received only RT (14.7 vs. 7.3
years). The survival of patients with codeleted tumors was
better than that of those with non-codeleted tumors re-
gardless of treatment, which emphasizes the prognostic
value of the 1p19q codeletion. The survival was not sta-
tistically different for patients with tumors that lacked the 1p
and 19q deletion, irrespective of treatment (median survival,
2.6 vs. 2.7 years), which suggests that the codeletion also has
predictive value. In another analysis of patients enrolled in
this study, IDH mutation status had predictive value as well;
although patients with codeleted tumors lived longest,
patients with non-codeleted IDH-mutated tumors also lived
longer after chemoradiotherapy compared to RT alone.8 The
implication here is that, for WHO grade III tumors, con-
ventionally labeled as oligodendroglioma, treatment with
chemoradiotherapy imparts a substantial survival advantage
when the tumors are either codeleted for 1p19q or are non-
codeleted tumors only with expression of an IDH mutation.
Non-codeleted tumors without IDH mutations have the
worst prognosis and do not benefit from the addition of
chemotherapy.
In the European Organization for Research and Treat-
ment of Cancer (EORTC) 26951 trial, 368 patients who had
predominantly grade III oligodendroglial tumors received
immediate RT only or RT followed by six cycles of PCV.
Patients with tumors that had the 1p and 19q codeletion
had better outcomes regardless of therapy (prognostic).
In addition, MGMT promoter methylation was of prog-
nostic value in this cohort. Similar to the results of RTOG-
9402, long-term follow-up showed that the addition of
PCV to RT significantly increased progression-free survival
(PFS; median, 157 vs. 50 months) in patients with the
1p19q codeletion, and there was a trend toward increased
overall survival (OS; OS not reached in the RT/PCV group
vs. OS of 112 months in the RT-alone group; hazard
ratio [HR] 0.56; 95% CI, 0.311.03). These two studies
confirmed the value of the 1p19q codeletion as an im-
portant prognostic and predictive marker and influenced
the design of studies in anaplastic glioma; in ongoing

international studies, patient arms are being stratified on
the basis of this biomarker. An international intergroup
phase III trial is being conducted in patients who have
newly diagnosed grade 3 glioma with the 1p19q status
codeletion.7 Patients are randomly assigned to two arms,
RT with concomitant and adjuvant temozolomide or RT
with adjuvant PCV.
WHO GRADE III ANAPLASTIC ASTROCYTOMA
The role of chemotherapy in anaplastic astrocytoma is not
well established. Most phase III trials have demonstrated
no benefit of chemotherapy compared with radiation
alone in this tumor. Carmustine and PCV are associated
with minimal improvement in survival. The Glioma Meta-
Analysis Trialists group showed a 6% increase in 1- and
2-year survival rates for patients who received chemo-
therapy (2-year survival, 37% vs. 31%), whereas a large
randomized trial of adjuvant PCV compared with RT
alone did not show any benefit from PCV.9,10 RTOG-9813
was a phase III study to compare radiation with bis-
chloroethylnitrosourea (BCNU) or lomustine to radiation with
temozolomide, and the results of this study demonstrated
no difference in survival between the two chemotherapy
arms. Molecular characterization in a subset of patients
showed that IDH mutation was a strong prognostic factor.
The number of patients was too small to determine any
differential benefit of the type of chemotherapy on the
basis of IDH mutation status.11
The NOA-04 phase III trial compared the efficacy of RT
followed by chemotherapy at progression to initial che-
motherapy followed by RT at progression in newly diagnosed
anaplastic gliomas and did not show any difference in the
median time to failure, PFS, or OS among the arms. The study
demonstrated the prognostic value of IDH1 mutations in
anaplastic gliomas, with a favorable impact that was more
distinct than that of 1p19q codeletion or MGMT promoter
methylation.12
A large international trial in which patients with newly
diagnosed non1p19q-codeleted grade III glioma were
randomly assigned to radiation with or without concom-
itant and with or without adjuvant temozolomide after
RT recently completed accrual, and initial interim analysis
showed a significant benefit with adjuvant temozolomide
(p = .0084). Results for concurrent temozolomide and for the
overall treatment regimen are not yet available. Tissue
acquisition was mandatory for this study and will allow
evaluation of the role of concurrent or adjuvant temozo-
lomide on the basis of molecular subgroups.
WHO GRADE II GLIOMA
Data and conclusions pertaining to WHO grade II gliomas
have largely been derived from patient subsets entered onto
therapeutic trials. As a consequence, these recommen-
dations do not apply to the patients with lowest-risk dis-
ease, that is, younger patients with completed resected
tumors, especially oligodendroglioma.
LOWER-GRADE GLIOMAS, MOLECULAR MARKERS, AND THERAPEUTIC CHOICES
Because of the relatively low proliferative index of grade II
glioma, these tumors were previously considered chemo-
therapy resistant. Reports of objective responses in patients
with LrGG, however, raised interest in the use of chemo-
therapy in the adjuvant setting. In a small Southwest On-
cology Group trial, there was no survival difference among
patients with incompletely excised grade II gliomas ran-
domly assigned to RT alone or to the combination of RT and
lomustine.13 The RTOG-9802 study examined the role of
adjuvant PCV chemotherapy for high-risk adults (i.e., those
of any age with tumors that had less than total resection, or
those older than age 40 with any resection) who had grade II
glioma. Two hundred fifty-one patients were randomly
assigned to RT alone or RT followed by six cycles of PCV. At a
median follow-up of 12 years, a significant improvement in
OS in the RT/PCV group (13.3 years) compared with the RT-
alone group (7.8 years) was reported.14
The significance of 1p19q, MGMT, and IDH was unknown at
the time of study initiation, and several molecular analyses
were post hoc, performed on non-mandatorily collected
tumor blocks, slides, or cores submitted for 117 patients; of
these, 113 (57 of 126 [45%] and 56 of 125 [45%] in the RT
alone and RT/PCV arms, respectively) were suitable for IDH-
R132H immunohistochemistry interpretation. IDH1-R132H
mutations were detected in 35 (61.4%) of 57 patients and 36
(64.3%) of 56 patients in the RT alone and RT/PCV arms,
respectively, and in 77.6%, 53.8%, and 48.0% of patients with
oligodendroglioma, oligoastrocytoma, and astrocytoma, re-
spectively. Tissue sufficient for determination of other IDH
mutations or of the 1p19q codeletion was available for
analysis in 29 and 34 patients in the RT and in the RT/PCV
arms, respectively. In a subset analysis of PFS by IDH1-R132H
mutation status, patients with mutations experienced sig-
nificantly longer PFS than those without (p , .001), regardless
of treatment, which established the mutation as prognosti-
cally significant. In addition, patients with tumoral IDH1-
R132H mutations had longer PFS if they received RT/PCV than
if they received RT alone (p = .003), which established the
mutation status as a predictive variable. The number of events
in patients without the IDH1-R132H mutation was too small to
determine the association of treatment effect in this subset.
In an exploratory subset analysis of OS by IDH1-R132H mu-
tation status, patients with mutations experienced signifi-
cantly longer OS than those without the mutation, regardless
of treatment (log rank p = .02). Median survival times with and
without the mutation were 13.1 and 5.1 years, respectively.
Patients with tumoral IDH1-R132H mutations also experi-
enced longer OS if they received RT/PCV than if they received
RT alone (log rank p = .02). The number of events in patients
without the IDH1-R132H mutation was too small to de-
termine the association of treatment effect in this subset.15
RTOG-0424 was a study of concurrent and adjuvant
temozolomide and RT in a high-risk low-grade glioma
population, and the 3-year OS rate was 73.1% (95% CI,
65.3%80.8%), which was significantly improved compared
with the prespecified historical control reported by Pignatti
et al (p , .0001).16 Molecular analysis on this trial is pending.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 77
CHANG ET AL
An ongoing intergroup phase III trial is attempting to address
the role of adjunctive temozolomide in LrGG.
ROLE OF RADIOTHERAPY
Historically, RT trials have established that earlier intervention
with RT prolongs PFS and reduces symptom burden, especially
related to seizures, but does not improve survival compared
with deferred RT.17 In addition, a categorical dose effect on
survival is not observed with RT in the 45- to 64-Gy range.18
Grade III tumors were historically labeled malignant gliomas
and were conglomerated in trials that included grade IV
glioblastomas, which made it difficult to discern the precise
survival advantage from RT. More contemporary trials in grade
II astrocytoma and oligodendroglioma, as well as in grade III
oligodendroglioma, have confimed that chemoradiotherapy
yields a survival advantage compared with RT alone. A com-
mon theme to emerge from these trials is that, for the fa-
vorable tumors, especially those with IDH mutations, a
dramatic survival advantage emerges with combination che-
moradiotherapy; in the case of grade III tumors, even those in
the 1p19q non-codeleted subset, a survival advantage with
chemoradiotherapy is observed if the tumor has IDH mutant
status. An important caveat here is that these patients have
prolonged survival, so concerns have been expressed about
possible cognitive decline after RT; in practice, some clinicians
simply treat with chemotherapy alone and reserve RT for
salvage therapy. Level-1 data to support this practice do not
exist, and, until it is categorically established that RT dose
reduction or dose elimination is safe, these patients should
continue to be treated with combination chemoradiotherapy.
The IDH wild-type tumors do not exhibit this survival advantage
with chemoradiotherapy, so it would be reasonable to consider
treating patients who have these tumors with RT alone.
The EORTC has completed a large, international, ran-
domized trial in 477 patients with WHO grade II tumors
(22033-26033), stratified by 1p deletion, and randomized to
RT alone or temozolomide alone. A difference between the
two treatment strategies was not observed for PFS, although
RT was numerically favored. However, molecular tumor
characterization may allow the treatment approach to be
personalized and one or the other treatment modality to be
selected. A post hoc analysis of molecular markers was done
in 407 patients and was reported recently. IDH1 or IDH2
mutations were detected in 85.8% of patients. Codeletions
of 1p19q were identified in 33%. MGMT was methylated in
90%, of which the majority, 86%, was IDH mutant. Mutation
of IDH1 or IDH2, regardless of 1p19q codeletion, was a
positive prognostic factor. Patients with IDH-mutated, non-
codeleted tumors had shorter PFS after treatment with
temozolomide than after RT (HR 1.86; 95% CI, 1.212.87; log
rank p = .0043), whereas no difference was observed be-
tween these treatments for patients with IDH wild-type
tumors and IDH-mutated, codeleted tumors.19
One additional study, the phase III German NOA-04 trial,
deserves mention, relative to the role of RT in LrGG. The
NOA-04 trial compared the efficacy of RT followed by
chemotherapy at progression with the reverse sequence in
78 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
patients with newly diagnosed anaplastic gliomas. Three
hundred eighteen patients, most of whom had grade 3
anaplastic astrocytoma (with very few oligodendroglioma),
were randomly assigned 2:1:1 (arms A:B1:B2) to receive
conventional RT (arm A), PCV (arm B1), or temozolomide
(arm B2) at diagnosis. At progression or unacceptable tox-
icity, patients in arm A were treated with PCV or temozo-
lomide (1:1 random assignment), whereas patients in arms
B1 or B2 received RT. The median PFS (HR 1.0; 95% CI,
0.71.3) and OS (HR 1.2; 95% CI, 0.81.9) were similar for all
three arms. Hypermethylation of the MGMT promoter (HR
0.59; 95% CI, 0.361.0) and mutations of IDH1 gene (HR 0.48;
95% CI, 0.290.77) reduced the risk of progression, and IDH
mutations had the largest impact. MGMT promoter meth-
ylation also was associated with prolonged PFS in the
chemotherapy and RT arm. Therefore, initial RT or che-
motherapy achieved comparable results in patients with
anaplastic gliomas.12 This trial has sometimes been used to
support the logic of initiating chemotherapy first, followed
by RT at progression, for grade II gliomas (both astrocytic and
oligodendroglial) and grade III oligodendroglioma, but it
must be borne in mind that the results may not necessarily
extrapolate to these entities.
SURGERY IN LOWER-GRADE GLIOMA
The role of surgical resection in adult diffuse gliomas is
twofold: diagnostic and therapeutic. Historically, the di-
agnostic grading of a glioma has been dependent upon the
type of procedure performed and the volume of tissue
specimen provided to the pathologist for review. Thus, a
less-extensive biopsy procedure can undersample a glioma,
which can result in diagnostic histologic undergrading. For
example, Glantz et al20 demonstrated that, in 262 patients
undergoing resection, 214 (82%) were ultimately rendered a
final diagnosis of glioblastoma (WHO grade IV) and 48 (18%)
were diagnosed with anaplastic astrocytoma (WHO grade
III). In contrast, of 67 patients undergoing stereotactic bi-
opsy, 33 (49%) were diagnosed with glioblastoma, whereas
34 (51%) were diagnosed with anaplastic astrocytoma.
These observations led to the conclusion that it was likely
that some of the anaplastic astrocytomas diagnosed by
stereotactic biopsy were undersampled and actually rep-
resented glioblastomas.20
A similar theme was noted by Jackson et al,21 in a study
based on biopsy specimens and the subsequent resection
specimens from the same patient (paired samples), without
intervening delay or therapeutic intervention. In this study,
the authors noted that the diagnoses rendered from the
biopsy specimen differed from the diagnoses achieved by
using the more extensive surgical resection specimen in 50
(49%) of 82 instances. They concluded that stereotactic
biopsy is frequently inaccurate in provision of a correct
diagnosis and thus recommended surgical resection, even
purely for diagnostic purposes.21
In a more recent analysis, Kim et al22 noted that molecular
testing can be used to resolve these diagnostic discrepancies
that develop because of limited pathologic sampling. Similar

to results by Glantz et al,20 these investigators noted a
volume-based discrepancy between diagnoses of grade IV
and grade III tumors, whereby grade IV diagnoses were more
common in larger resection specimens. Notably, however,
the frequency of IDH1 mutation was constant between the
two cohorts, which demonstrated that molecular status was
volume independent. Importantly, the diagnosis of ana-
plastic astrocytoma from a less-extensive resection was
associated with significantly poorer survival (glioblastoma-
like). Thus, the investigators concluded that, for smaller
surgical specimens, underdiagnosis of glioblastoma may
occur when the analysis is restricted to histopathology
alone.22 Moving forward, the WHO will now integrate
molecular scoring into the diagnostic categorization of these
lesions.23
With regard to the therapeutic benefit of resection, recent
studies have focused on the benefit of removal of the
nonenhancing tumor that makes up the majority (or en-
tirety) of an LrGG. Most studies of surgery for glioma are
retrospective and nonrandomized and, therefore, are po-
tentially biased because of patient selection. In a molecular
study, Beiko et al24 found that IDH1 mutation was in-
dependently associated with complete resection of en-
hancing disease in grade III and IV astrocytomas and that
additional resection of nonenhancing disease was associ-
ated with an additional survival benefit only in the IDH1-
mutant cohort.24 For LrGG, Shaw et al25 observed 111
patients who were assigned to observation after surgeon-
determined gross-total resection in the RTOG-9802 study of
low-risk, low-grade (WHO grade II) glioma.25 The most
favorable-risk cohort shared three factors: tumor diameter
less than 4 cm on preoperative MRI scan, oligodendroglioma
histology, and less than 1 cm of residual tumor on post-
operative MRI scan, indicative of the survival benefit
associated with more extensive resection. In a well-
characterized cohort, Smith et al26 demonstrated an asso-
ciation between gross-total resection of nonenhancing
tumor and survival in low-grade (WHO grade II) gliomas. The
majority of patients in these studies likely had IDH1-mutant
tumors.
Thus, the emerging molecular classification forms a
practical guide for surgical decision making in patients with
adult diffuse gliomas. For molecular glioblastomas, the
evidence supports a surgical goal of complete resection of
enhancing disease. There is no evidence yet in this pop-
ulation that surgical resection of nonenhancing disease
offers a survival benefit; surgical goals therefore should be
curtailed for lesions in eloquent cortex with a focus on
safety. For molecular astrocytomas, evidence supports a
surgical goal of maximal resection for both enhancing and
nonenhancing disease. The standard of care for subsequent
adjuvant treatment of patients with molecular astrocytoma
awaits guidance from ongoing randomized studies. Finally,
for molecular oligodendrogliomas, a surgical goal of maximal
safe resection of enhancing and nonenhancing disease again
is warranted but tempered with the knowledge that, for
these patients, well-established adjuvant therapies have
LOWER-GRADE GLIOMAS, MOLECULAR MARKERS, AND THERAPEUTIC CHOICES
been proven highly effective in the randomized studies
discussed in this article.
TARGETED THERAPY IN LOWER-GRADE GLIOMA
Aberrant signaling in pathways, including the PI3K/Akt/
mTOR network, have been identified in grade II glioma,
and clinical trials are ongoing to target this pathway as a
therapeutic approach.27 In addition, ongoing studies are
evaluating inhibitors of IDH.28 The ability to image levels of
the oncometabolite 2-hydroxyglutarate is an exciting area
of research to develop noninvasive robust biomarkers of
treatment response and clinical outcome in IDH-mutated
tumors.29 These approaches mandate the selection of pa-
tients on the basis of specific molecular/cytogenetic char-
acteristics and highlight the future of medical treatment of
LrGG in the genomic era.
CONCLUSION
There is increasing evidence that multiple molecular markers
are prognostic, and possibly even predictive, in patients with
LrGG. The 1p19q codeletion historically has conferred im-
proved prognosis and recently has been identified as a
predictive marker. IDH mutations, similarly, have also been
identified as prognostic and, possibly, predictive.5,8,11 By
using a combination of IDH1/2, 1p19q, and TERT mutations,
it is possible to subdivide these tumors into three working
subgroups: molecular glioblastoma, molecular astrocytoma,
and molecular oligodendroglioma. Effectively, this stratifies
LrGGs from the worst prognostic category that has outcomes
comparable to GBM to the best with very long survival rates
measured in decades and includes an in between category
as well; all categories likely differ in response to therapy.
Such stratification now calls into question both the existing
grade-based conventional therapeutic strategies and the
value of ongoing clinical trials that do not include these as
stratification variables.
For the worst prognostic group of LrGG, more effective
therapies might be necessary, because conventional ther-
apies are relatively ineffective; patients with these tumors
could be enrolled in clinical trials of glioblastoma, perhaps
as a separate subgroup. Among those with the best prog-
nosis, median survival exceeds a decade, and this subgroup
might include patients who can actually be observed in lieu
of immediate intervention. These patients might be suited
for treatment de-intensification, but this possibility raises
the conundrum of how to risk treatment de-intensification,
because even a modest loss in survival would take longer
than a decade to detect. One possible approach would be
to de-intensify only those components that have greater
toxicity; for example, perhaps the indirect data about the
efficacy of temozolomide in LrGGs would be adequate to
consider its use instead of PCV?11,30,31 From an RT per-
spective, perhaps these are the tumors better suited for
proton therapy, with its inherently lower integral dose.
How do we move this genomic information directly to the
therapeutic realm, specifically in terms of tailored therapies?
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 79
CHANG ET AL
IDH-directed therapies have entered phase I clinical testing,
but, with prolonged median survival rates, how exactly does
one establish the therapeutic potential of such an agent? Of
course, testing in the recurrence situation with response
rates or PFS as endpoints is one initial step, but making the
leap to a survival-based trial in the newly diagnosed context
will likely prove challenging. For example, one recent report
suggests that IDH inhibitors might in fact be radioprotective,
which potentially negates their clinical value. 32 In the
meantime, data are emerging that these IDH-mutated tu-
mors might be amenable to more complete resections and,
maybe, that these are the patients who, after a gross total
resection, could in fact receive observation only.24,33 Are
these perhaps also the patients best suited for and driv-
ing the lengthy survival rates associated with supratotal
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26. Smith JS, Chang EF, Lamborn KR, et al. Role of extent of resection in the
long-term outcome of low-grade hemispheric gliomas. J Clin Oncol.
2008;26:1338-1345.
27. McBride SM, Perez DA, Polley MY, et al. Activation of PI3K/mTOR
pathway occurs in most adult low-grade gliomas and predicts patient
survival. J Neurooncol. 2010;97:33-40.
28. Rohle D, Popovici-Muller J, Palaskas N, et al. An inhibitor of mutant IDH1
delays growth and promotes differentiation of glioma cells. Science.
2013;340:626-630.
29. Andronesi OC, Loebel F, Bogner W, et al. Treatment response as-
sessment in IDH-mutant glioma patients by non-invasive 3D functional
spectroscopic mapping of 2-hydroxyglutarate. Clin Cancer Res. 2016;22:
1632-1641.
30. Vogelbaum MA, Hu C, Peereboom DM, et al. Phase II trial of pre-
irradiation and concurrent temozolomide in patients with newly
LOWER-GRADE GLIOMAS, MOLECULAR MARKERS, AND THERAPEUTIC CHOICES
diagnosed anaplastic oligodendrogliomas and mixed anaplastic oli-
goastrocytomas: long-term results of RTOG BR0131. J Neurooncol.
2015;124:413-420.
31. Fisher BJ, Hu C, Macdonald DR, et al. Phase 2 study of temozolomide-
based chemoradiation therapy for high-risk low-grade gliomas: pre-
liminary results of Radiation Therapy Oncology Group 0424. Int J Radiat
Oncol Biol Phys. 2015;91:497-504.
32. Molenaar RJ, Botman D, Smits MA, et al. Radioprotection of IDH1-
mutated cancer cells by the IDH1-mutant inhibitor AGI-5198. Cancer
Res. 2015;75:4790-4802.
33. Duffau H. Long-term outcomes after supratotal resection of diffuse low-
grade gliomas: a consecutive series with 11-year follow-up. Acta
Neurochir (Wien). 2015;158:51-58.
34. Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations
produce 2-hydroxyglutarate. Nature. 2009;462:739-744.
35. Clinical Trial NCT02465060. NCI-MATCH: targeted therapy directed by
genetic testing in treating patients with advanced refractory solid tu-
mors or lymphomas. https://clinicaltrials.gov/ct2/show/NCT02465060.
Accessed November 11, 2015.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 81
DEVELOPMENTAL THERAPEUTICS AND
TRANSLATIONAL RESEARCH

Biomarkers, Blood-Based Testing,

and the Heterogeneous Tumor

CHAIR
Charles Swanton, MBPhD, FRCP, FMedSci
The Francis Crick Institute
London, United Kingdom

SPEAKERS
Julia A. Beaver, MD
U.S. Food and Drug Administration
Silver Spring, MD

Melissa Lynne Johnson, MD

Sarah Cannon Research Institute
Nashville, TN
 MANAGEMENT OF INTRATUMOR HETEROGENEITY

Tumor Evolutionary Principles: How Intratumor

Heterogeneity Influences Cancer Treatment and Outcome
Subramanian Venkatesan, BSc, and Charles Swanton, MBPhD, FRCP, FMedSci

OVERVIEW

Recent studies have shown that intratumor heterogeneity contributes to drug resistance in advanced disease. Intratumor
heterogeneity may foster the selection of a resistant subclone, sometimes detectable prior to treatment. Next-generation
sequencing is enabling the phylogenetic reconstruction of a cancers life history and has revealed different modes of cancer
evolution. These studies have shown that cancer evolution is not always stochastic and has certain constraints. Consid-
eration of cancer evolution may enable the better design of clinical trials and cancer therapeutics. In this review, we
summarize the different modes of cancer evolution and how this might impact clinical outcomes. Furthermore, we will
discuss several therapeutic strategies for managing emergent intratumor heterogeneity.

rule books of cancer evolution might have important

T he selection of fitter subclones in the context of tumor
evolution was postulated by Nowell in the 1970s.1 The
existence of multiple phenotypes within a single tumor was
determined 3 decades ago2; however, the emergence of
next-generation sequencing has enabled the more detailed
study of cancer evolution and intratumor heterogeneity.
Genome instability is one of the proposed hallmarks of
cancer and is believed to be acquired early in tumorigenesis,
promoting the acquisition of other cancer hallmarks.3,4 It
is a collective term, referring to a spectrum of different
genetic aberrations ranging from point mutations to chro-
mosomal rearrangements, gains, and losses.5,6 Genome
instability equips cancer with the potential to create new
genetic aberrations in daughter cells and to adapt to new
environments.3 Once one of these genetic aberrations
confers a fitness advantage, genetically distinct subclones
may arise within a single cancer. Many cancers show hall-
marks of genome instability that support the development
of intratumor heterogeneity, evidenced by elevated rates
of point mutations,7-9 chromosomal rearrangements,10 and
somatic copy-number aberrations.10,11 Intratumor hetero-
geneity and cancer evolution contribute to resistance to
therapy and therefore demand investigation.
As the number of studies reporting on the extent of
intratumor heterogeneity in different cancer types is rising
sharply, it is becoming clear that cancer evolution is not
always stochastic. Recurring commonalities observed within
each cancer type suggests there are certain rules and
constraints dictating how a tumor can evolve. Identifying
implications for designing trials and cancer treatments. In
this review, we will touch upon how intratumor heteroge-
neity may affect clinical outcome and discuss the different
modes of cancer evolution. We will also discuss different
therapeutic strategies for the management of intratumor
heterogeneity.
THE RELATIONSHIP BETWEEN INTRATUMOR
HETEROGENEITY AND CLINICAL OUTCOME
Genome instability and intratumor heterogeneity are closely
associated, as genome instability increases the rate of
mutation (in the broadest sense referring to nucleotide and
to whole chromosome level changes) and the subsequent
chance of subclonal (i.e., in a fraction of cancer cells) di-
versification (reviewed by Burrell et al12). The influence of
genome instability and intratumor heterogeneity upon clin-
ical outcome is becoming clearer. Chromosomal instability
(CIN) is a specific form of genome instability and refers to the
rate of acquiring whole-chromosome or segmental chro-
mosomal aneuploidies.13 CIN may contribute to extensive
intratumor heterogeneity in clear cell renal cell carcinomas
(ccRCC)14; therefore, the identification of CIN-driving events
may inform how to manage intratumor heterogeneity. In
some cases, genome-doubled tumors are thought to pre-
cede the acquisition of a CIN phenotype.15 The ability of a
diploid cell to tolerate a genome-doubling event sub-
sequently fosters the propagation of aneuploid cells and
the progressive evolution of chromosomally unstable tumor

From the UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, London, United Kingdom; The Francis Crick Institute, London, United Kingdom.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Charles Swanton, MBPhD, FRCP, FMedSci, Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 44 Lincolns Inn Fields, London WC2A 3LY;
email: charles.swanton@crick.org.uk.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e141

VENKATESAN AND SWANTON
cells.15 Emerging evidence suggests that genome doubling
itself is a predictor of a poorer relapse-free survival in early-
stage colorectal15 and ovarian cancers.16
Interestingly, a mouse model with a heterozygous knockout
of the gene centrosome-associated protein E (Cenp-e) led
to increased aneuploidy and CIN.17 The Cenp-e+/2 mice de-
veloped more spontaneous spleen and lung tumors compared
with the Cenp-e+/+ mice. In contrast, genetically (through
homozygous p19ARF deletion) and chemically (through 7,12-
dimethylbenz[a]anthracene exposure) induced tumorigen-
esis was inhibited in the Cenp-e+/2 mice compared with
wild-type mice. These results suggest that CIN, in some
cases, can both promote and inhibit tumorigenesis.17 This
study supports the mutational meltdown theory postulated
by Lynch et al regarding deleterious mutations in asexual
populations.18 Here, the accumulation of deleterious mu-
tations combined with the inability of sexual recombination
contributes to the extinction process, which they termed
mutational meltdown. Cancer cells also divide and re-
produce in an asexual manner; therefore, the observations
by Weaver et al17 suggested that the mutational meltdown
theory18 may also apply to human cancers. Our group in-
vestigated the association between the level of CIN and
clinical outcome.19,20 We found, in different cancer types,
that patients with tumors containing intermediate levels
of CIN had the worst prognosis, whereas tumors with
high levels of CIN were associated with improved prognosis
(Fig. 1).19,20 These observations have been recapitulated in
recent studies of high-grade serous ovarian cancer,21 es-
trogen receptornegative breast cancer,19,22 and a pan-
cancer study across 12 cancer types.23
Although the number of patients with ovarian cancer
studied by Schwarz et al and patients with esophageal cancer
studied by Murugaesu et al were probably not large enough
to detect the nonlinear relationship between the extent of
intratumor heterogeneity and response to therapy, they still
demonstrated that patients with more heterogeneous
cancers had poorer response.21,24 In glioblastoma, Kim et al
report that TP53 mutations coincide with higher frequencies
of subclonal mutations and better clinical outcome, which
KEY POINTS
Cancer evolution is not always stochastic and is
subjected to several constraints evidenced by parallel
and convergent evolution.
There is a trade-off between tumor fitness and genome
instability.
Different modes of cancer evolution may be operative
over the lifetime of a cancer.
Multiregion sequencing and/or longitudinal monitoring
of cancer subclones enables a better understanding of
evolutionary life histories.
Understanding cancer evolution may inform the better
design of clinical trials and cancer treatments.
e142 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
FIGURE 1. The Trade-off Between Genome
Instability/Intratumor Heterogeneity and Clinical
Outcome
might be related to the trade-off between tumor fitness and
genome instability as previously discussed (Fig. 1).25 Col-
lectively, these studies suggest a range of optimal genome
instability favoring the tumors fitness, which at the right
threshold, may negatively affect clinical outcome (Fig. 1).
However, beyond a certain threshold, excessive genome
instability may result in diminished cancer cell survival and
is paradoxically associated with an improvement in cancer
survival outcomes (Fig. 1).
The influence of specific somatic alterations on the rate of
evolution has been subject to investigation. Genomic ab-
errations in cancer may accumulate either gradually such as
through point mutations (microevolution), or in a punctu-
ated manner through processes such as chromoplexy,26 or
in a single catastrophic event such as through chromo-
thripsis (macroevolution).27 The distinction between these
different magnitudes of genomic changes might be of im-
portance for the rate of disease progression. For example,
chromothripsis was identified in a small subset of patients in
multiple myeloma and was often related to rapid relapse and
death within 1 to 2 years.28
It is of clinical importance to elucidate how cancers tol-
erate such somatic events and propagate diversity and
branched evolution, as this may inform how cancer prog-
resses and support new therapeutic approaches to limit
these processes. Through deep, multiregion, and longitu-
dinal sequencing studies of the primary tumor and metas-
tases, it might be possible to order somatic events more
effectively and identify genetic events enabling the toler-
ance and propagation of genome instability. For example,
prostate cancer metastases were enriched for TP53 muta-
tions, whereas this mutation was subclonal in the primary
tumor.29 Conceivably, metastasis may be enhanced by loss-
of-function of TP53, possibly allowing for greater tolerance
of genome instability and the subsequent gain of a
metastasis-driving event.
Unfortunately, the clinical effect of targeted therapeutic
drugs has been limited by the rapid acquisition of drug
resistance in the metastatic setting. There are now multiple
reports suggesting that drug-resistant subclones reside
within the tumor at low frequency prior to therapy in

melanoma,30 prostate cancer,31 colorectal cancer,32,33 ovarian
cancer,21 and medulloblastoma.34 We recently reported in a
study of nine cancer types that mutations in many driver
genes can be subclonal across multiple different tumor types.
These data suggest that targeting founder events present in
every tumor cell may facilitate a more effective drug devel-
opment process.35
MODES OF CANCER EVOLUTION
In the past decade, different modes of cancer evolution have
been discovered. Historically, cancer was believed to follow
the multistep process of oncogene activation, tumor sup-
pressor gene loss, and subsequent clonal sweeps by the
fittest clone.1,36 With current advances in next-generation
sequencing technology, the initial hypothesis has been re-
fined and additional models of macroevolution26,27,37 and
neutral evolution38-40 have been postulated. In this section,
we will summarize the current state of knowledge of cancer
evolution (Table 1 and Fig. 2).
Darwinian Cancer Evolution
Deep sequencing analysis of hematologic and solid tumors
indicate that cancer is usually of clonal origin and often
follows a branched tumor evolutionary pattern.41 Using
tumor purity estimates, local copy number aberrations, and
mutation variant allele frequency, it is possible to calculate
the cancer cell fraction of a mutation and phylogenetically
reconstruct the life history of cancers.42-45 The trunk of the
phylogenetic tree describes the clonal events where the
founder driver events are present. Trunk driver events are
present in all cancer cells derived from the cell of origin.
As the cancer genome evolves during cancer progres-
sion, subclonal events are introduced into a subset of the
progeny, termed branched events (Fig. 2A). A clonal sweep
occurs if a branch driver event increases the fitness of a
subclone to the extent that it out-competes all other sub-
clones in the tumor. This mode of cancer evolution has been
termed linear evolution (Fig. 2B). Reports suggest that
branched evolution is common in cancer, as there may
be one or more subclonal/branched driver events pre-
sent within distinct subclones of a tumor. Nevertheless,
in several cancer types, cases of linear evolution have been
documented such as in acute myeloid leukemia, 46,47
chronic lymphocytic leukemia, 48 and VHL-associated
ccRCC. 49
We have studied four clonally independent primary kidney
cancers in the context of a germline VHL mutation.49 Several
observations were made from this patient: (1) the tumors
were polyclonal, (2) the tumors shared no other muta-
tions apart from the germline VHL mutation highlighting
independent evolutionary trajectories despite similar mi-
croenvironments, and (3) the tumors showed signs of
evolutionary constraints shown by the absence of branched
evolution and the presence of convergent evolution toward
the PI3K-Akt-mTOR pathway (Fig. 2C).49 Convergent evo-
lution refers to the process of independent tumors within
MANAGEMENT OF INTRATUMOR HETEROGENEITY
the same patient acquiring (epi)genetic alterations in similar
genes, protein complexes, or signaling pathways (Fig. 2C).49
Conversely, parallel evolution refers to subclones derived
from the same parental clone acquiring (epi)genetic alter-
ations in similar genes, protein complexes, or signaling
pathways (Fig. 2D).50,51 Although many tumors follow a
branched evolutionary pattern, presumably many of these
tumors experience common selective pressures from the
microenvironment or constraints inherited from the pa-
rental founder cell, which force the different subclones to
independently converge on similar cellular processes. The
level of convergent and parallel evolution is of emerging
interest because of developments in the use of multiregion
and single cell sequencing (Table 1).
Up to this point, we have described cancer as co-evolving,
mutually independent subclones; however, reality is more
complex as these subclones also interact. In an environment
with limited space and nutritional resources, there are
complex dynamics of clonal cooperation and clonal in-
terference (Fig. 2E), which are only now beginning to be
understood. In vitro52-55 and in vivo54-57 data show that
subclonal populations can protect and/or drive cancer as a
whole. Marusyk et al elegantly demonstrated in a mouse
model that a minor subclone with inferior fitness drove
tumor growth in a noncell-autonomous fashion through
the secretion of a specific ligand.56 This enabled the tumor to
maintain growth, clonal diversity, and even metastatic po-
tential. These tumor phenotypes could be abrogated once
the driving subclones were omitted from the tumor, high-
lighting the importance of examining minor subclones in
addition to dominant subclones. Similar clonal dynamics
are likely also operative in patients. Clonal interference
between a dominant subclone and a minor subclone may
prevent the outgrowth of the minor subclone during tumor
progression (Fig. 2E). However, the harsh selective pressure
imposed by the tumor microenvironment, the cancer
therapeutics directed toward the dominant clone, or the
process of metastasis in general may permit a resistant
minor subclone residing in the tumor to emerge by com-
petitive release.58 Gatenby et al hypothesized that a tumor
may consist of chemotherapy-sensitive cells that have a
higher fitness in the absence of chemotherapeutic pressure
and suppress the outgrowth of less fit chemotherapy-
resistant subpopulation. They demonstrated that adapting
the chemotherapy dose according to tumor dynamicsthat
is, higher doses upon tumor growth and lower doses upon
tumor reductionwas able to stabilize the tumor and
prevent the resistant subpopulation from reaching lethal
proportions.58 This therapeutic strategy was appropriately
called adaptive therapy, and, related to this, it was recently
shown to be potentially relevant in the treatment of
BRAFV600E-mutant melanomas (Fig. 2F).59
A different approach to address an emerging treatment-
resistant subclone may include altering the drug instead
of the drug doses with the aim to eradicate the cancer
(i.e., sequential therapy; Fig. 2G). In sequential therapy,
the treatment is sequentially adapted according to the
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VENKATESAN AND SWANTON

evolution of new treatment-resistant events. The poten-
tial of sequential therapy has been demonstrated in the
treatment of drug-sensitive EGFR-driven (often EGFRL585R
or EGFR exon 19 deletion) lung cancer with first-generation
EGFR inhibitors (erlotinib or gefitinib). Tumors often
progress as a result of the emergence of an EGFRT790M
resistanceconferring mutation.60 However, this mutation
renders cancer cells sensitive to the third-generation EGFR
inhibitors, AZD929161 and rociletinib.62 Nevertheless, se-
quential therapy may eventually encounter a resistant
subclone that is not yet amenable to treatment because
treating tumors that harbor the EGFRT790M variant with
either AZD929163 or rociletinib 64 appears to select for the
re-emergence of EGFRT790M-negative cells, EGFRC797S
mutant cells, or EGFRT790M-positive cells with a yet un-
identified resistance event (Fig. 2G). Clonal interactions are
not limited to the primary tumor but also extend to the
metastatic sites. Phylogenetic reconstruction of the primary
tumor and the accompanying metastases is enabling a
clearer picture of the metastatic process. Studies by
Gundem et al and Hong et al in prostate cancer show that
the following patterns of metastasis occur frequently
(Fig. 2H): (1) multiple subclones can seed the same
metastatic site (termed polyclonal seeding), (2) combi-
nations of shared subclones between these polyclonal
seeds are recurring (hinting toward clonal cooperation),
(3) subclones within a metastasis can spread to another
metastatic site (termed metastasis-to-metastasis spread
or metastatic cross-seeding), and (4) tumor cells from
the metastasis may return back to the primary tumor
(termed self-seeding).65 The formation of metastatic sub-
clones were long thought to occur through the clonal se-
lection of the fittest and latest evolving subclone. However,
recent studies show that metastatic progression can also
occur through the early diverged clonal expansion of the
trunk clone.21,29

TABLE 1. Different Modes of Cancer Evolution Reported in a Selection of Different Cancer Types
Cancer Type Mode of Evolution
AML Branched evolution80,81
Parallel evolution81: FLT3-ITD
Linear evolution46,47,82
Breast Cancer Branched evolution83
Parallel evolution83: PTEN, FGFR2, TP53, RUNX1
Punctuated and catastrophic evolution7,83: chromoplexy, chromothripsis, kataegis
Colorectal Cancer Catastrophic evolution27: chromothripsis
Neutral evolution39,40
Esophageal Branched evolution24,84,85
Cancer
Catastrophic evolution27: chromothripsis
Parallel evolution24: NOTCH1, GNPTAB
Polyclonal tumorigenesis85
Follicular Branched evolution86,87
Lymphoma
Parallel evolution86,87: chromatin-modifying genes (KMT2D, KMT2C, EZH2, CREBBP, MEF2B, EP300, HIST1H1E,
HIST1H1C, SWI/SNF complex [ARID1A, SMARCA4])
Punctuated evolution7: kataegis
Glioma Branched evolution88,89 in distant relapse90
Catastrophic evolution27: chromothripsis
Linear evolution in local relapse25,90
Neutral evolution38,40
Parallel evolution25,90,91: EGFR, TP53, PTEN, RB1, NF1, CDKN2A/B
Melanoma Branched evolution30,92
Catastrophic evolution27: chromothripsis
Metastasic cross-seeding93
Neutral evolution38,40
Parallel evolution30,92,93: KRAS, BRAF, MEK1, PIK3R2, PHLPP1, CTNNB1
Multiple Branched evolution94-96
Myeloma
Linear evolution94-97
Parallel evolution96,97: NRAS, KRAS, BRAF, NF1, RASA2, FAM46C
Punctuated and catastrophic evolution28,96: kataegis, chromothripsis

Continued

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 MANAGEMENT OF INTRATUMOR HETEROGENEITY

TABLE 1. Different Modes of Cancer Evolution Reported in a Selection of Different Cancer Types (contd)
Cancer Type Mode of Evolution
NSCLC Branched evolution98,99
Neutral evolution38,40
Polyclonal tumorigenesis98
Punctuated and catastrophic evolution7,27,98,100: chromoplexy, chromothripsis, kataegis
Ovarian Cancer Branched evolution21
Metastasic cross-seeding21
Neutral evolution38,40
Prostate Cancer Branched evolution101,102
Punctuated and catastrophic evolution26: chromoplexy
Parallel evolution102: MYC, methylation sites
Metastasic cross-seeding103
Neutral evolution38,40
Polyclonal seeding103
Sporadic ccRCC Branched evolution45,51
Catastrophic evolution27: chromothripsis
Neutral evolution38,40
Parallel evolution45,51,68: mTOR pathway, SETD2, PTEN, KDM5C, PIK3CA, BAP1, PBRM1, SWI/SNF complex
VHL-associated Linear evolution49
ccRCC
Convergent evolution49: mTOR pathway (TSC1, mTOR)
Polyclonal tumorigenesis49
Abbreviations: AML, acute myeloid leukemia; NSCLC, nonsmall cell lung cancer; ccRCC, clear cell renal cell carcinoma.

Neutral Evolution mutations were clonal in individual tumor glands and it is

In addition to the model of Darwinian selection of the
fittest subclone, a different model was postulated by
Sottoriva et al termed the big bang model, or neutral
cancer evolution (Fig. 2I).39 In this study in colorectal
cancer, individual tumor glands and two bulk fragments
originating from the left and right side of the resected
tumors were subjected to different genomic techniques
including whole-exome sequencing and single nucleotide
polymorphism arrays. As expected, they found a pro-
portion of the aberrations to be clonal, but unexpectedly,
the same set of subclonal (or private) mutations could be
found in different tumor glands on opposite sides of the
resection. These observations suggest that once the initial
cell has transformed into a cancer cell, subclonal mutations
rapidly accumulate in the primordial tumor. Subsequently,
the daughter cells of specific subclones may migrate small
distances within the primordial tumor mass. Indeed, this
short-range cellular migration may be a basic feature of
aggressive tumor growth.66 The distance between these
daughter cells is presumably amplified by the subsequent
(big banglike) growth, possibly explaining why tumor
glands of the same subclone are scattered throughout the
tumor. Other explanations for the finding that exactly the
same subclonal mutations are found in different parts of the
colorectal cancer could include that these subclonal mu-
tations are acquired late in tumor evolution with the
subsequent migration of these cancer cells. However, as
the authors stressed, this is unlikely because these private
improbable that a whole gland would migrate.
This model of neutral cancer evolution states that after
malignant transformation, individual subclones grow at similar
rates, despite showing distinct mutational patterns. In this
context, the timing of a new mutation occurring is the major
determinant of its prevalence within the tumor, rather than
clonal selection for that mutation. In follow-up studies, the
role of neutral evolution across different cancer types was
investigated.38,40 These studies found that neutral evolution
may play an important role in tumor development of cervical
squamous cell carcinoma and endocervical adenocarcinoma,
colorectal, stomach, lung, prostate, bladder, and urothelial
cancers.38,40 However, once treatment has been initiated,
it is likely that other forms of Darwinian cancer evolution
take over and eventually force the selection of treatment-
resistant subclones.
APPROACHES TO TRANSLATE KNOWLEDGE OF
INTRATUMOR HETEROGENEITY INTO CANCER
TREATMENT
Over the past few years, the cancer research community has
hunted for substantially mutated genes or driver genes. The
underlying premise was that cancer cells have become
addicted to the driver gene and, consequently, inhibition of
these genes may halt tumor progression. However, the
presence of multiple subclones with different driver and
resistance mutations in a single tumor is a major hurdle for

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VENKATESAN AND SWANTON

FIGURE 2. Different Modes of Cancer Evolution Contribute to Different Patterns of Intratumor Heterogeneity

e146 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


targeted therapy. Cancer drug development is undoubtedly
made more costly by the ability of a resistant subclone to be
selected during treatment in a matter of weeks or months.
There is a need to implement the knowledge gained by
cancer evolutionary models into designing better anticancer
therapies. In this section, we will provide a brief summary
of different strategies incorporating knowledge of cancer
evolutionary medicine.
A therapeutic strategy that has been advocated by us and
others to maximize tumor response is to target trunk driver
events present in every tumor cell.67 In this case, it is im-
portant to accurately determine the clonal driver events.
Parallel evolution is widespread in different cancer types and
represents the constraints imposed on cancer evolution
(Table 1). Therefore, targeting parallel evolutionary events and
exploiting these cancer dependencies may provide a com-
pelling approach to therapy.49,68,69 Indeed, these observations
were initially made in ccRCC, in which rapalogs worked ex-
ceptionally well in tumors that harbored multiple mutations
that converged upon the mTOR pathway,68 suggesting that
parallel evolution could pose as an Achilles heel of cancer.
As cancer evolves during treatment, dynamic therapy
strategies may allow the clinician to maintain a stable
population of treatment-sensitive cells (adaptive therapy),58
or even force the tumor down a particular evolutionary
route resulting in acquired sensitivity to a different drug
(sequential therapy). The utility of sequential therapy has
recently been demonstrated in a patient with an ALK-
rearranged nonsmall cell lung cancer, who sequentially
responded to different generations of ALK inhibitors.70 To
inform the next step in adaptive and sequential therapy,
longitudinal monitoring of the cancer is essential. Liquid
biopsy analysis of circulating tumor DNA or circulating tumor
cells is a convenient way to monitor cancer genetic changes.
Furthermore, liquid biopsy has the potential to detect
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MANAGEMENT OF INTRATUMOR HETEROGENEITY
subclonal events,71-74 minimal residual disease, and the
acquisition of new somatic alterations associated with drug
resistance,31,32,75 and it can be used to monitor re-
sponse73,76 (reviewed in Crowley et al77 and Krebs et al78).
In addition to adapting treatment to the adapting cancer, it
may be attractive to interfere with the causes of genome
instability. Reducing genome instability may reduce the
adaptability of cancer cells to treatments. Conversely, in-
creasing genome instability may tip the cancer cell beyond
the levels of tolerance, forcing cell-autonomous lethality. As
there are many causes of genome instability (reviewed in
Aguilera et al6 and Burrell et al12), identifying the mecha-
nistic basis of micro- and macroevolutionary events may
enable the therapeutic intervention and prevention of major
resistance-forming events from occurring.
CONCLUSION
The number of studies investigating cancer evolution is rising
sharply and has contributed to early insights into cancer evo-
lutionary rule books. Sequencing of bulk tumor samples in
projects such as The Cancer Genome Atlas have set the foun-
dations for precision medicine; however, intratumor heteroge-
neity is still largely underestimated in these datasets. Multiregion
sequencing and longitudinal monitoring via liquid biopsy together
with postmortem studies is necessary to attain a more accurate
picture of cancer evolution. TRACERx (TRAcking nonsmall cell
lung Cancer Evolution through therapy [Rx]) is such a prospective
study, which aims to define the evolutionary trajectories
of nonsmall cell lung cancer.79
Although the complexities of cancer evolution are just
beginning to be understood, much has been learned over the
past decade. We anticipate that cancer evolutionary models
will inform clinicians how to design clinical trials and cancer
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e149
DEVELOPMENTAL THERAPEUTICS AND
TRANSLATIONAL RESEARCH

Biosimilars: Here and Now

CHAIR
Steven J. Lemery, MD, MHS
U.S. Food and Drug Administration
Silver Spring, MD

SPEAKERS
Francisco J. Esteva, MD, PhD
New York University Clinical Cancer Center
New York, NY

Martina Weise, MD
Federal Institute for Drugs and Medical Devices
Bonn, Germany
 BIOSIMILARS: HERE AND NOW

Biosimilars: Here and Now

Steven J. Lemery, MD, MHS, Francisco J. Esteva, MD, PhD, and Martina Weise, MD

OVERVIEW

Congress passed the Biologics Price Competition and Innovation Act (BPCI Act) as part of the Affordable Care Act on March
23, 2010. The BPCI Act authorized an approval pathway for biosimilar and interchangeable products. It defines biosimilarity
to mean that the biological product is highly similar to the reference product notwithstanding minor differences in clinically
inactive components and that there are no clinically meaningful differences between the biological product and the
reference product in terms of safety, purity, and potency of the product. The biosimilar pathway has the potential to
facilitate access to biologic products through increased competition, in the same manner as biosimilars have done for almost
10 years in Europe. The goal of a biosimilar program is not to independently establish safety and effectiveness for each
condition of use. Rather, the goal is to demonstrate biosimilarity through an extensive analytical characterization and a
targeted clinical program designed to assess for clinically meaningful differences, if they exist. The regulatory approaches in
both the United States and Europe involve a totality-of-the-evidence approach to demonstrate biosimilarity. Importantly,
the biosimilar pathway allows for extrapolation of data across indications so that a sponsor, with adequate scientific
justification, need not conduct clinical studies in each intended condition of use. Without extrapolation, development may
not be feasible for many products, and patients and resources could be diverted from clinical studies of newer agents for
cancer.

C ongress passed the BPCI Act on March 23, 2010, as part

of the Affordable Care Act. The BPCI Act created a new
abbreviated licensure pathway for biologic products that are
shown to be biosimilar to, or interchangeable with, a U.S.
Food and Drug Administration (FDA)-licensed reference
product. According to the BPCI Act, a reference product is
the single biologic product licensed (i.e., approved) by FDA
that the proposed biosimilar is being compared with in an
application.1 The statutory definition requires the reference
product to be licensed under Section 351(a) of the Public
Health Service Act. The reference product must be an orig-
inator drug approved based on a full dossier of preclinical and
clinical data, and not a biosimilar, which is licensed under
Section 351(k) and not 351(a).1
The abbreviated licensure pathway for biosimilar and in-
terchangeable products is possible because the proposed
product may rely for licensure on, among other things, publicly
available information on FDAs prior determination that the
reference product is safe, pure, and potent. This article will
discuss scientific considerations as understood by the authors
regarding the development and approval of biosimilar ther-
apeutic biologic proteins (e.g., monoclonal antibodies or
certain cytokines) in the United States. It also highlights the
experience of biosimilars in Europe. As such, this article
should not be considered formal or binding FDA or European
Medicine Agencies (EMA) advice on regulatory or policy
matters related to biosimilar drugs.
The goal of a biosimilar development program differs from
traditional drug development. The goal of a traditional drug
development program is to demonstrate that the biologic
product is safe and effective for one or more indications. The
objective of a biosimilar development program is to dem-
onstrate through a totality-of-the-evidence approach that
the biosimilar product is highly similar to the U.S.-licensed
reference product, notwithstanding minor differences in
clinically inactive components and that there are no clinically
meaningful differences between the biosimilar product and
the reference product in terms of safety, purity, and po-
tency.2 A biosimilar sponsor does not need to independently
establish the safety and effectiveness of its product; it es-
tablishes this through a demonstration of biosimilarity. The
biosimilar pathway also allows for extrapolation of data
across indications. With adequate scientific justification, a
sponsor would not need to conduct a clinical study to
support approval of a biosimilar for each indication in the
reference products label.
Although the biosimilar pathway is an abbreviated ap-
proval pathway, the data package required for approval of a

From the U.S. Food and Drug Administration, Silver Spring, MD; New York University Clinical Cancer Center, New York, NY; Federal Institute for Drugs and Medical Devices (BfArM), Bonn,
Germany.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Steven J. Lemery, U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993; email: steven.lemery@fda.hhs.gov.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e151

LEMERY, ESTEVA, AND WEISE
biosimilar product can be quite extensive. Therefore, the
development of these products by sponsors and the review
of these products by regulatory authorities, including FDA
and EMA, is quite thorough to ensure that the products are
highly similar and will be safe and effective. Ultimately, FDA
uses a totality-of-the-evidence approach to determine that a
product is analytically highly similar to the approved ref-
erence product and that there are no clinically meaningful
differences between the biosimilar product and the refer-
ence product.2 Likewise, EMA considers a totality-of-the-
evidence approach when evaluating biosimilars. Under the
provisions of the BPCI Act, FDA licensed the first biosimilar
product, Zarxio (filgrastim-sndz), on March 6, 2015.3-5
Because oncologists prescribe biologic products, they need
to familiarize themselves with biosimilar productshow they
are approved and how they will be incorporated into clinical
practice. This article describes biosimilar products and their
approval process. Aspects on incorporation of the products
into clinical practice may differ by state and are not covered in
this article.
Biosimilar products are not generic drug products. Fur-
thermore, the data package required to support the approval
of a biosimilar differs from a generic drug. Generic drugs are
copies of brand-name drugs. They contain the same active
ingredient as the reference listed drug (e.g., the brand-name
drug) and are the same in terms of dosage form, strength, and
KEY POINTS
Approval in the United States requires a biosimilar
product to be highly similar to the reference product
notwithstanding minor differences in clinically inactive
components and that there are no clinically
meaningful differences between the biological product
and the reference product in terms of safety, purity, and
potency of the product.
Although biosimilar products are not identical to the
reference product, the reference product also may differ
from batch to batch and may change over time. As such,
the biologic product a patient receives in clinical practice
is unlikely to be identical to the reference product
administered to patients in the clinical study or studies
that supported approval.
Comparative clinical studies in biosimilar development
programs should be directed toward an assessment of
clinically meaningful differences, if they exist, and not
directed toward independently establishing the safety
and effectiveness of the biosimilar product.
The BPCI Act allows for the potential, with adequate
scientific justification, to extrapolate data to support a
demonstration of biosimilarity in more than one
indication.
Both the United States and the EMA use a totality-of-
the-evidence approach when assessing whether a
product meets the standards to be designated as
biosimilar.
e152 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
route of administration. They also must be bioequivalent to
the reference listed drug.6
Unlike small molecule drugs, whose structure usually can be
completely defined and reproduced, biologic products typically
are more complex and difficult to characterize. In addition, all
biologics display a certain degree of microheterogeneity be-
cause of the inherent variability of the biologic systems from
which they are derived as well as their manufacturing pro-
cesses.7 The reference product manufactured by an originator
may differ from batch to batch and may change over time
because of modifications of the manufacturing process after
licensing. As such, the biologic product that a patient receives
in clinical practice is unlikely to be identical to the reference
product administered to patients in the clinical study or studies
that supported approval. However, product quality is tightly
controlled within predefined acceptance ranges, and changes
in the manufacturing processes are evaluated and approved by
the competent regulatory authority to ensure unchanged
clinical performance of the product. Since 1996, FDA has
approved many manufacturing process changes for refer-
ence biologic products based on demonstration of product
comparabilitybefore and after the process change(s)
often without the need for additional nonclinical or clinical
data. The EMA also has approved many such changes to
approved biologic products. These process changes can in-
clude changes in suppliers of cell culture media, new purifi-
cation methods, or new manufacturing sites. A 2013 report
from Dr. Schneider from the Danish Health and Medicines
Authority indicated that Remicade (infliximab) has undergone
over 35 manufacturing process changes since approval and
MabThera (rituximab) has undergone at least five process
changes.8
Both the biosimilar and reference product are essentially
different versions of the same active drug substance.19 As
such, scientific principles that underlie the comparability
exercise for manufacturing process changes of the originator
product are also applicable to the analytical similarity exercise
to demonstrate biosimilarity.9 Although the scientific prin-
ciples are applicable to both exercises, additional steps to
justify similarity are usually necessary in biosimilar develop-
ment, either analytically or clinically, because of differences in
cell lines and manufacturing processes, among others. Ulti-
mately, the sponsors, including the originators, and regulators
need to understand how any differences in the structure of
the product may affect the function of the product. They also
need to ensure that these differences are evaluated thor-
oughly to ensure safety and effectiveness of the product.
APPROACHES TO ASSESS ANALYTICAL
SIMILARITY
In the United States, a determination of biosimilarity re-
quires data demonstrating that the biologic product is highly
similar to the reference product, notwithstanding minor
differences in clinically inactive components. The FDA gen-
erally expects that the biosimilar product will be composed of
the same amino acid sequence as the reference product.2

Because of the complexity of biologic products, FDA expects
sponsors to characterize both their product and the reference
product. FDA also expects that this characterization will serve
as the foundation for the demonstration of biosimilarity.2
Such characterization generally will include analyses of mul-
tiple attributes including, but not limited to, primary struc-
tures (e.g., amino acid sequences), higher order structures,
enzymatic post-translational modifications (e.g., glycosylation
patterns), other variants (e.g., deamidation or charge vari-
ants), and any other intentional modifications (e.g., addition
of PEGylation).2
Comparative functional assays provide additional data
to support a determination that the biosimilar product
is highly similar to the reference product. For example,
comparative functional assays may include binding assays,
antibody-dependent cell-mediated cytotoxicity assays, and
cell-based bioactivity assays to assess the potential for cy-
tokine release.2 Furthermore, a sponsor should consider other
factors such as product expression systems, manufacturing
processes, impurities, and stability.2
The growing number of analytical tools allows sponsors
and regulatory agencies to better understand how attributes
of a protein or biologic product can affect the function of that
protein. As such, the comparative analytical characterization
in a biosimilar program is quite extensive.
A sponsor can submit analytical data to regulatory
agencies before clinical development. This allows regulatory
authorities to assess residual uncertainty regarding the de-
termination of whether the proposed biosimilar product is
biosimilar to the reference product, and what additional
studies are needed to support the determination that the
product is biosimilar. Factors considered in the assessment of
residual uncertainty may include: (1) which specific attributes
were tested, understanding that it is necessary to assess for
differences in any critical quality attributes; (2) the number of
attributes tested (in a theoretical example, a more extensive
characterization with a fingerprint-like analysis10 could re-
duce uncertainty); (3) the number of lots tested for both the
proposed biosimilar product and the reference product; and
(4) what differences, if any, were observed between products
and what impact the differences could have on safety and
efficacy.
CLINICAL STUDIES
As stated, the foundation of a biosimilar development
program is data demonstrating that the biosimilar product is
analytically highly similar to the reference product. In ad-
dition, the BPCI Act states that an application for a biosimilar
product must include, among other things, information from
animal studies and a clinical study or studies (including the
assessment of immunogenicity and pharmacokinetics or
pharmacodynamics) that are sufficient to demonstrate
safety, purity, and potency in one or more conditions of use
for which the reference product is licensed and for which
licensure is sought for the biosimilar product.1 However,
the BPCI Act provides FDA discretion to determine whether a
BIOSIMILARS: HERE AND NOW
particular element is unnecessary in an application to
support a demonstration of biosimilarity.
Comparative clinical study results (e.g., a clinical study
powered to demonstrate similar pharmacokinetic profiles
or a clinical study to demonstrate a lack of clinically mean-
ingful differences in safety and efficacy) cannot be used to
support that a proposed biosimilar product is biosimilar to the
reference product when the proposed biosimilar product has
otherwise not been demonstrated to be highly similar
to the reference product. Highly similar and no clinically
meaningful differences are two separate standards, each of
which needs to be met to support a demonstration of bio-
similarity. Clinical data cannot be used to overcome relevant
differences in quality attributes.2,11
In general, FDA expects an application for a biosimilar
product to include data from a clinical pharmacology study
demonstrating pharmacokinetic similarity between the
biosimilar product and the reference product.12 If one or
more relevant pharmacodynamic markers exist, demon-
stration of pharmacodynamic similarity may reduce residual
uncertainty and permit a more selective and targeted ap-
proach to additional clinical studies. Important elements
that FDA considers in the pharmacokinetic and/or pharma-
codynamic study include: (1) the appropriate (i.e., sensitive)
population to detect differences, if they exist; (2) the appro-
priate dose, which may differ from the approved dose and
ought to be on the steep part of the dose response curve; (3)
route of administration; and (4) and the assays used to measure
pharmacokinetic and/or pharmacodynamic markers.12
In some cases, a healthy volunteer population, if ethically
appropriate, may be the most appropriate and sensitive
population rather than a patient population for the phar-
macokinetic and/or pharmacodynamic similarity assessment
because tumor burden may increase the variability in phar-
macokinetic measurements of certain biologic products. With
justification, the dose and schedule of the biologic products
used in the study could be lower than the approved dose of
the reference product to improve the safety margin and/or
sensitivity of such a study.
The FDA recommends sponsors to pursue a step-wise
approach to biosimilar development. For example, FDA
can review the analytical data and clinical pharmacokinetic
and/or pharmacodynamic data and determine what residual
uncertainly exists before determining whether additional
clinical studies are necessary to address the uncertainty and
support a demonstration of biosimilarity. If sponsors request
FDA advice on the design of clinical studies before FDAs
review of analytical data, which does not follow the FDA-
recommended step-wise approach, FDA may assume residual
uncertainty exists. The FDA may recommend a more extensive
clinical program than otherwise might have been necessary.
Furthermore, the design of additional studies should be
influenced by the type of residual uncertainty. For example,
as a scientific matter, an adequate assessment of immuno-
genicity is expected in a biosimilar development program.2
The nature of the data and the design of a study to generate
comparative immunogenicity data may depend on specific
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e153
LEMERY, ESTEVA, AND WEISE
analytical characteristics of the biosimilar compared with the
reference product that could change the risk of an immune
response (e.g., different excipients or other formulation
changes) as well as the publicly known risk of immunogenicity
(and risk of adverse events if immunogenicity occurs) asso-
ciated with the reference product.
The objective of a comparative clinical study in a biosimilar
development program is to support a demonstration of no
clinically meaningful differences between the biosimilar
product and the reference product. In these comparative
clinical studies, this determination is not made by in-
dependently establishing the safety and effectiveness of the
biosimilar product. As such, some endpoints used for the
approval of the reference product in the oncology setting
(e.g., overall survival or progression-free survival) may be less
informative. This is because they are not only influenced by
the performance of the medicinal product but also by factors
such as the general health status of the patient. Therefore,
they are insufficiently sensitive to detect product-specific
differences between the reference product and the bio-
similar product, if they exist. In some cases, if scientifically
relevant, pharmacodynamic endpoints, such as objective re-
sponse rate, may be more appropriate. These endpoints
measure the pharmacological action of the biologic in a less
confounded way and may be more sensitive to any po-
tential differences in the biologic products.
If multiple indications are approved for the FDA-licensed
reference product, and the biosimilar sponsor intends to
seek licensure for more than one of these indications, FDA
may provide advice regarding which indication is more
sensitive in the assessment of clinically meaningful differ-
ences. Selection of a sensitive indication may allow a sponsor
to request extrapolation of data to other indications without
conducting additional clinical studies.
In general, FDA recommends that sponsors design com-
parative clinical studies to demonstrate that the proposed
biosimilar product has neither decreased nor increased ac-
tivity (e.g., efficacy) or has safety concerns (e.g., toxicity) that
differ from the reference product.2 Unless there is justifica-
tion for a one-sided test, or other design, such a comparative
clinical study generally uses a two-sided test based on a
prespecified similarity margin.2 The FDA will consider whether
the proposed study duration will provide sufficient exposure
to the proposed biosimilar and the reference product to
assess for clinically meaningful differences, and whether the
study is adequately designed to assess for potential differ-
ences in immunogenicity.2
Because FDA uses a totality-of-the-evidence approach to
support a demonstration of biosimilarity, it will consider
whether observed differences in a clinical study between the
proposed biosimilar and the reference product constitute
clinically meaningful differences. A comparative evaluation
of multiple data points in a comparative clinical study (e.g.,
efficacy and cardinal-safety findings), combined with phar-
macokinetic similarity and an extensive analytical comparison
demonstrating that the products are highly similar, will pro-
vide solid ground to conclude that the biosimilar product will
e154 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
be safe and effective for the proposed indications. The FDA
understands that because of chance, there may be differences
between the study arms in the incidence of certain adverse
events in a comparative clinical study. Therefore, sponsors
may discuss proposals with FDA to prioritize the collection and
analysis of certain cardinal or key adverse events of interest.
For example, anti-VEGF pathway antibodies increase the
risk of hypertension, epistaxis, proteinuria, and dysponia.
An analysis of these adverse events may be more relevant to
an assessment of no clinically meaningful differences for
anti-VEGF pathway antibodies than analyses of fatigue or
pain in a patient population with advanced cancer.
EXTRAPOLATION OF CLINICAL DATA ACROSS
INDICATIONS
The FDA has essentially allowed extrapolation of data for
approved biologic products without additional clinical studies
for years following the introduction of certain manufacturing
process changes. Many biologic drugs used in oncology are
approved for multiple indications, including nononcology
indications. Based on the BPCI Act, if the proposed product
meets the statutory requirements for licensure as a biosimilar
product based on, among other things, data derived from a
clinical study sufficient to demonstrate safety, purity, and
potency in an appropriate condition of use, the potential
exists for the biosimilar product to be licensed for one or more
additional conditions of use for which the reference product
is licensed.13 A conclusion of biosimilarity in one or more
indications potentially allows for extrapolation of data to
support a conclusion of biosimilarity for other indications.13
With adequate scientific justification, a sponsor would not
need to conduct a clinical study to support licensure of a
biosimilar for each condition of use for which the reference
product is licensed.
Sponsors need to provide scientific justification for such
extrapolation. Justification should include a discussion of
how the mechanism of action of the drug relates to each
condition of use; whether pharmacokinetics and/or phar-
macodynamics may differ in different patient populations;
differences in expected toxicities in different patient pop-
ulations; and any other factor that may affect the safety or
efficacy in the different patient populations.2,13 It is important
to note that differences among indications or conditions of
use do not preclude extrapolation or necessitate additional
clinical data. However, any differences need to be adequately
addressed with data and information to support extrapolation.
Ultimately, sponsors should consider conducting clinical
studies that are adequately sensitive to detect clinically
meaningful differences between the biosimilar product and
the comparator product and that would best reduce any
residual uncertainty regarding extrapolation based on the
factors described above. For example, choosing to conduct
the comparative clinical study in a relevant indication with a
consistent and/or large treatment effect may have greater
sensitivity to detect differences between the products, if
they exist. Also, choosing to conduct a comparative clinical

study in a relevant indication whose mechanism of action
overlaps with other indications being sought could reduce
the residual uncertainty regarding extrapolation.
Extrapolation can reduce the time and cost of develop-
ment by abrogating the need to conduct clinical studies for
each indication previously approved for the reference product.
Extrapolation is one of the tenets of the abbreviated approval
pathway for biosimilar products. When FDA approves a bio-
similar product, it has determined that the product meets
the requirements for approval and has been demonstrated to
have no clinically meaningful differences from the reference
product in terms of safety, purity, and potency, including any
indications that were supported by extrapolation.
In summary, extrapolation can be supported for a product
that is highly similar to the U.S.-licensed reference product
based on the totality of the evidence in which the biosimilar
product would be expected to be safe and effective for each
indication of use, even without conducting a separate clinical
study in each indication. Without extrapolation, for products
with multiple indications, sponsors would likely need to
conduct comparative clinical studies with thousands to tens
of thousands, or more, patients depending on the treatment
effect and the sensitivity of the population(s). Such a re-
quirement could have multiple consequences. These could
include keeping development costs high and rendering the
pathway infeasible and potentially diverting patients and
resources from clinical studies of newer therapies for cancer.
Despite these considerations, however, licensing of safe and
effective drugs is the highest priority for regulators and
extrapolation is only allowed if a sponsor provides adequate
scientific justification.
INTERCHANGEABILITY
The statutory provisions for interchangeability are unique to
the United States. According to the BPCI Act, for FDA to
determine that a product is interchangeable with a refer-
ence product, the product must be biosimilar to the ref-
erence product and can be expected to produce the same
clinical result in any given patient.14 Additionally, FDA must
determine that for a biological product that is administered
more than once to an individual, the risk in terms of safety or
diminished efficacy of alternating or switching between use
of the proposed interchangeable product and the reference
product is not greater than the risk of using the reference
product without such alternation or switching.14 Similar to
U.S. generic drugs, an interchangeable biologic product may
be substituted for the reference product without the in-
tervention of the health care provider who prescribed the
product.15 According to the BPCI Act, only a product des-
ignated as interchangeable may be substituted. Therefore,
the treating health care providerand not the pharmacist
can decide whether to prescribe a biosimilar product not
designated as interchangeable at any time, including deciding
whether to change their patient from one product to another.
Although most biosimilars in Europe are approved cen-
trally by EMA, individual member states make substitution
BIOSIMILARS: HERE AND NOW
policies.16 Currently, none of the European Union (EU) coun-
tries have authorized unrestricted automatic substitution.
Some countries (e.g., Belgium, Italy, Norway, and the United
Kingdom) prohibit pharmacy-level substitution, whereas other
countries (e.g., France, Germany, and the Netherlands) allow
substitution in certain instances. France permits substitution
of a biosimilar for the prescribed (reference) biologic in patients
who are treatment nave.17 The Dutch Medicines Evaluation
Board accepts substitution of biosimilars under the condition
that both the treating physician and the pharmacist are in-
volved.18 In Germany, the pharmacist may only substitute a
bioidentical product (i.e., a biosimilar from the same
manufacturer).
Importantly, lack of designation as interchangeable does
not imply that a biosimilar product is an inferior product
to a biosimilar that has also been determined to be in-
terchangeable with the reference product. By being bio-
similar, the biosimilar product has been determined to be
highly similar and has no clinically meaningful differences
from the reference product for the labeled conditions of use.
Nevertheless, a demonstration of interchangeability might
require additional data (e.g., to evaluate the risk of switching
or alternating) to address the additional standards, and
sponsors need to make a business decision about whether to
pursue a claim of interchangeability.
DISCUSSION
Biosimilar products are an additional treatment option for
health care providers and patients. They may help facilitate
access to treatment and decrease costs for patients and the
health care system in the United States, in the same manner
as these products have done for almost 10 years in Europe.
The FDA licensed the first biosimilar product, Zarxio (filgrastim-
sndz), on March 6, 2015.3
Health care providers in Europe have already gained sub-
stantial experience with safely prescribing biosimilar prod-
ucts. The legal pathway for authorizing biosimilar medicines
was established in 2003, and the first biosimilar product,
somatotropin, was approved in 2006.16,19,20 Approved bio-
similar products in Europe include hematopoietic growth
factors, such as filgrastim and epoetin, as well as insulin,
somatotropin, follitropin, and the monoclonal antibody
infliximab.9,20 The uptake of biosimilars in the EU has in-
creased steadily but at different rates in different countries.
Germany has shown the highest uptake of approximately
50% volume.21 In certain European countries, adoption of
such products has been widespread and thousands of pa-
tients have been safely treated with biosimilar drugs.16,22-26
Concerns about safety and efficacy have been voiced for
biosimilar filgrastim and epoetins, especially in extrapolated
indications for which no clinical data with the biosimilar have
been generated.9 Epoetins were among the first biosimilars
approved in the EU. The major concern with epoetins is the
rare development of neutralizing, cross-reacting anti-epoetin
antibodies that can cause pure red cell aplasia (PRCA).
Product-related factors, such as aggregation and contaminants
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e155
LEMERY, ESTEVA, AND WEISE
(e.g., leachables from rubber stoppers or tungsten from sy-
ringes), have been implicated in the development of anti-
epoetin antibodies.27,28
Although regulators and sponsors now better understand
the factors that contribute to immunogenicity, as a scientific
matter, both FDA and EMA expect an adequate assessment
of immunogenicity as part of biosimilar development pro-
grams. The EMA guideline on the development of biosimilar
epoetins requests clinical immunogenicity data with sub-
cutaneous use in patients with renal anemia and, therefore,
with the route of administration and in the patient population
at highest risk for developing PRCA.29 As such, immunogenicity
data from these patients can then be extrapolated to lower-risk
clinical settings, such as intravenous use or to immunocom-
promised patients who have chemotherapy-induced anemia.
The immunogenicity assessment of approved biosimilar
epoetins in Europe includes both prelicensing studies and,
because of the rarity of PRCA, extensive postmarketing
surveillance programs to gain a more precise estimate of its
frequency. Reassuringly, postmarketing studies and phar-
macovigilance surveillance in Europe confirm efficacy and
safety of licensed biosimilars, lending further support to the
adequacy of the respective scientific guidelines and approval
processes.22-25
Biosimilar products are not generics. Requirements for
approval of a biosimilar product differ in many ways from
generic drug products. Analytical testing for biosimilar drug
products is much more extensive and encompasses numerous
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Sections 351(k), 351(i)(2), and 351(i)(4).
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RegulatoryInformation/Guidances/UCM291128.pdf. Accessed March 17,
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3. U.S. Food and Drug Administration. BLA Approval Letter. http://www.
accessdata.fda.gov/drugsatfda_docs/appletter/2015/
125553Orig1s000ltr.pdf. Accessed January 7, 2016.
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Zarxio. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
ucm436648.htm. Accessed January 29, 2016.
5. Christl LD, Deisseroth A. Development and Approval of Biosimilar
Products. The ASCO Post. March 25, 2015;6.
6. U.S. Food and Drug Administration. Abbreviated New Drug Appli-
cation (ANDA): Generics. http://www.fda.gov/Drugs/DevelopmentApproval
Process/HowDrugsareDevelopedandApproved/ApprovalApplications/
AbbreviatedNewDrugApplicationANDAGenerics/. Accessed January 8, 2016.
7. Weise M, Bielsky MC, De Smet K, et al. Biosimilars: what clinicians
should know. Blood. 2012;120:5111-5117.
8. Schneider CK. Biosimilars in rheumatology: the wind of change. Ann
Rheum Dis. 2013;72:315-318.
9. Weise M, Kurki P, Wolff-Holz E, et al. Biosimilars: the science of ex-
trapolation. Blood. 2014;124:3191-3196.
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structural and functional assays using state-of-the art science.
In the United States, such comparative analytical testing must
show that the biosimilar product is analytically highly similar
to the reference product. Although the specific language of
the regulations differs in Europe, the same scientific principles
apply with regard to the requirements for demonstrating
analytical similarity.
In addition to analytical testing, biosimilar applications in
the United States generally will contain comparative data
from one or more clinical studies showing pharmacokinetic
similarity and, if necessary, an additional comparative clinical
study or studies to support a demonstration of no clinically
meaningful differences. Data in humans further serve to
reduce the residual uncertainty on the clinical impact arising
from any observed analytical differences and support a
demonstration of biosimilarity. Ultimately, FDA and EMA
determinations that a product is biosimilar based on a totality-
of-the-evidence approach to ensure that these products are
safe and effective for the labeled indications, including for the
treatment of patients with cancer. Such access will help to
facilitate treatment of patients with cancer in both the United
States and Europe.
ACKNOWLEDGMENT
The authors would like to thank Leah Christl, PhD, Associate
Director for Therapeutic Biologics, FDA, for providing
comments and edits to the manuscript.
10. U.S. Food and Drug Administration. Quality Considerations in Dem-
onstrating Biosimilarity of a Therapeutic Protein Product to a Reference
Product: Guidance for Industry. http://www.fda.gov/downloads/
drugs/guidancecomplianceregulatoryinformation/guidances/
ucm291134.pdf. Accessed March 17, 2016.
11. European Medicines Agency. Guideline on Similar Biological Medicinal
Products. http://www.ema.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2014/10/WC500176768.pdf. Accessed January 29,
2016.
12. U.S. Food and Drug Administration. Guidance for Industry: Clinical
Pharmacology Data to Support a Demonstration of Biosimilarity to a
Reference Product, Draft Guidance. http://www.fda.gov/downloads/
drugs/guidancecomplianceregulatoryinformation/guidances/
ucm397017.pdf.
13. U.S. Food and Drug Administration. Guidance for Industry on Bio-
similars: Q & As Regarding Implementation of the BPCI Act of 2009:
Questions and Answers Part I. http://www.fda.gov/Drugs/Guidance
ComplianceRegulatoryInformation/Guidances/ucm259809.htm.
Accessed January 8, 2016.
14. U.S. Food and Drug Administration. Information for Industry (Bio-
similars). http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/ApprovalApplications/Therapeutic
BiologicApplications/Biosimilars/ucm241720.htm. Accessed January 8,
2016.
15. U.S. Food and Drug Administration. Information for Consumers (Bio-
similars). http://www.fda.gov/Drugs/DevelopmentApprovalProcess/

HowDrugsareDevelopedandApproved/ApprovalApplications/Therapeutic
BiologicApplications/Biosimilars/ucm241718.htm. Accessed January 8,
2016.
16. Renwick MJ SK, Smolina K, Gladstone EJ, et al. Postmarket policy
considerations for biosimilar oncology drugs. Lancet Oncol. 2016;17:
e31-e38.
17. Generics and Biosimilars Initiative. France to Allow Biosimilars Sub-
stitution. http://gabionline.net/Policies-Legislation/France-to-allow-
biosimilars-substitution. Accessed January 29, 2016.
18. Medicines Evaluation Board. MEB Stance on Prescribing Biosimilars. http://
english.cbg-meb.nl/latest/news/2015/03/31/meb-stance-on-prescribing-%
E2%80%9Cbiosimilars%E2%80%9D. Accessed January 29, 2016.
19. European Medicines Agency. Questions and Answers on Biosimilar
Medicines (Similar Biological Medicinal Products). http://www.ema.
europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/
WC500020062.pdf. Accessed January 8, 2016.
20. European Medicines Agency. European Public Assessment Reports.
http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2
Flanding%2Fepar_search.jsp&mid=WC0b01ac058001d124&searchTab=
searchByAuthType&alreadyLoaded=true&isNewQuery=true&status=
Authorised&keyword=Enter+keywords&searchType=name&taxonomy
Path=&treeNumber=&searchGenericType=biosimilars&generics
KeywordSearch=Submit. Accessed January 8, 2016.
21. Generics and Biosimilars Initiative. Use of Biosimilars in Europe Differs
Across Countries. http://gabi-journal.net/news/use-of-biosimilars-in-
europe-differs-across-countries. Accessed January 29, 2016.
22. Michallet M, Luporsi E, Soubeyran P, et al; ORHEO study group. BiO-
similaRs in the management of anaemia secondary to chemotherapy in
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HaEmatology and Oncology: results of the ORHEO observational study.
BMC Cancer. 2014;14:503.
23. Dellanna F, Fluck RJ, Lonnemann G, et al. Results from a safety cohort of
patients with renal anemia receiving the biosimilar epoetinzeta: The
PASCO I study. Clin Nephrol. 2015;84:280-288.
24. Horbrand F, Bramlage P, Fischaleck J, et al. A population-based study
comparing biosimilar versus originator erythropoiesis-stimulating agent
consumption in 6,117 patients with renal anaemia. Eur J Clin Pharmacol.
2013;69:929-936.
25. Schmitt M, Publicover A, Orchard KH, et al. Biosimilar G-CSF based
mobilization of peripheral blood hematopoietic stem cells for autologous
and allogeneic stem cell transplantation. Theranostics. 2014;4:280-289.
26. Gascon P, Aapro M, Ludwig H, et al. Treatment patterns and outcomes
in the prophylaxis of chemotherapy-induced (febrile) neutropenia with
biosimilar filgrastim (the MONITOR-GCSF study). Support Care Cancer.
2016;24:911-925.
27. Boven K, Stryker S, Knight J, et al. The increased incidence of pure red
cell aplasia with an Eprex formulation in uncoated rubber stopper
syringes. Kidney Int. 2005;67:2346-2353.
28. Seidl A, Hainzl O, Richter M, et al. Tungsten-induced denaturation and
aggregation of epoetin alfa during primary packaging as a cause of
immunogenicity. Pharm Res. 2012;29:1454-1467.
29. European Medicines Agency. Committee for Medicinal Products for
Human Use: Guideline on non-clinical and clinical development of
similar biological medicinal products containing recombinant eryth-
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library/Scientific_guideline/2010/04/WC500089474.pdf. Accessed January
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e157
DEVELOPMENTAL THERAPEUTICS AND
TRANSLATIONAL RESEARCH

Clinical Trial Eligibility Criteria:

Tradition Versus Reality

CHAIR
Edward S. Kim, MD, FACP
Levine Cancer Institute, Carolinas HealthCare System
Charlotte, NC

SPEAKERS
Gwynn Ison, MD
U.S. Food and Drug Administration
College Park, MD

Jeffrey R. Infante, MD
Sarah Cannon Research Institute
Nashville, TN
 PRACTICAL VERSUS TRADITIONAL ELIGIBILITY CRITERIA

Transforming Clinical Trial Eligibility Criteria to Reflect

Practical Clinical Application
Edward S. Kim, MD, FACP, Jennifer Atlas, MD, Gwynn Ison, MD, and Jennifer L. Ersek, MSPH

OVERVIEW

Historically, oncology clinical trials have focused on comparing a new drugs efficacy to the standard of care. However, as our
understanding of molecular pathways in oncology has evolved, so has our ability to predict how patients will respond to a
particular drug, and thus comparison with a standard therapy has become less important. Biomarkers and corresponding
diagnostic testing are becoming more and more important to drug development but also limit the type of patient who may
benefit from the therapy. Newer clinical trial designs have been developed to assess clinically meaningful endpoints in
biomarker-enriched populations, and the number of modern, molecularly driven clinical trials are steadily increasing. At the
same time, barriers to clinical trial enrollment have also grown. Many barriers contribute to nonenrollment in clinical trials,
including patient, physician, institution, protocol, and regulatory barriers. At the protocol level, eligibility criteria have
become a large roadblock to clinical trial accrual. Over time, eligibility criteria have become more and more restrictive. To
accrue an adequate number of patients to molecularly driven trials, we should consider eligibility criteria carefully and
attempt to reduce restrictive criteria. Reducing restrictive eligibility criteria will allow more patients to be eligible for clinical
trial participation, will likely increase the speed of drug approvals, and will result in clinical trial results that more accurately
reflect treatment of the population in the clinical setting.

C linical trials and their availability for treatment of pa-

tients serve as a longstanding foundation in the prac-
tice of medicine and drug development. Through all phases
of study (I-IV), the risk-benefit ratio has always encompassed
assessing safety as well as offering opportunity for treatment
benefit. In the past, the primary focus of early-phase studies
was defining safe doses, and late-phase studies served as the
final hurdle to regulatory approval. Initially, with only lim-
ited treatments available, therapies were tested against best
supportive care. As more therapies were approved, combi-
nation therapies were compared with historical standards,
leading to the desire for homogenous patient populations.
Although homogenous populations allow for direct compar-
ison of study results, they also reduce the number of patients
eligible to participate in the study. From the perspective of
study investigators and sponsors, there may be an interest in
keeping study populations tight and homogenous to allow for
comparison with standard therapies; however, increasingly
strict eligibility criteria lead to increased difficulty in accrual.
With modern clinical trials incorporating biomarkers and
targeted therapies, there is less need to compare the results
of these trials to standard therapies, and thus trial eligibility
could be relaxed. Clinical models and structures that support
therapeutic development are not keeping pace with scientific
innovations.1 We must carefully evaluate the evolution of
clinical trial design and the corresponding eligibility criteria
based on molecular targets and drugs and, in turn, implement
these into the conduct of future clinical trials to successfully
incorporate the use of novel therapeutics into oncologic care
with results that are generalizable to the greater population.
IMPACT OF BIOMARKERS AND SURROGATE
ENDPOINTS ON CLINICAL TRIALS
Molecular medicine is quickly changing the landscape of
medical oncology. The era of molecular medicine is lead-
ing to drug approval at an unprecedented rate in oncology,
with more than 40 drug approvals based on specific tumor
biomarkers in the past decade.2 These drugs add to the
growing armamentarium of treatment options available to
patients with cancer. However, it is becoming apparent
that phenotypic characteristics are limited in their ability to
predict response. More recently, biomarkers are included as
critical components in modern clinical trials involving tar-
geted agents, shifting the priority to identifying targets

From the Department of Medicine, Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC; Office of Hematology and Oncology Products, Center for Drug
Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD; Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Edward S. Kim, MD, FACP, Solid Tumor Oncology and Investigational Therapeutics, Levine Cancer Institute, Carolinas HealthCare Stystem, 1021 Morehead
Medical Dr., Suite 3100, Charlotte, NC 28204; email: edward.kim@carolinashealthcare.org.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 83

KIM ET AL
for therapeutic development alongside drug development.
Consideration also must be given to appropriate choice of
primary endpoints. Although overall survival remains the
gold standard, progression-free survival, tumor response,
and duration of tumor response may serve as surrogate
endpoints in early-phase studies and may allow for early
approval. Interpretation of emerging data from trials is
hindered by a lack of specific reporting standards for bio-
markers.3 Stronger evidence-based outcomes incorporating
biomarkers could be achieved by implementing standard-
ized biomarker-reporting systems with molecular selection
criteria guided by the mutation gene at the variant level.3
As an example, listing specific variant mutations (e.g., del19,
T790) instead of listing a mutation generically as an EGFR
mutation would be more descriptive.
GOAL OF CLINICAL TRIALS
Clinical trials are fundamental to understanding the risks and
benefits of treatment in a specific intended population.
Clinical trials provide a formalized process of integrating
scientific findings into clinical practice in a safe and system-
atic manner. With increasing response rates noted in many
molecularly driven trials, small incremental gains may no
longer be adequate for drug approval. There needs to be a
focus on utilizing molecular medicine to achieve clinically
meaningful endpoints.
From a regulatory perspective, the U.S. Food and Drug
Administrations (FDA) primary objective in evaluating trial
eligibility criteria, from a first-in-human trial to a trial in-
tended to support a marketing application, is the safety of
the patient.4 Eligibility criteria that encourage clinical trial
accrual, permit patient access to investigational drugs, and
create clinical trial results that are generalizable to the
broader U.S. population are directly in line with FDAs
mission.
TRADITIONAL CLINICAL TRIAL ELIGIBILITY
CRITERIA AND DESIGN
Traditional clinical trials have been categorized on the basis
of phases of drug development. In phase I clinical trials, a
small number of patients are enrolled, and the focus is on
safety. The goal of phase I clinical trials is primarily to es-
tablish the maximum tolerated dose that would have
KEY POINTS
Discuss the impact of molecular medicine and
biomarkers in oncology clinical trials.
Review traditional versus modern clinical trial design.
Review of barriers to protocol enrollment.
Discuss issues related to traditional versus modern
clinical trial eligibility.
Discuss regulatory issues related to clinical trial
eligibility.
84 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
acceptable toxicity if the drug is found to have clinical ef-
ficacy. The most important endpoint traditionally in phase I
trials has been identifying dose-limiting toxicity (DLT). His-
torically, phase I trials have not restricted patient eligibility
on the basis of diagnosis or molecular phenotype; however,
this is changing.
From a regulatory standpoint, many deficiencies sent to
sponsors of investigational new drug applications (INDs) do
not pertain to the eligibility criteria, provided that the first-
in-human study is conducted in an appropriately advanced
cancer patient population, but pertain to the definition of
DLTs. The stringency applied to the DLT definition stems
from the interpretability of the study results, as potential
signals of toxicity should be captured as early in develop-
ment as possible. Unfortunately, the inflexible nature of the
commonly used 3+3 design of first-in-human trials may lead
to the premature discontinuation of dose escalation because
of toxicities that are either unrelated to the drug or are not
dose-dependent. To minimize the potential for premature
discontinuation of dose escalation, strict eligibility criteria
regarding organ function, life expectancy, comorbidities,
performance status, HIV status, and laboratory parameters
are instituted.
In phase II clinical trials, the primary objective is to de-
termine whether the therapy is effective. The primary
endpoints in these studies have historically been tumor
response and survival. Because of inconsistent factors, in-
cluding eligibility criteria and protocol design, phase II trials
can be difficult to interpret in comparison with one another.
Historically, phase III clinical trials have evaluated an ex-
perimental therapy in comparison with standard-of-care
therapy. Randomized clinical trials remain the gold stan-
dard. Following trials in these phases, sponsors present data
from their studies and file applications for approval. Federal
regulations govern aspects of IND applications and New
Drug Applications and Biologic License Applications. 5,6
Although there are no specific regulations regarding eligi-
bility criteria, deciding whom to include or exclude from a
trial may determine the difference between a successful trial
and a failed one.
Phase IV clinical trials, often referred to as postmarketing
surveillance trials, are completed after a drug has received
approval. Common reasons for conducting these trials in-
clude monitoring a drugs long-term efficacy, observing
the long-term toxicities and impact on quality of life, and
comparisons between a novel drug and other therapies that
are available on the market. The strict criteria developed
in the early-phase setting are not relaxed for later-phase
studies, as there is a legitimate interest to avoid confounding
of the interpretation of the results of trials by factors related
to the disease condition, rather than the therapeutic product.
The unintended consequence of this approach is that the
results of these studies may not be applicable to the patients
who eventually will receive the drug in the postmarketing
setting. Although postmarketing studies may capture some
of this information, they are not systematically per-
formed, resulting in off-label use without appropriate safety

information. Studying subgroups with broader eligibility
earlier in development may provide information that is more
useful to prescribers and patients in the postapproval set-
ting, where comorbidities are more frequent, and may aid in
making the benefit-risk calculation for a new agent with
more relevant data.
MODERN/PRACTICAL CLINICAL TRIALS
Modern trial designs, such as adaptive, umbrella, and basket
trials, have allowed the FDA to develop and implement
accelerated approval programs in some cases, based on
surrogate endpoints. A growing number of targeted ther-
apies have been adopted into the FDA programs that assist
with the accelerated development and approval of prom-
ising drugs (Fast Track designation, Breakthrough Therapy
designation, and Priority Review designation).7 The FDA
granted accelerated approval to 35 oncology products for
47 new indications from December 11, 1992, to July 1, 2010,
with clinical benefit confirmed in postmarketing trials for
26 of the 47 new indications, with subsequent conversion to
regular approval.8 The FDA has given breakthrough therapy
designation and accelerated approval to several targeted
drugs to be used in cancer therapy in an effort to speed
up the availability of promising drugs based on surrogate
endpoints felt to be reasonably likely to predict clinical
benefit in diseases with unmet medical needs or drugs that
have demonstrated a substantial improvement over current
available therapy. The median time between accelerated
approval and regular approval of oncology products was
3.9 years (range, 0.8-12.6 years), and the mean time was
4.7 years.8 Reduction in approval time clearly shows the
benefit of these FDA accelerated approval programs, with
the implication that appropriate postmarketing trials should
be completed to confirm efficacy results. Examples of tar-
geted therapies developed in conjunction with biomarkers
that received approval under expedited programs include
combination trametinib and dabrafenib for unresectable
or metastatic melanoma with BRAF V600E or V600K mu-
tations,9 osimertinib for metastatic EGFR T790M mutation-
positive nonsmall cell lung cancer (NSCLC),10 and erlotinib
and gefitinib for NSCLC with EGFR exon 19 deletions or
exon 21 (L858R) substitution mutations.11,12 There continues
to be a growing interest in developing tumor biomarkers to
assess the effectiveness of therapy, especially in relation to
targeted therapy, and in using surrogate endpoints as a basis
for accelerated approval by the FDA. We must continue to
strive to overcome the design and regulatory barriers that
exist so as not to impede approval of promising drugs.
Adaptive Trials
In 2004, the FDA published a critical path initiative docu-
ment highlighting the need for new, innovative clinical trial
designs as well as integration of biomarkers.13 Adaptive
designs, as defined by Vladimir Dragalin,14 are a multistage
study design that uses accumulating data to decide how
to modify aspects of the study without undermining the
PRACTICAL VERSUS TRADITIONAL ELIGIBILITY CRITERIA
validity and integrity of the trial. Adaptive clinical trial
designs are becoming more and more popular, as statisti-
cians can preplan adjustments to the study design on the
basis of data from the study itself. Multiple variations of
the adaptive design exist, and combinations can be used
simultaneously (multiple adaptive design). In the phase I
setting, adaptive dose-finding designs are used to establish
minimum and maximum dose levels and may be used in
conjunction with the group sequential design. The group
sequential design allows preplanned examination of the
study data to determine if the trial can be stopped early
because of efficacy or futility. In clinical trials involving the
use of biomarkers, biomarker-adaptive designs are used to
allow for changes to the study design on the basis of bio-
marker response.15,16
Phase I trials have increasingly been restricted to specific
tumor types known to harbor molecular targets or to tu-
mors that demonstrate the presence of a specific molecular
target.17 The use of contemporary designs in dose esca-
lation studies that allow for more flexibility with regard to
dose selection could permit the broadening of the eligi-
bility criteria. An adaptive design that allows for dose es-
calation, dose de-escalation, and dose re-escalation may
filter out potential signals of toxicity stemming from the drug
product, as opposed to the disease process or underlying
comorbidities.
Umbrella Trials
Umbrella trials involve the testing of a variety of drugs tar-
geting different mutations in a single cancer subtype. They
allow a large number of patients to be screened for multiple
biomarkers, which is particularly beneficial for low-prevalence
markers. These trials involve a group of two or more en-
richment designs, connected through a central infrastructure
that oversees screening and identification of patients. The
rationale for the umbrella trial design is to facilitate screening
and accrual to trials, with the goal of identifying a patient
population with the best chance for improved outcomes
with therapy. The BATTLE trial (Biomarker-Based Approaches
of Targeted Therapy for Lung Cancer Elimination) in 2005 is
an example of an umbrella trial. In the study, patients with
previously diagnosed and treated lung cancer underwent
repeat biopsies to assess biomarkers, which were used to
select treatment recommendations with one of several bi-
ologic agents.16 Other examples of umbrella trials include
ALCHEMIST, Lung-MAP, and I-SPY 2.18-20
Basket Trials
Basket trials are genotype-focused designs involving the
testing of a single drug on a specific mutation or mutations
in a variety of cancer types. Therefore, these trials have the
ability to include rare cancers that would be difficult to
study in randomized controlled trials.21 The basket trial
approach allows flexibility to continually open and close
treatment arms, which makes it possible to screen the
impact of many drugs over several different tumors under
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 85
KIM ET AL
one study. Patients are matched to the drug based solely on
the genetic abnormality, not on the type of cancer. One
example of a basket trial is vemurafenib in V600-mutated
nonmelanomas.22 In this trial, patients were enrolled into
prespecified cohorts of multiple tumor types. Cohorts were
closed or combined for tumor types with low accrual. Re-
sponse rate and progression-free survival were evaluated,
and the authors concluded that vemurafenib is active in
some, but not all, tumor types. The National Cancer In-
stitutes (NCI) MATCH is a basket/master trial, meaning that
new drugs can be added to the trial at any time. In 2015 the
NCI launched the NCI-MATCH trial (Molecular Analysis for
Therapy Choice), with plans to screen up to 3,000 patients,
with an enrollment of at least 1,000 individuals to a targeted
drug combination and independent of tumor histology in
patients with advanced solid tumors (gastrointestinal stro-
mal tumor, NSCLC, breast, gastric, melanoma, and thyroid)
and lymphomas.23 The primary objective of this trial is to
determine if the efficacy of targeted therapy is better than
that of standard therapy. Another example of the basket trial
approach includes the NCI M-PACT trial (Molecular Profiling-
Based Assignment of Cancer Therapy), which will randomly
assign patients with a known mutation in a specific genetic
pathway to either pathway-driven targeted therapies or a
treatment not known to be pathway-specific.24 These types
of trials will help answer questions about what types of
patients, tumors, or aberrations have the best outcomes
with molecularly targeted therapy compared with standard
chemotherapy.25
Registry Trials
Clinical studies are investigational in nature, whereas the
focus of registry studies is on observation. Registry studies
allow observational conclusions to be drawn from the
evaluation of multiple drugs directed at multiple biologic
targets in several cancers. As an example, the American
Society of Clinical Oncologys (ASCOs) TAPUR (Targeted
Agent and Profiling Utilization Registry Study) will enroll
patients with advanced solid tumors, B-cell non-Hodgkin
lymphoma, and multiple myeloma from three health care
systems, including the Carolinas HealthCare Systems Levine
Cancer Institute, with the goal of matching tumor profiles
with available agents. A molecular tumor board will review
the proposed drug-target match and report to the physician
on potential treatments either on or off the study. Safety and
efficacy outcomes will be recorded; however, the primary
endpoint is objective response rate.26
BARRIERS TO CLINICAL TRIAL ENROLLMENT
Many barriers to clinical trial enrollment exist and are
noted in the literature. These can be broken into several
broad categories: patient-level barriers (including socio-
demographic and disease-related barriers), physician-level
barriers, institutional-level barriers, and regulatory and
protocol-level barriers, including restrictive eligibility
criteria.
86 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
There are several obstacles to trial enrollment associated
with patient characteristics. Because of the more extensive
need for tissue and blood samples in molecularly driven
studies, some patients decline clinical trial enrollment because
of the fear that additional testing will delay the initiation of
critical antineoplastic therapy or out of fear of undergoing
additional procedures. Socioeconomic issues, including dis-
tance from centers with trials and frequency of follow-up
visits, may influence the populations enrolled on protocols.
Patients who lack insurance may present with more advanced
stages of cancer and symptomatic disease, precluding trial
enrollment. Because of socioeconomic differences, there are
subsets of patients with poor enrollment on clinical trials due
to lack of understanding of the rationale for the clinical studies
and/or mistrust of physicians. Christian et al27 reported that
although the enrollment of minority patients on clinical trials in
the United States has remained relatively stable, because the
overall number of individuals enrolled in trials has increased
over time, the minority percentage has therefore decreased. A
decreased number of minority patients represented in clinical
trials could lead to potentially important biologic differences
being overlooked.
Physician-driven barriers to protocol enrollment exist as
well. These include the complexity of protocol design and
eligibility criteria, lack of awareness of an available protocol,
absence of an available protocol for an individual patient, or
lack of consideration for clinical trial enrollment of patients
with decreased performance status. Sohal et al28 reported
that the lack of clinical trial access and a decline in functional
status or death were the most commonly cited reasons
patients were not enrolled on molecularly driven protocols
by their physicians. The inability of physicians to keep up to
date with the research literature of molecular compounds
and markers is overwhelming and will limit discussions with
patients about clinical trials.
Additionally, there are funding and regulatory barriers to
clinical trial enrollment that directly affect the protocol-
level barriers. With the evolution of trial design and safety
regulations, there is a growing number of mandated re-
quirements in an effort to standardize protocols. Typically,
criteria mandated for exclusion of certain patients perceived
as being potentially at higher risk to receive investigational
therapy. These patients at higher risk may be defined as
having a prior history of malignancy, active brain metas-
tases, suboptimal hepatic or renal function, or HIV positivity.
However, as the field becomes more comfortable with early
integration of available interdisciplinary data during the
course of drug development,1 the FDAs Office of Hematology
and Oncology Products would encourage sponsors to broaden
these criteria, allowing for the best examination of real world
experience as well as providing patients with life-threatening
diseases access to investigational agents. From a funding
perspective, increasing complexity of trials and eligibility
criteria has led to increased costs to conduct such studies.
With decreasing funding available, studies must be carefully
designed, as meaningful clinical benefits will likely be ex-
amined more closely in the future.

IMPORTANCE OF CLINICAL TRIAL ELIGIBILITY
Although eligibility criteria are a necessary aspect of clinical
protocols, their purpose is to define the characteristics of
the intended patient population to receive the study drug.
However, as trial designs adapt to incorporate molecular
medicine, so must eligibility criteria. From a design per-
spective, restrictions on eligibility are effective only if the
restrictions lead to increased statistical power of the study.29
In clinical practice, eligibility criteria employed on clinical
trials are rarely adhered to.
Traditionally, we have relied on the decision-making ca-
pacity of the individual physician, with consent of the pa-
tient, to determine eligibility for trial enrollment; however,
the paradigm has shifted over time so that all aspects of
the trial, including determination of patient eligibility, dose
modifications, and allowed supportive measures, are ex-
plicitly included in the protocol.29 Reevaluation of clinical
trial eligibility criteria, especially those related to the sci-
entific objective and generalizability of the results to
other populations, throughout the entire drug development
process should be considered, while keeping the safety of
the patient at the forefront.
RESTRICTIVE ELIGIBILITY CRITERIA: A
ROADBLOCK TO TRIAL ENROLLMENT
Although eligibility criteria remain an essential component
of clinical trials, the growing number of eligibility criteria and
complexity of trial designs has increasingly become a barrier
to trial enrollment. Eligibility criteria have generally been
categorized as inclusion (e.g., must have a specific molecular
aberration) versus exclusion criteria (e.g., evidence of brain
metastases). We assessed barriers to enrollment on trials,
including patient-related barriers, physician-driven barriers,
and funding and regulatory barriers.17 Protocol eligibility
criteria represent a modifiable barrier to increasing clinical
trial availability to a larger subset of patients. Table 1 lists a
comparison of traditional versus potential modern clinical
trial eligibility criteria.
Certain diagnostic restrictions are required to ensure that
patients enrolled on clinical protocols involving targeted
drugs would have a reasonable chance of clinical benefit.
Protocol barriers, such as tissue availability and specific
laboratory testing, are increasingly frequent requirements of
trials involving molecularly targeted agents. George29 de-
scribed the types of problems restrictive eligibility criteria
create in phase III clinical trials in cancer with regard to
scientific interpretation, medical applicability, complexity,
costs, and patient accrual. In molecularly driven trials, eli-
gibility criteria related to patient characteristics, including
restrictions on age, performance status, laboratory findings
addressing organ function, and history of previous cancer
diagnosis, previous antineoplastic therapy, or evidence of
metastatic disease to the brain, have become cumbersome.
Many restrictive criteria could be reevaluated when
considering the effects of traditional cytotoxic therapy
versus modern targeted therapy because these drug side-
PRACTICAL VERSUS TRADITIONAL ELIGIBILITY CRITERIA
effect profiles are quite different. As more clinical in-
formation about the toxicity profile of a particular drug is
obtained, the eligibility criteria for subsequent trials may be
tailored to account for this information. For example, if it is
observed that an agent causes hepatic toxicity during early
development, then the eligibility criteria for the subsequent
trials may be amended either to include more intensive
evaluation of hepatic injury and function and/or to exclude
patients with a certain degree of baseline hepatic impair-
ment. Dedicated studies in patients with hepatic dysfunc-
tion would also be informative, especially in diseases that
have a propensity to metastasize to the liver. However,
other criteria, such as a minimum age requirement or comor-
bidities (e.g., underlying HIV positivity), could be relaxed or
amended to allow for less stringent requirements as the de-
velopment progresses into later phases.17 Safety concerns are a
commonly cited cause for restrictive eligibility criteria. If a drug
has a toxicity profile known to be harmful in a particular subset
of patients, then these patients should be excluded. One ex-
ample of this would be giving bevacizumab to patients with lung
cancer with squamous cell carcinoma histology. Ideally, safety
criteria should be limited to those in which no medical judgment
is allowed. Increased complexity of protocol design and in-
structions on dose modifications do not replace a clinicians
judgment concerning an individual patients suitability for
clinical trial enrollment.
Patients with brain metastases are a patient subset
typically excluded from clinical trials. Over time, the
number of patients with brain metastases are likely to
increase in frequency, based on the natural history of
many tumor types and the sites of frequent brain me-
tastases. In addition, as adjuvant chemotherapy continues
to improve outcomes, it is likely that we will continue to
see more disease relapses in the brain given the limited
number of antineoplastic therapies that can penetrate the
blood-brain barrier. Carden et al30 advocate that we
should rethink exclusion of patients with asymptomatic
brain metastases from clinical trials. Because of the de-
velopment of more-sensitive brain-imaging techniques,
metastatic brain lesions are often detected earlier and
may be asymptomatic at the time of detection. In many
trials, brain imaging is a part of the screening workup for
trial eligibility. Traditionally, patients with brain metas-
tases have been excluded from trial participation because
of the shortened life expectancy associated with symp-
tomatic brain metastases and a concern that the patient
would not receive a sufficient duration of the study drug;
therefore, clinical benefit would not be expected and may
confound study results. Although safety is a priority,
universally precluding patients with brain metastases
from clinical trials limits their access to potentially ef-
fective therapy, making it difficult to extrapolate the use
of these drugs to the general population.
The more restrictive the eligibility criteria, the more
limited the heterogeneity of the study population, limiting
the ability to generalize trial results to the population who
will be treated off-study. We must be concerned that the
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KIM ET AL

TABLE 1. Comparison of Traditional Versus Potential Modern Clinical Trial Eligibility Criteria
Traditional Modern
Trial Methodology
Preclinical Data Less requirements, usually some diagnostic restrictions More diagnostic restrictions; usually require biopsy/tissue and
specific laboratory testing to identify actionable target
Clinical Trial Design Dose escalation Dose escalation with expansion cohorts
(Early Phase)
Clinical Trial Design Randomized registries Randomized in biomarker enriched population
(Late Phase)
Clinical Trial Maximum tolerated dose Response rate; however, FDA policies in place for Breakthrough
Endpoints Therapies and Accelerated Approval. Greater use of surrogate
(Early Phase) endpoints.
Clinical Trial OS, PFS OS
Endpoints
(Late Phase)
Patient Characteristics
Target Population Unselected Molecularly targeted subset
Age Typically restricted Typically restricted, but could advocate for broadening age re-
strictions given different side-effect profiles of these drugs
Performance Typically limited to ECOG PS 0-1 Could include EGOG PS 2
Status
Life Expectancy Typically, patients must be expected to live several months Could possibly be relaxed given different side-effect profiles
Organ Function/ Required; some patients may be excluded because of abnormal Required; some patients may be excluded because of abnormal
Laboratory laboratory values laboratory values. May require reevaluation as a result of
Abnormalities different side-effect profiles.
Medical History Required; some conditions are excluded Required; some conditions are excluded
Previous Therapy May exclude from trials looking at front-line therapy May exclude from trials looking at front-line therapy
Medications/ Less likely to exclude Increased concern for drug-drug interactions
Steroid Use
Comorbidities More stringent exclusion based on comorbidities (e.g., cardiac Some comorbidities traditionally restricting enrollment could be
comorbidities) relaxed
QOL/Depression Sometimes required that patients self-reported QOL/depression Could be relaxed; including patients with low self-reported QOL
scores are high enough for inclusion could be important for trials where efficacy is similar, but one
drug is better tolerated
Disease Characteristics
Confirmed Required Somewhat important, but druggable target is main driver
Diagnosis/Tumor
Histology
Target Lesion Required Required
Nontarget Lesion Usually not required May be required
Brain Metastases Traditionally excluded Traditionally excluded; possibly needs to be modified, especially
for patients with asymptomatic brain metastases
Metastatic Disease Usually allowable Usually allowable
Other Than Brain
Prior/Concurrent Usually excluded Usually excluded
Malignancy
Prior Progression Sometimes restricted in traditional trials Could be relaxed in trials of molecularly targeted drug
Prior Clinical Usually allowable Usually allowable
Response
Molecular Analysis
Biopsy/Specimen Not necessarily required Required
Study Therapy
Treated Previously Traditionally excluded Could be included if subsequent biopsies have target abnormality
With Study Drug
Known Sensitivity Not necessarily required Usually required
Other Investiga- Traditionally excluded Usually excluded
tional Drug
Continued

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 PRACTICAL VERSUS TRADITIONAL ELIGIBILITY CRITERIA

TABLE 1. Comparison of Traditional Versus Potential Modern Clinical Trial Eligibility Criteria (contd)
Traditional Modern
Toxicity More likely to exclude from trial or lead to patient coming off trial; Different side-effect profile than traditional cytotoxic therapy;
likely more grade 3 or 4 toxicity seen with traditional cytotoxic generally less grade 3 or 4 toxicity seen with targeted therapy
therapy
Investigator Traditionally more investigator judgment incorporated; drug or Less investigator opinion, shift to explicit instructions on all
Opinion combination therapy compared with physician preference protocol aspects
Regulatory
Consent/ Required Required
Compliance
Additional Not often required Often required for specimen collection/molecular analysis
Optional Consent
Abbreviations: FDA, U.S. Food and Drug Administration; OS, overall survival; PFS, progression-free survival; ECOG, Eastern Cooperative Oncology Group; PS, performance status; QOL,
quality of life.

study population is not accurately reflecting associated
toxicities seen with these novel agents if only the youn-
gest and healthiest patients qualify for study enrollment.
Unger et al31 found that clinical trial participation was
associated with better survival in the first year of en-
rollment, which was postulated to be related to exclusion
of patients having a poor prognosis with comorbidities
and decreased functional status.
Restrictive, complex eligibility criteria likely result in
decreased accrual rates. Slow accrual to clinical trials
means delays in answers to important clinical questions.
The negative impact of low accrual rates extends to pro-
longed trial duration, early closure of studies with poor
accrual, and delays in analysis of trial results.32 If eligibility
criteria are broadened, this may result in a faster accrual
rate and observation of a wider array of clinical toxicities
that more accurately reflect the general intended pop-
ulation. However, expanding clinical trial eligibility would
perhaps allow for trial conclusions to more accurately
mimic general clinical practice and allow for extrapolation
to patients who were not treated on-study.
FUTURE DIRECTIONS
Personalized, precision medicine will require the in-
corporation of clinical exams, molecular testing, and
utilization of information obtained from ongoing adaptive
clinical trials to determine the appropriate treatment for
each patient. There must be a concentrated effort to
limit restrictive eligibility criteria while allowing continued
modification of eligibility criteria as a drug moves through
the research process. ASCO initiatives support the evolution
of more practical, modernized, clinical trial design.1,17 At
the center of this movement for eligibility criteria reform
is the implementation of trials that involve targeted
therapies with molecular biomarkers. The higher the
strength of a drug and a specific molecular target mea-
sured on the tumor, the higher the priority of identifying
this patient population for treatment. In these settings,
an active drug-to-target (e.g., high response rate) should
supersede other potentially restrictive eligibility criteria.
Because many markers have low incidence rates, greater
collaboration will be needed to effectively complete
meaningful studies. We must continue to prioritize the
development of modernized, practical clinical proto-
cols and encourage enrollment in these innovative trials.
We must increase access and awareness of molecularly
driven protocols to include more patients as we answer
these important clinical questions and continue to in-
tegrate new targeted drugs and biomarkers into clinical
practice.

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therapy for lung cancer. Cancer Discov. 2011;1:44-53.
17. Kim ES, Bernstein D, Hilsenbeck SG, et al. Modernizing eligibility criteria
for molecularly driven trials. J Clin Oncol. 2015;33:2815-2820.
18. National Cancer Institute. ALCHEMIST (The Adjuvant Lung Cancer
Enrichment Marker Identifcation and Sequencing Trials): Question
and Answers. http://www.cancer.gov/newscenter/newsfromnci/2014/
ALCHEMISTlaunchQandA. Accessed February 2, 2015.
19. Lung-MAP. http://www.lung-map.org. Accessed January 28, 2016.
20. I-SPY 2 Trial. http://www.ispy2trial.org. Accessed January 28, 2016.
21. Siu LL, Conley BA, Boerner S, et al. Next-generation sequencing to guide
clinical trials. Clin Cancer Res. 2015;21:4536-4544.
22. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple
nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;
373:726-736.
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23. National Cancer Institute. NCI Molecular Analysis for Therapy
Choice Program (MATCH) & Pediatric MATCH. http://www.cancer.gov/
clinicaltrials/noteworthy-trials/match. Accessed February 2, 2015.
24. Do K, OSullivan Coyne G, Chen AP. An overview of the NCI precision
medicine trials-NCI MATCH and MPACT. Chin Clin Oncol. 2015;4:
31-38.
25. Kim ES. The future of molecular medicine: biomarkers, BATTLEs, and big
data. Am Soc Clin Oncol Educ Book. 2015;22-27.
26. Andrews A. ASCO and NCI launch largest precision medicine trials using
real-world evidence. Am Health Drug Benefits. 2015;8:37.
27. Christian MC, Trimble EL. Increasing participation of physicians and
patients from underrepresented racial and ethnic groups in National
Cancer Institute-sponsored clinical trials. Cancer Epidemiol Biomarkers
Prev. 2003;12:277s-283s.
28. Sohal DP, Rini BI, Khorana AA, et al. Prospective clinical study of
precision oncology in solid tumors. J Natl Cancer Inst. 2015;108:
djv332.
29. George SL. Reducing patient eligibility criteria in cancer clinical trials.
J Clin Oncol. 1996;14:1364-1370.
30. Carden CP, Agarwal R, Saran F, et al. Eligibility of patients with brain
metastases for phase I trials: time for a rethink? Lancet Oncol. 2008;9:
1012-1017.
31. Unger JM, Barlow WE, Martin DP, et al. Comparison of survival out-
comes among cancer patients treated in and out of clinical trials. J Natl
Cancer Inst. 2014;106:dju002.
32. Lara PN Jr, Higdon R, Lim N, et al. Prospective evaluation of cancer
clinical trial accrual patterns: identifying potential barriers to enroll-
ment. J Clin Oncol. 2001;19:1728-1733.
DEVELOPMENTAL THERAPEUTICS AND
TRANSLATIONAL RESEARCH

Immunotherapy: Beyond
Checkpoint Inhibitors

CHAIR
Gregory L. Beatty, MD, PhD
Hospital of the University of Pennsylvania
Philadelphia, PA

SPEAKERS
George E. Peoples, MD
Cancer Vaccine Development Program
San Antonio, TX

Marcela Valderrama Maus, MD, PhD

Abramson Cancer Center of the University of Pennsylvania
Philadelphia, PA
 ARMING THE IMMUNE SYSTEM TO PREVENT CANCER RECURRENCE

Arming the Immune System Through Vaccination to Prevent

Cancer Recurrence
Diane F. Hale, MD, Timothy J. Vreeland, MD, and George E. Peoples, MD

OVERVIEW

Cancer vaccines have the potential to provide a nontoxic treatment for the prevention of cancer recurrence in the adjuvant
setting. Many cancer vaccines have been tested in multiple phase III trials with minimal success. However, through these
failed clinical trials, we have learned that the ideal setting for vaccine therapy is the adjuvant setting. Also, we have learned
important lessons about patient selection to maximize the probability of success. This article will highlight some of the
successes, our trial results in the adjuvant setting, and future directions.

T he creation of a vaccine to prevent or cure cancer is a very

alluring goal, but the pursuit of this goal has been fraught
with difficulty. To create a cancer vaccine, the first key is to
find the perfect target: a tumor-associated antigen (TAA) or
antigens expressed on a high percentage of tumor cells but
not on normal cells. Once the target is identified, the goal is
to use an efficient, safe, and easily reproducible method to
stimulate the immune system to eliminate targeted tumor
cells. These goals have been approached in a number of ways
in the saga of cancer vaccine creation, but with few clinically
meaningful successes. To date, the majority of cancer vaccines
have been tested in the metastatic setting with disappointing
results. The high disease burden, immune escape mechanisms,
and immune suppression of the tumor micro-environment
encountered in the setting of metastatic or aggressive disease
is more than the immune system can overcome. This may not
be the ideal setting for cancer vaccines to become clinically
relevant, at least not as monotherapy.
There are, however, exceptions to the overall discouraging
results of vaccines in the metastatic setting, and important
lessons can be learned from these exceptions. The most
notable exception, and the only vaccine granted U.S. Food
and Drug Administrationapproval, is sipuleucel-T, an autol-
ogous dendritic cell vaccine directed against the TAA prostatic
acid phosphate. This vaccine is approved for use in metastatic,
asymptomatic or minimally symptomatic castration-resistant
(hormone-refractory) prostate cancer. The success of sipuleucel-
T in the metastatic setting is likely due to the indolent nature of
prostate cancer, which makes it a more realistic target for a
cancer vaccine, even in advanced disease. Similarly, subset
analyses from multiple trials of vaccines given to patients
with advanced cancers have shown that, although vaccines
produced disappointing results overall, they perform much
better in patients with minimal or no residual disease. Taken
as a whole, these results indicate that cancer vaccines per-
form better when used in patients with less aggressive dis-
ease, whether by biology or by disease burden.
Building on these lessons, cancer vaccines have been used
to treat patients with the absolute minimal disease burden
after they are rendered disease-free by standard-of-care
therapies. Priming the immune system to create an active
immune response to prevent recurrence rather than trying
to eradicate advanced, established, and aggressive disease is
very appealing. First, after patients complete and recover
from standard-of-care therapy (generally immunosuppres-
sive chemotherapy), they have improved immune function,
allowing a full development of antitumor immunity.1 Second,
in a disease-free state, there is theoretically less tumor-related
immune suppression, fewer immune escape mechanisms, and
no tumor microenvironment.1 With the bulk of tumor removed
or eradicated, the immune system can then be used to eliminate
the small number of tumor cells left after therapy, which is a
more realistic goal for this mechanism. Finally, the long-term
immune memory created by a successful cancer vaccine offers
continued protection against dormant circulating or dissemi-
nated tumor cells that may still be present or may re-emerge in a
disease-free host; this characteristic and distinct advantage
distinguishes active specific immunotherapy from traditional
cancer therapies. Consequently, cancer vaccines offer the unique
promise of long-term protection against cancer recurrence.

From the Department of Surgery, San Antonio Military Medical Center, Fort Sam Houston, TX; Department of Surgery, Womack Army Medical Center, Fort Bragg, NC; Cancer Vaccine
Development Program, San Antonio, TX; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: George E. Peoples, MD, Cancer Vaccine Development Program, c/o Metis Foundation, 300 Convent St., San Antonio, TX 78205; email: georgepeoples2@
hotmail.com.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e159

HALE, VREELAND, AND PEOPLES
Although using the vaccine platform to prevent recurrence
in the adjuvant setting is quite attractive, this setting has
unique challenges. There is less tolerance for toxicity when
patients are disease-free; therefore, any therapy being
added in the adjuvant setting must come with a very low
toxicity profile or else compliance is expected to be poor.
Also, proving a clinically substantial decrease in recurrence
can be quite challenging when evaluating patients with less
aggressive disease. The attractive aspect of studying a new
therapy in patients with advanced disease is the relatively
short time period needed to show a reduction in tumor
burden or improvement in progression-free survival. Con-
versely, in the adjuvant setting, the time period required to
reach a noteworthy number of recurrences may be quite
lengthy. Depending on the tumor biology and documented
recurrence rates, this may necessitate a trial spanning
multiple years and with large treatment groupsultimately
resulting in a very expensive trial. If the vaccine strategy is
truly more suitable in the adjuvant setting, these limitations
lead to a difficult first step to prove efficacy and likely explain
why this strategy has been around for so long but has so few
successes. As a result, much of the current evidence showing
benefit of vaccines comes from subset analyses of larger
trials focusing on patients with minimal disease burden.
We will review the evidence of vaccine success in patients
with minimal disease burden and current immunologic
vaccine therapies being studied in the adjuvant setting, and
we will lay out the best available data supporting this theory
with current successes. We will also discuss future plans for
combination therapies.
PROOF OF CONCEPT IN PHASE III TRIALS
Although developing and funding an adjuvant study may be
difficult, it has been attempted in several cancer types with a
variety of vaccine platforms. Table 1 summarizes the pre-
vious and current phase III trials of vaccines given in the
adjuvant setting (with no or minimal evidence of disease),
KEY POINTS
Cancer vaccines represent a nontoxic therapeutic
modality with great antitumor specificity.
Peptide vaccines effectively stimulate a specific immune
response and are simple, easily produced, and
efficiently exported to the community.
The adjuvant setting is an appropriate clinical setting to
test cancer vaccines as it optimizes the chances of an
effective immune response when the tumor burden is
the lowest.
Combinations of other immunotherapies with vaccines
may be even more clinically effective.
In the metastatic setting, combining vaccines as
T-celleliciting agents with checkpoint inhibitors may
synergistically enhance the benefits of each modality
and improve long-term clinical results.
e160 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
for the prevention of solid tumor recurrence. There have
been many vaccines that found clinical improvement in
phase II evaluation but failed to find clinical significance in
phase III. The lessons learned from previous trials have
assisted in creating improved trial designs and, most im-
portantly, selecting patients who will derive the most benefit
from a cancer vaccine. Highlighted below are a few key
phase III trials that demonstrate important points for future
trial design.
OncoVax is an autologous tumor cell vaccine combined
with bacillus Calmette-Guerin that has been studied
extensively in colon cancer. There have been three phase
III trials using this vaccine in the adjuvant setting after
resection of stage II/III colon and rectal cancer, enrolling a
total of 764 patients.2-4 The initial phase III trial enrolled
patients with both colon and rectal cancer. Overall, there
was no significant differences in the treatment groups, but
when breaking down the results by tumor type (colon vs.
rectal) and focusing only on those patients with colon
cancer, there was a significant improvement in both overall
survival (OS) and disease-free survival (DFS) for the vacci-
nated versus control patients (OS 83% vs. 52%, hazard ratio
[HR] 3.97; 95% CI, 1.2412.72; p = .020; DFS 67% vs. 44%, HR
2.67; 95% CI, 1.056.76; p = .039).2 This led to the second
phase III trial, which focused on patients with surgically
resected stage II/III colon cancer. Again, the overall results of
this trial failed to show a significant difference with treatment,
but within the subset of stage II disease, vaccinated patients did
show an improved recurrence free interval (p = .011) and 4-year
recurrence-free survival (88% vs. 74%, p = .032).3 The largest of
the phase III OncoVax trials enrolled 412 patients with surgically
resected stage II/III colon cancer and had a 7.6-year median
follow-up.4 This trial did not show a significant improvement in
OS, DFS, or time-to-recurrence with vaccination.4 Based on the
combined results of these trials, the next phase III OncoVax trial
is focused on patients with minimal disease, where subset
analysis has shown the most promise, enrolling only patients
with resected stage II colon cancer (NCT02448173). Overall, the
work with this vaccine nicely demonstrates identification of
patients with no evidence of disease with low disease burden
as the most suitable population for cancer vaccines.
A similar finding of improved outcomes in vaccinated
patients with lower disease burden was found in a trial using
vitespen for renal cell carcinoma. Vitespen (HSPPC-96) is an
autologous, tumor-derived, heat shock protein vaccine. In
the phase III evaluation, it was given to patients in the
adjuvant setting that were stage I-IV, surgically resected and
with no evidence of disease; with 1.9-year median follow-
up, there were no overall differences in recurrence events
(p = .506). However, on subset analysis of patients with
stage I/II disease, there was a decrease in recurrence for
patients who were treated with the vaccine versus patients
in the control group (15% vs. 27%, p = .056).5
Patient selection in trials using an adjuvant vaccine to
prevent recurrence is a key to demonstrate clinical efficacy.
Beyond a low disease burden, it is also important to un-
derstand the specific mechanism of action of each vaccine to
 TABLE 1. Adjuvant Phase III Solid Tumor Vaccine Trials
Solid Tumor Reference or
Type Vaccine Strategy Vaccine Type Immunoadjuvant Study Type No. Patients Study Name Results NCT Number
DENDRTIC CELL VACCINES
Melanoma DCaT-RNA DC Autologous tumor RNA loaded Adjuvant, NED, resected, monosomy 3 200* Currently enrolling, study start date June 2014, esti- NCT01983748
(Uveal) onto autologous DC mated primary completion June 2020
Glioblastoma DC Vax-L DC Autologous DC pulsed with au- Adjuvant, NED, new diagnosis in addition to 348* Active (not enrolling), study start date December 2006, NCT00045968
tologous whole tumor lysate standard of care, must be resected estimated primary completion September 2016
disease
Glioblastoma ICT-107 DC Autologous DC pulsed with 6 Adjuvant, evidence of disease after standard 414* Currently enrolling, study start date December 2015, NCT02546102
peptides (MAGE-1, HER2, AIM- of care , 1 cm3 of disease may be present estimated primary completion December 2019
2, TRP-2, GP100, IL-13Ra2)
PEPTIDE VACCINES
Breast E75 Peptide HER2/neu peptide vaccine GM-CSF Adjuvant, NED, high-risk for recurrence 700* PRESENT Active (not enrolling), study start date November 2011, NCT01479244
estimated primary completion date April 2018
Melanoma POL-103A Multiple Shed peptides from 3 allogenic Alum Adjuvant, NED, surgically resected, stage IIb, 1,059* MAVIS Currently enrolling, study start date April 2012, esti- NCT01546571
peptides melanoma cell lines IIc, III mated primary completion date July 2016
Melanoma Tyrosinase, gp100, Multiple GM-CSF Adjuvant, NED, surgically resected, stage IV 815 OS (p = .528), RFS (p = .131) NCT01989572
MART-1 Peptides
Melanoma GM2-KLH Protein GM2 antigen combined with KLH QS-21 Adjuvant, NED, stage II 1,314 EORTC 18961 Terminated after second interim analysis: 1.8 years Eggermont
to improve immunogenicity median follow-up, detrimental OS (HR 1.66; p = .02) et al19
and futile RFS (HR 1.00; p = .99). After 4-year follow-
up, vaccinated patients RFS 1.2% (HR 1.03) and OS
rate 2.1% (HR 1.16)
Melanoma MAGE-A3 Protein recMAGE-A3 AS15 Adjuvant, NED, stage IIIB-C 1,351* DERMA Terminated after showing lack of efficacy NCT00796445
Melanoma MART-1, NA17-A, Multiple Adjuvant, NED 13 Terminated for low accrual NCT00036816
(Ocular) gp100, peptides
tyrosinase
NSCLC MAGE-A3 Protein recMAGE-A3 AS15 Adjuvant, NED, MAGE-A3 positive, resected, 2,272 MAGRIT 38.8-month median follow-up, median DFS 60.5 Vansteenkiste
stage IB, II, IIIA months vaccine vs. 57.9 months control (p = .74) et al20
Glioblastoma Rindopepimut Peptide 14-mer peptide of EGFRvIII with GM-CSF Adjuvant, must have attempted surgical 700* ACT IV Active (not enrolling), study start date November 2011, NCT01480479
(CDX-110) KLH resection and chemoradiation, may have estimated primary completion date November 2016
evidence of disease, must have stable
disease from postoperative to
postchemoradiation
RCC HSPPC-96 Protein Autologous, tumor-derived, heat Adjuvant, NED, surgically resected, stage I-IV 728 1.9-year median follow-up, no difference in overall Wood et al5
(vitespen) shock protein recurrence events (37.7% vaccine vs. 39.8% control; p
= .506), slightly improved in stage I/II (15.2% vaccine
vs. 27% control; p = .056)
TUMOR CELL VACCINES
Pancreas Algenpantucel-L Tumor cell Alpha-1,3-glactosyltransferase Adjuvant, NED, resected pancreatic cancer 722* IMPRESS Active (not enrolling), study start date April 2010, NCT01072981
(hyperacute) expressing allogeneic pancre- stage I/II estimated primary completion date June 2016
atic tumor cell vaccine
NSCLC Belagenpumatecel- Tumor cell Allogenic tumor cell with anti- Adjuvant (maintenance after first-line che- 532 STOP Trial No difference OS (p = .594), no difference PFS (p = .947); Giaccone
L (lucanix) sense plasmid motherapy), evidence of disease allowed regression analysis found improved survival with et al21
to have SD (CR or PR) randomization within 12 weeks of completion of
chemotherapy (p = .002) and prior radiation im-
proved survival (p = .032)
Melanoma Polyvalent cultured Tumor cell Allogeneic melanoma vaccine BCG Adjuvant, NED, stage III/IV 1,656 MMAIT Terminated after interim analysis for futility: 5-year Morton et al22
allogenic mela- estimated survival 42.3% for stage IV and 63.4% for

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK

noma vaccine stage III
(canvaxin)

e161
ARMING THE IMMUNE SYSTEM TO PREVENT CANCER RECURRENCE

Continued
 TABLE 1. Adjuvant Phase III Solid Tumor Vaccine Trials (cont'd)

e162
Solid Tumor Reference or
Type Vaccine Strategy Vaccine Type Immunoadjuvant Study Type No. Patients Study Name Results NCT Number
Melanoma Polyvalent tumor- Tumor cell Allogeneic melanoma vaccine DETOX (detoxi- Adjuvant, NED, stage II/III 689 S9035 12.1-year median follow-up, ITT no difference in RFS Carson et al6
cell lysate fied Freund (p = .58) or OS (p = .61), subset analysis vaccinated
(melacine) adjuvant) and HLA-A2/Cw3+ 10-year RFS 66% vs. controls 54%
(p = .02)
Colon and Active specific Tumor cell Autologous tumor cells BCG Adjuvant, NED, stage II/III colon or rectal 98 93-month median follow-up, OS trend toward favoring Hoover et al2
HALE, VREELAND, AND PEOPLES

Rectal immunotherapy vaccine (p = .088), cohort analysis: colon cancer

(OncoVax) significant OS (p = .02) and DFS (p = .039) for vaccine,
no benefit in rectal
Colon Active specific Tumor cell Autologous tumor cells BCG Adjuvant, NED, stage II/III colon 254 8701 5.3-year median follow-up, recurrence free interval Vermorken et
immunotherapy (p = .023) improved in vaccine with larger impact on al3
(OncoVax) RFS (p = .032) in stage II vaccine
Colon Active specific Tumor cell Autologous tumor cells BCG Adjuvant, NED, stage II/III colon 412 ECOG E5283 7.6-year median follow-up, ITT no difference OS, DFS, or Harris et al4
immunotherapy time to recurrence, cohort analysis vaccinated pa-
(OncoVax) tient with treatment compliance signaled a trend in
DFS (p = .078) and OS (p = .12)
Colon Active specific Tumor cell Autologous tumor cells BCG Adjuvant, NED, stage II colon 550* Currently enrolling, study start date May 2015, esti- NCT02448173
immunotherapy mated primary completion date July 2020
(OncoVax)
Colon and Newcastle disease, Tumor cell Viral vector of autologous tumor Adjuvant, NED, after resection (to include 51 116.1-month follow-up for vaccine, 112.4-month Schulze et al23
Rectal virus-infected cells from resected liver liver metastasis resection) follow-up for control, no difference in OS, DFS, or
autologous tu- metastasis metastases-free survival. Subgroup analysis: advan-

2016 ASCO EDUCATIONAL BOOK | asco.org/edbook

mor cell vaccine tage for vaccinated colon OR (p = .042) and
(ATV-; NDV) metastases-free survival (p = .047)

*Anticipated number.
Abbreviations: DC, dendritic cell; NED, no evidence of disease; GM-CSF, granulocyte macrophage colony-stimulating factor; OS, overall survival; DFS, disease-free survival; NSCLC, nonsmall cell lung cancer; RCC, renal cell carcinoma; SD, stable
disease; CR, complete response; PR, partial response; BCG, bacillus Calmette-Guerin; ITT, intention-to-treat.

identify the patients who will have the best clinical benefit.
The Southwest Oncology Groups phase III trial of melacine
demonstrates the importance of human leukocyte antigen
(HLA) characteristics in patient selection and understanding
how the vaccine stimulates the immune system. Melacine
is a vaccine created from an allogeneic tumor cell line that
contains numerous melanoma-associated TAAs. The phase III
trial randomly selected 689 patients with stage II/III resected
melanoma to receive the vaccine or to be in the control group.
At a median follow-up of 12.1 years, the trial had an overall
negative result, but subset analysis demonstrated a significant
recurrence-free survival (RFS) and OS advantage in the pa-
tients who received the vaccine compared with the control
group when limiting analysis to patients with HLA-A2+ and/or
HLA-Cw3+ expression (5-year RFS, 78% vs. 65%; 10-year RFS,
66% vs. 54%; p = .02; 5-year OS, 90% vs. 76%; 10-year OS, 75%
vs. 63%; p = .01).6 These findings demonstrate the importance
of identifying the appropriate target population for a vaccine
and selecting patients with the appropriate biologic features.
PROOF OF EFFICACY
As previously discussed, demonstrating efficacy of a new
therapy in the adjuvant setting is inherently difficult, but it has
been done. We will highlight the work our group has completed
with cancer vaccines in the adjuvant setting; these trials are
summarized in Table 2. We have extensively researched three
HER2-based peptide vaccines (Fig. 1). These peptides (E75, GP2,
and AE37) were paired with an immunoadjuvant, granulocyte
macrophage colony-stimulating factor (GM-CSF) and given in
the adjuvant setting to disease-free patients with breast cancer
at high risk of recurrence. Two of the vaccines are HLA-A2 and
HLA-A3restricted (E75 and GP2) and directly stimulate
CD8+ T cells to generate immunity. The third, AE37, is a longer
peptide vaccine, is not HLA-restricted, and stimulates CD4+
T cells to create HER2-directed immunity. Similar to the HER2-
based peptide vaccines, we have also targeted folate binding
protein (FBP)-expressing tumors with a peptide vaccine (E39
and GM-CSF) in ovarian, endometrial, and breast cancers.
Lastly, we have recently expanded into an autologous dendritic
cell vaccine platform using autologous tumor lysate particle-
loaded dendritic cells in the adjuvant setting, targeting patients
with surgically resected melanoma.
E75 (Nelipepimut-S, NeuVax)
E75 (nelipepimut-S or NeuVax) is a peptide (KIFGSLAFL, HER2
aa: 369-377) derived from the extracellular domain of HER2
(Fig. 1) and given in combination with GM-CSF. Its immu-
nologic activity is mainly restricted to specific HLA types HLA-
A2 and HLA-A3, but with the possibility of binding several
other less common alleles HLA-A24 and HLA-A26. E75 was
evaluated in one of the largest adjuvant breast cancer
vaccine phase I/II trials to date, with 195 enrolled and 187
evaluable patients.7 Patients who were positive for HLA-A2/
A3 were placed in the treatment arm, and patients who were
negative for HLA-A2/A3 were followed prospectively in an
observational control group. This vaccine was found to have
ARMING THE IMMUNE SYSTEM TO PREVENT CANCER RECURRENCE
minimal toxicity with the majority of local and systemic
toxicities being grade 1. It was also able to produce effective
immunity to HER2. With a median follow-up of 60 months,
the vaccinated patients in this trial showed a trend toward
improved DFS with a 48% reduction in relative risk of re-
currence (RRR; p = .08).7 Given the dose escalation nature of
the first stage of the trial, some patients did not receive the
optimal dose of the vaccine. When we examined patients
based on dosing, we found a significant increase in DFS in
patients who received the optimal dosing regimen com-
pared with suboptimal dosed and observational controls
(94.6% vs. 87.1% vs. 80.2%, respectively; p = .05).7 During
this trial, it was discovered that, after completing the pri-
mary vaccination series, patients demonstrated waning
immunity to the targeted peptide. Therefore, a voluntary
booster program was instituted and patients received ad-
ditional booster inoculations every 6 months. When ex-
amining patients who were optimally dosed and boosted, we
found an improvement numerically in DFS versus all other
vaccinated patients versus the control arm (95.2% vs. 88.4%
vs. 80.2%; p = .11).7 Another important patient character-
istic, which had been previously demonstrated and was also
identified here, was the effect of HER2 expression on response
to the vaccine.8 For patients with non-overexpression of HER2
(immunohistochemistry [IHC] 1+ or 2+), there was a trend
toward improvement in 5-year DFS in vaccinated patients
versus the control (88% vs. 78%; p = .16).7 There were also
important limitations of this trial; there was no blinded,
placebo-treated control group receiving GM-CSF, which led to
questions about the effects of this immunoadjuvant therapy.
Thus, this feature was incorporated into our future trials.
Integrating the lessons learned from this initial trial, a phase
III trial was designed that included a GM-CSFtreated control
arm and optimal dosing of the vaccine to include a booster
series, and it enrolled only patients with HER2 1-2+ expression.
The phase III PRESENT (Prevention of Recurrence in Early Stage
node-positive breast cancer with low to intermediate HER2
Expression with NeuVax Treatment) trial was initiated in the
adjuvant setting for patients with high-risk HLA-A2+ or HLA-A3+
breast cancers who were deemed disease free after standard-
of-care therapy. The patients were randomly selected to re-
ceive E75 with GM-CSF or GM-CSF only. This trial has com-
pleted enrollment and is monitoring for the primary endpoint
of 3-year DFS.
AE37 and GP2
Our second large phase II peptide vaccine trial in the ad-
juvant setting, which is nearing completion, is a dual trial
testing GP2 and AE37. GP2 (IISAVVGIL, HER2 aa: 654-675) is a
peptide derived from the transmembrane domain of HER2
(Fig. 1). GP2 is a major histocompatibility complex (MHC)
class I peptide vaccine that stimulates antigen-specific CD8+
T cells in patients positive for HLA-A2 or HLA-A3. AE37
(GVGSPYVSRLLGICL, HER2 aa: 776-790) is the Ii-Key (LRMK)
hybrid of the HER2-derived MHC class II peptide, AE36, from
the intracellular domain of HER2 (Fig. 1) and is not HLA-
restricted. The trial design selected patients by HLA status,
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HALE, VREELAND, AND PEOPLES

TABLE 2. Current and Future Trials in the Adjuvant NED Setting to Prevent Recurrence
Solid
Tumor Vaccine No. Reference or
Type Vaccine Strategy Type Immunoadjuvant Phase Study Type Patients Result NCT Number
PEPTIDE
Breast E75 (NeuVax, Peptide HER2 (aa: GM-CSF II Adjuvant, NED, 195 Median follow-up 60 months; 5-year Mittendorf
nelipepi- 369-377) high-risk DFS ITT: 90% vaccinated vs. 80% et al7
mut-S) recurrence control (p = .08); subset populations
NCT00841399
with most benefit optimally dose 95%
vaccine vs. 80% control (p = .05) and NCT00854789
both optimally dosed and boosted:
95% vaccinated vs. 80% control (p =
.11)
Breast E75 (NeuVax, Peptide HER2 (aa: GM-CSF II Adjuvant, NED, 108* Anticipated start date March 2016, es- NCT02636582
(DCIS) nelipepi- 369-377) DCIS timated primary completion Sep-
mut-S) tember 2019
Breast AE37 Peptide HER2 (aa: GM-CSF II Adjuvant, NED, 298 Median follow-up 25 months; 5-year DFS Mittendorf
776-790 high-risk IIT: 81% vaccine vs. 80% controls (p = et al10
+LRMK) recurrence .70); subset populations with improved
NCT00524277
benefit HER2 1-2+ expressing tumors:
77% vaccine vs. 66% controls (p = .21)
and TNBC 78% vaccine vs. 49% controls
(p = .12)
Breast GP2 Peptide HER2 (aa: GM-CSF II Adjuvant, NED, 180 Median follow-up 34 months; 5-year Schneble
654-675) high-risk DFS IIT: 88% vaccine vs. 81% controls et al9
recurrence (p = .43); subset population with im-
NCT00524277
proved benefit HER3+ expressing tu-
mors: 94% vaccine vs. 89% controls (p
= .86)
Prostate E75 (NeuVax, Peptide HER2 (aa: GM-CSF I/IIA Adjuvant, NED 40 Median follow-up 58 months; PSA re- Gates et al24
nelipepi- 369-377) s/p resection, currence rate: 29% vaccine vs. 26%
mut-S) high-risk control (p = .9); DFS: 41.3 vs. 37.9
recurrence months (p = .6)
Ovarian E39 Peptide Folate bind- GM-CSF I/IIA Adjuvant, NED 51 Median follow-up 12 months; 5-year Greene
ing pro- DFS ITT: 43% vaccine vs. 34% control et al15
tein (aa: (p = .36); subset population with im-
NCT01580696
191-199) proved benefit optimally dosed
group: 86% vaccine vs. 34% control (p
= .03)
DENDRITIC CELL
Melanoma Dendritoma DC Autologous IL-2 I/IIA Adjuvant, NED 25 Median OS 16 months; overall 5-year Greene et al17
DC fused and ED, stage DFS: 29%; OS improvements in NED
with au- IV patients patients: 80% vs. ED 14% (p = .004)
tologous enrolled
tumor
lysate
Melanoma TLPLDC DC Autologous GM-CSF IIB Adjuvant, NED 120* Actively enrolling, estimated primary NCT02301611
DC loaded completion June 2018
with au-
tologous
tumor
lysate
COMBINATION
Breast E75 (NeuVax, Peptide and HER2 (aa: GM-CSF II Adjuvant, NED, 300* Actively enrolling, estimated primary NCT01570036
Nelipepi- monoclo- 369-377) high-risk recur- completion December 2016
mut-S) and nal and HER2 rence with
trastuzu- antibody monoclo- HER2 1-2+
mab nal expressing
(herceptin) antibody tumors
Breast E75 (NeuVax, Peptide and HER2 (aa: GM-CSF II Adjuvant, NED, 100* Actively enrolling, estimated primary NCT02297698
Nelipepi- monoclo- 369-377) high-risk recur- completion October 2016
mut-S) and nal and HER2 rence with
trastuzu- antibody monoclo- HER2 3+
mab nal expressing
(herceptin) antibody tumors
*Anticipated number.
Abbreviations: DC, dendritic cell; NED, no evidence of disease; GM-CSF, granulocyte macrophage colony-stimulating factor; OS, overall survival; DFS, disease-free survival; NSCLC,
nonsmall cell lung cancer; RCC, renal cell carcinoma; SD, stable disease; CR, complete response; PR, partial response; BCG, bacillus Calmette-Guerin; ITT, intention-to-treat; DCIS,
ductal carcinoma in situ; TNBC, triple-negative breast cancer; TLPLDC, tumor lysate particle-loaded dendritic cell.

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FIGURE 1. HER2 Peptide Vaccines (E75, GP2, AE37)
Abbreviations: MHC, major histocompatibility complex; HLA, human leukocyte antigen.
and placed the patients who were positive for HLA-A2/A3
into the GP2 trial and patients who were negative for HLA-
A2/A3 into the AE37 trial. Patients in both trials were then
randomly selected to receive the respective vaccine or the
control, GM-CSF alone. This dual trial has also completed
enrollment, with 298 patients enrolled in the AE37 trial and
180 patients in the GP2 trial.9,10 From the analysis of these
trials, we have established that the minimal toxicity in all
patients was primarily related to the GM-CSF given similar
toxicity levels between the vaccine and control arms.
The primary analysis of the GP2 trial revealed a 37% reduction
in RRR for the vaccinated arm with a 34-month median follow-
up. Vaccinated patients showed a nonsignificant increase in
estimated 5-year DFS (88% vs. 81%; p = .43). Interestingly,
subset analysis by HER2 expression in this trial showed that
the best DFS was found in patients with HER2 overexpression
(IHC 3+ or FISH+) who received the vaccine after completing
trastuzumab. Although intention-to-treat (ITT) analysis in this
subgroup showed a 94% estimated 5-year DFS in vaccinated
patients versus 89% in the control arms (p = .86), the per-
treatment analysis (excluding patients who experienced re-
currence during the primary vaccination series and therefore
did not complete the series) of HER2 overexpression showed
improved 5-year DFS in the vaccinated patients versus the
control (100% vs. 89%; p = .08). Although it is difficult to show a
statistically significant improvement over the already impres-
sive DFS of patients receiving standard-of-care trastuzumab,
based on these results, the GP2 vaccine appears to have
synergism with the HER2-directed trastuzumab.9
The primary analysis of the AE37 arms revealed no sig-
nificant difference in 5-year DFS for vaccinated versus
control patients (83.5% vs. 82.1%; p = .7). Again, planned
subset analysis revealed the patient populations with the
greatest benefit. First, patients with HER2 1-2+ expression
showed a trend of separation in the Kaplan Meier plots, with
5-year DFS enhanced in patients who were vaccinated versus
ARMING THE IMMUNE SYSTEM TO PREVENT CANCER RECURRENCE
controls (77% vs. 66%; p = .21) and a 32% reduction in RRR.
This was even more pronounced in patients with triple-
negative breast cancer, who experienced a 56% reduction in
RRR and had a trend toward improved 5-year DFS with the
vaccination (78% vs. 50%; p = .12). Patients with triple-
negative breast cancer currently have limited options for
long-term recurrence prevention, making the AE37 vaccine
an interesting option for future study.10
Overall, through these phase II studies, a potential benefit
of peptide vaccine therapy in the adjuvant setting was
identified in patient populations depending on biologic char-
acteristics of the tumor and synergy with current standard-
of-care therapy, specifically passive immunotherapy.
E39
Similar to HER2 expression in breast cancer, FBP has also
been found to be overexpressed in breast, lung, endome-
trial, and ovarian cancers and has been linked to a poor
prognosis.11-14 E39 (EIWTHSYKV, FBP aa: 191-199,) is an HLA-
A2restricted FBP peptide vaccine, also given with GM-CSF.
Our group has completed an initial phase I/IIA trial of the E39
with GM-CSF vaccine given in the adjuvant setting to pa-
tients with ovarian and endometrial cancers after they re-
ceived standard-of-care therapies. Similar to previous
peptide-based vaccine trials, there was minimal toxicity
with the treatment. Interim analysis after median follow-up
of 12 months revealed overall ITT 5-year estimated DFS was
43% for vaccinated patients versus 34% for controls (p = .36).
Like the initial E75 trial, given the phase I/IIA design of this
trial, not all patients received what was deemed to be the
optimal dose of the vaccine. In subset analysis based on
dosing, optimally dosed patients had a statistically signifi-
cant increase in survival over suboptimally dosed and control
patients (86% vs. 34% vs. 21%, respectively; p = .03). Because
of the aggressive nature of ovarian and endometrial cancers
as opposed to breast cancer, this trial was able to show a
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e165
HALE, VREELAND, AND PEOPLES
survival difference between groups in a relatively short
time.15
Tumor Lysate Particle-Loaded Dendritic Cell Vaccine
We are currently evaluating a novel dendritic cell vaccine
technology. The new technology revolutionizes the ability to
efficiently produce a personalized dendritic cell vaccine. The
vaccine is produced by loading autologous tumor lysate into
prepared yeast cell wall particles, which are naturally and
efficiently phagocytized by isolated and immature dendritic
cells. Along with the immunoadjuvant CpG, the loading
process matures the dendritic cells resulting in the final
product referred to as the tumor lysate particle-loaded
dendritic cell (TLPLDC) vaccine. The use of autologous tu-
mor lystate allows for the inclusion of the full range of
tumor antigens from a given patients tumor, making it
widely applicable to any patient and any tumor type.
TLPLDC can be created in 48 hours and requires only a small
amount of tumor (1 cm3). In comparison with previous
dendritic cell vaccine technologies, TLPLDC costs less and
requires fewer dendritic cells. This technology affords the
ability to create a personalized vaccine for any solid tumor
in an expeditious manner.
The TLPLDC vaccine technology builds from the previous
technology of dendritoma (fusion of dendritic cells with
autologous tumor), which is a relatively cumbersome
technique.16 We have completed a phase I/IIA trial of the
dendritoma vaccine in 25 patients with stage IV melanoma.
With a median follow-up of 16 months, the overall 5-year
DFS was 29%. Following the theme of previous trials, the
patients with no evidence of disease prior to initiation of
therapy experienced a significant benefit compared with
those with evidence of disease (80% vs. 14%; p = .004).17
Although these results are encouraging, the dendritoma
technology is too cumbersome and expensive to be evaluated
in a larger trial. The TLPLDC vaccine technology accomplishes
the same goal as the dendritoma technologythe introduction
of the entire antigenic repertoire from the autologous tumor
into the cytoplasm of the dendritic cell. The efficacy of the
TLPLDC vaccine has been confirmed in an ongoing basket trial of
multiple solid tumors.18 Current results from this ongoing phase
I/IIA trial indicate that the autologous TLPLDC vaccination is
well-tolerated and safe. The TLPLDC vaccine had clinical benefit
in 60% of patients, with 30% objective response including
complete response in metastatic melanoma.18 Therefore,
building on the results of the dendritoma trial in melanoma and
utilizing the improved TLPLDC technology (confirmed to be
effective in melanoma18), we have initiated a prospective,
randomized, blinded, placebo-controlled phase IIB trial in pa-
tients with fully resected stage III and IV melanoma to prevent
recurrence (NCT02301611), with estimated completion of the
primary endpoint in 2018.
Combination Immunotherapy
Exploring combination therapy of passive and active im-
munotherapies is a growing area of interest. During the
enrollment of the E75 and GP2 trials, the standard of care for
e166 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
breast cancer with HER2 overexpression changed based on
the approval of trastuzumab. During these trials, we were
able to compare patients who received a combination of
peptide vaccine and trastuzumab with patients in the control
arms, who received trastuzumab without a vaccine. From
these trials, there have been 89 patients with HER2 over-
expression who received trastuzumab, with 55 of these
patients also receiving one of our peptide vaccines. With a
median follow-up of 36 months, patients receiving the
combination of vaccine and trastuzumab had a 100% DFS
versus only 84% in those receiving trastuzumab alone
(p = .012; unpublished data from project narrative). To
further elucidate the potential for synergy and verify the
possible improved clinical benefit, we are currently enroll-
ing two separate trials combining E75 and trastuzumab
in the adjuvant setting. The first trial is focused on the
patients with HER2 overexpression (HER2 3+ or FISH+;
NCT01570036), and the second trial is enrolling patients
with HER2 non-overexpression (HER2 1-2+; NCT02297698).
In both trials, patients are randomly selected to receive
trastuzumab with E75 and GM-CSF versus trastuzumab and
GM-CSF alone. Patients with HER2 1-2+ expression cur-
rently have limited options in the adjuvant setting after
completion of chemotherapy, as they do not qualify to
receive trastuzumab. Our trial, along with the NSABP-47
trial, seeks to address the use of trastuzumab in this
population. Additionally, we seek to assess the vaccine in
this population as well as the toxicity associated with
trastuzumab alone or in combination with the vaccine in
these patients in the adjuvant setting.
Though beyond the scope of this article, vaccines may
now, largely for the first time, be successfully applied to the
nonadjuvant setting. Given the successes of checkpoint
inhibitors (anti-CTLA4 and PD-1) to protect and promote
endogenous antitumor T cells, there is now rationale for
combining tumor-reactive T-celleliciting vaccines with
clinically proven checkpoint inhibitors for patients with
larger tumor burdens. Furthermore, the knowledge gained
from the checkpoint inhibitorrelated studies underscores
why so many vaccines have previously failed to demon-
strate benefit in patients who have metastatic disease
with established tumors capable of suppressing/evading
the vaccine-induced immune response. To assess the likely
synergism between vaccines and checkpoint inhibitors,
we have initiated a new trial for patients with metastatic
melanoma receiving standard-of-care checkpoint inhibitors
but who have stable or slowly progressive disease. For
these patients, we will add a personalized TLPLDC vaccine
in combination with their checkpoint inhibitors. The end-
points of the trial are safety and tumor response.
CONCLUSION
Cancer vaccines represent a nontoxic therapeutic modality
with great antitumor specificity to prime the immune sys-
tem, but they have yet to be proven and/or gain acceptance
in clinical practice. Based on lessons learned from previous

trials, the most promising use of this therapy is to prevent
recurrence in disease-free patients. Our group has made
strides toward showing the efficacy of this approach with
multiple vaccines/strategies applied to several tumor types.
Additionally, there is potential synergistic clinical benefit of
combination therapy with monoclonal antibodies, which
needs to be further evaluated. Finally, with a better under-
standing of the tumor microenvironment and the tools to
protect tumor-reactive T cells in this hostile setting, cancer
vaccines may now, largely for the first time, be effective in
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munotherapy for human colorectal cancer: 6.5-year median follow-up of a
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3. Vermorken JB, Claessen AM, van Tinteren H, et al. Active specific
immunotherapy for stage II and stage III human colon cancer: a rand-
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notherapy for stage II and III colon cancer with an autologous tumor cell
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2000;18:148-157.
5. Wood C, Srivastava P, Bukowski R, et al; C-100-12 RCC Study Group. An
adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus
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phrectomy for renal cell carcinoma: a multicentre, open-label, rand-
omised phase III trial. Lancet. 2008;372:145-154.
6. Carson WE, III, Unger JM, Sosman JA, et al. Adjuvant vaccine immu-
notherapy of resected, clinically node-negative melanoma: long-term
outcome and impact of HLA class I antigen expression on overall
survival. Cancer Immunol Res. 2014;2:981-987.
7. Mittendorf EA, Clifton GT, Holmes JP, et al. Final report of the phase I/II
clinical trial of the E75 (nelipepimut-S) vaccine with booster in-
oculations to prevent disease recurrence in high-risk breast cancer
patients. Ann Oncol. 2014;25(9):1735-1742.
8. Benavides LC, Gates JD, Carmichael MG, et al. The impact of HER2/neu
expression level on response to the E75 vaccine: from U.S. Military
Cancer Institute Clinical Trials Group Study I-01 and I-02. Clin Cancer
Res. 2009;15:2895-2904.
9. Schneble E, Perez S, Murray J, et al. Primary analysis of the prospective,
randomized, phase II trial of GP2+GM-CSF vaccine versus GM-CSF alone
administered in the adjuvant setting to high-risk breast cancer patients.
J Clin Oncol. 2014;32 (suppl 26; abstr 134).
10. Mittendorf EA, Schneble EJ, Perez SA, et al. Primary analysis of the
prospective, randomized, single-blinded phase II trial of AE37 vaccine
versus GM-CSF alone administered in the adjuvant setting to high-risk
breast cancer patients. J Clin Oncol. 2014;32:5s (suppl; abstr 638).
11. Peoples GE, Anderson BW, Lee TV, et al. Vaccine implications of folate
binding protein, a novel cytotoxic T lymphocyte-recognized antigen
system in epithelial cancers. Clin Cancer Res. 1999;5:4214-4223.
12. Peoples GE, Anderson BW, Fisk B, et al. Ovarian cancer-associated
lymphocyte recognition of folate binding protein peptides. Ann Surg
Oncol. 1998;5:743-750.
13. Garin-Chesa P, Campbell I, Saigo PE, et al. Trophoblast and ovarian
cancer antigen LK26. Sensitivity and specificity in immunopathology and
ARMING THE IMMUNE SYSTEM TO PREVENT CANCER RECURRENCE
patients with metastatic disease if given in combination with
checkpoint inhibitors.
DISCLAIMER
The view(s) expressed herein are those of the author(s) and
do not reflect the official policy or position of San Antonio
Military Medical Center, Womack Army Medical Center, the
U.S. Army Medical Department, the U.S. Army Office of the
Surgeon General, the Department of the Army, Department
of Defense, or the U.S. Government.
molecular identification as a folate-binding protein. Am J Pathol. 1993;
142:557-567.
14. Li PY, Del Vecchio S, Fonti R, et al. Local concentration of folate bind-
ing protein GP38 in sections of human ovarian carcinoma by in vitro
quantitative autoradiography. J Nucl Med. 1996;37:665-672.
15. Greene J, Schneble E, Berry J, et al. Preliminary results of the phase I/IIa
dose finding trial of a folate binding protein vaccine (E39+GM-CSF) in
ovarian and endometrial cancer patients to prevent recurrence. J Clin
Oncol. 2015;33 (suppl; abstr e14031).
16. Holmes LM, Li J, Sticca RP, et al. A rapid, novel strategy to induce tumor
cell-specific cytotoxic T lymphocyte responses using instant den-
tritomas. J Immunother. 2001;24:122-129.
17. Greene JM, Schneble EJ, Jackson DO, et al. A phase I/IIa clinical trial in
stage IV melanoma of an autologous tumor-dendritic cell fusion
(dendritoma) vaccine with low dose interleukin-2. Cancer Immunol
Immunother. Epub 2016 Feb 19.
18. Greene J, Hale D, Schneble E, et al. Initial phase I/IIa trial results of an
autologous tumor lysate + yeast cell wall particles + dendritic cells
vaccine (TLPLDC) in patients with solid tumors. Cancer Immunol Res.
2016;4(suppl, abstr A044).
19. Eggermont AM, Suciu S, Rutkowski P, et al. Adjuvant ganglioside GM2-KLH/
QS-21 vaccination versus observation after resection of primary tumor
. 1.5 mm in patients with stage II melanoma: results of the EORTC 18961
randomized phase III trial. J Clin Oncol. 2013;31:3831-3837.
20. Vansteenkiste J, Cho B, Vanakesa T, et al. MAGRIT, a double-blinded,
randomized, placebo-controlled phase III study to assess the efficacy
of the recMAGE-A3 + AS15 cancer immunotherapeutic as adjuvant
therapy in patients with resected MAGE-A3-positive non-small cell lung
cancer (NSCLC). Ann Oncol. 2014;25(suppl 4):iv409-iv16.
21. Giaccone G, Bazhenova LA, Nemunaitis J, et al. A phase III study of
belagenpumatucel-L, an allogeneic tumour cell vaccine, as mainte-
nance therapy for non-small cell lung cancer. Eur J Cancer. 2015;51:
2321-2329.
22. Morton D, Mozzillo N, Thompson J, et al. An international, randomized,
phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic mela-
noma vaccine (MCV) or placebo after complete resection of melanoma
metastatic to regional or distant site. J Clin Oncol. 2007;25:8508.
23. Schulze T, Kemmner W, Weitz J, et al. Efficiency of adjuvant active
specific immunization with Newcastle disease virus modified tumor
cells in colorectal cancer patients following resection of liver metas-
tases: results of a prospective randomized trial. Cancer Immunol
Immunother. 2009;58:61-69.
24. Gates JD, Carmichael MG, Benavides LC, et al. Longterm followup as-
sessment of a HER2/neu peptide (E75) vaccine for prevention of re-
currence in high-risk prostate cancer patients. J Am Coll Surg. 2009;208:
193-201.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e167
GREGORY L. BEATTY

Overcoming Therapeutic Resistance by Targeting Cancer

Inflammation
Gregory L. Beatty, MD, PhD

OVERVIEW

Tumor-infiltrating myeloid cells are a prominent feature of most solid malignancies. This inflammatory immune response,
driven by tumor-intrinsic signaling pathways, is a major checkpoint to therapeutic efficacy achieved with immunotherapy
and standard cytotoxic therapies. To overcome therapeutic resistance mediated by cancer inflammation, ongoing clinical
trials are evaluating strategies that (1) deplete myeloid cells from tumors, (2) inhibit tumor-promoting properties of myeloid
cells, and (3) redirect myeloid cells with tumor-inhibitory activity.

outgrowth of nascent transformed cells,8,9 it has become

T he microenvironment that surrounds solid tumors is
fundamental to tumor biology and a critical barrier to
therapeutic efficacy. A defining feature of this microenvi-
ronment is a leukocyte infiltrate that can vary widely in
its complexity.1 For example, some tumors demonstrate a
robust infiltration of T lymphocytes, whereas others show a
near absence or a spatial restriction of T lymphocytes to the
tumor margin.2-4 In contrast, innate immune cells composed
of macrophages, granulocytes, and immature myeloid cells
are universally seen within tumors, although to varying
degrees.5 In some tumors, this innate immune inflammatory
response can be robust, even representing the majority of
the cellular mass of a tumor lesion.
Although inflammation is a well-recognized proponent of
cancer, the phenotype of tumor-infiltrating inflammatory
cells is pliable and strongly dependent on cues received
from the surrounding microenvironment.6 As such, tumor-
infiltrating leukocytes can acquire either pro- or antitumor
properties.7 With a rapidly advancing understanding of this
biology regulating the phenotype and recruitment of in-
flammatory cells to tumors, novel therapeutic targets have
been identified and are being investigated in early-phase
clinical trials for their potential to enhance current standard
therapies (e.g., radiation and chemotherapy) and to derail
resistance mechanisms to the success of T celldependent
immunotherapies.
INFLAMMATION: A HALLMARK OF CANCER
Although the immunosurveillance hypothesis proposed
by Thomas and Burnet in 1957 postulated a critical role for
the immune system in controlling the development and
increasingly clear that the immune system, in addition to its
potential to be harnessed for antitumor activity, can be a
major proponent of tumor development and a barrier to
therapeutic efficacy.5,10 This paradoxic role of the immune
system in cancer can be explained by the plasticity of the
immune system, which can acquire either pro- or antitumor
properties. For productive immunosurveillance to eliminate
cancer, components of innate and adaptive immunity must
be aligned or else peripheral tolerance will ensue.11 In many
settings, alignment is not achieved because leukocytes
recruited to tumors most often orchestrate an immuno-
suppressive, rather than an immunostimulatory, microen-
vironment that acts to spoil the antitumor potential of
the immune system.12 In preclinical models, elimination
of this myeloid response by inhibiting ICAM-1mediated
macrophage recruitment to tumors early during cancer
initiation can block tumor development.13 Similarly,
blockade of colony-stimulating factor 1/receptor colony-
stimulating factor 1 (CSF-1/CSF-1R) signaling, a key signaling
pathway for macrophages, can improve the response to
immunotherapy with PD-1 and CTLA-4 antagonists.14
Tumor-infiltrating inflammatory cells, including macro-
phages, dendritic cells, granulocytes, and immature mye-
loid cells, are commonly seen across a vast majority of solid
tumor types. These myeloid cell subsets are recruited to
tumors by a variety of chemoattractants released by both
malignant cells and nonmalignant cells residing within the
tumor microenvironment. Myeloid cells that infiltrate tu-
mors are primarily thought to originate from progenitors in
the bone marrow and are recruited to tumor tissue via the

From the Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA.

Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook.

Corresponding author: Gregory L. Beatty, MD, PhD, Abramson Cancer Center of the University of Pennsylvania, Smilow Center for Translational Research, Room 8-112, Bldg 421, 3400
Civic Center Blvd., Philadelphia, PA 19104-5156; email: gregory.beatty@uphs.upenn.edu.

2016 by American Society of Clinical Oncology.

e168 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


bloodstream.15 However, the spleen may also be an abundant
source of tumor-infiltrating myeloid cells.16 In contrast, the
contribution to the tumor microenvironment by tissue-
resident myeloid cells, which are derived from yolk-sac
progenitors, remains ill defined.17,18
The recruitment of myeloid cells to the tumor microen-
vironment is dependent on chemoattractants, such as
chemokine:chemokine receptor interactions.19 For example,
the chemokine CCL2 regulates myeloid trafficking through
interaction with chemokine receptor CCR2, which is
expressed at high levels on a subset of monocytes, com-
monly referred to as inflammatory or classical mono- vascular endothelial growth factor.25 In this study, neu-
cytes. In some cases, a single chemokine may bind to
multiple chemokine receptors. For example, CCL5 has
binding affinity for chemokine receptors CCR1, CCR3, and
CCR5. Similarly, a single chemokine receptor may also bind
multiple chemokines. For example, chemokine receptor
CCR5 can bind both CCL3 and CCL5. Together, this com-
plexity associated with expression of chemokine receptors
on distinct myeloid subsets and the interaction of chemo-
kine receptors with select chemokines determines, at least
in part, the heterogeneity of the myeloid infiltration into
tumors.
Both malignant and nonmalignant cells can release che-
mokines within the tumor microenvironment that act to
regulate the infiltration of myeloid cells. For example, in
preclinical models of breast cancer, CCL2 released by
both malignant and nonmalignant cells is required for
recruitment of CCR2+ monocytes to promote cancer
metastasis.20 However, the importance of tumor genetics
in defining the chemokine milieu within tumors is only
KEY POINTS
Tumor-infiltrating myeloid cells, including macrophages,
dendritic cells, granulocytes, and immature myeloid
cells, are a hallmark of solid malignancies.
Tumor-intrinsic oncogenic signaling pathways (e.g.,
Kras, PTEN/Akt/PI3K, WNT/b-catenin) shape the
composition, phenotype, and function of tumor-
infiltrating myeloid cells with implications for defining
tumor immunogenicity.
The pro- versus antitumor biology of myeloid cell
subsets within solid tumors is pliable and determined by
microenvironmental signals released by malignant and
nonmalignant cells.
Strategies to intervene on the myeloid response to
cancer include therapeutic approaches designed to (1)
deplete myeloid cells from the tumor
microenvironment, (2) inhibit the tumor-promoting
properties of myeloid cells, and (3) redirect tumor-
infiltrating myeloid cells with tumor-inhibitory
properties.
Therapeutic manipulation of tumor-infiltrating myeloid
cells holds promise for enhancing the efficacy of T-cell
immunotherapy and standard cytotoxic therapies.
OVERCOMING THERAPEUTIC RESISTANCE BY TARGETING CANCER INFLAMMATION
recently being unraveled. For example, activation of Kras in
pancreatic cancer induces the secretion of chemokines, such
as interleukin (IL)-8,21 and myeloid growth factors, including
granulocyte-macrophage colony stimulating factor,22 which
can promote the recruitment and differentiation of myeloid
cells with protumor activities.23 PTEN loss in preclinical
models of pancreatic cancer has also been associated
with a robust infiltration of inflammatory cells.24 In ad-
dition, PTEN loss in melanoma has been found to correlate
with T-cell exclusiona finding that was associated with an
increase in proinflammatory cytokines including CCL2 and
tralization of vascular endothelial growth factor enhanced
T-cell infiltration into tumors, and pharmacologic inhibition
of the PI3K pathway improved the effectiveness of antiPD1
immunotherapy. Similar findings have been reported with
activation of the b-catenin pathway, which was shown to
regulate the expression of tumor-derived chemokines,
specifically CCL4.26 Here, CCL4 was important for the re-
cruitment of dendritic cells involved in T-cell priming. This
emerging role for tumor-intrinsic signaling pathways in
regulating the recruitment of inflammatory cells has also
been observed in models of prostate adenocarcinoma,
where loss of Smad4 leads to hyperactivation of Hippo-YAP
signaling, which induces CXCL5 upregulation in cancer cells
and subsequent recruitment of immunosuppressive CXCR2+
CD11b+ Gr-1+ myeloid cells.27 Together, these studies sug-
gest the importance of tumor genetics in shaping the in-
flammatory immune response to cancer.
The phenotype of myeloid cells within tumors can be quite
variable and probably best described as a spectrum rang-
ing from pro- to antitumor based on functional properties
(e.g., T cellsuppressive activity, cytokine production, tumor-
icidal activity, pro- versus antiangiogenic properties, etc.).7
However, a diverse array of factors (e.g., extracellular matrix,
hypoxia, cytokines, and other soluble factors) can influence
the phenotype of a myeloid cell. As a result, the complexity
of the myeloid response to cancer has remained a challenge
to describe in vivo. Many attempts have been made to
categorize tumor-infiltrating myeloid cells based on protein
and molecular signatures determined under in vitro culture
conditions. For example, macrophages studied under dis-
tinct in vitro culture conditions with interferon gamma and
lipopolysaccharide or IL-4 and IL-13 can be classified as M1
or M2 macrophages, respectively.28 However, almost in-
variably when macrophages are obtained from in vivo
settings, they more commonly display a mixture of an M1
and M2 phenotype, thereby diluting the potential relevance
of this simplistic approach.29
In cancer, the myeloid cell-differentiation program be-
comes altered from the earliest stages of myelopoiesis,30
occurring within the bone marrow, through myeloid cell
transit in the peripheral blood to infiltration into the tumor
microenvironment.31 At each step along this lifecycle of a
tumor-infiltrating myeloid cell, soluble factors released in
response to cancer have been identified that shape myeloid
cell biology. For example, in pancreatic cancer, mobilization
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GREGORY L. BEATTY
of CCR2+ monocytes from the bone marrow into the pe-
ripheral blood is enhanced and correlates with elevated
serum levels of CCL2.32 Within the peripheral blood, human
monocytes are then exposed to serum-soluble factors that
can modulate monocyte biology. For example, in patients
with renal cell carcinoma, human blood monocytes were
found to be induced with pro-angiogenic properties by the
IL-1IL-1R cytokine axis even before entry into tumor tis-
sue.33 Once in the tumor microenvironment, tumor-derived
soluble factors then further shape the ultimate fate of
tumor-infiltrating myeloid cells. However, because the
secretome of malignant cells can vary between tumor-type,
the cellular fate of myeloid cells is tumor-specific and likely
differentially skewed between cancers and perhaps even
between lesions within the same patient.34,35
TARGETING INFLAMMATION FOR THERAPEUTIC
BENEFIT IN CANCER
Changes in inflammatory cell biology that occur in cancer can
affect the efficacy of standard treatments such as chemo-
therapy. In response to cytotoxic stress, tumor cells secrete
chemokines that can recruit myeloid cells, which may then
suppress the efficacy of chemotherapy and/or inhibit the
development of antitumor T celldependent immunity.10,36
Tumor-infiltrating inflammatory cells can also directly sup-
press T-cell antitumor immunity by producing immuno-
suppressive cytokines and depleting critical amino acids,
including tryptophan and arginine, which are necessary for
normal T-cell activity.37-39 For these reasons, strategies to
intervene on cancer-induced inflammation are actively
being investigated in early-phase clinical trials.
There are three potential approaches (Table 1) to altering
the inflammatory response to cancer including:
1. blocking inflammatory cell recruitment to tumors,
2. inhibiting tumor-promoting activities of myeloid cells,
and
3. redirecting tumor-infiltrating myeloid cells with anti-
tumor activity.
TABLE 1. Therapeutic Strategies to Cancer Inflammation in Solid Malignancies
Approach to Cancer Inflammation
Block Infiltration or Deplete Myeloid Subsets
Inhibit Protumor Activity
Redirect With Antitumor Activity
Abbreviations: CCL2, chemokine (C-C motif) ligand 2; CCR2, chemokine (C-C motif) receptor 2; CXCR1, chemokine (C-X-C motif) receptor 1; CXCR2, chemokine (C-X-C motif) receptor 2;
CSF-1, colony-stimulating factor 1; CSF-1R, colony-stimulating factor 1 receptor; TRAIL-R2, tumor necrosis factorrelated apoptosis-inducing ligand receptor 2; IDO, indoleamine 2,3
dioxygenase; JAK, Janus kinase; Sirpa, signal regulatory protein alpha.
e170 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Blocking Recruitment
Strategies to block inflammatory cell recruitment to tumors
involve the neutralization of chemokines with antibodies,
the delivery of small-molecule inhibitors to block chemokine
receptor signaling, and selective depletion of myeloid
subsets. For example, neutralizing antibodies against CCL2
(e.g., carlumab) and antagonists of CCR2 (e.g., PF-04136309
and CCX872) are being evaluated in early phase 1 stud-
ies in patients with advanced solid malignancies to block
monocyte recruitment to tumors. Similarly, antagonists of
CXCR1/2 (e.g., AZD5069 and reparixin) are being studied in
early-phase clinical trials to inhibit granulocyte recruitment to
tumors. To deplete myeloid cell populations, ongoing clinical
investigations are testing antagonists of CSF1R (PLX3397,
ARRY-382, IMC-CS4, FPA008, AMG820, and RO5509554)
and a chemotherapeutic agent, trabectedin, which was
found to selectively induce capsase-8dependent apoptosis
in monocytes via signaling through tumor necrosis factor
related apoptosis-inducing ligand receptor 2.40
Inhibiting Activity
Tumor-infiltrating myeloid cells are active components of
the tumor microenvironment. Within tumors, myeloid cells
shape the supply of nutrients important for T-cell activity
(e.g., tryptophan and arginine) and release soluble factors
(e.g., IL-6, IL-10, and transforming growth factor beta) that
can be immunosuppressive and supportive of tumor
survival.37,41-43 Ongoing studies are evaluating strategies to
inhibit indoleamine 2,3-dioxygenase (IDO), a key enzyme
expressed by myeloid cells and important for tryptophan
metabolism in tumors. In preclinical models, IDO inhibition
was shown to promote antitumor T-cell activity,37 and in
clinical trials, IDO inhibition has demonstrated safety and
tolerability.44,45 Similarly, early-phase clinical trials are un-
derway to evaluate the safety and preliminary efficacy of
inhibiting distinct signaling pathways in myeloid cells, such
as JAK/STAT signaling, which is important for the biologic
activity of cytokines, including IL-6 and IL-10 (Table 1).
Target Agents
CCL2/CCR2 Carlumab, PF-04136309, CCX872
CXCR1/CXCR2 AZD5069, reparixin
CSF-1/CSF-1R PLX3397, ARRY-382, IMC-CS4, FPA008, AMG820, RO5509554
TRAIL-R2 Trabectedin
IDO Epacadostat/INCB024360, indoximod, NLG919, 1-methyl-D-tryptophan
JAK Ruxolitinib, pacritinib, momelotinib, INCB039110
CD40 RO7007789/CP-870,893, APX005M, ADC-1013, Chi Lob 7/4, SEA-CD40
CSF-1R PLX3397, ARRY-382
CD47-Sirpa CC-90002, TTI-621

TABLE 2. Targeting Cancer Inflammation in Combination With Checkpoint Immunotherapy
Therapeutic Approach
Block Infiltration or Deplete Myeloid Subsets in Combination With Checkpoint Inhibition
Inhibit Inflammatory Signaling Pathways in Combination With Checkpoint Blockade
Redirect Inflammation in Combination With Checkpoint Blockade
Abbreviations: CXCR2, chemokine (C-X-C motif) receptor 2; CSF-1, colony-stimulating factor 1; CSF-1R, colony-stimulating factor 1 receptor; IDO, indoleamine 2,3 dioxygenase; CTLA4,
cytotoxic T-lymphocyteassociated protein 4; JAK, Janus kinase.
Redirecting Activity
The biology of tumor-infiltrating myeloid cells is pliable
and therefore may potentially be redirected from pro- to
antitumor or, alternatively, from immunosuppressive to
immunostimulatory. This premise forms the rationale for
therapeutic approaches designed to unleash the antitumor
potential of tumor-infiltrating myeloid cells. For example,
ongoing clinical studies are evaluating antagonists of the
CD47-Sirpa pathway, which delivers inhibitory signals to
macrophages and blocks macrophage phagocytosis of tumor
cells. In preclinical studies, CD47 antagonists have demon-
strated the capacity to induce macrophage-dependent an-
titumor activity46 and promote dendritic cellmediated
induction of T-cell antitumor immunity. 47 An alternative
approach to redirecting myeloid cells with antitumor
properties is to block signaling pathways (e.g., CSF-1), which
can instill macrophages with protumor functions.48 For
example, although antibody-based strategies that target
CSF-1R (e.g., IMC-CS4, FPA008, AMG820, RO5509554) may
deplete myeloid cells via antibody-dependent cellular
cytotoxicity,49 small-molecule inhibitors of CSF-1R (e.g.,
PLX3397, ARRY-382) have the potential for shifting the
polarity of myeloid cells from pro- to antitumor.48 Finally,
CD40 agonists have demonstrated the capacity to redirect
tumor-infiltrating myeloid cells with both tumoricidal and
antifibrotic activity.50,51 In recent years, several CD40 ago-
nists have been developed and are now undergoing clinical
investigation (Table 1).
Each of the aforementioned strategies for modulating cancer
inflammation is being evaluated in clinical trials. Although
merely manipulating the myeloid response to cancer is unlikely
by itself, to produce long-lasting and major tumor regressions,
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e173
DEVELOPMENTAL THERAPEUTICS AND
TRANSLATIONAL RESEARCH

Pharmacokinetics, Dynamics,
and Genomics in the Era of
Immunotherapy and Small
Molecules

CHAIR
Emiliano Calvo, MD, PhD
START Madrid, Centro Integral Oncologico
Clara Campal
Madrid, Spain

SPEAKERS
Christine Walko, PharmD, BCOP
Moffitt Cancer Center
Tampa, FL

E. Claire Dees, MD
The University of North Carolina at Chapel Hill
Chapel Hill, NC
 PHARMACOGENOMICS, PHARMACOKINETICS, AND PHARMACODYNAMICS OF TARGETED THERAPIES

Pharmacogenomics, Pharmacokinetics, and

Pharmacodynamics in the Era of Targeted Therapies
Emiliano Calvo, MD, PhD, Christine Walko, PharmD, FCCP, BCOP, E. Claire Dees, MD, and Belen Valenzuela,
PharmD, PhD

OVERVIEW

The complex nature of the pharmacologic aspects of cancer therapeutics has become more apparent in the past several years
with the arrival of a cascade of target-based agents and the difficult challenge of bringing individualized precision medicine to
oncology. Interpatient variability in drug action, singularly in novel agents, is in part caused by pharmacogenomic (PG),
pharmacokinetic, and pharmacodynamic (PD) factors, and drug selection and dosing should take this into consideration to
optimize the benefit for our patients in terms of antitumor activity and treatment tolerance. In this regard, somatic genetic
evaluation of tumors is useful in not only predicting response to initial targeted therapies but also in anticipating and guiding
therapy after the development of acquired resistance; therapeutic drug monitoring of novel small molecules and
monoclonal antibodies must be incorporated in our day-to-day practice to minimize the negative effect on clinical outcome
of interindividual variability on pharmacokinetic processes of these drugs for all patients, but especially for fragile patient
populations and those with organ dysfunction or comorbidities. For these populations, incorporating frailty assessment
tools into trials of newer agents and validating frailty-based dose adjustment should be an important part of further drug
development.

majority of patients. In fact, most failures in phase III1 trials

O ver the past several years, we have witnessed a dra-
matic and encouraging burst of newly approved anti-
cancer therapeutics. The treatment of cancer has continued
to shift from traditional cytotoxic therapies aimed at inhibiting
the growth of fast-dividing cells toward targeting a particular
cellular pathway that appears to be activated in a patients
particular cancer. The concept of individualized therapy
embraces the idea that each patient and his or her cancer
both have unique properties, including how the drug will be
handled in the body and whether it will be effective against
the patients cancer. Many of these new drugs are targeted
agents, small molecules, and monoclonal antibodies with
unique biologic effects and challenges in optimizing their clinical
use include variability in pharmacogenomics, pharmacokinetics,
and pharmacodynamics among patients with cancer.
Pharmacogenomic analysis of tumor tissue is an important
tool in identifying therapies that will be effective against
certain cancers while also preventing patients for whom
these therapies are unlikely to be effective from suffering
the physical and economic toxicities inherent to each
treatment. Tyrosine kinase inhibitors (TKIs) and monoclonal
antibodies are administered at fixed-flat or weight-based
doses, and frequently, they are not the right dose for the
are related to a lack of efficacy that can be attributed to
underdosing situations, because interindividual variability
in pharmacokinetic processes plays a critical role in drug
exposure variability and, consequently, in the clinical outcome
observed. In addition, dosing anticancer chemotherapy in
elderly individuals and frail patients has long been a problem in
oncology. Because the pivotal clinical trials of most anticancer
chemotherapeutics included only patients with normal organ
function and excellent performance status, we have limited
information in dosing a more real-world population.
Therefore, we review some of the data available on the vari-
ability in drug action, particularly in newer agents, caused by
genomic, kinetic, and dynamic factors and how dosing should be
approached in the context of individualized precision medicine.
ROLE OF PHARMACOGENOMICS IN THE
MOLECULAR ERA
The process of dissecting the heterogeneity of an individual
patients cancer begins as soon as a sample of the malignancy
is able to be assessed and subjected to a gamut of staining,
immunohistochemistry, fluorescence in situ hybridization,

From the DeBartolo Family Personalized Medicine Institute, H. Lee Moffitt Cancer Center, Tampa, FL; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Platform of
Oncology, Hospital Quiron,
Torrevieja, Alicante, Spain; START Madrid, Early Clinical Drug Development Program, Centro Integral Oncologico
Clara Campal, Madrid, Spain.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Emiliano Calvo, MD, PhD, START Madrid, Early Clinical Drug Development Program, Centro Integral Oncologico
~a, 10, 28050 Madrid,
Clara Campal, Calle On
Spain; email: emiliano.calvo@start.stoh.com.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e175

CALVO ET AL
and cytogenetics, as well as genetic and methylation as-
says in some instances. All of these provide both prog-
nostic and predictive information used to begin to narrow
down specific treatment options and expected outcomes.
The discovery of specific biomarkers has been essential for
drug development. For example, the initial trial of pan-
itumumab and best supportive care (BSC) compared with BSC
alone among patients with metastatic colorectal cancer that
had progressed after standard therapy demonstrated
an improvement in median progression-free survival (mPFS)
from 7.3 weeks to 8 weeks in the BSC and panitumumab
groups, respectively. In comparison, mean progression-free
survival (PFS) was 8.5 weeks and 13.8 weeks for the BSC
and panitumumab groups, respectively, suggesting the ex-
istence of a subset of patients who responded better to the
panitumumab.2 Unlike the story of the HER2-inhibitor tras-
tuzumab, overexpression of EGFR was not the predictive
biomarker for the EGFR inhibitor. Rather, mutations in the
Kirsten rat sarcoma (KRAS) oncogene downstream of EGFR
were predictive of responses to these inhibitors in colorectal
cancer, as evidenced by a secondary analysis of the same trial
showing KRAS mutations in 43% of the patients and corre-
lation with mPFS. For patients with wild-type KRAS, pan-
itumumab resulted in mPFS of 12.3 weeks compared with
7.3 weeks with BSC, whereas patients with KRAS mutations
had similar mPFS regardless of treatment (7.4 weeks com-
pared with 7.3 weeks in the panitumumab and BSC groups,
respectively).3 Based on these and additional findings, a newly
diagnosed metastatic colorectal cancer is standardly assessed
for the alterations in KRAS and NRAS and this helps to de-
termine whether EGFR-directed therapies such as cetuximab
KEY POINTS
Precision medicine in oncology must take into account
interpatient variability in drug action, particularly in
newer agents, caused by genomic, kinetic, and dynamic
factors.
Pharmacogenomics of somatic tumors, through genetic
analyses of solid samples and liquid biopsies of the
disease, relates not only to initial selection of therapy
but also to sequencing of therapy options.
Interindividual variability on pharmacokinetic processes
is a definite source of imprecision in the use of targeted
drugs, with profound clinical consequences, especially in
frail patients, that can be decreased through therapeutic
drug monitoring.
Measuring frailty might become an important focus of
oncology research, because some of these tools
accurately predict toxicity and may prompt
management change.
To continue to establish genetic biomarkers and
therapeutic drug monitoring of novel therapies, we
must evolve the designs of our clinical trials, make them
as inclusive as possible, and facilitate access to patients
willing to enroll in them.
e176 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
or panitumumab will be useful in the management of the
tumor.4 This emphasizes not only finding the right biomarker
for each agent but also ensuring that the selected patient
sample will assess the value of this biomarker. Ideal predictive
biomarker trials should include two comparison treatment
groups and should demonstrate that the outcome is different
for patients with biomarker-positive results compared with
those with biomarker-negative results.5
The role of somatic mutation testing has continued to
evolve past the initial diagnosis of tumors to help prioritize
and guide additional treatment options. Improved under-
standing of cancer biology and drug pharmacology has
allowed for expanded investigation into novel therapy
options. Greater understanding of the role of a mutated pro-
tein in a process essential to cancer survival, such as DNA
repair, has supported the interrogation of alterations in genes
involved in this process in terms of response to DNA-repair
inhibitors like the PARP inhibitor, olaparib. PARP inhibitors
were initially developed with the hope of taking advantage
of synthetic lethality for patients deficient in the tumor sup-
pressor genes BRCA1 and BRCA2. PARP is required for base-
excision repair of damaged DNA, whereas BRCA is involved
in homologous repair. In a BRCA1- or BRCA2-deficient tumor,
PARP is able to compensate for this loss of homologous repair;
thus, inhibition of PARP would ultimately result in cell death.6
The PARP inhibitor olaparib was initially approved by the U.S.
Food and Drug Administration (FDA) in December 2014 for
patients with ovarian cancer with defective BRCA genes. Nu-
merous other mutations can occur in genes involved in DNA
repair and are common in cancers, including prostate cancer.
The clinical efficacy of olaparib in metastatic castration-
resistant prostate cancer was assessed among 16 patients
with homologous deletions, deleterious mutations, or both in
DNA-repair genes. These genes included ATM, FANCA, CHEK2,
PALB2, and others, including BRCA1 and BRCA2. A response
was seen for 88% of patients, including four of five patients
with ATM alterations.7 Ongoing trials with olaparib and inves-
tigational PARP inhibitors are underway for patients with a
variety of tumor types with DNA-repair gene alterations.
As our knowledge about cancer biology grows, so too
does the cancers ability to overcome these novel therapies.
Somatic genetic evaluation of tumors is useful in not only
predicting response to initial targeted therapies but also
in anticipating and directing therapy after the development
of acquired resistance. EGFR-activating mutations were
identified in 2004 and are found for approximately 10%
of patients with nonsmall cell lung cancer (NSCLC) with
adenocarcinoma histology. The majority of these EGFR-
activating mutations occur in exons 18 to 21 and predict
response to EGFR TKIs including erlotinib, gefitinib, and
afatinib. Median PFS with these agents is approximately
9 to 14 months when resistance develops. The EGFR
T790M mutation is responsible for approximately 60% of the
acquired resistance and prevents TKI binding through steric
hindrance and increased EGFR affinity for ATP.8,9 Novel anti-
EGFR TKIs are being developed to overcome this specific
mutation and include the recently approved osimertinib,
 PHARMACOGENOMICS, PHARMACOKINETICS, AND PHARMACODYNAMICS OF TARGETED THERAPIES
which has affinity for both activating mutations in EGFR and
the T790M. The use of serial sequencing is necessary for
depiction of this mutational landscape. The value of this
sequential genetic analysis and integration with correlative
science is illustrated by a case report of a patient with NSCLC
harboring an anaplastic lymphoma kinase (ALK) rearrange-
ment. The patient was initially started on crizotinib and
developed resistance to the agent after 18 months. Genetic
analysis at this time showed an ALK C1156Y mutation known
to confer resistance to crizotinib. The patient was then treated
with ceritinib and other non-ALK directed therapies until she
was ultimately enrolled in a clinical trial with a novel ALK in-
hibitor, lorlatinib. The patient initially had a 41% decrease in
her tumor and a response that lasted for 8 months. After
progressive disease, a subsequent genetic analysis of the tu-
mor showed the C1156Y mutation but also a new L1198F
mutation. This later mutation results in resistance to lorlatinib
but paradoxically enhances response to the original crizotinib,
ultimately negating the C1156Y mutation.10 This was elegantly
demonstrated with correlative in vitro studies and crystal
structures of the mutations and drug therapies, underscoring
the importance of team science approaches to interrogating
extraordinary responding patients. Exploring and determining
the clinical effect a mutation can have on a particular protein
can help develop the library of known mutations and further
explore a variant of nearly known significance. These var-
iants are found in clinically relevant genes in areas of the gene
that are known to related to clinical function but the exact
variant itself has not been functionally characterized. En-
couraging collaborative science exploration of these variants
using functional assays and pharmacologic insight will help to
elucidate the clinical value of these types of variants.
Finally, it may not be the specific mutation itself but rather
a number of mutations that may help to predict benefit from
therapy. The search for a reproducible biomarker to predict
the response to novel immunotherapies, including the PD-1
inhibitors nivolumab and pembrolizumab as well as the CTLA-4
inhibitor ipilimumab, has yielded limited results. A promising
finding demonstrated across tumor types and immunother-
apies is the correlation between the number of mutations and
clinical response to treatment. Whole-exome sequencing of
34 patients with NSCLC treated with pembrolizumab dem-
onstrated longer PFS in tumors with a higher number of
nonsynonymous mutations (hazard ratio 0.19; 95% CI,
0.080.47, p = .0004). The median number of nonsynonymous
mutations among patients with a durable clinical response
and those without was 302 and 148, respectively.11 This was
also shown for patients with melanoma who were receiving
ipilimumab, in which those with more than 100 nonsyn-
onymous mutations as well as a specific neoantigen land-
scape demonstrated improved survival.12 Finally, tumors
with mismatch repair deficiency, which is associated with
a higher number of mutations, were also associated with
improved mPFS from pembrolizumab.13 The specific
mutation cut point is dependent on the analysis and will
need further prospective validation trials to confirm this
biomarker.
PHARMACOKINETICS VARIABILITY AND
THERAPEUTIC DRUG MONITORING OF
NEWER AGENTS
Oral Targeted Therapies
TKIs are the main oral targeted therapies and comprise a
growing group of drugs for the personalized treatment of
both hematologic and solid tumors. To date, more than 15
TKIs have been approved and many others are at different
stages of their clinical development.
Regarding the absorption process, limited solubility of TKIs
in the gastrointestinal tract, gastrointestinal surgery, and
first-pass metabolism by enterocytes and the liver are the
main factors limiting their oral absorption. Moreover, con-
comitant administration with food significantly modifies
plasma levels for some TKIs. For example, lapatinib and nilo-
tinib exposure is increased more than 50% with high-fat meals,
whereas no influence of food has been reported for imatinib,
dasatinib, sunitinib, or sorafenib absorption. In the opposite
case, drug exposure of axitinib and pazopanib is increased by
49% and twofold, respectively, under fasting conditions.1,14,15
Finally, adherence to treatment is another factor that deter-
mines variability in drug exposure. Thus, poor imatinib compli-
ance results in very low trough plasma concentrations, reduces
cytogenetic responses, and contributes to treatment failure.16,17
There are a number of important host-related variables
that are correlated with variability in toxic and therapeutic
drug response. For example, TKIs bind to plasma proteins,
mainly albumin and alpha-1-acid glycoprotein (AGP). Be-
cause the only unbound (free) drugs are pharmacologically
active, hypoalbuminemia secondary to cachexia or liver
metastases can increase the amount of free drug, leading to
increased toxicity. In fact, AGP levels have been correlated
with imatinib and erlotinib clearance. Sarcopenia and low
body mass index have been also shown to be predictors of
dose-limiting toxicity of sunitinib and sorafenib.18,19 The
major route of elimination of TKIs is metabolism by CYP3A4
enzymes. Hepatic expression on these enzymes may vary
more than 20-fold among patients and may lead to vari-
ability in plasma levels. Moreover, genetic polymorphisms
influence TKI metabolism, as has been determined for
CYP2D6 and gefitinib or UGT1A9 and sorafenib.16 It is also
important to take into account the potential inhibition or
induction of metabolic enzymes as a result of drugdrug
interactions because patients with cancer are frequently
receiving more than one drug treatment. Finally, chronic ad-
ministration may also induce drug elimination, as occurred
with imatinib among patients with a gastrointestinal stro-
mal tumor, in which clearance was increased by 33% after
3 months of treatment.20
There is accumulating evidence for potential benefits of
therapeutic drug monitoring (TDM) in the treatment of
TKIs.21 Relationships between exposure and response
(efficacy/toxicity) have been established for most TKIs. Area
under the plasma concentration-time curve (AUC) and
trough plasma concentration (Cmin) are the pharmacokinetic
parameters often correlated with clinical outcomes and/or
toxicity effects of TKIs in several types of cancer.22 For
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e177
CALVO ET AL
imatinib, the pharmacokinetic target has been retrospec-
tively established in both patients with chronic myeloid
leukemia (CML) and those with gastrointestinal stromal
tumor. For imatinib, a Cmin value below 1,000 ng/mL is
associated with lower clinical benefit and shorter time to
progression. To validate this pharmacokinetic target and
include TDM as a clinical routine tool for patients receiving
imatinib treatment, two prospective randomized controlled
trials were performed.22,23 The final results of the ran-
domized OPTIM imatinib study of 133 patients with chronic
phase CML were recently communicated,24 which showed
that only one-third of patients were correctly treated with
the standard fixed dose (i.e., these patients achieved the
Cmin threshold of 1,000 ng/mL) and two-thirds of patients
were not exposed enough to imatinib. The imatinib dose was
increased guided by TDM to obtain the Cmin target and
resulted in a higher major molecular response rate at
12 months (63% vs. 37%). Moreover, among 493 patients
with imatinib-resistant or imatinib-intolerant CML treated
with nilotinib, it was recently demonstrated that those who
had a nilotinib Cmin below 500 ng/mL had a significantly
longer time to achieve complete cytogenetic response and
molecular response. In addition, nilotinib Cmin was also
correlated with elevations in total bilirubin and lipase
levels.24 For dasatinib, results of the prospective OPTIM
dasatinib trial among patients newly diagnosed with
chronic-phase-CML demonstrated that a dasatinib maxi-
mum serum concentration (Cmax) above 50 ng/mL was as-
sociated with clinical response and a Cmin below 2.5 ng/mL
prevented fluid retention and pleural effusion.25 These re-
sults provide a strong rationale to use TDM as a new strategy
for optimizing the drug dosage to maximize the clinical
benefit (faster and more pronounced clinical responses) for
patients with CML and to promote another prospective
clinical trials to clarify the pharmacokinetic targets for more
TKIs.
Monoclonal Antibodies
The pharmacokinetics of monoclonal antibodies are complex
and different from others anticancer drugs but their in-
terindividual variability on pharmacokinetic processes is
similar to that observed for TKIs (for example, trastuzumab
clearance varies up to 40%). Monoclonal antibodies are
dosed by body weight or at fixed doses but high variability in
mAb exposure has been observed after their administration
at the labeled dose, supporting the need to individualize
dosing to account for variability and ensure efficacy.26,27
Absorption and elimination are the main sources of phar-
macokinetic variability. Absorption after subcutaneous or
intramuscular administrations is slow, incomplete, and
variable. The Cmax is reached between 2 and 8 days after
administration. Factors that have been identified as po-
tential sources to limit mAb absorption are loss through
presystemic catabolism, flow of blood and lymph, age, body
weight (especially in obese patients), and injection site.28
The elimination routes of monoclonal antibodies have not
e178 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
been totally elucidated and several mechanisms have been
proposed, including proteolysis by the liver and re-
ticuloendothelial system, target-mediated elimination, and
nonspecific endocytosis.29 Because the target-mediated
route of elimination depends on the amount of the target
expression and the affinity to binding, it leads to nonlinear
and time-dependent changes in clearance.
Although TDM studies for monoclonal antibodies are
limited, exposure-response relationships have been de-
scribed. Strong exposure response has determined for
trastuzumab. Thus, the results of a case-matched control
comparison study showed that patients with the lowest
quartile of trastuzumab exposure at the end of the cycle 1
(Cmin , 11.8 mg/L on day 21) had a median overall survival
8 months shorter than in the other quartiles, whereas no
relationship was found between exposure and toxicity.30
Based on these results, the FDA review team recommended
performing a prospective trial of trastuzumab TDM-dose
intensification among patients who were underexposed.28
An exposure-response relationship for trastuzumab-emtansine
was also found among patients with HER2-positive meta-
static breast cancer. After adjusting for baseline risk factors,
a higher trough concentration at day 21 (the end of cycle 1)
was associated with improved efficacy (measured as overall
survival, PFS, and objective response rates).31 These results
justify that trastuzumab-emtansine TDM-guided dosing
is a necessary tool to improve patient exposure and avoid
inadequate exposure.
For patients with metastatic colorectal cancer treated with
cetuximab, a relationship between trough serum concen-
tration and clinical benefit was also found. Thereby, patients
with a Cmin below the median value of 40 mg/L at day 14 had
significantly shorter mPFS than patients with a Cmin above
this value (3.3 vs. 7.8 months).32
Similar results to those seen in solid tumors had been
reported as well for hematologic malignancies. Thus, Cmin
values of alemtuzumab,27 rituximab,27 and obinutuzumab33
were higher in responders versus nonresponders and were
related to better clinical outcomes.
DOSING PATIENTS WHO ARE ELDERLY OR FRAIL:
PHARMACODYNAMIC CHALLENGES
Although people older than age 65 comprise approximately
60% of all patients with newly diagnosed cancer, only 36% of
patients enrolled in clinical trials are age 65 or older.34 This
becomes a more important disparity as the population ages
and as the population of patients with cancer ages. Many
oncologists empirically dose reduce older patients, often
without much data to guide them. There are growing efforts
among several collaborative and cooperative groups to
evaluate anticancer therapeutics specifically in elderly
populations. In addition, techniques for measuring frailty,
independent of age, have been developed, are being in-
corporated into clinical trials, and may help guide dosing.
Because marrow reserve and organ function often decline
with age, efforts to evaluate therapies specifically for patients
 PHARMACOGENOMICS, PHARMACOKINETICS, AND PHARMACODYNAMICS OF TARGETED THERAPIES
with organ dysfunction are particularly relevant to the ap-
propriate treatment of older adults with cancer.
Several commonly used cytotoxic chemotherapy regimens
have been evaluated for older patients and those with
impaired organ function. Yet there is variability in regard to
which traditional anticancer chemotherapy agents need
dose reductions in these populations. If we look at breast
cancer chemotherapy as an example, there appears to be no
age-related difference in toxicity in the common breast
cancer adjuvant therapy regimens, doxorubicin and cyclo-
phosphamide (AC) or cyclophosphamide, epirubicin, and
fluorouracil (CEF). One small study evaluated AC across a
range of ages and found no age-related differences in
neutropenia complications, cardiac dysfunction, or quality of
life.35 Another small study evaluated CEF and similarly found
no age-related difference in leukopenia or other toxicity
among patients older than age 70 compared with those
younger than age 70.36 In a large cooperative group trial
evaluating doses of AC, there was no difference in grade 4
toxicity across age strata.37 By contrast, several investigators
have found that the adjuvant regimen cyclophosphamide,
methotrexate, and fluorouracil (CMF) is less well tolerated
by older patients than by their younger counterparts.38,39
However, this disparity in toxicity may be partly explained by
age-related renal dysfunction. At least one study has shown
that apparent age-related differences in toxicity with CMF
were abrogated by dosing according to creatinine clearance
(CrCl).40
The Cancer and Leukemia Group B (CALGB; now ALLIANCE)
evaluated age-related toxicity in three of their trials of
adjuvant chemotherapy in node-positive breast cancer. The
regimens were three schedules of CAF, AC with paclitaxel, or
AC without paclitaxel and two schedules of AC followed by
paclitaxel. Interestingly, even in these relatively modern
trials (accrued from 1985 to 1999), only 7% of patients
enrolled were age 65 or older. Nevertheless, this pooled
retrospective analysis was able to show that patients age 65
or older are 66% more likely to have grade 4 hematologic
toxicity than younger patients, discontinue therapy early
more commonly, and have a higher incidence of treatment-
related death.41
More recently, several large randomized trials tested al-
ternate adjuvant breast cancer regimens in older popu-
lations. For example, in the Italian ELDA trial, women age 65
to 79 were randomly assigned to receive adjuvant CMF or
weekly docetaxel. No difference in disease-free or overall
survival was seen. The pattern of toxicity was notable for
worse hematologic toxicity in the CMF arm and worse
nonhematologic toxicity in the docetaxel arm. Furthermore,
docetaxel resulted in worse quality of life for participants.
Thus, docetaxel was not recommended as an acceptable
alternate for elderly patients.42 CALGB (now ALLIANCE)
conducted a randomized trial of adjuvant breast cancer
therapy for older patients comparing oral capecitabine to
either CMF or AC. This randomized study enrolled 633
patients, 65% of whom were older than age 70. Although
capecitabine was less toxic, it was found to be less
effective than the standard regimens. Thus, it also was not
recommended as an acceptable alternative for elderly
patients.43
The taxanes are one of the most widely used classes of
chemotherapy for breast cancer as well as for other tumor
types. The toxicity of this class of drugs has been specifically
evaluated in elderly patients in several trials. Docetaxel was
evaluated in the above-described trial.42 The relationship
between age and paclitaxel pharmacokinetics and toxicity
was evaluated in a CALGB trial, which enrolled 155 patients
ranging in age from 55 to 86. This study found age-related
decline in paclitaxel clearance and in severity of neutropenia,
which did not appear to result in adverse clinical sequelae
such as hospitalization or infection.44 In a subsequent pooled
analysis of two other cooperative group trials, these same
investigators again demonstrated an age-related increase in
leukopenia as well as anorexia, hyperbilirubinemia, and
neuropathy. However, no age-related difference in pacli-
taxel efficacy was noted.45 Finally, Hurria et al46 recently
evaluated nab-paclitaxel among older patients across an age
range. Although these investigators found an age-related
increase in AUC (borderline significance), there was no re-
lationship between age and dose reduction, dose omissions,
or grade 3 toxicity. However, the chemotherapy toxicity risk
score did predict increased toxicity. This score (which included
age and variables such as CrCl, anemia, hearing impairment,
falls, and need for assistance with instrumental activities of
daily living) is an attempt to capture frailty, which may be
more important than chronological age in toxicity prediction
and treatment and dosing decisions.46
Measuring frailty has become an important focus of ge-
riatric oncology research. Several tools have been de-
veloped, including the chemotherapy toxicity prediction tool
described above and used by the Cancer and Aging Research
Group (CARG)47 and the Chemotherapy Risk Assessment
Scale for High-Age Patients (CRASH) score.48 The types and
utility of geriatric assessments have recently been the
subject of a consensus paper from the International Society
of Geriatric Oncology.49An intriguing new imaging tool for
measuring frailty by assessing sarcopenia (or skeletal muscle
wasting) on CT scans has also been shown to predict che-
motherapy toxicity and outcomes (reviewed in Kazemi-
Bajestani et al50).
Although it is clear from multiple studies that some of these
tools measuring frailty accurately predict toxicity and may
prompt management change, studies validating that dosing
based on risk scores yield better outcomes still are needed.
Similar to our conundrum with the more traditional
chemotherapy drugs, we have little data to guide us in
treating elderly individuals, frail patients, or patients with
organ dysfunction with novel targeted agents. Table 1 reviews
many of the agents approved in 2014 to 2015, the age range
of patients enrolled in the pivotal trials, and data in the
package insert regarding dosing in geriatric patients and
those with organ dysfunction.
It is encouraging to note that the majority of the pivotal
trials for these newer targeted therapies enrolled a higher
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CALVO ET AL

TABLE 1. Recently Approved Anticancer Therapeutics

Median Package Insert Guidelines
Patient Age in
Mechanism Pivotal Trial, Geriatric Renal Hepatic
Drug Name Indication of Action Years (Range) Use Impairment Impairment Reference
Alectinib ALK plus NSCLC ALK inhibitor 54 (2979); No data No data in severe No data in Shaw et al55
18% age moderate
65 and older to severe
52 (2279); Ou et al56
10% age
65 and older
Belinostat Peripheral HDAC inhibitor 64 (2881); No need No data in CrCl , No data in OConnor et al57
T cell 48% age for dose 39 mL/min moderate
lymphoma 65 and older reduction to severe
Blinatumomab Ph- preB- Bispecific Ab 32 (1877); Patients older No data No data Topp et al58
cell ALL to CD19/CD3 13% age than age 65
65 and older had higher
neuro- and
infectious
toxicity
Ceritinib ALK plus ALK inhibitor 53 (2280); No difference in Dose reduce for No data in Shaw et al59
NSCLC 16% age toxicity or CrCl , 30 moderate
65 and older efficacy mL/min to severe
Cobimetinib BRAF MEK inhibitor 55 (2388) No data No data in severe No data in Larkin et al60
mutation moderate
melanoma to severe
Daratumumab MM Anti-CD38 64 (4476); No differences No dose No data in Lokhorst et al61
45% age in safety or adjustment moderate
65 and older efficacy needed to severe
Elotuzumab MM Anti-SLAMF7 67 (3788); No comment No data No data Lonial et al62
57% age
65 and older
Ibrutinib Mantle BTK inhibitor 67 (5678); Toxicity more No dose Dose reduce in Dreyling et al63
cell, CLL 62% age frequent adjustment mild. Avoid in
65 and older among for CrCl . 25 moderate
patients mL/min. No to severe
older than data for CrCl
age 65 , 25 mL/min
67 (3086) Byrd et al64
61% older
than age 65
Idelalisib CLL, B-cell PI3K-delta 71 (4890); Higher No dose Increased Furman et al65
NHL, SLL inhibitor 78% age incidence modification AUC if
65 and older of SAEs for CrCl . 15 LFTs . ULN
and death mL/min
Ixazomib MM Proteasome 55% age 65 No difference Dose reduce for Dose reduce Moureau et al66
inhibitor and older in safety or CrCl , 30 for total
efficacy mL/min bilirubin .
1.53 ULN
Levatinib Thyroid Kinase inhibitor 64 (NR); No difference Dose reduce for Dose reduce Schlumberger
cancer 45% age in safety or CrCl , 30 for Child- et al67
65 and older efficacy mL/min Pugh C
Necitumumab Squamous EGFR antagonist 62 (3284); Higher incidence No data No data Thatcher et al68
NSCLC 39% age of VTE among
65 and older patients older
than age 70
Nivolumab Melanoma AntiPD-1 59 (2388); No difference No need for No dose Weber et al69
squamous 35% age in safety or dose reduction reduction
NSCLC 65 and older efficacy in mild. No
data in
moderate
to severe

Continued

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 PHARMACOGENOMICS, PHARMACOKINETICS, AND PHARMACODYNAMICS OF TARGETED THERAPIES

TABLE 1. Recently Approved Anticancer Therapeutics (Contd)

Median Package Insert Guidelines
Patient Age in
Mechanism Pivotal Trial, Geriatric Renal Hepatic
Drug Name Indication of Action Years (Range) Use Impairment Impairment Reference
61 (3784); Borghaei et al70
37% age
65 and older
Olaparib BRCA PARP inhibitor 57 (2979); Grade 3 AEs No data if CrCl No data Kaufman et al71
mutation 20% age more , 50 mL/min
ovarian 65 and older frequent
cancer among
patients
older than
age 65
Osimertinib EGFR EGFR inhibitor 45% older Grade 3 and No data if No data in Ramalingam
mutation than age 65 4 AEs more CrCl , 30 moderate et al72
NSCLC frequent mL/min to severe
among
patients
older than
age 65
Palbociclib ER+ HER22 CDK4/6 inhibitor 63 (5471); No difference No dose No dose Finn et al73
breast 44% age in safety or reduction reduction
cancer 65 and older efficacy required for in mild; no
CrCl . 30 data in
mL/min. No moderate
data in severe to severe
Panobinostat MM Pan-deacetylase 63 (5659) More GI, No dose Dose San-Miguel
inhibitor 42% age cardiac, and reduction modification et al74
65 and older hematologic needed for mild
AEs in older and moderate
patients
Pembrolizumab Melanoma AntiPD-1 60 (2594) No difference No dose No dose Hamid et al75
39% age in safety or adjustment adjustment
65 and older efficacy needed needed in
mild. No
data in
moderate
to severe
Sonidegib Basal cell Smoothened 65 (2493) No difference in No dose No dose Migden et al76
carcinoma receptor 52% age effectiveness; adjustment adjustment
antagonist 65 and older higher incidence needed needed in
of grade 3 or mild. No data
4 AEs in older in moderate
patients to severe
Talimogene Melanoma Oncolytic virus 63 (2294) No difference No data No data Andtbacka et al77
Laherparepvec 48% age in safety or
65 and older efficacy
Abbreviations: ALK, anaplastic lymphoma kinase; NSCLC, nonsmall cell lung cancer; ALL, acute lymphoblastic leukemia; MM, multiple myeloma; CLL, chronic lymphocytic
leukemia; NHL, non-Hodgkin lymphoma; SLL, small lymphocytic lymphoma; HDAC, histone deacetylase; Ab, antibody; MEK, mitogen-activated protein kinase; BTK, Brutons
tyrosine kinase; PI3K, phosphoinositide 3-kinase; CDK, cyclin-dependent kinase; SAE, serious adverse event; VTE, venous thromboembolism; AE, adverse event; GI,
gastrointestinal; CrCl, creatinine clearance; AUC, area under the plasma concentration-time curve; LFT, liver function test; ULN, upper limit of normal; Ph, Philadelphia
chromosome.

proportion of older patients than the historical trials sum-
marized above. More than 40% patients were age 65 or older
in 12 of the 20 trials highlighted. The relationship between
age and toxicity appears to vary between drugs. Some
studies have noted increased toxicity in older patients
(ibrutinib, idelalisib, necitumumab, osimertinib, panobino-
stat, sonidegib, blinatumumab, olaparib). Others report no
age-related increase in toxicity (belinostat, ceritinib, dar-
atumumab, ixazomib, lenvatinib, nivolumab, palbociclib),
although most comment that sample sizes are small enough
to lessen confidence. These new targeted therapies and
immunotherapies also vary in need for dose reduction for
renal or hepatic dysfunction (Table 1).
Few targeted therapies have been specifically evaluated to
date in populations who have organ dysfunction or are el-
derly or frail. Several examples of treatments that have been
assessed in special populations include the CARG study of
bevacizumab among elderly patients51 and clinical trials of
pazopanib52 and sorafenib53 among patients with organ
dysfunction.

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CALVO ET AL
Some of the newer drugs shown in Table 1 have in fact
been evaluated in populations who are older than age 65
and are more representative of the disease population. For
example, in the pivotal study of idelalisib and rituximab in
relapsed chronic lymphocytic leukemia,54 78% of patients en-
rolled were age 65 or older, 40% had a CrCl below 60 mL/min,
and 85% had a Cumulative Illness Rating Scale score greater
than 6. Although patients older than age 65 benefited from
idelalisib similarly to their younger counterparts, the package
insert reveals that there were higher rates or serious adverse
events, treatment discontinuation, and death among patients
older than age 65 in this trial as well as the pivotal trials in
non-Hodgkin lymphoma and small lymphocytic lymphoma.
In conclusion, pivotal studies of recently approved drugs
generally have had higher representation of patients older
than age 65. This yields more information on toxicity in the
older population with these therapies. Unfortunately, it
appears that toxicity of many of these new targeted drugs is
higher in older patients. However, package inserts do not
give guidance on alternate dosing or schedules in older and
frail patients. In this special population, TDM or validated
frailty assessments could be useful tools to characterize the
real exposure and manage possible dose reduction accord-
ingly, minimizing the risk of greater reductions than those
that are really needed.
FUTURE DIRECTIONS OF PERSONALIZED
THERAPY ACCORDING TO PHARMACOGENOMIC,
PHARMACOKINETIC, AND PHARMACODYNAMIC
PARAMETERS
The role of somatic tumor genetics relates not only to initial
selection of therapy but also to sequencing of therapy op-
tions, and it must be optimized in standard clinical practice.
To continue to establish genetic biomarkers of novel ther-
apies, we need clinical trials and patients willing to enroll in
them. Enthusiasm behind basket trials must continue to fuel
histology agnostic, biomarker-driven trials that are as in-
clusive as possible for the tumor types in which they will be
most useful. In addition, novel methods of obtaining sam-
ples for genetic analysis are needed to address challenges of
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producible analytical methods to quantify plasma or serum
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cokinetic processes; and (4) highly qualified professionals
(within multidisciplinary teams) trained to translate the TDM
results and to propose new doses adjusted to individual
needs of each patient. This is a feasible way of optimizing our
current and future therapeutic armamentarium and it
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development. Ongoing efforts to assess approved antican-
cer therapeutics for older patient populations and those
with organ dysfunction are an important effort for the
oncology clinical research community.
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GASTROINTESTINAL (COLORECTAL) CANCER

Potentially Resectable Metastatic

Colorectal Cancer: A
Multidisciplinary Discussion

CHAIR
Gunnar Folprecht, MD
University Hospital Carl Gustav Carus
Dresden, Germany

SPEAKERS
David M. Liu, MD
University of British Columbia
Vancouver, BC, Canada

Laura A. Dawson, MD
Princess Margaret Cancer Centre
Toronto, ON, Canada

Steven J. Nurkin, MD
Roswell Park Cancer Institute
Buffalo, NY
GUNNAR FOLPRECT

Liver Metastases in Colorectal Cancer

Gunnar Folprecht, MD

OVERVIEW

Resection of colorectal liver metastases is a treatment standard because patients experience long-term disease-free survival
or are even cured after undergoing this procedure. Improved surgical techniques for liver resection in combination with
downsizing liver metastases by chemotherapy, interventions to induce liver hypertrophy before resection, and the use of
ablative techniques have allowed us to expand the indications for liver surgery and local treatment in situations with limited
metastatic colorectal cancer. Resectability and identification of patients who might benefit from liver surgery and local
ablative techniques are key factors for the treatment of patients with colorectal cancer. Despite the wide acceptance of liver
surgery and ablative techniques, there are many open questions on the management of limited metastatic disease, such as
which patients benefit from an aggressive surgical approach, what the indications for ablative and other local techniques are,
and what the role of chemotherapy is for patients with resectable or resected disease. Unfortunately, results of randomized
trials are only available for a limited number of these questions.

R esection of colorectal liver metastases is a treatment

standard because patients experience long-term disease-
free survival or are even cured after undergoing this pro-
cedure. Improved surgical techniques for liver resection and
downsizing liver metastases by chemotherapy, interventions
to induce liver hypertrophy before resection, and the use of
ablative techniques have allowed us to widen the indications
for liver surgery and local treatment in situations with limited
metastatic colorectal cancer.
Resectability and identification of patients who might benefit
from liver surgery and local ablative techniques are key factors
for the treatment of patients with colorectal cancer. Despite the
wide acceptance of liver surgery and ablative techniques, there
are many open questions on the management of limited
metastatic disease, such as which patients benefit from an
aggressive surgical approach, what the indications for ablative
and other local techniques are, and what the role of chemo-
therapy is for patients with resectable or resected disease.
Unfortunately, results of randomized trials are only available
for a limited number of these questions.
RESECTABILITY
Technical resectability is a necessary condition for the re-
section of metastases. For liver metastases, resectability is
determined by 25% to 30% of functional liver tissue with
sufficient inflow (portal vein/liver artery) and outflow (liver
veins). Conversion chemotherapy1,2 and several surgical
techniques can improve technical resectability (Fig. 1).
In daily clinical practice, technical resectability and prog-
nostic factors contribute to the decision making on whether
to resect liver metastases. A higher number of metastases, a
short disease-free interval before diagnosis of the metastases,
the presence of extrahepatic metastases, larger metasta-
ses, an advanced primary tumor stage, and elevated tumor
marker levels (carcinoembryonic antigen [CEA] or CA 19-9)
are important risk factors for the prognosis of patients.3 The
Memorial Sloan Kettering Cancer Center score4 is one of the
most widely used scores and is easily calculated. There is no
fixed upper limit for the number of liver metastases defining
nonresectability or a lower limit for the disease-free interval
before the (re)occurrence of liver metastases, however,
these two factors have often have an important influence in
daily treatment decisions. The lack of clear definitions on
prognostic factors limiting the value of resection contributes
to the high subjectivity of decisions and might explain the
high variability of treatment decisions observed, i.e., in surgical
reviews of CT scans the CELIM trial.2 Multidisciplinary care
team discussions can only partly overcome the lack of studies
defining limits for prognostic resectability.
In addition to technical resectability and tumor-related
prognostic factors, treatment decisions are driven by patient-
related comorbidity, which limits surgical treatment options
and chemotherapy tolerance (Fig. 1A). Systematic research
for comorbidity and multimodal treatment of liver metastases
is rare and is therefore not included in this review.

From the University Hospital Carl Gustav Carus, University Cancer Center, Medical Department I, Dresden, Germany.

Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook.

Corresponding author: Gunnar Folprecht, MD, Universitatsklinikum Carl Gustav Carus Dresden, Fetscherstrae 74, 01307, Dresden, Germany; email: gunnar.folprecht@
uniklinikum-dresden.de.

2016 by American Society of Clinical Oncology.

e186 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


Retrospective analyses have demonstrated that patients
who underwent resection for their metastases experienced
improved survival compared with patients with medical
treatment alone. This knowledge is based on retrospective
cohorts1,4 and patients resected for liver and lung metas-
tases in prospective trials.5 Unfortunately, these reports are
influenced by several biases.6 Resections are offered to
patients whose disease responded to chemotherapy and
who have a better prognosis, and the resection cohort
excludes patients who have an early disease progression, a
worsened performance status, or died before the decision
for resection (i.e., after conversion chemotherapy) could be
made.
The EORTC CLOCC trial7 was the first prospective ran-
domized trial to demonstrate a survival benefit of resection/
ablation versus systemic treatment alone. Patients with up
to 10 liver metastases were selected to receive medical
treatment alone or medical treatment with radiofrequency
ablation. For the vast majority of patients, radiofrequency
ablation was performed as an open procedure and com-
bined with resection. In the combined treatment arm, the
overall survival was significantly improved compared
with systemic treatment alone (8-year survival, 36% vs. 9%,
respectively; hazard ratio [HR] 0.58; 95% CI, 0.380.88;
p , .01).8 This trial demonstrated that resection/ablation
has a major impact on overall survival. Among patients with
up to 10 liver metastases without extrahepatic spread,
approximately 30% were cured by the combined treat-
ment. Furthermore, progression-free survival increased
from 9.9 months (chemotherapy alone) to 16.8 months
(combined modality treatment),8 allowing treatment-free
intervals.
Unfortunately, overall and disease-free survival rates after
resection decrease for patients with poor prognostic factors.
In the CELIM study, the median disease-free survival after
conversion therapy and resection was 16.8 months among
patients with less than five metastases, 8.2 months among
patients with 5 to 10 metastases, and 2.5 months among pa-
tients with more than 10 metastases.9 Similarly, patients with
KEY POINTS
Resection of (liver) metastases is part of standard
treatment in metastatic colorectal cancer.
Further trials are needed to better define limits of
resectability, especially among patients with a poor
prognosis.
Resectability can be improved by conversion
chemotherapy and surgical/interventional methods
requiring close multidisciplinary cooperation.
FOLFOXIRI-based regimens and EGFR combinations
(for RAS wild type disease) have demonstrated higher
response and resection rates in randomized trials
Perioperative FOLFOX therapy should be considered for
patients with higher risk factors and resectable disease.
LIVER METASTASES IN COLORECTAL CANCER
a Basingstoke risk score higher than 20 experience a median
survival of less than 1.5 years following liver resection.10 Al-
though patients were treated in the era of fluorouracil (5-FU),
survival for the highest risk group is probably not markedly
longer than in a general patient population with systemic
treatment alone.11,12 It is important to note that current
prognostic scores are not prospectively evaluated to be pre-
dictive for the benefit of resections. In addition, re-resections of
further metastases can be beneficial, and patients with ob-
served indications for re-resection have similar prognoses as
those with initial resections.13-15 Furthermore, surgery/ablative
techniques have the potential to contribute to therapy as a
further line of palliative treatment, but prospective trials among
patients with technically resectable, poor prognostic disease
are needed to determine which patients benefit most from
resections.
IMPROVING RESECTABILITY
Among patients whose disease is not regarded as suitable for
up-front resection due to the location of the metastases
(technical resectability) or poor prognostic factors, che-
motherapy is mostly the first treatment step, but other
interventions also can improve resectability.
Preoperative portal vein embolization of the liver seg-
ments planned for resection, which induces a hypertrophy of
the not-embolized liver segments, enlarges the remaining
functional liver tissue.16 This procedure is most frequently
applied before an extended right hemihepatectomy if the
left segments (2/3) are relatively small and often combined
with a two-step resection, i.e., resection of metastases in the
left segments before the right hemihepatectomy.17,18 The
relatively aggressive concept of a combination of a portal
vein ligation with an intraoperative in-situ splitting of the
liver (associating liver partition and portal vein ligation for
staged hepatectomy; ALPPS) induces a more rapid liver
hypertrophy and is followed by a second resection.19 In a
recently published register of 320 patients, second re-
section was performed 14 days after the first interven-
tion (median). During those 2 weeks, the functional
liver remnant increased from 21% to 40%.20 This tech-
nique increases the options for resection of liver me-
tastases and primary hepatobiliary cancers but was
associated with a 90-day mortality of 8.8% among pa-
tients with colorectal liver metastases of 5%.20 The com-
bination of ablation with resection of metastases provides a
more parenchymal-sparing approach for extensive liver
metastases.21
These techniques increase the level of treatment com-
plexity, and additional treatment steps need additional time
for procedures and/or patient recovery, especially in mul-
tistep resections for liver metastases or sequential re-
sections, i.e., of liver and lung metastases plus resection of
the primary. In the COIN, AIO 0207, and CAIRO3 trials in-
vestigating treatment-free intervals versus maintenance
therapy, the median time from end of chemotherapy
treatment until progression without chemotherapy was 3.0
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e187
GUNNAR FOLPRECT
FIGURE 1. (A) Dimensions of Resectability and (B) Heatmap Combining Prognostic and Technical Factors
to 4.1 months.22-24 This interval is shorter than the time
needed for two or three resections. In several centers,
chemotherapy is administered between treatment cycles,
but the number of required interventions may limit the
feasibility of resection at all metastatic sites.
CHEMOTHERAPY IN NONRESECTABLE DISEASE
There is a strong correlation between the response rate with
chemotherapy and the resection rate when different studies
are compared.25 Conceptually, the effect of shrinking larger,
technically nonresectable metastases is more obvious than
e188 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
when prognostic factors, such as a high number of metas-
tases, limit resection (Fig. 2). In the latter situation, che-
motherapy is often used to observe the course of disease
and to resect disease with less aggressive tumor growth.
With current regimens achieving response rates of 60%
65%, liver resections were reported in approximately 40% of
patients enrolled in trials focusing on liver-limited disease.26
In randomized trials, FOLFOXIRI (5-FU, leucovorin, ox-
aliplatin, and irinotecan) improved response27,28 and resection
rates28 compared with infusion chemotherapy doublets, as
did cetuximab/FOLFIRI (5-FU, leucovorin, and irinotecan)
compared with FOLFIRI alone.29 Bevacizumab improved

response rates in studies with IFL (irinotecan, 5-FU, leuco-
vorin) or fluoropyrimidine monotherapy30,31 but not when
combined with FOLFOX in first-line treatment.32
When EGFR antibodies and bevacizumab are directly
compared, higher response rates were reported in the
CALGB 80405 study,33 and nonsignificant trends were re-
ported in the FIRE3 and PEAK trials.34,35 Furthermore, dif-
ferences were observed for the non-RECIST evaluation of the
deepness of response favoring anti-EGFR antibodies.36
A literature-based meta-analysis of all three trials di-
rectly comparing anti-EGFR antibodies with bevacizumab
described a significantly higher response rate with anti-EGFR
antibodies (odds ratio 1.3; 95% CI, 1.11.6).37 Similarly, in
the CALGB study, 82 patients (14.2%) underwent resection
after treatment with cetuximab, and 50 patients (8.9%)
underwent resection after receiving bevacizumab-based
therapy.38 This difference is statistically significant (p , .01).
No differences in resection rates were reported in the FIRE3
and PEAK trials.34,35 Based on these results, FOLFOXIRI (or
EGFR-based therapies among patients with RAS wild-type
disease) might be optimal if conversion therapy is the primary
treatment aim.
During conversion chemotherapy, patients will have re-
sectable disease after a median treatment duration of
4 months. If resectability is not achieved within 6 months, it
is very unlikely that further chemotherapy will facilitate later
resections.2 Therefore, multidisciplinary discussion of the
treatment strategy might be scheduled every 2 months (or
after 3 and 6 months) during conversion chemotherapy. No
trial has been performed to determine the optimal duration
of neoadjuvant therapy when resectability is achieved.
When resectability was achieved within 3 to 6 months after
FIGURE 2. (A) Conversion Chemotherapy in Technical Nonresectable Metastases (B) Effect of Chemotherapy for
Patients With a High Number of Metastases
LIVER METASTASES IN COLORECTAL CANCER
preoperative treatment, it might be reasonable to orientate
on the treatment durations for patients with resectable
disease and to continue the preoperative therapy to
3 months and total chemotherapy duration to 6 months,
although on treatment durations are missing.
RESECTABLE LIVER METASTASES:
PERIOPERATIVE TREATMENT
Several studies on systemic or liver-directed chemotherapy
have investigated adjuvant or perioperative treatment
of resectable liver metastases. A meta-analysis of two
studiesboth closed early due to poor recruitment
demonstrated a strong trend towards improved overall
survival with adjuvant bolus 5-FU compared with surgery
alone (HR 1.32; 95% CI, 0.951.82; p = .095).39 The EORTC
trial 40983 (EPOC) randomly selected patients with up to
four metastases to receive perioperative treatment with
FOLFOX or liver surgery alone and showed a trend toward
improved disease-free survival with perioperative chemo-
therapy (HR 0.81; 95% CI, 0.641.02; p = .068). The overall
survival was not significantly different between both arms,
and the absolute difference in overall survival was relatively
small (3.4%; 95% CI, 7.113.8).40 A subgroup analysis of the
EPOC trial has shown interaction between CEA level, per-
formance status, and obesity on the chemotherapy effect;
the HR for patients with normal CEA, patients with a per-
formance status of 1 or higher, and obese patients (body
mass index $ 30) was greater than 1.0, suggesting harm
from perioperative treatment. The HRs for the opposite
groups (elevated CEA, performance status 0, and not obese)
were 0.60 or lower.41 Based on these results, it can be
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e189
GUNNAR FOLPRECT
speculated that perioperative therapy might be indicated for
patients with higher risk for recurrence and excellent per-
formance status.
This is especially important because the patients in the
trials mentioned above had relatively favorable risk
factors: In the EORTC EPOC trial,40 the majority of pa-
tients had a single liver metastasis and had metachro-
nous metastases. In resectable metastases, there is no
evidence for adding any antibodies to perioperative or
adjuvant chemotherapy.
The British New EPOC trial randomly selected patients
with liver metastases to receive perioperative chemotherapy
with or without the EGFR-antibody cetuximab. Progression-
free and overall survival were worse with the addition of
cetuximab.42 The background for these findings remained
unclear and was the subject of long discussions, i.e., whether
less extensive surgery and higher rates of positive margins or
unknown biologic aspects explain the unexpected outcome.43
With the missing benefit of adding any antibody in adjuvant
treatment in stage III colon cancer44,45 and the lack of positive
results in perioperative treatment of resectable metastatic
disease, FOLFOX remains the regimen with the best evidence
of potential benefit for patients with resectable disease and
might be indicated especially in the presence of higher risk
factors.
CHEMOTHERAPY AND LIVER TOXICITY
Liver-related toxicity was described for irinotecan (stea-
tohepatitis, 20%) and oxaliplatin (sinusoidal obstruction,
19%).46 Patients with steatohepatitis experience increased
mortality. In the EORTC 40983 study (investigating patients
with resectable disease), one of the 160 (0.6%) patients did
not undergo resection because of oxaliplatin-related liver
toxicity.47 Although chemotherapy-induced liver toxicity
was intensively discussed after these publications, this risk
has to be balanced in the context of patients with meta-
static, nonresectable (or poorly resectable) disease. Be-
cause operative morbidity increases with the number of
chemotherapy cycles,48 it is recommended to not further
extend preoperative chemotherapy if metastases become
resectable. Furthermore, surgical strategies for patients who
have been heavily pretreated must be adapted, i.e., by
parenchymal-saving resections.21
References
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2 trial. Lancet Oncol. 2010;11:38-47.
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e190 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
INTRA-ARTERIAL THERAPIES
High response rates in phase II trials using intra-arterial
chemotherapy have revived the discussion on this treat-
ment. In the French OPTILIV study, pretreated patients were
treated with systemic cetuximab and intra-arterial FOLFOXIRI.
The response rate was 41%, and 31% of patients were able to
undergo resection for their liver metastases.49 A protocol at
the Memorial Sloan Kettering Cancer Center used systemic
oxaliplatin and irinotecan combined with intra-arterial FUDR
in 49 pretreated patients, achieving response rate of 76%. In
total, 47% of patients were able to undergo resection in this
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Selective internal radiation therapy (SIRT) adds another
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limited or liver-dominant metastases were randomly se-
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CONCLUSION
Because multimodal treatment is associated with an im-
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multimodal treatment is crucial to the treatment of pa-
tients with metastatic colorectal cancer. Conversion
chemotherapy and ablative, interventional, and surgical
techniques can improve resectability and require a close
multidisciplinary cooperation. Sequencing of the treat-
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8. Ruers T, Punt CJA, van Coevorden F, et al. Radiofrequency ablation (RFA)
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9. Folprecht G, Gruenberger T, Bechstein W, et al. Survival of patients with
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study). Ann Oncol. 2014;25:1018-1025.
10. Rees M, Tekkis PP, Welsh FK, et al. Evaluation of long-term survival after
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11. Kohne CH, van Cutsem E, Wils J, et al; European Organisation for Re-
search and Treatment of Cancer Gastrointestinal Group. Phase III study
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without irinotecan in patients with metastatic colorectal cancer: Eu-
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testinal Group Study 40986. J Clin Oncol. 2005;23:4856-4865.
12. de Gramont A, Bosset JF, Milan C, et al. Randomized trial comparing
monthly low-dose leucovorin and fluorouracil bolus with bimonthly
high-dose leucovorin and fluorouracil bolus plus continuous infusion for
advanced colorectal cancer: a French intergroup study. J Clin Oncol.
1997;15:808-815.
13. Takahashi S, Inoue K, Konishi M, et al. Prognostic factors for poor
survival after repeat hepatectomy in patients with colorectal liver
metastases. Surgery. 2003;133:627-634.
14. Shaw IM, Rees M, Welsh FKS, et al. Repeat hepatic resection for re-
current colorectal liver metastases is associated with favourable long-
term survival. Br J Surg. 2006;93:457-464.
15. Lam VWT, Pang T, Laurence JM, et al. A systematic review of repeat
hepatectomy for recurrent colorectal liver metastases. J Gastrointest
Surg. 2013;17:1312-1321.
16. Makuuchi M, Thai BL, Takayasu K, et al. Preoperative portal emboli-
zation to increase safety of major hepatectomy for hilar bile duct
carcinoma: a preliminary report. Surgery. 1990;107:521-527.
17. Brouquet A, Abdalla EK, Kopetz S, et al. High survival rate after two-
stage resection of advanced colorectal liver metastases: response-
based selection and complete resection define outcome. J Clin
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18. Lam VWT, Laurence JM, Johnston E, et al. A systematic review of two-
stage hepatectomy in patients with initially unresectable colorectal liver
metastases. HPB (Oxford). 2013;15:483-491.
19. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation
combined with in situ splitting induces rapid left lateral liver lobe
hypertrophy enabling 2-staged extended right hepatic resection in
small-for-size settings. Ann Surg. 2012;255:405-414.
20. Schadde E, Raptis DA, Schnitzbauer AA, et al. Prediction of mortality
after ALPPS stage-1: an analysis of 320 patients from the international
ALPPS registry. Ann Surg. 2015;262:780-785, discussion 785-786.
21. Evrard S, Poston G, Kissmeyer-Nielsen P, et al. Combined ablation and
resection (CARe) as an effective parenchymal sparing treatment for
extensive colorectal liver metastases. PLoS One. 2014;9:e114404.
22. Adams RA, Meade AM, Seymour MT, et al; MRC COIN Trial Investigators.
Intermittent versus continuous oxaliplatin and fluoropyrimidine
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combination chemotherapy for first-line treatment of advanced
colorectal cancer: results of the randomised phase 3 MRC COIN trial.
Lancet Oncol. 2011;12:642-653.
23. Hegewisch-Becker S, Graeven U, Lerchenmuller CA, et al. Maintenance
strategies after first-line oxaliplatin plus fluoropyrimidine plus bev-
acizumab for patients with metastatic colorectal cancer (AIO 0207):
a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol.
2015;16:1355-1369.
24. Simkens LHJ, van Tinteren H, May A, et al. Maintenance treatment with
capecitabine and bevacizumab in metastatic colorectal cancer
(CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal
Cancer Group. Lancet. 2015;385:1843-1852.
25. Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant treatment of
unresectable colorectal liver metastases: correlation between tumour
response and resection rates. Ann Oncol. 2005;16:1311-1319.
26. Jones RP, Hamann S, Malik HZ, et al. Defined criteria for resectability
improves rates of secondary resection after systemic therapy for liver
limited metastatic colorectal cancer. Eur J Cancer. 2014;50:1590-1601.
27. Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and
bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014;371:
1609-1618.
28. Falcone A, Ricci S, Brunetti I, et al; Gruppo Oncologico Nord Ovest. Phase
III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan
(FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and
irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal
cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007;25:
1670-1676.
29. Van Cutsem E, Kohne C-H, Hitre E, et al. Cetuximab and chemotherapy
as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;
360:1408-1417.
30. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus iri-
notecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
N Engl J Med. 2004;350:2335-2342.
31. Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of
efficacy: the addition of bevacizumab to fluorouracil/leucovorin im-
proves survival for patients with metastatic colorectal cancer. J Clin
Oncol. 2005;23:3706-3712.
32. Saltz LB, Clarke S, Daz-Rubio E, et al. Bevacizumab in combination with
oxaliplatin-based chemotherapy as first-line therapy in metastatic
colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:
2013-2019.
33. Venook AP, Niedzwiecki D, Lenz H-J, et al. CALGB/SWOG 80405: phase III
trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/
leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET)
for patients (pts) with KRAS wild-type (wt) untreated metastatic ad-
enocarcinoma of the colon or rectum (MCRC). J Clin Oncol. 2014;32:5s
(suppl; abstr LBA3).
34. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus
cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for
patients with metastatic colorectal cancer (FIRE-3): a randomised,
open-label, phase 3 trial. Lancet Oncol. 2014;15:1065-1075.
35. Schwartzberg LS, Rivera F, Karthaus M, et al. PEAK: a randomized,
multicenter phase II study of panitumumab plus modified fluorouracil,
leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOL-
FOX6 in patients with previously untreated, unresectable, wild-type
KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014;32:
2240-2247.
36. Heinemann V, Stintzing S, Modest DP, et al. Early tumour shrinkage
(ETS) and depth of response (DpR) in the treatment of patients with
metastatic colorectal cancer (mCRC). Eur J Cancer. 2015;51:1927-1936.
37. Khattak MA, Martin H, Davidson A, et al. Role of first-line anti-epidermal
growth factor receptor therapy compared with anti-vascular
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endothelial growth factor therapy in advanced colorectal cancer:
a meta-analysis of randomized clinical trials. Clin Colorectal
Cancer. 2015;14:81-90.
38. Venook A, Niedzwiecki D, Lenz H, et al. CALGB/SWOG 80405: analysis of
patients undergoing surgery as part of treatment strategy. Ann Oncol.
2014;25:(suppl 4; abstr LBA10).
39. Mitry E, Fields ALA, Bleiberg H, et al. Adjuvant chemotherapy after po-
tentially curative resection of metastases from colorectal cancer: a pooled
analysis of two randomized trials. J Clin Oncol. 2008;26:4906-4911.
40. Nordlinger B, Sorbye H, Glimelius B, et al; EORTC Gastro-Intestinal Tract
Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen
undtumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie;
Australasian Gastro-Intestinal Trials Group; Federation Francophone de
Cancerologie Digestive. Perioperative FOLFOX4 chemotherapy and
surgery versus surgery alone for resectable liver metastases from co-
lorectal cancer (EORTC 40983): long-term results of a randomised,
controlled, phase 3 trial. Lancet Oncol. 2013;14:1208-1215.
41. Sorbye H, Mauer M, Gruenberger T, et al; EORTC Gastro-Intestinal Tract
Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen
und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie;
Australasian Gastro-Intestinal Trials Group; Federation Francophone de
Cancerologie Digestive. Predictive factors for the benefit of peri-
operative FOLFOX for resectable liver metastasis in colorectal cancer
patients (EORTC Intergroup Trial 40983). Ann Surg. 2012;255:534-539.
42. Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or
without cetuximab in patients with resectable colorectal liver metastasis:
the New EPOC randomised controlled trial. Lancet Oncol. 2014;15:601-611.
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EPOC trial change practice in the management of patients with re-
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44. Taieb J, Tabernero J, Mini E, et al; PETACC-8 Study Investigators.
Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in
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patients with resected stage III colon cancer (PETACC-8): an open-label,
randomised phase 3 trial. Lancet Oncol. 2014;15:862-873.
45. Allegra CJ, Yothers G, OConnell MJ, et al. Phase III trial assessing
bevacizumab in stages II and III carcinoma of the colon: results of NSABP
protocol C-08. J Clin Oncol. 2011;29:11-16.
46. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts
steatohepatitis and an increase in 90-day mortality after surgery for
hepatic colorectal metastases. J Clin Oncol. 2006;24:2065-2072.
47. Nordlinger B, Sorbye H, Glimelius B, et al; EORTC Gastro-Intestinal Tract
Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen
und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie;
Australasian Gastro-Intestinal Trials Group; Fede ration Francophone de
Cancerologie Digestive. Perioperative chemotherapy with FOLFOX4 and
surgery versus surgery alone for resectable liver metastases from co-
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48. Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoperative
chemotherapy on the risk of major hepatectomy for colorectal liver
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49. Levi FA, Boige V, Hebbar M, et al; Association Internationale pour la
Recherche sur le Temps Biologique et la Chronotherapie. Conversion to
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50. DAngelica MI, Correa-Gallego C, Paty PB, et al. Phase II trial of hepatic
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51. van Hazel GA, Heinemann V, Sharma NK, et al. SIRFLOX: randomized
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internal radiation therapy in patients with metastatic colorectal cancer.
J Clin Oncol. Epub 2016 Feb 22.
GASTROINTESTINAL (COLORECTAL) CANCER

Questions on Treatment of Locally

Advanced Rectal Cancer

CHAIR
Julio Garcia-Aguilar, MD, PhD
Memorial Sloan Kettering Cancer Center
New York, NY

SPEAKERS
Deborah Schrag, MD, MPH
Dana-Farber Cancer Institute
Boston, MA

Rob Glynne-Jones, MD, FRCP

Mount Vernon Cancer Centre
Middlesex, United Kingdom
GARCIA-AGUILAR, GLYNNE-JONES, AND SCHRAG

Multimodal Rectal Cancer Treatment: In Some Cases, Less

May Be More
Julio Garcia-Aguilar, MD, Rob Glynne-Jones, MBBS, FRCR, FRCP, and Deborah Schrag, MD, MPH

OVERVIEW

A series of clinical trials in the last several decades has resulted in the development of multimodality treatment of locally
advanced rectal cancer that includes neoadjuvant (preoperative) chemoradiotherapy, total mesorectal excision, and
postoperative adjuvant chemoradiotherapy. Owing to this regimen, patients with locally advanced rectal cancer have better
survival rates than patients with colon cancer, but at the cost of substantial morbidity and reduced quality of life. The
challenge is to identify treatment approaches that maintain or even improve oncologic outcomes while preserving quality of
life. We have identified different tumor characteristics that are associated with recurrence and probability of survival for
locally advanced rectal cancer. This risk stratification, based on baseline clinical staging and tumor response to chemo-
radiotherapy, has led us to question whether all patients with locally advanced rectal cancer require every component of the
multimodal regimen. In this article, we will review recent evidence that some patients with locally advanced rectal cancer
can be spared one or more treatment modalities without compromising long-term oncologic outcomes and while preserving
quality of life.

S urgical excision of the rectum and its mesorectal enve-

lope has been the mainstay of treatment for rectal cancer
for over a century.1 Despite advances in surgical technique
and perioperative care, total mesorectal excision remains
an operation associated with some mortality, substantial
morbidity, and sequelae that permanently impair quality
of life.2
CAN SURGERY BE AVOIDED FOR SELECTED
PATIENTS?
Some patients with locally advanced rectal cancer have a
pathologic complete response (pCR) to neoadjuvant che-
moradiotherapy. Patients with pCR experience lower local
recurrence and improved survival rates compared with
patients who do not experience pCR, raising the question of
whether the former need surgery.3 Given that the mortality,
morbidity, and long-term sequelae from multimodal therapy
are related to excision of the rectum, avoiding total mes-
orectal excision for selective patients who obtain a sustained
response to chemoradiotherapy will improve their quality
of life.
Although the evidence suggesting that some rectal cancers
can be treated with radiation alone is almost a century old,
it is Angelita Habr-Gama from Sao Paulo who should be
credited with the suggestion that patients with rectal cancer
who experience a clinically complete response (cCR) to
neoadjuvant chemoradiotherapy could achieve long-term
local tumor control without surgery.4
These ideas were initially received with disbelief, but
reports from other institutions have confirmed that surgery
can be avoided for select patients with rectal cancer who
received treatment with chemoradiotherapy. However, the
evidence supporting this treatment approach is based on
small institutional series of heterogenous groups of patients
who were staged using different imaging modalities, treated
according to diverse radiation and chemotherapy regimens,
evaluated at different times after completion of the neo-
adjuvant therapy, selected for observation using different
criteria, and followed for relatively short periods of time. In
spite of these limitations, clinicians are starting to accept a
paradigm shift for this selected group of patients with rectal
cancer with a cCR after neoadjuvant chemoradiation. Ac-
ceptance has often been accelerated by patients motivated
to avoid the consequences of a low colorectal anastomosis
or a permanent colostomy. The treatment plan after neo-
adjuvant therapy that consists of close active surveillance,
rather than surgery, is called watch-and-wait, wait-and-
see, or nonoperative management. We use the term
nonoperative management in this article.

From the Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medical Oncology, Mount Vernon Centre for Cancer Treatment, London, United
Kingdom; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: email: Julio Garcia-Aguilar, MD, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065;
email: garciaaj@mskcc.org.

2016 by American Society of Clinical Oncology.

92 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


Evidence Supporting Nonoperative Management
Most studies that have reported nonoperative management
outcomes in locally advanced rectal cancer have compared
recurrence and survival rates between patients with cCR
entered in a nonoperative management protocol and pa-
tients who had similar neoadjuvant treatment followed by
total mesorectal excision and subsequent pCR.
In Dr. Habr-Gamas protocol, clinical tumor response is
assessed 8 weeks after chemoradiotherapy.5 Patients with
persistent tumor undergo total mesorectal excision; those
with cCR undergo monthly evaluations including digital rectal
examination, proctoscopy, carcinoembryonic antigen (CEA)
blood testing, and biopsy of suspicious lesions. Patients found
to have tumor relapse are directed to surgery, whereas pa-
tients with a sustained cCR after 1 year continue surveillance
every 3 months for an additional year and every 6 months
thereafter. Of the patients treated according to this protocol,
27% experienced cCR after 1 year and were spared from total
mesorectal excision. Local relapse during follow-up beyond
1 year developed in 10% of patients treated with the
nonoperative management protocol, and all proceeded
to curative total mesorectal excision. The oncologic results in
this nonoperative management group were equivalent to
those of patients who had a pCR after total mesorectal
excision.
KEY POINTS
Treatment counseling should convey the risks and
benefits by using quantitative estimates expressed in
absolutenot relativeterms to empower informed
patient decision making.
Multimodality therapy provides excellent local tumor
control and long-term survival for patients with locally
advanced rectal cancer.
Phased-array MRI can define features associated with a
high risk of metastases and a high likelihood of local
recurrence.
Evidence supporting the use or non-use of adjuvant
chemotherapy in patients with rectal cancer is not
available, and so omission of this treatment can be
considered.
Select patients with rectal cancer who experience
complete clinical response after neoadjuvant therapy
can avoid total mesorectal excision, but the evidence is
still preliminary.
A selective approach to radiotherapy provision is
feasible with the provision that we use high-quality MRI
and optimal total mesorectal excision surgery.
Fluorouracil is best administered using an infusional
rather than a bolus schedule. Capecitabine is a
reasonable alternative to infusional 5-FU.
When FOLFOX is administered, it is essential to avoid
long-term toxicity by dose-reducing or discontinuing
oxaliplatin before peripheral neuropathy becomes
severe or persistent.
RECTAL CANCER TREATMENT: LESS MAY BE MORE
A group in the Netherlands reported their experience with
nonoperative management for 21 patients with cCR among
a total of 192 patients treated with chemoradiotherapy
between 2004 and 2010. After a mean follow-up of
25 months, local relapse developed in one patient who then
underwent curative salvage surgery; the other 20 patients
are alive without disease. Outcomes of patients treated with
the nonoperative management protocol who experienced
CR were similar to the outcomes of patients with pCR after
total mesorectal excision.6
Our group at the Memorial Sloan Kettering Cancer Center
reported the results of 32 patients with cCR treated with the
nonoperative management protocol who started neo-
adjuvant therapy between 2006 and 2010 and were fol-
lowed for a median of 23 months. We compared these
results with 57 patients treated during the same period who
underwent total mesorectal excision and had a pCR. The
total mesorectal excision group had slightly more proximal
tumors and received adjuvant treatment more often, and
also had more advanced tumors compared with the patients
treated with the nonoperative management protcol. Six of
32 patients (21%) experienced disease relapse and un-
derwent curative salvage surgery; distant metastasis de-
veloped in three of these patients. The 3-year disease-free
survival (DFS) and overall survival (OS) rates were not different
between groups.7 In an update to this series, we compared the
results of 73 patients with cCR treated with the nonoperative
management protocol and 72 patients treated with total
mesorectal excision who had pCR between 2006 and 2014.
Although relapse occurred among 19 of the 73 patients (26%)
treated with nonoperative management, 18 patients received
salvage therapy, and DFS and OS were equivalent between the
groups. In total, 56 of 73 patients (77%) who were treated
using the nonoperative management protocol preserved the
rectum after a median of 4 years of follow-up.8
Araujo et al reported a retrospective comparison of 42 pa-
tients with rectal cancer entered into a nonoperative man-
agement protocol with 69 patients treated with neoadjuvant
therapy and total mesorectal excision with subsequent pCR.
Nonoperative management was not an elective alternative and
was only considered for patients who refused surgery. Relapse
occurred in a total of 12 (28%) patients in the nonoperative
management group; local recurrence developed in five pa-
tients, distant metastasis developed in three patients, and both
local recurrence and distant metastasis occurred in four pa-
tients at a median of 2 years of follow-up. Four of the five
patients with isolated local recurrence had successful salvage
surgery. There was no difference in OS rates, but DFS was
reduced in the nonoperative management group compared
with the surgery group (61% vs. 83%). This study had several
unfortunate limitations including pretreatment tumor staging
performed by digital examination and a nonstandardized
definition of clinical response, and the groups were not
matched for important clinicopathologic variables such as
tumor distance from the anal verge.9
Li et al reported results from a cohort of 122 patients with
cCR among a total of 900 patients with stage II and III rectal
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 93
GARCIA-AGUILAR, GLYNNE-JONES, AND SCHRAG
cancer treated with chemoradiotherapy. Of the 122 pa-
tients, 92 had rectal resection and 30 entered a non-
operative management protocol. Both groups of patients
were well-matched for clinical characteristics and received
similar treatment. Recurrence and DFS rates were not sig-
nificantly different between groups.10
A group from the United Kingdom recently reported a
multi-institutional experience with a nonoperative man-
agement approach versus surgical resection for patients
with rectal cancer treated with chemoradiotherapy. In
contrast to the previous series, this study compared
the outcomes of 129 patients with cCR with 228 patients
who had surgical resection after chemoradiotherapy, in-
dependent of the pathologic stage. Neoadjuvant therapy
was similar between groups. After a median follow-up of
33 months from start of chemoradiotherapy, 44 (34%)
patients with cCR had local regrowth, corresponding to
an actuarial 3-year local regrowth rate of 38%. Similar to
previous findings, most local regrowths were on the bowel
wall, and most underwent successful salvage treatment. The
authors developed one-to-one paired cohorts (109 patients
in each group) using propensity-score matching for the key
confounders. The 3-year nonregrowth DFS rate (defined as
time until death, local recurrence, or distant metastasis, not
including local regrowths) was 88% for the nonoperative
management group and 78% for the surgical group (log rank;
p = .22). The colostomy-free survival rates were 74% and
47%, respectively. The authors concluded that nonoperative
management is safe in a multi-institutional setting, sup-
porting the standard adoption of this protocol. However, the
results of this study should be interpreted with caution, as
tumors in patients treated with nonoperative management
had an earlier pretreatment tumor stage, were less likely to
have nodal involvement, rarely had unfavorable histologic
features, and were more likely to have normal CEA levels. In
addition, comparing patients with and without cCR, in-
dependent of the pathologic stage, introduces substantial
bias, as tumor response is associated with improved out-
come compared with nonresponders.11
In summary, despite the relatively low-quality evidence,
these studies all suggest that most patients with cCR after
neoadjuvant chemotherapy can achieve prolonged local
tumor control without surgery. Tumor regrowth occurs in
some patients, but most can be effectively treated with
surgery. As the follow-up period in most of these series
is relatively short, long-term survival rates are still
unknown.
Challenges to Nonoperative Management of Rectal
Cancer
Although the above-mentioned studies all suggest that most
patients with cCR after neoadjuvant chemotherapy can
achieve prolonged local tumor control without surgery, a
number of questions must be answered before nonoperative
management can be considered a standard option for pa-
tients with locally advanced rectal cancer.
94 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
The proportion of patients who respond to chemo-
radiotherapy seems small, and the optimal time to assess
clinical response is unknown. Tumor response depends on
radiation dose, but doses beyond 54 Gy are rarely used in
these patients. Adding other drugs that are effective in colon
cancer as radiosensitizers beyond fluoropyrimidines has
been found to be ineffective or prohibitively toxic.12-15
Tumor response to chemoradiotherapy is closely associated
with time, and, for patients undergoing total mesorectal
excision after chemoradiotherapy, the proportion of tumors
with pCR increases with the time interval between che-
moradiotherapy and surgery.16 As prolonging the interval to
surgery and postoperative systemic chemotherapy may be
unsafe for patients at risk for distant metastasis, attempts
have been made to deliver systemic chemotherapy imme-
diately before or after chemoradiation.17,18 Delivering sys-
temic chemotherapy before surgery, rather than after, has
been shown to increase tumor response without delaying
the treatment of potential micrometastatic disease. In these
patients, the assessment of clinical response and the rec-
ommendation of nonoperative management or surgery are
performed at the completion of both chemoradiotherapy
and systemic chemotherapy. This approach has resulted in
pCR rates as high as 38% for patients with clinical stage II and
III disease, and it has the added advantage of increasing
compliance with adjuvant systemic chemotherapy and
shortening ileostomy time for patients with locally advanced
rectal cancer.17,18 The experimental arm of the RAPIDO trial
uses short-term radiation and consolidation chemotherapy;
the trials results are forthcoming.19
The lack of a reliable and uniform method of distinguishing
post-treatment scar from residual tumor in the bowel wall or
regional lymph nodes is the main obstacle to nonoperative
management for patients treated with neoadjuvant therapy.
Most authors agree that digital rectal examination, endos-
copy, and imaging studies should be used. A flat white scar
with or without telangiectasia and a normal digital exami-
nation are good predictors of pCR, whereas the presence of
superficial ulceration or a palpable modularity upon digital
rectal examination indicate an incomplete response.20,21
Although clinical assessment tends to underestimate tu-
mor response, there is always a possibility that tumors
are concealed in or behind apparently normal scar tissue
in the rectal wall. 22 Endorectal ultrasound, CT, and
18
F-fludeoxyglucose PET provide an estimate of tumor
regression but are not sensitive enough to identify pCR.23
Conventional MRI morphologic sequences (e.g., T2- and
T1-weighted images) cannot differentiate residual tumor
from surrounding fibrosis, but diffusion-weighted MRI
sequences may improve the diagnostic performance of
morphologic MRI sequences for differentiating pCR from
residual tumor. 24
The definition of response undoubtedly influences clinical
outcomes: a strict definition reduces the proportion eligible
but increases the chance of success with nonoperative
management, whereas less-strict criteria increase the
number of eligible patients but also risk of local tumor

regrowth and distant metastasis. Although there are cur-
rently no validated criteria defining clinical and radiologic
tumor response, a new set of criteria categorizing response
in a three-tier system is currently being tested in a pro-
spective clinical trial.25
A number of patients with apparent cCR develop tumor
regrowth during follow-up. As most regrowth occurs in the
bowel wall, repeated endoscopic examinations are essential.
Any suspicious changes in the scar should be biopsied. MRI
should also be performed regularly to detect nodal
regrowth. Changes in the size, contour, heterogeneity, or
restriction of diffusion should raise the possibility of relapse.
Repeated examinations and continuous monitoring are of-
ten necessary to confirm recurrence.
Ultimately, finding reliable predictors of response to
neoadjuvant therapy would help identify patients who
would most likely to benefit from nonoperative manage-
ment as well as reduce toxicity for patients whose disease
will likely have a poor response. Tumor size and stage seem
to predict response, with smaller early-stage tumors being
more likely to develop pCR. The search for molecular pre-
dictors of tumor response has not resulted in breakthrough
findings so far. We have previously shown that rectal tumors
with a KRAS mutation are less likely to respond to neo-
adjuvant therapy.26 However, these findings must be vali-
dated in large independent cohorts.
In summary, the nonoperative management approach is
an attractive alternative for patients with rectal cancer who
experience cCR after neoadjuvant therapy. However, evi-
dence supporting this approach is still relatively scarce and
too many questions about its safety remain to recommend
this approach outside of a clinical trial. Although a well-
designed phase III randomized trial comparing surgery
versus nonoperative management for patients with cCR
after neoadjuvant therapy may never be palatable to pro-
spective patients, a number of prospective registries and
phase II trials are currently open to accrual.
CAN WE AVOID NEOADJUVANT THERAPY OR
RADIOTHERAPY IN SELECTED PATIENTS?
Historically, surgeons reported a high pelvic recurrence rate
after radical surgery alone, resulting in a range of symp-
toms, including profuse mucinous discharge, bleeding, and
intractable pelvic pain.27 A landmark German study sub-
sequently established preoperative chemoradiotherapy
as the standard of care.28 Although the rates of local re-
currence reported before total mesorectal excision/
chemoradiotherapy came into widespread use would
not be acceptable today, these historical local recurrence
rates continue to dominate decision making.29 Many ad-
vocate the use of chemoradiotherapy for all patients staged
as cT3N0 or cT3N1 regardless of tumor site (low, middle, or
upper rectum), location (anterior or posterior), depth of
invasion, or proximity to other vital structures, despite the
ability of modern MRI to predict the risk of both local
recurrence and distant metastasis. The low rate of local
RECTAL CANCER TREATMENT: LESS MAY BE MORE
recurrence observed among patients with rectal cancer
treated with total mesorectal excision alone challenged the
benefit of neoadjuvant therapy for patients with low-risk
stage II rectal tumors30-32 and called for a more selective
approach, particularly for upper rectal cancer.33-35 In ad-
dition, for patients with a high risk of metastatic disease,
the integration of more active chemotherapy into the
preoperative setting has become more attractive either in
addition to or as an alternative for chemoradiotherapy. The
clinical and imaging features and histopathologic analysis
of tumor determine the inherent risks of both local re-
currence and distant metastasis.36,37 Variations in practice
and the different uptake of these modalities in rectal cancer
are common, as judgments are made on the balance of risk
and toxicity.
Surgery and radiotherapy often have permanent sequelae
resulting in an adverse effect on quality of life. Preoperative
chemoradiotherapy enhances local control and can be cu-
rative on its own for some patients, but it worsens the
constellation of changes in bowel function experienced by
many patients after sphincter-saving rectal cancer sur-
gery, known as low anterior resection syndrome. Many
patients complain of chronic pain.38 Despite potentially
confounding factors such as older age or the effects of
prior surgical procedures in the pelvis, these symptoms
are worsened by the addition of short-course pre-
operative chemoradiotherapy (SCPRT) or conventional
chemoradiotherapy.39 In the Dutch total mesorectal ex-
cision trial, 62% of patients who received SCPRT before
total mesorectal excision reported fecal incontinence,
compared with 38% in the total mesorectal excision alone
group.40 Hence, a paradox: as we are advocating less che-
moradiotherapy because surgery is getting better, we are
simultaneously advocating chemoradiotherapy to avoid
radical surgery.
Indications for Chemoradiotherapy
There are four main indications for delivering preopera-
tive radiotherapy or chemoradiotherapy. These comprise
unresectable or borderline resectable cancers; resectable
cancers with a high risk of local recurrence; early rectal
cancers in older or frail patients as an alternative to
surgery; and treatment with palliative intent. The radia-
tion oncologist should keep in mind that postoperative
chemoradiotherapy is associated with substantially more
acute and long-term morbidity compared with preopera-
tive utilization.28 Hence, postoperative chemoradiotherapy
is not usually part of the planned management and usually
reflects poor preoperative decisions, unexpected surgical
or histopathologic findings, or both.
Tumors are considered unresectable or borderline re-
sectable per initial MRI either because the primary tumor or
involved lymph nodes abut or breach the mesorectal fascia
or there is tumor outside the mesorectal fascia with local
extension to pelvic side-wall and sacrum or nodal involve-
ment in the lateral pelvic lymph nodes. Lateral pelvic lymph
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GARCIA-AGUILAR, GLYNNE-JONES, AND SCHRAG
node involvement may reach as high as 15% when tumors
are low and bulky with multiple visible and presumed in-
volved mesorectal nodes. These lateral pelvic lymph nodes,
although considered regional by the American Joint Com-
mittee on Cancer classification, are not routinely resected
during a standard total mesorectal excision operation. In
these circumstances, a degree of response to chemo-
radiotherapy is considered essential prior to surgery.41
Borderline resectable tumors are usually in the low or
midrectum. They demonstrate various adverse features
such as extension beyond the muscularis propria by 10 mm
to 15 mm, multiple nodal metastases in the mesorectum
(N2), or the presence of gross extramural vascular invasion.
These features are associated with a higher risk of local
recurrence and a high risk of metastatic disease. There are
sometimes less-evident clinical features that may alert the
surgeon to the potential difficulty of the operation and the
risk of not achieving an R0 resection. In particular, an an-
teriorly placed tumor at or below the level of the prostate,
in a large male with a narrow pelvis, is predictive of a
technically challenging dissection. The risk of a positive
circumferential resection margin in an anteriorly located
distal rectal cancer is as high as 30% even when treated with
an abdominoperineal excision. In these circumstances,
chemoradiotherapy to downsize the tumor will reduce the
risk of a circumferential resection margin or a defect in the
mesorectum.
Although the literature suggests that radiotherapy may
not fully compensate for a positive circumferential resection
margin, it may reduce the risk of local recurrence for patients
with a suboptimal total mesorectal excision surgery.42
Surgeons in the United Kingdom who are coming out of
training may have little experience and certainly face
a learning curve. As a radiation oncologist, without the
availability of records with multiple photographic images of
the surgical specimens to determine the quality of the
mesorectal excision in previous cases, I would likely rec-
ommend preoperative chemoradiotherapy. Recent data43
suggest that many patients with rectal cancer in the United
States are treated by surgeons who perform fewer than six
procedures per year. The circumferential resection margin
(when reported) in such cases has been documented as
positive in 17.2% of patients. Although SCPRT or chemo-
radiotherapy do not completely compensate for inadequate
surgery, there is sufficient historical data27,28,44,45 to argue
that surgeons entering the learning curve or practicing rectal
cancer surgery in a low-volume environment should offer
their patients neoadjuvant chemoradiotherapy or SCPRT,
even if the features mentioned in the preceding paragraph
are not necessarily present.
Preoperative radiation or chemoradiotherapy followed by
local excision is also an alternative to total mesorectal ex-
cision for patients with early stage rectal cancers treated
with curative intent.46,47 Chemoradiotherapy and local ex-
cision can also be used as a compromise treatment of pa-
tients with more advanced rectal cancers who refuse an
abdominoperineal excision of the rectum. Finally, radiation
96 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
or chemoradiotherapy with a brachytherapy boost may be
preferable to surgery for patients at high risk due to age or
multiple comorbidities.
MRI Is the Key to Selection
Modern phased-array coil MRI using various sequences and
multiple planes provides high-resolution tissue imaging and
excellent anatomic depiction of the rectum and other pelvic
structures relative to tumor location. MRI can predict in-
volvement of the mesorectal fascia with a sensitivity of 77%
(95% CI, 57%90%) and specificity of 94% (95% CI, 88%
97%).48 The MERCURY trial, a prospective observational
study that assessed the accuracy of MRI in predicting a
curative resection in rectal cancer, reported 92% specificity
in predicting a negative circumferential resection margin.49
On multivariate analysis, MRI involvement of the circum-
ferential resection margin was the only preoperative staging
parameter that remained predictive for local recurrence and
survival.50
Therefore, MRI is essential to stratify patients into risk
categories for local recurrence according to the proximity of
the tumor to the circumferential resection margin. These risk
categories are used to separate and select low-risk patients
who are unlikely to benefit from radiotherapy. MRI can also
define a group of patients with a high risk of recurrence
and metastases, typically suggested by extramural spread,
extramural vascular invasion, peritoneal reflection involve-
ment, and tumor proximity to the levator muscle and
sphincter. High risk of metastatic disease means that the
use of chemotherapy at systemically effective doses would
seem essential to improve survival rates for patients with
locally advanced rectal cancer. This raises the question of
whether chemoradiotherapy is required if neoadjuvant
chemotherapy is effective in downstaging the tumor.
When Can Radiation Be Omitted?
The risk of local recurrence for patients with locally advanced
rectal cancer is dependent on tumor stage, the distance of
the tumor from the anal verge, and the proximity of the
tumor to the mesorectal fascia.50
Tumors located in the upper rectum, distant from the
mesorectal fascia, have a low risk of local recurrence when
treated with total mesorectal excision. The added benefit of
radiation therapy in these patients has been questioned, as
radiation is associated with substantial toxicity including
bowel obstruction, hip fractures, sexual and urinary dys-
function, and proctitis.51-53 A growing body of evidence
suggests that radiation therapy could be safely avoided for
patients with intermediate-risk rectal cancer, such as rectal
cancers located between 5 cm to 12 cm from the anal verge
that do not threaten the mesorectal fascia on MRI.54,55
In a pilot phase II trial conducted at Memorial Sloan
Kettering Cancer Center, 32 patients with resectable clini-
cally staged II to III rectal cancer were treated with pre-
operative FOLFOX (oxaliplatin, 5-fluorouracil [5-FU], and
folinic acid) plus antivascular endothelial growth factor and

selective chemoradiotherapy based on tumor response.56
The 30 patients who completed preoperative chemotherapy
experienced tumor regression and underwent total meso-
rectal excision without preoperative chemoradiotherapy.
No local recurrences were noted at 4 years, and the DFS was
84%.56 These data were used as proof-of-concept for the
design of the phase II/III PROSPECT trial, which is now ac-
cruing worldwide. The overarching goal of this randomized
trial is to determine whether pelvic radiation therapy can be
used selectively for patients with locally advanced rectal
cancer.55 The trial utilizes selective rather than reflexive
chemoradiotherapy to individualize treatment based on
each patients response to neoadjuvant FOLFOX. The hope is
that a trial tailoring therapy more precisely, based on clinical
subgroups and tumor response to treatment, will help
eliminate the over- or undertreatment noted in previous
trials.54
In summary, chemoradiotherapy before total mesorectal
excision is currently the treatment of choice for patients with
high-risk locally advanced rectal cancer, including those with
involvement of the pelvic sidewall or mesorectal fascia. In
more straightforward cases, there is a question of whether
chemoradiotherapy alone or surgery alone should be con-
sidered given the long-term effects of both treatments. The
risks presented by either course should be estimated and
discussed with the patient. The argument for any of these
approaches rests on the provision of using good quality MRI,
good quality radiotherapy, and the surgeons record of good
performance of total mesorectal excision surgery within the
mesorectal plane.
ADJUVANT SYSTEMIC CHEMOTHERAPY FOR
LOCALLY ADVANCED (CLINICAL STAGE II AND III)
RECTAL CANCER
The controversy regarding adjuvant systemic chemotherapy
for rectal cancer is best understood in its historical con-
text. In 1990, an American consensus conference57 rec-
ommended postoperative chemoradiotherapy and systemic
5-FU on the basis of two randomized trials that demon-
strated better OS and reduced local and distant re-
currence rates compared with surgery alone or to
surgery with radiation. 58,59 These trials did not distin-
guish between postoperative chemoradiotherapy and
postoperative chemotherapy, and therefore the benefits
realized were bundled as a multicomponent package. Since
then, adjuvant systemic treatment has been an entrenched
ingredient of curative-intent treatment for locally ad-
vanced rectal cancer and, indeed, has been adopted as a
measure of care quality. Unfortunately, the evidence un-
derpinning this treatment recommendation is suboptimal,
particularly for patients with stage II locally advanced rectal
cancer.
The prevailing approach to curative-intent treatment of
rectal cancer for reasonably fit patients in the United States
is chemoradiotherapy followed by total mesorectal excision
and eight cycles of FOLFOX. The shift to neoadjuvant
RECTAL CANCER TREATMENT: LESS MAY BE MORE
chemoradiotherapy dates to 2004, when the German rectal
cancer trial demonstrated better local control with pre-
operative chemoradiotherapy with OS identical for pre- and
postoperative treatment.28,60 5-FUbased postoperative
chemotherapy was included in both arms of the German
trial. Also in 2004, the MOSAIC study in stage II and III colon
cancer compared 12 cycles of infusional 5-FU to 12 cycles
of FOLFOX and demonstrated superior survival with
FOLFOX.61,62 The benefits were not manifest in the stage II
subgroup. Although patients with rectal cancer were not
included, many clinicians have interpreted the results of
this study as pertinent to rectal cancer under the as-
sumption that if FOLFOX is preferable for stage III colon
cancer, then logically it should be preferred for stage II and
III rectal cancer as well.
The persistent controversy regarding adjuvant treatment
of rectal cancer can be traced to varying interpretations of
these foundational studies. One school of thought considers
the clear benefit from the original trials conducted in the late
1980s as compelling evidence for postoperative 5-FU as
part of the package. Many also accept the legitimacy of
extrapolating from colon to rectal cancer and therefore
including oxaliplatin with 5-FU. Adherents of the opposing
viewpoint correctly point out that there is a dearth of
high-powered studies examining postoperative systemic
chemotherapy among patients treated with chemo-
radiotherapy and that there is compelling evidence that
patients with stage II tumors and/or cPR have very favorable
prognoses, particularly in the setting of high-quality pre-
operative imaging and optimal surgical technique, even in
the absence of systemic treatment. Posthoc analyses of
complete responders to chemoradiotherapy treated with
and without chemotherapy have failed to show the com-
pelling advantage of the former approach.60,63,64
Does Systemic Chemotherapy Improve Rectal Cancer
Outcomes After Preoperative Chemoradiotherapy
and Surgical Resection?
Trials that have specifically addressed the benefit of systemic
chemotherapy compared with observation alone following
neoadjuvant chemoradiotherapy are few and have faced
considerable challenges. The EORTC 2991 study, which now
has 10 years of follow-up, used a two-by-two factorial design
to evaluate the inclusion of systemic chemotherapy in both
preoperative treatment and postoperative therapy.65 With
500 patients treated with adjuvant therapy and 500 without,
the power to detect small differences was necessarily lim-
ited. Although both DFS and OS rates favored the adjuvant
treatment arms, the differences were small: 3.3% for DFS
and 3.4% for OS at 10 years (Table 1). The primary im-
pediment to interpretation of this study is that it used a
much older systemic treatment regimen, Mayo Clinicstyle
bolus 5-FU, which is now recognized to have less efficacy and
greater toxicity than infusional regimens.
The Dutch Colorectal Cancer Group planned the PROCTOR/
SCRIPT trial with 840 patients to detect a difference between
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GARCIA-AGUILAR, GLYNNE-JONES, AND SCHRAG

TABLE 1. Outcomes of Patients With Rectal Cancer After Receiving Neoadjuvant Therapy and Subsequent
Treatment With Nonoperative Management or Total Mesorectal Excision

Interval to Salvage After Overall Survival Disease-Free

cCRs pCRs Regrowth in Regrowth in Regrowth in NOM vs. OM Survival NOM vs. Permanent Stoma Evidence
Reference (NOM) (OM) NOM (%) NOM (months) NOM (%)* (p value) OM (p value) NOM vs. OM Level**
Habr-Gama 71 22 2 (3) 60 2 (100) 5-year; 100% vs. 5-year; 92% vs. 0% vs. 41% 3B
et al 20045 88% (p = .01) 83% (p = .09)
Maas et al 21 20 1 (5) 22 1 (100) 2-year; 100% vs. 2-year; 89% vs. 0% vs. 45% 3B
20116 93% (p = .23) 91% (p = .77)
Smith et al 32 57 6 (19) 11 6 (100) 2-year; 96% vs. 2-year; 88% vs. NS 3B
20127 100% (p = .56) 98% (p = .27)
Araujo et al 42 69 5 (12) 48 4 (80) 5-year; 72% vs. 5-year; 61% vs. 7% vs. 19% 4
20159 90% (p = .32) 83% (p = .04)
Li et al 201510 30 92* 2 (7) 22 2 (100) 5-year; 100% vs. 5-year; 90% vs. 0% vs. 43% 4
96% (p = .26) 94% (p = .51)
*Patients with cCR subjected to surgery.
**Level according to Oxford Centre for Evidence-Based Medicine levels of evidence and grades of recommendations for therapeutic interventions.
Abbreviations: NOM, nonoperative management; TME, total mesorectal excision; cCR, clinically complete response; pCR, pathologic complete response; OM, operative management;
NS, not significant.

60% to 70% in OS.66 Unlike the EORTC 2291 trial, patients
were randomly assigned to receive 5-FU postoperatively
and after completing preoperative chemoradiotherapy.
PROCTOR/SCRIPT accrued poorly. It was amended to
substitute eight cycles of capecitabine for the original bolus
5-FU regimens, but it still did not accrue well and closed
after a total of 437 patients had been assigned. With 5 years
of follow-up, there is a 7% increase in 5-year DFS in the
adjuvant therapy arm. This difference did not reach signif-
icance. Moreover, OS is nearly identical between the arms.
An Italian trial reported by Cionini et al randomly assigned
635 patients with stage II/III rectal cancer to receive six
cycles of bolus 5-FU and leucovorin or observation, and it
found no difference in OS (Table 2).67
Overall, trials that have directly addressed the question of
the benefit of postoperative adjuvant systemic therapy for
patients with rectal cancer treated with neoadjuvant che-
moradiotherapy have not demonstrated the superiority of
treatment to observation. However, it is also fair to say that
these studies have not demonstrated the absence of benefit.
These trials had trouble accruing, were underpowered, and
used antiquated bolus 5-FU/leucovorin regimens. The only
study that included oxaliplatin68 failed to complete accrual
and was closed prematurely. As a result, clinicians who treat
rectal cancer do not have an answer to this fundamental
question. However, the low accrual rates in both the United
Kingdom and the Netherlands, attributed to lack of equipoise,
make it unlikely that trials with an observation arm will ever
be conducted. Instead, focus has shifted to intensive efforts to
characterize the phenotypes and genotypic subsets of rectal
cancer that are associated with poor prognosis and/or greater
responsiveness to systemic therapy and to tailor treatment
thresholds to risk. Indeed, most recent rectal cancer clinical
trials examine strategies for tailoring treatment to risk profile
to strike a balance between either under- or overtreatment.
Does the Addition of Oxaliplatin to 5-FU Improve
Outcomes Compared With 5-FU Alone?
More recent trials have assumed that systemic therapy is
beneficial and have focused on addressing the benefit of
adding oxaliplatin to 5-FU in postoperative adjuvant regi-
mens for rectal cancer. In the wake of MOSAIC, oncologists
have accepted the transitive principle and presumed that if
adding oxaliplatin is better than adjuvant infusional 5-FU/
leucovorin alone in colon cancer, the same must be true in
rectal cancer. Typically, the 12 cycles used in MOSAIC are

TABLE 2. Randomized Clinical Trials Comparing Postoperative Systemic Chemotherapy With Observation of
Patients With Rectal Cancer Treated with Preoperative Pelvic Radiotherapy
Disease-Free Survival Overall Survival
Study (Maturity) No. Patients Adjuvant Treatment Rx+ vs. Rx- Difference Rx+ vs. Rx- Difference Reference
EORTC2291 (10-year) 1,101 4 cycles of bolus 5-FU/LV every 47 vs. 43.7 3.3% 51.8 vs. 48.4 3.4% Bossett et al44,65
3 weeks
PROCTOR/SCRIPT 437; closed early 8 cycles of capecitabine or bolus 62.7 vs. 55.4 7.3% 80.4 79.2% Breugom et al66
(5-year) 5-FU/LV
CHRONICLE (3-year) 113; closed early 6 cycles of CaPOx 77.5 vs. 71.3 6.2% 87.8 vs. 88.8 21% Glynne-Jones et al68
Cionini 635 6 cycles of bolus 5-FU/LV every N/A N/A 68 vs. 64 4% Cionini et al67
4 weeks
Abbreviations: 5-FU, 5-fluorouracil; LV, leucovorin; Rx+, with treatment; RX-, without treatment; CaPOx, capecitabine and oxaliplatin; N/A, not applicable.

98 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


reduced to eight cycles. Somewhat arbitrarily, credit for
four cycles is given for chemoradiotherapy.
Notwithstanding the paucity of direct evidence that any
postoperative chemotherapy is superior to observation in
locally advanced rectal cancer, several randomized trials
have directly compared oxaliplatin with nonoxaliplatin-
containing regimens for postoperative adjuvant treatment
of rectal cancer. Specifically, the ECOG E320169 study sought
to compare eight cycles of postoperative 5-FU and leuco-
vorin with two to eight cycles of FOLFOX after standard
neoadjuvant chemoradiotherapy and surgery. The study
accrued fewer than 100 patients, with surveys indicating a
perceived lack of equipoise.
Fortunately, three non-U.S.based studies were more
successful. The PETACC-6 study randomly assigned 1,069
patients to receive either six cycles of adjuvant capecitabine
and oxaliplatin (CAPOX) or to capecitabine alone. Although
median follow-up was only 31 months, 3-year DFS rates were
nearly identical in both arms.70 The most recent study from
the German Rectal Cancer Group randomly assigned 1,265
patients to receive either four cycles of Mayo Clinicstyle
bolus 5-FU or eight cycles of postoperative FOLFOX. With
50 months of follow-up, 3-year DFS was 71.2% for 5-FU and
75.9% for FOLFOX, a difference of 4.7%.15 Mature data and a
final report have not yet been published. In contrast, the
recent randomized ADORE trial from South Korea revealed
an advantage for FOLFOX compared with Mayo Clinicstyle
bolus 5-FU/leucovorin. This study randomly assigned 321
patients and reported a 71.6% 3-year DFS rate in the FOLFOX
group compared with 62.9% in the 5-FU/leucovorin group.71
This difference was significant with a hazard ratio (HR) of
0.66 (95% CI, 0.430.99; p = .047). In the FOLFOX arm, the
3-year OS was 95% versus 85.7% in the control arm, a dif-
ference of 9.3% with a HR of 0.46 (95% CI, 0.220.97). This
study has been critiqued for its small sample size and the
different 5-FU backbones in the two arms. As a result, it is
unclear whether the better outcomes in the intervention
arm were attributable to the superiority of infusional versus
bolus 5-FU or to the addition of oxaliplatin.
Treatment Decision Making in the Absence of Perfect
Information
For patients treated with preoperative chemoradiotherapy,
decisions about postoperative systemic therapy must be
tailored to the risk of metastatic disease based on pathology.
They must also take into account the patients life expec-
tancy independent of the cancer, as well as the patients
preferences. In some contexts, decision making is easy. For
example, extrapolating from the MOSAIC trial, patients with
node-positive rectal cancer are often recommended eight
cycles of FOLFOX. For patients with no evidence of nodal
involvement and excellent response, chemoradiotherapy
may be omitted. In this context, it is important to attenuate
or remove oxaliplatin altogether before peripheral neu-
ropathy becomes severe (grade 3). Among patients who are
frail or do not tolerate oxaliplatin, some oncologists still
RECTAL CANCER TREATMENT: LESS MAY BE MORE
prefer to administer infusional 5-FU without oxaliplatin
rather than no adjuvant systemic therapy. Conversely, for
patients with substantial comorbidities that suggest life
expectancy of less than 5 years, omitting treatment seems
most appropriate.
The challenge arises in the treatment of patients with cT3
node-negative tumors with complete or favorable patho-
logic responses to neoadjuvant chemoradiotherapy in-
cluding cT3N0 and yT0N0, T1N0 or T2N0. In this context,
there is reluctance to administer postoperative FOLFOX
given its toxicity and the imperfect evidence supporting its
use. The focus of recent and current randomized trials is to
evaluate alternative preoperative management strategies
and completion of systemic chemotherapy prior to surgery,
so it is possible that this conundrum will eventually have less
salience.
Nevertheless, how can todays clinicians arrive at informed
decisions in the face of imperfect information? There are
two strategies that may be helpful. The first is careful
consideration of the most appropriate treatment prior to
initiation of any treatment. Although not infallible, MRI
staging helps to identify relatively small rectal cancers with
low likelihood of nodal involvement. For rectal tumors that
are cT2N0 or cT3N0, it makes sense to consider up-front
surgical resection. Many of these patients will have node-
negative disease and can reasonably avoid systemic therapy.
Patients with node-positive disease require both post-
operative chemoradiotherapy and systemic chemotherapy.
Although less well-tolerated than preoperative treatment, it
is important to recall that the German trial showed similar
OS irrespective of treatment timing.28,60
The second approach to adjuvant treatment recommen-
dations in clinical stage II rectal cancer or in the setting of
pCR to neoadjuvant chemoradiation is to scrutinize the
phenotypic and genotypic tumor characteristics for high-risk
features. Recently, Dalerba et al identified the transcription
factor CDX2 as a negative prognostic factor in stage II and III
colon cancer.72 They found that 4.1% of colon cancers lack
CDX2 expression. In patients with stage II disease, 5-year DFS
was approximately 50% for the subset lacking CDX2 ex-
pression and over 80% for the majority with CDX2 expres-
sion. Moreover, the 5-year DFS was 91% for the 23 patients
with CDX2-positive stage II disease treated with adjuvant
chemotherapy and 56% for the 25 patients with CDX2-
positive disease who did not receive adjuvant treatment.
Though information on the prevalence of CDX2 in patients
with rectal cancer is not yet available, administration of
adjuvant systemic treatment to patients with rectal cancer
lacking CDX2 expression is justified even in the setting of
node-negative disease or pCR, given the magnitude of this
finding. This study highlights the value of including tissue
correlatives alongside clinical trials and using bioinformatics
to identify heterogeneity of risk and treatment re-
sponsiveness. Further discoveries like these practice-
changing results are anticipated and will help us to tailor
adjuvant treatment recommendations to individual risk
profiles.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 99
GARCIA-AGUILAR, GLYNNE-JONES, AND SCHRAG
Practice Guidelines
A considerable body of evidence demonstrates favorable
outcomes among patients with average-risk stage II rectal
cancer treated with chemoradiotherapy who have complete or
near-complete pathologic response without adjuvant systemic
treatment. European and U.S. practice guidelines recommend
treatment decisions tailored to individual patient preferences
but interpret the evidence base somewhat differently. In the
United States, the 2015 National Comprehensive Cancer
Network guideline recommends postoperative adjuvant sys-
temic therapy for all patients treated with neoadjuvant che-
moradiotherapy irrespective of response.73 The inclusion of
oxaliplatin is suggested. In Europe, the European Society of
Medical Oncology guideline advises postoperative chemo-
therapy in stage III and high-risk stage II cancers.74 However, in
some countries, treatment is not consistently recommended in
the setting of complete pathologic response and a recent
European Society of Medical Oncology consensus statement
acknowledges persistent uncertainty.75
In summary, there is still much work to be done in elu-
cidating the circumstances in which adjuvant systemic
chemotherapy can be safely omitted from treatment for
locally advanced rectal cancer. Although there is some ev-
idence to suggest the safety of omitting this treatment for
some patients with stage II locally advanced rectal cancer,
this treatment is indispensable in many situations, notably
for patients with post-chemoradiotherapy invasive or node-
involved tumors and tumors lacking CDX2 expression.
CONCLUSION
All patients embarking on curative-intent therapy for rectal
cancer should be informed of the risks, benefits, and un-
certainties of surgery, chemoradiotherapy, and adjuvant
systemic therapy, the three pillars of treatment. Modern
MRI technology is essential to informed decision making, but
patients comorbidities, natural life expectancy, and pref-
erences must be considered. The conversations about
treatment recommendations must convey risks and benefits
in simple language that takes into account patients
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GASTROINTESTINAL (NONCOLORECTAL) CANCER

Biliary Tract Cancer: The New and

the Old

CHAIR
Mary F. Mulcahy, MD
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chicago, IL

SPEAKERS
John A. Bridgewater, MD, PhD
University College London Cancer Institute
London, United Kingdom

Karyn A. Goodman, MD
University of Colorado School of Medicine
Aurora, CO
BRIDGEWATER ET AL

Biliary Tract Cancer: Epidemiology, Radiotherapy, and

Molecular Profiling
John A. Bridgewater, MD, PhD, Karyn A. Goodman, MD, Aparna Kalyan, MD, and Mary F. Mulcahy, MD

OVERVIEW

Biliary tract cancer, or cholangiocarcinoma, arises from the biliary epithelium of the small ducts in the periphery of the liver
(intrahepatic) and the main ducts of the hilum (extrahepatic), extending into the gallbladder. The incidence and epidemiology
of biliary tract cancer are fluid and complex. It is shown that intrahepatic cholangiocarcinoma is on the rise in the Western
world, and gallbladder cancer is on the decline. Radiation therapy has emerged as an important component of adjuvant therapy
for resected disease and definitive therapy for locally advanced disease. The emerging sophisticated techniques of imaging
tumors and conformal dose delivery are expanding the indications for radiotherapy in the management of bile duct tumors. As
we understand more about the molecular pathways driving biliary tract cancers, targeted therapies are at the forefront of new
therapeutic combinations. Understanding the gene expression profile and mutational burden in biliary tract cancer allows us to
better discern the pathogenesis and identify promising new developmental therapeutic targets.

B iliary tract cancer, or cholangiocarcinoma, arises from

the biliary epithelium of the small ducts in the periphery
of the liver (intrahepatic) and the main ducts of the hilum
(extrahepatic). Extrahepatic biliary tract cancers include
gallbladder cancer, ampullary cancer, and cancer of the
pancreatic biliary ducts. Although extrahepatic cancers arise
from similar epithelia, their etiology can be very different
because of their anatomy.
The incidence of cholangiocarcinoma is modest in the western
world, between 0.35 to 2 per 100,000 annually; however, in
China and Thailand, the incidence can be up to 40 times the rate
observed in the United Kingdom and, thus, poses significant
public health questions (Fig. 1).1,2 The incidence of gallbladder
cancer tends to be closely associated with its primary etiology,
cholelithiasis. As such, the incidence is uniform for most of the
Western world, however, disease clusters are found in northern
India, Japan, and the Andes region (Fig. 2).3
The incidence of intrahepatic cholangiocarcinoma in the
Western world is rising.1 Data from the United Kingdom,
United States, and other countries show a consistent and
steady rise in the incidence of intrahepatic cholangiocarcinoma
from 0.1 to 0.6 per 100,000 over the last 30 years (Figs. 3
and 4).4-10 Several reasons have been cited for this change.
The International Classification of Diseases (ICD) for chol-
angiocarcinoma has been confusing.11 There are multiple
codes for cholangiocarcinoma depending on histology and
topography. This coding has recently changed three times (ICD-
0-1 to ICD-0-2 in 1993 and ICD-0-3 in 2001) and has been
adopted at different times in different countries. In ICD-0-2,
hilar cholangiocarcinoma could be classified pathologically us-
ing a histology code, rather than an anatomic code, but was
cross-referenced to the anatomic code for intrahepatic chol-
angiocarcinoma rather than extrahepatic cholangiocarcinoma.
Furthermore, hilar cholangiocarcinoma could also be correctly
reported as extrahepatic cholangiocarcinoma by using other
histology codes.12 Additionally, there have been local changes in
data collection, such as the loss of independent verification of
cause of death in the United Kingdom in 1993. The terminology
may also be difficult in certain locations such as in England and
Wales, where only 1% of cholangiocarcinomas were classified
as intrahepatic.5
This can be considered as an abrupt step change in the
recorded incidence, such as the step change in incidence in
2001 for intrahepatic cholangiocarcinoma.12 Despite these
noted step changes, the overall pattern is a rise in inci-
dence demonstrated across multiple international data sets.
Changes in technology, such as improved stenting, would
similarly present as step changes, although these are not
discernable in the data. Additionally, the incidence appears
consistent across different tumor sizes and mortality. The
overall picture presents an increase in incidence that ap-
pears to override short-term changes.

From the UCL Cancer Institute, London, United Kingdom; Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO; Northwestern University, Chicago,
IL; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Mary F. Mulcahy, MD, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 676 North St., Clair Suite 850, Chicago, IL 60611;
email: mmulcahy@nm.org.

2016 by American Society of Clinical Oncology.

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FIGURE 1. Incidence of Cholangiocarcinoma
One refuted hypothesis to explain the increase in intra-
hepatic cholangiocarcinoma is the increase in diagnoses
of intrahepatic cholangiocarcinomas that were previously
thought to be metastases from a carcinoma of unknown
origin. Again, if true, this is unlikely to have a substantial
impact on incidence, as the numbers are modest. A number
of criteria have been proposed to help differentiate between
KEY POINTS
The incidence of intrahepatic cholangiocarcinoma in the
Western world is rising, and the incidence of gallbladder
cancer is on the decline.
The tendency for cholangiocarcinomas to recur locally
provides a rationale for additional local therapy after
definitive surgery.
A recent meta-analysis of 10 retrospective studies
evaluating adjuvant radiotherapy after curative
resection for extrahepatic cholangiocarcinomas
demonstrated a significant benefit in overall survival for
patients receiving adjuvant therapy.
The landscape of molecular mutations in biliary tract
cancers has demonstrated multiple new targetable
mutations.
The majority of biliary tract cancer mediators seem to
affect the epigenetics and transcription.
BILIARY TRACT CANCER
intrahepatic cholangiocarcinoma and carcinoma of unknown
origin.13
The incidence of cholangiocarcinoma in Thailand dem-
onstrates the impact of chronic infection with liver fluke.
Liver cancers rival HIV/AIDS, road traffic accidents, and
stroke as a primary cause of death in Thai males.2 Endemic
liver fluke infection (Opisthorchis viverrini) is related to
eating raw or poorly cooked fish over 20 years or longer. The
picture in China and Korea is similar, although the de-
scription of data is less detailed, and the culprit organism is
Clonorchis sinensis.14 Fluke-related cancer has a distinctive
microRNA and mutational profile compared with chol-
angiocarcinoma of the Western world. The relationship to
malignancy appears to be related to the generation of radical
nitrogen species demonstrated in a murine model.
In the Western world, cholangiocarcinoma is associated
with chronic inflammation of the biliary tree and hepatic
parenchyma. The lifetime incidence of cholangiocarcinoma
in hepatitis C is modest at 3.5% at 10 years. The data on
primary sclerosing cholangitis (PSC) suggest a lifetime risk of
7% and rising, corresponding with the increasing incidence
of PSC. As for PSC, this increase is primarily among men age 40
or younger and appears to spare the small ducts.
Gallbladder cancer has a different pathophysiology and is
related primarily, but not entirely, to cholecystitis. The in-
cidence varies from England and Wales (0.1%) to the Czech
Republic (3.7%6.5%) and La Paz in Bolivia (7.5%13.2% per
100,000). The risk factors and demographics for gallbladder
cancer and gallstone disease closely parallel each other. As
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BRIDGEWATER ET AL
FIGURE 2. Incidence of Gallbladder Cancer
such, there is a predominance of women and known risk factors
for gallstone disease (age, obesity, multiple pregnancies, family
history of gallstones, and low levels of physical activity). Chronic
infection is also implicated with the relative risk consequent on
Salmonella (typhi and paratyphi) and Helicobacter (bilis and
pylori) isolation, between 2.6 and 7.5. Interestingly, only 1% of
patients with gallstones develop gallbladder cancer, suggesting
that any screening program should be targeted to higher-risk
groups.
The incidence of gallbladder cancer is decreasing in the
Western world and is related to the increase in routine
cholecystectomy. This is not the case in Chile, where public
health programs have diverted funding for cholecystectomy
to maternity services, resulting in a slow but substantial in-
crease in the rate of gallbladder cancer. Nevertheless, pro-
phylactic cholecystectomy programs have been proposed.
Primary sclerosing cholangitis and natural killer cell poly-
morphisms have been associated with gallbladder cancer.
Choledochal cysts have a 1% to 15% lifetime risk of de-
veloping into gallbladder cancer and cholangiocarcinoma. The
risk of finding malignancy is higher when the diagnosis is made
in adults, but recurrence is rare if it is resected.
ADJUVANT AND DEFINITIVE RADIOTHERAPY
FOR RESECTABLE AND LOCALLY ADVANCED
BILIARY TRACT CANCER
Role of Adjuvant Therapy for Biliary Tract Tumors
Complete resection remains the gold standard of treat-
ment and offers the best chance of cure for patients with
biliary tract cancers. The type and extent of resection are
e196 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
determined by the location of the tumor and the extent of
invasion into adjacent structures. Biliary tract tumors are
generally divided into intrahepatic cholangiocarcinomas,
perihilar and extrahepatic cholangiocarcinomas, and gall-
bladder tumors. For intrahepatic cholangiocarcinomas, which
are less common, a liver resection based on the anatomic
involvement of the liver is performed, whereas for extrahe-
patic cholangiocarcinoma, a pancreaticoduodenectomy may
be required depending on the level of disease within the
biliary tree. Gallbladder cancers are often incidentally found
after a nononcologic surgery, and a repeat oncologic resection
to obtain adequate margins at the liver parenchyma may be
necessary.
Even with a complete resection, the 5-year overall sur-
vival rates range from 21% to 63% for intrahepatic chol-
angiocarcinoma, 30% to 40% for perihilar lesions, and
20% to 54% for distal cholangiocarcinomas managed by
pancreaticoduodenectomy.15-17 The recurrence patterns
differ by primary site in the biliary tract. Investigators at the
Memorial Sloan Kettering Cancer Center reviewed the
patterns of recurrence among 156 patients with extrahe-
patic cholangiocarcinoma and gallbladder tumors who un-
derwent definitive resection. Two-thirds of the patients in
each group developed disease recurrence, with an isolated
locoregional disease as the first site of failure in 15% of
patients with gallbladder cancer compared with 59% of
patients with extrahepatic cholangiocarcinoma (p , .001).
By contrast, 85% of gallbladder cancers had distant spread as
the first site of failure compared with 41% of extrahepatic
cholangiocarcinomas (p , .001).18

FIGURE 3. Age-Standardized Mortality Rates per
100,000 in England and Wales5
Reprinted by permission from Macmillan Publishers Ltd: Gut. Taylor-Robinson SD
et al. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and
Wales 1968-1998. Gut. 2001;48:816-820. 2001.
The tendency for cholangiocarcinomas to recur locally
provides a rationale for additional local therapy after de-
finitive surgery. Although several phase II and retrospective
BILIARY TRACT CANCER
FIGURE 4. Age-Adjusted (1970 U.S. Standard)
Incidence Rates of Primary Intrahepatic
Cholangiocarcinoma in the United States, 197319971
Reprinted with permission. 2001 American Association for the Study of Liver
Diseases. All rights reserved. Patel T: Hepatology. 2001;33:1353-1357.
series suggest a benefit, phase III data are lacking.19-22
Moreover, the indications for postoperative radiation
therapy are not yet clear. The most important prognosti-
cator for survival is a complete (R0) resection23,24; none-
theless, the available data suggest isolated locoregional
recurrence rates of up to 60% after curative resection.25-27
A recent meta-analysis of 10 retrospective studies eval-
uating adjuvant radiotherapy after curative resection for
extrahepatic cholangiocarcinomas demonstrated a sig-
nificant benefit in overall survival for patients receiv-
ing adjuvant therapy.28 The pooled hazard ratio (HR) for
overall survival for the addition of adjuvant radiation
therapy versus surgery alone was 0.62 (95% CI, 0.480.78),
despite the fact that the radiotherapy cohorts more fre-
quently had positive margins (69% vs. 31%; p , 0.001).
The authors concluded that adjuvant radiotherapy ap-
peared beneficial, however, this meta-analysis ulti-
mately only included eight studies on extrahepatic
cholangiocarcinomas. Conversely, a Surveillance, Epidemi-
ology, and End Results (SEER) analysis of adjuvant radio-
therapy failed to show a survival benefit, but the authors
caution that key data, including margin status and the use
of combined chemotherapy that might impact on overall
outcomes for these patients, were not available through the
SEER database.29
The recently reported Intergroup phase II study, led
by the Southwest Oncology Group (SWOG), evaluated
the use of adjuvant chemotherapy (gemcitabine and
capecitabine) followed by chemoradiation (concurrent
radiotherapy and capecitabine) for resected extrahepatic
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BRIDGEWATER ET AL
cholangiocarcinoma or gallbladder tumors. There were a
total of 79 evaluable patients, 21 (32%) of whom un-
derwent an R1 resection and 49 (62%) of whom had ex-
trahepatic cholangiocarcinoma. Two-year overall survival
was 65% for all patients (67% and 60% in R0 and R1, re-
spectively). Median overall survival was 35 months, and
only 14 patients developed a local recurrence.30 Grade 3
and 4 adverse events were observed for 53% and 11% of
patients. These promising data demonstrate the feasibility
of adjuvant chemotherapy followed by chemoradiation for
resected extrahepatic cholangiocarcinoma and gallbladder
tumors.
Adjuvant radiotherapy may also benefit patients with
intrahepatic cholangiocarcinoma due to the high risk of
positive resection margins.15 An analysis of intrahepatic
cholangiocarcinoma patients from the SEER database dem-
onstrated an improvement in median survival for adju-
vant radiotherapy versus surgery alone (11 vs. 6 months,
respectively).31
Definitive Radiotherapy for Biliary Tract Tumors
In cases of unresectable nonmetastatic cholangiocarcinoma,
the use of radiotherapy may improve pain control and bil-
iary decompression. A recent retrospective review of 37 pa-
tients with unresectable extrahepatic cholangiocarcinomas
treated with radiotherapy at Duke University reported 2-year
actuarial overall survival and local control rates of 22% and
71%, respectively. Two patients were alive without evidence
of recurrence at the time of analysis, thus demonstrating long-
term survival in a small subset of patients.32 For intrahepatic
cholangiocarcinoma, a dosimetric analysis of patients treated
at The University of Texas MD Anderson Cancer Center
suggests that a biologically effective dose of greater than
80.5 Gy is associated with improved local control and long-
term survival.33
Several small, single-institution, prospective studies have
evaluated the use of stereotactic body radiotherapy for
hilar and intrahepatic cholangiocarcinomas, suggesting
that the higher dose per fraction is feasible and results in
encouraging local control rates for both peripheral and
central biliary tumors.34-40 Stereotactic body radiotherapy
allows for highly focal dose distributions and sparing of the
surrounding normal tissue; however, given the close
proximity of hilar masses to highly radiosensitive organs
such as the small bowel and stomach, stereotactic body
radiotherapy for hilar cholangiocarcinomas should be used
with caution and preferably on a clinical trial. A recent
multi-institutional phase II study of hypofractionated
proton therapy (median dose 58 Gy) for intrahepatic
cholangiocarcinoma demonstrated a local control rate of
94% and 2-year overall survival of 46%.41 Short-term
morbidity associated with radiotherapy includes nausea,
vomiting, malaise, fatigue, or weight loss and intermittent
fevers due to cholangitis. Long-term complications fol-
lowing radiotherapy are usually related to duodenal bleeding
or stricture.
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Brachytherapy
Brachytherapy has been used at numerous institutions.
Overall, there appears to be a small trend toward improved
survival with its use as a boost.42,43 Dose distributions can be
quite satisfactory with the use of Ir-192 catheters. Ideally, an
external beam dose designed to eradicate microscopic
disease (i.e., 45 to 50 Gy) is given first, followed by seed
placement designed to give an additional high dose to the
site of gross or highly suspect disease. Long-term compli-
cations secondary to the high doses and use of stents can
include stricture, bowel obstruction, and bleeding.
Bridge to Transplant
The role of liver transplantation for unresectable hilar
cholangiocarcinoma has been established by the excellent
results from the Mayo Clinic using 4,500 cGy neoadjuvant
chemoradiation and concurrent fluorouracil and a brachy-
therapy boost followed by liver transplantation.44 The 5-year
survival rate was 82%, which compared favorably to another
group of patients who underwent resection with a 5-year
survival rate of only 21%. It must be emphasized that
transplantation is reserved for highly selected patients, and
selection criteria are quite stringent.
Advances in Radiotherapy Techniques
The advancement of radiotherapy over the last 2 decades
has been a remarkable achievement that has improved
delivery, outcomes, and quality of care for patients with
primary biliary tumors. Historically, radiotherapy for ab-
dominal tumors has been limited by the tolerance of the
surrounding normal organs to even relatively low doses of
radiation. With the emergence of more conformal radio-
therapy techniques and sophisticated treatment-planning
software, more focal treatment fields are now possible.
Classic approaches to portals and fractionation have been
abandoned in favor of more focal techniques of irradiating
liver tumors, such as intensity-modulated radiotherapy,
image-guided radiotherapy, and the use of motion manage-
ment. When planning treatment using intensity-modulated
radiotherapy, the radiation dose is prescribed to the target
volume and strict dose constraints are placed on normal
tissues. A computer-optimized algorithm generates a plan to
deliver radiation of varying intensity to the target volume via
multiple beams or even via multiple arcs to meet the re-
quirements for the target volume coverage and normal
tissue constraints. The overall result is a highly conformal
dose distribution that is customized to the shape of the
tumor. The delivery of conformal intensity-modulated ra-
diotherapy plans is predicated on the ability to accurately
target the tumor during treatment, which has led to the
development of image-guided radiotherapy to reduce the
uncertainties of tumor positioning. Diagnostic-quality im-
aging can now be performed on the linear accelerator to
allow real-time assessment of tumor positioning while
the patient is on the table prior to treatment delivery.
Abdominal tumors can move with respiration, and, thus,

adaptations to account for motion or reduce motion have
been developed to allow accurate delivery of the focal ra-
diotherapy fields while patients are breathing. These motion
management techniques include using an abdominal com-
pression belt to minimize the excursion of the diaphragm
during respiration to reduce motion or to use respiratory
gating where the linear accelerator turn on and off with the
respiratory cycle. In summary, the emerging sophisticated
techniques of imaging tumors and conformal dose delivery
are expanding the indications for radiotherapy in the
management of bile duct tumors.
MOLECULAR TARGETS IN BILIARY TRACT
CANCERS
A majority of biliary tract cancers (. 90%) are well-
differentiated, mucin-producing adenocarcinomas, whereas
a very small proportion are squamous or small cell in
origin.45,46
Patterns of Molecular Drivers in Biliary Tract Cancer
As we understand more about the molecular pathways in-
volved in biliary tract cancers, targeted therapies are at the
forefront of new therapeutic combinations. The landscape
of molecular mutations in biliary tract cancers has dem-
onstrated multiple new targetable mutations. To date, Ross
et al has performed the most comprehensive review of the
molecular profile of biliary tract cancers.47 In this study, DNA
from 412 intrahepatic cholangiocarcinomas, 57 extrahe-
patic cholangiocarcinomas, and 85 gallbladder cancers were
extracted and next-generation sequencing (NGS) was per-
formed on these specimens. Genomic profiling encom-
passed 182 cancer-related genes plus 37 introns from 14
genes frequently rearranged in cancer. These results dem-
onstrate that biliary tract cancers all share genomic
aberrations in cell cycle regulators (specifically CDKN2B)
and chromatin remodeling (ARID1A). Intrahepatic chol-
angiocarcinomas feature FGFR fusions, IDH1/2 sub-
stitutions, BRAF substitutions, and MET amplifications with a
low KRAS mutational frequency.48 ERBB2 amplification and
TABLE 1. Incidence of Molecular Mutations in Biliary Tract Cancer as Determined by Genomic Sequencing
Mutation Intrahepatic Cholangiocarcinoma
ERBB2 Amplification 3%
BRAF Substitution 5%
KRAS 15%22%
PI3KCA Substitution 5%
FGFR1-3 Fusion 11%12.5%
CDKN2A/B Loss 18%
IDH1/2 Substitution 15%23%
ARID1A Alteration 11%20%
MET 4%
BAP1 9%25%
BILIARY TRACT CANCER
PIK3CA/mTOR pathway aberrations were more common in
extrahepatic cholangiocarcinomas and gallbladder tumors.
Mutations in TP53 have been long established in bili-
ary tract cancers, with incidence ranging around 44% to
47%. Incidence is seen more frequently in extrahepatic
cholangiocarcinoma compared with intrahepatic chol-
angiocarcinoma, with rates as high as 17.5% and 8.6%,
respectively.48 Multivariate analysis identified that TP53 and
KRAS are independent predictors of survival.48 Similar fre-
quency and mutational burden were seen in a study by Churi
et al in which NGS was performed using a panel of 46 cancer-
related genes.49 In addition to corroborating the findings by
Ross et al, Churi et al found that genetic aberrations in
chromatin-modulating genes, BAP1 and PBRM1, were as-
sociated with worse overall survival and higher frequency of
bony metastases for patients with extrahepatic chol-
angiocarcinoma. KRAS mutations have been shown to
occur at a higher rate in extrahepatic cholangiocarcinoma
(42%47%) compared with intrahepatic cholangiocarcinoma
(15.7%22%) and gallbladder cancer (11%19.2%), con-
firmed by whole-exome sequencing studies and genomic
profiling studies (Table 1).47-50
Chromatin-remodeling genes BAP1 (encoding a nu-
clear deubiquitinase), ARID1A (encoding a subunit of the
SWI/SNF chromatin-remodeling complexes), and PBRM1
(encoding a subunit of the ATP-dependent SWI/SNF chromatin-
remodeling complexes) have been observed in biliary tract
cancer. The incidence of ARID1A ranges from 11% to 20% in
intrahepatic cholangiocarcinoma specimens, although its
incidence is 12% in extrahepatic cholangiocarcinoma and
11% to 13% in gallbladder cancer.47-49,51 Similarly, BAP1 is
seen in 9% to 25% of intrahepatic cholangiocarcinomas
and 4% to 13% of gallbladder cancers. The incidence of
PBRM1 was 11% to 17% in intrahepatic cholangiocarcinoma,
7.7% in gallbladder cancer, and 3.5% to 5% in extrahepatic
cholangiocarcinoma. The frequency of these chromatin-
remodeling genes indicates that not only is chromatin
remodeling a key component in cholangiocarcinoma, but
these mutations may lend themselves to be sensitive to
therapeutic agents targeting the chromatin-remodeling
genes.47-49,51
Extrahepatic Cholangiocarcinoma Gallbladder Cancer
11% 16%
3% 1%
42%47% 11%19.2%
7% 14%
0 3%
17% 19%
3%4% 0
12% 11%13%
0 0
0 4%13%
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BRIDGEWATER ET AL
Molecular Targets
EGFR. The EGFR pathway is commonly expressed in biliary
tract cancer. According to one study, it is expressed in 100%
of intrahepatic cholangiocarcinomas, 52.6% of extrahepatic
cholangiocarcinomas, and 38.5% of gallbladder cancers.52
Erlotinib, a selective and reversible inhibitor of EGFR, has been
studied in the management of advanced biliary tract cancer in
several phase II studies. In a small phase II study evaluating
erlotinib for 42 patients, overall survival was 7.5 months and
median progression-free survival was 2.6 months.52 However,
definitive conclusions between HER1/EGFR status and re-
sponse rates could not be assessed due to the small sample
size. A large phase III study evaluating the efficacy of gem-
citabine and oxaliplatin with the addition of erlotinib was
conducted among patients with newly diagnosed metastatic
biliary tract cancer.53 A total of 268 patients were randomly
selected to receive either chemotherapy alone or in combi-
nation with erlotinib. The median progression-free survival
was 5.8 months in the combination arm compared with
4.2 months in the chemotherapy-alone arm (p = .087). Overall
survival was the same at 9.5 months in both arms (p = .611).
Erlotinib with chemotherapy failed to demonstrate superi-
ority in this study.
Monoclonal antibodies targeting EGFR used in combination
with chemotherapy have shown some success. Gruenberger
et al performed a phase II study using cetuximab in combi-
nation with gemcitabine and oxaliplatin (GEMOX).54 The
median progression-free survival was 8.3 months and overall
survival was 12.7 months. Interestingly, the response rate
was a remarkable 63%, with 30% of patients undergoing
curative surgery after treatment.
HER2. HER2 (ERBB2) mediates its signaling via the MAPK
and PI3K pathways. Expression of HER2 is seen in approxi-
mately 10% of gallbladder cancers and 26% of extrahepatic
cholangiocarcinomas.52 The California Consortium group
performed a phase II study of lapatinib, a dual HER2 and
EGFR inhibitor, for patients with advanced biliary tract
cancer.55 Among the 17 patients enrolled, no response was
seen in any of the patients. Similarly disappointing results
have been reported in other phase I studies of lapatinib.
VEGF. The VEGF pathway mediates its tumorigenic potential
not just by angiogenesis or vascular permeability, but also by
cell signaling for tumor initiation.50,56 VEGF expression has
been correlated with increasing grade, metastatic potential,
and overall prognosis.57
Bevacizumab, a recombinant humanized VEGF antibody,
has been studied in phase II trials for its efficacy in treatment
of biliary tract cancers. The combination of gemcitabine,
oxaliplatin, and bevacizumab (GEMOX-B) was evaluated
among 35 patients with advanced biliary tract cancer.58
FDG-PET scans demonstrated a significant decrease in
the standardized uptake value (SUV) of the tumors after
two cycles of treatment (p , .0001). The median
progression-free survival was 7.0 months. More recently, a
small first-line study evaluating the combination of
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gemcitabine, capecitabine, and bevacizumab had a median
progression-free survival of 8.1 months and overall survival
of 11.3 months. These results are similar to those ob-
served with traditional chemotherapy. Other antiangiogenic
agents, including sorafenib and sunitinib, have been eval-
uated in advanced biliary tract cancers, with response rates
less than 10% when given as either as monotherapy or as
combination therapy.59-61
PIK3/mTOR. The PI3K/mTOR signaling cascade is crucial for
cell growth and survival. It is a key component of many
cancers. A study documented the rate of activating muta-
tions in PI3K to be approximately 12.5%, exclusively in
gallbladder cancer. BKM120, an oral PIK3CA inhibitor, was
recently under clinical investigation, but the study was
closed due to poor accrual (NCT01501604). The mTOR
pathway has been targeted in several malignancies but has
shown disappointing results in small phase II studies. In an
Italian phase II study of everolimus, the median progression-
free survival was 3.2 months and overall survival was
7.7 months.62 Everolimus was used for patients with first-
line metastatic disease, with a median progression-free
survival of 6.0 months.63 It is unclear if larger studies will
have more promising results.
FGFR. The fibroblast growth factor (FGF) pathway and
fibroblast growth factor receptor (FGFR) genes are in-
volved in multiple biologic processes, ranging from cell
transformation, angiogenesis, and tissue repair to embry-
onic development. This pathway has been targeted
more recently in several malignancies including chol-
angiocarcinoma. Genomic profiling has demonstrated
that FGFR gene alterations are exclusively seen in intra-
hepatic cholangiocarcinoma, and its natural history is more
indolent.49 FGFR mutations and fusions have been observed
in 13.6% of intrahepatic cholangiocarcinomas and in 45%
of intrahepatic cholangiocarcinomas. The documented fu-
sions to date include: FRGR2-TACC3, FGFR2-BICC1, FGFR2-
AHCYL1, FGFR2-PPHLN1, and FGFR2-MGEA5.49,64,65 The
fusion protein results in morphologic changes at the
cellular level causing abnormal cellular proliferation.
There are a number of clinical trials currently under-
way using FGFR antibodies (NCT02508467, NCT02150967,
NCT01752920) and specific FGFR2 antibodies (NCT02368951,
NCT02265341, NCT02450136).
IDH1. Somatic mutations in IDH1 and IDH2 have been well
documented in several different studies and particularly in
intrahepatic cholangiocarcinoma. These mutations cause a
single amino acid change at a conserved arginine residue
within the isocitrate binding site of IDH1 (R132) or IDH2
(R172, R140), resulting in decreased enzymatic activity for
oxidative decarboxylation of isocitrate to a-ketoglutarate.66
It has been shown that inhibition of IDH gain of func-
tion mutations results in reversal of epigenetic methyla-
tion and cancer cell differentiation.67-69 Mutation rates for
IDH1/2 have been observed in 18% to 24% of intrahepatic

cholangiocarcinomas. Further, the rates of IDH1 (15%23%)
are far higher than IDH2 (3%4%) across all reported
intrahepatic cholangiocarcinoma sequencing.47-49,51 Inter-
estingly, 2-hydroxyglutarate, the by-product of enzymatic
activity of IDH1 and IDH2, can be detected in the serum and,
hence, can potentially be used as a biomarker.67,69,70 Studies
evaluating IDH1 inhibitors in cholangiocarcinoma are on-
going (NCT02481154, NCT02073994, NCT02496741)
MEK pathway. Activated RAS starts a phosphorylation
cascade, which involves RAF kinase, MEK1/2, and ERK1/2,
and, ultimately, these affect cellular function. Inhibition of
the MEK/ERK signaling pathway lends itself as a therapeutic
target for biliary tract cancer and other solid malignancies. A
phase II study of selumetinib in advanced biliary tract cancer
had a median progression-free survival of 3.7 months and
overall survival of 9.8 months, with a response rate of 12%.71
Interestingly, 68% of patients had stable disease; at least
12% had stable disease for longer than 1 year. In addition,
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5. Taylor-Robinson SD, Toledano MB, Arora S, et al. Increase in mortality
rates from intrahepatic cholangiocarcinoma in England and Wales
1968-1998. Gut. 2001;48:816-820.
6. von Hahn T, Ciesek S, Wegener G, et al. Epidemiological trends in in-
cidence and mortality of hepatobiliary cancers in Germany. Scand J
Gastroenterol. 2011;46:1092-1098.
7. Alvaro D, Crocetti E, Ferretti S, et al; AISF Cholangiocarcinoma com-
mittee. Descriptive epidemiology of cholangiocarcinoma in Italy. Dig
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8. Witjes CD, Karim-Kos HE, Visser O, et al. Intrahepatic chol-
angiocarcinoma in a low endemic area: rising incidence and improved
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9. Lee T-Y, Lin J-T, Kuo KN, et al. A nationwide population-based study
shows increasing incidence of cholangiocarcinoma. Hepatol Int. 2013;7:
226-232.
10. Utada M, Ohno Y, Tamaki T, et al. Long-term trends in incidence and
mortality of intrahepatic and extrahepatic bile duct cancer in Japan.
J Epidemiol. 2014;24:193-199.
11. Welzel TM, McGlynn KA, Hsing AW, et al. Impact of classification of hilar
cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and
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Inst. 2006;98:873-875.
12. Shaib YH, Davila JA, McGlynn K, et al. Rising incidence of intrahepatic
cholangiocarcinoma in the United States: a true increase? J Hepatol.
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BILIARY TRACT CANCER
the absence of ERK staining was associated with no re-
sponse. These results clearly point toward the MEK pathway
as a potentially promising targetable agent. Clinical studies
using other MEK inhibitors are underway.
CONCLUSION
With dismal overall prognosis for most cases of biliary tract
cancer, new novel therapeutic targets are clearly needed.
Biliary tract cancer is often associated with hypo- and
hypermethylation of promoters. Although several targets
(such as selumetinib and sunitinib) have focused on the
EGFR/HER2/VEGF pathways, the specificity of drugs tar-
geting these agents is likely to be low because the majority of
biliary tract cancer mediators seem to affect epigenetics and
transcription. Understanding the gene expression profile
and mutational burden in biliary tract cancer allows us to
better discern the pathogenesis and identify promising new
developmental therapeutic targets.
13. Al Ansari N, Kim BS, Srirattanapong S, et al. Mass-forming chol-
angiocarcinoma and adenocarcinoma of unknown primary: can
they be distinguished on liver MRI? Abdom Imaging. 2014;39:
1228-1240.
14. Sithithaworn P, Yongvanit P, Duenngai K, et al. Roles of liver fluke
infection as risk factor for cholangiocarcinoma. J Hepatobiliary Pancreat
Sci. 2014;21:301-308.
15. Carpizo DR, DAngelica M. Management and extent of resection for
intrahepatic cholangiocarcinoma. Surg Oncol Clin N Am. 2009;18:
289-305, viii-ix.
16. Jarnagin WR, Shoup M. Surgical management of cholangiocarcinoma.
Semin Liver Dis. 2004;24:189-199.
17. Fong Y, Blumgart LH, Lin E, et al. Outcome of treatment for distal bile
duct cancer. Br J Surg. 1996;83:1712-1715.
18. Jarnagin WR, Ruo L, Little SA, et al. Patterns of initial disease recurrence
after resection of gallbladder carcinoma and hilar cholangiocarcinoma:
implications for adjuvant therapeutic strategies. Cancer. 2003;98:
1689-1700.
19. Ben-David MA, Griffith KA, Abu-Isa E, et al. External-beam radiotherapy
for localized extrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol
Phys. 2006;66:772-779.
20. Cheng Q, Luo X, Zhang B, et al. Predictive factors for prognosis of hilar
cholangiocarcinoma: postresection radiotherapy improves survival. Eur
J Surg Oncol. 2007;33:202-207.
21. Kim TH, Han SS, Park SJ, et al. Role of adjuvant chemoradiotherapy for
resected extrahepatic biliary tract cancer. Int J Radiat Oncol Biol Phys.
2011;81:e853-e859.
22. Todoroki T, Ohara K, Kawamoto T, et al. Benefits of adjuvant radio-
therapy after radical resection of locally advanced main hepatic duct
carcinoma. Int J Radiat Oncol Biol Phys. 2000;46:581-587.
23. Schoenthaler R, Phillips TL, Castro J, et al. Carcinoma of the extrahepatic
bile ducts. The University of California at San Francisco experience. Ann
Surg. 1994;219:267-274.
24. Buskirk SJ, Gunderson LL, Schild SE, et al. Analysis of failure after cu-
rative irradiation of extrahepatic bile duct carcinoma. Ann Surg. 1992;
215:125-131.
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25. Cameron JL, Pitt HA, Zinner MJ, et al. Management of proximal chol-
angiocarcinomas by surgical resection and radiotherapy. Am J Surg.
1990;159:91-97.
26. Gonzalez Gonzalez D, Gerard JP, Maners AW, et al. Results of radiation
therapy in carcinoma of the proximal bile duct (Klatskin tumor). Semin
Liver Dis. 1990;10:131-141.
27. Schoenthaler R, Castro JR, Halberg FE, et al. Definitive postoperative
irradiation of bile duct carcinoma with charged particles and/or pho-
tons. Int J Radiat Oncol Biol Phys. 1993;27:75-82.
28. Bonet Beltran M, Allal AS, Gich I, et al. Is adjuvant radiotherapy needed
after curative resection of extrahepatic biliary tract cancers? A sys-
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Treat Rev. 2012;38:111-119.
29. Vern-Gross TZ, Shivnani AT, Chen K, et al. Survival outcomes in resected
extrahepatic cholangiocarcinoma: effect of adjuvant radiotherapy in a
surveillance, epidemiology, and end results analysis. Int J Radiat Oncol
Biol Phys. 2011;81:189-198.
30. Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809: a phase II
Intergroup trial of adjuvant capecitabine and gemcitabine followed by
radiotherapy and concurrent capecitabine in extrahepatic chol-
angiocarcinoma and gallbladder carcinoma. J Clin Oncol. 2015;33:
2617-2622.
31. Shinohara ET, Mitra N, Guo M, et al. Radiation therapy is associated with
improved survival in the adjuvant and definitive treatment of intra-
hepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 2008;72:
1495-1501.
32. Ghafoori AP, Nelson JW, Willett CG, et al. Radiotherapy in the treatment
of patients with unresectable extrahepatic cholangiocarcinoma. Int J
Radiat Oncol Biol Phys. 2011;81:654-659.
33. Tao R, Krishnan S, Bhosale PR, et al. Ablative radiotherapy doses lead
to a substantial prolongation of survival in patients with inoperable
intrahepatic cholangiocarcinoma: a retrospective dose response
analysis. J Clin Oncol. 2016;34:219-226.
34. Jung DH, Kim MS, Cho CK, et al. Outcomes of stereotactic body ra-
diotherapy for unresectable primary or recurrent cholangiocarcinoma.
Radiat Oncol J. 2014;32:163-169.
35. Mahadevan A, Dagoglu N, Mancias J, et al. Stereotactic body radio-
therapy (SBRT) for intrahepatic and hilar cholangiocarcinoma. J Cancer.
2015;6:1099-1104.
36. Barney BM, Olivier KR, Miller RC, et al. Clinical outcomes and toxicity
using stereotactic body radiotherapy (SBRT) for advanced chol-
angiocarcinoma. Radiat Oncol. 2012;7:67.
37. Ibarra RA, Rojas D, Snyder L, et al. Multicenter results of stereotactic
body radiotherapy (SBRT) for non-resectable primary liver tumors. Acta
Oncol. 2012;51:575-583.
38. Polistina FA, Guglielmi R, Baiocchi C, et al. Chemoradiation treat-
ment with gemcitabine plus stereotactic body radiotherapy for
unresectable, non-metastatic, locally advanced hilar cholangiocarcinoma.
Results of a five year experience. Radiother Oncol. 2011;99:120-123.
39. Goodman KA, Wiegner EA, Maturen KE, et al. Dose-escalation study of
single-fraction stereotactic body radiotherapy for liver malignancies. Int
J Radiat Oncol Biol Phys. 2010;78:486-493.
40. Tse RV, Hawkins M, Lockwood G, et al. Phase I study of individu-
alized stereotactic body radiotherapy for hepatocellular carci-
noma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2008;26:
657-664.
41. Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase II study of
high-dose hypofractionated proton beam therapy in patients with
localized, unresectable hepatocellular carcinoma and intrahepatic
cholangiocarcinoma. J Clin Oncol. Epub 2015 Dec 14.
42. Jarnagin WR. Cholangiocarcinoma of the extrahepatic bile ducts. Semin
Surg Oncol. 2000;19:156-176.
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43. Wolkov HB, Graves GM, Won M, et al. Intraoperative radiation therapy
of extrahepatic biliary carcinoma: a report of RTOG-8506. Am J Clin
Oncol. 1992;15:323-327.
44. Rea DJ, Heimbach JK, Rosen CB, et al. Liver transplantation with
neoadjuvant chemoradiation is more effective than resection for hilar
cholangiocarcinoma. Ann Surg. 2005;242:451-461.
45. Marino D, Leone F, Cavalloni G, et al. Biliary tract carcinomas: from
chemotherapy to targeted therapy. Crit Rev Oncol Hematol. 2013;85:
136-148.
46. Zhu AX, Hezel AF. Development of molecularly targeted therapies in
biliary tract cancers: reassessing the challenges and opportunities.
Hepatology. 2011;53:695-704.
47. Ross JS, Wang K, Catenacci DVT, et al. Comprehensive genomic profiling
of biliary tract cancers to reveal tumor-specific differences and genomic
alterations. J Clin Oncol. 2015;33(suppl; abstr 231).
48. Simbolo M, Fassan M, Ruzzenente A, et al. Multigene mutational
profiling of cholangiocarcinomas identifies actionable molecular sub-
groups. Oncotarget. 2014;5:2839-2852.
49. Churi CR, Shroff R, Wang Y, et al. Mutation profiling in chol-
angiocarcinoma: prognostic and therapeutic implications. PLoS One.
2014;9:e115383.
50. Merla A, Liu KG, Rajdev L. Targeted therapy in biliary tract cancers. Curr
Treat Options Oncol. 2015;16:48.
51. Jiao Y, Pawlik TM, Anders RA, et al. Exome sequencing identifies fre-
quent inactivating mutations in BAP1, ARID1A and PBRM1 in intra-
hepatic cholangiocarcinomas. Nat Genet. 2013;45:1470-1473.
52. Pignochino Y, Sarotto I, Peraldo-Neia C, et al. Targeting EGFR/HER2
pathways enhances the antiproliferative effect of gemcitabine in biliary
tract and gallbladder carcinomas. BMC Cancer. 2010;10:631.
53. Lee J, Park SH, Chang HM, et al. Gemcitabine and oxaliplatin with or
without erlotinib in advanced biliary-tract cancer: a multicentre, open-
label, randomised, phase 3 study. Lancet Oncol. 2012;13:181-188.
54. Gruenberger B, Schueller J, Heubrandtner U, et al. Cetuximab, gem-
citabine, and oxaliplatin in patients with unresectable advanced or
metastatic biliary tract cancer: a phase 2 study. Lancet Oncol. 2010;11:
1142-1148.
55. Ramanathan RK, Belani CP, Singh DA, et al. A phase II study of lapatinib
in patients with advanced biliary tree and hepatocellular cancer. Cancer
Chemother Pharmacol. 2009;64:777-783.
56. Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer.
2013;13:871-882.
57. Quan ZW, Wu K, Wang J, et al. Association of p53, p16, and vascular
endothelial growth factor protein expressions with the prognosis and
metastasis of gallbladder cancer. J Am Coll Surg. 2001;193:380-383.
58. Zhu AX, Meyerhardt JA, Blaszkowsky LS, et al. Efficacy and safety of
gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract
cancers and correlation of changes in 18-fluorodeoxyglucose PET
with clinical outcome: a phase 2 study. Lancet Oncol. 2010;11:
48-54.
59. Bengala C, Bertolini F, Malavasi N, et al. Sorafenib in patients with
advanced biliary tract carcinoma: a phase II trial. Br J Cancer. 2010;102:
68-72.
60. Moehler M, Kanzler S, Woerns S, et al. A randomized, double-blind,
multicenter phase II AIO trial with gemcitabine plus sorafenib versus
gemcitabine plus placebo in patients with chemotherapy-naive ad-
vanced or metastatic biliary tract cancer: first safety and efficacy data. J
Clin Oncol. 2011;29 (suppl; abstr 4077).
61. Yi JH, Thongprasert S, Lee J, et al. A phase II study of sunitinib as a
second-line treatment in advanced biliary tract carcinoma: a multi-
centre, multinational study. Eur J Cancer. 2012;48:196-201.
62. Buzzoni R, Pusceddu S, Bajetta E, et al. Activity and safety of RAD001
(everolimus) in patients affected by biliary tract cancer progressing

after prior chemotherapy: a phase II ITMO study. Ann Oncol. 2014;25:
1597-1603.
63. Yeung YH, Chionh FJM, Price TJ, et al. Phase II study of everolimus
monotherapy as first-line treatment in advanced biliary tract cancer:
RADichol. J Clin Oncol. 2014;32:5s (suppl; abstr 4101).
64. Sia D, Losic B, Moeini A, et al. Massive parallel sequencing uncovers
actionable FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic
cholangiocarcinoma. Nat Commun. 2015;6:6087.
65. Arai Y, Totoki Y, Hosoda F, et al. Fibroblast growth factor receptor 2
tyrosine kinase fusions define a unique molecular subtype of chol-
angiocarcinoma. Hepatology. 2014;59:1427-1434.
66. Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate
dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified
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through broad-based tumor genotyping. Oncologist. 2012;17:
72-79.
67. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet. 2014;383:2168-2179.
68. Rohle D, Popovici-Muller J, Palaskas N, et al. An inhibitor of mutant IDH1
delays growth and promotes differentiation of glioma cells. Science.
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tunities for translational research. BMB Rep. 2015;48:266-270.
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cogenes. Cancer Cell. 2010;17:215-216.
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2011;29:2357-2363.
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GASTROINTESTINAL (NONCOLORECTAL) CANCER

Designing Clinical Trials to

Achieve Breakthrough Results in
Upper Gastrointestinal
Malignancies

CHAIR
Lynn M. Matrisian, PhD, MBA
Pancreatic Cancer Action Network
Manhattan Beach, CA

SPEAKERS
Jordan D. Berlin, MD
Vanderbilt-Ingram Cancer Center
Nashville, TN

Markus Frederic Renschler, MD

Celgene Corporation
Summit, NJ
 LESSONS FROM PANCREATIC CANCER CLINICAL TRIALS

The Past, Present, and Future of Pancreatic Cancer Clinical

Trials
Lynn M. Matrisian, PhD, MBA, and Jordan D. Berlin, MD

OVERVIEW

Upper gastrointestinal malignancies comprise half of the deadliest cancers as defined by those with a 5-year survival rate less
than 50%. Using pancreatic adenocarcinoma (PAC) as an example, we retrospectively evaluated the success of phase III
clinical trials, examined the current landscape of clinical trials, and identified emerging areas that foretell the future for this
disease. Pancreatic and liver cancers are on the rise and will be the second and third leading causes of cancer deaths in 2030.
A total of 35 different agents or combinations have been tested in randomized phase III clinical trials for patients with
advanced PAC over the past 25 years, but only 11% have been incorporated into clinical practice. There has been a 37%
increase in the number of PAC trials open in the United States between 2011 to 2012 and 2014 to 2015. Enrollment has also
increased slightly, from 3.85% of the newly diagnosed cases in 2011 to 4.15% in 2014. However, the demand for patients far
exceeds the number of patients available for these trials. On the horizon is the realization that stratification of patients with
PAC using biomarkers that predict a high probability of a response could reallocate patients to faster, smaller trials with a
greater chance of a survival benefit. The current landscape of PAC clinical trials and the launch of the Pancreatic Cancer
Action Networks Know Your Tumor initiative indicate this shift is starting to occur, with particular emphasis on targeted
therapies, immunotherapies, and agents that disrupt the stroma.

H istorically, the big four cancers in the United States have

been considered lung, colorectal, breast, and prostate
because of their high incidence and mortality rates. How-
ever, trends are changing dramatically, and cancers that
have not been top of mind are becoming increasing
threats to public health in the United States. Eight major
cancers are considered the deadliest, characterized by
5-year survival rates below 50%.1,2 These eight cancers will
account for half of the cancer deaths in the United States this
year, and four of the eight cancers are diseases of the upper
gastrointestinal tract (i.e., pancreas, liver, esophagus, and
stomach).3 This article focuses on PAC, representing 95% of
pancreatic cancer diagnoses and defines the problem from
the perspective of a patient with PAC through the lens of an
advocacy organization and a medical oncologist working in
this field for many years. We outline some of the historical
challenges to successful clinical trial design and execution,
describe efforts currently underway, and highlight future
directions that may bring urgently needed progress to this
deadly disease. These insights provide lessons learned
relevant to deadly upper gastrointestinal malignancies in
general.
Although overall incidence and death rates for cancer in
the United States are declining, pancreatic cancer is on the
rise. It is the only major cancer with a 5-year relative survival
in the single digits. Despite pancreatic cancer being the 11th
most commonly diagnosed cancer in men and 9th in women,
deaths from it surpassed breast cancer and moved to the
third leading cause of cancer-related death in the United
States this year. An estimated 53,070 Americans will be
diagnosed with pancreatic cancer in 2016 and 41,780 are
expected to lose their lives to the disease.3
The threat of pancreatic cancer is only expected to in-
crease in the coming years. A 2014 study predicted that
pancreatic cancer deaths would surpass breast cancer and
further projects that pancreatic cancer deaths will exceed
those caused by colorectal cancer around 2020, positioning
pancreatic cancer as the second leading cause of cancer-
related deaths in the United States before 2030 (Fig. 1).4
Moreover, deaths from liver cancer have surpassed prostate
cancer this year, placing it among the top-five cancer killers
in the United States. Projections show that liver cancer
deaths will continue to rise quickly, leading to it becoming
the third leading cause of cancer-related death in the United
States by 2030.4
The clinical advances required to slow the alarming tra-
jectory of pancreatic cancer deaths will be made as a result
of clinical research. National Comprehensive Cancer Network

From the Pancreatic Cancer Action Network, Manhattan Beach, CA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Lynn M. Matrisian, PhD, MBA, The Pancreatic Cancer Action Network, 1500 Rosecrans Ave., Suite 200, Manhattan Beach, CA 90266; email: lmatrisian@pancan.org.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e205

MATRISIAN AND BERLIN
FIGURE 1. Projected Number of Cancer Deaths, 2010 to 2030
guidelines indicate that a clinical trial is the preferred course
of treatment at all stages of PAC.5 The Pancreatic Cancer
Action Network encourages all patients who call its Patient
Central call center to consider clinical trials when making
treatment decisions. But enrollment rates remain low, and
clinical trials do not always match patients needs, leading to
slow progress and continued poor outcomes for patients. The
KEY POINTS
Deaths from pancreatic cancer are rising, making the
disease the third leading cause of cancer deaths in the
United States in 2016.
Randomized phase III trials over the past 25 years have
resulted in a new standard of care for PAC 11% of the
time.
The number of clinical trials for PAC open in the United
States has increased by 37% over the past 5 years.
Although there has been a slight increase in the number
of patients who enroll in PAC trials from 3.85% in 2011 to
4.15% in 2014, the demand for patients to enroll in trials
far exceed the number of patients available, and it will
take, on average, more than 6 years to accrue those
trials open in 2014.
The landscape of current PAC clinical trials is changing,
with an increase in the number of neoadjuvant trials,
particularly focusing on radiation therapy and an
increase in the number of trials for previously treated
patients, such as for targeted therapies.
The Pancreatic Cancer Action Networks Know Your
Tumor initiative has offered molecular profiling
opportunities to more than 500 individuals from 38
states; 40% of them demonstrate an actionable
alteration that suggests a therapeutic option that
would not otherwise be identified for these
patients.
e206 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
following sections evaluate the past, present, and future of
pancreatic cancer clinical trials.
THE PAST
Progress in advanced PAC can be measured by treatment
options considered clinically meaningful enough to be
available as standard of care to patients: gemcitabine (ap-
proved by the U.S. Food and Drug Administration [FDA]
in 1996), FOLFIRINOX (positive phase III data published in
2011),6 gemcitabine with nab-paclitaxel (FDA approved in
2013) for first-line treatment, and the recent FDA approval
of irinotecan liposome injection (2015) for patients pre-
viously treated with gemcitabine. To achieve this degree of
success, a total of 35 different agents or combinations were
tested in 39 phase III clinical trials in advanced-stage PAC
between 1997 and 2015 (Fig. 2, unpublished data, LR, PhD
2016). Twenty-seven of these were tested in patients with
treatment-naive disease, and eight of the 35 agents or
combinations were tested in patients with previously
treated disease. Although the FDA approved the combina-
tion of gemcitabine and erlotinib in 2005 based on a hazard
ratio (HR) of 0.82 for overall survival, the modest improve-
ment in median survival of 6.2 months compared with
5.9 months with gemcitabine alone7 is generally viewed as
being insufficient to warrant the additional toxicity and
expense of erlotinib. Thus, the overall success rate of PAC
phase III trials is a dismal 11%, despite a prior phase II trial in
the majority of cases.
In the purest sense of trial design, the phase II trial is
written with the ultimate goal that (1) if the primary end-
point is positive, it will lead to a phase III trial, and (2) if
negative, the drug or regimen will not go further in that
setting. However, in 85% of the cases where we could
identify a prior phase II trial, a phase III trial was pursued
irrespective of the phase II not meeting its primary endpoint
(Rahib et al, unpublished data, 2016). The decision to

FIGURE 2. Agents/Combinations in Phase III Clinical Trials for Pancreatic Adenocarcinoma, 1992 to 2015
Abbreviation: FDA, U.S. Food and Drug Administration.
Adapted from Rahib et al (unpublished data, 2016).
proceed was based on encouraging secondary endpoints,
subset analyses results, or a second phase II trial conducted
elsewhere that showed promise. Factors that are not
mentioned but contribute to corporate go/no-go decisions
involve economic and logistic considerations by the trial
sponsors that are influenced by whether the trial is the first
indication for a new drug and by the size of the company.8 If
the past is prelude to the future, there is considerable
concern that the trend of negative phase III trials will
continue and thwart the chance for any major advancement
in PAC survival.
THE PRESENT
The Pancreatic Cancer Action Network maintains a data-
base of pancreatic cancer clinical trials in the United States
that is constantly updated to be able to give those who
contact the Patient Central call center accurate, up-to-date
information on clinical trials that match the patients stage
of disease and that are open within a distance they are
willing to travel. We analyzed the portfolio of pancreatic
cancer clinical trials in 2011 and 2012 by type, phase,
disease stage, and treatment approaches.9 We extended
this study to include the years 2013 to 2015 and report the
results in this article. We are encouraged to find that the
number of PAC-specific clinical trials open in the United
States has steadily increased between 2011 and 2015
(Fig. 3A). This trend is observed for all phases of clinical
trials, with the most dramatic growth observed in phase I
trials (Fig. 3B).
During 2011 to 2012, the majority of PAC clinical trials
were designed for patients with treatment-naive, metastatic
disease (51% of total PAC trials for these 2 years; Fig. 4).
Since then, there has been a dramatic shift toward a greater
number of trials to accommodate patients who have already
been treated. In fact, the majority of the trials during 2014 to
2015 focused on patients with refractory and previously
treated disease (38%), whereas the percentage of first-line
metastatic trials during 2014 to 2015 (22%) decreased by
more than two fold compared with 2011 to 2012. This shift
from metastatic/treatment-naive trials to trials for patients
with previously treated disease is viewed very positively
from a patient perspective. In 2011, we observed that two-
thirds of the patients that call the Pancreatic Cancer Action
LESSONS FROM PANCREATIC CANCER CLINICAL TRIALS
Networks Patient Central were ineligible for 90% of the
clinical trials that were open because they had already
started treatment.9 The increase in clinical trials that include
patients with previously treated disease opens up more
options and encourages a multistep treatment plan that
provides several opportunities for interventions that may
improve survival. In this respect, the study of patients with
more refractory disease in later line is encouraging, but we
acknowledge that due to the severity of this illness risks
missing potentially active agents if had they been studied in
an earlier line of therapy.
For patients with early-stage resectable disease, 13% of
trials were active for neoadjuvant treatment and 10% for
adjuvant treatment from 2011 to 2012. From 2014 to
2015, there was an approximately two fold increase in
trials for neoadjuvant treatment (24% of active trials)
and a slight decrease to 7% of the trials requiring patients
for adjuvant studies (Fig. 4). The increase in neoadjuvant
trials may be attributed to the recognition that even
patients with resectable PAC have dismal outcomes be-
cause of the rapid development of metastatic disease
a clinical observation that was supported with preclinical
evidence in 2012.10 In addition, the eligibility criteria for
neoadjuvant trials have shown an expansion to patients
with borderline resectable disease with the hope that
neoadjuvant treatment shrinks the tumor and permits a
negative margin resection.
The landscape of PAC clinical trials was also examined by
treatment type (Fig. 5A). Trials that focused on therapies
targeted to specific molecular pathways increased markedly
between 2011 and 2015, comprising 29% of the PAC
landscape from 2011 to 2012 and 40% from 2014 to 2015.
The majority of these targeted trials are for patients with
refractory disease and those who received previous treat-
ments (Fig. 5B) and include targets for PARP, JAK, WEE1,
mTOR, and several others.
In addition, trials focused on radiation therapy increased
from 13% of total PAC trials during 2011 to 2012 to 18%
during 2014 to 2015 (Fig. 5A). The majority of these trials
were in the neoadjuvant setting, which comprised 58% of
the total radiation trials from 2014 to 2015 (Fig. 5B). Many of
these neoadjuvant trials (. 50%) used intensity-modulated
radiotherapy or stereotactic body radiotherapy in combi-
nation with chemotherapy.
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MATRISIAN AND BERLIN
FIGURE 3. Pancreatic Adenocarcinoma Trials Open in the United States from 2011 to 2015
(A) Trials open (2011-2015) (B) Trials open by phase.
Trials focused on an immunotherapeutic approach were
relatively steady, with an average of 14 trials per year
over the past 5 years (Fig. 5A). There has been a change,
however, in the stage of disease of treatment. From 2011 to
2012, the majority of trials were for patients with meta-
static disease (52%), whereas from 2014 to 2015 the
majority of immunotherapy trials were for patients with
refractory disease and those who received previous
treatments (62%; Fig. 5B). Approximately 60% of these
trials involved a vaccine treatment, 20% included T-cell
modified therapy, and 7% included checkpoint blockade
therapy.
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As a result of regularly updating clinical trial information
stored in the organizations comprehensive database, the
Pancreatic Cancer Action Network has established strong
relationships with trial sponsors. These relationships
allowed the accumulation of data to estimate the number of
patients with pancreatic cancer in the United States who
were accrued to clinical trials in 2011,9 and this analysis was
repeated for 2014 clinical trials. Considering only those
patients with a PAC diagnosis who enrolled in trials (in
contrast to the previous analysis, which considered all
pancreatic cancer diagnoses), 1,612 patients with PAC en-
rolled in clinical trials in 2011 (93% of trials reporting), and

FIGURE 4. Pancreatic Adenocarcinoma Clinical Trials Open in the United States from 2011 to 2015 by Disease
Stage
1,835 patients with PAC enrolled in clinical trials in 2014
(94% of trials reporting). As a percentage of the estimated
number of new cases of PAC in that year (95% of the es-
timated total pancreatic cancer incidence),3 we calculate
that 3.85% of patients with PAC went on a clinical trial in
2011, and 4.16% went on a trial in 2014.
Although the slight increase is encouraging, the time it will
take to enroll patients with PAC in clinical trials based on this
accrual rate is unacceptably slow. For example, the number of
newly diagnosed patients with resectable disease who could
be eligible for clinical trials for neoadjuvant or adjuvant
treatment approaches in 2014 is estimated to be 4,178
(Table 1). However, the 47 trials that were open in these
categories required 3,437 patients, indicating that 82% of the
eligible patients in the United States would need to go on one
of these clinical trials to complete enrollment during that year.
The actual percentage of enrollment for these trials for 2014
was 10%, indicating that it would take 9.7 years to complete
enrollment of the neoadjuvant/adjuvant trials open in 2014.
On the other hand, it is encouraging that the time necessary to
complete enrollment of trials for patients with locally ad-
vanced and previously treated metastatic disease has de-
creased, from 9.0 years to 3.8 years and 7.1 years to 6.0 years,
respectively (Table 1). Nevertheless, for a disease with a 71%
1-year mortality, it is clear we must identify a new paradigm
for clinical advancement to accelerate progress.
THE FUTURE
There has been a palpable shift away from the nihilistic
attitude toward PAC that bodes well for the future for these
patients. In October 2015, the FDA approved irinotecan li-
posomal injection for patients with metastatic PAC who had
LESSONS FROM PANCREATIC CANCER CLINICAL TRIALS
received prior chemotherapy. Irinotecan liposome injection
was shown to improve overall survival by nearly 2 months
when administered in combination with fluorouracil and
leucovorin. This approval was a historic achievement, as it
was the first drug combination approved with an indication
specific to this patient population.11 As described above, in
the past few years, the amount of clinical trials focused on
patients with previously treated disease has increased. As
oncologists and patients are often eager to begin chemo-
therapy treatments as soon as possible upon diagnosis,
providing expanded options for patients with treatment-
refractory PAC fills a critical gap and has the potential to
positively affect patient outcomes.
Clinical research provides the evidence for treatments that
prolong survival. The randomized phase III trial is the gold
standard for FDA approval of new treatments and accep-
tance as standard of care. However, progress in pancreatic
cancer using this paradigm has been agonizingly slow. A
transformative shift in approach is emerging as a result of
the incorporation of molecular profiling as a basis of iden-
tifying subsets of patients with cancer with a high probability
of responding to a specific treatment. For example, the care
of patients with breast cancer is routinely stratified by their
estrogen receptor and HER2 status, and the genotyping of
nonsmall cell lung cancer for ALK translocations as an in-
dicator of specific chemotherapeutic treatments is be-
coming routine.
The ability to identify those patients whose disease has a
high probability of responding strongly to a specific treat-
ment has enormous implications for clinical trial design. For
example, a treatment with a true HR of 0.4 requires only
70 patients if all the patients enrolled in the trial have the
drug target.12 However, if the trial occurs in an unselected
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MATRISIAN AND BERLIN

FIGURE 5. Pancreatic Adenocarcinoma Clinical Trials Open in the United States from 2011 to 2015 by Treatment
Type
A
5
60 4

Phase 0 Phase I Phase II

50 21
22 Phase III Phase IV
Number of Active Trials

2
24
40

2 19
2
30 2
1 2 1
3 2
18
18
20 39 2
36 19
10 17
1 19
31 21 16 19
1
1 5 1
24 7 3
2 1 6 3 6 17 0
10 7 1 4
3 4 0 5
15 3 0 2 4 2 1
11 3 2 12 12
9 0
1 3 0 9 9 3 1 0
1 10 4
7 8 2 8 2 6 6 8 7
6 6 6 0
1 5 6 5 1 3 5 4 6
0
1 4 3 4 3 3 4 3
1 2 2 1 2 1 1 1
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
Immunotherapy Targeted Stroma Metabolism Radiaon Delivery Opmizaon Miscellaneous

B 70

60
Neoadjuvant
Adjuvant
50 Locally Advanced
31 35
Metastac; treatment nave
Number of Active Trials

27
40 7 Metastac; previously treated

5 3
30 0
4
4 7 1
25 2 2
1 5
2 6 5 3 8 4 6
20 19 24 21 2
21 7 6 1
5 6 3 2
4 6
1 0
3 3 1 2 5 1
1 4 4 6
10 9 19 2 5 1 9
8 8 6 8 5 1
0 0 4 3 4 11 4
7 15 16 1
0
1 0 5
2 2 10 0 1 1 5 5 2 12 6
1 1 3 0
1 1 1 8 9 2 0 3 3 3 7 7 6 2 0
2 3 9 0 3 2 6
3 3 3 2 2 0 5 1 0 2 7 7 7 2
2
1 1 2 1 1 1 2
4 4 0
1
0
2 2 2 0
3 0
1
2 2 2
1 0
1
2
0
1 1 1 1 1
1 2 1
1 2
2 2 0 2
0 0
0 0 0 0 0 0 0 0 0 0 1 1 1
0
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015
2011
2012
2013
2014
2015

Immunotherapy Targeted Stroma Metabolism Radiation Delivery Optimization Miscellaneous

(A) Trials open by treatment type and phase (B) Trials open by treatment type and disease stage

patient population, the number of patients needed is with pancreatic cancer, have resulted in relatively small
proportional to the prevalence of the target. Further, the observed HR and improvement in survival. Given that
observed HR decreases with proportion of patients. The pancreatic cancer is heterogeneous, it seems possible that
same treatment above requiring 70 selected patients, if a missing component is identification of patients who are
evaluated in an unselected population containing 20% of most likely to respond to specific treatments. Continuing
patients with the target, requires 1,750 patients, and the with the paradigm of treating all patients with the same
HR observed is only 0.84. A trial requires 29,620 patients if chemotherapeutic agents will continue to reap low rewards
the marker is present in only 5% of the unselected pop- and squander the precious resource of patients willing and
ulation. Past trials, in large numbers of unselected patients eligible to enroll in clinical trials.

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 LESSONS FROM PANCREATIC CANCER CLINICAL TRIALS

TABLE 1. Anticipated Total and Actual Accrual in the United States in 2011 and 2014
Distribution Est. No. No. of Potential Enrollment Capacity Enrolled Years to
Stage at Diagnosis Year (%) Patients* Trials Enrollment (%)** (%) Completion
Localized ([Neo] 2011 9 3,963 29 2,874 73 15 6.9
Adjuvant)
2014 9 4,178 47 3,437 82 10 9.7
Regional (Locally 2011 28 12,328 16 756 6 13 9.0
Advanced)
2014 28 12,998 12 800 6 27 3.8
Distant (Metastatic) 2011 53 23,336 62 6,394 27 18 6.2
2014 53 24,603 38 3,535 14 15 6.6
Metastatic; Previously 2011 27 11,668 12 524 4 14 7.1
Treated
2014 27 12,301 59 4,364 35 17 6.0
The distribution by disease stage was determined using the Surveillance, Epidemiology, and End Results (SEER) 18 2005-2011 Registry, All Races, both Sexes by SEER Summary Stage
2000 for localized, locally advanced, and metastatic. The number of estimated patients diagnosed with pancreatic cancer for each year was multiplied by 95% to account for pancreatic
adenocarcinomas only. The distribution of previously treated metastatic disease was determined by multiplying the percentage of patients with metastatic disease by 50%, as it is
reported that about 50% of patients with pancreatic cancer are eligible for second-line therapy.36-38
*The number of new patient cases of pancreatic cancer was estimated to be 44,030 for 2011 and 46,420 for 2014.
**Enrollment capacity is total potential enrollment for open trials divided by the estimated number of available patients for 2011 and 2014.

Percentage enrolled is the number of patients enrolled divided by the potential enrollment for trials within that subgroup for which accrual numbers were available for 2011 and
2014.

Years to completion is the number of potential enrollment divided by the accrual numbers (for each subgroup) for which accrual numbers were available for 2011 and
2014.

Is molecular stratification feasible in pancreatic cancer?
Recent genomics analyses have revealed high numbers of
genetic changes that contribute to the initiation and pro-
gression of PAC. Although we know that oncogenic KRAS
drives 95% of PAC cases, more recent studies have shown
greater genetic diversity than previously expected. Efforts
remain underway to devise methods to directly attack KRAS,
which would certainly be game-changing for the treatment
of PAC.13 In the meantime, identifying genetic changes and
signatures that could predict patient response to targeted or
more traditional therapies could have immediate and major
effect on patient care.
Results from the Australian Pancreatic Cancer Genome
Initiative within the International Cancer Genome Consor-
tium defined four subtypes of PAC: stable, locally rear-
ranged, scattered, and unstable. Of particular interest is the
unstable phenotype, which was observed in 14% of the
100 patient samples analyzed. Unstable genomes were found
to contain more than 200 structural variation events, which
often suggests damage to the DNA repair pathways.14 This
group and others have shown that patients with PAC who
have DNA damage repair alterations may be particularly
sensitive to platinum-containing chemotherapeutics and/or
PARP inhibitors. 15-17 A recent paper further refines the
molecular subtypes of pancreatic cancer based on genomic
analysis.18
An additional targeted therapeutic approach involves
assessing patients levels of hyaluronan (HA), which is a
glycosaminoglycan present in the microenvironment sur-
rounding PAC tumors. Hyaluronan contributes to elevated
interstitial pressure, and its inhibition with an agent called
PEGPH20 leads to the expansion of tumor-associated blood
vessels, allowing delivery of other drugs to the tumor.18,19
Interim analyses of a phase II randomized study of patients
with previously untreated metastatic PAC treated with
PEGPH20, nab-paclitaxel, and gemcitabine (PAG) or nab-
paclitaxel plus gemcitabine (AG) were presented at the
2015 American Society of Clinical Oncology Annual Meet-
ing. Among patients with high HA levels treated with PAG,
median progression-free survival was 9.2 months, which
was more than double that observed with AG alone
(4.3 months).20 This ongoing trial represents an example of
customizing treatment to a patients tumor characteristics
and provides promising preliminary evidence in favor of this
approach.
Finally, multiple studies are underway to investigate im-
munotherapy for the treatment of PAC. Pancreatic adeno-
carcinoma is known to be a highly immunosuppressive
disease, rendering immunotherapeutic approaches that
have shown success in other cancer types ineffective as
single agents in PAC. To combat this immunosuppression
and recruit T cells to the PAC microenvironment, immune
checkpoint inhibitors such as antiCTLA-4, antiPD-1, and
antiPD-L1 antibodies are being tested. Preliminary results
suggest that these tactics can be successful in combating
the immunosuppression but do not lead to cancer cell
death. Therefore, focus has shifted to combination of check-
point inhibitors with a therapeutic vaccine strategy or
other agents such as chemotherapy or radiation (e.g.,
NCT02303990).21-25
Correlative studies are revealing stratification approaches
that indicate patients most likely to respond to immuno-
therapeutic approaches, including antiCTLA-4 and anti
PD-1 therapy. A study published in 2015 showed that the
overall mutational load, neoantigen load, and expression of
cytolytic markers in the immune microenvironment of pa-
tients with metastatic melanoma were significantly associ-
ated with clinical benefit to ipilimumab.26 Another study,
also published in 2015 that included patients with nonsmall
cell lung cancer, melanoma, and renal cell cancer, showed

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MATRISIAN AND BERLIN
that nine out of 25 patients with PD-L1positive tumors had
an objective response to antiPD-1 therapy, while all 17
patients with PD-L1negative tumors had no response.27,28
Standardized testing of PD-L1 on tumor cells for the pre-
diction and evaluation of treatment efficacy is needed. In
addition, mismatch repairdeficient tumors may be sensi-
tive to immune checkpoint blockade. Currently, multiple
trials are underway testing the sensitivity of antiPD-1
therapy in this subset of patients in several gastrointes-
tinal cancers, including a phase II trial in patients with
previously treated advanced colorectal cancer,29 a phase III
first-line randomized trial comparing antiPD-1 therapy to
standard chemotherapy in patients with metastatic co-
lorectal cancer,30 and a phase II trial for patients with
previously treated colorectal and other gastrointestinal
cancers. This phase II trial reported promising response to
antiPD-1 therapy in noncolorectal gastrointestinal cancers
with mismatch repair deficiency, including ampullary, pan-
creas, biliary small bowel, and gastric cancers.31
As we gather more genomic, proteomic, and immune cell
information about PAC and accumulate evidence from this
and other cancer types about molecularly targeted treat-
ment approaches, efforts such as the Pancreatic Cancer
Action Networks Know Your Tumor precision medicine
initiative will play an important role in providing patients
access to personalized treatment approaches so that hy-
potheses on the predictive value of these markers can be
tested. Patients with pancreatic cancer across the United
States are able to access Know Your Tumor for multi-omic
molecular profiling information on their tumor by contact-
ing the Pancreatic Cancer Action Networks Patient Central.
A highly trained Patient Central associate determines the
eligibility and interest of the patient in enrolling in the
program and transfers suitable patients to a partnering
organization, Personalized Cancer Therapy, Inc. (doing
business as [d.b.a] Perthera). Perthera obtains patient
consent, talks to the treating physician, facilitates obtaining
suitable biopsy tissue according to standard operating
procedures, and sends the sample to appropriate diagnostic
laboratories. Multi-omic testing is performed, including
genomic, protein, and phosphoprotein analysis. The results
are returned to Perthera for data analysis and integration,
and an expert medical review is conducted that combines
this information with current literature and knowledge of
pancreatic cancer clinical trial results and the patients
history. The medical review team includes a medical on-
cologist with considerable experience and expertise in
treating pancreatic cancer. Treatment options are ranked
and include clinical trials with up-to-date information on
availability from the Pancreatic Cancer Action Network
database, solid tumor phase I trials, off-label treatments,
and standard of care options. The report is sent to the
treating physician, the patient, and the Pancreatic Cancer
Action Network, and outcomes data are collected from both
the patient and the treating physician. All patients using
Know Your Tumor are encouraged to participate in the
Pancreatic Cancer Action Networks patient-reported
e212 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
outcomes registry to obtain more detailed information on
their experience and the outcome of treatment. Since its
inception in June 2014 to December 2015, Know Your Tumor
has enrolled 496 patients with pancreatic cancer from 38
different states.32
There were 175 molecular profiles from Know Your Tumor
participants evaluated as of December 31, 2015. Of the 175
patients with completed reports, 58% were treated at an
academic institution or high-volume center, while 42% were
treated at a community center (Fig. 6). The distribution of
pathologic genomic alterations as determined by analysis
with the Foundation One panel of 343 genes is shown in
Fig. 7.32 Forty percent of patients had at least one actionable
alteration as defined based on a high response rate in pa-
tients with an identified molecular abnormality in any cancer
type, or based on a mechanism/pathway-defined implica-
tion of response to treatment.33 For example, 18% of pa-
tients tumors had alterations in genes involved in DNA
damage repair, including BRCA2, PALB2, ATM, and others
indicated in Fig. 7. These alterations suggest treatment
with a DNA-damaging agent such as platinum and/or a PARP
inhibitor. Based on patient follow-up as of December 31,
2015, 34 patients received their next line of treatment
consistent with the Perthera report, eight of whom enrolled
in a clinical trial and three of whom used an off-label
treatment. In addition, six patients received therapy that
was not indicated by the report. Although the numbers are
small, preliminary analysis suggests an improved outcome
for patients who followed options based on the Perthera
report compared with those who received treatment not
listed on the report (median overall survival 45 vs.
32 weeks).33
Clinical trials for pancreatic cancer are incorporating
biomarkers for patient selection. In January 2016, an analysis
of the Pancreatic Cancer Action Networks clinical trial da-
tabase revealed 21 of 174 (12%) clinical trials required a
molecular indicator for enrollment. It is anticipated that this
percentage will increase over time as more knowledge is
gained and a targeted approach is applied to the deadliest
cancers.
OTHER UPPER GASTROINTESTINAL CANCERS
Similar to pancreatic cancer, other upper gastrointestinal
cancers have also had limited successes. Biliary tract cancer
and hepatocellular cancers each have only one standard
regimen. After initial success with sorafenib as first-line
therapy for hepatocellular carcinoma, multiple other vas-
cular endothelial growth factor receptor (VEGFR) inhibitors
were unsuccessfully tested in phase III trials.34 Although it is
not surprising that other VEGFR inhibitors were tested, it is
remarkable that the sheer number of trials were conducted
and no other targets were evaluated in a substantive manner.
Similarly, based on almost no preclinical evidencesimply
overexpression of the proteinEGFR inhibitors were tested
in multiple randomized studies in gastroesophageal cancer,
all of which were negative.
 LESSONS FROM PANCREATIC CANCER CLINICAL TRIALS

FIGURE 6. Know Your Tumor Recruitment Across the United States and Community and Academic/High-Volume
Sites

The question for the future of all upper gastrointestinal
cancersand all cancers in generalis whether we can start
conducting smarter trials. In 2009, the State of the Science
meeting results for pancreatic cancer were published.35 The
meeting emphasized having preclinical data guide the de-
velopment of the clinical trials, rather than becoming an
afterthought used as rationalization for a planned study. As
noted above, designing clinical trials in the era of person-
alized medicine may allow for smaller trials with greater
effect. Others have recommended n of 1 studies, testing
different agents or combinations for an individual patient,
but how this can be done without simply being an anecdote

FIGURE 7. Pathogenic Alterations Observed by Next-Generation Sequencing in Know Your Tumor Participants

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MATRISIAN AND BERLIN
has yet to be defined. Smarter trials can be smaller, but it
unlikely that one patient can define the utility of a drug.
CONCLUSION
The lessons we have learned from pancreatic cancer reflect
the potential that exists in upper gastrointestinal malig-
nancies in general. Although we celebrate the few successes,
it is essential that we learn from the failures. Clinical trials
must be smarter in their design to conserve the precious
resource of patients willing to enroll in clinical trials. Ap-
plying biomarkers that identify patients with a high prob-
ability of response is one way to leverage remarkable
advances in cancer research with the practical outcome of
reducing the number of patients needed to identify a
clinically meaningful result. Initiatives such as the Pancre-
atic Cancer Action Networks Know Your Tumor provide a
mechanism to disseminate the practice of interrogating the
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molecular characteristics of the tumor from patients across
the United States and learn from them. This will set the stage
for vast improvements in the current approach and rapid
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deadliest cancers.
ACKNOWLEDGMENT
Pancreatic Cancer Action Network staff and associates that
contributed to this work include Lynn Matrisian, PhD, MBA
(concepts, writing, oral presentation); Lola Rahib, PhD (data
analysis, writing, figure preparation); Porsha James, MPH,
and Kyla Holmes (data collection for clinical trial landscape
and accrual); Allison Rosenzweig, PhD (writing); William
Hoos, MBA (concepts); and our partners from Personalized
Cancer Therapy, Inc. (Perthera) and the Know Your Tumor
initiative. We thank all trial sponsors that provided accrual
information.
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initiative: a national program of multi-omic molecular profiling (MoP)
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(suppl; abstr 279).
LESSONS FROM PANCREATIC CANCER CLINICAL TRIALS
33. Pishvaian MJ, Brody JR, Matrisian LM, et al. Multi-omic profiling (MoP)
for patients (pts) with pancreatic cancer (PDA): initial results of the
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282).
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4524).
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GASTROINTESTINAL (NONCOLORECTAL) CANCER

HER2, VEGFR, and Beyond:

Genomic Profiling of Upper
Gastrointestinal Tract Cancers
and the Future of Personalized
Treatment

CHAIR
Jaffer A. Ajani, MD
The University of Texas MD Anderson Cancer Center
Houston, TX

SPEAKERS
Adam J. Bass, MD
Dana-Farber Cancer Institute
Boston, MA

Jeeyun Lee, MD, PhD

Samsung Medical Center
Seoul, South Korea
LEE, BASS, AND AJANI

Gastric Adenocarcinoma: An Update on Genomics, Immune

System Modulations, and Targeted Therapy
Jeeyun Lee, MD, PhD, Adam J. Bass, MD, and Jaffer A. Ajani, MD

OVERVIEW

Gastric adenocarcinoma (GAC) is a global health burden on all societies, and it was the third-leading cause of cancer-related
mortality in 2012, causing 723,000 deaths worldwide. The prognosis of patients with metastatic GAC remains poor, with a
median overall survival of less than 1 year in patients treated with currently available therapies. A limited number of
therapeutic agents is currently available. Recent additions to the armamentarium include trastuzumab and ramucirumab,
which have shown some survival advantage when added to cytotoxic(s). Genomic analyses have defined various genotypes
of GACs. The novel genomic knowledge can lead to discovery of novel targets and novel therapeutic agents. In this update,
we focus on the current genomic data, targeted therapies including immune system modulators, and expand on HER2/neu
testing and the use of agents against this target. Several other facets of GAC and its therapy are not to be included in this
review but have been discussed elsewhere.

D eeper analysis of the genomic and molecular features of

GAC can provide multiple benefits to the study and
development of therapy for GAC that is clearly a hetero-
geneous entity. Gastric adenocarcinoma has been divided
into two primary histologic variants: the intestinal and
diffuse types. Beyond histology, there is discussion regarding
the differences in the GAC in Eastern and Western patients,
different features of GAC in the distal versus proximal
stomach, and differences relating to distinct molecular
etiologies and molecular subtypes of GACs. In this context,
modern genomic and molecular analyses can help delineate
subtypes of GAC and identify salient molecular features of
these distinct classes, information that is increasingly es-
sential to guide therapy, especially emerging targeted and
biologic agents.1-9
Recent years have witnessed a revolution in the capacity to
genomically and molecularly describe cancer. As these
technologies have become less costly, there have been
several large-scale efforts to molecularly detail this cancer.
Here, we will discuss two recent substantial efforts in this
realm, studies emerging from the Asian Cancer Research
Group10 (ACRG) and from The Cancer Genome Atlas11
(TCGA). TCGA, a consortium from the National Institutes of
Health, collected primary untreated gastric samples from
institutions across the world. These samples were all sub-
jected to a diverse array of molecular analyses including
whole-exome sequencing, microarray profiling of genomic
amplifications and deletions, messenger RNA (mRNA) and
micro-RNA expression analysis, and genome-wide DNA
methylation analysis with some samples also analyzed with
whole-genome sequencing or proteomic analysis. By con-
trast, the ACRG GAC study accrued from a single referral
hospital in South Korea, providing a more homogenously
treated cohort with richer clinical annotation relative to the
TCGA study. The ACRG samples were subjected to more
limited analysis including mRNA expression, somatic copy
number, and focused gene sequencing.
Each of these projects developed a four-group classifi-
cation structure for GAC, with these classification ap-
proaches having some overlapping but also distinct features.
The ACRG categories were determined on the basis of gene
expression profiling with the following features of GAC: (1)
microsatellite instability, (2) epithelial-to-mesenchymal tran-
sition (EMT) phenotype, (3) a p53 signature (CDKN1A and
MDM2 expressing), or (4) no p53 signature. Of these groups,
the cohort with microsatellite instability had improved sur-
vival, whereas the EMT group, which was composed mostly of
diffuse-type tumors, showed inferior survival. Furthermore,
after surgical resection, those with the EMT signatures also
showed greater rates of recurrence and an association with
subsequent peritoneal metastases. Although this EMT group
was largely diffuse-type tumors, the tumors in this group

From the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Kangnamgu, Seoul, South Korea;
Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson
Cancer Center, Houston, TX.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Jaffer A. Ajani, MD, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston,
TX 77030; email: jajani@mdanderson.org.

2016 by American Society of Clinical Oncology.

104 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


lacked other features that have been seen commonly in
diffuse GAC, such as mutation of CDH1, the gene responsible
for hereditary diffuse GAC, and recently identified DGC mu-
tations of the RHOA GTPase.12,13 As predicted, the cohort of
samples with deficient p53 activity possessed greater aneu-
ploidy and accompanying amplifications of oncogenes in-
cluding ERBB2 (HER2).
The TCGA classification derivation differed from the ACRG
in that it was based upon an integration of six distinct mo-
lecular platforms as opposed to the reliance upon mRNA
expression. Based upon observations from the molecular
data, tumors were divided into four groups: (1) GACs positive
for Epstein-Barr virus (EBV), (2) microsatellite instability, (3)
chromosomally unstable, and (4) genome stable. The latter
genome stable group represented the remnants after the
groups with EBV and microsatellite instability were excluded
and the remaining GACs were divided based upon possession
of aneuploidy (chromosomally unstable) or its absence (ge-
nome stable). A first notable difference compared with the
ACRG was that EBV-positive tumors emerged as a distinct
entity. This difference likely follows the inclusion of DNA
methylation analysis, which revealed a strong and highly
distinguishing methylation signature in this cohort. Beyond
methylation, however, EBV-positive GACs possess other
clinically relevant findings, including highly recurrent PIK3CA
mutations and genomic amplification of the genes encoding
PD-1 pathway activators PD-L1 and PD-L2, suggesting the
possible roles for PI3K pathway inhibitors, emerging immune
checkpoint agents, and, perhaps, DNA hypomethylating
agents. Like microsatellite instability GACs, EBV-positive GACs
have also been described to have a favorable phenotype.14
KEY POINTS
Patients with advanced GAC continue to have poor
quality of life, short survival, and limited therapeutic
choices. Many patients do not have access to clinical
trials when standard regimens have failed.
The empiric approaches that assume one-size-fits-all
have been ineffective methods to improve the outcome
of patients with GAC. Alternatives and customized
approaches must be considered.
The Cancer Genome Atlas study of GACs has uncovered
four genotypes with unique features. This discovery
needs to be fully exploited to find novel targets and
effective drugs.
Trastuzumab and ramucirumab (in combination with
cytotoxic[s]) have produced only minimum/modest
benefit for patients with GAC, emphasizing the need for
better therapies.
Since early results from checkpoint inhibitors show
promising results in some patients with GAC, rationally
designed multiprong approaches that combine immune
modulation, targeted agent(s), and conventional
cytotoxics may prove more advantageous than all
previous approaches.
GASTRIC ADENOCARCINOMA
Microsatellite instability was found as a distinct group by
the TCGA as well as ACRG effort. Microsatellite insta-
bilitypositive GACs possess marked hypermutation as a
result of the underlying defect in DNA mismatch repair.
These tumors also possess a relatively bland genomic copy
number pattern lacking frequent genomic amplifications of
genes such as ERBB2. However, a number of likely path-
ogenic mutations exist within this cohort, including mu-
tations in targetable genes such as ERBB2, ERBB3, and
PIK3CA, as well as oncogenes such as KRAS that lack ef-
fective inhibitors. A notable contrast with MSI-positive
colorectal cancer was the lack of activating BRAF mutations
within these GACs. One notable question regarding
microsatellite instability tumors, whose high mutation
burdens generate large number of neoantigens, will be the
potential efficacy of immune checkpoint inhibitors as have
shown efficacy in microsatellite instabilitypositive co-
lorectal cancers.15
Like the EMT group from the ACRG, the TCGAs genome
stable group primarily consist of those with diffuse histology.
The GACs in this so-called genome stable group get their name
from their lack of the hypermethylation prevalent in EBV-
positive, the hypermutation of microsatellite instability, or the
marked aneuploidy in chromosomally unstable GACs. Al-
though both the genome stable and EMT tumors were largely
diffuse type, their molecular features did differ as evidenced
by the common finding of both CDH1 and RHOA mutations in
the TCGA genome stable set. Despite these differences, results
from these two classification schemes provide insights into
diffuse GAC. First, GACs with diffuse histology span molecular
subtypes including those with microsatellite instability, EBV,
and marked aneuploidy. However, diffuse types are generally
less enriched in classic oncogenes and therapeutic targets such
as KRAS or ERBB2 that are more prevalent in other groups of
GACs, speaking to the clear remaining need to identify new
therapeutic approaches and vulnerabilities for these highly
aggressive tumors.
The largest group in the TCGA analysis, the chromosomally
unstable tumors, matches most closely the p53-deficient
tumors from the ACRG schema. As their names suggest,
the salient features of these GACs are the high degree of
structural genomic aberrations, leading to a high frequency of
genomic amplifications of bona fide oncogenes such as re-
ceptor tyrosine kinases ERBB2, EGFR, MET, or FGFR2; cell cycle
mediators such as CCND1, CCNE1, and CDK6; and transcription
factor oncogenes such as GATA4, GATA6, and MYC. These
genomic data speak for the potential for inhibitors for targets
other than HER2 to ultimately have roles in GACs. Indeed, the
emergence of approved inhibitors targeting specific cell cycle
kinases, such as the CDK4/6-directed agent palbociclib, should
be evaluated in specific sets of patients guided by genomic
data.
Comparing the TCGA chromosomally unstable group and
the ACRG p53-negative group, a notable difference is that
the TCGA chromosomally unstable class comprises a much
more substantial fraction of the total tumors than does the
p53-negative group. This difference may reflect not only the
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LEE, BASS, AND AJANI

TABLE 1. Major Clinical Trials in Gastric Adenocarcinoma With Targeted Agents

Patient Results
Type of Selection (Primary
Target Trial Study/Line Method Regimen Endpoint) Reference
HER2 ToGa Phase III/first HER2 IHC 5-FU/capecitabine + Positive (OS) Bang et al 20105
cisplatin 6 trastuzumab
HER2 LOGIC Phase III/first HER2 Lapatinib + XELOX Negative (OS) Hecht et al16
amplification
XELOX
HER2 TYTAN Phase III/second HER2 Paclitaxel + lapatinib vs. paclitaxel Negative (OS) Bang et al (2013)17
amplification
EGFR EXPAND Phase III/first All comer Cetuximab/XP vs. placebo/XP Negative (OS) Lordick et al18
EGFR REAL-III Phase III/first All comer Panitumumab/EOC vs. EOC Negative (OS) Waddell et al19
EGFR Nimotuzumab Phase II/second All comer Nimotuzumab/irinotecan vs. Negative Kim et al20
irinotecan
VEGF AVAGAST Phase III/first All comer XP/bevacizumab vs. XP Negative (OS) Van Cutsem et al21
MET RILOMET-1 Phase III/first MET IHC Rilotumumab/ECX vs. ECX Negative (OS) Iveson et al22
MET METGastric Phase III MET IHC Onartuzumab/FOLFOX vs. FOLFOX Negative (OS) Shah et al23
FGFR2 SHINE R-Phase II/second FGFR2 AZD4547/paclitaxel vs. paclitaxel Negative (PFS) Bang et al (2015)24
amplification
mTOR GRANITE Phase III/second All comer Everolimus vs. placebo Negative (OS) Ohtsu et al25
or third
AKT MK2206 Phase II/second All comer MK-2206 Response rate, 1% Ramanathan et al26
ATM Olaparib R-Phase II/second ATM IHC Paclitaxel/olaparib vs. Negative (PFS) Bang et al (2015)27
paclitaxel/placebo
VEGF MEGA R-Phase II/first All comer FOLFOX/aflibercept vs. FOLFOX Negative (6-mo PFS) Enzinger et al28
HER2 GATSBY Phase II/III/ second HER2 IHC TDM1 vs. paclitaxel or docetaxel Negative (OS) Kang et al29
VEGFR-2 RAINBOW Phase III/second All comer Paclitaxel/ramucirumab vs. Positive (OS) Wilke et al30
paclitaxel/placebo
VEGFR-2 REGARD Phase III/third All comer Ramucirumab vs. placebo Positive (OS) Fuchs et al31
Abbreviations: OS, overall survival; XP, capecitabine (Xeloda) and cisplatin; EOC, epirubicin, oxaliplatin, and capecitabine; IHC, immunohistochemistry; ECX, epirubicin, cisplatin, and
capecitabine; PFS, progression-free survival.

different classification schema but also the differences in the
populations studied. Chromosomally unstable tumors were
more prevalent in the proximal stomach, whereas other
groups were more prevalent in more distal regions. It is
well recognized that GAC in Western populations has, in
recent years, become increasingly a disease of the proximal
stomach, mirroring the rise of esophageal adenocarcinoma.
As this subset may be a more aneuploidy variant of GACs, a
cohort such as the TCGA group with more Western patients
would be expected to harbor higher degrees of aneuploidy.
Indeed, in the ACRG cohort, the percentage of diffuse-type
GACs was higher and proximal GACs lower than in the TCGA
study. Regardless of this difference, the prevalence of dis-
tinct oncogene amplification events in these tumors does
speak for the potential of these different alterations to serve
as biomarkers to guide therapy.
Overall, the most important lesson of these differences is
that it is beyond the time to try to devise singular approaches
for GAC. There are substantial molecular and etiologic dif-
ferences across these GACs. Furthermore, even within a
single molecular subtype, there remains highly relevant
heterogeneity. For example, even among the highly aneu-
ploidy GACs, optimal treatment of an ERBB2-amplified and
MET-amplified GACs will clearly differ. As we move forward
to developing new therapies, we will have to take into ac-
count this clear molecular heterogeneity that relates to
different etiologies of genomic instability, different micro-
bial etiologies, and GACs possessing distinct driving somatic
alterations. These differences will impact our approaches
both to standard conventional therapy, emerging targeted
therapies, and immunotherapy.
TARGETED THERAPIES AND IMMUNE SYSTEM
MODULATION TO TREAT GASTRIC
ADENOCARCINOMA
Table 1 summarizes representative important clinical trial
results in GAC.
Negative trials with targeted agents have substantially
outnumbered the positive trials (the ToGA, REGARD, and
RAINBOW trials) in GAC in the past decade. Among other
factors, major factors accounting for this negative outcome
may be (1) many trials did not select the patient population
based on specific target (lacking any biomarker) and did not
account for distinct molecular subtypes and how they may
impact response to therapy, (2) inaccurate biomarker for
selection patient selection (i.e., HER2, fluorescence in situ
hybridization [FISH] vs. HER2 immunohistochemistry [IHC];
FGFR2 FISH vs. FGFR2 IHC; MET FISH vs. MET IHC). There may

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be many other factors influencing the failure of various drugs
when investigated in the clinic.
In general, for the targeted agents, clinical trials in GAC for
unselected patient population have been largely disap-
pointing. One clear example is the EXPAND trial, where EGFR
inhibitors were given to all patients despite the prevalence of
EGFR gene amplification occurs in only approximately 5% of
GACs and EGFR protein overexpression in approximately 15%
to 20% of patients with GAC. Another EGFR-directed study
in unselected patients, the nimotuzumab/irinotecan second-
line trial, also failed to demonstrate survival benefit. However,
in subgroup analysis of the EXPAND trial, a subset of patients
with high EGFR overexpression by IHC showed survival benefit
from cetuximab compared with placebo.32 In line with this,
in the randomized phase II trial of nimotuzumab/irinotecan
versus irinotecan, a subset of patients with EGFR 2+/3+ by
IHC demonstrated superior progression-free survival (PFS)
and overall survival (OS).33 Based on this finding, a phase III
trial of nimotuzumab/irinotecan versus irinotecan with pa-
tients selected based upon EGFR2/3-positive IHC is currently
ongoing.
Recently, another disappointing result came from the
phase III RILOMET-1 trial that compared rilotumumab in
combination with epirubicin/cisplatin/capecitabine (ECX)
versus ECX alone as first-line chemotherapy administered
in patients with MET-positive GAC. There was worse sur-
vival in the arm containing the anti-HGFtargeted agent
rilotumumab.34 Moreover, there were no subgroups shown
to benefit from rilotumumab including those patients with
higher percentages of cells with greater than or equal to +1
MET expression by IHC.34 It is not yet reported whether
genomic amplification of the gene encoding MET influenced
survival or response to this agent. However, a phase I trial of
the MET kinase inhibitor AMG337 with 13 patients with
MET-amplified GAC demonstrated a response rate of 62%.35
Intriguingly, 40% to 50% of patients with MET-amplified GAC
enrolled on AMG337 trial harbored coamplification of HER2
and/or EGFR concurrently, suggestive of patients who might
benefit from combination targeted therapy.36 To further add
to the complexity, there was a substantial heterogeneity and
discordance in MET amplifications between the primary and
metastatic lesions in a single studied patient with GAC.
Hence, molecular profiling of a single tumor biopsied may
not be inadequate to guide targeted therapy in GAC.
Another lesson can be learned from the SHINE trial that
compared AZD4547, an FGFR2 inhibitor, administered in
patients with FGFR2-amplified GAC in the second-line
setting. Despite strong preclinical evidence for AZD4547
in FGFR2-amplified GAC preclinical models, the SHINE trial
failed to meet the primary endpoint, PFS, when AZD4547
was added to paclitaxel.24 The trial screened 960 patients
and randomly assigned 71 patients with 9% prevalence for
FGFR2 amplification. Although that trial was negative, in an-
other phase II trial with AZD4547 in FGFR1-, 2-, and 3-amplified
cancer, three of nine (33%) patients with FGFR2-amplified
GAC experienced a partial response. Notably, all responding
patients had FGFR2 copy number gain demonstrated in
GASTRIC ADENOCARCINOMA
plasma DNA and high FGFR2 copy number gain,37 suggesting
that optimal use of biomarkers may mark those for whom
this target may be effective. Hence, although the SHINE trial
did not meet its primary endpoint, it is not yet conclusive to
preclude FGFR2 inhibitor from clinical development, but
more optimized biomarker selection criteria are needed for
the future FGFR2 inhibitor trials.
There is emerging evidence that pembrolizumab/nivolumab
blocks binding of PD-L1 to its receptor, PD-1, resulting in T-cell
activation/proliferation. KEYNOTE-012, a phase IB study of
pembrolizumab in patients with metastatic GAC and PD-L1
tumor cell positivity by IHC demonstrated promising results.38
MEDI4736, another antiPD-L1 antibody, also has demon-
strated promising activity in GAC in an initial analysis.
Is It Time for Umbrella Trials in GAC?
Recently, even further complicating the clinical develop-
ment of targeted agents in GAC, TCGA and ACRG10,11
published comprehensive genomic data, and both groups
have reported on molecular subtypes of GAC (detailed
earlier). Given the tumor heterogeneity among patients
with GAC and within each patient, an umbrella trial has
been recently introduced.39-41 An umbrella (or basket) trial
investigates a single tumor type selected according to the
biomarkers relevant to one or more of the candidate drugs
and patients and directed toward different arms of the study
according to the molecular characteristics of the tumor.39
The Personalized Antibodies from Gastro-Esophageal Ade-
nocarcinoma (PANGEA) trial selects patients with GAC
according to biomarker status, such as MET amplification,
FGFR2 amplification, and KRAS amplification, to different
arms in first-line setting. Another trial, the Targeted Agent
Evaluation in Gastric Cancer Basket Korea (VIKTORY), assigns
patients with metastatic GAC according to RAS amplification,
RAS mutation, TP53 mutation, PIK3CA mutation, MEK high
versus low signature, MET amplification, and MET protein
overexpression to corresponding treatment arms in second-
line treatment. Patients without any of the designated
markers receive either mTOR inhibitor or Akt inhibitor with
paclitaxel.
HER2/NEU AS TARGET IN GASTRIC
ADENOCARCINOMA AND AN UPDATE ON HER2/
NEU TESTING
A small fraction of GAC in patients overexpresses HER2/neu
protein or have increase copy number of the ERBB2 gene.
The HER2/neu receptor is one of the four receptors in the
EGFR family. The intracellular domain has tyrosine kinase
activity. The HER2/neu receptor can be targeted by an
antibody (such as trastuzumab or pertuzumab, which can
prevent homodimerization or heterodimerization with other
family members) against the extracellular domain or re-
ceptor tyrosine kinase small-molecule inhibitors (such as
lapatinib). There have been several prospective phase III
trials that have investigated inhibition of HER2/neu signaling
in patients with HER2/neu-positive GAC.5,16,42 However,
only the ToGA trial showed statistically significant benefit
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LEE, BASS, AND AJANI
(p = .0046).5 Therefore, the use of trastuzumab in combi-
nation with chemotherapy in patients with HER2/neu-pos-
itive metastatic GAC is now considered a standard. We
discuss various aspects of targeting HER2/neu pathway and
HER2 testing.
The Receptor
The HER2/neu receptor is unique in that it lacks the ligand
binding cleft for extracellular growth factors that other
ERBB3 family members have. Its dimerization loop is ex-
tended like others, and the intracellular domain has ATP-
binding cleft.43 The ERBB2 gene, encoding HER2/neu, is
often amplified in many cancers including a fraction of GACs
(including in some squamous cell carcinoma of the esoph-
agus). The drugs that can inhibit HER2/neu receptors are
well described in a recent review.43 However, primary and
secondary resistance to HER2/neu inhibition, as with other
single targets, is a likely inevitable and universal phenom-
enon.44 Common mechanisms of HER2/neu directed ther-
apy resistance have not been extensively studied in GAC,
but, in breast cancer, it has been seen because of PTEN loss,
truncation of the receptor, activating mutations in PIK3CA,
or upregulation of other oncogenes (IGF1 or ERBB3).43,44
HER2/neu Test Results in Various Settings
In routine use, the presence of strong (3+) IHC staining has
been shown to have strong concordance with the presence
of amplification of ERBB2, leading this protein test alone to
be sufficient to guide the use of trastuzumab.5,45 However,
one issue to consider is the considerable heterogeneity in
staining for HER2/neu and the potential adequacy of a single
small biopsy to accurately assess HER2 status (as opposed
to a surgical specimen46-48). How many unique specimens
should be tested also remains unresolved.49-51 Similarly,
technical issues regarding the optimal copy numbers cutoffs
to use to guide use of anti HER2/neu agents are also a subject
of debate.52 In addition, whether there is concordance in
HER2/neu results if metastatic cancer or primary cancer is
tested, remains generally unresolved.53-55 Regarding prog-
nostic significance, HER2/neu positivity in a GAC does not
confer poor prognosis, but there are reports to refute this as
well.56-63
Testing for HER2/neu
Currently, we recommend the guidelines outlined by the
National Comprehensive Cancer Network (NCCN)64,65 until
formal guidelines to be published jointly by the American
Society of Clinical Oncology, College of American Patholo-
gists, and American Society of Clinical Pathologists become
available in early 2016. Patients with gastroesophageal
adenocarcinoma who have unresectable, advanced cancer
should be tested for HER2/neu, starting with IHC. If it is 3+
(positive), 1+ (negative), or 0 (negative), no further testing is
required. However, if it is 2+ (equivocal), then FISH for
amplification of ERBB2 is recommended. Currently, any
available tumor tissue should be tested.
108 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
In a biopsy specimen of GAC (or gastroesophageal ade-
nocarcinoma), if 5% of cells adequately stain for HER2/neu,
this is currently considered adequate to designate a positive
HER2/neu status; however, the presence of positive staining
in such a small fraction of the sampled area raises obvious
questions of sampling and whether such few cells really
represent the entire tumor (including metastatic tumor).
However, from surgical specimen, at least 10% of cells must
stain for HER2/neu designation. This is a bit better but still
raises the same questions.
Clinical Trials
The ToGA trial screened 3,803 patients with untreated,
advanced gastroesophageal adenocarcinoma and randomly
assigned 594 patients with HER2/neu positive tumors (as
defined for the purposes of this trial) to receive either
chemotherapy (fluoropyrimidine/cisplatin) and trastuzu-
mab or chemotherapy. The primary endpoint of improved
overall survival was achieved (13.8 months vs. 11.1 months;
p = .0046). Other endpoints (PFS and increase in response
rate) were also met. Trastuzumab was found safe to deliver
with standard chemotherapy. This trial led to worldwide
regulatory approval of trastuzumab and clinical adoption.
However, the benefit from trastuzumab diminished con-
siderably when the results were reanalyzed after a longer
follow-up by the U.S. Food and Drug Administration (the
hazard ratio increased from 0.73 to 0.80, and the overall
survival difference narrowed to a meager 1.4 months). This
would suggest considerable heterogeneity among patients
with HER2/neu-positive GACs and need for better agents.
This modest impact also suggests the need to refine our
identification of possible gradations of HER2/neu-positive
GACs. Furthermore, these results speak strongly to the need
to develop additional treatments for patients with HER2/
neu-positive GAC, both for up-front therapies and when the
resistance emerges.
In contrast to the ToGA trial of the therapeutic antibody
trastuzumab, results have been disappointing for HER2-
directed kinase inhibitors. Two trials studied the re-
versible EGFR/ERBB2 inhibitor lapatinib in the second-line
setting42 and in the first-line setting,16 both yielding
negative results. Ado-trastuzumab emtansine (T-DM1) is
an antibody-drug conjugate consisting of antibody
(trastuzumab) and cytotoxic (DM1). The EMILIA trial for
patients with HER2/neu-positive breast cancer was pos-
itive, resulting in a survival benefit of 5.8 months; how-
ever, a T-DM1 trial for HER2/neu-positive GAC in the
second-line setting was a disappointment.66 Currently,
trials are ongoing with higher doses of trastuzumab to
improve exposure and another that adds the second
antibody pertuzumab to trastuzumab in comparison with
trastuzumab (the JACOB trial). Additional mechanistic
study into the molecular effects of specific classes of anti-
HER2/neu agents and the mechanistic etiologies of both
de novo and acquired resistance are required to
establish a foundation for rational development of new
approaches for to target HER2-positive GACs.

FUTURE DIRECTIONS
Gastric adenocarcinoma remains a deadly disease with
significant molecular and histologic heterogeneity. Trials of
empirical chemotherapy, largely with a one-size-fits-all
approach have led to modest survival benefits and limited
options. Newer insights into the underlying etiology of
GACs does bring possible promise of new, improved
therapies. However, substantial work needs to be com-
pleted to identify optimal targets, optimal biomarkers, and
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characterization of gastric adenocarcinoma. Nature. 2014;513:202-209.
12. Kakiuchi M, Nishizawa T, Ueda H, et al. Recurrent gain-of-function
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13. Wang K, Yuen ST, Xu J, et al. Whole-genome sequencing and com-
prehensive molecular profiling identify new driver mutations in gastric
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14. van Beek J, zur Hausen A, Klein Kranenbarg E, et al. EBV-positive gastric
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GASTRIC ADENOCARCINOMA
the development of effective combination therapies to
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16. Hecht JR, Bang YJ, Qin SK, et al. Lapatinib in combination with cape-
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17. Bang Y-J RX, Taroh S, et al. A randomized, open-label, phase III study of
lapatinib in combination with weekly paclitaxel versus weekly paclitaxel
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abstr 11).
18. Lordick F, Kang YK, Chung HC, et al; Arbeitsgemeinschaft Internistische
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without cetuximab for patients with previously untreated advanced
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19. Waddell T, Chau I, Cunningham D, et al. Epirubicin, oxaliplatin, and
capecitabine with or without panitumumab for patients with previously
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open-label phase 3 trial. Lancet Oncol. 2013;14:481-489.
20. Kim YH, Sasaki Y, Lee KH, et al. Randomized phase II study of nimo-
tuzumab, an anti-EGFR antibody, plus irinotecan in patients with 5-
fluorouracil-based regimen-refractory advanced or recurrent gastric
cancer in Korea and Japan: preliminary results. J Clin Oncol. 2011;29:4s
(suppl 4; abstr 87).
21. Van Cutsem E, de Haas S, Kang YK, et al. Bevacizumab in combination
with chemotherapy as first-line therapy in advanced gastric cancer:
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J Clin Oncol. 2012;30:2119-2127.
22. Iveson T, Donehower RC, Davidenko I, et al. Rilotumumab in
combination with epirubicin, cisplatin, and capecitabine as first-line
treatment for gastric or oesophagogastric junction adenocarci-
noma: an open-label, dose de-escalation phase 1b study and a
double-blind, randomised phase 2 study. Lancet Oncol. 2014;15:
1007-1018.
23. Shah MA, Bang Y-J, Lordick F, et al. METGastric: A phase III study of
onartuzumab plus mFOLFOX6 in patients with metastatic HER2-
negative (HER22) and MET-positive (MET+) adenocarcinoma of the
stomach or gastroesophageal junction (GEC). J Clin Oncol. 2015;33
(suppl; abstr 4012).
24. Bang Y-J, Cutsem EV, Mansoor W, et al. A randomized, open-label phase
II study of AZD4547 (AZD) versus paclitaxel (P) in previously treated
patients with advanced gastric cancer (AGC) with fibroblast growth
factor receptor 2 (FGFR2) polysomy or gene amplification (amp): SHINE
study. J Clin Oncol. 2015;33 (suppl; abstr 4014).
25. Ohtsu A, Ajani JA, Bai YX, et al. Everolimus for previously treated ad-
vanced gastric cancer: results of the randomized, double-blind, phase III
GRANITE-1 study. J Clin Oncol. 2013;31:3935-3943.
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LEE, BASS, AND AJANI
26. Ramanathan RK, McDonough SL, Kennecke HF, et al. Phase 2 study of
MK-2206, an allosteric inhibitor of AKT, as second-line therapy for
advanced gastric and gastroesophageal junction cancer: A SWOG co-
operative group trial (S1005). Cancer. Epub 2015 Mar 30.
27. Bang YJ, Im SA, Lee KW, et al. Randomized, double-blind phase II trial
with prospective classification by ATM protein level to evaluate the
efficacy and tolerability of olaparib plus paclitaxel in patients with
recurrent or metastatic gastric cancer. J Clin Oncol. 2015;33:3858-3865.
28. Enzinger PC, McCleary NJ, Zheng H, et al. Multicenter double-blind
randomized phase II: FOLFOX + ziv-aflibercept/placebo for patients (pts)
with chemo-naive metastatic esophagogastric adenocarcinoma
(MEGA). J Clin Oncol. 2016;34 (suppl 4S; abstr 4).
29. Kang Y-K, Shah MA, Ohtsu A, et al. A randomized, open-label, multi-
center, adaptive phase 2/3 study of trastuzumab emtansine (T-DM1)
versus a taxane (TAX) in patients (pts) with previously treated HER2-
positive locally advanced or metastatic gastric/gastroesophageal
junction adenocarcinoma (LA/MGC/GEJC). J Clin Oncol. 2016;34
(suppl 4S; abstr 5).
30. Wilke H, Van Cutsem E, Oh SC, et al. RAINBOW: A global, phase III,
randomized, double-blind study of ramucirumab plus paclitaxel versus
placebo plus paclitaxel in the treatment of metastatic gastroesophageal
junction (GEJ) and gastric adenocarcinoma following disease progres-
sion on first-line platinum- and fluoropyrimidine-containing combi-
nation therapy rainbow IMCL CP12-0922 (I4T-IE-JVBE). J Clin Oncol.
2014;32 (suppl 3; abstr LBA7).
31. Fuchs CS, Tomasek J, Yong CJ, et al; REGARD Trial Investigators.
Ramucirumab monotherapy for previously treated advanced gastric or
gastro-oesophageal junction adenocarcinoma (REGARD): an in-
ternational, randomised, multicentre, placebo-controlled, phase 3 trial.
Lancet. 2014;383:31-39.
32. Lordick F, Kang Y-K, Salman P, et al. Clinical outcome according to tumor
HER2 status and EGFR expression in advanced gastric cancer from the
EXPAND study. J Clin Oncol. 2013;31 (suppl; abstr 4021).
33. Satoh T, Lee KH, Rha SY, et al. Randomized phase II trial of nimotuzumab
plus irinotecan versus irinotecan alone as second-line therapy for
patients with advanced gastric cancer. Gastric Cancer. 2015;18:
824-832.
34. Cunningham D, Tebbutt NC, Davidenko I, et al. Phase III, randomized,
double-blind, multicenter, placebo (P)-controlled trial of rilotumumab
(R) plus epirubicin, cisplatin and capecitabine (ECX) as first-line therapy
in patients (pts) with advanced MET-positive (pos) gastric or gastro-
esophageal junction (G/GEJ) cancer: RILOMET-1 study. J Clin Oncol.
2015;33 (suppl; abstr 4000).
35. Kwak EL, LoRusso P, Hamid O, et al. Clinical activity of AMG 337, an oral
MET kinase inhibitor, in adult patients (pts) with MET-amplified gas-
troesophageal junction (GEJ), gastric (G), or esophageal (E) cancer. J Clin
Oncol. 2015;33 (suppl 3; abstr 1).
36. Kwak EL, Ahronian LG, Siravegna G, et al. Molecular heterogeneity and
receptor coamplification drive resistance to targeted therapy in MET-
amplified esophagogastric cancer. Cancer Discov. 2015;5:1271-1281.
37. Smyth EC, Turner NC, Pearson A, et al. Phase II study of AZD4547 in FGFR
amplified tumours: gastroesophageal cancer (GC) cohort pharmaco-
dynamic and biomarker results. J Clin Oncol. 2016;34 (suppl 4S; abstr
154).
38. Muro K, Bang Y-J, Shankaran V, et al. Relationship between PD-L1
expression and clinical outcomes in patients (Pts) with advanced gastric
cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab
(Pembro; MK-3475) in KEYNOTE-012. J Clin Oncol. 2015;33 (suppl 3,
abstr 3).
39. Biankin AV, Piantadosi S, Hollingsworth SJ. Patient-centric trials for
therapeutic development in precision oncology. Nature. 2015;526:
361-370.
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40. Catenacci DV. Next-generation clinical trials: Novel strategies to address
the challenge of tumor molecular heterogeneity. Mol Oncol. 2015;9:
967-996.
41. Lee J, Kim KM, Kang WK, et al. Innovative personalized medicine in
gastric cancer: time to move forward. Clin Genet. 2014;86:37-43.
42. Satoh T, Xu RH, Chung HC, et al. Lapatinib plus paclitaxel versus pac-
litaxel alone in the second-line treatment of HER2-amplified advanced
gastric cancer in Asian populations: TyTANa randomized, phase III
study. J Clin Oncol. 2014;32:2039-2049.
43. Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets
systems biology. Nat Rev Cancer. 2012;12:553-563.
44. Holohan C, Van Schaeybroeck S, Longley DB, et al. Cancer
drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13:
714-726.
45. Chen M, Li Y, Ming Z, et al. Comparison of HER2 status by fluorescence
in situ hybridisation and immunohistochemistry in gastric cancer.
Contemp Oncol (Pozn). 2014;18:95-99.
46. Yoshida H, Yamamoto N, Taniguchi H, et al. Comparison of HER2 status
between surgically resected specimens and matched biopsy specimens
of gastric intestinal-type adenocarcinoma. Virchows Arch. 2014;465:
145-154.
47. Wang T, Hsieh ET, Henry P, et al. Matched biopsy and resection
specimens of gastric and gastroesophageal adenocarcinoma show high
concordance in HER2 status. Hum Pathol. 2014;45:970-975.
48. van Hagen P, Biermann K, Boers JE, et al. Human epidermal growth
factor receptor 2 overexpression and amplification in endoscopic bi-
opsies and resection specimens in esophageal and junctional adeno-
carcinoma. Dis Esophagus. 2015;28:380-385.
49. Grillo F, Fassan M, Ceccaroli C, et al. The reliability of endoscopic bi-
opsies in assessing HER2 status in gastric and gastroesophageal junction
cancer: a study comparing biopsies with surgical samples. Transl Oncol.
2013;6:10-16.
50. Ge X, Wang H, Zeng H, et al. Clinical significance of assessing Her2/neu
expression in gastric cancer with dual tumor tissue paraffin blocks. Hum
Pathol. 2015;46:850-857.
51. Qiu Z, Sun W, Zhou C, et al. HER2 expression variability between primary
gastric cancers and corresponding lymph node metastases. Hep-
atogastroenterology. 2015;62:231-233.
52. Kumarasinghe MP, de Boer WB, Khor TS, et al. HER2 status in gastric/
gastro-oesophageal junctional cancers: should determination of gene
amplification by SISH use HER2 copy number or HER2: CEP17 ratio?
Pathology. 2014;46:184-187.
53. Kochi M, Fujii M, Masuda S, et al. Differing deregulation of HER2 in
primary gastric cancer and synchronous related metastatic lymph
nodes. Diagn Pathol. 2013;8:191.
54. Cho EY, Park K, Do I, et al. Heterogeneity of ERBB2 in gastric carcinomas:
a study of tissue microarray and matched primary and metastatic
carcinomas. Mod Pathol. 2013;26:677-684.
55. Bozzetti C, Negri FV, Lagrasta CA, et al. Comparison of HER2 status in
primary and paired metastatic sites of gastric carcinoma. Br J Cancer.
2011;104:1372-1376.
56. Chen XZ, Zhang WH, Yao WQ, et al. Immunohistochemical HER2 ex-
pression not associated with clinicopathological characteristics of stage I-
III gastric cancer patients. Hepatogastroenterology. 2014;61:1817-1821.
57. Geng Y, Chen X, Qiu J, et al. Human epidermal growth factor receptor-2
expression in primary and metastatic gastric cancer. Int J Clin Oncol.
2014;19:303-311.
58. Geppert CI, Rummele P, Sarbia M, et al. Multi-colour FISH in oeso-
phageal adenocarcinoma-predictors of prognosis independent of stage
and grade. Br J Cancer. 2014;110:2985-2995.

59. Aizawa M, Nagatsuma AK, Kitada K, et al. Evaluation of HER2-based
biology in 1,006 cases of gastric cancer in a Japanese population. Gastric
Cancer. 2014;17:34-42.
60. Gomez-Martin C, Plaza JC, Pazo-Cid R, et al. Level of HER2 gene am-
plification predicts response and overall survival in HER2-positive ad-
vanced gastric cancer treated with trastuzumab. J Clin Oncol. 2013;31:
4445-4452.
61. Okines AF, Thompson LC, Cunningham D, et al. Effect of HER2 on
prognosis and benefit from peri-operative chemotherapy in early
oesophago-gastric adenocarcinoma in the MAGIC trial. Ann Oncol.
2013;24:1253-1261.
62. Yoon HH, Shi Q, Sukov WR, et al. Adverse prognostic impact of
intratumor heterogeneous HER2 gene amplification in patients with
esophageal adenocarcinoma. J Clin Oncol. 2012;30:3932-3938.
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63. Janjigian YY, Werner D, Pauligk C, et al. Prognosis of metastatic gastric and
gastroesophageal junction cancer by HER2 status: a European and USA
International collaborative analysis. Ann Oncol. 2012;23:2656-2662.
64. Ajani JA, Bentrem DJ, Besh S, et al; National Comprehensive Cancer
Network. Gastric cancer, version 2.2013: featured updates to the NCCN
Guidelines. J Natl Compr Canc Netw. 2013;11:531-546.
65. Ajani JA, DAmico TA, Almhanna K, et al; National Comprehensive
Cancer Network. Esophageal and esophagogastric junction cancers,
version 1.2015. J Natl Compr Canc Netw. 2015;13:194-227.
66. Kang YK, Shah MA, Ohtsu A, et al. A randomized, open-label, multi-
center, adaptive phase 2/3 study of trastuzumab emtasine (T-DM1)
versus a taxane (TAX) in patients with previously treated Her2 positive
locally advanced or metastatic gastric/gastroesophageal junction ad-
enocarcinoma. J Clin Oncol. 2016;34 (suppl 4S; abstr 5).
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 111
GASTROINTESTINAL (NONCOLORECTAL) CANCER

Localized Pancreatic Cancer:

Multidisciplinary Management
With Incorporation of ASCO
Guidelines

CHAIR
E. Gabriela Chiorean, MD
Fred Hutchinson Cancer Research Center
Seattle, WA

SPEAKERS
Diane M. Simeone, MD
University of Michigan
Ann Arbor, MI

Joseph M. Herman, MD, MSc

Johns Hopkins University School of Medicine
Baltimore, MD
 MULTIDISCIPLINARY TREATMENT IN PANCREATIC CANCER

Localized Pancreatic Cancer: Multidisciplinary Management

Andrew L. Coveler, MD, Joseph M. Herman, MD, MSc, Diane M. Simeone, MD, and E. Gabriela Chiorean, MD

OVERVIEW

Pancreatic cancer is an aggressive cancer that continues to have single-digit 5-year mortality rates despite advancements in
the field. Surgery remains the only curative treatment; however, most patients present with late-stage disease deemed
unresectable, either due to extensive local vascular involvement or the presence of distant metastasis. Resection guidelines
that include a borderline resectable group, as well as advancements in neoadjuvant chemotherapy and radiation that
improve resectability of locally advanced disease, may improve outcomes for patients with more invasive disease. Multi-
agent chemotherapy regimens fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel with
gemcitabine improved response rates and survival in metastatic pancreatic cancer and are now being used in earlier
stages for patients with localized potentially resectable and unresectable disease, with goals of downstaging tumors to allow
margin-negative resection and reducing systemic recurrence. Chemoradiotherapy, although still controversial for both
resectable and unresectable pancreatic cancer, is being used in the context of contemporary chemotherapy backbone
regimens, and novel radiation techniques such as stereotactic body frame radiation therapy (SBRT) are studied on the premise
of maintaining or improving efficacy and reducing treatment duration. Patient selection for optimal treatment designation is
currently provided by multidisciplinary tumor boards, but biomarker discovery, in blood, tumors, or through novel imaging, is
an area of intense research. Results to date suggest that some patients with unresectable disease at the outset have survival
rates as good as those with initially resectable disease if able to undergo surgical resection. Long-term follow-up and improved
clinical trials options are needed to determine optimal treatment modalities for patients with localized pancreatic cancer.

A pproximately 277,000 new cases of pancreatic cancer

are diagnosed each year in the world,1 among which
approximately 49,000 occur in both the United States2 and
Europe.3 Localized disease accounts for approximately 50%
of newly diagnosed patients, with the largest fraction, 35%,
being locally advanced, unresectable pancreatic cancer
(LAUPC) and 10% to 15% resectable or borderline resectable
pancreatic cancer (BRPC). The goals of care for patients with
localized pancreatic cancer are increasing the likelihood of
margin-negative resection, preventing metastatic spread,
converting unresectable into potentially resectable disease,
and overall improving patients quality of life. In this update
on multidisciplinary treatment of localized pancreatic can-
cer, we highlight standard and novel approaches, overview
ongoing controversies, and emphasize current clinical trials.
INTEGRATING MULTIMODALITY THERAPY IN
THE TREATMENT OF LOCALIZED AND LOCALLY
ADVANCED PANCREATIC CANCER
Resectable Pancreatic Cancer
Localized resectable pancreatic cancer represents less than
15% of all new diagnoses, and the National Comprehensive
Cancer Network (NCCN) guidelines recommend surgery fol-
lowed by adjuvant chemotherapy with gemcitabine or fluo-
rouracil (5-FU) as the current standard of care.4 Despite
perioperative mortality rates of less than 2% in experienced
centers, patients undergoing surgical resection followed by
adjuvant chemotherapy (gemcitabine or 5-FU) or chemo-
therapy plus chemoradiotherapy experience survival rates of
24 months and 5-year overall survival (OS) of 20% on average,
unchanged in the past few decades, mostly due to high rates
of systemic relapse.58 The EORTC 40013 randomized phase
II trial compared adjuvant gemcitabine (four cycles) with
gemcitabine (two cycles) plus gemcitabine-based radio-
therapy and showed similar OS rates (24 months), but local
relapse was improved in the chemoradiotherapy arm (15%
vs. 31%).9 Because 30% of patients with pancreatic cancer
experience relapse only locally after surgery,5 the potential
benefit of adjuvant chemoradiotherapy needs to be addressed
in a larger randomized trial. With many historical trials highly
criticized due to suboptimal chemoradiotherapy treatment
delivery (e.g., GITSG, EORTC, and ESPAC-1),6,10,11 the phase III
study RTOG-0848 (NCT01013649) in the United States is
currently evaluating the role of adjuvant chemoradiotherapy

From the Division of Hematology-Oncology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Radiation Oncology and Molecular
Radiation Sciences, Johns Hopkins University, Baltimore, MD; University of Michigan, Ann Arbor, MI.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: E. Gabriela Chiorean, MD, Fred Hutchinson Cancer Research Center, 825 Eastlake Ave. E, G4-833, Seattle, WA 98109-6248; email: gchiorea@uw.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e217

COVELER ET AL
when added after 6 months of gemcitabine compared with
gemcitabine alone (6 months). Until results from RTOG-0848
more clearly define the benefit of adjuvant chemoradiotherapy
in this patient population, in clinical practice, adjuvant
chemoradiotherapy is most commonly reserved for pa-
tients with margin-positive (R1 or R2) resection and/or
lymph nodepositive disease.12,13 Intensifying systemic
chemotherapy after pancreatic cancer resection is being
addressed in the adjuvant APACT study (NCT01964430),
using nab-paclitaxel with gemcitabine versus gemcitabine
alone, and the ACCORD 24 study (NCT01526135) with
modified FOLFIRINOX (mFOLFIRINOX) versus gemcitabine.
None of these latter studies incorporates chemoradiotherapy
in the adjuvant regimen.
Data in genetically engineered mouse models of pancre-
atic cancer suggest metastatic spread precedes local tumor
formation.14 Combined with evidence that there is a high
rate of disease recurrence following resection of stage I/II
disease suggests that even in the absence of radiologic
evidence of metastasis, more effective systemic chemo-
therapy should confer an increased likelihood of cure after
resection by successfully treating micrometastases as early
as possible. On this premise, neoadjuvant approaches have
been tested in resectable pancreatic cancer with the
KEY POINTS
Neoadjuvant multimodality therapy should be
considered for patients with borderline resectable and
locally advanced unresectable pancreatic cancer.
Induction chemotherapy for at least 2 to 3 months
selects patients without rapid disease metastasis who
may benefit most from the addition of radiotherapy.
Ongoing clinical trials will help define the role of
adjuvant radiotherapy for resectable patients
(RTOG0848), as well as for locally advanced
unresectable patients (RTOG1201).
Select patients with initially localized but unresectable
disease may undergo potentially curable surgical
resection after neoadjuvant therapy and have outcomes
comparable to patients with initially resectable disease.
Radiologic RECIST response does not adequately predict
resectability for patients with borderline resectable or
locally advanced unresectable pancreatic cancer.
Pathologic complete or near-complete response (often
defined as < 5% viable cells) to neoadjuvant therapy may
predict increased survival.
It is currently unknown whether borderline resectable
or locally advanced unresectable patients undergoing
induction (neoadjuvant) multi-agent chemotherapy will
derive additional benefit with the addition of
radiotherapy.
Novel combinations of systemic treatment and
radiotherapy modalities such as SBRT and IMRT may
provide superior resectability and local control.
Blood and tissue biomarkers may assist in determining
optimal neoadjuvant strategies.
e218 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
assumption of several advantages: prompt use of systemic
therapy to treat occult micrometastases, allowing a period of
time to observe the tumor biology during chemotherapy
exposure and avoiding unnecessary resection for rapidly
metastasizing tumors, improving the likelihood of margin-
negative resection, and improved chemotherapy delivery
compared with postresection, when complications may
delay or worsen chemotherapy tolerability. In a few in-
stitutional prospective studies of neoadjuvant chemother-
apy (gemcitabine/cisplatin and gemcitabine/oxaliplatin)
with or without chemoradiotherapy in radiographic re-
sectable disease, approximately 70% of patients underwent
surgical resection, and OS reached 27 to 34 months for
resected patients, possibly due to patient selection.1517
However, most patients in these studies still experienced
relapsed with metastatic disease. It is therefore not clear
that neoadjuvant therapy with standard chemotherapy
regimens confers higher OS compared with adjuvant ap-
proaches, and with no randomized studies to date, the NCCN
guidelines do not yet endorse neoadjuvant therapy for
patients with clearly resectable disease on baseline staging
CT scans, outside of clinical trials. For patients who receive
neoadjuvant therapy followed by resection, further adjuvant
therapy is recommended. This approach is being adopted by
the recently opened SWOG S1505 randomized phase II
study (NCT02243007), which compares mFOLFIRINOX with
nab-paclitaxel with gemcitabine for 3 months before and
3 months after surgery. A recent report suggests that a
subset of patients treated with neoadjuvant therapy who
undergo surgical resection and are found to have low lymph
node ratio (number of positive lymph nodes/number total
lymph nodes resected , 0.15) may have better survival
outcomes when also treated with adjuvant chemotherapy
(OS: 72 vs. 33 months; p = .008).18 In the absence of definitive
guidelines, clinical criteria for considering neoadjuvant
therapy in resectable pancreatic cancer are: large primary
tumors, high carbohydrate antigen 19-9 (CA19-9) levels
(. 1,000 U/mL), peripancreatic lymph node involvement by
cross-sectional imaging or endoscopic ultrasound, or equiv-
ocal radiologic features.19 Randomized phase II/III studies are
ongoing in resectable pancreatic cancer that may help clarify
the role of neoadjuvant versus adjuvant therapies: NEOPAC
(NCT01314027) compares adjuvant gemcitabine versus
neoadjuvant gemcitabine/oxaliplatin followed by adjuvant
gemcitabine, NEPAFOX (NCT02172976) compares adjuvant
gemcitabine versus neoadjuvant/adjuvant FOLFIRINOX,
and NEONAX (NCT02047513) compares adjuvant versus
neoadjuvant/adjuvant nab-paclitaxel with gemcitabine.
Defining a more effective neoadjuvant or adjuvant regi-
men would provide great benefit in improving survival
among resectable patients, in whom the therapy is geared
toward targeting micrometastatic disease.
Borderline Resectable Pancreatic Cancer
Patients with borderline-resectable pancreatic cancer (BRPC)
have localized disease, but less likely to be resected with
 MULTIDISCIPLINARY TREATMENT IN PANCREATIC CANCER

negative margins due to proximity or direct involvement of
venous and/or arterial vascular structures (# 180).20 In this
setting, although no particular chemotherapy with or without
a chemoradiotherapy regimen can be considered superior, the
NCCN guidelines do not recommend up-front surgery in this
category of patients when there is a high likelihood of positive
margins and instead recommend neoadjuvant therapy,
preferably at a high-volume center. Consensus opinions for
BRPC have recommended neoadjuvant multimodality treat-
ment mostly based on historical retrospective studies, which
showed increased probability of response (10%30%), re-
sectability (30%60%), and R0 resection (80%90%) with this
approach. 21-26 It is well described that R0 resections
are associated with improved OS rates (1823 months)
when compared with R1 (1415 months) or R2 resections
(1011 months).27-29 Recent retrospective studies with con-
temporary therapies FOLFIRINOX or nab-paclitaxel with
gemcitabine with or without chemoradiotherapy, often in-
cluding both patients BRPC or LAUPC, note encouraging results
with both regimens: resectability rates of 60% to 80% for
patients with BRPC and 80% to 90% R0 resections among
those resected.30-40 Patients undergoing surgical resection
had median progression-free survival (PFS) rates of 16 to
23 months and median OS rates of 24 to 30 months, similar to
historical results for patients with up-front resectable disease
(Table 1); in contrast, for patients whose disease remained
unresectable after neoadjuvant treatment, PFS and OS rates
were 9 to 10 and 12 to 15 months, respectively.30,32 Never-
theless, many of the retrospective studies included both pa-
tients with localized resectable and BRPC/LAUPC, making it
difficult to identify distinct results for individual subsets of
patients.
The prospective Alliance A021101 study (NCT01821612)
used neoadjuvant mFOLFIRINOX (four cycles) followed by
capecitabine-based chemoradiotherapy for patients with
BRPC.41 Resectable patients underwent surgery followed by
two cycles of adjuvant gemcitabine. Fifteen of the 22 treated
patients (68%) underwent surgical resection, among which
93% were R0 resections. The pathologic complete response
(pCR) and near pCR (, 5% residual tumor cells) were 9% and

TABLE 1. Multimodality Clinical Trials for BRPC and LAUPC With Emphasis on FOLFIRINOX and Nab-Paclitaxel/
Gemcitabine
Study No. of BRPC/LAUPC Treatment Resected (%) OS (Overall) Months OS (Resected) Months
26
Katz et al 129/0 Gem-platinum + CRT 66 22 33
Hosein et al30 14/4 FOLFIRINOX 6 CRT 75 (BRPC) Not reported Not reported
43 (LAUPC)
Kim et al25 39/6 Gem-oxaliplatin 6 CRT 63 18.4 (BRPC) 25.4
9.4 (LAUPC)
Faris et al51 0/22 FOLFIRINOX + CRT 23 3 year, 7% Not reached
Boone et al 31
12/13 FOLFIRINOX 6 SBRT 64 (BRPC) Not reported Not reported
20 (LAUPC)
Christians36 18/0 FOLFIRINOX 6 CRT 67 Not reported 22 months, 58%
Rose et al24 64/0 Gem-docetaxel 6 CRT 48 23.6 22 months, 81%
Paniccia et al 37
18/0 FOLFIRINOX 6 CRT 94 25 Not reported
Katz et al41 23/0 FOLFIRINOX + CRT 68 18 months, 50% Not reported
Blazer et al38 18/25 FOLFIRINOX 61 (BRPC) 21.2 Not reached
44 (LAUPC)
Khushman et al50 11/40 FOLFIRINOX 6 CRT 22 35.4 3-year 67%
Ferrone et al39 14/33 FOLFIRINOX 6 CRT 85 34 Not reached
Marthey et al 52
0/77 FOLFIRINOX 6 CRT 36 22 months, 77% 24.9 months, not reached
Nitsche et al53 0/14 FOLFIRINOX 29 1 year, 64% 31 months, not reached
Nanda et al40 15/29 FOLFIRINOX + CRT 41 1 year, 66% 18.6 months, not reached
Sadot et al55 0/101 FOLFIRINOX 6 CRT 30 26, if no PD on chemo Not reached
Idrees et al 32
58/28 FOLFIRINOX 6 CRT 84 27.4 Not reached
nab-P/Gem 6 CRT
Portales et al33 16/19 FOLFIRINOX 6 CRT 63 (BRPC) 24 53
37 (LAUPC)
Kim et al34 26/0 FOLFIRINOX 77 PFS 22.5 months Not reported
Peterson et al35 14/6 nab-P/Gem 25 Not reported Not reported
Dean et al 54
0/42 nab-P/Gem 6 CRT 19 Not reported 27.5
Abbreviations: BRPC, borderline resectable pancreatic cancer; LAUPC, locally advanced unresectable pancreatic cancer; OS, overall survival; CRT, chemoradiotherapy; SBRT,
stereotactic body radiotherapy; PD, progressive disease; chemo, chemotherapy; PFS, progression-free survival; nab-P, nab-paclitaxel; Gem, gemcitabine.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e219

COVELER ET AL
47%, respectively, and the RECIST response after pre-
operative therapy was 28% (two CR/four PR). Overall sur-
vival at 18 months was 50%. Based on the encouraging
resectability results, the prospective randomized phase II
Alliance A021501 study in BRPC using mFOLFIRINOX with or
without hypofractionated radiotherapy, either SBRT or
hypofractionated image-guided radiotherapy (HIGRT), is to
begin shortly. Some reports indicate that near-complete
pathologic complete response (near-pCR, with , 5% re-
sidual viable cells) or pCR to neoadjuvant therapy is asso-
ciated with long-term survival for resected patients (OS:
53 months or longer)32,42,43; however, analysis of larger
cohorts of patients will be needed to verify this observation.
Although it has been assumed that multi-agent chemo-
therapy will confer high response rates, radiologic RECIST
response after 2 to 3 months of neoadjuvant chemotherapy
for localized disease has not consistently shown meaningful
downsizing.26,41 At this time, lack of downstaging after neo-
adjuvant chemotherapy with or without chemoradiotherapy
for patients with BRPC should not deter exploration and
attempt at resection in the absence of local or metastatic
progression or other clinical deterioration factors in ap-
propriate surgical candidates.
Locally Advanced Unresectable Pancreatic Cancer
It has been observed in an autopsy series that up to one-third
of patients with pancreatic cancer die due to complications
from local progression and not metastatic disease, suggesting
that more aggressive local therapy may be appropriate in a
subset of patients.44 Locally advanced unresectable pancre-
atic cancer has traditionally been treated with both che-
motherapy and chemoradiotherapy, in various sequencing
approaches, with OS rates of 9 to 13 months and with some
studies (ECOG 4201: gemcitabine-based chemoradiotherapy
followed by gemcitabine versus gemcitabine alone),45 but not
others (FFCD-SFRO: 5-FU/cisplatin-based chemoradiotherapy
followed by gemcitabine vs. gemcitabine alone),46 showing
OS benefit with the addition of up-front chemoradiotherapy
(ECOG 4201: OS 11.1 vs. 9.2 months, p = .017 in favor of the
chemoradiotherapy arm, and FFCD-SFRO: OS of 13 vs.
8.6 months, p = .03 in favor of the chemotherapy arm). In a
meta-analysis of GERCOR studies, Huguet et al47 noted that
induction chemotherapy for 3 to 4 months may select patients
without rapid metastatic progression who may be the most
likely to benefit from additional chemoradiotherapy compared
with continuing chemotherapy alone. Based on these data, the
randomized phase III LAP-07 trial used 4 months of induction
chemotherapy with gemcitabine with or without erlotinib
and, if no progression, randomly assigned patients to con-
tinuing chemotherapy (for an additional 2 months) versus
capecitabine-based chemoradiotherapy. The OS rates for
patients able to undergo the randomization after induction
chemotherapy were similar: 16.7 versus 15.3 months (p = .83)
in the chemotherapy arm compared with the chemotherapy
plus chemoradiotherapy arm.48 Nevertheless, local progression
rates were improved with CRT, 34% vs. 65% (p , .0001).49
e220 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Similar to the efforts of intensifying multimodality therapy
in localized and BRPC, both FOLFIRINOX and nab-paclitaxel
with gemcitabine, with the addition of chemoradiotherapy
for select patients, have been extensively adopted for pa-
tients with LAUPC, to increase the chance of downstaging
and the potential for curative resection. Several institutional
and multi-institutional studies with FOLFIRINOX or nab-
paclitaxel with gemcitabine reported radiologic response
rates of 20% to 40%, resectability rates of 20% to 44%, with
R0 resection rates of 40% to 80% among resected patients
(Table 1).30-33,35,38-40,50-55 Notably, patients whose disease
becomes resectable after induction/neoadjuvant chemo-
therapy with or without chemoradiotherapy have an en-
couraging median OS of approximately 30 months and
2-year OS of 60% to 70%.38,39,49,50,54,55 A Massachusetts
General Hospital retrospective report compared patients
with initially resectable pancreatic cancer who underwent
surgery (87 patients) with patients who had initially unre-
sectable disease with either BRPC or LAUPC and who were
treated with neoadjuvant FOLFIRINOX with or without
chemoradiotherapy followed by surgery with or without
intraoperative radiation therapy if deemed resectable
(40 patients), and the authors noted that R0 resections were
86% versus 92%, and OS rates were longer in the initially
unresectable group (2-year OS: 5% vs. 70%; p = .008).39
As is the case with retrospective data, most of the in-
stitutional studies were heterogenous and included both
patients with BRPC and LAUPC. Prior to the use of novel
multi-agent chemotherapy regimens, a meta-analysis of
111 studies of 4,394 patients with resectable or BRPC/LAUPC
treated with neoadjuvant chemotherapy (with or without
chemoradiotherapy) noted overall responses of 34%, re-
section rates of 74% in initially resectable disease, and 33%
in BRPC/LAUPC, among which R0 resection rates were ap-
proximately 80%.22 Interestingly, OS after resection was
similar in both the initially resectable and unresectable
groups (23.3 months [range 1254 months] versus
20.5 months [range 962 months]). Nevertheless, patients
with disease deemed unresectable after neoadjuvant
therapy had poor outcomes, with OS of 8.4 months (range
614 months) among those initially resectable and
10.2 months (range 621 months) for those with initial
BRPC/LAUPC. A more recent meta-analysis of FOLFIRINOX-
based neoadjuvant therapy (with or without chemoradiotherapy)
in BRPC and LAUPC among 253 patients across 13 studies noted
an overall resection rate of 43% (of which 85% were R0 re-
sections) in all patients and 26% among those with LAUPC, but
long-term outcomes are not available.56
Compared with historical chemotherapy regimens that
rendered approximately 20% to 30% of the patients with
locally advanced and borderline pancreatic cancers resect-
able, but with high recurrence rates and OS rates less than
24 months,22 preliminary evidence from new retrospective
and small prospective studies using the highly active regi-
mens FOLFIRINOX and nab-paclitaxel with gemcitabine
seem to confer 10% to 20% higher resection rates and more
durable PFS and OS outcomes.

In the context of the novel multi-agent chemotherapy
backbones, the role of adding chemoradiotherapy has not
yet been defined. DPC4/SMAD4 has been identified as a
putative biomarker predictive of local progression when
intact or metastatic dissemination when mutated.44 The
RTOG1201 phase II randomized study (NCT01921751) will
prospectively test whether the DPC4 gene status identifies
patients with LAUPC more likely to benefit from chemo-
radiotherapy. In this study, 346 patients will be randomly
assigned to nab-paclitaxel with gemcitabine alone versus
nab-paclitaxel with gemcitabine plus standard-dose 50 Gy
of capecitabine-based radiotherapy (three-dimensional
conformal or intensity modulated radiotherapy [IMRT])
versus nab-paclitaxel with gemcitabine plus high-dose
60 Gy of capecitabine-based IMRT. In Europe, CONKO-007
(NCT01827553) will assess induction FOLFIRINOX or gem-
citabine followed by gemcitabine-based radiotherapy ver-
sus continuing chemotherapy, and the SCALOP-2 study
(NCT02024009) will use nab-paclitaxel with gemcitabine
(three cycles) followed by capecitabine-based radiotherapy
with or without the addition of nelfinavir, an HIV protease
inhibitor with radiosensitizing activity, versus nab-paclitaxel
with gemcitabine alone (six cycles). LAPACT (NCT02301143) is
an international randomized phase II study that will evaluate
induction nab-paclitaxel with gemcitabine for six cycles
and, if no progression, allow investigator choice of surgical
resection, chemoradiotherapy, or continued nab-paclitaxel
with gemcitabine.
Choosing the best radiosensitizing agent has been the subject
of many investigations. Gemcitabine has been found to be as
effective but better tolerated than 5-FU.57,58 More recently, the
randomized phase II SCALOP study using induction gemcitabine/
capecitabine followed by capecitabine-based or gemcitabine-
based radiotherapy found capecitabine to be more effective
than gemcitabine in prolonging OS (15.2 vs. 13.4 months;
p = .012) and improving tolerability.59
At this time, the NCCN guidelines recommend multi-agent
chemotherapy (at least 23 months and up to 68 months)
with the possibility of adding chemoradiotherapy for select
patients with LAPC who do not progress systemically after a
course of induction chemotherapy. The use of up-front
chemoradiotherapy should be reserved for patients pre-
senting with poorly controlled pain or local invasion with
bleeding (NCCN guidelines).
Novel Therapies in Pancreatic Cancer
Several studies have incorporated immunotherapeutics in
early-stage pancreatic cancer to prevent metastasis and im-
prove survival. IMPRESS (NCT01072981) was a phase III ran-
domized study among 722 patients with resected pancreatic
cancer treated with gemcitabine and fluoropyrimidine-based
radiotherapy with and without algenpantucel-L, a hyperacute
vaccine of two allogenic pancreatic cancer cell lines transduced
with the a-galactosyl transferase gene. Although results are
eagerly awaited (median OS: at least 28.5 in both arms
combined), this study will be the first to show the potential
MULTIDISCIPLINARY TREATMENT IN PANCREATIC CANCER
benefit of incorporating an immunotherapy to standard
therapies to reduce pancreatic cancer recurrence.60 The GVAX
pancreas vaccine, composed of granulocyte macrophage
colony-stimulating factorsecreting pancreatic cancer cell
lines, is currently being studied in combination with SBRT and
FOLFIRINOX for patients with resected pancreatic cancer
(NCT01595321). Given potential synergism, neoadjuvant and
adjuvant GVAX will be studied with and without immune
checkpoint inhibitors and chemoradiotherapy for patients
with resectable disease (NCT02451982), and in LAUPC, GVAX
with an immune checkpoint inhibitor will be added to SBRT
(NCT02648282). Therapies targeting the tumor stroma, in-
cluding the immune-suppressive compartment, are being
actively investigated for resectable and unresectable localized
pancreatic cancer. For example, tumor-associated macro-
phages (TAM)targeted therapies such as the CD40 agonist
RO7009789 alone and with nab-paclitaxel with gemcitabine
are being studied as neoadjuvant/adjuvant therapy in re-
sectable pancreatic cancer (NCT02588443). PF-04136309, a
novel chemokine (C-C motif) receptor 2 inhibitor capable of
depleting inflammatory immunosuppressive TAM in combi-
nation with FOLFIRINOX, showed encouraging preliminary
results, with 52% radiologic response rates among patients
with BRPC/LAUPC,61 and further studies are anticipated.
Stroma-depleting pegylated recombinant human hyaluroni-
dase, which targets tumor hyaluronan to potentially improve
chemotherapy delivery, is being tested in a neoadjuvant trial
with nab-paclitaxel with gemcitabine for patients with BRPC
(NCT02487277). Several other agents, including PARP in-
hibitors, are being studied with the goal of improved radio-
sensitization by preventing DNA repair (NCT01908478) or
among patients with BRCA mutations who may be more
therapeutically responsive to this class of inhibitors.62-65 Two
recent studies of large numbers of pancreatic cancers dem-
onstrating novel molecular subtypes, including an immune
subtype, may help us direct more personalized, effective
regimens to patients most likely to benefit.66,67
LOCALIZED PANCREATIC CANCER: HOW DOES
THE RADIATION ONCOLOGIST CONTRIBUTE?
What Is SBRT?
Radiation therapy has historically been delivered to pa-
tients with pancreatic cancer to improve local control,
delay disease progression, and ameliorate locally obstructive
symptoms such as pain. SBRT is a novel technique that allows
precise delivery of radiation to the tumor while minimizing
dose to surrounding normal structures. Recent advances in
image guidance, respiratory motion management, and ra-
diation technology over the past few decades allow for
millimeter accuracy that is necessary for this emerging
modality. Due to the high doses of radiation delivered in
such a short amount of time, SBRT requires close supervi-
sion, and advanced measures have been acquired to mini-
mize treatment-related toxicity. Image guidance throughout
the process of SBRT planning and delivery is achieved with
gold fiducial markers (or fiducials) that are placed in or
near the pancreatic tumor under endoscopic guidance.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e221
COVELER ET AL
A four-dimensional CT simulation scan can be used to de-
termine which patients require management of respiratory
motion to safely achieve an ablative dose to the tumor.
Personalization of treatment plans with dose modification
based on the location of the tumor to critical structures such
as the stomach or duodenum may be used to reduce ra-
diotherapy exposure to those tissues. Radiotherapy quality
assurance is also used to maintain consistent setup each day
such that SBRT can be safely and accurately delivered.
What Are the Potential Advantages of SBRT
Compared With Standard Chemoradiotherapy?
SBRT has become a standard treatment modality in several
malignancies such as lung, liver, brain, spine, and prostate
cancers, but it has not yet been established as such in the
management of pancreatic cancer. Nevertheless, SBRT has
been increasingly adopted in institutions worldwide for
patients with pancreatic cancer due to several advantages:
(1) SBRT can be delivered as a hypofractionated regimen
over 3 to 5 days (with dose ranging from 2540 Gy) in
comparison with 25 to 30 days with conventional chemo-
radiotherapy (dose range, 5054 Gy), (2) SBRT allows for
optimal local control while limiting the delay of alternative
therapies such as systemic full-dose chemotherapy or sur-
gical resection, (3) SBRT results in minimal acute side effects
and has been shown to improve pain while preserving
quality of life,68 and (4) the radiobiology of SBRT along with
the ability to escalate the dose to at least 50 Gy at the tumor
vessel interface may increase the likelihood of a margin-
negative resection. Therefore, patients with pancreatic
cancer, especially those with localized disease, have an
increased likelihood of achieving aggressive trimodality
therapy with a hope for prolonged survival. Because SBRT is
well tolerated and only involves a week of treatment, pa-
tients are able to focus their energy on achieving personal
treatment goals, whether this includes extending survival by
resuming chemotherapy, undergoing surgical resection, or
maximizing quality of life by returning to daily activities.
SBRT in Localized Pancreatic Cancer
Early studies reporting high rates of late gastrointestinal
toxicity sparked controversy over pancreatic SBRT69-71;
however, the abovementioned methods to prioritize safety
have emerged, and SBRT is now gaining traction as a fa-
vorable and highly effective local technique. Recent studies
report acceptable rates of late toxicity in concordance with
minimal acute toxicity.69,72-74 Thus far, there have been
more than 800 published cases of pancreatic cancer treated
with SBRT, and the toxicity, survival, and patterns of failure
data are promising.
Role of Neoadjuvant SBRT in Borderline Resectable
Pancreatic Cancer
A retrospective study included 73 patients with localized
pancreatic cancer (57 boderline resectable and 16 LAUPC) who
received induction chemotherapy followed by five-fraction
e222 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
SBRT (2530 Gy) at Moffitt Cancer Center was published
in 2013.75 Most patients received induction gemcitabine/
docetaxel/capecitabine (66%) or gemcitabine alone (25%),
whereas only 5% received induction FOLFIRINOX. Among the
patients with BRPC, 56% underwent surgery, with 97%
achieving a margin-negative (R0) resection and 9% pCR.
Median OS among the patients who underwent margin-
negative resection was significantly higher than for unre-
sected patients (19.3 vs. 12.3 months; p = .03). Furthermore,
this approach was well tolerated with no acute grade 3 or
worse toxicity reported and only 5.3% late grade 3 or worse
toxicity. More recently, this single-institution series was
updated to include a total of 159 patients (110 with BRPC
and 49 with LAPC).76 Among the patients with BRPC, 51%
underwent surgery with 97% achieving a R0 resection and
7% pCR. Median OS in the patients with resected BRPC was
34 months. Acute grade 3 toxicity or worse was 2%, and late
grade 3 toxicity or worse was 5%. The Johns Hopkins Uni-
versity School of Medicine reported on their study among
88 patients (14 with BRPC and 74 with LAPC) who received
induction chemotherapy followed by SBRT (2533 Gy). The
majority of patients (76%) received gemcitabine-based
chemotherapy as opposed to 5-FU-based (specifically,
FOLFIRINOX) chemotherapy. Of the 19 patients (22%) who
underwent surgery following SBRT, 84% had a R0 resection,
and 16% of patients had pCR.77 Median OS of resected
patients was 20.2 versus 12.3 months in unresected patients
(p = .07). Of note, only 11% of resected patients had BRPC.
Role of SBRT for Locally Advanced, Unresectable
Pancreatic Cancer
Results of SBRT among patients with LAUPC are encour-
aging. Early phase I/II studies using single-fraction SBRT
(25 Gy in one fraction) demonstrated excellent freedom
from local progression (FFLP) at 1 year (. 90%) and minimal
acute toxicity, but high rates of late grade 2 to 4 gastroin-
testinal toxicity were reported.70,71,78-80 A single-arm phase
II multi-institutional study evaluated whether gemcitabine
with fractionated SBRT (in five fractions of 6.6 Gy, for a total
33.0 Gy) could achieve reduced late grade 2 to 4 gastroin-
testinal toxicity compared with a historical cohort of patients
treated with gemcitabine and a single 25 Gy-fraction of
SBRT.68 Forty-nine patients with LAUPC received up to three
doses of gemcitabine (1,000 mg/m2) followed by a 1-week
break and SBRT (33.0 Gy in five fractions). Following SBRT,
patients continued gemcitabine until progression or toxicity.
Rates of acute and late toxicities (primary endpoint) grade
2 or worse gastritis, fistula, enteritis, or ulcers were 2% and
11%, respectively, and QLQ-C30 global quality-of-life scores
remained stable. Patients reported a notable improvement
in pancreatic pain (p , .001) 4 weeks after SBRT on the QLQ-
PAN26 questionnaire. Median OS was 13.9 months (95% CI,
10.216.7), and FFLP at 1 year was 78%. Four patients (8%)
with LAUPC at diagnosis underwent R0 resections and had
node-negative status; a fifth patient who was deemed re-
sectable declined surgery.

With the consideration that patients originally deemed
unresectable may become resectable, a shift toward neo-
adjuvant therapy in LAUPC has recently emerged. Of the
49 patients with LAUPC who were treated with induction
chemotherapy and SBRT at Moffitt Cancer Center, five (10%)
were resected with a 100% R0 resection rate.76 Patients with
LAUPC survived a median of 13.2 months. Johns Hopkins
reported 15 of 74 (20%) patients with LAUPC who went to
surgery with an 80% R0 resection rate and 13% pCR.77
Median OS was 18.4 months.
How Can We Improve the Impact of SBRT in Localized
Pancreatic Cancer?
In an initial pilot cooperative group study in BRPC (Alliance
A021101), FOLFIRINOX-based multimodality therapy was
shown to be well tolerated, and resectability and preliminary
OS were encouraging.41 The follow-up study (Alliance
A021501) will evaluate survival among patients with BRPC
randomly assigned to neoadjuvant mFOLFIRINOX with or
without hypofractionated radiotherapy, either SBRT or
HIGRT.
As we await results from cooperative group studies, it is
essential to pursue further understanding of the tumor
biology and immune response associated with pancreatic
cancer. It has been shown that radiotherapy not only induces
cell death through DNA damage, but also promotes anti-
tumor reactivity in certain solid tumors.81-83 SBRT specifi-
cally, with its highly ablative doses over a short course, has
been shown to be associated with radiation-induced
immunomodulation.84-86 Preclinical data suggest that radia-
tion increases antigen presentation by altering the immune-
phenotype of tumor infiltrating inflammatory cells, increases
T-cell infiltration, and induces proinflammatory cytokines that
promote tumor cell death.87,88
How Can We Optimally Measure Response to
Therapy, and Which Patients Should Be Taken to
Surgery?
The difficulty of selecting patients with localized pancreatic
cancer who are candidates for surgery following neo-
adjuvant therapy lies in the inadequacy of radiographic
imaging to depict treatment response and vessel involve-
ment. Two series have published on patients with BRPC who
have been successfully resected despite the lack of tumor
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36. Christians KK, Tsai S, Mahmoud A, et al. Neoadjuvant FOLFIRINOX for
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38. Blazer M, Wu C, Goldberg RM, et al. Neoadjuvant modified FOLFIRINOX
for locally advanced unresectable and borderline resectable adeno-
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39. Ferrone CR, Marchegiani G, Hong TS, et al. Radiological and surgical
implications of neoadjuvant treatment with FOLFIRINOX for locally
advanced and borderline resectable pancreatic cancer. Ann Surg. 2015;
261:12-17.
40. Nanda RH, El-Rayes B, Maithel SK, et al. Neoadjuvant modified
FOLFIRINOX and chemoradiation therapy for locally advanced pancreatic
cancer improves resectability. J Surg Oncol. 2015;111:1028-1034.
41. Katz MHG, Shi Q, Ahmad SA, et al. Preoperative modified FOLFIRINOX
followed by chemoradiation for borderline resectable pancreatic
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(suppl; abstr 4008).

42. Chatterjee D, Katz MH, Rashid A, et al. Histologic grading of the extent of
residual carcinoma following neoadjuvant chemoradiation in pancre-
atic ductal adenocarcinoma: a predictor for patient outcome. Cancer.
2012;118:3182-3190.
43. Zhao Q, Rashid A, Gong Y, et al. Pathologic complete response to
neoadjuvant therapy in patients with pancreatic ductal adenocarci-
noma is associated with a better prognosis. Ann Diagn Pathol. 2012;16:
29-37.
44. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the
primary carcinoma correlates with patterns of failure in patients with
pancreatic cancer. J Clin Oncol. 2009;27:1806-1813.
45. Loehrer PJ Sr, Feng Y, Cardenes H, et al. Gemcitabine alone versus
gemcitabine plus radiotherapy in patients with locally advanced pan-
creatic cancer: an Eastern Cooperative Oncology Group trial. J Clin
Oncol. 2011;29:4105-4112.
46. Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing
intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and
intermittent cisplatin) followed by maintenance gemcitabine with
gemcitabine alone for locally advanced unresectable pancreatic cancer.
Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol. 2008;19:
1592-1599.
47. Huguet F, Andre T, Hammel P, et al. Impact of chemoradiotherapy after
disease control with chemotherapy in locally advanced pancreatic
adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol. 2007;
25:326-331.
48. Hammel P, Huguet F, van Laethem JL, et al. Comparison of chemo-
radiotherapy (CRT) and chemotherapy (CT) in patients with locally
advanced pancreatic cancer (LAPC) controlled after 4 months of
gemcitabine with or without erlotinib: final results of the international
phase III LAP 07 study. J Clin Oncol. 2013;33:15s (suppl; abstr LBA4003).
49. Huguet F, Hammel P, Vernerey D, et al. Impact of chemoradiation on
local control and time without treatment in patients with locally ad-
vanced pancreatic cancer included in the international phase III LAP 07
study. J Clin Oncol. 2014;32 (suppl 5S; abstr 4001).
50. Khushman M, Dempsey N, Maldonado JC, et al. Full dose neoadjuvant
FOLFIRINOX is associated with prolonged survival in patients with lo-
cally advanced pancreatic adenocarcinoma. Pancreatology. 2015;15:
667-673.
51. Faris JE, Blaszkowsky LS, McDermott S, et al. FOLFIRINOX in locally
advanced pancreatic cancer: the Massachusetts General Hospital
Cancer Center experience. Oncologist. 2013;18:543-548.
52. Marthey L, Sa-Cunha A, Blanc JF, et al. FOLFIRINOX for locally advanced
pancreatic adenocarcinoma: results of an AGEO multicenter pro-
spective observational cohort. Ann Surg Oncol. 2015;22:295-301.
53. Nitsche U, Wenzel P, Siveke JT, et al. Resectability after first-line
FOLFIRINOX in initially unresectable locally advanced pancreatic can-
cer: a single-center experience. Ann Surg Oncol. 2015;22:1212-1220
(suppl 3).
54. Dean A, McGrath A, Youd J, Spry N. Nab-paclitaxel plus gemcitabine
followed by radiotherapy with concurrent 5-FU in locally advanced
unresectable pancreatic cancer. J Clin Oncol. 2016;34 (suppl 4S; abstr
430).
55. Sadot E, Doussot A, OReilly EM, et al. FOLFIRINOX induction therapy for
stage 3 pancreatic adenocarcinoma. Ann Surg Oncol. 2015;22:
3512-3521.
56. Petrelli F, Coinu A, Borgonovo K, et al; Gruppo Italiano per lo Studio dei
Carcinomi dellApparato Digerente (GISCAD). FOLFIRINOX-based neo-
adjuvant therapy in borderline resectable or unresectable pancreatic
cancer: a meta-analytical review of published studies. Pancreas. 2015;
44:515-521.
57. Crane CH, Abbruzzese JL, Evans DB, et al. Is the therapeutic index better
with gemcitabine-based chemoradiation than with 5-fluorouracil-based
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chemoradiation in locally advanced pancreatic cancer? Int J Radiat
Oncol Biol Phys. 2002;52:1293-1302.
58. Huang J, Robertson JM, Margolis J, et al. Long-term results of full-dose
gemcitabine with radiation therapy compared to 5-fluorouracil with
radiation therapy for locally advanced pancreas cancer. Radiother
Oncol. 2011;99:114-119.
59. Mukherjee S, Hurt CN, Bridgewater J, et al. Gemcitabine-based or
capecitabine-based chemoradiotherapy for locally advanced pancreatic
cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet
Oncol. 2013;14:317-326.
60. Coveler AL, Rossi GR, Vahanian NN, et al. Algenpantucel-L immu-
notherapy in pancreatic adenocarcinoma. Immunotherapy. 2016;8:
117-125.
61. Wang-Gillam A, Nyweing TM, Sanford DE, et al. Phase IB study of
FOLFIRINOX plus PF-04136309 in patients with borderline resectable
and locally advanced pancreatic adenocarcinoma. J Clin Oncol. 2015;33
(suppl 3; abstr 338).
62. Salo-Mullen EE, OReilly EM, Kelsen DP, et al. Identification of germline
genetic mutations in patients with pancreatic cancer. Cancer. 2015;121:
4382-4388.
63. Lowery MA, Kelsen DP, Smith SC, et al. Phase II trial of veliparib in
patients with previously treated BRCA or PALB2 mutated pancreas
adenocarcinoma. J Clin Oncol. 2015;33 (suppl 3; abstr 358).
64. Pishvaian MJ, Wang H, Zhuang T, et al. A phase I/II study of ABT-888 in
combination with 5-fluorouracil and oxaliplatin in patients with met-
astatic pancreatic cancer. J Clin Oncol. 2013;31 (suppl 4; abstr 147).
65. OReilly EM, Lowery MA, Segal MF, et al. Phase Ib trial of cisplatin,
gemcitabine, and veliparib in patients with known or potential BRCA or
PALB2-mutated pancreas adenocarcinoma. J Clin Oncol. 2014;32 (suppl
5S; abstr 4023).
66. Waddell N, Pajic M, Patch AM, et al; Australian Pancreatic Cancer
Genome Initiative. Whole genomes redefine the mutational landscape
of pancreatic cancer. Nature. 2015;518:495-501.
67. Bailey P, Chang DK, Nones K, et al; Australian Pancreatic Cancer Genome
Initiative. Genomic analyses identify molecular subtypes of pancreatic
cancer. Nature. 2016;531:47-52.
68. Herman JM, Chang DT, Goodman KA, et al. Phase 2 multi-institutional
trial evaluating gemcitabine and stereotactic body radiotherapy for
patients with locally advanced unresectable pancreatic adenocarci-
noma. Cancer. 2015;121:1128-1137.
69. Hoyer M, Roed H, Sengelov L, et al. Phase-II study on stereotactic
radiotherapy of locally advanced pancreatic carcinoma. Radiother
Oncol. 2005;76:48-53.
70. Schellenberg D, Goodman KA, Lee F, et al. Gemcitabine chemotherapy
and single-fraction stereotactic body radiotherapy for locally advanced
pancreatic cancer. Int J Radiat Oncol Biol Phys. 2008;72:678-686.
71. Schellenberg D, Kim J, Christman-Skieller C, et al. Single-fraction ste-
reotactic body radiation therapy and sequential gemcitabine for the
treatment of locally advanced pancreatic cancer. Int J Radiat Oncol Biol
Phys. 2011;81:181-188.
72. Tozzi A, Comito T, Alongi F, et al. SBRT in unresectable advanced
pancreatic cancer: preliminary results of a mono-institutional experi-
ence. Radiat Oncol. 2013;8:148.
73. Mahadevan A, Jain S, Goldstein M, et al. Stereotactic body radiotherapy
and gemcitabine for locally advanced pancreatic cancer. Int J Radiat
Oncol Biol Phys. 2010;78:735-742.
74. Timmerman RD, Kavanagh BD, Cho LC, et al. Stereotactic body radiation
therapy in multiple organ sites. J Clin Oncol. 2007;25:947-952.
75. Chuong MD, Springett GM, Freilich JM, et al. Stereotactic body radiation
therapy for locally advanced and borderline resectable pancreatic
cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys. 2013;
86:516-522.
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76. Mellon EA, Hoffe SE, Springett GM, et al. Long-term outcomes of
induction chemotherapy and neoadjuvant stereotactic body radio-
therapy for borderline resectable and locally advanced pancreatic
adenocarcinoma. Acta Oncol. 2015;54:979-985.
77. Moningi S, Dholakia AS, Raman SP, et al. The role of stereotactic body
radiation therapy for pancreatic cancer: A single-institution experience.
Ann Surg Oncol. 2015;22:2352-2358.
78. Koong AC, Le QT, Ho A, et al. Phase I study of stereotactic radiosurgery in
patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol
Phys. 2004;58:1017-1021.
79. Koong AC, Christofferson E, Le QT, et al. Phase II study to assess the
efficacy of conventionally fractionated radiotherapy followed by a
stereotactic radiosurgery boost in patients with locally advanced
pancreatic cancer. Int J Radiat Oncol Biol Phys. 2005;63:320-323.
80. Chang DT, Schellenberg D, Shen J, et al. Stereotactic radiotherapy for
unresectable adenocarcinoma of the pancreas. Cancer. 2009;115:665-672.
81. Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide
repertoire, enhances MHC class I expression, and induces successful
antitumor immunotherapy. J Exp Med. 2006;203:1259-1271.
82. Gameiro SR, Jammeh ML, Wattenberg MM, et al. Radiation-induced
immunogenic modulation of tumor enhances antigen processing and
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specific effector CD8+ T cells via dendritic cell activation. J Immunol.
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84. Zeng J, Harris TJ, Lim M, Drake CG, Tran PT. Immune modulation and
stereotactic radiation: Improving local and abscopal responses. Biomed
Res Int. 2013;2013:658126.
85. Neefjes J, Jongsma ML, Paul P, et al. Towards a systems understanding
of MHC class I and MHC class II antigen presentation. Nat Rev Immunol.
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86. Finkelstein SE, Timmerman R, McBride WH, et al. The confluence of
stereotactic ablative radiotherapy and tumor immunology. Clin Dev
Immunol. 2011;2011:439752.
87. Sharabi AB, Nirschl CJ, Kochel CM, et al. Stereotactic radiation therapy
augments antigen-specific PD-1-mediated antitumor immune re-
sponses via cross-presentation of tumor antigen. Cancer Immunol
Res. 2015;3:345-355.
88. Matsumura S, Demaria S. Up-regulation of the pro-inflammatory
chemokine CXCL16 is a common response of tumor cells to ionizing
radiation. Radiat Res. 2010;173:418-425.
89. Dholakia AS, Hacker-Prietz A, Wild AT, et al. Resection of borderline
resectable pancreatic cancer after neoadjuvant chemoradiation does
not depend on improved radiographic appearance of tumor-vessel
relationships. J Radiat Oncol. 2013;2:413-425.
GENITOURINARY (NONPROSTATE) CANCER

Elderly Patients With Bladder

Cancer: Perspectives From a
Surgeon, Medical, and Radiation
Oncologist

CHAIR
Supriya Gupta Mohile, MD, MS
University of Rochester Medical Center
Rochester, NY

SPEAKERS
Eila C. Skinner, MD
Stanford University School of Medicine
Stanford, CA

Nicholas D. James, BSc, MBBS, PhD

University of Warwick and Queen Elizabeth Hospital
Coventry, United Kingdom
EILA C. SKINNER

Treatment of Muscle-Invasive Bladder Cancer in Older

Patients
Eila C. Skinner, MD

OVERVIEW

Treatment of muscle-invasive bladder cancer in older patients is challenging. Definitive therapy of localized disease requires
either surgery or radiation therapy, ideally combined with systemic chemotherapy. However, current population data
suggest that less than half of patients older than age 70 are offered such treatments. We will review tools available to assess
the fitness of older patients for surgery, alternatives, and tips for perioperative patient treatment.

B ladder cancer is a disease of older patients, with in-

creasing incidence with age, and rarely seen before age
40. The majority of patients present with noninvasive tu-
mors that have a high recurrence rate but rarely develop
metastases. These are managed with transurethral resection
and intravesical therapy, both of which are generally well-
tolerated in older patients. However, 20% to 30% of patients
will present with an invasive, high-grade tumor that has a
high potential for metastasis. In general, muscle-invasive
tumors that are not treated will cause increasingly severe
local symptoms and, in most cases, death from metastatic
disease within 2 years. In recent years, urologists and ra-
diation oncologists have been called on to treat an increasing
number of patients older than age 75 with this type of
aggressive disease. Definitive therapy requires either radical
cystectomy or radiation therapy, with or without systemic
chemotherapy. However, current reports indicate that only
65% of patients age 71 to 80 and 35% of patients age 81 to 90
receive these treatments.1 A multidisciplinary approach is
required to identify older patients who should be offered
such treatments.
PATIENT EVALUATION
Initial evaluation of the patient with high-risk bladder cancer
requires careful evaluation of both the tumor and the pa-
tient. Tumor evaluation is identical regardless of age, and
it includes review of prior treatments, complete tumor
staging, review of pathology slides, and possible repeat
resection. Repeat resection with examination under anes-
thesia has been shown to improve accuracy of local staging.2
A full radiographic staging workup of a muscle-invasive
cancer should include a CT chest/abdomen/pelvis with
contrast and bone scan, or PET/CT scan. Although there are
mixed reports regarding the advantage of PET/CT over
standard CT with contrast, PET may improve detection of
occult metastases, which might be particularly useful in
older patients in whom the risk of surgery may not be
warranted if cure is unlikely.3
Patient evaluation in older patients requires some as-
sessment of fitness for surgery and a relative estimate of
complications related to the operation. There has been
considerable progress in this regard over the past few years
with the development of tools for assessment of older
patients. Ideally, the patient may be evaluated by a trained
geriatrician to perform a comprehensive geriatric assess-
ment.4 However, such specialists may not be readily avail-
able and the full assessment is not practical for the average
urologic oncology clinic.
A number of health domains have been shown to con-
tribute to overall frailty in older patients. In addition to
chronological age, these include cognitive function, de-
pendence in activities of daily living, nutritional status,
physical fitness, medical comorbidities, social support,
mood, and history of falls. Several authors have combined
factors that were predictive of morbidity and mortality from
surgery into simplified tests that could be applied in a
urology clinic with minimal extra training.5-14 Some of these
assessments focus on medical comorbidities, functional
status, cognition, and laboratory tests such as serum al-
bumin. These assessments also have been used in retro-
spective studies and applied to large databases such as the
National Surgery Quality Improvement Program.10,11,14
Others use actual tests of physical strength and mobility
(such as the get up and go test and grip-strength measure),
cognitive testing, and patient-reported signs such as weight
loss. These measures require a trained clinician to directly

From Stanford University School of Medicine, Stanford, CA.

Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook.

Corresponding author: Eila C. Skinner, MD, Stanford University School of Medicine, 300 Pasteur Dr., Suite S-287, Stanford, CA 94305; email: skinnere@stanford.edu.

2016 by American Society of Clinical Oncology.

e228 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


evaluate the patient prospectively.9,13 Regardless of the
particular measures used, most of these assessments have
correlated with surgical outcomes and have improved
predictive power compared with the surgeons intuition
after seeing the patient seated on the examination table.
Table 1 shows an example of one such tool that is relatively
straightforward to administer.9
Patients who score poorly on these tests have been shown
to have higher complications and higher mortality from
major abdominal surgery and, even in some cases, in less-
invasive procedures such as transurethral resection of the
prostate or sling.11 The results from these evaluations must
be interpreted in light of the severity of patient symptoms
and the likelihood that a nonoperative approach will be
successful. In addition, the degree to which these factors are
modifiable in a reasonably short time is unclear. However,
the knowledge about risks of surgery can help patients and
families decide on treatment options.
CHOICE OF TREATMENT
Three options should be discussed with every older patient
who presents with invasive localized bladder cancer: (1)
observation with symptom management alone; (2) radiation
therapy, with or without concomitant chemotherapy; and
(3) radical cystectomy, with or without chemotherapy
Partial cystectomy is appealing in this age group because it
has so much less morbidity, but it is only effective in rare
cases of an isolated tumor near the dome of the bladder and
is often associated with local recurrence. Similarly, tran-
surethral resection of the bladder tumor (TURBT) alone has
been associated with at least 50% local recurrence and
progression, even in highly selected patients.15 Only 5% to
KEY POINTS
Less than 50% of patients older than age 70 are currently
receiving definitive therapy for localized muscle-
invasive bladder cancer.
Mortality from radical cystectomy is approximately 10%
in older patients by 90 days.
A number of combined measures of frailty have been
shown to be predictive of morbidity and mortality of
major surgeries in older patients, including radical
cystectomy.
Combination treatment with chemotherapy plus
radiation therapy has been shown to be effective in
older patients, with similar overall survival to most
cystectomy series. However, toxicity may be significant,
and 10% to 20% of patients will require delayed
cystectomy because of invasive local recurrence or
complications from radiation.
A multidisciplinary approach with surgeons, medical
oncologists, and radiation oncologists can optimize
outcomes in this group of patients.
TREATMENT OF MUSCLE-INVASIVE BLADDER CANCER IN OLDER PATIENTS
10% of patients with reasonable life expectancy are can-
didates for either of these approaches.
Observation
The primary advantage of observation is avoiding the po-
tential risks and side effects associated with treatment, with
the implicit hope/expectation that the patient will die of
another illness before the bladder cancer causes morbidity.
Local symptoms may include bleeding, frequency and urgency,
incontinence, bladder pain, outlet obstruction, and upper-
tract obstruction. Symptom management may include repeat
TURBT or fulguration for bleeding, anticholinergics, catheter
drainage, and stents or percutaneous nephrostomy tube
placement. Unfortunately, once local symptoms become
problematic they often are refractory to these treatments
and patients may require multiple trips to the emergency
department, hospital admissions, transfusions, and painful
procedures. It is not uncommon for the 88-year-old patient
who is not thought to be a surgical candidate to end up
requiring a palliative cystectomy a year later when he or she
has metastatic disease. Thus, a patient who is believed to
have a 2-year life expectancy and is likely to survive the
surgery is often best treated with definitive therapy with
cystectomy or radiation.
Radiation Therapy
The advantage of radiation therapy is the avoidance of the
morbidity of surgery and the requirement for a urostomy.
Radiation therapy is most effective when combined with
sensitizing chemotherapy.16 The two most common regi-
mens are either weekly cisplatin or 5-fluorouracil and mi-
tomycin C for patients who are ineligible for cisplatin.16 The
two regimens have not been compared directly, but they
appear to have similar outcomes. There are also no ran-
domized studies directly comparing cystectomy and che-
moradiation, and retrospective comparisons are fraught
with selection bias. Nevertheless, overall survival rates ap-
pear similar to cystectomy series. Age alone does not appear
to affect the success of chemoradiation.17
Initial response to induction chemoradiation is approxi-
mately 70% in most patients.16-19 Local recurrence is observed
in 30% to 40% with approximately 10% to 30% of patients
requiring a subsequent cystectomy for persistent or recurrent
invasive disease. Noninvasive cancers also are common
during follow-up, emphasizing the need for continued cys-
toscopic surveillance. Endoscopic evaluation of the bladder
after radiation therapy can be difficult because of mucosal
ulceration and hyperemia that may require biopsy to dif-
ferentiate from recurrent cancer, especially carcinoma in situ.
Short-term bladder and bowel side effects are common
during radiation treatments, with grade 3 to 4 genito-
urinary toxicity ranging from 2% to 20%, and gastroin-
testinal toxicity approximately 10%. Approximately 10%
to 20% of patients also will have grade 3 to 4 hematologic
complications from the chemotherapy. Long-term grade 1
to 2 genitourinary side effects are observed in 10% to 25%
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EILA C. SKINNER

TABLE 1. The Edmonton Frail Scale9

Domain Item 0 Points 1 Point 2 Points
Cognition Imagine that this pre-drawn circle is a clock. No errors Minor spacing errors Other errors
I would like you to place the numbers in
correct position then place the hands to
indicate a time of 10 after 11.
General Health Status In the past year how many times have you 0 12 .2
been admitted to a hospital?
In general how would you describe your Excellent Fair Poor
health?
Very good
Good
Functional Independence With how many of the following activities 01 24 58
do you require help (meal preparation,
transportation, telephone, house-
keeping, laundry, managing money,
taking medication)?
Social Support When you need help, can you count on Always Sometimes Never
someone who is willing and able to
meet your needs?
Medications Do you use five or more different No Yes
prescription medications on a regular
basis?
At times do you forget to take your No Yes
prescription medications?
Nutrition Have you recently lost weight such that No Yes
your clothing has become looser?
Mood Do you often feel sad or depressed? No Yes
Continence Do you have a problem with losing control No Yes
of urine when you dont want to?
Functional Performance I would like you to sit in this chair with 010 seconds 1120 seconds . 20 seconds,
your back and arms resting. When I say unable or
Go please get up and walk at a safe requires
and comfortable pace to the mark on assistance
the floor (approximately 3 m) and then
return to the chair and sit down.
Total Score (of 17)

of patients, with grade 3 to 4 symptoms in 3% to 8%.
Approximately 2% to 3% require cystectomy for severe
local symptoms.20
Radiation therapy is most effective in patients with lower-
volume disease. Clinical cT2 (versus cT3), visibly complete
transurethral resection, and absence of hydronephrosis and
carcinoma in situ have been shown to be predictors of
better initial response.17,20 A number of radiation series in
the literature have excluded patients with these high-risk
characteristics.
Shipley and colleagues popularized endoscopic re-evaluation
of patients undergoing chemoradiation after approximately
4 weeks of treatment (40 Gy).17 At that point, salvage cys-
tectomy has minimally increased morbidity from the radiation
effects. This may be a reasonable approach in an older patient
who is still a good surgical candidate. This approach has not been
directly compared with a more standard practice of completing
all therapy and offering cystectomy for persistent or recurrent
disease. If a patient truly is not a surgical candidate, then there is
no rationale for an intermediate assessment and the follow-up
schedule also may be less intense. Salvage cystectomy after
chemoradiation is feasible but has increased complications
compared with nonirradiated patients, and neobladder re-
construction is only possible in selected patients.21
Radical Cystectomy
The advantages of cystectomy include management of local
symptoms and the potential for cure. The latter depends on
the pathologic stage of the tumor. For tumors that are organ-
confined on final pathology, the overall cure rate is above 70%
at 5 years. On the other hand, tumors that are already
metastatic to pelvic lymph nodes are only cured about 30%
of the time with surgery, even with the addition of adjuvant
chemotherapy.22 Neoadjuvant chemotherapy has been
shown to result in a 5% absolute improvement in overall
survival in patients undergoing cystectomy, and it is partic-
ularly helpful in patients with hydronephrosis, lymphovascular
invasion, a palpable mass under anesthesia, or invasion of the
prostate or uterus (cT3 or T4 disease). However, extravesical

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extension is encountered on final pathology in 50% of patients
even in the absence of any preoperative risk factors.23
Fitness of the patient to receive a cisplatin-based chemo-
therapy regimen should be assessed by a medical oncologist
because those regimens have the highest effectiveness.
However, up to 60% of patients older than age 70 may have an
estimated glomerular filtration rate of less than 60, which may
make them ineligible for cisplatin therapy.24 Other challenges
of delivery of effective systemic therapy include cardiac dis-
ease, hearing loss, neuropathy, and cognitive dysfunction.25
Expert geriatric assessment and treatment by oncologists ex-
perienced with treating older patients are both helpful. Pa-
tients of all ages tolerate chemotherapy better before surgery
than afterward. In the patient who is not able to receive a
standard cisplatin combination regimen, the decision between
surgery alone versus neoadjuvant chemotherapy with an al-
ternate regimen, such as split-dose cisplatin, gemcitabine plus
carboplatin, or a clinical trial, must be made on an individual
basis with consultation among the patient, oncologist, and
surgeon.
The morbidity of cystectomy and diversion is substantial,
with approximately 60% of patients suffering some type of
complication and about 15% to 20% suffering high-grade
complications.26-28 Overall mortality rate is about 1% to 2%,
but, in patients older than age 75, it is approximately 10% by
90 days following surgery.7,27-30 The most common major
complications include cardiovascular events, sepsis, and bowel
complications. The use of minimally invasive techniques gen-
erally has not improved outcomes except for decreased trans-
fusion requirements.31,32 Full recovery can take several months,
especially for older patients. A major concern is the potential loss
of capacity for independent living, both as a result of the basic
surgical recovery and difficulty in managing the urinary diversion.
Perioperative management. Once a patient and his or her
family have decided to pursue surgery, optimizing physio-
logic function before surgery is critical to minimizing risk.
These might include the following:
1. Nutritional assessment with improvement of malnu-
trition if possible with dietary supplementation
2. Cardiovascular and/or pulmonary evaluation to rule
out reversible ischemia or chronic obstructive pul-
monary disease
3. Optimization of other medical conditions such as di-
abetes and renal dysfunction (e.g., with drainage of an
obstructed kidney)
4. Smoking cessation at least 8 weeks before surgery
(ideally). There is no clear benefit and there may be an
increased risk of quitting for less than 8 weeks.33
Specific conditions that significantly increase risk of cystectomy
in older patients include cirrhosis, malnutrition, morbid obesity,
and chronic immunosuppression. None of these conditions is
easily reversed in the short period of time required for cancer
treatment. However, patients and their families must be aware
of the increased risk and, together with their physicians, should
take this into consideration when making decisions about
treatment.
TREATMENT OF MUSCLE-INVASIVE BLADDER CANCER IN OLDER PATIENTS
Because the average age of patients undergoing cystectomy
today is approximately age 70, most centers performing a
large number of cystectomies have experience with treat-
ment of older patients. Careful fluid management is critical in
this age group, especially in patients with cardiac disease.
Postoperative delirium is also more common in older patients
and avoidance of narcotics may be helpful.34 A low threshold
for diagnosis of infections is necessary because fever and
leukocytosis may be suppressed in this age group. Early
ambulation and aggressive physical therapy is helpful in
avoiding progressive weakness from inactivity, and often the
physical therapy should be continued at home.
Perioperative management strategies recently have fo-
cused on a multimodality approach called the ERAS (En-
hanced Recovery After Surgery) system. This was first
described in the colorectal literature and it has been adapted
to patients undergoing cystectomy.35 The ERAS system in-
cludes aspects of preoperative, intraoperative, and post-
operative management. The addition of an antagonist to
the m morphine receptor in the gut (alvimopam) has been a
critical element of this system, and it has been shown in a
randomized cystectomy trial to decrease hospital stay by at
least 1 day and markedly decrease ileus and the need for
nasogastric suction.36 Daneshmand and colleagues reported
on 110 patients treated with a modified ERAS protocol and
observed a median hospital stay of 4 days without an in-
crease in readmission.37 We have observed a similar im-
provement in average postoperative hospital stay at
Stanford from a median of 8 to 5 days with adoption of these
techniques.
Discharge management is also critical to the patients full
recovery from such major surgery. Patients of all ages who
have undergone cystectomy require assistance with basic
activities of daily living for at least 2 to 3 weeks after surgery.
Many older patients live with an older or frail spouse who is
unable to provide such support, or live alone without family
or other resources for such assistance. They may need to be
discharged to a convalescent facility. Discharge planning
should begin before surgery with a frank discussion of the
help required and resources available to the patient.
OUTCOMES
Major complications and death following radical cystectomy
are more common in patients older than age 70 than in
younger patients. A number of recent reports identify 90-day
mortality after cystectomy to be in the range of 10% to as high
as 32% for patients over age 85.7,27,28 Nevertheless, most older
patients recover after cystectomy, and the primary risk of
death in the first 2 to 3 years after surgery is metastatic disease
rather than competing causes of mortality. Continent diversion
has been performed successfully in selected older patients
who appear to have outcomes similar to younger patients.
Regaining continence may take longer in older patients who
undergo neobladder reconstruction. Although overall survival,
of course, is worse in older patients, there is controversy over
whether cancer-specific survival is worse in this age group.38,39
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e231
EILA C. SKINNER
CONCLUSION
Older patients with muscle-invasive bladder cancer
represent a particularly challenging group of patients to
treat. Patient evaluation and risk assessment are critical in
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1. Gray PJ, Fedewa SA, Shipley WU, et al. Use of potentially curative
therapies for muscle-invasive bladder cancer in the United States:
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2. Herr HW. Role of repeat resection in non-muscle-invasive bladder
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3. Rais-Bahrami S, Pietryga JA, Nix JW. Contemporary role of advanced
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4. Hurria A, Cirrincione CT, Muss HB, et al. Implementing a geriatric as-
sessment in cooperative group clinical cancer trials: CALGB 360401.
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6. Revenig LM, Canter DJ, Kim S, et al. Report of a simplified frailty score
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7. Morgan TM, Keegan KA, Barocas DA, et al. Predicting the probability of
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8. Robinson TN, Wu DS, Pointer L, et al. Simple frailty score predicts
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15. Cha EK, Donahue TF, Bochner BH. Radical transurethral resection alone,
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16. James ND, Hussain SA, Hall E, et al; BC2001 Investigators. Radiotherapy
with or without chemotherapy in muscle-invasive bladder cancer.
N Engl J Med. 2012;366:1477-1488.
17. Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-term outcomes of
selective bladder preservation by combined-modality therapy for in-
vasive bladder cancer: the MGH experience. Eur Urol. 2012;61:705-711.
18. Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with
muscle-invasive bladder cancer after selective bladder-preserving
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helping patients and families decide about treatment op-
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plinary approach can optimize patient outcomes.
combined-modality therapy: a pooled analysis of Radiation Therapy
Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233.
J Clin Oncol. 2014;32:3801-3809.
19. Rodel C, Grabenbauer GG, Kuhn R, et al. Combined-modality treatment
and selective organ preservation in invasive bladder cancer: long-term
results. J Clin Oncol. 2002;20:3061-3071.
20. Ploussard G, Daneshmand S, Efstathiou JA, et al. Critical analysis of
bladder sparing with trimodal therapy in muscle-invasive bladder
cancer: a systematic review. Eur Urol. 2014;66:120-137.
21. Eisenberg MS, Dorin RP, Bartsch G, et al. Early complications of
cystectomy after high dose pelvic radiation. J Urol. 2010;184:
2264-2269.
22. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment
of invasive bladder cancer: long-term results in 1,054 patients. J Clin
Oncol. 2001;19:666-675.
23. Culp SH, Dickstein RJ, Grossman HB, et al. Refining patient selection for
neoadjuvant chemotherapy before radical cystectomy. J Urol. 2014;
191:40-47.
24. Dash A, Galsky MD, Vickers AJ, et al. Impact of renal impairment on
eligibility for adjuvant cisplatin-based chemotherapy in patients
with urothelial carcinoma of the bladder. Cancer. 2006;107:
506-513.
25. Galsky MD. How I treat bladder cancer in elderly patients. J Geriatr
Oncol. 2015;6:1-7.
26. Shabsigh A, Korets R, Vora KC, et al. Defining early morbidity of radical
cystectomy for patients with bladder cancer using a standardized
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27. Comploj E, West J, Mian M, et al. Comparison of complications from
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2015;94:25-30.
28. Berger I, Martini T, Wehrberger C, et al. Perioperative complications and
90-day mortality of radical cystectomy in the elderly (75+): a retro-
spective, multicentre study. Urol Int. 2014;93:296-302.
29. Schiffmann J, Gandaglia G, Larcher A, et al. Contemporary 90-day
mortality rates after radical cystectomy in the elderly. Eur J Surg Oncol.
2014;40:1738-1745.
30. Zakaria AS, Santos F, Tanguay S, et al. Radical cystectomy in patients
over 80 years old in Quebec: a population-based study of outcomes.
J Surg Oncol. 2015;111:917-922.
31. Yuh BE, Nazmy M, Ruel NH, et al. Standardized analysis of frequency and
severity of complications after robot-assisted radical cystectomy. Eur
Urol. 2012;62:806-813.
32. Bochner BH, Dalbagni G, Sjoberg DD, et al. Comparing open radical
cystectomy and robot-assisted laparoscopic radical cystectomy: a ran-
domized clinical trial. Eur Urol. 2015;67:1042-1050.
33. Warner MA, Offord KP, Warner ME, et al. Role of preoperative cessation
of smoking and other factors in postoperative pulmonary complica-
tions: a blinded prospective study of coronary artery bypass patients.
Mayo Clin Proc. 1989;64:609-616.
34. Large MC, Reichard C, Williams JT, et al. Incidence, risk factors, and
complications of postoperative delirium in elderly patients undergoing
radical cystectomy. Urology. 2013;81:123-129.

35. Cerantola Y, Valerio M, Persson B, et al. Guidelines for perioperative
care after radical cystectomy for bladder cancer: Enhanced Recovery
After Surgery (ERAS()) society recommendations. Clin Nutr. 2013;32:
879-887.
36. Lee CT, Chang SS, Kamat AM, et al. Alvimopan accelerates gastroin-
testinal recovery after radical cystectomy: a multicenter randomized
placebo-controlled trial. Eur Urol. 2014;66:265-272.
TREATMENT OF MUSCLE-INVASIVE BLADDER CANCER IN OLDER PATIENTS
37. Daneshmand S, Ahmadi H, Schuckman AK, et al. Enhanced recovery pro-
tocol after radical cystectomy for bladder cancer. J Urol. 2014;192:50-56.
38. Horovitz D, Turker P, Bostrom PJ, et al. Does patient age affect survival
after radical cystectomy? BJU Int. 2012;110(11 Pt B):E486-E493.
39. Leveridge MJ, Siemens DR, Mackillop WJ, et al. Radical cystectomy and
adjuvant chemotherapy for bladder cancer in the elderly: a population-
based study. Urology. 2015;85:791-798.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e233
GENITOURINARY (NONPROSTATE) CANCER

Renal Cell Carcinoma: Systemic

Treatment, Evolving TKIs, and
Immuno-Oncology

CHAIR
Thomas E. Hutson, DO, PharmD, FACP
Texas Oncology
Dallas, TX

SPEAKERS
Brian I. Rini, MD, FACP
Cleveland Clinic Taussig Cancer Institute
Cleveland, OH

Robert A. Figlin, MD, FACP

Cedars-Sinai Medical Center
Los Angeles, CA
 THE EVOLUTION OF SYSTEMIC THERAPY IN mRCC

The Evolution of Systemic Therapy in Metastatic Renal Cell

Carcinoma
Thomas E. Hutson, DO, PharmD, FACP, Gregory R. Thoreson, MD, Robert A. Figlin, MD, FACP, and
Brian I. Rini, MD, FACP

OVERVIEW

The treatment landscape for renal cell carcinoma (RCC) is a dynamic process that has seen considerable change in recent
years. We have seen a rebirth of original breakthroughs with immune checkpoint inhibitors showing promise in patients with
treatment-refractory disease. The optimal sequencing of treatments and incorporation of novel therapeutics are actively
being investigated and have yet to be determined. The clinical challenges of this evolving treatment paradigm can be
attributed to cost considerations, toxicity, and defining endpoints in the management of advanced RCC. As novel thera-
peutics emerge, finding the optimal treatment regimen for patients will have an increasing focus on patient-centered
outcomes and improvement in quality of life in addition to improving survival.

M anagement of RCC continues to evolve, with many of

the recent advancements occurring in the treatment
of patients with metastatic disease. Approximately one in
three patients present with either regionally advanced or
metastatic disease, excluding candidacy for extirpative
surgery with curative intent and ultimately requiring sys-
temic therapy as their only option.1 The earliest forms of
systemic therapy emerged in the 1980s and were based on
adoptive immunotherapy. Observations at the National Institutes
of Health showed objective responses with the administration of
lymphokine-activated killer cells and recombinant interleukin-2
(IL-2) across four histologic cell types, including RCC.2 By the early
1990s, IL-2, interferon, or a combination of the two were widely
adopted, and in the early 2000s, this became the standard of
care.3,4 To date, the only durable complete responses observed in
metastatic RCC (mRCC) are with this modality of treatment.5 The
latter part of the decade ushered in the era of targeted therapies,
with pivotal clinical trials showing improved survival when
compared with interferon.6-8 This line of therapy is predicated
on inhibiting VEGF or mTOR. Recently, the treatment paradigm
has shifted back toward immunotherapy, with an immune
checkpoint inhibitor showing superiority over an mTOR in-
hibitor in a select patient population that demonstrated dis-
ease progression while on antiangiogenic therapy.9
This influx of new anticancer therapies in mRCC has
provided new opportunities to explore the therapeutic
potential of combination therapies. To date, combination
therapy in mRCC has not provided clinical benefit. Several
trials over the past decade have explored combinations,
largely of VEGF inhibitors plus VEGF inhibitors or VEGF in-
hibitors plus mTOR inhibitors.10-14 Collectively, these trials
failed because of either excessive toxicity preventing ad-
ministration of full doses of each agent/toxicity in general, or
lack of a proven efficacy advantage over monotherapy.
On this landscape, recent data regarding the combination
of a VEGF receptor inhibitor (lenvatinib) and an mTOR in-
hibitor (everolimus) is notable.15 A phase II study randomly
assigned 153 patients with mRCC who had received one
prior VEGF-targeted therapy to lenvatinib plus everolimus
compared with lenvatinib monotherapy compared with ever-
olimus monotherapy with a primary endpoint of progression-
free survival (PFS). Progression-free survival as initially reported
per investigator assessment, was 14.6 months for the combi-
nation arm, 7.4 months for the lenvatinib monotherapy arm,
and 5.5 months for the everolimus arm. Both lenvatinib-
containing arms were significantly longer in terms of PFS
than the everolimus arm (lenvatinib plus everolimus vs.
everolimus, hazard ratio [HR] 0.40; p = .0005; lenvatinib
vs. everolimus, HR 0.61; p = .048) but not significantly
different from each other (lenvatinib plus everolimus vs.
lenvatinib, HR 0.66; p = .12). Objective response rates also
favored the combination arm (43% vs. 27% vs. 6%). There was
considerable toxicity in the combination arm necessitating
that 71% of patients reduce their lenvatinib dose and 24%
discontinue for toxicity. Importantly, updated data using in-
dependent radiologic review of CT scans has been published.16

From the Texas A&M Health Science Center, Bryan TX; Baylor-Sammons Cancer Center, Dallas, TX; US Oncology, Texas Oncology, Charles A. Sammons Cancer Center, Baylor University
Medical Center, Dallas, TX; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Thomas E. Hutson, DO, PharmD, FACP, Texas Oncology, 3410 Worth St., Suite 400, Dallas, TX 75254; email: thomas.hutson@usoncology.com.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 113

HUTSON ET AL
These data demonstrate a reduction in the combination arm
PFS (to 12.8 months) and the response rate (to 35%). Thus, the
benefit of this specific combination over monotherapy remains
to be established in larger trials. The biology of why this
combination could have benefit where other similar combi-
nations have failed is unknown and also requires further study.
Cabozantinib, an oral small molecule inhibitor of tyrosine
kinases including MET, VEGF, and AXL, has shown recent
promise in patients with mRCC that has failed first-line
therapy with VEGFR-targeting tyrosine kinase inhibitors.
In a phase III clinical trial with 658 patients, cabozantinib
demonstrated improved PFS (7.4 vs. 3.8 months), overall
survival (HR 0.67), and objective response rates (21% vs. 5%)
when compared with everolimus.17 Cabozantinib, which is
currently approved by the U.S. Food and Drug Administration
(FDA) for the treatment of patients with progressive meta-
static medullary thyroid cancer, has previously been granted
Breakthrough Therapy and Fast Track designations and is
likely to be approved for treatment of refractory disease.18
As noted, checkpoint inhibition has undergone rapid
clinical development in mRCC with the FDA approval of nivo-
lumab for refractory disease. Several combination regimens of
immunotherapy or immunotherapy plus VEGF therapy have
been initially explored (Table 1). There is clinical rationale for
such combinations given the activity of each approach as
monotherapy, but also a biologic rationale, as VEGF may lead to
immune suppression and thus VEGF blockade may allow for
enhanced effect of immunotherapy.19,20 Nivolumab was
combined in a multicohort phase II trial with sunitinib and
separately with pazopanib. The pazopanib cohort was not
expanded because of liver function test (LFT) abnormalities
in the initial cohort of patients. The sunitinib cohort ex-
panded and demonstrated antitumor activity as evidenced
by a robust objective response rate.
KEY POINTS
The treatment of advanced renal cell carcinoma is a
dynamic process that has undergone considerable
change in the past 40 years with a recent rebirth of
immuno-oncology drugs.
Optimal sequence and combinations of novel therapies
are currently being investigated and pose considerable
challenges to providers.
Toxicity profiles of targeted therapies and immuno-
oncology agents are unique, and effective therapy
management must balance treatment dosing, duration,
and adverse event management.
A value-based framework for cancer care requires the
incorporation of effectiveness, safety, and efficiency
while maintaining incentives for the continued research
and development of novel oncologic therapeutics.
Defining endpoints for patients with metastatic renal
cell carcinoma continue to evolve, with an increasing
emphasis on patient-centered outcomes in addition to
survival data.
114 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
This combination, however, was not further pursued
clinically because of development of the nivolumab plus ipi-
limumab combination. This latter combination was evaluated
as part of the same clinical trial and also demonstrated re-
markable clinical activity (Table 1). Toxicity was higher in the
arm with the higher ipilimumab dosing and was also
unacceptably high in a small cohort (six patients) who
received a higher dose of both drugs. This combination is
being further pursued in a front-line phase III trial com-
pared with sunitinib. Accrual to this trial has been com-
pleted and results are pending.
Additional PD-1 or PD-L1 inhibitors have been initially
combined with anti-VEGF therapy. Pembrolizumab, a PD-1
inhibitor, was combined with pazopanib. Several patients
experienced LFT abnormalities necessitating interruption of
therapy, and other patients have been treated with a lower
initial dose of pazopanib. The safety of this particular combi-
nation awaits further experience. Pembrolizumab has also
been combined with axitinib. A small safety cohort of 11 pa-
tients demonstrated tolerability and early signs of efficacy. An
expansion cohort has been accrued to further clarify safety and
efficacy.
An alternative approach to checkpoint inhibition is an
antibody that blocks the ligand for the PD-1 receptor, PD-L1.
Atezolizumab is a monoclonal antibody that has been
studied in many solid tumors including RCC. An initial phase I
study of atezolizumab demonstrated the safety of mono-
therapy in RCC and other solid tumors, and a small expansion
cohort in RCC tested the combination of atezolizumab and
bevacizumab. This combination was well tolerated, with
early signs of efficacy in the form of tumor burden reduction.
A randomized phase II trial was then undertaken in front-line
mRCC randomly assigning patients to this combination,
atezolizumab monotherapy, or standard sunitinib with a
primary endpoint of PFS. This trial has completed accrual
with results pending. Importantly, this trial contains an
arm with antiPD-L1 monotherapy. Clinical and correlate
results from this arm may help identify if there is a subset
of patients with mRCC who can safely and effectively receive
single-agent checkpoint inhibition. A randomized phase III
trial has also begun with this combination in front-line mRCC,
randomly assigning patients to the combination or sunitinib
with a PFS/overall survival coprimary endpoint.
Challenges for managing RCC are not only considerations
of clinical algorithm development but also opportunities to
demonstrate value-based cancer care, especially in a disease
with multiple treatment approvals.21-23 The Institute of Medicine
has delineated six elements of value in cancer care: safety,
effectiveness, patient centeredness, timeliness, efficiency, and
equity. The American Society of Clinical Oncology has selected
three of these for its value-based framework for cancer care:
clinical benefit (effectiveness), toxicity (safety), and cost (effi-
ciency). The Memorial Sloan Kettering Cancer Center has added
to the dialogue by including research and development costs and
population health burden, and the National Comprehensive
Cancer Network has included elements of affordability. Health
economics research has started to delineate how patients with
 THE EVOLUTION OF SYSTEMIC THERAPY IN mRCC

TABLE 1. Select Studies of Combination Therapy in Renal Cell Carcinoma

No. Patient
Trial Patients Population Study Design ORR Median PFS Comments
Immunotherapy Plus Anti-VEGF Nivolumab Plus TKI
NCT01472081, 33 Front-line and Nivolumab 2 mg/kg every 52% 49 weeks; 78%
Phase I/II34 refractory mRCC 3 weeks + sunitinib 50 mg 4/2 progression-free
at 24 weeks
20 Nivolumab 2 mg/kg every 45% 31 weeks; 55% Pazopanib cohort not
3 weeks + pazopanib 800 mg/day progression-free expanded because of
at 24 weeks hepatic toxicity
Pembrolizumab Plus TKI
NCT02014636, 20 Front-line mRCC Pembrolizumab plus 40% NR AST and/or ALT elevations
Phase I/II35 pazopanib 600 mg every day . 5x ULN observed in
(10 patients) or 800 mg every 13 patients
day (10 patients)
NCT02133742, 11 Front-line mRCC Pembrolizumab 2 mg/kg 55% NR 41 additional patients
Phase IB36 every 3 weeks plus enrolled for further
axitinib 5 mg twice daily safety/efficacy
investigation
Atezolizumab Plus Bevacizumab
NCT01633970, 10 Front-line mRCC 1,200 mg IV every 3 weeks atezolizumab + 40% SD $ 24 weeks 9/10 patients remain
Phase IB37 bevacizumab 15 mg/kg every in 4 patients on treatment
3 weeks
NCT01984242 300 Front-line mRCC 1,200 mg IV every 3 weeks NR NR Accrual complete
Randomized atezolizumab +/2 bevacizumab
Phase II 15 mg/kg every 3 weeks vs. sunitinib
NCT02420821, 550 Front-line mRCC 1,200 mg IV every 3 weeks atezolizumab + NR NR Accrual ongoing
Phase III bevacizumab 15 mg/kg every
3 weeks vs. sunitinib
NCT02420821, 550 Front-line mRCC 1,200 mg IV every 3 weeks atezolizumab + NR NR Accrual ongoing
Phase III bevacizumab 15 mg/kg every
3 weeks vs. sunitinib
Immunotherapy Plus Immunotherapy
Nivolumab Plus Ipilimumab
NCT01472081, 47 Front-line and N3 + I1* 38% 33.3 weeks
Phase I/II38 refractory mRCC
47 N1 + I3* 40% 47.1 weeks Increased toxicity in
the I3
NCT02231749, 1,070 Front-line mRCC N3 + I1 NR NR Accrual complete
Phase III
*Arm N3 + I1; nivolumab 3 mg/kg + ipilimumab 1 mg/kg; Arm N1 + I3; nivolumab 1 mg/kg + ipilimumab 3 mg/kg.
Abbreviations: AST, aspartate transaminase; ALT, alanine aminotransferase; NR, no response; PFS, progression-free survival; ORR, overall response rate; ULN, upper limit of normal;
TKI, tyrosine kinase inhibitor; mRCC, metastatic renal cell carcinoma.

cancer value hope and the implications for cost-effectiveness
assessments of high-cost cancer therapies.24 A patients will-
ingness to pay for a hopeful therapy may be influenced by their
economic realities.25 In addition, consideration of quality-
adjusted cost of care has been used to measure the growth
and new innovation costs associated with novel therapies.26,27
Unfortunately, none of these growing health economic ap-
proaches to cancer care have been applied uniformly to the
growing portfolio of cancer treatments for RCC. This remains a
unique challenge in a disease with nine new drugs approved by
the FDA over the past decade.
The toxicity profiles of targeted therapies and immuno-
oncology agents are quite different, and their management
continues to evolve. Toxicities can generally be broken down
into three categories: side effects produced by the VEGF
inhibitors/tyrosine kinase inhibitors (i.e., sunitinib, pazopanib,
axitinib, sorafenib, and bevacizumab), mTOR inhibitors
(i.e., everolimus, temsirolimus), and more recently immuno-
oncology drugs (i.e., nivolumab). Effective therapy manage-
ment must be a balance between dosing, treatment duration,
and adverse event management.
The common adverse events associated with VEGF in-
hibitors include fatigue, hand/foot syndrome, hypertension,
hepatotoxicity, diarrhea, stomatitis, myelosuppression, and
proteinuria. For the mTOR inhibitors, fatigue, diarrhea, sto-
matitis, myelosuppression, pneumonitis, and infections are
the most common adverse events. Management of these
chronic toxicities is associated with improved dosing and
treatment duration and is best supported by aggressive ad-
verse event management.
Recent evidence has suggested that, for example, with
sunitinib, adjusting the dosing schedule to a 2:1 schedule
from the original 4:2 schedule allows for full dosing
maintenance of concentrations of drug with a possible

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 115

HUTSON ET AL
amelioration of toxicity. Black box warnings for pazopanib
and sunitinib for potential liver toxicity must guide treat-
ment management, as well as pneumonitis, a class effect
from mTOR inhibition characterized by noninfectious,
nonmalignant infiltrates associated with cough, dyspnea,
and radiographic findings of ground glass opacities and
focal consolidation. Several published summaries will guide
recommended adverse event management in mTOR-treated
RCC, especially for noninfectious pneumonitis, stomatitis, and
infections. The side effect profile from targeted agents is
usually quite predictable, and the optimal management will
increase drug exposure and improve overall outcome. Toxicity
is often treatable and can be managed with schedule changes
and treatment interruptions before dose reduction is
considered.
With the recently approved immuno-oncology agent, we are
now presented with a different spectrum of toxicitiesusually
of low frequencycalled immune-related adverse events,
which have timing that is less predictable than with adverse
events with targeted agents, can appear without warning, and
often require immune suppression with corticosteroids where
holding the drug is typically insufficient.
Several websites now have guides to immune-mediated
adverse reaction management, and physicians should fa-
miliarize themselves with these side effects. Interestingly,
the time to onset of selected treatment-related adverse
events for immuno-oncology agents such as nivolumab can
sometimes be weeks to months, and, as such, careful and
continual monitoring of the patient is required. Although
most side effects are low grade, grade 3 and 4 toxicities
can occur, especially immune-mediated pulmonary, he-
patic, gastrointestinal, and renal adverse reactions. Immune-
mediated endocrinopathies can be life threatening if not
approached appropriately. Recent evidence suggests that
immune suppression may not reduce the efficacy of immuno-
oncology approaches and, as such, might allow for the con-
tinued administration of these agents. These new therapies
have the potential to improve and prolong patients lives,
References
1. Howlader NA, Krapcho M, Garshell J. SEER Cancer Statistics Review,
1975--2012. Bethesda: National Cancer Institute; 2014.
2. Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic
administration of autologous lymphokine-activated killer cells and
recombinant interleukin-2 to patients with metastatic cancer. N Engl J
Med. 1985;313:1485-1492.
3. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2,
recombinant human interferon alfa-2a, or both in metastatic renal-cell
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4. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose
and low-dose interleukin-2 in patients with metastatic renal cancer.
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5. McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of
high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon
116 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
and optimizing toxicity management will mean keeping the
patient on drug while maintaining quality of life. The early
recognition and intervention for the successful management
of immune-related adverse events is critical with this new
class of drugs.
The traditional endpoints for approval of targeted ther-
apies in RCC have been PFS. For patients treated with tar-
geted agents, it is clear that improvements in PFS have been
associated with improvements in overall survival. It is in-
teresting to note that with the newer immuno-oncology
agents, overall survival has been the primary endpoint. With
the approval of nivolumab, there is evidence that overall
survival is benefited, while there is no apparent difference in
PFS, and as such, we may be seeing an evolution in endpoint
evaluations for patients with RCC.28-30 It is clear from a
patient perspective that overall survival benefits are critical.
This presents a challenge to the practicing physician because
we are typically used to using imaging as a surrogate in-
termediate endpoint for the evaluation of benefit for pa-
tients. With circumstances such as pseudo-progression or
early growth followed by regression, we now must re-
consider the use of imaging in deciding when and if to take a
patient off of systemic therapies.21 Further evolution in
endpoint evaluation in RCC will evolve, especially if bio-
markers become available to help identify populations of
patients most likely to benefit from systemic therapy.
The treatment landscape for RCC is a dynamic process that
has seen considerable change in recent years. We have
seen a rebirth of original breakthroughs with immune
checkpoint inhibitors showing promise in treatment re-
fractory disease, which may play a crucial role in combi-
nation therapies. The clinical challenges of this evolving
treatment paradigm can be attributed to cost consider-
ations, toxicity, and defining endpoints in the management
of advanced RCC. As novel therapeutics emerge, identifying
the optimal sequence and combinations of therapies will be
based on individual patient characteristics with an em-
phasis on improving quality of life and survival.
in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23:
133-141.
6. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa
in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124.
7. Escudier B, Eisen T, Stadler WM, et al; TARGET Study Group. Sorafenib in
advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134.
8. Hudes G, Carducci M, Tomczak P, et al; Global ARCC Trial. Temsirolimus,
interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med.
2007;356:2271-2281.
9. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 In-
vestigators. Nivolumab versus everolimus in advanced renal-cell car-
cinoma. N Engl J Med. 2015;373:1803-1813.
10. Rini BI, Garcia JA, Cooney MM, et al. Toxicity of sunitinib plus bev-
acizumab in renal cell carcinoma. J Clin Oncol. 2010;28:e284-e285;
author reply e286-e287.

11. Rini BI, Bellmunt J, Clancy J, et al. Randomized phase III trial of tem-
sirolimus and bevacizumab versus interferon alfa and bevacizumab in
metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014;32:
752-759.
12. Ravaud A, Barrios CH, Alekseev B, et al. RECORD-2: phase II randomized
study of everolimus and bevacizumab versus interferon a-2a and
bevacizumab as first-line therapy in patients with metastatic renal cell
carcinoma. Ann Oncol. 2015;26:1378-1384.
13. Negrier S, Gravis G, Perol D, et al. Temsirolimus and bevacizumab, or
sunitinib, or interferon alfa and bevacizumab for patients with ad-
vanced renal cell carcinoma (TORAVA): a randomised phase 2 trial.
Lancet Oncol. 2011;12:673-680.
14. Flaherty KT, Manola JB, Pins M, et al. BEST: a randomized phase II study
of vascular endothelial growth factor, RAF kinase, and mammalian
target of rapamycin combination targeted therapy with bevacizumab,
sorafenib, and temsirolimus in advanced renal cell carcinomaa trial of
the ECOG-ACRIN Cancer Research Group (E2804). J Clin Oncol. 2015;33:
2384-2391.
15. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the
combination in patients with metastatic renal cell carcinoma: a rand-
omised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:
1473-1482.
16. Motzer RJ, Hutson TE, Ren M, et al. Independent assessment of len-
vatinib plus everolimus in patients with metastatic renal cell carcinoma.
Lancet Oncol. 2016;17:e4-e5.
17. Choueiri TK, Escudier B, Powles T, et al; METEOR Investigators.
Cabozantinib versus everolimus in advanced renal-cell carcinoma.
N Engl J Med. 2015;373:1814-1823.
18. Viola D, Cappagli V, Elisei R. Cabozantinib (XL184) for the treatment of
locally advanced or metastatic progressive medullary thyroid cancer.
Future Oncol. 2013;9:1083-1092.
19. Shrimali RK, Yu Z, Theoret MR, et al. Antiangiogenic agents can
increase lymphocyte infiltration into tumor and enhance the effec-
tiveness of adoptive immunotherapy of cancer. Cancer Res. 2010;70:
6171-6180.
20. Kusmartsev S, Su Z, Heiser A, et al. Reversal of myeloid cell-mediated
immunosuppression in patients with metastatic renal cell carcinoma.
Clin Cancer Res. 2008;14:8270-8278.
21. Zon RT, Frame JN, Neuss MN, et al. American Society of Clinical On-
cology Policy Statement on Clinical Pathways in Oncology. J Oncol Pract.
2016;12:261-266.
22. Saltz LB. The value of considering cost, and the cost of not considering
value. J Clin Oncol. 2016;34:659-660.
23. Young RC. Value-based cancer care. N Engl J Med. 2015;373:2593-2595.
24. Neumann PJ, Cohen JT. Measuring the value of prescription drugs.
N Engl J Med. 2015;373:2595-2597.
THE EVOLUTION OF SYSTEMIC THERAPY IN mRCC
25. Lakdawalla DN, Romley JA, Sanchez Y, et al. How cancer patients value
hope and the implications for cost-effectiveness assessments of high-
cost cancer therapies. Health Aff (Millwood). 2012;31:676-682.
26. Lakdawalla D, Shafrin J, Lucarelli C, et al. Quality-adjusted cost of care:
a meaningful way to measure growth in innovation cost versus the value
of health gains. Health Aff (Millwood). 2015;34:555-561.
27. Stevens W, Philipson TJ, Khan ZM, et al. Cancer mortality reductions
were greatest among countries where cancer care spending rose the
most, 1995-2007. Health Aff (Millwood). 2015;34:562-570.
28. Hoos A, Wolchok JD, Humphrey RW, et al. CCR 20th Anniversary
Commentary: immune-related response criteriacapturing clinical ac-
tivity in immuno-oncology. Clin Cancer Res. 2015;21:4989-4991.
29. Wolchok JD, Hoos A, ODay S, et al. Guidelines for the evaluation of
immune therapy activity in solid tumors: immune-related response
criteria. Clin Cancer Res. 2009;15:7412-7420.
30. Nishino M, Giobbie-Hurder A, Gargano M, et al. Developing a common
language for tumor response to immunotherapy: immune-related re-
sponse criteria using unidimensional measurements. Clin Cancer Res.
2013;19:3936-3943.
31. Sonpavde G, Choueiri TK, Escudier B, et al. Sequencing of agents for
metastatic renal cell carcinoma: can we customize therapy? Eur Urol.
2012;61:307-316.
32. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in
metastatic renal-cell carcinoma. N Engl J Med. 2013;369:722-731.
33. Escudier B, Szczylik C, Porta C, et al. Treatment selection in metastatic
renal cell carcinoma: expert consensus. Nat Rev Clin Oncol. 2012;9:
327-337.
34. Amin A, Plimack ER, Infante JR, et al. Nivolumab (anti--PD--1; BMS--
936558, ONO--4538) in combination with sunitinib or pazopanib in
patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol.
2014;32:5s (suppl; abstr 5010).
35. McDermott DF, Infante JR, Chowdhury S, et al. A phase I/II study to
assess the safety and efficacy of pazopanib (paz) and pembrolizumab
(pembro) in patients (pts) with advanced renal cell carcinoma (aRCC).
Eur J Cancer. 2015;51:S519-S520.
36. Atkins MB, Gupta S, Choueiri TK, et al. Phase lb dose--finding study of
axitinib plus pembrolizumab in treatment--naive patients with ad-
vanced renal cell carcinoma. J Immunother Cancer. 2015;3:P353.
37. McDermott, D, Sznol M, Sosman JA, et al. 809O -- Immune correlates
and long term follow up of a phase Ia study of MPDL3280A, an engi-
neered PD--L1 antibody, in patients with metastatic renal cell carcinoma
(mRCC). Ann Oncol. 2014;25:iv280-iv304.
38. Hammers H, Plimack ER, Infante JR, et al. Expanded cohort results from
CheckMate 016: A phase I study of nivolumab in combination with
ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol.
2015;33 (suppl; abstr 4516).
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 117
GENITOURINARY (PROSTATE) CANCER

Contemporary Active Surveillance

for Prostate Cancer: Do We Need
Better Imaging and Molecular
Testing?

CHAIR
Edward M. Schaeffer, MD, PhD
Northwestern University
Chicago, IL

SPEAKERS
Jonathan I. Epstein, MD
Johns Hopkins University School of Medicine
Baltimore, MD

Peter L. Choyke, MD
National Cancer Institute at the National Institutes of Health
Bethesda, MD

Stacy Loeb, MD
New York University Langone Medical Center
New York, NY
 ACTIVE SURVEILLANCE FOR PROSTATE CANCER

Active Surveillance of Prostate Cancer: Use, Outcomes,

Imaging, and Diagnostic Tools
Jeffrey J. Tosoian, MD, MPH, Stacy Loeb, MD, MSc, Jonathan I. Epstein, MD, Baris Turkbey, MD,
Peter L. Choyke, MD, and Edward M. Schaeffer, MD, PhD

OVERVIEW

Active surveillance (AS) has emerged as a standard management option for men with very low-risk and low-risk prostate
cancer, and contemporary data indicate that use of AS is increasing in the United States and abroad. In the favorable-risk
population, reports from multiple prospective cohorts indicate a less than 1% likelihood of metastatic disease and prostate
cancerspecific mortality over intermediate-term follow-up (median 56 years). Higher-risk men participating in AS appear
to be at increased risk of adverse outcomes, but these populations have not been adequately studied to this point. Although
monitoring on AS largely relies on serial prostate biopsy, a procedure associated with considerable morbidity, there is a need
for improved diagnostic tools for patient selection and monitoring. Revisions from the 2014 International Society of Urologic
Pathology consensus conference have yielded a more intuitive reporting system and detailed reporting of low-intermediate
grade tumors, which should facilitate the practice of AS. Meanwhile, emerging modalities such as multiparametric magnetic
resonance imaging and tissue-based molecular testing have shown prognostic value in some populations. At this time,
however, these instruments have not been sufficiently studied to consider their routine, standardized use in the AS setting.
Future studies should seek to identify those platforms most informative in the AS population and propose a strategy by
which promising diagnostic tools can be safely and efficiently incorporated into clinical practice.

A ctive surveillance of prostate cancer with curative intent

was described in the mid-1990s, and early AS experi-
ences were reported in 2002.1,2 Under the AS approach, men
with favorable-risk cancers are monitored, and curative
intervention is pursued upon evidence of higher-risk
disease. Over the last 2 decades, AS has emerged as a
standard management option for men with very low-risk
and low-risk prostate cancer.3,4 Observations from two
large, prospective AS cohorts reach nearly 20 years of
follow-up and indicate very low likelihood of metastatic
disease or prostate cancerspecific mortality in appro-
priately selected men.5,6 Despite its utility in reducing
overtreatment, AS is not without morbidity. 7 The con-
temporary practice of AS remains largely based on fre-
quent clinical examination, serum prostate-specific antigen
(PSA) testing, and prostate biopsy,8 a procedure associ-
ated with patient discomfort and serious complications
including infection.9,10 Furthermore, these methods lack
sensitivity for detection of higher-risk disease, as evi-
denced by the substantial proportion of men meeting AS
criteria who demonstrate high-risk features at radical
prostatectomy.11,12
As such, there is a substantial need for more accurate methods
of patient selection and monitoring. An ideal diagnostic tool
would impart valuable diagnostic and prognostic information
with limited associated morbidity at a reasonable cost. Although
the ideal platform does not currently exist, advances in tech-
nology and improved understanding of the molecular basis of
prostate cancer have initiated progress toward that goal.13-16 For
example, the use and utility of multiparametric MRI (mpMRI)
of the prostate has increased substantially in recent years.17
Furthermore, clinically validated molecular tests have estab-
lished a prognostic role in some clinical contexts.18 These
platforms, along with a recently updated system of pathologic
grading, present a unique opportunity to improve the practice of
AS.19,20 This article aims to review the contemporary practice of
AS, including trends in use, outcomes, pathologic grading, MRI,
and tissue-based molecular testing.
TRENDS IN USE OF ACTIVE SURVEILLANCE
Although the AS approach was previously underutilized,21,22
recent data from multiple countries have confirmed in-
creasing use, corresponding with its inclusion in multiple
national guidelines and the availability of more data on

From the Brady Urological Institute, Departments of Urology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Urology and Population Health,
New York University, New York, NY; Molecular Imaging Program, National Cancer Institute, Bethesda, MD; Department of Urology, Northwestern University, Chicago, IL.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Edward M. Schaeffer, MD, PhD, Northwestern University, 303 East Chicago Ave., Tarry Building 16-713, Chicago, IL 60611; email: e-schaeffer@
northwestern.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e235

TOSOIAN ET AL
long-term outcomes.4-6 In the United States, as of 2006, low-
risk prostate cancer was managed conservatively for only 10%
of men.23 Since that time, however, there has been a major
expansion in use. By 2011, the New Hampshire State Cancer
Registry reported that this disease was managed expectantly
for 42% of low-risk patients.24 In a large registry from
Michigan, 49% of low-risk prostate cancers diagnosed in 2012
to 2013 were managed on AS.25 Finally, new data from the
CaPSURE clinical practice registry reported an increase in
conservative management for up to 40% of low-risk cases
from 2010 to 2013.26 Similarly, studies from Canada have
reported a reduction in the proportion of low-risk patients
undergoing radical prostatectomy.27
Corroborative findings have been observed in several
European studies. In the National Prostate Cancer Register
of Sweden from 2007 to 2011, AS was selected by 59% of
very low-risk patients and 41% of low-risk patients.28
Meanwhile, data from Germany demonstrated a decline in
the proportion of men with Gleason score 6 disease at
radical prostatectomy from 2000 to 2014.29 Despite these
favorable trends suggesting a reduction in the overtreat-
ment of low-risk prostate cancer, there continues to be
substantial variability in management patterns between and
within various clinical practice settings.30,31 Furthermore, in
some parts of the world, the use of AS continues to remain
more limited.32 Nevertheless, the indications for AS con-
tinue to expand in national guidelines, 33 and it can be
expected that this management paradigm will become
increasingly offered for favorable-risk disease in the future.
OUTCOMES OF ACTIVE SURVEILLANCE
The modern approach to AS was first described in 1995, and
numerous programs have now reported follow-up outcomes
KEY POINTS
Active surveillance represents a standard management
option for men with very low-risk and low-risk prostate
cancer.
With follow-up extending to 20 years (median 56
years), multiple AS cohorts report metastasis and
prostate cancer mortality in less than 1% of favorable-
risk men; these outcomes appear to be more frequent in
men who do not meet low-risk criteria, but higher-risk
populations have not been adequately studied.
Revisions to pathologic grading from the 2014
International Society of Urologic Pathology consensus
conference should facilitate a clearer understanding of
pathologic data and more accurate assessment of risk in
men bordering AS criteria.
Multiparametric MRI and tissue-based molecular
testing may improve extant monitoring protocols but
first require additional study and validation.
As the practice of AS continues to evolve, it is important
that modifications of protocols are based on evidence of
patient benefit.
e236 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
at 5 years and beyond.8 In Toronto, Klotz et al5 initiated a
program of AS aimed at low-risk and select intermediate-risk
patients. Their monitoring protocol includes PSA measure-
ments every 3 months for 2 years and then every 6 months,
with a confirmatory biopsy during the first year and then
every 3 to 4 years until age 80. Intervention was initially
recommended for histologic upgrading on rebiopsy and/or
PSA doubling time less than 3 years, but PSA changes now
trigger additional work-up rather than immediate in-
tervention. The most recent update of this cohort was
published in 2015, with a median follow-up of 6.4 years
(ranging up to 19.8 years). Of the 993 men to enroll in the
program since 1995, 28 (2.8%) developed metastases and 15
(1.5%) died of prostate cancer. Meanwhile, treatment rates
at 10 and 15 years were 36% and 45%, respectively.
More recently, extended follow-up was reported from the
Johns Hopkins AS program, which was also initiated in 1995.6
This program aims to enroll very low-risk patients (with a PSA
density , 0.15, clinical stage T1c, and Gleason score # 6 in a
maximum of two cores with # 50% cancer involvement in
any core). The protocol includes PSA and digital rectal ex-
amination (DRE) every 6 months and a yearly prostate bi-
opsy. At the most recent analysis, the cohort was composed
of 71% very low-risk men and 29% low-risk men. Triggers for
treatment included an increase in grade (Gleason score . 6)
or volume of cancer on biopsy. The 10- and 15-year cu-
mulative incidence of treatment was 50% and 57%, re-
spectively, with a median treatment-free survival of 8.5
years. Meanwhile, 15-year metastasis-free and cancer-
specific survival rates were 99.4% and 99.9%, respectively.
Table 1 presents published data from these two large
prospective cohorts.
Other U.S. centers have similarly reported intermediate-
term outcomes from AS. At the University of California, San
Francisco, prostate cancer has been managed among 810
men using an AS protocol based on quarterly PSA testing,
repeat biopsy within 12 months, and follow-up biopsy every
1 to 2 years depending on medical risk.34 Of these men, 69%
met strict eligibility criteria (PSA # 10 ng/ml, clinical stage
T1/T2, Gleason score # 6, # 33% positive biopsy cores,
and # 50% involvement of any core with cancer). The au-
thors reported a 5-year treatment-free survival of 60%, and
there were no prostate cancer deaths during a median
follow-up of 60 months.
At Royal Marsden in the United Kingdom, the eligibility
criteria for AS include age 5080, clinical stage T1/T2 disease,
PSA less than 15 ng/ml, Gleason score of 6 or less (as well as
Gleason 3 + 4 in men older than age 65), and 50% positive
biopsy cores or less.35 PSA and DRE are performed every
3 months in year 1, every 4 months in year 2, and every
6 months thereafter. A biopsy is performed at 18 to
24 months from diagnosis and then every 2 years. Triggers
for treatment are a PSA velocity greater than 1 ng/ml per
year, a Gleason score above 3 + 4, and/or more than 50%
positive cores on repeat biopsy. Among 471 men in the
program, 323 (68.6%) remained on AS at a median follow-up
of 5.7 years, and there were two prostate cancer deaths.

TABLE 1. Basic Characteristics of Two Large Prospective Active Surveillance Cohorts
Patient Selection Monitoring
Frequency of
Cohort No. of Patients GS 7, % Biopsy, Years
Toronto5 993 13 34
JHH6 1,298 0 1
Abbreviations: JHH, Johns Hopkins Hospital; GS, Gleason score; PCSM, prostate cancerspecific mortality.
*Proportion of patients during total follow-up; time-adjusted values not available.
Finally, 6-year follow-up data were reported for 439 men
from the Goteborg randomized trial of prostate cancer
screening who elected AS.36 The cohort composition was
51% very low risk, 36.7% low risk, 21% intermediate risk, and
1.4% high risk. The monitoring protocol included PSA testing
every 3 to 6 months and rebiopsy at varying intervals,
depending on clinical characteristics. Nearly one-half of the
cohort remained free from treatment at 10 years, and a
single patient died of prostate cancer at 12.7 years from
diagnosis. The most common reason for discontinuing AS
was an increase in grade or cancer involvement on repeat
biopsy, followed by increases in PSA.
In summary, these results demonstrate the durability and
safety of AS with careful patient selection and follow-up. At 5
years, the majority of men enrolling in these programs re-
main free from treatment, allowing preservation of quality
of life. Furthermore, the development of metastatic disease
or prostate cancer death is rare within the first 10 to 15 years
of AS. Available data suggest that inclusion of higher-risk
men and less frequent monitoring biopsy may be associated
with increased risk of adverse outcomes. An understanding
of these principles is crucial to appropriate patient education
and counseling.
UPDATED INTERNATIONAL SOCIETY OF
UROLOGIC PATHOLOGY GRADING AND
IMPLICATIONS ON ACTIVE SURVEILLANCE
In 1966, Donald Gleason37 developed the classification of
prostatic carcinomas using the architectural pattern rather
than cytology for assigning the grade. The underlying
principles of the Gleason grading system and its contribu-
tions to prostate cancer clinical management retain rele-
vance and influence over half a century from the time of
its development. However, a number of new clinical and
pathologic discoveries, changes in prostate cancer screening
and detection, and development of new methodologies
justified revisions of the original grading system at the 2005
and 2014 International Society of Urologic Pathology (ISUP)
consensus conferences.38,39
As it relates to AS, there are several major changes to the
Gleason grading system. The reporting of Gleason scores 25
has virtually disappeared from current clinical practice. In
Gleasons original data, Gleason scores 25 were seen in
27.9% of patients.40 Pathologists rendered a diagnosis of
Gleason score 24 in 22% to 24% of patients in the early
1990s compared with just 1.6% to 2.4% a decade later.41-43
Helpap and Egevad44 demonstrated that from 1996 to 2000
ACTIVE SURVEILLANCE FOR PROSTATE CANCER
Outcomes
Median Follow-up, Metastatic
Years 10-Year Treated, % 10-Year PCSM, % Disease, %*
6.4 36 1.9 2.8
5.0 50 0.1 0.4
and then to 2005, reported Gleason scores 24 decreased
from 2.7% to 0% and reported Gleason score 5 decreased
from 12.2% to 0.3%.
Another major divergence from the original Gleason
system is in the assignment of grade to cribriform glands.
Within Gleasons original illustrations of his cribriform
pattern 3, he depicts large cribriform glands.45 Cases graded
prior to 2005 as Gleason pattern 3 included large cribriform
glands that today would uniformly be called Gleason pattern
4.46,47 Historically, a diagnosis of Gleason score 6 cancer was
not as predictive of good behavior, with a higher rate of
progression and some men even dying of prostate can-
cer.47,48 Currently, it is recommended that all cribriform
glands be considered as Gleason pattern 4. Ill-defined glands
with poorly formed glandular lumina were not discussed or
depicted by Gleason as either Gleason pattern 3 or 4. It was
the consensus of the 2005 conference that poorly formed
glands should not be considered Gleason pattern 3. Con-
sequently, only individual well-formed glands are currently
graded as Gleason pattern 3.
The consequence of the above changes is that contem-
poraneously graded Gleason score 3 + 3 = 6 cancers are
incapable of metastatic behavior.47 Although occasional
publications (usually from large prostate cancer databases)
infrequently report otherwise, these reports are subjected
to incomplete submission of the prostate for histologic
examination, errors in data records, use of the older grading
system, and lack of recorded tertiary patterns, among other
limitations.49 Gleason pattern 3 in the setting of surrounding
Gleason pattern 4 may have metastatic potential as recently
shown in a case report supported by molecular evidence of
the clonal origin of the lethal cancer from a focus of Gleason
pattern 3 in the middle of higher-grade cancer.50
There has been a call to change the grading system for
prostate cancer, replacing Gleason score 3 + 3 = 6 disease
(and lower grades) with the term indolent lesion of epi-
thelial origin to mitigate anxiety and curtail overtreatment
of potentially indolent cancers.51 There exist numerous
clinical and morphologic reasons why Gleason pattern 3
should be classified as cancer.52 Rather than changing
Gleason score 6 to a noncancerous diagnosis, there is a
need to change the confusing and inconsistent manner in
which the pathologic grade is reported. One of the major
deficiencies of the current Gleason grading system is that the
lowest grade assigned in the contemporary setting is 6,
despite a scale which ranges from 2 to 10; such practice
implies that a Gleason score 6 is in the middle of the grading
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e237
TOSOIAN ET AL
scale in terms of aggressiveness. Similarly, patients with
Gleason score 3 + 4 = 7 may be overly concerned because a
score of 7 is closer to the maximum score of 10 than the
lowest score of 2.
To address these deficiencies with the original Gleason
grading system, along with other problems not relevant to
the practice of AS, a new grading system has been proposed.
This system is founded in the original Gleason system, yet it
is based on extensive subsequent research that has im-
proved the original system in its definition and application. If
one were developing a new prostate cancer grading system
de novo, the goal would be a simple system with the fewest
number of distinct grades that can adequately represent
established differences in prognosis.
The updated grade groups were originally developed in
2013 by Dr. Jonathan Epstein based on data from 7,869
patients who underwent radical prostatectomy at the Johns
Hopkins Hospital.19 This contemporary grading system was
subsequently validated in a cohort of 20,845 patients from
five academic institutions.20 Based on these data, the rates of
5-year biochemical recurrence-free survival for grade groups
15 based on radical prostatectomy grade were 96%, 88%,
63%, 48%, and 26%, respectively. The grade groups were also
predictive of outcomes based on biopsy grade when biopsy
was followed by radical prostatectomy or radiation therapy.
These grade groups were recently validated in a population-
based setting using data from the National Prostate Cancer
Registry of Sweden.53 With the new grading system, patients
can be assured that they have a grade group 1 of 5, which is
the lowest grade, or a grade group 2 of 5, which is still a
relatively low grade. The new grades would, for the fore-
seeable future, be used in conjunction with the Gleason
system. For example, Gleason score 3 + 3 = 6 is equivalent to
grade group 1. These definitions are listed in Table 2.
Another recommendation of the 2014 ISUP Consensus
conference was for pathologists to record the percentage of
Gleason pattern 4 present in Gleason score 7 cancers. This
recommendation is directly related to the practice of AS.
Traditionally, low-volume Gleason score 3 + 3 = 6 cancers
have been widely considered for a surveillance approach.
Depending on patient age, comorbidity, and other clinico-
pathologic characteristics, however, there may be a pro-
portion of Gleason score 3 + 4 = 7 cancers that could be
reasonably considered for AS if pattern 4 disease is minimal.
Currently, this information is not transparent in pathology
reports, in which the percentage pattern 4 in Gleason score
3 + 4 = 7 cancers can range from 1% to close to 50%. Based on
these and other improvements, the new grading system has
been accepted by the World Health Organization for the
2016 edition of Pathology and Genetics of Tumours of the
Urinary System and Male Genital Organs.39,54
MULTIPARAMETRIC MRI IN ACTIVE
SURVEILLANCE
Multiparametric MRI offers the ability to detect, measure, and
monitor prostate cancers in vivo, as well as direct biopsies to a
specific target or lesion.17 Currently, the main role of mpMRI in
e238 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
TABLE 2. Histologic Definition of the Updated Grading
System
Grade Gleason Score
Group Equivalent Characteristic Features
1 3+3=6 Only individual discrete well-formed glands
2 3+4=7 Predominantly well-formed glands with
a lesser component of poorly formed/
fused/cribriform glands
3 4+3=7 Predominantly poorly formed/fused/cribri-
form glands with a lesser component of
well-formed glands*
4 8 Only poorly formed/fused/cribriform
glands, predominantly well-formed
glands and a lesser component lacking
glands, or predominantly lacking glands
and a lesser component of well-formed
glands
5 910 Lack of gland formation (or necrosis) with or
without poorly formed/fused/cribriform
glands*
*For patients with greater than 95% poorly formed/fused/cribriform glands or lack of
glands on a core or at RP, the component of less than 5% well-formed glands is not
factored into the grade.
Poorly formed/fused/cribriform glands can be a more minor component.
AS is to determine the appropriateness of patient candidates.55
For instance, patients with apparently small, low-grade tumors
on random biopsy may in fact harbor larger, clinically significant
cancers that would render them inappropriate for AS. If
concerning lesions are detected on mpMRI, they can be ac-
curately sampled using various image-guided methods such as
transrectal ultrasonography (TRUS)/MRI fusion.
Multiparametric MRI has a high negative predictive value
for intermediate- and high-risk prostate cancers. Thus, a
negative MRI scan is good evidence that a clinically signif-
icant cancer is not present. Furthermore, when a lesion is
seen, mpMRI can provide insight regarding tumor behav-
ior.56,57 For instance, mpMRI has been used to predict
Gleason scores mainly through apparent diffusion coeffi-
cient (ADC) values derived from diffusion-weighted MRI.
Although there are strong inverse correlations between ADC
and Gleason grade, mpMRI cannot be considered a re-
placement for biopsy at this time.58,59 Nevertheless, ADC
values can provide useful information in stratifying patient
risk prior to biopsy. For instance, a lesion with very low ADC
values that is read as a low-grade tumor on biopsy should be
considered for rebiopsy based on the high risk of such a
lesion harboring a higher-grade tumor.
Despite its utility in lesion detection and targeting, mpMRI
does not routinely appear in decision-making algorithms and
clinical nomograms for AS. To date, there are no long-term
prospective studies regarding the use of mpMRI in AS. Using a
220 patient cohort, Shukla-Dave et al60 developed a nomo-
gram based on clinicopathological data and mpMRI findings;
this nomogram demonstrated a high area under the receiver
operating characteristic curve (AUC) of 0.854 for selecting
patients appropriate for AS. A follow-up study of 181 patients
revealed an AUC of only 0.738 for low-risk disease (defined
as # pT2, Gleason grade , 4, and tumor volume # 0.5 cc)

for those who underwent radical prostatectomy.61 The
National Cancer Institute nomogram, which uses only
mpMRI criteria, generated an AUC of 0.71 for predicting
candidates for AS in a cohort of 85 patients, 60 of whom had
very low-risk disease (# cT1c, PSA density , 0.15, biopsy
Gleason score # 6, # 2 positive biopsy cores, and # 50%
cancer involvement in any biopsy core).62 This nomogram was
developed with biopsy pathology as an endpoint, which is a
method that has not been validated. Thus, although mpMRI
appears to provide some incremental value in selecting
candidates for AS, it is far from perfect and remains limited by
an inability to consistently detect clinically significant lesions,
with reported false-negative rates of up to 16%.63
The utility of mpMRI for monitoring men on AS has not
been well established. Walton-Diaz et al64 reported a series
of 58 patients on AS with a median follow-up of 16.1 months
who underwent serial mpMRI with TRUS/MRI fusion-guided
biopsy. Upgrading to Gleason score 3 + 4 = 7 was docu-
mented for 17 men (29%), and the positive and negative
predictive values of mpMRI for Gleason score progression
were 53% (95% CI, 28%77%) and 80% (95% CI, 65%91%),
respectively. One recent retrospective study by Felker et al65
included 49 consecutive men with Gleason score 6 prostate
cancer who underwent mpMRI and targeted prostate biopsy
at baseline and again more than 6 months later. Over a mean
follow-up of 28.3 months (range, 1143 months), Gleason
score progression occurred for 19 patients (39%). The ad-
dition of serial mpMRI improved the detection of Gleason
score progression during follow-up.
Preliminary data indicate that mpMRI and targeted biopsy
provide incremental value in the selection of candidates for
AS. Performing mpMRI prior to entering AS can reduce the
number of inappropriate AS candidates by 29% (Figs. 1 and
2).62 Once a patient has initiated AS, mpMRI can be useful in
demonstrating lesion stability (Fig. 3) but currently lacks the
sensitivity to reliably detect higher-risk lesions during follow-
up. As such, continued serial biopsies are recommended
until mature data indicate that a stable mpMRI may in fact
preclude subsequent biopsy. Ultimately, additional studies
with longer follow-up are needed to establish the role of
mpMRI in the context of monitoring. This practice will
continue to evolve as larger studies are published.
MOLECULAR TESTING IN ACTIVE SURVEILLANCE
Several molecular profiling tests have been presented for use in
the AS setting. Unfortunately, these tools have yet to be
prospectively assessed in AS populations or with repeat lon-
gitudinal measures. Based on existing data, however, some of
which are derived from conservatively managed cohorts, it is
both reasonable and biologically plausible to consider some
molecular tests in the AS setting.18 Here, we briefly review the
molecular tests proposed for use in decisions about AS (Table 3).
Oncotype DX: Genomic Prostate Score
The Oncotype DX (Genomic Health, Redwood City, CA)
genomic prostate score (GPS) measures expression of a
ACTIVE SURVEILLANCE FOR PROSTATE CANCER
17-gene panel, including 12 genes from four pathways as-
sociated with carcinogenesis and five reference genes. Gene
expression levels are incorporated into an algorithm yielding
the GPS, which is measured from 0 to 100.66 The GPS is then
considered in the setting of traditional clinicopathologic risk
categories to determine a predicted likelihood of favorable
pathology. In an initial validation study, GPS from 395 men
with low- to low intermediaterisk disease were incor-
porated with preoperative models including the Cancer of
the Prostate Risk Assessment (CAPRA) score and National
Comprehensive Cancer Network (NCCN) risk categories.67 In
both models, a 20-unit increase in GPS was associated with
an approximate twofold increased odds of adverse pa-
thology at prostatectomy (model with CAPRA: odds ratio
[OR], 2.1; 95% CI, 1.43.2; model with NCCN risk classifi-
cation: OR,1.9; 95% CI, 1.32.8), defined as primary Gleason
pattern 4, any Gleason pattern 5, or nonorgan-confined
disease. In a subsequent study of 402 men with low to
intermediate-risk disease,68 a 20-point increase in GPS
similarly conveyed a significant increase in risk of bio-
chemical recurrence after treatment (hazard ratio [HR] 2.93;
95% CI, 2.034.15; p , .001) over a median follow-up of 5.2
years; GPS was also an independent predictor of biochemical
recurrence (BCR) in multivariable models with baseline
clinical factors. Although the test is yet to be assessed in an
AS cohort, one clinical utility study demonstrated a 10%
increased use of AS when GPSs were incorporated into
clinical decision making.69 However, the long-term effect of
these changes in management are unknown.
Prolaris: Cell Cycle Progression
The Prolaris platform (Myriad Genetics, Salt Lake City, UT) is
based on tumor cell proliferation as measured by quan-
titative reverse-transcription polymerase chain reaction
of a 46-gene panel, consisting of 31 cell cycle genes and
15 housekeeping genes.70 The output is reported as a cell
cycle progression (CCP) score categorized clinically as less
than 0, 01, 12, 23, and greater than 3. CCP scores were
retrospectively assessed for 349 men conservatively
managed within the Transatlantic Prostate Group.71
Ten-year rates of prostate cancer death associated with
CCP score groups less than 0, 01, 12, 23, and greater
than 3 were 19.3%, 19.8%, 21.1%, 48.2%, and 74.9%, re-
spectively. In multivariable analysis, the CCP score (HR for
one-unit change: 1.65; 95% CI, 1.312.09), Gleason score
greater than 7 (HR 1.90; 95% CI, 1.183.07), and PSA (HR
1.37; 95% CI, 1.051.79) significantly predicted prostate
cancer death. Perhaps most pertinent to the AS setting,
however, the CCP score was not independently predic-
tive of death for men with Gleason score 6 cancers (HR
1.30; 95% CI, 0.612.77). Two subsequent analyses
have been performed among treated populations. In one
multi-institutional study of men treated with radical
prostatectomy,72 a single-unit increase in CCP score on
biopsy was associated with increased risk of BCR (HR 1.47;
95% CI, 1.231.76) and metastasis (HR 4.19; 95% CI,
2.088.45) on multivariable analysis. In men treated with
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TOSOIAN ET AL

FIGURE 1. Use of MRI Prior to Enrollment in Active Surveillance

A 71-year-old man with a serum PSA of 5.47 ng/ml was found to have Gleason score 3 + 3 cancer (5%) on random biopsy. Due to rising PSA levels, he underwent MRI scan
prior to enrollment in active surveillance. (A) An axial T2-weighted MRI scan shows a PI-RADS 5 lesion in the left mid-anterior transition zone (arrow). (BD) The lesion is
positive on the apparent diffusion coefficient map (B), diffusion-weighted MRI (b = 2,000 mm/s2) (C), and dynamic contrast-enhanced MRI (D; arrows). A TRUS/MRI fusion-guided
biopsy revealed a high volume Gleason 3 + 4 score (100% core involvement with cancer with 30% Gleason pattern 4 of the entire cancer). The patient became an active treatment
candidate after multiparametric MRI and a TRUS/MRI fusion-guided biopsy approach.
Abbreviations: PI-RADS, Prostate Imaging Reporting and Data System; PSA, prostate-specific antigen; TRUS, transrectal ultrasonography.

radiation therapy, a one-unit increase in the CCP score was
similarly associated with a twofold increased risk of BCR
(HR 2.11; 95% CI, 1.054.25).73 Based on surveys of or-
dering physicians, use of the CCP score led to a change in
management selection in one-third to two-thirds of cases;
however, as with the clinical utility studies of Oncotype DX,
the long-term effect of these changes in management
based on Prolaris results is unknown.74,75
ProMark
The ProMark test (Metamark Genetics Inc, Augusta, GA) is
based on a quantitative proteomics profile uniquely
designed to yield prognostic value regardless of sampling
error. To do this, two tissue microarrays (TMAs) were de-
rived from a series of prostatectomy specimens, one using
the highest Gleason pattern observed in the specimen and a
second using the lowest.76,77 Both TMAs were tested using a
12-protein panel that demonstrated similar ability to dis-
criminate tumor aggressiveness (Gleason score $ 7, pT3b,
N1, or M1) based on the AUC (using the highest Gleason
pattern: AUC, 0.70; 95% CI, 0.620.77; using the lowest
Gleason pattern: AUC, 0.72; 95% CI, 0.640.79).77 This initial
panel was reduced to an eight-protein assay and validated
for predicting unfavorable pathology (Gleason score $ 4 + 3
or nonorgan-confined disease) in a cohort of matched
biopsy and prostatectomy specimens.78 Remarkably, using a
threshold score of less than 0.33 the test was 90% sensitive
for predicting favorable pathology, and above a score of 0.8
the test was 95% specific for unfavorable pathology. On
multivariable analysis, a score increase of 0.25 was associ-
ated with 3.1-fold increased odds of unfavorable disease
(OR, 3.1; 95% CI, 2.24.4).

FIGURE 2. Use of Various Modalities to Determine Treatment Approach

A comparison of pathology-defined candidates (top row) for active treatment (yellow) and active surveillance (orange) versus definitions based on multiparametric MRI, the
Epstein criteria, the DAmico criteria, and CAPRA score. Each patient is represented by a column of the array. Note that multiparametric MRI results most closely mirrored pathology
results with fewest false-positive decisions for active treatment in good active surveillance candidates.
Abbreviations: CAPRA, Cancer of the Prostate Risk Assessment; MP, multiparametric.
Reprinted from Turkbey et al55 with permission from the publisher.

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 ACTIVE SURVEILLANCE FOR PROSTATE CANCER

FIGURE 3. Use of MRI in Monitoring a Prostate Lesion During Active Surveillance

A 59-year-old man presenting with a serum PSA of 4.68 ng/ml. (AC) An axial T2-weighted MRI scan (A), apparent diffusion coefficient map (B), and b1500 diffusion-weighted MRI
(C) show a lesion in the left mid-peripheral zone (arrows). This lesion was biopsied and found to harbor Gleason 3 + 3 prostate cancer (10%). The patient elected active surveillance.
(DF) A 1-year follow-up MRI scan (serum PSA = 5.10 ng/ml) shows that the lesion is stable in size and MRI signal features. The follow-up biopsy also revealed Gleason 3 + 3 prostate
cancer (15%). MRI may become a tool for monitoring patients on active surveillance.
Abbreviation: PSA, prostate-specific antigen.

Phosphatase and Tensin Homolog Testing
The phosphatase and tensin homolog (PTEN) gene is located
on chromosome 10q and functions as a tumor suppressor in
the phosphoinositide 3-kinase/AKT pathway.79 PTEN in-
activation is an early event in carcinogenesis observed in up
to 40% of prostate cancers. Specifically, PTEN loss appears to
be associated with increasing likelihood of advanced grade
and stage, as well as early recurrence after treatment.80-82 As
such, PTEN loss detected by either fluorescence in situ
hybridization or immunohistochemical staining has been
proposed for prognostic use. One report from the Trans-
atlantic Prostate Group investigated PTEN in men with
conservatively managed prostate cancer with favorable
disease characteristics.83 In the population of men with a
Gleason score below 7, PTEN was highly predictive of
prostate cancer death (HR 8.13; 95% CI, 2.823.2). Limiting
its utility, however, PTEN loss was only present in 3% of this
population. Other contemporary studies have described
PTEN loss in 11% to 12% of favorable-risk study pop-
ulations.84,85 Findings from these studies have consistently
supported an association between PTEN loss on biopsy and
adverse clinicopathologic outcomes.84,85 Considering a
strong correlation with poor outcomes but its less than 15%
prevalence in potential AS candidates, there may be a role
for PTEN testing whereby PTEN loss is considered a high-risk
feature that may preclude management on AS.
Current Status of Molecular Testing
The true promise of molecular tests lies in their ability to
both improve upon and expand beyond biopsy. In addition

TABLE 3. Molecular Tests Proposed for Use in Active Surveillance

Test Manufacturer Platform Biologic Process Endpoints Assessed

Oncotype DX GPS Genomic Health (Redwood City, CA) qRT-PCR RNA quantification (gene expression) Likelihood of favorable
pathology at RP*
Prolaris CCP score Myriad Genetics (Salt Lake City, UT) qRT-PCR RNA quantification (gene expression) 10-year risk of PCSM
ProMark Metamark Genetics Inc. (Augusta, GA) QMPI Protein quantification Likelihood of unfavorable
pathology
Abbreviations: GPS, genomic prostate score; CCP, cell cycle progression; qRT-PCR, quantitative reverse-transcription polymerase chain reaction; QMPI, quantitative multiplex
proteomics imaging; RP, radical prostatectomy; PCSM, prostate cancerspecific mortality.
*Freedom from: primary Gleason pattern 4, any Gleason pattern 5, and nonorgan-confined disease.

Gleason score of 4 + 3 or greater or nonorgan-confined disease ($ pT3, N1, or M1).

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TOSOIAN ET AL
to practical considerations, the use of biopsy is limited by
sampling error and a dependence on subjective grading.86
Conversely, Long et al87 have demonstrated consistent gene
expression across multiple biopsy cores of a single patient,
supporting previous work revealing limited variation in gene
expression levels of highly expressed genes across multiple
biopsy cores, including both malignant and benign stromal
tissue.88 As others have noted, such consistent gene ex-
pression, despite tissue and tumor heterogeneity, supports
the notion that one can be confident in the overall prostate
biology based on analysis of a limited sample.89
Certainly there are many reasons for optimism in exploring
molecular tests in the AS setting. Contrary to pathologic
grading, molecular tests provide an objective result that
remains consistent across institutions. Beyond the platforms
discussed above, additional tests continue to emerge and
may prove useful. For example, the Decipher genomic
classifier (GenomeDx Biosciences, Vancouver, BC, Canada),
which has been previously validated for predicting metas-
tasis after surgery based on prostatectomy tissue,90-92 has
more recently demonstrated prognostic value in biopsy
specimens.93 At the same time, the majority of current
evidence has been gleaned from retrospective analyses of
cohorts that were not established with a surveillance ap-
proach in mind. Furthermore, these tests remain expensive
and their incremental value in the context of other di-
agnostics such as serum markers and MRI is unknown. For
example, the serum Prostate Health Index has demonstrated
predictive ability using baseline and longitudinal samples in
the AS setting and currently represents a less-invasive, more
affordable option.94,95 Acknowledging the entirety of the
data, we lack a definitive answer to the most fundamental
questions about molecular testing: does it work, and is it
cost-effective? Additional evidence for these important
questions is necessary and will ideally stem from pro-
spectively designed studies.
ACTIVE SURVEILLANCE: PRESENT AND FUTURE
An abundance of data indicate that the use of AS is rising
rapidly and that it is a safe option to minimize overtreatment
in men with favorable-risk prostate cancer.8 Nonetheless,
based on current methods of patient selection and moni-
toring, more than one in five men eligible for AS will have
evidence of more aggressive disease on prostatectomy.96
Conversely, some men who fail to meet conventional AS
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e242 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
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43. Steinberg DM, Sauvageot J, Piantadosi S, et al. Correlation of prostate
needle biopsy and radical prostatectomy Gleason grade in academic
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44. Helpap B, Egevad L. Correlation of modified Gleason grading of prostate
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45. Gleason DF. Histologic grading of prostate cancer: a perspective. Hum
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46. McNeal JE, Yemoto CE. Spread of adenocarcinoma within prostatic
ducts and acini. Morphologic and clinical correlations. Am J Surg Pathol.
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47. Ross HM, Kryvenko ON, Cowan JE, et al. Do adenocarcinomas of the
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48. Nakabayashi M, Hayes J, Taplin M-E, et al. Clinical predictors of survival
in men with castration-resistant prostate cancer: evidence that Gleason
score 6 cancer can evolve to lethal disease. Cancer. 2013;119:
2990-2998.
49. Kryvenko ON, Epstein JI. Re: nationwide prevalence of lymph node
metastases in Gleason score 3 + 3 = 6 prostate cancer. Pathology.
2015;47:394.
50. Haffner MC, De Marzo AM, Yegnasubramanian S, et al. Diagnostic
challenges of clonal heterogeneity in prostate cancer. J Clin Oncol. 2015;
33:e38-e40.
51. Esserman LJ, Thompson IM, Reid B, et al. Addressing overdiagnosis and
overtreatment in cancer: a prescription for change. Lancet Oncol. 2014;
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52. Carter HB, Partin AW, Walsh PC, et al. Gleason score 6 adenocarcinoma:
should it be labeled as cancer? J Clin Oncol. 2012;30:4294-4296.
53. Loeb S, Folkvaljon Y, Robinson D, et al. Evaluation of the 2015 Gleason
grade groups in a nationwide population-based cohort. Eur Urol. Epub
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54. Eble JN, Sauter G, Epstein JI, et al (eds). Pathology and Genetics of
Tumours of the Urinary System and Male Genital Organs. Lyon, France:
International Agency for Research on Cancer; 2004.
55. Turkbey B, Mani H, Aras O, et al. Prostate cancer: can multiparametric
MR imaging help identify patients who are candidates for active sur-
veillance? Radiology. 2013;268:144-152.
56. Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of
MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for
the diagnosis of prostate cancer. JAMA. 2015;313:390-397.
57. Panebianco V, Barchetti F, Sciarra A, et al. Multiparametric magnetic
resonance imaging vs. standard care in men being evaluated for
prostate cancer: a randomized study. Urol Oncol. 2015;33:17.e1-17.e7.
58. Turkbey B, Shah VP, Pang Y, et al. Is apparent diffusion coefficient
associated with clinical risk scores for prostate cancers that are visible
on 3-T MR images? Radiology. 2011;258:488-495.
59. Vargas HA, Akin O, Franiel T, et al. Diffusion-weighted endorectal MR
imaging at 3 T for prostate cancer: tumor detection and assessment of
aggressiveness. Radiology. 2011;259:775-784.
60. Shukla-Dave A, Hricak H, Kattan MW, et al. The utility of magnetic
resonance imaging and spectroscopy for predicting insignificant
prostate cancer: an initial analysis. BJU Int. 2007;99:786-793.
61. Shukla-Dave A, Hricak H, Akin O, et al. Preoperative nomograms
incorporating magnetic resonance imaging and spectroscopy for
prediction of insignificant prostate cancer. BJU Int. 2012;109:
1315-1322.
62. Stamatakis L, Siddiqui MM, Nix JW, et al. Accuracy of multiparametric
magnetic resonance imaging in confirming eligibility for active sur-
veillance for men with prostate cancer. Cancer. 2013;119:3359-3366.
63. Serrao EM, Barrett T, Wadhwa K, et al. Investigating the ability of
multiparametric MRI to exclude significant prostate cancer prior to
transperineal biopsy. Can Urol Assoc J. 2015;9:E853-E858.
64. Walton Diaz A, Shakir NA, George AK, et al. Use of serial multiparametric
magnetic resonance imaging in the management of patients with prostate
cancer on active surveillance. Urol Oncol. 2015;33:202.e1-202.e7.
65. Felker ER, Wu J, Natarajan S, et al. Serial MRI in active surveillance of
prostate cancer: incremental value. J Urol. Epub 2015 Dec 7.
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66. Knezevic D, Goddard AD, Natraj N, et al. Analytical validation of the
Oncotype DX prostate cancer assay - a clinical RT-PCR assay optimized
for prostate needle biopsies. BMC Genomics. 2013;14:690.
67. Klein EA, Cooperberg MR, Magi-Galluzzi C, et al. A 17-gene assay to
predict prostate cancer aggressiveness in the context of Gleason grade
heterogeneity, tumor multifocality, and biopsy undersampling. Eur
Urol. 2014;66:550-560.
68. Cullen J, Rosner IL, Brand TC, et al. A biopsy-based 17-gene genomic
prostate score predicts recurrence after radical prostatectomy and
adverse surgical pathology in a racially diverse population of men with
clinically low- and intermediate-risk prostate cancer. Eur Urol. 2015;68:
123-131.
69. Badani KK, Kemeter MJ, Febbo PG, et al. The impact of a biopsy based
17-gene genomic prostate score on treatment recommendations in
men with newly diagnosed clinically prostate cancer who are candidates
for active surveillance. Urol Pract. 2015;2:181-189.
70. Cuzick J, Swanson GP, Fisher G, et al; Transatlantic Prostate Group.
Prognostic value of an RNA expression signature derived from cell cycle
proliferation genes in patients with prostate cancer: a retrospective
study. Lancet Oncol. 2011;12:245-255.
71. Cuzick J, Berney DM, Fisher G, et al; Transatlantic Prostate Group.
Prognostic value of a cell cycle progression signature for prostate cancer
death in a conservatively managed needle biopsy cohort. Br J Cancer.
2012;106:1095-1099.
72. Bishoff JT, Freedland SJ, Gerber L, et al. Prognostic utility of the cell cycle
progression score generated from biopsy in men treated with pros-
tatectomy. J Urol. 2014;192:409-414.
73. Freedland SJ, Gerber L, Reid J, et al. Prognostic utility of cell cycle
progression score in men with prostate cancer after primary external
beam radiation therapy. Int J Radiat Oncol Biol Phys. 2013;86:848-853.
74. Crawford ED, Scholz MC, Kar AJ, et al. Cell cycle progression score and
treatment decisions in prostate cancer: results from an ongoing reg-
istry. Curr Med Res Opin. 2014;30:1025-1031.
75. Shore N, Concepcion R, Saltzstein D, et al. Clinical utility of a biopsy-
based cell cycle gene expression assay in localized prostate cancer. Curr
Med Res Opin. 2014;30:547-553.
76. Shipitsin M, Small C, Giladi E, et al. Automated quantitative multiplex
immunofluorescence in situ imaging identifies phospho-S6 and
phospho-PRAS40 as predictive protein biomarkers for prostate cancer
lethality. Proteome Sci. 2014;12:40.
77. Shipitsin M, Small C, Choudhury S, et al. Identification of proteomic
biomarkers predicting prostate cancer aggressiveness and lethality
despite biopsy-sampling error. Br J Cancer. 2014;111:1201-1212.
78. Blume-Jensen P, Berman DM, Rimm DL, et al. Development and clinical
validation of an in situ biopsy-based multimarker assay for risk strat-
ification in prostate cancer. Clin Cancer Res. 2015;21:2591-2600.
79. Leslie NR, Downes CP. PTEN function: how normal cells control it and
tumour cells lose it. Biochem J. 2004;382:1-11.
80. Lotan TL, Gurel B, Sutcliffe S, et al. PTEN protein loss by immuno-
staining: analytic validation and prognostic indicator for a high risk
surgical cohort of prostate cancer patients. Clin Cancer Res. 2011;17:
6563-6573.
81. Krohn A, Diedler T, Burkhardt L, et al. Genomic deletion of PTEN is
associated with tumor progression and early PSA recurrence in ERG
fusion-positive and fusion-negative prostate cancer. Am J Pathol. 2012;
181:401-412.
82. Liu W, Xie CC, Thomas CY, et al. Genetic markers associated with early
cancer-specific mortality following prostatectomy. Cancer. 2013;119:
2405-2412.
83. Cuzick J, Yang ZH, Fisher G, et al; Transatlantic Prostate Group. Prog-
nostic value of PTEN loss in men with conservatively managed localised
prostate cancer. Br J Cancer. 2013;108:2582-2589.

84. Lotan TL, Carvalho FL, Peskoe SB, et al. PTEN loss is associated with
upgrading of prostate cancer from biopsy to radical prostatectomy.
Mod Pathol. 2015;28:128-137.
85. Mithal P, Allott E, Gerber L, et al. PTEN loss in biopsy tissue predicts poor
clinical outcomes in prostate cancer. Int J Urol. 2014;21:1209-1214.
86. Amin MB, Lin DW, Gore JL, et al. The critical role of the pathologist in
determining eligibility for active surveillance as a management option in
patients with prostate cancer: consensus statement with recommen-
dations supported by the College of American Pathologists, In-
ternational Society of Urological Pathology, Association of Directors of
Anatomic and Surgical Pathology, the New Zealand Society of Pa-
thologists, and the Prostate Cancer Foundation. Arch Pathol Lab Med.
2014;138:1387-1405.
87. Long Q, Xu J, Osunkoya AO, et al. Global transcriptome analysis of
formalin-fixed prostate cancer specimens identifies biomarkers of
disease recurrence. Cancer Res. 2014;74:3228-3237.
88. Peng Z, Andersson K, Lindholm J, et al. Operator dependent choice of
prostate cancer biopsy has limited impact on a gene signature analysis
for the highly expressed genes IGFBP3 and F3 in prostate cancer epi-
thelial cells. PLoS One. 2014;9:e109610.
89. Reichard CA, Stephenson AJ, Klein EA. Applying precision medicine to
the active surveillance of prostate cancer. Cancer. 2015;121:3403-3411.
90. Erho N, Crisan A, Vergara IA, et al. Discovery and validation of a prostate
cancer genomic classifier that predicts early metastasis following radical
prostatectomy. PLoS One. 2013;8:e66855.
ACTIVE SURVEILLANCE FOR PROSTATE CANCER
91. Karnes RJ, Bergstralh EJ, Davicioni E, et al. Validation of a genomic
classifier that predicts metastasis following radical prostatectomy in an
at risk patient population. J Urol. 2013;190:2047-2053.
92. Den RB, Feng FY, Showalter TN, et al. Genomic prostate cancer classifier
predicts biochemical failure and metastases in patients after postoperative
radiation therapy. Int J Radiat Oncol Biol Phys. 2014;89:1038-1046.
93. Klein EA, Haddad Z, Yousefi K, et al. Decipher genomic classifier measured on
prostate biopsy predicts metastasis risk. Urology. Epub 2016 Jan 22.
94. Tosoian JJ, Loeb S, Feng Z, et al. Association of [-2]proPSA with biopsy
reclassification during active surveillance for prostate cancer. J Urol.
2012;188:1131-1136.
95. Hirama H, Sugimoto M, Ito K, et al. The impact of baseline [-2]proPSA-
related indices on the prediction of pathological reclassification at
1 year during active surveillance for low-risk prostate cancer: the
Japanese multicenter study cohort. J Cancer Res Clin Oncol. 2014;140:
257-263.
96. Tosoian JJ, JohnBull E, Trock BJ, et al. Pathological outcomes in men with
low risk and very low risk prostate cancer: implications on the practice
of active surveillance. J Urol. 2013;190:1218-1223.
97. Cooperberg MR, Cowan JE, Hilton JF, et al. Outcomes of active sur-
veillance for men with intermediate-risk prostate cancer. J Clin Oncol.
2011;29:228-234.
98. Han M, Partin AW, Zahurak M, et al. Biochemical (prostate specific
antigen) recurrence probability following radical prostatectomy for
clinically localized prostate cancer. J Urol. 2003;169:517-523.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e245
GENITOURINARY (PROSTATE) CANCER

Oligometastatic Disease in
Prostate Cancer: Treating the
Patient or the Scan?

CHAIR
Neha Vapiwala, MD
University of Pennsylvania
Philadelphia, PA

SPEAKERS
Christopher J. Sweeney, MBBS
Dana-Farber Cancer Institute/Harvard Cancer Center
Boston, MA

R. Jeffrey Karnes, MD
Mayo Clinic
Rochester, MN
 APPROACH TO OLIGOMETASTATIC PROSTATE CANCER

Approach to Oligometastatic Prostate Cancer

Brandon Bernard, MD, Boris Gershman, MD, R. Jeffrey Karnes, MD, Christopher J. Sweeney, MBBS, and
Neha Vapiwala, MD

OVERVIEW

Oligometastatic prostate cancer has increasingly been recognized as a unique clinical state with therapeutic implications. It
has been proposed that patients with oligometastases may have a more indolent course and that outcome may be further
improved with metastasis-directed local ablative therapy. In addition, there are differing schools of thoughts regarding
whether oligometastases represent isolated lesionswhere targeted therapy may render a patient disease freeor
whether they coexist with micrometastases, where targeted therapy in addition to systemic therapy is required for maximal
clinical impact. As such, the approach to the patient with oligometastatic prostate cancer requires multidisciplinary
consideration, with surgery, radiotherapy, and systemic therapy potentially of benefit either singularly or in combination.
Indeed, mounting evidence suggests durable disease-free intervals and, in some cases, possibly cure, may be achieved with
such a multimodal strategy. However, selecting patients that may benefit most from treatment of oligometastases is an
ongoing challenge. Moreover, with the advent of new, highly sensitive imaging technologies, the spectrum based on CT of
the abdomen and pelvis and technetium bone scan of localized to oligometastatic to widespread disease has become
increasingly blurred. As such, new MRI- and PET-based modalities require validation. As some clinical guidelines advise
against routine prostate-specific antigen screening, the possibility of more men presenting with locally advanced or de novo
oligometastatic prostate cancer exists; thus, knowing how best to treat these patients may become more relevant at a
population level. Ultimately, the arrival of prospective clinical data and better understanding of biology will hopefully further
inform how best to treat men with this disease.

O ligometastatic prostate cancer is increasingly being

considered as a unique clinical situation and challenge.
Historically, distinctions with respect to lesser or greater
extent of metastatic disease burden were not typically
made, as patients were all treated with androgen depriva-
tion therapy (ADT). Men with oligometastatic prostate
cancer were thus deemed incurable and treated systemically
with ADT alongside those with widespread metastases.
However, recent advances in imaging are identifying men
with potentially isolated metastases, and mounting evi-
dence suggests that durable control is attainable with
treatment modalities targeting oligometastases, either with
or without the use of systemic therapy.1-3 Such data support
the hypothesis that oligometastatic prostate cancer may
represent a unique biologic state with its own natural history
requiring a distinct therapeutic approach.4 That said, there
are currently no clear-cut data or validated tools to guide
optimal therapy for an individual patient. One school of
thought is to consider isolated lesions on imaging as rep-
resenting the only sites of disease, where local therapy is
sufficient. The other viewpoint is that oligometastatic
disease is most likely also associated with micrometastatic
disease; therefore, concurrent systemic therapy with lo-
calized therapy should be considered the optimal treatment.
In the latter case, disease at this stage is considered po-
tentially curable as it is with adjuvant systemic therapy (in
the form of ADT) to radiotherapy (RT) for high-risk localized
disease or microscopic lymph nodepositive disease fol-
lowing radical prostatectomy.5-8
With this uncertainty, there is provider and patient bias
toward certain treatmentsoptions include ADT alone,
focused ablative therapy of radiographic disease alone, or
both. Moreover, the role of docetaxel with ADT is also now a
matter for consideration. Specifically, some providers and
patients will prefer less therapy with possible risk of
undertreatment and poorer cancer control, whereas others
will prefer more therapy with risk of overtreatment and
consequent adverse events. Furthermore, with greater use
of highly sensitive imaging technologies (e.g., prostate-
specific membrane antigen [PSMA], choline, or sodium
fluoride [NaF] PET and total body MRI), patients are likely
being identified earlier in the natural history of the disease

From the Dana-Farber Cancer Institute, Boston, MA; Harvard Medical School, Boston, MA; Mayo Clinic, Rochester, MN; University of Pennsylvania, Philadelphia, PA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Neha Vapiwala, MD, Department of Radiation Oncology, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd., TRC 2 West, Philadelphia, PA 19104;
email: vapiwala@uphs.upenn.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 119

BERNARD ET AL
and would have been considered micrometastatic on
standard imaging (CT abdomen and pelvis and technetium
bone scan).1 It is clear in light of this latter observation that
incorporating these technologies into the staging and
monitoring of men with prostate cancer requires rigorous
testing to define how best to integrate them into standard
clinical care.
In 2012, the U.S. Preventive Services Task Force updated
their guidelines on prostate cancer screening to recommend
against prostate-specific antigen (PSA) screening in all men9;
since then, there has been a documented decrease in PSA
screening and in incidence of early-stage prostate cancer.10
It is yet unknown whether this change has increased the
number of men presenting with more advanced disease and
consequent higher risk of relapse following local therapy,
however it has been estimated that up to an extra 1,241 men
may die of prostate cancer in the United States per year from lack
of screening.11 Moreover, it is unknown whether there is an
absolute increase in the number of men presenting with de novo
metastatic prostate cancer. As a proportion of such men will have
oligometastatic disease at presentation, having a standardized
approach to its assessment and management is necessary.
To design a systematic approach to oligometastatic
prostate cancer, first and foremost a universally accepted
definition is required. To that end, variability exists regarding
what constitutes oligometastases, with cutoffs of both
three or fewer and five or fewer lesions used in the liter-
ature, and others in actual practice.3,12 Importantly, an
accepted definition should require that targeted treatment
of all metastatic lesions with surgery or RT is technically
feasible. In addition, standardization of imaging is para-
mount; given the uncertainty of the role of newer tech-
nologies in routine care, conventional imaging with bone
KEY POINTS
Oligometastatic prostate cancer is a unique clinical state
with an inherently more indolent tumor biology
susceptible to metastasis-directed focal ablative
therapy.
Oligometastatic prostate cancer may represent isolated
sites of disease or coexist with micrometastases.
Modern, highly sensitive imaging technology is
potentially identifying patients with oligometastatic
prostate cancer who would be deemed to have localized
disease or no evidence of radiographic disease by
standard imaging of CT of the abdomen and pelvis and
bone scan.
A multimodal approach to patients with oligometastatic
disease is needed, with evidence for surgery,
radiotherapy, and systemic therapy, alone or in
combination, improving patient outcomes.
Further prospective data are needed to best select
patients with oligometastatic prostate cancer most
likely to benefit from a given therapeutic approach.
120 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
scan and CT of the abdomen and pelvis remains the gold
standard to define oligometastatic prostate cancer.
To help set the stage, the following five cases detail the
spectrum of patients presenting with oligometastatic dis-
ease and different management strategies available:
1. A 63-year-old man diagnosed with a Gleason 9 adeno-
carcinoma of the prostate, PSA 11, and an isolated
biopsy-positive lesion at T11. He was started on ADT
with a PSA decline to 2.5 and received a radical pros-
tatectomy 2 months thereafter with negative margins.
Stereotactic radiosurgery was subsequently delivered to
T11, and ADT was continued, with a PSA nadir of 0.02
12 months after radical prostatectomy. At that time, a CT
urogram for nephrolithiasis showed multiple small
sclerotic bone lesions within the vertebral column
consistent with metastases. PSA has risen to 0.3 with a
testosterone level of less than 7.0 ng/dL (lower limit of
normal: 240 ng/dL) 16 months after ADT initiation.
2. A 66-year-old man presented with localized left hip pain
and a PSA of 1,244. CT showed an abnormal prostate
concerning for tumor, as well as an expansile lytic lesion
in the left pubic bone. Prostate biopsy confirmed Gleason
8 adenocarcinoma, and he was treated with concurrent
ADT plus RT to the prostate and isolated bone metas-
tasis. Six months after starting ADT, his PSA had fallen to
0.01. With his PSA still undetectable after 24 months of
therapy, ADT was stopped and he entered surveillance.
As of last follow-up, PSA was 0.04 with a testosterone
level of 168 3 years after ADT cessation.
3. A 60-year-old man with a PSA of 6.6 underwent a
prostate biopsy identifying Gleason 9 adenocarci-
noma. Subsequent radical prostatectomy found locally
advanced disease (pT3bN1M0) with evidence of
extracapsular extension, seminal vesicle invasion, and a
single positive lymph node. Postoperative PSA was 2.6,
and the patient received salvage treatment with
7 months of ADT and concurrent intensity-modulated
radiation therapy (5,040 cGy to the whole pelvis; 7,020
cGy to prostatic bed). His PSA became undetectable but
12 months later rose to 2.5, prompting reinitiation of
ADT and the eventual emergence of castration re-
sistance. Imaging demonstrated a single metastasis in
the left scapula. He was treated with seven cycles of
docetaxel; however, PSA continued to rise to 6.5. At that
time, left scapular pain and progression of the lesion on
bone scan led to treatment with 250 cGy of palliative RT
in 20 fractions (5,000-cGy total dose). His PSA has sub-
sequently dropped to 0.75 with resolution of symptoms.
4. A 50-year-old man underwent robotic-assisted radical
prostatectomy with pathology demonstrating pT3a NX
prostate adenocarcinoma. His received radiation ther-
apy to the prostatic fossa for a persistently elevated
PSA postoperatively. Following radiation, PSA remained
elevated. He was placed on ADT but developed

castration resistance with a rising PSA. When the
PSA rose to 3, 11C-choline PET/CT demonstrated
node-only disease in the pelvis and retroperitoneum
(Fig 1). He elected to undergo combined salvage
extended pelvic lymph node dissection and retro-
peritoneal lymph node dissection. Pathology dem-
onstrated 9 of 62 lymph nodes involved with prostate
adenocarcinoma. His PSA was less than 0.2 at 6 months
after surgery.
5. A 49-year-old man presented with an elevated PSA to
49. Prostate biopsy demonstrated Gleason 9 prostate
adenocarcinoma. CT scan revealed pelvic lymphade-
nopathy (Fig 2). Bone scan was without evidence of
osseous metastatic disease. He elected to proceed
with radical retropubic prostatectomy and extended
bilateral pelvic lymphadenectomy as part of a multi-
modal management plan. Surgical pathology dem-
onstrated Gleason 9 pT3b N1 (7 of 27 lymph nodes
positive) prostate adenocarcinoma. He is receiving 2
years of adjuvant ADT and underwent a course of
adjuvant pelvic radiation therapy at 6 months after
surgery.
FIGURE 1. Case 4
APPROACH TO OLIGOMETASTATIC PROSTATE CANCER
This review will outline the role of surgery, RT, and sys-
temic therapy in the management of oligometastatic pros-
tate cancer. Table 1 shows data from studies of focal therapy
with surgery or RT alone, systemic therapy with ADT alone,
or systemic therapy with ADT plus chemotherapy in men
with oligometastatic prostate cancer. Current evidence and
existing controversies will be discussed.
THE ROLE OF SURGERY IN OLIGOMETASTATIC
PROSTATE CANCER
The role of surgery in the management of oligometastatic
prostate cancer has received increased attention in re-
cent years. However, the concept of surgery for advanced
prostate cancer is not new. For instance, observational
studies from the 1990s reported improved oncologic out-
comes for men with pathologic lymph nodepositive (pN+)
prostate cancer treated with radical prostatectomy and ADT
compared with ADT alone, and prior radical prostatectomy
has been associated with improved overall survival (OS)
for men with metastatic disease.6-8,13 Given that aggres-
sive prostate cancer can persist even after 1 year of sys-
temic therapy, it is not surprising that surgery may improve
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 121
BERNARD ET AL
FIGURE 1. Case 4 (Contd)
A 50-year-old man that received salvage extended pelvic and retroperitoneal lymph node dissection for choline PET-positive disease post-RP and adjuvant RT with subsequent
PSA decline.
oncologic outcomes.14 Potential mechanisms include re-
ducing tumor burden (i.e., resetting the clock), preventing
continued metastatic spread from the primary, and relieving
tumor immune suppression.15
Surgery for Locally Advanced (Including Pelvic Lymph
Node) Disease
For men that have not had prior local therapy, radical
prostatectomy has been associated with improved oncologic
outcomes for men with pN+ disease in a number of ob-
servational studies. For example, in a matched comparison
of 79 men treated with radical prostatectomy and adju-
vant orchiectomy versus 79 men treated with orchiectomy
alone, 10-year OS was 66% versus 28% in favor of radical
prostatectomy.8 Similarly, an analysis of the Munich Cancer
Registry reported 10-year OS of 64% for completed versus
28% for aborted radical prostatectomy in men with pN+
disease.16 Although there is inherent potential for selection
bias toward radical prostatectomy for patients with more
favorable disease, there is remarkable consistency in reported
oncologic outcomes among observational studies with 10-year
cancer-specific survival (CSS) and OS ranging from 70% to 85%
122 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
and 50% to 75%, respectively, for men treated with radical
prostatectomy plus ADT, compared with 50% to 65% and 25%
to 30%, respectively, for ADT alone.17,18 Moreover, random-
ized data reinforce these figures. Among men treated with
radical prostatectomy and immediate ADT in ECOG 3886, OS
was 64% at a median of 11.9 years versus 45% in those
managed with radical prostatectomy alone.19 Notably among
those managed with ADT alone in EORTC 30846, 10-year OS
was approximately 30%, although approximately 40% of the
deaths were due to nonprostate cancer.20
Risk stratification is essential for men with pN+ disease,
as some will have durable oncologic control with surgical
resection alone, whereas others will require multimodal
therapy. One multi-institutional analysis reported that men
with two or fewer positive nodes had significantly better
15-year CSS than those with more than two nodes (84% vs. 62%;
p , .001) when treated with radical prostatectomy and
adjuvant ADT.21 Another study similarly identified more
than two positive nodes as an adverse prognostic feature,
along with Gleason score greater than 7.22 Most recently,
Moschini et al23 developed a risk score for cancer-specific
mortality (CSM) among pN+ men after radical prostatectomy
with 88% receiving adjuvant ADT. Points are added for three

FIGURE 2. Case 5
A 49-year-old man that received radical prostatectomy and up-front bilateral
extended pelvic lymphadenectomy for clinically lymph nodepositive disease
followed by adjuvant RT and long course ADT.
or more positive lymph nodes, Gleason 710 disease, positive
surgical margins, and absence of adjuvant RT to categorize
patients into risk groups with 10-year CSM ranging from 19%
to 46%.
There is increasing evidence that pN+ prostate cancer
does not uniformly signify systemic disease. In one study of
clinical recurrence patterns in 1,011 pN+ men after radical
prostatectomy, 57% of clinical recurrences were identified
at a single location, and of these, 51% were local or node-only at
the time of relapse.24 In light of such data, management of clinical
lymphadenopathy (cN+), which has traditionally been distin-
guished from cN0pN+ disease, deserves reconsideration. For
example, the National Comprehensive Cancer Network (NCCN)
recommends ADT with or without radiation therapy for men
presenting with cN1M0 disease.25 However, in a recent study of
302 men with pN+ disease, of whom 17% were cN+, the authors
noted no difference in CSS or OS between cN+ and cN0 pa-
tients.26 Such data suggest that appropriately selected men with
clinical lymphadenopathy may be treated with surgical resection
as an alternative to pelvic radiation as for cN0pN+ disease.
Surgery in Presence of Distant Metastatic Disease
In the absence of prior local treatment, there is considerably
less data on the role of surgery in the setting of distant
APPROACH TO OLIGOMETASTATIC PROSTATE CANCER
metastases.27 In a multi-institutional report of 106 men who
underwent radical prostatectomy/extended pelvic lymph
node dissection (ePLND) for M1a/M1b disease, CSS was
89% at a median of 22.8 months, and perioperative mor-
bidity was overall similar to that reported for radical
prostatectomy/ePLND for M0 disease.28 Another study
compared 23 patients with low-volume M1b disease (three
or fewer skeletal lesions) who underwent radical
prostatectomy/ePLND with 38 controls treated with ADT
alone.29 Cytoreductive radical prostatectomy was associated
with longer time to castration resistance (40 vs. 29 months),
improved clinical progression-free survival (PFS) (39 vs.
28 months), and improved CSS (96% vs. 84%). Population-
based data likewise support an oncologic benefit to local
therapy with surgery or radiation.30 A randomized trial eval-
uating best systemic therapy with or without local therapy in
the form of surgery or radiation for men with metastatic
prostate cancer should provide important prospective data
(NCT01751438).
Risk stratification to guide patient selection for surgery in
the setting of M1 disease is even more critical than for N+M0
disease. To this end, Fossati et al31 conducted a population-
based analysis of men with metastatic prostate cancer and
reported that baseline CSM risk significantly (p , .0001)
modified the oncologic benefit of local therapy (either
surgery or radiation), with no benefit to local therapy
beyond a specific threshold. Further studies are necessary to
determine which patient populations may derive greatest
benefit from cytoreductive radical prostatectomy in the
presence of M1 disease.
In the setting of clinical nodal recurrence following de-
finitive local therapy, salvage lymph node dissection (sLND)
has gained increased utilization, driven in part by improved
imaging modalities such as 11C-choline PET/CT. Principles of
surgery for oligometastatic nodal disease include availability
of accurate preoperative imaging, complete resection of all
radiographic disease, and acceptable morbidity. Although
randomized data are lacking, observational studies are
encouraging. One U.S. series reported that, of 52 men who
underwent sLND for nodal recurrence after radical prosta-
tectomy, 73% achieved undetectable PSA after surgery.32
In a follow-up study of 117 patients, the largest single series
to date, 5-year biochemical recurrence (BCR)free, radio-
logic recurrence-free, and CSS were 39%, 51%, and 97%,
respectively, after sLND with adjuvant ADT being given to
62.7% of patients.33 In a European series of 59 men who
underwent sLND, 59% achieved undetectable PSA, and
among these, the 8-year BCR-free survival was 23%.34 For the
overall cohort, 8-year clinical recurrence-free and CSS were
38% and 81%, respectively. A systematic review recently
synthesized the available data on sLND with or without ad-
juvant ADT from 12 observational studies, 5-year BCR-free
survival of 9% to 22%, and 5-year OS of approximately 75%.35
Favorable prognostic factors included complete PSA response
to surgery alone, fewer positive nodes, absence of retroperi-
toneal involvement, and lower preoperative PSA. What is not
known is the optimal utilization and duration of adjuvant
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 123
BERNARD ET AL

TABLE 1. Summary of Key Studies Evaluating Surgery, Radiotherapy, and Systemic Therapy in Oligometastatic
Prostate Cancer in the Post-PSA Era

Study No. of Patients Study Type Imaging Outcome

Surgery Alone
pN+ Disease
Engel et al16 938 Retrospective cohort N/A (pN+) 10-year OS of 64% with RP vs. 28% without RP
ECOG 388619 98 RCT N/A (pN+) 11.9-year OS of 64% with RP + immediate
ADT vs. 45% with RP + deferred ADT
EORTC 3084620 234 RCT N/A (pN+) 10-year CSS of 48% for immediate ADT vs.
44% for delayed ADT (none with RP)
sLND
Zattoni et al33 117 Case series 11
C-Choline PET/CT 5-year 69% BCR-free, 49% radiographic
recurrence-free, and 97% CSS
Suardi et al34 59 Case series 11
C-Choline PET/CT 8-year 23% BCR-free, 38% clinical
recurrence-free, and 81% CSS
M1 Disease
Sooriakumaran et al28 106 Case series Bone scan, CT 89% CSS at median of 22.8 months with
cytoreductive RP for M1 disease
Heidenreich et al29 61 Retrospective cohort Bone scan, CT CSS of 96% with RP + ADT vs. 84% with
ADT alone, at median of 34.5 months
RT Alone
Jereczek-Fossa et al59 19 Case series PET/CT 30-month PFS, 64%
Schick et al60 50 Case series PET/CT; bone scan 3-year OS, 92%
Decaestecker et al61 50 Case series PET/CT Median PFS, 19 months
Picchio et al62 83 Case series PET/CT PSA PR/CR, 83%
ADT Alone
Millikan et al47 84 Phase III RCT Bone scan Median OS, 94 months
S934663 798 Phase III RCT Bone scan; CXR Median OS, 83 months
GETUG 1553 102 Phase III RCT Bone scan; CT Median OS, 83 months
CHAARTED41 143 Phase III RCT Bone scan; CT 4-year OS, 60%
CHT
Millikan et al47 76 Phase III RCT Bone scan Median OS, 93.6 months
GETUG 1553 100 Phase III RCT Bone scan; CT 4-year OS, 70%
CHAARTED41 134 Phase III RCT Bone scan; CT 4-year OS, 70%
Abbreviations: N/A, not applicable; RCT, randomized controlled trial; RP, radical prostatectomy; BCR, biochemical recurrence; ADT, androgen deprivation therapy; PR, partial
response; CR, complete response; CXR, chest x-ray.

systemic therapy with ADT, and whether concurrent docetaxel
may possibly further improve these outcomes.
Studies on Resection of Distant Metastases After
Local Therapy
Data reporting outcomes of surgery in this setting have been
limited to retroperitoneal lymph nodes as part of sLND,
whereas stereotactic body radiation therapy (SBRT) has
generally been used for bone or visceral oligometastatic
disease.35,36 Although retroperitoneal disease portends a
worse prognosis, data suggest that a subset of patients
may achieve durable clinical recurrence-free survival with
sLND with or without adjuvant ADT. One study of sLND
reported 8-year clinical recurrence-free survival of 22%
for retroperitoneal nodal involvement versus 69% without
retroperitoneal disease.34 Another study noted 5-year
clinical recurrence-free survival of 11% with retroperitoneal
involvement versus 53% without retroperitoneal disease.37
The phase II randomized trial STOMP will evaluate the
role of metastasis-directed therapy with either surgery or
SBRT in oligometastatic recurrence following local therapy
(NCT01558427) compared with active surveillance with ADT
to be deferred in both arms until more than three meta-
static lesions develop.38 This should provide important data
regarding the potential oncologic benefit of both meta-
stastectomy and sLND as monotherapy.
Overall, emerging data suggest that surgery may represent
an important therapeutic modality in the management of
oligometastatic prostate cancer. Ultimately, optimal patient
selection is critical. Radical prostatectomy/ePLND is asso-
ciated with durable oncologic control in the setting of N+M0
disease, with emerging data for its use as local therapy in M1
disease. sLND is likewise associated with favorable oncologic
outcomes for oligometastatic nodal recurrence after local

124 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


therapy. Prospective studies will further inform these issues
and will also inform whether it can be used alone or in
combination with systemic therapy.
THE ROLE OF RADIATION THERAPY IN
OLIGOMETASTATIC PROSTATE CANCER
Radiation therapy is a well-established curative therapy for
intact localized and postoperative locally recurrent prostate
cancer, and an effective palliative therapy for symptomatic
metastatic disease. Conversely, its role in oligometastatic
disease in an effort to improve survival is unknown. Cur-
rently, the NCCN guidelines recommend considering RT for
metastases if symptomatic or residing in a weight-bearing
bone; otherwise, the mainstay for M1 disease remains
systemic with either medical or surgical castration, or
chemohormonal therapy (CHT).39 However, ADT is associ-
ated with a number of side effects and potential compli-
cations, so being able to delay ADT start and/or allow for
longer treatment breaks if given intermittently without
compromising survival is a worthy pursuit. Moreover, a
shorter course of ADT with concurrent RT to maximize
control may be another strategy to limit potential toxicity
associated with ADT. Plausibly, early detection of oligo-
metastases with sensitive, accurate imaging may allow for
more proactive therapy and eradication of locally measur-
able disease, delayed time to ADT, and, perhaps, cure if there
is no associated micrometastatic disease and radiation is
able to eradicate the isolated metastatic lesion(s). In the
setting of postprostatectomy biochemical failure, the me-
dian time from PSA recurrence to metastases may be long
(8 years in one study)40; regular monitoring and prompt
utilization of metastases-directed focal therapy upon their
development may further improve outcomes and avoid the
need for systemic therapy.
Recently, Ost et al36 conducted a review of studies
employing metastases-directed therapy for relapsed pros-
tate cancer. Of note, oligometastases were identified using
PET/CT in 98% of patients, and 78% of treated metastases
were nodal in origin. Although great heterogeneity among
patient populations and variable use of ADT and prophylactic
nodal irradiation made comparison among studies chal-
lenging, the authors found that around one-half of men were
progression-free 13 years after metastases-directed ther-
apy; however, over 60% had adjuvant ADT. Caution should
be taken when evaluating PFS between these various
studies, however, as different definitions were used among
them. In addition, although promising, the quality of the
evidence generated to date is insufficient to recommend this
approach as routine standard care.
The impact of RT, specifically, on PFS when used to treat
recurrent, treatment-naive oligometastatic prostate cancer
was recently the focus of a multi-institutional analysis.3 The
study included 163 patients with three or fewer metastases
each. The authors assessed for both local PFS and distant PFS,
and identified a RT dose of less than or equal to 100 Gy as being
associated with a lower local PFS at 3 years (79% vs. 99%;
APPROACH TO OLIGOMETASTATIC PROSTATE CANCER
p = .01). Also, a nonsignificant trend was observed for improved
median distant PFS with adjuvant ADT (25 vs. 18 months;
p = .09). As in the review by Ost et al, most of the patients were
staged using PET/CT36; however, as this technique is not
currently considered standard of care, extrapolating and ap-
plying these data to clinical practice is difficult.
An important consideration when applying RT in any disease
setting is the accurate deposition of dose to the target while
avoiding dose-limiting toxicity to surrounding tissue. There are
several factors in the evolution of modern RT that are helping to
mitigate this concern. Enhanced imaging modalities and image
registration have led to improved accuracy in RT target defi-
nition, while advances in both external patient and internal
organ immobilization and tracking permit more precise radi-
ation delivery. Furthermore, major technical evolutions in
hardware and software capabilities have enabled safe de-
livery of larger doses of radiation per treatment fraction
(i.e., hypofractionation); such dosing regimens are not only a
desirable from a patient convenience standpoint but can carry
greater radiobiological bang for your buck, delivering a po-
tentially higher biologically effective dose over a shorter time
period.2 Consequently, various hypofractionated radiation
therapy dosing schedules have been proposed for treatment in
the oligometastatic setting, including one fraction of 20 Gy,
three fractions of 10 Gy, five to six fractions of 5 or 6 Gy, and 10
fractions of 5 Gyall deemed to be of equivalent efficacy.2
In summary, a growing body of retrospective literature
suggests RT for oligometastatic prostate cancer is feasible,
effective, and without significant toxicity. Although un-
proven, its role as a solitary therapy or in conjunction with
systemic and/or surgical strategies is evolving, as is the goal
and ultimate intent (i.e., aggressive palliation vs. durable
control vs. eradication and cure) of its use. Whether the
primary function of radiation in the oligometastatic setting
to primary (if intact) and/or metastasis is to delay time to
ADT, to consolidate potentially curative multimodal ap-
proaches, or both, is to be determined. Numerous clinical
trials are currently in development that will provide pro-
spective data to better answer this question (NCT01859221;
NCT01777802; NCT02192788; NCT01558427).
THE ROLE OF SYSTEMIC THERAPY IN
OLIGOMETASTATIC PROSTATE CANCER
The cornerstone of therapy for metastatic prostate cancer
is ADT, either continuous or intermittent. Additionally,
chemotherapy has been shown to improve OS, both in
the hormone-sensitive and castration-resistant state.41-45 Al-
though not curative, goals of systemic therapy include disease
control, symptom reduction, reduction of morbidity, and life
prolongation. However, its role in oligometastatic prostate
cancer, specifically, is less clear. There is speculation that
control of micrometastatic disease, in conjunction with tar-
geted treatment to oligometastases, may improve outcome
and, in some, may possibly lead to cure. Chemotherapy may aid
by theoretically eliminating less androgen-sensitive tumor cells
and augment what can be achieved with ADT.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 125
BERNARD ET AL
Prognostically, it has been shown that patients with high-
volume disease (visceral metastases and multiple bone
metastases [e.g., four or more]) have worse outcomes.46,47
Furthermore, it was shown that those with five or fewer
bone metastases fared better than those with more than five
at time of relapse following RT for localized disease, with
distinct natural histories apparent for these patient sub-
sets.48 Thus, patients with low-volume metastatic prostate
cancer at time of relapse appear to innately have more
indolent biology and more favorable prognoses compared
with those with more widespread disease. Attempting to
improve their survival further with metastases-directed
therapy, with or without systemic therapy, is an area of
great interest.
Notably, it has been shown that delayed ADT for meta-
static prostate cancer does not negatively impact outcome
of patients with oligometastatic prostate cancer, with one
study reporting a median time from metastases to prostate
cancerspecific death of 82 months.49 Moreover, in men
with PSA-only relapse following radical prostatectomy and
deferred ADT, it has been demonstrated that metastasis-
free survival may serve as a surrogate for OS.50 This study
also identified number of metastases (three or fewer vs. four
or more, hazard ratio [HR] 0.50; 95% CI, 0.290.85; p = .012)
as an independent prognostic variable for OS, further im-
plying potential biologic differences between patients with
oligometastases and those with diffuse disease.50 It is
postulated that an improvement in outcome for those
with oligometastatic disease treated with focal ablative
therapy of their radiographic evident disease may be aug-
mented with systemic therapy in an attempt to eradicate
micrometastases.
Evidence for improved survival with early use of CHT
consisting of docetaxel chemotherapy plus ADT comes from
three randomized, controlled trials. The first to demonstrate
the benefit, E3805 (CHAARTED), documented a 13.6-month
OS advantage with ADT plus six cycles of docetaxel versus
ADT alone (HR for death 0.61; 95% CI, 0.470.80; p , .001).41
This benefit was even more pronounced in those with high-
volume disease (defined as visceral metastases, four or more
bone metastases with at least one beyond the vertebral
column and pelvis, or both), with an OS gain of 17.0 months
with CHT (HR 0.60; 95% CI, 0.450.81; p , .001). Further-
more, CHT conferred an 8.5-month improvement in me-
dian time to symptomatic, PSA, or radiographic progression
(HR 0.61; 95% CI, 0.510.72; p , .001). When patients with
protocol-defined low-volume disease were assessed as a
separate subgroup, there was also a 39% decrease risk of
deathbut there were far fewer events, and at time of the
first report, this was not statistically significant. This in-
dicates that these patients have a longer natural history with
ADT alone with 4-year OS of approximately 60%. Moreover,
some of these patients with a shorter life expectancy be-
cause of age and/or comorbidities may die of a competing
cause.
These data were supported by those from the STAMPEDE
trial, which used a multiarm, multistage platform design to
126 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
assess the value of adding docetaxel, zoledronic acid, or both
drugs combined to standard of care in men with high-risk,
locally advanced, metastatic or relapsed prostate cancer.42
Standard of care consisted of ADT for all subgroups, with RT
optional but later required for those with localized disease.
This study used a novel, flexible trial design to pragmatically
ascertain the impact of therapy along the spectrum of ad-
vanced prostate cancer, with 2,265 participants (76%)
having node-positive, node-unknown, or distant metastases.
The addition of docetaxel to standard of care resulted in a
10-month improvement in OS (HR 0.78; 95% CI, 0.660.93;
p = .006). Importantly, the effect of docetaxel plus standard
of care (ADT for M1 and ADT plus radiation for most of those
with M0) was consistent across all subgroups, suggesting
that locally advanced disease (with high risk of micro-
metastases) and node-positive patients also derived a
benefit from early CHT. However, the OS benefit with CHT
was strongest and significant (p = .005) for those with
metastatic disease (note that there was no breakdown by
volume of disease), with nonmetastatic patients deriving a
failure-free survival (FFS) benefit, although not enough
events have occurred for an OS benefit at this time. Con-
sistent with the benefit of CHT in localized high-risk setting is
the survival benefit seen with the phase III RTOG 0521 trial,
demonstrating a 32% reduction in risk of death at 4 years
with adjuvant CHT following concurrent ADT plus RT. In
addition, men that received docetaxel derived an improved
5-year FFS (HR 0.76; 95% CI, 0.571.00; p = .05). Likewise, the
phase III GETUG 12 trial showed CHT plus RT conferred a
reduction in risk of relapse or death of 29% at 8 years over
ADT plus RT alone51; longer follow-up is required to see
whether this benefit extends to OS as well.
The third trial, GETUG 15, was the first to explore CHT in
metastatic hormone-sensitive prostate cancer.52 Although
the early results did not suggest a benefit from CHT, longer
follow-up and harmonizing volume of disease definitions
with those of CHAARTED revealed more similar results to
those seen in CHAARTED, especially for those with high-
volume disease.53 Specifically, it was found that CHT resulted
in a 13.5-month improvement in median OS at 7 years
(HR 0.88; 95% CI, 0.681.14; p = .3), with a post hoc analysis
identifying a 22% reduction in risk of death in men with high-
volume disease, as per the CHAARTED definition.53 Fur-
thermore, radiographic PFS was greater in those that re-
ceived CHT in the total population (HR 0.69;95% CI,
0.550.87; p = .002) and in those with high-volume disease
(HR 0.61; 95% CI, 0.440.83; p = .002).
The utility of CHT in the subgroup of low-volume meta-
static hormone-sensitive prostate cancer is less well defined
at early follow-up of the CHAARTED trial. However, when
one considers the totality of the data of adjuvant therapy in
high-risk localized disease and benefit in the overall pop-
ulation of metastatic disease (STAMPEDE and CHAARTED),
it is quite possible that, for patients with oligometastatic
prostate cancer who are at risk for dying of their disease,
there is a benefit from CHT. At the other end of the
spectrum, studies for patients with low-volume disease

aimed at avoiding cytotoxic chemotherapy and its associ-
ated adverse events are currently under investigation, with
a different hormone-based approach using the competitive
androgen receptor antagonist, ARN-509, in combination
with ADT versus ADT alone in chemotherapy-naive pa-
tients with low-volume mHSPC (NCT02489318). Of note,
docetaxel can be prescribed per investigator choice in this
study.
Overall, collective data from GETUG 15, CHAARTED, and
STAMPEDE support the hypothesis that an aggressive ap-
proach with systemic therapy early in the metastatic setting
improves outcome. Indeed, a recent meta-analyses of data
from these studies confirmed the improved survival of CHT
over ADT (HR, 0.77; 95% CI, 0.680.87; p , .0001).54 It is
therefore logical to apply the principle of systemic therapy
with localized/focal ablative therapy in the setting of PSA
relapse and high-risk localized disease.
The large phase III RTOG 9601 trial tested whether
2 years of anti-androgen therapy plus salvage RT was
superior to RT alone in men with PSA relapse follow-
ing radical prostatectomy.55 Combined therapy resulted
in a 9% reduction in absolute incidence of metastases (14%
vs. 23%; p , .001) and 5% reduction in incidence of prostate
cancerspecific death (2.3% vs. 7.5%; p , .001) at 12 years.
Another retrospective study found that patients that re-
ceived salvage RT plus concurrent ADT had a decreased risk
of relapse when treated at a PSA relapse of less than or equal
to 0.5 ng/mL following prostatectomy, although the effect
appeared limited to those with negative surgical margins.56
This is further evidence that focal ablative therapy with
systemic therapy improves outcome in the relapsed setting
and supports the role of combined modality therapy in low-
volume recurrent disease.
In attempting to select those with oligometastatic disease
for further metastases-directed therapy, both deep PSA
nadir and absence of PSA progression on ADT may predict for
improved survival.57,58 Such patients may be the ones who
benefit the most from targeted treatments to select lesions.
In total, there is growing evidence that more aggressive
therapy early in the course of disease leads to improved
outcome, and therefore utilizing systemic therapy as part
of a multimodal approach with focal ablative therapy to
radiographic evident disease for patients with oligometa-
static prostate cancer should be considered.
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29. Heidenreich A, Pfister D, Porres D. Cytoreductive radical prostatectomy
in patients with prostate cancer and low volume skeletal metastases:
results of a feasibility and case-control study. J Urol. 2015;193:832-838.
30. Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with
metastatic prostate cancer benefit from definitive treatment of the
primary tumor? A SEER-based study. Eur Urol. 2014;65:1058-1066.
31. Fossati N, Trinh QD, Sammon J, et al. Identifying optimal candidates for
local treatment of the primary tumor among patients diagnosed with
metastatic prostate cancer: a SEER-based study. Eur Urol. 2015;67:3-6.
32. Karnes RJ, Murphy CR, Bergstralh EJ, et al. Salvage lymph node dis-
section for prostate cancer nodal recurrence detected by 11C-choline
positron emission tomography/computerized tomography. J Urol.
2015;193:111-116.
33. Zattoni F, Nehra A, Murphy CR, et al. Mid-term outcomes following
salvage lymph node dissection for prostate cancer nodal recurrence
status post-radical prostatectomy. Eur Urol Focus. Epub 2016 Feb 10.
34. Suardi N, Gandaglia G, Gallina A, et al. Long-term outcomes of salvage
lymph node dissection for clinically recurrent prostate cancer: results
of a single-institution series with a minimum follow-up of 5 years. Eur
Urol. 2015;67:299-309.
35. Ploussard G, Almeras C, Briganti A, et al. Management of node only
recurrence after primary local treatment for prostate cancer: a sys-
tematic review of the literature. J Urol. 2015;194:983-988.
36. Ost P, Bossi A, Decaestecker K, et al. Metastasis-directed therapy of
regional and distant recurrences after curative treatment of prostate
cancer: a systematic review of the literature. Eur Urol. 2015;67:852-863.
37. Rigatti P, Suardi N, Briganti A, et al. Pelvic/retroperitoneal salvage lymph
node dissection for patients treated with radical prostatectomy with
biochemical recurrence and nodal recurrence detected by [11C]choline
positron emission tomography/computed tomography. Eur Urol. 2011;
60:935-943.
38. Decaestecker K, De Meerleer G, Ameye F, et al. Surveillance or
metastasis-directed therapy for oligometastatic prostate cancer re-
currence (STOMP): study protocol for a randomized phase II trial. BMC
Cancer. 2014;14:671.
39. National Comprehensive Cancer Network. Prostate Cancer (Version
1.2016). http://www.nccn.org/professionals/physician_gls/pdf/prostate.
pdf. Accessed January 15, 2016.
40. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of pro-
gression after PSA elevation following radical prostatectomy. JAMA.
1999;281:1591-1597.
41. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in
metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:
737-746.
42. James ND, Sydes MR, Clarke NW, et al; STAMPEDE investigators. Ad-
dition of docetaxel, zoledronic acid, or both to first-line long-term
hormone therapy in prostate cancer (STAMPEDE): survival results from
an adaptive, multiarm, multistage, platform randomised controlled
trial. Lancet. Epub 2015 Dec 21.

43. Tannock IF, de Wit R, Berry WR, et al; TAX 327 Investigators. Docetaxel
plus prednisone or mitoxantrone plus prednisone for advanced pros-
tate cancer. N Engl J Med. 2004;351:1502-1512.
44. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine
compared with mitoxantrone and prednisone for advanced refractory
prostate cancer. N Engl J Med. 2004;351:1513-1520.
45. de Bono JS, Oudard S, Ozguroglu M, et al; TROPIC Investigators.
Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-
resistant prostate cancer progressing after docetaxel treatment:
a randomised open-label trial. Lancet. 2010;376:1147-1154.
46. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchi-
ectomy with or without flutamide for metastatic prostate cancer. N Engl
J Med. 1998;339:1036-1042.
47. Millikan RE, Wen S, Pagliaro LC, et al. Phase III trial of androgen ablation
with or without three cycles of systemic chemotherapy for advanced
prostate cancer. J Clin Oncol. 2008;26:5936-5942.
48. Singh D, Yi WS, Brasacchio RA, et al. Is there a favorable subset of
patients with prostate cancer who develop oligometastases? Int J
Radiat Oncol Biol Phys. 2004;58:3-10.
49. Makarov DV, Humphreys EB, Mangold LA, et al. The natural history of
men treated with deferred androgen deprivation therapy in whom
metastatic prostate cancer developed following radical prostatectomy.
J Urol. 2008;179:156-161, discussion 161-162.
50. Schweizer MT, Zhou XC, Wang H, et al. Metastasis-free survival is as-
sociated with overall survival in men with PSA-recurrent prostate
cancer treated with deferred androgen deprivation therapy. Ann Oncol.
2013;24:2881-2886.
51. Fizazi K, Faivre L, Lesaunier F, et al. Androgen deprivation therapy plus
docetaxel and estramustine versus androgen deprivation therapy alone
for high-risk localised prostate cancer (GETUG 12): a phase 3 rando-
mised controlled trial. Lancet Oncol. 2015;16:787-794.
52. Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with
docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15):
a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:149-158.
53. Gravis G, Boher JM, Joly F, et al; GETUG. Androgen deprivation therapy
(ADT) plus docetaxel versus ADT alone in metastatic non castrate
prostate cancer: impact of metastatic burden and long-term survival
analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol. Epub
2015 Nov 21.
APPROACH TO OLIGOMETASTATIC PROSTATE CANCER
54. Vale CL, Burdett S, Rydzewska LH, et al; STOpCaP Steering Group. Addition
of docetaxel or bisphosphonates to standard of care in men with localised
or metastatic, hormone-sensitive prostate cancer: a systematic review
and meta-analyses of aggregate data. Lancet Oncol. 2016;17:243-256.
55. Shipley WU, Seiferheld W, Lukka H, et al. Report of NRG Oncology/RTOG
9601, a phase 3 trial in prostate cancer: anti-androgen therapy (AAT)
with bicalutamide during and after radiation therapy (RT) in patients
following radical prostatectomy (RP) with pT2-3pN0 disease and an
elevated PSA. Int J Radiat Oncol Biol Phys. 2016;94:3.
56. Parekh A, Chen MH, Graham P, et al. Role of androgen deprivation
therapy in early salvage radiation among patients with prostate-
specific antigen level of 0.5 or less. Clin Genitourin Cancer. 2015;
13:e1-e6.
57. Hussain M, Tangen CM, Higano C, et al; Southwest Oncology Group Trial
9346 (INT-0162). Absolute prostate-specific antigen value after an-
drogen deprivation is a strong independent predictor of survival in new
metastatic prostate cancer: data from Southwest Oncology Group Trial
9346 (INT-0162). J Clin Oncol. 2006;24:3984-3990.
58. Hussain M, Goldman B, Tangen C, et al. Prostate-specific antigen
progression predicts overall survival in patients with metastatic prostate
cancer: data from Southwest Oncology Group Trials 9346 (Intergroup
Study 0162) and 9916. J Clin Oncol. 2009;27:2450-2456.
59. Jereczek-Fossa BA, Beltramo G, Fariselli L, et al. Robotic image-guided
stereotactic radiotherapy, for isolated recurrent primary, lymph node
or metastatic prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82:
889-897.
60. Schick U, Jorcano S, Nouet P, et al. Androgen deprivation and high-dose
radiotherapy for oligometastatic prostate cancer patients with less
than five regional and/or distant metastases. Acta Oncol. 2013;52:
1622-1628.
61. Decaestecker K, De Meerleer G, Lambert B, et al. Repeated stereotactic
body radiotherapy for oligometastatic prostate cancer recurrence.
Radiat Oncol. 2014;9:135.
62. Picchio M, Berardi G, Fodor A, et al. 11C-Choline PET/CT as a guide to
radiation treatment planning of lymph-node relapses in prostate cancer
patients. Eur J Nucl Med Mol Imaging. 2014;41:1270-1279.
63. Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous
androgen deprivation in prostate cancer. N Engl J Med. 2013;368:
1314-1325.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 129
GENITOURINARY (PROSTATE) CANCER

Precision Medicine in Advanced

Prostate Cancer: Understanding
Genomics, Androgen Receptor
Splice Variants, and Imaging
Biomarkers

CHAIR
Himisha Beltran, MD
Weill Cornell Medical College
New York, NY

SPEAKERS
Emmanuel S. Antonarakis, MD
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, MD

Gerhardt Attard, MD, PhD

The Institute of Cancer Research and The Royal Marsden Hospital
London, United Kingdom

Michael J. Morris, MD
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College
New York, NY
 TISSUE, LIQUID, AND IMAGING BIOMARKERS IN CRPC

Emerging Molecular Biomarkers in Advanced Prostate Cancer:

Translation to the Clinic
Himisha Beltran, MD, Emmanuel S. Antonarakis, MD, Michael J. Morris, MD, and
Gerhardt Attard, MD, PhD

OVERVIEW

Recent clinical and preclinical studies focused on understanding the molecular landscape of castration-resistant prostate
cancer (CRPC) have provided insights into mechanisms of treatment resistance, disease heterogeneity, and potential
therapeutic targets. This work has served as a framework for several ongoing clinical studies focused on bringing novel
observations into the clinic in the form of tissue, liquid, and imaging biomarkers. Resistance in CRPC typically is driven
through reactivation of androgen receptor (AR) signaling, which can occur through AR-activating point mutations, am-
plification, splice variants (such as AR-V7), or other bypass mechanisms. Detection of AR aberrations in the circulation
negatively impacts response to subsequent AR-directed therapies such as abiraterone and enzalutamide. Other potentially
clinically relevant alterations in CRPC include defects in DNA damage repair (at either the somatic or germline level) in up to
20% of patients (with implications for PARP1 inhibitor therapy), PI3K/PTEN/Akt pathway activation, WNT signaling pathway
alterations, cell cycle gene alterations, and less common but potentially targetable alterations involving RAF and FGFR2.
Imaging biomarkers that include those focused on incorporating overexpressed androgen-regulated genes/proteins, such as
prostate-specific membrane antigen (PSMA) and dihydrotestosterone (DHT) in combination with CT, can noninvasively
identify patterns of AR-driven distribution of CRPC tumor cells, monitor early metastatic lesions, and potentially capture
heterogeneity of response to AR-directed therapies and other therapeutics. This article focuses on the current state of
clinical biomarker development and future directions for how they might be implemented into the clinic in the near term to
improve risk stratification and treatment selection for patients.

the largest size.2 Further, molecular changes can occur in the

S everal drugs are either approved or in clinical develop-
ment for men with metastatic CRPC with varied mech-
anisms of action. Although many drugs have demonstrated
antitumor activity, and even an overall survival benefit in an
unselected population, the identification of biomarkers to
help select the best next-line systemic therapy for an in-
dividual patient is an unmet clinical need. Molecular bio-
markers have the potential to help clinicians with risk
stratification, inform patient selection for therapy, and assist
patient and family counseling (Fig. 1).
Primary prostate cancer is commonly multifocal at the
time of diagnosis. It has a long natural history with often
5 years or more before distant metastases are detected and
castration resistance ensues. In the monoclonal origin model
of clonal evolution supported by several studies,1,2 one
tumor clone/nodule present in a multifocal primary is re-
sponsible for metastasis. However, identification of that
dominant lesion at diagnosis is challenging because it may
not always be the lesion with the highest Gleason grade or of
tumor with disease progression and treatment resistance,
and there is recent evidence of polyclonal metastasis-to-
metastasis seeding.3 Therefore, assessment of the archival
primary tumor in making clinical decisions regarding sys-
temic therapies for patients with CRPC may not be adequate
or fully representative of the tumors current state.
Metastatic biopsies in advanced prostate cancer have not
been considered standard practice. To date, they have been
performed mainly in the context of clinical trials. Metastatic
biopsies can be challenging to perform because of the high
frequency of sclerotic bone-only metastases in CRPC, which
often require special biopsy procedures and tissue handling
for molecular profiling. Further, single-site metastatic bi-
opsies do not necessarily represent the entire metastatic
tumor burden of the patient because of intrapatient het-
erogeneity. Therefore, alternative approaches, such as
blood-based assays (e.g., circulating tumor cell, circulating
tumor DNA) and molecular imaging, may be more feasible

From Weill Cornell Medicine, New York, NY, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Memorial Sloan Kettering Cancer Center, Weill Cornell
Medicine, New York, NY; The Institute of Cancer Research, London, United Kingdom, The Royal Marsden Hospital, London, United Kingdom.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding Author: Himisha Beltran, MD, Weill Cornell Medicine, 413 East 69th St., New York, NY 10021; email: hip9004@med.cornell.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 131

BELTRAN ET AL
with the given advantage of performing serial assessments
during the course of a patients disease to track tumor
dynamics and treatment response.
THE GENOMIC LANDSCAPE OF CASTRATION-
RESISTANT PROSTATE CANCER:
CHARACTERIZATION OF METASTATIC
TISSUE BIOPSIES
Several recent studies have independently reported mo-
lecular data of tumors obtained from large cohorts of
patients with clinically localized prostate cancer4-6 and
metastatic CRPC.7-9 Certain genomic alterations, such as ERG
gene rearrangements and SPOP mutations, are present at
similar frequency in both localized and metastatic disease,
suggesting that these lesions predate metastatic spread.
Other alterations, such as AR point mutations or amplifi-
cation, are present primarily in CRPC (50%60%), which
suggests they are acquired following androgen depriva-
tion.10,11 The acquisition of activating alterations involving
AR (or AR cofactors) seems logical, as multiple studies have
confirmed that most castration-resistant prostate tumors
remain dependent on AR signaling.12 Mechanisms associ-
ated with reactivation of AR signaling in CRPC include ac-
quisition of AR genomic alterations, AR mRNA splice variant
expression (such as AR-V7), cofactor activation, AR bypass
(such as glucocorticoid receptor expression), or AR crosstalk
KEY POINTS
The study of biopsies from metastatic sites from patients
with advanced prostate cancer has revealed potentially
actionable or prognostic genomic alterations. Common
genomic alterations observed in CRPC are: ERG gene
fusion (40%50%), AR gene point mutation or
amplification (50%60%), TP53 mutation or deletion
(40%50%), PTEN deletion (40%50%), RB1 deletion
(20%), and alterations in DNA repair genes (20%).
Circulating tumor DNA analyses in patients with CRPC
have revealed intrapatient molecular heterogeneity and
the potential to track dynamic changes during the
course of therapeutic response and resistance in
patients with advanced prostate cancer.
Detection of the AR-V7 splice variant in circulating
tumor cells or AR genomic aberrations in circulating
tumor DNA has been associated with decreased clinical
response to abiraterone or enzalutamide. Prospective
trials underway are evaluating the prognostic and
predictive utility of AR-V7 and exploring novel agents
with potential activity against AR-Vexpressing CRPC.
Bi-allelic loss of DNA repair genes (e.g., BRCA1/2, ATM)
has been associated with clinical response to the PARP
inhibitor olaparib.
Advances in molecular imaging and assessment of bone
lesions have shown promise for early detection of
metastasis and detection of biologic heterogeneity
between sites.
132 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
pathways.13 What remains unclear is why some, but not all,
tumors in patients develop AR alterations and when they
occur during the course of AR-directed therapies. As de-
scribed below, liquid biopsies have shown promise as a
means to study AR dynamics during the course of treatment.
Clinical and preclinical studies investigating therapeutic
approaches to better target the AR (and AR splice variants) in
the face of AR-driven resistance are underway; these include
combined CYP17A1 inhibition and AR antagonism, targeting
the AR N-terminal or DNA binding domain, or AR degrada-
tion. A subset of CRPC also may lose AR independence be-
cause of loss of AR expression and/or signaling. Identifying
patients who will no longer benefit from AR-directed ther-
apies is also an area of biomarker investigation. One pro-
posed mechanism of AR independence includes the
development of epithelial plasticity associated with patho-
logic and molecular features of neuroendocrine cancer.14,15
There are several other genomic aberrations reported or
enriched in CRPC, some of which also occur at a lesser
frequency in primary disease, many predicted to be ac-
tionable (such as PI3K/Akt/PTEN, RAF, FGFR2, WNT pathway,
cell cycle, and DNA repair alterations; recently described in
Robinson et al8). This knowledge has served as a framework
for preclinical testing of novel agents and cotargeting ap-
proaches and the design of biomarker-driven clinical studies.
Present at similar frequency in approximately 40% to 50% of
primary prostate cancer and CRPC, the TMPRSS2-ERG gene
fusion is prostate cancerspecific and androgen-regulated,
making it an attractive drug target. TMPRSS2-ERG does not
encode for a chimeric protein; instead, it results in over-
expression of a truncated ERG protein in the setting of active
androgen signaling, driving a transcriptional program linked
to DNA damage and invasion.16 It is challenging to develop
drugs that target transcription factors, but short peptido-
mimetics that bind to ERG, bromodomain inhibitors, and
PARP inhibitors have been explored preclinically, and ola-
parib currently is being investigated in combination with
abiraterone in an ERG-fusion biomarkerstratified phase II
clinical trial (NCT01972217). Alteration of genes leading to
aberrant activation of the PI3K/Akt pathway, most com-
monly loss of PTEN, is implicated in 40% to 50% of CRPC cases
and is associated with signaling crosstalk with AR through
reciprocal negative feedback.17,18 Based on this, there are
several ongoing phase II trials investigating cotargeting of
both pathways (NCT01251861, NCT02525068, NCT02215096,
NCT02407054).
Somatic aberrations involving DNA defect repair genes
(such as deletions/mutations involving BRCA1/2, ataxia-
telangiectasia mutated [ATM], CHEK2, Fanconi [FANC]
genes) are present in up to 20% of CRPC tumors. Somatic loss
of the BRCA2 gene, for instance, occurs in approximately
3% of localized prostate cancer cases (TCGA)6 and 13% of
CRPC cases (SU2C-PCF).8 Notably germline mutations, un-
commonly present in patients diagnosed with localized
disease, are present at higher frequency in patients with
CRPC (in keeping with their association with more aggressive
disease at diagnosis).8,19,20 Tumors with defects in DNA

FIGURE 1. Schematic of Various Types of Molecular Biomarkers
This schematic illustrates various types of molecular biomarkers currently being tested in trials for patients with advanced prostate cancer, with a goal of ultimately
improving clinical decision making. Image credit: L.S. Beltran.
repair would be predicted to have disrupted homologous
recombination; therefore, they would be more sensitive to
inhibition of PARP1 or DNA cross-linking agents (such as
platinum chemotherapy) through a mechanism of synthetic
lethality. The PARP inhibitor olaparib has shown antitumor
activity in germline carriers of BRCA1/2 gene alterations
across cancer types, including prostate,21 and it is approved
for clinical use in patients with BRCA-mutated ovarian
cancer.
To investigate whether there are additional patients with
CRPC who may also benefit from PARP inhibition, such as
those with somatic alterations in DNA repair, Mateo et al
developed an adaptive design phase II trial of olaparib where
pretreatment tissue and blood biomarkers were in-
vestigated prospectively.19 In the 49 evaluable patients
enrolled in this study, overall response rate (defined by
TISSUE, LIQUID, AND IMAGING BIOMARKERS IN CRPC
either radiographic, prostate-specific antigen [PSA], or cir-
culating tumor cell [CTC] conversion) was 33% with 12
patients receiving olaparib for more than 6 months and four
patients receiving the drug for more than 12 months. The
majority of responders on the study were found to have
either germline or somatic alterations in DNA repair genes;
14 of 16 DNA-repair altered cases (88%) had a response to
olaparib, which was associated with prolonged overall
survival (median, 13.8 vs. 7.5 months in those without DNA
repair alterations). Based on these promising results, ola-
parib recently received a U.S. Food and Drug Administration
(FDA) breakthrough designation for patients with BRCA1/2-
or ATM-mutated metastatic CRPC who have received a prior
taxane-based chemotherapy and at least either enzaluta-
mide or abiraterone. A phase III study is planned. Reports
linking BRCA2 and FANCA alterations and platinum
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 133
BELTRAN ET AL
sensitivity in patients with CRPC also have been reported
recently.22,23
A question now is whether metastatic biopsies will soon be
warranted to look for DNA repair defects and, if so, when
should this be performed? Can these be detected reliably
using circulating tumor DNA or other noninvasive means?
Where will drugs such as PARP inhibitor or platinum che-
motherapy ultimately be used within the growing clinical
armamentarium of approved drugs? A higher frequency of
germline alterations involving DNA repair genes in CRPC has
not only therapeutic considerations but also familial im-
plications. Who and when to screen for germline alterations
and how genetic counseling and testing will be performed
and reimbursed are areas of active discussion.
Defects in DNA mismatch repair genes such as MLH1 and
MSH2 and microsatellite instability also occur at the somatic
level in up to 5% of prostate cancers8,24 and in the germline
DNA of Lynch syndrome families.25 This results in a hyper-
mutated phenotype with a mutation rate typically greater
than 10-fold higher than other CRPC tumors. Given obser-
vations in other tumor types linking mutation rates with
response to immune checkpoint inhibitors,26 identifying this
small subset of cases may have clinical implications in the
context of immunotherapies. The design and recruitment for
biomarker-enriched trials involving low-frequency subsets,
such as those patients with mismatch repair defects, are
challenging and rely on multi-institutional collaboration.
Although informative, most of the genomic studies per-
formed to date in CRPC have represented a snapshot in time.
How early events (such as SPOP, PTEN, or ERG) might co-
operate with potentially later events to drive tumor growth,
and how these affect response to subsequent therapies, the
tumor microenvironment, and the epigenetic landscape are
areas of active investigation. Translation of genomics into the
clinic also will require a better understanding of tumor
evolution and intrapatient heterogeneity. Longitudinal
studies, including the two SU2C-PCF Dream Teams, and
multisample cases (such as rapid autopsies) have started to
provide new insights that are having an impact on the clinical
interpretation of single-site biopsies in the context of routine
clinical care and insights into mechanisms of tumor evolution.
DEVELOPMENT OF PROGNOSTIC AND
PREDICTIVE CIRCULATING BIOMARKERS
Because serial metastatic biopsies are not always feasible or
safe for most men with CRPC, noninvasive assays including
CTCs and/or plasma DNA may be an effective means to
assess biomarker status and capture heterogeneity. Pro-
spective studies using the CellSearch system confirmed the
association between CTC count ($ in 7.5 mL) in patients with
advanced prostate cancer and worse clinical outcome.27 An
association with improved outcome for patients who had a
CTC conversion (from $ 5 to , 5) compared with those who
did not suggested that this approach could be used as an
early indicator of response and as a surrogate endpoint in
clinical trials. This led to the prospective evaluation of CTC
count in the phase III COU-301 trial of abiraterone and
134 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
prednisone in docetaxel-treated metastatic CRPC, which
showed that a biomarker panel containing CTC count and
lactate dehydrogenase level was a surrogate for survival at
the individual-patient level.28 Validation in additional pos-
itive phase III trials is now required.
Isolating and characterizing rare CTCs in the blood com-
partment composed of millions of white blood cells in-
troduces technologic and logistical challenges. Several more
recent platforms are showing promise in obtaining impor-
tant multiplex phenotypic data,29,30 and planned pro-
spective studies will investigate associations with clinical
behavior and outcome. Additionally, as described below, the
AdnaTest platform allows the capture of CTCs with pres-
ervation of mRNA quality, which can then be used to study
expression of candidate biomarkers such as AR-V7. Overall,
the number of CTCs is associated with number (and site) of
metastases.31,32 Using currently available platforms, the
majority of patients with low-volume metastases have fewer
than 510 CTCs in 10 mL of blood. Newer approaches may
improve on this detection rate or allow processing of larger
volumes of blood. An alternative approach to CRPC mo-
lecular characterization is to study tumor-specific aberra-
tions in cell-free DNA from plasma (i.e., the upper
compartment from blood centrifuged to precipitate the
cellular component).
Monitoring Plasma DNA to Modify Patient Treatment
Using next-generation sequencing approaches applied to
plasma DNA, tumor aberrations are detected in more than
95% of patients with progressing metastatic CRPC.33,34 These
are admixed with normal DNA at variable quantities, and
their relative abundance can provide information on tumor
behavior. Studies in prostate cancer and several other tumor
types have reported that changes in circulating tumor DNA
levels are associated with response to treatment and im-
provements in outcome.35-37 By monitoring sequential
plasma samples from patients with CRPC treated with
abiraterone, emergence or selection of an AR mutation
resulting in either a T878A or an L702H amino acid change
was observed in 15% to 20% of patients, often several months
before manifest clinical or radiologic progression.34,36 Pre-
clinical studies confirm that these two mutations are acti-
vated by progesterone or prednisolone respectively, both
present at increased levels in patients treated with abir-
aterone and supporting their causative association with
resistance.36,38 This was followed by a study of pre- and post-
treatment plasma samples from 100 patients treated with
abiraterone, the majority of whom were postdocetaxel and/or
had previously received potent AR-targeting agents. A mini-
mum circulating tumor content (7.5%, present in 80 of 97
pretreatment samples), defined as the abundance or allelic
frequency of tumor aberrations measured using a custom
panel including six informative prostate cancer lesions, was
mandated to allow evaluation of AR copy number gain. Data
reported include a strong association between pretreatment
AR copy number gain and/or T878A or L702H AR mutations
and PSA decline (4.9 and 7.8 times less likely to have a $ 50

or $ 90% decline) and overall survival (HR 7.33; 95% CI,
3.5115.34, p = 1.3 3 1029) and progression-free survival
(PFS; HR 3.73; 95% CI, 2.176.41, p = 5.6 3 1027).34 Similarly,
an association between AR copy number or an exon 8 AR
mutation and resistance to enzalutamide in 39 patients with
CRPC has been reported.39 Increased AR copy number is
associated with higher AR mRNA transcripts (in tumor tis-
sue),40 which drive resistance to androgen suppression
in vitro. Ongoing studies, as described below, will shed light on
the association between AR copy number and AR splice
variants and their association with other aberrations that
drive treatment resistance in CRPC. Overall, these data sup-
port the potential clinical applicability of circulating tumor
DNA studies in CRPC. Prospective evaluation of plasma AR
gene aberrations in randomized trials with novel and standard
AR targeting agents, taxanes, and radiopharmaceuticals are
now planned. Moreover, plasma DNA studies appear to
provide additional or complementary molecular data to tumor
biopsies,36,41 introducing the possibility of patient selection
for single-agent and combination therapeutic strategies tar-
geting additional targets, including DNA repair defects and
PI3K/Akt.
AR-V7 as a Clinical Biomarker
Androgen receptor splice variants are abnormally truncated
isoforms of the AR that are capable of activating tran-
scription of androgen-regulated genes without the re-
quirement of ligand.42-45 Although at least 22 AR splice
variants have been reported,8 AR-V7 is the most frequently
observed and the most abundant AR-V detected at the
mRNA and protein level in clinical specimens from patients
with CRPC. A number of retrospective studies have sug-
gested that the presence of AR-V7 is associated with more
rapid disease progression and shorter survival in men with
metastatic CRPC.46-49 The first prospective study to evaluate
the prognostic impact of AR-V7 was conducted by Efstathiou
et al.50 In that study, the detection of AR-V7 by immuno-
histochemistry in bone marrow biopsy specimens of patients
with CRPC was associated with resistance to enzalutamide;
AR-V7 protein was detected in 57% of men who developed
disease progression within 4 months of starting enzaluta-
mide and was not detected in any patient who responded to
enzalutamide for longer than 6 months (p = .02). These
findings were further corroborated in a separate study by
the same investigators evaluating the combination of
abiraterone and enzalutamide.51
More recently, Antonarakis et al52 reported a prospective
study assessing the prognostic role of AR-V7 detected at the
mRNA level by reverse-transcriptase (RT)-PCR from CTCs of
patients receiving abiraterone or enzalutamide. They found
that the presence of AR-V7 in CTCs was associated with
lower PSA response rate, shorter PFS, and shorter overall
survival compared with those patients without detectable
circulating AR-V7.52 Notably, the prevalence of AR-V7 was
higher in men treated with enzalutamide who previously had
received abiraterone and in men treated with abiraterone
who had previously received enzalutamide; AR-V7 prevalence
TISSUE, LIQUID, AND IMAGING BIOMARKERS IN CRPC
was lowest in men who had not received either agent. Ad-
ditionally, when assessing serial CTC samples over time, the
authors reported that all men with baseline detection of
AR-V7 remained AR-V7positive during the course of
therapy with abiraterone and enzalutamide, whereas 14%
of men with negative AR-V7 status at baseline converted
to AR-V7positive during treatment; these patients had
intermediate clinical outcomes.52
Another question is whether the presence of AR-V7 is
relevant in the setting of taxane chemotherapy, especially
because two preclinical studies have produced conflicting
results.48,53 Accordingly, Antonarakis et al54 performed a
second prospective study using their CTC-based AR-V7 assay
in 30 patients beginning treatment with docetaxel and seven
patients beginning treatment with cabazitaxel. The preva-
lence of AR-V7 in these patients, most of whom had pre-
viously received abiraterone and/or enzalutamide, was 46%.
PSA responses were observed in both AR-V7positive and
AR-V7negative men (41% vs. 65%; p = .19). Similarly, PFS
was not statistically different in patients who were AR-
V7positive and negative (p = .11). As a hypothesis-
generating exercise, Antonarakis et al incorporated data
from their prior study of 62 patients treated with abir-
aterone and enzalutamide and showed that clinical out-
comes appeared to be better with taxanes compared with
enzalutamide or abiraterone in men who were AR-V7
positive, although outcomes did not appear to differ by
treatment type in men who were AR-V7negative. More
specifically, in patients who were AR-V7 positive, PSA re-
sponses were higher in men treated with taxane compared
with enzalutamide or men treated with abiraterone (41% vs.
0%, p , .001), and PFS was longer in men treated with
taxane (HR 0.21, p = .003). Intriguingly, 58% of patients with
baseline AR-V7positive status converted to AR-V7
negative status during treatment with docetaxel or cab-
azitaxel. Whether such transitions in AR-V7 status may
resensitize such patients to further AR-directed therapies is
unknown.55
Taken together, the clinical data to date suggest that the
presence of AR-V7 may be a marker of resistance to AR-
directed therapy but not taxane chemotherapy; therefore, it
may represent a treatment selection biomarker in CRPC.
These findings now warrant further prospective validation
and clinical qualification before CTC-based AR-V7 testing
should be used in clinical practice to inform treatment
decisions. A number of AR-V7 biomarker validation studies
currently being conducted are summarized in a recent re-
view.56 The Sanofi-sponsored PRIMCAB trial (NCT02379390)
is investigating cabazitaxel chemotherapy versus AR-
directed therapy in men with metastatic CRPC who have
developed disease progression within 6 months of starting
abiraterone or enzalutamide. As a secondary endpoint, that
trial will prospectively evaluate baseline AR-V7 status from
CTCs as a putative predictive biomarker in this setting, in
which the prevalence of AR-V7 is expected to be about 33%.
The Johns Hopkins AR-V7 assay will serve as the central
laboratory for AR-V7 testing. Exploratory analyses will also
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 135
BELTRAN ET AL
evaluate transitions in AR-V7 status at the time of pro-
gression. In a Prostate Cancer Foundation (PCF)-sponsored
prospective biomarker trial (NCT02269982) coordinated by
the Duke Cancer Institute, three different CTC-based AR-V7
assays will be evaluated in 120 men with taxane-naive
metastatic CRPC and high-risk clinical features. In this
noninterventional trial, patients will receive standard-of-
care abiraterone or enzalutamide and then may also re-
ceive standard-of-care taxane at progression. AR-V7 testing
will be performed prior to AR-directed therapy, at pro-
gression on AR-directed therapy, and also at progression on
chemotherapy. Each patient will undergo AR-V7 testing with
three assays at each time point: the Johns Hopkins mRNA-
based assay, the Weill-Cornell mRNA-based assay (which
also evaluates other AR variants), and the EPIC Sciences
protein-based assay.
Although no approved agents currently directly target
AR-V7, a number of compounds are now in clinical devel-
opment; these are summarized in a recent review.56 Gale-
terone (Tokai Pharmaceuticals) is an oral drug with three
proposed mechanisms of action, including inhibition of
CYP17 lyase, antagonism of the AR ligand-binding domain,
and degradation of both full length AR (AR-FL) and AR splice
variants through a proteasome-dependent pathway.56,57
In a post hoc analysis of the phase II ARMOR2 trial, among
seven patients with AR C-terminal loss (as determined using
an immunohistochemistry-based CTC assay), six men
achieved more than a 50% PSA reduction with galeterone
treatment. Based on these preliminary data, a registration
phase III trial (ARMOR3-SV) was launched in 2015
(NCT02438007). Eligible patients are those with AR-V7
positive metastatic CRPC without prior treatment with novel
AR-directed therapies or taxane chemotherapies. AR-V7
testing will be conducted using a CLIA-certified assay de-
veloped by Qiagen. Patients who are CTC-positive and AR-
V7positive (148 total patients) will be randomly selected to
receive either galeterone or enzalutamide. Notably,
ARMOR3-SV is the first registration trial in prostate cancer to
use a biomarker-selection trial design.
EPI-506 (ESSA Pharma), an oral prodrug of EPI-002, is the
first drug reported as capable of targeting the AR N-terminal
domain.58 Specifically, EPI-506 binds covalently to the Tau5
region of the AF1 domain of the N-terminus, a region that is
responsible for 99% of the transcriptional activity of AR.
Because the N-terminus is present in both the AR-FL and in
all of the AR splice variants (including AR-V7), treatment with
EPI-506 would be expected to inhibit all forms of AR sig-
naling. Preclinical studies with EPI-002 have shown that this
compound has activity in several AR-V7expressing cell lines
and xenograft models.59 A phase I trial (including a sub-
sequent phase II expansion) using EPI-506 opened in 2016
(NCT02606123). Eligible patients are those with metastatic
CRPC who have previously received either abiraterone or
enzalutamide; one prior taxane is also permitted but not
required.60 Exploratory analyses of AR-V7 and plasma AR
gene aberrations also will be conducted, but this information
will not be used for patient selection or stratification.
136 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
In a drug library screen aimed at identifying FDA-approved
drugs capable of targeting AR-V7, the antihelminthic drug
niclosamide emerged as an unexpected success.61 Addi-
tional mechanistic studies suggested that this agent func-
tions by degrading AR-V7 through a proteasome-dependent
pathway and that AR-V7 degradation occurred more rapidly
than AR-FL degradation. Niclosamide demonstrated sub-
stantial antitumor activity in a number of AR-V7expressing
CRPC cell lines and xenograft models resistant to enzalu-
tamide, and the combination of niclosamide and enzaluta-
mide produced maximal tumor inhibition. Based on these
preclinical data, a phase I clinical trial was launched in 2015
(NCT02532114) for men with abiraterone-pretreated CRPC
who test positive for AR-V7 using an AR-V7 assay performed
at the University of Washington. In this trial, patients will
receive enzalutamide plus escalating doses of oral niclosa-
mide. Exploratory analyses will evaluate changes in AR-V7
status during the course of niclosamide treatment and at the
time of progression.
IMAGING METASTATIC DISEASE: CURRENT AND
FUTURE PERSPECTIVES
The tissue and blood-based technologies described above
may accelerate drug development and personalize clinical
decision making by yielding biomarkers for drug sensitivity
and response. Advances in imaging technology can hasten
the pace of such progress. Imaging is capable of not only
assessing disease extent and distribution, but it can also
identify biologic features of a patients totality of lesions
rather than those of a single biopsy or blood draw. Yet, of all
of the biomarkers used for prostate cancer staging
prognostication, prediction, response assessment, and bi-
ologic characterizationimaging has been one of the most
challenging to develop.
A substantial basis of these difficulties is that prostate
cancer is a bone-tropic solid tumor, which is difficult to
assess, much less measure. The Tc-99 MDP tracer is in-
corporated into reactive bone rather than the tumor.
Consequently, bone scintigraphy is more sensitive to pro-
gression than response. Importantly, in 20% to 50% of pa-
tients, the bone scan will paradoxically worsen shortly after
the patient is placed on effective therapy, which can thereby
mislead the inattentive clinician to interpret a worsening
scan as disease progression rather than response.62-64 De-
spite these limitations, bone scintigraphy is ubiquitously
available, inexpensive, and the existing standard for imaging
bone. Data collection by the Prostate Cancer Working Group
2s definition for disease progression was standardized,65
incorporated into case report forms, and then the definition
and data collection methods were prospectively validated
for reproducibility and tested for an association with overall
survival in three prospective clinical trials involving abir-
aterone (NCT00887198), enzalutamide (NCT01212991),
and orteronel (NCT01193244). These trials demonstrated
excellent concordance between central and investigator
reviewers. 66,67 In the first trial assessed, a significant
association between radiographic PFS and overall survival

was found (Spearmans coefficient, 0.72), and the endpoint
was used for regulatory approval of abiraterone for patients
with chemotherapy-naive CRPC.65,68,69 Newer methods of
using bone scintigraphy involve quantitative descriptors of
disease burden, such as the bone scan index, which is the
fraction of skeletal mass represented by tracer uptake70 and
can be used to describe both response and progression. The
bone scan index has been shown to be prognostic of overall
survival in a preliminary retrospective analysis,71 and au-
tomated systems are undergoing analytic validation.72-74
Bone-directed PET/CT imaging using 18F sodium fluoride
(NaF) may more accurately localize disease and produce a
quantitative output amenable to biomarker development
and modeling. However, it is still subject to flare phenomena
and does not directly demonstrate disease. Early studies
suggested that the modality was superior to both fluo-
rodeoxyglucose (FDG) PET and 99mTc-MDP single photon
emission computed tomography (SPECT) in detection of
bone metastases.75-77 These findings were supported by
subsequent meta-analyses, such as one analyzing 11 studies
involving 613 patients that concluded, on a per-patient basis,
NaF PET had a sensitivity and specificity of 96% (93%98%)
and 91% (88%94%) versus 88% (84%96%) and 80%
(75%84%) for bone scintigraphy.78 The National Oncology
PET Registry (NOPR) is examining the use of NaF PET for
clinical decision making. Data on 1,940 patients with pros-
tate cancer demonstrated that NaF PET findings prompted a
change in treatment in 41.8% of patients. However, NOPR
did not seek to, nor did it define, a standard definition of
either response or progression, nor assess whether the
change in treatment was justified or associated with patient
benefit. A preliminary multicenter study (NCT01516866)
recently has been completed that delineates the re-
producibility of NaF across centers and examines post-
treatment changes in patients treated with AR-directed
therapy and taxane chemotherapy. As it stands now, it is
not clear that NaF PET/CT confers clinically useful in-
formation as a response biomarker, and per the Prostate
Cancer Working Group 2 (and the soon-to-be published
Prostate Cancer Working Group 3), should be considered
investigational as an endpoint in clinical trials.79
Assessing the actual disease burden in a patient, as op-
posed to statistical risk assessments of either distant or
localized disease as determined by mathematical
modeling,80-82 is key to personalized decision making and
clinical trial design and risk stratification. Accurate staging is
particularly important for men with high-risk localized dis-
ease and for those whose disease has biochemically relapsed
following local therapy. In these cases, decision making
frequently occurs without the benefit of imaging findings
that declare the patients true distribution of disease. New
molecular imaging techniques appear to be superior to
standard cross-sectional imaging and bone scintigraphy,
although it is unclear how to best use this information for
clinical care.
Prostate-specific membrane antigen is a transmembrane
carboxypeptidase that is expressed in prostatic tissue,
TISSUE, LIQUID, AND IMAGING BIOMARKERS IN CRPC
upregulated in prostate cancer (especially CRPC), and
present regardless of disease site.83 In 1996, the FDA ap-
proved Indium (111In) capromab pendetide,84 based on an
antibody that targets the internal domain of PSMA. Newer
tracers, such as the Zr-89 labeled anti-PSMA antibody J591,
target the external domain of the molecule. A detailed
lesional analysis of 89Zr-J591 in men with CRPC, verified by
pathology, revealed 89Zr-J591 detected 491 osseous sites
compared with 339 by MDP in 50 patients.85 The overall
accuracy of 89Zr-J591 by pathology was 95.2% for osseous
lesions; however, the performance in soft tissue was less
accurate, at an accuracy of 60%. A major drawback of intact
antibodies is a long half-life, resulting in delays between
injection and imaging, which can be overcome by the use of
minibodies86 or small molecules that inhibit the enzymatic
site of PSMA. An illustrative example of a Zr-89 radiolabeled
minibody PET scan (IAB2M, ImaginAb, Inglewood, CA) with
detection of bone lesions in a patient with CRPC is shown in
Fig. 2. Although molecular imaging has the capacity to
demonstrate a greater extent of disease earlier in the dis-
ease course, what to do with that information clinically is
unknown.
The most commonly used anti-PSMA small molecule
ligand is Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)](68Ga-
DKFZ-PSMA-11), which has been extensively studied in
Europe. In a recent retrospective analysis, 319 patients with
progressive disease across a variety of clinical states were
scanned.87 On a lesional level, sensitivity and specificity were
76.6% and 100%, respectively. A patient-based analysis
revealed a sensitivity of 88.1%. Especially relevant for the
patient who experienced biochemical relapse was early
evidence that disease could be detected in patients with very
low PSA values. Lesions were detected in approximately 47%
(8/17) of patients with a PSA of less than or equal to 0.2, 50%
(5/10) of cases with PSA were 0.21 to less than or equal to
0.5, 58% (14/24) of cases with a PSA between 0.51 and 1,
72% (28/31) in the range of 0.5 to less than 1, and greater
than 90% with higher PSA values (where the number of
patients was much greater). In another large retrospective
analysis of 248 patients, detection rates were 96.8%, (PSA
value 2 ng/mL or higher), 93.0% (PSA value 1-2 ng/mL),
72.7% (PSA value 0.5-1 ng/mL), and 57.9% (PSA value 0.2-0.5
ng/mL).88 These analyses suggest that PSMA-based imaging
might detect disease at PSA ranges in which decisions about
salvage radiotherapy are indeed highly relevant, and would
appear to be more informative than standard imaging
modalities.89
11
C choline is chemically identical to physiologic choline
and is taken up by cancer cells requiring phospholipids to
create cell membranes. The detection of prostate cancer by
11
C choline was described in a recent pooled analysis of 12
studies involving 1,055 patients with biochemical relapse
who underwent either 11C choline or 18F fluorocholine. The
pooled sensitivity, specificity, and diagnostic odds ratio
was 85% (95% CI, 79%89%), 88% (95% CI, 73%95%), and
41.4 (95% CI, 19.7%86.8%), respectively.90 In another
meta-analysis involving 19 studies and 1,555 patients,91 a
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 137
BELTRAN ET AL
FIGURE 2. Imaging of Bone Lesions in a Patient With Castration-Resistant Prostate Cancer
Imaging of bone lesions of a patient with metastatic CRPC with bone scintigraphy (99mTc-MDP), FDG MIP, and a novel PSMA-directed PET scan using a Zr-89 radiolabeled
minibody (IAB2M, ImaginAb, Inglewood, CA). Although significantly more lesions are identified by IAB2M, whether the informative biomarker of novel imaging modalities, be it some
property of the SUV, lesion number, lesion location, change over time, or some other property, is as yet undefined.
Abbreviations: CRPC, castration-resistant prostate cancer; FDG MIP, fluorodeoxyglucose maximum intensity production; PSMA, prostate-specific membrane antigen; SUV,
standard uptake value.
pooled sensitivity of 85.6% (95% CI, 82.9%88.1%) and
specificity of 92.6% (95% CI, 90.1%94.6%) for all sites of
disease (prostatic fossa, lymph nodes, and bone) was re-
ported. However, 11C choline was relatively insensitive for
patients with PSA values less than 2 ng/mL, with a 5% de-
tection rate for PSA levels of less than 1 ng/mL, 15% for PSA
levels of 1 to 2 ng/mL, and 28% for PSA levels of greater than
2 ng/mL.92 As PSA increases, and particularly as PSA doubling
time decreases, 11C-choline PET is more likely to be posi-
tive.93,94 In the context of these European data and a small
number of U.S. studies, the FDA approved 11C choline for
patients with biochemical relapse after primary therapy
when conventional imaging does not indicate a definitive
sign of cancer. However, the modality has only limited
availability in the United States, and the indication makes a
particular point that the PET is not a replacement for tissue
sampling and testing.95
Numerous other tracers are being used or developed for
disease detection. However, there are limited prospective
studies to date that have an underlying hypothesis, adequate
power, and a preplanned strategy for confirming that im-
aging findings are true or false positives or negatives. Fur-
ther, the actionable findings of these imaging modalities, and
the clinical pathways that such findings should generate,
remain undefined. Detection of early distant disease pro-
vokes improvised surgical plans for local primary disease,
lymph node dissections in the salvage setting, irradiation of
individual metastatic foci for the oligometastatic setting, or
the institution of systemic therapy, in the absence of any data
that such maneuvers are beneficial, much less not harmful.
Trials to define these treatment algorithms must be per-
formed and currently are being planned and opened now.
As the age of molecular profiling in prostate cancer dawns,
imaging could allow for predictive biomarkers and treatment
selection by global assessments of a patients bony, nodal,
138 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
and soft-tissue disease. The image and the therapy could
also conceivably target the same molecule, such as PSMA.
An early example of the power of such technology is 16b-
18
F-Fluoro-5a-Dihydrotestosterone (FDHT), a fluorinated ligand
of the AR.96 FDHT is able to detect the presence of over-
expressed AR in CRPC, and can therefore be used to establish
drug targeting, as it was in the early clinical development of
enzalutamide.97 The tracer also was used to establish the
phase II dose of the AR antagonist ARN509.98 Although one
tracer can establish the targeting of the drug under study,
another could be used to detect post-treatment signaling, as
has been shown preclinically. For example, PSMA imaging
can be used to detect changes in AR signaling as a result of
treatment with enzalutamide.99 Ultimately, molecular im-
aging would not only be used as an early drug development
tool but as biomarkers of a patients susceptibility or re-
sistance to a given therapy, a means to capture differences
between metastatic lesions, and/or as an indicator of early
response.
CONCLUSION
Recent studies focused on integration of preclinical obser-
vations with clinical information, including specimens and
imaging, and patient response data have started to reveal
the intricacies underlying inter- and intrapatient hetero-
geneity in CRPC, possibly driving differences in clinical re-
sponse to systemic agents. Tissue, liquid, and imaging-based
biomarkers in prostate cancer hold great potential as bio-
markers for response assessments, staging and early de-
tection of disease, and biologic characterization and drug
development (Fig. 1). However, translation of such obser-
vations into the clinic to eventually impact care requires
prospective studies demonstrating clinical value of bio-
markers for prognostication or prediction of response. It is
crucial that development be performed with no less rigor

than a drug would be developed. For this to happen, more
prospective analytic and clinical validation studies must be
performed that are controlled for clinical states and have
prespecified endpoints, predefined interventions, and ad-
equate statistical power. The development of clinically
qualified biomarkers is compounded by the regulatory
framework for biomarker development, 100,101 which
requires a rigorous analytic validation process in which the
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45. Ware KE, Garcia-Blanco MA, Armstrong AJ, et al. Biologic and clinical
significance of androgen receptor variants in castration resistant
prostate cancer. Endocr Relat Cancer. 2014;21:T87-T103.
46. Guo Z, Yang X, Sun F, et al. A novel androgen receptor splice variant is
up-regulated during prostate cancer progression and promotes an-
drogen depletion-resistant growth. Cancer Res. 2009;69:2305-2313.
47. Hornberg E, Ylitalo EB, Crnalic S, et al. Expression of androgen receptor
splice variants in prostate cancer bone metastases is associated with
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48. Zhang X, Morrissey C, Sun S, et al. Androgen receptor variants occur
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One. 2011;6:e27970.
49. Qu Y, Dai B, Ye D, et al. Constitutively active AR-V7 plays an essential
role in the development and progression of castration-resistant
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50. Efstathiou E, Titus M, Wen S, et al. Molecular characterization of
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51. Efstathiou E, Wen S, San Miguel A, et al. Enzalutamide in combination
with abiraterone acetate in bone-metastatic castration-resistant
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52. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enza-
lutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:
1028-1038.
53. Thadani-Mulero M, Portella L, Sun S, et al. Androgen receptor splice
variants determine taxane sensitivity in prostate cancer. Cancer Res.
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54. Antonarakis ES, Lu C, Luber B, et al. Androgen receptor splice Variant 7
and efficacy of taxane chemotherapy in patients with metastatic
castration-resistant prostate cancer. JAMA Oncol. 2015;1:582-591.
55. Nakazawa M, Lu C, Chen Y, et al. Serial blood-based analysis of AR-V7
in men with advanced prostate cancer. Ann Oncol. 2015;26:
1859-1865.
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56. Maughan BL, Antonarakis ES. Clinical relevance of androgen receptor
splice variants in castration-resistant prostate cancer. Curr Treat
Options Oncol. 2015;16:57.
57. Kwegyir-Afful AK, Ramalingam S, Purushottamachar P, et al. Gale-
terone and VNPT55 induce proteasomal degradation of AR/AR-V7,
induce significant apoptosis via cytochrome C release and suppress
growth of castration resistant prostate cancer xenografts in vivo.
Oncotarget. 2015;6:27440-27460.
58. Andersen RJ, Mawji NR, Wang J, et al. Regression of castrate-recurrent
prostate cancer by a small-molecule inhibitor of the amino-terminus
domain of the androgen receptor. Cancer Cell. 2010;17:535-546.
59. Myung JK, Banuelos CA, Fernandez JG, et al. An androgen receptor N-
terminal domain antagonist for treating prostate cancer. J Clin Invest.
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60. Montgomery R, Antonarakis ES, Hussain M, et al. A phase 1/2 open-
label study of safety and antitumor activity of EPI-506, a novel AR N-
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prostate cancer (mCPRC) with progression after enzalutamide or
abiraterone. J Clin Oncol. 2015;33 (suppl; abstr TPS5072).
61. Liu C, Lou W, Zhu Y, et al. Niclosamide inhibits androgen receptor
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62. Johns WD, Garnick MB, Kaplan WD. Leuprolide therapy for prostate
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63. Pollen JJ, Witztum KF, Ashburn WL. The flare phenomenon on ra-
dionuclide bone scan in metastatic prostate cancer. AJR Am J
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64. Ryan CJ, Shah S, Efstathiou E, et al. Phase II study of abiraterone
acetate in chemotherapy-naive metastatic castration-resistant
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sponse. Clin Cancer Res. 2011;17:4854-4861.
65. Morris MJ, Farrelly JS, Fox JJ, et al. The Prostate Cancer Clinical Trials
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data accuracy and workload. J Clin Oncol. 2011;29 (suppl 7; abstr 121).
66. Ryan CJ, Smith MR, de Bono JS, et al; COU-AA-302 Investigators.
Abiraterone in metastatic prostate cancer without previous chemo-
therapy. N Engl J Med. 2013;368:138-148.
67. Beer TM, Armstrong AJ, Rathkopf DE, et al; PREVAIL Investigators.
Enzalutamide in metastatic prostate cancer before chemotherapy.
N Engl J Med. 2014;371:424-433.
68. Morris MJ, Molina A, Small EJ, et al. Radiographic progression-free
survival as a response biomarker in metastatic castration-resistant
prostate cancer: COU-AA-302 results. J Clin Oncol. 2015;33:
1356-1363.
69. Kluetz PG, Ning YM, Maher VE, et al. Abiraterone acetate in combi-
nation with prednisone for the treatment of patients with metastatic
castration-resistant prostate cancer: U.S. Food and Drug Adminis-
tration drug approval summary. Clin Cancer Res. 2013;19:6650-6656.
70. Imbriaco M, Larson SM, Yeung HW, et al. A new parameter for
measuring metastatic bone involvement by prostate cancer: the Bone
Scan Index. Clin Cancer Res. 1998;4:1765-1772.
71. Morris MJ, et al. Post-treatment serial bone scan index (BSI) as an
outcome measure predicting for survival. Genitourinary Cancers
Symposium Proceedings (2008).
72. Ulmert D, Kaboteh R, Fox JJ, et al. A novel automated platform for
quantifying the extent of skeletal tumour involvement in prostate
cancer patients using the Bone Scan Index. Eur Urol. 2012;62:78-84.
73. Anand A, Morris MJ, Kaboteh R, et al. Analytic validation of the au-
tomated Bone Scan Index as an imaging biomarker to standardize

quantitative changes in bone scans of patients with metastatic
prostate cancer. J Nucl Med. 2016;57:41-45.
74. Armstrong AJ, Kaboteh R, Carducci MA, et al. Assessment of the bone
scan index in a randomized placebo-controlled trial of tasquinimod in
men with metastatic castration-resistant prostate cancer (mCRPC).
Urol Oncol. 2014;32:1308-1316.
75. Grant, FD, Fahey FH, Packard AB, et al. Skeletal PET with 18F-fluoride:
applying new technology to an old tracer. J Nucl Med. 2008;49:68-78.
76. Schirrmeister, H, Glatting G, Hetzel J, et al. Prospective evaluation of
the clinical value of planar bone scans, SPECT, and (18)F-labeled NaF
PET in newly diagnosed lung cancer. J Nucl Med. 2001;42:1800-1804.
77. Hetzel M, Arslandemir C, Konig HH, et al. F-18 NaF PET for detection of
bone metastases in lung cancer: accuracy, cost-effectiveness, and
impact on patient management. J Bone Miner Res. 2003;18:
2206-2214.
78. Shen CT, Qiu ZL, Han TT, et al. Performance of 18F-fluoride PET or PET/CT
for the detection of bone metastases: a meta-analysis. Clin Nucl Med.
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79. Scher HI, Halabi S, Tannock I, et al. Trial design and objectives for
castration-resistant prostate cancer: updated recommendations from
the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;
34:1402-1418.
80. Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome
of salvage radiation therapy for recurrent prostate cancer after radical
prostatectomy. J Clin Oncol. 2007;25:2035-2041.
81. Stephenson AJ, Scardino PT, Eastham JA, et al. Postoperative no-
mogram predicting the 10-year probability of prostate cancer re-
currence after radical prostatectomy. J Clin Oncol. 2005;23:
7005-7012.
82. Kattan MW, Zelefsky MJ, Kupelian PA, et al. Pretreatment nomogram
for predicting the outcome of three-dimensional conformal radio-
therapy in prostate cancer. J Clin Oncol. 2000;18:3352-3359.
83. Foss CA, Mease RC, Cho SY, et al. GCPII imaging and cancer. Curr Med
Chem. 2012;19:1346-1359.
84. Schuster DM, Nieh PT, Jani AB, et al. Anti-3-[(18)F]FACBC positron emission
tomography-computerized tomography and (111)In-capromab pendetide
single photon emission computerized tomography-computerized to-
mography for recurrent prostate carcinoma: results of a prospective clinical
trial. J Urol. 2014;191:1446-1453.
85. Pandit-Taskar N, ODonoghue JA, Durack JC, et al. A phase I/II study for
analytic validation of 89Zr-J591 ImmunoPET as a molecular imaging
agent for metastatic prostate cancer. Clin Cancer Res. 2015;21:
5277-5285.
86. Pandit-Taskar N, ODonoghue J, Martin D, et al. First in human 89Zr-Df-
IAB2M anti-prostate specific membrane antigen (PSMA) minibody in
patients with metastatic prostate cancer. J Nucl Med. 2015;56:400.
87. Afshar-Oromieh A, Zechmann CM, Malcher A, et al. Comparison of PET
imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based
PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med
Mol Imaging. 2014;41:11-20.
TISSUE, LIQUID, AND IMAGING BIOMARKERS IN CRPC
88. Eiber, M, Maurer T, Souvatzoglou M, et al. Evaluation of hybrid (6)(8)
Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence
after radical prostatectomy. J Nucl Med. 2015;56:668-674.
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biochemical relapse of prostate cancer: a systematic review and meta-
analysis. Clin Nucl Med. 2013;38:305-314.
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emission tomography/computerized tomography to restage prostate
cancer cases with biochemical failure after radical prostatectomy and
no disease evidence on conventional imaging. J Urol. 2010;184:
938-943.
93. Giovacchini G, Picchio M, Scattoni V, et al. PSA doubling time for
prediction of [(11)C]choline PET/CT findings in prostate cancer pa-
tients with biochemical failure after radical prostatectomy. Eur J Nucl
Med Mol Imaging. 2010;37:1106-1116.
94. Krause BJ, Souvatzoglou M, Tuncel M, et al. The detection rate of [11C]
choline-PET/CT depends on the serum PSA-value in patients with
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95. U.S. Food and Drug Administration. FDA Approves Production of
Imaging Agent That Helps Detect Prostate Cancer. http://www.fda.
gov/NewsEvents/Newsroom/PressAnnouncements/ucm319201.htm.
Accessed April 27, 2016.
96. Scher HI, Sawyers CL. Biology of progressive, castration-resistant
prostate cancer: directed therapies targeting the androgen-
receptor signaling axis. J Clin Oncol. 2005;23:8253-8261.
97. Scher HI, Beer TM, Higano CS, et al; Prostate Cancer Foundation/
Department of Defense Prostate Cancer Clinical Trials Consortium.
Antitumour activity of MDV3100 in castration-resistant prostate
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98. Rathkopf DE, Morris MJ, Fox JJ, et al. Phase I study of ARN-509, a novel
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surement of androgen receptor signaling with a positron-emitting
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Information/Guidances/UCM230597.pdf. Accessed April 17, 2012.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 141
GYNECOLOGIC CANCER

Paradigm Shift in the

Management Strategy for
Epithelial Ovarian Cancer

CHAIR
Keiichi Fujiwara, MD, PhD
Saitama Medical University International Medical Center
Hidaka, Japan

SPEAKERS
Amit M. Oza, MD
Princess Margaret Cancer Centre
Toronto, ON, Canada

Jessica N. McAlpine, MD
University of British Columbia
Vancouver, BC, Canada
 PARADIGM SHIFT IN OVARIAN CANCER STRATEGY

Paradigm Shift in the Management Strategy for Epithelial

Ovarian Cancer
Keiichi Fujiwara, MD, PhD, Jessica N. McAlpine, MD, Stephanie Lheureux, MD, PhD, Noriomi Matsumura,
MD, PhD, and Amit M. Oza, BSc, MD, MBBS, FRCPC

OVERVIEW

The hypothesis on the pathogenesis of epithelial ovarian cancer continues to evolve. Although epithelial ovarian cancer had
been assumed to arise from the coelomic epithelium of the ovarian surface, it is now becoming clearer that the majority of
serous carcinomas arise from epithelium of the distal fallopian tube, whereas clear cell and endometrioid cancers arise from
endometriosis. Molecular and genomic characteristics of epithelial ovarian cancer have been extensively investigated. Our
understanding of pathogenesis of the various histologic types of ovarian cancer have begun to inform changes to the
strategies for management of epithelial ovarian cancer, which represent a paradigm shift not only for treatment but also for
prevention, which previously had not been considered achievable. In this article, we will discuss novel attempts at the
prevention of high-grade serous ovarian cancer and treatment strategies for two distinct entities in epithelial ovarian cancer:
low-grade serous and clear cell ovarian carcinomas, which are relatively rare and resistant to conventional chemotherapy.

W e have seen numerous advances in the field of ovarian

cancer in the past decade, yet overall survival sta-
tistics for this disease are essentially unchanged. Despite the
excellent design and execution of multiple screening trials,
the relative impact in terms of number of cases of early
ovarian cancer detected has been small and, unfortunately,
tempered by the number of unnecessary surgeries performed
as a result of abnormal screening results.1-4 New methods of
disease control are desperately needed, and this has prompted a
push to explore methods of primary prevention.
PROPHYLACTIC SALGINGECTOMY: SHOULD ALL
TUBES BE REMOVED?
In BRCA1/2-mutation carriers, risk-reducing bilateral salpingo-
oophorectomy has been shown to be highly protective for
ovarian cancer, with a reduced risk of at least 80% after sur-
gery.5,6 Most high-risk women have reportedly experienced a
high quality of physical and mental well-being after risk-reducing
bilateral salpingo-oophorectomy,7 and all-cause mortality is
significantly reduced by this procedure.5,8 However, risk-reducing
bilateral salpingo-oophorectomy is not recommended for the
general/low-risk population, because removal of the ovaries is
reportedly associated with increased mortality, coronary heart
disease, stroke, osteoporosis, and colorectal cancer.9,10
Alternative opportunities for prevention were inspired by
the appreciation of the role of the fallopian tube in ovarian
cancer (Fig. 1). The distal fallopian tube is the site of origin of
the majority of the most common histotype of epithelial
ovarian cancerhigh-grade serousin women with he-
reditary predisposition (e.g., BRCA1/2 mutation) and in
sporadic occurrences in the general population.11,12 In ad-
dition, the fallopian tube serves as a conduit for the passage
of endometrial inflammatory cytokines, infections, and/or
irritants to the ovary and peritoneal cavity.13 Ectopic en-
dometrium may undergo malignant transformation and is
the purported site of origin of the next two most common
histotypes of epithelial ovarian cancer: clear cell and
endometrioid cancers.14 Long-substantiated risk factors for
ovarian cancer make sense in the context of the critical role
that the fallopian tube plays in ovarian cancer. Inflammatory
conditions, such as pelvic inflammatory disease, incessant
ovulation, or irritants such as talc that have ascended from
the lower genital tract via the fallopian tube to the tubo-
ovarian junction, increase mutagenesis and increase the risk
of ovarian cancer. Interventions that decrease these parameters
(e.g., tubal ligation, ovarian quiescence during pregnancy, or
breast feeding) are associated with a decreased risk of ovarian
cancer.13 Large studies with international cohorts of women
who have undergone tubal ligation have shown a decrease in

From the Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan; Department of Gynecology and Obstetrics, University of British
Columbia, Vancouver, Canada; Division of Medical Oncology and Hematology, Bras Family Drug Development Program, Princess Margaret Cancer Centre, Toronto, Canada; Department
of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Keiichi Fujiwara, MD, PhD, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka 350-1241, Japan;
email: fujiwara@saitama-med.ac.jp.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e247

FUJIWARA ET AL
risk of developing ovarian carcinoma by 29% overall, with
histotype-specific variation in protective effects. The greatest
risk reduction was observed in endometrioid (52%) and clear
cell (48%) histologies.15 Risk reduction was only 20% in high-
grade serous carcinoma; however, given that this histotype
encompasses 70% of all epithelial ovarian cancers and accounts
for 90% of deaths, this impact is still substantial. A recent meta-
analysis of published series with tubal ligation data reported
similar findings,16 and, importantly, the protective effect (60%
risk reduction) of tubal ligation has also been observed in high-
risk populations (BRCA1/2-mutation carriers).17 Although not
the focus of this article, oral contraception pills have arguably
had the greatest success in ovarian cancer risk reduction globally
and across all histotypes; however, the mechanism for the
protective effect of the oral contraception pills is not fully
understood. Past and current hypotheses again suggest an
important role of the fallopian tube, and the influence of the
progesterone component of oral contraception pills on tubal
epithelial cell proliferation (differentiated and/or stem cell) is
under active investigation.
The Intervention: Is There an Opportunity to Remove
Fallopian Tubes?
Beginning in 2008, and then as a formal initiative in 2010, we,
as members of the British Columbia Ovarian Cancer Re-
search Team (OVCARE) that is based in Vancouver, have
suggested to gynecologic surgeons that they should consider
the following: perform bilateral salpingectomy in all women
at the time of hysterectomy (even when the ovaries are
being preserved) and perform bilateral salpingectomy in
place of tubal ligation for sterilization. In September 2010,
we circulated a DVD to all gynecologic surgeons in British
KEY POINTS
Appreciation of the changing landscape of epithelial
ovarian cancer enables the development of novel
strategies in treatment and prevention.
Opportunistic salpingectomy should be considered in
women undergoing gynecologic procedures with access
to the peritoneal cavity, at hysterectomy, or for
permanent sterilization. For women at increased risk of
ovarian carcinoma development, risk-reducing bilateral
salpingo-oophorectomy remains standard of care.
Accruing data support the safety, acceptability,
feasibility, and cost effectiveness of this procedure.
Low-grade serous ovarian cancer, a rare subtype of
ovarian cancer, is relatively chemotherapy resistant,
and current development focus is on targeted therapy
that is based on its distinct biology.
Clear cell ovarian cancer is also a distinct pathological
and clinical entity of rare epithelial ovarian cancer. Its
carcinogenesis from endometriosis is now becoming
clearer, and research on molecular characteristics of
clear cell ovarian cancer has led to the new trials of
target agents.
e248 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Columbia, which included a review of the rationale for
salpingectomy. This initiative has had a profound effect on
clinical practice in British Columbia: the proportion of
hysterectomies that had associated salpingectomies (ex-
cluding hysterectomies in which ovaries were removed, the
rate of which remains unchanged) increased from 8% in
2008 to 63% in 2011 and to 75% in 2013, and the proportion
of sterilizations by bilateral salpingectomy increased from
0.5% in 2008 to 33% in 2011 and to 48% in 2013.18 The
Society of Gynecologic Oncologists of Canada, U.S. Society
for Gynecologic Oncology, American College of Obstetrics
and Gynecology, and Royal Australian and New Zealand
College of Obstetricians and Gynecologists have all since
published statements that recommend consideration of
salpingectomy for all women at the time of gynecologic
surgery,19-22 and physician surveys show willingness to un-
dertake practice change.23-26 It is essential to clarify that this
campaign is aimed at women in the general (low-risk) population
who have a lifetime risk of developing ovarian cancer of ap-
proximately 1.7%; importantly, risk-reducing bilateral salpingo-
oophorectomy at age 40 or after completion of childbearing27 is
still recommended and represents the standard of care in high-
risk populations, such as in BRCA1/2-mutation carriers. A two-
step procedure of risk-reducing salpingectomy followed by
oophorectomy in high-risk women, although feasible, carries
increased surgical risks, and there is insufficient data to support
optimal timing or protective effect (if any) for breast and ovarian
cancers; thus, the two-step procedure is reserved for women
who are unwilling to undergo risk-reducing bilateral salpingo-
oophorectomy.28,29
We have termed this intervention in the low-risk pop-
ulation opportunistic salpingectomy, which suggests that
surgeons should take the opportunity to remove the fal-
lopian tubes if there is access to these anatomic structures
during other scheduled gynecologic procedures but should
not perform a procedure solely for the purpose of tubal
removal for ovarian cancer prevention. We have published
data from a time period 2 years prior and 2 years after the
formal introduction of this campaign, including data from
procedures performed on 43,931 women. We observed no
increase in major perioperative complications or events.
Blood loss, length of hospital stay, and readmission rates
were the same in patients who underwent opportunistic
salpingectomy and in patients who underwent hysterec-
tomy alone or tubal ligation procedures. 18 Potential
long-term hormonal consequences of opportunistic sal-
pingectomy have been investigated through measurement
of ovarian sonographic parameters and hormonal assays;
data are reassuring but have relatively short follow-up.30-32
Given that an earlier age at menopause has been associated
with increased mortality, it is imperative that this does not
offset any projected protective effect in ovarian cancer risk
reduction. Hysterectomy is known to affect ovarian reserve33,34
and the relative impact of opportunistic salpingectomy per-
formed with hysterectomy is likely small or immeasurable. To
answer this definitively we are studying our British Columbia
cohort of women who have undergone these procedures,

FIGURE 1. Role of the Fallopian Tube in Ovarian Cancer
comparing onset of menopause (defined as cessation of
menses for 1 year) in individuals who have undergone bilateral
salpingectomy versus tubal ligation for permanent sterilization.
In addition, there is a planned randomized clinical trial in the
United Kingdom in women who will undergo bilateral sal-
pingectomy either at hysterectomy or as a stand-alone pro-
cedure for contraception.35
Is the increased uptake of opportunistic salpingectomy
responsible in terms of use of resources and health eco-
nomics? Our group and others have shown that this pro-
cedure can be undertaken by different surgical routes
(vaginal, minimally invasive, laparotomy)18,36-38 so it does
not need to be limited to high-resource countries. Additional
operating room time needed for opportunistic salpingec-
tomy with hysterectomy is approximately 16 minutes, and,
in lieu of tubal ligation, the procedure requires approxi-
mately 10 minutes,18 a time that arguably is of no clinical
impact to the majority of women undergoing these pro-
cedures nor to the health systems where the procedures are
being performed. Cost analysis modeling, which considers
perioperative risks, impact on ovarian cancer risk reduction,
and morbidities associated with premature menopause
secondary to oophorectomy, found that opportunistic sal-
pingectomy with hysterectomy was less costly and more
effective than hysterectomy alone, reduced the number of
ovarian cancer occurrences, and prolonged the average life
expectancy. Opportunistic salpingectomy for sterilization
would be considered more costly than tubal ligation in terms
of operative time and complication risk; however, oppor-
tunistic salpingectomy was more effective at reducing risk of
PARADIGM SHIFT IN OVARIAN CANCER STRATEGY
ovarian cancer. The calculated number needed to treat to
prevent a single occurrence of ovarian cancer was accept-
able for both procedures.39
Measuring the Impact of Opportunistic
Salpingectomy
Finally, and most importantly, will this change in surgical
paradigm translate to a decreased incidence of ovarian
cancer? Proof of success of this initiative will be an observed
reduction in new occurrences of ovarian cancer, and we
anticipate there will be a shift in the distribution of histo-
types of epithelial ovarian cancer in the population of
women exposed to this procedure. The age of women un-
dergoing this procedure as part of hysterectomy or for
permanent sterilization is younger than the age of onset of
ovarian cancer in the general population, so we anticipate
that it will be at least 10 years and up to 20 years from the
start of our campaign before we will be able to discern a
difference that would provide definitive support for this
intervention. Pooling of our data with data from other
geographic areas that have adopted this practice may help
power the analysis and hasten results. Although nay-sayers
may be frustrated or unsatisfied with this lack of immediate
measurable impact, we hold to this long view and are very
encouraged by emerging evidence from other historical
cohorts that supports this intervention. In addition to the
strong protective effect demonstrated in women who have
undergone tubal ligation (outlined previously), there are
data from a small number of studies on women who have
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e249
FUJIWARA ET AL
undergone excisional tubal surgery (defined as complete
salpingectomy, distal fimbriectomy, or partial salpingectomy).
Researchers from the Rochester Epidemiology Project reported a
64% reduction in the risk of ovarian cancer after excisional tubal
sterilization compared with those without sterilization or with
nonexcisional tubal sterilization (odds ratio [OR] 0.36; 95% CI,
0.131.02).40 Danish researchers, who used a national database,
reported that bilateral salpingectomy reduced risk for ovarian
cancer by 42% (OR 0.58; 95% CI, 0.360.95).41 Most recently, a
retrospective population-based study that used Swedish health
registers reported that bilateral salpingectomy was associated
with a 65% reduction in risk (hazard ratio 0.35; 95% CI,
0.170.73).42 Both the Danish and Swedish studies examined
retrospective data and included women who underwent sal-
pingectomies for pathologic reasons (e.g., hydrosalpinx, pelvic
inflammatory disease, ectopic pregnancy), which makes them
significantly different from the women undergoing opportunistic
salpingectomy in British Columbia for the purposes of ovarian
cancer prophylaxis. We hypothesize that salpingectomy per-
formed for risk-reduction purposes may confer more protection
than those performed for other indications, because surgeons
will be more careful to remove the entire distal end of the
fallopian tube.
Published data reassure us of the safety of the procedure and
suggest that opportunistic salpingectomy should be easily within
the skill set of any pelvic/abdominal surgeon and can be per-
formed by multiple surgical routes; there is health economic
support, and the evidence of high uptake suggests feasibility. In
addition, there are numerous nononcologic arguments for tubal
removal, including prevention of hydrosalpinges, pyosalpinx, or
tubal prolapse that may require subsequent surgeries.43 However,
as we wait to definitively measure the impact of this procedure on
ovarian cancer risk, whether a woman undergoes opportunistic
salpingectomy will remain a decision between her and her
treating physician, and the decision requires good judgment and
common sense. Our first dictum as physicians is to do no harm.
FIGURE 2. Carcinogenesis Pathway in Low-Grade Serous Ovarian Cancer
Pictures courtesy of Dr. Patricia A. Shaw, University Health Network of Toronto.
e250 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
LOW-GRADE SEROUS OVARIAN CANCER
Current Clinical Practice
The standard strategy for advanced epithelial ovarian cancer
remains the combination of surgery and platinum/taxane-
based chemotherapy,44 which is primarily driven by activity
in unselected populations enrolled in clinical trials; the
populations are predominantly composed of women with
high-grade serous ovarian cancer. One of five histologic sub-
types of epithelial ovarian cancer, low-grade serous ovarian
cancer is a rare subentity with a specific genomic landscape, as
evidenced by a different natural history and pattern of re-
sponse to therapy.45 From available evidence, low-grade se-
rous ovarian cancer may arise after an initial diagnosis of serous
tumor of low malignant potential (Fig. 2) or de novo and does
not seem to be part of the hereditary breast-ovarian cancer
syndrome related to the BRCA1/2 gene mutation.46
The dogma of cytotoxic chemotherapy for all epithelial
ovarian cancers is evolving on the basis of the recent clinical
and molecular classification of the different subtypes of
epithelial ovarian cancer.47 To date, no prospective ran-
domized clinical trial data are available to provide guidance
about the optimal postoperative treatment of low-grade
serous ovarian cancer.48 Although available data are mostly
based on small retrospective, single-institution studies, che-
motherapy resistance is consistently reported in low-grade
serous ovarian cancer.48,49 From a single-institution database,
112 women with stages II to IV low-grade serous ovarian cancer
who underwent primary surgery followed by platinum-based
chemotherapy were retrospectively identified. Of these, 42
patients underwent second-look surgery, and 2, 13, and 24
had evidence of no residual disease, microscopically positive
disease, or macroscopically positive disease, respectively.50
Similar findings were reported with low-grade primary peri-
toneal cancer, with high rates of persistent disease at the
completion of adjuvant chemotherapy.51 This relative che-
motherapy resistance, possibly related to the nature of

low-grade serous ovarian cancer, was also observed in a
separate retrospective study that included patients treated
with neoadjuvant chemotherapy.52 Despite the receipt of a
taxane and platinum combination in the majority of the 25
patients with advanced low-grade serous ovarian cancer, only
one patient had a complete response (CR); an additional 21
women had stable disease, but two experienced progression
after neoadjuvant chemotherapy. Although CA-125 levels were
reduced by greater than 50% with chemotherapy in half of the
patients, radiologic response remained low.
Chemotherapy resistance also has been demonstrated in
the setting of recurrent disease. For example, in a retro-
spective study of 58 women with recurrent low-grade serous
ovarian cancer who received 108 separate chemotherapy
regimens,49 only four responses were seen (one CR and
three partial responses; overall response rate [ORR], 3.7%).
The ORR was 4.9% for the platinum-sensitive cohort and
2.1% for the platinum-resistant cohort. Stable disease that
was observed in 65 (60.2%) of 108 chemotherapy regimens
may have been related to tumor biology or may have been a
bias of assessmentmeasureable lesions can often appear
stable by RECIST criteria on CT scans53and not a true
therapeutic effect. As such, given the relative chemotherapy
resistance, we should consider making clinical trials the new
standard. Targeted biologically directed therapy is an in-
teresting area of investigation in low-grade serous ovarian
cancer, given the molecular characteristics of disease.
Compared with high-grade serous ovarian cancer, low-grade
serous ovarian cancer has lower expression of p53, WT1,
c-KIT, Ki-67, and MMP-954 but a higher expression of estrogen
receptor, progesterone receptor, and E-cadherin.55
Hormonal Therapy
Low-grade serous ovarian cancer often is diagnosed at a
younger age (43 to 55 years), so a higher proportion of
patients with low-grade serous ovarian cancer are pre-
menopausal at diagnosis; as such, hormonal status may
be implicated in pathogenesis. 56 Indeed, among the five
different subtypes of ovarian cancer, low-grade serous
ovarian cancer has the higher proportion of hormone
receptorpositive (progesterone receptor and/or estrogen
receptorpositive) tumors.57 In this large retrospective
study, strong progesterone but not estrogen receptor ex-
pression appeared to be associated with improved survival
after accounting for site, age, stage, and grade (p = .019 for
progesterone and p = .78 for estrogen receptor). But this
association was not statistically significant after adjusting for
residual disease in this subset of 64 patients with low-grade
serous ovarian cancer (p = .27 and .90, respectively).57 The
agents used as hormonal therapy, which are targeted
therapies against the progesterone receptor and estrogen
receptor, are mainly tamoxifen and aromatase inhibitors
(anastrozole and letrozole). A retrospective study in 64
patients with recurrent low-grade serous ovarian cancer
who received 89 separate hormonal regimens showed an
ORR of 9% (six CRs and two partial responses).58 In total, 61%
PARADIGM SHIFT IN OVARIAN CANCER STRATEGY
of the regimens resulted in a progression-free survival (PFS)
duration of at least 6 months. Regimens that involved treat-
ment of estrogen receptorpositive/progesterone receptor
positive disease produced a longer median time to progression
(8.9 months) than regimens that involved treatment of es-
trogen receptorpositive/progesterone receptor2negative
disease (time to progression, 6.2 months; p = .053). Given the
relatively favorable adverse effect profile and demonstrated
efficacy, hormonal therapy represents an interesting treatment
alternative.
The Mitogen-Activated Protein Kinase Pathway
The mitogen-activated protein kinase (MAPK) pathway is
activated and appears to play a prominent role in the
pathogenesis of low-grade serous ovarian cancer.59 Ap-
proximately 20% to 40% of low-grade serous carcinomas
have a KRAS mutation, whereas BRAF mutations are rare
(approximately 5%).60,61 KRAS is a frequent mutation de-
tected in advanced low-grade serous ovarian cancer, and the
BRAF V600E mutation is associated with serous borderline
tumors and early-stage low-grade serous ovarian cancer.62
As a result, the V600E mutation is associated with a better
clinical outcome. In a study of 23 patients with an original
diagnosis of serous tumor of low malignant potential who
subsequently experienced recurrence with a diagnosis of
low-grade serous ovarian cancer, patients with KRAS G12V
mutations experienced shorter survival times than those
with either KRAS G12D, wild-type, or rare KRAS variants
(hazard ratio 4.77; p = .023).63 Another retrospective study
showed the potential impact of mutational status; patients
with KRAS and BRAF mutations appeared to have better
overall survival than those with wild-type KRAS or BRAF.64
Additional investigations are warranted to elucidate the role
of the mutation type in low-grade serous ovarian cancer,
because this may have important clinical implications, such
as introduction of the analysis of BRAF/KRAS status in the
postdebulking setting to predict the risk of recurrence.65
The MAPK cascade is triggered by the binding of a ligand
that ultimately leads to phosphorylation of ERK.66,67 Thus,
MEK is a good candidate for targeted therapy, and a number
of MEK inhibitors (MEKi) have been developed.
The GOG-0239 open-label phase II study of patients with
recurrent low-grade serous ovarian cancer, by prospective
pathologic evaluation, received selumetinib (AZD6244)
a MEK1/2 inhibitor that targets the downstream effect of
activating BRAF and KRAS mutationsat a dosage of 50 mg
twice daily.68 The majority of patients had received three or
more prior chemotherapy regimens. Fifty-two women with
recurrent low-grade serous ovarian cancer were enrolled,
and the ORR was 15% (one CR and seven partial responses).
Another 65% of patients in the trial had stable disease, and
the median PFS was 11.0 months. The most common tox-
icities were gastrointestinal, dermatologic, and metabolic.
Three patients experienced grade 4 toxicitiesone each of
cardiac, pain, and pulmonary toxicity. Mutational analysis
was conducted on formalin-fixed, paraffin-embedded tumor
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FUJIWARA ET AL

samples from 34 patients enrolled in this trial, and the
primary tumor accounted for 82% of the cases. In these 34
cases, there were two BRAF mutations (6%) and 14 KRAS
mutations (41%), and 15% of tumors had NRAS mutations. In
this study, there was no correlation between mutations
of BRAF or KRAS and ORR; however, only hotspot muta-
tions were assessed. Tissue analysis of an extraordinary
responder who experienced a complete, durable, and ongoing
(. 5 years) response to selumetinib identified a previously
uncharacterized MAP2K1 deletion (Q56_V60del). Additional
investigations support that this novel deletion is a driver
alteration in this exceptional responder and serves as the
molecular basis for her dramatic, sustained response to the
MEKi.69 This finding may explain why targeted genotyping of
only the most common hotspot alterations in BRAF and KRAS
failed to ascertain the molecular basis for a subset of the
responses observed in the GOG-0239 trial and justify the
incorporation of broader profiling methods. After these
promising results, several studies have been designed, such
as the ongoing GOG-281 trial. GOG-281 is a randomized
phase II study between investigator choice (of letrozole,
tamoxifen, weekly paclitaxel, pegylated liposomal doxoru-
bicin, or weekly topotecan) and the MEKi agent trametinib
for recurrent low-grade serous ovarian cancer. The study
incorporates prospective pathology review, pretissue bi-
opsy, and blood collection for correlative analyses, such as
next-generation sequencing and proteomics. The primary
endpoint is PFS, the estimated enrolment is 250 patients,
and crossover at disease progression is allowed.
Several additional targeted studies are also ongoing in
this space. NCT01936363 was a randomized phase II trial
for recurrent low-grade serous ovarian cancer that com-
pared pimasertib (MEKi) plus or minus SAR245409a
phosphatidylinositol-4,5-biphosphate 3-kinase and mTOR.
This randomized phase II trial started, and patients were
recruited, but the trial subsequently was stopped because of
toxicity with the combination. No results have been pre-
sented or published as yet. The MILO trial (NCT01849874)
is a randomized, open-label phase III study between phy-
sician choice (paclitaxel, liposomal doxorubicin, topotecan)
and binimetinib, or MEK162, for recurrent low-grade serous
ovarian cancer. In addition, the RTM 1313 study is a ran-
domized phase II trial with patients with newly diagnosed
stages II to IV low-grade serous ovarian cancer that is in-
vestigating trametinib/GSK 214170550 every 3 weeks for six
cycles versus standard adjuvant chemotherapy carboplatin/
paclitaxel for six cycles. Taken together, biomarkers that predict
MEKi activity and the identification of MEKi-independent
compensatory pathways are needed.
Antiangiogenesis
The angiogenesis pathway may also be a therapeutic target
in patients with low-grade serous ovarian cancer. An initial
report of three patients with recurrent low-grade serous
ovarian cancer treated with bevacizumab, the monoclonal
antibody against the vascular endothelial growth factor
A (VEGF-A), showed sustained responses of 15-, 15-, and
22-month durations.70 From a retrospective cohort of 17
patients with low-grade serous ovarian cancer and serous
borderline tumors, two patients were treated with single-
agent bevacizumab, and the others were treated with a
combination of bevacizumab and chemotherapy.71 Fifteen
patients were evaluable for response; six had a partial re-
sponse, and five had stable disease that lasted 3 months or
longer. The response rate for the low-grade serous ovarian
cancer group was 55%. Therefore, additional studies to
evaluate the possible role of antiangiogenics in low-grade
serous ovarian cancer are warranted, potentially in com-
bination with MAPK inhibitors.
Future Directions
The insulin-like growth factor (IGF) pathway is another
pathway overexpressed in low-grade serous ovarian cancer,
and related effectors, such as PI3K/Akt/mTOR, have been
also described to play a role in disease pathogenesis.72
Activating mutations of PI3KCA are observed in approxi-
mately 40% of tumors, whereas inactivating PTEN mutations
are present in 3% to 8% of tumors.73 AMG-479, a fully human
antiinsulin-like growth factor receptor type I monoclonal
antibody, had been assessed in frontline and recurrent
settings in ovarian cancer but not specifically in low-grade
serous ovarian cancer (NCT00718523 and NCT00719212).
OSI-906, a tyrosine kinase inhibitor of both IGF-1R and the
insulin receptor was assessed in recurrent ovarian cancer
(NCT00889382).
On the basis of retrospective studies and ad hoc co-
operative group studies, low-grade serous ovarian cancer is
described as relatively chemotherapy resistant, which has
led to the investigation of novel therapies that are based on
the specific molecular pathways of low-grade serous ovarian
cancer. Although low-grade serous ovarian cancer is asso-
ciated with superior overall survival compared with the
other histologic subgroups of ovarian cancer, more than 70%
of low-grade serous ovarian cancer patients experience
relapse and die of their disease. There is an urgent clinical
need to develop additional trials of combination targeted
agents that are tolerable for the patients and that do not
significantly impinge upon quality of life. Because low-grade
serous ovarian cancer is a rare entity, the cooperation be-
tween different institutes is essential alongside a common
effort to reduce heterogeneity of grading and biases in
treatment and response evaluation.65
CLEAR CELL OVARIAN CANCER: TIME FOR A NEW
PARADIGM?
Clear cell ovarian cancer is a unique entity of adenocarci-
noma of the ovary. Sugiyama et al74 first reported that
advanced-stage clear cell ovarian cancer was less sensitive
than the serous counterpart to conventional chemotherapy
and provoked the discussion about its uniqueness.74
Recently, a marked ethnic difference in the incidence of
clear cell ovarian cancer has been recognized, although the

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reason is not clear. The incidence of clear cell ovarian cancer
is less than 10% in Europe and North America.75 However, in
Japan, the prevalence of clear cell ovarian cancer is in-
creasing, and now approximately 25% of epithelial ovarian
cancer is clear cell, according to the Japanese Society of
Obstetrics and Gynecology tumor registry data from 2014.74
A hypothesis for the reason of increasing incidence of this
disease in Japan is the increasing incidence of endometriosis.
An, association between clear cell ovarian cancer and
endometriosis has been reported (relative risk, 12.4).76 The
risk increased significantly when the patients were di-
agnosed at older ages (. 50), which suggests that the
malignant change of endometriosis occurs near menopause
stage. Pathogenesis of clear cell ovarian cancer from en-
dometriosis will be discussed later.
Clinical Features of Clear Cell Ovarian Cancer
Most clear cell ovarian cancer tumors are unilateral at di-
agnosis, and most are diagnosed at an early stage.77 In a
prospective randomized trial (JGOG 3017), the proportion of
patients with stage I disease was 67%.78 The incidence of
lymph node metastasis was 9.1% in apparent stage IA tu-
mors, 7.1% in stage IC tumors, and was 10.8% in pT2 tu-
mors.77 This stands in contrast with serous ovarian cancers,
which were associated with a higher incidence of lymph
node metastasis than nonserous tumors.79 Although it is
controversial, evaluation of lymph node status by surgical
staging is recommended, because lymph node involvement
in patients with clinical stage I clear cell ovarian cancer was
identified as a stronger prognostic factor.77
Management of clear cell ovarian cancer with positive
peritoneal cytology or surgical rupture remains unclear.
Disease progression was observed in 11% of stage IC
intraoperative rupture tumors but in only 3% of stage IA
tumors.77 Progression-free survival of the patients who had
stage IC tumors with ascites/malignant washing or ovarian
surface involvement was significantly worse than patients
who had stage IC disease with capsule rupture during sur-
gery (p = .04),77 which implies that positive peritoneal
FIGURE 3. Hypothetical Carcinogenic Pathway of Clear Cell Ovarian Cancer From Endometriotic Cyst
Abbreviations: IL, interleukin; HNF1b, hepatocyte nuclear factor 1-beta; CCOC, clear cell ovarian cancer.
PARADIGM SHIFT IN OVARIAN CANCER STRATEGY
cytology could suggest microscopic implantation of clear cell
ovarian cancer cells.
Another important recent observation is the incidence of
thromboembolic complication in clear cell ovarian cancer. It
has been reported to be higher than in other epithelial
ovarian cancers (16.9%27.3% vs. 0%6.8%),77 and it is also
associated with an elevated interleukin 6 level and with
worse prognosis.80
Chemotherapy Resistance
Several studies that retrospectively analyzed the prognosis
of patients in large randomized clinical trials have been
reported in terms of difference of prognosis between
pathologic subtypes.81,82 The survival was significantly
worse in clear cell than in the serous counterpart in ad-
vanced stages, which suggests that clear cell ovarian cancer
was resistant to conventional chemotherapy regimens. New
cytotoxic regimens, dose-dense paclitaxel regimen,83 and
CPT-11 plus cisplatin78 did not demonstrate a benefit for
clear cell ovarian cancer. Chemotherapy administered in-
traperitoneally using cisplatin and paclitaxel improved the
OS in optimally debulked stage III ovarian cancer, but a
survival benefit with intraperitoneal chemotherapy was not
observed in clear cell ovarian cancer and mucinous ade-
nocarcinoma.84 Therefore, finding new strategies for ad-
vanced or relapsed clear cell ovarian cancer is urgent.
Finding molecular pathologic characteristics of this disease
to direct improvement of targeted therapies is critical.
Pathogenesis of Clear Cell Ovarian Cancer From
Endometriosis
Investigators from Kyoto University have conducted a series
of excellent studies to delineate the pathogenesis of clear
cell ovarian cancer from endometriosis (Fig. 3).
They first analyzed the content of endometriotic cysts and
found that the cysts contained huge amounts of iron, oxi-
dative stress marker LPO, and 8-0HdG, a marker of DNA
damage caused by oxidative stress. When the content of an
endometriotic cyst or iron was added to immortalized
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FUJIWARA ET AL
ovarian surface epithelial cells, intracellular reactive oxygen
species was elevated, and the contents of endometriotic cyst
or iron increased DNA mutations. Therefore, researchers
hypothesized that iron-mediated reactive oxygen species
may cause DNA mutations and carcinogenesis.85
Next, researchers conducted a gene expression microarray
analysis and identified clear cellspecific genes, including
HNF1B, SOD2, ANXA4 HIF1A, IL6, and STAT3. They enriched
gene ontology terms related to oxidative stress and glucose
metabolism. Hepatocyte nuclear factor (HNF) 1-beta binds
to DNA as either a homodimer or a heterodimer with the
related protein HNF 1-alpha. HNF1 alpha and beta share
a common biding motif. Genes having the HNF1 binding
motif in promoter regions are candidate downstream genes
of HNF 1 beta. Interestingly, these genes were upregulated
in immortalized ovarian surface epithelial cells by adding the
content of endometriotic cysts or iron.86 Researchers also
conducted a methylation DNA microarray analysis, which
revealed that clear cell is distinct from other subtypes in terms
of methylation profile. Estrogen receptor pathway genes were
hypermethylated and downregulated, whereas HNF1 pathway
genes were hypermethylated and upregulated.87 Therefore,
clear cell ovarian cancerspecific gene expression seems to be
stabilized via epigenetic mechanisms.
The researchers also investigated the roles of HNF1B in
metabolism of clear cell ovarian cancer cells and found that
HNF1B increases glucose uptake by increasing expression
of a glucose transporter, GLUT1.88 A subsequent metab-
olome analysis was done and revealed that upregulated
HNF1B expression enhances anaerobic glucose metabolism.
Known as the Warburg effect, the enhanced anaerobic
glucose metabolism has been reported to cause resistance
to oxidative stress. Investigators also analyzed the re-
lationship between HNF1B and oxidative stress in clear cell
ovarian cancer. Knockdown of HNF1B decreased the amount
of glutathione, a redox substance. This was due to decreased
intracellular cystine, a substrate for the biosynthesis of
glutathione, via the decreased expression of rBAT, a cystine
transporter. Then, the investigators found that HNF1B
knockdown increased intracellular reactive oxygen species
and cytotoxicity by iron-induced oxidative stress. Further-
more, in hypoxia, suppression of HNF1B increased sensi-
tivity to cisplatin. Collectively, HNF1B in clear cell carcinoma
causes resistance to oxidative stress and platinum.89
Finally, researchers conducted an exome sequencing
analysis of clear cell ovarian cancer. ARID1A was the top-
mutated gene, and PIK3CA was the second one. Through an
integrated analysis of gene mutations and copy number
variations, researchers found that the KRAS-PI3K pathway,
SWI/SNF complex, and MYC-RB pathway were the most
frequently altered pathways (written communication with
N. Matsumura, February 2016).
The researchers hypothesize that iron-induced oxidative
stress may cause DNA damage and mutations of PIK3CA and
ARID1A, which may lead to carcinogenesis of clear cell
ovarian cancer. HNF1B plays an important role in the
Warburg effect and in resistance to oxidative stress. This
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may be important for progression in the stressful condition
of endometriotic cysts and platinum resistance. Epigenetic
changes, gene mutations, and copy number alterations may
cause stabilization of clear cell ovarian cancerspecific gene
expression and biologic features, including chemotherapy
resistance.
Molecular and Genomic Features of Clear Cell Ovarian
Cancer
Compared with other histologic types of epithelial ovarian
cancer, mutation in p53 is less frequent90 in clear cell ovarian
cancer, and mutation of BRCA1 and BRCA2 is also lower.91
Wilms tumor suppressor 1 gene (WT1) and the WT1-
antisense promoter were significantly methylated in clear
cell ovarian cancer (88.2%) compared with serous adeno-
carcinoma (24%).92 PTEN mutation is also frequently ob-
served (27.3%) in this disease.93 Multidrug resistance
protein 3 (MRP3)94 and HNF1B, which has antiapoptotic
effects, are highly expressed.95 More recently, frequent
alteration of ARID1A96 and PIK3CA97 has been reported.
Mabuchi et al showed that the Akt/mTOR pathway is
thought to be the most important passage for tumor growth
in clear cell ovarian cancer.98,99
Recently, Uehara et al100 conducted genomic analyses on
clear cell ovarian cancer and found that, by using micro-
array analysis, this disease could be classified into three
clusters: one that showed fewer alterations of PIK3CA and
ARID1A and a better prognosis compared with the two
other clusters, which had more alterations.100 This work
suggests that the genomic pattern may be a strong
prognostic factor.
Recently Closed or Ongoing Clinical Trials and Future
Directions
As mentioned earlier, the Japanese Gynecologic Oncology
Group conducted a randomized phase III trial to compare
conventional paclitaxel with carboplatin regimen versus an
irinotecan with cisplatin regimen for patients with newly
diagnosed stage I to IV clear cell ovarian cancer. This is the
first randomized trial specifically on this disease. Un-
fortunately, there was no survival benefit between the
regimens.78
On the basis of the molecular profile pattern of clear cell
ovarian cancer, the therapeutic target of interest involves
the Akt/mTOR pathway. The GOG-268 study tested one of
the mTOR inhibitors, temsirolimus, administered in com-
bination with paclitaxel and carboplatin for six cycles and
then given for 11 more cycles as a maintenance therapy.
Although the results will be presented this year at the
2016 American Society of Clinical Oncology Annual Meeting,
we await comparison of results in the United States and
South Korea with those obtained in Japan. In addition, the
translational component of this trial is underway to evaluate
the possible difference on molecular characteristics of ad-
vanced clear cell ovarian cancer between Japanese and non-
Japanese populations.

Antiangiogenetic agents are also of interest as therapeutic
targets for clear cell ovarian cancer. The GOG-254 study
evaluated the efficacy and safety of sunitinib and showed that
sunitinib was minimally active in the second- and third-line
treatments of persistent or recurrent clear cell ovarian cancer.
Another antiangiogenetic agent being tested is nintedanib,
and a Scottish group is conducting a randomized phase II study
to compare nintedanib to other chemotherapeutic agents.
Finally, immunotherapy that uses checkpoint inhibitors is
of interest as a treatment strategy. One recent publication
on an antibody to PD-1, nivolumab, showed promising signs
of efficacy for clear cell ovarian cancer.101
CONCLUSION
The treatment of epithelial ovarian cancer has been in-
formed by an improved understanding of the pathogenesis
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28. Chandrasekaran D, Menon U, Evans G, et al. Risk reducing sal-
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29. Kwon JS, Tinker A, Pansegrau G, et al. Prophylactic salpingectomy and
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30. Morelli M, Venturella R, Mocciaro R, et al. Prophylactic salpingectomy
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31. Venturella R, Morelli M, Lico D, et al. Wide excision of soft tissues adjacent
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32. Findley AD, Siedhoff MT, Hobbs KA, et al. Short-term effects of sal-
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33. Yuan H, Wang C, Wang D, et al. Comparing the effect of laparoscopic
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34. Wang HY, Quan S, Zhang RL, et al. Comparison of serum anti-mullerian
hormone levels following hysterectomy and myomectomy for benign gy-
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35. Manchanda R, Chandrasekaran D, Saridogan E, et al. Should oppor-
tunistic bilateral salpingectomy (OBS) for prevention of ovarian cancer
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trial? Int J Gynecol Cancer. 2016;26:31-33.
36. Robert M, Cenaiko D, Sepandj J, et al. Success and complications of
salpingectomy at the time of vaginal hysterectomy. J Minim Invasive
Gynecol. 2015;22:864-869.
37. Vorwergk J, Radosa MP, Nicolaus K, et al. Prophylactic bilateral sal-
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standard premenopausal hysterectomy: complications and re-
operation rate. J Cancer Res Clin Oncol. 2014;140:859-865.
38. Kamran MW, Vaughan D, Crosby D, et al. Opportunistic and interventional
salpingectomy in women at risk: a strategy for preventing pelvic serous
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39. Kwon JS, McAlpine JN, Hanley GE, et al. Costs and benefits of op-
portunistic salpingectomy as an ovarian cancer prevention strategy.
Obstet Gynecol. 2014;125:338-345.
40. Lessard-Anderson CR, Handlogten KS, Molitor RJ, et al. Effect of tubal
sterilization technique on risk of serous epithelial ovarian and primary
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41. Madsen C, Baandrup L, Dehlendorff C, et al. Tubal ligation and sal-
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42. Falconer H, Yin L, Gronberg H, et al. Ovarian cancer risk after sal-
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50. Gershenson DM, Sun CC, Lu KH, et al. Clinical behavior of stage II-IV low-
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51. Schmeler KM, Sun CC, Malpica A, et al. Low-grade serous primary
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52. Schmeler KM, Sun CC, Bodurka DC, et al. Neoadjuvant chemotherapy
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53. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation
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54. ONeill CJ, Deavers MT, Malpica A, et al. An immunohistochemical
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55. Wong KK, Lu KH, Malpica A, et al. Significantly greater expression of
ER, PR, and ECAD in advanced-stage low-grade ovarian serous car-
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56. Plaxe SC. Epidemiology of low-grade serous ovarian cancer. Am J
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57. Sieh W, Kobel M, Longacre TA, et al. Hormone-receptor expression
and ovarian cancer survival: an Ovarian Tumor Tissue Analysis con-
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58. Gershenson DM, Sun CC, Iyer RB, et al. Hormonal therapy for recurrent
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59. Romero I, Sun CC, Wong KK, et al. Low-grade serous carcinoma: new
concepts and emerging therapies. Gynecol Oncol. 2013;130:660-666.
60. Singer G, Oldt R III, Cohen Y, et al. Mutations in BRAF and KRAS
characterize the development of low-grade ovarian serous carcinoma.
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61. Wong KK, Tsang YT, Deavers MT, et al. BRAF mutation is rare in
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62. Grisham RN, Iyer G, Garg K, et al. BRAF mutation is associated with
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serous ovarian cancer. Cancer. 2013;119:548-554.
63. Tsang YT, Deavers MT, Sun CC, et al. KRAS (but not BRAF) mutations in
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64. Gershenson DM, Sun CC, Wong KK. Impact of mutational status on
survival in low-grade serous carcinoma of the ovary or peritoneum. Br
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65. Della Pepa C, Tonini G, Santini D, et al. Low-grade serous ovarian
carcinoma: from the molecular characterization to the best thera-
peutic strategy. Cancer Treat Rev. 2015;41:136-143.
66. Friday BB, Adjei AA. Advances in targeting the Ras/Raf/MEK/Erk
mitogen-activated protein kinase cascade with MEK inhibitors for
cancer therapy. Clin Cancer Res. 2008;14:342-346.
67. Jing J, Greshock J, Holbrook JD, et al. Comprehensive predictive
biomarker analysis for MEK inhibitor GSK1120212. Mol Cancer Ther.
2012;11:720-729.
68. Farley J, Brady WE, Vathipadiekal V, et al. Selumetinib in women with
recurrent low-grade serous carcinoma of the ovary or peritoneum: an
open-label, single-arm, phase 2 study. Lancet Oncol. 2013;14:134-140.
69. Grisham RN, Sylvester BE, Won H, et al. Extreme outlier analysis
identifies occult mitogen-activated protein kinase pathway mutations
in patients with low-grade serous ovarian cancer. J Clin Oncol. 2015;
33:4099-4105.
70. Bidus MA, Webb JC, Seidman JD, et al. Sustained response to bev-
acizumab in refractory well-differentiated ovarian neoplasms.
Gynecol Oncol. 2006;102:5-7.
71. Grisham RN, Iyer G, Sala E, et al. Bevacizumab shows activity in pa-
tients with low-grade serous ovarian and primary peritoneal cancer.
Int J Gynecol Cancer. 2014;24:1010-1014.
72. Groen RS, Gershenson DM, Fader AN. Updates and emerging ther-
apies for rare epithelial ovarian cancers: one size no longer fits all.
Gynecol Oncol. 2015;136:373-383.
73. Angarita AM, Cholakian D, Fader AN. Low-grade serous carcinoma:
molecular features and contemporary treatment strategies. Expert
Rev Anticancer Ther. 2015;15:893-899.
74. Sugiyama T, Kamura T, Kigawa J, et al. Clinical characteristics of clear
cell carcinoma of the ovary: a distinct histologic type with poor
prognosis and resistance to platinum-based chemotherapy. Cancer.
2000;88:2584-2589.
75. del Carmen MG, Birrer M, Schorge JO. Clear cell carcinoma of the
ovary: a review of the literature. Gynecol Oncol. 2012;126:481-490.
76. Kobayashi H, Sumimoto K, Moniwa N, et al. Risk of developing ovarian
cancer among women with ovarian endometrioma: a cohort study in
Shizuoka, Japan. Int J Gynecol Cancer. 2007;17:37-43.
77. Takano M, Kikuchi Y, Yaegashi N, et al. Clear cell carcinoma of the
ovary: a retrospective multicentre experience of 254 patients with
complete surgical staging. Br J Cancer. 2006;94:1369-1374.
78. Okamoto A, Sugiyama T, Hamano T, et al. Randomized phase III trial of
paclitaxel/carboplatin (PC) versus cisplatin/irinotecan (CPT-P) as first-
line chemotherapy in patients with clear cell carcinoma (CCC) of the
ovary: A Japanese Gynecologic Oncology Group (JGOG)/GCIG study. J
Clin Oncol. 2014;32:5s (suppl; abstr 5507).
79. Takeshima N, Hirai Y, Umayahara K, et al. Lymph node metastasis in
ovarian cancer: difference between serous and non-serous primary
tumors. Gynecol Oncol. 2005;99:427-431.
80. Matsuo K, Hasegawa K, Yoshino K, et al. Venous thromboembolism,
interleukin-6 and survival outcomes in patients with advanced ovarian
clear cell carcinoma. Eur J Cancer. 2015;51:1978-1988.
81. Winter WE III, Maxwell GL, Tian C, et al; Gynecologic Oncology Group
Study. Prognostic factors for stage III epithelial ovarian cancer: a Gyne-
cologic Oncology Group Study. J Clin Oncol. 2007;25:3621-3627.
82. Mackay HJ, Brady MF, Oza AM, et al; Gynecologic Cancer InterGroup.
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III/IV epithelial ovarian cancer. Int J Gynecol Cancer. 2010;20:945-952.
83. Katsumata N, Yasuda M, Isonishi S, et al; Japanese Gynecologic On-
cology Group. Long-term results of dose-dense paclitaxel and car-
boplatin versus conventional paclitaxel and carboplatin for treatment
of advanced epithelial ovarian, fallopian tube, or primary peritoneal
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cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet
Oncol. 2013;14:1020-1026.
84. Tewari D, Java JJ, Salani R, et al. Long-term survival advantage and
prognostic factors associated with intraperitoneal chemotherapy
treatment in advanced ovarian cancer: a gynecologic oncology group
study. J Clin Oncol. 2015;33:1460-1466.
85. Yamaguchi K, Mandai M, Toyokuni S, et al. Contents of endometriotic
cysts, especially the high concentration of free iron, are a possible
cause of carcinogenesis in the cysts through the iron-induced per-
sistent oxidative stress. Clin Cancer Res. 2008;14:32-40.
86. Yamaguchi K, Mandai M, Oura T, et al. Identification of an ovarian
clear cell carcinoma gene signature that reflects inherent disease
biology and the carcinogenic processes. Oncogene. 2010;29:
1741-1752.
87. Yamaguchi K, Huang Z, Matsumura N, et al. Epigenetic determinants of
ovarian clear cell carcinoma biology. Int J Cancer. 2014;135:585-597.
88. Okamoto T, Mandai M, Matsumura N, et al. Hepatocyte nuclear
factor-1b (HNF-1b) promotes glucose uptake and glycolytic activity in
ovarian clear cell carcinoma. Mol Carcinog. 2015;54:35-49.
89. Amano Y, Mandai M, Yamaguchi K, et al. Metabolic alterations caused
by HNF1b expression in ovarian clear cell carcinoma contribute to cell
survival. Oncotarget. 2015;6:26002-26017.
90. Ho ES, Lai CR, Hsieh YT, et al. p53 mutation is infrequent in clear cell
carcinoma of the ovary. Gynecol Oncol. 2001;80:189-193.
91. Kobel M, Kalloger SE, Boyd N, et al. Ovarian carcinoma subtypes are
different diseases: implications for biomarker studies. PLoS Med.
2008;5:e232.
92. Kaneuchi M, Sasaki M, Tanaka Y, et al. WT1 and WT1-AS genes are
inactivated by promoter methylation in ovarian clear cell adenocar-
cinoma. Cancer. 2005;104:1924-1930.
93. Sato N, Tsunoda H, Nishida M, et al. Loss of heterozygosity on 10q23.3
and mutation of the tumor suppressor gene PTEN in benign endo-
metrial cyst of the ovary: possible sequence progression from benign
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of the ovary. Cancer Res. 2000;60:7052-7056.
94. Ohishi Y, Oda Y, Uchiumi T, et al. ATP-binding cassette superfamily
transporter gene expression in human primary ovarian carcinoma.
Clin Cancer Res. 2002;8:3767-3775.
95. Tsuchiya A, Sakamoto M, Yasuda J, et al. Expression profiling in ovarian
clear cell carcinoma: identification of hepatocyte nuclear factor-1 beta
as a molecular marker and a possible molecular target for therapy of
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96. Wiegand KC, Shah SP, Al-Agha OM, et al. ARID1A mutations in
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97. Kuo KT, Mao tubal ligation, Jones S, et al. Frequent activating mu-
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174:1597-1601.
98. Hisamatsu T, Mabuchi S, Matsumoto Y, et al. Potential role of mTORC2
as a therapeutic target in clear cell carcinoma of the ovary. Mol Cancer
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99. Mabuchi S, Kawase C, Altomare DA, et al. mTOR is a promising
therapeutic target both in cisplatin-sensitive and cisplatin-resistant
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100. Uehara Y, Oda K, Ikeda Y, et al. Integrated copy number and expression
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101. Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e257
GYNECOLOGIC CANCER

Divide and Conquer: Epithelial

Gynecologic Cancers Beyond
BRCA

CHAIR
Elise C. Kohn, MD
National Cancer Institute at the National Institutes of Health
Bethesda, MD

SPEAKERS
Paul J. Goodfellow, PhD
The Ohio State University College of Medicine
Columbus, OH

Rebecca S. Kristeleit, MD, PhD

UCL Cancer Institute
London, United Kingdom
 TARGETING DNA REPAIR DEFICIENCY IN GYNECOLOGIC CANCERS

Gynecologic Cancers: Emerging Novel Strategies for Targeting

DNA Repair Deficiency
Rebecca S. Kristeleit, MD, PhD, Rowan E. Miller, MD, PhD, and Elise C. Kohn, MD

OVERVIEW

The presence of a BRCA mutation, somatic or germline, is now established as a standard of care for selecting patients with
ovarian cancer for treatment with a PARP inhibitor. During the clinical development of the PARP inhibitor class of agents, a
subset of women without BRCA mutations were shown to respond to these drugs (termed BRCAness). It was hypothesized
that other genetic abnormalities causing a homologous recombinant deficiency (HRD) were sensitizing the BRCA wild-type
cancers to PARP inhibition. The molecular basis for these other causes of HRD are being defined. They include individual gene
defects (e.g., RAD51 mutation, CHEK2 mutation), homozygous somatic loss, and whole genome properties such as genomic
scarring. Testing this knowledge is possible when selecting patients to receive molecular therapy targeting DNA repair, not
only for patients with ovarian cancer but also endometrial and cervical cancers. The validity of HRD assays and multiple gene
sequencing panels to select a broader population of patients for treatment with PARP inhibitor therapy is under evaluation.
Other non-HRD targets for exploiting DNA repair defects in gynecologic cancers include mismatch repair (MMR), checkpoint
signaling, and nonhomologous end-joining (NHEJ) DNA repair. This article describes recent evidence supporting strategies in
addition to BRCA mutation for selecting patients for treatment with PARP inhibitor therapy. Additionally, the challenges and
opportunities of exploiting DNA repair pathways other than homologous recombination for molecular therapy in gyne-
cologic cancers is discussed.

O ur increased understanding of cancer biology coupled

with increasingly refined technology to examine the cancer
genome has offered a rich supply of opportunities applicable
to improving outcomes in patients with gynecologic cancer.1
We now recognize at least six major interactive pathways
involved in DNA damage and repair.2 The most recent ex-
ample of molecularly targeted drug success in patients with
ovarian cancer is the development of PARP inhibitors as ther-
apeutics. The PARP inhibitor olaparib was the first drug
worldwide to be licensed in 2014 for a molecularly defined
population of patients with BRCA-mutated ovarian cancer.
The rapidity and success of identifying this molecularly di-
rected and defined therapeutic has catalyzed the gynecologic
cancer community to further explore the application of DNA
repair inhibitors as a class and question other ways DNA repair
defects might be harnessed for novel treatment approaches.
Targeting tumors with defective DNA repair exploits the
molecular differences between tumor and normal cells. This
mechanism is the basis for tumor-specific cell death induced
by PARP inhibitors in patients with BRCA-mutated ovarian
cancer.3,4 BRCA1 and BRCA2 are essential for maintaining
genomic stability through the error-free repair of DNA
double-strand breaks via the highly conserved homologous-
recombination repair (HRR) pathway.5 Although the syn-
thetic lethality between deleterious BRCA mutations and
PARP inhibition is well established,4,5 it is becoming increas-
ingly evident that gynecologic tumors have other molecu-
lar features, germline or somatic, which portend an HRD
or BRCA-like susceptibility to platinums and DNA repair in-
hibitors. Substantial efforts are underway to categorize the
breadth of molecular causes of HRD. Individual genetic mu-
tations and whole genome features, expressed as genomic
scarring, have been identified as HRD-causing and correlate
with potential responsiveness to DNA repair inhibitors.6-9 In
addition, defects in other DNA repair pathways, such as the
MMR pathway (common in patients with endometrial cancer)
and cell cycle checkpoint proteins, cause potential vulnera-
bilities that offer therapeutic possibilities (Fig. 1).10-13 Going
beyond BRCA-targeting in gynecologic cancers highlights the
potential for expanded therapeutic strategies. The pheno-
typic and genotypic consequences of HRD are a particular
vulnerability in patients with epithelial ovarian cancer, and
new insight shows how other events in endometrial, cervical,
and ovarian cancers also may yield a HRD phenotype. An

From the Department of Medical Oncology, University College London Hospital, London, United Kingdom; UCL Cancer Institute, University College London, London, United Kingdom;
Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Rebecca S. Kristeleit, MD, PhD, UCL Cancer Institute, 72 Huntley St., London WC1E 6BT United Kingdom; email: r.kristeleit@ucl.ac.uk.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e259

KRISTELEIT, MILLER, AND KOHN

immediate challenge is learning how best to navigate and FIGURE 1. Representation of the Main DNA Repair
apply the new information at both the scientific and clinical Pathways and Interaction
levels, where genetically defined treatment decisions are now
being made with patients.

HOMOLOGOUS-RECOMBINATION REPAIR AND

BRCA1/2
DNA is constantly subjected to damage by environmental
exposures and endogenous activities such as DNA replica-
tion and cellular free radical generation. These cause a variety
of DNA lesions, including base modifications, double-strand
breaks, and single-strand breaks.14 DNA repair is critical to
maintain genomic integrity by allowing cells to progress
through the cell cycle and complete replication without
errors.15 Homologous-recombination repair is the principle
mechanism by which double-strand breaks are repaired.
The BRCA1/2 genes, along with other genes in the Fanconi
anemia (FA) pathway, encode essential proteins for this
process. Homologous-recombination repair is a conserva-
tive form of DNA repair that restores the DNA to its original
sequence using the homologous normal DNA template dur-
ing S and G2/M phases of the cell cycle. When either BRCA1
or BRCA2 are defective, homologous recombination is dys-
functional and double-strand break repair proceeds using
error-prone nonconservative repair mechanisms such as NHEJ
and single-strand repair.5 Nonhomologous end-joining does
This figure represents the six main DNA repair pathways and their close but
not use a DNA template and occurs in G0 or G1, propagating discrete interaction. Targetable proteins associated with each pathway for which
error rather than repairing it.16 Any two free DNA break ends pharmacological agents exist appear in red.
Abbreviations: MMR, mismatch repair; BER, base excision repair; NHEJ,
are directly ligated during repair of double-strand breaks by nonhomologous end-joining; HRR, homologous recombination repair; NER,
NHEJ. nucleotide excision repair; TLJ, translesional joining.
A variety of mechanisms exist for repairing single-strand
breaks. These include base excision repair, nucleotide ex- PARP. PARP senses and binds to DNA-break sites, which
cision repair, and MMR, processes that are modulated by results in catalytic activation and the recruitment of other
components of the DNA repair complex.17 If a cell fails to
repair single-strand breaks before attempting replication, a
KEY POINTS double-strand break will then form.
Inherited mutations in the tumor suppressor genes BRCA1
The synthetic lethality and validity of using BRCA1/2 and BRCA2 account for the majority of familial ovarian
mutation as a biomarker predictive of response to PARP cancers.18 The BRCA1 and BRCA2 protein products function
inhibition has been confirmed in clinical trials of patients in multiple cellular pathways, including cell cycle regulation
with ovarian cancer. and maintenance of genome integrity.19 Cells with defective
Homologous recombinant deficiency (HRD) represents a HRR must rely on alternative pathways for DNA repair to
key vulnerability in patients with high-grade ovarian
survive, thereby providing potential therapeutic targets.
cancer and possibly other gynecologic cancers, which
can be exploited using PARP inhibitors.
Patients with epithelial ovarian cancer and germline or so-
Methods to identify HRD cancers and broaden the matic BRCA1 or BRCA2 mutations demonstrate impaired
applicability of DNA repair inhibitors are being ability to repair double-strand breaks through HRR, which
evaluated in the clinic. likely explains the increased sensitivity to platinum and the
Nonhomologous recombinant DNA repair pathways, potentially more favorable outcome compared with patients
such as mismatch repair and nonhomologous who are wild-type.20,21
end-joining, represent important targets for novel
therapeutic strategies in gynecologic cancer.
Targeting cell cycle checkpoint proteins such as CHK1,
HOMOLOGOUS-RECOMBINATION REPAIR
CHK2, and WEE-1 that regulate DNA damage and INHIBITION
repair is a promising therapeutic approach, particularly PARP Inhibition
in molecular subsets such as p53 mutant and PARP inhibitors were developed for BRCA1/2 mutant epi-
ARID1A-mutated gynecologic cancer. thelial ovarian cancer following observation that BRCA1/2
mutations greatly increased the in vitro sensitivity to PARP

e260 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


inhibition, exploiting a concept known as synthetic lethal-
ity.3,4 Synthetic lethality arises when a combination of de-
fects in two or more genes or proteins leads to cell death,
whereas a single defect is compatible with cell viability.
BRCA1/2 defective cells are dependent on non-HR DNA
repair and they are sensitive to any induction in double-
strand breaks. PARP inhibition produces stalled replication
forks, which increases the number of double-strand breaks
and leads to genetic chaos and cell death by apoptosis or
senescence.2 The synthetic lethality between BRCA1/2
mutations and PARP inhibition has been confirmed in
clinical trials.22-25 Multiple PARP inhibitors, including olaparib
(AZD2281), rucaparib (CO-338), veliparib (ABT888), and
niraparib (MK4827), are in clinical development either
as single agents or in combination therapy for the
management of patients with epithelial ovarian cancer
(Table 1).
Olaparib, (Lynparza/AZD2281) is the first licensed PARPi
for the treatment of BRCA-mutated epithelial ovarian can-
cer.26,27 The initial olaparib phase I study provided clinical
proof-of-concept of synthetic lethality between BRCA1/2
mutant tumors and PARP inhibition. Of the expansion phase
patients, 40% attained either RECIST partial or complete re-
sponse, CA-125 responses by Gynecological Cancer Intergroup
criteria, or both. Subsequent phase II studies evaluating olaparib
monotherapy in patients with relapsed epithelial ovarian cancer
have shown response rates of 31% to 41% in BRCA1/2-mutation
carriers and up to 21% in BRCA1/2 wild-type patients.28,29
A phase II trial investigating olaparib maintenance therapy
following an initial response to platinum therapy showed a
progression-free survival (PFS) extension from 4.3 months
with placebo to 11.2 months with olaparib (hazard ratio [HR]
0.18; 95% CI, 0.100.31) in tumors harboring BRCA1/2 mu-
tations. A benefit for olaparib maintenance in patients with
BRCA wild-type tumors was observed, although the magni-
tude was smaller (7.4 vs. 5.5 months; HR 0.54, 95% CI,
0.340.85).24,30 No overall survival (OS) benefit has been
observed at the current time of reporting, the reasons for
which are likely multifactorial.
Defects in Non-BRCA Homologous-Recombination
Repair Genes That Modulate Genomic Stability and
May Promote Sensitivity to DNA Repair Inhibitors
Genomic instability is an important therapeutic target in
gynecologic cancers, not just because of the advent of PARPi
but also because of the key roles of radiation and platinum
therapies in managing them. Platinum analogs induce intra-
and interstrand purine base cross-links (ICL), which form
covalent bonds and stress DNA repair. Repair of ICLs de-
pends on nucleotide excision repair and, secondarily, upon
double-strand break formation.14 The marked sensitivity of
epithelial ovarian cancer to platinum agents is thought to
be related to the high frequency of underlying HRR defects.
Germline or homozygous somatic mutations in other
members of the FA family, such as RAD51C, RAD51D, and
BRIP1, increase susceptibility to ovarian cancer.31-33 In vitro
TARGETING DNA REPAIR DEFICIENCY IN GYNECOLOGIC CANCERS
studies have demonstrated that deficiency in these genes
and in other HRR-associated proteins, such as ATM, CHEK1,
CHEK2 and CDK12, also confer sensitivity to DNA damage
and DNA repair inhibition.31,34-36 These have been found
in sporadic epithelial ovarian cancer and other cancers in
which they appear to function to create a BRCA mutation-
like phenocopy.37 Understanding other DNA damage mech-
anisms and potential targets across gynecologic cancers
can further extend the success of DNA repair inhibitors,
exemplified by PARP inhibitors.
The Cancer Genome Atlas (TCGA) identified mutations
now recognized to be related to the HRR pathway in ap-
proximately 30% of high-grade serous ovarian cancers.38
This included somatic mutations in BRCA1/2 (3%), ATM and
ATR (2%), the FANC family (5%), and hypermethylation of
RAD51C (3%), as well as germline mutations in BRCA1 (9%)
or BRCA2 (8%). EMSY amplification (13%), which is proposed
to inactive BRCA2, has not been validated in patients yet.
Pennington and colleagues used targeted capture and
massively parallel genomic sequencing to examine germline
and somatic loss-of-function mutations in 30 genes, in-
cluding 13 HRR genes in 390 epithelial ovarian cancers.36
Thirty-one percent of ovarian cancers had a deleterious
germline (24%) and/or somatic (9%) mutation in one or more
of the 13 HRR genes, with similar incidence in serous (31%)
and nonserous ovarian cancers (28%, p = .06). The germline
or somatic HRR gene mutations predicted platinum sensi-
tivity (p = .0002) and improved OS (p = .0006; Table 2). The
majority of germline and somatic HRR gene mutations were
in BRCA1/2, and 26% occurred in other HRR genes. A similar
frequency of mutations was observed in patients with non-
serous epithelial ovarian cancer but with a different spectrum
of targeted genes. The functionality of these additional
mutations has been observed with rucaparib in patients
with both germline and somatic RAD51C mutations within
the ongoing phase II ARIEL2 study (NCT01891344).39 It is
now being recognized in epithelial ovarian cancer and in
other tumor types that the presence of HRD might be a
viable strategy for selection for DNA repair inhibitor trials.
For example, 88% (14 of 16) of men with metastatic
castration-resistant prostate cancer in the TO-PARP phase II
olaparib study with a somatic mutation in an HRR gene,
including BRCA1, BRCA2, ATM, the FANC genes, and CHEK2,
responded to olaparib compared with only two of 33 (6%) of
patients who were wild-type.40
New Opportunities Leveraging Genomic Instability
Recent translational data show BRCA1/2-mutated epithelial
ovarian cancer has a greater immune infiltration.41,42 It has
been suggested that these cancers may have sensitivity to
immune checkpoint inhibitors targeting the PD-1/PD-L1
pathway. It is hypothesized that PD-1/PD-L1 targeting agents
may preferentially benefit these patients because BRCA1/2-
mutated and other HRR-deficient tumors have higher numbers
of neoantigens.41 This hypothesis remains to be tested in clinical
trials.
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e262
TABLE 1. Phase II/III Trials of PARP Inhibitors in Ovarian Cancer
PARP Inhibitor NCT Trial Number Phase Study Type Combination Comparator Platinum Status Previous Lines of Treatment Inclusion Criteria
KRISTELEIT, MILLER, AND KOHN

Olaparib (AZD2281) NCT02392676 III Maintenance NA Placebo PS $ 2 platinum sBRCA, sHRR

NCT01844986 III Maintenance NA Placebo PS 1 platinum gBRCA
(SOLO1)
NCT02477644 III First-line Olaparib in combination Placebo NA Treatment nave HGSOC/
(PAOLA-1) treatment with platinum-taxane endometrioid,
and bevacizumab and as stage IIIB-IV
maintenance therapy
NCT02446600 III Combination Olaparib and cediranib Platinum-doublet PS Any number of HGSOC/
NRG GY004 chemotherapy platinum regimes endometrioid
or gBRCA and
any high-grade
histology
NCT02502266 III Combination Olaparib and cediranib Chemotherapy, olaparib PR # 2 in platR setting HGSOC/

2016 ASCO EDUCATIONAL BOOK | asco.org/edbook

NRG GY005 alone or cediranib endometrioid
alone or gBRCA and
any high-grade
histology
ICON9 III First relapse, Olaparib with cediranib as Cediranib and placebo PS 1 platinum HGSOC
maintenance maintenance therapy as maintenance
following platinum-based therapy
chemotherapy with cediranib
Rucaparib (CO338) NCT01482715 II Maintenance NA NA PS $ 3 chemotherapy Any BRCA
NCT01968213 III Maintenance Placebo Placebo PS $ 2 platinum HGSOC or
(ARIEL3) endometrioid
Veliparib (ABT-888) NCT02470585 III First-line Veliparib in combination with Placebo NA Treatment nave HGSOC, stage III-IV
Treatment carboplatin and paclitaxel
and as maintenance therapy
NCT01113957 II Combination Veliparib and temozolamide Liposomal PR $ 1 platinum and # 3 HGSOC
Doxorubicin cytotoxic regimes
Niraparib (MK4827) NCT01847274 III Maintenance NA Placebo PS $ 2 platinum HGSOC gBRCA and
any high-grade
histology
NCT02354586 II Single Agent NA NA PS $ 2 chemotherapy HGSOC
Talazoparib (BMN673) Single-agent and combination phase I studies in multiple tumor types
Abbreviations: PR, platinum resistant ovarian cancer; PS, platinum sensitive ovarian cancer; HGSOC, High-grade serous ovarian cancer.
 TARGETING DNA REPAIR DEFICIENCY IN GYNECOLOGIC CANCERS

TABLE 2. Known Deleterious Homologous Recombinant Deficiency Gene Frequencies in Ovarian Cancer
HR-Path- Observed Frequency All Epithelial Observed Frequency High-Grade
way Gene Ovarian Cancer (%) Ovarian Cancer (%) References
RAD51C 0.412.9 1.9 Walsh et al8, Pennington et al36, Minion et al83, Cunningham et al84,
Song et al85
RAD51D 0.351.1 0.95 Pennington et al36, Cancer Genome Atlas Research Network38, Song
et al85
RAD51B 0.06 0.95 Cancer Genome Atlas Research Network38, Song et al85
RAD50 0.21.0 Walsh et al8, Minion et al83
RAD54L 0.5 Kristeleit et al86
ATM 0.80.86 0.321.0 Pennington et al36, Cancer Genome Atlas Research Network38,
Minion et al83
BRIP1 0.94.0 0.321.0 Walsh et al8, Pennington et al36, Cancer Genome Atlas Research
Network38, Ramus et al87
CHEK2 0.45.0 0.321.0 Walsh et al8, Pennington et al36, Cancer Genome Atlas Research
Network38, Minion et al83
FANCA 0.5 Kristeleit et al86
FANCI 0.5 Kristeleit et al86
NBN 0.21.0 0.631.0 Walsh et al8, Pennington et al36, Cancer Genome Atlas Research
Network38, Candido-dos-Reis71, Minion et al83
PALB2 0.22.0 0.63 Walsh et al8, Pennington et al36, Cancer Genome Atlas Research
Network38, Ramus et al87

The Need for Biomarkers: Identifying the Homologous
Recombinant Deficiency Signature
The ability to perform rapid whole-genome sequencing
makes it feasible to classify cancers according to their un-
derlying mutational spectrum. A series of in vitro studies has
confirmed the presence of large subchromosomal deletions
and other genomic changes that cause allelic imbalance
and confer an HRD phenotype.6,43,44 This has yielded se-
veral assays or weighted signatures now being examined
as companion diagnostic predictive biomarkers. This HRR-
deficient mutational signature or mutational scar in-
dicates reliance on error-prone DNA repair pathways.9
Array-based technology using single nucleotide poly-
morphisms genotyping and comparative genomic hybrid-
ization has demonstrated that the genomes of high-grade
serous ovarian cancer harbor common loss of single parental
alleles. Wang and colleagues examined loss of heterozy-
gosity (LOH) and copy number changes in patients with high-
grade serous ovarian cancer and divided patients into two
clusters of LOH high and LOH low.44 High-levels of LOH were
associated with platinum sensitivity and improved PFS.
BRCA1/2-mutant tumors fell within the LOH high group; an
increased sensitivity to platinum was seen in the LOH high
group even after exclusion of these patients. An LOH-based
score has been developed that is strongly associated with
functional defects in BRCA1/2 and other genes implicated in
the HRR pathway.6 Prospective validation of a genomic scar
LOH assay is ongoing within the ARIEL2 rucaparib PARP
inhibitor phase II trial (NCT01891344) to dichotomize BRCA
wild-type patients who benefit from rucaparib. Initial results
suggest increased activity for rucaparib within the BRCA-like
population with high genomic LOH compared with the low
LOH population (PFS 7.1 vs. 3.7 months; HR 0.61), although
the benefit was not as great as in the BRCA1/2 mutant cohort
(PFS 9.4 months).39 Additional assays to identify structural
changes associated with HRD include the large-scale tran-
sitions assay quantifying chromosomal breaks of at least
10 Mb45 and the telomeric alleic imbalance score,43 both of
which correlate with alterations in BRCA1/2 and other HRR
pathway genes in patients with ovarian cancer. Although each
of these assays offers the exciting prospect of identifying a
subset of BRCA-like tumors, which respond to HRR-directed
therapy, the relevance of each assay requires prospective
validation in clinical trials. As more data emerge from post hoc
analyses of tumor samples from completed studies, it is likely
that HRD mutational signatures for consideration of DNA
repair inhibition therapy will become more established.
DNA REPAIR INHIBITION BEYOND
HOMOLOGOUS-RECOMBINATION REPAIR
GENES
Nature has recognized the need to maintain genomic
integrity as demonstrated by at least six majorand
interactiveDNA repair pathways (Fig. 1). Dissection of HRR
has shown this interaction and identified new potential
targets for therapeutic intervention. Likewise, dissection of
developmental processes in patients with endometrial and
colon cancers, and now cervical cancers, has led to recog-
nition of other key DNA repair cancer risk genes. Some of
these risk genes are involved in other DNA repair or biologic
pathways critical to cellular survival.
Early results implicate deficiency in ARID1A, a key com-
ponent of the chromatin-remodeling complex, as sensitizing

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KRISTELEIT, MILLER, AND KOHN
tumor cells to PARP inhibition in vitro and in animal
models.46 ARID1A is a suppressor gene. It is recruited by the
homologous-recombinant protein ATR, upstream of the cell
cycle G2/M regulator, CHK1, to sites of DNA double-strand
breaks where it facilitates efficient processing of double-
strand breaks and sustains DNA damage signaling. Muta-
tions in ARID1A are common in clear cell and endometrioid
epithelial ovarian cancer occurring in up to 57% and 30%
of cases, respectively.47,48 Loss of ARID1A expression is also
common in patients with endometrioid endometrial cancer
(approximately 40%49), and similarly in patients with cer-
vical cancer. These results imply that DNA repair inhibitors
must be tested more broadly in patients with gynecologic
cancers.
DNA repair pathways have cell cycle specificity.50 Ac-
cordingly, many proteins of the cell cycle, especially within
the G2/M checkpoint, also regulate DNA damage and repair.
CHK1/2 and WEE-1 kinases are examples.51-53 Agents tar-
geting these kinases have minimal single-agent activity in
the absence of p53, or more likely, p53 and second (so
far undefined) mutations. Efficacy is much greater when
examined in a defined p53 mutant background in which
the G1/S checkpoint is aberrant and also in combination.
There is a subset of patients with ovarian cancer with wild-
type BRCA1/2 function and cyclin E amplification and
overexpression.38,54-56 Emerging data indicate that block-
ade of the G1/S checkpoint, such as with pertinent CDK
inhibitors, may unmask an unexpected sensitivity to DNA
repair inhibitors such as PARP inhibitors.57 Furthermore,
pharmacologic augmentation of hypoxia, such as in the use
of cediranib, can reduce expression of many key homologous-
recombinant proteins. This may underpin the activity of the
cediranib/olaparib combination in women who have wild-
type BRCA.58
Targeting Nonhomologous-Recombination Repair
DNA Repair Pathways
Mismatch repair deficiency. Mismatch repair deficiency is a
single-strand DNA repair mechanism. It maintains genomic
integrity by correcting base substitution mismatches and
small insertion-deletion mismatches generated by errors in
base pairing during DNA replication. Mismatch repair de-
ficiency is critical to maintaining genomic stability. Failure
to recognize and repair DNA mismatches results in micro-
satellite instability and a mutator phenotype, with mutation
rates 100- to 1,000-fold higher than in MMR proficient
cells.13 Loss of one of the MMR proteins (MSH2, MSH6,
MSH3, MLH1, and PMS2) is associated with an increased risk
of cancers, including endometrial, ovarian, colorectal, and
gastric cancers.59 Germline mutations in MMR genes give
rise to Lynch syndrome, which is associated with a 60% and
25% lifetime risk of developing endometrial and colon
cancers, and ovarian cancer, respectively.59,60 Somatic loss
of MMR genes can occur either by mutation or methylation,
such that MMR deficiency is associated with up to 30% of all
endometrial cancers.61
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No direct therapy exists to target MMR-deficient tumors;
however, in vitro data suggest a number of potential di-
rections, including inhibition of select DNA polymerases
through an accumulation of oxidative DNA damage. Spe-
cifically, MSH2 deficiency is synthetically lethal with in-
hibition of DNA polymerase b (POLB), the DNA polymerase
that catalyzes nuclear base excision repair. MLH1 deficiency
is synthetically lethal with inhibition of DNA polymerase g
(POLG), the only polymerase specific to mitochondrial DNA.62
Methotrexate has been shown to be lethal to MSH2-deficient
cells through the accumulation of nuclear oxidative DNA
damage,63 leading to an ongoing phase II trial in colorectal
cancer (NCT00952016). Perhaps more promising is the
ability to target secondary mutations that arise as a result of
MMR deficiency believed to drive the tumorigenic pheno-
type. Secondary mutations in the double-strand break DNA
repair gene MRE11 are commonly associated with MMR-
deficient colorectal cancer and lead to PARP inhibitor sen-
sitivity in vitro.64 The role of PARP inhibition in patients with
endometrial cancer is ready for assessing in clinical trial with
accompanying tissue analysis for microsatellite instability,
MRE11, and PTEN status.
The TCGA endometrial cancer group61 identified a second
subgroup of endometrial cancers characterized by muta-
tions in POLE, a catalytic subunit DNA polymerase epsilon
involved in nuclear DNA replication and repair. Muta-
tions in POLE resulted in an ultramutated phenotype with a
mutation frequency approximately 10-fold greater than
seen in microsatellite instability tumors. The POLE-mutated
subgroup also had extraordinarily good survival. Very pre-
liminary data suggest that the microsatellite instability/POLE
phenotype may result in marked increased frequency
in neoantigen production, rendering the tumors more
immunogenic and, therefore, vulnerable to immunother-
apy.65 Early preclinical data support the use of antiPD-
L1 therapy in POLE-hypermutated and microsatellite
instabilitypositive endometrial cancers because they
have greater expression of PD-1, PD-L1, and tumor in-
filtrating lymphocytes.66 Several clinical trials currently
underway are evaluating the role of antiPD-1/PD-L1 ther-
apy in endometrial cancer either as a single agent (e.g.,
NCT02628067) or in combination with carboplatin and
paclitaxel (NCT02549209).
Base excision repair. Many other potential targets have
been identified in other DNA repair pathways. The potential
therapeutic importance of DNA-PKcs in base excision repair
was identified during the demonstration that PARP was not
the base excision repair rate-limiting step.16 A normal role
of PARP is to maintain inactive DNA-PKcs, which keeps
NHEJ quiet. Agents now in clinical development are targeting
DNA-PKcs. DNA-PKcs has been implicated with adverse
outcome in patients with epithelial ovarian cancer, sug-
gesting they may be a clinically relevant target in gynecologic
cancer.67 TRC-102 is an experimental agent targeting base
excision repair that also can be considered for patients with
gynecologic cancers.

Cervical Cancer and DNA Repair Defects
The role of defective DNA repair in cervical cancer is less well
established. HPV infection and its associated production of
the oncoviral proteins E6 and E7 causes inactivation and
degradation of the p53 and pRB tumor-suppressor genes.
This results in cell cycle dysfunction and altered DNA repair
capacity.68 Because of defective DNA damage response,
cervical tumor cells are increasingly dependent on residual
repair pathways to cope with certain types of DNA damage.
In support of this, a correlation between response to DNA
damaging therapy and activation of DNA repair pathways
has been noted in clinical series, albeit involving relatively
small numbers of patients. Patients treated with chemo-
radiotherapy were found to have high expression of the
nucleotide excision repair protein ERCC1 associated with
a decreased PFS and worse OS 69 and activation of the
FA/BRCA pathway correlated with treatment failure; con-
versely, impaired NHEJ repair was related to increased OS in
patients treated primarily with radiotherapy.70 These ob-
servations suggest that therapeutic exploitation of DNA
repair pathways may be useful in potentiating chemo-
radiotherapy, which is the mainstay of treatment for cervical
cancer. Numerous early phase trials incorporating modu-
lators of DNA repair such as PARP, ATM and ATR inhibitors,
and triapine in combination with standard chemotherapy or
radiotherapy currently are underway in patients with ad-
vanced cervical cancer (NCT01281852, NCT02223923,
NCT02595879, NCT02466971).
NAVIGATING THE NEW INFORMATION
Picture the cartoon: a patient with the balloon above her
head full of question marks. The caption reads What do I
do? The most difficult question for providers and patients is
how to weigh progress and new agents in the context of
population data when addressing individual patient de-
cisions. As our understanding of the meaning and roles of
HRD mutation and dysfunction progresses, we complicate
informing patients.
We always start with whats simple. Germline deleterious
BRCA mutation in patients with ovarian cancer is the most
common and actionable finding that generally directs sim-
ple decisions as described above. BRCA mutation or geno-
mic instability as a result of HRD, in general, allows greater
confidence in the use of DNA damaging agents, DNA repair
inhibitors, cell cycle inhibitors, and novel combinations that
leverage these dysfunctional pathways. We know that BRCA-
mutation patients with ovarian cancer are more responsive
and have better PFS, at least in the first decade after
diagnosis.1,71-73 Newer data of small, unpublished numbers
suggest that any homozygous loss of BRCA1/2 may result in a
nearly identical phenotype to germline or somatic homo-
zygous loss, an HRD phenotype for which new directions
have been outlined.
Germline evaluations of BRCA and other recently identi-
fied HRD genes and broader gene panel testing are being
done for many patients, often without considering the
TARGETING DNA REPAIR DEFICIENCY IN GYNECOLOGIC CANCERS
implications of the potential findings or the treatment plan
that the results should inform.74 Using a targeted panel of
HRR genes may allow the identification of HRD cancers,
notwithstanding a number of limitations. With the exception
of BRCA1/2, each individual HRR gene defect is present at
very low frequency in patients with ovarian cancer, and
the overall numbers of additional HRD patients identified
by testing this way is small (Table 2).8,74,75 Homologous
recombinant deficiency arises via heterogenous mecha-
nisms, which include epigenetic changes, gene amplifica-
tions, and chromosomal translocations. Therefore, a suitable
and validated genomic platform is required to capture all
patients with potentially actionable HRR aberrations. A third
concern is that not all genes are equally important in de-
termining therapeutic response, and the number of variants
of uncertain significance is massive, leaving many patients
and physicians without guidance.
Addressing whether there is sufficient overall risk to
mandate germline testing for all women across all 11 or
more genes (panel testing) or to focus on validated bio-
marker(s) is critical. The latter would allow us to address the
more complicated question of the role of haplo-insufficiency
complementation in genomic instability of more than one
of the homologous-recombinant genes or homologous-
recombinant plus another DNA repair pathway gene. Fi-
nancial, personal, and family costs make navigating this new
information more complicated.
Applying the New Information
BRCA1 or BRCA2 germline or homozygous somatic muta-
tions are now considered predictive biomarkers for plati-
num- and PARP inhibitorsensitivity.36 A woman with a
BRCA1 or BRCA2 mutation who progresses on a platinum-
based therapy often will respond subsequently. Data are
limited to guide application of the platinum-resistant
moniker to such women. How to apply the growing data
related to complex DNA repair pathways and new agents
also is becoming more complex. The first question we need
to address urgently in the clinic is how to interpret loss of
sensitivity to such agents as the patient moves along the
treatment line. Acquisition of secondary mutations in BRCA1
or BRCA2 may result in resumption of BRCA1 or BRCA2
function.76,77 Estimates of frequency of these secondary
mutations range from single digits to nearly 40% of cases in
the small case numbers examined to date. Other potential
molecular events include loss of 53bp1, a regulator of the
poor fidelity NHEJ DNA repair pathway,78,79 and regula-
tion of phosphoproteins, such as DNA-PKcs,16 and others in
the DNA repair pathways, such as ATM and ATR.80-82 The
cause of true platinum resistance in these women is still a
conundrum.
WHERE TO GO NEXT?
DNA repair is a very complex series of parallel and interacting
pathways. There are several druggable targets within these
pathways. Progress in understanding these pathways and
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KRISTELEIT, MILLER, AND KOHN
TABLE 3. Defining the Decisions?
Event Implication in Cancer
Germline Deleterious gBRCA Presumed homozygous deletion, especially breast and
ovarian cancers
Somatic BRCA Mutation Role of haplo-insufficiency is unclear
BRCA1 Promoter Methylation Does not appear to confer stable gene downregulation
in ovarian cancer
BRCA1/2 Downregulation Ambient micro-environmental events may affect protein
production or stability
Cyclin E Overexpression Cell cycle dysregulation is associated with altered
balance in DNA damage repair
Unknown and Wild-Type Work still to do
identifying areas of commonality, such as the role of CHK1
in both the G2/M cell cycle checkpoint and downstream of
ATM and ATR in DNA repair, has led to new therapeutic
approaches. This is an example of the concept that targeting
sites of biochemical convergence may yield more than the
sum of the inhibition of single independent targets. Che-
motherapy is targeted therapy. Most chemotherapies target
DNA damage. We now add the therapeutic category of
DNA repair inhibitors. How to exploit this new and growing
therapeutic category in the context of the treatment of all
women with ovarian cancers is a challenge and a great
opportunity (Table 3). This growth provides great oppor-
tunities beyond BRCA.
CONCLUSION AND FUTURE DIRECTIONS
Targeting defective DNA repair represents a viable treat-
ment option for patients with gynecologic malignancies.
Defective HRR is a key vulnerability for patients with high-
grade serous epithelial ovarian cancer, which is present in up
to 50% of patients. The use of PARP inhibitors allows the
exploitation of molecular differences between tumor nor-
mal tissues. To maximize the benefit from PARP inhibition, it
is important to identify those tumors not only characterized
by BRCA1/2 mutations but also those with HRD as a result of
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56. Karst AM, Jones PM, Vena N, et al. Cyclin E1 deregulation occurs early
in secretory cell transformation to promote formation of fallopian
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agnosed with epithelial ovarian cancer. Clin Cancer Res. 2015;21:
652-657.
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74. Norquist BM, Pennington KP, Agnew KJ, et al. Characteristics of women
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2015;107:11.
GYNECOLOGIC CANCER

Intraperitoneal Chemotherapy for

Ovarian Cancer: Trials and
Tribulations

CHAIR
Helen J. Mackay, MD
Princess Margaret Cancer Centre
Toronto, ON

SPEAKERS
Charlie Gourley, PhD, FRCPE
University of Edinburgh Cancer Research UK Centre
Edinburgh, United Kingdom

Joan L. Walker, MD
The University of Oklahoma Health Sciences Center
Oklahoma City, OK
 INTRAPERITONEAL CHEMOTHERAPY IN THE TREATMENT OF OVARIAN CANCER

Update on Intraperitoneal Chemotherapy for the Treatment

of Epithelial Ovarian Cancer
Charlie Gourley, BSC, MBChB, PhD, FRCP, Joan L. Walker, MD, and Helen J. Mackay, BSc, MBCh, MD, MRCP

OVERVIEW

Surgical treatment and chemotherapy administration in women with epithelial ovarian cancer is more controversial today
than at any point in the last 3 decades. The use of chemotherapy administered intraperitoneally has been particularly
contentious. Three large randomized phase III studies, multiple meta-analyses, and now real-world data have demonstrated
substantial outcome benefit for the use of chemotherapy administered intraperitoneally versus intravenously for first-line
postoperative treatment of optimally debulked advanced ovarian cancer. Unfortunately, for each of these randomized
studies, there was scope to either criticize the design or otherwise refute adoption of this route of administration. As a result,
the uptake has been variable in North America, although in Europe it has been practically nonexistent. Reasons for this
include unquestionable additional toxicity, more inconvenience, and extra cost. However, 10-year follow up of these studies
demonstrates unprecedented survival in the intraperitoneal arm (median survival 110 months in patients with completely
debulked stage III), raising the possibility that by combining maximal debulking surgery with postoperative intraperitoneal
chemotherapy it may be possible to bring about a step change in the outcomes for these patients. In this review, we discuss
the rationale for administering chemotherapy intraperitoneally, the merits of the main randomized clinical trials, the
evidence regarding optimal regimes, issues of toxicity, port considerations, and reasons for lack of universal adoption. We
also explore potential clinical and biologic factors that may be useful for patient selection in the future.

W e have witnessed improvements in epithelial ovarian

cancer survival over the last 3 decades without seeing
significant improvements in disease-specific mortality rates
(Fig. 1). Epithelial ovarian cancer remains the leading cause
of death from gynecologic malignancy in North America with
the majority of women presenting with stage III or IV dis-
ease.1,2 Advances in genetic testing, counseling, and pre-
vention with risk-reducing salpingo-oophorectomy (and
salpingectomy) have the potential to produce further
modest decreases in ovarian cancer mortality in the future.3
However, we currently do not have a reliable population
screening test for epithelial ovarian cancer, and, given the
often nonspecific symptoms with which epithelial ovarian
cancer presents, it is likely the majority of patients will
continue to present with late-stage disease. Therefore,
optimizing treatment is critical if we are to improve outcome.
Retrospective analyses suggest that overall survival (OS) is
associated with younger age, good performance status,
lower stage of disease, and lower comorbidity scores.4,5
Although histologic subtype and tumor grade previously
were regarded as simply prognostic, it has now become clear
that they represent pathologic markers of what are essen-
tially discrete disease entities. These differ in terms of their
tissue of origin, stage of presentation, driver molecular
mutations, sensitivity to chemotherapy, and prognosis
(Fig. 2). Ultimately, it is very likely that these histologic
subtypes will require different treatment strategies.6
In clinical practice, only a few risk factors remain that can
be modified based on the decisions of patients and their
physicians. The surgical decision making and chemotherapy
administration choices, particularly for women with stage III
or IV epithelial ovarian cancer, can potentially affect survival.
Informed selection of the best treatment (including clinical
trial options) for any individual patient is most likely to be
achieved with enthusiastically committed multidisciplinary
teams working in high-volume institutions.7,8 Discussions
around chemotherapy administered intraperitoneally for
individual patients require this type of environment to allow
the patient to make an informed choice about care.
This article summarizes the history and role of chemo-
therapy administered intraperitoneally in epithelial ovarian
cancer, focuses on the practical choices that patients and

From the Edinburgh Cancer Research Centre, Medical Research Council, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom; Stephenson
Cancer Center, University of Oklahoma, Health Sciences Center, Oklahoma City, OK; Faculty of Medicine, University of Toronto, Sunnybrook Odette Cancer Centre, Toronto, Canada.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Helen J. Mackay, BSc, MBCh, MD, MRCP, University of Toronto, Sunnybrook Odette Cancer Centre, 2075 Bayview Ave., Toronto, ON M4N 3M5, Canada; email:
helen.mackay@sunnybrook.ca.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 143

GOURLEY, WALKER, AND MACKAY
FIGURE 1. Increase in Overall Survival Over Time for
Women Diagnosed With Ovarian Cancer
clinicians face (with an emphasis on emerging data), and
stresses the importance of building skilled multidisciplinary
teams for treating women undergoing intraperitoneal
treatment. Finally, we explore how emerging data on epi-
thelial ovarian cancer biology may be able to guide the
future of intraperitoneal therapy in this disease.
RATIONALE FOR INTRAPERITONEAL
CHEMOTHERAPY
The peritoneal cavity is the principle site of spread and
recurrence in women with epithelial ovarian cancer. Ad-
ministration of chemotherapy intraperitoneally is a means of
increasing the dose intensity delivered to the tumor and
KEY POINTS
Patients with epithelial ovarian cancer should be treated
by high-volume multidisciplinary teams.
Randomized phase III trial, meta-analysis, and real-
world data support the benefit of chemotherapy
administered intraperitoneally in the treatment of
select groups of women with epithelial ovarian cancer
following up-front optimal cytoreductive surgery.
The optimal intraperitoneal/intravenous chemotherapy
regimen has yet to be defined, and emerging data from
the randomized studies GOG 252, OV21/PETROC, and
JGOG iPocc will help clarify whether cisplatin
administered intraperitoneally can be replaced by
carboplatin administered intraperitoneally.
Discussion of chemotherapy administered
intraperitoneally to treat women diagnosed with
ovarian cancer is essential.
Understanding the biology underlying the success of
chemotherapy administered intraperitoneally is a
priority; initial data suggest exploration of tumors
deficient in DNA repair are of particular interest.
144 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
minimizes systemic toxicity, therefore, it is an attractive
therapeutic approach.9 Advantages of intraperitoneal ad-
ministration include high intraperitoneal concentration of
the drug, as well as a longer half-life of the drug in the
peritoneal cavity, compared with that observed with ad-
ministration intravenously alone. For cisplatin, historically,
the most extensively studied agent administered by the
intraperitoneal route in epithelial ovarian cancer translates
into a 10- to 20-fold greater exposure over that which is
achievable with the intravenously administrated route.10-12
Furthermore, preclinical studies suggested that cisplatin is
capable of penetrating small volume tumors (13 mm).
Hence, the hypothesis arose that the maximum benefit from
administration of the drug intraperitoneally was likely to be
demonstrated in patients with microscopic or low-volume
macroscopic disease.13 However, our understanding of why
the intraperitoneal chemotherapy route is more effective
may be oversimplified, and it has been challenged. Mea-
surement of drug in peritoneal fluid probably does not
represent actual tumor drug penetration in patients.14 There
may be added barriers in tumor implants, notably disordered
capillary architecture, fibrosis, and adhesions. Furthermore,
dose intensification of platinum administered intravenously
has failed to show a benefit in multiple randomized stud-
ies.15,16 However, these dose intensification studies did not
select neither patients with high-grade serous ovarian
cancer nor the subgroups with disease that we know to be
most sensitive to platinum (those exhibiting homologous
recombination deficiency, discussed below). As such, the
impact in the dose-dense arms of these studies (which were
twice the density of the control arm at most) in any patients
with disease sensitive to this approach would be diluted out
by the majority of patients whose tumor biology would make
them unlikely to benefit from this approach. Although the
intraperitoneal studies were similarly unselected for
immunohistologic or molecular subtype, the local dose in-
tensification in the intraperitoneal arm is potentially an
order of magnitude higher than in the intravenously ad-
ministrated arm. Under these circumstances, it may be
possible that the signal would be evident even without
preselection on the basis of histology or biology.
Other factors such as drug recirculation following peri-
toneal absorption may play a role in efficacy. Despite the fact
that chemotherapy administered intraperitoneally has been
studied for decades, we are still not fully aware of the key
biologic factors that determine its success.15,16 Moving
forward, a greater understanding of how tumor biology and
the immune and micro-environments are affected by
treatment administered intraperitoneally may help us un-
derstand how this treatment can best be deployed and
combined with the newer generation of targeted agents.
INTRAPERITONEAL CHEMOTHERAPY TRIALS IN
WOMEN WITH EPITHELIAL OVARIAN CANCER
Intraperitoneal chemotherapy is not a recent concept in the
treatment of epithelial ovarian cancer; it was originally used
 INTRAPERITONEAL CHEMOTHERAPY IN THE TREATMENT OF OVARIAN CANCER

FIGURE 2. Schema for GOG 252
in the 1950s to control ascites. Interest in chemotherapy
administered intraperitoneally as a strategy for reducing
the risk of disease recurrence and prolonging survival
emerged approximately 30 years ago. This resulted in a
number of randomized phase III studies that demonstrated
an improvement in survival for the combination of delivery
of chemotherapy intraperitoneally and intravenously over
chemotherapy administrated intravenously alone for
select patients following primary cytoreductive surgery
(Table 1).17-23 GOG 172, a randomized phase III study of
cisplatin administered intraperitoneally combined with
both delivery of paclitaxel intraperitoneally and intravenously,
published in 2006, demonstrated a 16-month improvement
in median OS over intravenous administration of the same
drugs alone.18 This prompted the National Cancer Institute
(NCI) to issue a rare clinical announcement regarding the
clinical utility of cisplatin-based chemotherapy adminis-
tered intraperitoneally in the treatment of patients with
small volume (, 1 cm), advanced-stage (stage III) epithelial
ovarian cancer following an attempt at maximal cytore-
ductive surgery. On average, intraperitoneal/intravenous
chemotherapy was associated with a 21.6% decrease in
risk of death (hazard ratio (HR) 0.78; 95% CI, 0.690.89,
the original clinical announcement can be viewed at ctep.
cancer.gov).
An update published in 2015 with a median follow-up
of 10.7 years showed that women who underwent
intraperitoneal/intravenous chemotherapy in GOG 172
continued to derive benefit with a median survival of
61.8 months (95% CI, 55.569.5 months) compared with
51.4 months (95% CI, 4658.2 months) for chemotherapy
administered intravenously alone.24 The recent Cochrane
Review, restricted to newly diagnosed patients receiving
treatment after primary cytoreductive surgery, accepted
data from eight randomized studies on 2,026 women and

TABLE 1. Summary of Randomized Clinical Trials of Intraperitoneal Chemotherapy for Up-Front Primary
Cytoreductive Surgery

No. of
Study/Reference Control Regimen Experimental Regimen Eligible Patients Patients
Kirmani et al20 Cisplatin 100 mg/m2 IV cyclophosphamide Cisplatin 200 mg/m2 IP; etoposide 350 mg/m2 IP Stage IIC-IV 62
600 mg/m2
Every 3 weeks x 6 Every 4 weeks x 6
SWOG 8501/ Cisplatin 100 mg/m2 IV; cyclophosphamide Cisplatin 100 mg/m2 IP; cyclophosphamide Stage III, 546
GOG 10417 600 mg/m2 IV 600 mg/m2 IV # 2 cm residual
Every 3 weeks x 6 Every 3 weeks x 6
Polyzos et al22 Carboplatin 350 mg/m2 IV; cyclophosphamide Carboplatin 350 mg/m2 IP; cyclophosphamide Stage III 90
600 mg/m2 IV 600 mg/ m2 IV
Every 3 weeks x 6 Every 3 weeks x 6
GONO19 Cisplatin 50 mg/m2 IV; cyclophosphamide Cisplatin 50 mg/m2 IP; cyclophosphamide Stage II-IV, 113
600 mg/m2 IV; epidoxorubicin 60 mg/m2 IV 600 mg/ m2 IV; epidoxorubicin 60 mg/m2 IV , 2 cm residual
Every 4 weeks x 6 Every 4 weeks x 6
GOG 114/ Cisplatin 75 mg/m2 IV; paclitaxel Carboplatin (AUC 9) IV every 28 days x 2; Stage III, 462
SWOG 922721 135 mg/m2 (24-hr) IV cisplatin 100 mg/m2 IP; paclitaxel # 1 cm residual
135 mg/m2 (24-hr) IV
Every 3 weeks x 6 Every 3 weeks x 6
Yen et al23 Cisplatin 50 mg/m2 IV; cyclophosphamide Cisplatin 100 mg/m2 IP; cyclophosphamide Stage III, 118
50 mg/m2 IV; epidoroxorubin/ 500 mg/m2 IV; epidoxorubicin/ # 1 cm residual
doxorubicin 50 mg/m2 IV doxorubicin 50 mg/m2 IV
Every 3 weeks x 6 Every 3 weeks x 6
GOG 17218 Cisplatin 75 mg/m2 IV; paclitaxel Paclitaxel 135 mg/m2 (24-hr) IV; cisplatin Stage III, 415
135 mg/m2 (24-hr) IV 100 mg/m2 IP; paclitaxel 60 mg/m2 IP on day 8 # 1 cm residual
Every 3 weeks x 6 Every 3 weeks x 6
Abbreviations: IP, intraperitoneally; IV, intravenously.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 145

GOURLEY, WALKER, AND MACKAY
concluded that women experienced increased survival if
they received intraperitoneal/intravenous chemotherapy
(HR 0.81; 95% CI, 0.700.9) and that intraperitoneal/
intravenous chemotherapy also prolonged the disease-
free interval (five studies, 1,311 women; HR 0.78; 95% CI,
0.70.86),25 thus potentially affecting quality of life going
forward.
Wright et al recently reported data on the real-world
uptake of intraperitoneal/intravenous chemotherapy in a
prospective cohort of 823 women with stage III optimally
cytoreduced epithelial ovarian cancer treated in six National
Comprehensive Cancer Network (NCCN) institutions.8 De-
spite the trial-based evidence and although adoption of
intraperitoneal/intravenous chemotherapy increased be-
tween 2007 and 2008, it plateaued with fewer than 50% of
eligible patients receiving intraperitoneal/intravenous
treatment. They also observed marked variation in up-
take between institutions from 4% to 67%, suggesting
underutilization of this effective treatment approach in
this subgroup of women.
WHY HAS INTRAPERITONEAL/INTRAVENOUS
CHEMOTHERAPY NOT BEEN UNIVERSALLY
ADOPTED?
Despite a proven survival benefit, clearly intraperitoneal/
intravenous chemotherapy has not been universally adop-
ted for the treatment of epithelial ovarian cancer. The
reasons behind this are numerous. The publication of each
positive intraperitoneal/intravenous randomized study has
been met with considerable debate over the interpretation
of the trial data.26 Arguments around the validity of the
conclusions drawn from GOG 172 have included statistical
analysis queries (intention-to-treat analysis, number of
patients lost to follow-up), and questions over second-line
treatment and scheduling effects.26 The most relevant
criticism of the pivotal intraperitoneal studies is the in-
equality of dose intensity between the treatment arms in
both GOG11421 and GOG17218 (Table 1). Given the fact that
paclitaxel administered intravenously weekly has been
shown to be superior to paclitaxel administered in-
travenously tri-weekly in one large randomized phase III
study,27 it could be argued that the administration of
an additional dose of paclitaxel on day 8 in the Armstrong
study was solely responsible for the benefit demonstrated.
However, a second randomized phase III study of weekly
versus triweekly paclitaxel administered intravenously did
not show superiority.28 In addition, the Alberts (GOG104)
study was a clean comparison of the same doses of cisplatin
administered intravenously or intraperitoneally, which
demonstrated substantial progression-free and OS advan-
tages,17 but it was overlooked in many areas of the world
because paclitaxel came to prominence and the comparator
arm in GOG104 was regarded as outdated. It does, however,
serve as a useful proof of principle regarding the advantages
that can be attributed purely to the route of administration.
In addition, when the two studies with unequal dose
146 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
intensities between the arms (GOG 114 and GOG 172)
were excluded from the analysis of a Cochrane systematic
review in 2011, the survival benefit remained in favor of
the intraperitoneal route of administration.25 In the real-
world analysis by Wright et al, 43% of patients received
modified intraperitoneal/intravenous regimens over time
(i.e., regimens differing from trial-specified protocols). De-
spite these modifications, women receiving intraperitoneal/
intravenous chemotherapy continued to derive benefit over
those who only received treatment intravenously (3-year OS
81% vs. 71%; HR 0.68; 95% CI, 0.470.99).8
Undoubtedly, delivery of intraperitoneal/intravenous
chemotherapy requires increased resources in terms of
both space and time to deliver compared with therapy
administrated intravenously. Because of placement of
catheters and regional delivery of drug, intraperitoneal/
intravenous chemotherapy is potentially associated with
greater toxicity, including catheter-related complications,
gastrointestinal toxicity, pain, and infection. These have
been reported across trials and supported in meta-ana-
lyses.25,29 However, real-world reports suggest many of
these potential issues can be overcome with time and de-
velopment of expertise.30,31 Furthermore, randomized data
and the NCI alert support the use of cisplatin administered
intraperitoneally.17-21,23 Cisplatin is known to be more toxic
than the standard of care carboplatin, which is administered
intravenously for epithelial ovarian cancer.32 To date, we do
not have randomized trial data to determine whether car-
boplatin administered intraperitoneally is equivalent to
cisplatin administered intraperitoneally in terms of its im-
pact on survival. However, preclinical and some clinical data
suggest that it might be equivalent in efficacy and less
toxic than cisplatin administered intraperitoneally.33 Results
from GOG 252 (NCT00951496) and OV21/PETROC (NCT00993655)
are awaited. These trials include direct comparison of
regimens, including cisplatin and carboplatin administered
intraperitoneally.
As yet, we have not arrived at the optimal intraperitoneal/
intravenous chemotherapy regimen, which balances efficacy
with toxicity and quality of life. Finally, effective and safe
delivery of intraperitoneal/intravenous chemotherapy re-
quires the multidisciplinary expertise of a skilled team, which
simply may not be available in smaller-volume centers.
Therefore, consideration for referral and management in
high-volume centers is appropriate. Even with all the con-
cerns that exist, it is clear that women who are appropriate
for intraperitoneal/intravenous chemotherapy should be at
least offered this as an option, and clinicians should be
considering how best to make it available to them.31
SURGICAL CONSIDERATIONS FOR
INTRAPERITONEAL CHEMOTHERAPY
The goal of ovarian cancer surgery whenever it is performed
is no gross residual disease or R0, as defined by Chi and
Bristow.7,34 This has been shown to result in improved
progression-free survival (PFS) and OS. Intraoperative

treatment decisions that have been demonstrated to in-
fluence patient survival and maximize surgical effort must
include a willingness to perform diaphragm resection,
splenectomy, bowel resections, and thorough peritoneal
and retroperitoneal resections of tumor. This requires ex-
perience and potentially a team of surgeons.35 Although an
R0 resection improves OS, it remains somewhat unclear
whether microscopic versus visible disease has an impact on
intraperitoneal chemotherapy effectiveness, as the allow-
able residual volume at the end of surgery differed in
the randomized trials (, 2 or , 1 cm). Many have made
the assumption that patients with microscopic disease
would derive the greatest benefit from intraperitoneal/
intravenous chemotherapy. However, in a subgroup analysis
of the GOG172 patient population, the 64% of women in
GOG172 who had macroscopic (gross) residual disease less
than or equal to 1 cm (which was the upper limit allowed by
study eligibility) had a significant improvement in OS (HR
0.75; 95% CI, 0.620.92).24 Further exploration of the effect
on larger-volume residual disease should emerge from GOG-
0252 and the Japanese iPocc trial (NCT01506856), both of
which enrolled a proportion of patients with larger-volume
residual disease.
Landrum looked into the effects of lymphadenectomy and
nodal metastasis on the benefit of administering chemo-
therapy intraperitoneally using data from both GOG 114 and
GOG 172. In these studies, despite undergoing cytoreductive
surgery to less than 1 cm, only 59% of women had lymph
nodes sampled or excised. Of the 254 women who had lymph
node evaluation, intraperitoneal benefit in terms of PFS and
OS was independent of nodal status. This suggests that
chemotherapy administered intraperitoneally may be equally
effective for patients with both intraperitoneal and retro-
peritoneal disease. Interestingly, the patients without lym-
phadenectomy did worse than patients with metastatic
tumor removed from their lymph nodes, although the de-
cision not to perform the lymphadenectomy may have been
secondary to some poor prognostic factor perceived by the
surgeon. An important long-term quality of life finding by
Landrum was a decrease in recurrence in the abdominal cavity
after intraperitoneal chemotherapy. Thus intraperitoneal/
intravenous treatment may spare patients from suffering
from ascites and an inability to eat when they recur.4
A key and controversial area around surgical decision
making in epithelial ovarian cancer is the choice of neo-
adjuvant chemotherapy followed by a definitive cytore-
ductive surgical attempt versus primary cytoreductive
surgery. Initially, neoadjuvant chemotherapy was consid-
ered only for those women who were medically unfit for
aggressive surgery or for women with a high tumor burden
(especially those with stage IV disease).36,37 In recent years,
the use of neoadjuvant chemotherapy has gained in pop-
ularity. This followed the publication of two studies: the
European Organization for Research and Treatment of
Cancer Gynecologic Cancer Group (EORTC GCG) 5597138 and
the CHORUS study,39 which demonstrated equivalence in
outcome with some reduction in morbidity for patients
INTRAPERITONEAL CHEMOTHERAPY IN THE TREATMENT OF OVARIAN CANCER
receiving neoadjuvant treatment. Neoadjuvant chemo-
therapy is usually platinum-based and administered in-
travenously; there is no role for intraperitoneal/intravenous
therapy in the preoperative patient. A recent study by Rosen
et al40 showed that the long-term survival for patients
undergoing primary cytoreduction was far superior to those
receiving neoadjuvant chemotherapy and delayed primary
surgery (9% vs. 41%, p , .0001). Although selection bias may
account for some of this difference, the percentage of long-
term survivors is strikingly low in neoadjuvant chemother-
apy studies.41 Patients undergoing optimal cytoreductive
surgery following administration of neoadjuvant chemo-
therapy were not included in the previous intraperitoneal/
intravenous randomized trials. Theoretically, they may
derive a similar level of benefit to women undergoing
up-front cytoreductive surgery from intraperitoneal/
intravenous chemotherapy delivery. The combination of
intraperitoneal/intravenous chemotherapy following neo-
adjuvant chemotherapy and optimal cytoreductive surgery
is being studied in the Gynecologic Cancer Intergroup study
OV21/PETROC. Women who had initial (clinical/imaging)
stage IIB-IV (intravenously based on the presence of pleu-
ral effusion alone) epithelial ovarian cancer and who had
received three or four cycles of platinum-based neoadjuvant
chemotherapy before definitive optimal cytoreductive
surgery (# 1 cm residual disease) were eligible for this trial.
Women were enrolled either intra- or postoperatively. This
study has now closed and the primary analysis is expected
shortly.
INTRAPERITONEAL PORT PLACEMENT
Essential to the delivery of chemotherapy administered in-
traperitoneally is the placement of an intraperitoneal port.
Consideration of port placement should occur at the time of
surgery when the port can be placed under direct visuali-
zation by the surgeon. This is the most time-efficient ap-
proach and prevents delays in the initiation of chemotherapy
postoperatively. Patients should be treated as soon as they
have resumed a normal diet and bowel function and are
ambulatory at home, which should occur within 21 days
of the primary surgery. Patients electing to receive in-
traperitoneal chemotherapy who do not already have
peritoneal catheters can have devices implanted by inter-
ventional radiologists or surgeons familiar with laparoscopic
techniques using the right upper quadrant entry techniques.
Minilaparotomy in the right lower quadrant is also generally
successful if resection of the terminal ileum or right colon did
not occur. Careful review of the cytoreduction operative
report can improve outcomes with intraperitoneal port
placement to avoid complications.42,43
The preferred location for port placement is the right
lower costal grill on the midclavicular line, below the location
where the breast or the bra may be uncomfortable in
a standing position. This site allows for posterior rigid
support that facilitates access. Ports also are installed over
the left side or right lower quadrant for convenience.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 147
GOURLEY, WALKER, AND MACKAY
Failures of intraperitoneal catheters can be corrected in-
frequently. Infected catheters should be removed and not
replaced. Blocked catheters can be replaced if the patient
has free intraperitoneal space remaining between bowel
loops and has not had peritonitis as a complication of having
undergone surgery or having received chemotherapy. Ac-
cess problems attributable to a rotated port can be easily
corrected. Most patients, however, resume their chemo-
therapy with treatment administered intravenously alone
when catheter complications occur.
INTRAPERITONEAL CHEMOTHERAPY: WHICH
REGIMEN?
The 2013 update of the NCCN Guidelines suggested an in-
traperitoneal regimen based on the experimental arm of GOG
172: cisplatin administered intraperitoneally 75 to 100 mg/m2
and a 3-hour infusion of paclitaxel intravenously on day 1 with
60 mg/mg2 delivered intraperitoneally on day 8. The reduced
dose of cisplatin administered intraperitoneally (75 mg/m2)
was included because of concerns over the toxicity of 100 mg/
m2 with patients who did not complete the planned six cycles
of intraperitoneal/intravenous therapy postsurgery. This
dosing is also reflected in the experimental arms of both GOG
252 and OV21/PETROC.44
Given the toxicity associated with cisplatin and the
emerging nonrandomized data on carboplatin administered
intraperitoneally, some centers have adopted intraperitoneal
carboplatin-based regimens.45,46 Randomized data to better
inform the selection of an intraperitoneal/intravenous regi-
men will be available soon from GOG 252 and OV21/PETROC.
Given that GOG 172 demonstrated an OS benefit in an
intention-to-treat analysis when the median number of
cycles delivered was three (although the studies to date have
looked at six cycles of chemotherapy), a question remains
as to whether six is the optimal number of intraperitoneal
treatments.18
When discussing chemotherapy options for patients
whose disease is optimally cytoreduced, clinicians face the
challenge of discussing three basic choices: (1) carboplatin
and paclitaxel administered intravenously every 3 weeks
(GOG 158, GOG 182), (2) carboplatin administered in-
travenously every 3 weeks with paclitaxel administered
intravenously weekly (JGOG-3016, GOG 262), or (3) an
intraperitoneal/intravenous regimen.32,42,47,48 The subset of
women with stage III optimally cytoreduced disease in ICON
7 did not derive benefit from the addition of bevacizumab to
carboplatin and paclitaxel administered intravenously every
3 weeks.49 Data from OV21/PETROC, GOG 252, and JGOG
iPocc (NCT01506856) studies are eagerly awaited because
they will provide information on the comparison of a dose-
dense intravenous regimen with intraperitoneal/intravenous
chemotherapy. This will address the question of dose density
that remains from the GOG 172 data. The role of bevacizumab
in combination with intraperitoneal/intravenous chemo-
therapy is being explored in GOG 252. The tolerability of the
regimen was established in a previous phase II trial, although
148 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
three bowel obstructions (7%) were observed.50 Further
safety data on the combination of bevacizumab and
intraperitoneal/intravenous therapy will be available from
GOG 252. GOG 262 is a study that compared carboplatin/
paclitaxel administered intravenously every 3 weeks with
carboplatin administered intravenously on day 1 with
weekly dosing of paclitaxel intravenously. Bevacizumab
was allowed as an (nonrandomized) option in both arms of
the trial. This study demonstrated that dose-dense pacli-
taxel improve PFS over the dosing of paclitaxel every
3 weeks, but this was only true in women not receiving
bevacizumab. The addition of bevacizumab appeared to
eliminate the beneficial effects of dose-dense pacli-
taxel.47 In GOG 252, bevacizumab is included on cycles
222, and the study was designed with the assumption
that there would be no interaction between the various
chemotherapy arms and bevacizumab, which would hide
the effects of the individual chemotherapy regimens. The
surprising results of GOG 262 raise concern that the ad-
dition of bevacizumab to all patients on GOG 252 may
have obscured the effects of the individual chemotherapy
regimens alone. Insufficient data exist at this time to rec-
ommend bevacizumab in combination with intraperitoneal/
intravenous chemotherapy as a standard-of-care option.
Results for GOG 252 are expected to be reported at the
Society of Gynecologic Oncology meeting in March 2016.
Ultimately, the factors that patients and families should be
empowered to consider when making decisions about ad-
juvant treatment will include convenience, potential toxic-
ities, and quality of life in addition to the data on efficacy.
PATIENT SELECTION FOR INTRAPERITONEAL
CHEMOTHERAPY
The last consideration is whether there are individual
patient findings that should be factored into decisions
regarding whether chemotherapy should be administered
intraperitoneally/intravenously or just intravenously to pa-
tients. It is now clear that at the immunohistochemic level,
epithelial ovarian cancer consists of at least five different
diseases.51-53 Although previous randomized studies of
intraperitoneal/intravenous chemotherapy versus in-
travenous chemotherapy did not select or stratify on the basis
of histologic subtype, it is now apparent that subtypes such as
low-grade serous, low-grade mucinous, and clear cell are less
sensitive to chemotherapy than high-grade serous or high-
grade endometrioid ovarian cancer. The low likelihood of a
considerable chemotherapy dose-response relationship in
these less-sensitive subtypes makes it difficult to justify
subjecting these patients to the additional toxicity of in-
traperitoneal chemotherapy. Rather, the main subgroup of
patients who should be considered for intraperitoneal ad-
ministration of chemotherapy are those with high-grade
serous ovarian cancer (patients with high-grade endome-
trioid cancer are an under-researched subgroup), but what
little evidence there is suggests they could be considered
similar to high-grade serous from a biologic perspective).

Currently, given the strong evidence of benefit from GOG
11421 and GOG17218 studies, there is insufficient evidence to
support any further patient selection based on biologic
subtype in patients with optimally cytoreduced disease who
have good performance status. However, the finding that
patients from the GOG 172 study with low-tumor BRCA1
expression (as assessed by immunohistochemistry) appeared
to benefit more from intraperitoneal/intravenous che-
motherapy than intravenous chemotherapy (median sur-
vival 84 compared with 48 months, p = .0002) than those
with normal BRCA1 expression (median survival 58 months
for intraperitoneal chemotherapy compared with 50 months
for intravenous chemotherapy) suggests that there are
molecular subgroups that may benefit more from the in-
traperitoneal route of delivery.54 The main molecular
characteristics underlying high-grade serous ovarian can-
cer have recently been uncovered (Fig. 3).51,55 Given the
strong preclinical and clinical data supporting a high level of
platinum sensitivity in BRCA1- and BRCA2-deficient ovarian
cancer cells, it is not surprising that patients with low
BRCA1 protein expression may derive particular benefit
from administration of chemotherapy intraperitoneally.
The question is whether this benefit applies only to tumors
that carry germline or somatic BRCA1 mutations, or whether
those patients with epigenetic BRCA1 inactivation, BRCA2
mutations, PTEN loss, EMSY amplification, or mutations in
other homologous recombination deficiency genes also de-
rive benefit. Although BRCA1 immunohistochemistry analysis
is notoriously inaccurate, the technology now exists to per-
form this other sequencing and copy number characterization
on archival formalin-fixed, paraffin-embedded material. This
retrospective analysis should be performed as a matter of
FIGURE 3. Molecular Subgroups of High-Grade Serous
Epithelial Ovarian Cancer
Abbreviations: HRD, homologous recombination deficient.
INTRAPERITONEAL CHEMOTHERAPY IN THE TREATMENT OF OVARIAN CANCER
urgency using material from randomized studies of in-
traperitoneal chemotherapy to demonstrate whether par-
ticular molecular subgroups have more to gain from
intraperitoneal treatment. It is already clear that some
molecular subgroups have a high incidence of primary
platinum resistance (Fig. 3; homologous recombination
proficient),55,56 and these patients may not benefit from
intraperitoneal therapy; instead, perhaps they should be
considered for dose-dense paclitaxel and carboplatin ad-
ministered intravenously, or trials of other novel therapies
in combination with their first-line chemotherapy, to op-
timize survival and avoid unnecessary toxicity.
Although cure is a word that most ovarian cancer on-
cologists try to avoid, this must be our aim. The survival that
has been demonstrated in patients with completely
cytoreduced disease and who received intraperitoneal
chemotherapy in the GOG172 study is a sea change in terms
of what we expect in this disease. It reinforces the argument
that in fit patients, maximal cytoreductive surgery followed
by intraperitoneal chemotherapy is the treatment likely to
produce the best possible outcome. However, the morbidity
induced by both these treatments makes it even more im-
perative that we are able to define whether it is only patients
with a particular biology (e.g., BRCA mutations or homolo-
gous recombination deficiency) that benefit. For these pa-
tients, full-on surgical/intraperitoneal chemotherapy with
or without PARP maintenance inhibitors (depending on the
outcome of currently running first-line PARP inhibitor
studies) could be adopted. For the patients with different
biology, alternative tailored approaches could be sought.
CONCLUSION
Large randomized phase III studies have been ubiquitously
positive, producing some of the best survival data ever seen
in the treatment of ovarian cancer. However, all of these
studies have had issues, either with the intravenous che-
motherapy (control) arm being perceived as no longer con-
temporary or the intraperitoneal (test) arm having higher
dose intensity than the control arm and, therefore, not
being a trial solely of route of administration. These apparent
shortcomings combined with undoubted toxicity of the ap-
proach have led to inconsistent uptake in North America and
Australia and negligible uptake in Europe. This seems a shame
given that the benefits in terms of outcome appear so
marked. Indeed, the benefits are well in excess of those
demonstrated in the first-line bevacizumab studies that led to
licensing and reimbursement of this agent across Europe.
Further work is required to improve the toxicity from
chemotherapy administered intraperitoneally and to iden-
tify the best regimen and determine the extent to which the
benefits witnessed also can be produced by dose-dense
approaches or the use of targeted agents. These latter
two questions may be answered to some extent by the
GOG252 study. Perhaps the most important question that
requires to be answered is exactly which molecular sub-
groups of ovarian cancer patients benefit most from
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 149
GOURLEY, WALKER, AND MACKAY
intraperitoneal treatment. If this can be established, these
patients may benefit greatly from an aggressive surgical and
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Oncol. 2011;29:4662-4668.
51. Bowtell DD, Bohm S, Ahmed AA, et al. Rethinking ovarian cancer II:
reducing mortality from high-grade serous ovarian cancer. Nat Rev
Cancer. 2015;15:668-679.
52. Kobel M, Kalloger SE, Boyd N, et al. Ovarian carcinoma subtypes are
different diseases: implications for biomarker studies. PLoS Med. 2008;
5:e232.
53. Vaughan S, Coward JI, Bast RC Jr, et al. Rethinking ovarian cancer:
recommendations for improving outcomes. Nat Rev Cancer. 2011;11:
719-725.
54. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved
survival in ovarian cancer patients treated with intraperitoneal cisplatin
and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;
108:1231-1237.
55. Patch AM, Christie EL, Etemadmoghadam D, et al; Australian Ovarian
Cancer Study Group. Whole-genome characterization of chemo-
resistant ovarian cancer. Nature. 2015;521:489-494.
56. Etemadmoghadam D, George J, Cowin PA, et al; Australian Ovarian
Cancer Study Group. Amplicon-dependent CCNE1 expression is critical
for clonogenic survival after cisplatin treatment and is correlated with
20q11 gain in ovarian cancer. PLoS One. 2010;5:e15498.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 151
GYNECOLOGIC CANCER

Neoadjuvant Chemotherapy:
Location, Location, Location

CHAIR
Alexandra Leary, MD, PhD
Gustave Roussy Cancer Center
Villejuif, France

SPEAKERS
Dennis Chi, MD
Memorial Sloan Kettering Cancer Center
New York, NY

Sean Kehoe, MD
University of Birmingham
Birmingham, United Kingdom
 KEEPING THE PEACE AND BALANCING THE BIOLOGY

Primary Surgery or Neoadjuvant Chemotherapy in Advanced

Ovarian Cancer: The Debate Continues
Alexandra Leary, MD, PhD, Renee Cowan, MD, MPH, Dennis Chi, MD, Sean Kehoe, MD, DCH, FRCOG, and
Matthew Nankivell, MSc

OVERVIEW

Primary debulking surgery (PDS) followed by platinum-based chemotherapy has been the cornerstone of treatment for
advanced ovarian cancer for decades. Primary debulking surgery has been repeatedly identified as one of the key factors in
improving survival in patients with advanced ovarian cancer, especially when minimal or no residual disease is left behind.
Achieving these results sometimes requires extensive abdominal and pelvic surgical procedures and consultation with other
surgical teams. Some clinicians who propose a primary chemotherapy approach reported an increased likelihood of leaving
no macroscopic disease after surgery and improved patient-reported outcomes and quality-of-life (QOL) measures. Given
the ongoing debate regarding the relative benefit of PDS versus neoadjuvant chemotherapy (NACT), tumor biology may aid
in patient selection for each approach. Neoadjuvant chemotherapy offers the opportunity for in vivo chemosensitivity
testing. Studies are needed to determine the best way to evaluate the impact of NACT in each individual patient with
advanced ovarian cancer. Indeed, the biggest utility of NACT may be in research, where this approach provides the op-
portunity for the investigation of predictive markers, mechanisms of resistance, and a forum to test novel therapies.

D espite the fact that most patients with ovarian cancer

have stage III or IV disease, advances in surgical and
medical therapies over the last 4 decades have significantly
improved the 5-year and overall survival (OS) for women
diagnosed with ovarian cancer.1,2 What used to be a death
sentence can now be considered a chronic disease in many
cases.3 However, ovarian cancer is still the leading gyne-
cologic malignancy cause of cancer-related deaths in high-
income countries.4 Furthermore, there is much work to be
done in efforts to improve not only OS and progression-free
survival (PFS), but also QOL.
According to the National Comprehensive Cancer Net-
work, the current primary treatment of advanced epithelial
ovarian cancer is optimal cytoreductive surgery followed by
six to eight cycles of dual-agent platinum- and taxane-
based chemotherapy.5 Cytoreductive surgery (also called
debulking) was initially proposed by Meigs in 1934.6 Forty
years later, Griffiths showed that survival depended on the
maximum diameter of residual disease left after cytore-
ductive surgery.7 Primary debulking surgery has since been
repeatedly demonstrated as one of the key factors in im-
proving survival and the cornerstone of ovarian cancer
treatment by many studies.8-10
There are some in the field of gynecologic oncology,
however, who propose that inherent tumor biology is more
important than surgical resection and question the value of
extensive cytoreductive surgeries as the first step of the
advanced ovarian cancer treatment plan. Within the last
decade, this issue has been widely debated. In 2008, Vergote
presented the data of the first randomized control phase III
trial comparing PDS versus NACT followed by interval
debulking surgery (IDS). The trial enrolled more than
600 women with bulky stage III or IV advanced ovarian
cancer and was conducted by the European Organisation
for Research and Treatment of CancerGynecologic Cancer
Group (EORTC-GCG) and the National Cancer Institute of
Canada (NCIC) Clinical Trials Group. They found no major
difference in the PFS and OS between the two treatment
arms and concluded that NACT with IDS was not inferior
and possibly safer than the current standard of care,
PDS.11,12 The recently published trial on primary chemo-
therapy versus primary surgery for newly diagnosed ad-
vanced ovarian cancer (CHORUS) supported the EORTC/NCIC
results. In the CHORUS trial, more than 550 women with
advanced ovarian cancer were randomly selected to receive
primary chemotherapy versus primary surgery, with similar

From the Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom; St. Peters
College, National Cancer Intelligence Network, Public Health England, National Health Service, Birmingham, United Kingdom; School of Cancer Sciences, University of Birmingham,
Birmingham, United Kingdom; Medical Research Council Clinical Trials Unit, University College London, London, United Kingdom; Gustave Roussy Cancer Centre, Translational Research
Laboratory, Gustave Roussy Cancer Centre, Villejuif, France.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Alexandra Leary, MD, PhD, Gustave Roussy Cancer Center, 114 Rue Edouard Vaillant, Villejuif, France; email: leary.alexandra@gmail.com.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 153

LEARY ET AL
conclusions that NACT/IDS yielded comparable survival
results and decreased surgical morbidity when compared
with PDS.13
THE ARGUMENT FOR PRIMARY DEBULKING
SURGERY
It Is Possible
It is well accepted that patients who undergo suboptimal
tumor cytoreductive surgeries are at risk for surgical mor-
bidity without deriving the survival benefit of the debulking
procedure.14,15 However, when a patient is treated with the
appropriate surgery by an experienced surgeon or team of
surgeons at an experienced hospital, optimal and even com-
plete gross resection (CGR) at the time of PDS is achievable
in a vast majority of cases. Reported optimal cytoreduction
rates in the literature range from 15% to greater than
85%.10,16 Many experts agree that this variation is not
caused by a difference in geography, case presentation,
and/or case selection, but is highly dependent on the surgical
training, expertise, commitment, and resources of the pri-
mary operating surgeon, team, and institution. Moreover,
greater than 40% of patients with advanced ovarian cancer
have bulky upper abdominal disease that is difficult to
resect, which is cited by many gynecologic oncologists as
the most common reason for a suboptimal outcome at the
time of PDS.17,18
To address, the widespread nature of advanced ovarian
cancer at presentation, two strategies have emerged. One
strategy, NACT for three or more cycles followed by the
cytoreductive procedure, IDS, followed by the completion of
up to six to eight total cycles of chemotherapy, has been
proposed as a viable method to decrease preoperative
disease burden, increase the rates of optimal cytoreduction,
and lower postoperative morbidity. The second strategy has
been to expand the surgical armamentarium of gynecologic
oncology surgeons to include extensive upper abdominal
KEY POINTS
When a patient is treated with the appropriate surgery
by an experienced surgeon or team of surgeons at an
experienced hospital, optimal and even complete gross
resection at the time of PDS is achievable in a vast
majority of cases.
With the median overall survival of 66 months for
patients with stage III, optimally debulked ovarian
cancer treated with intraperitoneal chemotherapy on
GOG 172 serves as the gold standard for quality care,
which all future studies should attempt to attain.
NACT may result in better patient-reported outcomes
and QOL measures with decreased morbidity when
compared with PDS.
The biggest utility of NACT may be in research, where
this approach provides the opportunity for the
investigation of predictive markers, mechanisms of
resistance, and a forum to test novel therapies.
154 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
surgical procedures as needed during their PDS. This ap-
proach also increases the rate of optimal cytoreduction,
without significantly increasing postoperative morbidity.
In 2009, Chi et al demonstrated a change in the surgical
paradigm at Memorial Sloan Kettering Cancer Center
(MSKCC) that incorporated splenectomy, distal pancrea-
tectomy, cholecystectomy, liver wedge resection, dis-
section of the porta hepatis, and diaphragm resection/
peritonectomy when necessary to achieve optimal PDS.
This paradigm change led to an improvement in optimal
primary cytoreduction from 46% to 80%. The rate of CGR
also more than doubled.19 Multiple U.S. and international
studies have supported these findings, demonstrating not
only the feasibility, but also the safety, of this approach in
expert centers, with the morbidity, mortality, and time to
start of chemotherapy not being statistically different
from that of pelvic limited surgery.20-24 The complexity of
the surgery alone is not a predictor of PFS or OS. When
cancer in these patients is optimally debulked to less than
1 cm of residual disease, they are afforded the same
survival rates as patients who required only standard
pelvic surgery.25-27
Because the surgeries can be more complex, preoperative
preparation is crucial, sometimes requiring consultation
with general surgeons, surgical oncologists, or hepatobiliary
surgeons to assist in the event that disease encountered
at PDS is difficult or impossible for the gynecologic oncol-
ogist to remove. This can sometimes be difficult at medical
centers with less experienced practitioners. Recent analyses
have shown that optimal cytoreductive surgery rates are
higher among more experienced surgeons at higher-volume
hospitals, with gynecologic oncologists at expert centers
attaining optimal resection rates of greater than 75%.10,28,29
This is in stark contrast to the 41% to 42% optimal cytoreduction
rates reported in the PDS arms of the EORTC/NCIC and
CHORUS PDS versus NACT/IDS trials (Table 1).12,13 More-
over, the median operating times of 165 and 120 minutes,
respectively, in the PDS arms of the two studies seems to be
inadequate for a complete surgical evaluation and attempt
at achieving optimal or no gross residual disease status.12,13
These findings question whether the PDS attempted in
these two trials were what one would see in more expe-
rienced, expert centers. Indeed, it is the duty of the op-
erating physician to give the patient the best chance
at achieving CGR, even if that means additional train-
ing, multispecialty consultation, or referral to another
surgeon.
It Decreases Chemoresistance
There are innate benefits to PDS. Large bulky tumors are
often necrotic and hypoxic. Their poor blood supply does not
often lend itself to maximal intravenous or intraperitoneal
chemotherapy delivery. Comparatively, smaller tumors are
well perfused and easier to target.30 At the time of diag-
nosis and the initiation of treatment, both chemotherapy-
sensitive and chemotherapy-resistant cells are present in a

TABLE 1. Randomized Trials of PDS Versus NACT/IDS
EORTC/ EORTC/ CHORUS
NCIC PDS NCIC NACT PDS
Number of 361 357 255
Patients
Residual 1 cm 42% 81% 41%
No Gross Residual 18% 45% 17%
PFS (months) 12 12 11
OS (months) 29 30 23
Abbreviations: IDS, interval debulking surgery; EORTC, European Organization for
Research and Treatment of Cancer; NCIC, National Cancer Institute of Canada; PDS,
primary debulking surgery; NACT, neoadjuvant chemotherapy; PFS, progression-free
survival; OS, overall survival.
patient. Primary surgery decreases the tumor burdens of
both of these cell lines and decreases the quantity of cells
that can spontaneously mutate to drug-resistant pheno-
types.31 Thus, surgical debulking aids in overcoming negative
tumor biology.32 Approximately 25% of patients have
platinum-resistant disease at the time of their first relapse,
and almost all patients who have disease recurrence will
eventually become chemotherapy-resistant.33 By initiating
chemical debulking first with the NACT approach, the tumor
cells have more time to build increased resistance. Breaking
up the chemotherapy by introducing IDS in the middle of the
six to eight cycles of chemotherapy may also have this effect.
It Yields Better Survival Outcomes
The median OS of 66 months in stage III ovarian cancer
patients who underwent optimal debulking and were
treated with intraperitoneal chemotherapy on GOG 172 was
stated to be the longest median survival ever reported in a
randomized phase III ovarian cancer GOG clinical trial.34
These results serve as a gold standard for quality care, which
future studies should try to attain. Although the PFS and OS
for the NACT arms of the EORTC/NCIC and CHORUS trials are
consistent with those described in other NACT studies, the
overall OS rates of 23 to 30 months in all four arms of these
studies, and, in fact, in essentially all studies advocating
the NACT/IDS approach, are very low (Table 1).12,13,35 In
contrast, a retrospective review of an identical sample
population of patients treated during the same time period
as the EORTC/NCIC trial at MSKCC, demonstrated a median
OS rate of 50 months for all patients treated with PDS.36 A
recent publication from the same institution reported a
median survival of 72 months for all patients who had
undergone PDS regardless of residual disease status (in-
cluding those who had both optimal and suboptimal
cytoreduction; Fig. 1).37
CHEMOTHERAPY FIRST: QUICKER
IMPROVEMENT IN QUALITY OF LIFE?
Quality of Life Is an Essential Parameter
QOL is an important parameter in the evaluation of ther-
apeutic interventions and is currently the main mecha-
nism to derive patients perspective regarding the impact
KEEPING THE PEACE AND BALANCING THE BIOLOGY
FIGURE 1. MSKCC Primary Cytoreduction OS and CGR
Rates
CHORUS
NACT
219
73%
39%
12
24
Abbreviations: MSKCC, Memorial Sloan Kettering Cancer Center; OS, overall
survival; CGR, complete gross resection; mos, months. CGR, complete gross
resection; PDS, primary debulking surgery.
of any medical intervention. Though not an integral part
of standard care, QOL measures are regularly used in
prospective clinical trials. Increasingly popular is the use
of patient-reported outcomes (PROs), in which QOL mea-
sures serve as an inherent element in addition to reported
adverse sequelae.38 The increasing importance of QOL is
accentuated by data demonstrating that it is also a predictive
variable for survival.39 Furthermore, a recent cost-efficacy
analysis of the GOG 218 trial determining the benefit of the
addition of bevacizumab to platinum-based chemotherapy
revealed that the incorporation of QOL outcomes made a
meaningful contribution to the results, rendering the ad-
dition of bevacizumab even less favorable compared with
the Markov model, which excluded QOL outcomes.40 In-
cluding QOL outcomes in noninferiority studies as a measure
of the morbidity and overall impact of an intervention is
undoubtedly of major importance.
Although both surgery and chemotherapy are essential
interventions in treating patients with advanced ovarian
cancer, there is a relative paucity of trials addressing the
role of surgery. The surgically based, randomized pro-
spective studies encompass the effect of IDS, the role
of secondary cytoreductive surgery at the time of re-
currence, the value of lymphadenectomy in debulking, and
delayed PDS.12,13,30,41-43 The EORTC/NCIC and CHORUS
studies are the only two reported prospective randomized
trials addressing the use of NACT in ovarian cancer. In
both trials, similar QOL assessment tools were used: the
EORTC QLQ-C30 questionnaire version 3, which consists
of global health status/QOL multifunctional scales and
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 155
LEARY ET AL
symptom scales combined with a scale regarding financial
difficulties; and the ovarian cancerspecific QOL (QLQ-
Ov28).44 These are well-validated and reliable question-
naires used frequently in ovarian cancer studies. The
assessments were administered before patient randomi-
zation at the end of the third and the sixth cycles of
chemotherapy and at 6- and 12-month follow-up visits. In
both studies, the end of the third cycle of chemotherapy
was the presurgical assessment in the NACT arm of the
studies.
An Evaluation of Quality of Life in EORTC 55971
The EORTC 55971 trial included QOL analysis from more
than 400 women from the institutions with best com-
pliance for QOL data collection. This provided sufficient
numbers to permit clinically meaningful differences to be
detected.44 Good compliance was defined as institutions
that had at least 50% compliance at baseline and 35%
compliance on average during follow-up over all enrolled
patients. The QLQ-C30 scales and single-item questions
were linearly transformed to a 0 to 100 scale and analyzed
according to the procedures recommended by the EORTC
QOL group. A higher score on the functional and global/QOL
scales indicated better QOL, whereas a higher score on the
symptoms scale indicated poorer QOL. At least a 10-point
alteration from baseline was necessary to indicate a ma-
jor change in QOL. The analysis was also repeated
with stratification factors at randomization including
country, method of tumor biopsy, International Federation
of Gynecology and Obstetrics stage, and largest tumor
diameter.
There were no differences noted in the QOL functioning
or symptom scales between the two arms except for
fatigue, pain, and dyspnea. These changes were deemed
clinically relevant because there was a 10-point change
from baseline. The level of fatigue improved in the PDS
arm at the third cycle of chemotherapy and persisted to
12 months, whereas in the NACT arm, the same im-
provement occurred, though was noted only at 6 months
(i.e., no changes during treatment, and persisted to
12 months). The pain scale also improved in both arms to
subsequent points of measurement. Regarding dyspnea,
an improvement was noted at the sixth chemotherapy
cycle and at 6 months in the NACT arm, but not the PDS
arm. Though these differences were noted, the overall
conclusion was that QOL did not differ between the treatment
strategies. However, there was an unusual and notable
finding. There was a significant survival difference between
institutions with good compliance collecting QOL measures
versus those who were less compliant: the median OS was
32 months versus 23 months (p = .0006). Additionally, the
optimal debulking rates were nearly twice that in selected
versus excluded institutions at 40% and 20%, respectively
(p = .001). Although there may be other explanations and
possible confounding factors, QOL data collection compliance
may also be an indicator of an institutions excellence.
156 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
An Evaluation of Quality of Life in CHORUS
The CHORUS trial measured similar QOL parameters within
the same time frame as the EORTC study. CHORUS reported
an equivalent survival pattern in each arm, but with lower
median survival rates at 22 months for PDS and 23 months
for NACT.13 Notably, the median age of women enrolled was
older, at age 65, and 19% had a performance status (PS)
score of 2 or 3. The older age and poorer PS probably
contributed, in part, to the lower median survival patterns.
For the purposes of this article, the QOL data were collected
from all possible cases and not confined to the centers with
better QOL data collection rates. There was sufficient data
available from 102 patients in the PDS arm and 117 in the
NACT arm. The Global QOL remained unchanged in both
arms, with mean scores of 51.5 (95% CI, 45.856.2) at
baseline to 69.2 (95% CI, 56.164.3) at 3 months, and 53.6
(95% CI, 48.658.7) to 58.6 (95% CI, 54.562.8; p = .58,
respectively). Again, accepting a 10-point change in the mean
score as being clinically significant, improvements were noted
in nausea/vomiting and dyspnea at 3 months compared with
baseline in the PDS arm. In the same time frame, diarrhea
symptoms improved in the NACT arm. In both arms, pain and
appetite scores improved, whereas abdominal/gastric
symptoms and peripheral neuropathy worsened. Not sur-
prisingly, chemotherapy-associated side effects worsened
in the NACT arm. These were the only parameters with
changes; however, they were not significant. However, if
the data are graphically demonstrated, as can be seen in
Fig. 2, over the 6-month period, the trend is that the NACT
arm showed an improving trend compared with the
PDS arm.
Hence, is NACT a quicker route to a better QOL compared
with the primary surgery approach? Both prospective ran-
domized trials seem to indicate that there are no major
statistical differences in QOL between PDS and NACT.
However, it may be argued that the trends are of more
importance than the exact numbers. Combined with other
FIGURE 2. CHORUS Global Quality of Life Evolution
Over Time
Abbreviation: QOL, quality of life.
 KEEPING THE PEACE AND BALANCING THE BIOLOGY

morbidity data, one could favor the neoadjuvant approach in to determine whether these genomic markers may in-
this patient population. fluence the therapeutic sequence for patients with ad-
vanced HGSOC.
BIOLOGIC CONSIDERATIONS REGARDING THE
THERAPEUTIC SEQUENCE
Evidence for NACT as a Driver of Chemotherapy
Histologic and Genomic Factors to Select Patients
Resistance
One argument proposed in support of NACT is to reduce
As previously mentioned, a risk of the neoadjuvant approach
tumor bulk and increase the chance of a complete and
is that treating a greater volume of a heterogeneous tumor
potentially less morbid surgical resection. This makes
with NACT may be driving platinum resistance.58 Retro-
biologic sense in chemotherapy-sensitive high-grade se-
spective studies have shown that NACT was associated
rous ovarian cancer (HGSOC), where response rates to
with a higher risk of platinum-resistant relapse, even when
first-line platinum-based chemotherapy approach 75%.
IDS resulted in complete macroscopic resection.59,60 In the
However, rare subtypes such as low-grade serous ovarian
case of platinum-sensitive progression, lower response rates
cancer (LGSOC) and mucinous ovarian cancer (mOC) are
to a platinum combination have been described after NACT,
much less responsive to standard first-line platinum-
suggesting that NACT may be compromising responsiveness
based therapy (Table 2).45-54 A small study on LGSOC
to subsequent therapy.59,61 Although this remains a hypo-
reported an objective response rate of 3.5% to platinum-
thetical risk, these studies are limited by their retrospective
based NACT, whereas only 20% of patients with advanced
nature and inherent biases that justified the decision to offer
mucinous ovarian cancer recruited to a randomized trial
NACT in the first place, which likely explain these patients
showed an objective response to a first-line platinum
poor outcomes. Similarly, studies evaluating whether the
combination.45,50 Although numbers of patients included
number of cycles of NACT influenced outcome have shown
in these reports were small, these data raise important
worse survival with more than three or four cycles of NACT
questions regarding the value of NACT in rare subtypes of
even when complete macroscopic resection was achieved at
epithelial ovarian cancer. A major concern with NACT is
IDS.62,63 Again, because of the retrospective nature of these
the risk of progression and loss of opportunity for patients
studies, the poor outcome for patients receiving more than
who might go from being candidates for a morbid, but
four cycles may simply reflect inherent differences in tumor
feasible, PDS to not being candidates for surgery at all. In
biology and chemotherapy responsiveness rather than a
this regard, tumor biology should clearly influence the
deleterious impact of more cycles of NACT. In fact, a more
therapeutic sequence and one could propose a histologically
recent meta-analysis of 21 studies failed to show that the
driven algorithm for patients with bulky epithelial ovarian
number of NACT cycles affected survival.64 The only avail-
cancer. Recent comprehensive genomic studies in HGSOC
able prospective data come from the two randomized
have started to identify candidate molecular predictors
controlled trials of PDS versus NACT, and these failed to
of platinum sensitivity (BRCA1/2 mutations or alterations
show a difference in PFS or OS, making it unlikely that NACT
in other homologous recombination genes) or resistance
is a major driver of platinum resistance.12,24
(CCNE1 amplifications).55-57 Future studies will be crucial
In vivo evaluation of chemotherapy responsiveness during
TABLE 2. Response to First-Line Platinum-Based NACT. As opposed to the adjuvant setting in which patients
Chemotherapy in Rare Subtype of Epithelial Ovarian are treated with no measurable disease, an advantage of
Cancer NACT is that it could offer the opportunity for an in vivo
evaluation of chemotherapy responsiveness. Careful mon-
No. of Patients itoring of tumor response during chemotherapy could
With Evaluable Activity
Disease (oRR) Reference(s) identify nonresponders early and justify treatment change in
an effort to improve the efficacy of NACT and long-term
LGSOC
patient outcomes. Some prospective studies in locally ad-
First-Line 24 , 5% Schmeler et al 45
Carboplatin- vanced breast cancer have started to suggest a role for
Paclitaxel response-adapted NACT where the neoadjuvant protocol is
CCC modified according to early tumor response. One trial
First-Line 4 studies, 2368 22%41% Kita et al, Sugyama showed an improvement in PFS and OS among patients with
Platinum- et al, Ho et al, and locally advanced breast cancer randomly selected to an
Based Takano et al 46-49 adaptive NACT strategy with a chemotherapy switch in
mOC case of poor response compared with standard NACT.65
First-Line 5 studies, 950 13%60% Hess et al, Alexandre Whether adaptive NACT could be beneficial in ovarian
Platinum et al, Pectasides cancer has never been investigated and may be limited by
Based et al, Gore et al, and
Shimada et al 50-54 the fact that measuring on-treatment response to NACT is
Abbreviations: oRR, objective response rate; LGSOC, low-grade serous ovarian cancer;
difficult in ovarian cancer.66 Neither improvement in CT
CCC, clear cell ovarian cancer; mOC, mucinous ovarian cancer. imaging nor biologic response by CA-125 are reliable for

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 157

LEARY ET AL
NACT response evaluation. 67 Other technologies such as
metabolic imaging by fluorodeoxyglucose-PET or circulat-
ing cell-free tumor DNA may offer early-response in-
formation during NACT for advanced ovarian cancer.
However, to date it is unclear how this information would be
clinically useful. A small subset of patients (15%) with HGSOC
are refractory and progress clinically and biologically during
NACT. The only value of identifying these early non-
responders would be if this could inform clinical decision
making. Unfortunately, ovarian cancer does not have an
effective alternative to standard neoadjuvant carboplatin
and paclitaxel.
In vivo evaluation of chemotherapy responsiveness
at IDS. Complete resection of all macroscopic disease at PDS
has been confirmed as a critical prognostic factor32; how-
ever, its value after NACT is less clear because visualization of
residual disease may be less reliable after chemotherapy.68
Studies have sought to evaluate whether the degree of
pathologic response to NACT could provide prognostic
information (Table 3).69-76 A number of studies have
confirmed the prognostic value of pathologic complete
response (pCR) after NACT. Among patients treated with
NACT and no residual disease at IDS, Ferron et al showed that
pCR with no viable tumor cells in the surgical specimen
occurred in 14% of patients and was predictive of PFS, but
the degree of histologic response was not.69 A larger study
(322 patients) confirmed pCR (defined as no residual tumor
cells in the surgical specimen) as predictive of both PFS and
OS, whereas a good response not amounting to pCR was
not prognostic.70 Several groups investigated composite
pathologic response scores, incorporating an assessment
of viable tumor cells, fibrosis, inflammatory changes, or
macrocytic infiltration, and have shown conflicting re-
sults using heterogeneous definitions for pathologic re-
sponse (Table 3).71-75,77 A more recent study suggested that a
three-tier histopathologic chemotherapy response score was
reproducible and prognostically meaningful for patients with
HGSOC treated with NACT, regardless of debulking status.76
Complete or near-complete pathologic response (defined as
a chemotherapy response score [CRS] of 3) was associated
with significantly improved PFS (18 vs. 12 months, p , .001)
and decreased risk of platinum-resistant relapse (odds ratio
[OR] 0.08; p , .001) compared with those tumors showing
less in vivo chemosensitivity (CRS scores of 1 and 2).
Although the authors concluded that the three-tier scoring
system may be useful, in fact, outcomes were only different
when considering CRS 3 versus CRS 1/2, making it more of a
two-tier system. In addition, CRS 3 included near-complete
responses defined as residual viable cells, or nodules larger
than 2 mm, and did not predict OS. Although the pathologic
response score may need refining and will require pro-
spective validation, taken together these data suggest that
an evaluation of in vivo response to NACT at the time of IDS
could offer useful prognostic information and may inform
postoperative management. The identification of a che-
motherapy response score to risk-stratify patients would
158 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
allow for optimization of postoperative management, con-
sideration of maintenance treatment, or participation in
clinical trials, with the aim of improving long-term outcome.
The question remains whether the degree of pathologic re-
sponse is prognostic, or whether the only valid surrogate for
OS is pCR strictly defined as no residual cancer cells within the
entire surgical specimen. Studies in breast cancer have shown
that complete response in both primary site and lymph nodes
(occurring in 18% of patients with NACT) is required to
predict a major improvement in OS,78 the biologic explanation
being that pCR is the evidence that other micrometastatic
deposits may have also been eradicated by NACT. In-
terestingly, the correlation between pathologic response and
OS was the strongest for triple-negative breast cancer, a
highly proliferative subtype that shares genetic homology
with HGSOC.
The Neoadjuvant Setting as a Tool to Evaluate
New Regimens
The neoadjuvant design may be useful to test new therapies
in a faster way and with fewer patients than is required for
large adjuvant trials. Given the strong correlation between
pCR and OS in breast cancer, new drugs are being evaluated
in randomized neoadjuvant trials in which the primary
endpoint is an improvement in pCR at surgery.79 pCR rates
are somewhat lower in ovarian cancer than in other tumor
types (6% to 12%), but randomized studies designed to test
the benefit of adding a new agent to standard chemo-
therapy, where the primary objective would be a major
improvement in pCR, could provide a useful signal-finding
strategy for new drugs. The advantages of this approach
are a translational research opportunity to identify pre-
dictive biomarkers and obtaining a rapid answer because
results are available within a few months of the last patient
who was randomly placed. In addition, the neoadjuvant trial
design allows the testing of a novel agent in treatment-naive
patients, as opposed to metastatic studies, where prior
exposure to multiple lines of chemotherapy may distort drug
activity. The U.S. Food and Drug Administration has recently
issued a statement that they will strongly consider evidence
from randomized controlled studies using pCR as an end-
point to allow accelerated approval of novel therapies.80
Although this guidance was designed for trials conducted in
breast cancer, using pCR as an endpoint has the potential to
help address unmet needs in high-risk populations in a far
shorter time frame than would be required via the con-
ventional approach to drug development.79
Translational Research Opportunities
Despite exquisite sensitivity to first-line platinum-based
chemotherapy, HGSOC almost invariably relapses. Yet the
mechanisms underpinning primary or acquired chemo-
therapy resistance are poorly understood (Fig. 3). HGSOC
is characterized by extreme genomic instability and
intratumoral heterogeneity (ITH).81 Inherent genetic in-
stability and ITH provide the ideal setting for adaptation and
 KEEPING THE PEACE AND BALANCING THE BIOLOGY

TABLE 3. Chemotherapy Pathologic Scores Evaluated in Retrospective Studies

Categories of Pathological Response No. of
Reference Score Patients Correlation of Pathological Score and Outcome
Ferron et al69 Group 1: No residual tumor cells 8 3-year PFS: 63% (p 5 .02 vs. groups 2/3)
(58 patients)
Group 2: Persistent disease with marked 14 3-year PFS: 12% (not significant)
changes
Group 3: Persistence of at least one site 36 3-year PFS: 19% (not significant)
with no chemotherapy effect
Petrillo et al70 pCR: No residual tumor cells 21 PFS: 36 months (p 5 .001 vs. micro/macroPR); OS: 72 months (p 5 .018 vs.
(322 patients) micro/macroPR)
MicroPR: Residual tumor foci # 3 mm 104 PFS microPR: 16 months vs. 13 months for macro PR (not significant); OS microPR:
38 months vs. 29 months for macroPR (not significant)
MacroPR . 3-mm foci 197
Le et al71 Score* 1-8: Some chemotherapy effect NA OS: Scores 1-8 vs. score 0 (73 months vs. 39 months; p 5 .14)
(62 patients)
Score 0: No chemotherapy effect NA
Le et al72 Marked/moderate necrosis 36 Improved PFS; HR 0.51; p 5 .048
(73 patients)
Little to no necrosis 37
Le et al73 Chemotherapy effect on omental 58 OS: 84 months
(66 patients) deposits
No omental response 8 OS: 31 months
Muraji et al74 Composite score** G2/3 72 Improved OS; HR 0.61; p 5 .03
(124 patients)
Composite score** G0/1 52
Sassen et al75 No residual tumor cells or foci , 5 mm 7 OS: 46 months; p 5 .02
(49 patients)
Tumor foci . 5 mm 42 OS: 27 months
Bohm et al76 CRS 3: No residual tumor cells or 19 Improved PFS: CRS 3 vs. CRS 1/2, (18 months vs. 12 months;
(71 patients) foci , 2 mm p , .001); OS: CRS 3 (45 months) vs. CRS 1/2 (28 months) not significant
CRS 2: Appreciable response 47
CRS 1: No or minimal response 5
Abbreviations: PFS, progression-free survival; OS, overall survival; IDS, interval debulking surgery; NA, not available; pCR, pathologic complete response; CRS, chemotherapy response
score; HR, hazard ratio; microPR, microscopic pathologic response; macroPR, macroscopic pathologic response.
*Score (0-8) of necrosis, fibrosis, macrophage infiltration, tumor inflammation.
**Composite score 5 degree of disappearance of tumor cells, displacement by necrosis and fibrosis, and inflammatory changes graded from 0 to 3, with G0 being no chemotherapy
effect and G3 being no viable tumor cells.

treatment escape and have been shown to drive the
accelerated acquisition of multidrug resistance.82 Evidence
in HGSOC cell lines suggests that relapse is not caused by
linear acquisition of genetic alterations, but rather to
treatment-induced selection and expansion of intrinsically
resistant clones.83 Most genomic studies to date in HGSOC
have focused on comprehensive analyses of the primary
tumor, but evidence is emerging that a comparison be-
tween matched tumor samples from diagnosis and IDS can
reveal the mechanisms accounting for the acquisition of
resistance in individual patients. For example, an enrich-
ment of ALDH1-positive cells in post-NACT samples has
been demonstrated in some patients and shown to cor-
relate with poor survival post-NACT, suggesting that a
cancer stem cell subpopulation may account for chemo-
therapy resistance.84 Studies among patients with germline
BRCA mutations treated with NACT have shown that, al-
though initial response rates to platinum are high, a subset
shows restoration of BRCA heterozygosity in the post-NACT
sample, suggesting a rapid expansion of subclones without
somatic LOH for the BRCA wild-type allele during
treatment.85
Profiling HGSOC at diagnosis when the bulk of dis-
ease is chemotherapy-sensitive and potentially highly
heterogeneous may be relatively uninformative. However,
identifying chromosomal alterations or somatic muta-
tional events that occur at low frequency at baseline and
are selected for during therapy could uncover new ther-
apeutic strategies to overcome platinum resistance. Given
the intrinsic chemotherapy sensitivity of the majority of
HGSOC, platinum-based chemotherapy will likely always
provide an essential component of the treatment strat-
egy; however, profiling the post-NACT tumor may identify
actionable targets and provide the rationale for sub-
sequent clinical trials testing novel agents as maintenance
therapy in an effort to eradicate the minimal residual dis-
ease post-chemotherapy.
FUTURE DIRECTIONS AND CONCLUSION
The discussed considerations truly underscore the need
for further research on the most appropriate sequence of
care for women with advanced ovarian cancer. Despite
years of debate and two randomized controlled trials,
the question of whether surgery or chemotherapy should
be the primary treatment strategy has yet to be an-
swered. Survival and QOL-related measures are both
of paramount importance because they pertain to

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 159

LEARY ET AL

FIGURE 3. The Neoadjuvant Setting: A Translational Research Opportunity

(A) Fifteen percent of HGSOC cases have refractory disease and progress on NACT. Prognosis is poor and studies are needed to characterize the profile of these primary
resistant tumors and develop effective alternatives to carboplatin and paclitaxel. However, HGSOC is very chemotherapy-sensitive and most show an initial response to
NACT and may progress to IDS. (B) A small subset (5% to 12%) show pCR with no residual tumor cells after NACT. Prognosis is excellent and studies should focus on
finding therapies that increase the proportion of patients achieving pCR. (C) Most HGSOC demonstrate initial sensitivity but despite complete debulking will relapse.
Identification of molecular alterations selectively enriched in these post-treatment tumors may uncover mechanisms of acquired resistance and identify new therapeutic
targets that could eradicate minimal residual disease.
Abbreviations: HGSOC, high-grade serous ovarian cancer; NACT, neoadjuvant chemotherapy; IDS, interval debulking surgery; pCR, pathologic complete response.

overall outcomes. Although we seek to answer these role for NACT in the laboratory and in clinical research.
questions, excellent clinical judgment is necessary to care- Much effort must be made to determine novel ap-
fully and aptly select the appropriate patient for each proaches to the management of this complicated and
treatment regimen. Furthermore, there is a definitive ever-evolving disease.

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GYNECOLOGIC CANCER

Practical Challenges in
Endometrial Cancer

CHAIR
Linda Duska, MD
University of Virginia Health System
Charlottesville, VA

SPEAKERS
Armin Shahrokni, MD, MPH
Memorial Sloan Kettering Cancer Center
New York, NY

Melanie Powell, MD
Barts Health NHS Trust
London, United Kingdom
DUSKA, SHAHROKNI, AND POWELL

Treatment of Older Women With Endometrial Cancer:

Improving Outcomes With Personalized Care
Linda Duska, MD, MPH, Armin Shahrokni, MD, MPH, and Melanie Powell, MD, FRCR, FRCP

OVERVIEW

Endometrial cancer is the most common gynecologic cancer, and with a median age of 62 at diagnosis, it affects a significant
number of older women. With increasing age and obesity rates in the worlds population, there is an anticipated concomitant
increase in older women with endometrial cancer. Older women are more likely to die of endometrial cancer compared with
younger patients. Reasons for this include more aggressive tumor biology, less favorable clinicopathologic features, and
more advanced disease. Other factors, however, such as reluctance to offer surgical treatment to the older patient and
increased complications of treatment are likely to be important. Management of endometrial cancer requires multidis-
ciplinary care (surgery, radiation therapy, and systemic therapy). For each treatment, the feasibility (related to technical
aspect of the procedure/treatment), side effects and safety (related to older-patient factors), and the overall benefit as it
pertains to older women with endometrial cancer should be assessed carefully with a multidisciplinary approach. Despite
the importance of these issues, the data are limited to answer these issues with clarity. In this article, we will review each
treatment modality for older women with endometrial cancer. We will introduce the components of comprehensive
geriatric assessment and their practical implication for older women with cancer in general and older women with en-
dometrial cancer specifically.

E ndometrial cancer is the most common gynecologic

cancer in the United States, with 54,870 cases expected in
2016.1 It is also a cancer of older women, with a median age
at diagnosis of 62.1 As the worlds population ages, we can
expect to see more cases of endometrial cancer in older
women. In particular, the oldest old, or those age 80 or
older, is the segment of the population that will see the
greatest growth in the next 2 decades. In the United States,
the number of residents over age 80 is expected to increase
from 3.3% in 2000 to 5.5% in 2030. At the global level, the
average annual growth rate of persons age 80 or older is
twice as high as the growth rate of the population over age
60 (3.8% vs. 1.9%).2 Obesity is also a considerable risk factor
for developing endometrial cancer, and obesity rates are
rising worldwide, with an associated increase in endometrial
cancer rates.3
Forty percent of women diagnosed with endometrial
cancer are age 65 or older (24%, age 6574; 12%, age 7584;
and 4%, age . 84).1 Notably, most deaths (67%) from en-
dometrial cancer occur in women over 65, with a median age
at death of 70 (28%, age 6574; 24%, age 7584; and 15%,
age . 84). There are a number of explanations that have
been postulated for the increased cancer-specific death rate
in older women, including: more advanced stage at di-
agnosis, higher tumor grade, more aggressive tumor biology,
and a selection bias by providers for less aggressive surgery
and less adjuvant therapy.
The standard-of-care treatment of most patients with
endometrial cancer is surgical and begins with hysterec-
tomy, including removal of the uterus, cervix, and bilateral
fallopian tubes and ovaries. Although the role of complete
lymphadenectomy (removal of bilateral pelvic and para-
aortic retroperitoneal lymph nodes) remains controver-
sial, most U.S. gynecologic oncologists follow the so-called
Mayo criteria with respect to staging and remove lymph
nodes for high-grade and/or deeply myoinvasive tumors.4
Surgery alone may be curative for early-stage, low-grade
disease, with radiation and/or chemotherapy recommended
for adjuvant therapy depending on stage of disease and
histology.
In the older woman, the management of endometrial
cancer may require a more multidisciplinary approach.
Older women are more likely to have high-grade disease,
poor histology, and advanced disease; require adjuvant
treatment; and experience disease recurrence. Gayar et al5
considered 121 patients age 75 and older with apparent

From the Division of Gynecologic Oncology, Obstetrics and Gynecology, University of Virginia School of Medicine, Charlottesville, VA; Memorial Sloan Kettering Cancer Center, Weill
Cornell Medicine, New York, NY; Department of Clinical Oncology, Barts Health NHS Trust, St. Bartholomews Hospital, London, United Kingdom.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Linda Duska, MD, MPH, University of Virginia School of Medicine, P.O. Box 800712, Charlottesville, VA 22903; email: lduska@virginia.edu.

2016 by American Society of Clinical Oncology.

164 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


early-stage disease, specifically considering tumor re-
currence and survival. When compared with patients
younger than age 75, the older patients had higher Fed-
eration Internationale de Gynecologie et dObstetrique
grade, higher stage tumors, more deep myometrial invasion,
and more lower uterine segment involvement. Tumor
recurrence rates were significantly higher in the older
patients (15% vs. 7%) and 5-year disease-specific survival
was 91% versus 96%. Interestingly, in this study, age alone
was not found to be a specific independent predictor of
recurrence or disease-specific survival. However, other
studies have demonstrated that cancer-specific mortal-
ity is higher in older women.6 In the robotic study from
Vaknin et al7 (in which all patients underwent hysterec-
tomy and pelvic node dissection), the elderly group of
patients (age 70 and older) had a higher rate of advanced
disease (39% vs. 18.7%; p = .04); of the eight patients in
the series who had positive nodes, six were older than
age 80.
The limited available data suggest that age alone should
not be a sole decision factor in prescribing treatment,
surgical and otherwise, for older women with endometrial
cancer. Instead, older patients with cancer should be
assessed for their fitness to receive any type of endometrial
cancer treatments. For older patients with (or without)
cancer, a comprehensive geriatric assessment (CGA) can
evaluate their fitness for treatment in much more detail. The
model proposes that older patients (regardless of their age)
who are fit should be offered standard-of-care treatment of
their endometrial cancer, whereas those who are frail re-
quire more extensive discussion about the risks of standard
cancer treatment. Involvement of the patients primary care
provider and/or geriatrician may assist in obtaining a better
understanding of both her overall fitness for treatment and
her goals of care.
In this article, we will discuss the approach to the older
woman with endometrial cancer, taking into account the
complexities of caring for a geriatric population with cancer.
KEY POINTS
Endometrial cancer is the most common gynecologic
cancer among older patients with cancer.
Older women with endometrial cancer are more likely
to be diagnosed with poor prognosis disease (higher
stage or high-risk histology) and more likely to die of
disease compared with younger patients.
Older patients with endometrial cancer are less likely to
be offered surgical therapy, retroperitoneal node
dissection, and adjuvant therapy.
Older patients should not be denied treatment (surgery
or adjuvant therapy) based on age alone.
Involving geriatricians and/or performing
comprehensive geriatric assessment may aid in
treatment decisionmaking.
MULTIDISCIPLINARY CARE OF OLDER PATIENTS WITH ENDOMETRIAL CANCER
We will discuss the holistic approach toward older patients
with cancer (as a part of person-centered care), the role and
outcome of surgery in older patients with endometrial
cancer, radiation therapy considerations in these patients,
and, finally, how CGA can be a useful tool for risk stratifi-
cation, management, and predicting outcomes of older
patients with cancer across the cancer care continuum.
Although a holistic approach such as the one described
below would likely benefit all patients considering cancer
care, it will clearly benefit the geriatric patient who may
suffer untoward effects of an overly aggressive treatment
approach.
HOLISTIC APPROACH TO OLDER PATIENTS WITH
CANCER
Person-centered care is a novel model of care that places
emphasis on the patient as a whole rather than just a
biomedical approach.8 Some of the major principles and
values of person-centered care include caring for the whole
person through a holistic approach, developing an individ-
ualized model of care, and understanding the patients
psychologic, social, and cultural complexity.9 To reach these
goals, person-centered care proposes to develop and en-
hance the connection between medical care and supportive
services and to provide multidisciplinary and team-based
care.
Older patients with cancer will benefit significantly from
person-centered care as a result of the increased complexity
of their care, their unmet needs, and the aging-related is-
sues. The approach begins with CGA. Over the past 2 de-
cades, investigators have developed CGA specific to the
cancer setting. Although there is no one standard instrument
to perform CGA,10 it is important for cancer care providers to
be familiar with the components of CGA (Fig. 1) and some of
the more common instruments, the likelihood of patients
having abnormal findings, the practical implications of such
findings, and the proper solutions (Table 1).
SURGERY IN THE OLDER WOMAN WITH
ENDOMETRIAL CANCER: SAFETY AND
FEASIBILITY
The goals of any medical or surgical intervention in the older
age group should be to maintain or maximize the potential
life span, maximize independent function, relieve suffering,
and maintain dignity. Although most modern series suggest
that surgery is feasible in the older woman, it is not without
morbidity. The older patient with endometrial cancer,
variably defined with respect to age parameters, appears to
suffer more postoperative morbidity than her younger
counterpart, regardless of surgical approach. There is also
morbidity from general anesthesia, required for all mini-
mally invasive procedures (but potentially avoidable in the
vaginal approach, which may be performed in some cases
under regional anesthesia). Physiologic changes associated
with increasing age must be considered, including reduced
ability to increase cardiac output, decreased capacity of the
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 165
DUSKA, SHAHROKNI, AND POWELL
FIGURE 1. Components of a Comprehensive Geriatric Assessment
respiratory system with reduced lung elastic recoil and in-
creased chest wall stiffness, decreased functional reserve,
and skin changes that may impact wound healing. These age-
related physiologic changes along with the medical
comorbidities that accompany aging must be carefully
considered when planning a surgical procedure.
In the relatively recent past, surgery for endometrial
cancer was traditionally performed via laparotomy, allowing
for complete removal of the uterus, cervix, and bilateral
tubes and ovaries along with a complete retroperitoneal
lymphadenectomy. With improvement in optics and
instrumentation, a minimally invasive approach became
more acceptable, and in fact became standard of care with
the publication of LAP2, a Gynecology Oncology Group
(GOG) study that compared oncologic outcomes between
laparotomy and laparoscopy in women with endometrial
cancer.11 The approval of the robotic system in the United
States in 2005, with its increased magnification, three-
dimensional optics, and wristed instruments, resulted in
an increased percentage of endometrial cancer procedures
performed via a minimally invasive approach. Finally, the
American Congress of Obstetrics and Gynecology has en-
dorsed the vaginal approach as the optimal approach for
benign hysterectomy; although this method does not always
allow removal of the tubes and ovaries and never allows
assessment of the retroperitoneal lymph nodes, it may be an
appropriate alternative for a patient who is too frail for an
abdominal operation and general anesthesia.
Several retrospective studies have addressed the safety of
surgery for endometrial cancer in the older woman. DeMarzi
et al12 analyzed operability, perioperative morbidity, and
mortality in 124 women age 65 and older who were un-
dergoing either open laparotomy or vaginal approach for
hysterectomy. For statistical purposes, the authors divided
the patients into younger than age 75 and 75 or older. Not
surprisingly, the vaginal approach was used more often in
the older patient group. Overall perioperative complication
166 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
rate was 13.1%, with the older group more likely to have
postoperative complications (23.1% vs. 8.5%). There were
no postoperative deaths. In a logistic regression model, age
75 or older, chronic lung disease, and the performance of
lymphadenectomy (discussed further below) correlated
with higher probability of perioperative morbidity. The
authors concluded that older patients should be offered
surgical treatment given the survival advantage associated
with surgery.
Other authors have also demonstrated the safety of
hysterectomy with or without lymphadenectomy in the
older population of patients. These studies are discussed
further below. It is notable, however, that in most of these
studies, the perioperative complication rate for the older
group of patients was higher than that of the younger group.
Perhaps more importantly, by their retrospective nature and
study design, these studies only report those women who
were felt to be good surgical candidates; they do not provide
information regarding patients who were not offered sur-
gery as a primary approach to cancer treatment.
Laparoscopy
Laparoscopy is the preferred surgical technique to lapa-
rotomy for endometrial cancer for multiple reasons, in-
cluding shorter hospital stay, shorter recovery period, less
discomfort (and therefore less use of postoperative narcotic
medications), and potentially improved quality of life. In
contrast to these benefits, laparoscopy requires longer
operating room (OR) time and steep Trendelenburg posi-
tioning, aspects of surgery that may be particularly difficult
for the older patient.
The LAP2 study was the first randomized study in the
United States to compare open laparotomy to laparoscopy
for the surgical treatment of endometrial cancer and
was a major impetus for the transition to minimally invasive
surgery for endometrial cancer in the United States.11 The
study was sponsored by the GOG, and patients were enrolled
 MULTIDISCIPLINARY CARE OF OLDER PATIENTS WITH ENDOMETRIAL CANCER

TABLE 1. Instruments and Practice Implication of Comprehensive Geriatric Assessment Components

Likelihood of
Component Instrument Description of Instrument Abnormality Practical Use Solution
Functional Activities of Daily Assesses patients ability to do bathing, dressing, 15%20% Could lead to malnutrition, dif- Assessing caregiver ability to
Activity Living grooming, feeding, walking, and bladder and ficulty to present to health take care of patients
bowel control care provider office needs
Involving social worker for
further support
Instrumental Activi- Assesses patients ability for telephone use, doing Up to 50%52 Could lead to malnutrition, lack Assessing caregiver ability to
ties of Daily Living laundry, shopping, preparing meals, doing of compliance with medica- take care of patients
housework, handling own medications, han- tions, difficulty to present to needs
dling money and finances, and transportation health care provider office
Involving social worker for
further support
Falls Number of falls in the past 6 or 12 months Up to 25%50 May lead to bone fracture, Referral to physical therapy
leading to interruption in Further exploration of the
cancer care context of falls
May need to avoid neurotoxic Assessment of patients
chemotherapy agents if falls medication list for
are a result of neuropathy sedatives
Use of assistive Not applicable Up to 25%53 May be suggestive of patients Referral to physical therapy
device history of falls, imbalance, or
fear of falling
Sensory deficit Observation, physical exam Hearing deficit Could lead to decline in quality of Referral to audiologist and/or
(hearing, vision) $ 33%54 life and cognitive function; ophthalmologist
patient may not hear the
medical instructions properly
May need to avoid ototoxic
chemotherapy agents
Emotional Geriatric Depression It has 30-, 15-, and four-item versions 10%65%57 Patients with depression could Explore the reasons for
Well-being Scale55,56 be at higher risk for receiving depression
(Depression) nondefinitive treatment and
worse overall survival58,59
Hospital Anxiety and Seven items related to depression and seven It increases the risk of being Refer to psychologist/
Depression items related to anxiety nonadherent to medical psychiatrist
Scale62 treatment60
Patient Health It has nine-, four-, and two-item versions Could be suggestive to multiple If depression is result of lack
Questionnaire63,64 other geriatrics deficits61 of proper social support,
refer to social worker
Emotional Distress Patient rates his/her distress level over the past About 40%66 It is usually suggestive of unmet More and better patient-
Well-being Thermometer65 two weeks from 010. Score of $ 4 is sug- needs66 physician communication
(Distress) gestive of high level of distress. could lower the distress
level67
Referral to social worker,
mental health service, and/
or chaplaincy service68
Social Support Medical Outcome Available in 19-, 12-, and four-item versions The exact likeli- Could be associated with more Referral to social worker
Study-Social Sup- hood of ab- psychosomatic symptoms72,73 might be needed
The 19- and four-item versions measure four
port Survey6971 normality is
social support domains: emotional, tangible,
unknown
affectionate, and positive social interaction.
Multidimensional 12-item questionnaire that categorizes patients Could be associated with worse Empower the limited but
Scale of Perceived social support into support he/she receives overall survival74,75 available social support for
76
Social Support from family, friends, and significant other the patient
Nutritional Mini-Nutritional Available in six-item questionnaire with the score Up to 65% could It could be multifactorial (dis- Referral to nutritionist
Status Assessment77 of 014 be at risk for ease progression, fatigue, al-
malnutrition78 tered taste, inability to
prepare meals, etc.)
Score of 811 is suggestive of being at risk for Patients with malnutrition have Explore other reasons for
malnutrition, and score of # 7 is suggestive of worse overall survival79 malnutrition besides can-
malnutrition. The longer version includes cer progression and/or
additional questions and the score ranges from side effects from
030. Score of 1723.5 is suggestive of being chemotherapy
at risk for malnutrition, and score of # 17 is
suggestive of being malnourished.

Continued

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DUSKA, SHAHROKNI, AND POWELL

TABLE 1. Instruments and Practice Implication of Comprehensive Geriatric Assessment Components (Contd)
Likelihood of
Component Instrument Description of Instrument Abnormality Practical Use Solution
Polypharmacy/ Beers criteria80 List of medications that could harmful for older Could be as Could lead to prolonged Referral to pharmacist
Potentially patients. The recommendations for harmful high as 50%81 hospitalization82
Inappropriate medications are categorized into avoid, and
Medication use with caution.
Polypharmacy Taking $ 5 medications is considered Could lead to drug-drug inter- Review medication list
polypharmacy83 action, noncompliance, and
increase in cost51
Taking . 10 is considered excessive Discontinue nonessential
polypharmacy47 medications, especially in
patients with limited life
expectancy
Check for drug-drug
interaction
Cognitive Mini-Cog84 Short instrument that takes about 2 to 3 minutes. About 20%,78 Patients could be at higher risk Referral to geriatrician, neu-
Status It includes three-word recall and clock but it varies by for delirium during hospital rologist, psychiatrist, or
drawing. age group stay43,85 neuropsychologist
Mini-Mental Status Administration of the test takes longer. It as-
Examination sesses cognitive domains of orientation, reg-
(MMSE)86 istration, attention and calculation, recall and
language.
Montreal Cognitive Administration of the test takes longer than
Assessment87 MMSE. It assesses visuospatial, naming,
memory, attention, language, abstraction,
delayed recall, and orientation of patients.
Blessed Orientation- Takes 10 minutes to administer. It has 26 ques-
Memory-Concen- tions and tests orientation, long-term mem-
tration test88 ory, recall, and concentration.
Comorbidity Charlson Comorbid- It is a method of categorizing comorbidities (a Varies by age Impacts overall survival90 Referral to primary care pro-
ity Index89 total of 22 conditions) based on the Interna- vider/geriatrician for opti-
tional Classification of Diseases, which can mizing comorbid condition
predict the 10-year mortality management
Adult Comorbidity It is a validated chart-based comorbidity It may negatively impact com-
Evaluation 2793 instrument pliance with cancer
treatment91
Each individual comorbid condi-
tion may have negative out-
come on survival92

from multiple sites across the United States. Notably, entry
into LAP2 required a laparoscopic lymphadenectomy as part
of the surgical staging procedure. Thirty-one percent of
patients in this study were age 70 or older, and 6.6% were
80 or older. Conversion to laparotomy occurred in 25.8%
of patients. Failure to successfully complete laparoscopy
was greater with increasing age (odds ratio 1.27; 95% CI,
1.141.42 for a 10-year increase in age), but the reasons for
this finding are not clear. Additionally, operating time was
significantly longer in the laparoscopy arm (204 vs. 103
minutes). The longer operating time is significant in the older
age group, in part because longer duration of anesthesia may
be associated with postoperative delirium, particularly in
patients with a pre-existing cognitive defect. There was
statistically significantly better quality of life across many
parameters in the laparoscopy arm at 6 weeks, but age was
not specifically considered as a factor for quality of life.13
Multiple single-institution studies have suggested that a
laparoscopic approach is safe in the older patient. Two
Italian studies found that laparoscopy was safe and feasible
and associated with lower blood loss, shorter hospital stay,
and lower complication rates. 14,15 It should be noted,
however, that in the study from Bogani et al,15 lymphade-
nectomy was not generally performed in the oldest patients.
In contrast, in the retrospective review of women age 65 and
older from Oklahoma, a more aggressive approach to
lymphadenectomy was undertaken. Sixty-seven women
underwent either laparoscopic hysterectomy or lapa-
roscopically assisted vaginal hysterectomy with lymphade-
nectomy. Laparoscopy was successful in 78% percent of
cases, and a complete node dissection was successfully
performed in all patients. Of note, the laparoscopic group
had a longer OR time than the comparison laparotomy group
(236 vs. 148 minutes). Despite the longer OR time, the
authors note there was no subsequent increase in morbidity
and mortality.16
Robotic Surgery
Robotic surgery, approved in the United States in 2005,
provides advantages over traditional laparoscopy, but there
are also patient-related drawbacks: in particular, once the
robot is docked, the patient must remain in steep Tren-
delenburg position. Prolonged Trendelenburg poten-
tially increases the potential risk of blindness in patients

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suffering from moderate- or high-pressure glaucoma17 and
may particularly impact the older patient with respect to
ability to ventilate and cardiac output.
Despite these concerns, several series suggest that ro-
botic surgery is safe and effective in the older patient, albeit
with a possible increased perioperative morbidity.1820 The
series from Guy et al, 18 for example, demonstrated in-
creased rates of perioperative surgical and medical com-
plications in the older age group with robotic surgery when
compared with younger patients with the same procedure.
Specifically, older patients had higher rates of periop-
erative surgical (8.3% vs. 5.2%; p , .001) and medical
(12.3% vs. 6.7%; p , .001) complications, longer length of
stay (2.00 vs. 1.67 days; p , .001), and lower rates of
discharge to home (88.8% vs. 96.8%; p , .001). As age
increased, perioperative surgical and medical complica-
tions also increased in a linear fashion. In contrast, in the
series of 41 women 70 and older from the series by Vaknin
et al,7 older and younger patients had the same rate of
postoperative complications. It is clear, however, that the
robotic approach is preferable to the open approach in the
older population. When compared directly to laparotomy,
the robotic approach was preferable for women age 70 or
older, with a decrease in complication rates, surgical blood
loss, and hospital stay.19
Lymphadenectomy
The role of lymphadenectomy in endometrial cancer con-
tinues to be one of some controversy, particularly in the
older patient. There is no doubt that adding lymph node
dissection will increase operating time as well as the po-
tential for perioperative morbidity. In the series by de Marzi
et al,12 performance of lymphadenectomy significantly in-
creased the rate of postoperative complications, but other
studies suggest that lymphadenectomy is safe in the older
patient.16,20 Although all patients in the study by Scribner
et al16 were staged, this practice led to a high conversion rate
to laparotomy and increased OR time. Other studies have
confirmed that staging procedures in elderly patients are
associated with a significantly longer operating time.21
Further studies are needed to weigh the benefits of lym-
phadenectomy on overall survival versus the potential
complications in this group of patients.
Surgery for the Older Patient With Cancer: Is There a
Bias?
Population database studies suggest that there is a selection
bias with respect to performing surgery for older patients,
both for hysterectomy and lymph node dissection. With
respect to hysterectomy specifically, two different SEER
analyses demonstrated that older patients with endometrial
cancer were less likely to have a hysterectomy.6,22 In the
study from Ahmed et al,22 a survival analysis was done within
each age group to compare the endometrial cancer-specific
survival rate of those who received cancer-directed surgery
(hysterectomy at a minimum) to those who did not. They
found a significant reduction in the hazard ratio (HR) for
MULTIDISCIPLINARY CARE OF OLDER PATIENTS WITH ENDOMETRIAL CANCER
cancer-specific death when cancer-directed surgery was
undertaken within each age category, adjusted for radiation
therapy, histology, and stage. Rauh-Hain et al23 performed a
similar analysis using the national cancer database, although
this group only considered women with advanced stage
(stage III or IV) disease and also demonstrated that elderly
women were less likely to be treated with surgery. Patients
younger than age 55 had surgery more frequently compared
with patients age 75 to 84 (97.2% compared with 95.8%;
p , .001) and age 85 or older (97.2% compared with 94.8%;
p , .001) and a higher rate of lymph node dissection (78.7%
compared with 70.5%, p , .001; and 78.7% compared with
59.5%, p , .001, respectively). In a multivariate analysis,
which took into account medical comorbidities as well as
adjuvant therapy, older women also had a higher risk of
death when compared with women younger than age 55
(women age 7584, HR 2.38; 95% CI, 2.142.65; women age
85 or older, HR 3.16; 95% CI, 2.763.61).
In contrast to the population-based studies above, most
single-institution studies from tertiary care centers, re-
ported in large part by gynecologic oncologists, suggest that
all patients should be offered surgery, regardless of age.
These types of retrospective reviews represent a selection
bias of sorts and by study design do not account for those
women who were never offered surgery. They do suggest,
however, that gynecologic oncologists may be more likely to
offer surgery to older women with endometrial cancer than
other providers.
It is also important to note that database studies by their
very nature cannot provide us with data regarding medical
comorbidities affecting the elderly or the desires of the
patient and her family regarding goals of care. In the study by
de Marzi et al,12 for example, three women in their late 80s
declined surgery; this patient decision to decline an offered
surgery would not be captured in a population-based da-
tabase study. Nevertheless, the studies point to an alarming
trend, confirming the national bias toward not offering
surgery to the older patient with endometrial cancer, re-
gardless of fitness.
Both population-based studies and institutional studies
suggest an age bias regarding lymph node dissection. In the
SEER study from Wright et al,6 older women were less likely
to have lymph node dissection performed when compared
with women age 65 to 69 (43.5% for women age 6569,
37.5% for age 8084, and 24.8% for women 85 and older).
Lowery et al20 reported similar results in their SEER analysis,
with lymph node dissection performed in 41% of the age 80
or older population. Institution-based studies from Europe
reveal similar results. For example, in the study by de Marzi
et al,12 lymphadenectomy was performed more often in
younger patients (84.5% in women younger than 75 vs.
15.5% in women 75 and older). Bogani et al15 noted that we
usually omit execution of retroperitoneal staging in this
group. In contrast, single-institution studies from the
United States report higher node staging rates in older
patients. This aggressive approach to lymphadenectomy,
however, is not without morbidity.
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DUSKA, SHAHROKNI, AND POWELL
In summary, surgery should be considered as a first step
for an older patient, if that patient is deemed medically fit. A
minimally invasive approach appears to be safe and offers
the best postoperative recovery despite longer operating
times. The role for complete lymphadenectomy is still
controversial, particularly in the population of older women,
and should be individualized; however, the plans for adju-
vant therapy should also be considered when planning the
surgical procedure.
RADIOTHERAPY FOR ENDOMETRIAL CANCER IN
THE OLDER PATIENT
Radiotherapy remains an essential component of the
treatment of both early and locally advanced endometrial
cancer. Over the past decade, data from large randomized
controlled trials have established the place of radiation in
adjuvant treatment of uterine cancers. Risk groups based on
clinicopathological factors have been devised to identify
those patients who might benefit most from additional
treatment (Table 2). In the older patient, in whom age itself
is a risk factor, the use of pelvic radiotherapy needs to be
considered carefully, balancing the advantage of high local
control rates with potential toxicity and lack of survival
benefit.24,25
Although initially slow to integrate new three-dimensional
radiotherapy planning techniques into routine treatment,
the gynecology oncology community has now embraced the
technology, and intensity modulated radiotherapy (IMRT),
volumetric modulated arc therapy (VMAT), and image-
guided radiotherapy are in widespread use. IMRT uses
multiple beams divided into smaller beamlets of varying
dose intensity, allowing more accurate shaping of the de-
livered dose to the target. This technique has been shown in
theoretical planning studies to reduce the dose to nearby
organs such as bowel and bladder by up to 60%26 and
translates to a reduction in both acute and late radiation
toxicity.27,28 The reduction in toxicity is likely to be especially
beneficial in an elderly population who have a higher in-
cidence of underlying bowel and bladder problems with
urgency and incontinence often present.
One of the downsides of IMRT is the high number of
monitor units needed to deliver the plan compared with
old-fashioned conventional treatment (estimated to be
two to three times higher), which leads to an increase in
lower dose radiation to other parts of the body. The
long-term effect of IMRT is not known, but the potential
TABLE 2. Suggested Radiotherapy by Risk Group
Low Risk Intermediate Risk
IA G1, G2, 1B G1 without LVSI 1A G3, IBG1 or 2, with LVSI
No treatment94 Vault brachytherapy95
Risk of relapse is 10% Brachytherapy will decease vaginal recurrence rate to 2%
Survival exceeds 95%
Abbreviation: LVSI, lymphovascular space invasion.
170 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
increased risk of second malignancy cannot be ignored
and is of particular significance when even older patients
may be expected to have a life expectancy exceeding
10 years.
A newer technique that provides similar highly conformal
radiation fields uses a continuous rotation of the radiation
source through 360 degrees. The advantage of this arc
technique is twofold. First, the speed of delivery is much
faster compared with IMRT. A typical pelvic field of two full
arcs might be delivered in less than 5 minutes. This is more
comfortable for patients, particularly the elderly, who
sometimes find it difficult to hold a full bladder. It may
thereby reduce the potential for inaccuracy as a result of
movement and also allow faster throughput in the working
day. Second, the number of monitor units required to deliver
arc treatment is approximately two-thirds that of IMRT,
leading to a lower total dose delivered to the patient.
Pelvic insufficiency fractures occur when the elastic re-
sistance of bone is reduced and unable to withstand the
stress of weight bearing and are most frequent in older
women with postmenopausal osteoporosis. Pelvic radiation
is also a recognized cause of pelvic insufficiency fractures
and, although not always symptomatic, may give rise to
significant pain. VMAT and IMRT, with careful planning to
avoid areas such as the sacrum, may reduce the incidence of
fractures, which is estimated to occur in up to 50% of pa-
tients who undergo pelvic radiotherapy.29,30
The integration of three-dimensional imaging into radio-
therapy and the use of intensity modulated radiation to
produce radiation treatment plans that maximize dose to
tumor while minimizing dose to normal tissues has been a
major step forward in radiotherapy. But it has also revealed
the uncertainties that exist in affirming that we are actually
treating what was intended. With shaping of fields and the
steep dose gradients around target, it has become more
important than ever to avoid a geographical miss of the
target either by not correctly identifying the target or
through internal organ movement. Delivering this highly
focused radiotherapy places the onus on the radiation on-
cologist to ensure accurate delineation of the radiation
target. Courses and online training aids have been de-
veloped, and atlases, comprising serial axial CT or MRIs with
anatomy clearly labeled, are now widely available to help the
oncologist.31,32 In particular, variation in bladder filling and
rectal dimensions, as a result of either gas or feces, may
have a significant impact on the position of the vagina and, if
present, the uterus and cervix. In elderly patients in whom
High Risk
1A G3 LVSI, IB G3, II, III
Pelvic radiotherapy94,96

constipation and or bladder weakness is often an issue,
careful consideration is needed as to how best to ensure
consistency in rectal and bladder dimensions on a day-to-day
basis. Daily use of enemas, which is advocated by many, is
not always appropriate for older patients who may find it
physically challenging to administer the enema and manage
the result. For all patients undergoing pelvic radiotherapy,
whether old or young, choosing an appropriate margin
around the clinical target volume has become as critical to
success as actually delineating the original target and must
be sufficient to avoid missing the target but not so large as to
lose the advantage of reducing the volume of normal tissue
irradiated.
In the past, simple kilovoltage imaging was the mainstay of
treatment verification. Its major limitation is that it only
displays bony anatomy. Although this is helpful in providing a
rapid check that the patient is correctly aligned, it gives no
indication as to how the target is positioned relative to the
radiation field. More sophisticated on-board CT imaging
features almost all modern linear accelerators, allowing real-
time visualization of not just bony landmarks but also other
internal structures and even tumors.
Many studies have been published looking at movement
of pelvic organs during a course of radiotherapy and
guidelines suggested on suitable margins to account for day-
to-day change in bladder and rectal filling.33,34 These mar-
gins, which are based on population data, are necessarily
generous, as allowance must be made for the largest move-
ment possible. So, although they are a practical way of ensur-
ing target coverage, they potentially lead to larger treatment
volumes and in particular more normal tissue likely to be
irradiated.35
Daily individualized image-guided adaptive radiotherapy is
the best way to ensure both accuracy of delivery and re-
duction of total volume irradiated. This has been made
possible with the ready availability of cone beam CT scanning
on linear accelerators, allowing a CT scan of the radiation
field to be obtained in just a few minutes immediately before
radiation that can then be merged and compared with the
original planning scan. Daily variation in organ movement
can be partly accounted for by creating a so-called library of
plans using differing margins around the target. Each day a
plan can be selected that is the best fit. This has been used
with some success in bladder cancer radiotherapy.36,37
Taking a daily cone beam CT with real-time review and
selecting a suitable plan on every patient requires time and
highly trained individuals. Most busy radiotherapy depart-
ments are short of one or both and cannot offer this approach
for all.
Older age confers an additional risk factor in uterine
cancer, and careful consideration should be given to offering
adjuvant treatment to this group. Modern radiation tech-
niques have given us treatment that is better tolerated with
improved delivery with significantly less severe acute and
late toxicity. These techniques combined with good medical,
nursing, and psychosocial support should mean that age
need not necessarily be a barrier to radiation.
MULTIDISCIPLINARY CARE OF OLDER PATIENTS WITH ENDOMETRIAL CANCER
THE UTILITY OF COMPREHENSIVE GERIATRIC
ASSESSMENT ACROSS ENDOMETRIAL CANCER
CONTINUUM
An approach toward whole care for the older patient with
cancer is critical for delivering best quality of care. Data on
older patients with endometrial cancer are just emerging;
however, data on older patients with various cancers in
different phases of their treatment prove the importance
of such an approach. Although health care providers rely
on standard methods of assessing functional status (e.g.,
Karnofsky performance status or American Society of An-
esthesiologists classification), CGA has been shown to be
complementary to standard assessment.38 Shared decision-
making among patients, families, and health care providers
may be impacted in up to 40% of cases as a result of new
information through performing CGA. Comprehensive ge-
riatric assessment can predict surgical complications, length
of stay, and hospital disposition following surgery, hospital
readmission, and overall survival.3941 Older patients with
cancer with cognitive deficits could be especially at high risk
for delirium, which can lead to prolonged hospital stay and
possibly poorer overall survival.40,42,43 Despite these data,
only 6.4% of surgeons use CGA in their preoperative eval-
uation, and only one out of three surgeons collaborates with
geriatricians to optimize care of older patients with cancer
preoperatively.44
Various models of collaborative care between geriatricians
and/or geriatric-allied health care professional and surgical
services have been proposed.45 Although the effectiveness
and sustainability of these models must be further exam-
ined, the importance of performing CGA in the preoperative
evaluation and acting proactively based on findings by in-
corporating different supportive services (e.g., physical
therapy, nutrition) is clear. As a result of these findings, the
American College of Surgeons and the American Geriatrics
Society have issued a best practice guideline to incorporate
geriatric assessment in the preoperative assessment of older
patients undergoing surgery to fully assess older patients for
their fitness to undergo surgery.46
For older patients with recurrent or metastatic endome-
trial cancer in need of chemotherapy, CGA has significant
value. Two major chemotherapy toxicity calculators (Cancer
and Aging Research Group47 and the Chemotherapy Risk
Assessment for High-Age Patients48) have developed based
on the concept of CGA. Although these two calculators can
be useful for oncologists, patients, and their families to
understand the risk of chemotherapy toxicity in older pa-
tients with cancer, the exact intervention based on this
finding is not clear. One approach would be to modify the
chemotherapy regimen for a patient at high risk for de-
veloping chemotherapy toxicity; however, another ap-
proach could be to involve and empower the primary care
provider/geriatrician to monitor these patients more in-
tensively for early and accurate detection of chemotherapy
toxicity and acting promptly and adequately to manage
these toxicities. Although these calculators are useful to give a
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 171
DUSKA, SHAHROKNI, AND POWELL
broad overview of patients risk for chemotherapy toxicities, it
is important to note any geriatrics deficit could be associated
with adverse outcomes and needs proper intervention.47,49
Moreover, CGA can help with selecting the proper che-
motherapy agent. For example, selecting a neurotoxic
chemotherapy agent for treatment of metastatic endome-
trial cancer when the patient has fallen multiple times as a
result of neuropathy secondary to poorly controlled di-
abetes may not be in the best interest of an older patient
with metastatic endometrial cancer. The need for in-
corporating CGA in daily oncology practice becomes much
more important when one study showed that only 10% of
patients who reported falls during CGA (performed as a
research tool) had a documented history of falls in their
medical chart by medical oncologists.50
For older patients with endometrial cancer who require
oral hormone therapy, the issue of polypharmacy needs to
be addressed, as polypharmacy could be associated with
lower compliance rate and drug-drug interaction.51 Referral
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GYNECOLOGIC CANCER

Symptom Management for the

Patient with Gynecologic Cancer

CHAIR
Linda Van Le, MD
The University of North Carolina at Chapel Hill
Chapel Hill, NC

SPEAKERS
Deborah Mayer, RN, PhD, AOCN, FAAN
University of North Carolina at Chapel Hill School of Medicine
Chapel Hill, NC

Mary McCormack, BSc, MSc, PhD, MBBS, FRCR

University College Hospital
London, United Kingdom
VAN LE AND MCCORMACK

Enhancing Care of the Survivor of Gynecologic Cancer:

Managing the Menopause and Radiation Toxicity
Linda Van Le, MD, and Mary McCormack, BSc, MSc, PhD, MBBS, FRCR

OVERVIEW

It is expected that there will be 290,000 cases of gynecologic cancers in 2016. Of these cancers, 60,000 will be endometrial and
22,000 will be ovarianthe two most common gynecologic cancers. Endometrial and ovarian cancers occur in menopausal
women with mean ages of 60 and 63, respectively. The majority of endometrial cancers are early stage, and 5-year survival is
considered good at upwards of 75%. For ovarian cancer, while survival rates have improved, the 5-year survival rate for the
most common stage (stage III) is 40%. Thus, a substantial number of patients with gynecologic cancer are menopausal, and
a significant number of patients are survivors, particularly of endometrial cancers. It will be important for survivors of
gynecologic cancers to receive care tailored to their needs as women and to mitigate gender-specific side effects of their
cancer treatment.

A ccording to the National Cancer Institute, an individual is

considered a cancer survivor from the time of diagnosis
through the balance of his or her life. The American Society
of Clinical Oncology (ASCO) endorses the importance of
survivorship care, broadly defined as care tailored to the
survivor.1 ASCO defines four components of survivorship
care: prevention and detection of new cancers and recurrent
cancer, surveillance for recurrence or new other primary
cancers, intervention for long-term and late effects from cancer
treatment, and coordination between specialists and primary
care providers to optimize survivor care.2 In the United
Kingdom, the National Cancer Survivorship Initiative, an ini-
tiative of the 2007 cancer reform strategy, was created to
support those living with and beyond cancer. In this article,
we address two important aspects of survivorship care for
women with gynecologic cancer: management of menopause
needs and care for the patient who has received radiation.
MANAGEMENT OF MENOPAUSE FOR PATIENTS
WITH CANCER
Menopause is the cessation of menstrual periods that occurs
at a median age of 52. Menopause occurs because of atresia
and dissolution of the original number of millions of oocytes
found at birth. For 5% of women, menopause may occur
after the age of 55 or between the ages of 40 and 45.
Menopause is officially declared after 12 months without
menses. The two most common symptom groups are va-
somotor symptoms (VMS) and genitourinary symptoms of
menopause (GSM).3
Vasomotor symptoms (hot flashes) occur in up to 80% of
postmenopausal women. A hot flash is characterized by
development of heat in the torso and face that disseminates
to the rest of the body. These last 2 to 4 minutes and are
associated with sweating, followed by chills. Hot flashes can
continue for years after menopause (mean 7 years), with a
minority of women continuing to have hot flashes beyond
10 years.
A second major area of discomfort for menopausal women
is GSM, which includes vulvovaginal atrophy and urinary
tract dysfunction. In the absence of circulating estrogens,
the vulva and vagina epithelium lose elasticity, and the
epithelium thins. Symptoms associated with this include
burning, pain, dyspareunia, development of vulvar fissures,
and introital narrowing. Women may be chronically un-
comfortable or uncomfortable at the time of intercourse.
Sexual activity and satisfaction may be diminished. Urinary
symptoms include dysuria and urinary frequency, and re-
current urinary tract infections may develop in patients
resulting from decreased integrity of the bladder epithelium.
Genitourinary symptoms of menopause may occur without
systemic vasomotor symptoms.
Other symptoms associated with menopause include
sleep disturbances (occurring independent of hot flashes),
depression, sexual dysfunction, joint pain, and cognitive
changes attributable to anxiety and depression. Physiologic
changes associated with menopause include bone loss and in-
creased risk of cardiovascular disease. The data supporting de-
velopment of dementia, arthritis, changes in body configuration,

From the Division of Gynecologic Oncology, University of North Carolina School of Medicine, Chapel Hill, NC; University College Hospital, London, United Kingdom.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Linda Van Le, MD, The University of North Carolina at Chapel Hill, Campus Box 7572, P.O. Box B103, Chapel Hill, NC 27599-7572; email: lvl@med.unc.edu.

2016 by American Society of Clinical Oncology.

e270 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


skin changes, and balance have not been definitively shown
to be attributable to menopause. There are no indications
for hormone treatment of prevention or protection of other
health risks such as cardiovascular disease or colon cancer.
For patients with cancer, menopause can be accelerated
as a result of cancer treatment, including chemotherapy,
radiation therapy, and surgery. Various chemotherapy drugs
potentially induce ovarian failure, either temporarily or
permanently. A prime example is the alkylating drug cy-
clophosphamide. The breast cancer regimen cyclophos-
phamide, methotrexate, and fluorouracil is known to induce
amenorrhea in 70% of patients. Younger patients may re-
cover ovarian function, whereas older patients are less likely
to do so. Pelvic radiation therapy is particularly toxic to the
ovaries. Although uncommon, young patients with ovarian
cancers and some patients with breast cancer will require
oophorectomy for successful treatment and will experience
menopause prematurely.
Treatment
Vasomotor symptoms can cause considerable discomfort
and affect quality of life. For mild symptoms, lifestyle
changes may suffice. Patients can wear light nightgowns, use
lighter bedding and cooling fans, drink cool water, and turn
down the thermostat at night. For patients with moderate to
severe VMS, estrogen replacement is the most effective
treatment. Hot flashes decrease by 75% compared
with 30%50% seen with administration of a placebo. For
patients without a uterus, estrogen treatment alone will
suffice. For patients with a uterus, addition of a progestin is
recommended. Currently, it is recommended that hormones
be offered to the immediately menopausal or younger
women requesting treatment of symptom relief. The En-
docrine Society recommends treating symptomatic women
if they have experienced menopause within 10 years or are
younger than age 60, and are without health concerns such
as cardiovascular disease or stroke.4 For patients with
cancer, there will occasionally be younger patients in need of
treatment. The Womens Health Initiative did not include
KEY POINTS
Vasomotor symptoms and genitourinary symptoms of
menopause affect up to 80% of postmenopausal women
and diminish quality of life.
Patients with hormone-dependent cancers should be
offered nonhormonal treatment first.
Gastrointestinal symptoms are the most common side
effect of pelvic radiotherapy, with up to 50% of patients
experiencing some form of late toxicity.
Urologic adverse events are more modest; however,
they increase over time.
The most common side effects resulting from
pelvic radiation therapy are pelvic insufficiency
fractures.
SURVIVOR CARE FOR THE PATIENT WITH GYNECOLOGIC CANCER
study of this group, however, it is extrapolated that hormone
replacement is similarly safe for the younger patient. Risks of
combined estrogen and progestin replacement include a
slightly increased risk of breast cancer, coronary artery
disease, stroke, and venous thromboembolism (VTE). When
estrogen alone is administered, only an increased risk of
thromboembolic events is observed without risk of car-
diovascular disease or breast cancer.5,6
There is a wide variety of choices for treatment of VMS.
Oral replacement is associated with higher levels of circu-
lating estrogen metabolites than estrogens administered via
other routes. Transdermal and cutaneous (gel or spray)
formulations are also available and felt to be as effective.
There is a benefit to a transdermal approach, which delivers
estrogen directly to the systemic circulation and bypasses
liver processing (first-pass effect); the transdermal formu-
lations do not result in a procoagulant affect and also do not
affect binding globulins, triglycerides, and C-reactive protein.
Patients with a uterus require addition of a progestin to de-
crease the risk of endometrial neoplasia. Progestins are also
available for transdermal, vaginal, or intrauterine delivery.
Duavee is a conjugated estrogen combined with bazedoxifene, a
selective estrogen receptor modulator (SERM). This drug pre-
vents hot flashes and bone loss. Bazedoxifene counteracts the
stimulatory effect of estrogen on endometrium and is not
expected to stimulate endometrial hyperplasia. Its effect on
breast and uterine cancers is unknown, and, as such, use of
Duavee is contraindicated for these patients. The overall rec-
ommendation for estrogen or estrogen/progestin treatment is
to use the lowest dose possible, and there is evidence that this is
effective for treatment of VMS.
There are many hormone replacement regimens for the
patient with VMS, and these can be delivered in many
different ways. Some commonly prescribed low-dose regi-
mens include: (1) 0.25 mg patch of Climara every week and
200 mg of Prometrium (micronized progesterone) orally
every day, (2) ClimaraPro patch applied weekly, and (3)
0.05 mg of estradiol taken orally every day and 2.5 mg of
medroxyprogesterone acetate taken orally every day (a generic
inexpensive combination of Estrace and Provera).
For some patients, a nonhormonal approach may be pre-
ferred. Use of selective serotonin reuptake inhibitors (SSRIs)
or serotonin and norepinephrine reuptake inhibitors is asso-
ciated with a 25%70% decrease in VMS. Paroxetine mesylate
is the only U.S. Food and Drug Administrationapproved SSRI
for treatment of hot flashes. Gabapentin has been shown to
improve hot flashes that predominate at night. Pregabalin,
venlafaxine, and desvenlafaxine are also effective for treat-
ment of hot flashes. The clonidine transdermal patch is an-
other nonhormonal option for treatment of hot flashes.
Phytoestrogens such as the isoflavone genistein and daidezein
found in soy products are often suggested as an alternative
to treatment, as are herbal remedies; however, there is no
evidence to support their efficacy in treatment of VMS.
Treatment of GSM includes estrogen. Some of these
symptoms may improve among patients already taking
hormone replacement for VMS. For the patient with only
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e271
VAN LE AND MCCORMACK
GSM, a vaginal formulation should be prescribed. A con-
tinuum of treatment exists for treatment of vaginal symp-
toms ranging from use of nonhormonal vaginal moisturizers
and lubricants to vaginal estrogens. Moisturizers can be used
regularly to decrease vaginal atrophy symptoms. Lubricants
are used in addition to moisturizers during intercourse to
alleviate local symptoms of irritation and pain. Neither of
these improves urinary symptoms, however. If the patient
requires escalation of treatment, vaginal estrogens are
available. It is best to use the lowest effective dose to
minimize systemic absorption. Options for treatment of
vaginal symptoms include use of a low-dose vaginal ring,
which can be placed every 3 months. Another low-dose
choice is use of vaginal estradiol tablets (10 mg twice a week
vaginally). Both of these preparations have not been ob-
served to increase systemic levels of circulating estrogen.
Estradiol creams and higher dose estradiol tablets increase
systemic levels of estrogen and require progestin supple-
mentation if a uterus is in place. A new SERM, ospemifene,
was approved in 2013 for treatment of vulvovaginal atro-
phy.7 Patients with cancer were excluded from enrollment in
ospemifene studies, therefore, there is no safety data for its
use for patients with cancer. Side effects of ospemifene
include increase of VTE and increase in VSM. See the Sidebar
for hormonal and nonhormonal treatment options.
Nonhormone-Dependent Gynecologic Cancers
There is no contraindication for hormone treatment of men-
opausal symptoms for patients with cervical or vulvar cancers.
A recent randomized controlled trial of hormone replacement
among patients with ovarian cancer showed no increase in
recurrence; relapse-free survival and overall survival appeared
to be improved in the hormone-treated group. For younger
patients with germ cell tumors, hormone treatment is advo-
cated. There are no data regarding safety of hormone treat-
ment for patients with sarcomas or carcinosarcomas.
Other than breast cancers, it is uncommon for non-
gynecologic cancers to be hormone dependent. Unless there
are contraindications to estrogen treatment, these cancers
can be treated as in general menopausal patients.
Hormone-Dependent Cancers
Patients with breast cancer requiring menopausal symptom
management constitute a unique patient group. In 2003, the
HABITS trial and Stockholm trial, both randomized trials
studying menopausal estrogen replacement among patients
with breast cancer, were stopped prematurely because of
the observation of an increased risk of recurrent cancer in
the treatment arms.8 Long-term follow-up of both has not
observed a difference in survival, and the Stockholm trial did
not observe an increase in recurrence in the treatment arm.
Nonetheless, because there has been no rigorous trial clearly
demonstrating safety of hormone replacement in this group,
nonhormonal treatment of VMS is recommended for pa-
tients with breast cancer. For GSM, vaginal moisturizers and
lubricants are recommended. If symptoms do not resolve
e272 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
with nonhormonal treatment, low-dose vaginal estrogens (pill,
ring, or cream) that are not associated with increased systemic
estrogen levels may be considered. For patients taking ta-
moxifen, low-dose vaginal estrogens can be offered; any
minimal increase in systemic estrogen resulting from vaginal
treatment is blocked by tamoxifen. For patients taking aro-
matase inhibitors, estrogen administration is not recom-
mended, and these patients should be offered nonhormonal
treatment. See the Sidebar for treatment options for GSM.
Patient with endometrial cancer also require thoughtful
management of menopause. The GOG 137 trial, published in
2006, studied 1,236 patients with stage I and II endometrial
cancer in a randomized control trial in which hormone re-
placement was offered to patients with endometrial can-
cer.9 This study was closed early because of enrollment
issues and was underpowered when it closed. It did conclude
that there was no notable difference in recurrence or death
between the treated and control patients. A 2014 meta-
analysis of hormone replacement for patients with endo-
metrial cancer concluded that there was no increased risk of
recurrence for these patients.10 However, there are no data
regarding hormone replacement for patients with advanced
disease. If estrogen treatment is chosen, the National
Comprehensive Cancer Network recommends waiting 6
12 months before starting estrogen treatment.
Granulosa cell tumors are uncommon and often hormone-
dependent. There are no data regarding the safety of hor-
mone treatment in this group, and these patients should be
offered nonhormonal management.
If estrogens are indicated for patients with VTE, a
transdermal approach should be offered. Administration
of paroxetine for patients taking tamoxifen should be
prescribed with caution. Paroxetine inhibits the cytochrome
450-enzyme system and can decrease the efficacy of tamoxifen.
Female patients with cancer may experience premature
menopause because of necessary cancer therapeutics or
undergo spontaneous menopause by virtue of their age.
Quality of life has been shown to improve when symptomatic
patients are treated. There are many nonhormonal formu-
lations, and it may be best to offer these first. However, some
patients may continue to be symptomatic from VSM, and
discussion of hormone treatment should be undertaken after
taking into consideration the patients cancer status. It is
widely acknowledged that definitive trials are lacking re-
garding treatment of hormone-dependent cancers. Given the
increase in the female survivor population, management of
menopause will require additional study in a timely fashion.
SURVIVING THE CURE: MANAGING THE LATE
EFFECTS OF RADIOTHERAPY
The late effects of radiotherapy (RT) are defined as those
that occur months to years after completion of a course of
RT. Such effects have become more important as the
number of long-term survivors increase. Pelvic RT is an
effective treatment of many gynecologic cancers but often
comes at a price. The extent of the problem is difficult to

gauge accurately, as these data have generally not been
collected prospectively in large randomized trials. Further-
more, patients may present to different specialists with
symptoms that are not immediately recognized as late ef-
fects of RT, therefore contributing to the general under-
reporting. The National Survivorship Initiative in the United
Kingdom11 identified four key needs of survivors of cancer:
A personalized survivorship care plan
Support to self-manage their condition where appropriate
Provision of information on long-term effects of living
with and beyond cancer
Access to specialist medical care for complications that
occur after cancer
There are wide variations (up to 23%) in the reported
prevalence of late toxicity following pelvic RT in women with
gynecologic cancers.12 The generally accepted prevalence
rate is approximately 10%.1315 It is likely that the classifi-
cation of the late effects together with underreporting will
contribute to some of this variation.
Gastrointestinal Toxicity
Gastrointestinal (GI) symptoms are the most common side
effect of pelvic RT, with up to 50% of patients experienc-
ing some form of late toxicity.16,17 A review of our in-
stitutional data showed that the mean time to presentation
of bowel symptoms was 8 and 10 months for women
following treatment of cervical and endometrial cancers,
respectively.18 Chronic GI symptoms include rectal bleeding,
FIGURE 1. Modified Algorithm for Approach to
Treating Patients With Gastrointestinal Symptoms
After Radiation Therapy
Abbreviations: QOL, quality of life; APC, argon plasma coagulation.
Adapted from Hauer-Jensen M, Denham JW, Andreyev HJ. Radiation
enteropathypathogenesis, treatment and prevention. Nat Rev Gastroenterol
Hepatol. 2014;11:470-479.
SURVIVOR CARE FOR THE PATIENT WITH GYNECOLOGIC CANCER
diarrhea, flatulence, frequency, urgency, incontinence, mal-
absorption, and pain. It is essential that the clinician take an
accurate and detailed history of the symptoms together with
establishing the precise details of all prior cancer therapies.
An initial assessment of the patient should include evalu-
ation to exclude anemia and thyroid abnormalities, and
cross-sectional imaging should be ordered to exclude cancer
recurrence prior to referral to a gastroenterologist. An al-
gorithm detailing an approach to the management of GI
radiation side effects, developed by colleagues at the Royal
Marsden Hospital in London, was published in a recent
Nature Reviews Gastroenterology & Hepatology review and
is presented in Fig. 1.19 Altered consistency of bowel habit,
frequency, urgency, and rectal bleeding are the most
commonly identified symptoms of late GI toxicity following
pelvic RT. Patients usually must undergo sigmoidoscopy/
colonoscopy for evaluation.20 The management of these
symptoms is complex and will depend upon the results of the
various investigations. Strategies include antibiotics to treat
small intestinal bacterial overgrowth, use of loperamide and
stoolbulking agents, and biofeedback to manage frequency
and urgency. Rectal bleeding from radiation-induced tel-
angiectasia is common, and, in the majority of patients, it is
mild and requires no specific therapy. However, rectal
bleeding leading to anemia can have a considerable impact
on the patients quality of life. Options for management
often vary with resources and expertise but may include use
of argon plasma coagulation embolization or hyperbaric oxygen
therapy (HBO).11 A randomized controlled trial was undertaken
to assess the role of HBO in the treatment of chronic refractory
radiation proctitis. The trial, when analyzed according to in-
tention to treat, demonstrated a notable improvement in the
Late Effects Normal Tissue Task Force-Subjective, Objective,
Management, Analytic score for patients treated with HBO. The
quality of life bowel bother subscale was also significantly
improved for patients who received HBO.21 Bowel obstruction,
perforation, and fistulas are uncommon, but more serious late
effects of RT are more frequently seen in survivors of cervical,
rather than endometrial, cancer.
Small intestinal bowel obstruction (SIBO) is estimated to
occur in 9% of patients after RT for gynecologic malignan-
cies.22 However, the rates have been shown to be influenced
by both prior laparotomy and body weight.23 Management
of SIBO depends largely on the frequency and severity of
symptoms, with some patients experiencing only intermittent
episodes of SIBO that can be managed conservatively. In others,
the symptoms persist and progress to total obstruction over
weeks or months, and such patients require surgical
intervention.24 The type of procedure performed will vary
according to both patient factors and surgical expertise. In
expert hands, resection of the injured bowel with anastomosis is
the preferred procedure permitting resumption of enteral
nutrition postoperatively.25 Ogino et al26 reported late rectal
grade 3/4 complication rates of 6.8% and 8.1%, respectively,
among patients following radical pelvic RT for cervical cancer.
This was predominantly rectal bleeding and rectovaginal fis-
tulae, although they did not differentiate further between the
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e273
VAN LE AND MCCORMACK
SIDEBAR. Nonhormonal and Hormonal
Treatment for Genitourinary Symptoms of
Menopause
Vaginal Moisturizers
Fresh Start
K-Y Silk-E
K-Y Liquibeads
Moist Again
Replens
Vaginal Lubricants
Astroglide
FemGlide
K-Y Jelly
Summers Eve
Vaginal Estrogen
Tablet: Estradiol (Vagifem) 10 mg daily first week, then two
times per week vaginally
Ring: Estradiol (Estring) 7.5 mg, insert every 90 days
Selective Estrogen Receptor Modulator: Ospemifeme
(Osphema), 60 mg orally daily
two. The fistula risk is less than 3% at 20 years, but pelvic surgery
before or after RT has been shown to almost double this risk.23
Urologic Complications
Grade 1 and 2 urologic adverse events are relatively com-
mon; however, the risk of major urinary tract complications
is more modest. Unlike GI complications, which usually
present within 2 years, the risk of urologic complications
increases over time. A retrospective review of the compli-
cations following radical RT for early-stage cervical cancer
concluded that the actuarial risk of grade 3/4 urologic
complications was 11.1% at 10 years, 13% at 15 years, and
14.4% at 20 years.23,27 The most common adverse events
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a Gynecologic Oncology Group study. Gynecol Oncol. 2004;92:744-751.
30. Craighead P, Shea-Budgell MA, Nation J, et al. Hyperbaric oxygen
therapy for late radiation tissue injury in gynecologic malignancies. Curr
Oncol. 2011;18:220-227.
31. Schmeler KM, Jhingran A, Iyer RB, et al. Pelvic fractures after radiotherapy
for cervical cancer: implications for survivors. Cancer. 2010;116:625-630.
32. Park SH, Kim JC, Lee JE, et al. Pelvic insufficiency fracture after ra-
diotherapy in patients with cervical cancer in the era of PET/CT. Radiat
Oncol J. 2011;29:269-276.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e275
HEAD AND NECK CANCER

Best of the Rest: Top Abstracts

on Head and Neck Cancer From
20152016 Oncology Meetings

CHAIR
Sue S. Yom, MD, PhD
University of California, San Francisco
San Francisco, CA

SPEAKERS
Andreas Dietz, MD
University of Leipzig
Leipzig, Germany

Apar K. Ganti, MD
University of Nebraska Medical Center
Omaha, NE
YOM, GANTI, AND DIETZ

Whats New in Head and Neck Cancer: Key Findings in

20152016 From ECCO/ESMO, ASTRO, and the
Multidisciplinary Head and Neck Cancer Symposium
Sue S. Yom, MD, PhD, Apar K. Ganti, MD, MS, FACP, and Andreas Dietz, MD

OVERVIEW

Scientific investigation is extremely active in the treatment, management, and optimization of therapies for patients with
head and neck cancer. These issues have undergone recent rapid evolution in response to a changing epidemiology based on
an increasing proportion of HPV-associated oropharyngeal cancer with advances in multimodality technologies to improve
outcomes and reduce toxicity. Choices of definitive treatment of various anatomic subsites are being refined, balancing the
relative indications and advantages of surgery or chemoradiation-based strategies. The major potential influence of HPV-
associated etiology on therapy selection, prognostic factors, response to treatment, survival outcomes, and post-treatment
surveillance has created a robust and distinct field of scientific inquiry around this patient subset. Meanwhile, for patient subsets
where prognosis remains poor, therapeutic intensification is being explored, and for recurrent/metastatic disease, improved
selection for salvage and novel systemic therapies are under development. For all patients with head and neck cancer, upholding
principles of equity and access to the highly specialized care that results in optimal outcomes should be the goal.

T his article summarizes selected findings in head and neck

cancer research that were presented at several major
meetings over the past year. The European CanCer Organi-
zation (ECCO) and the European Society for Medical Oncology
(ESMO) held a joint meeting, the European Cancer Congress,
from September 2529, 2015, in Vienna. The 57th Annual
Meeting of the American Society for Radiation Oncology
(ASTRO) took place in San Antonio, Texas, from October
1821, 2015. The 2016 Multidisciplinary Head and Neck
Cancer Symposium, a joint conference of the American Head
and Neck Society, American Society of Clinical Oncology, and
American Society of Radiation Oncology, took place in
Scottsdale, Arizona, from February 1820, 2016.
SURGERY AS A PRIMARY TREATMENT
MODALITY
At the 2015 European Cancer Congress, Cheng et al pre-
sented an analysis of data from Taiwan national health
insurance claims and the Taiwan cancer registry database,
including data from 1,698 patients with oropharyngeal and
1,619 patients with hypopharyngeal stage III/IVA cancer
diagnosed between 2004 and 2009.1 The researchers com-
pared outcomes among those who had surgery and those who
did not; in both groups, patients may or may not have received
concurrent chemoradiation therapy. Radical surgery was
performed on 35.29% and 37.63% of patients with stage III
and stage IVA oropharyngeal cancer, respectively, and 54.52%
and 48.85% of patients with stage III and stage IVA hypo-
pharyngeal cancer, respectively. Primary surgery was asso-
ciated with better overall cancer survival in most subset
analyses, but the potential effect of selection for surgery in
this population-based database could not be discounted.
Surgical treatment of advanced head and neck cancer is a
well-recognized weapon that is very often followed by ra-
diotherapy with or without chemotherapy, but in some cases,
surgery can be avoided and radiotherapy or chemoradiotherapy
is an appropriate standard of care. In many centers, the choice
of primary modality continues to be heavily influenced by local
factors such as experience or availability. These data further
underscore the need for prospective research to define the
relative roles of surgery and radiotherapy within curative
treatment paradigms for these subsites.
The importance of the prognostic features identified at
surgical pathology was highlighted by a presentation from
researchers in India. This group measured tumor thickness
using intraoral ultrasound (IOUS) and correlated it with the
risk of nodal metastasis in early N0 oral cancer. A prospective
study was carried out for patients with cT1-2N0 oral cavity

From the Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA; Department of Internal Medicine, University of Nebraska Medical
Center, Omaha, NE; Department of Head Medicine and Oral Health, University of Leipzig, Leipzig, Germany.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Sue S. Yom, MD, PhD, University of California, San Francisco, 1600 Divisadero St., San Francisco, CA 94115; email: yoms@radonc.ucsf.edu.

2016 by American Society of Clinical Oncology.

176 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


cancer in a high-volume head and neck surgical center from
2013 to 2015. A cutoff level of greater than 8.5-mm tumor
thickness on IOUS was derived (area under the curve, 0.81;
95% CI, 0.660.97; p = .005) that predicted lymph node
metastasis with a sensitivity and specificity of 88% and 60%,
respectively. Tumor thickness measuring less than 8 mm
and greater than 9 mm on IOUS developed 3.2% and 25.9%
lymph node metastasis, respectively (p = .01). This cutoff
recommendation could be valuable in designing clinical trials
based on indications for elective neck dissection in early oral
cancer.2
Meanwhile, a group from Belgium took a different ap-
proach to this problem, testing the clinical feasibility of
sentinel lymph node identification in a prospective phase II
study. The goal of the study was to reduce the electively
radiated volumes of the neck. Among 21 patients with cN0
oral cavity, oropharynx, larynx, or hypopharynx squamous
cell carcinomas, 99mTc nanocolloid injection was followed
with single-photon emission CT (SPECT).3 An average of 2.7
sentinel nodes were detected per patient. Only the neck
levels containing the four hottest draining nodes were
electively radiated. At a median follow-up of 14 months,
there were two fatal local relapses but no regional relapses.
HPV-ASSOCIATED OROPHARYNGEAL
SQUAMOUS CELL CARCINOMA
HPV-positive oropharyngeal squamous cell carcinoma (OPSCC)
is a distinct subtype of head and neck squamous cell carcinoma
(HNSCC) that has a significantly better prognosis compared
with HPV-negative OPSCC.4 However, it appears that smoking
history may be used to stratify HPV-positive OPSCC into more
distinct prognostic groups. Zevallos et al presented their study
of the molecular profile of HPV-positive OPSCC, an attempt to
KEY POINTS
Surgery and chemoradiation-based strategies are
considered appropriate up-front modalities for
definitive treatment, based on anatomic considerations,
the balance of toxicities, and morbidity.
For HPVassociated oropharyngeal cancers,
de-intensification of radiation therapy is under active
exploration in an attempt to reduce the long-term
toxicities of treatment.
Post-treatment surveillance remains a relatively
undefined area, although physical examination, direct
visualization, and patient-reported symptoms are
recognized as key indices to follow.
In the salvage setting, improved selection of patients for
surgical salvage may produce better outcomes, and
early results of reirradiation with novel technologies
such as proton beam therapy are promising.
For recurrent/metastatic disease, a number of
combinations of novel targeted therapies and/or
immunomodulatory therapies will move forward in the
near future.
WHATS NEW IN HEAD AND NECK CANCER
understand the underlying genetic basis for the differential
outcomes.5 They conducted targeted next-generation se-
quencing for 66 patients with HPV-positive OPSCC (40
had more than 10 pack years of smoking and 26 had less
than 10 pack years). The group with the lower smoking
history had better outcomes. TP53, CDKN2A, KRAS, and
NOTCH1 mutations were seen almost exclusively in the
high-smoking group, whereas HLA-A mutations were more
common in the low-smoking group.
In a more clinical vein, Lukens et al reviewed a series of 174
patients with HPV-positive OPSCC who had been surgically
treated with transoral robotic surgery and neck dissection
followed by adjuvant chemoradiotherapy. The focus was to
characterize the influence of lymph node characteristics
on the risk of distant metastasis. The follow-up was
38 months. The probability of distant metastasis increased
proportionately when patients had four or more involved
nodes. The risk of distant metastasis was 14% for four or
more nodes, 18% for five or more nodes, 22% for more than
six nodes, and 28% for more than seven nodes. On univariate
analysis, macroscopic/gross extracapsular extension (ECE) pre-
dicted distant metastasis, with distant metastasis developing in
20% of patients wtih ECE versus 4.2% of patients with micro-
scopic ECE, but on multivariate analysis, macroscopic/gross ECE
was not significant (p = .84).6
BIOLOGIC AND RADIOLOGIC PROGNOSTIC
FEATURES
Although various clinical factors, especially smoking, are
considered prognostic, there is a continued search for other
predictors of outcome that may be more biologically specific.
At ASTRO 2015, Khwaja et al presented a well-conducted gene-
expression profiling study of HPV-positive OPSCC.7 Patients
among whom distant metastasis developed had an E6 ex-
pression level that was twofold higher. In the validation
cohort, the authors were able to identify a cutoff level of E6
expression (7.3, by receiver operating curve analysis) that was
correlated to a fivefold higher risk of distant metastasis. The
only minor inconsistency in this study was that the patients
were treated with either chemoradiation or surgery followed
by postoperative radiation with or without chemotherapy.
From a different angle, radiographic predictors have been
an ongoing area of investigation that has yet to yield a clear
standard pretreatment measurement tool, perhaps because
assessment tools should be specific for the type of treatment
to be received. For example, a study from Australia analyzed
the possible predictive value of fluorodeoxyglucose (FDG)-
positron emission tomography (PETCT) after two cycles of
taxane/platinum/fluorouracil (5-FU) induction in correlation
with outcome. Although a high overall survival (OS) at 89.5%
was achieved, the FDG-PET/CTbased volumetric measures
were not predictive for locoregional control (impact of
changes of SUVmax not reported).8
More detailed data concerning off-target FDG-PET pa-
rameters for outcome prognosis after chemoradiotherapy
were reported from Germany. Early occurrence of mucositis
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 177
YOM, GANTI, AND DIETZ
higher than grade 1 was associated with better locoregional
control (p = .012) and OS (p = .017). Occurrence of dysphagia
higher than level 2, but not mucositis, at the end of treatment
was associated with favorable locoregional control (p = .031)
and OS (p = .008). Besides error-prone and observer-biased
determination of mucositis by clinical examination, the
evaluation of mucosa by PET during treatment showed a
superior correlation with patients outcome.9
Lastly, MAASTRO investigators reported a new radionomics
tool that has prognostic and predictive implications after
chemoradiotherapy. Five radiomic features of primary tumor
regions were evaluated. Strong correlations with OS were
described by combining special features. This noninvasive
new morphometric tool deserves further evaluation.10
DE-INTENSIFIED CHEMORADIOTHERAPY FOR
HPV-POSITIVE OROPHARYNGEAL SQUAMOUS
CELL CARCINOMA
Given the excellent prognosis of HPV-positive OPSCC, efforts
are underway to attempt de-escalation of therapy without
affecting outcomes. In a phase II trial that was reported at
ASTRO and the Multidisciplinary Head and Neck Cancer
Symposium, Chera et al included 43 patients with T0-3, N0-
N2c, and M0 HPV-positive OPSCC with a minimal or remote
smoking history.11,12 The treatment regimen was 60 Gy of
intensity-modulated radiation therapy with weekly cisplatin
(30 mg/m2). All patients then underwent a biopsy of the
primary site and a neck dissection of pretreatment positive
lymph node regions, irrespective of response. The patho-
logic complete response rate was 86%. The patients without
pathologic complete response had only microscopic foci of
residual disease. All patients were alive without recurrence
after a median follow-up of 21.3 months. The incidence of
acute Common Terminology Criteria for Adverse Events grade
3/4 toxicity was as follows: mucositis 34%, pain 5%, nausea
18%, vomiting 5%, dysphagia 39%, and xerostomia 2%. A
feeding tube was required temporarily for 39% of patients.
Likewise, in another attempt to decrease late toxicity
presented at both ASTRO13 and the Multidisciplinary Head
and Neck Cancer Symposium,14 Melotek et al incorporated
a response-adapted volume de-escalation approach using
response-to-induction chemotherapy as a guide to decrease
the extent of radiation volume in a nonselected population of
patients with locally advanced HNSCC. The regimen was
comprised of two cycles of chemotherapy (cisplatin 75 mg/m2,
paclitaxel 175 mg/m2, both on day 1, and weekly cetuximab
with or without everolimus). Patients with good response,
defined as a 50% reduction in the sum of gross tumor diameters,
received concurrent chemoradiation (paclitaxel, 5-FU, hydroxy-
urea, and 1.5 Gy twice-daily radiotherapy every other week).
The radiation dose was as follows: 75 Gy with the planning
target volume (PTV1) encompassing exclusively gross disease.
Patients with less than 50% response (NR) were treated with
volumes encompassing PTV1 and the next nodal station at
risk (PTV2) to 45 Gy, followed by a sequential boost to PTV1 to
75 Gy. Of the 94 patients in this study, 63% were HPV-positive.
178 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Thirty HPV-positive and seven HPV-negative patients had a
good response, as defined before. The 2-year progression-
free survival (PFS) and OS rates were 93.1% and 92.1% for
good response, HPV-positive OPSCC and 74.0% and 95.2% for
NR HPV-positive OPSCC, respectively.
It has been an ongoing active controversy as to whether
de-intensification with the use of cetuximab could risk
compromising outcomes. A new abstract on this subject was
presented at ASTRO 2015 but is unlikely to settle the debate.15
In this study, the investigators found that patients who had
cetuximab given concurrently with radiotherapy had higher
rates of distant metastases than those who had received
chemoradiotherapy with a platinum agent. Maturing results of
the major study addressing this question, RTOG 1016, which
tested cetuximab versus cisplatin in HPV-positive oropha-
ryngeal squamous cell carcinoma, are eagerly awaited.
INTENSIFICATION FOR HPV-NEGATVE
SQUAMOUS CELL CARCINOMA
Although the good prognosis of patients with HPV-positive
OPSCC has led to trials in therapeutic de-intensification, for
patients with HPV-negative HNSCC who had significantly
worse outcomes, systemic therapy intensification may be
warranted. In an abstract presented at the Multidisciplinary
Head and Neck Cancer Symposium, Melotek et al investigated
the addition of cetuximab to induction chemotherapy and
concurrent chemoradiation for patients with locoregionally
advanced HNSCC.16 Patients were randomly selected to receive
two cycles of weekly cetuximab, paclitaxel, carboplatin, and
either cetuximab, 5-FU, hydroxyurea, and 1.5 Gy twice-daily
radiotherapy every other week to 75 Gy (CFHX) or cetuximab,
cisplatin, and accelerated radiotherapy with delayed concom-
itant boost to 72 Gy in 42 fractions (CPX). Fifty-six patients with
HPV-negative HNSCC (32 receiving CFHX and 24 CPX) were
included in the trial. The 2-year PFS was 75.0% for CFHX and
70.8% for CPX. The 5-year PFS and OS for the HPV-negative
cohort were 65.9% and 72.5%, respectively, suggesting a
possible role for cetuximab for this group of patients.
SURVEILLANCE
The optimal frequency of follow-up imaging after definitive
curative-intent therapy has not been defined. The National
Comprehensive Cancer Network guidelines do not recom-
mend routine imaging in the absence of symptoms, except
chest CT scans as recommended for lung cancer screening (in
high-risk patients who meet the criteria). At the Multidisciplinary
Head and Neck Cancer Symposium, Frakes et al retrospectively
reviewed the charts of 246 patients with HPV-positive OPSCC
who were treated with definitive radiotherapy or chemo-
radiotherapy.17 Local control was achieved for 239 patients,
with a 3-year local control rate of 97.8%. All local failures
were detected by direct visualization or flexible laryngos-
copy. The 3-year regional control rate was 95.3%. Risk
factors for regional failure included patients who had in-
volvement of five or more nodes or level 4 lymph nodes. The
majority of regional recurrences (89%) were detected either

by symptoms or 3-month post-treatment PET/CT. Twenty-
one patients had distant metastases. Factors predicting for
distant metastases included lymph nodes larger than 6 cm,
bilateral lymphadenopathy, five or more nodes, or level 4
lymph node involvement. Of these 21 patients, 71% were
identified either from symptoms or on the 3-month post-
treatment imaging. These results suggest that if the 3-month
post-treatment PET/CT is negative, no further routine imaging
is necessary. The results also reiterate the importance of a good
history and physical examination, including direct visualization.
POST-TREATMENT NECK DISSECTION
The previously standard practice of planned neck dissection
after radiation-based definitive treatment has waned.
As presented at the European Cancer Congress, 147 patients
with locoregionally advanced stage IVA (52%) or IVB (46%)
HNSCC from Portugal were treated with induction taxane/
platinum/5-FU chemotherapy followed by chemoradiotherapy
from July 2008 to March 2014. Fifty-three patients (37%)
underwent neck dissection because of persistence of dis-
ease (4/53, 7.5%), suspicious imaging (40/53, 75.5%), or pre-
vious bulky disease (9/53, 17%). A majority of the positive neck
dissections were N2c, instead of N3. There was no meaningful
difference in OS between patients who did not have neck
dissection and those who had a negative neck dissection.
The authors conclude that prophylactic neck dissection did
not seem to improve OS.18
Adding to the increasing conservatism around post-
radiotherapy neck dissection, Mehanna et al presented a
late-breaking abstract examining differences in the quality of
life and functional outcomes of treatment between HPV-
positive and HPV-negative patients receiving primary che-
moradiotherapy, using patient data from the PET-NECK trial
previously presented at ASCO 2015.19 In this trial, the use
of PET surveillance reduced the rate of post-treatment neck
dissection to 20%, without affecting OS. The new presentation
reported that p16-positive subjects have major decreases in
quality-of-life scores during the acute phase of treatment and
may require additional support during that period, but that
they recover better than p16-negative subjects, who have
lower quality of life in the longer term and may need more long-
term support.
ACUTE AND LATE TOXICITY OF
CHEMORADIATION
As seen in the PET-NECK trial, toxicity remains an acute
and long-term concern for patients receiving chemoradiation.
Oral mucositis is one of the major acute adverse events as-
sociated with head and neck radiotherapy, with or without
chemotherapy, occurring in more than 90% of patients. The
incidence of severe mucositis (grade 3-4) is 66%,20 yet there
are no currently approved agents to decrease the burden
associated with this toxicity.
In this vein, Anderson et al presented a study of 46
patients who received increasing doses of GC4419, a su-
peroxide dismutase mimetic, and concurrent cisplatin-based
WHATS NEW IN HEAD AND NECK CANCER
chemoradiotherapy.21 The duration, incidence, severity, and
onset of severe oral mucositis seemed to be markedly improved
compared with historical controls. The efficacy of GC4419 was
duration dependent with maximum benefit seen among
patients who received 6 to 7 weeks of treatment. The drug
was well tolerated, with the main side effects being grade 3
gastroenteritis and nausea/vomiting (one patient each). In
addition, peri-infusional facial tingling was attributable to
GC4419. The dose levels chosen for a future randomized
controlled trial were 30 and 90 mg/day.
Regarding the early toxicity of systemic therapy, the first
safety report of the Italian INTERCEPTOR trial (randomized,
multicenter phase III study comparing chemoradiotherapy
vs. induction chemoradiotherapy followed by radiotherapy
and cetuximab) was presented at ECCO/ESMO, with 228
patients accrued thus far. The first 170 were considered in
the present analysis (85 patients in each arm). Overall, the
only significant difference between the two arms was grade 3 to
4 neutropenia (p = .017), and the trial will continue. The excess of
neutropenia was caused entirely by the induction phase.22
Late toxicity is likewise a concern, especially if consider-
ation is given to further intensification of standard chemo-
radiotherapy therapies. Twelve-year follow-up data from
Belgium at ECCO/ESMO compared two nonrandomized
chemoradiotherapy cohorts with a platinum-based induction
regimen followed by chemoradiotherapy. Induction was
associated with a significantly longer time to distant metas-
tases. A little over half (51.6%) of the induction patients sur-
vived beyond 5 years, whereas 5-year survival in the CCRT
group was 29.6%. Second HNSCC primaries and other malig-
nancies accounted for 47% of all deaths beyond 5 years. The
most important late local toxicities among surviving patients in
both groups were dysphagia and xerostomia.23
The radiation oncology community has debated for some
time whether proton beam therapy has the ability to im-
prove patient-reported outcomes compared with current
state-of-the-art photon-based techniques. Ahn et al presented
a series of 95 patients, of whom 57 (60%) were treated with
photon-based volumetric arc therapy (VMAT) and 45 (45%)
were treated with proton pencil beam scanning (PBS). Fifty-two
(55%) of the patients were irradiated after transoral robotic
surgery and 43 (45%) were treated definitively, with or without
concurrent chemotherapy. At the 6-month endpoint, using the
Performance Scale Status instrument, there was no overall
difference in diet, speech, or public eating. There was no overall
difference in gastrostomy usage. Data from the the EORTC
questionnaires showed there was no difference in global health,
physical function, or sensory domains. However, patients who
underwent VMAT lost 5.5% of baseline weight compared with
3.4% for those who underwent PBS. Patients undergoing VMAT
also used more pain medication. In particular, among patients
receiving concurrent cisplatin, PBS was significantly associated
with a higher global health score, less pain, lower painkiller use,
and lower percutaneous endoscopic gastrostomy use.24 Given
the inherent confounding factors that may be in play, further
study of these complex questions is needed and obtaining
higher-level evidence should be a priority.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 179
YOM, GANTI, AND DIETZ
SINONASAL TUMORS
Induction chemotherapy remains an area of controversy and
active ongoing interest in the treatment of sinonasal can-
cers. Response to induction chemotherapy before surgical
treatment of locally advanced epithelial sinonasal cancer is
recognized as a prognostic factor for outcome. Bossi et al from
Italy identified 63 patients with different types of advanced
epithelial sinonasal cancer who received platinum-based in-
duction chemotherapy, either associated with 5-FU and
lederfolin or 5-FU and docetaxel. For neuroendocrine
cancers, cisplatin and etoposide alternating with ifosfamide
and doxorubicin were used. Thirty-four patients had a
recurrence (28 at the locoregional level and six at distant
sites); 14 patients received salvage surgery (12 on primary
tumor and two on neck nodes), but only two of those
remained free of disease (one patient on T and one on N level).
With a median follow-up of 45 months, 5-year OS and disease-
free survival rates were 58% and 40%, respectively. Only
the response to induction chemotherapy retained prog-
nostic value for OS (p = .0017).25 Because of the rarity and
heterogeneity of these tumors, the current treatment options
remain unsatisfactory, and enrollment into international trials
is needed to make progress.
LOCALLY RECURRENT DISEASE MANAGEMENT
It is generally accepted that surgery has a major role for the
successful treatment of patients with locally recurrent HNSCC. A
retrospective analysis from Belgium had the goal of improving
the selection of patients for salvage surgery as well as identifying
the major negative prognostic features in surgical pathology. On
multivariate analysis, oropharyngeal primary site (p , .001),
positive resection margin (p = .002), extracapsular spread
(p = .003), and major postoperative complications (p , .001)
were independent negative prognostic factors for relapse-
free survival. These data underline the poor outcome of
recurrent oropharyngeal HNSCC and the need for highly
reflective indications for salvage surgery in this group.26
For patients who are not determined to be surgical can-
didates, reirradiation remains a generally unsatisfying enter-
prise. There is a wave of emerging data about the role of proton
beam radiation therapy for reirradiation of recurrent HNSCC. In
one retrospective analysis of an ongoing prospective data
registry presented at the Multidisciplinary Head and Neck
Cancer Symposium, Chang et al reported results for 90 pa-
tients who received reirridation with proton beam radiation
therapy between 2011 and 2014.27 The actuarial 6-month
locoregional control and OS were 86.5% and 84.1%, re-
spectively. There was one death as a result of disease pro-
gression. Grade 3 acute toxicity included mucositis (10.0%),
dermatitis (3.3%), dysphagia (2.2%), and esophagitis (1.1%). In
addition, there were three (5.3%) skin toxicities grade 3 or
worse: a neck ulcer, a chronic neck wound managed with
hyperbaric oxygen treatments, and a pneumocephalus from a
skull base defect. There was one death caused by treatment-
related bleeding. Short follow-up limits the conclusions that
can be drawn, although the low rates of toxicity are attractive.
180 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
More studies are needed to elucidate the role of proton beam
radiation therapy in HNSCC.
MANAGEMENT OF RECURRENT/METASTATIC
DISEASE
The LUX-Head and Neck-1 (LHN) trial demonstrated that
afatinib was associated with an improved PFS compared with
methotrexate (2.6 vs. 1.7 months; p = .03).28 In an attempt to
predict which subsets of patients would most benefit from
afatinib therapy, Cohen et al evaluated the association of
ERBB-related biomarkers and p16 on the antitumor activity of
afatinib and methotrexate.29 They noted that afatinib had a
higher response rate in EGFR-directed therapynaive patients
with p16-negative tumors (27.5% vs. 4.8%) and patients with
p16-negative and EGFR-amplified tumors (15.5% vs. 0%). In
contrast, no responses were observed among patients with
p16-positive disease, suggesting that EGFR targeting does not
have a role in HPV-positive HNSCC.
Adkins et al conducted a phase I study of cetuximab and a
suspension formulation of pazopanib among 22 patients with
incurable HNSCC.30 Both cetuximab-naive and cetuximab-
refractory patients were eligible. The regimen was well toler-
ated and the maximally tolerated dose was not reached for
pazopanib at the maximum dose level. Six patients achieved a
partial response (27%), with an additional 11 (50%) patients
achieving stable disease. Three of the six responses were seen
among patients with cetuximab- and platinum-resistant dis-
ease, suggesting that this combination may be worthy of future
study.
After failure of platinum, anti-EGFR, and taxanes, patients
with recurrent/metastatic HNSCC are considered refractory,
and methotrexate is the general option with palliative care
intent. Final results from the phase II French trial UNICANCER
ORL03 showed that cabazitaxel met the primary endpoint,
producing a 27.6% 6-week disease control rate with ac-
ceptable tolerability among heavily pretreated patients
with refractory recurrent/metastatic HNSCC.31 Among pa-
tients with recurrent/metastatic HNSCC refractory to prior
surgery, radiotherapy, or chemotherapy, preliminary phase II
data of first-line paclitaxel combined with panitumumab
showed clinical benefit (median PFS: 7.5 months; 95% CI,
4.98.3; and median OS: 9.9 months; 95% CI, 7.916.3).
This was a comparable efficacy to the standard-of-care
EXTREME regimen, but with a worse (unacceptable) safety
profile (15% fatal adverse events).32
So what can be currently expected for disease that is
refractory to first-line cetuximab and platinum? Retro-
spective Swiss data in a cohort of 117 patients described the
outcome after second-line regimens (monotherapies, mostly
with methotrexate [55%] or other agents [43%]; only one
patient received platinum combination chemotherapy).
More than half (54%) of the patients did not reach the
point of second-line treatment. The response rate (partial
response, complete response) in 49 patients was 8%, with
33% showing stable disease. Median PFS was 81 days
(95% CI, 5292) and OS was 184 days (95% CI, 115220).

In conclusion, second-line options after first-line cetux-
imab containing regimens are strongly limited.33
IMMUNE MODULATION IN SQUAMOUS CELL
CARCINOMA OF THE HEAD AND NECK
The advent of immunotherapy has heralded a new era in the
treatment paradigm for many malignancies, including HNSCC.
Multiple trials are underway evaluating the role of im-
munotherapies including PD-1 inhibitors in metastatic HNSCC.
Preclinical data suggest that radiotherapy may lead to anti-
tumor immune responses. In an attempt to identify immu-
nologic changes seen during radiotherapy, Sridharan et al
prospectively obtained blood samples from 16 consecutive
patients with HNSCC undergoing curative-intent radiotherapy
(with or without platinum-based chemotherapy) at the
beginning and end of therapy.34 The investigators found an
increase in the circulating CD8-positive T-effector cells,
CD4/PD-1positive cells, CD8/LAG3-positive cells, and regula-
tory T cells (Treg). There was an increase in PD-L1 levels, which
mirrored increases in CD8-positive T cells over the course of
therapy. Levels of CXCL10 decreased during treatment,
whereas those of CXCL16 increased. These findings dem-
onstrate the complex immunologic effects of chemoradiotherapy
and suggest mechanisms for potential synergy among che-
motherapy, radiotherapy, and immunotherapy in HNSCC,
which may be exploited in future trials.
Evaluation of these specific immunologic responses may
enable future optimization of the use of this novel class of
agents. In a similar experiment, Ferris et al found that a
combination of the Toll-like receptor 8 agonist motolimod
and chemotherapy resulted in a decrease in the pheno-
typic markers of suppression in Treg cells (CTLA-4, CD73,
and membrane-bound transforming growth factor-b) in tumor
and peripheral blood.35 In contrast, in nonresponders to
chemotherapy alone, they noted an induction of Treg cells.
Further data relevant to subgroups from KEYNOTE 012
have provided greater insight into the efficacy of the antiPD-1
antibody, pembrolizumab. In the subgroup analyses, the
overall response rate appeared higher for patients who
received fewer than two prior therapies (31/97; 32.0%; two
complete reponses vs. 29 partial responses) compared with
those who had received more than two prior therapies (10/63;
16.0%; 10 partial responses). The overall response rate for
subjects who were previously exposed to both platinum
and cetuximab therapy was 19.1% (18/94; 18 partial re-
sponses). Pembrolizumab appeared to provide the most
benefit for patients with recurrent/metastatic HNSCC who
have had smaller, less heavily pretreated tumors.36
As explorations of immunotherapy continue, new indica-
tions may emerge. The prevalence of PD-L1 on tumor- and
infiltrating immune cells as well as other characteristics
of immune biology were investigated among 161 patients
with nasopharyngeal carcinoma.37 PD-L1 expression was
detected at greater than 1% and greater than 5% cutoff of
induction chemotherapy in 75% and 17% of tumors, re-
spectively. Baseline clinical characteristics of stage, sex,
WHATS NEW IN HEAD AND NECK CANCER
and age, as well as clinical outcome data such as time to
local failure, PFS, and OS, did not correlate with PD-L1
expression at either of the cutoffs. Nonetheless, the high
PD-L1 expression rate will likely stimulate further studies
of checkpoint inhibitors in this subsite.38 Interestingly, plasma
Epstein-Barr virus DNA may correlate with response to pem-
brolizumab treatment in metastatic nasopharyngeal carcinoma.
CARE DELIVERY AND ECONOMICS OF
SQUAMOUS CELL CARCINOMA OF THE HEAD
AND NECK
With the current emphasis on equitable care delivery to all
patients, it is important to understand disparities in the care
of patients with HNSCC. Churilla et al sought to evaluate
the association between health insurance status and clinical
features at presentation, treatment received, and outcomes
among patients with HNSCC.39 Using the SEER database,
they analyzed 53,848 patients with squamous cell carcinoma
of the oral cavity, oropharynx, and larynx. They found that
a larger proportion of Medicaid (72.9%) and uninsured
patients (75.1%) had stage III or IV disease, compared with
insured patients (60.1%; p , .001). After adjusting for
clinical and demographic factors, uninsured patients were
less likely to receive cancer-directed surgery (odds ratio
[OR] 0.86; 95% CI, 0.770.97), whereas Medicaid and un-
insured patients were less likely to receive radiotherapy
(Medicaid: OR 0.77; 95% CI, 0.720.81; uninsured: OR
0.68; 95% CI, 0.620.75). On multivariate analysis, patients
with Medicaid (hazard ratio [HR] 1.55; 95% CI, 1.491.62)
or uninsured status (HR 1.48; 95% CI, 1.381.58) had
inferior OS compared with insured patients.
Disparities may exist across multiple facets and at multiple
levels across the cancer journey. It is recognized that opti-
mal cancer-related decision making requires very strong
collaborative work by experienced multidisciplinary teams,
and HNSCC outcomes have been previously reported to be
better in centers treating a high number of these patients.
An abstract presented at ASTRO 2015 analyzed the impact of
radiation oncology provider volume on the clinical outcomes
of patients.40 They found that for each additional patient with
head and neck cancer treated per year, there was a significant
reduction in the risk of gastrostomy tube placement (0.8%), the
rate of aspiration pneumonia (0.8%), and the incidence of a
secondary head and neck surgery (1.0%). Among patients
who received intensity-modulated radiation therapy, each
additional patient with head and neck cancer treated per
year by the radiation oncologist resulted in a decreased risk
of cancer-related death of 0.8%. Addressing disparities in
health care may involve not just providing availability of
basic services but focusing on access to high-level expertise
for these complex conditions.
Finally, another controversial issue revolves around the
relative costs of up-front surgery versus nonsurgical therapy.
There have been several conflicting reports on this question.
Pinheiro and Kramer retrospectively reviewed the records of
72 patients with T1-T3 OPSCC, of whom 42 were treated
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 181
YOM, GANTI, AND DIETZ
with a surgical approach (22 received adjuvant treatment),
and 30 were treated nonsurgically.41 In this small analysis,
cost was defined as the reimbursement for all charges in a
6-month episode of treatment after a positive biopsy. The
authors found that the cost was significantly lower for those
treated with surgery only compared with the nonsurgical
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group ($38,462 vs. $83,222; p = .03). The cost of surgery
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15. Weller MA, Ward MC, Berriochoa CA, et al. Cetuximab-based bioradiation
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based chemoradiation therapy in human papillomaviruspositive oro-
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16. Melotek JM, Haraf DJ, Blair EA, et al. Final results of a randomized phase
2 trial investigating the addition of cetuximab to induction chemo-
therapy and accelerated or hyperfractionated chemoradiation therapy
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analysis. Int J Radiat Oncol Biol Phys. 2016; 95:868.
17. Frakes JM, Naghavi AO, Strom T, et al. Detection of recurrence in human
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18. Pires da Silva I, Mouta J, Winckler P, et al. 2818 The role of neck dis-
section (ND) after neoadjuvant chemotherapy (CT) with docetaxel,
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19. Mehanna H, Wong WL, McConkey CC, et al. 11LBA Differences in the
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radiotherapy in PET-NECK - a multi-centre randomized phase III con-
trolled trial (RCT) comparing PETCT guided active surveillance with
planned neck dissection (ND) for locally advanced (N2/N3) nodal
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cancer (HNC) treated with primary radical chemoradiotherapy (CRT).
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20. Elting LS, Cooksley CD, Chambers MS, et al. Risk, outcomes, and costs of
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21. Anderson CM, Allen BG, Sun W, et al. Phase 1b/2a trial of superoxide
(SO) dismutase (SOD) mimetic GC4419 to reduce chemoradiation
therapyeInduced oral mucositis (OM) in patients with oral cavity or
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869-870.
22. Merlano M, Vecchio S, Bacigalupo A, et al. 2821 The phase III study
INTERCEPTOR in locally advanced head and neck cancer (LA-HNC).
Preliminary safety report. Eur J Cancer. 2015;51:S560.
23. Dewaele E, Vermorken J, Verschueren C, et al. 2817 12-year follow-up
(FU) data and late local toxicity of two cohorts of patients with
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(LA-SCCHN) treated with concomitant chemoradiation (CCRT) with or
without induction chemotherapy (ICT). Eur J Cancer. 2015;51:S563.
24. Ahn P, Sharma S, Zhou O, et al. A comparative quality of life cohort of
oropharyngeal squamous cell (OPSCC) patients treated with volumetric
modulated radiation therapy (VMAT) versus proton pencil beam
scanning (PBS). Int J Radiat Oncol Biol Phys. 2015; 93:S71.
25. Bossi P, Pala L, Orlandi E, et al. 2827 Role of induction chemotherapy in
the multimodal management of locally advanced epithelial sinonasal
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26. Hamoir M, Schmitz S, Holvoet E, et al. 2848 Salvage surgery in recur-
rent head and neck squamous cell carcinoma. Oncologic outcome and
prognostic factors. Eur J Cancer. 2015;51:S573.
27. Chang JHC, Romesser PB, Scher ED, et al. Proton beam reirradiation for
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28. Machiels JP, Haddad RI, Fayette J, et al; LUX-H&N 1 investigators. Afatinib
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after platinum-based therapy (LUX-Head & Neck 1): an open-label, ran-
domised phase 3 trial. Lancet Oncol. 2015;16:583-594.
29. Cohen E, Licitra L, Burtness B, et al. Neck squamous cell carcinoma (R/M
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30. Adkins D, Ley J, Wildes T, et al. A phase 1 trial of pazopanib added to
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the head and neck (SCCHN): final results of phase II trial UNICANCER
ORL03. Eur J Cancer. 2015;51:S557.
32. Del Barco Morillo E, Mesia R, Adansa Klain JC, et al. 2802 Phase II study
of first-line paclitaxel (PTX) with panitumumab (P) in patients with
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treatments after first line platinum and cetuximab treatment in patients
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with recurrent/metastatic (RM) head and neck squamous cell cancer
(HNSCC): a retrospective analysis. Eur J Cancer. 2015;51:S578.
34. Sridharan V, Margalit DN, Curreri SA, et al. Systemic immunologic ef-
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35. Ferris RL, Kansy BA, Gibson SP, et al. A phase 1b study of neoadjuvant
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36. Chow L, Mehra R, Haddad R, et al. 2866 Antitumor activity of the anti-
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 183
HEAD AND NECK CANCER

Integrating Immune Checkpoint

Inhibitors and Targeted Agents
With Surgery and Radiotherapy
for Patients With Head and Neck
Cancer

CHAIR
David M. Brizel, MD
Duke University Medical Center
Durham, NC

SPEAKERS
Andrew G. Sikora, MD, PhD
Baylor College of Medicine
Houston, TX

Nooshin Hashemi Sadraei, MD

University of Cincinnati
Cincinnati, OH
 IMMUNOTHERAPY FOR HEAD AND NECK CANCER

Immunotherapy and Checkpoint Inhibitors in Recurrent and

Metastatic Head and Neck Cancer
Nooshin Hashemi Sadraei, MD, Andrew G. Sikora, MD, PhD, and David M. Brizel, MD

OVERVIEW

Immune surveillance is well recognized as an important mechanism to prevent development or progression of head and
neck cancers. Head and neck cancer cells can escape the immune system through multiple mechanisms including de-
velopment of tolerance in T cells and inhibition of T-cellrelated pathways, generally referred to as checkpoint inhibitors.
This article highlights advances in immuno-oncology treatment approaches in recurrent and metastatic head and neck
squamous cell carcinoma. Clinical trials are discussed in detail, with an emphasis on response dynamics, oncologic efficacy,
safety, and tolerability of checkpoint inhibitors. In addition, developing concepts and ongoing studies in this setting are also
reviewed.

T umor cells release antigens, which are captured by an-

tigen presenting cells and subsequently presented to
T cells. Activated T cells then produce a cytotoxic response
resulting in cancer cell death. Memory T cells that are
formed subsequent to these events can result in a durable
antitumor response. However, T-cellrelated pathways can
cause inhibition of these immune responses and result in
tumor cells evading the immune system.1 These pathways
are generally referred to as checkpoints, which are re-
sponsible for preventing a chronic autoimmune or in-
flammatory status. Two of the most commonly discussed
checkpoint inhibitory mechanisms are CTLA-4 and PD-1/PD-L1,
which act at earlier and later stages of the immune re-
sponse to tumors.1,2 CTLA-4 is present on the surface of
CD4 and CD8 cells and, through binding to CD80 and CD86,
can transmit an inhibitory signal to T cells. CD28 has a
stimulatory effect on T cells and competes with CTLA-4 for
the same ligands (CD80 and CD86); however, CTLA-4 has
greater affinity and is able to overcome effects of stimu-
latory CD28.
PD-L1 can be found on tumor cells, as well as immune cells
and antigen presenting cells. PD-1 is primarily found on the
surface of T cells. PD-L1 is the main ligand for PD-1, which has
been associated with poor prognosis in many cancer types.
PD-1 is expressed on T cells upon activation and results in
negative regulatory effects on immune function.
PD-1 and PD-L1 both interact with other ligands, too. Most
importantly, PD-1/PD-L2 activation can have similar effects
as PD-1/PD-L1 engagement (although PD-L2 function is less
thoroughly understood). PD-L1 can also activate CD80,
which, as previously discussed, is a known ligand for CTLA-4.
These preclinical findings have led to a new generation of
clinical trials and novel treatments based on single and dual
inhibition of CTLA-4 and PD-1, and in combination with
cytotoxic and targeted therapies.
IMMUNE CHECKPOINT INHIBITORS IN
RECURRENT/METASTATIC HEAD AND NECK
SQUAMOUS CELL CARCINOMA
The majority of immune therapy in head and neck cancer has
so far focused on removal of the negative regulatory im-
mune pathways. Many ongoing studies are investigating
the role of immune checkpoint inhibitors in recurrent/
metastatic head and neck cancer, including single agent
and combination of checkpoint inhibitors as dual-inhibition,
combination with immunomodulators, vaccines, chemotherapy,
biologics, and targeted agents, as well as radiation. Most of
these studies have not yet reported their results.
PD-1 Inhibitor
PD-1 inhibition has been the most extensively studied im-
munotherapeutic strategy in head and neck squamous
cell carcinoma, particularly with the agent pembrolizumab
(formerly MK-3475). This agent has shown promising effi-
cacy compared with historical data and is thought to be well
tolerated (KEYNOTE 012; NCT01848834).3 In a large phase IB
study of pembrolizumab for patients with PD-L1positive

From the Division of Medical Oncology, University of Cincinnati College of Medicine, Cincinnati, OH; Department of OtolaryngologyHead and Neck Surgery, Baylor College of Medicine,
Houston, TX; Department of Radiation Oncology, Duke University Cancer Center, Durham, NC.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Nooshin Hashemi Sadraei, MD, The Vontz Center for Molecular Studies, University of Cincinnati, 3125 Eden Ave., Cincinnati, OH 45267; email: hashemnn@
ucmail.uc.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e277

HASHEMI SADRAEI, SIKORA, AND BRIZEL
recurrent/metastatic head and neck squamous cell carci-
noma, the overall response rate was approximately 20%,
which was similar among patients who were HPV-positive
or HPV-negative.4 PD-L1 positivity in this study was defined
as at least 1% or more stromal or tumor expression of PD-L1
by immunohistochemistry. Based on this definition, 78% of
screened patients were considered positive and eligible for
the study. Among patients with PD-L1 positivity, those with
higher PD-L1 expression demonstrated a much higher re-
sponse compared with those with a lower PD-L1 expression
(50% vs. 11%, respectively).4
Median progression-free (PFS) and overall survival (OS)
were favorable compared with historical cohorts of pa-
tients with heavily pretreated head and neck squamous
cell carcinoma; the median PFS was 9 months (range,
8 to 20 months) and the median OS was 12.6 months.
Unlike response rates, which did not seem to be affected
by HPV status, patients who were HPV-positive, as pre-
dicted, showed longer PFS and OS compared with pa-
tients who were HPV-negative (median PFS, 17 vs. 8 months,
respectively; median OS, not reached vs. 9 months,
respectively).
Subsequently, in a combined update of two cohorts of
patients with recurrent/metastatic head and neck squamous
cell carcinoma that was heavily pretreated, pembrolizumab
resulted in a response rate of 24% and an additional 25%
with stable disease,5 which was slightly improved compared
with earlier reports.4 The median survival in the combined
KEY POINTS
Immune surveillance is an important mechanism in
prevention of cancer development and inhibition of
growth of tumors and metastasis. Checkpoint pathways
prevent immune response through multiple methods
including CTLA-4 and PD-1/PD-L1 pathways.
A variety of immune checkpoint inhibitors (PD-1/PD-L1
and CTLA-4 inhibitors) have been studied in recurrent
and metastatic head and neck cancers with encouraging
efficacy and toxicity data.
Although many of these treatments are being used with
encouraging results in a variety of different
malignancies, there appears to be some differences in
patterns of response and toxicities, which may be
disease- or population-specific, to some extent.
Studies are ongoing to identify reliable biomarkers.
To date, despite common use of PD-L1 as a biomarker,
consensus in detection methods, definition of positivity,
and its use as a prognostic or predictive biomarker is
lacking, despite common use of PD-L1 as a biomarker.
In addition to checkpoint inhibition, a variety of other
immune therapy strategies are under investigation in
head and neck cancers, some of which include
combination strategies, positive costimulation, and
targeting HPV-specific antigens in treatment of
HPV-related disease.
e278 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
cohort of patients was 9.6 months (6.6 months to not
reached) with a 1-year estimated survival of 47%.5 This is a
very promising improvement compared with best historical
survival outcome data among patients with recurrent/
metastatic disease (median survival, 10.1 months with
chemotherapy doublet-cetuximab triplet regimen and
7.4 months with chemotherapy doublet therapy).6
Overall drug-related adverse events were 61%, with fa-
tigue (17%) being the most common, followed by endo-
crinopathies (hypothyroidism), low appetite, pyrexia, and a
variety of skin-related toxicities, each reported in 5% to 8%
of patients. Compared with the use of other checkpoint
inhibitors, mostly in melanoma, no colitis or pneumonitis of
any grades were observed, and high-grade toxicities (grade
3 and above) were seen in 12% of cases.4,5
Many randomized studies subsequently investigated the
role of PD-1 inhibitors in recurrent and metastatic disease.
A randomized study of pembrolizumab compared with
investigators choice chemotherapy (KEYNOTE-040) for
patients with platinum-refractory disease is nearing com-
pletion of accrual (NCT02252042),7 and another trial is a
three-arm randomized study in the first-line recurrent and
metastatic setting (KEYNOTE-048) that will evaluate stan-
dard platinum/5-fluorouracil/cetuximab compared with
pembrolizumab alone or combination of chemotherapy
plus pembrolizumab (NCT02358031).8
More recently, CheckMate 141, a study of nivolumab,
another PD-1 inhibitor, was stopped early due to a survival
advantage observed among patients who were treated with
nivolumab over investigators choice of therapy (cetuximab,
methotrexate, or docetaxel) in a second-line, recurrent/
metastatic setting. Details of the results have not yet
been released (NCT02105636). 9
PD-L1 Inhibitor
Durvalumab (formerly MEDI4736) is an antiPD-L1 mono-
clonal antibody that was evaluated in a large global, mul-
ticenter, multiarm phase I/II trial in multiple disease
sites, including head and neck squamous cell carcinoma
(NCT01693562/CD-ON-MEDI4736-1108).10 This large trial
included components of dose escalation and dose explo-
ration to define optimum biologic dose. Dose cohorts
started at 0.1 mg/kg and escalated in five consecutive co-
horts to 10 mg/kg, which was then taken to the expansion
phase as the selected dose. Although the overall rate of
drug-related adverse events was high (46%), 10 mg/kg of
durvalumab every 2 weeks resulted in grade 3 or 4 drug-
related adverse events (determined by investigators) in only
7% of patients with head and neck cancer, a rate that was
similar to other malignancies.11 Among all types of cancer,
fatigue, gastrointestinal symptoms, endocrinopathies,
dyspnea, peripheral neuropathy, and a variety skin rashes
were reported as more common drug-related adverse
events. Drug-related colitis did not occur, and drug-related
pneumonitis (grade 1 to 2 only) was only reported in 3%
of patients with head and neck cancer. There were no

drug-related discontinuations, and, overall, durvalumab was
well-tolerated among patients with head and neck cancer and
was similar to responses observed in other cancers.12 Among
eight tumor types, response was seen as early as 5 weeks and
was very durable (56 weeks) in some cases. Overall response
rate was 10%, which was generally higher among pa-
tients who were PD-L1positive (22% vs. 5%), and, once re-
sponse was achieved, duration of response was comparable
among patients who were PD-L1positive and PD-L1negative.11
Patients demonstrated a similar pattern: the response rate
was slightly higher among patients who were PD-L1
positive versus PD-L1negative (18% vs. 8%, respectively)
with a respectable duration of response (16 to over 55 weeks).
The overall response rate among patients with head and neck
cancer was 11%, and the disease control rate (response plus
stable disease) at 6 months was 15% (18% for PD-L1positive
vs. 11% for PD-L1negative).12
These findings were very encouraging from a safety and
tolerability standpoint and showed promising improvement
in response and duration of disease control, particularly in
the PD-L1positive population.
PD-L1 Inhibitor in Combination With CTLA-4 Inhibitor
A new series of combination studies in head and neck
squamous cell carcinoma were initiated based on additive or
synergistic effects of drug combinations observed in pre-
clinical studies or other diseases. The PD-1 (nivolumab) and
CTLA-4 inhibitor (ipilimumab) combination was shown to
be superior to CTLA inhibition alone among patients with
metastatic malignant melanoma and superior to either
CTLA-4 or PD-1 inhibition alone among patients who were
PD-L1negative, resulting in significantly prolonged PFS.13
Other emerging data support distinct mechanisms and a
synergistic effect of CTLA-4 and PD-L1 inhibition on immune
regulation, which results in improved tumor response in
mouse models and for patients.14
Multiple ongoing studies are currently evaluating the role
of dual checkpoint inhibition in head and neck squamous
cell carcinoma. Some of these studies are directed toward
PD-L1negative disease and others are stratified based on
PD-L1 status.
Patients with recurrent/metastatic head and neck squa-
mous cell carcinoma whose disease progresses during
platinum therapy will be offered PD-L1 inhibitor alone (those
who are PD-L1positive; 10 mg/kg durvalumab every
2 weeks; HAWK; NCT02207530)15 or those who are PD-
L1negative will be randomly assigned to one of three arms
to receive combination PD-L1 and CTLA-4 inhibition
(durvalumab and tremelimumab), PD-L1 inhibitor alone
(durvalumab), or CTLA-4 inhibitor alone (tremelimumab;
CONDOR; NCT02319044).16 The primary endpoint in both
studies is overall response rate. A separate large phase III
study will randomly assign patients after PD-L1 expression
based stratification to receive PD-L1 inhibitor alone (durva-
lumab), dual PD-L1/CTLA-4 inhibitor therapy (durvalu-
mab and tremelimumab), or standard-of-care single-agent
IMMUNOTHERAPY FOR HEAD AND NECK CANCER
chemotherapy. This study is powered to evaluate the coprimay
endpoints of PFS and OS (EAGLE; NCT02369874).17
PD-L1 Inhibitor in Combination With PD-1 Inhibitor
Some ongoing studies in advanced solid tumors are evaluating
dual PD-1 (MEDI0680)/PD-L1 (durvalumab) inhibition.18 These
studies are currently in earlier phases of dose escalation and
expansion (NCT02118337).19
ADDITIONAL IMMUNE THERAPY STRATEGIES
Positive Costimulation
Another strategy to augment immune system recognition
of cancer cells has focused on enhancement of positive
stimulatory pathways through cytokines and monoclonal
antibodies.
Preclinical data suggest that Toll-like receptor 8 (TLR8)
activation subsequently activates monocytes, natural killer
cells, and myeloid-derived dendritic cells and can potentially
have synergistic effect with chemotherapy and increase the
effectiveness of monoclonal antibody treatment.20
A randomized study of platinum/5-fluorouracil/cetuximab
plus a TLR8 agonist (VTX-2337) or placebo recently com-
pleted accrual in first-line recurrent/metastatic head and
neck squamous cell carcinoma (NCT01836029).21 Many
other products are being investigated as single agent or in
combination, including the CD137 agonist, urelumab
(NCT02110082, NCT02253992),22,23 and Ox40 monoclonal
antibodies (in other malignancies).
EGFR Monoclonal Antibody
Cetuximab is a mouse-human chimeric monoclonal antibody
against EGFR, a well-recognized target in head and neck
squamous cell carcinoma.24 Cetuximab has shown efficacy
in recurrent and metastatic head and neck squamous cell
carcinoma and in combination with radiation in the curative
setting.25,26 Several studies have demonstrated immuno-
modulatory effects with EGFR monoclonal antibodies
through multiple mechanisms including tumor-antigen
specific T-cell activation27,28 as a result of T-cell activation
through interaction with antigen presenting cells. Ongoing
studies are investigating cetuximab combination with
different checkpoint inhibitors, for example nivolumab
(NCT02124850),29 ipilimumab (NCT01860430),30 and ure-
lumab (NCT02110082).22
Therapeutic HPV Vaccines
Given the encouraging results with HPV-specific vaccine
prevention studies,31 many ongoing trials are focused on
treatment of already established HPV-related head and neck
cancer. Subcutaneous injection of HPV-16 peptide vaccine
for patients with recurrent/metastatic head and neck
squamous cell carcinoma was well tolerated and able to
stimulate cellular and humoral immune response.32 Other
studies have used bacterial or viral vaccine-base to deliver
tumor-specific antigen and to use the dual advantage of bacterial/
viral-induced immunogenicity as well as tumor-specific
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e279
HASHEMI SADRAEI, SIKORA, AND BRIZEL
antigens like E6 and E7, which have a well-established role
in HPV-related malignancies.33
Many such studies are ongoing or in the early develop-
ment phase and some include multiple HPV-related malig-
nancies (NCT02526316, NCT00019110).34,35
PREDICTORS OF RESPONSE TO CHECKPOINT
INHIBITORS
A post hoc analysis of nearly 200 patients treated with
pembrolizumab showed that patients who were less heavily
retreated (two or less prior lines of therapy) had higher re-
sponse rates compared with heavily pretreated patients (32%
vs. 16%, respectively). Patients who had smaller volumes
of disease had improved response compared with those
with larger volumes of disease (36% vs. 14%, respectively).5
Small-volume disease was defined in one study as being
less than the median of the sum of the size of the lesions,
where the median was 96 mm (range, 10 to 664 mm).5
Patients with higher PD-L1 expression seem to derive a
greater benefit as demonstrated by a much higher response
compared with those with a lower PD-L1 expression when
treated with pembrolizumab (50% vs. 11%, respectively)4 or
durvalumab (22% PD-L1positive vs. 5% PD-L1negative).12
Interestingly, unlike many prior chemotherapy studies,
patients with HPV-negative and HPV-positive disease did not
demonstrate different response rates when treated with
PD-1 inhibition (25% HPV-negative vs. 24% HPV-positive).5
RESPONSE EVALUATION
Many recent studies have acknowledged differences in time
to initiation of response, as well as patterns of response
between immune therapy and cytotoxic chemotherapy.
Although chemotherapy and targeted therapy directly exert
their effect on cancer cells and can result in a more rapid
development of response, radiographic responses to im-
mune therapy develop more slowly because of the nature of
its indirect effect on cancer cells through activation or
disinhibition of the immune system. The original CTLA-4
inhibitor studies in melanoma (with ipilimumab) showed a
rather slow time to initiation of response (3 to 4 months)36,37;
however, the more recent PD-1 (pembrolizumab) and PD-L1
(durvalumab) inhibitors demonstrate a shorter time to re-
sponse, as early as 5 weeks,12 with a median time to response
of 9 weeks (range, 7 to 18 weeks).5,38
One of the challenges in response assessment and de-
termination of progression of disease with such treatments
has been a concern for tumor-flare, a phenomenon that has
been attributed to initial T-cell infiltration into the tumor,
causing increase in the size of lesions. This finding has been
mostly reported among patients with melanoma who were
treated with CTLA-4 inhibition.37,39 Interestingly, unlike
patients with melanoma undergoing treatment with ipili-
mumab, there seem to be very few patients with head and
neck cancer who experience initial radiographic progression
of disease during treatment with PD-1 or PD-L1 inhibitors
who later show response to these treatments (for example,
e280 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
in the Keynote 012 pembrolizumab study, none of the
132 reported patients had a RECIST-defined radiographic
progression of disease prior to response).38 These data
suggest that, in comparison with patients with melanoma
receiving a CTLA-4 inhibitor, clinicians must have a lower
threshold for recognizing increase in size of disease as
true progression, especially if accompanied by worsening
symptoms.38,40
PROGRESS AND CHALLENGES
Immune-modulating treatments appear to have a clear
clinical benefit for patients with head and neck squamous
cell carcinoma, as shown by multiple clinical studies in the
recurrent/metastatic setting. This benefit seems to be in-
dependent of previous treatment, even being observed
among patients who have received multiple lines of therapy
and who have been assumed to have exhausted all options.
Although patients with poor performance status and mul-
tiple comorbidities have been excluded from these early
trials, the safety and toxicity profiles of these drugs have
been very promising, suggesting applicability to a wider
population of patients compared with many cytotoxic
chemotherapeutic agents.
Many questions remain to be answered. As far as design of
future studies, perhaps most importantly, we must address
whether the primary benefit should be measured by response or
survival. Although, among patients who have been heavily
pretreated, response rates of 10% to 20% are considered re-
spectable (compared with the 3% to 13% historical response rates
among previously treated recurrent/metastatic patients25,41-43),
it is the duration of response and the improvement in OS that
clearly differentiates these drugs from chemotherapy (median
time to progression, 2 to 4 months; median OS, 6 to 7 months
in chemotherapy studies of patients who were previously
treated25,41,43). The use of response as a primary endpoint for
some studies may therefore underestimate the actual benefit.40
It also appears that the Immune-Related Response Criteria
(irRECIST), which was originally developed based on response
evaluation for patients with melanoma who were undergoing
CTLA-4 inhibition, may not be the most accurate method of
measuring response (and hence benefit) across all checkpoint
inhibitors and all types of disease.39,40,44 The search for a re-
liable biomarker to predict clinic benefit continues. The
prognostic value of PD-1 and PD-L1 expression has varied
across studies, potentially because of the difficulty of accurately
quantifying expression levels and determining appropriate
cutoff levels for antigen positivity. An additional confounder
is that upregulation of PD-1 and PD-L1 can be induced by
interferon-gamma, one hallmark of a strong intratumoral T-cell
response.45-47 In fact, several studies across different cancer
types have shown positive association of PD-L1 expression with
survival in head and neck squamous cell carcinoma48,49 and
other cancers.50-52 This seemingly paradoxical association is
consistent with upregulation of PD-1/PD-L1 in response to host
immune pressure and suggests that these molecules may serve
as a potential biomarker of vigorous antitumor immunity.

As the field of biomarker research is evolving, an additional
candidate biomarker of response, consistent with PD-1/PD-
L1 axis upregulation induced by antitumor immune
response, is the presence of so-called T-cell inflamed
phenotype gene expression signatures,53 which has been
suggested to predict benefit from antiPD-1 in patients
with head and neck squamous cell carcinoma.54
CONCLUSION
In summary, even in the absence of a RECIST- or irRECIST-
defined response, there appears to be a heretofore
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HEAD AND NECK CANCER

Multimodality Management of
Locoregionally Recurrent or
Second Primary Head and Neck
Cancer

CHAIR
Stuart J. Wong, MD
Medical College of Wisconsin
Milwaukee, WI

SPEAKERS
Dwight E. Heron, MD
University of Pittsburgh Medical Center
Pittsburgh, PA

Kerstin Stenson, MD
Rush University Medical Center
Chicago, IL
WONG ET AL

Locoregional Recurrent or Second Primary Head and Neck

Cancer: Management Strategies and Challenges
Stuart J. Wong, MD, Dwight E. Heron, MD, MBA, FACRO, FACR, Kerstin Stenson, MD, FACS, Diane C. Ling,
MD, and John A. Vargo, MD

OVERVIEW

Treatment of patients with locoregional recurrent or second primary head and neck squamous cell cancer (HNSCC) has been
guided by well-reasoned principles and informed by carefully tested chemotherapy and radiation regimens. However,
clinical decision making for this population is complicated by many factors. Although surgery is generally considered the
treatment of choice for patients with HNSCC with recurrent disease or new second primary disease in a previously irradiated
field, operability of cases is not always straightforward. Postoperative treatment is frequently warranted but carries
significant risk. In addition, the rapid rise in the incidence of HPV-associated HNSCC raises the question of whether
established treatment paradigms should be re-examined in this population of patients with a much better prognosis than the
non-HPV population. Furthermore, new radiation techniques and new systemic agents show early promising results in
recent clinical studies, suggesting potential for practice-changing effects in the future management of this disease. This
article examines each of the treatment modalities used in the care of patients with HNSCC with recurrent or new second
primary disease and provides a perspective to aid clinicians in the management of this disease.

T he majority of patients newly diagnosed with HNSCC

present with locally advanced cancer and undergo
combined modality therapy, including radiation therapy. For
this patient group who subsequently fail in a local or regional
site, the therapeutic options are complicatedmost com-
monly because of overlap of the previous radiation portal. In
addition, the management of locoregional recurrent or
second primary head and neck cancer has grown in com-
plexity as a result of the increase of the relative incidence
of HPV-associated HNSCC compared with non-HPV HNSCC.
Practicing oncologists have more treatment options at their
disposal, which further complicates the treatment decision-
making process. For instance, reirradiation was considered
a treatment option limited to high-volume centers with
abundant experience with this therapy. It is now far more
acceptable to use reirradiation outside of the clinical trial
setting. The wide use of this salvage treatment modality is
evident by numerous publications demonstrating safety and
efficacy of concurrent chemotherapy and reirradiation.
It is well recognized that diagnosis of HPV-associated
HNSCC carries a more favorable prognosis compared with
non-HPV HNSCC.1 However, the failure pattern of HPV-
associated oropharynx cancer (OPC) and its sensitivity to
treatment in the setting of recurrent disease is less well
appreciated. Examination of the treatment for patients
with HPV-positive OPC in Radiation Therapy Oncology
Group (RTOG) studies provides a clear picture as to the
failure patterns of this patient population.2 This analysis
showed that following disease progression, 2-year overall
survival was nearly twice as high for patients with HPV-
positive OPC compared with patients who were HPV-
negative (55% vs. 28%, respectively). The majority of
these patients fail within 1 year after completing de-
finitive therapy. Although ostensibly it is logical to apply
the same oncologic principles to each of these two patient
groups, it is important to note that we do not have
abundant clinical trial information with long-term follow-
up data to guide these treatment decisions. The sequence
of salvage treatment options for these two categories of
patients given the differences in outcome remains the
subject of future investigation.
In the following discussion, we will review treatment
options for patients with recurrent and second primary
HNSCC in the context of the evolving epidemiologic patterns
of this disease. In particular, we will discuss surgical ap-
proaches to this disease, the use of new and conventional
radiation therapy techniques, and systemic therapeutic
options.

From the University of Pittsburgh Cancer Institute, Pittsburgh, PA; University of Pittsburgh School of Medicine, Pittsburgh, PA; Rush University Medical Center, Chicago, IL; Medical
College of Wisconsin, Milwaukee, WI.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Stuart J. Wong, MD, Medical College of Wisconsin, 9200 West Wisconsin Ave., Milwaukee, WI 53226; email: swong@mcw.edu.

2016 by American Society of Clinical Oncology.

e284 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


SURGICAL MANAGEMENT OF PREVIOUSLY
IRRADIATED HEAD AND NECK CANCER: SALVAGE
AND TREATMENT MANAGEMENT STRATEGIES
BEFORE AND AFTER REIRRADIATION
The goals of multimodality strategies for patients with ad-
vanced head and neck cancer encompass organ preservation
through less radical surgery while improving outcomes. As
survival improved and multimodality organ preservation
strategies became more successful, the role of surgery was
redefined and has become increasingly more prominent for
patients with recurrent disease. Most surgeons hold a general
dogma that performing surgery on a patient who has pre-
viously undergone radiation or chemoradiation (CRT) can be
a challenging task. The salvage surgical approach may be not
only technically challenging but also associated with a higher
incidence of complications, such as wound-healing problems,
fistula, and infection. This discussion will address some of the
challenges that patients with recurrent HNSCC confront when
they are faced with salvage surgery. Important preoperative
considerations will be discussed, specific site considerations
will be presented, and the rationale for surgical palliation will
be addressed.
Preoperative Considerations
Patient factors. Adequate access to nutrition is critical not
only for perioperative health and wound healing but also for
efficient postoperative care of the patient. Extended post-
operative nil per os status should be anticipated for patients
with previous radiation or CRT who undergo large re-
sections. One should strongly consider placement of a
gastric tube. Previous studies have shown the benefit of a
gastric tube compared with a nasogastric tube in terms of
patient comfort, cosmesis, durability, and ease of tube
feeding.3,4 It is also essential that patients are euthyroid
before any planned surgery. Thyroid-stimulating hormone
levels are routinely evaluated not only before surgery but
also for the entire lifetime of the patient who has undergone
radiation or CRT. Hypothyroidism negatively affects wound
healing and occurs in at least 40% of patients treated with
KEY POINTS
HPV remains prognostic in recurrent HNSCC, challenging
existing paradigms.
Salvage surgery remains standard whenever feasible.
Modern reirradiation with intensity-modulated
radiation therapy or stereotactic body radiation therapy
widens the therapeutic ratio of reirradiation.
The addition of cetuximab to 5-fluorouracil and cisplatin
has redefined the standard for systemic therapy in
HNSCC not amendable to surgery or reirradiation, even
in HPV-positive HNSCC.
Novel systemic therapies, including immune checkpoint
inhibitors, show promising early results warranting
additional ongoing prospective study.
RECURRENT HEAD AND NECK CANCER
radiation or CRT.5,6 For patients and physicians to gain
perspective and evaluate risk/benefit ratio of surgery, pa-
tients with advanced head and neck cancer who have
completed radiation or CRT need a full metastatic workup
before surgery. This includes CT scan of the head, neck, and
chest and/or PET scan.
Creating a safe wound. Experience and literature docu-
ment the increased risk of fistula and other complications for
patients undergoing salvage surgery who have received
prior radiation or CRT. Use of nonirradiated free tissue has
been shown to provide reliable reconstruction that allows
for maximal resection, unhampered by concerns of ade-
quate tissue availability.7-10 For patients who undergo
surgery after prior irradiation, free tissue transfer with
microvascular anastomoses allows for successful wound
rehabilitation.11 Paramount in caring for our patients who
will undergo resection in an irradiated bed is the surgeons
understanding of the type and volume of tissue needing
resection, the vulnerability of the surrounding structures,
and the amount of nonirradiated tissue needed to re-
construct the defect. In essence, a safe wound must be
created to limit the potential toxicity from wound break-
down after salvage surgery or tissue necrosis from reirra-
diation. A safe wound is one that will offer protection of
carotid and vertebral arteries (preventing major vessel
rupture) and cover potential exposed bone in a hostile
wound environment (fistula or tissue necrosis). Surgeons
must carefully evaluate preoperative imaging to determine
what anatomic areas will be vulnerable in these situations
(Figs. 1 and 2). Some patients are scheduled to undergo
(chemo-)reirradiation without planned prior surgery. The
team is responsible for determining if carotid arteries or
other areas will become exposed with the added high
FIGURE 1. Patient With Recurrent Palate Carcinoma
After Chemoradiation
Arrow shows internal carotid artery and adjacent tumor.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e285
WONG ET AL
FIGURE 2. Same Patient After Resection and
Reconstruction With Radial Forearm Free Flap
Vulnerable area of carotid is covered with healthy tissue.
radiation doses. If the patient is at risk for wound break-
down, if feasible, the surgeon should plan to cover vul-
nerable vessels or bony areas with vascularized tissue prior
to reirradiation. Often, the team must weigh the risk of
major vessel rupture (if the wound is not safe) with the risk of
delaying the start of reirradiation.
Rationale for salvage surgery. The treatment of patients with
recurrent advanced disease remains a challenge and demands
the thoughtful input of multidisciplinary teams. Although his-
torical series have shown overall poor prognosis for this group of
patients in general, surgical salvage is considered the standard
treatment and offers the best opportunity for locoregional
control and perhaps cure when compared with chemotherapy
or reirradiation alone. In arguably one of the most notable
studies of salvage surgery, Goodwin et al found that 2-year
survival was predicted by stage (73% for stage I and 22% for
stage IV; p = .0005) and site (laryngeal 76%, oral cavity 47%, and
pharyngeal sites 24%; p = .0645).12 Others have found that time
to recurrence and interval from previous radiation, use of
chemotherapy, comorbidity, performance status, pre-existing
organ dysfunction, and N3 neck disease are also negatively
correlated with survival.13-22 Surgical salvage, even with neg-
ative margins, is associated with high recurrence rates, with
approximately 67% overall failure rate. Multiple factors in-
cluding tumor-acquired radiation and chemotherapy resistance,
pathologic patterns of submucosal multiple microscopic nests,
and/or perineural, perivascular, or perilymphatic invasion are
thought to contribute to the recurrence rates after salvage
e286 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
surgery. The influence of these latter factors has driven on-
cologists and scientists to develop reirradiation treatment
strategies. Salvage surgery as a first step seems to positively
affect survival, as does concomitant chemo-reirradiation.22,23
Despite these improvements, acute and late treatment toxic-
ities remain high.
Specific Sites and Surgical Approaches
Neck management. Salvage neck dissections for isolated
neck recurrence or in combination with primary site re-
currence are a heterogeneous group. Dissections may be
straightforward radical neck dissection with coverage of
vessels with a simple pectoralis myocutaneous flap. Alter-
natively, salvage neck dissections may involve resection/
reconstruction of the carotid artery, cranial nerves, deep
neck muscles, and/or vertebral arteries. Jones et al noted a
31% 5-year survival in the 69 (of 589) patients undergoing a
second neck dissection. Younger and more fit patients and
those with low T and N stage at presentation had better
survival than older patients and those with high T and
N stage.24 Mourad et al presented data for 51 patients (nine
who had undergone prior radiation) who underwent carotid
resection and in-line carotid artery bypass grafting. There
was an 82% 2-year survival and low neuromorbidity (2 of 51
had perioperative stroke).25 These findings and others sup-
port aggressive neck resection and carotid replacement
particularly for younger patients.
Primary sites. There have been great technical advances in
surgical approaches for salvage of primary site recurrences.
These developments mirror those occurring in surgical ap-
proaches for the untreated patient. For example, in re-
current nasopharyngeal cancers, image-guided endosurgery
is precise and effective, offers improved recovery, and
is safer than open approaches.26 Salvage endoscopic
nasopharyngectomy has also been found to be superior to
intensity-modulated radiation therapy (IMRT) in terms of
survival and quality of life parameters.27 Transoral robotic
surgery has been found to be an oncologically sound al-
ternative to open surgical procedures and is superior in
terms of functional and recovery outcomes.28 In addition,
transoral laser microsurgery has been shown to have
comparable oncologic outcomes with superior function
and less morbidity compared with open partial or total
laryngectomy.29
Palliation
Survival statistics, surgical complication rates, and treatment
toxicities, as significant as they are, do not provide a full
picture of the positive and negative effects of surgical
treatment on patients with recurrent cancer. More impor-
tantly, surgery has a compelling role in palliation for patients
with recurrent head and neck cancers. All major U.S.
medical, ethical, and religious organizations recognize that it
is imperative to treat the distressing symptoms of patients
who are dying.30 Palliative surgical treatment is nuanced and

requires knowledge of a patients unique medical condition
at the time, as well as the patients personality and family
dynamics. A clear definition of palliative surgery has evolved
and remains consistent with those standardized principles of
palliative care in general: Surgical procedures used for the
primary intention of improving quality of life or relieving
symptoms caused by advanced disease.30
The indications for palliative surgery are not well de-
fined, though many would support palliative resection when
confronted with potential suffocation, carotid rupture,
prevention of quadriplegia (in the instance of tumor erosion
into cervical spine), or control of foul, ulcerative wounds.
Patients typically do not live longer (though a small per-
centage are cured by the operation with or without post-
operative adjuvant treatment), but there is great potential
for better living during the patients remaining life. The
pattern of disease progression can change, where instead of
dying with a painful, odiferous, ulcerative mass, the patient
is allowed to die of distant disease.31-34 Resource utilization
associated with palliative-intent surgeries have been shown
to be similar to that associated with curative intent sur-
geries.35 However, patients with palliative-intent surgery
have differing resource needs.
A quote by Gaisford perhaps best summarizes the goals in
palliative surgery: Palliative surgical procedures can be of
greater magnitude than curative operations, and the head
and neck cancer surgeon must be ready, willing, and
ablebut mostly willingto carry them out. There is in the
last analysis no absolute rulethe surgeon who accepts
patients with cancer for their initial care is obligated to care
for them throughout the course of their disease.36
The multidisciplinary teams ability to support our pa-
tients who undergo salvage surgery has improved over
the years through more robust reconstructions and ad-
vances in perioperative care. Nonetheless, salvage surgery is
nearly always radical, morbid, and technically challenging.
Awareness of a patients social support is as critical as
knowledge of their comorbidities and physical ability to
withstand an often-long operation with even longer re-
covery. What must be clear is the patients willingness to
accept that survival, not function, is the overriding goal in
salvage treatment. Some patients may want to maintain as
much quality of life (as defined by the individual patient) and
choose palliative chemotherapy or hospice care. Knowing
our patients well enough to help guide them in their choice
of treatment remains one of the great privileges of being a
doctor.
ROLE OF CONVENTIONAL AND ABLATIVE
RADIOTHERAPY IN THE MANAGEMENT OF
RECURRENT, SECOND PRIMARY, AND/OR
PREVIOUSLY IRRADIATED HEAD AND NECK
CANCER
Conventional Reirradiation
Historically, reirradiation to locoregional recurrences or
new primary cancers within a previously irradiated field has
been discouraged because of concern over excessive normal
RECURRENT HEAD AND NECK CANCER
tissue toxicity. An early retrospective study by the Institut
Gustave-Roussy reported outcomes on 169 patients with
unresectable disease treated with curative-intent full-dose
reirradiation with or without chemotherapy.37 At a median
follow-up of 70 months, the median overall survival was
10 months with an overall survival rate of 21% at 2 years and
9% at 5 years. This modest improvement in salvage outcome
came at the expense of high toxicity rates, with 46% of
patients experiencing grade 3 or greater mucositis. Others
have reported similar results using conventional radiation
therapy techniques.38-40
Two phase II RTOG trials using split-course hyper-
fractionated reirradiation and chemotherapy subsequently
followed. RTOG 9610 found that concurrent hydroxyurea
and 5-fluorouracil (5-FU) resulted in a median survival of
8.5 months and overall survival rates of 15.2% and 3.8% at
2 and 5 years, respectively.41 RTOG 9911 used concurrent
cisplatin and paclitaxel, achieving a slightly better median
survival of 12.1 months and a 2-year survival rate of 25.9%.42
However, high toxicity was reported in both studies, with a
63%78% rate of grade 3 or greater acute toxicity, 22%37%
rate of grade 3 or greater late toxicity, and overall 8%9%
treatment-related death.
Given the consistently high rates of toxicity reported,
many have questioned whether treatment toxicity out-
weighs the potential benefits of reirradiation, especially
given that the median survival only marginally exceeds the
6 to 9 months of chemotherapy alone.43-46 Efforts have been
made to identify patients who might benefit the most from
this highly aggressive approach. In RTOG 9610, an interval
of more than 1 year from prior radiation therapy was
identified as a significant predictor of improved survival
(median survival, 9.8 months vs. 5.8 months; p = .036).41 In
a long-term study at The University of Chicago, the authors
identified reirradiation dose, triple-agent chemotherapy
(cisplatin, paclitaxel, and gemcitabine), and surgery as in-
dependent prognostic factors for overall survival, progression-
free survival, and locoregional control.22 Nineteen (16.5%)
patients died of treatment toxicity in this study, attesting to
the morbidity of this approach. More recently, HPV status
has been shown to be strongly prognostic in the setting
of reirradiation and may help to select patients more likely
to benefit from aggressive salvage treatments such as
reirradiation.2,47
Intensity-Modulated Radiation Therapy
Recent technologic advances such as IMRT offer potentially
superior local control rates in the reirradiation setting
with fewer late effects compared with more conventional
techniques. For instance, Lee et al reported a 2-year
locoregional control rate of 52% compared with 20% among
patients treated with IMRT and those treated with con-
ventional radiation techniques, respectively.48 In addition,
patients with locoregional progression-free disease had
better 2-year overall survival compared with those with
locoregional failure, further demonstrating the need to
maintain locoregional control to improve survival. High
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WONG ET AL
treatment morbidity occurred, although at a lower rate than
reported in prior studies utilizing conventional techniques.
Acute and late-grade 3-4 toxicities were reported in 23% and
15% of patients, respectively.48 Similar findings have been
published by other authors.49-51
Stereotactic Body Radiation Therapy
Stereotactic body radiation therapy (SBRT) offers further op-
portunities to deliver highly conformal treatments with com-
parable local control and overall survival, shorter treatment
times, and decreased toxicity compared with conventional
techniques.52 The most common SBRT regimen consists of five
fractions delivered on alternating days,52 which has been
shown to be safer than treatment delivered on consecutive
days.53,54 There has been increasing interest in SBRT as an
alternative technique for reirradiation, with several phase I and
phase II trials showing promising safety and efficacy results.55-58
A phase I dose-escalation trial from the University of Pittsburgh
Cancer Institute showed that reirradiation up to 44 Gy using
SBRT is well tolerated in the acute setting.58 A subsequent
dose-escalation study identified a clear dose-volume response
with local control that became more prominent for gross tumor
volumes greater than 25 cc with longer follow-up times.59
The use of novel EGFR-targeted agents may help to further
improve disease outcome while minimizing additional toxicity.
Because concurrent cetuximab with radiation therapy has been
shown to significantly improve local control and survival for
primary head and neck cancer without major increases in
mucosal toxicity,60 there has been interest in the application of
this agent as a radiosensitizer in the reirradiation setting. This
was explored in a single-institution, matched, case-control
study, which found that cetuximab conferred a locoregional
and overall survival advantage without a major increase in
toxicity.61 In a subsequent phase II trial on SBRT with con-
current cetuximab for previously irradiated HNSCC, the authors
reported a median overall survival of 10 months, with a 1-year
progression-free survival rate of 60%. Acute and late-grade 3
toxicity were each observed in 6% of patients, much lower than
reported in studies of other techniques.57 A similar French
phase II study reported a median survival of 11.8 months, with
32% of patients experiencing grade 3 toxicities.55 However,
although the risk of severe late toxicity increases significantly
beyond 5 years,62 follow-up for most studies have been limited
to 1 to 2 years, pointing to the need for long-term studies.
Local control and lower rates of toxicity with SBRT may
theoretically affect quality of life. In a prospective evaluation
of patient-reported quality of life outcomes following SBRT
with or without cetuximab, overall quality of life and mul-
tiple domains commonly affected by reirradiation pro-
gressively improved following an initial 1-month decline,
speaking to the positive palliative benefits of improved local
control afforded by conformal reirradiation with SBRT.63
Postoperative Reirradiation
Reirradiation in the postoperative setting has been studied in
GETTEC/GORTEC 9901, a phase III trial in which patients who
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had previously undergone radiation were randomly assigned to
reirradiation (60 Gy over 11 weeks in 2 Gy daily fractions) with
concurrent hydroxyurea and 5-FU or observation following
salvage surgery. Disease-free survival and locoregional control
were both significantly superior in the reirradiation group, but
there was no difference in overall survival. The reirradiation
arm experienced significantly higher rates of grade 3-4 toxic-
ities compared with the observation arm (39% vs. 10%).64
These results support a high threshold for postoperative
reirradiation following salvage surgery. Primary considerations
include high complication rates from combined therapy, large
radiation volumes required to cover the postoperative bed,
high competing risks of outside-field recurrence (such as dis-
tant metastases and second primary cancer), and a lack of a
survival advantage. However, small-field postoperative reir-
radiation may be appropriate in select cases with high-risk
features such as extracapsular extension or positive margins.
The use of SBRT in this setting was recently explored in a
small retrospective study of 28 patients with high-risk fea-
tures (predominately extracapsular extension or close/positive
margins). At a median follow-up of 14 months, the 1-year
locoregional control and overall survival were 51% and 64%,
respectively, while rates of acute and late-grade 3 and higher
toxicities were low at 0% and 8%, respectively.23 The role of
postoperative SBRT is currently being explored in a randomized
phase II trial at the University of Pittsburgh Cancer Institute.
Considerations to Reduce Toxicity
Patient selection with regard to performance status, medical
comorbidities, time interval since last radiation, prior dose
received, extent of existing late toxicity burden, and tumor
location and size should be carefully performed. With regard
to treatment parameters, it has been reported that 96% of
failures occur within the gross tumor volume 95% isodose
line,65 suggesting that target volume should be limited to
only high-risk areas to minimize toxicity. A clinical target
volume confined to the gross target volume plus a margin is
recommended.48,49 Induction or concurrent systemic ther-
apy, including novel targeted therapy agents, may allow a
reduction in radiation dose. An ongoing phase II trial is being
conducted by the GORTEC to evaluate reirradiation using
a hyperfractionated scheme with concurrent cetuximab
(NCT01237483). Finally, recent technologic advancements
such as IMRT and SBRT offer potentially noninferior onco-
logic outcomes with lower toxicity rates compared with
conventional methods, although supporting phase III data
continues to evolve.
SYSTEMIC THERAPEUTIC OPTIONS FOR
RECURRENT/SECOND PRIMARY HEAD AND NECK
CANCERS
Combination Chemotherapy for Unresectable
Recurrent or Second Primary HNSCC
Systemic therapy, in general, is considered to be the
least effective of the three treatment modalities used in
the management of HNSCC. This is because, as a single

treatment modality, chemotherapy alone does not have the
capability of eliciting curative treatment effectsunlike
surgery or radiation therapy. In terms of achieving a cure for
head and neck cancer, the primary role of systemic therapy
is as a sensitizer for radiation therapy. As described in
the preceding section, reirradiation has the possibility of
achieving long-term tumor control and survival for patients
with unresectable, locoregional recurrent HNSCC. This raises
the difficult question that oncologists frequently struggle
with in the clinicwhether systemic chemotherapy or
concurrent chemo-reirradiation should be used as the first-
line treatment for a patient with unresectable locoregional
recurrent HNSCC. To address this question, it will be useful to
first review clinical trials that have examined systemic
chemotherapy regimens.
The EXTREME study was a phase III trial comparing cis-
platin, 5-FU, and cetuximab with cisplatin and 5-FU for
patients with HNSCC with recurrent or metastatic disease.66
A maximum of six cycles of chemotherapy was admin-
istered in both arms. In the experimental arm, weekly
maintenance cetuximab was prescribed following the
course of combination systemic therapy. The results of this
study demonstrated an overall survival advantage favoring
the experimental arm, with a median overall survival of
10.1 months and 7.4 months for the chemotherapy-
cetuximab arm compared with the chemotherapy-alone
arm, respectively. A subsequent ad hoc analysis of this
study showed that the beneficial effects of adding cetuximab
to chemotherapy were independent of HPV status.67 The
results of EXTREME study were surprising in the sense that
numerous phase III studies in the preceding decades failed to
demonstrate superiority of newer, presumably more active,
drug combinations compared with older, presumably less
active, drug regimens. ECOG 1395 was a phase III trial that
compared cisplatin and paclitaxel with cisplatin and 5-FU.46
The experimental armcisplatin and paclitaxelfailed to
demonstrate an overall survival advantage; the median
overall survival was 8.1 months and 8.7 months, re-
spectively, for the cisplatin-paclitaxel and the cisplatin/5-FU
arms. A preceding phase III study compared cisplatin plus
5-FU with either drug alone.68 Although the cisplatin/5-FU
arm achieved a higher overall response rate compared with
the single-agent arms, this did not translate into an im-
provement in overall survival. Hence, in the context of this
historical background it is clear why the results of the EX-
TREME trial were practice changing and why this regimen
has been solidified as the current standard of care.
Systemic Therapy Compared With Reirradiation
The results of the EXTREME study raise a logical and highly
clinically relevant question: will the EXTREME regimen
provide a superior outcome compared with concurrent
chemo-reirradiation for patients with unresectable locore-
gional recurrent HNSCC? To answer this question would
require a head-to-head study comparing these two ap-
proaches; to date no such data exist. However, it is
RECURRENT HEAD AND NECK CANCER
extremely unlikely that a study with this design will ever
come to fruition based on previous experience with this
disease.
RTOG 0421 (NCT00113399) was a phase III study launched
in 2005 that compared reirradiation and concurrent che-
motherapy with chemotherapy alone. This trial used the
cisplatin and paclitaxel reirradiation regimen of RTOG 9911
(as described in the preceding section), which showed an
incremental improvement over the preceding study, RTOG
9610. The 2-year survival rate demonstrated in RTOG 9911
was 26%, which compared favorably with survival data from
contemporary chemotherapy-alone studies.69 It was within
this backdrop that RTOG 0421 was launched.
Simultaneously, the GORTEC group initiated a phase III
study in France, GORTEC 9803, which also compared chemo-
reirradiation with chemotherapy alone.70 Unfortunately,
neither of these studies were able to complete accrual,
leaving this important clinical question unanswered. Even
though no conclusion could be drawn from these studies,
some useful observations were made. First, the inability to
complete these studies strongly suggested a bias on behalf
of treating physicians favoring reirradiation that hampered
accrual. Second, there seemed to be a shift in the wide-
spread use and acceptance of reirradiation. Since the early
days after reirradiation was first described,37,40 it had been
considered a novel and potential very dangerous therapy,
performed primarily at larger-volume academic centers with
experience in this technique. However, by the time RTOG
0421 was activated, a shift toward general acceptance of
reirradiation had occurred regarding the safety and a level of
comfort with the procedure. The confluence of these two
issues doomed these trials from achieving completion,
leaving the central question unanswered.
Both of RTOG 0421 and the GORTEC 9803 studies were
designed in an era prior to the availability of the results of the
EXTREME study. The positive results of the EXTREME trial
actually make the question of reirradiation or systemic
chemotherapy for unresectable recurrent HNSCC even more
relevant and pressing. So in the absence of high-level evi-
dence comparing reirradiation with systemic therapy, how is
it possible to choose the most appropriate therapy for a
patient with unresectable recurrent HNSCC in a previously
irradiated field?
Although a simple solution is not possible, a number of
considerations make it permissible to approach the decision
in a logical, evidenced-based manner. The first issue to be
considered is toxicity. Considerable toxicity is associated
with the EXTREME regimen; approximately 80% of patients
experienced grade 3 or 4 adverse events in either arm of the
EXTREME trial. Likewise concurrent chemo-reirradiation is
associated with high toxicity, including grade 5 events that
have been reported in nearly all studies examining con-
current chemo-reirradiationtypically in the range of
3%.71,72 Most of the deaths associated with reirradiation are
related to bleeding events; carotid rupture accounts for the
majority of life-threatening bleeding events. Hence, it is
advisable to carefully consider patients with tumors that
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WONG ET AL
have significant carotid involvement, such as circumferential
tumor encasement of the carotid. Likewise, structural issues
preclude other patients from reirradiation, such as recurrent
laryngeal cancer where retreatment can cause cartilaginous
necrosis. Similarly, patients may not be eligible for reirra-
diation when it is not feasible to spare the spinal cord from a
lifetime cumulative conventionally fractionated (1.8-2.0 Gy
per fraction) equivalent dose less than 54 Gy. A nomogram
published by Tanvetyanon et al provides a tool by which
practitioners can identify poor prognostic factors that may
help identify favorable populations and avoid exposure of
dangerous toxicity to other patients.15
Immune Checkpoint Inhibitors
The emergence of data indicating activity of immune
checkpoint inhibitors in HNSCC has potential major impli-
cations for management of this disease, including treatment
for patients with HNSCC with unresectable locoregional
recurrent disease. An expansion cohort of patients with
HNSCC were enrolled in the KEYNOTE-012 phase IB clinical
trial of pembrolizumab for recurrent and metastatic disease
who had 1% or greater PD-L1positive staining by immu-
nohistochemistry.73 Of the 56 evaluable patients, the best
overall response rate was 20%, with similar response rates
seen in patients with HPV-positive disease and those with
HPV-negative disease. An expansion cohort of patients with
PD-L1unselected HNSCC enrolled in the KEYNOTE-012
demonstrated a best overall response rate of 25% for all
patients, 21% for patients with HPV-positive disease, and
27% for patients with HPV-negative disease.74 Of note, both
of the reports included patients whose response was
ongoingsuggesting durable response to therapy.
In contrast to conventional chemotherapy regimens, such
as EXTREME, long-term durable response and survivorship
occurs in less than 5% of patients. Phase III studies of im-
mune checkpoint inhibitors for recurrent metastatic HNSCC
are in progress and potentially could establish a new
standard of care in years to come. If long-term survivorship is
achievable with immune checkpoint inhibitor therapy, this
treatment option would put systemic therapy in a playing
field with reirradiation.
References
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human papillomavirus (HPV) status in stage III-IV oropharyngeal
cancer (OPC) in RTOG 0129. J Clin Oncol. 2009;27:15 (suppl; abstr
6003).
2. Fakhry C, Zhang Q, Nguyen-Tan PF, et al. Human papillomavirus and
overall survival after progression of oropharyngeal squamous cell
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e290 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Emerging in the literature is a growing body of evidence
that suggests radiation therapy and immune checkpoint
have complimentary effects.75,76 These studies indicate that
immune checkpoint inhibitors can overcome the negative
effects of radiation on the tumor microenvironment. Con-
versely, these data also suggest that the antigenic response
to radiation therapy may induce a heightened effectiveness
from immune checkpoint inhibition. It is possible to now
speculate that by combining an immune checkpoint inhibitor
with reirradiation, the best of both worlds may be achievable
in a single treatment plan. In other words, it is conceivable
to concurrently potentiate the effects of reirradiation
(i.e., enhancing locoregional disease control) while simul-
taneously augmenting the systemic immunologic effects
(i.e., enhancing durable treatment response and long-term
survival). To test this hypothesis, a new study, the
KEYSTROKE trial (RTOG Foundation Study 3507), will com-
pare reirradiation with SBRT plus pembrolizumab with
reirradiation with SBRT alone. It is conceivable that future
studies examining immune checkpoint inhibitors with reir-
radiation may demonstrate favorable results that could
reduce our reliance on dogmatic approaches to patients with
unresectable recurrent or new second primary HNSCC.
CONCLUSION
Locoregional recurrent or second primary HNSCC in a pre-
viously irradiated field represents a challenging clinical
scenario for which surgical, reirradiation, and systemic
treatment options continue to evolve. As outlined herein,
management in general would favor salvage surgical re-
section for patients with resectable disease, followed by
consideration for adjuvant reirradiation with chemotherapy.
For patients with unresectable disease, modern reirradiation
(IMRT or SBRT) with concurrent systemic therapy is favored.
Finally, in cases where surgery is not feasible and reirra-
diation may pose too high of a risk of severe toxicity either
because of prior radiation dose to normal structures or
extent/involvement of the recurrence, palliative systemic
therapy is favored. Patients should be encouraged to enroll
in clinical trials incorporating novel systemic agents.
4. Wang J, Liu M, Liu C, et al. Percutaneous endoscopic gastrostomy versus
nasogastric tube feeding for patients with head and neck cancer:
a systematic review. J Radiat Res (Tokyo). 2014;55:559-567.
5. Rivelli TG, Mak MP, Martins RE, et al. Cisplatin based chemoradiation
late toxicities in head and neck squamous cell carcinoma patients.
Discov Med. 2015;20:57-66.
6. Cannon CR. Hypothyroidism in head and neck cancer patients: Ex-
perimental and clinical observations. Laryngoscope. 1994;104:1-21.
7. Kim AJ, Suh JD, Sercarz JA, et al. Salvage surgery with free flap re-
construction: factors affecting outcome after treatment of recurrent
head and neck squamous carcinoma. Laryngoscope. 2007;117:
1019-1023.

8. Dirven R, Swinson BD, Gao K, et al. The assessment of phar-
yngocutaneous fistula rate in patients treated primarily with definitive
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pharynx. Laryngoscope. 2009;119:1691-1695.
9. Kostrzewa JP, Lancaster WP, Iseli TA, et al. Outcomes of salvage surgery
with free flap reconstruction for recurrent oral and oropharyngeal
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and microvascular free flap reconstruction for recurrent head and neck
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cell carcinoma of the upper aerodigestive tract: when do the ends justify
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of selected T1-T3 nasopharyngeal carcinoma - A case-matched com-
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29. Canis M, Martin A, Ihler F, et al. Transoral laser microsurgery in
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33. Copeland EM III. The art of medicine at the end of life: a surgeons point
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35. Cullinane CA, Borneman T, Smith DD, et al. The surgical treatment of
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40. Haraf DJ, Weichselbaum RR, Vokes EE. Reirradiation with concomitant
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42. Langer CJ, Harris J, Horwitz EM, et al. Phase II study of low-dose
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43. Argiris A, Ghebremichael M, Gilbert J, et al. Phase III randomized,
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44. Bourhis J, Rivera F, Mesia R, et al. Phase I/II study of cetuximab in
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of cisplatin plus placebo compared with cisplatin plus cetuximab in
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48. Lee N, Chan K, Bekelman JE, et al. Salvage reirradiation for recurrent
head and neck cancer. Int J Radiat Oncol Biol Phys. 2007;68:731-740.
49. Sulman EP, Schwartz DL, Le TT, et al. IMRT reirradiation of head and neck
cancer-disease control and morbidity outcomes. Int J Radiat Oncol Biol
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50. Biagioli MC, Harvey M, Roman E, et al. Intensity-modulated radio-
therapy with concurrent chemotherapy for previously irradiated, re-
current head and neck cancer. Int J Radiat Oncol Biol Phys. 2007;69:
1067-1073.
51. Duprez F, Madani I, Bonte K, et al. Intensity-modulated radiotherapy for
recurrent and second primary head and neck cancer in previously ir-
radiated territory. Radiother Oncol. 2009;93:563-569.
52. Rwigema JC, Vargo JA, Clump DA, et al. Stereotactic body radiotherapy
in the management of head and neck malignancies. Curr Cancer Ther
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53. Kodani N, Yamazaki H, Tsubokura T, et al. Stereotactic body radiation
therapy for head and neck tumor: disease control and morbidity
outcomes. J Radiat Res (Tokyo). 2011;52:24-31.
54. Yazici G, Sanl TY, Cengiz M, et al. A simple strategy to decrease fatal
carotid blowout syndrome after stereotactic body reirradiaton for
recurrent head and neck cancers. Radiat Oncol. 2013;8:242.
55. Lartigau EF, Tresch E, Thariat J, et al. Multi institutional phase II study of
concomitant stereotactic reirradiation and cetuximab for recurrent
head and neck cancer. Radiother Oncol. 2013;109:281-285.
56. Comet B, Kramar A, Faivre-Pierret M, et al. Salvage stereotactic reir-
radiation with or without cetuximab for locally recurrent head-and-
neck cancer: a feasibility study. Int J Radiat Oncol Biol Phys. 2012;84:
203-209.
57. Vargo JA, Ferris RL, Ohr J, et al. A prospective phase II trial of re-
irradiation with stereotactic body radiotherapy plus cetuximab in pa-
tients with recurrent previously-irradiated squamous cell carcinoma of
the head and neck. Int J Radiat Oncol Biol Phys. 2015;91:480-488.
58. Heron DE, Ferris RL, Karamouzis M, et al. Stereotactic body radiotherapy
for recurrent squamous cell carcinoma of the head and neck: results of a
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1493-1500.
59. Rwigema JC, Heron DE, Ferris RL, et al. The impact of tumor volume and
radiotherapy dose on outcome in previously irradiated recurrent
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body radiation therapy. Am J Clin Oncol. 2011;34:372-379.
60. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for
squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:
567-578.
61. Heron DE, Rwigema JC, Gibson MK, et al. Concurrent cetuximab with
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of the head and neck: a single institution matched case-control study.
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HEALTH SERVICES RESEARCH AND QUALITY
OF CARE

Defining and Measuring Quality

CHAIR
Patricia A. Ganz, MD, FASCO
University of California, Los Angeles
Los Angeles, CA

SPEAKERS
David C. Miller, MD, MPH
University of Michigan Health System
Ann Arbor, MI

Michael J. Hassett, MD, MPH

Dana-Farber Cancer Institute
Boston, MA
GANZ, HASSETT, AND MILLER

Challenges and Opportunities in Delivering High-Quality

Cancer Care: A 2016 Update
Patricia A. Ganz, MD, FASCO, Michael J. Hassett, MD, MPH, and David C. Miller, MD, MPH

OVERVIEW

Herein, both the rationale and scope of current initiatives aimed at improving the quality of cancer care delivery in the United
States are described. First, we discuss a recent report from the Institute of Medicine that issued a strong call for both the
development of quality measures in oncology and implementation of a learning health care system in which data and
experience from clinical practice can inform continuous improvements in cancer care. Second, we review the multiple,
diverse initiatives that are underway to identify, test, and validate quality measures for the entire spectrum of cancer care.
Finally, we discuss regional quality improvement collaboratives as one successful approach to creating a cycle of quality
measurement, identification of best practices, and implementation of changes in practice patterns that ultimately yield
improved care and outcomes for patients with cancer.

I n 2013, the Institute of Medicine (IOM) released a report

with comprehensive, specific recommendations for im-
proving the quality of cancer care in the United States, with a
special focus on addressing the challenges associated with
the expanding number of patients with cancer and cancer
survivors.1 A major factor that will strain the cancer care
delivery system is the increasing numbers of persons older
than age 65 who will be at highest risk for the development
of cancer because of the known association of age with many
cancers (e.g., breast, colon, prostate, lung, bladder, kidney,
and lymphoma). In addition, the projected shortfall in on-
cology providers will exacerbate this situation.2 We also
anticipate tremendous growth in the number of survivors of
cancer who may remain on treatments for extended periods
of time and/or have long-term and late effects of treatments
that will require ongoing medical care and surveillance.3
The increasing cost of care complicates these demographic
changes and expanding demand for services. Costs are not
limited to pharmaceuticals, but also include widespread
adoption and use of many new and expensive technologies
in the diagnosis and treatment of cancer (e.g., next-
generation sequencing) to refine understanding of tumor
characteristics for use of more specific and directed ther-
apies. Furthermore, the extensive subtyping of cancers will
create many small subsets of patients with cancer, making
some types of cancer even rarer than before. Immuno-
modulatory treatments and cell therapies, although they
hold great promise, are substantially more expensive and
require individualized treatments that will be challenging to
deliver to large populations of patients. To some extent
these novel therapies remain experimental, but there is
tremendous demand by the public and clinicians to adopt
these therapies in the earliest stages of development. This
is the context for consideration of the challenges and
opportunities in the delivery of high-quality cancer care.
DIRECT RESPONSES AND CHAMPIONS FOR
SPECIFIC INSTITUTE OF MEDICINE REPORT
RECOMMENDATIONS
The IOM report specifically cited the central position of the
patient in the care delivery system and the importance of
effective communication of diagnosis, prognosis, and
treatment options at the point of care, with an emphasis on
patient preferences and shared decision making.1 Team-
based and coordinated care also were proposed as impor-
tant strategies to reduce the fragmentation of care and to
address the shortages of some clinicians, as well as to
maximize opportunities for receipt of psychosocial and
palliative care along with cancer-directed therapies. In ad-
dition, there was a strong call for the development of quality
metrics specific to oncology, elimination of wasteful and
low-value care, and for implementation of a learning health
care system in which information from clinical practice in the

From the Department of Health Policy and Management, UCLA Fielding School of Public Health, Center for Cancer Prevention and Control Research, Jonsson Comprehensive Cancer
Center, Los Angeles, CA; Department of Medicine, Harvard Medical School, Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA; Dow Division of Health Services
Research, Department of Urology, Institute for Healthcare Policy and Innovation, University of Michigan Medical School, Ann Arbor, MI.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Patricia A. Ganz, MD, Center for Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center, 650 Charles Young Dr. South, Room A2-125
CHS, Los Angeles, CA 90049; email: pganz@mednet.ucla.edu.

2016 by American Society of Clinical Oncology.

e294 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


real world could inform improvements in the delivery of
cancer care. Although the IOM report addresses many other
issues, the areas mentioned above have been the focus of
considerable activity in the last few years, and they will be
the major focus of this update.
Recommendations 1 and 2 from the IOM report focused
on the central role of engaged patients in delivering high-
quality cancer care. The goals of these recommendations are
to ensure that the cancer care team has provided patients
and their families with understandable information on
cancer prognosis, treatment benefits and harms, palliative
care, psychosocial support, and estimates of total and out-
of-pocket costs of cancer care. These recommendations
pertain to newly diagnosed patients at entry into the cancer
care setting, as well as patients with advanced and recurrent
cancer, where the goals also include providing patients with
end-of-life care consistent with their needs, values, and
preferences. The IOM report identified specific actors to
take the lead in accomplishing these goals, tasking a broad
array of stakeholders in developing better ways to com-
municate this complex information to patients and their
families, and calling out the need to develop a personalized
cancer care plan that would reflect the patients needs and
preferences.
This aspirational goal is very important, but it will take
some time to accomplish. However, we were heartened by
proposals from several organizations to modify cancer care
reimbursement to account for the complexity of initial di-
agnosis and treatment planning (American Society of Clinical
Oncology [ASCO] Plan), and an aggressive proposal for a
payment modification scheme from the Centers for Medi-
care & Medicaid Services (CMS) called the Oncology Care
Model (OCM),4 which identified the elements of patient-
KEY POINTS
The 2013 IOM report, Delivering High-Quality Cancer
Care: Charting a New Course for a System in Crisis,
identified the aging of the population, the exploding cost
of care, and fragmentation and complexity of cancer
treatment as major threats to the care delivery system.
Recommendations from the report are being
championed by various entities, and this article
highlights a number of areas of progress.
Measuring the quality of care is a major challenge, and
new strategies are being implemented to report on and
evaluate quality in cancer care delivery.
Among the experiments in place are physician learning
collaboratives, such as the Michigan Urological Surgery
Improvement Collaborative, to improve on the quality
of prostate cancer care delivery.
The development of new payment models that fund
episodes of care or provide reimbursement to groups of
physicians responsible for the entire continuum of
cancer care will likely hasten greater accountability and
coordination of care.
IMPROVING THE QUALITY OF CANCER CARE
centered care in their episode of care payment model di-
rectly from the IOM report (reflecting recommendation 10
and other aspects of the report). The latter also encouraged
participation from private health insurers. As of this writing,
the participating clinician groups and insurance plans have
not been announced, but this is expected to be implemented
in early 2016. Providing more financial resources to support
the degree of patient engagement in treatment decision
making and care, as well as ancillary supportive services, will
be critical if we are to enhance the delivery of quality cancer
care.
Other efforts underway have begun to address the cost of
cancer care and the development of tools to assist clinicians
at the point of care in discussing preferences and toxicities,
along with cost (multiple IOM report recommendations).
Among these are the ASCO Value Framework5 and work
underway by the National Comprehensive Care Network in
its framework for resource stratification. There is increasing
dialogue regarding these issues in the lay press and in
professional oncology journals.6 It is heartening to see so
many stakeholders beginning to focus on the value of care
that is being delivered, including elimination of low-value
and wasteful care.7-9 Additional efforts in progress are
working to promote a learning health care system (IOM
report recommendation 7), with multiple experiments in
progress and development of oncology-specific quality
metrics. To provide further elaboration on several of these
issues, the following sections describe ongoing research on
quality metrics and work being done to address the need to
improve the quality of cancer care.
METRICS FOR ASSESSING QUALITY OF CANCER
CARE
A fundamental requirement of any effort to improve the
quality of health care is the ability to measure practice
performance reliably, validly, and efficiently. Without
quality measures, identifying gaps in performance and
assessing the extent to which improvement efforts ame-
liorate these gaps are impossible. In fact, quality measures
could help address many of the challenges highlighted by the
IOM and outlined above, including the need to reduce care
fragmentation, improve access to psychosocial and palliative
care, administer precision cancer treatments, provide end-
of-life care consistent with patients wishes, and eliminate
wasteful low-value care. In this section, we will identify
organizations that have taken the lead in developing cancer
quality measures; provide an overview of the quality
measures that have been developed; and identify important
topics for which quality measures are lacking. Finally, we will
review some of the biggest challenges to the development
and use of measures to assess and improve care quality.
In the 2 decades since the IOM issued a call to action
through a series of landmark publications, including To Err Is
Human: Building a Safer Health System10 and Crossing the
Quality Chasm: A New Health System for the 21st Century,11
professional societies have taken the lead in developing
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e295
GANZ, HASSETT, AND MILLER
quality measures for cancer care. Substantial contributors to
this effort have included the American College of Surgeons/
Commission on Cancer, American Medical Association,
ASCO, American Society of Hematology, American Society
for Radiation Oncology, College of American Pathologists,
National Comprehensive Cancer Network, and National
Hospice and Palliative Care Organization. In addition, a
number of organizations have endeavored to collect and
endorse quality measures to facilitate their use, including
the Agency for Healthcare Research and Qualitys National
Quality Measures Clearing House12 and the National Quality
Forums (NQFs) endorsement process.13-15
The framework proposed by Donabedian16 defines three
types of quality measures: structure, process, and outcomes
(Fig. 1). Although all measure types are relevant to cancer
care, most available measures focus on processes because
they are easier to develop, implement, and interpret. In fact,
process-based quality measures are currently used to sup-
port accountability, pay-for-performance, contractual, and
regulatory programs such as the Physician Quality Reporting
System, Meaningful Use, alternative quality contracts, and
others.17-19 One notable exception is the Quality Oncology
Practice Initiative (QOPI) from ASCO, which was designed to
foster practice-based quality improvement specifically to
facilitate an oncology practices effort to monitor and improve
its performance.20-22 QOPI assesses performance relative to
more than 100 cancer-focused measures twice yearly for
hundreds of practices and thousands of patients.20-23
Although many valid and reliable process-based cancer
quality measures have been developed, existing measures tend
to cover a limited spectrum of cancer care services. Specifically,
they focus on common malignancies (i.e., breast cancer, co-
lorectal cancer, lung cancer), assess the performance of phy-
sicians or hospitals, focus on widely accepted standards, and
address initial management strategies. This leaves many im-
portant aspects of cancer care underevaluated, including less
common cancers, nonphysician providers, long-term follow-up
care, and end-of-life issues. In a 2009 report, the NQF high-
lighted these hurdles and suggested that building a compre-
hensive measurement system would require new measures to
be developed to address gaps in episodes of care and focus on
patients rather than individual providers or distinct care set-
tings.24 In 2012, the Measure Applications Partnership (MAP)
suggested that there was an immediate need to assess cross-
cutting aspects of care, meaning those that are relevant to all
patients with cancer throughout the trajectory of their illness.25
Both organizations noted that new measures should focus on
outcomes, care coordination, care transitions, quality of life,
patient safety, and experience of care.15,25
In December 2012, ASCO convened a Collaborative Cancer
Measure Summit to identify topics for which new quality
measures were needed.26 The summit, which was attended
by 12 specialty societies and patient advocacy organizations,
highlighted issues similar to those raised by NQF and the
MAP. Specifically, ASCO encouraged the development of
measures to address (1) the use of palliative care/hospice
services; (2) planning and counseling prior to therapy
e296 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
FIGURE 1. Schematic Example of Donabedian Model
Describing the Components of Quality Care
(e.g., treatment plan generation, fertility counseling);
(3) the provision of interdisciplinary and multidisciplinary
coordinated care; (4) comprehensive symptom assessment
and treatment; and (5) patient experience of care. Fur-
thermore, it emphasized the importance of measures that
assess outcomes, address cross-cutting topics that pertain to
different cancer types and care settings (e.g., chemotherapy-
induced nausea), and focus on issues of interest to patients
rather than the health care system.
Past efforts to develop and implement quality mea-
sures highlight a number of challenges that will have to be
addressed if we are to build the comprehensive measure-
ment system advocated for by IOM and NQF. First, we must
determine what aspects of care should be measured.
Usually, decisions regarding what to measure are based on
consensus opinions about which performance gaps are
important and where improvement efforts could have the
greatest impact rather than on the use of actual practice
performance data to identify substantial gaps and define
benchmarks.27 Second, we must gather the data needed to
assess performance efficiently and accurately. With limited
resources, we can only assess performance relative to a limited
set of measures. And third, we must interpret the results of
measurement efforts appropriately, so that the findings can be
used to create real and meaningful improvements in quality.
Figuring out what to measure seems simple, but it can
present a number of pitfalls. Historically, selecting topics for
measure development has followed one of two paths. In the
first, interested parties, often professional societies, lead
rigorous measure development efforts on topics that are of
particular interest to them. This tends to produce measures
for which there is high-quality evidence and widespread
consensus. However, measures can take a long time to
develop, are hard to update, and often focus on areas where
quality problems are less pronounced. In the second, hos-
pitals, clinics, and provider organizations develop measures
on their own to support local quality improvement efforts.
This provides more flexibility, but it can generate measures
based on lower-quality evidence or less consensus, and
testing for reliability and validity are less common. In both
paths, topic selection is usually driven by providers and
payers, rather than patients.

Once specifications have been developed, the next chal-
lenge is determining how to gather the data needed to
reliably and efficiently report on a measure. Three common
methods are used. Many measures rely on administrative
data collected for other purposes, such as claims for health
care services rendered. Administrative data are readily
available and are often based on a common standard (e.g.,
ICD-9, ICD-10, CPT), but they lack clinical granularity and
substantial data-quality issues can exist (i.e., missing data,
consistency, accuracy). Some measures depend on manual
data abstraction. This is often done by a cancer registrar (e.g.,
the National Cancer Databases Rapid Quality Reporting
System)28 or a quality improvement staff member (e.g.,
ASCOs QOPI).22 Although these data can be quite granular,
they are costly and time consuming to collect. With the recent
widespread adoption of electronic health records (EHRs),
there is growing interest in the use of EHR data for quality
measurement. EHR data offer great promise, but identifying
important concepts from these data can be challenging be-
cause they contain a lot of unstructured free text. EHRs
encourage users to enter information into structured data
fields to facilitate quality analyses, but this creates a burden
on EHR users who must spend time entering data that may
not be integral to the care they are providing.
After all the data have been collected, the final challenge is to
interpret the results. In many circumstances, there are justi-
fiable reasons for not providing recommended treatments,
making 100% concordance an unattainable goal. That said,
determining what the actual target should be is not straight-
forward. Using high-performing organizations to define a
benchmark is one option, but even high-performing organi-
zations can improve in some situations and adjusting for le-
gitimate differences between organizations can be difficult.
Models that account for health-risk and case-mix exist, but
they are imperfect, can be challenging to implement, and only
pertain to some measures.29-32 Often, organizations conducting
quality improvement projects select internal benchmarks and
plan to demonstrate improvement relative to past perfor-
mance. But, how much improvement can actually be attained?
Lastly, if suboptimal performance is identified, who should be
responsible for that deficiency? Attribution is a particular
challenge in oncology, in which care often requires a multi-
disciplinary approach spanning several different care settings.
These limitations notwithstanding, some organizations have
been able to apply quality measures in the real-world setting
and have used the results of these efforts to effect meaningful
improvements in cancer care quality. The third section of this
manuscript highlights a number of these successes.
USING PRACTICE VARIABILITY TO IDENTIFY
OPPORTUNITIES FOR INTERVENTIONS TO
IMPROVE QUALITY
The Role of Quality Improvement Collaboratives
As described previously, patients, providers, health care
payers, and policymakers are increasingly interested in
expanding efforts to measure and improve the quality of
cancer care. As one mechanism for achieving this goal, some
IMPROVING THE QUALITY OF CANCER CARE
physicians and surgeons have established practice- or hospital-
based regional quality improvement collaboratives.33,34 The
general organizational principles of such collaboratives include
centralized and standardized collection of high-quality clinical
outcomes data; provision of performance feedback to indi-
vidual clinicians and practices; identification of clinical care
processes (e.g., diagnostic tests, type of surgical procedure)
that correlate with optimal patient outcomes; implementation
of these best clinical practices; and dissemination of findings
from collaborative activities to benefit patients across a broad
geographic region.
The Michigan Urological Surgery Improvement Collab-
orative (MUSIC) is an example of such a collaborative.
Established in 2011 with funding and support from Blue
Cross Blue Shield of Michigan, MUSIC is a physician-led
quality improvement collaborative currently comprised of
42 urology practices and 235 urologists from across Mich-
igan (roughly 85% of the urologists in the state).35 The
collaborative also includes four patient advocates who play a
central role in all of our quality improvement activities. The
mission of MUSIC is to make Michigan the best place in the
world for prostate cancer care.
The collaborative is managed by a coordinating center,
housed administratively in the University of Michigan De-
partment of Urology, and governed by an executive com-
mittee (comprised of MUSIC urologists from across the
state) and a core set of operating principles. The partici-
pation of each individual practice has been reviewed and
deemed not regulated by a local institutional review board.
A centerpiece of the collaborative is a secure, web-based
clinical registry. In each practice, a trained data coordinator
screens case encounters to identify patients who are eligible
for inclusion in the MUSIC registry. Eligible cases include
patients undergoing prostate biopsy, as well as patients with
newly diagnosed prostate cancer that have not received
prior cancer-directed treatment. Data are collected on pa-
tient demographics, cancer severity (including pathologic
details from needle biopsies and radical prostatectomies),
utilization and outcomes for radiographic staging studies,
comorbidities, cancer-directed therapies, and perioperative
complications and patient-reported outcomes for men un-
dergoing radical prostatectomy. MUSIC uses multiple quality
assurance techniques to ensure the integrity of the registry
data.35 The overall quality of the registry is reflected in its
inclusion as a Qualified Clinical Data Registry for the CMS
Physician Quality Reporting System.
Translating Data Into Quality Improvement
Although essential, a registry (and its associated reports and
metrics) is only the first link in a chain that leads to improved
quality and better patient outcomes. Data from the registry
must be analyzed and presented back to clinicians in an
understandable and actionable format. Most importantly,
there must be engagement among participating clinicians,
including a desire to understand and respond to the data in
a way that ultimately yields better patient outcomes. Ex-
amples of such engagement include efforts to identify,
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e297
GANZ, HASSETT, AND MILLER
communicate, and disseminate specific processes of care or
techniques (e.g., postoperative pain control pathways) that
are used by higher performing surgeons or practices. Im-
portantly, the collaborative model relies on learning from all
participants because no single hospital, practice, or surgeon
excels in all clinical domains or has a monopoly on the
knowledge and experience that leads to superior outcomes.35
This learning most commonly occurs through direct in-
teractions and discussions at collaborative-wide meetings
held several times per year. The meetings are attended by
clinical champions from each participating hospital or prac-
tice. These individuals review data and engage in vigorous
discussion and learning with peers; they also maintain re-
sponsibility for sharing the data and lessons learned with
partners and clinical team members in their local practices
and hospitals. Ultimately, the quality improvement loop must
be closed by translating the knowledge gained in the col-
laborative into specific interventions that yield measurable
improvements in patient care. This cycle of data collection and
measurement, analysis, discussion, interventions and then re-
measurement is repeated for topics identified and deemed
important by collaborative members (Fig. 2).35 The net effect
is creation of an engine for comparative effectiveness re-
search that is linked to a statewide quality improvement
consortium that serves as the effector arm for translating data
into action and, ultimately, better patient outcomes.
Specific MUSIC Initiatives
In terms of specific quality initiative priorities, MUSIC is
focused on reducing morbidity with prostate biopsy, opti-
mizing radiographic staging for men with newly diagnosed
prostate cancer, improving patient outcomes after radical
prostatectomy, and leveraging clinical evidence and shared
decision making to enhance the appropriateness of local
therapy for men with early-stage prostate cancer. Several of
these initiatives are described in more detail below.
Reducing hospitalizations following prostate biopsy. Over
the last 2 years, MUSIC has implemented process changes
for antibiotic prophylaxis that have achieved and sustained a
large reduction in prostate biopsy-related infectious hos-
pitalizations. After identifying a baseline hospitalization rate
of approximately 1.5% (with wide variability across practices
in the state), and fluoroquinolone resistance as the root
cause for most episodes of postbiopsy sepsis, MUSIC de-
veloped two pathways to address the rising prevalence of
these bacteria.36 These included tailored antibiotic pro-
phylaxis based on results from a rectal swab culture and
augmented antibiotic prophylaxis (i.e., the addition of a
second agent to standard fluoroquinolone therapy) based
on each communitys local antibiotic resistance profiles. The
development of these pathways was based on published
literature in this area and the specific clinical experience of
MUSIC urologists with the lowest rates of hospitalization.
The net result of this intervention has been a nearly 50%
reduction in the frequency of these significant clinical events.
Our current statewide rate of hospitalization is among the
e298 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
FIGURE 2. Example of a Quality Improvement Cycle
lowest reported at approximately 0.7%.37 We also recently
disseminated a toolkit that discusses the components of a
biopsy bundle that may help to sustain and/or further reduce
the rate of infectious hospitalizations. In addition to the use of
tailored or augmented antibiotic prophylaxis, the bundle
includes the use of a needle disinfectant, a practice associated
with lower infection risk based on our own data in the MUSIC
registry and reports in the published literature.38
Optimizing radiographic staging for men with early-stage
prostate cancer. As one of its first activities, MUSIC
addressed ASCOs participation in the Choosing Wisely
priority of avoiding the use of staging radionuclide bone
scans and CT scans among men with early-stage prostate
cancer at low risk for metastases.39 By providing urologists
individual and practice-level feedback on their own practice
patterns relative to their peers, as well as levels of adherence
with guideline recommendations, the collaborative achieved a
rapid statewide decrease in the use of these radiographic
staging evaluations for men with low-risk tumors.40
However, based on further analysis of both the existing
literature and our own registry data, it became clear that
these imaging studies could safely be avoided in a much
larger population of men with newly diagnosed prostate
cancer. Therefore, we developed and disseminated new
imaging appropriateness criteria that both minimize un-
necessary imaging and are extremely unlikely to omit a
positive study. The published MUSIC imaging criteria
recommend a bone scan for men with a Gleason score of 8
or higher or prostate-specific antigen (PSA) level of 20 ng/mL
or higher, and a CT scan for men with a Gleason score of 8 or
higher or a PSA level of 20 or higher, or clinical stage greater
than or equal to T3.41,42 After baseline variation in imag-
ing practice patterns was established in 2012 and 2013, a
multidimensional quality improvement intervention was
implemented in 2014, which included video presentations,
dissemination of written guidelines, and site visits to each
practice. Each component of the intervention aimed to

educate providers on the use and rationale for the MUSIC
imaging criteria.
Among more than 10,000 patients newly diagnosed with
prostate cancer that were entered into the MUSIC registry
from March 2012 through July 2015, 8,271 patients (80%)
met the criteria to avoid imaging. Among this group of
patients, we observed a large decrease in the use of both
bone scans and CT scans from before and after dissemi-
nation of the improvement interventions. We estimate that
application of the MUSIC criteria for imaging saved patients
in Michigan from undergoing 196 and 260 potentially un-
necessary bone scans and CT scans, respectively, over an 18-
month period. By decreasing the use of both bone scans and
CT scans among men with prostate cancer at low risk for
metastases, this statewide intervention enhanced the value
of care for this patient population through targeted im-
provement interventions.
Patient-reported outcomes after radical prostatectomy.
Radical prostatectomy is a common treatment for men with
early-stage prostate cancer. Improving functional outcomes
after this procedure remains a priority for the urological
community. To address this quality improvement challenge,
MUSIC is also creating a statewide electronic infrastructure,
known as MUSIC-PRO, which will allow measurement of
urinary and sexual function outcomes at a population-level
across diverse academic and community practices.
MUSIC-PRO began with five practices in April 2014, and
expanded to 17 practices by December 2015. For men
undergoing radical prostatectomy in participating practices,
the coordinating center emails patients with a link to an
online questionnaire on urinary function (score range 0-21)
and erectile function (score range 0-30) before and at 3, 6,
12, and 24 months after radical prostatectomy. Patients
without email are provided with paper surveys. The results
of questionnaires are delivered to providers through the
registry, including patient-specific reports that can be
reviewed during clinic visits. Surgeons also receive summary
data on their own patients in comparison with patients in
their practice and at all sites.
Among 989 men participating in MUSIC-PRO through late
2015, the overall response rate was 85%, with 70% of the
surveys completed electronically. Across the collaborative,
52% and 71% of patients recovered urinary function (de-
fined as a score greater than 17) at 3 and 6 months, re-
spectively. However, recovery of urinary function varied
substantially across five pilot practices. Among patients with
good baseline erectile function (defined as a score greater
than 22), 15% and 21% recovered erectile function at 3 and
6 months.
We are now capitalizing on this variation in patient-reported
outcomes across practices and surgeons to identify top per-
formers and areas needing improvement. Further, these data
can be used for preoperative counseling and managing post-
operative expectations. Leveraging this infrastructure, MUSIC is
developing a menu of strategies designed to improve func-
tional recovery for patients across the state.
IMPROVING THE QUALITY OF CANCER CARE
In summary, the partnership with Blue Cross Blue Shield of
Michigan and patients with prostate cancer, urologists in
Michigan are collecting clinically credible data on prostate
cancer care and outcomes, comparing and capitalizing on
variation in performance among practices and individual
surgeons, sharing best practices, and implementing changes
in clinical behavior. The net result has been more efficient
utilization of health care resources, improved care delivery
in our own environments, and enhancements in the quality,
value, and outcomes of treatment provided to men in
Michigan with prostate cancer.
CONCLUSION
As can be seen by the preceding discussion, there are many
opportunities and challenges associated with improving the
quality of cancer care delivery. With so many different clinicians
involved in the care of patients with cancer (e.g., surgeons,
medical oncologists, radiation oncologists, diagnostic radiolo-
gists, pathologists, nurses, primary care providers, and internal
medicine specialists), it is challenging to identify which prac-
titioners are accountable for specific aspects of care. In
addition, as cancer is a disease process with many clinical
manifestations depending on the organ site and disease
presentation, there are many processes and outcomes of
care that need our attention. In terms of measurement, one
does not know where to start.
In contrast, the example of the hands-on urology col-
laboratives described in Michigan provides a window on
what can be accomplished when a group of clinicians set out
to examine how they are delivering care in specific situa-
tions. This is especially valuable when there is consensus on
what types of tests or procedures provide little value or
cause substantial morbidity. It is also important that ex-
amination of clinical management practices occurs in a safe
and constructive setting where the primary goal is to un-
derstand how and why some unnecessary tests or pro-
cedures are performed, and then to address the situation
based on this understanding. Learning how to implement
these best practices can be shared and supported through
the safety of the collaborative environment.
The issue of accountability for correct or harmful processes
or outcomes will likely be resolved with the emergence of
physician groups being merged into organizational units that
will deliver cancer care from diagnosis through end of life in a
bundled or episode-based reimbursement scheme, such as
accountable care organizations. Under this circumstance,
coordination and quality of care will be the preeminent goal,
and elimination of wasteful practices will be a central dogma.
Improvements in health and well-being will be the primary
goal, with measurement of patient-reported outcome mea-
sures (e.g., psychosocial well-being, control of symptoms).
The prevention of hospitalizations or emergency department
visits that are costly and dreaded by patients, will become
even more important. Fortunately, there are many experi-
ments in process across the country that will help bring these
important outcomes into mainstream cancer care.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e299
GANZ, HASSETT, AND MILLER
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HEALTH SERVICES RESEARCH AND QUALITY
OF CARE

Removing Barriers to Clinical Trial

Participation

CHAIR
Joseph M. Unger, PhD, MS
Fred Hutchinson Cancer Center
Seattle, WA

SPEAKERS
Archie Bleyer, MD
St. Charles Medical Center
Bend, OR

Elise Cook, MD, MS

The University of Texas MD Anderson Cancer Center
Houston, TX
 CLINICAL TRIAL PARTICIPATION

The Role of Clinical Trial Participation in Cancer Research:

Barriers, Evidence, and Strategies
Joseph M. Unger, PhD, Elise Cook, MD, Eric Tai, MD, and Archie Bleyer, MD

OVERVIEW

Fewer than one in 20 adult patients with cancer enroll in cancer clinical trials. Although barriers to trial participation have
been the subject of frequent study, the rate of trial participation has not changed substantially over time. Barriers to trial
participation are structural, clinical, and attitudinal, and they differ according to demographic and socioeconomic factors. In
this article, we characterize the nature of cancer clinical trial barriers, and we consider global and local strategies for reducing
barriers. We also consider the specific case of adolescents with cancer and show that the low rate of trial enrollment in this
age group strongly correlates with limited improvements in cancer population outcomes compared with other age groups.
Our analysis suggests that a clinical trial system that enrolls patients at a higher rate produces treatment advances at a faster
rate and corresponding improvements in cancer population outcomes. Viewed in this light, the issue of clinical trial en-
rollment is foundational, lying at the heart of the cancer clinical trial endeavor. Fewer barriers to trial participation would
enable trials to be completed more quickly and would improve the generalizability of trial results. Moreover, increased
accrual to trials is important for patients, because trials provide patients the opportunity to receive the newest treatments.
In an era of increasing emphasis on a treatment decision-making process that incorporates the patient perspective, the
opportunity for patients to choose trial participation for their care is vital.

T he path from initial development of a new cancer drug to

diffusion of the new therapy into the cancer treatment
community relies on clinical trials, which represent the final
step in evaluating the efficacy of new therapeutic ap-
proaches. It has been consistently estimated that less than
5% of adult patients with cancer enroll in cancer clinical
trials.1,2 Conversely, the vast majority of adult patients with
cancer (greater than 95%) do not participate in clinical trials,
even though 70% of Americans are estimated to be inclined
or very willing to participate in clinical trials.3 Thus, a large gap
exists between trial participation rates and the willingness of
patients to participate, suggesting that barriers to trial par-
ticipation are numerous and frequently insurmountable.
Barriers to trial participation have been the subject of fre-
quent study, but the rate of trial participation has not changed
substantially over time. The infrastructure supporting the
conduct of clinical trials has been designed to anticipate a
low, albeit steady, trial participation rate. The National Cancer
Institutes (NCI) cooperative group clinical trial treatment
program caps enrollment for its funded groups at 17,000 total
patients per year, representing 1% of the estimated 1.7 million
new cancer diagnoses in the United States in 2015.4,5
To understand the effect of clinical trial participation on
cancer population mortality and survival, one might
imagine a counterfactual system in which the cancer clinical
trial participation rate was much higher. Fortunately, such a
system already exists. Enrollment of children (younger than
age 15) to clinical trials has historically been much higher
than for adult cancers (greater than 50%).2,6,7 At the same
time, mortality rates have for children have been decreasing
since the 1970s, whereas for adults they have been de-
creasing only since the 1990s.8 The average reduction in the
rate of mortality from 1975 to 1995 was 2.6% per year for
patients younger than age 20.9 Interestingly, the reduction
was weakest among older children (age 15 to 19; 2.0% per
year), reflecting other studies which have found both lower
trial enrollment for adolescents and young adults with
cancer and lower rates of mortality reduction.10,11
These data are consistent with the idea that a clinical trial
system that enrolls patients at a higher rate produces
treatment advances at a faster rate, and concurrent survival
increases and mortality reductions in the cancer population.
In this context, the issue of clinical trial enrollment is viewed
as foundational, lying at the heart of the cancer clinical trial

From the Fred Hutchinson Cancer Research Center, Seattle, WA; The University of Texas MD Anderson Cancer Center, Houston, TX; Centers for Disease Control and Prevention, Atlanta,
GA; St. Charles Health System, Quality Department, Bend, OR.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Joseph M. Unger, PhD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, M3-C102, P.O. Box 19024, Seattle, WA 98109;
email: junger@fredhutch.org.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 185

UNGER ET AL
endeavor.12 Therefore, the identification of specific barriers
to trial enrollment and efforts to remove such barriers rep-
resent critical research objectives for cancer investigators.
In this article, we attempt to characterize the specific
barriers to cancer clinical trial participation. In addition, we
consider the distinction between clinical trial enrollment
between children and adolescents with cancer. As suggested
above, these age-proximal patient groups provide a natural
observational contrast illuminating the association between
clinical trial enrollment rates and corresponding improve-
ments in outcomes in the cancer population. We present
original data to make this case. Finally, we examine global and
local strategies to improve cancer clinical trial participation.
UNDERSTANDING BARRIERS TO CLINICAL TRIAL
PARTICIPATION
A patients decision of which cancer treatment to receive is
complex and deeply personal; the prospect of incorporating
clinical trial treatment into a patients care adds another
level of complexity. In this multifactorial decision-making
environment, patients may face several barriers to trial par-
ticipation. As a guide to understanding the trial decision-
making process, we present a simplified flow diagram (Fig. 1)
illustrating a representative pathway through which a patient
may receive care. This model has been the basis for multiple
studies examining barriers to clinical trial participation.13-15
The model indicates that after cancer diagnosis and a clinic
visit, an assessment of trial availability is made to identify
whether a trial exists at the institution for the patients
histology and stage. If a trial is available, an evaluation of trial
eligibility is made, and, if eligible, a trial is discussed with the
patient. The trial may then be offered to the patient, at which
KEY POINTS
Although barriers to trial participation have been the
subject of frequent study, the rate of trial participation
has not changed substantially over time.
Barriers to trial participation are structural, clinical, and
attitudinal, and they differ according to demographic
and socioeconomic factors.
An analysis of the specific case of adolescents with
cancer illustrates how a clinical trial system that enrolls
patients at a higher rate produces treatment advances
at a faster rate and corresponding improvements in
cancer population outcomes.
Fewer barriers to trial participation would enable trials
to be completed more quickly and would improve the
generalizability of trial results. Crucially, increased
accrual to trials is important for patients because trials
provide patients the opportunity to receive the newest
treatments.
In an era of increasing emphasis on a treatment
decision-making process that incorporates the patient
perspective, the opportunity for patients to choose trial
participation for their care is vital.
186 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
FIGURE 1. Model Pathway of Trial Enrollment Process
Abbreviation: SES, socioeconomic status.
point the patient makes a decision about whether to par-
ticipate. An important note is that under this model, patient
attitudes toward clinical trial participation only come into
play at the end of an otherwise long process.
We have categorized barriers to trial participation as
structural (especially the absence of an available clinical
trial), clinical (i.e., not meeting eligibility), attitudinal (with
respect to both patients and physicians), and demographic
and socioeconomic. It is recognized that there is greater
fluidity between these categories than the model allows,
but simplifications were made to facilitate discussion.
Structural Barriers
To participate in a clinical trial, patients must first have
access to a cancer clinic. Access to a clinic can be influenced
by many different structural factors such as transportation,
travel costs, access to insurance, and availability of child
care.16 Uninsured patients, in particular, present with later
stage of disease and have worse cancer outcomes.17,18 To
the extent that such patients present at their cancer di-
agnosis with a greater comorbid burden, their likelihood of
eventually participating in a clinical trial is lower.19
Once a patient has access to cancer care, a major structural
barrier pertains to the availability of a clinical trial for the
patients histology and stage. Multiple prospective studies of
the cancer care decision-making process have examined the
extent to which trials are unavailable for patients. Lara et al
prospectively tracked barriers to cancer clinical trials at the
University of California (UC) Davis Cancer Center from 1997
to 2000.20 Among patients considered for trial availability,
there was no trial available to 47% of patients (Table 1). Javid
et al registered patients to a prospective survey study prior
to their treatment decision regarding their cancer care at a
diverse set of eight institutions. No trial was available for
nearly half of the patients (46%).13 Together, these and
earlier studies consistently show that once a patient has
access to cancer care, the absence of an available clinical trial
precludes participation for about half of all patients.14,21,22

TABLE 1. Clinical Trial Enrollment Patterns for Multiple Studies in the Literature
No. Patients Examined* Trial Unavailable
Lara et al20 171 47%
13
Javid et al 9,09 46%
Klabunde et al14 2,339 60%
Begg et al21 3,534 33%
22
Hunter et al 44,156 60%
Average** 49%
*Assessed for trial availability.
**Unweighted.
Clinical Barriers
Even if a trial is available, patients may not be eligible. Studies
have found that a common reason for patient ineligibility
to available protocols is narrow eligibility criteria.3,14,21-24
Trial eligibility attempt to satisfy two opposing criteria.
On the one hand, eligibility must be sufficiently narrow to
produce a treatment effect that is approximately consistent
across the cohort. On the other hand, eligibility should be
sufficiently inclusive that the trial targets a meaningful pop-
ulation of patients for whom a new treatment would apply.25
Eligibility criteria may also exclude patients due to safety
concerns. However, trials are often criticized for having
eligibility criteria that are too narrow, sacrificing general-
izability.26 These exclusions also make trials less accessible
for patients.
In the previously described prospective studies of trial
barriers, ineligibility was identified as a reason for nonpartic-
ipation by 18% of all patients on average (Table 1).13,14,20-22,27
The dominant reason for ineligibility exclusions is likely ex-
clusions due to comorbid conditions. One recent study com-
prehensively cataloged the trial eligibility criteria for a set
of 21 trials in diverse cancer settings.28 The authors found
that the average number of eligibility criteria per trial was
16, 60% of which were related to comorbidity or perfor-
mance status. Although prespecified trial eligibility criteria
that protect patient safety are crucial, it is also possible that
certain kinds of exclusions are unnecessary. A recent report
indicated trial eligibility criteria have increased in recent years
for both academic group and pharmaceutical-sponsored
clinical trials.29 This trend not only renders trials less acces-
sible for many patients, it may also limit the generalizability
of trial results.
Physician Attitudes
As the agent linking patients to their cancer care, physicians
play an obvious and vital role in clinical trial participation.
A survey of oncologists in community cancer clinics found
that most agreed that clinical trials provide high-quality
care (87%) and benefit enrolled patients (83%).30 However,
physicians face their own barriers to trial enrollment, so
even if quality cancer care is assumed, physicians may treat
otherwise eligible patients off-protocol with one arm of
a trial, without actually entering the patient on the trial.31
CLINICAL TRIAL PARTICIPATION
Ineligible Trial Participation Rate Did Not Participate
8% 23% 22%
14% 16% 24%
16% 7% 17%
33% 16% 16%
18% 8% 14%
18% 14% 19%
Multiple earlier studies found physician decision or pref-
erence was the primary reason for nonparticipation in half of
the patients for whom a protocol was available and the
patient was eligible.21,22
A number of factors have been found to deter physician
recommendation for trial participation. In their role of
guiding patient care, physicians may have a strong inclina-
tion toward a specific treatment for a given patient.31-33 The
prospective study by Javid and colleagues found that the
nature of the study regimen was cited as a reason for not
discussing a trial with eligible patients by 56% of physi-
cians.13 Physicians are also frequently concerned that clinical
trial participation can interfere with the physician-patient
relationship.31,34,35 Random assignment into a phase III trial
in particular subjects the treatment choice to uncertainty,
and physicians may anticipate that the introduction of un-
certainty will subvert patient confidence in the physicians
expertise, even if, as indicated by the existence of a ran-
domized clinical trial, multiple treatments of potentially
similar efficacy are available.
Practical considerations may also influence physicians
willingness to participate in trials. Physicians often lack
appropriate incentives to participate in clinical research.36
The time spent attending to the details of clinical trial en-
rollment and explaining clinical trials to patients can often
be prohibitive for physicians.33 In addition, in a busy clinic
environment, physicians may be less likely to refer patients
to trials if they believe the process will be too time
consuming.30,31,37 Oncologists who consider trial paper-
work time consuming or who otherwise believe trial ef-
fort would be extra work are less likely to refer a patient
to a clinical trial.37 Finally, some physicians find the re-
quirement of obtaining informed consent to be problem-
atic, even though nearly all agree that informed consent is
necessary.30,31
Patient Attitudes
Efforts to reduce structural, clinical, and physician barriers to
trial participation are critical. However, the ultimate decision
regarding trial participation rests with the patient. In-
evitably, the decision about whether to participate in a trial
will reflect a patients personal preferences, which may also
be influenced by family and friends.38
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UNGER ET AL
Some proportion of patients are influenced by altruistic
motivations.15 However, the majority of patients are (ap-
propriately) concerned primarily with finding the best
possible treatment of their disease.15,39,40 In the absence of
other barriers, a patient who believes that the best possible
treatment option is to be found in a clinical trial is more likely
to participate in that clinical trial.33
Patients have frequently reported being uneasy or fearful
about the prospect of participating in a clinical trials.41 In
some cases this could be due to a residual mistrust of
medical science due to past abuses, such as the infamous
Tuskegee Syphilis Study or the history of human experi-
mentation with radiation following World War II.42,43 At-
tention in the last several decades to the process of rigorous
consent may have reduced these fears, especially for
younger generations of patients. Attention must also be paid
to providing consent forms which are easy to read, because
more complicated consent forms can induce anxiety.44
More generally, a fear of experimentation may be
expressed through a dislike of randomization.14,15,22,45-47
There is perhaps no stronger indication that a patient is
about to participate in an experiment than the revelation
that the patient will be randomly allocated to one of two or
more treatments. Fear of randomization has been identified
as the most commonly cited reason by patients for declining
trial participation.15 Recognizing this, some physicians avoid
the word randomization, relying instead on analogy to
describe the randomization process, though this may lead to
situations where patients sometimes do not understand that
their treatment has been randomly assigned.48,49
Patients are sometimes uneasy as well about the potential
toxic effects of chemotherapy in trials, especially for the
experimental therapies.38 Patients may already have a
strong sense of the particular treatment they wish to receive
after discussion with their physicians.33 Because trials
sometimes require more frequent monitoring than nontrial
care, traveling to and from a cancer clinic has been indicated
by many patients to be a reason for nonparticipation.15,20
Concern about how to pay for trials has been cited as a
reason for nonparticipation among about a quarter of pa-
tients, despite the fact that the majority of states mandate
that insurers cover the routine care costs of trials, as does
Medicare.15 In a review by Ford et al, cost concerns were
identified as the second most frequently indicated reason
for nonparticipation in trials in the literature.41
Demographic and Socioeconomic Disparities
Demographic and socioeconomic disparities in trial enroll-
ment can occur anywhere along the pathway from initial
clinic visit until the patient ultimately makes their treatment
decision. The most consistent and largest disparity pertains
to age.1,15,50-53 Hutchins et al found that patients in co-
operative group trials were much less likely to be age 65 or
older than those in the U.S. cancer population.50 Some
evidence suggests that attitudinal barriers on the part of
physicians play a role.13,54-56 In addition, older patients are
188 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
likely to have more comorbid burdens, inducing clinical
exclusions.57,58 To the extent that trials seek to reflect the
population of patients for whom new trial-proven treat-
ments will be administered, better representation of older
patients in trials is critical. Recognizing this, in 2000,
Medicare was directed to cover the routine care costs of
clinical trial participation for its patients.59 Unfortunately,
the proportion of older patients in trials remains well below
the expected rate.28,51
Evidence as to the association of race with trial partici-
pation is mixed. A study by Murthy et al found that black
patients were underrepresented in NCI-sponsored breast,
lung, colorectal, and prostate cancer clinical trials from 2000
to 2002.1,60 In contrast, in sequential studies within SWOG, a
national clinical trials consortium, black patients were en-
rolled to trials in a representative fashion over an extended
period of examination.28,50,53 This was confirmed in a sample
of older patients with breast cancer.61 Evidence has also
been mixed for Hispanic patients.1,53 Even if enrollment of
minorities is adequate in the treatment trial setting, en-
rollment of minority healthy volunteers for prevention trials
has been decidedly more difficult and has generated well-
designed outreach programs for large individual trials.62-65
Given the increasingly diverse nature of the U.S. population,
continued attention to this issue is required.
Females may be somewhat under-represented in the
nonsex-specific cancers, although the magnitude of the
disparity is likely small.28,50,53 In addition, some evidence
suggests that any sex disparity in clinical trial enrollment
could be age-related, with older women less likely to enroll
in trials than their younger counterparts.1 Such a pattern
might indicate generational differences in attitudes toward
clinical research.
The examination of socioeconomic factors as a barrier to
participation has historically been hindered by the lack of
collection of patient-level socioeconomic status (SES) data.
This is unfortunate given the frequency with which the direct
and indirect costs of trial participation have been cited as
meaningful barriers.41 Two recent articles overcame this
limitation. The first used a web-based survey to engage
patients in their decision-making process.15 Among the
numerous demographic and socioeconomic factors exam-
ined, patients with lower income (less than $50,000 per
year) were 29% less likely to participate in trials than higher-
income patients. Utilizing data from a prospective barriers
study, this observation was confirmed.13,66 Thus, the evi-
dence to date of income disparities in trial enrollment is
fairly consistent.61 Given that trial treatment costs are not
substantially different than nontrial treatment costs,67 this
suggests that marginal direct costs play a role. A prior study
of the effect of the 2000 Medicare policy change on trial
participation found that patients with Medicare plus private
insurance participated at a higher rate following the policy
change, whereas patients with Medicare alone participated
at rates similar to those prior to the policy change.53 This
finding points to the prohibitive influence of copays and
coinsurance for some patients.

EVIDENCE FOR THE BENEFIT OF CLINICAL TRIALS
ON CANCER POPULATION OUTCOMES
OBSERVED THROUGH THE RELATIVE LACK OF
PROGRESS IN ADOLESCENTS AND YOUNG
ADULTS
The potential barriers to trial enrollment that patients face
are numerous. But, just how important are clinical trials for
progress against cancer? The answer to this question is
crucial, because if trial participation is ultimately unrelated
to cancer population survival gains, the issue of barriers to
trial participation has little importance. To examine this, we
studied the relationship between adolescents and young
adults (AYAs) and cancer population outcomes over time.
This is an ideal group in which to examine the impact of
clinical trials given that since 1980, AYA patients have had a
slower rate of cancer population survival improvement than
younger and older age groups by 5% to 13% in absolute
differences (Fig. 2). Concomitantly, cancer has become the
most frequent cause of death due to disease in AYAs.68
During the past decade (2000 to 2009), deaths due to cancer
declined in all age groups except in young adults age 20 to
29; in 25- to 29-year-olds, deaths due to cancer actually
increased.69
The survival disparity between AYAs and other patients
may be due in part to early achievements in improving
survival for AYAs, after which resources were directed to-
ward research in other age groups. Also, cancer in AYAs have
potentially complex biologic signatures that neither pedi-
atric oncologists nor adult-treating medical and hematolo-
gist oncologists are accustomed to treating.70 AYAs are also
less likely to have health insurance,71 especially prior to the
FIGURE 2. Increase in Absolute Percentage of Annual
5-Year Cancer-Specific Survival Rates Since 1973 to
1975 by Calendar Year and Age
Baseline is 1973 to 1975 average. Kaposi sarcoma is excluded due to the HIV/
AIDS epidemic during the 1980s and early 1990s; thyroid cancer is excluded
because of overdiagnosis and increasing survival inflation. Regressions are 4
polynomials. Data source is SEER 9 regions.75
CLINICAL TRIAL PARTICIPATION
advent of the Affordable Care Act, which could be associated
with delays in diagnosis and compromises in optimum di-
agnostic and therapeutic interventions.72 At the same time,
AYAs have had the lowest participation in clinical trials in
absolute terms than any other major age group.10 The
central issue then is the extent to which lack of clinical trial
activity in AYA patients with cancer accounts for the relative
lack of progress in improving cancer population outcomes.
All Cancers
The Cancer Therapy Evaluation Program (CTEP) of NCIs
Division of Cancer Therapy and Diagnosis has patient accrual
data from phase I, II, and III cancer treatment trials con-
ducted by the NCI cooperative groups and NCI-designated
cancer centers. For this analysis, 371,302 patient entries
during 1997 to 2009 were examined. In addition, we used
cancer population data derived from the Surveillance, Epi-
demiology, and End Results registry, U.S. Census data, and
joinpoint statistical software analyses to examine trends in
U.S. cancer population estimates.73-78
Figure 3 shows the relationship between the average
percent change (APC) in the 5-year cancer-specific survival
rate from 1985 to 1999 and the accrual rate to national
cancer treatment trials during 2001 to 2006. Although this
comparison is confounded by time, there was a nearly 1:1
correlation over the entire age range that was strongly
significant. Patients age 15 to 34 had the lowest APC in
5-year survival. A similar pattern was found with respect to
cancer mortality, which isolates patients age 0 to 40 (Fig. 4).
Patients age 20 to 24 had a particularly poor reduction in
cancer mortality, as well as the lowest absolute number of
clinical trial accruals. In both cases, the correlation between
trial enrollment and, respectively, APC in 5-year survival and
mortality is clearly evident and highly significant (p , .001).
Acute Lymphoblastic Leukemia
The greatest effort during the last decade to increase ac-
cruals in AYAs was within the population with acute lym-
phoblastic leukemia (ALL), the most common pediatric
cancer. New clinical trials in ALL specifically designed for
AYAs were launched,79-81 the National Comprehensive
Cancer Network released practice guidelines for ALL,82 and
an increasing number of presentations and publications on
the topic occurred at national meetings and appeared in the
peer-reviewed medical literature.83-89 The effort was ef-
fective, with AYAs having the greatest accrual increase of all
cancers in ALL, up to twice that of the cancer with the next
greatest increase, acute myeloid leukemia.74,90 Perhaps in
part for this reason, the only increase in either absolute
accruals or accrual as a proportion of cases during the first
decade of the 21st century occurred among patients age
10 to 20 (Fig. 5).
Hence, the population with ALL was examined more
closely for a relationship between survival improvement and
clinical trial participation. As shown in Fig. 6, clinical trial
accruals as a proportion of ALL cases in the United States
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UNGER ET AL
FIGURE 3. Comparison of Average Percent Change in
the 5-Year Cancer Survival Rate and Treatment Trial
Accruals, by 5-Year Age Intervals
The open columns represent trial accruals during 2001 to 2006 and the colored
bars the average percent change (APC) in 5-year relative survival rate of all
invasive cancer except Kaposi sarcoma during 1985 to 1999. The red bars indicate
the adolescent and young adult (AYA) age group. The inset compares the APC in
5-year survival rate with the treatment trial accruals. Accrual data from the
National Cancer Institute Cancer Therapy Evaluation Program (CTEP) were
provided by Steve Friedman, Michael Montello, Troy Budd, and Samantha
Finnegan via the Freedom of Information Act. Survival data were obtained from
SEER 9 Regions.75 Kaposi sarcoma is excluded from the survival statistic because the
HIV/AIDS epidemic occurred during the 1980s and early 1990s, which substantively
altered the overall cancer survival rate in AYAs during those years.
during 2000 to 2009 drops precipitously for patients age
15 to 20. Figure 6 also shows the 5-year leukemia-specific
survival rate for patients with ALL as a function of single year
of age. Joinpoint analysis identified two inflections, ages 17 and
20, during which the 5-year survival rate decreased 23%. This
AYA ALL cliff constituted 30% of the overall decline from
95% at age 5 to less than 20% at age 70. The cliff patterns for
both accrual and survival are virtually superimposable,
which strongly suggests they are related, although other
factors, such as a switch from pediatric to adult treatment
regimens, could also contribute.91
Clinical Trials Effect Summary
These data enable three fundamental conclusions. First,
both survival prolongation and mortality reduction in pa-
tients with cancer are correlated with clinical trial activity.
Second, the dependency of survival prolongation on treat-
ment trial accrual has been apparent for all ages. Third, AYAs
have had the least trial participation and the least survival
prolongation and mortality reduction, particularly among
patients age 20 to 29.
It has been previously observed that the age-dependent
rate in the reduction of deaths attributed to cancer in the
United States is correlated with the age-dependent accrual
of young adults to national cancer treatment trials during the
same era.69 After suicide, cancer is the second leading cause
of death due to disease among AYAs. More is needed to
overcome the national AYA cancer-related death problem,
beginning with increased clinical trial availability, access,
190 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
referrals, participation, and conduct. Fortunately, NCI-
designated cancer centers are evaluating their own AYA
referral patterns and clinical trial determinants,92,93 and
intergroup efforts are underway within the current orga-
nizational structure of the federal clinical trials enterprise,
including the NCIs National Clinical Trials Network (NCTN),
to create novel opportunities for collaborative AYA oncology
research among the pediatric and adult NCTN groups.94,95 As
is done in England, age-specific biology, pharmacology,
proteomics, genomics, and clinician and patient behavior
studies embedded within clinical trials are required to
further improve survival for AYAs.96
GLOBAL AND LOCAL STRATEGIES TO IMPROVE
CLINICAL TRIAL PARTICIPATION
We have illustrated the nature of clinical trial enrollment
barriers and established the potential link between trial
enrollment and improvements in cancer population survival.
Efforts to improve trial enrollment of cancer patients are
clearly needed. In this context, we propose the following
global and local strategies to improve trial participation.
Overall Strategies
In 2010, the NCI and the American Society of Clinical On-
cology sponsored a Cancer Trial Accrual Symposium to
provide recommendations for trial recruitment. Summary
recommendations centered on the patient, community,
physician/provider, and site.97 This symposium led to many
recommendations at each level consistent with the over-
arching view that one size does not fit all when it comes
to recruitment to clinical trials. The organizers noted in
FIGURE 4. Comparison of Average Percent Reduction
in the Annual National Cancer Mortality Rate and
Treatment Trial Accruals, by 5-Year Age Intervals, Age
Younger Than 40
The open columns represent trial accruals during 2000 to 2006 and the colored
bars the average percent reduction in national cancer mortality rate during 1990
to 1998. The red bars indicate the adolescent and young adult (AYA) age group.
The inset compares the mortality rate reduction with the treatment trial accruals.
Accrual data from the National Cancer Institute Cancer Therapy Evaluation
Program (CTEP) were provided by Steve Friedman, Michael Montello, Troy Budd,
and Samantha Finnegan via the Freedom of Information Act. Mortality data were
obtained from the National Center for Health Statistics via the SEER program.78

FIGURE 5. Absolute and Relative Trial Accrual Rates to
NCI Treatment Trials: Comparison of 2001 to 2003
Versus 2007 to 2009 Estimates
Comparison of 2001 to 2003 versus 2007 to 2009 for annual accruals to
treatment trials sponsored by National Cancer Institute (NCI)-sponsored
cooperative groups and NCI-designated cancer centers (red curves) and accrual
proportion of all patients in the United States with invasive cancer into the trials
by 5-year age intervals (green curves), by single years of age. The heavy curves
represent 2007 to 2009 and the thin curves 2001 to 2003. Accrual data from the
NCI Cancer Therapy Evaluation Program (CTEP) were provided by Steve Friedman,
Michael Montello, Troy Budd, and Samantha Finnegan via the Freedom of
Information Act. Accrual proportion (%) was estimated from cancer incidence in
SEER 9 regions and population data from the U.S. Census Bureau.73,75
particular that although clinical trial enrollment barriers
have been extensively studied, Few rigorously conducted
studies have tested interventions to address challenges to
clinical trials accrual.97 In this broader context, the NCIs
AccrualNet website provides strategies, tools, and other
resources to support clinical trials.98
Global Strategies
At the beginning of this article, we delineated many of the
specific challenges to clinical trial enrollment. Given the
need to accrue large numbers of patients in a shortened
timeline and the increased complexity of U.S.-based clin-
ical trials, academic and industry sponsors are increasingly
exploring regions outside of the United States to conduct
trials, including in less developed regions of the world.
In the view of Barrios et al, the globalization of clinical trial
research is unavoidable.99 In a wide ranging review, they
propose the following solutions to some of the challenges
of clinical trial globalization:
1. Harmonize and share standards and goals for product
safety, quality, and efficacy.
2. Use finite resources more efficiently, share knowl-
edge, and optimize inspection resources.
3. Engage global partners to advance regulatory science
and public health solutions.
4. Implement risk-based monitoring and clinical inspection.
5. Incorporate error reduction strategies and consider
regional variations in the standards of care and their
effect on trial results.
CLINICAL TRIAL PARTICIPATION
6. Decentralize laboratories in favor of developing re-
gional expertise to provide carry-over benefits after
trial completion.
7. Streamline and advance bio-bank regulatory issues.
8. Invest in research and evidence-based cancer care
relevant to each region, including cancer registries
and clinical trial infrastructure.
In the authors view, the globalization of clinical research
is vital to speed up availability of life-saving medicines
throughout the world.99 In the setting of a domestic clinical
trial system that has been described as being in a state of
crisis, this view has added weight.12
The importance of differing cultural, scientific, ethical,
government, and logistic issues in each region must be
considered.100 One key ethical issue is whether the study
drug will be available at the end of the clinical trial. Avail-
ability may be affected by local religious customs concerning
contraceptive studies and ethical guidelines limiting pe-
diatric clinical trials. An additional ethical issue in low re-
source countries involves whether to develop local resources
for testing or to use international vendors for that purpose.
Although developing local resources provides an often needed
benefit, this could involve higher costs and may also be deterred
by local shipping laws and other logistic barriers.
An excellent example of global recruitment is the START
trial. 101 START is a multicenter, phase III, randomized,
double-blind, placebo-controlled trial of the cancer vaccine
tecemotide in patients with non-small cell lung cancer with
unresectable stage III disease. The trial is sponsored by
Merck KGaA and EMD Serono, Inc., in 275 study centers in
33 countries worldwide. A continuous series of strategies
was implemented for patient recruitment and retention
throughout the duration of the trial.102 These strategies
were referred to as the START global patient recruitment
and retention continuum, with the overarching purpose of
raising awareness of the START trial and keeping it in the
forefront in physician communities and in the local START
sites to increase patient enrollment and retention. The
strategies target physicians, research staff, local sites, pa-
tients, and the local community. Physicians were provided
START informational calls (sometimes physician-to-physician),
visits, and meetings, and START information at national on-
cology meetings. Research staff received START education,
and recruitment tools including motivational videos. The
local sites were offered additional site funding for acceler-
ated recruitment and START educational teleconferencing.
Patients received holiday and thank you cards and patient
START educational materials. The local community was
reached through local media outreach, public awareness
advertisements, and engagement of local site liaisons. En-
rollment to the trial occurred from 2007 through 2011 and
reached full accrual of 1,513 patients, indicating a highly
successful recruitment effort.
Domestic trials may also partner with international col-
laborators to augment trial enrollment. The SWOG SELECT
trial for prostate cancer prevention used similar recruitment
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UNGER ET AL
FIGURE 6. 5-Year Leukemia-Specific Survival Rates in
Patients with Acute Lymphoblastic Leukemia
Diagnosed From 2000 to 2012, and Estimated ALL
Treatment Trial Accrual Proportion From 2000 to
2009, by Single Years of Age
Each year of age was averaged from two consecutive years. Joinpoint analysis of
survival data identified ages 17 and 2074; linear regressions for survival data are for
age ranges 5 to 17, 17 to 20, and 20 to 70. Survival data were obtained from SEER 18
regions.77 Accrual data from the NCI Cancer Therapy Evaluation Program (CTEP) were
provided by Steve Friedman, Michael Montello, Troy Budd, and Samantha Finnegan
via the Freedom of Information Act. Accrual proportion (%) was estimated from
cancer incidence in SEER 9 regions and population data from the U.S. Census
Bureau.73,75
strategies as the START trial. The SELECT trial enrolled over
35,000 men in the United States, Canada, and Puerto Rico,
and completed enrollment 2 years ahead of schedule.62,63
On a smaller accrual scale, the contributions of the In-
ternational Breast Cancer Study Group, in collaboration with
the cooperative groups of the NCI, provided necessary ac-
crual to a trial evaluating ovarian failure in premenopausal
women with breast cancer.103
Local Strategies
Social media. Increasingly, social media platforms provide
an opportunity to communicate about clinical trials with
potential trial researchers and participants.104 The Quorum
Review Institutional Review Board (IRB) offered the fol-
lowing considerations for a plan to use social media in
research105,106:
1. Provide a rationale for the application of social media
to the target population.
2. Address the privacy and confidentiality concerns of
the social media applications to be used.
3. Vet all communications for sensitivity and potential for
harm, even if the content does not require IRB approval.
4. Provide a summary statement regarding the intended
uses of the social media account.
5. Closely monitor user-generated content (if allowed),
which is essential to a robust online community, for
patient protection and study integrity.
192 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Moreover, predetermined IRB-approved responses to
anticipated user-generated content should be available to
allow immediate responses when required, and links to
the study website should be included to allow for integration
of study platforms.
The U.S. Food and Drug Administration (FDA) has provided
no specific guidance on the use of social media in clinical
research.107 The Recruitment Information Sheet states that
in the case of direct advertising, the information and mode
of communication should be reviewed by the IRB for evi-
dence of coercion or implication of benefits to participation.
The Office of the Inspector General has released guidance
regarding the use of clinical trial websites, indicating that IRB
approval of a clinical trial listing, if limited to selected basic
information, is not required.108
InVentiv Health, a contract research organization, has
provided specific plans to assist researchers to plan digital
recruitment campaigns (Table 2).109 Their plans are pre-
mised on the idea that recruitment for global clinical trials is
an area ripe for re-engineering. More broadly, Facebook has
often been listed as the social media of choice; of the 73% of
online U.S. adults using social media, 71% use Facebook.
Often researchers using Facebook attempt to recruit from
the initial audience prior to forming a relationship. A better
approach may be to grow and engage your audience first,
before patients are recruited.110
Strategies to Address Demographic and
Socioeconomic Barriers
Elderly recruitment. Patients with concomitant illnesses
are often excluded from trials to ensure safety and to isolate
the cancer as the primary source of morbidity in the patient.
Unfortunately, this has the effect of excluding many patients
from trials, especially older patients with a greater comorbid
burden.28,57,58 Further, trials typically exclude patients with
prior cancers, even as the population of cancer survivors in
the United States is growing and which currently numbers
around 15 million.111 In this context, one strategy to remove
barriers to trials would be to remove unnecessary eligibility
criteria. Such an approach would improve access to trials,
especially for older patients, andbecause histology and
stage explain the vast majority of variation in cancer out-
comes, rather than comorbid conditionswould result in
only limited loss of power to test the efficacy of new
treatments.28 One study estimated that if protocol exclu-
sions related to organ system abnormalities and functional
status were relaxed, participation of older patients in clinical
trials would approach 60%, in line with cancer population
rates.51
Researchers should also consider increasing the number of
trials targeted to older patients, with due consideration to
potential safety issues.112 Several trials found no more
toxicity in elderly patients in chemotherapy-containing trials
than in younger patients, when patients were appropriately
selected.113,114 However, when chemotherapy was given
to patients age 80 or older, high risk of hospitalization or
 CLINICAL TRIAL PARTICIPATION

TABLE 2. Proposed Steps to Plan Digital Recruitment evidence that payment inducements do or do not affect
Campaigns109 assessment.123,124 A careful calibration of the size of any
monetary incentive would be necessary to avoid undue
Steps for Campaign influence.125
Steps for Strategy Development Implementation
Measures to address socioeconomic disparities in re-
Audit digital channels and social Place ads with key messages and cruitment may have a preferentially beneficial impact on
media sites to determine a call to action in the selected
where the targeted patients/ sites and social media platforms minority patients. For the SELECT trial, several strategies
caregivers can be found specifically addressed patients with low socioeconomic
Monitor existing online chats for Link banner or pop-up ads to status.61,62 SELECT provided funds to sites semiannually to
the area of research interest search engine results for offset travel expenses and meals, in addition to providing
to understand the issues and targeted health-related
concern to patients/caregivers searches
patient retention items. Larger supplemental site grants
and listen for patient speak so were awarded to 15 SELECT sites with potential to increase
it can be replicated in your minority recruitment through a competitive award mech-
messages
anism. These additional funds were most commonly used to
Map the recruitment messages Partner with advocacy groups and provide additional staff time for minority recruitment. Sites
to the targeted patients/ place trial ads on these groups
caregivers and appropriate online sites also provided reimbursement for food and/or trans-
channels portation costs expended to participate in the trial.62
Identify key bloggers and others Engage key opinion leaders as
who could eventually raise online ambassadors to raise
awareness and support trial awareness of the trial
participation
DISCUSSION
Both patients and physicians have been found to regard
Develop the creative concepts
for advertising and test the clinical trial participation as a positive approach to cancer
messaging and imagery for care.3 Despite this, the complexity of the enrollment process
effectiveness and the potential barriers faced by patients have combined
to make a successful clinical trial enrollment a rare event.
Clinical trials are the key step in advancing new treatments
treatment discontinuation as a result of toxicity (even with from the research setting to the cancer care clinic.
frequent dose modifications) were observed.115 The In- Therefore, a thorough understanding of the nature of trial
ternational Society of Geriatric Oncology recommends the enrollment patterns and barriers to enrollment is of para-
use of comprehensive geriatric assessment (CGA) in cancer mount importance. The literature indicates that structural
patients older than age 70.116,117 The CGA is time con- barriers preclude patient participation in trials for half of all
suming, often leading to physician abandonment. Fortu- cancer patients. Among patients for whom a trial is available,
nately, CGA time requirements have led to the development about half (or a quarter of all patients) are excluded due to
of prescreening tools used to determine whether full eligibility issues with trial exclusion criteria. The remaining
screening with CGA is required, though there are in- patients are sometimes not offered the chance to participate
consistent results regarding the validity of these tools.118-120 because of physician concerns, or decline due to patient
More generally, it is important to develop prediction models concerns. Structural, clinical, and attitudinal barriers to trials
capable of estimating risk of chemotherapy for octogenar- can differ according to some important factors, especially
ians and nonagenarians with regards to toxicity and hos- age. As a result, only a small portion of adult patients with
pitalization.115 A comprehensive approach to the evaluation cancer participate in trials, less than 5%, a rate that has
of the older patient with cancer considers the patients remained fairly constant over decades.
residence and fitness and includes an interdisciplinary team Increasing accrual to clinical trials is important for multiple
to provide individualized care.121 reasons. Faster accrual would enable trials to be conducted
more quickly. The predominant reason that trials fail to
Socioeconomic barriers. If marginal direct costs are pro- complete is poor accrual.126 These failures represent a lost
hibitive for some patients, then measures to cover these investment on the part of funding agencies. Moreover, when
costs would remove a critical barrier to enrollment. One clinical trials close because of failure to accrue, nonfinancial
approach would be to cover the excess costs of clinical trials costs are also incurred. Patients have exposures to study
for all patients, because even in an insured population, drugs with potential or realized adverse events. Patients and
copays and coinsurance have been shown to deter clinical research staff may experience psychologic effects such as
trial participation.53 Another potential approach would be to loss of trust and morale. Informed consent documents rarely
provide payments to patients. In the United States, the include the risk of closure because of lack of study partici-
practice of paying patients for trial participation is wide- pation, despite the fact that about one in four randomized,
spread, but also contentious, highly variable, and lacking in phase III trials have such an outcome.126
general guidance.122 One concern is that a payment in- The more rapid completion of trials would enable new
ducement might alter a subjects assessment of potential treatments to be developed more quickly. We have shown
risks or impair their judgment, although there is little data indicating a compelling relationship between the

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 193

UNGER ET AL
incidence of clinical trial enrollments and improvements in
cancer population survival outcomes. Our focus was a natural
observational contrast between AYAs and other age groups
with cancer. We found a slower rate of progress in AYAs
compared with younger and older patients, which underscores
the need to increase the number of clinical trials available to
AYAs with cancer and their participation in them. By extension,
this observation also points to the need to increase trial en-
rollment for patients of any age group, or any demographic
group, because this could have a beneficial impact on in-
creasing survival and reducing mortality from cancer.
Another important reason to increase clinical trial accrual is
to improve the generalizability of clinical trial results. Figure 7
illustrates how the vast majority of patients with cancer of all
agesbut, especially patients older than about age 15do
not participate in clinical trials.127 However, we have made
the case that there is a strong correlation between trial
participation and cancer population survival improvements.
Thus, trial results must generalize to nontrial patients, at
least to some degree. But, they may not do so in an efficient
manner, and cancer population survival gains may be lost in
the process. Under this rubric, greater participation leads to
greater generalizability, which leads to better cancer pop-
ulation outcomes. Patients who participate in cancer trials
are usually younger, healthier, and perhaps wealthier than
the typical patient who is not a trial participant. To the extent
that trials are more inclusive with respect to comorbid or
other conditions, adequately represent the demographic
makeup of the United States, and are easier to pay for, the
generalizability of trials would likely improve.
Finally, increased accrual to trials is important for patients,
because trials provide opportunity to receive the newest
treatments. The principle of equipoise posits that a properly
designed treatment trial tests a new or modified form of
therapy that is not known to have that benefit (otherwise
the trial would not be justified). In contrast, in addition to
access to the newest treatments, patients who participate
in clinical trials have other potential advantages, such as
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96. Stark D, Bowen D, Dunwoodie E, et al. Survival patterns in teenagers
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97. Denicoff AM, McCaskill-Stevens W, Grubbs SS, et al. The National
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98. AccrualNet. Strategies, tools, and resources to support accrual to
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99. Barrios CH, Werutsky G, Martinez-Mesa J. The global conduct of
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100. Tierney G, Sieher S. Key strategies for effective globalization of clin-
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101. Butts CA, Socinski MA, Mitchell P, et al. START: a phase III study of
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continuum for a phase III non-small cell lung cancer clinical trial. Paper
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April 2010; Bethesda, MD.
103. Moore HC, Unger JM, Phillips KA, et al; POEMS/S0230 Investigators.
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motherapy. N Engl J Med. 2015;372:923-932.
104. Frandsen M, Walters J, Ferguson SG. Exploring the viability of using
online social media advertising as a recruitment method for smoking
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105. Lamberti MJ, Kush R, Kubick W, et al. An examination of eClinical
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106. Top considerations for using social media in researchit all starts
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for-using-social-media-in-research.pdf. Accessed February 15, 2016.
107. U.S. Food and Drug Administration. Recruiting Study Subjects -
Information Sheet. www.fda.gov/regulatoryinformation/guidances/
ucm126428.htm. Accessed February 15, 2016.
108. Office of Inspector General. Clinical Trial Web Sites. A promising tool
to foster informed consent. http://oig.hhs.gov/oei/reports/oei-01-
97-00198.pdf. Accessed February 15, 2016.
109. InVentiv Health Clinical Division. E-Recruiting: using digital plat-
forms, social, media, and mobile technologies to improve clinical trial
enrollment. http://www.inventivhealth.com/docs/e-Recruiting_
Using_Digital_Platforms_Social_Media_and_Mobile_Technologies_
to_Improve_Clinical_Trial_Enrollment.pdf. Accessed February 15,
2016.
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116. Extermann M, Aapro M, Bernabei R, et al; Task Force on CGA of the
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117. Extermann M, Hurria A. Comprehensive geriatric assessment for older
patients with cancer. J Clin Oncol. 2007;25:1824-1831.
118. Hamaker ME, Jonker JM, de Rooij SE, et al. Frailty screening methods
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121. Balducci L, Colloca G, Cesari M, et al. Assessment and treatment of
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paying research participants. Contemp Clin Trials. 2005;26:365-375.
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125. U.S. Department of Health and Human Services. Federal Policy for the
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treatment trial results. J Natl Cancer Inst. 2014;106:dju027.
HEALTH SERVICES RESEARCH AND QUALITY
OF CARE

Using Social Media, Wearables,

and Electronic Medical Records to
Improve Quality of Cancer Care

CHAIR
Michael J. Fisch, MD, MPH
The University of Texas MD Anderson Cancer Center
Houston, TX

SPEAKERS
Arlene E. Chung, MD, MHA, MMCi
University of North Carolina at Chapel Hill School of Medicine
Durham, NC

Melissa K. Accordino, MD
New York-Presbyterian Hospital
New York, NY
FISCH, CHUNG, AND ACCORDINO

Using Technology to Improve Cancer Care: Social Media,

Wearables, and Electronic Health Records
Michael J. Fisch, MD, MPH, Arlene E. Chung, MD, MHA, MMCi, and Melissa K. Accordino, MD

OVERVIEW

Digital engagement has become pervasive in the delivery of cancer care. Internet- and cellular phonebased tools and
systems are allowing large groups of people to engage with each other and share information. Health systems and individual
health professionals are adapting to this revolution in consumer and patient behavior by developing ways to incorporate the
benefits of technology for the purpose of improving the quality of medical care. One example is the use of social media
platforms by oncologists to foster interaction with each other and to participate with the lay public in dialogue about science,
medicine, and cancer care. In addition, consumer devices and sensors (wearables) have provided a new, growing dimension
of digital engagement and another layer of patient-generated health data to foster better care and research. Finally,
electronic health records have become the new standard for oncology care delivery, bringing new opportunities to measure
quality in real time and follow practice patterns, as well as new challenges as providers and patients seek ways to integrate
this technology along with other forms of digital engagement to produce more satisfaction in the process of care along with
measurably better outcomes.

H igh-quality medical care is expected to be efficacious,

safe, timely, patient centered, efficient, and equitable.1
None of these attributes of high-quality medical care are
possible in a vacuum. Physicians must be engaged with each
other to share ideas, collaborate, and establish best practice
norms and creative new solutions. Social media has rapidly
become one of the normative approaches to foster these
critical connections. Compared with traditional media, social
media is updated more frequently and it is more interactive,
while also being archivable and searchable.2 Three major
needs for connection that social media helps oncologists
meet are (1) finding and prioritizing medical literature and
medical meetings information; (2) finding the current lo-
cation, interests, and qualifications of other physicians; and
(3) crowdsourcing or surveying each other about best
practices or approaches to clinical scenarios.
FINDING AND PRIORITIZING MEDICAL
LITERATURE
The medical literature is central to ongoing medical ed-
ucation. Early findings of new research as well as expert
summaries of existing literature are shared at medical
meetings, and this work is more formally disseminated in
medical journal articles. How oncologists and other health
professionals identify new information from meetings and
published literature and prioritize what to read continues
to evolve. Traditional techniques involved subscribing to
key journals, browsing other journals in shared collections
(libraries, offices), gathering in journal clubs, discussing
specific articles at morning reports or interdisciplinary
rounds, and attending local and national meetings where
new data are presented and reference literature is cited.
We occasionally visit online textbooks or information
resources and we also encounter lay press stories citing
medical articles. In todays world, as noted by Dr. Bryan
Vartebedian (@Doctor_V), weve reached a point where
social media is now part of the professional workflow.3
Oncology clinicians are finding both efficiency and en-
joyment from using social media platforms such as Twitter
to keep up with the medical literature and share in-
formation from meetings. On Twitter, one can follow
many key journals (and can even follow collections of
journals on a list) and quickly scan through articles as they
come out and are tweeted by the journals. More im-
portantly, when oncologists follow each other on Twitter
(and collections of colleagues on lists), there is a sort of
Bayesian quality to social media whereby the prior
probability of seeing an article or hearing about a new
finding at a meeting4 is enhanced by retweets that amplify
the most important articles.

From AIM Specialty Health, Chicago, IL; Outcomes Research Program, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC;
Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Michael J. Fisch, MD, MPH, AIM Specialty Health, 8600 West Bryn Mawr Ave., Suite 800, Chicago, IL 60631; email: fischm@aimspecialtyhealth.com.

2016 by American Society of Clinical Oncology.

200 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


FINDING AND CONNECTING TO OTHER
PHYSICIANS
In addition to curating the medical literature, Twitter and
other social media platforms (such as Facebook) also pro-
vide a venue for connection. For example, if a physician posts
or tweets the link to an article, other colleagues can reply
with their own comments. Patient and layperson perspec-
tives come forth frequently because others besides oncol-
ogists can see these tweets and engage in dialogue. This
element helps health professionals maintain a broader and
more patient-centered perspective on the literature. An ex-
ample of an exchange between oncologists and a cancer
survivor is shown in Fig. 1.
Twitter does not lend itself to in-depth analysis or detailed
commentary, as the comments are limited to 140 characters.
Oncology professionals also use Twitter to connect to blogs
with extended commentary on the literature and other key
issues in oncology care. These blogs can be individually
managed (such as 33charts by @Doctor_V) or they can be
guest blogs distributed by a physicians institution or pro-
fessional organization (such as the American Society of
Clinical Oncologys ASCO Connection) or through another
physicians popular blog (such as KevinMD). Another
professional-oriented site is ResearchGate. This site, which is
geared toward academic researchoriented professionals,
allows oncology professionals to connect directly with in-
vestigators to ask questions about their articles, to follow
their most recent publications, and to even request reprints
from individuals.
Doximity, a unique platform restricted to health pro-
fessionals with a National Provider Identifier number, is a
more restricted setting for conversation and, this is more
comfortable for some clinicians. Articles can be found
KEY POINTS
Social media is increasingly used by oncology clinicians
to find and prioritize medical literature, connect with
other providers, and interact with the public about
cancer care.
Consumer devices and sensors (called wearables) are
growing in popularity and allow for patient monitoring
in their own environments outside of clinical
encounters.
Patient-generated health data from wearables provide
an opportunity to enhance comparative effectiveness
research in oncology.
Electronic health records are widespread in oncology
and are being used to measure adherence to quality
metrics and often to connect with patients through
secure portals.
Electronic health records have the potential to improve
the quality of cancer care by enhancing education and
awareness of evidence-based guidelines and by serving
as a resource for quality assessment and as a tool for
clinical and population-based research
USE OF SOCIAL MEDIA IN ONCOLOGY PRACTICE
directly through Doximity and commented on and/or
liked. The latter allows others to see what articles are
most endorsed. The most powerful feature of Doximity is
that it allows clinicians to find each other by searching the
Doximity search engine (even when the physician you are
searching for has not engaged with Doximity). Try it: search
for yourself on this site. You will find that Doximity identifies
not only your location but also your medical school, resi-
dency and fellowship (along with listing your colleagues who
trained with you), certifications, licenses, and insurance that
your practice accepts. Individuals can also list their publi-
cations and other aspects about themselves by expanding
the profile. Physicians could, for example, search for col-
leagues in their residency and find out where they now
practice and their current specialty. In addition, Medstro has
emerged as another popular social network for physicians.
Medstro features discussion groups with a tight connection
to the New England Journal of Medicine, as well as contests
and interactive challenges featuring engagement with ac-
ademic subspecialty experts. Job searching is also integral to
both Doximity and Medstro.
CROWDSOURCING AND SURVEYING OTHER
PHYSICIANS
Social media provides a convenient mechanism for checking
in with other physicians, even when those physicians are
outside of the physicians local peer group or organization.
For example, if a clinician wonders Is there a valid in-
strument that can be used to measure fear of cancer re-
currence?, the question could be crowdsourced on Twitter
by simply typing the question and pressing send. This
would be distributed to the clinicians followers. One could
also distribute the question outside of ones followers to
other groups of oncology professionals using hashtags. For
example, adding #pallonc at the end of the question would
distribute the tweet not only to an individuals followers but
also to anybody else worldwide who is tuned in to this
topic by searching or streaming tweets with this hashtag.
Dr. Matthew Katz (@subatomicdoc), a radiation oncologist,
has led the oncology community by developing Cancer Tag
Ontology and Oncology Tag Ontology (via symplur.com) to
codify this way of indexing tweets.5
Another sort of question might be a clinical case scenario,
such as, Is there a role for post-treatment PET/CT following
chemoRT for stage III NSCLC? This type of question could be
directed to Twitter also, and those replying are likely to give a
short answer and include a link to a relevant article or web
resource. However, there is a forum for oncologists available
for addressing clinical scenarios via theMednet.org. This new
forum is facilitated by Dr. Nadine Housri (@nadinehousri),
who is also a radiation oncologist. It is free and, like Doximity,
restricted to health professionals. It is not a place for dis-
cussion of specific patients, but it is useful for general case
scenarios, and the forum is well facilitated and allows for
social interactions between various disciplines and be-
tween community and academic practitioners. Another
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 201
FISCH, CHUNG, AND ACCORDINO

FIGURE 1. Example of an Oncology-Related Exchange on Twitter

This example of an exchange on Twitter begins with a tweet by an oncology fellow in Boston sharing an ASCO Post article describing a peer-reviewed manuscript about the
association between symptoms and employment outcomes in cancer survivors. Hashtags and specific Twitter handles are used to help disseminate the tweet. A picture of the data is
also included by adding a tiny URL link to the picture file. A cancer survivor replies to the tweet, raising the issue of fear of recurrence. Another oncologist replies to the survivor,
referencing a specific article about key associations related to fear of recurrence.

kind of question that lends itself to social interaction
between physicians is How many oncologists are us-
ing the XYZ regimen in first-line treatment of multiple
myeloma? Dr. Simrit Parmar (@spa718), an academic
hematologist/oncologist, has developed a platform called
MDRing that works via the web or smartphone (as an
iPhone application) to bring cancer professionals to-
gether to answer survey-type questions like this. MDRing
has been used by clinical cooperative groups and other
organizations and by individual oncologists as an edu-
cational tool and a practical tool for clinical research
planning.
CONNECTING WITH PATIENTS
Physicians do not need social media to connect with their
own patients. Connecting with our patients occurs through
direct interactions and also through secure interactions
available through electronic health record (EHR) systems or

202 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


other platforms approved by our clinical organizations. It is
well recognized that use of social media can bring risks to
individual health professionals and their organizations.
Physicians must be aware of unintentional online disclosure
of patient information, because even subtle oversteps of
boundaries raise concerns for professional reputation and
responsibility.6 Nevertheless, there is nothing that prevents
our patients from engaging us through publicly available
social media sites such as Facebook and Twitter. Fear of this
sort of contact is one reason that some clinicians are re-
luctant to use social media. Dr. Don Dizon and a working
group of the ASCO Integrated Media and Technology
Committee noted that oncologists must not confuse the role
of provider of information and provider of care, must un-
derstand regulations related to state licensure and medical
records, must recognize the importance of transparency and
disclosure of potential conflicts of interest, and must avoid
disclosures of preliminary results or nonpublic information.7
Guidance is also commonly included in the social media
policies of health care organizations and clinical research
organizations.
With boundaries understood, it is appropriate for cli-
nicians to interact with patients and the lay public in the
broader sense. That is, individual cancer survivors and
their family members can be followed on social media,
and they are a key component of the healthy exchange of
ideas and perspectives about illness, science, and health
care. Oncologists can use this opportunity to help educate
the public, to advocate for science and for clinical trial
participation, and to promote good health behaviors and
principles of sound medical care. Social media can also be
used by oncologists to demonstrate their humanity,
compassion, and deep dedication to the service of others.
Some oncologists use Facebook for this purpose. For
example, Dr. Anas Younes (@DrAnasYounes), an academic
lymphoma specialist, has shared information about
lymphoma, cancer, and other health care topics using this
platform and built a following represented by greater than
1,500 likes on his Facebook page. Moreover, organi-
zations such as ASCO and specific health care organiza-
tions widely use public Facebook pages. The Mayo Clinic is
one example of a health care organization that has fully
embraced social media, adopting a patient-centered ap-
proach of reaching out to innovate in this evolving space
where patients are seeking information. The Mayo Clinic
Center for Social Media (#mccsm) has greater than 1.25
million followers on Twitter and greater than 750,000
likes on its public Facebook page. Of note, Facebook use
is most effective when the user is able to provide regular
input, whereas Twitter is easier to use sporadically. Other
social media platforms such as Instagram, Pinterest, and
even Snapchat are used less often for sharing information
about cancer, but there is certainly opportunity to har-
ness these popular sites for the same purposes. As noted by
Dr. Michael Thompson (@mtmdphd), social media platforms
will always evolve, but it is the content, curation, and
connectivity that matter.8
USE OF SOCIAL MEDIA IN ONCOLOGY PRACTICE
WEARABLE TECHNOLOGY
In addition to connecting through words and media, another
dimension of digital engagement comes from the growing
availability and affordability of various consumer devices
and sensors that can be worn or placed on the body. Known
as wearables, these devices provide an unparalleled op-
portunity to monitor a persons health and experience in his
or her real-world environment. The current model of health
care for treatment or prevention is still mainly focused on
face-to-face encounters with providers in the clinical setting;
however, as we move away from this traditional model of
care, wearables could provide additional insights about the
patient experience and enhance the quality of cancer care.
Wearable technology refers collectively to electronics that
can be worn on or close to the body. Wearables encompass a
growing number of different types of items such as wrist-
worn sensors that detect and measure physical activity and
intensity (such as a Fitbit device or Apple Watch), rings and
glasses with sensors, earbuds, and textiles or fabrics with
embedded sensors to monitor heart rate and temperature,
to more invasive versions such as an implantable microchip
or smart tattoo. It is estimated that there will be over 111
million worldwide shipments of wearables in 2016, with
most being in the form of watches and wristbands (92%).9
Users are almost equally split between males and females
and are mostly younger than age 55,9 although adoption
among older adults is expected to be the sector of largest
growth. It is also anticipated that the wearables market will
grow over 64% to $25 billion in 2019, with over 245 million
devices sold.10
HEALTH MEASUREMENT OPPORTUNITIES
THROUGH GROWING ADOPTION OF
WEARABLES
Patient-generated health data (PGHD) from wearables, such
as biometric data like heart rate and blood pressure readings
or physical activity data, are some of the more commonly
captured data from wearables. PGHD are defined as health-
related dataincluding health history, symptoms, biometric
data, etc.created, recorded, gathered, or inferred by or
from patients/caregivers to help address a health con-
cern.11 PGHD from wearables could provide a more holistic
view of the health and status of a patient.
As consumer adoption of wearables increases and there
are advances in the underlying technologies, the opportu-
nity to collect data on a population level is more feasible and
could provide important advances in oncology comparative
effectiveness research. Recently, there have also been
several key funding initiatives that aim to incorporate
wearable device data. For example, the National Institutes of
Health Precision Medicine Initiative Cohort Program will
capture physiologic and environmental exposures. More-
over, several of the Patient-Centered Outcomes Research
Institutefunded Patient-Powered Research Networks col-
lect PGHD from wearables in an effort to collect data
in a nationally representative sample at lower costs than
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 203
FISCH, CHUNG, AND ACCORDINO
traditional methods of data collection. Dietary data and
physical activity data are examples of data that are tradi-
tionally difficult to capture on a continuous basis in research
studies or for clinical care. Capturing data such as these
could be used to better understand the influence of these
factors on cancer risk and progression among populations of
patients.
Physical activity, in particular, is an important factor in
cancer survivorship, both for prevention and quality of life
and symptom management, and may also improve a
patients ability to tolerate cancer treatment by improving
fatigue, quality of life, and physical functioning.12-14
Pedometry using commercially available fitness trackers
such as Fitbits has shown that large decreases in daily
steps may correlate with more severe symptoms, im-
paired physical health, and restricted daily activities.15
Thus, tracking physical activity using a wearable device
could potentially be used for monitoring symptoms and
severity in those who may not be able to self-report
symptoms because of various barriers such as literacy
or severity of illness. The use of a wearable physical ac-
tivity tracker could also potentially monitor levels of
activity and provide a target for behavioral interventions
during treatment and survivorship using just-in-time
adaptive methodologies that would not have been pos-
sible without the real-time continuous activity tracking
afforded by wearables. One might imagine that a patient
with breast cancer undergoing treatment could wear a
physical activity tracker and that the PGHD captured
showed lower than usual levels of activity for this patient.
Decreased physical activity could trigger a cascade of
activities such as offering a patient-reported outcome
questionnaire to determine whether the patient has
worsening symptoms. If there was no detection of
worsening of symptoms, the patient could be encouraged
to be more active, which could be personalized based on
prior activity levels and other factors such as whether the
patient has anemia. The patient could receive a person-
alized and tailored text message to her wrist-worn
wearable about the benefits of activity during treat-
ment and could be given specific goals for increasing
activity safely. This PGHD could also be shared with her
oncologist and primary care physicians, such that the care
team was aware of the patients health status and ex-
periences, which could inform treatment decisions or
changes in management. Wearables could also be in-
tegrated with other smart home monitors and other
sensing systems, such as smart bottles that could detect
when a user has not opened a pill bottle and send alerts to
patients or caregivers, or these devices may be able to
detect a fall or impaired gait such that assistance could
be provided to prevent complications. Another scenario
in which wearables also have promise is for remote
monitoring for cardiovascular complications such as
arrhythmias during treatment with cardiotoxic chemo-
therapeutics and in survivorship care. As digital patient
engagement advances and matures, further applications
204 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
for wearables in cancer care are likely to emerge where
the wearable provides utility and value.
CHALLENGES IN THE USE OF WEARABLES
As is the case with other emerging technologies, the op-
portunity to monitor patients more continuously with
wearables comes with its own unique challenges. Because
the use of wearables in health care is still nascent, it is not
clear what types of data from wearables will be the most
effective to improve symptoms, the patient experience, and
short- and long-term health outcomes. Best practices for
integrating this PGHD into clinical workflows to ensure
appropriate review and action are not yet available, but as
practices and health care systems begin to have more ex-
perience with PGHD, there will be better guidance on how to
engage patients in a learning health ecosystem and what will
be acceptable within provider workflows. In addition, in the
next 2 years, the Office of the National Coordinator for
Health Information Technology will be developing a policy
framework for identifying best practices, gaps, and oppor-
tunities for the use of PGHD, which will provide further
guidance.
Among the largest vendors of EHRs, most allow patients to
submit wearables data in various formats for provider re-
view. An example of a wearables workflow within clinical
care might include the following: (1) a patient receives a
message from his or her provider in the patients portal
account, which provides instructions on how to connect the
wearable device account to allow for transmission of these
data to the health care system via the patient portal; (2) the
patient uses the wearable device for a certain interval to
capture data; and (3) the PGHD are transmitted either in real
time or asynchronously and made available for providers to
review within EHR workflows. Currently, data visualization
and presentation is generally constrained by the EHR ven-
dors specifications and is presented mostly in tabular for-
mat. These data are usually presented at the patient level
and not at a population level. Wearables could generate
large volumes of asynchronous or continuous streams of
data, which would be very challenging to manage and review
without intelligent filtering and summarization for both
patients and providers.16 Therefore, informatics solutions to
assist with transforming these data into actionable in-
formation will be imperative.
Current adoption of wearables is low and rarely sustained
beyond several months. However, this is felt to be attrib-
utable to cost, the lack of integration with other devices, and
the absence of interactive and dynamic feedback. Security
and privacy concerns are also a barrier to adoption. Overall,
the tangible benefits of wearables currently lag behind rapid
growth of the device market, so it is expected that adoption
will ramp up as software platforms provide better person-
alization and insights, which could also better sustain patient
engagement. In part, the lack of accurate, validated bio-
metric data from the majority of consumer wearables is
also a barrier to adoption within health care. In the present
state, it is difficult to decipher which wearable devices and

what types of PGHD will provide the most value within
cancer care. Current studies in progress piloting the use of
PGHD will be important in determining what may be the
most effective types of wearables or PGHD that could im-
prove the patient experience during cancer treatment and in
survivorship.
FUTURE DIRECTIONS WITH WEARABLES
As the wearables market matures, we will likely see a
movement away from primarily wrist-worn devices to body-
conforming sensors embedded in flexible patches or stickers
and toward medical-grade sensors that provide accurate and
valid data. In addition, we should see improvements in
physical comfort, devices being more unobtrusive, battery
life, and interoperability with other devices and software
applications. We will also see more of a connected eco-
system of appliances, home-based sensors, and wearables
such that richer information about an individuals activities
of daily living alongside biometric data could be captured.
These data could provide insights about various facets of a
patients health and environment, which, if collected on a
population level, could provide important insights about the
influence of behavioral, lifestyle, and environmental factors
on cancer risk and progression.
ELECTRONIC HEALTH RECORDS IN CANCER CARE
DELIVERY
Social media and wearables reflect interactions that occur
largely outside of the health care environment. In the very
fabric of health care delivery is the need to document health
status and elements of care. In recent years, the practice of
medical oncology has become increasingly complicated. As
reimbursement models transition from fee-for-service to
newer shared-risk models, a higher emphasis is placed on
the delivery of high-quality and high-value care. EHR use
reflects the new digital landscape that extends far beyond
mere documentation, as the EHR brings features that have
been shown to improve quality and efficiency of care.17 As
such, practices have been incentivized to use an EHR be-
cause it is seen as a generalizable intervention to expand the
use of technology to improve the quality of our care.18
Within oncology, EHR use can improve quality in real time
and can be used as a tool to measure adherence to quality
metrics within individual practices and help identify care
disparities.
An EHR, as defined by the Institute of Medicine, is an
electronic system with the ability to collect and store patient
data, supply information, permit providers to enter orders
(known as computerized provider-order entry), and provide
decision support. In addition, EHRs may be able to provide
electronic communication, administrative support, patient
support, and population health management reporting.19
Benefits of EHRs include improved quality of care by in-
creased provider adherence to evidence guidelines, re-
duction in medical errors by improvement in accuracy and
clarity of data, and the potential for cost reduction.20-24 EHRs
USE OF SOCIAL MEDIA IN ONCOLOGY PRACTICE
also have the ability to share secured information with
patients directly through portals, which may improve pa-
tient satisfaction through increased data sharing.25,26 Lim-
itations of EHRs include negative effects in provider-patient
communication, such as reduced eye contact, higher op-
erating costs, unreliability of electronic systems, and work-
flow limitations.27,28
There are notable racial and age-related disparities in
the delivery of cancer care.29-31 An evaluation of ad-
ministrative data showed a 66% increase in adoption of
basic EHRs in federally qualified health centers from 2010
to 2012 (from 29.8% to 49.6%). However, disparities
existed; centers with higher proportions of low-income
patients had lower EHR adoption rates compared with
centers with smaller proportions of low-income patients
(45.1% vs. 55.5%, p , .05).32 These results were similar
to another population-based study that showed EHR
adoption to be lowest in areas with high concentrations of
minority and low-income populations.33 In regard to EHR
portal access, disparities also exist. A review of four
university nephrology practices showed that older age
(odds ratio [OR] 0.29), black race (OR 0.50), and having
Medicaid insurance compared with private insurance
(OR 0.53) were associated with decreased portal enroll-
ment.34 Another cross-sectional evaluation of portal uti-
lization revealed that older and nonwhite patients were
less likely to enroll; after enrolling, younger patients and
men were less likely to solicit advice or medication refills
compared with older patients and women.35 Potential
barriers to portal enrollment include lack of resources,
patient comfort and proficiency, lack of provider enthu-
siasm and communication, health literacy, and distrust in
the health system.32,34,36-43 Interventions to reduce dis-
parities in enrollment must address both access and at-
titudinal barriers.
THE EFFECT OF ELECTRONIC HEALTH RECORDS
ON QUALITY OF CARE
EHRs have the ability to improve the quality of cancer care
in a multitude of ways, including educational alerts to im-
prove adherence to evidence-based guidelines, improved
patient communication through patient portals, as a re-
source for individual and practice-based quality self-
assessment, and as a tool for cancer care delivery research.
Educational electronic alerts have been successful
at improving quality measures in a number of clinical
settings.44-48 Kucher et al found that an EHR alert that
identified patients at risk for deep-vein thrombosis (DVT)
increased use of appropriate DVT prophylaxis and led to
reduced rates of venous thromboembolism.46 Another study
alerted providers to a patients risk of contrast-induced
acute kidney injury (AKI) when imaging studies with con-
trast were ordered. After the alert was implemented, rates
of prophylaxis increased and incidence of contrast-induced
AKI decreased.47 Selvan et al investigated an electronic alert
triggered by erythropoietin-stimulating agent (ESA) order
entry if a patients hemoglobin was 12 g/dL or above
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 205
FISCH, CHUNG, AND ACCORDINO
(considered inappropriate use) at a single institution.
Postalert rates of inappropriate ordering of ESAs decreased
by 80%.48 An EHR alert triggered by a patient-reported
pain score of 4 or greater led to increased documentation
of pain care plans for patients with cancer with moderate
to severe pain by 20%.49 Another EHR intervention, which
has the ability to provide real-time clinical decision sup-
port through a combination of alerts and links to clinical
guidelines, is ASCO CancerLinQ, a rapid learning system.50-52
A rapid learning system refers to a technology platform
that allows data to be collected from different EHR systems
to be collected, aggregated, analyzed, and translated into
information aimed to improve treatment and drive scientific
learning and discovery from every patient encounter.50,53,54
As health care delivery continues to shift toward system-
based practice, knowledge of detailed evidence-based
guidelines does not solely fall on individual providers but
rather the system as a whole, and EHRs have the capability of
providing this type of decisional support to improve quality
of care.
Another important quality measure in oncology is ensuring
that patients receive appropriate treatment of their indi-
vidual cancer.50 Because more cancer therapies are now
delivered orally, a focus on medication adherence is be-
coming increasingly important. Medication nonadherence is
common among patients with chronic conditions, in whom
adherence rates are estimated to be around 50%.55,56 In
women with early-stage hormone receptorpositive breast
cancer, noninitiation, early discontinuation, and non-
adherence to hormonal therapy are common and are as-
sociated with poorer survival.57-63 Approximately one-third
of patients with chronic myelogenous leukemia are non-
adherent to their tyrosine kinase inhibitors during treat-
ment, and this is associated with poorer outcomes, including
treatment resistance.64,65 Barriers to nonadherence are
multifactorial but include poor provider-patient communi-
cation, side effects, costs of and access to medications, and
patient behaviors and education.56,66-68 Through patient
portals, EHRs have the ability to help foster secure com-
munication and thus bridge the gap between patients and
providers and allow improved communication between all
members of the health care team, including staff who can
answer questions, provide symptom management, and
assist with prior authorizations to help offset high out-of-
pocket costs. A recent randomized trial demonstrated that a
web-based platform of symptom self-reporting between
patients with cancer who are receiving chemotherapy and
providers was associated with improved quality of life, fewer
hospitalizations, and a longer duration of palliative che-
motherapy.69 In addition, single-institution studies have
shown that access to medical records and the ability to
request medication refills (via patient portals) were both
associated with increased adherence to medications and
medical advice.70-72 Furthermore, patient portals may be a
valuable resource to provide patient education and even
individualized medication plans. Improved communica-
tion through the EHR may improve adherence to both
206 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
antineoplastic and supportive medications, and be as-
sociated with better quality of care.
To provide high-quality care, it is important to system-
atically assess our own practice to identify areas for im-
provement as well as disparities in care. The 1999 Institute of
Medicine report Ensuring Quality of Cancer Care called for a
system to measure and monitor quality of care and to reduce
disparities in cancer care.73 In response to this report, ASCO
developed the Quality Oncology Practice Initiative (QOPI) to
measure quality at the individual and practice levels by
medical record abstraction and facilitate continuous im-
provement.74 To globally address quality improvement
throughout the physician workforce, the Accreditation
Council for Graduate Medical Education has revised its
training requirements and implemented the Clinical
Learning Environmental Review (CLER) program designed to
improve education in patient safety and health care qual-
ity.75 As part of the CLER program, residents and fellows are
expected to receive specialty-specific data on their adher-
ence to quality metrics and benchmarks within their patient
populations, to identify and reduce health care disparities
within their practice, and to foster habits of continuous
practice improvement.75 Through ASCOs CancerLinQ proj-
ect, data from the EHR can be pulled to measure QOPI
compliance in real time.35 An EHR is a robust tool that can
pull individual and practice-specific data in real time to allow
providers the opportunity to measure their own perfor-
mances and compare themselves with their peers, and thus
foster practice improvements on the individual, practice,
and, potentially, global levels.
In addition to continuous improvement, EHRs can affect
cancer care delivery on a larger scale as a tool for cancer care
delivery research. An upcoming pragmatic trial to be con-
ducted through SWOG will use the EHR to assess the efficacy
of prophylactic colony-stimulating factors during the first
cycle of intermediate febrile neutropenia risk chemotherapy
(10%20%). Sites will be randomized to a standing-order
entry system for prophylactic colony-stimulating factors via
manipulation of the individual site EHR or usual care. In
addition to evaluating rates and resource utilization related
to febrile neutropenia, this study will evaluate whether a
standing-order entry system helps improve adherence to
clinical practice guidelines.76 Other areas for future cancer
care delivery research include improvement of content,
dissemination, and implementation of cancer survivorship
care plans; EHR triggers aimed at improving adherence to
medication at both the patient and physician levels; and EHR
educational alerts to help providers adhere to best practice
guidelines.77
Many opportunities exist to improve quality of care
among patients with cancer, especially in improving treat-
ment adherence and reducing disparities. The EHR is a
valuable tool to aid in this regard, both in daily clinical
practice and in cancer care delivery research. However,
much like social media and wearables, interventions to re-
duce disparities of adoption and patient participation are
needed.

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HEMATOLOGIC MALIGNANCIESLEUKEMIA,
MYELODYSPLASTIC SYNDROMES, AND
ALLOTRANSPLANT

Evolving Therapies in Acute

Myeloid Leukemia: Progress
at Last?

CHAIR
Daniel J. DeAngelo, MD, PhD
Dana-Farber Cancer Institute
Boston, MA

SPEAKERS
Eytan M. Stein, MD
Memorial Sloan Kettering Cancer Center
New York, NY

Farhad Ravandi, MD
The University of Texas MD Anderson Cancer Center
Houston, TX
DEANGELO ET AL

Evolving Therapies in Acute Myeloid Leukemia: Progress at

Last?
Daniel J. DeAngelo, MD, PhD, Eytan M. Stein, MD, and Farhad Ravandi, MD

OVERVIEW

Acute myeloid leukemia (AML) is an acquired disease characterized by chromosomal translocations and somatic mutations
that lead to leukemogenesis. Systemic combination chemotherapy with an anthracycline and cytarabine remains the
standard induction regimen for fit adults. Patients who achieve complete remission generally receive postinduction
therapy with cytarabine-based chemotherapy or an allogeneic bone marrow transplant. Those unfit for induction che-
motherapy are treated with hypomethylating agents (HMAs), low-dose cytarabine, or they are offered supportive care alone
with transfusions and prophylactic antimicrobials. The revolution in understanding the genetics of AML, facilitated by next-
generation sequencing, has led to many new drugs against driver mutations. Better methods of identification of leukemic
blasts have provided us with better means to detect the disease left behind after cytotoxic chemotherapy regimens. This
measurable residual disease has been correlated with poorer relapse-free survival, demonstrating the need for novel
strategies to eradicate it to improve the outcome of patients with acute leukemias. In this article, we discuss adapting and
improving AML therapy by age and comorbidities, emerging targeted therapies in AML, and minimal residual disease (MRD)
assessment in AML.

A cute myeloid leukemia is most commonly diagnosed in

older adults, with a median age of diagnosis of 66 years.1
Given the aging population in the United States, the in-
cidence of AML will grow dramatically in the coming
decades.2 Older patients with AML define a distinct subgroup
with a worse prognosis and different biological character-
istics as compared to their younger counterparts.3 In ad-
dition, many older patients have significant comorbidities
and functional impairment that further complicates thera-
peutic options.3,4 As a result of the biologic complexity, high
rates of chemotherapy drug resistance, and poor host fac-
tors, the 5-year disease-specific survival of patients older
than age 65 remains less than 5%.
In spite of the many advances made in other hematologic
diseases, induction chemotherapy with cytarabine and an
anthracycline remains the standard initial approach for older
patients with AML. Although associated with high rates of
death from toxicity, it still offers the best chance of longer-
term survival.5 Less-intensive treatment and palliative ap-
proaches are currently being explored for patients who
cannot tolerate standard anthracycline induction therapy.6
Previous studies have identified age, performance status,
comorbidities, and cytogenetic risk groups as important
factors in stratifying older patients with AML.7 However,
these factors do not sufficiently address the heterogeneity
present in this older population. New studies suggest
that geriatric evaluation including psychological, cognitive,
physical, and comorbidities can identify deficits affecting
morbidity and mortality among patients with cancer and
should be incorporated into the initial evaluation for older
adults with AML.8-11 In addition, molecular profiling can help
to further identify a biologically resistant group of patients
who may benefit from targeted therapeutic approaches.
Regardless of whether standard induction chemotherapy,
less-intensive therapy, or targeted approaches are used, the
definition of complete remission is being redefined by our
ability to detect small residual subclones or MRD.
ADAPTING AND IMPROVING THERAPY
ACCORDING TO AGE AND COMORBIDITIES
Acute myeloid leukemia is a clonal hematopoietic stem cell
disorder, for which the treatment, and in fact cure, hinges
upon the successful eradication of the leukemic clone. To
this end, induction chemotherapy is given to reduce the level
of the leukemic burden below the level of detection and to
restore normal hematopoiesis. Postremission consolidation,
alone or followed by an autologous or allogeneic stem cell
transplant, is then used to eradicate the remaining leukemic

From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY;
The University of Texas MD Anderson Cancer Center, Houston, TX.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Daniel J. DeAngelo, MD, PhD, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email: daniel_deangelo@dfci.harvard.edu.

2016 by American Society of Clinical Oncology.

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burden in hopes of cure. The backbone of remission in-
duction therapy for younger patients (age , 60) and a sub-
set of older patients deemed fit enough to undergo such
treatment has consisted of high-dose cytotoxic chemo-
therapy often consisting of 7 days of continuous infusion
cytarabine combined with 3 days of an anthracycline,
otherwise known as the 7 plus 3 regimen. Remission rates
with induction therapy vary and depend on many factors
including patient age, cytogenetics, molecular profiling,
antecedent hematologic disorder, prior chemotherapy, and
type of leukemia. Over the past several decades, induction
therapy has been intensified with the aim of improving
remission rates, extending disease-free survival and, ulti-
mately, overall survival. For elderly patients (age . 60)
induction strategies have concentrated on less-toxic in-
duction strategies using HMAs, monoclonal antibodies,
nucleoside analogs, and other novel compounds.
Health Care Utilization
Older patients with AML spend a large portion of their life
after diagnosis in the hospital or clinic. Given the short life
expectancy of the vast majority of older patients with AML
and the low likelihood of cure, it is important to consider the
impact of cancer therapy on their quality of life, which in-
cludes the time spent in the hospital and receiving medical
care throughout their illness. One randomized study com-
pared intensive induction versus supportive care of older
patients with AML, with hydroxyurea or low-dose cytarabine
used as cytoreductive agent when needed.12 In this study,
patients treated with intensive chemotherapy had a
10-week survival advantage compared with those treated
with supportive care. However, there were no major dif-
ferences in patients time spent in the hospital. Another
study looked retrospectively at 330 consecutive older pa-
tients diagnosed with AML to examine their health care
utilization.13 The median number of hospitalizations for the
entire cohort was 4.2 (range, 1 to 18). Patients who died
KEY POINTS
The treatment of AML, especially in elderly patients,
remains a difficult endeavor with high therapy-related
toxicity and poor long-term survival.
Efficacy of therapy in AML has been assessed by
morphologic assessment, with complete remission
correlating with improved outcomes.
Several retrospective studies have clearly demonstrated
the adverse prognostic value of persistent MRD after
induction and consolidation therapy.
Standardization and universal availability of these
assays are key to their potential future use to direct
risk-adapted therapy.
New target-specific agents with novel mechanisms of
action are likely to be more effective in eradicating MRD,
thereby improving outcomes.
EVOLVING THERAPIES IN ACUTE MYELOID LEUKEMIA
spent a mean of 28.3% of their life from diagnosis in the
hospital and 13.8% of their life attending outpatient ap-
pointments, and only 23% used hospice services. Within
30 days before death, 84.5% of patients were hospitalized,
and 61.0% died in the hospital. Although intensive induction
offers a minority of patients a potentially curative therapy,
the patients who died spent more than 50% of their life from
diagnosis in the hospital or clinic. However, with the in-
troduction of HMAs, as well as improvement in supportive
care measures, it is unclear whether the findings of this study
would be replicable in the modern era.
Pretreatment Evaluation
Induction chemotherapy is a complicated and rigorous pro-
cess that is required to obtain clinical remission.14 Before
the initiation of induction chemotherapy, it is important to
establish the presence of comorbid conditions that could
potentially complicate the treatment of the patient. It is
clear that all elements of the patients history and physi-
cal examination are important. However, particular atten-
tion should be paid to a prior history of a hematologic
disorderfor example, a myelodysplastic or myeloprolif-
erative disorder, prior therapy for malignancies including
chemotherapy or radiation therapy, and a family history of
disease. Patients with secondary or treatment-related AML
have a significantly worse prognosis, which is predominantly
influenced by the higher incidence of unfavorable cytoge-
netic abnormalities. A history of cardiac disease such as
congestive heart failure would mandate careful monitoring
and potential alteration of induction chemotherapy because
anthracycline-based regimens are standard. Patients typi-
cally receive large amounts of intravenous fluids that ac-
company initial chemotherapy as well as antibiotics and
blood and platelet transfusions, and therefore patients with
cardiac abnormalities at the time of diagnosis need rigorous
and careful monitoring.
A study of 101 patients with AML age 65 or older at the
Dana-Farber Cancer Institute underwent geriatric assess-
ment.15 With a median age of 72, only 38% of patients had a
hematopoietic stem cell transplant comorbidity index of
greater than 1, and only three patients required help with
activities of daily living. The majority of patients (78%) re-
ceived treatment and, of those, 45% underwent induction
chemotherapy and 44% received either decitabine or aza-
citidine. The 1-year disease-specific survival was 39%. On
multivariate analysis, age at diagnosis, cytogenetic risk
group, secondary AML versus de novo, comorbidity score
(hematopoietic stem cell transplant comorbidity index) of
at least 1, difficulty with strenuous activity, and pain were
independent prognostic factors for survival. The most
amazing fact is that even when the analysis was limited to
patients with ECOG performance status of 1 or lower, diffi-
culty with strenuous activities, pain, and comorbidity
remained independent predictors. Thus, geriatric assessment
variables are independent prognostic factors for survival,
even among patients with the best performance status.
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DEANGELO ET AL
Acute Myeloid Leukemia Ontogeny
Acute myeloid leukemia is a biologically heterogeneous
disease that is typically classified into three clinically
distinct categories. Secondary AML (s-AML) represents
transformation from a prior diagnosis of myelodysplastic
syndrome or myeloproliferative neoplasm (MPN); therapy-
related AML develops as a complication of exposure to
leukemogenic therapies; and de novo AML arises in the
absence of an identified exposure or prior stem cell dis-
order. A retrospective, targeted, mutational analysis of
194 patients with s-AML or therapy-related AML was
compared with 100 unselected older patients with AML.16
The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2,
ASXL1, EZH2, BCOR, or STAG2 was greater than 95% specific
for the diagnosis of s-AML. The presence of one of these
secondary-type mutations defines a subtype of elderly
de novo AML that share clinical and pathologic simi-
larities with confirmed cases of s-AML. Patients with
secondary-type mutations have a higher likelihood of in-
trinsic therapy resistance, as reflected by a lower rate
of complete remission with standard intensive induction
chemotherapy.3,17,18 In contrast, older patients with de
novo/pan-AML mutations achieved a higher rate of com-
plete remission and rarely required reinduction. Thus, ge-
netic ontogeny may highlight a subset of older patients with
secondary-type mutations who, on the basis of age, genetic
characteristics, and induction outcomes, may have had an
unrecognized period of antecedent myelodysplasia before
AML diagnosis. In elderly AML, genetic ontogeny may ac-
count for the differences in chemosensitivity and clinical
outcomes.
Less Intensive Strategies
Low-dose cytarabine (LDAC) has been used for the treat-
ment of elderly, unfit AML patients for several decades.
Many studies have highlighted the fact that even very small
doses of cytarabine (20 mg/m2 administered once or twice
daily for 1014 days per month) can induce complete re-
mission in 8% to 18% of patients with AML and can prolong
survival compared with best supportive care.19 However,
patients with adverse cytogenetics seldom achieve re-
mission with LDAC. Despite this, LDAC may still be a
therapeutic option for geriatric patients without poor-risk
karyotype AML who prefer to self-administer drugs at home
without the need for daily clinic visits or hospitalization.
Because of the tolerability of LDAC, there are many clinical
trials exploring the combination of LDAC with novel in-
vestigational agents in an attempt to improve outcomes.
Inhibitors of the DNA methyltransferase (DNMT) azaciti-
dine (Vidaza, Celgene) and decitabine (Dacogen, Bloo-
mington, MN) are approved for the treatment of patients
with myelodysplastic syndrome.20-22 The current World
Health Organization definition of AML now includes patients
with a blast count of between 20% and 29% because these
patients were previously considered as having myelodys-
plasia.23,24 The study by Fenaux et al demonstrated an
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improved median overall survival among patients treated
with acacitadine compared with conventional care ap-
proaches, which included supportive care, LDAC, and 7 plus 3.25
Although most studies using HMA therapy in AML pa-
tients demonstrate lower complete remission rates
(10%20%) compared with conventional intensive chemo-
therapy, approximately 30% of patients have evidence of
disease response or stabilization and, importantly, have
overall survival rates equivalent or superior to other con-
ventional treatments. In addition, HMA therapy is well
tolerated over long periods of time, with fewer hospital days
and transfusions.
At The University of Texas MD Anderson Cancer Center,
the outcomes of 671 older patients with AML treated
with up-front intensive chemotherapy or HMA therapy
were retrospectively analyzed.26 Although the complete
remission rates were significantly lower with HMA therapy
versus intensive chemotherapy (28% vs. 42%), there was no
difference in 8-week early death, 2-year relapse-free sur-
vival, or median overall survival (6.7 vs. 6.5 months). The
only group of patients who benefited from intensive in-
duction were those with NPM-1mutated AML, coming back
to the importance of AML ontogeny. The group from The
Ohio State University demonstrated a very high overall
response rate of 75% using a 10-day decitabine regimen,
even in those patients with a complex karyotype.27 How-
ever, the 10-day decitabine regimen is associated with
treatment mortality rates similar to those of intensive
chemotherapy in elderly individuals. Thus, the vast majority
of older individuals desiring largely outpatient therapy
should be considered for subcutaneous azacitidine, 5-day
decitabine, or LDAC therapy.
The novel nucleoside analog clofarabine (Genzyme,
Cambridge, MA) has been studied extensively in older pa-
tients with de novo AML. Clofarabine inhibits ribonucleotide
reductase and DNA polymerase. It is resistant to cleavage by
purine nucleoside phosphorylase and to deamination by
adenosine deaminase.28-30 A complete remission rate of
32% was seen in a phase II trial of patients with relapsed or
refractory hematologic malignancies.31,32 Clofarabine has
been combined in an effort to modulate cytarabine tri-
phosphate accumulation in subsequent phase I and II trials.33,34
Clofarabine as a single agent was studied in 112 patients
older than age 60 who were deemed to be unlikely can-
didates to benefit from standard conventional chemo-
therapy. A complete remission rate was 38%, and the
overall response rate was 46% with a median disease-free
survival of approximately 33 weeks.35 Clofarabine has now
been compared in multiple randomized phase III studies,
including the MRC study of older adults who are not fit for
chemotherapy, comparing low dose ara-c versus clofar-
abine. Although the clofarabine arm had a higher remission
rate, there was no difference in overall survival.36 In ad-
dition, the recent ECOG 2906 study was presented at the
American Society of Hematology (ASH) Annual Meeting
comparing 3 plus 7 versus clofarabine, and the standard
arm was superior.37

Conclusion
The treatment of AML, especially for elderly patients,
remains a difficult endeavor with high therapy-related
toxicity and poor long-term survival. The impact on health
care utilization should not be underestimated, even in those
patients choosing less-intensive strategies. It is hoped that
the development of targeted therapies either as single
agents of in combination with current modalities will result
in improved outcomes.
EMERGING TARGETED THERAPIES IN ACUTE
MYELOID LEUKEMIA
Acute myeloid leukemia is an acquired disease character-
ized by chromosomal translocations and somatic mutations
that lead to leukemogenesis. Systemic combination che-
motherapy with an anthracycline and cytarabine remains
the standard induction regimen for fit adults. Patients
who achieve a complete remission generally receive post-
induction therapy with cytarabine-based chemotherapy or
an allogeneic bone marrow transplant.34 Those unfit for
induction chemotherapy are treated with hypomethylating
agents or low-dose cytarabine, or they are offered sup-
portive care alone with transfusions and prophylactic
antimicrobials.35,38
The revolution in understanding the genetics of AML,
facilitated by next-generation sequencing, has led to many
new drugs against driver mutations. These novel thera-
pies have emerged in parallel with antibodies against cell
surface proteins expressed on leukemic myeloblasts. The
past 10 years have seen the development of small-molecule
inhibitors of commonly mutated proteins and antibody-based
therapies with early clinical efficacy unseen in prior studies.
Small-Molecule Inhibitors
A variety of mutated and overexpressed proteins contrib-
ute alone or in combination to leukemogenesis. This ever-
enlarging number of molecular targets has led to small
molecules that inhibit mutant or overexpressed proteins.
The list of agents in development is long, but a few inhibitors
stand out as showing exceptional promise in recent clinical
studies (Table 1).
TABLE 1. Response Rate in Clinical Trials of Targeted Agents for the Treatment of Acute Myeloid Leukemia*
Agent Mechanism of Action
Quizartinib FLT3 inhibitor
ASP-2215 FLT3 inhibitor with activity
against TKD resistance mutation
AG-221 IDH2 inhibitor
AG-120 IDH1 inhibitor
ABT-199 BCL-2 inhibitor
Abbreviations: AML, acute myeloid leukemia; CRc, cytogenic complete remission; ORR, overall response rate; R/R, relapsed/refractory; CRi, incomplete peripheral blood count
recovery; HMA, hypomethalyting agent.
*Response criteria between trials do not necessarily use the international working group criteria and, therefore, between-trial comparisons are difficult to make.
EVOLVING THERAPIES IN ACUTE MYELOID LEUKEMIA
The most targeted mutated protein is FLT3 because of
its role as the most common recurrent genetic alteration
among patients with de novo AML. FLT3 internal tandem
duplications (FLT3-ITD) occurs in 30% of AML patients and
portend a poor prognosis, particularly among patients with a
high allelic ratio.39,40
Midostaurin. Midostaurin (PKC-412) is a moderately potent
inhibitor of FLT3-ITD and FLT3 tyrosine kinase domain (TKD)
mutations and inhibits other kinases such as c-KIT, PDGFR-b,
VEGFR-2, and protein kinase C. A phase II study of mid-
ostaurin monotherapy for patients with relapsed and re-
fractory FLT3-positive AML showed minimal clinical activity;
only 1 patient achieved a partial remission (PR).41 A follow-
up phase IB study combined midostaurin with induction
chemotherapy (7 plus 3) without regard to FLT3 status and
demonstrated that the combination was safe and well tol-
erated; complete remissions were seen in 92% of patients
with FLT3-ITD compared with 74% of patients with FLT3 wild-
type.42 On the basis of these data, the RATIFY study, an
international randomized phase III study of midostaurin or
placebo in combination with induction and consolidation
chemotherapy, was designed. The outcomes, reported at
the 2015 American Society of Hematology (ASH) Annual
Meeting, showed improved 5-year overall survival in the
midostaurin arm (51.4% vs. 44.2%), regardless of whether
patients were censored at the time of stem cell transplant,
despite no difference in the rates of complete remission at
60 days.43 The superiority of midostaurin/chemotherapy
over placebo/chemotherapy was consistent regardless of
allelic burden (high vs. low), FLT3-ITD, or FLT3-TKD. Pa-
tients receiving midostaurin had an increased frequency of
grade 3-4 desquamating rash. The overall survival benefit
in combination with the favorable toxicity profile makes
midostaurin in combination with induction and consolida-
tion chemotherapy the new standard of care for patients
with FLT3-mutated AML.
Quizartinib. More potent inhibitors of FLT3-ITD and FLT3-TKD
are in development. Quizartinib is a selective inhibitor of
FLT3-ITD but lacks activity against FLT3-TKD. The composite
complete remission rate in phase II studies of quizartinib
Suggested Patient Population Notes
FLT3 + AML Single-agent activity against FLT3-ITD
Resistance emerges in most patients
FLT3-ITD or FLT3-TKD Single-agent activity against FLT3-ITD and FLT3-TKD
with CRc rate of 46% in relapsed/refractory AML
IDH2 mutated Single-agent activity (37% ORR) in R/R AML
IDH1 mutated Single-agent activity (35% ORR) in R/R AML
Ongoing investigation CR/CRi rate of 71% when combined with HMAs
in untreated AML in older patients
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DEANGELO ET AL

as a single agent in relapsed and refractory FLT3-mutated TABLE 2. Antibody-Based Therapies for Acute Myeloid
AML ranges between 44% and 54%.44-47 The median du- Leukemia (Excluding Immunotherapy) in Clinical
ration of response is between 11.3 and 12.7 weeks. Many Development
patients who receive quizartinib acquire mutations in
the TKD of the FLT3 gene (D835 and F691) and resistance Mechanism of
Agent Action Notes
to ongoing treatment. Because of this, quizartinib may be
best used as monotherapy bridge to a potentially cura- Gemtuzumab Anti-CD33 antibody-drug Withdrawn from U.S.
Ozagomicin conjugate market; efforts to
tive allogeneic bone marrow transplant. A randomized reintroduce on the
open-label phase III study of quizartinib versus chemo- basis of ongoing
therapy (NCT02039726) with a primary endpoint of overall clinical studies
survival is currently accruing patients, and a randomized Vadastuximab Anti-CD33 antibody-drug CR/CRi of 65% when
Tariline conjugate given in combination
double-blind study of quizartinib or placebo in combination (SGN-CD33A) with HMAs in older
with induction and consolidation chemotherapy is in devel- patients with
opment (NCT02668653). untreated AML in
ongoing study
Gilteritinib. Gilteritinib (ASP-2215), also a potent inhibitor IMGN779 Anti-CD33 antibody-drug Payload of alkylating
conjugate agent (DGN-462);
of FLT3, differs from quizartinib in its ability to inhibit both studies beginning
FLT3-ITD and FLT3-TKD mutations. Results of a phase I/II in early 2016
study among 165 patients receiving 80 mg or greater of Lintuzumab- Anti-CD33 antibody- Ongoing phase I/II study
gilteritinib were reported at the 2015 ASH Annual Meeting.48 AC225 radiopharmaceutical in combination with
Among patients with FLT3-ITD, the composite complete low-dose cytarabine
remission rate was 46%, and it was 9% for those with a JNJ-56022473 Anti-CD123 Antibody against CD123;
trials beginning
FLT3-TKD. Responses were similar regardless of whether
patients had received prior FLT3directed therapy. The KHK2823 Anti-CD123 Antibody against CD123;
trials beginning
median duration of response was 15.9 weeks, similar
ADCT-301 Anti-CD25 Antibody-drug conjugate
to what is seen in clinical studies with quizartinib. A phase against CD25; trials
I study of ASP2215 in combination with induction and beginning
consolidation chemotherapy is ongoing (NCT02236013), AGS67E Anti-CD37 Antibody-drug conjugate
and a randomized phase III study of ASP2215 versus salvage (Anti-CD37) against CD37; trials
chemotherapy is accruing patients (NCT02421939). beginning
Abbreviations: CR, complete remission; CRi, complete response with incomplete blood
count recovery; HMA, hypomethylating agent; AML, acute myeloid leukemia.
IDH1 and IDH2
IDH, the enzyme that converts isocitrate to alpha-ketoglutarate
in the mitochondria (IDH2) or the cytoplasm (IDH1) as part BCL-2 Inhibitors
of the citric acid cycle, is mutated in 15% and 10% of pa- BCL-2 overexpression has been implicated in the mainte-
tients with de novo AML, respectively.49 The prevalence of nance and survival of AML cells in vitro and is associated with
IDH mutations increases with age.50,51 Mutant IDH enzymes resistance to chemotherapy and poor survival among pa-
acquire neomorphic activity and catalyze the conversion of tients with AML. The BCL-2 inhibitor venetoclax (ABT-199)
alpha-ketoglutarate into beta-hydroxygutarate (2-HG). In- showed a complete remission/complete response with
creased intracellular 2-HG causes inhibition of TET enzymes incomplete blood count recovery in five of 32 patients
and subsequent arrest in myeloblast maturation.52-54 In- in a phase II clinical study.57 Preclinical models suggest that
hibitors of mutant IDH1 and mutant IDH2 are currently the combination of venetoclax and HMAs are synergistic. On
in phase I clinical trials (NCT02381886, NCT01915498, and the basis of preclinical data, a phase I study of the combi-
NCT02074839). nation of venetoclax and decitabine or 5-azacitidine was
Interim results of a phase I/II study of the IDH2 inhibitor initiated. As of September 2015, the overall response rate
AG-221 (Agios/Celgene), presented at the 2015 ASH Annual (34 patients) is 76%, with 71% of patients having a complete
Meeting, demonstrated an overall response rate of 37% remission or complete response with incomplete blood
among 159 patients with relapsed/refractory AML with count recovery, without differences in response between
a composite complete remission of 27%. Duration of patients who received decitabine or patients who received
response was 6.9 months.55 Similarly, a phase I study of 5-azacitidine.58 The study is proceeding to an expansion
the IDH1 inhibitor AG-120 demonstrated an overall re- stage (NCT02203773).
sponse rate of 35%, with a composite complete remission
rate of 33%.56 Accrual has started on a phase I study
exploring the safety of combining AG-120 and AG-221 Cell Surface Targets: Antibody-Based Therapy
with both induction and consolidation chemotherapy Antibody-based therapies against cell surface proteins, ei-
and with the HMA, 5-azacitidine (NCT02632708 and ther alone or conjugated to chemotherapeutic or radio-
NCT0267792). pharmaceutical agents, continue to be developed. To date,

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only one antibody-drug conjugate against CD33, gemtuzu-
mab ozagomicin, was granted accelerated approval by the
U.S. Food and Drug Administration but was subsequently
withdrawn from the market because of the inability to
confirm clinical benefit in a phase III study. Despite this, the
effort to target CD33 and other cell surface proteins
continues (Table 2).
Perhaps the antibody-drug conjugate with the most en-
couraging clinical data is SGN-CD33A, a novel antibody-drug
conjugate with highly stable dipeptide linkers that enable
uniform drug loading of a pyrrolobenzodiazapene dimer,
which cross-links DNA, leading to cell death. An interim
analysis of a phase I dose-escalation study of SGN-CD33A
among patients with relapsed CD33-positive AML or patients
who declined intensive therapy, the composite complete
remission rate was 27%.59 More impressive is an ongoing
study of SGN-CD33A in combination with HMAs (23 pa-
tients), where the complete remission/complete response
with incomplete blood count recovery rate is 65%.60 The
median overall survival has not yet been reached, and at a
median follow-up of 7.7 months, 72% of patients remained
alive and in the study. This impressive early clinical activity
has led to the development of the CASCADE study, a ran-
domized phase III study of HMAs in combination with
SGN-CD33A versus HMAs alone for patients with newly
diagnosed AML who are not candidates for intensive in-
duction chemotherapy.
MINIMAL RESIDUAL DISEASE ASSESSMENT IN
ACUTE MYELOID LEUKEMIA: DOES IT MATTER?
Why Is Detection of Minimal Residual Disease
Relevant?
Predicting outcome of therapy has been and continues to be
an integral component of the treatment of patients with
AML.61 This is based largely on the realization that certain
subtypes of AML are less sensitive to the effects of cyto-
toxic chemotherapy and, as such, less likely to be cured
with the established and currently available combina-
tion chemotherapy regimens. This prediction, be it highly
imperfect, has been largely used to determine the
best postremission strategy (including allogeneic stem cell
transplantation or continued chemotherapy) and has been
based mainly on pretreatment patient- and disease-related
variables such as age, performance status, cytogenetic and
molecular aberrations, and presence or absence of ante-
cedent hematologic disorders or prior DNA-damaging
therapy for other disorders or malignancies.61-64 As such,
this determination is based largely on collective historical
information and does not rely on the response of the in-
dividual patient to the specific therapeutic intervention he
or she received for induction of their initial remission.
Clearly, the sensitivity of an individual patients leukemic
cells to the initial therapy is likely to be important in de-
termining the degree of reduction of disease burden and the
probability that it would be associated with relapse-free
survival and cure.
EVOLVING THERAPIES IN ACUTE MYELOID LEUKEMIA
Lack of achieving a response to the initial therapy, per se,
identifies the individual as having a less favorable disease,
thereby diminishing their likelihood of survival.65 Tradi-
tionally, response has been determined using morphologic
assessment declaring a patient as being in complete re-
mission when microscopic examination of the bone mar-
row and peripheral blood fails to detect abnormal immature
cells, and there is evidence of resumption of normal bone
marrow function with normalization of peripheral blood
counts. This assessment is highly insensitive, typically relying
on the examination of only 500 cells in the marrow specimen
and is very much dependent on the skills of the examiner and
the sampling technique. It has also been clear that such
morphologic remission, although associated with a higher
likelihood of achieving a cure, is not equivalent with com-
plete eradication of the leukemia cells and, without further
postremission therapy, will likely be associated with relapse
in most, if not all, patients.66 This is a result of the persistence
of morphologically undetectable leukemia, commonly re-
ferred to a MRD. Detection of this residual leukemia is highly
dependent on the sensitivity and specificity of the technique
used, leading to its description by some as measurable
residual disease.67
Therefore, the traditional definition of complete remis-
sion is an insensitive and imperfect assessment of the
susceptibility of leukemic cells to the treatment admin-
istered. More sensitive assays such as multiparameter flow
cytometry (MFC), polymerase chain reaction (PCR) analysis
of aberrant and leukemia-specific genes, and, more recently,
next-generation sequencing have been used to try to detect
submicroscopic leukemia cells persisting in complete re-
mission, thereby providing an improved assessment of the
effectiveness of therapy.68 Several published reports among
patients with AML have examined the utility of such residual
disease assessment and have demonstrated the prognostic
value of detecting MRD at the time of morphologic remission
in AML. This section reviews the available literature and
discusses the potential ways that this can influence future
therapeutic decision making for patients with AML.
Available Assays for Detecting Minimal Residual
Disease
Currently available techniques for detecting residual dis-
ease in complete remission include MFC, which relies on
detection of leukemia-associated immunophenotypes, PCR,
and, more recently, next-generation sequencingbased
assays to detect aberrant genetic events in the leukemic
cells.69-71 Although karyotypic analysis to detect persistent
cytogenetically abnormal clones at the time of remission is
an old and less sensitive strategy, its value in predicting
outcome has been reported by several investigators.72,73
Leukemia-associated immunophenotypes are aberrant
patterns of antigen expression that can be identified in the
leukemic blasts of most patients at diagnosis.74,75 They in-
clude aberrant expression of lymphoid antigens, aberrant
expression levels of normal antigens, and co-expression or
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DEANGELO ET AL
asynchronous expression of early and late antigens, leading
to temporal aberrancy. The advantages of this assay include
its wide availability, its applicability to more than 95% cases
of AML, and its relative rapidity of assessment, which offers
its potential utility for rapid therapeutic decision making.
The disadvantages often include challenging interpretations
requiring expert analysis (multiple leukemia-associated
immunophenotypes in different blast subsets for the same
patients, potential for phenotypic shifts between diagnosis,
and relapse blasts) and lower sensitivity depending on the
antibody panel used.
Molecular markers such as gene fusion transcripts, gene
mutations, and aberrantly overexpressed genes have also
been used effectively as markers for detecting residual
leukemia burden.67,71 Quantitative reverse-transcription
PCR assays are now well established for detecting re-
current fusion transcripts such as PML-RARA, CBFB-MYH11,
and RUNX1-RUNX1T1 and have the advantage of being
highly sensitive and specific in these subsets of AML that
account for approximately 20% of cases overall.76 Their
value in predicting outcome is now universally accepted.
This is particularly true for patients with acute promyelocytic
leukemia in whom achievement of a complete molecular
remission with a sensitive assay is now considered as a
requisite for long-term leukemia-free survival.77
To increase the applicability of molecular testing to a larger
population of AML patients (particularly those with a normal
karyotype), a number of recurrent aberrant gene muta-
tions such as FLT3, NPM1, and DNMT3A have been evaluated
as markers for MRD assessment.78-80 However, despite
this, a large proportion of patients with AML lack a leukemia-
specific aberrant molecular target for MRD monitoring. This
has led some investigators to examine normal genes such as
WT1 that are overexpressed in leukemia cells as potential
markers for MRD assessment, establishing thresholds that
predict higher likelihood of disease relapse.81 Novel and
sensitive next-generation sequencing assays that can detect
all coexisting mutations in leukemic clones at the time of
diagnosis and remission have also begun to be used for MRD
monitoring, although there are few retrospective studies
reported to date.82 The advantage of molecularly-based
MRD monitoring is its high sensitivity, particularly using
the more modern assays.
Comparative studies evaluating morphology, flow, and
PCR assays in the same patients have been limited. In a study
from St. Jude Childrens Hospital, follow-up bone marrow
samples from 203 children and adolescents with newly di-
agnosed AML were evaluated by morphologic assessment,
flow cytometry, and PCR for fusion transcripts.83 Among
samples with more than 5% blasts by morphology, 8.2%
were MRD-positive ($ 0.1%) by flow cytometry, whereas
57.5% of samples with more than 5% blasts by morphology
were negative by flow. Virtually all (99%) of samples negative
by PCR were also negative by flow, but only 9.6% of sam-
ples positive by PCR were also flow-positive, with analy-
sis of RUNX1-RUNX1T1 and CBFB-MYH11 accounting for
most discrepancies. Flow MRD after induction was an
e308 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
independent prognostic factor for relapse on multivariate
analysis, and the prediction was not improved by PCR or
morphologic data.83 Other investigators have reported that
MRD by flow and type of response (complete remission,
complete remission with incomplete platelet recovery, or
complete remission with incomplete blood count recovery)
are important prognostic factors in AML and should be used
independently to predict outcome.84
Reported Studies of Minimal Residual Disease
Monitoring in Acute Myeloid Leukemia
The potential value of detection of aberrant mutant genes in
predicting outcome in AML is best apparent among patients
with normal karyotype, because this is the group in which
there is most uncertainty regarding the role of allogeneic
stem cell transplant in first remission. Mutations in several
genes including FLT3, NPM1, CEBPA, DNMT3A, TET2, and
IDH1/2 have been described and have been correlated with
outcome in large cohorts of patients with AML.85-87 Several
of these have been studied as potential markers for MRD
monitoring. The potential utility of mutant FLT3 as a marker
of MRD has been controversial, with some investigators
suggesting that it can be reliably used in complete remission
to predict relapse, and others arguing that it may not be ideal
because of the probability of its gain or loss at the time of
relapse.78,88 In contrast, the utility of NPM1 mutations as re-
liable markers of persistent disease is becoming more estab-
lished, with several studies demonstrating that, using real-time
quantitative PCR for NPM1, achieving an MRD-negative status
after induction and after consolidation is associated with a
considerable reduction in the risk of relapse and improvement
in survival.79,89,90 Most recently, a large prospective trial
conducted by the United Kingdom National Cancer Research
Institute AML Working Group (UK NCRI) further demonstrated
that MRD monitoring for mutated NPM1 was the only major
prognostic factor for relapse or death, and, on sequential
monitoring, relapse was reliably predicted by a rising level of
NPM1-mutated transcripts.91
The value of MRD monitoring for acute promyelocytic
leukemia and for core-binding factor (CBF) leukemias has
been more established. In a study by the U.K. group of
patients with acute promyelocytic leukemia treated with all-
trans retinoic acid and chemotherapy, persistent MRD after
consolidation and MRD recurrence were the most important
predictors of relapse in multivariate analysis.77 Similarly,
several studies have reported the value of establishing
thresholds for RUNX1-RUNX1T1 and CBFB-MYH11 after in-
duction and consolidation in predicting the likelihood of
relapse and survival.92-94 Furthermore, recent reports have
suggested a value for MRD-directed risk stratification to
improve outcome for patients with CBF AML.95
Although MFC has been extensively used to detect MRD
in pediatric studies (and particularly for patients with acute
lymphoblastic leukemia), data in the adult population are
more limited.96 Early reports using more limited assays
demonstrated the feasibility of this strategy in predicting

relapse and survival.97,98 Several reports in pediatric AML
further established the prognostic value of MRD assessed
by flow and demonstrated its potential use in risk-adapted
therapy.99,100 More recently, investigators from the HOVAN/
SAKK AML study group and the UK NCRI have reported the
prognostic value of flow-based MRD assessment in pre-
dicting the outcome in younger and older AML cohorts,
respectively.101,102 Furthermore, data from the Fred
Hutchison Cancer Center have clearly demonstrated that
patients transplanted in CR1 or CR2 have a substantially
lower likelihood of relapse post-transplant and improved
survival if they are determined to be MRD-negative using a
flow cytometrybased assay.103-105
Future Prospects for Minimal Residual Disease
Eradication Using Target-Specific Agents
Perhaps the most important value of persistent MRD is that
it indicates that continuation of current treatment strategy
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AML-15 trial. Blood. 2012;120:2826-2835.
95. Zhu HH, Zhang XH, Qin YZ, et al. MRD-directed risk stratification
treatment may improve outcomes of t(8;21) AML in the first complete
remission: results from the AML05 multicenter trial. Blood. 2013;121:
4056-4062.
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96. Paietta E. Minimal residual disease in acute myeloid leukemia: coming
of age. Hematology Am Soc Hematol Educ Program. 2012;2012:35-42.
97. San Miguel JF, Martnez A, Macedo A, et al. Immunophenotyping in-
vestigation of minimal residual disease is a useful approach for pre-
dicting relapse in acute myeloid leukemia patients. Blood. 1997;90:
2465-2470.
98. Venditti A, Buccisano F, Del Poeta G, et al. Level of minimal residual
disease after consolidation therapy predicts outcome in acute myeloid
leukemia. Blood. 2000;96:3948-3952.
99. Rubnitz JE, Inaba H, Dahl G, et al. Minimal residual disease-directed
therapy for childhood acute myeloid leukaemia: results of the AML02
multicentre trial. Lancet Oncol. 2010;11:543-552.
100. Langebrake C, Creutzig U, Dworzak M, et al; MRD-AML-BFM Study
Group. Residual disease monitoring in childhood acute myeloid
leukemia by multiparameter flow cytometry: the MRD-AML-BFM
Study Group. J Clin Oncol. 2006;24:3686-3692.
101. Terwijn M, van Putten WL, Kelder A, et al. High prognostic impact of
flow cytometric minimal residual disease detection in acute myeloid
leukemia: data from the HOVON/SAKK AML 42A study. J Clin Oncol.
2013;31:3889-3897.
102. Freeman SD, Virgo P, Couzens S, et al. Prognostic relevance of
treatment response measured by flow cytometric residual disease
detection in older patients with acute myeloid leukemia. J Clin Oncol.
2013;31:4123-4131.
103. Walter RB, Gooley TA, Wood BL, et al. Impact of pretransplantation
minimal residual disease, as detected by multiparametric flow
cytometry, on outcome of myeloablative hematopoietic cell trans-
plantation for acute myeloid leukemia. J Clin Oncol. 2011;29:
1190-1197.
104. Walter RB, Buckley SA, Pagel JM, et al. Significance of minimal residual
disease before myeloablative allogeneic hematopoietic cell trans-
plantation for AML in first and second complete remission. Blood.
2013;122:1813-1821.
105. Araki D, Wood BL, Othus M, et al. Allogeneic hematopoietic cell
transplantation for acute myeloid leukemia: time to move toward a
minimal residual disease-based definition of complete remission?
J Clin Oncol. 2016;34:329-336.
HEMATOLOGIC MALIGNANCIESLEUKEMIA,
MYELODYSPLASTIC SYNDROMES, AND
ALLOTRANSPLANT

Molecularly and Phenotypically

Defined Subtypes of Acute
Lymphoblastic Leukemia:
Implications for Management

CHAIR
Charles G. Mullighan, MD, MBBS, MSc
St. Jude Childrens Research Hospital
Memphis, TN

SPEAKERS
Sabina Chiaretti, MD, PhD
Sapienza University of Rome
Rome, Italy

Susan M. OBrien, MD
University of California, Irvine
Irvine, CA
CHIARETTI ET AL

Advances in the Genetics and Therapy of Acute Lymphoblastic

Leukemia
Sabina Chiaretti, MD, PhD, Valentina Gianfelici, MD, PhD, Susan M. OBrien, MD, and
Charles G. Mullighan, MBBS, MD

OVERVIEW

Acute lymphoblastic leukemia (ALL) remains an important cause of morbidity in children and adults. In this article, we
highlight advances in the genetics and therapy of three key subtypes of ALL: T-cell ALL, BCR-ABL1 (Philadelphia [Ph]
chromosonepositive), and Ph-like ALL. T-ALL is an aggressive disease that accounts for about 15% and 25% of ALL among
pediatric and adult cohorts, respectively, and exhibits a multistep nature of cancer initiation and progression. The integration
of cytogenetics, molecular biology, and immunophenotype analyses has led to the identification of defined T-ALL subgroups,
such as early T-cell precursor ALL and novel lesions with a prognostic role, for which specific inhibitors are being developed.
Phpositive ALL was historically regarded as a subtype of ALL with a poor prognosis, and allogeneic stem cell transplant was
recommended for all patients who could undergo this procedure. The deep complete responses seen with combination
tyrosine kinase inhibitors (TKIs) and chemotherapy in Ph-positive ALL, and the reports of long-term survival among some
patients not undergoing allogeneic stem cell transplant, has raised the question of whether there is a subset of patients who
could be cured without this intervention. Ph-like ALL is a subtype of B-progenitor ALL common among older children and
adults and associated with a diverse range of genetic alterations that activate kinase signaling. Ph-like ALL is also associated
with poor outcome, for which precision medicine trials identifying kinase alterations and testing TKI therapy are being
developed.

T -cell ALL (T-ALL) is a genetically heterogeneous disease

that is caused by the accumulation of lesions acting in a
multistep pathogenic process involving cell growth, pro-
liferation, survival, and differentiation during thymocyte
development.1 It accounts for about 15% and 25% of ALL
among pediatric and adult cohorts, respectively, and is
slightly more frequent in males than females, particularly
in older children and adolescents.2 As for other ALL sub-
types, prognosis is far superior for children than adults;
however, it must be emphasized that the outcome of
these patients is now similar to that of patients with
B-cell ALL (B-ALL) because of the use of more intensive
treatments.
Until recently, there was a limited understanding of the
genetic basis of T-ALL. The improvement of cytogenetic
assays and integration with techniques including gene ex-
pression profiling, single nucleotide polymorphism micro-
array analysis, and next-generation sequencing (NGS) have
enabled detailed characterization of the genomic complexity
of T-ALL. The most frequent lesions can be categorized as
chromosomal translocations, duplications and deletions of
DNA, deregulated gene expression, and mutations.
The most frequent translocations involve the 14q11 (T-cell
receptor alpha and delta, TRA and TRD) and 7q34 (TRB) re-
gions, juxtaposing the T-cell receptor (TCR) genes to pivotal
transcription factor genes, such as TAL1, TAL2, LYL1, OLIG2
(BHLHB1), LMO1, LMO2, TLX1, TLX3, NKX2-1, NKX2-2, NKX2-5,
HOXA genes, MYC, and MYB. Further improvement of cyto-
genetic analysis and the advent of NGS will likely result in
identification of additional partners of rearrangement to TCR
genes. Chromosomal rearrangements can also lead to fusion
genes, among which the most important from a clinical
standpoint are represented by those involving ABL1, mostly
represented by NUP214-ABL1, EML1-ABL1, and ETV6-ABL1
rearrangement, for which the addition of TKIs may be of
benefit, as well as those involving KMT2A (MLL; MLL-
rearranged). Finally, DNA copy number alterations are iden-
tified including deletion of CDKN2A/B and duplication of MYB.3
Gene expression profiling studies have refined the char-
acterization of molecular groups of T-ALL, which are reflective

From the Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy; Chao Family Comprehensive Cancer Center, School of Medicine, University
of California, Irvine, CA; Department of Pathology, St. Jude Childrens Research Hospital, Memphis, TN.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Charles G. Mullighan, MBBS, MD, St. Jude Childrens Research Hospital, 252 Danny Thomas Place, MS 342, Memphis, TN 38105; email: charles.mullighan@
stjude.org.

2016 by American Society of Clinical Oncology.

e314 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


of a maturational arrest and are characterized by the over-
expression of known transcription factors (TLX1, TLX3, TAL1,
LMO1, HOXA genes, NKX genes, LYL1, and MEF2C) and, more
importantly, to identify novel subgroups (early T-cell pre-
cursor ALL, see below).4-7
The most frequent mutations are those in NOTCH1 and
FBXW7, in genes involved in the JAK/STAT and Ras/PI3K/AKT
pathways, in epigenetic regulators (PHF6, SUZ12, EZH2,
TET2, H3F3A, and KDM6A), in transcription factors or reg-
ulators of transcription (i.e., LEF1, WT1, BCL11B) and genes
involved in mRNA maturation and ribosome activity
(i.e., CNOT3, RPL5, and RPL10). Furthermore, at relapse,
mutations of NT5C2 known to confer resistance to che-
motherapy with 6-mercaptopurine and 6-thioguanine are
common.8,9
NOTCH1 signaling is critical for T-cell differentiation, and
mutations in this gene are present in up to 60% of T-ALL
cases. In the same pathway, mutations in FBXW7, which
increase NOTCH1 stability, can be detected in about 20% of
cases. Although a favorable outcome has been overall re-
ported for NOTCH1 mutations, the scenario is more complex
if concomitant lesions are identified. Indeed, a comprehen-
sive prognostic model has been recently proposed by the
GRAAL group10 that defined low-risk patients as those har-
boring NOTCH1 and FBXW7 mutations and high-risk patients
as those without these mutations or harboring lesions in-
volving Ras/PTEN.
Similarly, the PI3K/PTEN/AKT/mTOR pathway is critical for
cell metabolism, proliferation, and survival. Several mech-
anisms can lead to its deregulation: mutations or deletions in
PTEN have been reported in around 12% of adults and 13%
to 22% of children, whereas PI3K and AKT mutations have
KEY POINTS
T-cell acute lymphoblastic leukemia is an aggressive
disease that accounts for about 15% and 25% of ALL
among pediatric and adult cohorts, respectively.
Recent scientific advances have allowed identification of
T-ALL subgroups such as early T-cell precursor ALL and
novel lesions with a prognostic role.
Ph-positive ALL was historically regarded as a subtype of
ALL with a poor prognosis, and allogeneic stem cell
transplant was recommended for all patients who could
undergo this procedure.
The deep complete responses seen with combination
tyrosine kinase inhibitors and chemotherapy in Ph-
positive ALL, and the reports of long-term survival in
some patients not undergoing allogeneic stem cell
transplant, has raised the question of whether there is a
subset of patients who could be cured without this
intervention.
Ph-like ALL, common among older children and adults, is
associated with poor outcome and is characterized by
a range of genetic alterations activating kinase signaling
that are sensitive to TKI therapy.
GENETICS AND THERAPY OF ACUTE LYMPHOLASTIC LEUKEMIA
been described in rare cases. Moreover, NRAS/KRAS mu-
tations are found in around 10% of adults and 4% to 10% of
children.10-14 Finally, interleukin (IL)-4 and IL-7 may upre-
gulate PI3K/AKT/mTOR signaling in T-ALL.15 The prognostic
role of PTEN and NRAS/KRAS alterations is still under in-
vestigation and may differ between children and adults.
Among children, the presence of inactivating PTEN lesions,
as well as NRAS/KRAS mutations, do not affect outcome,11,14
whereas among adults their presence is associated with
poorer prognosis.10,12
The JAK/STAT pathway is also often aberrantly activated in
T-ALL. Activating mutations are found mainly in IL7R, JAK1,
JAK3, and STAT5B; moreover, inactivating mutations and
deletions have been described in PTPRC and PTPN2, which
encode phosphatases that regulate the activation of JAK1.16,17
The prognostic role of these lesions is still debated; JAK1
mutations have been associated with chemotherapy refrac-
toriness but with contrasting results. Similarly, the prognos-
tic role of JAK3 mutations needs to be more extensively
assessed.18-21 Finally, STAT5B mutations have been correlated
with an increased risk of recurrence in pediatric cases.22,23
Given this complex genomic scenario, several targeted
approaches have been developed and might be used in the
context of a personalized medicine.
NOTCH1 inhibitors represent an attractive therapeutic
target, in light of the high incidence of mutations. g-secretase
inhibitors (GSI), in use for patients with Alzheimer dis-
ease, were the first compounds developed for T-ALL.
However, their side effects, particularly at the gastro-
intestinal level, made their use not feasible24; these effects
might be overcome by the concomitant administration of
dexamethasone.25
Similarly, PI3K/PTEN/AKT/mTOR inhibitors are appealing
agents. Among them, rapamycin has been extensively in-
vestigated. Although its use as a single agent can be limited
by the prolonged inhibition of TORC1 and activation of al-
ternative pathways, a synergistic effect between rapamycin
(or its derivatives) and various chemotherapeutic agents
(i.e., idarubicin, doxorubicin, and dexamethasone) have
been described.26 Therefore, several clinical trials are cur-
rently evaluating the effectiveness of the combination of
rapamycin derivatives with chemotherapy among pediatric
patients with relapsed ALL. In particular, in the phase I
RAD001 study, everolimus is combined with reinduction
chemotherapy for pediatric patients with relapsed ALL
(NCT01523977). Furthermore, a second phase I study
designed to assess the effectiveness of CCI-779 (temsirolimus)
among children whose disease has relapsed has recently
concluded, with results not published (NCT01403415).
The novel dual PI3K/mTOR inhibitor NVP-BEZ235 is an
orally bioavailable imidazoquinoline derivative, which ex-
erts antiproliferative and proapoptotic effects in several
T-ALL cell lines.27 Similarly, NVP-BKM120 is a proapoptotic
pan-PI3K inhibitor. Currently, two ongoing clinical trials are
evaluating the effectiveness of BEZ235 and NVP-BKM120
among patients with relapsed or refractory acute leukemia
(NCT01756118 and NCT01396499, respectively).
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e315
CHIARETTI ET AL
A variety of JAK inhibitors have been developed. The
JAK1/JAK2-selective inhibitor ruxolitinib is already approved
by the U.S. Food and Drug Administration (FDA) for the
treatment of patients with myelofibrosis, and the JAK3-
selective inhibitor tofacitinib received FDA approval for
the treatment of patients with rheumatoid arthritis. These
data demonstrate that JAK kinase inhibitors can be ad-
ministered safely and open new possibilities for the treat-
ment of T-ALL with IL7R, JAK1, or JAK3 mutations. In vitro
studies have shown the efficacy of ruxolitinib in reducing the
proliferation of cells that express mutations in JAK1, IL7R,
and PTPRC.16 Furthermore, Degryse et al showed that
treatment with the JAK3-selective inhibitor tofacitinib re-
duced the white blood cell count and caused leukemic cell
apoptosis in leukemic mice that expressed JAK3 mutant
variants.28
Finally, BCL-2 antagonists, and in particular ABT-199,
which have proven effective in chronic lymphocytic leuke-
mia, might also represent a therapeutic option in T-ALL;
a specific effect has been demonstrated in TLX3- or HOXA-
positive primary T-ALL and in more immature T-ALL,29 as well
as among patients who harbor STAT5B mutations.22
Lastly, the concomitance of different alterations suggests
that the combination of specific inhibitors that target dif-
ferent pathways might prove useful for these patients and
minimize the risk of resistance to treatment with single
agents.
EARLY T-CELL PRECURSOR ACUTE
LYMPHOBLASTIC LEUKEMIA
A distinct subgroup of T-ALL is represented by early T-cell
precursor ALL.6 This subset, initially identified by gene ex-
pression profiling, can be easily recognized by flow
cytometry because it is characterized by distinct cell surface
features: absence of CD1a and CD8, weak CD5 expression,
and the expression of one or more myeloid or stem cell
associated markers. Several genomic lesions have been
identified, including a low frequency of NOTCH1 mutations,
and mutations in DNMT3A, FLT3, IDH1, IDH2, and ETV6 have
been reported. Interestingly, FLT3 mutations can be de-
tected in up to 35% of cases, thus implying the possibility of
novel therapeutic strategies.30 Furthermore, mutations
occurring in genes that regulate cytokine receptor and Ras
signaling (67%), inactivating lesions that disrupt hemato-
poietic development (58%), and histone-modifying genes
(48%) have been reported, suggesting that early T-cell
precursor ALL shares a similar genomic background with
acute myeloid leukemia.
From a clinical standpoint, early T-cell precursor ALL was
initially associated with a dismal outcome because of its poor
response to chemotherapy and high rate of resistance or
early relapse.6 Notably, recent studies have reported poor
outcomes in cases with genomic rearrangements associated
with HOXA deregulation. Bond et al analyzed patients en-
rolled in the GRAAL-2003 and -2005 studies and showed that
patients with HOXA-positive disease had higher rates of an
e316 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
early T-cell precursorlike immunophenotype. Strikingly, the
presence of an early T-cell precursorlike immunophenotype
conferred marked differences in outcome within the HOXA-
positive group, which were mirrored by corresponding in-
creases in cumulative incidence of relapse. In contrast, these
survival differences were not seen among patients with
HOXA-negative disease, where early T-cell precursor and non-
early T-cell precursor cases had similar 5-year event-free
survival (EFS) and cumulative incidence of relapse.31 Simi-
larly, Matlawska-Wasowska analyzed a cohort of pediatric
and young adults and found overlap between MLL-rearranged
and the early T-cell precursor ALL cases, and confirmed that
both are risk features for induction failure.32
Overall, these findings lead to some important consider-
ations. The prompt recognition of early T-cell precursor
cases is improving outcome because patients are rapidly
directed toward intensive treatments, including allogeneic
transplant during the first complete response (CR). In con-
trast, refined molecular characterization is permitting fur-
ther stratification of these cases and recognition of very
high-risk cases. Finally, the presence of acute myeloid
leukemiarelated features prompts investigation of the
use of myeloid-directed therapies.
In conclusion, extensive research has refined the genomic
profile of T-ALL. In fact, improvement in cytogenetic and mo-
lecular analysis and the integration with immunophenotype
have led to the identification of different subgroups and
novel lesions that result in deregulated pathways. This effort
paves the way toward a personalized approach that can
include targeted therapies, depending on the underlying
molecular lesion(s), and possibly should include a combined
approach with conventional therapy and personalized tar-
geted approaches.
PHILADELPHIA CHROMOSOMEPOSITIVE ALL:
TRANSPLANT OR NO TRANSPLANT
Philadelphia chromosomepositive ALL was historically
considered one of the most high risk forms of ALL. Although
CR rates with induction chemotherapy were reasonable,
relapse was almost inevitable, and a key strategy was to get
patients to undergo allogeneic stem cell transplant (SCT),
which was considered the only potentially curative option.
Given the age of patients with ALL, in particular Ph-positive
ALL (which increases with each decade of life), many patients
were unable to be undergo this potentially curative therapy.33
Approximately 30% of patients were able to receive a SCT in
the past; in addition to older age, other contraindications to
SCT included lack of remission, early relapse, or poor per-
formance status from complications due to chemotherapy.34
Thus, long-term survival rates were quite poor.
The advent of TKI therapy has dramatically improved
outcomes for patients with Ph-positive ALL. Complete re-
sponses are substantially deeper than those achieved with
chemotherapy alone, as reflected in the high rate of major
molecular response (MMR) or complete molecular response
(CMR) after a combination of TKI and chemotherapy.35 The

fact that CMR can occur has raised the question of whether
some patients can be cured without undergoing SCT. Small
cohorts of patients who were not candidates for SCT and
were treated with chemotherapy and TKIs have provided
some information on long-term outcomes without SCT.
No randomized trials have addressed this issue, and
all of the published clinical trials regarding outcomes in
Ph-positive ALL include variable transplant approaches
(myeloablative versus reduced-intensity conditioning) and
choice, dose, and duration of TKI. Post-transplant mainte-
nance is an additional variable. Most data involve a com-
bination of imatinib and chemotherapy because imatinib
was the first available TKI. There are also some data that
autologous SCT may be beneficial in this setting. Autologous
SCT has not been shown to be an improvement over che-
motherapy in the overall treatment of ALL, but one of the
presumed reasons is the lack of true minimal residual dis-
ease (MRD) among patients prior to undergoing autologous
SCT. With a TKI and chemotherapy combination, this low
level or absence of disease is possible.
Bassan describes the northern Italy experience with 94 pa-
tients with Ph-positive ALL who received 600 mg of imatinib
daily with chemotherapy; 31 patients did not receive ima-
tinib and constituted a control cohort.36 Patients were to
undergo myeloablative allogeneic SCT (if related or unre-
lated donor was available) or autologous SCT followed by
imatinib maintenance. Nine patients, including four who had
not received imatinib, underwent autologous SCT and fur-
ther imatinib therapy, and their outcomes were similar to
patients undergoing allogeneic SCT. A multivariate model
suggested that imatinib and SCT favorably affected overall
survival (OS), but SCT included patients undergoing autol-
ogous SCT. A confounding element to the data is that
imatinib and/or dasatinib was administered to patients with
persistent or increasing partial CR after SCT.
The PETHEMA and GETH groups37 reported results from
30 patients who received 400 mg of imatinib daily and che-
motherapy. Sixteen patients underwent allogeneic (primarily
myeloablative) or autologous SCT. Interestingly, of the five
patients who underwent autologous SCT, four were MRD
negative. The only patient who was MRD positive experienced
relapse; none of the other four patients relapsed. Of the
patients who received imatinib maintenance, two were alive
at 40 and 60 months into CR. In a Saudi Arabian analysis of Ph-
positive pediatric ALL, SCT was limited to only children with
related donors.38 Twelve patients underwent allogeneic SCT
and 10 were treated with chemotherapy and imatinib. After a
median follow-up of 42.2 months, there was no statistical
difference in EFS or OS. Interestingly, two children who re-
lapsed after SCT responded to TKI and were still in CR.
Long-term follow-up of the GRAAPH-2003 trial was re-
cently published and involved 45 patients with Ph-positive
ALL.39 Notably, postremission therapy was partly decided by
MRD results. Imatinib doses of 600 to 800 mg per day were
given with consolidation chemotherapy and improved OS to
52% compared with 20% prior to imatinib. Overall survival
was 50% after myeloablative allogeneic SCT (24 patients),
GENETICS AND THERAPY OF ACUTE LYMPHOLASTIC LEUKEMIA
33% for patients without a SCT (nine patients), and 80% after
autologous SCT (10 patients). The favorable outcomes with
autologous SCT may also have been related to the re-
quirement that patients have a marrow MRD ratio of less
than 10e-4. Seven patients had a CMR. The three patients
who did not achieve a CMR experienced disease relapse
after SCT. Imatinib was given to four patients after SCT; three
were alive in first CR at 37, 41, and 46 months. Treatment-
related mortality was particularly high for patients who
underwent a matched unrelated donor SCT, and the authors
noted that whether autologous SCT with a low or negative
MRD level should be performed instead of allogeneic SCT
using an HLA-matched unrelated donor in patients with
Ph-positive ALL is a critical issue that should further be
addressed through a prospective controlled study.
Another trial that utilized MRD status to guide choice of
therapy was recently published. The GRAALL group ran-
domly assigned 268 patients with Ph-positive ALL to 800 mg
of imatinib therapy with either reduced-intensity chemo-
therapy (arm A) or hyperfractionated cyclophosphamide plus
vincristine, doxorubicin, and dexamethasone (hyperCVAD)
therapy (arm B).40 Patients then underwent allogeneic SCT
(myeloablative, later amended to allow reduced-intensity
conditioning) if they had a related or 9/10 or 10/10 HLA-
compatible unrelated donor. Other patients who experi-
enced MMR after two cycles (MMR2) were to undergo
autologous SCT. Thirty-nine patients were eligible for au-
tologous SCT and 28 of those patients underwent SCT during
first remission. Among patients who achieved an MMR2, the
outcome was similar for autologous and allogeneic SCT.
Allogeneic SCT was as effective for patients who did not
experience early MMR as for those who did. Of note, pa-
tients who underwent autologous SCT received mainte-
nance with a TKI, which was not planned for the allogeneic
SCT cohort. This again speaks to the question of the benefit
of autologous SCT compared with just continued TKI ther-
apy. The authors concluded that the data strongly sug-
gests that favorable patients with low white blood cell
count and/or those with good early MRD response could be
treated with nonallogeneic postremission therapies.
The UKALLXII/ECOG 299 is the largest prospective trial that
assessed the role of imatinib in the treatment of Ph-positive
ALL.41 The analysis compared outcomes of a large group of
patients treated between 1993 and 2003 (pre-imatinib) with
patients who received early or late imatinib (480 to 600 mg).
Both the CR and OS rates were better in the imatinib cohort.
The improvement in OS was derived partially from the use of
imatinib that enabled a higher percentage of patients to
undergo allogeneic SCT. There was also a modest benefit to
imatinib in terms of EFS. Again, a small number of five
patients underwent autologous SCT. There was one early
death and one relapse. The other three patients were alive in
CR at 3.5, 8, and 8 years. The conclusion was that the data did
not support the omission of allogeneic SCT from the
treatment of Ph-positive ALL, but that limited data on the
use of reduced-intensity conditioning suggested that it could
be beneficial. No attempt was made to allocate patients
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CHIARETTI ET AL
depending on their MRD status, and there was no analysis of
the relationship of MRD status to outcome.
The issue of the need for allogeneic SCT is also complicated
by the fact that most trials did not use TKI maintenance after
SCT. Recent data suggest that TKI maintenance after allo-
genic SCT can markedly improve outcomes. Pfeifer et al
performed a randomized trial of prophylactic or MRD-
triggered imatinib after allogeneic SCT.42 Five-year sur-
vival was high in both groups and substantially higher than in
their previous study in which the interval between SCT and
imatinib was 5 months compared with less than 2.5 months.
Early occurrence of MRD positivity or positivity at higher
levels identified a subset of patients who did not benefit
from imatinib; whether second-generation TKIs would
produce a better outcome in this group is not known.
In addition to using MRD as a potential decision-making
tool for the use of SCT, another question is: are there
prognostic factors beyond the presence of Ph positivity that
further define subgroups? Mullighan et al published data
that showed a high percentage of children with Ph-positive
ALL had a deletion in the Ikaros (IKZF1) gene.43 Kim et al
investigated its relevance among 118 adult patients with
Ph-positive ALL who received imatinib-based chemotherapy
and underwent allogeneic SCT (myeloablative or reduced-
intensity conditioning depending on age).44 IKZF1 deletions
were detected among 78.8% of patients and such patients
had a trend for a higher rate of relapse. However, in mul-
tivariate analysis, the MRD kinetics were most closely re-
lated to outcomes, whereas neither IKZF1 deletions nor their
functional subtypes were independently important.
Dose intensity of imatinib and the effect on outcomes has
not been well-explored in the setting of Ph-positive ALL. Lim
et al intended to administer 600 mg per day of imatinib to all
patients starting from day 8 of induction chemotherapy
through remission induction and consolidation chemo-
therapy.45 For patients not proceeding to SCT, a further
2 years of imatinib was planned. Lim et al showed that dose
intensity during the initial 7 to 8 weeks strongly correlated
with median CR duration as well as OS. The most common
reason for less dose intensity was gastrointestinal toxicity.
This suggests the choice of chemotherapy in conjunction
with imatinib might also be important.
In summary, the advent of TKIs has dramatically improved
the prognosis of patients with Ph-positive ALL. The goal of
treatment is still to deliver allogeneic SCT when possible.
However, long-term data from cohorts of patients who could
not undergo SCT suggest that a cure faction is possible even
without this intervention. The key question is, how can we
identify patients who may enjoy long-term survival without
the risks of SCT? Examining data across trials is complicated
by the fact that although most trials have used imatinib, the
doses have varied substantially and very little data using
second-generation TKIs exist. In addition, autologous
transplant has been used in a minority of patients, some of
whom have had long-term survival but most of whom also
received imatinib maintenance, raising the question of the
contribution of the autologous SCT versus continued TKI
e318 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
therapy. The general thinking is that long-term survival is not
possible without achieving MRD negativity. Thus, most
physicians would still recommend SCT for patients who did
not achieve this level of MRD. However, the question of
whether MRD status can be used to select patients for less-
intensive therapy has not yet been answered in a ran-
domized clinical trial. Of note, the upcoming Intergroup trial
of patients with Ph-positive ALL will randomly assign pa-
tients to SCT or no SCT (for patients who are MRD-negative).
This trial will provide important information about selecting
patients who may experience long-term survival without
undergoing SCT.
PH-LIKE ACUTE LYMPHOBLASTIC LEUKEMIA:
GENETICS, DIAGNOSIS, AND MANAGEMENT
Ph-like ALL is a recently described subtype of B-ALL
characterized by a gene expression profile similar to that
of BCR-ABL1 positive (Ph-positive) ALL, a diverse range of
genetic alterations activating tyrosine kinase signaling,
mutation of lymphoid transcription factor genes such as
IKZF1 (Ikaros), and poor outcome. The high frequency of
kinase activating alterations in this form of ALL and the
potential for targeting these lesions with currently avail-
able TKIs have resulted in intense interest in implementing
diagnosis and testing of Ph-like ALL and underlying genetic
alterations in prospective clinical trials.
In 2009, two groups identified childhood ALL cases in which
the gene expression profile of leukemic cells lacking a known
chromosomal rearrangement was similar to that of Ph-positive
ALL.46,47 The Childrens Oncology Group identified a group of
high-risk BCR-ABL1negative B-ALL cases with a high fre-
quency of IKZF1 alteration (which is also a hallmark of
Ph-positive ALL)43 and poor outcome that exhibited simi-
larity of the transcriptomic signature of these cases to that
of Ph-positive ALL using gene set enrichment analysis. The
Dutch used hierarchical clustering of gene expression
profiling data to show clustering of Ph-positive with
Ph-negative cases.47 As there is no single founding genomic
alteration (such as BCR-ABL1) common to all cases, and as
identification rests on demonstrating similarity with the
expression profile of Ph-like ALL, the frequency of Ph-like ALL
varies between studies and the gene expression classifier
used.48 However, multiple studies have shown that Ph-like
ALL is common, particularly with increasing age, and it
is associated with poor outcome and commonly harbors
kinase-activating lesions.
A study of over 1,700 childhood, adolescent (age 16 to 21),
and young adult (age 22 to 39) ALL cases performed by the
Childrens Oncology Group, the St. JudeWashington Uni-
versity Pediatric Cancer Genome Project, and institutions
studying adults with ALL defined the prevalence and genetic
basis of ALL.49 Using gene expression microarrays to define
the signature of Ph-positive ALL and statistical prediction,
Ph-like ALL was shown to be present in approximately 10% of
standard-risk childhood ALL cases, with prevalance in-
creasing by age to over 25% of cases among young adults.49

There are fewer data describing the prevalence of Ph-like ALL
in older adults. Data from the German Multicenter Study
Group for Adult ALL (GMALL) suggested that the frequency
of Ph-like cases peaked among adolescents with a sub-
sequent decline.50 Recent analysis of almost 700 adult ALL
cases from the United States, United Kingdom, and Europe
identified a frequency of 26% among young adults and 20%
among adult patients over the age of 40.51 A similar prev-
alence among adults was reported in 127 patients enrolled in
Dutch-Belgian HOVON protocols.52 The outcome of Ph-like
ALL is poor in the majority of studies,46,47,49,52-57 particularly
for adolescents and adults for whom EFS and OS rates are
equal or are inferior to other high-risk B-ALL subtypes such as
Ph-positive and MLL-rearranged ALL.52 An exception is the
St. Jude Total Therapy Study XV, in which children with
Ph-like ALL did not have an inferior outcome, although many
were reclassified as high risk due to suboptimal treatment
response (as measured by levels of MRD) and subjected to
more intensive therapy including allogeneic bone marrow
transplantation.58 Importantly, several children undergo-
ing bone marrow transplantation commonly had kinase-
activating lesions targetable with ABL1 inhibitors such as
imatinib and dasatinib.
Multiple chromosomal rearrangements, sequence muta-
tions, and structural genetic alterations activate cytokine
receptor and tyrosine kinase signaling pathways in Ph-like
ALL. Approximately half of cases have rearrangement of
CRLF2 (encoding cytokine receptorlike factor 2), either as a
rearrangement with the immunoglobulin heavy chain locus
(IGH-CRLF2) or a focal deletion upstream of CRLF2 resulting
in expression of a P2RY8-CRLF2 fusion, both of which result
in deregulated expression of intact CRLF2, which may be
detected by flow cytometry.59-61 Less commonly, a point
mutation of CRLF2 is present (p.Phe232Cys) that also
results in receptor activation.62 Approximately half of CRLF2-
rearranged cases have activating mutations of Janus kinases,
particularly in the pseudokinase domain of JAK2 but also in
JAK1 and JAK3. CRLF2, which forms a heterodimeric receptor
with IL-7 receptor alpha (IL7RA) for the cytokine thymic
stromal lymphopoietin (TSLP), is a scaffold for mutant JAK2,
and the two alterations are cotransforming. CRLF2 cases
lacking JAK2 mutations commonly have other mutations
deregulating JAK-STAT signaling, including mutations of
IL7R15,49 and deletions of SH2B3 (also known as LNK), which
is a negative regulator of JAK-STAT signaling.63,64
Initial sequencing studies of tyrosine kinase genes failed to
identify sequence mutations in Ph-like ALL apart from those
in Janus kinases.54 Subsequent transcriptome sequencing
(RNA-seq) of a small number of Ph-like ALL cases identified a
diverse range of chimeric fusions involving tyrosine cases in
cases lacking CRLF2 rearrangement.65 Transcriptome se-
quencing of over 150 cases, with whole-genome sequencing
of a subset, provided a detailed understanding of the genetic
alterations driving kinase signaling in Ph-like ALL.58 Cases
lacking CRLF2 rearrangements have alterations deregulating
multiple signaling pathways, including ABL1-class chro-
mosomal rearrangements, JAK2 rearrangements, EPOR
GENETICS AND THERAPY OF ACUTE LYMPHOLASTIC LEUKEMIA
rearrangements, mutations or deletions activating JAK-STAT
or FLT3 signaling, Ras mutations, uncommon kinase alter-
ations (e.g., NTRK3, FGFR1), and, in a proportion of cases, no
known kinase alteration. ABL1-class rearrangements include
those involving ABL1, ABL2 (also known as ABL-related
gene, or ARG), CSF1R (the macrophage CSF receptor), and
PDGFRB.66 In each case, the kinase is the 39 (C-terminal) fusion
partner and rearranged to multiple different 59 (N-terminal)
fusion partners, and the fusion preserves the tyrosine kinase
domain, resulting in activation of signaling. This group of
rearrangements is termed ABL1-class as the transforming
effects of each are abrogated by ABL1 inhibitors such as
imatinib and dasatinib. Cases with EBF1-PDGFRB rearrange-
ment exhibit a particularly high rate of suboptimal treatment
response, induction failure, and relapse.67 Similarly, JAK2
rearrangements involve a highly diverse range of fusion
partners (at least 20), preserve the JAK2 kinase domain,
remove part of or the entire inhibitory pseudokinase do-
main, and are particularly common with increasing age.
Rearrangements of EPOR (encoding the erythropoietin re-
ceptor) involve at least three different immunoglobulin and
immunoglobulin-like genes that result in deregulation of
receptor expression and truncation of the cytoplasmic tail of
the receptor, which results in stabilization of receptor ex-
pression and heightened JAK-STAT signaling following stim-
ulation with EPO.68
Several observations indicate that these alterations acti-
vate kinase signaling and are amenable to TKI therapy.
ABL1-class and JAK fusions expressed in cell lines result in
proliferation and activation of downstream signaling path-
ways, both of which are inhibited by TKIs. Human leukemic
cells also exhibit signaling activation sensitive to TKIs; TKIs
synergize with chemotherapeutic agents to inhibit pro-
liferation of human Ph-like ALL cells in vivo in xenograft
models. Ph-like cells also exhibit activation of additional
signaling pathways such as PI3K/mTOR signaling,69 and
combinatorial treatment with PI3K inhibitors and BCL-2
inhibitors with a TKI is efficacious.70-72 Anecdotal reports
also indicate that patients with Ph-like ALL are responsive to
the addition of TKI therapy.49,73-75 Multiple patients with
poorly responsive or refractory B-ALL have been found to
have Ph-like ALL by gene expression profiling and/or testing
for driving kinase rearrangements, and they have frequently
shown dramatic, complete, and durable responses with the
addition of a TKI, particularly for ABL1-class fusions. Im-
portantly, there are few data regarding the use of JAK in-
hibitors in Ph-like cases with JAK-STAT activating lesions.
Existing preclinical data suggest that Ph-like cases with JAK2
fusions, EPOR rearrangements, and IL7R/SH2B3 alterations
are sensitive to type I JAK inhibitors such as ruxolitinib,
particularly in combination with chemotherapy,49,65,76 but
CRLF2-rearranged cells are less responsive yet sensitive to
type II JAK inhibitors that inhibit JAK2 in its inactive
conformation.77
There is consequently great interest in identifying patients
with Ph-like ALL and defining the underlying genetic lesions
to implement logical TKI therapy. In view of the diverse range
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e319
CHIARETTI ET AL
of kinase-activating alterations, which continues to grow,
identification of all such lesions requires NGS-based tech-
nology. The most appropriate diagnostic approach used is
dependent on the clinical goal. For example, the majority of
cases with ABL1-class rearrangements can be readily de-
tected with fluorescence in situ hybridization for the kinase
rearrangements, and CRLF2 overexpression arising from
rearrangement can be identified by flow cytometry. However,
identification of all Ph-like cases requires gene expression
profiling using microarray, RNA-seq, or Taqman low-density
array (TLDA) approaches,78 which are informative for research
studies but less suited for real-time diagnostic testing. Several
commercial solutions for nucleic acid capture of kinase loci
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HEMATOLOGIC MALIGNANCIESLEUKEMIA,
MYELODYSPLASTIC SYNDROMES, AND
ALLOTRANSPLANT

Progress in Myeloproliferative
Neoplasms: Are We Ready?

CHAIR
Ruben A. Mesa, MD, FACP
Mayo Clinic
Scottsdale, AZ

SPEAKERS
Francesco Passamonti, MD
Fondazione IRCCS Policlinico San Matteo
Pavia, Italy

Jeffrey Tyner, PhD

Oregon Health & Science University
Portland, OR
MESA AND PASSAMONTI

Individualizing Care for Patients With Myeloproliferative

Neoplasms: Integrating Genetics, Evolving Therapies, and
Patient-Specific Disease Burden
Ruben A. Mesa, MD, and Francesco Passamonti, MD

OVERVIEW

Individualized medicine is important for patients with myeloproliferative neoplasms (MPNs), including essential throm-
bocythemia, polycythemia vera, and myelofibrosis, which are heterogeneous in terms of genetic mutation profile, prognosis,
disease burden, and symptoms. Status of MPN driver mutations in JAK2, CALR, and MPL (or lack of one of these mutations)
and other myeloid mutations (ASXL1, SRSF2, CBL, and IDH1/2, among others) affects diagnosis and prognosis. Management
begins with estimating the prognosis, disease burden including MPN symptoms, and prevention of vascular events. Al-
logeneic stem cell transplantation is the definitive therapy in a subset of patients with myelofibrosis, the majority of whom
receive JAK inhibition with ruxolitinib to relieve splenomegaly and symptoms and to prolong survival. Ruxolitinib is now a
second-line therapy in polycythemia vera, with pegylated interferon being evaluated as a potential front-line therapy
compared with hydroxyurea. The therapeutic landscape is evolving to include new JAK inhibitors, which may affect
cytopenias (pacritinib and momelotinib), combination therapies including ruxolitinib, and novel targets such as pentraxin
and telomerase. Assessing the therapeutic efficacy (including symptom impact) and toxicity of these new approaches is
necessary to determine longitudinal management of MPNs in clinical practice and is a key component of individualizing
care for patients with MPNs.

M yeloproliferative neoplasms account for three main

entities named polycythemia vera, essential throm-
bocythemia, and primary myelofibrosis.1,2 Polycythemia
vera is characterized by erythrocytosis with some degree of
leukocytosis and thrombocytosis and an overall increase in
bone marrow cellularity with well-defined symptoms.3 The
clinical picture of patients with essential thrombocythemia is
dominated by isolated thrombocytosis.4,5 Polycythemia vera
and essential thrombocythemia share several clinical fea-
tures, most prominently a high risk of thrombosis and a
predisposition to evolve into acute myeloid leukemia or
secondary myelofibrosis.6-8 Among MPNs, primary myelo-
fibrosis has the most heterogeneous clinical presentation,
including anemia, splenomegaly, leukocytosis or leukopenia,
thrombocytosis or thrombocytopenia, a variably high
symptom burden, and a variability of clinical responses to
therapy.9,10 A study among 1,581 patients with MPNs was
recently conducted at the Mayo Clinic in the United States
and at the University of Florence and Papa Giovanni XXIII
Hospital in Italy; median survival was 19.8 years, 13.5 years,
and 5.9 years for individuals with essential thrombocythemia,
polycythemia vera, and primary myelofibrosis, respectively.11
Classification of MPNs is performed according to the 2008
World Health Organization (WHO) criteria, which are based
on clinical, histopathologic, and molecular findings.12 An
updated WHO classification is expected in 2016, which will
likely include MPN driver mutations (JAK2, CALR, and MPL),
different cell count cutoffs, and an extended indication for
bone marrow biopsy.1
CLINICAL BURDEN OF MPNs: THE EFFECTS OF
MPN SYMPTOMS ON HEALTH-RELATED QUALITY
OF LIFE
Given their variable nature, MPNs have various clinical ef-
fects such as variable cytopenias, variable degrees of
splenomegaly, and a constellation of MPN-related symp-
toms.13 A patients clinical course is also affected by
comorbidities, therapy-related toxicity, and morbidity
owing to prior vascular events. Health-related quality of
life for patients with MPNs is a broader construct that
includes the above-listed features and also considers the
burden of medical care, disease-related financial burden
(e.g., decreased ability to work or medical disability),
and stress or effects on mood as a result of uncertainty

From the Mayo Clinic Cancer Center, Phoenix, AZ; Division of Hematology, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Ruben A. Mesa, MD, Mayo Clinic Cancer Center, 5777 East Mayo Blvd., Phoenix, AZ 85259; email: mesa.ruben@mayo.edu.

2016 by American Society of Clinical Oncology.

e324 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


about the future (Sidebar). As one quantifies MPN-
related symptom burden and assesses the effects of
therapy and disease course, it is important to consider
that MPN symptom burden and health-related quality
of life are interrelated but distinct concepts. For ex-
ample, one could theoretically improve a specific MPN-
associated symptom such as pruritus; however, if the
agent used to achieve that response led to problematic
toxicity (e.g., gastrointestinal), then the net effect on
health-related quality of life could be adverse despite
symptom-specific improvement.
MPN SYMPTOM BURDEN PLAYS AN IMPORTANT
ROLE IN MORBIDITY AND MORTALITY
Individualized management of MPNs recognizes that MPNs
can have a long disease course. Although MPNs are clonal
hematopoietic malignancies, their course can frequently
exceed a decade, even among some patients with secondary
myelofibrosis. As a result, the cumulative effects of symptom
burden, decreased health-related quality of life, comor-
bidities, and medication-related toxicity all affect morbidity
and mortality.14 Vascular events early in the course of MPNs
can affect disease morbidity, ranging from very serious
events such as intra-abdominal thrombosis (which can lead
to portal hypertension, esophageal varices, and risks of
hemorrhage) to the obvious implications of stroke and
myocardial infarction or the more subtle effect of MPNs on
cognition, chronic headaches, and erythromelalgia. The
burden of specific symptoms can be debilitating, ranging
from unrelenting pruritus (e.g., lack of relief has led to
KEY POINTS
Individualizing care for patients with MPNs begins with
an accurate assessment of prognosis with current
clinical scoring systems and an estimation of disease
burden.
Genetic mutation testing (driver mutations such as JAK2
V617F, CALR, and MPL) in MPNs is helpful in making the
initial diagnosis, and more extensive mutation testing
(ASXL1, IDH1/2, etc.) is helpful in refining the prognosis
in select clinical scenarios, such as equivocal candidates
for stem cell transplantation.
MPNs have a range of disease-associated symptoms
that arise from the clonal disease, are associated with
pathologic cytokines and inflammation, and directly
contribute to disease morbidity and mortality.
Alleviation of MPNs symptoms, now measurable
through standardized instruments, is an integral part of
assessing therapeutic effects in both clinical trials and
clinical practice.
JAK inhibition is the cornerstone of medical therapy for
problematic myelofibrosis and polycythemia vera.
Expanding investigations with interferons, new JAK
inhibitors, JAK inhibitor combinations, and new targets
are on the horizon.
INDIVIDUALIZED THERAPY FOR MYELOPROLIFERATIVE NEOPLASMS
suicide) to overwhelming fatigue (which can lead to
medical disability and exacerbate mood disturbances).15
The advancing symptom burden seen with secondary
myelofibrosis is not only a problematic feature of the
disease but also likely directly contributes to the mortality
of the disorder. Analysis of causes of death in secondary
myelofibrosis shows that approximately one-third of
patients will succumb to acute myeloid leukemia and
likely mortal complications of cytopenias; however, the
remainder of patients succumb to a variety of causes
exacerbated by the debilitation and hypercatabolic state
caused by the disease (e.g., thrombosis, infection, or
exacerbation of comorbidities such as congestive heart
failure). 14
The identification of symptoms prevalent among patients
with MPNs is not new; symptom burden has long been
recognized as a key clinical feature of MPNs. However, the
degree of symptom burden was first quantified in 2007 in
a web-based survey of more than 1,000 patients, conducted
by the CMPD Education Foundation and Mayo Clinic.13
Identified symptoms included fatigue, night sweats, pruri-
tus, and bone pain, among others.13
There is likely a pathogenetic link between the clonal
myeloid malignancy of an MPN and the patients direct
symptom burden. Part of this link may potentially be related
to inflammatory cytokines. Previous studies demonstrated
that interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor-alpha,
and interferons may have a direct link between these two
areas (particularly in constitutional symptoms such as fevers,
night sweats, and weight loss), as well as between symptoms
and prognostic significance.14 Indeed, increases in in-
flammatory cytokines were observed in early studies with
ruxolitinib and improvement in these cytokines was seen
with response to therapy.16
ASSESSMENT OF THE MUTATION PROFILE IN
MPNs
The same driver mutations of JAK2, MPL, and CALR genes are
present in polycythemia vera, essential thrombocythemia,
SIDEBAR. Factors Impacting Health-Related
Quality of Life for Patients With
Myeloproliferative Neoplasms
MPN-derived constitutional symptoms (i.e., pruritus, night
sweats)
MPN-derived spleen-oriented symptoms (i.e., discomfort
or pain)
MPN vascular symptoms arising from elevated blood
counts
Toxicity from MPN-directed therapies
Complications from earlier MPN-related events such as
thrombosis
Burden of medical care related to MPN
Financial burden related to illness
Stress related to uncertainty in health
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e325
MESA AND PASSAMONTI
and primary myelofibrosis, both in sporadic17-20 and in fa-
milial cases.21,22 These patients (10%15%, overall) are re-
ferred to as having triple-negative status. Among patients
with triple-negative status, new somatic JAK2 and MPL
variants have been discovered.23
In polycythemia vera, JAK2 mutations cover the whole
mutation profile, with V617F present among 95%97%
of patients4 and exon 12 mutations present among the
remainder.24 Very few patients present with CBL or LNK
mutations. MPL mutations have been identified in ap-
proximately 5% of patients with essential thrombocythemia
and in 5%10% of patients with secondary myelofibrosis.25
Mutations in the CALR gene have been mainly identified among
patients with essential thrombocythemia and/or primary
myelofibrosis without JAK2 or MPL mutations,18,26 covering
70% of the mutation profile for patients without JAK2/MPL
mutations.
Detection of JAK2 mutations is critical in the diagnostic
process of erythrocytosis and is a major criterion for diagnosis
of polycythemia vera.6 Regarding JAK2 allele burden, higher
burdens correlate unequivocally with enhanced myelopoiesis
of the bone marrow, leukocytosis, and increasing spleen size,
whereas they inversely correlate with platelet count.7,27 Al-
though allele burden quantification is of interest, it is not
mandatory to diagnose polycythemia vera; a qualitative test
on whole blood leukocytes is a correct approach outside of
the research setting.
Concerning CALR mutations, all of the described mutations
are found mainly in a heterozygous state and are insertions
or deletions (type 1, 52-bp deletion, p.L367fs*46; and type 2,
5-bp TTGTC insertion, p.K385fs*47) in the last exon encoding
the C-terminal amino acids of the CALR protein.18,26
Information on CALR mutation in essential thrombocy-
themia is summarized as follows.19,28-30 First, 40%50% and
30%40% of patients display type 1 and type 2 variants,
respectively. Compared with mutant JAK2, both variants
were associated with higher platelet and lower hemoglobin
and leukocyte counts. Patients with a CALR mutation have a
lower risk of thrombosis than patients with a JAK2 mutation.
Evolution from essential thrombocythemia to polycythemia
vera seems unusual (even impossible). Patients with a CALR
mutation were classified into the lower-risk groups with
regard to both the standard risk stratification for thrombosis
(older than age 60 and prior thrombosis) and the In-
ternational Prognostic System in Essential Thrombocythe-
mia (IPSET) score31 for survival.
In the largest collaborative trial including 617 patients with
primary myelofibrosis, individuals with a CALR mutation
had a lower risk of developing anemia, thrombocytopenia,
and marked leukocytosis compared with other subtypes.32
Patients with a CALR mutation also had a lower risk of
thrombosis compared with patients with a JAK2 mutation. In
other studies, CALR mutations had a favorable effect on
survival that was independent of both risk (as determined by
the Dynamic International Prognostic Scoring System
[DIPSS] Plus model) and ASXL1 mutation status.19 A sub-
sequent analysis identified that combined CALR and ASXL1
e326 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
mutation status was associated with different survival
(CALR+ASXL12 and CALRASXL1+ for best and worse sur-
vival, respectively).33 A recent analysis showed that the
favorable prognostic effect of CALR mutations on primary
myelofibrosis might be restricted to only those patients with
type 1 CALR mutations.34 In a recent study of 1,118 patients
with primary myelofibrosis, driver mutations were classified
prognostically in two distinct categories: favorable (type
1/type 1like CALR) and unfavorable (all other mutation
categories).35
On the basis of this information, molecular profiling of
MPN at diagnosis must include analysis of JAK2 (looking for
the V617F point mutation first),7 screening of exon 12
mutations of JAK2 (only in V617F-negative PV),24 and
screening of CALR and MPL mutations (in V617F-negative ET
and primary myelofibrosis).19
IS IT MANDATORY TO STUDY ADDITIONAL
MUTATIONS IN MPNs AT DIAGNOSIS?
Additional mutations of CBL, TET2, SF3B1, SRSF2, DNMT3A,
IDH1/2, EZH2, and ASXL1 genes are variably reported in
MPNs, although mainly among patients with secondary
myelofibrosis.36
A total of 879 patients with secondary myelofibrosis were
studied to determine the individual and combined prog-
nostic relevance of somatic mutations in ASXL1, SRSF2, EZH2,
TET2, DNMT3A, CBL, IDH1, IDH2, MPL, and JAK2.37 Of these,
ASXL1, SRSF2, and EZH2 mutations interindependently
predicted shortened survival. However, only ASXL1 muta-
tions remained significant in the context of the International
Prognostic Scoring System (IPSS) prognostic model.14
Leukemia-free survival was negatively affected by IDH1/2,
SRSF2, and ASXL1 mutations, whereas it was affected by
IDH1 and SRSF2 mutations in a Mayo Clinic cohort.37
Next-generation sequencing may simplify the identifica-
tion of new additional mutations. By applying this approach,
mutations other than JAK2, CALR, or MPL occur among more
than 80% of patients with primary myelofibrosis, including
those with triple-negative status. A prior study revealed that
the absence of such mutations is independently favorable
for survival, whereas the prognostic effect of their presence
is influenced by ASXL1, CBL, RUNX1, and SRSF2 mutations.38
These mutations are not routinely assessed at the time of
diagnosis in daily clinical practice, although they may be
useful in some clinical situations as discussed above.
WHICH PROGNOSTIC SCORE SHOULD BE USED
TO PREDICT SURVIVAL IN MYELOFIBROSIS?
IPSS and DIPSS Models Based on Clinical Parameters
The IPSS was defined in 2009 on the basis of 1,054 patients
with primary myelofibrosis, excluding post-polycythemia
vera and post-essential thrombocythemia secondary mye-
lofibrosis and prefibrotic primary myelofibrosis.14 Median
survival was 69 months. Parameters affecting the survival
and scoring system are reported in Table 1. For the low,
intermediate-1, intermediate-2, and high-risk categories,

median survival was 135 months, 95 months, 48 months, and
27 months, respectively.
The progressive nature of primary myelofibrosis gener-
ated interest in defining new so-called dynamic models, such
as the DIPSS and the DIPSS Plus model. In a nontime-
dependent analysis (models at diagnosis), patients are
assigned to a risk group on the basis of the assessment of
risk factors at diagnosis and they are followed in the same
category irrespective of the acquisition of other risk factors
during the disease course. According to a dynamic model,
patients contribute to the estimate of survival in a category
only as long as they do not acquire further risk factors, then
they shift to a higher category according to their new
score.
The DIPSS was developed based on a study of 525 patients
with primary myelofibrosis who were regularly followed,
using the same IPSS risk factors but a different scoring
system (Table 1).39 Median survival referring to patients
maintaining the same risk category over time was not
reached in the low-risk category, whereas median survival
was 14.2 years, 4 years, and 1.5 years in the intermediate-1,
intermediate-2, and high-risk categories, respectively.
The DIPSS Plus model was produced as a result of an
analysis of 793 patients with primary myelofibrosis; 428
patients were referred within their first year of diagnosis,
whereas 365 were referred after their first year of di-
agnosis.40 Unfavorable cytogenetics, red blood cell
transfusion need, and low platelet counts were added to
the DIPSS categories. For the low-, intermediate-1,
intermediate-2, and high-risk categories, median sur-
vival was 185 months, 78 months, 35 months, and
16 months, respectively.
TABLE 1. Clinically Driven Prognostic Model in Primary
Myelofibrosis
IPSS DIPSS DIPSS Plus
Age > 65 1 1 To assess DIPSS status**
Hemoglobin < 10 g/dL 1 2 To assess DIPSS status**
Leukocyte Count 1 1 To assess DIPSS status**
> 25 3 109/L
Blast Cells 1% 1 1 To assess DIPSS status**
Constitutional Symptoms 1 1 To assess DIPSS status**
Unfavorable Cytogenetics* No No 1 SRSF2 Mutation
Red Blood Cell Need No No 1 CALR Type 2, Type 2Like
Platelets No No 1 Unfavorable Cytogenetics*
< 100 3 109/L
Data are presented as points values unless otherwise indicated. IPSS categories are as
follows: low (score 0), intermediate-1 (score 1), intermediate-2 (score 2), and high
(score $ 3). DIPSS categories are as follows: low (score 0), intermediate-1 (score 1 to 2),
intermediate-2 (score 3 to 4), and high (score 5 to 6). DIPSS Plus categories are as
follows: low (score 0), intermediate-1 (score 1), intermediate-2 (score 2 to 3), and high
(score 4 to 6).
*Complex karyotype or a single abnormality or two abnormalities, including 18, -7/7q-,
i(17q), -5/5q-, 12p-, inv(3), or 11q23 rearrangement.
**DIPSS status of intermediate-1 (1 point); intermediate-2 (2 points); and high
(3 points).
Abbreviations: IPSS, International Prognostic Scoring System; DIPSS, Dynamic
International Prognostic Scoring System.
INDIVIDUALIZED THERAPY FOR MYELOPROLIFERATIVE NEOPLASMS
Molecular-Based Prognostic Models
On the basis of the IPSS and DIPSS prognostic models and the
available data on mutation platforms, it seemed obvious to
combine different clinical/molecular parameters with the
aim to distinguish patients at higher risk from those at lower
risk. To reinforce the role of mutations in disease prediction,
the additional prognostic value of the number of mutated
genes was taken into account.41 The presence of two or
more mutations predicted the worst outcomes. Median
survival was 2.6 years, 7.0 years, and 12.3 years for patients
with two, one, or no mutations, respectively. The presence
of two or more mutations was also associated with short-
ened leukemia-free survival.
By combining CALR, JAK2, MPL, triple-negative status, and
each single variable included in the IPSS, a molecular-based
risk model was developed.32 Five risk categories with sig-
nificantly different survival were identified. Although this
model was based on the three driver mutations and some
IPSS clinical parameters, the Mutation-Enhanced In-
ternational Prognostic Scoring System (MIPSS)42 also com-
bined additional mutations (ASXL1, SRSF2, EZH2, and
IDH1/2) previously identified by next-generation sequenc-
ing.37 Factors included in the MIPSS model are reported in
Table 2. Four risk groups were defined.
The Genetics-Based Prognostic Scoring System prognostic
model was developed to further integrate cytogenetic and
molecular profiles (Table 2). The four risk categories were
associated with different survival, ranging from 2.2 years to
more than 17 years.43 Figure 1 reports how to use this
clinicalmutational-based prognostic model in the clinical
practice.
TABLE 2. Genetically Driven Prognostic Model in
Primary Myelofibrosis
MIPSS GIPSS
Age > 6 1.5 2
Constitutional Symptoms 0.5 No
Hemoglobin < 10 g/dL 0.5 No
Platelets < 200 3 10 /L 9
1.0 No
Triple Negative 1.5 2
JAK2 or MPL Mutation 0.5 2
ASXL1 Mutation 0.5 1
0.5 1
No 2
No 3 for very high risk;
2 for high risk
Data are presented as points values unless otherwise indicated. MIPSS categories: low
(score 0 to 0.5), intermediate-1 (score 1 to 1.5), intermediate-2 (score 2 to 3.5), and
high (score $ 4).
*Very high risk indicates a monosomal karyotype, inv(3), i(17q), -7/7q-, 11q, or 12p
abnormalities; high risk indicates complex nonmonosomal karyotype, 2 abnormalities
not included in the very high-risk category, 5q-,18, other autosomal trisomies
except 19, and other sole abnormalities not included in other risk categories.
Intermediate risk indicates sole abnormalities of 20q-, 1q1, or any other sole
translocation, and Y or other sex chromosome abnormality. Low risk indicates normal
cytogenetics or sole abnormalities of 13q- or 19.
Abbreviations: MIPSS, Mutation-Enhanced International Prognostic Scoring System;
GPSS, Genetics-Based Prognostic Scoring System.
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MESA AND PASSAMONTI

PROGNOSTICATION IN POLYCYTHEMIA VERA
AND ESSENTIAL THROMBOCYTHEMIA
There is a global consensus that being age 60 or older at
diagnosis and presence of vascular events in the patients
history are the two most relevant prognostic factors in
predicting thrombosis in polycythemia vera and essential
thrombocythemia.44,45 Therefore, patients with at least one
of these risk factors at diagnosis are considered at high risk,
whereas those with none are considered at low risk.45 This
risk classification affects the therapeutic approach for pa-
tients with polycythemia vera and essential thrombocy-
themia. However, leukocyte counts, cardiovascular risk, JAK2/
CALR mutation status, and bone marrow features are reported
to affect thrombosis, progression, and survival.28,29,46,47
In polycythemia vera, the ECLAP study48 showed that
patients younger than age 65 without prior thrombosis have
an incidence of thrombosis of 2.5 per 100 persons per year,
those older than age 65 or with prior thrombosis have an
incidence of 5.0 per 100 persons per year, and patients older
than age 65 with prior thrombosis have an incidence of 10.9
per 100 persons per year.
In essential thrombocythemia, physicians can predict survival
according to the IPSET model,49 which was tested among 867
patients with WHO-defined essential thrombocythemia. The
model included the following parameters: older than age 60 (2
points), leukocyte count greater than 11 3 109/L (1 point), and
prior history of thrombosis (1 point). Three risk categories with
significantly different survival were identified: low (0 points,
median survival not reached), intermediate (1 to 2 points,
median survival 24.5 years), and high (3 to 4 points, median
survival 13.8 years).
Concerning thrombosis prediction in WHO-diagnosed
essential thrombocythemia, the IPSET thrombosis
model50 was generated for the same IPSET cohort but
considers risk factors including being older than 60 (1 point),
history of thrombosis (2 points), presence of cardiovascular
risk factors (1 point), and JAK2 (V617F) mutation (2 points).
On the basis of these factors, the IPSET thrombosis model
specifies the following risk categories: low (less than 2
points; thrombosis risk of 1.03 per 100 person-years), in-
termediate (2 points; thrombosis risk of 2.35 per 100
person-years), and high (more than 2 points; thrombosis
risk of 3.56 per 100 person-years). Although CALR mutation
status was introduced into the statistical analysis, the IPSET
model maintained its prognostic power.51
In another study, survival was assessed in 1,545 patients
with WHO-defined polycythemia vera.52 Parameters in-
cluded in this model were older age, leukocytosis, and

FIGURE 1. Stepwise Approach to Estimating Prognosis in Myeloproliferative Neoplasms Incorporating Clinical

Prognostic Scoring System and Then Refining Prognosis With Mutation Status

Abbreviations: DIPSS, Dynamic International Prognostic Scoring System; ET, essential thrombocythemia; f-up, follow-up; HR, high risk; Int-1, intermediate-1 risk; Int-2,
intermediate-2 risk; IPSET, International Prognostic Score Essential Thrombocythemia; IPSS, International Prognostic Scoring System; LR, low risk; Med OS, median overall
survival; PMF, primary myelofibrosis; PV, polycythemia vera; WHO, World Health Organization.

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 INDIVIDUALIZED THERAPY FOR MYELOPROLIFERATIVE NEOPLASMS

TABLE 3. Myeloproliferative Neoplasm Symptom Assessment Tools and Associated Instruments

Questionnaire Goals Number of Items Reference

Myelofibrosis Symptom Assessment Form Myelofibrosis-specific symptom assessment 20 Mesa et al53
(MF-SAF)
Includes the Brief Fatigue Inventory
Myelofibrosis Symptom Assessment Form Myelofibrosis symptom serial assessment on 7 Mesa et al54
2.0 (MF-SAF 2.0) clinical trials
Validated in the COMFORT-1 trial
Myeloproliferative Neoplasm Symptom As- Expanded to measure MPN symptoms across 27 Scherber et al15
sessment Form (MPN-SAF) ET, PV, and MF
Myeloproliferative Neoplasm Symptom As- Derived as a subset of the most representative 10 Emanuel et al55
sessment Form Total Symptom Score symptoms from MPN-SAF
(MPN 10 or MPN-SAF TSS)
Abbreviations: MPN, myeloproliferative neoplasm; ET, essential thrombocythemia; PV, polycythemia vera; MF, myelofibrosis.

venous thrombosis, which generated three risk categories
with different survival ranging from 10.9 to 27.8 years.
Figure 1 shows how to use prognostication in MPNs.
CREATION OF VALIDATION OF MPN SYMPTOM
ASSESSMENT TOOLS
The spectrum of symptom-related difficulties encountered
by patients with MPNs is varied and includes several areas of
symptom burden such as those that are constitutional in
origin and those that are those related to vascular flow or
enlargement of the spleen. Given that there were no vali-
dated instruments that incorporated this spectrum of dif-
ficulties, MPN-specific tools were necessary and were thus
developed utilizing the above-described 2007 web survey
as a foundation (Table 3).13 The Myelofibrosis Symptom
Assessment Form (MF-SAF) was the first instrument de-
veloped. The MF-SAF is a 20-item survey validated against
other outcome tools reported for patients with cancer and is
effective in capturing the presence and intensity of mye-
lofibrosis disease symptoms.53 Subsequently, this in-
strument was further refined to a seven-item instrument
(MF-SAF 2.0) for use specifically in myelofibrosis clinical
trials.54 In an effort to have a broader instrument that could
represent the difficulties seen in essential thrombocythemia
and polycythemia vera, the MF-SAF was expanded to 27
items and was named the MPN Symptom Assessment
Form.15 In addition to the initial MF-SAF questions related to
abdominal discomfort, fatigue, coughing, night sweats, bone
pain, weight loss, inactivity, abdominal pain, pruritus, fever,
and quality of life, there was an additional focus on mi-
crovascular symptoms including insomnia, sexual dysfunc-
tion, vertigo, lightheadedness, dizziness, numbness, tingling,
headaches, and concentration. Each individual symptom
had a potential score ranging from 0 (absent) to 10 (worst
imaginable/as bad as it could be). Further refinement of this
instrument for frequent serial use resulted in a 10-item total
symptom score (the MPN-SAF-TSS or MPN 10).55 These 10 core
items included worst fatigue, early satiety, abdominal dis-
comfort, concentration problems, inactivity, night sweats,
itching, bone pain, fever, and weight loss. We recommend
using the comprehensive MPN-SAF at diagnosis and at the time
of clinical changes, whereas the MPN 10 is helpful for routine
clinical monitoring visits or when used daily in a diary with
clinical trials. The tools are meant to be a springboard for
discussion between the patient and his or her provider,
and improvement in symptoms is always weighed against
medication-related toxicities.
WHAT LESSONS HAVE WE LEARNED FROM MPN
SYMPTOMS AND DISEASE FEATURES?
The MPN International Quality of Life Study Group has analyzed
the aggregate data gathered on symptom burden among pa-
tients with MPN to make several observations regarding these
diseases. Observations made across the spectrum of MPNs in-
clude that cytokine increases are likely linked to symptom bur-
den.16 It has been observed that certain symptom profile clusters
can exist among patients with MPNs, and these symptom clusters
may potentially correlate with disease phenotypes with clinical
features (and possibly biologic features as well).56 Clinically rel-
evant observations for problematic polycythemia vera (specifi-
cally that hydroxyurea treatment will fail for individual subgroups
or these individuals will have either palpable splenomegaly or a
persisting need for phlebotomies) show that patients with these
features all have worse symptom burden compared with patients
without these features. Furthermore, individuals who have more
than one of these problematic clinical features also have
worsening symptom burden.57 These latter observations may
have relevance regarding current choice of medical therapy.
DETERMINING A TREATMENT PLAN FOR
PATIENTS WITH MPNs
When determining the treatment plan for an individual
patient, it is necessary to consider the nuanced assessment
of prognosis, the importance of avoidance of vascular
events, the effect of symptom burden, the contribution of
splenomegaly to morbidity, and the likelihood of progres-
sion to acute myeloid leukemia.
Which Patients Are Candidates for Allogeneic Stem
Cell Transplantation and When?
Allogeneic stem cell transplantation can be curative for
patients with MPN; however, because of the associated

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MESA AND PASSAMONTI

TABLE 4. JAK Inhibitors and New Agents and Their Use, or Possible Use, in Myeloproliferative Neoplasm
Treatment

Agent Disease Trial Comments Reference

Ruxolitinib (Approved) MF COMFORT-1 and Improved splenomegaly Verstovsek et al63 and Harrison et al64
COMFORT-2
Improved MF-associated symptoms
Improved survival
PV RESPONSE Improved complete response rate Vannucchi et al78
(second
Improved splenomegaly
line)
Decreased PV-associated symptoms
Pacritinib MF PERSIST-1 and Improved splenomegaly Vannucchi et al70
PERSIST-2
Improved MF-associated symptoms
(ongoing)
Able to be given in full dose
regardless of thrombocytopenia
Improvement in anemia
Momelotinib MF SIMPLIFY-1 and Ongoing phase III trials NCT0196838 and NCT02101268
SIMPLIFY-2
SIMPLIFY-2
Combination Trials All Including a
Ruxolitinib Base
Plus Azacitidine (Hypomethylating) MF Phase II Ongoing trial NCT01787487, Daver et al73
Plus Danazol (Androgen) MF Phase II Ongoing trial NCT01732445, Gowin et al72
Plus Pegylated Interferon Alfa-2a MF Phase II Ongoing trial Mikkelsen et al76
(Interferon)
Plus Panobinostat (HDAC Inhibitor) MF Phase II Ongoing trial NCT01433445, Harrison et al75
Plus Pomalidomide (IMID) MF Phase II Ongoing trial NCT01644110, Stegelmann et al74
Plus BKM-120 (PI3K Inhibitor) MF Phase II Ongoing study Durrant et al83
Plus LDE-225 (Hedgehog Inhibitor) MF Phase II Ongoing trial NCT01787552, Gupta et al84
New Agents for MPNs Testing as
Single Agents
P1101/AOP2014 PV Phase III Ongoing trial NCT01949805
Proline Pegylated Interferon Alfa-2b
PRM-151 (Antifibrosis) MF Phase II Ongoing trial NCT01981850
Imetelstat (Telomerase Inhibitor) MF Phase II Ongoing trial NCT02426086
Abbreviations: MF, myelofibrosis; PV, polycythemia vera; HDAC, histone deacetylase; ET, essential thrombocythemia; IMID, immunomodulatory drug; PI3K, phosphoinositide
3-kinase.

expense and risk of transplant-related morbidity and mor-
tality, HSCT is currently limited to a subset of patients with
MF. The European Group for Blood and Marrow Trans-
plantation and the European LeukemiaNet international
working group recently provided indications for and man-
agement of allogeneic stem cell transplantation.58 Although
readers are referred to the guidelines by the European
Group for Blood and Marrow Transplantation and the Eu-
ropean LeukemiaNet for further information, some points
are summarized as follows. Patients with intermediate-2
or high-risk disease and who are younger than age 70
should be considered candidates for allogeneic stem cell
transplantation.59 Patients with intermediate-1 risk of disease
and who are younger than age 65 should be considered
candidates if they present with adverse cytogenetics, a per-
centage of blasts in peripheral blood greater than 2%, or re-
fractory, transfusion-dependent anemia. Decisions regarding a
pretransplant splenectomy should be made on a case-by-case
basis. Patients with intermediate-2 or high-risk disease lacking
an HLA-matched sibling or unrelated donor should be enrolled
in a protocol using HLA nonidentical donors; the optimal in-
tensity of the conditioning regimen must be defined.
What Options Are Available to Control Splenomegaly,
Cytoses, and Symptoms?
The European LeukemiaNet guidelines recommend control
of hematocrit and use of low-dose aspirin (unless contra-
indicated) for the prevention of thrombosis, as well as the
selective use hydroxyurea as the drug of choice when an
antimyeloproliferative effect is needed for patients with
MPNs. 45 However, data available on hydroxyurea are
scant, with the most complete study on hydroxyurea in
myelofibrosis retrospectively evaluating 40 patients.60
In the last few years, several medicines with anti-JAK
properties (named JAK inhibitors) have been studied
(Table 4).61 Among these, ruxolitinib is the only approved

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JAK inhibitor for MPNs and available for clinical practice.
Other compounds entered phase III investigation (fedrati-
nib,62 momelotinib, and pacritinib), and others are being
tested in phase I to phase II studies.
Ruxolitinib
Two prospective randomized trials with ruxolitinib have
been published: COMFORT-1 (155 patients treated with
ruxolitinib vs. 151 treated with placebo)63 and COMFORT-2
(146 patients treated with ruxolitinib vs. 73 treated with best
available therapy [BAT]).64 In the COMFORT-1 trial, the
primary endpoint (reduction of spleen volume of 35% or
more assessed by MRI) at week 24 was reached in 42% of
patients in the ruxolitinib arm and in 1% of the placebo arm.
At week 24, 46% of patients receiving ruxolitinib and 5% of
those receiving placebo experienced symptom alleviation by
at least 50%, as measured by the modified MF-SAF.53 Pa-
tients treated with ruxolitinib experienced relief of ab-
dominal discomfort, early satiety, night sweats, itching, and
musculoskeletal pain. In the COMFORT-2 trial, the primary
endpoint (the same as the COMFORT-1 study but evaluated
at week 48) was reached in 28% of patients treated with
ruxolitinib and in 0% of those receiving BAT. Mean im-
provements in Functional Assessment of Cancer Therapy
Lymphoma System scores from baseline were greater in the
ruxolitinib arm.
Improved survival was observed for ruxolitinib versus
placebo (27 vs. 41 deaths), with a hazard ratio of 0.58.65 The
3-year analysis of the COMFORT-2 trial confirmed that dose-
dependent anemia and thrombocytopenia were the most
common adverse events in the ruxolitinib-treated group, but
these events rarely led to discontinuation.66 Other adverse
events of interest included leukopenia, bleeding, infections,
thromboembolic events, elevated transaminase levels, in-
creased systolic blood pressure, and weight gain. The rate of
these events generally decreased with longer exposure to
ruxolitinib treatment, with the highest rates occurring within
the first 6 months of treatment. Among these events, in-
fections occurred in 50% of patients between weeks 0 and 24
and included bronchitis, gastroenteritis, nasopharyngitis,
and urinary tract infections. The rate of infections was 25%
for weeks 144 to 168. Finally, patients randomly assigned to
ruxolitinib showed longer overall survival than those ran-
domly assigned to BAT (hazard ratio 0.48).
Because all patients crossed over to ruxolitinib in both
studies, it is difficult to compare the effect on long-term
survival. In a recent study of COMFORT-2 participants,67
survival from diagnosis was compared for 100 patients with
intermediate-2 and high-risk primary myelofibrosis who
received ruxolitinib (the IPSS cohort) versus a comparable
group of 250 patients with primary myelofibrosis who re-
ceived conventional treatment (namely, the DIPSS cohort)
when at the same risk. Patients treated with ruxolitinib at
some point during their disease history had better survival
compared with those who continued standard treatment for
the full duration of follow-up, ultimately suggesting that
ruxolitinib affects the natural history of primary myelofibrosis.
INDIVIDUALIZED THERAPY FOR MYELOPROLIFERATIVE NEOPLASMS
Five-year results of the COMFORT-2 trial were recently
presented.68 At a median follow-up of 4.3 years, 27% of
patients in the ruxolitinib arm and 24% who crossed over
from BAT completed 5 years of on-study treatment; primary
reasons for premature discontinuation were adverse events
(24%) and disease progression (22%). Overall, 54% of pa-
tients in the ruxolitinib arm achieved a 35% or more re-
duction in spleen volume from baseline at any time during
treatment. The probability of maintaining this reduction was
0.51 at 3 years and 0.48 at 5 years. One-third of evaluable
patients with a JAK2 V617F mutation had a greater than 20%
reduction in allele burden and 16% improved fibrosis.
Results of the RESPONSE trial were published in 2015. This
phase III open-label study evaluated the efficacy and safety
of ruxolitinib versus BAT in 110 and 112 patients with
splenomegaly, respectively, who had either hydroxyurea-
resistant or hydroxyurea-intolerant polycythemia vera.
RESPONSE-2 is an ongoing study with a similar design but
includes patients without splenomegaly.69 The primary
endpoint is the proportion of patients who achieve both
hematocrit control through week 32 and a 35% or greater
reduction in spleen volume from baseline shown on imaging
at week 32.
The primary endpoint was achieved in 21% of patients
treated with ruxolitinib versus 1% of patients who received
BAT. Of patients who received ruxolitinib or BAT, 60% and
20% achieved hematocrit control and 38% and 1%
achieved a 35% or greater spleen volume reduction, re-
spectively. Complete hematologic remission was achieved in
24% and 9% of ruxolitinib-treated and BAT-treated patients,
respectively; 49% and 5% had a 50% or greater improvement
in MPN-SAF-TSS score at week 32. Herpes zoster (all grade 1
or 2) was reported in 6.4% and 0% of patients treated with
ruxolitinib and BAT, respectively. The rate of thromboem-
bolic events was lower in the ruxolitinib arm versus the BAT-
treated arm (one and six events, respectively).
Pacritinib and Momelotinib: JAK Inhibition and
Improving Cytopenias
Pacritinib is a JAK2 and FLT3 inhibitor that distinguished itself in
early testing by alleviating myelofibrosis-associated spleno-
megaly and symptoms without drug-emergent worsening of
anemia or thrombocytopenia (Table 4). The PERSIST-1 trial
demonstrated that pacritinib was superior to the best alter-
native therapy, even in those with severe thrombocytopenia
(i.e., platelets less than 50 3 109/L), for control of spleno-
megaly. Subset analysis presented at the 2015 American So-
ciety of Hematology Annual Meeting showed that all subgroups
(in terms of disease features, risks, demographics, and baseline
blood counts) of patients with myelofibrosis seemed to benefit
from pacritinib therapy.70 On the basis of these results, the
manufacturers of pacritinib are seeking U.S. Food and Drug
Administration approval for the drug for use for patients with
myelofibrosis with severe thrombocytopenia, which is cur-
rently an unmet MPN need.
Investigators of a randomized phase III trial (a JAK1 and
JAK2 inhibitor) are currently enrolling participants to study
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MESA AND PASSAMONTI
TABLE 5. Serial Use of Myeloproliferative Neoplasm Symptom Instruments in Randomized Clinical Trials
Disease Instrument
MF MF-SAF 2.0
MF EORTC QLQc30
MF mMF-SAF
MF MPN-SAF TSS
MF MPN-SAF TSS
PV MPN-SAF TSS
PV MPN-SAF
PV MPN-SAF
PV and ET MPN-SAF
Abbreviations: MF, myelofibrosis; MF-SAF, Myelofibrosis Symptom Assessment Form; MPN-SAF TSS, Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score;
mMF-SAF, Myeloproliferative Neoplasm Symptom Assessment Form; PV, polycythemia vera; ET, essential thrombocythemia.
momelotinib as a first-line treatment for myelofibrosis
compared with ruxolitinib. Building on the experience of
phase II trials, the SIMPLIFY 1 trial of momelotinib seeks to
demonstrate superiority of this agent, compared with rux-
olitinib, for myelofibrosis-associated anemia and non-
inferiority in regard to reduction in splenomegaly and
symptoms.
Combination JAK Inhibition: Ongoing Investigations
Multiple combination approaches, with a base therapy of
ruxolitinib, have been tested during the past 2 years. The
goals of combination therapy in the setting of myelofibrosis
are to augment single-agent ruxolitinib benefits by any of the
following: improvement of cytopenias, reduction in marrow
fibrosis, or deeper or broader molecular responses (either in
driver mutations such as JAK2-V617F or CALR or associated
mutations such as ASXL1 or IDH1/2). Updates presented at
the 2015 American Society of Hematology Annual Meeting
were most promising with combinations (Table 1) including
danazol (with activity for cytopenias),72 azacitidine (de-
crease in blasts),73 pomalidomide (improved anemia),74 and
panobinostat (deeper responses perhaps in fibrosis and
molecular markers).75 The addition of ruxolitinib to pegy-
lated interferon alfa-2a (IFN-a-2a) was also reported to help
overcome acquired resistance to single-agent interferon for
patients with a mixture of MPNs.76 Although all of these
trials showed benefits, given the significant activity of single-
agent ruxolitinib, randomized trials that compare these
agents with single-agent ruxolitinib will likely be required
to change practice patterns to include combination
approaches.
EVOLVING OPTIONS IN MPN MANAGEMENT:
EXPERIENCE INCORPORATING SYMPTOM
ASSESSMENT
The current standard across evaluating patients with MPNs
participating in clinical trials includes an important baseline
assessment of symptom burden and potential improvement
with therapy (Table 5). In the inaugural phase III trials of
ruxolitinib in myelofibrosis, it was identified that ruxolitinib
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Trial/Agent Reference
COMFORT-1 (ruxolitinib) Verstovsek et al63
COMFORT-2 (ruxolitinib) Harrison et al64
JAKARTA (fedratinib) Pardanani et al62
PERSIST-1 (pacritinib) Mesa et al77
PERSIST-2 (pacritinib); ongoing NCT02055781
SIMPLIFY (momelotinib); ongoing NCT0196838
RESPONSE (ruxolitinib) Vannucchi et al78
RELIEF (ruxolitinib) Mesa et al79
MPD-RC 112 (phase III) pegylated NCT01259856
interferon
affected both individual and aggregate symptoms for pa-
tients with myelofibrosis.63 Participants ability to track MPN
symptoms with a daily diary also gave insight into issues
regarding symptomatic rebound with withdrawal of the
medication as well as durability of response. In a phase III
study of the JAK inhibitor fedratinib, investigators also used
patient-reported outcomes with the MF-SAF and similarly
showed improvement in individual and aggregate symp-
toms.62 The PERSIST-1 study reported the ability to de-
termine symptomatic improvement across all subgroups
treated with pacritinib, and investigators subsequently an-
alyzed those individuals with severe thrombocytopenia with
the greatest unmet needs and the resolution of symptoms
compared with the best alternative therapy.77 Use of JAK
inhibitors as second-line therapy for polycythemia vera
demonstrated improvement in symptom burden alone or in
aggregate for patients who received ruxolitinib compared
with individuals who received best alternative therapy (in
whom hydroxyurea previously failed).78 In addition, these
similar methodologies were used in the RELIEF study com-
paring patients who were treated with ruxolitinib versus hy-
droxyurea and those with inadequate symptomatic control.79
In the majority of ongoing clinical trials not only for myelofi-
brosis but also essential thrombocythemia and polycythemia
vera (e.g., the randomized phase III trial of hydroxyurea vs.
pegylated IFN-a-2a; NCT01259856), researchers analyzed
symptomatic response as an important component of disease
activity, drug efficacy, and clinical trial endpoints.
SYMPTOMS AND MPNs: MAIN COURSE OR SIDE
DISH?
Treatment for an MPN includes many potential areas of
clinical benefit, such as improved splenomegaly, blood
count, progression-free survival, and symptom resolution.
All of these areas contribute to morbidity, are related to
activity against the disease-associated clone, and may affect
patient suffering and even survival. Symptom response
should be considered as an integral part of assessment
of MPN therapy response that is as important as other
clinical features. Current response criteria for myelofibrosis,

polycythemia vera, and essential thrombocythemia have all
adopted symptomatic improvement as an important com-
ponent of disease response.9,80 Symptomatic response for
therapy clearly must be weighed against the aggregate
impact of therapeutic efficacy. Clearly, the benefit of
symptomatic improvement can be diminished if significant
toxicity is experienced from a treatment. Individualizing care
for patients with MPNs requires an accurate assessment of
prognosis, a well-informed patient, good understanding of
the morbidity and mortality a patient may expect, a com-
prehensive therapeutic plan, and a nuanced assessment of
drug efficacy and toxicity.
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49. Passamonti F, Theile J, Barbui T, et al. A prognostic model to predict
survival in WHO-defined essential thrombocythemia: a study by the
IWG-MRT (International Working Group for Myeloproliferative Neo-
plasms Research and Treatment). Blood. 2011;118 (suppl; abstr 1746).
50. Barbui T, Finazzi G, Carobbio A, et al. Development and validation of an
International Prognostic Score of thrombosis in WHO-Essential
Thrombocythemia (IPSET-thrombosis). Blood. 2012;120:5128-5133;
quiz 5252.
51. Finazzi G, Carobbio A, Guglielmelli P, et al. Calreticulin mutation does
not modify the IPSET score for predicting the risk of thrombosis among
1150 patients with essential thrombocythemia. Blood. 2014;124:
2611-2612.
52. Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545
patients with contemporary polycythemia vera: an international study.
Leukemia. 2013;27:1874-1881.
53. Mesa RA, Schwager S, Radia D, et al. The Myelofibrosis Symptom
Assessment Form (MFSAF): an evidence-based brief inventory to
measure quality of life and symptomatic response to treatment in
myelofibrosis. Leuk Res. 2009;33:1199-1203.
54. Mesa RA, Gotlib J, Gupta V, et al. Effect of ruxolitinib therapy on
myelofibrosis-related symptoms and other patient-reported outcomes
in COMFORT-I: a randomized, double-blind, placebo-controlled trial.
J Clin Oncol. 2013;31:1285-1292.
55. Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm
(MPN) symptom assessment form total symptom score: prospective
international assessment of an abbreviated symptom burden scoring
system among patients with MPNs. J Clin Oncol. 2012;30:4098-4103.
56. Geyer HL, Scherber RM, Dueck AC, et al. Distinct clustering of symp-
tomatic burden among myeloproliferative neoplasm patients: retro-
spective assessment in 1470 patients. Blood. 2014;123:3803-3810.
57. Geyer HL, Scherber RM, Dueck AC, et al. Symptom severity and clinical
variables of polycythemia vera patients with splenomegaly, phlebot-
omy requirements and/or hydroxyurea use: a retrospective evaluation
of 1334 patients. Blood. 2014;124 (suppl; abstr 1848).
58. Kroger NM, Deeg JH, Olavarria E, et al. Indication and management of
allogeneic stem cell transplantation in primary myelofibrosis: a con-
sensus process by an EBMT/ELN international working group. Leukemia.
2015;29:2126-2133.
59. Kroger N, Giorgino T, Scott BL, et al. Impact of allogeneic stem cell
transplantation on survival of patients less than 65 years of age with
primary myelofibrosis. Blood. 2015;125:3347-3350, quiz 3364.
60. Martnez-Trillos A, Gaya A, Maffioli M, et al. Efficacy and tolerability of
hydroxyurea in the treatment of the hyperproliferative manifestations
of myelofibrosis: results in 40 patients. Ann Hematol. 2010;89:
1233-1237.
61. Passamonti F. Balancing efficacy and safety of JAK inhibitors in mye-
lofibrosis. Leuk Res. 2014;38:290-291.
62. Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib
in patients with primary or secondary myelofibrosis: a randomized
clinical trial. JAMA Oncol. 2015;1:643-651.
63. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-
controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;
366:799-807.

64. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus
best available therapy for myelofibrosis. N Engl J Med. 2012;366:787-798.
65. Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety and survival with
ruxolitinib in patients with myelofibrosis: results of a median 2-year
follow-up of COMFORT-I. Haematologica. 2013;98:1865-1871.
66. Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy,
safety, and survival findings from COMFORT-II, a phase 3 study com-
paring ruxolitinib with best available therapy for myelofibrosis. Blood.
2013;122:4047-4053.
67. Passamonti F, Maffioli M, Cervantes F, et al. Impact of ruxolitinib on the
natural history of primary myelofibrosis: a comparison of the DIPSS and
the COMFORT-2 cohorts. Blood. 2014;123:1833-1835.
68. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term efficacy and
safety in COMFORT-II, a phase 3 study comparing ruxolitinib with best
available therapy for the treatment of myelofibrosis: 5-year final study
results. Blood. 2015;126 (suppl; abstr 59).
69. Passamonti F, Griesshammer M, Cavo M, et al. Demographics, baseline
characteristics, and disease symptom burden in RESPONSE-2: a ran-
domized, phase 3 study of ruxolitinib in polycythemia vera patients (pts)
who are resistant to or intolerant of hydroxyurea (HU). Blood. 2015;126
(suppl; abstr 2807).
70. Vannucchi AM, Mesa RA, Cervantes F, et al. Analysis of outcomes by
patient subgroups in patients with myelofibrosis treated with pacritinib
vs best available therapy (BAT) in the phase III Persist-1 Trial. Blood.
2015;126 (suppl; abstr 58).
71. Gupta V, Mesa RA, Deininger MW, et al. Circulating cytokines and
markers of iron metabolism in myelofibrosis patients treated with
momelotininb: correlatives from the Ym-387-II Study. Blood. 2015;126
(suppl; abstr 1600).
72. Gowin KL, Kosiorek HE, Dueck AC, et al. Final analysis of a multicenter
pilot phase 2 study of ruxolitinib and danazol in patients with mye-
lofibrosis. Blood. 2015;126 (suppl; abstr 1618).
73. Daver N, Garcia-Manero G, Cortes JE, et al. 5-Azacytidine (AZA) in
combination with ruxolitinib (RUX) as therapy for patients (pts) with
myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). Blood.
2015;126 (suppl; abstr 823).
74. Stegelmann F, Bangerter M, Heidel FH, et al. A phase-Ib/II study of ruxolitinib
plus pomalidomide in myelofibrosis. Blood. 2015;126 (suppl; abstr 826).
INDIVIDUALIZED THERAPY FOR MYELOPROLIFERATIVE NEOPLASMS
75. Harrison CN, Kiladjian JJ, Heidel FH, et al. Efficacy, safety, and confir-
mation of the recommended phase 2 starting dose of the combination
of ruxolitinib (RUX) and panobinostat (PAN) in patients (pts) with
myelofibrosis (MF). Blood. 2015;126 (suppl; abstr 4060).
76. Mikkelsen SU, Kjr L, Skov V, et al. Safety and efficacy of combination
therapy of interferon-alpha2 + JAK1-2 inhibitor in the Philadelphia-
negative chronic myeloproliferative neoplasms. preliminary results
from the Danish Combi-Trial - an open label, single arm, non-
randomized multicenter phase II study. Blood. 2015;126 (suppl; abstr
824).
77. Mesa RA, Egyed M, Szoke A, et al. Results of the PERSIST-1 phase III
study of pacritinib (PAC) versus best available therapy (BAT) in primary
myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF),
or post-essential thrombocythemia-myelofibrosis (PET-MF). J Clin
Oncol. 2015;33 (suppl; abstr LBA7006).
78. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus
standard therapy for the treatment of polycythemia vera. N Engl J Med.
2015;372:426-435.
79. Mesa R, Vannucchi AM, Yacoub A, et al. The efficacy and safety of
continued hydroxyurea therapy versus switching to ruxolitinib in pa-
tients with polycythemia vera: a randomized, double-blind, double-
dummy, symptom study (RELIEF). Blood. 2014;124 (suppl; abstr 3168).
80. Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for poly-
cythemia vera and essential thrombocythemia: an ELN and IWG-MRT
consensus project. Blood. 2013;121:4778-4781.
81. Verstovsek S, Mesa RA, Foltz LM, et al. PRM-151 in myelofibrosis:
durable efficacy and safety at 72 weeks. Blood. 2015;126 (suppl; abstr
56).
82. Tefferi A, Lasho TL, Begna KH, et al. A pilot study of the telomerase
inhibitor imetelstat for myelofibrosis. N Engl J Med. 2015;373:908-919.
83. Durrant ST, Nagler A, Vannucchi AM, et al. An open-label, multicenter,
2-arm, dose-finding, phase 1b study of the combination of ruxolitinib
and buparlisib (BKM120) in patients with myelofibrosis: results from
HARMONY Study. Blood. 2015;126 (suppl; abstr 827).
84. Gupta V, Harrison CN, Hasselbalch H, et al. Phase 1b/2 study of the
efficacy and safety of sonidegib (LDE225) in combination with rux-
olitinib (INC424) in patients with myelofibrosis. Blood. 2015;126 (suppl;
abstr 825).
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e335
HEMATOLOGIC MALIGNANCIESLEUKEMIA,
MYELODYSPLASTIC SYNDROMES, AND
ALLOTRANSPLANT

Why Are Myelodysplastic

Syndromes So Difficult to Cure?

CHAIR
Stephen Nimer, MD
Sylvester Comprehensive Cancer Center
Miami, FL

SPEAKERS
Gregory A. Abel, MD, MPH
Dana-Farber Cancer Institute
Boston, MA

Rami S. Komrokji, MD
Moffitt Cancer Center
Tampa, FL
 FRAILTY, COMORBIDITY, AND QOL IN MDS

Integrating Frailty, Comorbidity, and Quality of Life in the

Management of Myelodysplastic Syndromes
Gregory A. Abel, MD, MPH, and Rena Buckstein, MD, FRCPC

OVERVIEW

Myelodysplastic syndromes (MDS) are a group of acquired hematopoietic stem cell disorders that manifest with progressive
bone marrow failure and have a propensity to transform into leukemia. Although an increase in biologic understanding of
MDS has led to improved patient risk stratification and prognostication, advances in treatment have lagged behind. While
hematopoietic cell transplantation (HCT) is a potentially curative option for some, most affected patients continue to be
treated with supportive care or with drugs that offer temporary palliation such as hematopoietic growth factors, DNA
hypomethylating agents, or immunomodulatory therapy. For several groups, such as those with intermediate-risk disease as
classified by the Revised International Prognostic Scoring System (IPSS-R) or those with higher-risk disease for whom
hypomethylating agents have failed, optimal treatment remains uncertain. Inclusion of patient-related factors such as frailty
and comorbid conditions into risk assessment can improve prognostication beyond the disease-associated variables in-
cluded in systems such as the IPSS-R. This article focuses on approaches to assessing and integrating frailty, comorbidities,
and quality of life into the treatment of patients with MDS.

M yelodysplastic syndromes are a group of acquired

hematopoietic stem cell disorders that manifest with
progressive bone marrow failure and have a propensity to
transform into acute myeloid leukemia.1 Although sup-
portive care had long been the standard for management of
MDS,2 there are now several medications widely used for its
treatment and many others under investigation.3 Still, only
about 50% of patients diagnosed with MDS are alive 3 years
after diagnosis, a figure even worse for those who develop
MDS related to prior treatment of cancer.4,5 The majority of
patients with MDS ultimately die of causes related to their
disease, such as infection, progression to acute myeloid
leukemia, and hemorrhage.6
For people living with MDS, the burden of disease can be
highly troublesome. For example, one study estimated the
3-year incidence of anemia, neutropenia, and thrombocy-
topenia to be 81%, 25%, and 41%, respectively, and 3-year
rates of hospitalizations (for infection or bleeding associated
with low blood counts), emergency department visits, and
transfusion to be 62%, 42%, and 45%.7 In addition, health
care costs are high, estimated at $51,066 yearly (2009 US$)
for patients who are transfusion-dependent (even without
accounting for the cost of current drug therapies).8 More-
over, patients with MDS suffer from impairment to their
quality of life (QOL),9 and, because the disease is incurable
except with allogeneic HCT, treatment decisions often focus
on improving QOL.
Determining the optimal treatment strategy is difficult for
patients with MDS due to the advanced age of affected
patients and heterogeneity in disease outcomes.10 Several
scoring systems have been developed to help guide clinical
decision making. These include the 1997 IPSS11 and its 2012
revision, the IPPS-R,12 the World Health Organization (WHO)
Prognostic Scoring System (WPSS),13 and the MD Anderson
Cancer Center MDS Model (MDACC Model).14 These sys-
tems use various combinations of histologic classification,
bone marrow blast percentage, cytogenetics, number and
severity of cytopenias, performance status, age, and red cell
transfusion dependence to assign patients to different risk
categories used by clinicians to tailor treatment approaches.
These include observation alone, supportive care with
transfusions, hypomethylating agents, immunomodulatory
drugs, HCT, and enrollment in clinical trials.
There are two groups of patients for whom current scoring
systems are of limited utility. First, the systems do not help
determine when patients with lower-risk disease at pre-
sentation should start therapy. Second, for patients in the
intermediate-risk categories, it is often unclear whether
treatments tailored to lower-risk or higher-risk patients are
more likely to be useful. Increasingly, molecular genetic

From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; Department of Medical Oncology/Hematology, Odette Cancer and
Sunnybrook Health Sciences Center, Toronto, ON, Canada.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Gregory A. Abel, MD, MPH, Dana-Farber Cancer Institute, 450 Brookline Ave., Dana 1106, Boston, MA 02215; email: gregory_abel@dfci.harvard.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e337

ABEL AND BUCKSTEIN
testing can aid in risk stratification15 beyond the systems
mentioned above, and, in some cases, can identify candi-
dates for specific clinical trials. Although such genomic
advances are promising, this article will address how three
additional concepts not specifically addressed in the risk
models abovefrailty, comorbidity, and QOLcan be for-
mally assessed and potentially help with treatment decisions
for patients with MDS.
FRAILTY
Although many definitions exist, geriatricians largely agree
that frailty is a state of high vulnerability for adverse health
outcomes, including disability, dependency, falls, need for
long-term care, and mortality.16 Frailty is common in older
patients with cancer and has been associated with treatment-
related toxicity, poor response to therapy, and worse overall
survival.17,18 Given the synergistic effects of chemotherapy
and underlying malignancy on the immune and hematopoietic
systems, older patients with blood cancers such as MDS are at
particular risk for the sequelae of frailty. For example, pre-
liminary work in older patients with lymphoma,19 acute myeloid
leukemia,20 myeloma,21 and MDS22 has revealed that markers
of frailty are independent prognostic factors for morbidity and
death in models that included conventional risk factors such
as disease risk group, comorbidity, and performance status.
Importantly, older patients with MDS have been shown to
be less likely to receive active treatment23 and are also less
likely to receive high-quality care such as baseline marrow
cytogenetic testing.24 Although such decisions may be
reasonable for elderly patients who are frail (e.g., a di-
agnostic bone marrow assessment with cytogenetic test-
ing may not be appropriate if a patient is too frail for
treatment), they are not reasonable for the elderly who are
robust. Stated another way, age is an imprecise proxy for
frailty.
A recent study assessed the impact of frailty on survival
in a large cohort of patients with MDS and chronic myelo-
monocytic leukemia (445 patients).25 Frailty was assessed by
clinical judgment and also with a combination of physical
measures such as hand grip strength26 and ability to get out
of a chair 10 times and walk 4 meters.27 Using a schema
KEY POINTS
Frailty is distinct from age, can be measured with
precision, and is associated with survival.
The MDS-specific comorbidity index is a scale that
reliably measures comorbidity for patients with MDS.
Depth of comorbidity can be integrated into decision
making for all levels of disease risk.
Worse quality of life predicts poorer survival in MDS,
even when accounting for disease risk.
MDS-specific quality of life can be measured with
precision, but how to best integrate these data into
clinical decisions remains to be discovered.
e338 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
developed by Rockwood and associates, known as the Clin-
ical Frailty Scale (CFS), patients were assigned scores of 1 to 9.
A score 1 indicates very fit, 4 indicates vulnerable, and 8
indicates very severely frail (Fig. 1). The median age of en-
rolled patients was 73 (similar to the median age that MDS is
diagnosed in the United States),5 and 79% of patients had
IPSS-R scores of intermediate or lower. Frailty was found to
correlate only modestly with Eastern Cooperative Oncology
Group (ECOG) performance status (r = 0.39; p , .0001), less
with comorbidity as assessed by the MDS-specific comor-
bidity index (MDS-CI28; r = 0.33; p , .0001), and minimally
with age-adjusted IPSS-R (r = 0.12; p = .03). Frailty improved
the prognostication of the IPSS-R in all but the highest-risk
group. In a multivariate analysis that included IPSS-R and
comorbidity scores, frailty was independently associated
with survival (hazard ratio [HR] 2.7; 95% CI, 1.74.2).
Moreover, incorporation of frailty improved MDS risk strat-
ification by 30%.
The goal of frailty screening is to estimate a patients
physiological age when considering treatment options and
goals of care. It can also help predict practical outcomes,
such as a tendency toward falls or hospital admission. Frailty
screening is not easily achieved with a self-administered
questionnaire, as cognitive issues may preclude completion,
and several aspects of frailty are best captured through
in-person functional examination. Many frailty assessment
instruments are based on Frieds phenotype model,29 which
assesses physiologic vulnerability: weight loss, poor grip
strength, slow gait speed, low physical activity, and self-
reported exhaustion. An alternative model defines frailty as
the cumulative effect of individual deficits and considers
more than 30 additional factors (e.g., self-reported health,
questions about functioning in the home, and presence of
chronic illnesses), creating a continuous index.30 A cumu-
lative frailty index may have improved discriminatory ability
compared with categorical measures and can incorporate
readily available clinical data.
Given its potential contribution to mortality, we suggest
that frailty be assessed in a rigorous manner for older
patients with MDS. Although the gold standard is com-
prehensive geriatric assessment with a trained geriatri-
cian,31 such an approach is not practical at most MDS
treatment facilities. The above mentioned 9-point CFS is
assessed based on clinical judgment and is highly corre-
lated with the more comprehensive Canadian Study of
Health and Aging Frailty Index (which assesses between
30-100 deficits).32 For those patients with MDS who are
of advanced age, or those who seem to lack physiologic
capacity, we suggest that clinicians consider patients as
fitting within one of three larger categories of the CFS: 1-3
(robust to prefrail), 4 (vulnerable), and 5-8 (frail). Clinicians
can assign a score by reviewing the patients history and
soliciting input directly from patients and caregivers,
asking Which do you think best describes you? and then
reading the descriptions from the most likely categories
(Fig. 1; we do not suggest specifying that this is for a frailty
assessment).

FIGURE 1. The Clinical Frailty Scale
Reproduced with permission from Rockwood et al.32
Routine geriatric screening assessment of newly pre-
senting elderly patients with blood cancers by a trained
nonphysician clinic assistant has been shown to be feasible
and to correlate with the aggressiveness of subsequent
treatment decisions.33 Unfortunately, there are currently no
guidelines regarding the incorporation of frailty assessment
into MDS clinical practice, and consensus recommenda-
tions are needed. For example, elderly, robust patients
with intermediate-risk MDS may be referred for reduced-
intensity conditioning HCT, while vulnerable and frail
patients might be referred for comprehensive geriatrician
management. By addressing activities of daily living, mobility/
fall risk, nutrition, poly-pharmacy, and mood, geriatric con-
sultation has been shown to not only impact oncologic
treatment decisions but also address many other comorbid
issues for older patients with cancer.34 Moreover, in a re-
cent systematic review of 18 publications assessing geriatric
domains for patients with blood cancers, physical capacity,
nutritional status, and comorbidity were found to have in-
dependent predictive value for survival and chemotherapy-
related nonhematological toxicity and often performed better
than age and performance status.35
COMORBIDITY
Patients with MDS are often of advanced age at diagnosis
such that the majority have at least one additional comorbid
condition.24,28 Although frailty is associated with comorbid
burden,36,37 it is felt to be an overlapping but distinct
concept.16 One explanation is that much of the frailty seen in
patients with a syndrome such as MDS may be due to the
FRAILTY, COMORBIDITY, AND QOL IN MDS
disease itself and cannot be attributed to additional
medical diagnoses. Thus, a patient with MDS and with no
comorbid conditionsor several comorbidities that are
well-managedmay still be considered frail due to the
effects of MDS alone (such as advanced anemia and/or
recurrent infections). Indeed, in the study of frailty among
patients with MDS cited above,25 both frailty and Charlson
Comorbidity Index (CCI)38 were independently prognostic
of overall survival in models that accounted for MDS
disease risk.
Analyses of MDS-related administrative data have dem-
onstrated that comorbidities are associated with worse
survival. In one study using registry data linked to Medicare
claims (SEER-Medicare; 1,708 patients), patients with
comorbid conditions had greater risk of death than those
without comorbid conditions. Compared with patients with
a CCI of 0 (no comorbidity), those with a CCI of 1 or 2
(HR 1.19; 95% CI, 1.051.36) and those with a CCI of 3 or
greater (HR 1.77; 95% CI, 1.502.08) had worse overall
survival.39 Another study characterized the impact of
comorbidities on overall survival for patients with MDS
using a clinical database,40 assessing comorbidity with
the Comorbidity Evaluation-27 (ACE-27) scale,41 a measure
originally developed for patients with head and neck
cancer. Among the 600 patients with MDS, 77% had at
least one comorbid condition, and, although there was no
significant association between level of comorbidity and
leukemic transformation, patients with the highest level of
comorbidity had a 50% decrease in survival compared with
those with none, independent of age and IPSS risk group. A
follow-up study with the same cohort stratified by the
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e339
ABEL AND BUCKSTEIN
revised IPSS found similar results.42 In both analyses,
comorbidity significantly impacted the median survival of
patients age 65 or younger but did not impact those older
than age 65.
One of the most important clinical situations in which
to formally assess comorbidity for patients with MDS is
when considering fitness for HCT. Many clinicians use the
HCT-comorbidity index (HCT-CI) for this purpose. The
HCT-CI is a measure developed by Sorror et al43 that has
been shown to have clinical utility specifically for patients
with MDS and acute myeloid leukemia.44 The HCT-CI was
developed to improve on the CCI, as some elements of the
CCIsuch as presence of AIDS, comorbid leukemia, and
comorbid lymphomawere not relevant for many pa-
tients who underwent HCT. The HCT-CI is comprised of
17 groups of disease, each weighted with points from 1 to
3. For example, the presence of diabetes merits 1 point,
and the presence of severe pulmonary disease merits
3 points. The resulting scores on the HCT-CI are: low
(0 points), intermediate (1 to 2 points), and high ($ 3
points).
In a retrospective analysis of patients with MDS from an
Austrian registry that used the HCT-CI (616 patients),45
the highest frequencies of specific comorbidities were
cardiovascular disease (28%), diabetes (12%), and prior
solid tumors (10%). Comorbidities were more frequent in
men and patients older than age 65; moreover, in mul-
tivariable models including age and IPSS, patients in higher
HCT-CI groups had worse overall survival (HR 1.26; 95% CI,
1.11.5). Building on the success of the HCT-CI for MDS
and other blood cancers, Della Porta et al created a
time-dependent, MDS-specific comorbidity index, the
MDS-CI.28
To create the MDS-CI, a learning cohort of 840 Italian
patients with MDS was assigned comorbidities using
HCT-CI definitions. Next, multivariable models were created
to assess risk of nonleukemic death, and each comorbidity
was given a score proportional to the regression coeffi-
cient of the resulting multivariable Cox proportional haz-
ards model. Only five of the 17 HCT-CI variables were
significant: cardiac disease (2 points), moderate to severe
hepatic disease (1 point), severe pulmonary disease
(1 point), renal disease (1 point), and current or prior history
of solid tumor (1 point). Points were added together to
create low risk (0 points), intermediate risk (1 to 2 points), or
high risk (. 2 points) scores. These categories identified
three groups that showed significantly different probabili-
ties of nonleukemic death and survival (p , .002 and
p = .005, respectively), a finding that was also repro-
duced in a validation cohort of German patients with MDS
(504 patients).
In a multivariable analysis including age, sex, WHO cate-
gories, cytogenetics, and transfusion-dependency, the MDS-
CI was an independent predictor of nonleukemic death (HR
1.89; p , .001) and survival (HR 1.67; p , .001).28 In ad-
ditional data sets, the MDS-CI has been shown to add
prognostic information beyond established risk scoring
e340 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
systems.46-49 For example, one study (318 patients) found
the MDS-CI to be more effective than the HCT-CI in prog-
nostication even when accounting for age, but only for
patients with lower-risk disease on the IPSS.46 Another study
(60 patients) found that the MDS-CI was able to identify
patients with improved outcomes after azacitidine,48 and
yet another (363 patients) found that the MDS-CI refined the
risk stratification of the IPSS-R.49
We suggest integrating the MDS-CI or the HCT-CI with
one of the commonly used MDS scoring systems such as the
IPSS-R or WPSS. A schema for practically doing so with the
WPSS is shown in Fig. 2.28 For example, for patients with
lower WPSS who are high risk on the MDS-CI, the focus
should be on preventing or ameliorating anemia, which
might exacerbate comorbid conditions. For patients who
are low risk on the MDS-CIparticularly those lacking
cardiac conditionsmore severe anemia might be toler-
ated. As another example, for patients with higher-risk
WPSS, clinical decisions regarding HCT can be helped with
the HCT-CI. If HCT is not available due to patient prefer-
ence or lack of suitable donor, the MDS-CI may also
help in addressing potential benefits of hypomethylating
agents, although more research is needed to evaluate
how comorbidity scores can predict clinical outcomes and
tolerance after therapy.
QUALITY OF LIFE
Quality of life is defined by the WHO as the net conse-
quence of life characteristics on a persons perception of
their position in life, in the context of the culture and value
systems in which they live, and in relation to their goals,
expectations, standards, and concerns.50,51 The key to
understanding patient-reported outcomes such as QOL is
that they are subjective and dynamic. Given that many
patients with MDS have a chronic illness with a rela-
tively long survival and opportunity for many lived experi-
ences with the disease and its consequence, QOL has been
demonstrated to be impaired for many affected pa-
tients.52,53 In a study of patients age 60 or older with acute
myeloid leukemia or advanced MDS (43 patients), although
initial QOL assessment was not associated with treatment
choice, 97% of patients reported that QOL was more im-
portant to them than length of life.54 Moreover, rigorous
measurement of QOL has been recognized as a priority for
MDS research.55-57
As an example, in one of the large clinical trials of aza-
citidine in MDS, QOL was found to be improved among
patients receiving therapy when assessed with a cancer-
related measure,58 data that undoubtedly helped lead to
regulatory approval of that medication. More recent work
by Efficace et al found that among patients with higher-risk
MDS (280 patients), self-reported fatigue (measured from
the cancer-specific EORTC QLQ-C30) had prognostic value
beyond standard MDS risk classification systems.59 Pa-
tients scoring equal or higher than the median on that
measures fatigue scale (34 or greater out of 100; higher

FIGURE 2. Schematic Representation of the Potential of Combined Use of WPSS and MDS-CI in Clinical Decision
Making in MDS
Reproduced with permission from Della Porta et al.28
scores or seen with more fatigue) had a worse median
overall survival than patients scoring lower than the median
(HR 1.6; p = .0013). In a multivariable analysis, high-risk IPSS
score (HR 2.5 vs. intermediate-2 risk; p = .004) and higher
fatigue score (HR 1.1 for every 10 points; p = .0007) were
both associated with poorer overall survival, a result also
seen when risk stratifying patients with the IPSS-R and the
WPSS.
Studies such as these argue that patient-reported out-
comes should be a paramount consideration when making
treatment decisions for patients with MDS, not only because
they can help determine if patients QOL will potentially
improve (or be harmed) by treatment, but also because they
may have prognostic value. Another question that arises is
whether QOL should be a primary consideration when de-
ciding on potentially curative therapy such as HCT. One
reason it might be a primary consideration is that pre-HCT
QOL likely adds prognostic information. Indeed, recent data
suggest that QOL prior to HCT for blood cancers is associated
with post-HCT mortality, even when controlling for per-
formance status and comorbidity.60,61 Still, another study
demonstrated that among patients with higher-risk MDS age
60 to 75 with good performance status, scores on several
QOL measures were not associated with ultimate receipt of
reduced-intensity allogeneic HCT.62 Given that the best
treatment of HCT-eligible older adults with MDS is not
known, these results suggest that QOL is either not well-
integrated into HCT treatment decisions or not rigorously
assessed.
This may be because most studies assessing QOL in
MDSincluding most of the ones aboveuse general
FRAILTY, COMORBIDITY, AND QOL IN MDS
measures such as the Short-Form Health Survey (SF-36)63
or cancer-specific scales such as the EOTC QLQ-C30
(EORTC-30)64 or the Functional Assessment of Cancer
Therapy-Anemia (FACT-An).65 Although these are useful,
they may not be specific enough to capture all of the
elements important to MDS-related QOL. Indeed, several
important questions about QOL in MDS remain unanswered.
For example, the impact of the erythropoiesis-stimulating
agents on patient-reported outcomes in MDS is still
unknown, with much contradictory data.66 In addition,
despite the existence of many associated studies, it is not
clear whether red cell transfusions improve MDS-related
QOL.67
Moreover, given the many ways that fatigue may affect
patient functioning, it has been shown that physicians
informal QOL assessment may not reveal what patients
actually experience. In a study pairing a total of 280 pa-
tients with higher-risk MDS with 68 physicians, patient-
physician concordance regarding assessments of overall
health on a seven-point scale was found only 28% of the
time (weighted kappa, 0.270).68 With no consistent way of
measuring QOL in MDS clinical studies, and clinicians
imperfect assessments of patients well-being and experi-
ences, an MDS-specific QOL instrument is needed to cap-
ture the experiences of patients with MDS in the modern
treatment era.
The Quality of Life in Myelodysplasia Scale (QUALMS)69
may help address this need. Developed after a series of
focus groups with patient with MDS and providers, and
validated by an international group of MDS researchers
(including the authors of this review),70 the QUALMS is a
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e341
ABEL AND BUCKSTEIN
SIDEBAR 1. Topics Addressed in the QUALMS, an
MDS-Specific Measure of Quality of Life70
Too tired for prior responsibilities
Low energy changes schedule
Feeling weak
Unable to participate in activities
Take into account fatigue when planning
Worry about becoming burden
Felt hopelessness
Change in bowels
Shortness of breath
Changing long-term plans due to health
Trouble concentrating
Life organized around medical appointments
Nauseated
No energy for routine tasks
Family relationships strained
Feeling grateful
Getting quality information
Feel gratitude when prior took for granted
Bruising
Avoiding crowds
Could not do anything about disease
Disease feels unpredictable
Lack of concrete answers
No clear information
Afraid of dying
Difficulty explaining MDS to others
Worry about progressing/leukemia
Anxious about tests or laboratory results
Angry about diagnosis
Worried about infection
Feel limited emotional support available
Worried about bleeding
Concerned about being a financial burden
Concerned about losing job
Too tired to drive
Afraid to have sex due to blood counts
Worried MDS treatment will stop working
Too tired to take care of family
brief (less than 10 minute) questionnaire consisting of
38 items (Sidebar 1). Scored on a scale of 0 to 100 (higher
score is correlated with improved MDS-specific QOL), the
QUALMS recently underwent validation in United States,
Canada, and Italy (255 patients), where patients were
assessed twice with the instrument and several others. The
measure was internally consistent (a = 0.92) and mod-
erately correlated with both the QLQ-C30 and FACT-An
scales. Moreover, patients with hemoglobin levels of
8 g/dL or lower scored lower than those with hemoglobin
higher than 10 g/dL (61.8 vs. 71.1; p , .001), and
transfusion-dependent patients scored lower than
transfusion-independent patients (62.4 vs. 69.7; p , .01).
There was good overall test-retest reliability among pa-
tients with stable hemoglobin (r = 0.81), and significant
changes for patients hospitalized or with infections
e342 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
between administrations (both p , .01). Principal com-
ponents analysis revealed physical burden, benefit-finding,
and emotional burden subscales. Additional validation ef-
forts are ongoing to determine the utility of the mea-
sure and subscales both for clinical trials and for clinical
decision-making.
We suggest that patients with MDS be asked specifically
about their QOLat diagnosis and after treatment has
begunusing a validated general, cancer, or MDS-specific
scale. If QOL is impaired, these data can be used together
with disease-specific risk factors and molecular genetic
studies to help inform treatment decisions. For example,
for patients with MDS who have low-risk-disease and
might otherwise be observed, reduced QOL may sig-
nify the need to start erythropoiesis-stimulating agents,
transfusions, or disease-modifying treatments earlier
than would otherwise be considered. Alternatively, for
patients with higher-risk disease who are being treated
with hypomethylating agents but do not seem to be
responding in terms of counts, formal documentation
of improved QOL may argue in favor of continuing
treatment.
CONCLUSION
Myelodysplastic syndromes are a group of diseases that
shorten life expectancy and negatively impact QOL. The
disease-related factors that predict survival and progres-
sion to acute myeloid leukemia are becoming increasingly
known but remain imprecise when patient-related factors
are excluded. Frailty and comorbidity have been con-
vincingly shown to further refine current clinical prog-
nostic risk scores. These factors are inextricably linked. We
believe a baseline frailty assessment does the best job at
staging the aging in MDS, and should be considered by all
clinicians at diagnosis and before initiating treatment. The
CFS is quick and simple to deploy in clinic. Patients deemed
vulnerable (score = 4) or mildly frail (score = 5) should have
poorly controlled comorbidities addressed, as these may be
contributing to frailty. Frankly frail patients (score = 6 or
higher) should be referred for comprehensive geriatric as-
sessment and management, which includes comorbidity
assessment.
We realize that it is not practical to assess every patient
with MDS formally for frailty and comorbidity, but since a
good medical history and physical examination will solicit
most comorbidity data, given the choice, we would start
with frailty assessment. On the other hand, patients with
MDS who are considered for allogeneic HCT should have
both frailty and comorbidity formally assessed (CFS and
HCT-CI or MDS-CI), regardless of age. Finally, MDS clinicians
must aim to both extend life as well as to improve its
quality. In addition to guiding therapeutic decisions as
discussed above, periodic rigorous assessment of QOL has
been shown to enhance the experiences of patients
with cancer71 and promises to do the same for patients
with MDS.

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 BEYOND HYPOMETHYLATING AGENTS IN MDS

Searching for a Light at the End of the Tunnel? Beyond

Hypomethylating Agents in Myelodysplastic Syndromes
Rami S. Komrokji, MD

OVERVIEW

Hypomethylating agents (HMAs) are the mainstay treatment of patients with myelodysplastic syndromes. Hypomethylating
agents remain the only treatment, other than allogeneic hematopoietic stem cell transplantation (AHSCT), that improves
overall survival (OS) for patients with higher-risk myelodysplastic syndromes. It is crucial to maximize the benefit of HMAs by
selecting the appropriate dosing and schedule and continuing therapy until clear evidence of lack of response or failure of
therapy. Strategies to improve outcome with HMAs include identifying tools and biomarkers for better patient selection,
namely the ability to identify those who achieve complete response (CR) or long duration of response, combination
strategies with HMAs aim to improve response rate or its duration. The outcome of patients with myelodysplastic syndromes
after HMA failure is poor for both patients with higher-risk and lower-risk disease and represents an unmet medical need.
The best outcomes after HMA failure are reported with AHSCT or novel agents in clinical trials. This article discusses the
maximizing benefit of HMAs, offers strategies to improve outcome with HMAs, and, finally, reviews selected novel agents in
development after HMA failure.

M yelodysplastic syndromes are a heterogeneous group

of neoplastic hematopoietic stem cell disorders. The
common features of the disease include (1) clinical pre-
sentation with variant cytopenias and resultant complica-
tions; (2) the presence of dysplastic morphologic cytology
features; (3) evidence of clonal hematopoiesis for the ma-
jority of patients, either by detection of chromosomal ab-
normalities, often copy number variation changes, or by
identification of somatic gene mutations most commonly
involving epigenetic deregulation or splicing machinery; and
(4) a tendency to progress to acute myeloid leukemia
(AML).1-3
The first step in managing myelodysplastic syndromes is
risk stratification after ensuring the proper diagnosis. The
disease staging not only provides the needed prognostic
information for patients and caregivers, but it also allows
physicians to tailor therapy accordingly. The International
Prognostic Scoring System (IPSS) had been the most widely
used tool for risk assessment in myelodysplastic syndromes.
A lump score is based on the percentage of myeloblasts,
cytopenia(s), and karyotype.4 New risk models including the
revised IPSS5 and MD Anderson models6,7 refine the staging
system in myelodysplastic syndromes. The integration of
somatic gene mutations information adds independent
prognostic value to the clinical risk models.8 Patients are
classified as having lower-risk myelodysplastic syndromes,
with expected OS measured in years and the goal of therapy
being alleviation of cytopenia, or higher-risk myelodysplastic
syndromes, with a short expected OS and therapy attempting
to alter the natural history of disease. The treatment options
for myelodysplastic syndromes remain limited. AHSCT is the
only curative option, which is offered to patients with higher-
risk myelodysplastic syndromes.9 The HMAs azacitidine and
decitabine are the only approved drugs for nondeletion 5q
myelodysplastic syndrome.
Epigenetic gene silencing is a well-described mechanism
by which tumor cells downregulate expression of tumor
suppression genes.10 Silencing is often accomplished by
methylation or histone deacylation. Hypomethylating agents
are a class of nucleoside analogs that induce hypomethylation,
allowing re-expression of epigenetically silenced genes. These
agents inhibit DNA methyl transferase by forming direct ad-
ducts after incorporation into DNA, resulting in global hypo-
methylation. Both agents are pyrimidine analogs; however,
decitabine as a deoxy-analog is incorporated solely into DNA,
whereas azacitidine has a ribose sugar structure and is
incorporated into RNA.11,12
This article aims to briefly summarize the current data
using HMAs for treatment of myelodysplastic syndromes,
discuss possible strategies to improve outcome using HMAs,
and focus on options for managing myelodysplastic syn-
dromes after HMA failure.

From the Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL.

Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook.

Corresponding author: Rami S. Komrokji, MD, Department of Malignant Hematology, Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL 33612; email: rami.komrokji@moffitt.org.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e345

RAMI S. KOMROKJI
HOW TO OPTIMIZE CURRENT USE OF
HYPOMETHYLATING AGENTS FOR TREATMENT
OF MYELODYSPLASTIC SYNDROMES
Hypomethylating agents are currently the standard of care
for treating patients with higher-risk myelodysplastic syn-
dromes. Azacitidine demonstrated an improvement in OS
compared with conventional care regimens in a randomized
phase III clinical trial. In the AZA-001 study, the median OS
was significantly prolonged with azacitidine treatment:
24.4 months versus 15 months with conventional care
regimens (p = .0001). The regimen consisted of 75 mg/m2
of azacitidine subcutaneously for 7 days every 28 days.13
For decitabine use in higher-risk myelodysplastic syn-
dromes, a phase III study comparing the U.S. Food and
Drug Administrationapproved decitabine inpatient reg-
imen with best supportive care failed to show an OS
advantage.14 The median OS with the commonly used
20 mg/m2 intravenously for a 5-day regimen every
28 days in higher-risk myelodysplastic syndromes is 19
to 20 months. 15,16
The key points in optimizing HMA use for patients with
higher-risk myelodysplastic syndromes include using a 7-day
azacitidine regimen, assessing initial response after four to
six cycles of therapy, and continuing therapy for patients
with stable disease or better response. The HMA emerged
as an acceptable alternative to intensive chemotherapy
prior to AHSCT.17 The role of HMA maintenance or treat-
ment of post-AHSCT relapse is being explored and could be a
promising strategy.18
Objective clinical responses are seen for only approxi-
mately one-half of the patients treated with HMAs, and the
CR rate is only 10% to 20%.13,15 Even among patients with
initial responses to HMA, the median response duration
is only 9 to 15 months, with the vast majority of patients
losing response within 2 years.
KEY POINTS
Hypomethylating agents are the only drugs that
potentially alter the natural history of myelodysplastic
syndromes and improve overall survival in higher-risk
disease.
Key points in maximizing benefit of HMAs include
using a 7-day regimen in higher-risk myelodysplastic
syndromes and continuing treatment for patients with
stable disease or better response.
Strategies to improve outcome with HMAs include
biomarker-driven patient selection, combination
strategies to improve response rates or duration, and
exploration of alternate doses.
The outcome after HMA failure is poor and represents
an unmet medical need.
The best outcomes after HMA failure are reported
among patients who proceed to allogeneic stem cell
transplantation or enroll in clinical trials studying novel
agents.
e346 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
In lower-risk myelodysplastic syndromes, the goal of HMA
use is to alleviate cytopenia. The 5-day regimen of azaciti-
dine every 28 days emerged as an acceptable regimen for
patients with lower-risk myelodysplastic syndromes. Lyons
et al19 randomly assigned patients with less than 10% my-
eloblasts to treatment with azacitidine at a dose of 75 mg/m2
for 5 days followed by 2 days of rest and then an additional
2 days of treatment (5-2-2), 50 mg/m2 for 5 days followed by
2 days of rest and then another 5 days (5-2-5), or 75 mg/m2
for 5 consecutive days. Among the 151 patients enrolled in
the study, no difference in response was observed among
the three regimens. Grade 3 or 4 hematologic toxicity was
lower among patients treated with the 5-day consecutive
regimen.19
POTENTIAL STRATEGIES TO IMPROVE OUTCOME
WITH HYPOMETHYLATING AGENTS IN
MYELODYSPLASTIC SYNDROMES
Biomarker-Driven Patient Selection
There are no clinical parameters that can clearly predict
response to HMAs. The MDS Clinical Research Consortium
explored the prognostic utility of the IPSS, the IPSS-R, the
MD Anderson Prognostic Scoring System, the World Health
Organizationbased Prognostic Scoring System, and the
French Prognostic Scoring System among 632 patients who
presented with higher-risk myelodysplastic syndromes and
were treated with azanucleosides as the first-line ther-
apy.20 No prognostic tool predicted the probability of
achieving an objective response. Nonetheless, all five tools
were associated with OS. The Groupe-Francophone des
My e lodysplasies (GFM) proposed a prognostic score for
azacitidine-treated patients with higher-risk myelodys-
plastic syndromes. Among 282 patients, the study sug-
gested that prior treatment with low-dose cytarabine
(p = .009), bone marrow blasts greater than 15% (p = .004),
and abnormal karyotype (p = .03) independently predicted
lower response rates. Complex karyotype predicted shorter
responses (p = .0003).21
Detection of certain somatic gene mutations may affect
response to HMAs. The presence of TET-2, DNMT3A, and
IDH-1/IDH-2 gene mutations was reported to be associated
with a higher response to HMAs. Among 213 patients with
myelodysplastic syndromes treated with HMAs, Bejar et al22
reported that clonal TET-2 mutations (allele fraction . 10%)
predicted response (odds ratio, 1.99; p = .036). Response
rates were highest in the subset of patients with a TET-2
mutant without clonal ASXL1 mutations (odds ratio, 3.65;
p = .009). Mutations of TP53 (hazard ration [HR] 2.01;
p = .002) and PTPN11 (HR 3.26; p = .006) were associated
with shorter OS but not drug response.22
Combination Strategies
The goals of this strategy would be to increase the fre-
quency, quality, and duration of clinical responses and ul-
timately delay/prevent the development of resistance and
prolong survival.23
 BEYOND HYPOMETHYLATING AGENTS IN MDS

A promising overall response rate (ORR) of 72% was reported There is unmet need for treating patients with myelo-
in an early phase trial of 36 patients with higher-risk myelo- dysplastic syndromes with TP53 mutation. The outcome for
dysplastic syndromes who received azacitidine at a standard these patients is poor.33,34 The median OS for patients with
dose of 75 mg/m2 per day concurrently with lenalidomide.24 detectable TP53 mutation at the time of AHSCT is less than
The North American Intergroup Study SWOG S1117 un- 1 year.35 Responses to HMAs, although not different, are
fortunately did not confirm those findings. In this phase II often short lived.22 APR-246 covalently binds to cysteines in
study, 277 patients were randomly assigned to azacitidine, mutant TP53 or TP63. The drug reconstitutes wild-type
azacitidine/lenalidomide, or azacitidine plus vorinostat. No conformation and function in mutant proteins by stabilizing
differences in response rate were observed; a tendency of protein folding.36 Preclinical data suggest intrinsic and ad-
longer duration of response (. 6 on therapy) was noted for the ditive in vitro schedule-dependent cytotoxicity with azaci-
azacitidine/lenalidomide arm. Overall response rate for pa- tidine when administered in sequential fashion (unpublished
tients with chronic myelomonocytic leukemia (CMML) was data). The MDS Clinical Research Consortium is launching a
significantly higher for lenalidomide plus azacitidine versus phase I/II study of APR-246 and azacitidine among patients
azacitidine (63% vs. 29%; p = .04), with a trend for longer with higher-risk myelodysplastic syndromes with TP53
response duration for combinations (p = .06).25 mutation. In addition, TP53 mutation is associated with
Histone deacetylase (HDAC) inhibitors are another group overexpression of PD-L1 and CTLA-4, which provides the
of agents that have been combined with azacitidine. As rationale to explore PD-L1 inhibitors and CTLA-4 in-
mentioned, the azacitidine/vorinostat combination did not hibitors in this population (unpublished data).
improve the response rate or OS over azacitidine mono- Other selected current HMA combination clinical trials in
therapy.25 In a randomized phase II trial of 150 patients, myelodysplastic syndromes are summarized in Table 1.
azacitidine/entinostat also did not improve outcomes.26
Finally, a randomized phase II study combining pracinostat
with azacitidine did not improve response rates.27 It is clear Alternative Dosing and Schedules
that concomitant use of HMAs and HDAC inhibitors does not Recent data presented on the 3-day use of azacitidine or
improve responses and an alternative schedule or sequence decitabine in lower-risk myelodysplastic syndromes are
must be pursued if such a combination is to be further encouraging. Among 91 patients with lower-risk myelo-
explored. dysplastic syndromes who were treated with either azaci-
There are ongoing or planned studies for other agents in tidine or decitabine in a 3-day regimen every 28 days, the
combination with HMAs. Vadastuximab talirine (SGN-CD33 ORR was 59%, and 29% of patients became RBC transfusion
A), a conjugated monoclonal antibody with a highly stable independent. Treatment was well tolerated and 1-year OS
linker, is a promising agent. An AML combination with was 86%.37 A randomized clinical trial comparing a 5-day
azacitidine or decitabine was explored in a phase I study in azacitidine regimen, a 3-day azacitidine regimen, or a 3-day
which six of 23 patients achieved CR and nine other patients decitabine is currently ongoing. The study also includes
had complete remission with incomplete count recovery randomly assigning nontransfusion-dependent patients to
(CRi). Seventy-two percent of patients were alive at a me- observation versus treatment.
dian 7.7 months of follow-up. Prolonged myelosuppression
was observed with treatment.28 In subtypes of myelodys- TABLE 1. Selected Hypomethylating Agent
plastic syndromes, PD-L1 expression on myeloblasts has Combination Strategies
been independently associated with myelodysplastic syn-
drome transformation to AML.29 Hypomethylating agents Drug Target Study Identifier
can enhance the expression of CTLA-4, PD-1, and PD-L1 Nivolumab PD-1 NCT02530463
among patients with myelodysplastic syndromes and AML.30
Lirilumab and nivolumab KIR and PD-1 NCT02599649
Ongoing and planned studies are exploring combining PD-L1
Atezolizumab PD-L1 NCT02508870
and PD-1 inhibitors in higher-risk myelodysplastic syn-
Deferasirox (ICL670) NF-kB NCT02038816
dromes. A study examining oral azacitidine combined with
darvalumab is ongoing. Pevonedistat (MLN4924; TAK-924) Eltrombopag TPO NCT02158936
is a first-in-class small molecule inhibitor of the neural Ibrutinib BTK NCT02553941
precursor cell expressed developmentally downregulated PF-04449913 Hedgehog pathway NCT02367456
protein 8activating enzyme.31 Pevonedistat had reported LDE255 Hedgehog pathway NCT02323139
single-agent clinical activity in a phase I study of patients Erismodegib Hedgehog pathway NCT02129101
with relapsed/refractory AML.31 Based on nonclinical Rigosertib PLK-1 NCT01926587
studies in AML models that demonstrated a synergistic le- Volasertib PLK-1 NCT01957644
thality in cell lines and tumor regression in murine xeno-
Sirolimus mTOR NCT01869114
grafts when pevonedistat was combined with azacitidine,
Vosaroxin Topoisomerase II NCT01913951
pevonedistat is being studied in combination with azaciti-
Abbreviations: HMA, hypomethylating agent; KIR, killer-cell immunoglobulin-like
dine in treatment-naive elderly patients with AML and receptor; NF-kB, nuclear factor-kappa B; TPO, thrombopoietin; BTK, Bruton tyrosine
higher-risk myelodysplastic syndromes.32 kinase; PLK, polo-like kinase.

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RAMI S. KOMROKJI
DEFINITION OF HYPOMETHYLATING AGENT
FAILURE AND THE EXPECTED OUTCOME
For higher-risk myelodysplastic syndromes, outcome after
HMA failure is poor.38-40 The median OS ranges from 4 to
6 months. Approximately 20% to 30% of patients progress to
AML. Hypomethylating agent treatment failure can be di-
vided into primary or secondary HMA failure. Primary failure
is defined as lack of initial response in which there is clear
evidence of progressive disease. Stable disease is more
controversial where no definitive increase in myeloblasts is
observed, but on the other hand no hematologic im-
provement is achieved by the International Working Group
(IWG 2006) criteria. In a landmark analysis of the AZA-001
study, patients who achieved hematologic improvement or
better response at 3, 6, and 9 months had better OS while
receiving azacitidine treatment compared with conventional
care regimens. For patients with stable disease, OS was the
same for azacitidine and conventional care regimens.
However, 19% of patients treated with azacitidine who had
stable disease at 3 months achieved hematologic im-
provement or better at 6 months compared with 13% for
patients treated with conventional care regimens. At
9 months, only 14% of patients who had stable disease with
azacitidine at 6 months achieved hematologic improvement
or better, whereas none of the patients who received
conventional care regimens did.41 Among 291 patients
treated with HMA, Nazha et al42 reported that 55% of pa-
tients achieved their best response at 4 to 6 months. Among
patients with stable disease at 4 to 6 months, 29 (20%)
achieved a better response at a later treatment time point.
Younger patients with lower bone marrow blast percentages
and intermediate risk per the IPSS-R were more likely to
achieve a better response after stable disease at 4 to
6 months. Patients with stable disease who subsequently
achieved CR had superior OS compared with patients who
remained with stable disease (28.1 vs. 14.4 months, re-
spectively; p = .04).42
The median OS for primary HMA failure was 5.5 months
in the rigosertib randomized clinical study.43 Second-
ary HMA failure is defined as a clear loss of initial re-
sponse (hematologic improvement or better by IWG 2006
criteria).
Outcome after HMA failure is also reported to be poor for
patients with lower-risk myelodysplastic syndromes. The
MDS Clinical Research Consortium reported median OS of
17 months after HMA failure.44 The definition of treatment
failure in lower-risk myelodysplastic syndromes is strictly
based on hematologic improvement, where there is lack of
hematologic improvement in primary failure, and hemato-
logic response is lost after treatment in secondary failure.
Primary failure should be assessed after at least four to six
cycles, in which treatment can be discontinued if there is no
clear evidence of hematologic improvement. There is
probably no value of achieving stable disease without he-
matologic improvement in lower-risk myelodysplastic syn-
dromes, especially if myeloblasts are not increased.
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Acute myeloid leukemia arising from myelodysplastic
syndrome is also characterized by a particularly poor prog-
nosis, especially if prior HMA has been received.38,45 The
median OS among 74 patients with higher-risk myelodys-
plastic syndromes who developed secondary AML after
azacitidine failure was 34 months with a 1-year survival
probability of only 8%.38 In another report, prior therapy with
HMAs for patients with myelodysplastic syndromes who
progressed to AML was independently associated with in-
ferior response and survival after intensive chemotherapy.45
HOW TO TREAT PATIENTS WITH
MYELODYSPLASTIC SYNDROMES AFTER
HYPOMETHYLATING AGENT FAILURE WHEN
THERE IS NO CLINICAL TRIAL
There are no standard treatment options for patients with
myelodysplastic syndromes after HMA failure. In lower-risk
myelodysplastic syndromes, lenalidomide may be used for
treatment of anemia; however, responses are much lower
when lenalidomide is used as a second-line therapy after
HMA failure rather than as first-line treatment after ery-
throid stimulating agents in nondeletion 5q myelodysplastic
syndrome.46
In higher-risk myelodysplastic syndromes, few studies
have addressed sequential use of HMAs. In a study of 14
patients, Borthakur et al47 reported that 28% responded to
decitabine after azacitidine failure. In another study, 21
patients (19%) responded to decitabine after azacitidine
failure and 10 (40%) responded to azacitidine after deci-
tabine failure.48 Harel et al reported response to decitabine
after azacitidine treatment among 7 of 37 patients (19%).49
Five of those responses were marrow CR or stable disease.49
These studies are limited by their retrospective nature, lack
of standard definition of HMA failure, and inclusion of pa-
tients who were nontolerant to the first agent.
The GFM reported no response to low-dose chemotherapy
after azacitidine failure among 18 evaluable patients. AHSCT
offers the best outcome for patients after HMA failure. An
analysis of 435 patients with higher-risk myelodysplastic
syndromes for whom azacitidine failed demonstrated that
participants who were offered an AHSCT or investigational
agents had better survival compared with those offered
supportive care or conventional chemotherapy, whether
low or intensive dose. The median OS after best supportive
care, low-dose chemotherapy, intensive-dose chemother-
apy, investigational therapy, or AHSCT was 4.1, 7.3, 8.9, 13.2,
and 19.5 months, respectively.38
NOVEL AGENTS FOR TREATMENT OF
MYELODYSPLASTIC SYNDROMES AFTER
HYPOMETHYLATING AGENT FAILURE
A comprehensive review of all novel agents tested after HMA
failure is beyond the scope of this review. The following are
selected examples of current agents in development.
 BEYOND HYPOMETHYLATING AGENTS IN MDS

Oral Azacitidine Among patients with HMA failure, 40% CRi/partial response
50
An oral formulation of azacitidine has been evaluated in was reported.57,58 In another study among patients with
three clinical studies to date. Results from a pilot study AML receiving tosedostat in combination with low-dose
indicated that azacitidine in an oral formulation was bio- cytarabine, a CR rate of 48.5% was reported for 16 of 33
available.51 This was confirmed when evaluating several patients; 33% of patients were still in remission after a
different formulations of the drug in a phase I study. Results median follow-up of 506 days.
from another phase I study of CC-486 among patients with Analysis of these patients cells identified a molecular
myelodysplastic syndrome, CMML, or AML indicated that signature associated with clinical response (clinical re-
administration on different treatment schedules (7 , 14 , and sponse vs. no clinical response). Results suggested that
21 days once a day and 14 and 21 days twice a day) was differentially expressed genes were associated with clinical
feasible and generally well tolerated and exhibited biologic response, including among biologically relevant pathways
and clinical activity.52 Responses for patients previously such as beta-catenin, tumor necrosis factor-alpha, nuclear
treated with subcutaneous/intravenous azacitidine were re- factor-kappa B, erythroblastosis oncogene B (ERB2), in-
ported. Oral azacitidine alone or in combination with a PD-L1 flammatory response, and epithelial-mesenchymal transi-
inhibitor is being tested for patients with HMA stable disease tion pathways.59
or after failure.
Thrombopoietin Stimulants
SGI-110 Thrombocytopenia treatment is challenging in myelodys-
SGI-110 is a dinucleotide of decitabine and deoxyguanosine plastic syndromes. Severe thrombocytopenia is more
that protects it from deamination. In a phase I study that commonly encountered in higher-risk myelodysplastic
included 14 patients with myelodysplastic syndromes after syndromes.60 Hypomethylating agents are currently the only
HMA failure, SGI-110 had a 4.5-fold longer half-life than available therapy. Romiplostim is an Fc-fusion dipeptide
decitabine. An equivalent or higher area under the curve was ligand of the thrombopoietin receptor. In a double-blind,
reached with lower Cmax compared with reference levels placebo-controlled study, 167 and 83 patients with low-
from intravenous decitabine (20 mg/m2). A dose-dependent or intermediate-risk myelodysplastic syndromes and
increase in demethylation was observed up to 60 mg/m2 thrombocytopenia were treated with 750 mg of romiplostim
daily for 5 days.53 In the phase II part of the study for per week or placebo, respectively. Results showed a sig-
treatment-naive elderly patients with AML or refractory/ nificant decrease in clinically relevant bleeding events for
relapsed AML, 43% and 16% remission rates were reported, romiplostim-treated patients with a baseline platelet count
respectively.54 of 20 to 50 3 109 cells/L (relative risk 0.35; p , .0001). In
addition, romiplostim produced a significant decrease in
Rigosertib platelet transfusion events versus placebo for patients with a
Rigosertib is a novel small molecule that targets pathways baseline platelet count of less than 20 3 109 cells/L (relative
including phosphoinositide-3 kinase and polo-like kinase. risk 0.71; p , .0001). Originally there was a concern about
Initial studies with both oral and intravenous rigosertib
indicated clinical activity in myelodysplastic syndromes and TABLE 2. Novel Agents in Myelodysplastic Syndromes
AML.55,56 Results from ONTIME, a phase III randomized After HMA Failure
clinical study comparing intravenous rigosertib with best
supportive care after HMA failure, were recently reported. Drug Target Study Identifier
ONTIME enrolled 299 patients and rigosertib was admin- Durvalumab PD-L1 NCT02281084
istered as 1,800 mg/24 hours for 72 hours as a continuous Atezolizumab PD-L1 NCT02508870
intravenous ambulatory infusion. The median OS was
Ipilimumab CTLA-4 NCT01757639
8.2 months for patients who received rigosertib compared
Nivolumab PD-1 NCT02530463
with 5.9 months for best supportive care (p = .33). For
patients with primary HMA failure, the median OS was Lirilumab and KIR and PD-1 NCT02599649
Nivolumab
8.6 months with rigosertib compared with 5.3 months for
FT-1101 BET NCT02543879
best supportive care (p = .04).43 Further studies are being
Omacetaxine NCT02159872
conducted specifically for patients with higher-risk disease
and primary HMA failure. Rigosertib in combination with CPI-613 Ketoglutarate dehydrogenase NCT01520805
azacitidine is being explored. TEN-010 Bromodomain NCT02308761
Selinexor Selective nuclear export NCT02228525

Tosedostat ASTX727 Oralcytidinedeaminaseinhibitor NCT02103478

E7727 with oral decitabine
Tosedostat is an aminopeptidase inhibitor that leads to
Vosaroxin Topoisomerase II NCT01980056
cellular amino acid deprivation. In a phase I study with 44
Abbreviations: MDS, myelodysplastic syndrome; HMA, hypomethylating agent; KIR,
participants, the maximum tolerated dose was reached at killer-cell immunoglobulin-like receptor; BET, bromodomain and extra-terminal family
180 mg with hepatic toxicity as the dose-limiting toxicity. of proteins.

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RAMI S. KOMROKJI
increased risk of AML transformation; however, this was not
confirmed on longer follow-up.61 Results of a multicenter,
randomized, double-blind, placebo-controlled phase II study
of romiplostim with azacitidine have been reported.62 Pa-
tients with IPSS low-risk and intermediate-risk myelodys-
plastic syndromes were randomly assigned to receive the
following in addition to azacitidine treatment: 500 mg of
romiplostim per week, 750 mg of romiplostim per week, or
placebo. The incidence of clinically relevant thrombocyto-
penic events for patients receiving 500 mg of romiplostim,
750 mg of romiplostim, or placebo was 62%, 71%, and 85%,
respectively. The rate of platelet transfusions was 46%, 36%,
and 69%, respectively.
The second approved thrombopoietin receptor agonist is
eltrombopag, an orally bioavailable agent that binds at a site
distinct from romiplostim.63 Preliminary results from a
phase II randomized study of eltrombopag versus placebo
for 70 patients with lower-risk myelodysplastic syndromes
were reported at the 2015 American Society of Hematology
Annual Meeting. Among 41 evaluable patients treated with
eltrombopag, 21 responded at week 8; nine of these patients
achieved CR (platelets . 100 3 109 cells/L). Twenty-four
patients completed 24 weeks of eltrombopag treatment at
the time of data reporting, in which 13 patients were still
responders (eight achieved CR).64
A phase I study of heavily treated patients with higher-risk
disease who were resistant to HMAs noted a transition to
transfusion independence for 30% of patients receiving
eltrombopag, with a median duration of response of
3.3 months. In higher-risk myelodysplastic syndromes,
concerns about increased myeloblasts, leukocytosis, and
bone marrow fibrosis were raised, particularly in CMML.65
H3B-8800
Splicing mutations are frequent among patients with
myelodysplastic syndromes. The splicing machinery muta-
tions occur in an exclusive manner and in a heterozygous
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27. Garcia-Manero G, Berdeja JG, Komrokji RS, et al. A randomized,
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47. Borthakur G, Ahdab SE, Ravandi F, et al. Activity of decitabine in patients
with myelodysplastic syndrome previously treated with azacitidine.
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Leuk Res. 2015;39:501-504.
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51. Garcia-Manero G, Stoltz ML, Ward MR, et al. A pilot pharmacokinetic
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extended dosing schedules of CC-486 (oral azacitidine) in patients with
lower-risk myelodysplastic syndromes. Leukemia. Epub 2015 Oct 7.
53. Kantarjian HM, Roboz GJ, Rizzieri DA, et al. Results from the dose
escalation phase of a randomized phase 1-2 first-in-human (FIH) study
of SGI-110, a novel low volume stable subcutaneous (SQ) second
generation hypomethylating agent (HMA) in patients with relapsed/
refractory MDS and AML. Blood. 2012;120 (abstr 414).
54. Jabbour E, Yee K, Kropf P, et al. First clinical results of a randomized
phase 2 study of SGI-110, a novel subcutaneous (SQ) hypomethylating
agent (HMA), in adult patients with acute myeloid leukemia (AML).
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55. Raza A, Greenberg PL, Olnes MJ, et al. Final phase I/II results of rig-
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57. Cortes JE, Feldman EJ, Yee K, et al. Results of the OPAL study: a phase II
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58. Lowenberg B, Morgan G, Ossenkoppele GJ, et al. Phase I/II clinical
study of tosedostat, an inhibitor of aminopeptidases, in patients with
acute myeloid leukemia and myelodysplasia. J Clin Oncol. 2010;28:
4333-4338.
59. Visani G, Loscocco F, Fuligni F, et al. Tosedostat plus low dose cytarabine
induces a high rate of responses that can be predicted by genetic
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thrombocytopenia in myelodysplastic syndromes. Cancer. 2007;109:
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patients (Pts) with low or intermediate-1 (int-1) risk myelodysplastic
syndrome (MDS): follow-up AML and survival results of a randomized,
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421).
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older adults with untreated AML. Blood. 2014;123:3239-3246.
HEMATOLOGIC MALIGNANCIESLYMPHOMA
AND CHRONIC LYMPHOCYTIC LEUKEMIA

Current Management Concepts:

Primary Central Nervous System
Lymphoma, Natural Killer T-Cell
Lymphoma Nasal Type,
Post-transplant
Lymphoproliferative Disorder

CHAIR
Thomas M. Habermann, MD
Mayo Clinic
Rochester, MN

SPEAKERS
Soon Thye Lim, MD
National Cancer Centre Singapore
Sinagpore

Tracy T. Batchelor, MD, MPH

Massachusetts General Hospital
Boston, MA
BATCHELOR, THYE, AND HABERMANN

Current Management Concepts: Primary Central Nervous

System Lymphoma, Natural Killer T-Cell Lymphoma Nasal
Type, and Post-transplant Lymphoproliferative Disorder
Tracy T. Batchelor, MD, MPH, Lim Soon Thye, MD, and Thomas M. Habermann, MD

OVERVIEW

Primary central nervous system lymphoma, natural killer T-cell lymphoma nasal type, and post-transplant lymphoproli-
ferative disorder are uncommon and complex lymphoproliferative disorders. These disorders present with different risk
factors, have complex tumor characteristics, and require unique therapeutic interventions. These diseases require a
multidisciplinary complex team approach. This article will update current management approaches and concepts.

P rimary central nervous system lymphoma (PCNSL) is

an extranodal non-Hodgkin lymphoma confined to
the brain, leptomeninges, eyes, or spinal cord. Natural
molecular mechanisms underlying transformation and lo-
calization to the CNS are poorly understood.4

killer (NK)/T-cell lymphoma disorders, more prevalent in
Asian countries and parts of Latin America, are categorized as
extranodal NK T-cell lymphoma nasal type and as aggressive
NK-cell leukemia. Post-transplant lymphoproliferative disorder
is applied to a group of lymphoproliferative disorders arising in
a pharmacologically immunocompromised host after solid
organ or allogeneic stem cell transplantation. In this article,
we will update discuss current management approaches
and concepts for these diseases.
PRIMARY CENTRAL NERVOUS SYSTEM
LYMPHOMA
Epidemiology
Primary central nervous system lymphoma accounts for
approximately 2% of all primary central nervous system
(CNS) tumors, with median age 65 at diagnosis.1,2 Since
2000, there has been an increase in the overall incidence of
PCNSL, especially in elderly individuals.
Pathology
Approximately 90% of PCNSL cases are diffuse large B-cell
lymphomas (DLBCLs), with the remainder consisting of T-cell
lymphomas, poorly characterized low-grade lymphomas,
or Burkitt lymphomas.3 More than 90% of primary CNS
DLBCL cases consist of the activated B-celllike subtype. The
Diagnosis and Prognostic Factors
Neurocognitive symptoms are the most common presenting
clinical features of PCNSL. The International PCNSL Collab-
orative Group has developed guidelines to determine extent
of disease.5 A gadolinium-enhanced brain MRI scan is the
most sensitive radiographic study for the detection of PCNSL
(Fig. 1). Most patients with PCNSL present with a single brain
mass. The diagnosis of PCNSL is typically established by a
stereotactic brain biopsy, cerebrospinal fluid (CSF) analysis,
or analysis of vitreous aspirate from patients with ocular
involvement. Given the possible delay in diagnosis and
treatment with the latter two methods, prompt stereotactic
biopsy is advised in almost all cases that are surgically ac-
cessible. Secondary CSF and ocular involvement occurs
among approximately 15%20% and 5%20% of patients
with PCNSL, respectively. Presenting symptoms of ocular
involvement include eye pain, blurred vision, and floaters.6
B symptoms such as weight loss, fevers, and night sweats are
infrequent in PCNSL. A thorough diagnostic evaluation is
needed to establish the extent of the lymphoma and to
confirm localization to the CNS. A lumbar puncture should
be performed if not contraindicated, and CSF should be
assessed by flow cytometry, cytology, and immunoglobulin
heavy chain gene rearrangement. Because extraneural
disease must be excluded to establish a diagnosis of pri-
mary CNS lymphoma, CT/PET scans of the chest, abdomen,

From the Division of Hematology/Oncology, Departments of Neurology and Radiation Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston,
MA; Department of Medical Oncology, National Cancer Centre, Duke-National University of Singapore Medical School, Singapore; Division of Hematology, Department of Medicine,
Mayo Clinic, Rochester, MN.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Thomas M. Habermann, MD, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905;
email: habermann.thomas@mayo.edu.

2016 by American Society of Clinical Oncology.

e354 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


FIGURE 1. MRIs From a Patient With Primary Central Nervous System Lymphoma
A T1-weighted, postcontrast, sequence (left) demonstrates homogenous enhancement of the tumor in the region of the left caudate nucleus. A T2/fluid-attenuated inversion
recovery sequence (right) demonstrates a hyperintense signal surrounding the tumor, reflecting vasogenic cerebral edema.
Courtesy of Priscilla Brastianos, MD.
and pelvis and a bone marrow biopsy and aspirate analysis
should be performed to exclude occult systemic disease.
Involvement of the optic nerve, retina, or vitreous humor
should be excluded with a comprehensive eye evaluation by
an ophthalmologist that includes a slit-lamp examination.
Blood tests should include serum lactate dehydrogenase
(LDH) and HIV serology.5
Two prognostic scoring systems have been developed
specifically for PCNSL.7,8 In a retrospective review of 105
patients with PCNSL, the International Extranodal Lym-
phoma Study Group identified the following as independent
predictors of poor prognosis: age older than 60, Eastern
KEY POINTS
The prognostic scoring systems in PCNSL, ENKL nasal
type, and PTLD are different than standard non-Hodgkin
lymphomas.
The most effective treatment in PCNSL is high-dose
methotrexate in combination with other agents, but
standardized induction and consolidation regimens
have yet to be defined.
ENKL is an Epstein-Barr virusrelated disorder. The
incorporation of radiation therapy with chemotherapy
is crucial.
Advanced ENKL should be treated with L-asparaginase
regimens.
Immunosuppression reduction and rituximab are key
management approaches in the initial approach to
PTLD.
POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
Cooperative Oncology Group performance status greater
than 1, elevated serum LDH level, elevated CSF protein
concentration, and involvement of deep regions of the brain.
For patients with zero to one factor, two to three factors, and
four to five factors, the 2-year survival proportions were
80%, 48%, and 15%, respectively. In another prognostic
model, patients with PCNSL were divided into three groups
based on age and performance status: (1) age younger than
50, (2) age 50 and older with a Karnofsky performance score
(KPS) of 70 or greater, and (3) age 50 and older with a KPS less
than 70. Based on these three divisions, significant differ-
ences in overall survival (OS) and failure-free survival were
observed (p = .0001).
Treatment
Defining response to treatment in PCNSL requires assess-
ment of all sites involved by the disease. The International
PCNSL Collaborative Group has established response criteria
that have been adopted into most prospective clinical trials
(Table 1).5
Corticosteroids decrease tumor-associated edema and
may result in partial radiographic regression of tumors. An
initial response to corticosteroids is associated with a fa-
vorable outcome in PCNSL.9 However, after they have an
initial response to corticosteroids, almost all patients quickly
experience relapse. Corticosteroids should be avoided prior
to a biopsy if possible, given the risk of disrupting cellular
morphology, which can result in a nondiagnostic pathologic
specimen.
Surgical resection is not part of the standard treatment
approach for PCNSL, given the multifocal nature of this
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e355
BATCHELOR, THYE, AND HABERMANN
TABLE 1. International PCNSL Collaborative Group Consensus Guidelines for the Assessment of Response in
Primary Central Nervous System Lymphoma5
Response Brain Imaging
Complete Response No contrast-enhancing disease
Unconfirmed Complete No contrast-enhancing disease
Response
Minimal enhancing disease
Partial Response 50% decrease in enhancement
No contrast-enhancing disease
Progressive Disease 25% increase in enhancing disease
Any new site of disease
Stable Disease All scenarios not covered by responses
above
Abbreviations: PCNSL, primary central nervous system lymphoma; NA, not applicable; RPE, retinal pigment epithelium; CSF, cerebral spinal fluid.
tumor and potential long-term morbidities.10 The role of
neurosurgery in PCNSL is to establish a diagnosis via ste-
reotactic biopsy.
Standardized induction and consolidation treatment of
PCNSL has yet to be defined. Historically, PCNSL was treated
only with whole-brain radiotherapy (WBRT) at doses ranging
from 36 to 45 Gy, which resulted in a high proportion of
radiographic responses but early relapse. In a multicenter
phase II trial, 41 patients were treated with WBRT to 40 Gy
plus a 20-Gy tumor boost and achieved a median OS of only
12 months.11 Given the lack of durable responses to radiation
and the risk of neurotoxicity associated with this therapeutic
modality, WBRT alone is no longer a recommended initial
treatment for most patients with PCNSL.
The most effective treatment of PCNSL is high-dose
methotrexate (HD-MTX) administered intravenously at
variable doses (18 g/m2), typically used in combination with
other chemotherapeutic agents and/or WBRT. However,
there is no consensus on the optimal dose of HD-MTX or on
the role of radiation in combination with methotrexate in
the management of PCNSL. A number of randomized trials
are ongoing to address these issues. Methotrexate doses of
3 g/m2 or greater result in therapeutic concentrations in
the brain parenchyma and CSF and lead to more durable
treatment responses when combined with WBRT.12-14 In a
phase II trial, 79 patients with PCNSL were randomly assigned
to receive either HD-MTX (3.5 g/m2, day 1) or HD-MTX
(3.5 g/m2, day 1) plus cytarabine (2 g/m2 twice a day, days
23). Each chemotherapy cycle was 21 days. All patients
underwent consolidative WBRT after induction chemo-
therapy. The HD-MTX plus cytarabine arm had a higher
proportion of complete radiographic responses and a su-
perior 3-year OS.14 However, it is now widely recognized
that there is a high incidence of neurotoxicity with com-
bined modality treatment that includes WBRT.15 The latter
observation prompted studies utilizing lower doses of
WBRT. In a multicenter phase II study, no significant
neurocognitive decline was observed after consolidative
reduced-dose WBRT (23.4 Gy) and cytarabine were
e356 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Steroid
Dose Ophthalmologic Examination CSF Cytology
None Normal Negative
Any Normal Negative
Any Minor RPE abnormality Negative
NA Normal or minor RPE abnormality Negative
NA Decrease in vitreous cells or retinal Persistent or
infiltrate suspicious
NA Recurrent or new disease Recurrent or positive
administered to patients who had achieved a complete re-
sponse (CR) to induction chemotherapy including HD-MTX.16
However, longer neuropsychologic follow-up of these pa-
tients is necessary to definitively assess the safety of this
regimen because numerous studies have demonstrated the
delayed neurotoxic effects of WBRT in the PCNSL population
and the reduced risk of neurotoxicity in regimens consisting
of chemotherapy alone.17,18 Given the risk of clinical neu-
rotoxicity, other studies have assessed whether WBRT can be
eliminated from the initial management of PCNSL. In a
multicenter phase III trial, patients were randomly assigned
to receive HD-MTXbased chemotherapy with or without
WBRT.19 The trial enrolled 551 patients; of these, 318 were
treated per protocol. Intent-to-treat analysis revealed that
patients treated in the combined modality arm (chemo-
therapy plus WBRT) achieved prolonged progression-free
survival (PFS) but had no improvement in OS, demonstrat-
ing that the elimination of WBRT from the treatment regimen
did not compromise OS. This has led to deferral of WBRT and
chemotherapy-alone approaches for patients with newly
diagnosed PCNSL. These approaches are based on a foun-
dation of HD-MTX. Variable doses and schedules of HD-MTX
have been used, but in general, a dose of 3 g/m2 or greater
delivered as an initial bolus followed by an infusion over
3 hours administered every 1021 days is recommended.20
Multiple phase II studies have reported on the safety, ef-
ficacy, and relatively preserved cognition of HD-MTXbased
chemotherapy regimens.21,22 Moreover, a longer duration
of induction chemotherapy with HD-MTX (more than six
cycles) results in higher CR proportions.16,21
Several first-generation chemotherapy regimens for
PCNSL included intrathecal chemotherapy. However, in non-
randomized studies that included intrathecal chemotherapy,
there was no improvement in outcomes versus regimens that
did not include intrathecal injections of chemotherapy.23,24
Rituximab is being incorporated in combination regimens
for PCNSL. When rituximab is administered intravenously at
doses of 375800 mg/m2, CSF levels from 0.1% to 4.4% of
serum levels are achieved. Despite limited CSF penetration,

radiographic responses have been observed for patients with
relapsed PCNSL treated with rituximab monotherapy.25 In a
cooperative group phase II study, 44 patients with PCNSL were
treated with induction chemotherapy consisting of 8 g/m2 of
HD-MTX (day 1), 375 mg/m2 of rituximab (day 3), and 150 mg/m2
of temozolomide (days 711), all drugs with demonstrated
efficacy as monotherapy in PCNSL.22 This induction chemo-
therapy was followed by consolidation chemotherapy con-
sisting of 5 mg/kg of intravenous etoposide as a continuous
infusion over 96 hours and 2 g/m2 of cytarabine every 12 hours
for 8 doses. Sixty-six percent of these patients achieved CR, the
median PFS of the entire group was 2.4 years, and the esti-
mated 4-year OS was 65%. These results are comparable to
regimens that include WBRT.
Given the limited durability of responses observed in many
studies of PCNSL, there is increasing interest in high-dose
chemotherapy (HDT) followed by autologous stem cell
transplantation (ASCT) as first-line consolidative therapy
for PCNSL. Conditioning regimens including thiotepa have
demonstrated the most encouraging results. In a multi-
center phase II study, 79 patients were treated with in-
duction HD-MTX, cytarabine, rituximab, and thiotepa, followed
by carmustine and thiotepa conditioning prior to ASCT. The
overall response rate (ORR) was 91%, 2-year OS was 87%, and
treatment-related deaths occurred among less than 10% of
enrolled patients. The toxicities, mostly cytopenias, were
manageable.26 There are three ongoing multicenter ran-
domized trials comparing the efficacy of consolidative
HDT/ASCT versus chemotherapy or WBRT for newly diagnosed
PCNSL (Table 2).
EXTRANODAL NATURAL KILLER/T-CELL
LYMPHOMA NASAL TYPE
Natural killer/T-cell lymphoma is more prevalent in Asian
countries and parts of Latin America.27 The World Health Or-
ganization (WHO) classification categorized these disorders as
extranodal NK/T-cell lymphoma nasal type (ENKL) and as ag-
gressive NK-cell leukemia.27,28 Histologically and phenotypically,
they are similar. The neoplastic cells are surface CD32 but
cytoplasmic CD3e+, CD56+, and cytotoxic molecule (granzyme B,
TIA1, and perforin) positive. Epstein-Barr virusencoded RNA
(EBER) in situ hybridization (ISH) is invariably positive.
Clinical Presentation, Diagnosis, and Staging
ENKL commonly involves the nasal cavity and upper aero-
digestive tract.28 Rarely, patients may present with non-
nasal lesions in the skin, gastrointestinal tract, and/or
testis. In such cases, it is important to exclude occult na-
sal involvement using either more sensitive radiologic
modalities such as PET/CT or nasal panendoscopy.27,29,30
This distinction is important because it affects staging and
treatment.
The minimum diagnostic criteria for ENKL include ap-
propriate histopathologic features, surface CD32, cyto-
plasmic CD3e+, CD56+, and EBER+.27,28 If CD56 is negative,
both cytotoxic molecules and EBER should be positive.
POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
A PET/CT scan is the preferred imaging modality.29-31 Bone
marrow biopsy is recommended, and EBER-ISH should be
considered to detect occult marrow involvement.32,33 Quan-
titative measurement of Epstein-Barr virus (EBV) DNA in cell-
free plasma, which has been shown to correlate with tumor
load and adverse outcomes, is recommended.34,35
Prognostic Factors
Several prognostic models for ENKL based on pretreatment
characteristics have been developed, including the In-
ternational Prognostic Index (IPI) and the Korean Prognostic
Index.36-39 Nonetheless, these models were based on data
from patients treated with cyclophosphamide, doxorubicin,
vincristine, and prednisolone (CHOP) or CHOP-like regimens.
Because prognostic factors are dependent on the efficacy
of the regimen used, they may not be applicable to pa-
tients who are increasingly treated with nonanthracycline-
containing regimens. Recently, combined evaluation of the
post-treatment Deauville score on a PET/CT scan as well as
EBV DNA was shown to be very effective in predicting risk of
treatment failure and may be more relevant.40
Management of Localized Nasal NK/T-Cell Lymphoma
Radiotherapy is a crucial treatment modality in localized ENKL,
and a dose in excess of 50 Gy is recommended.41 This requires
careful planning to cover the entire nasal cavity and involved
areas.42,43 Radiotherapy alone is insufficient to achieve high
cure rates, owing to both local and systemic relapses.44,45
However, results from early studies incorporating standard
CHOP and dose-intensified CHOP were disappointing.46,47
This high failure rate is attributed to the expression of the
multidrug resistance (MDR) gene in NK cells, a feature that is
recapitulated in neoplastic NK cells.
Subsequent approaches incorporated non-MDRrelated
agents and etoposide with radiotherapy (Table 3).48-52
However, the optimal sequence of chemotherapy and ra-
diotherapy remains to be determined.
In a phase II study of 27 patients with localized ENKL,
concurrent radiotherapy alone (50 Gy) with three cycles of
2/3 dexamethasone, etoposide, ifosfamide, and carboplatin
(DeVIC) resulted in an ORR of 81% and a CR rate of 77%.53
With a median follow-up of 67 months, the updated 5-year OS
and PFS were 73% and 67%, respectively.52 Acute toxicities
associated with this regimen were generally mild. In another
phase II study, 30 patients received concurrent radiotherapy
with cisplatin followed by three cycles of etoposide, ifosfa-
mide, cisplatin, and dexamethasone (VIPD).50 The CR and ORR
at best response were 80% and 83.3%, whereas the estimated
3-year PFS and OS were 85.2% and 86.3%, respectively. Acute
toxicities during concurrent chemotherapy were mild, but
62% of patients developed grade 3/4 febrile neutropenia
during VIPD therapy. A recent study of concurrent cisplatin
with radiotherapy followed by gemcitabine, dexamethasone,
and cisplatin (GDP) chemotherapy reported comparable
treatment outcomes and less toxicity.49
Because arranging timely radiotherapy may be challeng-
ing, sandwich protocols were explored.48,51 In one study,
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BATCHELOR, THYE, AND HABERMANN

26 patients received two cycles of L-asparaginase, vincris-
tine, and prednisone (LVP) followed by radiotherapy (56 Gy)
and two to four additional cycles of LVP.48 The ORR and CR
rate after initial chemotherapy were 92% and 88.5%, re-
spectively. The corresponding ORR and CR after completion
of radiotherapy and subsequent chemotherapy were 92%
and 88.5%, respectively. The reported 2-year OS and PFS
were 88.5% and 80.6%. Frontline use of sandwich gemci-
tabine, oxaliplatin, and L-asparaginase (GELOX) with radio-
therapy yielded similar ORR and CR rates of 96.3% and
74.1%.51 At present, the most active regimen for patients
with advanced ENKL is the steroid, methotrexate, ifosfamide,
54,55
L-asparaginase, and etoposide (SMILE) regimen. The ORR
and CR rates for patients with untreated NK/T-cell lymphoma
after two to three cycles of therapy were 81% and 60%,
respectively.54 The high induction response rate observed
suggests that SMILE with sandwich radiotherapy may be an
attractive approach but requires confirmation in a pro-
spective clinical trial.
A risk-adapted approach to the treatment of patients with
localized ENKL was proposed.56 Patients were classified as
low or high risk using five independent prognostic factors:
age older than 60, Eastern Cooperative Oncology Group
performance status of 2 or more, stage II disease, elevated
LDH level, and presence of primary tumor invasion. For high-
risk patients (defined as the presence of one or more adverse
factors), radiotherapy followed by chemotherapy was found
to be the most optimal sequence because it was associated
with the best OS.56 For low-risk patients (defined as no
adverse factors), radiotherapy alone achieved favorable
long-term survival.56 Neither induction nor consolidation
chemotherapy was beneficial. Although these results are in-
triguing, the conclusions are limited by the fact that more than
80% of the patients were treated with anthracycline-based
regimens, and these findings may not be applicable to patients
treated with contemporary regimens.
In summary, patients with localized ENKL should re-
ceive combination chemotherapy and radiotherapy. Both

TABLE 2. Randomized Trials in Primary Central Nervous System Lymphoma

Completed Trials
Trial Type Phase No. of Patients (Age) Description
Medical Research Council39 Induction II 53 Stopped early; CHOP vs. WBRT followed by CHOP
IELSG 20 (NCT00210314)14 Induction II 79 (1875) Induction arm 1: methotrexate 1 cytarabine 0 WBRT
Induction arm 2: methotrexate 0 WBRT
ANOCEF-GOELAMS Induction II 95 ($ 60) Arm 1: methotrexate, procarbazine, vincristine, cytarabine
(NCT00503594)31
Arm 2: methotrexate, temozolomide
G-PCNSL-SG-1 (NCT00153530)19 Consolidation III 551 ($ 18) Arm 1: methotrexate 6 ifosfamide 0 WBRT
Arm 2: methotrexate 6 ifosfamide

Ongoing Trials
Trial Type Phase No. of Patients (Age) Description
IESLG 32 (NCT01011920) Induction II 200 (1870) Induction arm 1: methotrexate, cytarabine
Induction arm 2: methotrexate, cytarabine, rituximab
Induction arm 3: methotrexate, cytarabine, rituximab,
thiotepa
ALLG/HOVON (EudraCT 2009- Induction III 200 (1870) Arm 1: methotrexate, BCNU, teniposide, prednisone 0
014722-42) cytarabine, WBRT
Arm 2: methotrexate, BCNU, teniposide, prednisone 0
cytarabine, WBRT
IESLG 32 (NCT01011920) Consolidation II 104 (1870) Consolidation arm 1: WBRT
Consolidation arm 2: HDT/ASCT
ANOCEF-GOELAMS (NCT00863460) Consolidation II 100 (1860) R-MBVP 0
Consolidation arm 1: HDT/ASCT
Consolidation arm 2: WBRT
RTOG 1114 (NCT01399372) Consolidation II 84 ($ 18) Methotrexate, procarbazine, vincristine, rituximab 0
Consolidation arm 1: WBRT (lower dose) 0 cytarabine
Consolidation arm 2: cytarabine
Alliance 51101 (NCT01511562) Consolidation II 160 (1875) Methotrexate, temozolomide, rituximab, cytarabine 0
Consolidation arm 1: HDT/ASCT
Consolidation arm 2: etoposide, cytarabine
Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone; WBRT, whole-brain radiotherapy; BCNU, bis-chloroethylnitrosourea; HDT/ASCT, high-dose
chemotherapy and autologous stem cell transplantation.

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TABLE 3. Combined Chemotherapy and Radiotherapy for Localized ENKL
Combination Therapy
Concurrent RT (50 Gy) with 2/3 DeVIC alone
30 mg/m2 of concurrent weekly intravenous cisplatin for 35 weeks with Sierra del Rio et al24
RT (4052.8 Gy) followed by 3 cycles of VIPD
30 mg/m2 of concurrent cisplatin weekly for 35 weeks with IMRT (56 Gy)
followed by 3 cycles of GDP
2 cycles of LVP RT (56 Gy) 24 cycles LVP
2 cycles of GELOX RT (56 Gy) 24 cycles GELOX
Abbreviations: ENKL, extranodal natural killer/T-cell lymphoma, nasal type; RT, radiotherapy; DeVIC, dexamethasone, etoposide, ifosfamide, and carboplatin; VIPD, etoposide,
ifosfamide, cisplatin, and dexamethasone; IMRT, intensive modulated radiotherapy; GDP, gemcitabine, dexamethasone, and cisplatin; LVP, L-asparaginase, vincristine, and
prednisolone; GELOX, gemcitabine, L-asparaginase, and oxaliplatin; ORR, overall response rate; CR, complete remission; PFS, progression-free survival; OS, overall survival.
concurrent chemoradiotherapy and sandwiched radiother-
apy approaches are appropriate (Table 4). Chemotherapy
regimens should incorporate non-MDRrelated agents and
etoposide. In comprehensive cancer centers where admin-
istering concurrent chemoradiation is feasible, radiotherapy
concurrent with 2/3 DeVIC is an attractive option based on its
robust clinical evidence and toxicity profile. There is a trend to
adopt sandwich radiotherapy or sequential approaches with
L-asparaginasebased regimens, which may be logistically less
complex to administer.
Management of Newly Diagnosed Advanced ENKL
Based on earlier studies57-59 that demonstrated the ef-
ficacy of L-asparaginase, a phase II trial involving the
SMILE regimen (Table 2)55 was initiated among 38 pa-
tients with newly diagnosed or relapsed/refractory dis-
ease. The primary endpoint of the study was ORR after
two courses of SMILE. The ORR and CR rates after 2 cycles
of SMILE were 79% and 45%, respectively. Interestingly,
there were no differences in response rates between
patients with untreated disease or those with a first re-
lapse. With a median follow-up of 24 months, the 1-year
OS rate was 45%. Of the 28 patients who completed
at least two courses of SMILE treatment, four received
further autologous hematopoietic stem cell transplantation
(HSCT), 17 received allogeneic HSCT, and seven received
chemotherapy alone. Although the 1-year OS and PFS of pa-
tients who received autologous HSCT seemed better compared
with those who received allogeneic HSCT or chemotherapy
alone, the differences were not statistically significant. Of note,
the regimen was associated with significant toxicities, with
grade 4 neutropenia occurring among 92% of patients.
Outside the context of a clinical trial, the efficacy and
safety of the SMILE regimen was studied in 87 patients
with either untreated or relapsed/refractory disease.54 The
median number of courses of SMILE administered was
three (range, 06). The ORR and CR rates were 81% and 66%,
respectively. Of note, the estimated 5-year OS for newly
diagnosed patients was similar to the 5-year OS for patients
with relapsed/refractory disease (47.3% vs. 52.3%, p = .17).
POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
No. of
Reference Patients ORR, % CR, % Survival Outcomes
Rubenstein et al and 27 81 77 5-year PFS, 67%; 5-year
Khan et al22,23 OS, 73%
30 83.3 80 3-year PFS, 85.2%; 3-year
OS, 86.3%
Batchelor et al25 32 90.6 84.4 3-year PFS, 84.4%; 3-year
OS, 87.5%
Illerhaus et al26 26 92.0 88.5 2-year PFS, 80.6%; 2-year
OS, 88.5%
Kwong et al27 27 96.3 74.1 2-year PFS, 86%; 2-year
OS, 86%
Intriguingly, among the patients with relapsed/refractory
disease who attained CR after induction SMILE chemo-
therapy, eight patients (28%) who went on to receive
consolidation HSCT remained in remission compared with
12 (41%) who received only chemotherapy. Consistent with
the SMILE regimen, the hematologic toxicities encountered
were significant, and care is required in its administration.
One recent study reported that the combination of gem-
citabine, oxaliplatin, L-asparagine, and dexamethasone may
yield similar efficacious results with fewer toxicities.60
Although consolidation treatment with autologous or allo-
genic HSCT for patients with advanced ENKL after induction
chemotherapy is feasible, its role remains contentious.61-63
Recent data suggest that the results of autologous HSCT are
comparable or inferior to L-asparaginasecontaining regi-
mens.54,64 The Asian Lymphoma Study Group examined the
outcome of allogeneic HSCT among 18 patients, 14 of whom
received SMILE prior to transplantation.65 With a median
follow-up of 20.5 months, 5-year OS and event-free survival
were 57% and 51%, respectively, comparable to the results
observed with SMILE.54 Four patients (22%) died of treatment-
related infective complications. Interestingly, the survival rates
of patients with CR1 and CR2 were similar, implying that al-
logeneic HSCT may not be necessary for a significant pro-
portion of patients achieving CR1 with L-asparaginase therapy.
Taken together, patients with newly diagnosed advanced
ENKL should be treated with L-asparaginasebased regimens
such as SMILE (Fig. 2). The role of consolidation autologous or
allogenic HSCT for patients attaining complete remission re-
mains debatable and best administered in the context of a
clinical trial.
Management of Relapsed/Refractory NK/T-Cell
Lymphoma
Patients who experience relapse after receiving L-asparaginase
based therapy are particularly difficult to treat. Gemcitabine-
containing regimens may be potentially effective.66 Several agents
are now approved for use in peripheral T-cell lymphoma
not otherwise specified, including romidepsin, pralatrexate,
and brentuximab vedotin.67-69 Their roles in ENKL remain to
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BATCHELOR, THYE, AND HABERMANN

TABLE 4. Selected Chemotherapy Regimens for ENKL can identify patients who are at risk for treatment failure.40
Future studies should examine the best consolidation ap-
Drug Regimen proaches in this group of patients. Finally, recent molecular
VIPD (repeat every Days 13: 100 mg/m2 of intravenous etoposide studies have identified aberrations involving the JAK/STAT
21 days)24 cascade and histone modificationrelated genes that may
Days 13: 1,200 mg/m2 of intravenous
ifosfamide offer opportunities for targeted therapy in future.71,72
Days 13: 33 mg/m2 of intravenous cisplatin
Days 13: 40 mg of intravenous or oral
dexamethasone POST-TRANSPLANT LYMPHOPROLIFERATIVE
GDP (repeat every Day 1 and 8: 1,000 mg/m2 of intravenous DISORDERS
21 days)25 gemcitabine The term post-transplant lymphoproliferative disorder (PTLD)
Days 14: 40 mg of oral dexamethasone is applied to a group of lymphoproliferative disorders arising
Day 1: 75 mg/m2 of cisplatin in a pharmacologically immunocompromised host after solid
LVP (repeat every Days 15: 6,000 IU/m2 of intravenous organ or allogeneic stem cell transplantation.73 PTLD is re-
21 days)26 L-asparaginase lated to EBV, but the number of EBV cases has increased from
Day 1: 1.4 mg/m2 of intravenous vincristine 10% (1990 to 1995) to 48% (2008 to 2013).74 Lymphoma after
Days 15: 100 mg of oral prednisolone solid organ transplantation represents about 21% of all
GELOX (repeat every Day 1 and 8: 1,000 mg/m2 of intravenous malignancies, whereas lymphoma represents 5% of all ma-
21 days)27 gemcitabine lignancies among the normal population. The biology, di-
Day 1: 130 mg/m2 of intravenous oxaliplatin agnosis, and management of this heterogeneous group of
Days 17: 6,000 U/m2 of intravenous disorders is different from other lymphoproliferative disor-
L-asparaginase ders. There are many variables in PTLD presentation, including
SMILE (repeat every Day 1: 2 g/m2 of intravenous methotrexate EBV serostatus prior to organ transplantation in the donor and
21 days)28,29 the recipient, histology, location of disease, stage of disease,
Days 24: 40 mg of oral dexamethasone (days
14) types and doses of immunosuppression agents in the course
Days 24: 15 mg 3 4 of intravenous or oral of the transplant, initial management strategies (surgery,
leucovorin immunosuppression reduction strategies), types of treat-
Days 24: 1,500 mg/m2 of intravenous ment (rituximab monotherapy or chemotherapy), presentation
ifosfamide from the time of transplantation, locations of extranodal dis-
Days 24: 100 mg/m2 of intravenous etoposide ease, comorbid conditions (other vital organ involvement),
Days 8, 10, 12, 14, 16, 18, and 20: 6,000 U/m2 of performance score, and active infections (cytomegalovirus,
intravenous L-asparaginase
fungal, etc.). International consensus development meetings
GOLD (repeat every Days 1: 1,000 mg/m2 of gemcitabine held in 1997 and 1998 addressed PTLD in working groups and
14 days)34
Day 1: 100 mg/m2 of intravenous oxaliplatin recommended management guidelines that set the stage for
Days 15: 10,000 U/m2 of intravenous future directions.75
L-asparaginase

Days 14: 20 mg of intravenous or oral dexa-
methasone twice a day
Abbreviations: ENKL, extranodal natural killer/T-cell lymphoma nasal type; VIPD,
etoposide, ifosfamide, cisplatin, and dexamethasone; LVP, L-asparaginase, vincristine,
and prednisone; GELOX, gemcitabine, oxaliplatin, and L-asparaginase; SMILE, steroid,
methotrexate, ifosfamide, L-asparaginase, and etoposide; GOLD, emcitabine,
oxaliplatin, L-aspariginase, and dexamethasone.
be determined, and caution is required when used outside the
context of a clinical trial. In one pilot study, romidepsin increased
the risk of EBV reactivation in patients with ENKL.70 Allogeneic
transplantation for patients achieving CR2 may be potentially
curable, but its role has not been confirmed in prospective trials.
An individual patient-based decision approach is suggested.
Future Directions
Current management strategies are summarized (Table 4).
Significant progress has been achieved over the years with the
adoption of combined modality approaches and intensified
L-asparaginasebased therapy. However, disease progression
remains a risk. Recent data showed that the post-treatment
Deauville score on a PET/CT scan and the presence of EBV DNA
Risk Factors for the Development of PTLD
PTLD has been highly associated with immunosuppression,
which creates a state of impaired T-cell immunity and EBV
infection. EBV has been implicated in 48%93% of all cases of
PTLD. Early PTLD occurs in the first 612 months, and late
PTLD occurs after 12 months. ISH studies on paraffin section
tissues determine EBV status. Late PTLD is associated with
negative EBV status and has an inferior prognosis.
The spectrum of PTLDs in the WHO classification include
early-type PTLD lesions (reactive plasmacytic hyperplasia
that is infectious mononucleosislike), polymorphic PTLD,
monomorphic PTLD (DLBCL, Burkitt lymphoma, plasmablastic
lymphoma, T-cell lymphomas, and composite lymphomas),
and Hodgkin lymphoma. Immunochemotherapy approaches
are histology dependent.76 There may be histologic overlap,
and there may be progressive transition from early PTLD
through polymorphic PTLD to monomorphic PTLD.
The Risk Factors for Surviving PTLD
The risk factors for surviving PTLD have been reported by
different groups. Leblond et al reported that a performance

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FIGURE 2. Management of Newly Diagnosed Natural Killer/T-Cell Lymphoma
score of 2 or more, number of extranodal sites (one vs. more
than one), primary CNS location, T-cell origin, monoclonality,
EBV-negative status, and treatment with chemotherapy
were poor prognostic factors for 61 patients.77 Ghobrial et al
reported on 107 patients in a multivariate analysis and
identified monomorphic disease, graft organ involvement,
and a performance score of 3 to 4 as adverse; patients with a
score of 0 to 1 versus 2 to 3 had superior outcomes (hazard
ratio 5.31; p , .0001).78 CNS involvement, bone marrow
involvement, and hypoalbuminemia were predictive of a
negative outcome among 81 patients.79 The PTLD prog-
nostic index was predictive of outcome. In a series of 70
patients from the PTLD-1 trial, an IPI score less than 3, lung
transplant, and response to rituximab were the strongest
predictors of outcome.80 The PTLD-2 trial and organ-
specific studies will define risk groups based on response
to rituximab monotherapy, IPI score, and the type of organ
transplanted.81,82
Management
The treatment of PTLD is complex and may include multiple
approaches.
Local therapy. A minority of patients with very limited
disease might be treated with surgical extirpation of lo-
calized radiation and minor immunosuppression reduction.
Emergent or palliative local radiation therapy has been
reported.
POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
Immunosuppression reduction. The hallmark of the initial
management of PTLD has been to reduce immunosup-
pression with a goal of restoring EBV-specific cellular im-
munity without inducing graft rejection. The initial
consideration for all patients should be a reduction in im-
munosuppression, irrespective of EBV status. Regression of
monoclonal and polyclonal lymphoproliferative disorders
after reduction of the doses of immunosuppressive agents
has been reported to be 20%85%.83 The approaches to
immunosuppression reduction have been empirical, pro-
spective clinical trials have not been reported, and approaches
are dependent on the organ transplanted. Consensus guide-
lines recommended the following and have evolved.75 For
critically ill patients with excessive disease, prednisone should
be decreased to 7.510 mg/day and all other immunosup-
pressive agents should be discontinued. If there is no re-
sponse (objective reduction in tumor mass within a period of
1020 days), then further interventions must be considered. In
less critically ill patients (the majority of patients), the initial
management strategy should include reduction of cyclospor-
ine, tacrolimus, prednisone, and related immunosuppressive
agents by at least 50%, and azathioprine or mycophenolate
mofetil should be discontinued. After a 14-day trial of de-
creased immunosuppression, a further decrease can be con-
sidered. This is one of the few examples in lymphoproliferative
disorders that patients are restaged with scans in such a short
period of time. Serial biopsies or other forms of graft organ
function monitoring are performed during this time period of
immunosuppression reduction to allow early detection of
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BATCHELOR, THYE, AND HABERMANN
allograft rejection. This is especially important in the rejection
of vital organs such as the heart, liver, and lung, which may
carry a risk of death. Clinical improvement occurs within
1.54 weeks. EBV-negative disease is less responsive to im-
munosuppression reduction, but successful outcomes have
been reported. In a series of 42 patients treated with
immunosuppression reduction alone or in conjunction with
surgical excision, the complete remission rate was 74%.84
The response rate was 89% if no risk factors were present
(elevated LDH, organ dysfunction, or multiorgan disease),
which is in contrast with two to three risk factors and a 0%
response rate. The long-term remission rates in two series
were 20% and 25%.78,84
Rituximab. Rituximab after reduction in immunosuppres-
sion is the standard of care for most CD20+ PTLD subtypes,
including polymorphic and monomorphic DLBCL disease.
The ORRs to rituximab therapy, in conjunction with opti-
mization of immunosuppression agents, are 44%75%, with
CR rates of 35%69%.85-88 The variable response rates relate
to whether the PTLD was early of late, the presence of EBV in
the tissue, LDH level, the type of organ transplanted, his-
tology, other comorbid conditions, retrospective versus pro-
spective reports, and duration of follow-up. There are no
randomized clinical trials comparing rituximab with other in-
terventions. Monotherapy trials have reported a median OS
of 2.4 years. An international phase II trial, PTLD-1, enrolled
152 patients to evaluate rituximab consolidation among patients
who had a CR after rituximab consolidation introducing risk-
stratified sequential treatment to PTLD management in a third
amendment to the trial. Patients were treated with 375 mg/m2
of intravenous rituximab on days 1, 8, 15, and 22. After restaging,
patients in CR were treated with 3-weekly courses of rituximab
monotherapy. The 70 patients who were treated with rituximab
followed by cyclophosphamide, adriamycin, vincristine, and
prednisone (CHOP-21) served as the control population. Of
148 patients, 37 (25%) achieved a CR with four cycles of rit-
uximab and went on to rituximab consolidation.89 The median
time to progression (TTP) was significantly longer than in the
corresponding group in the PTLD-1 trial (37 patients vs. 14
patients; p , .05). The addition of four doses of rituximab was a
predictor of OS, TTP, and PFS. Rituximab consolidation among
early rituximab responders resulted in significantly better
disease control and fewer toxicities compared with CHOP
consolidation. The PD-1 trial provides information to tailor
treatment.90
Immunochemotherapy in DLBCL PTLD. The response rates
to systemic chemotherapy during the 1980s were reported to
be less than 20%. This has changed over time. The PTLD-1 trial
demonstrated the efficacy and safety of 375 mg/m2 of rit-
uximab weekly for four doses followed by four cycles of CHOP-
21 with a median OS of 6.6 years.91 This study underwent three
amendments, and the protocol was amended. All patients
were initially treated with 375 mg/m2 of rituximab on days 1, 8,
15, and 22. Patients who were not in a complete remis-
sion were subsequently treated with rituximab and CHOP
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combination therapy (R-CHOP-21) with granulocyte-colony
stimulating factor for four cycles. There were 111 patients
who received R-CHOP consolidation, with an ORR of 85% (78 of
92) and a CR rate of 60% (55 of 92). The 3-year TTP was 73% in
the PTLD-1 trial among patients who were refractory to rit-
uximab induction. The treatment-related mortality was 7%.91
Chemotherapy. Immunosuppression reduction should be
considered, but, in late PTLD, doses are low. Indications for
initial treatment with chemotherapy include specific histolo-
gies, such as peripheral T-cell lymphoma not otherwise
specified, Hodgkin lymphoma, late PTLD, and other uncommon
lymphomas. These lymphomas must be treated with the
standard-of-care approaches for these specific histologies.
Stem cell transplantation. Patients who have failed other
approaches have been in long-term remission with autol-
ogous or allogeneic stem cell transplantation.92
Cellular immunotherapy. The transfer of selected or un-
selected EBV-specific cytotoxic T cells to patients with
EBV-positive PTLD to restore EBV-specific cellular immunity
as prevention or treatment has been under investigation. Of
114 patients who received infusions of EBV-specific cyto-
toxic T lymphocytes, none of 101 patients who received
prophylaxis developed PTLD, and 11 of 13 patients with
biopsy-proven or probable PTLD achieved a sustained
CR.93-95
Unique PTLD Scenarios
Burkitt lymphoma PTLD is rare and may be MYC negative, but it
is associated with 11q- gain/loss abnormality.95,96 In a retro-
spective review, 25 of 26 evaluable patients had a proven MYC
rearrangement. Intensive therapy was associated with toxicity-
related deaths in three of five patients.96 The German Study
Group on PTLD reported that four of five patients reached a
complete remission, and the authors concluded that sequential
immunochemotherapy was safe and effective.97
Primary CNS PTLD represents a distinct clinicopatho-
logic entity that occurs in 7%15% of patients with PTLD.
An international collaboration reported on 84 patients
treated over a 14-year period between 1997 and 2010.98
This entity is more commonly a late PTLD with median
time of solid organ transplantation to PTLD of 54 months;
94% of patients had EBV-positive disease the histology
was monomorphic for 83% (DLBCL in 66), and 79% had
received renal transplants. In addition, 37% of patients
had multifocal disease, and deep brain involvement was
seen in 33% of patients. Immunosuppression was decreased
in 93% of patients. Additional first-line treatment consisted
of HD-MTX (48%), high-dose cytarabine (33%) alone or in
combination with 20% receiving after methotrexate, brain
radiation (24%), and/or rituximab with 10% rituximab
alone. Methotrexate and rituximab was the most common
regimen administered to 12 patients (10%). The ORR was
60%. The median PFS was 8 months and median OS was
17 months. At a median follow-up of 43 months, the 3-year

FIGURE 3. Proposed Initial Management of PTLD
PFS and OS were 32% and 43%, respectively. In a multi-
variate analysis, lack of response to first-line therapy
(p = .0005) and increased LDH were associated with an
inferior OS (p = .02). The treatment-related mortality was
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54. Kwong YL, Kim WS, Lim ST, et al. SMILE for natural killer/T-cell lym-
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55. Yamaguchi M, Kwong YL, Kim WS, et al. Phase II study of SMILE
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HEMATOLOGIC MALIGNANCIESLYMPHOMA
AND CHRONIC LYMPHOCYTIC LEUKEMIA

PET-Directed Strategies in
Lymphoma

CHAIR
John A. Radford, MD
Christie Hospital NHS Foundation Trust
Manchester, United Kingdom

SPEAKERS
Franco Cavalli, MD
Oncology Institute of Southern Switzerland
Bellinzona, Switzerland

Ranjana H. Advani, MD
Stanford University School of Medicine
Stanford, CA
CAVALLI, CERIANI, AND ZUCCA

Functional Imaging Using 18-Fluorodeoxyglucose PET in the

Management of Primary Mediastinal Large B-Cell Lymphoma:
The Contributions of the International Extranodal Lymphoma
Study Group
Franco Cavalli, MD, Luca Ceriani, MD, and Emanuele Zucca, MD

OVERVIEW

Primary mediastinal large B-cell lymphoma (PMLBCL) is recognized as a distinct disease entity. Treatment outcomes appear better
than in other diffuse large B-cell lymphoma (DLBCL) types, partly because of their earlier stage at presentation and the younger
age of most patients. If initial treatment fails, however, the results of salvage chemotherapy and myeloablative treatment are
poor. The need to avoid relapses after initial therapy has led to controversy over the extent of front-line therapy, particularly
whether consolidation radiotherapy to the mediastinum is always required and whether the 18-fluorodeoxyglucose (18F-FDG)
uptake detected by PET-CT scan can be used to determine its requirements. Functional imaging using PET-CT generally allows
distinguishing of residual mediastinal masses containing active lymphoma from those with only sclerotic material remaining. The
International Extranodal Lymphoma Study Group (IELSG) conducted the prospective IELSG-26 study, which showed that a five-
point visual scale can be used to define metabolic response after immunochemotherapy and that a cut point based on liver uptake
discriminates effectively between high or low risk of failure, with 5-year progression-free survival (PFS) of 99% versus 68% and 5-
year overall survival (OS) of 100% versus 83%. This study also showed that a baseline quantitative PET parameter, namely the total
lesion glycolysis describing the metabolic tumor burden, can be a powerful predictor of PMLBCL outcomes and warrants further
validation as a biomarker. The ongoing IELSG-37 randomized study addresses the need for consolidation mediastinal radiotherapy
in patients in whom a complete metabolic response (CMR) can be seen on PET scans after standard immunochemotherapy.

P rimary mediastinal large B-cell lymphoma is recognized

by the World Health Organizations classification of
hematopoietic and lymphoid tissue tumors as a distinct
entity on clinicopathologic1,2 and molecular3-5 criteria. It
accounts for less than 5% of non-Hodgkin lymphomas and
comprises approximately 5%10% of the DLBCL.1,2,6 Patients
with PMLBCL tend to be younger than the other DLBCL cases
with a median age at diagnosis in the third to fourth decade
and a female preponderance.2,7 This lymphoma is clinically
characterized by a rapidly progressive anterior mediastinal
mass, often with local invasion and compressive syndromes,
and by recurrence at unusual sites, such as the liver, kidneys,
and central nervous system.6
BIOLOGIC PECULIARITIES OF PMLBCL
Primary mediastinal large B-cell lymphoma is considered to
typically arise from a small population of B cells within the
thymus and, thymic components such as Hassall corpuscles
may be identified in the pathology specimen.2
Cell of Origin and Immunophenotype
Immunohistochemical characterization and molecular studies
strongly suggest that PMLBCL is of germinal center or post-
germinal center origin.2,5 Phenotypic analysis shows positivity
for CD45, CD79a, CD22, CD19, and CD20, with negativity for
CD3, CD10, CD21, and class I/II major histocompatibility
antigens. Expression of surface immunoglobulins is lost
despite the presence of isotype-switched immunoglobulin
genes.1,8,9 CD30 staining is observed in most cases but is
weaker and less homogeneous than in Hodgkin lymphoma
or anaplastic large cell lymphoma1,5; BCL2 and BCL6 proteins
are often expressed.1
Molecular Genetics
Primary mediastinal large B-cell lymphoma is characterized
by peculiar genetic features that make this entity closer to
classic Hodgkin lymphoma than to DLBCL.3-5,10 The main
characteristics are represented by deregulated immune
checkpoint and JAK/STAT signaling, via DNA gains and

From the Oncology Institute of Southern Switzerland, Lymphoma UnitOspedale San Giovanni, Bellinzona, Switzerland.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Franco Cavalli, MD, Ospedale Regionale Bellinzona e Valli, Bellinzona, CH-6500, Switzerland; email: franco.cavalli@eoc.ch.

2016 by American Society of Clinical Oncology.

e368 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


amplifications at 9p, affecting PDL2 and JAK2, and recurrent
somatic mutations of the STAT6 and SOCS1 genes.1,5,9,11-15
There are also recurrent point mutations of the XPO1 gene,
coding for the Exportin-1 cargo protein that mediates the
nuclear export of multiple tumor suppressor proteins, in-
cluding p53. Although their biologic significance is still under
investigation, XPO1 mutations appear to be of potential
clinical relevance in terms of outcome prediction and dif-
ferential diagnosis with classic Hodgkin lymphoma and gray-
zone lymphomas.16,17
CURRENT CLINICAL CONTROVERSIES
The outcome of therapy for patients with PMLBCL is gen-
erally better than for those with other DLBCL types, possibly
also as a result of the younger age of the patients and earlier
stage at presentation. In untreated PMLBCL, the response
to combination chemotherapy is very good and is commonly
followed by consolidation involved-field radiotherapy (IFRT).
After the addition of rituximab to doxorubicin, cyclophos-
phamide, vincristine, and prednisone (CHOP) or CHOP-like
regimens, the reported PFS and OS rates at 3 years are
approximately 75%80% and 85%90%, respectively.18,19
However, there is a subset of patients in whom early re-
fractory disease develops, often during the initial courses of
treatment, with a high failure rate2,7: in the case this initial
treatment fails, the results of salvage chemotherapy and
myeloablative treatment are often very poor.20 The need to
maximize cure rates with initial therapy has led to contro-
versy over the utility of consolidation radiotherapy to the
mediastinum. The optimal chemotherapy regimen also re-
mains controversial.
The outcomes reported in the prerituximab era by several
European groups have suggested that third-generation
regimens (e.g., MACOP-B or VACOP-B) may be superior to
the CHOP regimen.21-25 Improved PFS and OS with more
aggressive chemotherapy regimens compared with CHOP-
like regimens were confirmed by a large European survey
conducted by the IELSG.26 This multinational retrospective
study (IELSG-9) compared the outcomes of patients with
KEY POINTS
PMLBCL is a distinct clinicopathologic and biologic type
of large-cell lymphoma.
Survival is usually excellent with intensive front-line
immunochemotherapy regimens, but the few patients
in whom it fails have a particularly dismal outcome.
18
F-FDG PET-CT is a very important staging tool for
patients with PMLBCL.
The metabolic activity on PET scans is a powerful
predictor of PMLBCL outcome.
An ongoing randomized study is addressing the need of
consolidation mediastinal radiotherapy in patients who
have shown a complete metabolic response on PET
scans.
ROLE OF PET IN THE MANAGEMENT OF PMLBCL
PMLBCL after first-generation (standard CHOP or CHOP-like
regimens), third-generation (dose-intensive/alternating reg-
imens such as MACOP-B, VACOP-B, ProMACE, CytaBOM), and
high-dose chemotherapy strategies with autologous stem cell
transplant, frequently including adjuvant radiation therapy. A
total of 426 previously untreated patients with confirmed
diagnosis were enrolled by 20 institutions. Projected 10-year
PFS rates were 35%, 67%, and 78%, after first generation, third
generation, and high-dose chemotherapy strategies, re-
spectively (p , .001). Projected 10-year OS rates were 44%,
71%, and 77%, respectively (p , .001), after median follow-
ups from diagnosis of 52.3 months, 54.9 months, and
35.8 months, respectively. Very similar results were reported
by other retrospective studies from Italy27 and North
America.18,28,29
In the last decade, the inclusion of rituximab as part of
initial therapy for CD20+ B-cell lymphomas has clearly im-
proved response rates and OS in several DLBCL randomized
trials.30,31 Although direct comparison between different
nonrandomized clinical studies with or without rituximab
is problematic, the rituximab regimen of CHOP (R-CHOP)
is likely to have also improved the outcome in PMLBCL.
Indeed, in a Canadian retrospective study, the addition of
rituximab to CHOP chemotherapy resulted in the same 5-year
OS obtained with more intensive regimens of MACOP-B/
VACOP-B.18 In the subgroup analysis of the MINT interna-
tional randomized trial, the subgroup of patients with PMLBCL
treated with rituximab plus chemotherapy (CHOP in most
cases) showed a significantly better 3-year PFS than did pa-
tients treated with chemotherapy alone (87.7% vs. 64.1%;
p = .005).32 Conversely, in a phase II Italian trial on MACOP-B/
VACOP-B plus rituximab followed by mediastinal IFRT, the PFS
improvement was not significant compared with historical
controls.33
Overall, the combination of immunochemotherapy plus
IFRT results in a 3-year PFS rate of 80%85%.32-34 Recent
guidelines35 recommended chemotherapy with a CHOP/
MACOP-Blike regimen plus rituximab, followed by medi-
astinal IFRT as standard front-line treatment of PMLBCL.
However, the role of adjuvant mediastinal irradiation in
patients who achieve CMR with chemotherapy remains
unclear. Retrospective series suggest that the best outcomes
are seen when consolidation radiotherapy is given to the
mediastinum,26,27 particularly in the large proportion of
patients with a residual mediastinal mass at completion of
chemotherapy.36,37 Indeed, before rituximab introduction,
the use of consolidation radiotherapy for PMLBCL was a
historical standard of care, based on poor results after CHOP
chemotherapy alone compared with the excellent results in
series where almost all patients underwent irradiation.2,7
This combined modality strategy was also preferred by many
to maximize cures at the first attempt because of the dismal
outcomes for patients in whom recurrent disease develops.7
However, concerns about long-term effects of mediastinal
radiotherapy, including coronary heart disease, valvular
disorders, heart failure, and risk of second tumors (mainly
cancers of the breast, lung, and thyroid), justify studies
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CAVALLI, CERIANI, AND ZUCCA

aiming to investigate scenarios where radiotherapy may be FIGURE 1. IELSG-37 Study Design
omitted.38-40 Because modern radiotherapy techniques may
minimize the morbidity to other tissues and/or reduce the
risk of long-term side effects,41-43 but do not completely
address the risks of late effects, safety remains a central
issue.44,45 For this reason, in a patient group dominated by
young women, some investigators have elected to exclude
consolidation radiotherapy. In a phase II study at the Na-
tional Cancer Institute, the use of dose-adjusted REPOCH
combined with rituximab seemed to allow omission of ra-
diotherapy without compromising cure rates (the event-free
survival rate was 93%, and the OS rate was 97%),46 and in the
BC Cancer Agency, the decision to spare radiotherapy in
patients with a negative 18F-FDG PET-CT at the completion of
R-CHOP, reduced the use of radiotherapy in patients from
80% to 38%, apparently with good outcomes.47 Unfortunately,
to date there are no published randomized trials in which this
question has been definitely answered.

THE IELSG-37 RANDOMIZED TRIAL

The ongoing IELSG-37 (NCT01599559) study was designed to
address the issue of the role of irradiation in the current
rituximab era offering randomization to standard radio-
therapy versus no further treatment for patients who were
found on PET scan to be tumor free at the end of initial
rituximab-chemotherapy treatment. The study design is
summarized in Fig. 1.
This is the first study on a large international basis that
aimed to define in a prospective, controlled way the role of
radiotherapy in first-line treatment of these patients. This
very ambitious study, to which more than 500 patients will
be enrolled (more than half of them have been enrolled so
far), aims at personalizing treatment and, it is hoped, will
determine whether radiotherapy can be safely spared in
patients achieving CMR indicated on PET scans after in-
duction immunochemotherapy. The use of PET in this trial is
based on the result achieved by the IELSG-26 study, which
will be described in the following section.
THE ROLE OF FUNCTIONAL IMAGING:
CONTRIBUTIONS FROM THE IELSG-26 STUDY
PET-CT is currently considered the best imaging tool for
staging and response assessment in 18F-FDGavid lympho-
mas,48 as defined by the recommendations of the Lugano
Classification for initial evaluation, staging, and response
assessment of Hodgkin lymphoma and non-Hodgkin lym-
phoma.49 PET-CT scans are increasingly used as prognostic
indicators in classic Hodgkin lymphoma50-53 and, to a minor
extent, in DLBCL.54-57 Although PMLBCL is an 18F-FDGavid
lymphoma,48,49,58 very few studies on the use of PET-CT have
focused specifically on PMLBCL.
Establishing whether residual masses, which are almost
invariably visible on CT scans at the completion of initial
chemotherapy, represent viable lymphoma or merely fi-
brotic scar tissue is a major problem in the clinical man-
agement of PMLBCL.59 Studies of functional imaging using
This is a prospective, randomized, noninferiority phase III trial that requires the
random assignment of 376 patients. Patients are treated with standard
immunochemotherapy regimens currently in use for PMLBCL (e.g., R-CHOP, DA-
EPOCH-R, R- ACVBP, R-VACOP-B, or R-MACOP-B). Restaging PET-CT scans will be
performed at 56 weeks after the last immunochemotherapy administration. Central
review of PET-CT scans is mandatory before randomization. All patients with
a negative PET-CT scan, either with complete or partial radiologic regression of the
mediastinal mass, will be randomly assigned to receive consolidation IFRT (30 Gy) or
observation. Based on the results of the previous IELSG-26 study, a negative PET scan
is defined using the liver uptake as the cutoff point (Figs. 2 and 3).
Abbreviation: IFRT, involved-field radiotherapy.
Gallium scans24 or, more recently, 18F-FDG PET-CT scans60
suggest that it may be possible to distinguish residual me-
diastinal masses, which contain active lymphoma, from
those in which only sclerotic material remains. However,
they have not clarified whether radiotherapy could be
avoided solely on the basis of a negative PET-CT scan.59,61
In a retrospective study of 54 patients with PMLBCL who
were treated with the R-CHOP/ICE dose-dense regimen
without mediastinal radiotherapy, the Memorial Sloan
Kettering Cancer Center group reported 3-year OS and PFS
rates of 88% and 78%, respectively, in patients who had
negative PET-CT scans at the end of the chemotherapy
regimen. Furthermore, an abnormal result in an interim PET-
CT scan was still evident in 47% of patients and did not
predict a worse PFS rate.62
In a BC Cancer Agency retrospective study of 196 patients
with DLBCL treated with R-CHOP (25 with PMLBCL) with a
residual mass of greater than 2 cm, post-therapy PET-CT scan
was negative in 62% of patients who were then only ob-
served, whereas 34% had a positive post-therapy PET-CT
scan and received radiotherapy (IFRT, 3040 Gy) to sites
noted as positive on PET-CT scan. No differences were
observed in terms of 3-year PFS (80% vs. 75%; p = .41)
between the patients with negative PET-CT versus positive
PET-CT scans.63

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PET-CT Response After Immunochemotherapy
Currently, the introduction of rituximab has changed the
therapeutic scenario, whereas the general use of 18F-FDG
PET-CT to evaluate mediastinal residual disease after che-
motherapy has led to the assumption that a lymphoma can
also be considered in complete remission in the presence
of a negative PET-CT scan showing residual lesion.64
Only scanty and mainly retrospective studies on the validity
of PET in response evaluation were specifically focused on
PMLBCL.65 The IELSG-26 study of PMLBCL represents a first,
and thus far unique, attempt to obtain data on this issue
in a prospective manner.66 This is the largest study on the
results of 18F-FDG PET-CT scanning in PMLBCL. The outcome
after induction treatment in this series, in which a majority of
patients received consolidation radiotherapy of treatment
with rituximab and anthracycline-containing chemotherapy,
is very good, with more than 90% of patients projected to
be alive and progression-free at 5 years despite a lower
proportion of patients classified as having CMR. Among 125
patients prospectively enrolled in this study, 115 were eligible
for central review of PET-CT scans at the completion of
standard immunochemotherapy, using the Deauville five-
point scale (Fig. 2).67 Consolidation radiotherapy was given
to 102 patients. Fifty-four patients (47%) achieved CMR,
defined as a completely negative scan or with residual
18
F-FDG activity equal to or below the mediastinal blood
pool (MBP) uptake. In the remaining 61 patients (53%), the
residual uptake was higher than the MBP but below the
liver uptake in 27 (23%), slightly higher than the liver uptake
in 24 (21%), and markedly higher in 10 (9%). Complete
metabolic response after immunochemotherapy predicted
higher 5-year PFS (98% vs. 82%; p = .0044) and OS (100% vs.
91%; p = .0298). Patients with residual uptake higher than
the MBP but below liver uptake had equally good outcomes,
without any recurrence. Using the liver uptake as the cutoff
for PET positivity (boundary of score 34) discriminated
most effectively between high or low risk of failure, with
5-year PFS of 99% versus 68% (p , .0001) and 5-year OS of
100% versus 83% (p = .0003). Moreover, moving the cut
point for the definition of CMR from the MBP to the liver
uptake increased the specificity, and the positive predictive
value rose from 18% to 32%, without loss of sensitivity (Fig. 3).
The use of liver uptake as the cutoff for PET positivity resulted
in a clearer distinction between risk subgroups, both in terms
of PFS (p , .0001) and OS (p = .0003). The International
Prognostic Index (IPI) and age-adjusted IPI at diagnosis and
the chemotherapy regimen did not significantly correlate with
the PET response, whereas initial bulky disease (. 10 cm) was
significantly associated with a persistent postchemotherapy
residual uptake above the liver cutoff (p = .005). This cor-
relation with tumor bulk was only of borderline significance
for the MBP cut point (p = .05).
This study is also the first attempt to validate the use of
PET-CT scanning in restaging an aggressive lymphoma at the
completion of chemotherapy using the Deauville criteria
originally developed for interim PET-CT evaluation during
ROLE OF PET IN THE MANAGEMENT OF PMLBCL
FIGURE 2. Deauville Criteria for the Visual
Interpretation of PET/CT Scan Using a Five-Point Scale
(Deauville Score)
Interim and end-of-treatment PET/CT scans are scored according to uptake in
sites involved at baseline PET/CT by lymphoma as: (1) no uptake, (2) 18F-FDG
uptake equal to or below the mediastinum blood pool uptake, (3) 18F-FDG uptake
equal to or below the liver uptake, (4) 18F-FDG uptake moderately higher than the
liver uptake, or (5) 18F-FDG uptake markedly higher (i.e., more than two-fold) than the
uptake in the liver and/or new lesions.67 At the end of treatment, a score of 13 is
currently considered to indicate a complete metabolic response in most instances,48
whereas a score of 4 or 5 is considered to indicate lymphoma persistence or
recurrence. When new areas of uptake are considered unlikely to be caused by
lymphoma, they are usually reported as Score X.48
Abbreviations: SUVmax, maximum standardized uptake value;18FDG,
18-fluorodeoxyglucose.
the treatment of DLBCL and Hodgkin lymphoma.67 A cutoff
point for PET positivity below the uptake in the liver dis-
criminates most effectively between groups of PMLBCL at
high or low risk of treatment failure.
The Problem of False-Positive PET-CT Scans After
Immunochemotherapy
Although the outcome of treatment was very good, after
immunochemotherapy a persistently positive PET-CT scan
was seen in more than half of the patients (53%, with
Deauville score 35), which contributed to a positive
predictive value substantially lower than that reported for
other types of DLBCL and Hodgkin lymphoma. With the use
of the liver cutoff point to define a CMR, the rate of patients
with PET-positive scans decreases (30% with score 4 or 5).
The results of IELSG-26 appear to be in line with those
observed in a series of patients treated with the infusional
doseadjusted R-EPOCH (DA-R-EPOCH) regimen, which
showed 50% PET positivity, defined by 18F-FDG uptake
greater than the MBP at the completion of chemotherapy
but only 3 of 18 progressions without the use of consoli-
dation radiotherapy in this group.46 Because all of the cases
that recurred had a standardized uptake value (SUV) of at
least 5, the authors suggested that radiotherapy might
reasonably be omitted for nearly all patients treated with
this regimen.46 The IELSG-26 study likely carries a similarly
high false-positive rate, although PMLBCL is clearly ra-
diosensitive, so it is also possible that the almost universal
use of radiotherapy in this study may have eliminated
residual lymphoma in some instances. However, the IELSG-
26 study design did not allow us to draw any conclusions
on the benefit of radiotherapy.
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CAVALLI, CERIANI, AND ZUCCA
FIGURE 3. IELSG-26 Study Results Using the Five-Point
Scale (Deauville Score) for the Visual Interpretation of
PET-CT Scans Obtained at 34 Weeks After
Immunochemotherapy
(A) PET-CT interpretation in a blind central review performed on 115 evaluable
patients and change in the positive predictive value induced by a shift of the
cutoff point for the definition of CMR from Deauville score 2 (MBP uptake) to
score 3 (liver uptake). (B) Kaplan-Meier estimates of OS in PMLBCL according to
positive PET using the MBP uptake (Deauville score 35) or the liver uptake as
a cutoff point (Deauville score 45).
Abbreviations: MBP, mediastinal blood pool; NPV, negative predictive value; PPV,
positive predictive value; OS, overall survival; CMR, complete metabolic response.
Modified from Martelli et al 201466.
PET-CT Response After Consolidation Radiotherapy
The evaluation of postirradiation PET-CT scans in the IELSG-
26 study has thus far been reported only as a meeting
abstract.68 In this study, 88 of 125 patients were eligible for
central review of PET-CT scans at 8 weeks after the com-
pletion of radiotherapy. The CMR (using the liver cutoff
point) rate increased from 74% after immunochemotherapy
to 89% after irradiation. At a median follow-up of 60 months,
no patients with CMR after radiotherapy have relapsed.
Notably, in this study the few patients with a Deauville score
of 4 also had an excellent outcome, suggesting that they do
not necessarily require additional therapy because the re-
sidual 18F-FDG uptake may be caused by an inflammatory
reaction. In this context, it seems worth mentioning that the
18
F-FDG uptake in untreated PMLBCL is likely a result of the
lymphoma cells that are the main component of the tumor,
even though a contributing microenvironment uptake cannot
be excluded58 given its relevant role in PMLBCL.5
In post-treatment evaluation of PMLBCL, because of their
thymic derivation and anatomic localization and young age
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of most patients, thymic rebound should also be considered
as a possible explanation of a positive PET scan.
Utility of Baseline 18F-FDG PET-CT Functional
Parameters in Defining Prognosis
Because a successful primary treatment is crucial for
PMLBCL, the early identification of high-risk patients at risk
for relapse is critical to allow for alternative therapeutic
strategy. Valuable prognosis factors are therefore warranted
for tailoring therapy and possibly reducing treatment tox-
icity, as IPI and age-adjusted IPI have proved not useful for
this purpose. Other proposed clinical predictors of survival
have not been validated prospectively, and biomarkers
useful for risk stratification are not yet available.58
In this sense, the IELSG-26 study also aimed at exploring
the potential of quantitative 18F-FDG PET-CT as a biomarker
in PMLBCL by investigating whether the main quantitative
baseline PET-CTderived metabolic parameters can predict
prognosis and aimed to compare them with the commonly
used clinical indices.69
The metabolic activity defined by maximum SUV (SUVmax),
the metabolic tumor volume, and the total lesion glycolysis
(TLG), an index of metabolic tumor burden, were measured in
103 patients on baseline 18F-FDG PET-CT using a practical and
reproducible method to segment the mediastinal mass, based
on the 25% thresholding of the tumor SUVmax.69 This method
was developed considering the specific presentation features
of PMLBCL, where the technical difficulties of quantitative
PET-CT are reduced because the tumor burden is mainly
limited to a unique bulky mass.58
All patients received combination immunochemotherapy
with doxorubicin and rituximab-based regimens; 93 received
consolidation radiotherapy. Cutoff points were determined
using the receiver operating characteristic curve.69
At a median follow-up of 36 months, PFS and OS rates were
87% and 94%, respectively. In univariate analysis, elevated
metabolic tumor volume and TLG were significantly associ-
ated with worse PFS and OS. Only TLG retained statistical
significance for both OS (p = .001) and PFS (p , .001) in
multivariate analysis. At 5 years, OS was 100% for patients
with low TLG versus 80% for those with high TLG (p = .0001),
whereas PFS was 99% versus 64%, respectively (p , .0001).69
This study represents the largest prospective series of
PMLBCL investigated with central review of PET-CT scans, in
which the quantitative functional parameters were ana-
lyzed. The PET-CT imaging was obtained by following a
strictly defined technical procedure, although detailed cross-
calibration for equipment at the different centers was not
possible. Total lesion glycolysis on baseline PET-CT appeared
to be a powerful predictor of PMLBCL outcomes and war-
rants further validation as a biomarker. Indeed, this easily
and early accessible parameter can help identify the few
patients who will eventually experience relapse and may be
useful for designing trials aimed at improving their poor
prognosis (e.g., using TLG to distinguish patients being
considered for elective front-line consolidation with myeloa-
blative therapies). However, despite the very high sensitivity

(92%) of TLG with a 98% negative predictive value for PFS, the
positive predictive value was only 36%. Hence, a better se-
lection of high-risk patients would be useful to choose those to
submit to intensive treatment.58
Integrative PET: A Novel Promising Tool
Integrative 18F-FDG PET in lymphoma is a new concept that
can be defined as a method of prognostic imaging, where
imaging data obtained with different techniques are com-
bined together or with data from other fields (clinical, bi-
ologic, molecular) to improve the risk stratification of
patients.70 In classic Hodgkin lymphoma, it has been sug-
gested that baseline metabolic tumor volume may be
combined with the interim PET-CT score to identify patients
at different levels of risk.71 Preliminary data from the IELSG-
26 series of PMLBCL showed that the combination of
baseline TLG with end-treatment PET-CT more accurately
identified patients at risk, improving the positive predictive
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0704).
35. Zinzani PL, Martelli M, Poletti V, et al; Italian Society of Hematology;
Italian Society of Experimental Hematology; Italian Group for Bone
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patients. Part I: primary lung and mediastinal lymphomas. A project of
the Italian Society of Hematology, the Italian Society of Experimental
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36. Mazzarotto R, Boso C, Vianello F, et al. Primary mediastinal large B-
cell lymphoma: results of intensive chemotherapy regimens
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tients. A single institution experience. Int J Radiat Oncol Biol Phys.
2007;68:823-829.
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37. De Sanctis V, Finolezzi E, Osti MF, et al. MACOP-B and involved-field
radiotherapy is an effective and safe therapy for primary mediastinal
large B cell lymphoma. Int J Radiat Oncol Biol Phys. 2008;72:1154-1160.
38. Hancock SL, Hoppe RT. Long-term complications of treatment and
causes of mortality after Hodgkins disease. Semin Radiat Oncol. 1996;6:
225-242.
39. van Leeuwen FE, Klokman WJ, Veer MB, et al. Long-term risk of second
malignancy in survivors of Hodgkins disease treated during adoles-
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40. Henderson TO, Amsterdam A, Bhatia S, et al. Systematic review: sur-
veillance for breast cancer in women treated with chest radiation for
childhood, adolescent, or young adult cancer. Ann Intern Med. 2010;
152:444-455.
41. Yoon M, Ahn SH, Kim J, et al. Radiation-induced cancers from modern
radiotherapy techniques: intensity-modulated radiotherapy versus
proton therapy. Int J Radiat Oncol Biol Phys. 2010;77:1477-1485.
42. Bucci MK, Bevan A, Roach M III. Advances in radiation therapy: con-
ventional to 3D, to IMRT, to 4D, and beyond. CA Cancer J Clin. 2005;55:
117-134.
43. Tsang RW, Gospodarowicz MK. Radiation therapy for localized low-
grade non-Hodgkins lymphomas. Hematol Oncol. 2005;23:10-17.
44. van Nimwegen FA, Schaapveld M, Cutter DJ, et al. Radiation Dose-
response relationship for risk of coronary heart disease in survivors of
Hodgkin lymphoma. J Clin Oncol. 2016;34:235-243.
45. Nieder C, Schill S, Kneschaurek P, et al. Comparison of three different
mediastinal radiotherapy techniques in female patients: Impact on
heart sparing and dose to the breasts. Radiother Oncol. 2007;82:
301-307.
46. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-
rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J
Med. 2013;368:1408-1416.
47. Savage KJ, Yenson PR, Shenkier T, et al. The outcome of primary me-
diastinal large B-cell lymphoma (PMLBCL) in the R-CHOP treatment era.
Blood. 2012;120:303.
48. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the
staging and response assessment of lymphoma: consensus of the In-
ternational Conference on Malignant Lymphomas Imaging Working
Group. J Clin Oncol. 2014;32:3048-3058.
49. Cheson BD, Fisher RI, Barrington SF, et al; Alliance, Australasian Leu-
kaemia and Lymphoma Group; Eastern Cooperative Oncology Group;
European Mantle Cell Lymphoma Consortium; Italian Lymphoma
Foundation; European Organisation for Research; Treatment of Cancer/
Dutch Hemato-Oncology Group; Grupo Espan ~ol de Medula Osea;
German High-Grade Lymphoma Study Group; German Hodgkins Study
Group; Japanese Lymphorra Study Group; Lymphoma Study Associa-
tion; NCIC Clinical Trials Group; Nordic Lymphoma Study Group;
Southwest Oncology Group; United Kingdom National Cancer Research
Institute. Recommendations for initial evaluation, staging, and response
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano class-
ification. J Clin Oncol. 2014;32:3059-3068.
50. Adams HJ, Nievelstein RA, Kwee TC. Prognostic value of interim FDG-PET
in Hodgkin lymphoma: systematic review and meta-analysis. Br J
Haematol. 2015;170:356-366.
51. Sickinger MT, von Tresckow B, Kobe C, et al. Positron emission
tomography-adapted therapy for first-line treatment in individuals
with Hodgkin lymphoma. Cochrane Database Syst Rev. 2015;1:
CD010533.
52. Gallamini A, Hutchings M, Rigacci L, et al. Early interim 2-[18F]fluoro-2-
deoxy-D-glucose positron emission tomography is prognostically su-
perior to international prognostic score in advanced-stage Hodgkins
lymphoma: a report from a joint Italian-Danish study. J Clin Oncol. 2007;
25:3746-3752.

53. Gallamini A, Barrington SF, Biggi A, et al. The predictive role of interim
positron emission tomography for Hodgkin lymphoma treatment
outcome is confirmed using the interpretation criteria of the Deauville
five-point scale. Haematologica. 2014;99:1107-1113.
54. Mamot C, Klingbiel D, Hitz F, et al. Final Results of a prospective
evaluation of the predictive value of interim positron emission to-
mography in patients with diffuse large B-cell lymphoma treated with
R-CHOP-14 (SAKK 38/07). J Clin Oncol. 2015;33:2523-2529.
55. Mikhaeel NG, Timothy AR, ODoherty MJ, et al. 18-FDG-PET as a
prognostic indicator in the treatment of aggressive Non-Hodgkins
Lymphoma-comparison with CT. Leuk Lymphoma. 2000;39:543-553.
56. Spaepen K, Stroobants S, Dupont P, et al. Prognostic value of positron
emission tomography (PET) with fluorine-18 fluorodeoxyglucose ([18F]FDG)
after first-line chemotherapy in non-Hodgkins lymphoma: is [18F]FDG-PET a
valid alternative to conventional diagnostic methods? J Clin Oncol. 2001;19:
414-419.
57. Zinzani PL, Fanti S, Battista G, et al. Predictive role of positron emission
tomography (PET) in the outcome of lymphoma patients. Br J Cancer.
2004;91:850-854.
58. Meignan M. Quantitative FDG-PET: a new biomarker in PMBCL. Blood.
2015;126:924-926.
59. Johnson PWM. IV. Masses in the mediastinum: primary mediastinal
lymphoma and intermediate types. Hematol Oncol. 2015;33(suppl 1):
29-32.
60. Zinzani PL, Tani M, Trisolini R, et al. Histological verification of positive
positron emission tomography findings in the follow-up of patients with
mediastinal lymphoma. Haematologica. 2007;92:771-777.
61. Kahn ST, Flowers C, Lechowicz MJ, et al. Value of PET restaging after
chemotherapy for non-Hodgkins lymphoma: implications for consol-
idation radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66:961-965.
62. Moskowitz C, Hamlin PA Jr, Maragulia J, et al. Sequential dose-dense
RCHOP followed by ICE consolidation (MSKCC protocol 01-142) without
radiotherapy for patients with primary mediastinal large B cell lym-
phoma. Blood. 2010;116:420.
ROLE OF PET IN THE MANAGEMENT OF PMLBCL
63. Sehn LH, Hoskins P, Klasa R, et al. FDG-PET scan guided consolidative
radiation therapy optimizes outcome In patients with advanced-stage
diffuse large B-cell lymphoma (DLBCL) with residual abnormalities on CT
scan following R-CHOP. Blood. 2010;-116:854.
64. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization
Project on Lymphoma. Revised response criteria for malignant lym-
phoma. J Clin Oncol. 2007;25:579-586.
65. Zinzani PL, Broccoli A, Casadei B, et al. The role of rituximab and positron
emission tomography in the treatment of primary mediastinal large B-
cell lymphoma: experience on 74 patients. Hematol Oncol. 2015; 33:
145-150.
66. Martelli M, Ceriani L, Zucca E, et al. [18F]fluorodeoxyglucose positron
emission tomography predicts survival after chemoimmunotherapy for
primary mediastinal large B-cell lymphoma: results of the International
Extranodal Lymphoma Study Group IELSG-26 Study. J Clin Oncol. 2014;
32:1769-1775.
67. Meignan M, Gallamini A, Meignan M, et al. Report on the First In-
ternational Workshop on Interim-PET-Scan in Lymphoma. Leuk Lym-
phoma. 2009;50:1257-1260.
68. Ceriani L, Martelli M, Zinzani PL, et al. Use of the Lugano classification
criteria for PET/CT assessment of primary mediastinal B-cell lymphoma
after immunochemotherapy and irradiation in the IELSG-26 study.
Hematol Oncol. 2015;33:143 (abstr 081).
69. Ceriani L, Martelli M, Zinzani PL, et al. Utility of baseline 18FDG-PET/CT
functional parameters in defining prognosis of primary mediastinal
(thymic) large B-cell lymphoma. Blood. 2015;126:950-956.
70. Meignan M, Cottereau AS. Integrative PET: a new concept for outcome
prediction in lymphoma. Clin Transl Imaging. 2015;3:343-344.
71. Meignan M, Itti E, Gallamini A, et al. FDG PET/CT imaging as a biomarker
in lymphoma. Eur J Nucl Med Mol Imaging. 2015;42:623-633.
72. Zucca E, Martelli M, Zinzani PL, et al. Prognostic models for primary
mediastinal B-cell lymphoma derived from 18-FDG PET/CT quantitative
parameters in the IELSG-26 study. Haematologica. 2014;99:524-525
(suppl; abstr S1346).
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LYNCH AND ADVANI

Risk-Adapted Treatment of Advanced Hodgkin Lymphoma

With PET-CT
Ryan C. Lynch, MD, and Ranjana H. Advani, MD

OVERVIEW

Although patients with advanced-stage classic Hodgkin lymphoma have excellent outcomes with contemporary therapy,
the outcomes of patients with refractory disease is suboptimal. Identification of these high-risk patients at diagnosis is
challenging as the differences in outcomes using clinical criteria are less marked using current modern therapy. Data suggest
that an interim PET-CT may be a powerful tool in risk-stratifying patients. Retrospective studies show that a negative interim
PET-CT after two to four cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is predictive of favorable outcome
independent of IPS score. Currently, there are several ongoing trials that aim to determine whether early-response as-
sessment can be used to select patients who might benefit from modifications of subsequent therapy, either by intensifying
or abbreviating regimens and/or omitting radiotherapy with promising early results. Longer follow-up is required to assess
whether this strategy impacts overall survival (OS). Herein, we review the results of recent trials using interim PET-CT-based
adaptive design in the treatment of advanced HL.

P atients with advanced-stage classic Hodgkin lymphoma

(defined in North America as clinical stage IIIIV disease
and early-stage disease with bulk or B symptoms) have
excellent outcomes with contemporary therapy with an OS
of greater than 80%.1,2
In the National Comprehensive Cancer Network guide-
lines, therapy choices for advanced-stage disease include
ABVD, Stanford V regimen (a combined modality approach
including mechlorethamine, doxorubicin, vincristine, vin-
blastine, bleomycin, etoposide, and prednisone), and the
German Hodgkin Study Group (GHSG) regimen escalated
BEACOPP ( escBEACOPP; bleomycin, etoposide, doxorubicin,
cyclophosphamide, vincristine, procarbazine, and predni-
sone) followed by radiotherapy given to PET-positive areas
greater than 2.5 cm after completion of chemotherapy.3 In
North America, ABVD is the most commonly used regimen
based on a balance of efficacy and toxicity, and escBEACOPP
is used more commonly in Europe. The latter has not been
widely accepted in North America largely because of increased
toxicity as well as an increased risk of sterility and secondary
cancers.1,4,5 Several randomized clinical trials have compared
some version of escBEACOPP to ABVD and have shown an
improved progression-free survival (PFS) without any impact
on OS.6-8 A recent long-term follow-up from the HD2000 trial
failed to confirm the PFS benefit with escBEACOPP mainly
because of higher mortality rates resulting from second
malignancies observed after treatment with escBEACOPP.9
Therefore, there is an ongoing debate regarding how to best
achieve a balance between aggressively curing the disease
with front-line therapy versus a gentler approach that may be
slightly less efficacious in the short term but with no long-term
OS difference. Attempts to identify patients who are defined
as high risk and thus might potentially benefit from a more
aggressive initial approach is also an evolving concept.
A commonly used index is the International Prognostic
Score (IPS), which has been used in some trials to stratify
patients (score $ 3 identifies a high-risk group10). However,
as the benefit of escBEACOPP has been observed across all
IPS risk groups, its utility in patient selection is limited.11
Additionally, the range of differences in outcomes between
groups in the contemporary era has also narrowed, and
other methods for patient selection are required.12,13
18-Fluorodeoxyglucose-(FDG)-PET/CT (or PET-CT) is an
important tool in the management of Hodgkin lymphoma
and has a well-established role in staging as well as response
assessment at the completion of therapy.14,15 Several studies
also suggest that a negative interim PET-CT after two to four
cycles of ABVD is predictive of favorable outcomes in-
dependent of the IPS score.16-20 The initial studies used
variable criteria to define a positive scan with a sensitivity of
67% to 100% and a specificity of 95% to 100% because of
inter-reader variability.14,21,22 Efforts to standardize response
criteria led to the development of the numeric five-point scale
(5PS), also known as the Deauville criteria. In this scale, FDG

From the Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Ranjana H. Advani, MD, Stanford University Medical Center, 875 Blake Wilbur Dr., Suite CC-2338, Stanford, CA 94305-5821; email: radvani@stanford.edu.

2016 by American Society of Clinical Oncology.

e376 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


uptake at sites of disease is compared with uptake in the liver
and the mediastinal blood pool. The specific criteria consist
of a score of the following: (1) no uptake; (2) uptake higher
than or equal to mediastinal blood pool; (3) uptake higher
than mediastinal blood pool, but uptake is lower than or equal
to liver; (4) uptake moderately higher than liver; (5) uptake
markedly higher than liver and/or new lesions; (X) new areas
of uptake unlikely to be related to lymphoma.23 A score of 13 is
considered to represent a complete metabolic response in
advanced Hodgkin lymphoma. The prognostic utility value of this
score was confirmed in an international study that showed a
3-year failure-free survival (FFS) of 28% and 95% for patients
with early PET-positive versus PET-negative disease respectively
(p , .0001).24 Additionally, the interobserver agreement was
also high between six independent reviewers. The reproducibility
has resulted in the Deauville criteria being endorsed as the
current recommended method for response assessment.25,26
This has resulted in numerous trials in Hodgkin lymphoma
based on interim PET-CTadapted strategies. These studies aim
to determine whether early-response assessment can be used
to select patients who might benefit from modifications of
subsequent therapy, either by intensifying or abbreviating
regimens and/or omitting radiotherapy. Herein, we review the
results of recent trials using interim PET-CTbased adaptive
design in the treatment of advanced Hodgkin lymphoma.
STUDIES EVALUATING THERAPY ESCALATION IN
PATIENTS WITH A POSITIVE INTERIM PET-CT
SCAN
Results of an early interim PET-CT is now a widely accepted
prognostic tool for patients with advanced Hodgkin lymphoma
KEY POINTS
Retrospective studies in advanced Hodgkin lymphoma
suggest that a negative interim PET-CT (variably defined)
after two to four cycles of ABVD is predictive of
a favorable outcome.
Several prospective trials aim to determine whether
early response assessment after two cycles of ABVD
using the five-point scale can be used to select patients
who might benefit from modifications of subsequent
therapy.
Results of several trials suggest that an interim
PETadapted approach of escalating therapy to a more
aggressive regimen is feasible and possibly associated
with better progression-free survival in patients with
PET-2positive disease after ABVD compared with
historical controls.
A major consideration for the escalation strategies is the
lack of a control arm in which ABVD therapy is continued
regardless of interim PET-CT results.
Interim results of the RATHL trial suggest that for
patients with a negative PET-CT after two cycles of
ABVD, bleomycin can be safely omitted from
subsequent cycles.
RISK-ADAPTED TREATMENT OF ADVANCED HL
treated with ABVD. Therefore, an adaptive treatment strategy
based on interim PET-CT results may help distinguish patients
with high-risk disease who could potentially benefit from a
change in therapy to an escalated regimen despite the in-
creased toxicity. This was evaluated in a retrospective analysis
of prospectively collected data in a study in which all patients
with PET-2positive disease after two cycles of ABVD received
four escBEACOPP plus four standard BEACOPP cycles, whereas
patients with PET-2negative disease continued on ABVD (total
of six cycles) followed by consolidative radiotherapy.27 At a
median follow-up of 34 months and a central radiology review
of PET-2 data using the Deauville criteria, the FFS in PET-
2negative versus PET-2positive group was 95% versus
62%, respectively (p , .001). The outcomes of patients with
PET-2positive disease (approximately 20% of patients) was
better than historical controls using ABVD.20
The efficacy of intensifying therapy to escBEACOPP for
patients with PET-2positive disease has also been tested in
several prospectively designed trials in advanced Hodgkin
lymphoma described below and summarized in Table 1.
Although most of the interim PET-positive arms do not
have a control group without escalated therapy, the sta-
tistical design is essentially based on the historical PFS data
described above.
The U.S. intergroup phase II trial S0816 led by the
Southwest Oncology Group (SWOG) reported preliminary
results in 357 patients with a median follow-up 28 months in
patients with advanced Hodgkin lymphoma. Patients re-
ceived two cycles of ABVD followed by a PET-CT with central
review.28 Those with a PET-2negative scan (82% of pa-
tients) defined as Deauville 13 continued with four more
cycles of ABVD, whereas patients with PET-2positive dis-
ease (Deauville 45) had a change in therapy to six cycles
of escBEACOPP. An interim analysis presented in 2013
reported a 1-year PFS for the PET-2positive group of 72%
(95% CI, 55%84%) and 85% in the PET-2negative group
(95% CI, 79%90%).
The U.K. RATHL trial included 1,214 patients and tested
a similar concept as the U.S. intergroup study. Patients with
advanced-stage Hodgkin lymphoma (stages IIBIV, or IIA
with bulk or three or more involved sites) received two
cycles of ABVD followed by a PET-CT. Patients with PET-
2negative disease (defined as Deauville 13) based on a
central review were randomly assigned to either ABVD or
AVD for four additional cycles.29,30 Patients with PET-
2positive disease (Deauville 45) received intensified
therapy with four cycles of BEACOPP-14 or three cycles of
escBEACOPP followed by another PET-CT. Patients whose
disease remained PET-3positive (performed after four
additional cycles of BEACOPP-14 or three of escBEACOPP)
were taken off study and given salvage treatment. Patients
with PET-3negative disease received two additional cycles
of BEACOPP-14 or one more cycle of escBEACOPP. Patients
who had a positive PET-2 scan (16% of all patients) had a
3-year PFS and OS of 68% and 86%, respectively, with no
difference in the nonrandomized comparison between
escBEACOPP and BEACOPP-14.
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LYNCH AND ADVANI

TABLE 1. Comparison of PET-Adapted Prospective Clinical Trials in Advanced Hodgkin Lymphoma

Results
Median
Study Trial Design PET-2 Results Clinical Stage Follow-up PFS/EFS/FFS OS
Trials With Treatment Escalated If PET-2 Positive
RATHL Two cycles ABVD interim PET-CT 16.1% positive IIBIV, IIA with 32 months 3-year PFS 3-year OS
(Johnson bulk or $ 3
et al,29 2015, involved
1,214 sites
patients)
PET2+: six cycles BEACOPP-14 or four PET2+: 68% PET2+: 86%
cycles escBEACOPP (taken off study
if PET+ after four cycles BEACOPP-14
or three cycles escBEACOPP)
AHL 2011 LYSA Standard arm 12.4% positive IIBIV 16.3 months 2-year PFS Not reported
Study
(Casanovas
et al,41 2015,
823 patients)
Six cycles escBEACOPP (regardless of Standard arm: 91.6%
result of interim PET-CT)
Experimental arm Experimental arm:
88.3%
Two cycles escBEACOPP interim Overall study cohort
PET-CT PET2+: 72.9%
PET2+: four cycles escBEACOPP Overall study cohort
PET22: 92.8%
(p , .0001)*
PET22: four cycles ABVD Standard PET22:
75.1%
Experimental
PET22: 70.8%
Israeli H2 (Dann IPS $ 3 14.2% positive IB, IIB, IIIIV 36 months 3-year PFS (all ad- Not reported
et al,35 2014, vanced HL regard-
183 patients) less of IPS)
Two cycles escBEACOPP, interim PET2+: 75%
PET-CT
PET2+: four cycles escBEACOPP + RT to
bulky mediastinal disease at EOT
IPS , 3
Two cycles ABVD interim PET-CT
PET2+: four cycles escBEACOPP + RT to
bulky mediastinal disease at EOT
Israeli Group Two cycles escBEACOPP interim 24.6% positive IIBIV (IPS $ 3) 5.6 years 5-year PFS 5-year OS
(Kedmi PET-CT
et al,39 2015,
69 patients;
24 patients
were treated
on the same
protocol
off-study)
PET2+: four cycles escBEACOPP PET2+: 60% PET2+: 79%
PET22: four cycles ABVD PET22: 80% PET22: 98%
HD18 (Borch- Two cycles escBEACOPP interim 40.0% positive IIB with bulky 35 months 3-year PFS 3-year OS
mann et al,34 PET-CT mediastinal
2014, 1,100 mass or EN
patients) involvement,
IIIIV
PET2+: randomized to four cycles PET2+: escBEACOPP, PET2+: escBEACOPP
escBEACOPP vs. one cycle escBEA- 91.4%; 96.5%,
COPP, then four cycles R-BEACOPP
R-BEACOPP, 93% R-BEACOPP 94.4%

Continued

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 RISK-ADAPTED TREATMENT OF ADVANCED HL

TABLE 1. Comparison of PET-Adapted Prospective Clinical Trials in Advanced Hodgkin Lymphoma

(Contd)
Results
Median
Study Trial Design PET-2 Results Clinical Stage Follow-up PFS/EFS/FFS OS
U.S. Intergroup Two cycles ABVD, interim PET-CT 77.7% negative IIIIV 28 months 1-year PFS Not reported
S0816 (Press
et al,28 2013,
357 patients)
PET2+: six cycles escBEACOPP PET2+: 72%
PET22: four cycles ABVD PET22: 85%
Trials With Treatment De-escalated If PET-2 Negative

RATHL Two cycles ABVD interim PET-CT 83.9% negative IIBIV, IIA with 32 months 3-year PFS 3-year OS
(Johnson bulk or three
et al,29 2015; or more in-
1,214 volved sites
patients)
PET22: randomized to four cycles PET22: ABVD, PET22: ABVD 97%,
ABVD vs. four cycles AVD 85.5%;
AVD, 84.5% AVD 97.5%
HD 0607 Two cycles ABVD interim PET-CT 80.5% negative IIBIV 34.3 months No interim data on No interim data on
(Gallamini randomized arms randomized arms
et al,31 2015,
773 patients)
PET2+: randomized to escBEACOPP + Overall study cohort Overall study cohort
BEACOPP (four + four) vs. four + four
and rituximab
PET22: four cycles ABVD. If CR, then 4-year FFS 4-year OS
randomized to RT vs. observation
PET2+: 62% PET2+: 86%
PET22: 85% PET22: 95%
HD 0801 Two cycles ABVD interim PET-CT 79.9% negative IIBIV Not reported PET2+: 78.6% Not reported
(Zinzani in abstract (81/103 patients)
32
et al, 2015, received
519 patients) HDC-ASCT,
PET2+: ifosfamide-containing salvage 2-year PFS
regimen HDC-ASCT
PET22: four cycles ABVD PET2+: 74%
PET22: 81%
Israeli H2 (Dann IPS $ 3 85.8% negative IB, IIB, IIIIV 36 months 3-year PFS (All Not reported
et al,35 2014, advanced HL
183 patients) regardless of IPS)
Two cycles escBEACOPP, interim PET22: 86%
PET-CT (p = .012)
PET22: four cycles ABVD, omit RT to
bulky sites
IPS , 3
Two cycles ABVD interim PET-CT
PET22: four cycles ABVD, omitting RT
to bulky sites
NCT013048490 Two cycles ABVD interim PET-CT 83.7% negative IIBIV 24.7 months 2-year EFS Not reported
(Ganesan
et al,36 2015,
50 patients)
PET2+: four cycles escBEACOPP PET2+: 50%
PET22: four cycles ABVD PET22: 82%
(p = .013)

Continued

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LYNCH AND ADVANI
TABLE 1. Comparison of PET-Adapted Prospective Clinical Trials in Advanced Hodgkin Lymphoma
(Contd)
Study Trial Design
HD18 Two cycles escBEACOPP interim
(Borchmann PET-CT
et al,34 2014,
1,100
patients)
PET22: randomized to Two cycles
escBEACOPP vs. four cycles
escBEACOPP
Abbreviations: ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AVD, doxorubicin, vinblastine, and dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin,
cyclophosphamide, vincristine, procarbazine, and prednisone; CR, complete remission; EFS, event-free survival; EN, extranodal; EOT, end of therapy; escBEACOPP, escalated-dose
BEACOPP; FFS, failure-free survival; HDC-ASCT, high-dose chemotherapy-autologous stem cell transplantation; HL, Hodgkin lymphoma; IPS, International Prognostic Score; LYSA,
Lymphoma Study Association; NCT, National Clinical Trial number; OS, overall survival; PET2+, interim PET-CT positive after 2 cycles of therapy; PET22, interim PET-CT negative after
two cycles of therapy; PFS, progression-free survival; R-BEACOPP, rituxumab plus BEACOPP; RT, radiotherapy.
* If comparison is statistically significant, p value is given.
A phase II multicenter Italian HD 0607 trial evaluated
773 patients with advanced Hodgkin lymphoma who received
two cycles of ABVD followed by an interim PET-CT. Patients
with PET-2negative disease (Deauville 13) continued with
four additional cycles of ABVD.31 Those in complete remission
(CR) after six cycles of ABVD were subsequently randomly
assigned to radiotherapy to sites of initial bulky disease versus
observation. Patients with PET-2positive disease (Deauville
45) were randomly assigned to either alternating cycles of
standard BEACOPP and escBEACOPP (four plus four) or the
four-plus-four regimen plus rituximab. Although there are no
data currently available comparing the randomized arms, at a
median follow-up 34.3 months, the overall 4-year FFS and OS
were 62% and 86% for patients with PET-2positive disease
and 85% and 95% for patients with PET-2negative disease
respectively.
The Italian HD 0801 trial tested an alternative aggressive
strategy in 519 patients. Treatment of patients with PET-
2positive disease after two cycles of ABVD was changed
to IGEV (ifosfamide, gemcitabine, vinorelbine) in preparation
for transplant.32 Patients in CR by PET-CT after IGEV received
an autologous transplant, whereas those not in CR received a
tandem autologous-allogeneic transplant. Of the patients
with PET-2positive disease 78.6% (81 of 103) received a
salvage regimen containing at least one autologous trans-
plant; 14.6% (15 of 103) of patients with PET-2positive
disease continued on ABVD per investigator decision due
to a minimally positive PET-CT. There was no significant
difference in 2-year PFS in the PET-2positive intention-to-
treat group (76%) and the patients with PET-2positive
disease who subsequently underwent salvage chemother-
apy and transplant (74%) with a 2-year PFS for patients with
PET-2negative disease of 81%, which was similar to that
observed in patients with PET-2positive disease.
The GHSG HD18 study evaluated 1,100 patients and
also used a PET-adaptive strategy intensifying therapy
based on interim PET results after two initial cycles
of escBEACOPP.33,34 Patients with PET-2negative disease
were randomly assigned to two versus four additional cycles
e380 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Results
Median
PET-2 Results Clinical Stage Follow-up PFS/EFS/FFS OS
60.0% negative IIB with bulky 35 months 3-year PFS 3-year OS
mediastinal
mass or EN
involvement,
IIIIV
PET22: no data PET22: no data
available available
of escBEACOPP (four or six total). No data from the PET-
2negative arm have been presented to date. In the PET-
2positive group, patients were randomly assigned to four
additional cycles of escBEACOPP versus one cycle of esc-
BEACOPP followed by four cycles of rituximab-escBEACOPP
(R-escBEACOPP). Patients with PET-CTpositive disease
greater than 2.5 cm at the end of treatment received ra-
diotherapy. Interim results of this trial reported no difference
in outcomes between the two arms. At a median follow-up of
35 months, the 3-year PFS for escBEACOPP was 91.4% (95%
CI, 87.0%95.7%) versus 93% for R-escBEACOPP (95% CI,
89.4%96.6%). Moreover, 3-year OS was not significantly
different between escBEACOPP and R-escBEACOPP (96.5% vs.
94.4%; p = .31).
The Israeli H2 study included 183 patients and stratified initial
treatment of patients with advanced-stage Hodgkin lymphoma
or early-stage Hodgkin lymphoma with B symptoms based
on the IPS score. 35 Patients with IPS scores lower than 3
(106 patients) were treated with two cycles of ABVD fol-
lowed by interim PET-CT. Patients with PET-2positive dis-
ease had therapy escalated to escBEACOPP. In contrast,
patients with IPS scores of 3 or lower started out with two
cycles of escBEACOPP, with patients with PET-2positive
disease continuing with escBEACOPP and patients with
PET-2negative disease deescalating therapy to four cycles
of ABVD (discussed in the next section). Among the 162
patients with advanced-stage disease, 26 had a positive PET-
2 scan. Interim results report a 3-year PFS for PET-2 negative
and PET-2 positive disease of 86% and 75%, respectively
(p = .012), with no difference in PFS based on IPS score.
An Indian phase II study evaluated two cycles of ABVD
followed by interim PET-CT in 50 patients with stage IIB-IV
Hodgkin lymphoma.36 Patients with PET-2positive dis-
ease were escalated to escBEACOPP and patients with
PET-2negative disease continued therapy with four addi-
tional cycles of ABVD. At a median follow-up 24.7 months,
the 2-year EFS for patients with PET-2negative disease
and patients with PET-2positive disease was 82% and 50%,
respectively (p = .013).

In addition to the above trials, there is an ongoing study
examining very early PET-adapted escalation with interim
PET-CT after one cycle of ABVD.37 No interim results have
been presented so far.
Cumulatively, results of all of the above trials suggest that
an interim PET-adapted approach of escalating therapy to a
more aggressive regimen is feasible and possibly associated
with better outcomes in patients with PET-2positive dis-
ease after ABVD compared with historical controls, albeit
with more toxicity.
A major issue with most of these trials is the lack of a control
arm in which ABVD therapy is continued regardless of interim
PET-CT results. Additionally, as discussed previously, the Deau-
ville scoring system has led to less inter-reader variability and
differences in outcomes between patients with PET-CTnegative
or PET-CTpositive disease are not as disparate as in the original
report by Gallamini et al.20,21,38
Therefore, long-term follow-up is critical to determine if
treatment modification translates into an OS advantage or
not. Until that is clearer, escalating therapy based on in-
terim PET-CT results should ideally be done in the con-
text of a clinical trial with strict definitions of PET-CT
interpretation.
STUDIES EVALUATING DE-ESCALATION OF
CHEMOTHERAPY IN PATIENTS WITH A NEGATIVE
INTERIM PET-CT SCAN
An alternate strategy for patients with advanced Hodgkin
lymphoma is to de-escalate chemotherapy in patients with
a negative interim PET-CT to mitigate some short- and long-
term toxicities.
The Israeli group was among the first to report on a de-
escalation strategy. Patients with stage IIBIV disease with
IPS of 3 or higher started therapy with two cycles of esc-
BEACOPP.39,40 For patients who had PET-2negative disease,
chemotherapy was de-escalated to four additional cycles of
ABVD, whereas patients with PET-2positive disease con-
tinued on escBEACOPP. Radiotherapy was administered to
initial sites of bulk ($ 10 cm) or mediastinal bulk at physician
discretion. The results of their prospective phase II study
were combined with additional patients who were treated
on the same protocol off-study (24 patients) for a total of 69
patients. With this de-escalation strategy, an interim PET-CT
predicted 5-year OS (PET-2 positive, 79%, vs. PET-2 negative,
98%; p = .015). The same group is currently evaluating in the H2
trial a similar strategy as used in the earlier study, in which
patients with PET-2negative disease after two cycles of esc-
BEACOPP had therapy de-escalated to four additional cycles of
ABVD without radiotherapy.35 Interim results for 183 patients
at a median follow-up of 36 months show a 3-year PFS for
patients with PET-2negative disease and those with PET-
2positive disease of 86% and 75%, respectively (p = .012), with
no difference in PFS based on IPS score.
The AHL 2011 study randomly assigned 823 patients with
stage IIBIV Hodgkin lymphoma to a standard arm that
received six cycles total of escBEACOPP regardless of results
RISK-ADAPTED TREATMENT OF ADVANCED HL
of interim PET after two cycles versus an experimental arm that
evaluated a PET-adapted de-escalation strategy.41 Patients with
PET-2positive disease continued with four additional cycles of
escBEACOPP, whereas for patients with PET-2negative dis-
ease, therapy was de-escalated to four cycles of ABVD. At a
median follow-up of 16.3 months, the 2-year PFS was similar in
the standard and experimental arms (91.6% vs. 88.3%; p = .79).
Overall in both arms, patients with PET-2positive disease
(97 patients) had a lower 2-year PFS than patients with
PET-2negative disease (72.9% vs. 92.8%; p , .0001). Standard-
arm patients with PET-2negative disease had a similar 2-year
PFS as the de-escalated experimental-arm patients with
PET-2negative disease (75.1% vs. 70.8%; not significant).
The U.K. RATHL trial randomly assigned patients with
Hodgkin lymphoma with a negative PET-CT after two cycles
of ABVD to continue with four additional cycles of ABVD
versus AVD (omitting bleomycin).29 Interim results of the
PET-2negative group (944 patients) with a median follow-up
of 32 months showed similar 3-year PFS for ABVD (85.45%;
95% CI, 83.4289.70) versus AVD (84.48%; 95% CI,
82.4788.97) with no difference in 3-year OS (ABVD, 97.0%;
95% CI, 94.598.4; AVD, 97.5%; 95% CI, 95.198.7). In ad-
dition, there were more grade 3/4 clinical pulmonary events
in the ABVD arm (12 total doses of bleomycin; 13 of 468
patients, 3%) versus the AVD arm (four total doses of
bleomycin; 6 of 440 patients, 1%).42 There was also a greater
decrease in lung diffusing capacity in patients who received
additional doses of bleomycin (8.7%; 95% CI, 6.1011.36).
As described earlier, the GHSG HD18 trial also randomly
assigned patients with PET-2negative disease to two versus
four additional cycles of escBEACOPP (four or six total).33,34
Although there have been no data presented yet from the
PET-2negative arm, the 3-year PFS for patients with PET-
2positive disease in this study exceeded 90%, suggesting
that the PET-2negative cohort is at lower risk with room for
de-escalation.
Cumulatively, the results of studies on continuing with
standard therapy (i.e., ABVD) after a negative interim PET-CT
scan report excellent outcomes and also support the
omission of bleomycin.
END OF THERAPY PET: WHEN SHOULD
RADIOTHERAPY BE GIVEN
Another ongoing debate is regarding the role of radiotherapy
in advanced Hodgkin lymphoma specifically because of concern
regarding late effects.43-46 Although the risk of late effects with
contemporary radiotherapy are lower, attempts to eliminate
radiotherapy are ongoing.1,47-49 Although radiotherapy is well
studied in the management of early-stage disease, its role in
patients with advanced Hodgkin lymphoma is less precise.
Historic data suggest that, with consolidative radiotherapy,
patients who achieve a partial remission (PR) using standard
definitions based on CT scans to assess response have out-
comes similar to those in CR.50-52 Therefore, radiotherpy has
commonly been used to consolidate sites of initial bulky dis-
ease especially in the mediastinum with improved outcomes
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e381
LYNCH AND ADVANI
in some series.52 Because current response criteria are now
based on PET-CT, the role of radiotherapy needs to be re-
evaluated. The only trial that has prospectively studied this
is the GHSG HD15 trial, in which patients with a residual mass
larger than 2.5 cm mass and PET positivity after six cycles of
escBEACOPP were treated with 30 Gy.1 The addition of PET-
CT to response assessment decreased the total number of
patients receiving radiotherapy when compared with the prior
GHSG HD9 trial (11% vs. 66%).53 The 4-year PFS curves for PET-
negative PR and CR/CRu post-treatment were similar at 92.1%.
Patients with residual PET positivity had excellent outcomes
with a PFS of 86.2% after radiotherapy.
When ABVD is used as the chemotherapy backbone, the
data are less clear as there are no trials that have evaluated
radiotherapy versus no radiotherapy. The GITL/IIL study
used radiotherapy at the completion of treatment25.2 Gy
in all patients to sites of initial bulk and 30.6 Gy to areas of
residual disease.6 However, the use of PET was not man-
dated by the protocol. No patients in the RATHL or U.S.
Intergroup trials received radiotherapy.28,29
The ongoing HD 0607 trial is randomly assigning patients
with PET-2negative disease who have received a total of six
cycles of ABVD to radiotherapy to initially bulky sites versus
observation, and results are awaited.31 Since July 2005, the
BC Cancer Agency has adopted a treatment strategy of six
cycles of ABVD for patients with advanced-stage Hodgkin
lymphoma (including stage I with bulk and stage II with B
symptoms and/or bulk) followed by observation with ra-
diotherapy used only for patients with PET-positive disease
at the end of therapy.54 Recent results suggest that post-
treatment patients with PET-negative disease had superior
5-year freedom-from-treatment failure (FFTF) compared
with those with PET-positive disease (89% vs. 56%; p , .00001).
In addition, there was no difference in 5-year FFTF in the
PET-negative group between bulky (112 patients) and non-
bulky (152 patients; 89% vs. 88.5%; p = .50) with similar OS
(96% vs. 94%, p = .51). Although the BC Cancer Agency data
support the lack of a benefit of radiotherapy in patients
who achieve CR by PET-CT at completion of chemotherapy,
the outcomes of patients with PET-positive disease after
ABVD is suboptimal with use of radiotherapy. Every attempt
should be made to rebiopsy such patients and consider salvage
therapy followed by autologous stem cell transplantation if
feasible.
For patients with stage III unfavorable disease (often treated
as advanced disease in the United States if bulky disease or B
symptoms), the EORTC/GELA/IIT H10 trial randomly assigned
patients to a standard arm (four total cycles of ABVD followed by
involved-node radiotherapy [INRT]), or an experimental arm
based on interim PET results.55 After two cycles of ABVD, patients
with PET-2positive disease received two cycles of escBEACOPP
followed by INRT. Patients with PET-2negative disease received
four additional cycles of ABVD (six total) without radiotherapy.
Interim analysis found an increase in events in the experimental
arm (16 vs. seven), which met prespecified significance for
futility, and therefore the experimental arm omitting radiotherapy
was closed to further accrual. The 1-year PFS for early-stage
e382 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
unfavorable patients with PET-2negative disease with
and without radiotherapy was 97.3% and 94.9%, respectively
(p = .026), with no difference in OS.
CONCLUSION
Interim PET-CT has emerged as a surrogate to better select
patients for therapy intensification or de-escalation. The
goal of these trials is to limit intensive chemotherapy/
radiotherapy to a subset of patients who might benefit
from an aggressive approach and spare the vast majority of
patients the associated toxicities. Early PFS and FFS data
suggest that there may be fewer earlier treatment failures in
patients with PET-2positive disease with escalation of
therapy compared with historical controls, although longer
follow-up is required to assess whether these strategies
actually translate to an OS advantage. Results with escala-
tion or de-escalation strategies appear largely similar, and
the two have not been compared. The U.K. RATHL trial
supports the omission of bleomycin in patients with a
negative PET-CT after two cycles of ABVD.
Although patients with interim or end-of-therapy PET-
2positive disease and PET-2negative disease have dif-
ferent outcomes with standard therapy, these are likely a
reflection of variable biology at diagnosis. The limitations of
clinical prognostic models have led to the development of
molecular and immune-based markers.56 Gene expression
profiling identified a signature of tumor-associated CD68+
macrophages, whose frequency correlated with treatment
failure and OS and outperformed the IPS as a prognostic
biomarker.57 Increase in CD68+ macrophages at diagnosis
has also been shown to correlate with positive interim PET-
CT using the Deauville scale.58,59 Correlative data from the
E2496 trial found that tumor-associated macrophages on
initial pathology was associated with a worse FFS and OS.56
An analysis of a cohort of GHSG patients found that ele-
vated serum levels of thymus and activation-regulated
chemokine/CCL17 at diagnosis were associated with an
increased risk of chemotherapy failure with multivariate
analysis (odds ratio, 3.052; 95% CI, 1.6055.804, p , .007)
when treated based on standard of care at the time of
diagnosis.60 A 23-gene panel has been developed that may
identify at diagnosis patients who are at increased risk of
treatment failure and death.61 All of these biomarkers hold
promise but require prospective validation. Additional
studies are also required to assess how they compare with
prognosis based on interim PET results.
Although the trials discussed in the risk-adapted strategies
described have largely used ABVD and escBEACOPP, there
are other novel combinations that are currently being
evaluated in phase III randomized trials due to excellent
initial results. A phase I pilot study showed an excellent CR
rate with the anti-CD30 antibody-drug conjugate, brentux-
imab vedotin plus ABVD (21 of 22 patients, 95%) or for
brentuximab plus AVD (24 of 25 patients, 95%) when used
up front for stage IIAX, IIBIVB Hodgkin lymphoma.62 Be-
cause of increased pulmonary toxicity seen when bleomycin
was used in conjunction with brentuximab vedotin,

the ongoing phase III multicenter study is evaluating
brentuximab plus AVD versus ABVD in Hodgkin lymphoma.63
A variant of BEACOPP called BrECADD has been tested
in an early-phase clinical trial with excellent results.64
BrECADD eliminates bleomycin, vincristine, procarbazine,
and prednisone and replaces them with brentuximab
vedotin, dacarbazine, and dexamethasone. BrECADD has an
18-month PFS of 89% (95% CI, 77%100%) with 18-month
OS of 100% in an early-phase trial. BrECADD is cur-
rently being compared with escBEACOPP in a randomized
frontline trial for advanced Hodgkin lymphoma (HD21 trial)
by the GHSG. Emerging data suggest that immune
checkpoint inhibitors are very effective in the relapsed/
refractory setting, and trials are underway in the frontline
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December 2015; Orlando, FL.
42. Hague C, Johnson P, Federico M, et al. Pulmonary function and grade 3/
4 clinical events in PET negative patients taking part in the international
rathl trial (CRUK/07/033): a comparison of 12 vs 4 doses of bleomycin.
Paper presented at: 13th International Conference on Malignant
Lymphoma; June 2015; Lugano, Switzerland.
43. van Leeuwen FE, Klokman WJ, Stovall M, et al. Roles of radiation dose,
chemotherapy, and hormonal factors in breast cancer following
Hodgkins disease. J Natl Cancer Inst. 2003;95:971-980.
44. Aleman BM, van den Belt-Dusebout AW, Klokman WJ, et al. Long-term
cause-specific mortality of patients treated for Hodgkins disease. J Clin
Oncol. 2003;21:3431-3439.
45. Myrehaug S, Pintilie M, Tsang R, et al. Cardiac morbidity following
modern treatment for Hodgkin lymphoma: supra-additive cardiotox-
icity of doxorubicin and radiation therapy. Leuk Lymphoma. 2008;49:
1486-1493.
46. Hodgson DC, Grunfeld E, Gunraj N, et al. A population-based study of follow-
up care for Hodgkin lymphoma survivors: opportunities to improve sur-
veillance for relapse and late effects. Cancer. 2010;116:3417-3425.
47. De Bruin ML, Sparidans J, vant Veer MB, et al. Breast cancer risk in
female survivors of Hodgkins lymphoma: lower risk after smaller ra-
diation volumes. J Clin Oncol. 2009;27:4239-4246.
48. Picardi M, De Renzo A, Pane F, et al. Randomized comparison of
consolidation radiation versus observation in bulky Hodgkins lym-
phoma with post-chemotherapy negative positron emission tomog-
raphy scans. Leuk Lymphoma. 2007;48:1721-1727.
49. Hodgson DC. Long-term toxicity of chemotherapy and radiotherapy in
lymphoma survivors: optimizing treatment for individual patients. Clin
Adv Hematol Oncol. 2015;13:103-112.
50. Aleman BM, Raemaekers JM, Tirelli U, et al; European Organization for
Research and Treatment of Cancer Lymphoma Group. Involved-field
radiotherapy for advanced Hodgkins lymphoma. N Engl J Med. 2003;
348:2396-2406.
51. Aleman BM, Raemaekers JM, Tomisic R, et al; European Organization for
Research and Treatment of Cancer (EORTC) Lymphoma Group.
Involved-field radiotherapy for patients in partial remission after

chemotherapy for advanced Hodgkins lymphoma. Int J Radiat Oncol
Biol Phys. 2007;67:19-30.
52. Johnson PW, Sydes MR, Hancock BW, et al. Consolidation radiotherapy
in patients with advanced Hodgkins lymphoma: survival data from the
UKLG LY09 randomized controlled trial (ISRCTN97144519). J Clin Oncol.
2010;28:3352-3359.
53. Diehl V, Franklin J, Hasenclever D, et al. BEACOPP, a new dose-escalated
and accelerated regimen, is at least as effective as COPP/ABVD in
patients with advanced-stage Hodgkins lymphoma: interim report
from a trial of the German Hodgkins Lymphoma Study Group. J Clin
Oncol. 1998;16:3810-3821.
54. Savage KJ, Connors JM, Villa DR, et al. Advanced stage classical Hodgkin
lymphoma patients with a negative PET-scan following treatment with
ABVD have excellent outcomes without the need for consolidative
radiotherapy regardless of disease bulk at presentation. Paper pre-
sented at: 57th American Society of Hematology Annual Meeting and
Exposition; December 2015; Orlando, FL.
55. Raemaekers JM, Andre MP, Federico M, et al. Omitting radiotherapy in
early positron emission tomography-negative stage I/II Hodgkin lym-
phoma is associated with an increased risk of early relapse: clinical
results of the preplanned interim analysis of the randomized EORTC/
LYSA/FIL H10 trial. J Clin Oncol. 2014;32:1188-1194.
56. Tan KL, Scott DW, Hong F, et al. Tumor-associated macrophages predict
inferior outcomes in classic Hodgkin lymphoma: a correlative study
from the E2496 Intergroup trial. Blood. 2012;120:3280-3287.
57. Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in
classic Hodgkins lymphoma. N Engl J Med. 2010;362:875-885.
58. Cuccaro A, Annunziata S, Cupelli E, et al. CD68+ cell count, early
evaluation with PET and plasma TARC levels predict response in Hodgkin
lymphoma. Cancer Med. Epub 2016 Jan 13.
59. Touati M, Delage-Corre M, Monteil J, et al. CD68-positive tumor-
associated macrophages predict unfavorable treatment outcomes in
classical Hodgkin lymphoma in correlation with interim fluorodeoxyglucose-
RISK-ADAPTED TREATMENT OF ADVANCED HL
positron emission tomography assessment. Leuk Lymphoma. 2015;56:
332-341.
60. Sauer M, Plutschow A, Jachimowicz RD, et al. Baseline serum TARC
levels predict therapy outcome in patients with Hodgkin lymphoma. Am
J Hematol. 2013;88:113-115.
61. Scott DW, Chan FC, Hong F, et al. Gene expression-based model using
formalin-fixed paraffin-embedded biopsies predicts overall survival in
advanced-stage classical Hodgkin lymphoma. J Clin Oncol. 2013;31:692-700.
62. Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined
with ABVD or AVD for patients with newly diagnosed Hodgkins lym-
phoma: a phase 1, open-label, dose-escalation study. Lancet Oncol.
2013;14:1348-1356.
63. National Institutes of Health. Phase 3 Frontline Therapy Trial in Patients
With Advanced Classical Hodgkin Lymphoma. https://clinicaltrials.gov/
ct2/show/nct01712490?Term=c25003&rank=1. Accessed January 6,
2016.
64. Borchmann P, Eichenauer DA, Plutschow A, et al. Targeted BEACOPP
variants in patients with newly diagnosed advanced stage classical
Hodgkin lymphoma: final analysis of a randomized phase II study. Paper
presented at: 57th American Society of Hematology Annual Meeting
and Exposition; December 2015; Orlando, FL.
65. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab
in relapsed or refractory Hodgkins lymphoma. N Engl J Med. 2015;372:
311-319.
66. National Institutes of Health. A Study of Brentuximab Vedotin Com-
bined With Nivolumab for Relapsed or Refractory Hodgkin Lymphoma.
https://clinicaltrials.gov/ct2/show/study/NCT02572167. Accessed Janu-
ary 6, 2016.
67. National Institutes of Health. ACP-196 in Combination With Pem-
brolizumab, for Treatment of Hematologic Malignancies (KEYNOTE145).
https://clinicaltrials.gov/ct2/show/NCT02362035. Accessed January 6,
2016.
68. Chiou VL, Burotto M. Pseudoprogression and Immune-Related Re-
sponse in Solid Tumors. J Clin Oncol. 2015;33:3541-3543.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e385
HEMATOLOGIC MALIGNANCIESLYMPHOMA
AND CHRONIC LYMPHOCYTIC LEUKEMIA

Chemoimmunotherapy Versus
Targeted Treatment in Chronic
Lymphocytic Leukemia: When,
How Long, How Much, and in
Which Combination?

CHAIR
John M. Pagel, MD, PhD
Fred Hutchinson Cancer Research Center
Seattle, WA

SPEAKERS
Jennifer R. Brown, MD, PhD
Dana-Farber Cancer Institute
Boston, MA

Michael J. Hallek, MD
University Hospital Cologne
Cologne, Germany
 MANAGEMENT OF CLL IN THE ERA OF NOVEL TARGETED THERAPIES

Chemoimmunotherapy Versus Targeted Treatment in Chronic

Lymphocytic Leukemia: When, How Long, How Much, and in
Which Combination?
Jennifer R. Brown, MD, PhD, Michael J. Hallek, MD, and John M. Pagel, MD, PhD

OVERVIEW

During the past 5 years, rapid therapeutic advances have changed the landscape of chronic lymphocytic leukemia (CLL)
therapy. This disease has traditionally been treated using cytotoxic chemotherapy regimens in combination with anti-
CD20 antibody treatment, and recent long-term follow-up data from multiple centers suggest that fit patients with CLL
with favorable disease featuresparticularly mutated immunoglobulin heavy chain variable region (IGHV) genes
derive very long-term benefit from the most potent of these regimens, namely the fludarabine, cyclophosphamide, and
rituximab (FCR) regimen. The advent of oral targeted therapies, particularly ibrutinib and idelalisib, has provided
generally well-tolerated and highly effective additional options that have come into widespread use in the relapsed
setting. Additional agents are advancing in clinical development, with the BCL-2 inhibitor venetoclax likely to be ap-
proved by the U.S. Food and Drug Administration (FDA) in 2016. With the development of these novel therapies for
patients with relapsed CLL, many unanswered questions remain, including the optimal sequence (first vs. second line),
duration, discontinuation, and combination of these agents. In addition, recent publications show the emergence of a
pattern of treatment resistance in certain subgroups of patients with del(17p) and complex karyotype that needs further
study and improvement. Because the field of CLL management has become much more complex, we focus here on
understanding the recent data and discuss many of the questions and controversies important for how we approach
patients with CLL.

C hronic lymphocytic leukemia is a heterogeneous neo-

plasm. Some patients never require treatment, whereas
others face an aggressive treatment course similar to
acute leukemia. In general practice, newly diagnosed
patients with asymptomatic early- or intermediate-stage
disease (Rai 0, I-II, Binet A or B) should be monitored
without therapy unless they have evidence of disease
progression or show clear symptoms caused by CLL.1
Several studies on early-stage CLL, as well as a meta-
analysis,2 have not been able to demonstrate a potential
benefit of early intervention therapy to date, and thus the
International Workshop on CLL guidelines1 remain the
standard determinant of therapy initiation. In CLL, the
absolute lymphocyte count should not be used as the sole
indicator for treatment because even markedly elevated
leukocyte counts rarely cause symptoms or complications.
It should be stressed that these recommendations have
not changed in the era of new targeted agents. Clinical
trials that test the early use of novel inhibitors are cur-
rently underway.3
USE OF CHEMOIMMUNOTHERAPY FOR PATIENTS
WITH FRONT-LINE AND RELAPSED DISEASE
Potential Advantages of Chemoimmunotherapy
Currently there remains a general consensus that no curative
treatment of CLL exists, with the exception of allogeneic
stem cell transplantation.4 Chemoimmunotherapy achieves
disease control and survival prolongation and has therefore
been the current standard treatment for patients with
previously untreated CLL.5-7 Additionally, though the outcome
following chemoimmunotherapy may be highly variable, im-
portant subgroups of patients show an excellent outcome,
corroborating its use as standard first-line therapy. On the
other hand, secondary malignancies are one of the most
concerning unwanted effects following chemoimmunotherapy
and the true long-term incidence in comparison with patients
with CLL not receiving chemoimmunotherapy needs to be
better defined.
The German CLL Study Group has previously shown in their
CLL8 study that the addition of the anti-CD20 monoclonal
antibody rituximab (R) to fludarabine and cyclophosphamide

From the Dana-Farber Cancer Institute, Boston, MA; University Hospital of Cologne, Cologne, Germany; Swedish Cancer Institute, Seattle, WA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: John M. Pagel, MD, PhD, Swedish Cancer Institute, 1221 Madison St., Suite 1000, Seattle, WA 98104; email: john.pagel@swedish.org.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e387

BROWN, HALLEK, AND PAGEL
(FC) improved both the progression-free survival (PFS) and the
overall survival (OS) of physically fit patients with previously
untreated symptomatic CLL.5 On the basis of these findings,
FCR has become a standard therapy for physically fit patients
with previously untreated CLL. In an updated report of this trial,
Fischer et al presented the results of an extended observation
time with a median follow-up of 5.9 years, with particular
emphasis on long-term follow-up for survival and adverse
events.8 This follow-up analysis of the CLL8 study continues to
demonstrate an improvement in PFS and OS in physically fit
patients treated with FCR when compared with FC. Patients
with del(17p) showed a significantly shorter OS than those in all
of the other cytogenetic subgroups. Conversely, of the patients
with del(11q), which is considered an adverse prognostic
group,9 patients with IGHV mutation responded very well to
FCR and, as a consequence, showed an outcome similar to
other patients without del(17p). FCR induced a higher rate of
prolonged neutropenia during the first year after the end of
treatment.
In multivariate analyses including the most commonly
used clinical and biologic prognostics, several predicted
OS. Each of these factors were shown to correlate with OS
in previous publications.9-16 The PFS for patients with
IGHV-mutated disease showed a significant difference in
favor of the IGHV mutation subgroup compared with un-
mutated disease. Most importantly, the IGHV mutation
subgroup treated with FCR showed a significantly longer PFS
and OS than those treated with FC. The median OS for
patients with IGHV-mutated CLL was not reached. More than
83% of the patients with an IGHV mutation treated with FCR
were still alive after almost 6 years of observation time.
Notably, cytogenetic subgroup analysis of patients with
IGHV mutation treated with FCR confirmed this excellent
outcome for all cytogenetic subgroups including del(11q),
except for patients with del(17p) and normal karyotype.
In a similar way, the University of Texas MD Anderson
Cancer Center group reviewed the phase II FCR study to
identify long-term disease-free survivors among the 300
patients included in the trial.17 At the median follow-up of
12.8 years, PFS was 30.9% (median PFS, 6.4 years). The
KEY POINTS
Chemoimmunotherapy remains an appropriate option
for many patients with CLL and in particular those with
most favorable features in the front-line setting.
The use of targeted novel agents has changed the
therapeutic landscape for treating relapsed, refractory
CLL.
Many unanswered questions remain for further
investigation, including those assessing the optimal
length of therapy, the sequencing of agents, and
understanding responses with class switching, as well as
questions focusing on the mechanisms of overcoming
resistance.
e388 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
12.8-year PFS was 53.9% for patients with mutated IGHV
(IGHV-M) and 8.7% for patients with unmutated IGHV (IGHV-
UM). A plateau was seen on the PFS curve for patients
with IGHV-M, with no relapses beyond 10.4 years in 42
patients (total follow-up, 105.4 patient-years). On multi-
variable analysis, IGHV-UM (hazard ratio [HR] 3.37; 95% CI,
2.185.21; p , .001) and del(17p) by conventional kar-
yotyping (HR 7.96; 95% CI, 1.0261.92; p = .048) were sig-
nificantly associated with inferior PFS. In a retrospective
report on 404 patients with CLL receiving front-line FCR,
Rossi et al also found that patients with CLL with mutated
IGHV and neither del(11q) nor del(17p) deletion had a very
high rate of long-term PFS, with OS similar to an age-
matched normal control population at 5 years.18
Taken together, most patients with IGHV-mutated CLL
seem to benefit substantially from FCR chemoimmunotherapy,
resulting in long-term control of the disease. This observed
benefit of FCR for the majority of patients with IGHV mutation
may announce the emergence of a therapeutic approach that
is guided by the IGHV mutational status. Secondly, given the
excellent PFS following first-line FCR therapy, it may be more
difficult to replace first-line chemoimmunotherapy with FCR
with novel agents in this specific subset of patients with CLL.
To test the value of newer targeted therapies against FCR
in previously untreated, fit patients with CLL, several phase
III trials have started that compare the potential of
chemotherapy-free treatment strategies with FCR or other
chemoimmunotherapies.19,20
Potential Disadvantages of Chemoimmunotherapy
One of the potential risks of chemoimmunotherapy is myelo-
and immunosuppression and, in its consequence, the onset
of myeloid malignancies (acute myeloid leukemia [AML] and
myelodysplastic syndrome [MDS]). Moreover, other cancers
may also be increased in CLL. Therefore, Benjamini et al
investigated the characteristics, incidence, outcomes, and
factors associated with second cancers for 234 patients
receiving FCR-based regimens in the front-line setting.21
They showed that the risk of second cancers was 2.38 times
higher than the expected risk for the general population.
Ninety-three patients (40%) had other cancers before FCR,
and 66 patients (28%) had them after FCR. Rates of therapy-
related acute AML/MDS (t-AML/MDS; 5.1%) and Richter
transformation (9%) were high, while solid tumors were not
increased.
In some contrast, in their follow-up report on the CLL8
protocol, Fischer et al were not able to report increased rates
of t-AML/MDS and Richter transformation following FCR
chemoimmunotherapy when compared with FC.22,23 The
frequency of secondary malignancies was also similar in both
arms. An increased frequency of Richter transformations
was noted in the FC but not FCR arm, in line with the cur-
rent literature.24,25 In addition, achievement of a response
seemed to correlate with a lower incidence of secondary
malignancies and Richter transformations.26 As CLL itself
appears to increase the risk of second malignancies, very

long-term follow-up studies of patients treated with
chemoimmunotherapy or with novel agents will be required
to accurately assess how either type of therapy influences
this risk.
PARAMETERS TO BE CONSIDERED FOR THE
CHOICE OF THE BEST THERAPY
Given the impressive number of choices, the selection of the
optimal treatment of a given CLL patient has become a task
that requires experience, good clinical judgment, and ap-
propriate use of diagnostic tools. The following parameters
should be considered before recommending a treatment of
CLL: (1) the clinical stage of the disease, (2) the symptoms of
the patient, (3) the fitness of the patient, (4) the genetic risk
of the leukemia, and (5) the treatment situation (first vs.
second line, response vs. nonresponse to the last treat-
ment).27 Using the assessment of these five parameters, the
following recommendations can be given.
First-Line Treatment
Treatment should be initiated for patients with advanced
(Binet C, Rai III-IV) or active symptomatic disease. In this
situation, patients must be evaluated for their physical
condition (or comorbidity). For patients in good physical
condition (go-go) as defined by a normal creatinine clear-
ance and a low score on the cumulative illness rating scale
(CIRS),28 patients should be offered combination therapies
such as FCR. Patients with a somewhat impaired physical
condition (slow-go) may be offered either chlorambucil in
combination with an anti-CD20 antibody (with obinutuzu-
mab being the most active agent). The aim of therapy in this
situation is symptom control. For patients with symptomatic
disease and with del(17p) or TP53 mutations, it has been
generally agreed that patients should receive ibrutinib as
first-line treatment.29,30
Second-Line Treatment
As a general rule, the first-line treatment may be repeated, if
the duration of the first remission exceeds 24 to 36 months.
The choice is more difficult in treatment-refractory CLL (as
defined by an early relapse within 612 months after the
last treatment) or in cases with the chromosomal aber-
ration del(17p). In principle, the initial regimen should be
changed. The following treatment options should be dis-
cussed: (1) kinase inhibitors such as idelalisib or ibrutinib,
(2) experimental protocols using other nonapproved drugs,
and (3) cellular therapies (e.g., chimeric antigen recep-
tor [CAR] T-cell therapy) and allogeneic stem cell trans-
plantation with curative intent in select patients.31 The
choice of one of these options may depend on the fitness of
the patient, the availability of the drugs, and the molecular
cytogenetics. Finally, it is important to emphasize that
patients with refractory disease should be treated within
clinical trials whenever possible.
MANAGEMENT OF CLL IN THE ERA OF NOVEL TARGETED THERAPIES
NOVEL TARGETED THERAPIES IN CHRONIC
LYMPHOCYTIC LEUKEMIA
The recent development of targeted therapies has revolu-
tionized the treatment landscape for patients with CLL,
particularly relapsed disease. The most advanced of these
molecules are FDA approved and include the first-generation
Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, and the PI3K
delta inhibitor, idelalisib. The BCL-2 inhibitor venetoclax has
been also expected to receive FDA approval in the first half of
2016. To understand how we might use these agents and
others as the field evolves, we will consider each target and
inhibitor in turn (Table 1 and Fig. 1).
BTK Inhibitors: Ibrutinib
Ibrutinib is the first-in-class inhibitor of BTK, which is critical
for B-cell survival and function but whose loss otherwise
causes few problems for patients with Bruton X-linked
agammaglobulinemia. Ibrutinib is a covalent inhibitor that
binds to Cys481 in BTK, resulting in prolonged target in-
hibition despite a short circulating half-life.32,33 Ibrutinib is a
potent inhibitor but not a specific one, inhibiting 19 other
kinases, several covalently, with IC50 greater than 100 nM.33
In fact, ibrutinib has been shown to covalently inhibit ITK,34 a
kinase important for T and natural killer cell activity that may
lead to impaired antibody-dependent cellular cytotoxicity.35
Nonetheless, the clinical activity of ibrutinib in CLL is
impressive. In the initial CLL-specific phase IB/II study,
nodal responses were noted to be very high initially, often
with increase in lymphocytosis, which then resolved
slowly over time.29 This observation, which is universal
with B-cell receptortargeting therapies, led to the defi-
nition of a new response categorypartial response (PR)
with lymphocytosisfor patients who meet all criteria for
PR except that their lymphocyte count is persistently el-
evated.36 Over time as the lymphocyte count decreases,
these responses have evolved to PR by standard criteria.1
Thus, at the time of the first single-agent report, the overall
response rate (ORR) was 71%, with an estimated 26-month
PFS of 75% for patients with a median of four prior ther-
apies.29 This study led to accelerated FDA approval in
February 2014 of ibrutinib for patients with CLL after at
least one prior therapy. The confirmatory registration trial,
RESONATE, randomly assigned patients with relapsed CLL
to ibrutinib or ofatumumab and demonstrated a significant
prolongation of both PFS (HR 0.22; p , .001) and OS (HR
0.43; p = .005) in the ibrutinib arm.37 The RESONATE-17
study was a phase II registration trial focused on patients
with relapsed del(17p) with one to four prior therapies and
early results demonstrated an estimated 12-month PFS of
79%.38 Based on these data, full FDA approval was granted
in July 2014 for patients with CLL after at least one prior
therapy, or patients with CLL with del(17p) in any line of
therapy.
Longer-term 3-year follow-up of the original phase IB/II
study was recently published and demonstrated that the
ORR has increased in the relapsed refractory cohort to 90%
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BROWN, HALLEK, AND PAGEL

TABLE 1. Current Novel Agents for Chronic Lymphocytic Leukemia

Agent Unique Features Select Key Trials Progression-Free Survival
BTK Inhibitors
Ibrutinib First-in-class BTK RESONATE, R/R CLL, ibrutinib vs. ofatumumab, FDA R/R CLL single-agent: 26 mos = 75%39
inhibitor approved37
RESONATE-17, R/R CLL and front-line 17p deletion del17p R/R CLL single-agent:
under FDA review38 12 mos = 79%38
RESONATE-2, first-line, ibrutinib vs. chlorambucil First-line single-agent:
FDA approved49 18 mos = 94%49
Acalabrutinib Lacks targeting of Phase I-II single-agent trial with ORR of 95%51 R/R CLL single-agent with median
ITK or TEC kinase 3 prior regimens: 12 mos = 100%51
BGB-3111 Targets BTK and TEC Phase I trial in first 14 patients with ORR of 93%52 N/A
but not ITK kinase
Pi3K Inhibitors
Idelalisib First-in-class PI3K Study 116, R/R CLL, idelalisib/rituximab vs. R/R CLL with rituximab (45% with
inhibitor targeting rituximab, FDA approved.57 del(17p)): median 19.4 mos57
d isoform
Study 115, R/R CLL BR/idelalisib vs. BR under FDA R/R CLL with BR: median 23.1 mos59
review59
Phase II first line, idelalisib and rituximab in 64 First line with rituximab: 36
patients older than age 65 with ORR of 97%64 mos = 83%64
Duvelisib Dual PI3K d and g Phase III R/R CLL, duvelisib vs. ofatumumab, R/R CLL phase I single-agent (52%
inhibitor under FDA review with del(17p)): 24 mos = 59%.66
TGR-1202 PI3K d inhibitor with Phase I, single-agent TGR-1202 in 20 patients N/A
once-daily dosing with R/R CLL with 88% nodal response67
Bcl-2 Inhibitor
Venetoclax Lacks targeting of Phase I/expansion R/R CLL, venetoclax single R/R CLL single agent: median
Bcl-xL agent, under FDA review72 25 mos72
Phase Ib R/R CLL, venetoclax and rituximab in R/R CLL with rituximab (33% with
49 patients with ORR of 86%73 del(17p)): 24 mos = 83%.73
Monoclonal Antibodies/Engineered Antibody-Like Molecules
Obinutuzumab Humanized anti- CLL11 first line, R/R CLL, obinutuzumab and First line with chlorambucil: median
CD20 antibody chlorambucil, FDA approved7 26.7 mos.7
Ofatumumab Humanized anti- First line, ofatumumab and chlorambucil First line with chlorambucil: median
CD20 antibody vs. chlorambucil, FDA approved87 22.4 mos.87
CLL refractory to fludarabine (F) and alemtuzumab Refractory to FA duration of
(A), FDA approved88 response = 6.5 mos.88
Ublituximab IgG1 antibody with Phase II R/R (40 patients) CLL with ibrutinib with N/A
unique binding ORR = 88% and 95% in high risk (20 patients)67
sequence
Phase III R/R CL, ublituximab and TGR-1202
vs. obinutuzumab and chlorambucil ongoing
Otlertuzumab Humanized anti- Phase I, single agent in 83 patients with R/R CLL R/R CLL with bendamustine:
CD37 Ig fusion with 23% ORR89 median 16.1 mos90
protein
Phase II R/R CLL, otlertuzumab and bendamustine
vs. bendamustine90
Abbreviations: N/A, not available; R/R, relapsed/refractory; BR, bendamustine and rituximab; BTK, Bruton tyrosine kinase; CLL, chronic lymphocytic leukemia; FDA, U.S. Food and Drug
Administration; mos, months; ORR, overall response rate.

with 7% complete remissions (CR) with a median time on
treatment of 23 months and 53% of patients remaining
on treatment.39 The estimated PFS at 30 months was
69%, indicating that although most patients remain in PR,
nonetheless they can maintain long-term remissions. In
addition, cytogenetic aberrations were also profoundly
predictive of PFS. Those patients with del(17p) had a median
PFS of 28 months, while the PFS for those with del(11q) was
74% at 30 months and for those with neither high-risk
deletion, it was 87%. In the RESONATE study, at present
with 16-month follow-up on the ibrutinib arm, no difference
in PFS has been seen between patients with and without
del(17p).40 However, among patients with disease that re-
lapsed on ibrutinib, both del(17p) and complex karyotype are
quite common, with the latter suggested to be more important
in two studies.41,42 Among patients with relapsing disease,
Richter transformation had a cumulative incidence of 4.5%
at 1 year in the largest study to date and was seen in 18 of
31 patients with relapsed disease with median survival
of 3.5 months.41 Chronic lymphocytic leukemia relapse
tended to occur later but was also aggressive with median
OS of 17.5 months. In a second study, median OS after

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FIGURE 1. Schematic Representation of CLL Lymphocyte Depicting the B-Cell Signaling Cascade and Novel
Therapeutic Agents and Their Associated Targets
discontinuing ibrutinib was only 3.1 months.43 Thus, disease
progression on ibrutinib has become a new unmet need for
patients showing aggressive disease that may be very dif-
ficult to treat. Ongoing work has focused on elucidating the
mechanism(s) of relapse; among patients with relapsing CLL,
mutations have been identified in the target Cys residue in
BTK that results in a change to Ser that abrogates covalent
binding, as well as activating mutations in PLCg, the im-
mediate downstream target of BTK.44,45 Little is yet known
about the biology of the Richter transformations.
Ibrutinib has been generally well tolerated with the most
common adverse events including mild diarrhea, nausea,
ecchymosis, and arthralgia; in most clinical trials, the rate of
discontinuation for adverse events has been 10%12%.37,39
However, this risk has been shown to be age-dependent,
with higher rates among those over age 70 and even more-so
among patients over age 80.41 Medically important adverse
events include atrial fibrillation that was increased in the
ibrutinib arm in RESONATE and occurred at 5%10% fre-
quency in most studies,37,38 as well as risk of major hem-
orrhage, which may be related, at least in part, to inhibition
of collagen-induced platelet aggregation by ibrutinib through
its effect on BTK and possibly TEC kinase.46,47 Because of the
latter risk, ibrutinib should be cautiously combined with
anticoagulation, if at all.
Increasing data have become available on the use of
ibrutinib as initial therapy for CLL. In the initial phase IB/II
study, 31 treatment-naive patients over age 65 with gen-
erally low-risk disease were enrolled, and, at the most recent
30-month follow-up, 81% remained on study treatment with
an ORR of 84% and 23% patients were in CR at this longer
follow-up.48 The PFS was 96% at 30 months with one relapse
and death in a patient with del(17p).39 RESONATE-2 was a
MANAGEMENT OF CLL IN THE ERA OF NOVEL TARGETED THERAPIES
registration trial for patients with previously untreated CLL
older than age 65 without del(17p) who were randomly
assigned to either single-agent ibrutinib or chlorambucil.
Ibrutinib significantly improved PFS (HR 0.16; p = .001), with
an estimated 18-month PFS of 94%, as well as ORR and OS,
and 87% of patients continue to take ibrutinib.49 Notable
serious adverse events among the 136 patients in the
ibrutinib arm included five major hemorrhages, two un-
explained sudden deaths, hypertension in 14%, and atrial
fibrillation in 6%. This study led to FDA approval of single-
agent ibrutinib for patients with previously untreated CLL in
early March 2016.
Next-Generation BTK Inhibitors
Given the success of ibrutinib, much interest has naturally
focused on efforts for continued improvement. To date, this
attention has largely been aimed at developing an equally
potent inhibitor that may be more specific for inhibition of
BTK in hopes of reducing the bleeding and cardiac toxicities
that appear to be because of ibrutinib-mediated off-target
effects. The first more specific inhibitor was CC-292, which
showed lower response rates and less durability of response
despite escalating to a high-dose and achieving high-levels of
BTK occupancy.50 The reason for this reduced activity has
been unclear but seems likely due to reduced bioavailability
or delivery of the drug to tumor. Within the past year,
however, two additional specific BTK inhibitors that bind
covalently to the same Cys target as ibrutinib have shown
promising results. Acalabrutinib (ACP-196) targets BTK but
not ITK or TEC and has been studied in a phase I and II
relapsed CLL single-arm study among patients with a me-
dian of three prior regimens and showed an ORR of 95%,
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BROWN, HALLEK, AND PAGEL
including 10% PR with lymphocytosis (PR-L) at 14.3 months,
with only two PFS events thus far (one death from pneumonia
and one CLL progression).51 With current early follow-up, no
events of major hemorrhage or atrial fibrillation have occurred.
Acalabrutinib has entered two registration trials, including a trial
head-to-head against ibrutinib in relapsed high-risk CLL. The
second drug, BGB-3111, targets BTK and TEC but not ITK. In a
phase I study across B-cell malignancies presented at the 2015
American Society of Hematology (ASH) Annual Meeting, 39 pa-
tients have been enrolled, and complete BTK occupancy has been
demonstrated in lymph node biopsies.52 The overall response
rate was 93% (13/14 patients) to date, and this study is ongoing.
PI3K Inhibitors: Idelalisib
The other critical target that led to an FDA-approved drug in
CLL has been the delta isoform of PI3 kinase (PI3K) that is
targeted by idelalisib. Expression of the delta isoform has
been shown to be limited to hematopoietic cells, and its
primary physiologic function appears to be in B cells based
on the phenotype of the knockout mouse.53 Most down-
stream PI3K signaling in CLL cells has been shown to go
through delta54,55 and can be inhibited in vitro and in vivo by
idelalisib.54-56 In the phase I relapsed CLL study, idelalisib
had a 72% ORR, including 33% PR-L.56 Median PFS across all
cohorts in this heavily pretreated population (median of five
prior regimens) was 15.8 months, while the median PFS at
the recommended phase II dose of 150 mg or more two
times per day was 32 months. Because of the persistence of
lymphocytosis over time in the phase I patients and the
ongoing evolution of the response criteria, it was decided to
study combination therapies with idelalisib in registration
trials. Three phase III randomized trials were designed for
patients with relapsed CLL: idelalisib/rituximab versus rit-
uximab (study 116), idelalisib/ofatumumab versus ofatu-
mumab (study 119), and idelalisib/bendamustine/rituximab
(BR) versus bendamustine/rituximab (BR) (study 115). Study
116 enrolled patients with relapsed CLL with increased
numbers of comorbidities, 45% of whom had del(17p), and
demonstrated significant improvements in both PFS (HR
0.25; median, 19.4 vs. 7.3 months at the second interim
analysis following crossover; p , .0001) and OS.57 No dif-
ference in PFS was seen based on the adverse prognostic
factors of unmutated IGHV or del(17p)/TP53 mutation.
These results led to the FDA approval of idelalisib with
rituximab in July 2014 for patients with relapsed CLL for
whom rituximab may be appropriate therapy. Subsequently,
study 119 results showed improved PFS for idelalisib with
ofatumumab (median, 16.3 months) versus ofatumumab
alone (median, 8 months; HR 0.27; p , .0001).58 The results
of idelalisib plus BR versus BR (study 115) were reported at
the ASH Annual Meeting in December 2015 and showed
significant improvement in median PFS 11.1 to 23.1 months
(HR 0.33; p , .0001).59 In this patient population with 33% of
patients with del(17p) and 30% of patients with refractory
CLL, OS was also significantly improved. Both of these studies
are expected to lead to additional indications for idelalisib.
e392 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Idelalisib shows a characteristic pattern of toxicity that
includes transaminitis at weeks 4 to 8, delayed colitis oc-
curring at a median of 7 months after starting treatment,
and a low-rate of drug-related pneumonitis occurring at a
median of 4 months. A recent summary of toxicity data
across eight trials of patients primarily with relapsed disease
demonstrated that grade 3 or greater transaminitis and
colitis were each seen in 14% of patients, and pneumonitis
was seen in 3%. These toxicities have been responsive to
drug hold and to corticosteroids, and recent data have
demonstrated CD8+ T-cell infiltrates in the liver60 and co-
lon61,62 of affected patients. An immunologic mechanism
of toxicity may not be surprising given that the delta iso-
form of PI3K has been shown to be critical for the survival
and function of regulatory T cells,63 and recent data have
demonstrated that early hepatotoxicity is associated with a
decrease in T regulatory cells 1 month after starting idela-
lisib.60 These toxicities do resolve with drug hold and/or
steroid use, and, following that, the majority of patients are
able to resume dosing at the same or lower dose. Colitis can
prove most troublesome but can be commonly managed by
oral budesonide with a prolonged slow taper.
Use of idelalisib in the up-front setting has been more
limited than ibrutinib. The study with the longest follow-up
was a phase II study of 64 patients older than age 65 treated
front line with idelalisib with rituximab. These results
showed a 97% ORR with 19% CR and 83% PFS at 36 months.64
Among nine patients with del(17p)/TP53 mutation, the ORR
and PFS were both 100%. However, toxicity was also higher,
with rates of 42% for grade 3 or higher diarrhea with long-
term follow-up and 23% for grade 3-4 transaminitis. These
higher rates of toxicity appear consistent with an immu-
nologic mechanism and recently reported high rates of grade
3-4 transaminitis among younger patients treated up front
with idelalisib.60 Randomized registration trials in previously
untreated patients were recently stopped due to excess
infectious deaths on the idelalisib arms, albeit without
mandatory prophylaxis.
Other PI3K Inhibitors
Two other PI3K inhibitors are in advanced clinical devel-
opment. Duvelisib is a dual PI3K delta and gamma inhibitor.
The gamma isoform of PI3K is expressed in CLL cells but also
in cells of the microenvironment, including T cells and
macrophages.65 The phase I study of duvelisib enrolled 55
patients with CLL with a median of four prior regimens, 89%
unmutated IGHV, and 52% with del(17p) or TP53 mutation.66
The ORR was 58% with an estimated 24-month PFS of 59%.
The recommended phase II dose was selected as 25 mg two
times per day, which reaches the IC90 for delta and the IC50
for gamma inhibition in vivo. A phase III registration trial in
relapsed CLL that randomly assigned patients to duvelisib or
ofatumumab has now completed accrual. TGR-1202 is a
next-generation PI3K delta inhibitor that has a different
chemistry and has been postulated to reduce the trans-
aminitis seen with other delta inhibitors. A phase I study

using TGR-1202 enrolled patients across multiple B-cell
malignancies, including 20 patients with CLL.67 Among the
patients with CLL, the nodal response rate was 88% (14/16)
and the PR rate was 63%. Thus far, the rates of grade 3-4
transaminitis (2%) and colitis (1%) have been much lower
than with the other delta inhibitors, but follow-up remains
shorter. TGR-1202 is being further evaluated in many on-
going phase I and II combination trials, with recent initiation
of a phase III registration trial.
Few studies of pan-PI3K inhibitors have been per-
formed in CLL. Pilaralisib has been reported to have a
similar pattern of response as delta inhibitors and a 50%
ORR in CLL, with PFS of 7.4 to 22 months and a 20% overall
response in lymphoma.68 This level of activity may not
be as high as the delta-specific inhibitors described
above. Voxtalisib had activity in follicular lymphoma but
was limited in other histologies. 69 This more limited
activity may reflect the pharmacologic properties of
these compounds in comparison with the delta-specific
inhibitors, so additional studies of pan-PI3K inhibi-
tors with better pharmacodynamic properties are still
warranted.
BCL-2 Inhibition
The BCL-2 specific inhibitor venetoclax is expected to receive
FDA approval in the first half of 2016. This drug represents
the culmination of 2 decades of structure-based design
targeted at BCL-2. Its predecessor navitoclax had clinical
activity in CLL70 but showed dose-limiting thrombocytopenia
because of the direct effect of navitoclax on BCL-XL in cir-
culating platelets, leading to their rapid clearance from the
circulation.71 Venetoclax only has activity against BCL-2 and
has not shown significant clinical thrombocytopenia.72 The
most substantial adverse event with venetoclax has been
tumor lysis syndrome, which led to several revisions of the
dosing schema during the phase I study. Ultimately, the
selected dosing schedule that has moved forward into all
other trials includes a risk stratification for tumor lysis that
dictates whether patients are admitted to the hospital for
first dose and starts all patients at a low dose of 20 mg daily
for a week, with increases to 50 mg, 100 mg, 200 mg, and
eventually to 400 mg daily, which is the recommended phase
II dose for patients with CLL.72 The phase I and expansion
cohort study enrolled 116 patients with a median of four
prior regimens and showed an ORR of 79% with 20% CR.
Median PFS was 25 months in the dose-escalation cohorts.
The CR rate suggests that venetoclax can more effectively
clear blood and bone marrow than the kinase inhibitors, and
this observation has been further supported by data from
the venetoclax combination study with rituximab, which
enrolled less heavily pretreated patients with a median of
two prior regimens.73 The overall response rate was 86%
with 47% CR, and, perhaps most impressively, the estimated
24-month PFS was 83%. Furthermore, half of both CR and PR
were minimal residual disease (MRD)negative in bone
marrow, for an overall rate of 55%.
MANAGEMENT OF CLL IN THE ERA OF NOVEL TARGETED THERAPIES
Venetoclax has also been investigated in very high-risk CLL
groups. A phase II potential registration study focused on
patients with relapsed disease with del(17p) who received
continuous single-agent venetoclax. The study enrolled 107
patients with a median of two prior regimens, and PFS at
12 months was estimated at 72% with OS estimated at 87%.
These data appear comparable to those of ibrutinib in a
similar study.38
UNANSWERED QUESTIONS
Despite the seminal advances seen to date with these novel
agents in CLL therapy, many practical questions remain. The
appropriate sequencing of these agents remains in question,
and the utility of class switching after drug failure has not
been fully elucidated. Questions also persist about the
unknown ability to stop one of these novel agents, partic-
ularly in more favorable, less-heavily pretreated patients
who may not require indefinite long-term therapy. At the
other end of the disease spectrum, will these agents be
meaningful options for patients with very aggressive dis-
ease, such as those with Richter transformation? Or will use
of these drugs result in increased rates of aggressive Richter
transformation? Recently there has also been keen interest
in combinations of targeted agents with standard chemo-
immunotherapeutic regimens. Will these combination ap-
proaches be critical to overcome drug resistance and lead to
major improvements in survival? What about combinations
of two (or even more) targeted agents? Furthermore, how
will these important advances translate from the major
academic centers, where there has been the vast majority of
experience with these agents, to the community setting and
standard clinical practice? Lastly, given this new landscape of
exciting agents, where do we use cellular therapies and
potentially curative stem cell transplantation as we move
forward? We should recognize, moreover, that follow-up
observation after beginning use with a kinase inhibitor has
been short relative to their projected duration of therapy,
and, thus, the full toxicity profiles of these agents have not
yet become completely known.
Can We Stop Therapy With the New Targeted Agents?
How long should patients remain on therapy with a kinase or
BCL-2 inhibitor? Although patients universally favor the use
of an oral regimen, the use of these agents indefinitely may
be less appealing to a large proportion of patients, especially
those who are treatment-naive or relatively early in their
treatment encounters. We previously acknowledged that
many patients with high-risk disease who have failed mul-
tiple lines of therapy will relapse very quickly after stopping
one of the kinase inhibitors. However, for those who may
have lower-risk disease and particularly those who might be
receiving single agents as first-line therapy, can, or should,
we stop therapy at some point and observe? Specifically, is
there a clinical marker such as the absence of any evidence of
MRD that would suggest appropriate discontinuation of a
novel drug therapy?
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e393
BROWN, HALLEK, AND PAGEL
Stopping therapy has the advantage of reducing toxicity
and reducing the selective pressure for resistance. It has
become widely accepted that assessment of MRD can be a
highly sensitive measure of disease burden, especially fol-
lowing CLL-directed chemoimmunotherapy, and has been
commonly defined as having less than one CLL cell in 10,000
leukocytes using standard four-color flow cytometric anal-
ysis.1 Compared with patients with MRD-positive disease,
achieving MRD negativity after treatment correlates with
longer disease-free intervals.74 If a patients disease be-
comes MRD negative, would this result allow for discon-
tinuation of the targeted drug therapy? Data addressing this
question are limited, but Ma et al presented a 2015 ASH
report in a small number of patients using venetoclax in
combination with rituximab where patients were permitted
to stop the BCL-2 inhibitor at any point desired. The data
demonstrated that 27 of 49 treated patients became MRD
negative in the bone marrow, and nine of those patients
stopped venetoclax between 10 and 36 months after beginning
therapy.73 All nine patients with MRD-negative disease remain
in CR with a median follow-up of 16 months. Of note, two
patients in CR but who had evidence of MRD in the marrow also
stopped treatment between 5 and 9 months, but both had
asymptomatic progression while off of therapy. Interestingly,
at least one of these patients responded to rechallenge with
the same regimen. These data clearly set the foundation for
early stopping studies and in particular for patients with
favorable-risk disease, although it must be noted that ven-
etoclax has been much more potent in inducing MRD nega-
tivity than the kinase inhibitors that may require combination
therapy to achieve appreciable rates of MRD negativity.
Can Further Advances Be Made With Combinations of
Therapies Using Targeted Agents?
Combining established therapies with new complementary,
perhaps synergistic, approaches to improve response rates
and deepen the quality of remissions remains a common
theme in oncology care. The promise of inducing more CR or
perhaps becoming MRD negative may translate to longer
durations of remission and improvements in survival. The
conclusions are not clear, but the rationale may be solid,
albeit primarily based on preclinical models. For example,
venetoclax was demonstrated in lymphoma xenograft
models to significantly control tumor growth and provide
synergy when combined with BR.71 In clinical practice,
several single-arm combination studies have been reported
with these novel agents and anti-CD20 antibodies, including
rituximab and ofatumumab or with chemoimmunotherapy,
particularly BR. The HELIOS trial randomly assigned patients
with relapsed CLL without del(17p) to BR versus BR with
ibrutinib and reported a significant improvement in PFS (HR
0.20; p , .0001) in the ibrutinib arm, but no difference in
OS.75 The CR rate was 21% by investigator assessment in
the investigational arm as compared with 5.9% with BR
alone. Whether BR with ibrutinib will prove to be signifi-
cantly better than ibrutinib alone remains unclear and may
e394 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
ultimately depend on whether the increased early CR rate
translates into improved PFS.
With the use of new targeted agents and combinations
with cytotoxic regimens such as BR, however, it is well
understood that there are increased associated treatment-
related toxicities. Perhaps a chemotherapy-free regimen,
even in the front-line setting, may be an attractive option for
patients who are older and who may have multiple comor-
bidities. The long-term complication of developing an MDS and
acute leukemia from the use of cytotoxic chemotherapy reg-
imens must also be considered. Therefore, specifically in
patients with a low to moderate tumor burden and nonlife-
threatening CLL, the improved responses and important
advances with combination therapies must result in large
improvements in long-term survival; otherwise, a more ag-
gressive regimen may not be warranted. Studies of combi-
nations of two novel agents have just begun, so neither the
efficacy nor toxicity of those regimens is yet known. Whether
concurrent combination therapy truly represents an ad-
vancement over sequential therapy with the multiple novel
targeted agents discussed here remains unclear, although it
has the theoretical benefit of reducing selection pressure for
resistance and may increase the rate of MRD negativity,
thereby allowing consideration of stopping therapy.
How Do We Sequence These Novel Agents?
Is switching drug class required or is an alternative kinase
inhibitor appropriate when a patient fails a targeted agent?
Recent data suggest that patients who discontinue a tar-
geted agent for adverse events have better outcomes than
those who progress, but because of the rapid evolution of
the targeted agents, little data are available addressing
approaches to sequencing these therapeutic agents once a
patient may have failed treatment. Limited data exist re-
garding practice patterns following ibrutinib or idelalisib
discontinuation. The response to subsequent therapies is
also largely unknown, particularly outside the context of
clinical research. A phase II, open-label, two-arm study
evaluating venetoclax monotherapy for patients with CLL
that had relapsed after or was refractory to either ibrutinib
or idelalisib, was presented at the 2015 ASH Annual
Meeting.76 In this early report, 41 patients had failed prior
ibrutinib, and 13 failed treatment with idelalisib, with three
patients who had failed both of these kinase inhibitors.
Approximately one-third of patients discontinued treatment
because of kinase inhibitor intolerance. About 8 weeks after
starting venetoclax, the majority of patients had resolution
of B-symptoms, with approximately 80% of patients having
normalization of their absolute lymphocyte count, which
occurred quickly at a median less than 1 month after starting
the BCL-2 inhibitor. In addition, a 50% or greater reduction in
nodal mass was achieved in almost three-quarters of pa-
tients after switching drug class. Overall, venetoclax mono-
therapy demonstrated an ORR of 61% in the ibrutinib
cohort and 50% in the idelalisib cohort, albeit with small
numbers of patients studied to date. Importantly, responses
 MANAGEMENT OF CLL IN THE ERA OF NOVEL TARGETED THERAPIES

were similar for patients who discontinued kinase inhibitors discontinuation. Reasons for discontinuation included 57%
for refractory disease compared with intolerance. Clearly with Richter, 25% with CLL progression, and 18% with other
continued treatment and extended follow-up will be re- events. The high rate of Richter appears reminiscent of the
quired to fully determine response rates and durability of reports to date of patients progressing on ibrutinib where
responses after class switching. there is also a 30%50% rate of transformation.41,43
Can switching to an alternative kinase inhibitor provide Whether these Richter events are the natural history of the
efficacy after failure from the first kinase inhibitor? A disease, if we are able to keep patients alive long enough or
multicenter retrospective cohort analysis among patients they represent a biologic evolution under strong selection
with CLL who discontinued ibrutinib or idelalisib therapy was pressure from the drugs remains to be seen. Survivals re-
also recently reported at the 2015 ASH Annual Meeting.77 A ported with venetoclax were somewhat better than pre-
total of 143 patients with CLL who had previously taken viously reported with ibrutinib, however, with 1-year OS of
ibrutinib and another 35 who had failed idelalisib switched 69% for those progressing with CLL and a median 1-year OS
to the alternate kinase inhibitor. Two-thirds of these pa- for those progressing with Richter.
tients had unmutated IGHV and more than one-third had
del(17p). More than 50% who failed either drug dis-
Will Novel Immunotherapies Overcome Resistance in
continued the kinase inhibitor because of toxicity, and
Patients With CLL?
another one-third of patients stopped therapy because of
Treatment of relapsed disease continues to be clinically
disease progression, while 6%8% discontinued because of
challenging, primarily because of eventual drug resistance.
Richter transformation. The ORR was 50% (all PR) after
There has been tremendous recent interest in novel im-
switching to the alternative kinase inhibitor. Therefore,
munotherapeutic approaches to treat patients with ad-
patients who discontinue a kinase inhibitor because of
vanced disease and overcome resistance. Blocking the
toxicity can achieve a durable response with an alternate
immune checkpoint PD-1 receptor to activate cytotoxic
kinase inhibitor, although one shorter than the response
T cells has been shown to have remarkable clinical results
durations reported when these drugs are used first; the
in a variety of advanced malignancies but as yet limited
median PFS from the start of the alternative kinase in-
evaluation in CLL.80-82 PD-1 has been shown to be highly
hibitor was 11.9 months, and the alternative kinase in-
expressed in CLL cells and is also expressed in the CLL mi-
hibitor choice did not affect PFS. Importantly the median
croenvironment.83 Preclinical data have demonstrated that
PFS was only 7 months for those who had failed the first
blocking PD-L1 in Tcl-1Tg mice can delay CLL progression.84
kinase inhibitor because of CLL progression, while a median
Data from an early efficacy report from a phase II trial
PFS was not reached after 6 months of median follow-up
presented at the 2015 ASH Annual Meeting explored PD-1
for those who failed because of kinase inhibitor in-
blockade in 20 patients with relapsed/refractory CLL, in-
tolerance. These data suggest that turning to an alternate
cluding seven with Richter transformation, of which five had
kinase inhibitor therapy following kinase inhibitor dis-
progressed after ibrutinib therapy.85 The ORR was limited at
continuation can be efficacious, particularly for patients
about 25%, yet interestingly, one patient with Richter
who discontinue kinase inhibitor because of intolerance. A
achieved a CR and two achieved a PR, suggesting that further
clinical trial targeting the kinase inhibitorintolerant pa-
assessment of PD-1 blockade may be appropriate for pa-
tient population will be undertaken to validate these
tients with highly aggressive disease and probably drug
findings prospectively.
resistance.
In addition, the use of CAR T cells has recently been in-
vestigated in an attempt to provide long-term immune
Will This New Area of Targeted Therapy Lead to the
surveillance and decrease relapse in aggressive B-cell ma-
Development of an Increased Rate of Richter
lignancies.86 Briefly, the CAR has been introduced into T cells
Syndrome?
by genetic modification designed to redirect T-cell specificity
An obvious unmet need remains how to treat Richter
to the CAR-targeted antigen. In particular, CD19-specific
transformation, which occurs in about 5%10% of patients
CAR-modified T cells have shown activity in aggressive
with CLL and transforms into a fast-growing lymphoma,
B-cell lymphoma and leukemia, although toxicity can be
typically diffuse large B-cell lymphoma.78 It is well un-
high. Currently, however, given the other options in CLL, CAR
derstood that Richter transformation carries a very poor
T-cell therapy remains an investigational approach that
prognosis and is commonly highly refractory to standard
should be limited to patients with aggressive relapsed, re-
treatments. Unfortunately, there is a paucity of data to help
fractory disease.
understand how these new targeted drugs will impact the
incidence of Richter transformation. At the 2015 ASH Annual
Meeting, the first report of outcomes after failure of vene- CONCLUSION
toclax was reported in 28 patients with CLL who had a Many unresolved and controversial issues remain with
median of four prior regimens and 59% with deletion of regard to the treatment of patients with CLL, including the
17p.79 Discontinuations occurred after a median 7.5 months identification of appropriate candidates for each category of
on venetoclax, with a median 12-month follow-up after therapy. Patients with low-risk IGHV-mutated disease in the

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e395

BROWN, HALLEK, AND PAGEL
front-line setting derive long-term benefit from chemo-
immunotherapy (e.g., FCR). Chemoimmunotherapy in gen-
eral has the benefit of planned short duration therapy with
long remission, in contrast to the targeted agents that to
date have largely been studied as continuous single agents
or continuously in combination with chemoimmunotherapy.
Randomized trials are comparing targeted agents with
chemoimmunotherapy, particularly in the front-line setting,
while in the relapse setting, targeted agents have been
preferred for most patients, although it remains unclear
whether single-agent therapy or combinations are optimal.
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e396 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
It appears likely that patients of all stages in disease evo-
lution may benefit from targeted kinase or BCL-2 inhibitor
agents, but questions regarding the use of these agents with
regard to sequencing, class switching, length of therapy, and
how to avoid or overcome resistance remain at the fore-
front. Nonetheless, the exciting clinical trial data with these
rational targeted therapies will soon translate to clinical
practice experience and set the stage for continued pro-
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HEMATOLOGIC MALIGNANCIESPLASMA CELL
DYSCRASIA

Consolidation and Maintenance:

Moving Beyond Autotransplant

CHAIR
Parameswaran Hari, MD, MRCP
Medical College of Wisconsin
Milwaukee, WI

SPEAKERS
Amrita Krishnan, MD
City of Hope
Duarte, CA

Ravi Vij, MBBS, MD

Washington University School of Medicine
St. Louis, MO
KRISHNAN ET AL

Moving Beyond Autologous Transplantation in Multiple

Myeloma: Consolidation, Maintenance, Allogeneic
Transplant, and Immune Therapy
Amrita Krishnan, MD, Ravi Vij, MD, MBA, Jesse Keller, MD, Binod Dhakal, MD, and Parameswaran Hari,
MD, MRCP

OVERVIEW

For multiple myeloma, introduction of novel agents as part of the front-line treatment followed by high-dose chemotherapy
and autologous hematopoietic stem cell transplantation (ASCT) induces deep responses in a majority of patients with this
disease. However, disease relapse is inevitable, and, with each relapse, the remission duration becomes shorter, ultimately
leading to a refractory disease. Consolidation and maintenance strategy after ASCT is one route to provide sustained disease
control and prevent repeated relapses. Though the consolidation strategy remains largely confined to clinical trials, sig-
nificant data support the efficacy of consolidation in improving the depth of response and outcomes. There are also in-
creasing rates of minimal residual diseasenegativity with additional consolidation therapy. On the other hand,
maintenance with novel agents post-transplant is well established and has been shown to improve both progression-free
and overall survival. Evolving paradigms in maintenance include the use of newer proteasome inhibitors, immunotherapy
maintenance, and patient-specific maintenancea concept that utilizes minimal residual disease as the primary driver of
decisions regarding starting or continuing maintenance therapy. The other approach to overcome residual disease is immune
therapeutic strategies. The demonstration of myeloma-specific alloimmunity from allogeneic transplantation is well
established. More sophisticated and promising immune approaches include adoptive cellular therapies, tumor vaccines, and
immune checkpoint manipulations. In the future, personalized minimal residual diseasedriven treatment strategies
following ASCT will help overcome the residual disease, restore multiple myelomaspecific immunity, and achieve sustained
disease control while minimizing the risk of overtreatment.

A utologous hematopoietic cell transplantation with high-

dose chemotherapy and autologous cell rescue is a
mainstay of therapy for patients with multiple myeloma and
ASCT (planned consolidation or maintenance), allo-HCT, and
emerging immune therapies, are discussed.

induces a response in a large proportion of patients. CONSOLIDATION THERAPY IN MULTIPLE

However, relapse is near universal as a result of either
measurable disease or minimal residual disease (MRD) after
ASCT, and multiple myeloma remains incurable.1 Effective
therapies for sustained disease control after ASCT and
prevention of repeated relapses in high-risk subgroups are
unmet needs. Consolidation and maintenance after ASCT is
one route to overcome residual disease, whereas immune
approaches such as allogeneic transplantation (allo-HCT),
adoptive cellular therapies, vaccines, or antibody-based
immune manipulations represent another approach. Allo-
HCT, despite its toxicities, has been known to cure a
minority of patients by establishing myeloma-specific
alloimmunity.2-4 Herein, potential treatments beyond
MYELOMA
Consolidation therapy following ASCT for multiple myeloma
implies a short period of intensive treatment with a single-
agent or a combination of agents. Depth of response is
widely accepted as prognostic for outcomes with multiple
myeloma, and this strategy further reduces disease burden
following ASCT.5,6 Yet, compared with lower-dose long-term
maintenance, consolidation mostly remains confined to
clinical trials. Historically, efforts of post-transplant con-
solidation have ranged from aggressive attempts to eradi-
cate disease with tandem autologous transplantation and
consolidation cytotoxic chemotherapy, to modern novel
agentbased approaches6,7

From the Judy and Bernard Briskin Center for Myeloma, City of Hope Cancer Center, Duarte, CA; Division of Medical Oncology, Washington University School of Medicine in St. Louis,
St Louis, MO; Division of Hematology Oncology, Medical College of Wisconsin, Milwaukee, WI.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Parameswaran Hari, MD, MRCP, Froedtert Hospital and Medical College of Wisconsin, 9200 West Wisconsin Ave., Milwaukee, WI 53226; email: phari@mcw.
edu.

2016 by American Society of Clinical Oncology.

210 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


TABLE 1. Lenalidomide and Bortezomib Monotherapy Consolidation
Consolidation Induction Comparison
Study Regimen Regimen Arm
Attal et al11
Lenalidomide VAD (46%) None
(614 patients)
VD (46%)
Uy et al13 Bortezomib Bortezomib-naive None
(40 patients)
Mellqvist et al14 Bortezomib Bortezomib-naive Placebo
(187 patients)
Abbreviations: PFS, progression-free survival; OS, overall survival; VAD, vincristine/doxorubicin/dexamethasone; VD, bortezomib/dexamethasone; VGPR, very good partial response;
nCR, near CR; NR, not reported.
TANDEM TRANSPLANTATION AND CYTOTOXIC
CHEMOTHERAPY
Initial efforts of post-ASCT consolidation therapy evolved
from the University of Arkansas Total Therapy trials and
mirrored prolonged treatment regimens in pediatric acute
lymphocytic leukemia. Total Therapy 1 (TT1) (which did not
include consolidation) used aggressive induction chemo-
therapy and tandem ASCT combined with maintenance
interferon (IFN) to produce results superior to contemporary
standard therapy in a SWOG cooperative group trial.8 Total
Therapy 2 (TT2), which expanded on TT1, evaluated ag-
gressive induction chemotherapy, tandem ASCT followed
by four cycles of dexamethasone, cisplatin, doxorubicin,
cyclophosphamide, and etoposide (DPACE) consolidation
chemotherapy; patients were then randomly assigned to
receive maintenance therapy with IFN with or without
thalidomide.9 Total Therapy 3 (TT3A) included the addition
of bortezomib-based chemotherapy induction, tandem
ASCT followed by DPACE plus thalidomide and bortezomib
(V-DTPACE) consolidation and then maintenance.10 The role
of maintenance in these trials was evaluated in a non-
randomized fashion, making its individual contribution dif-
ficult to discern; however, they spawned further interest for
improved post-ASCT strategies.
KEY POINTS
Induction with novel agent combinations followed by high-
dose chemotherapy ASCT is the standard of care in patients
with multiple myeloma who are eligible for transplant.
Relapse is inevitable in the majority of the patients
despite recent improvements in progression-free
survival.
Effective strategies to overcome residual disease and
prevent relapse is an unmet need.
Post-transplant consolidation and minimal residual
diseasedirected maintenance are promising new
avenues.
Emerging post-ASCT immunotherapy to establish
myeloma-specific immunity and allotransplant are tools
for long-term disease control, especially for young high-
risk patients.
BEYOND AUTOLOGOUS TRANSPLANTATION IN MULTIPLE MYELOMA
Before After
Duration Consolidation Consolidation PFS OS
2 cycles $ VGPR: 58% $ VGPR: 69% 4-year: 43% 4-year : 73%
(all treated) (p , .001) vs. 22% vs. 75%
6 cycles CR + VGPR: 43% CR + VGPR: 43% NR 3-year: 63.1%
6 cycles $ nCR: 20.1% $ nCR: 45.1% 27 vs. 3-year: 80%
20 months vs. 80%
$ VGPR: 39.7% $ VGPR: 70.9%
IMMUNOMODULATORY AGENT
CONSOLIDATION THERAPY
Novel agents such as proteasome inhibitors and immuno-
modulatory agents (IMIDs) have advanced all aspects of
multiple myeloma treatment. Evaluation of consolidation
therapy with IMID monotherapy was undertaken in a phase III
study by Intergroupe Francophone du Myelome (IFM 05-02;
Table 1).11 Newly diagnosed patients with multiple myeloma
who underwent post-ASCT consolidation therapy with lena-
lidomide were randomly assigned to receive maintenance
lenalidomide versus placebo. Two cycles of lenalidomide
(25 mg daily) improved the rate of complete response (CR) or
very good partial responses (PR) from 58% to 69% (p , .001),
respectively, among all participants, but maintenance was not
associated with improvement of overall survival (OS). A
similarly designed phase III U.S. study (CALGB 100104) lacked
the lenalidomide consolidation phase, but randomly assigned
patients to receive maintenance lenalidomide versus placebo
and reported an OS benefit in the maintenance arm.12 One of
the possible explanations for the lack of OS benefit in the
former study is that a short period of consolidation given to all
subjects in IFM 0502 may have abrogated the survival benefit
for protracted maintenance therapy.
PROTEASOME INHIBITORBASED
CONSOLIDATION
Bortezomib
Uy et al13 evaluated pre- and post-ASCT bortezomib con-
solidation in a phase II study with 40 patients (all newly di-
agnosed with multiple myeloma) who received two cycles of
intravenous bortezomib followed by ASCT, and six cycles of
intravenous bortezomib after ASCT. Only 28 patients received
post-ASCT bortezomib, with two upgraded responsesone
from very good PR to CR and one from PR to very good PR. The
3-year OS and disease-free survival (DFS) were 63.1% and
38.2%, respectively.13
The NORDIC Myeloma Study Group randomly assigned
bortezomib-naive patients post-ASCT to receive either no
further treatment or bortezomib consolidation for six cycles.
With a median follow-up of 38 months, PFS for the bortezomib-
treatment group was 27 months compared with 20 months
for the control group (p = .05), and no difference in OS.
Patients who experienced at least a very good PR
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KRISHNAN ET AL

TABLE 2. Bortezomib and Immunomodulatory Combination Consolidation Therapy

Consolidation Induction Comparator Before After

Study Regimen Regimen Arm Duration Consolidation Consolidation PFS OS
72
Cavo et al VTD VTD x 3 TD 2 cycles CR: 48.7% CR: 60.6% 3-year: 60% 3-year: 90%
(160 patients) (161 patients)
$ VGPR: 86.2% $ VGPR: 91.9%
p = NS (VGPR)
72
Cavo et al TD TD x 3 VTD 2 cycles CR: 40.4% CR: 46.6% 3-year: 48% 3-year: 88%
(161 patients) (160 patients)
$ VGPR: 81.4% $ VGPR: 88.2%
p = NS (VGPR)
17
Leleu et al VTD VTD No consolidation 2 cycles CR: 33% CR: 52% NR 3-year: NR vs.
(121 patients) (96 patients) 22 months
$ VGPR: 43% $ VGPR: 31%
p , .001 (CR)
73
Roussel et al RVD RVD None 2 cycles CR: 47% CR: 50% 3-year: 77% 3-year: 100%
(31 patients)
$ VGPR: 70% $ VGPR: 87%
Nooka et al18 RVD RVD None 3 years sCR approx. 20% sCR: 51% 32 months 3-year: 93%
$ VGPR approx. 85% $ VGPR: 96%
Moreau et al19 RVD RVD No transplant 2 cycles $ VGPR:73% $ VGPR: 81% 34 vs. 4-year: 81%
43 months vs. 83%
Abbreviations: PFS, progression-free survival; OS, overall survival; CR, complete response; NR, not reported; NS, not significant; RVD, lenalidomide/bortezomib/dexamethasone; TD,
thalidomide/dexamethasone; VGPR, very good partial response; VTD, bortezomib/thalidomide/dexamethasone.

demonstrated a prolonged PFS irrespective of bortezomib
consolidation. The beneficial effect of bortezomib consoli-
dation was confined to patients who did not have at least a
very good PR following ASCT. More importantly, PFS among
patients whose disease had a very good PR to therapy at
randomization was similar to patients whose disease re-
sponse improved to the very good PR category or better
during consolidation. These results provide substantial
support to the role of post-transplant consolidation to
further deepen disease response.14
Combination Therapy Bortezomib and
Immunomodulatory Agents
In a phase III trial, Cavo et al15 assessed the efficacy of
consolidation with thalidomide and dexamethasone (TD)
compared with bortezomib, thalidomide, and dexametha-
sone (VTD; Table 2). The patients were randomly assigned at
diagnosis to induction therapy with either VTD or TD, and all
underwent tandem ASCT followed by two 35-day consoli-
dation cycles with the same regimen as their induction
therapy (VTD vs. TD). CR rates after second ASCT was 48.7%
for the VTD group and 40.4% for the TD group, improving to
60.6% and 46.6%, respectively, following consolidation. PFS
was superior for the VTD group compared with the TD group
(60% vs. 48% at 3 years; p = .042).15 Notably, rates of CR and
at least very good PR favored VTD treatment, but were not
significant. The isolated impact of consolidation is difficult to
determine from this study.
Roussel et al16 investigated lenalidomide, bortezomib, and
dexamethasone (RVD) induction and consolidation therapy
in 31 patients with newly diagnosed multiple myeloma who
received three RVD induction cycles, followed by ASCT and
two RVD consolidation cycles with subsequent lenalidomide
maintenance for 1 year. The estimated 3-year PFS and OS
were 77% and 100%, respectively, and CR rates were 47%
following ASCT and 50% after RVD consolidation. Therapy
was tolerable, with no treatment-related mortality (TRM),
and 97% completed the planned sequence.16 Leleu et al17
retrospectively analyzed 121 patients with newly diagnosed
multiple myeloma across nine IFM centers who had received
three cycles of VTD induction, followed by ASCT and two
cycles of VTD consolidation. Complete response rates in-
creased from 33% after induction and ASCT to 52% following
consolidation. Compared with 96 similar patients treated
with VTD induction and ASCT without consolidation, CR rates
were superior and relapse risk were lower in the consoli-
dation arm.17
Nooka et al18 evaluated prolonged therapy with RVD in
45 patients with high-risk multiple myeloma (p53 deletion,
1p deletion, immunoglobulin heavy chain gene trans-
locations, or plasma cell leukemia). Patients received RVD
as consolidation/maintenance therapy post-ASCT for up to
3 years, followed by single-agent lenalidomide maintenance
thereafter. RVD consolidation/maintenance achieved at least
very good PR status in 96% of patients, and a stringent CR
(sCR) in 51%. Median PFS was 32 months with a 3-year OS of
93%a promising improvement in PFS and OS in this high-risk
group. Despite its length and intensity, therapy was well
tolerated overall.18
More recently, the second interim analysis of the IFM 2009
trial was reported.19 In this trial, RVD was administered for
eight cycles followed by 12 months of lenalidomide main-
tenance or RVD induction with RVD consolidation post-ASCT
followed by lenalidomide maintenance. Response to treat-
ment continued to deepen with progressive therapy, and at
least very good PR rates improved from 73% to 81% after RVD
consolidation. This study also showed an improvement in PFS
(median of 34 vs. 43 months) in the ASCT arm.

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 BEYOND AUTOLOGOUS TRANSPLANTATION IN MULTIPLE MYELOMA

TABLE 3. Carfilzomib-Based Consolidation Therapy

Induction Comparator Before After

Consolidation Regimen Regimen Arm Duration Consolidation Consolidation PFS OS
20
KTd (Sonneveld et al ; KTd None 4 cycles CR: 33% CR: 63% 3-year: 60% 3-year: 90%
91 patients)
$ VGPR: 76% $ VGPR: 89%
KRd (Jakubowiak et al21; KRd None 4 cycles $ CR: 27% $ CR: 77% 11 months: 99% 11 months: 100%
71 patients)
$ sCR: 22% $ sCR: 70%
Abbreviations: PFS, progression-free survival; OS, overall survival; KTd, carfilzomib/thalidomide/dexamethasone; KRd, carfilzomib/lenalidomide/dexamethasone; CR, complete
response; VGPR, very good partial response; sCR, stringent complete response.

Carfilzomib of MRD-negative response was significantly associated

In a multicenter phase II study from the European Myeloma
Network, the carfilzomib, thalidomide, and dexamethasone
(KTd) combination was investigated as induction and con-
solidation therapy in patients with multiple myeloma who
were previously untreated (Table 3). KTd was given in 28-day
cycles for up to four cycles and followed by ASCT. After ASCT
patients received four cycles of KTd consolidation therapy.
The at least very good PR rate increased from 68% after
induction to 76% after ASCT, and finally to 89% after
four cycles of consolidation. Progression-free survival at
36 months was 72%, and only 5% of patients discontinued
therapy.20 Pre- and post-transplant carfilzomib, lenalido-
mide, and dexamethasone (KRd) was studied in a phase II
trial. After KRd induction, ASCT and KRd consolidation (four
cycles) were administered followed by KRd maintenance
for nine cycles, and then lenalidomide maintenance off-
protocol. Rates of CR increased from 27% following ASCT to
77% after consolidation. At the conclusion of KRd treatment,
90% of patients demonstrated an at least CR with a 3-year
PFS and OS of 79% and 100%.21
CONSOLIDATION THERAPY AND MINIMAL
RESIDUAL DISEASE
The role of MRD evaluation in prediction of outcomes and
duration of therapy is increasing. Ladetto et al22 enrolled
patients whose disease had a very good PR following ASCT
and monitored MRD after four cycles of VTD consolida-
tion using polymerase chain reactionbased techniques
(Table 4).22 Molecular remission rates were 3% after ASCT
compared with 18% after VTD consolidation. Achievement
with improved median PFS (68 months vs. 23 months,
p , .0001).
In the study by Roussel et al,16 the outcomes of patients
who were MRD-negative (evaluated by marrow flow cytom-
etry) were impressive with a 3-year PFS of 100%.16 MRD
negativity rates steadily increased through induction to the
completion of consolidation. Jakubowiak et al21 assessed MRD
in a subset of patients whose disease had a CR using 10-color
flow cytometry and noted substantial improvements in MRD
negativity rates with consolidation therapy.21
CONSOLIDATION VERSUS MAINTENANCE
Current evidence does not enable a clear recommendation
of consolidation therapy for all patients after they have
undergone ASCT. Substantial data support its efficacy in
improving depth of response of multiple myeloma, which
has historically translated into improvements of survival
outcomes. The awaited results of the Blood and Marrow
Transplant Clinical Trials Network (BMT CTN) 0702 STAMINA
trial (NCT 1109004), compares three competing post-
ASCT strategies after initial ASCT: patients will be ran-
domly assigned to receive a second (tandem) ASCT, RVD
consolidation, or immediate initiation of lenalidomide
maintenance (Fig. 1). All arms will ultimately receive
lenalidomide maintenance based on the paradigm that
continuous therapy or maintenance is sufficient to control
residual disease. Additionally, an ongoing multicenter study
(NCT02253316) is evaluating the role of ixazomib-based
consolidation therapy followed by maintenance with MRD
post-ASCT (Fig. 2).

TABLE 4. Minimal Residual Disease With Consolidation Therapy

Before After
Consolidation Regimen Induction Regimen Comparator Arm Duration Consolidation Consolidation
VTD (Ladetto et al22; VAD None 4 cycles CR: 15% CR: 49%
39 patients)
MRD: 4.15log MRD: 10.09log
reduction* reduction*
VRD (Roussel et al16; VRD None 2 cycles MRD: 54% MRD: 58%
26 patients) negative negative
KRd (Jakubowiak et al21; KRd None 4 cycles MRD: 79% MRD: 90%
71 patients) negative negative
*Reduction from baseline levels.
Abbreviations: VTD, bortezomib/thalidomide/dexamethasone; VAD, vincristine/doxorubicin/dexamethasone; CR, complete response; MRD, minimal residual disease; KRd,
carfilzomib/lenalidomide/dexamethasone.

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KRISHNAN ET AL

FIGURE 1. CTN 0702 Study (STAMINA) Schema In the United States, therefore, interest shifted to lenali-
Mel 200 Transplant &
domide as a better-tolerated IMID maintenance strategy.25
Mel 200 Transplant
Lenalidomide Maintenance
Newly Diagnosed Lenalidomide. Three published phase III trials explored
VRD Consolidaon &
Transplant Eligible Mel 200 Transplant lenalidomide maintenance after ASCT (Table 6). The CALGB
Lenalidomide Maintenance
Mulple Myeloma
100104 Intergroup trial randomly assigned patients to re-
Mel 200 Transplant Lenalidomide ceive lenalidomide (10 mg daily escalated to 15 mg) or
Maintenance
observation after ASCT. The median time-to-progression
(TTP) was 46 months in the lenalidomide arm compared
with 27 months with placebo, which translated into an
MAINTENANCE THERAPY AFTER improved OS (88% vs. 80% at 3 years).12 A recently updated
TRANSPLANTATION: THE PAST AND THE FUTURE analysis showed a median TTP of 53 months compared with
The concept of sustained low intensity post-ASCT therapy 27 months as well as continued OS advantage.26 The phase III
(or maintenance) for patients with multiple myeloma dates IFM 05-02 trial, as noted previously, had the subtle, but
back to IFN, which was associated with improved PFS and important, difference that all patients received lenalidomide
OS in several trials.23 The advent of novel agents with im- consolidation followed by lenalidomide maintenance or
proved efficacy and toxicity supplanted IFN. Given emerging placebo.11 In this trial, although median TTP was superior for
immuno-oncologic approaches, this may also have been the lenalidomide arm (41 months vs. 23 months p , .001),
prescient in harnessing the immune system as the major there was no difference in OS. The lack of OS benefit may in
mechanism to maintain control against residual disease. part be attributed to lenalidomide consolidation and or an
imbalance of high-risk patients between arms. An Italian trial
(GIMEMA RV-MM-PI209) assigned patients to melphalan,
Maintenance Agents: Immunomodulatory Agents prednisone, and lenalidomide (MPR) or ASCT followed by
Thalidomide. Probably the largest body of clinical trial ex- second random assignment to maintenance lenalidomide or
perience has been with thalidomide maintenance therapy, no maintenance. The maintenance lenalidomide cohort in
although these trials differed with some having used tha- both the MPR and ASCT groups had superior PFS (but not
lidomide as part of induction continuing through mainte- OS).27 In all trials, the lenalidomide cohorts had a higher
nance, whereas others used it in conjunction with steroids, incidence of neutropenia. Even more important was the
and with major variation in thalidomide doses chosen. higher incidence of second primary malignancies (SPM) at
Table 5 outlines the major trials of thalidomide maintenance around 8% in the IFM and CALGB trials compared with 3% to
following ASCT. All studies of thalidomide maintenance 4% in the placebo arm. Strategies to minimize SPM risk
suggest improved PFS, but toxicity and tolerability remain without losing the benefit of maintenance are areas of study,
issues. In the IFM 99 trial, 39% of patients discontinued such as limiting the duration of maintenance, pre-assessing
thalidomide mainly due to neuropathy.24 In the MRC IX trial SPM risk, and MRD-based discontinuation.
with thalidomide maintenance after intensive (transplant) or A comparison of the recently reported IFM DFCI 2009 trial
nonintensive (chemotherapy only) pathways, 52% stopped with the ongoing DFCI (Dana-Farber Cancer Institute) BMT
therapy due to side effects, and thalidomide maintenance CTN Determination trial is expected to shed light on the
did not prolong PFS or OS in those with adverse cytogenetics. duration of maintenance lenalidomide and the impact of
MRD. As described previously, the IFM version of this phase
III trial incorporated 1 year of lenalidomide maintenance.19
FIGURE 2. Design of NCT02253316: Ixazomib,
In contrast, the DFCI version (DFCI10-106; NCT1208662)
Lenalidomide, and Dexamethasone Consolidation
follows the same overall schema, but lenalidomide main-
Therapy and Minimal Residual Disease
tenance continues until disease progression. The incidence
Autologous Stem of SPM as well as sequential evaluation of MRD by flow
Cell Transplant Completion of
Consolidation cytometry and next-generation sequencing is being evalu-
ated in both trials.28
Day 80-120:
MRD Assessment
Randomized to Randomized to
Maintenance Agents: Proteasome Inhibitors
Lenalidomide Ixazomib Bortezomib. Although there is a large body of evidence
Maintenance Maintenance
Consolidation with surrounding bortezomib maintenance (Table 5), most pro-
IRD Begins tocols used bortezomib administered intravenously, which
renders the toxicity data less relevant in the era of sub-
Assess Tolerability, PFS, OS cutaneous dosing. A large Dutch-German trial randomly
4 Cycles of IRD:
MRD Assessment assigned patients to receive bortezomib, doxorubicin, and
dexamethasone (PAD) or vincristine, doxorubicin, and
Abbreviations: MRD, minimal residual disease; IRD, ixazomib, lenalidomide, and
dexamethasone (VAD)29 induction followed by ASCT. The
dexamethasone; PFS, progression-free survival; OS, overall survival. PAD induction arm subsequently received bortezomib

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 BEYOND AUTOLOGOUS TRANSPLANTATION IN MULTIPLE MYELOMA

TABLE 5. Thalidomide and Bortezomib Maintenance Studies

Schedule Control CR PFS/EFS/TTP Reference

PAM + Thal 400 mg/day PAM or OBS NR 52% (3-year) Attal et al24
Thal 400 mg/day None 50% 72% (6-year) Barlogie et al74
Thal 200 mg/day + PSE 50 mg QOD PSE NR 42% (3-year) Spencer et al75
Thal 50 mg/day IFN 31% 50% (34-month) Lokhorst et al76
Thal 100 mg/day OBS NR 50% (30-month) Morgan et al25
Thal 200 mg/day + PSE 50 mg QOD OBS NR 32% (4-year) Stewart et al77
2
Bort 1.3 mg/m Q2 weeks Thal NR 50% (35-month) Sonneveld et al29
Bort + Thal Thal or IFN 19% 50% (45-month) Rosinol et al31
Abbreviations: CR, complete response; PFS, progression-free survival; EFS, event-free survival; TTP, time-to-progression; PAM, pamidronate; Thal, thalidomide; OBS, observation, NR,
not reported; PSE, prednisone; QOD, every other day; IFN, interferon; Bort, bortezomib; Q2, every two.

maintenance for 2 years, whereas the VAD arm received
thalidomide maintenance. Median PFS was 35 months in the
bortezomib-treated arm compared with 28 months in the
VAD/thalidomide-treated arm. A landmark analysis sug-
gested an OS benefit, although it is not clear if the benefit
was derived solely from the bortezomib maintenance or
induction, or from the higher discontinuation rates with
thalidomide maintenance. There was particular improve-
ment in the high-risk subgroup with 17p deletion that re-
ceived bortezomib (PFS of 26 months vs. 12 months in the
thalidomide arm).30 Another three-arm Spanish trial com-
pared bortezomib plus thalidomide, thalidomide, or IFN as
maintenance with a planned duration of 3 years. PFS was
superior with the bortezomib/thalidomide combination, but
there was no OS benefit.31
Carfilzomib and ixazomib. Other proteasome inhibitors
could offer the potential advantages of minimizing neu-
ropathy with possibly higher potency. Carfilzomib-based
combinations with lenalidomide have been described pre-
viously, whereas ixazomib maintenance is another attractive
option, given its oral administration and lower neuropathy
risk. As shown in Fig. 2, a current trial (NCT02253316) is
evaluating ixazomib, lenalidomide, and dexamethasone
consolidation followed by random assignment to ixazomib
or lenalidomide maintenance until disease progression.
Although not powered to show a benefit with either of the
maintenance arms, the tolerability and feasibility of ixazo-
mib maintenance and ongoing MRD assessments will be
valuable. In another phase II trial using ixazomib and
lenalidomide combination maintenance,32 ixazomib dose
was reduced to 3 mg or less (from the standard 4 mg) in
some patients because of the development of neuropathy.
Overall, the combination was well-tolerated, with the ma-
jority of patients still receiving treatment at 30-plus cycles
with an estimated 2-year PFS of 83%.
In the allogeneic setting, the BMT CTN 1302 phase II trial
for patients with protocol-defined high-risk multiple mye-
loma (NCT02440464) randomly assigned patients to receive
ixazomib maintenance or placebo starting at 60- to 120-days
after allo-HCT. Because bortezomib has been shown to
reduce graft-versus-host disease (GVHD), the effects of
ixazomib on GVHD and relapse rates are being evaluated.
Immunotherapy
Immunotherapy for multiple myeloma encompasses approved
myeloma-directed passive antibody or active approaches that
enhance tumor-specific immune responses. The post-ASCT
maintenance setting is the ideal platform for immunother-
apy, given low disease burden as well as a favorable immune
milieu. Multiple immunotherapy options are being evaluated
in trials designed to elicit antitumor immune responses, as well
as augment T-cell function (Table 7).
Daratumumab,33 the newly approved anti-CD38directed
antibody, has a half-life of 21 days, which makes it an at-
tractive maintenance option. An ongoing IFM phase III trial
(NCT02541383) for front-line therapy randomly assigns
patients to receive daratumumab maintenance for 2 years

TABLE 6. Lenalidomide Maintenance Studies

Outcome
Maintenance Planned Length
Study Comparison of Maintenance PFS OS
McCarthy et al12 Lenalidomide vs. placebo Until progression Median PFS (46 vs. 3-year OS (88%
(CALGB 100104) 27 months; p , .001) vs. 80%; p = .03)
Attal et al75 Lenalidomide vs. placebo Until progression, but Median PFS (41 vs. 4-year OS (73%
(IFM 0502) after 2 months lenalidomide terminated early for SPM 23 months; p , .001) vs. 75%; p = NS)
consolidation
Palumbo et al27 MPR vs. tandem ASCT followed Until progression Median PFS 41.9 vs. 3-year OS (88%
by lenalidomide vs. placebo 21.6 months; (p , .001) vs. 79.2%; p = .14)
Abbreviations: PFS, progression-free survival; OS, overall survival; SPM, secondary primary malignancies; NS, not significant; MPR, melphalan/prednisone/lenalidomide; ASCT,
autologous hematopoietic cell transplantation.

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KRISHNAN ET AL
TABLE 7. Comparison of Immunotherapy Maintenance Strategies
Therapy Advantage
Vaccine Ease of administration
Low toxicity
T-cellbased (Including CAR) Cytolytic trafficking to extramedullary sites
Antibodies Long half-life
Commercially available
Checkpoint Blockade Commercially available
Abbreviations: CAR, chimeric antigen receptor; MM multiple myeloma.
after ASCT. Elotuzumab, a natural killer (NK) celldirected
antibody requires lenalidomide to augment its activity. An
ongoing phase II trial (NCT 02420860) explores the combi-
nation of elotuzumab with lenalidomide following ASCT.
Emerging Paradigms in Maintenance
Patient-specific maintenance is a concept that utilizes MRD
as the primary driver of decisions regarding starting or
continuing maintenance therapy. Most ongoing phase III and
phase II trials are collecting MRD data at various points in
time, although the optimal method for MRD assessment is
debated (multicolor flow cytometry vs. sequencing). To a
smaller extent, decisions regarding choice of maintenance
drug are also patient- and disease-specific (e.g., bortezomib
for patients with t[4,14] or 17p deletion). Further refinement
of this concept with more targeted therapy based on genetic
sequencing is key. Lastly, augmenting immune function
through a variety of methods including adoptive cell ther-
apy, vaccines, checkpoint blockade, and myeloma-specific
antibodies will likely become the backbone of post-ASCT
interventions.
IMMUNOTHERAPY FOR MULTIPLE MYELOMA:
ALLOGENEIC TRANSPLANTATION AND BEYOND
Allogeneic transplantation is a well-established immunother-
apy strategy for multiple myeloma with evidence of the ex-
istence of a potent and often sustained graft-versus-myeloma
effect.4 Conventional myeloablative regimens resulted in pro-
hibitive TRM (40% to 60%), but apparent plateaus in transplant
survival curves indicated long-term disease control. The allo-
geneic arm of U.S. intergroup trial (S93-21) was prematurely
closed as a result of high early TRM (53%), but showed long
relapse-free survivorship of 39% at 7 years.34 Development of
nonmyeloablative and reduced-intensity conditioning regimens
has decreased TRM,35,36 but the lower TRM was negated by an
increase in relapse risk during later years.37 The risks of chronic
GVHD and the need for long-term immunosuppression remain
major challenges. The success of allo-HCT as a relapse pre-
vention strategy resides in the ability of donor-derived allor-
eactive T cells to eliminate or suppress multiple myeloma
propagating residual cells. Several lines of evidence point to this,
including the correlation of chronic GVHD with protection from
relapse,2,4 the ability of donor derived lymphocytes to eliminate
residual or relapsing disease,38 and lower relapse rates
216 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Disadvantage
Patient-specific (manufacturing)
Toxicity manufacturing
Infusional toxicity
Cytopenias
Low single-agent response rates in MM
observed in recipients of T-cell replete allografts compared
with recipients of T-cell depleted or syngeneic grafts.
Modern Randomized Trials of Allo-HCT
After promising phase II data, a series of randomized,
prospective studies explored the concept of decoupling
myeloablation and immune therapy by a tandem approach
involving an initial autologous myeloablative transplant
followed (within 3 to 6 months) by an allogeneic non-
myeloablative transplant from a matched sibling or un-
related donor. The results of this strategy have been
discordant in the front-line treatment of multiple myeloma.
Two major European studies39,40 reported favorable long-
term OS.41,42 In these studies, compared with tandem au-
tologous transplantation, a second (tandem) allo-HCT from
an HLA-matched donor (after a prior autograft) results in
superior PFS and OS despite an increase in early TRM. This is
in contrast to the U.S. study led by the BMT CTN in which no
survival or progression benefit was seen in the allo-HCT
group.2 Interestingly, in the larger European Group on Blood
and Marrow Transplantation (EBMT) study, in addition to
relapse risk being lower in the allograft arm, post-relapse
survival was also superior for the allo-HCT cohort compared
with tandem autograft recipients.42 This latter phenomenon
has been attributed to a synergy between novel agents and
the immune benefits of an allo-HCT.
As discussed in the maintenance section, more recent
studies incorporated maintenance agents (lenalidomide,
bortezomib, and others) in the post allo-HCT setting. These
results were discordant with the HOVON group,43 reporting
substantial GVHD that threatened the feasibility of planned
lenalidomide maintenance. In contrast, a multicenter U.S.
study,44 in a predominantly high-risk population, indicated
promising PFS and OS of 63% and 78%, respectively, at
18 months. A current multicenter U.S. study (BMT CTN 1302;
NCT02440464) uses the newly approved agent ixazomib in
maintenance after an allogeneic transplant in patients with
genetically defined high-risk multiple myeloma, plasma cell
leukemia, or early relapse after an ASCT.
On a practical basis, if allo-HCT is considered part of the
therapeutic armamentarium, clinicians are faced with two
major questions: (1) identifying the patients who benefit the
most from allo-HCT and (2) identifying the optimal time
point for referral for allo-HCT.

Who Should Be Considered for Allo-HCT for Multiple
Myeloma
In practical terms, this boils down to the identification of
patients who are at such high clinical or biologic risk that the
TRM risk of allo-HCT is balanced by the intrinsic negative
prognosis. Biologically, high-risk myeloma is defined by the
presence of chromosomal abnormalities t(4:14), t(14:16),
+1q21, 17p by fluorescence in situ hybridization (FISH); 13q
deletion by karyotyping or high-risk gene expression pro-
filing (GEP).45,46 Based on the recently developed R-ISS
staging system that incorporates disease burden and bi-
ology, the highest risk subgroup (stage III) had a predicted
5-year OS and PFS of 40% and 24%, respectively.47 Similarly,
relapse within 18 months of ASCT is an extremely negative
prognostic marker.48 Effective treatment that establishes
long-term disease control in these high-risk patient pop-
ulations is an unmet need, and allo-HCT becomes a con-
sideration. Both prospective and retrospective studies have
explored the role of allo-HCT in patients with high-risk
multiple myeloma with variable outcomes. The EBMT
NMAM 2000 study reported a 21% PFS at the 8-year follow-
up in patients with the higher risk deletion 13 (by FISH) who
underwent allo-HCT versus 5% in the tandem ASCT group.42
Knop et al showed that in the highest risk subgroup with
del(17p) and del(13q) abnormality,49 median PFS (p = .002)
and OS (p = .011) were superior compared with tandem
ASCT. In younger eligible patients with well-defined high-risk
features, it is reasonable to consider allo-HCT, especially
within a clinical trial and early in the clinical course (front-line
or first relapse). The mortality and morbidity in general has
steadily declined in recent years, making the short-term risks
lower than in published studies from a decade or more
ago.37 In contrast, after repeated relapses, allo-HCT itself is
associated with very poor survival, making this modality a
very poor late salvage option.50 In the United States, overall
allogeneic transplant activity has declined for patients with
multiple myeloma and more transplants, unfortunately, are
now suboptimally performed later in the disease course.
Timing of Allo-HCT for Relapsed Multiple Myeloma
Prospective data that demonstrated a benefit for allo-HCT
are all derived from the up-front setting after an initial ASCT.
Understandably in the modern era, patients and physicians
are still hesitant regarding a treatment with high immediate
TRM risk. In patients whose disease relapsed after an ASCT,
the benefit of allo-HCT was found to be highest when this
modality was used earlier in the disease course and when
used as a strategy for consolidation of remission induced
by salvage therapy.51,52 A donor versus no donor analysis
considered 169 consecutive patients who had relapsed after
an ASCT and underwent HLA-typing immediately after re-
lapse. The 2-year PFS was higher in the allo-HCT group (with
donors) at 42% compared with 18% in the no donor group
(p = .0001) with similar OS, although TRM was 22% versus
1% in the allo-HCT and ASCT groups, respectively.53 In another
prospective phase II multicenter EBMT trial, 49 patients who
had relapsed after a previous ASCT received allo-HCT from
BEYOND AUTOLOGOUS TRANSPLANTATION IN MULTIPLE MYELOMA
related or unrelated donors with an overall response rate of
90%, including a CR rate of 40%. Cumulative incidence of
1-year TRM was 25% and was significantly lower in transplants
from fully HLA-matched donors compared with mismatched
donors (10% vs. 53%, p = .001). After a median follow-up of
43 months, the 5-year PFS and OS were 20% and 26%, re-
spectively, and were greater in patients who demonstrated
post-transplant CR.54 In light of the above data, it is rea-
sonable to consider allo-HCT in high-risk patients who have
relapsed and who demonstrated a deep remission to salvage
regimens prior to allo-HCT.
Conditioning Regimen Intensity
The optimal intensity of conditioning regimens for allo-HCT is
still controversial for patients with multiple myeloma. Fully
myeloablative regimens have been largely abandoned,
whereas nonmyeloablative stem cell transplant regimens
(e.g., total body irradiation of 2 Gy) without anti-multiple
myeloma activity have been associated with lower TRM risk
but increased relapse.37 The pendulum of regimen intensity
has now swung back to reduced-intensity conditioning with
regimens that incorporate intermediate doses of active anti-
multiple myeloma therapy. The most popular approach in
the United States is a combination of fludarabine and
melphalan at a dose of 140 mg/m2 (CIBMTR data). The
addition of proteasome inhibitors to conditioning is being
explored as an additional strategy to increase the antineo-
plastic potential without incurring additional toxicity.
IMMUNE-BASED THERAPIES BEYOND ALLO-HCT
A variety of novel post-ASCT or allo-HCT immunotherapeutic
strategies are now being explored for patients with multiple
myeloma (Table 7). These include cellular approaches such
as myeloma-specific T cells (via T-cell expansion), marrow
infiltrating lymphocytes and redirected T cells with chimeric
antigen receptors (CAR T), and tumor-based vaccines to
induce myeloma-specific immunity in the context of en-
hanced antigen presentation. HCT provides an ideal platform
for additional immune-based therapies. The recovery phase
from ASCT (or other lymphodepleting therapy) represents
a favorable platform for adoptive cellular therapy. The
homeostatic lymphocyte proliferation following lympho-
penia is a context in which immune checkpoint blockers may
also be able to reverse multiple myeloma-associated T-cell
exhaustion. Additionally, lymphopenia resulting from ASCT
eliminates tolerogenic antigen-presenting cells and induces
cytokine release that generates a more favorable environ-
ment for adoptive T-cell therapy. Indirect evidence suggests
that the immune system can contribute to the clinical
benefits of ASCT. For example, patients with early lymphoid
recovery after ASCT have superior long-term outcomes.55
Donor Lymphocyte Infusion
Donor lymphocyte infusions have been used upon relapse
after allo-HCT and even to preempt relapse, but exacer-
bation of GVHD is a major risk. Disease control is gener-
ally superior in patients in whom GVHD develops.38
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 217
KRISHNAN ET AL
Donor lymphocyte infusions have been combined with
IMIDs or bortezomib.56 Preemptive donor lymphocyte in-
fusions at a defined time period has been used to enhance
reconstitution of donor T cells and antitumor immunity.57
Emergence of WT1-specific cytotoxic T lymphocytes (WT1-
CTL) has been correlated with better PFS after allo-HCT.
Infusion of donor-derived T cells directed against specific
myeloma antigens such as WT1 or cancer testis antigens58,59
is another promising area of adoptive T-cell therapy using
the allo-HCT platform.
Myeloma Infiltrating T Lymphocytes
Marrow lymphocytes in patients with multiple myeloma are
enriched for T cells with myeloma-specific antigen specificity.
Noonan et al60 described adoptive transfer of such autolo-
gous marrow-derived, ex vivo activated and expanded T cells
on day 3 after ASCT.60 They demonstrated measurable
myeloma-specific activity for the ex vivo expanded product
and persistence of myeloma-specific immunity even at 1 year.
CAR T-Cell Therapy
CAR T-cell therapy involves transducing activated T cells with
genes encoding T-cell receptors specific to the antigen of
interest. Although multiple myeloma is not a classic CD19-
positive malignancy, deep sustained response to anti-CD19
CAR T cells in conjunction with second salvage ASCT for
patients with relapsed/refractory multiple myeloma was
recently reported.61 Several promising antigenic targets
have been identified for the development of anti-multiple
myeloma CARs (40) such as Bcell maturation antigen
(BCMA), CD138, kappa light chains, and CS-1. Notably, allogeneic
CD19-directed CAR T cells (derived from donor lymphocytes)
have induced remissions without induction of GVHD in pa-
tients who relapsed after allo-HCT.61,62 Thus, the allo-HCT
or ASCT platform could be adapted to subsequent CAR T
technology.
Natural KillerCell Therapy
Natural killer cells have innate cytotoxicity against multiple
myeloma cells, while multiple myeloma exhibits specific
immune-evasive strategies to circumvent and attenuate NK-
cell function.63 Modulation of NK activity using anti-KIR Ab
IPH2101 (monoclonal antibody against inhibitory KIR on NK
cells) is being explored as a means to establish multiple
myelomaspecific immunity.64 Autologous-, allogeneic-, and
cord-derived NK cells have been found to be safe and ef-
ficacious for multiple myeloma.65 In a phase I study, up to
1 3 108 NK cells/kg freshly expanded cord blood NK cells
were found to be safe when given before high-dose melphan
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218 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
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73. Roussel M, Lauwers-Cances V, Robillard N, et al. Front-line trans-
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 221
HEMATOLOGIC MALIGNANCIESPLASMA CELL
DYSCRASIA

Defining and Redefining Myeloma

CHAIR
S. Vincent Rajkumar, MD
Mayo Clinic
Rochester, MN

SPEAKERS
Evangelos Terpos, MD, PhD
National and Kapodistrian University of Athens
Athens, Greece

Irene M. Ghobrial, MD
Dana-Farber Cancer Institute
Boston, MA
GHOBRIAL ET AL

Future Directions in the Evaluation and Treatment of

Precursor Plasma Cell Disorders
Salomon Manier, MD, Karma Z. Salem, MD, David Liu, MD, and Irene M. Ghobrial, MD

OVERVIEW

Multiple myeloma (MM) is an incurable disease that progresses from a premalignant stage termed monoclonal gammopathy
of undetermined significance (MGUS) and an intermediate stage of smoldering multiple myeloma (SMM). Recent major
advances in therapy with more effective and less toxic treatments have brought reconsideration of early therapeutic
intervention in management of SMM, with the goal of reducing progression of the disease before the occurrence of end-
organ damage to MM and improving survival. Key to this effort is accurate identification of patients at high risk of pro-
gression who would truly benefit from early intervention. In this review, we discuss the current definitions, risk factors, risk
stratification, prognosis, and management of MGUS and SMM, as well as new emerging therapeutic options under active
investigation.

M ultiple myeloma evolves through a spectrum of dis-

ease from a premalignant stage of MGUS to an inter-
mediate stage of SMM and finally presents with symptoms
and signs of end-organ damage that lead to the diagnosis of
MM.1 Recent studies have indicated that almost all cases of
MM are preceded by the precursor state of MGUS or SMM.2,3
Over the years, the diagnosis of MM required evidence of
end-organ damage attributable to the neoplastic clone of
plasma cells, the so-called CRAB criteria identified by hy-
percalcemia, renal failure, anemia, and osteolytic bone
lesions.4 This definition was intended to be conservative to
avoid unnecessary and toxic administration of chemotherapy
to patients with asymptomatic disease. However, with major
advances in therapy, and identification of potential biomar-
kers that can distinguish MM from premalignant stages, it
became necessary to revise the disease definition of MM.5-7
In 2014, the International Myeloma Working Group (IMWG)
updated the diagnostic criteria for MM to add three markers
that can identify additional patients not yet meeting CRAB
criteria who should nevertheless be treated. These were
termed myeloma-defining events (MDEs) and constituted
the presence of clonal bone marrow (BM) plasma cells
greater than or equal to 60%, serum free light chain (FLC)
ratio greater than or equal to 100, provided the involved
FLC level is higher than or equal to 100 mg/L, or more than
one focal lesion on MRI or CT and PET-CT.8
Importantly, the revised definition excluded patients
previously considered to have SMM with ultra-high risk
of progression (80% within 2 years) who are now classified
as MM based on the updated diagnostic criteria. However,
it should be noted that the revised diagnostic criteria for
MM upstages only a small proportion of patients with
SMM. Thus, SMM as an entity continue to be relevant and
important. Therefore, there is a need to better define the
clinical and molecular characteristics of patients with
MGUS and SMM that predict progression to MM. Here,
we review the diagnostic criteria and risks of progres-
sion for MGUS and SMM and delineate potential therape-
utic options that can be used for patients with high-risk
SMM.
DEFINITION, INCIDENCE, AND RISK OF
PROGRESSION OF MGUS
MGUS is a premalignant precursor of MM.9,10 It is defined
by a serum M-protein concentration lower than 3 g/dL and/or
an abnormal FLC ratio (, 0.26 or . 1.65), less than 10%
clonal plasma cells in the BM, and absence of MDEs or
evidence of Waldenstrom macroglobulinemia or amyloid-
osis (Table 1).8 When first clinically recognized, MGUS has
likely been present in an undetected state for a median
duration of more than 10 years.11
MGUS is present in over 3% to 4% of the population older
than age 5010 and increases with age to 8.9% in people older
than age 85.1 Therefore, one of the most important risk
factors for MGUS is age.1,12 In addition to an accumulation of
cases, the age-related increase in prevalence of MGUS is
related to a true increase in incidence with age.

From the Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Irene M. Ghobrial, MD, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02115; email: Irene_ghobrial@dfci.harvard.edu.

2016 by American Society of Clinical Oncology.

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Apart from age, there are several factors that are asso-
ciated with a higher risk of developing MGUS, including
African American race and a familial history of myeloma.
Other factors such as the presence of autoimmune disorders
are less well delineated. Persons of African and African
American descent have a threefold increased prevalence
even after adjusting for socioeconomic and other risk fac-
tors, suggesting a genetic predisposition among this pop-
ulation.13 An increased prevalence of MGUS in Africans
relative to Caucasians has also been reported in Ghana.14,15
Two studies have shown that the risk of MM and MGUS
is increased threefold in relatives of individuals with
MGUS.16,17 In addition, an increased risk of developing non-
Hodgkin lymphoma and chronic lymphoid leukemia was also
observed in this group. Collectively, these data are consis-
tent with an inherited twofold to fourfold genetic suscep-
tibility to MM.18 The genetic basis of inherited MM
susceptibility is incompletely understood. However, recent
genome-wide association studies (GWAS) identified seven
loci contributing to inherited genetic susceptibility to
MM.18-21 These seven loci were also associated with an
increased risk of developing MGUS.22 Another GWAS study
in the Nordic region identified a novel MM risk locus at
ELL2.23
There are three subtypes of MGUS: nonimmunoglobulin
M (IgM) MGUS, IgM MGUS, and light-chain MGUS. Non-IgM
MGUS carries a risk of progression to MM or solitary
plasmacytoma, whereas IgM MGUS is associated with a risk
of progression to Waldenstrom macroglobulinemia. Light-
chain MGUS is a newly discovered entity that is associated
with a risk of progression to the light-chain type of MM. All
forms of MGUS can progress to Ig light-chain amyloidosis.
MGUS is associated with a lifelong risk of transformation
to MM or a related malignancy at a rate of 1% per year.9 In
some patients, however, the risk may be as high as 58% in
20 years. The size and subtype of the M protein at diagnosis of
MGUS and an abnormal serum FLC ratio are well-established
prognostic factors for progression.24 As such, MGUS can be
risk stratified using three simple variables: the serum FLC
KEY POINTS
Multiple myeloma is always preceded by precursor
conditions including MGUS and smoldering myeloma.
The rate of progression of MGUS is at 1% per year, but
the rate of progression of SMM is 10% per year, with a
high rate of progression of 50% at 2 years for those with
high-risk features.
Patients with high-risk SMM should be offered clinical
trials to prevent progression or carefully observed to
avoid end-organ damage.
Patients with MGUS and SMM have different risk
stratifications and rates of progression.
Some patients may benefit from early therapeutic
interventions, specifically in high-risk SMM.
DIAGNOSIS AND MANAGEMENT OF MGUS AND SMOLDERING MYELOMA
TABLE 1. IMWG Diagnostic Criteria for MGUS, SMM,
and MDEs
IMWG Criteria, 2014 Version8
MGUS Serum M protein , 3 g/dL and/or abnormal FLC ratio
(, 0.26 or . 1.65) with increased level of appropriate
involved light chain
Clonal BM plasma cells , 10%
Absence of MDEs or amyloidosis
SMM Serum M protein . 3 g/dL
AND/OR clonal BM plasma cells . 10% and , 60%
AND/OR urinary monoclonal protein . 500 mg per 24
hours
Absence of MDEs or amyloidosis
MDEs Evidence of end-organ damage (CRAB criteria):
Hypercalcemia: serum Ca2+ . 0.25 mmol/L (. 1 mg/dL)
above upper limit of normal or . 2.75 mmol/L
(. 11 mg/dL)
Renal insufficiency: serum creatinine . 173 mmol/L
(. 2 mg/dL)
Anemia: hemoglobin value of . 2 g/dL below the lower
limit of normal or a hemoglobin value , 10 g/dL
Bone lesions: one or more lytic lesion(s) on skeletal
radiography, CT, or PET-CT
Clonal BM plasma cell percentage $ 60%
Involved/uninvolved serum FLC ratio $ 100
More than one focal lesions on MRI
Abbreviations: IMWG, International Myeloma Working Group; MGUS,
monoclonalgammopathy of undetermined significance; SMM, smoldering multiple
myeloma; MM, multiple myeloma; MDEs, myeloma-defining events; FLC, serum free
light chain; BM, bone marrow.
ratio, the size of the M protein, and the type of M protein
(Table 2). Patients with serum M protein , 1.5 g/dL, IgG
class, and normal FLC ratio are considered low-risk MGUS
and have only a 2% lifetime risk of progression. In general,
patients with MGUS must be reassessed in 6 months, and
if stable yearly thereafter. A number of lifestyle and envi-
ronmental risk factors have been proposed to increase the
risk of progression from MGUS to MM, including obesity,
immune dysfunction, and agricultural, chemical, and radia-
tion exposure. Of these, obesity is probably the most con-
sistently reported association.25-27 Studies are ongoing to
determine the mechanism of progression of MGUS and to
explore preventive strategies.
In addition to the risk of progression, MGUS can also be
associated with several other clinical problems including
sensorimotor peripheral neuropathy (MGUS neuropathy),
membranoproliferative glomerulonephritis, lichen myx-
edematosus (papular mucinosis, scleromyxedema), pyo-
derma gangrenosum, or necrobiotic xanthogranuloma.
DEFINITION, INCIDENCE, AND RISK OF
PROGRESSION OF SMM
SMM is a heterogeneous disease entity that includes pa-
tients with higher disease burden than in MGUS but remain
asymptomatic.28 The term SMM was first described by Kyle
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GHOBRIAL ET AL

TABLE 2. Risk of Progression of Monoclonal Gammopathy of Undetermined Significance to Myeloma or Related

Disorders

Cumulative Absolute Risk of

Relative Risk of Cumulative Absolute Risk of Progression at 20 Years Accounting
Risk Group Progression Progression at 20 Years (%)* for Death as a Competing Risk (%)**
Low Risk: Serum M Protein 1 5 2
< 1.5 g/dL, IgG Subtype,
Normal Free Light Chain Ratio
(0.261.65)
Low-Intermediate Risk: Any One 5.4 21 10
Factor Abnormal
High-Intermediate Risk: Any Two 10.1 37 18
Factors Abnormal
High Risk: All Three Factors 20.8 58 27
Abnormal
Adapted from Rajkumar et al56 with permission from the publisher.
*Estimates in this column represent the risk of progression assuming that patients do not die of other causes during this period.
**Estimates in this column represent the risk of progression calculated by using a model that accounts for the fact that patients can die of unrelated causes during this time.
Abbreviation: IgG, immunoglobulin G.

and Greipp in 198029 and was followed by many other
descriptions terming it indolent MM,30 or Durie Salmon
stage I.31 In 2003, the IMWG defined SMM as having a serum
M-protein level higher than or equal to 3 g/L and/or greater
than or equal to 10% monoclonal plasma cells in the BM
(Table 3).1,4 Although the incidence and prevalence of SMM
in the population is not well defined, it has been estimated to
represent approximately 8% to 20% of patients within the
MM spectrum.28
The update to the disease definition of MM automatically
resulted in revised diagnostic criteria for SMM as it excludes
patients with ultra-highrisk SMM who are now considered
as having overt MM (Table 1).8 Despite that, it remains a
major clinical dilemma with an overall risk of progression of
10% per year for the first 5 years, 3% per year for the next
5 years, and 1% per year for the last 10 years. This suggests
that the current definition of SMM is highly biologically
and clinically heterogeneous.32 Indeed, SMM represents a

TABLE 3. Risk Stratification of Patients with Smoldering Myeloma Based on Mayo Clinic and Spanish Criteria

Model Risk Factors No. of Risk Factors 5-Year Progression (%) Relative Risk
Mayo Clinic Model M protein $ 3 g/dL 1 25 1
$ 10% BM plasma cells 2 51 2.0
FLC ratio , 0.125 or . 8 3 76 3.0
Total 51 NA
Spanish (PETHEMA) Model $ 95% aPC 0 4 1
Immunoparesis 1 46 11.5
2 72 18
Total 46 NA
Proposed New Criteria for $ 10% BM plasma cells Serum M protein $ 30 g/L
High-Risk SMM
With one of the criteria in the IgA SMM
right column
Immunoparesis with reduction of two uninvolved Ig isotypes
Serum involved/uninvolved FLC ratio $ 8 (but , 100)
Progressive increase in M-protein level (evolving type of SMM)
BM clonal plasma cells 50% to 60%
aPC immunophenotype ($ 95% of BM plasma cells are clonal)
and reduction of one or more uninvolved Ig isotypes
t(4;14) or del 17p or 1q gain
Increased circulating plasma cells
MRI with diffuse abnormalities or one focal lesion
PET-CT with focal lesion with increased uptake without underlying osteolytic bone
destruction
Abbreviations: BM, bone marrow; FLC, serum free light chain; NA, not applicable, aPC, abnormal plasma cells; IgA, immunoglobulin A; SMM, smoldering multiple myeloma.

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clinical entity where a subset of patients have a very indolent
course of disease that mimics an MGUS-like state, whereas
others have a more aggressive course of disease that has
been described as early myeloma or CRAB-negative
myeloma. Unfortunately, there are currently no molecular
factors to differentiate these two clinically and biologically
distinct groups of patients. For this reason, additional studies
are required to identify markers of progression within these
patients.
There are three subtypes of SMM: IgA, IgG, and light chain.
The median time to progression (TTP) for IgA and IgG SMM
is 27 and 75 months, respectively.32,33 Light-chain SMM
has a cumulative probability of progression to active MM
or light-chain amyloidosis of 27.8% at 5 years, 44.6% at
10 years, and 56.5% at 15 years.34 The current factors as-
sociated with risk of progression are mainly based on the
level of tumor burden in these patients assessed by the
degree of tumor involvement in the BM and the quantifi-
cation of monoclonal protein in the peripheral blood.
The two most widely used risk stratification methods
are the Mayo Clinic32 and the PETHEMA Spanish group
classifications.35 The Mayo Clinic criteria are primarily based
on the levels of serum protein markers (serum protein
electrophoresis and FLC assay) and the percentage of plasma
cells in the BM.32,33 The risk stratification of the PETHEMA
Study Group, on the other hand, focused on the use of
multiparameter flow cytometry of the BM to quantify the
ratio of abnormal, neoplastic plasma cells to normal plasma
cells and reduction of uninvolved Igs.35 Interestingly, a head-
to-head comparison between the PETHEMA and the Mayo
Clinic risk models showed notable discordance reflected in
many patients being classified as high risk in one model and
low risk in the other model.36 Other risk factors that have
been examined include the role of IgA (vs. IgG) isotype, the
presence of proteinuria, circulating plasma cells, a high
proliferative rate of BM plasma cells, and abnormal MRI
findings.12,28,37
SMM can also be subclassified based on underlying cy-
togenetic abnormalities.38,39 Patients with t(4;14), 1q gain,
and/or del17p are considered high-risk SMM (median TTP of
approximately 24 months). Patients with hyperdiploidy are
considered intermediate-risk (median TTP of approximately
34 months). Other cytogenetic abnormalities including t(11;14)
are considered standard risk (median TTP, 54 months).
Patients with SMM who have no evidence of cytogenetic
abnormalities on fluorescence in situ hybridization (FISH)
studies are considered low risk (median TTP, 101 months).
An international workshop assembled to review cytoge-
netic studies to evaluate whether MGUS and SMM cases
have the same detectable anomalies that are often found in
MM.40 Point mutations in NRAS and KRAS, MYC upregulation,41
and gain or loss of chromosome 1q or 1p seem to correlate
with disease progression from MGUS and SMM.42 A pro-
gressive increase in the incidence of copy number ab-
normalities from MGUS to SMM and to MM has also been
recently observed.43 Although MM has more copy num-
ber abnormalities than its precursor states, MGUS is as
DIAGNOSIS AND MANAGEMENT OF MGUS AND SMOLDERING MYELOMA
genetically aberrant as MM and does not appear to be
associated with a particular chromosomal imbalance but
rather with an expansion of altered clones that are already
present in MGUS.43
A study of transcriptional profiling using gene expression
profiling has identified signatures that can identify patients
with MGUS versus SMM versus MM.44 However, this study
has major limitations given that the percentage of plasma
cells present in MGUS cases is low and the samples are
inherently contaminated with normal nontransformed plasma
cells.
Based on all these factors, a new classification for high-risk
SMM has been proposed by Rajkumar et al to identify pa-
tients at high risk of progression to MM (25% per year) as
defined by the criteria listed in Table 3.32,33,35,38,39,45-49
Although these biomarkers were defined before the re-
visions to the diagnostic criteria, because the proportion of
patients with SMM affected and upstaged as a result of the
new criteria are small, the effect on the estimates for
progression would likely be minimal. Identification of high-
risk SMM is of particular importance because these patients
are at considerable risk of end-organ damage and are
candidates for clinical trials and/or intervention.7 In con-
trast, patients with SMM without high-risk factors likely
have a risk of progression of 5% per year or less.
MANAGEMENT OF MGUS AND SMM
Patients with MGUS are not offered therapeutic options to
date and close observation is indicated in these patients. A
recent study demonstrated that prior knowledge of MGUS
and close monitoring had significantly better overall survival
(median survival, 2.8 years) than patients with MM without
prior knowledge of MGUS (median survival, 2.1 years).50 In
fact, low M-protein concentration (, 0.5 g/dL) at MGUS
diagnosis was associated with poorer MM survival, pre-
sumably because those patients were not closely followed
for disease progression.50
All patients suspected to have SMM need an MRI of the
spine and pelvis (or ideally whole-body MRI) or whole-body
CT or PET-CT.1,8,51 BM examination with FISH studies and
multiparametric flow cytometry are also required. The
standard of care for SMM remains observation with re-
evaluations of the patients every 34 months.1,8,49 In low-
risk patients, follow-up can be reduced to once every
6 months after the first 5 years. Imaging studies must be
repeated if changes in clinical features or M protein occur.
For patients at high risk, follow-up should continue in-
definitely, and should include periodic imaging studies to
rule out asymptomatic progression. Patients with SMM can
be initiated on therapy without waiting for CRAB features to
appear if follow-up testing shows the development of other
MDE or early detection of MM bone disease on the basis of
advanced imaging studies. Patients with a baseline MRI
showing diffuse infiltration, solitary focal lesion, or equivocal
lesions, need follow-up examinations in 36 months to rule
out progression.8
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GHOBRIAL ET AL
Investigators attempted to assess whether early thera-
peutic intervention can lead to substantial improvement in
survival and response.28 There are two major goals in early
therapeutic intervention: the first is prevention of pro-
gression, and the second is definitive therapy to achieve
complete remission with the hope that all subclones will be
eradicated at this early disease state and cure can be
achieved.37,52
The major barrier to early intervention has been defining
the group of patients who would truly benefit from this early
treatment as they would have otherwise progressed to
symptomatic disease. Indeed, if SMM is a heterogeneous
mix of patients with early myeloma and MGUS-like mye-
loma, then identification of those with early MM will allow
for intervention only in those patients who truly warrant
therapy.
Bisphophonates
Bisphosphonates have shown promise in reducing the risk of
skeletal-related events (SREs) in SMM, but have not been
shown to delay progression to MM or prolong survival. In
a randomized trial of pamidronate (once monthly for
12 months) versus observation, the incidence of SRE was
39% versus 73%, respectively (p = .009).53 In another trial of
zoledronic acid (monthly for 12 months) versus observation,
the incidence of SRE was 56% versus 78%, respectively
(p = .041).54 The reduction in SREs is an important endpoint,
and based on these two trials, consideration must be given
to bisphosphonates. We recommend once-yearly bisphospho-
nate in patients at low risk, and once every 34 months in select
patients with high-risk SMM.
Lenalidomide
The most critical study of therapy in SMM that has reignited
interest in therapeutic intervention in this patient pop-
ulation came from the PETHEMA group using lenalidomide
and dexamethasone compared with observation. Mateos
et al7 reported on 119 patients with high-risk SMM who
received either observation or lenalidomide and dexa-
methasone in an open-label randomized trial. Patients
treated with lenalidomide and dexamethasone had a su-
perior 3-year survival without progression to symptomatic
disease (progression-free survival; 77% vs. 30%; p , .001)
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31:4325-4332.
40. Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of
multiple myeloma: a workshop report. Cancer Res. 2004;64:1546-1558.
41. Chng WJ, Huang GF, Chung TH, et al. Clinical and biological implications
of MYC activation: a common difference between MGUS and newly
diagnosed multiple myeloma. Leukemia. 2011;25:1026-1035.
42. Chiecchio L, Dagrada GP, Protheroe RK, et al; UK Myeloma Forum. Loss
of 1p and rearrangement of MYC are associated with progression of
smouldering myeloma to myeloma: sequential analysis of a single case.
Haematologica. 2009;94:1024-1028.
43. Lopez-Corral
L, Sarasquete ME, Be`a S, et al. SNP-based mapping arrays
reveal high genomic complexity in monoclonal gammopathies, from
MGUS to myeloma status. Leukemia. 2012;26:2521-2529.
44. Zhan F, Barlogie B, Arzoumanian V, et al. Gene-expression signature of
benign monoclonal gammopathy evident in multiple myeloma is linked
to good prognosis. Blood. 2007;109:1692-1700.
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GHOBRIAL ET AL
45. Rosin~ol L, Blade J, Esteve J, et al. Smoldering multiple myeloma: natural
history and recognition of an evolving type. Br J Haematol. 2003;123:
631-636.
46. Dhodapkar MV, Sexton R, Waheed S, et al. Clinical, genomic, and
imaging predictors of myeloma progression from asymptomatic
monoclonal gammopathies (SWOG S0120). Blood. 2014;123:78-85.
47. Bianchi G, Kyle RA, Larson DR, et al. High levels of peripheral blood
circulating plasma cells as a specific risk factor for progression of
smoldering multiple myeloma. Leukemia. 2013;27:680-685.
48. Hillengass J, Fechtner K, Weber MA, et al. Prognostic significance of
focal lesions in whole-body magnetic resonance imaging in patients
with asymptomatic multiple myeloma. J Clin Oncol. 2010;28:1606-1610.
49. Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma.
Blood. 2015;125:3069-3075.
50. Sigurdardottir EE, Turesson I, Lund SH, et al. The role of diagnosis and
clinical follow-up of monoclonal gammopathy of undetermined signifi-
cance on survival in multiple myeloma. JAMA Oncol. 2015;1:168-174.
51. Blade J, Dimopoulos M, Rosin~ol L, et al. Smoldering (asymptomatic)
multiple myeloma: current diagnostic criteria, new predictors of out-
come, and follow-up recommendations. J Clin Oncol. 2010;28:690-697.
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52. Ghobrial IM, Landgren O. How I treat smoldering multiple myeloma.
Blood. 2014;124:3380-3388.
53. DArena G, Gobbi PG, Broglia C, et al; Gimema (Gruppo Italiano Malattie
Ematologiche DellAdulto); Multiple Myeloma Working Party; Gisl
(Gruppo Italiano Studio Linfomi) Cooperative Group. Pamidronate
versus observation in asymptomatic myeloma: final results with long-
term follow-up of a randomized study. Leuk Lymphoma. 2011;52:
771-775.
54. Musto P, Petrucci MT, Bringhen S, et al; GIMEMA (Italian Group for
Adult Hematologic Diseases)/Multiple Myeloma Working Party and the
Italian Myeloma Network. A multicenter, randomized clinical trial
comparing zoledronic acid versus observation in patients with
asymptomatic myeloma. Cancer. 2008;113:1588-1595.
55. Zingone A, et al. Phase II clinical and correlative study of carfilzomib,
lenalidomide, and dexamethasone followed by lenalidomide extended
dosing (CRD-R) induces high rates of MRD negativity in newly diagnosed
multiple myeloma (MM) patients. Blood. 2013;122:538-538.
56. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is
an independent risk factor for progression in monoclonal gammopathy
of undetermined significance (MGUS). Blood. 2005;106:812-817.
 IMAGING FOR MULTIPLE MYELOMA

The Role of Imaging in the Treatment of Patients With

Multiple Myeloma in 2016
Evangelos Terpos, MD, PhD, Meletios A. Dimopoulos, MD, and Lia A. Moulopoulos, MD

OVERVIEW

The novel criteria for the diagnosis of symptomatic multiple myeloma have revealed the value of modern imaging for the
management of patients with myeloma. Whole-body low-dose CT (LDCT) has increased sensitivity over conventional ra-
diography for the detection of osteolytic lesions, and several myeloma organizations and institutions have suggested that
whole-body LDCT should replace conventional radiography for the work-up of patients with myeloma. MRI is the best
imaging method for the depiction of marrow infiltration by myeloma cells. Whole-body MRI (or at least MRI of the spine and
pelvis if whole-body MRI is not available) should be performed for all patients with smoldering multiple myeloma with no
lytic lesions to look for occult disease, which may justify treatment. In addition, MRI accurately illustrates the presence of
plasmacytomas, spinal cord, and/or nerve compression for surgical intervention or radiation therapy; it is also recom-
mended for the work-up of solitary bone plasmacytoma, and it may distinguish malignant from benign fractures (which is
very important in cases of patients in biochemical remission with no other signs of progression). Diffusion weighted imaging
(DWI) seems to improve MRI diagnosis in patients with myeloma. PET/CT is a functional imaging technique, more sensitive
than conventional radiography for the detection of lytic lesions, which probably allows better definition of complete
response and minimal residual disease compared with all other imaging methods. PET/CT has shown the best results in the
follow-up of patients with myeloma and has an independent prognostic value both at diagnosis and following treatment.
PET/CT can also be used for the work-up of solitary bone plasmacytoma and nonsecretory myeloma.

L ytic bone disease is a major feature of multiple myeloma:

70% to 80% of patients have osteolytic lesions at diagnosis,
and up to 90% develop lytic lesions during the course of their
disease.1 The novel criteria for the diagnosis of symptomatic
multiple myeloma have revealed the value of modern imaging
for the management of patients with multiple myeloma, as
they include (1) the presence at least one lytic lesion detected
not only by conventional radiography but also by CT, whole-
body LDCT, or PET/CT, and (2) the presence of one or more
focal bone marrow lesions on MRI studies.2 Furthermore, novel
imaging techniques, such as MRI and PET/CT, provide prog-
nostic information and have been recently proven of value, for
the better definition of response to anti-myeloma therapy.
IS CONVENTIONAL RADIOGRAPHY THE GOLD
STANDARD FOR THE DIAGNOSIS OF BONE
DISEASE IN PATIENTS WITH MYELOMA IN 2016?
The Role of Whole-Body LDCT
Conventional radiography has been widely used for the
identification of osteolytic lesions both at diagnosis and
during the course of the disease. The skeletal survey (whole
body x-rays) at diagnosis should include plain radiographs of
the whole skeleton, as previously described.3 Osteolyses
have the typical appearance of punched-out lesions with
the absence of reactive sclerosis (Fig. 1) and are more
common in the vertebrae, ribs, skull, and pelvis.4 Although
the whole-body x-ray was the standard of care for many
years, it has several limitations: (1) for a lytic lesion to be-
come apparent, more than 30% loss of trabecular bone must
occur; (2) it is difficult to assess certain areas, such as the
pelvis and the spine; (3) there are limitations to the de-
tection of lytic lesion response to anti-myeloma therapy
because of delayed evidence of healing; (4) specificity is
reduced for the differential diagnosis of myeloma-related
fracture and benign fracture (very important, particularly in
cases of new vertebral compression fractures in the absence
of other criteria of relapse); (5) it is dependent on the ob-
server (there is very low reproducibility among centers;
higher number of osteolytic lesions detected in academic
centers compared with nonacademic centers); and (6)

From the School of Medicine, National and Kapodistrian University of Athens, Alexandra General Hospital, Athens, Greece; School of Medicine, National and Kapodistrian University of
Athens, Areteion Hospital, Athens, Greece.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Evangelos Terpos, MD, PhD, Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra General Hospital, 80 Vas. Sofias Ave.,
11528, Athens, Greece; email: eterpos@med.uoa.gr.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e407

TERPOS, DIMOPOULOS, AND MOULOPOULOS
studies are long and often not tolerable for patients in severe
pain.3,4 Thus, the development of novel imaging methods
has led to the substitution of whole-body x-ray by more
advanced techniques, such as the whole-body LDCT in many
European centers or by PET/CT in the United States.
Whole-body LDCT was introduced to allow the detection of
osteolytic lesions in the whole skeleton with high accuracy, no
need for contrast agents and low radiation dose compared
with standard CT (two- to threefold lower radiation dose
versus conventional CT).5,6 In several studies, whole-body LDCT
was found to be superior to whole-body x-ray for the detection
of osteolytic lesions (Table 1).5,7-11 In one of the largest studies
staging patients with myeloma, 61% of patients with normal
whole-body x-ray results had more than one osteolytic lesions
on whole-body LDCT.10 According to the new criteria for
symptomatic myeloma, these patients should receive therapy.
In the same study, the total number of lesions detected by
whole-body LDCT was 968 compared with 248 for whole-body
x-ray (p , .001), with the only limitation of this study being its
retrospective origin.10 In a more recent prospective study,
which included 52 patients with myeloma at diagnosis, whole-
body LDCT revealed osteolysis in 12 patients (23%) with
negative whole-body x-ray, and it proved to be more sensitive
than whole-body x-ray mainly in the axial skeleton (p , .001).
Whole-body LDCT was superior in detecting lesions in patients
with osteopenia and osteoporosis.11
In total, whole-body LDCT advantages over whole-body
x-ray include (1) superior diagnostic sensitivity for de-
piction of osteolytic lesions, especially in areas where the
whole-body x-ray detection rate is low (i.e., pelvis and spine);
(2) superiority in estimating fracture risk and bone instability;
(3) duration of the examination, which is 5 minutes or less, an
important issue for patients in extreme pain; (4) production of
higher-quality 3D high resolution images for planning biopsies
and therapeutic interventions; and (5) demonstration of
unsuspected manifestations of myeloma or other disease,
especially in the lungs and kidneys (33% in the study by Wolf
KEY POINTS
Whole-body LDCT is superior to conventional
radiography for the detection of osteolytic lesions, and it
is suggested to replace it in the work-up of patients with
myeloma.
MRI is the best imaging method for the depiction of
marrow infiltration by myeloma cells.
Whole-body MRI (or at least MRI of the spine and pelvis
if whole-body MRI is not available) should be performed
for all patients with smoldering multiple myeloma with
no lytic lesions to look for occult disease, which may
justify treatment.
PET/CT allows better definition of complete response
and minimal residual disease.
PET/CT has an independent prognostic value both at
diagnosis and after treatment.
e408 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
et al).5-11 Major disadvantages of whole-body LDCT include
increased length of time required for radiologists to report
their findings, lack of availability in several centers,2,5 and lack
of specificity for the differential diagnosis between malignant
and osteoporotic fractures, despite improvements during
recent years.12 Furthermore, although exposure to radiation
is much lower compared with standard CT, it continues to be
higher than whole-body x-ray: mean dose of whole-body
LDCT is approximately 3.6 and 2.8 mSv for females and
males, respectively, compared with 1.2 mSv for whole-body
x-ray.13 Nevertheless, the higher diagnostic accuracy of
whole-body LDCT and patient comfort, which is particularly
important for older patients, renders the dose/quality ratio
favorable for whole-body LDCT. For these reasons, the Eu-
ropean Myeloma Network has suggested that whole-body
LDCT replace conventional radiography as the standard im-
aging technique for evaluation of bone disease in multiple
myeloma, where available.14 Figure 2 shows images from a
whole-body LDCT study of one of our patients with myeloma.
The Value of MRI in Myeloma: Advantages and
Limitations
MRI detection of bone involvement in myeloma: comparison
with conventional radiography. MRI has been estab-
lished as a valuable technique for the diagnosis of bone
involvement in multiple myeloma. MRI detects bone mar-
row infiltration by myeloma cells; whole-body x-ray and CT
detect osseous destruction. Conventional MRI protocols for
multiple myeloma include T1-weighted, T2-weighted with
fat suppression, in- and opposed-phase imaging, and
contrast-enhanced T1-weighted sequences. Five MRI pat-
terns of marrow involvement have been recognized in
multiple myeloma: (1) a focal pattern that consists of lo-
calized areas of myeloma cell infiltration 5 mm or greater in
diameter (present in 30%50% of patients with multiple
myeloma); (2) a diffuse pattern characterized by almost
complete replacement of normal marrow by myeloma cells
(present in 25%40% of patients with multiple myeloma);
(3) a combined diffuse and focal pattern (present in 10% of
patients with multiple myeloma); (4) a normal bone marrow
pattern (present in 15%25% of patients with multiple
myeloma); and (5) a variegated or salt and pepper pattern
with innumerable small bone marrow focal lesions (present
in 1%5% of patients with multiple myeloma; Fig. 3).3,4,15
Several studies have shown that MRI is more sensitive than
whole-body x-ray for the detection of bone involvement in
multiple myeloma.16-19 The largest included 611 patients
who were treated with total therapy protocols in Arkansas.
MRI detected focal lesions in 74% of the patients, while
whole-body x-ray detected osteolytic lesions in 56% of them.
MRI was superior to whole-body x-ray particularly in
detecting bone involvement.16 A meta-analysis, which
compared the detection rate of different imaging tech-
niques, confirmed the superiority of MRI over whole-body
x-ray, mainly in the axial skeleton.20
Because of its high sensitivity in revealing bone marrow
involvement, MRI is now used for the discrimination

FIGURE 1. (A) Characteristic Punched-Out Lesions in the Skull and (B) Large Osteolytic Lesions in the Left
Humerus
between asymptomatic/smoldering and symptomatic mul-
tiple myeloma. Several studies have shown that approxi-
mately 40% to 50% of patients with normal whole-body x-ray
had abnormal findings on MRI examinations.17-19 Two
studies showed that patients with smoldering multiple
myeloma who had more than one focal lesion on MRI had a
median time to progression (TTP) to symptomatic disease
of 13 to 15 months and a 2-year probability of progression of
approximately 70%.21,22 In both studies, the presence of
more than one focal lesion on MRI was an independent
adverse prognostic factor for progression to symptomatic
disease. Based on these studies, the International Myeloma
Working Group (IMWG) included the use of whole-body MRI
(or MRI of the spine and pelvis if whole-body MRI is not
available) in the work-up for smoldering multiple myeloma.2
IMAGING FOR MULTIPLE MYELOMA
In this point, it is important to note the differences between
the detection rates of whole-body MRI, which is not avail-
able everywhere, and the detection rate of spine and pelvis
MRI. In a study of 100 patients with multiple myeloma and
monoclonal gammopathy of undetermined significance who
underwent whole-body MRI, 10% of patients presented with
focal lesions in the peripheral skeleton only; this is the
number of patients who will not be diagnosed with lesions if
an MRI of the spine and pelvis is performed, instead of
whole-body MRI.23
MRI detection of bone involvement in myeloma:
comparison with whole-body LDCT and PET/CT. In two
small studies, with 41 and 46 patients with newly diagnosed
multiple myeloma, respectively, whole-body MRI was able
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TERPOS, DIMOPOULOS, AND MOULOPOULOS

TABLE 1. Major Studies Comparing Whole-Body LDCT and Conventional Radiography

Study Study Design No. of Patients Reference Test Key Findings
Gleeson et al9 P 39 WBXR, WB-MRI, bone marrow WBLDCT . WBXR, superior detection rate, comparable
biopsy with WB-MRI
Kropil et al8 P 29 WBXR WBLDCT . WBXR, ratio of detection of lytic lesion
WBLDCT/WBXR = 2.06 (4.60 for the spine; 7 for the
skull; 2.54 for the pelvis and 2.07 for the thoracic cage)
Princewill et al10 R 51 WBXR WBLDCT . WBXR; ratio of detection of lytic lesion
WBLDCT/WBXR = 3.9 (74 for the thoracic cage; 6.67 for
the pelvis and the fat bones; 4.92 for the spine; 2.31 for
the long bone and 1.09 for the skull); 61% of the
patients upstaged with WBLDCT
Wolf et al11 P 52 WBXR WBLDCT . WBXR, particularly in the axial skeleton. 63%
patients upstaged with WBLDCT, 23% patients nega-
tive at WBXR and positive at WBLDCT
Abbreviations: P, prospective; WBRX; whole-body x-ray (conventional skeletal survey); WB-MRI, whole-body MRI; WBLDCT, whole-body low-dose CT; R, retrospective.

to detect a higher number of patients with bone marrow disease.24,25 However, in the largest comparison to date of
involvement compared with whole-body LDCT or PET/CT. 303 patients with myeloma, there was no superiority of MRI
The superiority of MRI over PET/CT was mainly because of over PET/CT for the detection of focal lesions; though, a
the higher sensitivity of MRI for the detection of diffuse diffuse MRI pattern of bone marrow involvement was not

FIGURE 2. Whole-Body LDCT Images Showing Lytic Lesions in the Skull, Spine, and Pelvis, Bone Marrow Deposits in
the Femoral Cavity, and Vertebral Body Fractures

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 IMAGING FOR MULTIPLE MYELOMA

FIGURE 3. MRI Patterns of Marrow Involvement in Myeloma

(A) Focal pattern: On T1-weighted images, focal lesions are darker than yellow marrow and slightly hypointense or isointense to intervertebral disc and muscle. (B) Diffuse
pattern: On T1-weighted images, the normal bone marrow signal is completely replaced by the abnormal process, and the intervertebral discs appear brighter or isointense
to the diseased marrow. (C) Variegated pattern: On T1-weighted images, the bone marrow is very inhomogeneous with innumerable small lesions.

included in this comparison.26 Finally, in a retrospective
study of 210 MRI and 210 PET/CT studies of patients with
multiple myeloma, MRI achieved better results than PET/CT
for the detection of myeloma at diagnosis and at progres-
sion; PET/CT, however, detected findings of response to anti-
myeloma therapy earlier than MRI.27
Prognostic significance of MRI. MRI patterns have been
compared with myeloma features at presentation. More
specifically, a diffuse MRI pattern correlated with high-risk
cytogenetics, advanced disease stage (ISS-3), and increased
angiogenesis.28-30 Patients with diffuse MRI pattern expe-
rienced poorer overall survival (OS) compared with pa-
tients with focal or normal patterns, both in the era of
conventional chemotherapy or in the era of novel anti-
myeloma agents.29-32 More importantly, in a study that
included 228 symptomatic patients who received first-line
therapy with bortezomib- or immunomodulatory drugbased
regimens, the combination of diffuse MRI pattern and high-
risk cytogenetics and ISS-3, identified a group of patients
who experienced poor outcome: a median OS of 21 months
and a 35% probability for 3-year OS.29 Similarly, in a recent
study of 161 patients with multiple myeloma who un-
derwent an autologous transplantation (ASCT), the combi-
nation of a high-risk MRI score (defined as the presence of
moderate to severe diffuse infiltration, or the presence of
more than 25 focal lesions on whole-body MRI or more than
seven focal lesions on axial MRI) and high-risk cytogenetics
identified a group of patients with median progression-free
survival (PFS) and OS of 23 and 56 months, respectively.33
The cut-off value of seven focal lesions on MRI was also used
by the Arkansas group to identify patients with inferior OS
(3-year OS probability: 73% vs. 86% for those with zero to
seven focal lesions).34 Despite the prognostic significance of
MRI, no treatment has been suggested to date for patients
with high-risk MRI features.

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TERPOS, DIMOPOULOS, AND MOULOPOULOS
The role of MRI in the follow-up of patients with
myeloma. Although there are several studies evaluating the
role of imaging at diagnosis, there are limited data for the
value of imaging during treatment and follow-up of patients
with myeloma. The IMWG suggests that there is no need to
repeat the skeletal survey in a patient who is responding to
treatment unless he develops bone symptoms and that
other imaging studies (CT, MRI, and PET/CT) to detect soft
tissue masses arising from bone lesions or extramedullary
disease may be indicated according to clinical circum-
stances.35 We believe that these recommendations must
be changed, as the physician cannot detect asymptomatic
increases in the dimensions of pre-existing lytic lesions or the
presence of new lytic lesions or new plasmacytomas (all are
criteria for defining disease progression36) without appro-
priate imaging.
Is there any role for MRI in this setting? And if yes, how
often must we repeat MRI after initial evaluation? Resolu-
tion of previously detected focal lesions occurred in ap-
proximately 60% of patients who were treated with total
therapy protocols in Arkansas. When the disease pro-
gressed, after the achievement of complete response (CR),
whole-body MRI revealed new focal lesions or enlargement
of previously detected focal lesions in 26% and 28% of
patients, respectively, while 15% of patients demonstrated
both of these features at their MRI evaluation.16 In general,
MRI findings of response to therapy (CR or partial response
[PR]) include resolution or decrease of the extent of focal
lesions or diffuse patterns in conventional chemotherapy or
novel anti-myeloma agent era.37-39 In a small study with 33
patients who underwent an ASCT, MRI had 79% accuracy
and 86% specificity but only 64% sensitivity for the detection
of remission because of false-positive results of nonviable
lesions.39 Thus, for better evaluation of remission, functional
imaging techniques (e.g., PET/CT or possibly DWI MRI) seem
to be more appropriate and will be discussed in the following
sections.
Regarding patients with smoldering multiple myeloma
with a negative MRI study at diagnosis, the timing of follow-
up with MRI and the significance of any findings on these
studies have not yet been established. In a single such study,
the Heidelberg group performed a second MRI 3 to 6 months
after the first in 63 patients with smoldering multiple my-
eloma. Approximately one-half of the patients showed
progression on MRI, while 40% developed symptomatic
disease, according to CRAB criteria (i.e., calcium, renal
failure, anemia, and bone disease).40 More data are needed
before recommending time intervals between the first and
subsequent MRIs for patients with smoldering multiple
myeloma.
Advantages and limitations of conventional MRI. The
major advantage of MRI over whole-body LDCT or con-
ventional CT is the discrimination between myelomatous
and normal marrow. This is extremely helpful in the di-
agnosis of the malignant or benign nature of a vertebral
fracture (Fig. 4). Several times, clinicians face the condition
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of a patient with myeloma in remission with a new vertebral
fracture and no other evidence of progression. MRI can offer
important information and is able to differentiate myeloma
from osteoporotic fractures in more than 90% of the cases.41
Furthermore, extramedullary plasmacytomas, present in up
to 20% of patients during the course of their disease, are
easily seen on whole-body MRI.42 MRI is also recommended
for the work-up of patients with a solitary plasmacytoma of
the bone. MRI may reveal unsuspected bone lesions in
approximately one-third of such patients43; in these pa-
tients, systemic treatment must be applied instead of ra-
diation therapy, which is the treatment of choice for solitary
bone plasmacytoma.44 MRI accurately localizes spinal cord
and/or nerve root compression for surgical intervention or
radiation therapy.2,4,15 Finally, avascular necrosis of the
femoral head and cardiac amyloidosis may also be evaluated
with MRI.45,46
Limitations of MRI include prolonged acquisition time,
availability issues, problems with claustrophobic patients
and with patients carrying metal devices in their body, and
high cost.15
Novel MRI techniques. DWI MRI, which derives its contrast
mainly from differences in the diffusivity of water mole-
cules in the tissue environment, is a novel and promising
MRI technique. DWI MRI uses the calculation of apparent
diffusion coefficient values to better evaluate myeloma
burden and MRI infiltration patterns.47,48 Apparent diffu-
sion coefficient values are higher in patients with multiple
myeloma at diagnosis, compared with patients in remission
20 weeks after initiation of treatment.49 DWI MRI was
found superior to whole-body x-ray for the detection of
bone involvement in 20 patients with relapsed/refractory
FIGURE 4. MRI Differentiating a Vertebral Fracture
Left: From an underlying tumor. Right: From an osteoporotic fracture without
signs of myeloma cell infiltration.

multiple myeloma in all areas of the skeleton except the
skull, where both examinations had equal sensitivity.50 In
another small study with 24 patients with myeloma (both
treated and untreated), DWI MRI was found more sensitive
than 18F-fluorodeoxyglucose (FDG)-PET in detecting mye-
loma lesions.51 In a recent study, 17 patients were eval-
uated using DWI MRI and FDG-PET/CT, and the findings
were compared with bone marrow biopsy data. In all
studied regions, whole-body DWI scores were higher
compared with FDG-PET/CT. DWI MRI was particularly
accurate in diagnosing diffuse disease (diffuse disease was
observed in 37% of regions imaged on whole-body DWI
scans compared with only 7% on FDG-PET/CT); both
techniques were equally sensitive in the detection of focal
lesions.52 Preliminary reports suggest that DWI MRI may be
used for the better definition of response to therapy, but
this has to be confirmed in larger studies and in comparison
with PET/CT results.48,53
Dynamic contrast-enhanced (DCE) MRI evaluates the
distribution of an intravenous contrast agent both inside and
outside the blood vessels over time. DCE MRI provides data
for the microcirculation of a specific area. In multiple my-
eloma, DCE MRI derives parameters correlated with mi-
crovascular density in the bone marrow both before and
after therapy,54-56 as well as with adverse disease features
and OS.57 Finally, the combination of DWI and DCE MRI
produced a score with 76% agreement with the IMWG
criteria of response to therapy in 27 patients with myeloma
under treatment.58 More data are needed to evaluate such
scores in larger studies.
PET/MRI represents a novel imaging modality with at-
tractive potential clinical applications. In multiple myeloma,
TABLE 2. Summary of the Novel IMPeTUs Criteria for the PET/CT Standardization for Multiple Myeloma
Lesion Type Site
Diffuse Bone marrow*
Focal Skull
Spine
Extraspinal
Lytic
Fracture At least one
Paramedullary At least one
Extramedullary At least one
*A if hypermetabolism in limbs and ribs.
**For nodal disease: C, cervical; SC, supraclavicular; M, mediastinal; Ax, axillary; Rp, retroperitoneal; Mes, mesenteric; In, inguinal.
For extranodal disease: Li, liver; Mus, muscle; Spl, spleen; Sk, skin; Oth, other.
Adapted by Nanni et al76 with permission.
Deauville five-point scale:
1 5 No uptake at all
2 # Mediastinal blood pool uptake (SUVmax)
3 . Mediastinal blood pool uptake, # liver uptake
4 . Liver uptake more than 10%
5 . Liver uptake (twice)
IMAGING FOR MULTIPLE MYELOMA
there is only one prospective study, which compared
PET/MRI with PET/CT in 30 patients with myeloma with both
techniques performed sequentially. There was high corre-
lation between the two techniques, regarding the number of
active lesions and average standardized uptake value
(SUV).59 Further studies with PET/MRI will reveal if there is
any value of this technique for patients with multiple
myeloma.
PET/CT and the Treatment of Patients With Myeloma
PET/CT detection of bone involvement in myeloma. FDG-
PET/CT is a functional imaging method that combines
demonstration of hypermetabolic activity in intramedullary
and extramedullary sites (PET) with evidence of osteolysis
(CT). Several studies have shown that PET/CT is more
sensitive compared with whole-body x-ray for the de-
tection of osteolytic lesions in multiple myeloma.25,60-62
This has been confirmed by the largest meta-analysis in
the field.20 The higher detection rate of PET/CT over
whole-body x-ray for the presence of osteolytic lesions is
especially important for patients with smoldering multi-
ple myeloma. In one study with 120 patients with smol-
dering multiple myeloma based on the previous IMWG
criteria,25 16% of patients with normal whole-body x-ray
had positive PET/CT results. The median TTP for patients
with positive PET/CT results was 1.1 years compared with
4.5 for patients with negative PET/CT results, while the
probability of progression at 2 years for patients with
positive PET/CT results was 58%.63 The largest study in the
field involved 188 patients with suspected smoldering
multiple myeloma examined with PET/CT. PET/CT was
positive in 39% of patients. The probability of progression
Number of Lesions (x) Grading
Deauville five-point scale
x =1 (no lesions) Deauville five-point scale
x = 2 (1-3 lesions)
x = 3 (4-10 lesions)
x = 4 (. 10 lesions)
x = 1 (no lesions)
x = 2 (1-3 lesions)
x = 3 (4-10 lesions)
x = 4 (. 10 lesions
Nodal**/extranodal Deauville five-point scale
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e413
TERPOS, DIMOPOULOS, AND MOULOPOULOS
to symptomatic multiple myeloma within 2 years was 75%
for patients with a positive PET/CT under observation
compared with only 30% for patients with a negative
PET/CT. This probability was higher if hypermetabolic
activity was combined with underlying osteolysis (2-year
progression rate: 87%). The median TTP was 21 months
compared with 60 months for patients with a positive
PET/CT and those with a negative PET/CT, respectively.64 The
results of these two studies support the integration of
changes in imaging requirements in the new IMWG di-
agnostic criteria for multiple myeloma; detection of osteolytic
lesions by PET/CT is a criterion for symptomatic multiple
myeloma.2
Compared with MRI, as mentioned previously, PET/CT
performs equally well in detecting focal lesions, but MRI
is better at detecting diffuse disease.24,25,62
TABLE 3. Advantages and Limitations of Different Imaging Techniques
Advantages
WBXR Cost
Availability
Historical use/validation
WBLDCT Increased sensitivity and specificity for the detection of lytic
lesions
3D structural information for CT-guided biopsy, surgery, and
radiotherapy planning
Can depict EMD, bone marrow involvement, and lytic lesions
Rapid acquisition time
Inexpensive compared with MRI and PET
Comfortable for patients
PET/CT Functional method
Assesses disease activity before and after treatment; better
definition of CR and MRD
Depicts extramedullary disease
Prognostic significance pre- and post-treatment
Novel radioisotopes may offer additional disease-relevant
information
MRI Is able to exclude smoldering/asymptomatic myeloma
No radiation exposure
Assesses bone marrow both diffuse infiltration and focal
bone marrow lesions
Superior for detection of spinal cord compression and soft-
tissue masses
Number of focal lesions has prognostic significance
Detects extramedullary disease
3D structural information for CT-guided biopsy, surgery, and
radiotherapy planning
Abbreviations: WBXR, whole-body x-ray; WBLDCT, whole-body low-dose CT; EMD, extramedullary disease; CR, complete response; MRD, minimal residual disease.
e414 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Value of PET/CT for better definition of CR to anti-myeloma
therapy. Data obtained from PET/CT of 40 patients with
multiple myeloma, including average SUV and FDG kinetic
parameters K1, influx and fractal dimension correlated
significantly with percentage of bone marrow infiltration by
plasma cells on trephine biopsies (PC %).65 Furthermore,
PET/CT efficiently detected extramedullary disease in pa-
tients both at diagnosis and at relapse.66 Consequently,
PET/CT was tested for better definition of CR in 282 patients
with multiple myeloma. It was performed at diagnosis and
every 12 to 18 months afterward. At diagnosis, 42% of
patients with multiple myeloma had more than three focal
lesions; in 50% of these patients, SUVmax was more than 4.2.
After treatment, PET/CT was negative for 70% of patients,
while 53% of patients achieved CR according to IMWG
criteria. Approximately 30% of patients at CR had a positive
Limitations
Poor sensitivity/low detection rate
Findings present only after advanced bone damage
Patient discomfort with repositioning, multiple films; long image
acquisition time
No evaluation of bone marrow; no differentiation between
malignant and benign fractures
Lack of accurate visualization of specific areas, such as the pelvis
and the spine
Difficulties in the assessment of lytic lesions response to anti-
myeloma therapy
Observer dependency
Unclear prognostic significance of lesion number
Relatively higher radiation exposure and more expensive than
WBXR
High cost
Limited availability
False-positive diagnoses because of infection/inflammation
Lack of standardization
Poor spatial resolution
High cost
Long acquisition time, claustrophobia
May exclude patients with indwelling metal objects; contrast
contraindicated in severe renal insufficiency

PET/CT. More importantly, PET/CT negativity was an in-
dependent predictor for prolonged PFS and OS in patients
with a CR. In addition, for patients with a CR, median PFS was
50 months for patients with a positive PET/CT and 90 months
for patients with a negative PET/CT.67 PET/CT, therefore,
provides more accurate definition of CR, and it has been
suggested that it should be incorporated to CR criteria.68
Prognostic significance of PET/CT. Several studies have
confirmed the value of PET/CT as an independent factor for
survival of patients with multiple myeloma both at di-
agnosis and after treatment.69-74 In 192 newly diagnosed
patients who underwent ASCT, the presence of extra-
medullary disease and SUVmax greater than 4.2 on PET/CT
performed at diagnosis and the persistence of FDG uptake
post-ASCT were independent variables adversely affecting
PFS.69 In the largest study in the field, 429 patients who
were treated with total therapy protocols in Arkansas were
evaluated with both MRI and PET/CT at diagnosis and seven
days post-ASCT. From the imaging variables, in the multivariate
analysis, only the detection of more than two osteolytic lesions
by whole-body x-ray at diagnosis and the detection of more
than three focal lesions by PET/CT 7 days post-ASCT were
independent prognostic factors for inferior OS. Limitation of
this study was the exclusion of the diffuse MRI pattern from the
analysis.34 Despite this limitation, studies reported to date
support the role of PET/CT after therapy, deeming it the best
imaging technique for the follow-up of patients with myeloma.
Indeed, in a recent study, 134 patients who were eligible for
treatment with ASCT were randomly assigned to eight cycles of
bortezomib-lenalidomide-dexamethasone (VRD) followed by
1-year maintenance with lenalidomide, or three cycles of VRD
followed by ASCT plus two cycles of VRD consolidation and
1-year lenalidomide maintenance. PET/CT and whole-body
MRI were performed after induction and before mainte-
nance. Both techniques were positive at diagnosis in more than
90% of patients. After induction therapy and before mainte-
nance, more patients continued to have positive MRI than
PET/CT (93% vs. 55% and 83% vs. 21%, respectively), possibly
because of earlier reduction of activity of PET/CT lesions. Both
after induction and before maintenance, normalization of
PET/CT and not of MRI could predict for PFS, while only
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e417
S. VINCENT RAJKUMAR

Updated Diagnostic Criteria and Staging System for Multiple

Myeloma
S. Vincent Rajkumar, MD

OVERVIEW

There has been remarkable progress made in the diagnosis and treatment of multiple myeloma (MM). The median survival of
the disease has doubled as a result of several new active drugs. These advances have necessitated a revision of the disease
definition and staging of MM. Until recently, MM was defined by the presence of end-organ damage, specifically hy-
percalcemia, renal failure, anemia, and bone lesions (CRAB features) that can be attributed to the clonal process. In 2014, the
International Myeloma Working Group (IMWG) updated the diagnostic criteria for MM to add three specific biomarkers that
can be used to diagnose the disease in patients who did not have CRAB features: clonal bone marrow plasma cells greater
than or equal to 60%, serum free light chain (FLC) ratio greater than or equal to 100 provided involved FLC level is 100 mg/L or
higher, or more than one focal lesion on MRI. In addition, the definition was revised to allow CT and PET-CT to diagnose MM
bone disease. These changes enable early diagnosis and allow the initiation of effective therapy to prevent the development
of end-organ damage for patients who are at the highest risk. A new staging system has been developed that incorporates
high-risk cytogenetic abnormalities in addition to standard laboratory markers of prognosis.

M ultiple myeloma evolves from a clinically silent pre-

malignant stage termed monoclonal gammopathy of
undetermined significance (MGUS).1,2 MGUS is a classic
premalignant condition with a low risk of malignant con-
version, but the risk of progression persists indefinitely. A
small subset of patients has an intermediate clinical phe-
notype between MGUS and MM, and they are referred to
as having smoldering multiple myeloma (SMM).3 MGUS
is associated with a risk of progression to MM or related
malignancy at a rate of approximately 1% per year, whereas
SMM has a much higher risk of progression of approxi-
mately 10% per year.4,5 MGUS and SMM are typically
asymptomatic and are typically diagnosed incidentally
when a monoclonal (M) protein is detected during labo-
ratory work-up of patients who have a wide spectrum of
clinical conditions.
Over the years the diagnosis of MM required evidence
of end-organ damage attributable to the neoplastic clone
of plasma cells: hypercalcemia, renal failure, anemia, and
osteolytic bone lesions, commonly referred to as CRAB
features.6 This definition was conservative and intended to
prevent patients with MGUS and SMM from receiving un-
necessary and toxic chemotherapy. With major advances in
therapy and identification of biomarkers that can distinguish
MM from premalignant phases, it became necessary to
revise the disease definition of MM.7-9
REVISED DIAGNOSTIC CRITERIA FOR MULTIPLE
MYELOMA
In 2014, the IMWG revised the diagnostic criteria for MM.10
The revised diagnostic criteria for MM allow the use of
specific biomarkers to define the disease in addition to the
established CRAB features. They also allow the use of
modern imaging tools to diagnose MM bone disease and
clarify several other diagnostic requirements. Table 1 pro-
vides the revised IMWG criteria for diagnosis of MM and
related plasma cell disorders.10
Myeloma-Defining Events
The diagnosis of MM requires 10% or more clonal plasma
cells on bone marrow examination or a biopsy-proven
plasmacytoma plus the presence of one or more
myeloma-defining events.10 Myeloma-defining events in-
clude the presence of one or more CRAB features, or one
or more biomarkers of malignancy. The three biomarkers
included in the definition of MM are associated with an
approximately 80% risk of progression to symptomatic end-
organ damage in two or more independent studies. They are
clonal bone marrow plasma cells greater than or equal to
60%, serum FLC ratio of 100 or higher, provided involved FLC
level is 100 mg/L or higher, or more than one focal lesion
on MRI.

From the Division of Hematology, Mayo Clinic, Rochester, MN.

Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook.

Corresponding author: S. Vincent Rajkumar, MD, Division of Hematology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: rajkumar.vincent@mayo.edu.

2016 by American Society of Clinical Oncology.

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Extreme bone marrow clonal plasmacytosis. Clonal bone
marrow plasma cell involvement of greater than or equal to
60% is extremely unusual in the absence of CRAB features.
In a Mayo Clinic study of SMM, only six of 276 patients (2%)
had clonal bone marrow plasma cells greater than or equal
to 60%. In that study, patients with this level of marrow
involvement progressed to symptomatic malignancy rapidly,
with a median progression-free survival of 7.7 months.7 In a
separate cohort of 651 patients with SMM, only 21 (3.2%)
had clonal bone marrow plasma cells greater than or equal
to 60%, and 95% of these patients progressed to having MM
within 2 years.7 A study of 96 patients with SMM from the
Greek Myeloma Group also found a markedly high risk of
progression in this subgroup of patients, with a median time
to progression (TTP) of 15 months.11 Similar results were
reported by the University of Pennsylvania; six of 121 pa-
tients (5%) with SMM had greater than or equal to 60% bone
marrow involvement, and all progressed to having MM in
less than 2 years.12
Marked elevation of serum involved/uninvolved FLC
ratio. In SMM, an abnormal FLC ratio is associated with a
higher risk of progression to MM.13 As the ratio increases,
so does the risk of progression. In a Mayo Clinic study of
586 patients with SMM, a markedly abnormal involved/
uninvolved FLC ratio ($ 100) was seen in 90 (15%) pa-
tients.8 The risk of progression to symptomatic end-organ
damage within the first 2 years with an FLC ratio of 100 or
higher was 72%; the risk of progression to MM or amyloid
light-chain amyloidosis in 2 years was 79%. A similar finding
was reported by Kastritis et al, who studied 96 patients with
SMM. In their study, 7% of patients with SMM had an
involved/uninvolved FLC ratio of 100 or higher, and almost
all progressed to symptomatic disease within 18 months.11
In a third study, at the University of Pennsylvania, patients
KEY POINTS
The diagnostic criteria for multiple myeloma and related
disorders have been updated by the International
Myeloma Working Group.
Patients with 60% or more clonal plasma cell
involvement of the marrow, serum free light chain ratio
of 100 or higher (provided involved free light chain
level 100 mg/L), and/or greater than one focal lesion
on MRI are defined as MM even in the absence of end-
organ damage.
Low-dose whole-body CT, MRI, and FDG-PET and FDG-
PET with PET-CT are more sensitive in detecting
myeloma and must be considered in diagnosis and
monitoring.
In terms of renal involvement, only light chain cast
nephropathy is considered a myeloma-defining event.
The Revised International Staging System has been
developed for myeloma that incorportates high-risk
cytogenetic abnormalities.
NEW DIAGNOSTIC AND STAGING CRITERIA IN MYELOMA
with SMM with an involved/uninvolved FLC ratio of 100 or
higher had a 64% risk of progression within 2 years.12 A
markedly abnormal FLC ratio is thus an accurate predictor of
patients who have a high risk of progression to end-organ
damage within a short period of time. To reduce the pos-
sibility of error, in addition to the FLC ratio being 100 or
higher, the IMWG also added a requirement for a minimal
involved FLC level of at least 100 mg/L to be considered as
a myeloma-defining event.10
MRI with more than one focal lesion. MRI imaging study of
the whole-body spine/pelvis can reveal focal or diffuse
changes in SMM. In a study by Hillengass et al, 23 of 149
(15%) patients with SMM had more than one focal lesion
seen on whole-body MRI.14 The median TTP in these patients
was 13 months, and the progression rate at 2 years was 70%.
These results were confirmed by Kastritis et al, who found
more than one focal lesion on spinal MRI in nine of 65
patients (14%) with SMM.15 The median TTP was 15 months
and 69% progressed to MM within 2 years. To increase
predictive value, the IMWG added a requirement that focal
lesions must be at least 5 mm or more in size and recom-
mended follow-up examinations in 3 to 6 months for pa-
tients who had a solitary focal lesion, equivocal findings, or
diffuse infiltration.10
Assessment of myeloma bone disease. There have been
many advances to imaging methods used to detect bone and
extramedullary disease in MM. These include low-dose
whole-body CT, MRI, and (18)Ffluorodeoxyglucose PET
(FDG-PET) and FDG-PET with PET-CT.16-22 The old IMWG
criteria for the diagnosis of MM primarily relied on con-
ventional radiographs to detect bone disease.6 A systematic
review compared MRI, FDG-PET, PET CT, and whole-body CT
to conventional whole-body skeletal radiography in MM.23
Newer imaging techniques had greater sensitivity compared
with radiographic bone survey for detection of MM bone
lesions, with as high as 80% more lesions detected by the
newer imaging techniques. CT and MRI performed equally
with respect to sensitivity.
Based on these studies, the revised IMWG criteria for MM
permit the use of CT, low-dose whole-body CT, PET-CT, and
whole-body CT to diagnose lytic bone disease in MM. One or
more sites of osteolytic bone destruction of at least 5 mm or
more in size is required. Increased uptake on PET-CT alone is
not adequate; there must be evidence of actual osteolytic
bone destruction on the CT portion of the examination. A
biopsy of one of the bone lesions should be considered if
there is any doubt about the diagnosis. These changes will
enable early and accurate diagnosis of MM. In addition to
these changes, the IMWG clarified that the presence of
osteoporosis, vertebral compression fractures, or bone
densitometric changes in the absence of lytic lesions is not
sufficient evidence of myeloma bone disease.
Because the accurate diagnosis of MM is critical, at least
one advanced imaging examination (PET-CT, low-dose
whole-body CT, or MRI of the whole body or spine) is
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S. VINCENT RAJKUMAR

TABLE 1. International Myeloma Working Group Diagnostic Criteria for Multiple Myeloma and Related Plasma
Cell Disorders

Disorder Disease Definition

Non-IgM MGUS All three criteria must be met:
Serum monoclonal protein (non-IgM type) , 3 g/dL
Clonal bone marrow plasma cells , 10%*
Absence of end-organ damage such as CRAB features that can be attributed to the plasma cell proliferative disorder
Smoldering MM Both criteria must be met:
Serum monoclonal protein (IgG or IgA) $ 3 gm/dL, or urinary monoclonal protein $ 500 mg per 24 h and/or
clonal bone marrow plasma cells 10%60%
Absence of myeloma-defining events or amyloidosis
MM Both criteria must be met:
Clonal bone marrow plasma cells $ 10% or biopsy-proven bony or extramedullary plasmacytoma
Any one or more of the following myeloma defining events:
Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder,
specifically:
Hypercalcemia: serum calcium . 0.25 mmol/L (. 1 mg/dL) higher than the upper limit of normal or
. 2.75 mmol/L (. 11 mg/dL)
Renal insufficiency: creatinine clearance , 40 mL/min or serum creatinine . 177 mmol/L (. 2 mg/dL)
Anemia: hemoglobin value of . 2 g/dL below the lower limit of normal, or a hemoglobin value
, 10 g/dL
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT
Clonal bone marrow plasma cell percentage $ 60%
Involved: uninvolved serum FLC ratio $ 100 (involved FLC level must be $ 100 mg/L)
. 1 focal lesion on MRI studies (at least 5 mm in size)
IgM MGUS All three criteria must be met:
Serum IgM monoclonal protein , 3 gm/dL
Bone marrow lymphoplasmacytic infiltration , 10%
No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatospleno-
megaly that can be attributed to the underlying lymphoproliferative disorder.
Light-Chain MGUS All criteria must be met:
Abnormal FLC ratio (, 0.26 or . 1.65)
Increased level of the appropriate involved light chain (increased kappa FLC in patients with ratio . 1.65 and
increased lambda FLC in patients with ratio , 0.26)
No immunoglobulin heavy-chain expression on immunofixation
Absence of end-organ damage that can be attributed to the plasma cell proliferative disorder
Clonal bone marrow plasma cells , 10%
Urinary monoclonal protein , 500 mg/24 h
Solitary Plasmacytoma All four criteria must be met:
Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
Normal bone marrow with no evidence of clonal plasma cells
Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
Absence of end-organ damage such as CRAB features that can be attributed to a lympho-plasma cell
proliferative disorder
Solitary Plasmacytoma With Minimal All four criteria must be met:
Marrow Involvement**
Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
Clonal bone marrow plasma cells , 10%
Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
Absence of end-organ damage such as CRAB features that can be attributed to a lympho-plasma cell
proliferative disorder
Abbreviations: MGUS, monoclonal gammopathy of undertermined significance; CRAB features, hypercalcemia, renal insufficiency, anemia, and bone lesions; MM, multiple myeloma; FLC, free light chain;
SMM, smoldering multiple myeloma.
*A bone marrow examination can be deferred for patients with low-risk MGUS (IgG type, M protein , 15 gm/L, normal FLC ratio) in whom there are no clinical features concerning for myeloma.
**
Solitary plasmacytoma with 10% or more clonal plasma cells is considered as MM.
Reproduced from Rajkumar et al.10

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 NEW DIAGNOSTIC AND STAGING CRITERIA IN MYELOMA

recommended for patients before concluding that a patient
has SMM or solitary plasmacytoma.10,24 The choice between
various imaging methods can vary depending on the clinical
situation and availability.
Other clarifications to MM diagnostic criteria. Several
clarifications to the diagnostic criteria for MM were made.
Importantly, the IMWG clarified that in terms of renal disease,
only suspected or proven light-chain cast nephropathy is
considered a myeloma-defining event. Other renal disorders
associated with M proteins, such as light-chain deposition
disease, membranoproliferative glomerulonephritis, and
amyloid light-chain amyloidosis, are considered unique dis-
eases and not MM. A renal biopsy to clarify the underlying
cause of renal failure is recommended for patients with
suspected cast nephropathy, especially if the serum involved
FLC levels are less than 500 mg/L.25 An estimated glomerular
filtration rate less than 40 mL/min is preferred to the serum
creatinine concentration for purposes of fulfilling the CRAB
criteria.
Solitary plasmacytoma. Solitary plasmacytoma is an early-
stage plasma cell malignancy that is in between MGUS/SMM
and MM along the spectrum of plasma cell disorders. It is
defined by the presence of a single biopsy-proven plas-
macytoma (bony or extramedullary) and a normal bone
marrow examination (Table 1). Treatment consists of radi-
ation therapy at 40 Gy to 50 Gy to the involved site.
Patients with an apparent solitary plasmacytoma who
have limited (, 10%) clonal marrow involvement are con-
sidered to have solitary plasmacytoma with minimal marrow
involvement. These patients are also treated similar to
patients with solitary plasmacytoma. The risk of recurrence
or progression to myeloma within 3 years is approximately
10% for patients with solitary plasmacytoma versus 20% to
60% for patients with solitary plasmacytoma and minimal
marrow involvement.
REVISED INTERNATIONAL STAGING SYSTEM FOR
MYELOMA
There is major variation in survival of MM depending on
host factors, tumor burden (stage), biology (cytogenetic
abnormalities), and response to therapy.26 Tumor burden
in MM has traditionally been assessed using the Durie-
Salmon Staging (DSS) 27 and the International Staging
System (ISS).28,29 Both these staging systems have some
limitations. The DSS primarily classified patients based on
tumor burden and had problems with reproducibility be-
cause some judgment is needed in interpretation of MM
bone disease. The ISS is more reproducible but includes a
host factor determinant, namely serum albumin. Thus,
outcome using ISS can be disproportionately affected by

TABLE 2. Cytogenetic Abnormalities on Clinical Course and Prognosis in Multiple Myeloma

Clinical Setting in Which Abnormality Is Detected

Cytogenetic Abnormality Smoldering Multiple Myeloma Multiple Myeloma
Trisomies Intermediate-risk of progression, median TTP of 3 years Good prognosis, standard-risk MM, median
OS 7-10 years
Most have myeloma bone disease at diagnosis
Excellent response to lenalidomide-based therapy
t(11;14) (q13;q32) Standard-risk of progression, median TTP of 5 years Good prognosis, standard-risk MM, median
OS 7-10 years
t(6;14) (p21;q32) Standard-risk of progression, median TTP of 5 years Good prognosis, standard-risk MM, median
OS 7-10 years
t(4;14) (p16;q32) High-risk of progression, median TTP of 2 years Intermediate-risk MM, median OS 5 years
Needs bortezomib-based initial therapy, early
ASCT (if eligible), followed by bortezomib-
based consolidation/maintenance
t(14;16) (q32;q23) Standard-risk of progression, median TTP of 5 years High-risk MM, median OS 3 years
Associated with high levels of FLC and 25% present
with acute renal failure as initial MDE
t(14;20) (q32;q11) Standard-risk of progression, median TTP of 5 years High-risk MM, median OS 3 years
Gain(1q21) High-risk of progression, median TTP of 2 years Intermediate-risk MM, median OS 5 years
Del(17p) High-risk of progression, median TTP of 2 years High-risk MM, median OS 3 years
Trisomies Plus Any One of the IgH Standard-risk of progression, median TTP of 5 years May ameliorate adverse prognosis conferred by
Translocations high risk IgH translocations, and del 17p
Isolated Monosomy 13, or Isolated Standard-risk of progression, median TTP of 5 years Effect on prognosis is not clear
Monosomy 14
Normal Low-risk of progression, median TTP of 7-10 years Good prognosis, probably reflecting low tumor
burden, median OS . 7-10 years
Abbreviations: TTP, time to progression; MM, multiple myeloma; OS, overall survival; ASCT, autologous stem cell transplantation; MDE, myeloma-defining event.
Reproduced from Rajan and Rajkumar.32

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S. VINCENT RAJKUMAR
TABLE 3. Revised International Staging System for Myeloma
Stage
Stage I
ISS stage I (serum albumin > 3.5, serum beta-2-microglobulin < 3.5) and
No high-risk cytogenetics
Normal LDH
Stage II
Neither stage I or III
Stage III
ISS stage III (serum beta-2-microglobulin > 5.5) and
High-risk cytogenetics [t(4;14), t(14;16), or del(17p)] or elevated LDH
Abbreviations: LDH, lactate dehydrogenase; ISS, International Staging System.
Derived from Palumbo et al.33
factors that are not disease-specific. Neither staging system
considers disease biologya key determinant of overall
survival in the disease.
Disease biology in MM is best reflected based on the
molecular subtype of the disease and the presence or ab-
sence of specific cytogenetic abnormalities.30,31 For exam-
ple, abnormalities such as t(4;14), t(14;16), t(14;20), gain
(1q), del(1p), and del(17p) influence disease course, re-
sponse to therapy, and prognosis in MM (Table 2).32 The
Revised International Staging System (RISS) combines ele-
ments of tumor burden (ISS) and disease biology (presence
of high-risk cytogenetic abnormalities or elevated lactate
dehydrogenase level) to create a unified prognostic index
that helps in clinical care as well as in comparison of clinical
trial data (Table 3).33 The RISS was developed based on a
study of 4,445 patients with newly diagnosed MM from
11 international trials. This study showed that the 5-year
survival rate of patients with stage I, II, and III RISS was 82%,
62%, and 40%, respectively. The RISS will be of importance in
References
1. Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of
undetermined significance (MGUS) consistently precedes multiple
myeloma: a prospective study. Blood. 2009;113:5412-5417.
2. Weiss BM, Abadie J, Verma P, et al. A monoclonal gammopathy pre-
cedes multiple myeloma in most patients. Blood. 2009;113:5418-5422.
3. Rajkumar SV, Merlini G, San Miguel JF. Haematological cancer: Rede-
fining myeloma. Nat Rev Clin Oncol. 2012;9:494-496.
4. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis
of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;
356:2582-2590.
5. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of
prognosis in monoclonal gammopathy of undetermined significance.
N Engl J Med. 2002;346:564-569.
6. International Myeloma Working Group. Criteria for the classification of
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2003;121:749-757.
7. Rajkumar SV, Larson D, Kyle RA. Diagnosis of smoldering multiple
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Frequency (% of Patients) 5-Year Survival Rate (%)
28 82
62 62
10 40
the clinic in terms of counseling patients regarding prog-
nosis, as well as in clinical trials to compare outcomes across
clinical trials.
FUTURE DIRECTIONS
The updated diagnostic criteria for MM represent a para-
digm shift in our approach to the disease. These changes will
allow us to intervene before end-organ damage in selected
patients who are at imminent risk of symptomatic pro-
gression. The revised staging system for MM allows us to
better predict outcome and tailor treatments accordingly.
Advances in imaging have not only enabled early and ac-
curate diagnosis, but also provide ways of monitoring re-
sponse to therapy. We must identify additional reliable
biomarkers of malignancy. We must also develop a portfolio
of clinical trials designed to determine whether early in-
tervention can improve survival or provide a path to
cure MM.
8. Larsen JT, Kumar SK, Dispenzieri A, et al. Serum free light chain ratio as a
biomarker for high-risk smoldering multiple myeloma. Leukemia. 2013;
27:941-946.
9. Mateos M-V, Hernandez M-T, Giraldo P, et al. Lenalidomide plus
dexamethasone for high-risk smoldering multiple myeloma. N Engl J
Med. 2013;369:438-447.
10. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma
Working Group updated criteria for the diagnosis of multiple myeloma.
Lancet Oncol. 2014;15:e538-e548.
11. Kastritis E, Terpos E, Moulopoulos L, et al. Extensive bone marrow
infiltration and abnormal free light chain ratio identifies patients with
asymptomatic myeloma at high risk for progression to symptomatic
disease. Leukemia. 2013;27:947-953.
12. Waxman AJ, Mick R, Garfall AL, et al. Modeling the risk of progression in
smoldering multiple myeloma. J Clin Oncol. 2014;32:A8607.
13. Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free
light chain ratio is an independent risk factor for progression of
smoldering (asymptomatic) multiple myeloma. Blood. 2008;111:
785-789.

14. Hillengass J, Fechtner K, Weber MA, et al. Prognostic significance of
focal lesions in whole-body magnetic resonance imaging in patients
with asymptomatic multiple myeloma. J Clin Oncol. 2010;28:1606-1610.
15. Kastritis E, Moulopoulos LA, Terpos E, et al. The prognostic importance
of the presence of more than one focal lesion in spine MRI of patients
with asymptomatic (smoldering) multiple myeloma. Leukemia. 2014;
28:2402-2403.
16. Dimopoulos M, Terpos E, Comenzo RL, et al; IMWG. International
myeloma working group consensus statement and guidelines regarding
the current role of imaging techniques in the diagnosis and monitoring
of multiple Myeloma. Leukemia. 2009;23:1545-1556.
17. Hillengass J, Landgren O. Challenges and opportunities of novel imaging
techniques in monoclonal plasma cell disorders: imaging early mye-
loma. Leuk Lymphoma. 2013;54:1355-1363.
18. Zamagni E, Cavo M. The role of imaging techniques in the management
of multiple myeloma. Br J Haematol. 2012;159:499-513.
19. Zamagni E, Nanni C, Patriarca F, et al. A prospective comparison of 18F-
fluorodeoxyglucose positron emission tomography-computed tomog-
raphy, magnetic resonance imaging and whole-body planar radiographs
in the assessment of bone disease in newly diagnosed multiple mye-
loma. Haematologica. 2007;92:50-55.
20. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in
multiple myeloma: diagnostic and clinical implications. J Clin Oncol.
2007;25:1121-1128.
21. Bartel TB, Haessler J, Brown TL, et al. F18-fluorodeoxyglucose positron
emission tomography in the context of other imaging techniques and
prognostic factors in multiple myeloma. Blood. 2009;114:2068-2076.
22. Waheed S, Mitchell A, Usmani S, et al. Standard and novel imaging
methods for multiple myeloma: correlates with prognostic laboratory
variables including gene expression profiling data. Haematologica.
2013;98:71-78.
23. Regelink JC, Minnema MC, Terpos E, et al. Comparison of modern and
conventional imaging techniques in establishing multiple myeloma-
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related bone disease: a systematic review. Br J Haematol. 2013;162:
50-61.
24. Dimopoulos MA, Hillengass J, Usmani S, et al. Role of magnetic reso-
nance imaging in the management of patients with multiple myeloma:
a consensus statement. J Clin Oncol. 2015;33:657-664.
25. Hutchison CA, Batuman V, Behrens J, et al; International Kidney and
Monoclonal Gammopathy Research Group. The pathogenesis and di-
agnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol.
2012;8:43-51.
26. Russell SJ, Rajkumar SV. Multiple myeloma and the road to personalised
medicine. Lancet Oncol. 2011;12:617-619.
27. Durie BG, Salmon SE. A clinical staging system for multiple myeloma.
Correlation of measured myeloma cell mass with presenting clinical
features, response to treatment, and survival. Cancer. 1975;36:
842-854.
28. Greipp PR, San Miguel J, Durie BG, et al. International staging system for
multiple myeloma. J Clin Oncol. 2005;23:3412-3420.
29. Hari PN, Zhang MJ, Roy V, et al. Is the International Staging System
superior to the Durie-Salmon staging system? A comparison in multiple
myeloma patients undergoing autologous transplant. Leukemia. 2009;
23:1528-1534.
30. Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed
symptomatic multiple myeloma: updated Mayo Stratification of My-
eloma and Risk-Adapted Therapy (mSMART) consensus guidelines.
Mayo Clin Proc. 2009;84:1095-1110.
31. Kumar S, Fonseca R, Ketterling RP, et al. Trisomies in multiple myeloma:
impact on survival in patients with high-risk cytogenetics. Blood. 2012;
119:2100-2105.
32. Rajan AM, Rajkumar SV. Interpretation of cytogenetic results in multiple
myeloma for clinical practice. Blood Cancer J. 2015;5:e365.
33. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging
System for multiple myeloma: a report from International Myeloma
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e423
HEMATOLOGIC MALIGNANCIESPLASMA CELL
DYSCRASIA

Multiple Myeloma: Are We Ready

for Personalized Therapy?

CHAIR
Nikhil C. Munshi, MD
Dana-Farber Cancer Institute
Boston, MA

SPEAKERS
Herve Avet-Loiseau, MD, PhD
University Hospital
Nantes, France

Sagar Lonial, MD, FACP

Winship Cancer Institute of Emory University
Atlanta, GA
 MINIMAL RESIDUAL DISEASE BY NEXT-GENERATION SEQUENCING

Minimal Residual Disease by Next-Generation Sequencing:

Pros and Cons
Herve Avet-Loiseau, MD, PhD

OVERVIEW

The wealth of data recently generated highlights that minimal residual disease (MRD)negative status can be achieved in a
large proportion of patients. These studies, in addition to a meta-analysis, clearly suggest significant improvement in both
event-free survival (EFS) and overall survival (OS) among those patients achieving MRDnegative status, especially with
sensitivity of one cell in 1 million bone marrow cells. There is an evolving consensus that achieving MRDnegative status
should become the ultimate goal of therapeutic intervention. Further future efforts should now be directed at determining
how MRD status can be used to guide and personalize further therapy including type of consolidation and maintenance
therapy.

T he treatment landscape for multiple myeloma (MM) has

been radically transformed during the past decade by the
introduction of several new drugs with different mecha-
nisms of action, which in turn has led to the improved
survival of patients with MM.1 Diagnostic and response
criteria in MM have used a combination of tumor burden
and functional consequences of tumor expansion (such as
CRAB features), with recent revisions incorporating thresh-
olds for the serum-free light chain (sFLC) ratio and bone
marrow plasma cell percentage as well as using bone lesions
on sensitive imaging as predictors of incipient progression to
MM and, therefore, as acceptable triggers for initiation of
therapy.2 Response evaluation in MM has traditionally been
based on assessing serum and/or urine monoclonal protein
concentrations via protein electrophoresis as a surrogate for
tumor burden with immunofixation, allowing for detection
of trace amounts of paraprotein. Thus, the most recent it-
eration of the response criteria was developed a decade ago
by the International Myeloma Working Group (IMWG; IMWG
Consensus Criteria for Response Assessment) and was based
on serum and urine protein electrophoresis, serum and urine
immunofixation, sFLC, and bone marrow plasma cell quan-
titation plus clonality assessment.3
The consensus criteria were uniformly incorporated into
clinical trials, allowing better comparison of different drugs,
drug combinations, and treatment strategies, and the re-
visions over the years have allowed it to stay ahead of the
advances in treatment. With the recent introduction of more
effective multidrug combinations, especially when used in
the context of allogeneic stem cell transplantation (ASCT),
post-transplant consolidation, and prolonged maintenance
therapy, nearly all patients achieve a treatment response,
with over 50% of these patients reaching complete re-
mission (CR) in some of the more recently reported studies
and up to 80% in recent phase II trials.4-9 Frustratingly, the
vast majority of patients experience relapse despite achiev-
ing such deep responses, reflecting persistent disease that
cannot be detected using the currently recommended disease
evaluation techniques. Consequently, new methods are ur-
gently required to detect and quantitate MRD beyond the
level of detection of the current clinical response criteria, and
there is a need to revise the current definition of disease
response for it to evolve in parallel to the changing treatment
paradigm.
DEPTH OF RESPONSE AND LONG-TERM
OUTCOME
The relationship between depth of response and long-term
outcomes has been one of the most debated topics in MM.
The relationship between CR and progression-free survival
(PFS) and/or time to progression (TTP) has been more
consistent than the relationship between CR and OS. This
putative incongruity is a frequent phenomenon in cancer
therapy and probably due to multiple factors, including
interactions between (1) disease biology, (2) different treat-
ment strategies after CR has been reached, and (3) the true
depth of response beyond the conventional (and low-sensitive)
approaches defining CR after different therapies. In this
context, several studies using newer and more sensitive

From the Laboratory for Genomics in Myeloma, Institut Universitaire du Cancer and University Hospital, Centre de Recherche en Cancerologie de Toulouse, Toulouse, France.

Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook.

Corresponding author: Herve Avet-Loiseau, MD, PhD, Unite de Genomique du Myelome, IUC-T Oncopole, 1 Avenue Irene Joliot-Curie, 31059, Toulouse, France;
email: avet-loiseau.h@chu-toulouse.fr.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e425

HERVE AVET-LOISEAU
techniques have been able to demonstrate the persistence
of MRD not detected by the current CR evaluation meth-
odologies in a significant fraction of patients. The level of
persistent MRD, undetected by conventional methods, is
likely to be one of the most important features contributing
to the link between the depth of response and long-term
outcomes. Independent of the method used to define MRD
(cell-based, molecular-based, or imaging-based), prior studies
consistently show that among patients who have achieved
CR, MRDpositive cases consistently have an inferior PFS
than patients with MRDnegative disease.10-16 Given the
substantial proportion of patients achieving CR with the cur-
rent therapies, it is time to go beyond the CR criteria and
define MRD assessment in MM.16
DETECTION OF MINIMAL RESIDUAL DISEASE IN
BONE MARROW
Bone marrow examination has been the cornerstone
of disease assessment in the absence of a measurable
monoclonal protein in serum or urine, whether this repre-
sents nonsecretory disease or complete response to ther-
apy. In recent years, increasingly sensitive assays have
been adopted for the evaluation of bone marrow aspi-
rates, including multiparameter flow cytometry (MFC),
allele-specific oligonucleotide polymerase chain reaction
(ASO-PCR), and next-generation sequencing (NGS) of im-
munoglobulin gene sequences, in an effort to increase the
sensitivity of detection of MM cells. Such methods allow
examination of several hundred thousand to millions of
bone marrow cells (or their corresponding amount of DNA)
per assay and can provide a quantitative assessment of any
residual tumor cells in the bone marrow in a relatively short
timeframe.
Multiparameter Flow Cytometric Methods for
Minimal Residual Disease Detection
First-generation MFC methods. Although MFC-based as-
sessment of bone marrow has been conducted in MM for a
number of years, it is only recently that the technology has
gained wide acceptance in the routine work-up of patients
with MM. The most commonly used surface markers used
KEY POINTS
Traditional complete response is not adequate for
predicting long-term outcome or acting as an endpoint
for clinical studies.
Newer technologies allow detection of myeloma cells in
bone marrow with great sensitivity.
All studies confirm that patients with MRDnegative
status have improved EFS and OS.
MRD status should become a standard in clinical studies
and be considered for intervention decision making in
the future.
e426 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
for discriminating and categorizing normal and MM plasma
cells include CD138, CD38, CD45, CD56, CD19, and cyto-
plasmic kappa and lambda immunoglobulin light chains.
Additional markers, many of which are aberrantly expressed
on MM plasma cells, have also been found to be of value and
include CD27, CD28, CD81, and CD117. However, given the
heterogeneity of expression of these markers and differ-
ences in both the number of events studied and in the
analytical strategies used, there has been significant con-
fusion in the field and inconsistent clinical interpretation of
results from different studies.20 Recently, attempts have
been made to develop consensus guidelines to standardize
the flow-based assessment of disease in MM and other
related plasma cell disorders.17,18
Several studies have demonstrated the utility of MFC in
the detection of MRD in the bone marrow. The Spanish
Myeloma Group (PETHEMA/GEM) used four-color flow
cytometry to study MRD among 295 patients with newly
diagnosed MM receiving uniform treatment including ASCT,
and they demonstrated that MRD was one of the most
important predictors of outcome.10 Minimal residual dis-
ease negativity at day 100 after ASCT correlated with im-
proved PFS and OS; furthermore, the impact of MRD
negativity was equally relevant among patients who had
achieved a conventional CR. Similarly, Rawstron et al eval-
uated the role of six-color MFC in the assessment of MRD at
various stages of therapy among patients with newly di-
agnosed MM who enrolled on the MRC IX clinical trial.13
Among patients undergoing ASCT, absence of MRD at day
100 was associated with substantially improved PFS, irre-
spective of cytogenetics or achievement of CR. Of note, in all
these studies, three- to six-color MFC approaches with a
sensitivity of one in 10,000 myeloma cells were used.
Thus, the recent advances in the flow technology allowing
interrogation of several million cells have significantly
improved the sensitivity of the assay, particularly when
combined with simultaneous usage of eight or more colors/
markers for an increased specificity. Recent consensus in-
dicates that such approaches are optimally suited for MRD
testing in the settings of multiple myeloma.20
Next-generation flow. Recent attempts at standardization
and automated read outs makes MFC an attractive test for
sensitive, routine detection of MRD in the bone marrow
compartment.21,22 However, to have uniform MFC-based
MRD response criteria, it is mandatory to have consensus in
the way MRD is evaluated; accordingly, concerted effort has
been put into effect to standardize the flow-based ap-
proaches and remove the subjectivity introduced by indi-
vidual interpretations by defining the reagent characteristics,
defining the acquisition and plasma cell identification pa-
rameters, and introducing novel common data analysis tools.
The current EuroFlow next-generation flow (NGF) method
for MRD detection in MM relies on two 8-color combinations
that combine surface antigens for the identification of
phenotypically aberrant clonal plasma cells, as well as
intracytoplasmic kappa and lambda light chain expression to

confirm their clonality. This two-tube NGF approach has now
been extensively validated (over 1,000 MRD samples). It is
very robust and improves reliability, consistency, and sensi-
tivity because of the acquisition of a greater number of cells.
One of the most attractive features of the eight-color
method is its balance between effectiveness (sensitivity plus
specificity) and wide availability because eight-color in-
struments are commonly used in many hospitals. To improve
efficiency in the laboratory and to reduce costs, it is antici-
pated that alternate single-tube 10- and 14-color methods will
be suggested by some centers. The single-tube approach will
undergo detailed cross-validation with the reference NGF
method for standardization. To fulfill criteria for NGF, doc-
umentation of cross-validation with reference NGF, ongoing
quality control assessment, routine assessment of more than
5 million cells to estimate MRD, and a sensitivity of one in
100,000 or higher is necessary.
Molecular Methods for Minimal Residual Disease
Detection
Allele-specific oligonucleotide polymerase chain reaction. The
other methodology that has been studied extensively in the
past and for which a wealth of data exist is ASO-qPCR, in-
cluding a few reports in which it has been compared head-to-
head with MFC assays. Despite MRD evaluation by ASO-qPCR
being a sensitive and specific approach, it is applicable in a
lower proportion of patients with MM and is more time-
consuming when compared with MFC. This technique is now
supplanted by NGS methods.
Next-generation sequencing. Recently, there has been sig-
nificant interest in NGS for detection of MM MRD in the
bone marrow, and data supporting its use continue to
emerge. Most of the published data have been generated
using the LymphoSIGHT platform (Sequenta/Adaptive Inc.),
which utilizes consensus primers for the amplification and
sequencing of immunoglobulin gene segments. Specifically,
genomic DNA is amplified using locus-specific primers
designed for IGH-VDJH or IGH-DJH or IGK. Once amplified, the
immunoglobulin gene DNA is sequenced and the frequencies
of the different clonotypes in the sample are determined.
Patients with detectable MM clones (. 5%) at baseline can
then be studied at subsequent time points to determine the
presence and quantity of that particular clone using se-
quencing approaches. Ladetto et al compared IGH gene
based MRD detection by ASO-qPCR and NGS to assess
whether NGS could overcome some of the limitations of ASO-
qPCR and further increase its sensitivity and specificity.23
Clonotypes identified by NGS and ASO-qPCR were identical or
greater than 97% homologous in 96% of cases, and both tools
appeared to have a sensitivity of approximately one in
100,000, but NGS has the added advantage of not requiring
patient-specific primers. Recent studies show that NGS can
achieve a sensitivity of one in 1,000,000.
Next-generation sequencing has been compared with
first-generation four-color MFC in one Spanish study.24 Bone
MINIMAL RESIDUAL DISEASE BY NEXT-GENERATION SEQUENCING
marrow samples from baseline and from the time of very
good partial response or CR from patients enrolled in the
GEM trials were studied by NGS to identify a tumor clo-
notype at baseline and then re-evaluated for the presence of
the same clonotype in the subsequent sample. A dominant
MM clone could be identified at baseline in 91% of the
patients. Of the 121 patients with an identifiable clonotype
at baseline, 110 had follow-up samples, of which 73%
remained positive by sequencing at MRD levels of one in
100,000 MM cells. Among patients who achieved a very
good partial response, an MRD-negative status (less than
one tumor cell in 100,000 cells) bestowed a better PFS and
OS. Among the group of patients with a CR, a higher pro-
portion of cases had MRD negativity that also associated
with improved PFS. Korde et al also used NGS in 43 patients
with MM treated with carfilzomib, lenalidomide, dexa-
methasone, and they observed a 12-month PFS for MRD-
negative versus MRD-positive patients of 100% and 79%,
respectively (p , .001).24 Results from the IFM-DFCI trial
that randomly selected 700 patients to receive either eight
cycles of VRD (arm A) or three cycles of VRD, ASCT, and
then two consolidation VRD cycles (arm B).25 All patients
then received lenalidomide maintenance for 12 months.
A total of 246 patients were evaluated by NGS before
maintenance and 178 after maintenance. Among the
patients in CR, the 4-year PFS was 83% and 30% for patients
who were MRD negative and MRD positive, respectively,
postmaintenance.
Comparison of Techniques for Minimal Residual
Disease Detection in Bone Marrow
As described above, various techniques have been studied
for detection of MRD. Each of these techniques (based on
the plasma cell phenotype and/or plasma cell genotype) has
advantages and disadvantages that must be taken into
consideration (Table 1). The ideal MRD test should fulfill
several relevant characteristics: (1) high applicability (use-
ful among most patients), (2) highly sensitive and specific,
(3) excellent feasibility (results can be obtained for most
patients), (4) easily accessible, (5) requirement for a limited
sample that can be transported with ease, (6) reproduc-
ibility, and (7) proven clinical value.
While none of these tests fully satisfies all these ideal
characteristics at the current time, NGS and NGF fulfill most
of them and can be translated into an advanced platform
that can be uniformly applied across institutions and coun-
tries. In terms of sensitivity, the different methodologies
have been reported to have variable levels of sensitivity.
Both NGF and NGS have been reported to have the ability to
detect one in 100,0001,000,000 MM cells in more recent
studies. We strongly encourage the inclusion of both meth-
odologies in prospective trials, to the extent possible, to
collect data that would allow us to better understand the
advantages and disadvantages of the individual approaches
as well as the sensitivity of detection required in various
clinical settings.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e427
HERVE AVET-LOISEAU

Table 1. Comparison of Different Bone Marrow Minimal Residual Disease Techniques

Characteristic ASO-qPCR MFC VDJ Sequencing
Applicability 60%70% Nearly 100% $ 90%
Need for Baseline Yes, requires production of Not required, abnormal plasma Baseline samples required for
Sample patient-specific probes cells can be identified in any sample identification of the dominant
by their distinct immunophenotypic clonotype; alternatively, a stored
pattern vs. normal plasma cells sample from time-point with
detectable disease can be used
to define baseline status
Sample Requirements , 1 million cells sufficient Recent, sensitive methodology , 1 million cells sufficient
requires over 5 million cells
to be analyzed
Sample Processing Can be delayed Needs assessment within 2448 Can be delayed; can use both fresh
hours; requires a fresh sample and stored samples
Sample Quality Not possible. Additional Immediate with global bone Not possible. Additional studies
Control studies required marrow cell analysis required.
Sensitivity $ 1 in 100,000 $ 1 in 100,000 $ 1 in 100,000
In frequent clones may not
be evaluable
Turnaround and Labor intensive, requires Can be done in few hours, automated Typically days for turnaround,
Complexity development of patient-specific software available requires intense bioinformatics
primers/probes, may take several support. Use of local laboratories
days may speed up turnaround.
Clonal Consideration Detects only single clone or Considers all clones with similar Can take into account all minor
some of the related clones phenotype but evolving clone with clones with infrequent occurrence
change in phenotype may not be
evaluable
Abbreviations: ASO-qPCR, allele-specific oligonucleotide polymerase chain reaction; MFC, multiparameter flow cytometry.

DETECTION OF BONE AND EXTRAMEDULLARY
DISEASE
The current approaches for the detection and measurement
of tumor burden after therapy relies on bone marrow as-
sessment. However, bone marrow involvement in MM can
be heterogeneous, thus increasing the likelihood of a false-
negative assessment. More importantly, it does not allow
detection of the disease outside the bone marrow. The rec-
ognition of extramedullary disease is increasingly encoun-
tered in the clinic as a result of more sensitive imaging studies
and extended survival of patients with MM.
18
F-fluorodeoxyglucose PET (FDG-PET) is a powerful tool
used to assess tumor metabolic activity and the effect of
therapy on the tumor cell metabolism. Multiple studies have
demonstrated a prognostic capacity related to the detection
of PET-positive lesions in patients with MM at diagnosis and
at time of relapse.26-31 In addition to the metabolic as-
sessment, the low-dose CT that is typically done for local-
ization along with FDG-PET allows for a sensitive screen for
the detection of MM-associated bone disease. In an initial
study from the University of Arkansas, complete FDG sup-
pression in the focal lesions before first transplantation was
associated with substantially improved survival outcomes.
In a subsequent study in the context of Total Therapy (TT) 3,
it was shown that persistent FDG avidity 7 days after initi-
ation of therapy was associated with poorer survival out-
comes and was independent of other prognostic factors. In
an Italian study, PET-CT was performed at diagnosis, after
thalidomide-dexamethasone induction therapy, and after
double ASCT among 192 patients with newly diagnosed MM.
Persistence of a standard uptake value (SUV) of greater than
4.2 after induction therapy predicted for early relapse, and
the 4-year PFS and OS were superior for those patients
with a negative PET-CT at day 100 post-ASCT. Recently, the
Italian group presented updated results from their study of
282 patients with newly diagnosed MM who had PET imaging
at baseline. After treatment, PET negativity was achieved in
70% of patients, whereas conventionally defined CR was
achieved in 53%. Among the patients in CR, 29% still had
positive PET, translating to an inferior PFS (44 vs. 84 months)
and OS (5-year estimate of 70% vs. 90%). In this study,
persistence of SUVmax greater than 4.2 was the single factor
independently associated with skeletal progression in the
absence of conventional measures of disease progression.
Similar data have been recently reported by the French group.
In the IFM-DFCI trial, which randomized high-dose melphalan,
PET-CT positivity premaintenance was predictive of a shorter
PFS and OS.
INCORPORATION IN CLINICAL PRACTICE
Having established that achieving MRD-negative status
provides significantly superior survival outcome and that we
can reliably measure MRD-negative status with a sensitivity
of one cell in 1 million, the next important question in
myeloma is how MRD status will inform our therapeutic
decision algorithm, to both provide the most effective
therapy and develop strategies to individualize therapy. The
questions to be answered are whether outcome is similar

e428 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


between patients achieving early MRD negativity versus
those who achieve late MRD-negative status following
multiple interventions. This may help determine the need
for consolidation therapy for a given patient. The next
question is whether patients with MRD-negative status can
get similar benefit with less intense (one drug vs. two drugs)
or shorter duration of maintenance. The last questions will
be whether the same principles apply to older individuals
and whether MRD negativity should also be an endpoint for
patients with relapsed disease.
CONCLUSION
In the era of novel agents and combination therapies
achieving very high conventional CR rates, MRD status is
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 NEW TARGETS AND AGENTS IN HIGH-RISK MULTIPLE MYELOMA

New Targets and New Agents in High-Risk Multiple Myeloma

Ajay K. Nooka, MD, FACP, and Sagar Lonial, MD

OVERVIEW

Advances in the treatment of multiple myeloma have resulted in dramatic improvements in outcomes for patients. The
newly emerging profiling of mutations emerging as a consequence of large prospective sequencing studies such as the
CoMMpass Study or other efforts from European investigators are not further helping to define the place and role for
personalized medicine in myeloma. While mutations such as NRAS, KRAS, and BRAF do occur in myeloma, it is not clear that
targeting them as a single drug strategy will result in meaningful responses or durations of response. Personalized medicine
in multiple myeloma at this time likely entails the use of risk-based approaches for maintenance therapy, the use of current
biology-based treatments such as proteasome inhibitors, and immunomodulatory agents, with an eye towards the use of
mutation-specific treatments in the setting of minimal residual disease or in concert with biology-based treatments overall.

T he improvement in outcomes of patients with high-risk

myeloma in recent years can be attributed to a con-
fluence of numerous factors. First, improved stratification of
patients with myeloma by their risk status has allowed us to
better define the high-risk myeloma subset. Improved
stratification enabled us to specifically focus on developing
treatment algorithms aimed at delivering uninterrupted
intensive antimyeloma therapies, with resultant improve-
ment in survival outcomes. Second, the availability of novel
therapies with proven clinical efficacy among patients with
myeloma, especially among high-risk patients, led to un-
precedented survival improvements. More importantly, vast
clinical experience with these newer agents has not only
enabled us to better manage the toxicities of new agents,
but has also enabled us to consciously withdraw from the
excessive use of cytotoxic agents, such as alkylating agents,
among these patients with a highly genomically unstable
disease. This has further led to minimizing regimen-related
toxicity and decreased the incidence of alkylator-related
secondary myelodysplastic syndromes. In this article, we
describe the clinical experience of effective antimyeloma
agents among high-risk patients and provide the rationale
for incorporating these most effective combination regi-
mens in the treatment of patients with high-risk myeloma.
CURRENTLY APPROVED AGENTS AND THEIR
ACTIVITY IN HIGH-RISK MYELOMA
Successfully treating high-risk patients requires two im-
portant steps. First, among all patients with myeloma, no-
where is the importance of achieving a complete response
(CR) more important than in the high-risk cohort. Attaining
CR using agents with novel mechanisms of action is critical to
success. Second, the treatment approach used must be well
tolerated and not induce further genomic changes leading to
drug resistance. This is important because long-term du-
ration of therapy is a critical part of this strategic approach
for high-risk patients. Although the high-risk myeloma
spectrum has been defined mostly by cytogenetics, a few
groups have identified high-risk patients based on the dis-
ease presentation as extramedullary myelomathat is,
plasma cell leukemiaand also by gene expression pro-
filing. We have incorporated these high-risk attributes in the
review of individual drugs
Immunomodulatory Drugs
Thalidomide. The use of thalidomide is currently limited
because of the availability of next-generation agents with
greater efficacy and safety. In the context of high-risk pat-
ents, thalidomide usage has not been shown to improve
prognosis. The MRC-IX trial evaluated its role among pa-
tients with adverse immunofluorescence with fluorescence
in situ hybridization (iFISH; defined as gain(1q), t(4;14),
t(14;16), t(14;20), del(17p), and del(1p32)) demonstrated no
progression-free survival (PFS) benefit and, in fact, worse
overall survival (OS).1 The poor survival among the high-risk
patients receiving thalidomide maintenance was attributed
to the clonal advantage of the high-risk patients, the se-
lective pressure of thalidomide accounting for acquired drug
resistance, and the subsequent poor survival after relapse.
Conflicting data were seen from the other groups that have

From the Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Sagar Lonial, MD, Emory University, 1365 Clifton Rd., Building C, Room 3003, Atlanta, GA 30322; email: sloni01@emory.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e431

NOOKA AND LONIAL
used metaphase cytogenetic abnormalities to define high
risk. The OS of the thalidomide arm of the Total Therapy 2
(TT2) regimen was superior among patients exhibiting cy-
togenetic abnormalities, but when examined in the context
of gene expression profiling data, the benefit of thalidomide
was limited to those patients with low-risk disease defined
by gene expression profiling.2 Several other studies have
repeatedly demonstrated the inability to induce responses
with the use of thalidomide among patients with high-risk
myeloma presenting with extramedullary myeloma.3,4 In
current practice, thalidomide has a nominal role in the
treatment of patients with high-risk myeloma.
Lenalidomide. The use of lenalidomide and dexametha-
sone as induction therapy among high-risk patients did not
yield superior results. Among 40 patients (16%) exhibiting
t(4;14), t(14;16), t(14;20), or del(17)p on FISH analysis, the
median PFS was 1.4 years (compared with standard-risk
median PFS of 3.4 years; p = .0002). Not surprisingly, the
5-year OS was 47% versus 77% (p = .0001), favoring the
standard-risk patients.5 Clearly, lenalidomide/dexamethasone
was deemed as a suboptimal induction regimen, and a shift
toward triplet induction regimen has been made by all
parties, at least for the high-risk subgroup. The results from
the FIRST trial also did not demonstrate any survival benefit
for transplant-ineligible patients exhibiting high-risk fea-
tures treated with lenalidomide/dexamethasone continu-
ously (Table 1).6 These results suggest that a modified
combination regimen such as lenalidomide, bortezomib, and
dexamethasone (RVD)-lite might be an appropriate in-
duction regimen for high-risk transplant-ineligible pa-
tients, though this has yet to be demonstrated. Among
patients with relapsed or refractory myeloma, Reece et al
evaluated the impact of cytogenetics, using lenalidomide/
dexamethasone in relapsed myeloma.7 Consistent with
other experiences, patients with del(17)p experienced
a worse outcome, with a median OS of 4.7 months. In
contrast, patients with t(4;14) experienced a median OS
similar to patients without any cytogenetic abnormalities,
suggesting lenalidomide/dexamethasone may abrogate the
KEY POINTS
Identification of risk status should be performed on all
patients at diagnosis.
Immune-based treatments may provide unique ways by
which to target high-risk myeloma.
Combination therapy with currently available novel
agents may help mitigate the outcomes of high-risk
disease.
Cellular immune-based treatments are currently in
evolution with rapidly expanding targets.
Specific mutation-driven treatments are in
development and may offer benefit as part of
a combination approach with biology-based treatments.
e432 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
poor prognosis conferred by t(4;14). Although additional
studies have confirmed that lenalidomide/dexamethasone
is a suboptimal regimen among patients with del(17)p, the
positive impact of this regimen on patients with t(4;14)
has never been recapitulated in any other trial to date.8,9
In the maintenance setting, Attal at al presented their
findings comparing fixed-duration lenalidomide mainte-
nance placebo post-transplant.10 They reported that the
presence of t(4;14) or del(17)p are independent com-
pared with risk factors for poor survival on the multi-
variate analysis, but they did not comment on the impact
of maintenance therapy on these high-risk patients.10
Pomalidomide. The influence of cytogenetics in patients
with relapsed or refractory myeloma treated with pomali-
domide and low-dose dexamethasone have been evaluated
by Dimopoulos and colleagues as a subgroup analysis from
the registration phase III MM003 trial. The results dem-
onstrate quite a variance between the outcomes of pa-
tients with del(17p) and t(4;14). The median PFS rates for
standard risk versus del(17p) versus t(4;14) were 4.2, 4.6,
and 2.8 months, respectively; the median OS rates were
14.0, 12.6, and 7.5 months, respectively, suggesting that
the pomalidomide/low-dose dexamethasone regimen may
overcome the poor prognosis of patients with del(17p) but
not t(4;14).11 Similar results were demonstrated in a dedi-
cated high-risk trial from the Intergroupe Francophone du
Myelome; patients with del(17)p and t(4:14) treated with
pomalidomide/low-dose dexamethasone achieved median
time to progression (TTP) for del(17p) and t(4;14) of 7.3
versus 2.8 months, and the 8-month OS was 41% versus
12.4%, respectively.12 This regimen could serve as an in-
teresting backbone upon which to further build combina-
tions that would benefit patients with del(17)p and t(4;14).
Based on this concept, IFM-2014-01 is evaluating the regi-
men of pomalidomide/low-dose dexamethasone with the
addition of ixazomib exclusively among patients with re-
lapsed or refractory high-risk myeloma who have received
more than two lines of therapy with an enrollment goal of
50 patients.
Proteasome Inhibitors
Bortezomib. The UAMS group as part of the Total Therapy 3
(TT3) experience incorporated bortezomib in the induction
treatment of myeloma. Compared with TT2, a meaningful
benefit was apparent among younger patients with high-risk
myeloma defined by GEP70. The 2-year event-free survival
rates (TT3 vs. TT2: 68% vs. 30%) and OS rates (TT3 vs. TT2:
75% vs. 50%) strongly favored inclusion of bortezomib in
induction therapy for patients with high-risk myeloma.13
Additionally, in the earlier relapsed trials with bortezomib,
Jagannath et al evaluated the utility of bortezomib among
high-risk cohorts (defined as del13 by FISH and/or meta-
phase cytogenetics). This analysis suggested that bortezo-
mib may be able to deliver responses uniformly, irrespective
of the risk status.14 Among patients with newly diagnosed
 TABLE 1. Outcomes Among Patients With High-Risk Myeloma From Newly Diagnosed Trials
Std Risk, High Risk,
No. No. t(4;14), del(17)p, Median
Study, Year/ Regimen (No. Patients Patients No. Patients No. Patients Std Risk t(4;14) del(17)p Follow-
Phase Patients) (%) (%) (%) (%) VGPR VGPR VGPR Std Risk PFS t(4;14) PFS del(17)p PFS Std Risk OS t(4;14) OS del(17)p OS up
Cavo VTD SCT 3 2 NR 53 (24) NR 15 (7) NR NR NR 74 69 69 NR NR NR NR
et al,16 VTD (236) vs.
NR 57 (26) 17 (8) 63 (3 y PFS) 37 (3 y PFS) 37 (3 y PFS)
2010/III TD SCT 3
2 TD (238)
Avet-Loiseau VDSCT (507) 106 (21) 54 (11) NR NR NR 36 mo 28 mo 14 mo 79% (4 y OS) 63% (4 y OS) 50% (4 y OS) 24
et al,15
2010/III
Sonneveld PAD SCT 3 NR NR 50/295 (17%) 39/312 (13%) 76% NR NR 27% 16% 22% 72% 52% 65% 94
et al,18 2 V (413) vs.
NR 56% 24% (5 y PFS) 8% (5 y PFS) 5% (5 y PFS) 64% (5 y OS) 33% (5 y OS) 18% (5 y OS)
2015/III VADSCT 32T
(4141)
Mateos VMP Rd 66 19 NR 63% 68% NR 32 mo 30 mo 30 mo 65% 45% 45% 37
et al,59 (sequential)
76 13 66% 46% 36 mo 24 mo 24 mo 72% (4 y OS) 27% (4 y OS) 27% (4 y OS)
2015/III (118) vs. VMPRd
alternating (115)
Avet-Loiseau Rd continuous 620 (81.3) 142 (18.7) NR 49.3% 30.2% 30.2% 31.1% 8.4% 8.4% 77.1% 40.7% 40.7% NR
et al,22 (248) vs. Rd18
47.3% 34.7% 34.7% 21.2% 17.5% 17.5% 71% 39.6% 39.6%
2015/III* (261) vs. MPT
(253) 38.8% 10.6% 10.6% 24.9% (3 y PFS) 14.6% (3 y PFS) 14.6% (3 y PFS) 64.8% (3 y OS) 46.8% (3 y OS) 46.8% (3 y
OS)
Nooka RVD SCT RVD N/A 45 (100) 2 (5) 19 (42) N/A 96% 96% N/A 32 mo 28 mo N/A 93% (3 y OS) 94% (3 y OS) 26
et al,19 (45)
2013
Abbreviations: VGPR, very good partial response; PFS, progression-free survival; OS, overall survival; mo, months; VTD, bortezomib, thalidomide, and dexamethasone; SCT, stem cell transplant; NR, not reported; TD, thalidomide and
dexamethasone; VD, bortezomib and dexamethasone; y, years; V, bortezomib; T, thalidomide; VMP, bortezomib/melphalan/prednisone; Rd, lenalidomide and dexamethasone; MPT, melphalan/thalidomide/prednisone; RVD, lenalidomide,
bortezomib, and dexamethasone.
*Cytogenetics available for 762 of 1,623 patients in the FIRST trial.

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NOOKA AND LONIAL
myeloma, several trials evaluated the impact of bortezomib
on high-risk patients. From the IFM trial that compared
bortezomib and dexamethasone to the chemotherapy
combination regimen vincristine, doxorubicin, and dexa-
methasone as induction therapy before high-dose therapy
and autologous transplant, differential outcomes were
observed for t(4;14) and del(17)p. Patients with t(4;14)
appeared to have significantly improved outcomes with
bortezomib/dexamethasone as induction therapy compared
with those with del(17)p (Table 1).15 Another induction trial
evaluated the impact of bortezomib, thalidomide, and
dexamethasone (VTD) versus thalidomide and dexametha-
sone on outcomes of high-risk cohorts including patients
with newly diagnosed myeloma. Cavo and colleagues
demonstrated that VTD with bortezomib as part of con-
solidation could eliminate the negative impact of t(4;14),
although this was not the case with the thalidomide/
dexamethasone arm.16 A subsequent trial, HOVON/GMMG,
also evaluated the impact of bortezomib as part of induction
and as maintenance.17 As illustrated in Table 1, the use of
bortezomib as maintenance therapy was able to reduce the
negative impact of high-risk cytogenetics on outcomes.
Prolonged bortezomib treatment mostly abrogated the
del(17p) effect on PFS and OS but had limited benefit among
patients with t(4;14).18 Our group evaluated the use of the
combination of RVD at modified doses as a post-transplant
maintenance strategy among patients with high-risk mye-
loma.19 The use of RVD maintenance after transplant sig-
nificantly improved PFS and OS for high-risk patients, greater
than what has been reported with single-agent maintenance
with either lenalidomide or bortezomib.
Carfilzomib. The efficacy of carfilzomib as a single agent was
evaluated among patients with high-risk myeloma in the PX-
171-003-A1 study. Patients with t(4;14) had the highest
overall response rate (ORR) of 38.9%. Those with del(17)p
had the lowest ORR of 16.7%. Among high-risk patients, the
median PFS and OS trended higher among the patients with
t(4;14). Among patients with t(4;14) only, the OS was
15.8 months, and, among all high-risk patients,20 the OS was
shorter compared with the standard-risk patients (9 vs.
23 months; Table 2). In the ENDEAVOR trial, a phase III
study that compared two proteasome inhibitors,21 carfil-
zomib with dexamethasone was superior to bortezomib/
dexamethasone among all patients with myeloma irrespective
of baseline cytogenetic risk status. However, the median
PFS for high-risk patients was lower compared with the
standard-risk patients. Carfilzomib/dexamethasone im-
proved the outcome of high-risk patients but did not
overcome the adverse impact of high-risk cytogenetics. A
similar experience from the ASPIRE trial that compared
carfilzomib, lenalidomide, and dexamethasone (KRD) with
lenalidomide/dexamethasone in a phase III trial dem-
onstrated KRD exerting higher-quality responses both
among the high-risk and standard-risk patients. The
overall responses among the high-risk versus standard-
risk patients with KRD was 79.2% versus 91.2% and for
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lenalidomide/dexamethasone was 59.6% versus 73.5%,
respectively. The median PFS among patients who received
KRD with standard risk versus t(4;14) versus del(17)p was
29.6, 23.1, and 24.5 months, and for Rd was 19.5, 16.7, and
11.1 months, respectively (Table 2). Though there are
several limitations to the data set including unavailability of
cytogenetics for more than half the patients, these results
suggest the proteasome inhibitor/immunomodulatory drug
combination can overcome the poor prognosis conferred
by these high-risk cytogenetics.22 In another recent trial
evaluating carfilzomib in combination with pomalidomide/
low-dose dexamethasone (KPD) for relapsed/refractory my-
eloma, high ORRs were seen with this combination, even
among patients with high-risk genetics (Table 2).23
Ixazomib. Ixazomib is the most recently approved oral
proteasome inhibitor that has been evaluated in the
TOURMALINE-MM1 trial. This phase III study randomly se-
lected 722 patients to receive lenalidomide/dexamethasone
or to receive ixazomib in combination with lenalidomide/
dexamethasone (IRD). The combination of IRD was shown
to be superior in delivering high or at least very good
partial response (VGPR) rates among both high-risk and
standard-risk patients. At least VGPR with IRD for standard
risk versus t(4;14) versus del(17)p was 51%, 53%, and 39%,
and for lenalidomide/dexamethasone was 44%, 28%, and
21%, respectively. The median PFS with IRD for standard
risk versus t(4;14) versus del(17)p was 20.6, 18.5, and
21.4 months, and for lenalidomide/dexamethasone was
15.6, 12, and 9 months, respectively (Table 2).24 These re-
sults also suggest the same observations seen with KRD,
a proteasome inhibitor/immunomodulatory drug combi-
nation is the most optimal regimen to deliver the best results
for patients with high-risk cytogenetics.
IMMUNE-BASED APPROACHES
Immunotherapeutic approaches as antimyeloma therapies
aimed at targeting the malignant plasma cell have been
explored for some time with limited success. Though iden-
tifying the ideal target was a major challenge, the current
clinical activity using the monoclonal antibodies targeting
SLAMF7 and CD38 demonstrate much promise. Acceptable
safety in combination with other antimyeloma agents allow
for their utility in treating myeloma, even among the pa-
tients heavily pretreated for myeloma. Furthermore, drug
development using novel immune-based antimyeloma ap-
proaches such as checkpoint inhibitors and cellular therapies
are highly promising.
Monoclonal Antibodies
Elotuzumab. Elotuzumab is a recently approved monoclo-
nal antibody targeting the surface protein SLAMF7. Its U.S.
Food and Drug Administration approval in combination with
lenalidomide and dexamethasone for the treatment of
patients with multiple myeloma who have received one to
three prior lines of therapies was based on the results
 TABLE 2. Outcomes Among Patients With High-Risk Myeloma From Relapsed/Refractory Trials
Std Risk, High Risk, del(17)p,
Regimen No. No. t(4;14), No. Median
Study, Year/ (No. Patients Patients No. Patients Patients Std Risk t(4;14) del(17)p PFS Std Risk t(4;14) del(17)p OS Std Risk t(4;14) del(17)p Follow-up
Phase Patients) (%) (%) (%) (%) VGPR VGPR VGPR (mo) PFS PFS PFS (mo) OS OS OS (mo)
Lonial ERd (321) 30 (9) 102 (32) NR NR NR 19.4 20.34 18.46 NR NR NR NR 24.5
et al,25 2015 vs.
31 (10) 104 (32) 14.9 15.74 14.85
Rd (325)
Avet-Loiseau KRd (396) 147 (37) 48 (12) 33 (69) 18 (38) 75.5 60.5% 60.5% 26.3 29.6 23.1 24.1 NR NR NR NR 32
et al,22 vs.
170 (43) 52 (13) 31 (60) 21 (40) 45.3 27% 27% 17.6 19.5 16.7 11.1
2015/III Rd (396)
Moreau IRd (360) vs. 199 (55) 75 (21) NR NR 51% 53% 39% 20.6 20.6 18.5 21.4 NR NR NR NR 23
et al,24 Rd (362)
216 (60) 62 (17) NR NR 44% 28% 15% 14.7 15.6 12.0 9.7
2015/III
Chng Kd (464) vs. 284 (61) 97 (21) NR NR 56.7% 44.3% 44.3% 18.7 NR 8.8 8.8 NR NR NR NR N/A
et al,21 Vd (465)
291 (63) 113 (24) NR NR 27.4% 27.5% 27.5% 9.4 10.2 6.0 6.0
2015/III
Reece Rd (130) 28 (21.5) 12 (9.2) NR NR NR 7.1 8 (TTP) 2.2 (TTP) 22.7 NR NR 4.7 19.7
et al,7 (TTP)
2009/II
Avet-Loiseau Rd (207) 7 (6) 14 (5) NR NR NR 9.6 5.5 15.1 9.4
et al15, 2010
Leleu Pd (50) N/A 50 (100) 22 (46) 32 (64) N/A 3% 9% 7.3 N/A 41% (8 mo TTP) 12.4% (8 mo TTP) 12 N/A NR NR 10
et al,12 (TTP)
2015/III
Dimopoulos Pd (302) vs. 126 (56) 99 (44) 44 (15) 44 (15) 6.8 2.3 6.8 4 4.2 2.8 4.6 12.6 14 7.5 12.6 15.4
et al,11 HiDex
66 (62) 41 (38) 15 (10) 23 (15) 1.4 0 0 1.9 2.3 1.9 1.1 7.7 9 4.9 7.7
2015/III (153)
Jakubowiak K (266) 167 (72.9) 62 (27.1) 18 (8) 30 (13) 8.4 0 0 4.6 4.5 3.5 19 11.8 7.0 N/A
et al,20
2013/II
Shah et al,60 KPd (32) 10 (31) 3 (10) 5 (15) 16% NR NR 7.2 NR NR 60% (12 mo) 20.6 NR NR 80% (12 mo) 26
2015/I
Abbreviations: VGPR, very good partial response; PFS, progression-free survival; OS, overall survival; mo, months; ERd, elotuzumab in combination with lenalidomide and dexamethasone; Rd, lenalidomide and dexamethasone; NR, not reported;
KRd, carfilzomib, lenalidomide, and dexamethasone; IRd, ixazomib in combination with lenalidomide and dexamethasone; Kd, carfilzomib and dexamethasone; Vd, bortezomib and dexamethasone; TTP, time to progression; Pd, pomalidomide and
low-dose dexamethasone; HiDex, high-dose dexamethasone; K, carfilzomib; KPd, carfilzomib in combination with pomalidomide and low-dose dexamethasone.
Note: unknown cytogenetic status: KRD, 201 (51%) vs. Rd, 174 (44%) from ASPIRE trial; unknown cytogenetic status: IRd, 86 (24%) vs. Rd, 84 (23%) from TOURMALINE-MM1 trial; unknown cytogenetic status: KD, (18%) vs. Vd, (13%) from
TOURMALINE-MM1 trial; unknown cytogenetic status for 47 patients in PX-171-003-A1 study. Available for 229 of 266 patients; MM003 cytogenetics available for 225 (75%) in Pd and 107 (70%) patients.

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NOOKA AND LONIAL
meeting the primary endpoint of PFS and ORR from the
ELOQUENT-2 trial. In this trial, 646 patients were ran-
domly selected to receive elotuzumab in combination with
lenalidomide and dexamethasone (ERD) or lenalidomide/
dexamethasone among patients sensitive to lenalidomide.
The ORRs were 79% and median PFS of 19.4 versus
14.9 months (p = .0014) favored the ERD arm.25 The 3-year
extended PFS was recently presented at the 2015 American
Society of Hematology (ASH) Annual Meeting and demonstrated
that more than one-quarter of the patients receiving ERD
continue to be free from progression, suggesting long-term
benefits with immune-based approaches. The prespecified
interim analysis for OS indicated a strong trend favoring ERD
(43.7 vs. 39.6 months; p = .0257).
Data regarding the efficacy of elotuzumab among patients at
high risk are very encouraging. Approximately 32% of patients
had the cytogenetic abnormality of del(17)p and 9% of patients
had t(4;14), and the outcomes for these patients have been
surprisingly comparable with those of the patients at standard
risk. The PFS benefit of the combination of ERD relative to
lenalidomide/dexamethasone was evident among both of
these subsets; hazard ratios (HR) for del(17)p and t(4;14) were
0.65 (95% CI, 0.450.94) and 0.53 (95% CI, 0.290.95), re-
spectively. At a median follow-up of 24 months, the PFS for
standard risk versus del(17)p versus t(4;14) patients were
similar at 19.4, 18.46, and 20.34 months, respectively.
Based on a phase I trial showing the tolerability of elo-
tuzumab in combination with bortezomib and dexametha-
sone (EVD) among heavily pretreated patients,26 another
randomized phase II trial was designed that randomly se-
lected 152 bortezomib-sensitive patients with myeloma who
had received one to three prior lines of therapy to receive
EVD or bortezomib/dexamethasone. At a median follow-
up of 27.3 months, a PFS benefit of close to 3 months
was observed for the EVD arm (EVD vs. bortezomib/
dexamethasone: 9.7 vs. 6.9 months, respectively; p = .018).
Similarly, the OS trended in favor of EVD (2-year OS, EVD vs.
bortezomib/dexamethasone: 73% vs. 66%).27
Multiple combination trials of elotuzumab with other
antimyeloma agents are ongoing. Study of the safety and
efficacy of elotuzumab in combination with RVD (ERVD)
among transplant-eligible patients is currently ongoing.
Preliminary data suggest that this as a safe combination.
Another trial (S1211) of RVD with or without elotuzumab
specifically focused on accruing newly diagnosed patients
with high-risk multiple myeloma is underway with an ex-
pected accrual of 122 patients. GMMG-HD6 in a randomized
phase III trial is evaluating the same combination (ERVD)
versus RVD among newly diagnosed transplant-eligible
patients. The study also has a second set of patients ran-
domly selected to receive RVD after receiving stem cell
transplant (SCT) versus ERVD consolidation and lenalido-
mide versus lenalidomide with elotuzumab maintenance,
with the primary endpoint of PFS. Another similarly designed
trial from the DSMM XVII evaluating the combination (KRD
vs. KRD with elotuzumab) also has a second trial of randomly
selected patients after receiving SCT and KRD versus KRD
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with elotuzumab consolidation to receive lenalidomide
versus lenalidomide with elotuzumab maintenance for the
primary endpoint of CR post-induction and 3-year PFS
post = first randomization. In the relapsed setting, trials of
elotuzumab in combination with pomalidomide and low-
dose dexamethasone (EPD; accrual goal: 60 patients) and
combination nivolumab to EPD (accrual goal: 40 patients)
are underway. More importantly, the safety and tolerability
of elotuzumab in combination with other monoclonal an-
tibodies such as lirilumab or urelumab are also ongoing.
Daratumumab. Daratumumab, a humanized IgG1 anti-
CD38 antibody, is the most active monoclonal antibody in
myeloma to date. It was recently approved in the United
States at the active dose of 16 mg/kg as a single agent
resulting in response rates of 29%.28 The combined results of
GEN501 part 2 and the SIRIUS trials comprising 148 patients
were presented at ASH 2015. At a median follow-up of
14.8 months, 50% of the responders were progression free
at 1 year. Among most patients, responses deepened with
continued treatment and were tolerated well. The 1-year OS
rate among this heavily pretreated patient population was
69% (95% CI, 60.4%75.6%) and the median OS was
19.9 months, demonstrating its efficacy as a single agent.29
More importantly, the minimal adverse event profile and the
established safety and tolerability of this antibody (48% of
patients had infusion reactions, mostly # grade 2) led to the
design of multiple combination trials.
Daratumumab in combination with lenalidomide/
dexamethasone, among patients with early-relapse multiple
myeloma who have received a median of two lines of therapy,
demonstrated response rates of 81%, and close to two-thirds
of patients who enrolled in the trial appeared to have
achieved at least a VGPR (63%).30 In this trial, the toxicity
profile was acceptable and more likely related to the lena-
lidomide than the daratumumab. Although greater than or
equal to grade 3 or worse toxicities were seen in 88% of
patients, most of these were at least grade 3 neutropenia
(78%) that have resolved with supportive growth factor
therapies. In another recent study presented by Chari et al,
the combination of daratumumab with pomalidomide/low-
dose dexamethasone among patients who have received four
lines of therapy resulted in response rates of 71% and at least
VGPR rates seen among 43% of patients. More than half (53%)
of patients were progression free at 1-year among this heavily
pretreated population.31 Daratumumab certainly has a good
safety and efficacy profile and can be combined with a
number of antimyeloma therapies. The question of whether
we can rechallenge with a subsequent daratumumab-based
combination therapy among those patients who are deemed
refractory to daratumumab single-agent therapy remains to
be answered. Data of responses among the high-risk patients
are encouraging. At least a 20% ORR among patients with
heavily pretreated, relapsed, refractory, high-risk multiple
myeloma and those with extramedullary myeloma as a single
agent is of great interest. More than one quarter of the
patients in the SIRIUS trial had either del(17)p (17%) or t(4;14)

(10%), and the responses were not limited to standard-risk
patients alone.28
Several daratumumab trials are in progress. The HOVON/
IFM trial is evaluating the combination of VTD with dar-
atumumab in the induction, consolidation, and daratumumab
maintenance for the primary endpoint of stringent complete
remission, PFS, and OS. From the Alliance groups, the
concept of evaluating lenalidomide/dexamethasone versus
daratumumab/lenalidomide/dexamethasone in transplant-
ineligible patients and RVD versus daratumumab with RVD
are in the concept phase. In the maintenance setting,
daratumumab/lenalidomide versus lenalidomide post-
transplant until progression or unacceptable toxicity is
under evaluation (communication with Dr. McCarthy).
Several other phase III trials of daratumumab in combination
with lenalidomide/dexamethasone versus lenalidomide/
dexamethasone or in combination with bortezomib/
dexamethasone versus bortezomib/dexamethasone have
completed accrual and are awaiting results. Several other
phase III trials in transplant-ineligible patients (daratumumab
with or without bortezomib/melphalan/prednisone) are
ongoing. Given the longer infusion times and the higher
rate of infusion reactions seen (although majority of these
are # grade 2), daratumumab is currently being evaluated as a
subcutaneous formulation with the addition of recombinant
human hyaluronidase (rHuPH20) among patients with multiple
myeloma.
A second CD38 monoclonal antibody, SAR650984 (isatux-
imab), in combination with lenalidomide/dexamethasone
demonstrated an ORR of 65% and VGPR rates of 32% among
patients with multiple myeloma who were heavily pretreated (six
prior lines of therapy).32 Patients experienced a median PFS of
6.2 months reported at a median follow-up of 6 months. Another
phase IB study of isatuximab in combination with pomalidomide
and dexamethasone is currently enrolling patients.
Cellular Therapies
The idea behind using cellular immunotherapies is to attain
similar benefits to those observed after allogeneic transplant
TABLE 3. Other Cellular Therapies
Cellular Therapy Identification
NK Cells NK cells are members of the cellular immune Given the depression of NK activity in
system that play a key role in defense
against viruses and tumors. In humans,
NK cells are identified as CD32CD56
lymphocytes but may differ in their
immunoregulatory role based on their
further expression.61
Tregs Tregs are CD4 + T-cell population
(CD4+CD25+FoxP3+ T cells), comprise
5%10% of peripheral CD4 T cells, and
are responsible for the control of
autoimmune phenomena.
Abbreviations: NK, natural killer; Tregs, regulatory T cells; ASCT, autologous stem cell transplant.
NEW TARGETS AND AGENTS IN HIGH-RISK MULTIPLE MYELOMA
and, at the same time, limiting the toxicities seen with an al-
logeneic transplant. The main goal of cellular therapies is to
induce a robust antimyeloma immune response that can have a
potential effect on disease control in the long term. The utility of
chimeric antigen receptor T cells (CAR-T cells), natural killer cells,
and regulatory T cells is encouraging but preliminary (Table 3).
CAR-T cells. Engineering autologous T cells to express antigen-
specific CAR-T cells can be a potential immune-based
therapeutic approach for B-cell malignancies. The utility of
CAR-T cells has also been recently investigated in myeloma
management. One of the means by which myeloma cells evade
immunosurveillance is by enabling mutations in the major his-
tocompatibility complex (MHC). T cells bind to the T-cell receptor
with the MHC on the tumor cell. However, in the presence of
MHC mutations, normal T cells cannot bind to MHC T-cell re-
ceptors. CAR-T cells have been genetically modified to have a
different extracellular antigen-binding site that allows CAR-T
cells to identify malignant cells without the use of the MHC.33 A
case of sustained CR to infusion of cytotoxic T lymphocyte (CTL)
019 cells in conjunction with autologous transplantation in a
patient with refractory myeloma was recently reported by
Stadtmauer and colleagues.34 They were able to demonstrate
that the clinically relevant target of CTL019 in this case may have
been non-neoplastic CD19+ cells, which have been implicated in
immune evasion and resistance to therapy in solid tumors.
However, one can argue the observed response could be at-
tributed to be a response from alkylating therapies alone based
on the normal reconstitution of CD19+ B cells and loss of de-
tectable CTL019. Nevertheless, the fact that six of the 10 patients
treated remained progression free is hypothesis-generating in
that this is not just an effect of melphalan alone. Additional
CAR-T cell studies are in progress, and early clinical results are
promising, though other targets such as B-cell maturation an-
tigen may prove to be more suitable for myeloma.35
Therapeutic Vaccinations
Dendritic cell vaccines. The utility of dendritic cell vaccines
is currently being explored in myeloma. Vaccines aimed at
Rationale Clinical Activity
refractory myeloma, and the idea of
enhancing NK efficacy to improve
antimyeloma activity has led to ongoing
trials exploring the utility of NK cellbased
therapy in myeloma.
They are believed to strongly inhibit Among 10 patients undergoing ASCT, Treg
antitumor immune responses among depletion for patients with myeloma was
patients with myeloma. It is unclear if deemed to be safe, and further studies to
Tregs play a role in protection from determine the role of Treg depletion are
malignancy, but Treg depletion leads to ongoing.62
induction of tumor rejection in murine
models. Treg depletion may enhance the
function of tumor antigenspecific T cells.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e437
NOOKA AND LONIAL
developing myeloma-specific immunity have become a
major area of focus. Currently, several groups are working on
either whole-cell or antigen-specific dendritic cell vaccines
to enhance innate immunity to obtain the antitumor effect.
Currently, these are early approaches and in phase I. A
dendritic cellmyeloma cell fusion vaccine study among
patients with multiple myeloma supported by the Bone
Marrow Transplant Clinical Trials Network as a post-
transplant maneuver to gain disease control is underway.
Peptide vaccines. PVX-410 is composed of a tetrapeptide
from three unique regions of myeloma-associated antigens
(XBP1, CD138, and CS1). The goal is to induce immunity
against myeloma cells by selectively stimulating tumor-
associated antigen-specific CTLs. The safety and tolerabil-
ity of PVX-410, alone and in combination with lenalidomide,
show considerable promise in treatment of patients with
smoldering myeloma.36 Future studies in combination with
MEDI4736, a PD-L1 antibody and lenalidomide PVX-410, will
be initiated shortly. Immucin, an anti-MUC1 signal peptide
vaccine, induced a robust CD8+- and CD4+-specific T-cell
response in all 15 patients following autologous SCT and
demonstrated a marked antitumor humoral response.37
Checkpoint Blockade
PD-1, or its ligand, PD-L1, interactions may indirectly
modulate the response to tumor antigens through T-cell/
antigen-presenting cell interactions. PD-1 engagement may
represent one way by which tumors evade immuno-
surveillance.38 The PD-1/PD-L1 pathway is shown by mul-
tiple groups to promote progression of myeloma indirectly
by undermining immune control of the malignancy.39 PD-1
blockade has been pursued as a promising therapeutic
strategy to reverse immune tolerance and enhance T-cell
effector function in several tumor types. The broad ex-
pression of PD-1 and its ligands in the microenvironment of
myeloma and the preclinical data reveal an important role of
the PD-1 pathway in immune evasion by myeloma cells, and
there may be immunotherapeutic potential of PD-1/PD-L
inhibition in myeloma. Several PD-1 antibodies such as
nivolumab, pidiluzumab (CT-011), and PD-L1 antibodies
(MEDI4736) are under investigation. Pembrolizumab, a
humanized IgG4 antiPD-1 monoclonal antibody designed
to block interaction of PD-1 with PD-L1 and PD-L2, was
evaluated in combination with immunomodulatory drugs
(lenalidomide/dexamethasone40 and pomalidomide/low-
dose dexamethasone41) with an intent to enhance tumor
suppression. The ORR with lenalidomide/dexamethasone
was 76% ($ VGPR 24%)40 and the ORR with pomalidomide/
low-dose dexamethasone was 60% ($ VGPR 19%), 41
showing impressive activity with a tolerable safety profile.
Forty-two percent of the patients in the pembrolizumab and
pomalidomide/low-dose dexamethasone studies exhibited
high-risk features (del 17p, t(4:14) and/or t(14:16)). Among
these high-risk patients, a 50% ORR was observed.41 Several
other combination trials with PD-1 antibodies and PD-L1
antibodies are under investigation
e438 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
TARGETED THERAPIES
Boise and colleagues have published an interesting model for
the two sides of myeloma therapy, the Tao of myeloma,
where Yin and Yang represented the normal plasma cell and
malignant plasma cell biology, respectively.42 Our current
agents have focused on the biology side of the Tao, but among
high-risk patients, focusing on the mutational profile and the
abnormal expression may be equally important.43
MDM2 Inhibitors Targeting p53 Deletion or Mutation
p53, a tumor suppressor gene located on the short arm of
chromosome 17, is implicated in normal cellular pro-
liferation, differentiation, and apoptosis. Loss of p53 is as-
sociated with poor survival among patients with myeloma
(del(17)p).44 Another protein, the murine double-minute 2
(MDM2), is a negative regulator of p53 and plays a role in
proliferation and survival of myeloma cells by suppressing
the p53 function. MDM2 inhibitors to block the MDM2-p53
protein-protein interaction have potential as antimyeloma
therapeutic strategies for patients with myeloma with
del(17)p; however, this hypothesis presumes there is a
normal and functional copy of p53 in the cell.45 There are
emerging data suggesting an increased frequency of p53
mutations among with del(17)p upon greater exposure
to treatment. This finding may limit the utility of MDM2
inhibitors. Currently, DS-3032b, an oral MDM2 in-
hibitor, is in initial trials for relapsed refractory myeloma
(NCT02579824).
BRAF Inhibitors
Prevalence of patients with myeloma with actionable BRAF
mutations (V600E) is much higher than what was originally
thought. Approximately 5% of patients harbor either a clone
or a subclone of BRAF V600E.46 It has been postulated that
myeloma clones harboring BRAF V600E might have a survival
advantage and likely present as aggressive, extramedullary
disease.47,48 Though recent analysis evaluating BRAF V600E
mutations in early-stage myeloma suggests no relation to
prognosis, this could represent the differential prognosis of
BRAF subclones at various phases of myeloma progression.46
There have been several reports of patients with BRAF-
mutated, relapsed, refractory myeloma who were treated
successfully with the BRAF inhibitor vemurafenib.47
MEK Inhibitors
The deregulation of the RAS/RAF/MEK/extracellular signal
regulated kinase (ERK; RAS/mitogen-activated protein
kinases) signal transduction pathway leads to abnormal
cellular proliferation, impaired apoptosis, enhanced an-
giogenesis, metastasis, and the development of drug re-
sistance.49 Activating RAS mutations, which have a reported
incidence varying between 32% and 50% in multiple mye-
loma, are also thought to deregulate this pathway.50 The
presence of RAS mutations have previously been shown to
confer clinical prognosis.50,51 Mutation-specific inhibitor use
in myeloma so far is in the early phases. Several factors that

are not understood fully limit the therapeutic application of
the KRAS/NRAS inhibitors in myeloma. Variability of the
dominant clone relative to size of the clonal population
carrying the KRAS/NRAS mutations point to the presence of
intraclonal heterogeneity and also the potential difficulties
in the use of targeted treatment strategies.43
FGFR3 Inhibitors
Simultaneous overexpression of two oncogenes, FGFR3
(fibroblast growth factor receptor 3) and MMSET (multiple
myeloma SET domain), represent a subset of patients with
myeloma with t(4;14) translocation, often indicating poor
prognosis.52 Though preclinical experience suggested anti-
myeloma activity in FGFR3-expressing cell lines,53 experi-
ence with small-molecule inhibitors has not made much
progress. It could represent that 30% of t(4;14) patients do
not express FGFR3.52 Further drug development with FGFR3
monoclonal antibodies54 and MMSET inhibitors55 are cur-
rently under evaluation.
BRD4 Inhibitors
Bromodomain (BRD) and extraterminal proteins play an
important role in cellular proliferation, cell cycle progres-
sion, and chromatin compaction. They use BRD modules
for lysine acetylation, a pivotal mechanism in chromatin
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e441
SZALAT AND MUNSHI

Next-Generation Sequencing Informing Therapeutic Decisions

and Personalized Approaches
Raphael Szalat, MD, and Nikhil C. Munshi, MD

OVERVIEW

Multiple myeloma is a heterogeneous disease featured by different molecular subtypes. In the last decade, new therapeutics
including second- and third-generation proteasome inhibitors and immunomodulatory agents, monoclonal antibodies,
and other novel targeted agents have completely transformed the outcome of the disease. The task ahead is to develop
strategies to identify effective combinations and sequences of agents that can exploit the genetic make-up of myeloma cells
to improve efficacy. Moreover, a subgroup of high-risk patients who experience early disease relapse and shorter survival
also requires early identification and specific intervention. Next-generation sequencing (NGS) technologies now allow us to
accomplish some of these goals. As described here, besides improving our understanding of the disease, it is beginning to
influence our clinical decisions and therapeutic choices. In this article, we describe the current state-of-the-art role of NGS in
myeloma from identifying high-risk disease, to drug selection, and, ultimately, to guide personalized therapy.

M ultiple myeloma is a clonal plasma cell disease that

evolves as a multistep process classically characterized
by a premalignant phase (monoclonal gammopathy of un-
determined significance), a nonsymptomatic phase (smol-
dering multiple myeloma), and, eventually, a symptomatic
disease that will be subjected to remissions and relapses
over time. Multiple myeloma is biologically highly hetero-
geneous, defined by two groupshyperdiploid and non-
hyperdiploid multiple myelomaaccording to karyotype
studies, and featured by 710 molecular subgroups based on
gene expression studies.1-3
The therapeutic landscape of multiple myeloma has been
transformed by the advent of new and very efficient drugs
including second and third generations of proteasome in-
hibitors as well as immunomodulatory agents and mono-
clonal antibodies. Such therapies have transformed patient
outcomes and quality of life.4-9 However, the majority of
patients experience relapse, and, for a subgroup of patients,
the prognosis remains poor with early relapse and short
survival. Risk stratification is crucial to identify these patients
and to develop and adapt treatment regimens accordingly.
The actual recommendations to assess multiple myeloma
risk at diagnosis are based on the combination of two bi-
ologic criteria determined by the International Staging
System (ISS; beta-2 microglobulin and albumin levels) and
three cytogenetic abnormalities (17p13 deletion, t(4;14),
and t(14;16)), usually identified by fluorescence in situ hy-
bridization.10,11 These criteria allow identification of patients
who experience shorter survival at diagnosis. A classification
combining these characteristics has also been proposed.10
To date, there are no validated criteria that take into account
the chemosensitivity of the disease or status and changes at
relapse. Furthermore, these criteria do not take into ac-
count the heterogeneity existing within patients to define
high or low risk. As an example, based on cytogenetic
classification, a combination of high-risk features such as
17p13 deletion may coexist with trisomies of some of the
chromosomes, a good-risk feature. A recent study by the
Intergroupe Francophone du Myelome has now reported
how the combination of these features change the outcome.
If patients have trisomies of chromosome 3 and 5 along with
other poor risk cytogenetics, the overall outcome may im-
prove; however, the presence of chromosome 21 trisomy
may further adversely affect the outcome.12,13 Conversely,
some patients not identified by the current stratification as
high-risk patients have an unpredicted short survival. With
the availability of additional novel therapeutic options, new
markers are now more important than ever in predicting not
only patient risk but also treatment selection and outcome
to provide the best available therapy in multiple myeloma.
Over last 15 years, various high-throughput technologies
have become available. DNA-based studies include whole-
genome and whole-exome sequencing, array comparative
genomic hybridization, and high-density single nucleotide
polymorphism arrays. These techniques allow identification
of recurrent mutations and affected pathways, mutational

From the Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; VA Boston Healthcare System, Boston, MA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Nikhil C. Munshi, MD, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email: nikhil_munshi@dfci.harvard.edu.

2016 by American Society of Clinical Oncology.

e442 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


signatures, features of clonality and clonal evolution, and
copy number alterations. At the RNA level, gene expression
profiling of the malignant plasma cells has been widely
evaluated and reported as a promising method for prog-
nostication in multiple myeloma.14-16 RNA sequencing is
now progressively replacing microarray by providing wider
information related to protein-coding RNA (gene expres-
sion, splicing and isoforms expression, fusions, mutations)
and to noncoding RNA (micro-RNA, long noncoding RNA,
small nucleolar RNA, small nuclear RNA, transfer RNA, ri-
bosomal RNA, and extracellular RNA). The clinical signifi-
cance of noncoding RNA, which constitutes a large volume
of RNA, is still being investigated. These and other tech-
nological advances including chromatin studies have been
explored and validated for their ability to risk stratify and
develop personalized effective therapy. In this article, we
describe the most recent and important findings generated
by NGS (Table 1) and how it may contribute to better
identify high-risk patients and to guide therapy in multiple
myeloma.
WHOLE-GENOME AND WHOLE-EXOME
SEQUENCING
Three independent large studies (total of 733 patients) have
evaluated the mutational profile of multiple myeloma by
whole-exome and/or whole-genome sequencing.17-19 These
studies have led to the discovery of the recurrent mutational
landscape in multiple myeloma. Although no universal driver
mutation has been discovered, KRAS, NRAS, FAM46C, DIS3,
BRAF, and TP53 have been identified as the most recur-
rent mutations. NRAS, KRAS, and BRAF, which are part of the
mitogen-activated protein kinase (MAPK) pathway, and
TP53 are also recurrently mutated in other malignancies.20
Along with the MAPK pathway, genes involved in the nuclear
factor (NF)-kappa B pathway are recurrently mutated in
up to 17% of multiple myeloma cases, suggesting that
KEY POINTS
Whole-genome and whole-exome sequencing have
identified recurrent mutations in multiple myeloma
including mutations associated with poor outcome
(ATM, ATR, TP53, and CCND1) and druggable target
mutations (BRAF, MAPK pathway, FGFR3).
Specific mutations, mutational load, copy number
abnormalities, and gene expression signatures are
reliable markers for prognostication in multiple
myeloma.
NGS data can be used to accurately evaluate response to
treatment characterizing minimal residual disease.
The molecular and genomic characteristics of a patient
continue to evolve and thus may require repeated
reassessment over disease course
New markers generated by NGS can be incorporated in
the clinical practice to elaborate a personalized therapy.
NEXT-GENERATION SEQUENCING
mutations in the MAPK and NF-kappa B pathway are most
probably drivers of myelomagenesis.19
Although most of the recurrent mutations do not appear
to correlate with survival, a global increased number of
mutations correlate with a higher risk of relapse and death.17
In one study, some less-recurrent mutations involving DNA
repair and apoptotic pathways have been reported to be
associated with poor survival. Indeed TP53, ATM, ATR, and
CCND1 mutations are significantly associated with poor
outcome.19 As described below, mutational information can
be used for various aspects of patient care in myeloma.
Besides prognostication, mutational profiling is beginning
to guide therapy and aid in development of personalized
medicine. The increasing number of targeted or nontargeted
therapies that are now available make this strategy par-
ticularly attractive. Thus, in a cohort of 133 patients with
relapsing myeloma, the presence of NRAS mutations eval-
uated by targeted sequencing was significantly associated
with poor response to bortezomib.21 Conversely, IRF4
mutations, if present, are associated with better outcome
with immunomodulatory agent therapy.19 MEK inhibitors
for MAPK pathway, ATR/ATM inhibitors, and CCND1 in-
hibitors are some examples of adapted strategies that
can now be considered for patients with these specific
mutations.
Study of NGS has confirmed that, at the time of diagnosis,
patients have a number of coexistent clones. Some muta-
tions, especially those occurring early in the tumor devel-
opment, are present in all cells and are called clonal
mutations. However, some mutations occur later and are
present in subset of cells; these are known as subclonal
mutations. The clonal and subclonal content changes and
evolves over time. In multiple myeloma, no clear data are
currently available to precisely understand the impact of
clonal composition on survival.17 When two or more samples
from the same patients are studied in myeloma, four distinct
patterns of clonal evolution are observed (linear, branching,
no change, and differential clonal response).17 This ability to
monitor the clonal evolution over time is also an important
source of information that can be exploited in clinic. More-
over, the study of types of mutations have now allowed
us to identify two signatures ascribed to mechanisms of
mutational processes.22 One of the two signatures belong to
the APOBEC family and is observed more often in relapsed
samples.17 These signatures should lead to new therapeutic
strategies that may reduce the genomic instability.
Targeted sequencing strategies focusing on a relatively
small number of genes are under evaluation.23,24 This has
included studies of frequently mutated groups of genes or in
one specific instance using deep sequencing of a single gene,
for example, IgH, to study minimal residual disease.25
RNA PROFILE
Gene expression profiling using microarrays has identified
different multiple myeloma subtypes.2,3,26-28 It has allowed
improved understanding of the myeloma biology, however,
it has not yet helped to select specific therapeutic agents
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SZALAT AND MUNSHI

TABLE 1. Genomic Methodologies and Their Practical Clinical Uses

Possible Results Clinical Application Comments
DNA-Based Studies
Whole-Genome or Mutations; clonality and clonal Identify mutations for prognostication This method provides extensive useful data but
Whole-Exome evolution; chromosome and druggable targets; identify clonal requires expertise to interpret data
Sequencing rearrangements content; Clonal evolution
Targeted Sequencing Identifies specific mutations; Identify specific mutations impacting Most practical clinically applicable method; MRD
minimal residual disease evalua- outcome and with potential for evaluation is becoming an important endpoint in
tion (IgH deep sequencing) therapeutic targeting; response therapy and also for prognostication; useful for
assessment for MRD personalized therapy in future
aCGH Evaluation of copy number abnor- Correlate copy number changes to Limited utilization as same information can be
SNP Array malities; identification of ampli- prognosis; correlate specific SNPs to obtained by WGS/WES
fications and deletions; identify disease occurrence by GWAS studies
specific SNPs
Methylation Array Regulation of gene expression; May inform utilization of methylation Currently not used to inform therapy; useful in
evaluation of promoter targeting agents research; future potential for personalized
methylation therapy as more agents targeting
methylation are developed
ChIP Sequencing Histone and other epigenomic Select epigenome targeting agents Will allow selection of agents in myeloma with
DNA-binding modifications specific epigenomic changes, however,
impacting gene expression currently remains investigational; useful in
research to understand biology
RNA-Based Studies
Microarray-Based Gene expression profile; micro-RNA GEP-based signatures allow risk Widely and commercially available; ease of utili-
Studies expression profile stratification zation of the data; being phased-out by RNA
sequencing
RNA Sequencing Gene expression profile; micro- Identify high-risk disease; may inform This method provides broader information and is
RNA; long noncoding RNA; alter- selection of agents in future more reliable for clinical trials; requires
nate splicing isoforms; mutations expertise to interpret data
Abbreviations: aCGH, array comparative genomic hybridization; ChIP, chromatin immunoprecipitation; GEP, gene-expression profiling; GWAS, genome-wide association study; MRD,
minimal residual disease; SNP, single nucleotide polymorphism; WGS, whole-genome sequencing; WES, whole-exome sequencing

that could be predicted to be effective. Using gene ex-
pression profiling, various gene expression signatures have
been developed that could identify patients with high- and
low-risk disease. Three different signatures have been
described; a 70-gene signature by the Arkansas group, a
15-gene signature by the Intergroupe Francophone du
Myelome, and a 92-gene signature by the HOVON
group.14-16 All three signatures identify around 20% to 25%
of patients who are high risk with less than 2-year survival.
However, each of these signatures includes distinct genes
with almost no overlap between the signatures, making its
practical and universal use complicated. A recent study has
proposed a combined unique signature that may be used in
clinical practice in the future.29
Importantly, RNA sequencing has now replaced micro-
array to study gene expression. This method allows study of
coding and noncoding RNA, identifying not only gene ex-
pression levels, but also differential splicing and isoform
expression, mutational profiling, and gene fusions. RNA se-
quencing data from a large cohort of uniformly treated
patients have also identified that alternative splicing and
small noncoding RNA expression patterns are specific in
multiple myeloma compared with normal plasma cells. In-
terestingly, within the same level of expression of a given
gene, only some isoforms are associated with poor out-
come,30 suggesting that post-translational regulation, such
as splicing, plays an important role in multiple myeloma
biology and that any new gene expression studies will re-
quire integration of these data in the future.31,32
NONCODING RNA
RNA sequencing data also provide information on long
noncoding RNA, which can significantly affect cellular bi-
ology. Large RNA sequencing data have identified a unique
long noncoding RNA pattern in multiple myeloma and an
independent, significant correlation with poor survival.33
Similarly, micro-RNAs are noncoding RNAs that affect
transcriptome function. It has been reported as a marker
for prognosis in multiple myeloma in several studies.34-37
In addition to prognostication, micro-RNA are being in-
vestigated as therapeutic targets with potential for de-
velopment of small molecules that affect micro-RNA
function.38-42
EPIGENOMIC MODIFICATIONS
DNA methylation and histone modifications that include
acetylation and methylation lead to modification of gene
expression and function. Histone methylation has been
studied, mostly in the t(4;14) of multiple myeloma cells that
overexpress histone methyl transferase and multiple mye-
loma SET domain (MMSET, NSD2, or WHSC1)regulating
gene expression43-45 and influence multiple myeloma cell
behavior.46,47 Although the impact of epigenomic changes

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 NEXT-GENERATION SEQUENCING

on outcome has not been studied in detail, it has already
provided various therapeutic targets including inhibitors of
histone deacetylase (HDACs) or enhancer of zeste homolog 2
(EZH2) inhibitors.48 Several studies have also demonstrated
that DNA methylation is differentially regulated in multi-
ple myeloma cells compared with normal plasma cells,
with a pattern of global hypomethylation and focal
hypermethylation.49-51 However, therapies targeting DNA
methylation have not been effective in multiple myeloma.
CLINICAL APPLICATION OF GENOMIC DATA
Prognostic Marker
Next-generation sequencing data enlighten the biology of
myeloma and provide information on disease behavior to
inform prognosis and, particularly, to define low- and
high-risk disease. To date, several validated markers can be
integrated and combined with ISS and cytogenetic features
to accurately identify low- and high-risk multiple myeloma.
Array comparative genomic hybridization and high-density
single nucleotide polymorphism arrays have been partic-
ularly useful to study large cohorts of patients. Major
findings have been amp(1q23.3), amp(5q31.3), and
del(12p13.31), which carry poor prognosis. Now, the newer
gene and micro-RNA expression signatures, and specific
mutations and clonal shifts, constitute the basis of new
markers of prognosis. An important challenge is to
generate a unique tool that would combine all of these
validated data. Ideally, such a tool would use gene and
micro-RNA expression signatures, copy number alter-
ations, chromosome rearrangements, and relevant muta-
tions for their prognostic value and possibly to be
potentially targeted by specific therapies. Additional data
concerning noncoding RNA, the roles of clonality and clonal
evolution, the roles of specific mutations, and epigenomic
and post-translational regulation are also under evaluation
and should provide even more reliable markers in the near
future (Table 2).
The feasibility of using a single or limited number of
techniques to get the most from this information is under
development. As an example, DNA and RNA sequencing can
provide most of the information.52 Although currently used
in a limited number of institutions for research purposes
only, routine DNA sequencingand in some cases, targeted
sequencingis performed along with either array-based
gene expression profiling or RNA sequencing. As an in-
tegrated approach of analysis is developed and validated, a
more robust prognostic model will be available for clinical
application. Moreover, the NGS data have revealed that a
substantial number of new mutations evolve at the time of
relapse and suggest the need to re-examine genomic profiles
on more than one occasion during the course of the disease.
Inform Therapy
The ability to characterize the prognosis of patients with
multiple myeloma by NGS can be used to rationally design a
personalized therapeutic plan at diagnosis and at relapse.
First, risk stratification allows for identification of high-risk
patients who may benefit from more intense therapeutic
interventions. Currently, the main focus of intensification for
these patients is in consolidation and maintenance thera-
pies. We suggest that patients identified as high risk at di-
agnosis should be treated with the most efficient and
available therapy as an induction regimen, including a
combination of immunomodulatory agents, proteasome
inhibitors, dexamethasone, and possibly a monoclonal an-
tibody. The impact of autotransplant among high-risk pa-
tients may not be of the same extent as among patients
with low-risk disease; however, it remains an important con-
solidation therapy. This phase must be followed for high-risk
patients by consolidation with a more intense regimen and a
two-drug maintenance regimen.53
Attempts at identifying effective therapy using gene ex-
pression profiling have not been very successful. 54 The

TABLE 2. New Markers Generated by Next-Generation Sequencing Under Evaluation to Predict High-Risk Multiple
Myeloma
Marker Method Potential Impact
Mutational Signature WES/WGS Distinct mutational processes may contribute differentially to tumor progression
May provide future therapeutic targets
Clonal and Subclonal WES/WGS Clonal content may have prognostic significance
Evolution
May predict treatment sensitivity
May require special consideration to judge response to therapy
Lnc-RNA Signature RNA-seq Lnc-RNA are involved in MM biology and may provide potential therapeutic targets
Lnc-RNA signature may have prognostic significance
RNA Splicing RNA-seq Differentially expressed isoforms constitute a marker of prognosis
Spliced isoforms have differential biologic activity making them attractive therapeutic targets with increased
specificity
Epigenomic Profile Microarray-ChIP Highly regulated region may correlate with patient outcome
Some epigenomic modifications have already been targeted in myeloma (panobinostat, HDAC inhibitor)
Abbreviations: ChIP, chromatin immunoprecipitation; lnc-RNA, long noncoding RNA; MM, multiple myeloma; RNA-seq, RNA sequencing; WGS, whole-genome sequencing; WES,
whole-exome sequencing.

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SZALAT AND MUNSHI

results suggest that a simple gene expression level is unable
to identify effective agents that can achieve complete
remission. The use of DNA sequencing seems particularly
promising to identify specific mutations that correlate
with a clinical response to therapy or those that are
druggable targets. A strategy that takes into account
mutations can be integrated into the patient assessment
plan. For example, the presence of NRAS mutations at
relapse is associated with low response to bortezomib,21
whereas the presence of IRF4 mutations confers higher
sensitivity to immunomodulatory agents.18 Currently, no
single agent that specifically targets a mutation is approved
for routine clinical use in multiple myeloma. However,
smaller studies have evaluated the efficacy of such targeted
agents. The presence of an activating BRAF mutation can be
specifically targeted using a BRAF inhibitor, and efficacy can
also be monitored using assays devised to detect the
presence of BRAF-mutated myeloma cells.55 In a single case
report, vemurafenib, which exclusively inhibits the V600E-
mutated BRAF, was effective for a patient with the BRAF
V600E mutation.56 Similarly, in a RAS-mutated, MAPK
pathwayactivated, relapsed, refractory myeloma, the
MEK inhibitor trametinib has been shown to achieve deep
response. A larger study of trametinib has also shown very
encouraging efficacy.57 Numbers of such druggable mu-
tations are being recognized, each in a small subset of
patients, with the potential to add a targeted agent for
these patients. The large NCI MATCH trial, which is eval-
uating targeted strategies for a number of malignancies, is
expanding to include myeloma. In this distinctive trial
concept, patients tumor cells are initially sequenced to
identify unique mutations and for those druggable muta-
tions, a specific inhibitor will be used to evaluate efficacy
across various malignancies. NCI MATCH and other similar
studies will usher in an era where therapy will be tailored to
molecular and genomic characteristics rather than just
phenotypic or pathologic diagnosis.
Mutations in SF3B1, FGFR3, ATM/ATR, IDH1/2, and CCND1
as well as RAS/RAF, NF-kappa B, and mTOR pathwayrelated
genes have been reported in myeloma. These mutations can
be targeted by appropriate inhibitors. To identify these
mutations, a targeted sequencing approach is being pur-
sued.52,58 The study of the epigenome has also provided
useful information to select a specific therapy that would
target DNA methylation or histone methylation or acety-
lation (MMSET expression abnormality, HDAC expression
changes). The development of new histone deacetylase
inhibitors and new histone methylase inhibitors is particu-
larly promising.9 However, some mutations may not have
any biologic impact because of low or no expression of the
mutated gene. We have observed that only a little over a
quarter of mutated genes are expressed, and the global
expression of mutated genes is lower than the expression of
nonmutated genes, with approximately only 25% expres-
sion. This low level of expression may be due to the level of
expression of the nonmutated allele or by the presence of
only a subclonal population featured by the mutation. Thus,
theoretically, the presence of mutation does not necessarily
mean that it has an important role and that we should
consider it as therapeutic target. This precision is important
for the interpretation of data in ongoing clinical studies.59
Mutational profiling ideally should be coupled with RNA
sequencing studies.
Important obstacles to these therapies must be consid-
ered as we develop personalized approaches (Table 3). The
major limitations may include a dynamic disease process
with a constantly evolving genome, the coexistence of
subclonal populations with only a subset of subclones that
harbor a mutation, and lack of expressed mutant alleles
making the presence of a mutation not a clinically important
target and rendering a specific targeted treatment in-
efficient. Moreover, other downstream activating mutations
in the same pathway may coexist and would make a targeted
therapy ineffective as well. In one study, a number of pa-
tients had coexistent KRAS and BRAF mutations.17 For these
patients, BRAF-directed therapy will not be effective. De-
spite these potential limitations, NGS is a promising tool
for targeted therapy or to identify a specific drug that
could be combined with current therapies including im-
munomodulatory agents, proteasome inhibitors, and mono-
clonal antibodies.
Response Assessment
Deep IgH sequencing has been used to evaluate minimal
residual disease in multiple myeloma. Next-generation se-
quencing has been recently reported to be especially useful

TABLE 3. Obstacles to Successful Therapeutic Application of Next-Generation Sequencing Data

Genomic Change Clinical Impact Possible Interventions to Overcome Obstacles

Subclonal Nature of Mutation
Lack or Limited Expression of the
Mutant Allele
Presence of Mutation Downstream
of Targeted Mutation
Evolution of New Driver Mutation
Limited clinical response despite effective
targeted therapy
Minimal to no effect of targeted agent
Transient or no response
Transient or no response
Evaluate subclonal response
Target multiple subclones, combination therapy
Must evaluate both mutation and expression
Select alternate target/s
Prefer targeting downstream mutation from the beginning
Resequence genome if response plateau or progression
Resequence genome if response plateau or progression
Direct therapy at new target or use broader multitarget agent

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to detect one cell among 1,000,000 in bone marrow, and the
absence of myeloma with such precision predicts superior
survival.25 This aspect of minimal residual disease is dis-
cussed in accompanying article. In regards to the evaluation
of agents targeting specific mutations, it is necessary to
consider clonal content; what proportion of myeloma cells
carry such a mutation? It is well described that some of the
driver mutations are subclonal and only present in small
number of cells. As we use specific inhibitors, this therapy
will potentially only impact the proportion of cells that carry
such mutations. Thus, the ability to detect a response at the
clonal level will be an important response criterion in the
future. For example, if 30% of cells contain a BRAF mutation
and BRAF-directed therapy is able to eliminate all of these
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suppressor genes in multiple myeloma. Blood. Epub 2010 Oct 20.
39. Roccaro AM, Sacco A, Thompson B, et al. MicroRNAs 15a and 16
regulate tumor proliferation in multiple myeloma. Blood. 2009;113:
6669-6680.
40. Fulciniti M, Amodio N, Bandi RL, et al. miR-23b/SP1/c-myc forms a feed-
forward loop supporting multiple myeloma cell growth. Blood Cancer J.
2016;6:e380.
41. Min DJ, Ezponda T, Kim MK, et al. MMSET stimulates myeloma cell
growth through microRNA-mediated modulation of c-MYC. Leukemia.
2013;27:686-694.
42. Rio-Machin A, Ferreira BI, Henry T, et al. Downregulation of specific
miRNAs in hyperdiploid multiple myeloma mimics the oncogenic effect
of IgH translocations occurring in the non-hyperdiploid subtype. Leu-
kemia. 2013;27:925-931.
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43. Pei H, Zhang L, Luo K, et al. MMSET regulates histone H4K20 methylation
and 53BP1 accumulation at DNA damage sites. Nature. 2011;470:
124-128.
44. Martinez-Garcia E, Popovic R, Min DJ, et al. The MMSET histone methyl
transferase switches global histone methylation and alters gene ex-
pression in t(4;14) multiple myeloma cells. Blood. 2011;117:211-220.
45. Kuo AJ, Cheung P, Chen K, et al. NSD2 links dimethylation of histone H3
at lysine 36 to oncogenic programming. Mol Cell. 2011;44:609-620.
46. Popovic R, Martinez-Garcia E, Giannopoulou EG, et al. Histone methyl-
transferase MMSET/NSD2 alters EZH2 binding and reprograms the
myeloma epigenome through global and focal changes in H3K36 and
H3K27 methylation. PLoS Genet. 2014;10:e1004566.
47. Marango J, Shimoyama M, Nishio H, et al. The MMSET protein is a
histone methyltransferase with characteristics of a transcriptional
corepressor. Blood. 2008;111:3145-3154.
48. Afifi S, Michael A, Azimi M, et al. Role of histone deacetylase inhibitors
in relapsed refractory multiple myeloma: a focus on vorinostat and
panobinostat. Pharmacotherapy. 2015;35:1173-1188.
49. Kaiser MF, Johnson DC, Wu P, et al. Global methylation analysis
identifies prognostically important epigenetically inactivated tumor
suppressor genes in multiple myeloma. Blood. 2013;122:219-226.
50. Walker BA, Wardell CP, Chiecchio L, et al. Aberrant global methylation
patterns affect the molecular pathogenesis and prognosis of multiple
myeloma. Blood. 2011;117:553-562.
51. Agirre X, Castellano G, Pascual M, et al. Whole-epigenome analysis in
multiple myeloma reveals DNA hypermethylation of B cell-specific
enhancers. Genome Res. 2015;25:478-487.
52. Bolli N, Avet-Loiseau H, Gimondi S, et al. Genomic landscape and its
prognostic implications in multiple myeloma using a targeted se-
quencing approach. Blood. 2015;126:370.
53. Lonial S, Boise LH, Kaufman J. How I treat high-risk myeloma. Blood.
2015;126:1536-1543.
54. Amin SB, Yip WK, Minvielle S, et al. Gene expression profile alone is
inadequate in predicting complete response in multiple myeloma.
Leukemia. 2014;28:2229-2234.
55. Raab MS, Lehners N, Xu J, et al. Spatially divergent clonal evolution in
multiple myeloma: overcoming resistance to BRAF inhibition. Blood.
Epub 2016 Feb 16.
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mutation in multiple myeloma. Cancer Discov. 2013;3:862-869.
57. Heuck C, Jethava Y, Khan RZ, et al. Targeted MEK inhibition in patients
with previously treated multiple myeloma. Blood. 2014;124:4775.
58. Heuck C, Chavan SS, Stein CK, et al. Comprehensive genomic profiling of
multiple myeloma in the course of clinical care identifies targetable and
prognostically significant genomic alterations. Blood. 2015;126:369.
59. Rashid NU, Sperling AS, Bolli N, et al. Differential and limited expression
of mutant alleles in multiple myeloma. Blood. 2014;124:3110-3117.
LUNG CANCER

Immunotherapy: Beyond
AntiPD-1 and AntiPD-L1
Therapies

CHAIR
Scott J. Antonia, MD, PhD
Moffitt Cancer Center
Tampa, FL

SPEAKERS
Edmund Moon, MD
Hospital of the University of Pennsylvania
Philadelphia, PA

Johan F. Vansteenkiste, MD, PhD

University Hospital KU Leuven
Leuven, Belgium
ANTONIA, VANSTEENKISTE, AND MOON

Immunotherapy: Beyond AntiPD-1 and AntiPD-L1

Therapies
Scott J. Antonia, MD, PhD, Johan F. Vansteenkiste, MD, PhD, and Edmund Moon, MD

OVERVIEW

Advanced-stage nonsmall cell lung cancer (NSCLC) and small cell lung cancer are cancers in which chemotherapy produces a
survival benefit, although it is small. We now know that antiPD-1/PD-L1 has substantial clinical activity in both of these
diseases, with an overall response rate (ORR) of 15%20%. These responses are frequently rapid and durable, increase
median overall survival (OS) compared with chemotherapy, and produce long-term survivors. Despite these very significant
results, many patients do not benefit from antiPD-1/PD-L1. This is because of the potential for malignancies to co-opt
myriad immunosuppressive mechanisms other than aberrant expression of PD-L1. Conceptually, these can be divided into
three categories. First, for some patients there is likely a failure to generate sufficient functional tumor antigen-specific
T cells. Second, for others, tumor antigenspecific T cells may be generated but fail to enter into the tumor parenchyma.
Finally, there are a large number of immunosuppressive mechanisms that have the potential to be operational within the
tumor microenvironment: surface membrane immune checkpoint proteins PD-1, CTLA-4, LAG3, TIM3, BTLA, and adenosine
A2AR; soluble factors and metabolic alterations interleukin (IL)-10, transforming growth factor (TGF)-b, adenosine, IDO, and
arginase; and inhibitory cells, cancer-associated fibroblasts (CAFs), regulatory T cells, myeloid-derived suppressor cells
(MDSCs), and tumor-associated macrophages. In this article, we discuss three strategies to generate more tumor-reactive
T cells for patients: antiCTLA-4, therapeutic tumor vaccination, and adoptive cellular therapy, with T cells redirected to
tumor antigens using T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene modification. We also review some of the
various strategies in development to thwart tumor microenvironment immunosuppressive mechanisms. Strategies to drive
more T cells into tumors remain a significant challenge.

STRATEGIES TO INCREASE THE NUMBER OF
TUMOR-REACTIVE T CELLS
AntiCTLA-4
CTLA-4 is an immune checkpoint protein. Unlike PD-1,
CTLA-4 for patients with cancer suppresses T cells within
the lymphoid compartment rather than within the tumor
microenvironment by limiting T-cell proliferation, and thus
preventing expansion of antitumor T-cell responses. Evidence
for this comes from a study demonstrating that among pa-
tients with melanoma who were treated with ipilimumab,
there was the appearance of tumor antigenspecific T cells
with specificities in the blood of clinically responsive patients
not present in pretreatment and not appearing in the blood
of clinically nonresponsive patients.1
the CTLA-4expanded T cells are prevented from being
functionally inhibited when they enter into the tumor mi-
croenvironment. We recently reported the results of two
separate trials with these monoclonal antibodies, one with
nivolumab (antiPD-1) and ipilimumab (antiCTLA-4) and the
other with MEDI4736 (antiPD-L1) and tremelimumab
(antiCTLA-4). The initial doses and schedules of the nivolumab/
ipilimumab combination were toxic and produced a response
rate of 15%; however, more tolerable doses have now been
discovered.4 The durvalumab/tremelimumab combination
was associated with manageable toxicity and produced re-
sponses for patients who were PD-L1 biomarkernegative to a
similar degree as antiPD-1 monotherapy for patients who
were PD-L1 positive.5

AntiPD-1/PD-L1 in combination with antiCTLA-4. Anti Lung Cancer Vaccines

CTLA-4 (ipilimumab) has not been tested as a single agent Melanoma-associated antigen 3 cancer vaccination and
for patients with NSCLC, but has some activity in combination MAGRIT. We start this section with the MAGRIT trial, as this
with chemotherapy.2,3 In combination with antiPD-1/PD-L1, is the largest vaccination study, in a population that has long

From the Department of Thoracic Oncology Moffitt Cancer Center, Tampa, FL; Respiratory Oncology Unit, University Hospital KU Leuven, Leuven, Belgium; Hospital of the University of
Pennsylvania, Philadelphia, PA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Scott J. Antonia, MD, PhD, Moffitt Cancer Center, 12902 Magnolia Dr., MRC 3-East, Tampa, FL 33612; email: scott.antonia@moffitt.org.

2016 by American Society of Clinical Oncology.

e450 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


been considered to be optimal candidates: patients with
minimal residual disease after definitive therapy. This is also
the largest therapeutic study overall in NSCLC, and the
program nicely shows how vaccines were developed in
NSCLC (Table 1).
The melanoma-associated antigen 3 (MAGE-A3) protein is
totally tumor-specific and present in approximately 35% of
early-stage NSCLC.6 In a mechanism-of-action study, it was
shown that MAGE-3 protein with adjuvant AS02B successfully
induced specific antibodies, CD8+, and CD4+ T cells (whereas
MAGE-3 protein alone did not).7 In the hypothesis-generating
phase II, double-blind, randomized, placebo-controlled trial,
182 patients with completely resected MAGE-A3positive stage
IB-II NSCLC received the MAGE-A3 cancer vaccine (recombinant
MAGE-A3 protein combined with an immunostimulant) or
placebo.8 No significant toxicity was observed, and a
potential predictive biomarker was suggested.9
The ensuing large phase III study, MAGRIT (MAGE-A3 as
Adjuvant NonSmall Cell Lung Cancer Immunotherapy) was
reported at the 2014 European Society for Medical Oncology
Congress (Table 2). Patients who were MAGE-A3 positive with
completely resected stage IB-II-IIIA NSCLC and adjuvant che-
motherapy, as clinically indicated, were randomly assigned 2:1
to receive MAGE-A3 vaccine or placebo. Almost 14,000 sur-
gical patients were screened; 4,210 patients were MAGE-A3
positive (33%) and 2,312 patients were randomly assigned.
The median disease-free survival (primary endpoint) was slightly
better with the MAGE-A3 cancer vaccine (60.5 vs. 57.9 months),
but the difference was unfortunately not significant (hazard
ratio [HR] 1.02; 95% CI, 0.891.18; p = .74). No subgroups with
potential benefit could be identified. The safety of this approach
as adjuvant therapy in NSCLC was confirmed, as there were
higher rates of mild injection-site reactions and flu-like symp-
toms than with placebo, but grade 3 and 4 treatment-related
symptoms and treatment-related signigicant adverse events
were infrequent. On the basis of this disappointing result,
further development of the MAGE-A3 vaccine in NSCLC has
been abandoned.
KEY POINTS
AntiPD-1/PD-L1 have clinical activity in lung cancer.
The majority of patients treated with single agent
antiPD-1/PD-L1 do not benefit.
Combination therapy with multiple immunotherapeutics
will be necessary to improve clinical efficacy.
Strategies are being developed to increase the number
of tumor antigen reactive T cells, to drive more of these
into the tumor parenchyma, and to block a variety of
immunosuppressive mechanisms in the tumor
microenvironment.
Given the heterogeneity regarding the specific ways that
individual tumors evade immune-mediated rejection,
relevant biomarkers will be necessary to guide therapy.
BEYOND ANTIPD-1 AND ANTIPD-L1 THERAPIES
TABLE 1. Steps in the Clinical Development of Cancer
Vaccines
Phase Objective Questions
Preclinical Expression Broadly expressed?
Conserved in metastatic cells?
Specificity Tumor specific or not?
Mechanism of Immunogenic Effective humoral and cellular
Action response?
Phase I-II Clinical effects Activity?
Tolerability?
Predictive biomarker?
Phase III Patient benefit Outcome (survival)?
TolerabilityQuality of life effects?
Predictive biomarker confirmed?
Other recent phase III trials. The mucin MUC1 expression is
altered, mainly by aberrant glycosylation, in many cancer
types, including NSCLC. The tandem repeat MUC1-peptide
in a liposomal formulation is the BLP-25, or tecemotide,
vaccine. START (Stimulating Targeted Antigenic Responses
to NSCLC Trial) was a phase III, double-blind, random-
ized, placebo-controlled trial comparing maintenance
therapy with tecemotide (829 patients) or placebo (410
patients) for patients with unresectable stage III NSCLC
who did not progress after sequential or concurrent
chemoradiotherapy.10 The primary endpointoverall
survivalwas not significantly different between the vac-
cine and placebo group (25.6 vs. 22.3 months). However,
preplanned subgroup analysis showed that the patients
treated with concurrent chemoradiotherapy (829 patients)
had a 10.2-month improvement in OS (30.8 vs. 20.6 months;
adjusted HR 0.78; p = .016). The consequential trial was
START 2, a similar large randomized, placebo-controlled trial
for patients who completed concurrent chemoradiotherapy
for unresectable stage III NSCLC (NCT02049151). However,
this trial and further development of tecemotide was
abandoned after disappointing results of a smaller trial
among Japanese patients with stage III NSCLC and concur-
rent chemoradiotherapy.
TG4010 is a vaccine based on a recombinant viral vector
(attenuated strain of vaccinia virus) expressing both the
tumor-associated antigen MUC1 and IL-2. This vaccine is
explored in the phase IIB/III TIME trial (NCT01383148). This
double-blind, placebo-controlled trial evaluates standard
first-line chemotherapy with or without TG4010 for patients
with MUC1-positive stage IV NSCLC. In the phase IIB part,
the predictive value of activated natural killer cells (triple-
positive activated lymphocytes [TrPAL], CD16+ CD56+ CD69+)
was evaluated on the basis of a progression-free survival (PFS)
endpoint.11 If patients with TrPAL lower than normal values
had a Bayesian probability of greater than 95% so that the
HR and PFS were less than 1, and if those with TrPAL values
greater than normal had a probability of greater than 80%
so that the HR for PFS was greater than 1, then the TrPAL
biomarker would be considered validated. The former was
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ANTONIA, VANSTEENKISTE, AND MOON

TABLE 2. Recent Randomized Trials of Cancer Vaccines

No.
Compound Trial Design Patients Study Population Treatment Arms Primary Endpoint Other Endpoints
MAGE-A3 Phase III RCT 2,270 Completely resected MAGE-A3 vaccine vs. Disease-free Prospective validation
(MAGRIT)5 MAGE-A3positive placebo survival: HR 1.02; 95% of predictive gene
stage IB-IIIA NSCLC CI, 0.891.18; p = .738 signature not
feasible
Tecemotide Phase III RCT 1,513 Stage III NSCLC after LBLP-25 vaccine vs. OS: HR 0.88; 95% CI, Subgroup analysis;
(START)6 chemoradiation placebo 0.751.03; p = .123 concurrent
therapy chemoradiation:
OS: HR 0.78; 95% CI,
0.640.95; p = .016
TG4010 Phase II B RCT 222 Untreated patients with Chemotherapy with TrPAL biomarker PFS: HR 0.74; 95% CI,
(TIME; stage IV MUC1- TG4010 vaccine vs. validation: 0.550.98
NCT01383148) positive NSCLC chemotherapy achieved in part
plus placebo
Phase III RCT 800 Untreated patients with Chemotherapy plus OS; phase III part Safety, response rate,
(TIME; stage IV nonsquamous TG4010 vaccine vs. ongoing duration of response
NCT01383148) MUC1-positive NSCLC chemotherapy
plus placebo
Belagen-pumatucel-L Phase III RCT 700 Advanced NSCLC in Belagen pumatucel-L OS: HR 0.94; 95% CI, Subgroup analysis;
(STOP)8 disease control after vs. placebo 0.731.20; p = .594 OS for patients
standard therapy with radiotherapy:
HR 0.61; 95% CI,
0.380.96; p = .032
Abbreviations: MAGE-A3, melanoma-associated antigen 3; HR, hazard ratio; NSCLC, nonsmall cell lung cancer; OS, overall survival; LBLP, stimuvax; RCT, randomized, placebo-
controlled trial; PFS, progression-free survival.

the case; the latter was not. Overall, median PFS was
5.9 months in the TG4010 group and 5.1 months in the
placebo group (HR 0.74; 95% CI, 0.550.98; p = .019). On
the basis of these findings, the phase III part of the trial
continues.
Belagenpumatucel-L is a vaccine based on a mixture of
allogeneic tumor cells with TGF-b2 antisense blockade as
adjuvant. It was studied in the phase III STOP (Survival:
Tumor-free, Overall, and Progression-free) trial for patients
with stage III-IV NSCLC achieving a response or dis-
ease control after first-line therapy.12 Median OS was
20.3 months with belagenpumatucel-L versus 17.8 months
with placebo (HR 0.94; p = .594). In the (small) subgroup of
patients treated with previous radiotherapy, the OS HR was
0.61 (p = .032).
Why were early positive findings not translated into pa-
tients benefits in phase III? Looking at MAGRIT, it was most
disappointing that the very well tolerated MAGE-A3 vaccine
could not enrich our adjuvant therapies in NSCLC, espe-
cially as no real progress in this setting has been seen for
more than a decade. Indeed, the IALT trial established
cisplatin-based chemotherapy as a standard for resected
stage II and IIIA tumors13 and was initially presented at the
2003 American Society of Clinical Oncology (ASCO) Annual
Meeting. Since then, we have witnessed failures of gefitinib,14
erlotinib,15 bevacizumab, and pharmacogenetically tailored
chemotherapy.16-18
MAGRIT was started on the basis of previously docu-
mented clear responses to the MAGE-A3 cancer vaccine in
metastatic melanoma,19 a phase II randomized study with an
HR for OS similar to modern adjuvant chemotherapy with an
agent with almost no grade 3/4 toxicity,8 and a predictive
gene signature from metastatic melanoma reproducible in
early-stage NSCLC.9 Differences in population (stage IB-II-IIIA
vs. IB-II), diagnostic testing (MAGE-A3 reverse transcriptase
polymerase chain reaction on formalin-fixed, paraffin-
embedded vs. fresh, frozen tissue), and drug composition
(adjuvants AS15 vs. AS02B) could be ruled out as causes of
the negative MAGRIT results in comparison with the initial
phase II randomized trial. Overinterpretation of the existing
data, as is the case for many compounds, may have been in
place: factors for the preclinical data were that most of the
immune responses were antibodies or CD4+ T cells, whereas
it was more difficult to demonstrate CD8+ T cells. For the
phase II randomized data, the sample size was limited, with
possible hidden imbalances across treatment arms. Another
factor was raising the bar in outcome compared with his-
torical data in the placebo arm, thus making it more difficult
to improve. Indeed, in the adjuvant landmark study IALT,13
the 5-year OS was 40.4% with surgery alone and 44.5% with
surgery followed by adjuvant chemotherapy. In MAGRIT, the
5-year OS in the placebo arm was 58.7%.
Where should we go with cancer vaccination in
NSCLC? Several recently reported phase III trials with vac-
cination approaches in NSCLC did not reach their primary
endpoint (MAGRIT, START, STOP). This essentially means
that immunologic response vaccines are not translated into
clinical benefits. Immunologic responses are measured in
the circulatory compartment, typically with antibody re-
sponses and less easily with specific lymphocyte responses,
and these may not be translated sufficiently in the peri-
tumoral stromal immune system because of the strong

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immunosuppressive environment on NSCLC. Indeed, find-
ings from recent years gave deeper understanding of the
numerous mechanisms of immune suppression induced
by cancer cells: inhibitory cells such as regulatory T-lymphocytes
and MDSCs, inhibitory molecules such as TGF-b and IDO,
and immune checkpointinhibiting pathways such as those
related to CTLA-4 and the PD-1 receptor and its ligand
(PD-L1). 20
Consequently, combination therapies of agents that re-
verse this immunosuppressive environment of NSCLC (such
as the monoclonal antibodies that inhibit the PD-1/PD-L1
pathway) with vaccination may be the best way forward.
Both complement each other in the loop of immune response,
vaccination with delivery and enhanced presentation of
antigens, and checkpoint inhibitors with alleviation of the
immune-suppressive tumor microenvironment. It would be
particularly interesting to deliver neo-antigens of neo-
epitopes, as the latter have recently been correlated with
the response to antiPD-1/PD-L1 therapies.21 Moreover,
this mutational load of neo-antigens and neo-epitopes is
particularly high in NSCLC found in smokers, especially
squamous cell lung cancer. Such mutational epitopes are
immunogenic when presented by major histocompatibility
complex (MHC)receptors and have recently been associated
with increased patient survival.22
Engineering T Cells for Lung Cancer and Thoracic
Malignancies
Efforts to redirect T cells to tumor. The more traditional
strategy of adoptive T-cell transfer involved polyclonal
expansion of tumor-infiltrating lymphocytes (TILs) from
tumor resection specimens and reinfusion of expanded
populations of naturally occurring tumor-reactive TILs back
into the patient. Although this strategy induced responses
for patients with metastatic melanoma,23-25 identification
and ex vivo culturing of TILs from most other solid tumor
types is difficult. Over the last 2 decades, this challenge has
been overcome by genetically modifying otherwise tumor-
nonreactive T cells to bear tumor reactivity. This involves
taking bulk CD8+ and CD4+ T cells via leukapharesis,
expanding them via coculture with artificial antigen-
presenting cells or microbeads coated with anti-CD3/CD28
protein, and transducing them to express either a TCR clone
or a CAR, conferring specificity to a tumor-associated anti-
gen (TAA). Transduction can be performed using viral sys-
tems (e.g., retrovirus and lentivirus) 26,27 and nonviral
systems (e.g., Sleeping Beauty transposon28 and mRNA
electroporation29).
T-cell receptor engineering involves the modification of
T cells to express high-affinity alpha/beta TCRs bearing
known specificity and avidity for TAAs (Fig. 1A).30 One major
advantage of TCR engineering is the ability to confer T-cell
reactivity against both surface and intracellular antigens.
One potential drawback is the potential generation of ad-
ditional, unintended receptor specificities via rearranged
pairing of the a and b chains with those of the endogenous
BEYOND ANTIPD-1 AND ANTIPD-L1 THERAPIES
TCRs. This could translate into increased toxicity. Another
limitation is that each TCR is specific for a given peptide-MHC
complex, thus making it applicable to patients who shared
both MHC alleles and TAAs.
Chimeric antigen receptor engineering artificially com-
bines a single-chain Fv fragment fused from the variable light
and heavy chains of a TAA-specific antibody with the CD3z-
signaling chain of the TCR.31 This so-called first-generation
CAR, which confers antigen-specific tumor lytic capability,
can be further modified to express one or more additional
costimulatory domains to increase T-cell persistence and
induce proliferation upon antigen-binding. CD28, 41BB,
and ICOS are a few examples of such domains that can be
included in these second- and third-generation CARs
(Fig. 1B).32 The advantages of CARs include highly specific
and avid recognition of the targeted antigen and MHC in-
dependent signaling initiated by antigen binding. However,
in general, CARs are only able to recognize antigens
expressed or presented on the cell membrane of target cells,
limiting the number of candidate TAAs that can be targeted
using CAR technology.
Tumor antigens as targets for genetically redirected
T cells. Both TCR and CAR engineering strategies to redirect
adoptively transferred T cells require choosing an optimal
TAA for targeting. Ideally, the targeted TAA is highly
expressed by tumor cells but not by vital normal tissues (or at
least expressed at low levels by normal tissues). Otherwise,
adoptively transferred T cells would be able to induce what
has been coined off-tumor, on-target toxicity. Tumor-
associated antigens that have been targeted via engineered
T cells in lung cancer and/or mesothelioma include (1)
NYESO1 (NCT01697527, NCT01967823), a cancer testis an-
tigen found in up to 30% of lung cancers;33 (2) VEGF receptor 2
(NCT01218867), expressed in the majority of lung cancer
samples;34 (3) MAGE-A3 (NCT02111850), found in up to
40% of lung cancers;6,35 (4) mesothelin (NCT02159716,
NCT01583686, NCT02414269),36,37 a molecule involved in
cell-cell adhesion but otherwise unclear in function,
expressed in virtually all mesothelioma samples of the epi-
thelioid subtype and up to 80% of lung cancer samples;38,39
and (5) Wilm tumor protein 1 (NCT02408016), Wilm tumor
suppressor gene 1, which encodes a transcription factor
essential in the normal development of the urogenital
system. Refer to the publications by Cheever et al40 and
Hinrichs and Restifo 41 for a more comprehensive review
of TAA targets for T-cell immunotherapy in thoracic
malignancies.
Challenges to genetically redirecting T cells to thoracic
malignancies. Engineered T-cell therapy has demonstrated
dramatic and durable responses in patients with melanoma
(TCR engineering)42 and leukemia.43 However, applying this
immunotherapeutic strategy to many other solid tumors,
such as lung cancer and mesothelioma,44,45 has been met
with many challenges, limiting the objective responses
among patients. There have been no published reports of
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ANTONIA, VANSTEENKISTE, AND MOON

FIGURE 1. Chimeric Antigen Receptors

Abbreviation: TAA, tumor-associated antigen.

clinical responses to TCR-engineered T cells among patients proportion of patients.36 The challenges inherent to solid
with lung cancer, and the limited data on the clinical ex- tumors have been described repeatedly for many years in
perience of CAR-engineered T cells for patients with me- naturally occurring TILs.46-48 T-cell receptorengineered
sothelioma describe partial responses in only a small T cells,49 and even CAR-engineered T cells, despite their

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built-in costimulatory signaling motifs,50 succumb to similar
changes. These challenges include, but are not limited to,
heterogeneous TAA expression and TAA shedding, short
T-cell survival/persistence, suboptimal T-cell trafficking, the
barrier of tumor-associated stroma, the presence of sup-
pressive immune cells, upregulation of inhibitory check-
points, the expression of regulatory genes, lack of oxygen
and cellular nutrients, and immunosuppressive soluble
factors. Moon et al50,51 recently demonstrated that both
TCR- and CAR-engineered T cells undergo profound sup-
pression of their tumor-lytic and cytokine secretion capa-
bilities, leading to an inability to cure human lung cancer
and human mesothelioma xenograft tumors. When these
TCR/CAR TILs were isolated and allowed to rest away from
the tumor microenvironment, they recovered a significant
degree of their antitumor effector function. Preclinical
studies such as these are being conducted in parallel with the
early-phase trials of adoptive T-cell therapy for thoracic
malignancies, testing ways to overcome the much antici-
pated challenges in the solid tumor microenvironment. We
describe a few salient examples.
The challenge of T-cell survival/persistence. There is a
positive correlation between survival/persistence of geneti-
cally engineered T cells and clinical response.52 There are
a few potential strategies of optimizing T-cell survival/
persistence in the context of solid tumors.
Host preparative conditioning regimens (e.g., fludarabine
and/or cyclophosphamide)53,54 can be administered prior to
adoptive transfer of genetically engineered T cells to reduce
the number of circulating T cells (i.e., lymphodepletion). This
will promote the in vivo expansion of transferred T cells by
limiting the competition for cytokines necessary for T-cell
survival/persistence (e.g., IL-7, IL-15).55 The majority of
ongoing trials in thoracic malignancies (see above) have
conditioning regimens incorporated in their protocols.
Another strategy is further genetically modifying the
TCR/CAR-bearing T cells to secrete the cytokines necessary
for their survival and persistence.56 In some cases, the same
cytokines can promote the secondary influx of other host
immune cells, leading to additional antitumor/stroma ef-
fects.57 Optimizing the combination of costimulatory do-
mains in CARs will also augment the cytokine secretion
profiles of transferred T cells, and the costimulatory motifs
being tested in CARs are constantly evolving.58,59
The challenge of tumor stroma. Stroma in both lung cancer
and mesothelioma consists of a multicellular matrix at the
invasion front of tumor and has a very crucial role in tumor
progression.45,60 Mesothelioma tumors have especially
pronounced stromal components compared with other solid
tumors.61 There is a complex network of cross-talk between
stromal cells and tumor cells via both cell-cell interactions
and soluble factors. Wang et al62 demonstrated the ability to
augment mesothelioma tumor control by combining CAR
T cells targeting CAFs and mesothelin-directed CAR T cells.
With the well-described observation that tumor progression
BEYOND ANTIPD-1 AND ANTIPD-L1 THERAPIES
is associated with hyaluronan accumulation in stroma, there
are efforts to combine hyaluronidase administration with
engineered T cells to overcome the stromal challenge.63
The challenge of inhibitory checkpoints. Checkpoint
blockade has recently received a lot of attention as a prom-
ising immunotherapeutic strategy in lung cancer.64 The most
studied checkpoint at the present time is PD-1, a negative
regulator of the T-cell immune response that signals upon
binding its ligands, PD-L1 and PD-L2, which are often highly
expressed in solid tumors and their tumor microenviron-
ments. However, the majority of patients treated with PD-1
checkpoint blockade demonstrate no objective clinical re-
sponse. One likely reason for this is that many patients tu-
mors lack sufficient infiltration of tumor-reactive TILs to be
unmasked by checkpoint blockade. Thus, combining adoptive
transfer of engineered tumor-reactive T cells with checkpoint
blockade may be the key to successfully applying immuno-
therapy to cancers such as lung cancer and mesothelioma.
Preclinical studies have already demonstrated the ability to
augment TCR and CAR human T-cell control of lung cancer
and mesothelioma tumors by combining them with PD-1
blockade.51
IMMUNOSUPPRESSION IN THE TUMOR
MICROENVIRONMENT
Immune Checkpoint Proteins
There are several T-cell surface receptors called immune
checkpoint proteins that deliver negative signals to T cells
when they engage their ligands expressed on tissue- or
antigen-presenting cells.65 This is a feedback mechanism
whereby immune responses are dampened when no longer
needed. This mechanism of control of T cells can be co-opted
by tumors to escape rejection by the immune system.66,67 A
hallmark of malignancy is an inflamed tumor microenvi-
ronment,68 and inflammatory cytokines such as g-interferon
can induce immune checkpoint ligand expression on tumor
cells.69 Therefore tumor antigenspecific T cells activated in
tumor-draining lymph nodes are shut down when they enter
into the tumor microenvironment.
AntiPD-1/PD-L1 antibodies have significant antitumor
activity in lung cancer. The discovery of aberrant expres-
sion of PD-L1 in tumors leads to the development of the
therapeutic strategy of monoclonal antibodies designed to
prevent PD-1 binding to PD-L1. There are a number of
different monoclonal antibodies specific to PD-1 or PD-L1
that are in clinical development for lung cancer, all having
similar tumor response rates of 15%20%.70 This demon-
strates that lung cancer is an immunotherapeutically re-
sponsive disease, and this strategy can have a major impact
on OS and, more importantly, can influence the tail of the
survival curve.
Other immune checkpoint proteins that may be opera-
tional within the tumor microenvironment. It is known
that the extracellular tumor microenvironment contains
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ANTONIA, VANSTEENKISTE, AND MOON
high levels of adenosine as a consequence of anaerobic
glycolysis in hypoxic regions and preferential utilization of
aerobic glycolysis for energy metabolism in nonhypoxic
regions (the Warburg effect), producing a relative excess of
AMP; and tumor cell expression of the ectonucleotidase
CD73 that catabolyzes AMP to produce adenosine.71,72 It
had been known that adenosine produced within the
hypoxic microenvironment of inflamed tissue functions to
limit the exuberance of inflammatory responses to reduce
collateral damage of normal tissue by inflammatory cells and
cytokines.73,74 This is because of a direct inhibitory effect of
adenosine on T cells that express adenosine A2ARs, a T-cell
surface immune checkpoint protein,75 and leads to the
discovery that adenosine in the tumor microenvironment
interferes with antitumor immunity,76 suggesting that an-
tagonism of the A2AR could be an effective cancer immu-
notherapeutic.77 Other immune checkpoint proteins that
can be expressed on T cells include BTLA, LAG3, and TIM3.
Antibodies that block the binding of these proteins to their
ligands are being developed and tested in clinical trials.
Immune Suppressor Cells
Cancer-associated fibroblasts. Tumors secrete a variety of
growth factors and cytokines, including TGF-b, platelet-
derived growth factor, basic fibroblast growth factor, IL-6,
and IL-1, to recruit and activate CAFs.4-8 Fearons group
first demonstrated that CAFs contribute significantly to
immunosuppression within the tumor microenvironment.78
Subsequently, it has been discovered that they do so
through a variety of mechanisms. Recent studies dem-
onstrated that CAFs suppressed T-cell proliferation more
efficiently than normal fibroblasts and collaborate with
tumor cells to create an immunosuppressive tumor micro-
environment in head and neck squamous cell carcinoma.10
Cancer-associated fibroblasts have been shown to protect
lung cancer cells from T-cellmediated destruction. Fibro-
blast activation protein (FAP)-apositive CAFs were able to
protect tumor cells from tumor necrosis factormediated
and interferon gmediated necrosis of tumor cells by T cells
and were also able to sequester T cells away from neoplastic
cells by expressing C-X-C motif chemokine ligand 12. When
FAP-apositive CAFs were depleted, immunologic detection
and destruction of tumor cells was restored, and interferon-g
or tumor necrosis factor were able to cause rapid hypoxic
necrosis.4,11,12 Inhibition of CXC receptor type 4 interacting
with C-X-C motif chemokine ligand 12 of CAFs was shown to
promote T-cell accumulation in the pancreatic tumor site
and synergize with antiPD-L1.13 Cancer-associated fibro-
blasts are also known to induce immune suppressor cell
types such as regulatory T cells and MDSCs, and immune
suppressor cells were reduced when CAFs were inhibited.14
Cancer-associated fibroblasts have also been shown to re-
cruit macrophages into tumors and activate M2 phenotypes
through secretion of IL-4, IL-6, and IL-8.9 All of these varied
mechanisms help to support an immunosuppressive, tumor-
promoting microenvironment.
e456 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Recently, two drugs have been approved for the treatment
of idiopathic pulmonary fibrosis, pirfenidone and nintedanib.
The fact that the fibroblasts in this disease resemble
CAFse.g., both express FAPled us to develop clinical
trials where these drugs will be repurposed as cancer im-
munotherapeutics. Because CAFs are also known to support
the malignant phenotype, these drugs may have anticancer
effects beyond relief of immunosuppression.
Myeloid-derived suppressor cells. Inflammation associ-
ated with the tumor microenvironment plays an important
role in the development and progression of lung cancer. In
the context of an inflammatory response, myeloid cells are
the primary recruited effectors. In lung cancer, these cells
are activated macrophages, granulocytes, and MDSC.79
Production of reactive oxygen and nitrogen species is one of
the major characteristics of all activated myeloid cells. The
formation of the free radical peroxynitrite (PNT) is the main
result of interaction between superoxide and nitric oxide.
Peroxynitrite can react directly with cysteine, methionine,
and tryptophan. A substantial number of studies have
demonstrated high levels of nitrotyrosine in lung cancer.
Gabrilovich et al79 demonstrated that MDSC can induce
T-cell tolerance via production of PNT and nitration/
nitrosylation of TCR and CD8 molecules on the surface of
T cells. T-cell receptors lose their ability to bind specific
peptide/MHC complexes and kill tumor cells.80
Synthetic triterpenoids work through activation of the
transcription factor Nrf2 (nuclear factor [erythroid-derived]
like 2), which induces the up-regulation of an array of anti-
oxidant molecules, such as glutathione, thioredoxin, catalase,
and superoxide dismutase.81 We are testing one such triter-
prenoid as an anticancer immunotherapeutic.
CONCLUSION
The discovery that blocking signaling through the T-cell
surface immune checkpoint protein PD-1 can produce a
very significant impact on clinical outcomes of patients with
lung cancer not only gives us effective drugs that work as
single agents, but perhaps more importantly has given
us the proof-of-principle that lung cancer is certainly an
immunotherapeutically responsive disease. With the dis-
covery of the many ways that tumors can evade rejection by
the immune system and the development of strategies to
thwart these comes real hope that we will be able to sig-
nificantly improve on results obtained with antiPD-1/PD-L1
blocking antibody monotherapy. It is clear that there is
considerable heterogeneity among patients with lung cancer
with respect to which of the numerous potential immu-
noevasive mechanisms is operational. This means that in all
likelihood we must interfere with several immunoevasive
mechanisms for individual patients and that we must de-
velop good biomarkers to identify which of these mecha-
nisms is operational among individual patients to choose
the proper combination of immunotherapeutics for each
individual patient.

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LUNG CANCER

Local Therapies in the

Management of Oligometastatic
and Metastatic NonSmall Cell
Lung Cancer

CHAIR
Puneeth Iyengar, MD, PhD
The University of Texas Southwestern Medical Center
Dallas, TX

SPEAKERS
Jessica S. Donington, MD
New York University School of Medicine
New York, NY

Robert D. Suh, MD
David Geffen School of Medicine at UCLA
Los Angeles, CA
IYENGAR ET AL

Local Therapy for Limited Metastatic NonSmall Cell Lung

Cancer: What Are the Options and Is There a Benefit?
Puneeth Iyengar, MD, PhD, Steven Lau, MD, PhD, Jessica S. Donington, MD, MSCR, and
Robert D. Suh, MD

OVERVIEW

Distant metastasis is common in nonsmall cell lung cancer (NSCLC) and typically associated with poor prognosis. Aggressive
local therapy including surgery and/or radiation for limited metastatic disease from colorectal cancer and sarcoma is
associated with survival benefit and has become part of the standard of care. In this article, we review the literature and
ongoing studies concerning surgery, radiation, and radiofrequency ablation for oligometastatic NSCLC.

N onsmall cell lung cancer continues to represent dis-

proportionately the number of patients with and the
number of patient deaths from cancer. Over 224,000 new
cases are expected in 2016,1 and the overall survival (OS) for
all these patients is anticipated to approach only 15%20%.
Hence, a need to offer better strategies to combat the
disease should be a priority. For early-stage disease, surgery
continues to represent the gold standard for treatment. In
medically inoperable patients, stereotactic ablative radio-
therapy (SABR), also referred to as stereotactic body radi-
ation therapy (SBRT), has become a more integral part of our
treatment armamentarium. For those patients at high risk
for SABR in this medically inoperable setting, potentially
because of previous irradiation, radiofrequency ablation
(RFA) has begun to take on a greater role. Despite relentless
advances in surveillance, imaging, and knowledge, the
number of patients at initial presentation with surgically
resectable local disease remains soberly small at under 30%,
compounded by the realization that many with resectable
disease are rendered medically inoperable by comorbid
disease.
Over recent decades, most importantly the last, evolu-
tionary inertia has refined local control measures on all
fronts, surgical and nonsurgical, through improved tech-
nology and its application and patient selection. Although
standard surgical lobectomy has been and is currently the
gold standard for early-stage NSCLC,2 noninvasive and
minimally invasive nonsurgical measures for local control
SABR and image-guided tumor ablation (IGTA), respectively,
have been increasingly accepted and used for local control
and cure for both medically inoperable but even medical
operable lung cancer patients.
Unfortunately, most patients with NSCLC are still di-
agnosed with advanced, metastatic disease. With the de-
velopment of targeted therapies and immunotherapies,
survival is improving. Yet, for a significant proportion of
patients with stage IV NSCLC, systemic agents offer limited
potential for durable control of disease. Historically, with
limited metastatic colorectal cancer and sarcomas, the use
of local therapies including surgery and/or radiation have
become part of the standard of care as a means of drastically
improving OS along with local control. It therefore begs the
question, as we try to identify more and more subsets of
patients with advanced NSCLC with favorable biology, if
there is a group of patients with limited metastatic NSCLC
who could benefit from local treatments in addition to their
systemic therapy regimens. If so, what would be the optimal
treatments, when should they be delivered, and what type
of benefit is realistic? Finally, it may be that local therapy in
limited metastatic NSCLC is not beneficial independent of
the favorable biology of this cohort. This information would
also be of vital importance to generate.
This article offers the current evidence for the use of local
therapiessurgery, radiation in the form of SABR or
hypofractionated regimens, and RFAas part of the overall
management for patients with limited metastatic NSCLC. For
SABR and RFA, there is additional information regarding
their general acceptance into more mainstream treatment,
starting with evidence of their role in early-stage disease.
As a note, unless considering the yet to be validated abscopal

From the Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX; NYU School of Medicine, New York, NY; Department of Radiological
Sciences, Thoracic Imaging and Intervention, and Diagnostic Radiology Education, David Geffen School of Medicine at UCLA, Los Angeles, CA; Department of Radiation Oncology, Harold
C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Puneeth Iyengar, MD, PhD, UT Southwestern Medical Center, 5801 Forest Park Rd., MC 9183, Dallas, TX 75235-9183; email: puneeth.iyengar@utsouthwestern.
edu.

2016 by American Society of Clinical Oncology.

e460 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook

 LOCAL THERAPY FOR LIMITED METASTATIC NSCLC

response associated with immunotherapy, there is no ac-
cepted role for the use of local therapies in the treatment of
widely metastatic NSCLC unless deemed necessary for
palliation or other improvement in quality of life.
SURGERY FOR METASTATIC NSCLC
Historically, surgery for patients with stage IV cancer was
limited to palliation, but in the 1980s, series began to appear
that reported prolonged survival following complete re-
section of primary tumors and oligometastatic disease in
selected patients. It is now recognized that there is a subset
of patients in whom an isolated metastasis represents the
entire disease burden, and removal can confer considerable
survival prolongation.
Surgery for metastases from numerous primary locations,
including the lung, has increased over the past decade.
Metastasectomy for primary NSCLC has been found second
in incidence only to colon cancers.3 An analysis from the
National Inpatient Sample uncovered a 5.8% average annual
percent increase in resections of NSCLC metastases between
2000 and 2011.3 This increase is attributed to several factors,
including more efficacious and better tolerated chemo-
therapies and the introduction of targeted agents, which
have slowed the progression of metastatic spread and al-
tered patterns of resistance. Simultaneously, there have
been improvements in surgical techniques, with increased
use of minimally invasive approaches, making resection
better tolerated and negating long interruption from sys-
temic treatments.
The majority of patients considered for resection of
metastatic NSCLC fall into three categories: those with an
isolated metastasis to the brain, adrenal glands, or con-
tralateral lung. Occasional patients with an isolated me-
tastasis to other sites are considered, but evidence for
prolonged survival following local therapy is sparse. Patients
who have previously undergone complete resection of early-
stage NSCLC and subsequently present with isolated oli-
gometastasis after thorough metastatic survey and have
good performance status should be considered for curative
intent resection. Similarly, patients who present de novo with a
single metastasis after full staging should be evaluated for
curative resection of both sites. An ongoing question in those
who present with synchronous disease is which treatment
should be undertaken first, the systemic or localized therapies?
Isolated Brain Metastasis
Some of the oldest series on surgical treatment of stage IV
NSCLC relate to treatment of isolated brain metastasis.4,5 Up
to one-quarter of all patients with stage IV NSCLC harbor
brain metastasis. Adenocarcinomas are associated with
higher rates of brain metastasis,6-8 but in 10% of patients
with metastatic adenocarcinoma, the brain is the only site of
involvement.9 Aggressive curative intent treatment of the
primary and metastatic site is encouraged in those with good
performance status and in whom both sites are amenable to
complete resection or ablation. Curative intent local treat-
ments can only be considered after a thorough search for
disease at other sites. Mediastinal lymph node involvement
portends poor prognosis,6-8,10,11 and therefore, invasive me-
diastinal staging is recommended prior to starting treatment.
Brain MRI is recommended in addition to PET/CT because
of increased sensitivity12 Multiple brain metastasis are not
an absolute contraindication to this aggressive treatment
approach, but most recommend three or fewer lesions.9
Treatment of the brain lesion can be by resection or radio-
surgery ablation. Radiosurgery has the advantage of being
able to be performed in almost any location, including the
brain stem.13-15
Five-year survival following definitive treatment of iso-
lated brain metastasis and primary NSCLC is 15% and not
significantly impacted by synchronous or metachronous
presentation. Results from several series with more than 20
patients are outlined in Table 1.4-8,10,16,17 Prognosis is im-
proved in patients who are younger, female, have a lower t-
stage, and good performance status.6-8 Administration of
adjuvant whole-brain radiation therapy (WBRT) following
resection or radiosurgery is recommended. Randomized data

KEY POINTS Table 1. Survival Outcomes for Patients With Isolated

Brain Metastasis Following Local Therapy of Primary
Many patients with NSCLC will be diagnosed with distant Tumor and Metastasis
metastasis, but a subset of patients with limited
metastatic disease may benefit from aggressive local Synchronous Metachronous
therapies. Survival (%) Survival (%)
Evidence supporting an aggressive approach to Author No. 2 years 5 years No. 2 years 5 years
oligometastatic NSCLC is limited but suggestive of 7
Bonnette et al 103 28 11 - - -
reasonable safety and efficacy.
The potential risks and benefits of aggressive local Girard et al8 51 42 N/R - - -
therapies for an individual patient should be openly Granone et al6 30 47 14 - - -
discussed prior to initiating treatment. Wronski
et al 4
86 14 8 145 29 17
Synchronous versus metachronous oligometastasis may
Nakagawa et al5 60 10 N/R 28 11 N/R
carry disparate prognosis to guide management.
Ongoing studies will clarify the roles of various local Flannery et al17 42 34 21 33 59 13
10
therapies in oligometastatic NSCLC. Furak et al - - - 45 N/R 16
Abbreviation: N/R, not recorded.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e461

IYENGAR ET AL
on WBRT in this setting are limited, but the sole trial
demonstrated a notable decrease in brain recurrence.18
There are also no randomized data specifically addressing
the use of adjuvant chemotherapy following complete
resection of stage IV disease, but with strong evidence sup-
porting adjuvant chemotherapy for completely resected stage
II and III,19 it is recommended for patients with completely
resected primary and brain metastasis.9
Isolated Adrenal Metastasis
In well-selected patients with isolated adrenal metastasis
from NSCLC, survival following complete resection is 25%.20-23
Similar to those with isolated brain metastasis, mediastinal
lymph node involvement portends a poor prognosis, so in-
vasive staging is recommended.24 Histology and laterality
appear to have no impact on survival, and adjuvant chemo-
therapy is recommended. Synchronous and metachronous
tumors have similar long-term survival rates, despite younger
age distribution in patients with synchronous presentation.25
Operative mortality is extremely low in reported series, and the
majority of patients die of disease progression.
M1a Disease
The appearance of bilateral NSCLC lesions with the same
histology is a staging challenge. In the absence of other
disease, it is difficult to distinguish bilateral primary tumors
from stage IVa disease. Analysis of mutational status and
genetic clonality difference are being investigated, but is not
clinically reliable at this time.26 The clinical judgment of an
experienced multimodality team is essential,9 and the cri-
teria described by Martini and Melamed in 1975 remains
relevant.27 As with isolated brain and adrenal metastasis, an
exhaustive search for additional metastatic disease and
invasive mediastinal staging are recommended prior to
considering resection. Parenchymal sparing resections are
typically recommended when possible in this setting.
Summary
Overall, with more data being generated regarding local
treatment of oligometastatic NSCLC, the role of surgery
will be more properly delineated with the goal of im-
proving progression-free survival (PFS) at the least and
ultimately OS.
RADIATION FOR METASTATIC NSCLC
Patients with metastatic cancer are historically considered
incurable, and their treatment is palliative in nature. However,
reports of patients long-term survival after surgical resection
of metastasis began to surface in the 1930s.28 The state of
limited metastatic disease without widespread progression
was ultimately termed oligometastasis in 1995.29 Oli-
gometastasis is now recognized as a unique clinical entity
in which aggressive, ablative therapies can result in long-
term cure.
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There are no prospective studies comparing surgical re-
section to radiation therapy for the treatment of oligome-
tastatic disease. Indeed, nonoperative approaches may be
preferred for some patients with oligometastasis because of
risks of surgical morbidity and mortality as well as comorbid
conditions common in patients with NSCLC, which may increase
such surgical risks. SABR adapts the techniques of stereotactic
radiosurgery for intracranial disease to the delivery of highly
conformal radiation to extracranial targets, and SABR is in-
creasingly used to treat oligometastasis.30
SABR Is Associated With Excellent Local Control and
Acceptable Toxicity
Phase I/II studies have described the use of SABR for oli-
gometastatic disease in the lung, liver, spine, and multiple
sites and reported local control rates of 70%90% with grade
3 or greater toxicity rates of less than 10%.31-36 For example,
Rusthoven et al31 enrolled 38 patients with 63 lung me-
tastases on a phase I/II protocol using SABR to 4860 Gy in
three fractions. Twenty-seven (71%) patients had been
previously treated with at least one systemic regimen. At a
median follow-up of 15.4 months, only one local failure was
observed. Importantly, only three (8%) patients experienced at
least 3 toxicity. Separately, Salama et al35 enrolled 61 patients
with 113 extracranial metastases on a dose-escalation protocol
using SABR to 2460 Gy in three fractions. Twenty-three (38%)
patients had received metastasis-directed therapy prior to
enrollment. The maximum tolerated dose was not reached.
At a median imaging follow-up of 15.0 months, 72 (64%)
lesions were controlled despite initially low radiation doses
on this protocol. At least grade 3 acute toxicity was observed in
only two (3%) patients, and at least 3 late toxicity was observed
in six (10%) patients. Furthermore, when patients with oligo-
metastatic disease treated with ablative local therapies ex-
perience distant progression, these failures tend to be limited
rather than widespread and more amenable to further ablative
therapies.37
Patient Selection in Oligometastatic NSCLC
Outcomes of NSCLC are worse than other cancers, and
whether an oligometastatic disease state exists in NSCLC is
debated. Ashworth et al38 performed a systematic review of
49 studies including 2,176 patients with one to five me-
tastases from NSCLC who underwent surgery or radiation.
Most (82%) patients had controlled primary disease, and
60% of studies were limited to intracranial metastasis.
Median survival was 14.8 months, median time to pro-
gression was 12 months, and median 5-year OS was 23.3%.
Control of primary disease, N stage, and disease-free interval
of at least 6 to 12 months prior to diagnosis of oligome-
tastasis were found to be prognostic on multivariable
analysis.
Ashworth et al39 subsequently performed an individual
patient data meta-analysis on 757 patients with 1 to 5
synchronous or metachronous metastases from NSCLC
who underwent surgery or radiation. Median survival was

26 months, median PFS was 11 months, and 5-year OS was
29.4%. Recursive partitioning analysis stratified patients
into low-risk (metachronous metastasis; 5-year survival
47.8%), intermediate-risk (synchronous metastasis, N0;
5-year survival 36.2%), and high-risk disease (synchro-
nous metastasis, N+; 5-year survival 12.1%).
De Ruysscher et al prospectively evaluated aggressive
treatment with curative intent in 39 patients diagnosed with
NSCLC and one to three synchronous metastases.40 Primary
disease was treated with radiation, and metastatic disease
was treated with either surgery (24%) or radiation (76%).
Twenty-seven (69.2%) patients had thoracic nodal in-
volvement, 34 (87.2%) patients had a single metastasis, and
17 (43.9%) patients had brain metastasis. Median survival
was 13.5 months, median PFS was 12.1 months, and 2-year
survival was 23.3%. No grade 3 toxicity or higher related to
treatment of oligometastatic disease was observed.
Thus, appropriate patient selection is warranted when plan-
ning for an aggressive approach using ablative local therapies.
Combined Therapy for Oligometastatic NSCLC
Although ablative local therapies may control known sites
of disease, most patients will ultimately progress. Novel
therapeutic approaches are therefore needed. One prom-
ising approach is the combination of SABR and systemic
therapies. Iyengar et al41 prospectively tested the use of
SABR and concurrent erlotinib in 24 patients with 52 ex-
tracranial metastases from NSCLC who had progressed after
at least one systemic regimen. SABR was delivered to all
active sites of disease. Median survival and PFS were 20.4
and 14.7 months, respectively. Only three local failures of 47
evaluable lesions were observed, and 10 patients progressed
at distant sites. Others have reported an abscopal effect on
unirradiated metastases from the combination of SABR and
immunotherapies.42,43
Summary
SABR for the treatment of oligometastatic NSCLC is effective
and well tolerated, and combined modality therapy is a
promising approach to improve outcomes. Two studies, one out
of MD Anderson Cancer Center (NCT01725165) and the second
out of UT Southwestern Medical Center (NCT02045446), are
using SABR and hypofractionated radiation in randomized
studies with systemic therapy to determine if local treatment
can improve PFS in patients with up to three and six sites of
limited metastatic disease, respectively. Other larger studies
with OS as an endpoint will hopefully best answer how ben-
eficial radiation may be in the stage IV NSCLC setting.
RADIOFREQUENCY ABLATION FOR METASTATIC
NSCLC
For those with NSCLC undergoing RFA, to date the most
studied thermal ablation technique, the medical literature
has focused on the high-risk, or medically inoperable,
population. RFA, or IGTA, can be considered for those
patients with locally recurrent cancer (oligorecurrent)
LOCAL THERAPY FOR LIMITED METASTATIC NSCLC
after local or even systemic therapy or with synchronous
or metachronous lung cancer, those with limited or low
volume metastases particularly after a prolonged disease-
free interval (oligometastatic), and those in need of palliative
and now even salvage therapy. Although multiple methods
for safe and effective local therapy are necessary, IGTA for
NSCLC is particularly poised for success, given it provides
the best balance of comparable survival, superior cost,
and experiential use patients with high-risk disease and
other emerging patient populations, much of which was
unfathomable a decade prior.
IGTA Efficacy
In 2007, Simon et al44 first published 5-year long-term safety
and efficacy data of RFA in 71 patients with stage I primary
lung cancer. Overall survival was reported at 78% at 1 year,
57% at 2 years, 36% at 3 years, and 27% at 4 and 5 years. The
authors re-emphasized that patients with treated cancers
3 cm and smaller versus cancers larger than 3 cm demon-
strated better OS at every annual time point: 83% versus
45% at 1 year, 64% versus 25% at 2 years, 57% versus 25% at
3 years, and 47% versus 25% at 4 and 5 years. In addition,
those patients with 3 cm and smaller tumors showed sig-
nificantly longer median time to progression: 45 versus
12 months. Although 27% 5-year OS appears dismal at first
glance, the study was quite remarkable in achieving this
survival in the high-risk population, estimated up to 30%
according to the Surveillance, Epidemiology, and End Results
(SEER) database in 2005,45 most therapeutically neglected
because of their medical ineligibility before this time. Since
2007, at least three additional series in patients with high-
risk disease have shown comparable or better 5-year OS:
24%, 25%, and 61%,46-48 the last being quite formidable
and a testament to long-term operator experience and the
benefits of lessons learned regarding patient and lesion
selection. In addition to single-center experience, the medical
literature includes the results of two multicenter trials. In
Lancet Oncology, the RAPTURE study demonstrated 48%
OS and 73% cancer-specific survival at 2 years for primary
lung cancer population of patients with high-risk disease.49
Moreover, pulmonary function tests did not show any signif-
icant decline in forced expiratory volume (FEV), FEV percentage
predicted, forced vital capacity (FVC), or FVC percentage
predicted, in any follow-up visits through 12 months,
compared with baseline values. The slight decrease in these
values in treated patients with lung cancer was not clini-
cally significant and was consistent with the progression of
underlying chronic pulmonary disease in this subgroup.
More recently, the results from the American College of
Surgeons Oncology Group (ACOSOG) Z4033 Trial were
published.50 The OS rate was 86.3% at 1 year and 69.8% at
2 years. The local tumor recurrencefree rate was 68.9% at
1 year and 59.8% at 2 years and worse for tumors at least 2 cm.
Not surprisingly, patients with tumors smaller than 2 cm and a
performance status of 0 or 1 achieved a statistically significant
improved survival of 83 and 78%, respectively, at 2 years.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e463
IYENGAR ET AL
Although not as mature as a technological application for
lung malignancies compared with RFA, microwave ablation
(MWA) and cryoablation, or percutaneous cryotherapy
(PCT), have more recently published 5-year results in the
treatment of early lung cancer in the medically inoperable
patient population, both having demonstrated comparable,
if not improved, OS and cancer-specific survival and local
control rates to RFA at 5 years with favorable complication
profiles.51,52 Yang et al51 reported OS rates at 1, 2, 3, and 5
years after MWA were 89%, 63%, 43%, and 16%, respectively.
Tumors that were 3.5 cm or smaller were associated with
better survival than were tumors that were larger than 3.5 cm.
The local control rates at 1, 3, and 5 years after MWA were
96%, 64%, and 48%, respectively. In patients undergoing PCT
for primary lung cancer, Moore et al52 in 2015 reported the 5-
year OS rate at 67.8%, the cancer-specific survival rate at 5
years at 56.6%, and the 5-year PFS rate at 87.9%.
Argued Comparability
Over the years, RFA has been unfavorably compared with
sublobar resection and SABR. However, upon closer scrutiny,
one major overlooked factor is that those patients treated
with RFA were always the sickest, the patients receiving RFA
in most, if not all, studies demonstrating statistically significant
poorer FEV in 1 second53 and older age54 compared with those
undergoing sublobar resection. Moreover, when comparing
patient demographics from the ACOSOG z4033 and z4032 and
RTOG 0236 trials, those patients enrolled in the z4033 were
significantly older and held significantly lower diffusion
capacity.55 And finally, Kwan et al56 recently argued com-
parable overall and lung-cancer specific survival between
RFA and sublobar resection in patients in the SEER database
when propensity scores were used to match patient subgroups.
In many circles, stereotactic body radiotherapy has been
largely hailed as the silver bullet against early-stage lung
cancer, setting new lofty standards for 5-year OS and local
recurrence ranging between 54% and 65% and 4% and 14%,
respectively.57,58 Although certainly impressive, the results
emerging from these and other similar series have not been
devoid of criticism. Deeper analyses show that not all treated
lesions were pathologically confirmed, with many radiograph-
ically diagnosed, prevalence of more indolent tumors specifically
adenocarcinoma in situ, and the treated population in-
cluded both patients with low-risk disease and those with
high-risk disease. In fact, when parsing out the high-risk
subgroup from the Onishi et al study in 2007,57 5-year OS
drops from the overall reported 65% to 35%, similar to
published 5-year RFA results. Unlike RFA, moreover, SABRs
higher potential for collateral injury to healthy peritumoral
lung may be detrimental in many patients with high-risk
disease with tenuous lung reserve.
Will Less Equivalent Local Control Be the Death of
Radiofrequency Ablation?
In ascending order, local control improves when comparing
RFA, MWA, cryoablation, SABR, and surgical lobectomy;
e464 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
however, despite enhanced local control, the rate of distant
disease remains highly variable between studies whether
comparing like or unlike therapies. Simply and most plau-
sibly, this variability is the direct result of already micro-
scopic disease at the time of treatment, in some surgical
series reported as high as 16% in 1-cm apical cancers.59 In
other words, even complete, or 100%, local control will have
already microscopic locoregional and distant disease. This is
further exacerbated in the high-risk population, which may
be ineligible for formal nodal staging through mediastino-
scopy, left to complete reliance on medical imaging, spe-
cifically CT-PET.
Ultimately, the rate of local and locoregional progression
may not negatively impact OS. Specifically in 2009, Lanuti
et al60 looked at locoregional recurrence in patients with
stage I lung cancer initially treated with RFA, and despite
retreatment with RFA, radiotherapy, chemoradiotherapy,
and chemotherapy, the authors found no notable difference
in 5-year overall and disease-free survival in patients re-
ceiving RFA without recurrence versus those patients with
treated recurrences.
Other Patient Populations
Helping to define a new patient population afforded lung
ablation, Kodama et al61 in 2012 showed 55.7% 5-year OS in
those patients with recurrent and second primary lung
cancers after surgical resection. Ridge et al62 in 2014 found
improved local progression after thermal ablation with
synchronous and metachronous lung cancers compared
with ablation of first primaries.
RFA has been studied in the advanced disease patient
population. Yu et al63 found RFA a useful tool to bridge from
failure of one therapy to the initiation of another therapy in
patients receiving EGFR. In some patients with advanced
disease, Gu et al64 found that patients receiving cryoablation
and gefitinib demonstrated significantly better survival at 1
year than those patients receiving gefitinib alone. Similarly,
Lee et al54 observed that even stage III and IV lung cancers
treated with RFA and chemotherapy demonstrated signifi-
cantly longer median OS than those treated with only
chemotherapy. In patients with localized recurrence after
initial local or systemic treatment failure, RFA, when added
to a predetermined treatment regimen, lengthened overall
and PFS.65,66
Cost Benefit
Although surgical resection showed OS superiority at 1, 2,
and 3 years, Alexander et al67 argued that this superiority
came at a significantly increased median cost per months
lived of 1.93 times from reimbursement rates from the study
state. When compared with other treatment modalities in
the setting of oligometastatic NSCLC, cryoablation appeared
the most cost-effective, even when added to the cost of best
supportive care or systemic regimens with an adjunctive
cost-effectiveness ratio of $49,008$87,074. In their study,
cryoablation was associated with very low morbidity and

local tumor recurrence rates for all anatomic sites and
possibly increased OS.68
Although prospective cost-efficacy studies comparing
IGTA and SBRT are nonexistent, with the exception of a
single study using Markov modeling and older RFA data,69
global Medicare reimbursement in Rhode Island for SABR
was 4.25 times that of RFA at $17,000 versus $4,000.70 If
the higher cost of SABR for better local control and arguably
better OS is justified remains to be seen in the high-risk
population, particularly given the microscopic locoregional
and distant disease rates and RFAs repeatability at lower
cost.
Summary
In summary, advances in thermal energy devices and de-
livery have led to improved control. As local control im-
proves, however, gains in survival will be limited for NSCLC,
given the limitations of radiographic staging and microscopic
lymph nodal and distant disease at the time of therapy
including ablation, rendering the need for adjuvant control
in some situations. Additive local control even in those with
advanced cancer appears to offer survival benefits in some
patient subsets with recurrent or advanced disease. When
critically compared with surgical resection and SABR, IGTA is
an attractive option with an acceptable threshold for local
control balanced with risk and cost without detriment to
survival.
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CONCLUSION
Most would agree that favorable biology is the primary driver of
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24. Porte H, Siat J, Guibert B, et al. Resection of adrenal metastases from
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71:981-985.
25. Tanvetyanon T, Robinson LA, Schell MJ, et al. Outcomes of adrenal-
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26. Wu CT, Lin MW, Hsieh MS, et al. New aspects of the clinicopathology
and genetic profile of metachronous multiple lung cancers. Ann Surg.
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27. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac
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28. Barney J, Churchill E. Adenocarcinoma of the kidney with metastasis to
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30. Pan H, Simpson DR, Mell LK, et al. A survey of stereotactic body ra-
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32. Rusthoven KE, Kavanagh BD, Cardenes H, et al. Multi-institutional phase
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33. Lee MT, Kim JJ, Dinniwell R, et al. Phase I study of individualized ste-
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1585-1591.
34. Wang XS, Rhines LD, Shiu AS, et al. Stereotactic body radiation therapy
for management of spinal metastases in patients without spinal cord
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35. Salama JK, Hasselle MD, Chmura SJ, et al. Stereotactic body radio-
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36. Milano MT, Katz AW, Zhang H, et al. Oligometastases treated with
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37. Milano MT, Philip A, Okunieff P. Analysis of patients with oligometa-
stases undergoing two or more curative-intent stereotactic radio-
therapy courses. Int J Radiat Oncol Biol Phys. 2009;73:832-837.
38. Ashworth A, Rodrigues G, Boldt G, et al. Is there an oligometastatic state
in non-small cell lung cancer? A systematic review of the literature. Lung
Cancer. 2013;82:197-203.
39. Ashworth AB, Senan S, Palma DA, et al. An individual patient data
metaanalysis of outcomes and prognostic factors after treatment of
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oligometastatic non-small-cell lung cancer. Clin Lung Cancer. 2014;15:
346-355.
40. De Ruysscher D, Wanders R, van Baardwijk A, et al. Radical treatment of
non-small-cell lung cancer patients with synchronous oligometastases:
long-term results of a prospective phase II trial. J Thorac Oncol. 2012;7:
1547-1555.
41. Iyengar P, Kavanagh BD, Wardak Z, et al. Phase II trial of stereotactic
body radiation therapy combined with erlotinib for patients with
limited but progressive metastatic non-small-cell lung cancer. J Clin
Oncol. 2014;32:3824-3830.
42. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of
the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:
925-931.
43. Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation
and ipilimumab in a patient with metastatic non-small cell lung cancer.
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44. Simon CJ, Dupuy DE, DiPetrillo TA, et al. Pulmonary radiofrequency
ablation: long-term safety and efficacy in 153 patients. Radiology. 2007;
243:268-275.
45. Mery CM, Pappas AN, Bueno R, et al. Similar long-term survival of
elderly patients with non-small cell lung cancer treated with lobectomy
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results database. Chest. 2005;128:237-245.
46. Huang L, Han Y, Zhao J, et al. Is radiofrequency thermal ablation a safe
and effective procedure in the treatment of pulmonary malignancies?
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47. Ambrogi MC, Fanucchi O, Cioni R, et al. Long-term results of radio-
frequency ablation treatment of stage I non-small cell lung cancer:
a prospective intention-to-treat study. J Thorac Oncol. 2011;6:
2044-2051.
48. Hiraki T, Gobara H, Mimura H, et al. Percutaneous radiofrequency
ablation of clinical stage I non-small cell lung cancer. J Thorac Cardiovasc
Surg. 2011;142:24-30.
49. Lencioni R, Crocetti L, Cioni R, et al. Response to radiofrequency ablation
of pulmonary tumours: a prospective, intention-to-treat, multicentre
clinical trial (the RAPTURE study). Lancet Oncol. 2008;9:621-628.
50. Dupuy DE, Fernando HC, Hillman S, et al. Radiofrequency ablation of
stage IA non-small cell lung cancer in medically inoperable patients:
Results from the American College of Surgeons Oncology Group Z4033
(Alliance) trial. Cancer. 2015;121:3491-3498.
51. Yang X, Ye X, Zheng A, et al. Percutaneous microwave ablation of stage I
medically inoperable non-small cell lung cancer: clinical evaluation of 47
cases. J Surg Oncol. 2014;110:758-763.
52. Moore W, Talati R, Bhattacharji P, et al. Five-year survival after cry-
oablation of stage I non-small cell lung cancer in medically inoperable
patients. J Vasc Interv Radiol. 2015;26:312-319.
53. Kim SR, Han HJ, Park SJ, et al. Comparison between surgery and
radiofrequency ablation for stage I non-small cell lung cancer. Eur J
Radiol. 2012;81:395-399.
54. Lee H, Jin GY, Han YM, et al. Comparison of survival rate in primary non-
small-cell lung cancer among elderly patients treated with radio-
frequency ablation, surgery, or chemotherapy. Cardiovasc Intervent
Radiol. 2012;35:343-350.
55. Crabtree T, Puri V, Timmerman R, et al. Treatment of stage I lung cancer
in high-risk and inoperable patients: comparison of prospective clinical
trials using stereotactic body radiotherapy (RTOG 0236), sublobar re-
section (ACOSOG Z4032), and radiofrequency ablation (ACOSOG
Z4033). J Thorac Cardiovasc Surg. 2013;145:692-699.
56. Kwan SW, Mortell KE, Talenfeld AD, Brunner MC. Thermal ablation
matches sublobar resection outcomes in older patients with early-stage
non-small cell lung cancer. J Vasc Interv Radiol. 2014;25:1-9.e1.

57. Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotactic
radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer:
updated results of 257 patients in a Japanese multi-institutional study.
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58. Uematsu M, Fukui T, Tahara K, et al. Long-term results of computed
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J Thorac Cardiovasc Surg. 2006;132:544-548.
60. Lanuti M, Sharma A, Digumarthy SR, et al. Radiofrequency ablation for
treatment of medically inoperable stage I non-small cell lung cancer.
J Thorac Cardiovasc Surg. 2009;137:160-166.
61. Kodama H, Yamakado K, Takaki H, et al. Lung radiofrequency ablation
for the treatment of unresectable recurrent non-small-cell lung cancer
after surgical intervention. Cardiovasc Intervent Radiol. 2012;35:
563-569.
62. Ridge CA, Silk M, Petre EN, et al. Radiofrequency ablation of T1 lung
carcinoma: comparison of outcomes for first primary, metachronous,
and synchronous lung tumors. J Vasc Interv Radiol. 2014;25:989-996.
63. Yu HA, Sima CS, Huang J, et al. Local therapy with continued EGFR
tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-
mutant advanced lung cancers that have developed acquired re-
sistance to EGFR tyrosine kinase inhibitors. J Thorac Oncol. 2013;8:
346-351.
LOCAL THERAPY FOR LIMITED METASTATIC NSCLC
64. Gu XY, Jiang Z, Fang W. Cryoablation combined with molecular target
therapy improves the curative effect in patients with advanced non-
small cell lung cancer. J Int Med Res. 2011;39:1736-1743.
65. Schoellnast H, Deodhar A, Hsu M, et al. Recurrent non-small cell lung
cancer: evaluation of CT-guided radiofrequency ablation as salvage
therapy. Acta Radiol. 2012;53:893-899.
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ablation as supplemental therapy after systemic chemotherapy for
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2013;201:1362-1367.
67. Alexander ES, Machan JT, Ng T, et al. Cost and effectiveness of radi-
ofrequency ablation versus limited surgical resection for stage I non-
small-cell lung cancer in elderly patients: is less more? J Vasc Interv
Radiol. 2013;24:476-482.
68. Bang HJ, Littrup PJ, Currier BP, et al. Percutaneous cryoablation of
metastatic lesions from non-small-cell lung carcinoma: initial survival,
local control, and cost observations. J Vasc Interv Radiol. 2012;23:
761-769.
69. Sher DJ, Wee JO, Punglia RS. Cost-effectiveness analysis of stereotactic
body radiotherapy and radiofrequency ablation for medically in-
operable, early-stage non-small cell lung cancer. Int J Radiat Oncol Biol
Phys. 2011;81:e767-e774.
70. Dupuy DE. Treatment of medically inoperable non-small-cell lung
cancer with stereotactic body radiation therapy versus image-guided
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Radiol. 2013;24:1139-1145.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e467
LUNG CANCER

Lung Cancer Screening and

Prevention

CHAIR
Denise R. Aberle, MD
David Geffen School of Medicine at UCLA
Los Angeles, CA

SPEAKERS
Abbie Begnaud, MD
University of Minnesota
Minneapolis, MN

Graham W. Warren, MD, PhD

Medical University of South Carolina
Charleston, SC
BEGNAUD, HALL, AND ALLEN

Lung Cancer Screening With Low-Dose CT: Implementation

Amid Changing Public Policy at One Health Care System
Abbie Begnaud, MD, Thomas Hall, MBA, and Tadashi Allen, MD

OVERVIEW

Screening for lung cancer with low-dose CT has evolved rapidly in recent years since the National Lung Screening Trial (NLST)
results. Subsequent professional and governmental organization guidelines have shaped policy and reimbursement for the
service. Increasingly available guidance describes eligible patients and components necessary for a high-quality lung cancer
screening program; however, practical instruction and implementation experience is not widely reported. We launched a
lung cancer screening program in the face of reimbursement and guideline uncertainties at a large academic health center.
We report our experience with implementation, including challenges and proposed solutions. Initially, we saw less referrals
than expected for screening, and many patients referred for screening did not clearly meet eligibility guidelines. We
educated primary care providers and implemented system tools to encourage referral of eligible patients. Moreover, in
response to the Centers for Medicare & Medicaid Services (CMS) final coverage determination, we report our programmatic
adaptation to meet these requirements. In addition to the components common to all quality programs, individual health
delivery systems will face unique barriers related to patient population, available resources, and referral patterns.

S ince the publication of the landmark NLST in 2011, many

health care systems prepared to implement a lung cancer
screening program. The NLST was the first randomized
controlled trial to show a mortality benefit when screening
high-risk populations for lung cancer with low-dose CT of the
chest.1 At the time of NLST publication, the most updated
guideline from the U.S. Preventive Services Task Force
(USPSTF) cited insufficient evidence to recommend for or
against screening for lung cancer.2 Similarly, the American
College of Chest Physicians recommended screening only
within the confines of a clinical trial.3
The University of Minnesota Health is an academic medical
practice in the center of a large metropolitan area. Our health
system affiliate, Fairview Health Systems, is one of several that
provide care throughout the state. One advantage of this
system is that any patient treated in the hospitals or clinics has a
universal electronic health record (EHR, Epic). However, dif-
ferent physician practice groups provide services within the
system. Imaging services are contracted to both University of
Minnesota physicians and a large community radiology practice.
MATERIALS AND METHODS
Determination of Need and Assessment of Resources
In early 2013, we gathered a team, consisting of repre-
sentatives from business development, thoracic oncology,
radiology, thoracic surgery, and pulmonology, to design the
program. Initial research included an assessment of available
clinical resources, a market analysis, and a cost analysis to
start the program. According to our estimates, approxi-
mately 94,634 people at high risk for lung cancer, based on
smoking history, live in the metropolitan area. Only one
other screening program was open in the area at the time of
our program planning and launch.
A team of clinicians with lung nodule management ex-
pertise is an integral component of a lung cancer screening
program.4 Our multidisciplinary thoracic oncology group
was established in 2011 and includes board-certified tho-
racic surgeons, radiation oncologists, thoracic and inter-
ventional radiologists, interventional pulmonologists, and
medical oncologistsall specializing in the care of patients
with lung cancer. An experienced, specialized team con-
tributes to optimizing outcomes of lung cancer screening by
avoiding unnecessary diagnostic procedures and achieving
the best possible outcomes for lung resection surgery.5 The
multidisciplinary team reviews indeterminate lung nodules
in a weekly lung nodule conference with diagnostic thoracic
radiology to recommend a patient-specific plan for diagnosis
and/or disease management. Minimally invasive diagnostic
testing is available at our institution, including percutaneous
lung biopsy, video-assisted thoracic surgery, and linear

From the Department of Medicine, University of Minnesota, Minneapolis, MN; Fairview Health System, University of Minnesota Cancer Care, Minneapolis, MN; Department of Radiology,
University of Minnesota, Minneapolis, MN.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Abbie Begnaud, MD, 420 East Delaware St., MMC 27, Minneapolis, MN 55455; email: abegnaud@umn.edu.

2016 by American Society of Clinical Oncology.

e468 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


probe endobronchial ultrasound and guided bronchoscopy
techniques (such as electromagnetic navigational bron-
choscopy and radial endobronchial ultrasound). The team
uses advanced diagnostic technologies with individualized
attention to lesion characteristics, patient preferences, and
medical comorbidities.
Program Planning
Establishing a workflow for ordering examinations, inter-
preting images, relaying results, and ensuring follow-up
was a crucial phase of planning. The follow-up is driven
by the guidelines by the National Comprehensive Cancer
Network, 6 American Association of Thoracic Surgery, 7
and American College of Radiology (ACR).8 Implementation
of the program required partnership with EHR builders,
billing and patient financial services, and communications
specialists.
Although self-referral for screening was initially consid-
ered, ultimately we required an order from a credentialed
provider for screening. Subsequently released CMS re-
quirements mandate an order and ordering provider, but
health systems might elect to offer screening to patients
with private insurance or those who would pay for services
out of pocket. The anticipation of need for result follow-up
influenced our decision to require all patients to have an
ordering provider for lung cancer screening.
A unique EHR order was created specifically for lung cancer
screening. The name of the order and associated search key
words included CT, lung cancer screening, and low- with the interpreting radiologist. The questionnaire assesses
dose CT. Initially the order had few mandatory responses
related to eligibility criteria: patients symptoms suggestive
of lung cancer, age, and smoking history. When this order is
signed, providers are also prompted to include in the pa-
tients printed after-visit summary the Lung Cancer
Screening, Frequently Asked Questions and Resources to
Help You Quit Smoking. Subsequent CMS requirements
changed the order to include the required elements for all
patients.
KEY POINTS
Executing a new preventive health care service requires
education of and acceptance from providers and
patients.
Implementing program for screening for a lung cancer
requires multidisciplinary collaboration.
Ensuring regulatory compliance and best practice in lung
cancer screening requires system tools and ongoing
oversight.
Despite education, providers may inappropriately refer
patients for lung cancer screening.
Electronic health record tools can be used to
supplement provider and patient education about and
compliance with lung cancer screening.
LUNG CANCER SCREENING WITH LOW-DOSE CT
Despite the limited screening interval and upper age limit
of 75 reported in the NLST, we predicted benefit from
continued annual screening. Hence, we added lung cancer
screening to the health maintenance activity where other
preventive health measures are tracked, including cancer
screenings and vaccinations. The American Association for
Thoracic Surgery also recommended annual screening for
people age 5579.7 Ultimately, the USPFTF and CMS re-
leased recommendations for both a broader age range and
screening extending beyond three annual examinations. We
educated primary care provider groups about screening
eligibility and the process we developed.
Early Implementation
After creating a new chest CT lung cancer screening order in
the EHR, establishing a result workflow with radiology, and
educating providers, our program launched on December
12, 2013. Because most insurance companies were not yet
covering lung cancer screening examinations, we offered the
service at $150, which was a fair market price at the time.
Several insurance companies began covering screening
throughout 2014, well before the updated USPSTF guideline.
At the time of screening, patients submit detailed in-
formation about their risk factors for lung cancer via a
questionnaire (developed with collaboration from academic
epidemiologists and clinical psychologists, subsequently
adapted to match CMS registry data requirements). Imaging
technologists enter the information into the EHR and share
each patients risk profile including smoking history, radon
and particulate exposures, family history of lung cancer, and
personal medical history.
We implemented a structured reporting system for results
called U-Lung-RADS, which was modeled after Bi-RADS and
was very similar to the system ultimately released by ACR in
April 2014 (Table 1).9 In addition to a numeric score based on
the likelihood of cancer, additional modifiers indicate the
presence of incidental or suspicious findings. We imple-
mented the ACR Lung-RADS 1.0 immediately after it was
released.
Our results follow-up team is comprised of a call center,
certified nurse specialists, and a physician. The team
monitors semiweekly and monthly reports for screening
examination results. All patients who were screened
receive a letter describing the results of the screening CT and
the next steps for follow-up in plain language. The follow-up
team also helps facilitate orders for follow-up scans and
appointments and verifies that they are performed. The
team also notifies the primary care physician of any in-
cidental findings. Incidental findings unrelated to lung
cancer were found in 7.5% of patients in the NLST,10
therefore a mechanism for management is imperative.
Patients who have Lung-RADs 1 or 2 (no suspicious findings)
and meet eligibility for screening have the lung cancer
screening topic added to their health maintenance modifier.
The health maintenance activity is visible to all providers,
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e469
BEGNAUD, HALL, AND ALLEN
TABLE 1. Lung-RADS Version 1.0 Assessment Categories
Category Descriptor Category Descriptor
Incomplete
Negative No nodules and definitely benign nodules
Benign Appearance or Nodules with a very low likelihood of becoming a
Behavior clinically active cancer due to size or lack of growth
Probably Benign Probably benign finding(s): short term follow-up
suggested, includes nodules with a low likelihood
of becoming a clinically active cancer
Suspicious Findings for which additional diagnostic testing and/or 4A
tissue sampling is recommended
Significant, Other
Prior Lung Cancer
Release date: April 28, 2014.
Abbreviation: LDCT, low-dose CT.
and, when overdue, an alert appears in the patients chart.
For any positive findings (Lung-RADS 3 or higher), the cer-
tified nurse specialist or physician is notified immediately so
that the patient can be discussed in multidisciplinary team
conference to establish a plan for follow-up or diagnostic
procedure. A unified EHR allows multidisciplinary chart and
image review as requested by ordering providers for ex-
ternally performed screening examinations with abnormal
findings.
Overcoming Barriers
Improving examination ordering rates. The number of
orders for screening has been less than expected relative to
the estimated eligible population. Several identifiable bar-
riers are likely responsible. First, adoption of new recom-
mendations usually grows over time.11 Adoption is almost
certainly limited by provider awareness of screening avail-
ability and eligibility, as well as the time required to in-
corporate yet another preventive care service into patient
interactions. Secondly, uncertainty regarding insurance
coverage may discourage health care providers from
ordering a screening. As we expand to new regions in the
state, we offer educational sessions to primary care practices
served by those centers. Furthermore, systemwide educa-
tional events have been held in the form of grand rounds at
multiple sites and lunch webinars for primary care providers.
An effective method of improving adoption of guidelines
for lung cancer screening may be to use the EHRs best
practice alert (BPA) functionality. A pop-up alert prompts a
health care provider about a clinical topic, including eligi-
bility for preventive care activities. Activating an alert for
lung cancer screening CT orders for all of our patients
who meet the criteria would probably improve ordering
rates and awareness among our ordering physicians.
e470 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Primary
Category Management
0 Additional lung cancer screening CT images and/or
comparison with prior chest CT examinations is
needed
1 Continue annual screening with LDCT in 12 months
2
3 6-month LDCT
3-month LDCT; PET/CT may be used when there is a
$ 8-mm solid component
4B Chest CT with or without contrast, PET/CT and/or tissue
sampling depending on the probability of malignancy
and comorbidities; PET/CT may be used when there is
a $ 8-mm solid component
S
C
However, implementing alerts like these must balance pa-
tient care and health care provider information overload and
alert desensitization.12 Moreover, in order for a BPA to be
useful, patients must have a very detailed smoking history
recorded in the EHR.
Improving examination completion rates. Even as exami-
nation orders increased, many went unscheduled and were
not performed. We believe this low completion rate to be
primarily due to reimbursement uncertainty and out-of-
pocket payment for the examination. Because several na-
tional private insurance companies added lung cancer
screening coverage prior to the USPSTF recommendation,
we eliminated the self-pay approach and began reviewing
orders for insurance eligibility. If an eligible patients in-
surance did not cover screening, they could receive the
screening examination under a local grant for this purpose.
Thus, we were able to remove a cash price barrier and offer
the procedure to all eligible patients as an insurance-neutral
screening examination. We notified providers about the
grant and elimination of the self-pay option using an internal
newsletter. We also sent letters that explained the benefits
of screening and offered examination with insurance or
grant coverage to all patients with orders that had not been
completed. Finally, our imaging centers do not proactively
schedule ordered examinations; rather, patients are asked
to initiate the scheduling process. Proactive scheduling of
ordered examinations by radiology would likely improve
completion rates as well.
Improving result reporting. Streamlining result reporting
also was an initial challenge. We believe it is important to
deliver results to patients in a way that minimizes anxiety
about abnormal findings. We envisioned an experienced

certified nurse specialist to deliver abnormal results along
with a treatment recommendation to the patient. However,
early examination results follow-up by the ordering provider
was generally not in accordance with national guidelines.
When this happened, we contacted the providers to notify
them of the service we intended to provide and revised
any misinformed recommendations. As providers learned to
trust that we would handle results follow-up, the process
became more streamlined. Primary care physicians are in-
formed of all patient communication and recommendations.
As a service to patients and providers who scheduled at a
non-university-affiliated imaging center in the health sys-
tem, we added an opt-in question to the imaging order in
September 2015. Ordering providers who opt-in transfer
nodule follow-up to the centralized results team.
Smoking Cessation Program
The effect of screening for lung cancer on smoking rates is
not fully known13 but thought to be most favorable when
smoking cessation assistance is offered with screening.14
Moreover, smoking cessation is an important part of pre-
ventive health and cost-effective lung cancer prevention.15
We use a variety of tools to help patients quit smoking. A
pharmacist provides pharmacologic assistance in medica-
tion therapy management for smoking cessation, and
smoking cessation tools are incorporated in the lung cancer
screening ordering process in the EHR. Furthermore, our
institution is a site for a National Institutes of Healthfunded
smoking cessation trial, with participation offered to
smokers who are being screened. Therefore, we consoli-
dated available institution resources within a website to
provide centralized access to smoking cessation assistance.
We incorporated smoking cessation resources in our lung
cancer screening FAQs, which was given to patients at the
time of order placement. Although many barriers to ideal
provision of smoking cessation assistance exist,16,17 it is
unequivocally recommended to accompany lung cancer
screening.4
Adapting to New Guidelines and CMS Requirements
Professional society guidelines. In late 2014, the American
College of Chest Physicians and the American Thoracic So-
ciety jointly published a statement that outlined the key
components of a high-quality lung cancer screening program
(Table 2).4 Guidelines are also available for lung cancer
screening from the ACR, Society of Thoracic Radiology,8 and
the American Association of Thoracic Surgeons.7 Our pro-
gram had already been built with these best practices in
mind and required no modifications to meet the guidelines.
CMS Decision Memo. The CMS Decision Memo was re-
leased in November 201418 and incorporated many of the
elements of a high-quality screening program previously
recommended (Table 3). In addition, a credentialed provider
must conduct a shared decision-making visit with the patient
when ordering the initial screening examination, document
LUNG CANCER SCREENING WITH LOW-DOSE CT
TABLE 2. Recommended Components of High-Quality
Lung Cancer Screening Program4
Policy in place to offer lung cancer screening only to patients who meet
criteria established by the U.S. Preventive Services Task Force. At
least 90% of patients screening should match this policy.
Annual screening until the age of 80, a person has not smoked for
15 years, or becomes unwilling or unable to undergo curative lung
resection surgery.
Technical specifications of CT conform to ACR-STR standards, and data
are collected to ensure mean radiation dose is in compliance with
those.
Threshold of nodule size that is considered positive, and data are
collected describing the number and size of nodules detected.
Structured reporting system, such as Lung-RADS, is used, and data are
collected on compliance with structured reporting.
Designated clinicians with expertise in lung nodule management
(diagnostic radiology, interventional radiology, pulmonary
medicine, thoracic surgery, medical oncology, radiation oncology)
use accepted lung nodule management strategy.
Integrated smoking cessation program and data collection related to
smoking cessation interventions offered.
eligibility and discussion of risks and benefits of screening,
and offer smoking cessation if applicable. The screening
order itself should also include eligibility criteria.
To render an interpretation that will be reimbursed by
CMS, radiologists must be board certified, experienced in
chest CT, and participate in continuing medical educa-
tion. Imaging centers eligible for reimbursement of lung
cancer screening must have experience with low-dose CT
lung cancer screening and be accredited as an advanced
diagnostic imaging center. In addition, effective radiation
dose of reimbursable examinations must be less than 1.5
mSv, and data must be collected and submitted to a CMS-
approved registry for each screening examination. Al-
though an extensive list of data elements was initially
proposed, the final Decision Memo included 10 data
elements pertaining to the ordering provider, inter-
preting radiologist, patient smoking history, and CT
scanner.
Adapting EHR tools. To facilitate compliance with CMS
requirements, we modified the EHR tools. In addition to
making modifications to the lung cancer screening imaging
order, we created a SmartSet, which is a bundle of orders
and documentation related to a topic. The SmartSet guides
clinicians on patient eligibility, required billing codes, sug-
gested wording for the shared decision-making visit, orders
for smoking cessation tools, and the imaging order. When
signed, the SmartSet outputs patient instructions with
screening FAQs and scheduling information. A BPA was
created to direct the ordering provider from the stand-alone
order to the SmartSet, as many providers had become ac-
customed to using the order laone.
RESULTS
Examination Ordering and Completion Rates
Systemwide, 902 unique patients received orders for
screening using low-dose CT. However, only 63% of these
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BEGNAUD, HALL, AND ALLEN

TABLE 3. CMS Lung Cancer Screening Eligibility Criteria19

Type
Beneficiary Eligibility Criteria
Reading Radiologist Eligibility
Criteria
Radiology Imaging Facility
Eligibility Criteria
Criteria
1. Age 5577
2. Asymptomatic (no signs or symptoms of lung cancer)
3. Tobacco smoking history of at least 30 pack-years (one pack-year 5 smoking one pack per day for one year; 1 pack 5
20 cigarettes)
4. Current smoker or one who has quit smoking within the last 15 years
5. Receives a written order for LDCT lung cancer screening that meets the following criteria:
a. For the initial LDCT lung cancer screening service: a beneficiary must receive a written order for LDCT lung cancer
screening during a lung cancer screening counseling and shared decision-making visit, furnished by a physician (as
defined in Section 1861(r)(1) of the Social Security Act) or qualified nonphysician practitioner (meaning a physician
assistant, nurse practitioner, or clinical nurse specialist as defined in 1861(aa)(5) of the Social Security Act). A lung
cancer screening counseling and shared decision-making visit includes the following elements (and is appropriately
documented in the beneficiarys medical records):
i. Determination of beneficiary eligibility including age, absence of signs or symptoms of lung cancer, a specific
calculation of cigarette smoking pack-years; and if a former smoker, the number of years since quitting;
ii. Shared decision-making, including the use of one or more decision aids, to include benefits and harms of
screening, follow-up diagnostic testing, overdiagnosis, false-positive rate, and total radiation exposure;
iii. Counseling on the importance of adherence to annual lung cancer LDCT screening, impact of comorbidities, and
ability or willingness to undergo diagnosis and treatment;
iv. Counseling on the importance of maintaining cigarette smoking abstinence if former smoker; or the importance
of smoking cessation if current smoker and, if appropriate, furnishing of information about tobacco cessation
interventions; and
v. If appropriate, the furnishing of a written order for lung cancer screening with LDCT.
b. For subsequent LDCT lung cancer screenings: the beneficiary must receive a written order for LDCT lung cancer
screening, which may be furnished during any appropriate visit with a physician (as defined in Section 1861(r)(1) of the
Social Security Act) or qualified nonphysician practitioner (meaning a physician assistant, nurse practitioner, or clinical
nurse specialist as defined in Section 1861(aa)(5) of the Social Security Act). If a physician or qualified nonphysician
practitioner elects to provide a lung cancer screening counseling and shared decision-making visit for subsequent lung
cancer screenings with LDCT, the visit must meet the criteria described above for a counseling and shared decision-
making visit.
c. Written orders for both initial and subsequent LDCT lung cancer screenings must contain the following information,
which must also be appropriately documented in the beneficiarys medical records:
i. Beneficiary date of birth;
ii. Actual pack-year smoking history (number);
iii. Current smoking status, and for former smokers, the number of years since quitting smoking;
iv. Statement that the beneficiary is asymptomatic (no signs or symptoms of lung cancer); and
National Provider Identifier (NPI) of the ordering practitioner.
1. Board certification or board eligibility with the American Board of Radiology or equivalent organization
2. Documented training in diagnostic radiology and radiation safety
3. Involvement in the supervision and interpretation of at least 300 chest CT acquisitions in the past 3 years
4. Documented participation in continuing medical education in accordance with current American College of Radiology
standards
5. Furnish lung cancer screening with LDCT in a radiology imaging facility that meets the radiology imaging facility
eligibility criteria below
1. Performs LDCT with volumetric CT dose index (CTDIvol) of # 3.0 mGy (milligray) for standard size patients (defined to
be 57 and approximately 155 pounds) with appropriate reductions in CTDIvol for smaller patients and appropriate
increases in CTDIvol for larger patients
2. Utilizes a standardized lung nodule identification, classification, and reporting system
3. Makes available smoking cessation interventions for current smokers and collects and submits data to a CMS-
approved registry for each LDCT lung cancer screening performed.

examinations have been completed (Fig. 1). Over time, both
examinations orders and completion rates increased. Since
the function has been offered, 81% of examinations com-
pleted opted in for centralized result management. Using
the Lung-RADS interpretation strategy, 70% of patients had a
positive finding (Lung-RADS 2 or higher). However, only 17%
of patients had a finding that required follow-up sooner than
annually (Fig. 2).
Patient Eligibility
EHR record of eligibility was measured by completed
smoking history tool. Of the 572 screening examinations
completed, less than 20% were eligible by smoking history
(Table 4). About one-third of patients had inadequate
smoking history as recorded in the EHR history tool to
determine eligibility. Many of these patients did report
smoking for at least 30 pack-years on the patient
questionnaire administered prior to low-dose CT. An-
other nearly one-third of patients were not eligible for
screening based on age or smoking history, as recorded.
Among patients who had smoking intensity (packs per
day and smoking years) recorded, implementation of a
BPA clarifying eligibility criteria had no impact on the
proportion of patients referred for screening who met
eligibility criteria (30 or more pack years). Similarly, the
proportion of screening referrals for patients whose
recorded quit smoking date was more than 15 years ago

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FIGURE 1. Lung Cancer Screening Order Completion
by Quarter
did not substantially change after implementation of
the BPA.
Counseling and Shared Decision-Making Visit
Nearly all examinations (95%) were ordered during an office
visit. Yet many of those did not have documentation of
counseling and a shared decision-making visit. Shared-
decision making documentation has improved over time
(Fig. 3), but, in January 2016, it still only occurred in half of
patients with completed screening examinations. Prior to
implementation of a BPA indicating CMS requirements, 87%
of patients did not have documentation of a shared decision-
making visit. Since the BPA function, compliance with shared
decisions-making documentation in patients with Medicare
or Medicaid has improved to 46%.
DISCUSSION
Lung cancer screening is a relatively new preventive health
care service (secondary prevention). As such, developing and
implementing new processes can be guided by national
leaders but must also be customized to meet the needs of
local and regional health care systems. We began implementing
FIGURE 2. Lung-RADS Results for Completed Orders
LUNG CANCER SCREENING WITH LOW-DOSE CT
TABLE 4. Patient Characteristics Contributing to
Eligibility for Lung Cancer Screening as Recorded in
Electronic Health Records
Patient Characteristics Number of Patients (572, %)
Current Smoker 268 (47%)
Former Smoker 282 (49%)
No Recorded Quit Date 48 (282 patients, 17%)
Quit > 15 years 31 (5%)
Pack-year < 30 117 (20%)
Inadequate Entry to Calculate 206 (36%)
Age-inappropriate 21 (4%)
Apparently Eligible 123 (22%)
a screening program before current regulatory requirements
were released.
Approximately one-third of the orders were for patients
whose eligibility for screening could not be confirmed.
Eligibility was unconfirmed due to insufficient documen-
tation of smoking history, documented smoking intensity
less than 30 pack-years, or quit more than 15 years prior to
examination. Our health system has had some success but
continues to optimize EHR tools to facilitate compliance
with recommended eligibility. Most patients did report
smoking history on prescreening questionnaires that was
adequate for lung cancer screening eligibility. We believe
that infrequent and inaccurate recording of smoking his-
tory by clinicians to be responsible. Furthermore, the EHR
tool for recording smoking history is inadequate to fully
capture the variability in smoking intensity over time that
describes many smokers habits. A tool that more specif-
ically captures light smoking, heavy smoking, and quit
periods can help record an accurate account of smoke
exposure. In addition to improving EHR tools and utiliza-
tion, confirmation of eligibility prior to screening using low-
dose CT will likely be needed to reach perfect compliance
with eligibility requirements.
Early orders had a low completion rate, which we believe
to be due to the absence of insurance coverage and the self-
pay cost of the examination ($150). After the CMS final
Decision Memo, examination orders quadrupled, supporting
our notion that uncertainty about reimbursement drove
initial low uptake. Feedback from providers suggests that
anxiety prevents patients from scheduling examinations
despite having the information to do so. Furthermore, in
most clinics, patients are asked to schedule examinations
themselves rather than having examinations scheduled
for them. Completion rates continue to improve, despite
having a patient-initiated scheduling system.
Our findings suggest that reimbursement-driven en-
forcement of patient eligibility as required by Medicare is
necessary to apply screening to the high-risk groups who are
most likely to benefit. We also concur with the need for
continued monitoring of screening outcomes through
national registries to further refine screening eligibility and
utility.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e473
BEGNAUD, HALL, AND ALLEN
FIGURE 3. Lung Cancer Screening Orders Completed in 2015 and Accompanied by Shared Decision Making
Documentation
Abbreviation: SDM, shared decision making.
This article demonstrates our experience implementing
a lung cancer screening program outside of a federally
supported clinical trial. Future trends will be greatly shaped
by outcomes reported from national registries and
by experience with pervasive screening in a climate of
References
1. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality
with low-dose computed tomographic screening. N Engl J Med. 2011;
365:395-409.
2. U.S. Preventive Services Task Force. Lung cancer screening: recom-
mendation statement. Ann Intern Med. 2004;140:738-739.
3. Bach PB, Silvestri GA, Hanger M, et al. Screening for lung cancer: ACCP
evidence-based clinical practice guidelines (2nd edition). Chest. 2007;
132:69S-77S.
4. Mazzone P, Powell CA, Arenberg D, et al. Components necessary for high
quality lung cancer screening: American College of Chest Physicians and
American Thoracic Society Policy Statement. Chest. 2015;147:295-303.
5. Farjah F, Flum DR, Varghese TK Jr, et al. Surgeon specialty and long-term
survival after pulmonary resection for lung cancer. Ann Thorac Surg.
2009;87:995-1004, discussion 1005-1006.
6. National Comprehensive Cancer Network. Lung Cancer Screening. https://
www.nccn.org/store/login/login.aspx?ReturnURL=http://www.nccn.org/
professionals/physician_gls/pdf/lung_screening.pdf. Accessed February
13, 2016.
7. Jaklitsch MT, Jacobson FL, Austin JH, et al. The American Association for
Thoracic Surgery guidelines for lung cancer screening using low-dose
computed tomography scans for lung cancer survivors and other high-
risk groups. J Thorac Cardiovasc Surg. 2012;144:33-38.
8. Kazerooni EA, Austin JH, Black WC, et al. ACR-STR practice parameter for
the performance and reporting of lung cancer screening thoracic
e474 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
reimbursement for eligible patients. As diagnostic radiology
technology improves and adjunctive methods of early de-
tection of lung cancer become available, the riskbenefit
ratio for screening for lung cancer will continue to evolve
and, ideally, improve.
computed tomography (CT): 2014 (Resolution 4). J Thorac Imaging.
2014;29:310-316.
9. American College of Radiology. Lung-RADS Version 1.0 Assess-
ment Categories Release date: April 28, 2014. https://www.acr.org/
~/media/ACR/Documents/PDF/QualitySafety/Resources/LungRADS/
AssessmentCategories.pdf. Accessed February 13, 2016.
10. Church TR, Black WC, Aberle DR, et al. Results of initial low-dose
computed tomographic screening for lung cancer. N Engl J Med.
2013;368:1980-1991.
11. Francke AL, Smit MC, de Veer AJ, et al. Factors influencing the
implementation of clinical guidelines for health care professionals:
a systematic meta-review. BMC Med Inform Decis Mak. 2008;8:38.
12. Ash JS, Berg M, Coiera E. Some unintended consequences of information
technology in health care: the nature of patient care information system-
related errors. J Am Med Inform Assoc. 2004;11:104-112.
13. Tanoue LT, Tanner NT, Gould MK, et al. Lung cancer screening. Am J
Respir Crit Care Med. 2015;191:19-33.
14. Park ER, Gareen IF, Japuntich S, et al. Primary care provider-delivered
smoking cessation interventions and smoking cessation among par-
ticipants in the National Lung Screening Trial. JAMA Intern Med. 2015;
175:1509-1516.
15. Villanti AC, Jiang Y, Abrams DB, et al. A cost-utility analysis of lung cancer
screening and the additional benefits of incorporating smoking ces-
sation interventions. PLoS One. 2013;8:e71379.

16. Manley MW, Griffin T, Foldes SS, et al. The role of health plans in
tobacco control. Annu Rev Public Health. 2003;24:247-266.
17. Panaitescu C, Moffat MA, Williams S, et al. Barriers to the provision
of smoking cessation assistance: a qualitative study among Ro-
manian family physicians. NPJ Prim Care Respir Med. 2014;24:
14022.
18. Centers for Medicare & Medicaid Services. Proposed Decision Memo
for Screening for Lung Cancer with Low Dose Computed Tomography
(LDCT) (CAG-00439N). https://www.cms.gov/medicare-coverage-database/
LUNG CANCER SCREENING WITH LOW-DOSE CT
details/nca-proposed-decision-memo.aspx?NCAId=274&NcaName=
Screening+for+Lung+Cancer+with+Low+Dose+Computed+Tomography+
(LDCT)&MEDCACId=68&IsPopup=y&bc=AAAAAAAAAgAAAA%3d%3d&.
Accessed February 13, 2016.
19. Centers for Medicare & Medicaid Services. Decision Memo for
Screening for Lung Cancer with Low Dose Computed Tomography
(LDCT) (CAG-00439N). https://www.cms.gov/medicare-coverage-
database/details/nca-decision-memo.aspx?NCAId=274. Accessed Feb-
ruary 13, 2016.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e475
 ADDRESSING TOBACCO WITH CANCER SCREENING AND TREATMENT

Lung Cancer Screening, Cancer Treatment, and Addressing the

Continuum of Health Risks Caused by Tobacco
Graham W. Warren, MD, PhD, Jamie S. Ostroff, PhD, and John R. Goffin, MD

OVERVIEW

Tobacco use is the largest preventable risk factor for the development of several cancers, and continued tobacco use by
patients with cancer and survivors of cancer causes adverse outcomes. Worldwide tobacco control efforts have reduced
tobacco use and improved health outcomes in many countries, but several countries continue to suffer from increased
tobacco use and associated adverse health effects. Continued tobacco use by patients undergoing cancer screening or
treatment results in continued risk for cancer-related and noncancer-related health conditions. Although integrating to-
bacco assessment and cessation support into lung cancer screening and cancer care is well justified and feasible, most
patients with cancer unfortunately do not receive evidence-based tobacco cessation support. Combining evidence-based
methods of treating tobacco addiction, such as behavioral counseling and pharmacotherapy, with practical clinical con-
siderations in the setting of lung cancer screening and cancer treatment should result in substantial improvements in access
to evidence-based care and resultant improvements in health risks and cancer treatment outcomes.

T obacco use, particularly combustible tobacco, remains

the leading preventable cause of cancer worldwide.
Since the original U.S. Surgeon Generals report (SGR) on
tobacco in 1964 concluding that smoking was causally linked
to lung and laryngeal cancer, there have been numerous
SGRs confirming the adverse effects of tobacco on a spec-
trum of diseases, including increased risk for developing a
wide range of cancers.1 The 2014 SGR extended findings of
prior reports by concluding that continued smoking by
patients with cancer and survivors of cancer causes in-
creased overall mortality, cancer-specific mortality, risk for
second primary cancer, and associations with increased
cancer treatment toxicity.2 As updated in the 2014 SGR,
smoking and tobacco addiction usually starts in youth,
continues into adulthood, and results in chronic exposure to
chemicals that lead to the development of cancer, heart
disease, pulmonary disease, and several other adverse
health conditions. Many of the effects of tobacco are partly
or entirely reversible, with reduced risks of adverse health
conditions associated with longer periods of smoking ab-
stinence. As it pertains to patients with cancer and the risk of
developing cancer, smoking cessation can reduce the risks of
developing cancer, can improve cancer treatment out-
comes, and can reduce or prevent the development of other
tobacco-related diseases.2
Although smoking cessation can reverse many of the
adverse effects of smoking among the general population
and among patients with cancer, most oncologists un-
fortunately do not address tobacco use by providing
evidence-based tobacco cessation support.3,4 There are
several potential reasons why oncologists and other pro-
viders may not provide cessation support,5 but the funda-
mental consequence is that many people continue to be
exposed to cancer risk and adverse cancer treatment out-
comes because they do not have access to evidence-based
tobacco cessation support. The overall purpose of this ed-
ucational article is to convey the continuum of risk associ-
ated with tobacco use cancer risk and cancer treatment
outcomes, discuss recent data as related to lung cancer
screening and cancer treatment in the context of tobacco
use, and provide practical considerations that can be helpful
to increase access to tobacco cessation support. There are
limited studies evaluating methods to implement smoking
cessation into lung cancer screening and cancer care.
However, this article will further elaborate on practical
clinical considerations that could be helpful in the design and
implementation of tobacco cessation approaches across the
continuum of cancer risk and treatment.
There are thousands of references describing the adverse
health risks associated with tobacco use and hundreds of

From the Departments of Radiation Oncology and Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC; Department of Psychiatry and Behavioral
Sciences, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Oncology, McMaster University, Hamilton, Ontario, Canada.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Graham W. Warren, MD, PhD, Department of Radiation Oncology, Medical University of South Carolina, 169 Ashley Ave., MSC 318, Charleston, SC 29425;
email: warrengw@musc.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 223

WARREN, OSTROFF, AND GOFFIN
large reviews describing specific areas of risk and risk mit-
igation as related to tobacco use. For the purposes of this
educational article, we will highlight substantial review work
presented over the past 50 years by the U.S. Public Health
Service (PHS) through updated SGRs that have focused on
tobacco-associated health risks, addiction, and mitigation,1
with particular emphasis on the 2014 SGR2 that summarizes
many current and former conclusions associated with to-
bacco use. Whenever possible, references will be provided
to online resources that keep information up to date, which
is important as related to ongoing product, use, and health
information related to tobacco.
WORLDWIDE TOBACCO USE AND THE
CONTINUUM OF RISK
Cigarette smoke is the predominant form of worldwide
tobacco consumption, although in different countries dif-
ferent patterns exist that are highly influenced by culture,
gender, governmental regulation, advertising, and
manufacturing. Readers are encouraged to review the fifth
edition of the Tobacco Atlas, updated in 2015,6 available
online and in print. Produced by the American Cancer So-
ciety and the World Lung Foundation, the Tobacco Atlas
highlights patterns of worldwide tobacco use. Highlights
from the Tobacco Atlas and 2014 SGR include the following:
Approximately 100 million people died of tobacco-
related causes in the 20th century and an estimated
1 billion people will die in the 21st century from tobacco-
related causes if current tobacco use patterns persist. An
estimated 50% of people who use tobacco will die of a
tobacco-related disease.
An estimated 5.8 trillion cigarettes were smoked world-
wide in 2014. In many high-income countries, tobacco
use has plateaued and in many cases decreased over the
past 30 to 40 years with concomitant decreases in
KEY POINTS
Tobacco use confers a continuum of risk across the
general population as well as among patients diagnosed
with cancer, justifying the need to address tobacco use
before, during, and after a cancer diagnosis.
Worldwide tobacco consumption patterns continue to
place a substantial burden on the economy and health of
people in every nation.
Addressing tobacco use is a critical component of lung
cancer screening and cancer treatment.
Although strong evidence exists for methods to help
patients stop tobacco use, clinical implementation is
limited with little evidence-based support.
Considering the clinical setting, available resources, and
method of tobacco assessment, cessation support and
developing a sustainable clinical approach are practical
considerations when implementing change to improve
access to tobacco cessation support.
224 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
mortality associated with tobacco-related diseases.
However, in most low- and middle-income countries,
tobacco use (particularly combustible tobacco use
[cigarette smoking]) is increasing. Growing tobacco
consumption in China has offset decreased tobacco
consumption in other developed countries, and one-
third of all male individuals who smoke are Chinese. In
many countries, male tobacco consumption is de-
creasing, whereas female tobacco use has remained
unchanged or is increasing.
Lung cancer, chronic obstructive pulmonary disease,
and heart disease are leading causes of death from
tobacco. More than 80% of lung cancer and lung cancer
deaths are attributed to smoking, and approximately
one-third of all cancer deaths are attributed to tobacco
use. However, tobacco use causes disease in almost
every organ in the body. Thus, continued tobacco use
after a cancer diagnosis results in continued risk to other
organs and decreases the effectiveness of cancer
treatment.
Exposure to secondhand smoke can confer similar dis-
ease risks in a dose- and time-dependent manner.
Higher risk is associated with higher and more prolonged
exposure.
Addiction has both behavioral and biologic underpin-
nings. Most people start using tobacco during childhood
or adolescence, primarily influenced by social pressure,
advertising, and curiosity. Chronic tobacco use and
addiction is reflective of nicotine dependence, which
can affect constitutively expressed nicotinic acetylcho-
line receptors in the brain and throughout the body.
Tobacco use has strong social associations, in that many
people who smoke often have friends and relatives who
smoke.
Tobacco use is higher among people with lower educa-
tion, among individuals with lower income, and among
people who are diagnosed with a psychiatric disease.
However, many financially disadvantaged people will
continue to expend resources to continue tobacco use.
Tobacco addiction usually starts early in life. Most
people have tried to stop smoking several times and
most continue to want to stop smoking. Tobacco ces-
sation is often very difficult and requires multiple at-
tempts to achieve success. However, people who have
quit smoking in the past remain at risk for relapse,
particularly if they are exposed to secondhand smoke.
It is estimated that worldwide tobacco use causes $1
trillion annually in economic damage, with $289 billion
spent in treating the health consequences of smoking in
the United States alone. Only a very small portion of
tobacco product revenues (typically much less than 1%)
are used for tobacco control initiatives.
Effective strategies to reduce tobacco use include in-
creased product taxation, smoke-free policies and laws,

legislative regulation, education such as graphic product
labels, limiting or eliminating marketing, increased
pricing, and providing smoking cessation resources.
International treaties and agreements, such as the
World Health Organization Framework Convention on
Tobacco Control, that coordinate these activities can be
highly effective in influencing national and international
change. However, litigation is a widely used method by
the tobacco industry to limit tobacco control initiatives.
Although it was discussed in both the 2014 SGR and the
Tobacco Atlas, an important topic to discuss individually is
continuously evolving tobacco product design. Changes
in cigarette design over the past 50 years have resulted in
cigarettes that are easier to inhale, leading to changes in
disease risk. For instance, lung cancer was once a rare
disease that significantly increased with the advent of mass
cigarette production and changes in cigarette design that
allowed deeper inhalation resulted in the shift of lung cancer
patterns from centrally to peripherally located cancers.7
Unfortunately, changes in tobacco design did not result in
improved health: recent data demonstrate that people who
smoke are now more heavily addicted, with continued in-
creased health risks.8 However, the benefits of cessation
remain intact with reduced health risks associated with
longer periods of cessation.
As new tobacco products are developed, it will take years
or decades to determine the risk. Electronic cigarettes (e-
cigarettes) or electronic nicotine delivery systems (ENDS)
are relatively new products with largely unknown health
effects and patterns of use. Although many online resources
are promoting the use of ENDS to facilitate tobacco ces-
sation, the effects of ENDS to assist in tobacco cessation are
not yet known and ENDS cannot yet be promoted as a to-
bacco cessation device.9 It is important to note that the
health effects of ENDS may be dependent on the population
in question: ENDS use by youth who have never used to-
bacco are likely to result in different health effects compared
with adults who smoke and transition to ENDS use.9 Cur-
rently, physicians and clinical providers are limited in pro-
viding evidence-based guidance regarding ENDS use
because most of the evidence is simply lacking at this time.
TOBACCO USE IN THE CONTEXT OF LUNG
CANCER SCREENING AND CANCER TREATMENT
When considering integration of tobacco cessation into early
detection of lung cancer, it is important to note that al-
though diagnosis with resectable nonsmall cell lung cancer
can result in 5-year survival exceeding 70%, most patients
with lung cancer are diagnosed with symptoms, are not
operable, and have a dismal long-term prognosis.10 Cap-
turing patients at an early curative stage is the optimal
strategy for managing lung cancer. Early efforts to screen for
lung cancer with chest x-rays or sputum cytology may have
resulted in a modest shift in staging, but with no effect on
survival.11 Subsequent screening of large cohorts with CT
scans suggested improved stage shifting and improved
ADDRESSING TOBACCO WITH CANCER SCREENING AND TREATMENT
survival. The large, randomized National Lung Screening Trial
(NLST) provided the first strong evidence of benefit from
screening with low-dose computed tomography (LDCT)
compared with chest x-ray.12 Investigators screened an el-
igible population (age 5574) who had at least a 30 pack-year
smoking history and reported smoking within the past 15
years, in which participants had a baseline LDCT scan that
was followed by two annual screening LDCT scans. With a
follow-up of 6.5 years, LDCT screening decreased lung
cancerspecific mortality by 20%, overall survival was im-
proved by 6.7%, and CT LDCT screening diagnosed more
stage I to stage II disease (57% vs. 39%). Based on NLST data,
several agencies have recommended LDCT screening for an
eligible population provided that screening is undertaken in
the setting of appropriate expertise.
With the advent of LDCT screening as evidence-based
medicine, it has been increasingly important to consider
the utility of smoking cessation at the time of CT screening.
Several advocates have promoted screening for tobacco use
and providing tobacco cessation support to people who use
tobacco. In general, as supported by current National
Comprehensive Cancer Network (NCCN) guidelines, smoking
cessation is recommended for any individuals who are
undergoing LDCT screening and reporting current tobacco
use.13 Newly released NCCN Smoking Cessation Guidelines
provide additional guidance and details for providing to-
bacco cessation support to patients with cancer as well as
patients undergoing LDCT screening.14
Perhaps the best evidence for promoting smoking ces-
sation in the context of LDCT screening is the recent report
by Tanner et al,15 who evaluated the effect of smoking and
smoking cessation on survival in the NLST. Current smoking
increased overall and cancer-specific mortality among in-
dividuals who participated in LDCT screening, but 7 years of
smoking cessation reduced mortality at a level comparable
to the benefit of LDCT, and 15 years of cessation reduced
mortality by 38%. Given the large population of current
smokers who are eligible for lung cancer screening, cost-
effectiveness is an important consideration for policy
makers considering implementation. Studies based on NLST
data suggest that screening for lung cancer may have an
incremental cost-effectiveness ratio (ICER) per quality of
life-year saved in the $50,000 to $80,000 range.16 It is al-
ready established that smoking cessation programs are
highly cost-effective with an ICER less than $9,000 per
life-year saved.17 Simulation work suggests that the addition
of a smoking cessation program to an LDCT screening
program can substantially improve cost-effectiveness.18 As
such, combining LDCT and smoking cessation programs may
add incremental treatment cost but also enhance cost ef-
ficiency and provide the proven health benefits associated
with each.
When considering tobacco use by patients with cancer, the
2014 SGR concluded that smoking by patients with cancer
and survivors of cancer caused adverse outcomes and that
smoking cessation improves cancer treatment outcomes.2
Smoking and tobacco products alter cancer biology, promoting
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 225
WARREN, OSTROFF, AND GOFFIN
increased proliferation, angiogenesis, migration, invasion,
metastasis, and resistance to cytotoxic cancer therapy.19
Examination of the exhaustive evidence in the 2014 SGR
demonstrates that one or more adverse effects of smoking
extend to virtually all cancer disease sites and cancer
treatments. As a result, the adverse effects of smoking are
generally ubiquitous across cancer as a whole and ad-
dressing tobacco use is pertinent to the treatment of all
patients with cancer. The authors are unaware of detailed
cost-benefit analyses for implementing smoking cessation
into the care of patients with cancer; however, given the
extremely high costs of treating cancer and the relatively low
cost of providing smoking cessation support, it is very likely
that implementing smoking cessation practices into cancer
care may be one of the most cost-effective methods to
improve cancer treatment outcomes.
LUNG CANCER SCREENING, CANCER
TREATMENT, AND TOBACCO CESSATION
The question arises as to whether a LDCT screening pop-
ulation is well suited to promoting smoking cessation.
Presumably, individuals participating in LDCT screening may
represent a population motivated to improve their health.
Compared with the general population, participants in the
NLST were more commonly married, better educated, more
frequently ex-smokers, and younger. Persistent smokers in
the NLST were associated with having lower education,
being unmarried, being younger, and having a heavier
smoking history.20 Similarly, in the NELSON screening study,
participants in the control arm were younger, were better
educated, were former smokers, and expressed a greater
willingness to quit smoking.21 Established evidence dem-
onstrates that smoking is associated with having a lower
socioeconomic status, having lower education, being un-
married, and having poor health in part attributed to poorer
health-promoting activities.2,6 Participating in a LDCT pro-
gram could reflect increased interest in quitting or
following a healthier lifestyle. Data suggest that non-
participants express feelings of protection based on personal
or family health status, indicate that they are too old for
screening, and express sentiments of fatalism, all charac-
teristics unlikely to compel action.22 Consideration must be
given as to how to recruit hard-to-reach populations.
When considering the effect of LDCT on smoking cessa-
tion, data suggest that participation in screening is associ-
ated with increased motivation to quit smoking.23 Although
NLST participants perceived a high risk of cancer as a result of
smoking, smokers doubted the benefits of quitting and had
low confidence in their ability to quit.24 A review of nine
cross-sectional, longitudinal and randomized controlled
studies examined the effect of CT screening for lung cancer
on smoking behaviors and found quit rates ranging from
6.6% to 42%.25 Investigators for the Danish Lung Cancer
Screening Trial found no difference between study arms in
smoking rates at 5 years, although the number of ex-smokers
increased significantly in both arms and a stated motivation
226 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
to quit correlated with actual cessation.26 Consistently
negative results from the Early Lung Cancer Action Program
demonstrated that baseline negative LDCT scan results were
associated with lower point abstinence rates at follow-up
compared with positive LDCT scan results, but they had no
significant effect on prolonged abstinence.27 However, NLST
participants with physicians who assisted with cessation and
arranged follow-up had a 40% to 46% higher rate of ab-
stinence at 1 year, although physician rates of assisting and
arranging were low.28
There have been several thoughtful recent reviews on
addressing tobacco use in the context of cancer care.29-32
The principles of addressing tobacco use mimic evidence-based
PHS guidelines in the general population33 recommending the
use of behavioral counseling and pharmacotherapy to help
patients quit smoking. The 5As model (Ask, Assess, Advise,
Assist, Arrange) is a widely accepted method of addressing
tobacco use. The 2As and R (or 2As and C) model refers to Ask,
Advise, Refer or to Ask, Advise, Connect, respectively, in which
patients are referred or connected to evidence-based smoking
cessation support through a dedicated tobacco cessation
program. As reviewed in these references, patients with
cancer are often receptive to smoking cessation support
but suffer from similar patterns of tobacco use and risk of
relapse compared with the general population. What is
particularly unique to patients with cancer is that many
newly diagnosed patients will receive cancer treatment
requiring multiple visits to an oncology provider over a
relatively short period of time. As such, patients with
cancer have much more frequent contact with medical
providers than the general population, and this provides an
ideal platform to address tobacco use at multiple visits and
support patients with cancer in an effective quit attempt.29-31
The concept of a teachable moment is ideal, in which
patients with newly diagnosed cancer are faced with a life-
changing situation and providers can take advantage of this
opportunity to assist patients in a beneficial change in health
habits. Reviews above and the American Society for Clinical
Oncology tobacco resources34 discuss these issues in greater
detail.
Despite the clinical need and rationale to address tobacco
use, recent surveys demonstrate that although approxi-
mately 90% of oncologists ask about tobacco use and ap-
proximately 80% advise patients to quit smoking, only 30%
to 40% provide assistance with quitting.3,4 Given the evi-
dence, one might question why many clinicians and on-
cologists do not readily incorporate tobacco cessation into
effective clinical practice. However, it is important to note
that approximately 90% reported believing that smoking
caused adverse outcomes for patients with cancer and that
smoking cessation should be a standard part of cancer care,
which suggests that efforts to convert physicians knowledge
base to a better understanding of the adverse effects of
smoking may not prove fruitful. A recent survey of LDCT
screening programs shows very similar findings, with 99%
reporting asking about tobacco use and 91% advising to quit,
but only 50% to 60% providing assistance with cessation and

38% discussing cessation medications.35 Analysis of predictive
barriers to providing cessation support suggests that a lack of
time, lack of cessation resources, and lack of education on
cessation methods are dominant barriers to providing ces-
sation support.5 However, the concern that patients do not
want help with tobacco cessation has been refuted in studies
demonstrating that approximately 80% to 90% of patients with
cancer automatically referred to receive smoking cessation
support (an opt-out approach to tobacco cessation) are
receptive to intervention36,37 and patients who quit smoking
had significant improvements in survival.38 Collectively, these
data support a substantial need to provide evidence-based
cessation support to participants in LDCT screening programs
as well as to patients with cancer to manifest in the numerous
health benefits associated with smoking cessation. However,
despite the potential public health benefits for further re-
duction in tobacco-related morbidity and mortality, it is un-
known whether screening and treatment centers will commit
the time and resources needed to ensure delivery of evidence-
based tobacco cessation treatment.35
PRACTICAL CONSIDERATIONS TO IMPLEMENT
CHANGE
Simply stated, asking patients about tobacco use and ad-
vising them to quit is performed by most clinicians and is
necessary, but patients have higher smoking cessation rates
when providers help them quit smoking. Resources noted
above expound on common evidence-based methods to
address tobacco use and assist patients in quitting
smoking.2,14,29-34 Readers are encouraged to review these
resources as needed. However, implementation of
evidence-based care requires careful consideration of clin-
ical resources, environment, and expertise. Several practical
considerations are important to consider when developing
approached to addressing tobacco use; unfortunately, the
evidence base is lacking as to the best approach. When
addressing tobacco use with LDCT or cancer care, it is im-
portant to consider the following:
What is the clinical setting? Consider opportunities to
integrate tobacco treatment with medical management
and engage patients in tobacco treatment efforts. Pa-
tients presenting for LDCT screening typically return
annually for repeat assessments unless an abnormal
finding requires further work-up. In this setting, LDCT
participants may be reticent to return for in-person
clinical support for tobacco cessation alone. In con-
trast, patients diagnosed with cancer often return fre-
quently and multiple times for work-up, management,
and follow-up. Considering delivery of tobacco cessation
in coordination with repeated cancer care visits may be
helpful to both patients and providers.
What resources are available to assess and address
tobacco use? One size does not fit all. Larger institutions
may have more resources to support development of
dedicated tobacco cessation programs, whereas small
clinics and individual providers may need to provide
ADDRESSING TOBACCO WITH CANCER SCREENING AND TREATMENT
cessation support themselves or refer to existing com-
munity resources. Considering the location where ces-
sation support is provided is important to consider.
Providing cessation support in a busy clinical setting
may be met with resistance, such as where patient wait
times for oncology care are often delayed because of
limited clinical space. This is particularly salient in clinics
where multiple clinicians use a single clinic room.
How will tobacco be assessed? Reviews above discuss
methods to assess tobacco. However, it is important to
consider how tobacco use assessments will be collected.
For instance, tobacco assessments collected by nurses
or other staff can permit identification of tobacco use
that can be presented to a physician prior to entering a
patient room. It also permits consideration of scheduling a
patient for cessation support while a physician is
interviewing a patient for LDCT screening or cancer care.
The use of electronic medical records or paper charts is
also important and clinic specific. Clinical infrastructure
and development of efficient assessment and treatment
systems can be critical to gaining the support of clinical
and administrative staff in a department. However, once a
patients tobacco use has been identified, all clinicians
should advise patients to quit smoking and either provide
cessation assistance or refer/connect patients to dedi-
cated cessation support programs.
How will tobacco cessation support be delivered? The
basic elements of providing tobacco cessation support
include assessing a patients willingness to quit and de-
veloping an individualized tobacco cessation approach
that incorporates counseling, pharmacotherapy, and
follow-up. Specialized training is available. However,
cessation support can be delivered by a broad variety of
providers, including physicians, physician assistants, nurse
practitioners, nurses, pharmacists, psychologists, and
other providers who have received tobacco treatment
education. Advice to quit smoking should be repeatedly
delivered by all clinical staff. Support in the United States
and many other countries can also be delivered using
quitlines (1-800-QUIT-NOW in the United States) and
community cessation programs. In the experience of the
authors, many institutions may already have programs or
clinicians available that are often underutilized.
How will a tobacco cessation program be maintained? In
the experience of the authors, successful implementa-
tion of a tobacco cessation effort by clinicians or ded-
icated cessation programs includes buy-in and
participation from patients, clinical staff, providers, and
administration. Educating about the importance of to-
bacco across the clinic, cancer center, or institution can
increase awareness and help sustain a tobacco cessation
initiative. Considering issues related to billing and re-
imbursement can facilitate implementation in many
cases, but given the high cost associated with cancer
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 227
WARREN, OSTROFF, AND GOFFIN
care, the cost savings associated with cessation by
helping prevent costs associated with increased cancer
treatment toxicity or progression to next-line cancer
therapy are likely substantial. Thus, perhaps billing and
reimbursement on the front end of clinical care should
not be the foremost concerns when implementing a
cessation approach. As noted above, most clinicians
fully support addressing tobacco but lack the education,
time, and resources to implement cessation support.5
CONCLUSION
Overall, the principles of tobacco use are relatively simple.
Tobacco causes adverse health effects and continued
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surgeongeneral.gov/priorities/tobacco/. Accessed February 1, 2016.
2. U.S. Department of Health and Human Services. The Health Consequences
of Smoking50 Years of Progress: A Report of the Surgeon General.
Atlanta, GA: U.S. Department of Health and Human Services, Centers for
Disease Control and Prevention, National Center for Chronic Disease
Prevention and Health Promotion, Office on Smoking and Health; 2014.
3. Warren GW, Marshall JR, Cummings KM, et al. Addressing tobacco use
in patients with cancer: a survey of American Society of Clinical On-
cology members. J Oncol Pract. 2013;9:258-262.
4. Warren GW, Marshall JR, Cummings KM, et al; IASLC Tobacco Control
and Smoking Cessation Committee. Practice patterns and perceptions
of thoracic oncology providers on tobacco use and cessation in cancer
patients. J Thorac Oncol. 2013;8:543-548.
5. Warren GW, Dibaj S, Hutson A, et al. Identifying targeted strategies to
improve smoking cessation support for cancer patients. J Thorac Oncol.
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6. American Cancer Society. The Tobacco Atlas. www.cancer.org/aboutus/
globalhealth/cancerandtobaccocontrolresources/the-tobacco-atlas.
Accessed February 1, 2016.
7. Warren GW, Cummings KM. Tobacco and lung cancer: risks, trends, and
outcomes in patients with cancer. Am Soc Clin Oncol Educ Book. 2013;
33:359-364.
8. Thun MJ, Carter BD, Feskanich D, et al. 50-year trends in smoking-
related mortality in the United States. N Engl J Med. 2013;368:351-364.
9. Brandon TH, Goniewicz ML, Hanna NH, et al. Electronic nicotine delivery
systems: a policy statement from the American Association for Cancer
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2015;33:952-963.
10. Goldstraw P, Crowley J, Chansky K, et al; International Association for the
Study of Lung Cancer International Staging Committee; Participating In-
stitutions. The IASLC Lung Cancer Staging Project: proposals for the
revision of the TNM stage groupings in the forthcoming (seventh)
edition of the TNM Classification of malignant tumours. J Thorac
Oncol. 2007;2:706-714.
11. Humphrey LL, Teutsch S, Johnson M; U.S. Preventive Services Task
Force. Lung cancer screening with sputum cytologic examination, chest
radiography, and computed tomography: an update for the U.S. Pre-
ventive Services Task Force. Ann Intern Med. 2004;140:740-753.
12. Aberle DR, Adams AM, Berg CD, et al; National Lung Screening Trial
Research Team. Reduced lung-cancer mortality with low-dose com-
puted tomographic screening. N Engl J Med. 2011;365:395-409.
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tobacco use will continue to promote adverse health risks.
This simple relationship is easy to apply to a chronic disease
state such as cancer. Addressing tobacco by assessing tobacco
use and providing evidence-based tobacco cessation support
is extremely important across the continuum of cancer
screening, diagnosis, and treatment. Although many evidence-
based approaches exist, most providers do not assist patients
with quitting smoking. However, smoking cessation is the best
method to reduce or eliminate the adverse health effects of
tobacco. Combining practical clinical considerations with
evidence-based tobacco cessation methods should result in
substantially increased access to cessation support and ulti-
mately result in improved patient outcomes.
13. National Comprehensive Cancer Center. NCCN Clinical Practice
Guidelines in Oncology (NCCN Guidelines): Lung Cancer Screening.
www.nccn.org/professionals/physician_gls/pdf/lung_screening.pdf.
Accessed February 1, 2016.
14. National Comprehensive Cancer Center. NCCN Clinical Practice Guidelines
in Oncology (NCCN Guidelines): Smoking Cessation. www.nccn.org/
professionals/physician_gls/pdf/smoking.pdf. Accessed February 1, 2016.
15. Tanner NT, Kanodra NM, Gebregziabher M, et al. The association be-
tween smoking abstinence and mortality in the National Lung Screening
Trial. Am J Respir Crit Care Med. Epub 2015 Oct 26.
16. Black WC, Gareen IF, Soneji SS, et al. Cost-effectiveness of CT screening in
the National Lung Screening Trial. N Engl J Med. 2014;371:1793-1802.
17. Cornuz J, Gilbert A, Pinget C, et al. Cost-effectiveness of pharmaco-
therapies for nicotine dependence in primary care settings: a multi-
national comparison. Tob Control. 2006;15:152-159.
18. Goffin JR, Flanagan WM, Miller AB, et al. Cost-effectiveness of lung
cancer screening in Canada. JAMA Oncol. 2015;1:807-813.
19. Sobus SL, Warren GW. The biologic effects of cigarette smoke on cancer
cells. Cancer. 2014;120:3617-3626.
20. Tammemagi MC, Berg CD, Riley TL, et al. Impact of lung cancer screening
results on smoking cessation. J Natl Cancer Inst. 2014;106:dju084.
21. Yousaf-Khan U, Horeweg N, van der Aalst C, et al. Baseline charac-
teristics and mortality outcomes of control group participants and
eligible non-responders in the NELSON lung cancer screening study.
J Thorac Oncol. 2015;10:747-753.
22. Patel D, Akporobaro A, Chinyanganya N, et al; Lung-SEARCH In-
vestigators. Attitudes to participation in a lung cancer screening trial:
a qualitative study. Thorax. 2012;67:418-425.
23. Ostroff JS, Buckshee N, Mancuso CA, et al. Smoking cessation following CT
screening for early detection of lung cancer. Prev Med. 2001;33:613-621.
24. Park ER, Streck JM, Gareen IF, et al. A qualitative study of lung cancer
risk perceptions and smoking beliefs among national lung screening trial
participants. Nicotine Tob Res. 2014;16:166-173.
25. Poghosyan H, Kennedy Sheldon L, Cooley ME. The impact of computed
tomography screening for lung cancer on smoking behaviors:
a teachable moment? Cancer Nurs. 2012;35:466-475.
26. Ashraf H, Saghir Z, Dirksen A, et al. Smoking habits in the randomised
Danish Lung Cancer Screening Trial with low-dose CT: final results
after a 5-year screening programme. Thorax. 2014;69:574-579.
27. Anderson CM, Yip R, Henschke CI, et al. Smoking cessation and relapse
during a lung cancer screening program. Cancer Epidemiol Biomarkers
Prev. 2009;18:3476-3483.

28. Park ER, Gareen IF, Japuntich S, et al. Primary care provider-delivered smoking
cessation interventions and smoking cessation among participants in the
National Lung Screening Trial. JAMA Intern Med. 2015;175:1509-1516.
29. Warren GW, Sobus S, Gritz ER. The biological and clinical effects of
smoking by patients with cancer and strategies to implement evidence-
based tobacco cessation support. Lancet Oncol. 2014;15:e568-e580.
30. Gritz ER, Toll BA, Warren GW. Tobacco use in the oncology setting: advancing
clinical practice and research. Cancer Epidemiol Biomarkers Prev. 2014;23:3-9.
31. Warren GW, Ward KD. Integration of tobacco cessation services into
multidisciplinary lung cancer care: rationale, state of the art, and future
directions. Transl Lung Cancer Res. 2015;4:339-352.
32. Karam-Hage M, Cinciripini PM, Gritz ER. Tobacco use and cessation for cancer
survivors: an overview for clinicians. CA Cancer J Clin. 2014;64:272-290.
33. Fiore MC, Jaen CR, Baker TB, et al. Treating Tobacco Use and De-
pendence: 2008 Update. Clinical Practice Guideline. Rockville, MD: U.S.
Public Health Service; 2008.
ADDRESSING TOBACCO WITH CANCER SCREENING AND TREATMENT
34. American Society of Clinical Oncology. Tobacco cessation and control
resources. www.asco.org/practice-research/tobacco-cessation-and-
control-resources. Accessed February 1, 2016.
35. Ostroff JS, Copeland A, Borderud SP, et al. Readiness of lung cancer
screening sites to deliver smoking cessation treatment: current prac-
tices, organizational priority, and perceived barriers. Nicotine Tob Res.
Epub 2015 Sep 7.
36. Warren GW, Marshall JR, Cummings KM, et al. Automated tobacco
assessment and cessation support for cancer patients. Cancer. 2014;
120:562-569.
37. Tang MW, Oakley R, Dale C, et al. A surgeon led smoking cessation
intervention in a head and neck cancer centre. BMC Health Serv Res.
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38. Dobson Amato KA, Hyland A, Reed R, et al. Tobacco cessation may
improve lung cancer patient survival. J Thorac Oncol. 2015;10:
1014-1019.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 229
LUNG CANCER

Lung Cancer, Small Cell Lung

Cancer: On the Move (Again?)

CHAIR
Walter J. Curran Jr., MD
Winship Cancer Institute
Atlanta, GA

SPEAKERS
Solange Peters, MD, PhD
Lausanne University
Lausanne, Switzerland

Maria Catherine Pietanza, MD

Memorial Sloan Kettering Cancer Center
New York, NY
 NEW APPROACHES TO PATIENTS WITH SMALL CELL LUNG CANCER

Seeking New Approaches to Patients With Small Cell Lung

Cancer
Marie Catherine Pietanza, MD, Stefan Zimmerman, MD, Solange Peters, MD, PhD, and Walter J. Curran Jr., MD

OVERVIEW

The fundamental approach to the treatment of small cell lung cancer (SCLC) has not changed in the last several decades, with
most advances being restricted to improved radiation approaches. The standard first-line chemotherapy regimen in the
United States and Europe remains cisplatin or carboplatin plus etoposide in the treatment of limited stage (LS-SCLC) and
extensive stage (ES-SCLC) disease. Radiation therapy is administered to those patients with LS-SCLC, whose cancer is
confined to the chest in a single tolerable radiation field. This article will summarize a number of exciting observations
regarding the biology of SCLC and how a deeper understanding of newly integrated targets and target pathways may lead to
new and better therapeutic approaches in the near future.

T he fundamental approach to the treatment of SCLC has

not changed in the last several decades, with most ad-
vances being restricted to improved radiation approaches.
The standard first-line chemotherapy regimen in the United
States and Europe remains cisplatin or carboplatin plus
etoposide in the treatment of LS-SCLC and ES-SCLC disease.
Radiation therapy is administered to those patients with
LS-SCLC, whose cancer is confined to the chest in a single
tolerable radiation field: data support initiation of radiation
during cycle one or two and use of hyperfractionated radi-
ation therapy,1-8 though there is an ongoing large national
cooperative group study addressing the question of stan-
dard hyperfractionation versus a higher total dose radiation
using modern radiation techniques (NCT00632853). More
recently, thoracic radiation therapy is being extended to
patients with ES-SCLC after response to chemotherapy, as a
phase III trial showed considerable reduction in intratho-
racic recurrence and in 2-year overall survival.9 Prophy-
lactic cranial irradiation is recommended to patients with
LS-SCLC and ES-SCLC demonstrating a response to front-
line platinum-based therapy, which has been shown to
decrease the risk of intracranial recurrence and improve
overall survival.10,11
Although the response rates to first-line treatment are as
high as 60%80% in SCLC, cure occurs only in approximately
20% of patients, restricted to those with LS-SCLC.12 Essen-
tially all patients with ES-SCLC, and the majority of patients
with LS-SCLC, suffer relapse within months of completing
initial therapy. Depending on the length of time a response
is maintained, which is the strongest predictor of outcome,
patients are defined as having sensitive or refractory disease.
Those patients who maintain a response to initial treatment
of 3 months or longer are defined as having sensitive disease;
additional chemotherapy yields response rates of 25% and
median survival from the time of relapse of approximately
6 months. Patients with refractory disease are those who
either have no response to initial therapy or progress within
3 months; these patients rarely benefit from additional
treatment, with response rates less than 10% and median
survival of 4 months.
Only one agent has been approved by the U.S. Food and
Drug Administration for recurrent or progressive SCLC:
topotecan.13-15 Unfortunately, for patients with SCLC whose
disease has progressed after first- and second-line treat-
ments, there are no accepted regimens. Although inves-
tigators have studied a wide range of rationally based
therapies in the hopes of improving outcomes, results have
not been favorable (reviewed in Pietanza et al16).
However, more recent insights generated from genomic
and proteomic studies, as well as pathway-specific investi-
gations, as indicated above, may lead to the development of
effective therapies, which are critically needed in SCLC.
POTENTIALLY TARGETABLE SCLC MOLECULAR
ALTERATIONS
The MYC gene family members of transcription factors,
which are contributors to oncogenesis, have been described
in approximately 20% of SCLCs.17 As stated above, previous
efforts to inhibit MYC activity proved to be difficult; however,

From the Merck Research Laboratories, Rahway, NJ; Department of Oncology, HFR Fribourg, Fribourg, Switzerland; Department of Oncology, Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland; Winship Cancer Institute of Emory University, Atlanta, GA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Walter J. Curran Jr., MD, Winship Cancer Institute of Emory University, 1365 Clifton Rd. NE, Room A1356, Atlanta, GA 30322; email: curran04@gmail.com.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e477

PIETANZA ET AL
further understanding of the biology of the disease has
revealed specific mechanisms by which MYC can be po-
tentially targeted. MYC is a transcriptional regulator of
aurora kinases A and B, which, in the absence of p53,
provide a growth advantage,18-21 and as such, favorable
antitumor activity may be demonstrated by inhibiting aurora
kinases.22 Multiple preclinical studies have suggested that
SCLCs with MYC alterations are sensitive to aurora kinase
inhibitors.18,22,23 Alisertib, a selective aurora kinase A
inhibitor, has been evaluated in a phase II clinical trial of
patients with recurrent or progressive SCLC and demon-
strated a response rate of 21% among patients with both
sensitive and refractory disease.24 To augment these results,
there is an ongoing clinical trial evaluating paclitaxel with or
without alisertib for the second-line treatment of patients
with SCLC (NCT02038647), as aurora kinase A has a key role in
mitotic spindle assembly.
Inhibiting key regulators of MYC transcription may be
another potential mechanism in SCLC. MYC transcription in
SCLC and other tumors is regulated by the bromodomain and
extraterminal (BET) family of bromodomain-containing
proteins, which bind acetylated lysines on histone tails
and recruit key transcriptional proteins.25,26 Inhibiting BET
has been shown to prevent interaction of BET proteins with
acetylated histones and halt assembly of an active gene
transcriptional complex, leading to focal chromatin re-
modeling and decreased inhibition of c-Myc. GSK525762 is a
small-molecule inhibitor of BET being evaluated in a phase I
clinical trial that includes patients with SCLC (NCT01587703).
The genomic studies completed in SCLC thus far have
found amplification of fibroblast growth factor receptor
(FGFR) 1 in approximately 6% of cases,27-29 and sensitivity to
FGFR inhibitors has been described in some, but not all, SCLC
tumors.22 Although the magnitude to which this subset of
SCLC is dependent on the FGFR pathway remains unknown,
there are clinical studies evaluating drugs targeting the
FGFR family members for patients with SCLC: including JNJ
KEY POINTS
SCLC is an aggressive malignancy, uniformly linked to
tobacco use, and has a unique biology.
The fundamental approach to the treatment of SCLC has
not changed in nearly 4 decades and incorporates use of
a platinum doublet and, when possible, radiation
therapy.
As the biology of this disease is elucidated, multiple
targets are being identified and new trials have been
developed.
The MYC gene family of transcription factors may be
a targetable entity to test new therapies against, in
particular, aurora kinase inhibitors.
Epigentic processes, such as gene promoter methylation
and histone acetylation, may be candidate targets to
test in SCLC.
e478 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
42756493 (a pan-FGFR inhibitor; NCT01703481),30 BIBF1120
(a multitargeted drug that inhibits FGFR, vascular endo-
thelial growth factor receptor, and platelet-derived growth
factor receptor; NCT02152059); and lucitinib (a potent
inhibitor of FGFR1/2, vascular endothelial growth factor
receptor 13, and platelet-derived growth factor receptor
a/b; NCT02109016).
PROBING THE EPIGENOME
Epigenetic processes, such as gene promoter methylation
and histone acetylation, are known to be dysregulated in
SCLC and lead to alterations in chromatin and other asso-
ciated factors that modify the ability of genes to be tran-
scribed.31 Acetyltransferases and histone deacetylases
regulate histone acetylation, which leads to increased ac-
cessibility of promoter regions and increased transcription
of genes.32,33 Vorinostat and belinostat, which are histone
deacetylase inhibitors, have synergistic activity when added
to topotecan and cisplatin/etoposide, respectively.34,35
Clinical trials investigating the combination of vorinostat
(NCT00702962) and belinostat (NCT00926640) with plati-
num and etoposide in the first-line treatment of patients
with ES-SCLC are in progress.
DNA REPAIR
SCLC has been characterized by aberrant expression of
DNA repair proteins, including O6 alkyl-guanine, DNA
alkyltransferase (MGMT), poly (ADP-ribose) polymerase-1
(PARP-1), checkpoint kinase-1 (Chk-1), BRCA-1, and RAD51.36,37
Therefore, multiple DNA repair pathways represent attractive
targets in SCLC.
Temozolomide is an oral alkylating agent with improved
outcomes in the presence of MGMT promoter hyper-
methylation.38,39 In a phase II clinical trial of patients with
relapsed sensitive or refractory SCLC, temozolomide dem-
onstrated an overall response rate of 20%, and responses
were noted in patients in need of third-line treatment and in
those with brain metastases.39 These findings led to the
addition of temozolomide to compendia of agents recom-
mended for use in the treatment of SCLC.40
PARP activity is essential for the repair of single-stranded
DNA breaks through the base excision repair pathway.41,42 In
preclinical SCLC models, PARP inhibitors have demonstrated
activity whether evaluated alone or in combination with
DNA-damaging agents, including temozolomide.37,43-46
Talazoparib (BMN673), a PARP inhibitor that both mediates
catalytic PARP1 inhibition and traps PARP1 and PARP2 en-
zymes at damaged DNA sites,47 has shown single-agent activity
in patients with sensitive relapsed SCLC, with a 10% overall
response rate and 25% clinical benefit response rate.48 The
PARP inhibitors, talazoparib, veliparib, and olaparib, are being
evaluated in combination with etoposide/platinum or temo-
zolomide for patients with newly diagnosed or relapsed SCLC,
respectively (NCT01286987, NCT01642251, NCT02289690,
NCT01638546, NCT02446704, and NCT02049593). Phase I

data reveal that veliparib can safely be administered with
etoposide and platinum in patients with untreated SCLC.49
Among the multiple functions of Chk-1 are activation of
S and G2/M phase checkpoints, preventing entry into mi-
tosis, and coordination of homologous repair.50,51 Additional
proteins necessary at the G2/M checkpoint include ataxia
telangiectasia and Rad3-related (ATR) and Wee-1. Inhibition
of Chk-1, ATR, or Wee-1 leads to G2 checkpoint abrogation
and, in p53-negative tumors, such as SCLC, sensitizes the
cancer cells to DNA-damaging agents, leading to mitotic ca-
tastrophe and cell death.50 The Chk-1 inhibitors LY2606368
and AZD7762 have demonstrated activity when administered
alone or with olaparib and cisplatin in preclinical SCLC
models.50,52,53 Numerous inhibitors of Chk-1 (LY2606368 and
AZD7762), ATR (AZD6738, VX970, and Wee-1; AZD1775) are in
clinical development, and two phase I trials are actively
recruiting patients with SCLC: topotecan with VX970 in
ES-SCLC (NCT02487095) and AZD1775 with olaparib in re-
fractory solid tumors (NCT02511795).
THE NOTCH DEVELOPMENTAL PATHWAY
The Notch pathway is essential in early lung development
and regulates stem cell self-renewal; thus, when abnormally
activated, it can cause neoplastic proliferation, representing
an early event in tumorigenesis.54-56 Recent comprehensive
genomic analyses have found that the NOTCH family genes
are mutated in 25% of human SCLC. Thus, this pathway is a
potential target in SCLC. Importantly, however, Notch sig-
naling can have oncogenic or tumor-suppressive effects
depending on the cellular content and can influence multiple
other oncogenic pathways.57
Overexpression of Notch2 and Notch3 receptors and
target genes has been noted in SCLC. In preclinical SCLC
models, tarextumab (OMP-59R5), which is a fully human
monoclonal antibody that selectively inhibits Notch2 and
Notch3 receptor function, has demonstrated delayed tu-
mor recurrence following the discontinuation of chemo-
therapy, as well as a reduction in cancer stem cell frequency
and tumorigenicity.58 A phase I study of tarextumab with
etoposide/platinum in patients with ES-SCLC has been
completed,59 and a randomized phase II study is ongoing
(NCT01859741).
ANTIBODY-DRUG CONJUGATES
Antibody-drug conjugates, composed of an antibody di-
rected to a well-characterized antigen on cancer cells, a
linker, and cytotoxic agent (payload), represent an ef-
fective mechanism of targeted drug delivery, resulting in
decreased toxicity and improved therapeutic index.60
Rovalpituzumab tesirine exploits the Notch pathway as the
humanized monoclonal antibody portion targets the cell
surface available Notch ligand delta-like protein 3 (DLL3),
which is overexpressed in SCLC tumor-initiating cells but
not in normal tissue.61 The phase I trial of rovalpituzumab
tesirine enrolled 73 recurrent patients with SCLC in need
of second- or third-line treatment and demonstrated a
NEW APPROACHES TO PATIENTS WITH SMALL CELL LUNG CANCER
response rate of 23% in those evaluable.62 Notably, among
the 27 patients with confirmed DLL3-high tumor expression,
the response rates were 44% and 45% in the second- and
third-line settings, respectively, which were durable.62
A phase II trial evaluating rovalpituzumab tesirine for third-
line treatment of patients with SCLC with DLL3-expressing
tumors (TRINITY; NCT02674568) has begun accrual and, if
positive, will fulfill an unmet need, as there are no ap-
proved agents in this setting for this malignancy.
A phase II study evaluating sacituzumab govitecan
(IMMU-132), an antibody-drug conjugate comprising SN-38,
the active metabolite of the topoisomerase I inhibitor,
irinotecan, conjugated to an antiTrop-2 humanized anti-
body has been enrolling patients with previously treated
SCLC and non-SCLC (NCT01631552). Interim results have
shown a response rate of 30% in 20 evaluable patients with
SCLC who had received a median of 2.5 prior lines of therapy
and median progression-free survival of 2.4 months.63 As
Trop-2 is a human trophoblast cell-surface glycoprotein
overexpressed in multiple epithelial tumors, including SCLC,
this antibody drug conjugate is being studied in other ma-
lignancies as well.
IMMUNOTHERAPY
Modulating the immune response may represent another
treatment modality for patients with SCLC, as supported by
clinical and preclinical data indicated above (and reviewed
in Pietanza et al64): the disease is associated with immu-
nogenic effects; PD-L1 expression on SCLC tumors corre-
lates with the presence of tumor-infiltrating lymphocytes;
and the malignancy is nearly entirely related to smoking
and characterized by an elevated mutation burden, which
are known to be markers of response to immune check-
point inhibitors.65-71
Patients with untreated stage IIIB/IV NSCLC or ES-SCLC
were administered paclitaxel and carboplatin alone or with
the addition of ipilimumab, a humanized IgG1 monoclonal
antibody against CTLA-4, given on two dosing schedules, in a
randomized, double-blind, three-arm phase II trial.72 Based
on the results from the patient with SCLC cohort that re-
ceived the phased dosing schedule of ipilimumab, admin-
istered with cycle three of paclitaxel and carboplatin, who
appeared to have improved immune-related progression-
free survival compared with those treated in the other two
arms,73 a randomized, multicenter, double-blind phase III
trial comparing the efficacy of platinum/etoposide with
or without ipilimumab in patients with newly diagnosed
ES-SCLC, with OS as the primary endpoint, has completed
accrual, and results are anticipated (NCT01450761).
Nivolumab, with and without ipilimumab, has been
evaluated in heavily pretreated patients with relapsed
SCLC as part of a phase I trial evaluating the agents in
various tumor types (NCT01928394). Early results indi-
cate response rates of 13% and 31%, when nivolumab
is administered alone or with ipilimumab, respectively,
regardless of PD-L1 tumor expression, previous lines of
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e479
PIETANZA ET AL
therapy, and platinum sensitivity.74 Notably, the re-
sponses are durable, with 1-year overall survival of 27%
and 48% for patients treated with nivolumab and nivo-
lumab with ipilumumab, respectively.74 These results
have led to the development of two phase III studies
among patients with SCLC evaluating nivolumab, nivo-
lumab with ipilimumab, or placebo (NCT02538666) in the
maintenance setting, in which there is no defined treat-
ment modality, and nivolumab compared with chemo-
therapy for those in need of second-line treatment
(NCT02481830).
As part of a phase IB multicohort study, pembrolizumab
has been evaluated among patients with relapsed SCLC with
PD-L1positive tumors (NCT02054806). The response rate
was 29%, with a median duration of response of 29 weeks.75
There are several ongoing trials of pembrolizumab in patients
with SCLC, including a phase II study of the agent as main-
tenance therapy after the completion of standard, first-line
chemotherapy in extensive-stage disease (NCT02359019),
a phase I trial evaluating pembrolizumab with concurrent
chemoradiation therapy (NCT02402920), and others in-
vestigating the drug alone (NCT02628067), with various
chemotherapy agents (NCT02551432, NCT02580994, and
NCT02331251), or with novel biologics (NCT02661100).
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Presented at: 16th World Conference on Lung Cancer; September 2015;
Denver, CO.
LUNG CANCER

Treatment of Lung Cancer in

Medically Compromised Patients

CHAIR
Jeffrey Crawford, MD
Duke University Medical Center
Durham, NC

SPEAKERS
Josephine Louella Feliciano, MD
University of Maryland Greenebaum Cancer Center
Baltimore, MD

Paul Wheatley-Price, MBChB, FRCP, MD

Ottawa Hospital Research Institute
Ottawa, ON, Canada
CRAWFORD, WHEATLEY-PRICE, AND FELICIANO

Treatment of Lung Cancer in Medically Compromised Patients

Jeffrey Crawford, MD, Paul Wheatley-Price, MBChB, FRCP, MD, and Josephine Louella Feliciano, MD

OVERVIEW

Outcomes for patients with lung cancer have been improved substantially through the integration of surgery, radiation, and
systemic therapy for patients with early-stage disease. Meanwhile, advances in our understanding of molecular mechanisms
have substantially advanced our treatment of patients with advanced lung cancer through the introduction of targeted
therapies, immune approaches, improvements in chemotherapy, and better supportive care. However, the majority of these
advances have occurred among patients with good functional status, normal organ function, and with the social and
economic support systems to be able to benefit most from these treatments. The aim of this article is to bring greater
attention to management of lung cancer in patients who are medically compromised, which remains a major barrier to care
delivery. Impaired performance status is associated with poor outcomes and correlates with the high prevalence of cachexia
among patients with advanced lung cancer. CT imaging is emerging as a research tool to quantify muscle loss in patients with
cancer, and new therapeutics are on the horizon that may provide important adjunctive therapy in the future. The benefits of
cancer therapy for patients with organ failure are poorly understood because of their exclusion from clinical trials. The
availability of targeted therapy and immunotherapy may provide alternatives that may be easier to deliver in this pop-
ulation, but clinical trials of these new agents in this population are vital. Patients with lower socioeconomic status are
disproportionately affected by lung cancer because of higher rates of tobacco addiction and the impact of socioeconomic
status on delay in diagnosis, treatment, and outcomes. For all patients who are medically compromised with lung cancer,
multidisciplinary approaches are particularly needed to evaluate these patients and to incorporate rapidly changing
therapeutics to improve outcomes.

S ince the pioneering work of Karnofsky, the relationship

between impaired functional status and poor outcome
in patients with lung cancer has been well established.1 For
patients with advanced cancer, a grading system including
both body mass index and percent weight loss is highly
predictive of survival outcomes across multiple tumor types
including lung cancer. 2 Weight loss per se is the result of
the process of cancer cachexia, which has been defined
as a multifactorial syndrome associated with ongoing loss
of skeletal muscle mass (with or without fat mass), which
cannot be fully reversed through conventional nutritional
support and leads to progressive functional impairment.3
This definition has been very useful as a framework for
better understanding of cachexia, both at the molecular and
clinical levels, with a focus on muscle and muscle wasting.
CANCER CACHEXIA
Cancer-induced muscle wasting results in accelerated
muscle loss and a decline in physical function. Approximately
half of the patients with advanced lung cancer have severe
muscle wasting at diagnosis, and muscle wasting will
develop in approximately two-thirds of patients during
treatment. It is also clear that muscle wasting, or sarcopenia,
is common in patients with lung cancer, regardless of body
weight, and may exist even among patients with obesity.
This population of patients with sarcopenic obesity is at
particular high risk of complications, including impaired
functional status.4
To better understand the impact of muscle wasting on
patients with cancer techniques have been developed using
standardized CT, which allows quantitative assessment of
skeletal muscle and other body tissues.5 By using this
technique for patients with advanced lung and gastroin-
testinal cancers, virtually 100% of patients with a body mass
index below 20 will have muscle wasting, 30%50% will have
muscle wasting with a normal body mass index, and as many
as 20% with obesity will have overt muscle wasting. Looking
across all patients with sarcopenia, the incidence of dose-
limiting chemotherapy toxicity is increased, and time to
progression and overall survival is reduced.
For the patient with cancer the disease process leads to a
decline in muscle mass and associated anorexia, fatigue, and

Department of Medicine and Solid Tumor Therapeutics Program, Duke Cancer Institute, Duke University Medical Center, Durham, NC; Division of Medical Oncology, University of Ottawa,
The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; University of Maryland Greenebaum Cancer Center, Baltimore, MD.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Jeffrey Crawford, MD, Duke Cancer Institute, DUMC 3476, Durham, NC 27710; email: crawf006@mc.duke.edu.

2016 by American Society of Clinical Oncology.

e484 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


reduced quality of life, with subsequent weakness, declining
muscle strength, and reduced mobility, disability, and im-
pact on physical performance. At a molecular level, this loss
of muscle mass is associated with changes in protein stores,
including enzymes and other regulatory proteins, altered
metabolism, such as insulin resistance, and impaired
immunity.
The molecular mechanisms behind the muscle loss that
occurs in cancer cachexia and other forms of cachexia is an
area of extreme active investigation. Other factors that
may lead to direct muscle atrophy through cytokines, such
as tumor necrosis factoralpha and interleukin-6, as well
as myostatin and activin, are also under active investigation.
A number of agents that affect these cytokine-mediated
pathways are in development.6 A second approach has
been to directly increase muscle growth signals through
androgenic anabolic steroids or selective androgen recep-
tor modulators (SARM), as well as ghrelin mimetics. A first-
in-class SARM, enobosarm, showed promising results on
improvement in muscle and physical function among pa-
tients with cancer cachexia.7 Subsequent phase III trials
among patients with advanced lung cancer receiving che-
motherapy showed an increase in muscle mass in the
enobosarm treatment group compared with overall decline
in muscle mass in the placebo population, but effects on
physical function using stair-climb power were inconsistent
between the trials.8 Phase II trials of anamorelin, a ghrelin
receptor agonist for patients with cancer cachexia, again
showed improvement in skeletal muscle mass.9 Phase III
trials have also been performed with this agent for patients
with advanced lung cancer and cachexia and have shown
improvement in skeletal muscle mass, compared with pla-
cebo controls. In addition, this agent has positive effects on
improving appetite and overall weight gain. Improvement
in function as measured by hand-grip strength, however,
was not observed.10 Multiple factors may explain the lack
of correlation between increase in muscle and lack of
KEY POINTS
Patients with lung cancer who are compromised
physically, medically, or socioeconomically are often
excluded from clinical trials and have poorer treatment
outcomes.
Cancer cachexia is clinically recognized by weight loss,
but the primary process is muscle loss, which occurs in
the majority of patients with advanced lung cancer,
regardless of body mass index.
Care for patients with cancer and organ failure requires
close integration with disease subspecialists.
Socioeconomic disparities affect lung cancer risk,
diagnosis, therapy, and outcomes.
New paradigms are needed that include
multidisciplinary approaches to improving outcomes of
medically compromised patients.
CACHEXIA, FATIGUE, AND PATIENTS WITH LUNG CANCER
functional improvement, including the duration of therapy,
the choice of the functional tests, and other factors. How-
ever, these agents and others in development represent
exciting possibilities for future therapeutics in the field of
cancer cachexia.11
At present, most importantly for us as clinicians is rec-
ognition of the presence of cachexia in our patients. Weight
loss remains the primary clinical criteria. By definition, any
patient with greater than 5% of body weight loss has ca-
chexia regardless of their overall body weight. Although this
only represents a portion of patients with muscle loss as
defined by CT imaging, weight loss at least allows us to
recognize this subset of patients who require additional
supportive care. Although current pharmacologic interventions
have not been established to be effective, exercise12 and
nutritional support13 continue to be important for the
multimodality treatment of patients with lung cancer at
all stages. It is hoped that in the years ahead, CT imaging
of muscle will move from an investigational tool to a
clinical measurement to enable us to assess the impact of
our interventions for our patients, which should be and
include pharmacologic approaches, nutritional support, and
exercise.
TREATMENT OF PATIENTS WITH ORGAN
FAILURE
For patients with lung cancer, choices of systemic therapy
are routinely informed by, and based on, protocols emerging
from clinical research. These guide the patient and clinician
about the gold standard options when making decisions
regarding optimal therapy. However, in reality, many pa-
tients seen daily in the clinic may not be eligible for a clinical
trial because of a variety of factors ranging from poor
functional status, comorbidities, other malignancies, non-
measurable disease, or blood work falling outside of specific
parameters, to name a few. It is reasonable, therefore, to
question the transferability of clinical trial results to a
general population, and it potentially means that the
standards of care options actually have a less solid evidence
base for many patients. In a recent analysis of 528 patients
who were newly diagnosed with stage IV nonsmall cell lung
cancer (NSCLC) and seen in consultation by medical on-
cologists, only 55% received systemic treatment.14 Further,
when simple and limited generic clinical trial inclusion cri-
teria were applied to these patients, only 27% would have
been trial-eligible.15 In additional analysis of this dataset,
the average survival of patients who received systemic
palliative chemotherapy was not significantly different
among patients who were considered trial eligible or trial
ineligible. An interpretation may be that clinical trial eligi-
bility is too strict and clinical judgment is more important.
Despite this, there is another small but important cohort of
patients with major medical comorbidities, or a formal di-
agnosis of organ failure, who appropriately are excluded
from clinical trials and for whom systemic therapy poses
specific and challenging problems. In a review of selected
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CRAWFORD, WHEATLEY-PRICE, AND FELICIANO
TABLE 1. Selected Recent Practice-Changing Trials in Lung Cancer and Organ Function Exclusions
Trial Author Year
First-Line Chemotherapy Schiller et al16 2002
17
Second-Line Chemotherapy Hanna et al 2004
Chemotherapy + Bevacizumab Sandler et al18 2006
Maintenance Ciuleanu et al19 2009
20
EGFR + Gefitinib Mok et al 2009
ALK + Crizotinib Shaw et al21 2013
Nivolumab Brahmer et al22 2015
recent practice-changing chemotherapy, targeted therapy,
and immunotherapy trials, patients with renal impairment,
hepatic impairment, or cardiac impairment would have been
excluded (Table 1).16-23 Therefore, how should clinicians
and patients approach decisions about systemic therapy in
the presence of organ failure, given the lack of available
evidence?
This article provides guidance on a reasonable and pragmatic
approach to making systemic therapy decisions for patients
with lung cancer and organ failure. In recognizing and accepting
that there is an absence of published data in the medical lit-
erature to provide clarity, these recommendations are the
considered views of the authors, but other reasonable and
well-planned approaches may have equal validity. It is also
important to recognize that there is a spectrum ranging from
normal organ function, through stages of organ impairment
or dysfunction to organ failure. This article is restricted to
discussing implications of systemic therapy for patients with
lung cancer and established organ failure.
The first recommendation is that these issues should
be discussed in a multidisciplinary format, and specific in-
teraction with specialists related to the particular organ
failure is advised (e.g., nephrology, hepatology, cardiology,
etc.). Further, additional consultation with a specialist on-
cology pharmacist is advised, particularly if the decision is
made to proceed with therapy. Patients should be fully
informed regarding relative benefits and harms from ther-
apy, the consequences of declining therapy, and that pro-
ceeding with treatment will almost certainly not be based
on level-one evidence. For patients with advanced disease,
consideration should be given to early palliative care spe-
cialist input and advanced care planning.
Understanding the cause and prognosis of organ failure is
self-evidently important. Some patients are diagnosed
with an acute organ failure directly related to the lung
cancer, and, if considered reversible, this should be ad-
dressed. For example in a patient presenting with acute
renal failure caused by hydronephrosis from retroperitoneal
lymphadenopathy, by inserting a nephrostomy tube, the
renal failure can be reversed and the barrier to systemic
therapy is removed. However, the remainder of this article
will address patients with pre-existing organ failure, rather
than organ failure secondary to the malignancy. In a recent
review of clinical indicators of 6-month mortality in advanced
e486 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
Renal Failure Liver Failure Heart Failure
Excluded Excluded Unstated
Excluded Excluded Unstated
Excluded Excluded Excluded
Excluded Excluded Excluded
Unstated Excluded Unstated
Excluded Excluded Excluded
Excluded Excluded Unstated
noncancer illnesses, Salpeter et al evaluated heart failure,
dementia, geriatric failure-to-thrive syndrome, hepatic cir-
rhosis, chronic obstructive pulmonary disease, and end-stage
renal disease. This list represented approximately 70% of the
noncancer diagnoses on admission to hospice.24 Clearly, not
all patients with these conditions die within 6 months, but the
authors identified common and disease-specific prognostic
indicators, including poor performance status (PS), malnu-
trition, comorbid illness, and organ dysfunction.
In the cancer clinic, the clinician must understand the
natural course of the organ failure pathology. For patients
with liver, kidney, or heart failure who may be waiting for
organ transplantation, the diagnosis of lung cancer un-
fortunately makes them ineligible for the transplant pro-
gram. Regarding prognosis of advanced organ failure, the
United States Renal Data System Annual Data Report, de-
scribes 3-year survival as 52% for patients receiving he-
modialysis for end-stage renal disease, and 61% for patients
receiving peritoneal dialysis. The risk of death is particularly
high in the first year of hemodialysis, with rates reported up
to 25%. The Canadian Organ Replacement Register Annual
Report describes a 5-year survival for patients on dialysis of
approximately 43%. For patients with end-stage heart fail-
ure, the 1-year survival is approximately 50%,25 which is not
dramatically different from patients with stage IV NSCLC
receiving first-line chemotherapy. The prognosis of patients
with liver cirrhosis is variable, depending on severity, eti-
ology, and the presence or absence of complications. The
Model for End-Stage Liver Disease (MELD) score is used to
assess the severity of chronic liver disease26 as an alternative
to the Child-Pugh scoring system. Salpeter et al24 reported
that patients with decompensated liver failure (the presence
of complications of cirrhosis) may have a median survival of
less than 6 months if associated with high MELD scores.
An understanding of competing morbidities therefore
clearly plays an important role in understanding the role
systemic therapy plays in lung cancer. In assessing the need
for adjuvant chemotherapy for patients with early-stage
disease, it is highly likely that any benefit from chemother-
apy (approximately 5%) will be outweighed by the competing
risks of the comorbid condition for patients with organ failure.
As an illustration, the adjuvant online program is used to
model potential benefits from adjuvant chemotherapy in
resected NSCLC. Figure 1, adapted from the adjuvant online

FIGURE 1. The Benefit of Adjuvant Chemotherapy for
a Patient With Stage IIA NonSmall Cell Lung Cancer,
With or Without Organ Failure
website, demonstrated that the absolute benefit of chemo-
therapy (notwithstanding the challenges of actually admin-
istering the treatment) is only modestly reduced but is now
seen in the context of lung cancer no longer being the primary
health threat in any event. In contrast to the curative situation
in which the prize of successful therapy is great, for patients
with metastatic disease the role of competing morbidities
and organ failure is even more striking. When the absolute
benefits, measured in terms of prolonged overall survival
from systemic therapy, may only be measured in a few
months in a healthy population, the benefits from palliative
systemic therapy in patients with significant comorbidities or
organ failure are likely to be further diminished. These issues
must be openly disclosed and discussed with patients prior to
any decision to attempt systemic therapy.
For many (or indeed the majority of) patients with advanced
lung cancer and coexisting organ failure, a palliative approach
may be the most appropriate. Based on the seminal publication
by Temel et al, early palliative care intervention is associated
with improved quality of life and longer survival.27 Therefore
a recommendation would be to initiate a palliative approach
to management of these patients, including discussions re-
garding advanced care planning and place of care. While
a cliche, for many patients facing an incurable lung cancer,
and barriers to therapy because of organ failure, we maybe
should consider care as being more important than treatment.
Specifically, patients with rapid decline, hospitalization, frailty,
and poor functional status should have serious consideration to
a purely palliative treatment plan.
After assessing patients with lung cancer, in the multi-
disciplinary context and taking into account the issues dis-
cussed, the decision may still be to proceed with therapy.
This should be on the understanding of the relative lack
of data, and then a choice of regimen based on an un-
derstanding of the drug metabolism, with appropriate dose
adjustments after dialogue with an oncology pharmacist.
Table 2 outlines common lung cancer drugs and their route
of elimination and recommendations for their use in renal or
CACHEXIA, FATIGUE, AND PATIENTS WITH LUNG CANCER
hepatic impairment and for patients receiving dialysis.
Tabular information is taken from product monographs and
selected references.28,29 Data on efficacy for these drugs in
these scenarios are largely limited to case reports.
In conclusion, patients with lung cancer and organ failure
represent a population excluded from clinical trials and
with a limited evidence base. The competing morbidity and
mortality mitigate against potential benefits from anti-
cancer systemic therapy. The newer generations of targeted
therapies and immunotherapies may be easier to deliver,
but limited data exist. Clinicians should discuss these cases
in a multidisciplinary environment, and early intervention
from palliative care specialists may be particularly appro-
priate. Finally, as a community, we should seek to perform
clinical trials in this population of patients with lung cancer.
TREATMENT OF LUNG CANCER IN MEDICALLY
COMPROMISED PATIENTS: COMPROMISED
SOCIAL AND ECONOMIC STATUS IN LUNG
CANCERIS IT REAL AND DOES IT MATTER?
Many factors can make a patient vulnerable to poor out-
comes with lung cancer. Biologic and patient-related factors
such as poor nutrition, functional status, or organ function
undoubtedly contribute to vulnerability to poor outcomes.
However, it is critical to recognize that poor socioeconomic
status (SES) can render a patient equally vulnerable to poor
outcomes from lung cancer. Socioeconomic status is often
defined as ones class or standing measured by education,
income, and occupation.30 Poor SES can affect the disease at
various stages including development, diagnosis, treatment,
and, ultimately, outcomes from lung cancer.7 There are
many confounders such as race, education level, and in-
surance status when evaluating socioeconomic disparities,
but these variables are intimately connected. Interventions
that target these vulnerable populations may minimize the
socioeconomic disparities that exist in lung cancer.
Socioeconomic disparities have also been shown to af-
fect lung cancer risk, diagnosis, therapy, and outcomes in-
ternationally. It is often difficult to separate socioeconomic
disparities from other sources of disparities in lung cancer
such as race and insurance. Here, we will discuss the role of
socioeconomic factors, with a focus on income, in the de-
velopment, treatment, and outcomes of lung cancer in the
United States.
Socioeconomic Factors Contribute to Disparities
in Lung Cancer Risk
Tobacco is the leading risk factor for lung cancer develop-
ment, and approximately 80%90% of lung cancers are
related to tobacco.31 Earlier age of smoking initiation has
been associated with a higher prevalence of smoking
through adulthood, lower cessation rates, and increased risk
of lung cancer. It is indisputable that these factors dispro-
portionately affect lower-income populations.32-35
Childhood poverty, for example, has been linked to as
much as a 33% higher likelihood of initiation and earlier
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CRAWFORD, WHEATLEY-PRICE, AND FELICIANO

TABLE 2. Common Lung Cancer Drugs and Recommendations for Use in Renal or Hepatic Impairment and for
Patients Receiving Dialysis

Drug Elimination Liver Renal Dialysis

Cisplatin Renal Not applicable Decrease depending on CrCl 50% post-HD or non-HD days
Carboplatin Renal Not applicable Calvert formula Calverts formula give on non-HD day
Docetaxel Liver Adjust Not applicable Before or after HD not removed by HD
Pemetrexed Renal Caution in severe dysfunction Avoid if CrCl # 45 Avoid
Paclitaxel Liver Adjust Not applicable Not removed by HD
Gemcitabine Urine (inactive Consider adjustment if bilirubin Caution (D/C if HUS) Give 6-12 hours before HD
metabolites) . 27
Vinorelbine Liver Adjust depending on bilirubin Not applicable Limited data, consider 20 mg/m2 on
non-HD day
Etoposide Liver/Renal Adjust depending on bilirubin Adjust 50% before or after HD
Gefitinib Liver Caution Caution if CrCl , 20 No information
Erlotinib Liver Caution Not applicable No information
Afatinib Liver Caution Caution if CrCl , 30 No information
Crizotinib Liver Adjust Caution if CrCl , 30 No information
Ceritnib Liver Adjust Caution if CrCl , 30 No information
Bevacizumab Reticulo-endothelial Not involved Not involved No information
system
Nivolumab Biochemical degrada- No effect in mild impairment No effect if CrCl $ 15 mL/min No information
tion; no liver or kidney (not studied in severe) (not studied if less)
involvement
Abbreviations: CrCl, creatinine clearance; HD, hemodialysis; HUS, hemolytic uremic syndrome.

onset of smoking (odds ratio [OR] 1.33; 95% CI, 1.081.63).34
The prevalence of smoking is significantly higher in people
who live below the poverty versus those who live above the
poverty level. At the census track level in the United States,
smoking rates in populations with incomes below $20,000
per year is estimated at 38.2% compared with 17.3%29.6%
in populations who have incomes above $20,000 per
year.36,37 In addition, it has been recognized that people in
lower-income groups are less likely to use clinically proven
smoking cessation treatments and have less successful quit
attempts.38,39
Many factors contribute to this disproportionate tobacco
epidemic. One factor is the tobacco industrys marketing
campaigns. The tobacco industry has marketed smoking
and tobacco products to target young, lower-income pop-
ulations for decades, and these campaigns have been re-
markably successful.40,41 Adolescents who are receptive to
tobacco advertising, such as those who can recognize to-
bacco advertising messages or who identify a favorite
tobacco advertisement, are 2.33.9 times as likely to begin
smoking in adolescence compared with those who are not
receptive to tobacco advertising.42 Other factors such as
placement of low-cost tobacco outlets in low-income areas
and environmental or social stressors exacerbate this epi-
demic as well.43
Despite antitobacco campaigns such as clean environment
bills and advertisements, the decline in smoking rates has
been larger among people above the poverty level. Pro-
grams like those that have raised the price of cigarettes,
reduced advertising to lower-income populations, or have
provided extra support to vulnerable populations have had
alleviated, but not eliminated, smoking-related disparities in
low-income populations.44,45 It is crucial to address smoking
uptake and prevalence in lower-income populations to fur-
ther reduce disparities in the development of lung cancer.
Socioeconomic Status Affects Stage at Diagnosis and
Receipt of Stage-Appropriate Therapy for Lung Cancer
Lung cancer prognosis depends on numerous factors including
stage at diagnosis and receipt of stage-appropriate therapy.
Unfortunately, socioeconomic factors, including lower income,
are associated with diagnosis of lung cancer at later, less
curable stages.46,47 Numerous studies have demonstrated
that patients with lower income and Medicaid insurance or
no insurance are more likely to have advanced disease.7,48
For example, in areas where there is less than 10% poverty,
52%54.6% of patients have distant metastases compared with
areas with more than 20% poverty, where 56.8%59% of
patients have metastatic lung cancer.2 Similarly, in an analysis
of the Florida Cancer Registry, 25% of individuals from areas
with less than 5% poverty have localized disease compared
with only 22% of those from areas with more than 15% poverty
(p , .001).49 Presentation at later stages may be related to
numerous factors, such as a lower likelihood of being under the
care of a health provider who could potentially recognize the
signs of lung cancer or economic stressors that prevent in-
dividuals from seeking care.50
One potential factor that may widen the disparity in stage at
diagnosis in lower-income populations may be with the use and

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uptake of lung cancer screening. The National Lung Screening
Trial (NLST) has demonstrated that lung cancer screening with
low-dose CT scan can reduce lung cancer mortality by 20% and
that more lung cancer cases were diagnosed at earlier stages of
disease for patients who underwent a low-dose CT.51 However,
this research population of over 53,000 individuals represented a
population of largely white, highly-educated former smokers.51
It is largely unknown how these results translate or can be
applied to lower-income populations who are more likely to be
current smokers and less likely to be under the care of a health
care provider. Furthermore, it is largely unknown what health
care providers beliefs and attitudes are toward lung cancer
screening and how often screening guidelines are adhered to in
the era after the National Lung Screening Trial results were
published in various practice settings.52,53 It is likely that as lung
cancer screening becomes more refined and used, similar so-
cioeconomic disparities in screening will become apparent, and
efforts to empirically reduce this are important.
Lower socioeconomic groups are more likely to experience
delays in therapy from the time of diagnosis and less likely to
undergo stage-appropriate therapy for lung cancer.54,55 For
example, in a large population-based Surveillance, Epidemi-
ology, and End Results (SEER)-Medicare analysis, those with
incomes of less than $25,000 were more likely to have delays in
guideline-concordant lung cancer care (hazard ratio [HR] 0.89;
95% CI, 0.80.98; p # .05).54
As has been observed for other malignancies such as breast
or colon cancer, in which disparities have become apparent,
lack of awareness, lack of access, or mistrust of the health care
system may contribute to socioeconomic and racial disparities
in screening rates, stage at diagnosis, therapy, and survival.
Provider factors, such as whether a health care provider has
knowledge or understanding about the diagnosis or man-
agement of lung cancer, can also affect this receipt of therapy.
For example, even after the NLST results were published, many
physicians are not aware of who would be eligible for lung
cancer screening, even at an NLST site.52 In addition, lower
income has been associated with a lower likelihood of referral
to an oncologist, as well as lower likelihood of receipt of
guideline-appropriate therapy for locally advanced and
advanced NSCLC.56 Furthermore, health system barriers
such as lack of access to specialists can also influence the
diagnosis and receipt of therapy for lung cancer.
Lower Income Associated With Poorer Outcomes
From Lung Cancer
Although there are many confounders when evaluating so-
cioeconomic disparities in lung cancer outcomes, such as
smoking status, race, or medical comorbidities, individuals
with lower incomes have inferior outcomes from lung cancer.
In population-based studies, even when controlling for other
prognostic factors, lower income (, $46,000 compared
with . $46,000) was associated with inferior 30-day and
long-term survival after surgical resection.55,57 Low income
has also been independently associated with inferior survival
in advanced lung cancer.58,59 Furthermore, lower income was
CACHEXIA, FATIGUE, AND PATIENTS WITH LUNG CANCER
significantly associated with lower rates of hospice utilization
in elderly patients with advanced lung cancer.60
We Can Learn From Other Cancers Where
Socioeconomic Disparities Have Been Reduced
As health care providers, we have an opportunity to learn
from successful programs that have reduced cancer dis-
parities by targeting vulnerable populations. One highly
successful program implemented by the Delaware Cancer
Consortium, for example, mandated a statewide program
to increase colorectal cancer (CRC) screening in high-risk
populations (African Americans and under- or uninsured
patients) and demonstrated remarkable success.61 This
program used nurse navigators and care coordinators to
recruit vulnerable populations, funded screening for
treatment for CRC, and accomplished its goal of reducing
CRC screening, treatment, and survival disparities. In 9 years,
the disparities in screening rates, stage at diagnosis, and
mortality were almost eliminated. Similarly, because the CRC
program has been so successful, Delaware has also recently
launched a comprehensive program for lung cancer screening.62
In this program, education about screening is targeted
toward health care providers and patients. Patients who
are potentially eligible for screening are given access to
patient navigators and care coordinators who assist them
with receiving counseling and assistance with smoking
cessation. Eligible participants are also able to establish
care with a primary care provider who will order screening if
appropriate and recommend follow-up or referrals to
providers for further workup. Furthermore, participants
who are diagnosed with lung cancer will also be able to
TABLE 3. Contributing Factors to Economic Disparities
and Possible Interventions
Contributing Factor Intervention
Age at Smoking Initiation Interventions to target peer
groups 43,63,64
Smoking Prevalence Clean air laws62
Smoke-free multi-unit housing62
Prohibit tobacco sales near schools62
Prohibit outdoor advertisements62
Prohibit distribution of free or low-
cost tobacco 43,62
Smoking Cessation Reduce low-cost tobacco sale
outlets43
Financial incentives65
Increased access to smoking cessation
support65,66
Stage at Diagnosis and Receipt Education to providers61
of Therapy
Awareness (Patient and Education on screening61
Provider)
Access to Care Payment for therapy61
Fear of Diagnosis Patient and nurse navigators61,62
Establish care with a provider61,62
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CRAWFORD, WHEATLEY-PRICE, AND FELICIANO
receive therapy for their diagnosis with minimal to no
cost.
Despite improvements in early detection of lung cancer
and in therapeutics, the toll from lung cancer remains dismal
and disparities at all stages of lung cancer diagnosis and
management persist and, in many situations, continue to
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2010;21:1395-1403.
29. Brandes JC, Grossman SA, Ahmad H. Alteration of pemetrexed excretion
in the presence of acute renal failure and effusions: presentation of a
case and review of the literature. Cancer Invest. 2006;24:283-287.
30. Baker EH. Socioeconomic status, definition. The Wiley Blackwell
Encyclopedia of Health, Illness, Behavior, and Society. Hoboken, NJ:
Wiley-Blackwell; 2014.
31. U.S. Department of Health and Human Services. The Health Conse-
quences of Smoking: A Report of the Surgeon General. Atlanta, GA: U.S.
Department of Health and Human Services, Centers for Disease Control
and Prevention, National Center for Chronic Disease Prevention and
Health Promotion, Office on Smoking and Health; 2004.
32. Chen J, Millar WJ. Age of smoking initiation: Implications for quitting.
Health Rep. 1998;9:39-46.

33. Wiencke JK, Thurston SW, Kelsey KT, et al. Early age at smoking initiation
and tobacco carcinogen DNA damage in the lung. J Natl Cancer Inst.
1999;91:614-619.
34. Gilman SE, Abrams DB, Buka SL. Socioeconomic status over the life
course and stages of cigarette use: initiation, regular use, and cessation.
J Epidemiol Community Health. 2003;57:802-808.
35. Hegmann KT, Fraser AM, Keaney RP, et al. The effect of age at smoking
initiation on lung cancer risk. Epidemiology. 1993;4:444-448.
36. King BA, Dube SR, Tynan MA. Current tobacco use among adults in the
United States: findings from the National Adult Tobacco Survey. Am J
Public Health. 2012;102:e93-e100.
37. Agaku IT, King BA, Dube SR; Centers for Disease Control and Prevention.
Current cigarette smoking among adults - United States, 2005-2012.
MMWR Morb Mortal Wkly Rep. 2014;63:29-34.
38. Burns ME, Fiore MC. Under-use of tobacco dependence treatment
among Wisconsins fee-for-service Medicaid recipients. WMJ. 2001;
100:54-58.
39. Fu SS, Kodl MM, Joseph AM, et al. Racial/Ethnic disparities in the use of
nicotine replacement therapy and quit ratios in lifetime smokers ages
25 to 44 years. Cancer Epidemiol Biomarkers Prev. 2008;17:1640-1647.
40. Hackbarth DP, Silvestri B, Cosper W. Tobacco and alcohol billboards in
50 Chicago neighborhoods: market segmentation to sell dangerous
products to the poor. J Public Health Policy. 1995;16:213-230.
41. Yerger VB, Przewoznik J, Malone RE. Racialized geography, corporate
activity, and health disparities: tobacco industry targeting of inner
cities. J Health Care Poor Underserved. 2007;18:10-38.
42. Evans N, Farkas A, Gilpin E, et al. Influence of tobacco marketing and
exposure to smokers on adolescent susceptibility to smoking. J Natl
Cancer Inst. 1995;87:1538-1545.
43. Cantrell J, Anesetti-Rothermel A, Pearson JL, et al. The impact of the
tobacco retail outlet environment on adult cessation and differences by
neighborhood poverty. Addiction. 2015;110:152-161.
44. Vijayaraghavan M, Messer K, White MM, et al. The effectiveness of
cigarette price and smoke-free homes on low-income smokers in the
United States. Am J Public Health. 2013;103:2276-2283.
45. Haas JS, Linder JA, Park ER, et al. Proactive tobacco cessation outreach
to smokers of low socioeconomic status: a randomized clinical trial.
JAMA Intern Med. 2015;175:218-226.
46. Halpern MT, Ward EM, Pavluck AL, et al. Association of insurance status
and ethnicity with cancer stage at diagnosis for 12 cancer sites: a ret-
rospective analysis. Lancet Oncol. 2008;9:222-231.
47. Schwartz KL, Crossley-May H, Vigneau FD, et al. Race, socioeconomic
status and stage at diagnosis for five common malignancies. Cancer
Causes Control. 2003;14:761-766.
48. Slatore CG, Au DH, Gould MK; American Thoracic Society Disparities in
Healthcare Group. An official American Thoracic Society systematic
review: insurance status and disparities in lung cancer practices and
outcomes. Am J Respir Crit Care Med. 2010;182:1195-1205.
49. Yang R, Cheung MC, Byrne MM, et al. Do racial or socioeconomic
disparities exist in lung cancer treatment? Cancer. 2010;116:2437-2447.
50. Pateman K, Ford P, Fitzgerald L, et al. Stuck in the catch 22: attitudes
towards smoking cessation among populations vulnerable to social
disadvantage. Addiction. Epub 2015 Nov 28.
CACHEXIA, FATIGUE, AND PATIENTS WITH LUNG CANCER
51. Aberle DR, Adams AM, Berg CD, et al; National Lung Screening Trial
Research Team. Reduced lung-cancer mortality with low-dose com-
puted tomographic screening. N Engl J Med. 2011;365:395-409.
52. Lewis JA, Petty WJ, Tooze JA, et al. Low-dose CT lung cancer
screening practices and attitudes among primary care providers at
an academic medical center. Cancer Epidemil Biomarkers Prev.
2015;24:664-670.
53. Lam VK, Miller M, Dowling L, et al. Community low-dose CT lung cancer
screening: a prospective cohort study. Lung. 2015;193:135-139.
54. Nadpara P, Madhavan SS, Tworek C. Guideline-concordant timely
lung cancer care and prognosis among elderly patients in the United
States: a population-based study. Cancer Epidemiol. 2015;39:
1136-1144.
55. Melvan JN, Sancheti MS, Gillespie T, et al. Nonclinical factors associated
with 30-day mortality after lung cancer resection: an analysis of 215,000
patients using the national cancer data base. J Am Coll Surg. 2015;221:
550-563.
56. Goulart BH, Reyes CM, Fedorenko CR, et al. Referral and treatment
patterns among patients with stages III and IV nonsmall-cell lung
cancer. J Oncol Pract. 2013;9:42-50.
57. Khullar OV, Gillespie T, Nickleach DC, et al. Socioeconomic risk factors
for long-term mortality after pulmonary resection for lung cancer: an
analysis of more than 90,000 patients from the national cancer data
base. J Am Coll Surg. 2015;220:156-168.
58. Tannenbaum SL, Koru-Sengul T, Zhao W, et al. Survival disparities in
non-small cell lung cancer by race, ethnicity, and socioeconomic status.
Cancer J. 2014;20:237-245.
59. Erhunmwunsee L, Joshi MB, Conlon DH, et al. Neighborhood-level
socioeconomic determinants impact outcomes in nonsmall cell lung
cancer patients in the Southeastern United States. Cancer. 2012;118:
5117-5123.
60. Mack JW, Chen K, Boscoe FP, et al. Underuse of hospice care by
Medicaid-insured patients with stage IV lung cancer in New York and
California. J Clin Oncol. 2013;31:2569-2579.
61. Grubbs SS, Polite BN, Carney J Jr, et al. Eliminating racial disparities in
colorectal cancer in the real world: it took a village. J Clin Oncol. 2013;31:
1928-1930.
62. Healthy Delaware. https://www.healthydelaware.org/lung. Accessed
January 13, 2016.
63. Lipperman-Kreda S, Friend KB, Grube JW. Rating the effectiveness of
local tobacco policies for reducing youth smoking. J Prim Prev. 2014;35:
85-91.
64. Lee YO, Jordan JW, Djakaria M, et al. Using peer crowds to segment
Black youth for smoking intervention. Health Promot Pract. 2014;15:
530-537.
65. Parks MJ, Slater JS, Rothman AJ, et al. Interpersonal communication and
smoking cessation in the context of an incentive-based program: survey
evidence from a telehealth intervention in a low-income population.
J Health Commun. 2016;21:125-133.
66. Christiansen BA, Reeder KM, TerBeek EG, et al. Motivating low socio-
economic status smokers to accept evidence-based smoking cessation
treatment: a brief intervention for the community agency setting.
Nicotine Tob Res. 2015;17:1002-1011.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e491
MELANOMA/SKIN CANCERS

Clinical Conundrums in
Melanoma Therapy

CHAIR
Janice M. Mehnert, MD
Rutgers Cancer Institute of New Jersey
New Brunswick, NJ

SPEAKERS
Robyn Saw, MBBS, FRACS, MS
Melanoma Institute Australia and The University of Sydney
North Sydney, Australia

Sapna Pradyuman Patel, MD

The University of Texas MD Anderson Cancer Center
Houston, TX
 BIOMARKERS FOR IMMUNOTHERAPY

Biomarkers for Immunotherapy: Current Developments and

Challenges
Kristen R. Spencer, DO, MPH, Jianfeng Wang, MD, Ann W. Silk, MD, Shridar Ganesan, MD, PhD,
Howard L. Kaufman, MD, and Janice M. Mehnert, MD

OVERVIEW

Immunotherapy has revolutionized cancer therapy and has been named the cancer advance of the year for 2016. Checkpoint
inhibitors have demonstrated unprecedented rates of durable responses in some of the most difficult-to-treat cancers;
however, many treated patients do not respond, and the potential for serious side effects exists. There is a growing need to
identify biomarkers that will improve the selection of patients who will best respond to therapy, further elucidate drug
mechanisms of action, and help tailor therapy regimens. Biomarkers are being explored at the soluble, cellular, and genomic
levels, and examples in immunotherapy include serum proteins, tumor-specific receptor expression patterns, factors in the
tumor microenvironment, circulating immune and tumor cells, and host genomic factors. The search for reliable biomarkers
is limited by our incomplete understanding of how immunotherapies modify the already complex immune response to
cancer, as well as the contribution of immuno-editing to a dynamic and inducible tumor microenvironment and immune
milieu. Furthermore, there has been little extension of any candidate assay into large, prospective studies, and the lack of
standardization in measurement and interpretation restricts their validity. Both tumor-infiltrating lymphocytes and PD-L1
expression within the tumor microenvironment have been recognized as having both prognostic and predictive value for
patients treated with immunotherapy. Alternately, a larger panel of gene signatures, chemokines, and other factors that
correlate with response has been proposed. In this article, we will explore the status of current biomarker candidates.

S ince ipilimumab entered the treatment landscape in

2011, immunotherapy has continued to revolutionize
cancer therapy. In fact, immunotherapy was recently named
the American Society of Clinical Oncologys top cancer ad-
vance of the year for 2016.1 A number of U.S. Food and Drug
Administration (FDA)approved agents are available for an
increasing number of difficult-to-treat cancers, such as
melanoma, renal cell carcinoma (RCC), and lung cancer,
among others. In contrast with most chemotherapy and
targeted therapies, immunotherapy offers the possibility
of durable response, sometimes even without continued
treatment.2-4 However, objective responses among patients
treated with single-agent regimens are seen in less than one-
half of patients treated. Combination immune checkpoint
inhibitor therapy raises response rates but also increases
toxicity and cost.5 Thus, to optimize selection of appropriate
patients for immunotherapy and avoid unnecessary toxi-
city and health care costs, there is a clear need to identify
truly predictive, and not simply prognostic, biomarkers of
response.
Understanding which factors predict clinical benefit with
immunotherapy can improve the selection of tumor types
and patient subsets who will respond, illuminate the
mechanism of action of novel immunotherapeutic ap-
proaches, and potentially inform which patients require
single-agent versus various combination strategies, which
are increasing in availability. This review focuses on the de-
velopment of biomarkers for immunotherapy at the soluble,
cellular, and genomic levels. Examples of biomarkers in the
immunotherapy landscape include (1) soluble factors such
as serum proteins, (2) tumor-specific factors such as receptor
expression patterns and components of the microenviron-
ment, and (3) host genomic factors.6-8 Despite the interest in
biomarker development for immunotherapy, validated bio-
markers have remained an elusive goal.
WHY ARE BIOMARKERS CHALLENGING IN
IMMUNOTHERAPY?
Our incomplete understanding of the mechanisms of action
of specific immunotherapies makes it difficult to identify a
surrogate marker that adequately captures the process
across different classes of drugs.9 Many published analyses
of potential predictive biomarkers for immunotherapy are

From the Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Janice M. Mehnert, MD, Rutgers Cancer Institute of New Jersey, 195 Little Albany St., New Brunswick, NJ 08901; email: mehnerja@cinj.rutgers.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e493

SPENCER ET AL
retrospective, with limited extension into large prospective
trials. In addition, there has been substantial variability in
standardization, measurement, and interpretation of early
biomarker assays.10 Furthermore, biomarker development
in immunotherapy is challenged by the fact that immuno-
therapy targets are often inducible and dynamic over time
and location. This is a function of the complex tumor mi-
croenvironment and the contribution of immuno-editing
to the immune milieu. The tumor microenvironment in-
volves complicated interactions between several types of
infiltrating immune cells such as monocytes, neutrophils,
dendritic cells, T and B cells, eosinophils, basophils, mast
cells, and natural killer (NK) cells as well as the heteroge-
neous tumor cells themselves and their companion stromal
cells, including tumor-associated macrophages, fibroblasts,
adipocytes, and endothelial and other cells.11 The local
environment is further complicated by microniches cre-
ated by alterations in perfusion, oxygenation, electrolyte
levels, and the subsequent development of resistant tumor
cells surviving in nutrient- and oxygen-deprived condi-
tions.11,12 Thus, these microniches likely represent distinct
microenvironments with different cell types and factors,
all within one tumor deposit. Finally, incomplete immuno-
editing may result in selective pressure on tumor cells,
resulting in resistant tumor cell clones and immune
escape. 11
Despite these challenges, clinical research of immuno-
therapy over the last several years has confirmed the im-
portance of tumor-infiltrating lymphocytes within the tumor
microenvironment as having both prognostic and predictive
value for patients with cancer and for treatment with im-
munotherapy, respectively. There have also been several
trials of T-cell checkpoint inhibitors in which PD-L1 ex-
pression in the tumor microenvironment has been
KEY POINTS
Checkpoint inhibitors have demonstrated
unprecedented rates of durable responses in difficult-
to-treat tumors; however, many treated patients still do
not respond.
Biomarkers remain a critical missing link in attempting
to identify appropriate candidates for immunotherapy
and tailoring immunotherapy treatment regimens.
Examples of biomarkers being explored in
immunotherapy include serum proteins, tumor-specific
receptor expression patterns, factors in the tumor
microenvironment, circulating immune and tumor cells,
and host genomic factors.
The identification of appropriate biomarkers has been
limited by little extension into large prospective trials
that can validate their use and variability in assay
development and interpretation.
Tumor-infiltrating lymphocytes, tumor PD-L1
expression, tumor mutational burden, and several other
factors are being considered as candidate biomarkers.
e494 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
associated with more favorable outcomes, although this has
not been uniformly demonstrated. Other groups have used
a larger panel of gene signatures, including T helper (Th)
1 cytokines, chemokines, and other factors, that correlate with
therapeutic responses. These studies collectively suggest
that there may be host, tumor, and immune factors that can
be used for biomarker development. The importance of the
tumor microenvironment has been appropriately stressed,
but, practically, the ability to use serum or peripheral blood
biomarkers is of major clinical utility. We will explore the
status of current biomarker candidates from both com-
partments (Table 1).
PERIPHERAL BLOOD BIOMARKERS
Candidate biomarkers from serum, plasma, or peripheral
blood must be accurately and reproducibly measurable,
clinically feasible, cost-effective, and prospectively validated
in randomized clinical trials. Putative biomarkers in blood
might be soluble factors such as serum proteins, circulating
tumor DNA, or other cellular factors such as tumor cells,
T-cell subsets, or other immune cell populations. The serum
factors may be single or could include a panel of factors
preferably measured by a single, validated assay. To date,
most published analyses of peripheral blood biomarkers in
immunotherapy have been retrospective and hypothesis
generating, although important information has been gained
that illuminates the mechanisms of clinical benefit with some
approaches and has helped inform subsequent clinical trial
design.
Serum Soluble Biomarkers
The potential role of soluble serum proteins was first sug-
gested by studies of high-dose interleukin-2 (HD IL-2) among
patients with advanced melanoma and RCC in the 1990s.
High pretreatment serum levels of IL-6 and C-reactive
protein (CRP) were identified as possible prognostic markers
for treatment failure and shorter overall survival (OS) in
metastatic RCC after IL-2 therapy.13 Later, a French multi-
institutional study revealed that high pretreatment serum
values of CRP were independent predictors of resistance to
IL-2 therapy among patients with metastatic melanoma.14
More recently, in a retrospective analysis of patients with
advanced melanoma, pretreatment serum VEGF and fi-
bronectin, as measured by a customized proteomics array,
were found to inversely correlate with clinical response to
IL-2 treatment.15 In this trial, high levels of these proteins
were associated with lack of clinical response and decreased
OS. A prospective study of patients with melanoma being
treated with IL-2 (Melanoma SELECT) has been completed
and will help to confirm the validity of these markers as
predictive biomarkers.
Elevated levels of VEGF and CRP have similarly been as-
sociated with clinical outcomes for patients treated with
ipilimumab, an antibody that targets the T-cell checkpoint
CTLA-4 and was approved by the FDA in 2011 for the
treatment of patients with advanced melanoma. In an
 BIOMARKERS FOR IMMUNOTHERAPY

TABLE 1. Potential Predictive Biomarkers for Immunotherapy

Type Source Biomarker Clinical Significance
Soluble Serum IL-6 High levels are prognostic for HD IL-2 treatment failure and shorter OS
in metastatic RCC13
CRP High levels predict resistance to HD IL-214; decreasing levels during ipilimumab
therapy are associated with disease control and survival18
VEGF High levels are an independent predictor for lack of response to HD IL-215 and are
associated with decreased OS16
LDH Low pretreatment levels predict benefit from ipilimumab17; decreasing levels
during ipilimumab therapy are associated with disease control and survival18
sCD25 High levels predict resistance to ipilimumab19
NY-ESO-1 antibody Seropositivity has greater likelihood to respond to CTLA-4 blockade29,30
Cellular Peripheral blood Neutrophils/leukocytes High counts are prognostic for HD IL-2 treatment failure and shorter OS21
Lymphocytes Immediate lymphocytosis is associated with response to HD IL-2 therapy26
+
CD8 T cells Presence is associated with clinical benefit to CTLA-4 blockade30
ALCs Increasing counts during ipilimumab therapy are associated with an improved
OS18,23; however, this may occur in all patients regardless of benefit27
Eosinophils Increasing counts during ipilimumab therapy are associated with an improved OS23
+ +
CD4 ICOS T cells Increase in frequency after ipilimumab46
MDSCs Low frequency predicts benefit from ipilimumab therapy25
Tumor PD-L1 Refer to Table 2
TILs CD4+ICOShigh T cells Increased frequency correlates with clinical benefit in ipilimumab41,44-46
+
CD8 T cells PD-1/PD-L1 expression on these cells predicts response to PD-1 blockade47,55,57
Genomic Tumor Tumor mutation loads Predict clinical benefit to ipilimumab8,75 and PD-1 blockade7
MMR Predicts clinical benefit to PD-1 blockade76,77
Abbreviations: IL, interleukin; HD, high-dose; OS, overall survival; RCC, renal cell carcinoma; CRP, C-reactive protein; LDH, lactate dehydrogenase; NY-ESO-1, NY-esophageal
cancer 1; ALC, absolute lymphocyte count; ICOS, inducible T-cell costimulator; MDSC, myeloid-derived suppressor cell; TIL, of tumor-infiltrating lymphocyte; MMR, mismatch
repair.

analysis of sera collected from 176 patients with melanoma
treated with ipilimumab, pretreatment VEGF of 43 pg/mL
or greater was associated with decreased OS.16 In addition,
elevated serum lactate dehydrogenase (LDH) levels have
demonstrated a negative predictive value, with limited long-
term benefit from ipilimumab treatment found among
patients with baseline serum LDH greater than twice the
upper limit of normal in a cohort of 166 patients from the
Netherlands.17 These findings were also reported in an in-
dependent cohort of 64 patients from the United Kingdom.
Simeone et al18 also found that decreasing levels of serum
LDH and CRP between baseline and the end of ipilimumab
treatment at week 12 were significantly associated with
both disease control and survival for 95 patients treated with
ipilimumab (p , .0001). Although they are often commer-
cially available, these laboratory assessments are not fac-
tored into current clinical algorithms for making treatment
decisions. Another soluble factor that has been proposed is
baseline serum concentrations of soluble CD25, the alpha
chain of the IL-2 receptor, which independently predicted
OS in a large retrospective trial of 262 patients. Low levels
of CD25 were associated with favorable outcomes and ele-
vated levels predicted resistance to ipilimumab therapy, a
finding rooted in preclinical studies demonstrating that
blockade of the IL-2 receptor subunits abrogated the anti-
tumor efficacy of CLTA-4 blockade.19 It is not currently clear
whether these biomarkers are predictive or merely prog-
nostic factors. The prospective SELECT trial may help clarify
this important distinction.
Peripheral Blood Cellular Biomarkers
Similar to serum soluble factors, cells in the peripheral blood,
such as T cells, NK cells, dendritic cells, macrophages, and
tumor cells, have been studied as both prognostic and
predictive factors in multiple clinical trials. Elevated pe-
ripheral blood neutrophil and monocyte counts were as-
sociated with poor survival among patients with metastatic
melanoma20 and were an independent prognostic factor for
short OS among patients with stage IV melanoma un-
dergoing IL-2based immunotherapy in the retrospective
European Organisation for the Research and Treatment of
Cancer 18951 study.21 Interestingly, neutrophil and mono-
cyte counts did not predict clinical benefit in a recent ret-
rospective trial of 36 patients treated with ipilimumab,
although an early increase in eosinophil count was associ-
ated with improved clinical benefit,22 a finding reported
previously23 that can perhaps be explained as a sign of a
developing inflammatory response. In this analysis, myeloid-
derived suppressor cells (MDSCs), a heterogeneic immu-
noregulatory population of immune cells, were also negatively
correlated with clinical benefit. This finding was consistent with
reports of poorer prognosis for patients with increased MDSCs

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e495

SPENCER ET AL
during the first 24 weeks of treatment and improved outcome
with low baseline MDSC counts.24,25
Lymphocytes are perhaps the most frequently studied
peripheral blood component as predictors of response to
immunotherapy. It is well established that initial lympho-
penia and rebound lymphocytosis are hematologic side
effects of IL-2. A strong positive association between clinical
response and the degree of lymphocytosis immediately after
therapy has been reported.26 In a study of ipilimumab
treatment, decreasing regulatory CD4+FoxP3+ T cells and
increasing absolute lymphocyte counts (ALCs) during
treatment were significantly associated with both disease
control and survival.18 This same trend of increasing ALCs
correlating with improved clinical benefit has been reported
elsewhere,23 but a pooled analysis of data from several
studies noted this increase among all patients treated re-
gardless of benefit.27 Martens et al28 recently reported a
composite analysis suggesting that a signature of low LDH,
absolute monocyte counts, high relative lymphocyte counts,
eosinophil counts, and regulatory T cells are associated with
favorable outcomes among 209 patients, suggesting that
evaluating multiple dynamic cell populations may be nec-
essary to achieve predictive power.
Finally, the presence of induced autoimmunity has long
been hypothesized to predict clinical benefit from immu-
notherapy. Metastatic melanoma has been associated with
spontaneous antibody formation to a variety of common
tumor antigens, including differentiation antigens gp100,
tyrosinase, and Melan-A/melanoma antigen recognized by
T-cells 1 (MART-1), as well as cancer/testis antigens mela-
noma associated antigen 3 (MAGE-3) or NY-esophageal
cancer 1 (NY-ESO-1). As many as 50% of patients with ad-
vanced melanoma with NY-ESO-1expressing tumors spon-
taneously develop antibody.29 The patients with NY-ESO-1
seropositivity at baseline showing responses or with sero-
negativity showing a seroconversion had a greater likelihood
of experiencing clinical benefit 24 weeks after treatment
with ipilimumab (an antiCTLA-4 antibody) than their se-
ronegative counterparts.30
TUMOR CELL PHENOTYPE AND TUMOR
MICROENVIRONMENT BIOMARKERS
Although blood is more easily accessible, there is clear
evidence that activity within the tumor microenvironment
provides important clues as to how an individual tumor and
patient may respond to immunotherapy.
Tumor-Infiltrating Immune Cells as Biomarkers
Tumors with an active immune microenvironment, as ex-
emplified by infiltration of activated, effector T cells, may be
better primed to respond to immunotherapy. Indeed, an-
alyses of melanoma samples revealed that two distinct
phenotypic classes of tumor microenvironments exist: those
with a high prevalence of T cells (T-cell predominant or T-cell
inflamed) and those without T cells (T-cell poor or nonT-cell
inflamed; Fig. 1).31,32 The T cellinflamed tumors harbor
e496 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
large numbers of T cells at the tumor periphery, with in-
creased expression of T-cell activation markers, type 1 in-
terferon signatures, and high levels of Th1 cytokines and
chemokines that can effectuate T-cell recruitment and ef-
fector functions. In contrast, the nonT cellinflamed tumor
microenvironment has few, if any, effector T cells, although
these tumors may contain evidence of chronic inflammation
with tumor-associated macrophages, MDSCs, Th2 cytokines,
and chemokines, resulting in an immunosuppressed mi-
croenvironment that allows tumor progression. The precise
underlying mechanisms that mediate the type of immune
microenvironment in cancer are not completely understood.
Nonetheless, there have been several tumor-derived soluble
and cell membrane factors that may be responsible for the
observed phenotypic differences. For example, some tumor
cells in an inflamed environment will express high levels of
T-cell checkpoints, such as PD-L1, B7H4, Tim-3, Lag-3, and
others that can disable tumor-infiltrating effector cells.
Furthermore, various metabolic changes within inflamed
tumors, such as beta-catenin expression and intracellular
hypoxia and metabolic demand, or release of soluble
factors, such as indoleamine-2,3-dioxygenase, IL-10, VEGF,
and transforming growth factor-beta may result in in-
hibition of effector T cells. Some tumors may also exhibit
high levels of CD4+FoxP3+ regulatory T cells. These events
have a cumulative effect of ultimately preventing effector
T-cell function despite their abundance (Fig. 1).31 The
importance of T cells within the tumors has been under-
scored by the prognostic influence of such cells in a variety of
solid tumors, including colorectal, hepatocellular, gallblad-
der, pancreatic, esophageal, ovarian, endometrial, cervical,
bladder, nonsmall cell lung, prostate, head and neck, and
breast cancer.33-36
Currently, there is some controversy about which immune
cells are important in terms of promoting antitumor im-
munity versus tumor progression. The most important cells
for promoting antitumor immunity are likely CD8+ cytotoxic
T cells, CD4+ Th1 cells, NK cells, and mature dendritic cells.
The tumors with this lymphocyte-predominant infiltrate
pattern do seem to benefit more from tumor immunotherapy
than cancers without these tumor-infiltrating lymphocytes
(Fig. 1).31 The elegant work of Galon et al34 suggests that when
colorectal cancer lesions were analyzed for simply CD3+ T cells
or CD8+ T cells, a significant improvement in overall survival
was seen. In a different series, T cellinfiltrated melanomas,
especially those with high CD8+ T-cell content, were more
likely to be associated with high PD-L1 expression, improved
prognosis, and longer time to development of brain metas-
tases.37 The presence of intratumoral CD3+ T cells is also
correlated with improved progression-free survival (PFS)
and OS among patients with advanced ovarian carcinoma.38
High peritumoral densities of infiltration of lymphocytes
expressing the T-cell activation markers CD25 or OX40 were
associated with longer survival of patients with cutaneous
malignant melanoma.39 Concurrent high CD8+ and CD4+ T-cell
infiltration in nonsmall cell lung carcinoma was found to be
an independent favorable prognostic factor.40
 BIOMARKERS FOR IMMUNOTHERAPY

FIGURE 1. Tumors Exhibiting a T CellInflamed or Non-T-Cell-Inflamed Phenotype

(Top) Some tumors exhibit a T cellinflamed phenotype. In these tumors, a large number of tumor-infiltrating lymphocytes (TILs) and chemokines that recruit T cells are found.
Negative immune regulators including Fox P3+ regulatory T cells, PD-L1, and indoleamine-2,3-dioxygenase (IDO) are present as well; a type 1 interferon signature may also be present.
(Bottom) In contrast, some tumors exhibit a non-T-cellinflamed phenotype with an inverse pattern in which TILs are absent but chronic inflammation, as evidenced by common
suppressive cytokines, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSCs), exists.31,73

Additional studies of markers of immune activation, such
as inducible T-cell costimulator (ICOS), a T cellspecific
molecular that belongs to the CD28/CTLA-4 family and is
expressed only after T-cell activation, have been performed.
ICOS is thought to play an especially important role in T-cell
survival, proliferation, and generation of memory T cells. In a
neoadjuvant trial of 12 patients with bladder cancer treated
with ipilimumab, investigators demonstrated an increase in
peripheral and intratumoral ICOShighCD4+ T cells, which may
have an association with good clinical responses to ipili-
mumab therapy.41 Similar findings have been reported in
patients with prostate cancer, breast cancer, or mesothe-
lioma treated with ipilimumab or tremelimumab.42-45 A
statistically significant increase in the frequency of ICOS+
CD4+ T cells measured by flow cytometry in the peripheral
blood from patients with melanoma was found after ipili-
mumab treatment.46 These data suggest that the frequency
of ICOS+ CD4+ T cells may be useful in monitoring the biologic
activity of antiCTLA-4 therapy.
In contrast with the lymphocytes and activation markers
mentioned thus far, the presence of CD4+FoxP3+ regulatory
T cells, MDSCs, tumor-associated macrophages, and Th2-
type cytokine profiles has been associated with poor
prognosis or lack of response to immunotherapy. Th17 cells
are also controversial with mixed correlations in clinical
reports.
PD-1/PD-L1 Biomarkers in Development
Among the most important potential biomarkers of the last
few years are PD-1 and PD-L1 (Table 2). PD-1 is expressed in
the majority of tumor-infiltrating T cells, including antigen-
specific CD8+ T cells. PD-1 expression occurs after T-cell
activation and has been used as a marker of T-cell ex-
haustion. The PD-1 receptor binds to two ligands, which have
been designated PD-L1 and PD-L2. When PD-1 is engaged, it
results in T-cell elimination and PD-1 is thus considered a
T-cell checkpoint whose physiologic function is likely designed
to eliminate activated T cells once they have completed their
effector functions. When the interaction between PD-1 and
PD-L1 is inhibited (for example, with antiPD-1 or antiPD-L1
antibodies), T cells remain activated, mediating antitumor
activity.47 Interestingly, PD-L1 expression has been detected
in several different types of tumor cells, including mela-
noma, nonsmall cell lung cancer, RCC, bladder cancer,
gastric cancer, ovarian cancer, B-cell lymphoma cells, Merkel
cell carcinoma, and Hodgkin lymphoma (Table 2).

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TABLE 2. Summary of PD-L1 Expression and Response to Therapy in Various Clinical Trials

First Author Tumor Type Therapy Cutoff (%) Biomarker Results

48
Topalian Advanced melanoma, NSCLC, Pembrolizumab 5 0 of 17 patients with PD-L1negative tumors had
CRPC, RCC, and CRC objective response
Borghaei51 Advanced nonsquamous NSCLC Nivolumab vs. 1, 5, and 10 Nivolumab had superior efficacy to docetaxel, greater
docetaxel with higher tumor membrane PD-L1 expression
Muro80 Gastric Pembrolizumab 1 Tumor PD-L1 expression was associated with ORR
Taube53 Melanoma, NSCLC, RCC, Nivolumab 5 Tumor cell PD-L1 expression correlated with objective
CRC, CRPC response
Disis68 Recurrent/refractory ovarian Avelumab 1 Trend toward better response rates in PD-L1positive
cancer tumors
Garon49 Advanced NSCLC Pembrolizumab 50 PD-L1 expression in at least 50% of tumor cells correlated
with improved efficacy
Powles69 Bladder Atezolizumab 1, 5, and 10 PD-L1positive tumors at . 5% had particularly high
(antiPD-L1) response rates
Weber66 Advanced melanoma progressed Nivolumab vs. 5 Higher response rates with nivolumab correlated with
on antiCTLA-4 therapy investigators positive tumor PD-L1 expression, but patients with
choice PD-L1negative tumors still had benefit
Weber65 Advanced melanoma progressed Nivolumab 1 and 5 PD-L1 positivity correlated significantly with better
on prior therapy/CTLA-4 therapy response but negativity did not rule out response
Kefford67 Melanoma Pembrolizumab 1 PD-L1 positivity associated with improved ORR and
PFS, but activity observed in patients with low PD-L1
expression
Robert70 Metastatic melanoma Nivolumab vs. 5 Nivolumab-treated patients had improved objective
dacarbazine response rate and overall survival, regardless of
PD-L1 status
Motzer71 Metastatic RCC Nivolumab 1 and 5 Response rates were higher with greater PD-L1
expression ($ 5%), but those with lower expression
(, 5%) also had meaningful responses
Brahmer50 Advanced progressed squamous Nivolumab vs. 1, 5, and 10 Expression of PD-L1 was neither prognostic nor
NSCLC docetaxel predictive of benefit
Herbst57 Advanced melanoma, NSCLC, Atezolizumab 5 Response correlated with PD-L1 expression by
RCC, and other tumor-infiltrating immune cells, but correlation
between response and PD-L1 expression by tumor cells
was not significant
Abbreviations: NSCLC, nonsmall cell lung cancer; CRPC, castration-resistant prostate cancer; RCC, renal cell carcinoma; CRC, colorectal cancer; ORR, overall response rate; PFS,
progression-free survival.

In early phase I clinical studies of PD-1 blockade, clinical
responses were noted among patients with melanoma, RCC,
and nonsmall cell lung cancer.48 In many studies, a cor-
relation between clinical response and the presence of
PD-L1 expression on tumor cells was reported, although
this was not seen in every trial (Table 2). Based on this
unexpected finding, some clinical trials used baseline
PD-L1 expression as a criterion for study participation.
A clinical trial of pembrolizumab, a monoclonal antibody
that targets PD-1, was conducted in previously treated
patients with PD-L1 expressing nonsmall cell lung cancer
and demonstrated an objective response rate of 19%,
leading to FDA approval of the agent but only for patients
whose tumors stain positive for PD-L1. 49 Other clinical
studies using nivolumab, a comparable antiPD-1 agent,
also showed significant clinical responses in patients
with nonsmall cell lung cancer resulting in FDA approval
without requiring pretreatment PD-L1 expression test-
ing because this was not used as a study eligibility
criterion. 50,51
There are multiple challenges with using PD-1 and PD-L1
expression as biomarkers. First, PD-L1 expression is heter-
ogenous and dynamic within an individual. PD-L1 expression
can be induced by activated tumor-specific T cells, further
demonstrating that PD-L1 expression is a dynamic, not a
static, process.52,53 PD-L1 expression is often heterogeneous
within a sample, thus using focal expression may reflect the
biology of the tumor or may simply be sampling error.53
Furthermore, PD-L1 expression is often discordant between
the primary lesion and its metastases, and a positive marker
in one may not be reflective of the other.48,52,54 Additionally,
multiple cell types within a tumor besides the tumor cells
themselves may express PD-L1, such as lymphocytes and
macrophages, potentially altering readings,55 especially if
these inflammatory cells represent the host immune re-
sponse to tumor.56 A higher number of PD-1 and PD-L1
expressing tumor-infiltrating CD8+ T cells was associated
with clinical responses among patients with metastatic
melanoma treated with pembrolizumab.55 In a study eval-
uating MPDL3280A, an antiPD-L1 antibody, in multiple

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cancer types, responses were observed in patients with
tumor-infiltrating immune cells expressing high levels of
PD-L1.57 These results suggest that PD-1/PD-L1expressing
tumor-infiltrating immune cells may be predictive of tumors
likely to be responsive to T-cell checkpoint blockade and may
serve as a predictive biomarker. In most of these studies,
however, there was a low rate of clinical response observed
in patients with tumors having low levels of PD-1/PD-L1
expression. Thus, the sensitivity and specificity must be
better defined to avoid overtreatment of patients positive
for PD-1/PD-L1 who will not respond and undertreatment of
patients negative for PD-1/PD-L1 who might respond.
SPECIFIC PD-1/PD-L1 BIOMARKER ASSAYS
Although the immunohistochemistry (IHC) assay for PD-L1 is
affordable and relatively easy to perform on tissue, it is
limited by factors such as adequacy and abundance of the
sample. The PD-L1 ligand has only two hydrophilic regions
where antibodies bind, and IHC antibodies seemingly bind
at a different site than therapeutic antibodies, possibly
compromising the efficacy of the technique.52,58,59 Different
IHC antibodies and staining techniques introduce further
variability into the test and may influence positive or neg-
ative test rates.52 Without standardization across assays, it
becomes difficult to compare clinical trial results, especially
if the assays details are not easily available. Indeed, in a
recent study by McLaughlin et al60 testing two antiPD-L1
rabbit monoclonal antibodies, nearly 25% of lung cancer
samples that were positive for PD-L1 with one antibody tested
negative with the second. Especially pertinent to recent in-
vestigations, different assessment methods such as reading
tumor cells or tumor-infiltrating lymphocytes or both, dif-
ferent scoring methods such as percent staining positive or
H score, and different cutoff values set for positive or negative
results (1%, 5%, 10%, or even 50%) prevent standardization
across tumor types and same therapies.52
In October 2015, the FDA gave the first regulatory approval
to an immunotherapy biomarker to Mercks PD-L1 com-
panion diagnostic assay. This assay, PD-L1 IHC 22C3
pharmDx, uses the monoclonal antibody clone 22C3 for
membrane staining of tumor and/or infiltrating immune
cells in formalin-fixed, paraffin-embedded samples, with
a positivity cutoff of 1% or greater. The biomarker was
evaluated in the KEYNOTE-001 study of pembrolizumab in
patients with advanced nonsmall cell lung cancer. To
clinically validate the assay, 495 patients were assigned
either to a training group (one-third) or a validation group
(two-thirds). Data obtained from the training group were
used to establish the cutoff for PD-L1 positivity, which was
ultimately defined as expression in 50% of tumor cells. The
outcomes data from the validation group were analyzed
using the 50% cutoff defined by the training group. Patients
with a score of 50% or greater had a higher response rate,
longer PFS, and longer OS. Given the link between PD-L1
expression defined by the PD-L1 IHC 22C3 pharmDx assay
and efficacy with pembrolizumab, the FDA approved the
BIOMARKERS FOR IMMUNOTHERAPY
assay as a companion diagnostic for the indication of
identifying patients with nonsmall cell lung cancer for
treatment with pembrolizumab.49,61,62
The antiPD-1 antibody nivolumab also has a companion
diagnostic PD-L1 assay. PD-L1 IHC 28-8 pharmDx uses the
monoclonal antibody 28-8 to score tumor cell membranes in
formalin-fixed, paraffin-embedded tissue. Although the
original CheckMate 057 study of nivolumab versus docetaxel
was conducted among an unselected population of patients
with advanced nonsquamous nonsmall cell lung cancer, a
retrospective analysis of the data showed that patients
whose tumors expressed PD-L1 at a low threshold value of
1% or greater had a more significant improvement over
docetaxel than PD-L1negative patients across all end-
points. However, the retrospective PD-L1 testing was only
performed on 78% of the patient specimens, which may
introduce selection bias.51,61 This may be reflected in the
premarket approval from the FDA, which states that PD-L1
expression as detected by the 28-8 pharmDx assay in non-
squamous nonsmall cell lung cancer may be associated
with enhanced survival from nivolumab.61,63 This assay was
approved by the FDA in late 2015 in association with the
expanded approval of nivolumab in previously treated
nonsmall cell lung cancer.
The POLAR study examined the efficacy of the PD-L1 in-
hibitor atezolizumab versus docetaxel among patients with
advanced nonsmall cell lung cancer of squamous and non-
squamous histologies. This study used an SP142 antibody to
the membranes of tumor cells and tumor-infiltrating immune
cells. The data confirmed the efficacy of atezolizumab in-
dependently of PD-L1 expression, but the superiority of
atezolizumab over docetaxel was more pronounced with
higher expressions of PD-L1 as measured by the SP142 assay.61,64
As noted elsewhere, clinically meaningful responses have
been seen among patients whose tumors have been defined
as negative for PD-L149,65-71 (Table 2). In addition, among
patients receiving combination checkpoint inhibitor ther-
apy, responses among patients with PD-L1positive and
PD-L1negative results were similar.72 Given that a negative
result may still have considerable variability and may
exclude a patient from a therapy that could confer significant
clinical benefit, perhaps the more appropriate immediate
use of a PD-L1 biomarker is not to exclude patients with
negative results from treatment, but to better refine pre-
dictors of response by evaluating PD-L1 expression in
combination with other putative predictive markers to
better improve the sensitivity and specificity.73
TUMOR GENOMIC BIOMARKERS
The ability of T-cell checkpoint inhibitors to induce an ef-
fective immune response in some cancers raises the critical
question of what antigen(s) are being targeted by the ac-
tivated T cells. It was originally hypothesized that the
mechanism of antitumor activity might be through stoking
pre-existing, ineffective tumor-reactive T cells. In several
recent studies, however, it has become clear that clinical
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SPENCER ET AL
responses to T-cell checkpoint inhibitors are correlated with
overall mutation burden in the tumor cell.7,8,74,75 This
finding suggested that the T-cell response may be targeted
not to established antigens, but to so-called neoantigens,
that evolve as the mutation rate increases in the tumor cell.
Most of these mutations are likely passenger mutations
that may be influencing the immuno-editing process and
placing selective pressure on the immune system to pro-
mote tumor elimination through new, previously unedited
antigens. Although this is an intriguing hypothesis, further
work is needed to firmly establish whether mutation burden
or neoantigen emergence can be predictive biomarkers for
tumor response to immunotherapy agents.
A recent study using whole-exome sequencing (WES) to
analyze the potential effect of cancer genomes on the re-
sponse to ipilimumab among 64 patients with melanoma
confirmed that a high mutational load and the number of
nonsynonymous mutations per exome were significantly
correlated with improved OS.75 Using a bioinformatics
pipeline, the authors identified 101 tetrapeptide (four amino
acid) motifs within the nonamer (nine amino acid) peptides
sitting in the peptide-binding grooves formed by major
histocompatibility complex class I molecules. These tetra-
peptides were shared exclusively among patients in the
discovery cohort who had long-term clinical benefit. A re-
cent correction to the original report clarified that this
analysis did not have a true independent validation set
because all samples were used in the process of identifying
the final set of neoantigens.74
Indeed, mutation burden may be as predictive as neo-
antigen load in the landscape of response to immuno-
therapy. Rizvi et al7 observed that a high mutational burden
may be predictive of response to immunotherapy. Using
WES of nonsmall cell lung cancers treated with pem-
brolizumab, this study revealed higher nonsynomymous
mutation burden in tumors, and clinical responses were
correlated with molecular signature characteristics of to-
bacco carcinogen-related mutagenesis, higher neoantigen
burden, and DNA repair pathway mutations. In one re-
sponder, pembrolizumab enhanced neoantigen-specific
CD8+ T-cell reactivity that was associated with tumor re-
gression. In a series of 110 patients with melanoma, overall
mutation load, neoantigen load, and expression of immune
microenvironment cytolytic markers were associated with
clinical benefit, but no recurrent neoantigen peptide se-
quences predicted responder patient populations.8 There-
fore, although it is intriguing, the neoantigen hypothesis
needs further validation in other cohorts.
Although heavy mutation burdens may be seen in lung and
melanoma tumors, which are often generated by exogenous
environmental insults such as tobacco and ultraviolet light,
gene mutations that beget mutations, such as DNA mis-
match repair (MMR) gene deficiency, can also result in a
heavy mutational burden and may be useful to predict re-
sponse to immunotherapy. A phase II study evaluated the
response to pembrolizumab therapy among patients with
MMR-deficient cancers. Although 0% of patients (zero of 18)
e500 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
with MMR-proficient colorectal cancer responded to ther-
apy, 40% of patients (four of 10) with MMR-deficient co-
lorectal cancer and 71% of patients (five of seven) with
MMR-deficient noncolorectal cancer had immune-related
objective responses.76,77 Further WES revealed much higher
somatic mutation loads with a mean of 1,782 mutations per
tumor in MMR-deficient tumors, compared with a mean of
only 73 mutations per tumor in MMR-proficient tumors.
Mutations in other enzymes involved in DNA replication and
repair, such as the DNA polymerase epsilon gene (POLE) and
DNA polymerase delta 1 (POLD1), have been implicated in
the generation of a high mutation burden and associated
with response to immunotherapy. The POLE mutation is
associated with disruption of the exonuclease activity re-
quired for proofreading function and results in a high mu-
tational burden or ultramutator phenotype.78 Both POLE
and POLD1 mutations have been noted among patients with
nonsmall cell lung cancer who are responsive to pem-
brolizumab, and POLE and POLD1 are associated with high
mutational burdens.7 In addition, a case of an exceptional
response to pembrolizumab for a patient with endometrial
cancer whose tumor had a somatic POLE mutation was
recently reported.79 These data suggest that the presence of
MMR deficiency or POLE mutation may identify a subset of
seemingly diverse cancers that are especially vulnerable to
immune checkpoint blockade, although this approach must
be validated in further prospective studies.
FUTURE DIRECTIONS
The progress in tumor immunotherapy over the last 5 years
has been truly remarkable, with several monotherapy and
combination therapy regimens demonstrating impressive
clinical benefit across numerous solid and hematologic
malignancies. The ability to have a predictive biomarker to
better select appropriate patients for specific treatment
regimens and help define prognosis and other important
patient outcomes is a high priority in the field. Although
several soluble factors and cell-surface receptors in the
peripheral blood and tumor microenvironments have been
proposed, none have yet been fully validated in prospective,
randomized clinical trials. Putative biomarkers of interest
include the number and location of tumor-infiltrating im-
mune cells, PD-1 and PD-L1 expression, and host genomic
factors, such as mutation burden and neoantigen emer-
gence. Biomarker development also depends on having stan-
dardized, reproducible, and feasible assays that can be rapidly
completed with clearly defined cutoff values and with high
sensitivity and specificity. Although it may be premature to
recommend any of the current biomarkers for routine clinical
practice, there should be a high priority to include biomarkers
in clinical trial design for ongoing investigations of tumor im-
munotherapy regimens. Combination strategies and/or larger
panels may be of special interest for improving the predictive
power of contemporary biomarkers. As the use of immu-
notherapy is further optimized and novel combination
approaches are developed, biomarker investigation will

assume a critical role to inform the rational selection of
patients for this treatment approach.
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for anti-PD-1/PD-L1 clinical trials. Pigment Cell Melanoma Res. 2015;28:
245-253.
55. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces re-
sponses by inhibiting adaptive immune resistance. Nature. 2014;515:
568-571.
56. Bhaijee F, Anders RA. PD-L1 expression as a predictive biomarker: is
absence of proof the same as proof of absence? JAMA Oncol. 2016;2:
54-55.
57. Herbst RS, Soria J-C, Kowanetz M, et al. Predictive correlates of response
to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature.
2014;515:563-567.
58. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in
cancer immunotherapy. Mol Cancer Ther. 2015;14:847-856.
59. Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the
treatment of advanced human cancer. Clin Cancer Res. 2013;19:
1021-1034.
60. McLaughlin J, Han G, Schalper KA, et al. Quantitative assessment of the
heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA
Oncol. 2016;2:46-54.
61. Jrgensen JT. Companion diagnostic assays for PD-1/PD-L1 checkpoint
inhibitors in NSCLC. Expert Rev Mol Diagn. 2016;16:131-133.
62. U.S. Food and Drug Administration. Premarket approval (PMA) for
PD-L1 IHC 22C3 pharmDx. http://www.accessdata.fda.gov/scripts/
cdrh/cfdocs/cfpma/pma.cfm?id=P150013. Accessed October 2, 2015.
63. U.S. Food and Drug Administration. Premarket approval (PMA) for
PD-L1 IHC nivolumab pharmDx. http://www.accessdata.fda.gov/scripts/
cdrh/cfdocs/cfpma/pma.cfm?id=P150025. Accessed October 9, 2015.
64. Spira AI, Park K, Mazieres J, et al. Efficacy, safety and predictive bio-
marker results from a randomized phase II study comparing
MPDL3280A vs docetaxel in 2L/3L NSCLC (POPLAR). J Clin Oncol. 2015;
33 (suppl; abstr 8010).
65. Weber JS, Kudchadkar RR, Yu B, et al. Safety, efficacy, and biomarkers of
nivolumab with vaccine in ipilimumab-refractory or -naive melanoma.
J Clin Oncol. 2013;31:4311-4318.
66. Weber JS, DAngelo SP, Minor D, et al. Nivolumab versus chemotherapy
in patients with advanced melanoma who progressed after anti-CTLA-4
treatment (CheckMate 037): a randomised, controlled, open-label,
phase 3 trial. Lancet Oncol. 2015;16:375-384.
67. Kefford R, Ribas A, Hamid O, et al. Clinical efficacy and correlation with
tumor PD-L1 expression in patients (pts) with melanoma (MEL) treated
with the anti-PD-1 monoclonal antibody MK-3475. J Clin Oncol. 2014;
32:5s (suppl; abstr 3005).
68. Disis ML, Patel MR, Pant S, et al. Avelumab (MSB0010718C), an anti-PD-
L1 antibody, in patients with previously treated, recurrent or refractory
ovarian cancer: a phase Ib, open-label expansion trial. J Clin Oncol. 2015;
33 (suppl; abstr 5509).
69. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment
leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:
558-562.
70. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated
melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330.
71. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal
cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015;
33:1430-1437.
72. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in
advanced melanoma. N Engl J Med. 2013;369:122-133.
73. Mahoney KM, Atkins MB. Prognostic and predictive markers for the new
immunotherapies. Oncology (Williston Park). 2014;28:39-48.
74. Chan TA, Wolchok JD, Snyder A. Genetic basis for clinical response to
CTLA-4 blockade in melanoma. N Engl J Med. 2015;373:1984.
75. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response
to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189-2199.

76. Kelderman S, Schumacher TN, Kvistborg P. Mismatch repair-deficient
cancers are targets for anti-PD-1 therapy. Cancer Cell. 2015;28:11-13.
77. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-
repair deficiency. N Engl J Med. 2015;372:2509-2520.
78. Hussein YR, Weigelt B, Levine DA, et al. Clinicopathological analysis of
endometrial carcinomas harboring somatic POLE exonuclease domain
mutations. Mod Pathol. 2015;28:505-514.
BIOMARKERS FOR IMMUNOTHERAPY
79. Mehnert JM, Panda A, Zhong H, et al. Exceptional response to PD-1
antibody treatment in a POLE-mutant endometrial cancer (Abstract).
Mol Cancer Ther. 2015;14:PR05.
80. Muro K, Bang YJ, Shankaran V, et al. Relationship between PD-L1 expression
and clinical outcomes in patients (Pts) with advanced gastric cancer treated
with the anti-PD-1 monoclonal antibody pembrolizumab (Pembro;
MK-3475) in KEYNOTE-012. J Clin Oncol. 2015;33 (suppl 3; abstr 3).
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e503
MELANOMA/SKIN CANCERS

Curing High-Risk Melanoma: Are

We There Yet?

CHAIR
Sanjiv S. Agarwala, MD
St. Lukes Medical Center
Easton, PA

SPEAKERS
Alexander C.J. van Akkooi, MD, PhD
Netherlands Cancer Institute Antoni van Leeuwenhoek
Amsterdam, Netherlands

Michael B. Atkins, MD
Lombardi Comprehensive Cancer Center
Washington, DC

Paul Lorigan, MD
Institute of Cancer Sciences, University of Manchester
Manchester, United Kingdom
 SURGICAL MANAGEMENT OF MELANOMA

Surgical Management and Adjuvant Therapy for High-Risk and

Metastatic Melanoma
Alexander C.J. van Akkooi, MD, PhD, Michael B. Atkins, MD, Sanjiv S. Agarwala, MD, and Paul Lorigan, MD

OVERVIEW

Wide local excision is considered routine therapy after initial diagnosis of primary melanoma to reduce local recurrences, but
it does not impact survival. Sentinel node staging is recommended for melanomas of intermediate thickness, but it has also
not demonstrated any indisputable therapeutic effect on survival. The prognostic value of sentinel node staging has been
long established and is therefore considered routine, especially in light of the eligibility criteria for adjuvant therapy (trials).
Whether completion lymph node dissection after a positive sentinel node biopsy improves survival is the question of current
trials. The MSLT-2 study is best powered to show a potential benefit, but it has not yet reported any data. Another study, the
German DECOG study, presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting did not show any
benefit but is criticized for the underpowered design and insufficient follow-up. There is no consensus on the use of adjuvant
interferon in melanoma. This topic has been the focus of many studies with different regimens (low-, intermediate-, or high-
dose and/or short- or long-term treatment). Adjuvant interferon has been shown to improve relapse-free survival but failed
to improve overall survival. More recently, adjuvant ipilimumab has also demonstrated an improved relapse-free survival.
Overall survival data have not yet been reported due to insufficient follow-up. Currently, studies are ongoing to analyze the
use of adjuvant antiPD-1 and molecular targeted therapies (vemurafenib, dabrafenib, and trametinib). In the absence of
unambiguously positive approved agents, clinical trial participation remains a priority. This could change in the near future.

S urvival rates differ according to the stage of melanoma,

and, even for the low stages of melanoma, the 10-year
survival rates differ largely, from 93% in stage IA to 39%
in stage IIC.1 Since the last update in the American Joint
Committee on Cancer (AJCC) staging system, a number of
treatment breakthroughs have occurred in terms of im-
provement in systemic therapy (e.g., immune checkpoint
inhibitors, BRAF/MEK inhibitors [BRAFi/MEKi]),2-12 which
may ultimately affect these survival rates. Nevertheless,
these survival rates illustrate the fact that already some
patients with melanoma and only primary tumors without
(nodal) metastases will be likely to progress and can be
considered high risk. Moreover, it demonstrates the fact that
surgery can be curative for the majority of patients with
early-stage melanoma.
SURGICAL TREATMENT OF THE HIGH-RISK
MELANOMA PATIENT: IS THERE A STANDARD?
Primary Tumor
After diagnosis, most physicians recommend performing
a wide local excision with a certain margin. An important
question is whether an increasing margin will improve
overall survival (OS). This was the topic of a few prospective
randomized controlled trials comparing 1-cm with 3-cm,
2-cm with 5-cm, and 2-cm with 4-cm resection margins.13-15
The World Health Organization trial by Cascinelli et al
compared 1-cm margins with 3-cm margins for two Breslow
thickness groups, less than 1-mm Breslow and 1.012.00-mm
Breslow, and did not find any significant difference in local
recurrence rate or in OS after a median follow-up of 12 years
among a total of 612 patients.13,14 The Swedish group
compared 2-cm with 5-cm margins for 0.82.0 mm Breslow
thickness tumors in 989 patients and found a nonsignificant
hazard ratio (HR) of 0.96 (95% CI, 0.751.24) for OS and 1.02
(95% CI, 0.801.30) for recurrence-free survival after a me-
dian follow-up of 11 years (range 717 years).15 Similar results
are reported in the other studies by Khayat et al, Karakousis
et al, Thomas et al, and Gillgren et al.16-19
In contrast to these randomized controlled trials, Haydu
et al analyzed 2,131 patients with pT2 tumors from a single
institution.20 They found that there was a significantly worse
disease-free survival for patients with a margin less than
8 mm on pathologic analysis (corresponding to , 1 cm
clinically) compared with a 8- to 16-mm margin (corresponding

From the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; St. Lukes
University Hospital, Temple University, Allentown, PA; University of Manchester, The Christie NHS Foundation Trust, Manchester, United Kingdom.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Alexander C.J. van Akkooi, MD, PhD, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands;
email: a.v.akkooi@nki.nl.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e505

VAN AKKOOI ET AL
to 12 cm clinically; p = .044), however, this did not translate
into any OS difference.20
Interestingly, an update of the prospective randomized
controlled trial by Thomas19 discussed at the 2015 ASCO
Annual Meeting by Hayes et al21,22 did show, for the first
time, a difference in melanoma-specific survival (HR 1.27;
95% CI, 1.021.59; p = .036) in favor of the 3-cm margin
group compared with the 1-cm margin group. All patients in
this U.K. study had melanomas with a Breslow thickness
of greater than 2 mm, and 453 patients underwent a 1-cm
resection margin compared with 457 patients undergo-
ing a 3-cm resection margin. Although there were more
melanoma-related deaths in the 1-cm resection margin
group, the number of nonmelanoma-related deaths increased
in the 3-cm group. Therefore, the OS did not significantly differ
between the two groups.22 At the same time, this study has
also been criticized for the fact that patients were not staged
by sentinel node procedure and, therefore, an undetected
misbalance in this important staging factor might explain
the imbalance in the survival outcomes.23 Thus, the authors
practice-changing conclusion that a lesser margin has a det-
rimental effect on a patients survival cannot be simply ac-
cepted yet.
Sentinel Node
Multiple institutional and multicenter studies have verified
the prognostic information collected from the sentinel node
status of patients, not only for intermediate thickness but
also for thick melanoma.24-30 There is ongoing debate on the
interpretation of the results with respect to the interim and
final data of the Multicenter Selective Lymphadenectomy
Trial-1 (MSLT-1).28,31-34 The authors of the MSLT-1 study
concluded that: Biopsy-based staging of intermediate-
thickness or thick primary melanomas provides important
prognostic information and identifies patients with nodal
metastases who may benefit from immediate complete
lymphadenectomy. Biopsy-based management prolongs
disease-free survival for all patients and prolongs distant
KEY POINTS
Sentinel node staging provides optimal staging
information and is required for participation in adjuvant
therapy trials.
Surgery alone can be curative for primary melanomas,
locoregional disease, and in selected stage IV cases.
Adjuvant interferon has not demonstrated unequivocal
results but is the only approved adjuvant therapy in
many countries.
Adjuvant therapy with checkpoint inhibitors (antiCLTA-
4 and antiPD-1) and targeted therapies are ongoing,
and the results are pending.
AntiCTLA-4 has demonstrated a progression-free
survival benefit, but its effect on overall survival is not
clear yet.
e506 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
disease-free survival and melanoma-specific survival for
patients with nodal metastases from intermediate-thickness
melanomas.28 This is formally a completely correct con-
clusion because there is a clear benefit of 12.3% (69.8%
[6 4.4%] for sentinel nodepositive versus 57.5% [6 5.4%]
for observation nodepositive; HR 0.56; 95% CI, 0.370.84;
p = .006) in melanoma-specific survival after 10 years.28
However, the study has been criticized for a number of
reasons. First, the benefit was only found in a post hoc
subgroup analysis, but no difference in survival was seen
between the primary randomized study groups (wide local
excision plus observation versus wide local excision plus
sentinel node biopsy), with a 10-year melanoma-specific
survival of 78.3% (6 2.0%) compared with 81.4% (6 1.5%),
respectively (p = .18).28,34 This is reflected in potential
overtreatment (minimal sentinel node tumor burden; prog-
nostic false positivity) and under-treatment (worse outcome
of patients with false-negative disease compared with pa-
tients with sentinel nodepositive disease), which do not
influence the subgroup analysis but do influence the pri-
mary randomized study groups and primary endpoint of the
study.32-34
Therefore, the true therapeutic benefit of a sentinel node
procedure remains a matter of debate. Nonetheless, today
most surgeons, dermatologists, and other melanoma spe-
cialists worldwide consider sentinel node biopsy a standard-
of-care procedure for optimal staging and, therefore, part of
the workup of intermediate thickness and thick melanomas
($ pT1b = $ 1.00-mm Breslow or in case of , 1.00-mm
Breslow when the tumor is ulcerated or if there is one or
more dermal mitosis present), who do not yet have clini-
cally apparent detectable metastases. With the potential
for more effective adjuvant therapy options as approved
therapies in the stage IV setting complete testing in the
stage III population, this need for optimal staging will only
increase.
Lymph Node Dissections
Lymph node dissections can be divided into three categories:
(1) elective (or prophylactic) lymph node dissection, (2) ther-
apeutic lymph node dissection, and (3) completion lymph
node dissection.
Elective lymph node dissection is currently an abandoned
procedure. Four prospective randomized controlled trials
from the 1970s and 1990s have sought to find a survival
benefit for elective lymph node dissection but have
failed.35-38 The morbidity of elective lymph node dissection
was high, and, in the case of trunk or head and neck mel-
anomas, it could be unclear which nodal basin should be
prophylactically removed. Subgroup analyses from the
Cascinelli et al and Balch et al studies did seem to indicate a
potential benefit for patients with intermediate thickness
melanoma, who did indeed have nodal involvement.37,38
This was the starting point for the MSLT-1 study.
Therapeutic lymph node dissection is performed for clini-
cally apparent detectable nodal metastases at presentation

or during follow-up. If staging imaging examinations (CT,
PET-CT, and/or MRI) do not indicate any distant metastases,
surgeons worldwide will propose this to patients. Five-year
survival rates differ depending on the type of dissection (neck,
axilla, or groin), the number of lymph nodes involved, and the
presence of extracapsular extension. The AJCC database re-
ports survival between 59% for stage IIIB and 40% for stage
IIIC.1 Some institutional databases report even worse out-
come of 20%40%.39-45
One prospective randomized controlled trial, MSLT-2
(NCT00297895), is evaluating the therapeutic value of com-
pletion lymph node dissection after a positive sentinel node
biopsy, which compares with nodal observation by periodic
ultrasound.46,47 This study has completed accrual but needs
to complete follow-up before initial outcomes can be re-
ported. Therefore, there is no consensus yet on this topic,
which is illustrated by several studies demonstrating a dis-
tribution of around 50% for completion lymph node dissec-
tion compared with 50% for nodal observation in the United
States/North America, Europe, and Australia.48,49
At the 2015 ASCO Annual Meeting, Leiter et al reported on
the results of the prospective randomized controlled trial
German DECOG group study, which also compared com-
pletion lymph node dissection with nodal observation. In a
total of 483 patients (242 of whom underwent completion
lymph node dissection versus 241 of whom underwent nodal
observation), with a median follow-up of 34 months, there
were no differences in recurrence-free survival, distant
metastasesfree survival, or melanoma-specific survival.50
However, this trial was criticized for the lack of mature
follow-up and was likely to be underpowered compared with
the MSLT-2 trial, which accrued nearly 2,000 patients. The
very recent results of the Sunbelt Melanoma Trial confirm
the DECOG results, by showing again that there was no
difference in overall survival after CLND. However, this was
not the primary focus of this study and potentially un-
derpowered to look at that.51 Finally, there is a question if all
patients with tumor-bearing sentinel nodes might benefit
from completion lymph node dissection or if some patients
with minimal sentinel node tumor burden might not benefit
as their prognosis is comparable to patients with sentinel
nodenegative disease.52-54 This topic is being addressed by
the EORTC 1208 Minitub (NCT01942603) prospective
registry.
In-Transit/Distant Metastases
The latest AJCC staging system considers in-transit meta-
stases as stage IIIC, and they have a poor 5-year survival rate
of 46% or 69% (with and without regional lymph node
involvement, respectively).1 Read et al reported rates of
40% or 59% (with and without regional lymph node in-
volvement, respectively),55 and Pawlik et al reported a rate
of 54%.56 None of these studies reported the type of in-
transit metastases (cutaneous or subcutaneous) or number
of metastases (single or multiple), and they also did not
report on the type of treatment (e.g., surgery, amputation,
SURGICAL MANAGEMENT OF MELANOMA
radiotherapy, isolated limb perfusion/infusion, systemic
therapy). However, regardless of this heterogeneity, most
surgeons and other melanoma-treating specialists will
concur that, in the absence of distant metastases on dis-
semination examination (CT, PET-CT, or MRI), a locoregional
treatment with curative intent is the preferred approach.
However, with the advent of more effective systemic
therapies, it may become reasonable to first treat such
patients with systemic treatment (particularly immuno-
therapy) and save surgical resection as a salvage procedure
for residual disease.
Surgical treatment of distant metastases is a rare phe-
nomenon because usually the amount of lesions is too
many for complete resection of all with any potential clin-
ical benefit. However, there are a few scenarios where one
might consider surgery for a patient with stage IV disease.
Obvious reasons are in the case of symptoms such as bowel
obstruction, bleeding, and pain for palliative reasons. But
there is potential for cure in a highly selected patient cohort.
Typical selection criteria are one, two, or three or more
lesions; M1a, M1b, or M1c disease; and the disease-free
interval before the development of these distant metasta-
ses. Howard et al demonstrated in these cases a 4-year
survival rate of 20.8% for patients undergoing surgery as part
of their treatment compared with 7.0% for patients who
were not eligible for surgery and received systemic therapy
only (prior to checkpoint inhibitors/BRAFi/MEKi).57 A se-
lected subgroup of patients who only received surgery could
achieve even a 4-year survival of 45.7%.57 Similar rates have
been shown by Sosman et al (31% at 4 years).58 In general,
surgical resections with curative intent are reserved for this
highly selected (biased) patient cohort.
Future Projections
With the introduction of effective systemic therapy (e.g.,
immune checkpoint inhibitors, BRAFi/MEKi), the role of
surgery will be subject to change. Primarily, staging for
adjuvant therapy through standard of care sentinel-node
biopsy will no longer be a matter of debate. The question of
whether completion lymph node dissection is necessary
after a positive sentinel node will be a matter of debate at
first (upcoming 1020 years) but is likely to evolvesimilarly
to the situation in breast cancer, where it is reserved for
cases who did not respond to the systemic therapy or as a
salvage procedure after progression. At the same time,
surgery for patients with stage IV disease will also evolve.
Patients with solitary residual disease (near complete re-
sponse to systemic therapy) or with a mixed response
(progression of solitary lesion, when all others show re-
sponse) will be the target of surgical resection. Finally, locally
advanced (unresectable) disease will be the target of neo-
adjuvant induction treatment to allow complete resection.
Surgical Conclusions
Wide local excision is recommended to reduce local re-
currence rates, but it does not influence survival. Worldwide,
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e507
VAN AKKOOI ET AL
there is no consensus on whether performing a sentinel node
procedure and/or completion lymph node dissection has a
proven therapeutic benefit. Sentinel node staging and sub-
sequent completion lymph node dissection in the case of
positive sentinel node biopsy provides optimal staging in-
formation and is required to allow patients to be included in
adjuvant therapy trials. Locoregional treatment is considered
with curative intent for in-transit metastases. Highly selected
patients with stage IV disease might benefit from surgical
resection. The role of surgery for melanoma will evolve be-
cause of the introduction of effective systemic therapy, with
an increasing need for optimal staging, increasing salvage
surgery after near complete response or in case of mixed
response, and neoadjuvant approaches after induction treat-
ment of locally advanced disease.
ADJUVANT THERAPY FOR PATIENTS WITH
RESECTED HIGH-RISK AND STAGE IV MELANOMA
The past 5 years have seen dramatic improvements in the
outcomes for patients with metastatic melanoma, evi-
denced by an improvement in the expected median survival
of patients from 9 months to approximately 2530 months
and durable treatment-free responses from 10% to as high
as 50% in this short period of time.59,60 Linked to this, a
number of new immunotherapy and targeted therapy agents
have been licensed both as single agents and in combinations.
There is a high expectation that outcomes for patients will
continue to improve based on the evaluation of new agents
and the rapidly increasing understanding of the molecular
basis of resistance to both targeted therapy and immuno-
therapy and how this can be circumvented.
Advances in the field of adjuvant therapy of melanoma
have been significantly less dramatic than for metastatic
melanoma. Despite the approval of two new agents (ipili-
mumab and pegylated interferon [PEG-IFN]), the past
5 years have not seen any improvement in OS in any adjuvant
therapy study. However, it is too early to draw any con-
clusions about the use of targeted therapy or checkpoint
inhibitors as adjuvant therapy, as the studies are either still
recruiting or have not yet been fully reported. Until then, IFN
remains a treatment option in the United States and in many
European countries, although there is no consensus on the
exact indication group, dose, and/or duration of treatment.
The U.S. Food and Drug Administration (FDA) approved
ipilimumab in October 2015 based on the improvement in
relapse-free survival (RFS), but with absent OS data at this
moment, a definitive recommendation for its use cannot yet
be made.
We discuss the current role of adjuvant therapy in mel-
anoma and highlight potential developments in the next
5 years.
Challenges in Evaluating Adjuvant Trials
A number of challenges arise when examining individual
studies and comparing different adjuvant therapy trials. The
AJCC staging system reflects the understanding of staging at
e508 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
the time of its publication; however, it is at the mercy of
rapidly advancing technology and the inconsistent appli-
cation of this both across and within trials. Sentinel node
biopsy has been clearly established as a very strong prog-
nostic factor for primary melanoma.1,28 However, the
emergence of molecular-based diagnostic techniques means
that much a smaller tumor burden can be detected in the
lymph node, and the clinical implications and optimum
treatment of microscopic nodal disease has not yet been
established.40 At a more basic level, not all older trials man-
dated sentinel node biopsy, so the prognosis for patients with
stage II disease varies greatly, making this the most hetero-
geneous stage group. The use of sentinel node biopsy and
more sensitive imaging for detection of distant metastatic
disease have resulted in stage migration with improvement in
the median survival for patients with stage II, III, and IV disease,
making it difficult to compare trials where different staging
techniques were performed.
Tumor ulceration is an independent prognostic factor for
survival across all stage groups. Although there is an ac-
cepted definition of tumor ulceration, there remains the
potential for differences in interpretation of the morpho-
logic features defining tumor ulceration. Newer clinical trials
require central review of pathology specimens to minimize
uncertainty and standardize staging; this is particularly im-
portant for ulceration and sentinel node biopsy involvement.
However, older studies on which many management guide-
lines are based did not require this.
Identifying the appropriate clinical endpoint for an adju-
vant therapy study in melanoma has become increasingly
difficult. Until recently, there was no concern that a potential
benefit in an adjuvant therapy study could be confounded by
subsequent therapy treatment in the advanced disease
setting; this is clearly not the case at present. There remains
major discussion about the validity of recurrence-free sur-
vival as a clinically useful endpoint in its own right.61 It is clear
that patients do value time without disease, even if this is
at the expense of treatment-related toxicity.62 Increas-
ingly, there is a phenomenon of patients wishing to remain
disease-free as long as possible in an attempt to bridge to
emerging new and potentially more effective agents and/or
clinical trials for the treatment of metastatic disease. Other
questions that must be considered include the potential
toxicity of adjuvant therapy, the cost implications of this, and
whether these treatments are more effective and/or cost-
effective in the adjuvant or metastatic disease settings.
Although some of these challenges are easily addressed,
others will require clinical trials that include quality of life
and cost-effectiveness endpoints.
Adjuvant Interferon
The role of IFN as adjuvant treatment of melanoma remains
unclear, leading to a lack of consensus across Europe and the
United States. A number of randomized trials have in-
vestigated the use of adjuvant IFN-a for the treatment
of patients with high-risk melanoma following surgical

resection. The results of these trials have, however, been
inconsistent, with some suggesting a survival benefit for
IFN-a and others showing no difference. High-dose IFN-a
has been approved since 1996 based on the results of the
ECOG 1684 trial of 287 patients with stage IIB/III melanoma,
which showed a benefit for high-dose IFN-a on both RFS and
OS.63 Updated results with a median follow-up of 12.6 years
showed that the RFS benefit was maintained (HR 0.72;
p = .02), but the HR for OS had decreased from 0.67 to 0.82 and
was no longer significant (p = .18), though clearly the effect
of competing causes of death on survival may have con-
tributed to this.64 The ECOG 1690 trial compared high- and
low-dose IFN-a with observation in 624 patients with stage
IIB/III disease and showed only a marginal benefit of RFS for
both regimens and no OS benefit for either treatment.65 As
this trial included patients with T4 primary tumors (stage II)
and did not require regional nodal staging, many patients
relapsed in regional nodes. Crossover of patients in the
observation arm to the then FDA-approved high-dose IFN
regimen after lymph node recurrence was cited as a possible
contributing cause for the lack of difference. Intergroup
E1694 compared high-dose IFN-a-2b with the GM2-KLH
vaccine in patients with resected stage IIB and III
melanomathe same population studied in ECOG 1684 and
1690.66 The trial was closed prematurely when interim
analysis disclosed a significantly worse RFS and OS for pa-
tients treated with the GM2-KLH vaccine compared with the
high-dose IFN-a (HR 1.47 and 1.52, respectively). Although
there was some initial concern that patients who were
administered the GM2-KLH vaccine fared worse than they
would have on observation, a subsequent trial comparing
the vaccine with observation in patients with stage II mel-
anoma showed no significant difference in OS, perhaps
mitigating this concern.
Very recently, the results of the Sunbelt Melanoma Trial
were published. This trial examined high-dose adjuvant IFN
after sentinel nodepositive disease in one node versus
observation versus high-dose IFN in the case of more than
one positive lymph node. Also, patients with sentinel node
immunohistochemistrynegative but reverse transcription-
polymerase chain reactionpositive disease were randomly
assigned into three groups: observation, complete lymph
node dissection, or complete lymph node dissection plus
TABLE 1. Outcome According to Dose of Interferon
Overall Risk (95% CI)
Dose EFS
High (1,196 patients) 0.83 (0.720.96)
PEG-IFN (1,256 patients) 0.83 (0.761.00)
Intermediate (2,243 patients) 0.84 (0.740.95)
Low (2,732 patients) 0.85 (0.770.94)
Very low (484 patients) 0.99 (0.801.23)
Overall (95% CI) 0.86 (0.810.91)
Abbreviations: EFS, event-free survival; OS, overall survival; PEG-IFN, pegylated-
interferon.
SURGICAL MANAGEMENT OF MELANOMA
high-dose IFN. The concept of the study, when designed in
1997, was to find out if patients with minimal disease
(sentinel node negative, but RT-PCR positive) would be the
group with the most benefit. The trial did not demonstrate
any OS benefit.51 The subgroup of patients with ulceration
did show a benefit for disease-free survival but not for OS.
The amount of ulcerated patients in this study was minimal,
which might be the explanation for the lack of OS benefit in
this group.
In Europe, low-dose IFN-a was approved based on a
French trial of 499 patients with stage II disease, which
showed an RFS benefit (p = .035) and a trend toward an
improvement in OS (p = .059).67 More recently, in 2011, the
FDA approved PEG-IFN for patients with stage III melanoma
based on the EORTC 18991 trial of 1,256 patients.68 The trial
first reported in 2007 with a median follow-up of 3.8 years.
There was a significant improvement in RFS in favor of PEG-
IFN-a-2b (HR 0.82; p = .011), however, there was no sig-
nificant effect on either distant metastasis-free survival or
OS. Subgroup analysis showed that the benefit was only seen
in patients with microscopic nodal disease, and there was
also an improvement in distant metastasis-free survival.
Updated results with a median follow-up of 7.6 years
showed the effect on RFS had deteriorated from an HR of
0.82 to 0.87.69 In addition, the greatest benefit was seen for
the patients with microscopic nodal disease (N1) who had
ulcerated primary tumors (RFS HR 0.72; OS HR 0.59), with no
benefit seen in nonulcerated tumors.
Other studies have looked at dose and duration of
treatment, and many did not use a no-treatment control
arm. Shortening the regimen to a month of high-dose therapy
administered either once or multiple times has not been
successful.70-73 Five meta-analyses have been reported.74-78
The two meta-analyses by Mocellin included studies without
an active treatment control arm.74,75 A recent meta-analysis
reported on 17 trials published between 1995 and 2011.76
Adjuvant IFN was associated with a significantly improved
disease-free survival (HR 0.83; 95% CI, 0.7887; p = .00001)
and OS (HR 0.91; 95% CI, 0.8597; p = .003). This translated
into an improvement in OS from 46.1% to 49.1% at 5 years and
from 37.1% to 39.9% at 10 years. There was no clear evidence
that a particular dose or duration of treatment or patient
subgroup benefitted differently. However, ulceration status
affected IFN benefit on event-free survival and OS. For
ulcerated melanoma, IFN increased event-free survival from
26.9% to 32.9% at 5 years and from 20.4% to 27.3% at 10 years
(Table 1).
The interaction between ulceration and response to IFN is
OS
not universally accepted. No interaction has been seen in the
0.93 (0.801.08) studies from ECOG (Kirkwood, personal communication) or
0.96 (0.821.11) from the Nordic group.79 This is being examined pro-
0.91 (0.791.04) spectively in an EORTC trial 18081 (NCT01502696).
0.86 (0.770.96) To look further at whether progression-free survival
0.96 (0.761.21) predicts for OS with IFN treatment, Suciu and colleagues
0.90 (0.850.97) examined 12 studies involving 6,708 patients for which in-
dividual patient data were available to produce a training
set. This was then validated on published data from 5,774
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e509
VAN AKKOOI ET AL
patients from a further 13 studies, including studies with an
active treatment control arm. The results showed that both
individual and trial level correlations were close, suggesting
that for adjuvant IFN trials, there is a strong surrogacy of RFS
for OS.80
Non-IFNBased Adjuvant Therapy Approaches
Other approaches to adjuvant treatment have been pursued
over the past two decades with most showing mixed re-
sults. These have included biochemotherapy, granulocyte-
macrophage colony-stimulating factor with or without
peptide vaccinations, and bevacizumab. More encouraging
data are emerging with the checkpoint inhibitor ipilimumab,
and there is great optimism surrounding the potential value
of the PD-1 pathway inhibitors. These approaches are de-
scribed below.
Biochemotherapy. Cisplatin and interleukin-2 (IL-2)based
biochemotherapy produced encouraging results in a series
of phase II trials in patients with stage IV melanoma. These
results prompted the Southwest Oncology Group (SWOG) to
perform a phase III cooperative group trial (S0008) in which
biochemotherapy was compared with high-dose IFN.81 The
trial randomly assigned 432 patients with high-risk mela-
noma to either three cycles of cisplatin, vinblastine,
dacarbazine, IL-2, and IFN-a given over a 9-week period or
to high-dose IFN-a for 1 year. At a median follow-up of
7.2 years, the biochemotherapy regimen significantly pro-
longed RFS (median 4.0 vs. 1.9 years, and 5-year RFS rate 48%
vs. 39%; HR 0.75; 95% CI, 0.580.97).81 However, there was no
significant difference in the OS (5-year rate 56% for both
treatment arms; HR 0.98; 95% CI, 0.741.31).81 The bio-
chemotherapy regimen was substantially more toxic, with
grade 3 or 4 side effects (consisting primarily of hematologic
and gastrointestinal toxicity) observed in 76% of participants.
Neurologic, psychiatric, and hepatic toxicities were the most
frequent with high-dose IFN-a. Biochemotherapy toxicities
were limited to the 9-week treatment period, while IFN-a
toxicities were distributed across the year of treatment. Even
though the biochemotherapy regimen was the first to
produce a significant improvement in RFS compared with an
active control arm, the lack of OS benefit coupled with the
failure of this regimen to show an OS benefit relative to
chemotherapy alone in patients with stage IV disease has
limited its acceptance in the adjuvant setting.
Granulocyte-macrophage colony-stimulating factor.
Granulocyte-macrophage colony-stimulating factor (GM-CSF)
has been reported to prolong survival in patients with
resected stage IV disease in a single-arm trial,82 prompting its
evaluation in a randomized controlled trial (E4697).83 In this
multicenter trial, 815 patients with high-risk stage III or
completely resected stage IV melanoma were randomly
assigned to receive GM-CSF or placebo. Patients who were
HLA-A2positive were randomly assigned to peptide vacci-
nation or placebo, in combination with GM-CSF or placebo;
e510 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
patients who were HLA-A2negative received only GM-CSF or
placebo. There was no benefit associated with the use of the
peptide vaccine.83 There was no significant difference in ei-
ther OS (5-year survival rate 52% vs. 49%; HR 0.94; 95% CI,
0.771.15) or RFS (median RFS 11.4 vs. 8.8 months, and 5-year
RFS rate 31% vs. 27%; HR 0.88; 95% CI, 0.741.04; p = .131),
when GM-CSF was compared with placebo. Exploratory an-
alyses showed a trend toward improved OS in patients with
resected visceral metastases who received GM-CSF, but this
observation required independent validation especially given
that this was not a protocol stratification factor.83 Given these
mixed results, GM-CSF is generally not recommended for use
in the adjuvant setting.
Bevacizumab. Bevacizumab was reported to have some
activity in patients with advanced melanoma, prompting its
study in the adjuvant setting. In a phase III multicenter trial
conducted in the United Kingdom, 1,343 patients with
resected stage IIB, IIC, or III disease were randomly assigned
to receive 1 year of bevacizumab treatment (7.5 mg/kg every
3 weeks) or to observation.84 At a median follow-up of
25 months, there was no significant difference in OS, which
was the primary endpoint of the trial (HR 0.97; 95% CI,
0.781.22; p = .76).84 However, there was a significant in-
crease in the disease-free interval (1-year and 2-year
disease-free rates 77% vs. 70% and 59% vs. 57%, re-
spectively; HR 0.83; 95% CI, 0.700.98), and an insignificant
trend toward improved distant metastasis-free survival (HR
0.88; 95% CI, 0.731.06; p = .18).84 Interpretation of the trial
and the potential role of bevacizumab will require further
follow-up to assess the 5-year OS rate. Until then, the use of
bevacizumab in the adjuvant setting for patients with ad-
vanced melanoma is not recommended.
Ipilimumab. Ipilimumab was approved for use in patients
with stage IV disease in 2011 based on its being able to
prolong median OS.2 The approved regimen in the stage IV
setting (3 mg/kg every 3 weeks for four doses) was also
shown to produce a durable effect on OS extending out to
10 years.85 The encouraging initial studies with ipilimumab
in the stage IV setting prompted its study in the adjuvant
setting. Two randomized phase III trials compared with
placebo (EORTC 18071) or high-dose IFN (ECOG 1609) have
completed accrual. In the EORTC 18071 trial, patients with
resected stage III melanoma were randomly assigned to
receive ipilimumab 10 mg/kg or placebo every 3 weeks for
four doses and then every 3 months for up to 3 years.86
Results showed improved median recurrence-free survival
of 26.1 months with ipilimumab compared with 17.1 months
with placebo (HR 0.75; p = .0013).86 In subgroup analyses,
patients with microscopic lymph node disease or ulcerated
primary lesions demonstrated the most benefit. Impor-
tantly, there was a high rate of grade 3-5 immune-related
adverse events in patients receiving ipilimumab (43%
compared with 2% with placebo).86 These included five
treatment-related deaths, despite treatment with immu-
nomodulatory therapy. Although these data are provocative

and have led to the recent FDA approval of ipilimumab for
patients with resected stage III melanoma, it is as yet unclear
whether this reduction in recurrence rate with ipilimumab
represents an improvement over adjuvant IFN therapy and
whether this benefit will translate into an improvement in
OS. Furthermore, the approved adjuvant dose of 10 mg/kg is
over three times higher than the approved dose in meta-
static melanoma, with the potential for higher toxicity. These
questions are being addressed by the U.S. Intergroup E1609
study, which randomly assigned patients with resected stage
III-IV melanoma to ipilimumab 10 mg/kg or 3 mg/kg or high-
dose IFN.87 The study completed accrual of more than 1,500
patients in the summer of 2014 and is pending analysis for
coprimary endpoints of RFS and OS. Long-term survival data
from both of these adjuvant studies will ultimately be nec-
essary to determine the true effectiveness of adjuvant
ipilimumab therapy relative to either high-dose IFN or
observation.
MAGE-A3 vaccine. The DERMA (ADjuvant ImmunothERapy
with MAGE3 in MelanomA) was a double-blind, randomized,
placebo-controlled phase III study of recombinant MAGE-A3
with AS15 antigen-specific cancer immunotherapeutic (ASCI)
in patients with MAGE-A3positive resected stage IIIB/C
disease. MAGE-A3 is expressed on approximately 60% of
melanoma specimens. The study was based on an EORTC
phase II study of patients with stage IV M1A disease that
identified a superior survival benefit for patients receiving
the MAGE-A3 vaccine treated with the AS15 rather than
the ASO2B adjuvant (HR 0.55; 95% CI, 0.281.06).88
Furthermore, a genetic predictor identified a group of pa-
tients receiving MAGE-A3 with AS15 ASCI with a better OS
(HR 0.27; 95% CI, 0.080.89).88 The study screened 3,914
patients and randomly assigned 1,344 patients 2:1 to 13
intramuscular injections of vaccine or placebo. The study
failed to meet its coprimary endpoint of disease-free survival
in either the overall population of patients studied or in
those with the potential predictive gene signature.88
Ongoing Adjuvant Studies
PD-1 pathway blockers. In the meantime, the field has
moved on to examine potentially more exciting checkpoint
inhibitors: those blocking the PD-1 pathway. PD-1 inhibitors
have proven to be less toxic and more active than ipili-
mumab in patients with established, unresectable meta-
static melanoma.9,89 Given their favorable therapeutic index
and ability to produce durable off-treatment benefit in
patients with advanced melanoma, there is much interest in
developing this class of therapies as adjuvant treatment for
patients with high-risk resected melanoma. Results from a
phase I trial of nivolumab plus a multipeptide vaccine in
33 patients with resected stage IIIC or IV melanoma showed a
relatively low relapse rate (30%) during a median follow-up
period of 32.1 months from trial enrolment. Median RFS
was estimated to be 47.1 months.90 Phase III trials with
nivolumab and pembrolizumab in patients with resected
SURGICAL MANAGEMENT OF MELANOMA
stage III and IV melanoma are currently underway. These
include Checkmate-238 (NCT02388906) comparing ipilimu-
mab 10 mg/kg (according to the EORTC 18071 schedule) to
nivolumab 3 mg/kg administered intravenously every
2 weeks; EORTC 1325 (KEYNOTE-054; NCT02362594) protocol
comparing pembrolizumab (200-mg flat dose) with placebo;
and the SWOG S1404 protocol comparing pembrolizumab
(200-mg flat dose) with high-dose IFN (NCT02506153).
Checkmate-238 completed accrual in September 2015.
EORTC 1325 and SWOG S1404 are actively accruing patients.
Molecularly targeted therapies. The selective inhibitors of
the mutant BRAF kinase (vemurafenib and dabrafenib) have
been shown to be superior to dacarbazine in patients with
stage IV BRAFV600-mutant melanoma, leading to their FDA
approval.3,8 More recently, the combination of dabrafenib
and the MEK inhibitor trametinib have been proven to
produce superior response rate, median progression-free
survival, and median OS compared with single-agent dab-
rafenib or vemurafenib in this patient population.7,8 Based
on these encouraging results, clinical trials have begun testing
these agents in patients with high-risk resected BRAF-mutant
melanoma. In the COMBI-AD trial, approximately 850 patients
are to be randomly assigned to receive either dabrafenib
with trametinib or placebo and treated for up to 1 year
(NCT01682083). This trial completed accrual in December
2014 and is pending analysis. In the BRIM 8 study, up to
775 patients with stage IIC to stage IIIC resected melanoma
will be randomly assigned to receive vemurafenib or placebo
for up to 1 year. The study is currently recruiting at 187 sites in
29 countries (NCT01667419).
The results of these trials are eagerly awaited, especially
the assessment of whether these active agents can eliminate
the last tumor cell in the low-volume adjuvant setting and
thereby actually prevent, not just delay, disease recurrence.
Adjuvant Therapy Conclusions
The role of adjuvant therapy in patients with resected high-
risk melanoma remains unsettled. Although several ap-
proaches have shown improvements in RFS, only the high-dose
IFN regimen has shown an improvement in OS. The extent of
this survival benefit remains controversial. Although multiple
meta-analyses have suggested that the benefit of IFN on OS is
small (under 10%), these usually (1) include studies using
different dose levels of IFN rather than simply the high-dose
regimen, (2) include the E1690 study data despite its survival
endpoint being potentially confounded by crossover to then
FDA-approved IFN use, and (3) exclude the overwhelmingly
positive E1694 trial because it involved a vaccine control arm.
The unresolved question is: do you base a decision on the
results of the individual trials or the meta-analyses? The choice
for some is further complicated by the toxicity of the high-
dose IFN regimen, which is clearly more than desirable for the
adjuvant setting.
The benefit of ipilimumab on RFS appears to be equivalent
at least to that of high-dose IFN and was sufficiently robust as
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e511
VAN AKKOOI ET AL
to garner FDA approval. Given that the major effect of
ipilimumab in patients with stage IV disease is on OS, it is
likely that the RFS benefit of ipilimumab will ultimately
translate into a survival benefit. Nonetheless, many will be
unwilling to prescribe ipilimumab given the high incidence of
high-grade toxicity, including five deathsan outcome that
is difficult to swallow in a population in whom as much
as half might remain disease-free in the absence of any
treatment.
Absent an unambiguously positive approved agent for
adjuvant therapy in melanoma, clinical trial participation
remains the priority. The most promising approaches cur-
rently under study include BRAF inhibitors and PD-1 pathway
blockers. The BRAF inhibitors have powerful antitumor ef-
fects in patients with BRAF-mutant melanoma. Thus, they
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nodes to be considered negative? Ann Oncol. 2006;17:1578-1585.
53. van der Ploeg AP, van Akkooi AC, Haydu LE, et al. The prognostic
significance of sentinel node tumour burden in melanoma patients: an
international, multicenter study of 1539 sentinel node-positive mela-
noma patients. Eur J Cancer. 2014;50:111-120.
54. van der Ploeg AP, van Akkooi AC, Rutkowski P, et al. Prognosis in pa-
tients with sentinel node-positive melanoma is accurately defined by
the combined Rotterdam tumor load and Dewar topography criteria.
J Clin Oncol. 2011;29:2206-2214.
55. Read RL, Haydu L, Saw RP, et al. In-transit melanoma metastases: in-
cidence, prognosis, and the role of lymphadenectomy. Ann Surg Oncol.
2015;22:475-481.
56. Pawlik TM, Ross MI, Johnson MM, et al. Predictors and natural history of
in-transit melanoma after sentinel lymphadenectomy. Ann Surg Oncol.
2005;12:587-596.
57. Howard JH, Thompson JF, Mozzillo N, et al. Metastasectomy for distant
metastatic melanoma: analysis of data from the first Multicenter Se-
lective Lymphadenectomy Trial (MSLT-I). Ann Surg Oncol. 2012;19:
2547-2555.
58. Sosman JA, Moon J, Tuthill RJ, et al. A phase 2 trial of complete resection
for stage IV melanoma: results of Southwest Oncology Group Clinical
Trial S9430. Cancer. 2011;117:4740-06.
59. Daud A, Ribas A, Robert C, et al. Long-term efficacy of pembrolizumab
(pembro; MK-3475) in a pooled analysis of 655 patients (pts) with
advanced melanoma (MEL) enrolled in KEYNOTE-001. J Clin Oncol. 2015;
33 (suppl; abstr 9005).
60. Grob JJ, Amonkar MM, Karaszewska B, et al. Comparison of dabrafenib
and trametinib combination therapy with vemurafenib monotherapy
on health-related quality of life in patients with unresectable or
metastatic cutaneous BRAF Val600-mutation-positive melanoma
(COMBI-v): results of a phase 3, open-label, randomised trial. Lancet
Oncol. 2015;16:1389-1398.
61. Flaherty KT, Hennig M, Lee SJ, et al. Surrogate endpoints for overall
survival in metastatic melanoma: a meta-analysis of randomised
controlled trials. Lancet Oncol. 2014;15:297-304.
62. Kilbridge KL, Cole BF, Kirkwood JM, et al. Quality-of-life-adjusted sur-
vival analysis of high-dose adjuvant interferon alpha-2b for high-risk
melanoma patients using intergroup clinical trial data. J Clin Oncol.
2002;20:1311-1318.
63. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b
adjuvant therapy of high-risk resected cutaneous melanoma: the
Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;
14:7-17.
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VAN AKKOOI ET AL
64. Kirkwood JM, Manola J, Ibrahim J, et al. A pooled analysis of eastern
cooperative oncology group and intergroup trials of adjuvant high-dose
interferon for melanoma. Clin Cancer Res. 2004;10:1670-1677.
65. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose in-
terferon alfa-2b in high-risk melanoma: first analysis of intergroup trial
E1690/S9111/C9190. J Clin Oncol. 2000;18:2444-2458.
66. Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b
significantly prolongs relapse-free and overall survival compared with
the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III
melanoma: results of intergroup trial E1694/S9512/C509801. J Clin
Oncol. 2001;19:2370-2380.
67. Grob JJ, Dreno B, de la Salmoni`ere P, et al. Randomised trial of in-
terferon alpha-2a as adjuvant therapy in resected primary melanoma
thicker than 1.5 mm without clinically detectable node metastases.
Lancet. 1998;351:1905-1910.
68. Eggermont AM, Suciu S, Santinami M, et al. Adjuvant therapy with
pegylated interferon alfa-2b versus observation alone in resected stage
III melanoma: final results of EORTC 18991, a randomised phase III trial.
Lancet. 2008;372:117-126.
69. Eggermont AM, Suciu S, Testori A, et al. Long-term results of the
randomized phase III trial EORTC 18991 of adjuvant therapy with
pegylated interferon alfa-2b versus observation in resected stage III
melanoma. J Clin Oncol. 2012;30:3810-3818.
70. Agarwala SS, Lee SJ, Flaherty K, et al. Randomized phase III trial of high-
dose interferon alfa-2b (HDI) for 4 weeks induction only in patients with
intermediate- and high-risk melanoma (Intergroup trial E 1697). J Clin
Oncol. 2011;29 (suppl; abstr 8505).
71. Payne MJ, Argyropoulou K, Lorigan P, et al. Phase II pilot study of in-
travenous high-dose interferon with or without maintenance treatment
in melanoma at high risk of recurrence. J Clin Oncol. 2014;32:185-190.
72. Pectasides D, Dafni U, Bafaloukos D, et al. Randomized phase III study of
1 month versus 1 year of adjuvant high-dose interferon alfa-2b in
patients with resected high-risk melanoma. J Clin Oncol. 2009;27:
939-944.
73. Hauschild A, Weichenthal M, Rass K, et al. Efficacy of low-dose in-
terferon alpha2a 18 versus 60 months of treatment in patients with
primary melanoma of .= 1.5 mm tumor thickness: results of a ran-
domized phase III DeCOG trial. J Clin Oncol. 2010;28:841-846.
74. Mocellin S, Lens MB, Pasquali S, et al. Interferon alpha for the adjuvant
treatment of cutaneous melanoma. Cochrane Database Syst Rev. 2013;
6:CD008955.
75. Mocellin S, Pasquali S, Rossi CR, et al. Interferon alpha adjuvant therapy
in patients with high-risk melanoma: a systematic review and meta-
analysis. J Natl Cancer Inst. 2010;102:493-501.
76. Suciu S, Ives N, Eggermont A, et al. Predictive importance of ulceration
on the efficacy of adjuvant interferon-a (IFN): An individual patient data
(IPD) meta-analysis of 15 randomized trials in more than 7,500 mel-
anoma patients (pts). J Clin Oncol. 2014;32:5s (suppl; abstr 9067).
77. Wheatley K, Ives N, Eggermont A, et al. Interferon-alpha as adjuvant
therapy for melanoma: an individual patient data meta-analysis of
randomised trials. J Clin Oncol. 2007;25 (suppl; abstr 8526).
78. Wheatley K, Ives N, Hancock B, et al. Does adjuvant interferon-alpha for
high-risk melanoma provide a worthwhile benefit? A meta-analysis of
the randomised trials. Cancer Treat Rev. 2003;29:241-252.
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79. Hansson J, Aamdal S, Bastholt L, et al. Two different durations of ad-
juvant therapy with intermediate-dose interferon alfa-2b in patients
with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial.
Lancet Oncol. 2011;12:144-152.
80. Suciu S, Eggermont A, Lorigan P, et al. Relapse-free survival (RFS) as a
surrogate endpoint for overall survival in adjuvant Interferon trials in
patients with resectable cutaneous melanoma: an individual patient
data meta-analysis. In: ESMO 2014 Congress. Madrid, Spain; 2014.
Abstract 1089PD.
81. Flaherty LE, Othus M, Atkins MB, et al. Southwest Oncology Group
S0008: a phase III trial of high-dose interferon Alfa-2b versus cisplatin,
vinblastine, and dacarbazine, plus interleukin-2 and interferon in pa-
tients with high-risk melanomaan intergroup study of cancer and
leukemia Group B, Childrens Oncology Group, Eastern Cooperative
Oncology Group, and Southwest Oncology Group. J Clin Oncol. 2014;32:
3771-3778.
82. Spitler LE, Weber RW, Allen RE, et al. Recombinant human granulocyte-
macrophage colony-stimulating factor (GM-CSF, sargramostim) ad-
ministered for 3 years as adjuvant therapy of stages II(T4), III, and IV
melanoma. J Immunother. 2009;32:632-637.
83. Lawson DH, Lee S, Zhao F, et al. Randomized, placebo-controlled, phase
III trial of yeast-derived granulocyte-macrophage colony-stimulating
factor (GM-CSF) versus peptide vaccination versus GM-CSF plus peptide
vaccination versus placebo in patients with no evidence of disease after
complete surgical resection of locally advanced and/or stage IV mel-
anoma: a trial of the Eastern Cooperative Oncology Group-American
College of Radiology Imaging Network Cancer Research Group (E4697).
J Clin Oncol. 2015;33:4066-4076.
84. Corrie PG, Marshall A, Dunn JA, et al. Adjuvant bevacizumab in patients
with melanoma at high risk of recurrence (AVAST-M): preplanned in-
terim results from a multicentre, open-label, randomised controlled
phase 3 study. Lancet Oncol. 2014;15:620-630.
85. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term
survival data from phase II and phase III trials of ipilimumab in unre-
sectable or metastatic melanoma. J Clin Oncol. 2015;33:1889-1894.
86. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab
versus placebo after complete resection of high-risk stage III melanoma
(EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol.
2015;16:522-530.
87. Tarhini AA. Melanoma and Skin Cancer: Adjuvant Therapy for High-Risk
Melanoma. Physicians Education Resource, LLC. http://www.gotoper.
com/publications/ajho/2014/2014nov/adjuvant-therapy-for-high-risk-
melanoma. Accessed March 16, 2016.
88. Dreno B, Thompson JA, Smithers BM. DERMA, a double-blind, placebo
controlled Phase III study to assess the efficacy of MAGE-A3 cancer
immunotherapeutic adjuvant therapy in patients with resected MAGE-
A3 positive Stage III melanoma. Proc SMR. 2015.
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Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J
Med. 2015;372:2521-2532.
90. Gibney GT, Kudchadkar RR, DeConti RC, et al. Safety, correlative
markers, and clinical results of adjuvant nivolumab in combination with
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2015;21:712-720.
PATIENT AND SURVIVOR CARE

Cancer Survivorship: Is Every

Patients Journey the Same?

CHAIR
Michael T. Halpern, MD, PhD
University of Arizona College of Public Health
Tucson, AZ

SPEAKERS
Mary S. McCabe, RN, MA
Memorial Sloan Kettering Cancer Center
New York, NY

Mary Ann Burg, PhD, MSW, LCSW

University of Florida
Gainesville, FL
 THE CANCER SURVIVORSHIP JOURNEY

The Cancer Survivorship Journey: Models of Care, Disparities,

Barriers, and Future Directions
Michael T. Halpern, MD, PhD, Mary S. McCabe, RN, MA, and Mary Ann Burg, PhD, MSW, LCSW

OVERVIEW

Although the number of long-term cancer survivors has increased substantially over past years, the journey of survivorship
does not always include high-quality, patient-centered care. A variety of survivorship care models have evolved based on
who provides this care, the survivor population, the site of care, and/or the capacity for delivering specific services. Other
areas of survivorship care being explored include how long follow-up care is needed, application of a risk-based approach to
survivorship care, and the role of the survivor in his or her own recovery. However, there is little evidence indicating whether
any models improve clinical or patient-reported outcomes. A newer focus in survivorship care has included assessment of
potential disparities; the sociodemographic characteristics of population subgroups associated with barriers to receiving
high-quality cancer treatment may also affect the survivorship period. Developing policies and programs to address dis-
parities in survivorship care is not simple, and examining how financial hardship affects cancer outcomes, reducing economic
barriers to care, and increasing incorporation of patient-centered strategies may be important components. Here too, there
is little evidence regarding the best strategies to address these disparities. Barriers to providing high-quality, patient-
centered survivorship care include lack of evidence, lack of a trained survivorship workforce, lack of reimbursement
structures/insurance coverage, and lack of a health care system that reduces fragmented care. Future research needs to
focus on developing a survivorship care evidence base, exploring strategies to facilitate provision of survivorship care, and
disseminating best survivorship care practices to diverse and international audiences.

A s of January 2014, there were approximately 14.5 million

cancer survivors in the United States; this number is
expected to grow to 19 million by 2024.1 Substantial in-
creases in the number of cancer survivors have also been
reported in other countries2-4; for example Maddams et al
projected that the number of cancer survivors in the United
Kingdom will increase by approximately one million per
decade.5 The rapidly increasing numbers of cancer survivors
is the intended consequence of improvements in early
cancer diagnosis and cancer treatment. As these two aspects
of cancer care will likely continue to improve, the number of
cancer survivors will correspondingly continue to increase.
The title of the corresponding American Society of Clinical
Oncology (ASCO) 2016 Annual Meeting Education Session,
Cancer Survivorship: Is Every Patients Journey the Same?
is largely rhetorical. Clearly, the journey for every cancer
survivor is not the same. However, this raises the question:
why doesnt every cancer survivor receive high-quality and
comprehensive care tailored to his or her needs, situation,
and risk factors? The goal of this article is to explore some of
the factors that lead to differences in the survivorship journey,
to identify challenges or barriers to providing high-quality
survivorship care, and to suggest potential directions for
future research to enhance the survivorship experience.
DEFINITION OF SURVIVORSHIP
In exploring causes of variation in the survivorship journey, a
key issue is how the term cancer survivor is defined. As
with other aspects of survivorship and survivorship care,
there is not consensus on this definition. Some organiza-
tions, such as the National Coalition for Cancer Survivorship
and National Cancer Institutes Office of Cancer Survivor-
ship, define survivors as individuals with cancer from the
time of diagnosis and for the balance of life, and include in
their definition family, friends, and caregivers of individuals
with cancer. In contrast, others define survivors as in-
dividuals who are diagnosed with cancer and have com-
pleted potentially curative treatment, until either death or
recurrence. The Institute of Medicines (IOMs) 2005 report
From Cancer Care to Cancer Survivor: Lost in Transition
acknowledges the definition of survivors used by the National

From the Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ; Memorial Sloan Kettering Cancer Center, New York, NY; University of Central Florida School
of Social Work, Orlando, FL.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Michael T. Halpern, MD, PhD, University of Arizona, Mel and Enid Zuckerman College of Public Health, 1295 North Martin Ave., Tucson, AZ 85724; email:
mthalpern@email.arizona.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 231

HALPERN, MCCABE, AND BURG
Cancer Institutes Office of Cancer Survivorship but then
focuses on the period following first diagnosis and treatment
and prior to the development of a recurrence of the initial
cancer or death.6 This report highlights the potential
distinction between a survivor and the period of care re-
ferred to as survivorship. Jefford et al reports that the
definition of survivorship used in the United Kingdom is the
period after completion of initial treatment, regardless of
whether the person is free from cancer at that time.7
More broadly, there is disagreement regarding whether
the term cancer survivor should be used at all. As discussed
by Bell and Ristovski-Slijepcevic, some disagree with the
term survivor being used for individuals who have expe-
rienced cancer.8 This term is not used in other medical
conditions; people who have had heart attacks are not called
heart attack survivors.8 As an alternative, the U.K. National
Health Services has used the term living beyond cancer in
some of their materials.
MODELS OF SURVIVORSHIP CARE
As survivorship takes its place as a formal part of the cancer
care continuum, there are increasing international efforts di-
rected toward the development and, most recently, the
evaluation of models of care delivery. This activity has resulted
in a growing body of literature describing and comparing
various configurations of health care services and models of
KEY POINTS
There are increasing international efforts directed
toward models of care delivery for survivorship. Models
may be based on the care provider, survivor population,
care site, service delivery capacity, follow-up care
duration, and the survivors role in recovery.
There are four categories of care: nurse-led survivorship
care models, risk-based care plans, rehabilitation-
focused care models, and self-management techniques
for post-treatment recovery.
The burden of cancer is disproportionate across
subpopulations, with gender, race, ethnicity, age,
income, health insurance, place of residence, and access
to health care contributing to cancer disparities. These
factors may lead to disparities in survivorship care and
influence survivorship experiences.
Developing policies and programs to address disparities
in survivorship care may include examining how
financial hardship affects cancer outcomes, reducing
economic barriers to care, and increasing incorporation
of patient-centered, integrated strategies into oncology
care.
There are four main barriers to the provision of
survivorship care: lack of evidence, lack of a trained
survivorship care workforce, lack of reimbursement
structures/insurance coverage for survivorship care
services, and lack of a cohesive health care system that
would reduce fragmented care.
232 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
follow-up care for the period following treatment.9,10 As one
might expect, a variety of models have evolved based on the
provider, survivor population, site of care, and capacity for the
delivery of specific services. In addition, the type of survi-
vorship care model is influenced by the design of the health
care delivery system(s) and payment mechanisms for health
care. Despite these differences, the major goals of care for
cancer survivors transcend national health care systems and
focus on improved survival, long-term health, and the highest
quality of life possible, including both physical and psychosocial
well-being.11 However, many recommendations for survivor-
ship care are largely based on expert consensus. At present,
there is only limited evidence regarding services that improve
outcomes for cancer survivors, and there is essentially no in-
formation regarding the costs of providing these services
relative to their benefits.
In the United States and elsewhere, the IOM report, From
Cancer Patient to Cancer Survivor: Lost in Transition, has
served as the foundational document for establishing the
essential elements of care to be included in any survivorship
care model: surveillance for recurrence, screening for sec-
ond cancers, assessment and intervention of long-term/late
effects, counseling for healthy living, and communication/
coordination with primary care.6 However, since this doc-
ument was published in 2006, a number of countries, such as
the United Kingdom and Canada, have developed a national
strategy for cancer survivorship. In the United Kingdom, the
National Cancer Survivorship Initiative was launched in 2008
as a partnership between the Department of Health, which
has responsibility for the National Health Service, and
Macmillan Cancer Support, a large British charity.12 To date,
the National Cancer Survivorship Initiative has promoted
novel, proactive approaches to identifying groups at in-
creased risk and customizing interventions for them.12 In
Canada, although the provision of health care is a provin-
cial responsibility, the Canadian Partnership Against Cancer
implemented a national strategy in 2007.13 Similar to the
United Kingdom, Canadian Partnership Against Cancer has
focused on the concept of risk stratification to inform care
pathways. Other nations, such as Australia, have developed
regional plans with the state government organizing the
initiative. This allows for pilot projects that are specific to the
patient population of the region.7 In both examples of na-
tional and regional planning, there has been a population
focus on survivorship care with an expectation and often a
requirement for the implementation of pilot models that will
be assessed and revised as necessary.
In addition to the growing international acknowledgment
that individuals treated for cancer continue to have health
care needs, there has been an evolution in thinking about
who provides this care, how long follow-up is needed, and
the role of the survivor in his or her own recovery. Initially,
the focus of post-treatment services was generic, with a
spotlight on surveillance for recurrence and the oncology
specialist providing the follow up. But more recently, there
have been proposals and studies conducted across the globe
where models apply a risk-based approach to care so that

the unique needs of survivors are addressed while effi-
ciently applying health care resources. Although there are an
expanding number of survivorship models to consider, some
important types of models are worth highlighting because
they are applicable across countries and have the potential
to transform the delivery of survivorship care. This article
will briefly highlight four important categories of care: (1)
nurse-led survivorship care models as an important way to
redesign the survivorship work force; (2) risk-based care
plans where survivorship services are stratified based on
need and the primary care provider (PCP) is a partner in care;
(3) care models focused on a rehabilitation; and (4) efforts to
introduce self-management techniques for post-treatment
recovery.
First, there has been an increasing interest internationally
in the development of nurse-led survivorship clinics where
nurses are responsible for a variety of services. Although the
nurse is the health care provider common to this model, the
services range from active responsibility for the medical
follow up to providing counseling and education about late
effects. In the United States, these clinics have been focused
primarily on the nurse practitioner (NP) as either an in-
dependent provider of the post-treatment care or as an
individual who provides a onetime consultation visit. In the
independent model, the survivor transitions from the on-
cologist to the NP who is then responsible for all the ele-
ments included in the IOM report and provides the patient
and PCP with the treatment summary and survivorship care
plan. In contrast, the consultation visit allows the oncologist
to continue providing follow-up care, but the NP provides a
one-time visit focused on the psychosocial issues, makes
appropriate referrals, and provides a survivorship care plan
to the survivor and PCP.
Watts and colleagues have published an important de-
scription of the NP role in implementing Wagners chronic
care model that includes shared visits and group visits,
both of which are relevant to oncology follow-up care.14 In
Australia, research is ongoing to evaluate nurse-led survi-
vorship care for specific patient populations. For example,
researchers at the Peter MacCallum Cancer Centre conducted a
randomized study comparing the effect of their SurvivorCare
(SC) intervention with usual care for colorectal cancer survi-
vors. This new intervention includes the provision of educa-
tional materials, a survivorship care plan, and a tailored, nurse-
led post-treatment consultation followed by three telephone
calls. The addition of SurvivorCare to usual care did not have a
beneficial effect on distress, supportive care needs, or quality
of life, but patients who received SurvivorCare were more
satisfied.15 Researchers at Peter MacCallum Cancer Centre also
implemented and evaluated a nurse-led consultation that
includes a tailored education package, a psychosocial assess-
ment, and the provision of a tailored survivorship care plan for
long-term survivors of Hodgkin lymphoma.16 In the United
Kingdom, a nurse-led service model has been successfully
implemented for men treated for prostate cancer. During the
evaluation period, the researchers found that 90% of the in-
vited men participated in the survivorship services, which
THE CANCER SURVIVORSHIP JOURNEY
included face-to-face supportive care visits with the nurse
and a 6-week education program.17
Another important approach to survivorship care is one
that focuses not on the oncology providers but rather on the
PCP. Using a risk-based approach to care where survivors are
stratified as being at low, medium, or high risk for recurrence
and late effects, one can integrate the PCP in a shared-care
model or transition all the post-treatment care to the PCP at
varying points based on the potential for cancer-related
risks. Having the PCP as a focus of the post-treatment care
has been integral to survivorship planning countries
throughout Europe and in Canada where the pan-Canadian
Guideline for Survivorship services recommends that the
PCP be integrated early to provide survivorship services.18
Increasingly, this model is gaining traction in the United
States for reasons of manpower concerns, a better un-
derstanding of the shared care model successfully used by
other specialties, and the growing number of older cancer
survivors for whom the PCP is essential.
As with other survivorship models, the availability and
uptake of a rehabilitation care model will depend on the
health care system of the country and how well established
this service is as usual care. Because rehabilitation services
after illness are well developed throughout much of Europe,
survivorship services can and are applied within this con-
struct and include psychosocial care, exercise, and physical
therapy. For example, in Germany, rehabilitation has long
been established as standard care to promote recovery after
acute illness, but it has focused on returning to work and is
done as an inpatient service. However, studies have shown
that patients prefer outpatient services, which may make
them more accessible in the future.19 In Belgium, a study was
conducted to offer adult cancer survivors access to a re-
habilitation program that included physical training and
psychosocial support during a 12-week program. Repeated
measures showed improvements in physical ability and
quality of life and a decrease in fatigue.20 In contrast, in the
United States, rehabilitation services are separate and re-
ferrals are made primarily to meet physical and vocational
needs. The current state of rehabilitation across the globe
requires greater evaluation where these services are well
developed but not yet routinely offered to individuals after
cancer treatment.
Finally, self-management is increasingly discussed in re-
lationship to cancer survivorship care. It is a component of
chronic care management that offers methods for patient
empowerment and prepares individuals by providing them
with the skills and knowledge to play a role in optimizing
their health. In both the United Kingdom and Canada, na-
tional guidance has promoted such an approach to care
using a variety of interventions such as counseling, psycho-
education, and other forms of professional ad peer sup-
port.18,21 Many of the self-management programs in the
United States build on the successful chronic disease self-
management model developed by Lorig and Barlow, with a
focus on promoting lifestyle change and psychosocial
health.22 Although it is a concept well suited to survivorship
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 233
HALPERN, MCCABE, AND BURG

care, self-management, to date, has not become a well- type of treatment received. Black men are known to have
evaluated component of survivorship care in the United lower odds of having radical prostatectomy than white
States. men, and they also report lower quality of life related to
physical (urinary, bowel, and sexual dysfunction) and psy-
chological functioning post-treatment compared with white
CONTRIBUTING FACTORS TO DISPARITIES IN men.26,29 The type of treatment a patient with cancer re-
CANCER SURVIVORSHIP ceives is an important factor in what survivors experience
We know that the burden of cancer is disproportionate in
after treatment, and the type of treatment received is a
the population. Evidence for population health disparities
function of clinical considerations and current treatment
in cancer incidence, morbidity, and mortality are indisput-
options. However, treatment choice also varies by more
able, and some of these disparities are projected to increase
modifiable factors, including what the provider commu-
in the future.23-26 Gender, race, ethnicity, age, income, health
nicates to the patient about treatment options, patient
insurance, place of residence, and access to health care are all
preferences, patient access to treatment centers, and
factors that contribute to cancer disparities. Being black in
patient ability to cover the costs of treatment. In the case of
America is particularly associated with higher risk for poor
race disparities in prostate cancer post-treatment, symp-
outcomes in cancer. For example, it is well documented that
toms apparently cannot be explained by clinical factors as
black women present with later-stage breast cancers and
much as lower socioeconomic status, being uninsured, and
more aggressive tumors, which contributes to higher mor-
having treatment in a county hospital compared with a
tality and morbidity compared with white women, and black
private hospital.29
men have higher prostate cancer incidence, more aggressive
Race and ethnic differences in the survivorship experience
disease, and the highest mortality of any population group
may be more common than we currently know, and much
from prostate cancer.24 Overall, compared with the white
more research is needed to fully understand variability in
populations, the black population is less likely to survive most
cancer outcomes. For example, there is now evidence that
forms of cancer regardless of stage of diagnosis, tumor
black pediatric cancer survivors experience increased rates
characteristics, and comorbidity.24
of anthracycline-related cardiotoxicities compared with
Ethnic identity is associated with disparities in cancer
white pediatric cancer survivors30; vitamin D deficiency rates
morbidity and mortality, but the trends are not straight-
in black and Hispanic breast cancer survivors are more
forward. Cervical cancer is an example of the complex
prevalent than among white breast cancer survivors; and
contribution of ethnic status to cancer rates and outcomes.
minority women breast cancer survivors suffer from dis-
Cervical cancer incidence is higher in Hispanic women64%
turbed sleep at higher rates than white breast cancer
higher than for non-Hispanic white women. Cervical cancer
survivors.31
incidence is also 30% higher in Native Hawaiian/Pacific Is-
Obesity may be an important crosscutting factor in dif-
lander women compared with non-Hispanic white women.
ferential cancer outcomes and side effects. Overall, cancer
Although American Indian/Alaskan Native women have
survival rates are lowest among the black population and
lower incidence of cervical cancer than white women, they
Native American/Pacific Islanderstwo population subgroups
experience increased mortality from cervical cancer.27
with a high prevalence of obesity.28,32 Obesity may also
Cancer survival for almost all cancers is less for Alaska Na-
contribute to racial and ethnic differences in certain persistent
tives than for the white population for almost all cancers.28
adverse effects of cancer treatment, including lymphedema,
The reasons for race and ethnic disparities in cancer rates
cancer-related fatigue, and chemotherapy-induced peripheral
and outcomes are complex, with the main causes including
neuropathy.32
both biologic and social factors. For example, the dramatic
problem of cancer disparities in the Alaska Native population
is believed to be associated with this ethnic groups unique
exposure to multiple infectious and carcinogenic agents,
REDUCING DISPARITIES OVER THE
their unique geographic problems with access to care, and
SURVIVORSHIP CONTINUUM
Although it is clear that there are subgroups of patients with
their not so unique problems with obesity, smoking, physical
cancer who are experiencing poorer outcomes than others,
inactivity, and alcohol consumption.28
solutions to closing this gap are not simple. One important
avenue of research is examining how financial hardship
DISPARITIES IN THE SURVIVORSHIP EXPERIENCE affects risk for poor cancer outcomes. Minority patients are
Are there reasons to believe that there is diversity in how more likely to experience greater financial hardship in the
cancer is experienced across population subgroups, similar wake of cancer than other groups.33 Cancer treatment is
to the diversity in cancer incidence and outcomes? We still expensive, and out-of-pocket costs are particularly prob-
know very little about how racial and ethnic minorities lematic for those with public health insurance or no health
experience life after cancer compared with the white ma- insurance, those with incomes under 100% of the poverty
jority, but there is evidence that side effects from cancer level, and those age 50 to 64.34 Financial circumstances may
treatment are different to some degree. For example, side constitute a barrier to good follow-up care among survivors.
effect profiles for men with prostate cancer may differ by For example, decreased and discontinued hormonal therapy

234 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


adherence in women with breast cancer, delayed medical
care and prescription renewals, and higher levels of unmet
needs in cancer survivors are associated with low income
status.35-37
National oncology organizations wide endorsement of
cancer treatment summaries and cancer survivor care plans
was based on the hope that these tools would improve the
post-treatment quality of care and increase patient self-care
following cancer treatment.6 The study conducted by Kent
et al in 2013 asked survivors if they had received a treatment
summary; only 17.6% had received one whereas 62.6%
wanted but did not receive one. Those who did not receive a
treatment summary had a higher number of health in-
formation needs.37 Would the receipt of cancer care sum-
maries or cancer treatment plans help reduce race and
ethnic disparities in cancer outcomes through improved
follow-up care? In qualitative studies, minority cancer sur-
vivors believed that survivorship care plans would be useful
in navigating post-treatment health care.38,39 However, to
date, research has not conclusively demonstrated effect of
survivorship care plans on survivors outcomes or on dis-
parities in survivorship care. One systematic review of
outcomes of survivorship care plan found they had no effect
on survivor distress, satisfaction with care, cancer care co-
ordination, or oncologic outcomes.40 And ultimately, there is
limited use of cancer care plans in oncology settings for a
variety of practical reasons.41
ASCOs Recommendations for Elimination of Cancer Care
Disparities in the United States called for reducing economic
barriers to care along with increasing research on disparities,
increasing minority enrollment into clinical trials, and in-
creasing diversity of the oncology workforce.42 How have we
done so far? The expansion of insured minority Americans
under the Affordable Health Care for America Act has not
solved the problem of out-of-pocket and rising costs of cancer
care as a barrier to receiving high-quality survivorship care.
Women and minorities remain severely under-represented in
cancer clinical trials.43 There have been gains in the numbers
of minority medical school graduates, but there is still a severe
under-representation of minority physicians in oncology: in
2013, only 2.3% of oncologists were black.44
The 2008 IOM report, Cancer Care for the Whole Patient:
Meeting Psychosocial Health Needs, promoted a standard
of care that incorporates patient-centered and integrated
strategies into routine oncology care, including identifying
psychosocial health needs, connecting patients and families
to needed services, supporting patients in managing illness,
and coordinating the psychosocial and biomedical health
care services.45 New transdisciplinary research on cancer
disparities supports the notion that environmental factors
are important in cancer outcomes, specifically the role of
accumulated social stress (such as chronic exposure to
poverty and violence) in the alteration of an individuals
neuroendocrine stress response and how it influences tumor
biology and cancer progression.46,47 We cannot reverse our
patients life experiences, but we can incorporate knowledge
of the role of the social environment and social stress in
THE CANCER SURVIVORSHIP JOURNEY
new models of care. We need models of care that support
patient self-management within continued, patient-centered
follow-up care services. To begin to reverse disparities in
cancer outcomes, we must provide cancer survivors with
rational and practical supportspecifically the services of
integrated social work professionalsto help them secure
social services and basic need referrals and to provide
psychosocial support to increase their opportunity to have
similar experiences in cancer as the most privileged patients
with cancer.
BARRIERS TO PROVIDING HIGH-QUALITY
SURVIVORSHIP CARE
There are multiple reasons that every survivors journey
is not the same. Earle and Ganz discuss an illuminating
framework for understanding the barriers to providing high-
quality survivorship care.48 In this framework, physicians
incorporate something new into their practice only if at least
one of three conditions is met: (1) it has clearly been shown
to be better for their patients; (2) they are specifically re-
munerated for it; or (3) it is more efficient for them in their
practice. Earle and Ganz state that at the time of their
manuscript, survivorship care as envisioned by the IOM
report does not readily meet any of these criteria.
In the context of this framework, we discuss below four
barriers to the provision of survivorship care: lack of evi-
dence, lack of a trained survivorship care workforce, lack of
reimbursement structures/insurance coverage for survi-
vorship care services, and lack of a cohesive health care
system that would reduce fragmented care.
Lack of Evidence for Survivorship Care
The basis for many of the barriers to providing high-quality
care to all survivors is the lack of evidence regarding best
practices for survivorship care. As discussed by McCabe et al,
much of the literature on survivorship care is based on
analyses of existing datasets or surveys.49 Few prospective
comparative studies have examined the benefits (in health
or economic terms) of alternative programs or models of
care for cancer survivors. Furthermore, even the available
databases are limited. In describing programs for childhood
cancer survivors, many of which have been in existence
substantially longer than have programs for adult cancer
survivors, Eshelman-Kent et al reported that only 41% of
participating Childrens Oncology Group centers indicated
having a database that tracked survivors health outcomes.50
The evidence base demonstrated that improved outcomes
associated with survivorship care are extremely limited.
More importantly, there is almost no information on
whether one type of survivorship care model results in
better outcomes compared with another type of model, or
even what a survivorship care model is.51 When assess-
ment of survivorship programs have been performed, these
assessments have generally focused on patient-reported
outcomes such as quality of life. Although these are
clearly important, there is a critical lack of information on
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 235
HALPERN, MCCABE, AND BURG
long-term outcomes, including survival and costs, associated
with survivorship care.51 In addition, although efforts to
incorporate survivorship care plans into survivorship care
are becoming more widespread, there is little evidence that
these plans have substantial or sustained benefits among
survivors.40
Lack of a Trained Survivorship Care Workforce
Reports have discussed current and projected future short-
ages among the oncology workforce.52 This shortage is made
more acute by the increase over time in resource utilization
intensity for cancer care. As discussed by Bunnell and Shul-
man, among individuals diagnosed with cancer, there has
been an increasing number of physician visits and infusion
visits per patient.53 Related to the lack of reimbursement
for survivorship services (discussed later), this workforce
shortage highlights the opportunity costs associated with
survivorship care; that is, oncologists have insufficient time
available to engage in all patient activities and may be able
to earn greater reimbursement by providing cancer treat-
ment rather than survivorship care. Furthermore, developing,
implementing, and operating survivorship programs is time
consuming. Among institutions providing care for survivors
of childhood cancer, the most commonly reported barrier
was lack of dedicated time for developing late effects care
programs.50
Other models of survivorship care, including shared care
with primary care physicians and involvement of advanced
practice providers (physician assistants and NPs), have been
discussed as strategies to improve survivorship care in the
context of oncologist shortages. However, shortages among
primary care physicians and increased numbers of patients
with health insurance (following implementation of the
Affordable Care Act) who need primary care services may
limit the ability to implement shared care survivorship
models.53 There are also substantial differences between
PCPs and oncologists regarding the perceived role of PCPS in
survivorship care. In a U.S. physician survey, most PCPs
supported a shared care model, whereas most oncologists
favored an oncologist-based model of survivorship care.54 A
majority of oncologists (87%) did not feel that PCPs should
take on the primary role of cancer follow up. Similarly,
Potosky et al reported that oncologists were less likely than
PCPs to believe that PCPs could conduct appropriate testing
for breast cancer recurrence or could provide care for late
effects of breast cancer.55 These findings suggest that de-
spite workforce shortages, U.S. oncologists may not be
accepting of opportunities to share care or transition care for
survivors to PCPs. However, involvement of other health
care professionals in survivorship care may be more com-
mon in other countries. For example, in a survey of Italian
oncologists, Numico et al reported that only 55% and 30% of
oncologists in Italy indefinitely follow patients with breast
cancer and patients with colorectal cancer, respectively,
while other oncologists discharge survivors to PCPs usually
after 5 years.56
236 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
A potential strategy to address oncology workforce short-
ages related to survivorship care is to enhance training in
this area. Rowland et al highlighted the need to train the
next generation of health care providers about survivorship
issues and to attract clinicians and researchers to this area.57
McCabe et al also discussed expanding and coordinat-
ing educational opportunities for medical professionals
as a strategy toward improving overall survivorship care.49
Essential topics specified for survivorship education curricula
included survivors quality of life, health promotion, palliative
care, and prevention, diagnosis, and treatment of recurrences,
secondary cancers, and late-occurring complications.
Lack of Reimbursement for Survivorship Care Services
Lack of reimbursement for survivorship care is largely a
problem in the United States, which lacks a national health
care system. However, many of the issues related to this
barrier apply globally to physicians, when there is a need to
prioritize the cancer care services provided. Survivorship
care can be time consuming. Eshelman-Kent et al reported
that an initial visit with survivors of childhood cancer re-
quired 122 minutes, whereas subsequent annual visits were
91 minutes.50 In a survey of Australian oncologists and
nurses who provided breast cancer survivorship care, one-
third of these specialists reported spending more than 25%
of their clinical time providing follow-up care.58
Most U.S. insurers do not provide additional reimbursement
for survivorship care, which may include psychosocial support
and care planning services. As presented in the 2009 IOM
report Ensuring Quality Cancer Care Through the Oncology
Workforce: Sustaining Research and Care in the 21st Century:
Reimbursement for survivorship care does not cover the
costs of providing appropriate monitoring and support for
the physical, social, and emotional effects in the short and
long term course for the disease and treatment of cancer. In
order to offer these services, institutions that do provide this
care absorb the cost or must seek funding from other
sources. Many community-level institutions and smaller-
scale providers simply cannot afford to do so.59, p. 32
McCabe et al also discuss these barriers, commenting
on the limited reimbursement for components of survi-
vorship care.49 These authors highlight that this may result
in a misalignment of resource utilization, with revenue-
generating services (such as surveillance testing) being
overused and non-revenue-generating survivorship care
services (such as care coordination) being underused. These
nonreimbursed services may be time intensive. However,
although care coordination between oncologists and PCPs
is almost always highlighted as an important component of
survivorship care, definitions for care coordination vary
greatly, and little evidence is available showing the health
or economic benefits of care coordination for cancer
survivors.
Furthermore, it may be more efficient (and equally effec-
tive) to provide certain survivorship care services by email or
telephone rather than in person, but many insurers reimburse

only for face-to-face delivery of care, resulting in a financial
disincentive for provision of remote services.
Lack of a Cohesive Health Care System That Would
Reduce Fragmented Care
Approximately 75% of survivors experience long-term or late
effects of cancer and cancer treatment.4 These long-term
and late effects can involve all body systems and can affect
all aspects of health. As such, we need a diverse range of
health care providers to support cancer survivors. As dis-
cussed by Landier, the complexity of survivorship care cor-
responds to the diversity of patient characteristics, diagnoses,
treatments, and potential sequelae:
Consequences of cancer treatment span the medical, psy-
chosocial, socioeconomic and spiritual domains, and survi-
vors and their healthcare providers often lack awareness of
treatment-related risks and the potential interactions of
these risks with common comorbidities, such as obesity,
diabetes, cardiovascular disease, anxiety, and depression. 60
This diversity in symptoms experienced and health care
services needed among cancer survivors almost guarantees
that their health care will be fragmented. Even dedicated
and well-staffed cancer survivorship programs and health
care systems may not be able to provide care for all the
possible needs of survivors in a timely manner.
FUTURE AREAS OF FOCUS FOR SURVIVORSHIP
CARE RESEARCH
Based on the information summarized above, we recom-
mend consideration of several areas for future research on
survivorship care. We must focus on the continued devel-
opment of an evidence base for survivorship care. This
should include rigorous assessments of the following:
Effect of different types of models of care, including
personnel providing survivorship care, use of health
information technologies and care not administered
face to face, and comorbidities and risk adjustment
Needed resources (including funding, time, and person-
nel) to implement different types of survivorship care
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asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 239
PATIENT AND SURVIVOR CARE

Cancer Treatment as an
Accelerated Aging Process

CHAIR
Arti Hurria, MD
City of Hope
Duarte, CA

SPEAKERS
Hyman B. Muss, MD
University of North Carolina at Chapel Hill School of Medicine
Chapel Hill, NC

Lee Jones, PhD

Memorial Sloan Kettering Cancer Center
New York, NY
HURRIA, JONES, AND MUSS

Cancer Treatment as an Accelerated Aging Process:

Assessment, Biomarkers, and Interventions
Arti Hurria, MD, Lee Jones, PhD, and Hyman B. Muss, MD

OVERVIEW

An accumulating body of evidence supports the hypothesis that cancer and/or cancer treatment is associated with
accelerated aging. The majority of these data come from the pediatric literature; however, a smaller yet growing body of
literature points toward similar findings in the geriatric population. This is a key survivorship issue the growing number of
older adults with cancer face, along with the short- and long-term impact of cancer therapy on the aging process. This article
will review clinical and biologic markers of aging in older adults with cancer, use cardiovascular disease as a model of
accelerated aging, and discuss potential interventions to decrease the risk.

T he U.S. population is aging with the number of in-

dividuals age 65 or older anticipated to double between
2010 and 2030.1 This growing population is at risk for cancer
because the majority of cancer incidence and mortality occurs
in individuals age 65 and older. Together, the aging of the U.S.
population and the association of cancer and aging is cul-
minating in a 67% increase in cancer incidence in individuals
age 65 or older in the United States from 2010 to 2030.2
However, many of these individuals will survive cancer, and
the majority of cancer survivors are older adults. Presently,
there are 8 million cancer survivors age 65 or older in the
United States, and this number is anticipated to continue to
grow to 11 million by 2020.3
A key survivorship issue facing these older adults is the short-
and long-term impact of cancer therapy on the aging process.
It has been suggested that cancer and/or its treatment may
contribute to an accelerated aging phenotype.4 The majority of
these data come from the pediatric literature, in which can-
cer survivors are more predisposed to the development of
frailty as well as chronic conditions such as myocardial in-
farction, congestive heart failure, and second cancers.5-7 There
is a smaller yet growing body of literature pointing toward
similar findings in the geriatric population. This article will
review clinical and biologic markers of aging in older adults with
cancer, use cardiovascular disease as a model of accelerated
aging, and discuss potential interventions to decrease the risk.
THE CLINICAL ASSESSMENT OF AGING
The aging process is unique to the individual, and chrono-
logical age is a poor descriptor of an older adult. For example,
two individuals who are chronologically age 75 can have very
different functional ages. At the extremes, one individual
could be wheelchair-bound in a nursing home, and another
may be a marathon runner; distinguishing the difference in
functional age between these two individuals can be per-
formed with the eyeball test from the door of the ex-
amination room. However, for most clinical situations, an
individuals outward appearance can be deceiving, and an
individuals functional age can be quite difficult to determine
without a more detailed evaluation. There are two main
ways in which an oncologist can get a better sense of the
functional age of an older adult. The first is through performing
a geriatric assessment, and the second is by assessing frailty.
Both of these methods are discussed below.
A geriatric assessment identifies factors other than
chronological age that can predict the risk of morbidity and
mortality in older adults. These include functional status,
cognition, comorbidity, psychological state, social support,
and nutritional status. There is a growing body of literature
regarding the benefits of performing a geriatric assessment
in older adults with cancer.8 In patients with cancer, this
assessment can identify areas of vulnerability not otherwise
detected in a routine history and physical examination,
predict cancer treatment toxicity and survival, and serve as a
platform for interventions to decrease toxicity risk.8 Short
geriatric assessment tools for oncologists have been de-
veloped that are feasible to implement in both daily clinical
practice and among patients enrolled in clinical trials. Ge-
riatric assessment tools that can be mailed to the patient and
completed prior to the office visit, as well as computerized

From the City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA; Memorial Sloan Kettering Cancer Center, New York, NY; The University of North
Carolina at Chapel Hill, Chapel Hill, NC.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Arti Hurria, MD, City of Hope, 1500 East Duarte Rd., Duarte, CA 91010; email: Ahurria@coh.org.

2016 by American Society of Clinical Oncology.

e516 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


geriatric assessment tools, have also been evaluated.9-11
Abbreviated geriatric assessment screening tools are avail-
able; however, a consensus has not been reached regarding
which tool could identify those patients who would benefit
from a more detailed geriatric assessment.12
There are compelling geriatric assessment findings in
cancer survivors that support the hypothesis that cancer and
its treatment may impact the aging process. Cancer survivors
are more likely to report poorer physical and mental health-
related quality of life compared with adults with cancer.13,14
Older cancer survivors are more likely to have limitations in
performing activities of daily living as well as mobility lim-
itations compared with older adults without a history of
cancer.15 There is an increase in the number of comorbidities
in individuals who are cancer survivors compared with
those without a history of cancer.16 Furthermore, specific
comorbid conditions may be linked to the treatment the
patient has receivedfor example, congestive heart failure
(among patients receiving anthracycline-based therapies),17
peripheral neuropathy (among patients receiving taxanes),18
and declines in bone health (among patients receiving aro-
matase inhibitors).19,20 A study of the neuropsychological
function of older patients (age 6070) with breast cancer
demonstrated that those who were exposed to chemo-
therapy were at higher risk for posttreatment cognitive de-
cline and factors associated with cognitive agingsuch as
lower cognitive capacity (low cognitive reserve) and apoli-
poprotein (ApoE4+) statusinteract with chemotherapy
treatment to increase the risk of cognitive decline.8
Another means of assessing the aging process, which
comes primarily from the geriatric literature, is measuring
frailty. Frailty can be defined as a decrease in physiologic
reserve that places an individual at increased risk for adverse
events such as hospitalization, falls, and poorer overall
survival. There are two main methods of assessing frailty in
the geriatric population. The first was proposed by Fried
KEY POINTS
Cancer and/or its treatment may contribute to an
accelerated aging phenotype.
A key survivorship issue facing older adults is the short-
and long-term impact of cancer therapy on the aging
process.
Clinical (geriatric assessment) and biologic markers of
aging hold great promise as independent predictors of
patient outcomes including toxicity, functional reserve,
and survival.
Standard cancer treatment causes significant and
marked impairments in global cardiovascular function,
which may persist years after the cessation of primary
therapy.
Structured exercise training may be an effective strategy
to mitigate acute and long-term impairments in
cardiovascular function in patients both during and
following primary adjuvant therapy.
CANCER TREATMENT AND ACCELERATED AGING
TABLE 1. The Frailty Phenotype21
Categorizations Criteria
Frailty Phenotype: Presents Unintentional weight loss
With 3 Criteria ($ 10 pounds in past year)
Self-reported exhaustion
Intermediate or Prefrail Weakness (lowest 20th percentile in
Phenotype: Presents grip strength)
With 1 or 2 of the Criteria
Slow walking speed (lowest
20th percentile on a timed walk of
15 feet)
Low physical activity (lowest quintile of
kilocalories per week)
et al21 utilizing data from the Cardiovascular Health Study.
They identified a phenotype for frailty among over 5,000
community-dwelling men and women age 65 or older
(Table 1), which consists of weight loss, exhaustion, slow
walking speed, weakness, and low physical activity. Patients
who were defined as frail or prefrail, compared with nonfrail,
were at increased risk for hospitalization, falls, decreased
mobility, decline in the ability to complete activities of daily
living, and mortality over the subsequent 3 and 7 years.
Rockwood and Mitnitski22 defined another method of
assessing frailty that is based on the accumulation of deficits.
Deficits captured in a geriatric assessment are tallied and
provide a composite index of the degree of frailty. These
methods of describing frailty have mainly been used as
research tools rather than tools used in daily clinical practice.
BIOMARKERS OF AGING AND CANCER THERAPY
Geriatric assessment is the cornerstone for assessing
function in patients with cancer prior to treatment. It can be
helpful in predicting survival, treatment-related toxicity, and
other outcomes. However, geriatric assessment can be time
consuming, and many clinicians do not have the resources to
perform a geriatric assessment in daily practice. Biomarkers
of aging may help fill this gap.23 The term biomarker has
many definitions; the World Health Organization has
defined a biomarker as almost any measurement reflecting
an interaction between a biological system and a potential
hazard, which may be chemical, physical, or biological. The
measured response may be functional and physiological,
biochemical at the cellular level, or a molecular interaction.
A list of potential biomarkers is provided in Table 2. For this
review, we will focus on several categories of potential
biomarkers, including chronic inflammatory markers,
markers of cellular senescence, and sarcopenia to explore
how they might be further evaluated with the goal of de-
fining markers that can independently predict outcomes in
older patients with cancer. Several excellent reviews of this
topic have been recently published.23,24
Inflammatory markers have been extensively studied, and
increased levels have been shown to correlate with frailty,
functional decline, and survival.24 These markers now are
receiving wide attention, as there is good evidence that
chronically elevated levels may accelerate or exacerbate the
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HURRIA, JONES, AND MUSS
TABLE 2. Potential Biomarkers of Treatment-Related Toxicity and Aging
Marker Source
Chronic Inflammatory Serum or plasma
Markers
Telomere Length Leukocyte DNA
p16INK4a T lymphocyte RNA
Sarcopenia DEXA scan
CT scan
Bioelectrical
Impedance
Maximal Oxygen O2 and CO2 of inhaled and exhaled air
Consumption
(VO2max)
Abbreviations: ELISA, enzyme-linked immunosorbent assay; CRP, C-reactive protein; TNF-a, tumor necrosis factor a; IL1RA, IL-1 receptor agonist; s-VCAM, soluble vascular cell
adhesion molecule; q-PCR, quantitative polymerase chain reaction; FISH, fluorescent in situ hybridization; STELA, single telomere length analysis; RT-qPCR, quantitative reverse
transcription polymerase chain reaction; DEXA, dual-energy x-ray absorptiometry.
Modified from Hubbard et al.23
aging process. These markers, which include interleukins,
tumor necrosis factors, and others, have been studied
extensively in frail patients in whom they independently
correlate with other measures of physical function.
Interleukin-6 (IL-6) has probably been the most extensively
studied cytokine and has been shown to predict functional
decline, including a diminution in the ability to perform
activities of daily living, poor ambulation, and decreased
mobility.25 There also appears to be a major relationship
between inflammatory markers and cell senescence. Se-
nescent cells are viable and capable of secreting proin-
flammatory markers that have led to the definition of a
senescence-associated secretory phenotype.26 To date,
however, none of these markers has assumed a major role in
clinical care or further studies designed to see if any single
marker or combination might have an independent role in
the management of the older patient with cancer. These studies
would test whether such markers could be independent pre-
dictors of treatment tolerance, including acute and chronic
toxicities, functional loss, and cognitive decline.
Telomere length as well as the proteins that play a role in
telomere length are also of great interest as markers that
may predict survival, functional status, and toxicity,27,28 and
studies are underway to further define the potential role of
telomere length as a predictor of cancer-related outcomes.
Another emerging marker of great potential benefit as a
predictor of toxicity and outcomes is p16ink4a. This gene, in
which expression increases 10-fold with aging, codes for a
protein that blocks cyclin-dependent kinase, which leads to
cell senescence.29 In animal models, there is a clear direct
relationship between p16ink4a expression and organ age.30
In addition, human studies have shown a strong association
of p16ink4a expression and T-cell aging in patients infected
with HIV,31 senescence of human mesenchymal stem cells,32
and hospital stay after coronary artery bypass.33
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Association With Association With
Test Frailty/Function Mortality
ELISA Yes (CRP, IL-6, TNF-a, Yes (CRP, IL-6,
D-dimer, IL1RA) D-dimer, s-VCAM)
q-PCR or southern blot Yes Yes
FISH
STELA
RT-qPCR Maybe Unknown
Commercially available software Yes Yes
for body composition analysis
Incremental exercise testing Yes Yes
Other markers of potential interest include the mea-
surement of sarcopenia; recent data show the utility of
using CT scans of the abdomen as a valid measure of
muscle mass and a tool to predict cancer clinical out-
comes.34 This is of great interest, as CT scans are widely
used in management of patients with cancer. The role of
maximum oxygen consumption (VO2max) as a biomarker of
aging and treatment effect is discussed elsewhere in this
review.
THE EFFECT OF CANCER TREATMENT ON
BIOMARKERS OF AGING
There is little doubt that the treatment of cancer, especially
radiation therapy and chemotherapy, greatly accelerates
aging.35,36 A recent overview of survivors of childhood
cancer showed that these individuals were at greatly in-
creased risk for substantial comorbidity and premature
death.35 Data from one of the large cohorts described in this
review demonstrated the cumulative prevalence for a se-
rious or life-threatening chronic condition of 81% by age 45;
in addition, there was an extremely high incidence of second
neoplasms that was directly related to the radiation dose. In
another study of survivors of childhood cancer, the preva-
lence of prefrailty and frailty were 31.5 and 13.1% among
women and 12.9 and 2.7% among men, respectively. This
prevalence of frailty among young adult survivors of cancer
with a mean age of 34 years was similar to that of adults age
65 or older.37
Operative procedures result in a cascade of cytokine and
acute-phase responses including IL-6, white cell count, and
C-reactive protein. In a systematic review that included 164
studies involving 14,362 patients, IL-6 and C-reactive protein
responses were clearly associated with the magnitude and
invasiveness of the operative procedure. Colorectal cancer

surgery resection was associated with the highest acute
increase in cytokines.38 Although of concern in the short run,
it is not likely that surgical procedures directly accelerate
aging. Radiation therapy is clearly related to the formation
of proinflammatory cytokines and may result in progres-
sive and long-term tissue damage.39 As shown in survivors
of childhood cancer, radiation is associated with the ac-
celerated development of second malignancies as well as
other comorbidities. Studies testing how biomarkers might
be used to predict radiation toxicity in individual patients
and possible interventions to ameliorate radiation effects
are needed. As the childhood cancer survivorship studies
show, chemotherapy also is a major cause of accelerated
aging. This has been well demonstrated in vitro40 and in
animal models.30 Chemotherapy has a major effect on
telomere length41 and has been associated with telomere
shortening in hematopoietic stem cells42 as well as in pe-
ripheral blood mononuclear cells in patients given repetitive
standard-dose chemotherapy for solid tumors.43 Further-
more, telomere shortening was shown to be greater in older
patients given combined chemotherapy and radiation for
head and neck cancer when compared with younger
patients. 44
p16ink4a has major promise as a biomarker of chemo-
therapy toxicity. p16ink4a expression increases approxi-
mately 10-fold between ages 20 and 80, and this dynamic
range provides for a more robust marker as a predictor of
molecular aging. In one study of women receiving adjuvant
chemotherapy for early-stage breast cancer, p16ink4a
expression measured in peripheral blood T cells increased
by almost one log2 order of magnitude immediately after
treatment and remained elevated 12 months after treat-
ment. 45 This change corresponds to almost a 15-year
increase in chronologic age. In this study, the cytokines
VEGFA and monocyte chemotactic protein-1 also signifi-
cantly increased and remained elevated at 12 months,
but telomere length was not affected. In a cross-sectional
cohort of patients in the same study, prior chemother-
apy exposure was independently associated with in-
creased p16ink4a expression comparable to 10 years of
chronologic aging. Current studies are underway explor-
ing the potential role of p16ink4a as a predictor of toxic-
ity and subsequent comorbidity in patients receiving
chemotherapy.
There is no doubt that chemotherapy and radiation
therapy accelerate aging. This is an especially concerning
observation in younger patients, for whom the dramatically
improved survival rates for many childhood cancers are
now associated with the early development of comor-
bidities and an increased risk of second cancers, and in
older patients, in whom such changes may result in the
development of new comorbidities or accelerate previous
noncancer-related illness. Several biomarkers of aging are
now available that might prove to identify those patients
most vulnerable to cancer treatment and allow for the earlier
testing of interventions that might minimize treatment related
toxicity.
CANCER TREATMENT AND ACCELERATED AGING
ACCELERATED AGING IN PATIENTS WITH
CANCER: CARDIOVASCULAR AGING AS A MODEL
As described in the preceding sections, older patients with
cancer are subject to the deleterious effects associated with
normal aging but experience the confounding effects of
cancer treatment that can lead to an accelerated aging
phenotype, characterized by a notable impairment in
physical functioning and other parameters. In current
practice, the extent of functional decline or physical func-
tioning is typically assessed using performance status
scoring systems, evaluated either by the Karnofsky Perfor-
mance Scale (KPS) or the Eastern Cooperative Oncology
Group (ECOG) scale. However, performance status scoring
systems are subjective and lack sensitivity to discriminate
between individuals, particularly those defined as having a
good (i.e., KPS . 70; ECOG 0 to 1) performance status.46,47
As a result, performance status measurements are often
supplemented with the use of other more objective mea-
sures of overall physical functioning such as the compre-
hensive geriatric assessment or measurement of cardiac
and lung function via resting assessment of left ventricular
ejection fraction and pulmonary function testing, re-
spectively. Although these tools provide valuable information
regarding physical functioning, treatment eligibility, and risk
stratification, they do not provide evaluation of global car-
diovascular function and reserve. Indeed, cardiac function is
only one organ component that contributes to the integrative
capacity of the cardiovascular and musculoskeletal system to
transport and use oxygen (O2) for adenosine triphosphate
resynthesis.48 The efficiency of O2 transport and utilization
determines an individuals cardiovascular performance (or
exercise capacity). An incremental cardiopulmonary exercise
test with gas-exchange measurement, to assess peak oxygen
consumption (VO2peak), provides the gold-standard assess-
ment of exercise capacity. VO2peak is inversely correlated with
cardiovascular and all-cause mortality in a broad range of
adult populations.49-53 On this basis, several groups have
started to examine whether the cardiopulmonary exercise
test provides a marker of physiologic aging in the oncology
setting both during and following primary adjuvant therapy.
Cancer Therapy-Induced Changes in Exercise Capacity
No prospective, observational studies have examined lon-
gitudinal changes in exercise capacity during and following
adjuvant therapy in patients with solid tumors; nevertheless,
it is possible to glean initial data in the context of randomized
controlled trials of exercise training among patients assigned
to the usual care condition. For example, Courneya et al54
performed an exercise randomized controlled trial among
242 operable patients with breast cancer receiving standard
adjuvant chemotherapy. Among the 82 women assigned to
usual care (i.e., chemotherapy only), exercise capacity as
measured by VO2peak declined approximately 5% from
baseline (following the first cycle of chemotherapy) to fol-
lowing the completion of chemotherapy (median 17 weeks).
Similarly, van Waart et al55 reported that exercise capacity,
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HURRIA, JONES, AND MUSS
as measured by a maximal cycle ergometer test, decreased
approximately 18% from prechemotherapy to immediately
postchemotherapy. Finally, Hornsby et al56 reported that
12 weeks of standard neoadjuvant chemotherapy was as-
sociated with a 9.5% decline in VO2peak from pre-
chemotherapy to postchemotherapy. The impairment in
exercise capacity also appears to extend to other tumor sites
receiving other anticancer regimens. For example, Segal
et al57 reported that 6 months of androgen deprivation
therapy with or without radiation therapy was associated
with an approximately 10% decline in VO2peak among men
with advanced prostate cancer. Similarly, West et al58 found
that standard neoadjuvant chemoradiation in patients with
rectal cancer caused a 16% decline in VO2peak. The long-term
clinical importance of this decline is not known; however,
VO2peak typically declines 10% every decade in healthy
women, indicating that short-term chemotherapy may
cause the equivalent of a decade of physiological aging.59
Of importance, the decline in exercise capacity may not
recover, even years following the cessation of primary
therapy. For example, Jones et al59 found that despite
normal resting cardiac function (i.e., left ventricular ejection
fraction $ 50%), VO2peak was, on average, 22% below that of
age-matched sedentary women in 140 patients with early-
stage breast cancer a mean of 27 months following the
completion of primary adjuvant therapy. In corroboration,
Khouri et al60 found that VO2peak was, on average, 20% below
that of age-matched sedentary women in 57 patients with
early-stage breast cancer a mean of 26 months following the
completion of primary therapy. The persistent impairment
in exercise capacity also appears to extend beyond operable
breast cancer to other cancer sites. For example, Adams
et al61 performed a study of survivors with Hodgkin disease
(48 patients, mean of 14 years after diagnosis) and found
that VO2peak was significantly reduced in 30% of survivors.
Again, the clinical and prognostic importance of these dec-
rements is currently not known, but because exercise capacity
is a strong independent predictor of both cardiovascular as
well as all-cause mortality in noncancer populations, the
observed impairments are alarming and create a strong ra-
tionale for the development and testing of interventions to
prevent and/or treat the observed impairments.
Efficacy of Exercise Training Countermeasures
Aerobic (exercise) training is the most effective therapy to
improve VO2peak in healthy individuals given that it improves
the reserve capacity of all O2 transport organs, which to-
gether lead to favorable improvements in exercise capac-
ity,48 although fewer trials have examined the efficacy of
exercise on exercise capacity, as measured by VO2peak, in
patients with cancer, with the vast majority of work to date
in women with early-stage breast cancer. In a recent meta-
analysis of six exercise training randomized controlled trials
(involving 571 patients) that assessed the effects of exercise
training in adults with cancer, exercise training led to a
significant improvement in VO2peak (mean weighted
e520 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
difference = +2.90 mL $ kg21min21; 95% CI, 1.164.64),
compared with nonexercising sedentary control partici-
pants.62 However, the data from individual studies are more
heterogeneous. For instance, Courneya et al54 reported that
supervised aerobic training was superior to usual care
(chemotherapy only) for improving VO2peak in 242 patients
with operable breast cancer receiving standard adjuvant
chemotherapy. Interestingly, aerobic training was associ-
ated with a nonsignificant improvement in VO2peak (+0.5 mL
$ kg21min21) but completely abrogated the VO2peak decline
observed in the usual-care group. Further work from this
group found that supervised exercise training following
standard (i.e., three times per week, at 25 to 30 minutes/
session), higher volume (i.e., three times per week, at 50 to
60 minutes/session), or combined (i.e., three times per week
of combined aerobic and resistance training) prescriptions
did not mitigate the considerable declines in VO2peak among
301 patients with breast cancer receiving conventional
adjuvant therapy. In contrast, Jones et al63 tested the effi-
cacy of supervised aerobic training consisting of three
sessions per week at 55%100% of VO2peak for 2060 min per
session following a nonlinear prescription in patients with
breast cancer receiving neoadjuvant chemotherapy; spe-
cifically, in nonlinear prescriptions, aerobic training sessions
are sequenced in such a fashion that training-induced
physiologic stress is continually altered in terms of in-
tensity and duration in conjunction with appropriate rest
and recovery sessions to optimize cardiovascular adapta-
tion. Attendance and adherence rates to aerobic training
were 82 and 66%, respectively. Intention-to-treat analysis
indicated that VO2peak increased by 2.6 6 3.5 ml/kg/min
(+13.3%) in the chemotherapy plus aerobic training group,
whereas it decreased by 1.5 6 2.2 ml/kg/min (28.6%) in the
chemotherapy only group (between-group difference, p =
.001). In the oncology setting, approximately five additional
studies, both during and following adjuvant therapy, have
examined the safety, tolerability, and preliminary efficacy of
nonlinear aerobic training, compared with a usual care (no
exercise training) control group. Overall, exercise pre-
scriptions adhering to a nonlinear approach appear to be
safe (low adverse event rate), tolerable (mean adherence $
75% of prescribed sessions both during and after primary
adjuvant therapy), and efficacious, conferring favorable
improvements in VO2peak, quality of life, and other physi-
ologic outcomes.64
In summary, the extant evidence indicates that patients
with cancer experience considerable and marked impair-
ments in exercise capacity during cancer therapy that appear
to persist even years following the completion of primary
treatmentsuch decrements are consistent with an
accelerated cardiovascular aging phenotype and may, in
part, contribute to the increased risk of cardiovascular
disease, frailty, and functional dependence in certain cancer
populations. Based on current data, supervised aerobic
exercise training appears to be a safe, tolerable, and effi-
cacious intervention strategy to potentially offset as well as
recover impaired cardiopulmonary function in a broad range

of patients with cancer. The mechanisms, optimal timing,
type, and schedule of exercise training, as well as the long-
term clinical implications of declines and/or improvements
in exercise capacity, are a high research priority in geriatric
oncology.
CONCLUSION
An accumulating body of evidence is supporting the hy-
pothesis that cancer and/or cancer treatment is associated
with accelerated aging; however, several gaps in knowledge
remain, and future research is needed to understand the
implications of these findings, as well as ways to decrease
the risk. This unmet need formed the basis for a research
conference of the Cancer and Aging Research Group, Na-
tional Institute on Aging, and National Cancer Institute, ti-
tled Design and Implementation of Intervention Studies to
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PATIENT AND SURVIVOR CARE

New and Improved? Use of White

Blood Cell Growth Factors in
Oncology Practice

CHAIR
Thomas J. Smith, MD, FACP, FASCO, FAAHPM
Johns Hopkins University School of Medicine
Baltimore, MD

SPEAKERS
Gary H. Lyman, MD, MPH, FASCO, FACP, FRCP
Fred Hutchinson Cancer Research Center
Seattle, WA

James O. Armitage, MD
University of Nebraska Medical Center
Omaha, NE
SMITH AND HILLNER

Real-World Conundrums and Biases in the Use of White Cell

Growth Factors
Thomas J. Smith, MD, FACP, FASCO, FAAHPM, and Bruce E. Hillner, MD, FASCO

OVERVIEW

We present the 2015 American Society of Clinical Oncology (ASCO) white cell growth factors, or colony-stimulating factor (CSF),
guidelines, updated from 2006. One new indication has been addeddose-intense chemotherapy for bladder cancerto
accompany the existing use for dose-dense breast cancer chemotherapy. Colony-stimulating factors remain appropriate for
any regimen where the risk of febrile neutropenia is about 20% per cycle and dose reduction is not appropriate. Based on new
evidence from multiple trials, CSF use is no longer indicated in treatment of lymphoma unless there are special risk factors. The
United States accounts for 78% of the sales of CSF. The panel approved the use of all biosimilars, but the cost savings will
be small as the price is about 80% of the branded CSFs. More biosimilars at lower cost are awaited. Methods to reduce use
without harm to patients, by requiring justification according to accepted guidelines, are ongoing.

n 2015, the ASCO guideline on the use of CSFs was updated.1

I The panel reviewed 66 publications that met eligibility criteria,
including 41 randomized trials.
Since the preceding update in 2006, what has changed? Also,
what is likely to change in the near future? The short answer is
that, unless you treat bladder cancer or lymphoma, not much
has changed, and there are no major practice-changing im-
plications for most oncologists. The Sidebar summarizes the
guideline report. The subsequent commentary is our own
perspective and is not necessarily that of ASCO or the panel.
NEW REASONS AND SITUATIONS WHEN
COLONY-STIMULATING FACTORS ARE
INDICATED
There is now one additional regimen to add to the short list
of indicated combinations for dose-dense chemotherapy,
high-dose methotrexate/vinblastine/doxorubicin/cisplatin
(M-VAC) chemotherapy in urogenital cancers. In a phase
III clinical trial with 7.3 years of follow-up time, the median
and 5-year overall survivals were 15.1 months and 21.8% in
the high-dose M-VAC arm, compared with 14.9 months and
13.5% in the M-VAC arm (hazard ratio for mortality, 0.76).2
As the authors noted, the toxicity was not worse, fewer
people died of their cancers, and high-dose M-VAC
produces a borderline statistically significant relative re-
duction in the risk of progression and death compared to
M-VAC.2 A similar result of equal efficacy and response
rates with less toxicity (major toxicity rate, 32% vs. 55% for
regular M-VAC) was found with the use of neoadjuvant
M-VAC with CSF support.3,4
There are now two clinical settings in which dose-dense
chemotherapy is indicated instead of usual-dose chemo-
therapy, breast cancer and uroepithelial cancer. As noted in
the guideline, dose-dense regimens that require a CSF
should only be used within an appropriately designed clinical
trial or if supported by convincing efficacy data.1
For those oncologists who use high-dose chemotherapy
and stem-cell transplantation, CSFs may be used alone, after
chemotherapy, or with plerixafor to help mobilize stem cells.
This has been standard practice for many years.5,6
NEW REASONS AND SITUATIONS WHEN
COLONY-STIMULATING FACTORS ARE NO
LONGER INDICATED
The major change in the 2015 guideline was a recommen-
dation to not routinely use CSFs in the treatment of diffuse
B-cell non-Hodgkin lymphoma in nonelderly patients (youn-
ger than age 65 years with no major comorbidities) on the
basis of the lack of compelling benefit for 14-day CHOP
(cyclophosphamide, doxorubicin, vincristine, and prednisolone)
versus 21-day CHOP in two large definitive trials that had
median follow-up times of 5 and 4 years.7,8 The same
conclusion held for a trial in older patients, in which there
was no benefit of 14-day versus 21-day R-CHOP (CHOP +
rituximab).9 This guidance is in line with expert opinion ex-
pressed elsewhere and with worldwide common practice.10

From the Harry J. Duffey Family Palliative Care Program of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Hillner Consulting, LLC, Richmond, VA;
Massey Cancer Center, Virginia Commonwealth University, Richmond, VA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Thomas J. Smith, MD, Sidney Kimmel Comprehensive Cancer Center, 600 North Wolfe St., Blalock 369, Baltimore, MD 21287; email: tsmit136@jhmi.edu.

2016 by American Society of Clinical Oncology.

e524 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


FIGURE 1. Amgen Sales of Colony-Stimulating Factors Compared With World Population
NEW PRODUCTS THAT MAY REDUCE THE AMOUNT
SOCIETY PAYS FOR COLONY-STIMULATING
FACTORS
Filgrastim and peg-filgrastim are expensive. Despite in-
troductions to the market more than 15 years ago, their
prices are actually increasing. As reported in the Amgen
annual report, the 2014 Neulasta sales increased 7 percent
year-over-year for the fourth quarter and 5 percent for the
full year driven mainly by price.11 In 2014, the U.S. sales for
Amgen were $4.488 billion from peg-filgrastim and fil-
grastim; in contrast, the sales to the rest of the world were
just $1.267 billion (Fig. 1).11
These are just revenues to Amgen and do not represent
what patients and payers actually paid. The United States
represents 4.5% of the world population12 and uses 20% of
the worlds supply of energy13; the United States purchases
KEY POINTS
CSFs are indicated to give dose-intense chemotherapy
for adjuvant breast cancer and neoadjuvant and
metastatic uroepithelial cancers using intensified
M-VAC.
CSFs are indicated when the risk of febrile neutropenia is
about 20% and dose reduction is not an appropriate
strategy; most regimens have a risk of febrile
neutropenia that is less than 20%.
CSFs are not indicated in the routine treatment of
lymphoma with regimens such as R-CHOP.
The United States uses nearly 80% of the worlds supply
of CSFs, far more than any nation, and the price
continues to rise, therefore attempts to reduce use will
increase.
The use of biosimilars for CSFs was strongly endorsed by
the committee and the U.S. Food and Drug
Administration.
ISSUES ON THE USE OF WHITE CELL GROWTH FACTORS
78% of the worlds CSF sales. How much of the current U.S.
use is related to income generation from CSF sales compared
with patient demand or physician training may shift and is
worthy of study as large institutional providers and practices
begin switching to accountable care models with global
payments.
What is the potential impact on the U.S. oncology mar-
ketplace if we accept (as the ASCO panel and the U.S. Food
and Drug Administration [FDA] have) that biosimilars are
indeed biosimilar? As the guideline stated, pegfilgrastim,
filgrastim, tbo-filgrastim, and filgrastim-sndz (and other
biosimilars, as they become available) can be used for the
prevention of treatment-related febrile neutropenia. The
choice of agent depends on convenience, cost, and the
clinical situation. Tbo-filgrastim has captured approxi-
mately 20% of the worldwide market for filgrastim.14 The
manufacturer, Teva, has stated that tbo-filgrastim now
claims 38% of the market share for in-hospital use in the
United States.15 Balugrastim (manufactured by Teva), a
recombinant protein that combines albumin and human
granulocyte CSF (G-CSF), was compared with pegfilgrastim
in a trial with 256 patients who had breast cancer, and
balugrastim had noninferior results, maintained a 1-day
duration of severe neutropenia, and had a slightly shorter
recovery of absolute neutrophil counts in cycle 1.16 How-
ever, Teva withdrew its U.S. application for FDA approval for
balugrastim. Teva has released another long-acting bio-
similar CSF in Europe, lipegfilgrastim, that will be in direct
competition with pegfilgrastim. Preliminary results showed
equal efficacy.17,18 We could not find any estimates of the
cost impact.
The economic impact of the biosimilars for this indication
has been modest; tbo-filgrastim was priced at approximately
80% of the price of its direct competitor.19 More direct ways
to reduce overall CSF use (specifically, peer-to-peer review
anytime a CSF is ordered) are also successful,20 but most
U.S.insurers and Medicare have not taken that approach
to date. ASCO, in its initial wave of Choosing Wisely topic
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e525
SMITH AND HILLNER

SIDEBAR. 2015 Recommendations for the Use of White Blood Cell Growth Factors: ASCO Clinical Practice
Guideline Update*
Primary prophylaxis with a CSF starting with the first cycle and continuing through subsequent cycles of chemotherapy is rec-
ommended in patients who have an approximately 20% or higher risk for febrile neutropenia based on patient-, disease- and
treatment-related factors. Primary CSF prophylaxis should also be given in patients receiving dose-dense chemotherapy when
considered appropriate. Consideration should be given to alternative, equally effective and safe chemotherapy regimens not re-
quiring CSF support when available. (Type: evidence-based, benefits outweigh harms. Evidence quality: high. Strength of recom-
mendation: strong.)
Secondary prophylaxis with CSFs is recommended for patients who experienced a neutropenic complication from a prior cycle of
chemotherapy (for which primary prophylaxis was not received), in which a reduced dose or treatment delay may compromise
disease-free or overall survival or treatment outcome. In many clinical situations, dose reduction or delay may be a reasonable
alternative. (Type: evidence-based, benefits outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
CSFs should not be routinely used for patients with neutropenia who are afebrile. (Type: evidence-based, benefits outweigh harms.
evidence quality: high. Strength of recommendation: strong.)
CSFs should not be routinely used as adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. However,
CSFs should be considered in patients with fever and neutropenia who are at high-risk for infection-associated complications, or who
have prognostic factors that are predictive of poor clinical outcomes. (Type: evidence-based, benefits outweigh harms. Evidence
quality: high. Strength of recommendation: strong.)
Dose-dense regimens with CSF support should only be used if supported by convincing efficacy data or within an appropriately
designed clinical trial. Efficacy data support the use of dose-dense chemotherapy in the adjuvant treatment of high-risk breast cancer,
and the use of high-dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin in urothelial cancer. There are limited and
conflicting data on the value of dose-dense regimens with CSF support in non-Hodgkin lymphoma, and it cannot routinely be
recommended at this time. (Type: evidence-based, benefits outweigh harms. Evidence quality: high for breast cancer and lymphoma,
intermediate for urothelial cancer. Strength of recommendation: strong for breast cancer and lymphoma, moderate for urothelial
cancer.)
CSFs may be used alone, after chemotherapy, or in combination with plerixafor to mobilize peripheral-blood progenitor cells.
Choice of mobilization strategy depends in part on type of cancer and type of transplantation. (Type: evidence-based, benefits
outweigh harms. Evidence quality: strong. Strength of recommendation: high.)
CSFs should be administered after autologous stem-cell transplantation to reduce the duration of severe neutropenia. (Type:
evidence-based, benefits outweigh harms. Evidence quality: high; Strength of recommendation: strong.)
CSFs may be administered after allogeneic stem-cell transplantation to reduce the duration of severe neutropenia. (Type: evidence-
based. Evidence quality: low. Strength of recommendation: weak).
Prophylactic CSF for patients with diffuse aggressive lymphoma age 65 years and older treated with curative chemotherapy (cy-
clophosphamide, doxorubicin, vincristine, prednisone and rituximab,) should be considered, particularly in the presence of
comorbidities. (Type: evidence-based, benefits outweigh harms. Evidence quality: intermediate. Strength of recommendation:
moderate.)
The use of CSFs in pediatric patients will almost always be guided by clinical protocols. As in adults, the use of CSFs is reasonable for the
primary prophylaxis of pediatric patients with a high likelihood of febrile neutropenia. Similarly, the use of CSFs for secondary
prophylaxis or for therapy should be limited to high-risk patients. (Type: evidence-based, benefits outweigh harms. Evidence quality:
high. Strength of recommendation: strong.)
For pediatric indications in which dose-intense chemotherapy is known to have a survival benefit, such as Ewing sarcoma, CSFs should
be used to enable the administration of these regimens. (Type: evidence-based, benefits outweigh harms. Evidence quality: high.
Strength of recommendation: strong.)
CSFs should not be used in pediatric patients with nonrelapsed acute lymphoblastic leukemia or nonrelapsed acute myeloid leukemia
who do not have an infection. (Type: informal consensus. Evidence quality: intermediate. Strength of recommendation: moderate.)
Pegfilgrastim, filgrastim, tbo-filgrastim, and filgrastim-sndz (and other biosimilars, as they become available) can be used for the
prevention of treatment-related febrile neutropenia. The choice of agent depends on convenience, cost, and the clinical situation.
There have been no further data comparing granulocyte-CSF (G-CSF) and granulocyte macrophageCSF since the 2006 update;
therefore, there is no change in the recommendation regarding their therapeutic equivalency.(Type: evidence-based, benefits
outweigh harms. Evidence quality: high. Strength of recommendation: strong.)
Current recommendations for the management of patients exposed to lethal doses of total-body radiotherapy, but not doses high
enough to lead to certain death due to injury to other organs, includes the prompt administration of CSF or pegylated G-CSF. (Type:
formal consensus (by others), benefits outweigh harms. Evidence quality: intermediate. Strength of recommendation: moderate.)

*Reproduced from the ASCO guidelines; bold and italics emphasis added by the authors.

e526 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


recommendations, has promoted a reduction in use of
CSFs in support of noncurative-intent chemotherapy.21
Overall, there has been no concerted effort by ASCO to
reduce use among its members; we could envision a
concerted social marketing effort that involves patients,
providers, and payers, much like survivorship initiatives.
A recent review noted that physician training, experi-
ence, and compensation all appeared to play large roles
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consultation optimizes pegfilgrastim use with no adverse clinical con-
sequences. J Oncol Pract. 2012;8:e14s-e17s (suppl).
21. Schnipper LE, Smith TJ, Raghavan D, et al. American Society of Clinical
Oncology identifies five key opportunities to improve care and reduce
costs: the top five list for oncology. J Clin Oncol. 2012;30:1715-1724.
22. Barnes G, Pathak A, Schwartzberg L. G-CSF utilization rate and pre-
scribing patterns in United States: associations between physician and
patient factors and GCSF use. Cancer Med. 2014;3:1477-1484.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e527
GARY H. LYMAN

Issues on the Use of White Blood Cell Growth Factors in

Oncology Practice
Gary H. Lyman, MD, MPH

OVERVIEW

Appropriate use of myeloid growth factors may reduce the risk of neutropenic complications including febrile neutropenia (FN)
in patients receiving cancer chemotherapy. The recently updated American Society of Clinical Oncology (ASCO) Guidelines on
the Use of the White Blood Cell Growth Factors recommends routine prophylaxis with these agents starting in the first cycle
when the risk of FN is 20% or greater. However, the risks for neutropenic complications and the risk of serious adverse
consequences from FN vary considerably with different chemotherapy regimens as well as other disease-, treatment-, and
patient-specific risk factors. Considerably more information is now available on the major risk factors for FN. Multivariable risk
models combining factors look promising but require further validation. Most clinical studies of myeloid growth factor
prophylaxis assessed relative risk (RR) of FN but were not powered to evaluate the effect of prophylaxis on disease-free or
overall survival. Accumulating evidence suggests, however, that the appropriate use of these agents in selected patients may
improve both short-term and long-term survival by reducing the immediate risk of mortality accompanying patients with high-
risk disease developing FN as well as improving disease-free and overall survival by enabling the delivery of full dose intensity
chemotherapy and reducing the risk of disease recurrence in patients treated with curative intent. Further studies to evaluate
risk factors and models for FN are needed to guide clinical and shared decision making for the optimal personalized use of these
agents and offer patients at increased risk the best chance of long-term disease control.

rates in randomized controlled clinical trials (RCTs).11 A

M yelosuppression including neutropenia represents a
major toxicity associated with systemic cancer che-
motherapy and is associated with considerable morbidity,
mortality, and costs.1 Such complications may result in dose
reductions or treatment delays, potentially compromising
disease control and survival outcomes.2-6 Prophylactic my-
eloid growth factors may be used to reduce the risk of
neutropenic complications and enable safe delivery of
planned chemotherapy dose intensity on schedule when
indicated. Guidelines on the use of myeloid growth factors
were recently updated by ASCO.7 The first question posed to
the panel related to what factors clinicians should consider
when selecting patients for primary prophylaxis of FN with a
colony-stimulating factor (CSF). Several studies demon-
strated that the risk of an initial episode of FN is greatest
during the first cycle of treatment when patients are gen-
erally receiving full dose intensity.8-10
RISK FACTORS AND MODELS FOR NEUTROPENIA
COMPLICATONS
The risk of FN for patients with cancer who are receiving
systemic chemotherapy is generally based on reported
threshold risk of FN of 20% for routine use of prophylactic
CSFs has been recommended by guidelines from ASCO,
the National Comprehensive Cancer Network (NCCN), and
the European Organisation for the Research and Treat-
ment of Cancer (EORTC) based on results from RCTs of
prophylactic use.7,12-14 However, the risk of chemotherapy-
induced neutropenia and its complications are likely under-
reported in RCTs, with reported rates varying considerably
for common chemotherapy regimens.15,16 Rates of FN ob-
served in observational or real-world patient populations
appear to be consistently greater than those reported
among selected patients accrued to RCTs.17 Additional risk
factors for chemotherapy-induced neutropenia and its
complications have been identified based on patient char-
acteristics, cancer type, and variation in chemotherapy
treatment intensity and intent (cure vs. palliation).18-21 The
updated ASCO CSF guidelines distinguish between risk
factors other than the chemotherapy regimen that increase
the likelihood of FN (Sidebar 1) and those that also increase
the risk of serious medical consequences or death for pa-
tients who develop FN (Sidebar 2). Although there is some

From the Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, and the University of Washington, Seattle, WA.

Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook.

Corresponding author: Gary H. Lyman, MD, MPH, Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, M3-B232,
P.O. Box 19024, Seattle, WA 98109-1024; email: glyman@fhcrc.org.

2016 by American Society of Clinical Oncology.

e528 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


SIDEBAR 1. Patient Risk Factors for Febrile
Neutropenia7
In addition to chemotherapy regimen and type of malig-
nancy, consider these factors when estimating a patients
overall risk of febrile neutropenia19,26,34:
Age 65 or older
Advanced disease
Previous chemotherapy or radiation therapy
Pre-existing neutropenia or bone marrow involvement
with tumor
Infection
Open wounds or recent surgery
Poor performance status or poor nutritional status
Poor renal function
Liver dysfunction, most notably elevated bilirubin
Cardiovascular disease
HIV infection
Multiple comorbid conditions
overlap between the individual factors, the latter are im-
portant to note even among patients who are considered to
be at low or intermediate risk for developing FN. The NCCN
and EORTC guidelines also identify risk factors for developing
FN for clinicians to consider in addition to the chemotherapy
regimen when estimating a patients individual risk of FN,
supporting the concept of personalized supportive care in
oncology.12,14,22
Because of the number of identified risk factors, un-
certainty about their relative importance, and the potential
KEY POINTS
Routine prophylaxis with the white blood cell growth
factors is recommended starting in the first cycle of
cancer chemotherapy when the risk of febrile
neutropenia (FN) is 20% or greater.
The risk of neutropenic complications and associated
infectious complications vary with different
chemotherapy regimens and other disease-, treatment-,
and patient-specific risk factors.
Risk models combining multiple individual risk factors
look promising but require further validation and
improvement.
Appropriate use of the white blood cell growth factors
may improve survival by both reducing the risk of death
associated with FN and improving overall survival by
enhancing delivery of full-dose chemotherapy on
schedule reducing the risk of disease recurrence and
disease-specific mortality.
Further investigation is needed on risk factors and
models for FN to guide clinicians and patients on the
appropriate use of these agents and to provide optimal
treatment to affect long-term disease control and
survival.
RISK FACTORS AND RISK MODELS FOR FEBRILE NEUTROPENIA
SIDEBAR 2. Patient Risk Factors for Poor Clinical
Outcomes From Febrile Neutropenia or
Infection7
Sepsis syndrome
Age 65 or older
Severe neutropenia
Neutropenia expected to be longer than 10 days in
duration
Pneumonia
Invasive fungal infection
Other clinically documented infections
Hospitalization at the time of fever
Prior episode of febrile neutropenia
for intercorrelation between risk factors, there has been
an increasing interest in the development and validation
of multivariable risk models for chemotherapy-associated
neutropenia and its complications. There have been a
number of modeling efforts to predict the risk of serious
complications including death for patients with established
FN.23-25 Although model performance has generally been
limited and has challenged broad utilization of these models,
some institutions and clinicians have used these to identify
patients at low risk for FN for possible outpatient man-
agement. Attention has recently shifted to creating risk
models for the development of FN in ambulatory patients
receiving cancer chemotherapy.26,27 Clinical practice guide-
lines discuss the importance of patient-specific risk factors
and the need for prospective data on the risk of FN in the
unselected general cancer population.7,12
Lyman et al26 reported on a prospective cohort study of
patients with cancer who were treated at oncology practices
throughout the United States. The study was undertaken to
explicitly evaluate the incidence of and risk factors for
neutropenic events among patients with cancer who were
receiving systemic chemotherapy. Consecutive eligible pa-
tients with solid tumors or malignant lymphoma initiating a
new chemotherapy regimen were enrolled. Patient de-
mographics and clinical variables included age, sex, eth-
nicity, employment and educational status, performance
status, body surface area, cancer type, disease stage, history
of prior cancer and treatment, concomitant medications,
baseline hematology and chemistry results, and planned
chemotherapy treatment including drugs, dose, and sched-
ule. Neutropenic events reported included neutropenia
(absolute neutrophil count [ANC] nadir , 1.0 3 103/mm3),
severe neutropenia (ANC nadir , 0.5 3 103/mm3), and FN
(fever/infection and ANC nadir , 1.0 3 103/mm3). The
primary outcome of the study was severe or FN in cycle 1
owing to the dominant risk of events in the first cycle
and their major effect on subsequent risk and treatment
decisions.2,3,10 In the multivariable model based on nearly
2,500 patients, important prognostic factors for neutropenic
complications included a history of previous chemotherapy
as well as baseline leukopenia, hepatic or renal dysfunction,
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e529
GARY H. LYMAN
FIGURE 1. Febrile Neutropenia in Patients With High-
Risk and Low-Risk Disease Receiving Chemotherapy
(A) KaplanMeier plot displaying the cumulative proportion of patients experiencing
one or more episodes of febrile neutropenia over time in days after chemotherapy
initiation for patients at high risk and patients at low risk based on the risk model. (B)
Hazard function plot displaying the distribution of hazard rates for febrile neutropenia
over time in days after chemotherapy initiation for patients at high risk and patients at
low risk based on the risk model.
Abbreviation: HR, hazard ratio.
Reprinted from Lyman et al.26
delivered chemotherapy relative dose intensity, and the use
of a prophylactic myeloid growth factor. Based on the
median predicted risk of neutropenic events, 34% of patients
classified as high risk experienced events in cycle 1 compared
with 4% among patients at low risk. The cumulative risk of FN
with repeated cycles of chemotherapy for patients at high
and low risk is shown in Fig. 1. KaplanMeier estimates of the
cumulative risk of FN over the first three to four cycles of
chemotherapy were approximately 20% for patients at high
risk compared with 5% for patients at low risk. Additional
external validation of the risk model is currently being
pursued in different settings and patient populations. It is
anticipated that targeted application of a prophylactic
myeloid growth factor starting in cycle 1 among patients
identified as being high risk for early events based on this
model will likely reduce the risk of these serious and
e530 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
potentially life-threatening complications of cancer treat-
ment while allowing for the safe and adequate delivery of
effective chemotherapy dose intensity. Alternatively, the
identification of patients at low risk for early neutropenic
complications may provide reassurance and cost savings in
settings in which more aggressive supportive care is not
warranted. Importantly, among patients receiving chemo-
therapy who were considered to have an intermediate risk
for FN based on clinical guidelines, approximately one-
half were classified as high risk and one-half were classified
as low risk based on the risk model incorporating other
patient-, disease-, and treatment-related factors. In a sub-
sequent prospective cohort study of nearly 1,000 patients
being treated by 124 community oncologists, a priori
physician-assessed risk of FN as well as the decision to use
prophylactic CSF correlated poorly with the FN risk esti-
mated by the risk model.28
Personalization of supportive care strategies such as the
appropriate and targeted use of myeloid growth factors in a
fashion similar to the personalization of targeted cancer
therapies offers considerable potential for more effective,
safe, and cost-effective cancer care along with improved
survival and quality of life for patients with cancer.22
MYELOID GROWTH FACTORS AND SURVIVAL
Myeloid growth factors have been developed and approved
for reducing the risk of neutropenic complications including
severe neutropenia and FN. Nevertheless, FN can be a life-
threatening complication of cancer chemotherapy by di-
rectly leading to infectious complications and death or
indirectly by prompting a reduction in chemotherapy in-
tensity or duration, resulting in greater risk of disease re-
currence and cancer-related mortality (Fig. 2). In a recent
analysis of patients with cancer receiving systemic chemo-
therapy who were included in a large U.S. health claims
database, Lyman et al29 estimated a 35% increase in early
FIGURE 2. Dual Impact of Neutropenia on Risk of
Infection and Chemotherapy Dose Intensity
Schematic diagram of the dual effects of neutropenic complications including
febrile neutropenia on both early and overall survival based on reductions in the
risk of febrile neutropenia and early infectious complications while enabling the
delivery of full-dose chemotherapy on schedule and potentially reducing the risk
of disease recurrence and cancer-associated mortality.

mortality and a 15% increased risk of all-cause mortality
overall among patients experiencing FN. Although a favorable
effect of myeloid growth factors on survival of patients with
cancer is therefore plausible, data directly addressing this
issue are limited. Most pivotal clinical trials of myeloid growth
factors have been designed to evaluate their effect on severe
neutropenia or FN during the period of chemotherapy de-
livery, with limited follow-up beyond the treatment period.
Therefore, none of these trials were individually powered to
address the issue of disease-free or overall survival, and only
early mortality was reported. In a systematic review and
meta-analysis of the 17 RCTs of primary prophylaxis with
granulocyte-CSF (G-CSF) including about 3,500 patients with
solid tumors or lymphoma, a significant reduction in the risk of
FN as seen in each individual trial was confirmed (RR, 0.54;
95% CI, 0.43-0.67; p , .001).30 Importantly, in this pooled
analysis, reductions in the risk of infection-related mortality
(RR 0.55; 95% CI, 0.330.90; p = .018) as well as early all-cause
mortality (RR, 0.60; 95% CI, 0.430.83; p = .002) were ob-
served. Although a fourfold increase in reported bone pain
was noted, average delivered chemotherapy relative dose
intensity was significantly greater for patients who were
randomly assigned to receive prophylactic G-CSF.
Concern has been raised about the potential for an in-
creased risk for developing acute myeloid leukemia (AML) or
myelodysplastic syndrome (MDS) among patients treated
with myeloid growth factors. In an analysis of data from the
Surveillance, Epidemiology, and End ResultsMedicare linked
files, Hershman et al31 observed a doubling of the risk of
subsequent AML or MDS, from 0.7% to 1.8% with CSF support
among older women diagnosed with early-stage breast
cancer from 1991 to 1999 who received myeloid growth
factors with their adjuvant chemotherapy. A more recent
systematic review of RCTs among patients receiving systemic
chemotherapy and randomly assigned to receive G-CSF
support or not and reporting on the occurrence of AML/
MDS or all second malignancies and a minimum follow-up of
24 months or more identified 25 eligible trials involving more
than 12,000 patients.32 With an average follow-up of
60 months in these RCTs, AML, or MDS was observed in 0.36%
of controls and 0.79% of patients treated with G-CSF, with a
RR of 1.92 (95% CI, 1.193.07; p = .007) and an absolute risk
difference (ARD) of 0.41% (95% CI, 0.10%0.72%; p = .009). At
References
1. Kuderer NM, Dale DC, CrawfordJ, et al. Mortality, morbidity, and cost associated
with febrile neutropenia in adult cancer patients. Cancer. 2006;106:2258-2266.
2. Lyman GH, Dale DC, Crawford J. Incidence and predictors of low dose-
intensity in adjuvant breast cancer chemotherapy: a nationwide study
of community practices. J Clin Oncol. 2003;21:4524-4531.
3. Lyman GH, Dale DC, Friedberg J, et al. Incidence and predictors of low
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RISK FACTORS AND RISK MODELS FOR FEBRILE NEUTROPENIA
the same time, the RR for all-cause mortality with and without
G-CSF support was 0.897 (95% CI, 0.8570.938; p , .001) with
an ARD of 3.40% (95% CI, 2.00%4.80%; p , .001),
representing a nearly 10-fold greater reduction in mortality
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16 RCTs reporting to have delivered chemotherapy intensity
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in patients treated with G-CSF compared with controls. These
results were subsequently extended in a systematic review of
RCTs of patients receiving cancer chemotherapy and ran-
domly assigned to G-CSF or control and reporting all-cause
mortality with a minimum follow-up of 24 months but re-
moving the requirement for reporting of AML or MDS.33
Among about 61 eligible RCTs involving nearly 10,000 pa-
tients, the RR for all-cause mortality observed was 0.93 (95%
CI, 0.900.96; p , .001). Greater reductions in mortality were
observed among trials with longer follow-up, when treatment
was clearly for curative intent, and when survival was the
primary study outcome. In subgroup analyses by study design,
greater reductions in all-cause mortality were observed when
G-CSF support enabled chemotherapy treatment with a dose-
dense schedule, greater treatment intensity, or the addition
of one or more additional myelosuppressive agents than
when both study arms were intended to receive the same
chemotherapy drugs, dose, and schedule.
Although the potential effect of myeloid growth factors on
overall survival has not been completely evaluated, the
available evidence suggests no deleterious effects of CSF
support of cancer chemotherapy and raises the potential
for a favorable effect on both early- and overall all-cause
mortality, most notably for patients treated with curative
intent and when CSF support enables treatment enhance-
ment for patients with responsive and potentially curable
malignancies. Although an increased risk of AML or MDS
remains, available studies cannot clearly differentiate be-
tween the direct effects of the myeloid growth factor and
the enabling effects of delivering more intensive treatment
with known leukemogenic chemotherapeutic agents. In
total, the apparent reduction in all-cause mortality appears
to overshadow the potential small increased risk associated
with AML or MDS in this setting.
5. Shayne M, Culakova E, Wolff D, et al. Dose intensity and hematologic
toxicity in older breast cancer patients receiving systemic chemo-
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6. Shayne M, Culakova E, Poniewierski MS, et al. Dose intensity and
hematologic toxicity in older cancer patients receiving systemic che-
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7. Smith TJ, Bohlke K, Lyman GH, et al; American Society of Clinical On-
cology. Recommendations for the use of WBC growth factors: American
Society of Clinical Oncology clinical practice guideline update. J Clin
Oncol. 2015;33:3199-3212.
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8. Lyman GH, Morrison VA, Dale DC, et al; OPPS Working Group; ANC
Study Group. Risk of febrile neutropenia among patients with
intermediate-grade non-Hodgkins lymphoma receiving CHOP che-
motherapy. Leuk Lymphoma. 2003;44:2069-2076.
9. Lyman GH, Delgado DJ. Risk and timing of hospitalization for febrile
neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemo-
therapy for intermediate-grade non-Hodgkin lymphoma. Cancer. 2003;
98:2402-2409.
10. Crawford J, Dale DC, Kuderer NM, et al. Risk and timing of neutropenic
events in adult cancer patients receiving chemotherapy: the results of a
prospective nationwide study of oncology practice. J Natl Compr Canc
Netw. 2008;6:109-118.
11. Lyman GH. Risk assessment in oncology clinical practice. From risk factors
to risk models. Oncology (Williston Park). 2003; 17(Suppl 11):8-13.
12. National Comprehensive Cancer Network (ed). NCCN Clinical Practice
Guidelines in Oncology: Myeloid Growth Factors. Fort Washington, PA:
National Comprehensive Cancer Network Inc; 2015.
13. Schnipper LE, Smith TJ, Raghavan D, et al. American Society of Clinical
Oncology identifies five key opportunities to improve care and reduce
costs: the top five list for oncology. J Clin Oncol. 2012;30:1715-1724.
14. Aapro MS, Bohlius J, Cameron DA, et al; European Organisation for
Research and Treatment of Cancer. 2010 update of EORTC guidelines
for the use of granulocyte-colony stimulating factor to reduce the
incidence of chemotherapy-induced febrile neutropenia in adult pa-
tients with lymphoproliferative disorders and solid tumours. Eur J
Cancer. 2011;47:8-32.
15. Dale DC, McCarter GC, Crawford J, et al. Myelotoxicity and dose in-
tensity of chemotherapy: reporting practices from randomized clinical
trials. J Natl Compr Canc Netw. 2003;1:440-454.
16. Kuderer NM, Wolff AC. Enhancing therapeutic decision making when
options abound: toxicities matter. J Clin Oncol. 2014;32:1990-1993.
17. Truong J, Lee EK, Trudeau ME, et al. Interpreting febrile neutropenia
rates from randomized, controlled trials for consideration of primary
prophylaxis in the real world: a systematic review and meta-analysis.
Ann Oncol. Epub 2015 Dec 27.
18. Laskey RA, Poniewierski MS, Lopez MA, et al. Predictors of severe and
febrile neutropenia during primary chemotherapy for ovarian cancer.
Gynecol Oncol. 2012;125:625-630.
19. Lyman GH, Abella E, Pettengell R. Risk factors for febrile neutropenia
among patients with cancer receiving chemotherapy: a systematic
review. Crit Rev Oncol Hematol. 2014;90:190-199.
20. Weycker D, Li X, Barron R, et al. Importance of risk factors for febrile
neutropenia among patients receiving chemotherapy regimens not
classified as high-risk in guidelines for myeloid growth factor use. J Natl
Compr Canc Netw. 2015;13:979-986.
21. Weycker D, Li X, Edelsberg J, et al. Risk of febrile neutropenia in patients
receiving emerging chemotherapy regimens. Support Care Cancer.
2014;22:3275-3285.
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22. Kuderer NM, Lyman GH. Personalized medicine and cancer supportive
care: appropriate use of colony-stimulating factor support of chemo-
therapy. J Natl Cancer Inst. 2011;103:910-913.
23. Klastersky J, Paesmans M. The Multinational Association for Supportive
Care in Cancer (MASCC) risk index score: 10 years of use for identifying
low-risk febrile neutropenic cancer patients. Support Care Cancer. 2013;
21:1487-1495.
24. Talcott JA, Siegel RD, Finberg R, et al. Risk assessment in cancer patients
with fever and neutropenia: a prospective, two-center validation of a
prediction rule. J Clin Oncol. 1992;10:316-322.
25. Carmona-Bayonas A, Jimenez-Fonseca P, Virizuela Echaburu J, et al.
Prediction of serious complications in patients with seemingly stable
febrile neutropenia: validation of the Clinical Index of Stable Febrile
Neutropenia in a prospective cohort of patients from the FINITE study.
J Clin Oncol. 2015;33:465-471.
26. Lyman GH, Kuderer NM, Crawford J, et al. Predicting individual risk of
neutropenic complications in patients receiving cancer chemotherapy.
Cancer. 2011;117:1917-1927.
27. Jenkins P, Scaife J, Freeman S. Validation of a predictive model that
identifies patients at high risk of developing febrile neutropaenia fol-
lowing chemotherapy for breast cancer. Ann Oncol. 2012;23:
1766-1771.
28. Lyman GH, Dale DC, Legg JC, et al. Assessing patients risk of febrile
neutropenia: is there a correlation between physician-assessed risk and
model-predicted risk? Cancer Med. 2015;4:1153-1160.
29. Lyman GH, Michels SL, Reynolds MW, et al. Risk of mortality in patients
with cancer who experience febrile neutropenia. Cancer. 2010;116:
5555-5563.
30. Kuderer NM, Dale DC, Crawford J, et al. Impact of primary prophylaxis
with granulocyte colony-stimulating factor on febrile neutropenia and
mortality in adult cancer patients receiving chemotherapy: a systematic
review. J Clin Oncol. 2007;25:3158-3167.
31. Hershman D, Neugut AI, Jacobson JS, et al. Acute myeloid leukemia or
myelodysplastic syndrome following use of granulocyte colony-
stimulating factors during breast cancer adjuvant chemotherapy.
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32. Lyman GH, Dale DC, Wolff DA, et al. Acute myeloid leukemia or
myelodysplastic syndrome in randomized controlled clinical trials of
cancer chemotherapy with granulocyte colony-stimulating factor:
a systematic review. J Clin Oncol. 2010;28:2914-2924.
33. Lyman GH, Dale DC, Culakova E, et al. The impact of the granulocyte
colony-stimulating factor on chemotherapy dose intensity and cancer
survival: a systematic review and meta-analysis of randomized con-
trolled trials. Ann Oncol. 2013;24:2475-2484.
34. Hosmer W, Malin J, Wong M. Development and validation of a pre-
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PATIENT AND SURVIVOR CARE

Optimizing Palliative and

End-of-Life Care: Evidence-Based
Practice Improvement

CHAIR
Thomas W. LeBlanc, MD, MA
Duke University Medical Center
Durham, NC

SPEAKERS
Jennifer S. Temel, MD
Massachusetts General Hospital Cancer Center
Boston, MA

Timothy D. Gilligan, MD, MSc

Cleveland Clinic
Cleveland, OH
NICKOLICH ET AL

Discussing the Evidence for Upstream Palliative Care in

Improving Outcomes in Advanced Cancer
Myles S. Nickolich, MD, Areej El-Jawahri, MD, Jennifer S. Temel, MD, and Thomas W. LeBlanc, MD, MA

OVERVIEW

Palliative care has received increasing attention at the American Society of Clinical Oncology (ASCO) Annual Meeting since
the publication of its provisional clinical opinion on the topic in 2012. Despite frequent discussion, palliative care remains a
source of some controversy and confusion in clinical practice, especially concerning who should provide it, what it en-
compasses, and when and how it can help patients and their families. In this article, we provide a formal definition of
palliative care and review the state of the science of palliative care in oncology. Several randomized controlled trials now
show that palliative care improves important outcomes for patients with cancer. Related outcome improvements include a
reduction in symptoms, improved quality of life, better prognostic understanding, less depressed mood, less aggressive end-
of-life care, reduced resource utilization, and even prolonged survival. As such, ASCO recommends early integration of
palliative care into comprehensive cancer care for all patients with advanced disease and/or significant symptom burden.
Our aim is that this summary will facilitate greater understanding about palliative care and encourage further integration of
palliative care services into cancer care. More research is needed to illuminate the mechanisms of action of palliative care
and to improve the specificity of palliative care applications to unique scenarios and populations in oncology.

P alliative care has received increasing attention at the

ASCO Annual Meeting since the publication of its
Provisional Clinical Opinion: The Integration of Palliative
Care Into Standard Oncology Care in 2012.1 In that paper,
ASCO recommended early concurrent palliative care as part
of standard cancer care for all patients with metastatic
disease and/or significant symptom burden. This recom-
mendation was based on a growing amount of evidence
about the many benefits of adding specialist palliative care
to standard oncology care, including data from several
large randomized controlled trials.
Despite frequent discussion at ASCO Annual Meetings
since then, palliative care remains a source of some con-
troversy and confusion in clinical practice, especially con-
cerning who should provide it, what it encompasses, and
when and how it can help patients and their families.
WHAT IS PALLIATIVE CARE?
The term palliative care is sometimes misunderstood as
being synonymous with end-of-life care. To address this
misperception, the Center to Advance Palliative Care (CAPC)
conducted a public opinion polling study in 2011, to de-
velop a new definition of palliative care. According to this
definition:
Palliative care is specialized medical care for people with
serious illness. It focuses on providing patients with relief
from the symptoms, pain, and stress of a serious illness
whatever the diagnosis. The goal is to improve quality of life
for both the patient and the family. It is appropriate at any
age and at any stage of a serious illness. It can be provided at
the same time as disease treatment to help people live as
well as possible while facing illness.2
Although other organizations, such as the National Com-
prehensive Cancer Network and the World Health Organi-
zation, have also posed definitions of palliative care, we prefer
the clarity and inclusivity of the CAPC definition. Palliative care
seeks to improve quality of life by providing additional sup-
port to the patient and caregiver(s), to assist with symptom
burden, psychosocial needs, spiritual well being, communi-
cation, and understanding of prognosis, treatment decision
making, transitions of care, existential issues, and end-of-life
scenarios. Although palliative care is appropriate for many
patients with serious illness, this article focuses on patients
with cancer.
There are different levels of palliative care, each of which is
provided by different members of the care team. Oncolo-
gists often provide basic palliative care, including pain and
other symptom management. This type of palliative care is
referred to as primary palliative care, generalist palliative

From Duke University Hospital, Durham, NC; Massachusetts General Hospital, Boston, MA; Duke Cancer Institute, Durham, NC.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Thomas W. LeBlanc, MD, MA, Duke University Medical Center, P.O. Box 2715, Durham, NC 27710; email: thomas.leblanc@duke.edu.

2016 by American Society of Clinical Oncology.

e534 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


care,3 or sometimes just supportive care.4 Although it is entirely
appropriate that the oncology care team provides primary
palliative care, this is not always sufficient to meet the needs of
patients and families. In cases of complex and/or unmet needs,
patients may benefit from a higher level of palliative care, often
called specialty palliative care or secondary palliative care. This
type of palliative care is provided by specialists with formal
training in palliative care and related specialties. Specialty
palliative care is akin to the expert care a cardiologist provides
to a patient with severe heart failure, even though the pa-
tients primary care physician may also be monitoring the
cardiac status of the patient.
This distinction is critical because some oncologists mis-
understand palliative care to suggest that they should pass off
their primary palliative care responsibilities to someone else.
Rather, when we talk about specialty palliative care, we are
referring to care that is provided in addition to the primary
palliative care already being provided by the oncologist. This
type of care is additive, not duplicative, and should not be
misconstrued as any sort of transferal of responsibility. In-
deed, data from randomized controlled trials suggest that that
the focus of palliative care specialists is quite different from
that of oncologists.5 Together, oncologists and palliative care
specialists working collaboratively can provide more com-
prehensive care for patients with cancer and their families.
WHICH OUTCOMES IMPROVE WITH UPSTREAM
PALLIATIVE CARE?
Symptom Management
In a large cluster-randomized controlled trial by Zimmermann
et al6 with patients with advanced solid tumors (lung, gas-
trointestinal, genitourinary, breast, and gynecologic), patients
who were randomly selected to receive early palliative care
had a significant reduction in symptom intensity at 4 months
by the Edmonton Symptom Assessment Scale, compared
KEY POINTS
Palliative care improves important outcomes for
patients with cancer, as shown in at least five
randomized controlled trials to date.
ASCO recommends early integration of palliative care
into comprehensive cancer care for all patients with
advanced disease and/or significant symptom burden.
Outcome improvements seen with early palliative care
include a reduction in symptoms, improved quality of
life, better prognostic understanding, less depressed
mood, improved end-of-life outcomes, reduced
resource utilization, and even prolonged survival.
More research is needed to illuminate the mechanisms
of action of palliative care and to improve the specificity
of palliative care applications to unique scenarios and
populations, such as patients with hematologic
malignancies, caregivers, and across various tumor
types and treatments.
WHATS THE EVIDENCE BASE FOR PALLIATIVE CARE IN ONCOLOGY?
with those randomly assigned to receive standard care
(21.34 vs. +3.23; p = .05).6
Quality of Life
Early palliative care also improves quality of life for patients
with advanced cancer. In the ENABLE II study by Bakitas
et al,7 patients with advanced gastrointestinal, breast, lung,
or genitourinary cancer were randomly assigned to receive a
nurse-led palliative care intervention or standard care within
8 to 12 weeks of diagnosis. Patients who were randomly
assigned to receive early palliative care had better quality of
life per the Functional Assessment of Cancer Therapy
Palliative Care scale (mean difference of 4.6; p = .02).7
Similarly, in a large randomized controlled trial by Temel
et al,8 patients with advanced nonsmall cell lung cancer
(NSCLC) who were randomly assigned to receive early
outpatient palliative care within 8 weeks of diagnosis had a
significant improvement in quality of life, per the trial
outcome index subscale of the Functional Assessment of
Cancer TherapyLung scale at 12 weeks, compared with
those assigned to usual care (59.0 vs. 53.0; p = .009).8 This
finding was also confirmed in the trial by Zimmermann
et al6 where patients assigned to receive the palliative care
intervention per the Quality of Life at the End of Life scale
experienced improvements seen at 3 months, compared
with those receiving standard care (2.33 vs. 0.06; p = .05).6
Early palliative care also improves quality of life for pa-
tients in the emergency department setting.9 In a study by
Grudzen et al,9 patients with advanced cancer who pre-
sented to the emergency department at a quaternary care
center were randomly assigned to receive a palliative care
consult from the inpatient team and subsequent follow-
up visits in the outpatient palliative care clinic compared
with usual care. Patients who were randomly assigned
to palliative care experienced greater improvements in
quality of life scores by the Functional Assessment of
Cancer TherapyGeneral (FACT-G) scale at 12 weeks
(5.91 vs. 1.08; p = .03).9
Prognostic Understanding
Unfortunately, many patients with advanced, incurable
cancer misunderstand their prognoses and the goals of their
cancer treatments. In a study by Weeks et al,10 patients with
stage IV lung or colorectal cancer were asked to identify the
goal of their prescribed chemotherapies. Sixty-nine percent
of patients with lung cancer and 81% of those with colorectal
cancer mistakenly thought that their palliative chemotherapy
regimens were prescribed with intent to cure.10 Interestingly,
early palliative care mitigates this problem. In the randomized
controlled trial by Temel et al,11 patients with advanced
NSCLC who were randomly assigned to receive early palliative
care were more likely to retain or develop an accurate un-
derstanding of their prognoses compared with patients who
received standard care (82.5% vs. 59.6%; p = .02).11 Of note,
patients in the early palliative care arm who reported an
accurate understanding of prognosis were also less likely to
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e535
NICKOLICH ET AL
receive chemotherapy near the end of life (9.4% vs. 50%;
p = .02), an indicator of higher-quality end-of-life care
among patients with advanced cancer.
Caregiver Outcomes
In addition to direct patient benefits of early palliative care,
caregivers also appear to benefit from the early introduction
of palliative care. In the ENABLE III study by Bakitas et al,7 the
caregivers of patients assigned to early palliative care received
an additional caregiver-focused intervention. These care-
givers reported better depression scores at 3 months, per
the Center for Epidemiologic StudyDepression scale (mean
difference, 23.4; p = .02). Furthermore, caregivers whose
loved ones died during the study also had reduced stress
burden, as measured on the Montgomery-Borgatta Caregiver
Burden stress subscale.12 The inclusion of a caregiver-
specific intervention in this study is unique compared with
other randomized studies of early palliative care done to
date, and results suggest that it is an important area for
future research and intervention development.
Mood
Mood disorders are major contributors to morbidity in
patients with advanced cancer. Palliative care clinicians are
more likely than oncologists to focus on coping skills and
psychosocial concerns, which suggests that a role for early
palliative care is to improve mood among patients with
advanced cancer.5 Indeed, decreases in median survival
have been observed in patients with advanced NSCLC and
comorbid mood disturbance, with median survival times of
only 5.4 months for those with major depression compared
with 10 months for those without (p = .001).13 In the ran-
domized controlled trial by Temel et al,8 patients with ad-
vanced NSCLC who received early palliative care had lower
rates of depression than patients who received usual care,
as measured by both the Hospital Anxiety and Depression
Scale (16% vs. 38%; p = .01) and the Patient Health
Questionnaire9 (4% vs. 17%; p = .04). Interestingly, 42.9%
of patients who received early palliative care also showed an
improved depression response compared with 0% of pa-
tients in the usual-care control arm at 12 weeks. Of note,
rates of new antidepressant prescriptions and mental health
visits did not differ significantly between the two groups,
which suggests that early specialist palliative care indeed
affects mood.8 Similarly, in the ENABLE II study by Bakitas
et al,7 patients who received early palliative care had
less depressed mood by Center for Epidemiologic Study
Depression scale (mean difference, 21.8; p = .02).7
End-of-Life Outcomes
In the randomized controlled trial by Temel et al,8 patients
who received early palliative care also received less aggres-
sive end-of-life care (palliative care vs. control, 33% vs. 54%;
p = .05). Here, aggressive end-of-life care was a composite
outcome defined by the presence of at least one of the
following criteria: receipt of chemotherapy within 14 days
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before death, no hospice care, or admission to hospice 3 or
fewer days before death. In addition, more patients in the
palliative care arm had documented resuscitation prefer-
ences in the outpatient setting (53% vs. 28%; p = .05).8
The use of intensive care unit (ICU) services for patients
with advanced cancer is another useful marker of aggressive
end-of-life care, and palliative care appears to improve this
outcome as well. For example, in a retrospective study in the
Veterans Affairs system, patients who were observed by an
inpatient palliative care team had a 42% lower ICU admission
rate than control patients.14 However, in the study by
Grudzen et al,9 emergency departmentinitiated pallia-
tive care consultation (with outpatient follow-up there-
after) did not yield any reduction in ICU admissions.9
In the ENABLE II study, there were no differences in
number of days hospitalized, days in the ICU, or frequency of
emergency department visits.7 Similarly, ENABLE III found no
differences in relative rates of days hospitalized, days ad-
mitted to an ICU, emergency department visits, chemo-
therapy within the last 14 days of life, or death at home.15
However, both groups in this study received palliative care,
so it may be that late palliative care improves these out-
comes similarly to earlier palliative care. Because there was
not a control arm of patients who received no palliative care
in this study, a direct measure of the impact of palliative care
on this outcome is not possible.
Survival
Beyond improvements in symptom burden and quality of
life, early palliative care is also associated with improved
survival. In the randomized controlled trial by Temel et al,8
patients with metastatic NSCLC who received early palliative
care lived nearly 3 months longer than patients who received
standard care (median, 11.6 vs. 8.9 months; p = .02). This
difference was despite less aggressive end-of-life care.8
Similarly, in the ENABLE III study, patients who received early
palliative care had significantly longer 1-year survival rates
than those who received delayed palliative care; the dif-
ference was 15% at 1 year (63% vs. 48%; p = .038).15
Resource Utilization
Palliative care also appears to improve resource utilization
among patients with advanced cancer. However, these data
come from studies of hospitalized patients who received
inpatient palliative care consultations. For example, in
retrospective a study by May et al,16 inpatient palliative care
consultation was associated with significant cost savings
among patients with advanced cancer (p # .01), particularly
for those with more comorbidities. Overall, palliative care
consultation yielded a 32% reduction in hospital costs when
initiated within 2 days of admission for patients with cancer
and multiple comorbidities.16 A prospective cohort study, also
by May et al,17 demonstrated that cost savings may vary on
the basis of the timing of consultation. In this study, earlier
palliative care consultation for hospitalized patients with
advanced cancer resulted in more cost reduction than did later

consultation, with mean reductions in costs of 24% (day 2) and
14% (day 6). Inpatient palliative care consultation within at least
6 days of admission had an estimated mean treatment effect
of 2$1,312 (p = .04) compared with usual care, and, within
2 days of admission, palliative care consultation had a more
pronounced cost reduction (2$2,280; p = .002).17 Within the
Veterans Affairs setting, inpatient palliative care consultation
was associated with similar cost reductions in retrospective
analyses. Unadjusted total direct per day costs for patients
who received a palliative care consultation were $891
versus $1,287.60 for usual care (p , .0001).14
HOW DOES PALLIATIVE CARE IMPROVE THESE
OUTCOMES?
There has been much discussion about the mechanism of
action of early palliative care in patients with advanced
cancer. Part of the difficulty in understanding the mecha-
nism stems from the fact that the interventions studied thus
far have varied significantly. Some, such as ENABLE III, were
largely telephone based and provided by nurses,15 whereas
others were based in the outpatient clinic and provided by
specialist palliative care clinicians.6,8 Additional challenges
stem from the heterogeneity of populations included in
studies to date. Although palliative care mechanisms of
action are ultimately unknown, clues from published studies
point toward key ingredients in the interventions. For
example, a qualitative analysis of documentation from one
early palliative care study demonstrated that palliative care
clinicians spend much of their time on three primary areas:
(1) managing symptoms, (2) facilitating coping, and (3)
serving as a bridge between the patient and oncologist.18
These elements map relatively nicely to the associated
outcome improvements in symptoms and quality of life,
mood, and prognostic understanding that are seen with
early palliative care, and these areas are different from the
usual focus of oncologists in the clinic. However, more re-
search is needed to better understand the most important
components of early palliative care interventions, which will
thereby allow for more streamlined implementation and
dissemination across cancer types and practices.
FUTURE DIRECTIONS
Although specialist palliative care is clearly helpful for pa-
tients with advanced solid tumors, it is likely that there are
differences in needs across tumor types and stages. Fur-
thermore, differences in patient characteristics may herald
different palliative care needs. For example, recent evidence
suggests that early palliative care in advanced lung cancer
may be more effective among younger than older patients.19
Differential efficacy may be true across other patient types
and diseases as well. However, although it seems obvious
that patients with heart failure likely have different needs
than patients with advanced lung cancer, it is less clear whether
such differences exist among patients with gastrointestinal
cancers versus lung cancers, for example. More research is
needed in this area.
WHATS THE EVIDENCE BASE FOR PALLIATIVE CARE IN ONCOLOGY?
The hematologic malignancies population is a particularly
unique area for additional exploration. A growing amount of
literature demonstrates sizeable gaps in end-of-life quality
measures and unmet palliative care needs among patients
with hematologic malignancies. For example, patients with
hematologic malignancies are more likely than patients with
solid tumors to be admitted to hospice services within the last
3 days of life.20 Similarly, patients with hematologic malig-
nancies are more likely than patients with solid tumors to
receive inpatient or nursing facilitybased hospice care at the
end of life.21 Unique challenges exist to providing palliative
care to patients with hematologic malignancies because of
several complex factors, including differences in prognoses,
disease trajectories, treatment types and intensities, and
treating clinicians.22 Additional study is needed in the area of
hematologic malignancies and bone marrow transplantation,
and novel interventions to address the unique needs and
issues of these populations also are needed.
Although more research is needed to better understand
how palliative care improves outcomes and how to integrate
these services in different cancer populations, there is
simultaneously a workforce crunch in the field. The palliative
care workforce is unfortunately not large enough to meet
the needs of all patients with cancer. To date, there are
greater than 7,000 board-certified palliative care specialists
in the United States, and there are greater than 100 fel-
lowship training programs. However, projections suggest
that this structure is inadequate to meet the needs of the
U.S. population.23,24 Furthermore, additional education is
needed in the provision of primary palliative care by on-
cologists and others.25-27 Simply put, specialist palliative
care is a scarce resource. As we develop a better un-
derstanding of how palliative care improves outcomes, we
can better apply this scarce resource judiciously.
Caregivers represent another key area of unmet need. To
date, there is little caregiver-focused work in the palliative care
literature, yet there are many reasons to think that caregivers
have unique needs that require novel solutions. In other
words, it is likely that specific interventions are needed to
support these important and often overlooked members of a
patients support system. The ENABLE III study is a wonderful
example of the promise for caregiver-specific interventions,12
however, much more research is needed in this area.28
We must also develop innovative delivery models and
reimbursement structures to facilitate early palliative care
for patients with cancer. Constraints within current models
for providing palliative care through hospice services often
creates an either/or mentality, wherein patients are re-
quired to forego cancer therapies to receive these services.
This is particularly problematic in hematologic malignancies,
for which beneficial palliative treatments, such as blood
product transfusions and antimicrobials, are often not
feasible within the hospice care setting.29-31 However, amid
the recent growth of targeted biologic therapies for advanced
solid tumors, this problem is increasing among patients with
solid tumors as well. For example, we know that EGFR in-
hibitors may palliate bothersome symptoms and improve
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK e537
NICKOLICH ET AL
quality of life for patients with advanced lung cancer, yet
these are not generally reimbursed under hospice care
models. As data increasingly demonstrate the beneficial
impact of early concurrent palliative care, we must develop
better models to facilitate its delivery as part of standard
cancer care, to supersede the barriers inherent in current
reimbursement constraints. New, developing models of so-
called open access care promise to do just this and are a
beacon of hope that allow patients to receive both cancer
treatment and hospice care.
References
1. Smith TJ, Temin S, Alesi ER, et al. American Society of Clinical Oncology
provisional clinical opinion: the integration of palliative care into
standard oncology care. J Clin Oncol. 2012;30:880-887.
2. Center to Advance Palliative Care. 2011 Public Opinion Research on
Palliative Care. https://www.capc.org/media/filer_public/18/ab/
18ab708c-f835-4380-921d-fbf729702e36/2011-public-opinion-
research-on-palliative-care.pdf. Accessed March 20, 2016.
3. Quill TE, Abernethy AP. Generalist plus specialist palliative care:
creating a more sustainable model. N Engl J Med. 2013;368:1173-1175.
4. Hui D, Finlay E, Buss MK, et al. Palliative oncologists: specialists in the
science and art of patient care. J Clin Oncol. 2015;33:2314-2317.
5. Yoong J, Park ER, Greer JA, et al. Early palliative care in advanced lung
cancer: a qualitative study. JAMA Intern Med. 2013;173:283-290.
6. Zimmermann C, Swami N, Krzyzanowska M, et al. Early palliative care
for patients with advanced cancer: a cluster-randomised controlled
trial. Lancet. 2014;383:1721-1730.
7. Bakitas M, Lyons KD, Hegel MT, et al. Effects of a palliative care in-
tervention on clinical outcomes in patients with advanced cancer: the
Project ENABLE II randomized controlled trial. JAMA. 2009;302:
741-749.
8. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients
with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:
733-742.
9. Grudzen CR, Richardson LD, Johnson PN, et al. Emergency
departmentinitiated palliative care in advanced cancer: a randomized
clinical trial. JAMA Oncol. Epub 2016 Jan 14.
10. Weeks JC, Catalano PJ, Cronin A, et al. Patients expectations about
effects of chemotherapy for advanced cancer. N Engl J Med. 2012;367:
1616-1625.
11. Temel JS, Greer JA, Admane S, et al. Longitudinal perceptions of
prognosis and goals of therapy in patients with metastatic non-small-
cell lung cancer: results of a randomized study of early palliative care.
J Clin Oncol. 2011;29:2319-2326.
12. Dionne-Odom JN, Azuero A, Lyons KD, et al. Benefits of early versus
delayed palliative care to informal family caregivers of patients with
advanced cancer: outcomes from the ENABLE III randomized controlled
trial. J Clin Oncol. 2015;33:1446-1452.
13. Pirl WF, Greer JA, Traeger L, et al. Depression and survival in metastatic
non-small-cell lung cancer: effects of early palliative care. J Clin Oncol.
2012;30:1310-1315.
14. Penrod JD, Deb P, Luhrs C, et al. Cost and utilization outcomes of
patients receiving hospital-based palliative care consultation. J Palliat
Med. 2006;9:855-860.
15. Bakitas MA, Tosteson TD, Li Z, et al. Early versus delayed initiation of
concurrent palliative oncology care: patient outcomes in the ENABLE III
randomized controlled trial. J Clin Oncol. 2015;33:1438-1445.
e538 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
CONCLUSION
Palliative care is specialized care for people with serious
illnesses. When added to standard cancer care, specialty
palliative care improves many outcomes for patients and
their caregivers, including symptom burden, quality of life,
mood, prognostic understanding, end-of-life outcomes,
resource utilization, and even survival. However, more re-
search is needed to illuminate mechanisms of action and to
improve the specificity of palliative care applications to
unique scenarios and populations.
16. May P, Garrido MM, Cassel JB, et al. Palliative care teams cost-saving
effect is larger for cancer patients with higher numbers of comorbid-
ities. Health Aff (Millwood). 2016;35:44-53.
17. May P, Garrido MM, Cassel JB, et al. Prospective cohort study of hospital
palliative care teams for inpatients with advanced cancer: earlier
consultation is associated with larger cost-saving effect. J Clin Oncol.
2015;33:2745-2752.
18. Back AL, Park ER, Greer JA, et al. Clinician roles in early integrated
palliative care for patients with advanced cancer: a qualitative study.
J Palliat Med. 2014;17:1244-1248.
19. Nipp RD, Greer JA, El-Jawahri A, et al. Age and gender moderate the
impact of early palliative care in metastatic nonsmall-cell lung cancer.
Oncologist. 2016;21:119-126.
20. OConnor NR, Hu R, Harris PS, et al. Hospice admissions for cancer in the
final days of life: independent predictors and implications for quality
measures. J Clin Oncol. 2014;32:3184-3189.
21. LeBlanc TW, Abernethy AP, Casarett DJ. What is different about patients
with hematologic malignancies? A retrospective cohort study of cancer
patients referred to a hospice research network. J Pain Symptom
Manage. 2015;49:505-512.
22. LeBlanc TW, El-Jawahri A. When and why should patients with he-
matologic malignancies see a palliative care specialist? Hematology (Am
Soc Hematol Educ Program). 2015;2015:471-478.
23. Lupu D, Friedman L, Alderman J, et al; American Academy of Hospice
and Palliative Medicine Workforce Task Force. Estimate of current
hospice and palliative medicine physician workforce shortage. J Pain
Symptom Manage. 2010;40:899-911.
24. Kamal AH, Bull J, Wolf S, et al. Characterizing the hospice and palliative
care workforce in the U.S.: clinician demographics and professional
responsibilities. J Pain Symptom Manage. 2016;51:597-603.
25. Ramchandran K, Tribett E, Dietrich B, et al. Integrating palliative care
into oncology: a way forward. Cancer Contr. 2015;22:386-395.
26. Buss MK, Lessen DS, Sullivan AM, et al. A study of oncology fellows
training in end-of-life care. J Support Oncol. 2007;5:237-242.
27. Buss MK, Lessen DS, Sullivan AM, et al. Hematology/oncology fellows
training in palliative care: results of a national survey. Cancer. 2011;117:
4304-4311.
28. Kamal AH, Dionne-Odom JN. A blue ocean strategy for palliative care:
focus on family caregivers. J Pain Symptom Manage. 2016;51:e1-e3.
29. Odejide OO. A policy prescription for hospice care. JAMA. 2016;315:
257-258.
30. LeBlanc TW. Addressing end-of-life quality gaps in hematologic cancers:
the importance of early concurrent palliative care. JAMA Intern Med.
2016;176:265-266.
31. LeBlanc TW. Palliative care and hematologic malignancies: old dog, new
tricks? J Oncol Pract. 2014;10:e404-e407.
PATIENT AND SURVIVOR CARE

Rehabilitation of Patients and

Survivors: Seizing the Opportunity

CHAIR
Catherine M. Alfano, PhD
American Cancer Society
Washington, DC

SPEAKERS
Andrea L. Cheville, MD, MSCE
Mayo Clinic
Rochester, MN

Karen Mustian, PhD, MPH

University of Rochester Medical Center
Rochester, NY
 DEVELOPING HIGH-QUALITY CANCER REHABILITATION PROGRAMS

Developing High-Quality Cancer Rehabilitation Programs: A

Timely Need
Catherine M. Alfano, PhD, Andrea L. Cheville, MD, MSCE, and Karen Mustian, PhD, MPH

OVERVIEW

The number of survivors of cancer in the United States, already 14.5 million, is growing with improved cancer treatment and
aging of the population. Two-thirds of cancer survivors will be older than age 65 and are likely to enter cancer treatment
already deconditioned and with multiple comorbidities. Survivors of cancer face numerous adverse consequences of cancer
treatment that add to or exacerbate the effects of existing comorbidities and increase risk of functional decline. Many of
these problems are amenable to rehabilitation interventions, but referral to cancer rehabilitation professionals is not a
standard part of care. We present an expanded prospective model of surveillance, cancer rehabilitation assessment, and
referral efforts using a multidisciplinary team approach. In this model, cancer rehabilitation begins at the time of cancer
diagnosis and continues through and beyond cancer treatment. Physical impairments and psychosocial symptoms are
assessed and treated, and lifestyle and exercise interventions are provided to optimize functioning, health, and quality of
life. We present a stepped-care framework to guide decisions on when, how, and where to refer survivors to cancer
rehabilitation specialists depending on safety requirements and needs. This model has the potential to result in early
identification of symptoms and impairments, appropriate referral and timely treatment, and, in turn, will better address and
minimize both acute and long-term cancer morbidity.

survival15 and increased risk for exacerbation of comorbid

A n estimated 14.5 million survivors of cancer currently
live in the United States.1 This population will increase
dramatically in the coming decade because of increased
uptake of cancer screening, improved methods of early
detection, better multimodal cancer treatments, and the
aging of the population.2,3 National reports have docu-
mented that survivors of cancer have complex needs.4-8
These include management of chronic and late effects of
cancer and comorbid conditions; surveillance and treatment
of recurrence and second cancers; help with psychological,
social, economic, and family concerns; support to improve
lifestyle behaviors; and interventions to increase adherence
to long-term treatment and follow-up care guidelines. Given
that most cancers are diagnosed in older adults, an esti-
mated two-thirds of all survivors of cancer will be age 65 or
older by 2020.2 This growing number of older survivors of
cancer presents a unique challenge to the health care system
because they are more likely to have multiple chronic dis-
eases and experience poorer physical functioning than
younger survivors of cancer.9,10 Cancer and chronic illness
also may have interactive adverse effects on health and
psychosocial outcomes among older adult survivors of
cancer. Chronic conditions may limit the intensity and du-
ration of cancer treatment,11-14 contributing to poorer
conditions or further declines in physical functioning post-
treatment.11,16,17
The United States is currently struggling to identify a
coordinated medical and public health approach to meet
the needs of our growing population of cancer survivors.
Predicted shortages in oncologists,18 primary care practi-
tioners,19 and other medical health professionals un-
derscore the need for effective and efficient care for cancer
survivors. We have argued that a solution to this health care
crisis lies in defining a new model of comprehensive cancer
rehabilitation, involving a multidisciplinary team of pro-
viders that aims to optimize the patients physical, psy-
chological, vocational, and social functioning given the limits
imposed by the chronic or late-effects of cancer treatment
and other comorbid conditions.20
THE CASE FOR COMPREHENSIVE CANCER
REHABILITATION
The Institute of Medicine has defined the four pillars of
survivorship care: (1) surveillance for recurrence, second
cancers, and late effects; (2) intervention for treatment
consequences; (3) prevention of recurrence, new cancers,

From American Cancer Society, Washington, DC; Department of Physical Medicine and Rehabilitation, Program to Enhance Care Experiences Through Research, Center for the Science of
Health Care Delivery, Mayo Clinic, Rochester, MN; University of Rochester Medical Center, Wilmot Cancer Institute, Rochester, NY.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Catherine M. Alfano, PhD, American Cancer Society, 555 11th St. NW, Suite 300, Washington, DC 20004; email: catherine.alfano@cancer.org.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 241

ALFANO, CHEVILLE, AND MUSTIAN
late effects, and comorbidities where possible; and (4) co-
ordination of care between primary care, oncology, and
other specialists.4 Comprehensive cancer rehabilitation
delivered using a multidisciplinary team is an essential
component of survivorship care that addresses these four
pillars. First, it treats the acute and chronic effects of cancer
and prevents or mitigates the effects of late-occurring
problems. Survivors of cancer can face numerous adverse
consequences of cancer treatment, many of which are
amenable to rehabilitation interventions. These include
fatigue, cognitive dysfunction, pain syndromes, peripheral
neuropathy, sexual dysfunction, balance and gait problems,
upper- or lower-quadrant mobility issues, lymphedema,
bladder and bowel problems, stoma care, problems with
swallowing or dysphagia, communication difficulty, and
psychosocial problems such as depression, anxiety, or fear of
recurrence, among others.21,22 In a comprehensive reha-
bilitation model, the multidisciplinary team evaluates the
sum total of problems that a survivor faces and coordinates
treatment rather than other fragmented models of care that
treat each symptom or impairment separately. Second, the
comprehensive cancer rehabilitation team can address pre-
existing or treatment-related comorbid conditions. Bone
loss, diabetes, cardiovascular disease, congestive heart failure,
adverse body composition, and renal disease are common in
cancer survivors.4 These can be managed through rehabili-
tation interventions that include medication, counseling,
behavior change and promotion of healthy diets, physical
activity, and weight control.21 Third, these health promotion
interventions, along with self-management skills provided in
the context of comprehensive cancer rehabilitation, have the
KEY POINTS
Survivors of cancer can face numerous adverse
consequences of cancer treatment, many of which are
amenable to rehabilitation interventions.
Using an expanded prospective model of surveillance for
comprehensive cancer rehabilitation, assessment and
referral efforts begin at the time of cancer diagnosis,
continue through and beyond treatment, and use a
multidisciplinary team approach.
The model facilitates the identification and treatment of
physical impairments and psychosocial problems and
other problematic symptoms, and provides exercise,
nutrition, and weight management interventions to
optimize functioning, health, and quality of life.
Survivors of cancer can be treated in one of four levels of
stepped care or inpatient rehabilitation depending on
safety requirements and needs.
This expanded prospective model of surveillance for
cancer rehabilitation has the potential to result in early
identification of symptoms and impairments and
appropriate referral and timely treatment and, in turn,
will better address and minimize both acute and long-
term cancer morbidity.
242 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
potential to decrease the risk of further late effects (e.g.,
cardiac, pulmonary, endocrine, or bone complications of
cancer treatment)21 and may even reduce the risk of
second malignancies.23-29 Finally, comprehensive cancer
rehabilitation focuses jointly on optimizing functional
status and quality of life, preserving the ability to remain in
life roles (including the workforce),30 and maximizing
health and longevity.
A PROSPECTIVE MODEL OF SURVEILLANCE FOR
COMPREHENSIVE CANCER REHABILITATION
A prospective model of surveillance has been developed by a
team of stakeholders as a best practice model for cancer
rehabilitation.31 In this model, rehabilitative efforts begin at
the time of cancer diagnosis and continue through treat-
ment and after treatment ends, using a multidisciplinary
team approach. The model specifies that a multidimen-
sional, comprehensive assessment is conducted at the
preoperative evaluation to establish baseline functioning,
identify patients with pre-existing conditions that may place
them at higher risk for the development of treatment
toxicities and impairments during/after treatment, and refer
patients with current problems for interventions to improve
their symptoms and function. Ideally, this is a clinical
evaluation that includes a history focusing on symptoms and
current exercise and a physical examination that objectively
assesses the patients range of motion, strength, sensation,
reflexes, and gait accompanied by performance testing (e.g.,
The Timed Up and Go, Repeated Sit to Stand tests, and Short
Physical Performance Battery). This may be obtained or
supplemented with patient-reported outcome (PRO)based
measurement of survivors symptoms and functioning, al-
though limited information is available on the sensitivity and
specificity of PROs in identifying cancer survivors in need of
cancer rehabilitation services.32,33 After the preoperative
assessment, the prospective surveillance model specifies
ongoing surveillance efforts with repeated assessments
postoperatively, throughout cancer therapies, and after
treatment ends. This allows for monitoring of the devel-
opment of treatment toxicities or impairments and fa-
cilitation of appropriate and timely referrals to cancer
rehabilitation providers. The reassessments also provide
opportunities for assessment and referral for exercise,
nutrition, and weight management interventions. The
ongoing surveillance also allows the treatment team to
ensure the resolution of problems over the long term.
Though not explicitly stated by the original stakeholder
group, a prospective surveillance model for comprehensive
cancer rehabilitation must incorporate assessment and re-
ferral for mental health problems and palliative care needs in
addition to impairment-driven rehabilitation and health
behavior interventions to meet survivors ongoing needs.
Although this model has been outlined by a multidisciplinary
group of stakeholder experts, it has not been extensively
tested for effects on clinical outcome or health care costs.34
The model assumes that prospective surveillance will result

in early identification of symptoms and impairments, ap-
propriate referral and timely treatment, and, in turn, will
better address and minimize both acute and long-term
cancer morbidity. The model has the potential to achieve
the triple aim set forth by the Institute for Healthcare Im-
provement35 of facilitating better care for individuals, better
health for populations, and lower per capita costs. However,
future health care delivery research must test these as-
sumptions. Although early research suggests substantial
cost savings of implementing this model early compared
with treating advanced-stage problems, at least in the case
of breast cancerrelated lymphedema,36 future research
must include assessment of cost outcomes as previously
described.34
LEVELS OF CANCER REHABILITATION STEPPED
CARE
The expanded prospective model of surveillance presents a
framework for evaluating the needs of people with cancer
and triaging them into appropriate pathways of care based
on their need for cancer rehabilitation. But what type of care
they should receive and who should deliver the care are
issues that continue to challenge the rehabilitation com-
munity. Below we present a stepped-care framework to
guide decisions on when, how, and where to refer survivors
to cancer rehabilitation specialists depending on safety
requirements and needs. Note that all levels may involve
physical, occupational, or speech therapy; psychosocial and
cognitive interventions; exercise prescription; and lifestyle
recommendations as dictated by the needs of the individual.
The disciplines and services that provide these different
interventions, the environment in which they are provided,
and the degree of integration of the team will differ
depending on numerous factors. These include the strengths
and expertise of individual providers and existing services,
geographic proximity and communication among services,
and facility and system resources.
Level I: General Conditioning Activities, Unspecialized
In the absence of any cancer-specific morbidity, virtually all
survivors of cancer emerge from their cancer treatment with
poorer aerobic fitness and muscle quality than when they
began.37 For this reason aloneapart from secondary
cancer prevention38,39education and/or prescriptive
counseling on progressive aerobic conditioning, resistance
training, and the benefits of exercise in general should be
integral to any cancer survivorship program. This should be
supplemented by psychosocial counseling to enhance par-
ticipation in activities and address participation barriers
where needed. This represents the most basic level of
stepped cancer rehabilitation. In the future, efforts to create
more precision medicine approaches to exercise prescrip-
tion will help guide the type and dose of exercise chosen. For
now, for survivors of cancer who have exercised in the
past and lack concerning impairments or comorbidities,
counseling can be quite rudimentary, taking the form of
DEVELOPING HIGH-QUALITY CANCER REHABILITATION PROGRAMS
educational print materials or videos. More formal coun-
seling by an exercise or rehabilitation professional, enroll-
ment in a conditioning program with clinical oversight, and
more intensive behavioral counseling represent the next
two levels of increasingly time- and resource-intensive re-
habilitation. Efficacious models of cardiac and pulmonary
rehabilitation offer a potential framework for the latter, with
pilot studies of their utility for survivors of cancer showing
promise.40,41 As yet, center-based conditioning programs for
cancer survivors have not been developed in the United
States, but successes in Canada and Europe attest to their
value.42,43
Several options are available for practitioners and in-
stitutions interested in making general conditioning guid-
ance and training available to survivors of cancer. Physical
therapists without specialized cancer rehabilitation training
routinely deliver deconditioning-directed care, and they are
well equipped to individualize programs and transition
cancer survivors to home-based maintenance programs.
However, in the absence of functional impairments or
steady, ongoing improvement, payer coverage for physical
therapy may be limited. For survivors of cancer without
concerning impairments or comorbidities that would require
physical therapy or medical oversight, the LIVESTRONG at the
YMCA 12-week programs offer services and support de-
livered by athletic trainers and exercise professionals. These
services extend well beyond conditioning, although the re-
covery of strength and aerobic fitness are principle program
goals. There are currently approximately 460 LIVESTRONG
programs in the continental United States. Referral to
medically oriented gyms offers another option. Medically
oriented gyms are facilities typically staffed by physical
therapists and/or athletic trainers with expertise in chronic
illness and the care of frail patients, but they may lack
cancer specialization. Medically oriented gyms require out-
of-pocket payments. However, some payers will cover the
initial exercise prescription, professional oversight and
monitoring, and other services provided in these facilities.
These programs can be supplemented with counseling to
support behavioral changes as needed.
Level II: General Conditioning Activities, Specialized
Higher or more specialized levels of cancer rehabilitation
along the stepped-care continuum require care from clini-
cians with some degree of specialization in cancer re-
habilitation. The most prevalent need at this level is for
general conditioning among survivors of cancer who lack
specific cancer- or cancer treatmentrelated impairments
but have sufficient vulnerability to warrant specialist over-
sight. Survivors of cancer frequently have or are at risk for
conditions potentially exacerbated by exercise. Theoretically,
these individuals should have a rehabilitation team with at
least one cancer rehabilitation specialist, although empirical
validation of this need is lacking. Psychosocial counseling
to address barriers to participation or self-management
strategies may be needed. Research has established the
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 243
ALFANO, CHEVILLE, AND MUSTIAN
beneficial and safe nature of resistive training when con-
ducted under the close supervision of exercise professionals
trained in lymphedema and other cancer treatmentrelated
risks.44,45 In some clinical settings, there may not be therapists
with specific cancer rehabilitation training. In these cases, a
rehabilitation savvy oncologist or cancer rehabilitation phy-
sician may provide generally trained therapists with a detailed
physical or occupational therapy prescription with clear
precautions. They also may serve as a resource for these
noncancer trained treating professionals.
Level III: Impairment-Directed Care, Uncomplicated
This level of cancer rehabilitation need is broad because it
encompasses focal cancer- and cancer treatmentrelated
impairments that limit function but are uncomplicated by
symptoms or other systemic concerns. These impairments
generally can be managed by physical and occupational
therapists with a moderate degree of cancer specialization.
Care focuses on treating the impairment(s) to optimize
function and also on increasing activity levels with an end
goal of enabling the cancer survivors to safely participate in
lifestyle behaviors without oversight if possible. This level of
care also is more likely to require psychosocial counseling to
help survivors cope with problematic symptoms, body image
concerns, or other mental health issues and support be-
havior change efforts. The impairments that fall into this
category are as varied as they are numerous. They include,
but are not limited to, cranial nerve 11 palsy, radiation-
induced fibrosis, axillary web syndrome (variant Mondor
disease), contractures from sclerodermiform graft versus
host disease, persistent chemotherapy-induced peripheral
neuropathy (CIPN), surgical donor site morbidity (e.g., post
transverse rectus abdominis [TRAM] flap reconstruction),
and secondary myofascial dysfunction. A rapidly growing
body of literature describes the diagnosis and evidence-
based treatment of many of these impairments.46-48 Efforts
are underway to make treatment guidelines widely available
to practicing therapists. Fortunately, specialty conferences
and other educational opportunities are a rapidly increasing
means by which therapists can refine their expertise and
benefit from collective experience. Ideally, a cancer reha-
bilitation physician specialist is available to consult on
complex or nonresponding cases, although in less complex
cases, a physician need not evaluate these impairments and
thereby potentially delay their timely treatment.
Level IV: Impairment-Directed Care, Complicated
The most resource-intensive form of outpatient cancer re-
habilitation along the stepped-care continuum is specialist
physiciandirected evaluation and treatment. This should be
reserved for patients with problematic symptoms (e.g., in-
tensely painful axillary cording or severe or refractory im-
pairments) because such care may prove to be time-consuming
and costly for cancer survivors with depleted energy and
resources. At times, the sheer number of co-occurring im-
pairments may necessitate physician involvement in cases
244 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
such as allogeneic bone marrow transplant recipients who
commonly have CIPN, steroid myopathy, joint contractures,
and generalized deconditioning.49 The need for a cancer
rehabilitation physician inevitably will vary across settings
because many quaternary cancer centers have seasoned
teams with therapists accustomed to managing challenging
impairments. Level IV care is likely to involve coordinating
care among more members of the multidisciplinary team as
physical, occupational, speech and language, and psycho-
social therapies all may be needed. As in level III care, level IV
care focuses on treating impairments, ongoing symptom
management, and increasing activity levels to enable the
survivor of cancer to safely transition to participate in
lifestyle behaviors without oversight if possible.
Inpatient Cancer Rehabilitation. Inpatient cancer re-
habilitation delivered by a multidisciplinary team of pro-
viders through consultation and liaison and postacute care
services clearly is a vital component of comprehensive
cancer care. In fact, the overwhelming majority of physical
impairments, at least among patients with stage IV disease,
are detected when patients are hospitalized.50 Goals of care
are similar to higher outpatient levels: treating impairments,
psychosocial and other problematic symptoms, optimizing
functioning, and supporting exercise and dietary changes to
the extent possible. All hospitals and inpatient cancer
centers offer physical and occupational therapy services.
Most have dietitians and some have rehabilitation-oriented
mental health specialists, but the availability of a re-
habilitation physician specialized in cancer is less consistent.
Even when lacking cancer rehabilitation expertise, the in-
volvement of a rehabilitation physician in the management
of hospitalized patients offers salient advantages to a cancer
rehabilitation program, providing particularly effective and
expeditious advocacy for appropriate postacute care ser-
vices.51 Such optimized discharge planning with the in-
volvement of rehabilitation specialists has been shown to
reduce 30-day readmissions and costs per episode of care,
issues that are becoming increasingly important with the
rapid adoption of bundled payment.
IMPLEMENTATION OF QUALITY CANCER
REHABILITATION CARE
The drive to prevent and reverse disablement has spurred
care providers to develop cancer rehabilitation programs
across diverse delivery settings. This drive has been further
intensified by the American College of Surgeons Commission
on Cancer standard that accredited institutions provide
cancer rehabilitation services.52 Despite increased aware-
ness, patient access to appropriate cancer rehabilitation
services remains hampered by an unfortunate legacy of the
decades-long marginalization of cancer rehabilitationthe
fragmentation of rehabilitation disciplines and the persis-
tence of a severely limited workforce that has proven slow to
expand. Because of low referral rates from oncology clinical
practices, rehabilitation medicine has not been incentivized

to develop cancer rehabilitation positions or training pro-
grams. The limited availability of cancer rehabilitation
programs, even in large, high-volume cancer centers,20 and
the varied services provided by the few established pro-
grams has afforded oncology clinicians minimal opportunity
to learn how to effectively capitalize on the expertise of their
rehabilitation medicine colleagues to improve patient out-
comes. This self-perpetuating cycle has been hard to break.
Even today, oncology trainees seldom learn how and when
to refer their patients for rehabilitation services.
Several approaches have been established and/or are
being actively tested to overcome workforce limitations. The
first, structured rehabilitation provider trainings and certi-
fications, have gained broad traction. CARF International
introduced accreditation standards for cancer rehabilitation
specialty programs in 2014 that can be applied to hospitals,
health care systems, outpatient clinics, and community-
based programs. The Survivorship Training and Rehab
(STAR) program, a commercial entity, offers web-based
trainings to physical and occupational therapists linked to
examinations that, when passed, lead to institutional STAR
certification. The impact of CARF standards or STAR certi-
fication on care quality and effectiveness have not been
characterized. The American College of Sports Medicine
(ACSM) also has developed educational guidelines and a
certifying examination for cancer exercise trainers who work
with survivors. The certification provides a professional
competency benchmark for oncology professionals who are
looking for exercise-referral options in their local commu-
nities.53 Again, the care implications of practitioner certifi-
cation are not known. However, the fact that a practitioner
or institution has gone to the trouble of seeking, identifying,
and achieving CARF, STAR, or ACSM certification attests to
their interest and potential skill in cancer rehabilitation.
Another approach to workforce expansion is the enhance-
ment of noncancer physical or occupational therapy services
available in most U.S. communities through the direction
and support of physician and therapist cancer rehabilitation
specialists at tertiary cancer centers. Data collection for the
federally funded Collaborative Care to Preserve Perfor-
mance in Cancer (COPE) trial finished in 2015.54 COPE is
rigorously assessing whether a telemedicine approach that
leverages limited cancer rehabilitation clinical expertise to
deliver evidence-based treatment by local generalist phys-
ical therapists is a useful near-term and cost-sensitive means
of addressing current workforce limitations.
EXERCISE AS AN ESSENTIAL COMPONENT OF
CANCER REHABILITATION, ESPECIALLY FOR
OLDER ADULTS
The team that created the prospective model of surveillance
for cancer rehabilitation described exercise as an essential
component of cancer rehabilitation.31 Therefore, exercise is
integrated into each of the stepped-care levels described
above. This importance of exercise is especially true for
deconditioned and older adult survivors of cancer. A growing
DEVELOPING HIGH-QUALITY CANCER REHABILITATION PROGRAMS
body of literature demonstrates that maintaining moderate
to high levels of physical activity through formal exercise
interventions is an effective method for treating both the
physical and psychological declines experienced by older
patients with cancer as well as younger cancer survivors.55-77
Research shows that adults with cancer decrease their
physical activity levels after diagnosis and during treatment
and often do not return to their pretreatment activity levels
without formal exercise interventions.78-80 This tendency
toward declining physical activity is reinforced as pa-
tients often are advised to limit activities when they are
older, fatigued, or experiencing other toxicities and side
effects, especially cardiac, orthopedic, or functional
comorbidities.9,75,77,81-83
Exercise improves a wide array of physical and psycho-
logical symptoms, including muscle atrophy and weakness,
fatigue, obesity, immune function, insomnia, anxiety, cognitive
decline, and impaired quality of life, among others.55-74,84-88
Epidemiologic data also suggest that increased physical activity
through regular exercise reduces the risk of cancer recurrence
and cancer mortality.39,89-90 The ACSM published public health
recommendations for exercise among survivors of cancer.91
Geriatric survivors of cancer should start low and progress to
150 minutes of moderate-intensity or 75 minutes of vigorous-
intensity aerobic exercise per week; 20 to 30 minutes of
strength training across all the major muscle groups two to
three times per week; and regular stretching daily each
week.91-94 Despite these published public health guide-
lines, it is estimated up to 70% of survivors do not meet
these ACSM public health recommendations.95 This lack of
regular exercise is especially problematic for older survi-
vors of cancer when combined with the considerable
physical and psychological comorbidities, symptoms, and
side effects they experience.
Despite the numerous benefits of exercise as part of
cancer rehabilitation, the majority of survivors of cancer
report that they do not discuss exercise with their treating
oncologist or primary care physician during their cancer
treatment and recovery.96-98 However, research shows that
cancer survivors of all ages want their oncologists to initiate
discussions about exercise and make appropriate referrals.98
Survivors prefer to receive information on exercise early in
the treatment trajectory and throughout the post-treatment
period.99 Given the benefits of exercise during and after
cancer treatments, routine discussions about exercise be-
tween oncologists and their older patients who are survivors
of cancer, along with appropriate referrals to a qualified
exercise physiologist or cancer rehabilitation therapist as
needed, could significantly improve prognosis, recovery, and
multiple domains of quality of life for older individuals.
Managing Risk and Contraindications for Exercise
As part of the prospective surveillance model for cancer
rehabilitation, it is essential to identify and address potential
contraindications (e.g., orthopedic, cardiopulmonary, on-
cologic) that might affect exercise safety and tolerance.53
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 245
ALFANO, CHEVILLE, AND MUSTIAN
Contraindications do not mean that a geriatric survivor of
cancer cannot exercise at all. As described above in the levels
of stepped care, contraindications simply require specific
modifications to the exercise regimen or care environment
(e.g., facility-based vs. home) so that the individual can
exercise safely and still achieve the desired physical and
mental health benefits.53 Although active exercisers or those
at low to moderate risk based on the ACSM guidelines are
not required to obtain medical clearance to continue or
begin a low to moderate exercise program, most geriatric
survivors of cancer will need and benefit from further
medical assessment because their exercise risk will be
moderate to high.53 These geriatric survivors of cancer will
benefit from additional medical assessment by qualified
medical professionals including oncologists, surgeons,
cardiologists, orthopedists, and neurologists, among
others, because these consultations will provide important
information required by exercise physiologists to appro-
priately modify an exercise prescription and account for
cancer-specific cardiovascular, pulmonary, metabolic, or-
thopedic, neurologic, or other comorbidities.53 These
additional medical evaluations should be conducted
before initiation of any baseline exercise testing that
precedes developing an exercise prescription and sub-
sequent exercise participation.53
Exercise Prescription for Older Adult Survivors of
Cancer
Testing, prescription, and monitoring of exercise should be
done by qualified exercise professionals, especially for ge-
riatric survivors of cancer at moderate risk beginning or
continuing vigorous exercise and those at high risk beginning
or continuing any level of exercise.53 Exercise prescriptions
for geriatric survivors of cancer should be individualized and
tailored based on the older individuals health status, disease
trajectory, previous and/or current treatment, current fitness
level, past and present exercise participation, and individual
preferences to be safe and effective.91,92 Moderately intense
aerobic exercise prescriptions (55%75% of heart rate maxi-
mum100) scheduled over as little as 10 minutes and no more
than 90 minutes a day 3 to 7 days per week are effective at
reducing symptom burden and improving quality of life among
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57. Campo RA, Agarwal N, LaStayo PC, et al. Levels of fatigue and distress
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63. Sprod LK, Mohile SG, Demark-Wahnefried W, et al. Exercise and
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patients. J Geriatr Oncol. 2012;3:90-97.
64. Sprod LK, Janelsins MC, Palesh OG, et al. Health-related quality of life
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65. Sprod LK, Palesh OG, Janelsins MC, et al. Exercise, sleep quality, and
mediators of sleep in breast and prostate cancer patients receiving
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67. Janelsins MC, Davis PG, Wideman L, et al. Effects of tai chi chuan on
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68. Peppone LJ, Janelsins MC, Kamen C, et al. The effect of YOCAS yoga
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69. Peppone LJ, Mustian KM, Janelsins MC, et al. Effects of a structured
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73. Mustian KM, Sprod LK, Janelsins M, et al. Multicenter, randomized
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75. Mustian KM, Sprod LK, Palesh OG, et al. Exercise for the management
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Hematol Rev. 2012;8:81-88.
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79. Courneya KS, Friedenreich CM. Relationship between exercise pattern
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81. Mustian KM, Peppone LJ, Palesh OG, et al. Exercise and cancer-related
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82. Mustian KM, Morrow GR, Carroll JK, et al. Integrative non-
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83. Bellizzi KM, Mustian KM, Bowen DJ, et al. Aging in the context of
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loss and builds muscle in postmenopausal breast cancer survivors:
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107. Mustian KM, Janelsins M, Sprod L, et al. YOCAS Yoga significantly
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113. Adamsen L, Midtgaard J, Rorth M, et al. Feasibility, physical capacity,
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Oncologist. 2011;16:1649-1657.
asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 249
PEDIATRIC ONCOLOGY

Controversies in Germline
Genetic Testing and Disclosure
in Pediatric Oncology

CHAIR
Kim E. Nichols, MD, PhD
Childrens Hospital of Philadelphia
Philadelphia, PA

SPEAKERS
Angela R. Bradbury, MD
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA

Lainie Friedman Ross, MD, PhD

The University of Chicago Medicine
Chicago, IL
 PEDIATRIC GENETIC TESTING FOR CANCER

The Advantages and Challenges of Testing Children for

Heritable Predisposition to Cancer
Chimene Kesserwan, MD, Lainie Friedman Ross, MD, PhD, Angela R. Bradbury, MD, and Kim E. Nichols, MD

OVERVIEW

The increased application of germline genetic testing is expanding our understanding of the risk factors associated with
childhood cancer development, and, in some cases, such testing is also informing clinical management. Nonetheless, the
incorporation of genetic testing into the pediatric oncology setting is complex and associated with many ethical and practical
challenges. The decision as to whether to pursue clinical genetic testing for hereditary cancer predisposition for children should
always be guided by the best interest of the child. Despite this fundamental ethical principle, patients, parents, and health care
providers may differ in their opinions. Clinical genetic testing to detect the presence of predisposition syndromes associated
with childhood-onset cancers, particularly those for which surveillance and preventive measures have proven to enhance
outcome, is currently well accepted. On the other hand, clinical genetic testing of children for syndromes associated with adult-
onset cancers has raised many concerns about the potential for psychological harm and disrespect of patient autonomy. As
a consequence, such testing is not encouraged. The challenges surrounding germline genetic testing are further complicated
when testing is done in the research setting and/or when it involves whole-exome or whole-genome sequencing approaches,
which can uncover genetic variants that may or may not be associated with the disease under study. Accordingly, there is great
debate around these processes and the most appropriate approaches regarding the return of test results. Future research is
needed to enhance knowledge about how best to incorporate genomic information into clinical practice.

T he increased incorporation of genetic and genomic

testing in the pediatric oncology setting, including the
use of larger and more comprehensive multigene panels and
whole-exome sequencing, has greatly facilitated the iden-
tification of children with underlying predisposition syn-
dromes. In this article, we discuss the advantages and
complexities related to germline genetic testing, with an
emphasis on the evaluation of children for heritable cancer
risk. We provide an ethical framework with which to ap-
proach clinical genetic testing in children and then discuss
the advantages and challenges related to testing children in
the clinical and research settings.
ETHICAL FRAMEWORK FOR APPROACHING
CLINICAL CANCER GENETIC TESTING IN
PEDIATRICS
Professional guidelines regarding the clinical genetic testing
of children all agree that the guiding principle should be this
standard: the best interest of the child.1-8 What this principle
means and how it should be applied in different clinical
settings are less clear. Although physicians may know what is
medically best for the child, the parents calculation considers
what is best for the child by incorporating and balancing many
types of needs and interests. That is, parents consider not only
the childs medical needs but also the childs social, cultural,
religious, and economic needs and interests. Ethical contro-
versies related to clinical genetic testing of children include
the following: (1) whether to focus exclusively on the childs
self-regarding interests (e.g., concerns about the childs own
medical well-being) or to include other-regarding interests
(e.g., concerns about the needs and interests of family
members who may be affected by the information learned
from the childs genetic test results); (2) how to balance the
childs present-day needs and interests with his or her future
needs and interests; and (3) whether to include the childs
present and future autonomy interests (as well as present
and future privacy rights).8-10
In the context of clinical genetic testing of children, the
childs best interest will focus on the diagnosis of conditions
that require immediate attention. Traditionally, a physician
orders one or more genetic tests targeted to diagnose a
childs symptoms or phenotype. The increasing use of ge-
nomic sequencing has increased the number of successful

From the Department of Oncology, St. Jude Childrens Research Hospital, Memphis, TN; Departments of Pediatrics, Medicine, and Surgery, MacLean Center for Clinical Medical Ethics,
The University of Chicago, Chicago, IL; Department of Medicine, Department of Medical Ethics and Health Policy, Perelman School of Medicine of the University of Pennsylvania,
Philadelphia, PA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Kim E. Nichols, MD, 262 Danny Thomas Place, Memphis, TN 38105; email: kim.nichols@stjude.org.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 251

KESSERWAN ET AL
diagnoses but has also resulted in discoveries of variants of
unknown significance and secondary and incidental find-
ings. We provide an ethical framework for clinical genetic
and genomic testing in minors, examine scenarios that involve
predictive genetic testing in minors for cancer-predisposing
conditions by using single-gene testing, and then consider
scenarios in which genomic sequencing, rather than targeted
testing, is used.
Predictive Testing for Cancer Predisposition
Syndromes That Present in Childhood
In 2012, the American Academy of Pediatrics (AAP) and
the American College of Medical Genetics and Genomics
(ACMG) published a joint policy statement and technical
report on clinical genetic testing in children. 4,5 Earlier
statements made by these organizations objected to the
predictive testing in children1,3 but did not distinguish be-
tween testing for conditions that present in childhood and
those that present in adulthood. The timing of when a
condition is expected to present is crucial, because it affects
the relative importance of the childs role in the decision-
making process, whether the child has a right to privacy from
his or her parents, and whether the parents have a right to
make such decisions on behalf of their child.
Of the cancer-predisposing conditions that present in child-
hood, some will be early-onset (e.g., hereditary retinoblas-
toma), and others will present in adolescence or young
adulthood (e.g., hereditary paraganglioma/pheochromocytoma
syndrome [HPPS]). Both of these are autosomal dominant,
therefore a child whose parent had one of these conditions is at
KEY POINTS
The guiding principle regarding clinical genetic and/or
genomic testing of children should always be the best
interest of the child.
Diagnostic genetic testing of a child with cancer can
guide disease management and allow for the initiation
of surveillance for second primary cancers.
Predictive genetic testing for an underlying
predisposition syndrome can identify children at
increased cancer risk and allow for patient and family
education, behavioral modification, and cancer
surveillance. Importantly, such testing can also
eliminate these procedures for children whose genetic
test results are negative.
Cancer genetic testing of children should take into
account the availability of evidence-based cancer
surveillance and risk-reduction strategies and the
probability of developing a malignancy during
childhood.
Whether to return genetic research results to research
participants is a subject of active debate. A clear plan for
return of genetic research results to research
participants should be formulated prior to recruitment
and explained during the informed consent process.
252 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
50% risk of inheriting a disease-causing mutation in RB1 or in one
of the genes associated with HPPS. Clinically, one needs to know
whether a child carries an RB1 mutation in infancy because the
cancer usually presents before age 5. In contrast, tumors as-
sociated with HPPS do not generally appear before adolescence,
so genetic testing is recommended at approximately age 10 or 5
to 10 years before the earliest HPPS-associated cancer identified
in the family.
Consider, then, the case of a child whose father developed a
paraganglioma at age 25 and was found to carry a causal
mutation in one of the HPPS genes. It is recommended to start
screening for HPPS-associated tumors at age 10 in mutation-
positive children.11 Before the HPPS-associated genes were
discovered, it was advocated that all children whose par-
ents had manifestations of HPPS begin lifelong biochemical
screening for abnormally high levels of catecholamines and
undergo annual physical examinations, starting at age 10, with
attention to the symptoms associated with paragangliomas
or pheochromocytomas, such as high blood pressure, heart
palpitations, anxiety, or headache.12 Today, only those in-
dividuals with germline HPPS-associated genetic mutations
need to undergo surveillance including MRI screening.11,12
What if the father wanted to test the child for the presence
of HPPS mutation when he was an infant? The arguments
to support waiting until the child is 10 years old are to avoid
demands for earlier initiation of annual surveillance screen-
ing; to reduce parental anxiety; and to allow the child to
participate in the decision-making process. However, all three
arguments can be refuted. First, the data find that par-
ents rarely demand inappropriate treatments or initiation
of therapies earlier than necessary.13 Second, testing is only
done in children with a known family history, so parental
anxiety already exists, and testing would allow half of the
parents to be reassured.5,8,13 Furthermore, data show that
many individuals find uncertainty worse than a positive test
result.14,15 Third, although ethics supports the inclusion of
children to the extent that they are able to assent, the child in
this scenario does not really have a choice. Although mature
children can refuse to participate in many types of research,
refusal by a child of clinically indicated care is more restricted
when diagnosis, surveillance, and treatment can prevent
serious morbidity or mortality. This is not to ignore the mature
child, but respect can be shown in other ways (e.g., expla-
nations of what at-risk status means and what the tests can
determine). Of note, given that the child in question is at 50%
risk of inheriting a syndrome in which tumors can be suc-
cessfully treated if diagnosed early, his parents right to re-
fuse is also restricted, given the states obligation, as parens
patriae, to protect children from abuse and neglect. If the
child and his parents both refuse genetic testing, they could
opt for regular screening (perhaps not the best approach, but
one that can be considered good enough).16
The arguments to allow parents to test a young child before
it is clinically indicated are to reduce parental anxiety and to
permit them to make other life plans for the child and the
family. The AAP/ACMG guidance gives parents wide leeway for
conditions that present at any point in childhood, because

parents are the presumptive decision makers for their minor
children.5 Genetic counseling can help parents decide when
this testing is appropriate for their child, and the decision to
test the child in this scenario at either age should be respected.
Predictive Testing for Cancer Predisposition
Syndromes That Present in Adulthood
Some parents seek genetic testing of minors for adult-onset
conditions, although surveillance is not needed until adult-
hood. The 2012 AAP/ACMG statement recommends against
predictive genetic testing for adult-onset disorders, because
the information is not necessary in childhood and because a
delay of testing allows the child to make this decision as an
adult for himself or herself (the concept of a childs right to an
open future17,18); respects the right to privacy that an adult
has, even against his or her own parents; and avoids un-
necessary anxiety created by the time span between testing
and clinical relevance.5 The AAP/ACMG proscription is not
absolute but, rather, acknowledges that exceptional cir-
cumstances exist. It permits predictive genetic testing to
resolve disabling parental anxiety or to support life-planning
decisions that parents sincerely believe to be in the childs
best interest particularly when parents and mature ado-
lescents jointly express interest in proceeding.5
Genomic Sequencing for Cancer Predisposition and
Other Conditions
The 2012 AAP/ACMG statement did not address the use of
genomic sequencing because this test was still considered a
research tool and the guidance focused on clinical care. One
month later, however, the ACMG unilaterally proposed that,
whenever clinical genomic sequencing was performed, the
sample should be interrogated opportunistically for 56 genes
that are highly penetrant in high-risk populations regardless
of the reason for sequencing, the age of the patient, or the
consent of the patient and physician.19
The Association of Molecular Pathologists objected be-
cause interrogating a sample for these 56 genes requires
additional time, resources, and expertise, and the ACMG
policy required no ones permission, so it was not clear who
was ordering the tests, who was willing to receive and
convey the results to patients and families, and who was
going to pay for this analysis.20 Others involved in pediatrics
and genetics objected to such testing because most of the 56
genes were associated with conditions that would not
present until adulthood,21-23 and the AAP/ACMG consensus
was that it was not in the childs best interest to routinely
test for adult-onset conditions.4,5 The ACMG responded that
such testing was indeed in a childs best interest because it
could identify disease-causing mutations that may be
present in their parents.24 One year later, the ACMG revised
the recommendations to allow patients (and surrogates) to
opt out of the screening of these 56 genes and to allow
health care professionals to limit the amount of information
requested.25
PEDIATRIC GENETIC TESTING FOR CANCER
As genomic sequencing becomes cheaper, faster, and
more readily available, questions will continue to emerge
about its appropriate use. In 2015, the American Society of
Human Genetics published updated guidelines for genetic
testing of minors that examined single-gene and genomic
sequencing methodologies for both the clinical and research
settings.8 The American Society of Human Genetics con-
cluded that targeted tests, or selective sequence analysis,
are usually preferable to less-discriminate data acquisition
when the clinical challenge can be addressed through a
targeted approach.8 However, even if the ACMG list of 56
genes is not intentionally interrogated when a childs blood
is sequenced, and even if sequencing is focused on analyzing
genes that are relevant to the childs condition, testing may
still identify incidental findings (such as variants in genes that
predispose to other health problems or variants that are only
relevant to reproductive decision making [e.g., carrier sta-
tus]). When the sample comes from a child, some seek to
limit disclosure of findings to those conditions that may
manifest in childhood, whereas others seek to limit disclosure
to childhood conditions for which early surveillance or treat-
ment can affect outcomes.23,26-30 Some support a policy of
strict nondisclosure of incidental findings to minors and their
parents, but others support pre- and post-test counseling and
disclosure of incidental findings as agreed upon by parents,
physicians, and when possible, the child.22,26-30 The clinical,
psychological, and economic costs and benefits of these
various approaches on families and on the health care system
remain uncertain and will need to be carefully evaluated.
CLINICAL FRAMEWORK FOR APPROACHING
CANCER GENETIC TESTING IN PEDIATRICS
The germline genetic testing of children with cancer is
primarily pursued for diagnostic or predictive purposes.
Diagnostic testing can explain tumor formation, provide
prognostic information, and guide decisions about cancer
treatment. It is recommended that patients with cancer
and Li-Fraumeni or Gorlin syndrome for example, who
harbor germline mutations in TP53 or PTCH1 respectively,
not be exposed to ionizing radiation because of the in-
creased risk for secondary radiation-induced cancers.
Simiarly, patients with cancer and genetic syndromes
associated with defective DNA repair, such as Fanconi
anemia, should not be treated with conventional doses of
myelosuppressive chemotherapy and/or radiation because
of the excess toxicity associated with these approaches.
Genetic information can also guide the surgical approach
to cancer treatment, when no surgery or organ-sparing
surgery of paired at risk organs (e.g., the eyes in children
with hereditary retinoblastoma or the kidneys in children
with WT1-associated hereditary Wilms tumor) is preferred
over removal of an entire organ.
Predictive testing derives its benefit from the tenet that
early detection of tumors will lead to prevention or sur-
veillance interventions that reduce overall morbidity and
mortality. In light of this issue, the American Society of
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TABLE 1. Cancer Predisposition Syndromes and Associated Physical Findings

Syndrome Physical Findings
Disorders Associated With Defects in DNA Repair
Ataxia Telangiectasia Ataxia
Telangiectasia
Cafe-au-lait macules
Bloom Syndrome Small size for age
Erythematous skin lesions on the nose and cheeks (butterfly rash)
Underdeveloped malar and lower mandibular areas
Fanconi Anemia Radial ray anomalies: malformations of thumbs, forearms
Short stature
Pigmentary skin changes: cafe-au-lait macules, hypopigmentation
Other anomalies: small eyes, narrow ear canal and abnormal pinna, micropenis
Nijmegen Breakage Syndrome Microcephaly
Growth retardation
Rothmund-Thomson Syndrome Poikyloderma
Dysplastic nails
Rudimentary or hypoplastic teeth
Radial ray anomalies
Acral keratosis
Werner Syndrome Short stature
Premature graying of the hair
Xeroderma Pigmentosum Acute sun sensitivity
Marked freckle-like pigmentation
Severe keratitis
Photophobia
Squamous cell cancer of skin
Acquired microcephaly
Inherited Bone Marrow Failure Syndromes
Diamond-Blackfan Anemia Microcephaly
Growth retardation
Ocular hypertelorism, ptosis
Congenital glaucoma, congenital cataract
Webbed neck, short neck
Klippel-Feil anomaly (short neck, low hair line and/or limited range of motion in the neck due to
fusion of cervical vertebrae)
Sprengel deformity (high scapula)
Flat thenar eminence
Triphalangeal, bifid, hypoplastic, or absent thumb
Dyskeratosis Congenita Dystrophic nails
Dental abnormalities (hypodontia, early tooth loss)
Lacy reticular pigmentation of the upper chest and/or neck
Alopecia
Premature graying of the hair
GATA2 Deficiency Cutaneous warts
Lymphedema of extremities
Shwachman-Diamond Syndrome Short stature
Failure to thrive and poor growth
Continued

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 PEDIATRIC GENETIC TESTING FOR CANCER

TABLE 1. Cancer Predisposition Syndromes and Associated Physical Findings (Contd)

Syndrome Physical Findings
Neurocutaneous Syndromes
Neurofibromatosis Type 1 Cafe-au-lait macules
Freckling in the axillary and/or inguinal regions
Hypopigmented macules
Lisch nodules
Macrocephaly
Neurofibromas
Short stature
Tibial pseudarthrosis
Neurofibromatosis Type 2 Cafe-au-lait macules
Cutaneous schwannomas
Tuberous Sclerosis Complex Hypomelanotic macules
Angiofibromas
Shagreen Patch
Confetti skin lesions
Dental enamel pits
Ungual fibromas
Neuroendocrine Syndromes
Carney Complex Spotty skin pigmentation of lips, conjunctiva and inner or outer canthi, vaginal and penile mucosal
surfaces
Blue nevi
Cafe-au-lait macules
Cutaneous and mucosal myxomas
Acromegaly
Multiple Endocrine Neoplasia Type 1 Cutaneous collagenomas
Facial angiofibromas
Multiple Endocrine Neoplasia Type 2B Marfanoid habitus
Neuromas of lips and tongue
Overgrowth Syndromes
AIP-Related Familial Isolated Pituitary Gigantism or acromegaly
Adenomas
Beckwith-Wiedemann Syndrome Macroglossia
Macrosomia
Ear lobe creases, helical pits
Hemihyperplasia
Omphalocele
Umbilical hernia
Diastasis recti
Nevoid Basal Cell Carcinoma Syndrome Coarse facial features, frontal bossing
(Gorlin Syndrome) Macrocephaly
Palmar and plantar pits
Preaxial or postaxial polydactyly
Basal cell carcinomas
PTEN Hamartoma Tumor Syndrome Macrocephaly
Trichilemmomas
Lipomas
Oral mucosal papillomas
Acral keratosis
Hemangiomas
Penile freckling
Continued

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TABLE 1. Cancer Predisposition Syndromes and Associated Physical Findings (Contd)

Syndrome
Simpson-Golabi-Behmel Syndrome
Sotos Syndrome
Intestinal Polyposis Syndromes
Constitutional Mismatch Repair Defect
Familial Adenomatous Polyposis Syndrome
Peutz-Jeghers Syndrome
RASopathies
Cardiofaciocutaneous Syndrome
Costello Syndrome
Noonan Syndrome
Noonan Syndrome With Multiple Lentigines
Physical Findings
Macrocephaly
Macrosomia
Long narrow face with bitemporal narrowing
Long chin
Overgrowth
Sparse frontotemporal hair
Cafe-au-lait macules
Hypopigmented macules
Dental abnormalities: missing or supernumerary teeth
Epidermoid cyst
Osteomas of the skull and/or mandible
Pilomatricomas
Melanotic macules around the mouth, eyes, nostrils, and perianal area
Coarse facial features
Bitemporal narrowing
Hypertelorism, downslanting palpebral fissures, and hypoplasia of the supraorbital ridges
Low set ears, ear lobe creases
Macrocephaly relative to body size
Short neck
Short stature
Keratosis pilaris
Lymphedema
Coarse facial features
Curly or sparse fine hair
Deep palmar or plantar creases
Friendly, sociable personality
Full lips, large mouth
Papillomata of the face and anal region
Short stature
Ulnar deviation of wrists and fingers
Coarse facial features
Downslanted palpebral fissures
Vivid blue or blue-green irises
Fullness of upper eyelids and ptosis
Low set posteriorly rotated ears with fleshy helices
Broad or webbed neck
Short stature
Pectus deformity of chest
Widely set nipples
Cryptorchidism
Coarse facial features
Downslanted palpebral fissures
Widely spaced eyes and ptosis
Low set ears, posteriorly rotated with thick helices
Lentigines
Cafe-au-lait macules
Continued

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 PEDIATRIC GENETIC TESTING FOR CANCER

TABLE 1. Cancer Predisposition Syndromes and Associated Physical Findings (Contd)

Syndrome Physical Findings
Short stature
Cryptorchidism
Disorders of Sex Chromosomes

Klinefelter Syndrome Gynecomastia and/or small genitalia

Tall stature
Turner Syndrome Short stature
Webbed neck
Low hair line
Shield-like chest
Wide-spaced nipples
Lymphedema of hands and feet
WT1-Related Disorders
Denys-Drash Syndrome Ambiguous genitalia
Frasier Syndrome Ambiguous genitalia
Wilms Tumor, Aniridia, and Growth Aniridia
Retardation Syndrome Ambiguous genitalia
Other
Rubinstein Taybi Syndrome Convex nasal bridge with low hanging columella
Downslanting palpebral fissures
Broad radially deviated thumbs
Broad terminal phalanges
Grimacing smile
Pilomatricomas
Talon cusps (extra cusp-like projection of the primary or permanent anterior teeth)
Undescended testis

Clinical Oncology (ASCO) advises that cancer genetic test-
ing of children take into account the availability of evidence-
based risk-reduction strategies and the probability of
developing a malignancy during childhood. 31 Currently,
there are only a limited number of conditions for which effective
preventive measures are known to exist. One such example is
multiple endocrine neoplasia type 2 (MEN2), which is caused by
germline RET gene mutations. Predictive RET gene testing is the
clinical standard of care for all individuals with a positive family
history of MEN2 because of the very high risk to develop early-
onset medullary thyroid cancer in affected individuals, including
children. Prophylactic thyroidectomy during childhood is
therefore indicated for anyone who harbors a pathogenic gain-
of-function RET gene mutation because this procedure greatly
reduces or even eliminates the risk of developing thyroid
cancer. Risk stratification that is based on RET genotype
can inform decisions about the age to perform the prophylactic
thyroidectomy.32 The identification of a predisposing germline
mutation also guides strategies for cancer monitoring. Although
surveillance protocols are under investigation for many con-
ditions, effective approaches do exist for certain conditions,
such as familial ademonatous polyposis, Beckwith Wiedeman
syndrome, Li-Fraumeni syndrome, and the WT1-associated
Wilms tumor syndromes, among others.33-38
Factors to Consider When Pursuing Clinical Cancer
Genetic Testing in Children
The factors most commonly used to prompt referral of a
child to a cancer genetics specialist include a personal
medical or family history consistent with, or suggestive of,
an underlying hereditary cancer syndrome. The personal
features that most support an underlying cancer predis-
position in a child include the presence of: a clinical or
molecular diagnosis of a known predisposition syndrome;
very early onset or adult-type tumors (e.g., epithelial breast
or colon cancer); multifocal tumors; bilateral involvement of
paired organs (e.g., eyes, kidneys, adrenal glands, breasts);
specific cancer types and histologic features (e.g., medullary
thyroid cancer and MEN2); second primary neoplasms; and
specific physical findings (examples of these physical find-
ings are provided as a reference and listed in Table 1).
The family history is also a key factor that helps guide
a cancer genetics evaluation. ASCO has recognized the
importance of an adequate family history in the identifi-
cation of patients whose cancers may be associated with
inherited genetic factors. For each relative of a child with
cancer, it is important to record whether that relative de-
veloped cancer and, if so, to also record the type of cancer
and its histologic features; the age at cancer diagnosis; laterality;
maternal or paternal lineage relationships of affected relatives

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KESSERWAN ET AL
TABLE 2. Family History Features Suggestive of an
Underlying Cancer Predisposition
Feature Findings
Pattern of Three generations affected by cancer (on the same
Cancer side of the family)
Occurrence
Three or more family members with the same type of
cancer (on the same side of the family)
One or more first-degree relatives with cancer (parent,
child, sibling)
Age of Cancer Earlier than expected age of onset for cancer type
Onset
Cancer Type/ Adult type cancers in children (e.g., epithelial cancers
Presentation such as adenocarcinoma of the breast, ovary, and
colon)
Constellation of tumors consistent with a familial
syndrome (e.g., breast and ovarian cancer in
hereditary breast and ovarian cancer syndrome;
uterine and colon cancer in Lynch syndrome)
Multiple primary cancers
Bilateral or multifocal cancers
Ethnic Ashkenazi Jewish background
Background
Consanguinity
Other Features Clinical or molecular diagnosis of a predisposition
syndrome in a close relative
with cancer; ethnicity; and results of prior genetic testing.39 A
minimum adequate family history should include cancer in first-
and second-degree relatives of the proband and no less than a
three-generation pedigree. Table 2 lists the family history
features suggestive of an underlying predisposition.
Guidelines for the Referral of Children for Clinical
Cancer Genetic Testing
The ACMG and National Society of Genetic Counselors
(NSGC) have issued practice guidelines to facilitate id-
entification and referral of adults with cancer and at-risk
individuals to a cancer genetics specialist. 40 Currently,
guidelines dedicated to the evaluation of children are
lacking. Tables 3, 4, and 5 provide practical information to aid
in the genetics referral of children with liquid, central
nervous system (CNS), and non-CNS solid tumors.
Challenges Associated With Cancer Genetic Testing in
Children
Despite the benefits of childhood cancer genetic testing,
several challenges remain. First, providers often lack the
time, tools, or expertise to collect and meaningfully interpret
family history information. Furthermore, it is important to
recognize that family histories may appear negative because
of inaccurate or inadequate medical information and be-
cause of incomplete penetrance or presence of de novo
germline mutations. Providers must not overlook the pos-
sibility of an underlying syndrome, even if the family history
appears negative. This is particularly true for children who
have cancers that are known to have a heritable basis in a
clinically relevant proportion of cases (e.g., retinoblastoma,
adrenocortical carcinoma, paraganglioma). Second, consensus
258 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook
guidelines for cancer surveillance of many predisposition
syndromes that affect children do not yet exist. Multicenter,
prospective studies to assess the clinical utility of surveillance
protocols are critically needed. Third, there remains concern
that the testing of children for cancer predisposition will cause
adverse psychological outcomes for the child, the parents, and
other family members. Although it has been reported that
some children experience distress, discrimination, guilt, or
regret, most of the published literature indicates that there is
no increase in mean anxiety, depression, and distress scores
as a result of testing.41,42 Fourth, the increasing use of mul-
tigene panel and genomic testing has increased the difficulty
level and time required to adequately counsel patients and
parents. A 2015 ASCO policy statement highlights the el-
ements of pretest counseling recommended for multigene
panel testing. In addition to including the general compo-
nents of traditional counseling, the possibility of detecting
predisposing mutations not suggested by the personal or
family history factors, and the implications of positive results
in lesser-penetrance genes are key points to address.43 The
counseling process should include a discussion of variants of
unknown significance, which remain a source of confusion
for health care providers and patients. Providers should
ensure that families comprehend the concept of variants of
unknown significance and recognize that the presence of
such variants does not generally change clinical manage-
ment. They should consult the literature and seek the as-
sistance of experts for additional opinions, when necessary.
Given the challenges associated with genetic and genomic
testing, interpretation of test results, and the potential
impacts on clinical management, it is recommended that
children who are candidates for cancer genetic or genomic
testing be referred to physicians and genetic specialists with
clinical expertise and research interests in these subject
areas.
GUIDELINES AND CHALLENGES RELATED TO
RESEARCH GENETIC TESTING AMONG CHILDREN
As large, prospective, cohort studies with banked DNA in-
creasingly have been used to evaluate the effects of genes,
the environment, and lifestyle, there has been increasing
debate about the obligations, if any, to share individual
genetic research results with research participants.44 The
traditional approach has been to not share individual re-
search results with research participants or, in the setting of
pediatrics, with their parents or surrogates.45,46 This tradi-
tional approach is rooted in distinctions between the goals of
research and clinical care.27,45,47,48 Classically, the primary
goal of research is to create generalizable knowledge to
ultimately benefit a population as a whole. In contrast, the
goal of clinical care is to benefit an individual patient and
improve health outcomes. Arguments against returning
individual research results include blurring this important
distinction between research and clinical care,27,47-51 the
potential for misunderstanding or over-interpretation of the
clinical significance or limitations of genetic results identified
 PEDIATRIC GENETIC TESTING FOR CANCER

TABLE 3. Indications for Consideration of Genetics Evaluation in Children With Hematopoietic Malignancies
Type of
Hematopoietic Consider Referring for Genetics Evaluation Cancer Predisposition
Malignancy When Any of the Following Is Present Syndrome(s) to Consider Gene(s)
ALL Family history of LFS-associated tumors LFS TP53
Hypodiploid ALL LFS TP53
Cafe -au-lait macules CMMRD MLH1, MSH2, MSH6, PMS2, EPCAM
Family history of Lynch syndromeassociated tumors
Consanguinity
Pure red cell aplasia DBA RPL11, RPL26, RPL35A, RPL5, RPS7,
RPS10, RPS17, RPS19, RPS24,
RPS26, RPS29, GATA1
Pancreatic insufficiency SDS SBDS
Growth failure
Bone marrow failure
Family history of ALL Familial ALL caused by PAX5 PAX5
mutations
Family history of ALL Familial ALL caused by ETV6 ETV6
mutations
Thrombocytopenia
Family history of ALL Familial ALL caused by SH2B3 SH2B3
mutations
AML/Myelodysplastic Family history of LFS-associated tumors LFS TP53
Syndrome
Cafe -au-lait macules CMMRD MLH1, MSH2, MSH6, PMS2, EPCAM
Family history of Lynch syndromes-associated tumors
Consanguinity
Cafe -au-lait macules FA BRCA2, BRIP1, ERCC4, FANCA, FANCB,
FANCC, FANCD2, FANCE, FANCF,
Radial ray defect
FANCG, FANCI, FANCL, PALB2,
Growth and developmental delay RAD51C, SLX4, XRCC2
Microcephaly
Skeletal anomalies
Pure red cell aplasia DBA RPL11, RPL26, RPL35A, RPL5, RPS7,
RPS10, RPS17, RPS19, RPS24,
RPS26, RPS29, GATA1
Pancreatic insufficiency SDS SBDS
Growth failure
Bone marrow failure
Neutropenia Severe congenital neutropenia/ CSF3R, ELANE, G6PC3, GF11, HAX1,
Kostmann syndrome JAGN1
Pigmentary changes (neck/chest) Dyskeratosis congenita ACD, C16orf57, CTC1, DKC1, NHP2,
NOLA3, PARN, RTEL1, TERT, TERC,
Pulmonary fibrosis
TINF2, WRAP53
Bone marrow failure
Dysplastic nails
Oral leukoplakia
Family history of AML Familial AML caused by CEBPA CEBPA
mutations
Family history of AML Familial platelet disorder with RUNX1
predisposition to acute
Thrombocytopenia
myelogenous leukemia
Cytopenias MonoMac syndrome/Emberger GATA2
syndrome
Immunodeficiency and increased risk for M. avium
complex infection
Lymphedema
Radial ray defect Rothmund-Thomson syndrome RECQL4
Poikiloderma
Sparse hair/nail abnormalities
Continued
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KESSERWAN ET AL
TABLE 3. Indications for Consideration of Genetics Evaluation in Children With Hematopoietic Malignancies
(Contd)
Type of
Hematopoietic Consider Referring for Genetics Evaluation
Malignancy When Any of the Following Is Present
JMML Family history and/or features of RASopathies or NF1 Noonan syndrome and related
RASopathies
Mosaic Monosomy 7 Family history of monosomy 7
Non-Hodgkin Males with B-cell lymphoma and a history of EBV
Lymphoma infection and/or family history of XLP features
Cafe -au-lait macules
Family history of Lynch syndromeassociated cancers
Consanguinity
Gait abnormalities
Cutaneous and/or ocular telangiectasia
Males with lymphoma, immunodeficiency, and/or
eczema
Thrombocytopenia, small platelets
Failure to thrive
Males with humoral immunodeficiency
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CMMRD, constitutional mismatch repair deficiency; DBA, Diamond-Blackfan anemia; EBV, Epstein-
Barr virus; FA, Fanconi anemia; JMML, juvenile myelomonocytic anemia; LFS, Li-Fraumeni syndrome; NF1, neurofibromatosis type 1; NF2, neurofibromatosis type 2; SDS, Shwachman-
Diamond syndrome.
in the research setting,47,48,50 maintenance of privacy and
the right of the participant to not know,52 the prohibitive
costs for research team and biobanks,53-55 and the potential
negative impact on research progress if costs are shifted to
cover return of results at the expense of discovery.27,53,56
Yet, this traditional framework has been questioned over
time, given an increasing appreciation that some genetic
findings identified in the research setting could significantly
affect the health of a research participant.27,45,46,47,57-59
Others have argued that returning individual genetic re-
search results should be considered on the basis of the
principles of beneficence, autonomy, reciprocity, and respect
for persons, and, in pediatrics, that the return of individual
genetic research results is in the best interest of the child.57-64
This debate has become more and more important with
the advent of next-generation sequencing, which allows
multiple genes or the entire genome to be sequenced rapidly
and at relatively accessible costs.48,65-67 Now, there are
numerous ways that potentially clinically significant genetic
findings can be identified in the research setting. First, many
studies designed to evaluate the genetic underpinnings of
disease evaluate a number of genes suspected to be related
to a specific condition. Even if these genes are not known to
have any relationship to the health of research participants
at the time they enroll in the study, the level of evidence may
accumulate over time, such that they become clinically
actionable in the future. Second, a research study may se-
quence large portions of the genome but only invest in the
interpretation of genetic variants related to the disease of
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Cancer Predisposition
Syndrome(s) to Consider Gene(s)
BRAF, CBL, HRAS, KRAS, MAP2K1,
MAP2K2, NRAS, PTPN11, RAF1,
RIT1, SHOC2, SOS1
NF1 NF1
Familial mosaic monosomy 7 Unknown
syndrome
X-linked lymphoproliferative SH2D1A
disease
CMMRD MLH1, MSH2, MSH6, PMS2, EPCAM
Ataxia-telangiectasia ATM
Wiskott-Aldrich syndrome WAS
X-linked agammaglobulinemia BTK
interest. Nonetheless, other potentially actionable muta-
tions (e.g., the 56 highly penetrant genes outlined by the
ACMG) may have been sequenced, but the interpretation
and variant calling required to return individual results to
research participants would require additional resources
beyond the scope of the scientific aims. Third, somatic tumor
profiling (e.g., sequencing of tumors to identify acquired
genomic aberrations that can be used to identify targeted
therapy) can indirectly or directly reveal inherited variants of
clinical significance.66,67 Many somatic sequencing plat-
forms use a normal sample for subtraction analysis to clarify
which variants are tumor specific. Dedicated analysis of the
normal or germline sample may identify inherited muta-
tions. Tumor-only sequencing (those that do not include a
normal or germline sample) may also identify potential
germline mutations, because any variant found in the cancer
could, in theory, reflect variation in the normal DNA. Thus, a
germline susceptibility to cancer may be incidentally iden-
tified in the process of cataloging somatic mutations. Given
the increasing range of scenarios in which research can
identify potentially clinically significant genetic variants,
there is an increasing need to clarify what obligations re-
search teams have to return genetic research results to
participants.
Guidelines Regarding Returning Research Results
In 1999, the National Bioethics Advisory Commission advised
against return of incidental research findings, except in rare
 PEDIATRIC GENETIC TESTING FOR CANCER

TABLE 4. Indications for Consideration of Genetics Evaluation for Children With Central Nervous System, Spinal, or
Intracranial Tumors
Consider Referring for Genetics Evaluation When Any Cancer Predisposition
Type of Tumor of the Following Is Present Syndrome to Consider Gene(s)
Astrocytoma Anaplastic/high grade and family history of LFS TP53
LFS-associated tumors
Subependymal giant cell astrocytoma Tuberous sclerosis complex TSC1, TSC2
Cortical tuber
NF1 features NF1 NF1
Family history of NF1
Cafe-au-lait macules CMMRD MLH1, MSH2, MSH6, PMS2,
EPCAM
Family history of Lynch syndrome-associated cancers
Consanguinity
Atypical Teratoid/ Refer all RTPS SMARCB1, SMARCA4
Rhabdoid Tumor
Cerebellar Refer all VHL VHL
Hemangioblastoma
Choroid Plexus Refer all LFS TP53
Carcinoma
Endolymphatic Sac Refer all VHL VHL
Tumor
Ependymoma Spinal ependymoma NF2 NF2
Glioblastoma Cafe-au-lait macules CMMRD MLH1, MSH2, MSH6, PMS2,
EPCAM
Family history of Lynch syndrome-associated cancers
Consanguinity
Family history of LFS-associated tumors LFS TP53
Medulloblastoma Age , 3 NBCCS/Gorlin syndrome PTCH1, SUFU
Desmoplastic/extensive nodularity
Macrocephaly
Basal cell carcinoma
Palmar/plantar pitting
Jaw keratocysts
Calcification of the falx
Sonic Hedgehog subtype LFS TP53
Family history of LFS-associated tumors
Cafe-au-lait macules CMMRD MLH1, MSH2, MSH6, PMS2,
EPCAM
Family history of Lynch syndromeassociated cancers
Consanguinity
Family history of polyps, early-onset colon cancer FAP APC
Cafe-au-lait macules Fanconi anemia BRCA2, BRIP1, ERCC4, FANCA,
FANCB, FANCC, FANCD2,
Radial ray defect
FANCE, FANCF, FANCG, FANCI,
Developmental delays FANCL, PALB2, RAD51C, SLX4,
Microcephaly XRCC2

Skeletal anomalies
Multiple congenital anomalies
Meningioma Clear cell subtype Predisposition to clear cell SMARCE1
meningiomas
Macrocephaly NBCCS (Gorlin syndrome) PTCH1, SUFU
Basal cell carcinoma
Palmar/plantar pitting
Jaw keratocysts
Calcification of the falx
Personal/family history of Schwannomas NF2 NF2
Continued

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KESSERWAN ET AL
TABLE 4. Indications for Consideration of Genetics Evaluation for Children With Central Nervous System, Spinal,
or Intracranial Tumors (Contd)
Consider Referring for Genetics Evaluation When Any
Type of Tumor of the Following Is Present
Neurofibroma Refer all
Personal/family history of Schwannomas
Optic Pathway Glioma Family history or features of NF1
Pineoblastoma Family history of DICER1-associated tumors
Family history of retinoblastoma
Pituitary Blastoma Refer all
Schwannoma Refer all
Abbreviations: CMMRD, constitutional mismatch repair deficiency; FAP, familial adenomatous polyposis; LFS, Li-Fraumeni syndrome; NBCCS, nevoid basal cell carcinoma syndrome;
NF1, neurofibromatosis type 1; NF2, neurofibromatosis type 2; RTPS, rhabdoid tumor predisposition syndrome; VHL, Von Hippel-Lindau; yo, years old.
circumstances. Since this initial guidance, various organi-
zations, advisory commissions, and scholars have provided
additional guidance statements, which reflect a growing
consensus that there may be some cases in which re-
search participants should be offered the option of learning
about research results that could significantly affect their
health.45,68-72 Although the 2013 ACMG statement proposes
that laboratories have a fiduciary responsibility to seek and
report mutations in a minimum list of 56 genes (23 of which
are cancer related) regardless of test indication or age,
these recommendations have been controversial and were
designed specifically for sequencing in clinical care as op-
posed to research.21,22,66,73-81 There currently is no con-
sensus list of actionable genes for obligatory disclosure in
the research setting.19,82-84 Later in 2013, the Presidential
Commission for Bioethical Issues published Anticipate and
Communicate: Ethical Management of Incidental and Sec-
ondary Findings in the Clinical, Research and Direct-to-
Consumer Contexts, which provides guiding principles
and general recommendations for the return of incidental
findings in the research setting.85 Key recommendations
included the following: (1) anticipating the potential for
incidental genetic findings; (2) communicating the poten-
tial and plans for returning individual results in advance
(e.g., at the time of consent to the study); and (3) honoring
the right of participants to refuse receipt of incidental
genetic research findings. Importantly, the Presidential
Commission rejected an obligation to opportunistically
seek actionable genetic variants (e.g., secondary findings)
in the research setting, highlighting the negative impact
this could have on the research enterprise, in which society
has a significant interest.85 In addition, the Commission
emphasized the need for additional research, deliberation,
and context-specific guidelines from professional orga-
nizations. These recommendations are consistent with
recommendations published by other expert groups and
represent a growing consensus that some analytically
valid genetic research findings should be considered for
return to participants and, in pediatrics, to parents and
surrogates.27,45,46,52
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Cancer Predisposition
Syndrome to Consider Gene(s)
NF1 NF1
NF2 NF2
NF1 NF1
DICER1 syndrome DICER1
Hereditary retinoblastoma RB1
DICER1 syndrome DICER1
NF2 NF2
Familial schwannomatosis SMARCB1
Remaining Areas of Controversy and Unique
Considerations for Children
Despite this emerging consensus, there remain many areas
of continued debate. There is no consensus on criteria or
settings in which there is an obligation to return action-
able research findings to pediatric research participants,
their parents, or their surrogates45,51,52,59,86,87 Although the
clinical utility or actionability of results is often used as a
deciding factor, defining actionability is challenging, par-
ticularly as commercial tests become available prior to ev-
idence of clinical utility.88 There are additional complexities
in pediatrics, given that some conditions (e.g., adult-onset
conditions such as adult cancer or Alzheimer disease) may
not be immediately relevant to the child but could be im-
mediately relevant to his or her relatives.46 Although some
have argued that this is sufficient rationale to return results
in the pediatric setting, others have rejected this rationale
for justifying the return.19,27,46 Second, the duration of
obligations has been debated. Can research teams be held
responsible for returning results that may not become ac-
tionable until many years after the research was completed
and when they may not have remaining funding or resources
to support the return of results? This is particularly relevant in
pediatric research, because a child may not have the ability to
make an informed decision about receiving research results
at the time of enrollment but may be able to do so in the
future.46 Third, there is debate about whether genetic re-
search results must be conducted or confirmed in a Clinical
Laboratory Improvement Amendments (CLIA)certified lab-
oratory prior to return of results to research participants.
Some groups argue that only select results (e.g., those that are
clearly clinically actionable and have been confirmed in a CLIA
laboratory) should be returned.51,87,89 Yet, many research
investigations occur in non-CLIA certified laboratories, and
such requirements would significantly increase costs, detract
from the research at hand, and create barriers to returning
potentially actionable genetic research findings. Thus, others
argue that genetic research results should be offered to
participants, and, in pediatrics, to their parents or surrogates,
to let them make decisions about which results they would
 PEDIATRIC GENETIC TESTING FOR CANCER

TABLE 5. Indications for Consideration of Genetics Evaluation for Children With Solid Tumors
Type of Solid Tumor by Consider Referring When Any Cancer Predisposition
Anatomic Location of the Following Is Present Syndrome to Consider Gene(s)
Breast