Professional Documents
Culture Documents
PRINCIPLES
AND PRACTICE
OF GYNECOLOGIC
ONCOLOGY
E D ITE D BY
Richard R. Barakat, MD, FACOG, FACS
Chief, Gynecology Service, Department of Surgery
Ronald O. Perelman Chair in Gynecologic Surgery
Vice Chairman, Clinical Activities, Department of Surgery
Memorial Sloan-Kettering Cancer Center
New York, New York
Andrew Berchuck, MD
Director, Division of Gynecologic Oncology
Department of Obstetrics and Gynecology
Director, Gynecologic Cancer Program
Duke Cancer Institute
Duke University Medical Center
Durham, North Carolina
Maurie Markman, MD
Senior Vice President for Clinical Affairs
National Director of Medical Oncology
Cancer Treatment Centers of America
Philadelphia, Pennsylvania
Sixth Edition
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Principles and practice of gynecologic oncology.6th ed. / editor, Richard R. Barakat ... [et al.].
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-4511-7659-9 (alk. paper)
ISBN-10: 1-4511-7659-7 (alk. paper)
I. Barakat, Richard R.
[DNLM: 1. Genital Neoplasms, Female. WP 145]
RC280.G5
616.99'465dc23
2013005965
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D E D I C ATI O N
This book is dedicated to our familiesCatherine Barakat
and children Joanna, Richard Jr., and Christian Barakat;
Brabham Morgan Randall and children Ken, Morgan, and
Marycobb Randall; Tomes Markman and children Margaret,
Jonathan, Timothy, and Elisabeth Markman; and Amy Berchuck
and children Samuel, Jacob, and Benjamin Berchuck. Their
patience, good humor, encouragement, and love have inspired
us throughout our careers. In this regard, they have each made
significant contributions to this book.
C O NTR I B UTI N G AUTH O R S
vi
CONTRI BUTI NG AUTHORS vii
Department of Pathology and Laboratory Harpreet Pannu, MD Royal Victoria Hospital, Jewish General
Medicine Associate Professor of Radiology Hospital
Indiana University Health North Hospital Department of Radiology Montreal, Quebec, Canada
Indianapolis, Indiana Weill Cornell Medical College
Marcus E. Randall, MD, FACR, FASTRO
Associate Attending
Jeffrey C. Miecznikowski, PhD Markey Foundation Endowed Chair
Department of Radiology
Associate Professor Department of Radiation Medicine
Memorial Sloan-Kettering Cancer Center
Department of Biostatistics University of Kentucky
New York, New York
University at Buffalo Chair and Professor
Assistant Professor of Oncology Richard Penson, MD, MRCP Department of Radiation Medicine
Department of Biostatistics Associate Professor UK Albert B. Chandler Hospital
Roswell Park Cancer Institute Department of Medicine Lexington, Kentucky
Buffalo, New York Harvard Medical School
Laurel W. Rice, MD
Clinical Director Medical Gynecologic
Bradley J. Monk, MD Chair and Professor
Oncology
Professor Department of Obstetrics and Gynecology
Department of Medical Oncology
Division of Gynecologic Oncology University of Wisconsin Madison
Massachusetts General Hospital
University of Arizona College of Medicine Madison, Wisconsin
Boston, Massachusetts
Phoenix Kenneth Rolston, MD
Creighton University School of Medicine Jacobus Pfisterer, MD
Professor Professor of Medicine
Phoenix Campus Department of Infectious Diseases, Infection
Director, Division of Gynecologic Oncology University of Kiel
Director Control and Employee Health
University of Arizona Cancer CenterPhoenix University of Texas MD Anderson Cancer
St. Josephs Hospital and Medical Center, A Gynecologic Oncology Center
Kiel, Germany Center
Dignity Health Member Houston, Texas
Phoenix, Arizona Marie Plante, MD
Sharon Romano-Fitzgerald, MD
Associate Professor
John W. Moroney, MD Fellow
Department of Obstetrics and Gynecology
Assistant Professor Department of Gynecologic Oncology
Laval University
Department of Obstetrics and Gynecology Walter Reed National Military Medical
Chief, Division of Gynecology
Wright State University Center and Medical Oncology Branch,
Department of Obstetrics and Gynecology
Staff, Gynecologic Oncology Center for Cancer Research, National
LHtel-Dieu de Qubec
Department of Obstetrics and Gynecology Cancer Institute
Quebec City, Canada
Wright Patterson Medical Center Bethesda, Maryland
Dayton, Ohio Russell K. Portenoy, MD
Jason Rownd, MS
Professor
Andreas Obermair, MDVIE Senior Medical Physicist
Department of Neurology and
Director of Research Department of Radiation Oncology
Anesthesiology
Queensland Centre for Gynecological Cancer Medical College of Wisconsin
Albert Einstein College of Medicine
Herston, Brisbane, Australia Milwaukee, Wisconsin
Bronx, New York
Chair, Department of Pain and Palliative Paul J. Sabbatini, MD
Roisin OCearbhaill, MB BCh, BAO
Medicine Associate Professor of Medicine
Assistant Member
Beth Israel Medical Center Weill Cornell Medical College
Department of Gynecologic Medical Oncology
New York, New York Attending Physician
Memorial Sloan-Kettering Cancer Center
Instructor Gynecologic Medical Oncology Service
Robert Press, MD, PhD
Department of Medicine Department of Medicine
Clinical Professor
Weill Cornell Medical College Memorial Sloan-Kettering Cancer Center
Department of Medicine
Assistant Attending New York, New York
NYU School of Medicine
Gynecologic medical Oncology Chief Medical Officer Amar Safdar, MD
Memorial Sloan-Kettering Cancer Center Department of Medical Affairs Associate Professor of Medicine
New York, New York NYU Medical Center Department of Infectious Diseases and
New York, New York Immunology
Kunle Odunsi, MD, PhD
NYU School of Medicine
Professor Scott C. Purinton, MD, PhD Director, Transplant Infectious Diseases
Department of Obstetrics and Gynecology Assistant Professor
Department of Medicine
State University of New York Department of Obstetrics and Gynecology
NYU Langone Medical Center
Chairman Mercer University School of Medicine
New York, New York
Department of Gynecologic Oncology Assistant Professor
Roswell Park Cancer Institute Anderson Cancer Institute Surgical Associates Vikrant V. Sahasrabuddhe, MBBS, MPH,
Buffalo, New York Anderson Cancer Institute DrPH
Memorial University Medical Center Associate Investigator
Neeta Pandit-Taskar, MD Savannah, Georgia Division of Cancer Epidemiology and Genetics
Associate Professor
National Cancer Institute
Department of Radiology Denis Querleu, MD Rockville, Maryland
Weill Cornell Medical College Chair
Associate Attending Department of Obstetrics and Gynecology Bachir Sakr, MD
Department of Radiology McGill University Medical Oncologist
Memorial Sloan-Kettering Cancer Center Chief Women and Infants Hospital
New York, New York Department of Obstetrics and Gynecology Providence, Rhode Island
x CONTRI BUTI NG AUTHORS
T
he landscape of cancer care is changing rapidly and dramatically, with truly exciting
developments in our understanding of cancer biology and the resulting explosion in
translational research at the fore. In their preface to the third edition of Principles
and Practice of Gynecologic Oncology, published in 2000, our predecessors, the founding
editors of the PPGO textbook, William J. Hoskins, MD, Carlos A. Perez, MD, and Robert C.
Young, MD, anticipated the further growth of multidisciplinary therapy for the treatment
of gynecologic cancers, and predicted that over the next decade it will involve the active
partnership of the laboratory scientist. Now, 13 years later, as we publish the sixth edition
of PPGO, multidisciplinary approaches are at the heart of cancer care, multimodal strate-
gies offer improved clinical outcomes in a wide variety of settings and new possibilities in
patient quality of life, and targeted therapies now enable the development of truly innova-
tive approaches to individualized treatment.
For the current, sixth edition of PPGO, we have sought to create a text reflective of the
changes in the field of gynecologic oncology, and, in so doing, to continue to build on the
important contribution to the medical literature of the textbooks founding editors. To do
this most effectively, we have brought on as editor Dr. Andrew Berchuck, Chief of Gyneco-
logic Oncology and Director of Gynecologic Cancer Research at the Duke University Can-
cer Institute, a practicing oncologist and distinguished researcher who has made significant
contributions to the understanding of the molecular pathogenesis of ovarian and endome-
trial cancer. We are pleased to be able to incorporate his expertise and thoughtful editorial
contributions in the current edition.
This textbook has been designed for specialists who care for women afflicted with
gynecologic cancer, including surgeons, medical oncologists, radiation oncologists, pa-
thologists, and nurses. It will also serve as a valuable resource for residents and fellows in
training for a career in cancer care. As in past editions, we are certain that this new edition
contains the most up-to-date information available about the treatment of gynecologic
cancers. Returning readers will see changes withinincluding an attractive and effective
new four-color layoutas well as much that is familiar. The textbooks first section is now
Etiology, Prevention, and Molecular Biology and includes new chapters on Molecular
Pathogenesis of Gynecologic Cancers and Hereditary Gynecologic Cancers; Section II,
now Diagnostic and Therapeutic Modalities, features new chapters on Minimally
Invasive Surgery, Diagnostic Imaging, and Comparative Effectiveness Research in
Gynecologic Oncology. In Section III, Disease Sites, we remain committed to the mul-
tidisciplinary theme of the textbook, with chapters authored by teams consisting of a sur-
geon, a medical oncologist, a radiation oncologist, and a pathologist. The textbooks final
section, Special Management Topics, focuses on all of the auxiliary concerns so important
in the care of all cancer patients, tailored for the GYN oncology setting. As in previous edi-
tions, we have rotated approximately 30% of the authors, and all chapters have been either
completely rewritten or extensively updated, including the chapters on the three major
diseasesovarian, uterine, and cervical cancer.
With this new edition we are very pleased to be able to offer readers a dynamic online
full-color companion to the printed textbook. Viewable through a browser or as a down-
load to your tablet or smartphone, this unique digital version offers the textbook content
in a searchable, interactive format with ongoing updates that reflect new developments in
the field. Additionally, the entire text plus up to date content has been incorporatedinto
LWWOncology.com, a comprehensive database of the most authoritative content in o ncology
today, available to individuals and institutions. Readers can now use the digital v ersion of the
book in the context of clinic and conferences, and as an authoritative source of knowledge
available in real time.
xi
xii PREFACE
Finally, we wish to thank the readers for their ongoing support, and we look forward
to their feedback on the current edition. We will continue to strive to improve the content
and quality of this comprehensive textbook, and we hope that Principles and Practice of
Gynecologic Oncology, Sixth Edition will contribute to the knowledge and wisdom of all
those entrusted with the care of women afflicted with gynecologic cancer.
Richard R. Barakat, MD
Andrew Berchuck, MD
Maurie Markman, MD
Marcus E. Randall, MD
AC K N OWLE D G M E NT S
T
he editors acknowledge the contributions of numerous individuals without whom
this book would not have been possible. The talented staff of the publisher,
Lippincott Williams & Wilkins, especially Jonathan Pine, Senior Executive
Editor; and Emilie Moyer, Senior Product Manager, provided invaluable encouragement,
direction, and guidance during the creative process and in technical execution. Shailaja
Subramanian provided outstanding production services. From the Gynecology & Breast
Services Academic Office, Department of Surgery, Memorial Sloan-Kettering Cancer
Center (MSKCC), we acknowledge the invaluable contributions of editors Jennifer Grady
and Alexandra MacDonald. Their attention to detail, patience, and communication skills
were of the utmost importance throughout the publication process. MSKCC Department
of Surgery editors Carol Hoidra, George Monemvasitis, David Sewell, and Shan-san Wu
contributed their skills and expertise during the proofreading process. Our appreciation
for all their efforts cannot be adequately expressed, but we hope they know how much we
value their contributions.
xiii
C O NTE NT S
Dedicationv 11 Diagnostic Imaging 244
Contributing Authors vi Evis Sala, Yulia Lakhman, Weining Ma, Harpreet Pannu,
Preface xi Duan Li, Neeta Pandit-Taskar, and Hedvig Hricak
Acknowledgmentsxiii
12 Biologic and Physical Principles of Radiation
Oncology284
SECTION I: ETIOLOGY, PREVENTION, Beth A. Erickson, Jason Rownd, and Kevin Khater
AND MOLECULAR BIOLOGY
13 Principles of Chemotherapy in Gynecologic
1 Epidemiology of Gynecologic Cancers1 Cancer 342
Michael A. Bookman
Louise A. Brinton, Vikrant V. Sahasrabuddhe, and
Britton Trabert 14 Pharmacology and Therapeutics in Gynecologic
2 Molecular Pathogenesis of Gynecologic Cancer370
Cancers30 David S. Alberts, Hilary Calvert, Maria Lluria-Prevatt,
Paul H. Sugarbaker, and Bradley J. Monk
Andrew Berchuck, Douglas A. Levine, John H. Farley, and
Michael J. Birrer 15 Immunotherapy of Gynecologic
3 Hereditary Gynecologic Cancers 60 M
alignancies 434
Paul J. Sabbatini, Kunle Odunsi, Jacobus Pfisterer, and
Karen H. Lu, Andrew Berchuck, and Noah D. Kauff
George Coukos
4 Invasion, Metastasis, and Angiogenesis 72
16 Hormones and Human Malignancies 457
Sharon Romano-Fitzgerald, Alexandre Buckley de Meritens,
G. Larry Maxwell, Mian M. K. Shahzad, and
Angeles Alvarez Secord, and Elise C. Kohn
Laurel W. Rice
5 Development and Identification of Tumor Serum
Markers89 17 Clinical Trials Methodology and
B
iostatistics 481
Aleksandra Gentry-Maharaj, Ian Jacobs, and
Mark F. Brady, Jeffrey C. Miecznikowski, and
Usha Menon
Virginia L. Filiaci
6 Cancer Prevention Strategies 115
18 Comparative Effectiveness Research in
Mary B. Daly
G
ynecologic Oncology 501
7 Preinvasive Disease of the Lower Genital Laura J. Havrilesky, Shalini L. Kulasingam,
Tract129 Elizabeth L. Jewell, and David E. Cohn
Britt K. Erickson, Kenneth H. Kim, Mark H. Einstein, and
Warner K. Huh
SECTION III: DISEASE SITES
xiv
CONTENTS xv
1
CHAPTER
Epidemiology
of Gynecologic Cancers
Disease-oriented texts often include a chapter on epidemiology of large cohort studies focused on women, such as the Nurses
or etiology, which is considered perfunctory if the book is used Health Study and the Million Women Study, and these have
by therapists whose daily practice is rarely influenced by these provided much useful information regarding etiologic factors
considerations. This is not the case for physicians who treat for gynecologic cancers. However, these investigations, which
patients with gynecologic cancers, because these clinicians collect baseline information and then follow subjects forward
have frequent opportunities to interpret epidemiologic find- in time to capture information on incident cancers, are often
ings and make observations of etiologic importance. More- limited in terms of the exposure information that is captured.
over, public health measures based on epidemiologic findings They also are not usually useful for exploring risk factors for
influence gynecologic practice perhaps more than any other rare malignancies, and thus, we also depend on results from
clinical discipline. In particular, epidemiologic data are critical case-control investigations to clarify risks. Although these
for the prevention and early diagnosis of cervical and uterine studies more often raise concerns regarding the possible role of
cancers. selection and recall biases because of the retrospective nature
From the observation 150 years ago of the rarity of cer- of the information gathered from women with certain cancers
vical cancer in nuns to the most recent follow-up studies of and nondiseased comparison subjects, they oftentimes collect
type-specific human papillomavirus infection, determining more exposure information that can be informative in terms
the cause, natural history, and prevention of this disease has of controlling for the influence of confounding factors and as-
focused on sexual practices and suspect infectious agents. sessing interactions between risk factors (effect modification).
Screening interventions based on natural history studies have The issue of control for confounding (i.e., disentangling effects
fundamentally altered the usual presentation of this disease, of correlated variables in terms of identifying the indepen-
and as more information about preceding infectious processes dence of effects) is an important issue for both case-control
becomes available, even more radical changes in presentation and cohort studies.
and management are likely. In the studies reviewed below, various measures of risk are
The probable estrogenic cause of endometrial cancer was discussed, including relative risks (RR) from cohort studies and
proposed by etiologically oriented gynecologists decades before odds ratios (OR) from case-control studies. The RR from a co-
its demonstration by epidemiologists. Unfortunately, this did hort study represents the incidence of disease in women exposed
not prevent the largest epidemic of iatrogenic cancer in recorded to a factor compared to the incidence in unexposed women.
history (i.e., endometrial cancer caused by unopposed estrogen The OR from a case-control study is an approximation of the
therapy). The resurgent interest in menopausal hormone ther- RR determined by comparing the odds of developing the dis-
apy, effects of progestins added to this regimen, and associated ease based on an exposure compared to the odds based on lack
risk-benefit questions are certain to link the epidemiologist of the exposure. There are uncertainties with both these mea-
and the gynecologist for the foreseeable future. The iatrogenic sures, which are influenced by the prevalence of the exposure,
chemoprevention of endometrial and ovarian cancers through the incidence of the disease, the numbers of cases included in
oral contraception has similarly thrust the two disciplines to- a study, and the amount of random variability inherent in the
gether around issues ranging from basic biology to risk-benefit data-collection process. In an attempt to quantify the random
assessments. error that underlies the risk estimate, the RRs or ORs are usu-
The rich tradition of the mingling of epidemiology and gyne- ally accompanied by derived 95% confidence intervals (CI). The
cologic oncology has led to better opportunities for prevention, 95% CI means that if the data collection and analysis were rep-
screening, and gaining insights into basic mechanisms of dis- licated an infinite number of times, the CI would include the
ease than for any other subspecialty concerned with cancer. This true risk estimate 95% of the time. Significantly elevated or de-
chapter is written with the aim of clarifying how epidemiology creased risks are indicated, respectively, if the lower confidence
is an integral part of the effort to reduce the morbidity and mor- limit exceeds 1.0 or the upper confidence limit is less than 1.0.
tality from gynecologic cancers in women. Thus significance levels are comparable, although not precisely
In this chapter, we review results from a number of epide- equivalent, to p < 0.05, which is commonly used as a standard
miologic investigations, mainly observational studies, includ- level of acceptance of a risk that is interpreted as importantly
ing cohort and case-control studies. There have been a number elevated or decreased.
1
2 CHAPTER 1 EPI DEM IOLOGY OF GYN ECOLOGIC CANCERS
< 3.7 < 7.5 < 11.2 < 15.0 < 18.7
FIGURE 1.1. International incidence for uterine cancer (per 100,000 woman years) age-standardized to the world population, 2008.
Source: Ferlay J, Shin JR, Bray F, et al. GLOBOCON 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research
on Cancer, 2010; Available from: http://globocan.iarc.fr, acced on 23 March 2012.
CHAPTER 1 EPI DEM IOLOGY OF GYN ECOLOGIC CANCERS 3
100 100
10
Whites
Blacks
1
2529
3034
3539
4044
4549
5054
5559
6064
6569
7074
7579
8084
85+
Age in years
FIGURE 1.2. Age-specific uterine cancer incidence rates by race, U.S. SEER-
17, 20002008. 1
19731977
19781982
19831987
19881992
19931997
19982002
20032008
affect risk by causing structural or biochemical changes that al-
ter the sensitivity of the endometrium to circulating hormones.
An additional area of interest is the effect of exposure to Year of diagnosis/death
fertility drugs, given several studies that have shown that users
of ovulation-inducing drugs are at an increased risk of develop- FIGURE 1.3. Uterine cancer incidence and mortality trends among US
ing uterine cancers (13,14). Although this observation requires women, SEER-17, 19732008.
replication, it is of interest given the structural similarity of
clomiphene and tamoxifen, which has been extensively linked
with the occurrence of uterine cancers (discussed in more detail
below). atwofold risk associated with natural menopause after the age
The relationship of risk to breast-feeding remains contro- of 52 years compared to before the age of 49 years (16). It has
versial. Although some studies suggest that prolonged lactation been hypothesized that the effect of late age at menopause on risk
may offer protection (15), this has not been noted in all inves- may reflect prolonged exposure of the uterus to estrogen stimu-
tigations (11). lation in the presence of anovulatory (progesterone-deficient)
cycles. The interrelationships among menstrual factors, age, and
weight are complex, and the biologic mechanisms of these vari-
ables operating in the pathogenesis of uterine cancer are subject
Menstrual Risk Factors to substantial speculation.
Early ages at menarche have generally been related to an elevated
risk for uterine cancer in many studies. A recent report from a
large multicenter prospective cohort reported a 30% reduction Exogenous Hormones
in risk with late age at menarche and an inverse dose-response
Oral Contraceptives
trend (11). Stronger effects of ages at menarche may prevail for
younger women (11). The extent to which these relationships re- The use of combination oral contraceptives may reduce the risk
flect increased exposure to ovarian hormones or other correlates of uterine cancer by 40% to 60%, and long-term use may de-
of early menarche (e.g., increased body weight) is unresolved. crease the risk further (11,17). One meta-analysis noted that the
Most studies have indicated that age at menopause is directly decreased risk persisted more than 20 years after ceasing use
related to the risk of developing uterine cancer. Approximately (18). In several studies, the greatest reduction in risk was as-
70% of all women diagnosed with uterine cancer are postmeno- sociated with high-progestin-dose pills, although recent findings
pausal. Most studies support the estimate that there is about indicate that this may be true only among obese women (19).
4 CHAPTER 1 EPI DEM IOLOGY OF GYN ECOLOGIC CANCERS
Menopausal Hormones the range of 15 g or greater. The risk for more high-risk endome-
trial cancer histologies may be especially elevated (33).
It is well established that unopposed estrogens are associated
with a 2- to 12-fold elevation in uterine cancer risk (20). In most
investigations, the increased risk does not become apparent until
the drugs have been used for at least 2 to 3 years, and longer use Anthropometry and Physical Activity
of estrogens is generally associated with higher risk. The highest Obesity
RRs have been observed after 10 years of use (up to 20-fold),
although it is unclear whether risk increases after 15years. Most Obesity is a well-recognized risk factor for uterine cancer and
but not all studies have found that cessation of use is associated may account for up to 25% of cases (34). Very heavy women
with a relatively rapid decrease in risk, although a number of appear to have exceptionally high risks (29). Although studies
studies have found significantly elevated risks to persist 10 or have demonstrated significant positive trends of uterine cancer
more years after last usage. Although higher doses of estrogen with both weight and various measures of obesity, including
are associated with the greatest elevations in risk, one study BMI (weight / height2), height has not been consistently associ-
showed that even 0.3 mg of unopposed equine estrogen can re- ated with risk. Obesity appears to affect both premenopausal
sult in a significant increase in risk (21). and postmenopausal uterine cancer.
This large body of evidence linking estrogen use to increases Although initial studies hypothesized that adolescent and
in the risk of uterine cancers has led to estrogens being pre- long-standing obesity may be more important than adult
scribed in conjunction with progestins among women who have weight, recent studies support that contemporary weight and
not had a hysterectomy. Progesterone has been shown to cause weight gain during adulthood are the most important predictors
regression of endometrial hyperplasia, the presumed precur- of uterine cancer risk (29,35). Relationships with obesity may
sor of uterine cancers (22). The large Womens Health Initia- be stronger for postmenopausal disease and among women not
tive (WHI) clinical trial showed that women assigned to 0.625 exposed to exogenous hormones (29,36).
mg of conjugated equine estrogen plus 2.5 mg of medroxypro- Recent interest has focused on determining whether the dis-
gesterone acetate daily had a lower hazard ratio (0.81, 95% tribution of body fat predicts uterine cancer risk. A number
CI:0.481.36) than those assigned to placebo, but this risk was of studies have shown that central obesity may have an effect
based on relatively small numbers of endometrial cancers and independent of overall body size (29), although not all studies
short follow-up (23). Similar observational results derive from confirm this relationship.
the Million Women Study in the United Kingdom, where usage
of continuous combined therapy resulted in a relative risk of Physical Activity
0.71 (95% CI: 0.560.90) (20).
Although a number of studies indicate that the excess risk Recent investigations have focused on the role of physical activ-
of uterine cancer associated with estrogens can be signifi- ity in the etiology of uterine cancer. A potential relationship is
cantly reduced if progestins are given for at least 10 days each biologically appealing given that physical activity can result in
month (24,25), some studies have shown that subjects pre- changes in the menstrual cycle, body fat distribution, and lev-
scribed progestins for less than 10 days per month (sequential els of endogenous hormones. Accumulating evidence suggests
users) experience some increase in risk, with only a slight re- a protective effect of physical activity on uterine cancer risk
duction compared to estrogen-only users (26,27). The sharp independent of relationships with body weight. A recent meta-
contrast between the effects of <10 and 10 days of proges- analysis of prospective studies demonstrated a decreased risk of
tin use has led to the suggestion that the extent of uterine uterine cancer with moderate-to-vigorous physical activity in-
sloughing or of terminal differentiation at the completion dependent of relationships with known potential confounders,
of the progestin phase may play a critical role in determining namely obesity, menopausal hormone therapy use, and parity
risk. It remains questionable whether 10 days of progestin (37). Generally, studies that have evaluated occupational and
administration per month is sufficient for complete protec- recreational physical activity have reported decreased risks.
tion, particularly for long-term users (24). Few studies have Inadequate physical activity has been evaluated as a potential
had large numbers of long-term sequential users, but there is risk factor for uterine cancer; specifically sedentary behavior, of-
some evidence that this pattern of usage may result in some ten measured as sitting time, has been associated with increased
persistence of risk (28). risk of uterine cancer (37,38). It is still not clear, however, from
Studies have shown that the effects of hormonal therapy the existing studies if the association is independent of moder-
(both unopposed estrogens as well as combination therapy) ate-to-vigorous physical activity or body weight (37). Indirect
may vary by user characteristics, most notably by a womans support for a link between sedentary behavior and uterine can-
body mass. A number of studies have shown that the adverse ef- cer risk comes from occupational studies, in which the increased
fects of unopposed estrogens were greatest in nonobese women risk among women with sedentary jobs is very clear.
and that the beneficial effects of combined therapy were greatest
in obese women (20,28,29).
Most data regarding effects of hormones derive from stud- Cigarette Smoking
ies on users of pills. Unresolved is whether the use of estrogen A reduced risk of uterine cancer among smokers has been re-
patches, creams, or injections can affect risk; given relationships ported, with current smokers having approximately half the risk
of risk with even low-dose estrogens, it is plausible that these of nonsmokers (3941). Cigarette smoking has been linked to
regimens may confer some increase in risk. an earlier age at natural menopause in some populations and to
reduced levels of endogenous estrogens. Reduced risks may be
more pronounced in parous or obese patients (42).
Tamoxifen
At present, biologic mechanisms underlying the inverse re-
A number of clinical trials and one population-based case-con- lationship of smoking to uterine cancer risk remain elusive.
trol study have demonstrated an increased risk of uterine cancer Alterations in endogenous hormones or metabolites are likely
among tamoxifen-treated breast cancer patients (30,32). This involved. In one report (43), the inverse association of smoking
is consistent with tamoxifens estrogenic effects on the endo- with uterine cancer risk appeared to be more strongly related to
metrium. Elevated risks have been observed primarily among higher serum androstenedione levels than to lower serum estro-
women receiving high cumulative doses of therapy, usually in gen levels, except perhaps among overweight women.
CHAPTER 1 EPI DEM IOLOGY OF GYN ECOLOGIC CANCERS 5
certain environmental agents may affect risk. Given the well- testosterone levels (27,102,104). It has been hypothesized that
recognized influence of hormones on the disease, there has been this may reflect a role of chronic anovulation and progesterone
particular concern about a potential role for certain endocrine deficiency in premenopausal women, whereas after menopause,
disruptors, including dichlorodiphenyltrichloroethane (DDT). aromatase and local conversion of estrone from androstenedi-
Several studies have addressed this issue by comparing dichlo- one may be involved (105).
rodiphenyldichloroethylene (DDE) levels (the active metabolite Obesity, which is hypothesized to reflect elevated estrogen
of DDT) in the sera of cases and controls, finding no significant levels, seems to represent a key risk factor for both uterine car-
differences (8890). Several studies have focused on effects of cinoma and endometrial hyperplasia, but the mechanisms medi-
electromagnetic radiation as a risk factor, but findings regarding ating this are unclear. A case-control analysis of serum estrogen
electric blanket or mattress covers have produced mixed results levels (102) reported that the risk associated with obesity was
(91,92). not entirely mediated by estrogens, especially among premeno-
Data for occupational exposures are limited. Elevated endo- pausal women, whereas a cohort study of postmenopausal
metrial cancer rates have been found among teachers in Califor- women showed that elevated serum estrogen levels appeared
nia (93) and individuals exposed to animal dust and sedentary to account for the majority of the risk associated with obesity
work in Finland (94). The extent to which these relationships (106). A potential role for insulin and insulin-like growth (IGF)
reflect the influence of social class is unknown. factors has been suggested, although studies generally have not
found support for a role of either c-peptide (107) or IGF (108)
levels.
Etiologic Heterogeneity
In 1983, Bokhman (95) proposed that endometrial cancers
could be divided into two broad types: Type I, the predomi- Conclusions
nant form, which has a hormonally driven etiology, and Type A unified theory of how risk factors for uterine cancer might
II, which is unrelated to typical endometrial cancer risk fac- operate through one common hormonal pathway has been
tors, not associated with endometrial hyperplasia, and gen- suggested. Estrogen promotes proliferation in the endome-
erally clinically aggressive. Subsequent clinicopathologic trium, which is opposed by progesterone. Therefore, expo-
studies led to the view that most Type I cancers correspond sure to estrogen, particularly bioavailable estrogen that is
histologically to endometrioid adenocarcinomas, whereas weakly bound or unbound to plasma protein, is viewed as
Type II cancers encompass most nonendometrioid histologic a critical carcinogen. Functional ovarian tumors, PCOS, late
types, with serous carcinoma representing the prototype (96). menopause, and administration of exogenous estrogens and
Differences in molecular markers according to histology sup- sequential oral contraceptives and menopausal hormone ther-
port the notion of at least two broad classes of endometrial apies produce higher levels of estrogen exposure without the
carcinoma (97,98). antiproliferative effects of progesterone. Obesity could also
Although it is generally now embraced that there are at least contribute in a variety of ways (109). Adipose tissue is the pri-
two main biological types of endometrial cancer (and possibly mary site for conversion of androstenedione to estrone, which
more), most epidemiologic studies have assessed risk factors is the primary source for estrogen after menopause. Obesity
for endometrial cancer overallwhich essentially represent the is associated with higher conversion rates and/or elevated
risks for the predominant Type I tumors, especially in largely plasma levels of estrogen in postmenopausal women. In ad-
Caucasian populations. Registry data consistently have shown dition, obesity is related to lower levels of SHBG and more
that Type II cancers occur at older ages and more often affect frequent anovulatory menstrual cycles (i.e., less progesterone).
non-White women compared with Type I tumors. Some epide- Vegetarianism is associated with lower plasma estrogen levels,
miologic investigations have found that Type II cancers are less presumably on the basis of the relationship of diet composi-
strongly linked to classic Type I risk factors, such as obesity, tion to estrogen metabolism. The beneficial effects of combi-
nulliparity, and hormones (99,100), but these have involved nation oral contraceptives and continuous progestins added
relatively limited numbers of nonendometrioid cancers, incom- to menopausal hormone therapy presumably operate through
plete collection of relevant risk factors, and unstandardized the antiestrogenic effects of progesterone. The peculiar age in-
pathologic classification of tumors. cidence patterns for uterine cancer (i.e., extremely rare under
age 45 years, followed by a rapid and progressive rise from
ages 45 to 60 years) could also reflect the waning influenceof
Biologic Mechanisms Underlying Risk progesterone. Nulliparity, hypertension, diabetes, the absence
of smoking, and race may yet be added to the unifying scheme
Factor Associations as knowledge of endocrinologic mechanisms in endometrial
Many of the identified risk factors are thought to operate tissue increases.
through alterations in various endogenous hormones. The Although there are several identified risk factors for uterine
majority of studies have found increased risks associated cancer (Table 1.1), important gaps in knowledge currently limit
with higher levels of circulating estrogens among postmeno- a full understanding of the proposed carcinogenic process. We
pausal women that persisted after adjustment for the effects need to understand when in a womans life obesity matters most
of body mass (27,101). Although based on relatively small and how risk is influenced by weight loss; whether the number
numbers, several studies have shown that estrogens appear of adipocytes, their fat composition, or other factors determine
less predictive of premenopausal disease (27,102), suggesting peripheral conversion of androstenedione; and the precise hor-
that anovulation or progesterone deficiency might be more monal mechanisms associated with vegetarianism. Perhaps the
influential. most important gap is in understanding the basic mechanism
Less well investigated is whether other endogenous hor- of estrogen carcinogenesis. It is unclear whether estrogens are
mones are related to uterine cancer risk. Key and Pike (103) complete carcinogens, classic promoters that affect initiated
suggested that uterine carcinogenesis is dependent on uterine cells, or growth stimulants for abnormal cells or carcinogens
mitosis, which is increased by estrogens and reduced by pro- that act on vulnerable genetic material. The epidemiologic data
gesterone, but risk associated with progesterone levels has not are consistent with estrogens acting at a relatively late stage of
been well explored. Several studies have shown positive asso- carcinogenesis, emphasizing the need for further investigations
ciations of uterine cancer risk with serum androstenedione and to identify tumor initiators.
CHAPTER 1 EPI DEM IOLOGY OF GYN ECOLOGIC CANCERS 7
19781982
19831987
19881992
19931997
19982002
20032008
a
Relative risks depend on the study and referent group employed.
Year of diagnosis/death
< 3.7 < 4.9 < 6.4 < 8.5 < 14.6
FIGURE 1.6. International incidence rates for ovarian cancer (per 100,000 woman years) age-standardized to the world population, 2008.
Source: Ferlay J, Shin JR, Bray F, et al. GLOBOCON 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research
on Cancer, 2010; Available from: http://globocan.iarc.fr, acced on 23 March 2012.
CHAPTER 1 EPI DEM IOLOGY OF GYN ECOLOGIC CANCERS 9
women who had not undergone surgery. A subsequent meta- (145). One study, however, found some suggestion that free tes-
analysis reported a 37% reduced risk of ovarian cancer with tosterone might play a role in early onset ovarian cancers (142).
physical activity levels on ovarian cancer risk, although results Fruits and Vegetables and
are inconclusive, with some studies showing inverse relations, Micronutrient Intake
others showing positive associations, and still others noting no
association. The most recent meta-analysis reported a 19% risk Although some studies have suggested that ovarian cancer risk
reduction associated with recreational activity, although the as- might be reduced by higher consumption of fruits and vegetables
sociation was not statistically significant when only cohort in- (177,185) or fiber (186,187), while others, including a pooling
vestigations were considered (164). project of 12 cohort studies, fail to support these relationships
(188). Some studies showed inverse associations with particular
nutrients, such as vitamins A, C, E, beta-carotene, folate, or me-
thionine (189192), although results have not been consistent
Cigarette Smoking across studies. A meta-analysis evaluating vitamin D and ovar-
In general, cigarette smoking is not considered a major risk fac- ian cancer risk reported no association (193). Further clarifica-
tor for ovarian cancer. However, a number of studies have found tion of effects may require evaluating associations according to
evidence that there may be an increased risk of mucinous tumors other risk factors and within histologic subgroups.
associated with smoking (172). In a systematic review, smoking
was found to lead to a significant doubling in risk for muci-
nous tumors but not an increased risk for endometrioid or clear Alcohol and Caffeine
cell tumors (173). The risk of mucinous cancers increased with A number of studies have examined the effects on ovarian can-
amount smoked but returned to that of never smokers within cer risk related to alcohol consumption. Most have not found
20 to 30 years of stopping smoking. Fewer studies have evalu- any convincing relationships, including a pooled analysis of
ated effects of passive smoking on ovarian cancer risk, with no 10cohort studies (194).
consensus as to whether this might alter risk or have histologic Caffeine and ovarian cancer risk has been evaluated in stud-
specificity (174,175). ies of coffee consumption, tea consumption, and both com-
bined. Coffee consumption was linked to an elevated risk of
ovarian cancer in several early studies and a recent cohort study
(195); however, additional studies have not replicated the as-
Dietary Factors sociation (196,197). One study on coffee and tea consumption
Ecologic studies of dietary factors and ovarian cancer risk led suggested an inverse association with coffee consumption, but
to the hypothesis that high intake of fat, milk, and eggs may be concluded that this was not due to caffeine intake since no rela-
related to an increased risk of ovarian cancer while high intake tionship was observed with tea consumption (198). A systematic
of fruits and vegetables may be related to a decreased risk (44). review of tea consumption reported no association with ovar-
However, the majority of the observational studies targeting ian cancer risk (199); however, a subsequent meta-analysis re-
food classes, lactose and dairy foods, fats, vitamins/nutrients, ported reduced ovarian cancer risk with green tea consumption
fiber, fruits, and vegetables, provide conflicting results. and no association with black tea consumption (64). Finally, a
cohort study reported a modest inverse association of caffeine
consumption with ovarian cancer; however, this association was
Lactose Consumption
specific to nonhormone users (200). Overall, there are no consis-
Findings linking higher consumption of yogurt, cottage cheese, tent patterns between caffeine consumption and ovarian cancer;
and other lactose-rich dairy products with an increased risk it may be that more detailed information on source of caffeine,
of ovarian cancer (176) were viewed with interest given that frequency, and duration need to be evaluated.
galactose-related enzymes can influence gonadotropin levels,
which are hypothesized to be crucial ovarian cancer risk de-
terminants. The majority of subsequent studies failed to show
increases in risk with lactose consumption or galactose me- Host Factors
tabolism (177;178), although a few studies have provided some A family history of ovarian cancer is the strongest risk factor
support for the hypothesis (179,180). Results from the Nurses identified to date. Which family member was affected is less
Health Study suggest that further attention may be warranted important than the total number of affected relatives or their
regarding effects for serous tumors (181). age at diagnosis. Women with two or more affected relatives
or whose relative was diagnosed before 50 years of age expe-
rience the highest risks (201). Approximately 5% to 10% of
Fat Intake ovarian cancer patients have a first-degree relative with ovarian
The Womens Health Initiative Dietary Modification Random- cancer (202). Family histories of breast and colon cancer are
ized Control Trial evaluated the effects of a low-fat dietary also associated with increased ovarian cancer risk but slightly
pattern on chronic disease incidence, and reported a decreased less strongly than a family history of ovarian cancer.
risk of ovarian cancer associated with the intervention (a 20% Inherited mutations in two autosomal dominant genes
reduction in total fat intake) (48). Although some case-control BRCA1 and BRCA2are strongly linked to familial ovarian
studies have reported higher risks of ovarian cancer associated cancer (and breast and other cancers) (203). Whereas the life-
with intake of fatty foods (e.g., butter and meats) as well as time probability of developing ovarian cancer in most women is
types of fat, the observational data are not entirely consistent. 2%, the probabilities in women with a family history or women
Cohort studies have also been inconsistent, with earlier stud- with a BRCA1/2 mutation are 9.4% (204) and 15% to 40%
ies reporting no relationship with dietary fat consumption and (205), respectively. Despite these increases, BRCA1/2 mutations
recent studies reporting a small, albeit increased, risk with to- explain less than one third of the elevated risk in women with
tal fat, fat from animal sources, polyunsaturated fats, and trans familial ovarian cancer (201). Lynch syndrome, or hereditary
fat. A meta-analysis of 12 cohort studies found no overall as- non-polyposis colorectal cancer (HNPCC), is related to muta-
sociation with fat, cholesterol, or egg intake, but suggested that tions in mismatch repair genes and reported to be associated
very high levels of saturated fat intake may increase risk (182). with a 12% lifetime risk of ovarian cancer (206). Disease het-
Additional meta-analyses reported no association between red erogeneity is influenced by high-penetrance genetic variation,
meat and inconsistent results for high intake of processed meat whereby mutations in BRCA1/2 lead to the development of se-
(183,184). rous cancers and mutations of DNA mismatch repair genes are
CHAPTER 1 EPI DEM IOLOGY OF GYN ECOLOGIC CANCERS 11
more frequently associated with mucinous and endometrioid arise in the ovary but rather from transplanted endometriotic
tumors (207). tissue. Tubal ligation also appears to be more strongly inversely
Talc Conclusions
Like asbestos, over-the-counter talc such as asbestos, is a silicate Much of the clinical and epidemiologic evidence concerning
that has been studied in relation to ovarian cancer risk. The pub- risk factors for ovarian cancer implicates ovulatory activity
lished case-control studies generally report positive associations (Table1.2). Conditions associated with reduced ovulation, for
between ovarian cancer and perineal talc exposure; summary example, pregnancy and oral contraceptives, consistently reduce
estimates suggest a 30% increase in risk (208,209). However, a risk. Combining these and other menstrual factors into single
lack of consistent statistical significance and inconsistent asso- ovulatory age or lifetime ovulatory cycles indexes has gen-
ciations with different patterns of talc use raise questions about erally produced the expected associations with ovarian cancer
the validity of this association. risk; that is, older ovulatory ages (224) or higher cycle counts
(225) increase risk. However, the misclassification inherent in
these indexes is sufficient to generate different risk estimates
(226), and the magnitude of risk reduction for short-term oral
Environmental and Occupational contraceptive use or a single pregnancy exceeds the propor-
Risk Factors tional decrease in ovulatory cycles that would be expected to be
associated with these exposures.
Certain occupations came under scrutiny when studies linked
hair dyes and triazine herbicides to ovarian cancer (210,211).
Record linkage studies in Finland (212), Norway (213), Swe-
Table 1.2 Risk Factors for Ovarian Cancer
den (214), Canada (215), and the U.S. (93,216) suggested a pat-
tern of increased risks among certain professions (e.g.,teachers, Factors Influencing Risk Estimated Relative Riska
health care workers) or with particular occupational expo-
sures (e.g., solvents, asbestos). It was recently concluded in a Demographic factors
Monographs Working Group of the International Agency for Older age 3.0
Research on Cancer (IARC) that asbestos exposure is associ-
ated with ovarian cancer; a subsequent meta-analysis of occu- Residency in North America, Northern 2.05.0
pational cohorts reported increased ovarian cancer mortality Europe
among women occupationally exposed to asbestos (217). Until Higher levels of education or income 1.52.0
additional data address the potential for inconsistent or chance
findings and the challenge of finding large populations with suf- White ethnicity 1.5
ficient data on other potential confounding variables, occupa- Exposures that increase risk
tional exposures beyond asbestos will likely not be considered
major risk factors for ovarian cancer (218). Nulligravity 2.03.0
History of infertility 2.05.0
Early age at menarche 1.5
Etiologic Heterogeneity
Late age at natural menopause 1.52.0
A unified ovarian cancer progression model has not yet been
established, and growing evidence demonstrates that subtypes Long-term use of menopausal estrogens 3.05.0
of ovarian carcinomas have different molecular, pathological, Perineal talc exposure 1.52.0
and clinical characteristics, suggesting that there may be several
distinct disease entities (219). Specifically, ovarian cancer sub- Female relative with ovarian cancer 3.04.0
types have been described to molecularly and morphologically Endometriosis 1.52.0
resemble cancers of other sites: fallopian tube (serous), endo-
metrium (endometrioid), gastrointestinal tract (mucinous) and Pelvic Inflammatory Disease 1.52.0
unspecified glycogenated epithelium (clear cell) (220). Exposures that decrease risk
As previously discussed, some risk factors have been shown
to have distinctive effects for certain subtypes of ovarian cancer, History of hysterectomy or tubal 0.50.7
but there have been inconsistent findingsmost likely reflect- ligation
ing small numbers in the studies of some of the rarer subtypes. Use of oral contraceptives 0.30.5
Probably one of the more consistent findings is the propensity
of endometriosis to predispose to clear cell and endometrioid
tumors (149151), suggesting that a subset of disease does not a
Relative risks depend on the study and referent group employed.
12 CHAPTER 1 EPI DEM IOLOGY OF GYN ECOLOGIC CANCERS
The putative mechanisms behind ovulatory inhibition and reproductive or lifestyle factors that are consistently associated
the risk associated with increased ovulation (227) raise addi- with other reproductive cancerssmoking, obesity, menopausal
tional questions. An early report suggested, based on the associ- hormone therapyhave been published with such diversity that
ations with parity and infertility, that an unidentified endocrine traditional attempts to summarize quantitatively the divergent
abnormality predisposed women to relative or absolute infer- data likely will not prove to be useful. Although it is tempt-
tility and ovarian cancer. The protection associated with oral ing to attribute the differences to histology-specific associations,
contraceptives seems unlikely to fit this hypothesis unless, in such hypotheses will require substantially more epidemiologic,
some improbable manner, their use induces an endocrine milieu clinical, genetic, and transitional data before their acceptance is
similar to that underlying fertility. certain.
A second popular unifying hypothesis is that ovarian cancer The highly penetrant genes account for only a small propor-
is the result of accumulated exposure to circulating pituitary tion (10%) of women who develop ovarian cancer, but a better
gonadotropins (228). Although this is consistent with the par- understanding of the mechanisms behind those risks could in-
ity, menopause, and oral contraceptive associations, a study that troduce immediate benefits for high-risk women. A clear picture
directly measured gonadotropin levels failed to find a relation- has emerged for some protective factors, such as oral contracep-
ship with subsequent development of ovarian cancer (141). This tives and parity, but risk associated with other important pub-
theory also fails to account for the risks associated with clini- lic health issues, such as smoking, obesity, and physical activity,
cal infertility, and it predicts that menopausal hormone therapy remains uncertain. Continued attempts to account for the dif-
would decrease risk, because both exposures are associated with ferences between studies should help delineate the spurious as-
reduced gonadotropin levels. sociations from the etiologically relevant risk factors. Doing so
A third explanation points to a biologic effect of ovulation should help identify targets for improving detection, treatment,
on ovarian surface epithelium. Ovulation prompts a cascade and prevention of this deadly tumor.
of epithelial events, including minor trauma, increased local
concentrations of estrogen-rich follicular fluid, and increased
epithelial proliferation. Such proliferation, particularly near
the point of ovulation, can recruit inclusions into the ovarian CERVICAL CANCER
parenchyma. Some or all of these incessant ovulation events
may lie on the causal path to ovarian cancer (229,230). This is Chronic persistent infection with carcinogenic genotypes of sex-
consistent with most of the endocrine-related risk factors except ually transmitted human papillomavirus (HPV) is the causative
for the risks associated with clinical infertility. agent of virtually all cases of cervical cancer (231). Of the more
Although it has been hypothesized that epithelial inclusion than 150 genotypes of HPV, several dozen can infect the ano-
cysts give rise to ovarian tumors, cancer precursors of ovarian genital epithelium and more than 15 (including HPV 16, 18, 26,
surface epithelium remain unclear and progress in understand- 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, 82) can cause
ing ovarian carcinogenesis, as previously mentioned, is partly anogenital cancer. Individual genotypes differ greatly in carci-
limited by this lack of clarity on the tissue of origin of ovarian nogenic risk, and HPV16 is by far the most carcinogenic type,
epithelial carcinomas. Nearly all other epithelial gynecologic accounting for half of cervical cancer cases globally (231,232).
cancers arise via a sequence of events whereby the normal ep- Reflective of the necessary, but not sufficient role of HPV in
ithelium undergoes conversion to a precursor lesion that can the causation of cervical cancer, several other etiologic cofactors
then become an invasive neoplasia. Cervical intraepithelial neo- are involved. The remarkable body of evidence developed over
plasia, the precursor of cervical cancer, is probably the most the past three decades in the understanding of HPV epidemiol-
well-known example. More recently, increasing evidence indi- ogy has provided transformative clinical applications aimed at
cates that at least a subset of high-grade serous ovarian cancers cervical cancer prevention and control. The pathogenesis, diag-
arise from high-grade intraepithelial serous carcinomas in the nosis, and prevention aspects of cervical cancer are detailed in
fallopian tube fimbria and spread to the ovary (220). This could Chapter 7. The current chapter will concentrate mainly on the
help explain the inconsistent reduced risks associated with tubal descriptive epidemiology of invasive cervical cancer, the natural
ligation and hysterectomy, given that the fallopian tubes would history of HPV infection, and the broad relationships with ma-
be removed only in a subset of these procedures. jor etiologic risk factors.
No single theory adequately incorporates the available data.
A unifying hypothesis may lie in a combination of ovulation,
hormones, and local effects. Additional factors, such as ge- Demographic Patterns:
netic alterations; androgens, progestagens, and other hormones
(227); inflammation (128); and endometriosis (152), also ap- Global and United States
pear to be important. According to the latest global data compiled by the IARC, cervi-
Each hypothesis identifies testable possibilities. Discrimi- cal cancer is the third most common cancer (after breast and
nating between the roles of voluntary versus involuntary in- colorectal cancers) among women worldwide (233,234). It is
fertility could identify the mechanisms underlying the role of the first or the second most common (after breast cancer) in
parity. Characterizing the specific reproductive abnormalities less-developed countries. There were more than 529,000 inci-
associated with clinical infertility could reveal new biologic dent cases estimated in 2008 and a 5-year prevalence of more
mechanisms involved in ovarian carcinogenesis. Exploring than 1.5 million cases (233). Cervical cancer accounted for ap-
the interactive contributions of the hormones along the hypo- proximately 275,000 deaths worldwide in 2008, or just under
thalamicpituitarygonadal axis could explain how specific one tenth of the total number of female cancer deaths (233). The
hormones seem to influence risk at different time periods. In cancer burden (incidence and mortality) is disproportionately
addition, verifying that inflammation or related conditions and high (greater than 85%) in the developing world.
pathways play an etiologic role in ovarian carcinogenesis could The incidence rate per 100,000 women-years for invasive
open new lines of inquiry. cervical cancer in various geographic areas is highly variable,
Ovarian cancer epidemiology presents both simple and com- reflective of differences in HPV infection and access to screen-
plex patterns. Rates have slowly declined over the last 40 years, ing services (234) (Figs. 1.7 and 1.8). The highest age-standard-
and virtually all studies show consistent associations with some ized rates were reported from sub-Saharan Africa (31.7 per
exposures, such as oral contraceptives, parity, and family history. 100,000), with some countries (Guinea, Zambia, Comoros,
But where some uncertainty exists, it is substantial. Forexample, Tanzania, Malawi, Mozambique, and Swaziland) having rates
CHAPTER 1 EPI DEM IOLOGY OF GYN ECOLOGIC CANCERS 13
FIGURE 1.7. Global incidence of cervical cancer. Geographic distribution of the world age-standardized incidence rate of cervical
cancer, by country, estimated for 2008 (per 100,000 women/year). The counts in parentheses in the legend correspond to the number of
countries in each ASIR range.
Source: Data from Arbyn M, Castellsague X, de Sanjose S, et al. Worldwide burden of cervical cancer in 2008. Ann Oncol. 2011, with permission.
higher than 50 per 100,000. Other regions of the developing multiparity appears to be a cofactor for progression of HPV
world, including South Central Asia (24.6), Latin America and infection to cervical neoplasia. In the latter half of the last cen-
the Caribbean (23.5), and the Pacific Islands (23.7), also have tury, effective screening contributed to a further reduction in
high burdens. The case burden of disease as reflected by annual cancer incidence and mortality, particularly among women aged
new incident cases and deaths due to cervical cancer is high- between 30 and 74 years, because of targeting of this age group
est in India (>134,000 cases and >72,000 deaths), followed in many countries (Fig. 1.10).
by China, Brazil, Bangladesh, and Nigeria (233). An analysis In the U.S. and many other developed nations, rates of squa-
of population-based surveys from 57 representative countries mous cell carcinomas, accounting for approximately 80% of
has indicated that the coverage of cervical cancer screening in invasive cervical cancers, have declined steadily since the in-
developing countries is on average 19%, compared to 63% in troduction of Pap smear screening, while adenocarcinomas
developed countries, and there is a wide variation in coverage (accounting for approximately 15%) have not (240,241). In
levels within developing countries (235) (Fig 1.8). fact, rates of cervical adenocarcinomas have risen in the past
An examination of age-specific cervical cancer incidence, in two to three decades in various countries, including the U.S.,
countries prior to introduction of screening has demonstrated relative to both rates and absolute numbers of squamous cell
that the median age of cervical cancer diagnosis worldwide is carcinomas.
between 40 and 60 years (mean ~50 years). Rates begin to in- The 5-year survival rate for cervical cancer is 67.9% (238),
crease around age 25, with an unusually early plateau or peak with survival being highly dependent on stage at diagnosis.
starting at age 40 to 50 (236). Incidence rates increase with age, Younger women and White women are more likely than older
and the age structure reflects that cervical cancers originate from women and Black and Hispanic women, respectively, to be di-
HPV infections transmitted mainly in late adolescence and early agnosed with localized cancer, which carries a good prognosis.
adulthood.
It is reported that 12,710 women were diagnosed with
and 4,290 died from cervical cancer during 2011 in the U.S.
(237). The overall age-adjusted incidence rates for invasive cer- Human Papillomavirus
vical cancer based on SEER data suggest an incidence rate of For more than a century, epidemiologic studies have suggested
8.1 per 100,000 women for the period 2004 to 2008 (238). an association between sexual activity and cervical cancer, but
Regional differences in incidence, with excesses particularly proof that HPV is the sexually transmitted agent responsible
in underserved regions in the Southeastern and Southwestern for this association was not achieved until sensitive methods for
U.S.are apparent (239). Substantial racial/ethnic differences in detecting HPV DNA were developed. The recognition of the key
incidence rates persist. Compared with Whites and Asian and etiologic role of HPV infection has profoundly altered the epi-
Pacific Islanders, incidence rates were higher among Black, demiologic study of cervical cancer. The epidemiologic associa-
American Indian and Alaska Native, and Hispanic women tion between HPV infection and cervical cancer fulfills all of the
(239) (Fig1.9). established epidemiologic criteria for causality. As a result, HPV
Cervical cancer rates began to fall during the early twenti- is now accepted to be the central, necessary causal factor for
eth century, even before the advent of cytologic screening. Re- virtually all cases of cervical cancer in the world (231,242). It is
duced parity may have contributed to this pattern, given that increasingly clear which previously established epidemiologic
14 CHAPTER 1 EPI DEM IOLOGY OF GYN ECOLOGIC CANCERS
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
Latvia
Luxembourg
Sweden
Germany
Czech Republic
Austria
Finland
France
Denmark
Ukraine
Belgium
Hungary
Croatia
Estonia
Russia
Kazakhstan
Israel
Uruguay
Italy
Bosnia
Portugal
Australia
UK
Spain
Brazil
Dominican Republic
Netherlands
Ireland
Mexico
Paraguay
Vietnam
Mauritius
China
Georgia
UAE
Tunisia
Malaysia
Cote d'lvoire
Guatemala
Morocco
South Africa
Comoros
Myanmar
Zimbabwe
Phillipines
Burkina Faso
India
Chad
Ghana
Kenya
Laos
Nepal
Mauritania
Zambia
Ethiopia
Bangladesh
Malawi
40 40
35 35
30 30
Rate per 100,000
20 20
15 15
10 10
5 5
0 0
75
80
85
90
95
00
05
08
<1
4
9
15 14
20 19
25 24
30 29
35 34
40 39
45 44
50 49
55 54
60 59
65 64
70 69
75 74
80 79
4
+
1
5
8
85
19
19
19
19
19
20
20
20
10
Transient infection HPV viral persistence FIGURE 1.11. An epidemiologic model of the natural
history of cervical carcinogenesis. The major steps in
cervical carcinogenesis can be broadly categorized in the
following stages: (I) exposure/acquisition of new human
papillomavirus (HPV) infection that may cause transient
cytological changes, a majority of which clear spontaneously;
(II) persistence of few carcinogenic HPV infections and
progression to precancerous lesions (cervical intraepithelial
neoplasia 3 [CIN3]); and (III) development of invasion.
The pictures in the top row show cytological changes and
those in the bottom row show corresponding colposcopic
impressions of the various stages of the natural history of
cervical carcinogenesis.
Source: From Schiffman M, Castle PE, Jeronimo J, et al. Human papillomavirus and
cervical cancer. Lancet. 2007, with permission.
in samples obtained from infected women) in predicting per- The immune response to HPV is an important determinant
sistence and progression of infection is complicated and var- of viral clearance versus persistence and, by extension, a ma-
ies by HPV type (253). A clear trend of increasing prospective jor determinant of cervical cancer risk (261). However, despite
risk with increasing viral load has been demonstrated only for our growing understanding, many aspects of the interactions
HPV16. Viral load assessment is not useful clinically (254). Al- between HPV and the host immune system remain unknown
though studies suggest that women with prevalent infections (262). The key immune responses involved in the clearance of
may be more likely to acquire additional infections, infection HPV infections are known to be cell-mediated, although neu-
with one HPV type does not seem to influence the risk of per- tralizing antibodies are highly protective after immunization
sistence and development of precancer from another concurrent with HPV virus-like-particle (VLP)-based vaccines (263). The
infection (244). immune response to naturally acquired HPV infection has not
HPV type greatly affects both the absolute risk of viral persis- been quantified adequately and is difficult to study given the
tence and of progression to precancer associated with viral persis- lack of site-specificity, challenges in serological assay develop-
tence (255,256). The most common carcinogenic type, HPV16, ment and validation, and the fact that seronegativity might not
is also the most common type in the general population, linked always reflect susceptibility. Responses to measure HPV vaccine
to its greater propensity to persist (247,256). Although certain responses, on the other hand, have been extensively developed
noncarcinogenic types (e.g., HPV61) can also be persistent and and are currently being standardized for facilitating interna-
common, they do not cause malignant transformation (256,257). tional epidemiology studies and future vaccine development and
The average time of viral persistence that leads to diagnosable evaluation (264).
precancer is not clear. The average age at microscopic diagnosis A major unresolved question of HPV natural history relates
of precancer is approximately 25 to 30 years (258), approxi- to the lack of understanding of viral latency (265). In long-
mately 5 to 10 years after the average peak ages of carcinogenic term studies, virtually all HPV infections become undetectable
HPV prevalence and associated minor cytologic abnormalities by sensitive HPV DNA tests, usually within 2 years, except for
in screening populations. Biomarkers that predict persistence of those that lead to precancer. However, it is unknown if this
cervical precancer and offer better discrimination of transform- lack of detection reflects true virological clearance or a latent
ing versus transient HPV infections are increasingly available stage due to immunologic control that permits long-term pres-
(259). Because the presence of HPV DNA is not specific enough ence (latency) below levels of detection. Indeed, neither the
to predict persistent HPV infection, other newer biomarkers cause of reemergence (reactivation) of viral types seen in im-
such as the use of cellular correlates (e.g., p16INK4a and ki-67) of munocompromised individuals (e.g., transplant patients and
increased expression of viral oncoproteins or increased expres- HIV-immunosuppressed women) is known, nor is the clinical
sion of HPV viral oncogenic transcripts (e.g., E6/E7 mRNA) can significance of latency in terms of the fraction that can prog-
allow triage for colposcopy after a mildly abnormal or border- ress to precancers and cancers clear (265). In the era of HPV
line cytology or a positive HPV DNA test (259). The advances vaccination, many of these issues will acquire increased signifi-
in cancer epigenetics have led to a strong focus on methylation- cance, especially with the emergence of HPV genotyping assays
based biomarkers for many cancer sites, including the cervix. In in clinical practice.
addition, several recurring chromosomal imbalances have been Precancerous lesions (CIN3, in particular) tend not to regress
observed for cervical precancer and are currently being explored over short-term follow-up; however, even among precancerous
as biomarkers along with other newer approaches such as micro- lesions, risk and timing of invasion versus eventual regression
RNAs (miRNA) and proteomics (259). are matters of probability. The absolute risk of untreated pre-
Noncarcinogenic HPV infections are capable of producing cancer developing into invasive disease is argued, with estimates
lesions falsely diagnosed as precancer, especially CIN2, showing averaging 30% but ranging from 10% to 90% (266). The high
that this level of abnormality is not a perfect surrogate for can- ratio of precancerous lesions to cancers supports the belief that
cer risk (260). Still, because of the U.S. emphasis on safety and many cases of precancer, particularly CIN2, would not invade
concern over loss to follow-up, treating precancer (except as ap- but rather would regress if followed for many years. Screened de-
propriate in very young women, etc.) is a valid clinical strategy tected cases of invasive cancer, on average, occur approximately
to provide a margin of safety, given that it is not yet possible to 15 to 20 years or later than precancer, suggesting a long sojourn
know which lesions pose a threat. Eventually, better accuracy time in the precancerous state (236). The median age moves to-
based on molecular profiling is the goal. ward even older ages as the quality of screening decreases, and
CHAPTER 1 EPI DEM IOLOGY OF GYN ECOLOGIC CANCERS 17
the average stage of cancer at diagnosis also worsens due to this not clear. Mechanisms underlying the association between par-
diagnostic delay. ity and cervical neoplasia include trauma during parturition,
not past smoking, with no clear trend with time since stop- Infectious Agents Other than H PV
ping smoking. Among current smokers, evidence of increasing
risk has been found with increasing intensity and duration (or HPV infection is known to be the central, necessary cause of
early start) of smoking. Several investigations have attempted cervical cancer, but other sexually transmitted agents could in-
to define possible mechanisms by which smoking might alter crease the risk of cervical cancer among HPV-infected women.
cervical epithelium (286). Some investigations have looked into Of the other agents examined, herpes simplex virus (HSV-2)
measurement of tobacco-driven carcinogens such as polycyclic was originally hypothesized to play a central role, but most at-
aromatic hydrocarbon-DNA adducts in cervical tissue of HPV- tention now is focused on Chlamydia trachomatis. Although
infected women (287). The immunosuppressive effects of smok- residual confounding by some aspect of HPV infection has not
ing may cause disturbance in the early immune responses or been completely ruled out, despite adjusting for HPV exposure
increase persistence through increased production of reactive using DNA tests and/or serology, Chlamydia trachomatis sero-
oxygen species (288). positive women are at increased risk compared to seronegative
women (295).
Women with HIV and acquired immunodeficiency syndrome
Host Factors (AIDS) have higher prevalence, incidence, and persistence of
Whereas humoral (antibody-mediated) immunity appears to HPV infection and precancerous lesions, strongly associated
play a central role in preventing HPV infection (as in pro- with immunosuppression (296). It is also well established that
phylactic vaccines), elimination of HPV seems more closely re- the incidence of cervical cancer is increased several fold in both
lated to mounting an effective cellular immune response (262). women with HIV/AIDS as well as those who are iatrogenically
Impaired cellular immunity, attributable to human immunode- immunosuppressed (e.g., organ transplant recipients), thus re-
ficiency virus (HIV) infection, transplantation, or immunosup- inforcing the primary mediating role of immunosuppression in
pressive drugs, has been shown to increase HPV prevalence, increasing this risk (297). However, it is also hypothesized that
persistence, warts, CIN, and cancer (289,290). In contrast, interaction between HPV and HIV in the affected cervical tissue
deficiencies in humoral immunity appear unrelated to these leads to the persistence of HPV infection and cervical neoplasia
conditions. by various mechanisms including depletion of Langerhans cells
Polymorphisms in the human leukocyte antigen (HLA) genes (298), host immune response (299), or via proinflammatory
have been implicated in the risk of HPV-associated diseases. cytokine expression (300). An alternative explanation is at the
HLAs are important determinants of the efficiency of antigen cellular level; HIV-specific Tat protein upregulates expression
presentation to immune effector cells and, therefore, may influ- of HPV E6 and E7 oncogenes and enhances their oncogenetic
ence the outcome of HPV infections (291). Both Class I HLA transformation efficacy (301). These two mechanisms are, how-
genes (those that encode HLA molecules that are present in all ever, not exclusive, and a joint effect(s) most likely takes place at
nucleated cells) and Class II HLA genes (those that encode HLA early precancerous stages.
molecules that are present in lymphocytes and other immune-re-
lated cells) are involved in immune presentation (277). To date,
HLA Class II genes have been more extensively studied than Risk Factors for Cervical
HLA Class I genes for their association with cervical cancer. A
protective role for HLA DRB1*13 in cervical cancer has been Adenocarcinoma
consistently described in several populations. Activating combi- While infection with a carcinogenic HPV is a necessary cause
nations of HLA Class I alleles and the killer immunoglobulin- of both squamous cell carcinomas and adenocarcinomas, the
like receptor confers susceptibility to cervical cancer, whereas distribution of carcinogenic HPV types and variants detected
inhibitory combinations are associated with protection against in these two tumor types vary (302). Multiple studies suggest
the disease (291). that HPV18 accounts for a relatively higher percentage of ad-
Although the biological basis is unknown, studies from enocarcinomas as compared to squamous cell carcinomas (249),
nationwide tumor, twin, and other family registries in Scan- although more recent evidence is pointing to an increasingly eq-
dinavian countries indicate that cervical cancer aggregates in uitable role of HPV18 as well as HPV16 (248,303).
families (292). In general, an approximate twofold increase in Interpreting increasing rates of cervical adenocarcinomas
risk of precancer or invasive cervical cancer relative to general over time poses challenges because of gradual improvements in
population risk is observed in family members of cervical can- clinical practices (including the use of devices to obtain better
cer patients. It is not settled how much of this elevation in risk endocervical sampling), stricter criteria for adequate Pap tests,
among relatives of individuals affected with cervical cancer development of cytologic criteria for recognizing adenocarci-
can be attributed to shared environment versus genetic effects noma in situ (AIS) and, recently, formal inclusion of the AIS
(292,293). category in the new Bethesda System (304). In addition, pro-
posed but unsubstantiated explanations for these upward trends
include increased rates of HPV infection without improved cy-
Nutrients tologic detection of AIS, a specific increase in rates of HPV 18
The influence of nutrient status on risk of cervical neoplasia has infection, and increased exposure to HPV cofactors specific to
received substantial research attention. While dietary factors adenocarcinoma (236).
such as antioxidant micronutrient intake are likely important Although our understanding of the etiology of cervical ad-
in cervical carcinogenesis, methodological difficulties prevent enocarcinoma is incomplete, a picture is emerging in which
establishment of firm associations between a specific aspect of adenocarcinoma seems to share some risk factors with cervical
nutritional status and HPV infection or cervical cancer risk. A squamous carcinomas (acquisition of HPV through sexual con-
recent meta-analysis of case-control studies have suggested pre- tact) and others with uterine carcinoma (a tumor etiologically
ventive effects of micronutrients such as folic acid, vitamins B, related to hormones). While adenocarcinoma has most risk fac-
C, and E, and beta-carotene (294). However, lack of prospec- tors in common with squamous cell carcinoma, an important
tive studies and randomized trials preclude definitive evidence exception is smoking, which does not seem to increase the risk
regarding role of supplementation. The association of low folate for adenocarcinoma (305). In contrast, increased weight (or re-
levels and high homocysteine levels with risk of cervical cancer lated measures) appears to be related to increases in the risk of
has led to interest in markers of one-carbon metabolism and cervical adenocarcinomas (306). Oral contraceptives and meno-
DNA repair (259). pausal hormone therapy have been linked to an increased risk
CHAPTER 1 EPI DEM IOLOGY OF GYN ECOLOGIC CANCERS 19
for AIS or adenocarcinoma (307). The increased risk of cervical Cancer of the vulva occurs significantly more frequently
adenocarcinoma associated with obesity and reduced risk with among women with primary cancers of the cervix, and the
of trophoblastic processes. When the trophoblast malfunctions, symptoms is for a much shorter period of time, the use of cyclic
mutagenic, teratogenic, lethotoxic, and carcinogenic compounds progestin in combination with estrogen is advised if indicated,
gain access to the developing embryo, causing injury and death. and regular endometrial sampling is frequently practiced for
The genotype of hydatidiform mole results in a trophoblast that long-term estrogen users.
malfunctions, and exposure to certain environmental agents Although past alterations in patient management led to a de-
during the molar pregnancy may promote choriocarcinoma. Be- cline in uterine cancer, current events make future patterns less
fore implantation, the trophoblast forms most of the embryonic clear. Previous enthusiasm for long-term treatment of large seg-
tissue, which already metabolizes environmental agents. Even ments of the population of menopausal women with hormones
preimplanted moles, with their impaired metabolic capabilities, to control symptoms and prevent osteoporosis and heart disease
may increase the toxicity of environmental agents and promote may have implications for endometrial cancer in the future. On
carcinogenesis. the other hand, current patterns of use of oral contraceptives
Recent advances in identifying genetic and molecular mark- could lead to reductions in endometrial cancer rates in the gen-
ers involved with partial versus complete moles (334,365) open eral population. The impact of widespread oral contraceptive
a number of avenues for assessing the interaction of these mark- use at young ages on endometrial cancer risk at older ages is
ers with a variety of proposed environmental risk factors. This not well studied. However, if it is anywhere near the reduced
could include a focus on early stages in the disease process or risk seen at young ages, the resulting reduction in uterine cancer
on factors involved in the progression of molar pregnancies to overall could be substantial.
more invasive complications. With further research, it is also possible that pharmacologic
interventions aimed specifically at groups at high risk for uterine
cancer due to endogenous hormonal factors could be justified.
More must be learned about the associations of risk for endo-
metrial cancer and the quantitative levels of estrogens and other
SU MMARY hormones and their relative proportions. Once these factors are
known, women with PCOS, diabetes, morbid obesity, or other
The goal of both medical practice and epidemiology is to re- predisposing conditions could be evaluated for unfavorable hor-
duce morbidity and mortality. For many diseases, the focus has mone profiles and appropriately targeted for treatment.
turned to the ultimate aim of prevention. The link between iden- Although a substantial amount has been learned about ovar-
tification of etiologic factors and possibilities for prevention is ian cancer risks, the prospects for meaningful preventive mea-
well illustrated for tobacco-and alcohol-related tumors and for sures aimed at this tumor are probably worse than for other
those associated with specific pharmaceutical, radiogenic, and gynecologic malignancies. Although several ovarian cancer risk
occupational exposures. Fortunately, for gynecologic cancers, factors seem to indict ovulatory activity as a common pathway
there are a number of identified etiologic factors that are also to increased risk, the mechanism by which this occurs is un-
amenable to preventive approaches. known. Even if some of the hypothesized mechanisms prove to
Undoubtedly, the prospects for prevention are best for cervi- be correct, it is unclear how reasonable any interventions may
cal cancer. For some time, secondary prevention in the form of be. However, if the long-term effect of oral contraceptive use
screening for pathologic precursors of invasive disease has been on ovarian cancer risk is similar to its short-term effect, a sub-
the hallmark of the public health approach to this malignancy. stantial decline in ovarian cancer rates should result from pill
The establishment of HPV as a central etiologic agent for the use patterns of the past 40 years. Another reason for the limited
disease presents other avenues for prevention, including appli- prospects for prevention is that for several risk factors (e.g., pro-
cation of recently developed vaccines against the virus. Knowl- tection associated with hysterectomy) no credible mechanism
edge of when and how infection and other factors operate in has been suggested. The associations promising the greatest op-
the natural history of the disease has revolutionized screening portunities for preventive actions are several recently suggested
strategies and shifted treatment from cell ablation to antiviral dietary relationships, specifically, decreased risks with consump-
therapies. As always, combined laboratory, clinical, and epide- tion of diets high in fruits and vegetables and certain micro-
miologic research is needed to realize these propositions. nutrients. However, these observations need to be replicated in
Many believe that more is known about the cause of uterine additional studies. Because of the preventive implications, at-
carcinoma than for almost any other tumor. A unified theory tempts at confirmation should have high priority.
of how all risk factors may operate through a final common For cervical cancer, uterine cancer, and ovarian cancers, much
estrogenic pathway is popular and well supported. A womans is known about the risk factors. However, less is known about
hormonal milieu may prove to be favorable to modification the precise biologic mechanisms through which the known risk
at a practical level. There is substantial evidence that elimina- factors operate. There is substantial enthusiasm for current in-
tion of obesity and a reduction in fat in the diettwo interven- terdisciplinary studies that incorporate state of the art labora-
tions actively promoted for other reasonsreduces endometrial tory assays into robust epidemiologic research designs focused
cancer risk. After the epidemic of uterine cancer due to use of on answering these mechanistic questions. Even among some of
unopposed estrogen therapy, changes in the management of the more conservative etiologists, there is a belief that the gyne-
menopause occurred, resulting in a marked decline in the rates cologic oncologist may soon be able to intervene much earlier
of uterine cancer. More care is devoted to identifying women in the natural history of these diseases, and in some instances,
who truly need estrogen therapy, treatment of menopausal engage in primary prevention.
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Molecular Pathogenesis
of Gynecologic Cancers
MICHAEL J. BIRRER
30
CHAPTER 2 MOLECU LAR PATHOGEN ESIS OF GYN ECOLOGIC CANCERS 31
Hereditary Cancer:
Sporadic Cancer:
Birth Cancer
FIGURE 2.1. All cancers are genetic. Hereditary cancers differ from sporadic cancers by virtue of association
with a predisposing mutation inherited through the germ line. In contrast, all of the mutations in sporadic cancers are
acquired somatically.
required for its development and progression. The histopatho- TCGA and these findings have been incorporated into this chap-
logic progression through hyperplasia, dysplasia, carcinoma in ter. The International Cancer Genome Consortium (ICGC) is per-
situ, and invasive carcinoma, reflects the multistep, multigenic forming similar genomic analyses of human cancers. Both TCGA
nature of malignant transformation. Cancers may arise through and ICGC are depositing their data online in the public domain
the accumulation of acquired (somatic) alterations or through to stimulate further research. Thefull spectrum and complexity
the inheritance of an alteration in the germline followed by the of the genomic alterations in a single cancer can be best captured
acquisition of additional somatic alterations (Fig. 2.1). Heredi- in a Circos plot (Fig. 2.2), which uses a circular ideogram layout
tary cancers are discussed in detail in Chapter 3. to facilitate the display of changes across the genome.
The techniques used to study genetic alterations have evolved An understanding of the molecular pathogenesis of cancer pro-
dramatically. Advances in the 1980s and 1990s enabled the dis- vides the opportunity to better define subgroups within a given
covery of several genes that frequently play a role in the develop- type of cancer that may differ with respect to clinical behavior or
ment of cancers, including the KRAS and HER-2/neu oncogenes outcome. In addition, the identification of specific mutations has
and the TP53 and RB1 tumor-suppressor genes. It became ap- facilitated the development of therapies that target these altera-
parent that the spectrum of driver alterations varies considerably tions (4,5). In this regard, monoclonal antibodies and small mol-
between cancer types, and among cancers of the same type. More ecules targeting aberrantly expressed cellular proteins that drive
recently, powerful new technologies have enabled comprehensive malignant growth have been successful in treating some cancers
genomic studies. The Human Genome Project was completed in (e.g., trastuzumab targets HER-2/neu in breast cancer, gefitinib,
2004 and provided a road map of the entire genome, including and erlotinib target EGFR in lung and other cancers). However,
the approximately 18,000 protein-encoding genes. The HapMap resistance to therapy often occurs due to mutational heterogeneity
project then catalogued the millions of common single nucleo- both within the primary tumor and in metastases as clonal evolu-
tide polymorphisms (SNPs) in the genome that change a single tion develops over time. Unfortunately, many cancers, including
base in the DNA sequence. More recently the 1000 Genomes most gynecologic cancers, have not proven easily amenable to
Project has characterized rarer germline genetic variants. A road targeted therapy, perhaps because their growth is not driven by a
map of normal human genetic variation and the development single altered gene or pathway. Successful therapy may require the
of faster and cheaper next generation DNA sequencing has use of multiple agents that target more than one gene or pathway.
allowed mutational analysis of complete cancer genomes. It has In several types of common cancers, analysis of known
been shown that cancers typically have about 30 to 100 acquired druggable molecular targets has become part of the standard
mutations. However, cancers are continually evolving due to ge- of care. Companion molecular diagnostic tests are often requi-
netic instability and contain subclones that differ with respect to site to guide selective use of expensive targeted agents in patients
their mutational profile. A small number of genes are mutated in most likely to benefit. As the cost of genomic analyses of cancers
a high fraction of cancers (e.g., KRAS, TP53) likely reflecting the continues to fall, it will be increasingly feasible to perform full
strong selective advantage these alterations confer. A much larger sequencing of cancers to look for less commonly mutated tar-
number of genes are mutated at considerably lower frequencies. gets. This has the potential to facilitate even greater individual-
The terms mountains and hills have been used to describe ization of therapy based on the unique profile of alterations in a
genes that are commonly versus rarely mutated. Mutations in cancer, but the utility of this approach remains unproven.
cancers typically target multiple biological pathways (3). Several Finally, an increased understanding of the molecular patho-
genes in a pathway may be mutated, but driver mutations in genesis provides the opportunity to explore new approaches to
a pathway often are mutually exclusive when they involve the early detection and prevention. This has been realized for cervi-
same pathway (e.g., KRAS and BRAF). cal cancer with the identification of the human papilloma virus
The Cancer Genome Atlas (TCGA) Project sponsored by the leading to creation of a vaccine. In ovarian and endometrial
National Cancer Institute is performing a comprehensive genomic cancers, genetic changes that occur early in the development of
characterization of all common forms of human cancer. Ovarian cancers have the potential to serve as biomarkers for early detec-
and endometrial cancers were among the first to be studied by tion and as surrogate endpoints in prevention studies.
32 CHAPTER 2 MOLECU LAR PATHOGEN ESIS OF GYN ECOLOGIC CANCERS
FIGURE 2.2. Circos plot of somatic mutations in COLO-829. Chromosome ideograms are shown around the outer ring and are
oriented pterqter in a clockwise direction with centromeres indicated in red. Other tracks contain somatic alterations (from outside
to inside): validated insertions (light green rectangles); validated deletions (dark green rectangles); heterozygous (light orange bars), and
homozygous (dark orange bars) substitutions shown by density per 10 megabases; coding substitutions (colored squares: silent in gray,
missense in purple, nonsense in red, and splice site in black); copy number (blue lines); regions of loss of heterozygosity (LOH) (red lines);
validated intrachromosomal rearrangements (green lines); validated interchromosomal rearrangements (purple lines).
Source: Pleasance ED, Cheetham RK, Stephens PJ, et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 2010;463(7278):191. [PMID: 20016485]
Gene Expression
E2F Rb p53
P
Cdc25c
Rb Wee1
p21
Mik1
P
P
CDK 4 CDK 2 CDK 2 Cdc 2 Cdc 2
M G1 S G2 M
FIGURE 2.3. Molecular control of cell-cycle progression. A linear version of the various stages of the cell cycle is shown
with the various cyclin/cyclin-dependent kinase complexes corresponding to the stages that they control.
and braincells are long lived and proliferation rarely occurs. activation of caspases and lead to apoptosis via the extrinsic
Complex molecular mechanisms have evolved to closely regu- pathway. The intrinsic apoptosis pathway is activated in re-
late proliferation. These involve a finely tuned balance between sponse to a wide range of stresses including DNA damage and
growth stimulatory and inhibitory signals. deprivation of growth factors. The intrinsic apoptosis pathway
Increased proliferation is one of the hallmarks of cancer. There is regulated by a complex interaction of pro- and antiapoptotic
may be increased activity of genes involved in stimulating pro- proteins in the mitochondrial membrane that affect its perme-
liferation (oncogenes) and/or loss of growth-inhibitory (tumor- ability. Proteins that increase permeability allow release of cyto-
suppressor) genes. In the past, it was thought that cancer might chrome c, which activates the apoptosome complex leading to
arise solely because of more rapid proliferation or a higher frac- activation of caspases that effect apoptosis. Conversely, proteins
tion of cells proliferating. It is now clear that this was an overly that stabilize mitochondrial membranes inhibit apoptosis. The
simplistic view. Although increased proliferation is a characteris- first major insight that led to the understanding of the intrinsic
tic of many cancers, the fraction of cancer cells actively dividing apoptosis pathway was the finding that an activating transloca-
and the time required to transit the cell cycle is not always strik- tion of the BCL-2 gene in B-cell lymphomas results in essentially
ingly increased. Altered regulation of proliferation is only one of complete inhibition of apoptosis (9). Subsequent studies demon-
several factors that contribute to malignant transformation. strated that the antiapoptotic effect of BCL-2 is attributable to
stabilization of the mitochondrial membrane. Additional genes
related to BCL-2, such as BAD, BCL-XL and others, also block
apoptosis by inhibiting membrane permeability. Other genes
Cell death in the BCL family, such as BAX and BAK, increase membrane
In addition to being driven by increased proliferation, growth permeability and are pro-apoptotic. An understanding of the
of a cancer may be attributable to cellular resistance to death. complex system of checks and balances involved in regulation
At least three distinct types of cell death pathways have been of apoptosis provides opportunities for the development of tar-
characterized, including apoptosis, autophagy, and necrosis (8). geted therapies (10).
In addition to restraining the number of cells in a popula-
tion, apoptosis serves an important role in preventing malig-
Apoptosis nant transformation by allowing for elimination of cells that
The term apoptosis derives from Greek and alludes to a pro- have undergone genetic damage. Following exposure of cells to
cess akin to leaves dying and falling off a tree. Apoptosis is an mutagenic stimuli, including radiation and carcinogenic drugs,
active energy-dependent process that involves cleavage of the the cell cycle is arrested so that DNA damage may be repaired.
DNA by endonucleases and proteins by proteases called cas- If DNA repair is not sufficient, apoptosis occurs so that dam-
pases. Morphologically, apoptosis is characterized by conden- aged cells do not survive. This serves as an anticancer surveil-
sation of chromatin, nuclear and cytoplasmic blebbing, and lance mechanism by which mutated cells are eliminated before
cellular shrinkage. The molecular events that effect apoptosis they become fully transformed. The TP53 tumor-suppressor
in response to various stimuli are complex and have only been gene is a critical regulator of cell cycle arrest and apoptosis in
partially elucidated, but several reliable markers of apoptosis response to DNA damage. Many of the molecules involved in
have been discovered including annexin V, caspase-3 activation, apoptosis reside in the mitochondria and are encoded by mito-
and DNA fragmentation. chondrial DNA. Mutations in mitochondrial DNA have been
External stimuli such as TNF, TRAIL, Fas and other death shown to be frequent in cancer and may play a role in evasion
ligands that interact with cell surface receptors can induce of apoptosis (11).
34 CHAPTER 2 MOLECU LAR PATHOGEN ESIS OF GYN ECOLOGIC CANCERS
Epigenetic Changes
Epigentics comprises heritable changes that are not due to al-
fully transform a cell. Many cancers are genetically unstable and
terations in DNA sequence (28,29). Methylation of cytosine
this leads to accumulation of a substantial number of secondary
residues that reside next to guanine residues (CpG dinucleo-
changes and the development of subclones that play a role in
tides) is the primary mechanism of epigenetic regulation, and
evolution of the malignant phenotype.
this process is regulated by a family of DNA methyltransfer-
eases. CpG dinucleotides are asymmetrically distributed with
about half of human genes containing CpG-rich regions termed
Inherited Cancer Susceptibility CpG islands at their transcriptional start sites. Most genes
Although most cancers arise sporadically due to acquired ge- are regulated without changing the methylation status of the
netic damage, inherited mutations in cancer susceptibility genes CpG sites, but permanent silencing of genes associated with
are responsible for some familial cases. The age of cancer onset X-chromosome inactivation and genomic imprinting is due to
is younger in these families and it is not unusual for some in- heritable methylation of CpG islands.
dividuals to be affected with multiple primary cancers. Tumor- Most cancers have globally reduced DNA methylation,
suppressor genes and DNA repair genes have been implicated which may lead to activation of some genes. Conversely, selec-
most frequently in hereditary cancer syndromes. The most com- tive hypermethylation of CpG islands in the promoter regions
mon forms of hereditary cancer syndromes predispose to breast/ of tumor-suppressor genes may lead to gene inactivation (e.g.,
ovarian (BRCA1/2 genes) and colon/endometrial (DNA mis- BRCA1, MLH1). In addition, loss of silencing of imprinted
match repair genes) cancers. Although affected individuals carry genes that stimulate proliferation, such as IGF2, may provide an
the germline alteration in every cell of their bodies, paradoxi- oncogenic stimulus. Acetylation and methylation of the histone
cally, cancer susceptibility genes are characterized by a limited proteins that coat DNA represent another level of epigenetic
repertoire of cancers. The penetrance of cancer susceptibility regulation that is altered in cancer. The underlying cause of epi-
genes is incomplete, as all individuals who inherit a mutation genetic alterations in cancer remains poorly understood.
do not develop cancer. The emergence of cancers is dependent
on the occurrence of additional genetic alterations. Hereditary
cancer syndromes are covered in detail in Chapter 3. Alterations in Signal Transduction
In addition to the high-penetrance mutations noted above that
cause familial cancer syndromes, low-penetrance genetic variants Pathways in Malignant Transformation
may also affect cancer susceptibility, albeit less dramatically (27). Alterations in genes that stimulate cellular growth (oncogenes)
There are over 10 million polymorphic genetic loci in the human can cause malignant transformation when they become overac-
genome, most of which are SNPs (e.g., CCA to CAA). Many of tive (2). In some cancers, amplification of oncogenes occurs with
these SNPs are common, with the rarer of the two alleles occurring resultant overexpression of the corresponding protein. Instead
in more than 5% of individuals. Genome wide association studies of two copies of one of these genes, there may be many ad-
have discovered a number of SNPs that affect the risk of ovarian ditional copies. Some oncogenes may become overactive when
cancer by 10% to 20% per rare allele copy (27). A more complete affected by gain of function point mutations. Finally, oncogenes
understanding of the genetic factors that affect cancer susceptibil- may be translocated from one chromosomal location to another
ity could facilitate implementation of screening and prevention ap- and come under the influence of gene promoters that cause over-
proaches in subsets of the population at increased risk. expression. This latter mechanism frequently occurs as a driving
36 CHAPTER 2 MOLECU LAR PATHOGEN ESIS OF GYN ECOLOGIC CANCERS
event in the development of leukemias and lymphomas, but is autocrine growth stimulation might be a key strategy by which
infrequent in gynecologic cancers. However, some other types of cancer cell proliferation becomes autonomous has received con-
solid tumors may have translocations that represent significant siderable attention. In this model, it is postulated that cancers
driver events, such as those involving the ALK receptor gene secrete stimulatory growth factors that then interact with recep-
in lung cancer. These have been targeted successfully with the tors on the same cell. Although peptide growth factors provide a
monoclonal antibody crizotinib (30). growth stimulatory signal, there is little evidence to suggest that
Loss of tumor-suppressor gene function also plays a role in overproduction of growth factors is a precipitating event in the
the development of most cancers. This usually involves a two- development of most cancers. Increased expression of peptide
step process in which both copies of a tumor-suppressor gene growth factors likely facilitates, rather than drives, malignant
are inactivated. This often involves mutation of one copy of a transformation.
tumor-suppressor gene and loss of the other copy due to dele- Cell membrane receptors that bind peptide growth factors
tion of a segment of the chromosome where the gene resides are composed of an extracellular ligand binding domain, a
(e.g., RB1). There is also evidence that some tumor-suppressor membrane-spanning region, and a cytoplasmic tyrosine kinase
genes may be inactivated due to methylation of the promoter re- domain (31,32). Binding of a growth factor to the extracellular
gion of the gene (e.g., MLH1, BRCA1). The promoter is an area domain results in dimerization and conformational shifts in the
proximal to the coding sequence that binds transcription factors receptors and activation of the inner tyrosine kinase. The ki-
that regulate whether or not the gene is transcribed from DNA nase transfers a phosphate group from ATP to specific tyrosine
into RNA. When the promoter is methylated, it is resistant to residues both on the growth factor receptor itself (autophos-
activation and the gene is essentially silenced despite remaining phorylation) and on molecular targets in the cell interior leading
structurally intact. This two-hit paradigm of tumor-suppressor to activation of secondary signals that stimulate proliferation.
gene inactivation is relevant to both hereditary cancer syn- Growth of some cancers is driven by overexpression of receptor
dromes, in which one mutation is inherited and the second ac- tyrosine kinases. The epidermal growth factor receptor (EGFR)
quired, and to sporadic cancers, in which both hits are acquired. family of receptor tyrosine kinases plays a significant role in the
Tumor-suppressor gene products are found throughout the cell, development of several types of cancers, and includes ErbB-1
reflecting their diverse functions. (EGFR), ErbB-2 (HER-2/neu), ErbB-3, and ErbB-4. These recep-
The sections below will review the role of oncogenes and tors are activated by binding of ligands, including EGF, trans-
tumor-suppressor genes in signal transduction pathways that forming growth factor-a, amphiregulin, and the neuregulins.
regulate cellular growth and metabolism (3). These pathways Because receptor tyrosine kinases are located on the cell sur-
are complex and have considerable overlap and redundancy face, they are appealing therapeutic targets. A number of agents
(31), and an exhaustive discussion is beyond the scope of this that target the EGFR family have been developed and translated
book. Pathways for which there is less evidence of a role in into clinical practice. Trastuzumab is a monoclonal antibody
driving the development of gynecologic cancers, such as the that binds to HER-2/neu, and it is widely used in the treatment
Hedgehog, Notch, and cytokine pathways, are not covered. of breast cancers that overexpress this receptor (33). Cetuximab
is a monoclonal antibody that targets the extracellular domain
of EGFR, whereas gefitinib is a direct inhibitor of the EGFR
Peptide Growth Factors and Receptor tyrosine kinase (34). Lapatinib is a dual EGFR/HER-2 kinase
inhibitor. Likewise, therapeutic approaches have been developed
Tyrosine Kinases that target other receptor tyrosine kinases. Imatinib antagonizes
Peptide growth factors in the extracellular space, such as those of the activity of the BCR-ABL, c-kit, and platelet-derived growth
the EGF, PDGF, and FGF families, stimulate a cascade of molecu- factor (PDGF) receptor tyrosine kinases and has proven highly
lar events that leads to proliferation by binding to high affinity effective in treatment of chronic myelogenous leukemias and
cell membrane receptors (Fig. 2.4). Growth factors are involved gastrointestinal stromal tumors.
in normal cellular processes such as stromal-epithelial communi-
cation, tissue regeneration, and wound healing. The concept that
Nonreceptor Kinases and Phosphatases
Receptor Tyrosine Following interaction of growth factors with cell membrane
Kinase receptors, secondary molecular signals are generated to trans-
mit the growth stimulus to the nucleus. This function is served
by a multitude of complex and overlapping signal transduction
Plasma pathways that occur in the inner cell membrane and cytoplasm.
Membrane Many of these signals involve phosphorylation of proteins by
Raf enzymes known as nonreceptor kinases. The kinases that are
Ras
GDP
GTP involved in growth regulation are of two types, those that phos-
Ras
the inner aspect of the cell membraneand are positively regu- activating MAP kinases (MEK) which translocate to the nu-
lated by Grb and SOS in response to receptor tyrosine kinases cleus. Mutations in the BRAF gene occur in many cancers that
A B
Trastuzumab (anti-ErbB2) IGF1
ErbB1 ErbB2
IGF1R
ErbB2 ErbB1
P P
P Tyr Tyr P Gefitinib P Tyr Tyr P
Farnesyltransferase
Inhibitors
PI3K RAS
ABL RAS SRC
Imatinib
Dasatinib PIP3 PTEN
RAF Sorafenib
PDK
MEK MEK Inhibitors
mTOR
AKT Inhibitors
MAPK
Foxo mTOR
Nucleus
MAPK
MYC
Transcription of
JUN Nucleus genes needed for
FOS apoptosis and
apoptosis cell
Foxo Synthesis of proteins
cycle arrest
Myc/ Gene transcription needed for cell growth
Jun/Fos and cell cycle
progression
FIGURE 2.5. A: The ras/raf/MEK/MAPK pathway is activated by multiple growth factor receptors (here exemplified by ErbB1 and ErbB2) as well as
several intracellular tyrosine kinases such as SRC and ABL. Activated RAS stimulates a sequence of phosphorylation events mediated by RAF, MEK, and ERK
(MAP) kinases. Activated MAP kinase (MAPK) translocates to the nucleus and activates proteins such as MYC, JUN, and FOS that promote the transcription
of numerous genes involved in tumor growth. B: The phosphatidylinositol 3-kinase (PI3K) pathway is activated by RAS and by a number of growth factor
receptors (here exemplified IGF1R and the ErbB1/ErbB2 heterodimer). Activated PI3K generates phosphatidylinositol-3,4,5-triphosphate (PIP3), which
activates phosphoinositide-dependent kinase-1 (PDK). In turn, PDK phosphorylates AKT. PTEN is an endogenous inhibitor of AKT activation. Phosphorylated
AKT transduces multiple downstream signals, including activation of the mTOR and inhibition of the FOXO family of transcription factors. mTOR activation
promotes the synthesis of proteins required for cell growth and cell cycle progression.
38 CHAPTER 2 MOLECU LAR PATHOGEN ESIS OF GYN ECOLOGIC CANCERS
PI3K/AKT/mTOR Pathway
Phosphatidylinositol 3-kinases (PI3Ks) are a class of lipid ki- Extracellular Frizzled
nases that phosphorylate phosphoinositides (PIs) at the position Intracellular
D3 of the inositol ring (40). Extracellular molecules such as
growth factors are the main effectors for PI3K pathway acti-
vation through the interaction with receptor tyrosine kinases Dishevelled
and G protein-coupled receptors (Fig. 2.5B). Phosphorylated PIs
serve as plasma docking sites for the recruitment of pleckstrin-
homology domain containing proteins such as AKT and its
upstream activator PDK1. PI3K activation is one of the main
causes of increased proliferation and resistance to apoptosis. APC GSK3 WNT
The PIK3CA gene is one of the most frequently mutated onco- Degradation
Conductin
genes in human cancers. catenin
Alterations in PI3Ks and downstream effectors, including Axin Nuclear
AKT and mTOR, frequently are involved in initiation and main- + WNT
accumulation
tenance of the tumorigenic phenotype. The PI3K-AKT pathway
promotes cell growth and survival and inhibits apoptosis and au- Destruction complex
tophagy through several mechanisms. AKT activates the mam-
FIGURE 2.6. Wingless (WNT)/-catenin signaling. WNT extracellular
malian target of rapamycin (mTOR) pathway (Fig. 2.5B) and
ligands bind Frizzled receptors and regulate the phosphorylation status of axin.
modulates genes that inhibit cell cycle progression (e.g., cdks,
Axin functions as part of the destruction complex that regulates the stability
CHK1, and MDM2). AKT targets include the pro-apoptotic of -catenin, a transcriptional regulator.
effectors BAD and BAX, which are inhibited by phosphoryla-
tion respectively at Ser136 and Ser184, resulting in inhibition
of the apoptotic response. AKT also inhibits the expression of development, cell differentiation, and cell polarity (Fig. 2.6).
BH3-only proteins such as BAD and BIM through effects on b-catenin activity is regulated by the WNT pathway (31). The
transcription factors, such as Forkhead family proteins (e.g., WNT family of genes encodes secreted peptides that interact
FOXO3a) and p53. AKT also influences p53 activity through with Frizzled family cell surface receptors. Frizzled activates the
MDM2 phosphorylation at Ser166 and Ser186, which promotes intracellular Dishevelled protein resulting in an increase in the
its translocation to the nucleus, with subsequent destabilization. amount of b -catenin translocated to the nucleus. Dishevelled ac-
AKT can phosphorylate and activate IB kinase-a, which in complishes this by inhibiting a complex of proteins that includes
turn phosphorylates IB, targeting it for degradation. This leads axin, GSK-3b, and APC that normally promote proteolytic deg-
to nuclear translocation and activation of the transcription fac- radation of b -catenin. This allows b -catenin to enter the nucleus
tor NF-B and transcription of NF-Bdependent pro-survival and interact with TCF/LEF family transcription factors to pro-
genes. mote gene expression.
The PTEN tumor suppressor is the most important nega- Genes encoding WNT signaling inhibitors are often down-
tive regulator of the PI3K signaling pathway (41). It is a lipid regulated during carcinogenesis and driver mutations in several
and protein phosphatase that removes phosphates in opposition of these genes (APC, Axin, GSK-3b, b -catenin) occur frequently
to PI3K tyrosine kinases. Its ability to dephosphorylate phos- in human cancers, including endometrial cancers. Germline mu-
phatidylinositol 3,4,5-trisphosphate (PIP3) resulting in phos- tations in the APC gene are responsible for familial adenoma-
phatidylinositol 4,5-bisphosphate (PIP2) inhibits oncogenic tous polyposis of the colon.
PI3K-dependent signaling. Although PTEN is a tumor suppres-
sor and may be completely lost due to mutation and deletion of
the two copies of the gene, mutational inactivation of one copy
of the gene (haploinsufficiency) also appears to facilitate malig- Nuclear Oncogenes
nant transformation. If proliferation is to occur in response to signals generated
Both genetic and epigenetic alterations affect the activity of in the cell membrane and cytoplasm, these events must lead
this pathway (40). Mutations in the PIK3CA gene that lead to to activation of nuclear transcription factors and other gene
increased activity frequently occur in human cancers, including products responsible for stimulating DNA replication and
ovarian and endometrial cancers. PTEN is frequently targeted cell division (Fig. 2.5A). Expression of several genes that en-
by either germline or somatic mutation, and is the second most code nuclear proteins increases dramatically within minutes
frequently mutated gene in human cancers. In addition, loss of of treatment of cells with peptide growth factors. Once in-
heterozygosity or promoter hypermethylation occurs in a broad duced, the products of these genes bind to specific DNA regu-
range of cancers including endometrioid ovarian and endome- latory elements and induce transcription of genes involved in
trial cancers. Inhibition of the PI3K/Akt/mTOR pathway repre- DNA synthesis and cell division. Examples include the FOS
sents an attractive therapeutic approach (42). and JUN genes, which dimerize to form the AP1 transcription
complex. When inappropriately overexpressed these transcrip-
tion factors can act as oncogenes. The MYC family of nuclear
transcription factors is often involved in the development of
WNT Pathway human cancers, including some ovarian cancers, due to am-
-catenin (CTNNB1) is involved along with cadherins in cell- plification/overexpression. Many of the nuclear regulatory
cell adhesion junctions and may play a role in inhibition of genes such as MYC that control proliferation also impact the
excessive growth when cells come in contact with each other. threshold for apoptosis. Thus, there is overlap in the molecular
-catenin also may be translocated to the nucleus and play a pathways that regulate the opposing processes of proliferation
role in regulating transcription of genes involved in embryonic and apoptosis.
CHAPTER 2 MOLECU LAR PATHOGEN ESIS OF GYN ECOLOGIC CANCERS 39
Genes involved in chromatin remodeling also that have wild-type p53 protein and prevent it from oligimerizing and in-
been implicated as oncogenes (e.g., ARID1A). Finally, genes teracting with DNA. Because inactivation of both TP53 alleles
Pol II RISC
m7
AAA
ORF Translation
Drasha 3 UTR
Mature Mature
miRNA siRNA
Pre-miRNA
RISC
miRNA:miRNA*
duplex
Helicase
Pre-miRNA Dicer
Dicer Helicase
Degradation
Cell membrane
Foreign dsRNA *miRNA
*siRNA
VHL tumor suppressor gene, providing a link between the loss repair and nonhomologous end joining (NHEJ). Loss of DNA
of a tumor suppressor and the altered metabolic phenotype of repair activity increases the likelihood of mutations being fixed
MLH1 PMS2
2
MSH2 MSH6 MSH2 MSH6
C G A C G A C G A
Mismatch
G T T G T T G T T
Excision,
MLH1 MLH3 DNA synthesis
ligation
MSH2 MSH3 MSH2 MSH3
A A A
C
C
C
C
C
C
C A C A C A
Insertion/
deletion loop G T T G G T G T T
FIGURE 2.9. Mismatch repair pathways. Mispaired bases due to errors in DNA replication or other causes are recognized by the
mismatch repair machinery. The initial step involves recognition of simple mismatches by MSH2 and MSH6 (upper panel), or recognition of
insertion/deletion loops by MSH2 and MSH3 (lower panel). Subsequent steps involve recruitment of MLH1 and PMS2 to mismatch sites,
or MLH1 and MLH3 to insertion/deletion loop sites. This is followed by excision of the respective lesions, DNA synthesis, and ligation to
complete the repair.
42 CHAPTER 2 MOLECU LAR PATHOGEN ESIS OF GYN ECOLOGIC CANCERS
XPC complex
TFIIH complex
T
T
T
C A C A (XPB, XPD)
Global Unwinding
genome G A A T G A A T XPG
(XPA, RPA)
UV
Oxidative ERCC1/XPC
damage Open intermediate Excision
XPG
POL II POL II
CSA
CSB (XPA, RPA)
T
T
T
TFIIH
C A C A
Transcription Unwinding
coupled G A A T G A A T XPG
C G A C G A
X-ray
XRCC G G T G G T
FIGURE 2.10. Nucleotide excision repair and base excision repair. Nucleotide excision repair is activated in response to bulky lesions that are generated, for
example, by UV irradiation (upper panels). Global genome repair involves proteins identified by complementation groups in patients with xeroderma pigmentosa
(XP proteins). Initial recognition of lesions occurs by a complex containing xeroderma pigmentosa C. Transcription coupled repair also involves proteins identified
by mutation in Cockayne syndrome (CS proteins), and occurs when RNA polymerase II stalls at the site of lesions. Stalled RNA polymerase II recruits Cockayne
syndrome B to the site of damage. Subsequently, DNA is locally unwound around the injured site by a TFIIH complex containing XPB and XPD. This process
also involves XPG, CSA, and other proteins for TCR. Once unwound, XPA and replication protein A contribute to stabilization of an open intermediate and
recruitment of the ERCC1 and XPF endonucleases that excise the lesion. Subsequent steps involve DNA synthesis and ligation to complete the repair. In BER
(lower panels), abasic sites generated by spontaneous hydrolysis, action of DNA glycosylases, or X-rayinduced single-strand breaks are recognized by the APE1
endonuclease, as well as PARP and XRCC1. Subsequent repair is influenced by PARP-mediated ADP ribosylation of histones and other proteins, while XRCC1
serves as a scaffold for recruitment of DNA polymerase b and DNA ligase 3. These latter enzymes catalyze nucleotide reinsertion and ligation into the injured
strand as part of the short patch repair pathway (major BER pathway).
CHAPTER 2 MOLECU LAR PATHOGEN ESIS OF GYN ECOLOGIC CANCERS 43
to chemicals and X-rays that do not distort the DNA helix. Sin- gaps and DNA interstrand cross-links (Fig. 2.11) (55,64). The HR
gle bases in DNA can be damaged by several mechanisms, the pathway involves the following basic steps. Double stranded breaks
Homologous Recombination
RAD51 complex Homology search/ DNA synthesis/
strand invasion ligation
RPA
MRN
MRN RPA
RAD51 complex
Double holliday junction
Resolvases BLM/
TOPO 3
brain, and biliary tract. Colorectal cancer is the most common microsatellite instability (MI) and associated hypermutation.
malignancy in Lynch syndrome, which also is sometimes called These cancers have a background mutation rate (BMR) that is
KAGKGRTGV125
R130fs
G165R
R172fs
H196fs
C211fs
C218fs
N262fs
D268fs
R308fs
D312fs
N329fs
G127V
H123D
C124R
V158fs
P169fs
S302fs
K313fs
S338fs
S370fs
R130Q
R130P
Y138C
T319fs
K342N
A126S
C136F
N323T
R130L
L112V
V275L
R130*
R233*
R335*
E150*
I168fs
K260*
I300fs
D52fs
C71fs
R74fs
D92G
L140*
E40fs
V45fs
A72fs
N31K
K66N
D92E
L23fs
A34V
P96A
I33S
I67T
e4-2
e9-1
141
I4fs
I33
Q623E
D32G
G34R
D32N
G34V
G34E
D32Y
S33C
S37C
S45C
S33Y
S37A
S33F
S37F
T41A
I35S
FIGURE 2.14. Overexpression of HER-2/neu in ovarian cancer. A: Serous ovarian cancer. B: Immunostaining for HER-2/neu demonstrates intense cell
membrane staining indicative of overexpression.
efficacy in breast cancer and often is administered with chemo- an early event that is found in serous tubal carcinoma in situ
therapy in the context of both adjuvant therapy and treatment (Fig. 2.15) (144). About two-thirds of high-grade serous ovar-
of metastatic disease (158). The use of this drug is restricted to ian cancers have TP53 missense mutations in in the DNA bind-
patients whose cancers are shown to overexpress HER-2/neu ing regions of exons 5 through 8 of the gene that result in p53
based on immunohistochemical analysis of protein levels and/ protein overexpression due to increased stability of the protein.
or FISH analysis of gene amplification in paraffin tumor tissue Codons 175, 248 and 273 are mutational hot spots. These mis-
blocks. A study performed by the Gynecologic Oncology Group sense mutants act as dominant negative transforming genes due
found that only 11% of ovarian cancers exhibited significant to their nonfunctional transcriptional activity. Loss of the other
HER-2/neu overexpression (159). The response rate to single- copy of the TP53 gene is not required. Most TP53 missense
agent trastuzumab therapy was disappointingly low (7%), but mutations are transitions rather than transversions or micro-
there may be some benefit using it in regimens that also include deletions (170), which suggests that they occur spontaneously,
cytotoxics or other biological agents. rather than due to exogenous carcinogens.
The cyclin dependent kinases (cdk) inhibitors act as tumor Overexpression of mutant p53 protein may be associated
suppressors by virtue of their inhibition of cell cycle progres- with somewhat worse survival in advanced stage ovarian can-
sion from G1 to S phase. Expression of several cdk inhibitors cers (167,169,171). However, reports in the literature are in-
appears to be decreased in some ovarian cancers. CDKN2A consistent and are often confounded by the inclusion of ovarian
(p16) undergoes homozygous deletions in about 15% of ovar- cancers of various stages, grades, and histological types. Most
ian cancers (160). There is evidence to suggest that CDKN2A high-grade serous ovarian cancers that do not overexpress p53
(161) and CDKN2B (p15) (162) may be inactivated via tran- protein have TP53 mutations that result in truncated protein
scriptional silencing due to promoter methylation rather than products (166,171). These are usually accompanied by loss of
mutation and/or deletion. Likewise, decreased expression of the the other copy of the gene, consistent with the classic two hit
p21/WAF1 cdk inhibitor has been noted in a significant fraction
of ovarian cancers despite the absence of inactivating mutations
(163). Loss of p27 (CDKN1B) also may occur and correlates Table 2.4 Characteristics of Common Invasive
with poor survival in some studies (164). It has been suggested Epithelial Ovarian Carcinomas
that aberrant expression of p27 in the cytoplasm may be most
associated with poor outcome (165). Endometrioid/ High-grade Low-Grade
Mucinous Clear Cell Serous Serous
Origin Unclear Endometriosis Fallopian Fallopian
Mutations Tube Tube
TCGA performed sequencing of the coding regions and splice Epithelial Epithelial
sites of about 18,500 genes in DNA isolated from 316 high- Cells Cells
grade serous ovarian cancers (145). The extent of this sequenc- Typical Early Early Advanced Early
ing effort in ovarian cancer was unprecedented and would not stage
have been possible without the recent development of massively
Survival Favorable Favorable Poor Favorable
parallel sequencing technologies. Although several genes were
identified that are mutated at low frequencies, TP53, BRCA1 Commonly KRAS PTEN TP53 KRAS
and BRCA2 were confirmed to be the most frequently genes in altered
genes HER-2/neu CTNNB1 BRCA1 BRAF
high-grade ovarian cancers. (b -catenin)
ARID1A BRCA2
TP53
The TCGA study validated the prior finding that mutation of the PPP2R1A
TP53 tumor suppressor gene is the most frequent genetic event PIK3CA
in high-grade serous ovarian cancers (Table 2.4) (166169). Itis
CHAPTER 2 MOLECU LAR PATHOGEN ESIS OF GYN ECOLOGIC CANCERS 51
C D
FIGURE 2.15. Overexpression of mutant TP53 in serous tubal carcinoma in situ (A, B) and in high-grade serous ovarian cancer (C, D).
model of tumor-suppressor gene inactivation. TCGA found of two genetic alterations, which on their own are nonlethal, but
TP53 mutations in 303 of 316 samples, suggesting that this is together result in a lethal phenotypeled to interest in inhibi-
essentially a requisite event in the development of high-grade tors of enzymes such as poly-ADP ribose polymerase (PARP)
serous cancers. that are involved in single stranded BER (177). Inhibition of
PARP leads to the persistence of DNA lesions normally repaired
by HR and makes HR-deficient cells particularly sensitive to
BRCA1 and BRCA2 chemotherapy-induced DNA injury (178). PARP inhibitors have
BRCA1 and BRCA2 germline mutations were found in 9% and been shown to be selective for cells with defects in the repair of
8% of high-grade serous cases respectively in the TCGA study, double-strand DNA breaks by HR, particularly in the context
and somatic mutations occurred in an additional 3% (145). Si- of BRCA1 or BRCA2 mutation. While normal cells can repair
lencing of BRCA1 due to promoter methylation was observed in the damage and survive, the BRCA-deficient cells cannot acti-
11% of cases as has been previously described (172,173). Defec- vate the HR system and therefore die (179). PARP inhibitors
tive HR repair of double stranded DNA damage due to loss of have demonstrated promising results in ongoing trials in ovar-
BRCA1/2 was predicted in 31% of high-grade serous ovarian ian cancer (180).
cancers. Other genes in the HR pathway are inactivated in some While only a minority of high-grade serous ovarian cancers
cancers and the HR pathway may be compromised in about half have germline BRCA1 or BRCA2 mutations, sporadic ovarian
of cases (Fig. 2.16). Patients with BRCA1 or BRCA2 mutations cancers can harbor acquired genetic and epigenetic defects in
have increased sensitivity to platinum chemotherapy and favor- BRCA1/2 and in other HR genes and proteins, such as RAD51
able survival relative to sporadic cases (174,175). Conversely, that may contribute to a BRCAness profile(181). Given the
the emergence of platinum resistance in these cancers may oc- shared role that BRCA1 and BRCA2 have with other DNA
cur due to back mutations in which the normal BRCA1 or repair genes, defects in these other DNA repair proteins could
BRCA2 sequence is restored (176). influence response to treatment, recurrence rates, and overall
Cancers with defects in the double stranded DNA HR re- survival and increase sensitivity to platinum drugs and PARP
pair pathway can be targeted effectively by inducing a second inhibitors. In this regard, it was shown using the TCGA data
hit in the form of inhibition of the single stranded DNA repair that a DNA repair pathway score was predictive of outcome in
pathway. This concept of synthetic lethalitythe combination ovarian cancer (182).
52 CHAPTER 2 MOLECU LAR PATHOGEN ESIS OF GYN ECOLOGIC CANCERS
FIGURE 2.16. Genomic fingerprint of HR pathway alterations. Each column represents an individual case; each row represents a gene. Only cases
with HR defects (N = 154) are shown. HR: homologous recombination.
Source: The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609615.
Overexpression of p53 protein is rare in stage I serous bor- that the ovarian tumor represents a metastasis from the endo-
derline tumors and well-differentiated serous cancers, but occurs metrium (205). In other cases, the PTEN mutation seen in the
to the development of gestational trophoblastic disease. How- and cell invasion (237,238). In one study in which genomic
ever, the presence of two identical copies of each chromosome techniques were used to compare gene expression between
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carcinomas. J Clin Oncol. 2011;29:30083015. primary or recurrence? Comparative patterns 18 E6 proteins with p53. Science. 1990;248:
177. Annunziata CM, OShaughnessy J. Poly (ADP- of p53 and K-ras mutations suggest that serous 7679.
ribose) polymerase as a novel therapeutic borderline ovarian tumors and subsequent se- 213. de Boer MA, Jordanova ES, Kenter GG, et al.
target in cancer. Clin Cancer Res. 2010;16: rous carcinomas are unrelated tumors. Cancer High human papillomavirus oncogene mRNA
45174526. Res. 2001;61:72647267. expression and not viral DNA load is associated
CHAPTER 2 MOLECU LAR PATHOGEN ESIS OF GYN ECOLOGIC CANCERS 59
with poor prognosis in cervical cancer patients. and in advanced-stage cervical carcinoma. Genes indicators of distant metastasis for early-stage
Clin Cancer Res. 2007;13:132138. Chromosomes Cancer. 1999;24:144150. invasive cervical cancers. J Natl Cancer Inst.
60
CHAPTER 3 H EREDITARY GYN ECOLOGIC CANCERS 61
were found in 10 (9.9%) of 101 patients without any family that patients with advanced stage BRCA1-associated disease
history of breast or ovarian cancer in first- or second-degree had a median survival of 77 months compared to a median sur-
Therapeutic Implications
Natural History of BRCA -associated BRCA1 and BRCA2 are known to be necessary for repair of
Ovarian Cancer double strand DNA breaks through homologous recombination
Over a dozen studies have reported on differences in outcome (23, 24). Therefore, tumor cells from BRCA-associated ovarian
between BRCA-associated and sporadic ovarian and fallopian cancers that have no working copy of either BRCA1 or BRCA2
tube cancers (8, 1019). In the first study to address this issue, are believed to be exquisitely sensitive to agents that induce dou-
Rubin and colleagues, utilizing a case-control design, reported ble strand DNA breaks, such as platinum-based chemotherapy.
on 53 patients with a deleterious BRCA1 mutation. They found While this mechanism likely explains at least some of the survival
62 CHAPTER 3 H EREDITARY GYN ECOLOGIC CANCERS
advantage seen in BRCA-associated ovarian cancer, until recently uncertain significance, as it is frequently not possible to char-
knowledge of this information did not provide a new therapeutic acterize whether the protein can tolerate the resulting amino
opportunity as almost all patients with serous ovarian cancer re- acid substitution or if the substitution will cause abrogation of
ceive platinum-based chemotherapeutics as part of first-line ther- protein function.
apy. In 2005, however, 2 independent groups hypothesized that Genetic counselors and other appropriately trained genetic
the BRCA-dependent homologous recombination pathway could professionals can assist in determining what are the most appro-
be stressed by inhibiting poly (ADP-ribose) polymerase (PARP), priate genetic tests for an individual patient. In addition, they
an enzyme necessary for the repair of single strand DNA breaks can assist in interpreting the results in context with the family
(25, 26). If this enzyme (and repair of single strand DNA breaks) history. Further, the genetic counselor can assist in identifying
is inhibited during DNA replication, the advancing replication who is the most appropriate individual to initiate genetic testing
fork converts single stand DNA breaks into double strand breaks with, as in many families, it may be more informative to initi-
to be repaired by homologous recombination. In patients with a ate testing in a relative other than the present individual. Lastly,
germline mutation in BRCA1 or BRCA2, the single nonmutant al- genetic counselors can help identify other relatives who should
lele is sufficient for allowing repair in non-tumor-associated cells. be informed of a potential inherited risk (39) and can assist pa-
However, tumor associated cells have lost both working alleles of tients with plans for such communication.
either BRCA1 or BRCA2 and therefore cannot utilize homologous
recombination, forcing the cell to use error-prone nonhomologous
end joining, which frequently leads to complex rearrangements and
eventual apoptosis (27). CANCER RISKS ASSOCIATED WITH
The first clinical data supporting the potential utility of PARP
inhibitors in BRCA-associated tumors were published in 2009 A BRCA1 OR BRCA2 M UTATION
(28). In this phase 1 trial, 60 patients, including 22 with either
For women with mutations in BRCA1, lifetime risks, through age
a documented BRCA1 or BRCA2 mutation, received increasing
70, of pelvic (ovarian, fallopian tube, or primary peritoneal) can-
doses of a novel PARP inhibitor, olaparib. Radiologic response
cer are on the order of 39% to 46%. For women with mutations
or stable disease was observed in 11 (9 ovarian and 2 breast
in BRCA2, the lifetime risk of pelvic cancer is 12% to 20% (40,
cancer) of 19 patients with heavily pretreated BRCA-associated
41). The average age of diagnosis of BRCA1-associated pelvic can-
ovarian, breast or prostate cancer. This was followed shortly
cers is 53, which is approximately 10 years earlier than the average
thereafter by a phase 2 study evaluating activity of olaparib
age of diagnosis of sporadic ovarian or fallopian tube cancer. Inter-
at two dose levels in 57 patients with BRCA-associated pelvic
estingly, the average age of BRCA2-associated pelvic cancer is 60 to
serous cancer (29). In this series, 11 of 33 patients treated at
62 years, which is no earlier than seen with sporadic disease (5, 8).
the higher dose level had complete or partial response and an
When considering the timing of risk-reduction approaches, it is also
additional 12 patients had stable disease. Given the promising
important to know risks of cancer by the age of menopause. For
results of these first two trials, there are over a dozen ongoing
women with BRCA1 mutations, 10% to 21% will develop pelvic
or planned trials of PARP inhibitors in BRCA-associated pelvic
cancer by age 50, but only 2% to 3% of women with BRCA2 mu-
serous cancer (30). Further, given that 9% to 15% of sporadic
tations will develop pelvic cancer by the same age (41, 42).
ovarian cancer has silencing of the homologous recombination
Breast cancer risks are also markedly elevated for women with
pathway through methylation of the BRCA1 promoter (17, 31,
mutations in these genes, with risks of breast cancer approaching
32), PARP inhibitors are also being actively investigated for
65% to 74% by age 70 for both carriers of BRCA1 and BRCA2
treatment of sporadic disease.
mutations (40, 41). Breast cancer also occurs substantially earlier
than seen in the general population, with 26% to 34% of carriers of
either BRCA1 or BRCA2 mutations developing breast cancer by
Genetic Counseling for Hereditary age 50 (40, 41, 43).
Breast and Ovarian Cancer Syndrome A number of genome-wide association studies (GWAS) have
identified single nucleotide polymorphisms (SNPS) that modify
Approximately 1 in 345 to 1 in 800 women have a BRCA1
breast and/or gynecologic cancer risk in the setting of a BRCA1
or BRCA2 mutation associated with hereditary breast and
or BRCA2 mutation (44). Unfortunately, none of these markers,
ovarian cancer (33, 34). Hereditary breast and ovarian cancer
alone or in combination, has been shown to alter BRCA-associated
syndrome is seen in all racial and ethnic groups. However, due
cancer risk at a magnitude necessary to appreciably guide recom-
to the phenomenon of genetic drift, several racial and ethnic
mendations for risk-reduction strategies (45).
groups have seen a marked increase in the population frequency
of specific mutations, known as founder mutations. Best known
of the founder mutations are the 185delAG and 5382insC mu-
tations in BRCA1 and the 6174delT mutation in BRCA2 that
are collectively found in 1 of 40 individuals of eastern European GU I DELI N ES FOR OFFERI NG
Jewish (Ashkenazi) heritage. Increased incidence of BRCA mu- GEN ETIC RISK ASSESSM ENT
tations has also been seen in individuals of Icelandic, Swedish,
Dutch, Polish, French Canadian, and Hungarian descent. FOR H EREDITARY BREAST AN D
The vast majority of deleterious mutations in BRCA1 and OVARIAN CANCER SYN DROM E
BRCA2 are nonsense mutations that lead to a premature stop
codon and a truncated protein. While most protein-truncating Several organizations have proposed guidelines for offering ge-
mutations are detected by direct sequencing of BRCA1 and netic risk assessment for hereditary breast and ovarian cancer
BRCA2, approximately 6% to 18% of clearly deleterious muta- syndrome. Likely, most relevant to the gynecologic oncologist
tions are caused by large genomic deletions or rearrangements are the guidelines jointly published by the American College
that will not be picked up on direct sequencing and need to of Obstetricians and Gynecologists (ACOG) and the Society of
instead be screened for by methods such as MLPA (3537). Gynecologic Oncology (SGO) (6) and those published by the
Additionally 6% to 17% of individuals undergoing direct se- National Comprehensive Cancer Network (NCCN) (7). Briefly,
quencing of BRCA1 or BRCA2 will have a missence mutation both of these guidelines state that hereditary cancer risk assess-
identified that causes a single amino acid substitution in the ment is a process that: (a) should include assessment of risk, ed-
protein (38). These missense mutations are termed variants of ucation, and counseling; (b) should be conducted by a physician,
CHAPTER 3 H EREDITARY GYN ECOLOGIC CANCERS 63
twice-yearly transvaginal ultrasound and CA-125 screening in development of stage II to IV breast cancer associated with MRI
women with BRCA1 or BRCA2 mutations was associated with screening = 0.30; 95% CI, 0.120.72) (55). Currently both the
possibly acceptable 71% sensitivity, 91% specificity, and 50% National Comprehensive Cancer Network and the American
positive predictive values. Importantly, a similar screening pro- Cancer Society recommend the combination of annual mam-
gram at Cedars-Sinai Medical Center could not replicate these mography and annual breast MRI, beginning by age 30, for
results. In this series of 213 women at increased risk of ovar- breast screening in women with BRCA mutations (7, 52).
ian cancer, including 33 with mutations in BRCA1 or BRCA2,
only 4 of 8 invasive ovarian cancers were screen detected, and
3 of the 4 screen detected cancers were stage IIIc (48). In 2007, Chemoprevention
Hermsen and colleagues reported on the experience of 888
women with BRCA1 or BRCA2 mutations who participated in Ovarian/ Fallopian Tube Cancer
ovarian cancer screening with annual transvaginal ultrasound Multiple studies have suggested that use of oral contraceptives in
and CA-125 for a mean of 1.7 years between 1993 and 2005. the general population is associated with a substantial and long-
In this study, 5 of the 10 incident invasive cancers presented as lasting reduction in the risk of ovarian cancer (56). Given this,
interval cancers with a normal screening result 3 to 10 months several authors have examined the impact of oral contraceptives
prior to diagnosis. Further, of the 5 screen detected cancers, 4 on ovarian cancer risk in the setting of BRCA1 or BRCA2 muta-
were stage III or IV, leading the authors to conclude that annual tions. In a recent meta-analysis of 5 case-control and retrospec-
screening is not efficacious (49). tive cohort studies, Iodice and colleague found that ever use of
Of note, all of the studies to date commenting on ovar- oral contraceptives was associated with a significant reduction
ian cancer screening in BRCA mutation carriers have been in ovarian cancer risk in both BRCA1 (summary relative risk =
retrospective case series and not rigorously conducted pro- 0.51; 95% CI, 0.400.65) and BRCA2 (summary relative risk =
spective screening trials. Two such prospective trials spe- 0.52; 95% CI, 0.310.87) mutation carriers (57). Further, lon-
cifically targeting women at familial/inherited risk are either ger use was associated with a greater risk-reduction, with a 36%
ongoing or recently completed, but not reported. In the re- risk reduction seen for each 10 years of use (summary relative
cently completed Gynecologic Oncology Group study 0199, risk = 0.64; 95% CI, 0.530.78).
a prospective study of risk-reducing salpingo-oophorectomy When caring for women with BRCA1 or BRCA2 mutations,
and longitudinal CA-125 screening among women at increased it is important, however, to evaluate for both breast and ovarian
genetic risk of ovarian cancer, participants elected either surveil- cancer risk, and the data regarding breast cancer risk has been
lance with annual transvaginal ultrasound and every 3 month somewhat more conflicting. Of 5 published studies addressing
CA-125 interrogated with the risk of ovarian cancer (ROCA) al- the impact of oral contraceptives on breast cancer risk in BRCA1
gorithm or risk-reducing salpingo-oophorectomy (RRSO) (50). mutation carriers, 3 suggested an increased risk of breast cancer
All participants in the study were genotyped, and just under 400 with oral contraceptive use and 2 showed no increase in risk
of the approximately 1600 women who elected surveillance (5862). Similarly in the 3 studies reporting on breast cancer
had a BRCA mutation. The study has completed data collec- risk with oral contraceptive use in BRCA2 mutation carries, 2
tion and is currently in analysis. The UK familial ovarian cancer studies suggested an increased risk, and one study showed no
screening study (UK FOCSS) is the other ongoing large-scale increase in risk (58, 60, 62). In the Iodice meta-analysis, neither
trial of women at familial or inherited risk (51). In this study, ap- BRCA1 (summary relative risk = 1.09; 95% CI, 0.771.54) nor
proximately 2350 women with greater than a 10% lifetime risk BRCA2 (summary relative risk = 1.15; 95% CI, 0.612.18) mu-
of ovarian cancer are being followed with annual transvaginal tation carriers demonstrated a statistically significant increased
ultrasound and every 4 month CA-125 also interrogated with risk of breast cancer with oral contraceptive use. However, oral
the ROCA algorithm. Study results are expected in 20132014. contraceptive formulations used before 1975 were associated
Until results from GOG 199 and UK FOCSS are available, with an increased risk of breast cancer (summary relative risk
despite the absence of clear evidence for benefit, women with = 1.47; 95% CI, 1.062.04). Given the data currently available,
mutations in BRCA1 or BRCA2 likely should be recommended it likely still makes sense to counsel patients that oral contra-
to consider ovarian cancer screening with transvaginal ultra- ceptives may be associated with some adverse impact on breast
sound and CA-125 determinations every 6 months from age 30 cancer risk. This potential risk, however, needs to be balanced
to 35 until they undergo definitive risk-reduction with risk-re- against the risk of unintended pregnancy and the benefit of oral
ducing salpingo-oophorectomy (7). contraceptives on ovarian cancer risk.
this study, tamoxifen appeared to be associated with a reduction reduction in breast cancer risk (HR = 0.53; 95% CI, 0.290.96).
of contralateral breast cancer risk in both BRCA1 (odds ratio However when BRCA1 and BRCA2 mutation carriers were
Timing of procedure. For most women with mutations in either developing synchronous or metachronous cancers. In a study
BRCA1 or BRCA2, RRSO should generally be considered between that examined 101 women with Lynch syndrome who had de-
age 35 and 40 and when childbearing is complete (6). For women veloped both GI cancer and gynecologic cancer, 51% presented,
with BRCA1 mutations, this age is recommended because only at a median age of 44, with their gynecologic cancer first, and
2% to 3% of women with mutations in this gene will develop pel- 49% presented with their GI cancer first (98).
vic serous cancer by age 40, but 10% to 21% of BRCA1 mutation Prior to the discovery of the genes responsible for Lynch syn-
carriers will develop pelvic serous cancer by age 50 years (4042). drome, criteria were formulated to identify families with Lynch
For women with BRCA2 mutations, the risk of pelvic serous cancer syndrome for research studies. The initial Amsterdam I criteria
by age 50 is only 2% to 3%. However, women with BRCA2 muta- focused on colon cancer and were subsequently revised (Amster-
tions who defer RRSO until the age of natural menopause, likely damII), to include all Lynch syndromeassociated cancers. The
lose the profound reduction against BRCA2-associated breast can- criteria include: (a) three or more relatives with Lynch syndrome
cer conferred by RRSO (74). For women with BRCA2 mutations associated cancers, (b) two affected relatives in successive gen-
who have already had bilateral mastectomy and ovarian ablation erations, (c) one affected relative is a first-degree relative of the
is not being utilized as part of adjuvant therapy for a prior breast other two, and (d) one or more relatives with Lynch syndrome
cancer, RRSO likely can be reasonably deferred until the mid-40s. associated cancer diagnosed before the age of 50 years.
Mastectomy
Several studies have demonstrated that risk-reducing mastectomy Pathology
(RRM) in women with BRCA1 or BRCA2 mutation is associated Unlike the ovarian cancers associated with BRCA1 and BRCA2
with an approximately 90% reduction in the risk of new breast mutations, the endometrial cancers associated with Lynch syn-
cancer (85, 86). Importantly, the impact on life expectancy may drome span a broader spectrum. In a study by Broaddus et al.,
be markedly less, as the majority of these cancers in women un- 43 of 50 (86%) endometrial cancers were endometrioid histol-
dergoing both mammography and breast MRI will be diagnosed ogy, with the remainder being papillary serous carcinoma, clear
at a curable stage. In a decision analysis by Kurian et al. RRM cell carcinoma, and malignant mixed mullerian tumors (99).
at age 40 (in addition to RRSO at age 40 and breast screening Interestingly, all of the nonendometrioid tumors in this study
starting at age 25) only increased the probability of survival to occurred in patients with MSH2 mutations. Among all of the
age 70 from 74% to 77% in carriers of BRCA1 mutations and patients with Lynch syndrome, 78% were diagnosed at stage I,
from 80% to 82% in carriers of BRCA2 mutations (87). Given 10% at stage II, and 12% at stage III or IV. Lymph-vascular space
these relatively small absolute changes in survival, either inten- involvement was noted in 24% of the cases, and 26% had deep
sive breast screening or risk-reducing mastectomy is likely a rea- myometrial involvement that was defined as invasion greater
sonable option for a woman with a BRCA1 or BRCA2 mutation. than 50%. Endometrial cancers that arise in the lower uterine
segment are rare in the general population, but are seen more
frequently in women with Lynch syndrome. In a study by Westin
et al., almost one third of patients with endometrial cancers
LYNCH SYN DROM E arising in the lower uterine segment were suspected to have
Lynch syndrome, based on tumor studies or germline testing
(100). This characteristic phenotype is similar to the increased
Epidemiology proportion of right-sided colon cancers seen in individuals with
Approximately 5% of endometrial cancer cases may be attrib- Lynch syndrome. Other pathologic features that have been seen
uted to an inherited predisposition (88). Lynch syndrome, or more frequently in Lynch syndromeassociated colon cancers,
hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, including poor tumor differentiation and tumor infiltrating lym-
accounts for the majority of these cases. Individuals with Lynch phocytes, have not been seen consistently in Lynch syndrome
syndrome have a germline mutation in one of four genes in the associated endometrial cancers.
DNA mismatch repair family; MLH1, MSH2, MSH6, or PMS2. The ovarian cancers seen in Lynch syndrome also have a dif-
While Lynch syndrome has historically been characterized by an ferent stage and histology spectrum from that seen in women
increased risk for colorectal cancer, women with Lynch syndrome with sporadic disease. In a recent series, 22 (47%) of 47 Lynch-
also have a substantial risk for endometrial cancer. The estimated associated epithelial ovarian cancers presented at stage I. Further,
risk for colon cancer in women is 40% to 60% and in men as serous cancers were underrepresented in this series, accounting
high as 80% (89, 90). In women, the lifetime endometrial cancer for only 28% of tumors. Endometrioid, clear cell, and mucinous
risk is approximately 40% to 60%. In a study specifically looking histologies were seen in 35%, 17%, and 5%, respectively (101).
at individuals with MSH6 mutations, risk for endometrial cancer
was 26% by age 70 and as high as 44% by 80 years of age, and
lifetime risk of colon cancer was 10% by age 70 and 20% by age Genetic Risk Assessment for
80 (91). Women with Lynch syndrome also have an approximate
5% to 10% lifetime risk for developing ovarian cancer. Other Lynch Syndrome
cancers associated with Lynch syndrome include cancers of the For gynecologic oncologists, identifying Lynch syndrome in a pa-
stomach, small bowel, renal pelvis and ureter, and brain. tient with endometrial cancer has important implications for both
In the general population, Lynch syndrome occurs in about 1 the woman with cancer and for her family members. Individuals
in 600 to 1 in 3000 individuals (92, 93). In a population-based with Lynch syndrome are at significant lifetime risk of developing
study on endometrial cancer patients, the incidence of Lynch a second primary malignancy. Therefore, when an endometrial
syndrome was 2.3%, which is similar to the 2.2% incidence of cancer patient is identified as having Lynch syndrome, appropri-
Lynch syndrome among colon cancer patients (94). For women ate colon cancer screening can be initiated. In addition, if a specific
with endometrial cancer under the age of 50, the proportion with mutation in one of the DNA mismatch repair genes is identified in
Lynch syndrome increases to 5% to 9% (9597). The mean age the endometrial cancer patient, her family members can undergo
of diagnosis for endometrial cancer in women with Lynch syn- targeted predictive genetic testing for the same mutation.
drome is 47 years, which is substantially lower than the mean Historically, guidelines to assist physicians in identifying
age of diagnosis of endometrial cancer in the general population, patients with Lynch syndrome have focused on colon cancer
60 years. Women with Lynch syndrome are at increased risk of patients. The Bethesda criteria, which were established in 1997
CHAPTER 3 H EREDITARY GYN ECOLOGIC CANCERS 67
and revised in 2004, assist physicians in identifying colon cancer less than 50, patients with endometrial cancer with molecular
patients who may have Lynch syndrome (102). However, it has or immunohistochemical evidence of a mismatch repair defect,
(107, 108) (Table 3.5). Colon cancer screening is recommended reduction in reported pain when the procedures were done con-
in individuals with Lynch syndrome every 1 to 2 years starting currently under sedation.
at the age of 20 to 25 years (or 30 years in patients with known In the general population, progestin-based oral contracep-
MSH6 mutations). Jarvinen et al. reported a reduction in the inci- tives have been shown to decrease endometrial and ovarian
dence of invasive colorectal cancer from 16% to 6% (p = 0.014), cancer risk by 50% (56, 115, 116). Progestin therapy is also
with a relative risk of death of 0.34 (95% CI, 0.170.68) in effective at reversing complex atypical hyperplasia and early
individuals with Lynch syndrome who received colonoscopy or endometrial cancer (117, 118). While there are no epidemiologic
sigmoidoscopy and barium enema every 3 years compared to data to support the role of progestins or progestin-based oral
those who received no routine screening (109). contraceptives as chemoprevention in women known to have
In contrast to colon cancer screening, there are no proven Lynch syndrome, a short-term biomarker study demonstrated a
screening strategies for the early detection of endometrial or significant decrease in endometrial proliferation using both 150
ovarian cancer in women with Lynch syndrome. Two European mg depo medroxyprogesterone acetate and 30 g ethinyl estra-
studies reported a high false-positive rate and poor efficacy using diol/0.3 mg norgestrol oral contraceptive pill (119). An ongoing
measurement of endometrial stripe by transvaginal ultrasound trial is examining the use of the levo-norgestrel IUD as a chemo-
as an endometrial cancer screening tool (110, 111). More prom- preventive in women with Lynch syndrome.
ising, two studies have reported identification of premalignant
lesions and endometrial cancers in asymptomatic women with
Lynch syndrome using office endometrial biopsy as a screening
Risk-Reducing Surgery
strategy (112, 113). One of these studies included 175 women with Risk-reducing hysterectomy and salpingo-oophorectomy are
known MLH1, MSH2, or MSH6 gene mutations and reported reasonable options for prevention of endometrial and ovarian
a stage migration with 7% of women in the surveillance group cancer in women with Lynch syndrome. A multi-institutional ret-
presenting with Stage III/IV disease versus 17% of women who rospective study of women with Lynch syndrome demonstrated
presented symptomatically (112). The second study on 100 that the incidence of endometrial cancer fell from 33% to 0%
women from Lynch kindreds reported that routine endometrial in women who underwent hysterectomy, and the incidence of
sampling resulted in a significantly higher rate of malignancies ovarian cancer fell from 5.4% to 0% in women who underwent
and premalignancies compared with prior historical controls in salpingo-oophorectomy (120). The risk of primary peritoneal
which routine annual endometrial sampling was not performed cancer after oophorectomy in women with Lynch syndrome is
(6.3% vs. 1.4%, p = 0.026) (113). No studies have examined unclear, although one case report has been published (121). It
the mortality impact of annual endometrial sampling in women is also important to note that occult endometrial cancers have
with Lynch syndrome. Consensus guidelines currently recom- been found in asymptomatic women at the time of risk-reducing
mend consideration of annual surveillance with endometrial hysterectomy and salpingo-oophorectomy (122124).
biopsy for evaluation of the uterus and transvaginal ultrasound Women with Lynch syndrome should be counseled that the
for evaluation of the ovaries (108). It is important to emphasize estimated risk for endometrial cancer by age 40 does not exceed
to the patient that data to support these recommendations are 2% and the estimated risk of ovarian cancer by age 40 does not
limited. A study by Huang et al. demonstrated the feasibility exceed 1% (90). Therefore, women with Lynch syndrome can
and acceptability of performing the annual endometrial biopsy, complete childbearing prior to consideration of risk-reducing
while the patient is sedated for the screening colonoscopy in surgery. In addition, there does not appear to be a contraindi-
women with Lynch syndrome (114). There was a substantial cation to estrogen replacement therapy after risk-reducing sur-
gery. Two studies have performed cost-effectiveness analyses of
options for gynecologic risk reduction in women with Lynch
syndrome (125, 126). Both studies found that risk-reducing hys-
Table 3.5 Risk-Reduction Recommendations for terectomy and salpingo-oophorectomy led to both the lowest
Women with Lynch Syndrome cost and the greatest increase in quality-adjusted life years.
For patients undergoing colonic resection for a Lynch-
Gastrointestinal associated colorectal cancer, it may be reasonable to discuss
Colonoscopy every 12 years beginning at age 2025 (or age 30 concomitant hysterectomy with BSO. However, for premeno-
for women with MSH6 mutations) pausal patients who are diagnosed with Lynch syndrome at the
Consider esophagogastroduodenoscopy(EGD) every 23 years same time as their colorectal cancer, there can be substantial
beginning at age 3035 fertility and psychosocial issues associated with this approach.
Consider capsule endoscopy every 23 years beginning at age
3035
Consider chemoprevention with aspirin or NSAIDs
Gynecologic
OTH ER I N H ERITED SYN DROM ES
Patients should be aware that abnormal vaginal bleeding war-
WITH A GYN ECOLOGIC CANCER
rants evaluation
Consider screening with annual endometrial biopsy and trans- COM PON ENT
vaginal ultrasound beginning at age 30
Consider chemoprevention with oral contraceptives or progestins Cowden Syndrome, Li-Fraumeni syndrome, and Peutz-Jeghers
Consider risk-reducing hysterectomy with bilateral salpingo- syndrome are rare autosomal dominant inherited cancer suscep-
oophorectomy between age 35 and 40 and when childbearing is tibility syndromes that include gynecologic cancers as part of
complete their cancer spectrum.
Urologic
Consider annual urinalysis starting at age 2530
Cowden Syndrome
Adapted from Lindor NM, Petersen GM, Hadley DW, et al. Recommendations Cowden syndrome is caused by germline mutations in the
for the care of individuals with an inherited predisposition to Lynch syndrome: a
systematic review. JAMA 2006;296(12): 15071517 and National Comprehensive
PTEN gene. Individuals with Cowden Syndrome are at in-
Cancer Network: NCCN Clinical Practice Guidelines in OncologyColorectal creased risk for both benign and malignant processes. These
Cancer Screening. Version 2.2012. http://www.nccn.org. 2012. include gastrointestinal polyps, thyroid disease, benign breast
CHAPTER 3 H EREDITARY GYN ECOLOGIC CANCERS 69
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40. Antoniou A, Pharoah PD, Narod S, et al. Aver- 57. Iodice S, Barile M, Rotmensz N, et al. Oral con- tion of BRCA1- and BRCA2-associated breast
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41. King MC, Marks JH, Mandell JB. Breast and ovar- and BRCA2 mutation carriers. J Natl Cancer Inst. JAMA. 2010;304(9):967975.
ian cancer risks due to inherited mutations in BRCA1 2002;94(23):17731779. 76. Manchanda R, Drapkin R, Jacobs I, et al. The role of
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43. Ford D, Easton DF, Stratton M, et al. Genetic het- use, and breast cancer before age 50. Cancer Epide- oophorectomy in patients with germline mu-
erogeneity and penetrance analysis of the BRCA1 miol Biomarkers Prev. 2006;15(10):18631870. tations in BRCA1 or BRCA2. J Clin Oncol.
and BRCA2 genes in breast cancer families.The 61. Gronwald J, Byrski T, Huzarski T, et al. Influence of 2007;25(20):29212927.
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Genet. 1998;62(3):676689. cer risk in BRCA1 mutation carriers from Poland. reducing salpingo-oophorectomy in BRCA mu-
44. Barnes DR, Antoniou AC. Unravelling modifi- Breast Cancer Res Treat. 2006;95(2):105109. tation carriers: role of serial sectioning in the
ers of breast and ovarian cancer risk for BRCA1 62. Brohet RM, Goldgar DE, Easton DF, et al. Oral detection of occult malignancy. J Clin Oncol.
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45. Stadler ZK, Thom P, Robson ME, et al. Genome- from EMBRACE, GENEPSO, GEO-HEBON, and pathologic findings of prophylactic salpingo-
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46. Surveillance, Epidemiology, and End Results (SEER) 63. King MC, Wieand S, Hale K, et al. Tamoxifen and 80. Yates MS, Meyer LA, Deavers MT, et al. Micro-
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preventive surgery and screening for breast and 2001;286(18):22512256. 81. Medeiros F, Muto MG, Lee Y, et al. The tubal fim-
ovarian cancer in BRCA mutation carriers. J Clin 64. Lakhani SR, Van De Vijver MJ, Jacquemier J, et al. bria is a preferred site for early adenocarcinoma
Oncol. 2002;20(5):12601268. The pathology of familial breast cancer: predictive in women with familial ovarian cancer syndrome.
48. Liede A, Karlan BY, Baldwin RL, et al. Cancer value of immunohistochemical markers estrogen The Am J Surg Pathol. 2006;30(2):230236.
incidence in a population of Jewish women at receptor, progesterone receptor, HER-2, and p53 82. Shaw PA, Rouzbahman M, Pizer ES, et al. Can-
risk of ovarian cancer. J Clin Oncol. 2002;20(6): in patients with mutations in BRCA1 and BRCA2. didate serous cancer precursors in fallopian tube
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49. Hermsen BB, Olivier RI, Verheijen RH, et al. No effi- 65. Foulkes WD, Metcalfe K, Sun P, et al. Estrogen re- Pathol. 2009;22(9):11331138.
cacy of annual gynaecological screening in BRCA1/2 ceptor status in BRCA1- and BRCA2-related breast 83. Powell CB, Chen LM, McLennan J, et al. Risk-
mutation carriers; an observational follow-up cancer: the influence of age, grade, and histological reducing salpingo-oophorectomy (RRSO) in BRCA
study. Br J Cancer. 2007;96(9):13351342. type. Clin Cancer Res. 2004;10(6):20292034. mutation carriers: experience with a consecutive
50. Greene MH, Piedmonte M, Alberts D, et al. A 66. Narod SA, Brunet JS, Ghadirian P, et al. Tamoxifen series of 111 patients using a standardized surgical-
prospective study of risk-reducing salpingo- and risk of contralateral breast cancer in BRCA1 pathological protocol. Int J Gynecol Cancer. 2011;
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among women at increased genetic risk of ovar- Hereditary Breast Cancer Clinical Study Group. 84. Kuhn E, Kurman RJ, Vang R, et al. TP53 muta-
ian cancer: design and baseline characteristics: a Lancet. 2000;356(9245):18761881. tions in serous tubal intraepithelial carcinoma and
Gynecologic Oncology Group study. Cancer Epi- 67. Weitzel JN, Robson M, Pasini B, et al. A com- concurrent pelvic high-grade serous carcinoma
demiol Biomarkers Prev. 2008;17(3):594604. parison of bilateral breast cancers in BRCA evidence supporting the clonal relationship of the
51. Rosenthal AN. Ovarian cancer screening in the carriers. Cancer Epidemiol Biomarkers Prev. two lesions. J Pathol. 2012;226(3):421426.
high-risk populationthe UK Familial Ovarian 2005;14(6):15341538. 85. Meijers-Heijboer H, van Geel B, van Putten WL,
Cancer Screening Study (UKFOCSS). Intl J Gyne- 68. Kauff ND, Satagopan JM, Robson ME, et al. et al. Breast cancer after prophylactic bilateral
col Cancer. 2012;22 (suppl. 1):S27S28. Risk-reducing salpingo-oophorectomy in women mastectomy in women with a BRCA1 or BRCA2
52. Saslow D, Boetes C, Burke W, et al. American with a BRCA1 or BRCA2 mutation. N Engl J mutation. N Engl J Med. 2001;345(3):159164.
Cancer Society guidelines for breast screening Med. 2002;346(21):16091615. 86. Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral
with MRI as an adjunct to mammography. CA 69. Rebbeck TR, Lynch HT, Neuhausen SL, et al. prophylactic mastectomy reduces breast cancer
Cancer J Clin. 2007;57(2):7589. Prophylactic oophorectomy in carriers of BRCA1 risk in BRCA1 and BRCA2 mutation carriers:
53. Brekelmans CT, Seynaeve C, Bartels CC, et al. Effec- or BRCA2 mutations. N Engl J Med. 2002;346(21): the PROSE Study Group. J Clin Oncol. 2004;
tiveness of breast cancer surveillance in BRCA1/2 16161622. 22(6):10551062.
CHAPTER 3 H EREDITARY GYN ECOLOGIC CANCERS 71
87. Kurian AW, Sigal BM, Plevritis SK. Survival expression in primary endometrial cancer. Gynecol 119. Lu K, Chen L, Lynch H, et al. A prospective,
analysis of cancer risk reduction strategies Oncol. 2009;114(3):486490. multi-center randomized study of oral contracep-
basement membrane
FIGURE 4.1. Paradigm of cancer progression. Progression from the earliest detectable event of complex hyperplasia to overt invasive
and metastatic malignancy is over a decade for endometrial and cervical cancers. The new recognition of the tubal epithelium as the source for
type 2 high-grade serous ovarian cancer leaves this time frame still undetermined. Where identified early, each of these cancers has a high cure rate
and long overall survival. However, when identified at or beyond the stage of microinvasion, progressive disease and death from disease is common.
72
CHAPTER 4 I NVASION, M ETASTASIS, AN D ANGIOGEN ESIS 73
growth (1). Many proangiogenic and antiangiogenic factors are the vasculature. Their staging is dependent on the extent of local
secreted into and by elements of the tumor microenvironment structural invasion and/or lymph node status. In most solid
Angiogenesis
A
Spheroid
Ovarian
epithelium
Ovarian
tumor
Basal
membrane
Stroma
Angiogenesis
B (VEGF, FGF,
lymphatic spread etc)
followed by late
hematogenous spread
FIGURE 4.2. Ovarian cancer: shedding and spreading. The primary ovarian tumor located in the ovarian stroma metastasizes in two different ways.
The first mechanism (A), occurring early is by shedding cancer cells into the peritoneal cavity after reaching the ovarian surface; the second mechanism (B), later
occurring, is invasion into surrounding tissues. Cells shed in the peritoneal fluid, form spheroids that have acquired mechanisms to resist anoikis. These spheroids
will then implant on the peritoneal mesothelial surface and cause stromal activation with desmoplasia, inflammation, and angiogenesis. ECM: extra-cellular matrix;
FGF: fibroblast growth factor; MMPs: matrix metalloproteinases; VEGF: vascular endothelial growth factor.
74 CHAPTER 4 I NVASION, M ETASTASIS, AN D ANGIOGEN ESIS
Sir James Paget stated in 1889 that the microenvironment of other immune cells, endothelial cells, and stromal cells (20).
each organ, the soil, influences the survival and growth of tumor Cancer cells may also cause transdifferentiation of host cells.
cells, the seed (16,17). Multiple overlapping signal and adhesion Tumor-released inflammatory cytokines act on local cells to
networks cooperate to enable molecular and structural remod- convert host fibroblasts into cancer-associated fibroblasts
eling of tissues that overall support tumor invasion, growth, and (CAFs). Activated CAFs help promote ovarian and endome-
metastatic dissemination. Cellular behavior and the activation trial tumor cell invasion through activation and production
or inactivation of genes are influenced heavily by the microenvi- of growth factors, such as tumor growth factor- (TGF) and
ronment (1,14). Gene expression profiling and proteomics have chemokines(14,30,31). CAFs are part of a paracrine loop that
identified a variety of factors that are upregulated in the micro- increases cancer cell invasion (30). Furthermore, there are multi-
environment of gynecological tumors. This reinforces the idea ple cell interactions and stimulatory and inhibitory factors lead-
that complex interplay of molecules and signals are needed for ing to feedback loops that help amplify and sustain the tumor
tumor sustainability. Additionally, the microenvironment has a cells in this environment (32).
plasticity that allows participating elements to vary throughout Communication between tumor cells and host cells at distant
the events of cancer progression. The flexibility of the microen- tissue sites via circulating factors, immune cells, chemokines,
vironment supports survival of the tumor cells and their ability and growth factors can prime and direct the location of future
to withstand an otherwise harsh environment with elements of metastatic tumor growth (33). Tumor-associated macrophages,
hypoxia, metabolic stress, and inflammation (3). recruited by the presence of the tumor, alter the local chemo-
kine balance resulting in directed migration, proliferation, and
differentiation of the vascular cell network and inflammatory
infiltrate of the tumor microenvironment. This functions to
Inflammation/Priming support tumor growth, both at the primary tumor and upon
Inflammation may promote carcinogenesis and dissemination metastasis(20). Shibuya and colleagues demonstrated enhanced
through several mechanisms affecting growth, invasion, angio- matrix metalloproteinase (MMP)-9, a protease that breaks down
genesis, and neoplastic changes (18). These inflammatory mech- the ECM, was measured in the lung preceding demonstrable
anisms include but are not limited to the production of reactive tumor cell metastasis, suggesting that this was induced by sig-
oxygen species and free radicals that directly damage DNA and nals from the distant primary tumor in a paracrine fashion(34).
proteins, and production of proinflammatory/proangiogenic Therefore, the role of the immune system in cancer is complex
molecules, such as cytokines, tumor necrosis factor- (TNF), and supports the idea that a permissive microenvironment is
and interleukins (18). Various immune cells have been found as critical for the initiation of tumor growth and establishment of
part of the tumor inflammatory infiltrate. Among them, macro- metastatic lesions at secondary sites (15).
phages play a central role in most solid malignancies (19). Some
T cells facilitate invasion of tumor cells by altering macrophages
into a more invasive phenotype in an IL-4 dependent manner
supporting the idea that inflammation mediators play a role in Chemokines/Growth Factors
cancer progression (20). Inflammatory factors can also increase Chemotactic cytokines, known as chemokines, are small,
inflammatory enzymes such as cyclooxygenase-2, which lead to secreted proteins or peptides that help regulate cell motility.
the production of other proinflammatory products (21). Studies Their primary function is chemoattraction and activation of
have shown an inverse relationship between nonsteroidal anti- leukocytes that then recruit other immune and/or inflamma-
inflammatory drugs and reduced risk of ovarian and cervical tory cells from the blood to the affected site. These proteins are
cancers (18,22,23). implicated in initiation and progression of cancer (35). Cancer
Multiple causes of local inflammation including exposure cells and many cells in the malignant microenvironment produce
to talc, asbestos, and presence of endometriosis and recurrent and/or respond to chemokines in an autocrine or paracrine man-
pelvic inflammatory disease have been identified as putative ner via chemotaxis, migration up a concentration gradient, or
risk factors for ovarian cancer (24,25). Cervical cancer studies chemokinesis, migration within a chemoattractant milieu(32).
have shown that, in addition to HPV, other sexually transmitted Chemokines and their receptors act at many stages of tumor
infections such as herpes simplex virus and Chlamydia are asso- progression, ranging from cell transformation, angiogenesis
ciated with increased risk of carcinoma in situ and/or invasive promotion, to tumor and supporting cell growth. Tumor cell
cervical cancer (26). It is believed that the subsequent inflamma- passage through the ECM, the vasculature, and/or lymphatics
tory response and micro-ulceration that follows these non-HPV is mediated by chemokines (35). Growth factors, differentiated
infections increase the epithelial cell repair and proliferation, from chemokines by their definition initially as growth pro-
permitting or promoting transformation (27). One study reported moters for epithelial not inflammatory cells, also play a role in
that cervical inflammation, independent of infections, was asso- tumor ascites formation, motility, invasion, and migration (24).
ciated with squamous metaplasia of the cervix, a precursor to One of many important chemokine pairs is the receptor
malignancy (28). CXCR4 and its ligand CXCL12. Together, they activate signal-
The menstrual cycle is a physiologic inflammatory process. ing pathways that enhance proliferation, migration, angiogene-
The endometrium is a dynamic cyclic organ with cycles of sis, and invasion of gynecologic cancers (36,38). Normal ovaries
growth, remodeling, differentiation, and angiogenesis. Estrogen express very little CXCR4; whereas, it is expressed in approxi-
drives these changes by facilitating the release of inflammatory mately 60% of ovarian cancers. CXCL12 is expressed in more
mediators from the epithelial, stromal, and vascular cells of the than 90% of ovarian cancers (37). CXCR4 was found to be the
endometrium (18,29). Increased exposure of the endometrium only receptor of 14 chemokine receptors studied to be expressed
to inflammation occurs by the same mechanisms that are con- in ovarian cancer cells (38). Its expression is an independent
sidered risk factors for endometrial cancer. These endometrial negative prognostic factor for progression-free and overall sur-
risk factors include unopposed estrogen use, polycystic ovarian vival in ovarian cancer (39). AMD3100, a CXCR4 inhibitor,
syndrome, excessive menstruation, obesity, and diabetes. There- blocked CXCL12-stimulated migration of ovarian cancer cells
fore, it is believed that inflammation alone or in conjunction in vitro (40,41). Blockade of CXCR4/CXCL12 activation led to
with estrogen plays a role in the development of endometrial reduced tumor growth and prolonged survival in ovarian cancer
cancer (18). xenografts (37).
Tumor cells coopt normal host cells and rely on communica- Interleukins-8 (IL-8) and -6 (IL-6) are multifunctional chemo-
tion with other cell types including macrophages, T cells and kines that are secreted by multiple cell types, including monocytes,
CHAPTER 4 I NVASION, M ETASTASIS, AN D ANGIOGEN ESIS 75
neutrophils, endothelial and mesothelial cells, and tumor cells. are found in patients with recurrent ovarian cancer (51). Lack
They are usually activated during an inflammatory response of specificity and sensitivity of circulating ATX concentration
LPA
RTK
ras
raf
RHO-GEF
PI3K MEK ERK MAPK
RHOA
PTEN Akt p-Akt NFKB
Cytoskeletal
Cell contraction,
survival p -mTOR mTOR cell rounding
growth
HIF-1 expression
VEGF expression
FIGURE 4.3. Molecular pathways. LPA is a well-recognized and potent prosurvival and angiogenic factor produced and
secreted by ovarian cancer. LPA signals through the LPA receptor, a 7-pass transmembrane G-protein coupled receptor. LPA
promotes expression of VEGF for angiogenesis and cell survival through the PI3K/AKT, NFB, and MAPK signaling pathways.
Receptor tyrosine kinases, RTK, are a broad family of receptors for multiple growth factors. Their activation also promotes
cell survival, invasion, angiogenesis, and proliferation through the ras, PI3K/AKT, NFB, and MAPK pathways. ERK: extracellular
regulated kinase; MAPK: mitogen-activated protein kinase; MEK: MAP-ERK kinase; mTOR: mammalian target of rapamycin; NFB:
nuclear factor B; Rho-GEF and RHO A are Rho family GTPases.
76 CHAPTER 4 I NVASION, M ETASTASIS, AN D ANGIOGEN ESIS
and inhibiting them decreases cancer invasiveness (58). Rho by tumor progression, new signals are propagated that can pro-
GTPase family members Rho, Rac, and CDC42 have roles mote tumor growth, survival, and metastasis (14,66).
in membrane trafficking, cell adhesion, and remodeling of the
actin cytoskeleton in gynecologic and other cancers (32). Inhibi-
tion of Rho kinase significantly inhibited LPA-induced invasion CellCell Interactions
and motility in human ovarian and cervical cancer cells in a dose-
Cadherins are calcium-dependent transmembrane glycoproteins
dependent manner in vitro and in xenograft models (58,65).
that are expressed in the early stages of development of various
Activation of these Rho kinase pathways lead to actin polym-
tissues. There are three primary cadherins: epithelial (E), neural
erization, followed by formation of membrane protrusions that
(N), and placental (P) (67). Each, found commonly in desmo-
are required for migration (32). Similar studies are under way
somes and cell junctions, activates intra- and intercellular com-
for endometrial and cervical cancer (61).
munication (14). The cadherin intracellular portion connects,
through - and/or -catenin, to actin microfilaments, anchor-
ing cells to one another (2). Additionally, cadherins interact
with various cell surface receptors, including receptor tyrosine
ADH ESION kinases, such as epidermal growth factor receptor, to propagate
intracellular signals resulting in migration, apoptosis, growth
The concept of shedding and spreading in ovarian and other control, and differentiation of tumor cells (66).
gynecologic cancers underscores the need for cells to attach E-cadherin, a metastasis suppressor molecule, is the most
to secondary sites and initiate secondary tumor masses. The studied member of the cadherin family (68); its downregulation
most common sites of such adhesion is the mesothelial lining has been associated with transition to a mesenchymal pheno-
of the peritoneum, bowel serosa, or vessel walls (63,64). This type, increased invasiveness, tumor progression, and poor sur-
occurs via adhesion molecules, of which there are four catego- vival (2,69,70). When E-cadherin expression is decreased, it is
ries: integrins, cadherins, immunoglobulin super family adhe- countered by upregulation of N- and P-cadherins. This cadherin
sion molecules (CAMs), and selectins. Each class has different switch also has been noted during normal development when
structure, functions, and binding partners, and is expressed in migration, budding, and other invasive behaviors are necessary,
various degrees on the surface of different cells (Fig. 4.4). They such as during embryogenesis (71). Physiologic cadherin switch-
participate in cellcell and/or cellsubstratum binding, yield- ing occurs when cells have reached their secondary site and the
ing a complexity of adherence and signaling possibilities. When cadherins again switch and cells alter phenotype. This behavior,
expression or function of adhesion molecules becomes altered mimicked in tumor during epithelialmesenchymal transition
Cellular transformation
and tumor proliferation
Lose of cell-cell and
cell-matrix adhesion
Basal membrane
Extra-cellular matrix
Attached Unattached degradation by proteases
integrin integrin (MMPs) and invasion.
Integrins
Cadherins
Extracellular matrix
PI3K and NFKB Caspase 8
p53
Bcl2
D
N
A
FIGURE 4.4. Invasion. Cancer cells lose their cell-to-cell (cadherin) and cell-to-matrix (integrin) attachment
releasing single cells and allowing for cell migration. The release of proteases (MMPs, serine proteases) promotes ECM
degradation forming tracks for cancer cells to migrate and invade surrounding tissues. Integrins can initiate prosurvival or
proapoptotic signals depending on their attachment to the ECM. Metastatic cancer cells have acquired mechanisms to
resist anoikis.
CHAPTER 4 I NVASION, M ETASTASIS, AN D ANGIOGEN ESIS 77
albeit without a secondary cadherin switch, leads to release of RGD and integrin binding has been used to focus drug
-catenin and its translocation to the nucleus (3). -catenin then and immunotherapy delivery in preclinical models (87,88).
further expansion of the tumor would require new blood vessel the basement membrane has defects in its structure leading to
formation (124126). Not only do these new vessels provide immature and leaky vessels (139,140). Splitting is a different
E: Lumen formation
endothelial cell
pericyte VE-cadherin Pericyte
containing recruitment
extracellular matrix
adherent juctions (PDGF)
red blood cell
glycoprotein
adherent junction
C: ECM D: Endothelial
B: Release of remodeling
proteases cell migration
(MMPs) (sprouting)
A: Endothelial cell
activation
(VEGF, FGF)
Basal
membrane
FIGURE 4.5. Angiogenesis sprouting. A. Endothelial cells are activated by multiple angiogenic factors secreted by tumor cells and cells
of the tumor microenvironment. B, C. Proteases are released with the resulting remodeling of the extracellular matrix. D. Activated endothelial
cells migrate into the stroma forming endothelial cords in the sprouting process. E. After cellular polarization, negatively charged glycoproteins and
the cytoskeleton retract, forming a vascular lumen. Pericytes are recruited for maturation of the blood vessel, mainly through the action of PDGF.
80 CHAPTER 4 I NVASION, M ETASTASIS, AN D ANGIOGEN ESIS
be found expressed on other cells, including ovarian cancer whether multitargeted agents will offer greater clinical benefit
cells (148). Activation of VEGFR1 and -2 is important for the than specific VEGF pathway inhibitors (179).
recruitment, stimulation, and proliferation of endothelial cells,
resulting in angiogenesis. Activation of VEGFR2 by VEGF-A has
a major permeability-enhancing effect important in the forma-
tion of ascites (128,149). VEGF-C and D activate VEGFR3 Lymphangiogenesis
and stimulate lymphangiogenesis. The lymphatic system is composed of the lymphatic vessels and
Upregulation of VEGFs is mediated by tissue hypoxia, hypo- lymphoid tissue. It has three primary physiologic functions:
glycemia, and growth factors. The tumor microenvironment (a)maintenance of the blood volume through reabsorption of
is hypoxic and acidic, both of which stimulate angiogenesis by interstitial fluid; (b) immunological surveillance; and (c) trans-
induction of the hypoxia-inducible factor 1 (HIF-1) (10,150). port of fat from the bowel to the liver. The first two functions are
VEGF and VEGFR-1 are under the transcriptional regulation by involved in cancer progression and metastasis (180). There are
HIF-1(151). HIF-1 is overexpressed in several solid tumors, three main elements in lymphangiogenesis, VEGF-C, VEGF-D,
including ovarian carcinomas (152). Tumor growth factor signal- and their receptor, VEGFR3 (180). These VEGFs also are
ing cascades, such as the LPA, NF-B, and phosphatidylinositol-3' induced by hypoxia and angiogenic signals, tumor cells, infil-
kinase (PI3K) pathways, are activated by tumor and stromal- trating inflammatory cells, and stromal cells. Lymph vessels are
induced growth factors and can result in VEGF induction in ovar- low-pressure vessels with limited basement membrane and no
ian cancer (153156). stromal components, permissive to entry and exit of tumor cells,
Ovarian carcinomas that have high expression of VEGF immune cells, and pathogens and therefore are a ready route
were found to result in shorter patient survival (157); concor- for metastasis (181183). High expression of VEGF-D in epi-
dant results were found with serum concentrations of VEGF thelial ovarian tumor was associated with higher FIGO stage,
suggesting poor patient prognosis (158). VEGF is secreted into intratumoral lymphatic vessels, tumor lymphatic invasion, and
malignant ascites by ovarian cancer cells, contributing to the lymph node metastasis. VEGF-D, intratumoral lymphatics, and
increasing ascites burden through its effects on vascular perme- lymphatic invasion are independent prognostic factors for over-
ability (159161). all survival and disease-free survival in patients with epithelial
ovarian carcinoma (184).
Platelet-Derived Growth Factor
Platelet-derived growth factor (PDGF) stimulates angiogenesis
and also activates stromal and tumor cells (162165). Its expres- M ETASTASIS
sion has been demonstrated in epithelial ovarian carcinomas
but not in borderline ovarian tumors (166). PDGF is a dimeric Metastasis, the spread of malignant cells from the primary
protein composed of two closely related A- and B-chain poly- tumor to other sites, is the culmination of the steps discussed
peptides encoded by independent genes (167). Three heterodi- abovegain and loss of cell and matrix adhesion, proteolysis,
mers are formed that act in an autocrine and paracrine fashion and migrationand requires cancer cells to overcome many
in ovarian cancer and angiogenesis through two receptors, barriers for successful travel and secondary growth. Cancer cells
PDGFR and (166). PDGF-BB stimulates migration of endo- utilize physiologic mechanisms that maintain cellular and tissue
thelial cells by increasing transcription and secretion of VEGF homeostasis, to promote tissue invasion, cell survival and pro-
by PDGFR-expressing endothelial cells; activation of PI3K is liferation. Survival in alternative microenvironments requires
important for this response (163,168). PDGF-mediated secre- that successful metastasis also use mechanisms to overcome loss
tion of VEGF protected endothelial cells in vitro from apoptosis of critical stimuli, such as matrix attachment and nutritional
caused by serum starvation, indicating an indirect role of PDGF restriction (2,3,185).
in supporting tumor angiogenesis through activation of survival
pathways (168). The presence and potential prognostic value of
the PDGFs and PDGFRs in ovarian cancer has not translated
to clinical value as most of the multikinase inhibitors tested to Anoikis
date, such as imatinib, with inhibition of PDGFR activity have Anoikis, derived from Greek and meaning homelessness (5,186),
shown limited activity in gynecologic cancers (166,169172). is a specific apoptotic process triggered by loss of, or inappro-
priate cell attachment to the ECM. It is a physiologic phenom-
enon that maintains cell and tissue homeostasis. Resistance
Fibroblast Growth Factor to anoikis is important to cancer cells because it allows them
The fibroblast growth factor (FGF) family includes several to resist apoptosis during the metastatic process, such as upon
ligands interacting with four FGF receptors (FGFR). Gene single cell release from a primary tumor and migration within
amplification of FGFR2 has been found in ovarian and endome- the matrix or when floating in effusions (11,187). Cellcell
trial cancer (173). FGFs are involved in proliferation, migration, adhesion prevents anoikis, even in the setting of ECM detach-
and differentiation of vascular endothelial cells in a VEGF- ment (188). Ovarian cancer cells shed into the peritoneal fluid
independent manner; they also are secreted by and/or effect a form viable clusters, resist anoikis, and later can adhere and
wide variety of other cell types in the tumor microenvironment. invade into serosal mesothelium (189).
FGF-1 and -2 are potent direct and indirect angiogenic factors. The mechanism by which anoikis is triggered relies on the loss
They also stimulate the secretion of other angiogenic factors of interaction between integrins and the ECM. This causes loss of
including angiopoietin 2 and VEGF (174,175). FGF-2 also inter- prosurvival signaling through Akt/PI3K and the raf-ERK path-
acts with PDGF-BB, stimulating angiogenesis and attraction of way (Fig. 4.4) (4,190). Suspended cells and attached cells have
vascular smooth muscle to stabilize newly formed vessels (176). very different cytoskeletal structures suggesting that the cytoskel-
FGFR1-IIIc responds to VEGF and is implicated in resistance to eton also regulates survival signaling in anoikis. The disruption of
anti-VEGFR therapy. The combination of anti-VEGFR and anti- structural elements or changes in cell shape might trigger anoikis
FGFR therapy is has been examined in mouse models and was (191) making the cytoskeleton a therapeutic target.
successful after failure of single agent anti-VEGFR treatment Cancer cells resist anoikis by constitutive activation of sur-
(156,177). FGF has been found in high concentrations in ascites vival pathways or inhibitors of apoptosis. In ovarian cancer TrkB,
of ovarian cancer patients (178). It remains to be determined a neurotrophic tyrosine kinase receptor is a potent suppressor of
CHAPTER 4 I NVASION, M ETASTASIS, AN D ANGIOGEN ESIS 81
caspase-associated anoikis that is found to be overexpressed in of patients. Predictive biomarkers function to differentiate out-
ovarian cancer (192). TrkB was found overexpressed in high- come to intervention, such as therapy or radiation, whereas prog-
Bevacizumab
and enzastaurin
50
Bevacizumab
Bevacizumab and sorafenib GOG
40 NCIC
PFS 6 mo (%)
NCI
30 Australian
Sorafenib
Temsirolimus multicenter
20 DFCI
JHMI
Imatinib
10
FIGURE 4.6. Angiogenic agents in ovarian cancer. Results of phase IIII trials of antiangiogenic agents alone
and in combinations are plotted. Response rate and frequency of 6-month progression-free survival are shown.
82 CHAPTER 4 I NVASION, M ETASTASIS, AN D ANGIOGEN ESIS
Molecular-Targeted Agents: Monoclonal of inhibition of EGFR has been seen. Currently, there is no role
Antibodies for EGFR interruption in gynecologic malignancies.
Trastuzumab is a monoclonal antibody against EGFR-2
Antiangiogenic antibodies. Bevacizumab is a recombinant (Her2) that prolongs survival in Her2-positive breast cancer in
humanized version of the murine antihuman VEGF monoclonal both the adjuvant and metastatic settings (216,217). The only
antibody. This VEGF-neutralizing antibody inhibits VEGF- role for trastuzumab in gynecologic cancers to date appears to
induced signaling, resulting in reduced angiogenesis and tumor be in combination with chemotherapy and/or other HER2/EGFR
growth. It has been U.S. FDA-approved for renal cell, lung, inhibitors in uterine papillary serous cancers (218). Rare cases of
and colon cancers. In metastatic colon cancer, it prolonged true mucinous ovarian cancer have been found expressing very
survival when given in combination with chemotherapy; activ- high Her2 and responding to trastuzumab. This observation is
ity has been shown in breast, ovarian, endometrial, and cervi- being followed.
cal cancers (200205). One of the first observations of activity
of bevacizumab was reduction in gynecologic cancer ascites
burden (206208). Single-agent bevacizumab (GOG 170D) Molecular Targeted Agents: Kinase Inhibitors
demonstrated a 21% response rate, with 40% surviving Antiangiogenic Agents. A number of small-molecule inhibitors
progression free at least 6 months (209). Progression-free sur- of the VEGF receptors and other angiogenic pathways have been
vival at 6-month rate was 23.9% and 40.4% in cervical (GOG developed and reached clinical trials. VEGFR2 is most commonly
227C) and endometrial cancer (GOG 229E), respectively targeted with preclinical data showing this approach to be active
(202,205). in reducing endothelial cell proliferation, migration, and vascular
The addition of bevacizumab to front-line chemotherapy development, and xenograft models have confirmed activity in a
and to maintenance therapy in epithelial ovarian cancer was number of solid tumors (219).
evaluated in two pivotal phase III trials, GOG 218 and ICON 7.
GOG 218 was a three-arm, placebo-controlled trial of front-line Selective VEGFR Inhibitors. Cediranib is an oral tyrosine kinase
paclitaxel and carboplatin to which either concurrent bevaci- inhibitor (TKI) that targets all three VEGFRs and c-kit. Two
zumab or concurrent and maintenance bevacizumab were added. phase II single-agent studies in recurrent EOC have been con-
A progression-free benefit was seen in women who received both ducted. Partial response frequency ranged from 13% to 17%,
concurrent and maintenance bevacizumab at 15 mg/kg (14.1 with hypertension and fatigue being the most common grade 3
vs. 10.3 months; HR, 0.717; p < 0.0001) (179). No significant adverse events (220). Cediranib is being evaluated in combina-
difference in overall survival has been demonstrated (39.7 vs. tion with carboplatin and paclitaxel in a phase III trial (ICON6)
39.3 months; p = 0.45). ICON 7, a randomized phase III trial, in women with recurrent disease (221).
evaluated first-line paclitaxel/carboplatin alone or in combination
with bevacizumab followed by bevacizumab maintenance using Mixed Kinase Inhibitors, Including VEGFRs. Sorafenib is an oral
7.5 mg/kg (210). Progression-free survival was enhanced in the Raf-kinase and VEGFR-2 inhibitor that has been approved for
bevacizumab arm (HR, 0.81; 95% CI, 0.700.94; p = 0.0041), treatment of metastatic renal cell and hepatocellular cancers
and interim analysis has revealed no significant improvement (222,223). Single-agent sorafenib in women with recurrent ovar-
in overall survival. A post-hoc exploratory subgroup analysis ian cancer resulted in partial response in 2 patients, 20 with stabi-
found a survival improvement for patients with stage IV or lization, and 6-month progression-free survival was 24% (GOG
stage IIIC disease with >1 cm residual tumor (HR, 0.64; 95% 170F) (224). A randomized phase II study comparing main-
CI, 0.480.85; p = 0.002). tenance sorafenib 400 mg twice daily to placebo in advanced
The addition of bevacizumab to second-line chemotherapy ovarian or primary peritoneal cancer in complete remission fol-
was evaluated in platinum-sensitive recurrent ovarian cancer. lowing surgery and one previous chemotherapy regimen has been
The phase III OCEANS trial was a two-arm, placebo-controlled reported as negative (IGCS, 2012). A phase I trial of sorafenib
study of gemcitabine and carboplatin, with experimental arms and bevacizumab in combination yielded a response rate of 47%
of concurrent and maintenance bevacizumab until disease pro- in heavily pretreated ovarian cancer patients (197,225); evalu-
gression. Patients who received concurrent and maintenance ation of tumor biopsies, cytokine concentrations, and vascular
bevacizumab had a longer progression-free survival (12.4 imaging confirm an antiangiogenic signaling effect of the combi-
vs.8.4 months; HR, 0.484; 95% CI, 0.3880.605; p < 0.0001) nation. A phase II trial of bevacizumab combined with sorafenib
(211). Again, there was no difference in overall survival. The is presently accruing at the National Cancer Institute.
results of GOG 218, ICON 7, and OCEANS have raised signifi- Nintedanib (BIBF1120) inhibits VEGFRs 1, 2, and 3, PDGFR-
cant questions regarding patient selection, dose, duration, and and -, and FGFRs 1, 2, and 3. A phase 2 placebo-controlled
timing of therapy. nintedanib maintenance trial in patients who responded to pre-
There are several randomized trials evaluating bevacizumab vious (at least second-line) chemotherapy reported a 36-week
and chemotherapy in recurrent (GOG 213 and AURELIA) and progression-free survival of 16.3% versus 5.0% with placebo
newly diagnosed (GOG 241, 252, and 262) ovarian cancer, cer- (p = 0.06) (226). The most common significant adverse effects
vical cancer (GOG 240), and endometrial cancer (86P). Bevaci- in the nintedanib arm included elevated transaminases and
zumab is also being evaluated in combination with a variety of diarrhea. A phase III randomized placebo-controlled trial of
agents including mTOR, PARP, VEGFR, and SRC inhibitors, as nintedanib in combination with carboplatin and paclitaxel fol-
well as with vascular disrupting agents. lowed by maintenance nintedanib or placebo (AGO-OVAR12/
LUME-Ovar1) in first-line treatment of EOC has completed
Anti-EGFR family antibodies. Cetuximab is a recombinant chi- enrollment.
meric antibody to EGFR that is presently approved for treat- Pazopanib is a TKI that targets all three VEGFRs, both
ment of metastatic colon cancer and unresectable head and neck PDGFRs, and c-kit. The phase II trial of pazopanib in ovarian
cancer, with activity in breast and non-small cell lung cancer. cancer patients with initial complete CA125 response yielded a
However, cetuximab has minimal activity as a single agent and CA-125 response rate of 31%, where 29% of patients with mea-
lacks significant activity in combination with chemotherapy or surable disease had stabilization (227). A phase III randomized
radiation in patients with recurrent ovarian (GOG 146P) or placebo-controlled maintenance trial of pazopanib 800 mg daily
cervical cancer (GOG 227E, 76DD) (212215). The high inci- (AGO-OVAR16) has completed enrollment and is maturing.
dence of gastrointestinal and metabolic toxicity has precluded Pazopanib has also been evaluated in cervical cancer (228) with
further development. Similar minimal activity of other methods improved progression-free survival (HR, 0.66; 90% CI, 0.480.91;
CHAPTER 4 I NVASION, M ETASTASIS, AN D ANGIOGEN ESIS 83
p = 0.013) and overall survival (HR, 0.67; 90% CI, 0.460.99; effective than alone. Both targeted agents with cytotoxics and
p = 0.045) compared to lapatinib, an EGFR/Her2 TKI. There multitargeted agent studies have been initiated. To date, these
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5
CHAPTER
Tumor markers are defined as molecules or substances produced and positive predictive value (PPV, percentage of patients with
by malignant tumors that enter the circulation in detectable positive test that have the cancer, true positives) (Table 5.2). An
amounts. They indicate the likely presence of cancer or provide ideal tumor marker should have a 100% sensitivity, specificity,
information about its behavior. In management of cancer, the and PPV. However, in practice such a marker does not exist. As
most useful biochemical markers are the macromolecular tumor the majority of markers are tumor-associated rather than tumor-
antigens, including enzymes, hormones, receptors, growth factors, specific, and are elevated in multiple cancers, benign and physi-
biologic response modifiers, and glycoconjugates. A substantial ologic conditions, they lack specificity. In addition, if sensitivity is
number of substances have been investigated as potential tumor low, a normal result may not exclude malignancy. Tumor markers
markers over the past decade and the list is continually growing discovered thus far contribute to differential diagnosis but are
owing to new technology employed in biomarker discovery. not themselves diagnostic. This restricts their use, with few excep-
Tumor markers can be used for risk stratification, screen- tions, to monitoring therapeutic response and follow-up. Tumor
ing, differential diagnosis, prognosis, predicting, and monitor- markers currently used in nongynecologic malignancies include:
ing response to therapy and detecting recurrence (Table 5.1).
1. Carcinoembryonic Antigen (CEA), the most commonly
The performance of a tumor marker depends on its sensitiv-
elevated marker in colorectal cancer, whose preoperative
ity (percentage of patients with cancer correctly identified as a
assessment is recommended by the American Society of
result of a positive test), specificity (percentage of the population
Clinical Oncology (ASCO) as it may complement surgical
without cancer correctly identified as a result of a negative test),
staging and help in choosing the most appropriate surgical
treatment. Abnormal preoperative levels may also indicate
higher risk of recurrence but there is no concrete evidence
Table 5.1 Tumor Markers and Their Potential Uses as to whether patients with colorectal cancer would benefit
from adjuvant therapy based on preoperative CEA alone(1).
1. Risk stratification CEA is, however, not used in screening or early diagnosis.
2. CA-15-3, measurements of which have been advocated
Adjusting risk categorization for an individual without the disease. (ASCO) in monitoring response to treatment in breast cancer
The marker could then be used in screening or prevention if these
when the disease is not measurable.
are proven to be effective
3. Prostate-specific antigen (PSA) is used in screening for prostate
2. Screening cancer but its use as a stand-alone marker is not recommended.
Screening to detect cancer earlier than it would have been using Most guidelines recommend a PSA test followed by digital rec-
clinical signs and symptoms tal examination with definitive diagnosis always requiring a
biopsy. PSA may have a role in detecting disease recurrence
3. Differential diagnosis and monitoring treatment in patients with prostate cancer (2).
Use of serum and tissue tumor markers to establish the tissue of
origin of a newly diagnosed cancer by differentiating between the
cancer and benign conditions
4. Prognosis Table 5.2 Parameters of Tumor Marker Assays
Markers used to determine prognosis in a patient, i.e., risk of invasion True Tumor Status
and metastasis in the absence of therapy
Tumor Marker Result Positive Negative
5. Prediction
Ability of a marker to determine the likelihood of sensitivity or Positive A B
resistance to specific therapy (True positives) (False positives)
6. Monitoring Negative C D
Monitoring patients either during or after therapy to determine the (False negatives) (True negatives)
status of the cancer. Patients are usually monitored during primary
therapy but also during therapy for metastatic disease to determine
if the patient is responding to the treatment of if an alternative Sensitivity = True positives / All with tumor = A / A + C
Specificity = True negatives / All tumor free = D / D + B
therapy is needed Positive predictive value (PPV) = True positives/All with positive tumor-marker
result = A / A + B
89
90 CHAPTER 5 DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS
Women have approximately a 1% to 2% lifetime risk of devel- Disease Condition CA-125 elevations
over 35 kU/L (%)
oping ovarian cancer (OC) and it accounts for 4% of cancers
diagnosed in women, with over 225,000 new cases diagnosed Benign Overall (all benign tumours)c 29%
worldwide each year (3). Incidence rates are highest in the U.S. ovarian
disease Ovarian cystsc 14%
and Northern Europe and lowest in Africa and Asia. It is associ-
ated with the highest mortality rates of all female genital tract Germ cell tumours (mature teratoma)c 21%
malignancies. Around 85% of cases occur over the age of 50,
Sex cord stromal tumours (thecoma, 52%
and 80% to 85% of cancers are epithelial in origin. Epithelial
fibrothecoma)c
ovarian cancer (EOC) may be serous, mucinous, endometrioid,
clear cell, transitional, and undifferentiated. The most common Cystadenoma, adenofibroma, 20%
histologic subtype of EOC is serous OC, which usually presents cystadenofibromac
at advanced stages and has the poorest outcomes (4). However, Serous epithelial tumoursc 20%
in the reproductive age group germ cell tumors, granulosa cell/
sex-cord tumors, mucinous, and endometrioid tumors are more Mucinous epithelial tumours c
18%
common. Only a few tumor markers have been validated for Benign, NOS c
27%
clinical use with the best known among them being cancer anti-
gen 125 (CA-125). Benign, other (normal ovaries)c 22%
Benign Abscess/hydrosalpinx/PODc 37%
disorders
of the Fibroid (leiomyomas) c
26%
CA-125 female Acute salpingitis d
40.4%
CA-125 was first described by Bast et al. in 1981. It is a 200-kDa genital
glycoprotein recognized by the OC-125 murine monoclonal tract Chronic salpingitis d
8.3%
antibody (5). CA-125 carries two major antigenic domains: Pelvic inflammatory diseasee 29.4%
domain A (binds monoclonal antibody OC-125) and domain B
(binds monoclonal antibody M11) (6). The current second-gen- Endometriosis/endometrioma c
67%
eration heterologous CA-125-II assay incorporates M11 and Endometriosis (Stage I) d
8.0%
OC125 antibodies, while the original homologous assay was
with OC125 alone. Currently there are a number of CA-125 Endometriosis (Stage II) d
19.6%
assays that correlate well with each other (7,8). Endometriosis (Stage I/II combined)d 11.5%
CA-125 is expressed by amniotic and coelomic epithelium
during fetal development. It is widely distributed in adult tissues Endometriosis (Stage III)d 44.7%
(mesothelial cells of the pleura, pericardium and peritoneum, Endometriosis (Stage IV) d
86.7%
tubal, endometrial and endocervical epithelium) but is not
expressed by the surface epithelium of normal fetal and adult Endometriosis (Stage III/IV 50.4%
ovaries with the exception of inclusion cysts, areas of metapla- combined)d
sia, and papillary excrescences (9). It therefore lacks complete Endometriosis (overall)d 24.3%
specificity for OC.
The level of CA-125 in body fluids or ovarian cysts does not Other Cirrhosis d
67.1%
correlate well with serum levels. This is probably due to the disordersd
Cirrhosis + ascitesd 100.0%
serum concentration being reflective not only of the produc-
tion of the antigen by the tumor but other factors that affect Acute pancreatitis d
32.2%
its release into the circulation. The widely adopted cut-off at Chronic active hepatitis d
9.1%
35 kU/L routinely used in clinical practice is based upon the dis-
tribution of values in 99% of 888 healthy men and women (10). Chronic pancreatitis d
1.9%
However, levels of CA-125 tend to be lower in postmenopausal Renal failured 14.6%
women or in patients who have undergone hysterectomy;
levels of 20 U/mL and 26 U/mL have been suggested (1113). Heart failuref 14.7%
Approximately 85% of patients with epithelial ovarian Diabetes d
0.0%
cancer have CA-125 levels of greater than 35 U/mL (10,14).
Raised serum levels are found in 50% Stage I and greater than Ovarian According to histology
90% Stage II-IV cancer (15) (Table 5.3). CA-125 levels are more cancerd
Serous 80.0%
frequently elevated in serous compared to mucinous, clear
cell, and borderline tumors (1517). CA-125 can be elevated in Mucinous 69.0%
other malignancies (pancreas, breast, colon, and lung cancer) Endometrioid 75.0%
(Table 5.4) and in benign conditions (Table 5.3) and in physio-
logic states such as pregnancy, endometriosis, and menstruation Clear cell 78.0%
(15). Diagnostic accuracy of raised CA-125 in postmenopausal Undifferentiated 88.0%
women is improved by absence of many of these nonmalignant
conditions (Table 5.3). (Continued)
CHAPTER 5 DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS 91
Table 5.3 CA-125 Elevations in Benign Disorders Table 5.4 CA-125 Elevations in Nonovarian
when mammography became available. The initial study of Screening for ovarian cancer continues to be investigated in
62,000women aged between 40 to 64 years lasted over 25 years the research setting with CA-125 the only tumor marker cur-
and provided the first experimental evidence of the efficacy of rently being explored in large trials. When it is interpreted using
the breast cancer screening strategy (19). In the 1970s, lung can- a cut-off, 2.9% of healthy postmenopausal women will have
cer screening trials using chest radiograph and sputum cytology elevated CA-125 levels, limiting its use as a stand-alone test (21).
were initiated, followed by the first colorectal cancer screening In the multimodal screening strategy, this is overcome by use of
trial in 1975. Trials of prostate and ovarian cancer screening transvaginal ultrasound (TVS) as a second-line test in women
started in the 1990s (20). with elevated CA-125 levels so that high specificity (99.9%) and
Screening can also contribute to primary prevention, as in four or less operations for each OC detected can be achieved
colorectal cancer screening, where removal of adenomas sub- (22,23). Ovarian morphology has been used to refine algorithms
stantially reduces the incidence of colorectal cancer. However, for interpreting TVS in postmenopausal women with elevated
there are downsides to screening too. Breast cancer screen- CA-125 (24,25). Over the last decade, CA-125 interpretation in
ing has had a lot of criticism in recent years as it picks up less the context of screening has been further improved by a more
aggressive forms of the disease, ductal carcinoma in situ (DCIS) sophisticated approach incorporating age, menopausal status,
that would have otherwise gone unnoticed during an individu- and the rate of change of CA-125 values over time (2628).This
als lifetime. Compliance with colorectal cancer screening is an statistical algorithm (Risk of Ovarian Cancer, ROC), based on
issue probably due to the nature of the test. Prostate screening the age-specific risk of the disease and the behavior of CA-125
has been hampered by low sensitivity of the PSA test when used with time in women with ovarian cancer versus normal con-
alone. trols, has improved both the sensitivity and specificity of CA-125
CHAPTER 5 DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS 93
interpretation (28). Prospective evaluation of the ROC algorithm For primary invasive ovarian cancers, the sensitivity of multimodal
in a randomized controlled trial (RCT) of 13,582 postmenopausal screening remained at 89%, whereas that of the ultrasound-based
Level I screen
CHAPTER 5
Repeat
Level I
Low risk screen
Multimodal group
Intermediate risk Normal
50,640
Referral to
Level II
Elevated risk Abnormal Gynaecological
screen
Oncologist
202,638 Normal
Postmenopausal Ultrasound group Unsatisfactory
women 50,639
>50-74 Normal Repeat
Level I
screen
Primary endpoint-Ovarian cancer mortality
Control group
101,359 Secondary endpoints
Physical morbidity
DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS
Cost
Compliance
Psychological morbidity
Screening continues up to December, 31, 2011, with women receiving between 7 and 11 screens
All participants are being followed up through a flagging study with the NHS Information Centre for Health and Social Care in England and Wales
and via the Central Services Agency and Cancer Registry in Northern Ireland and by postal follow-up until December 31, 2014,
Final outcome will be reported in 2015
FIGURE 5.1. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Women in the trial, based on the risk of ovarian cancer (ROC) value,
are triaged into low risk (ROC, <1 / 3,500), and returned to annual screening with the next blood test in one year; intermediate risk (<1 / 1,000 and <1 / 3,500) with a repeat CA-125
in 12 weeks; and elevated risk (>1 / 1,000) with Level II screen (CA-125 and TVS) scheduled in 68 weeks, with earlier screens arranged where there was a high index of suspicion. Those
with persistent abnormalities on Level II screen are referred to a gynecologic oncologist. The screening protocol has been described in detail elsewhere. Roc, risk of ovarian cancer; TVS,
transvaginal ultrasound.
4,913 ineligible Study group
(prior oophorectomy)
Abnormal screen
28,816 Referral to 212 118
(either CA-125,
5,386 did not receive Annual CA-125 for 6 years physician
any screening TVS or both)
Annual TVS for 4 years
78,237
women
>50-74 years
CHAPTER 5
Control group
39,122 176 100
Primary endpoint - Ovarian cancer mortality
Ovarian cancers
diagnosed in Ovarian cancer
the two groups deaths
FIGURE 5.2. Prostate Lung Colorectal and Ovarian (PLCO) Cancer Screening Trial. Women in the trial underwent 4 annual screens with CA-125 (interpreted using
a cut-off of 35 kU/L) and TVS and 2 further screens with CA-125 alone. If an abnormality was detected on screening, the women underwent referral to their physician. Final outcome
(OC mortality) was reported in 2011. TVS, transvaginal ultrasound.
DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS
95
Type I, slow growing cancers with good prognosis such as low- vascular endothelial growth factor (VEGF) (81%), MUC1 (62%),
grade serous, low-grade endometrioid, clear cell, mucinous, and mesothelin (MES) (34%), HE4 (32%), and CA-19-9 (29%). MES
transitional (Brenner) carcinomas, and more aggressive Type II, and HE4 showed the greatest specificity when reactivity with nor-
which include high-grade serous, high-grade endometrioid, mal tissues was considered. Differential expression was also found
undifferentiated tumors and carcinosarcomas (47). Screening for HK10, osteopontin, DF3, and MUC1 (59). Several of these
strategies including biomarker discovery and refining of ultra- markers are currently being assessed in nested case control studies
sound indices need to take into account both types with a focus using serum samples from ovarian cancer screening trials.
on detection of type II cancers, which account for over 80% of The screening trials in the general population have focused on
OC mortality. To date, the goal of screening was limited to detec- postmenopausal women as around 90% of ovarian cancers are
tion of early-stage disease (48,49) but the work of Crumet al. sporadic and occur in women from the general population over
supports a model of fimbrial-ovarian serous neoplasia, with a the age of 50. A number of risk factors affect ovarian cancer risk
proportion of serous OCs starting as premalignant serous tubal in the general population, such as oral contraceptive use, parity,
intraepithelial cancer (STIC) lesions in the distal fallopian tube and hysterectomy, which can be used to determine an individuals
and spreading to the ovary (50). This raises the possibility of risk. Recent efforts have focused on identification of low- and
primary prevention in the future. moderate-penetrance genes that predispose women to ovar-
In a 1980s biobank study, CA-125 was found to be raised ian cancer (6063). It is therefore very likely that population-
in 59 out of 236 (25%) stored serum samples collected from screening strategies in the future will use a risk-stratification tool
women with ovarian cancer 5 years before diagnosis (13). Data that combines these factors.
from a Japanese OCS study indicate that, in serous-type ovarian
cancer, first elevation of CA-125 to diagnosis has a shorter inter-
val compared with those with nonserous-type disease (1.4 vs.
3.8 years; p = 0.011). Although 47% of nonserous-type ovarian Additional Markers
cancers developed from slightly elevated CA-125 levels between In the past few years, major efforts have been made to iden-
35 and 65 kU/L, 75% of serous ovarian cancers developed sud- tify either a better marker or a panel of markers that would
denly from a normal CA-125 level (<35 kU/L) (51). A model of improve the performance of CA-125 in the context of screening.
natural history of OC developed by Brown and Palmer suggests However, most of the studies used clinical samples (rather than
that on average, it takes over 4 years for in situ, stage I or stage II preclinical samples), so their findings are more relevant to dif-
cancers to become clinically apparent, and approximately 1 year ferential diagnosis of benign from malignant masses, avoiding
for stage III/IV cancers (52). Serous cancers are less than 1 cm unnecessary operations in women with benign lesions and ensur-
in diameter during the occult period. The model suggests that ing that surgery, where there is high suspicion of ovarian cancer,
for a screening strategy to be able to detect 50% of the cancers is undertaken by trained gynecologic oncologists in tertiary-care
before they progress to stage III, an annual screen would have to centers (6466). Using a CA-125 cut-off of 35 kU/L combined
detect tumors 1.3 cm in diameter (53). Unpublished data from with imaging has been shown to achieve a sensitivity of 94% and
UKCTOCS suggest that detecting such small high-grade serous specificity of 90% for differential diagnosis of ovarian cancer
cancers may be feasible using the ROC algorithm. from benign disease (67). The performance of various other mark-
Recently, using samples from 112 OC patients and 706 con- ers to detect ovarian cancer has been evaluated: Interleukin-6
trols from PLCO, Urban et al. demonstrated that Human Epi- (IL-6), Interleukin-7 (IL-7), soluble Interleukin-2 receptor (sIL-
didymis protein 4 (HE4) had higher sensitivity of confirming Type 2R), Tumor Necrosis Factor (TNF), Soluble receptors of TNF
II cancers (40% vs 20%) than Type I cancers (18.8% vs 56.2%) (sTNF-R), Macrophage Colony-Stimulating Factor (M-CSF),
compared to TVS. HE4 had higher sensitivity (35.7%) than TVS CA-15-3, CA-72-4 or TAG-72, CA-19-9, OVX1, CASA/OSA,
(28.6%) as a first-line test. The sensitivity of HE4 was improved Growth factors, Tetranectin, Tumor-Associated Trypsin Inhibi-
by using TVS as a second-line test. Combination of HE4 and tor (TATI), GAT (Galactosyltransferase associated with tumor),
CA-125 (32.1%) had a better sensitivity than TVS alone (20.2%). LASA (lipid-associated sialic acid), VEGF (vascular endothelial
However, the authors stress that diagnosing HE4-associated growth factor), IAP (immunosuppressive acid protein), Lyso-
tumors is not necessarily better than diagnosing TVS-associated phosphatidic Acid (LPA), Prostasin, Cadherin, Shed glycans,
tumors in terms of outcome (54). Dipeptase 1; however, despite a plethora of studies, none been
Whether a raised CA-125 in asymptomatic postmenopausal shown to be useful in clinical practice. Limited sensitivities and
women is a predictor of nongynecologic cancer is not yet clear. Data specificities constrain their use in screening.
from the RCT of 22,000 postmenopausal women (22) reported The only promising marker in the last decade has been
that elevated serum CA-125 was not a predictor of a nongyneco- serum human epididymis protein 4 (HE4). Preclinical samples
logic malignancy on mean follow-up of 2,269 days (55). However, from asymptomatic women from the PLCO trial were used to
it was associated with significantly increased risk of death from assess the performance of 49 ovarian cancer biomarkers using
all causes in the next 5 years (56). In contrast, data from the Nor- the ProBE design (68) of a prospective-specimen collection, with
wegian OCS trial of 5,500 women showed that breast and lung retrospective-blinded evaluation study design (69). The perfor-
cancer were overrepresented among women with elevated CA-125 mance of standard tumor markers, such as CA-125, HE4,
(57). Both trials indicate that elevated CA-125 is a risk factor CA-72.4, and CA-15.3, in prediagnostic samples drawn within
for death from malignant disease. These data indicate that steps 6 months of cancer diagnosis was comparable to that in clinical
should be taken to rule out other malignancies such as breast, lung, samples. Performance was poorer for markers such as prolactin,
and pancreas in asymptomatic postmenopausal women with rising transthyretin, or apolipoprotein A1, which may reflect the indi-
CA-125 levels with no evidence of gynecologic malignancy. vidual response to the cancer, in prediagnostic specimens. Serum
One of the limitations of CA-125 is that 15% to 20% of ovarian CA-125 remained the single best biomarker for ovarian cancer,
cancers do not express the antigen. This may partly be caused by with sensitivity of 86% (95% CI, 0.760.97) in cases where
CA-125 forming circulating immune antibodies containing com- blood was drawn within 6 months of diagnosis, with the second
plexes bound to the free antigen (58). Rosen et al. (59) explored best marker being HE4, with sensitivity of 73% (95% CI, 0.60
10 potential serum markers that could complement CA-125 in 65 0.86). For all markers, sensitivity declined in specimens more
ovarian cancers with weak or absent CA-125 tissue expression. All remote than 6 months from diagnosis. However, the limitation of
specimen lacking CA-125 expressed human kallikrein 10 (HK10), this study was that CA-125 was used in real time for triaging
human kallikrein 6 (HK6), osteopontin, and claudin 3. A small pro- women for diagnostic work up for ovarian cancer (70). A
portion of CA-125 negative ovarian cancers expressed DF3 (95%), recent study by Anderson et al. (71) using specimens from the
CHAPTER 5 DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS 97
disease (90). In a study of 118 patients with FIGO stage I epithe- monitor the clinical course of ovarian cancer and its response
lial OC, compared to those with stage I and preoperative serum to chemotherapy (108). However, CA-125 should not be used
CA-125 levels <65 U/mL, stage I patients with preoperative serum as the sole criterion to determine clinical response (109) as studies
CA-125 65 U/mL had a significantly longer survival (91). This involving second-look laparotomy have confirmed that CA-125
finding has been confirmed in a study of 600 patients from gyne- values of less than 35 U/mL do not exclude active disease (110).
cologic cancer centers in Australia, USA, and Europe with stage I The pattern of CA-125 over time is a more useful parameter than
epithelial ovarian cancer. On multivariate analysis, preopera- using an arbitrary cut-off level (100,101,111,112). Precise math-
tive serum CA-125 greater than 30 U/mL and age greater than ematical definitions to evaluate response to treatment have been
70 years at diagnosis were the only independent predictors for suggested with 50% response corresponding to a 50% decrease
overall survival (OS). Levels of CA-125 of 30 U/mL (over his- in CA-125 after 2 samples, confirmed by a third sample collected
tologic cell type, sub-stage and grade) were able to identify a sub- at least 28 days later and a 75% response defined as a serial
group of FIGO stage I patients with a genuinely good prognosis decrease over 3 samples of greater than 75% (113,114). Preche-
and survival who could possibly be spared from adjuvant chemo- motherapy CA-125, its half-life, nadir concentration, and time to
therapy (92). Additional parameters such as cyclooxygenase-2 nadir have a univariate prognostic value for disease-free and OS
overexpression in combination with preoperative CA-125 level in a multicenter French study (115).
of under 30 U/mL have been recently found to be independent
predictors of survival in univariate and multivariate analyses (93).
However, CA-125 does not appear to be an independent prognos-
Detecting Recurrence
tic factor in advanced ovarian cancer (90). Among patients with elevated CA-125 levels at diagnosis, serial
Postoperative CA-125 levels have been found to be significant monitoring following initial chemotherapy can lead to the early
prognostic factors (87). Patients with a low CA-125 prognostic detection of recurrent disease. Median lead-time prior to clinical
score composed of two CA-125 values, one taken preoperatively progression of 63 to 99 days has been demonstrated between
and the other taken 1 month after surgery, have significantly marker detection of disease progression and clinically apparent
better prognosis than patients with high scores (94). In the progressive disease (116,117). The value of marker lead-time
immediate postoperative period, CA-125 levels can be elevated depends ultimately on a patients remaining therapeutic options,
as a result of the abdominal surgery and irritation of the perito- and the clinical value of this approach is unclear (118).
neal cavity; therefore, measurements are best postponed for at In a study of 39 patients with elevated serum CA-125 at time
least 4 weeks (95). of diagnosis and complete clinical and radiographic response to
During primary chemotherapy, serum CA-125 half-life is an initial treatment with normalization of serum, Santillan et al.
independent prognostic factor in patients with advanced epi- reported that a relative increase in CA-125 of 100% (odds ratio
thelial ovarian cancer, both for complete remission and survival [OR] = 23.7; 95% CI, 2.9192.5) was significantly predictive
(9698). The most commonly used cut-off is a CA-125 half-life of of recurrence. From baseline CA-125 nadir levels, an absolute
20 days (98100). In patients with CA-125-positive tumors, other increase in CA-125 of 5 U/mL (OR = 8.4; 95% CI, 2.232.6)
useful prognostic indicators of survival are the serum CA-125 and 10 U/mL (OR = 71.2; 95% CI, 4.8 to >999.9) were also
levels prior to third course of chemotherapy (96,101,102) and significantly associated with the likelihood of concurrent disease
the slope of the CA-125 exponential regression curve. In patients recurrence. These data suggest that for patients in complete clin-
treated on maintenance chemotherapy and achieving a clini- ical remission, a progressive low-level increase in serum CA-125
cally defined complete response to primary chemotherapy with levels is strongly predictive of disease recurrence (119).
a baseline CA-125 level of 35 U/mL, the baseline CA-125 level CA-125 measurements together with thin-section computer
before initiation of maintenance chemotherapy strongly predicts tomography (CT) and careful review of the clinical history have
the risk of subsequent relapse. Patients with premaintenance been recommended in follow-up of patients with ovarian car-
baseline CA-125 values 10 U/mL have a superior progression cinomas (120). However, a study of 58 patients with recurrent
free survival compared to those with higher levels even if in the ovarian cancer revealed that 98% of recurrences were identified
normal CA-125 range (103). by physical examination and CA-125, with ultrasound and CT
Serum CA-125 continues to be of prognostic significance not providing additional clinically relevant information during
when ovarian cancer recurs, with patients with normal serum follow-up (121).
CA-125 levels (35 U/mL) at relapse having a better prognosis In a population-based study of 331 Dutch EOC patients, van
than patients with elevated levels (104). Altena et al. showed a significant association of CA-125 nadir
Apart from CA-125, other markers have been evaluated 5 kU/L with both longer PFS and longer OS (log-rank test p <
as those with prognostic value. More recently, soluble MUC1 0.01 and p = 0.03, respectively). It was also an independent prog-
and serum MUC1-specific antibodies have been shown to be nostic variable (HR = 1.51; 95% CI, 1.042.31) for PFS next
prognostic for poor clinical response and reduced OS in both to histologic type, FIGO stage, and residual tumor after surgery
platinum-resistant as well as platinum-refractory OC treated (122). However, the MRC OVO5/EORTC55955 trial has shown
with interleukin 2 (IL-2) (105). The mean levels of anti-MUC1 no value in CA-125 monitoring in the follow-up of ovarian
IgG was higher in patients with progressive disease, both at cancer patients. The trial included 1,442 patients with normal
early (p = 0.025) and late (p = 0.052) time points during the CA-125 level following platinum-based therapy. Patients whose
IL-2 treatment. levels rose to twice the upper limit of normal (529 women) were
Another marker, survivin, with levels higher in serous OC randomized to immediate (based on CA-125 levels) or delayed
than in benign epithelial tumors, could not be used for differen- chemotherapy (the latter when signs and symptoms of recur-
tial diagnosis of OC from benign masses but could be used as a rence were present). The women randomized to monitoring
prognostic marker for OC as its levels were positively correlated started chemotherapy at a median of 4.8 months earlier than
with age, advanced stage, and poor disease-free survival (106). those in the delayed arm but this did not result in difference in
survival between the arms (early arm: median 25.7 months, 95%
CI 23.027.9; delayed arm: median 27.1, 95% CI 22.830.9;
Monitoring Response to Treatment HR: median 0.98, 95% CI 0.801.20; p = 0.85). Therefore, Rus-
It is now established that serum CA-125 levels reflect progression tin suggests that CA-125 should only be measured if there is a
or regression of disease in over 90% of ovarian cancer patients suspicion of relapse or at patients request (123). The pattern of
with elevated preoperative levels (107) (Fig. 5.1). These findings CA-125 throughout a patients clinical course of the disease is
have resulted in the widespread use of serum CA-125 levels to presented in Figure 5.3.
CHAPTER 5 DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS 99
10000
Clinical relapse
Completion of chemotherapy
Prior to 3rd cycle of chemotherapy
Start of chemotherapy
Debulking surgery-Stage IIIc, residual tumour-2 cm nodules
FIGURE 5.3. Correlation between serum CA-125 and clinical course in ovarian cancer.
lower sensitivity than CA-125 for early stage disease, but has bet-
HE4 ter sensitivity and specificity in differential diagnosis of benign
Human epididymis protein 4 (HE4) is a glycoprotein in the from malignant pelvic masses, especially in premenopausal
epithelial cells of the epididymis. In ovarian cancer, increased patients (124). Although HE4 has recently been shown to improve
serum levels and expression of the HE4 WAP four-sulphide core the performance of CA-125 (129), in a Swedish study of 114 OC,
domain 2 (WFCD2) gene have been demonstrated (124). 45 borderline and 215 patients with benign ovarian tumors,
Mean serum HE4 in patients with malignant ovarian lesions Partheen et al. showed that HE4 did not out-perform CA-125
(248.7 pM) is much higher than in controls (34.1 pM) or women (benign vs. malignant AUC 86.8% for CA-125 and 84.4% for
with benign lesions (39.1 pM) (Table 5.8). HE4 levels are HE4; benign versus Stage I OC 72% for HE4 and 76% for
decreased in pregnancy (median levels of 30.5 pmol/L) (125) and CA-125) (130). Very recently, Schummer et al. demonstrated that
levels around 50 and 60 have been demonstrated in pre- and post- in patients who are developing a recurrence, HE4 rises earlier than
menopausal women, respectively (126), which increase with age CA-125 with a lead-time of up to 4.5 months (131). It can also be
(median 109.5 pmol/L in women over 80). HE4 levels are lower in elevated in patients who do not express CA-125 at sufficient levels
many of the benign conditions that usually elevate CA-125 levels to make a clinical decision. MMP7 and Mesothelin are, however,
(Table 5.9), especially in women with endometriosis. not as useful in predicting recurrence to add to CA-125. However,
HE4 can also be elevated in other cancers (Table 5.10). Ini- as HE4 levels fail to normalize at the end of treatment, it is pos-
tial report stated that its specificity is superior to CA-125 (124) sible that it can be used as a marker predicting poor prognosis.
and of particular value for early-stage disease (127). Combining Recent developments with regard to the HE4 marker include
CA-125 with HE4 has been found to increase sensitivity while its commercial availability (when combined with CA-125) as
maintaining high specificity (127); but more recently, it has been a test for preoperative prediction of low/high risk of epithe-
reported not to be superior to CA-125 in clinical setting (128). lial OC as well as being approved by the U.S. Food and Drug
More recently, the superiority of HE4 in differential diagnosis Administration for monitoring recurrence or progression of
of ovarian cancer as a single marker was reported. Moreover, the epithelial ovarian cancer. For the former, it is included in the
diagnostic prediction (AUC 0.864) was improved by Risk of Risk of Ovarian Malignancy Algorithm (ROMA), a qualitative
Malignancy (ROMA) index (AUC 0.897) (129). Serum HE4 has serum test that combines the results of HE4 EIA, ARCHITECT
CA-125 II and menopausal status into a numerical score. In pre-
menopausal women, ROMA value 13.1% predicts high risk
Table 5.8 Mean Levels of Serum HE4 in Normal of epithelial OC; ROMA value 27.7% is deemed to represent
Controls and Benign and Malignant high risk of OC in postmenopausal women (132).
When looking at new biomarkers/combination of markers, it
Lesions
is important to establish the normal range in healthy individuals,
Condition Serum HE4 level (mean) especially if the marker has been shown to be very promis-
ing, such as HE4. The normal range for HE4 has recently been
Normal Control 34.1 pM established in serum samples from 1101 healthy women and 67
pregnant women. HE4 concentration increased with advancing
Benign Lesions 39.1 pM
age (>40). Median serum HE4 levels in premenopausal women
Malignant Lesions 248.7 pM (46.6 pmol/L) were significantly lower than in postmenopausal
women (57.6 pmol/L; p < 0.001). The upper 95th percentile
Source: Wang S, et al. The Application of HE4 in Diagnosis of Gynecological for HE4 levels was 89 pmol/L for premenopausal women,
Pelvic Malignant Tumor. Clin Oncol Cancer Res. 2009; 6: 72-74. 128 pmol/L for postmenopausal women, and 115 pmol/L for
100 CHAPTER 5 DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS
Table 5.9 Elevations of HE4 and CA-125 in Women with Benign Disease and Ovarian Cancer
HE4 > 89.1 pM (premenopausal women);
HE4 > 128 pM (postmenopausal women) CA-125 > 35 U/mL
Benign disease
a
Overall (all benign tumors) 8% 29%
Ovarian cysts 8% 14%
Germ cell tumors (mature teratoma) 1% 21%
Sex cord stromal tumors (thecoma, fibrothecoma) 24% 52%
Cystadenoma, adenofibroma, cystadenofibroma 20% 20%
Serous epithelial tumors 8% 20%
Mucinous epithelial tumors 13% 18%
Benign, NOS 9% 27%
Endometriosis/endometrioma 3% 67%
Abscess/hydrosalpinx/POD 13% 37%
Fibroid (leiomyomas) 8% 26%
Benign, other (Normal ovaries) 5% 22%
HE4 > 140 pmol/L CA-125 > 35 U/mL
Ovarian cancer b
Overall 75.2% 80%
Stage III 58.3% 54.2%
Stage III 78.8% 86.5%
Stage IV 79.6% 85.7%
Serous papillary 84.4% 84.4%
Mucinous 43.8% 68.8%
Other histologies 57.9% 68.5%
Moore et al. Comparison of HE4 and CA-125 levels in benign gynaecological disease. Am J Obstet Gynecol 2012.
a
Escudero JM, et al. Comparison of serum human epididymis protein 4 with cancer antigen 125 as a tumor marker in patients with malignant and nonmalignant diseases.
b
all women. In pregnant women, median HE4 concentrations plasma of cancer patients (141,142). Recently, in colorectal can-
were significantly lower than their premenopausal counterparts cer the pattern of methylation of serum DNA has been shown to
(p < 0.001) (133). HE4 levels appear to be lower in the Asian be a prognostic factor (143).
population (HE4 of 33.2 pmol/L) (134). This has implication for In OC, DNA methylation profiles have been shown to predict
further clinical application of the test in different populations. active disease (144), predict response to treatment (components
of the WNT pathway has shown that methylation of NKD1 and
DVL1 were independent predictors of progression free survival,
Glycodelin whilst DVL1 and NFATC3 methylation were significantly associ-
ated with response to treatment) (145) and OS, as secreted frizzled-
Glycodelin was first described as a marker with a role in OC in related proteins sFRP5 promoter was shown to be significantly
2001 (135). Since then, limited studies reported evaluating its methylated in OC and was associated with worse 5-year OS when
expression mainly in tissue rather than serum. Tissue expression compared to unmethylated sFRP5 (52% vs. 88%, p = 0.03) (146).
data suggests that in serous OC, glycodelin expression carries a
better prognosis (136). An ELISA-based assay was only introduced
in 2005 (137). A panel including HE4, Glycodelin, MMP7, SLPI,
Plau-R, MUC1, Inhibin A, PAI-1, and CA-125 evaluated in serum Salivary Transcriptomes as
samples from women with OC and healthy controls showed Novel Markers
a sensitivity ranging from 59.5% to 80.5% while maintaining high Novel biomarker strategy, using salivary transcriptomes as pos-
specificity. However, for detecting disease recurrence, a panel con- sible biomarkers for OC, has been recently been evaluated in 11
sisting of HE4, Glycodelin, MMP7, and CA-125 had a sensitivity OC patients and 11 controls. In a validation set of 21 OC
of 100% when compared to CA-125 alone (96%) (138). Although patients and 35 healthy controls, combination of 5 biomarkers
this data is promising, further evaluation of glycodelin is required. (AGPAT1, B2M, BASP2, IER3, and ILI1) yielded high sensitivity
(85.7%) and specificity (91.4%) (147).
Alpha-Fetoprotein
Alpha-Fetoprotein (AFP) is an oncofetal protein produced by the
M ICRORNA-BASED OVARIAN fetal yolk sac, liver, and upper gastrointestinal tract. Elevated
CANCER BIOMARKERS levels of AFP occur in pregnancy and benign liver disease. Serum
levels are raised in most patients with liver tumors and in some
MicroRNAs (miRNAs) are noncoding RNAs that regulate gene patients with gastric, pancreatic, colon, and bronchogenic
expression by translational inhibition or mRNA degradation. malignancies have elevated AFP levels (154). AFP levels were
102 CHAPTER 5 DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS
investigated in 135 patients with germ cell tumors and elevated was no significant correlation between tissue hCG expression
levels were found in all patients with endodermal sinus tumors, and overall ovarian cancer patient survival, a subgroup analysis
62% with immature teratomas and 12% with dysgerminoma revealed an increased 5-year survival in LH-R positive/FSH-R
(159). AFP also accurately predicts the presence of yolk sac ele- negative and hCG positive tumors (hCG positive 75% vs. hCG
ments in mixed germ-cell tumors (160). Although AFP production negative 50.5%) (169). LH-R has previously been shown to be
in epithelial ovarian cancers is extremely rare, a case of ectopic of prognostic value. This study highlights that both hCG and
production of AFP by an ovarian endometrioid tumor has been LH-R may be useful targets in novel cancer therapies.
described in the literature (161). Muller and Cole have comprehensively reviewed the litera-
In women with endodermal sinus tumors, AFP is a reliable ture on hCG and its role in cancer. With regard to gynecologic
marker for monitoring therapeutic response and detecting malignancies, they state that the serum free b -subunit or its uri-
recurrence (162,163). On univariate analysis, AFP levels of over nary degradation product b -core fragment is produced by 68%
1,000 ng/mL, age over 22, and histology were found to be major of ovarian, 51% of endometrial and 46% of cervical malignan-
prognostic factors in 43 patients with ovarian and extragonadal cies. The free b -subunit enhances growth and invasion in all
germ-cell tumors (164). these malignancies and is therefore associated with poor prog-
Recently, a sensitive chemiluminescence (CL) imaging immu- nosis. However, they stress that in clinical practice, confusion
noassay method for detection of multiple tumor markers with arises when a patient presents with persistent low positive hCG
high throughput, easy operation, and low cost was developed. in the absence of pregnancy and absence of obvious malignan-
The proof of concept study included 5 markers (alpha-fetopro- cies (170). The first aim is to rule out a tumor then consider a
tein, CA-125, CA-153, and CEA) to screen patients with liver, false positive test by assaying hCG in the urine. A further possi-
breast, or ovarian cancers. The method showed very good repro- bility in women aged over 35 with oligomenorrhea, amenorrhea
ducibility, accuracy, and wide detection range, thus making it an or following bilateral salpingo-oophorectomy is pituitary hCG.
ideal platform to study the performance of the panel in clinical
and preclinical sets of samples from OC patients (165).
Inhibin and Related Peptides
Inhibins and activins are structurally related dimeric proteins
Human Chorionic Gonadotropin first isolated from ovarian follicular fluid on the basis of their
Human chorionic gonadotropin (hCG) is synthesized in preg- ability to modulate pituitary follicle-stimulating-hormone secre-
nancy by the syncytiotrophoblast. It is a glycoprotein hormone tion. They are members of a larger group of diverse proteins, the
made up of 2 dissimilar covalently linked subunits a and b. Pro- transforming growth factor-b (TGF-b) superfamily, which are
duction of hCG by the tumor is accompanied by varying degrees involved in cell growth and differentiation. Inhibin is a heterodi-
of release of the free subunits into circulation. Recent advances meric glycoprotein composed of a common a -subunit and one of
in our understanding of hCG/hCG-b synthesis by trophoblastic two b -subunits, resulting in either inhibin A (abA) and inhibin
and nontrophoblastic tissues alongside an improvement in tech- B (ab B), for which specific immunoassays are now available.
niques measuring hCG have helped define its role in the clini- The serum also contains immunoreactive forms of the a -subunit
cal practice. hCG is elevated in virtually all cases of gestational not attached to the b -subunit, the most abundant of which is
trophoblastic disease (hydatidiform mole, invasive mole, and pro-a C and pro-aN-a C. The pro-aC assay measures these pre-
choriocarcinoma) and serves as an ideal tumor marker. There is cursor forms of inhibin. The original Monash assay detected
a close correlation between hCG levels and tumor burden and immunoreactive inhibin that included a range of inhibin-related
hCG levels are used in staging and clinical management. Serum peptides in addition to biologically active inhibin dimers.
hCG can also be detected in patients with nontrophoblastic can- In 1989, Lappohn et al. (171) reported elevated serum immu-
cers. Although gynecologic cancers are prominent in this group, noreactive inhibin concentration in women with granulosa-cell
the sensitivity of using hCG is lower than for other markers in tumors. Numerous studies have since confirmed serum inhibin
current use except in germ-cell tumors with a chorionic compo- elevation in ovarian sex cord/stromal tumors and established
nent (166). its role in differential diagnosis and surveillance of these malig-
In a retrospective analysis of 113 patients with stage IC to IV nancies (172174). The major molecular forms detected are
malignant ovarian germ cell tumors, both on univariate and mul- bioactive dimeric inhibins A and B (175,176). Antimllerian
tivariate analyses, stage of disease and elevation of serum hCG-b hormone, or mllerian inhibitory factor, is another member of
and AFP were significant predictors of OS, whereas age at diag- the TGF-b superfamily that is being investigated as a marker for
nosis was of no prognostic value (167). It is worth noting that granulosa-cell tumor (175,177,178).
this is the first study to demonstrate stage and tumor markers as In epithelial ovarian cancer, the role of the inhibin pep-
prognostic parameters in patients with malignant ovarian germ tides remains to be determined. Using the initial nonspecific
cell tumors and may help in deciding on therapeutic regimen. Monash assay, elevated serum inhibin levels were reported in
In a series of 424 pediatric patients with a mean age 12.5 years, 25% to 90% of women with epithelial ovarian cancer (179
tumor markers were elevated in 54% of the cases with elevated 181). In 2004, an ELISA for total inhibin was developed (182).
b -human chorionic gonadotropin (b -hCG), alpha fetoprotein Tsigkou et al. investigated the sensitivity/specificity of serum
(AFP), and CA-125 being significantly associated with malignancy total inhibin for epithelial ovarian cancer in 89 postmeno-
(p < 0.02), but an elevated CEA was not (p = 0.1880). However, pausal women with stage II to III epithelial ovarian cancer and
the best indicators of malignancy in these young patients were found that patients with serous or mucinous tumors showed
complaint of a mass or precocious puberty, a mass exceeding 8 cm the highest total inhibin levels. At 95% specificity, the total
or a mass with solid imaging characteristics (168). inhibin assay detected 93% of serous and 94% of mucinous
In 2012, Lenhard et al. showed that 67% of OC and 26.7% of tumors (183). Mucinous ovarian cancers are most likely to be
benign ovarian tumors had hCG-positivity in the serum with sig- associated with increased inhibin levels (173,184). In contrast,
nificantly higher hCG serum concentrations in patients with OC using specific assays that measure bioactive dimeric inhibin
compared to benign ovarian tumors (p = 0.000). Ovarian cancer A, elevated serum levels were only found in 5% to 31% of
tissue was positive for hCG expression in 68%. Although the women with epithelial ovarian cancer (173,184,185). Overall,
hCG tissue expression differed by grade, it did not by histo- the picture is emerging that dimeric inhibin A and B levels are
logic subtype. Increased hCG expression was found in mucinous not informative in epithelial ovarian cancer, and total inhibin/
OCs at Stage II compared to stage I (p = 0.018). Although there pro-a C immunoreactive forms are the most commonly elevated
CHAPTER 5 DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS 103
of the inhibin-related peptides (183,185,186). Furthermore, breast, ovarian, and testicular cancers. Recently it has been shown
although there is preferential secretion of precursor forms of that the malignant phenotype of ovarian cancer cells can be
Table 5.11 Elevations in Inhibin or CA-125 Levels in Women with Ovarian Cancer
Cancer Group Elevations in Inhibina Levels (%) CA-125 > 35 kU/L (%) Inhibin + CA-125 (%)
a
Total inhibin.
Source: Robertson DM, Pruysers E, Jobling T. Inhibin as a diagnostic marker for ovarian cancer. Cancer Lett 2007;249(1):1417.
104 CHAPTER 5 DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS
Epithelial cancers
Clinical practice CA-125 is the main markerwhen CA-125 levels after surgery Serial CA-125 levels CA-125 detects recurrence with
combined with menopausal status and during chemotherapy reflects clinical course a sensitivity of 84%94% and
and ultrasound features in the are independent prognostic in 90% of positive a false-positive rate of <2%.
risk of malignancy index (RMI), indicators. Various criteria tumors and are Median lead-time compared
a sensitivity of 71%85% and are used based on CA-125 used routinely for with clinical diagnosis of
specificity of 96%97% is achieved. half-life. monitoring patients. recurrence is 6099 days.
CEA HE4 HE4
Research Serum CA-125 being assessed in screening Inhibin pro-a C/total inhibin, Kallikrein 8, mesothelin, CASA Osteopontin, TPS
trials in the general (UKCTOCS) and high-risk kallikreins, mesothelin, prostasin, CYFRA 21-1, M-CSF,
(UKFOCSS) and trials by GOG and CGN osteopontin, M-CSF, TPS, proteomic TATI, VEGF, CASA,
in the USA populations. Results from PLCO markers (profile, transthyretin, tetranectin
reported in 2012, results from the other tri- apolipoprotein A)
als expected in 2013/14. Main emphasis on
algorithms to interpret serial CA-125 and
transvaginal ultrasound as a second-line test.
CA-15-3, CA-72-4, CA-19-9, HE4 CASA
TATI, GAT, free serum DNA
methylation, free glycans,
IL-7, TNF a receptors
HE4
microRNAs
metabolite profiling
DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS
Germ-cell tumors
Clinical practice Serum AFP in tumors with
endodermal sinus/yolk sac elements,
serum b -hCG in tumors with chori-
onic elements
Research M-CSF especially in dysgerminomas
Sex cord stromal
tumors
Clinical practice Inhibin in granulosa-cell tumors Inhibin in granulosa-
cell tumors
CHAPTER 5 DEVELOPM ENT AN D I DENTI FICATION OF TU MOR SERU M MARKERS 107
investigating its role in cervical carcinoma. Tsai et al. detected marker for diagnosis and prognosis of cervical cancer. Zhang etal.,
elevated CYFRA 21-1 levels in 14% of controls, 35% of patients in plasma samples of 109 patients with cervical cancer, 138 patients
with stage IB-IIA squamous-cell carcinoma of the cervix, and 64% with cervical intraepithelial neoplasia (CIN), and 80 healthy vol-
of patients with stage IIB-IV disease (306). Although CYFRA unteers, found a correlation between increased circulating Bmi-1
21-1 was related to tumor stage and size in patients with cervical mRNA level and reduced disease-free survival (DFS) (p = 0.001)
cancer(307) and there was a positive correlation with SCC, its sen- and OS (p = 0.015). Circulating Bmi-1 mRNA was an independent
sitivity and specificity for detection of squamous-cell carcinoma of prognostic factor for DFS and OS (321).
the cervix were lower than SCC (306,308,309). In cervical adeno- DNA methylation markers may be useful in detecting cervi-
carcinoma, it was elevated in 63% of patients (309). CYFRA 21-1 cal cancer metastasis. Methylation of the protein tyrosine phos-
may have a role in follow-up of women with cervical cancer(310). phatase receptor type R (PTPRR) promoter has an important
In the study by Pras et al. (298) elevated CYFRA 21-1 levels after role in metastasis and may be a biomarker of invasive cervical
chemoradiation for cervical cancer indicated residual tumor in cancer (322).
70% of patients. Nonetheless, the evidence available so far does
not justify the routine measurements of these markers.
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6
CHAPTER
MARY B. DALY
115
116 CHAPTER 6 CANCER PREVENTION STR ATEGI ES
Europe Asia
59,931 cases/yr 265,884
cases/yr
HPV 16/18
76%
Oceania
2004 cases/yr
FIGURE 6.1. Age-standardized rates of new cases of cervical cancer per 100,000 women, 2002.
CHAPTER 6 CANCER PREVENTION STR ATEGI ES 117
16 58.7%
Squamous epithelium
Superfical zone
Midzone
Basal layer
Basement membrane
Dermis
Episome
(IgG1) subclass (18). In these early trials, vaccine efficacy against investigate the efficacy of Gardasil among older women, 3,891
infection with HPV-16/18 and against CIN 2+ at 6.4 years of women aged 24 to 45 years were randomized to vaccine or pla-
follow-up was 100% (29). cebo. Efficacy against persistent infection and cervical lesions
Subsequently, 2 vaccines have been developed for use in hu- was 89% (36). Side effects in all of the studies were minimal
mans, Gardasil (Merck), a quadrivalent vaccine that includes and included discomfort at the injection site and occasional
HPV-16, -18, -6, and -11 and is formulated with aluminum adju- mild fever. Anti-HPV antibody titers remain high 5 years after
vant, and a bivalent vaccine Cervarix (GlaxoSmithKline), which administration. In June 2006, Gardasil received FDA approval
includes HPV-16 and -18 and is formulated with a proprietary for the vaccination of women aged 9 to 26, followed closely by
adjuvant, AS04, which contains aluminum and a bacterial lipid. approval for its use in children and adults aged 9 to 26 years by
Gardasil has undergone several randomized, placebo-controlled the European Commission.
trials among over 21,000 women. In a U.S. multicenter proof The initial trial of Cervarix randomized 1,113 women aged
of principle study, 2,391 young women aged 16 to 25 were 15 to 25 years to receive a bivalent HPV-16, -18 vaccine versus
assigned to a monovalent yeast-derived HPV-16L1 VLP, formu- placebo. No cases of persistent HPV-16 or HPV-18 were seen
lated on aluminum adjuvant, by intramuscular injection at day in the women vaccinated according to protocol, whereas there
0, month 2, and month 6 or placebo. The primary outcomes were seven cases of infection in the control group. The vaccine
were persistent HPV-16 infection and HPV-16related carci- was 95% effective against persistent infection and 93% effec-
noma in situ CIN 2 and 3. At a follow-up of 48 months, admin- tive against cytologic abnormalities even when including those
istration of the three-dose regimen of HPV-16 vaccine resulted women who did not complete the vaccine regimen. In an ex-
in a 94% reduction in persistent HPV infection in those treated tended follow-up of 776 women, the vaccine continued to dem-
according to protocol. The vaccine was 100% effective in pro- onstrate 98% efficacy at close to 4 years (37,38). The Papilloma
tecting against HPV-16related CIN 2 and 3 (30). TRIal against Cancer In young Adults (PATRICIA) randomized
A phase 2 dose-ranging assessment of immunogenicity and 18,644 women to 3 doses of Cervarix versus hepatitis A vaccine.
efficacy was conducted in the United States, Brazil, and Europe At a mean of 34.9 months follow-up, HPV vaccine efficacy, as-
among 552 women aged 16 to 23 years. Women were ran- sessed in women who were seronegative DNA for HPV-16/18 at
domized to 1 of 3 vaccine doses versus placebo given at day 1, baseline, against CIN 2+ lesions was 92% (39).
month2, and month 6. At close to 3 years of follow-up, vaccine There was also efficacy against CIN 3+, especially in the
efficacy for reduction of persistent HPV infection was 90% and 15- to 17-year age group (40). Furthermore, the vaccine pro-
for clinical disease (cytologic abnormalities, CIN, cervical can- vided cross-protective efficacy against 4 oncogenic nonvaccine
cer, or external genital lesions) was 100%. Vaccine efficacy was types: HPV-33, HPV-31, HPV-45, and HPV-51 (41).
similar for each of the three doses. All women who received the Overall, achieving close to 100% effective vaccination of a
vaccine developed high antibody titers by month 7 (31). Early cohort of 12-year-old girls is estimated to result in a 76% re-
data on vaccine efficacy found similar results with 2 versus duction in the incidence of cervical cancer (42). Mathematical
3doses, which if borne out, is likely to improve compliance (32). modeling has been used to estimate the clinical benefits and
The two pivotal phase 3 trials enrolled more than 18,000 cost-effectiveness of a population-based HPV-16/18 vaccination
women and included both precancerous lesions, CIN 2, CIN program in Africa (Fig. 6.5). Parameters considered were the
3, adenocarcinoma in situ (AIS), or invasive cervical cancer natural history of HPV and cervical cancer, age at vaccination,
with documented HPV-16 or -18 in DNA from the involved vaccine cost, vaccine efficacy, waning immunity, the risk of re-
tissue, vulvar and vaginal lesions, and genital warts as out- placement with other oncogenic strains of HPV, age at onset
comes. Women with evidence of previous infection with HPV, of screening, and screening intervals. A review of 27 studies of
or with cytologic abnormalities, were not excluded. At 3 years, cost-effectiveness models found considerable variability in the
vaccine efficacy in those women treated according to protocol incremental cost-effectiveness ratios (ICER) due to the differ-
was 99%, with only one case of CIN 3 occurring among the ent assumptions made. Overall, however, the implementation of
vaccine recipients. In the intent to treat population, which in- routine vaccination programs for adolescent girls is consistently
cluded women with prevalent HPV-16/18 infection and women shown to be cost-effective compared to screening alone (43). The
who did not complete the vaccination schedule, CIN 2/3 and Advisory Committee on Immunization Practices (ACIP) of the
AIS were reduced by 44% (33,34). The vaccine was also effi- Centers for Disease Control and Prevention (CDC) recommends
cacious against high-grade vulval and vaginal lesions (35). To routine vaccination for HPV of girls age 11 to 12 (range, 9 to
50% Coverage
160
75% Coverage
140
100% Coverage
120
100
80
60
40
20
0
15 20 25 30 35 40 45 50 55 60 65 70 75 80
Age (years)
FIGURE 6.5. Impact of HPV-16/18 vaccines on incidence of cervical cancer.
CHAPTER 6 CANCER PREVENTION STR ATEGI ES 119
26 years) and has added Gardasil to its Vaccines for Children abstinence-based messages, and may increase high-risk sexual
program (44,45). Similarly, the American Academy of Pediatrics behavior. There is no data, however, to suggest that fear of HPV
Legend
Prostate, 52 Breast, 47
Breast, 44
Ovary, 52
that is, the likelihood that a mutation will actually result in the genetic mutation with other genetic and/or environmental
ovarian cancer, is estimated to range anywhere from 36% to factors, and suggests that these genes may function as gate-
46% for BRCA1 mutation carriers, and from 10% to 27% for keepers and, when lost, allow other genetic alterations to ac-
BRCA2 mutation carriers (66). Some mutations may be more cumulate. Ovarian cancer is also included in the phenotype of
specifically related to ovarian cancer risk than others. An ovar- the recently described mismatch repair genes associated with the
ian cancer cluster region has been identified, for example, in hereditary nonpolyposis colon cancer (HNPCC), or Lynch syn-
exon 11 of BRCA2, which is associated with a higher rate of drome, in which the lifetime risk for ovarian cancer is estimated
ovarian cancer than other mutations in the gene. The wide vari- to be approximately 12%, and the median age at diagnosis 42.7
ation in penetrance observed may also reflect the interaction of years (67) (Fig. 6.7). The identification of hereditary syndromes
Legend
Male
Lynch Syndrome Family Pedigree Female
Proband
Deceased
Cancer
Colon, 45 Breast, 51
Ovary, 50
Uterus, 35
Colon, 45 Uterus, 47
Colon, 62
of ovarian cancer provides new opportunities to understand the gonadotropins and protect against chronic inflammation associ-
biology of the disease and to devise novel preventive strategies. ated with pelvic inflammatory disease (79). In addition to these
potential mechanisms, a 3-year study on primates demonstrated
that the progestin component of an OCP had a potent effect
Prevention on apoptotic and TGF-b signaling pathways in the ovarian epi-
thelium, raising the possibility that progestin-mediated biologic
Risk Avoidance and/or Adoption effects may underlie the protective effects of OCPs (80). The use
of Protective Practices of OCPs appears to decrease a womans risk for ovarian cancer
by 30% to 60%. Risk reduction is apparent with as little as 3
The available evidence regarding factors that lower ovarian months of use, increases in magnitude with increased duration
cancer risk has been based primarily on the results of case- of use, and persists for as long as 10 years after discontinua-
control studies retrospectively comparing the reproductive, tion of use. The risk reduction applies to nulliparous as well as
hormonal, or behavioral characteristics of ovarian cancer cases parous women, to all histologic subtypes, including tumors of
with matched controls, not on prospective randomized trials. low malignant potential, to women with a hereditary risk for
These studies have consistently shown an inverse association of ovarian cancer, is consistent across races, and is independent of
ovarian cancer with increasing parity, with the first birth confer- age at use or menopausal status (70,81,82). Although there has
ring significantly more protection (35%) than subsequent births never been a randomized clinical trial to demonstrate the pro-
(15%). The protective effect of pregnancy occurs regardless tective effect of OCPs on ovarian cancer risk, it is often recom-
of fertility history and is not age dependent (68). Pregnancy is mended empirically to women with a family history of ovarian
characterized by a prolonged period of anovulation as well as cancer to reduce their risk.
high levels of circulating progesterone, which may cause termi- Epidemiologic and laboratory evidence suggest a potential
nal differentiation of premalignant cells (69,70). role for retinoids as preventive agents for ovarian cancer (83).
The evidence supporting a protective effect of breast-feeding Retinoids are natural and synthetic derivatives of vitamin A.
against epithelial ovarian cancer risk is weak and inconsistent. They have great potential for cancer prevention, due to a broad
Some studies suggest a 10% to 20% decrease in ovarian can- range of important biologic effects on epithelial cells, including
cer risk associated with breast-feeding. In those studies that are inhibition of cellular proliferation, induction of cellular differen-
positive, the impact of breast-feeding on ovarian cancer risk ap- tiation, induction of apoptosis, cytostatic activity, and induction
pears to be greatest for the first 6 months of lactation with no of TGF-b. The most significant evidence supporting a rationale
apparent increase in ovarian cancer protection with longer-term for retinoids as chemopreventive agents for ovarian cancer is that
lactation (71,72). of a chemoprevention study in Italy, which suggested an ovar-
Several studies have examined the association of hormone ian cancer preventive effect from the retinoid 4-HPR. Among
replacement therapy (HRT) with ovarian cancer risk. While the women randomized to receive either 4-HPR or placebo in a trial
majority find a modest increase in risk, most lack statistical sig- designed to evaluate 4-HPR as a chemopreventive for breast car-
nificance. The strongest association is seen in endometrioid his- cinoma, significantly fewer ovarian cancer cases were noted in
tologies, where relative risks range from 1.2 to 5.5 (73). the 4-HPR group as compared to controls (84).
Several retrospective and prospective studies have examined Vitamin D is a fat-soluble vitamin that is essential as a posi-
associations between dietary factors and ovarian cancer risk. tive regulator of calcium homeostasis. The vitamin D receptor
Modest levels of protection have been reported for fruits and and the retinoic acid receptors share strong homology and read-
vegetables in general, and for vitamin A and b -carotene in par- ily dimerize, making it likely that vitamin D and retinoids have
ticular, although findings are inconsistent (74,75). While there is common signaling pathways in the cell (85). Vitamin D has been
some case-control data that invasive ovarian cancer is reduced shown to have diverse biologic effects in epithelial cells relevant
among women who report frequent high-intensity exercise, the to cancer prevention, including retardation of growth, induction
relationship between physical activity and ovarian cancer risk is of cellular differentiation, induction of apoptosis and upregu-
inconsistent, and may differ by histologic type (65,76,77). lation of TGF-b (86). With regard to ovarian cancer, a recent
study has correlated population-based data regarding ovarian
cancer mortality in large cities across the United States with
Chemoprevention geographically based long-term sunlight data reported by the
The majority of theoretical models of ovarian cancer chemo- National Oceanic and Atmospheric Administration. The study
prevention have been based on the assumption that the origin demonstrated a statistically significant inverse correlation be-
of ovarian cancer is the OSE. As the paradigm has shifted to tween regional sunlight exposure and ovarian mortality risk
identifying the epithelial surface of the fallopian tube as the site suggesting that sunlight induces production of native vitaminD
of origin, it is not clear how to interpret the previous theories. in the skin (87). However, a systematic review of 20 ecologic
Prior research has explored the presence of receptors for most and case-control studies failed to find consistent evidence for
members of the steroid hormone superfamily, including recep- a relationship between vitamin D exposure and ovarian cancer
tors for progestins, retinoids, androgens, and vitamin D. Proges- incidence or mortality (88).
tins, retinoids, and vitamin D have been shown to exert a broad Epidemiologic studies have suggested that use of NSAIDs
range of common biologic effects in epithelial cells, including may lower ovarian cancer risk (89). Several biologic mecha-
induction of apoptosis, upregulation of transforming growth nisms have been proposed to account for the chemopreventive
factor-b (TGF-b ), cellular differentiation, and inhibition of effects of NSAIDs, including inhibition of ovulation, inhibition
proliferation. In addition to hormonal agents, there is growing of COX, and downregulation of prostaglandins, enhancement
evidence that nonsteriodal anti-inflammatory drugs (NSAIDs) of the immune response, and induction of apoptosis (70,90,91).
may have ovarian cancer preventive effects (78). It is yet to be Similarly, dietary antioxidants have shown an inverse asso-
demonstrated that these agents are active in the fallopian tube ciation with ovarian cancer (92). Despite a growing body of
epithelium. preclinical data indicating chemopreventive effects of several
To date, only OCP use has been consistently shown to be agents, clinical research exploring their efficacy to reduce rates
protective against ovarian cancer. OCPs were first introduced of ovarian cancer is hindered by the relatively low incidence of
in the United States in the 1960s. Most formulations include the disease, insufficient understanding of the preclinical course
estrogen, progesterone, or a combination of the 2. In addition to of ovarian cancer, the lack of validated preclinical biomarkers,
suppressing ovulation, OCPs also reduce pituitary secretion of and inadequate screening strategies.
CHAPTER 6 CANCER PREVENTION STR ATEGI ES 123
Surgical Prophylaxis
Table 6.3 Ovarian CancerMajor Points
of the ovaries among all women undergoing hysterectomy for have a 40% to 60% risk of endometrial cancer. The mean age at
benign conditions. However, data do not support the removal diagnosis in this group is approximately 50 years (67). Epigen-
of the ovaries at the time of hysterectomy for benign disease etic silencing of the Lynch syndrome genes by hypermethylation
in women at average risk of ovarian cancer, among whom the is also thought to contribute to endometrial cancer risk (114).
negative cardiovascular and metabolic impact of early surgical Endometrial cancer is also a component of Cowden syndrome,
menopause outweighs any potential benefit (108,109). in which it is estimated that mutations in the PTEN gene con-
fer a lifetime risk for endometrial cancer of approximately 6%,
with most cases occurring between the ages of 38 and 59 years
(115). Type 2 serous endometrial cancer is uncommon and is
EN DOM ETRIAL CANCER not related to unopposed estrogen exposure.
Risk Factors
Endometrial cancer is the most common gynecologic cancer in Prevention
the United States. Over 45,000 new cases are diagnosed each Risk Avoidance and Uptake
year, and there are 8,100 deaths annually (16). Unlike many
other tumors, the incidence and mortality from endometrial
of Protective Behaviors
cancer is increasing, with a lifetime risk of 3% and a 16% risk It has been estimated that approximately 40% of endometrial
of death (110,111). The increasing incidence of endometrial cancers are attributable to excess body weight in developed
cancer is thought by some to be related to the increased preva- countries (112) (Fig. 6.9). Maintenance of ideal body weight,
lence of obesity (112). Worldwide, there are 287,900 estimated regular physical activity, and control of diseases associated with
new cases per year (113). The relatively low case fatality rate endometrial cancer (diabetes, hypertension, and thyroid disease)
is due to early detection and treatment of early-stage disease. are prudent approaches to reduce disease risk. Vigorous physi-
The majority of risk factors associated with type 1 (endome- cal activity helps to control, prevent, or reverse weight gain, im-
trioid) endometrial cancer, viz. increased age, nulliparity, early prove insulin sensitivity and reduce circulating estrogen levels,
age at menarche, late age at menopause, obesity, long-term use thus leading to a 22% reduction in endometrial cancer (116).
of unopposed estrogen replacement therapy, polycystic ovary Tamoxifen is a proven chemotherapeutic strategy to reduce the
syndrome (PCOS), and the use of tamoxifen, are all thought to incidence of breast cancer in women at increased risk. While
exert their effect through estrogen-induced endometrial prolif- acting as an estrogen antagonist in the glandular epithelium of
eration leading to hyperplasia and malignant transformation. the breast, tamoxifen acts as an agonist in the endometrium,
The increased risk associated with diabetes, hypertension, and increasing the risk of postmenopausal bleeding, endometrial
thyroid disease also suggests a role for altered growth hor- hyperplasia, endometrial polyps, and endometrial cancer. Al-
mone pathways in addition to the steroid hormone pathways though the absolute numbers were small, the relative risks for
(Fig.6.8). There are also genetic syndromes associated with en- endometrial cancer in the National Surgical Adjuvant Breast and
dometrial cancer. Women with germ-line mutations in the DNA Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT)
repair genes associated with the HNPCC or Lynch syndrome for women on the tamoxifen arm compared to placebo were
SHBG
Aromatase
Ovary
Androgens
(genetically susceptible
Endometrium
women only?)
IGF1 IGFBP1
Bioavailable
Bioactive IGF1
oestrogens
Chronic
Progesterone
anovulation Endometrial
cancer
CHAPTER 6 CANCER PREVENTION STR ATEGI ES 125
Mortality from Cancer According to FIGURE 6.9. Relative risk of death among US women by BMI.
Uterus
Kidney
Cervix
Pancreas
(highest BMI category)
Esophagus
Type of Cancer
Gallbladder
Breast
NHL
Liver
Ovary
Colorectal
MM
0 1 2 3 4 5 6 7
Relative Risk of Death
2.53 (95% CI, 1.354.97) for all women, and 4.01 (95% CI,
1.7010.90) for women aged 50 years and older (117). Women
Table 6.5 Endometrial CancerMajor Points
considering the use of tamoxifen for breast cancer risk reduction The major risk factors for type 1 endometrial cancer exert their
should carefully weigh the greater than two-fold risk of endome- effect through estrogen stimulation of the endometrial surface
trial cancer with the benefits as they make their decision (118). epithelium.
Altered growth hormone pathways may also be involved in endo-
Chemoprevention metrial carcinogenesis.
The addition of a progestin to the estrogen component of HRT Hereditary forms of endometrial cancer have been associated with
has been shown to eliminate the increased risk of endome- the Lynch syndrome and with Cowden syndrome.
trial cancer. Progesterone controls many pathways resulting in
The majority of endometrial cancers present at an early stage with
growth inhibition and tissue homeostasis, and reverses the estro- abnormal uterine bleeding.
gen effect on the endometrium, thus preventing the development
of hyperplasia. The use of combined estrogen and progesterone Endometrial cancer screening is not recommended for the general
OCP decreases the risk of endometrial cancer by 50%, although population, although women with a hereditary risk are recom-
their effectiveness in obese women is not clear (119). Oral pro- mended to undergo annual endometrial biopsy.
gestins have long been used to reverse premalignant hyperplasia Prophylactic hysterectomy in high-risk women has been shown to
and to prevent the development of endometrial carcinoma (111). protect women from subsequent endometrial cancer.
More recently, progestin-releasing intrauterine devices (IUDs),
which deliver local therapy to the endometrium and spare some
of the systemic effects, have been studied as an alternative to oral however, it is not clear if this protection would translate into a
progestins both for women with early-stage endometrial cancer significant survival benefit. This study also found 100% protec-
who desire to preserve fertility, and among those taking adjuvant tion from ovarian cancer, which may warrant the consideration
tamoxifen following breast cancer treatment (115,120). of prophylactic total abdominal hysterectomybilateral salpingo-
oophorectomy (TAH-BSO) in this population. Alternatively, rou-
Surgical Prophylaxis tine endometrial biopsies starting at age 30 to 35 years may be
suggested in women with Lynch syndrome to detect early, prema-
It is thought that the majority of invasive endometrial cancers lignant endometrial lesions (123) (Tables 6.5 and 6.6).
progress through a series of premalignant stages, simple hyper-
plasia, complex hyperplasia, simple atypical hyperplasia, and
complex atypical hyperplasia, all of which may present with
abnormal vaginal bleeding (121). Conservative management of Table 6.6 Endometrial CancerRemaining
these conditions involves the use of progestational agents, which Questions
results in a complete regression of atypical hyperplasia in 50%
Can interventions targeting weight control and physical activity
to 94% of cases. Even in complete responders, however, there is
impact the incidence of endometrial cancer?
a high rate of recurrence, and definitive therapy of atypical hy-
perplasia is hysterectomy (53). Among women with documented What are the most effective forms of progesterone-containing con-
germ-line mutations associated with the Lynch syndrome, a ret- traceptive preparations for reducing the incidence of endometrial
rospective study found that prophylactic hysterectomy conferred cancer?
100% protection from subsequent endometrial cancer (122). Does prophylactic hysterectomy translate into a survival benefit?
Because of the high success rate for endometrial cancer treatment,
126 CHAPTER 6 CANCER PREVENTION STR ATEGI ES
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unknown mutation status. BJOG Int J Obstet of BRCA1 or 2 genes? Rationale and preliminary gestin intrauterine device in an adolescent with
Gynaecol. 2011;118(7):814824. development. Gynecol Oncol. 2011;121:472476. grade 2 endometrial cancer. Obstet Gynecol .
97. Hirst JE, Gard GB, McIllroy K, et al. High rates 105. Green MH, Mai PL. Schwartz PE. Does bilateral 2012;119(2):423426.
of occult fallopian tube cancer diagnosed at pro- salpingectomy with ovarian retention warrant 116. Moore SC, Gierach GL, Schatzkin A, et al.
phylactic bilateral salpingo-oophorectomy. Int J consideration as a temporary bridge to risk- Physical activity, sedentary behaviours, and the
Gynecol Cancer. 2009;19:826829. reducing bilateral oophorectomy in BRCA1/2 prevention of endometrial cancer. Br J Cancer.
98. Finch A, Beiner M, Lubinski J, et al. Salpingo- mutation carriers? Am J Obstet Gynecol. 2010;103:933938.
oophorectomy and the risk of ovarian, fal- 2011;204:19e16. 117. Freedman AN, Yu B, Gail MH, et al. Benefit/
lopian tube, and peritoneal cancers in women 106. Hankinson SE, Hunter DJ, Colditz GA, et risk assessment for breast cancer chemopre-
with a BRCA1 or BRCA2 Mutation. JAMA. al. Tubal ligation, hysterectomy, and risk of vention with raloxifene or tamoxifen for
2006;296(2):185192. ovarian cancer. A prospective study. JAMA. women age 50 years or older. J Clin Oncol.
99. Van der Kolk DM, de Bock GH, Leegte 1993;270(23):28132818. 2011;29:23272333.
BK, et al. Penetrance of breast cancer, ovar- 107. Cibula D, Widschwendter M, Mjek O, et al. 118. Gabriel EM, Jatoi I. Breast cancer prevention. Ex-
ian cancer and contralateral breast cancer in Tubal ligation and the risk of ovarian cancer: pert Rev Anticancer Ther. 2012;12(2):223228.
BRCA1 and BRCA2 families: high cancer in- review and meta-analysis. Hum Reprod Update. 119. Schmandt RE, Iglesias DA, Co NN, et al. Un-
cidence at older age. Breast Cancer Res Treat. 2011;17(1):5567. derstanding obesity and endometrial cancer risk:
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100. Yang KY, Caughey AB, Little SE, et al. A cost- ovaries be removed or retained at the time of necol. 2011:518525.
effectiveness analysis of prophylactic surgery hysterectomy for benign disease. Hum Reprod 120. Chin J, Konje JC, Hickey M. Levonorgestrel
versus gynecologic surveillance for women Update. 2010;16(2):131141. intrauterine system for endometrial protec-
from hereditary non-polyposis colorec- 109. Berek JS, Chalas E, Edelson M, et al. Prophy- tion in women with breast cancer on adju-
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7
CHAPTER
Preinvasive Disease of the
WARNER K. HUH
129
130 CHAPTER 7 PREI NVASIVE DISEASE OF TH E LOWER GEN ITAL TR ACT
Alpha
12
13
1
MfPV8
MfPV11
Mf MfPmPV1 fPV4
11 2
MfPV9
MfPV5
M
MfPV7
PV V P 3
HPV42
HPV32
M V10 3
7
H HP H PV7
33 58 V34
V
9
HPV10
HP V94
HP PV2 8
M
HPV117
V6
H V2
HP 29 3
HPV54
V7 P PV18
H
HPV78
fP
H 45
P
HP
7
7
0 V9
HPV
7
V6
V
V7
HP 9
V3 68
H
HP PV 59 Omega
2
V5 5
P
H V 3 H V
HP
P
8 HP 16 H 5 5
Dyodelta
1
V9
V8 6 69
V
HPV31 HP 3
HP V4 HP V2 HPV
HP PV7 HP 1
V5 2
HPV
H 0
4 HPHPV3 0 6 Lambda
V3
HP 53
10
74
HPVPV56
4
HPV HPV4
PPPV1 H
HPV66
2
Kappa
HPV13
4 3
HPV6 1
V1 V6
HPV11
HPV27 1 CP CP 1
4 V1 PV
1
PI
PV PV V1
Fd LrP V1
SsP
HPV2
Um
HPV57
PcP PlpPV1 Sigma
UuPV1
Mu
HPV81
HPV62
V1
2
HP
HPV V72 SfP 1 EdPV
1
Nu
61 OcPV1
HPV41 lota
1 Psi
HPV
HPHPV 87 HPV1
3
V8 86
HP 4 HPV63
2
H
P
HP V1
V 14
MnPV1
RaPV1 CcPV1
Dyozeta
HP V8HPV 83 CmPV1
Theta
H P
V9 9 10
H 71
PePV1
Cg
P
PV
0 2
V 1
10
Eta
V
FcPV1
6
BPV1 FIPV1
14 4
Dyoepsilon
BPV2
Fd
CcPV1 5
Dyotheta
PV
2 OvPV1 1
AaPV 2 Delta
1
RtPV
1 1
OaPV aPV2
3
1
V4 PV O
2 Ec
5 CP PV 5
5 Ec BPV 8
HPV96
2
V3 CPV V
BP
4 HPV92 CP
Epsilon
HPV76
HPV75 V1
1
3
V6
HPV49 Tm
HPV11
5
BP
Zeta
7 V3 1
HPV104 BP PV
MfPV2 Ch
6 HPV10
V1 0 9 Dyoiota
V1 PV 1
HPV11
3
111 12
2 M
aP BP V4 B sPV Rho
HPV HPV9 V1 BP P
Chi
1
EePV
V iP
HP m
2 Xi Phi
1
M 2
1
1 V
7
V3 7 80
PV
10
PV
V1 124 V93
V1103 V10 nP
V2
V2 98
Tt
HP PV1 PV
23
V1
2
PV Mf
HPPV HP R
38
HP PV
cP
2
1 PV
H H Omikron
4
HP HPV HP
V1
HP
5
PV C V7
V2 14
V1
M
HPV
Tt PV3 CP
HP HPV2
88 HP9
HPV19
0
HP
HPV25
1
HPV21
HPV47
V1
Tt
H 08
0
V5
HPV12
1
Cg
HPV HP18
P
HPV105
100
HPV65
HPV8
HPV95
Upsilon
HPV99
HPV4
2
PV
36
HPV
HP PV1 3
HP 119
V2 20
H V2
12 H
7
121
HP
HPVPV48 0
6
2
V
V6
HP
HPV
5
1
50
1
HP
1
H
4 Tau
10
1 6
Beta 3
V1
8 Pi
HP
Dyoeta
Gamma
for the viral proteins E1 and E2, which initiate viral replication (HSPG), specifically syndecan-1, which is found in the extracel-
and transcription (16). The URR is necessary for the regulation lular matrix of epithelial cells (19). Laminim-5 may be another
of gene expression, replication of the genome and packaging of specific extra-cellular matrix receptor involved in binding and
virus particles. cell entry (20,21). Though the main target of HPV are the kera-
The URR primarily regulates the transcription of proteins in tinocytes of the epithelium, HPV virus-like particles have also
early infection including proteins E6, E7, E1, and E2. The late been shown to attach to cells important in immune function
promoter is activated during the productive phase of the viral such as dendritic cells and Langerhans cells (22).
life cycle and results in transcription of the capsid proteins (L1 The binding of HPV to cell surface receptors in the basal
and L2) as well as E1, E2, E4, and E5. cells over the basement membrane then initiates conformational
changes in L2, which exposes additional binding sites (23,24). HPV
then enters the cells via endocytosis. Most studies suggest clathrin
or caveolin-dependent endocytosis (25), although internalization
HPV Lifecycle independent of these proteins has also been described (26).
Like other viruses, HPV must deliver its genome to the host cell Once inside the basal epithelial cells, the viral genome begins
and subsequently exploit the cellular machinery for its own pur- to replicate and maintains about 50 to 100 copies per cell. The
poses. HPV infects the host at sites of epithelial microtrauma, life cycle of HPV is closely linked to the state of differentiation
where the HPV particle can gain access to the actively proliferat- of the squamous epithelium of the natural host tissue. In normal
ing basal cells of the epithelium (Fig. 7.3). The mechanisms of cell squamous human epithelium, the basal layers (stratum basale)
entry are complex and continue to be better elucidated (17). The are the areas of active cell division. After division, the daughter
HPV particle interacts with the cell surface via its major and mi- cells migrate away from the basal cells (stratus spinosum) and no
nor capsid proteins (L1 and L2). a -6-Integrin had initially been longer progress through the cell cycle. Instead, these terminally
suggested as a receptor; however, controversies exist regarding differentiated cells produce highmolecular-weight keratins until
its specific involvement with HPV (18,19). Attachment receptors eventually the nuclear envelope breaks down and the cells become
for HPV particles are likely heparan sulfate proteoglycans empty keratin-filled sacs (stratum corneum).
CHAPTER 7 PREI NVASIVE DISEASE OF TH E LOWER GEN ITAL TR ACT 131
the cells reach higher epithelial layers the late promoter is acti-
E6 vated and late gene transcription and translation occur. There
new host.
E1
Oncogenic Proteins
The oncogenic potential of high-risk HPV is primarily attrib-
uted to the E6 and E7 proteins. E6 and E7 proteins differ in
high-risk and low-risk types. These proteins do not have intrin-
5.0 3.0 sic enzymatic activities, but instead interact directly and indi-
rectly with other cellular proteins affecting cell cycle regulation.
4.0 In addition to their individual effects, their combined effects are
E2 likely synergistic. In transgenic mouse models, the combinations
L2 of E6 and E7 have resulted in particularly aggressive invasive
E4 cancers (27).
E5
HPV E7
FIGURE 7.2. Schematic of genomic organization of HPV.
Source: Reprinted with permission from Wright TC, Ferenzy AF, Kurman RJ. Precancerous lesions of
The E7 protein is responsible for immortalizing cells infected
the cervix. In: Kurman RJ, ed. Blausteins Pathology of the Female Genital Tract. 4th ed. New York, NY: with HPV, primarily by affecting the cells transition from G1
Springer-Verlag; 1994:229241. into S-phase. E7 has a variety of targets including the retino-
blastoma (Rb) protein family, histone deacetylases, cyclins,
cyclin-dependent kinases (cdks) and cdk inhibitors (28). E7 is
When the HPV-infected basal cell divides, the viral DNA composed of 98 amino acids and is divided into 3 domains.
segregates with the 2 daughter cells, 1 cell remains as part CR1 is the amino terminus consisting of amino acids 1 to 20.
of the basal epithelium while the other migrates to the next The CR2 domain (amino acids 21 to 39) contains a sequence
layer. Because terminally differentiated cells of the upper that binds E7 to retinoblastoma tumor-suppressor proteins. The
epithelial layer contain little or no enzymes, in order to repli- CR3 domain (amino acids 40 to 98) contains zinc finger motifs
cate, the virus causes the cell to reenter S phase, causing only that are essential for protein folding (29).
partial instead of terminal differentiation. Thus the viral genome Rb proteins regulate the cell cycle by controlling the transi-
replication is synchronous with the cellular DNA replication. tion at the G1/S phase. Rb is hypophosphorylated and bound
HPV infected cells migrate away from the basal layer and as to E2F, a cellular transcription factor. In its bound state, Rb and
Late
Keratin
promoter
Stratum synthesis;
activated;
spinosum nuclear
genome
breakdown
amplification
Infection;
Cell division;
Stratum early
DNA
basale promoter
synthesis
activation
E2F inhibit cellular proliferation. In normal cells, when cyclin- E2 therefore regulates E6 and E7 and loss of E2 expression can
kinase complexes phosphorylate Rb, E2F is released and tran- lead to carcinoma due to the unrestricted effects of E6 and E7
scription of S phase genes occurs. E7 disrupts this process. The (47). Like E1, other interactions have been noted between E2
CR1 and CR2 domains of E7 bind to and degrade hypophos- and various proteins involved with transcription as well as mi-
phorylated Rb, disrupting the Rb-E2F complex (30,31). E2F is tosis and cell division. E1 and E2 expressions are early events in
released, which results in the expression of S-phase genes. the natural history of cervical dysplasia.
The zinc finger region of E7 can interact with the class I
histone deacetylases (HDACs). Through deacetylation of his-
tones, HDACs induce chromatin remodeling (32). E7 binding Viral Integration and Transformation
to HDACs causes progression into S-phase thereby lengthening
the life of the cell. to Malignancy
Independent of these effects, continuous activity of the E7 HPV genomes infect the cell via circular extra-chromosomal
protein leads to increasing genomic instability, which leads to copies; however, over time, its viral genome can become inserted
more dysregulated cell growth and eventually cancer. It has been into host cell DNA, a process called integration. In low-grade
observed that cells expressing E7 show irregularities in numerous cervical intraepithelial neoplasia (CIN), the HPV DNA is main-
centrosomes leading to aberrant mitotic spindle poles, thereby tained in its closed, circular, episomal shape. However, in most
affecting chromosome number during replication (33). E7 expres- high-grade CIN and cancers, the HPV DNA becomes integrated
sion is a late event in malignant transformation. in the host chromosomal DNA (4750). Many believe this is
a necessary event to cervical carcinogenesis (51). Integrated
HPV has been found to be present in 83% of invasive cervical
cancers, as compared to 8% of low-grade CIN, suggesting that
HPV E6 integration is highly associated with the transition of low-grade
Like E7, E6 is a small 151 amino acid protein that induces to high-grade lesions (52,53). Integration occurs at random sites
important changes in the host cell. It also lacks endogenous in the host DNA; however, breaks in the HPV viral episome
enzymatic activity and binds to cell cycle-regulatory proteins, seem to occur at regions of genomic instability, such as fragile
affecting life cycle and immortalization. sites. Often the E2 ORF is disrupted during these breaks (54).
E6s most notable effect is its ability to bind to p53. p53 is a As noted previously, E2 concentration affects the transcription
transcriptional activator and is an important tumor-suppressor of E6 an E7. Thus, once integration has occurred, disruptions
gene. p53 induces expression of genes involved in apoptosis in the E2 ORF lead to increased production of E6 and E7,
and cell cycle arrest. p53 levels typically increase in response thereby promoting immortalization and the oncogenic potential
to stress, DNA damage, or abnormal cellular proliferation of the cell.
(e.g.,radiation exposure, hypoxia, and infection). This increase
in p53 corresponds to arrest in the G1 phase of the cell cycle,
thereby allowing for repair of DNA damage or progression to
apoptosis. In HPV infected cells, E6 binds to p53 and causes SECTION 2: EPI DEM IOLOGY OF
degradation of the protein through a ubiquitin-dependent path-
way. Thus less apoptosis and growth-arrest occurs, leading to H PV I N FECTIONS
cellular proliferation (34).
E6 has also been shown to interact with other proteins that Prevalence
are involved in a variety of cellular functions. E6 binds to tran- HPV is the most common of all sexually transmitted infections;
scriptional co-activators CBP/p300, further downregulating while age, race, geographic region, and other modifiable risk fac-
p53-mediated transcription (35). E6 also interacts with the PDZ tors also correlate with new infections, age, and sexual behav-
proteins, which are involved in cell signaling and cell-to-cell iors are most clearly linked to new HPV infections. Early studies
adhesions, which ultimately affects lifecycle and carcinogenesis likely underestimated the prevalence of HPV infections. As
(3638). newer molecular technologies have been developed, detection of
In addition to its inhibition of apoptosis through p53 inter- viral infection improved, even at low levels (55). In addition to
action, E6 also upregulates the cellular telomerase complex. By variability surrounding detection methods, HPV positivity may
synthesizing new DNA, telomerase maintains the length of the be episodic, corresponding to times of viral shedding.
telomeric DNA at each end of a chromosome. Without this, Utilizing polymerase chain reactions (PCR) on self-collected
the telomeres shorten with each cell division until they reach a cervicovaginal specimens from over 4,000 US females, ages 14
critically short length and can no longer replicate. Therefore, by to 49, the prevalence of HPV infection was recently estimated
up-regulating the cellular telomerase complex, E6 further immor- as part of the 2011 National Health and Nutrition Examina-
talizes the host cell (39,40). E6 expression is a late event in malig- tion Survey (NHANES) (1) (Fig. 7.4). The overall prevalence of
nant transformation. the 37 separate types was 42.5%. Prevalence was lower among
females aged 14 to 19 (32.9%) and highest among females 20
to 24 years (53.8%), which is the peak age of new exposures. In
HPV E1/E2 that study, prevalence varied by race with non-Hispanic Blacks
having the highest prevalence (59.2%) followed by Mexican
Both E1 and E2 are proteins necessary for HPV DNA replication. Americans (44.2%) and non-Hispanic Whites (39.2%). HPV
E1 first initiates viral replication by binding near the start site of positivity was significantly associated with poverty, sexual activ-
transcription. E1 complexes with the E2 protein, then binds to ity (including number of partners, age, and first encounter) and
the viral genome, which initiates helicase activity (41). E1 also history of genital warts.
binds various other nuclear proteins for further replication of the
viral DNA (4244).
E2 is involved with DNA replication as well as genome tran-
scription. In addition to forming a complex with E1 to assist HPV Prevalence Worldwide
in replication, E2 also works on the upper regulatory region to Worldwide age-related trends are similar to US cohorts (56).
affect transcription of early genes (45,46). High concentrations Women less than 25 years old showed the highest prevalence
of E2 repress transcription and low levels activate transcription. of HPV infection, and in most regions of the world showed an
CHAPTER 7 PREI NVASIVE DISEASE OF TH E LOWER GEN ITAL TR ACT 133
40 the most common (57). Additional data from the NHANES survey
showed that men have a higher incidence of oral HPV infection of
30
10% versus 4% (58). In contrast to trends in women, prevalence
20 of any HPV infection was not affected by age. Only low-risk HPV
infections increased with age. Clearance of HPV infections seems
10 to occur quicker in men, with an average clearance time of any
0
HPV infection of approximately 6 months. In one study, nearly
1419 2024 2529 3039 4049 5059
75% of HPV infections in men were cleared within 1 year (57).
Male circumcision significantly reduces genital HPV prevalence in
Age (years)
men, which has led some to suggest circumcision as a method to
reduce HPV-related disease burden in endemic communities where
FIGURE 7.4. U.S. Prevalence of HPV infections in Women. vaccination and screening is not yet feasible (59). In contrast to
Source: Reprinted with permission from Hariri S, Unger ER, Sternberg M, et al. Prevalence of genital squamous cell carcinomas (SCC) of the female genital tract, HPV
human papillomavirus among females in the United States, the National Health And Nutrition has only been detected in half of invasive penile SCC (60).
Examination Survey, 20032006. J Infect Dis 2011;204:566573.
Sources: Richardson H, Kelsall G, Tellier P, et al. The natural history of type-specific human papillomavirus infections in female university students. Cancer Epidemiol
Biomarkers Prev 2003;12:485490. Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med
1998;338:423428. Dalstein V, Riethmuller D, Pretet JL, et al. Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a
longitudinal French cohort study. Int J Cancer 2003;106:396403. Bae J, Seo SS, Park YS, et al. Natural history of persistent high-risk human papillomavirus infections in
Korean women. Gynecol Oncol 2009;115:7580.
studies of HPV negative women at baseline who initiated inter- partner, including number of lifetime partners (79) and multiple
course confirm precedent sexual activity with new HPV infections coincidental partners, have all been implicated in risk of HPV
(10). Furthermore, the rate of acquisition correlates with increas- acquisition (10). The rate of having new partners and having
ing number of sexual partners (74). Data regarding concordance known a new partner for shorter periods of time before having
and HPV transmission efficacy among couples are conflicting. In vaginal intercourse are also associated with increased risk of
trials of young women and their male partners, HPV concordance HPV infection (66,79).
ranged from 40% to 60%. Specific mechanisms that determine Additionally, co-infection with other sexually transmitted dis-
the efficiency of HPV transmission and concordance are poorly eases and vaginal infections has been associated with increased
understood although it appears that length of sexual activity susceptibility to HPV infection. Both bacterial vaginosis and
may increase concordance (7577). Additionally, viral shedding trichomoniasis are associated with HPV infection although the
may occur based on asynchronous replicative cycles of the HPV correlation is not as strong with development of CIN (84,85). A
virus; thus, couples may appear to be less concordant than they history of herpes simplex virus infection and vulvar warts also
really are at any specific time (68). In addition to cervical, vaginal, increase the incidence HPV infection (66). A history of previous
and penile detection, HPV has been detected on areas of unpro- chlamydial infection has long been implicated in the develop-
tected genital skin such as the vulva and scrotum, providing an ment of invasive squamous cell carcinoma of the cervix (8688).
explanation as to why condoms offer some but not complete pro- Hypotheses regarding pathogenesis include induction of squamous
tection against HPV infection (78). metaplasia at the transformation zone, increase in microabrasions,
as well as interference with immune surveillance (88,89). More
recent cohort studies have found that the role of chlamydia in
SECTION 3: ADDITIONAL RISK carcinogenesis is likely related to both in promoting the acquisi-
tion and persistence of HPV infections (9092). Chlamydia has
FACTORS FOR DEVELOPM ENT OF not been implicated in the development of adenocarcinoma in situ
PREI NVASIVE LESIONS OF TH E (AIS) or invasive adenocarcinoma (88).
LOWER GEN ITAL TR ACT
Although HPV has been implicated as the most important and
necessary risk factor for development of preinvasive lesions of
Tobacco
the lower genital tract, other risk factors have been identified In 2004, the IARC added cervical cancer to the list of cancers
that either increase the risk of HPV infection or potentiate the causally related to smoking (93) based on analysis of numerous
progression of HPV infection to malignant transformation. trials in the prior decade. As more epidemiologic and natural
history trials were performed, conflicting data emerged on the
association between cigarette smoking and HPV acquisition,
persistence, and progression. Confounding variables have also
Sexual History been a factor; women who smoke are less likely to be compli-
Even before data convincingly linked HPV to the development ant with screening guidelines (94) and more likely to have more
of cervical cancer, it was well recognized that various aspects of social stressors (95).
a patients sexual history put women at increased risk for devel- Most studies agree, though, that current smoking increases
oping preinvasive and subsequent invasive lesions of the cervix, the prevalence of and persistence of HPV infection, particu-
vagina, and vulva. larly those that have a high-risk HPV type (9699). Addition-
Sexual history and behaviors strongly correlates with risk ally, most trials suggested delayed clearance of HPV infection
of acquiring HPV infection and developing preinvasive lesions in women who smoke (100,101). Compared to nonsmokers and
(66). Overall, the number of recent and total lifetime male part- former smokers, current smokers have higher high-risk HPV
ners increases the rate of HPV infection, particularly high-risk viral loads (102).
HPV infection (66,7982). The most recent data from the U.S. The effects of smoking on the development of lower geni-
Centers for Disease Control (CDC) data show that number of tal tract neoplasia are multifactorial. Nicotine and other by-
lifetime partners is an independent risk factor for all races ex- products of cigarette smoke have been readily identified in the
cept non-Hispanic Black women, where no independent correla- cervical mucus of smokers (103). Benzo[a]pyrine, a known
tion is seen (83). human carcinogen, has been found in cervical mucus and has
Early onset of sexual activity has also been shown as an been specifically noted to potentiate the HPV 16 and HPV
independent risk factor for HPV infection in some studies 18 viral lifecycle (104). It has long been known that smoking
(81,83). Some studies suggest that frequency of intercourse with causes a local immunological effect whereby the function of
ones partner may also play a role (10). Characteristics of the Langerhans cells are significantly decreased, thus affecting the
CHAPTER 7 PREI NVASIVE DISEASE OF TH E LOWER GEN ITAL TR ACT 135
innate immune system (105). Studies of women with preinvasive preinvasive lesions were only marginally increased (119). A U.S.
and invasive disease have shown that compared to nonsmokers, cohort of transplant recipients was analyzed and only vulvar
= Squamous epithelium
= Columnar epithelium
OSCJ = Original squamocolumnar junction
NSCJ = New squamocolumnar junction
T-zone = Region between original and new
squamocolumnar junction
FIGURE 7.6. Impact of age on the location of the squamocolumnar junction. As females age, the location of the
squamocolumnar junction on the cervix moves. The movement of the squamocolumnar junction defines the
transformation zone.
through the epithelium, the lesion is CIN 2; and if the extent is 4% to 10% (131,132). A retrospective analysis of the ASCUS-
greater than two-thirds, the lesion is termed CIN 3. In order to LSIL Triage Study (ALTS) (133) found that a diagnosis of CIN
better classify the degree of CIN, molecular markers can be used 1 on pathology (compared to a negative biopsy, or no biopsy
by pathologists. For instance, p16INK4a is a validated marker for taken) was not a risk factor for developing CIN 3. Therefore,
biologically relevant CIN (125). CIN 1 is considered a nonneoplastic lesion and is not a disease
This classification system was developed when all of CIN that should require any extirpative treatment.
was thought to be a spectrum of disease. Now we understand Without treatment, high-grade CIN has at least a 30% prob-
that CIN 1 usually represents a benign process that is merely ability of becoming invasive cancer. This was shown in an un-
a cytomorphologic representation of an active HPV infection; fortunate retrospective trial of a prospectively followed cohort
whereas higher-grade lesions, especially CIN 3, are truly prema- of women followed over a 30-year period beginning in the
lignant. CIN 2 is a poorly reproducible category, with high levels 1960s in New Zealand. If adequately treated, however, very few
of inter-observer variability (126). In one trial, agreement be- women with CIN 2/3 will recur or develop invasive cancer (9).
tween pathologists was as low as 13% in the category of CIN 2
compared with 81% agreement with CIN 3 lesions (127). CIN 2
is now considered an equivocal diagnosis because it can include Glandular Dysplasia and
either benign HPV effects or precancerous lesions (125). In an
analysis of a vaccine trial, agreement between biopsy and LEEP Adenocarcinoma In Situ
specimen improved when CIN 2 and CIN 3/AIS were grouped Although the majority of preinvasive cervical lesions are of squa-
as a single predictive measure of high-grade disease (128). Due mous cell histology, approximately 3% represent precursors to
to limitations surrounding reproducibility, many institutions invasive adenocarcinoma (134). While HPV 16 is the most com-
characterize lesions as either CIN 1 or CIN 2/3 (also known as monly identified subtype in glandular lesions, HPV 18 causes a
CIN 2+); and often include additional molecular markers such greater proportion of glandular as compared to squamous lesions
as p16INK4a and other proliferation markers to improve clinically (135). Contrary to popular conceptions regarding preinvasive
relevant disease ascertainment (Fig. 7.7). glandular lesions, the majority are solitary. Multifocal (or skip
In CIN 1, the lower third of the epithelium displays nuclear lesions) do occur, but only in 10% to 15% of cases. Though
atypia of immature basaloid cells while the remainder of the glandular lesions can be found higher in the endocervical canal,
epithelium often shows the additional cytopathic effects, termed the majority occur at the squamocolumnar junction (136).
koilocytosis, which are directly related to an active HPV infec- Preinvasive glandular lesions can be divided into the catego-
tion. Koilocytes are cells with atypical nuclei and perinuclear ries of endocervical glandular dysplasia (EGD) and AIS. These
clearing, also known as vacuolization; they can be seen in both categories differ by degree of nuclear stratification, nuclear
CIN 1 and CIN 2/3, although it is more common in CIN 1. The atypia, and numbers of mitosis and apoptosis. Additionally, im-
large, perinuclear vacuole is often a result of activation of viral munohistochemistry, such as staining for a proliferative marker,
E5 and E6 proteins (129). Ki-67, may also be used to help differentiate between the two
categories (137). An additional category, termed glandular
atypia, encompasses nonpremalignant lesions with atypia associ-
ated with inflammation or previous radiotherapy. Rare variants
Natural History of CIN of AIS have been described including endometrioid, intestinal,
CIN 1 is the most common histologic diagnosis after col- serous, and clear cell histologies.
poscopic biopsy. Fortunately, very few of these lesions actually Histologically, AIS is characterized by enlarged glandular
progress to a higher grade of CIN. Most will remain persistent cells with large, hyperchromatic nuclei (Fig. 7.8). Unlike the
or regress spontaneously as the HPV infection is cleared(130). cytopathic effect of koilocytosis seen in HPV infected squamous
In both prospective and retrospective trials, incidence of cells, endocervical cells show decreased cytoplasm and minimal
CIN2/3 18 to 24 months after diagnosis of CIN 1 ranges from intracellular mucin. Structurally, glandular cells are crowded
CHAPTER 7 PREI NVASIVE DISEASE OF TH E LOWER GEN ITAL TR ACT 137
C D
E F
FIGURE 7.7. A: Normal squamous epithelium; B: CIN 1; C: CIN 2; D: CIN 3; E: Low-power view of P16 staining on cervical biopsy containing CIN 2/3;
F: High-power view of p16 staining on cervical biopsy containing CIN 2/3.
Source: Images courtesy of University of Alabama at Birmingham.
with pseudostratification. Unlike squamous lesions, apoptosis Atypical glands that extend greater than 5 mm from the unin-
is a common feature in glandular lesions and is seen in higher volved glands are usually termed invasive, whereas lesions within
frequency in AIS compared to invasive adenocarcinoma (138). 5 mm are considered early invasive disease. Other features dis-
Diagnosing early invasive endocervical adenocarcinoma is tinguish invasion from in situ lesions including stromal reaction
sometimes more challenging than diagnosing squamous lesions (desmoplasia, inflammation), confluence of glands, and solid
due to the complex growth patterns of endocervical glands. components.
138 CHAPTER 7 PREI NVASIVE DISEASE OF TH E LOWER GEN ITAL TR ACT
Vagina
Vaginal intraepithelial neoplasia (VAIN) is another lesion that is
part of the HPV spectrum in the lower genital tract. Its occurrence
is less common and represents only 0.5% of all lower genital tract
intraepithelial neoplasias. VAIN is most often found in the upper
vagina and is most often multifocal. Many cases occur after hys-
terectomy and occult vaginal malignancy is uncommon (146).
Recurrence is more common with multifocal disease and ranges
from 20% to 60% after treatment with laser or 5fluorouricil
(146,147). Recurrence is uncommon after partial vaginectomy
(147). HPV infection is implicated in the pathogenesis of over
half of VAIN (148). The histologic features of VAIN are similar to
B those of CIN and VIN. Due to its infrequency, there are no current
FIGURE 7.8. Adenocarcinoma in situ (AIS). A: High-power view.
recommendations for vaginal cancer screening. Most screening
B: Low-power view. Normal endocervical glands in the upper left.
recommendations do not recommend performing vaginal cuff
Source: Images courtesy of University of Alabama at Birmingham cytology after a hysterectomy (149).
Vulva
Vulvar intraepithelial neoplasia (VIN) is increasing in incidence SECTION 5: SCREEN I NG
in the United States, with a 400% increase in preinvasive lesions
and a 20% increase in invasive lesions between 1973 and 2000 With the advent of successful screening for preinvasive disease
(139). Classification of preinvasive vulvar disease has under- of the lower genital tract, effective treatments of precancerous
gone many changes. In 2003, the WHO classified VIN in a lesions has also emerged, subsequently affecting the overall dis-
3-grade system for all types, similar to preinvasive cervical dis- ease burden of invasive lower genital tract malignancies.
ease. Then, in 2004, the International Society for the Study of Cervical cancer screening is hailed as one of the major
Vulvovaginal Disease (ISSVD) reclassified VIN into 2 categories: public health advances in the 20th century. Initially seeking
usual-type VIN, which is associated with HPV infection; and determinants of the ovulation cycle in guinea pigs, Dr. George
differentiated VIN, which is usually not associated with HPV Papanicolaou evaluated the vaginal smear as an indicator of
CHAPTER 7 PREI NVASIVE DISEASE OF TH E LOWER GEN ITAL TR ACT 139
hormone status. Eventually he studied human subjects and inci- improvements to overcoming the human error is the ability to
dentally found a malignancy on a vaginal smear. More than a run HPV testing, which is highly sensitive and is not dependent
<21 years No screening recommended HPV testing is not recommended in this age group
2129 years Cytology alone every 3 years HPV testing is not recommended in this age group
3065 years Preferred = Co-testing (HPV and Cytology)
-or-
Acceptable = Cytology alone every 3 years
>65 years No screening following adequate negative prior screening If history of CIN 2+, continue screening for 20 years
After Hysterectomy No screening Applies only to women with no cervix and no history of CIN 2+
HPV Vaccinated Follow age-specific recommendations (same as unvaccinated women)
Source: Adapted from Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American
Society for Clinical Pathology Screening Guidelines for the prevention and early detection of cervical cancer. J Low Genit Tract Dis 2012;16(3):175204, with permission.
140 CHAPTER 7 PREI NVASIVE DISEASE OF TH E LOWER GEN ITAL TR ACT
Atypical Squamous Cells of most common cytologic abnormality, half of all women with
CIN 2/3 have a preceding diagnosis of ASC-US (168,169,170).
Undetermined Significance Though only 0.2% of women with ASC-US cytology have in-
Figure 7.10 shows the distribution of Abnormal Cervical Cy- vasive disease, women with cervical cancer often present with
tology. ASC-US is the most common cytologic abnormality ASC-US cytology (171). Thus, further evaluation of women
but the most poorly reproducible category (126). The rate of with this abnormality is warranted. The preferred approach
CIN 2/3 with ASC-US cytology varies depending on popula- to management of ASC-US is reflex high-risk HPV testing fol-
tions studied from 5% to 27%. However, because it is the lowed by colposcopy if the HPV test is positive (Fig. 7.9).
Diagnostic
HSIL Negative Cytology Other Manager Per
Excisional @ either visit @ both visits Results ASCCP Guideline
Procedure+
Routine
Screening
Colposcopic Examination*
Routine
Colposcopy Screening
Digene Hybrid Capture 2 QIAGEN, Germantown, 16, 18, 31, 33, 35, 39, 1. ASC-US triagel March, 2003
High-Risk HPV DNA Test MD 45, 51, 52, 56, 58, 59, 2. Co-testing in women
and 68 >30 years old
Cervista HPV HR Hologic, Bedford, MA 16, 18, 31, 33, 35, 39, 1. ASC-US triage March, 2009
45, 51, 52, 56, 58, 59, 2. Co-testing in women
66, and 68 >30 years old
Cervista HPV 16/18 Hologic, Bedford, MA 16, 18 1. Triage for follow up of women March, 2009
>30 years old with negative
cytology and positive high-risk
HPV.
Cobas HPV Test Roche Molecular Specifically identities 1. ASC-US triage April, 2011
Systems, Pleasanton, CA 16 and 18 while 2. mCo-testing in women
concurrently testing for >30 years old
31, 33, 35, 39, 51, 52, 3. Triage for follow up of women
56, 58, 59 66 and 68 >30 years old with negative
cytology and positive high-risk
HPV testing
APTIMA HPV Assay Gen-Probe, San Diego, 16, 18, 31, 33, 35, 39, 1. ASC-US triage February, 2012
CA 45, 51, 52, 56, 58, 59, 2. Co-testing in women
66, and 68 >30 years old
Source: Adapted from Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society
for Clinical Pathology Screening Guidelines for the prevention and early detection of cervical cancer. J Low Genit Tract Dis., 2012;16(3):175204, with permision.
those who are high-risk HPV-positive but HPV 16 and HPV 18 see-and-treat strategy, pooled analysis of trials utilizing visual
negative can be followed in a year with repeat cytology or HPV inspection performed in developing nations revealed a sensitivity
testing (149). of 62% to 80% and specificity of 77% to 84% to detect high-
Primary HPV testing as the sole screening modality has been grade CIN (187).
investigated in multiple international trials, and shows prom- VIA and VILI with see-and-treat strategies appears to be
ise in upfront screening strategies (166,180,181). In general, cost-effective. A study that modeled screening strategies in India,
it has demonstrated improved sensitivity compared to cytol- Kenya, Peru, South Africa, and Thailand showed that screening
ogy, although specificity may be lower. Because of its improved women once per lifetime with visual inspection effectively re-
specificity over HPV testing alone, cytology may be used as a duced cervical cancer mortality by over 25% at an acceptably
follow-up test after a positive HPV test (182). Because no large low cost in relation to each nations gross domestic product (188).
trials have evaluated the most effective strategies in managing Population-based studies on VIA have yielded mixed results. In a
the results of HPV testing in the primary screening setting in the south Indian population, cervical cancer mortality was reduced
United States, HPV testing is not yet recommended in the United by 25% with VIA compared to no screening (189). In the largest
States for use as a primary upfront screening test. prospective trial enrolling over 130,000 women in rural India,
one-time screening methods of HPV testing, cytology, and VIA
were compared. Compared with a control group, only HPV
Additional Screening Strategies testing reduced the rate of cervical cancer (190). Thus once per
lifetime HPV testing in women over 30 has been proposed as an
In addition to cervical cytology and HPV testing from liquid- effective method of cervical cancer reduction in low-resource
based cytologic specimens, other innovative techniques are being settings (190).
used in populations with limited access to standard screening
approaches. In an attempt to make high-risk HPV testing more
efficient, less invasive, and less costly, self-HPV testing has devel-
oped. Self-sampling demonstrates high concordance with physi-
cian collected samples (183). Prospective trials involving women SECTION 6: H PV VACCI NATION
who did not attend routine cervical screening programs in the
Netherlands showed that, because of a higher participation rates, With an improved understanding of the role of HPV infection
detection rate of CIN was higher than in the regularly screened in the natural history of preinvasive and invasive lesions of the
population (184,185). lower genital tract, prophylactic vaccination has emerged as an
In developing nations where the cost of frequent follow-up important element in cervical cancer prevention (Table 7.4).
exams and testing is prohibitive, visual inspection tests have The L1 capsid protein, which is 1 of 2 viral capsid proteins
emerged as an important method of screening and treatment. of the HPV virus, is the primary target for prophylactic vacci-
With a bright halogen lamp, visual inspection with acetic acid nation. Vaccines consist of recombinant L1 proteins that form
(VIA) or Lugols iodine (VILI) is performed and positive lesions virus-like particles (VLPs), which are combined with different
are referred to colposcopy with directed biopsy. Additionally, adjuvants. Adjuvants stimulate the immune system and increase
positive lesions can be treated immediately, bypassing the need the response to vaccination and are aluminum based. VLPs pri-
for follow-up colposcopy. This is an efficient method of screen- marily induce a humoral response with neutralizing antibodies,
ing and treatment, and health care providers can be trained but they also induce cell-mediated immune responses. Neutraliz-
easily in visual inspection, thereby further improving its fea- ing antibody responses are logs higher than that generated from
sibility (186). Although significant verification bias exists in a a response to a new HPV infection.
144 CHAPTER 7 PREI NVASIVE DISEASE OF TH E LOWER GEN ITAL TR ACT
a
Merck & Co., Inc., Whitehouse Station, NJ, USA.
b
GlaxoSmithKline, Rixenstart, Belgium.
Currently, 2 vaccines are approved in the United States for against HPV 16- and 18-mediated CIN 3 lesions was 100% in
the prevention of cervical cancer. The quadrivalent vaccine women who were HPV negative at the time of vaccination. The
(Merck & Co., Inc., Whitehouse Station, NJ, USA) contains vaccine was also effective against other lesions caused by HPV
VLPs to HPV types 6, 11, 16, and 18 and the bivalent vaccine types 31, 33, and 45, which are closely related to HPV 16 and
(Glaxo Smith Kline, Rixenstart, Belgium) contains VLPs to HPV 18 (194). Specifically, in women who were HPV-negative at the
types 16 and 18. time of vaccination, there was 93% efficacy against all CIN 3,
The FDA originally approved the quadrivalent vaccine in irrespective of HPV type, as well as 100% efficacy against all
2006 for girls and women aged between 15 and 25 years for AIS (195). High rates of efficacy even in non-HPV 16- or 18-
the prevention of cervical cancer caused by HPV types 16 and mediated lesions suggest that the vaccines effects may be more
18, precancerous genital lesions caused by HPV types 6, 11, 16, far reaching. Of note, these high clinical efficacy rates were associ-
and 18 and genital warts caused by HPV types 6 and 11. The ated with high cross-protective immune responses as well (196).
federal advisory committee on immunization practices (ACIP) HPV vaccination has not been shown to be therapeutic against
recommended routine vaccination of all 11- and 12-year-old preexisting HPV infections. Therefore, the HPV vaccine is most
girls. The three shot vaccination series can begin as young as effective if it is administered prior to the onset of sexual ac-
age 9, and can be given to women up to age 26. In 2008, the tivity. Additionally, the vaccine is not infectious and does not
quadrivalent vaccine was also approved for the prevention of contain anything that would be teratogenic and is considered
vaginal and vulvar cancer in this same population. The follow- teratogenicity category B. Routine pregnancy testing prior to
ing year, its use was expanded to the prevention of genital warts administration is not necessary and lactating women can safely
due to HPV type 6 and 11 in boys and men aged between 15 receive the vaccine (197). Based on the natural history of HPV
and 25. In 2010, the FDA further expanded the indications to infection and development of preinvasive and invasive disease,
include the prevention of anal cancer and associated premalig- it may take at least 15 years before there is a significant impact
nant lesions caused by these same HPV types. In 2011, the ACIP on the incidence of CIN 2/3 and perhaps 30 years before there
recommended routine vaccination of all boys, ages 11 and 12. is a change in cervical cancer incidence.
The vaccine series can be given to boys as young as age 9 and up HPV vaccination programs are being instituted worldwide.
through age 22 for most men. The FDA approved the bivalent HPV vaccination presents unique challenges in both high- and
vaccine in 2009 for the prevention of cervical cancer and pre- low-resource settings, including an older age of vaccination,
cancerous lesions cause by HPV 16 and 18 in women from 15 a 3-dose regimen at a high cost relative to other childhood
to 25 years of age. The ACIP recommendations for the bivalent vaccines, and potential socio-cultural concerns about HPV
vaccine mirror those for the quadrivalent vaccine, except the being a sexually transmitted disease. Uptake of vaccination
bivalent vaccine is not approved for use in males. seems to be most affected by coverage of the vaccine at the
Multiple phase III trials have been conducted to evaluate the state or national level. In the United States, it is estimated
efficacy of these vaccines (191193). These trials were blinded, that almost 50% of adolescents received at least 1 dose and
placebo-controlled trials with endpoints that included develop- only 32% received all 3. Vaccine uptake varies significantly by
ment of CIN as well as external genital lesions for the quadriva- state, likely a reflection of variability of state funding (198).
lent vaccine. In an international trial that enrolled over 17,000 Worldwide, rates are slightly higher in other high-resource set-
women aged between 16 and 26, the quadrivalent vaccine was tings. In Manchester, UK, the uptake of 2 doses was reported
99% effective in preventing HPV 16 and 18 preinvasive or in- at 55%; 3-dose coverage in southern Australia was 69% and
vasive lesions in a 3-year follow up period in women who were in Denmark, 62% (199201). Despite many barriers to HPV
HPV naive at baseline. In an intention-to-treat analysis where vaccination, it is apparent that when communities make a fo-
women with preexisting infections were included, there was cused effort to promote vaccination through financial coverage
considerably less efficacy against incident of CIN 2/3 or AIS or public health awareness, high levels of vaccine uptake are
due to any HPV type, thus proving that it works primarily as a noted (202).
prophylactic vaccine (192). This trial also showed that the quad- Over 85% of cervical cancer cases occur in the developing
rivalent vaccine was effective in preventing 96% of CIN 1, 100% world (203), yet patients in these nations are less likely to
of VIN 1 and 99% of condyloma in HPV naive women (191). receive HPV vaccination. Despite its high cost relative to other
The four-year follow-up of a bivalent HPV vaccine trial, childhood vaccines, in nations with high incidence, emerging
which enrolled over 18,000 young women, showed similar effi- models suggest that vaccination is cost-effective (204). More-
cacy against development of CIN 3 and AIS. Specifically, efficacy over, HPV vaccination has recently been made more affordable
CHAPTER 7 PREI NVASIVE DISEASE OF TH E LOWER GEN ITAL TR ACT 145
at a subsidized price of 5 US dollars per dose (198). This has programs in communities in India, Peru, Uganda, and Viet-
prompted research into the most effective strategies for large- nam. Remarkably, complete vaccination (i.e., all 3doses) was
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8
CHAPTER
151
152 CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE
Table 8.1 National Institute for Health and Clinical Table 8.2 Multifactorial Index of Cardiac
Excellence Recommendations for Risk
Preoperative Testing Risk factor Points
Study Age (years) Recommendation S3 gallop or increased jugular venous pressure 11
Chest X-ray Any age Cardiovascular surgery Myocardial infarction in previous 6 months 10
60 or Grade 4 surgery and ASA 3 More than 5 premature ventricular ectopic beats per 7
older or greater with cardiovascular minute
disease
Rhythm other than sinus or premature atrial contractions 7
Electrocardiogram 1639 ASA 2 or greater with
cardiovascular disease or Age >70 years 5
cardiovascular surgery Emergency noncardiac operative procedure 4
4059 As above, plus grade 4 surgery
Significant aortic stenosis 3
if ASA 2 or greater with
renal disease, or ASA 3 with Poor general health status 3
respiratory disease
Abdominal or thoracic surgery 3
6079 As above, plus grade 2 surgery
if ASA 2 or greater with Possible total 53
renal disease, or ASA 3+ with
respiratory disease or grade 3
surgery or greater Source: Adapted from Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial
index of cardiac risk in noncardiac surgical procedures. N Engl J Med.
80 or older Consider deferring if grade 1 1977;297:845880, with permission.
surgery
Full blood count 1659 ASA 3 with renal disease, or myocardial infarction (MI) had a greater interval from onset
grade 3 or greater surgery of pain until arrival at hospital, were less likely to be treated
60 or As above, plus grade 2 or with thrombolytics and b-blocking agents, were less often evalu-
older greater surgery ated with invasive methods, had higher rates of reinfarction, and
had greater mortality (9).
Hemostasis 16 or older Never recommend, may be
considered
In the assessment of perioperative risk, cardiac risk factors
are certainly one of the top concerns for clinicians. There have
Renal function 1559 ASA 2 or greater with renal been a number of reviews and different systems created for
disease, ASA 3 or greater with the purposes of assessing cardiac risk for patients undergoing
cardiovascular disease, ASA 2 noncardiac surgery (1013). Realize that approximately 1 in 12
or greater with cardiovascular patients (>65 years old) will have significant coronary artery dis-
disease with grade 3 or greater
surgery, ASA 3 or greater with
ease (14). It is estimated that over 30% of patients undergoing
respiratory disease, with grade major elective surgery have at least one cardiac risk factor (15).
3 or greater surgery Cardiac risk indices have been published by at least 10 differ-
ent investigators (16). Goldman et al. published the Multifacto-
60 or As above, plus ASA 2 with rial Index of Cardiac Risk (MICR) in 1977 (17). This risk index
older cardiovascular disease, with was the first large, prospective, multivariate analysis of patients
grade 2 or greater surgery, or
any grade 3 surgery
undergoing noncardiac surgery. They used definite endpoints of
cardiac death, ventricular tachycardia, pulmonary edema, and
Urinalysis 16 or Never recommended, may be myocardial infarction. The MICR involves nine independent
older considered risk factors to create a point risk index and predict morbidity
and mortality (Tables 8.2 and 8.3). One weakness of this index
is underestimating risk in vascular surgery patients. Nonethe-
ASA, American Society of Anesthesiologists.
ASA grade: ASA 1, normal/healthy; ASA 2, mild systemic disease; ASA 3 severe less, these criteria have been validated and have stood the test of
systemic disease. time. In response to a shift in the literature from calculation of
Surgery grade: grade 1, minor surgery; grade 2, intermediate surgery; grade 3, risk with indices to clinical decision making, especially in regard
major surgery; grade 4, extensive surgery.
Source: From St. Clair CM, Shah M, Diver EJ, et al. Adherence to evidence-based
guidelines for preoperative testing in women undergoing gynecologic surgery.
Obstet Gynecol. 2010;116(3):694700, with permission. Table 8.3 Multifactorial Index of Cardiac Risk,
Cardiac Risk Class, Morbidity, and
been published on this subject. In 2001, the National Heart, Mortality
Lung, and Blood Institute (NHLBI) launched the Heart Truth Cardiac Risk Total Points Morbidity (%) Mortality
Project to promote education about heart disease among
women(9). Statistics have shown that only one of three primary Class I 05 0.7 0.2
physicians correctly cited coronary artery disease as a leading Class II 612 5.0 1.6
cause of death in women. Similarly, studies have demonstrated
that women are less often counseled on cardiac risk factors, less Class III 1225 11.5 2.3
often prescribed lipid-lowering medications, less often offered Class IV >26 22.2 55.6
invasive procedures, and less often prescribed cardiac reha-
bilitation. There is a lack of health care provider knowledge of Source: Adapted from Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial
the guidelines for prevention of cardiovascular disease (CVD) index of cardiac risk in noncardiac surgical procedures. N Engl J Med.
in women (10). Further, compared to men, women who had a 1977;297:845850, with permission.
CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE 153
Table 8.5 Management of Diabetes Medications Table 8.6 Perioperative Blood Glucose Control:
Before Surgery in Patients Who Must An Endocrine Society Clinical Practice
Be NPO (continued) Guideline
Night before Recommendation
Medication Type Surgery Morning of Surgery Number
Premixed Insulins Give full dose Give half dose 5.3.1 All patients with type 1 diabetes who
Humulin 70/30 undergo minor or major surgical procedures
receive either continuous insulin infusion or
Novolin 70/30 subcutaneous basal insulin with bolus insulin
as required to prevent hyperglycemia during
Humalog 75/25 the perioperative period
Novolog 70/30 5.3.2 Patients with diabetes should discontinue oral
Rapid-acting Insulin Give full dose with Hold and noninsulin injectable antidiabetic agents
meals before surgery with initiation of insulin therapy
in those patients that develop hyperglycemia
Aspart during the perioperative period
Discontinue all oral anti-diabetic and Give supplemental insulin glulisine according If the fasting and predinner BG is between
noninsulin injectable medications to the sliding scale (below) for blood 100140 mg/dL and no hypoglycemia the
glucose >140 mg/dL previous day: no changes
Starting total daily dose (TDD): If patient is able and expected to eat, give If the fasting and predinner BG is between
0.5 units/kg-actual body weight supplemental glulisine before each meal and 140180 mg/dL and no hypoglycemia the previous
at bedtime following the usual column day: increase insulin TDD by 10% every day
*Reduce TDD to 0.3 units/kg actual body If the patient is not able to eat, give If the fasting and predinner BG is >180 mg/dL
weight in patients 70 years of age and/or supplemental glulisine every 6 hours and no hypoglycemia the previous day: increase
serum creatinine 2.0 mg/dL (612612) following the sensitive column insulin TDD by 20% every day
Give half of the TDD as insulin glargine, Blood Insulin Insulin If the fasting and predinner BG is between
at the same time once daily and half as Glucose Sensitive Usual Resistant 7099 mg/dL and no hypoglycemia: decrease
insulin glulisine in three equally divided (mg/dL) (units) (units) (units) insulin TDD by 10% every day
doses before each meal. Hold insulin
glulisine if patient not able to eat 141180 2 4 6
Source: Adapted from Umpierrez GE, Smiley D, Jacobs S, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with Type 2
diabetes undergoing general surgery (RABBIT 2 Surgery). Diabetes Care. 2011;34:256261, with permission.
In addition, the basal/bolus group had fewer wound infections, stated that insufficient numbers of patients with severe hypo-
pneumonias, episodes of bacteremia, respiratory failure, and thyroidism precluded recommendations for perioperative care
acute renal failure as compared to the SSI group. There also was of these patients(72). In another retrospective study, Ladenson
a nonsignificant trend toward fewer postsurgical ICU admis- et al. reviewed perioperative complications among hypothyroid
sions and shorter ICU stays than in the SSI group (69). Table 8.7 patients undergoing surgery, finding more intraoperative hypo-
demonstrates the basal/bolus method to control hyperglycemia tension in noncardiac surgery, more heart failure in cardiac
in type 2 diabetics postoperatively. surgery, and more gastrointestinal and neuropsychiatric com-
plications. They also noted that patients were unable to mount
fever in the face of infection, although infection rates were not
different. Further, no differences were found in the duration of
Thyroid Disorders hospitalization, perioperative arrhythmias, delayed anesthesia
When patients give history of hypothyroidism or hyperthyroid- recovery, pulmonary complications, or mortality (73).
ism during evaluation for surgery, thyroid-stimulating hormone Patients with mild to moderate hypothyroidism requiring
(TSH) and thyroxine (T4) levels should be obtained. The pri- urgent surgery may have it without delay. These patients may
mary objective is to determine if the patient is euthyroid or not, have more minor complications of ileus, postoperative delirium,
prior to surgical intervention so as to avoid the complications of or infection without fever. Patients with severe hypothyroidism
myxedema or thyroid storm in the postoperative period. (myxedema coma, decreased mentation, pericardial effusions,
Hypothyroidism is a common condition in the United States, heart failure, or very low levels of thyroxine) who are to undergo
affecting approximately 1% of all patients and 5% of the popu- urgent/emergent surgery will need intravenous levothyroxine
lation over the age of 50 and it develops 10 times more often (200500 g given during 30 minutes) followed by daily doses
in women than men (70). Decision to operate on patients with of 50 to 100 g intravenously. These patients will likely need
hypothyroidism will depend upon the level of hypothyroidism stress-dose glucocorticoids (see Adrenal Suppression section)
and the urgency of the surgery. Hypothyroidism can influence started prior to, during, and continued after surgery due to coex-
many physiologic functions, such as myocardial function, res- isting adrenal insufficiency (or due to the fact that intravenous
piration, gastrointestinal motility, hemostasis, and free water replacement with levothyroxine may precipitate adrenal insuf-
balance (46,71). Although there have been no prospective, ficiency) (46,73,74).
randomized studies looking at the surgical outcome of hypo- Myxedema coma is a rare condition, with an incidence of
thyroid patients versus controls, several retrospective case- 0.22 per million patients per year. Most of the cases (80%) occur
matched control studies have evaluated hypothyroid patients among hospitalized, elderly (older than 60 years) women with
undergoing surgery. A study by Weinberg et al. demonstrated long-standing hypothyroidism, but it can occur at any age (75).
no differences between hypothyroid and euthyroid controls for Amajority of the cases will occur in the postoperative period due
perioperative complications. In addition, no differences in out- to inciting causes such as infections, cold exposure, sedatives,
come were seen when hypothyroidism was stratified by thyrox- analgesics, and other medications. The mortality from this dis-
ine levels. The investigators concluded that patients with mild ease is high (80%), but has been decreasing in recent years due
to moderate hypothyroidism should not be denied needed sur- to increased awareness, testing, and improved perioperative care
gery in order to correct the metabolic problem. They further (7678). Myxedema coma is characterized by severely depressed
158 CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE
mental status, seizure, hypothermia, bradycardia, hyponatremia, orally, every 6 hours) may be used, but must not be given sooner
heart failure, and hypopnea. Although maintenance of normo- than 1 hour after the administration of the thionamide dosage;
thermia by warming is tempting, the resulting vasodilatation otherwise thyroid hormone synthesis will be enhanced by the
may cause cardiovascular collapse in patients with intravascular iodine treatment. In severe cases of thyroid storm, plasmapheresis
volume depletion, cardiac insufficiency, and pericardial effusion/ and therapeutic plasma exchange may be needed. b-blockade is
tamponade, and should be performed carefully if at all (76). critical to ameliorate the manifestations of thyroid excess and
Myxedema coma is a medical emergency and necessitates urgent does so by correcting the heart rate, reducing cardiac oxygen
administration of levothyroxine. An initial intravenous bolus of demand, decreasing agitation, convulsions, psychotic behavior,
200 to 500 g should be given, followed by 50 to 100 g intra- and tremors. Propranolol is the most commonly used agent and
venously daily. Dehydration is frequently present and aggressive dosages of 60 to 80 mg given orally every 4 hours or 0.5 to 1 mg IV
volume resuscitation with dextrose and normal saline should be followed by subsequent doses of 2 to 3 mg every several hours
instituted. Intravenous glucocorticoids should be administered are recommended. Another theoretic benefit of b-blockade is
(50 mg hydrocortisone IV, 4 times daily) because of frequent the inhibition of conversion of T4 to T3. One other medication
adrenal insufficiency. Resolution of symptoms, if properly treated, which has a high therapeutic benefit is the administration of
should begin within 24 hours. corticosteroids, which not only inhibits the conversion of T4 to
Patients using thyroid replacement preparations can have their T3, but also treats adrenal insufficiency which may have occurred
doses held during the immediate postoperative period until they due to the rapid turnover of cortisol. Acetominophen is preferred
are able to tolerate oral intake, as the half-life of these drugs is 5 to salicylates, as the latter may exacerbate thyrotoxicosis by
to 9 days (71). decreasing thyroid protein binding and increasing free T3 and
The causes of hyperthyroidism are many, but the most com- T4. Finally, a thorough search for the precipitating cause of the
mon cause is Graves disease. This autoimmune disorder, caused by thyroid storm should be undertaken immediately, with the most
an antibody directed to thyroid-stimulating hormone receptors, common cause in the perioperative period being infection (75).
results in increased thyroid hormone production. The clinical signs
of hyperthyroidism include tachycardia, atrial fibrillation, fever,
tremor, goiter, and ophthalmopathy (47). Most complications
occurring in hyperthyroid patients undergoing surgery involve Adrenal Suppression
cardiac function, as T4 and T3 have direct inotropic and chrono- How patients respond to stress is directly related to the
tropic effect on the heart and a vaso-dilatory effect on peripheral hypothalamic-pituitary axis (HPA), and any defect in this cycle
vasculature, resulting in the activation of the renin-angiotensin- can have dramatic effects in the perioperative period. The most
aldosterone system. All of these events result in a high cardiac out- common cause of primary adrenal insufficiency (AI) is auto-
put state, which increases cardiac work and oxygen requirements immune adrenalitis, where the adrenal cortex is destroyed and
and can result in myocardial infarction (75). Arrhythmias are very the patients endogenous production of glucocorticoid steroids
common in the face of hyperthyroidism, with atrial fibrillation is reduced or ceases. Secondary AI is characterized by atrophy
occurring in 10% to 20% of patients (7982). Again, level of con- of the adrenal cortex as a result of deficient adrenocorticotro-
trol prior to the operation will determine the perioperative outcome phic hormone (ACTH) stimulation. The most common cause of
for the patient. Patients with controlled hyperthyroidism should secondary AI is administration of exogenous corticosteroids
be instructed to take their antithyroid medications in the morning which feeds back to cause a decrease in hypothalamic cortico-
of the day of surgery. Patients with mild hyperthyroidism may tropin-releasing hormone and subsequent decreased pituitary
have surgery with preoperative beta-blockade. However, patients ACTH secretion. Although there is remarkable variability in
with moderate or severe disease should have surgery canceled individual response to a particular dose and length of treatment
until a euthyroid state is attained (83). with steroids, in general, any patient who received the equiva-
The greatest perioperative risk for patients who have undi- lent of 20 mg per day of prednisone for more than 5 days is at
agnosed hyperthyroidism or who are inadequately treated, is risk for HPA suppression. If the duration of steroid treatment is
a rare, yet life-threatening condition known as thyroid storm. 1 month or longer, the patient will have HPA suppression, which
This thyroid emergency usually occurs intraoperatively or can last for 6 to 12 months after stopping therapy. Whereas an
48 hours postoperatively. The mortality of thyroid storm is 10% equivalent dose of prednisone 5 mg (or less) for any period of
to 75% and requires treatment in a critical care environment time will not usually suppress the HPA axis (8688). Assessment
(70). Symptoms are nonspecific and include hyperpyrexia, tachy- of adrenal function (ACTH stimulation tests) in the periopera-
cardia, delirium, nausea and vomiting, and diarrhea (84). Treat- tive period has not been shown to be sensitive or specific in iden-
ment of thyroid storm is aimed at stopping production of thyroid tifying patients who are at risk for AI and who might respond to
hormone and treating the systemic effects of the decompensated supplemental corticosteroids (8992).
patient. Antithyroid medications such as carbimazole, methim- Recently, Marik and Varon performed a meta-analysis of the
azole, and propylthiouracil (PTU) are used to inhibit the new world literature concerning perioperative stress doses of cortico-
synthesis of thyroid hormones. Unfortunately, there are no IV steroids for patients who take corticosteroids chronically. Their
preparations for these compounds, so they must be administered search revealed two randomized controlled trials (RCTs) and
enterally or per rectum as retention enemas or suppositories. seven cohort studies, for a total of 315 patients. Although the
Recent guidelines from the American Thyroid Association and number of patients is small, the two RCTs showed no differ-
the Association of Clinical Endocrinologists recommend that ences in the hemodynamic profiles of patients receiving stress
propylthiouracil be started with a loading dose of 500 to 1000 mg doses of corticosteroids, compared to patients receiving only
followed by 250 mg every 4 hours, and methimazole should be their usual daily dose of corticosteroid. Similarly, in 5 of the 7
administered at daily doses of 60 to 80 mg (85). Administer- cohort studies, patients who continued to receive their usual
ing these drugs in this sequence will provide more rapid clinical daily doses of corticosteroids without additional stress doses,
improvement because propylthiouracil has the added advantage did not develop unexplained hypotension or adrenal crisis peri-
of inhibiting conversion of T4 to T3, which methimazole does operatively. The remaining 2 cohort studies each had 1 patient
not do. These drugs prevent synthesis of new thyroid hormone, but who stopped their usual daily dose of corticosteroid preopera-
will not stop release of stored thyroid hormone. Either inor- tively, and each developed unexplained postoperative hypoten-
ganic iodine or lithium carbonate (for patients who are allergic sion, which responded to hydrocortisone and fluid therapy. The
to iodine; 300 mg orally every 6 hours) must be given. Lugols authors recommend that patients receiving therapeutic doses
solution or a saturated solution of potassium iodide (35 drops of corticosteroids, who undergo surgery, do not routinely need
CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE 159
Hyponatremia
Hyperkalemia
Hypotension
Eosinophilia
OR
stress doses of corticosteroids as long as their usual daily dose of the drug (such as poor wound healing, fluid retention, and
is continued. In addition, adrenal function testing is not recom- increased risk of infection) versus the benefits of supporting the
mended for these patients because the test is overly sensitive and HPA axis in a surgically stressed patient.
does not predict which patient will develop adrenal crisis. Fur-
ther, patients who have primary adrenal insufficiency and who
are taking physiological replacement doses of corticosteroids
will require supplemental stress doses of corticosteroids in the RENAL RISK ASSESSM ENT
perioperative period (93).
Figure 8.1 outlines an algorithm that may be helpful in guid- Chronic kidney disease (CKD) affects over 13 million Americans
ing clinicians in their decision-making about stress-dose steroids (20 years and older; CKD stage 2 or worse) (94), with most hav-
for patients who take them chronically. Giving stress dose gluco- ing a glomerular filtration rate (GFR) of less than 60 mL/min/
corticoids needs to be weighed against the potential side effects 1.73 m2 (95). The most common form of renal failure facing the
160 CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE
surgeon is acute kidney injury (AKI) occurring during the post- with loop-acting diuretics. Sodium polystyrene sulfonate
operative period, which will be discussed below in the section on (Kionex, Kayexalate) may be used as an exchange resin in
postoperative/critical care. Since 2002, a uniform classification the gastrointestinal tract. Forty grams dissolved in 80 mL of
system for CKD was introduced, stratifying CKD into 5stages sorbitol (or more to promote elimination) and given orally will
based on estimation of GFR and documentation of renal injury bind one millimole of potassium for each gram given. Alter-
(95). Class 5 CKD, or end-stage renal disease (ESRD), includes natively, 50 to 100 g of sodium polystyrene sulfonate may be
patients who require renal replacement therapy (usually dialy- dissolved in 200 mL of water and may be given rectally as a
sis) for treatment (94). With the aging population, increas- retention enema by inserting a Foley catheter into the rectum
ing prevalence of diabetes and hypertension, and advances in and filling the balloon (104). These administrations should be
dialytic therapy, the number of patients living with CKD is repeated every 2 to 4 hours until the potassium level is in a
increasing (94). Therefore, surgeons must be cognizant of the normal range (see section below on potassium derangements).
potential perioperative risks associated with these patients. Caution with the use of this resin in postoperative patients is
The predominant causes of CKD are diabetes and hyperten- urged, as intestinal necrosis has been reported (106).
sion, accounting for 71% of all patients who are dialysis depen- Most patients with CKD have or will develop anemia due to
dent (94). Patients with these underlying diseases tend to have erythropoietin deficiency during the course of their disease and,
other comorbid conditions such as coronary artery disease and prior to the introduction of erythropoietin stimulating agents
peripheral vascular disease. Evaluation of CKD patients undergo- (ESAs), were transfusion dependent. In recent years, the use of
ing surgery should focus on four areas: cardiac evaluation, fluid ESAs has come under scrutiny. Recent reviews have demonstrated
and electrolyte management, anemia, and bleeding diatheses. Of that raising the hemoglobin levels above 11 g/dL in patients with
course, glycemic control for diabetics and blood pressure control CKD resulted in a 1.14-fold increase in the odds ratio of death.
for hypertensive patients is obvious. These results highlight the need to carefully manage hemoglobin
CVD has long been recognized as the leading cause of death levels with ESAs within a recommended range of 9 to 11 g/dL
among ESRD patients, which occurs in 50% of patients (107,108). In urgent situations, transfusion of blood is necessary
(94,96,97). However, patients with other stages of CKD, even to maintain hemoglobin prior to and during surgery.
minor derangements, have an increased risk of CVD. A recent CKD patients have an increased risk for bleeding complica-
study correlated stage of CKD with odds ratios (ORs) for car- tions. Platelet dysfunction caused by renal failure is multifactorial,
diovascular risk, demonstrating a graded increase in risk with with retained uremic toxins, abnormal binding of von Willebrand
increasing stage of CKD (OR-15 for Stage I to OR 20 to 1000 factor, abnormal platelet arachidonic acid metabolism, and excess
for stage V) (97). The disease factors which contribute to CVD vascular prostacyclin and nitric oxide production all being impli-
among CKD patients include microalbuminuria/proteinuria, cated (109). The bleeding time provides the best correlation with
hypertension, diabetes, dsylipidemia, and smoking (98). In addi- risk of clinical bleeding in CKD patients. If a patient has demon-
tion, many CKD patients will have coronary artery disease (23% strated prior bleeding because of uremic platelet dysfunction, these
to 40%) (99101), and many ESRD patients (70% to 80%) will patients must be treated with 1-deamino-8-D-arginine vasopressin
develop ventricular hypertrophy due to hypertension and severe (dDAVP) intravenously, or intranasally and with cryoprecipitate
anemia. This hypertrophy results in a decreased myocardial cap- to prevent bleeding during surgery (110). In addition, patients
illary density and diastolic and systolic dysfunction, all of which may be treated with intravenous conjugated estrogens (0.6 mg/
leads to disturbances in intra-ventricular conduction, electrical kg) if they are given 4 to 5 days prior to surgery (104,111).
excitability, and ventricular arrhythmias (102). Therefore, these Furthermore, with reduced or absent renal function, these
patients may benefit from a formal cardiac clearance from a car- patients metabolize drugs such as antibiotics, anesthetics, and
diologist prior to surgical intervention. analgesics poorly. Drug administration in ESRD must be done
The capacity of the failing kidney to maintain volume and judiciously with careful attention to the pharmacokinetics of
electrolyte homeostasis is achieved through adaptive processes, particular drugs. Multiple guidelines exist that can direct drug
which are limited in their ability to respond to physiological dose reductions for patients with ESRD (112,113).
stresses, placing well-compensated patients, in the premorbid
state, at increased risk of fluid and electrolyte disturbances dur-
ing the perioperative period (103). Intraoperative and periopera-
tive fluid management in the patients with CKD must therefore H EPATIC RISK ASSESSM ENT
take into account the reduced capacity for both water excretion
and conservation. Excessive free water administration must An increasing number of patients with chronic liver disease,
be avoided to prevent iatrogenic hypotonicity, while providing advanced or end stage, will require non-liver transplant
sufficient free-water to prevent hypertonicity. Electrolyte status surgery (114). Reasons for this increase are; an aging popula-
should be monitored frequently and water administration tion, better long-term survival of patients with liver cirrhosis,
adjusted if hypo- or hypernatremia ensues (104). ESRD patients and continuously improving outcomes after surgery and critical
who are dependent upon dialysis will need to be euvolemic prior care medicine (115). Historically, liver dysfunction was related
to surgery. Thus, communication with the patients nephrologist tochronic viral or alcoholic hepatitis. While the incidence of these
is paramount. Details about the operation should be discussed, conditions has not changed dramatically in recent years, the rising
with planned preoperative dialysis (without heparin 24 hours rate of obesity has led to nonalcoholic fatty liver disease, which
prior to surgery) and postoperative dialysis on the day of surgery is increasingly recognized as the most common cause of chronic
for large intraoperative fluid loads. Electrolytes should be moni- liver disease (CLD) in the United States (116).
tored in the immediate postoperative period, with hyperkalemia As mentioned earlier, thorough preoperative evaluation of
being aggressively managed with dialysis, or medically if neces- patients includes a comprehensive history and physical examina-
sary. Acute hyperkalemia may be treated with glucose and insulin, tion, with laboratory testing based upon historical and physical
which will drive the Na/K-ATPase pump resulting in an increase findings. Routine testing of liver function or coagulation in asymp-
of intracellular potassium and lowering of extracellular potas- tomatic patients rarely yields abnormal results or changes in peri-
sium. Ten milliliters of calcium gluconate can afford cardiopro- operative management (7). However, patients with history of
tection and membrane stabilization in patients with abnormal liver disease, jaundice, blood transfusions, the use of alcohol or
electrocardiograms (ECGs) (105). Decreasing total body potas- other recreational drugs, hepatitis, or physical findings of icterus,
sium is the final step in the treatment of hyperkalemia. In non- hepato-splenomegaly, palmar erythema, or spider nevi should be
oliguric patients, renal potassium excretion may be enhanced tested to rule out occult or active liver diseases (115).
CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE 161
Table 8.8 Child-Turcotte-Pugh (CTP) Table 8.9 Model for End-stage Liver Disease
Classification of Liver Disease and (MELD) Score
Operative Mortality MELD Score = (9.6 loge[Creatinine]) + (3.8 loge[Bilirubin]) +
11.2 loge[INR]) + 6.4
Score
Creatinine levels above 4.0 mg/dL, are assigned 4.0 mg/dL. Levels
Component 1 Point 2 Points 3 Points under 1.0 mg/dL are assigned 1.0 mg/dL. If the patient has had
dialysis twice in the previous week, the value is assigned 4.0 mg/dL
Ascites None Controlled with Treatment-
medication refractory Bilirubin levels below 1.0 mg/dL are assigned 1.0 mg/dL
Encephalopathy Absent Grade III; Grade III-IV; INR levels below 1.0 are assigned 1.0
Controlled with treatment
medication refractory The maximum score is 40. Scores calculated greater than 40, are
assigned a value of 40.
Albumin g/L >3.5 2.83.5 <2.8
MELD Score Less than 10 1015 Greater
Billirubin mg/dL <2 23 >3 than 15
No Yes
No Further Pre-op Testing Preop evaluation-ECG, CXR, Laboratory-pre-albumin, albumin, LFTs, PT/PTT, INR, lactate,
needed ammonia level; additional evaluation as indicated by comorbidity
FIGURE 8.2. Preoperative evaluation and risk stratification in suspected liver disease.
ECG, electrocardiogram; LFTs, liver function tests; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; PT, prothrombin time; PTT, partial prothrombin time; INR, international
normalization ratio; CLD, chronic liver disease; CTP, ChildsTurcottePugh; MELD, model of end-stage liver disease.
Source: Adapted from Hanje AJ, Patel T. Preoperative evaluation of patients with liver disease. Nat Clin Pract Gastroenterol Hepatol. 2007;4:266276 and Hoetzel A, Ryan H, Schmidt R. Anesthetic considerations for the
patient with liver disease. Curr Opin Anesthesiol. 2012;25(3):340347.
gynecological malignancies or benign conditions (126,127). include the Subjective Global Assessment (SGA), the Patient-
Among malnourished gynecologic oncology patients, patients Generated Subjective Global Assessment (PG-SGA), Nutrition
have been found to have an increased risk of postoperative com- Risk Index (NRI), the Mini Nutritional Assessment (MNA),
plications, longer lengths of stay, hospital readmissions, reop- Prognostic Nutritional Index (PNI), and the Nutritional Risk
erations, earlier cancer recurrences, and residual tumor after Screening 2002 (NRS-2002) (Table 8.11). Although just examples
initial surgery (127129). The methods for assessing malnutri-
tion has varied among investigators and has included weight
loss over a given time, various objective anthropometric param-
eters (e.g., weight loss, body mass index, triceps skinfold thick- Table 8.10 Measurement of Nutritional Depletion
ness, and arm circumference), biochemical testing (e.g., serum
albumin, prealbumin, total protein, transferrin, hemoglobin, Depletion
and vitamins), and immunologic testing (skin sensitivity tests) Parameters Mild Moderate Severe
(Table 8.10) (130).
Nutrition screening refers to the initial clinical evaluation Triceps skin fold (TSF) % 5090 3050 <30
Standard
that can quickly identify patients at high risk for malnutrition
and who, later, may undergo a more formal and extensive nutri- Mid-arm muscle circumference 8090 7080 <70
tional assessment. Such instruments are the Malnutrition Screen- (MAMC) % Standard
ing Tool (MST) and the Malnutrition Universal Screening Tool Albumin g/dL 3.03.4 2.13.0 <2.1
(MUST), which have been used in oncology patients (Table 8.11).
Logically, identifying patients at nutritional risk, by screening, Total lymphocyte count 12001500 8001200 <800
(TLC) Cmm
will mark them for subsequent formal nutrition assessment, and
identify opportunities for medical nutrition therapy, which ulti- Weight loss, % initial
mately should improve patient outcomes. Unfortunately, this
In 1 week <1 12 >2
sequence of assumptions has never been subjected to prospective
confirmation in clinical trials (131). In 1 month <2 25 >5
Many nutrition assessment tools have been developed, includ-
In 3 months <5 5.07.5 >7.5
ing subjective and objective data to assign risk, and some have
been validated in cancer patients, including gynecologic cancer In 6 months <7.5 7.510.0 >10.0
patients. Those instruments that have been used in cancer patients
CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE 163
patients undergoing major cancer operations. The risks and costs is crucial in presurgery medication management. Patients should
of routine perioperative NST outweigh benefits in terms of sur- be counseled on the use of nonprescription medications, such
gical outcomes in cancer patients (125,138). as aspirin, nonsteroidal anti-inflammatories, ginkgo biloba, saw
Several RCTs have been done to evaluate NST in cancer palmetto, garlic, ginseng, and vitamin E, as they have antiplatelet
patients undergoing surgery. The largest trial, the Veterans components and may enhance bleeding risk (144, 145). If possi-
Affairs Cooperative Study, randomized 395 surgical (abdomi- ble, anemia should be corrected preoperatively. The use of recom-
nal or noncardiac thoracic surgeries) patients, mostly male, to binant human erythropoietin with concurrent iron and folic acid
receive at least 7 days of preoperative and 3 days of postop- supplementation 2 to 3 weeks preoperatively has been shown to
erative TPN or to receive no perioperative nutritional supple- reduce allogeneic blood transfusions in patients undergoing elec-
mentation. The TPN group had a greater number of infectious tive surgery (146). It has been estimated that 60% of all blood
complications, mostly among patients classified as borderline or transfused in the United States is given to surgical patients.
mildly malnourished compared to the unfed patients (14.1% Numerous studies have shown the benefit of starting medica-
vs. 6.4%). However, a subset of severely malnourished patients tions, such as statins and b-blockers, in the preoperative setting
derived benefit from lower operative complication rates (5% vs. to reduce cardiac risk (147). The perioperative use of b-blockers
43%, p = 0.03) without incurring an increase in infectious com- has been shown to reduce the incidence of postoperative myo-
plications. The overall 30- and 90-day mortality rates were not cardial ischemia, myocardial infarction, and cardiac mortality
different between the groups (31). Meijerink et al. completed by decreasing myocardial oxygen consumption and workload,
a trial of preoperative nutrition among 151 patients undergo- although this has not been studied specifically in the morbidly
ing surgery for gastric or colorectal cancer and randomized to obese population (147). Current ACC/AHA guidelines recom-
preoperative TPN versus enteral nutrition (EN) versus standard mend that b-blockers should be continued in patients undergoing
oral diet (SOD). The authors found that there was no difference surgery who are receiving b-blockers to treat angina, symptomatic
in mortality among the groups. However, patients who were arrhythmias, hypertension, or other ACC/AHA class I guideline
severely malnourished and received either TPN or EN had fewer indications (148). For high-risk patients not receiving b-blockade,
intra-abdominal abscesses than the MOD, but there was a dif- therapy should start before elective surgery, with the dose titrated
ference in infectious morbidity between the TPN and EN groups to achieve a heart rate at rest of 50 to 60 beats/minute (149).
(140). A similar study by Bozzetti et al. randomized severely The perioperative use of b-blockers in high-risk patients undergo-
malnourished patients undergoing resection of gastric or colonic ing major noncardiac surgery is supported by the published data.
malignancies to 10 days of preoperative and 9 days of postoper- However, studies have questioned the benefits of this approach in
ative TPN or SOD with hypocaloric TPN postoperatively only. moderate-risk patients and report that the potential harm in low-
The TPN only group showed lower noninfectious postoperative risk groups might outweigh the benefit, stressing the importance
complication rates and mortality (141). And finally Wu et al. of patient selection (150).
randomized 468 patients to pre- and postoperative TPN/EN Statins have also been shown to be effective cardioprotective
versus postoperative hypocaloric PN among moderately to drugs in the perioperative setting (147). Statins have been shown
severely malnourished patients undergoing surgery for gastro- to act as plaque stabilizers and therefore possibly decrease
intestinal cancers. The investigators found fewer complications, the risk of thromboembolic events (147,151). With their low
lower mortality, and shorter lengths of stay among the full side effect profile and well-documented benefits, statins should
nutrition support group (142). Because of the findings of these be strongly considered for all obese patients with elevated serum
trials, ASPEN and ESPEN suggest that perioperative NST may cholesterol or triglycerides (152).
be beneficial in moderately or severely malnourished patients if Close to 2 million patients undergo coronary angioplasty
administered for 7 to 14 days preoperatively. The potential ben- each year in western countries, and >90% of these patients
efits of NST must be weighed against the potential risks of the will have coronary stents placed as part of their intervention
NST itself and of delaying the operation. The authors direct the (153,154). Patients with bare metal stents are normally taking
reader to reviews of these recommendations, which have been low-dose aspirin 81 mg. It is recommended that they stop taking
done by Huhman and August (for ASPEN) (125) and Braga et aspirin 7 days before surgery (155,156).
al. (for ESPEN) (139). Patients with drug-eluting stents take oral aspirin 81 mg, or
even aspirin 325 mg, and, for the first 12 months after stent
placement, daily oral clopidogrel 75 mg (156,157). Ideally, these
patients should not undergo elective surgery, within the first
PREPAR ATION FOR SU RGERY 12 months after stenting. After the first 12 months, both medi-
cations are recommended to be stopped 7 days before surgery to
reduce the risk of intra- and postoperative bleeding (155).
Medication Management It is not uncommon for gynecologic oncology patients to
In preparation for surgery, patients may need to decrease or undergo neoadjuvant chemotherapy. Most gynecologic oncolo-
stop taking certain medications, especially those associated gists would agree that the timing of surgery in relation to chemo-
with higher incidence of anti-coagulation risks. Appropriate therapy is crucial. In most cases, the surgical intervention should
notice and clear instructions should be given to patients in this replace a cycle of chemotherapy. With regard to bevacizumab,
case, as some medications require several days of cessation to special considerations should be taken into account since there
produce desired results. It will take approximately 4 days after is the added risk of bowel perforation and poor wound healing.
warfarin therapy is discontinued for the international normal- The incidence, type, and timing of postsurgical bleeding events
ized ratio (INR) to reach 1.5 for those patients with INR levels and wound-healing complications were assessed in surgical
between 2.0 and 3.0. Many patients on warfarin do not need to patients in the AVastin And DOcetaxel (AVADO) and Avastin
be covered with heparin therapy preoperatively. Administration THErapy for advaNced breAst cancer (ATHENA) trials. Both
of treatment-dose intravenous heparin or low-molecular-weight study protocols followed recommendations to withhold bevaci-
heparin (LMWH) while the INR is subtherapeutic is recom- zumab for at least 6 weeks before elective surgery, and to wait
mended for patients with a history of mechanical mitral valve, 28days (or until the wound was fully healed) after major surgery
ball and cage valve, acute venous, or arterial thromboembolism before recommencing bevacizumab therapy (158). Another study
within 3 months of surgery, or atrial fibrillation with a history of by Erinjeri et al. investigated how the timing of administration
thromboembolic stroke (143). A thorough discussion pertaining of bevacizumab affected the risk of wound healing in patients
to usage of over-the-counter medications and herbal supplements undergoing chest-wall port placement. They concluded the risk
CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE 165
of a wound dehiscence requiring a chest wall port explant in during surgery is reduced. ANH obviates the costs of blood test-
patients treated with bevacizumab was inversely proportional to ing, storage, or wastage because all blood collected during ANH
the interval between bevacizumab administration and port place- is kept in the operating room and returned to the patient before
ment, with significantly higher risk seen when the interval is less the end of surgery. It is simple to perform and more convenient
than 14 days (159). Scappaticci et al. assessed postoperative for the patient. Since the blood is collected at point-of-care there
wound healing complications in two randomized trials of 5 mg/ is no possibility for clerical error or contamination. ANH has
kg bevacizumab in colorectal cancer treatment. Bevacizumab been shown to be a cost-effective yet underutilized strategy to
administered in combination with 5-fluorouracil/leucovorin- reduce allogeneic blood transfusions (170172). ANH in which
based chemotherapy 28 to 60 days after primary cancer sur- the blood is kept in a continuous circuit with the patient is often
gery caused no increased risk of wound healing complications a workable alternative for a Jehovahs Witness patient (170,173).
compared with chemotherapy alone. While wound healing The utilization of erythropoietin in oncology patients should
complications were increased in patients who had major sur- on a case by case basis due to recent evidence of adverse effects
gery during bevacizumab therapy, the majority of bevacizumab- in oncology patients (174).
treated patients experienced no complications (160).
Bowel Preparation
Blood Banking It is generally accepted that full mechanical bowel preparation is
significance (177,178,180,183). However, serious and fatal met- prophylaxis prior to colorectal surgery, due to longer half-life and
abolic derangements have been reported, and caution should broad spectrum coverage (198). An appropriate alternative for
be used in elderly patients or when prescribing multiple dose surgical procedures with a higher chance of bowel resection or
regimens (182185). The FDA suggests obtaining posttreat- injury is cefazolin plus metronidazole or ampicillin-sulbactam
ment laboratory evaluation (basic metabolic panel, calcium, (200). Cefoxitin is another option, but availability has been lim-
phosphate), especially if more than 45 mL is taken in a 24-hour ited. Most patients with a penicillin allergy can be treated with
period (182). Low-volume bowel preps are now available, such cefazolin; however, when allergy prohibits the administration of
as Suprep (sodium sulfate, potassium sulfate, and magnesium a cephalosporin, alternative regimens are clindamycin with genta-
sulfate). Generally, the risk of electrolyte abnormalities are lower micin, a fluoroquinolone, or aztreonam (197). Itani et al. reported
with these newer preps; however, posttreatment laboratory eval- on a randomized, double-blinded trial in patients undergoing
uation should be considered (186). elective colorectal surgery that suggested ertapenem as an effec-
Although regarded as being essential in preventing complica- tive alternative to cefotetan (201). Ertapenem has received FDA
tions of colorectal surgery, the necessity of mechanical bowel approval for prophylaxis for elective colon resection; however,
cleansing has been strongly disputed for the past 15 years. the 2006 Medical Letter guidelines caution against the routine
The claims that preoperative mechanical bowel preparation use of ertapenem for surgical prophylaxis due to cost and con-
reduces anastomotic leakage and SSI are based on observational cerns that this practice may result in increased rates of antibiotic
studies and expert clinical experience. Since 1992, several pro- resistance (200).
spective randomized trials reported that elective colon and When considering dosing orders to achieve and maintain
rectal surgery may be performed safely without mechanical effective tissue levels, parenteral antibiotics should be given
bowel preparation. All patients in these trials received systemic within 1 hour (between 1 and 2 hours for fluoroquinolones and
antibiotics. However, the majority of these trials were greatly vancomycin) prior to skin incision as a loading dose (197). For
underpowered, with a 60% or greater chance that a type II patients weighing >70 kg, the dosage should be doubled (i.e.,
error occurred (187,188). In 2006, Bucher et al. published a cefazolin 2 g intravenously [IV]) or weight-based dosing should
meta-analysis of 1,297 patients from 7 randomized, controlled be used. Repeat doses should be given intraoperatively for surger-
trials and concluded that mechanical bowel preparation does ies lasting longer than 3 to 4 hours or when blood loss exceeds
not reduce the incidence of infectious complications and may 1,000 mL (198,200). Guidelines from the National Surgical
be harmful with respect to leakage at the anastomosis (189). Site Infection Project recommend that prophylactic antibiotic
Another meta-analysis of 1,592 patients (9 trials) came to the use for abdominal or vaginal procedures end within 24 hours
same conclusions and stated that the dogma that mechanical of the operation (197). The majority of the published evidence
bowel preparation is necessary before elective colorectal surgery supports the use of an appropriately timed administration of a
should be reconsidered (190). In a survey of members of the single dose of antibiotic and indicates that repeat doses postop-
American Society of Colon and Rectal Surgeons, essentially all eratively are unnecessary and subject the patient to the potential
routinely used mechanical bowel preparation, although 10% emergence of resistant organisms (195,197,198,200).
questioned its importance. Of the 515 surgeons who responded The American College of Surgeons and the National Surgical
to the questionnaire, 47% routinely used sodium phosphate, Quality Improvement Plan employ a prospective, peer-reviewed
32% routinely used PEG, and 14% alternated between the database to quantify 30-day risk-adjusted surgical outcomes
2agents (191). that encompass such variables as preoperative risk factors and
The importance of appropriate intravenous antimicrobial postoperative mortality and morbidity, allowing comparison of
prophylaxis in patients undergoing colorectal surgery is well outcomes among all hospitals in the program. Enrolled hospitals
established and was discussed earlier in this chapter. There are abstract case data into the database, the data are quantified, and
conflicting opinions and data regarding whether preoperative the database generates comprehensive semiannual reports to
oral antibiotics as part of a bowel preparation add any additional the hospitals as well as real-time, continuously updated, online
benefit for reduction of SSI (192,193). Although there are still benchmarking reports (202).
strong proponents of this practice (194), oral antibiotic usage with Surgical site infections account for nearly 40% of nosocomial
preoperative mechanical bowel cleansing is declining (191). infections in surgical patients and occur in up to 20% of patients
undergoing abdominal surgery (195,197). They are a significant
source of postoperative morbidity, resulting in longer hospital
stays, increased rates of intensive care unit admissions, hospital
Infection Prophylaxis readmissions, and subsequently increased costs. Mortality rates
The use of prophylactic antimicrobials plays a large role in increase 2 to 3 times for patients with an SSI as compared to
reducing the rates of surgical site infections (SSIs) and should be patients who do not develop an SSI (203,204). In addition to the
used in clean or clean-contaminated operations, which include administration of preoperative antimicrobial prophylaxis, pre-
most procedures performed by gynecologic oncologists. Radical operative skin preparation is used to reduce the risk of SSI by
pelvic surgery introduces women to a higher risk of postopera- decreasing the microbial count at the projected site of incision.
tive infection secondary to several potential factors: lengthened A meta-analysis of 6 trials concluded that although whole-body
operating time, average of age of patient requiring this specific scrubs or showers with antiseptic agents such as chlorhexidine
surgery, increased blood loss, anemia, potential hypothermia, or povidone-iodine prior to surgery reduce bacterial counts on
probable poor nutritional status, the presence of tumor, prior the skin, this practice did not reduce wound infection rates(205).
pelvic irradiation, diabetes, obesity, peripheral vascular disease, Surgical infection occurrences are noted to be influenced by both
and a history of postsurgical infection (195,196). Prophylactic patient and operative environmental factors. Therefore, patients
antibiotics should provide coverage consistent with the microbial undergoing surgery should be instructed to bathe or shower nor-
milieu most likely to be encountered. In gynecologic oncology mally the night or morning prior to surgery, removing any debris
surgery, the most common infecting organisms are coliforms, from the skin surface and decreasing environmental contaminants.
enterococci, streptococci, clostridia, and bacteroides. Inappropriate hair removal techniques can traumatize the skin
Several guidelines for antibiotic prophylaxis in surgery and provide an opportunity for colonization of microorganisms.
have been published (195,197,199,200). Most reports recom- There is no evidence that hair removal prior to surgery will pre-
mend cefazolin for gynecologic procedures. Although no longer vent or reduce SSI. To the contrary, meta-analysis evaluating hair
available, cefotetan had been the preferred antibiotic for pro- removal techniques demonstrated a twofold increase in SSI when
phylaxis in longer radical gynecologic operations, as well as for patients underwent hair removal by shaving versus clipping
CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE 167
Right Atrium
30
20
10
0
Right Ventricle
30
20
10
0
Pulmonary Artery
30
20
10
0
Pulmonary Artery Branch
30
20
10
FIGURE 8.3. Pulmonary artery catheter wave-form readings as the catheter passes through the heart into
the pulmonary artery. Y-axis is reading in millimeters of mercury (mm Hg).
PAOP and the calculated cardiac output, differentiation between added to give a sample known as the mixed venous blood. By
volume depletion and cardiogenic disease states can be made evaluating the oxygen saturation of this blood, oxygen delivery
(see section on shock). Newer PA catheters have been developed can be calculated (Table 8.12). This measurement is perhaps the
that can calculate right ventricular ejection fraction. most important function of the PA catheter, and current tech-
By taking a blood sample from the tip of the PA catheter, nology allows this function to be continuous via an infrared
the most desaturated blood in the body is retrieved. In normal sensor at the tip of the PA catheter. For example, if oxygen deliv-
circulation, the blood from the superior vena cava and the infe- ery is determined to be low, there are only 3 situations that the
rior vena cava mix, and the blood from the coronary sinus is clinician can influence: increase cardiac output (with fluid, chro-
notropes, or inotropes), increase the hemoglobin, or increase
the oxygen saturation. In a patient with a major operation and
medical comorbidities, the measurement of a normal oxygen
delivery provides reassurance to the clinician that end organs
are being perfused.
FIGURE 8.4. Chest radiograph showing proper placement of pulmonary O2 extraction ratio = (CaO2 CvO2)/CaO2 [25%]
artery catheter in the pulmonary artery (arrow shows tip of pulmonary
catheter). Values in brackets are normal values.
CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE 169
Calculation of the systemic vascular resistance (SVR) is an acute increase in myocardial oxygen demand and is mainly
also possible with a PA catheter. Because the SVR is a calcu- reserved for cardiac arrest or severe circulatory failure. Nor-
lated value and not directly measured, inaccuracies are inherent epinephrine and phenylephrine are pure a-mimetic agents, uti-
and overinterpretation of this value is cautioned. Rather than lized for vasoconstriction (neurogenic shock). In most situations
relying on the calculated SVR, the clinician should have com- of shock, fluid resuscitation is preferred to administration of
plete understanding of the measured blood pressure and car- a-agents. Although these agents will give a false sense of secu-
diac output and the ramifications therein to make therapeutic rity that the blood pressure is normal, one must remember that
decisions (SVR combines the 2 previously mentioned measured the vasoconstriction underperfuses capillary beds, leading to an
variables). increased incidence of renal hypoperfusion (acute renal injury),
In one study of ovarian cancer patients undergoing cytore- splanchnic hypoperfusion (resulting in translocation of gut flora),
ductive surgery, 18% of patients had indications for PA catheter and a myriad of other problems (220,221).
use (214). Because of the issues of volume status in these patients, Vasopressin has emerged as an option similar to epineph-
PA catheter placement for postoperative fluid management may rine, with some important differences. This antidiuretic hor-
be especially helpful. mone in high doses provides potent vasoconstriction and leads
to improved cerebral and coronary blood flow in shock states.
Unlike epinephrine, there is less increase in myocardial oxygen
Acute Postoperative Myocardial Infarction demand and less propensity for inducing arrhythmias.
MI usually manifests with acute chest discomfort, elevated car- Amrinone (or inamrinone) is a phosphodiesterase inhibitor
are encountered, such as ARDS, hypercarbia, and acidosis, pres- an inflammatory response consisting of increased production
sure control (PC) is used. This mode is similar to the neonatal of cytokines, leukotrienes, endothelial adhesion molecules, and
pressure-cycled ventilator where the maximum pressure is set and interleukins. These molecules, which are useful in the defense of
the flow rate is decreased but the inspiratory time is lengthened the host organism, are particularly detrimental to pulmonary
to achieve proper ventilation. Airway pressure release ventilation endothelium. ARDS is the result of some inciting cause and does
(APRV), high-frequency jet ventilation, and inverse ratio ventila- not arise de novo as a primary problem. A study of patients who
tion are other advanced modes, the discussion of which is beyond develop multiple organ dysfunction syndrome (MODS), a state
the scope of this chapter. where sequential organ failure leads to patient death, has shown
that the lung may be the first organ system susceptible to these
circulating inflammatory mediators (239). In addition to support-
Setting the Ventilator ive treatment for ARDS, operative injuries or postoperative com-
Initial ventilator settings require a rate of 12 to 14 breaths per plications (e.g., intra-abdominal abscess, anastomotic leak) must
minute with a tidal volume of 6 to 8 cc/kg. This is a departure be sought and ruled out.
from the traditional 12 cc/kg, which has been determined to In 1994, a consensus of American and European intensiv-
result in greater alveolar trauma and increased risk for the devel- ists defined the criteria for ARDS and a lesser form of the dis-
opment of ARDS (232). After initial setting of the ventilator, ease described as acute lung injury (ALI) (237). Criteria include
measurements of pH, PO2, and PCO2 from arterial blood gas are (a)acute onset after defined insult; (b) bilateral diffuse infiltrates
used to make further ventilator adjustments. on chest radiograph; (c) no evidence of left atrial hypertension,
Hypernatremia is an uncommon finding and is related to large flattening of the T waves, depression of S-T segments, promi-
volumes of free water loss (through insensible routes such as nent U waves, and prolongation of the Q-T interval. Treatment
breathing, sweating, and ventilation), diabetes insipidus, adrenal is accomplished by replacement of potassium either orally or
hyperfunction, or ingestion or administration of increased sodium intravenously, depending upon the severity of symptoms and
solutions. Again, the symptoms are predominantly CNS ori- whether or not the patient is able to take oral preparations.
ented because of brain cell dehydration. Symptoms rarely occur Intravenous replacement of potassium can be done at approxi-
until serum sodium levels exceed 160 mEq/L. In addition, the mately 10 mEq/hour and should not be more concentrated than
rapidity at which the derangement occurs determines the symp- 40 mEq/L. If less fluid is desired, 20 mEq can be placed in 100 mL,
toms manifested. Treatment is carefully done with replacement but administration should not exceed 40 mEq/hour (247).
of free water. Replacement too rapidly can cause cerebral edema
and herniation. Patients with chronic hypernatremia need free
water administration, which decreases the serum sodium no
Magnesium Derangements
faster than 0.7 mEq/L. Most magnesium in the body is confined to the intracellular
space and bone. Less than 1% of total body magnesium is in the
serum. Of the magnesium in the serum, 60% is ionized, 25% is
Potassium Derangements protein bound, and 15% is complexed with nonprotein anionic
Whereas sodium is the major extracellular cation, potassium is species (247). Magnesium is absorbed in the small intestine,
the major intracellular cation by a ratio of 30:1. The intracel- directed by levels of vitamin D, and filtered by the kidney for
lular potassium concentrations tend to be relatively constant, excretion. Approximately 40% of renally excreted magnesium is
whereas the extracellular concentrations vary depending upon reabsorbed in the ascending loop of Henle. Loop diuretics, hyper-
renal function/excretion. The majority of potassium secretion magnesemia, hypercalcemia, acidosis, and phosphate depletion
occurs in the distal tubule and the collecting duct of the nephron. result in increased excretion of magnesium.
Secretion is stimulated by increased urine flow, increased sodium Patients with renal failure and receiving magnesium-
delivery, high potassium levels, alkalosis, aldosterone, vasopres- containing antacids or laxatives can become hypermagnesemic.
sin, and -adrenergic agonists. Insulin causes potassium to move In addition, patients with acidosis and dehydration may become
into cells (as previously mentioned), reducing the extracellular hypermagnesemic. Patients present with CNS depression, loss of
concentration of potassium. Serum potassium levels are further deep tendon reflexes, and ECG changes (prolonged P-R inter-
affected by the acid-base status of patients. In alkalotic states, val and QRS complex) in the face of elevated magnesium levels
the potassium shifts into cells in exchange for hydrogen ions, (greater than 8 mg/dL). As levels rise, patients will develop coma,
whereas in acidotic states the exchange is opposite. respiratory failure, and/or cardiac arrest. Acute treatment of
The predominant reason for hyperkalemia in a postoperative hypermagnesemia is slow IV infusion of 5 to 10 mEq of calcium.
patient is renal dysfunction or failure. When these patients become Because the etiology of this condition is usually renal failure,
critically ill, serum potassium concentrations can increase by 0.3 withholding magnesium-containing preparations may be all that
to 0.5 mEq/L/day in noncatabolic patients and 0.7 mEq/L/day is necessary. In severe instances, hemodialysis is required.
in catabolic patients. It is important to rule out a spuriously In gynecologic oncology patients, the overwhelming reason
elevated level secondary to hemolysis at the time of the blood for hypomagnesemia is a history of cisplatin administration.
draw either from too small a gauge of needle or simply from the However, other conditions such as hypoparathyroidism, malab-
application of the tourniquet and squeezing (247). sorptive states, chronic loop diuretic use, and the diuretic phase
Hyperkalemia changes the membrane potential established of acute renal failure can cause hypomagnesemia. Symptoms are
by differences between the intracellular and extracellular milieu. similar to hypocalcemia, with muscle weakness, fasciculations,
This increased concentration has deleterious effects on cardiac tetany, hypokalemia, and ECG changes (Q-T prolongation,
muscle function, causing peaked T waves, flattened P waves, torsade de pointes). Treatment can be accomplished with oral
prolonged QRS complexes, and deep S waves on the ECG, and preparations in less acute situations. However, large doses may
possibly resulting in ventricular fibrillation and cardiac arrest. produce diarrhea, worsening the situation. Intravenous boluses
Skeletal musculature is also affected with paresthesias and weak- of 2 to 3 g followed by infusions of 1 to 2 mEq/kg/day can be
ness, which can progress to a flaccid paralysis. utilized for patients with severe symptoms.
Treatment for hyperkalemia has been outlined in the section
on renal risk factors. The mainstay is saline diuresis unless ECG
changes are present, then infusion of calcium gluconate can be
Calcium Derangements
lifesaving. Utilization of 25 to 50 g of glucose and 10 to 20 units Almost all the calcium in the body is in bone, stored as hydroxy-
of regular insulin can drive potassium intracellularly and tran- apatite crystals, and provides a supply that can be exchanged
siently lower plasma levels. Ultimately, definitive therapy relies to the serum. Calcium homeostasis is controlled by parathyroid
upon increased excretion of potassium. For each gram of sodium hormone (PTH), controlling intestinal absorption of calcium,
polystyrene sulfonate (Kayexalate, given in the doses previously renal excretion of calcium, and exchange of calcium from the
mentioned) used either orally or rectally, 0.5 mEq of potassium bone. In the serum, calcium exists in three phases: 45% as an
will be removed. Finally, in patients not responding to these ionized form, which is responsible for most of the physiologic
therapies or patients with renal failure, hemodialysis may be function of calcium; 40% in a protein bound form, bound
indicated. mostly to albumin; and 15% in a nonionized form, complexed
Hypokalemia is caused by decreased intake, increased gas- with nonprotein anions that do not easily dissociate. A serum
trointestinal losses (vomiting, diarrhea, fistulae), excessive renal total calcium level is usually obtained when assessing calcium
losses (metabolic alkalosis, magnesium deficiency, hyperaldoste- homeostasis, as measurement of ionized calcium is cumbersome.
ronism), a shift of potassium into the intracellular space (acute The total calcium levels change by 0.8 g/dL for each 1 g/dL change
or uncompensated metabolic alkalosis, glucose and insulin of albumin (up or down) (247).
administration, catecholamines), or any combination thereof. A In gynecologic oncology patients with hypercalcemia, the
reduction of serum potassium by 1 mEq/L represents a total underlying malignancy is usually the etiologic agent. Hypercal-
body deficiency of about 100 to 200 mEq. (Remember that total cemia may be caused by direct bony involvement or, more com-
exchangeable potassium is approximately 3,000 mEq, with monly, secretion of PTH-like peptides and/or other humoral factors,
the majority being intracellular and thus the majority of the which increase serum calcium levels. Other reasons for hypercalce-
loss[247].) Symptoms of hypokalemia cause ECG changes with mia include primary, secondary, or tertiary hyperparathyroidism,
CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE 175
After calculation of caloric requirements, the composition administration, blood glucose measurements by finger stick are
of the TPN solution to be administered should be determined. required so that hyperglycemia is avoided. For the first several
Because there are many different types of TPN preparations avail- days, measurement of serum electrolytes, with adjustments being
able, consultation with the nutrition team or pharmacists in an made daily, is necessary.
individual hospital is necessary to arrive at the desired solution. As previously mentioned, complications from venous access
In aerobic situations, glucose is the primary substrate for energy are some of the drawbacks of TPN administration. Other com-
expenditure. It provides 3.4 kcal/g and is usually given in a con- plications include metabolic derangements, which most often
centrated form in order to provide 70% of the calculated calories. are mild but need correcting as soon as they are identified,
The remaining 30% of calories is provided by lipid preparations. abnormalities of liver function tests, the clinical significance of
Not only does this component have denser caloric content (it pro- which is unclear (267), and cholelithiasis/cholecystitis secondary
vides 9 kcal/g), but administration precludes the development of a to gallbladder sludge.
fatty acid deficiency. Adjustment of the composition of TPN may
be necessary depending upon the disease state (e.g., more contri-
bution of kilocalories from fat vs. carbohydrate in a ventilated Renal Issues
patient because of the respiratory quotient of fat vs. glucose). Acute renal failure (ARF) or hospital-acquired renal insufficiency
Protein requirements are provided by amino acid solutions (HARI) continues to be a common problem among postsurgical
and are determined by the patients age, sex, nutritional status, patients. Although the incidence of HARI is 1.5 patients per 1,000
ongoing stress, and comorbid conditions. In general, 25% of admitted, the impact of HARI on morbidity and mortality is quite
that can induce ATN include aminoglycoside antibiotics and Hypovolemic shock secondary to inadequate preload can be the
iodinated contrast media. Approximately 15% of patients who result of excessive or ongoing blood loss or inadequate replace-
receive aminoglycosides will have nephrotoxicity, and serum ment or both. Certainly, after radical debulking procedures or
levels of these antibiotics need to be carefully monitored (272). major extirpative procedures, the potential for postoperative
Iodinated contrast media, used in multiple radiographic proce- hemorrhage exists. Tachycardia, hypotension, and oliguria
dures, induces ATN by impairing nitric oxide production and are typical clinical signs. In the face of these clinical signs, the
increasing free radical formation (273,274). Diabetic patients surgeon should have high suspicion for active bleeding and be
with creatinine clearance rates less than 50 mL/minute are at preparing to return the patient to the operating room for correc-
particularly high risk (275). tion. Measurement of hemoglobin or hematocrit can be normal
The final reason for ARF in the postoperative gynecologic in the setting of acute blood loss since a decrease in red cells
oncology patient is outflow obstruction. Because of the radical is accompanied by a decrease in mass. Once fluid is given for
pelvic procedures performed by gynecologic oncologists, ureteral resuscitation, dilution will occur and the hemoglobin/hematocrit
injury is possible and needs to be excluded early in the evalua- will fall. With invasive monitoring, the CVP will be low, as will
tion of patients with ARF. Prompt reversal of the obstruction can cardiac output and the PAOP. As the stroke volume decreases to
further limit renal damage. inadequate amounts, the heart compensates by increasing the
In general, expected postoperative urinary output should heart rate in order to maintain cardiac output. The treatment
be maintained at 0.5 mL/kg of weight per hour. Most oliguria in these cases is aggressive volume resuscitation and control of
can be treated with intravascular expansion in the first 24 to ongoing blood loss. The controversy between resuscitation with
48 hours postsurgery. Hypoperfusion of the renal parenchyma colloid (albumin, plasma) or crystalloid (normal saline or lac-
must be avoided to prevent ATN from occurring. The definition tated Ringers solution) remains ongoing. The SAFE study is a
of ARF is not standardized, but includes rising serial creatinine large, randomized controlled double blind study that compared
measurements, urine output less than 400 mL/24 hours, or, in albumin to saline infusion in the intensive care unit. It failed to
drastic situations, the initiation of dialysis (269). Once diagnosed, demonstrate a beneficial effect (282).
calculating the fractional excretion of sodium (FENa) or chlo- Endpoints of resuscitation include normalization of serum
ride can help to discern between prerenal causes or renal causes lactic acid and base deficit. Measurement of the base deficit via
(hypoperfusions vs. ATN). The formula is presented below (269): an arterial blood gas analysis has become an effective means for
following response to resuscitation. Following large operations
FENa = (urine Na level serum Cr level) / (serum Na level
where patients are admitted to the ICU and where large, expected
urine Cr level) 100%
fluid shifts occur, the base deficit should be monitored serially
If the FENa is less than 1% and the urine specific gravity is until it has returned to normal. If a patient has a worsening base
greater than 1.025, the diagnosis is hypoperfusion. However, if deficit (i.e., becomes more negative), then a search for other prob-
ischemia has occurred, the FENa will be greater than 4% and the lems, such as ongoing hemorrhage, subacute anastamotic leak(s),
urine specific gravity will fall to 1.010 because of tubular dam- or tissue ischemia, must be made and be addressed before the
age and loss of renal concentrating mechanisms. One cannot base deficit will normalize. The base deficit should normalize
calculate FENa in patients who have received diuretics or hyper- within the first 24 hours after surgery.
osmotic agents (e.g., mannitol or contrast media). If prerenal In the case of continued or rapid bleeding, the obvious course
and renal causes of low urine output have been excluded, ultra- of treatment is reoperation. A number of options are now avail-
sonography may be useful in evaluating for outflow obstruction. able intraoperatively in these situations. Obvious bleeders are
Once the underlying causes for HARI have been elimi- controlled and ligated. Raw surfaces can be coagulated, treated
nated (e.g., hypoperfusion, obstruction, sepsis), only time can with fibrin sealants or absorbable hemostatic powders. Damage-
be offered as treatment. Therapies such as low-dose dopamine, control packing has been shown to increase survival in the dir-
furosemide, or mannitol administration, or atrial natriuretic est situations. Massive transfusion, defined as greater than 1.5
peptide use have not demonstrated prevention of or improved blood volumes, presents a number of additional problems. These
recovery from HARI (276281). Dialysis remains the only inter- patients will have a dilutional coagulopathy, hypocalcemia, and
vention that can support patients until return of renal function. hyperkalemia. After 6 to 8 red blood cell transfusions have been
Indications for dialysis include (a) hyperkalemia, metabolic aci- given in rapid fashion for massive bleeding, some would advocate
dosis, or volume expansion that cannot be controlled; (b) symp- empiric fresh frozen plasma and platelets. Platelet transfusion is
toms of uremia or encephalopathy; or (c) platelet dysfunction indicated for a platelet count <50,000 in the actively bleeding
inducing a bleeding diathesis (269). patient. The trauma literature supports the use of high product
ratio during massive transfusion to improve mortality; however,
this has yet to be demonstrated in the general surgical population
(283). Attention to delivery of warm transfusions is critical as
Shock hypothermia and acidosis will promote coagulopathy and wors-
Definition ening in bleeding. Once any of the lethal triad (hypothermia,
acidosis, and coagulopathy) is manifested then the operation
Shock is defined in its simplest terms as a decrease in tissue per- needs to be quickly terminated even if this means damage-control
fusion below the lowest metabolic needs of the tissue bed. This packing and transport to an ICU setting.
usually results in a depletion of stored energy and an increase
in anaerobic metabolism with a buildup of lactic acid in addi-
tion to other toxic waste products. Hypotension is incorrectly Cardiogenic Shock
thought of as a defining component of shock. Hypotension A patient with adequate preload who shows signs of poor per-
often leads to hypoperfusion, but the hypotensive patient is not fusion secondary to poor cardiac output is categorized as being
in shock until evidence of hypoperfusion occurs. Various types in cardiogenic shock. The etiology may be a decrease in con-
of shock exist. tractility (secondary to myocardial infarction) or an increase
in afterload (severe hypertension). Typically, pump failure
results in decreased stroke volume and backup of fluid into the
Hemorrhagic Shock pulmonary circulation. This leads to pulmonary edema and
The first thought for a surgeon managing a postoperative patient decreased oxygen delivery. The most common provocation for
who manifests signs and symptoms of shock is hemorrhage. pump failure is the over-administration of fluid in a patient with
CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE 179
compromised ventricular function. Treatment consists of diuresis agents depends on the epidemiologic characteristics of the par-
and optimization of cardiac output without increasing myocar- ticular ICU and host factors such as the severity of illness, infec-
dial oxygen demand (a difficult task). In the case where signifi- tion site(s), neutropenia, and organ dysfunction. Fluconazole
cant failure has led to hypotension, dopamine and dobutamine has excellent activity against Candida albicans, but infections
are usually the drugs of choice. The usage of these drugs was caused by Candida glabrata or Candida krusei must be treated
discussed previously. Digoxin is commonly used for increasing with amphotericin B or caspofungin. Amphotericin B should not
contractility, but its effects are minor in the acute setting. In addi- be used in patients with renal failure, and azoles and echinocan-
tion to inotropic support, correction of electrolyte disturbances dins (caspofungin) should be used with caution in patients with
(particularly potassium, calcium, and magnesium), maintenance hepatic dysfunction. Antifungal therapy should be continued
of proper systemic oxygen saturation, and analgesia are impor- for 14 days past the first negative blood culture for candidemia
tant factors in decreasing myocardial stress. or until clinical microbiological or radiographical resolution
of the infection (288). In addition to antifungal therapy, it is
generally recommended that all patients with candidemia have
Septic Shock a dilated eye exam by an ophthalmologist and that all catheters
Septic shock has commonly been defined as hypotension related to be removed if possible (although tunneled catheters are at less
infection with eventual organ failure secondary to hypoperfusion risk) (287).
despite adequate fluid resuscitation. This definition has changed
with that of SIRS and is discussed in the section on Sepsis and
Abdominal Infections
Sepsis and Systemic Inflammatory Gram-negative and gram-positive organisms as well as fungi
Response Syndrome cause systemic sepsis and septic shock. Early recognition is cru-
cial to patient survival because mortality rates are exceedingly
Inflammation is the bodys initial response to tissue injury pro- high if the full clinical picture of shock and organ dysfunction
duced by chemical, mechanical, or microbial stimuli. Inflamma- develops. Septic shock is divided into an early hyperdynamic
tion is an exceedingly complex cellular and humoral response state and a late hypodynamic state.
involving interaction between the complement, kinin, coagulation, Low systemic vascular resistance, splanchnic vasoconstric-
and fibrolytic cascades. The goal of inflammation is to enhance tion, and increased cardiac output characterize the hyperdynamic
the movement of nutrients and phagocytic cells to the injury site phase of shock. Venous capacitance is increased and results in
in order to prevent invasion of microbes and limit the extension diminished effectiveness of the circulating blood volume. Aggres-
of injury. As a local response, this is beneficial, but appropri- sive volume resuscitation must be provided to restore cardiac
ate regulation is necessary to prevent a pathologic, exaggerated preload and ventricular filling. These patients are best managed
systemic response, which is clinically identified as SIRS. Sepsis is in an ICU with the placement of an arterial line, a PA catheter,
the clinical syndrome of SIRS that is due to severe infection. The and a bladder catheter. Appropriate cultures should be obtained
mediator response in SIRS can be divided into 4 phases based on and intravenous broad-spectrum antibiotics should be started
the cytokine/cellular response: induction, triggering of cytokine within the first hour of recognition of severe sepsis. Laboratory
synthesis, evolution of cytokine and coagulation cascade, and tests of immediate concern include arterial blood gas determina-
elaboration of secondary mediators leading to cellular injury. The tions, creatinine, electrolytes, lactate, coagulation panel, and a
three most important mediators operating in SIRS appear to be complete blood count. Oxygenation and ventilation should be
tumor necrosis factor- (TNF-), interleukin-1 (IL-1), and inter- optimized with mechanical ventilation if indicated. If hypoten-
leukin-6 (IL-6). The microcirculation endothelium is the key tar- sion persists after optimization of the PCWP, the use of norepi-
get for injury in the sepsis syndrome (296). nephrine or dopamine may be necessary. Surgical debridement or
In 1992, the American College of Chest Physicians and the manipulation of infected material should not be performed until
Society of Critical Care Medicine published definitions for SIRS the patient has been stabilized.
and sepsis (Table 8.18) with the goal of standardizing terminol- Early goal-directed therapy of the septic patient has been
ogy to aid clinicians in the diagnosis and treatment and to aid shown to improve survival. During the first 6 hours of resusci-
in the interpretation of research in this field (297). Many have tation, the goals of therapy as outlined by the Surviving Sepsis
criticized the 1992 consensus definitions as too nonspecific to Campaign guidelines include CVP of 8 to 12 mm Hg, mean
be of use. In 2001, a group of experts reconvened and expanded arterial pressure 65 mm Hg, urine output 0.5 mL/kg/hour,
the list of signs and symptoms of sepsis to reflect clinical bedside and central venous or mixed venous oxygen saturation 70%. If
experience. In addition to the original criteria, altered mental during the first 6 hours oxygen saturation goals are not achieved
status, oliguria, skin mottling, coagulopathy, hypoxemia, hyper- despite appropriate CVP, then transfusion of red blood cells to
glycemia in the absence of diabetes, thrombocytopenia, and achieve a HCT >30% and/or initiation of a dobutamine infu-
altered liver function tests can also be used to establish the diag- sion is the next step (301).
nosis of sepsis (298). In the hypodynamic phase of septic shock, hypotension results
The host response, more than the pathogen, is the primary from cardiac output deterioration. The patient is often cool,
determinant of patient outcome. Failure to develop a fever, leu- mottled, oliguric, diaphoretic, and confused. The etiology of the
kopenia, and hypothermia are associated with increased fatality hypodynamic cardiovascular response to sepsis may be inadequate
rates in patients with sepsis and are thought to represent abnor- volume resuscitation, underlying cardiac disease, or myocardial
malities in the hosts inflammatory response. Other risk factors dysfunction associated with sepsis. This is a state of gross decom-
for mortality from sepsis include age greater than 40, underlying pensation with global tissue hypoxia and is associated with greater
medical conditions, malnutrition, immune suppression, and can- mortality.
cer. The presence or absence of a positive blood culture does not Numerous clinical trials have attempted to find specific
influence outcomes; however, sepsis due to a nosocomial infection agents that could modulate the underlying disease process in
has a higher mortality than community-acquired infection (299). sepsis. Candidate therapies included agents that target media-
Sepsis with acute organ dysfunction (severe sepsis) is a com- tors of inflammatory response, agents that boost the immune
plex condition that represents a major challenge to the critical care system, and prostaglandin inhibitors, but none was shown to be
team and carries a crude mortality rate of 28% to 50% (300). beneficial. One such agent, drotrecogin alfa (activated-Xgris),
is a recombinant form of human activated protein C, an endog-
enous protein with antithrombotic, pro-fibrinolytic, and anti-
Table 8.18 Definitions for Systemic Inflammatory inflammatory properties that is frequently deficient in sepsis.
Although initial studies (The Recombinant Human Activated
Response and Sepsis (SIRS)
Protein C Worldwide Evaluation in Severe Sepsis-PROWESS)
SIRS Two or more of the following in the setting of showed a clinically significant reduction in the 28-day all-cause
aknown cause of inflammation: mortality rate due to severe sepsis (302), results from a sub-
sequent trial, the PROWESS-SHOCK trial, failed to demon-
Temperature >38C or <36C
Pulse >90 strate any significant benefit in 28-day all-cause mortality. The
Respirations >20/min or Paco2 <32 mm Hg drug was subsequently withdrawn from the market in October
WBC count >12,000 or <4000 cells/mm3 or >10% 2011 (303).
band forms In addition to early goal-directed therapy with hemodynamic
interventions that balance systemic oxygen delivery with oxygen
Sepsis SIRS due to known infection
demand, other management strategies have shown in randomized,
Severe sepsis Sepsis with evidence of organ dysfunction, controlled trials to reduce mortality associated with severe sepsis.
hypoperfusion, or hypotension These include limiting the tidal volume to 6 to 7 mL/kg ideal body
Septic shock Sepsis with hypotension despite adequate fluid weight for patients requiring mechanical ventilation for ARDS,
resuscitation the use of moderate-dose corticosteroids (hydrocortisone 200 to
300 mg and fludrocortisone 50 g daily) for 7 days in patients
Source: Adapted from 1991 American College of Chest Physicians/Society of with refractory septic shock, and maintaining serum glucose levels
Critical Care Medicine Consensus Conference definitions, with permission. <180 mg/dL (301). These therapies are not mutually exclusive,
CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE 181
and optimal patient management may require a combination prediction models were designed as tools to be used in critical
of approaches. Some of these strategies vary dramatically from care research in order to stratify patients by severity of illness.
traditional approaches and will require education and established They have not been validated for making decisions relating to
protocols to safely incorporate them into practice. individual patients.
Abdominal compartment syndrome (ACS) is an important
but often unrecognized cause of acute deterioration of a patient
Multiple Organ Dysfunction Syndrome after massive fluid resuscitation for septic or hypovolemic shock.
Although ACS can impair the function of every organ system, it
Multiple organ dysfunction syndrome (MODS) is defined as the
is generally manifested as hypotension, reduced urine output,
development of progressive physiologic dysfunction of two or
and decreased pulmonary compliance. Most commonly associ-
more organ systems after an acute threat to systemic homeo-
ated with trauma patients, it has also been observed in patients
stasis (297). An acute threat can include SIRS, sepsis, massive
with massive ascites, bowel obstruction or ileus, peritonitis,
trauma, burns, ischemia, or reperfusion injury. Patients usually
pancreatitis, and intraperitoneal blood. Intra-abdominal pres-
present with pulmonary dysfunction, which typically develops
sure (IAP) is usually measured indirectly by a balloon-tipped
early in the course of SIRS or sepsis. Renal dysfunction will pres-
catheter in the bladder. Intra-abdominal hypertension is defined
ent as a prerenal azotemia unless the initial insult stimulated
as an IAP of 12 mm Hg or greater recorded by a minimum of
a sudden oliguric acute tubular necrosis. Hyperbilirubinemia is
3 standard measurements conducted 4 to 6 hours apart (307).
the earliest indication of hepatic dysfunction. Gastrointestinal
ACS is defined by an IAP of 20 mm Hg or greater and single or
abnormalities include ileus, stress ulcers, diarrhea, and mucosal
Norepi, norephinephrine; Dob, dobutamine; Dop, dopamine; Epi, epinephrine; FIO2, fraction of inspired oxygen; PaO2, partial pressure oxygen.
a
Values are with respiratory support.
b
To convert bilirubin from mg/dL to mol/L, multiply by 17.1.
c
Adrenergic agents administered for at least 1 hour (doses given are in g/kg per minute).
Source: From Ferreira FL, Bota DP, Bross A, et al. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001;286:17541758, with
permission.
182 CHAPTER 8 PERIOPER ATIVE AN D CRITICAL CARE
Analgesia Sedation
Pain management for critically ill patients is a universal goal To further combat anxiety and agitation associated with hospi-
for all involved in their care. Patients who are not satisfied with talization and pain, sedatives are commonly added to routine
the treatment they receive for pain may become more stressed medication administration. The physical environment of the
and irritable, sleep less, and have a poor opinion of the care ICU, limited ability to communicate, sleep deprivation, and
they are receiving on the whole. Pain may contribute to pul- medical circumstances precipitating the ICU admission are con-
monary dysfunction through localized guarding and general- tributing factors creating anxiety in critically ill patients. Efforts
ized muscle rigidity that restricts movement of the chest wall to reduce anxiety, including frequent reorientation, provision of
and diaphragm. Unrelieved pain also evokes a stress response adequate analgesia, and optimization of the environment, may
characterized by tachycardia, increased myocardial oxygen con- be supplemented with sedatives. Agitation is also common in
sumption, hypercoagulability, immunosuppression, and persis- ICU patients; however, not all patients with anxiety will exhibit
tent catabolism (310). The combined use of effective analgesia agitation. Sedatives reduce the stress response and improve
and sedation may ameliorate the stress response and diminish tolerance to routine ICU procedures. For example, the use of
pulmonary complications in postoperative critically ill patients. sedation medication may be necessary to facilitate mechanical
A comprehensive overview of pain management is covered in ventilation. Generally, sedatives should be administered inter-
Chapter 32; therefore, only key aspects of pain management mittently to determine the dose needed to achieve the sedation
applicable to patients in the ICU will be addressed. goal, but they may be given as a continuous infusion if necessary.
Pharmacologic therapies include opioids, NSAIDs, and Daily interruption of sedative infusion is associated with shorter
acetaminophen. ASHP guidelines recommend fentanyl, hydro- duration of mechanical ventilation, shorter ICU stays, and fewer
morphone, and morphine given as a continuous infusion or instances of posttraumatic stress disorder (311,312). Benzodiaz-
scheduled doses rather than as needed. Fentanyl has the most epines are sedatives and hypnotics that cause anterograde amne-
rapid onset and shortest duration, but repeated dosing may sia but lack analgesic properties. Midazolam has a rapid onset
cause accumulation and prolonged effects. Fentanyl may also and short duration of effect with single doses, making it ideal
be administered via a transdermal patch to hemodynamically for treating acutely agitated patients or for brief sedation with
stable patients with more chronic analgesic needs, but it is not invasive procedures. Lorazepam has a slower onset but fewer
recommended for the management of acute pain. Morphine potential drug interactions because of its metabolism via gluc-
has a quick onset but longer duration of action, so intermit- uronidation (Table 8.20).
tent doses may be given. However, morphine causes histamine Propofol is an intravenous general anesthetic that has seda-
release, which contributes to hypotension, especially in a hemo- tive and hypnotic properties at lower doses. Like the benzodi-
dynamically unstable patient. Hydromorphones duration of azepines, propofol has no analgesic properties. Propofol has a
action is similar to morphine but lacks an active metabolite rapid onset and short duration of sedation once discontinued.
or histamine release, making it an ideal drug for continuous Propofol is a phospholipid emulsion that provides 1.1 kcal/mL
infusion and for use in patients who cannot tolerate hypo- from fat and should be counted as a caloric source. Long-term
tension. Meperidine has an active metabolite that causes infusions may result in hypertriglyceridemia and monitor-
neuroexcitation including apprehension, tremors, delirium, and ing is recommended after 2 days of use (308). Physiologic
seizures, so its use is not recommended in critically ill patients dependence and potential withdrawal symptoms have been
who may need repeated doses. The characteristics of analgesics described in ICU patients who have been exposed to more than
and sedatives commonly used in ICU patients are summarized 1 week of sedative or narcotic therapy, including the use of
in Table 8.20. propofol(313).
Table 8.20 Characteristics of Selected Analgesics and Sedatives Frequently Used in Critically Ill Patients
Active Metabolites
Agent Indication (Effect) Adverse Effects Intermittent Dose (IV)a Infusion Dose Range
Fentanyl Pain No metabolite, Rigidity with high doses 0.351.5 g/kg q 0.51 h 0.710 g/kg/h
patient
accumulates
Hydromorphone Pain None 1030 g/kg q 12 h 715 g/kg/h
Morphine Pain Yes (sedation) Histamine release 0.010.15 mg/kg q 12 h 0.070.5 mg/kg/h
Ketorolac Pain None GI bleeding, renal 1530 mg q 6 h; decrease
if >65 yr; avoid >5 day use
Midazolam Acute agitation Yes (prolonged 0.020.08 mg/kg q 0.040.2 mg/kg/h
sedation) 0.52 h
Lorazepam Sedation None Solvent-related acidosis/ 0.020.06 mg/kg q 26 h 0.010.1 mg/kg/h
renal failure in high
doses
Propofol Sedation None Elevated triglycerides 580 g/kg/min
Haloperidol Delirium Yes (EPS) QT interval prolongation 0.030.15 mg/kg q 0.040.15 mg/kg/h
0.56 h
Neuromuscular Blockade
Table 8.21 Commonly Used ICU Drugs
Neuromuscular blocking agents (NMBAs) can be used in con- Associated with Deliriuma
junction with sedatives to facilitate mechanical ventilation, to
manage intracranial pressure in head trauma, to ablate muscle Anesthetics Anticonvulsants Atropineb
spasms, and to decrease oxygen consumption only when all
other means to accomplish these aims have failed (309). Pan- Lidocaine Carbamazepine Cimetidineb
curonium is a long-acting NMBA that is effective for up to Propofol Phenobarbital Corticosteroidsb
90 minutes after intravenous bolus dose of 0.06 to 0.1 mg/kg.
It can be used as a continuous infusion by adjusting the dose Phenytoin Digoxinb
to the degree of neuromuscular blockade that is desired. Since Antibiotics
pancuronium is vagolytic, 90% of patients will have an increase
in heart rate of greater than 10 beats per minute. For patients Amphotericin B Antihypertensives Narcotic analgesics
who cannot tolerate an increase in heart rate, vecuronium can Aztreonam Diltiazem Fentanyl
be used. If neuromuscular blockade is necessary for patients
with significant hepatic or renal failure, cisatracurium or atra- Cephalosporins Enalapril Meperidineb
curium should be used. Patients receiving any NMBA should Ciprofloxacin Hydralazine Morphine
be assessed using electronic twitch monitoring with a goal of
Doxycycline Methyldopa
have the responsibility to help identify the person or persons goals of care. For example, a goal for survival until the patients
who have knowledge of the patients values and preferences in important loved ones can gather to say their good-byes may
order to assist with medical decisions on the patients behalf. justify short-term continuation of ventilator support. If the only
This process can become difficult in circumstances when family goal is patient comfort, then such treatment should be stopped.
members or others close to the patient are in disagreement as to The withdrawal of life-sustaining treatment is a clinical pro-
who should be the surrogate or what the patient would prefer. cedure that deserves the same preparation and expectation of
In these cases, health care providers should be knowledgeable quality as other medical procedures. Honest, caring, and cul-
of applicable legal directives and their ethical responsibility to turally sensitive communication with the patients loved ones
act in their patients best interest. Consultation with the institu- and the patient, if competent, should include explanations of
tions ethics committee may be helpful in trying to reach con- how therapies will be withdrawn, what symptoms are expected,
sensus (319). Although not responsible for the patients death, strategies to assess and ensure the patients comfort, and infor-
those close to the patient often are left with feelings of guilt and mation about the expected survival after interventions are with-
anxiety in addition to their bereavement. It is important that the drawn. Informed consent should be documented along with a
health care providers support the family both before and after formulated plan for withdrawing care (320). Adequate analge-
the decision to withhold or withdraw life-sustaining treatment sia and sedation should be prescribed to relieve symptoms of
has been made, not imparting any personal bias. pain, dyspnea, and anxiety during the dying process. Intrave-
End-of-life care of patients in the ICU requires a dramatic nous opioids and shorter acting benzodiazepines are the drugs
paradigm shift in attitude and interventions from intensive res- of choice. The clinicians primary goal should be to prevent suf-
cue-type care to intensive palliative care. When considering the fering and ensure the patients comfort even if doing so uninten-
array of interventions that may be discontinued or held, phy- tionally hastens the patients death. For this reason, palliative
sicians and surrogates should focus on clearly articulating the care teams might be useful (320).
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The management of most human cancers involves multimodal oncology as a career must be completely familiar with the pelvis,
therapy, and this is especially true for female genital malignan- abdomen, retroperitoneum, and the lymphatic drainage of the
cies. Although some early gynecologic cancers can be eradicated female genital tract. No amount of surgical skill or knowledge of
by surgery alone, and chemotherapy as a single modality can cancer therapy can compensate for the lack of this knowledge.
often cure gestational trophoblastic malignancies, the optimal Lymphatic drainage from the cervix follows the uterine
treatment for the majority of gynecologic malignancies requires arteries and cardinal ligaments to the pelvic lymph nodes that in-
surgery combined with chemotherapy and/or irradiation. clude the external iliac, internal iliac (hypogastric), and obturator
In this chapter, surgery is discussed both as a separate disci- node groups (Fig. 9.1). From these pelvic lymph nodes, the drain-
pline and as an integral part of multimodal therapeutic planning. age proceeds superiorly through the common iliac and presacral
Although specific operations and relatively new surgical tech- lymph nodes and then up to the paraaortic nodes.
niques are described for some disease sites, many procedures are The lymphatic drainage from both the uterine corpus and the
addressed more completely in surgical texts and atlases to which ovaries follows one of three routes (Fig. 9.1): (a) along the uterine
the reader is referred (13). The role of surgical intervention in arteries in the broad ligaments to the pelvic nodes, (b) in channels
the treatment of gynecologic cancers is addressed herein with following the round ligaments to the inguinal lymph nodes, or (c)
a more philosophic approach than would be taken in a surgi- along the ovarian lymphatics in the infundibulopelvic ligaments
cal atlas. However, select illustrations and tips are included that directly up to the paraaortic nodes.
have enabled us to approach various radical procedures more The anatomy of the paraaortic lymph nodes has been well
confidently and safely. The major goal of this chapter is to give described by Fowler and Johnson (4). The paraaortic lymph
the reader an appreciation and understanding of the surgical nodes are part of the lumbar lymph node group. Usually, six
principles of the subspecialty of gynecologic oncology. subgroups of retroperitoneal nodes in the paraaortic region are
recognized: paracaval, retrocaval, interaorto-caval, preaortic,
paraaortic (left side), and retroaortic. The preaortic group drains
the abdominal part of the gastrointestinal tract down to the mid
TECH N ICAL ASPECTS OF SU RGERY rectum, whereas the retrocaval and retroaortic groups have no
special area of drainage. The paracaval, interaorto-caval, and
Many physicians who practice the art and science of surgery tend paraaortic (left side) nodes receive lymphatic drainage from the
to focus on the technical craft of the specialty only when teach- iliac lymph nodes, ovaries, and other pelvic viscera (apart from
ing young surgeons. At other times, we are acutely aware that the alimentary tract), and therefore it is these groups of nodes
the most difficult part of our practice is the decision of whether that are sampled in the surgical staging of gynecologic malignan-
or not to utilize surgical therapy. Preoperative and postoperative cies. However, systematic paraaortic lymphadenectomy should
management is also demanding since therapy must be tailored for address all major regions, including paracaval, retrocaval, inter-
individual patients depending not only on their specific disease aorto-caval, preaortic, paraaortic, and retroaortic nodes.
but also on their overall medical status. Owing to the significance There are typically 15 to 20 paracaval and paraaortic nodes
of these pressing issues, we often take for granted the many years per side. They are located adjacent to the inferior vena cava
of preparation and experience in the craft of surgery. (IVC) and aorta, anterior to the lumbar spine, extending bilater-
Mastering the skills of surgery involves a thorough understand- ally to the medial margins of the psoas major muscles, and up to
ing of proper technique. It also requires frequent and consistent the diaphragmatic crura (4). The paracaval and paraaortic nodes
practice to keep surgical maneuvers well honed. For the student, usually dissected in gynecologic oncology span the region from
this means actual practice in tying knots, manipulating instru- the aortic bifurcation up to either the inferior mesenteric artery
ments, and suturing. For the accomplished surgeon, it means that (IMA) or the renal veins.
a sufficient case load must be maintained to ensure adequate prac- The first major blood vessel encountered during a caudad-
tice of the technical art of the specialty. The surgeon should also to-cephalad paraaortic node dissection is the IMA (Fig. 9.1). The
keep abreast of new suture materials, instruments, and technical IMA originates from the anterior surface of the aorta, approxi-
developments. mately 3 to 4 cm above the aortic bifurcation. Next, the right and
left ovarian arteries arise from their respective sides of the aorta,
about 5 to 6 cm above the bifurcation (Fig. 9.1). The right ovarian
vein inserts into the right side of the inferior vena cava (IVC),
Anatomy approximately 1 cm below the right renal vein. The left ovarian
There is no substitute for a detailed knowledge of the anatomy of vein does not insert directly into the IVC, rather follows a path
the pelvis and abdomen. The physician who pursues gynecologic close to the left ureter inserting into the left renal vein lateral to
190
CHAPTER 9 SU RGICAL PRI NCI PLES I N GYN ECOLOGIC ONCOLOGY 191
IVC Aorta
Left kidney
Superior mesenteric
artery
Left ureter
Inferior mesenteric
artery
Right ureter
Left common iliac
artery and vein
Hypogastric
artery and nodes
External iliac
nodes Uterosacral
ligament
Rectum Bladder Uterus FIGURE 9.1. The pelvic and paraaortic lymph nodes
and their relationship to the major retroperitoneal vessels.
the left border of the aorta. Three to four pairs of lumbar arteries reflects primarily to the diaphragm; the posterior left coronary
and veins arise from the posterior surfaces of the aorta and IVC, ligament lies higher than the esophageal hiatus and the esopha-
respectively. gus is generally not encountered. The coronary ligaments on each
The gynecologic oncologist who operates on patients with ad- side delineate the larger bare area of the liver on the right and a
vanced ovarian carcinoma often encounters disease being spread smaller bare area on the left, which underlie the central tendon
across upper abdominal structures such as the diaphragm, liver, of the diaphragm. The right phrenic nerve penetrates this central
pancreas, and spleen. Debulking of tumor from these areas has tendon lateral to the vena caval foramen on the right and is usu-
been demonstrated to improve the rate of optimal cytoreduc- ally not encountered until the bare area is exposed. The left
tion and subsequent survival (5,6). Anatomic considerations for phrenic nerve may penetrate the left diaphragm muscle above the
diaphragm surgery include the relevant hepatic attachments and central tendon and is a consideration during left-sided anterior
the underlying central vasculature (7,8) (Fig. 9.2). The anterior diaphragm surgery.
hepatic attachment is the falciform ligament, which contains the In the left upper quadrant of the abdomen, the spleen lies un-
ligamentum teres in its infrahepatic portion, and attaches the der the 9th, 10th, and 11th ribs. It is situated adjacent and slightly
liver to the anterior abdominal wall in its membranous hepatic deep to the stomach and colon, lateral to the pancreas, and sits
portion. As the falciform ligament continues superiorly, its peri- on the superior aspect of the left kidney. The posterior aspect of
toneal surface divides laterally on each side to form the ante- the spleen is in contact with the adrenal gland as well as Gerotas
rior right and left coronary ligaments. These coronary ligaments fascia of the kidney. The tail of the pancreas often approaches
reflect off the liver capsule and delineate the posterior extent of the splenic hilum and sometimes contacts the spleen. The spleen
peritoneum covering the superior diaphragm. The IVC lies to the varies in size between individuals, but in general measures 12 cm
right side of this falciform ligament division. The right and left in length, 7 cm in width, and 3 to 4 cm in depth. The peritoneum
hepatic veins drain into the anterior surface of the IVC at the creates folds that form the suspensory ligaments of the spleen. The
level of this peritoneal reflection. The anterior coronary ligaments four main suspensory ligaments are gastrosplenic, splenorenal,
continue laterally and inferiorly along the posterior liver edge, splenophrenic, and splenocolic ligaments. The splenophrenic and
where they join the posterior right and left coronary ligaments splenocolic ligaments are avascular. The gastrosplenic ligament
to form the right and left triangular ligaments, respectively. The contains the short gastric vessels. The splenorenal ligament has
right triangular ligament reflects from the liver to the diaphragm, an anterior and posterior aspect and surrounds the splenic hilum.
right kidney, and right adrenal gland. The left triangular ligament The splenic hilum contains the splenic artery, splenic vein, and
192 CHAPTER 9 SU RGICAL PRI NCI PLES I N GYN ECOLOGIC ONCOLOGY
Falciform
lig.
Gastrophrenic
IVC lig.
en
lee
le
Gastrohepatic lig. Sp
Sp
(lesser omentum) Stomach
Hepatoduodenal Splenorenal
lig. lig.
Gastrosplenic
lig.
Greater
omentum
FIGURE 9.2. Peritoneal reflections of the liver: the lesser omentum (hepatogastric and hepatoduodenal ligaments) and
its relation to the coronary ligament of the liver and diaphragm.
Source: Reprinted with permission from Skandalakis JE, Gray SW, Rowe JR, eds. Anatomical Complications in General Surgery. New York, NY: McGraw-Hill; 1983.
sometimes the tail of the pancreas. The splenic vessels sometimes intraperitoneal exposure (Fig. 9.5) (2). Additionally, extraperito-
branch before entering the spleen. The splenic artery is tortuous neal access to the pelvic and paraaortic nodes can be achieved
and is one of the three branches of the celiac trunk. It runs along through a J-shaped incision (10) or a sunrise incision (11).
the superior aspect of the pancreas and gives rise to the short Transverse incisions offer the advantages of being the best
gastric arteries prior to entering the spleen, which course in the cosmetic incisions for pelvic surgery while also being the least
gastrosplenic ligament and supply the portion of the greater cur- painful, resulting in less interference with postoperative pulmo-
vature of the stomach, superior to the splenic artery (Fig. 9.3) (9). nary function. In addition, compared to vertical incisions, trans-
The splenic artery also gives rise to the left gastroepiploic artery, verse incisions are allegedly stronger and allow better exposure
which supplies the remainder of the greater curvature of the to the pelvic sidewalls. Many gynecologic oncologists use trans-
stomach and the gastrocolic omentum. The splenic vein is slightly verse incisions when performing a radical hysterectomy or pelvic
inferior and follows the course and branching of the artery. exenteration.
In performing the Maylard incision, it is recommended that
the deep inferior epigastric vessels be isolated, sectioned, and
ligated prior to dividing the rectus muscle (Fig. 9.6) (2). Occa-
Patient Positioning sionally, the pelvic surgeon will make a Pfannenstiel incision and
Patient positioning for radical gynecologic oncology procedures find it inadequate. When more exposure is needed, the appropri-
is often critical in improving exposure, particularly in obese ate maneuver is to convert the Pfannenstiel to a Cherney-type
patients. For most women undergoing radical hysterectomy, incision. This conversion can be accomplished by dissecting the
ovarian cancer cytoreduction, or pelvic exenterative proce- rectus muscles from the pyramidalis muscles and the anterior
dures, we prefer the low lithotomy position using Allen stirrups rectus sheath, and then transecting the rectus tendons at their
(Fig. 9.4) (1). The buttocks should extend 2 to 3 cm over the insertion into the pubic bone.
end of the table. This position allows simultaneous access to
the perineum and abdomen. The weight of the leg should be on
the foot with the legs well padded and attention paid to prevent Lymph Node Dissection
pressure on the calf and the peroneal nerve. To further improve
pelvic exposure, a blanket or pad can be placed under the small The surgical technique used to dissect the pelvic and paraaortic
of the back. lymph nodes involves either a transperitoneal or extraperitoneal
approach. The approach utilized is generally dictated by the pri-
mary site of disease and the planned accompanying procedure.
In cases of endometrial and ovarian carcinoma where the antici-
Abdominal Incisions pated procedure includes a hysterectomy and/or surgical debulk-
Abdominal incisions in gynecologic oncology vary with the ing, the approach is invariably transperitoneal. However, in the
indication for the procedure, associated preoperative conditions pretreatment surgical staging of patients with advanced-stage
(such as the presence of ascites or bowel obstruction), suspicion of cervical cancer, the transperitoneal approach has been associated
upper abdominal pathology, and the presence of a previous abdom- with significant radiation-induced intestinal morbidity due to
inal scar. Incisions for surgery for gynecologic oncology patients postoperative adhesion formation (12). Therefore, current clinical
should be highly individualized. Three basic incisions are used for trials that require pretreatment surgical staging recommend that
CHAPTER 9 SU RGICAL PRI NCI PLES I N GYN ECOLOGIC ONCOLOGY 193
Transverse
anastomosis
Transverse
anastomosis
Hepatic
artery
Penultimate
Inferior polar
arteries
2 1
3
Genitofemoral nerve
Right colon
Circumflex iliac vein
External iliac Right ureter
artery and vein
Obturator
nerve
Common
iliac vessels
Duodenojejunal
flexure
Cecum
Peritoneal
incision Inferior mesenteric
artery
Vena cava
Aorta
Right ureter
FIGURE 9.11. Extended peritoneal incision. The peritoneal incision is extended over the right ureter around the cecum and
cephalad along the right paracolic gutter.This allows for mobilization of the small bowel mesentery as well as the ascending colon.
Source: Reprinted with permission from Fowler JM, Johnson PR. Transperitoneal para-aortic lymphadenectomy. Oper Tech Gynecol Surg 1996;1:9.
of the right colon (Fig. 9.11) (4). The small bowel can then be
packed into the upper abdomen or completely removed from the
peritoneal cavity and stabilized outside of the abdominal cavity
or put into a bowel bag outside the abdomen. The duodenum is
retracted superiorly, allowing identification and ligation of the
right ovarian artery and vein. The lymphatic tissue can then be
safely dissected off of the right side of the aorta and the anterior
surface of the IVC up to the level of the renal veins.
The left paraaortic lymph nodes may be removed through the
same peritoneal incision. Sharp dissection is used to identify the
left common iliac artery, left side of the aorta, IMA, left ureter,
and left psoas muscle (Fig. 9.12). The ureter is again mobilized
laterally. The lymphatic tissue lateral to the left common iliac
artery and aorta is then removed in a caudad-to-cephalad direc- Right ureter Inferior mesenteric
tion. The left paraaortic lymph nodes lie lateral and partially artery
behind the aorta. In dissecting these nodes, judicious use of vas-
cular clips or the use of electrosurgery will help prevent trou-
blesome bleeding from the lumbar vessels. Safe removal of the
lymph nodes above the IMA frequently requires identification Right ovarian
and division of the left ovarian artery and vein, and occasionally Left ureter
artery and vein
ligation of the inferior mesenteric artery. Left ovarian
To remove right-sided paraaortic nodes via the lateral artery and vein
approach, the right paracolic gutter is incised along the line
of Toldt (Fig. 9.13). The peritoneum is elevated off the psoas
muscle and the incision is extended up to the hepatic flexure of
the colon. Using sharp and blunt dissection, the right colon is
reflected medially. The ureter and ovarian vessels can be identi-
fied attached to the undersurface of the reflected peritoneum. FIGURE 9.12. Removal of the left paraaortic nodes through the same
They may be left attached or mobilized laterally for better peritoneal incision. The dissection also proceeds in a cephalad direction,
exposure. Further medial mobilization of the colon exposes again using hemostatic clips on the lateral and medial margins. Care should
the IVC and aorta. With the essential structures identified, the be taken to avoid injury to the inferior mesenteric artery that arises
lymphatic tissue can then be dissected as previously described approximately 3 to 4 cm above the aortic bifurcation.
CHAPTER 9 SU RGICAL PRI NCI PLES I N GYN ECOLOGIC ONCOLOGY 197
Gallbladder
Liver
Duodenum
Kidney
Right colon
Liver
Right colon
Gallbladder
Left paracolic
gutter
Left colon
Aorta
Right ureter
Right ovarian
artery and vein
FIGURE 9.14. With the ureter and ovarian vessels identified, the dissection
begins at the right common iliac artery and proceeds cephalad up to the third FIGURE 9.16. The lateral approach to the left paraaortic nodes is accomplished
portion of the duodenum. by retracting the descending colon medially and incising along the line of Toldt.
198 CHAPTER 9 SU RGICAL PRI NCI PLES I N GYN ECOLOGIC ONCOLOGY
Renal vein
Kidney
Left ureter
6 cm
Inferior
mesenteric
artery
FIGURE 9.17. Using sharp and blunt dissection, the left colon can be FIGURE 9.19. The sunrise incision. In the center, the incision is
mobilized medially, exposing the left ureter, ovarian vessels, and aorta. approximately 6 cm above the umbilicus. The incision is carried laterally in a
downward fashion to the level of the iliac crests.
Source: Reprinted with permission from Gallup DG, Talledo OE. Surgical Atlas of Gynecologic Oncology.
Again, the ureter and ovarian vessels are identified on the un- Philadelphia, PA: WB Saunders Co.; 1994:118.
dersurface of the reflected peritoneum, and they may be left
attached or mobilized laterally for better exposure (Fig. 9.17). above the IMA requires mobilization of the splenic flexure of the
After further mobilization of the left colon and identification colon, division of the left ovarian artery and vein, and occasion-
of the aorta and the IMA, the left-sided nodes are removed in a ally ligation of the inferior mesenteric artery.
caudad-to-cephalad direction (Fig. 9.18). Dissection of the nodes
Extraperitoneal Approach to the Paraaortic
Nodes
The extraperitoneal approach to the paraaortic lymph nodes by
means of a supraumbilical transverse sunrise incision was initially
described by Gallup et al. (11). The skin incision is made 6 cm
above the umbilicus in the midline and is carried laterally and
caudad to the level of the iliac crests bilaterally (Fig. 9.19) (2).
The fascia is incised transversely. The rectus muscles are dis-
Renal vein sected off of the anterior-lying fascia cephalad and caudad. The
right rectus muscle is transected. The right transversus muscle is
Kidney then identified and transected caudally and laterally. The hand of
the operator is inserted deep into the incision until the right psoas
muscle and external iliac vessels are palpated. The peritoneum is
then bluntly dissected from caudad and lateral to cephalad and
Inferior medial, separating it from the underlying common iliac vessels
mesenteric
until the great vessels are exposed (Fig. 9.20) (2). If the perito-
artery
neum is inadvertently entered, it must be closed immediately.
After identification of the right ureter and ovarian vessels,
the right paraaortic nodes can be removed. In thin patients, the
left paraaortic nodes may be able to be removed through a right
abdominal approach. However, if exposure is difficult, the left
rectus and transversus muscles can be transected and the perito-
neum mobilized medially in a similar fashion to gain access to
the left paraaortic nodes.
FIGURE 9.18. Dissection begins at the left common iliac artery and
Radical Hysterectomy
proceeds cephalad using hemostatic clips. Care should be taken to avoid injury Although radical hysterectomy is a traditional procedure in gyn-
to the inferior mesenteric artery that arises approximately 3 to 4 cm above ecologic oncology, with a history of almost 100 years, its per-
the aortic bifurcation. formance is still poorly standardized. Different terminology and
CHAPTER 9 SU RGICAL PRI NCI PLES I N GYN ECOLOGIC ONCOLOGY 199
FIGURE 9.22. Resection lines for types B, C1, and C2 radical hysterectomy FIGURE 9.24. Resection lines for types B, C1, and C2 radical hysterectomy
on the lateral parametrium. A. paravesical space; B. vaginal vein; C. internal on the dorsal parametrium after dissection of the mesoureter from the
iliac vein; D. uterine vein; E. uterine artery; F. pararectal fossa. sacrouterine ligament. A. ureter; B. mesoureter; C. space between the
sacrouterine ligament and mesoureter; D. branches of the hypogastric plexus
(white strips); E. sacrouterine ligament; F. cervix.
between the ureter and the sacral bone), containing major branches
of the hypogastric plexus, is separated laterally from the uterosac-
ral ligament, which allows for an adequate resection of the lat- parametrium is completely separated from the pelvic side wall
ter. On the lateral parametrium, the caudal resection margin is until the sacral bone is reached. On the ventral parametrium the
indicated by the vaginal vein, the largest parametrial vein, which ventral resection margin is formed by the urinary bladder. As a
guarantees the preservation of splanchnic nerves in the caudal part consequence, major branches of vegetative nerves are sacrificed
of the lateral parametrium. Ventrally, the ureter is only partially during the C2 type procedure.
dissected from the ventral parametrium, allowing for limited resec-
tion of the proximal supraureteral part of the ventral parametrium.
The radicality of the C2 procedure, which corresponds to the
type III radical hysterectomy, is different from the nerve spar- Ovarian Cancer Debulking
ing procedure, aiming at removal of the majority of all three The goal of ovarian cancer debulking or cytoreduction is to
parametrial parts (Figs. 9.22, 9.23, and 9.24). The C2 procedure remove all or as close as possible to all grossly visible and palpa-
requires complete dissection of the ureter from the lateral and ble tumor (17). The surgeon operating on patients with advanced
ventral parametria and deeper dissection of the rectum from the ovarian cancer should be familiar with the techniques used to
dorsal parametria. The resection line on the dorsal parametria clear tumor from the pelvis and the upper abdomen.
is deep below the former rectal attachment, causing unavoid-
able damage of the hypogastric plexus, so the dissection of the
Removal of Pelvic Disease
nerve from the uterosacral ligament is not required. The lateral
Ovarian malignancy often presents with large pelvic masses fill-
ing the pelvis. An initial incision over the lateral pelvic sidewall
just anterior to the external iliac artery will allow adequate
visualization of the ureter and the ovarian vessels (Fig. 9.25).
The paracolic gutters can be incised cephalad along the avascu-
lar line of Toldt for more adequate exposure of the retroperito-
neal space. To avoid further troublesome hemorrhage with large
adnexal masses, if a hysterectomy is part of the planned proce-
dure, the uterine vessels can be separately isolated and divided
similar to a modified radical hysterectomy. When the anatomy
is distorted by peritoneal implants, the ureters may need to be fol-
lowed down to the tunnel and retracted laterally prior to removal
of the uterus.
In cases where the pouch of Douglas is deeply infiltrated by
disease, especially if it involves the rectosigmoid colon, a reverse
hysterectomy can facilitate complete removal of the infiltrated
peritoneum and help identify the rectovaginal plane sparing
a larger part of the rectum for further anastomosis. The term
modified posterior exenteration is commonly used for the above
procedure, as it aims at en bloc removal of the uterus, adnexa,
infiltrated peritoneum, and the rectum. The procedure starts
with the incision of the vesical peritoneal plica and dissection
FIGURE 9.23. Resection lines for types B, C1, and C2 radical hysterectomy of the urinary bladder down to the level of the vaginal fornix.
on the ventral parametrium. A. paravesical space; B. umbilical ligament; In cases of carcinomatosis on the peritoneal plica, a ventral peri-
C. ureter. tonectomycomplete dissection of the infiltrated peritoneum
CHAPTER 9 SU RGICAL PRI NCI PLES I N GYN ECOLOGIC ONCOLOGY 201
FIGURE 9.25. The ovarian vessels are skeletonized and divided at the pelvic
brim. Early control of these vessels will help reduce blood loss during the
later dissection. The ureter can be mobilized off the medial leaf of the broad FIGURE 9.26. The posterior vaginal wall is grasped and retracted cephalad.
ligament and retracted laterally on a Penrose drain or vessel loop. The uterus can now be sharply dissected off of the rectosigmoid.
Source: Reprinted with permission from Gallup DG, Talledo OE. Surgical Atlas of Gynecologic Oncology. Source: Reprinted with permission from Gallup DG, Talledo OE. Surgical Atlas of Gynecologic Oncology.
Philadelphia, PA: WB Saunders Co.; 1994:92. Philadelphia, PA: WB Saunders Co.; 1994:103.
from the urinary bladderis part of the procedure. The ret- advanced-stage ovarian cancer patients, the surgeons armamen-
roperitoneum is opened laterally above the large vessels, both tarium should include the ability to remove disease involving
round ligaments are cut, the ureters are identified, and then the upper abdominal structures such as the liver, diaphragm, spleen,
ovarian vessels are ligated and cut. The peritoneum is dissected and pancreas (5).
from both ureters and the sigmoid colon is divided above the Adequate exposure is the most important factor in determin-
level of tumor infiltration. In some cases the infiltrated perito- ing whether resection of diaphragm disease can be performed
neum is densely adherent to the ureter in the lateral parametria, safely (7). Once an exploratory laparotomy has been performed
so the complete removal of the tumor requires unroofing of the and the presence of bulky diaphragm disease confirmed on one
ureter in its parametrial part, and its dissection from the cervix or both hemidiaphragms, the midline incision is extended to the
and infiltrated parametria, identical to that performed during a xiphoid process. For maximum exposure, the incision can be ex-
radical hysterectomy. Once the uterine vessels are ligated bilater- tended to the sternum to the right of the xiphoid, or in some
ally, the rectovaginal space between the vagina and the infiltrated cases the xiphoid can be divided or removed. The procedure can
pouch of Douglas is opened, the uterosacral ligaments are cut, almost always be performed through this midline incision, and
and a reverse hysterectomy is completed by the incision of the although extending a subcostal incision 2 to 3 cm below the cos-
vagina at the level of the vaginal fornix (Fig. 9.26). The vagina tal margin has been described, we have not generally found this
is sutured. At this stage, the specimen is fixed in the pelvis only to be necessary.
by the rectum and pararectal ligaments. It allows for the retrac- The extent of liver mobilization required depends on the dis-
tion of the specimen cephalad, and in most cases partial cranial tribution of tumor involving the hemidiaphragm. Large volume
dissection of the infiltrated pouch of Douglas from the rectum, disease is common on the right side, and a greater proportion
aiming at preservation of a larger part of the rectum for further of the right hemidiaphragm is obscured by the liver. A right-
anastomosis. After cutting pararectal ligaments, the exenterative sided liver mobilization will be described primarily. Tumor in-
part of the procedure is completed by the incision of the rectum volvement on the left diaphragm is more easily resected without
below the level of tumor involvement. Low rectal anastomosis in fully mobilizing the liver, although in certain cases splenectomy
this setting is generally performed and, in well-trained hands, is may be necessary to clear the metastatic deposits on the left
associated with a low rate of complications (18,19). diaphragm.
The infrahepatic edge of the falciform ligament containing
the ligamentum teres is grasped between two Kelly clamps, and
Upper Abdominal Disease is divided and ligated. The suture on the lower edge is left long
A recent meta-analysis by Bristow et al. demonstrated that to aid with downward traction of the liver and remaining falci-
expert centers with primary optimal cytoreduction rates of 75% form ligament. The falciform ligament should be transected all
or greater provided their patients with a 50% improvement in the way to the coronary ligament. This can be used for traction
overall survival when compared to less experienced centers of the liver. The coronary ligament is incised from the falciform
with primary optimal cytoreduction rates of 25% or less (20). to the right triangular ligament. Care must be taken in the area
A subsequent study by Chi et al. illustrated that in order to of the hepatic notch. The hepatic notch contains the right hepatic
achieve primary optimal cytoreduction rates of 75% or more in vein as it enters the inferior vena cava and is found lateral to the
202 CHAPTER 9 SU RGICAL PRI NCI PLES I N GYN ECOLOGIC ONCOLOGY
union of the falciform and coronary ligaments. If further mobi- line with 3-0 delayed absorbable suture, either continuously or
lization of the liver is necessary, the lateral attachments may be interrupted, is optional.
incised and the liver bluntly lifted off Gerotas fascia of the right
kidney and diaphragm.
The extent of diaphragm peritonectomy is determined by the
distribution of the tumor implants, and the method can be mod- Continent Urinary Diversion
ified accordingly. When a full right diaphragm peritonectomy Over the past two decades, interest in performing continent
is performed, the peritoneum on the anterior edge of the dia- urinary diversions for patients with gynecologic malignancies
phragm is incised along the costal margin using either cautery has emerged. Most gynecologic oncologists will use a modifica-
or Metzenbaum scissors. This anterior free edge is grasped with tion of the Indiana (22) or Miami (23) pouch. Poor candidates
several Allis or Mixter clamps, which are then retracted inferi- for continent urinary diversion include those with crippling
orly to visualize the line of attachment between the diaphragm arthritis or those psychologically unable to tolerate frequent
and its overlying peritoneum. The plane between is developed self-catheterization of the pouch.
with a combination of blunt and sharp dissection as determined A modification of these pouches is shown (2). The colon is
by the patients tissue laxity and/or peritoneal adherence. This transected just proximal to the hepatic flexure (Fig. 9.27). The
may not be possible if the tumor has extended through the peri- colon is then detubularized by a longitudinal incision along the
toneum and diaphragm. tinea. The continent mechanism is created by two maneuvers.
If tumor implants are securely fixed to the diaphragm muscle First, the terminal ileal segment is tapered down over a #14 French
and/or are suspicious for full thickness diaphragm involvement, Foley catheter by using a gastrointestinal anastomosis (GIA) sta-
diaphragm resection should be considered. The technique for pling device along the antimesenteric border of the ileum. The
diaphragm resection depends largely on the size of the lesion to second maneuver is to plicate the ileocecal valve by placing con-
be resected. Small penetrating lesions can be resected using the centric purse-string sutures of 0 silk or polypropylene around it.
EndoGIA stapler alone without entering the pleural cavity. The The ureters are then implanted under direct vision (Fig. 9.28) (2).
lesion is grasped with a long Allis clamp, the diaphragm tented After closing the pouch, the ileal stoma can be brought out in
downward away from the lung, and the EndoGIA used to staple several areas of the abdominal wall (Fig. 9.29) (2). Some use the
and divide the tented diaphragm and invasive lesion. Larger umbilicus as the exit site. The ureteral stents can exit the abdomen
lesions require entry into the pleural space and this is gener- via the ileal stoma or through separate incisions in the pouch and
ally performed sharply with a Metzenbaum scissors to avoid abdominal wall. The use of a Penrose drain and a cecostomy tube
an inadvertent cautery burn to the lung. Once entered and the for irrigation to remove mucus is optional.
lung visualized/retracted, cautery can be used to circumscribe
the lesion and resect it en bloc with the peritoneal, muscular,
and pleural layers. The defect can almost always be closed
primarily with limited tension, using interrupted horizontal
Abdominal Closure
mattress or figure-of-eight permanent sutures. Larger defects With the advent of more recently published closure methods
that cannot be closed primarily without significant tension and newer suture materials, the vertical, allegedly stronger para-
should be closed with a permanent mesh secured to the peri- median incision is unnecessary. A midline incision is preferable
toneal diaphragm surface with interrupted permanent sutures in modern-day gynecologic oncology. It is the least hemorrhagic
(21). The majority of patients undergoing diaphragm resection of all incisions, and rapid entry is feasible. Exposure is excellent,
can have their pleural cavity closed and the air from the thorax and minimal nerve damage occurs.
evacuated using the red Robinson catheter. A purse-string suture In the past, many surgeons have advocated the relatively time-
is placed widely around the hole and a #14 French red Robinson consuming Smead-Jones closure (24). However, in the 1980s
catheter is passed through the hole into the pleural cavity. The it was noted that midline incisions could be safely closed with
anesthesiologist is asked to give the patient a maximal inspira- a running, mass closure. In 1989, Gallup et al. (25) reported on
tion, suction may be applied to the catheter, and the catheter 210 patients, most of whom were at high risk for evisceration.
is pulled as the purse-string suture is tied down. For patients In those who had midline incisions closed with a running, mass
undergoing more extensive resections or with other reasons to closure using #2 monofilament polypropylene suture, no evis-
benefit from prolonged pleural drainage, such as pleurodesis, cerations occurred. Since that publication, several series have
a chest tube can be placed in the operating room and removed published excellent results using monofilament absorbable or
postoperatively as required. monofilament permanent sutures in a running, mass closure
To remove tumor from the left upper quadrant, occasionally method (2628). Fascial closure should be performed with
a splenectomy with or without distal pancreatectomy is required. a suture length to wound length ratio of at least 4:1 (29). In
Usually, the initial step is to enter the lesser sac to evaluate the addition, a randomized trial in nongynecologic cancer patients
posterior aspect of the stomach and pancreas. The gastrosplenic demonstrated that placement of fascial sutures 5 to 8 mm from
ligament and then the short gastrics are carefully divided. The the fascial edge (as compared to the traditional >10 mm from
spleen is mobilized medially and out of the left upper quadrant the fascial edge) results in fewer surgical site infections and
by dividing the splenophrenic and splenocolic ligaments and the fewer ventral hernias (28).
other attachments to the adrenal gland and Gerotas fascia of the
left kidney. The spleen can now be elevated out of the splenic bed
and into the incision. The splenic hilum is now grasped between
the fingers. Palpation of the pancreas is attempted. Identifica- SU RGICAL MANAGEM ENT OF
tion of the pancreas may be facilitated by viewing the hilum GYN ECOLOGIC CANCER
posteriorly. The anterior splenorenal ligament is entered sharply.
The splenic artery and vein can then be identified. These ves- The gynecologic oncologist must be able to evaluate the woman
sels should be ligated and divided separately. The splenic vessels with a genital tract malignancy, direct her management, perform
may also be ligated prior to elevating the spleen in cases where the necessary surgical procedures, and supervise her postopera-
lateral mobilization is not possible secondary to tumor and/or tive care and surveillance. A patient who is managed by a surgeon
dense adhesions. A linear stapler may be placed across the tail who is not a gynecologic oncologist may receive an operative
of the pancreas if necessary to remove tumor involving the procedure that is inappropriate or inadequate. Over 20 years ago,
distal pancreas and/or splenic hilum. Reinforcement of this staple McGowan et al. (30) reviewed the intraoperative evaluation of
CHAPTER 9 SU RGICAL PRI NCI PLES I N GYN ECOLOGIC ONCOLOGY 203
Hepatic flexure
Site of resection
Superior mesenteric
artery
Right colic artery
Middle colic
artery
Ascending colon
Jejunal
arteries
Ileal
Site of
Cecum 12 cm resection
Site of resection
Appendix
FIGURE 9.27. The anatomic location and vascularity of the right colon segment utilized for formation of the continent
urinary pouch. Illustrated are the anatomic sites of division for creation of the continent pouch.The ascending colon is divided
distal to the right colic artery. The terminal ileum is divided approximately 12 cm from the ileocecal valve. The resection can
be accomplished with the use of surgical staplers or by intestinal clamps. If the appendix is present, it should be removed.
The ileocecal segment has a rich blood supply derived from the right colic artery and the ileocolic artery. If one is performing
the Miami pouch type of urinary diversion, the transverse colon would be divided distal to the middle colic artery.
Source: Reprinted with permission from Gallup DG, Talledo OE. Surgical Atlas of Gynecologic Oncology. Philadelphia, PA: WB Saunders Co.; 1994:186.
291 women with primary ovarian cancer. Ninety-seven percent of In the four decades since the establishment of gynecologic
the patients who underwent surgery by a gynecologic oncologist oncology as a subspecialty, cancer therapy has become increas-
received complete staging operations, but only 52% and 35% ingly sophisticated and complex, and it is difficult for any one
had adequate operations performed by an obstetrician-gynecolo- physician to master all the skills necessary for treating gynecologic
gist or a general surgeon, respectively. malignancies. More often, we must use multimodal therapy and
Two more recent British studies retrospectively analyzed the participate in multidisciplinary care. There are many medical and
outcomes of over 1,800 patients with ovarian cancer (31,32). Both radiation oncologists who have specialized in gynecologic cancer,
studies found on multivariate analysis that patients survival was and they are integral members of the multidisciplinary team. The
adversely affected when their initial operation was performed by a Gynecologic Oncology Group (GOG), with its emphasis on mul-
general surgeon, as opposed to a gynecologic surgeon. These results tidisciplinary research, has demonstrated the effectiveness of such
are similar to those obtained by Nguyen et al. in an American an approach.
national survey of ovarian carcinoma (33). Eisenkop et al. ana- Another important factor in providing optimal patient care is
lyzed the outcomes of 263 patients with stages IIIC and IV ovar- the environment in which gynecologic oncology is practiced. The
ian carcinoma (34). When the primary surgery was performed by facilities used by the gynecologic oncologist should offer state-
gynecologic oncologists, as compared to general obstetricians- of-the-art radiation therapy and chemotherapy. Patients should
gynecologists and general surgeons, the rate of optimal cyto- receive care tailored to the type and extent of their disease and
reduction was significantly higher, the operative mortality not have their treatment determined by the limitations of the
substantially lower, and the median survival significantly longer. available facilities. Mortality rates for complex oncologic pro-
Accordingly, other countries have attempted to centralize the cedures, such as pelvic exenteration, have been demonstrated
care of patients with ovarian cancer so that they are primarily to be significantly lower in hospitals where the procedures are
operated on by gynecologic oncologists (35,36). However, pat- performed with a relatively high volume as compared to those
terns of care studies in the United States have demonstrated that in which the procedures are performed infrequently (41). The
a significant percentage of women with ovarian cancer are not recent meta-analysis performed by Bristow et al. evaluated 81
receiving their primary treatment from gynecologic oncologists studies involving 6,885 patients with advanced ovarian cancer
(37,38). Consequently, in this country, many women with ovar- (20). This study demonstrated a 50% increase in median sur-
ian cancer are still not receiving the recommended comprehensive vival if patients primary surgery was performed at an expert
primary surgery (39,40). center compared to less experienced centers.
204 CHAPTER 9 SU RGICAL PRI NCI PLES I N GYN ECOLOGIC ONCOLOGY
1. 2.
1 cm
A
Right ureter
Left ureter
B 8F ureteral stent
FIGURE 9.28. A, B: Prior to beginning the continent diversion, the ureters have been transected (usually at the pelvic brim) and
mobilized so that they are able to be brought to the area where the continent pouch will be located without tension. If necessary,
the left ureter can be brought through or under the mesentery of the colon to facilitate its placement into the urinary pouch. An
appropriate site is selected on what will be the posterior wall of the pouch, and a long thin clamp is used to perforate the colon and
pull the ureter through. An approximately 1-cm segment of ureter is brought into the pouch. For ease of ureterointestinal
anastomosis, the ureter should be secured posteriorly to the pouch by suturing the adventitial tissue of the ureter to the
seromuscular layers of the pouch with 3 or 4 permanent 3-0 sutures. The ureter is spatulated to increase the lumen diameter. The
ureter is sutured directly to the colon and is not tunneled. We use 4-0 polyglycolic suture. This is a full-thickness approximation of
the colon and ureter. Once both ureters have been sutured into the pouch, 2 #8 French ureterointestinal stents or long pediatric
feeding tubes are placed retrograde into the renal pelvis. If a feeding tube is used, it should be sutured to the ureter with 4-0
chromic to ensure against displacement due to ureteral peristalsis. Note the 3 concentric sutures at the ileocecal valve.
Source: Reprinted with permission from Gallup DG, Talledo OE. Surgical Atlas of Gynecologic Oncology. Philadelphia, PA: WB Saunders Co.; 1994:191.
Stoma
may be adequate for establishing the extent of spread of a cancer,
14F catheter Ileocecal valve but not for providing histologic cell type and grade for the pri-
mary diagnosis. The histologic diagnosis of ovarian or fallopian
tube carcinoma requires surgical exploration.
Ureteral stents The current International Federation of Gynecology and
Cecostomy tube Obstetrics (FIGO) staging system of gynecologic cancers requires
surgical staging for vulvar, endometrial, and ovarian cancer. Cer-
vical cancer remains a clinically staged disease, although many
Penrose drain centers use surgical staging (by laparotomy or laparoscopy) for
treatment planning. Table 9.2 lists the current methods of stag-
ing for the various gynecologic malignancies.
The initial surgical procedure in a patient with known or
suspected gynecologic cancer should be performed by a trained
gynecologic oncologist because the accuracy of diagnosis and stag-
B ing significantly influences subsequent therapy. As stated earlier,
numerous studies have demonstrated that ovarian cancer staging
FIGURE 9.29. A, B: The site for the ileal stoma is selected on the anterior operations performed by general obstetricians-gynecologists or
abdominal wall and then incised through all abdominal tissue layers. The general surgeons are inadequate much more frequently than if the
stoma is created for catheterization and the #14 French catheter should exit operation is performed by a gynecologic oncologist. Young et al.
the pouch through this stoma. It is critical that the ileal segment be at a 90 (44) reported excellent survival in patients with early ovarian can-
angle with the abdominal wall so that catheterization is a straight shot. The cer, but stressed that these data were applicable only to patients
pouch may be sutured to the abdominal wall to accomplish this. All stents with adequate surgical staging.
and drainage tubes are brought out through the anterior abdominal wall and In addition to the anatomic site and stage of disease, the plan
secured. The pouch may also be anchored posteriorly (i.e., to the sacrum). of therapy for most gynecologic malignancies is also influenced
Source: Reprinted with permission from Gallup DG, Talledo OE. Surgical Atlas of Gynecologic Oncology.
Philadelphia, PA: WB Saunders Co.; 1994:193. by the histologic cell type and histologic grade (differentiation)
of the cancer. The cooperation of the surgeon, pathologist, and
cytologist cannot be overemphasized in the diagnosis and stag-
and certain criteria must be fulfilled before the diagnosis can be ing of cancer. It is the surgeons responsibility to provide the
made. For women who fall into one of these high-risk catego- pathologist or cytologist with a complete clinical history and an
ries, surgical removal of the tubes and ovaries (and the uterus indication of what he or she hopes to learn from the anatomic
in HNPCC) should be considered after childbearing is complete specimen. Without this communication, the pathologist and
(42,43). Before that time, close monitoring is essential. cytologist will be unable to provide the information needed to
direct the clinical care of the patient. Both the pathologist and
the cytologist must be sure that the surgeon is aware of any spe-
cial handling that is necessary for a particular specimen. There is
Diagnosis and Staging no excuse for misinterpretation of a tissue or cytologic specimen
The diagnosis of any gynecologic cancer requires a surgical biopsy. because of a failure in communication.
The manner in which the histologic diagnosis is obtained varies
with the disease and the clinical situation. A punch biopsy or
an instrument biopsy may be sufficient for the diagnosis of an
invasive cancer of the vulva, vagina, or cervix, but an excisional Surgery as Primary Therapy
biopsy is necessary for the diagnosis of microinvasive or preinva- Surgery is usually the treatment method of choice for preinvasive
sive cancer. A fine-needle aspiration biopsy for cytologic analysis diseases of the vulva, vagina, and cervix, for which local excision
206 CHAPTER 9 SU RGICAL PRI NCI PLES I N GYN ECOLOGIC ONCOLOGY
is both diagnostic and curative. Surgical margins should clear only Surgery as salvage therapy may also play an important role
gross and microscopic disease; removal of large areas of normal tis- in the management of ovarian, fallopian tube, and some endo-
sue is not required. For microinvasive lesions of these organs, wide metrial cancers. For patients who have not been cured by initial
local excision with a 1- to 2-cm normal tissue margin is appropriate. therapy and chemotherapy, second attempts at cytoreduction
Localized disease, such as stage I vulvar cancer, stage I pos- may be beneficial, provided that reasonable salvage therapy is
terior vaginal cancer, and stage IA2/IB1 cervical cancer, are usu- available (4951).
ally managed by radical resection of the primary tumor and
regional lymphadenectomy. Some centers utilize sentinel lymph
node evaluation instead of complete regional lymphadenectomy.
In these surgical procedures, the operations themselves are de-
Surgery for Metastatic Disease
signed to be curative without adjunctive therapy unless high-risk In selected cases, distant metastases from gynecologic tumors
conditions are identified. As described in the chapter on vulvar may be curable by surgical resection, or the resection may pro-
cancer, there is a trend toward more conservative therapy for duce a prolonged disease-free interval. Fuller et al. (52) reported
vulvar malignacies. This allows preservation of normal tissues on 15 patients who underwent pulmonary resection of distant
and prevents some of the disfigurement that can be associated metastases from a variety of gynecologic malignancies. They
with this surgery. Surgery may be curative without adjuvant reported a 5-year survival rate of 36% and a 10-year survival
therapy for other cancers as well, including early-stage endo- rate of 26%. Patients with solitary metastases had a median sur-
metrial cancer, stage IA ovarian cancer, and early sarcomas of vival of 64 months, with a median survival of 48 months for
the uterus. those with multiple metastases. Levenback et al. (53) reported
Findings at surgery may indicate the need for additional their experience with 45 patients who underwent pulmonary
treatment. This therapy is usually called adjuvant therapy. It is resection of metastases from uterine sarcomas. From the date of
administered because of the potential for occult spread of dis- the pulmonary resection, the 5-year survival rate was 41%, with
ease based on a surgical finding (e.g., positive lymph nodes). The a 10-year survival rate of 35%. The investigators found a statis-
use of adjuvant therapy requires that information be available tically improved chance of survival for patients who developed
to allow the selection of patients with a high risk of recurrence. pulmonary metastases 1 year or longer from their original therapy
These risk groups are defined for each disease site in the appro- and for those with unilateral metastases. There was no statistical
priate chapters of this book. difference in survival based on the number of nodules (in one lung),
the size of the lesion, the age of the patient, or the use of postresec-
tion adjunctive therapy. However, the small number of patients in
Surgery Combined with Other Therapies this study precluded adequate evaluation of these factors.
In some cancers of the female genital system, surgery is the corner- Resection of intra-abdominal or pelvic disease may offer pal-
stone of treatment but is not curative when used alone. Primary liation by removal of tumor bulk, or may allow chemotherapy
cytoreduction of gross disease is vital in advanced ovarian and or irradiation a greater chance of eradicating disease. Resection
fallopian tube cancer, but it is of little benefit without adjunctive of tumors that have a poor blood supply often leaves behind
therapy. Chemotherapy after surgery is a vital and necessary part smaller tumors with a better blood supply that are more amena-
of the treatment regimen for these cancers. For patients with clin- ble to treatment with chemotherapy or irradiation. Resection of
ical stage I or II endometrial cancer who have high-grade cancer bulk disease also increases the number of residual tumor cells that
or deep myometrial penetration, surgical removal of the uterus is enter the active cell cycle, in which they may be more responsive
an extremely important part of therapy. However, depending on to these adjunctive therapies. The availability of new techniques
the histopathologic findings of the surgical specimens, additional for intraoperative electron beam irradiation or intraoperative
regional radiotherapy and/or chemotherapy may be indicated. It brachytherapy may result in more utility for resection of distant
is the responsibility of the gynecologic oncologist to coordinate and regional metastatic disease.
surgical therapy with chemotherapy and/or radiation therapy to There is increasing evidence that salvage therapy in ovarian
ensure that the patient receives optimal care. and fallopian tube cancers is likely to be effective only in patients
with minimal residual disease. Secondary cytoreduction or resec-
tion of regional and distant metastases may play an important
Surgery as Salvage Therapy role in the treatment of these patients. Recent reports have dem-
Occasionally, surgical resection can be curative in patients in onstrated promising results with surgical resection of isolated
whom other therapies have been unsuccessful. These surgical metastases to the parenchyma of the liver and spleen (54,55).
procedures are almost always extensive and produce some limi-
tation of function. After the failure of other therapies, radical
surgery may be the patients last chance of survival. The classic Surgical Procedures for
examples of this situation are vulvar, vaginal, cervical, or uterine
cancers that have not been cured by primary surgery and irra- Specialized Care
diation or irradiation alone. In such cases, pelvic exenteration Surgical placement of indwelling intravenous access systems
with removal of virtually all pelvic tissues may offer the only allows patients to receive chemotherapy and nutritional supple-
possibility for a cure. Five-year survival rates of 23% to 61% ments and to have necessary blood samples drawn with relative
have been reported after pelvic exenteration (4547). ease and comfort. Placement of these devices, usually semiper-
The possibility of cure with pelvic exenteration is not without manent subcutaneous systems, is safe, contributes to the patients
cost. The loss of the bladder and the rectum often requires per- well-being, and allows for more effective therapy.
manent stomas, and sexual function is impaired or lost in many The use of intracavitary therapy requires the temporary or
patients. For some patients, reconstructive techniques can pre- semipermanent placement of chest tubes or intraperitoneal access
vent the need for stomas and may also restore sexual function. devices. Results of many studies confirm that peritoneal access or
These procedures are described in detail in other chapters in vascular access devices placed totally beneath the skin have a low
this book. During the last three decades, improvements in initial infection rate and a low rate of malfunction (56,57). Implanted
surgery and radiation therapy along with refinements in selec- arterial infusion devices are being evaluated in research studies to
tion criteria have made operations like pelvic exenteration infre- allow direct infusion of therapeutic agents into a tumor mass by
quent (48). Today, most patients experience distant failure rather means of the arterial system. This therapy often requires intra-
than regional failure, and they are therefore not candidates for abdominal surgery to place the device into the appropriate portion
attempts at curative pelvic exenteration. of the vascular system.
CHAPTER 9 SU RGICAL PRI NCI PLES I N GYN ECOLOGIC ONCOLOGY 207
through the new millennium. New materials, new surgical instru- surgery was successful, the postoperative care required committee
ments, and new devices will be invented, and many of these will meetings and its outcome was often less than successful.
make surgical treatment better. Laparoscopic surgery has made a These same founders realized that, although training can
significant impact on our specialty, as well as on the other surgical produce a qualified surgical oncologist, the complete care of the
specialties. With robotic surgery, the complexity of cases that can cancer patient requires knowledge of the basic biologic, physical,
be successfully performed with minimally invasive surgery appears and pharmacologic principles of radiation therapy and chemo-
to have increased, and standard gynecologic oncologic staging pro- therapy. This does not mean that the gynecologic oncologist must
cedures appear to be very amenable to the robotic platform. be a radiation oncologist or a medical oncologist, but it does de-
Innovative methods of supportive care will be developed to mand that he or she know enough to ensure proper integration
advance the technical capabilities that we now possess, such as of all therapeutic modalities. Throughout the United States, this
computerized anesthesia machines and transesophageal ultra- collaboration in the care of patients with gynecologic cancer has
sound. Anesthetic agents will become better and safer, and will produced multidisciplinary teams of gynecologic oncologists,
be joined by a new generation of antibiotics and cardiovascular radiation oncologists, medical oncologists, and pathologists who
medications. We will be able to treat the older patient surgically provide state-of-the-art cancer care. The GOG, a national cooper-
with relative safety, which is especially important because of ative research group, has demonstrated how this multidisciplinary
the increased incidence of cancer in the elderly, and because of approach to gynecologic oncology research can be achieved.
the advancing age of our population. Our responsibilities in- Despite the emphasis on multidisciplinary care, the gyneco-
clude staying abreast of these advances and judiciously integrat- logic oncologist should maintain active involvement during all
ing them into our practices. aspects of a patients care. The principle of being the patients
physician until she is either cured or dies of her disease has been
an integral part of our subspecialty and must be maintained. The
constant involvement of the gynecologic oncologist through all
Changes in the Indications for Surgery phases of cancer treatment ensures optimal integration of sur-
Early diagnosis will change the indications for surgery and the gery, irradiation, and chemotherapy. The patient receives con-
types of procedures that should be done. We will be able to treat tinuous care and the reassurance of a physician who is involved
more patients with less disfigurement and with greater preser- at each stage of her therapy and follow-up.
vation of function. A larger proportion of patients will present
with early disease, allowing surgery to be used more frequently
for definitive cure.
Better adjunctive therapies will increase the importance of CONCLUSION
initial surgical therapy. More patients will benefit from surgi-
cal cytoreduction to minimize disease. The availability of effec- After three and a half decades, the gynecologic oncologist has
tive irradiation, chemotherapeutic, and biologic regimens will emerged as a surgical oncologist for women. The specialist has
make adjuvant therapy feasible in more cases, and it will become sufficient familiarity with radiation oncology and medical on-
more important for us to identify risk groups who are likely to cology to ensure the proper integration of all modalities of treat-
develop recurrent disease after surgery. ment, and he or she is able to apply surgical skills for primary
therapy, secondary therapy, reconstruction, and palliation. The
gynecologic oncologist stands in the obstetrics and gynecology
Multidisciplinary Therapy community, but has one foot in the community of surgeons.
The emergence of cooperative research groups, particularly
and Primary Care the GOG, has allowed a generation of gynecologic oncologists
In outlining the extent of surgical training required for the gyne- to develop superior clinical research skills. These skills must be
cologic oncologist, the founders of this discipline were careful to continually stressed in the training of young oncologists and as
include adequate training that would enable the gynecologic on- an integral part of the practice of our subspecialty. A growing
cologist to become an accomplished abdominopelvic surgeon. The number of young oncologists are receiving additional training in
gynecologic oncologist must be trained to perform the gyneco- basic research. This training is vital for the continued develop-
logic, gastrointestinal, and urologic surgery necessary to manage ment of the subspecialty and for progress toward the prevention
gynecologic cancer and its potential complications. As stated by and care of gynecologic cancers. Our position in the arena of
John L. Lewis Jr. (64), in reference to pelvic exenteration by a team clinical practice is well established, and we must now establish
of gynecologists, general surgeons, and urologists, Even when the ourselves equally well as scientists and surgical researchers.
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Early history of laparoscopic surgery in gynecologic oncology of complications following laparoscopic surgery are related to
came to an end when the whole range of surgical procedures trocar insertion.
used in uterine cancer, including pelvic exenteration, was For that reason, the open technique in which the fascia and
demonstrated to be feasible laparoscopically (1). In a second the peritoneum are surgically opened and the trocar inserted
phase, accumulation of evidence including long-term follow- under direct visualization is considered by many to be the saf-
up of patients managed laparoscopically, results of randomized est access technique. However, this is likely not to be true in
controlled studies, and meta-analysis has led to unanimous patients with a history of laparotomy, as the majority of bowel
acceptance of the concept of minimal invasive surgery (MIS) adhesions are located on the midline below the umbilicus, at a
in gynecologic cancer. However, notwithstanding the spread of location where even an open technique can result in bowel
the technique in almost every country in the world, the open injury. Bonjer et al. (2) reviewed the literature and compared data
approach is still widely used in small institutions with limited between 12,444 open laparoscopic and 489,335 closed laparo-
caseload, or in academic centers without trained teachers and scopic cases. Rates of visceral and vascular injury were 0.083%
proctors, which implies that more efforts still have to be made in and 0.075%, respectively, after closed laparoscopy, and 0.048%
teaching and in concentrating the management of gynecologic and 0.0%, respectively, after open laparoscopy (p = 0.002).
cancer in experienced hands. Mortality rates were 0.003% for the closed and 0.0% for the
In this chapter, the evidence of short- and long-term benefits open laparoscopy techniques. In another randomized trial of
and safety of the laparoscopic approach, the teaching and learn- blind versus open laparoscopy for laparoscopic cholecystectomy,
ing issues, and the new technical developments will be detailed. the major complication rate was 4% in the blind group and 1.3%
in the open group, respectively (p < 0.05) (3). However, a large
series comparing 8,324 cases of direct laparoscopic entry versus
1,562 cases of open laparoscopy for gynecologic procedures
BASICS OF LAPAROSCOPIC did not show a difference in the rate of major complications.
SU RGERY I N GYN ECOLOGIC On the opposite, there were more conversions to laparotomy in
the open technique group (4). A review on laparoscopic entry
CANCER concludes that there is no evidence that the open entry technique
The goal of this section is not to describe the standard tech- is superior or inferior to other entry techniques currently avail-
nique of laparoscopy; this can be found in general gynecology able (level II-2C evidence) (5). The visual entry cannula system
textbooks. Two issues will be addressed: the risk of bowel and may represent an advantage over traditional trocars, as it allows
vascular complications related to the laparoscopic approach, a clear optical entry; however, that does not necessarily avoid all
and the pitfalls of the laparoscopic approach in cancer patients. visceral or vascular injuries (5).
Indeed, the potential for inducing severe intraoperative surgical In patients with prior midline incisions, the use of the Veress
complications and to favor tumor growth and port-site implants needle in the left upper quadrant to first insufflate the abdomen
is not negligible. The goal of this section is to contribute to the prior to the trocar entry is favored. Once the pneumoperitoneum
prevention of such complications. Additional tips to make the is established, the location of the first trocar is chosen at a place
laparoscopic surgeons life easier will also be given. An insight where the absence of adhesion is evident, as assessed by a 5-mm
on training issues that are critical to the development of lapa- endoscopy through the left upper quadrant or the use of the
roscopic surgery versus open and robot-assisted laparoscopic bubble test. This test consists in exploring the abdominal cavity
surgery will conclude the section. by puncturing the abdominal wall using a fine needle plugged to
a syringe containing 1 to 2 mL of saline. If bubbles are not freely
aspirated, there is a suspicion of bowel or omental adhesions.
Using multiple punctures if necessary, an area free of adhesions
Laparoscopic Entry large enough to safely accommodate the endoscope is defined.
Laparoscopic surgery was initially performed via CO2 insuffla- Although the umbilicus is the traditional site of placement of the
tion to create a pneumoperitoneum through the umbilicus a first trocar, one must be prepared to use any position in the mid-
place where the layers of the abdominal wall are fused followed line or any site of the abdomen, provided the risk of adhesion is
by blind insertion in the umbilicus of a 10-mm trocar to accom- low. It is the policy of the senior author to combine this technique
modate the endoscope. This mode of entry was responsible for (left upper quadrant insufflation, bubble test) with the use of tro-
bowel and vascular complications, some of them lethal. The use of car insertion under direct vision using the Ternamian trocar (6).
disposable trocars with retractable blades for direct trocar inser- The ancillary trocars are placed under laparoscopic vision.
tion did not appear to significantly reduce the risk of bowel or Generally, one 10-mm trocar is placed in a suprapubic location.
vascular injuries. This is of particular concern since the majority Two 5-mm trocars are then placed on the horizontal line of the
210
CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER 211
umbilicus, 10 cm lateral to it. This trocar position has many examination after routine resection of trocar site in 66 patients
advantages. It allows access to the entire abdomen, from the who underwent laparotomy after diagnostic laparoscopy (12).
pelvis to the diaphragm. It provides an adequate angulation This implies that complete cytoreduction must be followed by
between instruments, with a maximum distance between tro- trocar site resection. The conclusion is that port-site implant is
cars. It provides a direct access, with a virtually 0-degree angle, not a complication of laparoscopic surgery in the absence of
to the ureteric tunnel at the time of radical hysterectomy. It is ascites or peritoneal malignancy. The early reports of port-site
more adapted to performance of procedures at the abdominal metastases may have been the result of faulty technique resulting
level such as omentectomy or paraaortic lymph node dissec- in direct contamination of the abdominal wall by tumor cells.
tion. Finally, it avoids injuring the iliohypogastric nerves that Finally, it is logical to place all trocars in the midline when
run oblique in the abdominal wall below the umbilical horizon- performing a laparoscopic evaluation of a clinically advanced
tal line, thus avoiding short and long-term postoperative pain. adnexal or peritoneal cancer, to avoid muscle involvement and
Any adhesion impairing vision or correct placement of trocar to easily resect the trocar sites at the time of final laparotomy.
is taken down. When extensive adhesions are encountered, the In addition, it is advised against placing the optical trocar in the
first 5-mm trocar is placed in an area free of adhesions. Scissors umbilicus, which is a preferential site for abdominal wall tumor
are then introduced and other adhesions are divided to place the even in the absence of surgical scar, and would have to be fully
other trocars. resected at the time of final surgery.
muscle, the external iliac artery and vein, and the superior vesi- open abdominal staging for endometrial cancer (44). Overall,
cal artery. The paravesical space is then developed between the lymphoceles were diagnosed in 15.4% and 1.4% of patients
superior vesical artery and the external iliac vessels. The lateral who had open and laparoscopic staging, respectively. Symptom-
wall of the bladder is retracted medially along with the superior atic lymphoceles were more frequent after open staging than
vesical artery. This exposes the Coopers ligament and allows after laparoscopy. Lymphorrhea occurred in 1 and 4 patients
identification of the obturator pedicle. The obturator nerve is after laparoscopic and open surgery. No difference in the inci-
the deep limit of the dissection. The nodes are separated from dence of lymphedema was observed.
the obturator nerve and the external iliac from the Cooper liga-
ment area to the bifurcation of the common iliac vessels. The
nodes located between the 2 landmarks (referred to as obturator
nodes) can then be firmly grasped and detached. The external Transperitoneal Aortic Dissection
iliac artery and vein are then freed from the pelvic side wall. The The transperitoneal approach has been the first described tech-
nodes located between the artery and vein, and the nodes located nique. It mimics the open surgery approach while requiring a
between the artery and the genitofemoral nerves are dissected. much shorter peritoneal incision and virtually no mobilization
Finally, after retracting medially the external vessels, additional of the right colon. As for every upper abdominal procedure, the
obturator nodes can be identified and retrieved. surgeon stands between the patients legs with the monitor at the
head of the bed. The bowel loops are packed along with the omen-
tum in the left upper quadrant. The dorsal peritoneum is opened
Perioperative Outcomes
easily dissected from the left side. After preparation of the space Extraperitoneal Pelvic Node Dissection
(see below), an 8- to10-mm Hg pressure is enough to maintain
the working space. Laparoscopic pelvic lymphadenectomy can be performed using
Extraperitoneal aortic dissection has been first reported by the direct extraperitoneal approach. Historically, this approach
Vasilev and McGonigle in a small series (48). The mature tech- was the first application of panoramic surgical endoscopy in
nique has been fully described in earlier papers from French oncology. This approach starts with a blind digital preparation
groups (49). An extraperitoneal approach to the aorta is begun of the preperitoneal space or with the use of direct vision tro-
by using a 3-cm incision made in the left lower quadrant, medial car devices. A midline suprapubic access or an infraumbilical
to the iliac spine. The successive layers of the abdominal wall are access may be used. Ancillary trocars are placed in the preperi-
transected, including the parietal fascia, leaving the parietal toneal space.
peritoneum intact. Using finger dissection, the peritoneal sac is This approach which has no definitive benefit over the trans-
elevated off the underlying structures. A 10-mm incision of the peritoneal approach while featuring all the shortcomings of the
anterior axillary line and a 5-mm incision in the left upper quad- extraperitoneal approach, and which is limited to the pelvic area,
rant are made to accommodate corresponding blunt trocars that has been largely abandoned in the gynecologic field. However, it is
are inserted under finger guidance in the extraperitoneal space. still used in urologic indications, with similar results compared to
A second ancillary trocar is introduced in the infracostal area in the transperitoneal approach (54) and has been recently rediscov-
the midaxillary line. A laparoscopic balloon trocar is then intro- ered more than 20 years after having been pioneered by Dargent
duced in the first incision. It will accommodate the endoscope. (55). It may be useful in cases where the pelvic cavity is not acces-
The extraperitoneal space is inflated while the peritoneal cavity sible or not easily accessible such as in pregnancy more than 16
is exsufflated. The initial landmarks (psoas muscle, left common weeks or when severe postoperative adhesions are present.
iliac artery, and left ureter) are identified; the initial dissection An innovative variant has been described recently using the
plane is found between the ureter and the common iliac artery. same left lateral approach as used to perform an aortic dissection
The space is developed by elevating the peritoneal sac along with (56). The method may be useful to retrieve pelvic nodes when
the ureter. Access is gained to the presacral area and then to the deemed necessary at the time of surgical staging of advanced
right common iliac area. Further development is obtained in the cervical cancer, or to shorten the transperitoneal step of the sur-
cephalic direction by clearing the psoas muscle and the lateral gical staging of endometrial or ovarian cancer. However, but in
aspect of the left common iliac artery and of the aorta. The infe- some favorable cases, it is limited to the left pelvic area.
rior mesenteric artery and the left renal vein are generally identi-
fied by following the left ovarian vein up to the point where it
ends. The nodes are then separated from the vessels and from Laparoscopic Identification of
the sympathetic chain by a combination of hemostasis and sec-
tion. Multifunction instruments are more adapted, as they avoid Sentinel Nodes
changing instruments and allow to overcome the fact that only The laparoscopic identification of sentinel nodes can be consid-
two ancillary instruments can routinely be placed in the narrow ered as the symbol of the trend toward minimizing the surgical
retroperitoneal space. trauma of staging gynecologic malignancies and optimally using
Sonoda et al. (50) reported on a large series of 111 patients with the possibilities of laparoscopic surgery. The original goal of
locally advanced cervical cancer who underwent surgical stag- the sentinel node concept was to avoid a complete lymphad-
ing. The mean duration of the procedure was 157 46 minutes enectomy in node-negative patients and, in some circumstances,
and the average number of nodes was 19. The mean postopera- in node-positive patients as well. The laparoscopic approach
tive stay was 2 days. Perioperative complications occurred in is fully adapted to the objectives of a pre-therapeutic workup
14 patients. The majority of these complications were symptom- procedure: defining the extent of disease and commensurate
atic lymphoceles that occurred in 11 patients: 8 of these lym- therapy without exposing the patient to an excessive risk; in
phoceles were drained under radiologic guidance, 2 required a addition, the magnification associated with the laparoscopic
catheter placed under anesthesia, and 1 required laparoscopic view is ideal to identify minute lymphatic channels. The devel-
drainage. The rate of symptomatic lymphoceles was later opment of endoscopic gamma probe has made possible the use
reduced by opening the peritoneum at the end of the procedure of the combined (isotopic and colorimetric) assays that are man-
(marsupialization of the peritoneum) to drain the retroperito- datory to increase the accuracy of the method.
neal fluid into the peritoneal cavity. Technically, the identification and retrieval of pelvic sentinel
The typical indication for extraperitoneal aortic dissection nodes involves several steps. Intracervical injection of radiola-
is the patient with locally advanced cervical carcinoma. Knowl- beled colloid is performed before the surgery. Planar or Single-
edge of the status of the aortic nodes allows tailoring of the photon emission computed tomographycomputed tomography
radiation therapy fields. With this indication, common iliac (SPECT-CT) imaging is a useful tool in locating sentinel nodes,
nodes are generally removed along with the aortic nodes. The particularly the nodes located outside the field of usual pelvic
potential benefit of surgical staging of locally advanced cervical lymphadenectomy (57,58,59). Injection of blue dye is performed
cancer is based on the lack of sensitivity of positron emission at the time of surgery. The 4-quadrant approach is being gradu-
tomography in the identification of micrometastases less than ally replaced by a 2-quadrant approach that reduces the risk
5 mm (51), knowing that the group of patients with small lymph of injecting the pouch of Douglas. After having established the
node metastases is the most likely to benefit from surgical laparoscopic view, the surgeon uses the gamma-probe to globally
removal of nodes (52). However, the indication and extent of the locate nodes before incising the peritoneum in front of the hot
dissection, including or not the supramesenteric nodes, is still node. Blue lymphatic channels may also be identified occasion-
controversial (53). ally below the peritoneum. The peritoneum is then incised. On
The finding that this approach is more feasible than the trans- either side, the node closest to the cervix (the closest at isotopic
peritoneal approach for aortic dissection, particularly in obese identification, the first to be connected to a blue channel coming
patients, has led to the adoption of the extraperitoneal route as from the cervix) is bluntly dissected. Special care must be taken
an elective choice in the staging or restaging of obese endometrial not to injure adjacent structures, as the sentinel node technique
or ovarian cancer patients. In such patients, the aortic dissection does not imply identifying at first the major anatomical land-
is performed retroperitoneally following which the other steps of marks of the area.
the procedure are performed transperitoneally. To achieve this, Several systematic reviews (60,61), 2 prospective multi-
the extraperitoneal trocars are replaced in the peritoneal cavity. center studies (62,63), and the recent report of pioneers in the
CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER 215
field (64) have established the diagnostic value of sentinel node is low. The rate varies greatly among the studies according to the
identification in the staging of uterine cancer. Detection rate is preoperative selection criteria used and the study design. In 1994,
97% to 99% using the combined technique (60,64). Laparo- Canis et al. (67) published an extensive, retrospective 12-year
scopic sentinel node identification is highly reliable, with 100% analysis with long-term follow-up of 757 patients from 1980 to
sensitivity, using the full pelvic dissection as the gold standard. 1991. The rate of inadvertent malignancy was 2.5% (19 of 757),
However, definitive conclusions can be drawn only when sen- including 12 borderline and 7 invasive cancers. Additionally,
tinel nodes are identified bilaterally (60,64). This implies that 27 masses were falsely diagnosed as malignant (3.6%), which
full dissection remains mandatory on the site where no sentinel means that these patients had an unnecessary laparotomy. Canis
has been identified. The sentinel node concept does not apply to et al., based on that experience, considered laparoscopic man-
massive involvement of the nodes, stressing the fact that care- agement of pelvic masses to be safe and reliable. The findings of
ful preoperative imaging is required to identify patients with this early publication have been consistently confirmed in sev-
grossly enlarged nodes. Interestingly, 17% of sentinel nodes are eral studies. Leng et al. retrospectively reviewed a series of 2,083
found in aberrant locations and would have been missed by patients laparoscopically managed for adnexal masses. Sixteen
a standard lymph node dissection. Frozen section of sentinel patients had a malignant or borderline tumor, 14 of them were
nodes is of value only if positive, as over 40% of positive nodes diagnosed intraoperatively. No adverse outcome related to lapa-
are identified after ultrastaging involving serial sections and roscopic diagnosis was reported in this study (68). A random-
immunohistochemistry in cervical cancer (64). Interestingly, of ized controlled study on 102 patients comparing laparotomy
the metastatic sentinel lymph node (SLN) metastases not identi- to laparoscopy showed that inadvertent cyst rupture was frequent
The accuracy of the frozen section (FS) is also size-dependent: have to be used to control bleeding. The omentectomy generally
for masses larger than 10 cm, FS becomes less reliable (77). starts at the left splenic flexure. The transverse colon is identified
These results confirm that FS is a useful but inconsistently reli- by elevating the omentum. The assistant constantly stretches the
able tool to guide the intraoperative management. Thus, an omentum to constantly identify the angle between the omentum
alternate effective policy consists in removing every adnexal and the transverse colon. The cutting instrument is used parallel to
mass without spillage or contamination of the abdominal the caudal aspect of the transverse colon and gradually detaches
wall, waiting for definitive pathology and then planning when- the omentum from the colon, taking care not to injure the trans-
ever necessary for definitive laparoscopic staging and manage- verse colon. The omentum is then placed either in a bag, or left in
ment of the disease. the pouch of Douglas if a hysterectomy is planned.
The concept that patients with a suspicious pelvic mass should Infragastric omentectomy is less frequently performed laparo-
necessarily undergo laparotomy has been challenged. A diagnostic scopically. It requires two additional steps: separating the trans-
laparoscopy can be performed regardless of the ultrasonographic verse colon from the gastrocolic ligament, and controlling the
appearance of the pelvic mass, although an immediate laparot- vascular supply at the level of the greater curvature of the stomach.
omy is recommended for staging and management of obvious Separating the transverse colon is achieved by cutting the perito-
cancer cases at laparoscopy. Laparoscopic management of high- neal layer attaching the omentum to the transverse colon, then
risk pelvic masses can be successfully performed in an oncology elevating the omentum from the mesocolon while entering the
referral population if there is expertise in operative laparoscopy, lesser sac. Controlling the vessels of the greater curvature of
availability of immediate and accurate pathologic evaluation, the stomach is best achieved using blocking clips (Hem-o-lok)
and appropriate further treatment where indicated (78). In some inserted via a 10-mm instrument. Incidentally, a similar technique
cases, having an onsite oncologist skilled in advanced laparo- is used to prepare omental flaps when necessary.
scopic procedures allows laparoscopic completion of the stag- The technique of appendectomy is beyond the scope of this
ing procedure. However, when skilled assistance is unavailable, chapter. Briefly, the appendix is grasped and elevated, the meso-
it is best to terminate the laparoscopic procedure after a cancer appendix is coagulated and cut, the base of the appendix is tied
diagnosis and to promptly refer the patient for definitive surgery. using a loop or a blocking clip, and the appendix is divided.
Laparoscopy for the management of pelvic masses can eliminate
the need for unnecessary laparotomy in most cases. Statistically,
the majority of them will be benign and can be adequately man-
aged laparoscopically. However, surgeons should be technically Laparoscopic Assessment of Advanced
meticulous to minimize the risk of ovarian cyst rupture and spill- Adnexal or Peritoneal Malignancy
age, and specimens should always be retrieved intact through an
endobag to reduce the risk of trocar-site metastasis.
Assessment of Resectability
In a series reported by Havrilesky et al., the ovarian malig- The technique described in this section refers to the assessment
nancies discovered at the time of laparoscopy for pelvic masses of the peritoneal disease in patients with advanced ovarian can-
were managed laparoscopically and this was not associated with cer characterized by ascites, carcinomatosis, and omental cake,
an adverse outcome (79). Lcuru et al. found no deleterious to take biopsies and select the patients for optimal surgical
influence of laparoscopy as first surgical access on outcome of debulking by laparotomy. Unfortunately, there is no perfect tool
patients with early-stage ovarian cancer (80). to determine preoperatively whether patients can be optimally
debulked surgically, or be proposed neoadjuvant chemotherapy.
CT scan can be used for this purpose, and biopsies under radio-
Abdominal Staging or logic guidance may be performed. However, CT scan may under-
estimate the extent of the disease, in particular the extent and
Restaging Procedures location of carcinomatosis, and biopsy under radiologic guidance
Working in the upper abdomen generally requires using the is not always feasible. Other malignancies, particularly of gastro-
same position of the surgeon and the same placement of tro- intestinal origin (such as colon, pancreas, stomach, and others), or
cars adopted to perform a transperitoneal aortic dissection: tro- rare peritoneal malignancies (mesothelioma) can mimic adnexal
cars are placed lateral to the umbilicus, and the surgeon stands or peritoneal cancer. Definitive pathologic diagnosis is critical
between the legs of the patient. Some advise to place the endo- before initiation of any chemotherapy. This is why laparoscopy
scope in the suprapubic area. Alternatively, the surgeon can use has become a valuable diagnostic tool in the workup of advanced
the position adopted to perform an extraperitoneal aortic dissec- peritoneal disease.
tion: 2 trocars are placed in the left flank, and the surgeon stands The diagnostic laparoscopic procedure can have some pitfalls:
on the left side of the patient, working horizontally. This position first, the presence of a large amount of ascites may lead to a
is quite ergonomic, and can be used to perform an omentectomy reduced visibility; second, the gastrointestinal (GI) anatomy can be
after an extraperitoneal aortic dissection, after replacement of distorted, or the colon and/or small bowel may be adherent to the
the trocars in the abdominal cavity. anterior abdominal wall or omentum, which may increase the risk
Taking peritoneal biopsies is straightforward. A grasping of bowel injury. The entire abdominal cavity may not be accessible
forceps creates a fold on the peritoneum. The fold is incised, to laparoscopic vision. Lastly, the issue of trocar-site implantation
taking care not to injure underlying structures. The peritoneal remains controversial, particularly in patients with adenocarci-
flap is then elevated and excised. The same technique is used to noma, ascites, and carcinomatosis (see section on Port-site metas-
perform biopsies of undersurface of the diaphragm. Once the tasis and risk of tumor dissemination). Technical details have been
diaphragmatic peritoneum is incised, the pressure of the CO2 provided in this section concerning port-site metastases: placing the
contributes to develop the space between the peritoneum and trocars in the midline, preventing port-site metastases, and excising
the muscle fibers. There is usually no need for hemostasis or the trocar sites at the time of laparotomy are mandatory.
specific instrumentation. Diagnostic accuracy essentially depends on the quality of
Omentectomy is a mainstay of peritoneal staging. Infra- sampling. Prediction of resectability is a much more complex
colic omentectomy is the standard diagnostic procedure. The question, as it depends on the skills and aggressivity of the
procedure is straightforward using the modern multifunction surgeon. Angioli et al. reported on 87 patients with advanced
instruments that allow to grasp, to apply hemostasis, and to ovarian cancer who underwent first a diagnostic open laparos-
cut. Controlled bipolar energy with cutting or ultrasonic shears copy (81). In 61% of patients, optimal cytoreductive surgery
can indifferently be used. Additional bipolar cautery or clip may was deemed possible and those patients underwent a laparotomy
CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER 217
these instruments have been raised, no objective detrimental less postoperative pain in a randomized trial (92). However,
effect on cancer outcome has been demonstrated. In addition, vaginal hysterectomy has a shorter operating time, and possibly
at least one needle holder is necessary to complete the closure of less complications, as evidenced in another randomized trial in
the vagina laparoscopically. women with benign uterine disease (93). This is true even in
The round ligaments are typically divided using monopolar patients generally deemed to present a contraindication of vagi-
cautery. Preventive hemostasis of infundibulopelvic ligaments is nal surgery (94).
achieved using bipolar cautery, or blocking clips, or any other In gynecologic oncology, most of the literature refers to the
adapted device. The only potential danger is the ureter, which is combination of hysterectomy and lymph node dissection in
running at a distance from the ovarian vessels if the correspond- the surgical management of endometrial cancer, thus making
ing adnexa is grabbed and firmly moved medially to stretch the the analysis of perioperative data concerning hysterectomy by
infundibulopelvic ligament. The peritoneum of the posterior leaf itself more difficult. However, high level evidence in favor of
of the broad ligament is then divided in the direction of the laparoscopic surgery including data from controlled studies is
torus uterinus, taking care to incise the peritoneum only and available. Interestingly, one of the studies from the Netherlands
not to injure the underlying vessels. The uterine insertion of the compared only hysterectomy in a cohort of endometrial cancer,
uterosacral ligaments is then cauterized and cut. The peritoneum with no interference of lymph node dissection (95).
of the ventral part of the pouch of Douglas is opened. The peri- Hauspy et al. recently reviewed the literature until January
toneum of the vesical fold is then incised and the vesicouterine 2009 (96). They reviewed 23 articles: 5 were randomized con-
septum is developed, down to the point where the anterior vagi- trolled trials (RCTs), 4 were prospective reviews, and 14 were
nal cul-de-sac delineated by the cul-de-sac presentator is fully retrospective reviews. More recently, a meta-analysis of the avail-
separated from the bladder. The uterine pedicles are then visible able randomized trials has been published (38). Estimated blood
in either broad ligament. The ascending branches are cauterized loss and hemoglobin or hematocrit change was consistently less
and cut slightly above the uterine isthmus. The last attachments after laparoscopy in the six studies where they were reported
of the uterus are then cauterized and cut medial and caudal to (95101).
the uterine vessels. The lateral cul-de-sacs, featuring their char- After combining the data from all of the RCTs included in
acteristic white color, are freed from the surrounding tissues. their meta-analysis, Zullo et al. found that intraoperative com-
The vagina is incised anteriorly and then grabbed. The vaginal plications rates were not different between laparoscopy and
incision is completed using a monopolar hook. The uterus is laparotomy (RR, 1.25; 95% CI, 0.991.56) without significant
delivered. Hemostasis is checked and completed if necessary heterogeneity across the studies (98). They found a significant
using bipolar cautery. The vaginal cuff is closed by a continuous advantage of laparoscopy over laparotomy in terms of post-
suture running from one angle of the vagina to another. operative complications (RR, 0.71; 95% CI, 0.630.79) with
significant heterogeneity across the studies. In a recent study, a
Laparoscopic Management of the Upper Pedicles significantly higher proportion of patients in the open surgery
group experienced adverse postoperative grade 3 or higher
and Vaginal Hysterectomy (23.2% vs. 11.6%) (102).
This option is more appealing to surgeons who have been trained The largest randomized trial is the LAP2 study (99) that was
in vaginal surgery. The management of the infundibulopelvic and designed to compare laparoscopy versus laparotomy for com-
round ligaments is straightforward even for any modern gyneco- prehensive surgical staging and management of stage I to IIA
logic surgeon, and does not require specific training. The lapa- uterine cancer including hysterectomy, salpingo-oophorectomy,
roscopic management of the upper pedicles can be occasionally pelvic cytology, and pelvic and paraaortic lymphadenectomy.
complemented by the division of the posterior leaf of both broad Patients were randomly assigned to laparoscopy (n = 1,696) or
ligaments, thus favoring the vaginal mobilization of the uterus, open laparotomy (n = 920). A significantly longer operative time
and by the coagulation of the origin of the uterine arteries that is (204 vs. 130 minutes) was observed in the laparoscopy group.
routinely identified at the time of lymph node dissection. Intraoperative complication rates were similar. Laparoscopy
The technique of vaginal hysterectomy is beyond the scope of had significantly fewer moderate to severe postoperative adverse
this textbook. The uterine cervix is firmly grabbed using grasp- events than laparotomy (14% vs. 21%). Hospitalization of more
ing forceps. The full thickness of the vagina is incised. The pouch than 2 days was significantly lower in laparoscopy versus lapa-
of Douglas is entered, and the vesicouterine space is developed. rotomy patients (52% vs. 94%). Although pelvic and paraaortic
Interestingly, the remaining steps can be completed using the nodes were not removed in 8% of laparoscopy patients and 4%
instruments and the technique of laparoscopic surgery: serial of laparotomy patients (p < 0.0001), no difference in overall
bipolar coagulation and division of the attachments of the cervix, detection of advanced stage was seen. The study has a major
the isolation and placement of a blocking clip on each uterine shortcoming related to its multicentric design: a high conversion
artery mimic in a retrograde way the technique of laparoscopic rate. About 25.8% of patients assigned to the laparoscopic arm
hysterectomy (91). Obviously, both vaginal and laparoscopic were converted to laparotomy, reflecting the learning curve of
techniques are minimally invasive and are complementary. The some investigators, particularly for node dissection. However, as
patient highly benefits from any combination of both techniques, it is likely that further training would have resulted in even bet-
and the surgical technique by both approaches is improved by ter results of laparoscopic surgery, this does not weaken the con-
the dual training. clusions of the paper. This study gives evidence that laparoscopic
surgical staging for uterine cancer results in fewer complications
Perioperative Outcomes: Evidence-Based Benefits and shorter hospital stay.
A few recent open series specifically addressed the issue of
of Laparoscopic Surgery complications. Tinelli et al., in 2011, compared the complication
Simple hysterectomy technique and results are extensively docu- rates of laparoscopic and open surgeries in a multicenter series
mented in the literature addressing benign gynecology proce- of 226 women with early stage endometrial cancer (103).
dures. It conveys obvious advantages over the open procedure. Patients underwent total hysterectomy and pelvic dissection.
With exceptions, the choice should be made between the laparo- One patient of the laparoscopy group had an uretero-vaginal
scopic and the vaginal approach. When the choice is open, with fistula and another patient had a ureteral stricture temporarily
a patient suitable for both approaches, and a surgeon trained treated with a stent. One patient of the laparoscopy group had a
in both techniques, full laparoscopic hysterectomy may be the bowel perforation due to dense adhesions with the peritoneum
preferable approach, as it has been found to be associated with under the umbilicus, resolved with a bowel resection and an
CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER 219
end-to-end anastomosis. In 3 patients of the laparoscopy group They also found that in the hospital perspective, laparoscopy
a vaginal cuff dehiscence was observed and in one case a pel- was least expensive compared to laparotomy only if hospital
vic lymphocyst was reported. Barnett et al., in 2011, retrospec- stay after open surgery was more than 2.9 days (109).
tively compared a group 107 women patients who underwent
laparoscopy with a group of 269 patients matched on age and Conclusion
body mass index (104). Adverse event rates were nonsignificantly
different between cohorts (37% laparoscopy vs. 43% laparot- There is thus definitive evidence of the short-term benefit and cost-
omy). Laparoscopy had higher unexplained rates of mild sensory effectiveness of laparoscopic hysterectomy in gynecologic cancer
peripheral nerve deficit (5% vs. 0%) and lymphedema (7% vs. patients. This includes patients with comorbidities, obesity, or
1%), whereas laparotomy had higher rates of cellulitis (16% vs. advanced age. The issue of the obese patient will be addressed
7%) and open wound infections (9% vs. 2%). in a specific section later in the chapter (The Case of The Obese
Palomba et al. reported in 2012 on 1012 endometrial can- Patient). Regarding comorbidity, Tozzi et al. found that patients
cer patients operated between 2000 and 2010 in 6 Italian cen- with serious comorbidities benefit the most from laparoscopy
ters (105). Although retrospective, the study reflects the use and (111). The case of the elderly patient has been addressed in the
benefits of laparoscopic surgery in clinical practice out of the gynecologic oncology literature. Siesto et al. reported a series of
experimental setting of pioneering centers. Overall, 403 patients 48 patients older than 65 years (112). This group of patients was
were managed laparoscopically while 609 had open procedures. comparable to younger patients in operative time, blood loss,
Advanced stage, grade 3, and papillary serous subtypes were need for blood transfusions, nodal count, and intraoperative and
cauterized at a distance from the ureter and then cut. The vesi- The median blood loss was 230 mL. The mean operation time
couterine ligament is then delineated between the vesicouterine was 162 minutes. In 5 cases, conversion to open surgery was
space and the ureter; it is stretched by the combined use of the necessary due to bleeding (3 cases), bowel injury (one case),
cul-de-sac presentator and of an instrument elevating the bladder. and hypercapnia (one case). Other major intraoperative
Bipolar cautery can then be safely applied midway between the injuries occurred in 12 patients (4.1%). Postoperative compli-
uterus and the bladder. The bladder base is thus fully separated cations occurred in 10.8% patients, ureterovaginal fistula in
from the uterus and upper vagina. 5 cases, vesicovaginal fistula in 4, ureterostenosis in 3 cases,
The dorsal steps can be achieved before or after the ventral deep venous thrombosis in 9 cases, lymphocyst in 4 cases,
steps. The peritoneum of the posterior leaf of the broad liga- lymphedema in 5cases, and one case with trocar insertion site
ments is incised down to the uterosacral fold. The sacrouterine metastasis.
space is found immediately lateral to the uterosacral fold. Once In 2009, Pellegrino et al. reported the surgical outcome in a
the sacrouterine space is found and developed, the hypogastric series of 107 patients (120). Conversion to laparotomy was nec-
nerve and the ureter can be moved medially. The rectouterine essary in 6 patients. Median blood loss was 200 mL and median
ligaments are cauterized and cut at a distance (generally 1 cm) duration of surgery was 305 minutes. Minor intraoperative com-
from the uterus. The peritoneum of the pouch of Douglas is then plications occurred in 2 patients. Five patients needed a second
incised and the rectovaginal septum is developed down the pos- surgery for postoperative complications. In 2010, Lee et al. (121)
terior vaginal cul-de-sac. published a series of 139 patients. Average operation time was
The excision of the paracervix (cardinal ligament, lateral 231.1 minutes. Major intraoperative complications included
parametrium) is the next step. The extent of the excision defines one great vessel injury, one ureteral injury, one colon injury, and
the radicality. The dorsal aspect of the cardinal ligament has been 6 cystotomies. In 2011, Yan et al. evaluated the morbidity and
made visible after the section of the rectovaginal ligament. The oncological outcome in another large series of 240 cervical can-
ventral aspect is delineated by opening a narrow space below the cer patients treated with laparoscopic radical hysterectomy and
ureter (retrovesical fossa). The paracervix is then cauterized pelvic lymphadenectomy (122). The conversion rate was 1.25%.
and divided. It generally contains the deep uterine vein that can Intraoperative and postoperative complications occurred in 7%
be skeletonized and then electively cauterized and transected. and 9% patients, respectively.
The caudal aspect is then freed from the paracolpos from the A number of retrospective comparative studies are available.
line of division to the vagina. To achieve this, the paracervix is Only series of over 50 patients with laparoscopic radical hyster-
firmly grasped and elevated. Successive small cauterizations and ectomy will be mentioned. In 2004, Jackson et al. reported on
divisions are made in a horizontal plane until the white structure 57 women candidates for laparoscopic radical hysterectomy (123).
of the vaginal is visible. The vagina is then divided using the Conversion to laparotomy occurred in 5 cases. A matched con-
monopolar hook at 1 cm distance from the cervix. The uterus is trol group of radical abdominal hysterectomy was constituted.
delivered vaginally. The vaginal cuff is sutured using intraperi- Statistically significant differences were found: duration of sur-
toneal suturing techniques. The integrity of the ureter and the gery was shorter (median 180 vs. 120 min), blood loss was less
hemostasis are checked before closing the trocar sites. (median 350 vs. 875 mL), and hospital stay was less (median 5
days vs. 8 days) in the laparoscopic surgery group. There were
Preoperative Data, Complication Rate, and no statistically significant differences with regard to nodal yield,
completeness of surgical margins or perioperative complication
Postoperative Outcome rate. Four major complications (8%, 3 cystotomies and one
Noncomparative data in large series are available, as reported by enterotomy) occurred in the laparoscopic surgery group and
Spirtos et al. (115) in 2002 on 78 patients. In that series, 94% three in the open surgery group (6%, one pulmonary embolism,
of the procedures were completed laparoscopically. The mean one ureteric injury, and one major hemorrhage). Steed et al.
operative time was 205 minutes, and the mean blood loss was compared 71 patients managed laparoscopically to 205 patients
225 mL. One patient required a blood transfusion. Three patients managed by laparotomy (124). No conversion occurred in the
had unintended cystotomies, 2 patients required laparotomy to laparoscopic group. Blood loss was 300 mL in the laparoscopy
control bleeding, and one patient suffered an ureterovaginal group versus 500 mL in the open surgery group. Operative time
fistula. Pomel et al. (116) reported in 2004 on 50 patients. The was longer (3.5 vs. 2.5 h) in the laparoscopy group, in which an
median operating time was 258 minutes. No conversions to increased perioperative complication rate was observed, with
laparotomy were required. Ten patients had early complications 7 cystotomies, one ureteral injury, one bowel injury, and a lon-
(within 2 months of surgery); 3 of them required reoperation. ger time to normal urine residual. In 2007, Frumovitz et al.
Three patients had late complications (more than 2 months after (125) compared patients undergoing total laparoscopic radical
surgery); 2 of them required reoperation. Three patients experi- hysterectomy with patients undergoing total abdominal radical
enced recurrence with a median follow-up time of 44 months. A hysterectomy. The mean estimated blood loss was significantly
Chinese group (117) reported in 2007 the largest series ever pub- lower in the laparoscopic-surgery group than in the open-surgery
lished. Among 317 candidates to laparoscopic radical hysterec- group (319 vs. 548 mL). The average operative time was signifi-
tomies with lymphadenectomy, 313 procedures were completed cantly longer with laparoscopic surgery (344 vs. 307 min), but
laparoscopically. Four patients were converted for bleeding the median hospital stay was significantly shorter (2 vs. 5 days).
(n = 2), colon injury, and hypercapnia. Five cystotomies and 5 Infectious morbidity was substantially less frequent (18% vs.
vascular injuries were repaired laparoscopically. Postoperative 53%) after laparoscopic approach. In 2007, Li et al. reported
complications occurred in 5% of patients, including five uterero- on a series of 90 laparoscopic radical hysterectomies that were
vaginal fistulas, one with stenosis of the ureter and 4 with vesico- compared to 35 open radical hysterectomies performed during
vaginal fistula. In the same year, an Indian group reported on 248 the same period of time (126). Two cases were converted to lapa-
patients with stage IA2-IB1 cervical cancer (118). No patients rotomy. Consistent with other reports, they found an increased
were converted to laparotomy. Fifteen intraoperative complica- operating time (263 vs. 217 min) for laparoscopic procedures.
tions were managed laparoscopically and 17 had postoperative However, they did not find a reduced blood loss. Interestingly,
complications within 2 months of surgery. they investigated the time to recover bowel movements and found
In 2008, Chen et al., in the same team as Xu et al., reported on a significantly reduced time after laparoscopy (2 vs. 2.4 days).
295 procedures (119), 290 of which were successful. Para-aor- In 2009, Malzoni et al. compared 2 series of laparoscopic
tic lymphadenectomy was performed in 156 patients (52.9%), (n = 65) and open (n = 62) radical hysterectomies (127). Consistent
and pelvic lymphadenectomy was performed in all 295 patients. with earlier reports, there was less blood loss (55 vs. 145 mL),
CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER 221
median operating time was longer (196 vs. 152 min), and hospi- mainly in terms of blood loss and hospital stay. The outcome
tal stay was shorter (4 days vs. 7 days) in the laparoscopy group. balance combining improved quality of life (QOL) without
The specific question of the extent of parametrial resection and compromising survival is in favor of adopting MIS as the gold
its relationship with urinary complications has been addressed in standard for radical hysterectomy.
two studies. Ghezzi et al. (128) compared radical hysterectomy
specimens of sequential patients undergoing laparoscopic radical Nerve-sparing Radical Hysterectomy (Type C1)
hysterectomies (n = 50) with those of historical controls selected Nerve-sparing radical hysterectomy has been designed to pre-
from women who have had conventional open radical hysterec- vent the frequent urinary dysfunctions associated with classi-
tomy (ORH; n = 48). The parametrial width was similar between cal (type C) radical hysterectomy. Logically, the magnification
laparoscopic and abdominal radical hysterectomies. Uccella et al. and lighting provided by the laparoscope has also been used to
compared 50 laparoscopic surgeries to 48 patients historical achieve a precise dissection of the pelvic autonomic nerves.
cohort managed by open surgery. There was no statistically signifi- The technique was pioneered by Possover et al., who identified
cant difference in intraoperative urinary complications between the middle rectal artery as a landmark separating the neural part
the groups. Four intraoperative urinary tract injuries in the lap- from the vascular part of the paracervix (135). The bladder func-
aroscopic surgery group (3 cystotomies and 1 ureteral lesions, tion was significantly less altered after their attempt at preserving
all repaired laparoscopically) and 2 in the open surgery group the neural part of the paracervix (cardinal ligament).
(2 cystotomies) occurred. Urinary postoperative complications Since 2010, several investigators reported on full laparoscopic
were: 1 ureterovaginal, 1 vesicovaginal fistula, and 1 delayed nerve sparing radical hysterectomy (LNSRH). Liang et al. (136)
without additional risk of urinary complications. The concept Pahisa (142) included 67 patients in the study group. The
has been proved in a comparative study of radical hysterecto- number of pelvic nodes, disease-free margin, and complications
mies with or without paracervical dissection, which concluded rate were similar in the study and control groups, but blood
that adding a bilateral paracervical lymphadenectomy does not loss and blood transfusion rates were marginally less in the CS
increase the preoperative complications and urinary dysfunctions group. Operating time was longer in the first 20 CS patients, but
rates (114). it became comparable to open surgery once the learning curve
was completed. Hospital stay was significantly shorter in the CS
Laparoscopico-Vaginal Operations group and so was the bladder function recovery time. However,
no differences were seen regarding long-term urinary and bowel
The combination of laparoscopic lymph node dissection and
functions between groups. Six percent from the CS group and
radical vaginal surgery was a major breakthrough in gynecologic
13% from the open surgery group had recurrence. Mortality
oncology. The question is the current place of combined tech-
rates were 3% and 9%, respectively.
niques (137). The key issue is training in radical vaginal surgery.
Full description of the technique can be found in textbooks (91).
Although the Schauta operation is mastered by only a few Schautheim
gynecologic oncologists, it is of note still the best option in partic- In 2007, Leblanc described a technique that involved making
ular patients, such as patients with stage 4 uterine prolapse. The the vaginal cuff as a first step of the procedure, thus making the
technique involves, after laparoscopic lymphadenectomy, creat- laparoscopic step easier (91,145).
ing and incising the vaginal cuff, opening the pouch of Douglas, In conclusion, radical vaginal hysterectomy combined with
opening the paravesical and pararectal spaces, developing the laparoscopic lymphadenectomy or laparoscopico-vaginal pro-
vesicouterine space, and identifying the ureters in the bladder cedures are still a safe alternative to full laparoscopic radical
pillar. The uterine arteries are then controlled and the paracervix hysterectomy in the treatment of early stage cervical cancer in
are then divided under direct vision of the ureters. Type A or B selected patients. In clinical practice, the various minimally
radical hysterectomies, according to tumor extent, are achievable invasive techniques for radical hysterectomy are not concurrent
without the perineotomy used by the early pioneers. but complementary, and indication of each method is adapted
Only the laparoscopico-vaginal operations and their results to the individual patient. The full laparoscopic procedure has
are in the scope of this chapter. Two combinations are available: gained more acceptance.
the Coelio-Schauta procedure a name designed by Dargent It must be stressed that familiarity with the radical vaginal
after the French coelioscopie (for laparoscopy) and the hysterectomy technique would facilitate performing specific
Schautheim a hybrid name designed by Leblanc after the fertility-sparing radical vaginal trachelectomy in young women
Schauta and Wertheim eponyms. The former name describes with early cervical cancer. Training programs in gynecologic
a surgery starting laparoscopically and finished vaginally. The oncology should continue to cultivate radical vaginal surgery
latter describes a procedure starting vaginally and finished training, or alternately selected patients should be referred to a
laparoscopically. few centers that have kept a sufficient experience in this technique.
Coelio-Schauta
After the initial description of laparoscopically assisted radical
Laparoscopic Radical Trachelectomy
vaginal hysterectomy involving a laparoscopic step (division of the Radical trachelectomy is a conservative variant of radical hys-
uterine artery and of the superficial uterine vein at its origin) and a terectomy for young patients affected by early invasive cancer
vaginal management of the ureters and cardinal ligaments (1011), on the superficial aspect of the cervix. The first pregnancies
several variants of different extent have been described (138). were described by Dargent, who used a laparoscopico-vaginal
Large series have been published with reassuring results. approach allows successful outcomes.
Sardi et al. (141) reported on 47 patients who underwent a pro- Contrary to radical hysterectomy, the vaginal approach
cedure closer to a classical radical vaginal hysterectomy than a (Dargent operation) remains the gold standard approach for
laparoscopically assisted procedure. After 4 years, the overall radical trachelectomy. Its oncological and pregnancy outcomes
survival was 100% for stage IA, 88% for stage IB1, and 85% have been extensively documented in large series (146,147,148).
for stage IB2. They suggested that 20 cases were needed to obtain As it is essentially a radical vaginal procedure, associated with a
the minimum skill to perform CS. Hertel et al. (142) reported a laparoscopic lymphadenectomy, a topic that has been addressed
large series of 200 patients with cervical cancer stages IA to IIIA above, the Dargent operation is beyond the scope of this chapter
who underwent a variety of radical hysterectomies, including and will only be briefly described.
type III (type C) procedures. A variant including laparoscopic The operation proceeds the same way as the Coelio-Schauta. The
nerve sparing preservation has also been described (140). first difference is that the uterine artery is preserved. The second
Two studies compared the safety, efficacy, and short-term ben- and major difference is that the uterus is divided 5 mm below the
efits of the Coelio-Schauta (CS) procedure with open Wertheim/ isthmus. The specimen is sent to the laboratory for assessment
Meigs radical abdominal hysterectomy in cervical cancers. of its superior margin by frozen section. The cavity is sounded
Sharma et al. (143) retrospectively analyzed records of 35 con- and a dilator is inserted to widen the canal and facilitate the
secutive stage IB patients undergoing Coelio-Schauta for early reconstruction. Once the results of the frozen section determine
cervical cancer and 32 ORHs. There were statistically significant negative margins, the reconstruction is undertaken. The pouch
differences between CS and ORH for duration of surgery (mean of Douglas is closed with a running suture. An isthmic cerclage,
160 vs. 132 min), intraoperative blood loss (479 vs. 715 mL), using the same suture used for the conventional prophylaxis of
hospital stay (mean 5 vs. 9.3 days), postoperative complications miscarriage, is then placed. Finally, an isthmovaginal anastomosis
(6 vs. 20 patients), and duration of bladder catheterization (mean is performed using Sturmdorf stitches or interrupted sutures
4.4 vs. 8.8 days). Four CS patients and no open-surgery patients approximating the vaginal mucosa and the isthmic mucosa with
had urinary tract injury. None had long-term sequelae. Their great care not to involve the internal os.
data confirmed that although CS is a suitable alternative to ORH Abdominal techniques have been developed, and quickly
for small-volume stage IB1 cervical cancer with similar clinical mimicked by laparoscopic procedures (149) involving a variety
efficacy and a superior postoperative recovery and postoperative of combination of vaginal and laparoscopic steps. The laparo-
morbidity profile, urinary tract trauma is a clear risk in the early scopic step is generally used for the resection of parametrium.
stages of the learning curve. The uterine artery can be preserved. Nerve-sparing techniques
CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER 223
have been described (150,151). The full procedure can be com- pelvic defect to cover. Interestingly, the older group of patients is
pleted laparoscopically, but the surgeon may elect to use a vagi- thus more amenable to laparoscopic pelvic exenteration.
nal step that may involve incision of the vagina, retrieval of the
specimen, and uterovaginal anastomosis.
In the largest series to date, 27 patients underwent laparo-
Other Procedures
scopic radical trachelectomy (152). The mean operating time was General surgery procedures associated with gynecologic malig-
290 minutes and the mean estimated blood loss was 332 mL. nancies, such as colostomy or splenectomy for isolated metastasis
There were no perioperative complications requiring further sur- can be performed laparoscopically or hand-assisted by laparos-
gical management. After a median follow-up time of 31 months, copy (157) (see also corresponding section below). Laparoscopy
there was one recurrence and death from disease. Regular may help the radiation therapist or medical oncologist through
menstruation returned in 24 patients. Six patients attempted to the placement of pelvic displacement prosthesis, and guiding the
conceive, and three succeeded. placement of interstitial radiation implants (interstitial brachy-
therapy implants, placement of intraperitoneal port-a-cath [158]).
Laparoscopic ligation of the hypogastric artery has been described
Laparoscopic Pelvic Exenteration as an alternative to embolization in severe hemorrhage related to
Positive peritoneal cytology, microscopic or macroscopic peri- uterine cancers. We have managed laparoscopically lymphocysts
toneal disease, and positive aortic nodes are contraindications by intraperitoneal marsupialization, and vaginal eviscerations by
to exenteration. As all these conditions can be ruled out using laparoscopic omentoplasty combined with vaginal closure. New
the BMI (163). While former studies suggested that obesity can recurrence, and long-term QOL issues will be addressed, with an
be the limiting factor when attempting lymph node dissection, emphasis on large series, comparative studies, and randomized
more recent reports show similar lymph node counts regardless controlled studies.
of BMI in endometrial cancer patients (164).
Laparotomy in the obese patient obviously prolongs hospital
stay and increases wound complications. As a result, more mor- Endometrial Cancer
bidity is seen in the open group than in the laparoscopic group. The mainstay of surgery for endometrial cancer is simple hyster-
When comparing group of patients managed laparoscopically ectomy with bilateral salpingo-oophorectomy, along with retro-
with a historical group managed by laparotomy, several out- peritoneal staging according to guidelines.
comes are significantly improved: shorter hospital stay, less pain
medication, and smaller drop in postoperative hematocrit, at the
expense of longer operative time. Oncological Outcomes
In the LAP2 study, conversion rates were 27% in patients Six randomized studies comparing oncological outcomes after
with BMI greater than 35 kg/m2 and 57% in women with BMI laparotomy and laparoscopy, respectively, are currently avail-
greater than 40 kg/m2 (101). The high conversion rate reflects able. The first 5 were included in a meta-analysis published then
the multicentric design of the study, including less experienced updated by Palomba et al. in 2009 (171). Only three studies
surgeons. In contrast, conversion rate was only 10.6% of 47 were selected, resulting in a sample of 359 patients (97,124,170).
obese patients and 7% in 85 with BMI higher than 40 in mono- No significant heterogeneity was observed among studies. No
centric series (163,165). significant effect of laparoscopic approach on the disease-free
A French study investigated the feasibility of laparoscopic and survival, overall survival, and cancer-related survival (OR 0.95,
vaginal surgical approaches in obese patients with endometrial 0.96, 0.91, respectively).
cancer (164). After matching 41 obese patients treated by laparos- Long-term outcomes of the randomized controlled LAP2
copy with 29 obese patients treated by laparotomy, hospital stay study were published in 2012 (173). The primary study end
was found to be significantly shorter in the laparoscopy group point was noninferiority of recurrence-free interval. Non-
(3.8 vs. 7.4 days), whereas pelvic nodes counts (16.3 vs. 11.5), inferiority was defined as no more than a 40% increase in the
operative time (149.9 vs. 167.9 min), and disease-free survival risk of recurrence with laparoscopy compared with laparotomy.
(93% vs. 80%) were similar in both groups. One patient treated Laparoscopy was compared with laparotomy regarding recur-
by laparotomy never received intended radiotherapy because of a rence after surgical management of uterine cancer stage I to
delay greater than 3 months caused by cutaneous necrosis. IIA. Patients were randomly allocated (2 to 1) to laparoscopy
In a recent series from Louisville (167), 168 women underwent (n = 1,696) versus laparotomy (n = 920). The estimated haz-
surgery: laparotomy n = 103 and laparoscopy n = 65, including ard ratio for laparoscopy relative to laparotomy was 1.14 (90%
12 of them converted to laparotomy. There were 29 patients with confidence interval 0.921.46). The actual recurrence rates were
BMI over 35 who were managed laparoscopically. Complica- substantially lower than anticipated, resulting in an estimated
tion rates were significantly lower after laparoscopy compared to 3-year recurrence rate of 11.4% with laparoscopy and 10.2%
laparotomy: overall complications 53.8% versus 73.8 (p = 0.01); with laparotomy. The estimated 5-year overall survival was
grade 3 complications, 9.2 versus 34.0 (p < 0.01); greater than almost identical in both arms at 89.8%.
or equal to 3 wound complications, 3.1 versus 22.3 (p < 0.01); In a comparative historical study, Ghezzi et al. (174) presented
and greater than or equal to 3 wound infections, 3.1 versus 20.4 the outcomes of consecutive patients with clinical stage I endo-
(p = 0.01). metrial cancer managed laparoscopically with greater than 3-year
The limitations mentioned above can be overcome using follow-up (median follow-up of surviving patients, 52 months).
refinements of laparoscopic technique. Suspension of the sigmoid Data from 117 consecutive women were compared with a histori-
colon may help. Correct placement of trocars, above the umbi- cal cohort of 122 consecutive patients with endometrial cancer
licus, helps to keep a proper distance between the endoscope, who had undergone open surgery. The laparoscopy and laparot-
the pelvic contents, and the symphysis pubis. Furthermore, the omy groups were similar with regard to potentially confounding
extraperitoneal technique can be used for aortic dissection. The factors. Similar 3-year recurrence-free survival rates (91.4% vs.
technique overcomes the obstacles mentioned above, as the bowel 88.5%), as well as similar 3-year overall survival rates (94.0% vs.
is not in the way, a Trendelenburg position is not required, and 93.4%) were observed in the 2 groups.
the ergonomy of the surgeon is more acceptable. This approach
has been successful in 92% of obese patients in the Mayo Clinic
Rochester team (168). In the same mindset of combining avail- Quality-of-Life Issues
able approaches, Benedetti-Panici et al. used a combination of Patients who undergo laparoscopic surgery seem to report a
laparoscopy and transverse minilaparotomy, with a success rate higher level of satisfaction with laparoscopy when compared to
of 87% in a series of 39 none of the conversions in this series patients treated with total abdominal hysterectomy. They benefit
was related to obesity (169). from a shorter recovery time and are able to return to work and
The literature on radical hysterectomy and obesity is scant. full activity more quickly. In a recent prospective, randomized
Moss et al. (170) reported on the laparoscopic management of study comparing laparoscopy to laparotomy in the management
15 patients with early-stage cervical cancer and BMI greater than of endometrial cancer, Zullo et al. (175) prospectively demon-
30 (up to 56). No case was converted to laparotomy. This group strated that patients treated with laparoscopy did indeed have
was compared to a group of 43 patients with BMI less than 30. improved QOL for the first 6 months after surgery.
Median duration of surgery, estimated blood loss, median hos- Quality of life up to 6 months after surgery was also assessed
pital stay, number of retrieved nodes, length of vaginal cuff, and in an RCT comparing total laparoscopic hysterectomy with
parametrial excision were not affected by obesity. total abdominal hysterectomy for stage I endometrial cancer
(100). A total of 361 participants were enrolled and 332 com-
pleted the QOL analysis. Analysis was done according to the
Surgical Management of intention-to-treat principle. In the early phase of recovery, and
up to 6 months after surgery, patients who had laparoscopic
Gynecological Malignancies surgery reported significantly greater improvement in QOL
This section describes oncological issues related to the incor- from baseline, in all subscales apart from emotional and social
poration of laparoscopic surgery in the management. Survival, well-being that are related to patients dealing with cancer.
CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER 225
GOG LAP2 also required patients to complete QOL assess- open surgery. Although the median follow-up was only 26 months,
ments at baseline and then at 1, 3, and 6 weeks, and 6 months the recurrence rates for the laparoscopic and laparotomy groups
postoperatively (176). The first 802 eligible patients random- were similar. Sobiczewski et al. (185) found a similar 3-year
ized in LAP2 participated in the QOL study. Within 6 weeks of survival in 22 IA-IIA cervical cancer patients managed laparo-
surgery, patients assigned to laparoscopy reported significantly scopically, compared to 58 patients who underwent laparotomy.
better QOL on all scales other than fear of recurrence. In sum- However, they observed intraperitoneal recurrence in 2 patients.
mary, during this 6-week postoperative period, patients assigned The largest comparative study with follow-up has recently
to laparoscopy were found to have superior QOL, fewer physi- been published by Nam et al. (186). A total of 263 patients
cal symptoms, less pain and pain-related interference with func- with stage IA2 to IIA cervical cancer were followed up over
tioning, better physical functioning and emotional state, earlier 24 months and matched to an equivalent number of patients with
resumption of normal activities, earlier return to work, and better comparable prognostic factors. Compared with open surgery,
body image as compared to those assigned to laparotomy. laparoscopic surgery was not associated with a higher risk of
The Dutch randomized study also addressed the QOL of recurrence (hazard ratio = 1.28; 95% CI 0.622.64) or death
endometrial cancer patients having undergone hysterectomy (hazard ratio = 1.46; 95% CI 0.623.43). Specifically, 16 versus
and bilateral salpingo-oophorectomy (95,109). The results of 15/263 had recurrent disease and 12 versus 11 died of disease
this study are not consistent with others, as laparoscopy patients in the laparoscopy and open surgery groups, respectively. Even
scored significantly higher only on the physical functioning sub- in patients with tumors greater than 2 cm in diameter, the risks
scale at 3 months after the procedure. Median quality adjusted of recurrence were not higher for laparoscopic radical hysterec-
proportion of patients with locally advanced cervical who have In a retrospective review of 20 laparoscopic staging cases
low-volume metastases and negative PET scans in the aortic area and 30 laparotomy staging controls, Chi et al. (194) found no
(51,188). The proportion is higher in patients with positive pelvic differences between the 2 groups in pelvic or paraaortic lymph
nodes at PET-scans (22%) as compared with patients with no node counts and omental specimen size. While there were no
pelvic node uptake (12%). As a consequence, aortic dissection complications in the laparoscopy group, there were 3 minor
using the lateral extraperitoneal laparoscopic technique has been complications in the laparotomy group (2 wound infections and
adopted by a number of institutions to define the extent of radia- one postoperative ileus). The laparoscopy group had a signifi-
tion fields (189). In this setting, common iliac dissection is gener- cantly longer operative time (321 vs. 276 min) but significantly
ally added. However, to perform a pelvic dissection or not is still less blood loss (235 vs. 367 mL), and a shorter hospital stay (3.1
controversial. The therapeutic value of dissection that removes vs. 5.8 days).
positive nodes and identifies a subgroup of patients likely to ben- In a comparative retrospective study comparing 17 patients
efit from extended field radiation therapy (52), has been suggested managed by laparoscopy to 19 patients managed by open sur-
but has yet to be demonstrated by a controlled study. gery, Park et al. (195) confirmed that the number of lymph nodes
retrieved and operating time was similar. The laparoscopy group
Completion Hysterectomy after Radiation Therapy had significantly less estimated blood loss, faster return of bowel
movement, and a shorter postoperative hospital stay compared
The issue of completing definitive radiation therapy by a hyster-
to the laparotomy group. Transfusions were required only in 2
ectomy in locally advanced cervical cancer is controversial. Some
laparotomy patients, and postoperative complications occurred
patients with incomplete response to radiation therapy with con-
only in 4 laparotomy patients. In contrast with more reassur-
comitant chemotherapy may benefit from salvage surgery. The
ing data, they observed that 2 patients with stage IA grade 1
extent of such a surgery is adapted to the size and localization
and 2 disease in laparoscopy group had recurrence with 1patient
of persistent disease. Should the team decide to perform such
dying of disease.
a surgery, the elective choice is a type A radical hysterectomy,
Although there are no randomized trials comparing both
which is potentially associated with less complications. Only one
approaches, it appears that a comprehensive laparoscopic of
paper addressed the issue of laparoscopic surgery in this context.
patients with early-stage ovarian cancer is feasible and accurate.
Colombo et al. (190) retrospectively reviewed 102 patients and
The morbidity is lower compared to the same procedure done by
were able to compare 46 laparoscopic with 56 abdominal radi-
laparotomy. However, this procedure should only be performed
cal hysterectomies after radiation therapy. Seven patients in the
by experienced and skilled laparoscopists capable of performing
laparoscopic group required conversion to laparotomy (15%).
advanced and complex oncologic laparoscopic procedures, and
Mean estimated blood loss (200 vs. 400 mL) and the median
with a careful follow-up of patients.
duration of hospital stay (5 vs. 8 days) were significantly lower
in the laparoscopic group. Morbidity rates and urinary com-
plications were reduced in the laparoscopic group (p = 0.04). Laparoscopic Surgical Management of
Local recurrence rates, disease-free, and overall survival rates Early-Stage Adnexal Cancer
were comparable in the 2 groups.
There are uncertainties that are still not well answered with
regard to the safety and efficacy of minimally invasive surgery
Ovarian Cancer in early-stage ovarian cancer. Until such solid data are available,
oncologists should remain very cautious with regard to the use of
Reassessment of Apparent Early Ovarian Cancers laparoscopy in the management of suspicious complex adnexal
On occasion, despite thorough preoperative investigation, patients masses and early-stage ovarian cancer. First and foremost, mini-
are operated on for a presumed benign ovarian mass, yet an unex- mal access surgery should not compromise outcome, particu-
pected diagnosis of ovarian cancer occurs on final pathology, or larly for patients with early-stage disease who have an excellent
the operating surgeon does not feel comfortable completing the prognosis.
staging procedure. In such situations, a complete surgical reassess- This being stated, two series involving a substantial number
ment is required. In presumed stage I disease, the chances of finding of patients have been published. Nezhat et al. reported in 2009
more advanced disease in the peritoneum and/or lymph nodes is a series combining restaging surgeries, surgeries for borderline
in the range of 20% to 30%. Laparoscopy may be an excellent tumors, and including 25 full laparoscopic management of early
alternative to complete the surgical management and staging as ovarian cancers presenting as ovarian masses (196). There were
contralateral bilateral salpingo-oophorectomy and hysterectomy 20 epithelial ovarian tumors and 5 were germ-cell or sex-cord
along with a complete pelvic and paraaortic node sampling, an stromal tumors. Only one patient with clear cell carcinoma of
infracolic omentectomy, and a complete peritoneal assessment may the ovary recurred after a mean follow-up of 56 months. A series
be performed laparoscopically. An extensive review of this indica- of 82 cases has been published by Ghezzi et al. in 2012 (197).
tion has recently been published by Iglesias and Ramirez (191). Although including 17 patients who had reassessment only and
Over a 10-year experience, Leblanc et al. laparoscopically were not studied separately, 3-year overall survival and 3-year
restaged 42 patients with apparent early ovarian cancer and 7 disease-free survival were 97% and 91.2%, respectively, in the
with fallopian tube cancers (192). Only one patient had to be subgroup of 34 patients who had reached or exceeded 3 years
converted to a laparotomy because of adhesions, and 19% of follow-up. No conversion to laparotomy occurred in this series.
patients were upstaged as a result of the staging procedure. The Thirteen patients (15.8%) experienced postoperative complica-
authors concluded that laparoscopic surgery meets the standards tions. Only one patient had intraoperative hemorrhage requir-
of a complete staging procedure, spares the patients the incon- ing blood transfusion. These results are reassuring and confirm
venience of a laparotomy, and accurately identifies patients with the findings of an earlier report (198) in which 2 patients in a
more advanced disease who require adjuvant chemotherapy. series of 24 presented with recurrent disease after a 46-months
In a recent GOG trial, Spirtos et al. completed the staging follow-up.
of incompletely staged gynecologic malignancies including
ovarian and fallopian tube cancers. They noted a conversion Laparoscopic Debulking of Advanced
rate of 20% to laparotomy, most often due to the presence of
adhesions. Nevertheless, nearly 70% of patients had a success- Ovarian Cancer
ful complete laparoscopic staging and 11% were found to have Some investigators have elected to debulk laparoscopically
more advanced disease (193). advanced ovarian cancers, mainly after neoadjuvant therapy.
CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER 227
The debulking procedure relies on the electrosurgery or use of their results regarding the laparoscopic restaging of borderline
devices such as the Argon Beam Coagulator. tumors and confirmed the feasibility of that surgical approach.
Trinh et al. reported in 2004 on 36 patients with chemosensi- In their series of 42 patients, there were no conversions and no
tive (recurrence after 6 months) recurrent ovarian cancer iden- intraoperative or postoperative complications. As expected, they
tified on the basis of rising CA-125 (199). About 34 patients noted that ovarian cystectomies were associated with a higher
underwent successful laparoscopic debulking without requiring risk of persistent lesions, and the risk of upstaging was higher in
laparotomy, 32 had all visible disease resected at laparoscopy cases of serous borderline tumors (209).
and 6% had surgical complications. Median time for surgery
was 2.6 hours, median blood loss 70 mL, and median hospital
stay 1 day. Seventy-four percent had a complete response after
Radical Surgery for Vaginal Cancer
laparoscopic debulking and chemotherapy with a median pro- Surgery for the management of cancers of the vagina and/or
gression-free survival of 1.1 years. In the same team, Fanning et vulva includes lymph node dissection. For cancers of the upper
al. (200) reported on 23 procedures without conversion to lapa- half of the vagina, the management is similar to that of patients
rotomy. Median operative time was 2.3 hours and median blood with cervical cancers. Open surgery is the standard, but full lapa-
loss was 340 cc. Median length of stay was 1 day. Six patients roscopic surgery or laparoscopically assisted vaginal radical sur-
(24%) had postoperative complications; none were grades 34. gery can be used as well. The best indication for laparoscopy may
They stated that the patients were successfully cytoreduced lapa- be for the reoperation of patients with incidental cervical cancer
roscopically. However, although all tumors were debulked to less discovered at simple hysterectomy. Again, a full laparoscopic
carcinomas of the fallopian tube, ovary, and peritoneum. The oncology, ovarian transposition has been proposed in patients
authors hypothesized that this procedure might protect BRCA with cervical or vaginal cancer managed by preoperative brachy-
carriers from high-grade serous pelvic carcinoma while preserv- therapy. In this context, before definitive radiation therapy or
ing their ovarian function until completion of their childbearing postradiation hysterectomy, adnexal transposition is more likely
desire or the age of natural menopause. to preserve the ovarian vascular supply. Again, laparoscopy is the
In their seminal paper, they established a surgical technique preferred approach for the same reasons.
consisting of removing the tube and the adjacent portion of the The benefit of prevention of estrogen deficiency is minimal
ovary. To fully preserve the blood supply to the ovary, care is considering: (a) the availability in gynecologic cancer patients of
taken to remove the tube without coagulating the utero-ovarian hormone replacement therapy, (b) the risk of ovarian failure imme-
artery. This is achieved by carefully controlling the tubal ves- diately after transposition, and (c) the frequency of early meno-
sel after transection of the isthmus. The medial part of the ovary pause when the ovaries are transposed. On the other hand, the
attached to the fallopian tube by the tubo-ovarian ligament is psychological benefit of retaining normal ovaries and a normal
then excised. Approximately one-quarter of the ovary is removed. hormonal cycle is not to be neglected. The preserved ovaries are
Care is taken to preserve the infundibulopelvic blood supply to available for assisted reproductive technologies followed by surro-
the uterus. To achieve this step of the operation, efficient hemo- gate pregnancy. However, the benefit decreases with age. The age of
stasis, minimal trauma to the remaining ovary, and preservation 40 is generally considered as the upper age limit for ovarian trans-
of the specimen for pathological examination are required. The position. The risks are represented by the high incidence of ovarian
authors compared four methods of partial ovarian transection: cysts and by the risk of ovarian metastasis from cervical cancer. An
sharp division, stapler, bipolar division, and harmonic scalpel. estimate of the risk is available in a large study by Shimada et al.
Fourteen women were enrolled in a pilot study. They underwent (212). The incidence of ovarian metastasis in patients with cervi-
radical fimbriectomy, and after assessment of hemostasis, had cal cancer was 0.22% for stage IB, 0.75% for stage IIA, 2.17%
definitive oophorectomy in the same operating session. Sharp and for stage IIB with squamous cell carcinoma, and 3.72%, 5.26%,
EndoGIA appeared to be the safest methods of ovarian resection and 9.85%, respectively, in adenocarcinoma. Ovarian metastasis
providing the best specimen quality for pathological examination. occurred more frequently among patients with adenocarcinoma
The benefit of approach in terms of fertility and prevention of than among those with squamous cell carcinoma (5.31% vs.
ovarian cancer is still hypothetical and is currently assessed in a 0.79%). Outcome for patients with ovarian metastasis was poor. In
prospective study in France. Although it does not prevent type 1 that study, the presence of ovarian metastasis did not correlate with
ovarian cancer, it might be preferable to no prophylactic surgery lymph node involvement or parametrial invasion, in contrast with
at all, as it prevents fallopian tube cancer or ovarian cancer pre- earlier studies. Ovarian preservation is thus safe in young patients
cursor, and may prevent type 2 ovarian cancer, which is the most presenting with early squamous cell carcinoma of the cervix. It can
frequent histologic subtype observed in BRCA carriers. Indeed, be proposed at the time of a staging laparoscopy for sentinel node
Leblanc et al. found p53 signature and/or overexpression of procedure or staging lymph node dissection (213).
KI 67 in four tubes or inner part of the ovary. No cancer precursor The technique of adnexal transposition is based on several
was identified in the remaining part of the ovaries. principles. (a) The adnexa is detached from the cornua and left
If the proof of concept is obtained in the future, laparoscopic with the infundibulopelvic vascular supply. Kinking or torsion
radical fimbriectomy may benefit a subset of BRCA carrier patients. of the adnexal pedicle must be avoided to preserve the vascular
Women who undergo radical fimbriectomy should continue to supply. (b) The ovaries must be placed intraperitoneally as high,
receive regular multimodal evaluation and be advised of the risks anterior, and lateral as possible to reduce exposure to radiation
involved until they finally accept secondary oophorectomy after therapy. In this regard, placing radiopaque clips on the most
completion of fertility desire or after the age of 40. caudal aspect of the transposed ovaries is of help to estimate the
dose of radiation therapy received by the ovaries. (c) The high
positioning of the adnexa must be secured with a minimum of
Laparoscopic Ovarian/Adnexal direct trauma to the ovary by suturing or manipulation, using
the tube to anchor the adnexa. Staples, tackers, or blocking
Preservation clips can be used to attach the fallopian tube to the peritoneum.
Discussion about the indication for ovarian preservation at the The pedicle can be left in the peritoneal cavity after division
time of radical hysterectomy for cervical cancer is beyond the of the peritoneum of the paracolic gutter. It may be preferable
scope of this chapter. From a technical point of view, laparoscopic not to incise the peritoneum, and rather create a peritoneal
ovarian preservation is straightforward. Bipolar cautery followed tunnel between the pelvis and a peritoneal opening created at
by section, or more sophisticated instruments ensuring preventive the appropriate location. The adnexa is pushed in the tunnel
hemostasis and section, is used to gradually separate the adnexa and retrieved in the peritoneal cavity through the high opening.
from the uterus. It is advised not to divide too close to the uterus, The technique has the advantage of further maintaining the high
as the vascular supply is more easily controlled stepwise at a 1-cm position of the adnexa, and avoiding the risk of bowel obstruc-
distance from the uterus. The round ligament is divided first. The tion secondary to an incarceration of a bowel loop below the
isthmus of the fallopian tube and the internal tubal artery are adnexal pedicle. However, the success rate of the procedure may
coagulated and divided. A firm divergent traction of the uterus be as low as 65% (214). Incidentally, the successful laparoscopic
and the adnexa stretches the area of the utero-ovarian vessels and management of a metastatic adenocarcinoma arising on a trans-
the utero-ovarian ligament. These structures are gradually cauter- posed ovary has been reported (215).
ized and cut. The ovaries are left in place in the pelvis or alter-
nately can be transposed if a postoperative radiation therapy in
young women is expected.
The main indication for ovarian or adnexal transposition is N EW TECH N IQU ES I N M I N I MAL
the case of young patients undergoing pelvic radiation therapy I NVASIVE SU RGERY
for malignant disease such as lymphoma, pelvic sarcoma, or
rectal cancer. In this context, ovarian transposition is the pre- Some limitations of laparoscopic surgery are overcome by the
ferred option to keep functional tubes. Laparoscopy is the logical development of new techniques. The case of the big mass may be
approach in this indication. It results in shorter recovery and managed using the hand-assisted laparoscopy (HAL). The limi-
reduced adhesion formation rate, which is especially important tations due to surgeons fatigue or the difficulties of laparoscopic
in patients when radiation therapy is to be given. In gynecologic training are addressed by the development of robotic-assisted
CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER 229
laparoscopic surgery (RALS). A number of investigators are followed by a focused minilaparotomy can be chosen depending
pushing the envelope and are investigating a further reduction on the presentation.
of trocar incision, in size (microlaparoscopy), or in number Benedetti-Panici et al. recently assessed the role of LGM
(single-port), or using natural orifices transluminal endoscopic using a transverse incision in morbidly obese patients (169).
surgery (NOTES). There were 39 patients with BMI equal to or over 40 underwent
a variety of gynecologic surgical procedures including surgical
management of early endometrial cancer. LGM was feasible in
34 patients. Peritoneal malignancy was found in two patients.
Hand-Assisted Laparoscopy In three patients, conversion to laparotomy was necessary due
Hand-assisted laparoscopy (HAL) has been introduced as an to adhesions, parametrial involvement, and vascular injury,
adjunct to conventional laparoscopic surgery to facilitate the respectively. The use of transverse minilaparotomy is logical
surgery and reduce the rate of conversion to laparotomy. It is in obese patients with early uterine malignancy. In contrast,
used more frequently by gastrointestinal (GI) and genitourinary primary laparoscopy avoids inadapted transverse incision in
(GU) surgeons, and procedures such as splenectomy, pancre- patients with peritoneal spread.
atectomy, hepatectomy, nephrectomy, prostatectomy, aortofem-
oral bypass, and colectomy have been successfully performed
by HAL. The HAL approach implies a 6- to 8-cm skin incision
to place the gel port through which the surgeons hand and the Microlaparoscopy
the real benefits of this new technique. The absence of any vis-
ible scar (the memory of the operation), and the reduction in Table 10.1 Theoretical Considerations for
postoperative pain (still to be demonstrated) must be balanced, Robotic-Assisted Surgery in
as for SPLS, with significant technical difficulties related to the Gynecologic Oncology
method: first is the risk of intra-abdominal infection and spill-
age by the opening of a hollow viscus (that needs to be securely Advantages Disadvantages and Concerns
closed at the end of the procedure by a clip or a suture) and the Intuitive operation Short-term outcome: lack of levelI
difficulty to sterilize flexible endoscopes and operative channels. Increased dexterity evidence.
Control of the gas pressure through endoscope is another dif- Improved vision Long-term oncologic outcome: no
ficulty and a technologic challenge. Then the absence of tactile Faster adoption data presently available
sensation due to the length of the endoscope and flexible instru- Availability of MIS to Increased operative time compared
ments, not compensated by a stereoscopic vision (as in robotics), most patients. to open surgery.
the disorientation due to the use of a flexible endoscope, which Reduced Cost
should be compensated in the future by a navigation system Complication rates Upfront high cost of system
using either augmented or virtual reality. A dissection through Pain Significant maintenance cost
a colpotomy may be questionable from an oncological point of Bleeding, transfusion rate Instruments cost.
view. Finally, the sexual outcomes of this vaginal scar should be Length of hospital stay
assessed. However, in spite of these current drawbacks, NOTES compared to open surgery.
Seamon et al. at Ohio State University compared robotic surgery with superior short-term results and similar oncologic outcomes
and open surgery in obese patients with endometrial cancer and (Table 10.2). A prospective randomized trial comparing mini-
demonstrated that robotic procedures were associated with a mally invasive radical hysterectomy (laparoscopic or robotic)
reduced transfusion rate and fewer complications, be it wound with laparotomy is currently underway (252).
or other complications (243). Robotic-assisted MIS was shown
to be not only feasible, but also appeared to neutralize the risk Robotic Radical Parametrectomy
factors for surgery associated with obesity. In the report by Lau
et al. obese patients had the same clinical outcome with similar Only 2 studies presently report on small series of patients following
perioperative experiences, and low conversion rates (5.6%), com- radical parametrectomy performed using the robot. Ramirez and
pared with nonobese women. The conversions were all at the colleagues reported on 5 cases with squamous cell carcinoma of
end of the procedure only to remove enlarged uteri that could the cervix (253). None of the patients needed adjuvant treatment
not be delivered intact via the vagina (244). These authors then following the radical parametrectomy. One patient had an intraop-
adopted side docking and in patients with enlarged uteri, bisected erative cystotomy, and a second patient presented with a vesicovag-
the specimens within large endobags introduced via the vagina at inal fistula and a lymphocyst. During the short follow-up reported
the end of procedure, with a decrease of conversions to below 1% (mean, 7.5 months; range, 1.413.8) no recurrences were observed.
(244). Overall, in light of the reduced morbidity and high patient Vitobello and colleagues recently reported on 11 cases, 5 with
satisfaction, robotic surgery appears superior for obese women, squamous cell carcinoma of the cervix, 2 with adenocarcinoma
and should be considered when counseling these patients with of the cervix, and 4 with a recurrence of endometrial carcinoma
gynecologic cancers for surgery (243,244,245,246). (254). One intraoperative cystotomy occurred and one patient suf-
fered an intra-abdominal hemorrhage 15 days after surgery. Three
patients required adjuvant treatment. In a median follow-up period
Applications of Robotic Surgery in of 19 months (836), one patient experienced a recurrence. These
results are comparable to the reported results of open and lapa-
Gynecologic Malignancies roscopic radical parametrectomy (255257). The authors of both
robotic reports concluded that this procedure is feasible and can be
Cancer of the Cervix
performed with an acceptable complication rate.
Robotic Radical Hysterectomy
Radical hysterectomy is a complex surgery with well established Robotic Radical Trachelectomy
potential complications. The average blood loss during laparot- In view of the small number of surgeons mastering the advanced
omy is around 500 mL. Loss of bladder sensation and lympho- vaginal surgical skills required for performing Dargents, or the
cyst formation were each reported in about 5% to 15% of cases, laparoscopic skills required for performing laparoscopic radical
and urinary tract injuries occur in 1% to 2.5% of cases. More trachelectomy, robotic surgery might offer an attractive alterna-
severe complications, such as urinary fistulas or rectal injury, tive (258). Nick and colleagues (259) recently compared a series
occur in up to 5% of patients. of 12 cases of radical robotic trachelectomy with 25 cases of
In spite of the reports of the advantages of the laparoscopic open radical trachelectomy. Robotic radical trachelectomy was
over the open approach, laparoscopic radical hysterectomy has associated with significantly less bleeding and shorter hospital
scarcely been adopted in surgical practice, remaining in the stay. Operative time, rate of serious complications, and histo-
hands of a few highly skilled surgeons, due to the inherent com- pathologic results were comparable. Four patients of the robotic
plexity and difficulty of the technique. group required conversion to hysterectomy due to close mar-
With the advent of the robotic platform, several programs gins (<5 mm) found on the intraoperative frozen section biopsy.
that did not offer MIS for patients with cancers of the cervix in The rate of hysterectomy was significantly higher than in the
view of the perceived complexity of the laparoscopic approach patients who underwent open surgery.
for radical hysterectomy, shifted uneventfully to robotic sur-
gery, allowing more patients to benefit from the minimal
invasive approach (247,248,249). Similar to laparoscopy, the Endometrial Cancer
MIS approach using the robotic platform was associated with In the last 20 years a considerable amount of data supporting
reduced blood loss and transfusion rates, fewer complications, the use of laparoscopy rather than laparotomy in the treatment
and significantly shorter postoperative length of stay when com- of endometrial cancer were presented, culminating in the LAP2
pared to radical hysterectomy by laparotomy (Table 10.2). trial, a large randomized phase III trial performed by the Ameri-
The currently published studies, although limited by small can Gynecologic Oncology Group (101). Despite this compelling
group sizes and short follow-up periods, support equivalent evidence, the adoption of laparoscopic surgery for endometrial
oncologic outcome with laparotomy, laparoscopic, or robotic cancer staging was slow and only a minority of the patients ben-
radical hysterectomy. Nezhat et al. compared radical hysterec- efitted from its advantages. In a survey taken among members
tomy following robotic surgery (13 patients, median follow-up of the Society of Gynecologic Oncologists in 2005, only 8% of
12 months) and laparoscopic approach (31 historical patients, responders performed more than 50% of their endometrial cancer
median follow-up 29 months) (250). There were no recurrences staging procedures laparoscopically (234).
in either group. Magrina et al. followed 27 patients after robotic Since the approval of the DaVinci surgical system for use in
radical hysterectomy for early cervical cancer (251). At a mean gynecologic surgery in 2005, endometrial cancer has been the
follow-up length of 31 months (range, 1251), no patient had most widespread indication for robotic surgery in gynecologic
experienced recurrence. Cantrell et al. retrospectively assessed oncology. Several investigators have reported on their experi-
the progression-free survival and overall survival for 63 women ence with the use of the DaVinci system for surgical staging of
with cervical cancer who underwent type III robotic radical hys- endometrial cancer (Table 10.3), and compared their results to
terectomy (249). Median follow-up was 12.2 months (range, historic cohorts treated either by laparotomy or laparoscopy.
0.236 months). The comparison was made to a similar histori- The results were grouped in 2 meta-analyses (260,261) that
cal group of ORHs. There was no statistically significant differ- were published in 2010 (Table 10.3). The results of these meta-
ence in progression-free survival (94% vs. 89%, p = 0.27) or analyses are slightly different due to different inclusion criteria.
overall survival at 36 months (94% vs. 93%, p = 0.47). Overall, in both meta-analyses, when robotic-assisted staging
Overall, early evidence suggests that robotic radical hysterec- surgery was compared to conventional laparoscopy (Table 10.3),
tomy may be a valid alternative to open radical hysterectomies, no differences were found in operation time, lymph node yield,
CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER 233
Table 10.2 Comparative Studies Evaluating Radical Hysterectomy in Function of Surgical Approach
Year of
Authors Publication Method Methodology N Age BMI
Ko et al. (279) 2008 RRH/ORH RS, HC 16/32 42.3/41.7 27.6/26.6
Nezhat et al. (250) 2008 RRH/ORH PNR 13/30 54.8/46.8 NA
Fanning et al. (280) 2008 RRH RS 20 44 NA
Boggess et al. (284) 2008 RRH/ORH RS/HC 51/49 47.4/41.9 (S) 28.6/26.1 (NS)
Magrina et al. (251) 2008 RRH/LRH/ORH CC 27/31/35 50/54.9/50.9 27.2/26.8/27.3
Maggioni et al. (281) 2009 RRH/ORH CC 40/40 44.1/49.8 24.1/23.6
Oleszczuk et al. (282) 2009 VRARH PS 12 44 24
Lowe et al. (283) 2009 RRH PS 42 41 25.1
Halliday et al. (248) 2010 RRH/ORH PS, HC 16/24 49/47 26/25
RRH, robotic radical hysterectomy; ORH, open radical hysterectomy; LRH, laparoscopic radical hysterectomy; RS, retrospective study; HC, comparison to historic
cohort; PNR, prospective nonrandomized study; CC, case control study; PS, prospective study; NS, nonsignificant; S, significant.
or complication rates. The estimated blood loss was lower for However, it remains a challenge for advanced stage disease. The
robotic-assisted procedures with a lower transfusion rate, reaching full staging of ovarian cancer requires access to all abdominal
statistical significance in one of the meta-analyses. The conversion quadrants, making it frequently necessary to undock the robot
rate to open surgery was found to be lower in patient operated at some stage of the surgery, insert additional trocars, move the
with the DaVinci system (4.9 vs. 9.9%, p = 0.06 in the study robot or the operating table, and re-dock the arms to the trocars,
by Gaia et al. [260] and OR 0.24; CI, 0.090.64 in the study by with associated difficulties for anesthesia, the operating team, and
Reza et al. [261]). The comparison between robotic-assisted arm collisions.
and open surgery showed significant prolongation of operation Recently, Magrina et al. (262) retrospectively compared
time when the robot was used. However, this was balanced by the perioperative outcomes and survival of 25 patients who
a reduction in perioperative complications, blood loss, transfu- underwent robotic-assisted primary surgery for ovarian can-
sion rate, and length of stay, a motivating trade-off for the longer cer with matched groups of patients that were treated by either
durations of surgery. The number of dissected lymph nodes was laparotomy or laparoscopy. They concluded that laparoscopy
significantly higher in the robotic cases. or robotic surgery were superior to laparotomy for tumors
These reports support the feasibility and short-term safety requiring the excision of the primary tumor alone or with one
of robotic surgery for endometrial cancer staging procedures. additional major procedure. When the operation required two
In view of the FDA approval in 2005, long-term oncologic out- or more additional procedures, laparotomy was the preferred
comes have not yet been published, but short-term outcome method of surgery. In this series, survival was not affected by the
with 2-year disease-free survival was reported to be at least as type of surgical approach.
good as open surgery in one recent publication (236). A recent update (unpublished) on this patient series reveals
a total of 32 patients with invasive epithelial ovarian cancer,
7 patients with stage IV disease, and 18 patients with stage III,
Ovarian Cancer half of whom had received neoadjuvant chemotherapy, and
Robotic-assisted surgery has been reported to be adequate for sur- 4 patients were above the age of 80. Two patients underwent
gical treatment and restaging procedures of early ovarian cancer. conversion at the end of the procedure to fully and safely remove
234 CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER
Table 10.3 Comparative Studies Evaluating Hysterectomy and Staging for Endometrial Cancer in Function
of Surgical Approach
Year of
Authors Publication Methodology Method N Age BMI
Velijovich et al.a,b (288) 2008 PS HC RH/LPS/LPT 25/4/131 59/54/63 28/25/32
Boggess et al.a,b (247) 2008 PS HC RH/LPS/LPT 103/81/138 62/62/64 33/29/35
Bell et al.a,b (263) 2008 RS RH/LPS/LPT 40/30/40 63/68/72 33/32/32
DeNardis et al. a,b
(285) 2008 PS HC RH/LPT 59/106 59/62 28/34
Seamon et al.a,b (286) 2009 PS HC RH/LPS 105/76 59/54 34/29
Lowe et al. (283) 2009 RS RH 405 62 32
Cardenas-Goicoechea et al.a (287) 2010 RS RH/LPS 102/173 62/60 32/32
Lau et al. (236) 2012 PS HC RH/LPT+LPS 143/160
Gaia et al. (260) 2010 Meta-analysis RH/LPS 424/396 61/60 33.3/31.2
RH/LPT 333/606 61/63 33.9/35.5
Reza et al. (261) 2010 Meta-analysis RH/LPS/LPT 329/191/415
Estimated Length
Operative Intraoperative Postoperative Blood Transfusion Conversion of Stay
Authors Method Time (min) Lymph Nodes Complications Complications Loss (mL) Rate (%) Rate (%) (Days)
Velijovich et RH/LPS/ 283/255/139 17.5/20.3/13.1 4/0/3 16/0/ 25 (NS) 66/75/197 1/0
al.a,b (288) LPT (S) (S)
Boggess RH/LPS/ 191/213/146 33/23/15 1/3.7/0.7 4.9/9.9/28.9 191/213/146 1/2.5/1.5 2.9/4.9 1/1.2/4.4
et al.a,b (284) LPT
Bell et al.a,b RH/LPS/ 166/253/317 17/17/15 0/3.3/2.5 7.5/23/25 166/250/316 5/10/15 0/0 2.3/2/4
(263) LPT
DeNardis et RH/LPT 177/79 (S) 18.6/18 (S) 3.6/20.8 (S) 105/241 (S) 0/8.5 (S) 5.4 1/3.2 (S)
al.a,b (285)
Seamon RH/LPS 242/287 (S) 31/33 4/3 7.6/10.3 88/200 (S) 3/10 (S) 12.4/20 (S)
et al.a,b (286)
Lowe et al. RH 170 15.5 3.5 14.6 87 6.7 1.8
(283)
Cardenas- RH/LPS 237/178 (S) 22/23 (NS) 2/3.5 (NS) 24.5/28.3 109/187 (S) 2.9/1.7 (NS) 1/5.2 (NS) 1.9/2.3
Goicoechea (NS)
et al.a (287)
Lau et al. RH/ 241/207 (S) 11.3/11.5 2.8/3.1 (NS) 10.5/38.8 (S) 73/266 (S) 1.4/6.3 (NS) 4.2e 1/5 (S)
(236) LPT+LPS (NS)
Gaia et al. RH/LPS 219/209 (NS) 28.5/25.6 Woundc 2/2.8 91.6/182 (S) 2.6/5 (NS) 4.9/9.9 1.35/1.9
(260) (NS) (NS) (p = 0.06) (S)
RH/LPT 207/130 (S) 27.4/22.2 Woundc 101/291 (S) 1.7/7.2 1.2/3.9
(NS) 1.8/13.7 (S) (p = 0.06) (S)
Reza et al. RH/LPS NS NS 8.3/13 (NS)d RH < LPS RH < LPS; RH < LPS RH <
(261) 76 mL OR = 0.24 OR = 0.43 LPS (S)
p = 0.03 (S) (S) 0.17
RH/LPT RH > LPT RH > LPT (S) 7.1/27 (S)d RH<LPT RH<LPT RH <
(S) 89.25 5.91 (S) 152 mL (S)OR = LPT (S)
0.25 2.7
PS, prospective study; RS, retrospective study; HC, comparison to historic cohort; RH, robotic hysterectomy; LPT, laparoscopy; LPS, laparoscopy.
a
Data included in the meta-analysis of Gaia et al.
b
data included in the meta-analysis of Reza et al.
c
Only wound complication reported.
d
Overall complication rate.
e
Conversions at the end of surgery, only for the removal of specimens too large to be delivered intact via the vagina.
CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER 235
pelvic tumor invading the rectosigmoid. One 88-year-old patient articulating but straight shaft instrument are limiting factors in
succumbed to sepsis following bowel perforation. single port usage.
A prototype single-port robotic system (single-site) was
developed by Intuitive Surgical, as an add-on to the da Vinci Si
Cost Analysis system. The port has 5 channels. One channel is for an 8.5-mm
The main barrier to the implementation of robotics mentioned scope, two for the robotic arms via curved crossing cannulae,
repeatedly by health care professionals, administrators, and one for the assistant port, and the fifth for CO2 insufflation. The
policymakers concerns the high upfront capital cost, the annual surgical instruments used are semi-flexible and cross each other
maintenance cost, and the cost of proprietary disposable at the insertion point to allow triangulation at the surgical field.
robotic instruments. Using theoretic decision modeling, some At this time, the robotic arms lack the endowrist articulation
groups found robotics not economically attractive compared feature. A uterine manipulator is used to maintain proper expo-
to laparoscopy. On the other hand, when compared to laparot- sure (268). The prototype was used by Escobar et al. to perform
omy, the combination of reduced hospital stay and fewer com- total hysterectomy and bilateral salpingo-oophorectomy in 8
plications in patients undergoing robotics contributes to an cadavers, with a success rate of 87.5%. Technical difficulties
overall lower cost for the robotic-assisted procedures, as was were noted in one cadaver, with an estimated BMI of 56, includ-
demonstrated in patients undergoing radical hysterectomy for ing complex docking and exposure problems. A second cadaver
cancer of the cervix (248), and in patients undergoing staging with previous midline abdominal surgery also presented prob-
procedures for endometrial cancer (236,263). The Canadian lems for docking (269). The safety and feasibility of the sin-
Interestingly, the unequivocal benefit of MIS is in coherence 303 patients had same-day discharge (median stay, 295 min).
with the trend toward shorter hospital stay imposed by the cur- Among outpatients, seven (4.8%) were readmitted within 3 weeks
rent financial constraint on health care cost. In the Ghezzi et al. of surgery. No patients with same-day discharge had a major
experience (272), length of hospital stay has decreased signifi- acute postoperative complication (273). Another series of
cantly over time for all disease sites. The final achievement of the 18 outpatient extraperitoneal aortic dissections has also been
effort to reduce hospital stay is day surgery. The Toronto experi- reported (274).
ence of day care major laparoscopic surgeries, including radical Early criticisms that only carefully selected patients may
hysterectomies and aortic node dissection, shows that 48.5% of benefit from laparoscopic surgery are now irrelevant. As soon
20
500
10
0 0
99 00 01 02 03 04 05 06 07 08 09 10 11 99 00 01 02 03 04 05 06 07 08 09 10 11
0 0
99 00 01 02 03 04 05 06 07 08 09 10 11 99 00 01 02 03 04 05 06 07 08 09 10 11
10 10
0 0
99 00 01 02 03 04 05 06 07 08 09 10 11 99 00 01 02 03 04 05 06 07 08 09 10 11
FIGURE 10.1. Global installations of robots, 19992011. Countries are represented in the legend in descending
order of the number of robots installed (figure prepared based on data obtained from Intuitive Surgical,
Sunnyvale, CA).
CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER 237
Adoption
15%
13%
100 10%
8%
80 5%
3%
60 0%
88
90
02
06
10
00
98
92
94
96
04
08
19
19
20
19
20
20
20
19
19
19
20
20
40 Year
99
00
01
02
03
04
05
06
07
08
09
10
11
19
19
20
20
20
20
20
20
20
20
20
20
20
20
$0
50 100 150 200 250 300 350 400 450 500
$1,000,000
$2,000,000
$3,000,000
$4,000,000
$5,000,000
$6,000,000
$7,000,000 Prostatectomy Hysterectomy
$8,000,000
Nephrectomy Cardiac Surgery
$9,000,000
Annual Caseload
as the senior author implemented a program favoring laparo- period. While laparoscopy was performed in about 20% of
scopic surgery in a cancer center, over 90% of surgeries for uter- the cases in the first 2 years, it increased to 83% in the last
ine cancer were performed laparoscopically (275). In the Oslo year of the period (276). A group in Italy recently reported on
University Hospital, records from all women having a hyster- 383 consecutive women undergoing surgery for the treatment
ectomy due to premalignant or malignant endometrial changes of an apparently early-stage gynecologic cancer. Integration
during the years 2002 to 2009 were examined retrospectively. of minimal access surgery proceeded sequentially to include
A total of 521 hysterectomies were performed during the study endometrial, ovarian, and cervical cancer patients. The annual
238 CHAPTER 10 M I N I MALLY I NVASIVE SU RGERY I N GYN ECOLOGIC CANCER
11
98
99
00
01
02
03
04
05
06
08
09
10
07
allow for further developments of MIS in gynecologic oncology
19
19
20
20
20
20
20
20
20
20
20
20
20
20
that will reduce the indications for laparotomy in gynecologic
cancer patients.
FIGURE 10.5. Scientific peer reviewed publications on LESS in the PubMed
database, presented as number per year.
LESS : Laparo-Endoscopic Single-Site
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Diagnostic Imaging
244
CHAPTER 11 DIAGNOSTIC I MAGI NG 245
Table 11.1 The Choice of Imaging Modality in Endometrial, Cervical, and Ovarian Cancer
Pathology Imaging Modalities
US (TA/TVS/SHG) CT MRI PET/CT
Endometrial Evaluation of Detection of enlarged lymph Delineating the origin of the Detection of extrauterine
Cancer the endometrium nodes primary tumor (endometrial vs. disease
in patients cervical) when the biopsy results Monitoring treatment
presenting with Detection of distant metastases are inconclusive response in selected cases
postmenopausal (lung, liver, etc.)
bleeding Assessment of the depth of Detection of distant
Identification of peritoneal myometrial invasion and cervical metastases in patients
Double-layer nodules in serous papillary and stromal invasion (improves with suspected recurrence
endometrial clear cell carcinoma pretreatment risk stratification) within the pelvis; detecting
thickness >5 mm on Detection of recurrent pelvic and unsuspected distant
TVS determines the Evaluation of disease extent in metastases significantly
distant metastatic disease the pelvis
need for endometrial alters treatment choices
sampling Detection of enlarged lymph nodes
measurement. The normal endometrium is echogenic. However, amaximum of 8 mm (Fig. 11.1). Before ovulation, a trilaminar
the thickness and echotexture of the endometrium vary with the appearance of the endometrium has been described. The central
hormonal status of the patient. At the end of the menses, the thin echogenic line represents a reflective artifact and/or mucus
endometrial stripe is highly echogenic and measures approxi- and secretions between the anterior and posterior layers of the
mately 2 to 3 mm (Fig. 11.1). During the secretory stage, the endometrium. Subjacent is the second layer, which is the relatively
endometrium becomes less echogenic and thickens, reaching hypoechoic functionalis layer. The third layer is the surrounding
246 CHAPTER 11 DIAGNOSTIC I MAGI NG
deeper basalis layer, which remains echogenic. Following ovula- ovulation, one follicle becomes dominant, reaching a maximum
tion, the functionalis layer becomes thicker and more echogenic diameter of 2.0 to 2.5 cm. Following ovulation, the corpus luteum
than during the proliferative phase, and the entire stripe may develops. The corpus luteum may contain debris and/or hemor-
reach 15 mm in thickness and is more uniformly echogenic just rhage and often involutes, appearing to be crenelated just prior to
prior to menstruation (7). In some patients, the innermost layer menstruation. The ovaries atrophy with menopause and contain
of myometrium is relatively hypoechoic compared to the imme- fewer follicles. Therefore, postmenopausal ovaries are more dif-
diately adjacent endometrium and is termed the subendometrial ficult to visualize with US. In women taking HRT, less ovarian
halo. The subendometrial halo is less commonly visualized in atrophy will occur and follicles will continue to develop.
postmenopausal women. Neither the subendometrial halo nor Doppler evaluation of ovarian blood flow is best performed
fluid or debris within the endometrial cavity should be included during days 3 to 7 of the menstrual cycle. The ovary undergoing
in measurements of the endometrial stripe. At SHG, the endo- ovulation in a given cycle demonstrates a relatively high-velocity,
metrium should be homogeneous, symmetric, and regular with- low-resistance arterial waveform with continuous forward dia-
out mass effect (Fig. 11.2). The sum of the width of the two stolic flow. The contralateral ovary will typically demonstrate
layers should not exceed the maximum acceptable width for the a higher-resistance, low-velocity arterial waveform with either
patients hormonal status. very low or no diastolic flow.
In postmenopausal women, the uterine corpus atrophies
until it approximates the length of the cervix. Similarly, there
is atrophy of the endometrium which appears as a thin, regular Computed Tomography
echogenic line <5 mm in width (8). In women taking hormonal CT is the primary imaging modality for staging and treatment
replacement therapy (HRT), less uterine and endometrial atro- follow-up of patients with ovarian cancer. It is also routinely
phy occurs (9). Women taking sequential HRT are best exam- used for detection of distant metastatic disease and lymphade-
ined following withdrawal bleeding and the progesterone phase nopathy in patients with advanced endometrial, cervical, and
of their cycle when the endometrium is expected to be at the vulvar cancer as well as detection of recurrent gynecologic
thinnest. malignancies. CT rather than US-guided biopsy can be useful
The US appearance of the ovaries also changes with the patients masses that are small and/or difficult to access (1,1012).
hormonal status. The premenopausal ovary has a relatively homo- Advantages of CT include ready availability, short image
geneous outer cortex with a more echogenic central stroma. Small acquisition times, large field of view, high spatial resolution, and
anechoic follicles are commonly seen peripherally (Fig. 11.1). At rapid three-dimensional (3-D) reconstructions. Disadvantages
CHAPTER 11 DIAGNOSTIC I MAGI NG 247
of CT include the use of ionizing radiation, degradation of for staging of endometrial and cervical cancers (13,14), and may
image quality by patient body habitus or metallic implants, such be useful for staging of ovarian cancer in selected patients. In
as a hip prosthesis, and the morbidity and mortality associated addition, MRI can often differentiate radiation fibrosis from
with iodinated contrast agents. recurrent tumor (15) and is useful in the detection of recurrent
gynecologic malignancies. The accuracy of MRI assessment of
Technique lymph node involvement is similar to that of CT; both rely on
size criteria to detect lymphadenopathy (16).
Contrast-enhanced CT of the abdomen and pelvis is performed in Although MRI is still relatively expensive, it minimizes costs in
the portal venous phase, 70 seconds following an injection of intra- some clinical settings by limiting or eliminating the need for more
venous low osmolar contrast medium; this enhances blood vessels expensive and/or more invasive diagnostic or surgical procedures
and viscera, allowing easier identification of enlarged lymph nodes (17,18). There are at least three cost-minimizing indications for
and parenchymal lesions, especially in the liver and spleen. Oral MRI in the evaluation of women with gynecologic malignancy:
contrast medium is utilized to opacify the small and large bowel, (a) staging of invasive cervical carcinoma as an adjunct to clinical
which allows detection of bowel serosal deposits. In some centers, examination; (b) the preoperative management of women with
patients receive 500 mL of diluted oral contrast medium the eve- endometrial cancer (19-21); and (c) the characterization of inde-
ning preceding the examination and an additional 500 mL, 45 min- terminate adnexal lesions on US (18,22).
utes before the CT scan. In other protocols, the patient receives Advantages of MRI include superior soft-tissue contrast,
600 to 1,000 mL of dilute oral contrast at least 1 hour before the absence of ionizing radiation, and multiplanar capability. MRI
examination, coupled with a 200-mL dilute contrast enema. is the modality of choice for patients with allergies to iodin-
ated intravenous contrast media or renal impairment. However,
Normal Anatomy clinicians should be aware that gadolinium contrast agents
used in MRI have recently been associated with the develop-
On CT, the vagina, cervix, and uterine corpus can be differenti-
ment of nephrogenic systemic fibrosis (NSF), a rare progressive
ated based on both morphologic and enhancement character-
connective tissue disease, in patients with end-stage renal dis-
istics (Fig. 11.3). The uterine corpus appears as a triangular
ease and/or acute renal failure. One disadvantage of MRI rela-
or ovoid soft-tissue mass posterior to the urinary bladder. The
tive to CT is the need for longer acquisition times. In addition,
cervix is a more rounded structure. At the level of the fornix,
MRI is contraindicated in patients with pacemakers, cochlear
the vagina has a flat rectangular or crescentic shape. Follow-
implants, certain vascular clips, metallic objects in the eye, and
ing bolus intravenous contrast administration, the myometrium
neural stimulators. Furthermore, some patients may experience
in the uterine corpus enhances to a greater degree than that of
claustrophobia and may require sedation in order to complete a
the cervix (Fig. 11.3). The endometrium can often be delineated
diagnostic examination.
from the enhancing myometrium. The broad and round liga-
ments can be seen coursing laterally and anteriorly, respectively.
Occasionally, the uterosacral ligaments are depicted as arc-like Technique
structures extending from the cervix to the sacrum. Patients are asked to fast for 4-6 hours prior to MRI examina-
In the premenopausal patient, the normal ovaries are routinely tion in order to limit motion artifacts from bowel peristalsis (23).
seen, usually posterolateral to the uterine corpus and medial to An antiperistaltic agent, such as glucagon or hyoscine butyl bro-
the external iliac vessels (Fig. 11.3). Their uniform soft-tissue den- mide, is recommended to further reduce motion artifacts (24).
sity is punctuated by small cystic regions representing follicles. In The patient is asked to void before the examination, as a full
the postmenopausal patient, the ovaries are small and less readily bladder may cause ghosting and motion artifacts that degrade
detected. images. Patients are imaged in the supine position using a pelvic
surface array multichannel coil (e.g., a cardiac coil usually offers
the best image quality) (23,25). Endoluminal coils (endorectal
Magnetic Resonance Imaging and endovaginal) can provide high-resolution images of small
MRI is the modality of choice for staging of uterine corpus and tumors of the cervix and aid detection of early parametrial inva-
cervix malignancies. MRI has been shown to be superior to CT sion (26,27). However, their field of view is limited in assessing
248 CHAPTER 11 DIAGNOSTIC I MAGI NG
large tumors, extra-uterine extension to adjacent organs and the and serosal implants, when ovarian cancer is suspected (32,33).
pelvic sidewall, and detecting pelvic lymph nodes; consequently, Routine use of dynamic multiphase contrast-enhanced 3D
endoluminal coils are not widely used in gynecological imaging. T1-weighted sequences is not recommended for staging patients
Vaginal opacification with gel, yielding high signal intensity on with cervical carcinoma. However, these sequences may be very
T2-weighted images (T2WI), may be useful in cases where there useful for accurate delineation of small cervical tumors in patients
is suspected cervical tumor extension into the vagina, particu- being considered for fertility sparing surgery (i.e., trachelec-
larly into the posterior vaginal fornix (28). tomy) (34) and to differentiate tumor recurrence from radiation
The basic imaging protocol for gynecologic MRI includes fibrosis in patients with cervical cancer (15).
T1-weighted images (T1WI) of the pelvis in the axial plane Increasingly, diffusion-weighted MRI (DW-MRI) is routinely
and T2WI in the axial and sagittal planes. When T1WI shows incorporated in MRI staging protocols for uterine malignancies.
high signal intensity within the adnexa, which may represent DW-MRI can be useful for accurately determining the depth
fat or hemorrhage, fat-saturation T1-weighted images (T1WFS) of myometrial invasion in patients with endometrial cancer.
are mandatory to differentiate between the two. Staging of It can be particularly helpful for tumors that are either iso- or
gynecological malignancies requires large field of view axial hyper-intense relative to the myometrium on T2WI or when the
T1WI and/or T2WI of the pelvis and abdomen to identify use of intravenous contrast medium is contra-indicated, and it
enlarged lymph nodes, hydronephrosis, as well as bone mar- may replace dynamic imaging in the future (35,36). DW-MRI
row changes (20,29). High resolution, small field of view, axial may also improve detection of drop metastases in the cervix
oblique (short axis) T2W fast spin-echo (T2W FSE) images or metastatic foci outside the uterus, such as in the adnexa or
taken parallel to the short axis of the uterine corpus are essen- peritoneum (3537).
tial to accurately evaluate the depth of myometrial invasion
in endometrial carcinoma (30). In the assessment of patients
with cervical cancer, high resolution small field of view axial
Normal Anatomy
oblique (short axis) T2W FSE images parallel to the short Pelvic anatomy is exquisitely depicted on MRI. On T1WI, the
axis of the cervix are crucial for identification of parametrial normal pelvic musculature and viscera demonstrate homoge-
invasion (31). neous low to intermediate signal intensity. Cortical bone dem-
Dynamic multiphase contrast-enhanced MRI, using onstrates low signal intensity, and fatty marrow is high in signal
3-dimensional gradient echo T1WI, after intravenous gadolin- intensity. Similarly, intrapelvic fat demonstrates high signal
ium administration, is often performed in staging patients with intensity. It is the soft-tissue contrast provided by the T2WI,
endometrial cancer. It is useful in the characterization of com- however, that is the basis for the strength of MRI in pelvic imag-
plex adnexal lesions, and can aid detection of small peritoneal ing. On T2WI, the uterus, cervix, and vagina all exhibit distinct
CHAPTER 11 DIAGNOSTIC I MAGI NG 249
layers of different signal intensitythe so-called zonal archi- represents the mucosal folds or plicae palmatae. The vagina
tecture. The endometrium shows high signal intensity, while demonstrates two zones on T2WI, the bright vaginal mucosa
the outer myometrium is intermediate in signal intensity, being and the intermediate signal intensity vaginal wall.
higher in signal intensity than striated muscle (Fig. 11.4). Inter- Following the administration of intravenous gadolinium, the
posed between these two layers is a narrow band of lower signal zonal anatomy of the uterus is demonstrated on fat-saturated
intensity, the junctional zone, which corresponds to the inner- T1W images. The normal endometrium and outer myometrium
most myometrium. The low signal intensity of the junctional enhance to a greater extent than the junctional zone. Similarly,
zone reflects its low water content relative to the rest of the in the cervix, the inner cervical mucosa and outer smooth mus-
myometrium, which may be a function of its lesser amount of cle enhance more than the fibrocervical stroma. The parame-
extracellular matrix per unit volume (38,39). The three zones trial tissues, vaginal wall, and submucosa also enhance after
seen on MR images are not comparable to the different zones gadolinium administration.
seen on US (40). MRI provides good visualization of the endo- The ovaries display homogeneous low to intermediate sig-
metrium, including the varying width of the endometrium (both nal intensity on T1WI, whereas on T2WI, the follicles appear
leaflets) seen with the menstrual cycle (41). In postmenopausal brighter than the surrounding stroma (Fig. 11.4). The normal
women not receiving exogenous hormones, uterine zonal anat- fallopian tubes are not routinely seen unless they are dilated.
omy is indistinct, and the endometrium typically measures less
than 5 mm (41).
The cervix also demonstrates zonal architecture on T2WI
(Fig. 11.4). There is an inner area of high signal intensity, which Positron Emission Tomography/
represents epithelium and mucus, and an outer area of predomi-
nantly low signal intensity, which represents fibrous cervical Computed Tomography
stroma (42,43). Interposed between the high signal intensity The main applications of FDG-PET/CT in gynecologic oncol-
endocervical canal and the low signal intensity fibrocervical ogy are staging of cervical cancer and detection of recurrent
stroma is a feathery layer of intermediate signal intensity, which ovarian, cervical, and endometrial cancer. FDG-PET/CT is the
250 CHAPTER 11 DIAGNOSTIC I MAGI NG
of the FIGO staging system for endometrial cancer, but both to assess the depth of myometrial invasion or cervical stroma
MRI and CT are increasingly playing a crucial role in risk strati- involvement (69). For detection of deep myometrial invasion, the
fication and surgical treatment planning (64). sensitivity and specificity are 83% and 42%, respectively (69),
with an overall staging accuracy of 58% to 76% (70).
Ultrasound
US has little role in staging endometrial carcinoma. However, in Magnetic Resonance Imaging
centers with no access to MRI, US may be of value for assessing Almost all patients with endometrial cancer undergo surgery as
the presence of myometrial invasion in stage I disease. Myometrial their primary treatment, during which the FIGO staging infor-
invasion is documented when the tumor mass disrupts the suben- mation is obtained. Therefore, the role of pretreatment MRI in
dometrial halo and/or extends into the subjacent myometrium. endometrial cancer continues to be debated (21). However, only
TVS has been reported to have a sensitivity of 77% to 100%, a a relatively small percentage of patients have disease beyond the
specificity of 65% to 93%, and an overall accuracy of 60% to uterus (71). There is considerable controversy regarding system-
76% in assessing the degree of myometrial invasion (65). Assess- atic lymphadenectomy, with conflicting evidence regarding the
ment of myometrial invasion is more difficult when the myome- survival benefits associated with the procedure (7275). In addi-
trium is thinned or distorted by fibroids (66). Three-dimensional tion, many patients with endometrial cancer have high surgical
SHG has been reported to be more accurate than TVS in detecting risks secondary to obesity, diabetes, and cardiovascular disease.
myometrial and cervical invasion by endometrial carcinoma (67). Due to these factors, the extent of surgery is individualized in
clinical practice: (a) Patients with a low risk of disease beyond
the uterus may undergo more limited surgery, possibly involving
minimally invasive surgical techniques and avoiding lymphad-
Computed Tomography enectomy, thus reducing the risk of complications, particularly
CT is most commonly used in the assessment of advanced dis- in high surgical risk cases; and (b) patients with a risk of disease
ease and performs as good as MRI in identifying extrauterine beyond the uterus undergo complete surgical staging.
spread and enlarged lymph nodes (65). On contrast-enhanced Prognostic features that predict disease beyond the uterus
CT, endometrial cancer is usually of slightly lower attenuation include the tumor histology and the presence of lymphovascular
than the myometrium, but delineation of the tumor is difficult space invasion, deep myometrial invasion, and cervical involve-
as there is relatively little contrast difference between tumor and ment. Assessment of these factors together allows preoperative
the myometrium (68). CT is not sensitive or specific enough risk stratification for surgical planning. Of these four important
252 CHAPTER 11 DIAGNOSTIC I MAGI NG
prognostic factors, only one is available preoperatively without signal intensity than the endometrium on T2WI. On dynamic
the help of imaging: tumor histology, including grade and cell multiphase contrast-enhanced 3D T1WI, the tumor enhances
type, is available following pipelle or hysteroscopic sampling, homogeneously, more slowly, and less avidly than the adjacent
although sampling error results in approximately 15% of cases myometrium. On DW-MRI, the tumor is of high signal intensity
being up-graded at the final histology (76). Lymphovascular with corresponding low signal intensity (restricted diffusion) on
space invasion is the single best predictor of nodal involvement, the apparent diffusion coefficient (ADC) maps.
but its presence can only be determined after hysterectomy. Stage I tumors are confined to the uterine corpus and account
MRI can accurately assess the depth of myometrial invasion for more than 80% of cases. Stage IA includes disease involv-
and cervical stromal invasion, which in turn correlate with the ing the endometrium, seen as focal or diffuse thickening of the
likelihood of lymph node metastasis and overall patient survival endometrium as well as disease which invades less than 50% of
(50,77). Hence, in combination with tumor histology and grade, the myometrium. Tumor that invades more than 50% of myome-
MRI aids the patients preoperative risk stratification and ulti- trium represents stage IB disease (Fig. 11.6). Delayed postcontrast
mately guides treatment planning. The National Cancer Insti- 3D T1W images (2-5 minutes post gadolinium injection) facilitate
tute in France has recently incorporated MRI into the standard evaluation of deep myometrial invasion, since these images pro-
preoperative assessment of patients with endometrial carcinoma vide maximum tumor-to-myometrium contrast (Fig. 11.6). This
(78). The European Society for Urogenital Imaging (ESUR) also increases staging accuracy in cases where the tumor signal inten-
recommends MRI for staging of high-grade endometroid adeno- sity is isointense to normal myometrium on T2WI or where tumor
carcinomas (type I histology) as well as serous papillary and extends into the uterine cornu, when it can be difficult to accu-
clear cell adenocarcinomas (type II histology) (20). rately evaluate the depth of myometrial invasion on T2WI alone
MRI can be also very useful in patients with low-grade endo- due to myometrial thinning (46,49,51,8084). However, one
metrial carcinoma who wish to preserve their fertility. The goal must be cautious as peritumoral inflammation can lead to over-
is to exclude any myometrial invasion so these patients can estimation of the depth of invasion on contrast-enhanced images.
undergo treatment with high-dose progesterone and endometrial Other reported pitfalls in assessing the depth of myometrial inva-
re-sampling. Finally, MRI is valuable in determining the site of ori- sion in endometrial carcinoma include leiomyomas, adenomyosis,
gin of newly diagnosed uterine adenocarcinoma (corpus vs. cervix) loss of juntional zone definition, and myometrial compression by
when clinical and/or histologic evaluation is indeterminate (79). polypoid tumor. These can also be minimized by the addition of
dynamic multiphase contrast-enhanced 3D T1WI and DWI to
Criteria for M RI interpretation according to T2WI (36,48,8385). For assessing the depth of myometrial inva-
sion, reported sensitivities of MRI range from 70% to 95%, while
tumor stage reported specificities range from 80% to 95% (36,50,51,83,86).
MRI criteria for evaluation of endometrial cancer follow the Stage II disease is characterized by direct invasion of the cervical
FIGO staging system (Table 11.2) (63). Endometrial cancer is stroma. On T2WI, cervical stromal invasion is represented by inter-
usually isointense to the myometrium on T1WI and of lower mediate to high signal intensity tumor disrupting the normal low
Table 11.2 FIGO Staging of Endometrial Carcinoma with Corresponding MRI Findings
FIGO Stage Description of Stage MRI Findings
a
Positive cytology obtained at peritoneal washings should be recorded, but does not alter any stage.
CHAPTER 11 DIAGNOSTIC I MAGI NG 253
FIGURE 11.6. Stage IB endometrial carcinoma. Sagittal and axial T2W FSE (A, E), sagittal and axial gadolinium-enhanced 3D T1W GRE (B, F), DW (C, G) MR
images and the corresponding ADC maps (D, H) show an endometrial carcinoma (T in A-H) which extends into the outer myometrium (arrow in A-H). Deep
myometrial invasion was confirmed at histopathology.
signal intensity cervical stroma. The enhancement of cervical mucosa serosal involvement. Tumor deposits may be identified in the
on the delayed phase (2-5 minutes) can confidently exclude cervical adnexa, even in the absence of serosal invasion, especially with
stroma invasion (68). In detecting invasion of the cervical stroma, high-grade, clear cell or serous papillary tumors (Fig. 11.7); DWI
MRI has overall accuracy of 90% to 92% with sensitivity and speci- can aid detection in these cases (36). In stage IIIB disease, tumor
ficity of 75% to 80%, and 94% to 96%, respectively (4951). extends into the upper vagina or parametria (Fig. 11.8), either
Stage III is classified as locoregional spread of disease. In directly or as metastatic disease. It is of paramount importance
stage IIIA disease, there is invasion of uterine serosa or adnexa that the surgeon is made aware of parametrial invasion, as in
(Fig. 11.7). Disruption of the low signal intensity uterine serosa its presence, a simple hysterectomy will not be possible and a
and/or irregular uterine contour on T2WI (Fig. 11.7) and the more radical surgical approach will be required. The presence of
loss of the normal rim of brightly enhancing myometrium on enlarged regional lymph nodes indicates stage IIIC disease (IIIC1
dynamic multiphase contrast-enhanced 3D T1WI indicate involving pelvic nodes; IIIC2 involving paraaortic nodes with or
254 CHAPTER 11 DIAGNOSTIC I MAGI NG
FIGURE 11.7. Stage IIIA endometrial carcinoma. Sagittal T2W FSE MR image (A) shows a tumor deposit on the
serosa of the sigmoid colon (M in A) from a grade 3 endometrioid endometrial carcinoma (T in A). Axial T2W FSE MR
image (B) in a different patient shows a clear cell endometrial carcinoma (T in B) with metastases to both ovaries (M in B).
without pelvic nodal involvement). A short-axis diameter of 1 cm detection of nodal disease. Direct comparison of MRI with
or greater is used to diagnose nodal involvement on MRI (49,87). FDG-PET/CT has demonstrated no statistically significant dif-
Stage IV is defined by tumor extension beyond the true pel- ference in the detection of lymph node metastases in patients
vis or invasion of the bladder or rectal mucosa. On MRI, loss with endometrial cancer (89). The added value of FDG-PET/CT
of low signal intensity of the bladder or rectal wall and tumor is the detection of distant metastatic deposits, for which it has
invading the mucosa indicate stage IVA disease. Bullous edema been found to have sensitivity of 100% and specificity of 94%
of the bladder is a frequent sign of tumor in the subserosal or (89). Kitajima et al. demonstrated that the sensitivity of FDG-
muscular layer of the bladder, but does not qualify for stage PET/CT in detecting involved nodes of 4 mm or less was 16.7%;
IVA disease. In stage IVB disease, distant metastases (including for nodes measuring 5 to 9 mm, the sensitivity was 66.7%; and
nodal enlargement above renal veins or in the inguinal region), for nodes 10 mm or greater, it rose to 93.3% (90). For nodal
malignant ascites, or peritoneal deposits are present. The latter metastases, a sensitivity of 50% and a specificity of 86% have
are more common with high-grade, clear cell or serous papil- been reported, on a per patient basis. Overall, the sensitivity of
lary tumors, as clinically, they behave like ovarian cancer with a FDG-PET/CT for preoperatively predicting nodal metastasis is
propensity to spread along the serosal and peritoneal surfaces. not optimal for guiding lymphadenectomy.
Distant metastases (lung, liver, and bone) is rare at presentation.
FIGURE 11.8. Stage IIIB endometrial carcinoma. Sagittal (A) and axial (B) T2W FSE MR images show an
endometrial carcinoma (T in A, B) which invades the cervical stroma (arrow in A) and extends into the right
parametrium (arrow in B).
CHAPTER 11 DIAGNOSTIC I MAGI NG 255
the most common sites being lymph nodes (46%) and the vagi- unsuspected distant metastases, the presence of which signifi-
nal vault (42%) (92). Less frequently, recurrent disease may cantly alters treatment options (94,95). A recent study compared
manifest as peritoneal carcinomatosis (28%) or distant metas- PET integrated with low-dose, unenhanced CT to PET inte-
tases in liver, lung, or bone (92). Routine follow-up has a poor grated with contrast-enhanced CT (95). It concluded that PET
yield in detecting recurrence in the asymptomatic patient, but with contrast-enhanced CT is an accurate imaging modality for
recognizing those patients who are at an increased risk of recur- the assessment of endometrial cancer recurrence and the use of
rence and the likely time scale for recurrence can help in select- contrast reduces the frequency of equivocal interpretations (95).
ing a suitable approach for follow-up imaging. FDG-PET/CT resulted in a change of management in 42% of
At present, follow-up of patients treated for endometrial patients (95). PET is reportedly useful in posttherapy evaluation
cancer usually consists of regular clinical evaluation. The use of and surveillance of patients with suspected recurrence, but it does
imaging and its impact on the management of these patients is not have any proven value in asymptomatic patients (96,97).
not well defined. CT performs well in the detection of recurrent
pelvic and distant metastatic disease (Figs. 11.9 and 11.10), with
an overall accuracy of 92% (93). MRI has a role in the evaluation
of surgical resectability, if the pelvis is the sole site of recurrence.
On T2WI, vaginal vault recurrence is seen as loss of the linear, UTERI N E SARCOMA
low signal intensity of the vaginal vault and an associated soft
tissue mass of high signal intensity, similar to that of the primary Uterine sarcomas are rare, aggressive tumors of mesenchymal
tumor (Fig. 11.9). FDG-PET/CT is helpful in assessing patients origin that account for 2% to 3% of all uterine malignancies.
with suspected disease recurrence within the pelvis, by detecting They differ from endometrial carcinomas with regard to their
A B
FIGURE 11.10. Recurrent endometrial carcinoma. Axial contrast-enhanced CT images through the lower chest (A) and pelvis (B) demonstrate lung
nodules (white arrows in A) and a soft tissue mass with osseous destruction (white arrow in B), both proven to be recurrent endometrial cancer.
256 CHAPTER 11 DIAGNOSTIC I MAGI NG
clinical behavior, pattern of spread, and management. Although marked vascular and lymphatic invasion, with separate myome-
there are no specific imaging findings for uterine sarcomas, imag- trial tumor nodules within invaded vessels, are highly sugges-
ing (MRI) can be useful to make a correct preoperative diagno- tive of ESS (102,108,109). Intravenous leiomyomatosis is also
sis and evaluate the extent of disease (CT). On MRI, cases that in the differential diagnosis if there is involvement of periuterine
arise within the endometrium may be indistinguishable from vessels.
endometrial carcinoma, whereas those that arise from the myo- LMS account for approximately one-third of primary uterine
metrium, usually leiomyosarcomas, may be indistinguishable sarcomas (98). Most arise de novo, but they may rarely (0.2%)
from degenerating leiomyomas. However, if there are features result from sarcomatous transformation within a benign leio-
suggesting the diagnosis preoperatively, alerting the surgeon can myoma. On MRI, in contrast to benign leiomyomas, which have
alter management by changing the extent of primary surgery or a well-defined margin, LMS are usually irregular and ill-defined.
by indicating that surgical management is preferable to embo- They commonly cause massive uterine enlargement with areas
lization or high-intensity focused US. CT can be a very helpful of heterogeneous enhancement, extensive necrosis (>50%) and
adjunct for detection of distant metastatic disease (usually in the hemorrhage as well as extrauterine tumor nodules (Fig. 11.11)
lungs) and recurrence. (102). LMS demonstrate early hematogenous spread to the
Uterine sarcomas are divided into three main subtypes: car- lungs and liver. Although MRI cannot reliably differentiate
cinosarcoma, endometrial stromal sarcoma (ESS), and leiomyo- most cases of sarcomatous transformation of a leiomyoma from
sarcoma (LMS). Carcinosarcoma accounts for approximately a benign degenerating leiomyoma, features most suggestive of
50% of all uterine sarcomas (98) and can arise anywhere along sarcomatous transformation include irregular margins, necrosis,
the Mllerian axis. Risk factors include a previous history of and rapid growth.
radiotherapy for an unrelated pelvic malignancy and long-
term tamoxifen use (99,100). Carcinosarcomas do not have a
pathognomonic appearance on MRI and may be indistinguish-
able from endometrial carcinomas (101,102). However, when
compared with endometrial carcinoma of a similar size, car- GESTATIONAL TROPHOBLASTIC
cinosarcomas are heterogeneous tumors with areas of hemor- DISEASE
rhage and necrosis, and enhance more avidly than the adjacent
normal myometrium. They demonstrate deep myometrial inva- Introduction
sion, cervical stromal invasion, and metastatic nodal disease Gestational trophoblastic disease (GTD) encompasses a spectrum
(101,103,104) more often than do endometrial carcinomas and of placental lesions including hydatidiform mole, invasive mole,
hence have a poorer prognosis (105-107) choriocarcinoma, and placental site trophoblastic tumor. The role
ESS accounts for 10% of primary uterine sarcomas (98). It of imaging in GTD is to distinguish benign disease from retained
can be subdivided into low- and high-grade categories, which products of conception, and to document metastatic disease or to
have distinctly different presentations and outcomes (108). evaluate for persistent disease. No specific imaging findings allow
Apreoperative diagnosis of high-grade ESS is readily established differentiation between the different GTD lesions (110112).
at histopathology whereas low-grade ESS may be difficult to dis-
tinguish from benign endometrial stromal cells in a small sample
obtained at curettage. As low-grade ESS usually occurs in young
women in whom malignancy is not suspected, the role of MRI is Primary Detection, Characterization,
important in providing a clue for preoperative diagnosis.
On MRI, ESS commonly appears as a polypoid mass of Staging, and Monitoring for Recurrence
homogeneous high signal intensity on T2WI, although areas of of Gestational Trophoblastic Disease
necrosis or hemorrhage may also be seen (102,108). The low-
Ultrasound
grade ESS may be a mimicker of adenomyosis; however, the
presence of multiple intra-tumoral flow voids due to neovas- TVS is considered the study of choice in the evaluation of sus-
cularity, multiple marginal tumor nodules, continuous tumor pected GTD. In patients with GTD, TVS examination most
extension along vessels, ligaments, and fallopian tubes due to commonly demonstrates a soft-tissue mass distending the
FIGURE 11.11. Leiomyosarcoma. Sagittal T2W FSE (A) and axial gadolinium-enhanced 3D T1W GRE (B) MRI
images show an enlarged heterogeneous uterus (T in A, B) with areas of necrosis in keeping with a leiomyosarcoma.
CHAPTER 11 DIAGNOSTIC I MAGI NG 257
A B
FIGURE 11.12. Hydatidiform mole. Gray scale sagittal ultrasound image of the uterus (A) demonstrates an echogenic, heterogeneous mass within
the endometrial canal (white arrows in A). Axial contrast-enhanced CT image (B) in the same patient demonstrates enhancing soft-tissue distending the
endometrial canal (white arrow in B). Gray scale ultrasound image (C) of the right ovary and contrast-enhanced CT image (D) through the pelvis in the
same patient demonstrate bilateral enlarged ovaries with innumerable theca lutein cysts (white arrows in C, D).
endometrial cavity. Typically, the mass is echogenic and heteroge- Computed Tomography
neous, containing numerous cystic spaces (Fig. 11.12) (110,113,
The role of CT in the evaluation of GTD is primarily limited to the
114). In the case of complete hydatidiform mole, the small cystic
detection of metastatic disease. Uterine enlargement is the most
spaces correspond to the hydropic villi (110). Hydropic degener-
common CT feature of GTD. Following administration of intra-
ation of the placenta may have a similar US appearance. The mass
venous contrast, uterine enhancement is typically heterogeneous
is usually extremely vascular, demonstrating increased vessel
with focal enlargement or irregular hypodense regions within the
density and an abnormal uterine arterial waveform character-
myometrium (Fig. 11.12) (116). These low-attenuation areas cor-
ized by high peak systolic velocity and high diastolic blood flow
respond to foci of hemorrhage and/or necrosis (116). Contrast-
(low resistance index [RI]) compared to the normal uterine arte-
enhanced CT often demonstrates vascular uterine lesions and
rial waveform (115). Irregularity of the border of the mass or
dilated uterine vessels in the broad ligaments (116).
asymmetric extension of the mass into the myometrium suggests
Locoregional spread is characterized by avidly enhancing soft-
myometrial invasion.
tissue nodules in the parametria and/or obliteration of the pelvic
The ovaries may become enlarged with numerous theca
fat and/or muscle planes. GTD spreads hematogenously, with the
lutein cysts (Fig. 11.12). This ovarian enlargement can result in
lungs being the most common site of metastatic disease. Metastases
symptomatic ovarian torsion or hemorrhage (116). However,
to the lung, liver, and brain are vascular and prone to hemorrhage
theca lutein cysts may not be detected in the early stages of the
(116). CT detects these metastatic lesions in the usual manner. Tro-
disease (114).
phoblastic emboli to the lungs may produce symptoms of acute
US can be helpful in assessing for persistent or recurrent
pulmonary embolism and occasionally result in large intravascular
disease by documenting an endometrial mass (117). GTD is
masses (116).
the most common cause of uterine vascular malformations.
These vascular malformations usually present after treatment is
complete and can be easily diagnosed with US. They can be
Magnetic Resonance Imaging
treated with uterine artery embolization under fluoroscopic MRI is primarily used for staging and detecting recurrent dis-
guidance (118). ease. On T2WI, GTD is seen as a heterogeneous, predominantly
258 CHAPTER 11 DIAGNOSTIC I MAGI NG
CERVICAL CANCER
Introduction
The role of imaging in patients with cervical cancer includes
evaluation of extent of disease, monitoring treatment response,
and detecting tumor recurrence. MRI is the modality of choice
for evaluating disease extent and monitoring treatment response;
CT and PET/CT are utilized in the evaluation of distant meta-
static disease or when MRI is contraindicated. CT, MRI, and
PET/CT are useful in the evaluation of recurrent disease.
B
Primary Detection and Characterization
of Cervical Cancer FIGURE 11.13. Partial mole. Sagittal (A) and axial (B) T2W FSE MR
Cervical cancer is usually detected at Pap smear test or by phys- images demonstrate a heterogeneous mass within the uterus (white arrows).
ical examination. Imaging plays no role in the detection and Fetal abdomen (black arrow in A) and umbilical cord (black arrow in B) can
be seen adjacent to the mass.
characterization of cervical cancer.
Thus, it allows uniformity of staging for all patients worldwide;
this is particularly important because cervical carcinoma is most
Staging Cervical Cancer prevalent in countries where surgical and diagnostic resources
FIGO classification is the most widely used staging system for are limited.
cervical carcinoma (63,122). FIGO staging of cervical carcinoma Clinical staging of cervical cancer has inherent deficiencies
is clinical and does not rely on surgico-pathological findings. in evaluating several important prognostic factors including
CHAPTER 11 DIAGNOSTIC I MAGI NG 259
tumor size, parametrial and pelvic sidewall invasion, and nodal compared MRI, CT, and FIGO clinical staging in the pretreat-
metastasis. When compared with surgical staging, clinical FIGO ment assessment of early invasive cervical cancer (126,127). The
staging can be erroneous in up to 32% of patients with stage study found that MRI was equivalent to CT for overall preoper-
IB disease and up to 65% of patients with stage III disease ative staging. However, MRI performed significantly better than
(123,124). This is problematic, as accurate pretreatment evalu- CT for tumor visualization (127) and determination of parame-
ation of these prognostic factors determines the appropriate trial invasion (128). Reader agreement was higher for MRI than
choice of initial treatment for ensuring the best possible patient for CT (126). In this study, the sensitivity, specificity, and nega-
outcome. tive predictive value (NPV) of CT in staging cervical carcinoma
There are two standard primary treatment options for of stage IIB or greater were 42%, 82%, and 84%, respectively
cervical cancer: (a) radical surgery in early-stage disease (IA, IB1 (126). Despite its limitations, CT is a valuable complement to
and IIA1) or (b) primary radical radiotherapy with concurrent clinical staging because of its accuracy in detecting advanced
administration of platinum-based chemotherapy for patients disease (129,130).
with bulky IB2/IIA2 disease (tumors larger than 4 cm) or locally
advanced disease (stage IIB or greater). Therefore, the FIGO
staging committee has acknowledged that clinical staging errors
Magnetic Resonance Imaging
occur with reasonable frequency and the 2009 revision has, for MRI is considered the best single imaging study for cervical
the first time, encouraged the incorporation of cross-sectional cancer and can accurately determine tumor location (exo-
imaging techniques (MRI/CT) into the evaluation and treat- phytic or endocervical) and size; presence of invasion into the
A B
FIGURE 11.14. Stage IVA cervical carcinoma. Contrast-enhanced CT images at two levels (A, B) demonstrate a heterogeneous mass arising in the
cervix (black asterisk) with extension into the uterus (white arrow in A) and bladder (black arrow in B). Note the loss of the normal periureteral fat plane
around the left ureter (white arrow in B).
260 CHAPTER 11 DIAGNOSTIC I MAGI NG
100%) for excluding bladder and rectal invasion, thereby Criteria for M RI interpretation According to
negating the need for cystoscopic or endoscopic staging proce- Tumor Stage
dures (17,128,142).
MRI is highly accurate for detecting nodal enlargement, MRI is complementary to clinical assessment in staging cervical
which is crucial for treatment planning (143,144). Surgically carcinomas of FIGO stage IB1 or greater. In single-institution
treated stages IB and IIA survival rates decrease from 85% studies, MRI has been shown to be better than either CT or physi-
90% to 50%55%, respectively, in the presence of pelvic nodal cal examination in demonstrating parametrial invasion. The stag-
metastases (141). Although FIGO staging does not include sur- ing accuracy of MRI ranges from 85% to 96% (132,139,149).
gical lymph node assessment (122), nodal metastases are an Recommendations for diagnostic evaluation of tumor staging are
important factor in the choice of adjuvant radiotherapy. Surgi- derived from the FIGO clinical staging system (Table 11.3).
cal lymphadenectomy is the gold standard in the diagnosis of Stage I tumors are confined to the cervix. In stage IA, disease
nodal metastases, but it carries a risk of complications. There- is microinvasive and cannot be seen on MRI. Stage IB is defined
fore, preoperative assessment of nodes with imaging is impor- as clinically visible tumor limited to the cervix and is subdi-
tant (145). Finally, MRI is also routinely used in monitoring vided by size into IB1 (<4 cm in greatest dimension) (Fig. 11.15)
treatment response, detection of recurrence, identifying com- and IB2 (>4 cm in greatest dimension). The tumor appears as
plications of the disease and its treatment (146), and planning intermediate signal intensity mass in contrast to the low signal
radiotherapy (147,148). intensity cervical stroma on T2WI (132).
Stage II is defined as tumor growth beyond the cervix but tumor compression or inflammation, which can obscure the real
without extension to the pelvic sidewall or the lower third of the tumor boundary. False positive parametrial invasion can also
vagina. In stage IIA, there is invasion of the upper two-thirds of occur due to postbiopsy hemorrhage. These factors must be con-
the vagina without parametrial invasion. Segmental disruption sidered when making treatment decisions (138,141).
of the hypointense vaginal wall is demonstrated on T2WI. Stage Stage III cervical cancer is defined as tumor extension into
IIA is again subdivided by size into stage IIA1 (<4 cm in great- the lower third of the vagina and/or pelvic sidewall. In stage
est dimension) and stage IIA2 (>4 cm in greatest dimension); IIIA, there is invasion of the lower third of the vagina without
this subdivision reflects a difference in prognosis similar to that extension to the pelvic sidewall. When the tumor extends to the
observed between stages IB1and IB2, which is in turn reflected pelvic sidewall or causes hydronephrosis, it is stage IIIB. Tumor
in differing treatment strategies (122). On MRI, stage IIB disease visualized within 3 mm of the obturator internus, levator ani,
is seen as disruption of the low signal intensity stromal ring on and piriformis muscles or the iliac vessels is suggestive of stage
T2WI; a spiculated tumor to parametrium interface, overt soft IIIB disease (138).
tissue extension into the parametria (Fig. 11.16) and encase- Stage IV indicates adjacent organ invasion and/or distant
ment of the peri-uterine vessels are additional signs of stage IIB metastatic disease. Disruption of low signal intensity bladder
that enhance diagnostic confidence (131). If the intact periph- mucosa (Fig. 11.17) or rectal wall by high signal intensity tumor
eral low signal intensity stromal rim of the cervix is greater on T2WI with tumor involving the mucosa constitutes stage
than 3 mm (hypointense rim sign), parametrial invasion can IVA disease. Direct invasion of the rectum is uncommon, as the
almost be excluded with specificity of 96% to 99% and NPV of Pouch of Douglas separates the posterior fornix from the rec-
94% to 100% (25,138,139). An important pitfall is the over- tum, making the uterosacral ligaments the preferred route for
estimation of parametrial invasion on T2WI with large tumors rectal invasion. By adopting a low threshold for invasion, the
(accuracy of 70%) compared to smaller tumors (accuracy 96%) absence of bladder or rectal invasion can be diagnosed with suf-
(132,138,141). Large tumors can cause stromal edema, from ficient confidence using MRI (NPV = 100%) to safely obviate
FIGURE 11.16. Stage IIB cervical carcinoma. Sagittal (A), and axial oblique (B) T2W FSE MR images show a large
cervical cancer (T in A, B). On the axial oblique image there is a spiculated tumor to parametrium interface on the
right and a tumor nodule present in the left parametrium in keeping with bilateral parametrial invasion (arrows in B).
262 CHAPTER 11 DIAGNOSTIC I MAGI NG
FIGURE 11.17. Stage IVA cervical carcinoma. Sagittal (A) and axial oblique (B) T2W FSE MR images show a
large cervical cancer (T in A, B) that invades the cervical stroma and extends into both parametria as indicated by a
spiculated tumor to parametrium interface. Tumor also invades the bladder mucosa (black arrows in A, B) and both
distal ureters (white arrows in B) causing bilateral hydronephrosis.
the need for invasive cystoscopic or endoscopic staging in the biomarker, predicting treatment response, pelvic recurrence risk,
majority of patients with cervical cancer (142). In stage IVB, and disease-specific survival in patients with cervical cancer.
distant metastatic disease is present. Increasingly, FDG-PET/CT is being advocated to aid delivery
of intensity-modulated radiation therapy (IMRT) (161,162). In
a study on 452 patients treated with curative intent (135 with
Positron Emission Tomography/Computed IMRT) based on FDG-PET/CT, the IMRT group showed better
Tomography overall survival, although recurrence-free survival did not reach
FDG-PET is useful in staging patients with advanced cervical statistical significance (161).
cancer, especially in the detection of lymph node metastases
(Fig. 11.18). Although lymphadenopathy is not part of the
FIGO staging system, it is considered stage IVB disease and Monitoring Treatment Response and
knowledge of its presence is therefore crucial when developing
a treatment plan. Conventional cross-sectional imaging modali-
Detecting Recurrent Cervical Cancer
ties rely on size criteria for the diagnosis of lymphadenopa- Recurrent cervical cancer typically occurs early in the course of
thy, and, therefore, microscopic disease often goes undetected. disease (60% to 70% percent of cases occur within two years
FDG-PET is better than the conventional imaging modalities of starting treatment) (163). Salvage treatment may prolong
in the detection of lymphadenopathy in patients with cervical survival, particularly when the recurrence is detected at an
cancer, with sensitivities of 75% to 100% and specificities of early stage. Location of the recurrent disease and initial ther-
87% to 100% (150153). Reinhardt et al. (154) found that apy will determine the course for subsequent treatment. Recur-
in the detection of involved lymph nodes, sensitivity, specific- rent disease restricted to the vaginal vault or pelvic sidewalls
ity, and positive predictive value (PPV) were 91%, 100%, and may be treated with chemoradiotherapy, if this has not been
100%, respectively, for FDG-PET, as compared to 73%, 83%, given previously. Patients previously treated with chemoradio-
and 67%, respectively, for MRI. Another study demonstrated therapy who develop central recurrence may be suitable for
that the accuracy of FDG-PET in the detection of lymph node pelvic exenteration. Distant metastatic disease may be treated
metastasis was 88%, compared to 75% with MRI (155). FDG- with chemotherapy, and the patient may be offered clinical
PET also improves initial staging in cases of advanced disease trial entry. It is imperative to accurately identify those patients
by demonstrating unexpected sites of disease beyond the pelvis deemed suitable for such radical steps as pelvic exenteration,
or retroperitoneum, such as supraclavicular nodal metastases which is associated with considerable morbidity (164). There
(156). PET or PET/CT has been found to alter management in is, however, no consensus regarding routine follow-up imaging.
a significant number of patients with advanced disease (FIGO Imaging is only undertaken if indicated by clinical symptoms
IIB-IVB) at presentation (157). In contrast, the value of FDG- or signs, or in cases treated with fertility-preserving radical
PET in early-stage disease (FIGO I to IIA) is questionable. Many trachelectomy.
studies have reported low sensitivities for the detection of nodal
metastases, ranging from 25% to 73%. Chao et al. concluded Ultrasound
that PET/CT has a limited role in staging for patients with early-
stage disease and should not replace lymphadenectomy for the Currently, there is no role for US in the evaluation of cervical
detection of lymph node metastases (157). cancer response to chemoradiotherapy or in the detection of
FDG-PET has prognostic value in patients with cervical can- recurrent disease.
cer (158). Kidd et al. found that the maximum SUV (SUV[max])
of the primary cervical tumor at diagnosis was a sensitive bio-
marker of treatment response and prognosis for patients with
Computed Tomography
cervical cancer (159). Recently, the same group (160) reported CT is useful for the detection of tumor recurrence in the pelvis
that the SUV(max) of pelvic lymph nodes is a prognostic following hysterectomy as well as the assessment of metastases
CHAPTER 11 DIAGNOSTIC I MAGI NG 263
to the peritoneum and solid organs (particularly the liver, lungs, soft-tissue asymmetry, soft-tissue mass, compression and inva-
and adrenal glands) (93), but it has limited value for detecting sion of adjacent organs, tumor extension to the pelvic sidewall,
recurrent tumor after chemoradiotherapy, because of poor soft- and hydronephrosis (165). Pelvic and paraaortic nodal metasta-
tissue contrast between the recurrent tumor and the irradiated ses are also often present in patients with recurrent disease and
cervix (93,130). CT features of recurrent pelvic tumor include are well depicted by CT (93).
264 CHAPTER 11 DIAGNOSTIC I MAGI NG
Magnetic Resonance Imaging pelvis is the sole site of recurrence. On T2WI, vaginal vault recur-
rence is seen as loss of the linear, low signal intensity of the vaginal
In patients treated with primary chemoradiotherapy, MRI is rou-
vault and an associated soft tissue mass of high signal intensity,
tinely used to monitor response during and at the completion of
similar to that of the primary tumor. MRI is superior to CT in
treatment (29). Change in tumor size on sequential MRI is the
distinguishing radiation fibrosis from recurrent disease. On MRI,
standard method for evaluating response to chemoradiotherapy
tumor recurrence appears as a region of intermediate to high sig-
in patients with advanced cervical carcinoma. Decrease in tumor
nal intensity on T2WI compared to the low signal intensity irradi-
volume can be seen as early as 2 months after treatment and pre-
ated cervix (Fig. 11.19). However, the appearance of recurrence
dicts a good prognosis (166). The reconstitution of the normal low
can be indeterminate, particularly within the first six months
signal intensity cervical stroma is the most reliable indicator of a
after treatment (177). In patients with a history of remote radia-
tumor-free postradiation cervix (167,168). If a small area of resid-
tion therapy (>1 year), the difference in signal intensity between
ual tumor is detected at the completion of treatment, there is a win-
posttreatment fibrosis and recurrent tumor is statistically signifi-
dow of opportunity to offer exenterative surgery. These patients
cant, and a sensitivity of 86% and a specificity of 94% have been
should undergo FDG-PET/CT before surgery to exclude distant
reported for detection of recurrent cervical cancer by MRI (178).
spread of disease. If, after chemoradiation, the patient is found to
Recurrent tumor is more reliably identified on dynamic
have a complete response, no further routine imaging is required.
contrast-enhanced images, as an area showing increased enhance-
Physiological imaging with DW-MRI and DCE-MRI are com-
ment, than on T2WI (15). The accuracy of dynamic contrast-
plimentary to standard morphological response assessment by
enhanced MRI for identifying recurrent disease approaches 85%
MRI. Pretreatment DCE-MRI parameters can predict response
compared to 64% to 68% for unenhanced T2W images (15,179).
to chemoradiotherapy and may enable alteration of treatment
On DW-MRI, hyperintense signal on high-b-value images associ-
strategy in patients with advanced cervical cancer (169172).
ated with lower ADC values suggests active tumor (180).
DW-MRI has the potential to be used as a response biomarker,
to provide a surrogate end-point in the assessment of treatment
response in advanced cervical cancers. Measurement of ADC Positron Emission Tomography/Computed
values has been shown to have potential for monitoring early
response to chemoradiotherapy (173176). Tomography
MRI plays an important role in evaluation of recurrent cervical In patients with cervical cancer, there is a role for FDG-PET
cancer. It is useful in the evaluation of surgical resectability, if the in treatment response assessment, where findings of residual
FIGURE 11.19. Recurrent cervical carcinoma. Axial oblique T2W FSE MR (A), unenhanced CT (B), FDG-PET (C),
and fused PET/CT (D) images show cervical cancer recurrence in the vaginal vault (T in A-D).
CHAPTER 11 DIAGNOSTIC I MAGI NG 265
metabolically active disease, 3 months after completion of treat- general population. Therefore, efforts at screening patients for
ment, may be used to guide additional therapy (181). ovarian carcinoma have focused on high-risk populations. Risk
PET/CT plays an important role in the management of factors include older age, high socioeconomic status, factors that
patients with suspected recurrent cervical cancer. In this con- increase the number of ovulatory cycles such as early menarche,
text, the applications of PET/CT include detection of recurrent nulliparity, and late-onset menopause, and having a first-degree
disease (Fig. 11.19) at the primary site, assessment of nodal dis- relative with ovarian carcinoma (189,190). Approximately 10%
ease, and detection of distant metastases and radiotherapy field of ovarian carcinomas are believed to be due to an inherited
planning (88,182). FDG-PET/CT is increasingly used in identi- susceptibility. Three syndromes have been described: the breast/
fying pelvic recurrence with sensitivity, specificity, and accuracy ovarian cancer syndrome; the Lynch 2 syndrome, or the heredi-
of 92.0%, 92.6%, and 92.3%, respectively (183). In addition tary nonpolyposis colorectal cancer syndrome; and hereditary
to local recurrence, FDG-PET/CT is able to detect peritoneal site-specific ovarian cancer. In 1994, a National Institutes of
dissemination, paraaortic lymph node metastasis, pelvic lymph Health (NIH) consensus conference (191) recommended that
node metastasis, and lung metastases. Mittra et al. showed that screening be offered to women with two or more first-degree
posttreatment surveillance with PET/CT is highly effective in relatives with ovarian carcinoma. It is also recommended that
identifying both residual/recurrent disease and distant metas- women with an inherited predisposition to ovarian cancer be
tases. All 30 patients in the study had a change in their man- screened (191193). In practice, many women with a single
agement on the basis of the PET/CT findings (184). Similarly, first-degree relative are enrolled in screening programs.
Pallardy et al. found that the use of FDG-PET/CT in patients Most screening programs for ovarian cancer rely on a combi-
Conversely, mural nodules, mural thickening or irregularity fibrothecomas are solid but benign. Furthermore, pedunculated
(Fig. 11.21), solid components, thick septations (>3 mm), and fibroids, dermoids, and endometriomas can masquerade as solid
associated findings such as ascites, peritoneal implants, and/or ovarian lesions.
hydronephrosis, suggest malignancy. Such US descriptors have The use of color and pulse Doppler in the evaluation of ovar-
been reported to have a high sensitivity but lower specificity for ian masses is controversial, with some investigators considering
malignancy (197,199,200). The lower specificity reflects over- blood flow characteristics to be merely confirmatory, but others
lap in the imaging appearance of benign, borderline, and malig- considering the Doppler examination to be a helpful discrimi-
nant lesions. For example, benign lesions such as hemorrhagic nator (201203). Malignant lesions more often demonstrate
cysts, cystadenomas, or cystadenofibromas may have thick sep- increased vessel density and tortuosity than benign lesions,
tations and apparent mural nodules; borderline tumors may but significant overlap exists. Malignant ovarian lesions also
have minimal findings; and Brenners tumors, fibromas, and tend to demonstrate higher peak systolic velocities and lower
CHAPTER 11 DIAGNOSTIC I MAGI NG 267
resistive indices than benign masses, but again, considerable and poorly defined, and amorphous, coarse calcifications and
overlap exists and no discriminatory cut-off values are accepted contrast enhancement may be seen in the cyst wall or soft-tissue
(201203). components. In a study of 143 patients with CT and histopathol-
Scoring systems have been proposed to standardize evalu- ogy, features suspicious for malignancy in cystic lesions included
ation of ovarian masses in an attempt to improve specificity multilocularity, irregular wall thickening, and soft tissue nod-
(204,205). Using a stepwise logistic regression analysis to deter- ules, while unilocular homogeneous lesions with thin walls and
mine the most discriminating gray-scale and Doppler sono- smooth contours tended to be benign (214). Secondary findings
graphic features of malignancy, Brown et al. (204), reported of peritoneal deposits, ascites, and other metastases also aid in
that a multiparameter approach, which assessed for nonhyper- distinguishing malignant from benign lesions (Figs. 11.22 and
echoic solid components, central blood flow on color Doppler, 11.23). Since the CT appearance of ovarian metastases is indis-
ascites, and thick septations, had 93% sensitivity and specific- tinguishable from a primary ovarian neoplasm, the stomach and
ity for malignancy. To achieve 100% sensitivity, specificity was colon should be carefully examined as potential primary tumor
dropped to 86% in this study (204). However, Timmerman et al. sites when an ovarian mass is detected on CT (215).
(206) have reported similar results and interobserver variabil-
ity when readers used subjective criteria for evaluating ovarian
masses. Combining Doppler with gray-scale imaging improves
Magnetic Resonance Imaging
the diagnostic assessment of ovarian lesions (Fig. 11.21). A MRI is the modality of choice for characterization of adnexal
meta-analysis of 46 studies compared the relative utility of lesions which are indeterminate on US (Fig. 11.20). Ovarian
gray-scale imaging, color Doppler, and Doppler flow analysis masses at times can grow large, and it can be difficult to deter-
for interrogating adnexal masses, and found that the combina- mine the organ of origin on US and/or CT. Uterine fibroids and
tion of these methods was more powerful than their individual other pelvic masses can also grow to a large size and mimic
use (207). ovarian tumors. The multiplanar capabilities of MRI are helpful
Three-dimensional US may improve characterization of in this situation and often help to delineate the organ of origin
adnexal masses. In one study of 71 pelvic masses, 3-D power of a large pelvic mass and characterize its nature.
Doppler US improved the specificity and PPV compared to con- It is important to recognize that as there are no MRI signal
ventional 2-D US from 54% to 75% and from 35% to 50%, intensity characteristics that are specific for malignant epithelial
respectively (208). Contrast-enhanced US has also been used for tumor; such tumors must be distinguished based on morphologic
characterization of adnexal masses. Malignant ovarian lesions criteria. Primary and ancillary criteria have been proposed for
show a slower washout of contrast medium than do benign characterizing an adnexal mass as malignant on MRI. A study
lesions (209211). The development of diagnostic criteria for of 60 lesions (216) established five primary criteria for malig-
the kinetics of contrast enhancement may increase the specificity nancy: size greater than 4 cm; solid mass or large solid compo-
of US for adnexal malignancies (209). nent; wall thickness greater than 3 mm; septal thickness greater
than 3 mm; and/or the presence of vegetations or nodularity and
necrosis (Fig. 11.24). Four ancillary criteria of malignancy were
Computed Tomography also established: involvement of pelvic organs or pelvic sidewall;
CT is not the study of choice to evaluate a suspected ovarian peritoneal, mesenteric, or omental disease; ascites; and adenopa-
lesion; however, on CT, ovarian lesions may be detected inciden- thy. The presence of one or more of the five primary criteria,
tally and characterized. The sensitivity, specificity, and accuracy coupled with a single criterion from the ancillary group, correctly
of CT for distinguishing benign versus malignant lesions are characterized 95% of malignant lesions (216).
reported to be 89%, 96% to 99%, and 92% to 94%, respec- Dynamic multiphase contrast-enhanced MRI is useful for the
tively (212,213). evaluation of adnexal cystic lesions, as it may help differentiate
On CT, ovarian cancer demonstrates varied morphologic solid components or papillary projections (Fig. 11.24) from clots
patterns, including a multilocular cyst with thick internal sep- and debris (32,217). Semiquantitative analysis of enhancement
tations and solid mural or septal components (Fig. 11.22), a curves shows that early initiation and high rate and magnitude
partially cystic and solid mass, and a lobulated, papillary solid of enhancement are associated with malignancy (32). Dynamic
mass (Fig. 11.23). The outer border of the mass may be irregular contrast-enhanced MRI (DCE-MRI) can help distinguish among
268 CHAPTER 11 DIAGNOSTIC I MAGI NG
FIGURE 11.22. Ovarian carcinoma. Axial contrast-enhanced CT images demonstrate bilateral complex cystic and
solid adnexal lesions (T in A), omental cake (OC in B), a peritoneal deposit in the gastrohepatic ligament (arrow in C),
as well as ascites and bilateral pleural effusions largest on the right (E in D).
FIGURE 11.23. Ovarian carcinoma. Axial contrast-enhanced CT images demonstrate bilateral solid adnexal lesions
(T in A), omental cake (OC in B), peritoneal deposits in the pouch of Douglas (PD in A) and subcapsular liver deposits
(arrows in B).
CHAPTER 11 DIAGNOSTIC I MAGI NG 269
benign, borderline, and invasive tumors. Amplitude and maxi- specificity, NPV, PPV, and accuracy of 18F-FDG PET/CT were
mal slope of enhancement reportedly achieve 100% sensitivity 87%, 100%, 81%, 100%, and 92%, respectively, compared
with 72% and 92% specificity, respectively, in identifying histo- with 90%, 61%, 78%, 80%, and 80%, respectively, for TVS.
logical invasion (33). A recent study suggested threshold criteria The investigators concluded that FDG-PET/CT provided addi-
for presence of malignancy; maximum solid tumor enhance- tional value to TVS for the differentiation of benign from malig-
ment of more than 250 had 100% sensitivity, specificity, and nant pelvic lesions. However, the major pitfall of the study was
accuracy for prediction of malignancy in preoperative indeter- the lack of comparison with MRI, which remains the modality
minate adnexal masses (281). of choice for characterizating adnexal lesions. Therefore, cur-
A controversy remains regarding the utility of DW-MRI for rently, there is no convincing evidence or justification to sug-
differentiating benign from malignant ovarian tumors. Nakayama gest the use of PET/CT for characterization of indeterminate
et al. (219) found no significant difference in ADC values between adnexal lesions; instead, PET/CT should be reserved for staging
the benign and malignant cystic ovarian lesions. There was a and follow-up of patients with ovarian carcinoma.
wide variation in the ADC values of malignant ovarian tumors,
which was related to their morphological heterogeneity. Recently,
Thomasin-Naggara et al. (220) found that the presence of low-
signal-intensity solid components on high-b-value DW images
Staging Ovarian Cancer
was the most significant criterion for predicting a benign lesion. The FIGO staging system for ovarian cancer is surgically based.
In their study, all masses that displayed low signal intensity It does not formally include imaging, but the FIGO committee
within the solid components on both T2WI and DW-MRI were encourages the use of imaging techniques, if available, to assess
benign. However, ADC values do not contribute in differentiating the important prognostic factors such as disease resectability and
benign from malignant adnexal lesions owing to a considerable lymph node status. The standard of care for patients with newly
overlap of mean and lowest ADC values between the two groups diagnosed advanced ovarian cancer has been comprehensive
(219221). These findings reflect the histological heterogeneity staging laparotomy and primary optimal surgical cytoreduction
of ovarian neoplasms, as high ADC values in malignant lesions followed by adjuvant chemotherapy (226,227). However, the
may arise from desmoplastic stroma, whereas low ADC values use of neoadjuvant chemotherapy followed by interval debulk-
in benign lesions, such as fibromas, result from compact cellular ing surgery (IDS) as a suitable alternative (228,229) is supported
organization (220). More recently, the same group reported that by recent multicenter randomized controlled trials (230,231).
the addition of DCE-MRI and DW-MRI to conventional MRI Imaging is therefore of paramount importance in helping triage
improved diagnostic accuracy in the characterization of complex patients for appropriate management by accurately evaluating
adnexal masses, allowing accuracy of 95% (222). the extent of anatomical location of peritoneal spread, which
in turn dictates the feasibility of cytoreductive surgery and pre-
Positron Emission Tomography/Computed dicts the likelihood of optimal primary cytoreduction. Imaging
by US and CT is also used to guide ovarian mass/omental biopsy,
Tomography which is needed prior to neoadjuvant chemotherapy.
Currently, FDG-PET has little role in the primary detection of
ovarian cancer. A study by Hubner et al. (223) found good cor-
relation between FDG-PET and histologic findings in women
Ultrasound
with suspected ovarian cancer imaged prior to laparotomy. Spe- US has a limited role in the staging of ovarian cancer except in
cifically, the sensitivity, specificity, accuracy, PPV, and NPV of detecting the presence of ascites. Transabdominal US is an excel-
FDG-PET were 83%, 80%, 82%, 86%, and 76%, respectively. lent modality not only for identifying ascites, but also for guid-
A further study found that PET-CT imaging had a sensitivity of ing paracentesis as well as omental/peritoneal biopsy. However,
100% and a specificity of 92.5% for the detection of malignant the detection of stage II and III disease by US is limited. Peri-
masses (224). Castelluci et al. (225) compared the accuracy of toneal implants can sometimes be documented on careful US
18F-FDG PET/CT and TVS in distinguishing malignant from examination. The specificity of US examination in documenting
benign pelvic lesions in 50 consecutive patients. The sensitivity, abdominal spread of disease has been reported to be slightly
270 CHAPTER 11 DIAGNOSTIC I MAGI NG
higher than that of CT or MRI (232). However, the sensitivity and describe the volume and extent of disease for optimal cyto-
of US for the detection of implants less than 2 cm (stage IIIB) is reductive surgery. Relative criteria for nonoptimally resectable
lower than that of CT or MRI owing to a limited field of view disease have been developed (242). They include: lymph node
and decreased spatial and soft-tissue resolution (232.233) US, enlargement above the renal hilum; presence of abdominal wall
therefore, should only be used for specific indications. invasion; parenchymal liver metastases and subcapsular liver
metastases; peritoneal implants of >2 cm along the diaphragm,
lesser sac, porta hepatis, intersegmental fissure, and gall bladder
Computed Tomography fossa; gastrosplenic; gastrohepatic ligament; and small bowel
CT is the primary cross-sectional imaging modality used to stage mesentery. However, it is important to realize that these criteria
ovarian cancer. It is complimentary to surgical staging identifying may vary and will depend on the aggressiveness of the surgical
possible sites of unsuspected disease, which include the pelvic peri- procedure and on the performance status of the patient. There-
toneum, paraaortic nodes, diaphragm, and chest (234,235). Sev- fore, the criteria should only be used as a basis for a multidisci-
eral clinical studies have demonstrated that the thorax frequently plinary consensus. It is important to note that upper abdominal
harbors undiagnosed pleural disease at the time of the initial diag- disease and pleural metastases can be surgically resected, but
nosis, and that this is likely to affect survival even in cases of opti- this requires careful planning as it involves a team of surgeons
mal debulking (236238). In addition, a recent study found that (e.g., liver surgeons for hepatic resection, and thoracic surgeons
moderate-to-large pleural effusion on preoperative CT was associ- for video-assisted thoracoscopic resection of pleural disease).
ated with a decrease in overall survival in patients with stage III or
IV ovarian cancer after controlling for age, preoperative CA-125, Criteria for CT Interpretation According
surgical stage, ascites, and cytoreductive status (239).
Cytoreductive surgery is the treatment of choice for patients to Tumor Stage
with ovarian cancer. Optimal cytoreductive surgery (residual CT staging of ovarian cancer should be performed after admin-
disease <1 cm) is a very strong predictor of survival, (240) and istration of both intravenous and oral contrast medium, the
even after the threshold for optimal cytoreduction has been latter being crucial for detection of tumor deposits along the
reached, it is important to remove as much of the residual tumor small and large bowel serosa. Recommendations for diagnostic
as possible (241). Accurate imaging will help guide the surgeon evaluation of tumor staging are derived from the FIGO surgical
to areas of disease that may be difficult to identify surgically, staging system (Table 11.4).
The presence of ascites does not affect staging unless malignant cells are present.
a
Liver capsule metastasis are Stage III, liver parenchymal metastasis are stage IV.
b
Stage I ovarian cancer is limited to either one (stage IA) or metastasis can occur by hematogenous dissemination. Distinc-
both (stage IB) ovaries; no tumor is present on the ovarian sur- tion between these different types of liver metastases is impor-
face, and no malignant cells in the ascites or peritoneal wash- tant for the selection of an appropriate treatment approach.
ings. In stage IC the tumor is still limited to one or both ovaries Perihepatic metastases without parenchymal invasion can be
but there is a capsular rupture, tumor is present on the ovar- resected directly. However, surgical removal of perihepatic
ian surface, and/or malignant cells are present in the ascites or metastases with parenchymal invasion requires liver resection.
peritoneal washings. Ascites on CT is easily identified; however, Information obtained from CT about liver involvement (includ-
the distinction between stage IC and stage III, or subtle perito- ing involvement of liver regions that are difficult or impossible
neal disease, is often difficult to make out and has significant to explore surgically) is very useful to the gynecologic surgeon,
clinical implications. In one series of patients, the presence of who can obtain appropriate hepatobiliary surgical consulta-
ascites on CT had a PPV of 72% to 80% as a sign of peritoneal tion and necessary equipment in the surgical room. Knowledge
metastasis (235). of the extent of liver involvement is also important in surgical
Stage II disease is characterized by local extension of tumor planning. The presence of multiple perihepatic metastases with
confined to the pelvis but with no upper abdominal involvement. parenchymal invasion in multiple regions of both lobes of the
In stage IIA disease there is extension and/or tumor implants are liver precludes surgical resection.
found in the uterus or fallopian tube(s), but there are no malig- Capsular implants on the surface of the liver/spleen are
nant cells in the ascites or peritoneal washings. Stage IIB disease seen as well-defined, biconvex and peripheral soft-tissue nod-
is characterized by extension into and/or implants on other pel- ules studded along the peritoneal surface of the liver. They may
at the time of surgical staging is associated with an improved abdominal MRI, especially in distinguishing peritoneal/serosal
5-year disease-specific survival rate, even when adjusted for age, deposits from bowel, is limited to specialist centers. Thus MRI is
stage, grade, and number of positive lymph nodes (257,258). best reserved for problem solving and for staging ovarian cancer
This may be because occult micrometastatic disease that is resis- in patients for whom CT is contraindicated. The latter include
tant to chemotherapy is removed (257). However, identifying pregnant patients, patients with renal insufficiency, and those
enlarged lymph nodes preoperatively will guide the surgeon in with contraindications to contrast media.
planning the retroperitoneal dissection. Dynamic multiphase contrast-enhanced MRI has high per-
Stage IV disease is defined by distant metastasis beyond the lesion sensitivity (95%) and specificity (80%) for detecting
peritoneal cavity, and it occurs via hematogenous spread. It is peritoneal dissemination (259). Peritoneal/serosal implants and
the least common mode of tumor spread in ovarian carcinoma omental cake are best seen on delayed (5 min) images. How-
but typically occurs in the solid abdominal organs such as the ever, longer delays beyond 5 min should be avoided as ascites
liver, spleen, kidneys, adrenals, brain, and bone. Hematogenous may also enhance, impairing visualization of subtle peritoneal
metastases are uncommon at the time of diagnosis. The sensi- implants. Hepatic surface implants are usually well defined,
tivity of CT for the detection of extrapelvic disease is approxi- biconvex, and peripheral, and they indent the liver. True intra-
mately 95% to 100% for liver involvement and 50% to 60% parenchymal hepatic metastases are often ill-defined, circular,
for nodal involvement (243,247). Overall staging accuracy for and partially or completely surrounded by liver tissue.
CT has been reported to be 77% (243). CT also has a high PPV Recently, there has been a growing awareness of the potential
for imaging bulky disease and is therefore useful for identifying of DW-MRI in improving the mapping of the extent of ovarian
patients with inoperable disease (243,247). cancer and quantifying its early treatment response (260265).
The omental cake and peritoneal deposits retain high signal
intensity with increasing b values against a background of sup-
Magnetic Resonance Imaging pressed signal from surrounding ascites, bowel contents, and fat,
The overall staging accuracy of MRI in patients with ovarian increasing conspicuity (260,266) (Fig. 11.25). Fujii et al. showed
malignancy is 75% to 78% (216,243), which is comparable that DW-MRI is highly sensitive (90%) and specific (96%) in
to that of CT. However, MRI is recommended as a second- delineating the extent of peritoneal dissemination, with satisfac-
line technique for the staging of ovarian cancer, in the pelvis tory interobserver agreement ( = 0.77) (260) The combination
(232,233), where it has some advantages. The main reasons for of DW-MRI and gadolinium-enhanced MRI has been reported
MRI being used only in selected cases are the long examina- to improve the accuracy of tumor detection (accuracy of 84% to
tion time and the technical difficulties in covering a large field 88% compared to 52% to 72% for gadolinium-enhanced MRI
of view with adequate resolution. Expertise in interpreting alone and 71% to 81% for DW-MRI alone (267). Preliminary
results also show significantly lower ADC in peritoneal deposits evaluate treatment response and to assess suspected relapse with
than in primary ovarian tumors and omental cake, suggesting rising CA-125 levels or clinically suspicious symptoms. Rising
that site-specific diffusion patterns may reflect disease heteroge- CA-125 levels may, however, precede clinical recurrence with
neity in ovarian cancer (268). a median lead time of 3 to 5 months (275). CT is reproducible,
widely available, and well understood. Ultrasound is often used
Positron Emission Tomography/Computed as the initial examination to investigate new symptoms. MRI
is reserved as a problem-solving technique to clarify the nature
Tomography of indeterminate masses on CT. MRI is also particularly use-
There is growing evidence that FDG-PET/CT may play a role ful if there is suspicion of pelvic sidewall invasion or if surgical
in preoperative staging of patients with advance ovarian can- resection of a pelvic recurrence is planned (279). Emerging data
cer. FDG-PET/CT can lead to stage migration (269). This is an suggest that PET/CT may help in the assessment of patients with
important finding, as accurate pretreatment staging is one of elevated CA-125 levels but negative imaging findings.
the determinants of the amount of residual tumor after primary
surgery, which is the strongest predictor of patient outcome. Ultrasound
FDG PET/CT has sensitivity ranging from 62% to 100%
and improves overall diagnostic accuracy by 5% to 22% com- US plays a limited role in the detection of recurrent ovarian can-
pared to CT alone (270272). Fused PET/CT makes a greater cer. US has the greatest sensitivity in detecting recurrent tumor
incremental contribution to per-lesion accuracy in extra-pelvic in the pelvis or around the liver and right hemidiaphragm in the
FIGURE 11.26. Recurrent ovarian carcinoma. Contrast-enhanced CT images in a patient with a previous history
of ovarian cancer. A large solid mass is seen in the right adnexa (T in A). Multiple peritoneal deposits are seen in the
undersurface of the right hemidiaphragm as well as a large subserosal liver deposit with deep invasion into the liver
parenchyma (arrows in B).
274 CHAPTER 11 DIAGNOSTIC I MAGI NG
CT has been used to more objectively assess residual disease If recurrent ovarian cancer is detected by CT, determination
following surgery. Two studies have compared the surgeons of resectability is an important next step. Currently, there is
operative assessments of residual disease to those identified on no consensus on CT criteria for determining nonresectability.
postoperative CT in patients with advanced ovarian carcinoma However, Funt et al. (288) determined that hydronephrosis and
reported to have undergone optimal primary cytoreductive invasion of the pelvic sidewall were most indicative of tumor
surgery. They found that there was only a 52% to 58% cor- nonresectability. CT-guided biopsy can be used to confirm sus-
relation between surgeons assessments and postoperative CT pected recurrence (1).
evaluations of residual disease in patients for whom surgeons
had reported optimal cytoreduction (286,287). Whereas the Magnetic Resonance Imaging
reliability of the direct visualization and palpation at comple-
MRI plays an important role in evaluation of resectability of
tion of surgery is unquestionable, the estimation of the size
recurrent tumor in the pelvis. Recurrent tumor invading the pel-
or the volume of residual disease is far from accurate. Therefore,
vic sidewall represents nonresectable disease (Fig. 11.27). Pelvic
the additional value of postoperative CT may lie in those cases
muscle or bone invasion confirms sidewall involvement but this
where there is surgical small-volume residual disease (visible but
should also be suspected when tumor lies within 3 mm of the
reported as <1 cm) (287).
pelvic sidewall or when the iliac vessels are surrounded or dis-
Second-look surgery is no longer routinely performed; there-
torted by tumor (Fig. 11.27). A few studies that compared MRI to
fore, imaging diagnosis of recurrence is important, as secondary
second-look laparotomy found that dynamic multiphase contrast-
cytoreduction is only considered if complete resection is possi-
enhanced MRI is comparable (sensitivity 90% and specificity
ble with no residual tumor. CT is widely used to assess suspected
88%) to laparotomy (sensitivity 88% and specificity 100%) and
relapse with rising CA-125 levels or clinically suspicious symp-
superior to serum CA-125 (sensitivity 65% and specificity 88%)
toms. The sensitivity of CT ranges from 51% to 84% and its
for detecting recurrent peritoneal and serosal deposits (259,291).
specificity ranges from 81% to 93% (288290). False-positive
results are usually caused by misdiagnosis of adherent bowel
loops as a tumor mass. The sensitivity of CT for disease detec- Positron Emission Tomography
tion is proportional to lesion size. Many studies report limita- FDG-PET/CT has been shown to be an extremely useful adjunct
tions in the detection of small tumor nodules in the mesentery in the evaluation of recurrent ovarian cancer (Fig. 11.28). It has
and along peritoneal surfaces (288,290). However, the use of sensitivity, specificity, and accuracy of 72% to 100%, 40% to
sagittal and coronal reformatted images improves the detection 90%, and 77% to 91%, respectively, for localization of clinical
of peritoneal implants (248). and biochemical recurrence (292296); in comparison, the
performance of contrast-enhanced CT in assessing recurrence of distant lymph nodes (290). These preliminary data suggest
is inferior (accuracy 43% to 89%), primarily because of low that tumor size, number, and SUV(max) may have potential
tumor burden at relapse and distortion of pelvic anatomy after as prognostic biomarkers for patients with recurrent ovarian
cytoreductive surgery (297,298). In two meta-analyses, PET/ cancer.
CT had the highest pooled sensitivity and specificity (91% and In response assessment, a metabolic response defined as a
86%, respectively) compared to PET and CT alone, MRI, and minimum decrease in SUV of 20% after the first cycle and 55%
CA-125 (299,300). In prospective studies, PET/CT upstaged after the third cycle of neoadjuvant chemotherapy was shown to
disease compared to purely anatomical imaging in 55% to 64% predict macroscopically tumor-free surgery and median overall
of patients by depicting additional sites and altered decisions on survival more accurately than clinical, biochemical and histo-
clinical management in 34% to 59% of cases, with 44% to 57% pathological criteria (305). In another study, a cut-off value of
of changes rated as high impact (301304). Fagotti et al. (294) 65% SUV reduction had 90% sensitivity, 82% specificity, and
assessed the role of a multimodal approach in the preoperative 86% accuracy in predicting histological response (306).
work-up of patients with recurrent ovarian cancer by prospec-
tively comparing laparoscopy and PET/CT. They reported that
combined PET/CT and laparoscopic evaluation had a NPV of
88.9%, a specificity of 59.3%, a PPV of 78.8%, a sensitivity of VAGI NAL CANCER
95.3%, and an accuracy rate of 81.4%. The number of recur-
rent nodules identified by PET/CT corresponded to the number Vaginal cancer is most often diagnosed and staged clinically.
found at laparotomy in only 23 patients (40.3%), whereas 15 of Diagnostic imaging is often performed only for the detection
30 patients were correctly diagnosed (50.0%) by staging lapa- of pelvic lymphadenopathy or metastatic disease, with imaging
roscopy, suggesting that these techniques are complementary playing no role in the detection and characterization of vagi-
due to the potential of each one to identify a different site of nal cancer. On MRI, vaginal tumors appear isointense on T1W
disease recurrence. A recent study found that in patients with sequences and may only be apparent if they alter the vaginal
recurrent ovarian cancer, size, number, and SUV(max) of perito- contour. On T2W sequences, a vaginal tumor appears as an
neal deposits were significantly associated with poor survival, as intermediate to high signal intensity soft-tissue mass (Fig. 11.29)
were the long- and short-axis diameters, number, and SUV(max) (307309).
276 CHAPTER 11 DIAGNOSTIC I MAGI NG
FIGURE 11.29. Vaginal carcinoma. Sagittal (A) and axial T2W FSE MR images demonstrate soft tissue thickening
of the posterior vaginal wall (arrow in A, B).
Staging of vaginal cancer is most often clinical (63); however, treatment selection, treatment planning, and prognosis of
MRI has a limited role in the staging of vaginal cancer. MRI cri- patients with vulvar cancer, and relapse in the lymph node basin
teria that correlate to the FIGO staging system have been devel- is associated with extremely poor survival. There is no role for
oped. Stage I disease is defined as tumor that has invaded the diagnostic imaging in the primary detection and characteriza-
epithelium but is confined to the vaginal mucosa. These lesions tion of vulvar cancer. However, imaging (MRI) may play a role
may be occult on MRI, or there may be abnormal high T2W in evaluation of the local extent of disease in advanced cases,
signal penetrating the vaginal wall. The surrounding perivaginal especially if urethral invasion is suspected, as well as in the evalu-
fat is preserved. ation of lymphadenopathy (US, CT, MRI) and distant metastatic
Vaginal tumor that has invaded the paravaginal tissues but disease (CT and PET/CT).
does not involve the pelvic sidewall is considered stage II disease. Vulvar cancer appears on US as a soft-tissue mass with inter-
With stage II disease, the normally high-T2W-signal perivaginal nal vascularity. On CT, vulvar cancer appears as a nonspecific
fat is invaded by intermediate signal tumor. soft-tissue mass. On MRI, it demonstrates intermediate signal
Tumor that extends to involve the pelvic sidewall and/or pel- intensity on T1W sequences and high signal intensity on T2W
vic adenopathy defines stage III disease. Tumor contiguous with sequences (Fig. 11.30). MRI may be used to evaluate tumor
the levator ani, obturator internus, or the piriformis muscle is extension into adjacent structures (i.e., urethra) (311,312). MRI
diagnostic of pelvic sidewall invasion. Pelvic adenopathy is diag- may also be used to differentiate recurrence from posttherapy
nosed in the usual manner on MRI. changes, with the former demonstrating high signal intensity on
Stage IV is defined as tumor invading the bladder and/or rec- T2W images, and the latter demonstrating intermediate signal
tum and/or extrapelvic spread of disease. MRI is particularly intensity on T2W sequences.
well suited for imaging stage IV disease because of its multipla- The surgical management of early-stage vulvar cancer is
nar capabilities. Invasion of the bladder and/or rectum is diag- now more conservative, and an individualized approach is
nosed by identifying disruption of the normal high-T2W-signal increasingly used to improve the outcome and reduce the com-
mucosa of the bladder and/or rectum. Extrapelvic metastases plication rate related to lymphadenectomy (313). Lymphade-
are diagnosed in the usual manner. nopathy in vulvar cancer is usually treated by surgical lymph
Although these staging criteria have been developed, care node dissection. However, sentinel lymph node excision is now
must be taken when using MRI for the evaluation of vaginal being recommended in selected patients with early-stage squa-
cancer. It has been shown that inflammatory changes and/or mous cell carcinoma (tumor <4 cm in diameter and clinically
congestion of the vagina may appear similar to carcinoma (307 nonsuspicious groin nodes) as a means to avoid the operative
309). CT and US have little role in the staging of vaginal cancer, morbidity associated with inguinofemoral lymphadenectomy
although CT can be used for the detection of pelvic lymphade- (314316). Patients with tumor larger than 4 cm in diameter
nopathy. Very little data is available on the utility of FDG-PET and with suspected groin nodes will undergo radical excision
in vaginal cancer. Lamoreaux et al. demonstrated that FDG-PET and lymphadenectomy.
was superior to CT in the detection of the primary tumor and The combination of lymphoscintigraphy with technetium-99
pelvic adenopathy in patients with vaginal cancer (310). m-labeled nanocolloid and blue dye is the most accurate tech-
Complications from vaginal cancer and/or vaginal cancer nique for sentinel node detection (315). Patients with a positive
treatment can be imaged with US, CT, and/or MRI depending sentinel node should undergo a full inguinofemoral lymphad-
on the clinical concern. Known complications include fistulae, enectomy followed by a postoperative radiation therapy to the
fluid collections, and postradiation therapy colitis. Fistulae are involved groin and pelvis. However, if sentinel lymph nodes are
best diagnosed with contrast-enhanced CT or MRI. negative, no further treatment is indicated. All vulvar cancers
located within 1 cm of midline structures (clitoris, vagina, or
anus) have the potential to spread to both groins, and should
be treated by radical wide local excision and bilateral inguino-
VU LVAR CANCER femoral lymphadenectomy.
US combined with fine-needle aspiration biopsy (FNA) of
Vulvar cancer is diagnosed and staged clinically. Local tumor suspicious-looking nodes has been shown to influence surgical
extension and lymph node status play an important role in management with sensitivity, specificity, NPV, and PPV of 80%,
CHAPTER 11 DIAGNOSTIC I MAGI NG 277
100%, 93%, and 100%, respectively (317319). More recently, times, and wide availability. CT is the modality of choice for
in a multi-center setting, high-resolution MRI sequences have staging ovarian cancer, detecting distant metastases and lymph-
been shown to achieve an accuracy of 87% in detection and adenopathy in endometrial and cervical cancer, and evaluating
characterization of inguinal (Fig. 11.30) and pelvic lymph nodes recurrent pelvic malignancies. Both US and CT are used to guide
(312), indicating that MRI may be useful to triage patient for percutaneous drainage and biopsy.
US-guided biopsy versus sentinel lymph node detection. MRI plays important roles in the management of gynecologi-
Very little has been published on the use of FDG-PET for vul- cal malignancies, ranging from initial evaluation of disease extent,
var cancer. In one study, FDG-PET had sensitivity of 80%, speci- to aiding treatment selection, to follow-up. In patients with endo-
ficity of 90%, PPV of 80%, and NPV of 90% in the detection of metrial cancer, MRI improves pretreatment risk stratification. It
pelvic adenopathy (320). Although these results are promising, enables accurate surgical planning and selection of patients for
more research in this area is needed. pelvic or paraaortic lymph node dissection in high-risk disease,
whilst obviating the need for extended surgery in patients with
low-risk disease. In patients with cervical cancer, MRI improves
FIGO clinical staging accuracy, leading to better treatment selec-
CONCLUSION tion and planning. In those patients who wish to preserve fertility,
MRI plays a paramount role in assessing eligibility for fertility-
Increased use of CT, MRI and PET/CT for staging gynecologic sparing surgical procedures. In patients with ovarian cancer, MRI
pelvic malignancies has led to a significant decline in the use is a problem-solving modality. There is growing evidence that
of conventional and invasive radiologic studies such as intrave- DW-MRI may enable more accurate mapping of the extent of
nous urography and barium enema, which are now considered peritoneal disease than does CT. MRI certainly plays an impor-
obsolete at most institutions. In addition, although US is the pri- tant role in patients with recurrent ovarian cancer by assessing
mary imaging modality for characterizing ovarian masses and resectability in cases of solitary pelvic recurrences.
evaluating the endometrium, US is no longer used for primary FDG-PET/CT is increasingly being used to evaluate gyneco-
gynecologic cancer staging. logic malignancies. It is useful in the primary staging of cervical
CT has a central role in pelvic imaging, mainly because of cancer as well as the detection of recurrent ovarian, cervical, and
its relatively low cost, high spatial resolution, fast examination endometrial cancers.
278 CHAPTER 11 DIAGNOSTIC I MAGI NG
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carcinoma. Cancer. 2005;103(7):13971401. patients. Br J Cancer. 2007;96(12):18171822. value of positron emission tomography with
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R ADIATION ONCOLOGY AS
A SPECIALTY INTRODUCTION TO RADIOBIOLOGY
Radiation oncology is a specialty focused primarily on the Radiobiology is the study of the action of ionizing radiations
treatment of malignancies, although there are a number of on living things (1). It is important for radiation oncologists to
benign diseases for which radiation can be used. Training in know the most appropriate dose to potentially eradicate the
radiation oncology begins with internship, followed by 4 years tumor and the normal tissue tolerance doses for those organs in
of residency. Board certification follows, requiring successful the radiation field. The published literature includes clinical and
completion of both written and oral exams. Residency train- laboratory data to support various dose/fractionation schemes
ing includes an in-depth understanding of the natural history as well as acceptable dose ranges to the normal tissues. The size
and treatment of all malignancies including the roles of surgery and histology of the tumor as well as the relationship of the
and systemic therapy in this era of multimodality therapies. An tumor to the normal organs within the radiation field will help
in-depth understanding of surgical procedures, pathology, and to determine the total dose and the dose per fraction. Almost
radiologic anatomy, as well as the efficacies and toxicities of every radiation oncologist approaches treatment planning by
systemic therapy, is required. Formal instruction in physics and considering whether the therapy is curative verses palliative. If
radiobiology is also part of the residency training. Subspecial- curative, then the focus becomes identifying the location of the
ization can follow with a specific practice focus on gynecologic disease and how best to eradicate it. Typically, radiation and
or other cancers. Only a few centers sponsor fellowships, which chemotherapy treatments take place over many months, and
are usually focused on brachytherapy or other special proce- upon completion of treatment, if there is still a clonogenically
dures. Brachytherapy skills are especially important in the cura- viable cell that remains, then the tumor will ultimately recur.
tive treatment of patients with gynecologic cancer. In addition, Clinical radiobiology focuses on steps that maximize the chance
contemporary treatment of gynecologic malignances requires for cure and decrease the chance for side effects.
mastery of rapidly evolving technology for delivering external As in pharmacology, radiation effects exhibit a sigmoidal
beam irradiation with techniques such as intensity-modulated doseresponse curve. In the case of radiation, the interpretation
radiation therapy (IMRT) and image-guided radiation therapy of the curve becomes far more complex because multiple inde-
(IGRT). Radiation oncologists are important contributors in pendent processes govern responses to radiation. Pharmacology,
the management of individual patients and in multidisciplinary on the other hand, tends to be simpler because classic examples
tumor boards. Having a knowledgeable and subspecialized can be described by a ligand binding to a group of receptors
radiation oncologist and gynecologic oncologist paired is a initiating subsequent events. Keeping this in mind, consider the
great benefit to all. In addition to radiation oncologists, other following theoretical doseresponse curve for tumor control
allied health professionals are integral to the radiation oncol- probability and normal tissue complications in the presence and
ogy department and treatment delivery. Radiation therapists are absence of chemotherapy (Fig. 12.1). Ideally, there is a great
the individuals who actually operate the radiation equipment deal of separation between the curve on the left, representing
and deliver the radiation treatments. Some of them will obtain chances of tumor control, and the curve on the right, represent-
a Bachelor of Science degree followed by a 13-month training ing the chance for toxicity. An intolerable situation is where the
program in radiation therapy. Alternatively, a 2-year associate curves are close together since, as they approach one another,
degree in diagnostic radiology can be obtained followed by 1 to the chances of control and toxicity become equal and the thera-
2 years in radiation therapy training. Dosimetrists are primar- peutic range (TR) narrows. Therefore, the most important goal
ily responsible for planning the radiation therapy or dosimetry of radiobiology is to understand the basic science behind the
prior to treatment delivery. Most of these individuals are former interaction of radiation and cells with the hope of maximizing
radiation therapists. An additional 1 to 2 years of training under the risk-benefit ratio for patients.
a physicist and board-certified dosimetrist and additional years
of practice are required to be eligible for board certification.
Radiation physicists supervise and review the work of dosime- Models for Cell Kill
trists. Physicists are also integral to the introduction and mainte-
nance of the rapidly evolving technology in radiation oncology
Tumor Control Probability
departments. They are very involved with quality assurance The simplest model one can envision for the sterilization of can-
and radiation safety. They can be Masters-level or PhD-level cer cells by radiation in a given volume is the log cell kill model.
physicists and should be board certified. A typical course of radiation therapy is given in 10 to 40 fractions
284
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 285
Lethal effect
on tumor
with
chemotheraphy/
without TR
Necrosis of
Percent effect
FIGURE 12.3. Cell culture technique used to generate a cell survival curve. A cell suspension is used to plate
Petri dishes with a known number of cells, which are subsequently irradiated. Viable cells will form colonies after
incubation. The number of viable cells divided by the plating efficiency is used to calculate the surviving fraction.
The experiment is repeated over a wide range of doses to produce the cell survival curve.
However, plotting this on a logarithmic scale would yield a per- outcomes of photon interaction with the DNA backbone. Because
fect straight line, indicating that a single isotope is involved. DNA is composed of a double helix with multiple local base pairs
Consider a slightly more complex situation where the decay acting cooperatively, a single-strand nick is thought to be incon-
is represented by 2 radioactive isotopes with similar half-lives. sequential and is repaired by the cellular machinery (Fig. 12.5B).
Plotting this on a linear scale would also reveal an exponential In fact, multiple single-strand nicks can occur, and if they are
curve, which is unrevealing by inspection. However, creating a remote from one another, a normal cell can repair the damage
plot on a logarithmic scale would yield 2 lines superimposed on with little chance of a deleterious outcome (Fig. 12.5C). However,
one another, clearly indicating that 2 radioisotopes are involved. 2 opposing single-strand breaks locally disrupt cooperativity, and
Two theoretical experimental cell survival curves are shown a double-stranded break (DSB) develops.
in Figure 12.4 under LDR (low-dose-rate) and HDR (high-dose-
rate) radiation conditions. The curve for LDR is best fit by a
straight line, while the HDR curve is shown to have 2 compo-
nents, an earlier linear component mirroring the LDR curve fol- Dose
lowed by a quadratic component. At higher doses of radiation,
the HDR curve always has a higher proportion of cell kill than
the LDR curve for any given dose. Linear
The rate at which radiation is delivered causes dramatic
differences in the shape of the cell survival curve. This is best e LDR
p+
described by considering the linear-quadratic model with DNA Effect D
as the lethal target. The evidence for DNA as one of the targets
e
for radiation is substantial: (a) incorporation of radioactive tri- Quadratic p+
tium into DNA causes cell death at greater rates than cytoplas-
mic tritium (2); (b) halogenated pyrimidines, when present in e
p+
DNA, increase the cells inherent radiosensitivity in an amount D2
proportionate to the degree of incorporation; (c) a correlation HDR
between radiation, DNA double-stranded break repair, and clo-
nogenic survival has also been observed; (d) the concentration
FIGURE 12.4. Cell killing by radiation is largely due to aberrations caused
of DNA in the nucleus correlates positively with radiosensitivity
(3); (e) microirradiation techniques have shown the nucleus to by breaks in 2 chromosomes. The dose-response curve for high-dose-rate
irradiation is linear-quadratic: the 2 breaks may be caused by the same
be the most radiosensitive organelle (4). electron (dominant at low doses) or by 2 different electrons (dominant
In most instances, radiation must cause DNA damage that at higher doses). For low-dose-rate irradiation, where radiation is delivered
results in a net loss of genetic material, thereby causing a lethal over a protracted period, the principal mechanism of cell killing is by the
outcome. Radiation exerts most of its deleterious effects by caus- single electron. Consequently, the LDR survival curve is an extension of
ing breaks in the DNA backbone. Figure 12.5 shows possible the low-dose region of the HDR survival curve.
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 287
Symmetrical translocation
not lethal but may activate
an oncogene
FIGURE 12.6. Most biologic effects of radiation are due to the incorrect joining of breaks in 2
chromosomes. For example, the 2 broken chromosomes may recombine to form a dicentric
(a chromosome with 2 centromeres) and an acentric fragment (a fragment with no centromere). This
is a lethal lesion resulting in cell death. Alternatively, the 2 broken chromosomes may exchange broken
ends, called symmetrical translocation, which does not lead to death of the cell, but in a few special cases
activates an oncogene by moving it from a quiescent to an active site.
288 CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY
T N N
2.5
Rodiosensitivity
Influence of Oxygen on Rodiosensitivity
100 2.0
Smax
1.5
T
Percent Survival
= 2.7
10 20 30 40 50 60 70 80 90 100 760
10 100% Oxygen
mm Hg
Nitrogen
1
500 1,000 1,500
Dose rods
FIGURE 12.7. Influence of oxygen tension on radiosensitivity. Survival curve for human embryo liver cells in
tissue culture irradiated with and without oxygen.
Source: From Johns HE, Cunningham JR. The Physics of Radiology. 3rd ed. Springfield, IL: Charles C Thomas; 1972, with permission.
of radiation, there is very little b kill; however, at higher doses, to note that this model makes no statement about what the tar-
the b component increases exponentially because of D2. Under gets actually are. Since we already know that the primary target
LDR conditions, the b component is absent, leaving only a kill. is DNA, which can trigger multiple complicated events such as
This is best explained by the idea that b kill involves damage to repair and apoptosis, the multitarget single hit model falls short
one chromosome and so is more easily repaired provided that of perfection. Nevertheless, it is a good model for understanding
the radiation dose rate and rate of DSB formation is not signifi- the general shapes of survival curves. Contrast this model to the
cantly greater than the cells repair capacity. single-target single hit model, which states that a cell needs only
to sustain a single hit for lethality, and is described mathemati-
cally by Survival = eD/Do. Therefore, even at very low doses of
DNA Damage Repair and the Shape of radiation, there will be cell kill. Note that this model does not
Cell Survival Curves have an extrapolation coefficient.
Referring back to Figure 12.7, the cell survival curve under
The concept that DNA damage repair drives the shapes of cell anoxic conditions can be interpreted as having a higher extrapo-
survival curves is well illustrated by experiments showing the lation coefficient when compared to 100% oxygen. The extrap-
effectiveness of oxygen as a sensitizer. Oxygen is known to olation coefficient is shown diagrammatically by following the
chemically modify radiation-induced DNA damage making it dotted lines of the survival curves back to the y-intercept. The
irreparable (8). This is known as the oxygen fixation hypothesis. dotted line crosses the y-intercept at n.
Therefore, under anoxic conditions, DNA damage repair would The inset shows a doseresponse relationship between oxygen
be expected to increase considerably. Figure 12.7 shows an exper- and radiosensitivity. The typical sigmoidal relationship is lost
iment on cultured human embryo liver cells irradiated under because oxygen is extremely effective at fixing DNA damage
100% oxygen and nitrogen conditions. Hypoxia causes the cell even at low pressures. In fact, only approximately 20 mm Hg or
survival curve to shift to the right and change shape. 2% to 3% oxygen is required to achieve the maximum oxygen
Up to this point, the linear-quadratic model has been used to effect. The half-maximum sensitization is typically observed at
describe cell survival curve experiments. Another way to describe 3 mm Hg or 0.5% of oxygen.
the observations is using the multitarget single hit model, which The linear-quadratic model is stated more explicitly by the
simply states that multiple targets within a cell must be damaged following equation:
for a lethal outcome. Therefore, at very low doses of radiation,
there will be nearly 100% survival. The model is described math- ln S = D + D2
ematically by Survival = 1 (1 eD/D0)n, where D is dose deliv- where S is the surviving fraction and the remaining parameters
ered, D0 is the amount of radiation to achieve approximately , , and D are the same definitions as above. The formula was
63% cell kill. The parameter n is the extrapolation coefficient used to generate Figure 12.8. The dashed line represents the
or the number of targets in each cell, and is identified by where component and is generated by extrapolating the initial slope of
an imaginary straight line drawn back from the linear portion the curve to higher doses of radiation. The point at which the and
of the cell survival curve crosses the y-intercept. It is important kill are equal is shown, and the dose at which this occurs is called
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 289
PUMA
Cyt C
P53 E6 BID
Cyt C
Mitochondrial Injury
HPV Oncogenes Initiating the Intrinsic
P21 Pathway for Apoptosis
Aka M
Waf1
Cip1 BAX BAK CASPASE 9
Cyclin B
R7 CDK1
G1 G2
Cyclin D
CDK4
E2F Cyclin A
Cyclin D
CDK2
CDK4
Rb Rb Rb
phosphoryl
PO4
Cyclin E CASPASE 3 APOPTOSIS
E2F CDK2
S
Transcription
factor
FAS - L TNFRI
BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY
CASPASE 8
FAS
FAD
TNF
TRADD
FIGURE 12.10. The cell cycle and important molecular biologic pathways driving cell cycle arrest, aptoptosis, and survival are shown. The solid pentagon denotes a net inhibitory step and the open
circle indicates a downstream step.
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 291
Figure 12.10 is G0, which is a stable state of the cell and is typi- 13 and mutations can cause a number of tumors, the earliest of
cally observed with well-differentiated cells that have reached end which to manifest is retinoblastoma. Knudsonetal. developed
stage of development and are no longer dividing (i.e., neuron). the two-hit hypothesis for the inheritance pattern of this dis-
There are three major classes of proteins that orchestrate the ease (16). He recognized that there were 2 forms: (a) sporadic,
cell cycle in mammalian cells: (a) cyclins, (b) cyclin-dependent which comprises 60% of the cases of retinoblastoma, whereby
kinases (cdk in mammals, cdc in yeast), (c) proteins that regu- mutations occur as random events in both alleles. Patients typi-
late (a) and (b). Cyclins are generally synthesized and degraded cally have unilateral disease and a marginal risk for developing
for each phase of the cell cycle. Alone they have no intrinsic second malignancies in response to radiation; and (b) Inherited,
enzymatic activity; rather, they bind to and activate cdks. Mono- where a germ-line mutation results when an abnormal allele
meric cdks are protein kinases that are inactive and require asso- is inherited from a parent. Patients with this form of retino-
ciation with a specific cyclin and phosphorylation of a series of blastoma are more likely to develop bilateral disease and have
conserved threonine residues to become active. Cyclin D/cdk4 is a profound sensitivity toward developing radiation-induced
involved with G1 phase of the cell cycle, cyclin E/cdk2 with G1 to second malignancies. Rb acts by binding and inhibiting E2F,
S phase, cyclin A/cdk2 with S to G2, and cyclin B/cdk1 with M. a transcription factor essential for G1. Phosphorylation of Rb
results in release of inhibition of E2F and subsequent cell cycle
progression. Human papillomavirus gene product produces an
Cellular Response to Radiation oncogene, E7, which binds to Rb and releases inhibition of E2F,
When a cell is irradiated, there are, in general, four possible out- thereby promoting cell division (17).
0 1 2 4 6 8 10 15 20 25 40
Preim-
Organo-
plan- Fetal period
genesis
tation
Congenital
anomalies
Permanent
Animal Prenatal Neonatal death growth
studies death Temporary retardation
growth
retardation
Microcephaly
Japanese Loss of
survivors embryos Mental Mental
retardation retardation
High risk 4x lower risk
Mental
Severe retardation
Patients Microcephaly
medically abnormalities
irradiated in many Stunting of
growth
organs Few
abnormalities
0 1 2 4 6 8 10 15 20 25 40
Gestation (week)
.
FIGURE 12.11. Summary of the effects of radiation on the developing embryo and fetus from 3 principal sources:
medical radiation, laboratory animal studies, and survivors of the atomic bomb attacks on Nagasaki and Hiroshima. The animal
studies indicate a wide range of structural abnormalities during organogenesis, whereas the principal effect observed in
humans is reduced head diameter with or without severe mental retardation.
Source: Modified from Hall EJ. Radiobiology for the Radiologist. 4th ed. Philadelphia: JB Lippincott Co.; 1994, with permission.
during this period. Most of the cell molecular machinery is by approximately 40% above the spontaneous rate. Doses as
geared toward completing mitosis and any DNA double- low as approximately 10 mGy increase the risk, and the excess
stranded breaks are passed along to the daughter cells and are absolute risk is around 6% per gray. Solid tumors have a lon-
typically fatal. Since embryos and fetuses are composed of rap- ger latency period of approximately 20 to 40 years, whereas
idly dividing cells, they are exquisitely sensitive to radiation and leukemias have an average latency of around 7 years. When
exhibit an extremely low threshold dose. Gestational age is also counseling the pregnant patient or worker, it is important to
a key determinant when predicting outcomes of radiation expo- let them know the magnitude of and potential for side effects.
sure. As Figure 12.11 shows, exposure of several gray during the According to the International Council of Radiation Protection
first 1 to 2 weeks of gestation (peri-implantation stage) results (ICRP) Publication 84, doses less than 1 mGy may be consid-
in loss of the embryo. However, if the embryo survives the ered negligible, which is the approximate dose of normal back-
insult, it will go on to develop without obvious abnormalities. ground radiation (20). Exposures above 1 mGy require a more
This phenomenon is termed the all or nothing effect. Dur- in-depth discussion with the patient. ICRP Publication 84 pro-
ing weeks 2 to 6, the period of organogenesis is occurring and vides detailed risk assessments and counseling guidelines for
exposure at this point results in congenital anomalies, neona- in utero exposure.
tal death, and temporary growth retardation. Doses as low as
2 Gy have a 70% mortality. The fetal period occurs beyond
6 weeks and exposure results in permanent growth retardation.
Occupational Exposure
Irradiation during weeks 4 through 16 may produce severe eye, Once pregnancy has been declared, the employee is encouraged
skeletal, and genital organ abnormalities as well as microceph- to formally inform her employer. Further, the radiation safety
aly and mental retardation. According to the Japanese survival officer should interview her, her employment should be evalu-
data, the risk is approximately 40% per gray. Exposure during ated for exposure history, and steps should be taken to minimize
weeks 16 through 20 may cause a less severe form of stunt- exposure. The National Council on Radiological Protection
ing of growth, microcephaly, and mental retardation. After recommends that the embryo/fetus have limited exposure to less
30 weeks, low doses of radiation do not typically result in gross than 0.5 Sv/month (21).
abnormalities.
and not charged particles. Kerma and absorbed dose, although This equation is solved using an exponential solution:
they have equivalence to the roentgen and exposure, can be
A = Aoet
defined equally for photons and charged particles.
where A is the initial activity, is the decay constant, and t is
some unit of time later. Other important units for radioactivity
and radioactive decay are the half-life, T1/2, and the average life,
Ta. The half-life is the amount of time necessary to reduce the
R ADIATION PRODUCTION original amount of material by half. This is also equivalent to
reducing the original activity by half. T1/2 is related to the decay
constant by T1/2 = 0.693/. The average life represents the period
Radioactive Isotopes of time that a hypothetical source would need, if it retained its
As mentioned before, -rays are typically derived from radioac- original activity for a fixed period of time (Ta) before suddenly
tive isotopes, such as 60Co. Electrons or beta particles also come decaying to zero activity, to produce the same number of disin-
from radioactive isotopes. In fact, most radioactive material tegrations over an infinite amount time by the same source if it
produces a combination of photons (gamma rays) and electrons decayed exponentially. Ta is related to the decay constant and
during the decay process. Radioactivity is the result of an atom the half-life by Ta = 1/ = 1.44 T1/2.
changing its energy state, usually to a lower energy state, Radioactive isotopes can occur naturally or be created arti-
by the emission/absorption/internal conversion of photons or ficially. Artificially created isotopes are usually created by neu-
electrons in the atom. These processes result in disintegrations tron bombardment of otherwise stable isotopes. The resulting
or radioactive decay, whereby the atom releases photons or elec- interactions produce atoms that are inherently unstable and will
trons or both during the change in energy states. The release decay to a more stable form with a predictable half-life, releas-
of these particles is a form of radiation (or energy) that can be ing energy or radiation through this decay. Naturally occurring
used to irradiate tissues. The absorbed dose resulting from this radioactive isotopes originally come from one of three standard
radiation depends on the energy and particle type as mentioned seriesthe uranium series, the actinium series, and the thorium
above, as well as the tissue in which it interacts. seriesso named because of a dominant radioactive isotope in
Radioactivity, or activity, is denoted by the symbol A and is each series. In general, the higher the atomic number, the more
defined as the number of disintegrations per unit of time. The likely an isotope will be radioactive. Table 12.2 lists many of the
following relationship defines activity, the decay constant, and more common radioactive isotopes and their physical proper-
ultimately the half-life for a radioactive material: ties. For gynecologic cancers, use of radium 226 (226Ra) sources
is now historic. Though cost-effective because of its long half-
A = N/t = N life (1,622 years), radium releases a by-product, radon gas, if
(Continued)
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 295
the integrity of the source capsule is compromised. This could Figure 12.16 shows a simplified drawing of a linac. The gantry
60
3-D conformal approach (27). Bladder and rectosigmoid doses
can also be reduced. Margin sizes around the target and blad-
der and rectal filling are important considerations, as are immo-
bilization techniques when using IMRT. Target delineation and
normal organ delineation are extremely important when using
40 IMRT. What is not defined is either not adequately treated or
spared(28). RTOG 0418 defined parameters for contouring of
targets and normal organs, margin size, and dose volume con-
straints in the postoperative setting in early cervical or endome-
trial cancers (29). An online atlas available on the RTOG website
20 was developed to improve consistency between multiple con-
touring physicians and continues to be used to guide in target
delineation even though the protocol has been completed (30).
230 kV (2 mm Cu HVL) This same atlas has been used in GOG studies, which include
IMRT techniques with minor modifications over time. A normal
0 tissue-contouring atlas is also available on the RTOG website
0 4 8 12 16 20 24 28 (31).Other atlases are available to guide radiation oncologists in
Depth (cm) defining these structures of interest (32,33). When using IMRT to
treat the intact uterus, bladder filling can have even more influ-
FIGURE 12.14. Typical X-ray or photon beam central-axis percentage ence on the position of the uterus, and the vagina and uterus can
depth-dose curves for a 10 10 cm beam for 230 kV (2 mm Cu HVL) at move several centimeters as a result (34,28). Stool in the rectosig-
50 cm SSD, 60Co and 4 MV at 80 cm SSD, and 6 MV, 10 MV, 18 MV, and 25 MV moid can also cause movement of the adjacent pelvic organs and
at 100 cm SSD. The last 2 beams coincide at most depths but do not coincide alter the dose distribution in the rectosigmoid.
in the first few millimeters of the build-up region. The 4-MV, 6-MV, Where there is more controversy is in the use of IMRT for
18-MV, and 25-MV data are for the Varian Clinic 4, 6, 20, and 35 units, respectively, intact cervical cancer. Use of IMRT in the definitive manage-
at the Department of Radiation Oncology, Washington University in St. Louis. ment of cervical cancer has been piloted at the University of
Source: From Cohen M, Jones DEA, Greene D. Central axis depth dose data for use in radiotherapy. Br J
Radiol. 1972;11:21, with permission.
Chicago(35). In their series, IMRT has reduced both acute and
late gastrointestinal (GI) toxicities and helped to spare bone mar-
row during treatment (35). Other series have shown a similar
radiation therapy (IMRT) treatment. In IMRT treatments, the decrease in toxicity with use of IMRT (36). There is concern in
MLCs are used to create many small fields of radiation within a this setting about organ motion relative to the dose distribu-
larger treatment field. By opening and closing these small fields, tion. This can be due to bladder or rectosigmoid filling, disease
the intensity at any point within the large field can be modu- regression, or sporadic motion (3740). Careful attention to
lated to give more or less dose to the tissues directly exposed organ filling, patient immobilization, and margin size can help
to the radiation. At one gantry angle, the IMRT field may need to minimize such motion which could compromise target and
to spare a critical normal structure but still treat the target to normal organ doses (28). Daily CT imaging prior to treatment
a lower dose, while in another gantry angle, that same critical can also help to assess for this motion and adapt the treatment
structure may be out of the field and the target can get a higher plan as needed (41,39). A consensus guideline has been published
intensity to compensate for the lowered intensity in the first to begin to define the most appropriate clinical target volume for
field. This adaptability allows the radiation treatment planner intact cervical cancer with recognition of the significant uncer-
to create and deliver very complex treatment fields that improve tainties caused by motion in this setting (42). Practice guidelines
target coverage while attempting to spare normal tissues. In for IMRT have been published by ASTRO and ACR (43,44). Use
practical terms, IMRT treatment plans are an improvement of of IMRT for extended field irradiation to treat the pelvic and
the more conventional three-dimensional (3-D) conformal treat- paraaortic regions, is successfully implemented to decrease dose
ment plans. 3-D conformal treatment plans use fewer fields to to the small bowel, kidneys, liver, spinal cord, and bone mar-
achieve nominal coverage of the treatment target. At each gan- row (Fig. 12.20). Selective boosting of gross nodal disease may
try angle, the radiation is either hitting the target/normal tissue allow for safer dose escalation (37,39,4547). IMRT techniques
or not with a simple shaped treatment field. Normal tissues may have also been used for whole abdominal irradiation to reduce
be impossible to spare relative to adjacent targets. IMRT treat- doses to the gastrointestinal tract, liver, kidneys, and bone mar-
ment plans may use similar gantry angle setups, but with the row and to increase dose to the peritoneal surfaces and lymph
additional intensity modulation, the IMRT fields can create a nodes (48,49) as well as for vulvar cancers to help spare the
complicated dose distribution within the patient. In some cases, upper femur as well as the small bowel and bone marrow (50).
where the normal tissues are relatively far from the target tis- A pivotal treatment technique for the success of IMRT is
sues, there may be no benefit or rationale for the more complex image-guided radiation therapy (IGRT) (41,39,51). Histori-
IMRT treatment plan compared to 3-D conformal treatment cally, treatment setups were verified by orthogonal radiographs
plans. In cases where the proximity of normal tissues and target and treatment fields by port films or X-rays of the treatment
vary across a field and between gantry angles, IMRT may prove fields superimposed on the patient. Modern linacs have added
the more efficient treatment plan to protect normal tissues while on-board imaging (OBI) that allows the treatment fields to
focusing dose onto the target (Fig. 12.18). be recorded electronically at every treatment setup using an
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 297
B 5 0 5
100
90
80
70
A 60
5 0 5
100
50
90
80
70 40
10
60
40 30
30
5
20
20
10
C 5 0 5
D 5 0 5
100
100
90
80 90
70 80
20
10
60 70
10 50 60
40 50
30 40
25 35
30
20
FIGURE 12.15. Isodose distributions for different quality radiation. A: 200 kVp, SSD = 50 cm, HVL = 1 mm Cu, field size =
10 10 cm. B: 60Co, SSD = 80 cm, field size = 10 10 cm. C: 4-MV X-rays, SSD = 100 cm, field size = 10 10 cm. D: 10-MV
X-rays, SSD = 100 cm, field size = 10 10 cm.
Source: From Khan FM. The Physics of Radiation Therapy. 2nd ed. Baltimore: Williams & Wilkins; 1994, with permission.
298 CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY
Beam Position 1
(Vertically downward)
Patient
FIGURE 12.16. Example of multifield radiation therapy using parallel opposite beams with an isocentrically mounted
radiation source.
electronic portal-imaging device (EPID). By comparing com- high-density objects within the patient, that is, hip prostheses.
puter generated radiographs (DRRs or digitally reconstructed In either case, the CT image at the time of treatment and its
radiographs) with the actual patient images, discrepancies in corresponding isocenter location are compared to the treatment
field shape and patient setup can be corrected before the deliv- planning CT and isocenter for agreement. Adjustments for rota-
ered treatment. This type of corrective behavior before treat- tion, lateral, vertical, and longitudinal discrepancies are made
ment is the foundation of IGRT. The latest variation on IGRT prior to treatment. The intent of these IGRT treatments is to
is the addition of computed tomography (CT) scanners within improve the accuracy of the treatment setup on a daily basis
the linear accelerator to verify more completely the correct relative to the original treatment plan. This enables decreasing
alignment of the patient on the treatment table prior to treat- the size of the radiation fields, as there is not as much need for
ment. CT scans are obtained prior to each treatment. In some a large margin on the target, which can decrease normal tis-
cases, the CT scans are constructed based on the photon beams sue irradiation and even allow for dose escalation to the target.
(MV) that will be used for treatment. In other cases, a different Guidelines for use of IGRT have been published by ASTRO and
photon source (kV) is used to reconstruct the CT scan. Because ACR (52). On-line MR imaging has recently been added to radi-
cone beam CT (CBCT) or megavoltage CT (MVCT) uses a ation treatment machines and will allow for better soft-tissue
high-energy photon beam to gather the information for recon- resolution of intact cancers such as cervical or vaginal cancers
struction, the image quality suffers because of poor soft-tissue to guide treatment accuracy.
contrast. KVCT or normal CT images, because they use a lower Intensity-modulated arc therapy has been used to deliver
energy photon beam to reconstruct the patient image, have bet- IMRT. Tomotherapy is one form of arc therapy. TomoTherapy
ter soft-tissue contrast, but are prone to distorting artifacts from (Fig. 12.21) is a special type of linac/CT combination (51).
Primary
Collimator
Upper
Collimator
Lower
Collimator
Symmetric Independent
A B Mode Mode
FIGURE 12.17. A: Multileaf collimator. B: Treatment technique for breast cancer using independent collimators.
Source: From Purday JA, Klein EE. External photon beam dosimetry and treatment planning. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology. 3rd ed. Philadelphia,
PA: Lippincott-Raven Publishers; 1998:281, with permission. Source: Courtesy of Varian Associates, Palo Alto, California, USA.
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 299
Colon
Paraaortic LN
45 Gy
Kidney
30 Gy
Spinal cord
20 Gy
A
Small bowel Common iliac LN
Computerized Dosimetry
In a modern radiotherapy department, computers are necessary to
accurately calculate the absorbed doses to tissues. These absorbed
doses within tissues are termed isodoses, or lines of the same dose.
To initiate this process, CT images are acquired of the area of
interest at a pretreatment planning session or simulation. These
scans are typically obtained on the CT simulator. Treatment tar-
gets such as pelvic/para-aortic lymph nodes, the uterus, or vagina
are identified through contouring on these images, as are normal
tissues such as the rectosigmoid, bladder, large and small bowel,
kidneys, stomach, and spinal cord. Dose goals are identified for
the targets and normal tissues. A dosimetrist uses this informa-
tion to design the radiation treatment plan. Treatment beams are
planned and the resulting dosimetry is reviewed by the treating
physician and a physicist and altered as needed to best address
the tumor and avoid the normal organs and tissues. In order for a
computer treatment planning system to do all this, the depth dose
and dose profiles for all of the treatment beams (photons and
electrons) must be accurately entered into the planning system.
There are varying complexities of treatment plans that might
be used. For simple targets, such as metastatic cancer to the
spine, a simple single field or parallel opposed, two-dimensional
(2-D) plan might be all that is required. Complexities of internal
anatomy and external surface contours can be ignored while
still successfully delivering a palliative treatment plan to the
patient. More complicated target definitions might require spe-
cific and accurate knowledge of adjacent internal anatomy and
the details of the patients surface in order to accurately deliver a
successful treatment plan. In these cases, a 3-D conformal treat-
ment plan is developed. In still more complicated target/normal
tissue regions, IMRT treatment planning might be required in
order to give sufficient dose to the target while minimizing the
dose to an adjacent normal tissue. The goal for most treatment
plans is to treat the target to a specified dose while minimizing
dose to adjacent normal tissues.
In all of these examples, the word target is used. The goal
is to encompass the target with the desired dose. Targets are
more formally defined in ICRU 50 (57). Figure 12.24 illustrates
the gross target volume (GTV), the clinical target volume (CTV),
the planning target volume (PTV), and the treated volume. Each
B of the target or tumor volumes is larger than the previous target
volume by some margin. The CTV includes all of the GTV plus
FIGURE 12.20. A: Contours of enlarged paraaortic nodes with margin possible microscopic extensions. The PTV includes all of the CTV
are shown in close proximity to small bowel. B: IMRT plan for extended plus a margin to account for possible geometric uncertainties of
field irradiation in axial, coronal, and sagittal projections. the patient or treatment margin. The irradiated volume includes
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 301
? MV linac
Physical center of tungsten
target is located at center
of girdle
Primary slide
collimator
Patented robust
multi-leaf Full 360 rotation
collimator
Tomotherapy
Patient assembly MVCT and treatment
radiation fan beam / gantry
motion
5 to 40 mm half shown for clarity
4 beamlets available Patient couch
beam width
at center
10' - ?"
Side view
Front view
Imaging and treatment
geometry 27' - 15"
B
21' - 0"
Site plan
FIGURE12.21. A: Helical TomoTherapy device commercially available for IMRT. B: Diagrammatic representation of the device.
Source: Courtesy of TomoTherapy Inc., Madison, Wisconsin, USA.
all of the PTV plus any margins that might be included in the greater distance from the patient (100 cm) than with brachy-
treatment plan to provide minimum dose coverage to the PTV. therapy. With external beam irradiation, the tumor and/or
tumor bed are typically irradiated along with adjacent tissues at
risk such as lymph nodes. External beam irradiation typically
is much more penetrating than brachytherapy unless electron
Brachytherapy Principles beam external irradiation is used. With electron beam therapy,
Brachytherapy is a term with Greek roots where brachy means superficial structures such as the skin and or superficial lymph
short distance. With brachytherapy, a highly concentrated nodes are optimally treated unlike the deep abdominopelvic
dose of radiation is delivered to immediately surrounding tis- tissues, which are best irradiated with the penetrating photons
sues within millimeters to several centimeters of the applicators produced by a linear accelerator.
that carry the radioactive sources (58). This allows for a high There are different types of brachytherapy or radioactive
dose of radiation to be delivered to closely approximated tumor implants (58). Temporary implants are used most frequently and
and to relatively spare surrounding normal tissues such as the are categorized as interstitial or intracavitary. With interstitial
rectosigmoid, bladder, and small bowel. This is in comparison brachytherapy, the radioactive sources are transiently inserted
to teletherapy, where tele means far distance and refers to into tumor-bearing tissues directly through placement in hollow
external beam irradiation where the radiation source is at a needles or tubes. With intracavitary brachytherapy, radioactive
302 CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY
6 MeV 9 MeV
A
98 100 100
95 C
90 2
80 98
60 70 95 90 B K
40 50 80
20 30 70 60
10
50
4 40
30 20 H I
10
12 MeV L
F D
M
2 E
100 G
98
95
90 4 J
90
70
60
50
40
30 6
20
10 A
16 MeV 20 MeV
100
100
2
98 98
95 4
95
90
80 90
70 6
60 80
50
40 70
30 B
20 8 60
50
10
40
30 FIGURE 12.23. A: The basic components and motions of a radiation therapy
20
10 simulator. A, gantry rotation; B, source-axis distance; C, collimator rotation;
D, image intensifier (lateral); E, image intensifier (longitudinal); F, image intensifier
10 (radial); G, patient table (vertical); H, patient table (longitudinal); I, patient table
12
(lateral); J, patient table rotation about isocenter; K, patient table rotation about
pedestal; L, film cassette; M, image intensifier. Motions not shown include field
size delineation, radiation beam diaphragms, and source-tray distance. B: Three-
FIGURE 12.22. Electron beam central axis isodose curves for a 10 10 cm dimensional simulator that is basically a modified CT scanner with a flat couch
field at 100 cm SSD. These data are for the Varian Clinac 20 at the Department suite for treatment planning.
Source: From Van Dyk J, Mah K. Simulators and CT scanners. In: Williams JR, Thwaites DI, eds. Radiotherapy
of Radiation Oncology, Washington University in St. Louis, MO.
Physics. New York, NY: Oxford Medical Publications; 1993:118 (Fig. 7.3). Reprinted by permission of
Source: From Glasgow GP, Purdy JA. External beam dosimetry and treatment planning. In: Perez CA,
Oxford University Press.
Brady LW, eds. Principles and Practice of Radiation Oncology. 2nd ed. Philadelphia,
PA: JB Lippincott Co.; 1992:208245, with permission.
sources are placed into naturally occurring body cavities or patients with microscopic or very thin residual tumor deposits
orifices such as the vagina or uterus using commercially avail- following debulking.
able hollow applicators such as a vaginal cylinder or tandem Dose rate is also an important variable in brachytherapy.
and ovoids. Temporary surface applications or plesiotherapy Traditional LDR irradiation has been used for decades in gyne-
for ophthalmic or skin tumors and intraluminal applications cologic cancers using 226Ra and 137Cs sources for intracavitary
in the esophagus, bronchus, and bile duct are other possible insertions and low activity 192Ir sources for interstitial insertions.
approaches. Permanent interstitial implants entail insertion HDR brachytherapy has gradually been introduced over the last
of radioactive seeds (iodine 125 [125I]; gold 198 [198Au]; pal- several decades and entails the use of a highly radioactive (10Ci)
ladium 103 [103Pd]) directly into tumor-bearing tissues to emit 192
Ir source. There are several definitions for the dose rates used
radiation continuously as they decay to a nonradioactive form in brachytherapy. The ICRU 38 classifies LDR as 0.4 to 2 Gy/hr,
(58). Radioactive sources are also sealed or unsealed, referring MDR (medium dose rate) as 2 to 12 Gy/hr, and HDR as >12 Gy/hr
to whether they are solid (137Cs; 192Ir) or liquid radioisotopes (59). More standard ranges for LDR are 40 to 100 cGy/hr, and
(phosphorus 32 [32P]). The most common sealed radioactive for HDR 20 to 250 cGy/min, which is 1,200 to 15,000 cGy/hr.
sources used for gynecologic brachytherapy are 192Ir and 137Cs. Pulsed dose rate (PDR) is increasingly popular with the scarcity
Historically, unsealed radioactive sources such as 32P have of available new 137Cs sources. Rather than using a high-activity
been used to treat the entire peritoneal cavity in ovarian can- 10
Ci 192Ir source with short dwell times as in HDR, PDR uses a
cer. The limitation of this source was that the beta rays emitted medium-strength 192Ir source of 0.5 to 1.0 Ci with dose rates of
penetrated only a distance of 3 mm, making it useful only for up to 3 Gy/hr. The radiation with PDR is typically delivered in
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 303
Historical Background
The use of radiation in the treatment of gynecologic cancers has
a rich history. Roentgen rays were used externally as early as
1902 to treat cervical carcinoma and radium rays in 1906. In
Europe, the use of intracavitary radium was reported in 1903 for
the treatment of inoperable uterine cancers (64). In 1913, Robert
Abbe was the first to report a true cure with a patient alive and B A A B
well after 8 years of follow-up (65). In those early years, there
was little knowledge of the biologic effects of radiation on the
normal and tumor tissues. Typically, a uterine tandem was used 2 cm
alone without vaginal colpostats. There was little understanding
of the dose distribution in the tumor and surrounding normal
tissues, and implant duration, and thereby dose, was entirely
empirical. Complications and failures were common.
point A and the vagina, bladder, and rectum are used as con- or normal tissue anatomy and is in a steep dose gradient and
temporary guidelines for determining implant duration and, sensitive to displacement (92,93). Point A can be identical for
therefore, dose. implants that differ in fundamental ways and deliver different
overall 3-D dose distributions.
Point A Redefined
The failure of localization radiographs to show the surfaces
of the ovoids made implementation of the initial definition
of point A difficult. The definition of point A was modified in
1953 to be 2 cm up from the lower end of the intrauterine
source and 2 cm laterally in the plane of the uterus, as the
external os was assumed to be at the level of the vaginal for-
nices (Fig. 12.28) (71). This definition of point A is currently
used at many institutions (86,87). A seed or marker ball placed
near the exocervix and coincident with the tandem flange is
used to identify the exocervix on the localization films. This
definition, however, becomes problematic when the cervix pro-
trudes between the ovoids (Fig. 12.29). This causes a resul-
tant increase in dose rate at point A because point A lies in 3 cm
the higher dose bulge around the ovoids (81). The variation
A B
of point A often occurs in a high-gradient region of the iso-
dose distribution. A consistent location for dose specification
should fall sufficiently superior to the ovoids where the dose 2 cm
distribution runs parallel to the tandem (Fig. 12.30) (88,89).
In patients with deep vaginal fornices, reverting to use of the
ovoid surface rather than the exocervix can help to solve this
problem (88,89).
Limitations of Brachytherapy
Systems: Point A
It has become clear over time that points A and B are not ana-
tomic sites. The actual specification is related to the position of
the intracavitary sources rather than to an anatomical structure.
Lewis et al. also demonstrated that point A does not maintain
a constant relationship to any specific structure and its position
varies with the type of applicator, individual tumor anatomy,
and age of the patient. No correlation was found between point FIGURE 12.28. Revised Manchester system definition of point A.
B and the pelvic wall (90,91). Potish also questions the validity Source: From Morita K. Cancer of the cervix. In: Vahrson HW, ed. Radiation Oncology of Gynecologic Cancers.
of point A as its position bears no fixed relationship to tumor 1st ed. Berlin, Heidelburg, New York: Springer-Verlag; 1997:185, with permission.
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 307
40
15
B A A B
A 68 R/hr 2 cm 2 cm 50
10 40 30
85 R/hr A
Ao Ao
X X
Ovoid 10 80 70 60
Af 90
X
90 100
80 2 cm
100 2 cm
Washer 70
60
FIGURE 12.29. The definition of point A using the revised Manchester 100
definition becomes problematic when the cervix protrudes between the 80 90
40 70
ovoids, causing an increase in dose rate at point A. Use of the classical 60
Manchester definition of point A (point A defined from the level of the upper 50 Vs Vd
vaginal fornices rather than the location of the exocervix) may be helpful.
Source: Reprinted with permission from Batley F, Constable WC. The use of the Manchester system for
treatment of cancer of the uterine cervix with modern afterloading radium applicators. Am J Roentgenol
FIGURE 12.30. Variations of point A based on definition. A consistent
Rad Ther. 1967;18:397.
location for dose specification should fall superior to the ovoids where the
dose distribution runs parallel to the tandem and not close to bulge of the pear.
Source: Reprinted with permission from Nag S, Chao C, Erickson B, et al. American Brachytherapy
Society recommendations for low-dose rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol
Limitations of Brachytherapy Biol Phys. 2002;52(1):38.
A B
FIGURE 12.31. A: Anteroposterior view of intracavitary insertion for carcinoma of the uterine cervix. B: Lateral view of same implant.
Isodose curves (cGy/hr) are superimposed.
Source: From Perez CA, Grigsby PW, Williamson JF. Clinical applications of brachytherapy. I: Low dose-rate. In: Perez CA, Brady LW, eds. Principles and Practice of Radiation Oncology. 3rd ed.
Philadelphia, PA: Lippincott-Raven Publishers; 1998:487, with permission.
The American Brachytherapy Society (ABS) has been piv- was defined as residual tumor following external beam on
otal in developing guideline for the treatment of gynecologic clinical examination as well as the high signal regions on T2
cancers and these will be sited throughout this text for both FSE images in the cervix and paracervical tissues. The high-
LDR and HDR brachytherapy. Initially published by Nag et risk clinical target volume (HRCTV) included the GTV as well
al. (88,89) these have recently been updated and published as the entire cervix and the extracervical tumor spread at the
(107,61). The HDR guidelines, in particular, emphasize the time of brachytherapy. The high risk volume refers to tissues
importance of image guidance in brachytherapy planning. with a major risk of local recurrence because of residual mac-
CT is excellent for delineation of the normal pelvic organs, roscopic disease, which require a high dose of radiation, similar
but is poor in defining tumor in the cervix or vagina. With to that delivered traditionally to point A. The Intermediate Risk
CT-based computerized dosimetry, rectosigmoid and bladder CTV (IR CTV) was defined as encompassing the high risk CTV
doses can more accurately be determined than with local- with a margin of 5 to 15 mm, and refers to tissues carrying a
ization films. Even when using CT compatible applicators, significant microscopic tumor load. Doses of approximately 60
however, the boundaries between structures of interest are Gy are intended for this volume. With these different regions of
poorly defined. The value of MR in the imaging of gyneco- risk defined according to physical examination and MR at the
logic cancers lies in its multiplanar capability and superior time of brachytherapy, dose volume parameters were defined for
soft-tissue resolution, compared to CT, enabling delinea- the GTV, HR CTV, IR CTV, and the organs at risk (OARS). For
tion of tumor within the cervix, uterus, and vagina as well the rectum, contouring included the outer wall from the ano-
as within the parametrial and vaginal tissues (108,109). rectal junction to the rectosigmoid flexure and the sigmoid
Tumors of the cervix display moderately increased signal on contour continued alone until the sigmoid was approximately
T2-weighted images relative to normal cervical stroma, per- 2 cm form the uterus. The small bowel was contoured only if
mitting definition of tumor volume. This is an advantage within 2 cm of the uterus. The outer contours of the bladder
during brachytherapy as one can assess the proximity of the were also defined (113,110). D100 and D90, as well as V100,
tumor to the applicator and the subsequent dose distribution were recommended for reporting as well as the minimum dose
throughout the tumor volume. The excellent soft-tissue reso- in the most irradiated tissue volume for 0.1 cc, 1 cc, and 2
lution of MRI allows visualization of residual tumor in rela- cc of the OARs, contouring the outer walls only (110). The
tion to the isodose distribution around the MRI compatible radiobiological model equivalent dose (EQD2) is used to sum
brachytherapy applicators (Figs. 12.33 and 12.60) (108111). the external beam and HDR doses together over the course of
The dose distribution can then be optimally conformed to the treatment so that a cumulative biologically weighted dose is
defined target volume while accurately defining and limiting available. This allows for systematic evaluation of the doses to
the dose to the adjacent normal organs at risk. The Gyn GEC the targets and normal organs over the course of treatment and
ESTRO working group began to develop guidelines for record- for comparison between centers.
ing and reporting 3-D image-based treatment planning for Additionally, the use of dosevolume histogram analysis may
cervix cancer brachytherapy in 2000. The guidelines were pub- add new insight into optimizing local control and decreasing
lished in 2005, which described a methodology using MR at the morbidity with a better understanding of the importance of
time of brachytherapy to define the GTV and CTV (112,113). dosevolume relationships. Data from Potter et al. have shown
The gross tumor volume (GTV) at the time of brachytherapy a decrease in complications and an increase in local control
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 309
FIGURE 12.32. A: Sagittal, coronal, and axial CT images with MRI/CT compatible applicator in place showing
the isodose distribution around the applicator and within the surrounding tissues. B: Axial CT at the level of the
Foley catheter bulb near the traditional ICRU 38 bladder and rectal points. Contrast is present within the bladder
and rectum as well as the bladder catheter bulb.
with the use of MRI-guided brachytherapy for cervical cancer (Fig. 12.34) (59). This was developed so that comparisons could
(114,115). The ABS supports these guidelines and has incor- be made between centers using different brachytherapy systems.
porated them into its latest guideline document (107). Though It provides definitions for determining dose to the bladder and
frequently confused, the ICRU 38 system (Dose and Volume rectum in addition to other characteristics of the implant.
Specification for Reporting Intracavitary Therapy in Gynecol- Updated ICRU guidelines are forthcoming, with an emphasis on
ogy) is a dose reporting system, not a dose specification system 3D planning and dose specification.
310 CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY
A B
FIGURE 12.33. Axial A: and sagittal B: MRI images with MRI compatible applicator in place with contours of the gross target
volume (GTV) and high risk clinical target volume (HRCTV) as well as the rectum, sigmoid and bladder.
Brachytherapy Applicators
Given the importance of brachytherapy, it is important to select
the appropriate applicator to accommodate patient anatomy
and the disease and shape the associated isodose distribution to
FIGURE 12.34. Reference points for bladder and rectal brachytherapy
encompass the disease. Tumor volume and patient anatomy are
key in this decision. Tumor size and shape are variable, and there doses proposed by ICRU.
Source: From Commission on Radiation Units and Measurements. Report 38: Dose and Volume
is a multitude of applicators available to address these diverse Specification for Reporting Intracavitary Therapy in Gynecology. Bethesda, MD: International Commission
presentations. on Radiation Units; 1985:11, with permission.
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 311
regular ovoids with resultant higher doses to the rectum and consideration for patients with a narrow vagina or with distal
bladder. Appropriate source strength and treatment duration vaginal disease.
adjustment are important considerations to prevent complica-
tions. Fletcher tandems are available in 4 curvatures, with the
greatest curvature used in cavities measuring >6 cm and lesser The Importance of Optimal
curvatures used for smaller cavities (Fig. 12.26). A flange with
keel is added to the tandem once the uterine canal is sounded, Applicator Placement
which approximates the exocervix and defines the length of Geometrically optimal intracavitary implants improve outcome
source train needed. The keel prevents rotation of the tandem over suboptimal implants. Corn et al. reported an analysis of
after packing. The distal end of the tandem near the cap is the 1978 and 1983 PCSs, which attempted to analyze the out-
marked so that rotation of the tandem after insertion can be come of cervical cancer patients by the technical quality of the
assessed. PDR adapted applicators are also now available but implant. A technically good implant correlated significantly
are much more like HDR applicators than their LDR equiva- with improved local control, with a trend toward improved
lents (60,61). survival (139). In a review of the RTOG 0116 and 0128 trials,
The Henschke tandem and ovoid applicator was initially the quality of applicator placement was statistically related to the
unshielded (126,128) but later modified with rectal and bladder risk of local recurrence and disease-free survival (140). Perez et
shielding (100,101,61). It consists of hemispheroidal ovoids with al. observed that inadequate insertions increased the incidence
the ovoids and tandem fixed together. Sources in the ovoids are of pelvic failures (116) and that the quality of the intracavitary
A B
FIGURE 12.35. MRI/CT compatible tandem and cylinder applicator with associated isodose distribution in A: axial and B: sagittal views, demonstrating
the close proximity to the rectum due to the absence of packing or rectal retraction.
312 CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY
40 Gold
10
marker Gold 20
seeds marker 35
seeds 40
Vaginal cylinder
Template Rectal cylinder
Cover plate
The Syed-Neblett and MUPIT templates are particularly carcinomas (142). Attention to the depth of needle insertion as
suited for treatment of vaginal disease as the vaginal obturator well as to the number and location of needles is key in achieving
needles can be strategically loaded to encompass disease from an optimum implant (142,149). Additionally, modification of
the fornices to the introitus. Additionally, the obturator needles the ring and ovoid applicators to accommodate a limited num-
can be advanced directly into the cervix, along with a uterine ber of needles to improve tumor coverage has been reported
tandem, and may be essential to deliver tumorcidal radiation recently, with improved local control in patients with bulky
doses to the cervix by preventing a central cold spot, espe- IIB and IIB disease (115,155157). In these applications, only
cially if an intrauterine tandem is not used (142,144,145). Use 10-20% if the dwell time is contributed from source positions
of an intrauterine tandem along with interstitial needles has in the needles and the remainder by the intracavitary compo-
been statistically associated with an improvement in overall sur- nent of the applicator (107). Individualized computer-generated
vival in stage IIIB cervical cancer (154). The more peripheral dosimetry is an integral part of interstitial dose delivery. CT
needles are used for implantation of the parametria, which is imaging following needle implantation has proven very help-
often underdosed in intracavitary approaches. Modifications ful to identify tumor volume and critical normal structures,
of these standard templates have evolved and other innovative confirm the adequacy of needle placement in relation to these
templates have been developed for vulvar, vaginal, and cervical structures or needed adjustments, analyze and manipulate the
314 CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY
FIGURE 12.40. Axial CT scan with needles inserted into the cervical
and paracervical tissues between the bladder and rectum. Isodose curves
shown are 80%, 100%, and 120% of the prescription dose.
FIGURE 12.39. LDR Syed-Neblett templates (top to bottom)
Gyn 1, Gyn 2, Gyn 3.
Source: Reprinted with permission from Erickson B, Gillin M. Interstitial implantation
of gynecologic malignancies. In: Nag S, ed. Principles and Practice of Brachytherapy.
New York, NY: Futura; 1997:518.
dose distribution related to these structures, and assist with dose radiation is delivered. After the implant, selective external irra-
specification and the integration of external beam irradiation diation boosting can be done as needed. The total LDR dose to
(142,158). Postprocedure epidural anesthesia provides optimal the reference volume from the combined implant and external
pain control and allows the needles and tandem to be manipu- beam approximates 70 to 85 Gy over 8 weeks (144).
lated outside the operating room if necessary. Modification of
the planned source placement based upon the location of spe-
cific needles and critical structures can therefore be made before
or after source loading (144). HDR Brachytherapy for Cervical Cancer
With LDR techniques, traditional LDRs are the goal Though LDR techniques have been the traditional standard for
(142,61), achieved through differential loading (core sources decades for gynecologic brachytherapy, there appear to be some
1/2 activity of peripheral sources) of low-activity sources. inherent advantages with the implementation of HDR techniques
Reference dose rates, of 60 to 80 cGy/hr are optimal. The (159161). Because the treatment time is very short, treatment
implant dose rates as well as the dose homogeneity and distri- is performed on an outpatient basis without the need for several
bution, can be manipulated by selectively changing the activity days of bed rest, with greater patient acceptance and comfort.
associated with a particular needle or needles or by selectively This allows treatment of some patients with medical co mor-
unloading, either immediately or during the implant, strategic bidities, which would prohibit LDR techniques because of the
needles in the pattern. With HDR techniques, optimization of prolonged bed rest. With the shorter treatment time, the implant
the dose distribution with predetermined parameters for the reproducibility is superior to traditional LDR approaches as
reference dose, normal organ doses, and dose homogeneity more stable positioning of applicators is possible. The shortened
can produce even more ideal implant dosimetry (Fig. 12.40). treatment time provides a greater degree of certainty that the
Typically, total LDR doses to the tumor volume or reference sources will remain in the 3D positions documented in the iso-
isodose from the implant range from 23 to 40 Gy over 2 to dose distributions, and that applicator displacement as a func-
4 days for a total dose of 70 to 80 Gy (158,61,142). The total tion of time will be decreased. The use of external applicator
HDR dose will be approximately 60% of the total LDR dose fixation devices allows more constant and reproducible geom-
and will be given in divided fractions. There is not a consistent etry of source positioning (161163). The newer systems, which
data relative to EQD2 doses when using 3-D image-based HDR allow a single source to dwell at a site for a calculated period
interstitial brachytherapy techniques. These seems to be a con- of time, combined with dose optimization software programs,
sensus that the doses are lower than with combined intracavitay provide a significant further improvement in the ability to shape
HDR and external beam, perhaps on the order of an EQD2 of the dose distribution. The small source size allows for finer incre-
75 to 80 Gy (107). With either approach, careful attention to ments in source location and relative weighting for each source
significant hot spots within the implant and doses to the bladder, location than with the fixed source sizes and activities inherent
rectosigmoid, and vaginal surface are requisite to obtaining the to the LDR 137Cs sources (89,163,164). This allows for greater
best outcome (145,153,142,144). precision coupled with greater flexibility and perhaps a reduc-
External whole pelvic irradiation (39.6 to 45.0 Gy) gener- tion in normal tissues doses. Additionally, the rectal retraction
ally precedes implantation. For either LDR or HDR, one or two devices available with the HDR applicators maximize displace-
template implants can be done 1 to 2 weeks following external ment of the rectum for short periods of time and may give supe-
beam. With HDR, 1 to 2 fractions can be delivered per day over rior and more predictable displacement than traditional vaginal
a period of 2 to 5 days, whereas with LDR, continuous hourly gauze packing (161163). These 2 factors lead to improved dose
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 315
vaginal applicator surface is important. If using a volume-based these organs. Additionally, disease regression and vaginal nar-
approach, dose specification to the HR CTV while negotiat- rowing will vary from fraction to fraction and can also result
ing the doses to 2 cc of the bladder and rectosigmoid is key. in changes in dose distribution. A change in applicator can
With either approach optimization of the dose distribution also result in changes in dose distribution, as can changing the
follows and enables design of a more ideal dose distribution ovoid or ring size, ovoid separation, and tandem curvature. The
(Fig. 12.45). The term optimization refers to the process of ovoids may also change in separation and their relative position to
achieving certain dose values at points or volumes within the the tandem over time if there is not a fixed relationship between
implant. It is not the simple generation of a standard dose distri- the tandem and ovoids (181,183186). Jones et al. found that
bution by using fixed dose points around the applicator (107). when treatment planning was not performed for each fraction
The goal is to match the dose distribution to point A or the HR and only the initial dosimetry was used, there was increased dose
CTV while simultaneously avoiding the OAR. Inherent to opti- to at-risk normal organs (186). This is also true when using a tan-
mization is starting with a standard plan of loading the tandem dem and ring, even though it has a fixed geometry. The applicator
and the vaginal applicator and then modifying the dwell times position relative to the pelvic organs is the important factor rather
and dwell weights to reduce dose to the OAR and ensure opti- than the relationship of the tandem to the ring (Fig. 12.46).
mal tumor coverage (107). Excessive optimization can alter the
pear shape to a less desirable configuration with the same point
A dose (176,177). When altering the standard dwell times and
weights, it is important to also monitor changes in the dose, Dose-Fractionation Schemes
FIGURE 12.46. Variation in anatomy between fraction 2 A: and fraction 3 B: of a 5-fraction high-dose-rate course.
Note the difference in the position of normal organs at the level of point A between fractions 2 and 3.
FIGURE 12.47. Midline blocks: A midline block defined by the leaves of EXTERNAL BEAM I RR ADIATION
the multileaf collimator used to shield the central pelvic structures. Note the FOR GYN ECOLOGIC CANCERS
unblocked bladder and sigmoid that may get some of the brachytherapy dose
and all of the external beam dose.
Cervical and Vaginal Cancers
In cervical and vaginal cancers, the role of external beam irradia-
rates at the surface of the applicator should be in the range of 80 tion is to shrink bulky tumor prior to implantation to bring it
to 100 cGy/hr, and perhaps 50 to 70 cGy/hr if the prescription within range of the high-dose portion of the intracavitary dose
is at 0.5 cm (204). Total vaginal surface doses of 50 to 80 Gy distribution, improve tumor geometry by shrinking tumor that
are reported most frequently in the literature. When used with may distort anatomy and prevent optimal brachytherapy, and
external beam, cumulative doses of 60 to 100 Gy at the vaginal sterilize paracentral and nodal disease that lies beyond reach of
surface are reported in the literature. Doses in excess of 80 Gy the intracavitary system (77). Some institutions maximize the
to the vaginal mucosa are not necessary in the setting of adju- brachytherapy component of the treatment regimen and perform
vant therapy and can be associated with increased morbidity. the first intracavitary insertion after 10 to 20 Gy with subsequent
For a vaginal recurrence of endometrial cancer, doses of 80 Gy external beam delivered with a central block (222). Other institu-
and higher may be needed when combining external beam and tions treat the whole pelvis to 40 to 50 Gy and perform brachy-
brachytherapy (210). therapy once the external beam is completed. The total dose at
Vaginal brachytherapy alone is generally considered an point A or the HR CTV, however, should remain the same, stage
option for patients treated with hysterectomy, with either no for stage. Implementing brachytherapy early with subsequent
or selective lymph node sampling, who are thought to be at reliance on only the implant to treat the central disease may be
low risk for lymph node metastases. These patients typically considered an advantage as a greater portion of the central dose
have grade 1 or 2 disease without significant myometrial inva- is delivered with the implant, with relative sparing of the bladder
sion (<1/3) (211,212,198). Additionally, vaginal brachytherapy and rectum, perhaps permitting delivery of a higher central dose
alone is considered an option at some institutions in the setting over a shorter period of time (223). More reliance, however, is
of a negative pelvic lymph node dissection, even when high-risk placed on the extremely complex match between the intracavitary
factors such as high grade or deep myometrial invasion are pres-
ent (212214,198).
There is great debate about whether a vaginal cuff boost is
routinely necessary in addition to external beam irradiation
for early-stage endometrial cancer and little data to support it
(215,216,198). Practice patterns are based more on institutional
tradition and individual preference rather than prospective ran-
domized trials. The rationale for use of a vaginal boost is the
supposition that there may be a critical dose needed at the vagi-
nal apex to optimally decrease the likelihood of a vaginal apex
recurrence. Doses in excess of the 45 to 50 Gy typically deliv-
ered with external beam may be necessary if there are micro-
scopic tumor cells embedded in the hypoxic vaginal cuff.
There are some clinical situations in which more complex
brachytherapy procedures are required in the treatment of endo-
metrial cancer. Patients with bulky stage II endometrial cancers
may benefit from preoperative radiation with external beam
alone, brachytherapy alone, or a combination of the two. Tan- A
dem and ovoids or tandem and ring or cylinder applicators are
used in this setting. Medically inoperable endometrial cancer is a FIGURE 12.48. A: High-dose-rate domed vaginal applicator.
rare phenomenon in the current era of aggressive surgical staging. Source: Courtesy of Nucletron.
320 CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY
C D
FIGURE 12.48. (continued) B: Low-dose-rate Fletcher ovoids with associated radiograph. Lateral radiographs are shown of cylinder C: and ovoids D:
with bladder bulb contrast in both and rectal contrast in C:. CT-based dosimetry for a vaginal cylinder revealing the relationship of the dose distribution to
the cylinder surface and adjacent bladder and rectum.
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 321
system and the edge of the midline block, making good implant radiation resistance, may actually be the result of a marginal
geometry imperative when brachytherapy contributes a large por- miss due to external beam field design. Placement of radiation
tion of the central dose. Those who prefer to deliver an initial 40 fields must take into account the alteration of the spatial rela-
to 45 Gy of external beam first believe that the ability to deliver a tionship between the tumor and normal anatomy due to indi-
homogeneous distribution to the entire region at risk for micro- vidual anatomic, tumor-induced, or treatment-related positional
scopic disease and the ability to have more shrinkage of central variations of the uterus and cervix, as well as knowledge of the
disease prior to intracavitary irradiation outweigh other con- location of the regional lymphatics (234,236). Radiation oncol-
siderations. The brachytherapy dose is accordingly decreased to ogists must be aware of these patterns of disease spread as well
respect normal tissue tolerance. In addition to causing regression as have an in-depth understanding of CT anatomy when design-
of central disease, the external beam fields are also directed at the ing radiation fields following CT simulation. Identification and
regional lymph nodes at risk. In cervical and vaginal cancer, the contouring of enlarged nodes in nodal regions at risk, as well as
risk of pelvic lymph node involvement is related to the stage of identification of the iliac vessels, which serve as surrogates for
disease, tumor size, and lymphatic vascular space invasion. Other the location of unenlarged lymph nodes, are important in subse-
histomorphologic factors influencing lymph node involvement in quently defining radiation field borders (Fig. 12.51). Addition-
cervical cancer include pathologic tumor diameter, depth of stro- ally, contouring of the entire uterus and portions of the vagina
mal invasion, uterine body involvement, parametrial spread, and will also ensure that these tissues are included in the radiation
the number of cervical quadrants involved by tumor (224). Early fields (Fig. 12.51). Reliance on boney anatomy alone for radia-
necropsy studies reported the lymphatic pathways for patients tion field design rather than on CT-defined targets is discour-
FIGURE 12.51. Digitally reconstructed AP A: and lateral B: radiographs with associated contoured targets including the pelvic lymph nodes and
uterus/cervix/parametia and vagina. Note the multileaf collimator leaves defining the field shape in accordance with coverage of the targets of interest.
horizontal line, parallel to the treatment couch that divides the extend directly around the rectum. Kim et al. found that the
mid-rectum and intersects the sacrum between the second and most common site of an inadequate margin was near the por-
third sacral segments (S23 interspace), and the anterior border tion of the lateral field blocking the rectum. On CT, it was found
by a horizontal line, parallel to the treatment couch from the that tumor often fell along the lateral aspect of the rectum. The
anteroinferior lip of L5 to the anterior aspect of the pubic sym- second most common site of inadequate margin was the poste-
physis (235). These standard lateral fields are too narrow. For rior border at the S23 interspace (232). Zunino et al. also found
the lateral fields, careful consideration needs to be given to the inadequate posterior border margins when the uterus was both
anterior border to include the external iliac nodes. Based on lym- retroverted and anteverted (Fig. 12.52) (237). The reason for
phangiography, Pendlebury et al. found that to cover the external narrow lateral fields is typically concern over the rectum and the
iliac nodes, the anterior border of the lateral field was some- small bowel. Russell et al. have included the entire sacrum in the
times as much as 2 cm anterior to the pubic symphysis (231), lateral fields of all patients with cervical cancer treated at their
which was later confirmed by Bonin et al. (229). Chun et al. institution, and they have reported no increase in acute or late
found that based on CT definition of the external iliac lymph morbidity. When present, all rectal injuries observed have been
nodes, when using standard lateral fields, only 50% of the on the anterior rectal wall due to the proximity of the implants
patients studied had adequate coverage of these nodes (230). used in the definitive management of these patients (235). Greer
Additionally, the anterior border must also be drawn to include et al. also reported no increase in late rectal complications when
the entire uterus, given the interconnecting lymphatics of the including the entire sacrum in the field (239). It may also be a
uterus and cervix and the possibility of lower uterine segment/ mistake to avoid the chance of a marginal miss by treating just
endometrial extension (Fig. 12.52) (227,232,236). Enlargement with anterior and posterior fields, as in most cases some of the
of the uterine fundus by the presence of hematometra or massive small bowel can be omitted from the lateral fields when using
fundal extension of cancer can displace the fundus anteriorly imaged-based planning (235). Gerstner et al. found that by
and cephalad, as can an anteverted or retroverted uterus using beams eye viewbased 3D treatment planning, though the
(232,237,243). The prone position may accentuate this dis- rectal volume treated increased to avoid a marginal miss, there
placement (234,236). The anterior field border should be based was an overall reduction in the lateral field treatment volume as
on CT or MRI delineation of the tumor and/or normal anatomi- compared to standard treatment fields due to beam shaping to
cal variants to avoid underdosing of these structures exclude portions of the bladder and small bowel and bladder
(230,232,234,235,237,242,243). The posterior border of the distention (242). MRI has been found to be an invaluable tool
lateral fields must be designed carefully. Based on intraoperative for delineating normal anatomy and the extent of cervical tumor
findings, Greer et al. showed that the cardinal and uterosacral involvement because of its superior soft-tissue contrast when
ligaments extend posterior to the rectum and sigmoid in their compared to CT. MRI also allows direct imaging in sagittal,
attachments to the sacrum. As part of the parametria, these tis- coronal, and transverse plains (237). Sagittal MRI images are
sues often contain nodes, even in early disease (IB and II, 22.5%) exceedingly helpful in designing radiation fields (Fig. 12.52).
or are involved by direct extension and need to be covered in Design of the anterior and posterior borders of the lateral fields
most patients by including the entire sacrum in the lateral fields can be especially influenced by these images (234237,243).
(239). If there is uterosacral ligament involvement, it is espe- Thomas et al. performed MRI rather than CT in the treatment
cially important to include the entire sacrum in the lateral fields, position, and found better delineation of the tumor volume due
although some institutions will use this as a criterion for APPA to the superior contrast resolution (236). Lymphangiograms are
fields alone (226). The internal iliac lymph nodes can also lie very helpful in defining the location and architecture of lymph
very close to the rectum and splitting of the rectum can result in nodes when designing radiation fields, and are especially helpful
a marginal miss of these nodes (Fig.12.53) (228). For posterior in designing the lateral fields and subsequent nodal boost fields
cervical lesions, there can also be direct extension to the supe- (229,231,237,244). They do not routinely image the internal
rior rectal nodes or sacral lymph nodes (224). Tumor can also iliac lymph nodes, although sometimes these will fill
324 CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY
A B
FIGURE 12.52. (AB): Traditional lateral fields are superimposed on sagittal MRI scans to evaluate target coverage with traditional fields.
Note in A: that the traditional lateral fields would not completely cover the uterine fundus, and that in B: the traditional lateral field would cut
through cervical tumor within the anteverted uterus.
Source: Reprinted with permission from Zunino S, Rosato O, Lucino S, et al. Anatomic study of the pelvis and carcinoma of the uterine cervix as related to the box technique. Int J Radiat Oncol
Biol Phys. 1999;44(1):5657.
A B
FIGURE 12.53. A: The location of the presacral lymph nodes mandates including the entire sacrum to cover disease in the uterosacral and cardinal
ligaments and superior rectal (pre-sacral) nodes. The right lateral sacral node (solid arrow) is medial to the hypogastric vessels (open arrow). B: Note the
proximity of the internal iliac lymph node (solid arrow) to the rectum. This spatial relationship would exclude partial blocking of the rectum on the lateral fields.
Source: Reprinted with permission from Park J, Charnsangavej C,Yoshimitsu K, et al. Pathways of nodal metastases from pelvic tumors: CT demonstration. Radiographics. 1994;14(6):1311.
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 325
in a retrograde manner. Unfortunately, lymphangiography is may exceed the anticipated 5% of the primary pelvic dose when
available at only a few institutions due to the fact that it is time using a 5 to 6 half-value layer (HVL) midline block. Midline
consuming for both the radiologist and patient, and fewer radi- blocks that are too narrow may not adequately shield the blad-
ologists are trained in such procedures (229). Positron emission der and rectosigmoid given their ability to move in and out of
tomography (PET)/CT scans have largely replaced lymphangio- the blocked field. Filling and emptying of these organs may also
grams at most institutions with Medicare approval in 2005 and alter their position relative to the block. Eifel et al. point out that
can detect involved pelvic and paraaortic lymph nodes better the distance between the distal ureters is usually 4 to 5 cm. A
than CT alone (245248). PET does not rely on lymph node size narrow block may fail to shield a portion of the ureters during
alone, unlike CT; rather, it relies on metabolic alterations for external beam (257). Reviewing the M.D. Anderson experience,
detection of disease. PET has better accuracy than can be Eifel et al. detected an increase in complications in patients with
achieved with CT or MRI with a sensitivity of 85% to 90%, a midline blocks (4 cm) used throughout the course of external
specificity of 95% to 100%, and overall accuracy of 90% to beam. Since the ureters are typically 2 to 3 cm from midline, the
95%. Nodes as small as 6 mm can be imaged with PET, provid- explanation for the ureteral stenosis could have been an overlap
ing information to guide therapy and predict outcome. between the external beam fields and the high-dose region of the
intracavitary implants (257). A margin of 0.5 cm lateral to the
lateral ovoid surface is recommended in designing the width of
the midline block for each patient to protect the implanted vol-
Midline Blocks ume. If the intracavitary system is broad, a wide midline block
images to include the disease and exclude small bowel (234). to bulky nodes or residual parametrial disease while sparing
Logsdson and Eifel suggest boosting residual lateral pelvic wall adjacent normal structures (35,47,46).
disease after 40 to 45 Gy whole pelvis to 60 to 62 Gy to small
volumes (85). Perez et al. found a trend toward increased pelvic
control with point B doses (defined at 6 cm lateral to the central
axis) >45 Gy (116,262). In the 1973 and 1978 PCS, there was Endometrial Cancer
no relationship between lateral dose >60 Gy and either infield For endometrial cancer, many of the same nodes are at risk as
pelvic control or survival, but the lateral dose did impact compli- in cervical cancer, but the spread of disease is not as predictable
cations with an increase above 50 Gy (118,120,121). There was with the paraaortic nodes independently at risk. The presacral
a trend toward decreased failure with increasing parametrial nodes are also not at risk unless there is cervical involvement.
doses in stage III disease (119). Perez et al. found that the inci- Both the pelvic and paraaortic nodes are at risk in all sites of
dence of pelvic recurrence was correlated with tumor size and uterine involvement, and grade, myometrial invasion, and lym-
dose of irradiation delivered to the lateral parametrium. There phatic vascular space invasion are more predictive of risk than
was an increase in the incidence of pelvic recurrence in patients location (267271). Cervical and lower uterine segment involve-
receiving less than 50 Gy, but no correlation with increasing ment also increases the likelihood of pelvic and paraaortic lymph
doses of irradiation (263). Doses needed to eradicate parametrial node metastases compared to fundal location, as do increasing
disease in the literature are typically around 60 Gy, combining histologic grade and myometrial invasion. In the surgical stag-
the external beam doses with the implant doses. The proximity ing series of Boronow et al., 18 of 222 patients had lower uter-
of small bowel can make this a risky proposition. Perez et al. ine segment involvement and 6 (33%) had pelvic lymph node
noted that with doses below 50 Gy to the lateral pelvic wall, the metastases (270,272). In the final GOG surgical staging series
risk of small bowel complications was about 1% and somewhat report, by location, patients with fundal lesions had a 4% risk
higher with larger doses (141). In a later series, grade 3 small of paraaortic and 8% risk of pelvic lymph node involvement,
bowel sequelae were 1% with doses of 50 Gy and 2% to 4% whereas patients with lower uterine segment involvement had
with doses over 60 Gy (p = 0.04) (264). At present, Perez et al. a 16% risk of pelvic and 14% risk of paraaortic lymph node
recommend limiting the small bowel doses to less than 60 Gy. involvement (274).
Ferrigno et al. found an increase in small bowel complications In endometrial cancer, external beam irradiation is generally
when parametrial boosts were above 59 Gy. They recommended recommended for patients thought to be at significant risk for
dropping the superior border of the parametrial fields to the lymph node metastases and/or a vaginal cuff recurrence. Tradi-
S23 level and limiting the total dose to 54 Gy (194). The use of tionally, this has been recommended in the absence of a lymph
concurrent chemoradiation may allow a decrease in these doses, node dissection or a limited lymph node sampling. External
but data is too preliminary to conclude what this dose should be. beam irradiation is also still delivered at many institutions in the
When there is uterosacral space involvement, thought should be setting of a negative lymph node dissection when high risk fea-
given to the use of a supplemental posterior oblique external tures such as deep myometrial invasion, high grade, lymphatic
beam boost (226). Grigsby et al. used PET/CT scans to evaluate vascular space invasion, lower uterine segment involvement, or
lymph node size, irradiation dose, and patterns of failure. The cervical invasion are present (273,274).
parametrial and lymph node boost doses used were in the range External beam irradition typically covers the upper one-half
of 9.0 to 14.4 Gy following large field doses of 50.4 Gy. Radia- to two-thirds of the vagina, the pelvic lymph node regions, and
tion dose and lymph node size were not significant predicators the surgical bed (Fig. 12.54). External beam field design must
of lymph node failure. The risk of an isolated lymph node failure necessarily include the pelvic lymphatics with exclusion of as
was <2% (265). A reoperation series following definitive irra- much small bowel as possible. Treatment of the patient in the
diation and chemotherapy was reported by Houvenaegel et al. prone position with a full bladder will help to exclude at least
After 45 Gy and whole pelvis and selective parametrial or nodal some small bowel in most patients unless these loops are fixed
boosting to 55 to 60 Gy, 15.9% of patients had biopsy-proven in the pelvis (Fig. 12.55). It is important, however, for the lateral
residual disease in the pelvic nodes and 11.7% of paraaortic fields to also cover the course of the external iliac nodes, which
nodes (266). Use of IMRT may be a method to increase dose are quite anterior in the pelvis and require inclusion of some
A B
FIGURE 12.54. Digitally reconstructed AP A: and lateral B: radiographs with nodal volumes contoured as well as the vaginal apex and the fields
defined by the leaves of multileaf collimator. This is a standard field design for patients with endometrial cancer.
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 327
FIGURE 12.55. A: Utility of the prone technique for small bowel displacement as shown on a sagittal and axial CT scan of a
patient with endometrial cancer planned in the prone position. B: Radiographs of the pelvis showing significant amount of small bowel
in the radiation fields.
small bowel in the lateral fields to be adequately covered. Doses in position of the uterus when prone, the impact and variability
of 45 to 50.4 Gy are typical, with some institutions treating of bladder filling, and the potential daily variation in the setup
to 40 Gy and as high as 60 Gy to reduced fields in the setting (278,280,281). There is also some concern that, in patients with
of nodal disease. Whole pelvic fields are generally reduced or a intact uteri, the prone position may increase the volume of the
midline block is added after variable doses. rectum treated (280). CT-based dosimetry has documented that
Prone techniques have been used in the treatment of many the prone position, particularly with bladder filling, can alter the
other pelvic malignancies to attempt to exclude small bowel position of the uterus within the radiation field (234,236,281).
from the field. Use of a belly board device to further enhance Hence, if patients are simulated prone, it is even more impera-
small bowel displacement has become standard practice for tive to use CT- or MRI-based dosimetry in the prone position
many pelvic malignancies (275277). Use of prone position with to make sure that the entire uterus is in the pelvic fields, and
or without a belly board for the treatment of patients with cervi- it is also imperative to consistently fill or empty the bladder
cal cancer has been reported in a few series, in the postoperative (281,282). IGRT may also be helpful in ensuring that the daily
(275,276,278280) and definitive settings (275277,280,281). setup is reproducible and reliable.
Prone positioning with the belly board has been used extensively
for patients with rectal cancers when using a PA and two lateral
fields. Concern over use of this technique for patients with gyne-
cologic malignancies when adding a fourth field (AP) to cover Extended Field Irradiation
the external iliac nodes has been raised by Ghosh et al. due to the Extended field irradiation refers to inclusion of both the pel-
uncertainty in source to skin distance (SSD) and variation in vic and paraaortic nodes in the radiation fields. Common indi-
tissue thickness from the anterior field. In patients who under- cations for extended field irradiation in gynecologic cancers
went postoperative irradiation for cervical cancer, they observed include patients with positive paraaortic nodes or those with
that the small bowel was best excluded from the APPA fields positive pelvic nodes or bulky primary lesions feared to be at
when the patient was positioned prone without the belly board, risk for microscopic paraaortic disease (Fig. 12.56). Extended
thereby compressing the small bowel laterally out of the APPA fields include more normal organs than pelvic fields alone. Limi-
fields. They recommended an alternating routine (278). Bladder tation of dose to the small bowel, kidneys, liver, stomach, and
distention can also help to optimally displace bowel when using spinal cord are essential. Three-dimensional conformal tech-
the belly board (275,277). Concern over use of the belly board niques are helpful in achieving an acceptable therapeutic ratio.
in patients treated with definitive versus postoperative irradia- Use of IMRT has recently been piloted in this setting with fur-
tion for cervical cancer is also raised due to the potential change ther attempts to decrease acute and late toxicity (Fig. 12.20).
328 CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY
Skin
Pelvic and Inguinal Irradiation When treating abdominopelvic tumors with radiation, often
External beam fields will necessarily include the inguinal lymph there will be minimal skin reactions due to the skin-sparing
nodes in patients with vulvar cancer or distal vaginal cancers or quality of the high-energy radiation beams used to treat these
when cancer of the cervix or endometrium involves the distal sites deep within the body. Contrastingly, when treating the
vagina. Risk of femoral head necrosis or femoral neck fractures vulvar and inguinal regions, where electrons or lower energy
is increased in this setting. Recent use of IMRT to treat vulvar X-rays are more often used, there can be marked skin reac-
and vaginal cancers has been published with success (50). tions. Skin reactions are also more likely to develop in skin
folds such as the inguinal creases or intergluteal fold. The cells
in the basal layer of the skin are very sensitive to radiation, but
because of the time required for these differentiating cells to
Whole-Abdominal Irradiation move from the basal layer to the keratinized layer of skin, there
is a 2- to 3-week delay between the start of radiation and the
Whole-abdominal irradiation is used to cover the entire abdom-
appearance of skin reactions. Erythema is the first visible skin
inopelvic cavity in ovarian cancers or high-risk uterine cancers
reaction due to dilation of the small capillaries and is usually
such as those with positive peritoneal washings or adnexal
seen about the third week of radiation. Other skin reactions
involvement (IIIA disease). This requires limiting the radia-
include dry desquamation and moist desquamation occurring
tion dose to a maximum of 30 Gy to the entire abdomen and
after the 4th week of radiation. Moist desquamation occurs
using lower fraction sizes of 150 to 170 cGy. This will reduce
with transient loss of the epidermis and exposure of the dermis.
both acute and late toxicities. Careful attention to and limita-
Serous fluid often oozes from the exposed and inflamed dermis
tion of the dose of radiation delivered to the liver and kidneys
(286,290). These effects may be enhanced by the combination
requires selective blocking of these structures at different doses
of irradiation and some chemotherapeutic agents, particularly
(283,284). IMRT techniques are also being explored for whole-
actinomycin D and doxorubicin (Adriamycin) (293). It is also
abdominal irradiation to reduce doses to the GI tract, liver,
well known that chemotherapy agents such as Adriamycin or
kidneys, and bone marrow and increase dose to the peritoneal
gemcitabine can recall radiation reactions after the original
surfaces and lymph nodes (48,49).
reaction has subsided (291,292). Radiation-induced skin reac-
tions are treated with various topical ointments and creams as
well as with sitz baths and special emphasis on cleansing all
stool and urine gently from the perineum. Additionally, if the
Radiation-Induced Tissue Effects distal vagina or vulva is in the radiation field, patients may also
Side effects that develop during the course of radiation and per- complain of dysuria or painful defecation, which is due to the
sist for 3 months or less following completion of radiation are caustic effects of the urine and stool on the denuded epithe-
termed acute side effects. Those toxicities that develop later than lium of the distal vagina, perianal area, and vulva. Diarrhea
3 months after the completion of radiation are termed late or control and use of barrier creams to protect the irritated skin
chronic effects. The late effects of radiation are due to damage from stool and urine will help to minimize discomfort and has-
at the capillary level where there is endothelial cell prolifera- ten skin healing. Sulfa-based creams and Domeboro soaks can
tion resulting in less diffusion of oxygen into the tissues with be used to expedite healing. Return of the epidermis can take
resulting fibrosis. There is less resistance to infection, trauma, 10 to 14 days. Residual surviving basal cells form islands of
or functional stress due to this change in vasculature and cir- regeneration, which proliferate to re-epithelize the area. Islands
culation (285,286). When treating gynecologic cancers, the of skin forming in the desquamated skin herald skin renewal.
normal tissues most often incidentally irradiated in the pelvis The new skin is thin and pink with gradual return to normal
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 329
in 2 to 3 weeks (286). Late manifestations of radiation on the The TD 5/5 for whole liver is 30 Gy in 2 Gy fractions (286,287).
skin include depigmentation, subcutaneous fibrosis, dryness and Small portions of the liver can receive up to 70 to 90 Gy. Mean
thinning with loss of apocrine and sebaceous glands, thinning or liver doses of <28 to 32 Gy at 2 Gy per fraction are recom-
loss of hair, and telangiectases. Necrosis of the skin is rare and mended (298).
generally occurs only with very high doses of radiation in excess
of 60 Gy (286,293).
Kidney
The kidneys are very sensitive to small doses of radiation, and
Bone Marrow/Pelvic Bones a common goal is to avoid greater than 18 to 20 Gy whole
The lymphocytes are the most radiosensitive cells in the bone kidney dose. When delivering whole-abdominal irradiation, the
marrow. The rate of fall of the various components of the mar- kidneys are at risk and must be blocked at acceptable doses to
row is a function of the half-lives of the mature cells. These half- prevent renal failure. When delivering paraaortic irradiation,
lives are as follows: erythrocytes, 120 days; granulocytes, 6.6 the kidneys are also at risk and treatment planning CT scans can
hours; and platelets, 8 to 10 days (286). Pelvic irradiation may help to define which beam angles are best to irradiate the nodal
cause transient lymphopenia. This is even more of an issue when regions yet miss, in part, the kidneys. When planning radiation
whole-abdominal or extended-field irradiation is used due to fields, sometimes one kidney will need to be irradiated more
the increased bone marrow in the radiation fields. This decrease than the other and the equivalent of one kidney must be spared.
DVH parameters with morbidity (301). Vaginal narrowing and Increased peristalsis, disturbance of the absorption mechanisms,
shortening is a late sequela of radiation, which can alter and and a decreased transit time also occur. Patients will report
impede sexual function. Combined brachytherapy and external increased flatulence and noisy bowel sounds. Rarely patients will
beam irradiation will cause more late effects than either modality report nausea. Implementation of a low residue diet, hydration,
alone. Use of a vaginal dilator or intercourse 2 to 3 times/week and use of antimotility agents can be very helpful. Some patients
can help to keep the vagina open. Use of lubrication with inter- may be lactose and fat intolerant as well. Judicious use of narcot-
course as well as estrogen creams to build up the vaginal mucosa ics to calm the bowel can also be helpful. Concurrent 5-FU or
can also make intercourse more comfortable (293,302). Rarely, gemcitabine can worsen small bowel toxicity with diarrhea from
with excessive doses of radiation, patients can develop vaginal the 5-FU often appearing before the radiation enteritis has had
necrosis. This is due to a change in blood supply to the vaginal time to evolve. The late effects of radiation on the small bowel
tissues and is much more common at the introitus than at the can be a continuation of the acute effects. Some patients will
vaginal apex, perhaps due to the vascular supply of the vagina. experience chronic diarrhea that will require a permanent change
The posterior vaginal wall is most frequently involved (300). in diet. Certain foods may trigger diarrhea such as those high in
Interstitial implants are more likely to cause necrosis than intra- fiber or fat. Spicy foods and MSG may also trigger diarrhea.
cavitary implants. Hydrogen peroxide douches, antibiotics, and Areas of narrowing corresponding to regions of high dose or
hyperbaric oxygen therapy can help the vaginal tissues to heal adhesions can occur in the small bowel loops and lead to partial
(303,304). Narcotics are often necessary to control the associated obstruction of the small bowel. Patients may report abdominal
pain until healing has occurred. Trental (pentoxifylline) can also pain and distention followed by diarrhea and relief of these
help soft-tissue necrosis to heal (305). The uterus is very resistant symptoms. A complete bowel obstruction would also be charac-
to high doses of radiation as is evident in patients treated with terized by abdominal pain and distention in addition to vomiting
external beam and brachytherapy for cervical cancer. Rare cer- and lack of bowel movements. Small bowel obstructions occur
vical necrosis can occur and will respond readily to hyperbaric in approximately 5% of irradiated patients and surgical inter-
oxygen treatments and pentoxifylline (286,304,293). There may vention is required in some to relieve these obstructions. Prior
be an increased risk of this in patients using cocaine. Necrosis can surgeries or a history of a perforated appendix or pelvic abscess
also be caused by recurrent tumor, and distinguishing recurrent as well as inflammatory bowel disease can increase the risk of
disease from necrosis can be very difficult and sometimes will small bowel toxicity as can the use of chemotherapy. Hyper-
mandate surgical intervention (286). tension and diabetes can also be risk factors as can thin body
habitus. Radiation to large volumes of bowel or high doses to
even small volumes of bowel can lead to bowel obstructions. The
ileum is the most common loop of bowel involved (286). Mal-
Stomach, Small and Large Intestine absorbtion of fats, carbohydrates, protein, B12, and lactose can
The stomach is lined with a mucous membrane, which is colum- occur in some patients. Excessive bile salts can reach the colon
nar epithelium and sensitive to radiation. Like the small and and act as a cathartic, and medications such as cholestyramine
large bowel reactions, the stomach lining develops erosions and can be helpful in controlling the resultant loose stools.
thinning and subsequent edema and ulceration. Symptoms can Small bowel doses should be limited to 45 to 50 Gy with 60 Gy
include nausea, vomiting, reflux, and pain. Use of prophylactic maximum (264).Current recommendations for small bowel
antiemetics and proton pump inhibitors can decrease the acute dose/volume constrains are as follows: The absolute volume of
effects of radiation. Acid production can be decreased during small bowel receiving >15 Gy should be <120 cc when delineat-
radiation and for up to 1 to 2 years after. Late effects can include ing individual loops of bowel. If the entire peritoneal space is
gastritis and ulceration with associated bleeding. Progressive defined, the volume of small bowel receiving >45 Gy should be
fibrosis can lead to gastric outlet obstruction and rarely perfo- <195 cc (306).
ration, all of which are dose and volume dependent (286). The The rectosigmoid mucosa is also a rapid renewal system
entire stomach can tolerate doses of 45 to 50 Gy, but data on similar to the small bowel. When the rectum is included in the
maximum tolerated doses are inadequate (306). irradiated volume, there is rectal discomfort with tenesmus
The acute effects of radiation on the small intestine are and mucous production, sometimes mixed with blood in the
due to the inherent radiation sensitivity of the rapidly divid- stools. Patients may report frequent and sometimes painful
ing undifferentiated crypt of Lieberkuhn cells. The normal evacuations of only small amounts of stool mixed with mucus.
lining of the GI tract is a self-renewing tissue. These undiffer- Hemorrhoids may worsen during radiation. This constellation of
entiated stem cells normally migrate and differentiate upward symptoms is termed proctitis. Medications to decrease the num-
from the lower half of the crypts to the tips of the intestinal ber of stools as well as antispasmodic agents can be helpful. Suppos-
villi as they mature, providing a continuous supply of surface itories or foams with steroids can be helpful, as can topical perianal
cells as they divide. Their function is to primarily form absorp- skin ointments and lotions. Uncontrolled radiation enteritis can
tive cells but also mucous-secreting goblet cells and endocrine worsen radiation proctitis due to frequent stooling through the
cells (285,286,290). The mature cells at the surface of the villi irritated rectum. For late effects, if the dose of radiation is large
are repeatedly sloughed and replaced by the cells, which origi- enough, it may cause temporary or permanent ulceration and
nate in the crypts. These undifferentiated crypt cells are the most bleeding due to telangiectasias (Fig. 12.57). Cortisone-containing
sensitive to radiation and are preferentially depleted, leading to rectal suppositories and foams or sulfasalazine instillations can
loss of mature replacement cells at the surface of the villi. When also help to heal the bleeding and ulcerated rectal mucosa as can
these mature mucosal cells cannot be replaced, the villi shorten argon laser ablation of the telangiectasias.
and the loss of absorbtive function of the small intestine occurs. Hyperbaric oxygen therapy can be helpful in controlling
This loss of function results in fluid and nutrient wasting, diar- bleeding when severe (304,307,308,309). Fibrosis, stenosis,
rhea, and dehydration. This constellation of symptoms is termed perforation, and fistula formation are rarer (Fig. 12.58). In
acute radiation enteritis. Fortunately, re-epithelialization occurs general, doses in excess of 60 Gy are necessary to produce this
within several days due to recovery of the rapidly dividing crypt more advanced radiation damage to the small bowel and recto-
cells (290). Mucosal healing will occur within 10 to 14 days sigmoid (310). Fecal diversion may be necessary in the setting
if radiation is terminated, and symptoms will accordingly of stenosis, necrosis, or fistula formation. Retrospective analy-
improve and resolve in most patients. It is common to observe ses have shown that limited volumes of the rectum can tolerate
watery diarrhea with intermittent abdominal cramping starting about 75 Gy (external beam and brachytherapy) with accept-
in the second or third week of abdominal or pelvic irradiation. able morbidity (257,264).
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 331
A B
FIGURE 12.58. Radiation-induced sigmoid stricture noted on a contrast study, A: full view, B: magnified view, following definitive chemoradiation.
332 CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY
important determinant of normal tissue complications. Attempts should be identified and sigmoid in addition to rectal points
have been made to determine the maximum tolerable normal should be evaluated, as should bladder and vaginal points.
tissue dose with an acceptable risk of complications. There is no Various methods for determining normal tissue doses have been
consensus as to what these values should be. Point doses may or described. When possible, the doses to the normal critical struc-
may not coincide with complication risk, as they do not account tures should be less than the dose at point A, perhaps in the
for the volume of organ irradiated. They are also not defined range of 50% to 80%. The portions of the rectum and sigmoid
consistently. Maximum bladder point doses of 75 to 80 Gy and that are above the range of the rectal retractor are most often the
rectal doses of 70 to 75 Gy are guidelines (82,264,312,310). hot spots, and every effort must be made to decrease the dose
The ratio of dose to the rectal point and bladder point and to the rectosigmoid relative to the point A dose. Consideration
dose to point A is also important with a low incidence of rectal to decreasing the dwell times or turning off dwell positions in
(0.3%vs. 5%) and bladder (2% vs. 2% to 5%) complications the tandem should be given. To avoid underdosing endometrial
when this ratio was less than 80% (264). Other factors such as extension of tumor, at least treating 4 cm above the exocervix so
external beam dose and intracavitary dose rate are also impor- that point A is not in a region of dose constriction may be wise.
tant in the etiology of complications. The volume of rectum and Tandem lengths of 6 to 8 cm are typical. If there is endometrial
bladder irradiated is an important variable in the development extension, a longer tandem may be needed. Additionally, use of a
of complications in addition to the cumulative dose (315). Both tapered tandem will decrease sigmoid, bladder, and small bowel
external beam and use of tandem and cylinder applicators can doses (175). Contrast in the sigmoid is helpful in making these
increase the volume of bladder and rectum treated (130,316). decisions. CT scanning after applicator placement is exceedingly
Stage, patient age, and medical comorbidities such as hyperten- helpful and much more reliable in assessing the proximity of the
sion, diabetes, diverticulitis, or inflammatory bowel disease may sigmoid to the tandem and in manipulating the dose distribu-
also increase the risk of complications, as can the administration tion (Fig. 12.59). Assessment of the anterior and posterior uter-
of chemotherapy. Individual radiosensitivity may also impact ine wall thickness measured on CT with the applicator in place,
complication risk (317). along the course of the tandem, as well as the measured distances
from the tandem to the rectosigmoid, small bowel, and bladder,
can help to guide dose prescription and potentially decrease tox-
icity if the distribution is altered appropriately (105). Sigmoid
Bladder and RectosigmoidHDR doses can often be higher than the rectal ICRU doses (324). Van
Acceptable normal tissue doses are even more debatable in HDR Lancker and Storme have not found point A or normal tissue
than LDR. Using HDR techniques, the therapeutic range is nar- dose points helpful as predictors of complications, but rather
rower and the risk of complications seems to rise faster than the that volume calculations were extremely helpful in predicting
rate of improved tumor control. Available clinical data also sug- complications, and they found a significant correlation between
gests that in addition to total HDR dose, the most important fac- rectal complications and the ICRU reference 60 Gy isodose vol-
tor in late complication development is the dose per fraction and umes (333). Dose volume data appears to be more helpful than
the number of fractions (162,317,318). The organ most at risk point dose data in predicting for complications. Using CT or
for complications is the rectosigmoid, whereas the bladder com- MR based volume planning, the EQD2 limit to the D2cc (the
plication risk is comparatively low (188,319,320). Rectal and minimum dose in the most irradiated 2 cm3 normal tissue vol-
sigmoid complications occur earlier than bladder complications ume for the rectum and sigmoid is 70-75 Gy and for the bladder,
(317,318). Rectal bleeding is the most frequent rectal morbidity 90 Gy (112,113,115,107). Georg et al. found that for the rec-
occurring in approximately 30% of patients (257,319,320,321). tum, a significant dose effect was found for all DVH parameters
To avoid excessive morbidity, better physical dose distributions for any grade of complication as well as for G2 to G4 side effects
must be achieved with HDR to reduce doses to critical normal with the exception of the D0.1cc. For G2 to G4 rectal toxicity, a
structures. This implies the use of rectal and bladder displace- threshold of 60 Gy (EQD2) was observed with a 10% incidence
ment. Fowler has speculated that if only 80% of the tumor dose at 78 Gy and a 20% incidence at 90 Gy. For bladder, no signifi-
is received by the critical normal tissues, then 4 to 6 HDR frac- cant dose response was observed for G1 to G4 side effects, but
tions can be used safely, whereas 12 to 16 fractions would be for complications of >G2, dose effect curves could be generated
required if the normal structures receive 90% of the point A for all DVH parameters that were statistically significant. For
dose, and 30 fractions if the normal structures received 100% bladder, there was a 5% risk of G2 to G4 morbidity with a D2cc
of the HDR dose (162,322). Rectal retractors have become an of 70 Gy, a 10% risk of G2 to G4 morbidity with a D2cc of
integral component of insertion techniques and perhaps improve 101 Gy, and a 20% risk of G2 to G4 morbidity with a D2cc of
the effectiveness and reproducibility of rectal displacement over 134 Gy (334,335). Late bladder sequelae have been infrequent
gauze vaginal packing (162,161,163). Whatever the case, a rec- in patients with such doses but longer follow-up is needed to be
tal retractor, vaginal speculum blade, or gauze packing should be certain as the late effects in the bladder can be quite delayed in
used to displace the rectum (170,189). their appearance (115). Georg et al. and Kook et al. also found
Various disparate recommendations concerning normal tissue a correlation between rectal dose volume parameters and endo-
fraction size and total dose exist in the literature. Sakata et al. scopically defined mucosal changes as well as clinical side effects
found that the probability of rectal complications increased dra- (337,336).
matically above a maximal rectal dose (Deq) of 60 Gy (323).
Cheng et al. found that patients with >62 Gy of summed exter-
nal beam and intracavitary doses to the proximal rectum and
>110 Gy maximal proximal rectal BED had significant increase FUTU RE FOCUS
in complications (324). Takeshi et al. noted that radiation dose
significantly impacted rectal dose complication rate with an Reduction of morbidity and improvement in local control and cure
increase above 65 Gy (325).Various recommendations for rec- is a common goal in the treatment of patients with gynecologic
tal and bladder tolerance doses are in the literature using point cancers. Use of 3-D and functional imaging will be increasingly
doses and timedose fractionation (TDF) and biologically equiv- important to define tumor and normal tissues. This can perhaps
alent dose (BED) values (194,257,259, 320,326332). When allow escalation of dose to the tumor and reduction of dose to the
using point doses, it is very important to choose points related to critical normal tissues. There has been, however, a reluctance to
critical structures very carefully on the orthogonal films. Rectum vary from traditional dose specification as good outcomes have
above the level of the vaginal applicators and rectal retractor been published at institutions skilled in the care of gynecologic
CHAPTER 12 BIOLOGIC AN D PHYSICAL PRI NCI PLES OF R ADIATION ONCOLOGY 333
FIGURE 12.59. Radiograph of the pelvis with a tandem and ovoid applicator in place demonstrates the circuitous course of the sigmoid A:. The axial CT
scan B: demonstrates a more accurate relationship of the sigmoid to the uterine tandem and the need to limit dose to this loop of sigmoid positioned very
close to the high-dose region of the implant.
FIGURE 12.60. B, C: MRI of the pelvis with an MRI/CT compatible applicator ring B: and ovoids C: in
place. Note the associated dose distribution relative to visible tumor within the cervix and the bladder, rectum
and sigmoid.
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Principles of Chemotherapy
in Gynecologic Cancer
MICHAEL A. BOOKMAN
342
CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER 343
V (t) 1016
1014
1 kg mass
1012
32 cm mass
8 cm mass
1010 4 cm mass
2 cm mass
1 cm mass
Number of cells
108 0.5 cm mass
1 mm mass
106
104
Table 13.2 Relationship of Chemotherapy Agents to Intracellular Targets and Cell-Cycle Progression
Cell-Cycle
Classification Specificity Cellular Targets and Mechanisms Examples
Inhibition of G1, S Inhibition of nucleotide synthesis and Antifolates (methotrexate, pemetrexed), nucleoside
DNA synthesis metabolism. Inhibition of thymidylate synthase, analogues (6-mercaptopurine, 5-fluorouracil,
and repair thymidylate phosphorylase, dihydrofolate cytarabine, fludarabine, gemcitabine), hydroxyurea
reductase, ribonucleotide reductase
S Stabilization of DNA-topoisomerase II Anthracyclines (doxorubicin, daunomycin, idarubicin,
cleavable complex, DNA intercalation, epirubicin), anthracenediones (mitoxantrone),
+/ free radical formation epipodophyllotoxins (etoposide), actinomycin D
S Stabilization of DNA-topoisomerase I Camptothecins (topotecan, irinotecan)
cleavable complex
Alkylating G1, G2, S Direct DNA damage, DNA adduct formation, Radiation, platinum compounds (cisplatin, carboplatin,
agents and related free radical production, strand breakage oxaliplatin), bleomycin, mitomycin C, nitrogen
compounds mustard, nitrosoureas, ecteinascidin
Antimicrotubule M Inhibition of tubulin polymerization Vinca alkaloids (vinristine, vinblastine, vinorelbine),
reagents colchicine
Promotion of tubulin polymerization Taxanes (paclitaxel, docetaxel), epothilones
Kinesin spindle proteins Investigational agents
Cell cycle agents G1, S, G2, M Mitotic checkpoint control, cyclin-dependent Flavopiridol, investigational agents
kinases (CDK), aurora kinases
Signal transduction G0, G1, S, G2 Growth factor sequestration, receptor Trastuzumab, cetuximab, pertuzumab, aflibercept,
modulators blockade bevacizumab
Inhibition of tyrosine kinase-mediated signal Erlotinib, gefitinib, desatinib, imatinib, sorafenib,
transduction sunitinib, lapatinib
Modulation of protein kinase C Bryostatin, enzastaurin
Inhibition of hormonal pathways Tamoxifen, raloxifene, anastrazole, letrozole, fulvestrant,
megestrol, mifepristone, flutamide, leuprolide
Gene regulation NA Gene regulation by inhibition of promoter Azacytidine, suberoylanilide hydroxamic acid
methylation, DNA methyltransferase, or (vorinostat, belinostat)
histone deacetylase
Protein NA Posttranslational protein modifications, Tipifarnib, bisphosphonates
modifications inhibition of farnesylation
Inhibition of the proteasome complex and Bortezomib
clearance of ubiquinated proteins
In addition to achieving local delivery, most drugs must be small-volume residual disease at the time of second-look lapa-
internalized within tumor cells to achieve cytotoxicity. Internal- rotomy (27,28) and primary treatment of small-volume residual
ization can be accomplished by passive diffusion, active trans- disease following initial cytoreductive surgery (29). In view of
port, pinocytosis, or receptor-mediated endocytosis. Molecular the risk of systemic nonhematologic toxicity from intraperito-
targeting has also been utilized to enhance the delivery of con- neal cisplatin, there has been renewed interest in the substitution
ventional cytotoxic agents to tumors, based on expression of of intraperitoneal carboplatin, which differs in terms of reduced
tumor-associated antigens, or the presence of specific receptors. protein binding and increased overall time required for in situ
Many chemotherapeutic agents are lipophilic and highly activation (via aquation), with the possibility that clinical out-
protein bound in plasma, particularly to albumin. Commonly comes could be different between the 2 agents, and this is cur-
used agents with greater than 95% protein binding include rently under investigation in a phase 3 randomized trial.
cisplatin, paclitaxel, docetaxel, etoposide, and the active metab- In contrast to cisplatin, paclitaxel is poorly absorbed from the
olite of irinotecan (SN-38). Agents with less protein binding peritoneal compartment, suggesting that patients might benefit
include doxorubicin (75%), topotecan (35%), gemcitabine from combined intravenous and intraperitoneal administration
(10%), carboplatin (<5%), and ifosfamide (<5%). It is gener- to optimize tumor drug exposure. As a single agent, intraperi-
ally the unbound free drug that mediates toxicity, and any toneal paclitaxel demonstrated a 61% pathology-confirmed
condition associated with variability in protein binding can complete response rate among 28 assessable patients with ini-
have an impact on cumulative drug exposure. For example, the tial microscopic disease (30). However, only 1 of 31 patients
toxicity of chemotherapy is frequently accentuated in patients (3%) with greater than microscopic disease achieved a complete
6079 3059
2029 3039 4049 5059 6069 7079 80+ 2029 3039 4049 5059 6069 7079 80+
FIGURE 13.4. Distribution of renal function in nondiabetic adults. Weighted distribution of predicted GFR (mL/min/1.73 m2) based on the MDRD formula from
the Third National Health and Nutrition Examination Survey (NHANES III).
Source: From Clase CM, Garg AX, Kiberd BA. Prevalence of low glomerular filtration rate in nondiabetic Americans: Third National Health and Nutrition Examination Survey (NHANES III). J Am Soc Nephrol.
2002;13:13381349, with permission.
toxicity is generally increased, overall benefits from active che- or inulin, remains the standard for comparison with indirect esti-
motherapy regimens can still be demonstrated, as illustrated by mates, but these assays are rarely used in clinical practice due to
the analysis of data from several breast cancer trials (34). Studies cost and complexity.
in ovarian cancer have indicated that age is an adverse prognos- Staging of chronic renal disease has been used to reflect overall
tic factor, but there are insufficient data to determine how the severity and guide management decisions, including dose modi-
benefits of treatment change with age. In part, this is related to fications. The most commonly used staging system is from the
the underutilization of chemotherapy in elderly patients (35) and National Kidney Foundation (42). The formula derived from the
reduced enrollment of elderly patients on clinical trials (36). From Modification of Diet in Renal Disease (MDRD) study has been
that perspective, it is important to define tolerable and effective incorporated in standardized laboratory reports (39). However,
treatment regimens that can be safely administered in elderly the MDRD has not generally been validated for actual drug dos-
patients, incorporating supportive care, geriatric assessment, and ing. As a result, the Cockroft-Gault (40) and Jelliffe (41) formulae
adjustments for age-related changes in vital organ function (37). are more commonly used for drug dose calculation (Table 13.3).
In surveying the general nondiabetic female population, the The situation has become further complicated by an interna-
incidence of moderate renal insufficiency dramatically increases tional effort to recalibrate creatinine standards based on isotope
with age, which is of particular relevance to the care of women dilution mass spectrometry (IDMS). These new standards have
with gynecologic cancer (38). For example, in the 60 to 69 year now been adopted by all major vendors and commercial labora-
age group, over one-third of women have an estimated glomerular tories. The relationship between old (pre-IDMS) and new (IDMS)
filtration rate (GFR) of less than 60 mL/min/1.73 m2 (Fig. 13.4). creatinine values within the same patient is variable, depending
In addition, serum creatinine levels can be inappropriately low on the specific vendor and equipment. In general, IDMS stan-
in women with gynecologic cancer, as a consequence of reduced dards will lower the serum creatinine value by approximately
muscle mass, malnutrition, post-operative recovery, or third-space 12%. Using the IDMS creatinine value will therefore increase
fluid accumulation. In those settings, any of the standard formu- the estimated GFR, and could lead to higher doses of chemo-
lae will overestimate GFR, with potential clinical consequences. therapy, particularly carboplatin, with an impact on hematologic
Clearly, universal caution in dosing drugs with high renal clear-
ance, especially carboplatin, is required.
Several methods are available to estimate GFR and classify
the extent of renal injury based on age, sex, serum creatinine, Table 13.3 Commonly Utilized Formulae to
and other factors (3941). In general, serum creatinine is the Estimate Creatinine Clearance
dominant factor, and it remains unclear whether minor differ-
ences between formulae might have meaningful and/or consis- Formula Name Estimation of Creatinine Clearance (CrCl)
tent clinical consequences with regard to drug dosing. In most Cockcroft-Gault CrCl (mL/min) = (140 age) weight (kg)
cases, it is sufficient to estimate GFR rather than obtain a pre- formula (40) (0.85 if female)/serum Cr (mg/dL) 72
cise measurement. However, all of these formulae are based on
stable normalized biologic parameters and are less useful in the Jelliffe CrCl (mL/min) = {98 [0.8 (age 20)]}
formula (41) (0.9 if female)/serum Cr (mg/dL)
setting of dynamic changes following acute renal injury, or other
nonrenal fluctuations in serum creatinine. MDRD GFR (mL/min/1.73 m2) = 170 [serum Cr (mg/
While urine collection for estimation of creatinine clearance formula (39) dL)]0.999 (age)0.176 (0.762 if female) (1.180
(based on measured creatinine in the urine over a period of time) if African American) [SUN (mg/dL)]0.170
might appear to provide a better estimate of GFR, it is also subject [Alb (g/dL)]+0.318
to clinical variability, due to different rates of creatinine tubular
secretion. Utilization of direct techniques to measure actual GFR, Alb, serum albumin concentration; Cr, creatinine; GFR, glomerular filtration
rate; MDRD formula, the Modification of Diet in Renal Disease study equation;
such as clearance of 51Cr-ethylenediamine tetraacetic acid (EDTA) SUN, serum urea nitrogen concentration.
CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER 349
a
Can be administered at full doses in anephric patients receiving hemodialysis.
Metabolism and Pharmacogenomics grouped into 18 families, with 3 families (CYP1, CYP2, and
Drugs can be metabolized in the liver, in other normal host tis- CYP3) that have evolved to handle the majority of exogenous
sues, or within tumors. Aside from those agents with extensive agents. In particular, CYP3A4 catalyzes the biotransformation
renal clearance, hepatic metabolism usually predominates. A of more than half of our commonly used drugs (48), setting the
large number of microsomal and cytoplasmic enzymes contribute stage for numerous drug-drug interactions.
to this process, with associated genetic polymorphisms that can Phase II reactions further increase water solubility by con-
account for individual variability in clearance, efficacy, resistance, jugation to a large polar entity, such as glucuronic acid, sulfate,
and the risk of hepatic or nonhepatic toxicity. Techniques for acetate, glycine, glutathione, or a methyl group. These reac-
screening and identification of pharmacogenomic elements are tions result in the formation of nontoxic substances that can be
expanding, with potential implications for individualized drug excreted in the bile or urine. The predominant enzymes include
selection, dosing, prediction of efficacy, and risk of toxicity. UDP-glucuronyl transferases (UGT1 and UGT2), sulfotransfer-
Phase I reactions are characterized by attachment of polar ases, and glutathione S-transferases.
groups to lipophilic compounds to facilitate water solubility, Phase III reactions directly promote biliary excretion medi-
primarily through the cytochrome P450 superfamily of mixed ated by transporter proteins, which are members of the adenosine
function oxidases (CYP). Over 50 individual proteins have been triphosphate (ATP)-binding cassette (ABC) superfamily.
350 CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER
With awareness of polymorphisms in key enzymes, it has practice, the occurrence of excessive hematologic and/or nonhe-
been possible to identify individuals with a dramatic increased matologic toxicity in an individual patient is usually attributed
risk of toxicity. For example, dihydropyrimidine dehydroge- directly to the chemotherapy and managed with treatment modi-
nase (DPD) controls the rate-limiting step in fluoropyrimidine fications, rather than ascribed to a potential drug interaction.
metabolism, and approximately 10 variant DPD alleles occur When they occur, interactions can be critical, and some of the
with sufficient frequency to merit consideration of screening, as more important drug interactions are listed in Table 13.5. Par-
patients can be at risk for life-threatening mucosal injury and ticular attention should be placed on drugs that could alter renal
bone marrow suppression after receiving a single standard dose function, such as aminoglycoside antibiotics, nonsteroidal anti-
of 5-fluorouracil. While methods are available for screening, inflammatory agents, and diuretics, in patients with reduced
the potential reduction in risk needs to be balanced against the fluid intake. Typical of in vivo interactions relevant in gyneco-
costs of a widespread screening program (49). Fluorouracil, or logic cancer chemotherapy are the displacement of methotrexate
the pro-drug capecitabine, is not used in the primary treatment from its transport protein by aspirin or sulfonamides, suppres-
of gynecologic cancers, with the exception of some chemoradia- sion of pseudocholinesterase by alkylating agents with increased
tion strategies and occasional palliative management of recur- apnea duration during succinylcholine-assisted general anesthe-
rent disease. sia, impairment of doxorubicin clearance by preadministration
Uridine diphospho-glucuronosyl-transferase 1A1 (UGT1A1) of paclitaxel, and impairment of paclitaxel clearance by pread-
is responsible for glucuronidation of bilirubin and a number of ministration of cisplatin.
drug metabolites, most notably SN-38, the major active metabo- Increased attention has been focused on drug metabolism and
lite of irinotecan. As such, patients with a deficiency in UGT1A1 potential interactions with CYP isozymes, particularly CYP3A4,
are at increased risk for life-threatening diarrhea and bone mar- which has been linked to the metabolism of nearly half of all
row suppression after receiving irinotecan and potentially other pharmaceutical agents (48). These interactions are guided by
camptothecin derivatives with SN-38 metabolites (50). The several common principles. Drugs that are substrates for the
UGT1A1*28 promoter mutation has been studied most exten- same isozyme may competitively inhibit metabolism, but these
sively. However, mutations in the coding region can also occur, interactions are usually not of clinical consequence. Drugs that
particularly in Asian populations, and may predict for efficacy in directly inhibit CYP isozymes without being a substrate for that
addition to toxicity (51). Gilberts syndrome is associated with isozyme are more likely to have clinical consequences. In this
a mild unconjugated hyperbilirubinemia and reduced activity regard, itraconazole, ketoconazole, and fluconazole can inhibit
of UGT1A1 that is also associated with an increased risk of CYP3A4 at low concentrations, and erythromycin can inhibit
toxicity in both homozygous and heterozygous patients (52). CYP3A4 via covalent binding and inactivation. Other drugs
The ABC family of drug efflux proteins is also involved in act as inducers of CYP isozymes by increasing gene expres-
biliary transport of camptothecins. Polymorphisms of ABCB1, sion or protein levels, such as glucocorticoids, barbiturates, and
also known as p-glycoprotein or multidrug resistance protein 1 rifampin, which can increase the net activity of CYP3A4, result-
(MDR-1) as well as ABCC2, also known as canalicular multi- ing in decreased concentrations of susceptible compounds. In
specific organic anion transporter (cMOAT) or MRP2, appear addition, many drugs that interact with CYP3A4 are natural
to have an impact on the clinical efficacy and toxicity (neutro- products and may also interact with ABC family drug efflux
penia and diarrhea) associated with irinotecan therapy in Asian pumps, including MDR-1. Among the anticancer agents that
patients (53). are substrates for CYP3A4 are cyclophosphamide, ifosfamide,
Dose modifications should be considered for patients with docetaxel, etoposide, paclitaxel (also CYP2C8), docetaxel,
liver disease (54), particularly for paclitaxel, docetaxel, nanopar- vincristine, vinblastine, tamoxifen, and gefitinib (57). CYP2C9
ticle albumin-bound paclitaxel (55), doxorubicin, and the Vinca and CYP2D6 are inhibited by imatinib, and doxorubicin can
alkaloids (vincristine, vinblastine, and vinorelbine), which are inhibit CYP2D6. Cyclosporine and verapamil can increase con-
primarily metabolized in the liver and/or excreted in the bile. centrations of doxorubicin and etoposide, probably through
Excessive toxicity may occur with doses that would ordinarily be blockade of the P170 drug efflux pump (Table 13.6).
acceptable, and guidelines for treating patients with impaired liver Owing to the diversity and rapid adoption of new compounds,
function should be consulted. However, variability in nonhepatic information regarding drug interactions is best obtained from
clearance, compensatory host adaptations, and interactions with online databases, such as the Medical Letter (http://www.medi-
other drugs, make these recommendations less reliable than those calletter.com), Micromedex (http://www.micromedex.com), the
provided for patients with renal dysfunction. For example, dose Drug Interaction Database from the University of Washington
reduction of etoposide in the setting of biliary obstruction remains (http://www.druginteractioninfo.org), Medscape (http://reference.
controversial and may not be required (56). medscape.com/drug-interactionchecker), the package insert, or
directly from the manufacturer.
Drug Interactions
During routine care, patients may receive a variety of drugs, DRUG RESISTANCE AN D TU MOR
including antiemetics, antihistamines (H1 and H2), steroids, non- CELL H ETEROGEN EITY
steroidal anti-inflammatory agents, anticoagulants, narcotics,
and anti-infective agents. In addition, older patients are frequently The curative potential of chemotherapy is limited by the
receiving medication to manage underlying comorbidities, such emergence of drug resistance, which can be either intrinsic or
as diabetes, hypertension, and elevated cholesterol. In view of the acquired, and may involve one drug or multiple agents (pleio-
number and diversity of medications in common use, it is some- tropic resistance). Of interest, tumors with intrinsic or primary
what surprising that most interactions with cytotoxic chemo- drug resistance to natural products often arise from duct cells or
therapy appear to be of little consequence. However, prospective cells lining excretory organs (58). These cells, which normally
studies of chemotherapy administration in noncancer volunteers detoxify, transport, and excrete a wide variety of toxic com-
are impractical, and many potential interactions have not been pounds, may retain these normal functions after transformation,
fully explored. In fact, patients are likely to be excluded from manifesting as chemoresistance.
enrollment on clinical trials on the basis of concomitant medica- Intrinsic drug resistance is inferred based on clonal survival
tions, rather than prospectively collecting valuable data to docu- of tumor populations after initial chemotherapy exposure. Solid
ment safety or the need for treatment modifications. In clinical tumors are thought to consist of a mixture of clonal variants
CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER 351
with different pre-existing mutations and patterns of resistance. resistance to alkylating agents, especially platinum compounds,
Following repetitive cycles of chemotherapy, a process of clonal mediated through a completely different set of cellular mecha-
selection can occur, enriching for resistant populations, even nisms, including reduced cellular uptake due to loss of mem-
while there could be a reduction in clinical tumor volume asso- brane transport proteins, increased detoxification of reactive
ciated with elimination of more sensitive tumor elements. intermediates by glutathione production, increased damage
Acquired resistance develops from cumulative somatic muta- tolerance due to defective detection and/or apoptotic signaling,
tions, regulation of gene expression (including epigenetic pro- and expanded capacity for DNA repair (62).
cesses), or other phenotypic alterations, over a period of time.
From a clinical perspective, the end result of this process is indis-
tinguishable from acquired resistance. However, acquired resis-
tance is more likely to have a reversible component that could Multidrug Resistance
influence the timing and selection of subsequent chemotherapy. After exposure to a potential MDR 1 substrate, tumor cells will
The most well-documented specific example is amplification develop cross resistance to a variety of structurally and function-
of the dihydrofolate reductase (DHFR) gene, which is associ- ally unrelated agents derived from natural products. This pleio-
ated with acquired resistance to methotrexate (59). DHFR gene tropic resistance is associated with increased drug efflux and a
amplification is not generally observed prior to methotrexate net lowering of intracellular drug concentration. Although rela-
exposure and can be reversed in the absence of drug exposure. tively uncommon in newly diagnosed ovarian cancer (63,64),
From the perspective of gynecologic oncology, there are 2 with increased utilization of natural products, including taxanes,
major patterns of drug resistance that emerge with continued etoposide, and liposomal doxorubicin, this pattern of resistance
treatment. The first is broad-based multidrug, or pleiotropic, generally emerges over a period of time.
drug resistance that has been associated with overexpression of Other chemotherapeutic agents, including nucleoside ana-
MDR 1 (P 170 glycoprotein) and/or other membrane-associated logues, are not substrates for MDR 1 and remain unaffected by
transport proteins (60,61). This multidrug resistance phenotype increased expression. In some resistant cell lines, a collateral
has maximal impact on natural products and their analogs, includ- sensitivity to gemcitabine has been observed, characterized by
ing the anthracyclines, Vinca alkaloids, and taxanes. The second is increased uptake and phosphorylation, which could be reversed
352 CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER
Table 13.6 Specific Mechanisms of Tumor Platinum Resistance and DNA Repair
Drug Resistance Although a number of DNA alkylating agents and radiation are
Resistance Specific Cellular Target used in the treatment of gynecologic cancer, platinum derivatives
Mechanism Examples or Effects are the most important compounds in clinical practice. The dra-
matic success of platinum-based therapy is nearly overshadowed
Impaired 5-Fluorouracil Reduced levels by the emergence of platinum resistance, and this observation has
activation of thymidylate stimulated a substantial body of research over the last 35 years.
synthase, thymidylate
phosphorylase, or
As a highly polar compound, cisplatin enters cells relatively
dihydropyrimidine slowly, and uptake can be influenced by local cation concen-
dehydrogenase trations, pH, and the presence of reducing agents, prompting
a search for membrane transporter proteins that could supple-
Methotrexate Reduced intracellular ment passive diffusion. The major transporter involved in cop-
polyglutamation
per homeostasis, copper transporter-1 (CTR1), has now been
Doxorubicin Low P450 enzymes shown to have a substantial role in cisplatin influx (68). Down-
Cyclophosphamide, Decreased microsomal regulation of CTR1 expression can reduce cisplatin uptake,
ifosfamide transformation leading to one mechanism of resistance. Targeted methods to
safely and selectively increase platinum uptake in tumors are
Gemcitabine Decreased deoxycytidine not yet available. However, it has been observed that ovarian
kinase
cancer cell lines can rapidly downregulate membrane CTR1
Increased drug Natural products Increased MDR 1 (P 170) after cisplatin exposure, followed by proteasomal-mediated
efflux degradation (69), suggesting that sequence and schedule of
Topotecan, Increased BCRP
mitoxantrone (ABCG2) drug administration could have an impact on platinum uptake.
JM-118, or cis-ammine-dichloro-cyclohexylamine-platinum (II),
Increased drug Alkylating agents, Elevated glutathione and retains activity in tumor cells that have lost CTR1 (70). In that
inactivation platinum other cellular thiols context, it is interesting to note that satraplatin (JM-216), an
Accelerated Alkylating agents, Induction of DNA repair orally active carboplatin analogue that undergoes biotransfor-
DNA repair platinum, radiation enzymes mation to JM-118, has demonstrated promising activity in the
Increased Alkylating agents, Loss of DNA mismatch treatment of prostate cancer (71).
damage tolerance platinum, radiation repair Human ovarian cell lines resistant to alkylating agents, cispla-
tin, and irradiation contain elevated levels of cellular glutathione
Transport defects Melphalan Reduced carrier-mediated (GSH). Using resistant cell lines, it has been possible to demon-
uptake strate a restoration of drug sensitivity by exposure to the syn-
Gemcitabine Decreased nucleoside thetic amino acid buthionine sulfoximine (BSO), which inhibits
transporter gamma-glutamylcysteine synthetase, causing GSH depletion (72).
Platinum Decreased copper The exact mechanism by which GSH and other thiol compounds
transporter-1 modulate cytotoxicity is unknown, although they can interfere
with the formation of DNA-platinum adducts (73). There is also
Target alterations Methotrexate DHFR gene amplification evidence of increased drug metabolism through GSH-linked
Paclitaxel, Increased tubulin-3 transferases, which can vary for specific platinum compounds
docetaxel isoforms or mutations (74), and which may also contribute to cisplatin-mediated neph-
Hydroxyurea, Decreased ribonucleotide rotoxicity (75). Although clinical trials of BSO with melphalan
gemcitabine reductase have documented an 80% to greater than 90% reduction in
tumor-associated GSH levels (76,77), this approach has not yet
Glucocorticoids Decreased receptor been demonstrated to improve the outcomes of platinum-based
binding
therapy.
Camptothecins Decreased topoisomerase-I In view of the prominent role of thiols in mediating a subset
Anthracyclines, Decreased of platinum resistance, a sterically hindered platinum complex,
etoposide topoisomerase-II picoplatin (JM473, ZD0473), was developed with the expec-
tation that it would favor interacting with DNA rather than
glutathione or metallothioneins (78). A phase 2 trial in recur-
rent ovarian cancer documented response rates of 8.4% in
by verapamil, an inhibitor of MDR 1 (65). This has not yet been platinum-resistant disease and 32.4% in platinum-sensitive dis-
validated in the clinical setting. ease, similar to expectations with cisplatin or carboplatin (79).
Other energy-dependent transporter proteins have been iden- Of interest, there was no documented peripheral neuropathy or
tified in resistant cell lines that may not overexpress MDR 1. nephrotoxicity even in this group of patients with prior plati-
These include the multidrug resistance-associated protein (MRP), num therapy, implicating thiol reactions in the generation of
which is representative of a family of cMOAT proteins (66). these nonhematologic toxicities.
Similar to MDR 1, these proteins include multiple transmem- Enhanced capacity for DNA damage tolerance and repair
brane domains but appear to have more broad tissue distribu- can play a role in drug resistance to alkylating agents and cis-
tion and greater association with intracellular membranebound platin. Human ovarian cancer cell lines resistant to melphalan
compartments. Another member of the family with relevance demonstrate increased ability to repair DNA, and this pheno-
to gynecologic cancer is the breast cancer resistance protein type can be reversed by aphidicolin, a potent inhibitor of a and
(BCRP) or ABC protein G2 (ABCG2) that dimerizes to form b DNA polymerase (80). Increased damage tolerance is another
a membrane-associated energy-dependent drug efflux pump mechanism that contributes to resistance and is perhaps best
responsible for atypical multidrug resistance following exposure to illustrated by the mismatch repair system. Errors in DNA repli-
mitoxantrone or camptothecins, including topotecan. Overex- cation following platinum adduct formation can be detected by
pression of BCRP has been documented in ovarian cancer cells the postreplicative DNA mismatch repair system, which contains
resistant to topotecan (67). several well-characterized genes, including MLH1 and MSH2.
CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER 353
Of note, cellular attempts to repair platinum alkylation by this is not tumor specific, and has been associated with increased
mechanism are not successful, as the repair is directed at the hematologic toxicity, requiring adjustments in dose and sched-
nascent daughter DNA strand rather than the platinated parental ule to safely administer multiple cycles of chemotherapy. Second,
strand. Eventually, abortive attempts at repair are associated with PARP inhibitors can be administered as a single agent following
apoptotic cell death. Thus, loss of mismatch repair can actually completion of primary therapy, creating a synthetic lethal para-
promote cell survival by ignoring DNA damage in noncritical digm for tumors with HRD. In this regard, it is important to
areas of the genome and has emerged as another mechanism of note that these defects are not simply limited to inherited muta-
drug resistance. tions of BRCA1 or BRCA2, but include somatic (intra-tumoral)
Loss of MLH1 or other mismatch repair genes is not uncom- mutations, methylation status, and mutations in other genes
mon in ovarian cancer and appears to increase after exposure associated with DNA repair, exceeding 50% overall incidence
to carboplatin or cisplatin (81). In addition, functional loss of in patients with high-grade serous or endometrioid histology, as
MLH1 activity in patients with ovarian cancer can also occur reflected in data from The Cancer Genome Atlas project (94).
through hypermethylation-mediated silencing of the MLH1 gene Clearly, in spite of considerable wide-ranging research, plati-
following exposure to platinum and has been correlated with num resistance remains a major challenge in the treatment of
poor survival (82). Preclinical models with platinum-resistant cell gynecologic cancers, particularly high-grade serous ovarian cancer.
lines have shown improved treatment outcomes following expo-
sure to 2-deoxy-5-azacytidine (decitabine), which blocks DNA
methylation, unmasking expression of MLH1 (83). However, this
Taxane Resistance
to flavopiridol, an inhibitor of cyclin-dependent kinase activity, spectrum and severity of host toxicity. Dose intensity is a stan-
which has been shown to accelerate catabolism of the M2 sub- dardized measure of the amount of drug administered over time,
unit protein through the proteasome complex (107). Increased most commonly expressed as mg/m2 per week.
levels of target gene expression or protein, including thymi- Preclinical studies demonstrate a sigmoidal relationship
dylate synthase, thymidylate phosphorylase, and dihydropyrim- between dose and tumor response. This is characterized by a
idine dehydrogenase, have also been associated with resistance lag phase and a lower-limit threshold for observing benefit; a
to 5-fluorouracil in colon cancer, and have been correlated with linear phase, where increases in dose are matched by improved
clinical outcomes following 5-fluorouracil treatment (108,109). efficacy; and a plateau, where toxicity continues to increase
Even a superficial analysis of these specific examples would sug- but there is no incremental improvement in response. In highly
gest potential strategies for screening of tumor tissue to guide responsive tumors (e.g., choriocarcinoma, dysgerminoma), the
the selection of optimal chemotherapy regimens, providing a entire dose-response curve is shifted to the left, with the result
basis for the application of tissue, gene, and protein arrays. that standard chemotherapy doses are already situated near
the upper plateau, and further dose increases are unlikely to
achieve any improvement in clinical outcomes. In resistant
tumors (e.g., previously treated cervical cancer), the curve is
Tumor Profiling shifted to the right, and is also flattened, reducing the maxi-
Solid tumors have traditionally been considered to be a homo- mal potential benefit and increasing the risk of toxicity. For
geneous collection of clonally derived cells with similar features, heterogeneous tumors with sensitive and resistant populations,
but it is now clear that tumors are composed of subpopulations such as epithelial ovarian cancer, it is unlikely that increased
with diverse biologic characteristics. Through genetic instabil- dose intensity would achieve long-term clinical benefit. How-
ity and epigenetic processes, such as gene promoter methylation ever, lower-than-standard doses are potentially suboptimal, and
and histone modifications, these subpopulations may exhibit dif- arbitrary dose reductions or delays for nonphysiologic factors
ferent properties, with an impact on chemotherapy response. In should be avoided. True dose-intense regimens have not been
addition, there can be variability in the potential for metastatic demonstrated to improve long-term clinical outcomes in women
spread among cells that appear to be similar at a morphologic with gynecologic cancer, with the possible exception of recur-
and genetic level (110). Recognition of tumor heterogeneity has rent germ cell tumors.
altered our understanding of tumor behavior, with broad implica- The dose intensity hypothesis has been extensively evalu-
tions for multiagent and multimodality treatment programs. ated in the setting of advanced ovarian cancer, beginning with
Following the development of model systems for screening a series of retrospective reports (114). However, within practi-
new anticancer compounds, it is not surprising that attention cal dose ranges that can be achieved in the clinical setting, pro-
was focused on the process of screening actual human tumor spective randomized trials have not demonstrated significant
cells for sensitivity and resistance to chemotherapy agents (111). improvements in either disease-free or overall survival (115).
A variety of methods have been developed utilizing clonogenic While frontline studies focused on platinum dose intensity, the
survival, 3H-thymidine incorporation, vital dye exclusion, treat- question of paclitaxel dose intensity was also addressed in the
ment of transplanted tumor xenografts, and colorimetric analysis setting of recurrent disease, again without evidence of improved
of adenosine triphosphate levels. Although there is relatively good outcomes.
correlation between high-level resistance to individual agents Dose intensity is limited by acute (single-cycle) and cumu-
demonstrated in vitro and lack of a clinical response in vivo, lative (multicycle) nonhematologic and hematologic toxicity.
it is more difficult to predict sensitivity to specific agents, or to Although multiple cycles of high-dose carboplatin and pacli-
guide the utilization of drug combinations (112), reflecting tumor taxel (with or without topotecan or gemcitabine) can be safely
cell heterogeneity, assay complexity, and inability to evaluate the administered with hematopoietic progenitor and growth factor
tumor-host relationship, including the impact of angiogenesis, support, it is more difficult to overcome serious nonhematologic
cytokines, and immune response. A nonrandomized trial in recur- toxicities. Thus far, there is no evidence that a two- to three-
rent ovarian cancer suggested good correlation between ex vivo fold increase in carboplatin dose intensity and cumulative dose
assay sensitivity and clinical response (113), but this may be no delivery is associated with a substantial improvement in clinical
better than selecting reasonable agents based on routine clinical outcomes (116118), and it is unlikely that this approach will
factors, especially in the setting of recurrent disease. Importantly, be further evaluated.
there is a lack of prospective randomized data to validate these In contrast, there is renewed interest in dose-dense therapy,
approaches, as well as concern for the cost and complexities asso- in which a series of 2 or 3 individual single agents are sequen-
ciated with obtaining and shipping fresh tumor tissue. tially administered at maximal tolerated doses using short cycle
With the rapid development of gene expression and proteomic intervals. This approach has been favorably evaluated in the
arrays, mutational analysis, RNA sequencing, whole genome adjuvant therapy of breast cancer (119), although it has not
scanning, and whole genome sequencing, these questions have been clearly established if the clinical benefit is secondary to
been carried to a new level of sophistication, as illustrated by dose density or weekly scheduling of specific components. In
The Cancer Genome Atlas project (94). In addition, as drug devel- ovarian cancer, the Japanese Gynecologic Oncology Group
opment has shifted toward molecular-targeted agents, there has (JGOG) has conducted a phase 3 trial using standard sched-
been a request from FDA to incorporate predictive or selective uling of carboplatin together with weekly dose-dense schedul-
biomarkers in regulatory filing, even though the cellular path- ing of paclitaxel, with improved progression-free and overall
ways and regulatory networks are not always well understood. survival (120), and other groups are working to validate and
Finally, large population-based molecular data repositories are extend these observations. Overall hematologic toxicity was
under development, with the potential to rapidly identify targets, increased with dose-dense therapy, and it remains unclear if the
select patients, and evaluate new drugs without randomized trials, therapeutic advantage is more dependent on optimal schedul-
raising a number of interesting questions. ing of paclitaxel, or the cumulative dose delivered. Short cycle
intervals may offer a safer approach for intensification by rein-
forcing normal biologic rhythms that can accelerate repair and
minimize host toxicity. For other drugs without known schedule
Dose Intensity and Density dependence (such as cisplatin or carboplatin), weekly divided
The dose and frequency of drug administration can contribute to doses may not have a therapeutic advantage, and could possibly
the overall effectiveness of a treatment regimen, as well as the be less effective, due to lower peak serum concentrations.
CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER 355
prolonged treatment-free interval generally receive a platinum- it has been difficult to establish an advantage in overall survival.
based combination. Phase 3 studies in endometrial cancer (131) and uterine mixed
The decision to embark on antineoplastic drug therapy Mllerian tumors (132) have documented improved survival
is obviously complex. Optimal patient care demands careful with the use of adjuvant combination chemotherapy compared
review of the multiple factors affecting therapy to maximize any to whole abdomen radiation in selected patients with high-risk
opportunity for improving survival and quality of life. disease, increasing the overall proportion of patients who receive
adjuvant therapy.
Concurrent chemotherapy with radiation (chemoradiation)
Choice of Specific Chemotherapeutic refers to the use of chemotherapy to sensitize the tumor to the
effects of radiation delivered with curative intent. This has been
Regimens most extensively studied in the primary management of locally
After the decision to use chemotherapy has been made, the advanced cervical cancer, where platinum-based chemoradia-
appropriate regimen must be selected. The physician is aided in tion has been proven to be superior to radiation alone (133).
this task by the results of randomized trials and evolving stan- In general, the duration of chemotherapy coincides with the
dards of care, including published practice guidelines. However, duration of external beam radiation. Although the preferred
not every patient can receive standard therapy because of weekly dose of cisplatin might appear to be low, these regimens
idiosyncratic reactions, vital organ dysfunction, prior treatment, generally exceed the overall dose intensity of cisplatin when
or other factors. Practical individualized decisions are facilitated used to treat advanced disease, and patients require monitoring
by the logical grouping of chemotherapeutic agents in several to avoid cumulative toxicity and treatment interruptions.
classes with similar pharmacologic properties, mechanisms of Neoadjuvant chemotherapy generally refers to the use of
action, and spectrum of toxicity. The most important classes are chemotherapy in the management of locally advanced disease in
the platinum-based alkylating agents, nonplatinum alkylating situations where it would be difficult or impractical to perform
agents, antimetabolites, antitumor antibiotics, antimicrotubule immediate surgery or radiation. Following a response to initial
agents, nucleoside analogs, hormones, and newer molecular tar- chemotherapy, there is an expectation that morbidity associated
geted therapies. with the overall treatment program can be minimized in conjunc-
A number of combination regimens have been evaluated in tion with a reduction in radiation treatment volume or extent
the management of gynecologic cancer, and some have been of surgery. This approach is most often considered in advanced
widely adopted as standard of care for primary management of cervical cancer, where high initial response rates to neoadjuvant
advanced-stage or recurrent disease. Phase 3 trials have demon- therapy have been observed. However, the long-term benefit of
strated the superiority of specific regimens, such as paclitaxel with this approach has not been established. Neoadjuvant therapy
either cisplatin (121) or carboplatin (122) in ovarian cancer; a is also a consideration in advanced ovarian cancer, particularly
triplet combination of paclitaxel, cisplatin, and doxorubicin with in patients with large-volume ascites, pleural effusions, diffuse
granulocyte colony-stimulating factor (G-CSF) in endometrial small-volume disease, or comorbidities that might increase sur-
cancer (123); cisplatin with either paclitaxel (124) or topotecan gical risk (134). In this setting, it has been difficult to conduct
in cervical cancer (125); and ifosfamide with paclitaxel in uterine randomized neoadjuvant trials owing to impaired performance
mixed Mllerian tumors (126). status, the desire to establish a definitive tissue diagnosis, and
However, none of the standard combinations for advanced the bias toward initial cytoreductive surgery.
ovarian, endometrial, or cervical cancer has been directly com-
pared to sequential therapy with the best active single agents,
and the superiority of combination therapy has not been fully
established. In the setting of ovarian cancer, phase 3 trials have Monitoring of Tumor Response
suggested that sequential therapy with platinum followed by Generally accepted criteria for evaluation of responses are neces-
paclitaxel may offer similar long-term outcomes to a combina- sary to facilitate treatment decisions and comparisons among dif-
tion of platinum and paclitaxel (127,128). Although the initial ferent regimens. Several standards have been used, including those
frequency of tumor response is often increased with combina- developed by the World Health Organization (WHO). However,
tion therapy, long-term outcomes such as overall survival and in 2000, an international working group including the European
symptom-adjusted quality of life can be similar for patients who Organization for Research and Treatment of Cancer (EORTC),
receive optimal sequential therapy with single agents. This is pri- the National Cancer Institute of Canada (NCIC), and the National
marily related to the advanced stage of disease at the time of initial Cancer Institute (NCI) of the United States developed, validated,
treatment with systemic chemotherapy and the lack of curative and published new Response Evaluation Criteria in Solid Tumors
therapy for the majority of patients. As such, if individual patient (RECIST 1.0), which were widely adopted within clinical trials
circumstances contraindicate the use of a standard combination and updated as RECIST 1.1 in 2009 (135).
regimen, it remains a reasonable option to begin therapy with RECIST is based on the prospective designation of measur-
one of the active single agents. In addition to their application able lesions, 10 mm in one dimension (longest axis) on com-
as primary therapy for advanced disease, combinations can also puted tomographic (CT) imaging, and at between 1 and 5 target
be employed as adjuvant therapy for patients with early-stage lesions that can be reproducibly measured to determine tumor
disease at increased risk for recurrence and for patients with late response, as well as nontarget lesions that are used to cor-
recurrence after good response to initial therapy. roborate response. Lymph nodes represent a special category, as
Adjuvant chemotherapy refers to the initial use of systemic normal anatomic structures, and must be 15 mm on the short
chemotherapy after surgery and/or radiation therapy has been axis to qualify as a measurable or target lesion. Helical CT and
performed with curative intent and there is no evidence of residual magnetic resonance imaging (MRI) are the preferred techniques
disease. Adjuvant chemotherapy is considered if the subsequent to monitor tumor response, and the same technique that is used
risk for recurrence after initial definitive therapy is relatively high for initial assessment should be used for subsequent measure-
(generally greater than 20%), but it is not routinely recommended ments. With the expanding use of positron emission tomogra-
when the risk of recurrence is less than 10%. In the adjuvant ther- phy (PET) and merged PET-CT imaging, it is important to note
apy of epithelial ovarian cancer, long-term results from random- that PET data are not included in RECIST, but the CTcompo-
ized trials have documented a reduction in the risk of recurrence nent of a PET-CT study can be used for RECIST if the CT is of
after platinum-based chemotherapy (129,130). However, in care- sufficient diagnostic quality. The use of physical examination is
fully staged patients (to exclude occult advanced-stage disease), restricted to cutaneous lesions or superficial adenopathy that
CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER 357
can be directly measured with calipers. The omission of findings are not validated for seeking regulatory approval of new treat-
on bimanual pelvic examination poses a particular challenge ments. Overall, RECIST is more detailed and specific than previ-
for monitoring regional disease in patients with gynecologic ous response criteria, and is also more demanding of the clinical
tumors, and most of these findings would be categorized as non- team and radiologist, particularly if there are a large number of
target lesions, unless confirmed on radiographic imaging. An target and nontarget lesions.
overview of RECIST determinations is provided in Table 13.8. Complete Response (CR) refers to the complete disappear-
The summary response designation within RECIST integrates ance of all objective evidence of tumor, including normalization
the findings from target and nontarget lesions, as well as serum of tumor markers, and a resolution of all signs and symptoms
tumor markers (if applicable). Serum tumor markers are not suf- referable to the tumor. Complete regressions of cancer are gen-
ficient to declare response but, if initially elevated, must normalize erally those associated with a prolongation of survival.
to designate a complete response. International criteria to declare Partial Response (PR) refers to at least a 30% decrease in the
disease progression on the basis of a serial elevation in CA-125 sum of the longest diameter of all measurable lesions (shortest
have been widely adopted (136,137), but there is incomplete diameter for lymph nodes). Usually, this would be accompanied
agreement on criteria to define a partial response during treat- by some degree of subjective improvement and the absence of
ment (138). Changes in CA-125, alone, without other evidence any new lesions during treatment. Partial remissions are gener-
of disease, are not recognized within the RECIST paradigm and ally accompanied by improved well-being for a period of time
but are not expected to improve overall survival. A variety of
terms have been used to designate lesser responses (e.g., minor
by repeat assessments no less than 4 weeks after the criteria for response are first
met. The duration of overall response is measured from the time that criteria and Supportive Care
are met for CR or PR (whichever status is recorded first) until the first date
that recurrence or PD is objectively documented, taking as reference for PD the Chemotherapeutic regimens are universally toxic, with a narrow
smallest measurements recorded since the treatment started. margin of safety, and it is generally necessary to adjust individual
b
Target lesions include measurable lesions up to a maximum of 2 lesions per doses in accordance with patient tolerance. Initial dosing is derived
organ and 5 lesions in total, representing all involved organs, selected on the
basis of size (lesions with the longest diameter) and suitability for accurate from body surface area, weight, renal function, and hepatic func-
repeated measurements. tion. However, there are a number of other factors that could fur-
Nontarget lesions include all other lesions (or sites of disease) to be identified ther influence tolerance, including nutritional status, performance
and recorded at baseline. Serial measurements of these lesions are not required, status, extent of disease, exposure to prior therapy, third-space
but the presence or absence of each should be noted throughout follow-up. fluid accumulations, metabolic polymorphisms, and uncharacter-
c
In the case of SD, follow-up measurements must have met the SD criteria at least ized drug interactions. Current dose algorithms generally fail to
once after study entry at a minimum interval (in general, not less than 6 to 8 weeks)
that is defined in the study protocol. SD is measured from the start of the treatment address these factors, although emerging pharmacodynamic and
until the criteria for disease progression are met, taking as reference the smallest pharmacogenomic research has improved individualized dosing
measurements recorded since the treatment started. in selected cases.
358 CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER
Optimal dosing in obese patients has been questioned, as or combinations, essentially deviating from FDA-approved indi-
the distribution and metabolism of drugs within adipose tis- cations. As these modifications become integrated with clinical
sue could vary from other compartments. Obesity is also a risk practice, limited supporting data emerge, usually from nonran-
factor for cancer development and is common in the setting of domized trials, but the primary FDA-approved dose and schedule
endometrial cancer. In addition obesity is associated with a num- is rarely changed. Many agents in common use today, including
ber of other comorbidities or metabolic conditions that could polyethylene glycol (PEG)-liposomal doxorubicin, topotecan,
alter drug kinetics or the risk of toxicity. For these reasons, and paclitaxel, docetaxel, and gemcitabine, are frequently modified in
in view of toxicity observed within previously radiated endome- accord with emerging clinical experience, but without changes in
trial cancer patients, GOG has previously capped the body sur- the FDA-approved regimen. It is thus important for the clinician to
face area (BSA) used for initial drug dosing to a value of 2.0m2. be aware of emerging data, as well as data from pivotal trials that
However, actual data to reinforce this decision are limited (140), were used to support original FDA registration.
and a recent guidelines panel recommended that obese patients In view of the narrow safety margin for chemotherapy, it is
should receive full weight-based dosing without arbitrary reduc- important that all orders be reviewed by a nurse and pharmacist
tions or caps (141). with oncology experience. Height, weight, calculation of body
Consistent and standardized monitoring of host toxicity will surface area, ideal weight adjustments (if appropriate), pertinent
help to avoid life-threatening events and assist in the implemen- laboratory values, and methods of dose calculation should be
tation of dose adjustments. The Cancer Therapy Evaluation clearly indicated and verifiable. Templated orders encourage
Program (CTEP) of the NCI has developed a detailed and compre- systematic review and can reduce the risk of error. In addition, it
hensive set of guidelines for the description and grading of acute is preferable to have defined dose levels to account for expected
and chronic organ-specific toxicity in collaboration with the FDA, treatment modifications rather than relying on percentage-based
international cooperative groups, and the pharmaceutical industry. modifications. For example, it is not always obvious if a percent-
Most clinical research protocols have incorporated these criteria, age refers to the degree of dose reduction or the amount of drug
which are also applicable to the grading of toxicity for standard to be administered, which becomes compounded over multiple
chemotherapy regimens outside of a clinical trial. The current cycles, with the potential for more than one modification. One
version of the Common Terminology Criteria for Adverse Events convenient method of structured dose modification is illustrated
(CTCAE) is available in electronic format from CTEP (http://ctep. in Table 13.10. With this approach, modifications for the sub-
cancer.gov/protocolDevelopment/). Basic hematologic parameters sequent course of therapy are implemented according to the
from CTCAE version 4 have been summarized in Table 13.9.
An unintended consequence of our current regulatory envi-
ronment is that most new medications receive single-agent FDA
approval at a dose and schedule that is close to the maximally Table 13.10 Representative Drug Dose
tolerated dose (MTD), increasing the likelihood of host toxicity, Modifications for Hematologic Toxicity
particularly when administered over multiple cycles. The associa-
tion between dose and toxicity is usually dramatic at levels close Category CTCAE Dose or Schedule
to the MTD. As such, a modest reduction in dose or an adjust- (Timing) Parameters Grade Modifications
ment in schedule can have a substantial impact on acute and Granulocytes >1,500/mm3 0, 1 Full doses of all drugs.
cumulative toxicities. The impact of these minor modifications (day of
<1,500/mm3 2, 3, 4 Delay until recovered.
on efficacy is generally unknown, but unlikely to be as dramatic therapy)
If delay >7 days, reduce
as the impact on toxicity, and many clinicians frequently make doses by one level or add
modifications in the starting dose and/or schedule of single agents G-CSF. If delay >14 days,
reduce doses by one level
and add G-CSF.
Table 13.9 CTCAE Grading of Myelosuppression Platelets WNL 0 Full doses of all drugs.
(day of
Grade therapy) < LLN to 1 Delay until recovered.
75,000/mm3
Adverse Event
Terminology 1 2 3 4 <75,000/mm3 2, 3, 4 Delay until recovered.
If delay >7 days, reduce
White LLN <3,000 <2,000 <1,000 doses by one level.
Blood Cell to to to
Decreased 3,000 2,000 1,000 Granulocytes >1,000/mm3 0, 1, 2 Full doses of all drugs.
(per mm3) (cycle nadir)
<500/mm 3
4 Reduce doses by one level.
Neutrophil LLN <1,500 <1,000 <500 for 7 days If already reduced, add
Count to to to G-CSF for future cycles.
Decreased 1,500 1,000 500 <1,000/mm3 3, 4 Add G-CSF for current
(per mm3) with fever episode, reduce doses by
Anemia LLN to <10.0 <8.0; Life-threatening one level for future cycles.
(Hemoglobin) 10.0 to 8.0 transfusion consequences, If already reduced, add
(g/dL) indicated urgent G-CSF for future cycles.
intervention Platelets 50,000/mm3 3 Full doses of all drugs.
indicated (cycle nadir)
<50,000/mm 3
3, 4 Reduce doses by one level.
Platelet Count LLN <75,000 <50,000 <25,000 with bleed
Decreased to to to
(per mm3) 75,000 50,000 25,000 <25,000/mm3 4 Reduce doses by one level.
LLN, lower limit normal (institutional). CTCAE, Common Terminology Criteria for Adverse Events; G-CSF, granulocyte
colony-stimulating factor; LLN, lower limit normal; WNL, within normal limits.
Source: CTCAE, Common Terminology Criteria for Adverse Events, version Dose reductions for individual drugs within a combination regimen should
4.03, Cancer Therapy Evaluation Program, National Cancer Institute. http://ctep. be based on the likelihood that a particular drug contributes to the observed
cancer.gov/protocolDevelopment/ (Published June 14, 2010). hematologic toxicity.
CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER 359
degree (grade), duration, and timing of toxicity experienced dur- auditing (146,147). A Medicare National Coverage Determi-
ing the preceding course. Although treatment can be delayed on a nation also limited reimbursement to patients with confirmed
week-by-week basis to allow for recovery, delays of greater than hemoglobin of >10 g/dL (148). Patients with anemia should
2 weeks should be avoided through dose modification and utiliza- undergo evaluation of iron stores, with appropriate use of iron
tion of hematopoietic growth factors. With expanded utilization replacement, prior to initiation of ESA.
of combination regimens, it is also helpful to know the patterns of
toxicity associated with individual drugs, as it might be appropri-
ate to modify one component rather than an entire regimen.
Gastrointestinal Toxicity
Most anticancer agents are associated with some degree of
nausea, vomiting, and anorexia. There are 3 major categories
Bone Marrow Toxicity of nausea and vomiting: anticipatory, occurring prior to actual
Bone marrow toxicity is the most common dose-limiting side administration of chemotherapy; acute onset, beginning within
effect associated with cytotoxic drugs, and neutropenia is the 1 hour of chemotherapy administration and persisting for less
most common manifestation of bone marrow toxicity, occurring than 24 hours; and delayed, beginning more than 1 day after
7 to 14 days after initial drug treatment and persisting for 3 to chemotherapy administration and persisting for several days.
10 days. CTCAE grading criteria are summarized in Table 13.9. Prophylactic management of these adverse effects improves
For purposes of dose modification, the absolute neutrophil count patient acceptance and facilitates completion of therapy with
following 5-fluorouracil-based chemotherapy or radiation have utilization of central venous ports, as malfunctions in the needle,
failed to document any clinical improvement with sucralfate, hub, or tubing can be associated with gradual extravasation that
which can bind to ulcerated mucosa (152,153). However, ran- will not be apparent for several hours (159). Small series have
domized placebo-controlled trials have demonstrated that mul- reported a limited experience with local infiltration or topical
tiple intravenous doses of recombinant keratinocyte growth application of steroids, n-acetylcysteine, dimethyl sulfoxide
factor (palifermin) before and after treatment can reduce the (DMSO), and hyaluronidase, with variable results, and recom-
incidence and severity of chemotherapy-induced oral stomatitis mendations are imprecise. However, single or multiple intrave-
associated with bolus 5-fluorouracil (154), high-dose chemo- nous doses of dexrazoxane, a topoisomerase II catalytic inhibitor,
therapy, or concurrent chemoradiation (155,156). In general, appear to offer specific protection against injury from anthracy-
dose-limiting mucosal injury is uncommon with platinum-based clines, including doxorubicin and daunorubicin (160,161). Skin
combinations, taxanes, and other single agents used in the treat- necrosis from some extravasations may eventually require surgi-
ment of gynecologic cancer. While many patients might develop cal debridement and skin grafting.
some degree of diarrhea in the setting of concurrent pelvic
chemoradiation, palifermin has not been specifically evaluated
in that setting.
In refractory cases, patients should be screened for secondary Neurotoxicity
infectious complications, such as candidiasis and herpes simplex. Peripheral neuropathy is the most common neurotoxicity
Following treatment with irinotecan, noninfectious secretory diar- encountered in gynecologic oncology and is a particular risk with
rhea is a well-recognized dose-limiting toxicity associated with administration of cisplatin, paclitaxel, docetaxel, nanoparticle
local exposure to the active metabolite SN-38 and is generally albumin-bound (NAB) paclitaxel, epothilones, Vinca alkaloids, and
managed with prophylactic antimotility agents and intravenous hexamethylmelamine (162,163). Although less common with
hydration, with utilization of octreotide in severe cases. Diarrhea carboplatin than cisplatin, neuropathy can still occur, particu-
can also result from diffuse mucosal injury following adminis- larly in combination with paclitaxel. Peripheral neuropathy gen-
tration of doxorubicin (including PEG-liposomal doxorubicin), erally begins with symptoms of paresthesia accompanied by loss
5-fluorouracil, methotrexate, and other agents. In the setting of of vibratory and position sense in longer nerves associated with
recent surgery and chemotherapy, patients are also at increased the feet and hands. It then progresses to functional impairment,
risk for infectious diarrhea, and screening for Clostridium difficile with gait unsteadiness and loss of fine motor coordination, such
is appropriate. as trouble buttoning clothes and writing. This is closely followed
by loss of deep tendon reflexes and eventual development of
motor weakness. With paclitaxel and other nonplatinum agents,
this is almost always reversible but may require several months
Alopecia posttherapy for substantial improvement. In more severe cases,
Scalp alopecia is one of the most emotionally taxing side effects accompanied by neuronal injury or demyelination, recovery may
of chemotherapy. Aside from long-lasting alopecia that follows require active neuronal regeneration over an extended period of
cranial irradiation, it is almost always reversible, but it can be a time, and symptoms may persist for the lifetime of the patient.
major deterrent to successful chemotherapy. Total scalp alopecia In current clinical practice, neurotoxicity from widely utilized
is particularly common with drugs like doxorubicin and pacli- microtubule-stabilizing agents is predominant (164,165). The
taxel, and there is generally some degree of partial alopecia with frequency of moderate to severe toxicity is more common with
cisplatin, carboplatin, cyclophosphamide, docetaxel, Vinca alka- paclitaxel, compared to docetaxel or epothilones. Risk appears
loids, and 5-fluorouracil. In a minority of cases, patients treated related to peak levels associated with individual doses, as well as
with paclitaxel will also experience loss of eyelashes, eyebrows, cumulative doses over multiple cycles, which is further compli-
and other body hair, which can be particularly distressing. cated by alternative schedules and newer drug formulations. For
A variety of physical techniques have been devised to minimize example, although the risk associated with NAB-paclitaxel on the
alopecia, including scalp tourniquets and ice caps designed to FDA-approved 3-week schedule is at least as high as paclitaxel
decrease scalp blood flow. Although partially effective, they are (166), the risk is reduced with NAB-paclitaxel administered on a
rarely successful with extended chemotherapy. weekly schedule, even with higher cumulative doses. In addition,
as the primary means of assessment is clinical, reported frequen-
cies vary widely in clinical trials, reflecting variability in docu-
menting history, and subjective and objective findings.
Skin Toxicity If related to cisplatin, neuropathy can continue to progress
Skin toxicities that occur during chemotherapy include allergic after therapy has been discontinued owing to ongoing axonal
or hypersensitivity reactions (HSR), skin hyperpigmentation, demyelination and loss, with long-term persistence of symptoms.
photosensitivity, radiation recall reactions, nail abnormalities, Cisplatin has also been associated with permanent ototoxicity
folliculitis, palmar-plantar erythrodysesthesia (PPE, hand-foot and, at higher doses, with loss of color vision (167) and auto-
syndrome), and local extravasation necrosis. Many of these are nomic neuropathy. Oxaliplatin can produce a long-term periph-
drug specific and self-limited, but occasionally they may be dose eral neuropathy similar to cisplatin (168), but it is also associated
limiting. with transient acute reactions, including paresthesia and cold-
PPE is a reversible but painful erythema, scaling, swelling, or sensitive laryngeal dysesthesia (169), which may reflect blockade
ulceration involving the hands and feet. This occurs more often of membrane ion channels (170). Infusions of calcium and mag-
with chronic oral or intravenous medications, weekly treatment nesium have been used to ameliorate acute oxaliplatin reactions
regimens, and formulations that increase drug circulation time, (171), but the potential risk of interfering with clinical response
such as prolonged oral etoposide, weekly and continuous-infusion has not been resolved.
5-fluorouracil, capecitabine, and PEG-liposomal doxorubicin, Although some patients report transient distal paresthesia
where it has emerged as a major dose-limiting toxicity (157). after a single dose of paclitaxel, the onset of persistent neuropa-
Extravasation necrosis is a serious complication seen after thy is generally more gradual. Neuropathy can become clinically
tissue infiltration of vesicant drugs such as doxorubicin, dactino- apparent after 2 to 3 courses of therapy, with mild symptoms that
mycin, mitomycin C, and vincristine (158). These drugs should resolve between cycles. Careful questioning and examination may
always be administered through a freely flowing intravenous reveal subtle findings at an earlier stage, and functional assess-
line with careful monitoring. Caution is also required during ments have been developed that demonstrate good concordance
CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER 361
Genitourinary Toxicity
Renal toxicity is a well-recognized side effect of cisplatin, with Other Significant Toxicities
implication of specific local metabolites, even though only a A comprehensive discussion of all potential toxicities for cur-
small fraction of cisplatin is cleared by renal excretion. In con- rently available chemotherapeutic agents is beyond the scope
trast, carboplatin undergoes extensive renal clearance with little of this chapter, and additional information is available through-
risk of toxicity. Indeed, with increased substitution of carbopla- out the text. Nevertheless, a variety of other important toxici-
tin for cisplatin, and with a reduction in overall cisplatin dose ties are occasionally encountered in regimens commonly used
intensity, there has been a decline in clinical familiarity with in gynecologic oncology. These include cardiac toxicity from
cisplatin-mediated nephrotoxicity. However, the expanded uti- cumulative doxorubicin exposure, radiation recall vasculitis
lization of concurrent cisplatin and pelvic radiation for manage- from doxorubicin, pulmonary fibrosis from bleomycin, gonadal
ment of early-stage cervical cancer has renewed awareness of dysfunction in premenopausal women from alkylating agents,
this potential problem, particularly as commonly utilized weekly and secondary acute leukemia from the chronic administration
dosing can exceed 100 mg/m2 over a 3-week period. Careful of alkylating agents, particularly melphalan, in ovarian cancer.
attention to hydration status and saline-driven urinary output
before, during, and immediately after therapy is required to
reduce the risk associated with this serious complication (177).
Another troublesome side effect is hemorrhagic cystitis, DEVELOPM ENTAL CH EMOTH ER APY
which can be seen with cyclophosphamide or ifosfamide, attrib-
uted to the metabolite acrolein. With moderate-dose cyclophos-
phamide, this complication can be prevented by maintaining Background
high urinary output, which reduces overall urothelial exposure The identification, evaluation, and regulatory approval of effec-
to the toxic metabolites. However, patients receiving combina- tive drugs for cancer treatment is a long, complicated, and
tion regimens often have reduced oral intake postchemother- expensive process. Of note, it has been argued that the expanded
apy, and selected patients receiving cyclophosphamide might availability of only 17 existing generic chemotherapeutic agents
benefit from supplemental intravenous hydration. The risk of would substantially improve worldwide mortality from cancer
cystitis is essentially 100% with ifosfamide, even with aggressive (185). However, most cases of advanced disease remain incurable
hydration, but this can be prevented with simultaneous admin- with current treatments. Promising candidates are identified and
istration of mesna, which binds and neutralizes acrolein in the prioritized through preclinical screening, utilizing derivatives
urine (178). of previously defined active agents or established drug classes or
362 CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER
new compounds engineered to interact with a specific target. In treated at very low (nonefficacious and nontoxic) doses, while
addition, there continues to be broad screening of natural prod- providing greater precision for estimating the MTD and DLT at
ucts isolated from terrestrial and marine sources (186). Some higher doses.
evidence of antitumor activity during screening must be demon- With the shift from conventional cytotoxic agents to molecular-
strated before clinical trials are undertaken. Thus far, all useful targeted agents, the traditional phase 1 paradigm needs to be
antitumor agents have demonstrated antitumor activity using in reexamined. Many agents, such as human monoclonal antibod-
vitro or in vivo screening systems. ies, may not demonstrate traditional dose-limiting or dose-related
These traditional approaches are being increasingly chal- toxicities, and phase 1 studies can reach their highest predeter-
lenged by the large number of new genes and potential targets mined dose level without achieving DLT or defining a tradi-
identified through molecular biology, genomics, and proteomics. tional MTD. In addition, these agents are frequently intended
Principles of genomic libraries, solid-phase organic synthesis, and for chronic administration, and cumulative toxicity over multiple
combinatorial chemical library generation have been adopted cycles is perhaps more relevant than acute toxicity during the first
by the pharmaceutical industry to promote high-throughput cycle. Finally, with an identified biologic target, it is also impor-
screening. As new targets are identified, a large number of tant to consider the optimal biologic dose that achieves a desired
related compounds can be created, beginning with lead natural level of receptor blockade or signal transduction inhibition. With
products or known reagents, and then screened for improved these considerations, it is apparent that a modified phase 1 design
target binding and/or inhibition of target function. Substantial utilizing expanded cohorts treated for multiple cycles, with labo-
bioinformatics resources are required to manage and analyze the ratory-based correlates, would provide better data to guide large
large amount of data generated from these processes, but the randomized trials.
accumulation of gene expression and proteomic data can facili- Tumor response is not a primary endpoint within a phase 1
tate pre-discovery modeling of potential targets and reagents trial, which will typically include patients representing a vari-
prior to making decisions about actual development. To some ety of primary tumor types with multiple prior therapies. Some
extent, these processes have evolved in parallel, as it is clear that phase 1 studies have included an expanded cohort to confirm
agents generated from a library or a database will still require safety and targeting, or an embedded phase 2 component to
some form of biologic validation prior to entering complex and estimate clinical activity. These integrated strategies conserve
expensive clinical studies. patient resources while accelerating the overall development
After antitumor activity has been identified, the new agent process, but with some risk of missing smaller treatment effects.
must be formulated for human use and produced in sufficient Phase 1 studies can also serve to evaluate new combinations
quantities to support clinical trials. This is never a trivial achieve- that build on standardized chemotherapy regimens to estab-
ment, as was evident from the natural supply limitations and lish feasibility and tolerability of the proposed regimen before
formulation problems encountered in early trials with paclitaxel embarking on larger trials. In certain situations, such as epithelial
(187) and the camptothecins (188). Clinical-grade material is ovarian cancer, phase 1 trials may enroll newly diagnosed patients
then subjected to detailed preclinical toxicology tests in animals. without prior therapy, as the experimental combinations gener-
These toxicology trials are done in several animal species and ally incorporate other known active agents.
may explore different schedules of drug administration to provide
a basis for clinical development. As such, they are time consum-
ing, complex, and expensive.
Phase 2 Trials
After all of the steps of preclinical testing are completed, new After the recommended dose and schedule have been defined,
agents can enter clinical evaluation. As such, clinical trials are the regimen can receive focused evaluation in patients with a
the primary means utilized to evaluate new agents in a system- specific cancer diagnosis, usually in the setting of measurable
atic manner. All physicians and patients are urged to consider disease after 1 (or 2) prior chemotherapy regimens. Phase
participation in clinical trials, which are available for almost all 2 trials are designed and powered based on a surrogate end-
diagnoses and treatment circumstances. Sponsors of clinical tri- point that is thought to reflect potential clinical benefit, such
als include the NCI in collaboration with individual institutions as response rate, disease stabilization rate, biochemical (tumor
and national groups, such as the GOG, as well as the pharma- marker) response rate, or the proportion of patients alive and
ceutical industry and individual institutions. progression-free at a specific time interval. In general, each phase
2 trial tests a single hypothesis, to determine if the new agent or
regimen crosses a threshold based on historical data in the same
patient population with an appropriate degree of power (type II
Clinical Trials or error) and precision (type I or error). Through this pro-
Detailed rationale and methodology for clinical trials design has cess, new agents are selected for further development or
been covered in other sections. This material is provided to high- rejected. In order to conserve patient resources and minimize the
light key concepts related to investigational drug development. number of patients who might receive ineffective therapy, most
phase 2 studies utilize a multi-stage accrual design with early-
stopping parameters, as proposed by Gehan (189) and modified
Phase 1 Trials by Simon (190).
Phase 1 trials are typically first-in-human studies for new com- This strategy was developed to efficiently screen conventional
pounds and employ a dose- and/or schedule-escalating design to cytotoxic agents, one at a time, without direct comparisons
determine the dose-limiting toxicity (DLT), maximally tolerated between agents. It has obvious limitations when applied to tar-
dose (MTD), and pharmacokinetic parameters applicable to geted molecular agents, which may not have the same potential
each regimen. In the most common model, accrual is suspended to elicit a measurable tumor response, or may be designed to
when more than one DLT event occurs within a dose level (2 work in conjunction with conventional therapy. As such, there
of 6 patients), as this would generally exceed predefined limits is a risk that modest but clinically important treatment effects
for the MTD. Modifications of the standard dose-escalation could be missed.
schema have been developed to enroll fewer patients at lower Traditional phase 2 trials utilize a single arm without ran-
dose levels with greater dose increments between successive dose domization. However, there are circumstances where random-
levels in the absence of toxicity. As the MTD is approached, the ization is appropriate (191193). Randomized phase 2 trials
dose level increments are reduced and accrual can be expanded. allocate patients among 2 or more treatment arms to minimize
These newer methods aim to minimize the number of patients potential differences in prognostic factors or other variables.
CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER 363
Each arm is then independently tested against the same histori- FDA Approval and Postmarketing Studies
cal threshold value. Using this approach, one or both arms can
be selected for further clinical development. Such randomized Following a successful phase 3 trial or, preferably, a group of
trials are generally underpowered for direct comparison of related trials, a sponsor can apply to FDA for marketing approval
response rate and survival between each arm, owing to the lim- for a specific disease indication. This triggers a detailed review
ited number of patients. of data by the Oncology Drug Advisory Committee (ODAC),
In view of the number of new agents that merit evaluation, which then issues a recommendation to FDA, followed by for-
it would be appealing to have a more efficient paradigm that mal review and a decision by FDA, which may grant approval
could incorporate combinations (with a reference arm) and or request additional data. In the United States, all commercial
offer the ability to compare and select among agents within marketing requires FDA approval for at least one specific indi-
the same general class. In practical terms, this has proven diffi- cation. The average time from initial drug discovery to applica-
cult, due to the need to involve multiple sponsors with different tion for an FDA-approved indication is 10 to 12 years, involving
investigational agents. When early-phase data appear interesting considerable expense and effort, as noted above. Supplemental
but might not support a fully powered phase 3 trial, there have phase 4 or postmarketing studies can be required by FDA as
been randomized designs that incorporate an embedded phase part of the approval process or be performed by the sponsor
2 component to confirm disease-specific activity and feasibility to evaluate alternative drug formulations or resolve questions
prior to enabling full phase 3 accrual. regarding dose, schedule, or toxicity. In addition, phase 4 stud-
ies may involve substitution of the new agent in combination
chemotherapeutic regimens already established for the disease.
evaluated in conventional phase 1 dose-escalating trials. Bone adopted in clinical practice (paclitaxel followed by cisplatin) is
marrow recovery usually proves to be the dominant factor in both less toxic and potentially more efficacious, and this was
cycle timing, and in practice most combinations can be repeated empirically extended to carboplatin-based combinations. In part,
every 3 to 4 weeks. Dose-dense strategies have also been devel- this sequence was based on practical considerations related to
oped using weekly or biweekly schedules. the risk of acute paclitaxel HSR, which can require interruption
Several combinations were evaluated in epithelial ovarian can- of treatment, and it was more acceptable to administer the car-
cer, in an effort to improve on the results obtained with a standard boplatin after it was clear that the patient had already tolerated
combination of carboplatin and paclitaxel (Table 13.12). Each of the paclitaxel.
the selected agents (topotecan, gemcitabine, and PEG-liposomal A different pattern was observed with sequences of platinum
doxorubicin) had demonstrated independent single-agent activity and topotecan. Preclinical models have consistently favored the
against recurrent ovarian cancer, and could interfere with repair of sequence of cisplatin followed by topotecan, which has been
platinum-DNA adducts, providing a clinical and scientific ratio- postulated to interfere with repair of platinum-mediated DNA
nale for the combinations. However, based on completed phase damage. In a phase 1 clinical trial, treatment with cisplatin on
3 trials in approximately 12,000 women, none of the combina- day 1 was associated with increased bone marrow toxicity,
tions achieved an improvement in clinical outcomes, providing compared with the reverse sequence (198). In this instance, the
additional support for a shift in developmental priorities toward sequence recommended for further clinical evaluation was also
molecular-targeted agents and other novel approaches (194). more toxic, and the question of antitumor efficacy remains to
be resolved. When combined with carboplatin, the risk of hema-
tologic toxicity was further accentuated, and a similar sequence-
Drug Interactions, Scheduling, dependent relationship was identified (199). Once again, higher
doses of topotecan could be safely administered using the reverse
and Sequence sequence of drug administration (with carboplatin on day 3).
Drugs should be used in their optimal dose and schedule. How- Topotecan has also been evaluated in sequence with docetaxel
ever, new combinations have the potential to alter the pharma- (200), showing a reduction in docetaxel clearance associated
cokinetics, bioavailability, toxicity, and efficacy of individual with increased neutropenia when topotecan was administered
components based on substrate-dependent effects, such as a prior to docetaxel, emphasizing that each new combination may
reduction in nucleotide pools or altered metabolism. Therefore, require independent evaluation.
the optimal dose and schedule for individual agents within a Even with a single drug, the schedule of administration can
combination might differ from their use as single agents. have a significant impact on host toxicity and potential efficacy
As an illustration, the impact of sequence variations using (Table 13.13). Early studies with paclitaxel utilized an arbitrary
cisplatin or carboplatin with either paclitaxel or topotecan has 24-hour infusion, which was selected to reduce the risk of HSR.
been explored in phase 1 clinical trials. Prior administration Preclinical data suggested that prolonged exposure (96 hours)
of cisplatin can delay subsequent clearance of paclitaxel when might have greater efficacy. Owing to increased bone marrow
administered as a 24-hour infusion (195). The mechanism for and mucosal toxicity, the MTD was lowered, and the frequency
this effect is unknown, but it is not attributable to platinum- of serious neuropathy was reduced. However, the 96-hour
mediated renal dysfunction. Instead, it has been postulated to regimen was not demonstrated to have significant activity in
occur following cisplatin-mediated inhibition of cytochrome patients with recurrent ovarian cancer (201). In addition, the
P450 mixed-function oxidases that participate in paclitaxel efficacy of a 3-hour infusion was comparable to a 24-hour infu-
metabolism. This enzymatic effect is not shared by carboplatin, sion in a phase 3 trial (202), reinforcing a clinical shift toward
and prior carboplatin exposure has not been demonstrated to the convenient 3-hour schedule, which achieved a higher MTD,
interfere with clearance of paclitaxel. However, most combina- primarily due to a marked decrease in bone marrow toxicity, but
tions with carboplatin have utilized a shorter (3-hour) paclitaxel with an increased incidence of neuropathy. This was followed by
infusion, to minimize hematologic toxicity. Earlier preclinical phase 1 evaluation of a weekly low-dose 1-hour infusion, which
models had demonstrated enhanced cytotoxicity when pacli- was almost devoid of serious toxicity, including a decreased
taxel was administered prior to cisplatin and antagonism by incidence of alopecia, with maintenance of clinical efficacy
the reverse sequence (196, 197). Thus, the schedule ultimately (203). Thus, the optimal preclinical regimen (96-hour exposure)
CHAPTER 13 PRI NCI PLES OF CH EMOTH ER APY I N GYN ECOLOGIC CANCER 365
Table 13.13A Impact of Paclitaxel Infusion Duration and Schedule on Toxicity and Efficacy
Paclitaxel Dose and Schedule Dose-Limiting Toxicities
Infusion Dose Interval Single-Agent Unit Dose
Duration (hr) (wk) (mg/m2/d) Neutropenia Mucositis Alopecia Neuropathy Antitumor Efficacy
96 34 80120 +++ ++ +++ + +++
24 3 135 ++ 0 +++ ++ +++
3 3 175 + 0 +++ +++ +++
1 1 6080 0 0 + + +++
was superseded in the clinical setting by an unexpected series Topotecan was also evaluated as a prolonged intravenous infu-
of observations from empiric phase 1 trials, yielding decreased sion for 21 days to maximize the duration of exposure (207).
toxicity, improved convenience, and the potential for increased Although the study was conducted in a different patient popula-
efficacy. tion, the overall response rate (35%) was similar to the 5-day
Table 13.13B Impact of Topotecan Infusion Duration and Schedule on Toxicity and Efficacy
Topotecan Dose and Schedule Dose-Limiting Toxicities
Infusion Single-Agent Unit
Duration (days) Dose Interval (wk) Dose (mg/m2/d) Neutropenia Mucositis Alopecia Neuropathy Antitumor Efficacy
21 4 0.40 +++ 0 0 0 +++
5 34 1.25 +++ 0 0 0 +++
3 3 2.00 +++ 0 0 0 ++
1 3 8.50 +++ 0 0 0 +
1 1 1.75 ++ 0 0 0
1 1 4.00 + 0 0 0 +
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177. Santoso JT, Lucci JA 3rd, Coleman RL, et al. trial of a new chemotherapeutic agent. J Chronic and pharmacologic study of paclitaxel adminis-
Saline, mannitol, and furosemide hydration in Dis. 1961;13:346353. tered weekly in patients with relapsed ovarian
The determinants of effective cancer drug therapies include drug dependent on measuring multiple plasma levels, often at the
disposition, tumor kinetics, and drug resistance. These factors limit of drug assay sensitivity.
profoundly influence the cytotoxicity of each anticancer drug
and must be considered in designing therapeutic regimens.
These principles are discussed in Chapter 15. In this chapter, Pharmacokinetic Models
we elaborate on the basic and clinical pharmacology of can-
cer chemotherapeutic and biologic agents and provide a limited The pharmacokinetics of virtually all anticancer drugs requires
discussion of cytotoxic, molecularly targeted antiangiogenesis 2- or 3-compartment models for their mathematic description.
and modulating/supportive care drugs useful in the treatment of These models are commonly referred to as biphasic or triphasic
patients with gynecologic cancer. models (i.e., 2 or 3 phases observed on semilogarithmic plots).
Conceptually, the one-compartment model relates to a drug
that remains confined to the intravascular space after intra-
venous injection, and the 2- or 3-compartment model allows
the pharmacokinetic description of anticancer drugs whose
DETERM I NANTS OF EFFECTIVE ultimate targets are beyond the intravascular space in tumor
DRUG TH ER API ES tissues.
370
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 371
0.1
more hematologic, gastrointestinal, metabolic, and neurologic the IP space and optimize the IP clearance rates. Generally, it
toxicity compared to intravenous paclitaxel and cisplatin (7); is suggested to administer the IP drug dose in the first liter of
however, the dose of cisplatin on the IP arm was 33% higher peritoneal dialysate, followed by a second liter of dialysate to the
than that of the IV arm. When combining the toxicity data point of mild abdominal discomfort.
across IP randomized trials, only acute gastrointestinal toxicity Ultimately, the effectiveness of IP therapy depends on the
(p = 0.01) and fever (p=0.04) are significantly higher among inherent cytotoxic potency of the individual agent and its abil-
patients treated with IP therapy and ototoxicity was signifi- ity to penetrate from the outer surface to the inner core of IP
cantly higher among patients receiving IV treatment as com- tumors. The degree of tumor penetration depends on the molec-
pared to those receiving IP therapy (p = 0.004) (6). A study ular weight, charge, and chemical structure of the compound.
of patient quality of life within GOG-172 demonstrated that There is an inverse relationship between molecular weight and
patient quality of life was significantly lower during IP treat- tumor penetration. The higher the molecular weight of the anti-
ment compared to IV therapy, but 1 year after treatment, the cancer drug, the lower the degree of tumor penetration. Indeed,
overall quality of life of patients receiving IP or IV therapy was one advantage of cisplatin over carboplatin as an IP agent is its
equivalent (8). However, long-term neurotoxicity remained lower molecular weight. Los and colleagues (16) demonstrated
higher among patients treated with IP therapy. These short- and in IP ovarian cancer animal studies that it requires almost
long-term effects should be balanced against the documented 10 times more IP carboplatin than cisplatin to achieve similar
16-month improvement in survival compared with IV cisplatin/ intratumoral concentrations; however, there is renewed interest
paclitaxel (p = 0.03) (7). This increase in survival is similar to to develop IP carboplatin plus IP and IV paclitaxel regimens to
that achieved when IV cisplatin was initially added to primary reduce the potential for cisplatin-paclitaxel-induced peripheral
combination chemotherapeutic regimens for the treatment of neuropathy (see Special Applications, in Carboplatin section
this disease (9). below) (17).
The incremental increase in cisplatin efficacy associated
with IP administration likely results from the delivery of
approximately 20-fold greater concentrations of cisplatin
into the IP space than is achievable with IV administration.
Anticancer drugs with known activity against ovarian cancer
that undergo slow clearance from the IP space into the sys- PERIOPER ATIVE CH EMOTH ER APY
temic circulation without causing significant chemical perito-
nitis are the favored IP compounds. Clearly, paclitaxel falls
AS A PLAN N ED PART OF TH E
into this category. IP administration of this large taxane mol- CYTOREDUCTIVE SU RGICAL
ecule results in 1,000-fold greater concentration time prod- I NTERVENTION FOR PERITON EAL
ucts in the IP space than is achievable with IV administration M ETASTASES
(10). In contrast, cisplatin undergoes rapid clearance from
the systemic circulation after administration via the IP route. Oncologists agree that a combination of meticulous cytoreduc-
Caution must be taken when considering other agents for tive surgery plus treatment with cancer chemotherapy is nec-
research-based IP administration, as some cytotoxic agents essary for optimal treatment of gynecologic malignancies. The
have not demonstrated efficacy and have been associated with prevention and treatment of peritoneal metastases from ovarian
excessive toxicity when given IP (e.g., mitoxantrone, doxoru- cancer is the most obvious challenge for this combined treat-
bicin) (1114). ment plan. Also, endometrial cancer frequently causes perito-
As with the IV administration of anticancer drugs, the drug neal metastases and has been considered for not only systemic
clearance rate from the IP space is the most useful pharmacoki- but also local-regional (IP) chemotherapy administration. Uter-
netic parameter for comparing drugs that are administered by ine sarcoma is another gynecologic malignancy that may be
the the IP route in the treatment of ovarian cancer. The perito- significantly benefited. Finally, low malignant potential ovarian
neal clearance rate can be calculated by dividing the drug dose cancers that fail a surgery alone approach may progress with
by its IP concentration time product, which must be measured disease confined to the abdominal and pelvic surfaces. Cytore-
with repeated IP fluid content sampling. Intraperitoneal drugs ductive surgery with perioperative chemotherapy is a treatment
with slow clearance rates are favored because they result in pro- option for these patients.
longed exposure of the IP tumor bed to high concentrations of The principles of cytoreductive surgery utilizing visceral
anticancer drug. It is also possible to assess the pharmacokinetic resections and peritonectomy procedures have been well
characteristics of drug doses by comparing their peak IP concen- described in the gynecologic oncology and surgical oncology
tration with peak plasma concentration after IP dosing or com- literature. Surgical cytoreduction is an essential part of optimal
paring their IP concentration time product (AUCIP) with their treatment. However, chemical cytoreduction with cancer che-
plasma concentration time products (AUCIV) after IP dosing. motherapy employed as a planned part of the operative inter-
Virtually all commonly used drugs administered intraperitone- vention presents a new dimension in an attempt to optimize the
ally in patients with ovarian cancer have peak or concentration management of gynecologic malignancy (18). Hyperthermic
time product ratios of more than 20. In some cases, the perito- perioperative chemotherapy (HIPEC) is used in the operating
neal exposures can be much greater. For example, paclitaxel IP room as part of the surgical procedure. In addition, normo-
exposure with IP therapy is 300 to nearly 3,000 times greater thermic early postoperative IP chemotherapy (EPIC) is admin-
than with IV treatment (15). istered in the first few postoperative days. As surgeons have
Except for drugs whose cytotoxicity depends on continu- ascended the learning curve for this combination of extensive
ous exposure, such as cytarabine and methotrexate, drugs used surgery combined with perioperative chemotherapy, the mor-
by the IP route should be administered relatively rapidly in at tality rate has been reduced to 1% or less. Also, grade III and
least 2 L of peritoneal dialysate and remain within the perito- grade IV adverse events have been reduced to 20% (19). Most
neal space without removal. For schedule-independent drugs, it recent publications associate the morbidity and mortality with
is important to maintain high concentrations as long as pos- the extensive cytoreductive surgery and estimate the adverse
sible within the IP space to improve efficacy. It is of considerable outcomes from the perioperative chemotherapy to be unusual.
interest that as the IP dialysate volume decreases, a drugs IP Of course, knowledgeable management of both aspects
clearance rate increases rapidly. Thus, large volumes of IP fluid of the combined treatment is an absolute requirement for
increase the chances for uniform drug distribution throughout success.
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 373
gastrointestinal malignancy from the natural history of the dis- receiving 175 mg/m2 paclitaxel. Infection (generally oral can-
ease. As surgeons learn to modify their surgical procedures in didiasis and respiratory system events) occurred in approxi-
order to ensure a safe cytoreductive procedure, more effective mately 23% of patients receiving albumin-bound paclitaxel.
combinations of both IV and IP chemotherapy used as HIPEC Anemia occurred among 33% of patients (severe anemia in 1%
and EPIC become promising clinical approaches. of cases). Severe cardiotoxicity occurred in approximately 3%
of patients. Dyspnea (12%) and cough (6%) were also reported
among patients receiving albumin-bound paclitaxel. Patients
with neutrophil counts of less than 1,500 cells/mm3 should not
CLI N ICAL PHARMACOLOGY receive albumin-bound paclitaxel, as it may lead to bone mar-
OF ACTIVE DRUGS AGAI NST row suppression, which can result in infection.
GYN ECOLOGIC CANCERS
We discuss below in alphabetical order the clinical pharmacology Altretamine
of cytotoxic, biologic/molecularly targeted and modulating/
supportive care drugs with demonstrated activity against gyne- Chemistry
cologic cancers. We also include several U.S. Food and Drug Altretamine (hexamethylmelamine, Hexalen), a synthetic cyto-
Administration (FDA)-approved drugs for other indications that toxic antineoplastic s-triazine derivative, is FDA approved for
may prove active against gynecologic cancers. the treatment of persistent or recurrent ovarian cancer after
The terminal-phase plasma half-life ranges from 4.7 to 10.2 hours doxorubicin, and cisplatin (CHAP) without evidence of increased
(45). The interpatient variability of AUCs, ranging from 1.2 to hematologic toxicity (5456). Leukopenia below 3,000 cells/mm3
60.1 mg/L h, is most likely due to the differences in the rate at occurred in less than 15% of the patients on a variety of
which the drug is metabolized. intermittent- or continuous-dose altretamine regimens. Less
than 1% had leukopenia below 1,000 cells/mm3. When given in
Administration and Dosage high doses over a 21-day course, nadirs of leukocyte and platelet
counts were reached by 3 to 4 weeks, and normal counts were
The recommended dose for altretamine as a single agent for observed by 6 weeks. With continuous administration, nadirs
use in the palliative treatment of patients with ovarian cancer is are reached in 6 to 8 weeks.
260mg/m2/day, orally, for 14 to 21 consecutive days in a 28-day
cycle (46). The total daily doses should be given as 4 divided
oral doses after meals and at bedtime. Compliance to this regi- Bleomycin
men in a small group of patients with relapsed ovarian cancer Chemistry
was documented at greater than 95% (47). There is no pharma-
cokinetic information on this dosing regimen and the effect of Bleomycin (Blenoxane), an antineoplastic, is a mixture of com-
food on altretamine bioavailability in humans. In combination plex glycopeptides originally isolated from a strain of the fungus
regimens, altretamine is typically used at a dose of 150 mg/m2/day Streptomyces verticillis. The primary components are bleomy-
for 7 to 14 days of monthly cycles (48,49). cins A2 and B2. The family of bleomycin glycopeptides have a
Altretamine should be temporarily discontinued for 14 days or relatively high molecular weight and are quantitated in units
longer and subsequently restarted with a 20% to 25% dose reduc- of cytotoxic activity (i.e., roughly 1 U/mg of polypeptide pro-
tion for any of the following side effects: gastrointestinal intol- tein). Bleomycin is used as palliative treatment in patients with
erance unresponsive to symptomatic measures; leukocyte count advanced cervical (57) and vulvar cancers. Other clinical indica-
less than 2,000/mm3 or granulocyte count less than 1,000/mm3; tions include squamous-cell carcinomas of the head and neck,
platelet count less than 75,000/mm3; or progressive neurotoxic- lymphomas, and testicular carcinoma. The molecular formula
ity. If neurologic symptoms fail to stabilize on the reduced-dose of bleomycin A2 is C55H84N17O21S3 (molecular weight = 1,414),
schedule, altretamine should be discontinued. and the molecular formula of bleomycin B2 is C55H84N20O21S2
(molecular weight = 1,425).
Side Effects and Toxicities
Mechanism of Action
Altretamine is administered at a dose of 260 mg/m2 (single agent)
Although the exact mechanism of action is unknown, a key to
or 150 mg/m2 (in combination) on an intermittent schedule
its activity is the isolation of native compounds from S. verticillis
and is relatively well tolerated. Single-agent data for this drug
as coordinated Cu(II) complexes, which are inactive as anti-
are available for 1,014 patients (50). With high, continuous daily
tumor agents. When complexed with ferrous iron, bleomycin
dosing, nausea and vomiting were the dose-limiting toxic effects,
becomes a potent oxidase, producing DNA strand breaks by
and a form of reversible peripheral neurotoxicity occurred occa-
oxygen free radicals. Its unique mechanism of action is schedule
sionally. Myelosuppression was mild to moderate. Leukocyte
dependent and cell cycle dependent for the G2 phase.
and platelet counts usually recovered within 1 week of therapy
The oxygen radicals produced by the bleomycin-iron com-
discontinuation.
plex bound to DNA primarily cause single-strand breaks and
In a study of 395 patients with advanced ovarian cancer
to a lesser degree, double-strand breaks. There is a subsequent
treated with altretamine-containing combination regimens with
release of base propenals of all 4 DNA bases: guanine, thymine,
or without cisplatin, no additional effect of altretamine on the
adenine, and cytosine. These modified free bases result from
incidence or severity of neurotoxicity could be demonstrated
cleavage of the deoxyribose sugar at the 3 to 4 bond. There
(51). Peripheral neuropathy and central nervous system symp-
is an apparent specificity for the release of thymine and for
toms are more likely to occur in patients receiving continuous,
DNA binding at guanine-rich sequences in actively transcribed
high-dose daily altretamine administered on an intermittent
genes (58). The linker regions of DNA between nucleosomes
schedule than in those receiving moderate doses. Neurologic
comprise an important site for specific strand cleavage by bleo-
toxicity reverses after the drug is discontinued. Pyridoxine
mycin (59). Several mechanisms have been theorized to explain
should not be used concomitantly with altretamine to reduce
the development of resistance to bleomycin. Less important
neurotoxicity because clinical trials data suggest it may inhibit
mechanisms appear to include DNA repair, membrane altera-
cytotoxic activity. Concurrent administration of altretamine and
tions, and decreased drug accumulation. The primary mecha-
antidepressants of the monoamine oxidase (MAO) inhibitor
nism probably involves metabolic inactivation of bleomycin by
class may cause severe orthostatic hypotension. Cimetidine, an
a cytosolic hydrolase, which is in the cysteine proteinase fam-
inhibitor of microsomal drug metabolism, increased altretamines
ily. The enzyme inactivates bleomycin by replacing a terminal
half-life and toxicity in a rat model.
amine with a hydroxyl group. The distribution of bleomycin
In 2 phase II studies of single-agent altretamine, at a dose of
hydrolase appears to explain some of the relative resistance
260 mg/m2 for 14 to 21 days of each monthly cycle, the most
and sensitivity to bleomycin in normal tissues. Normal tis-
common toxicity was grade 2 to 3 nausea (23%) (52,53). In a
sues with high intrinsic hydrolase activities, such as the liver,
consolidation therapy phase II trial, only 3 patients (4%) experi-
spleen, intestine, and bone marrow, are not targets for bleomy-
enced any grade 4 toxicity: granulocytopenia (2 patients) and anx-
cins toxic effects. In contrast, lung tissues and skin have low
iety/depression (1 patient). The most common grade 3 toxicities
levels of hydrolase activity and are particularly susceptible to
were malaise, fatigue, or lethargy in 7 patients (7%) and nausea
bleomycin-induced toxicity. However, there appears to be no
in 6 patients (6%). Aside from these, there were no other grade
direct correlation between hydroxylase levels in tumor cells and
3 or 4 toxicities in more than 5% of patients (53).
bleomycin-induced cytotoxicity (59). The development of other
With continuous high-dose daily drug administration, nau-
methods of bleomycin metabolism by tumor cells may be
sea and vomiting of gradual onset occur frequently. Although in
responsible for the emergence of drug resistance (60).
most instances these symptoms are controllable with antiemet-
ics, the severity sometimes requires altretamine dose reduction
or, rarely, discontinuation. Drug Disposition
Data from 3 large clinical trials demonstrated that altretamine Bleomycin is eliminated predominantly by urinary excretion.
can be added to full therapeutic doses of cyclophosphamide, This accounts for 45% to 62% of a dose after 24 hours. In
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 377
the blood, the drug is rapidly cleared, and 2 phases of elimina- Infrequent side effects include headache, pain at tumor site, and
tion are apparent. As a practical point, this means that greater anaphylactoid reactions. An idiosyncratic reaction consisting
than 95% of a dose has been completely eliminated by 24 hours primarily of mucositis and skin rash has also been reported (74).
(about 6 half-lives) (61). If administered by an intracavitary
route, a large percentage of a bleomycin dose is absorbed, and Special Precautions
the fractional systemic bioavailability is approximately 45% for
intrapleural or intraperitoneal injections. The drug appears to Bleomycin should be used with extreme caution in patients with
efflux more slowly from the peritoneal cavity. This suggests that significant renal impairment or compromised pulmonary func-
there is significantly greater local drug retention in the intraperi- tion; frequent radiographs are recommended. Because up to 70%
toneal space. This may explain some of the drugs unique efficacy of a bleomycin dose is eliminated by renal excretion, the bleo-
by intracavitary administration (62,63). An increased exposure mycin dose should be reduced for individuals with severe renal
to drug in these local compartments is also reflected by the ten- insufficiency. Unfortunately, there are no prospectively evaluated
fold higher drug levels achieved with IP or intrapleural therapy dosing nomograms for bleomycin dose adjustment. An empiric
than with equivalent IV dosing. dose-adjustment formula has been described (64). The percent-
Renal insufficiency markedly alters bleomycin elimination age dose reductions that are indicated by applying this for-
(64,65). This effect becomes most pronounced in patients with mula to a normal creatinine clearance (CrCl) of 120mL/min
creatinine clearance values less than 25 to 35 mL/min (64). In and a fractional urinary drug excretion of 0.45 are as follows:
these patients, the volume of distribution is unaltered at about CrCl > 35 mL/min, no dose reduction required; CrCl=20 mL/
min, 50% dose reduction; CrCl = 15 mL/min, 52% dose reduc-
CrCl = Creatinine clearance; Age = Age in years; Sex = 1 if review, transient elevations in serum creatinine and blood urea
female, 0 if male; SCr = Serum Creatinine in mmol/L; Wt = nitrogen were described in 7% and 16% of patients, respec-
Weight in kg. tively (113). Measured creatinine clearances dropped in 25%
Both the CG calculation of creatinine clearance and creatinine of patients, and a slight increase in uric acid was described in
clearance based on a 24-hour urine collection result in a system- the same percentage of patients. However, there can be a sig-
atic underestimation of the carboplatin AUC by approximately nificant loss of serum electrolytes, including potassium (16% of
10% (103105). This level of bias may be deemed acceptable in patients) and magnesium (37%). Serum calcium is only rarely
view of the clinical utility of substituting creatinine clearance for decreased after carboplatin treatment (113).
GFR. Significantly, the accuracy of the CG calculation depends A few cases of carboplatin-induced hematuria have been
on the method used for measuring creatinine. When the CG described. Hepatic enzyme elevations occasionally occur with
formula was derived, a colorimetric reaction was used that sig- carboplatin (113). Alkaline phosphatase was transiently increased
nificantly overestimates the plasma level of creatinine. A more in 36% of patients and serum glutamic oxaloacetic transami-
accurate measurement uses an enzymatic method (106). The use nase (SGOT) or serum glutamic pyruvic transaminase (SGPT) in
of a more accurate method combined with the CG formula leads about 15% of patients. Serum bilirubin levels are rarely elevated
to an unexpectedly high dose of carboplatin. Recently, creati- (4%) (113).
nine measurements in the United States have been standardized Neurotoxicity is uncommon after carboplatin and was
using isotope dilution mass spectrometry, leading to potential described in only 25 of 428 (6%) patients treated on a variety of
overdosage in some trial protocols and a recommendation for schedules for different tumor types (113). Mild paresthesias have
a dose cap (107). The issue of using a creatinine-based estimate been reported in a few patients receiving cumulative carboplatin
of the GFR has been approached by Wright et al. (106) where doses of more than 1.6 g/m2 (111). Unlike cisplatin, these periph-
alternatives to the CG formula are proposed for use with differ- eral nerve toxicities rarely produce any disabling symptoms. In
ing creatinine assays. most cases, no neurotoxicity was attributed to the drug.
The Calvert formula has been prospectively evaluated by Ototoxicity does not appear to be problematic with carbo-
Sorenson et al. (108) in 24 previously untreated ovarian cancer platin, and only 8 of 710 (1.1%) patients have described clinical
patients and was found to predict more accurately carboplatin hearing deficits, mainly tinnitus (113). However, if pretreat-
exposure than calculation of dose based on body surface area. ment and serial audiometric tests are performed, as many as
The AUC of carboplatin as calculated by the Calvert formula 15% of the patients may have some decrease in audio acuity.
accurately predicted the level of myelosuppression as deter- Fortunately, ototoxicity from carboplatin sometimes improves
mined by the relative decrease in the platelet count (108). after therapy is halted. Like cisplatin, greater ototoxicity from
Although formula-based dosing is normally used, the rec- carboplatin can be expected in patients with preexisting hearing
ommendation dosage for single-agent carboplatin in mg/m2 loss or in those concurrently being given other ototoxic drugs,
in ovarian cancer patients with good bone marrow reserve, based such as aminoglycosides.
on body surface area, is 360 mg/m2 given IV every 4 weeks. Other rare carboplatin toxicities include alopecia (2% of
Because renal excretion is the primary route of carboplatin elim- patients), mucositis (2%), skin rash (1.7%), injection-site irrita-
ination, the carboplatin dose must be reduced for patients with tion without extravasation necrosis (0.4%), and a flu-like syn-
compromised kidney function. The drug manufacturers pack- drome (1.3%) (113). The same study described alterations in taste
age insert recommends carboplatin doses of 250 and 200 mg/m2 sensation. Skin disorders from carboplatin treatment may appear
for patients with creatinine clearances of 41 to 59 and 16 to 40 as an erythematous rash in exposed areas and do not occur in all
mL/min, respectively. patients who had developed similar rashes on cisplatin (111).
The most frequently used primary chemotherapeutic regi- Although carboplatin-associated hypersensitivity reactions
men for advanced ovarian cancer is a combination of paclitaxel rarely occur when the drug is administered as part of an ini-
(175 mg/m2 by 3-hour IV infusion) followed by carboplatin (at tial chemotherapeutic regimen, subsequent administration of
a targeted AUC of 5 or 6 by 30- to 60-minute IV infusion) every carboplatin in the setting of second-line or salvage therapy is
21 days (if blood counts are adequate) for 6 cycles (109). associated with an increased risk of hypersensitivity. It has been
estimated that greater than 25% of patients who receive more
than 6 courses of platinum-based (i.e., cisplatin or carbopla-
Side Effects and Toxicities tin) chemotherapy develop sensitivity to carboplatin (114). The
Although the activity is comparable to cisplatin, carboplatin is onset of symptoms may occur during the carboplatin infusion
better tolerated, as measured by toxicity [e.g., low incidence of or up to 3 days after drug administration. Mild reactions consist
alopecia (110)] and quality of life analysis (91). The usual dose- of localized itching and erythema, primarily of the palms and
limiting toxicity of carboplatin is bone marrow suppression, soles, and/or facial flushing, whereas severe reactions can cause
particularly thrombocytopenia (111). Leukopenia and anemia diffuse erythema, tachycardia, wheezing, facial edema, chills,
also occur but are less severe. rigors, throat and chest tightness, dyspnea, vomiting, alterations
The platelet nadir is achieved 2 to 3 weeks after an IV bolus in blood pressure (both hypotension and hypertension), and in
injection, and recovery is generally complete 4 to 5 weeks after extreme cases, respiratory arrest. Mild cases may respond to
dosing. However, patients with poor bone marrow reserve from IV diphenhydramine (50 mg) or oral diphenhydramine (25 to
previous chemotherapy or radiation therapy can have more pro- 50 mg every 4 to 6 hours), and additional courses of carbo-
found thrombocytopenia and leukopenia with carboplatin treat- platin can be administered. Severe hypersensitivity reactions
ment. Cell depletion may persist for several weeks after dosing. typically necessitate the discontinuance of carboplatin; how-
Nausea and vomiting induced by carboplatin is much less ever, some patients are able to receive additional courses of
severe than with cisplatin and rarely lasts beyond 24 hours. In a carboplatin with administration of corticosteroids for several
study of 943 ovarian cancer patients randomized to carboplatin, days prior to carboplatin administration. Hypersensitivity
only 9% experienced greater than grade 2 nausea and/or vomit- reactions may also occur when carboplatin is administered
ing (110). Emesis can usually be blocked entirely with aggressive by the IP route (115).
therapy using antiemetic drug combinations (112). Diarrhea has Platinum-based chemotherapy (either cisplatin or carboplatin)
been reported in only 6% of patients and constipation in 3% of has been shown to increase the risk of leukemia in ovarian can-
carboplatin-treated patients (113). cer patients (116). Following carboplatin-based chemotherapy,
Nephrotoxicity has been reported with carboplatin, but it is the estimated relative risk of leukemia is 6.5 (95% confidence
much less common and less severe than with cisplatin. In a large interval, 1.1 to 9.4). The relative risk increases as a function of
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 381
both cumulative dose and duration of treatment. Patients who possible efficacy of IP carboplatin and trials to determine the
receive 4,000 mg or more of carboplatin have a relative risk optimal dosing schedule.
of 7.6 of developing leukemia, whereas patients who receive Because of its relative lack of nonhematologic side effects,
more than 12 months of carboplatin-based chemotherapy have carboplatin has become the platinum analog of choice for bone
a relative risk of 7.0. Although radiation therapy alone does not marrow transplantation regimens. A regimen developed at
increase the risk of leukemia, radiation therapy administered in Loyola University that consists of high-dose carboplatin com-
combination with platinum-based chemotherapy is associated bined with cyclophosphamide, mitoxantrone, and autologous
with a significantly higher risk of leukemia than platinum-based bone marrow support was selected for an intergroup phase III
chemotherapy without radiation (p = 0.006). The average time study of high-dose versus standard-dose chemotherapy for ovar-
to onset of secondary leukemia is 4 years after the diagnosis of ian cancer patients with low-volume, persistent disease follow-
ovarian cancer. Although the potential benefits of platinum-based ing primary chemotherapy (GOG-164). Although this study was
chemotherapy for ovarian cancer far outweigh the risk of sec- closed in May 1999 because of inadequate patient accrual, the
ondary leukemia, the dose-dependent leukemogenic potential of high-dose regimen was well tolerated among the 24 patients on
platinum-based chemotherapy should be considered during its the trial. With adequate hydration and mannitol diuresis to pre-
administration to patients with early-stage disease. vent nephrotoxicity, nonhematologic side effects were predomi-
With the high doses of carboplatin used in autologous bone nantly mucositis, ototoxicity, and diarrhea (117).
marrow transplantation programs, other severe toxicities may
occur. These include hepatotoxicity (both hepatitis and cholesta- Cisplatin
In vitro studies have shown that the copper transporter, CTR1, complexes if directly admixed with mannitol and stored for 2to
plays a regulatory role with respect to the uptake of platinum 3 days (149). Short-term (<24 hours) admixtures, however, have
drugs (139). In a study of 40 patients with ovarian carcinoma, been successfully used. Needles or IV sets containing aluminum
Yoo-Young Lee et al. showed that high CTR1 expression was should not be used in the preparation or administration of cis-
specifically associated with sensitivity to platinum-based therapy platin, because this drug rapidly reacts with aluminum, resulting
and prolonged progression-free survival while low CTR1 expres- in a loss of drug potency and the formation of a black precipi-
sion and high STR2 expression were associated with resistance tate (150).
to platinum-based therapy and shorter survival (140). To protect against nephrotoxicity, it is critical that a high
Mechanisms of resistance also include the increased inac- urinary output be maintained during cisplatin therapy. Several
tivation of thiol-containing proteins such as glutathione and methods of accomplishing this have been recommended; how-
glutathione-related enzymes, a deficiency in mismatch repair ever, the most widely practiced method involves prehydration
enzymes (e.g., hMHL1, hMSH2), and decreased drug accumu- and mannitol diuresis (151). If cisplatin is administered in a
lation due to alterations in cellular transport (79). hospital setting, patients should receive hydration with 1 to 2 L
A study of hMLH1 methylation in the plasma DNA of of fluid prior to cisplatin. Mannitol diuresis is accomplished by
ovarian cancer patients at presentation and relapse showed no diluting the cisplatin in 2 L of normal saline containing 37.5 g
correlation with outcome at presentation, but high methylation of mannitol. The solution is then infused over 6 to 8 hours. Ade-
was associated with poorer outcome following relapse (141). quate hydration and urinary output should be maintained during
Whether this was due to resistance to platinum drugs is not the next 24 hours. A safe outpatient procedure using concur-
clear because the report does not document the treatments given rent mannitol that appears to prevent serious nephrotoxicity has
following relapse. Further, a follow-on randomized phase II also been reported (152). The desired dose of cisplatin plus 50 g
study using decitabine to induce demthylation of the HMLH1 mannitol is diluted to 1 L with 5% dextrose plus 0.45% sodium
promoter showed an inferior outcome in the decitabine arm chloride, USP. This solution may then be infused at a rate of no
(142). The clinical relevance of mismatch repair defects in the more than 1 mg/min. For patients with known cardiac disease, the
response to platinum agents remains uncertain. dose may be placed in 200 mL of a 10% mannitol solution and
Recent evidence also suggests that resistance to platinum and infused at a rate of no more than 1 mg/min. This is followed by
other agents may be mediated by factors in the tumor environ- 200 mL of additional 10% mannitol. An alternative is to add the
ment rather than in the tumor cell itself. Roodhart et al. have drug to 400 mL of 10% mannitol that is then brought up to a 1-L
identified 2 distinct platinum-induced polyunsaturated fatty volume with normal saline containing 3 g of magnesium sulfate
acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and and administered IV over 1 hour (153).
hexadeca-4,7,10,13-tetraenoic acid (16:4[n-3]), that in minute Intraperitoneal cisplatin administration and nursing guide-
quantities induce resistance to a broad spectrum of chemothera- lines are described in detail elsewhere (154,155), using the
peutic agents, including platinum agents (143). GOG-172 regimen adapted to a 3-hour paclitaxel infusion
(IV paclitaxel 135 mg/m2 over 3 hours day 1 + IP cisplatin
Drug Disposition 100 mg/m2 day 2 + IV paclitaxel 60 mg/m2 day 8). A totally
implantable device (IV port, such as single-lumen venous-access
Cisplatin demonstrates a triphasic disappearance curve with a
catheter: 9.6F, Port-A-Cath or Bardport) is surgically placed
t1/2 of 20 minutes, a t1/2 of 48 to 70 minutes, and a terminal-
in the IP space at least 2 days before cisplatin administration.
phase half-life of 24 hours (144). The first 2 phases of disappear-
Placement can be done at the time of surgery or postoperatively
ance represent clearance of free drug from the plasma, and the
(e.g., laparoscopically). It is important to note that peritoneal or
third phase is probably removal of drug from the plasma pro-
fenestrated catheters can lead to fibrous sheath formation, small
teins. The ratio of cisplatin to total free platinum in plasma has a
bowel obstruction and performation, and should be avoided
great deal of interpatient variability: from 0.5 to 1.1 after a dose
(156). Day 2 IP administration requires that cisplatin be mixed
of 100 mg/m2. Three hours after a bolus injection and 2 hours
in 1 L of normal saline and then warmed to body temperature.
after a 3-hour infusion, 90% of the plasma protein is bound to
The 1-L cisplatin solution is instilled as rapidly as possible into
the platinum in cisplatin, not the cisplatin itself. The complexes
the IP space via the catheter and should be followed by up to
between albumin and platinum are slowly eliminated with a min-
one additional liter of saline to the point of mild abdominal
imum half-life of 5 days or more (145). Ninety percent of the drug
discomfort. The cisplatin solution is allowed to remain in the
that is excreted is removed by renal mechanisms (i.e., glomerular
IPcavity (i.e., the fluid is not drained). Concurrently, at least 1L
filtration and tubular secretion), and less than 10% is removed
normal saline must be administered IV along with 40 gm man-
by biliary excretion. Fecal excretion appears to be insignifi-
nitol to assure a brisk diuresis to eliminate the cisplatin. Since
cant. The total proportion of a given dose that is excreted is
cisplatin has the potential to be highly emetogentic, it is impor-
variable and has been reported to be between 31% and 85%
tant to consider an aggressive antiemetic regimen (154,157).
after 51 days (146). The remainder stays bound to tissues for
A retrospective analysis by Levin and Hryniuk (158)
very long periods. Schierl et al. reported 2 long-term biological
strongly suggests that cisplatin efficacy against ovarian cancer is
half-lives of platinum of 16 and 720 days and showed that, of
directly correlated with cisplatin dose intensity (i.e., mg/m2/wk).
an administered dose of 800 mg cisplatin, 1 mg remained in a
Typical high-dose regimens include 20 mg/m2 daily for 5 days
long-term pool after 3,000 days (147). There is a potential for
repeated every 3 weeks, 100 to 120 mg/m2 IV every 3 to 4 weeks,
accumulation of ultrafilterable platinum plasma concentrations
or 100 mg/m2 on day 1 and day 8 repeated every 20 days
whenever cisplatin is administered on a daily basis but not when
(159,160). Holleran and DeGregorio (161) prepared an excellent
dosed on an intermittent schedule.
review of high-dose (200 mg/m2/course) cisplatin. Dose-limiting
toxicities with the higher dose regimens include severe, relatively
Administration and Dosage irreversible neurotoxicity and myelosuppression. Responses have
Cisplatin may be administered IV or IP. Cisplatin should be been seen in conventional-dose cisplatin-refractory patients, but
mixed only in solutions containing 0.9% or more sodium they generally are of relatively short duration.
chloride, because drug stability is directly related to the
concentration of the salt. When admixed with dextrose-
containing solutions, by chromatographic analysis, the drug Side Effects and Toxicities
appears to be relatively unstable, with decomposition evident Dose-related nephrotoxicity is the major dose-limiting toxicity
by 2 hours (148). Platinum also can form significant, colored of cisplatin. It is manifested by renal tubular damage resulting in
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 383
an elevation of BUN (blood urea nitrogen) or serum creatinine. treatment and may persist for 24 to 48 hours. Delayed nausea and
The peak detrimental effect on renal function usually occurs vomiting, lasting from 3 to 5 days, also may occur. The combina-
between the tenth and twentieth day after treatment. The renal tion of a 5-HT3 inhibitor (e.g., ondansetron or granisetron) with
damage is usually reversible. Patients concomitantly receiving dexamethasone (10 to 40 mg IV) has reduced the incidence of
gentamicin and cephalothin have been shown to be at greater severe nausea and vomiting by as much as 75% (170). Delayed
risk of developing acute renal failure (162). nausea and vomiting can be eradicated by continuation of oral
Madias and Harrington (163) have characterized the renal low-dose dexamethasone (with or without a 5-HT3 inhibitor) for
damage of cisplatin as being similar to mercury nephrotoxicity. the first 5 days after platinum treatment (171). Other less effective
Pathologically, renal tubular necrosis, degeneration, and intersti- antiemetic regimens to prevent cisplatin-induced nausea and vom-
tial edema without glomerular changes are observed. Although iting include prochlorperazine, dexamethasone, and lorazepam;
clinically overt renal toxicity may be common, it is usually metoclopramide and dexamethasone; metoclopramide and meth-
reversible. However, some degree of long-term damage is likely. ylprednisolone; or metoclopramide and lorazepam (112,172).
The renal-protective effect of hydration and mannitol is well Anaphylactic hypersensitivity reactions consisting of tachycar-
established in animals and humans, and renal impairment can dia, wheezing, hypotension, and facial edema, occurring within
be prevented (152). a few minutes of IV administration, have occurred occasion-
Ototoxicity, manifested by high-frequency hearing loss ally after a dose of cisplatin given to previously treated patients
(above the frequency of normal speech), may be seen in as many (173,174). These hypersensitivity reactions have been controlled
as 30% of patients treated with cisplatin (164). Hearing impair- with corticosteroids, epinephrine, or antihistamines. Wiesenfeld
tumor) epithelial ovarian cancer when it is administered by protein. The latter type of lesion is generally considered to be
the IP route as part of a primary, combination chemother- innocuous, but the relative significance of the other cross-links
apy regimen. A pivotal phase III trial, GOG-172, determined is still in contention. DNA intrastrand cross-links are more fre-
that the IP administration of cisplatin 100 mg/m2 (on day 2, quent than interstrand cross-links and are more often consid-
preceded by IV paclitaxel 135 mg/m2 over 24 hours on day1 ered to be the critical lesions.
and followed by IP paclitaxel 60 mg/m2 on day 8, every 3 weeks These 2 classes can be differentiated by the structure of
for 6 cycles) was associated with a highly significant 16-month the cross-links in DNA. Generally, the entire mustard is involved
increase in overall survival compared with the standard treat- in the cross-link, with the 2 mustard arms linked usually to the
ment arm (IV cisplatin 75 mg/m2 plus IV paclitaxel 135 mg/m2 N7 position of guanine. Since these guanines can be separated
over 24 hours every 3 weeks for 6 cycles) in patients with by several bases in DNA, the linkages represent particularly
advanced, optimal ovarian cancer (4). Despite the higher inci- bulky lesions.
dence of toxicity in the IP arm, these effects appear to be of
short duration, as patients treated IP and IV reported equivalent Drug Disposition
quality of life 1 year post treatment (8). As a result, the National
After IV administration, approximately 15% of the drug is excreted
Cancer Institute issued a Clinical Announcement on January 5,
unchanged in the urine and the remainder as metabolites. The
2006 recommending IP therapy as the preferred treatment for
plasma half-life of the parent compound after doses of 6 to
optimal, advanced ovarian cancer (181).
80 mg/kg appears to range from 4.0 to 6.5 hours (186,187).
Intraperitoneal therapy is not recommended for patients
Approximately 50% of the alkylating metabolites (but not
who have suboptimal cytoreductive surgery (i.e., >1 cm in larg-
parent drug) is bound to plasma proteins.
est diameter of a tumor nodule), because IP cisplatin (as well as
Although cyclophosphamide is exclusively excreted by the
other cytotoxic agents) only penetrates a few millimeters into
kidney, because of the unionized nature of the intact drug mol-
tumor plaques (16). Additional considerations regarding the
ecule, tubular reabsorption is avid. Hepatic inactivation appears
appropriate patient selection for consideration of IP therapy are
to be the major mechanism of active drug elimination. The mean
discussed in detail elsewhere (154,155,182).
renal clearance of intact drug is approximately 11 mL/min, or
Multiple phase III studies have shown that cisplatin-based
15% of creatinine clearance, but renal elimination remains the
chemotherapy as an adjunct to radiation therapy improves sur-
major route of disposition of the more polar, less lipid-soluble
vival in cervical cancer patients (47,183185).
metabolites (188). There can be significantly prolonged retention
of active (alkylating) metabolites in patients with severe renal
Cyclophosphamide failure, and doses should be adjusted accordingly.
Chemistry
Dosage
Cyclophosphamide (Cytoxan, Neosar, CTX, CPM, and Endoxan)
Cyclophosphamide is active in many different types of malig-
is an alkylating agent that before the advent of paclitaxel was
nancies. The dosing schemes are numerous and depend on the
used in the primary chemotherapy of advanced, epithelial-type
particular disease. There are two general categories of treatment
ovarian and endometrial cancer. It is no longer often used in
schedules exist. In the method generally used to treat ovarian and
the treatment of gynecologic cancers because of the more effec-
endometrial cancers, an intermediate dose (600 to 1,000mg/m2)
tive agents currently available (e.g., paclitaxel). It is occasion-
is given all at once over a short period. This treatment approach
ally used in the third-line treatment of ovarian cancer and as a
usually involves other drugs, such as cisplatin, carboplatin, or
second-line agent in the treatment of choriocarcinoma. It is a
doxorubicin, whose additive toxic effects must be considered in
cyclic phosphamide ester of nitrogen mustard and is referred to
selecting the dose and frequency of cyclophosphamide adminis-
chemically as 2-[bis-(2-chloroethyl)amino]tetrahydro-2H-1,3,2,-
tration. Adequate hydration for 72 hours before and following
oxazaphosphorine 2-oxide monohydrate. Its molecular weight is
high-dose treatment with cyclophosphamide is recommended to
279.1. The monohydrate is unionized and lipid soluble; in nor-
reduce cyclophosphamide-induced hemorrhagic cystitis (189).
mal saline or water, it is soluble to a maximum of 4% at room
An alternative continuous low-dose regimen for cyclophos-
temperature.
phamide has been developed. Doses of 25 to 50 mg/day are
given on a continuous basis. Used in this way, it was originally
Mechanism of Action thought that cyclophosphamide acted as an accidental anti-
Cyclophosphamide, a bifunctional substituted nitrogen mustard, angiogenic agent (190). It is usually well tolerated with few side
was synthesized in 1958 in an attempt to achieve greater selective effects. Colleoni and colleagues published the results of a trial
toxicity for tumor tissue. The N-methyl moiety of nitrogen mus- of continuous low-dose cyclophosphamide with methotrex-
tard is replaced with a cyclic phosphamide group, resulting in a ate in breast cancer and showed antitumor activity that cor-
stable, inactive compound. The bis-(2-chloroethyl) group cannot related with vascular endothelial growth factor levels (191).
ionize until the cyclic phosphamide is opened at the phosphorus- Further, Miscoria and colleagues found an association between
nitrogen linkage. progression-free survival and thymidine phosphorylase levels
Activation of cyclophosphamide is a multistep process. The (192). A suggestion has been made that the acrolein metabolite
liver microsomal P450 mixed-function oxidase system converts of cyclophosphamide acts as an antiangiogenic agent (193). The
the parent drug to 4-hydroxycyclophosphamide. This metabo- use of cyclophosphamide in this way has come to be known as
lite exists in equilibrium with the acyclic tautomer, aldophos- metronomic dosing. In addition to the antiangiogenic effect,
phamide. These compounds may be further oxidized by hepatic metronomic cyclophosphamide may also have an immune regu-
aldehyde oxidase to the inactive metabolites of carboxyphos- latory function (194). Ge et al. (195) showed that metronomic
phamide and 4-ketocyclophosphamide. Nonenzymatic conver- cyclophosphamide induced an increase in the number of breast
sion to the cytotoxic compounds of phosphoramide mustard cancer reactive t-cells and that this correlated with disease stabi-
and acrolein occurs in susceptible peripheral tissues. lization in breast cancer.
Most of the alkylating agents, like cyclophosphamide, are There have been a large number of trials of the metronomic
bifunctional, which facilitates their reaction with 2 cellular mol- approach in a range of tumor types, including ovarian can-
ecules. Accordingly, they can cross-link the 2 opposite strands cer. These have been reviewed (196). Activity is frequently
of DNA to give an interstrand cross-link, react with 2sites on reported, but the heterogeneous nature of the trials, the fre-
the same strand (intrastrand cross-link), or cross-link DNA to quent combination with established antiangiogenic agents,
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 385
and the lack of randomized trials makes the overall role of this by microsomal enzymes in the liver (200,201). These enzymes
approach undefined. may be activated by drugs like phenobarbital or inhibited by
drugs like proadifen (SKF 525A). Because active and toxic
Side Effects and Toxicities metabolites are generated by the reactions of these enzymes and
cyclophosphamide, many potential drug interactions may exist.
Myelosuppression consisting primarily of leukopenia is the Barbiturates and other inducers of hepatic microsomal
usual dose-limiting toxic effect of cyclophosphamide. Both the enzymes, such as phenytoin and chloral hydrate, may increase
nadir and time of bone marrow recovery are rapid at 8 to 14 and the rate of hepatic conversion of cyclophosphamide to its toxic
18 to 21 days, respectively. Although this drug has long been metabolites. Similarly, cyclophosphamide may block the metabo-
considered to be platelet sparing, significant thrombocytopenia lism of barbiturates, increasing sedative effects. Although the clin-
can also occur at very high doses (>1.5 g/m2). ical significance of these reactions is not clear, cyclophosphamide
Acute, sterile hemorrhagic cystitis, believed to be due to the toxicity may be increased by the H2-histamine blocker cimetidine
acrolein metabolite, is an infrequent toxic manifestation, but (202). Cimetidine, but not ranitidine, may increase cyclophos-
is occasionally dose limiting. It is understandably more com- phamides myelotoxicity through an increase in the concentration
mon in poorly hydrated or renally compromised patients. The time product of its active metabolites (e.g., 4-hydroxycyclophos-
onset of this complication may be delayed from 24 hours to phamide and phosphoramide mustard) (203). Thus, H2-blockers
several weeks. It is detected by gross hematuria or a microscopic such as ranitidine may be safer to use than cimetidine when high
hematuria of greater than 20 erythrocytes per high-power field. doses of cyclophosphamide are administered.
The bleeding may persist but is usually transient. Prophylactic
is collected as the intact molecule. Some monolactone forms of Dactinomycin is highly potent and is typically dosed in
dactinomycin are recovered in the urine. micrograms per kilogram. Doses must be calculated and pre-
Using a more specific radioimmunoassay, a much shorter pared carefully to prevent inadvertent overdosage. No specific
dactinomycin half-life is described (t1/2 = 0.78 minutes, t1/2 = antidote to overdosage is known, although granulocyte colony-
3.5 hours) (210). The discrepancies between these and Tattersalls stimulating factors may be useful.
findings reflect the differences in the assays used. Dactinomycin is a potent immunosuppressant and can inhibit
the effectiveness of vaccinations given after drug administration.
Administration and Dosage The drug also produces radiation recall skin and soft-tissue dam-
age if given after ionizing radiation.
Dactinomycin is administered by slow IV push or, preferably,
into the tubing of a freely running IV solution. A 5- to 10-mL
flush of 5% dextrose in water (D5W) or normal saline is recom- Docetaxel
mended before and after IV push administration to assure vein
patency and to flush any remaining drug from the tubing. Chemistry
Dactinomycin is commonly given IV in short pulse doses Docetaxel (Taxotere) is a semisynthetic analog of paclitaxel and
of 500 g/m2 daily for as long as 5 days in adults. The dose for has a FDA-approved indication for locally advanced or meta-
each 2-week cycle should not exceed 15 g/kg/day or 400 to static breast cancer after failure of prior chemotherapy. It is also
600 g/m2/day for 5 days. FDA approved for locally advanced or metastatic non-small
A wide variety of dosing regimens have been employed. cell lung cancer after failure of prior platinum-based chemo-
Several clinical studies have documented equal efficacy and therapy. It also has shown marked antitumor activity against a
toxicity for single-dose dactinomycin regimens (211,212). In non- variety of solid tumors, including both platinum-sensitive and
metastatic gestational trophoblastic cancer, a single IV dose of platinum-refractory epithelial ovarian cancer (216,217). The
1.25 mg/m2 every 14 days produced a 99% remission rate after natural component of docetaxel is 10-deacetyl baccatin III,
4 courses of therapy (212). Compared with 5 divided doses of which is extracted from the needles of the European yew tree
500 g/m2/day, the single-dose method produced slightly greater (Taxus baccata L.) (217). Docetaxel has a molecular weight of
mild-to-moderate toxic effects. 861.9 and the empirical formula C43H53NO14 3H2O. Unlike
paclitaxel, which uses a polyoxyl compound (Cremophor) as a
diluent, docetaxel is formulated in Tween 80 and alcohol.
Side Effects and Toxicities
Bone marrow depression is the usual dose-limiting toxic effect Mechanism of Action
of dactinomycin. It is usually manifested 7 to 10 days after dos-
ing. All blood elements are affected, but primarily, the platelets In a manner similar to paclitaxel, docetaxel promotes microtubule
and leukocytes are depressed. Combined with gastrointestinal assembly and inhibits the depolymerization of tubulin. However,
reactions, myelosuppression appears to be dose limiting as compared with paclitaxel, the microtubules formed by docetaxel
well as dose dependent (213). Immunosuppression is another are more slowly reversible, and there are differential effects on tau
well-known effect of dactinomycin. Patients should not receive binding sites and on microtubule-associated proteins. Docetaxel-
this drug during viral infection because of the risk of developing induced stabilization of microtubules halts cellular division in
disseminated disease. M phase, thereby preventing cell replication.
Severe gastrointestinal consequences, such as vomiting, can
occasionally represent the acute dose-limiting toxic effects of Drug Disposition
dactinomycin. Vomiting can persist for 4 to 20 hours, but it can The pharmacokinetics of docetaxel when administered as an IV
be controlled by combination antiemetic regimens (214). Muco- infusion lasting from 1 to 24 hours has been investigated in a
sitis can also be severe. It is characterized by severe oral ulcer- number of studies (218). When administered as a typical 1-hour
ations and diarrhea in 30% of patients. Reversible alopecia may infusion at doses of 70 to 100 mg/m2, pharmacokinetics reveals
occur with dactinomycin. A variety of other skin manifestations triphasic elimination with plasma AUC of 3.13 to 4.83 mg/mL/
have been reported, including acneiform changes, erythema, and hour, a peak plasma concentration of 2.57 to 3.67 g/mL, and a
hyperpigmentation. terminal-phase plasma half-life of 13.6 hours. There is very lim-
Dactinomycin is toxicologically similar to the anthracyclines ited renal excretion of docetaxel; the 24-hour urinary excretion
and characteristically interacts with radiation therapy, produc- was 1.4% of the dose administered. Plasma drug clearance was
ing delayed radiation recall skin damage. Previously irradi- determined to be 21.3 L/hour/m2 (219).
ated or even irritated skin may become reddened and inflamed
after drug administration. Frank necrosis is sometimes reported. Administration and Dosage
Oral ulcers may also develop after radiation therapy. These reac-
tions may occur months after radiation therapy. Experimentally, All patients receiving docetaxel should be premedicated with oral
radiation therapy given after dactinomycin does not produce corticosteroids such as dexamethasone 16 mg/day (e.g., 8 mg BID)
this effect. for 3 days beginning 1 day prior to docetaxel administration in
Dactinomycin potentiates pulmonary radiation and order to reduce fluid retention and the risk of hypersensitivity
decreases radiation tolerance by at least 20%. Reintroduction reactions.
of dactinomycin following pulmonary radiation has resulted Docetaxel is commercially available in single-dose 20- and
in fatal pulmonary fibrosis (215). As noted in the Special Pre- 80-mg vials with accompanying diluent vials. Both the docetaxel
cautions section below, dactinomycin is highly ulcerogenic if vials and the diluent vials should stand at room temperature
extravasated. for approximately 5 minutes prior to mixing. The entire con-
tents of the diluent vial should be aseptically transferred to the
docetaxel vial, and the resulting contents should be gently
Special Precautions rotated for 15 seconds to promote complete mixture. The result-
Dactinomycin is extremely damaging to soft tissue, and every ing concentration of docetaxel is 10 mg/mL. Foam may be pres-
effort should be made to assure vein patency during adminis- ent owing to the Tween 80; however, it should largely dissipate
tration. Extravasations characteristically result in immediate within a few minutes. The infusion solution is prepared by
pain and swelling followed by indolent, poorly healing necrotic aseptically withdrawing the proper amount of docetaxel with
ulcers (214). a calibrated syringe and adding it to a 250-mL infusion bag or
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 387
bottle containing either 0.9% sodium chloride or 5% dextrose and/or severe hypertension) occur in less than 2% of docetaxel
solution to produce a final concentration of 0.3 to 0.9 mg/mL. administrations (236). Initial symptoms of hypersensitivity to
The infusion solution should be mixed by manual rotation and docetaxel therapy generally occur within minutes of the start
inspected for particulate formation and/or discoloration. Solu- of the first or second course of docetaxel and resolve rapidly
tions that are cloudy or that contain particulate matter should with interruption of the infusion. Patients can be successfully
be discarded. rechallenged with docetaxel therapy following medication with
The recommended dose of docetaxel for salvage chemo- corticosteroids, antihistamines, and H2-agonists.
therapy of breast cancer is 60 to 100 mg/m2 IV as a continuous Dermatologic toxicities typically appear as maculopapular
1-hour infusion every 3 weeks. For non-small cell lung cancer, the eruptions and desquamation generally localized to the extremi-
recommended dose is 75 mg/m2 IV as a continuous 1-hour infu- ties. Nail changes, including onycholysis, may also occur. Skin
sion every 3 weeks. The optimal dosing schedule for docetaxel changes are largely self-limiting and may be alleviated with glyc-
in gynecologic cancers is presently undefined. A 100-mg/m2 dose erin/chlorhexidine ointment or oral pyridoxine. This side effect
administered as a 1-hour infusion every 3 weeks has been used can often be prevented with prophylactic oral steroids and H1-
in phase II trials. Other tolerable docetaxel dose schedules that and H2-agonists (237). Recurrent skin toxicity refractory to oral
have been identified in phase I studies are: 50 mg/m2/day on days prophylactic medication and pyridoxine therapy may respond to
1 and 8 every 3 weeks; 70 to 90 mg/m2 by 24-hour continuous local hypothermia during docetaxel administration (238).
IV infusion every 3 weeks; 80 to 100 mg/m2 by 6-hour infusion
every 3 weeks; 14 mg/m2/day for 5 days by 1-hour infusion every Special Precautions
In DNA, the amino sugar projects into the minor groove and bile, and feces (255). Human tissues with high drug concentra-
can interact electrostatically with negatively charged phosphate tions (in descending order) include liver, lymph nodes, muscle,
groups in the DNA strand to stabilize the aglycone moiety. bone marrow, fat, and skin (256). The drug does not distribute
Doxorubicin can also form complexes with iron or copper by into the central nervous system.
means of the hydroquinone moieties (243). Metal-iron doxoru- There is a significant distribution of doxorubicin into human
bicin complexes may contribute to cardiotoxicity by enhancing breast milk (257). Doxorubicin levels of 0.24 M and 0.2 M
redox cycling of the quinone moiety to produce membrane- of doxorubicinol have been measured in human milk. They pro-
damaging oxygen free radicals (244). duce cumulative AUCs in breast milk of 9.9 and 16.5 M hour,
Doxorubicin hydrochloride is freely soluble in water, slightly respectively. Both of these values were greater than concurrent
soluble in normal saline, and very slightly soluble in alcohol. plasma AUC values. However, doxorubicin does not appear
Doxorubicin also is commercially available in a polyethyl- consistently to pass the placenta. Except for one study reporting
ene glycol (PEG)-coated (pegylated, Stealth) liposomal form (see low drug levels in placental blood of 0.78 to 1.19 nmol/g and no
Liposomal Encapsulated Doxorubicin section below). drug in cord blood plasma, several other trials detected no drug
in amniotic fluid after doxorubicin administration to pregnant
patients (258260).
Mechanisms of Action
Doxorubicin is extensively metabolized and eliminated pri-
DNA Binding. The anthracyclines, including doxorubicin, prob- marily as glucuronide conjugates of the parent aglycone or its
ably have several modes of action. The anthracycline portion hydroxylated congener, doxorubicinol (255,261). The conju-
of the molecule appears to intercalate between stacked nucleo- gated metabolites are exclusively excreted in the bile and feces.
tide pairs in the DNA helix by means of PP-type bonds (245). Overall, biliary excretion accounts for approximately 40% of
The drug may also bind ionically around certain base pairs of an administered dose (262). Approximately 42% of the biliary
DNA (adlineation). The overall effect of this is interference with drug is parent doxorubicin, 22% is doxorubicinol, and 36% is
nucleic acid synthesis, specifically an inhibition of DNA synthe- other metabolites (262). Only 5% to 10% of the administered
sis (246). However, preribosomal RNA synthesis is also affected drug is excreted in the urine as doxorubicin (40%), doxorubi-
by the drug binding to DNA, preventing DNA-directed RNA cinol (29%), and other metabolites (31%).
and DNA transcription (247). In liver disease, patients with cholestasis have delayed doxoru-
Mechanisms other than intercalation may also contribute to bicin clearance and experience exaggerated toxic reactions from
the antitumor effect of the doxorubicin molecule. The contribution standard doses (263). However, hepatoma patients with cirrhosis
of alkylation to antitumor effects has not been established. or simple hepatocellular enzyme elevation appear to have nor-
mal doxorubicin clearance and toxic effects from standard doses
Free-Radical Formation. Oxygen free-radical intermediates
(264). Although obesity reduces clearance of doxorubicin in adult
containing an unpaired electron can be formed by doxorubicin.
cancer patients (265), there were no differences in doxorubicin
This can react rapidly with oxygen to form superperoxide, and
toxicity between normal, mildly obese, and obese patients.
with hydrogen peroxide, highly reactive hydroxyl radicals can
There is some evidence that repeated doxorubicin dosing
form. These radicals damage membrane lipids by peroxidation,
alters pharmacokinetics (266,267). In these reports, doxoru-
break DNA strands by attacking ribose-phosphate bonds, and
bicin levels were lower after repeated dosing, which suggests
directly oxidize purine or pyrimidine bases, thiols, and amines
increased drug clearance. However, because neither toxicity nor
(244,248). Free-radical mechanisms have most often been asso-
response rates are altered, the clinical significance of these obser-
ciated with cardiotoxicity.
vations has not been established. Age may also be a factor. In one
Doxorubicin appears to be active in all phases of the cell
trial, the highest clearances of doxorubicin were observed in the
cycle, and although maximally cytotoxic in S phase, it is not
younger patients (268). These observations suggest that higher
phase specific (249). Cells exposed to lethal doxorubicin con-
peak doxorubicin levels may be achieved in older patients.
centrations in G1 can proceed through S phase but are then
The hepatic extraction ratio for doxorubicin in humans is
blocked and die in G2. Higher concentrations can also produce
0.45 to 0.50, and systemic drug levels are approximately 25%
an S-phase blockade (250).
lower with intraarterial administration compared with IV dos-
Inhibition of DNA Topoisomerase II. Topoisomerases are ing (269). Several studies have shown that the pharmacokinetics
enzymes capable of covalent binding to DNA, forming tran- of intraarterial drug is similar to that of IV doses (256,270).
sient breaks in one strand (TOPO-I) or 2 strands (TOPO-II). The relatively low hepatic extraction rate and similar overall
This activity is highly phase dependent for G2, and in the case disposition patterns provide little pharmacokinetic rationale for
of TOPO-II, normally mediates strand passage to facilitate intraarterial administration as a means of localizing doxorubicin
DNA condensation or decondensation (251). Doxorubicin and effects to the liver (271).
other DNA intercalators inhibit the strand-passing activity of
TOPO-II by increasing and stabilizing the initial enzyme-DNA
Administration and Dosage
(cleavable) complexes. This leads to protein-linked DNA double-
strand breaks that are roughly proportional to the cytotoxic Short IV push infusions and IV bolus injections have been used
potency of the drug in vitro (252). with doxorubicin. A slow IV push over several minutes, with
constant monitoring of the patient and blood return, can help
minimize the chance of serious tissue damage from extrava-
Drug Disposition sation. A 5- to 10-mL flush of normal saline or D5W before
Doxorubicin pharmacokinetics is usually described using a and after administration is strongly recommended to test vein
2-compartment or 3-compartment open model. The drug is patency and flush any remaining drug from the tubing. Alterna-
rapidly distributed in body tissues, and approximately 75% tively, injection into the side port of a running IV infusion has
of the drug is bound to plasma proteins, principally albumin also been recommended. The patient should be asked to report
(253). In the blood, the free doxorubicin fraction depends on the immediately any change in sensation during the administra-
hematocrit, with more free drug being available in patients with tion. Old venipuncture sites or infusion sites previously used for
reduced hematocrit (254). The avid binding to DNA is believed administering blood, antibiotics, or other medications should
to explain the prolonged terminal elimination half-life of 30 not be used to administer doxorubicin. Heparin locks (unless
to 40 hours, the large apparent volume of distribution of up to recently inserted) are not recommended because the drug is
28 L/kg, and the incomplete (50%) total recovery of drug in urine, chemically incompatible with sodium heparin.
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 389
Table 14.2 Intravenous Dosing Guidelines for Table 14.3 Modifications of Doxorubicin Doses
Doxorubicin
Condition Recommended Dose Modification
Average Cumulative
Prior doxorubicin Limit total cumulative lifetime dose
Dose Intravenous Tolerable Dosec
(by IV bolus) to 550 mg/m2 (285)
(mg/m2)a Method Schedule (mg/m2)
Prior chest Reduce total dose limit to 300350 mg/m2
6075b Bolus Every 3 wk 550
Radiation therapy
30 Bolus 3 successive 550
Obesity Base dose on ideal body weight (265)
days, every 3 wk
Heptabillary Reduce dose for elevated serum bilirubin
20 Bolus Weekly 750
dysfunction (give 50% of dose for serum bilirubin of
60 96-hr infusion Every 34 wk 1,000 1.21.9 g/dL, and give 25% of dose for
serum bulirubin 3.0 mg/dL (282)
Use indocyanine green disappearance rate
a
Lower doses should be administered to patients with hepatobiliary dysfunction
as an Indicator of doxorubicin clearance
and for poor bone marrow reserve or performance status.
b
Allows for greater dose intensity in breast cancer. Infusion method Greater cumulative (total) dose may be
c
Represents average total cumulative dose tolerated without clinical evidence of afforded by weekly bolus doses or continuous
Prolonged infusions increase the incidence and severity of Note: Average safe cumulative doxorubicin dose is 750 mg/m2 using standard
infusion schedules.
stomatitis and dermatologic reactions. Administration through
tunneled central venous catheters or indwelling vascular access Average safe cumulative doxorubicin dose is 1,000 mg/m2 when administered
a
ports is mandatory for all prolonged infusions. Careful patient with a 96-hour infusion schedule.
and site monitoring are required because doxorubicin extrava-
sation from central vascular access devices can occur.
Numerous dosing schedules have been reported. The indi- Cardiac consequences from the drug have included acute
vidual doxorubicin dose depends on clinical variables, including effects, such as a rare pericarditis-myocarditis syndrome or elec-
the cumulative dose administered to date and the potential for trophysiologic aberrations, and a total-dose-related cardiomyop-
interaction with other drugs or radiation (Table 14.2). As a single athy (279,280). Nonspecific electrocardiographic changes during
agent, doses of 60 to 75 mg/m2 as a single IV injection have been infusion or immediately afterward may be seen. These include
used and repeated no more often than every 3 weeks. An alterna- T-wave flattening, ST depression, supraventricular tachyarrhyth-
tive scheme uses 20 to 30 mg/m2 given daily for 3 consecutive mias, and extra systolic contractions (281). These conduction
days and repeated in 3 weeks (272). When used in combination abnormalities are generally transient, not associated with severe
therapy, the most commonly used dosage is 40 to 60 mg/m2 morbidity, and do not require dose modification.
given as a single IV injection every 21 to 28 days. Cardiomyopathy from doxorubicin is dose related. It presents
Both the dose and rate of dosing (dose intensity) can have initially as a clinical syndrome identical to classic congestive heart
therapeutic impacts for different agents and tumors (273). Clini- failure. It is usually irreversible, but symptoms can be managed
cal studies with doxorubicin show that greater dose intensity is with standard medical therapy involving digitalis, glycosides, and
associated with enhanced response rates in breast cancer (274). diuretics. Potential risk factors for doxorubicin cardiotoxicity
The doses compared in this trial were 70 mg/m2 every 21 days include cumulative doses greater than 550 mg/m2, prior mediasti-
for 8 cycles versus 35 mg/m2 every 21 days for 16 cycles. nal irradiation (20 Gy), age greater than 70 years, and preexist-
Dose adjustments are required in a number of clinical set- ing cardiovascular diseases, such as prior myocardial infarction or
tings (Table 14.3), specifically in the case of hyperbilirubinemia. long-standing hypertension (282). Anthracycline-induced cardio-
A 50% dose reduction is indicated if plasma bilirubin concen- myopathy can also occur 4 to 20 years after the drug is stopped at
tration is 1.2 to 3.0 mg/dL, and the dose must be reduced by standard dose limits (283). The administration of anthracyclines
75% if plasma bilirubin concentration reaches 3.1 to 5.0 mg/dL. incorporated into liposomes is one method that may significantly
reduce the risk of cardiac toxicity (see Liposomal Encapsulated
Doxorubicin section below) (284).
Side Effects and Toxicities At total doses under 500 mg/m2, the incidence of cardio-
The single acute dose-limiting toxicity for doxorubicin is bone myopathy is less than 1%; between 501 and 600 mg/m2, it is
marrow suppression. The most commonly seen dose-limiting 11%; and the incidence is 30% for doses above 600 mg/m2.
toxicity is leukopenia, with a nadir at 10 to 14 days. Other In a retrospective cardiotoxicity study of 4,018 patient records,
hematologic toxicities, such as anemia and thrombocytopenia, Von Hoff and associates (285) described an overall incidence of
have been reported, but they are rare and generally less severe. 2.2% for doxorubicin-induced congestive heart failure. In this
Recovery from myelosuppression is usually prompt, with reso- analysis, there was no influence of performance status, sex, race,
lution often within about 1 week after the nadir. and tumor type on the incidence of cardiomyopathy. However,
Doxorubicin is known to produce local skin and deep-tissue elderly patients were at greater risk even after adjustment for the
damage at the site of inadvertent extravasations (275,276). normally decreased cardiac function in this group. The major
Ulcers result in 33% of extravasations. The lesions undergo determinants were the dose, the schedule of administration, and
a slow, indolent expansion and occasionally involve ten- the age of the patient. A weekly doxorubicin dosing schedule
dons and other deep structures. They characteristically do was associated with significantly less congestive heart failure
not heal and are associated with prolonged local drug reten- than an every-3-week dosing schedule. Continuous IV infusions
tion (277). Reilly and colleagues (275) recommend early sur- over 96 hours also can significantly lessen doxorubicin cardio-
gical debridement, with skin grafting and tendon repair for toxicity (286).
serious infiltrations. Numerous pharmacologic antidotes have Dexrazoxane (Zinecard) is a chemoprotective agent with an
been evaluated, but few have demonstrated unequivocal clinical FDA-approved indication for reducing doxorubicin-associated
efficacy. The application of cold, topical dimethylsulfoxide is cardiomyopathy in women with metastatic breast cancer who
recommended (278). have received a cumulative doxorubicin dose of 300 mg/m2 and
390 CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER
who, in their physicians opinion, would benefit from further highly soluble in methanol and chloroform, slightly soluble in
doxorubicin therapy (see Modulating Agents section below). ethanol, and sparingly soluble in water. Because of poor water
There is evidence that doxorubicin is a radiosensitizing or solubility, the commercial drug is dissolved in an ethanol-based
radiomimetic agent and can cause reactivation of tissue reac- cosolvent system.
tions in areas previously irradiated (287,288). Radiation recall Etoposide was originally synthesized from P. embodi (294).
reactions have also been reported in areas of previous drug infil- Structure-activity studies show that the hydroxyl group at the
tration. A particularly sensitive area for serious recall toxicity is C-4 position is required for activity and that alterations at this
the esophagus (289). site can dramatically affect activity.
Other toxic effects are observed in rapidly proliferating nor-
mal tissues. These include marked alopecia in all hairy body Mechanism of Action
areas. Stomatitis may occur at high doses and is more pro-
There is marked schedule dependence for etoposide cell killing,
nounced when the drug is given on consecutive days. It generally
and cytotoxic effects are maximal in G2 phase (295). There is
begins in the sublingual and lateral tongue regions as a burning
also some activity against cells in late S phase, and the drug can
sensation with noticeable erythema. The initial inflammation
halt cell cycle traverse at the S-G2 interphase (296).
typically progresses to ulceration after a few days. Anal fissures
Etoposide produces protein-linked DNA strand breaks by
or proctitis have been rarely reported. Nausea and vomiting are
inhibiting DNA TOPO-II enzymes (297). This normal mamma-
common but of moderate intensity. Diarrhea is rare with con-
lian enzyme mediates double-strand-passing activities in G2 phase
secutive daily dosing, and the emetic effects are generally limited
to condense or decondense supercoiled DNA (298). Drug-induced
to the first day of treatment. Hyperpigmentation of the skin,
inhibition of TOPO-II is an energy-dependent process that is
especially the nail beds, may occur. Extravasations of doxorubi-
influenced by dose and duration of exposure.
cin are known to cause severe ulceration and soft-tissue necrosis
Etoposide does not bind directly to DNA, but rather stabilizes
(275,276). Vein patency should be assured before injection and
a transition form of the DNA-TOPO-II complex (297). The num-
constantly monitored during administration.
ber of single and double DNA strand breaks reflects the cytotoxic
As discussed later in this chapter, pegylated liposomal encap-
dose-response curve (299). Etoposide and intercalative drugs,
sulation dramatically alters the pharmacokinetic profile of
such as doxorubicin, poison TOPO-II enzymes by stabilizing
doxorubicin and, hence, the drugs toxicity profile.
an otherwise transient form of TOPO-II covalently linked with
DNA (252). Normal TOPO-II strand-passing activity is thereby
Drug Interactions blocked, and cell progression out of G2 phase is halted (251,300).
Doxorubicin is believed to interact with numerous other drugs. The production of cytotoxicity by etoposide may ultimately
Most of these effects have been described only in experimental involve chromosomal breaks characterized as sister chromatid
systems, and their clinical significance is, therefore, unknown. exchanges (301).
However, several potentially significant interactions have been Another postulated etoposide mechanism involves microsomal
described in cancer patients. Altered doxorubicin disposition is activation to reactive intermediates capable of generating oxygen
postulated with -interferon, and substantial doxorubicin dose free radicals (299). Nucleoside transport is also inhibited at high
reductions are required (290). The combination of doxorubicin drug concentrations, but whether this makes a major contribution
with H2-antihistamines, such as ranitidine or cimetidine, may also to the antitumor effect is unknown (302).
increase toxicities significantly and necessitate drug dose reduction.
Drug Disposition
Special Applications A 2-compartment open pharmacokinetic model appears to
Doxorubicin has been investigationally administered intrapleu- describe adequately etoposide disposition in cancer patients
rally to patients with malignant pleural effusions (291). Doses (303). The terminal half-life of the drug appears to be approxi-
of 30 mg were diluted in 20 mL of saline and administered by mately 7 hours and is independent of the dose, route, or method
paracentesis needle as a bolus. Eight of 11 patients responded of administration (304). Renal excretion appears to account for
to doxorubicin, including one complete response. This response approximately 30% of overall drug elimination. Approximately
rate was superior to nitrogen mustard or tetracycline. Toxicity 42% to 66% of radiolabeled drug is recovered in the urine, of
included pain or fever in 20% of patients and nausea or vomit- which less than half is parent etoposide.
ing in 45% of patients. No alopecia or hematologic toxicity was With standard doses of etoposide, no drug is detectable
reported. Markman and colleagues (292) combined doxorubicin in the cerebrospinal fluid (CSF), and even after doses of 400 to
(3 mg) with cytarabine (61 mg) and cisplatin (100 mg/m2) in 800 mg/m2, CSF levels were less than 2% of concurrent plasma
the treatment of 7 cancer patients with malignant pleural effu- levels (305). Despite the low distribution of drug into the CSF,
sions. Two ovarian cancer patients responded, and no significant mean levels of 1.4 g/g (range, undetectable to 5.9 g/g) have
systemic toxicities were reported. All injections were given in been measured in brain tumor tissue (306). The drug also dis-
250mL of saline, and aggressive hydration was given to coun- tributes into myometrial carcinoma and normal myometrium,
teract cisplatin nephrotoxicity. achieving levels 50% of those in the blood (307).
Biliary secretion of parent drug accounts for 2% or less of
the dose, although fecal recovery of drug and metabolites is
Etoposide variable, ranging from 1.5% to 16.3% (308). However, patients
with obstructive jaundice excrete a larger fraction of the dose in
Chemistry urine (46%) than do unaffected patients (35%), which suggests
Intravenous etoposide (VP-16) is used commonly in combina- that there is a slight decrease in hepatic drug metabolism with a
tion chemotherapy regimens for the treatment of patients with commensurate increase in renal clearance (305).
germ-cell tumors of the ovary (206). Oral etoposide has activity The plasma protein binding of etoposide is normally high,
as a salvage agent for refractory or recurrent ovarian cancer averaging 95% in typical patients (309). The free (unbound)
(293). It is a semisynthetic epipodophyllotoxin derived from the fraction of etoposide can vary from 6% to 37% among patients.
root of Podophyllum (the May apple plant, or mandrake). The Patients with increased bilirubin or decreased albumin may have
chemical name is demethylepipodophyllotoxin 9-[4,6-O-(R)- an increase in the free fraction even though systemic clearance is
ethylidene--D-glucopyranoside]. Etoposide has the molecular unaltered (309). Myelosuppression may also be commensurately
formula of C29H32O13 and a molecular weight of 588.58. It is increased in these patients. Other conditions that may decrease
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 391
etoposide clearance include prior cisplatin therapy, obesity, and dosing include more frequent administration to take advantage
elevated alkaline phosphatase levels (310). of cell cycle-dependent cytotoxicity, an approximate doubling of
The absolute oral bioavailability of etoposide gelatin capsules oral doses due to 50% bioavailability for the gelatin capsules,
ranges from 25% to 74%, with a mean of 48% (311). Some and significant dose reductions for combinations of etoposide
patients experience a 30% change in overall bioavailability with other myelosuppressive drugs or for patients with poor
(both increased and decreased) with repeat dosing. Neither food bone marrow reserve or poor performance status. In general,
nor other chemotherapeutic agents appear to alter etoposide etoposide doses can be repeated every 3 to 4 weeks depending on
absorption (312). Wide variations in peak levels and AUC values the leukocyte count. A pharmacokinetic study in patients with
were also described in this trial. obstructive jaundice showed that no significant dose reductions
are needed if renal function is normal (320).
Administration and Dosage
Etoposide must be diluted prior to use with either 0.5% dextrose Side Effects and Toxicities
or 0.9% sodium chloride to give a final concentration of 0.2 to Side effects and toxicities for oral and IV administration of etopo-
0.4 mg/mL. Etoposide should be given by IV infusion over a 30- side as a single agent are similar. The principal toxicity of etopo-
to 60-minute period. Severe hypotension may occur if the drug side is dose-related and dose-limiting bone marrow suppression.
is given too rapidly. Although not a vesicant, extravasation of Leukopenia and thrombocytopenia can occur, but leukopenia
the drug should be avoided (313). Examine all solutions for fine consistently predominates, with a nadir at approximately 16 days
precipitates; mix before use. Precipitation may occur if the solu- and with recovery usually beginning by days 20 to 22.
Special Applications was twice as long as that for the low dose of 5-FU. Their data
Despite preclinical data showing peritonitis with IP injections, were compatible with a product-inhibition model. Yoshida and
combinations of etoposide and cisplatin have been administered coworkers (336) found positive correlations between the dose and
safely by the IP route. Barakat et al. (327) performed a phase serum steady-state levels (CSS) and areas under the concentration-
II study of 3 courses of IP cisplatin 100 mg/m2 plus etoposide time curves (AUC). Patients who developed toxic reactions had
200 mg/m2 as consolidation therapy in patients with stages II greater CSSs and AUCs. However, there were no correlations
to IV epithelial ovarian cancer with negative second-look sur- between serum levels and patient response to therapy.
geries. When compared with a similar group of contempora- 5-FU and FUDR are extensively metabolized in the liver
neous patients who did not receive consolidation therapy, the (hepatic metabolism can detoxify up to 80% of the total dose).
disease-free survival distribution between the 2 groups (using the However, there is no absolute documentation that patients
log-rank test) was found to be significant (p = 0.03) in favor of with impaired liver function require dose reductions of 5-FU
consolidation therapy (327). European researchers have used a (337); however, patients should be monitored as they may be
combination of etoposide 350 mg/m2 IP followed by cisplatin at increased risk of toxicity. As much as 15% of a dose may be
200 mg/m2 IP with IV sodium thiosulfate (4 g/m2 bolus followed found intact in the urine by 6 hours, with 90% of this excreted
by 12 g/m2 over 6 hours) protection every 4 weeks for 4 to in the first hour. Depressed renal function does not generally
6cycles in ovarian cancer patients with either no residual disease require dosage adjustment for 5-FU.
or minimal residual disease at second-look surgery. The regimen 5-FU distributes to all areas of body water by simple dif-
was fairly well tolerated, although there was one study-related fusion. Significant quantities of the drug may enter the central
patient death from a bowel perforation and resulting complica- nervous system, and after 15 mg/kg given IV, CSF levels of 6 to
tions. Other major clinical complications were nausea, vomiting, 8 10-6 M are obtained after 30 minutes. These levels persist
and the formation of intra-abdominal adhesions. Grade 3 to for several hours and slowly subside. Although distribution to
4 leukopenia and thrombocytopenia occurred in 30% and brain tissue is less rapid, abnormal areas, such as those with
6%of cycles, respectively (328). neoplasms, may more readily take up the drug.
Etoposide in combination with other chemotherapeutic 5-FU achieves high and persistent levels in effusions after IV
agents and autologous stem-cell rescue is often used in salvage administration. Hepatic administration through the portal vein
therapy for germ-cell tumors or metastatic trophoblastic disease. or artery also achieves high concentrations in the liver paren-
Two commonly used regimens are bleomycin, etoposide, and cis- chyma and produces relatively low systemic levels.
platin (BEP); and ifosfamide, carboplatin, and etoposide (ICE) Santini and colleagues (338) showed that therapeutic moni-
(329,330). toring of 5-FU levels in patients with head and neck cancer can
be used to improve the therapeutic index of the drug (i.e., less
toxicity with maximal efficacy).
5-Fluorouracil and Floxuridine
Chemistry Administration and Dosage
5-Fluorouracil (5-FU) is a fluorinated pyrimidine differing from Doses of 5-FU to be given by the IV push route do not require
the normal DNA substrate, uracil, by a fluorinated number further dilution from the commercial solution. Vein patency
5 carbon (chemically, 5-fluoro-2,4(1H,3H)-pyrimidinedione). should be assured before giving a dose, with a 5- to 10-mL flush
5-FU has activity as a second-line agent in advanced ovar- of normal saline or D5W and another flush after the dose to
ian and cervical cancers and, in combination with cisplatin, rinse the remaining drug from the tubing. For short infusions
is used as an adjunct to radiation therapy in women with (<24 hour), the rate of administration is not critical, and the
locally advanced cervical cancer. Floxuridine (FUDR) is dose should be given at a rate compatible with the particular
highly similar to its prodrug, 5-FU. The discussion of FUDR vein selected. The patient should be continuously monitored to
in this chapter will be limited to its special application as an guard against extravasation. Most doses can be conveniently
IP-administered agent for salvage therapy for ovarian cancer. given over 1 to 2 minutes in this fashion.
5-FU is light sensitive and precipitates at low temperatures or, Continuous infusions (over 4 to 5 days) may maximize effi-
occasionally, with prolonged standing at room temperature. cacy of this cycle-specific drug and lessen hematologic toxicity
It has the molecular formula of C4H3FN2O2 and a molecular (339341). Infusions of the drug may be added to a conve-
weight of 130.08. nient volume of D5W or normal saline, and each reconstituted
daily dose can be administered over 24 hours. Commonly, the
Mechanism of Action daily dose of the drug is added to 1 L, although volume is not
5-FU acts as a false pyrimidine or antimetabolite ultimately critical.
to inhibit the formation of the DNA-specific nucleoside base Regimens reported for the use of 5-FU include the use of a
thymidine. There are at least 3 mechanisms of action: inhi- loading dose, weekly IV bolus, continuous infusions over 4 to
bition of thymidylate synthase by 5-fluoro21-deoxyuridine- 5 days or over 6 weeks, and oral dosing. 5-FU may be administered
5-monophosphate (FdUMP), the active metabolite of 5-FU; intravenously as a bolus, rapid injection on a monthly (425 to
incorporation of 5-fluorouridine triphosphate (FUTP) into cel- 450 mg/m2 IV on days 1 to 5 every 28 days) or a weekly schedule
lular RNA; and incorporation of FUTP into cellular DNA (331). (500 to 600 mg/m2 every week for 6 weeks, every 8 weeks), or
5-FU is a cell cycle phase-specific agent with cytotoxic effects continuous IV infusion (24-hour infusion 2,400 to 2,600 mg/m2
seen maximally in S phase. every week; 96-hour infusion 800 to 1000 mg/m2/day; or 120-hour
infusion 1,000 mg/m2/day on days 1 to 5 every 21 to 28 days)
(79). Oral doses of up to 15 to 20 mg/kg/day for 5 to 8 days
Drug Disposition have been used (342). However, the efficacy of oral 5-FU has not
There is disagreement over whether 5-FU is eliminated by a been confirmed at this time (see Capecitabine section above for a
2-compartment or 3-compartment model (2,332,333). Fraile discussion of the oral prodrug of 5-FU).
and associates (334) demonstrated that plasma levels of 5-FU The loading dose scheme calls for one course of 400 to
after oral administration are quite erratic. Schaaf and colleagues 500 mg/m2 (12 mg/kg; maximum of 800 mg) daily for 5 days
(335) documented that the pharmacokinetic characteristics of every 28 days given as a single daily bolus injection or as a
5-FU are nonlinear. Doubling of the dose was accompanied by a 4-day continuous infusion. This is followed by a weekly main-
decrease in nonrenal clearance. The half-life from the high dose tenance regimen. Horton and coresearchers (343) and Jacobs
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 393
and coworkers (344), however, strongly associated the use of the capecitabine, BOF-A2, ftorafur, UFT, and S-1 (349,350).
loading dose with significant morbidity and occasional fatali- Although there is no indicated treatment for PPE, the incidence
ties, and suggested that it offers no greater antitumor efficacy has been reduced to a few percentage points by limiting 5-FU
over a weekly bolus injection of 15 mg/kg given IV. continuous infusion durations to 21 days with at least 1 addi-
Maintenance of 5-FU dosing regimens include the following: tional week off drug. Possible therapies that are yet to be evalu-
200 to 250 mg/m2 (6 mg/kg) every other day for 4 days, repeated in ated in clinical trials include DMSO, systemic corticosteroids,
4 weeks (if toxicity has resolved); or 500 to 600 mg/m2 (15 mg/kg), and pyridoxine (vitamin B6) (349,351).
given IV weekly as a continuous infusion or bolus injection (with Hyperpigmentation over the veins used for 5-FU admin-
and without the loading dose). istration has been observed (352). In one instance, the veins
By continuous infusion, higher daily doses have been suc- remained patent, but there was marked darkening of the skin
cessfully used, and many investigators have reported lessened immediately over the vein.
hematologic toxicity and enhanced efficacy. Most of a dose is 5-FU may also cause an acute cerebellar syndrome that can
eliminated by the liver and the remainder by the kidney. There- persist beyond the period of actual treatment (353,354). Neu-
fore, marked dysfunction in either system probably requires a rotoxicity may be evidenced by headache, minor visual distur-
dose reduction. bances, cerebellar ataxia, or all 3. This is a rare complication.
There are 2 commonly used dosing regimens for 5-FU The neurotoxic metabolite is probably fluorocitrate.
combined with leucovorin: 370 mg/m2/day of 5-FU for 5 days Cardiotoxicity is a rare but potentially serious toxicity attrib-
plus leucovorin given as a continuous infusion of 500 mg/m2/day, utable to 5-FU. The incidence of cardiotoxicity may vary from
The procedure was relatively well tolerated locally, although (70 to 285 minutes) at various total doses (500 to 3,600 mg/
there were 2 instances of catheter-related bacterial peritonitis m2) (372). There is a three- to fourfold interpatient variability
that were easily managed. Concentrations of 4 103 M for in pharmacokinetics. As noted above, gemcitabine is metabo-
36 hours caused mucositis, pancytopenia, and alopecia. The sys- lized intracellularly by deoxycytidine kinase to form the active
temic toxicities were quite severe with the highest dose tested diphosphate and triphosphate metabolites. The drug is inacti-
(8 103 M). Pharmacokinetic studies revealed first-order drug vated both intracellularly and extracellularly by cytidine deami-
elimination, with an IP half-life of 72 to 112 minutes. Intra- nase to form difluorodeoxyuridine (dFdU). Of the administered
peritoneal drug levels were 300-fold greater than simultaneous gemcitabine dose, 99% is excreted in the urine either as the par-
plasma levels. Intraperitoneal 5-FU administration appears to ent compound (<10%) or as dFdU (373,374).
produce high drug concentrations with minimal systemic tox- Dutch researchers have performed a pharmacokinetic schedule-
icity. Objective responses were documented in 2 of 7 patients finding study of gemcitabine plus cisplatin. Gemcitabine
studied in this phase I investigation. The investigators recom- 800 mg/m2 was administered as a 30-minute infusion either
mended further IP 5-FU investigation at initial drug concentra- 4 hours before, 24 hours before, 4 hours after, or 24 hours after
tions of 4 103 M (500 mg/L) for 36 hours (361). administration of cisplatin 50 mg/m2 by 1-hour IV infusion.
Suhrland and Weisberger (362) used intracavitary 5-FU Neither of the dosing schedules that used a 4-hour interval
to manage malignant pleural effusions from carcinoma of between drug administrations resulted in significant pharma-
the breast and lung tumors and to control malignant ascites cokinetic or pharmacologic differences. However, when gem-
from ovarian carcinoma. Approximately 38% of the patients citabine was administered 24 hours before cisplatin, there was a
responded to a single intracavitary dose of 2 to 3 g. For peri- twofold decrease in the plasma AUC of platinum. Furthermore,
cardial effusions, doses of 500 to 1,000 mg were used. Repeat when the order of the drugs was reversed (i.e., cisplatin was
dosing was not necessary. Patients with pleural effusions also administered 24 hours before gemcitabine), there was a 1.5-fold
tended to respond better than those with ascites. Although side increase in the concentration-time product of the active triphos-
effects were minimal in this study, some systemic toxicity was phate metabolite of gemcitabine within white blood cells. On
consistently produced. the basis of these results, the investigators conducted a phase II
study of the cisplatin/gemcitabine combination wherein cispla-
tin was administered 24 hours prior to gemcitabine (375).
Gemcitabine
Chemistry Administration and Dosage
Gemcitabine (Gemzar) is a relatively new chemotherapeutic Gemcitabine should be diluted in 0.9% sodium chloride to a
agent that was approved by the FDA in 1995 for the treatment concentration of no greater than 40 mg/mL (higher drug con-
of patients with advanced pancreatic cancer based on an increase centrations may result in incomplete dissolution). Gemcitabine
in survival and clinical benefit (improvement in pain and perfor- is generally administered as a 30-minute IV infusion at a dose of
mance status). The combination of gemcitabine plus cisplatin also 1,000 mg/m2; infusion durations of greater than 60 minutes are
is FDA approved and is considered standard therapy for patients associated with dose-limiting flu-like symptoms (376).
with advanced non-small cell lung cancer. Gemcitabine has dem- The standard dosing schedule used for treatment of pan-
onstrated significant activity in advanced ovarian cancer patients creatic cancer is 1,000 mg/m2 by 30-minute IV infusion once
and is active against refractory ovarian cancer and cervical cancer, weekly for 7 weeks for cycle 1 followed by a 1-week rest and
as well as other solid tumors (363367). Gemcitabine is a syn- then 1,000 mg/m2 once weekly for 3 weeks followed by a 1-week
thetic nucleoside analog with a structure that is highly similar to rest for subsequent cycles (377).
deoxycitidine and cytosine arabinoside (ara-C). Gemcitabine HCl Multiple phase II studies of single-agent gemcitabine in
is 2-deoxy-2,2-difluorocytidine monohydrochloride ( isomer). refractory/recurrent ovarian cancer have used a dosing schedule
The empiric formula for gemcitabine is C9H11F2N3O4 HCl and of 800 to 1,250 mg/m2 once weekly for 3 weeks followed by a
the agent has a molecular weight of 299.66. week of rest; however, doses above 1,000 mg/m2 may be associ-
ated with higher toxicity (364,366,378).
Mechanism of Action In vitro studies have shown synergism between gemcitabine
Gemcitabine is a prodrug and undergoes multiple phosphoryla- and cisplatin in a variety of human cancer cell lines (379,380).
tions by deoxycytidine kinase at the intracellular level to form It is believed that this synergism is primarily the result
the active diphosphate and triphosphate metabolites. The tri- of increased platinum-DNA adduct formation (380). An increase
phosphate is incorporated into DNA as a fraudulent base pair. in DNA-platinum adducts has also been demonstrated for
Following the insertion of gemcitabine, one additional deoxy- the combination in the clinical arena (381). As noted (see
nucleotide is added to the end of the DNA chain before repli- Drug Disposition section above), the interval between cisplatin
cation is terminated. This process is known as masked chain and gemcitabine administration can affect both pharmacoki-
termination and prevents exonucleases from excising off the netic and pharmacologic parameters (375). This combination
fraudulent base pair (368,369). The diphosphate inhibits ribo- appears to be especially promising for patients with advanced
nucleotide reductase and thereby depletes the deoxynucleotide ovarian cancer. Several phase II studies have been conducted
pools that are necessary for DNA synthesis and repair (370). in previously untreated ovarian cancer patients using a dosing
Inactivation of gemcitabine occurs when the drug is metabolized schedule of cisplatin (75 to 100 mg/m2) on day 1 followed by
by cytidine deaminase (both intracellulary and extracellulary) to gemcitabine 1,250 mg/m2 days 1 and 8 (363,382,383). Others
form difluorodeoxyuridine (371). have performed phase II studies of gemcitabine plus cisplatin for
patients with relapsed ovarian cancer after prior platinum-based
chemotherapy and have determined that cisplatin 30 mg/m2
Drug Disposition plus gemcitabine 600 to 750 mg/m2 on days 1 and 8 every 21 days
Following administration of gemcitabine 1,000 mg/m2 by is an active and tolerable regimen that demonstrated activity in
30-minute IV infusion, the parent compound undergoes rapid platinum-resistant patients (130,384).
clearance in a diphasic manner. The plasma half-life and clearance A phase III study comparing 4 different carboplatin-
are dose, age, and gender dependent. Gemcitabine pharma- based regimens with the standard regimen of carboplatin +
cokinetics were evaluated in 353 patients with varied solid paclitaxel for the first-line treatment of ovarian cancer showed
tumors using short infusions (<70 minutes) and long infusions very similar survival and progression-free survival for the
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 395
gemcitabine-containing arm, confirming the activity of gemcitabine lessthan10% of patients following gemcitabine administration.
but not demonstrating superiority over standard treatment. This toxicity generally occurs within a few hours of treatment
and resolves within 6 hours (385).
Fatal pulmonary toxicity (acute respiratory distress syn-
Side Effects and Toxicities drome) has been reported as a rare side effect of gemcitabine
Gemcitabine-induced toxicity is highly schedule dependent; therapy (387). Symptoms include progressive dyspnea, tachy-
small daily doses are associated with greater toxicity than large pnea, marked hypoxemia, and bilateral interstitial infiltrates
doses administered on a weekly basis (385). The dose, schedule, consistent with pulmonary edema. Some patients have responded
and duration of infusion of gemcitabine directly affect the toxic- to the termination of gemcitabine therapy and treatment with
ity profile (385). Infusion durations of more than 60 minutes are corticosteroids and diuretics. Prior radiation therapy to the medi-
associated with increased myelosuppression and hepatic toxic- astinum may be a risk factor for gemcitabine-induced pulmonary
ity, whereas the administration of small daily doses results in edema (387,388).
dose-limiting flu-like symptoms (371,376). When gemcitabine Possible incompatibilities between gemcitabine solutions and
is administered using the standard weekly dosing schedule, ther- other drug solutions have not been studied.
apy is generally well tolerated and bone marrow suppression is
the major dose-limiting toxicity.
Analysis of safety data from 22 completed clinical trials in
Ifosfamide
which gemcitabine was administered on a weekly basis to 979 Chemistry
plasma decay with a half-life of 6.9 hours and a metabolized Morgan and colleagues (402) evaluated several IV push and
urinary recovery fraction of 72.8%, in contrast to the biexpo- infusion dose schedules in non-small cell lung cancer: 700 to
nential decay (plasma half-life 15.2 hours) of a single-bolus 900mg/m2/day by IV push for 5 days repeated every 3 weeks;
dose of ifosfamide (5,000 mg/m2). This finding suggests that 700 to 1,000 mg/m2/day for 5 days repeated every 3 weeks plus
the metabolic disposition of the drug may be dose dependent. 1 g/day of oral ascorbic acid; 4 g/m2 slow infusion repeated every
These half-lives are approximately twice those reported for 3 weeks; and 900 mg/m2 by IV push weekly. There appeared to
cyclophosphamide. Of note, a longer ifosfamide half-life may be be less hematuria produced with the sequential 5-day schedule
seen in obese patients who are more than 20% over ideal body with concomitant ascorbic acid.
weight. The renal clearance rate of ifosfamide is about twice Rodriguez and colleagues (403) described a 47% response
that for cyclophosphamide: 21.3 versus 10.7 mL/min in bolus rate in leukemia patients with continuous infusions of ifosfamide
dosing and 18.7 versus 10.7 mL/min with fractionated doses. at 1,200 mg/m2/day given for 5 days. Significant genitourinary
Only about half of an ifosfamide dose is metabolized compared toxicity was not encountered, and myelosuppression predomi-
with approximately 90% for cyclophosphamide. This reflects nated as the dose-limiting toxicity. In combination with other
a substantial difference in the metabolic clearance capacity for cytotoxic drugs, such as doxorubicin or lomustine (CCNU), a
the 2 analogs. Although more intact (inactive) ifosfamide than single IV push dose of 1,000 mg/m2 (not to exceed 12,500 g total)
cyclophosphamide is renally excreted, urinary alkylating activity has been recommended.
persists longer with ifosfamide.
Creaven and coworkers (395) demonstrated that because
unchanged ifosfamide, but not metabolites, penetrates the Side Effects and Toxicities
blood-brain barrier, alkylating activity in the CSF may occur Creaven and associates (395) reviewed the clinical toxicity of
but is probably negligible. ifosfamide given as a large bolus injection (200 to 10,000 mg/m2)
and in a fractionated 3-day (2,400 mg/m2/day) schedule. Urinary
tract toxicity is the dose-limiting factor with both schedules.
Administration and Dosage The clinical hallmark is hemorrhagic cystitis, which is caused
Ifosfamide is reconstituted by the addition of sterile water to by excretion of active alkylating metabolites into the urinary
the vial, which should be shaken to dissolve. Ifosfamide may bladder. Vigorous hydration with oral and IV fluids and con-
be further diluted to a concentration of 0.6 to 29.0 mg/mL in comitant mesna are needed to prevent serious ifosfamide-
5% dextrose or 0.9% sodium chloride. It is administered intra- induced bladder damage. Hydration may also overcome the
venously, usually by a short infusion. Ifosfamide may also be antidiuretic effects of this drug. Nelson and colleagues (398)
administered by slow IV push in a 75-mL minimal volume of used IV furosemide (20 to 40 mg) to maintain adequate urine
sterile saline solution but not water and infused over at least flow in a phase I study of ifosfamide. Diuretic responses usually
30 minutes or by continuous infusion over 5 days. Large single occurred within 1 hour.
doses of ifosfamide produce much more toxicity than fraction- Symptoms of dysuria and urinary frequency appear to par-
ated schedules, which are therefore preferred in solid-tumor allel those of hematuria. The onset of symptoms is 1 to 2 days
treatment regimens. Adequate hydration of the patient before after injection, with an average duration of 9 days (range, 1 to
and for 72 hours after ifosfamide therapy is recommended to 41 days) (404). Dose-related ifosfamide-induced nephrotoxic-
reduce the incidence of drug-induced hemorrhagic cystitis. The ity was detected by elevation of BUN, producing subsequent
use of a concurrent prophylactic agent for hemorrhagic cystitis, dose-related uremia in 66% of patients receiving 150 mg/kg.
such as mesna (Mesnex), is required to prevent severe hematuria Other lesions seen at autopsy (4 of 7 patients) included evi-
from high-dose ifosfamide. At least 2 L of fluid each day is rec- dence of acute tubular necrosis and pyelonephritis. At low
ommended to produce a copious urine output. daily doses, granular cylindruria was seen in all patients,
Continuous infusions of ifosfamide over 24 hours have also denoting marked tubular damage. The cylindruria cleared
been given every 3 weeks (397). Mesna can be given concurrently within 10 days of drug discontinuance (404). DeFronzo and
in the same infusion container or as a 4-hour intermittent IV co-researchers (405) also described glomerular dysfunction
bolus (398). However, renal toxicities may be increased with the and a Fanconi-type picture in a patient treated with ifosfamide.
single, large infusions. Extravasation of the drug should not cause Prior cisplatin therapy may also increase ifosfamide-induced
tissue necrosis, but one such case has been described (399). nephrotoxicity (406,407).
The FDA-approved dose for testicular cancer is 1,200 mg/m2/ Nausea and vomiting appear to be common and are more
day for 5 consecutive days every 21 days. Other dosage sched- severe after a rapid injection of large ifosfamide doses. Emesis
ules include 2,000 mg/m2 IV continuous infusion on days 1 to 3 typically begins within a few hours of administration and per-
every 21 days as part of the MAID regimen (mesna, Adriamycin, sists for an average of 3 days (range, 1 to 28 days) (404).
infosfamide, dacarbazine) for soft-tissue sarcoma; 1,000 mg/m2 Hematologic toxicity from ifosfamide usually involves only
on days 1 and 2 every 28 days as part of the ICE regimen (ifos- a mild to moderate degree of leukopenia in most patients. In a
famide, carboplatin, etoposide) for non-Hodgkins lymphoma; review by Creaven and coworkers (395), significant thrombocy-
and 1,000 mg/m2 on days 1 to 3 every 21 to 28 days as part of topenia was not encountered for any of the dose schedules used.
the TIC regimen (paclitaxel, ifosfamide, carboplatin) for head Lethargy and confusion are seen with high doses of ifos-
and neck cancer (79). famide and may be caused by the chloracetaldehyde metabolite.
A phase II study evaluated ifosfamide (1,500 mg/m2 IV over Nelson and associates (398) observed that this lasted from 1 to
1 hour, days 1 to 3) with mesna in combination with paclitaxel 8 hours, was spontaneously reversible, and was related to the
(175 mg/m2, IV over 3 hours on day 1) and cisplatin (75 mg/m2 passage of intact drug into the central nervous system (CNS).
IV over 2 hours on day 2) as first-line therapy in advanced, Seizures, ataxia, stupor, and weakness have been reported after
suboptimally debulked epithelial ovarian cancer patients (400). ifosfamide. These effects may be increased by concomitant neuro-
This regimen was associated with an 85% objective response toxic drugs, such as certain antiemetics, tranquilizers, narcotics,
rate and a median overall survival of 52.8 months in 22 patients and antihistamines. There is a single case report of nonconvul-
with stage III or IV disease. A regimen of paclitaxel (175 mg/m2), sive status epilepticus associated with ifosfamide therapy. The
ifosfamide (5,000 mg/m2), and cisplatin (75 mg/m2 or 50 mg/m2 patient responded to discontinuation of the ifosfamide and phe-
in irradiated patients) every 21 days in 45 recurrent or persistent nytoin therapy (408). Although alkylating metabolites appear
cervical cancer patients was associated with a 67% objective to penetrate the bloodbrain barrier, the levels achieved are too
response rate (401). low to be useful in the treatment of CNS tumors (395).
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 397
Alopecia is usually seen with ifosfamide, especially when large has a molecular weight of 677.19 and the empirical formula is
bolus doses are used. In a study by Van Dyk et al. (404), the aver- C33H38N4O6 HCl 3H2O.
age onset of maximal hair loss was 19 days (range, 11 to 32 days)
after the start of treatment. Mechanism of Action
Hepatic enzyme elevations have been described in some
patients. The elevations in alkaline phosphatase and serum Irinotecans cytotoxicity is believed to be related to the inhibition
transaminase are transient and typically resolve rapidly without of TOPO-I, an enzyme necessary for DNA replication (298).
sequelae. Irinotecan is activated to the active metabolite SN-38 by
the liver (409). Irinotecan and SN-38 bind to the transient
TOPO-I-DNA complex, stabilize the complex, and thereby pro-
Special Precautions mote DNA single-strand breaks. These strand breaks prevent
The patient must be kept well hydrated during ifosfamide ther- DNA replication and result in cell death (298,409). Current
apy to reduce the potential for hemorrhagic cystitis. The use of research suggests that the cytotoxicity of irinotecan is due to
mesna given IV or orally is required to prevent hemorrhagic cys- DNA damage produced during DNA synthesis. Mammalian
titis. Table 14.5 outlines the recommended mesna schedule for cells cannot repair these double-strand breaks.
ifosfamide uroprotection.
Patients who have received previous or concurrent therapy Drug Disposition
with radiation or cytotoxic drugs may require significant ifos-
famide dosage reductions. Dose reductions should also be con- Pharmacokinetic studies performed by Rothenberg et al. (410)
reduce dose by 25% before returning to the original dose level; rate averages 11% (430). Melphalan penetration into cerebro-
grades 2 to 4delay up to 2 weeks until resolved, if no resolution spinal fluid is low. Plasma protein binding ranges from 60% to
to grades 0 to 1, discontinue; grades 3 to 4after delay and 90%, and approximately 30% is irreversibly bound to plasma
resolution to grades 0 to 1, decrease dose by 25%, if no resolu- proteins.
tion, discontinue). To help relieve pain from PPE, topical wound Studies of melphalan metabolism, using an isolated per-
care, elevation, and cold compresses may be used as supportive fused rat liver model and in vitro rat microsomal enzyme
care (351). Topical DMSO has been used to treat skin extrava- preparations, have documented insignificant hepatic biotrans-
tions (99% DMSO 4 times daily up to 14 days), but has yet to formation (431).
be evaluated in a randomized trial (349). Other possible thera- Two groups of investigators have reported that the systemic
pies that are yet to be evaluated in clinical trials include systemic availability of melphalan is increased if the drug is administered
corticosteroids and pyridoxine (vitamin B6) (351). in the fasting state. The presence of a large meal appears to
Infusion-related reactions occur in less than 10% of patients enhance melphalan degradation at the alkaline pH found in the
treated with liposomal doxorubicin and are most common dur- upper small bowel before systemic absorption (432,433).
ing the first course of treatment. Symptoms may include flushing, Patients with multiple myeloma receiving IV melphalan
shortness of breath, facial swelling, headache, chills, back pain, achieved longer durations of survival than those receiving the
tightness in the chest and throat, and hypotension. Alopecia has oral formulation. Furthermore, a significantly lower dose of IV
been observed in only 15% of ovarian cancer patients treated drug was associated with life-threatening leukopenia and infec-
with liposomal doxorubicin. tious complications compared with the oral formulation (433).
tumor growth despite aggressive chemotherapy. Several mecha- Methotrexate undergoes a variable degree of polyglutama-
nisms have been postulated to explain this relatively universal tion intracellularly. The polyglutamated forms of the drug are
phenomenon. positively charged and do not readily pass through cell mem-
Melphalan therapy has been used in autologous bone mar- branes. Methotrexate polyglutamates form an intracellular
row transplantation. A series of studies have been reported pool of active drug that is retained for long periods, sometimes
for high-dose (120 to 225 mg/m2) IV-administered melphalan months, after a single dose (443). The ability of tumor cells to
against adult melanoma, breast, and colon cancers (438,439). add t-glutamyl residues to methotrexate may be a key determi-
Although the resulting high response rates appear to be prom- nant of antitumor activity.
ising, most have been partial, and survival advantages have The effects of methotrexate are rapidly reversible as free
not yet been established. In general, these high doses of mel- methotrexate leaves the cells. The normal intracellular levels of
phalan have been tolerated relatively well, with diarrhea and dihydrofolate are very low (108 M) but increase greatly after
stomatitis becoming severe and dose-limiting at doses greater methotrexate administration.
than 200 mg/m2. Resistance to methotrexate may develop as a result of ele-
Because ovarian cancer remains confined to the IP space for vated dihydrofolate reductase activity or defective transport
most of its natural history, there has been increasing interest in of methotrexate into malignant cells. Increased dihydrofolate
the IP administration of cytotoxic drugs to patients with minimal reductase enzyme levels may also result from amplification of the
residual IP disease (i.e., plaques <1 cm in diameter) after aggres- dihydrofolate reductase gene, a process associated with homo-
sive cytoreductive surgery or primary chemotherapy. Melphalan geneously staining regions of chromosomes and an unstable
exhibits a high degree of in vitro cytotoxicity compared with inheritance mediated by double minutes or extra chromosomal
other standard chemotherapeutic agents when tested against fresh DNA fragments (444). Certain quinazolines have been shown
human ovarian cancer tumors at drug concentrations achievable to be effective inhibitors of thymidylate synthetase and may
by IP administration (440). In addition to its high degree of cyto- be useful clinically in overcoming this type of resistance (445).
toxicity, melphalans high molecular weight ensures a relatively In vitro studies and clinical experimentation with high-dose
low clearance from the peritoneal space. therapy indicate that a major mechanism of resistance is prob-
In a phase I dose-finding study, Howell and coworkers (441) ably secondary to decreased cellular uptake.
showed that an IP melphalan dose of 70 mg/kg was tolerated, Methotrexate is classified as a cell cycle phase-specific anti-
with only moderate leukopenia (median nadir 2,000 cells/L) metabolite with activity mostly in S phase. Experimentally,
and thrombocytopenia (median nadir 69,000 platelets/L) methotrexate synchronizes tumor cells in S phase about 36 to
and no evidence of peritoneal irritation. The peak perito- 72 hours after administration (446).
neal concentration averaged 93-fold greater than the plasma The enhanced toxic effect on tumors compared with normal
concentration, and total drug exposure for the peritoneal cavity tissue from high-dose methotrexate with leucovorin rescue
averaged 63-fold greater than that for the plasma. may be a result of bypassing normal carrier-mediated cell mem-
brane transport of methotrexate. Leucovorin and its metabo-
Methotrexate lite, 5-methyltetrahydrofolate, share a common influx transport
site with methotrexate. There appear to be at least 2 active
Chemistry transport carrier systems involved in the influx and efflux of
methotrexate and folates (447). If normal cells are rescued with
Methotrexate is an active drug in the first-line treatment of
calcium leucovorin, methotrexate can then exert a relatively
gestational choriocarcinoma, chorioadenoma destruens, and
greater toxic effect on the tumor cells. Selective rescue of normal
hydatidiform mole. It is used in the prophylaxis and treatment
cells may be mediated by a slower rate of DNA synthesis relative
of meningeal leukemia, and is used in combination with other
to the tumor cell or to tissue-specific differences in transmem-
agents for the treatment of breast cancer, epidermoid cancers of
brane transport.
the head and neck, advanced mycosis fungoides, advanced non-
Hodgkins lympoma, lung cancer, and metastatic squamous-cell
cancer of the cervix. Methotrexate is a cell cycle-specific antifo- Drug Disposition
late analog, which differs from folic acid in 2 substitutions: an
Orally administered methotrexate is rapidly but incompletely
amino group for a hydroxyl in the pteridine portion of the mol-
absorbed from the gastrointestinal tract. It reaches peak blood
ecule and a methyl group on the amino nitrogen between the
levels in approximately 1 hour. Approximately 50% to 60% of
pteridine nucleus and the benzoyl group of 4-amino-10-methyl
the drug in the blood is bound to plasma proteins. Methotrex-
folic acid. Chemically, methotrexate is N-[4-[[(2,4-diamino-6-
ate is widely distributed to body tissues. In conventional doses,
pteridinyl)methyl]benzoyl]-L-glutamic acid. It is a weak acid,
methotrexate is excreted unchanged in the urine. In high doses,
with a molecular weight of 454.45 and a molecular formula
it is partially metabolized to 7-hydromethotrexate, which is only
of C20H22N8O5. It is only slightly soluble in water and alcohol.
slightly soluble in acidic solutions. Approximately 1% to11%
Sodium methotrexate is water soluble and is used in injectable
of a dose is excreted as the 7-hydroxy metabolite, and this may
preparations.
comprise as much as 35% of the drug level in the terminal elimi-
nation phase. Only about one-third of an oral dose is absorbed,
Mechanism of Action but intramuscular absorption is almost 100% (448).
Free intracellular methotrexate tightly binds to dihydrofolate The hepatic extraction coefficient for methotrexate appears
reductase, blocking the reduction of dihydrofolate to tetrahy- to be very low, and intraarterial hepatic doses show metabo-
drofolic acid, the active form of folic acid. As a result, thymi- lism and pharmacokinetics similar to those of IV doses (449).
dylate synthetase and various steps in de novo purine synthesis Methotrexate is both filtered at the glomerulus and actively
that require 1-carbon transfer reactions are halted. This in turn secreted by the renal tubule. Drugs that interfere with renal
arrests DNA, RNA, and protein synthesis. excretion of weak acids, such as probenecid, sulfinpyrazone,
Amino acid syntheses blocked by methotrexate include those and salicylates, may reduce the rate of methotrexate excretion.
requiring 1-carbon transfer, such as the conversion of glycine to Probenecid has been used successfully in one study to produce a
serine and homocysteine to methionine. Experimental studies prolonged elevation of plasma methotrexate levels from other-
have shown that thymidylate synthetase is inhibited at metho- wise low doses of methotrexate (450).
trexate concentrations of 108 M or less, but inhibition of purine Plasma decay of methotrexate levels have been reported to be
synthesis requires concentrations of 107 M or greater (442). biphasic and possibly triphasic. Huffman and associates (451)
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 401
reported half-lives after a 30 mg/m2 dose to be triphasic: 0.750 Dermatologic side effects include erythematous rashes, pruri-
0.11, 3.49 0.55, and 26.99 4.44 hours, respectively. Stoller tus, urticaria, folliculitis, vasculitis, photosensitivity, depigmen-
and colleagues (452) reported a biphasic plasma decay for high- tation, or hyperpigmentation. Alopecia may occur, with several
dose therapy of 2.06 0.16 and 10.4 1.8 hours. Wang and months being required for regrowth. CNS effects include diz-
coresearchers (453) reported age-dependent biphasic elimination ziness, malaise, and blurred vision. Encephalopathy also has
of high-dose methotrexate. been reported. Intrathecal administration has been followed by
Patients with pleural effusions may accumulate methotrex- increased CSF pressure, convulsions, paresis, and a syndrome
ate that slowly distributes from this compartment back into the resembling the Guillain-Barr syndrome (384). Deaths have
plasma to increase systemic exposure and the risk of toxicity been reported after intrathecal therapy. Renal failure may occur
(454). Effusions should be drained before administration of in patients receiving methotrexate, especially in high doses. This
methotrexate. risk may be decreased by alkalinization of the urine to increase
methotrexate solubility and by giving large quantities of fluid.
Other reactions rarely reported include chills and fever, osteopo-
Administration and Dosage rosis, and pulmonary reactions, mainly fibrosis (456).
Methotrexate may be given by the oral, intramuscular, IV
(IV infusion or push), intraarterial, or intrathecal routes. For Drug Interactions
treatment of neoplastic disease, oral administration of low-dose
Potential drug interactions have been postulated to occur with
methotrexate is preferred, owing to the rapid absorption of the
other protein-bound drugs, such as salicylates, sulfonamides,
penetrates into ascites fluid and reaches maximal concentrations include thrombocytopenia, circulating schistocytes, and acute
of 0.05 g/mL 1 hour after administration. This distribution renal failure. Histopathologic examinations of the kidneys
represents approximately 40% of the total plasma exposure. reveal fibrin thrombi in arterioles, tubular atrophy, and wide-
The drug also appears to slightly concentrate in cervical tissues spread glomerular necrosis.
after IV administration (475). Veno-occlusive disease of the liver has been reported after
With intraarterial administration, the hepatic extraction of high-dose mitomycin therapy and autologous bone marrow
mitomycin averages only 23% (476). The calculated relative transplantation (482). Signs include progressive hepatic dys-
advantage for hepatic arterial infusions is only 2.5- to 3.6-fold function, abdominal pain, and ascites. Although this rarely has
greater than for other methods. been observed with low-dose therapy, it appears to be much
more frequent after high-dose regimens.
Administration and Dosage Alopecia may occur after mitomycin therapy, but it is usually
not severe. Rarely, purple bands in the nail beds correspond to
Sterile water (10 mL) should be added to each 5-mg vial of
sequential doses of the drug. Lethargy or weakness may occur
mitomycin and shaken gently to dissolve. Mitomycin should be
and can last from several days to 3 weeks. Fatigue and some
administered IV to avoid extravasation of the drug. If extrava-
drowsiness or confusion has also been observed. Dose-related
sation occurs, severe local tissue necrosis may occur (477). The
skin reactions and fever with drug administration are occasion-
drug is usually given by a slow IV push, with continuous patient
ally seen.
monitoring to lessen the chance of extravasation. Short infusions
Severe soft-tissue ulcers may also be expected if the drug
in 100 to 150 mL of D5W or normal saline have also been used.
metabolism and subsequent biliary excretion (497). Approxi- The FDA-approved recommended regimen for salvage
mately 70% to 80% of the drug is eliminated by fecal excretion. therapy for patients with platinum-refractory ovarian cancer is
paclitaxel 135 or 175 mg/m2 administered IV over 3 hours every
3weeks, but the optimal regimen has not clearly been established.
Administration and Dosage Paclitaxel has been administered by various other schedules
All patients undergoing paclitaxel therapy should receive pre- during investigational studies in patients with solid tumors,
medication to prevent severe hypersensitivity reactions. A rec- including 135 to 250 mg/m2 as a 24-hour continuous infusion
ommended regimen is dexamethasone (either 20 mg orally the every 3 weeks; 212 to 225 mg/m2 as a 6-hour infusion every 3 weeks;
night before treatment and the morning of treatment, or 20 mg 30 mg/m2 as a 1-hour infusion daily for 5 days every 3 weeks;
IV 30 minutes before paclitaxel delivery) plus diphenhydramine 30 mg/m2 as a 6-hour infusion daily for 5 days every 3 weeks; 120 to
(50 mg) and famotidine (20 mg) IV 30 minutes before chemo- 140 mg/m2 as a 96-hour infusion every 3 weeks; and 150 mg/m2
therapy (498). For the majority of patients, administration of as a 120-hour infusion every 3 weeks (177). Most recently,
dexamethasone 20 mg IV 30 to 60 minutes before paclitaxel IP therapy for optimally debulked advanced ovarian cancer
is sufficient and has been proven to be effective in preventing demonstrated a significant survival advantage with a regimen
hypersensitivity reactions. of IV paclitaxel on day 1, IP cisplatin on day 2, and IP paclitaxel
Paclitaxel is commercially available as an injection concen- on day 8 (see Intraperitoneal Drug Pharmacokinetics and Cispla-
trate in 30-mg (5 mL), 100-mg (16.7 mL), and 300-mg (50 mL) tin sections of this chapter for more details on this IP regimen)
multidose vials. Before infusion, paclitaxel must be diluted with (4,154,155,502).
treatment of small-cell lung cancer after failure of first-line che- lactone and hydroxy acid forms of topotecan at 2 hours, after
motherapy. Topotecan is a semisynthetic analog of camptothecin. a 30-minute infusion, reliably predicted the lactone form AUC,
The parent compound is derived from the bark of an ornamental the hydroxy acid AUC, the total topotecan AUC, and the clear-
tree native to Asia, Camptotheca acuminata. Sodium camptoth- ance rate.
ecin was studied in clinical trials in the late 1960s through the
early 1970s. However, clinical development of this agent was Administration and Dosage
halted despite evidence of a variety of tumor responses because
Each 4-mg vial of topotecan should be reconstituted with 4 mL
of severe and unpredictable toxicities (e.g., myelosuppression
of sterile water. The resulting solution can be further diluted
and hemorrhagic cystitis) (520). Topotecan and other camptoth-
with either 0.9% sodium chloride or 5% dextrose. Because the
ecin analogs (e.g., irinotecan) have been formulated in an effort
active lactone form of topotecan is subject to a pH-dependent
to overcome unacceptable toxicities and to increase cytotoxicity
hydrolysis to the inactive hydroxy acid, consideration should
and water solubility. Topotecan incorporates a stable basic side
be given to maintenance of an acidic pH during drug infusion.
chain at the 9-position of the A-ring of 10-hydroxycamptoth-
When the topotecan lactone is dissolved in 5% dextrose, only
ecin, which increases aqueous solubility. The molecular weight
approximately 10% is converted to the hydroxy acid (415).
is 457.9 (the HCl salt) and the formula is C23H23N3O5 HCl
Because the product does not contain an antibacterial preserva-
(the free base has a molecular weight of 421.5). The chemical
tive, it should be used immediately once constituted.
name of topotecan is (S)-10-[(dimethylamino)methyl]-4-ethyl-
Parenteral topotecan has been administered by IV infusions
4,9-dihydroxy-1H-pyrano[3,4:6,7] indolizino [1,2-b]quinoline-
varying in length from 30 minutes to 21 days (409). As dis-
Although the results of the study described in the above para- may have activity as a radiation-sensitizing agent (541). However,
graphs led to the FDA approval of topotecan as salvage therapy this apparent synergistic relationship remains to be explored in
for patients with ovarian cancer, with a recommended dose level clinical trials.
of 1.5 mg/m2/day for 5 days, it is important to note that the
patients in this European study only received one prior plati- Special Applications
num-based chemotherapeutic regimen, and that most received
cisplatin (not carboplatin), and none had received prior pacli- Phase I trials of IP topotecan have demonstrated the feasi-
taxel. In general, topotecan-induced myelosuppression is more bility of IP administration and a favorable toxicity profile
severe in patients who have previously received carboplatin and/ (542,543). Pharmacokinetic studies revealed that the pharma-
or multiple prior chemotherapeutic regimens. For this reason, cologic advantage associated with IP administration of topo-
many clinicians use an initial topotecan dose of 1.25 mg/m2/day tecan (expressed as the ratio of the peritoneal to plasma AUC)
and/or administer prophylactic G-CSF. was 31.2 (543). In a Netherlands study, patients were treated
with escalating doses (5 to 30 mg/m2 every 21 days). The dose-
limiting toxicity was acute hypotension, chills, and fever at
Special Precautions the 30-mg/m2 dose level (542). The University of California,
Because topotecan has a high rate of renal excretion and a modest San Diego study treated patients with escalating doses from
hepatic clearance, a clinical study was conducted to evaluate the 2 to 4 mg/m2 every 21 days. The MTD of IP topotecan was deter-
impact of renal and hepatic dysfunction on toxicity in patients mined to be 4 mg/m2 every 21 days, and the recommended dose
undergoing treatment with topotecan on a daily 5 dosing for further phase II study was 3 mg/m2. The dose-limiting toxic-
schedule (534,535). Pharmacokinetic analyses showed clear cor- ity was neutropenia. Other toxicities included anemia, vomiting,
relations between creatinine clearance and plasma clearance of fever, and abdominal pain (543).
both topotecan and topotecan lactone (r2 = 0.65, p < 0.0001).
Although the standard dose for patients with good renal func-
tion is 1.5 mg/m2/day 5 days, this study determined that the Vinblastine Sulfate
recommended starting dose for patients with moderate hepatic
dysfunction (creatinine clearance of 20 to 39 mL/min) was 0.75 mg/ Chemistry
m2. The investigators urged extreme caution with topotecan Vinblastine (Velban) is used in the treatment of germ-cell tumors
administration in patients with more profound renal insufficiency of the ovary (544) and has demonstrated activity in early clinical
and recommend further dose reductions for heavily pretreated trials of cervical, endometrial, and ovarian cancers (544,545). In
patients (534). Hepatic insufficiency did not appear to exacerbate combination with other agents, it has also demonstrated activity
hematologic toxicity (534). Nonhematologic toxicity appeared to in early trials of ovarian cancer (546). Vinblastine, is the sulfate
be unaffected by either renal or hepatic insufficiency. salt of an alkaloid isolated from Vinca rosea (periwinkle). It
is structurally related to vincristine, another alkaloid isolated
Drug Interactions from the same plant. Vinblastine sulfate is a white to off-white
crystalline powder that is freely soluble in water, soluble in
Drug sequence of the paclitaxel/topotecan combination had no methane, and slightly soluble in ethanol. Its empiric formula is
apparent impact on hematologic toxicities or pharmacologic C46H58N4O9 H2SO4, and it has a molecular weight of 909.07.
behavior (536). However, drug sequence of the cisplatin/topotecan
combination did have a significant impact on toxicity and topo-
tecan pharmacokinetics. Prior administration of cisplatin signifi- Mechanism of Action
cantly reduced the clearance of topotecan (possibly as a result of Vinblastine binds to tubulin and inhibits microtubule assembly.
subclinical nephrotoxicity) and increased hematologic toxicity This inhibition prevents mitotic spindle formation and results in
(508). In GOG-182, carboplatin was administered on day 3 of an accumulation of cells in metaphase (547).
a daily 3 topotecan administration schedule, because admin- Vinblastine is considered cell cycle phase specific for mitosis;
istration of carboplatin on day 1 was associated with excessive however, the cytotoxic effect probably occurs in S phase and is
neutropenia and thrombocytopenia (537). expressed only in M phase. At high doses, direct effects may be
There has been interest in sequential administration of topote- expressed in S and G1 phases. Vinblastine is assumed to have
can (TOPO-I inhibitor) with TOPO-II inhibitors (e.g., doxorubi- stathmokinetic (cell cycle arrest) effects similar to vincristine.
cin, etoposide). The rationale is that administration of a TOPO-I
inhibitor would induce upregulation of TOPO-II in tumor cells
and thus enhance cytotoxicity. One clinical/translational study Drug Disposition
of topotecan (0.17 to 1.05 mg/m2/day as a 72-hour continuous After IV administration, vinblastine is rapidly cleared from
infusion on days 1 to 3) followed by etoposide (75 or 100 mg/m2/ the plasma and concentrated in various tissues. The apparent
day as a 2-hour infusion daily on days 8 to 10) failed to show reli- volume of distribution for the central compartment is quite
able downregulation of TOPO-I and upregulation of TOPO-II large (3 to 4 times the blood volume). Vincristine and vindesine
following administration of topotecan (538). Although signifi- approximate total body water in their distributions. There is a
cant clinical activity was observed in this phase I study in patients triphasic vinblastine elimination pattern, with average half-lives
with various solid tumors, the investigators concluded that the of 3.7 minutes, 1.6 hours, and 24.8 hours, respectively (548).
toxicity and translational research results did not support a sig- The drug also localizes in platelet and leukocyte fractions of
nificant synergistic advantage of this combination. Another study whole blood (549). A radiolabeled drug study showed that uri-
of the TOPO-I and TOPO-II inhibitor combination therapy (IV nary elimination accounts for approximately 33% of the total
topotecan 0.5 mg/m2 per day for 5 days and oral etoposide 50 mg vinblastine radioactivity, with 21% appearing in the stool, both
twice daily for 7 days of every 21-day cycle, with dose escalation after 72 hours (549). A large portion of the radiolabel was
of topotecan 0.75 and 1.0 mg/m2) found the combination to be retained in the body: 73% remained at 6 days after dosing.
safe and effective in small-cell lung cancer patients; however, the Apparently, insufficient amounts of the drug pass the blood-
incidence of grades 3 to 4 neutropenia was 25%, and 2 patients brain barrier to produce an effective concentration in the central
died from neutropenic sepsis (539). nervous system. Vinblastine is partially metabolized in the liver.
TOPO-I is a biochemical mediator of radiosensitization in Most of the drug is, therefore, ultimately excreted intact in the
cultured mammalian cells by camptothecin derivatives (540). bile or the urine. Toxicity may be increased if there is obstructive
There are in vitro and in vivo data suggesting that topotecan liver disease, and doses should be greatly reduced.
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 409
Administration and Dosage Other side effects include a reversible and mild alopecia, rashes,
The solution for administration is usually prepared by adding and photosensitivity reactions. Transient hepatitis has also been
10 mL of sodium chloride solution (which may be preserved reported on the continuous-infusion regimen.
with phenols or benzyl alcohol) to the 10-mg vial. The use of There have been several reports of a Raynauds phenomenon
other solutions is not generally recommended. The resultant associated with vinblastine or bleomycin in treating testicular can-
solution has a concentration of 1 mg/mL and a pH of 3.5 to cer. The reaction consists of a delayed presentation of a cold feeling
5.0. Solutions prepared with preserved sodium chloride injec- in the hands with physical evidence of cyanosis (551). Ginsberg
tion may be stored in the refrigerator (protected from light) for and coworkers (552) demonstrated a case of vinblastine-associated
28 days without significant loss of potency. syndrome of inappropriate antidiuretic hormone (ADH) secretion,
Vinblastine is usually given by the IV push technique, with which was previously thought to occur only with vincristine.
the total dose being delivered over approximately 1 minute. This The drug is well documented as a teratogen in humans, and
is usually accomplished by slowly pushing the dose through the as with most anticancer drugs, usage in pregnancy is strongly
injection site of a running IV infusion. Alternatively, the drug contraindicated (553).
may be given directly into the vein. If this method is followed,
the double-needle technique should be used: do not use the same Special Precautions
needle to withdraw the dose from the vial that is used for the Avoid extravasation of vinblastine. If extravasation occurs, stop
direct injection into the vein. Vinblastine is very irritating and the administration of the remaining drug immediately. Dorr and
should not be given intramuscularly or subcutaneously. Vein Alberts (554) favor injection of a corticosteroid into the infiltra-
in the urine and feces, respectively; however, recovery was severe), asthenia (29%, 5% severe), injection-site reactions
incomplete in pharmacokinetic studies (563,564). (26%, 2% severe), anorexia (15%, 1% severe), diarrhea (15%,
1% severe), stomatitis (14%, 0% severe), pain (13%, 2% severe),
Administration and Dosage paresthesia (13%, <1% severe), fever (11%, 1% severe), and alo-
pecia (10%, <1% severe) (570). Vinorelbine-induced nausea and
Vinorelbine is a vesicant and requires careful administration. The
vomiting are generally mild and are readily controlled with stan-
drug should be diluted in a syringe or IV bag to a concentration
dard antiemetic medication (570). Injection-site reactions include
of 1.5 to 3.0 mg/mL (syringe) or 0.5 to 2 mg/mL (IV bag). When
erythema, warmth, pain, and phlebitis. Repeated administration
using a syringe or IV bag, vinorelbine should be diluted with dex-
of vinorelbine can result in discoloration of the vein. As discussed
trose (5%) or sodium chloride (0.9%). When using an IV bag,
above, shortening the injection duration to 6 to 10 minutes sig-
it may also be diluted with sodium chloride (0.45%), Ringers
nificantly reduces the incidence of injection-site reactions (565).
injection, or lactated Ringers injection. Diluted vinorelbine
Injection-site pain and pain of unspecified etiology has been
should be administered over 6 to 10 minutes into a side port of
reported with administration of vinorelbine as a single agent
a free-flowing IV line closest to the IV bag. Following vinorel-
(570). Additionally, acute tumor pain has been reported in
bine administration, the vein should be flushed with at least 75
several cancer patients who received treatment with vinorel-
to 125 mL of IV solution. Longer IV infusions (e.g., 20 minutes)
bine plus a platinum-containing agent (either carboplatin or
are associated with a higher incidence of phlebitis (565).
cisplatin) (571,572).
Vinorelbine solution is incompatible with fluorouracil, mito-
Pulmonary toxicity is an infrequent side effect of vinorelbine.
mycin, and thiotepa. It is also incompatible with several antibiotics
Approximately 5% of patients experience dyspnea. Some cases of
(including a number of cephalosporins, amphotericin B, ampicil-
dyspnea are characterized by rapid onset during administration
lin, piperacillin, and trimethoprim-sulfamethoxazole), acyclovir,
and resolve with bronchodilator therapy. Other cases occur usu-
furosemide, ganciclovir, methylprednisolone, and sodium bicar-
ally within 1 hour of vinorelbine infusion and are characterized
bonate (566).
by life-threatening progressive dyspnea and the development of
Vinorelbine is generally administered at a dose of 30 mg/m2
interstitial infiltrates (570,573). The coadministration of mitomy-
every week. This dosing schedule has been used in combination
cin may increase the pulmonary toxicity of vinorelbine (573).
chemotherapeutic regimens; however, the recommended dosing
Rare side effects of vinorelbine include pancreatitis, PPE
schedule in combination with cisplatin (100 mg/m2 every 4 weeks)
(with prolonged infusions), paralytic ileus, and syndrome of
is weekly administration of vinorelbine at a dose of 25 mg/m2.
inappropriate ADH secretion (574577).
Attempts to increase vinorelbine dose intensity using a daily 3
every 21 days dosing schedule with or without G-CSF have not
been successful (567,568). However, Weiss et al. (569) reported Special Precautions
that continuous infusion of vinorelbine at doses of 8 to 10mg/m2/ Vinorelbine extravasation can result in severe local irritation, tis-
day with concurrent administration of G-CSF results in a twofold sue necrosis, and phlebitis. If extravasation occurs, the injection
increase in vinorelbine dose intensity without increasing toxicity. should be halted immediately and any remaining portion of the
dose should be injected into a different vein. Specific antidotes
Side Effects and Toxicities for vinorelbine extravasation have not been studied; however, vin-
The primary dose-limiting toxicity of vinorelbine is myelosuppres- blastine extravasation reactions may be ameliorated with the use
sion, chiefly granulocytopenia (36% of patients, <500 cells/mm3). of corticosteroid injections followed by cold compresses (554).
A safety summary of data from North American clinical trials
reported that when vinorelbine was administered at a dose of Drug Interactions
30 mg/m2/week to patients with breast cancer and non-small cell In that vinca alkaloids are metabolized by the cytochrome P450
lung cancer, 64% of patients experienced grades 3 to 4 granulo- 3A system, coadministration of strong P450 inhibitors, such as
cytopenia, 50% experienced grades 3 to 4 leukopenia, and 9% erythromycin and ketoconazole, could potentially reduce vinorel-
developed grades 3 to 4 anemia. Despite the high incidence of bine clearance and increase toxicity (578,579). Doxorubicin and
granulocytopenia, most events were uncomplicated and only 7% etoposide also are metabolized by the P450 system, and coadmin-
of patients required hospitalization for fever and/or infection. istration of these drugs with vinorelbine could potentially affect
The death rate due to sepsis was 1% to 2%. Myelosuppression vinorelbine metabolism (578).
was noncumulative, and the incidence of grades 3 and 4 granulo- Mitomycin is known to exacerbate vinca alkaloid-induced pul-
cytopenia declined during later cycles of vinorelbine therapy. The monary toxicity (580), and the combination of high-dose vinorel-
granulocyte nadir typically occurred on day 14 of treatment, with bine (50 mg/m2 on days 1 and 21) plus mitomycin (15 mg/m2 on
recovery of the granulocyte count within 7 days (570). day 1) has been associated with life-threatening acute pulmonary
Vinorelbine therapy is frequently associated with transient toxicity characterized by rapid onset of severe, progressive dyspnea
increases in liver enzymes, especially alkaline phosphatase. Vir- and the development of bilateral interstitial infiltrates (573).
tually all patients experience a rise in alkaline phosphatase, with The combination of paclitaxel and vinorelbine has been asso-
approximately 25% developing grade 3 toxicity and an addi- ciated with severe neurotoxicity including grade 4 motor neurop-
tional 2% experiencing grade 4 elevations. Increases in AST and athy, irreversible ototoxicity, and vocal cord paresis (581,582). In
ALT also occur in more than half of all patients. However, most one report of clinical experience in 5 patients with preexisting,
patients with liver enzyme increases remain asymptomatic and mild to moderate, paclitaxel-induced sensory neuropathy, the
do not require dose modification of vinorelbine. Total bilirubin combination of vinorelbine 25 to 30 mg/m2 followed by pacli-
also can be elevated: 10% of patients experience some degree taxel 150 mg/m2 by 3-hour infusion every 2 weeks resulted in
of increased bilirubin, with 2% experiencing grade 4 elevation. severe, slowly reversing motor neuropathy in all 5 patients. Four
Because of the high incidence of liver and bone metastases in the of the 5 patients required the use of a wheelchair (581).
study population (breast cancer and non-small cell lung cancer
patients), the proportion of these toxicities that is directly attrib-
utable to vinorelbine therapy is unknown (570). Special Applications
Other common toxicities associated with vinorelbine when On a well-tolerated weekly dose schedule for vinorelbine, Bajetta
administered as a single agent at a dose of 30 mg/m2/week by a and colleagues (583) noted 4 partial responses and one com-
20-minute IV infusion include nausea (38% overall, 2% severe), plete response in 31 patients (24 platinum-resistant, 4 platinum-
vomiting (17% overall, 2% severe), constipation (31%, 3% sensitive, 5 with undetermined sensitivity) for an overall
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 411
response rate of 15% (95% CI of 5.1, 37.9%). A phase II trial heart disease, an increased incidence of ischemic cardiovascular
(vinorelbine 30 mg/m2 weekly infusion) in persistent or recur- events has been seen. It can also cause a decrease in bone min-
rent ovarian cancer found a 29% objective response rate; granu- eral density and an elevation in serum cholesterol.
locytopenia was a dose-limiting but manageable toxicity (557).
This is consistent with previous findings of a 21% response rate Drug Interactions
in the population of heavily pretreated and platinum-resistant
ovarian cancer patients (583). Coadministration of anastrozole and tamoxifen in breast can-
cer patients reduced anastrozole plasma concentrations by 27%.
Estrogen-containing regimens should not be coadministered as
they may diminish its pharmacologic action. The drug does not
Molecularly Targeted Agents appear to alter the effect of warfarin or inhibit cytochrome P450.
Estrogen Receptor/ Progesterone
Receptor-targeted Agents Special Applications
According to the National Comprehensive Cancer Network
Anastrozole Clinical Practice Guidelines in Oncology for Uterine Neoplasms
(586), anastrozole (as well as other AIs) is listed as a possible
Chemistry
substitute for progestational agents or tamoxifen in treating
Anastrozole (Arimidex) is FDA approved in 3 settings to treat post- asymptomatic or low-grade metastases. It is hypothesized that
elimination half-life is 2 days. The major excretion route is via and AUC up to 33% increase) but does not affect its half-life
the kidneys. Steady-state plasma concentration is reached in 2 to (12 to 16 hours).
6 weeks of daily 2.5 mg dosing. These concentrations are up to
2 times higher than after a single dose. Steady state levels can be Administration and Dosage
maintained for long periods of time without continuous accu-
mulation of letrozole. MPA is administered at 5 or 10 mg/day for endometrial hyper-
plasia for 12 to 14 consecutive days every month. For abnormal
uterine bleeding or amenorrhea, MPA is generally administered
Administration and Dosage for a shorter duration (e.g., 5 to 10 consecutive days). Patients
Letrozole is administered orally at 2.5 mg per day. Letrozole can experience withdrawal bleeding for 3 to 5 days following the
be taken at any time during the day regardless of food intake. treatment cycle. Medroxyprogesterone acetate is recommended
Treatment is indicated until disease progression. to be used with 0.625 mg conjugated estrogens in women with
a uterus to avoid the risk of endometrial cancer. Women without
Side Effects and Toxicities a uterus may receive estrogen without a progestin. In addition
to the tablet form for oral intake, there is an intramuscular (IM)
Letrozole has a more favorable toxicity profile compared to depot formulation that may permit alternative treatment regi-
tamoxifen, with greater or equivalent efficacy in breast cancer mens. The IM formulation of MPA was compared to oral meges-
patients (595). The most common side effects (>20%) include hot trol acetate for the treatment of menopausal symptoms in breast
flashes and arthralgia. Bone pain, flushing, sweating, asthenia, cancer patients. In this short-term study, the IM formulation
edema, back pain, nausea, hypercholesterolemia, and dyspnea provided superior benefit to patients and may be an alternative to
each occur in less than 20% of patients. long-term oral progestin therapy (598).
MPA, it has the empirical formula C24H34O4, and has a molec- acetate in trial GOG-0224 [A Randomized, Controlled Phase II
ular weight of 384.51. Megestrol acetate is an FDA-approved Evaluation Of Megestrol (Megace) in Different Dose and
progestin that is used for the palliative treatment of advanced Sequence in the Treatment of Endometrial Intraepithelial Neo-
carcinoma of the breast or endometrium (i.e., recurrent, inop- plasia (EIN) from a Referred Cohort of Atypical Endometrial
erable, or metastatic disease). The precise mechanism by Hyperplasia or EIN)]. GOG-0224 is designed to provide objec-
which megestrol acetate produces its antineoplastic effects tive data toward a standard treatment regimen for the care of
against endometrial carcinoma is unknown. However, there women with EIN or AEH in addition to understanding the
is evidence to suggest a local effect as a result of the marked actual mechanism of action of progestational agents in the
changes brought about by the direct instillation of progesta- endometrium.
tional agents into the endometrial cavity. The antineoplastic Megestrol acetate 80 mg BID 3 weeks, alternating with
action of megestrol acetate on carcinoma of the breast is better tamoxifen 20 mg BID 3 weeks orally, has been shown by the
understood. Progestational agents like megestrol acetate modify GOG to be the most active regimen in treating advanced endo-
the action of other steroid hormones and exert a direct cyto- metrial carcinoma (605). Among 56 eligible patients, 15 patients
toxic effect on tumor cells. Pharmacologic doses of megestrol responded (12 complete, 3 partial), for an overall response rate
acetate not only decrease the number of hormone-dependent of 27% (90% CI: 17% to 38%). In 8 of 15 (53%) respond-
human breast cancer cells but also is capable of modifying and ers, response duration exceeded 20 months. The response rate
abolishing the stimulatory effects of estrogen on these cells. It was 38% in patients with histologic grade 1 tumors (n = 16),
has been suggested that progestins may inhibit cell growth in 24% in those with grade 2 disease (n = 17), and 22% among
Tamoxifen Citrate
Administration and Dosage
Megestrol acetate is supplied in 20 mg and 40 mg tablets for oral Chemistry
intake. Although the recommended dosage for breast cancer is Tamoxifen citrate (Nolvadex) is a nonsteroidal agent with anties-
160 mg/day (40 mg q.i.d.), and for endometrial carcinoma it is trogenic properties. It is indicated for the treatment of metastatic
40 to 320 mg/day in divided doses, there are a wide variety of breast cancer in men and women. In premenopausal women, it
dose and schedules implemented therapeutically for precancer- is an alternative to oophorectomy or ovarian irradiation. ER+
ous conditions (e.g., Atypical Endometrial Hyperplasia [AEH]). tumors are more likely to respond. Tamoxifen is also indicated
as adjuvant treatment in node-positive and -negative breast can-
Side Effects and Toxicities cers. Thirdly, it is indicated in women with ductal carcinoma in
situ (DCIS) to reduce the risk of invasive carcinoma. Finally, it is
The side effect profiles of the progestational agents such as
approved to reduce the incidence of breast cancer among high-
megestrol acetate or MPA are similar. However, weight gain is
risk women. Tamoxifen competes with estrogen for binding sites,
a common side effect with megestrol acetate. Thrombophlebi-
which explains its increased effectiveness in ER+ tumors. Chemi-
tis and pulmonary embolism have been reported with megestrol
cally, tamoxifen is (Z)2-[4-(1,2-diphenyl-1-butenyl) phenoxy]-N,
acetate. Other toxicities include heart failure, nausea and vom-
N-dimethylethanamine 2-hydroxy-1,2,3-propanetricarboxylate
iting, edema, breakthrough menstrual bleeding, dyspnea, tumor
(1:1), and has a molecular weight of 563.62.
flare (with or without hypercalcemia), hyperglycemia, glucose
intolerance, alopecia, hypertension, carpal tunnel syndrome,
mood changes, hot flashes, malaise, asthenia, lethargy, sweating, Mechanism of Action
and rash. In general, severe toxicities with progestational agents Tamoxifen, like raloxifene and toremifene, is a nonsteroidal
are rare. selective estrogen receptor modulator (SERM). All 3 agents are
competitive inhibitors of estrogen binding to ER, and all have
Special Precautions mixed agonist and antagonist activity, depending on the target
tissue. These mixed activities have led to the redesignation of this
Megestrol acetate should be used with caution in patients with class of compounds from anti-estrogens to SERMs.
a history of thromboembolic disease. Exacerbation of preexist- SERMs provide some protection against menopausal bone
ing diabetes with increased insulin requirements has also been loss, presumably due to their partial agonist activity. However,
reported in association with the use of megestrol acetate. the increase in bone density is substantially less than that seen
with estrogen. SERMs lowers the serum total and low-density
Drug Interactions lipoprotein (LDL)-cholesterol concentrations (by 12% and 19%,
Drug interactions with megestrol acetate have not been evaluated. respectively, in one report), although they do not increase serum
HDL-cholesterol. Tamoxifens antagonist effect is particularly
prominent with respect to breast cancer. Finally, tamoxifen is an
Special Applications estrogen agonist in the endometrium.
In general, progestational agents are currently used in the Most receptors of the steroid family, with the exception of
treatment of endometrial hyperplasia at a variety of doses the ER, are classically viewed as translocating receptors. That
and schedules. The GOG is currently investigating megestrol is, they move from a principally cytoplasmic distribution in the
414 CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER
absence of hormone to a predominantly nuclear localization more severe liver abnormalities including fatty liver, cholestasis,
in hormone-stimulated cells. However, the ER appears to be hepatitis, and hepatic necrosis. Ocular disturbances, including
predominantly nuclear both in the presence and absence of hor- corneal changes, decrement in color vision perception, retinal
mone. The ER operates as a ligand-dependent transcription fac- vein thrombosis, and retinopathy have been reported in patients
tor; attachment of estrogen hormone to the ERs ligand-binding receiving tamoxifen. An increased incidence of cataracts and the
domain results in either direct binding of the ER to estrogen need for cataract surgery have been reported in patients receiv-
response elements (EREs) in the promoter of target genes or to ing tamoxifen.
a protein-protein interaction with coactivators at their respec-
tive promoter sites (607). Subsequently, the hormone-receptor Drug Interactions
complex is able to bind to estrogen-specific response elements
that activate or repress expression of genes whose protein prod- When tamoxifen is used in combination with coumarin-type anti-
ucts are responsible for the physiologic actions of the hormone. coagulants, a significant increase in anticoagulant effect may occur.
Estrogen exerts its effect through 2 receptors, ER and ER.
The exact function of ER and ER is under study, but they Special Applications
appear to have different biological functions, as indicated by Some ovarian cancers express hormonal receptors, a factor sup-
their distinct expression patterns. porting the investigation of tamoxifen in the treatment of ovar-
ian malignancies (611). It has demonstrated activity in patients
Drug Disposition with platinum-refractory ovarian cancer, with response rates
ranging from 13% to 17% (with some complete responses), and
Peak plasma concentrations (average 40 ng/mL) take place
with durations ranging from 4.4 months to more than 5 years
approximately 5 hours after dosing. The decline in plasma
(611614). In the series by Hatch and colleagues (611), patients
concentrations is biphasic, with a terminal elimination half-
with ovarian cancer who had complete or partial responses on
life of about 6 days. Steady-state concentrations for tamoxifen
tamoxifen were more likely to have an ER+ tumor (89% ER+)
are achieved in approximately 4 weeks after initiation of ther-
than those who had stable disease or progression on tamoxifen
apy. Tamoxifen is extensively metabolized, with N-desmethyl
(59% had elevated ER). The favorable toxicity profile of tamox-
tamoxifen being the major metabolite. Approximately 65%
ifen makes it an ideal agent to consider in patients with refrac-
of the administered dose is eliminated in the feces within
tory ovarian cancer. In addition to activity in ovarian cancer, the
2weeks(608).
NCCN also lists tamoxiifen as an active agent in endometrial
cancer (586).
Administration and Dosage
Tamoxifen is available in 10- and 20-mg tablets for oral admin- Leuprolide Acetate
istration. The recommended dosage is 20 to 40 mg/day; when
the higher daily dose is prescribed, it should be divided into Chemistry
2doses of 20 mg (morning and evening). Leuprolide acetate (Lupron) is a synthetic nonapeptide ana-
log of naturally occurring gonadotropin-releasing hormone
Side Effects and Toxicities (GnRH), also known as Luteinizing-hormone-releasing hor-
mone (LHRH). The analog possesses greater potency than
Tamoxifen causes estrogenic changes of the vaginal and cervi- the natural hormone. It indicated in the palliative treatment
cal squamous epithelium and increases the incidence of cervical of advanced prostate cancer. The chemical name is 5-oxo-L-
and endometrial polyps (609). It is associated with an increased prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-
risk of uterine malignancies (endometrial adenocarcinoma and leucyl-L-arginyl-N-ethyl-L-prolinamideacetate. GnRH agonists
uterine sarcoma). Other serious adverse events associated with are synthetically modeled after the natural GnRH decapeptide,
tamoxifen treatment include stroke, deep vein thrombosis, and with specific amino acid substitutions typically in positions 6
pulmonary embolism. A discussion weighing the benefits versus and 10. Other than leuprolide acetate, other agonists include:
the risks should take place prior to treatment with tamoxifen; (a) Buserelin (Suprefact, Suprecor); (b) Nafarelin (Synarel) (only
however, the benefits have been determined to outweigh the a single substitution at position 6); (c) Histrelin (Supprelin LA,
risks in women who take tamoxifen to reduce the risk of breast Vantas); (d) Goserelin (Zoladex); and (e) Deslorelin (Suprelorin,
cancer recurrence. The National Adjuvant Breast and Bowel Ovuplant). These medications can be administered intranasally,
Project (NSABP P-1) found a higher incidence of the following by injection, or by implant. Injectables have been formulated for
side effects for tamoxifen versus placebo, respectively: vaginal daily, monthly, and quarterly use, and implants can last from 1
discharge (54.7 vs. 34%); cold sweats (21.4% vs. 14.8%); hot to 12 months.
flashes (77.7% vs. 65.1%); night sweats (66.8% vs. 54.9%);
and genital itching (47.1% vs. 38.3%) (610). Serious adverse
events reported more frequently among women taking tamoxi- Mechanism of Action
fen compared to palcebo in the NSABP P-1 trial included uterine GnRH agonists do not quickly dissociate from the GnRH recep-
malignancy, uterine sarcoma, stroke, and pulmonary embolism. tor. As a result, initially there is an increase in FSH and LH
secretion (so-called flare effect). However after approximately
Special Precautions 10days a profound hypogonadal effect (i.e., decrease in FSH and
LH) is achieved through receptor down-regulation by internal-
Tamoxifen is contraindicated in patients with known hypersen- ization of receptors. Generally, this induced and reversible hypo-
sitivity to the drug or any of its ingredients. In the treatment gonadism is the therapeutic goal.
of DCIS, tamoxifen is contraindicated in women who require
concomitant anticoagulant therapy or in women with a his-
tory of deep-vein thrombosis or pulmonary embolus. As with Drug Disposition
other additive hormonal therapy (estrogens and androgens), Following a single injection of 7.5 mg of leuprolide acetate
hypercalcemia has been reported in some breast cancer patients (depot Lupron), the mean plasma leuprolide concentration is
with bone metastases within a few weeks of starting treatment almost 20 ng/mL at 4 hours and 0.36 ng/mL at 4 weeks. The
with tamoxifen. Tamoxifen has been associated with changes mean steady-state volume of distribution of leuprolide following
in liver enzyme levels, and on rare occasions, a spectrum of IV bolus administration to healthy male volunteers was 27 L.
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 415
In vitro binding to human plasma proteins ranged from 43% proliferate, and assemble into tubes during this process. In normal
to 49%. In healthy male volunteers, a 1-mg bolus of leuprolide tissues, blood vessel growth is tightly controlled by numerous
administered IV revealed that the mean systemic clearance was angiogenesis-stimulating factors and angiogenesis-inhibiting
7.6 L/h, with a terminal elimination half-life of approximately factors. Vascular endothelial growth factor (VEGF), angiopoi-
3hours based on a 2-compartment model. Following adminis- etin, and platelet-derived endothelial-cell growth factor (PD-
tration of depot Lupron 3.75 mg to 3 patients, less than 5% of ECGF) are 3 of the most extensively studied growth factors
the dose was recovered as parent or one of its major metabolites that appear to function primarily as angiogenesis-stimulating
in the urine. factors. Other growth factors and cytokines, such as basic fibro-
blast growth factor (bFGF), have multiple functions in addition
Administration and Dosage to angiogenesis stimulation (619). Naturally occurring factors
that suppress angiogenesis include angiostatin, endostatin,
The recommended dose of depot Lupron has traditionally been interferon-, interferon-, interferon-, interleukin-1, interleu-
7.5 mg monthly. Other recently approved doses and schedules kin-12, platelet factor-4, thrombospondin-1, 1,2-methoxyestra-
include 22.5 mg every 3 months, 30 mg every 4 months, and 45 mg diol, tissue inhibitor metalloproteinases (TIMPs), and, at high
every 6 months. concentrations, tumor necrosis factor- (620,621).
In the early 1970s, Folkman (622) pioneered the study of
Side Effects and Toxicity tumor angiogenesis with his observation that the growth of
Side effects of GnRH agonists are signs and symptoms of hypoes- tumor nodules to a diameter of greater than 1 to 2 mm required
and proliferation. Bevacizumab contains human framework bevacizumab-associated toxicities in ovarian cancer have been
regions and the complementarity-determining regions of a murine recently reviewed by Randall and Monk (648).
antibody that binds to VEGF. Bevacizumab has an approximate
molecular weight of 149 kDa. Bevacizumab is produced in a Special Precautions
mammalian cell (Chinese Hamster Ovary) expression system in
a nutrient medium containing the antibiotic gentamicin. Genta- The warnings and precautions include the following:
micin is not detectable in the final product. Nongastrointestinal fistula formation: Discontinue bevacizumab
Though the inhibition of tumor angiogenesis was originally if fistula formation occurs.
thought to simply deny a tumor nutrients and oxygen, VEGF Arterial thromboembolic events (ATE) (e.g., myocardial
inhibition has also been shown to induce so-called vascular nor- infarction, cerebral infarction): Discontinue bevacizumab for
malization, a restoration of normal structure, function, and flow severe ATEs.
to the disorganized, leaky vessels characteristic of malignant Hypertension: Monitor blood pressure and treat hyperten-
tumors, which improves the delivery of oxygen, nutrients, and sion. Temporarily suspend bevacizumab if not medically con-
cytotoxic chemotherapy to the tumor. Because VEGF also plays trolled. Discontinue bevacizumab for hypertensive crisis or
an important role in normal physiologic processessuch as fetal hypertensive encephalopathy.
development, stabilization of damaged endothelia, and wound Reversible posterior leukoencephalopathy syndrome (RPLS):
healingVEGF inhibition carries a unique toxicity profile that Discontinue bevacizumab.
involves normal tissues, tumor tissues, and the interface of Proteinuria: Monitor urine protein. Discontinue for nephrotic
them both. Despite uncertainty regarding these toxicities, the syndrome. Temporarily suspend bevacizumab for moderate
need for novel antitumor agents was an overriding force for the proteinuria.
clinical investigation of bevacizumab. Infusion reactions: Stop for severe infusion reactions.
Ovarian failure: Inform females of reproductive potential of
Drug Disposition the risk of ovarian failure with bevacizumab.
According to the package insert, The pharmacokinetic profile
of bevacizumab was assessed using an assay that measures total Drug Interactions
serum bevacizumab concentrations (i.e., the assay did not dis- A drug interaction study was performed in which irinotecan was
tinguish between free bevacizumab and bevacizumab bound to administered as part of the FOLFIRI regimen with or without
VEGF ligand). Based on a population pharmacokinetic analy- bevacizumab. The results demonstrated no significant effect
sis of 491 patients who received 1 to 20 mg/kg of bevacizumab of bevacizumab on the pharmacokinetics of irinotecan or its
weekly, every 2 weeks, or every 3 weeks, the estimated half-life of active metabolite SN38. In a randomized study in 99 patients
bevacizumab was approximately 20 days (range 11 to 50 days). with NSCLC, based on limited data, there did not appear to
The predicted time to reach steady state was 100 days. The accu- be a difference in the mean exposure of either carboplatin or
mulation ratio following a dose of 10 mg/kg of bevacizumab paclitaxel when each was administered alone or in combination
every 2 weeks was 2.8. The clearance of bevacizumab varied with bevacizumab. However, 3 of the 8 patients receiving Avastin
depending on body weight, gender, and tumor burden. After cor- plus paclitaxel/carboplatin had substantially lower paclitaxel
recting for body weight, males had a higher bevacizumab clear- exposure after 4 cycles of treatment (at day 63) than those at
ance (0.262 L/day vs. 0.207 L/day) and a larger Vc (3.25 L vs. day 0, while patients receiving paclitaxel/carboplatin without
2.66 L) than females. Patients with higher tumor burden (at or bevacizumab had a greater paclitaxel exposure at day 63 than
above median value of tumor surface area) had a higher beva- at day 0.
cizumab clearance (0.249 L/day vs. 0.199 L/day) than patients Finally, there was no difference in the mean exposure of
with tumor burdens below the median. There has been no evi- interferon alfa administered in combination with bevacizumab
dence of lesser efficacy (hazard ratio for overall survival) in males when compared to interferon alfa alone.
or patients with higher tumor burden treated with bevacizumab
as compared to females and patients with low tumor burden.
Special Applications
The relationship between bevacizumab exposure and clinical
outcomes has not been explored. Bevacizumab has clear clinical activity in ovarian, endome-
trial, and cervical cancers. However, anti-angiogenesis agents
have also been noted to control symptomatic effusions such
Administration and Dosage as malignant ascites (649) and pleural effusions (650). In fact,
Bevucizumab is usually administered in gynecologic cancers at one case report noted the use of bevacizumab in a woman with
15 mg/kg IV once every 21 days until disease progression or refractory ovarian granulosa-cell carcinoma and symptomatic
unacceptable toxicity. However, ICON7 (638) also showed ascites (651).
activity of 7.5 mg/kg IV once every 21 days, and 28-day regimens
generally use 10 mg/kg IV once every 14 days.
One approach that holds promise for the improvement of the elimination half-life, apparent volume of distribution, and clear-
therapeutic index is the concept of modulation, or the use of ance of total folate were not significantly different among the
drugs with little or no cytotoxic activity to modulate the efficacy 3treatments.
of standard anticancer drugs. Modulating agents can be divided
into 3 main classes based on their ability to: (a) protect host Administration and Dosage
tissue from the toxic effects of the cancer drugs; (b) potentiate
Leucovorin calcium rescue is indicated after high-dose metho-
anticancer drugs; and (c) reverse acquired drug resistance. In
trexate therapy in steosarcoma. Leucovorin calcium is also
this section, we discuss agents with chemoprotective abilities
indicated to diminish the toxicity and counteract the effects of
used with chemotherapy in the treatment of gynecologic cancers.
impaired methotrexate elimination and of inadvertent overdos-
Agents such as erythropoiesis-stimulating agents and myeloid
ages of folic acid antagonists.
growth factors are discussed elsewhere. Amifostine (652) and
Leucovorin calcium is indicated in the treatment of megalo-
dexrazoxane (653) are not commonly used agents in gyneco-
blastic anemias due to folic acid deficiency when oral therapy is
logic oncology and are thus not considered.
not feasible. Leucovorin is also indicated for use in combination
with 5-fluorouracil to prolong survival in the palliative treatment
of patients with advanced colorectal cancer. In advanced colorec-
Chemoprotective Agents tal cancer, either of the following 2 regimens is recommended:
Leucovorin 1. Leucovorin administered at 200 mg/m2 by slow IV injection
Dosage and Administration and several are advanced in clinical development and are show-
Oprelvekin is administered subcutaneously (to the abdomen, ing significant activity in ovarian cancers arising in BRCA1 and
thigh, hip, or upper arm) at a dose of 50 g/kg daily. Patients BRCA2 mutation carriers.
with renal impairment (creatinine clearance less than 30 mL/min)
should receive half the normal dose (e.g., 25 g/kg daily). Chemistry
Oprelvekin should be initiated within 24 hours of the comple-
tion of chemotherapy until the patients platelet count is at least All the PARP inhibitors currently in clinical development mimic
50,000/L. Treatment generally lasts between 10 and 21 days, the nicotinamide moiety of NAD. A common structural feature
and is not recommended beyond 21 days. retains the 3-carboxamide substituent of the benzamide portion
of the molecule in the sin configuration, which is optimal for
binding to the active site (669). Compounds currently in clinical
Side Effects and Toxicities development include olaparib, veliparib, rucaparib, and BMN
Allergic reactions may occur with oprelvekin, and patients should 673. Another compound, iniparib, showed early promise in a ran-
be counseled to be aware of potential allergic symptoms. Treat- domized phase II trial in triple negative breast cancer (670). How-
ment with oprelvekin may also cause severe fluid retention. ever, this result was not confirmed in a subsequent phase III study
Fluid balance should be monitored during treatment. Other seri- (671). Although this compound seems to have some activity, both
ous adverse effects associated with oprelvekin treatment include anecdotally in BRCA-related pancreatic cancer (672) and on subset
cardiovascular events and anemia. analysis in combination in triple negatives breast cancer (673), it
Ixabepilone
Eribulin Chemistry
Chemistry Ixabepilone is a semi-synthetic epothilone microtubule inhibitor.
Epothilone is a natural product isolated from a myxobacterium,
Eribulin is a synthetic derivative of the natural product Halichon- Sorangium cellulosum. Ixabelipone is modified by replacing
drin B, a product originally isolated from a marine sponge. It acts the naturally occurring lactone in the macrocycle by a lactam,
as a microtubule dynamics inhibitor. The chemical name for indented to reduce the rate of metabolism of the ring. The
eribulin mesylate (the injectable form) is 11,15:18,21:24,2 chemical name for ixabepilone is (1S,3S,7S,10R,11S,12S,16R)-
8- Triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2-i] 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-
furo[2,3:5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)- 2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[14.1.0]
one, 2-[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3- heptadecane-5,9-dione, and it has a molecular weight of 506.7.
methoxy-26-methyl-20,27-bis(methylene)-, (2R,3R,3aS,7R,8aS,
9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-,
methanesulfonate (salt). It has a molecular weight of 826.0 (729.9 Mechanism of Action
for free base). The empirical formula is C40H59NO11 CH4O3S. Ixabepilone stabilizes -II and -III microtubules, leading to
the death of proliferating cells via a block in the mitotic phase of
Mechanism of Action the cell cycle. Ixabepilone has a low affinity for the efflux pump
proteins MRP1 and P-glycoprotein, which are known causes of
Eribulin binds to tubulin and sequesters it into nonproductive resistance to taxanes. It is also active in human tumor xeno-
aggregates, thereby inhibiting mitosis and causing a G2/M cell grafts that over-express III tubulin isoforms or have tubulin
cycle block. mutations conferring resistance to taxanes. Further, it is active in
human tumor xenograft models that are resistant to other com-
monly used anticancer drugs such as anthracyclines and vinca
Drug Disposition
alkaloids [H73].
Eribulin is administered intravenously. The majority of the
dose is excreted unchanged in the feces, with only approxi-
mately 9% in the urine. There is little metabolism, with
Drug Disposition
approximately90% of the drug being excreted unchanged. The Following IV injection of ixabepilone, the mean volume of dis-
volume of distribution is approximately 40 L and the half-life tribution has been reported as in excess of 1,000 L, indicating
about 40 hours. a very high tissue distribution [H73]. The clearance has been
CHAPTER 14 PHARMACOLOGY AN D TH ER APEUTICS I N GYN ECOLOGIC CANCER 421
reported as 475 247 mL/min/m2, the half-life at 14 hours is common and has been reported in approximately 65% of
[H74]. Plasma protein binding was in the region of 67% to 77% patients treated, with 14% to 21% being grade 3/4.
[H73]. Ixabepilone is eliminated primarily as the metabolized
drug in the feces. Approximately 86% of an administered dose
was eliminated in 7 days, with 65% of the dose in the feces and
Drug Interactions
21% of the dose in the urine. Unchanged ixabepilone was 1.6% Drug interactions are to be expected with other drugs that are
and 5.6% of the recovered dose, respectively. Ixabepilone is metabolized by (e.g., ketoconazole) or induce (e.g., rifampin)
extensively metabolized in the liver, and studies with human liver CYP3A4. These 2 drugs have been shown to increase and
microsomes suggest that CYP3A4 is the primary route [H73]. decrease the exposure to ixabepilone by +79% and 43%,
respectively. It is recommended that strong inhibitors or induc-
ers of CYP3A4 are avoided where possible, and dose modi-
Dosage fications are considered when any strong or weak inducer of
The recommended dosage of ixabepilone is 40 mg/m2 admin- inhibitor is used [H73].
istered intravenously over 3 hours every 3 weeks. Dose adjust-
ments are recommended for hematological and neurological
toxicities. One of the license indications for ixabepilone is for use
Clinical Summary
in combination with capecitabine (see below). Ixabepilone with Ixabepilone is licensed for use as monotherapy for the treatment
capecitabine is contraindicated in patients with AST or ALT >2.5 of metastatic or locally advanced breast cancer after the failure
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Immunotherapy of Gynecologic
Malignancies
PAUL J. SABBATINI KUNLE ODUNSI JACOBUS PFISTERER
GEORGE COUKOS
The natural clinical history of ovarian cancer makes it Observations in patients with ovarian cancer strongly support
particularly suited for the evaluation of immune-based strategies. a role for immune system involvement in patient outcome. For
Although the majority of patients are diagnosed with advanced example, the 5-year overall survival in epithelial ovarian can-
disease, 70% are in a complete clinical remission following cer has been correlated to the presence or absence of tumor
initial cytoreductive surgery and platinum and taxane-based infiltrating lymphocytes (TIL) (38% vs. 4.5%, p < 0.001) (12).
primary chemotherapy (1). However, only 30% of optimally A second study also showed improved survival in patients with
debulked stage III patients will remain disease-free with a median increased frequencies of intraepithelial CD8+ TIL (55 months vs.
progression-free interval of approximately 24 months (2). 26 months; HR = 0.33; 95% CI, 0.180.60; p = 0.0003) (13).
Despite the high relapse rate, many patients return to a complete In contrast, patients with increased numbers of immune sup-
or partial clinical remission following additional chemotherapy, pressive CD4+CD25HI regulatory T-cells (Tregs) have reduced
but ever-shortening intervals of response are seen (3). Despite survival (14). The process is made more complex when we rec-
this chronic course of relapse and response, the median survival ognize that not only can the immune system protect the host
of optimally debulked patients exceeded 60 months in a study against tumor development, but it is thought to select cancer cells
evaluating intraperitoneal (IP) therapy as part of primary treat- of lower immunogenicity which can escape early immunity due to
ment (4). Neither higher doses nor protracted schedules, nor changes in gene expression. This actually leads to an outgrowth
non-cross-resistant consolidation chemotherapy has provided of tumors with the capacity to escape recognition and this process
additional benefit. Ovarian cancer patients with minimal disease has been termed immunoediting (15). The immunoediting or
burdens are therefore appropriate candidates for the evaluation immune sculpting process, therefore, is responsible for shap-
of immune-based strategies, which typically have excellent side- ing the immunogenicity of the tumors that will eventually form.
effect profiles. Considering the effectors of the immune system in the context of
With regard to other gynecologic malignancies, the majority both of these processes is important in order to develop immune
of immune strategies being evaluated in patients with cervical directed therapies with the greatest chance of success (16,17).
cancer target human papillomavirus, and this subject is covered The mechanism by which tumors escape from immune sur-
separately in the appropriate chapter (5). The evaluation of veillance is complex. An alteration in the function of almost
immune-based approaches for the treatment of endometrial can- every process discussed herein to facilitate immune activa-
cer is limited but interest is growing (6). Targets such as human tion has been postulated to participate in the ways tumors can
trophoblast cell surface marker (TROP-2), Wilms Tumor Gene evade immune detection. In some cases, antigen presentation is
(WT-1), and a variety of cancer testis antigens have been shown down regulated, or gene deletions or rearrangements may cause
to be expressed in endometrial cancers which has prompted early reduced expression of the MHC-I complex thus preventing
stage trials with dendritic cell vaccines and adoptive cellular T-lymphocyte activation (18,19). Tumors can also secrete pro-
therapy as two examples (7,8). The bulk of the clinical informa- teins that inhibit T-cell effector action or that promote the
tion available to date with regards to immunotherapy when one development of regulatory T-cells that suppress immune
excludes cervical carcinoma, however, remains in patients with function(20). A recent observation showed that certain melano-
ovarian cancer. mas can actually remodel their stromal microenvironment so it
resembles lymphoid tissue which recruits regulatory cells to pro-
mote tolerance and allow tumor progression (21). Other mech-
anisms include the downregulation of intracellular adhesion
CANCER IMMUNOLOGY: OVERVIEW molecules(22), changes in molecules responsible for apoptosis
signaling (23), or the development of peripheral tolerance(24).
The immune system evolved to fight foreign invaders such as Based on the increasing number of interacting mechanisms with
bacteria, viruses, and parasites. However, strong evidence sug- putative activity that allow immune escape, approaches directed
gests that it also plays a crucial role in controlling or rejecting against multiple mechanisms will likely be needed in order to
incipient cancers. William B. Colley first observed regression in eradicate immune tolerant tumor cells (25).
patients with sarcoma contracting accidental erysipelas as
early as 1893 (9). Since patients with competent immune sys-
tems still develop cancers, and spontaneous remission of tumors
is rare, enthusiasm for the effectiveness of immune system con- Innate Immunity
trol has waxed and waned over the decades. The fact that animal The immune system is broadly divided into 2 arms, innate
models with a variety of deficiencies in immunologic compo- and active immunity, but there are multiple examples of cross
nents consistently develop carcinoma has allowed the concept communication between them. Recent data, for example, show
of immunosurveillance to be sustained and developed (10,11). that neutrophil survival is influenced by T cell responses (26).
434
CHAPTER 15 I MM U NOTH ER APY OF GYN ECOLOGIC MALIGNANCI ES 435
Innate immunity is present at birth and does not require adap- that have receptors with the best fit to the antigen itself (for
tation to react against microorganisms or tumors. It includes B cells) or antigen/MHC complex (for T cells) are stimulated
physical barriers (mucous membranes, skin), chemical compo- to proliferate and this subpopulation is quickly expanded (33).
nents (compliment, hydrolytic enzymes), and multiple other
cellular components. For example, natural killer cells are lym-
phocytes that are programmed to recognize and destroy tissues
that have been altered or stressed, e.g., by viruses or by malignant Humoral Immunity
transformation (27). They do not have antigen specific receptors B cells recognize antigens usually in their natural configuration(32).
but instead have inhibiting receptors that can recognize MHC An individual host has a repertoire of B cells that are capable
class I molecules on normal cells, which prevents their activation of generating antibodies against the full range of pathogens
(28). MHC I expression is aberrant or absent on many virus and encountered in the environment. To do this, the total popula-
tumor infected cells (29). Another component includes macro- tion of B lymphocytes expresses a diverse repertoire of immuno-
phages, which play many roles in immunity and inflammation, globulins. Each B cell expresses immunoglobulin against a single
including production of a multitude of soluble secreted proin- antigenic determinant, with the immunoglobulin expressed at
flammatory proteins, which are growth factors for other cells the cell surface of the B cell where it acts as a specific receptor
of the immune system, for neovasculature, and for cancer cells. to transduce signals in response to that antigen (34). Once acti-
These growth factors include cytokines and chemokines, and vated, the B cell is to create an individual monoclonal antibody
they support the growth, movement, and survival of immune and (mAb). The diversity of specificities in different B cells is gener-
available, antibody responses mature through immunoglobulin of B7 is sufficient to activate nave T cells. Within several days
gene rearrangements into the higher affinity IgG classes. These following T-cell activation, a second molecule, CTLA-4, appears
are capable of improved binding to antigen as well as receptors on the T-cell surface to provide a brake to the T-cell response.
on the bone marrow-derived cells for the Fc domain, expand- CTLA-4 also binds B7 molecules, but with much higher affinity,
ing potential effector functions. The responses to most nonpro- therefore displacing CD28 activation signals. CTLA-4 signaling
tein antigens are IgM class and generally do not mature to IgG leads to down-regulation of the T-cell response. The manipulation
responses. The IgM pentamer structure is specialized to increase of CTLA-4 activity has recently been shown to have therapeu-
avidity of binding to multimeric antigens and to efficiently acti- tic efficacy with recent data showing tumor responses in patients
vate effector functions such as complement (38). Activation of with melanoma (50,51). A variety of other co-stimulatory mol-
complement, which includes blood components with different ecules are up-regulated on the surface of activated T cells, includ-
enzymatic properties, results in opsonization (coating of patho- ing OX40 and 4-1BB, which promote survival of T cells and help
gens by complement components), recognition by complement generate long-lived T-cell memory responses (52,53). Once T cells
receptors on macrophages, monocytes, neutrophils, and den- are activated by professional antigen-presenting cells (primarily
dritic cells, with subsequent activation of these cells leading to dendritic cells), they gain a variety of effector functions, including
phagocytosis and/or killing. In addition, complement can form the production of cytokines and cytotoxic molecules, which lead
a membrane attack complex, which creates holes in membranes to death of target cells.
of target pathogens and cancer cells, producing complement-
dependent cytotoxicity (CDC) (39,40). IgG antibodies are syn-
thesized following immunoglobulin gene rearrangements, with
switches in Fc domains, as the B cell matures in response to Antigen-Presenting Cells
T-cell help. IgG antibodies usually have higher affinity, and can Dendritic cells are the prototype professional antigen-presenting
be found in the extracellular space as well as in the blood. IgG1 cells and are the critical link between innate immunity and
and IgG3 antibodies in humans are especially effective at acti- acquired immunity. These are phagocytic cells that sit on epi-
vating complement and also at sensitization of pathogens for dermal surfaces, including skin and mucosal membranes, con-
killing by NK cells, macrophages, and other cells with comple- stantly sampling their environment to search for infectious
ment receptors and immunoglobulin Fc receptors (41). organisms. Although dendritic cells continuously ingest mol-
Opsonization for ingestion and destruction by phagocytes ecules from their environment, uptake of antigen is insufficient
can occur through complement activation, but also occurs to activate dendritic cells. Rather, dendritic cells have a set of
directly as a consequence of engagement of Fc receptors on receptors, most notably the toll-like receptors (TLRs), which
phagocytic cells. Antibodies complexed to antigen bind to Fc can recognize lipid-containing molecules and CpG-rich DNA
receptors, which can lead to activation signals through activat- and poly-U RNA sequences produced specifically by microbial
ing Fc receptors (e.g., FcRIII), but activation can be countered organisms. Engagement of TLR signals for activation of the den-
by IgG binding to the inhibitory Fc receptor, FcRIIB. Fc recep- dritic cell, with increased expression of MHC and B7 molecules,
tors, which are bound effectively by IgG1 and IgG3 subclasses of and movement of cells with captured antigen to draining lymph
human antibodies, are expressed on monocytes, macrophages, nodes. It is in draining lymph nodes that dendritic cells acti-
NK cells, neutrophils, mast cells, and other cells. Cross-linking vate appropriate T cells that recognize that particular antigen
of Fc receptors leads to activation of the cells, in some cases lead- presented by MHC molecules. Subsequently, activated T cells
ing to antibody-dependent cell-mediated cytotoxicity (ADCC) can then travel from the draining lymph node to distant sites of
of tumor cells through production of cytotoxic molecules, such infection or tumor to carry out the effector functions. One of the
as perforin and granzyme by NK cells and reactive molecular central problems for cancer immunology is that dendritic cells
species by macrophages (4244). Monoclonal antibodies are may ingest and process cancer antigens, but without activation
commonly used for cancer therapy. Antitumor effects can be through TLRs or other receptors, the dendritic cells remain inca-
mediated in part by antibody binding to critical molecules on pable of activating T cells (because of insufficient expression of
the surface of tumor cells, for example by inhibiting tumor cell co-stimulatory molecules, such as B7) and do not move to drain-
attachment or growth receptors. However, generally interac- ing lymph nodes. In fact, insufficiently activated dendritic cells
tions of antibody with cell antigen are not very effective unless presenting antigens can induce anergy, a form of immune toler-
Fc receptormediated effector mechanisms are also activated. ance where T cells become paralyzed and incapable of respond-
ing to cognate antigens. This is one of the mechanisms used to
maintain immune tolerance to self to prevent autoimmunity, but
also presents a major hurdle for cancer immunity. Cancer cells
Cellular Immunity do not have any readily apparent mechanism to activate den-
Tlymphocytes recognize processed (digested) molecules that dritic cells, although several self molecules, including heat shock
complex with MHC molecules within antigen-presenting cells. protein, hyaluronate, and uric acid crystals have been suggested
The antigen/MHC molecules are then trafficked to the cell sur- to cause activation.
face for recognition by T-cell receptors, which are encoded by
genes of the immunoglobulin family. Similar to generation of
antibodies, great diversity of T-cell receptors is generated by
rearrangements of these immunoglobulin family genes. Each Helper and Regulatory T Cells
monoclonal T-cell receptor must bind to its cognate antigen/ Several types of T cells are activated by dendritic cells, and
MHC complex (CD4 cells bind to MHC class II molecules, which type is influenced by whether antigens are presented by
and CD8 cells bind to MHC class I molecules) presented on the MHC class I or MHC class II molecules on antigen-presenting
surface of antigen-presenting cells (45,46). Signaling from the cells. MHC class I molecules complexed with antigen stimulate
T-cell receptor following engagement of antigen/MHC com- CD8+ T cells that are cytotoxic and kill target cells (infected cells
plex is insufficient to activate the T cell. Additional signals are or tumor cells). Antigens presented by class II MHC molecules
required (co-stimulatory signals or signal 2). The most impor- stimulate CD4+ helper T cells. Helper T cells produce chemo-
tant co-stimulatory signal in T cells comes from the T-cell surface kines and cytokines to help recruit and orchestrate other com-
molecule CD28, which engages B7 molecules (CD80 and CD86) ponents of the immune system. Helper T cells come in several
on antigen-presenting cells (4749). Engagement of T-cell recep- types and different cytokines in the milieu determine what
tor by antigen/MHC in conjunction with CD28 engagement type of T cell is generated. Each type of helper T cell mediates
CHAPTER 15 I MM U NOTH ER APY OF GYN ECOLOGIC MALIGNANCI ES 437
A critical component of any immune approach is a consid- is best used in combination with vaccines or Toll-like receptor
eration of immune escape. Tumors escape destruction by the agonists (75,76), because alone it can accelerate the deletion of
immune system via a variety of active, regulatory mechanisms. tumor-specific cytotoxic lymphocytes (77). Additional value of
These include downregulation of MHC and tumor antigen loss CD40 ligation is provided by the fact that ovarian cancers, like
(69), stimulation of the inhibitory receptors on T-cells such as many tumors, express the CD40 receptor (7881) and respond
CTLA-4 (70), PD-1 and LAG-3 (71), tumor overproduction of to CD40 agonists with apoptosis and growth inhibition in vitro
indoleamine 2,3-dioxygenase (IDO) (72), induction of increased and in vivo (80,82,83).
tumor infiltration by regulatory CD4+CD25+ T cells (Tregs) (73)
and also certain types of natural killer T (NKT) cells that inhibit
tumor immune destruction (74). Overcoming these mechanisms Effector T-cell Activation
is the goal of immunomodulation.
T-cell activation is triggered through the T-cell receptor by
recognition of the cognate antigen complexed with MHC. This
activation is regulated by complex signals downstream of CD28
family immune receptors, which includes costimulatory (CD28
I MM U NOMODU LATION and ICOS) and inhibitory receptors (CTLA-4, PD-1 and BTLA).
PD-1 and CTLA-4 are induced on T cells following a TCR signal,
Multiple potential difficulties remain in developing new immu- and result in cell cycle arrest and termination of T-cell activa-
notherapy approaches, including insufficient activation of den- tion. The use of blocking CTLA-4 or PD-1 mAbs can sustain the
dritic cells by cancer cells, inhibition of responses by Treg cells, activation and proliferation of tumor-specific T cells, preventing
and both intrinsic and extrinsic mechanisms that down-regulate anergy or exhaustion and thereby allowing the development of
T-cell responses, e.g., signaling through CTLA-4. These check- an effective tumor-specific immune response.
points all participate to dampen immune responses against
cancer. Modulating immune check points by activation of effec-
tor cells, depletion of Tregs or activation of professional APCs
could substantially improve the therapeutic efficacy of vaccines CTLA-4 Blockade
or adoptively transferred T cells. The development of functional CTLA-4 is the best characterized among the inhibitory B7
antibodies is now enabling effective immunomodulation as receptors. As with CD28, CTLA-4 also binds CD80 and 86
shown in Figure 15.1. Passive therapy with monoclonal anti- expressed by APCs, but provides inhibitory signals to the T cell,
bodies or with adoptive cellular treatments may also be able to serving as a negative feedback loop. In animal models, CTLA-4
bypass some of these checkpoints. proved critical in the normal functioning immune system.
CTLA-4 knockout mice develop uncontrolled lymphoprolifera-
tion with early lethality. Furthermore, administration of CTLA-4
blockade significantly enhanced antitumor immunity in a vari-
Dendritic Cell Activation ety of mouse models and with various therapeutic combinations
The main mechanism of immune stimulation by CD 40 ligands including vaccine, TLR agonist, chemotherapy and radiation ther-
is activation of DCs resulting in increased survival, upregula- apy. The mechanism by which CTLA-4 blockade induces tumor
tion of costimulatory molecules, and secretion of critical cyto- regression is not fully understood. Although Treg constitutively
kines to T cell priming such as IL-12. This promotes antigen express CTLA-4, CTLA-4 blockade had no effect on the num-
presentation, priming and cross priming of CD4+ and CD8+ ber or function of Treg in cancer patients. It seems that CTLA-4
effector T cells (75). However, agonistic anti-CD40 antibody blockade activates directly CD4 and CD8+ T effector cells
by removing an inhibitory checkpoint on proliferation and tumor-infiltrating tolerogenic DCs and myeloid derived suppres-
function (84). The combination of direct enhancement of Teff cell sor cells express PD-L1 (92,93). Furthermore, expression levels
function and inhibition of Treg activity is essential for mediating the correlate with disease course. Although PD-1 signaling can occur
full therapeutic effects of anti-CTLA-4 antibodies during cancer at very low levels of receptor expression, elevated levels of PD-1
immunotherapy (85). have recently been attributed functional significance. During con-
Based on these data, several clinical studies have been under- ditions of chronic antigen persistence (such as in chronic viral
taken to assess the efficacy of a CTLA-4 antagonist antibodies infections), antigen specific effector T cells expressing high lev-
in the setting of human cancer. The majority of clinical data els of PD-1 were demonstrated to be functionally exhausted,
to date have emerged from studies in patients with melanoma i.e., unable to proliferate, secrete IL-2, or kill target cells (94).
(reviewed in (86)). Phase II studies with ipilimumab monother- It has been shown recently that tumor infiltrating lymphocytes
apy showed objective responses at a dose of 3 to 9 mg/kg every in metastatic melanoma and other tumors expresses higher levels
3 weeks, with 10 mg/kg showing the best risk-benefit profile. of PD-1 than CD4+ and CD8+ cells in the peripheral blood of
Ipilimumab (3 mg/kg every 4 weeks x 4) administered in com- healthy patients and exhibit phenotypic and functional char-
bination with chemotherapy (dacarbazine) resulted in enhanced acteristics of exhausted T cells with impaired effector function.
objective response rates without added toxicity. Ipilumimab These findings suggest that the tumor microenvironment can
has also been combined successfully with IL-2 (720,000 U/kg lead to up-regulation of PD-1 on tumor-reactive T cells and con-
every 8 hours x 15 (OR rate of 22% - 3 CRs) or melanoma tribute to impaired antitumor immune responses (95). Indeed,
vaccine (OR rate of 13% - 2 complete responses). In addition, constitutive or inducible expression of PD-L1 by tumors con-
CD25-expressing cells used in patients with melanoma, ovarian with a significant reduction in the viral load of high-risk HPV
cancer and renal-cell carcinoma (110113). Although effective (p=0.0313) (128).
in short-term infusions, these conjugates are quite immunogenic
and induce neutralizing antibodies, which hamper their long-
term application.
Interleukin-2
Another agent is Daclizumab, which is an FDA-approved IL-2 is a T-cell growth factor that plays a central role in the
humanized IgG1-kappa mAb that binds specifically to CD25 immune system with data showing IL-2induced CD4+ T cell
(114). It has been used in autoimmune disorders (115,116), acute expansion in patients with HIV infection (129) as well as clinical
graft-versus-host disease (117), and in cancer patients with CD25+ responses in renal cell cancer and malignant melanoma result-
T-cell malignancies (118). The advantage of Daclizumab is that it ing in an indication for treatment by the U.S. Food and Drug
is well tolerated, and has a half-life of 20 days (119). In a recent Administration for these tumors (120,121). It has been shown
study, Daclizumab was used in a single dose of 1 mg/m2 prior to activate tumor-associated macrophages and upregulate IFN-
to hTERT peptide vaccine for metastatic breast cancer. Total stimulated genes (130). Based on the toxicity of intravenous
CD4+CD25+ and CD4+CD25+FoxP3+ cells remained suppressed IL-2 administration, studies in ovarian cancer focused on IP
for several weeks after a single infusion. administration. A phase I-II study (131) of IP IL-2 in patients
with laparotomy-confirmed persistent or recurrent ovarian
cancer after 6 courses of prior platinum-based chemotherapy
had shown an overall response rate of 25.7%, with an over-
Cytokines all 5-year survival probability of 13.9%. A more recent study
Cytokines play important roles in immune modulation. Many shows that IP IL-2 administration in patients with ovarian
cytokines, including IL-2, IL-3, IL-4, IL-6, IL-10, IL-12, tumor cancer increases CD4+CD25 high T-cells which highly express
necrosis factor- (TNF-), macrophage colony-stimulating final FOXP3 and suppress Treg cells. This suggests that IL-2 has a
factor, and IFNs, have been studied for their roles in tumor treat- critical role in maintaining the Treg pool as well as enforcing
ment. Some cytokines (IL-2 and IFN-) have been approved by Treg cell tumor trafficking in humans and may lend itself to
the U.S. Food and Drug Administration (FDA) specifically for combination studies of other agents targeting different immune
the treatment of melanoma and renal-cell carcinoma though checkpoints (132,133). A disadvantage of frequent administra-
enthusiasm for use has waned given the systemic toxicity profile tion of intravenous high-dose IL-2 is the occurrence of dose-lim-
(120,121). Ovarian cancer ascites is rich with cytokine expres- iting side effects. Therefore, delivery of IL-2 from an expression
sion and the study of the ascitic fluid should help to better plasmid has been evaluated for the treatment of ovarian cancer.
understand the immune interactions between tumor and host IP treatment of ovarian tumors with an IL-2expressing plas-
which is complex. A recent analysis showed ascites to be high mid resulted in an increase in local IL-2 levels, a change in the
in pro-inflammatory cytokines IL-6, IL-8 and the immune sup- cytokine profile of the tumor ascites, and a significant antitumor
pressive cytokines IL-10, CCL22 and TGF-B in most samples. effect in a mouse model (134). A recent in vitro study in colorec-
Interestingly, high IL-6 expression predicted residual disease tal cancer showed the ability of plamids expressing murine IL-2
after debulking and was highest at recurrence (122). to enhance the antitumor activity of viral vector immunization
against a cancer mucosa antigen showing the tolerability and
possibility of combining plasmid-derived IL-2 production with
Interferons other immunotherapeutic strategies as well (135).
Although the full extent of action of IFN in patients with ovar-
ian cancer is unknown, several mechanisms have been proposed:
(a) stimulation of NK cells and macrophages, both of which
Interleukin-12
are known to have antitumor properties (21); (b) antiangiogenic IL-12 is a cytokine mainly produced by activated monocytes,
effects; and (c) inhibition of expression of dysregulated onco- tissue macrophages, and B cells. It can induce IFN- and together
genes (such as HER2/neu) and thereby improving the responsive- with IL-2 becomes a potent activator of cytotoxic T lympho-
ness of cisplatin-resistant cells (123). A Gynecologic Oncology cytes and NK cells (136,137). Whereas IL-4 and IL-10 mediate
Group Study evaluated administration of systemic IFN- to the development of Th2-type immunity, IL-12 initiates the dif-
patients with advanced ovarian cancer where patients with mea- ferentiation to the Th1 phenotype. In addition, IL-12 produc-
surable disease showed a low response rate of approximately tion can be negatively or positively regulated by cytokines.
10% (124). The role of intravenous IFN- as a maintenance For example, IL-10 and IL-4 have been shown to inhibit the
treatment after initial surgical resection and chemotherapy was production of IL-12 (138), whereas IL-2 and IFN- enhance its
also evaluated by a randomized phase III study and showed no production. In addition, IL-12 has potent antimetastatic and
benefit (125). Systemic IFN- was also associated with frequent antitumor effects in several murine tumor models, as well as in
dose-limiting toxicity. Because of the poor response rate and human tumor cells in vitro and in vivo (139). Ascitic IL-12 had
frequent toxicity of systemic administration, further studies been shown to be an independent prognostic factor for adverse
were focused on IP administration of IFN-. Multiple clinical outcome in ovarian cancer (140) though later there was uncer-
trials with IP IFN therapy were carried out leading to a ran- tainty over this finding as a result of a possible statistical flaw (141).
domized trial of adjuvant intraperitoneal -interferon in stage A phase II GOG clinical trial (142) evaluated intravenously
III ovarian cancer patients who had no evidence of disease after administered recombinant human IL-12 in patients with recur-
primary surgery and chemotherapy by the Southwest Oncology rent or refractory ovarian cancer. Myelotoxicity and capillary
Group (126). The trial was closed early but there was no difference leak syndrome were the major adverse events. Partial response
between the study arms with regard to progression-free survival rate was on 3.8% with no complete responders. Recent focus
(p = 0.56). In cervical cancer, monotherapy with IFN- had has shifted to evaluating the administration of IL-12 express-
minimal activity (127). Studies evaluating intralesional inter- ing DNA. Two studies have evaluated this strategy in patients
feron in HPV associated diseases (cervix and vulvar cancer) with malignant melanoma with patients showing response of
have waned as directly targeted immunologic approaches greater than 30% in 5 of 12 patients receiving intratumoral
against the virus have emerged. Nonetheless, a recent study uti- injections; or CR in 2 of 19 and PR or SD in 8 of 19 patients
lizing intralesional IFN = 2 b in high grade cervical intraepi- using electroporation of plasmid coding IL-12. More investiga-
thelial neoplasia showed a 60% response rate. Treated patients tion in this area including other tumor types is warranted and
also expressed more Th1 (IFN-, TNF-, IL-2) cytokines, ongoing (143,144).
CHAPTER 15 I MM U NOTH ER APY OF GYN ECOLOGIC MALIGNANCI ES 441
Ovarian 4/5 3/5 5/5 4/5 99/133b 5/5 18/19 5/5 5/5 53/62c
Endometrial 4/5 2/5 4/5 3/5 2/5 5/5 4/5 3/5 5/5
Melanoma 0/5 0/5 0/5 0/5 0/5 10/10 0/10 0/5 0/5 0/4
Small-cell Lung 0/5 0/5 0/5 2/5 1/5 6/6 4/6 2/5 4/5 0/2
Prostate 4/5 3/5 1/5 3/5 3/5 5/5 2/5 1/5 5/5 0/5
a
All the tumor tissues were stained by avidin-biotin complex immunoperoxidase methods (155). Figures are the number of tumor specimens with >50% positive tumor
cells by immunohistochemistry.
b
From Federici MF, et al. Selection of carbohydrate antigens in human epithelial ovarian cancers as targets for immunotherapy: serous and mucinous tumors exhibit
distinctive patterns of expression. Int J Cancer 1999;81(2):193198.
c
From Kabawat SE, et al. Immunopathologic characterization of a monoclonal antibody that recognizes common surface antigens of human ovarian tumors of serous,
endometrioid, and clear cell types. Am J Clin Pathol 1983;79(1):98104.
442 CHAPTER 15 I MM U NOTH ER APY OF GYN ECOLOGIC MALIGNANCI ES
The extensive expression of CA-125 in over 80% of serous Immunotoxins, Drugs, and Cytokines
and endometrioid ovarian cancers has been well documented
since the early 1980s (157). Following the successful cloning Drugs, toxins, and cytokines conjugated to mAbs have been
of CA-125 and identifying it as a complex mucin, it has been evaluated in numerous cancers. Immunotoxins incorporate an
termed MUC-16 (158,159). Multiple efforts to target MUC-16 antibody-binding domain and a toxin joined by a chemical
as a logical target for immunotherapy are underway. cross-linker, peptide, or disulfide bond. The specific targeting
afforded by mAbs and the relative potency of the toxin moi-
ety present potential therapeutic advantages. Early conjugates,
which have generally not been successful, linked antibodies to
Antibody Conjugates standard anticancer drugs such as doxorubicin or vinblastine.
In an attempt to add to the efficacy of unconjugated antibod- It is generally not possible to deliver comparable levels of cyto-
ies, efforts have been made to optimize the antitumor activity toxic agents as intravenous administration using this approach.
by conjugating with radionuclides, toxins, cytotoxic drugs, or This field is advancing by replacing murine antibodies with
second antibodies. The choice of conjugates and specific anti- humanized versions and conjugating agents that are both spe-
bodies is influenced by features such as antigen internalization, cific and functional at lower doses (167). Multiple agents are
lysosomal degradation, shedding, and heterogeneity of expres- being evaluated though none have proven efficacy in gynecologic
sion. The mechanism can be complex in that for some internal- tumors to date.
ization is a prerequisite for cellular toxicity; while in others it
may result in reduced efficacy and increased host toxicity due to
intracellular catabolism (160). Other Selected Clinical Trials with
Monoclonal Antibodies
Radionuclides Monoclonal Antibodies Targeting CA-125
A variety of radionuclides have been conjugated with antibodies CA-125, a tumor-specific antigen that is found in 97% of patients
for imaging and treatment. The optimal radionuclide for cancer with late-stage ovarian cancer, was first described by Bast et al.
therapy is dependent on many factors (161). Radioconjugates as an antigen that is elevated in the serum of patients with epi-
with (i.e., 131I and 90Y) and (i.e., 211At and 212Bi) emitters have thelial ovarian cancer (157). CA-125 has been cloned and iden-
been proposed for regional therapy of peritoneal implants (162). tified as the mucin MUC-16 (168), as shown in Figure 15.2.
Estimates of dosimetry suggest that adequate therapy (i.e., 20 Studies have shown that MUC-16 has a variety of functions and
Gy) could be delivered to tumors with a depth less than 300 contributes to ovarian cancer cell growth, survival and inva-
g using 211At, less than 0.1 cm using 131I, and less than 1 cm siveness (169). Recent data suggest that expression is extended
using 90Y when conjugated to antibodies. The relatively low to digestive tract adenocarcinomas, and moderate expression
radiation dose makes the intraperitoneal delivery route attrac- likewise correlates with poor survival (p < 0.001) (170). The
tive in order to put the source close to the tumor implants in sheer size of the MUC-16 complex has made selecting appropri-
the case of ovarian cancer. Delivery of effective radiation dose ate sequences for incorporation into vaccines difficult, and ini-
is greatly influenced by the extent of tumor binding, depth of tial studies focused on antibodies which could be raised against
tumor penetration, catabolism, and relative distribution between CA-125.
tumor and normal tissues. Antibody-radionuclide conjugates Monoclonal antibodies including anti-idiotypic antibodies
have been successfully developed for non-Hodgkins lymphoma have been used as CA-125 targets. The historical rationale for
resulting in drug approvals with CD20 targeted agents (163).
Randomized clinical data in ovarian cancer are sparse with two
larger studies having been reported. A randomized trial of 251
patients with Stage 1a or 1b grade 3, or 1c, or 2 ovarian cancer
with no macroscopic residual disease were randomized to intra-
peritoneal radioactive chromic phosphate (32P) versus cisplatin
and cyclophosphamide chemotherapy. The cumulative incidence
of recurrence at 10 years was 35% (95% CI, 27%45%) ver- Terminal Repeats
sus 28% (95% CI, 21%38%) favoring chemotherapy (p = ns). Containing CA-125
The toxicity profile of 32P was worse (164). Antigen
The SMART study was a large randomized study which
evaluated intraperitoneal yttrium-90-labeled HMFG1 murine
monoclonal antibody in patients with ovarian cancer after a
surgically defined complete remission. The MUC-1 antigen that
90
Y-muHMFG1 is directed towards is well established as an
immunotherapy target and is overexpressed on 90% of adeno- External Domain
carcinomas including that of ovarian cancer. The phase II data With Cleavage Site
supporting the use of 90Y-muHMFG1 administered intraperito-
Trans-membrane
neally in patients in first remission was promising with a Cox Domain
model estimate of 10 year survival at 70% compared to 32% of
case matched controls (p = 0.003) (165). Patients were stratified
using a second surgical assessment where disease status at sec-
ond look remains a powerful predictor of ultimate progression- Cytoplasmic Domain
free and overall survival (166). Despite the strong preclinical
and clinical data supporting this approach, at a median fol-
lowup of 3.5 years, relapses occurred in 98 versus 104 patients
(p = ns). While there is no randomized evidence supporting 35,000 bases, 150,000 bp on chr 19q13.2
efficacy of radioconjugates in gynecologic malignancies to date,
the number of candidate agents for investigation continues to
increase and earlier phase trials are ongoing. FIGURE 15.2. Proposed MUC-16 structure.
CHAPTER 15 I MM U NOTH ER APY OF GYN ECOLOGIC MALIGNANCI ES 443
an anti-idiotype vaccine was an attempt to augment both anti- complete clinical remission after primary surgery and platinum/
body and T-cell responses by using antibody facsimiles of the taxane based chemotherapy were randomized 2:1 in a phase III,
native antigens with the goal of overcoming poor immunogenicity. double blinded, placebo controlled, multicenter study. Abavo-
Tumor-associated antigens are traditionally weakly immuno- vomab 2 mg or placebo was given as 1 ml sc every 2 weeks
genic as the large majority of them in humans are nonmutated for 6 weeks (induction phase), then every 4 weeks (maintenance
self-antigens. This approach attempted to present the desired phase) until recurrence or up to 21 months after randomization
epitope to the now tolerant host in a different molecular environ- of last patient. Primary endpoint was recurrence free survival;
ment but the problem with many tumor antigens is that they are secondary end-points were overall survival and immunological
ill-defined chemically and difficult to purify and produce (171). response. The characteristics of 888 patients were: mean age,
The immune network hypothesis set out to transform epitope 56.3 years; ECOG PS maximum of 1 in more than 99%; serous
structures into idiotypic determinants expressed on the surface papillary subtype in 81.5%; FIGO stage III in 85.9%; CA-125
of antibodies. It was originally proposed in the 1970s (172), and 35 U/ml after the third cycle FLCT in 80.9% of patients.
assumes that immunization with a given antigen will generate The mean exposure to study treatment was 449.7 333.08
the production of antibodies against this antigen (termed Ab1). days. The hazard ratio of recurrence free survival for treat-
Ab1 can generate anti-idiotypic antibodies against Ab1, termed ment group using ( 1 cm, > 1 cm) tumor size categorization
Ab2. Some of the anti-idiotypic antibodies (Ab2) express the was 1.099 (95% CI, 0.9191.315; p = 0.301). The hazard ratio
internal image of the antigen recognized by the Ab1 antibody of overall survival for the treatment group using tumor size
and can be used as surrogate antigens. Immunization with Ab2 catheterization ( 1 cm, > 1 cm) was 1.150 (95% CI, 0.872
interval of 2.0 months. Based on infrequent HER2 expression, (phenotype and polarization) of antibody and T-cell responses;
and the low rate of objective responses, the clinical value of and (c) developing combinatorial approaches with adoptive
single-agent trastuzumab appears limited in these patients. The T cell or immunomodulation therapy to maximize activation
potential role on combination with chemotherapy is unknown and function of vaccine-primed effector cells in vivo.
but the broad applicability will be limited by the frequency of
expression. Pertuzumab is a recombinant humanized monoclo-
nal antibody binding to the HER 2 dimerization domain which Vaccines Designed Primarily to
stoically blocks the pocket required for dimerization (190).
A randomized phase II trial evaluated pertuzumab in platinum Generate Antibody Responses
sensitive disease with a comparison of platinum based therapy Most current vaccines seek to generate cellular responses (often
with or without pertuzumab. Results are pending publication. with an accompanying humoral or integrated response).
Studies are simultaneously looking to characterize the affected However, based on the cell surface target antigen selection pro-
molecular pathways particularly in patients with response as col- cess appropriate for antibody recognition described above, and
lateral signaling may play an important role in further tumor advances in the chemical and enzymatic synthesis of carbohy-
growth (191). drate and glycopeptide antigens and optimization of adjuvant
The growth and metastasis of malignant neoplasms require use, the exploration of a variety of synthetic antigen vaccines
the presence of an adequate blood supply, and recent data have with antibody production as the endpoint was feasible (203-205).
confirmed the therapeutic potential of multiple antivascular After defining targets to include GM2, Globo-H, Lewisy, sialyl
strategies. The role of bevacizumab and other antivascular Tn (STn), Tn, Thompson Friedreich antigen (TF), and mucin 1
agents are discussed in the appropriate chapters regarding the (MUC-1) (66,155,156,206), a series of phase I univalent trials
treatment of patients with ovarian cancer. were performed. The most immunogenic approach was identi-
fied to include chemical conjugation of the antigen to a highly
immunogenic carrier protein (keyhole limpet hemocyanin
Monoclonal Antibodies Targeting EPCAM (KLH) plus the use of a potent immunological adjuvant such as
(Antiepithelial Cell Adhesion Molecule) the saponin QS-21 or OPT-821 (207). Preclinical data supported
The tri-functional antibody catumaxomab (EPCAM X anti-CD33) the hypothesis that polyvalent vaccines would likely be required
has been evaluated in patients with malignant ascites (192). The due to tumor cell heterogeneity, heterogeneity of the human
phase II/III trial randomized patients to standard paracentesis immune response, and the correlation between overall antibody
or paracentesis with antibody delivered via the intraperitoneal titer against tumor cells and antibody effector mechanisms(208).
route. Puncture free survival was longer in the catamaxomab Preclinical models further showed that a heptavalent KLH con-
group (median 46 days) than the control group (median 11 jugate plus QS-21 vaccine induced antibody titers comparable
days) with hazard ratio = 0.254, p < 0.0001. There was a cor- to those induced by monovalent vaccines containing Tn, STn,
relation between humoral response and clinical outcome (193). TF, MUC-1 and Globo-H. Lower titers were produced against
Additional study is ongoing. Lewisy and GM2 (209). Some antigens have required modifica-
tion for optimal immunogenicity resulting in trimers or clusters
(c) of Tn, STn, and TF rather than unmodified monomers
Monoclonal Antibodies Targeting Antigens in (210,211). A pilot trial of a heptavalent vaccine-KLH conju-
Cervical and Endometrial Cancer gate plus QS-21 in patients with epithelial ovarian, fallopian
tube, or peritoneal cancer in either a first (following persistence
There are no approved antibody strategies targeting antigens and additional treatment), second, or third remission (212).
in cervical or endometrial cancer to date. Vascular endothe- The administered heptavalent vaccine contained GM2 (10 g),
lial growth factor targeted approaches are ongoing in patients Globo-H (10 g), Ley (10 g), Tn-MUC1 (3 g), Tn(c) [clusters]
with cervical carcinoma and endometrial cancer, and these (3 g), STn(c) (3 g) and TF(c) (3 g) individually conjugated
are discussed in the appropriate chapters. Epidermal growth to KLH and mixed with adjuvant QS21 (100 g). Vaccinations
factor targeted approaches have also being evaluated in patients were administered at weeks 1, 2, 3, 7, and 15. ELISA assays
with cervical cancer. The epidermal growth factor receptor were tested against the following target antigens: Tn-MUC1-
is overexpressed in 85% of patients with invasive cervical can- 32mer, GM2, Globo-H ceramide, Ley ceramide, desialated ovine
cer (194). Cetuximab is a chimeric IgG1 mAb that antagonizes submaxillary mucin (DOSM) expressing Tn, OSM express-
normal ligand receptor interactions. A phase II trial by the ing STn, and desialated porcine submaxillary mucin (DPSM)
Gynecology Oncology Group evaluated single agent cetux- expressing TF. IgM and IgG antibody titers were measured by
imab in 38 patients. No clinical responses were detected (195). ELISA as described previously (213215). Fluorescent-activated
Cetuximab was also evaluated in 76 patients in combination cell-sorting (FACS) was performed as previously described to
with cisplatin chemotherapy in treated and chemotherapy nave demonstrate antibody binding to the cell surface of the cell
patients. Response rates of 9% and 16% respectively were line MCF-7. MCF-7 was chosen as it is known to express each
seen with no evidence for a benefit of cetuximab over cisplatin of the 7 antigens (213215). Side effects were limited to fever
alone (196). and local injection site reactions which were self limited. After
immunization median IgM titers were as follows: Tn-MUC-1
1:640 (IgG 1:80), Tn 1:160, TF 1:640, Globo-H 1:40, and STn
1:80. Eight of nine patients developed responses against at least
CANCER VACCI N ES three antigens. FACS and CDC analysis showed substantially
increased reactivity against MCF7 cells in 7/9 patients, with
Vaccines remain a backbone in the approach to ovarian can- some increase seen in all patients (212). This has led to Gyne-
cer immunotherapy (197201). Similar to experiences in other cology Oncology Group Trial 255 (NCT00693342) which is
immunogenic tumors (202), vaccines have shown limited a randomized trial in ovarian cancer patients with second or
efficacy as monotherapy in patients with advanced recurrent third complete clinical remission receiving either the adjuvant
disease. Clearly, much work is required to improve their perfor- alone (OPT-821) versus the multivalent antigen construct + OPT-
mance. Current efforts to improve vaccines are directed broadly 821. The endpoint is the proportion of patients disease free at
towards (a) optimizing the choice of antigens; (b) improving 12 months (35% vs. 50%) and accrual is currently ongoing with
vaccine delivery systems to maximize the magnitude and quality a target accrual of 154 patients.
CHAPTER 15 I MM U NOTH ER APY OF GYN ECOLOGIC MALIGNANCI ES 445
recurrence, but has been a major challenge for all tumor immu- preclinical immunization studies. Neglia et al. (255) evaluated
notherapy approaches. Recent studies indicate that inhibition of FR-a cDNA after ligation into the VR1012 (Vical) expression
mTOR activity switches Tbet for Eomesodermin expression and vector under transcriptional control of the cytomegalovirus
slants CD8+ effector cells for memory precursor like phenotype promoter. Purified plasma DNA was injected into BALB/c mice
(244246). Moreover, in vivo murine studies have shown that three times at 14-day intervals. At 10 days after the second
sirolimus augments antigen specific vaccination by inducing a injection, sera (100%) showed antibody titers against synge-
long lasting, tumor protective memory T-cell response. There- neic C26 cells transduced with FR-a, but not against unmodi-
fore, this trial will test whether mTOR inhibition will condition fied C26 cells. Specific cytotoxic T lymphocyte activity against
vaccine induced Tcells for enhanced persistence, antigen recall FR-atransduced C26 cells could be seen in splenocytes from
and tumor efficacy. all immunized animals. Challenge by subcutaneous injection
with FR-atransduced C26 cells (administered 10 days after
third injection) showed a statistically significant delay in tumor
Granulocyte Macrophage Colony growth (255). Further studies by Peoples et al. showed that both
immunodominant E39 (folate-binding protein [FBP]) (194202),
Stimulating Factor (GM-CSF) Secreting and subdominant E41 (FBP) (246, 248255), epitopes of human
Tumor Vaccines high-affinity FBP are presented by HLA-A2 in both ovarian and
Granulocyte-macrophage colony-stimulating factor (GM-CSF) breast cancers (256). Tumor-associated lymphocytes stimulated
has a variety of properties desirable for vaccine production with FBP peptides exhibit cytotoxicity not only against pep-
investigated preclinical use of replication-restricted herpes sim- use of ex vivo expanded TILs has yielded the best clinical immu-
plex virus (HSV) 1 to infect autologous tumor cells for vaccine notherapy results to date. The advantages of TIL-based adoptive
preparation. HSV-infected tumor cells used directly or pulsed therapy include the presence of spontaneously occurring T cells
on dendritic cells elicited potent antitumor immune response with natural avidity against tumor which have escaped thymic
in the mouse, which was superior to the use of UV-irradiated deletion; the use of a polyclonal population of T cells, which can
tumor cells (218,264,265). Thus, whole tumor antigen vaccines limit immunologic escape of tumors; and the natural selection of
can produce objective response if immunogenicity is increased patients whose tumor microenvironment is already conducive
through the use of pathogens. An alternative approach to deliver to T-cell homing. Initial studies using TILs in the treatment of
effectively whole tumor antigen is by using dendritic cells (DCs). metastatic melanoma during the late 1980s and early 1990s
In a pilot study using mature DCs pulsed with whole autologous demonstrated objective antitumor responses, but they were
tumor lysate, 3 of 6 subjects demonstrated remission inversion, short-lived. Based on animal studies showing that host lym-
i.e., their progression-free survival postvaccination was longer phodepletion prior to T-cell transfer enhances persistence of
than the interval between prevaccine recurrence and prior che- T cells and antitumor response, a scheme of incremental lym-
motherapy treatment (266). phodepletion through high dose nonmyeloablating chemo-
Although whole tumor vaccines offer distinct advantages, therapy and added whole body radiation was tested. Infused
some drawbacks warrant consideration. First, surgical procure- cells were both long-lived, and highly penetrating, showing
ment of large number of autologous tumor cells may not be regression of voluminous metastatic tumors, with up to 16%
possible in many patients. Alternatives to this limitation exist, complete response and 72% overall objective response rates in
including use of allogeneic cell lines or the use of tumor mRNA. recent reports with maximal lymphodepletion and radiation.
RNA electroporation of DCs is a convenient approach to gener- T cell persistence correlated with long lasting responses (103,202).
ate a potent tumor vaccine (218). An additional concern with Although these are phase I studies accruing a highly selected
whole tumor vaccination relates to the inclusion of a large num- cohort of patients with metastatic melanoma with preexisting
ber of self antigens, which could potentially drive tolerogenic antitumor immunity, whose tumors yield tumor-reactive TILs,
responses, i.e., expand Treg rather than cytotoxic lymphocyte the results clearly demonstrate the power of adoptive immuno-
responses. Recent work has demonstrated that DCs can be therapy and dispel the assumption that immunotherapy can only
polarized ex vivo with the use of interferons, Toll-like recep- control small tumors (271). Interestingly, adoptive transfer of
tor agonists or p38 mitogen-activated protein kinase (MAPK) CD8+ clones expanded ex vivo to large numbers and transferred
inhibitors to drive cytotoxic lymphocytes and Th17 effector following lymphodepletion did not result in objective tumor
cells at the expense of Treg activity (267). On the other hand, response in melanoma, indicating that polyclonal T cells, a mix-
if immunization is successful, there may be increased concern ture of memory and effector cells, and CD4+ cells are necessary
for breaking tolerance to self antigens, leading to immunopa- for tumor rejection (272).
thology. To date, pilot studies with whole tumor vaccines have Although TIL-based adoptive therapy has been mainly tested
reported no autoimmunity in patients with ovarian cancer. in melanoma, there is evidence that it is also an important oppor-
A major limitation of cancer vaccines presently stems from tunity in ovarian cancer. In the early 1990s, ovarian cancers
the inability to elicit a rapid and overwhelming T-cell response, were found to yield reactive TILs after IL-2 culturing in vitro
which is required to reject established tumors. A potential solu- that may be amenable to adoptive transfer (273,274). Moreover,
tion to this limitation is provided by combinations with immu- pilot clinical trials of adjuvant therapy with adoptive transfer
nomodulation therapy previously discussed aiming at breaking of tumor-derived lymphocytes expanded ex vivo with IL-2, fol-
peripheral tolerance mechanisms, which may reduce the number lowing surgical debulking and frontline chemotherapy, showed
of tumor reactive T cells required to reject tumors. For example, a marked survival advantage (275,276). Stage III EOC patients
a recent study has shown that immunomodulation through treated with consolidation adoptive transfer of expanded TILs
blockade of the endothelin B receptor, a VEGF-regulated gene, after completion of cisplatin-based frontline chemotherapy
markedly increases the efficacy of weak vaccines by reversing (n = 13) had 3-year overall survival rate of 100%, while that of
the inhibitory function of tumor endothelium and enabling a control group of patients (n = 10) receiving only chemotherapy
homing of tumor-reactive T cells (268,269). Furthermore, deple- was 67.5% (p < 0.01). The 3-year disease-free survival rate of the
tion of Treg is a likewise critical maneuver to enhance vaccine patients in the TIL group and in the control group was 82.1%
therapy (107). A pilot study at the University of Pennsylvania and 54.5%, respectively. While these results can be limited by the
is testing this hypothesis by administering partially mature lack of randomization, they nevertheless support the feasibility of
DCs pulsed with autologous tumor cell lysate to subjects with adoptive therapy for ovarian cancer (275).
recurrent ovarian cancer in combination with immunomodula- Optimization of adoptive TIL therapy is a matter of intense
tion with oral metronomic cyclophosphamide (to deplete Treg) investigation and currently directed at: a) optimizing methods
(270) and bevacizumab (to disrupt the blood-tumor endothelial to select tumor-reactive TIL and expand them under optimal
barrier) (269). An additional approach to enhance the efficacy costimulation conditions that allow preferential expansion of
of vaccines may be provided by combination with postvaccine specific T-cell phenotypes; and b) optimizing host and/or tumor
adoptive transfer of ex vivo expanded T cells. conditioning. As shown in the melanoma trials, although infused
cells had an effector phenotype (CD27 CD28 CD45RA CD62L
CCR7), TILs that persistent at two months in association with
tumor regression were characterized by a less differentiated phe-
ADOPTIVE CELLU LAR TH ER APY notype (CD27+ CD28+ CD45RA+ but CD62L CCR7) and lon-
ger telomeres (277281). These results argue that use of memory
Effective cancer immunotherapy is dependent on the presence rather than effector cells may be more convenient for adoptive
of large numbers of antitumor lymphocytes with appropriate transfer (282), which has been confirmed by mouse models (283).
homing and effector functions that enable them to seek out and Because TILs comprise a large number of tumor-reactive effec-
destroy cancer cells in vivo. The adoptive transfer of ex vivo tor cells, identification of culture conditions that preferentially
expanded tumor-reactive T cells holds the potential of achieving expand memory phenotypes is a priority. Recent technological
this condition in a short period of time, as shown in Figure 15.3. advances with the development of artificial antigen-presenting
Clinical trials testing spontaneous or induced polyclonal or oli- cells (aAPCs) expressing a variable repertoire of costimula-
goclonal T cells conducted in the past two decades have pro- tory molecules and cytokines has generated new opportunities
vided crucial lessons that can guide further optimization. The to provide the desired costimulatory molecules and cytokines
CHAPTER 15 I MM U NOTH ER APY OF GYN ECOLOGIC MALIGNANCI ES 449
to re-educate TILs, improving their potency and function in Recently, the clinical feasibility, safety, and preliminary efficacy
vivo. Carl June and colleagues recently described the develop- of redirecting T cells of patients with melanoma using a TCR spe-
ment of a next generation K562-based aAPC platform capable cific to MART-1, a melanoma antigen, was demonstrated (286).
of expressing multiple gene inserts, including human lymphocyte The genes encoding and chains of the TCR were cloned from
antigen (HLA)-A2, CD64 (the high-affinity Fc receptor) CD80, a TIL clone derived from a patient demonstrating a near-complete
CD83, CD86, CD137L (4-1BBL) and CD252 (Ox40L), and a regression of metastatic melanoma after adoptive cell transfer of
variety of T cell supporting cytokines (284). Cell-based aAPCs TILs. Gene transfer resulted in transfection of 30% of CD8+ cells.
have proven to be more efficient at activating and expanding Adoptive transfer of TCR-transduced cells in 15 patients resulted
CD8+ CD28 T cells, and antigen-specific T cells, than the mag- in durable engraftment at levels exceeding 10% of peripheral
netic bead-based aAPC (284). Importantly, TILs from ovarian blood lymphocytes for at least 2 months after the infusion. High
cancer patients undergo robust expansion while maintaining sustained levels of circulating, engineered cells at 1 year after
their tumor reactivity after K562-based aAPC stimulation (Powell infusion was observed in 2 patients who demonstrated objective
and colleagues, unpublished). regression of metastatic melanoma lesions (286). TCR-based engi-
A proportion of patients are not eligible for TIL-adoptive neering represents a potentially powerful strategy for ovarian can-
therapy, because tumors are either unresectable or yield no cer therapy as TCRs that recognize HLA-A2 restricted epitopes
tumor-reactive TILs. One strategy to overcome the daunt- from known ovarian cancer antigens such as NY-ESO-1, p53, and
ing task of raising large numbers of tumor-reactive T cells is others are available for clinically testing as well (287290). Opti-
by engineering T cells to redirect their specificity. This can be mization through selection of naturally occurring or recombinant
accomplished by transducing lymphocytes to express a cloned high affinity receptors, engineering to prevent recombination with
T-cell receptor (TCR) with high affinity to tumor-associated epi- endogenous TCR, and the use of lentiviral vectors developed in
topes. In this case, the cloned heterodimeric TCR is transduced the June lab with transfection efficiency above 90% are poised to
to mixed peripheral blood T cells isolated from the patient, cre- improve this approach significantly (291).
ating a large amount of bispecific T cells, which are polyclonal An alternative strategy to engineer T cells with redirected spec-
with respect to their original TCR, but potentially monoclonal ificity is through genetic modification to recognize antigens in an
for the cloned TCR (if recombination with endogenous TCR is MHC-unrestricted fashion through the use of chimeric immuno-
minimized) (285). Alternatively, T cells can be transduced with receptors (CIR), fusion genes encoding an extracellular domain
a chimeric immunoreceptor (see below). that specifically binds to tumor epitopes through a single chain
450 CHAPTER 15 I MM U NOTH ER APY OF GYN ECOLOGIC MALIGNANCI ES
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16
CHAPTER
Hormones and Human
Malignancies
457
458 CHAPTER 16 HORMON ES AN D H U MAN MALIGNANCI ES
Cholesterol
Pregnenolone
2 3
Androstenedione
5 4
Testosterone Estrone
4 5
Estradiol
FIGURE 16.1. Molecular biology of steroid hormone synthesis. Notice the important role of aromatase in the conversion of androgens
to estradiols.
is a peptide linker that connects the DBD to the ligand-binding and ER- is encoded by the ESR2 gene. The ESR1 and ESR2
domain (LBD). The E region is a multifunctional domain genes are located on the 6th and 14th chromosomes (6q25.1
and contains amino acids involved in ligand binding, recep- and 14q23), respectively (23).
tor dimerization, nuclear localization, coactivator/corepressor In humans, the ERs exhibit 96% and 58% homology in
interaction, and ligand-dependent activating function (AF-2). their DBD and LBD, respectively. These structural differences in
The F region is a variable extension of the E region. ERs lead to discrete ligand affinities and physiological proper-
ties. For example, estrone and raloxifene bind preferentially to
ER-, while estriol and genistein have higher binding affinity
for ER-. Furthermore, tamoxifen and raloxifene exhibit partial
Estrogen Receptors agonist activities after binding to ER-, while they act as pure
The ER mainly functions as a ligand-regulated, DNA-binding antagonists when bound to ER- (24). This is thought to result
transcription factor, resulting in modulation of gene expression from distinct conformational changes induced by ligand binding
of proteins involved in key pathways related to cancer progres- in the two receptors (25).
sion. However, additional ER functions, independent of DNA Both ERs are widely expressed in many tissue types; how-
binding, have also been reported (19,20). ERs can be recruited ever, there are important differences in the pattern of their
to the DNA by indirect tethering through other DNA-bound expression. ER- is the predominant ER isoform in many tis-
transcription factors, including members of the activating sues, including breast cancer, endometrium, ovarian stroma,
protein-1 (AP-1) transcription family (4,21,22). Due to alter- and the hypothalamus. ER- has notably higher expression in
native RNA splicing, several isoforms of the ER are known to ovarian granulosa cells, prostate gland, gastrointestinal tract,
exist, but ER- and ER- are considered to be the main iso- endothelial cells, heart, lung, kidney, brain, and bone (2628).
forms. We now know that ER- is encoded by the ESR1 gene However, some expression of both receptors is observed in
N A/B C D E F C
AF-1 AF-2
DBD LBD
Nuclear Localization
Coactivator/Co-repressor
FIGURE 16.2. Functional domains of the human estrogen receptor. The A/B domain is highly variable among
the different members of this family and contains the hormone-independent activating 1, or AF-1, domain. The
C region consists of the DNA-binding domain (DBD). The D domain is a peptide linker that connects the DBD
to the ligand-binding domain (LBD). The E region is a multifunctional domain and contains the LBD as well
as amino acids involved in receptor dimerization, nuclear localization, coactivator/corepressor interaction, and
ligand-dependent activating function (AF-2). The F region is a variable extension of the E region.
CHAPTER 16 HORMON ES AN D H U MAN MALIGNANCI ES 459
many tissues. Data now indicate a correlation between ER- of fos-related antigen 1 (fra-1) and regulates uterine stromal
transcript levels and expression of oncogenes in cancer cells differentiation and remodeling during early pregnancy (43). An
and also suggest a role of ER- in endometrial carcinogenesis additional mechanism of ER action involves cross-talk with
(29). As noted above, ER- and ER- have been shown to have growth factors including insulin-like growth factor 1 (IGF-
unique physiologic properties. In addition, they are capable of 1), epidermal growth factor (EGF), and transforming growth
forming ER-a (aa) or ER-b (bb) homodimers or (ER-/ER-) factor (TGF-) (44,45). EGF can mimic the effects of E2 on
heterodimers, thus influencing each others function (30). In the reproductive tract. This effect is dependent on ER- because
this context, ER- has been shown to function as a dominant it can be blocked by ER antagonists and is absent in ERKO
inhibitor of ER- (21). Therefore, it is likely that normal physi- mice, despite an intact EGF signaling cascade (46). Mechanisms
ologic function in E2 responsive tissues relies on the relative for this cross-talk involve signal transduction from growth fac-
expression ratio of ER- and ER- in those tissues. Recently, tor receptors via the ras/raf/MAPK, as well as the AKT/PI3K
Iyer and colleagues have shown that estrogen promotes ER- cascade intermediaries culminating in the phosphorylation and
negative breast tumor growth by recruitment of pro-angiogenic activation of ERs AF-1 domain (47). AKT activation results
bone marrow-derived myeloid cells in murine xenograft models, in cell survival and inhibition of apoptosis. In normal tissue,
and the researchers demonstrated that ER- expression is pres- this pathway is kept in check by a phosphatase called PTEN.
ent only in bone marrow-derived cells and this expression was PTEN is a tumor suppressor that negatively regulates the PI3K/
required and sufficient to promote breast tumor growth when AKT pathway by dephosphorylating PIP3. The activation of
challenged with estrogen (31). the PI3K/AKT pathway is particularly relevant in endometrial
Table 16.1 Summary of Findings from Estrogen Receptor Knockout Mice Experiments
Phenotype
Organ ERKO a ERKO `a ERKO
Pituitary gland High LH None High LH
Ovary Hemorrhagic cysts, high estrogen and Reduced ovulation Anovulatory, sex-reversed follicles
testosterone due to high LH, anovulatory with Sertoli-like cells
Endometrium Estrogen insensitive, no growth or Normal growth and response to Estrogen insensitive, no growth or
induction of estrogen-responsive genes estrogen induction of estrogen-responsive genes
Breast No pubertal development Normal development and lactation No pubertal development
cancer incidence. In this analysis, the rate of invasive breast can- combined E2 and progestin (95). Data from a prospective, ran-
cer was increased in patients receiving progestin plus estrogen domized trial is not available to answer this question.
(HR, 1.24, weighted p < 0.003) (86). Extended follow-up of the
patients from the WHI intervention trial was continued among Oral Contraceptives
8,052 surviving participants (95%) in a post-intervention study
for a mean of 8 years. More breast cancers were diagnosed among Since their introduction in the 1960s, oral contraceptives
women receiving CEE plus MPA versus placebo (HR, = 1.27; 95% (OCPs) have been taken by over 200 million women through-
CI, 1.061.51) (87). Estrogen plus MPA had a greater influence out the world. The CGHFBC performed a meta-analysis of 54
on breast cancer incidence than placebo if initiated closer to epidemiologic studies on 53,297 women with breast cancer and
menopause (88). The breast cancer developing in patients receiv- 100,239 women without breast cancer. Women who were cur-
ing the hormonal regimen was also not restricted to hormone rent users or had used OCPs in the previous 10 years were at an
receptorpositive tumors (89). increased risk of breast cancer (RR, 1.24; 95% CI, 1.151.33).
Further analysis has revealed that breast cancer diagnosed Among women taking OCPs, the breast cancers that developed
in women receiving CEE plus MPA, when compared with pla- were less advanced than those diagnosed in women with no
cebo patients diagnosed with breast cancer, were more likely history of OCP use (96). Because the results from this meta-
to have metastatic node involvement, even though between the analysis reflected data from studies completed over the prior
two groups the tumors were similar in terms of grade and his- 25 years, the Womens Contraceptive and Reproductive Experi-
tology (88). The combination of CEE plus MPA compared with ences (Womens CARE) study was initiated in an effort to pro-
vide a more contemporary analysis of the relationship between
increased risk of ovarian cancer was noted among women with 10 to 21 days each month: RR, 2.5; 95% CI, 1.15.5) (108).
a history of either estrogen (OR, 1.43; 95% CI, 1.022.00) or Subsequent data from the same investigators suggested that use
estrogen with sequentially added progestins (OR 1.54; 95% CI, of a continuous progestin HRT regimen may actually be protec-
1.152.05), particularly with hormone use exceeding 10 years. tive against endometrial cancer (109). The largest case-control
However, use of estrogen with continuously added progestin was study of continuous HRT involved 79 case subjects and 88 con-
not associated with an increased risk of ovarian cancer when trol subjects, and it revealed that the RR of patients receiving
compared with nonuse (102). The latter 2 studies suggest that continuous HRT was 1.07 (95% CI, 0.801.43) (92). Data from
HRT regimens containing both E2 and progestin may not have the WHI indicated that the HR for endometrioid endometrial
the increased risk of ovarian cancer observed with E2 therapy cancer (EEC) was 0.81 (95% CI, 0.481.36) in patients receiv-
alone. However, the WHI recently identified, in women taking ing continuous HRT with average follow-up of 5.6 years (103).
continuous combined HRT, an HR of 1.58 (95% CI, 0.773.24) Extended follow-up of the patients from the WHI intervention
for developing invasive ovarian carcinoma (103). The impor- and post-intervention trials over 8 years revealed that the inci-
tance of the presence or absence of progesterone in HRT, as well dence of endometrial cancer was still decreased among patients
as the type and potency, remains to be elucidated. receiving CEE plus MPA compared with placebo, but this obser-
vation was not statistically significant (HR, 0.78, 0.521.16) (87).
Women with a history of ovarian cancer. Only one random- There has recently been some suggestion that the degree of
ized, controlled clinical trial exists evaluating the risk of ovar- endometrial cancer risk reduction may be dependent on the type
ian cancer recurrence in patients receiving HRT. This study was of progestin used in the continuous HRT regimen. A Swedish
designed to detect a 20% difference in survival between the two case-control study found that patients with a continuous HRT
treatment groups. In this study, 130 patients less than 59 years involving testosterone-derived progestins (i.e., norhisterone,
of age with invasive ovarian cancer were randomized to contin- norhisterone acetate, levonorgestrel, lynestrenol) were associ-
uous E2 HRT or no supplementation. The median disease-free ated with a lower RR of endometrial cancer than those patients
interval for women receiving HRT versus those not receiving whose regimens involved progesterone-derived progestins (i.e.,
HRT was 34 months and 27 months, respectively, not reach- medroxyprogesterone) (110). Data from the Continuous Hor-
ing statistical significance (104). Multiple epidemiologic studies mones as Replacement Therapy (CHART) study found no evidence
have revealed that OCPs are not a risk factor for ovarian cancer, of endometrial hyperplasia in participants who received nor-
but rather a means of prevention. See below. ethindrone acetate (a testosterone-derived progestin). In this
clinical trial, 1,265 patients were randomized to placebo ver-
Endometrium sus one of eight treatment groups involving either various doses
of unopposed ethinyl estradiol or various combinations of
Hormone Replacement Therapy ethinyl estradiol plus norethindrone. A total of 1,134 endome-
Women without a history of endometrial cancer. Multiple case- trial biopsies were performed over a 2-year follow-up period
control and cohort studies also have suggested that the risk of among women who received the combination HRT regimen;
endometrial cancer is elevated among patients receiving unop- 1,232 biopsies were performed in the women given unopposed
posed estrogen. A meta-analysis of 30 studies indicated that the E2. As the dose of unopposed ethinyl estradiol was increased,
summary RR of endometrial cancer was 2.7 for patients receiv- there were increased percentages of subjects with endometrial
ing unopposed estrogen (105). The use of unopposed estrogen hyperplasia. There were no cases of hyperplasia noted among
has also been shown to be associated with the development of the subjects who received different doses of the testosterone-
endometrial hyperplasia. In the Postmenopausal E2/Progestin derived progestin norethindrone. The protective effect was
Intervention (PEPI) trial, 875 patients were randomized to noted even among patients randomized to receive doses of nor-
receive one of five regimens: (a) placebo; (b) CEE, 0.625 mg/day; ethindrone as low as 0.2 mg (106). In contrast, the PEPI trial
(c) CEE, 0.625 mg/day plus continuous MPA, 2.5 mg/day; identified hyperplasia by a surveillance endometrial biopsy in
(d) CEE, 0.625 mg/day plus MPA, 10 mg for 12 days each 3 of 339patients who received E2 with a progesterone-derived
month; or (e) CEE, 0.625 mg/day plus micronized progesterone progestin. Further studies are needed to determine the degree of
(MP), 200 mg/day for 12 days per month. Patients receiving endometrial cancer risk influenced by the progestational activity
unopposed estrogen had a significantly increased risk of atypi- of the progestin.
cal adenomatous endometrial hyperplasia (34% vs. 1%) (106).
The addition of progestin to HRT has been shown to elimi- Women with a history of endometrial cancer. The use of E2
nate the increased risk of hyperplasia associated with unopposed among patients with endometrial cancer is controversial. In vitro
E2. Although progestins have been associated with the effective treatment of Ishikawa endometrial cancer cells with estrogen upreg-
treatment of endometrial hyperplasia, the data supporting the ulates ER expression and augments growth in endometrial cancer
protective effects of progestins in HRT are limited. Many of cells (111,112). However, in vivo growth of residual microscopic
the initial HRT regimens combining progestin and estrogens uti- endometrial cancer in patients has not been proven to date. Four ret-
lized the progestin for 7 days a month (107). Subsequent studies rospective cohort studies have evaluated patients with early-stage
have recommended prolongation of the progestin component endometrial cancer receiving E2 postoperatively. Creasman et al.
to at least 10 days each month. A case-control study of 832 evaluated 221 patients with stage I disease, of whom 47 received
endometrial cancer patients and 1,114 controls in Washington postoperative HRT and 174 did not (113). Patients receiving
State revealed that patients using a regimen of estrogen com- HRT were followed for a median of 26 months. Regression anal-
bined with progestin (0.625 mg/day CEE, 2.5 mg/day MPA) had ysis revealed that there was no increased risk of recurrent disease
a significantly lower RR (RR, 1.4; 95% CI, 1.01.9) of endome- associated with HRT use, even when adjusting for age, tumor
trial cancer compared with patients who had taken unopposed grade, myometrial lymph node status, and peritoneal cytology.
estrogen (RR, 4.0; 95% CI, 3.25.1). However, patients receiv- A subsequent study by Lee et al. (114) compared the outcomes of
ing less than 10 days of cyclic progestin had an RR that was 44 low-risk endometrial cancer patients (stage IA/IB G1/G2 dis-
much higher (RR, 3.1; 95% CI, 1.75.7) than patients receiving ease) who received HRT following treatment, with 62 patients
10 to 21 days of cyclic progestin (RR, 1.3; 95% CI, 0.82.2). who received no HRT. There were no recurrences observed among
Patients using either regimen of cyclic combination HRT had the endometrial cancer patients receiving HRT for a median
an increased risk of endometrial cancer when these regimens duration of 64 months. Investigators from the University of
were taken for a duration exceeding 5 years (cyclic progestin California, Irvine, have also failed to demonstrate an increased
<10days per month: RR 3.7; 95% CI, 1.78.2; cyclic progestin risk of recurrent disease associated with postoperative HRT (115).
CHAPTER 16 HORMON ES AN D H U MAN MALIGNANCI ES 463
In the first study, investigators evaluated 123 women with surgi- attempt to avoid the increased risk of secondary malignancies,
cal stage I and II endometrial cancer. Sixty-one women received while maintaining the same or greater effectiveness. Results from
postoperative estrogen, and the mean duration of follow-up was the Multiple Outcomes of Raloxifene Evaluation (MORE) study
40 months. The disease-free interval was not significantly short- indicate that patients receiving raloxifene had a lower incidence
ened among the patients receiving E2 (116). The second study of breast cancer without any increase in endometrial cancer risk
was a retrospective cohort study that involved 75 patients with (118,121). However, the primary endpoint in this investiga-
stage IIII disease who received HRT (51% E2 only, 49% E2 tion was risk reduction of fracture in postmenopausal women
with added progestin) postoperatively. This group of patients with osteoporosis. In the National Surgical Adjuvant Breast
was then matched according to decade of age at diagnosis and and Bowel Project Study of Tamoxifen and Raloxifene (STAR)
stage of disease to a group of endometrial cancer patients in the P-2 trial, investigators found that raloxifene is as effective
study cohort not receiving HRT. Both groups were comparable as tamoxifen in reducing the risk of invasive breast cancer.
in terms of parity, tumor grade, depth of myometrial invasion, Although the overall risk of developing endometrial cancer was
histology, lymph node status, surgical treatment, concurrent similar in patients on raloxifene versus tamoxifen (RR, 0.62;
morbidities, and postoperative radiation. The patients receiv- 95% CI, 0.351.08), the incidence of hyperplasia was lower in
ing HRT were followed for a mean interval of 83 months, and the raloxifene group (RR, 0.16; 95% CI, 0.090.29) (122). Sev-
the patients not receiving HRT were followed for a comparable eral other SERMs are under investigation. The results of ongo-
interval of 69 months. Patients using HRT had a longer disease- ing clinical trials will confirm these preliminary findings and
free interval compared with nonusers of hormones. Among the establish the applicability of this contemporary generation of
colorectal cancer (HNPCC). Desmoid tumors are fibroaponeu- may decrease the risk of a given malignancy. Prospective clini-
rotic tumors that occur rarely in the general population but can cal trials are mandatory for evaluating potential strategies for
be found in 12% to 17% of patients with FAP (126). Tamoxifen preventing human malignancies.
has been shown to have growth inhibition in desmoid tumor
cell lines in an E2-independent mechanism (127). According to
the practice guidelines of the Standard Task Force of Colon and Breast Cancer Chemoprevention
Rectal Surgeons, high-dose tamoxifen (120 mg/day) and other
SERMs may be used in the treatment of aggressive desmoid SERMs
tumors. This recommendation is weak (level III) and based on Reducing the incidence of breast cancer has the potential to
limited descriptive European case series (128,129). The use of provide a major impact on the morbidity of the disease and its
tamoxifen in the prevention or treatment of primary colorectal treatment, cost to the individual and to society, and overall can-
cancer is not advocated. cer mortality. Epidemiologic studies indicate that E2-mediated
events play a role in the development of breast cancer. Tamoxifen,
Phytoestrogens a SERM, has been utilized as a chemopreventive agent for breast
Increased rates of breast, colon, ovarian, and endometrial cancer in four randomized, prospective, placebo-controlled clini-
cancer are found in Western societies. Phyto-E2s are possible cal trials. Raloxifene, a second-generation SERM, was investi-
dietary mediators of increased cancer risk that are subdivided gated in the MORE trial, in which the primary endpoint was risk
into two groups: isoflavonoids and lignans. Isoflavonoids are reduction of fracture in postmenopausal women with osteopo-
compounds with inherent estrogenic activity that can lead to rosis; the incidence of breast cancer was a secondary endpoint.
low IGF expression and inhibition of aromatase and growth fac- These 5 studies are reviewed and summarized below.
tors, resulting in a possible chemoprotective effect in the breast. National surgical adjuvant breast and bowel project breast
Lignans are compounds formed from plant lignan precursors by cancer prevention trial (P-1). In 1992, the National Cancer
intestinal microflora. Both isoflavonoids and lignans are found Institute, in collaboration with the NSABP, initiated the Breast
in foods such as whole grain rye bread, soybeans, and red clover. Cancer Prevention Trial (BCPT, P-1) (132). The primary goal
Studies suggest that the development period during which the was to determine whether tamoxifen administered for 5 years
isoflavonoid is ingested is important in modulation of future prevented breast cancer in women at high risk, including women
cancer risk. Ingestion of soy before or during adolescence may 60 years or older, women 35 to 59 with a 5-year predicted risk
decrease the risk of future breast cancer. However, there is no of breast cancer of at least 1.66%, or women who had a history
convincing evidence indicating that soy or other isoflavonoids of lobular carcinoma in situ (LCIS). Risk was estimated using
are protective against breast cancer or colon cancer if ingested the Gail model (133). Each of the 13,388 women enrolled was
during adulthood (118,130). There is a paucity of data regard- randomly assigned to receive tamoxifen 20 mg/day or placebo.
ing the association between isoflavonoids and other cancers The median follow-up time was 54.6 months, with 175 cases of
affecting women. A case-control study using a Hawaiian group invasive breast cancer in the placebo group compared with 89 in
revealed that the high consumption of soy products in adults the tamoxifen group (RR, 0.51; 95% CI, 0.390.66; p < 0.00001).
significantly decreased the risk of endometrial cancer, even Tamoxifen reduced the incidence of ER+ tumors by 69%,
after accounting for confounding influences (118,131). Large, but there was no difference in the incidence of ER- tumors.
population-based studies are needed to determine the effects of Major toxicities included endometrial cancer (RR = 2.53) and
isoflavonoids on specific cancer risk, particularly since they are thromboembolic disease (RR = 3.01). The P-1 data has been
becoming a more common component of the American diet. updated recently, and they have confirmed that the magnitudes
Lignans can be indirectly measured via urinary enterolactone. of desirable and undesirable effects of tamoxifen are similar to
Although women with breast cancer have significantly lower lev- what was observed in the original report (134).
els of urinary enterolactone, it is unknown whether higher levels
of enterolactone are protective against breast cancer or whether Italian tamoxifen prevention study. Recruitment for this double-
they are a marker for an unknown chemoprotective compound blind, placebo-controlled, randomized trial began in October 1992
associated with a healthier diet. High enterolactone production and ended in July 1997, and included healthy women aged 35 to
has been associated with inhibition of colon cancer in animal 70 years (135). The trialist and data-monitoring committee ended
models, but elevated levels have not been confirmed to be pro- recruitment because 26% of women dropped out of this study;
tective against colon cancer in humans (118,130). In contrast, 5,408 women were randomized to receive tamoxifen 20 mg/day
obesity as well as increased dietary fat intake is associated with or placebo for 5 years. Women were allowed to take HRT. The
decreased levels of urinary lignans, suggesting that the increased primary endpoints were reduction in the frequency and mortality
risk of cancer associated with obesity may be in part related to of breast cancer. At a median follow-up of 46 months, 19 cancers
lignan production. were diagnosed in the tamoxifen arm and 22 among women in the
placebo arm (p = 0.6). A 2007 update reported (after 11 years of
follow-up) that although there was no overall difference in breast
cancer between patients receiving placebo versus tamoxifen, high-
HORMON ES AN D TH E PREVENTION risk breast cancers were much less often found among women
receiving tamoxifen (RR, 0.24; 95% CI, 0.100.59) (136).
OF H U MAN CANCERS
Royal Marsden Hospital chemoprevention trial. This trial was
Chemoprevention can be defined as the use of specific natural initiated in 1986 as a preliminary pilot study for the International
or synthetic chemical agents to reverse, suppress, or prevent the Breast Cancer Intervention Study (IBIS-I) (137). The aim of this
progression toward malignancies. Human carcinogenesis pro- study was to assess whether tamoxifen would prevent breast
ceeds through multiple discernible stages of molecular and cellu- cancer in healthy women at increased risk for the disease based
lar alterations, thus providing the scientific rationale for clinical on family history only. Each participant had at least onefirst-
cancer chemoprevention. The necessary requirements for evalu- degree relative under the age of 50 with breast cancer, one
ation of chemoprevention include (a) identification of high-risk first-degree relative with bilateral breast cancer, or one affected
individuals based on family history and/or genetic mutations; first-degree relative of any age and another affected first-degree
(b) identification of putative surrogate endpoints or biomarkers or second-degree relative. The women were allowed to take HRT
for cancer; and (c) the possibility that relatively nontoxic agents during this study. The participants, 2,494 women between the
CHAPTER 16 HORMON ES AN D H U MAN MALIGNANCI ES 465
ages of 30 and 70, were randomized to tamoxifen 20 mg/day or cancer of 1.66% or higher as determined by the Gail model.
placebo. The median follow-up was 70 months, and 2,471 of the Eligible women included postmenopausal women 35 years
women were analyzed. The frequency of breast cancer was the or older with no prior history of invasive breast cancer or DCIS.
same for women receiving tamoxifen and placebo (tamoxifen = 34, Postmenopausal women aged 35 or older with a history of LCIS
placebo = 36; RR, 1.06; 95% CI, 0.71.7), and there appeared were also eligible. Preliminary results of the STAR trial revealed
to be no interaction between the use of HRT and the effect of that tamoxifen and raloxifene were as effective as tamoxifen
tamoxifen on breast cancer occurrence. An update of this trial in reducing the risk of invasive breast cancer (RR, 0.70; 95%
reported that contrary to the initial published findings based on CI) (122). Recent updates of the STAR trial have shown after
5-year follow-up, there was a clear reduction of invasive estrogen- 8 years of follow-up that raloxifene is less effective than tamoxi-
positive cancers at 10 years (6.2% vs. 5.2%), and the effect was fen in reducing invasive cancer, but it is less often associated
even larger at 15 years (9.6% vs. 7.5%) (138). with endometrial cancer or endometrial hyperplasia (144). In
addition, patients treated with raloxifene are diagnosed with
International breast cancer intervention study (IBIS). Random- endometrial polyps and have fewer hysterectomies while in
ization occurred to tamoxifen 20 mg/day or placebo for 7,152 treatment, compared with women who receive tamoxifen (145).
women, aged 35 to 70 years and at high risk for breast cancer (139).
Eligible women had risk factors for breast cancer indicating at
least a twofold relative risk among those aged 45 to 70 years, Aromatase Inhibitors
a fourfold relative risk among those aged 40 to 44 years, and Aromatase inhibitors (AIs) are being considered for use in breast
a tenfold relative risk among those aged 35 to 39 years. The
in women with BRCA mutations confirms an earlier report of a studies demonstrate that the reduced risk depends on the duration
47% reduction in this patient population (151). The age at risk- of OCP use. The risk is reduced by 20% with 1 year of use, 40%
reducing depends on the type of mutation and the family history with 2 years of use, and 60% with 4 or more years of use (159).
(152). The American College of Obstetricians and Gynecologists A preliminary analysis of the Centers for Disease Control and
has recommended that women who are either at average risk of Prevention (CDC) Cancer and Steroid Hormone (CASH) study
ovarian cancer or undergoing a hysterectomy for benign con- attempted to characterize the protective effect of specific OCP
ditions, and must make a decision about prophylactic oopho- formulations on EEC risk by comparing 187 endometrial cancer
rectomy, should be provided an overview of recent studies that cases with 1,320 controls (160). The CASH study determined
suggest a negative health impact (particularly on cardiovascular that continuous OCP formulations provided protective effects
disease risk) when performed before the age of menopause, par- (RR, 0.4; 95% CI, 0.20.9) while sequential OCPs did not
ticularly in the absence of estrogen replacement (153). (RR, 2.1; 95% CI, 0.85.8). Similarly, in the WHO Collabora-
tive Study of Neoplasia and Steroid Contraceptives, 132 cases
of EEC and 835 matched controls were evaluated to determine
Phytochemicals the protective effects of OCPs on endometrial cancer. Investiga-
Phytochemicals with potential anticancer properties span a wide tors found that the risk of EEC was decreased among women
range of chemical types and activities. Their presence, concen- who had a history of combination OCP use (OR, 0.53; 95% CI,
tration, and bioavailability in any of thousands of plant species 0.290.97) (161). In both the CASH and the initial WHO study,
used by humans are variably and incompletely documented. Sev- combination OCP formulations were not categorized according
eral studies have specifically examined the effects of vegetable to the potency of estrogen and progestin, thereby preventing an
and fruit intake on breast cancer risk. These studies suggest a assessment of the effects on EEC risk according to the potency
protective effect of vegetable intake, particularly those rich of the hormonal components.
in carotenoids. Beta-carotene intake has been associated with To better understand the protective effects of combination
lower breast cancer risk in several studies (154,155,156). High OCPs, 2 case-control studies have attempted to evaluate pro-
dietary fiber intake has also been associated with a lower risk of gestin and estrogen potency of OCP formulations in relation to
breast cancer (157). The multiplicity of phytochemical actions EEC risk. Following further enrollment of patients in the WHO
at different sites in the process of tumorigenesis complicates the Collaborative Study of Neoplasia and Steroid Contraceptives,
investigative effort needed for the development of chemopreven- investigators reported an analysis of 220 cases of EEC and 1,537
tive agents from this class of compounds. controls (162). In this study, a lower risk of EEC was observed
with high progestin potency OCP formulations compared with
low progestin potency. Although the number of patients using
high-potency progestin was very small in this study, the results
Endometrial Cancer Chemoprevention suggested that high progestin potency OCP formulations could
Chemoprevention strategies for endometrioid endometrial cancer be more protective against EEC. A second case-control study
(EEC) have been based on the observation that exposure to E2 evaluated 316 cases and 501 controls from women in the King
with insufficient progestational stimulation predisposes women or Pierce counties of Washington. The relative risk for women
to EEC and its precursor lesion, atypical endometrial hyperplasia. who had used a high progestin potency OCP (RR 0.3; 95%
While marked obesity, use of exogenous E2, early menarche, and CI, 0.10.9) was as low as the relative risk for women using a
diabetes have been identified as risk factors for the development low-potency progestin (RR, 0.2; 95% CI, 0.10.8) (118). These
of EEC, only early menarche has been associated with serous car- results did not find a potency-dependent protective effect, and
cinoma, as well as its precursor lesion, endometrial intraepithelial suggested that the progestin potency was adequate to achieve
carcinoma (EIC) (158). This observation, as well as other inves- a protective effect against endometrial cancer in most combi-
tigational work, supports the existence of a dualistic model for nation OCP formulations. The methods of classifying proges-
endometrial carcinogenesis, where atypical endometrial hyper- tin potency were the same in both the WHO study and the
plasia and EEC are E2-related, and EIC and serous carcinoma are Washington State study, thereby eliminating differences in clas-
E2-unrelated. Further delineation of E2-independent pathways of sification as a reason for the different findings from these two
endometrial carcinogenesis will be necessary to develop chemo- studies. Details regarding the specific OCPs taken by case and
prevention strategies for serous carcinoma, which accounts for a control subjects were not reported in the Washington State
minority of endometrial carcinomas but a disproportionate num- study. The OCP formulations used in the second WHO study
ber of endometrial cancer deaths. Chemoprevention strategies for contained progestins that are no longer used in OCPs marketed
EEC, because of its clear association with E2, have been more in the United States. A third case-control study using data from
easily identified, and are described below. the CASH study included 434 endometrial cancer cases and
2,557 control subjects. Overall, high-potency OCPs did not con-
Continuous Combined H RT fer more protection than low-potency OCPs. However, among
women with a BMI >22.1 kg/m2, those who used high progestin
Premature termination of one comparison (continuous com- potency OCPs had a lower risk of endometrial cancer than those
bined HRT: daily conjugated equine E2 0.625 mg and medroxy- who used low potency OCPs (OR, 0.31; 95% CI, 0.110.92);
progesterone acetate 2.5 mg) in the WHI primary prevention those with a BMI <22.1 kg/m2 did not (OR, 1.36; 95% CI, 0.39
trial occurred because cardiovascular disease and breast cancer 4.70) (163). The small number of cases that were overweight
were increased, recognizing that colorectal cancer, endometrial (BMI >25 kg/m2) or obese (BMI >30 kg/m2) prevented an analysis
cancer, and osteoporotic fractures were reduced (85). The reduc- with sufficient power to detect a statistically significant modifying
tion seen in the incidence of EEC with continuous HRT is in effect of overweight status or obesity on the relationship between
agreement with case-control studies that have documented a progestin potency and endometrial cancer risk. However, these
reduction in the incidence of this malignancy in women taking findings suggest that high-potency OCPs may be associated
continuous combined HRT (108,109,110). with a greater protective effect than low-potency OCPs among
women with a higher BMI who are at the greatest risk of endo-
metrial cancer. Obese women often develop Type I endometrioid
Oral Contraceptives endometrial cancer. Population-based data have suggested that
There is substantial evidence that ever-use of OCPs reduces the endometrial cancerrelated mortality may be increased among
risk of EEC by approximately 50%. Numerous epidemiologic obese women, compared with nonobese women, suggesting
CHAPTER 16 HORMON ES AN D H U MAN MALIGNANCI ES 467
that prevention in this group of high-risk patients may not (182). As is the case with breast cancer, further investigative
only affect morbidity but also mortality. Although the biologic efforts are necessary to establish the role of phytochemicals in
mechanism(s) that underlie the protective effect of progestins the prevention of endometrial cancer.
have not been well characterized, a growing body of evidence
has implicated apoptotic and transforming growth factor-beta
(TGF-) signaling events as important mediators of the chemo-
preventive effect of progestins in the endometrium. Progestins Ovarian Cancer Chemoprevention
have been shown to induce apoptosis in endometrial glands and Although efforts to improve the survival of ovarian cancer patients
stroma, an effect that is modulated by a number of well-known continue to focus on the development of more effective systemic
apoptosis-related proteins (164166). therapies, the prevention of ovarian cancer is an area of increasing
interest. As is the case with breast cancer, assessment of prevention
efforts must be analyzed by genetic predisposition. In genetically
Intrauterine Devices uncharacterized U.S. women, the lifetime risk of developing ovar-
Seven studies have reported the relationship between previ- ian cancer is approximately 1.5%. BRCA1 mutations increase the
ous copper or nonmedicated intrauterine device (IUD) use and risk to 30% to 60%, while women who harbor a mutant BRCA2
endometrial cancer (167173). In all but one study, previous IUD gene have an estimated risk of 10% to 30% (183). Precancerous
use was associated with a decreased risk of EEC. The one study lesions have not been well-defined for ovarian cancer, although
where this relationship was not validated was based on research phenotypic changes have recently been described (184). Future
an odds ratio of 0.44 (95% CI, 0.280.68) (201,202). Impor- was conducted in northern Italy between the years 1985 and
tant differences exist between the two studies, most notably that 1992, with 709 cases of colorectal cancer and 992 control sub-
the controls in the Narod et al. study were all mutation carriers, jects (209). Ever-use of OCPs versus never-use through use of a
while in the Modan et al. study only 1.7% of the controls car- multiple logistic regression was associated with a reduced risk
ried the mutation. The use of OCP as a chemopreventive agent of colorectal cancer (RR, 0.58; 95% CI, 0.360.92). Further,
against ovarian cancer should be considered in BRCA carriers. there was a suggestion that duration of use (i.e., more than 2
Little is known about the mechanism of the protective effect years) was associated with increased protection. More recently,
of OCPs against ovarian cancer, although it has been postulated the Nurses Health Study cohort identified 502 cases of colorec-
that a major mechanism of OCP protection relates to a decrease in tal cancer among participants between 1980 and 1992 (210).
ovulatory cycles. There are data to suggest that an increased rate Among women using OCPs, use for 6 or more years was asso-
of apoptosis in aberrant epithelial cells, secondary to the proges- ciated with a 40% reduction in risk of colorectal cancer (RR,
tational component, may also play an important role. Rodriguez 0.60; 95% CI, 0.400.89). The trend for the duration effect was
et al. examined the effect on ovarian epithelium of levonorges- statistically significant (p = 0.02). Several smaller studies, all
terol in 130 ovulatory macaque monkeys (203). These authors with serious limitations in study design and/or execution, have
demonstrated significantly increased apoptotic cell counts in the reported varying results regarding the relationship between
ovarian epithelium of animals exposed to progesterone, leading OCPs and colorectal cancer.
to the hypothesis that progestin-induced apoptosis of the ovarian
epithelium is responsible for the chemopreventive effect of OCPs.
despite numerous clinical trials over the past 60 years that have Median survival of patients with metastatic breast cancer is
attempted to address this issue. Various strategies of ovarian between 2 and 3 years. In premenopausal women, regression
suppression/ablation, tamoxifen, and/or chemotherapy alone or of advanced breast cancer as a result of prophylactic oopho-
in combination have been evaluated. The EBCTCG overview rectomy was first described in 1896 (230). In multiple series of
analysis has confirmed that adjuvant tamoxifen confers a sur- premenopausal women with metastatic breast cancer, where
vival benefit for ERpositive patients, regardless of menopausal hormone receptor status was unknown, oophorectomy resulted
status. Accumulated clinical trial data as well as the EBCTCG in cancer regression in 30% to 40% of cases. In premenopausal
overview analysis have confirmed that ablation of functioning women with known ERpositive tumors, a 50% to 60% regres-
ovaries significantly improves survival in breast cancer patients sion after oophorectomy has been noted.
younger than 50 years of age, at least in the absence of chemo- Endocrine therapy for postmenopausal women with
therapy (223). In the last several years, several investigations advanced, hormonally responsive ER+ breast cancer is based on
have supported the utilization of tamoxifen and ovarian sup- the observation that greater than three-fourths of these patients
pression/ablation as adjuvant therapy in premenopausal women respond to HT. In contrast, only 11% of patients with hormone
with early-stage, receptorpositive breast cancer (224228). receptornegative tumors show a response. Tamoxifen was
Two basic strategies exist to abrogate ovarian function. the gold standard of first-line HT for metastatic breast cancer
Ovarian suppression (OS) refers to the use of temporary means for more than 40 years. However, third-generation AIs have
to suppress ovarian function, generally with luteinizing hor- eclipsed tamoxifen in the treatment of postmenopausal women
mone releasing hormone (LHRH) analogs. Ovarian ablation with metastatic estrogen-dependent breast cancer (231). Sev-
(OA) refers to permanent strategies using either oophorectomy eral large, multinational randomized trials have been under-
or ovarian radiation. Despite the clear benefits seen with OA/OS taken to assess the efficacy and toxicity of AIs in breast cancer
as compared with no adjuvant therapy, the additional benefits in the advanced setting. Results from these trials have demon-
of OA/OS in women who have also received chemotherapy is strated the superiority of third-generation AIs over tamoxifen in
less clear. With the known advantages of both chemotherapy advanced disease (232235).
and OA/OS alone as monotherapies, additional studies were Importantly, AIs were demonstrated to exhibit a much less
designed to evaluate the benefit of adding OA/OS to standard adverse toxicity profile compared with tamoxifen, particularly
chemotherapeutic regimens, as well as the reverse scenario of concerning development of deep vein thrombosis and pul-
assessing the benefit of chemotherapy when added to OS/OA. monary emboli (236). Such evidence has led to the approval
In aggregate, these studies do not show a clear overall survival of third-generation AIs as first-line therapeutics for advanced
benefit with the addition of OS/OA to chemotherapy, although a breast cancer.
small benefit appears to emerge, particularly in younger women Fulvestrant, an anti-estrogen receptor (anti-ER) drug, is a
with hormone-responsive disease. Selective ER Down Regulator (SERD) that destroys ERs and
There is a persistent need to define optimal endocrine ther- decreases the number of PRs in breast cancer cells. Fulvestrant
apy in premenopausal women with hormone receptorpositive is now approved for tamoxifen-resistant tumors. Furthermore,
breast cancer. Several ongoing trials are expected to definitively it has been established that fulvestrant and exemestane are
address the various roles of combining chemotherapy, OS/OA, equally active and well-tolerated in a meaningful proportion of
tamoxifen, and AIs in premenopausal patients with early-stage postmenopausal women with advanced breast cancer who have
hormone receptorpositive breast cancer. Contemporaneous tri- experienced progression or recurrence during treatment with a
als, such as the Suppression of Ovarian Function Trial (SOFT), nonsteroidal AI (237).
Tamoxifen and Exemestane Trial (TEXT), Premenopausal
Endocrine Responsive Chemotherapy (PERCHE), and Austrian
Breast and Colorectal Cancer Study Group (ABCSG), hope- Endometrium
fully will provide direction. Additionally, biomarker and phar-
macogenomic data will help further supplement individualized Hormonal Treatment of Endometrioid
patient decision-making. Endometrial Cancer
Consideration of maintaining fertility is an issue for a sub-
set of premenopausal women with early-stage breast cancer. The median survival of women with advanced or recurrent EEC
The prevention of premature ovarian failure after cytotoxic is less than 1 year. When the best chemotherapeutic regimen avail-
chemotherapy utilizing GnRH analogs for temporary ovarian able is used, the complete response rate in those patients with
suppression has been investigated by several studies. Several advanced-stage EEC is only 22%. Histologic grade is known to
Phase II studies have reported a high rate of preserved men- be a predictor of stage and survival, with grade 3, poorly differ-
struation in treated patients. Other studies have suggested no entiated cancers portending a higher risk of extrauterine disease
benefit, with tamoxifen use in either case not being routinely and thus poorer survival. Furthermore, Carcangiu et al. evalu-
considered. Recently, in a prospective study, Munster et al. ran- ated 183 patients with EEC, establishing a correlation between
domized premenopausal women to receive either triptorelin or the International Federation of Gynecology and Obstetrics
no triptorelin during adjuvant chemotherapy. The women were (FIGO) grade and hormone receptor expression (238). The rec-
further stratified by age (<35, 35 to 39, and >39 years); estrogen ognized association of higher grade with lower ER/PR expres-
receptor status; and chemotherapy regimen. Objectives included sion carries implications for the use of HT in advanced EEC.
the resumption of menses and serial monitoring of FSH and A majority of advanced cases of EEC are grade 3 lesions, limiting
inhibin A and B levels. The authors concluded that when women the use of HT in this patient population.
were stratified for age, estrogen receptor status, and treatment
regimen, amenorrhea rates on triptorelin were comparable with Advanced or Recurrent Endometrioid
those seen in the control group (229).
Endometrial Cancer
Hormonal Therapy for Metastatic Progestational agents. The use of progestational agents
in women with advanced or recurrent EEC has been under
Breast Cancer investigation for several decades. Several different types of pro-
Metastatic breast cancer (MBC) remains a major therapeutic gestational agents have been investigated, including hydroxy-
challenge, whether it is the first presentation of breast cancer progesterone caproate (Delalutin), medroxyprogesterone acetate
or a recurrence after prior treatment of early-stage disease. (MPA, Provera), and megestrol acetate (Megace). A majority of
CHAPTER 16 HORMON ES AN D H U MAN MALIGNANCI ES 471
studies evaluating this treatment modality have included small a third-generation SERM, is a potent E2 antagonist in mammary
numbers of patients with no stratification for well-recognized and uterine tissues, with enhanced bioavailability and antiestro-
predictors of response. In the last decade, several studies with genic activity compared with raloxifene. This SERM elicited a
larger patient sample size, clearer eligibility criteria, and clearer complete response in 1 and a partial response in 8 of 29 patients
definition of response and toxicity have evaluated the effective- with advanced EEC, with an overall response rate of 31%. The
ness of progestational agents in the treatment of advanced or median duration of response was 13.9 months, with minimal
recurrent EEC. Thigpen et al. evaluated women with advanced toxicity. All responses occurred in progestin-sensitive patients.
or recurrent EEC who were randomized to receive either oral The relatively high response rate and the favorable toxicity pro-
MPA 200 mg/day or oral MPA 1,000 mg/day until unacceptable file make this agent worthy of further investigation (247,248).
toxicity or disease progression (239).
The overall response rates (complete plus partial) favored the Aromatase inhibitors. Anastrozole and letrozole are active,
low-dose regimen (25% and 16% for low- and high-dose regi- highly selective, nonsteroidal, competitive inhibitors of the
mens, respectively). The median progression-free survival (PFS) enzyme aromatase. It has been shown that significant amounts
time was 3.2 months for the low-dose regimen and 2.5 months of aromatase are found in endometrial cancer, with low amounts
for the high-dose regimen. There was an association, including being present in the surrounding normal endometrial tissue.
patients receiving both dosing regimens of MPA, between Rose et al. recently found that in 23 patients anastrozole at 1 mg
response and histologic grade, with well-differentiated tumors a day for 28 days has minimal activity, with only a 9% partial
responding more frequently than poorly differentiated lesions. response rate and a progression-free interval of 1 to 6 months in
Abbreviations: RR, response rate; PFS, progression-free survival; OS, overall survival; MPA, medroxyprogesterone acetate; NR, not reported; MA, megestrol acetate.
orally for 2 years, or were observed only (n = 134) after surgical complete response (CR) and partial response (PR). CR is defined
therapy. After 56 months of follow-up, no benefit was observed as no abnormality or as hyperplasia without atypia in CAH or
from adjuvant progestin or tamoxifen therapy after surgical EEC patients. PR is defined as CAH in EEC patients. Twenty-six
treatment in early-stage EEC. However, given the low frequency evaluable patients have been enrolled thus far: 18 had CAH, and
of recurrence in this patient population, larger randomized stud- 8 had EEC. The overall 12-month response rate was 58%. At
ies are needed to fully evaluate the role of progestational agents 12 months, 11 patients had CR (1 with EEC, 10 with CAH); 1
as adjuvant therapy in early EEC. patient had PR (EEC); 2 patients had stable disease (CAH); and
5 patients had progressive disease (4 with EEC, 1 with CAH).
Seven of the 26 patients did not reach the 12-month mark in the
Progestational Agents as Primary Therapy for study. After stratification for histology, response rate was 85%
Endometrioid Endometrial Cancer for CAH (13 evaluable) and 33% for EEC (6 evaluable). The
Several small series have retrospectively reported on the use of LIUS has encouraging activity in CAH and EEC. Response may
progestational agents alone, not preceded by hysterectomy, in the be predicted by presence of exogenous progesterone effect (260).
treatment of patients with EEC, either because of the desire to
maintain fertility or because of comorbid conditions. No random-
ized, controlled studies evaluating progestational agents in either Ovary
clinical scenario are available. Montz et al., in a prospective pilot Hormones and their receptors have been associated with ovar-
study, reported on the use of the progesterone IUD in women ian cancer and may be related to its causation. Some data suggest
with presumed stage IA, grade 1 EEC, who were at significant that hormonal therapies may have an effect on ovarian cancer in
risk for perioperative morbidity (258). Follow-up endometrial palliative settings (261). Several investigators have established
biopsies were negative in 7 of 11 patients at 6 months, and in 6 of that hormone receptors are expressed in epithelial ovarian
8 patients at 12 months. Recently, Ramirez et al. searched MED- cancer, and that significant alterations occur with malignant
LINE and other databases for English language articles describ- transformation. Rao and Slotman reviewed 45 series, including
ing patients with grade 1 EEC treated with hormonal therapy. 2,508 ovarian cancer patients, and reported that 67% of tumors
Ultimately, 81 patients in 27 articles were included in the study. expressed ER and 47% expressed PR (262). The expression of
Sixty-two patients (76%) responded to treatment. The median the ERs and PRs has been found to correlate with long-term
time to response was 12 weeks (range, 460 weeks). Fifteen survival in invasive ovarian cancer. The ERPR+ phenotype pre-
patients (24%) who initially responded to treatment recurred. The dicted a more favorable tumor biology and long-term survival
median time to recurrence was 19 months (range, 644 months). (263). A large number of hormonal agents have been evaluated
Ten (67%) of the patients with recurrence ultimately underwent in the treatment of ovarian cancer, including SERMs, E2, pro-
total abdominal hysterectomy. Residual endometrial carcinoma gestins, androgens, AIs, and GnRH agonists. Progestin therapy
was found in 6 of the 10 patients (60%). Twenty patients were in patients with advanced ovarian cancer has a global response
able to become pregnant at least once after completing treatment. rate of 8% to 15% (264). Tamoxifen, in preclinical studies,
No patients died of their disease. Further investigation is needed inhibits ovarian cell growth in vitro, providing rationale for the
into this approach to the primary management of EEC (259). use of this agent in the treatment of ovarian cancer. Several stud-
More recently, Westin et al. from M. D. Anderson Cancer Center ies have evaluated the activity of single-agent tamoxifen in the
prospectively evaluated, in a single-arm phase 2 study, the levo- treatment of advanced ovarian cancer (Table 16.4) (265282).
norgestrel intrauterine system (LIUS) in the treatment of com- Perez-Garcia and Carrasco reviewed the literature evaluat-
plex adenomatous hyperplasia (CAH) and EEC grade 1. After ing single-agent tamoxifen in the treatment of patients with
confirmation of no extrauterine disease, dilation and curettage advanced ovarian cancer, most of whom were heavily pretreated
was performed and the LIUS was placed. Endometrial biopsies and refractory to chemotherapy (283). A total of 648 patients
were performed every 3 months. The primary efficacy end-point were included with an overall response rate (ORR) of 13% (95%
was pathological response rate (RR) at 12 months, defined as CI, 10.415.6; range, 56), including a 4% complete response
CHAPTER 16 HORMON ES AN D H U MAN MALIGNANCI ES 473
Note: CR, complete response; CT, chemotherapy; NS, not stated; OR, overall response; PR, partial response; SD, stable disease.
a
Only evaluable patients are included (but prior CT lines refer to the whole population).
b
With a loading dose of 100 mg/24 h during 1 d (Osborne et al. [272]), 40 mg/24 h during 7 d (Weiner et al. [282]), and 40 mg/24 h during 30 d (Ahlgren et al. [265]).
c
Calculated over the number of patients included in trials that report these data.
rate and a 9% partial response rate. In 38% of patients, stable or peritoneum. Further study is warranted to determine whether
disease was noted. These results are not entirely dissimilar from ER/PR expression status is a predictive biomarker for this rare
those seen with progestins. cancer subtype (284).
Gershenson et al. recently studied the role of tamoxifen in The role of GnRH agonists in the management of refractory
women with low-grade serous ovarian tumors. They identified ovarian cancer has been evaluated in multiple studies and has been
64 patients with recurrent low-grade serous carcinoma of the summarized by Paskeviciute et al. (285). GnRH agonists induced
ovary or peritoneum. Patients median time to progression (TTP) an overall objective response in 8.5% of refractory ovarian cancer
and median overall survival (OS) were 7.4 and 78.2 months, patients, with disease stabilization in 23% of these women.
respectively. Patients received 89 separate hormonal patient Several investigators have compared chemotherapy and hor-
regimens, which produced an overall response rate of 9% (6 monal therapy with chemotherapy alone, primarily in patients
complete responses and 2 partial responses). Sixty-one percent with advanced ovarian cancer. However, these studies had small
of the patient-regimens resulted in a PFS of at least 6 months. patient sample size and were not randomized, controlled studies.
Patient regimens involving ER+/PR+ disease produced a longer Emons et al. randomized 135 patients with advanced ovar-
median TTP (8.9 months) than patient regimens involving ER+/ ian cancer to receive the GnRH triptorelin or placebo, following
PR disease (6.2 months; p < 0.053). This difference approached, surgery and chemotherapy, until the patients death or termi-
but did not reach statistical significance. The authors concluded nation of the trial. There were no significant differences in OS
that hormonal therapies have moderate antitumor activity in or PFS between the groups, with documented gonadotropin
patients with recurrent low-grade serous carcinoma of the ovary suppression (286).
474 CHAPTER 16 HORMON ES AN D H U MAN MALIGNANCI ES
At least four randomized studies comparing chemotherapy 13 weeks (range, 1036). Of 33 patients evaluable for radiologi-
and MPA or a GnRH versus chemotherapy alone in ovarian cal response, 3 (9%) had a partial remission, and 14 (42%) had
cancer patients have been reported. These studies contain many stable disease at 12 weeks. Eleven patients (26%) had a PFS of
of the same flaws as noted throughout this discussion, namely, > 6 months. This is the first study of a hormonal agent in a pre-
small sample size and no stratification for optimal versus subop- selected group of ERpositive ovarian cancer patients. Further
timal surgical status, menopausal status, and histologic status. studies must be undertaken.
Argenta et al. evaluated fulvestrant in women with recurrent As previously stated, in patients with ovarian cancer, receptor
ovarian or primary peritoneal cancer. Thirty-one women were status does not reproducibly correlate with prognostic factors,
enrolled, and 26 women (median age, 61 years) met inclusion including survival or disease-free interval. However, receptor
criteria and received at least one dose. Patients had received a status may be useful in predicting response to hormonal agents.
median of five prior chemotherapeutic regimens (range, 213). Although several investigators have approached this question,
One CR (4%), one PR (4%), and 9 patients with SD (35%) were results are inconclusive. The ascertainment of receptor status as
observed, using response evaluation criteria in solid tumors a predictor of hormonal activity in ovarian cancer will require a
(RECIST) (CA-125 level). Using modifed-RECIST criteria, randomized clinical trial comparing hormonal activity in patients
13 patients (50%) achieved SD. The median time to disease pro- expressing hormone receptors versus those with no receptor
gression was 62 days (mean, 86 days). Grade I toxicity included expression, controlling for the many variables recognized as
headache (1 patient) and bromhidrosis (2 patients). Fulvestrant important prognosticators in ovarian cancer.
was well-tolerated and efficacious. Objective response rates
were low, but disease stabilization was common (287).
Smyth et al. in a phase II study of letrozole evaluated the
efficacy of this aromatase inhibitor in preselected ER positive Colon
relapsed epithelial ovarian cancer patients (288). The primary The clinical data available evaluating the relationship between
end-point was response according to CA-125 and RECIST. hormones and colon cancer relate primarily to hormones as risk
Marker expression was measured by semiquantitative immu- factors for the development of this common human malignancy.
nohistochemistry in sections from the primary tumor. Of There is a plethora of data in colon cancer cell lines regard-
42 patients evaluable for CA-125 response, 7 (17%) had a ing the effect of hormonal agents on cell growth, as well as cell
response (decrease of >50%), and 11 (26%) patients had not death. To date, there are no clinical studies evaluating the treat-
progressed (doubling of CA-125) following 6 months of treat- ment of colon cancer, either in the adjuvant setting or otherwise,
ment. The median time taken to achieve the CA-125 nadir was with hormonal agents.
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17
CHAPTER
Clinical Trials Methodology
and Biostatistics
VIRGINIA L. FILIACI
Issues involved in the design, conduct, and analyses of clinical a sufficient number of cases. Despite these insights, medicine all
trials are presented in this chapter. Phase 1, 2, and 3 trials are too frequently continued to consist of a mixture of herbal con-
presented, as well as screening trials. Statistical jargon and coctions, purging, bloodletting, and astrology.
481
482 CHAPTER 17 CLI N ICAL TRIALS M ETHODOLOGY AN D BIOSTATISTICS
It had long been appreciated that there is a potential for mis- trials specifically for gynecologic malignancies was the Surgi-
guided inference about the effectiveness of a treatment when cal Ovarian Adjuvant Group. This group was formed in the
the comparison involves a group with a dissimilar prognosis. late 1950s, initiated a few trials, and then disbanded in 1964.
The apparent benefits attributed to a new treatment might in Starting in 1963, the Surgical Endometrial Adjuvant Group was
fact be biases due to prognostic differences in patients between one of the earliest efforts toward a multidisciplinary group. This
treatment groups. One of the earliest clinical trials to attempt multidisciplinary cooperative group included gynecologic sur-
to address this bias was reported in 1898 by Johannes Fibiger geons, medical oncologists, pathologists, radiation oncologists,
(6). Four hundred and eighty-four patients admitted to his clinic and biostatisticians. It was from this group that the Gynecologic
with diphtheria were given either standard care or diphtheria Oncology Group (GOG) was eventually formed in 1970 to deal
serum twice daily. In order to disassociate the mode of treatment with a broader range of gynecologic malignancies (18). Over the
from the individuals prognosis, the patients treatment was to following 10 years, the field of gynecologic oncology matured.
be determined by the day of clinic admission, and it alternated Board certification procedures for gynecologic oncologists were
from day to day (7). Using this type of procedure to disassoci- developed, fellowship programs were initiated in the comprehen-
ate prognosis from treatment is only partially effective, since sive cancer centers, and a professional Society of Gynecologic
the practitioner or the subject knew which treatment would be Oncologists was organized in 1969.
applied, and this knowledge may have influenced the individuals
decision to participate in the study. Therefore, masking the
treatment assignment so that it cannot be part of the decision
to participate in the trial is important for controlling this source Classification of Study Designs
of selection bias. In general, a clinical trial is any experiment involving human sub-
Treatment randomization in agricultural trials was performed jects that evaluates an intervention that attempts to reduce the
as early as 1926 (8). However, it was not until the 1940s when impact of a specific disease in a particular population. When an
Corwin Hinshaw (9), using a coin toss, and later Bradford Hill intervention is applied in order to prevent the onset of a particular
(10), using random numbers in sealed envelopes, established the disease, the trial is classified as a primary prevention trial. For
methodologic importance of randomizing treatments in clinical example, a primary prevention trial may evaluate healthy life-
trials. Balancing the unpredictable and spontaneous remissions styles or a vitamin supplement in a population of individuals who
exhibited by some patients with pulmonary tuberculosis moti- are considered to be at risk for a particular disease. Secondary pre-
vated Amberson (8) and later Hinshaw (9). While methodologic vention trials evaluate interventions that are applied to individuals
principles motivated Hill, the short supply of streptomycin after with early stages of a disease in order to reduce their risk of pro-
World War II provided the opportunity to use randomization as gressing to more advanced stages of the disease. Tertiary interven-
an equitable way to distribute the drug (11). tion trials are aimed at evaluating interventions that reduce the
One of the first randomized clinical trials in the study of gyne- risk of morbidity or mortality due to a particular disease.
cologic malignancies was initiated in 1948 (12). This trial com- Clinical trials that evaluate methods for detecting a disease in
pared ovarian irradiation to standard treatment for breast cancer. a preclinical state are called screening trials. Early detection may
Initially, shuffled sealed envelopes were used to designate treat- mean diagnosing a malignancy in an early stage (e.g., the use of
ment. However, this procedure was later changed due to admin- mammography in the detection of breast cancer) or in a prema-
istrative difficulties so that treatment depended on the womans lignant state (e.g., the use of Papanicolaou smear in the detection
date of birth. This later procedure is susceptible to the same selec- of cervical intraepithelial neoplasia). There are typically 2 inter-
tion bias mentioned in Fibigers trials, since the treatments were ventions in a screening trial. The first intervention is the screening
not masked. program (e.g., annual mammograms), which involves individuals
Despite these methodological advances, the inadequate jus- who appear to be free of the disease. However, once the disease is
tification for selecting one medical procedure over another led detected in an individual, a secondary intervention (e.g., surgery)
one contemporary physician to express his frustration: is performed in hopes of stopping the disease from progressing
to more advanced stages. Consequently, screening trials require
Early in my medical career I was appalled at the willy-
both interventions to be effective. An effective screening proce-
nilly fashion by which treatment regimens slipped in
dure is useless if the secondary intervention does not alter the
and out of popularity. How many operations that I was
course of the disease. On the other hand, an ineffective screening
trained to do or medicines that I was instructed to give
procedure would cause the secondary intervention to be applied
because of somebodys conviction they were beneficial
indiscriminately.
passed into oblivion for no apparent reason, only to be
Nonexperimental studies (or observational studies) can be
replaced by others of equally dubious worth? (13)
classified into 3 broad design categories: cohort (or prospec-
The first randomized clinical trial at the National Cancer tive), case-control (or retrospective), and cross-sectional. In a
Institute (NCI) was begun in 1955 (14). This trial involved 65 cohort study, individuals are initially identified according to
evaluable patients with acute leukemia from 4 different insti- their exposure status, which can include environmental, genetic,
tutions. The trial incorporated many elements that should be lifestyle, or therapeutic treatment factors. These individuals
part of any modern clinical trial: uniform criteria for response are then followed in order to determine who develops the dis-
assessment, a randomized comparison of at least 2 treatment ease. The aim of these studies is to assess whether the exposure
regimens, and a complete accounting of all patients entered. is associated with the incidence of the disease under study. This
The published report included considerations for such issues design is in contrast to the case-control study, which identifies
as patient selection bias and the studys impact on the patients individuals on the basis of whether they have the disease and
welfare (15). The first NCI randomized clinical trial in solid then measures and compares their exposure histories. Measur-
tumors followed shortly thereafter and was organized by the ing exposure may be as simple as questioning the individuals
Eastern Group for Solid Tumor Chemotherapy (16). By 2010, about their personal or employment history, or it may involve a
there were 12 NCI-sponsored cooperative groups conducting more sophisticated assessment such as analyzing the individuals
clinical trials and the annual funding for these groups was $163 biologic specimens for markers of exposure. Though the case-
million dollars (17). control study is susceptible to several methodological flaws,
In the late 1950s, most patients with gynecologic cancers it has the advantage of often being less expensive, easier, and
were included incidentally in small trials to screen new agents for quicker to perform than a cohort study, especially when the dis-
broad-range activity. The first NCI-sponsored group to organize ease is rare. The power of the case-control design is apparent
CHAPTER 17 CLI N ICAL TRIALS M ETHODOLOGY AN D BIOSTATISTICS 483
from a review of the case-control studies published between susceptible to subjective interpretation. In some cases clinical
1975 and 1985(19), which demonstrated the deleterious effects response can be considered unreliable, since it is not uncommon
of exogenous estrogens in perimenopausal women. Finally, the for experts to disagree when interpreting the same radiograms
goal of the cross-sectional study is to describe the prevalence (21). Third, endpoints that are directly relevant to the patient
of a disease and an exposure in a population during a specific are preferable, although valid surrogate endpoints are consid-
period of time. These studies can often be conducted more ered indirectly relevant to the patient. Finally, endpoints which
quickly than either the cohort or case-control study, but they are not too expensive or inconvenient for the patient are pre-
are often not used when the time between exposures and the ferred. It is not always possible for a single endpoint to exhibit
disease onset is long, as it is for cancer. all of these characteristics simultaneously. For example, avoid-
ing death is extremely relevant to a patient with a lethal dis-
ease like advanced gynecologic cancer. Also, survival can be
measured very reliably. However, most cancer patients will not
Components of a Clinical Trial only receive the treatments prescribed by the study, but, after
Objectives exhibiting signs of disease progression, they also receive other
anticancer therapies. In this case, the validity of overall survival
In clinical oncology research, where the disease is often fatal, comparisons is suspected since they not only reflect the effects of
the ultimate purpose of a research program is to develop a treat- the study treatment, but also the effects of other therapies that
ment plan that puts the patients into a disease-free state, reduces are external to the study. For example, a meta-analysis of those
suppose an investigator initiates a randomized clinical trial com- endpoint for trials involving women with advanced ovarian can-
paring two treatments with time to disease progression being cer. It is important to recognize that while the general validity
the primary endpoint. The protocol indicates that the patient of PFS for predicting overall survival in this patient population
should be assessed after each cycle of therapy. However, suppose has been established, PFS comparisons in a particular study can
that a cycle duration is 2 weeks for one treatment group, and be biased. One source of bias arises from using different disease
4 weeks for the other treatment group. Using a more intense assessment schedules for each treatment group either intention-
assessment schedule for 1 treatment group would tend to detect ally or unintentionally. Delaying assessments for 1 treatment
failures earlier in that group. Therefore, the time-to-failure com- group artificially increases the apparent time to progression.
parison between treatments would systematically favor the sec- Survival time is generally not susceptible to this source of bias.
ond treatment group. Progression-free interval (PFI) may be a reasonable endpoint
When there are recognized sources of error, it is important in trials involving patients with early or locally advanced cancer.
that the study design implement procedures to avoid or mini- PFI should be distinguished from PFS. The difference resides in
mize their effect. For example, random error in many cases can how patients, who die without any evidence of disease progres-
be accommodated by either increasing the number of individu- sion are handled in the analysis. Patients who die without evi-
als in the study, or in some cases by increasing the number of dence of progression are censored at the time of their death in a
assessments performed on each individual. Systematic measure- PFI analysis, but considered an uncensored event in a PFS analy-
ment error cannot be addressed by increasing the sample size. sis. If deaths due to non-cancer-related causes are common, then
In fact, increasing the sample size may exacerbate the problem selecting PFI as the study endpoint will generally increase the
since small systematic errors in large comparative trials contrib- studys sensitivity for detecting active treatments. In this case,
ute to the chances of erroneously concluding that the treatment however, the analysis needs to consider procedures that will
effect is significant. The approaches to controlling sources of account for treatment-related deaths, which may occur prior to
systematic error tend to be procedural. For example, treatment disease recurrence. Simply censoring the time to recurrence in
randomization is used to control selection bias, placebos are used these cases can make very toxic treatments appear more effec-
to control observer bias, standardized assessment procedures tive than they actually are.
and schedules are used to control measurement bias, and strati- There have been a number of studies that provided evidence
fied analyses are used to control biases due to confounding. For that a new treatment increases the duration of PFS, but not over-
an extensive description of biases that can occur in analytic all survival. For example, OVAR 2.2, a second-line treatment trial
research see Sackett, 1979 (26). involving patients with platinum-sensitive ovarian cancer, indi-
cated that carboplatin and gemcitabine significantly decreased
the hazard of first progression or death (PFS) 28% (hazard ratio
Surrogate Endpoints
= 0.72, p = 0.003) when compared to carboplatin alone (32).
Surrogate endpoints do not necessarily have direct clinical rel- However, there was no appreciable difference between the treat-
evance to the patient. Instead, surrogate endpoints are interme- ment groups with regard to the duration of overall survival (haz-
diate events in the etiologic pathway to other events that are ard ratio = 0.96, p = 0.735). Also, 3 trials evaluating maintenance
directly relevant to the patient (27). The degree to which a treat- bevacizumab for first- and second-line treatment of ovarian
ments effect on a surrogate endpoint predicts the treatments cancer reported significant prolongation in the duration of PFS
effect on a clinically relevant endpoint is a measure of the sur- (3335), but no difference in overall survival. Therefore, while
rogates validity. The ideal surrogate endpoint is an observable PFS may be a good surrogate for overall survival, it appears to
event that is a necessary and sufficient precursor in the causal be susceptible to a small but not insignificant chance of false-
pathway to a clinically relevant event. Additionally, the treat- positive prediction. It is noteworthy, however, that results from
ments ability to alter the surrogate endpoint must be directly PFS seldom lead to false-negative predictions. In other words, it
related to its impact on the true endpoint. It is important that is very rare for the results of an oncology trial to indicate that a
the validity and reliability of a surrogate endpoint be established new treatment prolongs overall survival but does not delay the
with appropriate analyses and not simply presupposed (28,29). onset of recurrence or progression. It seems reasonable to expect
Surrogate endpoints are sometimes justified on the basis of an that an anticancer treatment that prolongs survival should exert
analysis that demonstrates a statistical correlation between the its influence by delaying the onset of new or increasing disease.
surrogate event and a true endpoint. However, while such a cor- This has prompted some investigators to recommend using
relation is a necessary condition, it is not a sufficient condition both PFS and overall survival as trial endpoints (3638). Spe-
to justify using a particular surrogate as an endpoint in a clinical cifically, trials involving patients with advanced-stage cancer are
trial. For example, CA-125 levels following 3 cycles of treat- designed to assess overall survival in the final analysis, but PFS
ment of ovarian cancer have been shown to be associated with is monitored at scheduled interim analyses. If the trials evolving
the subsequent overall survival (30). Women with newly diag- evidence indicates that there is insufficient PFS benefit, then the
nosed ovarian cancer whose serum CA-125 levels normalize at trial may be stopped early and concluded that the treatment has
the end of 3 cycles of standard treatment tend to survive longer insufficient activity to warrant further investigation in the target
than those who have abnormal levels. However, it has not (yet) population. This procedure tends to halt trials of inactive treat-
been demonstrated that the degree to which any particular treat- ments early, but continues trials of active agents to completion.
ment reduces CA-125 levels reliably predicts its effects on clini- Response (disease status) assessed via reassessment laparot-
cally relevant endpoints, like overall survival. omy following treatment has been proposed for use as a study
The most frequently cited reasons for incorporating surro- endpoint in ovarian cancer trials (39). The justification is that
gate endpoints into a study include reduction in study size and patients with no pathologic evidence of disease are more likely
duration, decreased expense, and convenience. to experience longer survival than those with evidence of dis-
ease. The principal drawback to this endpoint is that reassess-
Primary Endpoints in Gynecologic Oncology ment laparotomy is a very onerous procedure for the patient,
and many patients refuse reassessment surgery, or the surgery
Treatment Trials may become medically contraindicated. Even among highly
The Food and Drug Administration (FDA) organized a confer- motivated and very persuasive investigators the percent of
ence to consider endpoints for trials involving women diag- patients not reassessed is typically greater than 15%. These
nosed with advanced ovarian cancer (31). Meta-analyses were missing evaluations can significantly undermine the interpret-
presented, which indicate that PFS can be considered a valid ability of a study.
CHAPTER 17 CLI N ICAL TRIALS M ETHODOLOGY AN D BIOSTATISTICS 485
To date, PFS has not been formally validated for use in tri- The ideal situation is when every patient who meets the eli-
als involving patients with advanced cervical, endometrial, or gibility criteria of a clinical trial is asked to participate. This is
vulvar cancers. In the absence of a formally validated endpoint, seldom possible since not all physicians, who treat such patients,
overall survival or symptom relief are reasonable endpoints. participate in the study. Also, not all patients wish to be involved
Since relief from symptoms is susceptible to assessment bias, in a clinical trial. Impediments in traveling to a participating
trials utilizing this endpoint should use validated instruments treatment center further reduce the target population. The
(See Measurement Errors) and consider blinding the study treat- source population is the subset of patients in the target popula-
ments whenever possible. tion who have access to the study. Figure 17.1 displays common
The endpoint selection for trials involving patients with restrictions that can limit the entry of patients to a clinical trial.
recurrent cervical cancer has been controversial. Historically, Restricted access to the study may contribute a biased sam-
some trials have been designed with clinical response as the pri- ple from the target population, referred to as selection bias.
mary endpoint. However, survival is a preferable primary end- For example, participating investigators at university hospitals
point. The rationale for this choice arises from the observation might tend to enroll disproportionately more patients with can-
that treatments that have demonstrated an improvement in the cer who have undergone very aggressive initial cytoreductive
frequency of response have not consistently prolonged survival surgeries than their counterparts at community hospitals.
(4042). While subsequent therapies may have distorted the A potentially useful approach for determining the necessity
cause-effect relationship, the effect is probably at best minimal of a particular eligibility criterion is to clearly identify its func-
since there are no known treatments that have consistently dem- tion. In addition to defining the target population, there are 4
sions for patients with cancers originating in the fallopian tube Target population
or peritoneum frequently come from the results of trials involv- Access to the study
ing patients with advanced ovarian cancer. Ideally, the size of a
Source population
subgroup represented in a study should be in proportion to their Safety or other
presence in the target population. The degree to which a study considerations
sample reflects the target population determines the generaliz- Eligible population
ability or external validity of the study results. Eligibility crite- Patient and physician
ria should reflect a concern for the generalizability of the trial acceptance
Cisplatin and Paclitaxel in Patients with Suboptimal Stage III & with Paclitaxel [NSC #125973] Administered by Either 24-Hour
IV Epithelial Ovarian Carcinoma). This study was designed to Infusion or 96-Hour Infusion in Patients with Selected Stage III
assess the value of secondary cytoreductive surgery in patients and Stage IV Epithelial Ovarian Cancer), which compares 2 dif-
with Stage III ovarian cancer. All patients who entered into this ferent paclitaxel infusion durations in patients with advanced
study were to receive 3 courses of cisplatin and paclitaxel. After ovarian cancer and has 34 eligibility criteria.
completing this therapy they were then randomized to either
3 additional courses of chemotherapy or interval secondary
cytoreductive surgery followed by 3 additional courses of che-
motherapy. The eligibility criteria exclude those patients who
Phases of Drug Development trials
had only microscopic residual disease following their primary The traditional approach to identifying and evaluating new drugs
cytoreductive surgery since there is no scientific reason to expect has relied on sequential evidence from Phase 1, 2, and 3 clinical
that interval cytoreduction would be of any value to patients trials. Each of these study designs stems from very distinct study
with no gross residual disease. objectives. Phase 2 trials build on the evidence gathered from
Clinical investigators frequently implement eligibility crite- Phase 1 trial results, and similarly Phase 3 trials build on Phase 2
ria in order to promote homogeneity in patient prognoses. The and Phase 1 trial results. The investigation of a given treatment
desire to attain a study population with homogeneous prognoses may be halted at any phase, either due to safety and/or efficacy
is a common reason for excessive eligibility criteria. However, the issues. Depending upon the underlying investigation, the time
concept is both unattainable and overemphasized. This notion from the initiation of a Phase 1 trial for a given treatment to the
may arise from an investigators attempt to duplicate the experi- completion of a Phase 3 trial often spans several years.
mental method conducted in the laboratory. It is standard prac-
tice in laboratory experiments on animals to use inbred strains
in an effort to control genetic variability. In large-scale clinical
Phase 1 Trials
trials, this approach seldom has merit in light of the cost to gen- The purpose of a Phase 1 therapeutic trial in cancer-related
eralizability. Eligibility criteria should be as broad as possible in research is to determine an acceptable dose or schedule for a
order to enhance generalizability. For example, GOG Protocol new therapy as determined by toxicity and/or pharmacoki-
165 (A Randomized Comparison of Radiation Plus Weekly netics. A Phase 1 trial marks the first use of a new experimen-
Cisplatin versus Radiation plus PVI [Protracted Venous Infusion] tal agent in humans. Most Phase 1 trials escalate the dose or
5-FU in Patients with Stage II-B, III-B and IV-A Carcinoma of schedule of the new agent after either a pre-specified number
the Cervix) includes patients with no surgical sampling of the of consecutive patients has been successfully treated or within
paraaortic lymph nodes. Previous GOG trials required sampling an individual as each dose is determined to be tolerable. The
of these nodes. However, there is no evidence or sound biologi- usual Phase 1 trial of a cytotoxic agent attempts to balance the
cal justification to support the notion that the relative treatment delivery of the greatest dose intensity against an acceptable risk
benefit depends on the extent of surgical staging. This is not to of dose limiting-toxicity (DLT). The conventional approach
say whether or not surgical staging is itself beneficial. increases the dose after demonstrating that a small cohort of
Eligibility criteria can be justified on the basis of logistic con- consecutive patients (3 to 6) is able to tolerate the regimen. How-
siderations. For example, a study that requires frequent clinic ever, once an unacceptable level of toxicity occurs (e.g., two
visits for proper evaluation or toxicity monitoring may restrict or 3 patients experiencing DLT), the previously acceptable dose
patients who are unable to arrange reliable transportation. The level is used to treat a few additional patients in order to pro-
potential problem with such a restriction is how it is structured. vide additional evidence that the current dose has an accept-
A criterion requiring that the patient have a car at her disposal is ably low risk of DLT. If this dose is still regarded as acceptable,
probably too restrictive in a trial of women with advanced cervi- it becomes the dose and schedule studied in subsequent trials
cal cancer, since patients from this target population tend toward and it is referred to as the recommended dose level (RDL). The
poorer socio-economic status (SES) and may not have access to RDL should not be confused with the maximum tolerated dose
private transportation. Such a restriction erodes the generaliz- (MTD). The MTD is a theoretical concept used to design a Phase 1
ability of the trial by over sampling patients with higher SES trials, while the RDL is an estimate of the MTD, which may
and may prolong study accrual. Moreover, complicated eligibil- or may not be accurate. Due to the limited number of patients
ity criteria are more likely to function ineffectively. In general involved in a Phase 1 trials outcome measures such as response
complicated eligibility restrictions should be avoided. and survival are not the primary interest in these studies. When
Eligibility criteria based on regulatory considerations include these outcomes are reported, they are considered anecdotal evi-
institutional and governmental regulations that require a signed dence of treatment activity. Eligibility criteria for Phase 1 trials
and witnessed informed consent and study approval by the local in oncology often limit accrual to patients in whom conven-
Institutional Review Board. These restrictions are required in tional treatments have failed.
most research settings and are not subject to the investigators Alternative strategies for estimating the MTD have been pro-
discretion. posed. The primary motivation for these newer strategies is to
Currently many biostatisticians believe that eligibility criteria reduce the number of patients treated at therapeutically inferior
in oncology trials tend to be too restrictive and complicated doses and to reduce the overall size of the study. One of these
(43,44). Overly restrictive or complex eligibility criteria hamper alternatives implements a Bayesian approach and is referred to as
accrual, prolong the studys duration, and delay the reporting of the continual reassessment method (CRM) (46). It has the attrac-
results. The Medical Research Council has demonstrated that tive feature of determining the dose level for the next patient
it is possible to conduct trials with simple and few eligibility based on statistically modeling the toxicity experience of the pre-
criteria (45). The ICON3 (International Collaborative Ovarian viously treated patients. While the traditional approach has been
Neoplasms) trial compares standard carboplatin or cisplatin criticized for treating too many patients at subtherapeutic doses
adriamycin cyclophosphamide regimen with paclitaxel plus car- and providing unreliable estimates of the MTD, CRM has been
boplatin in women with newly diagnosed ovarian cancer. This criticized for tending to treat too many patients at doses higher
trial has 6 eligibility criteria, 3 of which are for safety: (a) fit than the MTD (47). Refinements to CRM have been proposed
to receive, and no clear contraindication to, chemotherapy, (b) (48) and found to have good properties when compared to alter-
Absence of sepsis, and (c) bilirubin less than twice the normal native dose-seeking strategies (49). Another family of designs
level for the center. This is in sharp contrast to GOG Protocol termed the accelerated titration design (ATD) allows doses to
162 (A Phase 3 Randomized Trial of Cisplatin [NSC #119875] be escalated within each patient and incorporates toxicity or
CHAPTER 17 CLI N ICAL TRIALS M ETHODOLOGY AN D BIOSTATISTICS 487
pharmacologic information from each course of therapy into While precision is one important goal in cancer trials, there is
the decision of whether to further escalate or not (50). Both the also a concern for reducing the number of patients treated with
modified CRM and ATD designs can provide significant advan- inferior regimens. For this reason many Phase 2 cancer trials
tages over the conventional Phase 1 design. use multistage designs. Multistage designs implement planned
Special Phase I study designs are often recommended for tar- interim analyses of the data and apply predetermined rules to
geted agents. These studies will often incorporate a biomarker assess whether there is sufficient evidence to warrant continuing
endpoint that signals either the activation or deactivation of a the trial. These rules, which are established prior to initiating the
targeted pathway. As the dose is increased for small cohorts of study, tend to terminate those trials with regimens having less
individuals, the biomarker is measured and toxicity is monitored than the desired activity, and tend to continue to full accrual of
simultaneously. Then, statistical models are used to determine a those trials with regimens having at least a minimally acceptable
safe dose where the targeted pathway is consistently activated level of activity. Two-stage designs that minimize the expected
or inhibited (51). sample size when the new treatment has a clinically uninterest-
Even though the majority of Phase 1 trials in cancer research ing level of activity have been proposed for single-arm studies
follow what was described above, it should be mentioned that (53) and multiarm studies (54). In the cooperative group setting,
alternative Phase 1 trials may arise in other settings such as there is often a need for flexibility in specifying exactly when the
medical device trials, prevention trials, education intervention interim analysis will occur. This is due to the significant adminis-
trials, and behavior modification trials, where the first phase trative and logistic overhead of coordinating the study in several
of investigation may actually utilize healthy subjects, such as clinics. Therefore, designs that do not require that the interim
controls, the definition of disease and the eligibility criteria can values of the treatment difference that can be reasonably con-
be applied consistently to both treatment groups. Also, the stan- sidered consistent with the data from the trial. An inconclusive
dard procedures for measuring the endpoint can be uniformly trial is characterized by having such broad confidence intervals
applied to all patients. Inclusion of prospectively treated con- that the data cannot distinguish between A being preferred or B
trols within the clinical trial requires a method of assigning the being preferred (see Figure 17.2). This is a typical consequence
treatments to patients. Randomization and its benefits are dis- of a small trial. On the other hand, if the confidence interval
cussed in a later section. entirely excludes the region where A is better than B, then we can
It is useful to distinguish Phase 3 objectives as having an conclude that B is significantly better than A (see Fig. 17.2). Note
efficacy, equivalency, or noninferiority design consideration. that in this case the lower bound of the confidence interval may
An efficacy design is characterized by the search for an inter- extend into the region of clinical indifference, but the confidence
vention strategy that provides a therapeutic advantage over the interval must exclude the region below (left of) 0 difference.
current standard of care. An equivalency trial seeks to demon-
strate that 2 interventions can be considered sufficiently similar Equivalency trials. The equivalency study design is perhaps
on the basis of outcome that 1 can be reasonably substituted for a misnomer, since it is actually impossible to generate enough
the other. Noninferiority trials seek to identify new treatments data from any trial to definitively claim that the 2 treatments
that reduce toxicity, patient inconvenience, or treatment costs are equivalent. Instead, an investigator typically defines the lim-
without significantly compromising efficacy. its for treatment differences that can be interpreted as clinically
irrelevant. If it is a matter of opinion for what differences in
Efficacy trials. Efficacy designs are very common in oncology effect sizes can be considered clinically irrelevant, this issue
trials. Examples include: trials that assess the benefit of adding can become a major source for controversy in the final inter-
chemotherapy to radiation for the treatment of early-stage cer- pretation of the trial results. Survival or progression-free sur-
vical cancer or trials that compare standard versus dose intense vival endpoints are seldom used in equivalency trials; however,
platinum regimens for treating ovarian cancer. In each of these bio-equivalency designs are sometimes used for drug develop-
cases, the trial seeks to augment the standard of care in order to ment. For example, if 1 agent is known to influence a particu-
attain a better treatment response. From the outset of these trials lar biologic marker, then it may be desirable to design a trial
it is recognized that the treatment benefit may be accompanied to determine whether a new agent is as effective at modifying
by an increased risk of toxicity, inconvenience, or financial cost. the expression of this biomarker. In this case, an investigator
However, it is hoped that the benefits will be sufficiently large has some notion about the acceptable range of activity that can
to offset these drawbacks. Suppose treatment A is the standard be considered clinically biologically equivalent. These studies are
of care for a particular target disease population. The quantita- designed so that, within tolerable limits, the treatments can be
tive difference between treatments with respect to a particular considered equivalent.
outcome (BA) can be described on a horizontal axis as in Notice that the results from the inconclusive trial in
Figure 17.2. If we are reasonably certain that the difference Figure 17.2 cannot be interpreted as demonstrating equivalency.
between treatments is less than 0 (left of 0) then we would con- Even though the estimated difference between the treatments is
sider treatment A to be better. On the other hand, if the treat- nearly 0, the confidence interval cannot rule out treatment dif-
ment difference is greater than 0 (right of 0) then we would ferences that would lead to preferring A or B. Caution should
conclude that the new treatment, B, is better. Furthermore, we be exercised in interpreting the results from studies that con-
can use dotted lines to demarcate on this graphic a region in clude therapeutic equivalency when only a small difference
which the difference between A and B is small enough to war- between treatments with regard to the outcome is observed and
rant no clinical preference for A or B. Consider the results from it is declared to be not statistically significant. Even results from
a trial expressed as the estimated difference between treatments moderately large trials, which suggest therapeutic equivalence,
and the corresponding 95% or 99% confidence interval super- may in fact be due to inadequate statistical power to detect clini-
imposed on this graph. The confidence interval depicts those cally relevant differences.
A is clinically equivalent to B
0
Treatment A is preferred Region of indifference Treatment B is preferred
Difference between treatment A and B
FIGURE 17.2. Graphical representation of the point estimates and confidence intervals describing the results
from 4 hypothetical trials.
CHAPTER 17 CLI N ICAL TRIALS M ETHODOLOGY AN D BIOSTATISTICS 489
Noninferiority trials. A noninferiority study design may be con- occur when there is an association between treatment choice
sidered when the currently accepted standard treatment is associ- and prognosis. It need not be intentional. When a physicians
ated with significant toxicity and a new and less toxic treatment interest in a trial or a patients decision to participate in the trial
becomes available. The goal of this type of study is to demonstrate depends on the assigned treatment, a nonrandom association
that substituting the new treatment for the current standard treat- between treatment and prognosis can be introduced. Finally,
ment does not compromise efficacy appreciably (6063). Refer- randomization provides the theoretical underpinning for the
ring to Figure 17.2, the trial seeks to provide sufficient evidence significance test (70). In other words, the probability of a false-
to be reasonably certain that the difference between A and B lies positive trial as stated in the study design is justified with ran-
above the lower boundary of the indifference region. This lower domization. It is important to recognize that these advantages,
boundary is often called the noninferiority margin. which are provided by randomizing the study treatments, are
The justification for the noninferiority margin selected in a forfeited when all of the randomized patients are not included
particular study is often controversial. If this margin is set too in the final analyses.
low, then the study has an unacceptably high probability of rec- It is sometimes argued that since many factors that influence
ommending an inferior treatment. If it is too high, then the trial prognosis are known, perhaps other approaches to allocating
utilizes too many clinical and financial resources. In order to treatments can be considered, and statistical models should be
select an appropriate margin of noninferiority, it is important to used to adjust for any imbalances in prognosis. However, the
recognize that even though a noninferiority trial may explicitly conclusions from this type of trial must be conditioned on the
compare only 2 treatments, implicitly there is a third treatment completeness of knowledge about the disease and the accept-
randomly selecting a series of blocks from the 6 distinct possi- or when it is logistically difficult (e.g., the evaluating physician
bilities. There are 3 features of blocked randomization that may must be kept isolated from the treatment of the patient). In the
be problematic. First, the probability of a particular treatment absence of blinding, care should be taken that the method of
being allocated is not the same throughout the study, as in sim- measuring the endpoint is precisely stated in the protocol and
ple randomization. Taking the example above, every 4th treat- consistently applied to each patient uniformly. Trials that assess
ment is predetermined by the previous 3 allocations. Second, the quality of life or relief from symptoms should give serious con-
use of small blocks in a single-clinic study may undermine con- sideration to treatment blinding.
cealment and allow an investigator to deduce the next treatment. Schulz et al. (78) have reviewed 110 randomized clinical trials
This potential problem can be corrected by continually changing published between 1990 and 1991 from 4 journals dedicated to
the block size throughout the assignment list. Third, large block obstetrics and gynecology. Thirty-one of these trials reported being
sizes can subvert the benefits of blocking. As block sizes increase, double-blinded. Schultz et al. conclude that blinding should have
the procedure resembles simple randomization. been used more often, despite frequent impediments. Moreover,
The statistical efficiency of the study can be further enhanced blinding seemed to have been compromised in at least 3 of the tri-
by stratifying patients into groups with similar prognoses and als where it was implemented.
using separate lists of blocked treatments for each stratum. This
procedure is called stratified block randomization. It is worth Placebo A placebo is an inert treatment. Placebos blind the
noting that using simple randomization within strata would patient, and usually the physician as well, to the knowledge of
defeat the purpose of stratification, since this is equivalent to whether an experimental or an inert treatment is being given.
using simple randomization for all patients. Likewise, trials that Placebos are frequently used in trials where there is no accepted
stratify on too many prognostic factors are likely to have many standard treatment and the endpoint is susceptible to measure-
uncompleted treatment blocks at the end of the study, which ment bias. The use of a placebo is also important when the end-
also defeats the intent of blocking (76). point can be affected by the patients psychological response to
When it is desirable to balance on more than a few prog- the knowledge of receiving therapy combined with a belief that
nostic factors, an alternative is dynamic treatment allocation; the therapy is effective. This phenomenon is aptly named the
one particular type being minimization. Whereas stratified block placebo effect. In such circumstances, the use of a placebo
randomization will balance treatment assignments within each provides a treatment-to-control comparison that measures only
combination of the various factor levels, minimization tends to the therapeutic effect. Note that the placebo effect is a dis-
balance treatments within each level of the factor separately. tinctly different type of measurement bias from those that have
Each time a new patient is entered into the study, the number of been previously discussed. Careful ethical considerations must
individuals who share any of the prognostic characteristics of the precede the use of a placebo or sham procedure in any clinical
new patient is tabulated. A metric, which measures the imbalance trial (79).
of these factors among the study treatments, is computed as if GOG Protocol 137 (A Randomized Double-Blinded Trial of
the new patient were allocated to each of the study treatments Estrogen Replacement Therapy versus Placebo in Women with
in turn. The patient is then allocated to the treatment that would Stage I or II Endometrial Adenocarcinoma) was a randomized
favor the greatest degree of balance. In the event that the proce- double-blinded comparison of estrogen replacement therapy
dure indicates equal preference for two or more possible treat- versus a placebo in women who had a total abdominal hys-
ment allocations, simple randomization can be used to determine terectomy and bilateral salpingo-oopherectomy for early-stage
the patients treatment assignment. endometrial cancer. One primary reason for the use of a pla-
cebo in this trial was the potential for differential measurement
bias being introduced by the physician monitoring patients on
estrogens much more closely due to the anticipation of adverse
Masking Treatments events.
Concealment Concealment refers to the procedure in which
the assigned study treatment is not revealed to the patient or
the investigator until after the subject has successfully enrolled Factorial Designs
in the study. The purpose of concealment is to eliminate a bias Factorial designs are used when several interventions are to be
which can arise from an individuals decision to participate in studied simultaneously. The term factorial arises from historical
the study depending on the treatment assignment (77). Conceal- terminology in which the treatments were referred to as factors.
ment is an essential component of randomized clinical trials. Each factor has corresponding levels; for example, an investigator
may wish to compare a study agent administered at 3 dose levels:
Blinding Blinding is a procedure that prevents the patient or high-dose, medium-dose, and none. The total number of factor
physician from knowing which treatment is being used. In a combinations being studied is the product of the number of levels
single-blinded study the patient is unaware of which study treat- for each factor or treatment. For example, a trial that evaluates
ments she is receiving. A double-blinded study results in a situa- treatment A at three levels and treatment B at 2 levels is called a
tion in which neither the patient nor the health care provider is 3-by-2 (denoted 3 2) factorial design. If the relative effects due
aware of that information. One purpose of blinding is to avoid to the various levels of treatment A are independent of the levels
measurement bias, particularly differential measurement bias (see of B, the two treatments (A and B) can be evaluated simultane-
Endpoints section). This type of bias occurs when the value of a ously. The factorial design provides a significant reduction in the
measurement is influenced by the knowledge of which treatment required sample size when compared to a study that evaluates all
is being received (see Historical Perspective section). It can occur levels of A and B separately. The key assumption necessary for a
when the measurement of an endpoint is in part or totally subjec- factorial design is that all treatments can be given simultaneously
tive. Most methods for assessing pain are subjective and require without interaction or interference.
treatment blinding in order to promote the studys validity. The most commonly utilized factorial design is the 2 2
Oncology trials frequently do not implement blinding for factorial design that includes 2 distinct treatment regimens at
several reasons. It is rather difficult to blind treatments when each of 2 factor levels. For example, suppose individuals enter-
various treatment modalities are used (e.g., surgery versus ing a cancer prevention trial are randomly assigned to receive
radiation therapy, or intravenous versus oral administrations), vitamin E and beta carotene while the respective factor lev-
when good medical practice is jeopardized (e.g., special tests els are placebo-A or 50 mg/day for vitamin E, and placebo-B
are required to monitor toxicity due to particular treatments), or 20 mg/day for beta carotene. There are 4 treatment
CHAPTER 17 CLI N ICAL TRIALS M ETHODOLOGY AN D BIOSTATISTICS 491
control procedures for collecting the clinical data can target biologic processes. The technologies in Table 17.1 use hybrid-
those data items that are required for the specific study objec- ization and sequence-based platforms such as gene expression
tives. Fourth, the patients treatment and follow-up assess- microarrays and RNA-Seq to obtain data matrices.
ments can be standardized and optimized in accordance with Several of the common high-throughput assay platforms
the goals of the study. When samples are retrospectively col- used in experiments designed for cancer diagnosis are listed in
lected, the laboratory analysis is performed using previously Table 17.1. These platforms were chosen to illustrate the diver-
archived specimens that may have been originally collected sity of platforms available for interrogating deoxyribonucleic
for another purpose. The investigator using a retrospec- acid (DNA), ribonucleic acid (RNA), or proteins.
tive approach is a prisoner to the procedures that were
set down before the current study goals were contemplated
and therefore, they may not be optimal for his intended objec- Preprocessing High-Throughput (HT) Platforms
tives. For instance, the samples may have come from patients In short, pre-processing algorithms are required in nearly all
who are not representative of the target population. This high-throughput technologies listed in Table 17.1. This is due
reduces the generalizability of the study results. The specimens to the fact that HT platforms measure both biologic signal and
may have been obtained, prepared or stored using outdated or technical signal. Therefore, the goal of preprocessing algorithms
less than optimal procedures for his laboratory tests. This could is removal of the technical signal. This technical signal can be
introduce biases in the measurements or reduce the power of considered in terms of background correction and normaliza-
the study. tion to adjust across experiments. The background corrections
and normalization account for technical artifacts that can occur
due to either the array construction or laboratory procedures
Biomarker Development Process that introduce systematic errors in the signal on individual
In the following sections, we discuss a common TR study design arrays or across arrays. Often these pre-processing techniques
for a biomarker: (a) biomarker discovery and (b) biomarker are specific to the platform employed (see, for example, Miec-
validation. In short, these steps are presented in Figure 17.3 znikowski et al. [85]) and therefore it is impractical to review all
(Discovery and Test Validation Stage). of the available pre-processing methods here.
occurrence. When there are 10,000 null hypotheses tested, In certain immunohistochemistry assays the results should
as may be typical for some HT studies, even if all of the null be performed by at least 2 different observers who are blinded
hypotheses were true, one would expect 500 null hypotheses to the clinical data. This may alleviate the subjectivity in these
Even with the requirement of an independent dataset, there different cohorts of patients. Initially, the pilot projects studied
may still be levels of validation evidence. For example, a lower glioblastoma multiforma (GBM) and cystadenocarcinoma of
level of validation evidence may be independent sets of spec- the ovary, but have now expanded to cover roughly 20 different
imens and clinical data collected at a single institution using cancer types. For each cancer type, the patient cohorts (collected
carefully controlled protocols, with samples from the same from different sites) include several hundred individuals and
patient population. Meanwhile, a higher level of validation evi- the platform techniques include gene expression profiling, copy
dence would be independent sets of specimens and clinical data number variation profiling, SNP genotyping, methylation profil-
collected at multiple institutions ing, and microRNA profiling. These data will be made publicly
Additionally, it should be stressed that the independent available, making the TCGA dataset a great resource for future
validation dataset must be relevant to the intended use of the can- research using meta-analysis and integrative analysis techniques
didate biomarker test. Patients in the independent dataset should that were not previously available.
have the same type of disease, the same stage and same clinical
setting for which the candidate test is intended to be used in the Developing Translational Research Studies
future. Ideally, the specimens for independent confirmation will
have been collected at a different point in time, at different insti-
and Reporting Results
tutions, from a different patient population, with samples pro- Guidelines have been developed to promote accurate and com-
cessed in a different laboratory to demonstrate that the test has plete reporting of results from biomarker studies. Throughout this
broad applicability and is not overfit to any particular situation. section, the importance of having well-defined questions for the
proposed data is stressed. In other words, serious thought, plan-
ning, and discussions amongst a team of scientists are necessary
Publicly Available Data to successfully perform biomarker analysis, including discovery,
These datasets can help with the development process, and fur- verification, and validation.
ther they can complete the puzzle in systems biology, for exam- In the discovery phase it is important that the proposed tech-
ple, provide the proteomics story if you only have genomic data. nology has been validated, see for example, technical replication
They can be used in an integrative analysis and a meta-analysis. studies in Strand et al. (127), Callesen et al. (128); Leyland-Jones
These meta-analyses can strengthen the conclusions drawn from et al. (129), De Cecco et al. (130), Hicks et al. (131), Benton et al.
an individual researchers study. They may also offer insights (132), Freidin et al. (133), and Lawrie et al. (134). During the
from other study populations. discovery phase, it is also important to consider differences in
As deoxyribonucleic acid (DNA) microarray technology has material preparation, for example, frozen tissue samples versus
been widely applied to detect gene activity changes in many paraffin embedded tissues as discussed in Nowak et al. (135),
areas of biomedical research, development and curation of online and Mittempergher et al. (136). During the verification phase,
microarray data repositories are at the forefront of research these issues also may play a role; however, other concerns
endeavors to use and reuse this mounting deluge of data. Several may arise such as the level of concordance in signal necessary
representative repositories of microarray datasets are ArrayEx- between the discovery platform and the verification platform.
press at the webpage http://www.ebi.ac.uk/arrayexpress/, Gene Ultimately, after discovery and verification, a lockdown model is
Expression Omnibus (GEO) (119) at the webpage http://www. carried forth to validation. This, so called, lockdown model can
ncbi.nlm.nih.gov/geo/, Stanford Microarray Database (SMD) at be interpreted in a decision theoretic setting; each future sample
the webpage http://smd.stanford.edu/ and Center for Information must be classified or the outcome predicted based only on the
Biology Gene Expression Database (CIBEX) (120) at the webpage model and a given sample signal from the intended technology.
http://cibex.nig.ac.jp/index.jsp. Also a new database called Andu- In the validation phase, it is important to note that there is
ril which has been recently developed and described in Ovaska et a major difference between answering a priori defined hypoth-
al. (121) now provides comprehensive storage of the massive data eses and providing conclusions from exploratory analyses. Con-
including single base pair mutation, copy number change or dele- clusions drawn from exploratory data analysis are descriptive
tions of genes, differential gene expression, and epigenetic changes results and typically need to be confirmed in a validation data-
like methylation profiles. A somewhat recent comparison of the set, while a priori hypothesis lead to stronger conclusions and
available microarray databases was provided in Gardiner-Garden do not necessarily need an external validation. Care should be
and Littlejohn (122). Statistical packages in R have also been cre- given in reporting unanticipated significant effects, as these are
ated that allows users to easily import data from databases like most likely due to chance and thus unlikely to be validated in
ArrayExpress into Bioconductor packages (123). other studies. Most importantly, researchers should keep in mind
Concordant with the development of online data reposito- that, in the long term, the success of biomarker studies should
ries, researchers have developed specific data standards required be measured by the clinical improvement in patient outcomes.
for microarray analysis. The data standard concept describes There have been a prodigious number of biomarker stud-
the minimum information about a microarray experiment ies reported in the literature; however, a surprising number of
(MIAME) that is needed to enable the interpretation of the these results are irreproducible. The reasons for these discrep-
results of the experiment and to potentially reproduce the ancies may lie in the differences in methodological procedures,
experiment (124). MIAME compliance will ensure that bio- inadequate control of false-positive findings, improper valida-
logical properties of the samples and the phenotypes that were tion procedures, variability in the patient sampling, or any num-
assayed were correctly recorded, thus, ensuring, that the data ber of other differences in study design, conduct, or analytical
can be quickly assessed for its suitability in studying new ques- procedures. Many published studies lack adequate information
tions. The public repositories including ArrayExpress (146), that would allow an evaluation of quality or comparability. In
GEO (125), and CIBEX (120) are all designed to hold MIAME order to promote clear and complete reporting of biomarker
compliant microarray data. studies, the REMARK guidelines have been developed (137).
Especially exciting for oncologists, multiple platforms of These guidelines make specific recommendations for preparing
microarray data from The Cancer Genome Atlas (TCGA) are translational research presentations, reports, and publications
now available through the data portal at http://tcga-data.nci. with regard to describing patient and sample characteristics,
nih.gov/tcga/tcgaHome2.jsp. The TCGA project is further assay methodology, study design, methods of data analysis,
described in Stratton et al. (126), but in short, represents one and results. While these recommendations have been distilled
of the first large-scale attempts to study the multiple types into bullets in Table 17.3, useful additional information can be
of genetic mutations involved in multiple cancer types from found in the REMARK document (137).
CHAPTER 17 CLI N ICAL TRIALS M ETHODOLOGY AN D BIOSTATISTICS 495
Source: Reprinted with permission from REMARK Criteria: REporting Recommendations for Tumor MARKer Prognostic studies. Mittempergher L, de Ronde JJ,
Nieuwland M, et al. Gene expression profiles from formalin fixed paraffin embedded breast cancer tissue are largely comparable to fresh frozen matched tissue. PLoS
One. 2011;6(2):e17163.
496 CHAPTER 17 CLI N ICAL TRIALS M ETHODOLOGY AN D BIOSTATISTICS
Specificity (80%)
Phase II/III) study have also been proposed (144, 145). Cur- that incorporates a biomarker into a clinical trial depends on
rently, adaptive designs for targeted therapies are an area of 1) the study objectives, 2) how well the agents mechanism of
intense biostatistical research. action is understood, 3) how well the role of the target is under-
Careful planning is necessary for incorporating biomarkers stood, and 4) how well the selected biomarker captures the state
into clinical trials. The appropriate choice of the trial design of the target.
ugh
way
tar
en
target pathways
g
hro
t e hway
ath
ffe
ct t
et p
ct o
t
Effe
targ
n
Biomarker
correlation with
Biologic
target Target
FIGURE 17.5. Schematic of the causal relationships and correlations between treatment, biomarker,
biologic target, and clinical outcome.
498 CHAPTER 17 CLI N ICAL TRIALS M ETHODOLOGY AN D BIOSTATISTICS
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18
CHAPTER
Comparative Effectiveness
Research in Gynecologic
Oncology
501
502 CHAPTER 18 COM PAR ATIVE EFFECTIVEN ESS RESEARCH I N GYN ECOLOGIC ONCOLOGY
Cost-Minimization Analyses
CER and Cost-Effectiveness In some cases, alternative medical decisions have approximately
While CER is broadly defined as any methodology that com- equivalent effectiveness but potentially different costs. In such
pares the benefits and harms of alternative strategies in health cases, the effectiveness component of a CEA may not be needed.
care, the most common CER studies fall within the field of CMAs assume comparable effectiveness between strategies and
CHAPTER 18 COM PAR ATIVE EFFECTIVEN ESS RESEARCH I N GYN ECOLOGIC ONCOLOGY 503
choose a preferred strategy based on the mean cost of each (6). invasive surgery results in cost savings to society (7,9,10). Other
For example, a recent decision analysis comparing the costs of perspectives of health economic models include the patient and
three different surgical approaches to endometrial cancer staging hospital perspectives. A hospital perspective model might be
assumed equal survival outcomes between strategies and therefore used to inform the decision to purchase expensive equipment
did not incorporate effectiveness (7). such as robotic surgery platforms or an intraoperative radio-
therapy facility.
Cost-Utility Analyses Define the question Once the models perspective has been
CUA is a form of CEA in which effectiveness is adjusted based on determined, the clinical problem, standard approach, and any
the quality of life that is associated with each strategy. In CUAs, alternatives must be defined (11). The alternatives to the inter-
utilities are the measurement used for quality of life and repre- vention of interest should always include a standard of care
sent the preferences of an individual or a society for a particular approach or even a do nothing approach. Next, a conceptual
health outcome. A utility is a number between 0 and 1, with 1 model for the analysis is developed, which outlines the possible
representing perfect health and 0 representing death. The most consequences of each intervention. Decision models are often
common metric used for comparison of strategies in a CUA is a used as the conceptual framework for CEAs and have become
quality-adjusted life year (QALY). The QALY quantifies both dif- an integral part of CEA studies.
ferences in survival and in quality of life between strategies. In an
oncology CUA, the QALY is usually derived as the product of the Develop a decision tree A simple decision tree begins with
HIV
1-pHIV
UTILITY
Live
1 no HIV
Accept Transfusion pHIV
1
Die
pDie Without Transfusion
0
FIGURE 18.1. Simple decision tree representing the choice to accept or refuse a blood transfusion for severe anemia.
The blue square is the decision node, green circles are chance nodes, and the red triangles are terminal nodes. Probabilities
of events are depicted beneath each branch. Payoffs are listed to the right of terminal nodes. Three parameters are
modeled as variables and have been given numeric values defined beneath the decision node. pHIV is the probability of
being infected with HIV should the patient accept a transfusion. pDieWithoutTransfusion is the probability of death from
severe anemia without a transfusion. Utility is the quality-of-life-related value of living with HIV, where 0 represents death
and 1, perfect health.
It is important to note that the ICER is not estimated by Multiple sampling simulations of the model may then be run,
dividing the cost of one intervention by the measure of its own each of which results in an individual cost-effectiveness compari-
effectiveness. This average cost-effectiveness ratio is not compa- son or estimate. Multiple simulations allow for construction of a
rable to the ICER and is not a useful metric in cost-effectiveness cost-effectiveness scatterplot and the ability to express confidence
analyses (12). intervals around the ICER estimate (Fig. 18.3), which effectively
In the United States, an intervention has traditionally been allows quantification of the total impact of uncertainty on the
considered cost-effective relative to an alternative strategy if the model and the confidence that can be placed in the analysis results.
ICER is less than $50,000 per quality-adjusted life year (QALY)
(6). While ICER thresholds of $50,000 per QALY are theoretically
used in decision making, they are not strictly applied. Social norms
may raise this value such that interventions costing up to $100,000 I N PUT DEVELOPM ENT FOR H EALTH
or even greater per QALY have sometimes been considered cost- ECONOM IC MODELS
effective (13). The term cost-effective does not mean that a
strategy saves money but rather that the additional cost of the The following section details methods for the development of
intervention is worthwhile, usually from the perspective of society. input data for health economic models.
Sensitivity Analyses
Uncertainty in health economic analyses may exist about such Estimation of Costs
input parameters as cost, survival, or clinical probabilities. To Cost definitions The costs incorporated into a CEA depend
assess the impact of such uncertainty on the findings of a deci- on the studys perspective. The standard CEA or CUA is per-
sion model, a sensitivity analysis can be performed. The simplest formed from a societal perspective (6). However, alternative
form of sensitivity analysis is a one-way analysis. Estimates are perspectives include those of the patient, hospital, or a third-
varied one parameter at a time to evaluate the impact made by party payer. In a societal perspective analysis, the costs included
the changes on the outcome or conclusions of the model (14). are all of those borne by society and should therefore include
For example, in the simple model describing the decision to both direct and indirect costs. Direct costs include direct medi-
accept or refuse a blood transfusion, varying the probability cal costs (e.g., professional and hospital costs, diagnostic tests
of death due to anemia or the utility related to quality of life and procedures) and direct nonmedical costs (such as travel
with HIV has an impact on the expected value of each deci- to receive care). Indirect costs account for lost productivity due to
sion (Fig. 18.2AB). Likewise, a two-way sensitivity analysis time off work for illness, both for the patient and any caregivers.
can be performed to evaluate the impact of varying two model When a health economic model is performed from a non-
parameters simultaneously (Fig. 18.2C). When variation in the societal perspective, the scope of the costs included may be nar-
key parameters of a model over their confidence intervals or rower. For example, in an analysis performed from a third-party
expected range of values does not change the models results, payer perspective, lost productivity would not be included.
the model is said to be insensitive to these variations and its con-
clusions can be more strongly interpreted. Models whose out- Which costs to include When developing a model to com-
comes change significantly when key estimates are varied over pare two strategies, it is important to remember that all medical
aclinically reasonable range should be interpreted with caution. costs do not necessarily need to be incorporated if it can rea-
Most clinical models are fairly complex and may war- sonably be assumed that they do not differ between strate-
rant the use of multiple simultaneous sensitivity analyses. In a gies. For example, for a comparison of 2 alternative surgical
Monte Carlo probabilistic sensitivity analysis, each variable in approaches to a disease, the cost of identical preoperative
the model can be sampled from a probability distribution rep- evaluation and laboratory testing need not be incorporated.
resenting its value (15). Sampling parameter values from prob- Likewise, for a cost comparison of a Phase III clinical trial, the
ability distributions (rather than from a simple range of values) costs and consequences of adverse events that do not differ sig-
places greater weight on likely combinations of parameter values. nificantly between treatment arms may be omitted. Conversely,
CHAPTER 18 COM PAR ATIVE EFFECTIVEN ESS RESEARCH I N GYN ECOLOGIC ONCOLOGY 505
0.767
0.900 pDieWithout
UTILITY
Transfusion = 0.200
EV = 0.800 0.545
0.850
0.800 0.323
Accept Transfusion
Refuse Transfusion
0.750 0.100
0.010 0.070 0.130 0.190 0.250 0.010 0.070 0.130 0.190 0.250
pDie Without Transfusion pDie Without Transfusion
Sensitivity Analysis
on the value of utility
1.00 Accept Transfusion FIGURE 18.2. A. One-way sensitivity analysis on
0.90 the probability of death from anemia without a blood
Refuse Transfusion
0.80 transfusion. When the probability of death from anemia
Threshold Values: exceeds the threshold value of 0.2, the expected value
Expected Value
CE Scatterplot
80K
70K
60K
Cost ($)
50K
FIGURE 18.3. Cost-effectiveness scatterplot resulting from a Monte
40K IV Carbo/Pac - GOG 158 Carlo probabilistic sensitivity analysis for a model comparing intravenous
IP Cis/Pac - GOG 172 carboplatin/paclitaxel to intraperitoneal cisplatin/paclitaxel and intravenous
30K paclitaxel for advanced ovarian cancer. The simulation was repeated 10,000
times with sampling of key model parameters (cost, survival, and probability
20K of adverse events) from probability distributions. This simulation resulted in
an estimate of 95% confidence intervals to surround the primary incremental
cost-effectiveness ratio estimate.
10K Source: Reprinted with permission from Havrilesky LJ, Alvarez-Secord A, Darcy KM, et al.
3.70 4.00 4.30 4.60 4.90 Cost effectiveness of intraperitoneal compared with intravenous chemotherapy for women with
optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol.
Effectiveness (QALYs) 2008;26(25):41444150. (114)
Abbreviation: CE, cost-effectiveness; QALY, quality-adjusted life year.
506 CHAPTER 18 COM PAR ATIVE EFFECTIVEN ESS RESEARCH I N GYN ECOLOGIC ONCOLOGY
if there are global downstream effects on health care costs that rate of febrile neutropenia, the cost of a hospitalization for this
result from an intervention, such as fewer subsequent hospi- diagnosis should be incorporated into the cost of each strategy
talizations or emergency department visits, these should be in proportion to the probability of the event in each treatment
incorporated. group. Adverse events whose frequencies are not significantly
different between strategies or that do not generate additional
Costs versus charges When performing a health economic cost (e.g., grade 1 anemia) may reasonably be omitted from a
analysis, it is important to distinguish costs from charges. CEA. However, models should adjust for quality of life differ-
Charges represent what the provider or hospital asks an indi- ences resulting from adverse events.
vidual to pay for a service, and not the reimbursement provided
by either a private third-party payer or Medicare. Because reim- Cost collection as a component of Phase III trials While
bursements by the CMS are generally considered to approxi- many cost-effectiveness studies are performed following com-
mate the cost of providing a service, it is standard to use pletion of the clinical trials from which the data is derived,
national Medicare reimbursements to approximate the costs such analyses are ideally planned and executed in conjunc-
of medical tests, procedures, or services in a health economic tion with prospective Phase III trials. The International Soci-
analysis (16). If a Medicare reimbursement is not available for ety for Pharmacoeconomics and Outcomes Research (ISPOR)
a particular aspect of medical costs, charges may be used to cal- Task Force on Good Research Practices recommends that
culate costs using a cost-charge ratio. Cost-charge ratios allow a collection of health economic data should be fully integrated
calculation of the proportion of hospital charges that represent into Phase III studies (16). In a Phase III trial, prospective
cost to the hospital. Cost-charge ratios are specific to individual economic data is usually collected by accounting for differ-
hospital departments and may be available from CMS (http:// ences in health resource utilization between treatment groups.
www.cms.gov). Ideally this might include an accounting of all health-related
encounters in each treatment group. However, logistical con-
Surgical costs Health economic analyses in gynecologic siderations during trial planning often require prioritization as
oncology may include an estimate of the costs of surgical proce- to which data elements will be collected. Therefore, it is often
dures. CMS reimbursements may be used to approximate these appropriate to choose to focus on big ticket items as well as
costs from a societal perspective. Direct surgical costs include resources that are expected to differ between treatment arms.
professional fees (surgeon, anesthesiologist, and pathologist), Resource utilization collection is accomplished by means of
the cost of hospital recovery, and the costs of any tests or pro- subject diaries in which outpatient and inpatient encounters
cedures performed in the postoperative period. Postoperative as well as travel and caregiver time may be recorded. Once
outpatient care is usually part of a global fee that includes resource utilization collection is accomplished, national fee
the first 90 days of postoperative care, and is therefore not schedules and reimbursements are generally used to assign
included separately. Likewise, the reimbursement for recovery costs to each element.
in the hospital or ambulatory surgery center is usually deter-
mined by a CMS code, and this reimbursement covers tests
and inpatient care. However, additional procedures performed
postoperatively are associated with additional professional Modeling Effectiveness
fees. Effectiveness in CER should be reported in units of relevant
clinical outcomes. For example, in oncology studies, effec-
Costs of hospitalization The cost of a hospitalization may tiveness might be expressed as the number of cases of can-
be estimated for health economic models using the Diagnosis cer prevented, the number of unnecessary surgical procedures
Related Group (DRG), a CMS code that takes into account avoided, or the number of cancer recurrences prevented. How-
the primary diagnosis and the patients comorbidities, and is ever, it is most common in oncology CER to quantify effec-
used to determine the reimbursement Medicare provides to the tiveness using survival. Thus, in cost-effectiveness analyses
hospital. An alternative method for estimating the cost of an the comparison of alternative strategies might be described in
inpatient hospital stay is to use the AHRQs Healthcare Cost terms of the cost per additional year of life, or QALY, saved.
and Utilization Project (HCUP) Nationwide Inpatient Sample While overall survival is a standard outcome in both CER
(NIS) (http://www.hcup-us.ahrq.gov/). This large all-payer pub- and clinical trials, progression-free survival (PFS) may also be
lic database provides inpatient data from a national sample reported.
of over 1,000 hospitals in 44 states and is released annually.
Mean and median charges and costs of all hospitalizations for Modeling survival Survival outcomes may be modeled in
a specific primary or secondary diagnosis can be obtained by several ways. One simple method is to assign a survival time
entering ICD-9 codes. Results can be stratified by demographic (e.g., mean survival in years) to each relevant branch of a simple
information. decision tree. While this method accomplishes the assignment
of a survival value to each branch of the model, it does not
Outpatient treatment costs Outpatient treatments in gyne- account for additional costs or changes in quality of life that may
cologic oncology often refer to chemotherapy. Cost tabulation need to be applied only to subjects who are still alive at a
should include the CMS reimbursements for the individual che- later time. For example, it may be useful to apply the cost of
motherapy drugs and any other medications infused based on additional cycles of treatment or adverse events to only those
the designated J code for each drug. Tests performed routinely individuals remaining alive or progression-free at a specific time
over the course of a cycle of treatment should also be included. point. An alternative, and more common, method is to use a
Finally, the costs of infusion at an outpatient facility should be modified Markov state transition model to represent survival
included using appropriate CPT codes. (see the section Construction of a Markov natural history model
below). When a modified Markov approach is used, costs of
Adverse events When 2 or more strategies are compared events that are applied only if a subject is alive or has relapsed
using a health economic model, it is critical that the adverse may be applied at each relevant time point. Likewise, changes in
events associated with each strategy be accounted for. Specifi- quality of life during or after treatment may also be quantified.
cally, when severe adverse events result in additional medical In the context of comparing effectiveness results of a prospective
or nonmedical costs, these costs should be incorporated as well. clinical trial, raw survival data can be used to model Kaplan-
For example, if one chemotherapy strategy results in a higher Meier survival curves directly (Fig. 18.4).
CHAPTER 18 COM PAR ATIVE EFFECTIVEN ESS RESEARCH I N GYN ECOLOGIC ONCOLOGY 507
Functional assessment of cancer therapy (FACT) is a 33-item Construction of a Markov natural history model For cre-
scale developed to measure quality of life in patients undergoing ating a Markov model, the natural history of a cancer is bro-
cancer treatment (30). It is commonly used in RCTs conducted ken up into a defined, mutually exclusive, and exhaustive set
by the Gynecologic Oncology Group (GOG). The FACT con- of states. For cervical cancer, these states would include: well,
sists of a core instrument (FACT-G) that can be supplemented human papillomavirus (HPV) infection, preinvasive disease,
by various subscales based on the malignancy of interest. While undetected invasive cancer (Stages I though IV), detected inva-
conversion of FACT scores to utilities has been studied (31,32), sive cancer (Stages I though IV), cancer death, and death from
these methods have not been fully validated. Recent data from other causes. For epithelial ovarian cancer, which does not have a
the GOG has further evaluated the ability to convert FACT universal preinvasive state, natural history states might include:
scores to utilities in patients with ovarian cancer, arguing for well, undetected and detected invasive cancer (Stages I through
a prospective trial attempting to address this issue [Hess LM, IV), cancer death, and death from other causes (Fig. 18.6).
Brady WE, Havrilesky LJ, Cohn DE, Monk BJ, Wenzel L, Cella Once the states have been defined, movement (usually referred
D. Comparison of methods to estimate health state utilities for to as transition) between the states is defined based on knowl-
ovarian cancer using quality of life data: A Gynecologic Oncol- edge of the cancers natural history. For example, a woman can-
ogy Group study. Gynecol Oncol. 2012 Oct 30. pii: S0090- not enter Stage II cervical cancer without first having been in
8258(12)00851-7. doi: 10.1016/j.ygyno.2012.10.024. [Epub Stage I. The arrows in Figure 18.6 depict allowed transitions
ahead of print]] between states that have been defined for an ovarian cancer nat-
To date, the TTO and SG methods are the most accepted ural history model (36). Once the states and allowed transitions
methods to develop utility scores. While the use of quality of have been identified, probabilities of moving from one state to
life instruments eases the labor-intensiveness of collecting pref- another over a fixed period of time are needed to populate the
erences using the TTO and SG methods, many question the model. During each cycle of the model, allowed transitions
validity of the use of indirect methods such as quality of life between states occur. The cycle length of the model is a time
instruments to construct CUAs. At present, there is no clearly period chosen to correspond to a period that takes into account
superior method for determining utility scores either directly or the natural history of the disease as well as the timing of screen-
indirectly. Moreover, some believe that utilities should best be ing, diagnosis, and treatment recommendations. For most can-
derived from patients as they best know their disease condition cers a year is sufficient, although shorter or longer time periods
(33). Others feel that the preferences of the general public are can be used. The probabilities corresponding to the chosen time
most relevant because society as a whole must delegate distri- period for the model (referred to as a Markov cycle) are usually
bution of its health care resources (34). As economic analyses obtained from the epidemiologic literature, an analysis of an
evolve, the limitations of preference ratings should be examined epidemiologic study, or expert opinion. Together, the states,
and a consistent method of developing utility scores should be allowed transitions, and probabilities constitute the model.
determined to allow for better comparisons to be made across Once programmed, the model can be used to calculate differ-
cost-utility studies. ent outcomes. Usually, the outcomes are calculated for a cohort
CHAPTER 18 COM PAR ATIVE EFFECTIVEN ESS RESEARCH I N GYN ECOLOGIC ONCOLOGY 509
Well
Benign
oophorectomy
Stage I cancer Stage I cancer
undetected detected
Ovarian cancer
survivor
Stage II cancer Stage II cancer
undetected detected
Death from
another cause
Stage III cancer Stage III cancer Death from
undetected detected another cause
Death from
ovarian cancer
FIGURE 18.6. Influence diagram for models of the natural history of ovarian cancer. Arrows represent allowed transitions between health states.
Diamonds represent terminal states.
Source: Reprinted with permission from Havrilesky LJ, Sanders GD, Kulasingam S, et al. Development of an ovarian cancer screening decision model that incorporates disease heterogeneity:
implications for potential mortality reduction. Cancer. 2011;117(3):545553. (36)
(or cohorts) of women who are assumed to enter the model Validation Model validation (confirming that a calibrated
at a given age and then followed until death or a later age model predicts results that are consistent with observed results
(i.e.,100years). from screening trials) can be achieved in a number of ways. The
most robust method is to compare model-predicted outcomes
Calibration An important step in developing a model is obtain- with actual outcomes. For example, Havrilesky et al. constructed
ing probabilities or estimates for key variables (referred to as a natural history model accounting for the observed heterogene-
parameters) from the literature. However, often there are few ity of epithelial ovarian cancers. Validation was performed by
available estimates, estimates of varying degrees of quality, or simulating the published prevalence phase of the UK Collabora-
even no existing estimates for a given model parameter. The tive Trial of Ovarian Cancer Screening (UKCTOCS) by entering
selection of a given clinical estimate is important since this the age and prevalence of disease from the trial population as
affects the credibility of the models aggregate result. Calibra- well as the reported sensitivity and specificity of the trials mul-
tion is a process that involves comparing the model-predicted timodality screening algorithm. The model predicted the stage
results to observed data to ensure a reasonably good fit of one distribution of cancers detected by screening and the positive
to the other. Model calibration involves several steps: (a) identi- predictive value of the multimodality prevalence screen within
fication of calibration endpoints (for cancer this usually means their reported 95% confidence intervals (36). To the degree that
age-specific cancer incidence, but can also include stage distri- simulated results do not reproduce those observed in a clinical
bution and age-specific mortality curve); (b) establishment of trial, the question arises whether there are key input parameters
criteria for determining how well the model-predicted data fit or model structural differences that affect the conclusions. A
the observed data. This may be visual inspection or use of a model can then be revised to determine whether the prediction
statistical goodness of fit test; (c) adjustment of the set of model is improved in an iterative process. Usually, the initial decision
input parameters (i.e., probabilities); and (d) comparison of to conduct a modeling study is based on the fact that there are
model-predicted outcomes to observed outcomes using the pre- no observed data that exist to answer a given question. In this
specified criteria and repeating steps 3 and 4 until a satisfactory case, model validation is achieved by comparing the results from
calibration is achieved (37). models built by different, independent groups, to evaluate for
Figures 18.7 and 18.8 show the calibration results for 2 mod- similarity. This approach has been adopted by Cancer Interven-
els (ovarian and cervical) that used visual inspection to achieve tion and Surveillance Modeling Network (CISNET). CISNET
calibration (36,38). Another calibration method uses goodness is a consortium of National Cancer Institute (NCI)-sponsored
of fit statistics and then selects parameter sets that best fit the investigators that uses statistical modeling to study cancer con-
observed cancer incidence curve. This latter method improves trol interventions in prevention, screening, and treatment and
upon visual inspection in a few ways: (a) the calibration goal their effects on population trends in incidence and mortality. The
is formally stated, which can aide with reproducibility and models in this consortium were independently developed and
(b)instead of one good fitting set, multiple sets are used, which have been calibrated to US data. The U.S. Preventive Services
can account for parameter uncertainty (39). Task Force has used the results from modeling studies conducted
510 CHAPTER 18 COM PAR ATIVE EFFECTIVEN ESS RESEARCH I N GYN ECOLOGIC ONCOLOGY
0.016
0.01
0.008
0.006
0.004
0.002
0
20 30 40 50 60 70 80 90 100
Age (years)
FIGURE 18.7. Calibration of ovarian cancer natural history model on the age-related incidence of ovarian cancer
in the US. Blue line represents model output; red dots represent SEER data.
Source: Reprinted with permission from Havrilesky LJ, Sanders GD, Kulasingam S, et al. Development of an ovarian cancer screening decision model that
incorporates disease heterogeneity: implications for potential mortality reduction. Cancer. 2011;117(3):545553. (36)
30
25
Cancer Incidence (per 100,000)
20
FPO
15
10
0
19 24 29 34 39 44 49 54 59 64
Age (years)
FIGURE 18.8. Calibration of a model of the natural history of cervical cancer on the age-related incidence of
cervical cancer in Canada.
Source: Reprinted with permission from Kulasingam SL, Rajan R, St Pierre Y, et al. Human papillomavirus testing with Pap triage for cervical cancer prevention
in Canada: a cost-effectiveness analysis. BMC Med. 2009;7:69. (38)
by this group to inform their recommendations for colorectal Other important outcomes include cancer incidence, stage distri-
and breast cancer (40,41). bution, and mortality. If the cohort of women is modeled over a
sufficiently long period of time, the model can be used to calculate
life expectancy, lifetime costs, and quality-adjusted life expectancy.
Simulation of Screening
The impact of screening, diagnosis, and treatment can be tracked
using a Markov model. Markov models can be programmed Cervical Cancer
to keep count of the outcomes associated with diagnosis, treat- For cervical cancer, modeling has played a particularly prominent
ment, and screening. Examples include the average number of role in informing decisions regarding which screening and triage
false-positive or false-negative screening test results, the number tests to adopt, how frequently women should be screened, and
of diagnostic procedures such as colposcopy or laparoscopy per- whether the addition of vaccination to screening is cost-effective.
formed, number of preinvasive lesions detected, and treatments. This prominent role is due to the fact that trials of new screening
CHAPTER 18 COM PAR ATIVE EFFECTIVEN ESS RESEARCH I N GYN ECOLOGIC ONCOLOGY 511
tests include follow-up and treatment that often differ from clini- In terms of the age to begin and end screening, these have for the
cal practice, or are conducted in non-US populations with different most part been based on epidemiologic data showing that cancer
screening histories. Modeling studies can also be used to project incidence peaks in the late 30s to mid-40s, but that the incidence
both short- and long-term results from trials. For example, trials of CIN peaks in the 20s. Given this, guidelines have usually called
for the HPV vaccines used cervical intraepithelial neoplasia (CIN) for screening in the late teens and early 20s, although there has
grade 2 or higher as primary outcomes. However, cancer incidence been a shift toward a recommendation to begin screening in the
and death are more important outcomes for policy makers. Mod- 20s in more recent years (59,60). Canfell et al. modeled the impact
eling has been used to estimate the potential cost-effectiveness of of changing the UK screening guidelines to begin at 25 years of
adding vaccination to screening. More recently, modeling has been age, instead of 21 years (61). They found that if the age to start
used to justify the expanded coverage of HPV vaccines to include screening was delayed until 25, the lifetime risk of cancer would
boys. The following sections describe how natural history models be minimally affected (cumulative lifetime incidence decreasing
of HPV and cervical cancer are constructed, and how such models from 0.63% to 0.61%) due to the low incidence of cancer in
have been used to inform policies regarding screening and vacci- young women (61). More recently, Kulasingam et al. modeled
nation for cervical cancer prevention. the impact of varying the age to begin screening in 1-year incre-
ments from age 15 years to age 25 years on cancer incidence and
Natural history of cervical cancer Natural history models mortality (62). They showed that screening in the teens was asso-
have primarily used the CIN nomenclature to characterize pro- ciated with a high number of additional diagnostic procedures
gression from HPV infection through preinvasive disease to and small reductions in lifetime risk of cancer compared to delay-
Of the different HPV and cytology strategies that have been still unknown. These include, but are not limited to, the per-
compared for cost-effectiveness, one strategy in particular formance of cytology and HPV tests such as hybrid capture 2
shows promise across a range of analyses and settings. HPV that are not type-specific, whether predicted reductions in CIN
DNA testing followed by triage based on cytology for women and cancer are achieved, and whether vaccination will affect
with positive HPV results has been identified as a potentially screening behavior, in particular, screening participation. Under
cost-effective strategy compared to both cytology alone and the assumption that vaccines will markedly reduce cancer
the co-testing strategies (66,67). This strategy, which uses a incidence and mortality, potentially cost-effective approaches
sensitive test first (HPV), followed by a specific test (cytology), to screening vaccinated cohorts of women include strategies
allows one to maximize detection of high-grade disease, while that use a less frequent screening interval, delayed age of first
potentially minimizing false-positives, thereby reducing the screening, and/or use of a strategy based on HPV DNA testing
costs of screening. Results from ongoing trials, such as the followed by cytology (66,75). Preliminary modeling to exam-
HPV-FOCAL trial in Canada, which has recently reported pre- ine the impact of cross-protection and broad spectrum vaccines
liminary validation of this strategy, will be needed to confirm (such as the Merck octavalent vaccine that is currently in early
whether the modeling predictions are correct (68). trials) suggests that far fewer screens than are currently rec-
ommended will be needed to achieve significant reductions in
Quantifying the impact of HPV vaccination Two types of cervical cancer (76).
models have been used to explore HPV vaccine effectiveness: Modeling has been used extensively in cervical cancer to
Markov state transition cohort models (described above) and inform how we should approach screening and add HPV vac-
dynamic transmission models, with a third category hybrid cination programs to screening programs. Given the develop-
models that use a combination of the two (69). Dynamic models ment of new tests for cervical cancer and new vaccines that
track population changes over time by taking into account births cover more HPV types than the first generation of HPV vac-
as well as deaths. Importantly, dynamic transmission models also cines, modeling will continue to play a key role in determining
explain how infection with HPV depends on patterns of sexual the most effective and cost-effective strategies for prevention of
behavior and the distribution of infection in the population (70). cervical cancer.
As such, a strength of dynamic models is that they can be used
to determine herd immunity, explore the relative value of vacci-
nating boys in addition to girls, and explore how sexual mixing
patterns (how men and women form partnerships and how these Ovarian Cancer
affect transmission) affect the age at which vaccination should Because the majority of ovarian cancers are diagnosed at an
begin and age(s) for catch-up programs (i.e., vaccination offered advanced stage, there has been considerable interest in designing
to girls and/or women who are not part of the optimal age group screening strategies to diagnose and treat women earlier, in the
but who may still derive a benefit). These indirect effects are not hopes of improving survival outcomes. While screening for breast
captured by Markov models; as a result, Markov models may and colon cancer has been proven to reduce mortality, no screen-
underestimate the effect of vaccination. Hybrid models use both ing test for ovarian cancer has yet been proven effective. Several
approaches generating HPV incidence under different vaccina- key parameters may impact the success of any cancer screening
tion scenarios from a dynamic model, which is then used as an program: (a) availability of effective treatment for screen positive
input to the Markov model. A recent modeling study conducted individuals; (b) sufficiently high disease prevalence; (c) existence
using multiple, independently developed HPV and cervical can- of an effective screening test; and (d) acceptable cost or cost-
cer models concluded that vaccination of girls prior to the age of effectiveness of the screening program. Each of these parameters
sexual debut has the potential to considerably reduce the burden is addressed below in the context of development of a screening
of CIN and cervical cancer (71). This is especially true if a long test for epithelial ovarian cancer.
duration of vaccine efficacy and high vaccine coverage are mod-
eled. Vaccine price has also consistently been shown to impact the Effectiveness of treatment Pathologic and genetic data now
cost-effectiveness of adding vaccination to screening or adding suggest that epithelial ovarian cancer is a heterogeneous disease,
HPV vaccines to existing vaccine programs. Indeed, if HPV vac- with a number of different precursor lesions. Many high-grade
cines are priced below certain thresholds for different countries, serous ovarian cancers likely originate in the fallopian tubes,
HPV vaccination could potentially be cost-saving compared to while some clear cell and endometrioid lesions may originate in
not screening (72). Of note, across a range of analyses, vaccina- endometriosis. Because there is no universal, clearly defined pre-
tion of girls only prior to onset of sexual activity, as opposed cursor lesion for all epithelial ovarian cancer, the target lesion for
to vaccination of boys and girls plus catch-up vaccination, has the screening tests that are currently in Phase III trials is stage I
been shown to have the most attractive cost-effectiveness profile. disease. Targeting early-stage disease is appropriate because
However, under conditions of low coverage, as has occurred in survival from epithelial ovarian cancer diagnosed at stage I is
the US, extending vaccination to boys is potentially cost-effective encouraging. Women with stage I disease with low-risk features
(73). On the basis of these results, and survey data showing low may be cured without the need for adjuvant treatment, while
uptake of the HPV vaccines in the U.S., the Centers for Disease those with higher risk stage I disease may still achieve excellent
Control and Prevention Advisory Committee on Immunization outcomes following 3 to 6 cycles of platinum-and taxane-based
Practices decided to extend HPV vaccine recommendations to chemotherapy (77).
include boys in addition to girls (http://www.immunize.org/acip/
acipvax_hpv.asp). In terms of which vaccine to use (bivalent or Disease prevalence Perhaps the biggest challenge to the
quadrivalent), modeling from the UK suggests that the bivalent development of a successful ovarian cancer screening program
vaccine (which is targeted at 2 carcinogenic HPV types, 16 and is the low prevalence of this disease. The lifetime incidence of
18) would need to be less costly than the quadrivalent vaccine ovarian cancer in the U.S. is approximately 1.4%. In postmeno-
(which protects against the same HPV types, 16 and 18, as well pausal women, the most likely target population for a screen-
as 2 types associated with >90% of genital warts) to be equally ing program, its prevalence is approximately 40 per 100,000
cost-effective (66,74). women. Disease prevalence has a direct impact on the achiev-
able positive predictive value of a screening test, which defines
Screening in the era of HPV vaccines The issue of whether the number of diagnostic procedures or surgeries that would be
and how screening should change in the era of HPV vaccines required to diagnose one case of ovarian cancer. Expert opinion
is complex and will depend on a number of factors that are suggests that the minimal acceptable positive predictive value
CHAPTER 18 COM PAR ATIVE EFFECTIVEN ESS RESEARCH I N GYN ECOLOGIC ONCOLOGY 513
for an ovarian cancer screening test should be 10%. To achieve of screening more frequently, increasing the frequency actually
this value in the postmenopausal population, a screening test reduced cost-effectiveness. Both models reinforced the impor-
needs to have a specificity exceeding 99.6%. tant link between specificity and positive predictive value. An
annual screening test with a sensitivity of 85% and specificity
Effectiveness of screening test To date, no screening of less than 99% would have a positive predictive value not
test for ovarian cancer has been proven effective in reducing exceeding 4%. However, at a specificity of 99.9%, the positive
mortality from this disease. Two large randomized trials have predictive value for annual screening was excellent at 22%.
recently been performed to evaluate screening strategies utiliz- Annual screening of a population of women aged 50 to 85 years
ing the CA-125 serum test and transvaginal ultrasound. The at average risk of ovarian cancer with a test at 85% sensitiv-
Prostate, Lung, Colorectal, and Ovarian (PLCO) screening ity and 95% specificity was predicted to improve life expec-
trial randomized 78,216 women to either usual care or a com- tancy 2.92 days on average, with an ICER of $73,469/YLS
bination of annual CA-125 for 6 consecutive years and annual compared to no screening. However, simulated screening of a
transvaginal ultrasound for 4 consecutive years (78). Follow- high-risk population of women aged 50 to 85 years with a
up of test results was determined by each subjects primary relative risk of developing ovarian cancer of 2 resulted in an
physician. After a median follow-up of 12.4 years, there was no improvement in the ICER to $36,025/YLS when compared to
difference in stage distribution at diagnosis of ovarian cancer no screening. In sensitivity analysis, key factors in achieving a
(77%78% stage IIIIV) and no difference in ovarian cancer cost-effective screening test (defined as an ICER of less than
mortality between the screened and unscreened groups. How- $50,000/YLS) were an inexpensive test, a very high test specific-
Comparative effectiveness of screening Several groups Primary prevention in high-risk women Women who
have used mathematical modeling to determine the likely success are carriers of genetic mutations in BRCA1 or BRCA2 are at
and cost-effectiveness of screening strategies. Skates and Singer markedly increased risk for ovarian cancer; the average risk
designed the first reported stochastic simulation model of the of developing ovarian cancer by age 70 is 39% (95% confi-
natural history of ovarian cancer. This model, which assumed dence interval [CI], 18%54%) for BRCA1 mutation carriers
orderly progression from stage I to stage IV and estimated the and 11% (CI, 2.4% 19%) for BRCA2 mutation carriers (84).
mean time spent in stage I at 9 months based on the expert Likewise, women with Lynch syndrome-associated MLH1 and
opinion of gynecologic oncologists, suggested that screening MSH2 mutations have up to 20% (CI, 1%65%) and 24%
using CA-125 could potentially save 3.4 years of life per case (CI, 3%52%) risk, respectively, of developing ovarian can-
of cancer detected (81). Urban et al. subsequently modified the cer by the same age (85). Although the prevalence of genetic
Skates and Singer model and performed a cost-effectiveness mutations predisposing women to ovarian cancer in the general
assessment of several screening strategies. The authors reported population is low, the high risk of cancer among women who
that multimodality screening with CA-125 followed by trans- are mutation carriers underscores the importance of modifying
vaginal ultrasound only if CA-125 was positive or doubling was their likelihood of developing cancer.
potentially cost-effective compared to single test strategies and The choice of a risk-reduction strategy for women at elevated
no screening (82). risk is an individual one and commonly includes screening strate-
More recent screening models have incorporated new data gies and prophylactic surgery. Unfortunately, screening high-risk
about the pathophysiology and progression of ovarian cancer. women with available modalities has not yet proven successful
Havrilesky et al. constructed a natural history model that, based (8688). In a BRCA1/2 mutationcarrying population, bilateral
on the physical proximity of the ovaries to upper abdominal salpingo-oophorectomy (BSO) has been demonstrated to reduce
organs such as small bowel and omentum, allowed progression of the risk of ovarian, tubal, or peritoneal cancers by 80% and the
stage I cancers either to stage II or directly to stage III (83). Dis- risk of breast cancer by 50% (89). In addition, several groups
ease incidence, mortality, and stage distribution were calibrated have designed health-economic decision models demonstrating
to reflect Surveillance Epidemiology and End Results (SEER) that prophylactic surgery is both effective and cost-effective in
data. A modified version of this model was designed to account women at high genetic risk for ovarian cancer (9093). How-
for the heterogeneity of ovarian cancer by modeling aggres- ever, surgical prophylaxis performed prior to menopause is
sive and indolent phenotypes with different rates of progres- accompanied both by potential harm and the certain premature
sion (36). These models highlighted factors that are important loss of ovarian function and is not generally recommended in
to the success of a screening program. For example, increasing the general population (94,95). Despite the effectiveness of pro-
the frequency of screening had a more favorable impact on phylactic BSO, some women at high risk prefer alternatives that
reducing cancer mortality than increasing the sensitivity of the are less invasive, do not result in early menopause, and preserve
individual screening test. However, due to the increased cost fertility. The GOG is currently completing a nonrandomized
514 CHAPTER 18 COM PAR ATIVE EFFECTIVEN ESS RESEARCH I N GYN ECOLOGIC ONCOLOGY
prospective trial comparing longitudinal screening with CA-125 concluded that it may not be possible to adopt this therapy as
and ultrasound to risk-reducing BSO in a high genetic risk pop- first-line for all advanced-stage ovarian cancer patients because
ulation (96). This trial includes both subsequent cancer diag- it would cost the province of Ontario an additional CaD
noses and quality-of-life assessments, and may be informative $9 million a year. Berger et al. investigated the cost-effectiveness
from a comparative effectiveness standpoint. of cisplatin plus paclitaxel from the perspective of various
European countries national health services. The incremental
costs of cisplatin plus paclitaxel per life-year saved were evalu-
ated for Germany (US $9,362), Spain (US $6,395), France (US
COM PAR ATIVE EFFECTIVEN ESS OF $6,642), Italy (US $11,420), the Netherlands (US $7,796), and
TH ER APEUTICS I N GYN ECOLOGIC the UK (US $6,403) (110).
CANCERS Carboplatin and paclitaxel are now both marketed as gener-
ics, and therefore these prior studies are less applicable than
The comparative effectiveness literature regarding therapeutic when originally published. Given the current low cost of pacli-
interventions for gynecologic malignancies is reviewed in the taxel, any clinically superior regimen using this drug is also
next section. likely to be found cost-effective. Chan et al. have recently per-
formed an economic analysis based on results of a Phase III Jap-
anese GOG trial (100), demonstrating that weekly dose-dense
paclitaxel is cost-effective compared to a 3-week regimen in the
Ovarian Cancer setting of primary treatment (111).
Chemotherapy for newly diagnosed ovarian cancer The
standard treatment for ovarian cancer is primary surgical stag- Intraperitoneal chemotherapy The NCCN Guidelines for
ing with maximum possible cytoreduction followed by chemo- ovarian cancer recommend intraperitoneal (IP) chemotherapy
therapy. Intravenous chemotherapy usually consists of a taxane as primary/adjuvant therapy for optimally debulked (<1cm)
and a platinum agent for 3 to 6 cycles; patients with advanced stage II or greater ovarian cancer treatment (112). Three Phase III
intraperitoneal disease are often candidates for intraperitoneal clinical trials have identified advantages to the use of IP che-
chemotherapy (97). The addition of bevacizumab to primary motherapy for adjuvant treatment of stage III ovarian cancer
chemotherapy followed by consolidation bevacizumab has been (97,113,114). The most recent of these studies demonstrated
found to provide a short-term additional benefit in Phase III tri- an overall survival advantage of 16 months in the IP arm at
als (98,99). Likewise, dose-dense paclitaxel was associated with the expense of increased risk of adverse events and a significant
clinical benefit in one Phase III trial and is now under investiga- reduction in quality of life.
tion by the GOG (100). As novel chemotherapy regimens for Two analyses have evaluated the cost-effectiveness of IP che-
primary treatment emerge, some consideration should be given motherapy for the primary treatment of stage III ovarian cancer.
not only to the number of months of survival benefit, but to the When comparing IP to intravenous (IV) chemotherapy, Bristow
costs and effects on quality of life of each. etal. reported that IP chemotherapy was potentially cost-effective
compared to IV, with an ICER of $37,454 per QALY (115).
Introduction of taxanes The first cost-effectiveness studies Havrilesky et al. reported an estimate of $180,022 per QALY
in ovarian cancer chemotherapy were performed in response when using a 7-year time horizon, which was consistent with the
to the introduction of taxanes into the frontline chemotherapy current duration of survival results from GOG 172 (116). How-
regimen for this disease. Two independent RCTs, conducted by ever, when the time horizon was extended to a lifetime under the
the GOG 111 and a European-Canadian Intergroup (OV-10), assumption that any survival advantage realized with IP chemo
demonstrated that cisplatin plus paclitaxel as primary che- would persist over that period, the ICER of IP chemotherapy
motherapy is superior to previous therapy of cisplatin plus dropped to $32,053 per QALY. Also of note, under the assump-
cyclophosphamide in clinical response rate, progression-free tion that IP chemotherapy is equally effective as an outpatient
survival, and overall survival (101103). Three Phase III RCTs regimen, the ICER of IP compared to IV chemotherapy becomes
subsequently proved similar efficacy of paclitaxel in combi- even more attractive. While both studies informally incorporated
nation with either carboplatin or cisplatin for the adjuvant quality of life based on the FACT surveys administered to patients
treatment of ovarian cancer (104106). The carboplatin com- enrolled on GOG trials of chemotherapy, neither performed a
bination was better tolerated and has subsequently become a validated utility assessment. Conclusions that may be drawn from
standard first-line treatment (107). these studies are that IP chemotherapy is potentially cost-effective
When first introduced, paclitaxel-cisplatin was a more for women with stage III disease, but that more formal incorpora-
expensive therapy than the old standard of cyclophosphamide- tion of quality of life, longer term follow-up of the results of the
cisplatin. A number of cost-effectiveness investigations were per- last Phase III study, and investigation of less costly outpatient IP
formed using data from GOG 111, which compared cisplatin regimens would strengthen this conclusion (115,116).
plus paclitaxel to cisplatin plus cyclophosphamide. From the per-
spective of a US oncology practice, the total drug costs for cisplatin Bevacizumab Bevacizumab is an anti-vascular endothelial
plus paclitaxel were 4 times higher than those for cisplatin plus growth factor (VEGF) inhibitor of angiogenesis and is FDA-
cyclophosphamide (US $9,918 vs. US $2,527; year of costing not approved for treatments of renal cell carcinoma, colorectal can-
specified) (108). Compared with cisplatin plus cyclophospha- cer, glioblastoma, and non-small cell lung cancer. The ICON7
mide, the incremental costs per year of life gained for cisplatin and GOG 218 Phase III clinical trials of newly diagnosed ovar-
plus paclitaxel therapy were US $19,820 for inpatient treatment ian cancer independently reported a small 2- to 6-month PFS
and US $21,222 for outpatient treatment. These incremental advantage to the addition of bevacizumab to primary combi-
costs fall well within the generally accepted cost-effective range nation carboplatin/paclitaxel, followed by 14 to 22 additional
for new therapies. cycles of consolidation bevacizumab in the absence of progres-
Several cost-effectiveness analyses examined the addition of sion (98,99). Even prior to the initial presentation of this data in
paclitaxel to first-line therapy from the perspective of health sys- ovarian cancer, questions were raised about the cost of universal
tems outside the US. From a Canadian health system perspec- bevacizumab. Cohn et al. performed a cost-effectiveness analy-
tive, cisplatin plus paclitaxel had an ICER of CaD $32,213 (1993 sis examining the likely clinical benefit of bevacizumab and the
costs for drug and hospital costs) per life-year gained compared cost of the drug as well as its associated adverse events. This
to cyclophosphamide-cisplatin (109). The investigators originally analysis demonstrated that there was no reasonable scenario
CHAPTER 18 COM PAR ATIVE EFFECTIVEN ESS RESEARCH I N GYN ECOLOGIC ONCOLOGY 515
under which bevacizumab could be considered cost-effective by Recurrent ovarian cancer that occurs within 6 months of
existing measures (117). completing a first-line chemotherapy regimen has a poor prog-
A subset analysis of the ICON7 data revealed that the main nosis, with cure being very unlikely. Rocconi et al. performed
benefit appears to be confined to women with high-risk disease a cost-effectiveness analysis of treatment options for recurrent
such as those suboptimally cytoreduced and those with stage IV platinum-resistant ovarian cancer and concluded that only best
disease (99). While, ideally, treatment of a smaller subset of supportive care (no chemotherapy) was clearly cost-effective,
women with ovarian cancer who are most likely to benefit would while second-line monotherapy was possibly marginally cost-
make this drug more cost-effective, initial attempts at model- effective (ICER $64,104/YLS) as well (126). Even without incor-
ing this scenario did not demonstrate this to be a cost-effective poration of toxicity rates and costs, the authors found that
alternative (118). combination chemotherapy regimens were never cost-effective
for platinum-resistant disease due to unfavorable ICERs.
Consolidation therapy Consolidation regimens that have
been studied for ovarian cancer are paclitaxel and bevacizumab;
both have proven PFS benefits but neither has demonstrated
an overall survival benefit. Lesnock et al. performed a cost- Cervical Cancer
effectiveness analysis of consolidation therapy following carbo- Primary treatment The standard treatment of cervical
platin/paclitaxel, comparing 12 months additional paclitaxel to cancer has been established for very early-stage and locally
17 cycles of additional bevacizumab. Clinical data were derived advanced-stage disease. However, there is continued debate over
rate (recurrence or death) is low. The result of these characteris- of the world. This group also performed a meta-analysis of
tics is that any intervention must be extremely powerful to dem- 12 trials of laparoscopic endometrial cancer surgery and reached
onstrate a statistically significant improvement in cancer specific the conclusion that laparoscopy was cost-effective compared to
outcomes. As such, randomized clinical trials for cases that are laparotomy (10), acknowledging that the lack of quality-of-life
at low- or intermediate-risk for recurrence may take a long time data precluded a definitive statement regarding the utility of this
to accrue and demonstration of significance may be challenging. procedure from a societal perspective.
The CER approaches, therefore, may be quite relevant in endo-
Laparoscopy versus robotic surgery. In 2006, the FDA cleared
metrial cancer. CER in endometrial cancer spans the aspects of
the first computer-aided (robotic) surgical system for hyster-
surgical management, the use of adjuvant radiation and chemo-
ectomy. There has subsequently been a rapid incorporation of
therapy, surveillance for disease recurrence, and the evaluation
robotic surgery into gynecologic cancer practices, mainly for
and management of individuals at risk for or diagnosed with
the treatment of endometrial cancer. Initial reports of this surgi-
Lynch syndrome-associated cancers.
cal approach demonstrated feasibility and acceptable toxicity.
However, the initial purchase price of the robot (>$1 million),
Perioperative Setting yearly maintenance contract (>$100,000 annually), and limited
use disposable instruments add a fixed cost to this procedure
CER techniques have been most commonly utilized in the evalu-
over laparoscopy or laparotomy. Given the expense of robotic
ation of surgical management of endometrial cancer, and most
surgery, analyses of the cost of robotic surgery have been pub-
commonly are related to the cost-effectiveness of various inter-
lished, often with differing conclusions. Initially, Bell et al.
lymph node metastasis, routine lymphadenectomy was more have begun utilizing immunohistochemistry (IHC) for the DNA
cost-effective than a strategy wherein lymphadenectomy is mismatch repair genes as an initial screen for Lynch syndrome.
performed selectively, assuming a lower rate of adjuvant radia- Health economic studies of this strategy have demonstrated
tion in the staged patients (144). Importantly, these authors did that utilizing IHC in patients with a first-degree relative with
not include an analysis of complications or quality of life in a Lynch-associated cancer is cost-effective (152). Other inves-
their models. Another approach to address the role of surgical tigators, while acknowledging that clinical judgment is key to
staging would be to develop a test that could predict, prior to the interpretation of their model, have shown that the routine
surgery, which patients are at highest risk for the presence of use of IHC, with a subsequent triage to genetic testing if IHC is
lymph node metastasis. Havrilesky et al. modeled such a hypo- abnormal, is potentially cost-effective when compared to other
thetical test and determined that a test that could reliably pre- screening strategies (153).
dict lymph node metastasis could be cost-effective as long as it Additionally, the cost-effectiveness of strategies to prevent
was fairly inexpensive (145). Importantly, the cost-effectiveness the disease in probands with known Lynch syndrome has been
of such a strategy is independent of the cost of adjuvant therapy evaluated. Kwon et al. demonstrated that in this population,
in their model. annual surveillance with endometrial biopsy, pelvic ultrasound,
and CA-125 at 30 years plus risk-reducing hysterectomy and
Adjuvant radiation therapy. A number of studies have been per- oophorectomy at 40 years is the most effective strategy, though
formed analyzing the comparative cost and cost-effectiveness substantially more expensive than preventative surgery alone or
of adjuvant radiation in patients with endometrial cancer. screening alone, with an additional $194,000 spent per increase
Lachance et al. reported a model that included patients with in year of survival compared to the next best strategy (93). The
stage I endometrial cancer, and evaluated strategies of obser- cost-effectiveness of risk-reducing surgery has also been con-
vation, vaginal brachytherapy, and pelvic teletherapy (146). firmed by Yang et al., who demonstrated that this intervention
The authors estimated that vaginal brachytherapy would sig- is more cost-effective than either yearly examination or yearly
nificantly reduce recurrences at an expense of almost $66,000 invasive screening for malignancy (154).
per survivor. While teletherapy could reduce recurrences as well,
its use was associated with greater expense without an increase
in survival beyond that of vaginal brachytherapy. In another
study in patients with early-stage disease at intermediate risk Summary
for recurrence, Rankins et al. created a decision model demon- Gynecologic oncology provides a rich opportunity to investigate
strating that the cost-effectiveness of adjuvant pelvic teletherapy the comparative effectiveness of various diagnostic, therapeu-
was dependent on the risk of recurrence and the efficacy of tic, screening, and preventative strategies. While the field is still
adjuvant therapy; in the population enriched for a high risk for relatively young, substantial knowledge about these strategies
recurrence, radiation was cost-effective (147). These data sug- has been gained through CER techniques and modeling. Con-
gest that routine adjuvant radiation for early-stage endometrial tinued investigation with refinement of CER tools for the inves-
cancer is not cost-effective. However, in patients at a high risk tigation of gynecologic cancer is needed to advance the state of
for recurrence, this balance shifts, with adjuvant therapy becom- knowledge.
ing adequately cost-effective to recommend its use. Again, these
studies are plagued by their lack of information on quality of
life, specifically given the increasing data suggesting a deterio-
ration of the quality of life domains of sexuality, urinary, and
KEY POI NTS
intestinal functions in patients receiving certain forms of radia-
tion for endometrial cancer (148). 1. Comparative effectiveness research (CER) provides
the framework for studies that compare the potential
Surveillance for endometrial cancer recurrence. Given that the harms and benefits of strategies to prevent, diagnose,
survival of women with endometrial cancer is approximately or treat gynecologic malignancy.
85% overall, investigators have challenged the notion that rou- 2. Health economic studies, including cost-effectiveness
tine intermittent surveillance for pelvic examination and vaginal and cost-utility analyses, are a subset of CER in which
cytology (with or without chest imaging) is cost-effective or medical interventions are compared on the basis of
even necessary for most women with endometrial cancer. In sup- their relative costs, as well as their potential harms
port of the trend toward decreased intensity of surveillance, it and benefits.
has been estimated that the cost of routine vaginal cytology to 3. A key factor in the development of a cost-utility model
identify a single asymptomatic recurrence is more than $44,000 is the incorporation of quality of life, which requires a
(149). Whether the identification of this asymptomatic individ- preference-based utility. The utility may be derived using
ual leads to improved outcomes is even less certain (150). a variety of quality-of-life-related instruments. Use of
the utility allows the results of a model to be expressed
Lynch syndrome. From clinic-based studies, it is estimated that in QALYs, which is a standard effectiveness outcome.
2.3% of patients with endometrial cancer have Lynch syndrome 4. The results of health economic decision models are
as the cause of their disease (151). Given the relatively low highly dependent on their perspective and the assump-
prevalence of the disease, the ability to distinguish these patients tions made in their construction.
from all those with sporadic disease would be enormously ben- 5. Uncertainty in health economic models is best described
eficial, as the probands and their families could be introduced using multiple sensitivity analyses.
to prevention and screening interventions that might decrease 6. There is a growing body of CER evidence to guide
the risk of dying from Lynch-related malignancies. However, the clinical and resource allocation decisions in gynecologic
clinical Amsterdam criteria are relatively insensitive and non- oncology.
specific in identifying Lynch syndrome. Thus, many institutions
CHAPTER 18 COM PAR ATIVE EFFECTIVEN ESS RESEARCH I N GYN ECOLOGIC ONCOLOGY 519
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19
CHAPTER
Vulva
David H. Moore, Wui-Jin Koh, and William P. McGuire contributed to prior edi-
tions of this chapter
523
524 CHAPTER 19 VU LVA
by the fusion of the labia minora (prepuce and frenulum) and be identified only by the use of various lymphatic mapping tech-
is approximately 2 to 3 cm anterior to the urethral meatus. It is niques. The SLN is frequently found medial to the femoral vein
composed of erectile tissue organized into the glans, body, and just above the adductor muscle. Second echelon lymph nodes
two crura. Two loosely fused corpora cavernosa form the body may be in the groin or pelvis. Cloquets node, or the most supe-
of the clitoris and extend superiorly from the glans, ultimately rior inguinal lymph node, is located under the inguinal ligament.
dividing into the two crura. The crura course laterally beneath Lymphatic drainage from the SLN is sequentially to the external
the ischiocavernosus muscles and attach to the ischial rami. iliac, common iliac, and aortic lymph nodes (Fig. 19.1AC).
The vaginal vestibule is situated in the center of the vulva and The fossa ovalis is a crescent-shaped terminus of the fascia
is homologous to the male distal urethra. It has squamous muco- lata and the site where vascular and lymphatic structures meet
sal epithelium that is demarcated bilaterally and posteriorly by with the femoral vessels. The cribriform fascia is a term widely
the junction with the keratinized epithelium at Harts line, located used in the literature describing the anatomy of the groin and
on the medial labia minora and inferiorly on the perineal body. is said to cover the fossa ovalis. The cribriform fascia is hard to
The vagina, urethra, periurethral glands, minor vestibular glands, identify and is more of a lamina than an actual fascia. SLN
and the Bartholins glands open onto the vestibule. Anteriorly, the biopsy with lymphatic mapping deemphasizes the need to iden-
minor small vestibular glands are located beneath the vestibular tify the cribriform structure and focuses the surgeons attention
mucosa and open onto its surface predominantly on the more on functional in vivo surgical anatomy rather than textbook de-
anterior vestibule. The vestibular bulbs, a loose collection of bi- scriptions of lymph node locations.
lateral erectile tissue covered superficially by the bulbocavernosus
muscle, are located laterally. The Bartholins glands, two small,
mucus-secreting glands situated within the subcutaneous tissue of
the posterior labia majora, have ducts opening onto the postero- EPI DEM IOLOGY
lateral portion of the vestibule. The perineal body is a 3 to 4 cm
band of skin and subcutaneous tissue located between the poste- An estimated 4,490 women were diagnosed with vulvar can-
rior extensions of the labia majora. It separates the vaginal vesti- cer in the United States in 2012, and approximately 950 will
bule from the anus and forms the posterior margin of the vulva. die of the disease (1). Vulvar squamous cell carcinoma accounts
for approximately 3% to 5% of all gynecologic malignancies
and 1% of all carcinomas in women, with an incidence rate of
Vascular Anatomy 1 to 2 per 100,000 women (1). Most vulvar cancers occur in
postmenopausal women in the seventh decade, although more
and Neurologic Innervation recent reports have identified a trend toward younger age at
The vulva has a rich blood supply derived primarily from the diagnosis (5,6). Earlier observational studies suggested associa-
internal pudendal artery, which arises from the anterior division tions between hypertension, diabetes mellitus, and obesity and
of the internal iliac (hypogastric) artery, and the superficial and vulvar carcinoma; however, subsequent analyses have not con-
deep external pudendal arteries, which arise from the femoral firmed the prognostic significance of these diagnoses (7).
artery. The internal pudendal artery exits the pelvis and passes Several infectious agents have been proposed as possible
behind the ischial spine to reach the posterolateral vulva, where etiologic agents in vulvar carcinoma, including granulomatous
it divides into several small branches to the ischiocavernosus infections, herpes simplex virus, and, most notably, human pap-
and bulbocavernosus muscles, the perineal artery, artery of the illomavirus (HPV). HPV infection is present in virtually 100%
bulb, urethral artery, and dorsal and deep arteries of the clito- of women with cervical cancer. The relationship between HPV
ris. Both external pudendal arteries travel medially to supply infection and vulvar cancer is much less straightforward. This is
the labia majora and their deep structures. These vessels anas- likely due to the different etiologic pathways that are believed
tomose freely with branches from the internal pudendal artery. to be responsible for vulvar cancer. These different etiologic
Innervation of the vulva is derived from multiple sources and pathways are discussed in detail in the chapter on preinvasive
spinal cord levels. The mons pubis and upper labia majora are disease; however, because of subject matter overlap, some of the
innervated by the ilioinguinal nerve (L1) and the genital branch data related to HPV and invasive squamous cell carcinoma of
of the genitofemoral nerve (L12). Either of these nerves may the vulva are discussed here.
be easily injured during pelvic lymph node dissection, with re- Vulvar condylomas have a well-described relationship to HPV,
sulting paresthesias. The pudendal nerve (S24) enters the vulva and strong associations between vulvar condylomas and the later
in parallel with the internal pudendal artery and gives rise to development of vulvar cancer have been identified (8). The role
several branches that innervate the lower vagina, labia, clitoris, of HPV in the development of premalignant and malignant le-
perineal body, and their supporting structures. sions of the vulva has become clearer as molecular techniques
for HPV detection and mutational analyses have improved (9).
Earlier studies identified HPV DNA in both invasive and car-
Groin Anatomy cinoma in situ lesions via immunohistochemistry. More recent
studies have used DNA detection methods such as polymerase
and Lymphatic Drainage chain reaction (PCR) and in situ hybridization to detect high-risk
Vulvar lymphatics run anteriorly through the labia majora, turn serotypes (9). Among HPV serotypes, 16 is the most common;
laterally at the mons pubis, and drain primarily into the super- however, many other serotypes, including 18, 31, 33, and others,
ficial inguinal lymph nodes. Dye studies by Parry-Jones demon- have been implicated (9). HPV DNA can be identified in approxi-
strated that vulvar lymphatic channels do not extend laterally to mately 85% of intraepithelial lesions (range, 42% to 100%), but
the labiocrural folds and do not cross the midline, unless the site is seen in only 10% to 50% of invasive lesions (9). The reason
of dye injection is at the clitoris or perineal body (3). such a wide range of associated HPV is seen associated with vul-
The vulvar lymphatics drain to the superficial inguinal lymph var intraepithelial neoplasia (VIN) and vulvar cancer has to do
nodes located within the femoral triangle formed by the inguinal with differences between studies regarding which VIN subtypes
ligament superiorly, the border of the sartorius muscle laterally, (usual or differentiated) are being studied, different DNA detec-
and the border of the adductor longus muscle medially. There tion methods with different sensitivity, and differences between
are 8 to 10 inguinal lymph nodes lying along the saphenous studies regarding which HPV serotypes are being assayed.
vein and its branches between Campers fascia and fascia over- Although HPV DNA is associated with the vast majority of
lying the femoral vessels (Fig. 19.1AC) (4). The first draining intraepithelial lesions (~85%), it is much less commonly seen in
lymph node is termed the sentinel lymph node (SLN) and can association with invasive lesions (~40%) (9). Marked differences
CHAPTER 19 VU LVA 525
Superficial
epigastric vein
Inguinal ligament
Superficial
circumflex
iliac vein
Femoral vein
Sentinel
lymph
nodes Lateral accessory
saphenous vein
Iliac
Obturator
Vesical
Deep
Clitoris
DISEASE SITES
Labia
Sartorius
Adductor longus
Fourchette
Perineum
B +C
FIGURE 19.1. These historic figures illustrate some of the problems depicting the lymphatic anatomy of the groin. A and B illustrate vessels, muscles, and nerves
accurately. A refers to sentinel nodes; however, this is based on location rather than a mapping procedure, which is misleading. B shows nodes between the femoral
artery and vein. Lymph nodes between the vessels are common in the pelvis but not in the groin. C: shows direct drainage from the clitoral area of the vulva to
pelvic lymph nodes. This drainage pattern is not observed with preoperative or intraoperative lymphatic mapping studies.
between HPV positivity in VIN and vulvar cancers are also seen (11,13). Smoking is an independent risk factor for the develop-
with respect to age. Basta et al. conducted a retrospective case ment of squamous cell carcinoma of the vulva, although the
control study examining the coexistence of HPV and the inci- reason for this is unclear. One hypothesis is that genetic varia-
dence of both VIN and stage I vulvar cancer. HPV infection was tions in T-cell-mediated IL-2 responses among smokers may
present in 61.5% of cases of VIN and vulvar cancer in women explain differential susceptibility to the development of squa-
aged less than or equal to 45 years, and in 17.5% or women mous vulvar carcinomas (12). Significant correlations between
older than 45 years (10). smoking status, historical number of sexual partners, history
Chronic immunosuppression and tobacco smoking have also of genital warts, and a history of an abnormal Pap smear have
been linked as cofactors for the development of invasive vulvar been detailed by Brinton et al. (Table 19.1) (7).
cancer (11,12). Vulvar cancer incidence is increased in female Chronic vulvar inflammatory lesions, such as vulvar dys-
renal transplant patients as well as women with HIV and AIDS trophies, including lichen sclerosus (LS), lichen planus, lichen
526 CHAPTER 19 VU LVA
Table 19.1 Relative Risks of In Situ and Invasive Vulvar Cancers by Selected Risk Factors
In situ Series Invasive Series
Source: Reprinted with permission from Brinton LA, Nasca PC, Mallin K, et al. Case-control study of cancer of the vulva. Obstet Gynecol. 1990;75:864.
simplex chronicus, squamous cell hyperplasia, and vulvar intra- etiologic pathways (19). According to their studies, two histo-
epithelial neoplasia II/III (usual as well as differentiated types), logic subtypes, those with basaloid or warty features, are associ-
particularly differentiated VIN (dVIN), have been suggested as ated with HPV, whereas keratinizing squamous carcinomas are
precursors of invasive squamous cancers (14,15). Carli et al. not. Furthermore, basaloid or warty carcinomas are associated
suggested a possible role of LS as a precursor to vulvar cancer with classic risk factors for cervical carcinoma, including age at
based on their observation that 32% of vulvar cancer cases not first intercourse, lifetime number of sexual partners, prior ab-
related to HPV were associated with LS (16). More recently, normal Pap smears, smoking, and lower socioeconomic status.
in a pathologic reevaluation of patients with a diagnosis of LS Keratinizing squamous carcinomas are weakly linked to these
who were followed clinically for a minimum of 10 years, van de factors, and in some cases not at all.
Nieuwenhof and colleagues identified concordant diagnoses of Mitchell et al. evaluated 169 women with invasive vulvar
LS in 58/61 patients who did not progress to cancer, and con- cancers and noted that second genital squamous neoplasms oc-
cordant diagnoses of LS in only 29/60 patients who were identi- curred in 13% of cases (20). The risk of a second primary tumor
fied with a subsequent diagnosis of vulvar cancer. The majority was significantly increased in cancer cases with HPV DNA, in-
of patients reclassified as having something other than LS were traepithelioid growth pattern, or adjacent dysplasia. These ob-
considered to have dVIN (25/31 patients). This study highlights servations support the concept that some squamous lesions may
dVIN as a uniquely at-risk histology that deserves prompt treat- be initiated by sexually transmitted viruses capable of produc-
ment and close follow-up. Differentiated vulvar intraepithelial ing neoplastic change within the entire field of the lower genital
neoplasia is often found in lesions, previously diagnosed as LS, tract. The obvious clinical implication of this observation is that
that have progressed to vulvar squamous cell carcinoma (15). a patient with an established squamous lesion of the vulva, va-
In an observational study of women with carcinoma in situ, gina, or cervix needs to be evaluated and monitored for new or
7 of 8 untreated cases progressed to invasive carcinoma within coexistent lesions at other sites.
8 years, and 4 of 105 treated women presented with invasive tu-
mors from 7 to 18 years later (17). In a subsequent study of 405
cases of VIN 2 to 3, Jones et al. found that 3.8% of patients had
developed invasive cancer despite therapy, and 10 untreated pa- NATU R AL H ISTORY
tients had developed invasive cancer in 1.1 to 7.3 years (mean, (PATTERNS OF SPREAD)
3.9 years) (18). Although some intraepithelial lesions regress
spontaneously, it appears that a significant number persist or Vulvar cancers metastasize in 3 ways: (a) local growth and
progress to invasive cancer. extension into adjacent organs, (b) lymphatic embolization to
Trimble et al. postulated that squamous carcinoma of the regional lymph nodes in the groin, and (c) hematogenous dis-
vulva may represent a final common endpoint of heterogeneous semination to distant sites.
CHAPTER 19 VU LVA 527
DISEASE SITES
cians should be encouraged not to excise a lesion if avoidable, to
facilitate the sentinel node procedure by a gynecologic oncolo-
gist. Figure 19.2 illustrates a relatively early-stage vulvar cancer.
DIAGNOSTIC EVALUATION
The evaluation of a patient with vulvar cancer must take into
consideration the clinical extent of disease and the presence of
FIGURE 19.2. Early-stage vulvar cancer. FIGURE 19.3. Advanced vulvar cancer.
528 CHAPTER 19 VU LVA
neoplasms (27). Lymphoscintigraphy will be discussed later in more recently in 2009 (Table 19.2) (28,29). The 2009 revision
this chapter. was performed to address issues with the 1995 version, namely,
the lack of a useful prognostic spread among stages, as well as
significant prognostic heterogeneity among stage III patients.
Since the 1995 revision, much has been learned about the sig-
STAGI NG nificance of the number of involved nodes, the size of inguinal
metastases, and nodal morphology.
The International Federation of Gynecology and Obstetrics The technique recommended by the International Society for
(FIGO) adopted a modified surgical staging system for vulvar the Study of Vulvar Disease, the International Society of Gyne-
cancer in 1989. This staging system was revised in 1995 and cologic Pathologists, the College of American Pathologists, and
Table 19.2 Integrated 2009 FIGO and AJCC Staging System for Squamous Cell Carcinoma of the Vulva
FIGO AJCC
T N M
DISEASE SITES
to the nonkeratinized squamous mucosa of the vestibule, also
the World Health Organization to assess depth of stromal inva-
known as Harts line (35).
sion is to measure from the base of the epithelium (epithelial
Most vulvar squamous carcinomas arise within areas of epi-
stromal junction) at the nearest superficial dermal papillae to
thelium associated with a recognizable epithelial cell abnormal-
the deepest point of tumor penetration (30). These definitions
ity. Approximately 60% of cases have adjacent HSIL (VIN3).
and methods of measurement are supported by the recent CAP-
In cases of superficially invasive squamous carcinoma of the
ASCCP LAST terminology project (Fig. 19.4) (31).
vulva, the frequency of adjacent HSIL (VIN 3) approaches 85%
Among squamous cell carcinomas limited to the vulva, those
(36). Lichen sclerosis, usually with associated hyperplastic fea-
with a DOI less than or equal to 1 mm are associated with a
tures, and/or HSIL (VIN 3), can be found adjacent to vulvar
<1% risk for lymph node metastasis. Tumors with a DOI of 1.1
squamous cell carcinoma in 15% to 40% of the cases (37,38).
to 3.0 mm are associated with lymph node metastases in 6%
Granulomatous disease is also associated with vulvar squamous
to 12% of patients, and approximately 15% to 20% of tumors
cell carcinoma; however, this is not a commonly associated find-
with a DOI of 3.1 to 5.0 mm are associated with positive lymph
ing in the United States. Thus, vulvar squamous cell carcinoma
nodes (32).
precursors can be considered in distinct groups: those associ-
In the 2009 revision, all stage I and stage II patients have un-
ated with HPV, usual VIN, and those that are not (e.g., those
involved lymph nodes. There is no clear definition of how many
associated with LS, chronic granulomatous disease) (see Epide-
lymph nodes constitutes an adequate evaluation. SLN biopsy is
miology section).
not mentioned as a requirement; however, the emphasis on the
size of micrometastases in stage III implies that an SLN biopsy is
performed either alone or as part of a lymphadenectomy.
The new staging system adds 3 pathologic groupings within Epithelial Carcinomas
stage III (a, b, and c), each of which contains prognostic signifi-
cance. These 3 groups are number of positive nodes, size of the
Squamous Cell Carcinomas
largest inguinal node metastasis, and the presence or absence The term microinvasive carcinoma is not recognized as meaning-
of extracapsular extension. These pathologic features have been ful in reference to vulvar cancer because there are no commonly
shown in multiple studies to be the strongest predictors of mor- agreed on pathologic criteria established for this term. The re-
tality related to vulvar cancer (28). cent CAP-ASCCP terminology committee on Lower Anogenital
The other notable difference in the new schema is the absence tract terminology (the LAST committee) stated that the de-
of stage difference based on unilaterality versus bilaterality of scriptor superficially invasive squamous cell carcinoma be
groin involvement; any groin metastasis is considered stage III defined as stage IA carcinoma, and that the term microinvasive
530 CHAPTER 19 VU LVA
Table 19.3B
Clinical Staging Pathologic Staging
T N M T N M
0 Tis N0 M0 0 Tis N0 M0
IA T1a N0 M0 IA T1a N0 M0
IB T1b N0 M0 IB T1b N0 M0
T2a N0 M0 T2a N0 M0
IIA T2b N0 M0 IIA T2b N0 M0
T3a N0 M0 T3a N0 M0
IIB T3b N0 M0 IIB T3b N0 M0
T4a N0 M0 T4a N0 M0
IIC T4b N0 M0 IIC T4b N0 M0
III Any T >N0 M0 IIIA T1-4a N1a M0
T1-4a N2a M0
IIIB T1-4b N1a M0
(continued)
CHAPTER 19 VU LVA 531
T1-4b N2a M0
T1-4a N1b M0
T1-4a N2b M0
T1-4a N2c M0
IIIC T1-4b N1b M0
T1-4b N2b M0
T1-4b N2c M0
Any T N3 M0
IV Any T Any N M1 IV Any T Any N M1
Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision
of the primary melanoma with clinical assessment for regional and distant metastases.
Source: Reprinted with permission from Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. New York, NY: Springer; 2009.
carcinoma not be used in reference to vulvar squamous cell dimension (Fig. 19.5). Tumors with confluent growth, by defini-
carcinoma (31). The DOI is defined as the measurement from tion, have a DOI exceeding 1 mm. Confluent growth is char-
the epithelial dermal junction of the most superficial adjacent acteristic of deeply invasive squamous cell carcinomas that are
dermal papillae to the deepest point of invasion (31). In com- associated with stromal desmoplasia, resulting in fibrovascular
parison, tumor thickness is measured from the overlying surface stromal changes adjacent to the interconnected cords of tumor.
epithelium or from the bottom of the granular layer if the surface Compact (pushing; well-differentiated) growth is squamous
is keratinized, to the deepest point of invasion, as specified by the tumor growth that maintains continuity with the overlying epi-
International Society of Gynecologic Pathologists (ISGYP), the thelium and infiltrates as a well-defined and well-circumscribed
World Health Organization, and FIGO (Fig. 19.4). tumor mass, without islands of infiltrating tumor remote from
Stage I squamous carcinomas of the vulva with a DOI of 3 the tumor mass. Tumors with compact growth typically have
mm have a lymph node metastasis rate averaging 12%. Tumors thickness of 5 mm or less and rarely invade vascular space.
with a DOI of 5 mm or more have a lymph node metastasis rate They are characteristically well-differentiated, with the tumor
of at least 15%. Tumors with a DOI of 1mm or less carry little cells resembling the squamous cells of the adjacent and over-
risk of lymph node metastasis (30). lying epithelium. There is usually minimal stromal desmopla-
DISEASE SITES
DOI and tumor thickness are separately defined and mea- sia, although there may be a lymphocytic inflammatory cell
sured because considerable variations can exist among measure- infiltrate.
ments from various superficial points in tumors of approximately Finger-like (spray or diffuse; poorly differentiated) growth
1mm (Fig. 19.4) (39). There are significant differences between is characterized by a trabecular appearance with small islands
tumor DOI and thickness when superficially invasive tumors are of poorly differentiated tumor cells found within the dermis or
measured. Tumors with invasion deeper than 1 mm can be read-
ily measured by determining thickness, but tumors with surface
ulceration may have a thickness, as measured from the surface,
significantly less than the DOI. With large tumors, thickness may
be the only reliable measurement because of the lack of identifi-
able adjacent dermal papillae.
In addition to tumor stage and depth or thickness, other
pathologic features include vascular space invasion, growth pat-
tern of the tumor, grade of the tumor, and tumor type. Vascular
space involvement can be defined as tumor within an endothelial
lined vascular space. Strict pathologic criteria require that the
tumor be attached to the wall of the vessel, but this is not ob-
served in all cases. Vascular space involvement by squamous cell
carcinoma of the vulva is associated with a higher frequency of
lymph node metastasis and a lower overall 5-year survival rate.
No reliable methods unambiguously predict lymph node metas-
tasis by quantitation of vascular space involvement by tumor.
Tumor growth pattern influences the rate of lymph node
metastasis and survival in tumors exceeding 1 mm in DOI. In
stage IA vulvar carcinomas, tumor growth pattern does not in-
fluence the risk of node involvement (32). Three factors describe FIGURE 19.5. Confluent pattern of invasion. The tumor has a compact,
tumor growth patterns: confluent; compact (pushing pattern); pushing growth pattern with a well-defined tumor-dermal interface. The tumor
and finger-like (or spray or diffuse), a pattern also described as diameter exceeds 1 cm, and has finger-like growth pattern, with small,
poorly differentiated (32). Confluent growth is defined as a tu- variable-sized tumor nests within the adjacent dermis. The adjacent dermis has
mor mass composed of interconnected tumor exceeding 1mm in a desmoplastic, fibrotic appearance.
532 CHAPTER 19 VU LVA
DISEASE SITES
teristically lacking. Because of its excellent prognosis, strict skin, and metastatic small cell carcinoma. Basaloid squamous
histologic criteria should be used in the diagnosis of verru- cell carcinoma can be distinguished by its lack of characteris-
cous carcinoma. Squamous carcinomas with focal verrucous tic basal cell growth pattern, and the presence of intracellular
features should not be described or diagnosed as verrucous bridges. Nuclear pleomorphism is typically much greater in ba-
carcinoma. saloid squamous cell carcinoma than in basal cell carcinoma.
Basal cell carcinomas express BerEP4 on histochemical study,
an antigen not expressed by basaloid squamous cell carcinomas
(38). Basaloid squamous cell carcinomas are typically associ-
ated with HPV 16, which is not typically associated with basal
cell carcinoma. Merkel cell tumors and other neuroendocrine
tumors of the vulva are typically subcutaneous or dermal nod-
ules, and not intraepithelial lesions (see the section on neuroen-
docrine tumors).
enolase, synaptophysin, chromogranin, and low-molecular- transitional cell carcinomas each composing approximately 5%
weight keratin. Keratin study, such as with cytokeratin 20, of the primary Bartholins gland tumors (58).
demonstrates a distinct perinuclear cytoplasmic dot. Dense core Carcinoma of Bartholins glands generally occurs in older
neurosecretory granules are seen by electron microscopy. These women and is rare in women younger than 50. In clinical prac-
features differentiate it from basal cell or squamous cell carci- tice, it is generally advisable to excise an enlarged Bartholins
noma (38). Merkel cell tumors frequently have both regional gland in a woman 50 years of age or older, especially if there is
lymph node and distant metastases and are associated with a no known history of prior Bartholins cyst. If a cyst is drained
poor prognosis. and a palpable mass persists, excision is also indicated. Fine
needle aspiration of a Bartholins mass for cytologic evaluation
Peripheral Neuroectodermal Tumor/Extraosseous Ewing may help to establish a positive diagnosis.
Sarcoma. Peripheral neuroectodermal tumor/extraosseous Primary carcinomas within Bartholins glands are usually
Ewing sarcoma (PNET) is a rare neuroendocrine vulvar neoplasm solid tumors and are often deeply infiltrative. A variety of his-
that has been reported in childhood and women of reproductive tologic types of adenocarcinoma have been described within
age. The tumor may present as a subcutaneous or polypoid mass Bartholins glands. Mucinous, papillary, and mucoepidermoid
and clinically may resemble a cyst or be ulcerated (53,54). On carcinoma tumor types have been described, in addition to ad-
microscopic examination the tumor is circumscribed and mul- enosquamous, squamous, and transitional cell carcinoma. Ad-
tilobulated, without capsule but nonencapsulated, and contains enocarcinoma of Bartholins glands is typically immunoreactive
small cells with little cytoplasm and nuclei with hyperchromatic for carcinoembryonic antigen (38). Histopathologic features
and finely granular nuclear chromatin. Some cells have small that identify a carcinoma arising in Bartholins glands include a
nucleoli, and mitotic figures are usually common, with mitotic recognizable transition from a Bartholins gland to tumor. The
counts from 3 to exceeding 10 per 10 high power fields. Numer- histopathologic tumor type must be consistent with an origin
ous patterns of growth may be seen with highly cellular undiffer- from a Bartholins gland, and the tumor must not be metastatic
entiated areas, areas with cyst formation containing eosinophilic to a Bartholins gland.
proteinous material, rosettes with Homer-Wright rosettes, and These malignancies are characteristically deep and difficult
follicle-like structures. to detect in their early growth. Approximately 20% of women
The cells of PNET have periodic-acid Schiff (PAS) stain- with primary carcinoma of Bartholins glands have metastatic
ing cytoplasm that digests with diastase, and typically express tumor to the inguinofemoral lymph nodes at the time of primary
CD99 and vimentin. Although, as in Merkel cell tumors, focal tumor diagnosis.
reactivity for synaptophysin and neuron-specific enolase may be
present, cytokeratin reactivity is not present but may be focally
immunoreactive in some cases. Adenocarcinoma Arising
Dense core neurosecretory granules, as seen in Merkel in Vulvar Skin Appendages
cell tumor by electron microscopy, are not present. Cytoge-
netic study of these PNET tumors demonstrates translocation The vulvar labia majora were once thought to be within the
t(11;22)(q24;q12) in approximately 90% of cases. This trans- milk line, but this has been significantly challenged by Van der
location can also be demonstrated with fluorescence in situ hy- Putte, who observed that the milk line did not involve the vulva
bridization, or reverse transcriptase polymerase chain reaction in the human (59). The breast-like tumors found are believed
(RT-PCR) (53,54). to arise from specialized anogenital glands that reside in the in-
tralabial sulci and may be the origin of papillary hidradenoma.
Both benign and malignant breast-like tumors have been ob-
Urothelial/Transitional Cell Carcinoma served within the vulva (60). Fibroadenoma, intraductal pap-
illoma, and lactating adenoma have been observed. Primary
Urothelial carcinoma may be a primary tumor of the vulva,
adenocarcinoma of the vulva may arise in specialized anogenital
usually arising within the Bartholins glands. More commonly,
glands, which reside in the intralabial sulcus and are believed to
urothelial carcinoma is metastatic to the vulva, having arisen
be the origin of papillary hidradenoma of the vulva, as well as
within the bladder or urethra. In rare instances, the tumor pres-
the breast-like tumors seen within the vulva, and these glands
ents as a Paget-like lesion of the vulva (see section on Pagets
may resemble breast tissue (59,60).
disease) (55).
Microscopically, urothelial carcinomas are composed of rela-
tively uniform cells; nuclear pleomorphisms may be marked in Adenosquamous Carcinoma
high-grade urothelial neoplasms. The cytoplasm is eosinophilic Adenosquamous carcinomas are epithelial tumors composed
without apparent inclusions or keratin formations, although of both malignant squamous and gland-forming elements. Ad-
focal keratin formation may be seen. The tumors may exhibit enosquamous carcinomas account for approximately 5% of all
papillary-like growth. tumors of Bartholins glands. These tumors may be composed of
a poorly differentiated squamous component mixed with cells
Adenocarcinoma and Carcinoma bearing small glandular lumens containing mucin.
of Bartholins Glands
Adenoid Cystic Carcinoma
Most primary adenocarcinomas of the vulva arise within Bar-
tholins glands. Adenocarcinoma may also arise from other Adenoid cystic carcinoma arising within the vulva most com-
glands or skin appendages of the vulva, including sweat glands monly arises within the Bartholins glands and composes ap-
and Skenes glands (56). Clear cell adenocarcinoma arising in en- proximately 15% of all carcinomas of Bartholins glands.
dometriosis has been reported in the groin (57). Invasive vulvar Microscopically, adenoid cystic carcinomas are composed of
Pagets disease has given rise to adenocarcinoma (Fig. 19.13). relatively uniform small cells with regular, round nuclei and
Primary malignant tumors arising within Bartholins glands minimal cytoplasm. The cord-like or nested arrangement con-
include adenocarcinoma and squamous cell carcinoma, which tains gland-like lumens that include an acellular eosinophilic
occur with approximately equal frequency and account for ap- material. Electron microscopy has documented that this mate-
proximately 80% of all primary malignant tumors in this site. rial is basement membranelike material rather than a secretion.
Adenoid cystic carcinomas compose approximately 15% of These tumors are therefore more properly considered a variant
all primary carcinomas, with adenosquamous carcinomas and of squamous cell carcinoma than adenocarcinoma.
CHAPTER 19 VU LVA 535
Carcinomas of Sweat Gland Origin neoplasm extending from the bladder and/or urethra (55). These
cells have been reported from a vaginal cytology specimen from
Primary carcinomas of sweat gland origin are relatively rare a woman with a PUIN lesion (63).
within the vulva, composing approximately 10% of all vulvar Cutaneous Pagets disease is most commonly a primary in-
malignant tumors. A variety of sweat gland carcinomas in this traepithelial neoplasm. In such cases the intraepithelial Pagets
site have been described, including eccrine adenocarcinoma, ec- disease may have an associated invasive Pagets disease. In rare
crine porocarcinoma, and clear cell hidradenocarcinoma (56). cases, cutaneous Pagets disease may be a manifestation of an
Primary adenocarcinomas of apocrine gland origin have also underlying cutaneous adenocarcinoma (55). Cutaneous Pagets
been described arising within the vulva, and some of these have disease is characterized by the presence of Pagets cells, which
been associated with vulvar Pagets disease. These should be dis- are found within the involved epithelium. A Pagets cell is rela-
tinguished from the benign papillary hidradenoma, which typi- tively large, with a prominent nucleus that typically has coarse
cally arises in the intralabial papillary sulcus from specialized chromatin and a prominent nucleolus. On hematoxylin and eo-
anogenital glands and contains a myoepithelial cell population, sin staining, the cytoplasm is distinctly pale compared with the
distinguishing it from adenocarcinoma (59). surrounding keratinocytes. The cytoplasm may be vacuolated or
appear foamy and typically is somewhat basophilic (Fig. 19.9).
Vulvar Pagets Disease and Paget-Like Lesions Pagets cells of cutaneous origin are rich in carcinoembryonic
Vulvar Pagets disease typically presents as an eczematoid, red, antigen (CEA), which can be identified with immunoperoxidase
weeping area on the vulva, often localized to the labia majora, techniques (55). Pagets cells also express cytokeratin 7 (CK-7)
perineal body, clitoral area, or other sites. This disease typically and gross-cystic-disease fluid protein-15 (GCDFP-15) (55,64).
occurs in older, postmenopausal Caucasian women, although it Pagets cells infrequently express CA-125, and estrogen recep-
has been described in a premenopausal woman. Because of its tor is generally negative (65). Immunohistochemical study for
eczematoid, or cake-icing appearance, it is not unusual for CK-7 is useful in many cases to identify the Pagets cells that are
vulvar Pagets disease to be misdiagnosed as eczema or contact strongly CK-7 positive, whereas the adjacent epithelial cells are
dermatitis. Approximately 15% of women with vulvar Pagets negative (66). Invasive Pagets disease 1 mm or less in DOI has
disease have underlying primary adenocarcinoma, usually aris- reportedly little risk for recurrence (65).
ing within apocrine glands or the underlying Bartholins glands The differential diagnosis of Pagets disease of cutaneous
(Fig. 19.9). The Wilkinson and Brown etiologic classification of origin includes PUIN/Pagets disease of urothelial origin, Pagets
vulvar Pagets disease divides Pagets disease into 2 main groups: disease of colorectal origin/or other related adenocarcinoma, su-
those of cutaneous origin and those of noncutaneous origin perficial spreading malignant melanoma, pagetoid reticulosis, and
(55). The 2 most common types of noncutaneous Pagets disease the pagetoid variant of vulvar intraepithelial neoplasia, which are
are those associated with colorectal adenocarcinoma and those keratinocytic cells resembling Pagets cells. These can all be dif-
associated with bladder urothelial carcinoma. Women with Pag- ferentiated by immunoperoxidase techniques because melanomas
ets disease of the colorectal type usually present with a lesion do not express cytokeratin, but usually express S100 protein,
that involves the perianal skin, and this lesion is a manifesta- HMB45, and Melan-A, which are absent in Pagets cells (55,67).
tion of underlying colon or rectal adenocarcinoma. Women with The Paget-like cells in PUIN express uroplakin-3, but do not ex-
Paget-like disease (Pagetoid urothelial intraepithelial neoplasia press GCDFP-15. Adenocarcinoma cells of colonic, anal, or rectal
[PUIN]) typically present with a lesion involving the periure- origin express CEA, as well as caudal homeobox (CDX), whereas
thral area and vulvar vestibule (55,61,62). In these cases there Pagets disease of cutaneous origin does not express CDX. HSIL
is associated bladder and/or urethral urothelial carcinoma with (VIN 3) of pagetoid type may microscopically resemble Pagets
DISEASE SITES
the extension of the neoplastic urothelial cells to the epithelium disease or melanoma, but the cells of LSIL or HSIL (VIN 1-VIN
of the vulva (55,61). In cases of PUIN, total deep vulvectomy 23) do not express CEA, S100, or melanoma antigen (55,61).
is not indicated because there is no associated underlying cu-
taneous adenocarcinoma. The tumor cells are from the bladder Vulvar Malignant Melanoma
and/or urethra, representing an intraepithelial transitional cell
Malignant melanoma of the vulva accounts for approximately
9% of all primary malignant neoplasms on the vulva, and vulvar
melanoma accounts for approximately 3% of all melanomas in
women. This tumor occurs predominantly in Caucasian women,
with approximately one-third of the cases occurring in women
younger than 50, and the mean age at diagnosis is 55 years (68).
The peak frequency occurs between the sixth and seventh de-
cades, and the highest incidence is in women 75 years of age
of older, where the age-specific incidence is reported to be 1.28
per 100,000 (69). The most common presenting symptom is
bleeding; however, pruritus, pain, dysuria, and a palpable mass
may all be symptoms (69,70,71). The tumor may arise from a
preexisting pigmented lesion or from normal-appearing skin.
The primary site on the vulva may be the clitoris, labia minora,
and labia majora, where melanomas occur with approximately
equal frequency (72). The tumor may be elevated, nodular, or
ulcerated. Although tumors are usually pigmented, approxi-
mately one-fourth are nonpigmented, amelanotic melanomas, a
melanoma type that clinically and pathologically may resemble
squamous carcinoma. In the clinical setting, the differential di-
agnosis includes pigmented condyloma acuminatum, pigmented
FIGURE 19.9. Pagets disease. The large cells with prominent cytoplasm and HSIL VIN, atypical genital nevus, large vulvar nevi, melanosis of
large nuclei represent the intraepithelial Pagets cells. A few small gland-like the vulva, or other malignant tumors, including malignant soft-
intraepithelial structures are formed by the Pagets cells. tissue tumors (61,73).
536 CHAPTER 19 VU LVA
Vulvar malignant melanomas may be subclassified into or may not contain pigment. The form of the cells ranges from
3specific categories: superficial spreading malignant melanoma, epithelioid to spindle shaped; in some cases, the spindle cell type
nodular melanoma, and mucosal lentiginous melanoma, which may predominate. The spindle cells may be relatively small, with
is also referred to as mucosal/acral lentiginous melanoma (74). oval nuclei and elongated cytoplasm. They may infiltrate the ad-
In the vulva, some cases are mixed or cannot be specifically clas- jacent dermis in cords and sheets.
sified. Mucosal lentiginous melanomas are the type most com- Malignant melanomas typically express S100 antigen,
monly reported on the vulva, accounting for over one-half of the HMB45, and Melan-A and lack cytokeratin or CEA. The micro-
cases in larger series (69,74). Nodular melanomas are second in scopic differential diagnosis for superficial spreading malignant
frequency, accounting for approximately one-fifth of the cases, melanoma is primarily vulvar Pagets disease, pagetoid reticu-
and have the overall worst prognosis of the melanoma types, losis, and Kaposis sarcoma. Immunohistochemical techniques
usually related to the greater thickness and deeper invasion at are essential in discriminating superficial spreading melanoma
the time of presentation. Superficial spreading melanomas are from Pagets disease (see the section on vulvar Pagets disease)
the least common type in the vulva. Some variation in the fre- (67). Nonpigmented nodular melanomas may mimic squamous
quency of these types in the vulva is present in the literature, cell carcinoma or spindle cell neoplasms of various types. In
primarily related to some variations in pathologic classification these circumstances, immunoperoxidase procedures are of great
(6872,74,75,76). value, because squamous cell carcinomas typically do not ex-
Histopathologic differentiation of melanoma type is based press S100 protein, HMB45, or Melan-A, and melanomas do
on identification of a superficial spreading component. Mu- not express cytokeratin (63).
cosal lentiginous melanomas have the neoplastic melanocytes Tumor thickness is the most important measurement in eval-
clustered in the dermal-epithelial junction and have both radial uating malignant melanoma (68). The Clark level definitions
growth and vertical growth. Superficial spreading melanomas describe the extent of dermal and subcutaneous involvement
have radial growth involving 4 or more rete lateral to their by the melanoma (77). Measurements for vulvar melanomas
vertical or infiltrative growth (61). Nodular melanomas show can be applied as for skin and mucous membranes, as described
minimal or no radial growth. Superficial spreading malignant by Breslow (78). With the Breslow method, the thickness mea-
melanoma characteristically shows junctional melanocytes with surement for cutaneous melanomas requires measurement from
radial growth, and a vertical growth pattern may be absent. The the top of the granular layer to the deepest point of invasion.
tumor cells are highly variable in appearance but commonly are Malignant melanomas that have a thickness of up to 1mm are
relatively large, with nuclei showing minimal variation in size generally considered of minimal risk of recurrence. Melano-
and containing prominent nucleoli (Fig. 19.10). These cells may mas at Clark level 2 or thickness of 1.49 mm or less, or tumor
volume of 100 mm3, also correlate with good prognosis (79). A
poor prognosis is correlated with Clark level 5, thickness >2 mm,
or mitotic count exceeding 10/mm2. Other prognostic factors
include mitotic rate and reaction and surface ulceration (80).
Vulvar melanoma has been described as being associated
with NRAS codon 12 mutation, as more commonly seen in sun-
exposure-related melanomas; however, most mucosal non-
sun-exposure-related melanomas do not express NRAS exon 2
mutations (81).
Melanomas arising in the vulva may metastasize to other
sites within the lower female genital tract, including the cervix,
vagina, urethra, and rectum. Distant metastasis is common with
disseminated disease. Survival after recurrence is poor: approxi-
mately 5%.
Vulvar Sarcomas
Leiomyosarcoma. Leiomyosarcoma is the most frequent pri-
mary vulvar sarcoma. It most commonly arises in the labia ma-
jora or Bartholins gland area, although these smooth muscle
tumors may arise in the clitoris and labia minora. The tumors
are generally larger than 5 cm in diameter when first diagnosed
and may be deep within the subcutaneous tissue.
On microscopic examination, these tumors are composed of
interlacing spindle shaped cells, sometimes with an epithelioid
appearance. Features of leiomyosarcoma include an infiltrat-
ing border and metastasis. Microscopic criteria for diagnosis
require determination of the mitotic figure count. In cases with
minimal pleomorphism, it is generally accepted that the diagno-
sis of leiomyosarcoma can be made with a mitotic count of 10
or more per 10 high power fields. Tumors that have an infiltrat-
ing border or nuclear atypia with pleomorphism and mitotic
count of 5 or more per 10 high power fields are classified as
leiomyosarcoma. There are tumors that may show no signifi-
cant atypia, have a diameter exceeding 5 cm, have an infiltrating
margin, and have a low mitotic count, up to 5 per 10 high power
FIGURE 19.10. Malignant melanoma. The tumor is within the dermis and fields. It is preferable to classify them as smooth muscle tumors
contains dark melanin pigment. Junctional growth is seen within the overlying of uncertain malignant potential, because the risk of recurrence
epithelial dermal junction. is uncertain (38,82,83).
CHAPTER 19 VU LVA 537
Malignant Fibrous Histiocytoma. Malignant fibrous histiocy- Other Sarcomas and Soft-Tissue Tumors
toma (MFH) arises from histiocytes with fibroblastic differen-
tiation. It is considered the second most common sarcoma of the A partial list of primary sarcomas of the vulva includes angio-
vulva and has its peak frequency in middle age. MFH typically sarcoma, Kaposis sarcoma, hemangiopericytoma, rhabdomyo-
presents as a solitary mass that may appear somewhat brownish sarcoma, alveolar soft part sarcoma, and liposarcoma. Sarcoma
or pigmented, secondary to areas of focal hemorrhage within botryoides is a variant of rhabdomyosarcoma that may involve
the tumor. the vulva, but most cases arise within the vagina or base of the
On microscopic examination, the tumor is characterized bladder. Kaposis sarcoma and angiosarcoma should be differ-
by a complex interlacing cellular growth pattern with marked entiated from bacillary angiomatosis, which is a benign pseudo-
nuclear pleomorphism, including multinucleated cells and large neoplastic infectious process (87).
bizarre cells. Abnormal mitotic figures may be apparent. Micro- Aggressive angiomyxoma is well-documented as a primary
scopic variants of this tumor include inflammatory, giant cell, soft-tissue tumor of the vulva and pelvis that occurs predomi-
myxoid, and angiomatoid types (57,84). On immunoperoxidase nately in women of reproductive age. It is locally aggressive but
study, these tumors contain a1 antitrypsin and a1 antichymo- rarely metastatic (82,88). It typically presents as a deep soft-
trypsin. MFH is typically infiltrative, with infiltrative margins, tissue mass or pelvic mass, sometimes mimicking a Bartholins
and may involve the underlying fascia. Involvement of the fas- cyst or inguinal hernia. In the pelvis, it may displace other pelvic
cia is associated with a higher risk of local spread and distant organs and may be best appreciated on radiologic studies.
metastasis. The tumor is typically poorly circumscribed and difficult to
discriminate from adjacent soft tissue. On microscopic exami-
nation, the tumor has many blood vessels. The tumor consists
Epithelioid Sarcoma. Epithelioid sarcoma may arise within predominantly of spindle to stellate shaped cells, with relatively
the labia majora, subclitoral area, and clitoris (85). Its mi- small uniform nuclei representing predominately fibroblasts and
croscopic features may resemble squamous carcinoma, ma- myofibroblasts. Mitotic figures are very rare. The tumor stroma
lignant melanoma, malignant rhabdoid tumor, or lymphoma. varies from myxoid to densely collagenous. Nerves, small glan-
Epithelioid sarcoma is usually relatively superficial, arising in dular structures with mucin-secreting columnar cells, and other
and involving the reticular dermis, but it may occur in deeper epithelial elements may be found trapped within the tumor. The
structures. differential diagnosis is as for angiomyofibroblastoma (AMF),
On microscopic examination, the tumor is nodular and may summarized below.
have areas of necrosis. The tumor cells have an epithelioid appear- AMF is a rare, benign tumor of soft-tissue origin that occurs
ance with eosinophilic cytoplasm, but there may be metaplastic predominantly in the female genital tract (89). When involving
components, including cartilage and bone. On immunohisto- the vulva, it usually presents as a soft subcutaneous mass, but
chemistry, this tumor contains cytokeratin, which does not dis- may occasionally be pedunculated (89).
tinguish it from epithelial tumors, but is of value in differentiating On microscopic examination, the tumor usually has well-
it from malignant melanoma or other types of soft-tissue tumors. demarcated borders. Variable cellularity is present with an
Epithelioid sarcoma rarely metastasizes, although local recur- edematous appearance. The cells are spindle shaped, plasmacy-
rence is a risk. The differential diagnosis for this tumor includes toid or epitheloid in appearance, and mitotic figures are rare.
squamous cell carcinoma, malignant melanoma, lymphoma, and Cells were present in most cases. Cells may be clustered about
malignant rhabdoid tumor, all of which are capable of distant blood vessels. The tumor is vascular with small to medium sized
metastasis and aggressive behavior (85). Immunoperoxidase vessels. Some inflammatory cells, commonly lymphocytes or
studies are of value in differentiation but have not been of value mast cells, may be seen around the vessels.
DISEASE SITES
in differentiating epithelioid sarcoma from malignant rhabdoid The differential diagnosis includes aggressive angiomyxoma,
tumor. The distinction of these 2 tumors is based primarily on atypical myxoid fibroepithelial stromal polyp, Bartholins cyst,
microscopic features. lipoma, and leiomyoma. The reader is referred to additional texts
on these and other soft-tissue tumors of the vulva (38,82,83).
Malignant Rhabdoid Tumor. Malignant rhabdoid tumor has
been described in the vulva and, like epithelioid sarcoma, may be
relatively superficial and contain tumor cells with an epithelioid
appearance with eosinophilic cytoplasm. Unlike epithelioid sar- Metastatic Tumors to the Vulva
coma, malignant rhabdoid tumors have relatively pleomorphic
nuclei. Metaplastic elements are usually not present. Malignant Most metastatic tumors to the vulva involve the labia majora
rhabdoid tumor also has eosinophilic cytoplasmic inclusions, or Bartholins glands. In the vulva, they usually present as sin-
which are not present in epithelioid sarcoma. These inclusions gle or multiple intradermal or subcutaneous nodules but may
give some of the cells the appearance of signet ring cells. Ma- present as a Bartholins gland mass (58,90,91,92). Metastatic
lignant rhabdoid tumor has a lobulated architecture but lacks tumors account for approximately 8% of all vulvar tumors,
necrosis or granulomatous features, which are often found in and in approximately one-half of the cases the primary tumor
epithelioid sarcoma (82,83,85). was in the lower genital tract, including the cervix, vagina,
endometrium, and ovary. Cervical carcinoma is the most com-
mon origin of contiguous metastasis. Local metastasis second-
ary to contiguous involvement of the vulva from urothelial
Yolk Sac Tumor carcinoma of the bladder or urethra, or anorectal carcinoma,
Yolk sac tumor (endodermal sinus tumor) is a rare germ cell may involve the vulva and present as a Paget-like lesion (see
tumor of the vulva, primarily arising in the labia or clitoral Pagets disease and Paget-like lesions in this section) or a vul-
areas (38,86). The age range of patients is from just under 2 to var or groin node mass (55,93). Remote metastases have been
26 years. Distinctive microscopic features are similar to endo- observed from tumors arising in breast, kidney, stomach, lung,
dermal sinus tumor in the ovary, including the Schiller-Duval and other sites. Malignant melanoma and neuroblastoma can
bodies, distinctive eosinophilic globules that are PAS positive also metastasize to the vulva, as can gestational choriocarci-
and contain a -fetoprotein, and the presence of a -fetoprotein noma and malignant lymphomas. In approximately 10% of
within the tumor, as demonstrated by immunoperoxidase the cases, the primary site of the metastatic tumor cannot be
technique. identified.
538 CHAPTER 19 VU LVA
FIGURE 19.12. A hot blue sentinel node identified through a small incision.
Frozen section is requested only if the sentinel node is grossly suspicious.
FIGURE 19.11. Transdermal localization of sentinel node using a handheld Immunohistochemical staining is performed if the routine hematoxylin and
gamma counter. The probe has a collimator and is pointed away from the eosin staining does not reveal metastatic disease. After a sentinel node is
primary tumor. Radioactivity will fall off rapidly until the sentinel node is removed, the wound is explored with the gamma counter to assure that there
encountered. Mark the site of an increase in activity. is not another sentinel node in the field.
the assessment of lymphatic metastases may ultimately be re- tumor was more than 2 cm from the midline, a unilateral SLNB
duced to the biopsy of one or 2 identifiable nodes. and inguinofemoral lymphadenectomy were performed. If the
Based on these early results, 2 large multi-institutional trials tumor was within 2 cm of the midline, or involving the midline,
were initiated to determine the utility of sentinel lymph node bilateral inguinal lymphadenectomies were performed. The false-
biopsy (SLNB) in women with vulvar caner. The GROINS V trial negative rate was 8.3%, and the false-negative predictive value
used a prospective, observational design, enrolling 403 evalu- (FNPV) was 3.7% for the entire cohort. The FNPV is a prediction
able women with tumors 4cm who underwent SLNB alone. of the chance of a positive nonsentinel lymph node when the SLN
Of these, 276 women had a negative SLNB and were closely is free of tumor and a lymphadenectomy has not been performed.
observed for recurrence during a 2-year follow-up period. Eight In GOG 173 the FNPV by groin was 2.7%; for patients with tu-
patients (2.9%) suffered a groin relapse. When patients with mors less than 4 cm, it was 2.0%. This means that a patient with
multifocal primary tumors were removed from the analysis, the a tumor less than 4 cm, no palpable lymph nodes, and a negative
relapse rate was only 2.3% (121). SLNB has a 2% chance of a groin relapse (122). The results of
The second study, GOG 173, employed a validation design. these studies indicate that, for well-selected women in the care of
All women underwent SLNB followed by unilateral or bilateral a surgeon experienced with this technique, the risk of groin re-
inguinofemoral lymphadenectomy. Five hundred and fifteen lapse following a negative SLNB is 2% to 3% (Table19.4). This
women were enrolled, and 418 were evaluable. If the primary compares favorably with superficial inguinal lymphadenectomy,
DISEASE SITES
Table 19.4 SLNB Sensitivity Analysis
SLNB FNPV
Analysis Result Present Absent Total Sensitivity 90% CI NPV (%) 90% CI (%) 90% CI
CI, confidence interval; FNPV, false-negative predictive value; NPV, negative predictive value; SLNB, sentinel lymph node biopsy.
Source: Reprinted with permission from Levenback CF, Ali S, Coleman RL, et al. Lymphatic mapping and sentinel lymph node biopsy in women with squamous cell
carcinoma of the vulva: a Gynecologic Oncology Group study. J Clin Oncol. 2012;30(31):37863191.
540 CHAPTER 19 VU LVA
as reported by Stehman et al. for the GOG (123). As with all was more than 2 cm from a midline structure. There were 234
surgical innovations, individual practitioners must use care women enrolled on GOG 173 who had a preoperative lymphos-
when implementing new procedures. Gynecologic oncologists cintigraphy (LSG) and at least one SLN identified during surgery.
can learn the procedure from peers or from surgical oncologists There were 105 women with midline primary tumors and 32
treating melanoma or breast cancer patients. Prior to adopting women had unilateral drainage on preoperative LSG. Four of
this as his / her standard, each gynecologic oncologist should these patients had lymph node metastases on the side that did not
determine his/her own false-negative rate by performing SLNB have LSG drainage. There were 65 women with tumors located
followed by inguinofemoral lymphadenectomy in approximately within 2 cm of the midline but not directly involving a midline
10 cases. Some practices see very few vulvar cancer patients, structure. Twenty-seven women (42%) had unilateral drainage
in which case referral is appropriate. Considered together, the on LSG and bilateral surgical groin evaluation. None of these
GROINS V and GOG 173 trials strongly support an assertion patients had metastases to the side without LSG drainage. These
that, under the appropriate circumstances, SLNB should be of- data support the time-honored oncologic surgical experience
fered to eligible women with vulvar cancer. that midline tumors can have bilateral drainage and a unilateral
It is important to note that the SLN undergoes pathologic LSG should not result in omission of one side. Conversely if the
ultrastaging with serial sectioning and immunohistochemical tumor looks lateralized and that is confirmed by LSG, unilateral
staining if routine hematoxylin and eosin staging does not re- SLNB is appropriate (128). The authors routinely obtain preop-
veal metastatic disease. In most studies, including GOG 173 and erative LSG, preferably by SPECT/CT (Fig. 19.16), regardless of
GROINS V, approximately half of the lymph node metastases the location of the primary, since it helps confirm the location of
are detected by IHC. SLNB has the promise of reducing the the SLN and the lymphatic drainage pattern.
number of unnecessary lymphadenectomies performed in node- The survival for women with adequate resection of a pri-
negative women while at the same time identifying additional mary squamous carcinoma limited to the vulva and with nega-
women who may benefit from adjuvant therapy. tive nodes is 90% or better. Stage II patients who have negative
The combination of local vulvar resection and SLNB holds margins and nodes but involvement of the lower vagina or ure-
the promise of improved outcomes for many women with vul- thra should obtain similar results.
var cancer. Preservation of sexual function and body image, a
reduction in the risk of lymphedema, and more focused use of
adjuvant therapy are all possible.
Clinical Stage III and IV
Patients with Clinical Stage I / I I Cancers at Presentation
Tumors at Presentation Some women have lymph node metastases detected by preop-
erative physical examination or diagnostic imaging or at the
Tumors demonstrating a DOI of the vulvar stroma of 1 mm or time of their primary surgery. If a node is grossly involved at
less (1 mm) have minimal risk for lymphatic dissemination. Ex- this point, most gynecologic oncologists will proceed with in-
cisional procedures that incorporate a 1-cm normal tissue mar- guinofemoral lymphadenectomy on the assumption that there is
gin are likely to provide curative results (124). Patients in this a high likelihood of additional positive lymph nodes.
category represent the only subset for whom surgical evaluation Clinical stage II/III tumors often extend to adjacent mucosal
of the inguinal lymph nodes can be omitted. These so-called su- structures the inguinal lymph nodes. Many are bulky; how-
perficially invasive carcinomas tend to arise in younger patients ever, some are of limited volume but are considered high stage
with intraepithelial squamous lesions (VIN) that are commonly because of proximity to critical midline structures. Some pri-
associated with oncogenic HPV infections. Occult invasion in mary tumors can be curatively excised by radical vulvectomy
lesions thought to be intraepithelial is common (125,126). Con- or by some variation of pelvic exenteration and vulvectomy.
sequently, the entire lower genital tract and vulva should be Surgical resection of 1 to 1.5 cm of the distal urethra in or-
carefully evaluated before surgical resection of these lesions is at- der to achieve a negative surgical margin does not appear to
tempted. The risk of vulvar recurrence or development of a new compromise bladder continence (128). Though radical surgery
lesion at another vulvar site is significant. After primary therapy, is an option for patients with locally advanced tumors, contem-
these patients should undergo frequent follow-up examinations. porary therapeutic strategies have centered upon sequenced ra-
Management of clinical stage I and II vulvar cancer includes diotherapy or radiochemotherapy followed by radical surgery
wide radical excision of the primary tumor with unilateral or bi- as a means to preserve either urinary or fecal continence or both.
lateral SLNB plus or minus inguinofemoral lymphadenectomy. Vulvar cancers are sufficiently sensitive to therapeutic radiation
The operation removes the primary tumor with a wide radial such that function-sparing operations are feasible in selected
margin of normal skin (2 cm), along with a deep margin to the patients with advanced disease who receive combined modal-
deep perineal fascia; thus, the vulvar specimen will contain tumor, ity treatment (129). For patients with stage IVA tumors, similar
skin, subcutaneous fat, vascular perforators and dermal lymphat- experiences have been reported; ultraradical (exenterative) re-
ics. This approach provides excellent long-term survival and local sections may also be considered for selected patients. Although
control in approximately 88% of patients (127). Every attempt occasional cures have been described with innovative combina-
should be made to preserve structures such as the clitoris and tions of surgery, radiation, and radiochemotherapy, treatment
urethral meatus. Deep margins are rarely a problem except on of patients with stage IVB vulvar cancer should be considered
the perineum, where there is little or no subcutaneous fat. In this palliative.
case, removal of the capsule of the anus or some of the sphincter
muscle itself can be performed without a loss of anal function.
Closure of vulvar defects for small primary tumors can usu-
ally be achieved with simple mobilization of the skin and fat Node-Positive Cancers
surrounding the vulva. In cases where primary closure is not An optimal management strategy for clinically apparent node-
possible, any one of a number of plastics closures are useful positive patients is yet to be defined. Two factors impact man-
(discussed later). Consultation with a plastic surgeon in such agement of regional disease: radiation can have a significant
cases can be invaluable. impact on sterilizing or eradicating small volume nodal disease,
A subanalysis of GOG 173 data also provides guidance re- and surgical resection of bulky nodal disease also improves re-
garding when unilateral groin evaluation is safe. GOG 173 re- gional control and probably enhances the curative potential of
quired bilateral lymph node evaluation except when the tumor irradiation. In multivariate analysis, Hyde et al. found that, for
CHAPTER 19 VU LVA 541
DISEASE SITES
remain about the management of SLNB positive patients. any pigmented vulvar lesion should be considered for biopsy.
Cutaneous melanoma has evolved significantly over the past
45 years. Because of the rarity of vulvar melanoma, it has not
been clear whether extrapolation of prognostic and treatment
Recurrent Cancer data from cutaneous nonvulvar disease is appropriate for vulvar
Regardless of initial treatment, vulvar cancer recurrences can be melanoma patients. Thus, until recently multiple authors have
categorized into 3 clinical groups: local (vulva), groin, and dis- described their experience with vulvar melanoma using one or
tant. The reported experience with local recurrence at the vulva more different staging systems (e.g., Breslows depth, Clarks
is surprisingly good. Recurrence-free survival can be obtained in levels, AJCC staging), making standardization of prognostic
up to 75% of cases when the recurrence is limited to the vulva groups and treatment strategies difficult. Recently, Moxley etal.
and can be excised with a gross clinical margin (133,134). The reported a multi-institutional retrospective examination of 77
observation that many of these vulva recurrences occur at sites patients with vulvar melanoma. Presenting staging data (via
remote from the initial primary tumor or that they occur years AJCC, Breslows thickness, and Clarks levels) and treatments
after apparently successful primary treatment suggests that some were correlated with outcomes, specifically recurrence and over-
recurrences probably represent new primary tumors rather than all survival. Among the 3 staging methods, only AJCC staging
the development of new disease. Recurrences in the groin, how- was significantly correlated with overall survival, although Bre-
ever, are almost universally fatal. A few patients may be saved slows thickness was significantly associated with likelihood of
by resection of bulky disease and local radiation, perhaps even recurrence (34).
using intensity modulated radiotherapy (IMRT) in patients who The primary treatment modality for vulvar melanoma is
have had prior pelvic radiation. Patients who develop distant surgical excision. Radical vulvectomy with bilateral inguino-
metastases are candidates for palliative systemic cytotoxic or femoral lymphadenectomy has been the historical treatment
targeted chemotherapy or transition to comfort care. of choice (136,137). Because most failures are distant though,
radical local resection does not appear to enhance survival.
Furthermore, many patients with vulvar melanoma are elderly,
Nonsquamous Histologies
with coexisting medical problems, making less radical and mor-
Because nonsquamous vulvar malignancies are exceedingly bid surgery compelling. More recent reviews recommend some
rare, relatively little definitive information is available regard- form of hemivulvectomy or wide local excision along with in-
ing optimal treatment and long-term outcome. Most available guinal lymphadenectomy or SLN mapping (34,110,137). DOI
information is derived from isolated case reports or small series and the presence of ulceration are significant prognostic factors
spanning long periods of time. and should be considered in treatment planning. Look et al.
542 CHAPTER 19 VU LVA
reported a series of vulvar melanoma patients in whom none occur, particularly in tumors removed with suboptimal resection
of the patients with lesion depth of 1.75 mm experienced a margins.
recurrence and suggested that these patients could be treated
with wide local excision. In contrast, all patients with lesion
depth of >1.75 mm recurred despite radical tumor excision Adenocarcinoma
(75). Based on information derived from large series of patients
with cutaneous melanomas at nongenital sites, regional lymph- Patients presenting with vulvar adenocarcinoma should first un-
adenectomy should probably be considered a prognostic rather dergo an extensive clinical evaluation to determine whether the
than a therapeutic procedure. In a multivariate analysis of 644 lesion in question represents a primary versus metastatic tumor.
patients with vulvar melanoma, Sugiyama et al. reported 5-year Despite the paucity of data regarding the evaluation and treat-
disease-specific survival rates of 68%, 29%, and 19% for pa- ment of vulvar adenocarcinoma, resection of localized disease
tients with zero, one, and 2 or more positive lymph nodes, re- by radical wide excision, hemivulvectomy, or radical vulvectomy
spectively (135). Lymphadenectomy can be avoided in patients seems appropriate (148). The incidence of groin node metasta-
with superficial melanomas (<1 mm, Tis, and Clarks level I), for ses is approximately 30% (149). Some form of inguinal lymph-
whom the risk of metastatic disease is negligible. SLN identifi- adenectomy should be included with primary surgical resection.
cation and biopsy have been increasingly applied to the surgical Radiation therapy may have a role in enhancing local control
management of cutaneous malignant melanomas, and multiple for women with large primary tumors or inguinal metastases.
authors assert that for those surgeons who are competent with The effectiveness of chemotherapy is unknown, although a sin-
the technique, SLN mapping and biopsy should be considered gle case report documents a response with pegylated liposomal
a standard practice, with false-negative rates extrapolated from doxorubicin in adenocarcinoma of the vulva (150).
squamous carcinoma of the vulva comparable to other disease
sites such as breast cancer and cutaneous, nonvulvar melanoma
(34,138). Pagets Disease
Radiation therapy may be useful in enhancing local and Pagets disease is associated with an underlying invasive adeno-
regional control for some high-risk patients. Despite reported carcinoma component in approximately 15% of cases (151). As
complete clinical response rates and local tumor control rates many as 20% to 30% of patients will have or will later develop
of 50% to 70% for patients with localized recurrences treated an adenocarcinoma at another nonvulvar location (152), although
with radiation therapy, alone or in combination with hyperther- more recent series suggest a lower incidence of secondary malig-
mia, these modalities have rarely been used in the primary treat- nancies (153). Observed sites of nonvulvar malignancies develop-
ment of vulvar melanoma (139,140). ing in patients with extramammary Pagets disease include breast,
Systemic chemotherapy, in either an adjuvant or salvage set- lung, colorectum, gastric, pancreas, and upper female genital tract.
ting, is considered palliative; durable responses are rare, and ad- Screening and surveillance for tumors at these sites should be con-
verse effects are usually considerable. Interferon alpha-2b has sidered in patients with Pagets disease.
been shown to have activity in patients with small volume tumor Pagets disease should be resected with a wide margin. If un-
burden; however, because of its narrow therapeutic index, its derlying invasion is suspected, the deep margins should be ex-
use is typically available only at high volume centers. Multiple tended to the perineal fascia. Some suggest careful assessment
cytotoxic chemotherapeutics have demonstrated activity. Most of the surgical margins using multiple frozen sections to ensure
notable among these are dacarbazine (DTIC), temozolomide, complete excision (154,155). This approach can be cumbersome
and platinum-based regimens, which yield response rates from and may not influence the long-term incidence of recurrence.
7% to 12%. Novel combinations of IL-2 and cytotoxic chemo- Pierie et al. showed that patients with microscopically positive
therapy are also commonly employed; however, to date, such margins had a significantly higher rate of recurrence; however,
approaches have not been shown to be superior to standard sal- with extended follow-up, all patients eventually recurred (154).
vage therapies. Because of the relatively poor response rates to Others have shown that despite surgical efforts to the contrary,
cytotoxic agents, in recent years much emphasis has been placed microscopically positive margins are frequent, and disease recur-
on using small molecule inhibitors, or biologic agents targeting rence is common regardless of margin status (156). Repeat local
well-characterized genetic mutations in melanomas. The best excision of recurrent disease is usually effective in the absence of
characterized melanoma mutations for which there are biologic invasion (157).
inhibitors are B-Raf, c-Kit and CTLA-4 (141).
Overall survival rates in women with vulvar melanoma are
approximately 50% (142,143). Patients with superficial lesions Nonsurgical Therapy
have an excellent chance for cure after surgical resection, but Imiquimod is an immune modulator that is believed to affect
patients with deeper lesions or metastases at the time of diag- the function of the Toll-like receptor (Tlr) as a costimulatory
nosis have a more limited prognosis. These patients are good molecule for T-cell-mediated immune response to malignant
candidates for investigational trials. cells. It has well-documented activity for treatment of genital
warts as well as vulvar dysplasia. It also reportedly has activity
in extramammary Pagets disease. In several small case series,
Verrucous Carcinoma complete response (CR) rates of as much as 92% have been
reported (158,159,160).
Verrucous carcinomas are locally invasive and rarely metasta-
size (144). Consequently, treatment by radical wide excision is
usually curative (145). Local recurrence can occur, especially
when the tumor has been inadequately resected. Vulvar Sarcomas
The specific histologic types are described in the pathology sec-
tion of this chapter. All types of vulvar sarcoma are rare, but
leiomyosarcoma, MFH, and rhabdomyosarcoma predominate
Basal Cell Carcinoma (161,162). Cures have occasionally been obtained with aggres-
Basal cell carcinomas should be removed by excisional biopsy sive resection of either primary or locally recurrent disease. The
using a minimum surgical margin of 1 cm (146). Lymphatic or results of regional and systemic therapy for leiomyosarcoma
distant spread is exceedingly rare (147). Local recurrence may are disappointing. These patients are excellent candidates for
CHAPTER 19 VU LVA 543
DISEASE SITES
Metastatic Tumors to the Vulva Inguinofemoral Lymphadenectomy
Appropriate surgical management of the groin nodes has been
Treatment of secondary vulvar tumors should be directed
evolving for many years. Original descriptions of radical vul-
against the primary tumor. As with bulky vulvar cancers, a mul-
vectomy included en bloc resection of the vulva with inguinal
timodal approach seems to provide some opportunity for long-
and pelvic lymph nodes. The extent of lymphadenectomy was
term survival, along with enhanced local tumor control and
steadily reduced, first eliminating the pelvic node dissection and
organ preservation.
then reducing the extent of the groin dissection. The concept of
Cutaneous vulvar lymphatic metastases may occur as in tran-
superficial inguinal lymph adenectomy was proposed in the late
sit tumor emboli from anorectal tumors or as retrograde flow
1970s; however, this approach was ultimately rejected by gy-
metastases when bulky tumors of the cervix or uterus obstruct
necologic oncologists due to an unexpectedly high relapse rate
the normal lymphatic drainage patterns (Fig. 19.14). These me-
(Table 19.5).
tastases are multiple and are often bilateral. Their histology re-
flects that of the primary tumor. Because this metastatic pattern
is associated with advanced tumors, the primary tumor should
be readily detectable by examination.
Table 19.5 Unanticipated Groin Failure in
Patients with Negative Superficial
Lymphadenectomy
SU RGICAL TECH N IQU ES
Investigators No. %
Wide Radical Excision Burke et al. (165) 4/76 5.2
Several names have been applied to the procedures used to re- Berman et al. (65) 0/50 0
sect small vulvar cancers: partial deep excision, radical wide
excision, radical local excision, wide local excision, modified Stehman et al. (166) 6/121 5.0
radical vulvectomy, and hemivulvectomy. Regardless of the Gordinier et al. (170) 9/104 8.6
preferred nomenclature, the surgical procedure should be ad-
equately defined and described. Surgical incisions are devised Total 19/351 5.4
to allow for at least a 1 to 2 cm resection margin encompassing
544 CHAPTER 19 VU LVA
DISEASE SITES
15% to 20% of cases (165,166,167). As with other techniques,
the incidence and severity of groin complications such as infec-
tion, wound breakdown, or lymphocyst formation is still high
(168). There are few if any indications for radical vulvectomy as
Radical Vulvectomy the primary treatment for vulvar cancer.
In very rare circumstances, radical vulvectomy may be indicated
for recurrent vulvar cancer. The classic description of radical
Pelvic Exenteration
vulvectomy and bilateral lymphadenectomy can be described as
based on either a butterfly or longhorn approach. The but- Curative resection may still be possible when vulvar recur-
terfly incisions use convex wings over the groin and around rence extends to the vagina, proximal urethra, or anus. Selected
the anus to facilitate closure of the defect (Fig. 19.18). The long- patients have achieved long-term survival after pelvic exentera-
horn incisions were developed to limit skin resection over the tion for such recurrences (169,170). The surgical approach in
groin in an attempt to reduce wound breakdown (164). The these cases should be individualized to the size and location of the
arcing superior incision is placed from the lateral margins of recurrent tumor, prior therapies, and the age and overall health
the groin dissection across the mons pubis. The lateral vulvar of the patient. Patients considered for pelvic exenteration should
incisions are placed at the labiocrural folds, because these topo- have a thorough preoperative evaluation to exclude the presence
graphical landmarks represent the most lateral location of the of regional and/or distant metastases. Frequently, anterior or pos-
superficial vulvar lymphatics. The perianal incision is placed to terior exenteration with an extended vulvar phase will provide
allow resection of the perineal body. These incisions are taken excellent resection margins while allowing preservation of either
to the level of the deep inguinal and perineal fascia and permit urinary or fecal continence. The techniques used to perform the
enbloc removal of both superficial and deep groin nodes, the exenteration are identical to those routinely used for the treat-
entire vulva, and an intervening skin bridge. ment of women with recurrent cervical carcinoma. Multiple vul-
After removal of the specimen, the skin and mucosal edges var and perineal reconstructive techniques have been described
are undermined to permit mobilization and primary closure for coverage of large surgical defects (171,172,173,174).
with delayed absorbable suture. Some degree of tension at the
suture lines is unavoidable, particularly in the perineal body
Resection of Groin Recurrence
and periurethral areas. Closed suction drains are usually placed
in the groin sites to remove excess lymphatic- and serous-fluid Patients who develop isolated groin recurrence should be
accumulations and are usually removed when drain output is treated with multimodality treatment if radiotherapy is still an
minimal (5 to 14 days). option. Surgical resection should be viewed with caution in the
546 CHAPTER 19 VU LVA
Note: 5-FU, 5-fluorouracil; CDDP, cisplatin; Mito, mitomycin C; RT, radiation therapy.
Although the published experiences with preoperative single- disease in the vulva (115). These results are all the more notable
modality radiation therapy are small, several investigators have considering the relatively low dose of radiation used in these
reported excellent responses and high local control rates after typically bulky, advanced tumors. Building on this experience,
treatment of advanced tumors with relatively modest doses of investigators sought to study weekly cisplatin chemotherapy co-
radiation therapy followed by local resection (187,188). These administered with radiation (GOG protocol 205). On this trial,
reports provided emerging evidence that radiation could signifi- 58 evaluable patients with untreated locally advanced T3 or T4
cantly debulk advanced local disease and allow for more conser- disease not amenable to standard radical vulvectomy underwent
vative, viscera-sparing surgery while preserving good local control. preoperative radiochemotherapy (196). On this contemporary
Data have emerged supporting the therapeutic benefit of radio- study, radiation totaled 57.6 Gy in 32 uninterrupted daily frac-
chemotherapy, typically followed by limited surgical resection, in tions of 1.8 Gy. Cisplatin (40 mg/m2) chemotherapy was admin-
addressing locally advanced disease (Table 19.6) (115,189,190). istered weekly. Following vulvar excision or biopsy, 37 (64%) of
These trials were initially prompted by extrapolation from supe- 58 patients had no residual tumor in the pathologic specimen.
rior local control and survival outcomes after radiochemotherapy It is important to be cautious in designing aggressive treat-
for anal cancer (189,190). Typical regimens have included com- ment protocols for this group of patients, who are often elderly
binations of radiation coadministered with 5-fluorouracil (5-FU), and have coexistent medical problems. Serious pulmonary
and cisplatin or mitomycin C. Most investigators have observed toxicity has been observed in patients treated with bleomycin
remarkable regressions of bulky lesions with radiochemotherapy, (193,194). In the largest published series of patients treated with
DISEASE SITES
suggesting that therapeutic responses may be better than would mitomycin C and 5-FU, hematologic tolerance was acceptable,
be expected with radiation alone. Randomized trials of the role but the administered dose of mitomycin C was more conserva-
of radiochemotherapy have not been done and are unlikely to be tive than is usually used in the treatment of anal cancers (195).
feasible within this disease, given the small number of patients Other investigators have confirmed the increased toxicity asso-
and heterogeneity of clinical presentation. However, recent single ciated with concurrent radiochemotherapy, especially with the
experimental arm trials have demonstrated improved local con- use of mitomycin Cbased regimens (196).
trol and survival when concurrent cisplatin chemotherapy was Following radiochemotherapy for locally advanced disease,
added to radiation in locally advanced vulvar cancers (191,192). it remains undefined whether surgery is necessary in those who
The most compelling data in support of concurrent radio- achieve complete clinical response. In GOG 101, approximately
chemotherapy in the management of locally advanced disease 70% of patients who achieved complete clinical response were
come from 2 large prospective phase 2 trials performed by the found to have no pathologic residual in the surgical specimen.
Gynecologic Oncologic Group (GOG protocols 101 and 205). In In GOG 205, 34 of 37 patients (92%) underwent surgical bi-
the first study (GOG protocol 101), 71 evaluable patients with opsy only to assess radiochemotherapeutic response. Of these
locally advanced T3 or T4 disease who were deemed not resect- 34 women, 29 (78%) had biopsies showing a complete response
able by standard radical vulvectomy underwent preoperative ra- to radiochemotherapy. At this point, we continue to recommend
diochemotherapy. Chemotherapy consisted of 2 cycles of 5-FU biopsies of the original tumor bed in patients who achieve com-
and cisplatin. Radiation was delivered to a dose of 47.6 Gy, using plete clinical response. In those with residual vulvar disease after
a planned split-course regimen, with part of the radiation given radiochemotherapy, surgical resection would be individualized
twice daily during the 5-FU infusion. Patients underwent planned and tailored to the extent and location of residuum.
resection of the residual vulvar tumor, or incisional biopsy of
the original tumor site in the case of complete clinical response,
4to 8 weeks after chemoradiotherapy. A complete clinical tumor
response was noted in 33 of 71 patients (47%). Following vulvar Treatment of Regional Disease
excision or biopsy, 22 patients (31%) were found to have no Although radical inguinal lymphadenectomy has historically
residual tumor in the pathologic specimen. In all, only 2 of 71 been considered the treatment of choice for regional manage-
patients (3%) had unresectable disease after radiochemotherapy, ment of invasive vulvar carcinoma, a number of retrospective
and in only 3 patients was it impossible to preserve urinary and/ studies have suggested that regional prophylactic radiation
or gastrointestinal continuity following complete resection of the therapy is an effective method of preventing groin recurrences
primary tumor residuum. With a median follow-up interval of with minimal morbidity (197,198). In a large single-institution
50 months, 11 patients (16%) have developed locally recurrent retrospective analysis, Katz et al. reported no differences in the
548 CHAPTER 19 VU LVA
DISEASE SITES
used to detect enlarged nodes that may not be appreciated on clin- in this disease.
ical exam and to determine the appropriate electron energy. Gross Furthermore, robotic stereotactic body radiosurgery has been
disease in the groin or vulva may be boosted with en face electron attempted in patients with recurrent disease after previous ir-
fields. In some cases, interstitial implants or en face electron fields radiation. Here, radiation is delivered using a linear accelerator
may be used to boost the dose to the primary site. If radiation is mounted on an industrial robotic arm. By allowing pencil-
directed to the regional nodes only, with intentional sparing of the beam noncoplanar radiation delivery, robotic stereotactic body
FIGURE 19.21. Intensity modulated radiation therapy in the management of vulvar cancer.
Source: Reprinted with permission from Beriwal S, Heron D, Kim H, et al. Intensity-modulated radiotherapy for the treatment of vulvar carcinoma: a comparative dosimetric study with early
clinical outcom.e. Int JRadiat Oncol Biol phys. 2006; 64:13951400.
550 CHAPTER 19 VU LVA
radiosurgery delivers accurate and precise radiation (0.4 mm the femoral heads to less than 35 Gy should minimize the risk of
precision) at an escalated dose per fraction that is consid- this complication. It is not known whether severe osteoporosis
ered ablative (>8 Gy per fraction). In one report, 3 women contributes to femoral head complications. In general, with care-
underwent palliative stereotactic body radiosurgery (8 Gy ful treatment planning techniques, the risk of major late compli-
3fractions = 24Gy) with complete regression of their bulky vul- cations following regional nodal radiation, either electively or
var tumors (212). While the treatment was successful, inability adjuvant to lymph node dissection, is low (197). It has been sug-
to identify occult microscopic disease at the time of radiosurgical gested that concurrent chemotherapy may increase the risk, but
planning led to disease relapse outside and abutting the radio- this remains to be adequately substantiated (191,208).
surgical target in all 3 women. Incorporating advanced imaging, The effect of radiation therapy on the long-term cosmesis
such as 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) scans, im- and function of the vulva is poorly understood. Although treat-
proves target localization and is likely to improve the therapeutic ment with radiation or radiochemotherapy and wide excision is
usefulness of this approach (213). becoming a more accepted alternative to extensive surgery for
selected patients, and major complication rates appear to be ac-
ceptable, very little has been reported regarding more subtle late
Acute Complications of Radiation Therapy effects of such treatment in the vulva. Late effects are dose re-
Acute radiation reactions are brisk, and doses of 35 to 45 Gy lated. Better information will become available only as treating
routinely induce confluent moist desquamation. However, with physicians record and report the late cosmetic and functional
adequate local care, this acute reaction usually heals within results of treatment (191,214).
3 to 4 weeks. Sitz baths, steroid cream, and treatment of possi-
ble superimposed Candida infection all help to minimize the dis-
comfort. If the patient is sufficiently flexible, she may be placed
in a frog-leg position during treatment to minimize the dose and CH EMOTH ER APY
ensuing skin reaction on the medial thighs; care must then be
taken, however, to deliver an adequate dose to the vulvar skin. Primary Treatment of Advanced Disease
Although most patients will develop confluent mucositis by the
fourth week of treatment, this is usually tolerated if the patient The majority of patients diagnosed with vulvar cancer can be
is warned in advance and assured that the discomfort will re- cured with surgery with or without postoperative radiation
solve after treatment is completed. Although a treatment break therapy; thus, chemotherapy monotherapy has traditionally been
is occasionally required, delays should be minimized, because used solely for salvage therapy. Patients with advanced vulvar
they may allow time for repopulation of tumor cells. cancers tend to be older, with significant medical comorbidities,
making them poor candidates for cytotoxic therapy because of
concomitant diseases that increase the likelihood for significant
Late Complications of Radiation Therapy adverse effects. Furthermore, recurrent vulvar cancer often occurs
in the setting of extensive prior surgery and/or radiation therapy,
Many factors add to the late morbidity of radiation treatment in
making tolerance to cytotoxic therapy poor.
patients with vulvar carcinoma. Patients with advanced vulvar
carcinomas often are treated with radiation therapy following
radical surgery, which may include extensive dissection of the
inguinal and possibly pelvic nodes. Large ulcerative cutaneous Squamous Cell Carcinoma
lesions frequently have superimposed infection. Patients are of-
Cytotoxic Chemotherapy
ten elderly and may have complicating medical conditions, such
as diabetes, multiple prior surgeries, and osteoporosis. The con- Squamous carcinoma is the only histologic type of vulvar cancer
tribution of concurrent chemotherapy to local morbidity is not for which there is significant data assessing the utility of cyto-
yet clearly defined but may contribute to bowel and bone com- toxic chemotherapy in recurrent or advanced primary vulvar
plications (208,209). cancer not amenable to surgery or radiotherapy. A number of
The incidence of lower extremity edema after inguinal irra- drugs have undergone phase 2 testing (Table 19.7) (215218).
diation alone is negligible (197,203). Radiation therapy is likely Among these, only doxorubicin and bleomycin appear to have
to contribute to the cumulative incidence of peripheral leg edema significant clinical activity. Cisplatin, a drug that has demon-
following radical node dissection, but there was no difference strated broad activity in most gynecologic tumors (e.g., epithe-
evident in the GOG randomized study of radiation (16%) versus lial ovary, endometrial adenocarcinoma, and endometrial mixed
pelvic node dissection (22%) (204). Femoral head fractures have mesodermal tumors and squamous carcinoma of the cervix),
occasionally been reported in patients treated with irradiation to has notably little activity as monotherapy in vulvar and vaginal
the inguinal nodes (187,195). Techniques that limit the dose to squamous tumors. Paclitaxel dosed at 175 mg/m2 every 3 weeks
a
Five of 6 responses with no prior therapy; one of 16 responses in refractory disease.
b
No patient with prior radiation therapy or chemotherapy; responses were the same for primary therapy and recurrences; 8 patients had resectable disease after
chemotherapy.
was evaluated in the EORTC phase 2 trial 55985. Thirty-one Women with HPV infections, in situ vulvar disease, long smok-
patients with metastatic or locally advanced carcinoma of the ing history, and other genital neoplasms are at risk for devel-
vulva were treated, and 29 were assessable for response. Grade oping vulvar cancer. Careful screening targeted at women
3 or 4 toxicity was seen in 27.6% of patients, and objective with these high-risk factors may lead to improvements in early
responses were seen in just 13.8% of patients. diagnosis.
Several drug combinations have also been used in squamous The survival rate for women with nodal spread is one-half that
vulvar cancer, most commonly as neoadjuvant therapy for pa- for women without nodal disease who have similarly sized pri-
tients with inoperable disease. Combinations used in vulvar mary tumors (Fig. 19.22). Improvements in the use of molecular
squamous cancer are detailed in Table 19.8 (219,220). markers for metastatic disease and biologic aggressiveness would
Recognition of the fact that Epidermal Growth Factor Re- be helpful for triaging higher risk patients into more effective ad-
ceptor (EGFR) expression via immunohistochemical staining is juvant therapies. And, of course, there is a dire need for better
elevated in malignant vulvar tumors has led to the use of EGFR treatment options for node-positive patients.
DISEASE SITES
tyrosine kinase inhibitors (TKIs) as monotherapy and in com-
bination with cytotoxic chemotherapy for use in palliation of
advanced and recurrent vulvar cancer patients. Olawaiye in
2007 reported 2 dramatic partial responses to single agent er- SEQU ELAE OF TREATM ENT
lotinib in women with advanced, treatment refractory disease;
Bacha in 2010 reported a PR in a woman with advanced disease Immediate complications such as wound infection and lymphocyst
(221,222). A phase 2 GOG trial using erlotinib in advanced or were common in the radical vulvectomy era. These complications
recurrent vulvar cancer patients is under way. occur much less frequently due to less radical surgery and innova-
tions such as prophylactic antibiotics and closed suction drains.
Breakdown of the vulvar incision is increased in patients who are
smokers, have vasculopathy, and display chronic poor hygiene.
RESU LTS OF TH ER APY Lymphedema starts to appear within weeks of surgery. The
severity is related to the extent of groin surgery, wound compli-
The overall results of therapy for women with squamous cancers cations, postoperative radiation therapy, and preexisting condi-
of the vulva are excellent based largely on the fact that approxi- tions of the lower extremities. Lymphedema is not limited to the
mately two-thirds of patients present with early-stage tumors. lower leg and thigh. It may also include the mons, groins, and
Five-year survival rates for vulvar cancer have improved over hips. The use of SLNB reduces but does not eliminate wound
the past 2 decades. Landrum et al. used GOG data to perform complications and lymphedema.
an historical comparison between patients treated between 1977 Pressure stockings, sequential compression devices, lymph-
and 1984 (n = 577) with patients treated between 1990 and edema massage, and microvascular surgery have been used to
2005 (n = 175). Stratification into minimal, low, intermediate, manage lower extremity lymphedema, with limited results. Pre-
and high risk groups was performed to enable comparisons. vention of lymphedema with the use of SLNB is the best strategy
Patients treated in the era of less radical surgery and mod- for limiting the adverse effects of this complication.
ern chemoradiation fared better than historical comparisons, All gynecologic surgery, especially surgery for vulvar cancer,
with 5-year survival by risk group (minimal high) of 100% can have an adverse effect on body image and sexual function. In-
versus 97.9%, 97% versus 87.4%, 82% versus 74.8%, and formed consent obtained for vulvar cancer surgery should include
100% versus 29.0% (96). a discussion regarding these risks. No assumptions regarding a
Several strategies to enhance survival for women with vul- womans sexual activity should be made based on age or mari-
var cancer are evident. High-risk patients can be educated and tal status. We have found that preoperative consultation with a
screened more consistently for the development of early cancer. sexual health expert can be invaluable for many women.
552 CHAPTER 19 VU LVA
80 Bilateral inguinal 31
Unilateral and bilateral pelvic 14
Proportion surviving
60
40
20
0
0 12 24 36 48 60 72 84 96
Time (in months)
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Management of vulvar melanoma. Gynecol On- ments in the surgical approach. Am J Obstet for the development of lymph node metastasis
col. 1992;45:254258. Gynecol. 1973;117:483489. in vulvar squamous carcinoma. Gynecol Oncol.
144. Gallousis S. Verrucous carcinoma: report of 165. Hacker NF, Leuchter RS, Berek JS, et al. Radical 1990;37:916.
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Obstet Gynecol. 1972;40:502506. tomy through separate groin incisions. Obstet Prognostic factors in carcinoma of the vulva.
145. Japaze H, Dinh TV, Woodruff JD. Verrucous car- Gynecol. 1981;58:574578. Gynecol Oncol. 1985;20:364367.
cinoma of the vulva: study of 24 cases. Obstet 166. Burrell MO, Franklin EW 3rd, Campion MJ, 186. Faul CM, Mirmow D, Huang Q, et al. Adju-
Gynecol. 1982;60:462467. et al. The modified radical vulvectomy with vant radiation for vulvar carcinoma: improved
146. Breen JL, Neubecker RD, Greenwald E, et al. groin dissection: an eight-year experience. Am J local control. Int J Radiat Oncol Biol Phys.
Basal cell carcinoma of the vulva. Obstet Gyne- Obstet Gynecol. 1988;159:715719. 1997;38:381385.
col. 1975;46:122125. 167. Siller BS, Alvarez RD, Conner WD, et al. T2/3 187. Hacker NF, Berek JS, Julliard GJF, et al. Preop-
147. Hoffman MS, Roberts WS, Ruffolo EH. vulva cancer: a case-control study of triple in- erative radiation therapy for locally advanced
Basal cell carcinoma of the vulva with ingui- cision versus en bloc radical vulvectomy and vulvar cancer. Cancer. 1984;54:20562064.
nal lymph node metastases. Gynecol Oncol. inguinal lymphadenectomy. Gynecol Oncol. 188. Jafari K, Magalotti M. Radiation therapy in car-
1988;29:113117. 1995;57:335340. cinoma of the vulva. Cancer. 1981;47:686691.
148. Copeland LJ, Sneige N, Gershenson DM, et al. 168. Gaarenstroom KN, Kenter GG, Trimbos JB, 189. Moore DH, Ali S, Koh WJ, et al. A phase II trial
Bartholin gland carcinoma. Obstet Gynecol. et al. Postoperative complications after vulvec- of radiation therapy and weekly cisplatin che-
1986;67:794799. tomy and inguinofemoral lymphadenectomy motherapy for the treatment of locally-advanced
149. Leuchter RS, Hacker NF, Voet RL, et al. Primary using separate groin incisions. Int J Gynecol squamous cell carcinoma of the vulva: a gyne-
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150. Huang GS, Juretzka M, Ciaravino G, et al. Lipo- cancer. Gynecol Oncol. 1995;58:189193. comes after radiation therapy with concurrent
somal doxorubicin for treatment of metastatic 170. Forner DM, Lampe B. Exenteration in the treat- weekly platinum-based chemotherapy or every-
chemorefractory vulvar adenocarcinoma. Gyne- ment of stage III/IV vulvar cancer. Gynecol On- 3-4-week 5-fluorouracil-containing regimens for
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1992:131135. carcinoma of the vulva. Acta Radiol Oncol. cies. J Nucl Med Radiat Ther. 2011; http://
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1993;27:209212. 205. Parthasarathy A, Cheung MK, Osann K, et al. 2003;17:683701.
193. Iversen T. Irradiation and bleomycin in the treat- The benefit of adjuvant radiation therapy in 215. Deppe G, Bruckner HW, Cohen CJ. Adriamycin
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194. Scheistroen M, Trope C. Combined bleomycin 206. Oonk MH, van Hemel BM, de Hullu JA, et al. 216. Thigpen JT, Blessing JA, Homesley HD, et al.
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Acta Oncol. 1992;32:657663. vival in early stage vulvar cancers: results from of the vulva: a Gynecologic Oncology Group
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positivity in squamous cell carcinoma of the diation therapy. Technol Cancer Res Treat. Size of sentinel-node metastasis and chances
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20
CHAPTER
Vagina
DISEASE SITES
cularis, and adventitia. The inner mucosal layer is formed by a
thick, nonkeratinizing, stratified squamous epithelium overlying Preaortic
a basement membrane containing many papillae. The epithe-
lium normally contains no glands, but is lubricated by mucous
secretions originating in the cervix. The epithelium changes little
in response to the reproductive cycle. Beneath the mucosa lies
a submucosal layer of elastin and a double muscularis layer,
highly vascularized with a rich innervation and lymphatic drain-
age. The muscularis layer is composed of smooth muscle fibers, Sup. gluteal
arranged circularly in the inner portion and longitudinally in the Anal
outer portion. A vaginal sphincter is formed by skeletal muscle Vesical rectal Interiliac
at the introitus. The adventitia is a thin, outer connective tissue
layer that merges with that of adjacent organs.
The proximal vagina is supplied by the vaginal artery branch
from the uterine or cervical branch of the uterine artery. It runs
along the lateral wall of the vagina and anastomoses with the
inferior vesical and middle rectal arteries from the surrounding
viscera (1). The accompanying venous plexus, running paral- Inf. gluteal
lel to the arteries, ultimately drains into the internal iliac vein.
The lumbar plexus and pudendal nerve, with branches from the
sacral roots 2 to 4, provide innervation to the vaginal vault.
The lymphatic drainage of the vagina is complex, consisting
Femoral
of an extensive intercommunicating network. Fine lymphatic
vessels coursing through the submucosa and muscularis coalesce
FIGURE 20.1. Lymphatic drainage of the vagina.
into small trunks running laterally along the walls of the vagina.
Source: Reprinted from Plentl AA, Friedman EA. Lymphatic system of the female genitalia. In: Plentl
The lymphatics in the upper portion of the vagina drain primar- AA, Friedman EA, eds. The Morphologic Basis of Oncologic Diagnosis and Therapy. Philadelphia, PA: WB
ily via the lymphatics of the cervix; the upper anterior vagina Saunders; 1971:55, Figure 5-2. Used with permission.
557
558 CHAPTER 20 VAGI NA
of the vagina may be associated with several presumed precur- III, although no substantial data are available. Chyle et al. (14)
sor lesions including adenosis, endometriosis, and mesonephric noted a 10-year actuarial pelvic nodal failure rate of 28% and a
rests. 16% inguinal failure rate in patients who had local recurrence,
Clear cell adenocarcinoma (CCA) related to in utero DES in contrast to 4% and 2%, respectively, in the group without
continues to receive attention as the prototypical example of local recurrence (p < 0.001). The incidence of clinically posi-
disease caused by an endocrine-disrupting chemical (61). The tive inguinal nodes at diagnosis as reported by several authors
incidence of CCA of the vagina and cervix is increased 24-fold ranges from 5.3% to 20% (19,35).
in daughters of women who were exposed to DES in utero dur- Distant metastasis may occur, primarily in patients with
ing the first 16 weeks of pregnancy (28,62). Specific suggested advanced disease at presentation, or those who recurred after
mechanisms of carcinogenesis focus on the retention of nests primary therapy. In the Perez et al. series (19), the incidence of
of abnormal cells of mllerian duct origin, which, after stimu- distant metastasis was 16% in stage I, 31% in stage IIA, 46%
lation by endogenous hormones during puberty, are promoted in stage IIB, 62% in stage III, and 50% in stage IV. In the larg-
into adenocarcinomas. The median age at diagnosis in the DES- est series reported to date by Hellman et al., distant metastases
exposed patients is 19 years (28,61), whereas prior to this re- at diagnosis were rare at 2%, and in 5 of the 7 patients with
port, most patients with CCA of the vagina were elderly. The distant metastases, the tumor involved the entire vagina (36).
incidence of CCA in the exposed female population from birth Robboy et al. reported that metastases to the lungs or supracla-
to 34 years is estimated to be between 0.14 and 1.4 per 1,000. vicular lymph nodes represented 35% of recurrences in young
Approximately 90% of the patients had stage III disease at women with CCA, a proportion much greater than found with
diagnosis and most cases involved the anterior upper third of SCC of the cervix or vagina (37).
the vaginal wall. Fortunately, the incidence of this tumor has
decreased in recent years, and may decrease even more since the
practice of prescribing DES during pregnancy has been discon-
tinued. Palmer et al. (30) assessed the influence of postnatal fac-
tors on the development of CCA in women exposed to DES in CLI N ICAL PRESENTATION
244 cases compared with 244 age-matched non-DES-exposed
women. Neither oral contraceptive use nor pregnancy was as-
sociated with risk of CCA (30). Vaginal Intraepithelial
NeoplasiaCarcinoma In Situ
VAIN most often is asymptomatic (17). In modern practice,
VAIN is usually detected by cytological evaluation performed
NATU R AL H ISTORY OF TH E following hysterectomy as part of a surveillance strategy in
DISEASE (PATTERNS OF SPREAD) patients with a history of CIN or invasive cervical carcinoma.
In these cases, VAIN has a predilection for involvement of the
The majority (57% to 83%) of vaginal primaries occur in the upper vagina, likely secondary to a field effect. A discharge
upper third or at the apex of the vault, most commonly in the may be present, but is likely secondary to superimposed vaginal
posterior wall; the lower third may be involved in as many as infections. It should be noted that evidence-based guidelines do
31% of patients (15,21,33). Lesions confined to the middle not support routine cytological studies following hysterectomy
third of the vagina are uncommon. The location of the vaginal for noncervical pathology. The American Cancer Society 2012
carcinoma is an important consideration in planning therapy guidelines indicated that surveillance cytology in such patients
DISEASE SITES
and determining prognosis. Vaginal tumors may spread along is not necessary. Rather, surveillance cytology post hysterectomy
the vaginal walls to involve the cervix or the vulva. However, if should be limited to those patients with a prior history of CIN
biopsies of the cervix or the vulva are positive at the time of ini- or invasive cervix cancer (38).
tial diagnosis, the tumor cannot be considered a primary vagi-
nal lesion. Because of the absence of anatomic barriers, vaginal
tumors readily extend into surrounding tissues, such that a le-
sion on the anterior wall may infiltrate the vesicovaginal septum Invasive Squamous Cell Carcinoma
and/or the urethra; those on the posterior wall may eventually In patients with invasive disease, irregular vaginal bleeding,
involve the rectovaginal septum and subsequently infiltrate the often postcoital, is the most common presenting symptom fol-
rectal mucosa. Lateral extension toward the parametrium and lowed by vaginal discharge and dysuria. Pelvic pain is a rela-
paracolpal tissues is not uncommon in more advanced stages of tively late symptom generally related to tumor extent beyond
the disease as well as involvement of the obturator fossa, car- the vagina (12). In a series of 84 patients with invasive carci-
dinal ligaments, lateral pelvic walls, and uterosacral ligaments. noma, including 55 with SCC, Tjalma et al. noted that 62% of
The issue of regional nodal metastasis, both the incidence of patients had vaginal discharge, 16% had positive cytology, 13%
occult nodal disease and the anatomic pathways of lymphatic had a mass, 4% had pain, and 2% had dysuria. Forty-seven per-
spread, is somewhat controversial. The incidence of positive cent of the lesions were located on the posterior wall and 24%
pelvic nodes at diagnosis varies with the stage and location of on the anterior wall; 29% had involvement of both walls (39).
the primary tumor. Because the lymphatic system of the vagina In 10% to 20% of the patients, no symptoms were reported,
is so complex, any of the nodal groups may be involved, regard- and the diagnosis was made by cytological examination.
less of the location of the lesion (2). Involvement of inguinal
nodes is most common when the lesion is located in the lower
third of the vagina. There does seem to be a significant risk of
nodal metastasis for patients with disease beyond stage I. Al- Other Histologies
though data on staging lymphadenectomy are sparse, 2 studies The most common presenting symptom in patients with CCA is
reported a significant incidence of nodal disease in early-stage vaginal bleeding (50% to 75%) or abnormal discharge. More
vaginal carcinoma. In Al-Kurdi and Monaghans series (34), advanced cases may present with dysuria or pelvic pain (26).
the incidence of pelvic nodal metastasis was 14% and 32% Cytology is abnormal in only 33% of cases. Therefore, in ad-
for stages I and II, respectively, whereas in the Davis et al. se- dition to 4-quadrant cytology, Hanselaar et al. recommended
ries (24), the incidence was 6% and 26% for stages I and II, palpation of the entire vaginal vault to assess for submucosal
respectively. The incidence is expected to be higher for stage irregularity (40). The majority of CCA lesions are exophytic,
560 CHAPTER 20 VAGI NA
Source: From FIGO Committee on Gynecologic Oncology. Current FIGO staging Source: American Joint Committee on Cancer (AJCC). Vagina. In: Edge SB, Byrd
for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic DR, Compton CC, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York,
neoplasia. Int J Gynaecol Obstet. 2009;105(1):34. Used with permission. NY: Springer-Verlag; 2010:469472. Used with permission.
CHAPTER 20 VAGI NA 561
DISEASE SITES
ongoing care. However, it can be difficult even for the experi-
enced examiner to differentiate between disease confined to the Gastrointestinal stromal tumor
mucosa (stage I) and disease spread to the submucosa (stage II)
(13,33,48). Solitary fibrous tumor
Pelvic computed tomography (CT) scan is generally per- Synovial sarcoma
formed to evaluate inguinofemoral and/or pelvic lymph nodes,
as well as extent of local disease. In patients with vaginal mel- Endometrial stromal sarcoma
anoma or sarcoma, chest, abdomen, and pelvic CT scans are Malignant peripheral nerve sheath tumor
often part of the workup. Magnetic resonance imaging (MRI)
has emerged as a potentially important imaging modality in the Angiomyofibroblastoma
evaluation of vaginal cancers, predominantly intermediate sig- Other mesenchymal tumors
nal intensity on T1-weighted images and high signal intensity on
T2-weighted images (49). Taylor et al. (49) concluded that MRI Miscellaneous tumors
identified over 95% of primary vaginal tumors and enabled ra- Melanoma
diologic staging, which correlated with outcomes. An additional
role of MRI is differentiation of tumor from fibrotic tissue in Yolk sac tumor (endodermal sinus tumor)
patients with suspected recurrent vaginal carcinoma (50). Peripheral primitive neuroectodermal tumor/Ewing sarcoma
Positron emission tomography (PET) is evolving as a modal-
ity of potential use in the evaluation of vaginal cancer that al- Wilms tumor
lows detection of the extent of the primary as well as abnormal Hematolymphoid tumors
lymph nodes more often than does CT scan. PET/CT was evalu-
ated in a prospective registry study in 23 patients comparing the Non-Hodgkins lymphoma
results of CT and whole-body PET (51). CT visualized the intact Leukemia/myeloid sarcoma
primary tumor in 43% of patients as compared to PET, which
visualized 100% of all intact primary tumors. Furthermore, all
abnormal lymph nodes visualized by CT were also detected by
PET, with the addition of 4 additional foci consistent with nodal cure, therapeutic planning will be guided by disease volume
metastasis found on PET imaging (51). assessment utilizing CT, MRI, and/or PET/CT, even though
In modern practice, for the majority of patients with dis- such radiologic modalities are not allowed for purposes of
ease volume and/or location requiring definitive RT to achieve staging.
562 CHAPTER 20 VAGI NA
squamous intraepithelial lesion (LSIL) being equivalent to and is the precursor lesion for CCC, but can also be seen in
VAIN1 and high-grade squamous intraepithelial lesion (HSIL) non-DES-exposed women. Microscopically, the involved mu-
being equivalent to VAIN23 (55). cosa may have glandular epithelium at the surface or glands in
VAIN1 is appropriately considered a premalignant lesion the lamina propria. The glandular epithelium may be mucinous,
as high risk HPV types have been identified in 76% of VAIN1 tuboendometrial (which may be ciliated), or composed of cuboi-
lesions, with low-risk types in the remainder (60). VAIN23 dal embryonic type cells (55). While a risk factor for CCC, most
almost always has detectable high risk HPV DNA, with HPV cases will spontaneously regress (55). When adenosis is seen in
type 16 being the most common type, present in 50% to 54% of association with a CCC, the adenosis is likely to be cytologically
cases (55,60). The natural history of untreated VAIN is not well atypical and of the tuboendometrial type (53).
understood, but with treated cases there is an approximately Primary vaginal adenocarcinomas not associated with DES
5% risk of progression to invasive SCC (53). exposure have a much higher median age at presentation (54
years) than DES-associated cases (63). Prognosis is significantly
worse than other primary carcinomas, with a 5-year survival
Glandular Tumors and Precursors rate of 34%, compared to 58% for SCC (63) and 93% for DES-
associated CCC (53).
Vaginal CCS (Fig. 20.4) are grossly nodular or polypoid. While endometrioid adenocarcinoma involving the vagina is
Microscopically, these tumors are similar to clear cell carcinoma most commonly of endometrial origin, primary endometrioid
(CCC) of the ovary or endometrium and they are composed of adenocarcinoma also occurs. It is the second most common type
variable sized glands lined by cuboidal epithelium with variable of primary vaginal adenocarcinoma (after CCC) (64). In one
nuclear enlargement and atypia (53). The cytoplasm may be series of 18 cases, the mean patient age was 60 years, 16 pa-
clear due to cytoplasmic glycogen, but this is not a requirement tients had previously had a hysterectomy, 14 patients had vagi-
for diagnosis and some cases may have scant or predominantly nal endometriosis (a presumed precursor lesion), and none of
eosinophilic cytoplasm. Some tumor cells may have large nu- the patients had a history of DES exposure (64). These tumors
clei that protrude into the glandular lumens (hobnail cells). have histologic features typical of endometrial endometrioid ad-
A tubulocystic pattern, with variable sized glands, sometimes enocarcinomas: glandular architecture with columnar cells and
with areas of flattened epithelium and papillary tufting, is char- flat luminal borders and squamous or mucinous metaplasia in
acteristic, but solid and papillary patterns may also be seen (55). some cases (64). In some cases, papillary architecture may sug-
Most cases will have associated vaginal adenosis. gest a diagnosis of serous carcinoma or squamous metaplasia
The most critical histological differential diagnostic consid- with cytoplasmic glycogen may suggest a diagnosis of CCC, but
eration is Arias-Stella reaction (such as in vaginal endometrio- careful attention to the morphology of the glandular areas and
sis), so patient history concerning the presence or absence of the usual presence of associated endometriosis may be helpful
current or recent pregnancy should be obtained. Microglan- in diagnosing endometrioid adenocarcinoma. As primary vagi-
dular hyperplasia, which may occur in adenosis as well as in nal adenocarcinomas are much less common than secondary
the endocervix, may also enter the differential diagnosis (53). tumors, the possibility of a primary tumor in the endometrium,
Vaginal metastases of renal cell carcinoma have been reported ovary, and colon must be carefully excluded (64).
with some frequency, sometimes preceding the diagnosis of a Primary serous adenocarcinoma has been reported as a pri-
renal tumor, and may need to be excluded with immunohisto- mary tumor in the vagina. Metastasis from the endometrium or
chemical evaluation (53). ovary must be excluded. CCC is also in the differential diagnosis
Vaginal adenosis, the presence of mllerian-type glandular as it may have papillary architecture and lack clear cytoplasm
epithelium in the vagina, is related to prenatal DES exposure
DISEASE SITES
and may easily be confused with serous carcinoma. A recent
carcinoma in a patient with possible in utero DES exposure
was reported as grade 2/3 clear cell and focal papillary serous
carcinoma, but not histologically illustrated (65).
Primary vaginal mucinous adenocarcinoma resembling cer-
vical mucinous adenocarcinoma (lacking goblet cells) has been
reported following hysterectomy, presumably arising from ad-
enosis or endocervicosis (66). Exclusion of a metastasis, espe-
cially from the endocervix, endometrium, or ovary, is necessary
to establish this diagnosis.
Very rare cases of primary vaginal adenocarcinoma of intestinal
type have been reported (67). These tumors are not related to DES
exposure and are composed of mucin-producing malignant glands,
often with intraluminal nuclear debris (dirty necrosis) (67).
Immunohistochemically, these tumors are diffusely positive for
CDX-2 and cytokeratin 20, markers of intestinal differentiation
(not necessarily origin), so clinical, endoscopic, and radiologic ex-
clusion of origin from a colorectal, endometrial, ovarian, or other
primary is necessary to establish this diagnosis(67).
Mesonephric adenocarcinoma, carcinoma thought to arise
from the remnants of the mesonephric ducts, is one of the rar-
est primary vaginal tumors. The mean patient age in one series
FIGURE 20.4. High magnification view of a vaginal clear cell carcinoma. The
was 41 years, and the presentation may be a multicystic vaginal
characteristic tubulopapillary architecture is seen with glands lined by cuboidal mass (68). The tumors histologically are seen as crowded glands
epithelium with prominent scalloped luminal surfaces and nuclei that protrude
or tubules composed of low columnar or cuboidal epithelium
into the gland lumens (hobnail nuclei). There are occasional papillae that
extend into the spaces and single tumor cells that appear to lie unattached containing eosinophilic secretion (69). A variety of patterns
within the gland lumens. There is high-grade nuclear atypia and marked may be seen, but the glandular (ductal) pattern is the most com-
hyperchromatism in some of the nuclei. Typically, clear cytoplasm is focally mon and may closely resemble an endometrioid adenocarci-
present but much of the malignant epithelium has scant or eosinophilic noma(68). Association with mesonephric remnants, present in
cytoplasm. the lateral wall of the vagina, or mesonephric hyperplasia, is key
564 CHAPTER 20 VAGI NA
to recognizing a tumor as a mesonephric carcinoma (68). The with granular eosinophilic cytoplasm, expression of chromo-
tumor cells lack clear cytoplasm and staining for mucin and gly- granin and synaptophysin, and absence of expression of keratin
cogen are negative, but PAS staining may demonstrate basement AE1/AE3, actin, desmin, and HMB-45 (77,78). Catecholamine
membrane material around the tubules (55). The immunohisto- hypersecretion is a potential concern during biopsy or surgical
chemical profile, positive for cytokeratin AE1/AE3, cytokeratin treatment (78).
5/6, CD10, vimentin, and calretinin and negative for carcinoem-
bryonic antigen, cytokeratin 20, estrogen receptor protein, and
progesterone receptor protein, may be useful for differentiating
this tumor from other adenocarcinomas (68,69). The prognosis Mixed Epithelial
of these rare tumors is not yet well established, but may be better and Mesenchymal Tumors
than that of mllerian adenocarcinomas (68). Some cases may Carcinosarcoma/malignant mixed mllerian tumor (MMMT)
have an associated spindle cell component (malignant mixed has been reported as a primary vaginal tumor (79). The epithe-
mesonephric tumor) and may have heterologous elements such lial component in the reported cases of primary vaginal MMMT
as rhabdomyosarcoma or atypical cartilage (68). is usually SCC (79). Absence of sarcomatoid component kera-
As primary vaginal carcinomas are rare and metastases rela- tin staining has been suggested as a criterion for differentiat-
tively common, metastatic carcinoma should always be consid- ing MMMT (sarcomatoid component keratin negative) from
ered in the differential diagnosis of a glandular vaginal tumor. sarcomatoid carcinoma (sarcomatoid component keratin posi-
Metastases may be from a number of sites that may have rela- tive)(79). Because the epithelial component is usually squamous
tively large undiagnosed primary tumors, such as the uterus, and because a recent case was associated with VAIN3 and high-
ovary, and kidney. Pancreatic carcinoma may also present with risk human papillomavirus infection (79), it could be argued
vaginal metastases (70). Isolated vaginal metastases of rectal ad- that these cases likely represent sarcomatoid carcinomas with
enocarcinoma have been seen and may respond well to local loss of sarcomatoid component keratin expression.
excision and chemotherapy (71). Myoepithelial neoplasms similar to those more commonly
Pagetoid adenocarcinoma in situ has been seen involving vagi- seen in the salivary glands, with oval epithelioid cells with co-
nal epithelium, believed to represent direct extension from origin expression of keratin and desmin and/or smooth muscle actin,
in the cervix (72). The cells are admixed with the squamous epi- have been reported (80). The examples from the vagina have
thelium, have pale cytoplasm, and stain immunohistochemically been benign (80).
with cytokeratin 7 and p16 (73). Extension of Pagets disease
of the vulva into the vaginal epithelium is also a consideration.
Mesenchymal Tumors
Sarcomas represent 3% of primary vaginal cancers. There are
Other Epithelial Tumors several primary mesenchymal tumors that may occur in the va-
Adenosquamous carcinomas compose approximately 2% of gina and the histologic diagnosis of this group of tumors may
primary vaginal carcinomas (55). These tumors are composed be very challenging. There are 2 tumors, rhabdomyosarcoma
of a mixture of glandular and squamous components, lack asso- and leiomyosarcoma, that are of special interest because of their
ciated adenosis or endometriosis, and may behave aggressively. relative frequency at this site. Before establishing a diagnosis of
Primary glassy cell carcinoma has been the subject of a single a primary vaginal sarcoma, however, a variety of other lesions
case report (73). Glassy cell carcinoma is considered a variant with spindle cell morphology must be excluded including sarco-
of poorly differentiated adenosquamous carcinoma with poor matoid carcinoma, spindle cell melanoma, leiomyosarcoma or
prognosis (73). The tumors are histologically composed of nests endometrial stromal sarcoma of uterine origin, and metastatic
of cells with abundant eosinophilic or amphophilic cytoplasm sarcoma. Mesenchymal tumors can be grouped as predomi-
with a ground glass appearance, prominent cell membranes, nantly round cell tumors, spindle cell tumors with high cellular-
large nuclei, and cytoplasmic mucin positivity (73). ity, and spindle cell tumors with low cellularity.
Adenoid cystic carcinoma may involve the vagina, but if seen The most important round cell mesenchymal tumor at this
on a biopsy, it is likely to be of Bartholin gland origin and would site is rhabdomyosarcoma (also known as sarcoma botryoides),
be considered a vulvar, rather than vaginal, primarily (74). These the most common sarcoma of childhood (Fig. 20.5). Genital
tumors are composed of nests of basaloid epithelial cells with tract rhabdomyosarcoma may involve the vagina or the cervix
cribriform architecture with hyaline stroma (composed of base- and accounts for only 0.003% of genital tract malignancies
ment membranelike material and mucin) within the rounded (81). The median patient age at presentation is 2 years (82), but
spaces. Perineural invasion is commonly seen. rare cases may occur in adults (55). Pediatric rhabdomyosarco-
Primary vaginal small cell (neuroendocrine) carcinoma is mas are of embryonal subtype in 95% of cases and the botryoid
very rare with fewer than 25 cases reported (75). The mean variant was the most common, 80% of the total cases (82).
age at presentation is 59 years and postmenopausal bleeding is The tumors are commonly polypoid (or similar in appear-
the usual presenting symptom (75). Most small cell carcinomas ance to a bunch of grapes, leading to the designation botryoi-
will express a neuroendocrine marker such as synaptophysin. des) and are composed histologically of poorly differentiated
Secondary involvement of the vagina by a cervical or other neu- tumor cells with overlying benign squamous epithelium. There
roendocrine carcinoma must, of course, be excluded in order to may be a hypercellular band composed of cells with very little
establish this diagnosis. TTF-1, an immunohistochemical stain visible cytoplasm immediately deep to the squamous epithelium
often used as a marker of lung or thyroid origin is frequently (cambium layer). Below this, the cellularity is variable and may
positive in extrapulmonary small cell carcinomas so immuno- be sparse with cytologically atypical round or occasionally spin-
reactivity does not prove that a tumor is metastatic at this site. dle-shaped nuclei widely spaced in edematous stroma. Mitotic
Prognosis is very poor with only about 15% of patients surviv- figures are usually frequent and the Ki-67 labeling index is high.
ing more than 1 year (75). Primary vaginal small cell carcinoma Histologically recognizable skeletal muscle differentiation in the
may cause Cushing syndrome due to adrenocorticotropic hor- form of strap cells is not always seen and is not a requirement
mone production by the tumor (76). for diagnosis. Immunohistochemical staining for desmin and
Vaginal paraganglioma is another epithelioid tumor that has muscle-specific actin (muscle markers) and myoglobin and myo-
been the subject of single case reports (77,78). These tumors genin (striated muscle markers) may be useful in confirming the
have a characteristic nested pattern with round or polygonal cells diagnosis (53,55).
CHAPTER 20 VAGI NA 565
DISEASE SITES
epithelial membrane antigen and/or keratin. gelatinous consistency and histologically by spindle and stellate
Smooth muscle neoplasms are composed of fascicles cells with cells in myxoid stroma and blood vessels of varying size includ-
oval to elongated nuclei and eosinophilic cytoplasm. Vaginal ing thick-walled vessels (84, 89). Immunohistochemical stain-
smooth muscle tumors may be benign or malignant. Leiomyomas ing for estrogen receptor protein, progesterone receptor protein,
are the most common vaginal stromal tumors, may have a simi- desmin, and CD34 are positive, but these markers also label the
lar presentation compared to leiomyosarcoma, and may enlarge other tumors in this differential diagnosis (84). HMGA2, the
rapidly during pregnancy (55). Histologic criteria have varied product of a transcription factor gene subject to rearrangement
over time, but a smooth muscle tumor over 3 cm with 5 or more in aggressive angiomyxoma, may prove to be useful in the differ-
mitotic figures per 10 high power fields and moderate to marked ential vs. the histologically similar lesions (84). Initial treatment
cytologic atypia should be considered a leiomyosarcoma (53,55). is surgical, but treatment of recurrent tumors with hormonal
Some leiomyomas from pregnant women may have increased mi- therapy or radiotherapy has also been attempted (89).
totic activity (55). Angiomyofibroblastoma and myofibroblastoma are related
Leiomyosarcomas are the most common vaginal sarcoma mesenchymal tumors that may occur in the vulva or vagina and
in adults and present most commonly with vaginal bleeding in may be related to tamoxifen treatment (90,91). Angiomyofi-
a patient above the age of 40 (53,55). Histologically, they are broblastoma is a circumscribed, nonencapsulated, cytologically
similar to the much more common uterine leiomyosarcomas. bland, spindle cell tumor with variable cellularity, edematous
These tumors invade locally and have hematogenous metasta- zones, prominent thin-walled vessels, and insignificant mitotic
ses. Primary treatment is surgical and the 5-year survival of ap- activity (84,90). Stromal lymphocytes and mast cells, multi-
proximately 35% (53). nucleate cells, and tumor cell aggregation around blood vessels
Gastrointestinal stromal tumors (GIST) may rarely present may be seen in some cases (84). Immunohistochemical staining
as a rectovaginal septal mass and in this situation they are likely for vimentin, desmin, PTEN, CD34, estrogen receptor protein,
to be misdiagnosed as a smooth muscle tumor (83,84). Correct and progesterone receptor protein are expected to be positive,
diagnosis of this tumor is important because of the malignant and that for smooth-muscle actin and S-100 protein will be
potential of this tumor, the lack of effectiveness of conventional negative (90). Angiomyofibroblastoma is benign but must be
chemotherapy and radiotherapy, and because of the existence distinguished from the aggressive angiomyxoma (90).
of specific treatment (Imatinib mesylate) for this tumor (83,84). Myofibroblastoma is a spindle cell tumor that arises from
GISTs in this location are spindle cell tumors with a median the subepithelial stroma of the vagina and is usually not asso-
mitotic count of 15 per 10 high power fields (83). Immunohis- ciated with tamoxifen treatment (91). The cells may be ovoid
tochemical stains for KIT (CD117) and CD34 are positive and or stellate, are arranged among thick collagen bands, and stain
stains for desmin and estrogen receptor protein are negative (84). immunohistochemically for vimentin, desmin, and CD99 while
566 CHAPTER 20 VAGI NA
staining for smooth muscle actin is negative (91). These tumors these tumors may have a variety of histologic patterns, but a
may recur locally, but metastasis has not been reported (91). mesh-like microcystic pattern with hyaline globules is com-
Occasional stromal tumors may have epithelioid morphol- monly seen (96). Reticular, solid, and papillary patterns, some-
ogy, composed of round or polygonal cells with abundant times with columnar cells surrounding a fibrovascular core
cytoplasm in a solid pattern. Once the possibility of a carci- (Schiller-Duval bodies) may also be seen (53,96). Immunohis-
noma, a neuroendocrine tumor (such as carcinoid tumor or tochemical staining for a -fetoprotein may be helpful if positive,
paraganglioma), or a melanoma have been excluded, there are a but is poorly sensitive. Glypican 3 and SALL4 are newer, more
variety of epithelioid stromal tumors that are potential diagnos- sensitive, markers for yolk sac tumor that have recently been
tic possibilities. These include a smooth-muscle tumor or GIST used investigated at other sites and may also be useful for vagi-
with epithelioid morphology, granular cell tumor, alveolar soft nal yolk sac tumor (9799). Correct diagnosis is critical as these
part sarcoma, and perivascular epithelioid cell tumor. tumors respond well to platinum-based chemotherapy and sur-
Primary vaginal perivascular epithelioid cell tumor has been gical treatment may not be necessary (95).
the subject of reports of single cases in an adult (92) and in Along with rhabdomyosarcoma (see above) and hematolym-
a child (93). These tumors, also known as PEComa, clear cell phoid neoplasms (see below), a few rare sarcomas are possible
myomelanocytic tumor, or extrapulmonary clear cell sugar considerations in the small round cell tumor differential diag-
tumor, are composed of sheets of tumor cells with central round nosis. Peripheral primitive neuroectodermal tumor and Ewing
nuclei, prominent nucleoli, and abundant eosinophilic or clear sarcoma are considered related neoplasms that show neuroec-
cytoplasm (92,93). Pigment production by the tumor may be todermal differentiation and share characteristic chromosomal
prominent and the tumors stain immunohistochemically for translocations, usually t(11;22), which result in fusion of the
HMB-45, desmin staining is variable, and they are negative EWSR1 and FLI-1 genes (100). These are very rare tumors,
for S-100 protein, keratin, chromogranin, and synaptophysin which usually present in young adults (100,101). Histologically,
(92,93). The cellular morphology, pigment, and HMB-45 ex- the tumors are lobulated at low magnification with solid cellular
pression could potentially lead to confusion with melanoma, aggregates separated by fibrous septae. At high magnification,
but the absence of staining for S-100 and variable staining for the tumor cells have relatively uniform hyperchromatic nuclei
desmin may be helpful. and scant to moderately abundant eosinophilic cytoplasm.
Squamous and glandular differentiations are not seen and only
a minority of cases will have rosette formation by the tumor
cells (100). Immunoreactivity for CD99 and FLI-1, absence of
Miscellaneous Tumors staining for muscle markers, and molecular identification of
Primary vaginal malignant melanomas comprise 3% to 8% of the characteristic t(11;22) are confirmatory (100,101). Reverse
primary vaginal malignant tumors (52,55). In the NCDB report transcriptase polymerase chain reaction or fluorescent in situ
by Creasman et al. (5), vaginal melanomas represented 4% of hybridization molecular studies are considered the gold stan-
primary vaginal cancers. Trimbles examination of the Surveil- dard for the diagnosis of these tumors (100).
lance, Epidemiology, and End Results (SEER) data on 30,295 A single case of primary vaginal extrarenal teratoid Wilms
melanomas found 51 vaginal melanomas (0.3% of all melano- tumor (nephroblastoma) has recently been reported (102). This
mas), with an annual incidence of 0.026 per 100,000 (32). They tumor had areas of undifferentiated malignant cells (blastoma
most commonly present with vaginal bleeding, usually involve component), but the spindle cell and epithelial/tubular compo-
the distal one-third of the vagina, and have a mean age at pre- nent typical of Wilms tumor were also present along with het-
sentation of 61 years (94). The tumors are commonly nodular, erologous cartilage, skeletal muscle, squamous epithelium, and
ulcerated, and pigmented, but they may also be amelanotic (55). mucinous epithelium (103).
Microscopically, melanomas may have rounded, epithelioid cells
or be composed of spindle-shaped cells. Adenocarcinoma or
poorly differentiated squamous carcinoma (in the case of mela-
nomas with rounded cells) or sarcoma or sarcomatoid carcino- Hematolymphoid Tumors
mas (in the case of spindle cell melanoma) may be differential Primary non-Hodgkins lymphoma of the female genital tract
diagnostic considerations and immunohistochemical staining is rare, less than 1% of extranodal lymphomas, but second-
for S-100 protein, HMB-45, and MelanA are often helpful in ary involvement in advanced lymphoma is significantly more
confirming the diagnosis of melanoma. Excluding metastatic common. The mean patient age is approximately 52 years and
melanoma may be difficult, but the presence of an extensive lat- patients may present with a mass, vaginal bleeding, or urinary
eral junctional component would favor a primary melanoma symptoms (104). Lymphoma limited to the vagina has been the
(53) and a history of melanoma elsewhere would certainly raise subject of occasional case reports and may clinically closely
the possibility of metastasis. mimic a carcinoma (105,106). Very rare reports of other tumors
Clarks level, assigned based on histologic levels in the skin, such plasmacytoma and eosinophilic granuloma also exist (55).
is not appropriate at this site, but depth of invasion (measured Correct preoperative diagnosis of extranodal non-Hodgkins
in mm) should be reported. Almost all cases are greater than lymphomas is essential to avoid radical surgery and allow spe-
2mm in depth (53). In a recent series of stage I cases, the median cific treatment. B symptoms such as fever, weight loss, night
tumor size was 3.0 cm and the median depth of invasion was sweats, and fatigue are usually absent (105). The differential
7 mm (94). Of the patients surgically treated with lymph node diagnosis may include inflammatory conditions and a variety
dissection, 25% had positive pelvic or inguinal lymph nodes of tumors that may have inconspicuous cytoplasm including
(94). The reported prognosis is worse than that of cutaneous small cell carcinoma, melanoma, endometrial stromal sarcoma,
melanoma, with 5-year survival rates of 5% to 20% for vaginal and primitive neuroectodermal tumors (104). The tumors may
melanoma (53,55). be diffuse large B-cell lymphomas or follicular lymphomas
The vagina is the primary site of rare pediatric extragonadal (104,105). One recently reported case of primary vaginal diffuse
yolk sac tumors. These tumors (also known as endodermal sinus large B-cell lymphoma was associated with immune thrombocy-
tumor) may clinically present similarly to rhabdomyosarcoma, topenic purpura (107).
with a friable polypoid mass associated with vaginal bleeding in Myeloid sarcoma, a tumor composed of malignant myelo-
a child (95,96). Most of the reported tumors have been in pa- blasts, is also known as granulocytic sarcoma and chloroma.
tients 4 years of age or younger (53). Serum a -fetoprotein eleva- These tumors may present as a vaginal mass in the absence of
tion may be helpful in suspecting the diagnosis. Histologically, a history of acute myeloid leukemia (AML), although patients
CHAPTER 20 VAGI NA 567
presenting with myeloid sarcoma will generally progress to survival was 63.2% for patients below the age of 60 years com-
AML relatively rapidly (108). Histologically, the tumors are pared with 25% for those over 60 years of age (p < 0.001).
composed of small to intermediate size cells with scant cyto- Similar findings were reported by Eddy et al. (113) and in the
plasm, fine chromatin, and frequently with crush artifact (108). NCDB of the American College of Surgeons (5), showing bet-
Immunohistochemical staining for keratin and neuroendocrine ter survival in younger patients (90% versus 30%, respectively).
markers, muscle markers, melanoma markers, and B- and T-cell However, most of these series do not correct for death second-
markers will be negative (108). Myeloperoxidase, lysozyme, ary to intercurrent disease in the elderly population. No statisti-
CD43, and CD68 are among the useful positive markers for this cal significance of age to survival was found in the series of Dixit
potentially difficult to diagnose neoplasm (108). et al. (114) and Perez et al. (35).
With regard to the histological type and grade, several series
(16,123,126) have shown the histological grade to be an inde-
pendent, significant predictor of survival. However, the histol-
ogy of the tumor (SCC vs. other) has not been found to be a
PROGNOSTIC FACTORS prognostic factor for survival among the patients with invasive
I N FLU ENCI NG CHOICE OF tumors. Chyle et al. (14) noted a higher incidence of local re-
TREATM ENT currence in patients with adenocarcinoma compared with SCC
(52% and 20%, respectively, at 10 years), as well as a higher
incidence of distant metastases (48% and 10%, respectively),
Invasive SCC and lower 10-year survival rate (20% vs. 50%). A report by
As with most primaries, stage of disease is the dominant prog- Frank etal. (63) compared outcome of patients with non-DES-
nostic factor in terms of ultimate outcome (14,16,18,19,35, associated adenocarcinoma of the vagina to that of patients
109120). In Perezs series, including 212 patients with primary with SCCs. They found a 5-year overall survival rate of 34% in
vaginal carcinomas treated with definitive RT, the 10-year actu- the adenocarcinoma group compared to 58% for the patients
arial disease-free survival was 94% for Stage 0, 80% for StageI, with SCC (p > 0.01) (63).
55% for Stage IIA, 35% for Stage IIB, 38% for Stage III, and An increased propensity for distant metastases to the lung
0% for those with Stage IV (35). In a recent SEER analysis of and supraclavicular nodes has been reported in patients with
over 2000 patients by Shah et al., the 5-year disease-specific sur- CCA (37). Stage, tubulocystic pattern, size less than 3 cm, and
vival was 84% for stage I, 75% for stage II tumors, and 57% for depth of invasion less than 3 mm were all noted to be associated
women with advanced disease (121). with superior survival (40).
The impact of lesion location has been controversial. Several Vaginal melanoma has a higher propensity for development
investigators (14,23,122,123) have shown better survival and of distant metastases, and affected patients do more poorly than
decreased recurrence rates for patients with cancers involving patients with SCC. A review by Reid et al. of 115 vaginal mela-
the proximal half of the vagina when compared with those in noma patients noted that depth of invasion and size of lesion
the distal half or those involving the entire length of the vagina. (>3 cm) adversely impacted survival, but stage did not, perhaps
Tarraza et al. (124) reported that upper-third lesions develop because it was known for only 42 of the 115 patients in the
local recurrences more frequently, and lower-third lesions de- series. (31) Patients with malignant mesenchymal tumors of the
velop a disproportionate number of sidewall and distant recur- vagina do worse than those with invasive SCC due to a higher
rences. Chyle et al. (14) observed a 17% rate of pelvic relapse in propensity for development of local recurrence and distant me-
patients with upper vaginal tumors, 36% in those with middle tastases. Specific, adverse prognostic factors for vaginal sarcoma
DISEASE SITES
or lower vaginal tumors, and 42% with whole-vaginal involve- identified by Tavassoli and Norris (127) included infiltrative
ment. However, a larger series failed to note any difference in versus pushing borders, high mitotic rate of 5 or more mitoses
site of recurrence based on primary lesion location (3,35). In ad- per 10 HPFs, size greater than 3 cm in diameter, and cytological
dition, lesions of the posterior wall have a worse prognosis than atypia. However, in a SEER analysis by Shah et al. (121), there
those involving other vaginal walls (10-year recurrence rates of was no difference in 5-year disease specific survival between all
32% and 19%, respectively) (14), which probably reflect the histological types, although vaginal melanoma was associated
greater difficulty of performing adequate brachytherapy proce- with an increased risk of mortality in their multivariate model
dures in this location. (HR 1.51).
The prognostic importance of lesion size has been controver- Overexpression of HER2/neu oncogenes in squamous cancer
sial, with an adverse impact noted with increasing size on multi- of the lower genital tract is a rare event that may be associated
variate analysis in several series (14,16,39,117,121) contrary to with aggressive biologic behavior (128). Waggoner et al. (129),
Perez et al.s (3,35) findings. In the Chyle et al. series (14), lesions in a group of 21 women with CCA of the vagina and cervix, ob-
measuring less than 5 cm in maximum diameter had a 20% ten- served a more favorable prognosis in gynecologic tumors with
year local recurrence rate compared to 40% for those lesions an overexpression of wild-type p53 protein than in tumors con-
larger than 5 cm. Similarly, in the Princess Margaret Hospital ex- taining mutated TP53 genes.
perience, tumors larger than 4 cm in diameter fared significantly Lymph node metastasis at diagnosis portends a poor progno-
worse than smaller lesions (16). In the Perez et al. series (35), sis. However, this has not been extensively evaluated in vaginal
stage was an important predictor of pelvic tumor control and cancer. The only report of outcome based on lymph node status
5-year disease-free survival, but the size of the tumor in stageI is by Pingley et al. (130). They reported a 56% DFS for patients
patients was not a significant prognostic factor. However, in without lymph node involvement and 33% for those with meta-
stage IIA disease, lower pelvic tumor control and survival were static lymphadenopathy at presentation.
noted with tumors larger than 4 cm. In stages IIB and III, tumor In a recent series by Tran et al, which included only invasive
size was not a significant prognostic factor, probably related to SCC, prior hysterectomy as well as normal pretreatment/treat-
the difficulty in assessing size and the fact that higher doses of ment hemoglobin levels were favorable prognostic factors on
RT were delivered for larger tumors. Stock et al. (21) reported multivariate analysis in the treatment of vaginal cancer (119).
that disease volume, a likely surrogate for stage or lesion size, In their review, it is recommended to consider transfusion with
adversely impacted survival as well as local control. packed red blood cells to maintain normal hemoglobin levels as
Age has also been reported as a significant prognostic fac- this approach has had some success in cervical cancer patients.
tor with increasing age correlating with poorer survival Possible explanations for improved outcomes in women with
(23,117,125). In the Urbanski et al. series (23), the 5-year previous hysterectomies included possible increased surveillance
568 CHAPTER 20 VAGI NA
with detecting vaginal cancer at an earlier stage, or simply less has largely replaced surgery as primary therapeutic modality, in
vaginal substrate for tumorigenesis to occur within (119). Chyle order to maximize cure and improve quality of life, with iso-
et al. (14) and Hellman et al. (117) also found that previous lated central failures offered exenteration (33). Even in patients
hysterectomy had more favorable outcome; however, this result with early stage I invasive tumors involving the middle or upper
did not hold up on multivariate analysis. third of the vagina, surgical treatment requires radical vaginec-
tomy and pelvic lymph node dissection. Frequently the patient
has undergone previous hysterectomy, but if the uterus is still
present, concurrent hysterectomy may be necessary to achieve
GEN ER AL MANAGEM ENT: adequate margins. Lindeque (305) pointed out that most tumors
TREATM ENT OPTIONS AN D require removal of the full length of the vagina, although in lo-
OUTCOM E BY FIGO STAGES calized lesions a partial colpectomy may be performed. Although
radical surgery in the past precluded vaginal function, this has
Owing to its rarity, data concerning the natural history, prog- improved significantly by the use of split-thickness grafts and
nostic factors, and treatment of vaginal carcinoma derive from myocutaneous flap (136). Gracilis myocutaneous flaps and rec-
small, single institutions, retrospective studies. Most of the tus abdominis myocutaneous flaps have been commonly used
currently available literature in terms of radiotherapeutic and for neovaginal reconstruction following radical pelvic surgery,
surgical techniques refers to primary SCC of the vagina. It is with superior results noted in those undergoing rectus abdomi-
important to recognize the complexity of the management of nis reconstruction (136).
patients with carcinoma of the vagina and the need for an indi- Given the potentially devastating functional results often as-
vidualized approach after careful assessment by the gynecologic sociated with radical surgery, definitive RT has largely replaced
oncologist and radiation oncologist. With adequate therapy, the surgery as the primary therapeutic modality in patients with
survival rates of patients with carcinoma of the vagina are com- vaginal cancer, in order to maximize cure and improve qual-
parable with those reported for carcinoma of the cervix, which ity of life. Furthermore, most patients are elderly, and a radical
range from 20% to 80% at 5 years, depending on stage of the surgical approach is often not feasible. Despite the acceptance
disease (15,20,33,47,123,131). Perez et al. (4) noted a some- of RT as the treatment of choice for this disease, the optimal
what higher incidence of pelvic failures in patients with carci- approach for each stage is not well defined in the literature.
noma of the vagina compared with 1,054 patients with invasive A combination of limited surgery and RT has been suggested
cervical carcinoma, although the differences are not statistically to improve outcome, although the complication rates may in-
significant. Creasman et al. (5), in the NCDB report based on crease (137). Frank et al. (48) suggest that radiation treatment
4,885 patients with primary vaginal cancer, found the survival be individualized with the optimal treatment approach selected
rate at 5 years to be 96% for stage 0, 73% for stage I, 58% for according to the tumor size, tumor site, extent of disease, and
stage II, and 36% for stages III and IV. In addition, survival response to initial RT. Intracavitary and interstitial irradiation
was better in the younger patients (90% vs. 30% in the older is used in small superficial stage I disease. External beam RT
patients). (EBRT) in combination with intracavitary (ICB), and/or inter-
In most patients, the primary treatment modality is RT, as stitial (ITB) brachytherapy is generally used for more extensive
reported by the Society of Gynecologist Oncologists in practice stage I-II disease. Data regarding the use of cytotoxic therapy in
guidelines published in 1998 (5). However, several surgical series vaginal carcinomas are based on underpowered phase II trials of
have reported acceptable to excellent outcomes in well-selected various monotherapies or extrapolated from SCC of the cervix,
patients, with survival rates after radical surgery for stage I dis- which has a similar biology.
ease ranging from 75% to 100% (5,13,24,33,39), although few
studies directly compare the 2 treatment modalities. The SEER
analysis by Shah et al. (121) showed that among women with FIGO Stage 0: Vaginal Intraepithelial
stage I disease, those treated with RT only or RT and limited
surgery or no treatment, had worse outcome than those treated NeoplasiaCarcinoma In Situ
with surgery alone (generally involving radical or exenterative VAIN has been approached both surgically and medically by
procedures). However, only women with stage I disease who re- multiple investigators. Treatment options range from partial
ceived no treatment had a statistically significant increased risk or complete vaginectomy to more conservative approaches
of mortality (HR 2.23; 95% CI, 1.015.03). such as local excision, electrocoagulation, laser vaporization,
Local excision and partial and complete vaginectomy have topical 5% fluorouracil (5-FU) administration, or ICB. For pa-
given way to a more individualized approach that takes into con- tients in whom invasive disease cannot be ruled out, as well as
sideration the patients age, the extent of the lesion, and whether for those who fail conservative therapy, surgical resection re-
it is localized or multicentric. There is evidence that patients mains the treatment of choice. Overall, the reported control
with CIS-VAIN and early stage I, primarily with a lesion located rates are very similar among the different approaches, ranging
in the apex and upper third of the posterior and lateral walls from 48% to 100% for laser (138140), 52% to 100% for
of the vagina or distal third of the vagina, and highly selected colpectomy (5,132,133,141), 75% to 100% for topical 5-FU
women with stage II vaginal cancers can be successfully treated (142145), and 83% to 100% for RT (14,16,131), (Table 20.3)
with surgery alone (13,21,24,39,132,133). These patients could (5,14,16,35,131133,140145). The degree of VAIN and the
be approached with radical hysterectomy, upper or partial vagi- age and general health of the patient are important treatment
nectomy, and pelvic lymphadenectomy, provided that adequate considerations. A therapy appropriate for CIS in a woman
margins are obtained (13,15,21,24,33). If the margins are found with good performance status and many anticipated years of
to be close or positive after resection, adjuvant RT is recom- life expectancy may not be appropriate for a woman with mul-
mended. In addition, surgery could be considered in younger tiple comorbidities who may succumb to one of her other ill-
patients with a desire to preserve ovarian function (134) and/ nesses before the CIS would be expected to progress to invasive
or a functional vagina (21), patients with verrucous carcinoma carcinoma.
(135), those with nonepithelial tumors, and patients with local- The anatomic constraints posed by the location of the va-
ized pelvic failures after radiation. gina with the close proximity of the bladder and rectum led to
For the most part, surgical resection often requires a radical the use of the CO2 laser as a relatively noninvasive surgical ap-
approach, resulting in urinary and fecal diversion in order to se- proach (139,140). Data published by Hoffman et al. (133), who
cure adequate margins (13,33). For those patients, definitive RT performed upper colpectomy in 32 patients, of whom 31 had
CHAPTER 20 VAGI NA 569
Laser Therapy
Julian et al. (140) 10 Used to effect colpectomy 80%
Hoffman et al. (139) 26 3 of 11 failures had invasive disease 58%
Recommended excision. Not ideal
Topical 5-FU
Woodruff et al. (145) 9 1%2% 5-FU q month 88%
Piver et al. (144) 8 20% 5-FU bid 5 d 75%
Could use 5% or 10%
Petrilli et al. (143) 15 5% 5-FU bid 5 d 80%
Repeat in 12 wk
Krebs (142) 31 One-third applicator 81%
q wk 10 wk
Surgical Excision
Creasman et al. (NCDB) (5) 23 96%
Fanning et al. (132) 15 Used LEEP, 1 patient had cancer 100%
Robinson et al. (141) 46 CUSA29 primaries 66%
CUSA17 recurrent 52%
Hoffman et al. (133) 32 28% invasive cancer out of 23 with VAIN 83%
Irradiation
Chyle et al. (14) 37 83%
Kirkbride et al. (16) 14 100%
Perez et al. (131) 20 94%
5-FU, 5-fluorouracil; bid, twice a day; CUSA, Cavitron ultrasonic aspirator; LEEP, loop electrosurgical excision procedure; NCDB, National Cancer Data Base.
DISEASE SITES
undergone prior hysterectomy and 14 prior therapy for VAIN, day, and weekly administrations, with control rates ranging
and found a 28% risk of invasive disease, in addition to reports from 75% to 88% (142,144,145,147). However, we prefer
of invasive disease in the laser failures, and in patients who had the schedule suggested by Krebs et al. of one-third applicator
undergone upper colpectomy for presumed VAIN, prompted weekly for 10 weeks (142). It is important that the perineal
some to begin to use the laser to effect colpectomy (140). Later skin be protected with a topical ointment such as zinc oxide to
series have used novel approaches with the Cavitron ultrasonic prevent painful vulvar erosions regardless of which 5-FU ap-
aspirator (CUSA) (141) to effect partial colpectomy with sat- plication schedule is chosen. More recently, investigators have
isfactory results, at least in the reporting investigators hands. demonstrated the feasibility and likely efficacy of Imiquimod
In a series of 52 patients reported by Diakomanolis et al., in (Aldara) in the treatment of VAIN, although large series re-
which 28 underwent laser and 24 had partial colpectomy, re- main to be performed (148). In the study by Haidopoulos etal.,
sults were found to be operator dependent, but they favored 6 out of 7 patients with high-grade dysplasia (VIN 23) re-
partial colpectomy for unifocal disease and laser ablation for gressed to either no evidence of dysplasia or VIN 1 following
multifocal disease (138). Overall, the control rates following la- Imiquimod treatment (148). Application of 0.25 g of Imiqui-
ser vaporization range from 58% to 100% (139,140). Patients mod 5% intravaginally once weekly for 3 weeks was effective
most likely to fail after vaporization are those with anatomic and well tolerated. Larger studies are required, but this regimen
distortion caused by scarring (133). In general, patient accep- appears to be promising, with a simpler dosing regimen, and
tance is high and scarring is minimal (146). lower toxicity when compared to 5-FU (148).
Even though partial colpectomy has many advocates for fo- Partial or total vaginectomy has been considered by many
cal VAIN without any prior history of pelvic RT, patients who to be an acceptable treatment for VAIN (127). However, one
had received prior pelvic RT for other gynecologic malignan- of its main drawbacks is shortening or stenosis of the vagina,
cies, wherein partial colpectomy would have high risk of fistula frequently with poor functional results. Hoffman et al. (133) re-
formation, may benefit from a medical approach with topical ported a 17% recurrence rate in a series of 32 patients with CIS
application of 5-FU. This creates a desquamation of the vagi- of the vagina who underwent upper vaginectomy. In this series,
nal squamous epithelium, which later reepithelializes with pre- 44% had received prior therapy, including laser vaporization, or
sumably normal cells. Multiple schedules have been suggested topical 5-FU and local excision. Nine patients (28%) were found
since the first use of 5-FU, including monthly, daily, twice a to have invasive cancer upon final pathologic examination. Four
570 CHAPTER 20 VAGI NA
of 9 patients with invasive carcinoma showing more than 3.5- after radical surgery for stage I disease ranging from 75% to
mm infiltration were treated subsequently with RT, 3 of these 100% (5,14,21,24,33,39). Cases in which surgery may be the
patients remained free of disease. Of the 5 patients with less preferred treatment include selected stage I-II patients, with le-
than 2 mm invasion, 1 received RT for local recurrence, and the sions at the apex and upper third of the posterior or lateral va-
remaining 4 patients were without disease after surgery alone. gina that could be approached with radical hysterectomy, upper
Overall, 5 of 9 patients with microinvasive carcinoma required vaginectomy, and pelvic lymphadenectomy providing adequate
RT in addition to surgery, and only 72% of all patients treated margins (10,12,18,21) and very superficial lesions that may be
with surgery remained free of disease at last follow-up. Of 23 removed with wide local excision. Lesions in the lower third of
patients with VAIN 3, 19 (83%) remained without evidence of the vagina would require vulvovaginectomy in addition to dis-
recurrence at a mean follow-up of 38 months. Hoffman et al. section of inguinofemoral nodes or even exenteration to achieve
(133) advocated upper vaginectomy with 1 cm margins when negative margins (13,15,21,33). If the margins are found to be
there were concerns about possible invasion, and when the le- close or positive after resection, adjuvant RT is recommended.
sion was confined to the upper one-third or one-half of the va- However, for lesions at other sites, and those cases requiring
gina. To minimize postoperative stenosis, they (133) recommend more extensive resection, definitive RT is the treatment of choice
not closing the mucosa, using a dilator with estrogenic vagi- since it offers excellent results (4), with isolated central failures
nal cream, and consideration of a skin graft. Prior RT is prob- postradiation being offered exenteration (33).
ably a contraindication to vaginectomy owing to significantly Creasman et al., in a review of the NCDB for cancers of the
increased morbidity. Control rates of 66% to 100% following vagina, noted superior survival in those patients undergoing sur-
partial colpectomy effected with a traditional surgical approach gery (5). However, they and Tjalma et al. (39) recognized that
(133,149), with CUSA (141), or with the loop electrosurgical there may be bias in surgical series, such that younger, healthier
excision procedure (LEEP) (132) have been achieved. patients with better performance status are more likely to be
Radiation therapy has a long history of documented effi- offered radical surgery, whereas older patients with multiple co-
cacy with control rates ranging between 80% and 100%, and morbid medical conditions are offered RT.
a significantly better therapeutic ratio than other modalities Ball and Bermans series (13) included 58 patients: 27 stage
(14,16,18,35,47,150). Using conventional low-dose-rate (LDR) I and 18 stage II disease. Twenty-seven patients were managed
ICB techniques, the entire vaginal mucosa should receive be- primarily with surgery, with an overall 78% 5-year survival
tween 50 and 60 Gy, given the high incidence of multicentricity; rate, 84% in patients with stage I, and a 63% rate in those
the area of involvement should receive 70 to 80 Gy, in 1 or 2 with stage II disease, which is comparable to the results re-
implants, prescribed to the mucosal surface (131). Higher doses ported by Perez et al. in their RT series (4,35). Rubin et al. (33)
may cause significant vaginal fibrosis and stenosis. Perezetal. reported 75 cases of vaginal cancer: 14 patients with stage I
reported only 1 distal local failure in the 20 patients treated and 35 patients with stage II. RT was the primary modality
for CIS (131). Pelvic recurrences or distant failures have not used in this series; however, 8 patients (5 with stage I and 3
been observed in the absence of invasive component, after ICB with stage II) underwent primary surgery with curative intent.
(44,131,151). Six of these 8 patients survived 5 years, and the local control
There have been some reports in the literature regarding rate for stage I patients was 80%. However, only 1 patient
the use of high-dose-rate (HDR) ICB for patients with VAIN3. with stage II was a long-term survivor. This surgical outcome
Ogino et al. (152) reported 6 patients treated with HDR to a compares unfavorably with the remaining patients in whom
mean dose of 23.3 Gy (range, 15 to 30 Gy), none of whom RT was the primary modality. In general, patients with lesions
developed recurrent disease. Limited rectal bleeding and moder- that could be encompassed by radical vulvovaginectomy with
ate to severe vaginal mucosa reactions were noted in patients or without hysterectomy did better than those requiring exen-
treated to the entire length of the vagina. MacLeod et al. (153) teration. Rubin et al. (33) advocated that exenteration should
reported on 14 patients with VAIN 3 treated with HDR-ICB be reserved for those with central failure after RT, or as pri-
to a dose of 34 to 45 Gy in 4.5- to 8.5-Gy fractions. With a mary therapy in those with disease not fixed to the bone. Davis
median duration of follow-up of 46 months, 1 patient had per- et al. (24) reported on 52 patients with cancer of the vagina
sistent tumor and another showed progression of tumor with treated with surgery alone in a series that included 89 cases.
an overall local control of 78.5%; 2 patients developed grade 3 In this nonrandomized series, an 85% 5-year survival rate was
vaginal toxicity. Mock et al. (154) reported 100% recurrence- achieved in stage I patients compared to 65% in those treated
free survival in 6 patients with CIS treated with HDR-ICB. At with RT (24). Of 45 patients with stage II disease, 49% sur-
the present time, no definite conclusions can be drawn from vived after surgery, 50% after RT, and 69% after surgery and
the limited data published in the literature regarding the use of RT.
HDR-ICB. Based on the excellent local control and functional The Peters et al. series (110) included 86 vaginal carcinomas,
results obtained with LDR-ICB, this remains, in our opinion, the with an overall survival rate of 56%. Most were treated with
treatment of choice when definitive RT is used. RT. However, 12 highly selected patients had surgery, with a
Estrogen therapy should be considered in women who are 75% survival rate. The investigators suggested that vaginectomy
postmenopausal or have undergone RT, provided the possibility with radical hysterectomy, if the uterus was still in place, should
of invasive disease has been eliminated. The effect of irradiation be limited to those with superficial disease because the closeness
on ovarian function, as well as occasional fibrosis of the vagi- of the bladder and rectum limited the true radicality of surgical
nal vault, makes this treatment currently unacceptable except in approaches. Gallup et al. (15) reported 28 cases, of which 57%
cases resistant to conservative therapy. were stage Ito II lesions (only 3 patients had stage II), and of
these, 83% survived. Most patients in this series received RT;
however, all 3 patients with stage I disease who were treated
with surgery survived. Extent of surgery and median follow-up
Invasive SCC were not stated.
In the largest single-institution series reported to date
Surgical Approach and Outcomes by Stock et al. (21), of 100 patients with carcinoma of the
In general, SCC of the vagina has been treated with RT. How- vagina (including 85 with SCC), a 47% 5-year survival rate
ever, several surgical series have reported acceptable to excel- was achieved. In this series, 40 patients were treated with sur-
lent outcomes in well-selected patients, with survival rates gery alone, 47 with radiation alone, and 13 with combination
CHAPTER 20 VAGI NA 571
therapy. Overall, 5-year survival was 47%. Survival for stage I gracilis flap. Long-term follow-up has been favorable for the
patients was 56% when treated with surgery versus 80% for former, while only preliminary data is available for the latter
those who received RT, whereas for stage II patients, the sur- (157,158).
vival rates were 68% and 31% after surgery and RT, respec-
tively (21). The investigators acknowledged that the apparent
surgical superiority for stage II patients may have been due to
Radiation Approach: Outcomes
selection bias in that those treated with RT alone were more Stage I. In patients with stage I lesions, usually 0.5 to 1 cm thick,
likely to have had stage IIB disease with extensive paracolpos that may involve 1 or more vaginal walls, it is important to in-
involvement, and those with lesser involvement were prefer- dividualize radiation therapy techniques to obtain optimal func-
entially offered surgery. Stock advocated RT for stage II pa- tional results. Most investigators emphasize that brachytherapy
tients with extensive paracolpos. Stock et al. concluded that alone is adequate for superficial stage I patients with 95% to
for upper-third vault lesions, radical hysterectomy and pelvic 100% local control rates when using low-dose-rate (LDR) ICB
lymphadenectomy with upper vaginectomy should be offered and ITB techniques(4,18,110,123).
to those with stage I lesions, with a consideration for wide local Superficial lesions with less than 3 mm invasion can be
excisions, and postoperative RT for patients with small lesions. adequately treated with ICB alone, using afterloading vaginal
If there was extension to the paracolpos, RT should be recom- cylinders. The entire length of the vagina is generally treated
mended; however, in very well-selected patients, there might be to a mucosal dose of 60 Gy, and an additional mucosal dose
a role for surgery (21). of 20 to 30 Gy is delivered to the area of tumor involvement
Tjalma et al. reported on 55 cases of SCC of the vagina, in- (131). Mucosal doses of 80 to 100 Gy are typically delivered,
cluding 27 cases with stage I and 12 with stage II disease, with depending on the diameter of the cylinders, when prescribing
a median follow-up of 45 months (39). Of the 27 cases with 65 to 70 Gy to the tumor area, at 0.5 cm depth beyond the
stage I disease, 26 underwent surgery, and 4 of them received vaginal surface (131). For lesions thicker than 0.5 cm at the
some form of postoperative RT. A 91% 5-year survival rate was time of implantation, it is advisable to combine ICB and ITB
achieved for stage I disease. Surgery was a part of the primary with a single-plane implant to increase the depth dose and limit
management for 6 of the 12 patients with stage II disease. In the excessive irradiation to the vaginal mucosa. With LDR-ICB a
multivariate analysis, age and lesion size were the only prognos- dose of 60 to 65 Gy is delivered to the entire vaginal mucosa;
tic factors. Tjalma et al. concluded that surgery should be con- the dose to 0.5 cm depth from the ICB should be calculated; an
sidered part of the therapeutic approach for stage I and minimal additional 15 to 20 Gy at a depth of 0.5 cm beyond the plane
stage II disease (39). However, as Stock et al. suggested (21), and of the implant will be delivered with the ITB such that the base
later Creasman et al. (5) and Tjalma et al. (39) concurred, such of the tumor receives between 65 and 70 Gy, with the involved
apparent improvement in small surgical series may be second- vaginal mucosa receiving an estimated 80 to 100 Gy. The proxi-
ary to a selection bias such as patients with better performance mal and distal vaginal mucosal doses should be limited to 140
status and smaller lesions are selected for surgery, whereas older and 98Gy, respectively (131).
patients with more comorbid medical conditions and larger There are no well-established criteria regarding the use of
stage I to II lesions undergo RT. external beam RT (EBRT) in patients with stage I disease. Perez
While several series have reported on primary surgical ap- et al. (4,35) did not find a significant correlation between the
proaches, including exenteration for patients with advanced technique of irradiation used and the probability of local or
stage IIIIV SCC, achieving control rates as high as 50% for pelvic recurrence, probably since the treatment technique var-
highly selected patients (13,15,21,33), the number of patients ied based on tumor-related factors. There is general consensus
DISEASE SITES
treated in any single series is so small that in modern prac- that EBRT is advisable for larger, more infiltrating or poorly
tice, primary exenteration for advanced disease would not be differentiated tumors that may have a higher risk of lymph node
recommended as the preferred approach (137). Therefore, ad- metastasis. The whole pelvis is treated with 10 to 20 Gy; an
vanced-stage patients should receive definitive RT, probably in additional parametrial dose should be delivered with a midline
combination with concurrent chemotherapy, although the role block (5 half-value layer [HVL]) to give a total of 45 to 50Gy
of combined modality therapy is unknown. to the parametria and pelvic side walls (4,35). Chyle et al. (14)
With regard to the surgical technique, if a complete vagi- recommended EBRT in addition to brachytherapy for stage I
nectomy is to be undertaken, most experts have suggested a disease to cover at least the paravaginal nodes, and, in larger
combined abdominoperineal approach, with the perineal inci- lesions, to cover the external and internal iliac nodes. Ninety-
sion in the pubocervicovesical fascia made beneath the urethra five percent to 100% local control has been achieved with in-
and above the rectum so as to avoid the hemorrhoidal plexus. tracavitary and interstitial techniques, with 5-year survival for
Some have suggested that the perineal incision can be made patients with stage I disease treated with RT alone ranging from
before or after the abdominal incision to perform the radical 70% to 95% (Table 20.4) (4,18,21,23,48,123).
abdominal resection. However, we would favor performing the Stage II. Patients with stage IIA tumors have more advanced
abdominal incision, first mobilizing the bladder, urethra, and paravaginal disease without extensive parametrial infiltration.
rectum down to the perineum, and dividing the paracolpos at These patients are uniformly treated with EBRT followed by
the side wall, mobilizing the ureters, and harvesting the nodes ICB and/or ITB. Perez et al. (35) showed that in stage IIA,
such that if unresectable disease is found, the patient would the local tumor control was 70% (37/53) in patients receiv-
be spared a perineal incision. Given the large defect that is left ing brachytherapy combined with EBRT, compared with 40%
after surgical resection, placement of a gracilis myocutaneous (4/10) in patients treated with either brachytherapy or EBRT
flap allows not only coverage of the defect, but may serve as alone. Generally, the whole pelvis receives 45 Gy followed by an
a neovagina in the sexually active woman (155,156). Alterna- additional boost using a combination of LDR-ICB or LDR-ITB
tively, 2 new techniques have been described with excellent re- in order to deliver a minimum of 30 to 35 Gy 0.5 cm beyond
sults. Vaginal reconstruction can be performed with the use of the deep margin of the tumor (in addition to the whole pelvis
vicryl mesh combined with a pedicle omental grafter with a dose, to a total tumor dose of 75 to 80 Gy). Double-plane or
deep inferior epigastric perforator flap. Both techniques have volume implants may be necessary for more extensive disease.
been shown to be effective, and when performed at the time The superiority of the combination of EBRT and brachytherapy
of pelvic exenteration, carry the additional benefit of avoiding over EBRT or brachytherapy alone has been shown as well in
an additional surgical incision, as required for creation of a other series (14,21,122).
572 CHAPTER 20 VAGI NA
DISEASE SITES
RT, radiotherapy; S, surgery; St, stage; Yr, year.
MeV). For patients with positive pelvic nodes, or those patients
with advanced disease not amenable to interstitial implant, ad-
a
Twenty patients with St III-IV were treated with chemotherapy ditional boost to the areas of gross disease, as defined by CT
(5-FU mitomycin C) and radiotherapy.
scan, should be given using conformal therapy to deliver a to-
tal dose between 65 to 70 Gy, when feasible, with high-energy
photons.
This will be followed, in some cases, by bilateral pelvic sidewall Intensity modulated radiation therapy (IMRT) is another po-
boosts from 50 to 55 Gy. High-energy photons (10 MV) are tential therapeutic option in pelvic tumors that require the treat-
usually preferred. CT simulation is highly encouraged since it ment of the inguinofemoral region as well as delivering higher
allows a more accurate delineation of the regional lymph node doses to the gross disease while reducing the dose to the bladder
areas, rather than relying on pelvic bony anatomy (165). Treat- and rectum (Fig. 20.8) (163,164,168172). It is postulated that
ment portals cover at least the true pelvis with 1.5- to 2.0-cm the use of IMRT may reduce acute and long-term toxicity by
margin beyond the pelvic rim. Superiorly, the field extends to minimizing the dose to organs at risk (OAR). This is a topic
either L45 or L5S1 to cover the pelvic lymph nodes up to of current investigation in a phase II RTOG trial (0529), in
the common iliacs, and extends distally to the introitus to in- which IMRT to the pelvic and inguinal nodes is being combined
clude the entire vagina. The distal margin of the tumor should with chemotherapy for anal cancer in a multi-institutional set-
be identified with a radiopaque marker or bead at the time of ting. Moran et al. (168) performed a dosimetric comparison of
the simulation. Lateral fields, if used, should extend anteriorly the MSBT technique to IMRT for treatment of pelvic/inguinal
to adequately include the external iliac nodes, anterior to the nodes in variety of patients, including those with the diagno-
pubic symphysis, and at least to the junction of S23 posteriorly ses of primary vaginal cancers (168). The doses to the bladder,
to adequately cover the presacral nodes (Fig. 20.6). rectum, small bowel, and bone marrow were higher using the
In patients with tumors involving the middle and lower vagina MSBT technique compared to IMRT plan; however, the treat-
with clinically negative groins, the bilateral inguinofemoral ment planning process (including contouring) was 40 minutes
lymph node regions should be treated electively to 45 to for the MSBT plan compared to approximately 6 hours for
50Gy(35). Planning CT is recommended to adequately deter- the IMRT plan (168). At this time there is not sufficient data
mine the depth of the inguinofemoral nodes. In patients with on outcomes to routinely recommend the use of IMRT for the
distal vaginal lesions it is often necessary to treat the vulva in treatment of primary vaginal cancer when the inguinofemoral
order to achieve adequate tumor coverage, in which case the pa- nodes must be irradiated. Certain clinical scenarios may war-
tient should be placed in open-leg position to reduce the vulvar rant the use of IMRT, such as those patients who require doses
skin reaction (48). greater than 50 Gy to the pelvis or inguinofemoral region or
574 CHAPTER 20 VAGI NA
FIGURE 20.6. Proximal third vaginal cancer, invasive squamous cell carcinoma, with mid-third of the vagina squamous cell carcinoma in situ,
without involvement of inguinofemoral nodes. Digital Reconstructed Radiographs (DRRs). A: AP/PA whole pelvis fields. B: Right/Left lateral
whole pelvis fields, intended to treat the entire length of the vagina. C: Axial, saggital, and coronal isodose distributions.
when radiation must be delivered to an area that has previously alone. Low-dose-rate (LDR)-ICB is performed using vaginal cyl-
been irradiated. inders such as Burnett, Bloedorn, Delclos (173), or MIRALVA
Independently of the technique to be used, it is important to (Nucletron Veenendaal, the Netherlands) (174) loaded with
keep in mind that the overall treatment time (7 to 9 weeks) has been cesium 137 (137Cs) radioactive sources. Choo et al. (175) evalu-
found to be a significant treatment factor predicting tumor control ated the depth distribution of lymphatics lying beneath the
(130,150), although this has not been universally recognized (35). mucosal surface of the vagina in 31 patients who underwent
full-thickness vaginal biopsy or resection for benign or malig-
nant lesions. In their series, 95% of vaginal lymphatic channels
Low-Dose-Rate Intracavitary Brachytherapy were located within a 3 mm depth from the vaginal surface,
VAIN and small T1 lesions with less than a 0.5-cm depth can confirming the adequacy of prescribing the dose to a depth of
be adequately treated with intracavitary brachytherapy (ICB) 5mm for superficially invasive lesions (173).
CHAPTER 20 VAGI NA 575
DISEASE SITES
FIGURE 20.7. Vaginal cancer with distal third vaginal involvement, squamous cell carcinoma. Technique for pelvic and inguinofemoral nodal
irradiation. A: Digital reconstructed radiographs. AP field intended to treat pelvis and groins; PA field intended to treat the pelvis only, in
order to decrease the dose to the femoral heads; small AP photon field for additional daily boost to the inguinofemoral nodes. B: Axial,
saggital, and coronal isodose distributions.
Delclos afterloading vaginal cylinders have a central hollow the bladder, and/or the rectum. It is recommended that the larg-
metallic cylinder in which the sources are placed, and plastic est possible diameter that can be comfortably accommodated
rings of varying diameter (2.5 to 4 cm), 2.5 cm in length, which by the patient should be used to improve the ratio of mucosa to
are inserted over the cylinder. Domed cylinders are used to ir- tumor dose, and to eliminate vaginal rugations. The cylinders
radiate the vaginal cuff homogeneously, when indicated. Delclos can be mounted in the vaginal component of an intrauterine
recommended a short 137Cs source to be used at the top to ob- tandem, or along the stem of a dome cylinder. Before the cylin-
tain a uniform dose around the dome, because a lower dose oc- ders are mounted over the vaginal component of an intrauterine
curs at the end of the linear cesium source (173). Some cylinders tandem, this is inserted into the uterus (when present) and the
have a lead shielding to protect selected portions of the vagina, cylinders are fitted along the protruding tandem. To minimize
576 CHAPTER 20 VAGI NA
FIGURE 20.8. A: Axial dose distribution intensity-modulated radiation therapy plan for vaginal cancer. B: Saggital dose distribution
IMRT plan for vaginal cancer. C: Coronal dose distribution IMRT plan for vaginal cancer. D: Beam arrangement IMRT plan for vaginal
cancer.
the rotation of the tandem, a flat, round flange with keel is technology allows the reduction of radiation exposure to hospi-
placed below the last cylinder and is kept in position with some tal personnel and optimization of the isodose distribution.
packing if required. In general, the vulva is sutured-closed with
praline or silk for the duration of the implant in order to secure
the position of the applicators (Fig. 20.9). In general, the vulva is High-Dose-Rate Intracavitary Brachytherapy
sutured closed for the duration of the implant in order to secure The International Commission of Radiation Units (ICRU) de-
the position of the applicators. fines HDR brachytherapy as exceeding 12 Gy/hour (35). High-
In patients with upper vagina lesions with less than a 0.5 cm dose-rate intracavitary brachytherapy (HDR-ICB) is typically
depth of invasion, vaginal colpostats alone (after hysterectomy) performed with a 10 Ci single iridium-192 (192Ir) source (Micro-
or in combination with intrauterine tandem, loaded with 137Cs Selectron HDR, Nucletron). The applicators are similar to those
sources similar to that used in treatment of cervical cancer, can described for LDR.
be used to treat the proximal vagina to a minimum dose of 65 Limited information regarding HDR-ICB in the treatment of
to 70 Gy, estimated to 0.5 cm depth, including the contribution primary carcinoma of the vagina is available (22,154,176180).
of EBRT if given. When indicated, the remainder of the vagina Fewer patients have been treated compared with LDR-ICB,
can be treated by performing a subsequent implant using vagi- follow-up for most series is short, publication bias is likely, and
nal cylinders (generally 50 to 60 Gy prescribed to the vaginal there is no agreement on treatment regimen. With HDR there
surface). It is important to avoid the placement of a protrud- is a need to adjust the total dose and additional fractionation
ing source over the vulva, with the subsequent increased risk of is necessary, compared with LDR brachytherapy, because of the
complications. When appropriate dose specification points are biologically equivalent dose considerations. Generally, the num-
chosen, a very uniform dose distribution over the entire length ber of insertions ranges from 1 to 6 (median, 3), with the dose
of the vagina can be obtained. Perez et al. and Slessinger et al. per fraction ranging from 300 to 800 cGy (median, 700 cGy).
(174) designed and constructed a vaginal applicator, MIRALVA, HDR-ITB has also been reported by Kushner et al. (177);
which incorporates 2 ovoid sources and a central tandem that in this report, the Syed Template Applicators were used. Newer
can be used to treat the entire vagina (alone or in combination HDR compatible interstitial systems are available including the
with the uterine cervix). The applicator has vaginal apex caps M.A.C. (Mick-Alektiar-Cohen) HDR-GYN Contour Template,
and additional cylinder sleeves to allow for increased dimen- compatible with ultrasound stabilizing devices, and the Miami
sions. A tandem in the uterus can be used if clinically indicated, Multi-Channel Vaginal Applicator (Mick Radio-Nuclear Instru-
using standard loadings, depending on the depth of the uterus. ments Inc., Mount Vernon, NY) (Fig. 20.10).
The vaginal cylinder or uterine tandem never carries an active Stock et al. (22) described results in 15 patients with car-
source at the level of the ovoids to prevent excessive doses to the cinoma of the vagina treated with HDR brachytherapy; dose
bladder or rectum. The use of LDR remote control afterloading per fraction ranged from 3 to 8 Gy, with a median dose of
CHAPTER 20 VAGI NA 577
DISEASE SITES
FIGURE 20.9. AP (A) and lateral views (B) of vaginal cylinders only. AP (C) and lateral views (D) of
intrauterine tandem and vaginal cylinders.
7 Gy, for a total median dose of 21 Gy. The median interval stage I, 47% for stage II, and 40% for stage III. Survival closely
between fractions was 2 weeks. Brachytherapy was combined paralleled tumor control. There was no significant difference
with EBRT (30 to 63 Gy, with a median dose of 42 Gy, 1.8 to in outcome in the LDR or HDR groups. Acceptable morbidity
2.92 Gy per fraction). The median total tumor dose from both of therapy was noted for all 49 patients, but no comment was
components was 63 Gy. The 5-year actuarial survival rate was made comparing LDR with HDR (22).
50% with brachytherapy, compared with 9% in the EBRT-alone Nanavati et al. (178) reported 13 patients with primary vagi-
patients (p < 0.001), although a larger percentage of stage IV nal cancer (5 St I, 4 St IIA and 4 St IIB) treated with external
lesions (36%) were in the EBRT-alone group than in the brachy- beam RT (45 Gy) and HDR-ICB (2028 Gy in 34 fractions,
therapy group (5%). Local tumor control rates were 50% for calculated at 0.5 cm from the surface of the applicator). All
13 patients had a complete response, and local control was implants are readily controlled distribution of the radioactive
achieved in 92% of the patients with a median follow-up of sources and easier modification of the dose distribution. The
only 2.6years (range 0.7 to 5.2 years). Originally the planned main advantages of a permanent seed implant include relative
dose was 2100 cGy in 3 fractions, 700 cGy/fraction, but because safety/simplicity, easy applicability, cost-effectiveness, and abil-
of reports of decreased complications with increased fraction- ity, in most cases, to be performed using local anesthesia. As
ation, the planned dose was changed to 2000 cGy in 4 equal a general rule, temporary implants are more commonly used
fractions. The investigators did not observe any acute or chronic in the curative treatment of larger gynecologic malignancies,
intestinal or bladder grade 3 or 4 toxicity. However, moderate whereas permanent implants are usually performed for smaller
to severe vaginal stenosis occurred in 46% of the patients. They volume disease.
recognize that late-occurring toxicity could be missed at a me- The number and strength of the radioactive sources and their
dium follow-up of 2.6 years (178). intended distribution within the target volume are determined
Kucera et al. (176) reported on 190 patients with invasive preoperatively, making use of available guidelines such as nomo-
carcinoma of the vagina. Eighty were treated with intracavitary grams, tables, and computer-assisted optimization techniques.
HDR-ICB with or without EBRT. These patients are compared Following this it is necessary to specify an approximate dose
with a historical group of 110 patients treated with intracavi- rate to the target volume, which requires careful localization
tary LDR brachytherapy with or without EBRT. No significant of the sources and computer calculation of the 3-dimensional
differences were found for stages, tumor grade, or location be- radiation dose distribution. Finally, a dose prescription, based
tween the 2 groups. The crude 5-year survival rates for all pa- upon the treatment volume, tumor sensitivity, dose rate, prior
tients were 41% in the LDR group, 81% in stage I, and 43% treatments and tolerance of normal surrounding tissues is
in stage II. Overall actuarial 3-year survival and disease-specific required (152).
survival rates for all patients in the HDR series were 51% and When performing an interstitial procedure, freehand im-
66%, respectively. Disease-specific 3-year survival rates were plants or template systems designed to assist in preplanning
83% in stage I and 66% in stage II. There were no significant and to guide and secure the position of the needles in the target
differences in local and distant recurrences between the treat- volume can be employed. Popular commercially available tem-
ment modalities. Complications analysis showed no significant plates include the Syed-Neblett device (SNIT) (Alpha Omega
differences between the HDR and LDR series. Similar results Services, Bellflower, California, USA) (186), the modified Syed-
were published by Mock et al. (154) in 86 patients treated with Neblett (187), and the MUPIT (Martinez Universal Perineal
HDR-ICB alone or in combination with EBRT with fairly good Interstitial Template) (188). All rely on pelvic examination to
toxicity profile. However, Kushner et al. (177) reported on 19 help guide the location and depth of needle placement. These
patients with vaginal cancer treated with different combinations templates generally consist of a perineal template, vaginal ob-
of EBRT and intracavitary and interstitial HDR brachytherapy, turator, and 17-Gy hollow guides of various lengths that can
with a low (39.3%), 2-year progression-free survival and 15.8% be afterloaded with 192Ir sources. The vaginal obturator is cen-
serious late complications including ureteral stenosis, painful trally drilled so that it can allow the placement of a tandem to
vaginal necrosis, and small bowel obstruction. be loaded with 137Cs sources. This makes it possible to com-
Many aspects remain unknown or not well understood in bine an interstitial and intracavitary application simultaneously
the use of HDR-ICB in vaginal cancer treatment. These include (Fig. 20.11). The major advantage of these systems is greater
the radiobiological equivalency of HDR to LDR, fractionation control of the placement of the sources relative to tumor volume
schedule, total dose, specification of dose prescription, and how and critical structures due to the fixed geometry provided by
to combine HDR with EBRT and/or LDR brachytherapy. In the template and central cylinder. In addition, improved dose-
addition, optimization approaches and methods of dose cal- rate distributions are obtained by means of computer-assisted
culation, such as the inclusion of anisotropic corrections, are optimization of the source placement and strength during the
not well described in the sparse literature available to date planning and loading phase (Fig. 20.12).
(181,182). Li et al. (182) have shown that when optimized dose Owing to the inaccuracies of pelvic examination and close
distribution at a distance from the cylinder surface is calculated proximity of the rectum and bladder to the target volume, there
using an accurate dose calculation model, the vaginal mucosa exists a serious risk of either underdosing the target volume or
dose becomes significantly higher than calculated, and therefore causing bladder and rectal morbidity. In order to improve the
should be carefully monitored. These factors could result in an accuracy of target localization and needle placement, several
increased incidence of severe complications, such as vaginal ne- investigators have explored performing ITB under transrectal
crosis and rectovaginal or vesicovaginal fistulas (177,183,184).
In our opinion, until further data are available with longer fol-
low-up, as well as a better understanding of the physical and
radiobiological principles involved in HDR-ICB, its use should
be cautiously considered in the radiotherapeutic management of
primary vaginal carcinoma.
Interstitial Brachytherapy
Interstitial brachytherapy (ITB) is an important component in
the treatment of more advanced primary vaginal carcinomas,
typically in combination with EBRT and/or ICB. In the first
place, a careful definition of the target volume, which is the
gross tumor volume (based on clinical, radiologic, and operative
findings) and a margin of adjoining normal tissue, is required.
Other considerations include whether a permanent (198Gold or
125
Iodine) or temporary implant (192Iridium) is optimal, the ge-
ometry of the implant (e.g., single or double plane or volume
implant), source distribution, dose rate, and total dose, based
upon tumor size, location, local extent, and proximity of nor-
mal structures (185). The principal advantages of temporary FIGURE 20.11. Syed-Neblett and modified templates.
CHAPTER 20 VAGI NA 579
FIGURE 20.12. A: AP and B: lateral radiographs of an interstitial and intracavitary implant in carcinoma of
the vagina using the modified Syed-Neblett template. C: Three-dimensional isodose distribution, Ir192 only; D: Ir192
plus Cs137.
DISEASE SITES
ultrasound (TRUS) (189), CT and/or MRI-planned implants Shah et al. (194) reported on toxicity after needle puncture
with endorectal coil (204), laparotomy, and laparoscopic guid- of visceral organs during interstitial brachytherapy without as-
ance (187193). While laparotomy facilitates the displacement sistance of image guidance during the placement (194). They
of bowel during the procedure by using slings or tissue expand- imaged 36 patients after needle placement with a postoperative
ers and/or lysis of adherent bowel there is some degree of associ- CT scan and found bowel puncture in 26 patients and bladder
ated morbidity, such as ileus, bleeding, and increased operative puncture in 19 patients; however, they found no relationship
time. Laparoscopy is a shorter and less invasive procedure. An between visceral puncture and the incidence of acute or late gas-
open retropubic approach allows direct visualization of the trointestinal or urinary toxicity. They did note that needles that
bladder and urethra during interstitial implantation of anterior perforated the bowel or bladder were not loaded or the dwell
vaginal malignancies and facilitates negotiation of the pubic times were minimized in these areas and conclude that toxicity
arch. Paley et al. (193) described a technique using an open may be related to the dose received by the normal structures
retropubic approach for Syed template interstitial implants in rather than the occurrence of visceral puncture (194).
anterior vaginal tumors under direct visualization. Real time Tewari et al. (195) described results in 71 patients who un-
TRUS-guided Syed-Neblett template implantation technique derwent ITB with (61 patients) or without (10 patients) EBRT.
was reported by Stock et al. (189). TRUS allows the ultrasound Patients included those with stage I (10 patients), Perez modi-
(US) probe to be in closer proximity to the pelvic structures fication stage IIA (14 patients), Perez modification stage IIB
(cervix, parametria, and vagina) than trans-abdominal US and (25 patients), stage III (15 patients), and stage IV (7 patients)
can more accurately guide needle placement into tumor and disease. Each implant delivered a total tumor dose reaching
avoid needle insertion into critical surrounding normal tissues. 80 Gy integrated with EBRT. Local control was achieved in
Transverse US imaging is used to assure that the needles cover 53 patients (75%). With a median follow-up of 66 months the
the target area and do not enter the bladder, rectum or small 5- and 10-year actuarial disease-free survival rates were both
bowel. The longitudinal mode of the US probe is equally impor- 58%. By stage, 5-year disease-free survival rates included stage
tant in the implant procedure due to its ability to guide the op- I, 100%; stage IIA, 60%; stage IIB, 61%; stage III, 30%; and
timum depth of needle insertion. With this technique, invasive stage IV, 0%. Stage and primary lesion size independently influ-
laparotomy and/or laparoscopy can often be avoided, provid- enced the survival rates. Significant complications occurred in
ing an interactive, noninvasive technique allowing for highly 9patients (13%) including necrosis (n = 4), fistulas (n = 4), and
accurate needle placement (189). small bowel obstruction (n = 1) (195).
580 CHAPTER 20 VAGI NA
Stryker (196) treated 40 patients with vaginal carcinoma; a median follow-up of 50 months, the 5-year overall, progres-
14had a history of prior hysterectomy. There were 4 treatment sion-free, and local relapse-free survival rates were 66%, 75%,
groups: EBRT and intracavitary brachytherapy (group WPIC, and 92% respectively. Sinha et al. (120) reported on 11 of 45
n = 15), EBRT and interstitial brachytherapy (group WPIS, patients that received concurrent cisplatin with radiation that
n=10), EBRT alone (group WP, n = 7), and brachytherapy alone failed to show a benefit in disease control with the addition
(group BA, n = 2). The 5-year disease-specific survival rates were of chemotherapy; however these patients had more advanced
68% for 28 patients with SCC and 50% for 6 patients with FIGO stages which has shown to be a major determinant of
adenocarcinoma. The 5-year survival rates were 78% for stage I failure and survival.
disease, 63% for stage II, 33% for stage III, and 50% for stage In a study by Panici et al. (202), 11 patients received neoad-
IV (p = 0.2). Local failure occurred in 2 patients (13%) in the juvant chemotherapy with paclitaxel and cisplatin for 3 courses
WPIC group, 2 (20%) in WPIS, 3 (43%) in WP, and 1 (50%) in followed by radical surgery for patients with FIGO stage II vagi-
BA. Nine patients (26%) had late small/large intestine or blad- nal cancer. They found complete clinical responses in 3 (27%)
der morbidity. Vaginal morbidity occurred in 15 patients (44%) patients, partial clinical responses in 7 (64%) patients, and
(196). 1 patient with stable disease (9%). At a median follow-up of
75months, 91% are alive and 73% are disease-free.
Studies of primary chemoradiation in primary vaginal can-
Role of Chemotherapy and Radiation cer are small or heterogeneous populations, including cervical
The control rate in the pelvis for stage III to IV patients is rela- and vulvar cancers, making it difficult to truly assess the role
tively low, and about 70% to 80% of the patients have persis- of combined-modality therapy in the management of locally
tent disease or recurrent disease in the pelvis in spite of high advanced disease. No randomized trials comparing radiation
doses of EBRT and brachytherapy. Failure in distant sites does with or without chemotherapy have been reported. Further in-
occur in about 25% to 30% of the patients with locally ad- vestigation is needed to determine the therapeutic efficacy of the
vanced tumors, which is much less than pelvic recurrences. concurrent chemoradiotherapeutic and the optimal chemothera-
Therefore, there is a need for better approaches to the manage- peutic regimen.
ment of advanced disease such as the use of concomitant chemo- Published data on cervical cancer have demonstrated an
radiotherapy. Agents such as 5-FU, mitomycin-C, and cisplatin advantage in locoregional control, overall survival, and disease-
have shown promise when combined with RT, with complete free survival for patients receiving cisplatin-based chemother-
response rates as high as 60% to 85% (197,198), but long-term apy concurrently with RT (203206). The only drug common
results of such therapy have been variable. In these small stud- to all the studies was cisplatin, suggesting it may be the only
ies, many of the patients had advanced (stage III) disease at the agent needed to improve radiation sensitivity. Based on these
initiation of combined-modality therapy, perhaps explaining the data, as well as data on locoregionally advanced vulvar cancer
lack of long-term disease control. (136,207) consideration should be given to a similar approach
Evans et al. (197) found no local recurrences, however, in patients with advanced vaginal cancer. In a recent SEER anal-
among patients achieving a complete response with RT and ysis for vaginal cancer, using the year 2000 as a surrogate for
5-FU plus mitomycin C (12 of 25 patients), with a median fol- the introduction of chemoradiation in cervical cancer, a trend
low-up period of 28 months, suggesting that local control may toward lower risk of death after 2000 in their multivariate
be improved with combined-modality therapy since local failure model was found, as compared with women diagnosed between
is common with radiation alone in large-volume pelvic disease. 1990 and 1994 (HR 0.83, p = 0.07) (121). Randomized trials
The survival for the entire population was 56% (66% for pa- comparing radiation therapy alone to chemoradiation therapy,
tients with primary vaginal cancer). Only 2 patients had severe however, are unlikely due to small patient numbers.
complications, although the investigators recognize that longer
follow-up is probably required to assess the true incidence of
late effects.
More sobering are the data from Roberts et al. (198), who PATTERNS OF FAI LU RE I N SCC
reported 67 patients with advanced cancers of the vagina, cer-
vix, and vulva treated with concurrent 5-FU, cisplatin, and RT. At least 85% of patients who recur will have a component of lo-
Although 85% experienced a complete response, 61% of the coregional failure, and the vast majority of these recurrences will
cancers recurred, with a median time to recurrence of only 6 be confined to the pelvis and vagina. The rate of locoregional
months and an overall survival at 5 years of 22%. Further, 9 recurrence in stage I is approximately 10% to 20% versus 30%
of 67 patients (13%) developed severe late complications, of to 40% in stage II. The pelvic control rate for patients with stage
which 8 required surgeries. Kersh et al. (199) reported that 5 of III and stage IV is relatively low and about 50% to 70% of the
8 vaginal cancer patients achieved local control with combined patients have recurrences or persistence in spite of well-designed
modality therapy. RT. The median time to recurrence is 6 to 12 months. Tumor
Dalrymple et al. (200) published a small study including 14 recurrence is associated with a dismal prognosis, with only a
patients, primarily stages I and II SCC of the vagina, treated few long-term survivors after salvage therapy (159). Failure in
with reduced doses of RT (median 63 Gy) concurrently with dif- distant sites alone or associated with locoregional failure does
ferent 5-FUbased chemotherapeutic regimens. They reported a occur in about 25% to 40% of patients with locally advanced
93% control rate (4 patients died of intercurrent disease with no tumors (Table 20.6) (48,159,208213). It is important to recog-
evidence of tumor), probably reflecting a more favorable stage nize that analysis of RT doses and techniques and their impact
distribution. Interestingly, none of the patients required inter- on local/pelvic tumor control are fraught with difficulty since
stitial implants and no patients developed fistulas. The authors the available data are retrospective and not the result of pro-
indicate that this approach, similar to the one used in the man- spective randomized or dose escalation studies. Andersen (12)
agement of anal and vulvar cancer, would allow reducing the has shown that the combination of EBRT and brachytherapy
RT dose with the subsequent improvement in organ function and tumor dose over 70 Gy were associated with improved local
and late toxicity. control. In the Stanford experience (20), earlier stage and higher
Samant et al. (201) reviewed institutional data on 12 patients RT dose had a positive influence on survival. Nine of 16 patients
(50% FIGO St III or IVA) treated with concurrent radiation and receiving lesser than or equal to 75 Gy had recurrent disease
weekly cis-platinum chemotherapy (40 mg/m2 for 5 weeks). At versus 3 of 22 receiving greater than 75 Gy. Larger series have
CHAPTER 20 VAGI NA 581
not found a significant impact of the RT dose and recurrence of treatment time on pelvic tumor control. Nevertheless, these
rate, probably because larger tumors received higher EBRT and investigators advocate completion of treatment within 7 weeks
brachytherapy doses (14,35). The M. D. Anderson series (48) to 9 weeks.
did not find dose lower than or greater than 75 Gy to be associ-
ated with improved pelvic control or disease-specific survival,
the only 2 statistically significant factors being the stage of the
TREATM ENT COM PLICATIONS
DISEASE SITES
disease and the size of the tumor over 4 cm.
Perez et al. (4,35) observed increased tumor control in pa- AN D TH EI R MANAGEM ENT
tients with stages IIA to IVA with EBRT and brachytherapy
compared to patients receiving brachytherapy alone. In patients Clearly, the knowledge of common acute and late complica-
with stage I disease, no correlation was found between the tech- tions with standard RT and consideration of risk factors may
nique of RT used and the incidence of local or pelvic recur- improve the therapeutic ratio of RT for gynecological malignan-
rences. In addition, they suggested that doses in the range of 70 cies in general and for vaginal cancer in particular (228). The
to 75 Gy to the primary tumor volume and 55 and 65Gy to the anatomic location of the vagina places the lower gastrointesti-
medial parametria for patients with more advanced disease are nal and genitourinary tracts at greatest risk for complications
necessary to optimize tumor and pelvic control. Furthermore, after surgery or RT. Although in most of the retrospective series,
of 100 patients with primary tumors involving the upper and the investigators comment on the nature of the complications
middle third of the vagina who received no elective irradiation encountered, little information is typically given regarding their
to the groins, none developed metastatic inguinofemoral lymph prevention or management (13,15,21,33,110,133). In modern
nodes, which is in contrast to 3 of 29 (10%) patients with lower- oncology, survival rate is the primary endpoint in treatment
third primaries and 1 of 20 patients with tumors involving the evaluation, but the analysis of treatment complications and
entire length of the vagina. Of 7 patients with initially palpable quality of life is of crucial importance.
inguinal lymph nodes treated with doses to around 60 Gy, only The acute and chronic pathophysiology of vaginal RT has
1 developed a nodal recurrence. The investigators recommended been well described by Grigsby et al. (215). As an immediate
that elective RT of the inguinal lymph nodes should be carried response to high-dose RT, there is loss of most or all of the vagi-
out only in patients with primary tumors involving the lower nal epithelium, especially in areas in proximity to brachyther-
third of the vagina. Similar results were published by Stock et al. apy sources. Clinically, the severity of the acute effects (edema,
(21) and Stryker (196). Lee etal.(150) identified overall treat- erythema, moist desquamation, and confluent mucositis with or
ment time as the most significant treatment factor predicting without ulceration) varies in intensity and duration depending
pelvic tumor control in 65 patients with carcinomas of the va- upon patient age, hormonal status, tumor size, stage, RT dose,
gina treated with definitive RT. If the entire course of RT, includ- and personal hygiene. These effects usually resolve within 2 to
ing EBRT and brachytherapy, was completed within 9 weeks, 3 months after completion of therapy. In some patients, there
pelvic tumor control was 97% in contrast to only 57% when is progressive vascular damage with subsequent ulcer forma-
treatment time extended beyond 9 weeks (p < 0.01). Conversely, tion and mucosal necrosis, which may require up to 8 months
Perez et al. (35) did not find a significant impact of prolongation for healing. Chemotherapy concurrently with RT enhances the
582 CHAPTER 20 VAGI NA
DISEASE SITES
than systemic estrogens. Some patients with severe radiation
sequelae, such as fistula formation, will respond to conservative treated with more radical surgery. Local therapy consisted of
treatment with antibiotics and periodic limited debridement of vaginectomy in 9 cases, local excision alone in 17 cases, and
necrotic tissue. Delanian et al. (223) published a randomized local irradiation (with or without local excision) in 17 cases.
trial demonstrating the effectiveness of the combination of pent- The subgroup of patients receiving local irradiation had a recur-
oxifyllin and vitamin E in the regression of radiation-induced rence rate of 27%, similar to that of the conventional therapy
fibrosis. group and more favorable than that of either the subgroup
Patients with more severe gastrointestinal or urinary late ef- treated with vaginectomy or local excision alone. Recurrences
fects will require urinary or fecal diversion with possible de- were more frequently noted in patients with tumors greater than
layed reanastomosis. Occasionally, repair of the fistula may be 2cm, with invasion of 3 mm, and with a predominant histo-
attempted by employing a myocutaneous graft in which the logic pattern other than tubulocystic. Pelvic lymph node metas-
skin, subcutaneous fat, and muscle are mobilized using a vas- tases were noted at death in 12% of patients. They advocated
cular pedicle to maintain the blood supply to the pedicled graft a combination of wide local excision and extraperitoneal node
(Martius flap), or by excision of the necrotic tissue with reestab- dissection followed by brachytherapy for patients desirous of
lishment of organ continuity (such as in the treatment of high fertility preservation (103).
rectovaginal fistula). A detailed review of the pathogenesis and In a subsequent report, Senekjian et al. (229) reviewed the
management of potential late effects of treatment is not within experience with 76 cases with stage II CCA from the Registry
the scope of this chapter, and may be found in the chapter on for Research on Hormonal Transplacental Carcinogenesis. The
management of complications of gynecologic cancer treatment overall 5- and 10-year survival rates were 83% and 65%, re-
(see Chapter 30). spectively. Of the 76 patients, 22 received surgery exclusively
It is likely that improvements in modern practice such as ad- (either radical hysterectomy with vaginectomy, 13 patients, or
vancements in surgical techniques (such as more generous use of exenterative type procedure, 9 patients), 38 received RT alone,
myocutaneous flaps) (131,224), improved supportive care dur- 12 received combination therapy, and 4 underwent other ap-
ing the immediate postoperative stay, the use of more sophis- proaches. Patients treated with primary RT achieved an 87%
ticated RT field setting (3-dimensional conformal therapy and 5-year survival rate versus 80% for those treated with surgery
IMRT) and treatment delivery, more accurate brachytherapy and 85% for those receiving both treatments. The investigators
techniques, and dose calculations have the potential to lessen concluded that most patients with stage II vaginal CCA should
complication rates post therapy, regardless of which modality be treated with combination EBRT and brachytherapy; how-
is used. ever, small, easily resectable lesions in the upper fornix might
584 CHAPTER 20 VAGI NA
undergo resection, allowing better preservation of coital and survival was found among the different surgical procedures
ovarian function (229). (31). In a meta-analysis of essentially the same patient popula-
In 1989, Senekjian et al. (226) reported their experience of tion (n= 119 patients), Van Nostrand et al. (236), after adding
20 pelvic exenterations for CCA of the vagina, including 13 for 8 of their own cases, reached different conclusions. They stated
primary lesions and 7 for recurrent disease. The 9 patients with that radical surgery is recommended for patients with primary
stage II disease treated with primary exenteration were com- vaginal melanomas of less than 10 cm2. In the Van Nostrand etal.
pared with the 67 who had other modalities of therapy; no sig- series of their own 8 patients with vaginal melanoma, includ-
nificant difference in the survival experience was noted between ing 4 treated conservatively and 4 undergoing radical surgery,
the 2 groups. They reported a 72% success rate if the exen- the only long-term survivor was in the radical surgery group. In
terations were done as part of primary therapy. They advocated their review of the literature, comprising a total of 119 patients,
reserving exenterative approaches for those who have failed RT there was 48% 2-year survival rate if treated with radical sur-
in order to maximize quality of life for the greatest number of gery (50 patients) versus only 20% if treated conservatively (69
patients (226). patients) (p < 0.005). Therefore, Van Nostrand etal. advocated
There are few published reports regarding the use of systemic radical excision for those vaginal melanomas less than 10 cm2
therapy for CCA. Fowler et al. (230) reported 1 complete and 1 in area (236).
partial response after treatment with melphalan (1 mg/kg qd 5 Not all authors support a radical resection approach. Bu-
days). Robboy et al. (37) reported responses in recurrent disease chanan et al. (232) performed a literature review of 66 cases
to both 5-FU and vinblastine. reported since the publication of Reid et al. (31). Survival was
influenced by tumor size, with a median survival time of 41
months of those with lesions lesser than 3 cm and 21 months
in those with larger lesions. However, there was no statistically
NON EPITH ELIAL TU MORS significant difference in median survival or 2- and 5-year sur-
vival among the various surgical strategies. Hence, many inves-
OF TH E VAGI NA tigators have adopted the suggestion of Irvin et al. (234) that
if distant failure and death are expected, quality of life should
Melanoma of the Vagina be optimized by wide excision followed by RT to affect local
Vaginal melanoma is an exceedingly rare entity. Therefore, the control, while obviating the need for disfiguring radical surgery
number of patients with vaginal melanoma is too small to per- (182). In the Irvin et al. series (234), all patients treated with
mit prospective controlled trials. Melanoma of the vagina, with wide local excision or brachytherapy alone developed recurrent
its propensity to develop distant metastases and its lack of a disease locally, whereas those patients treated with radical surgi-
recognized precursor lesion, has presented therapeutic chal- cal resection or with wide local excision followed by high-dose-
lenges for surgeons. Investigators have reported small series per-fraction EBRT maintained locoregional control until death.
with generally disappointing results irrespective of treatment Recent retrospective data suggest that vaginal melanoma is
modality (245250). Because of the reputation of melanoma as reasonably radioresponsive and possibly radiocurable (234,237).
a radioresistant tumor, it is not surprising that radical surgery Volumes and doses of irradiation are similar to those used for
has been considered to be the treatment of choice in operable epithelial tumors, ranging from 50 Gy for subclinical disease to
patients. However, limited data are available that validate its 75 Gy for gross tumors. Retrospective analysis suggested a dose-
efficacy. Although 75% 2-year survival has been achieved after response curve of melanoma to external beam irradiation as the
radical excision in small series (236), most series report 5-year dose per fraction is increased and fractions of 3.5 Gy 3 times
survival rates of 5% to 30% regardless of radicality of surgery weekly to 5 Gy twice weekly have been used to treat melanoma
(38,245250). because of a large Dq observed in in vitro studies (238,239).
Levitan et al. (235), in their review of the literature, indicated However, the Radiation Therapy Oncology Group conducted
that although the 2-year survival following radical surgery was a prospective randomized study (RTOG 8305) (240) evaluat-
better (20% to 40%) than with any other therapy, the 5-year ing the effectiveness of high-dose-per-fraction irradiation in the
survival rates were equally poor (average 8%) regardless of type treatment of melanoma. Patients with measurable lesions were
of therapy. Furthermore, the incidence of distant recurrence was randomized to 4 8.0 Gy in 21 days once weekly to 20 2.5 Gy
not influenced by the extent of surgical resection. Geisler et al. in 26 to 28 days, 5 days a week. One hundred thirty-seven pa-
(233) published the Indiana University experience using pelvic tients were randomized and 126 patients were evaluable; strati-
exenteration for malignant melanomas of the vagina or urethra fication was performed on lesions lesser than 5 cm or 5 cm.
with more than 3 mm of invasion. None of the 4 patients in- There was no difference between the 2 arms in terms of response
cluded in this study had recurrences, and 3 patients remained rate (complete responses 24.2% and 23.4% in the 4 8.0 Gy
alive with a minimum follow-up of 31 months. Conversely, Bon- and in the 20 2.5 Gy arms, respectively) (240).
ner et al. (231) reported 9 cases of vaginal melanoma: Three Harwood and Cummings (241) described a complete re-
received wide local excisions and 6 underwent radical surgery sponse in 4 patients with vaginal melanoma treated with irra-
(including exenterations and radical vaginectomies with or diation, although 2 subsequently relapsed; complete response
without hysterectomies), with a 29% actuarial 5-year survival to irradiation was seen in 1 patient who was alive and well 10
rate. All 9 patients suffered locoregional recurrence. The investi- months after treatment. Harrison et al. (242) reported that 1 of
gators advocated that surgery alone was ineffective in obtaining 3 patients with vaginal melanoma treated with irradiation sur-
local control, and that preoperative RT should be considered vived 7.5 years; the other 2 died with distant metastases but had
(231). local tumor control. Rogo et al. (243) reported on 22 cases of
Reid et al. (31) reported an overall 17% 5-year survival rate vulvovaginal melanoma treated with conservation surgery or ir-
in a report of 15 patients, including 13 who underwent surgery. radiation, or both. Eight patients (36%) were alive 5 years after
In addition, they reviewed the literature, summarizing the re- treatment, and 4 were alive 10 years after treatment. Inguinal
sults achieved in 115 patients with vaginal melanoma, and com- lymph node recurrences and distant metastases were the most
pared outcomes for the 55 patients who underwent some form common modes of failure. Results were comparable with those
of surgery, including the 24 treated conservatively with wide obtained with radical surgery.
local excision or partial vaginectomy, to the 31 treated with In the Petru et al. series (237) of 14 patients, the 3 long-
more radical excisions. No difference in survival or disease-free term survivors received either primary RT after biopsy only,
CHAPTER 20 VAGI NA 585
or adjuvantly after local excision. Tumor size was found to be ifosfamide alone, which has produced the highest response rate
prognostically important, with 43% of patients with tumors 3 among these agents (250,251). Doxorubicin remains the stan-
cm surviving longer than 5 years, compared with 0% of patients dard therapy for leiomyosarcoma (252).
with tumors greater than 3 cm. The median overall survival was Embryonal rhabdomyosarcoma (RMS) of the vagina, the
10 months, and the 5-year DFS and overall survival rates were most common pediatric vaginal tumor, is such a rare lesion that
14% and 21%, respectively. The authors concluded that pro- no single institution has sufficient experience to identify supe-
longed local control could be obtained with RT as an adjunct rior therapeutic strategies. Rather, cooperative efforts through
to more limited surgery, or even with RT alone, primarily in the Intergroup Rhabdomyosarcoma Study Group (IRSG)
patients with lesions 3 cm in diameter. through numerous clinical trials have demonstrated that the use
In summary, given that the high incidence of distant metastasis of multimodality therapy with wide local excision and cytotoxic
remains a major factor in limiting curability, a more conserva- chemotherapy with or without RT makes it possible to avoid
tive treatment approach might be more reasonable in selected exenterative surgery and optimize quality of life for these young
patients. Patients with vaginal melanoma should probably be patients (251255). Prior to the modern era of multimodality
managed in a manner similar to that recommended for cutaneous therapy, Hilgers reported that only 20% to 30% 5-year survival
lesions (244). Wide local excision with 1- to 2-cm margins should rates were achieved with the use of exenterative-type surgery
be the surgical treatment of choice for most primary vaginal alone (256). Later, several small series noted that 70% survival
melanomas since radical surgery has failed to improve long-term could be achieved if RT and combination cytotoxic chemother-
survival. The role of adjuvant RT is unclear, but it appears to im- apy including vincristine, actinomycin D, and cyclophospha-
prove survival in some series. The use of systemic chemotherapy mide (VAC) were given in addition to radical surgery (256258).
and/or immunotherapy has been very disappointing in the limited After complete resection, irradiation of the entire pelvis is not
published data (245). required, thus avoiding its adverse effects.
In a series of reports from the IRSG, survival rates in excess of
85% have been achieved utilizing VAC chemotherapy and wide
excision with or without adjuvant RT, sparing the great major-
Sarcomas of the Vagina ity of patients from exenterative surgery (253255,259,260). In
Sarcomas represent 3% of vaginal primaries (5), with leio- a subsequent report, Andrassy et al. (261) from the IRSG sum-
myosarcoma representing 50% to 65% of vaginal sarcomas. marized the outcome of 72 patients with embryonal RMS of
Unfortunately, most of the sarcomas are diagnosed at an ad- the vagina treated on 4 IRSG trials. Over the course of the 4
vanced stage. Histopathologic grade appears to be the most IRSG trials, the need for radical resection decreased from 100%
important predictor of outcome. Most vaginal leiomyosarco- to 13%, with continued improvement in disease-free survival
mas arise from the posterior wall of the vagina. Radical surgi- (261Andrassy et al. suggested that after biopsy to document
cal resection, such as posterior pelvic exenteration, offers the RMS, multiagent induction chemotherapy with doxorubicin,
best chance for cure for vaginal leiomyosarcomas (5,246). The cisplatin, vincristine, actinomycin D, and cyclophosphamide
largest series on vaginal sarcomas reported to date included 17 should be utilized, then local resection undertaken, with radical
cases, of which 35% had received prior RT. This series, which resection being reserved for those with persistent or recurrent
included ten leiomyosarcomas, 4 malignant mixed mllerian disease (261). In addition, several non-IRSG series have shown
tumors (MMMTs), and 3 other sarcoma types, noted that all that combination chemotherapy with or without RT leads to
were resistant to chemotherapy, and all of the failures were first sufficient tumor shrinkage, and that less radical resections can
noted as pelvic recurrences. There were only 3 survivors seen, become feasible (259,260), allowing preservation of anatomy
DISEASE SITES
and all had undergone exenterative surgery. The 5-year survival and function.
rate was 36% in patients with leiomyosarcoma and 17% in Flamant et al. (259) reported 11 cases of vaginal RMS (8 stageI,
those with MMMT (247). 2 stage II, 1 stage III) in whom 100% survival was achieved with
Vaginal MMMTs occur more commonly in postmenopausal multimodality therapy. Eight patients received neoadjuvant che-
women. In approximately half of the cases there is a history of motherapy, generally a VAC regimen, and all patients underwent
prior pelvic RT (247,248). Despite surgery and adjuvant RT, brachytherapy (doses of 26 to 75 Gy), followed by maintenance
patients usually do poorly, with a high incidence of local and chemotherapy and VAC alternating with VAD (vincristine, doxo-
distant recurrences. The treatment of choice is complete surgical rubicin, dacarbazine). Seven patients underwent ovarian transpo-
resection, followed by EBRT and ICB in an attempt to decrease sition in an attempt to preserve function. The investigators noted
the local recurrence rate. partial ovarian insufficiency in 1 patient without ovarian trans-
The roles of adjuvant chemotherapy and RT in vaginal sar- position. They recommended brachytherapy at a total dose of
comas have not been clearly defined, primarily owing to limited approximately 50 to 60 Gy (259).
patient numbers and even fewer data where chemotherapy was
used as the primary treatment rather than as salvage therapy at
recurrence. Adjuvant RT seems to be indicated in patients with
high-grade tumors and locally recurrent low-grade sarcomas. Lymphomas and the Vagina
According to Peters et al. (247), the most common site of failure Lymphomatous involvement of the vagina most often represents
is the pelvis. In 50% of patients with recurrence, it is the only site metastatic spread from another primary site. Although surgery
of failure. Extrapolating data from the Gynecologic Oncology (including radical hysterectomy, pelvic lymphadenectomy, vagi-
Group (249) for uterine sarcomas and considering patterns nectomy, and exenteration) has been performed in the past,
of failure, patients with localized MMMTs would be appropri- more recent reports suggest that combination RT and chemo-
ately treated with pelvic exenteration, or with more limited sur- therapy can achieve excellent results. Radical surgery in such
gical resection followed by postoperative RT, unless the patient patients then should be avoided, as lymphoma represents a sys-
has received prior pelvic RT. Since patterns of failure suggest temic disease. Following biopsy, patients with lymphoma should
that local therapies only reduce the local recurrence rate and do be managed with chemotherapy alone or combined chemora-
not improve survival, consideration should be given to adjuvant diation. Extrapolation from patients with similar tumors aris-
treatments with agents that are active in similar tumors arising ing in extranodal sites would suggest that RT has its primary
in the uterus. Agents found to be active in MMMT of the uterus role in preventing local recurrence in patients who present with
include ifosfamide, cisplatin, and paclitaxel, although it remains bulky disease. In some patients who have a rapid and complete
unclear whether any combination of these agents is better than response to multiagent chemotherapy, RT may not be indicated
586 CHAPTER 20 VAGI NA
since the combination of both modalities increases the risk of suggesting the potential role of radiation-induced melanoma in
second malignancies. Harris and Scully noted in a clinicopatho- non-sun-exposed areas such as the genital tract.
logic series of 25 lower genital tract lymphomas, including 4 Malignant transformation occurs in the neovaginal epithe-
vaginal lymphomas, that definitive local therapy prevented re- lium, in relation with local carcinogenic environmental factors
lapse (262). Prevot et al. (263) and Perren et al. (264) also ad- as well as possible viral infection, with the subsequent risk of
vocated the use of less extensive surgery, with RT plus cytotoxic malignancy. Therefore, it is important to emphasize the need for
multiagent chemotherapy such as CHOP (cyclophosphamide, regular follow-up visits with Pap smears. The elapsed time be-
hydroxydaunomycin [doxorubicin], Oncovin [vincristine], tween the construction of the neovagina and the development
prednisone) or BACOP (bleomycin, Adriamycin [doxorubicin], of malignancy ranges between 10 and 30 years. The optimal
cyclophosphamide, Oncovin [vincristine], prednisone) for 4 to treatment is not well defined. Radical surgery resection when
6 cycles to affect local control with better preservation of fertil- possible should be the treatment of choice, since definitive RT
ity in patients with stage IE and nonbulky tumors of low and seems to be associated with higher failure rates (227). Adjuvant
intermediate grade. RT could be considered in patients with positive margins or
positive nodes (277).
leg edema, and hydronephrosis. It is important to evaluate for and the choice is based on patient and tumor-related factors,
regional and/or distant metastasis by physical examination and as well as the experience of the radiation oncologist. When us-
imaging studies such as CT or MRI scans. More recently, the ing EBRT, multiple-beam arrangements utilizing 3-dimensional
positron emission tomography (PET) scan has been used to treatment planning are favored. Only limited doses are possible,
document the extent of recurrent disease (282), but both false- and the physician might consider a hyperfractionated regimen in
positive and false-negative results have been reported. an attempt to decrease the incidence of late toxicity.
Generally, patients with isolated pelvic or regional recur- In patients with small, well-defined vulvovaginal or pelvic
rences after definitive surgery who have not received prior RT recurrences, reirradiation using primarily interstitial techniques
are managed with EBRT, often in conjunction with brachyther- has been attempted with control rates between 50% and 75%
apy (16,21,24). Concurrent cisplatin-based chemotherapy may and grade 3 or higher complication rates between 7% and 15%
also be recommended (23). Salvage options for patients with (285389). The rationale, logistics, and selection of implant
central recurrence after definitive or adjuvant RT are limited to technique when performing an ITI were reviewed earlier in the
radical surgery, usually exenterative (16,21,23,24). In selected chapter. Permanent radioactive seed implants (e.g., 198Gold) in
patients with small volume disease, reirradiation using inter- patients with small vaginal recurrences often provide long-lasting
stitial radiation implants or highly conformal 3-dimensional tumor control in elderly or medically debilitated patients previ-
EBRT may be feasible. Response rates with chemotherapy are ously treated with definitive doses of RT (301). In a series by
low and the impact on survival is limited. Further, response to Brabham and Cardenes (307), 19 patients with low volume
chemotherapy in central pelvic recurrences following RT tends recurrent gynecologic malignancies (4 vaginal primaries) were
to be less common than response at distant sites. Additionally, treated with permanent interstitial implants using 198Gold. Com-
prior high-dose radiation therapy compromises bone marrow plete response was observed in almost 95% of patients and local
tolerance of many agents that are active in this tumor (e.g., if- control was achieved in 63%; however the authors emphasize
osfamide and doxorubicin). However, chemotherapy-responsive that these results are in a selected patient population with small
patients can obtain meaningful palliation in many cases. volume recurrences no thicker than 1 cm (161).
Other potential treatment options include the use of sur-
gery and intraoperative RT (IORT) with intraoperative elec-
tron beam (290,291), laparotomy, or laparoscopically guided
Surgical Considerations placement of HDR catheters (192,291293), which allows di-
Despite thorough clinical evaluation of patients considered being rect visualization of the target volume and displacement and/
excellent candidates for salvage surgery, this will be aborted in or shielding of the surrounding normal tissues. However, the
over 25% of the cases because of advanced disease found at the published series are generally small, including a wide spectrum
time of the exploratory laparotomy (283). Pelvic exenteration of patients with different gynecologic malignancies, varying
results in long-term functional and psychological changes that amounts of residual disease, and disparate initial therapies. The
have not been adequately studied (284). Surgical refinements locoregional recurrence and distant metastasis rates after IORT
have done much to improve body image changes associated vary between 20% and 60% and 20% and 58%, respectively.
with pelvic exenteration. The purposes of vaginal and perineal The 3- to 5-year actuarial survival is poor, ranging from 8%
reconstruction following radical pelvic surgery for recurrent to 25%. Grade 3 or higher toxicity has been reported in about
gynecologic cancer are primarily twofold: to restore or create 35% of patients (290,291). In the Memorial Sloan-Kettering
vulvovaginal function, and thereby minimize the effects of sur- Cancer Center experience using radical surgical resection and
gical treatment on body image and normal sexual activity, and HDR-IORT, patients with complete gross resection had a 3-year