Multidisciplinary Management of

Hepatocellular Carcinoma
Hepatocellular Carcinoma: Overview
Burden of HCC
Surveillance and diagnosis
Staging and treatment algorithms
Early HCC
Intermediate HCC
Advanced HCC
A look to the future
HCC: Common and Increasing
694,000 deaths from liver cancer yearly worldwide
[1]
Age-adjusted US incidence has increased 2-fold from 1985-
1998
[2]
Expected to continue to increase until 2015-2020
[3]
American Cancer Society statistics for liver cancer in 2010
[4]
Estimated new cases: 24,120
Estimated deaths: 18,910
5th leading cause of cancer deaths in males
1. GLOBOCAN 2008.
2. SEER stat fact sheets: liver and intrahepatic bile duct.
3. Llovet JM. J Gastroenterol. 2005;40:225-235.
4. American Cancer Society. Cancer facts & figures 2010.
Burden of HCC in the United States
Annual prevalence, incidence, and survival with HCC
estimated from SEER database
Distribution of costs estimated from 392 HCC patients
Annual estimated cost of HCC in the United States:
$454.9 million
Per-patient cost: $32,907
Healthcare costs accounted for 89.2% of cost
Lost productivity accounted for 10.8% of cost
Malignant Transformation
Multistep
Normal liver
Liver cirrhosis
Hepatitis C
Hepatitis B
Ethanol
NASH
Epigenetic alterations
Genetic alterations
HCC
[2]
Dysplastic nodules
[1]
Potential Targets
Oxidative stress
and inflammation
Viral
oncogenes
Carcinogens
Growth factors Telomere
shortening
Cancer stem
cells
Loss of cell cycle
checkpoints
Antiapoptosis Angiogenesis
1. Tornillo L, et al. Lab Invest. 2002;82:547-553.
2. Verslype C, et al. AASLD 2007. Abstract 24.
Patients for Whom HCC Surveillance Is
Recommended
Asian males HBV carriers older than 40 yrs of age
Asian female HBV carriers older than 50 yrs of age
HBV carrier with HCC family history
African/N American blacks with HBV
Cirrhotic HBV carriers
Hepatitis C with cirrhosis
Stage 4 primary biliary cirrhosis
Genetic hemochromatosis and cirrhosis
Alpha-1 antitrypsin deficiency and cirrhosis
Other cirrhosis
80% of patients with HCC have underlying cirrhosis
Bruix J, et al. AASLD HCC guidelines. July 2010.
Simonetti RS, et al. Dig Dis Sci. 1991;36:962-972.
AASLD Surveillance Guidelines
Surveillance recommended in at-risk groups
Specific hepatitis B carriers
Nonhepatitis B cirrhosis
HCC surveillance should be performed with ultrasound
Patients should be screened at 6-mo intervals
Increased surveillance interval in patients at higher
risk not needed
Staging Systems and Treatment
Strategies in HCC
Variables Used in HCC Staging Systems
System Tumor Staging Liver Function Health Status
Europe-US
GETCH/
French
PVT; AFP < 35 or > 35 ug/L Bilirubin, alkaline phosphatase Karnofsky
CLIP Number of nodules, tumor > or < 50% area of
liver, and PVT;
AFP< 400 or 400 ng/mL
CTP No
BCLC Tumor size, number of nodules, and PVT CTP PST
TNM Number of nodules, tumor size, presence of
PVT, and presence of metastasis
No No
Asia
JIS TNM CTP No
Okuda/
Tokyo
Tumor > or < 50% of cross-sectional area of
liver
Ascites, albumin, and bilirubin No
CUPI TNM; AFP< 500 or 500 ng/mL Bilirubin, ascites, alkaline
phosphatase
Symptoms
Marrero JA, et al. Hepatology. 2005;41:707-716.
Comparison of HCC Staging Systems
BCLC system uses key independent predictors of survival
Performance score, portal vein thrombosis, tumor
diameter
Compared with other staging systems in cohort study
BCLC had best stratification of survival across all
stages
BCLC was only system to have independent predictive
value on survival
BCLC is the only staging system that stratifies patients
into treatment groups
Marrero JA, et al. Hepatology. 2005;41:707-716.
BCLC Staging System
Terminal
stage (D)
Okuda 1-2, PS 0-2, Child-Pugh A-B
Multinodular, PS 0
N1, M1, PS 1-2 < 3 cm, PS 0
Intermediate
stage (B)
Okuda 3, PS > 2,
Child-Pugh C
Very early stage (0)
Single < 2 cm
Carcinoma in situ
Early stage (A)
Single or 3 nodules
Advanced stage (C)
Portal invasion,
PS 0, Child-Pugh A
HCC
Llovet JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer
Institute. 2008;100(10):698-711, by permission of Oxford University Press.
Stage 0 Stage A-C Stage D
Child Pugh Score
Partial Liver Resection
Adjuvant Therapy in the Resection Setting
Recurrence following resection
Approximately 50% at 3 yrs
Approximately 70% at 5 yrs
Positive results for several types of adjuvant therapy in
this setting
However, no standard-of-care adjuvant therapy for
HCC patients undergoing resection
Large, randomized, controlled trials of adjuvant therapy
following resection ongoing
Llovet JM, et al. Hepatology. 1999;30:1434-1440.
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
Liver Transplantation for HCC:
Milan Criteria (Stage 1 and 2)
5-yr survival with transplantation: ~ 70%
5-yr recurrent rates: < 15%
+
Absence of macroscopic vascular invasion,
absence of extrahepatic spread
Single tumor, not > 5 cm
Up to 3 tumors, none > 3 cm
Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.
Llovet JM. J Gastroenterol Hepatol. 2002;17(suppl 3):S428-S433.
Candidates for RFA/PEI
Includes individuals who are not candidates for surgery
Radiofrequency ablation generally preferred over
percutaneous ethanol injection
Necrotic effect more predictable across tumor sizes
Meta-analyses suggest survival benefit with
radiofrequency ablation vs percutaneous ethanol
injection
Bruix J, et al. AASLD HCC guidelines. July 2010.
Liver transplantation RFA/PEI
Curative treatments (30%); 5-yr survival: 40%-70%
TACE
Single
Increased
Associated
diseases
Normal
No Yes
Sorafenib
Portal pressure/bilirubin
3 nodules 3 cm
Resection
Symptomatic
(20%); survival <
3 mos
RCTs (50%); 3-yr survival: 10%-40%
Terminal
stage (D)
Okuda 1-2, PS 0-2, Child-Pugh A-B
Multinodular, PS 0
N1, M1, PS 1-2 < 3 cm, PS 0
Intermediate
stage (B)
Okuda 3, PS > 2,
Child-Pugh C
Very early stage (0)
Single < 2 cm
Carcinoma in situ
Early stage (A)
Single or 3 nodules
Advanced stage (C)
Portal invasion,
PS 0, Child-Pugh A
HCC
BCLC Staging and Treatment Strategy
Llovet JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer
Institute. 2008;100(10):698-711, by permission of Oxford University Press.
Treatment of Intermediate HCC
Liver transplantation RFA/PEI
Curative treatments (30%); 5-yr survival: 40%-70%
TACE
Single
Increased
Associated
diseases
Normal
No Yes
Sorafenib
Portal pressure/bilirubin
3 nodules 3 cm
Resection
Symptomatic
(20%); survival <
3 mos RCTs (50%); 3-yr survival: 10%-40%
Terminal
stage (D)
Okuda 1-2, PS 0-2, Child-Pugh A-B
Multinodular, PS 0
N1, M1, PS 1-2 < 3 cm, PS 0
Intermediate
stage (B)
Okuda 3, PS > 2,
Child-Pugh C
Very early stage (0)
Single < 2 cm
Carcinoma in situ
Early stage (A)
Single or 3 nodules
Advanced stage (C)
Portal invasion,
PS 0, Child-Pugh A
HCC
Unresectable HCC
BCLC Staging and Treatment Strategy
Llovet JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer
Institute. 2008;100(10):698-711, by permission of Oxford University Press.
Llovet JM, et al. Hepatology. 1999;29:62-67.
Natural History of Nonsurgical HCC
Study Design: Control Arm of 2 RCTs
102 untreated cirrhotic patients with unresectable
HCC
Managed with symptomatic treatment
Median survival of 17 months (range: 1-60 months)
1-yr survival was 54%
2-yr survival was 40%
3-yr survival was 28%
Radiofrequency Ablation
RFA in combination with
Chemoembolization
Bland Embolization and TACE
Radioembolization
Llovet JM, et al. Hepatology. 2003;37:429-442.
Arterial Embolization for HCC
Meta-analysis of 6 RCTs (2-Yr Survival)
Random Effects Model,
OR (95% CI)
Author, Journal Yr Patients, n
Lin, Gastroenterology 1988 63
GETCH, NEJM 1995 96
Bruix, Hepatology 1998 80
Pelletier, J Hepatol 1998 73
Lo, Hepatology 2002 79
Llovet, Lancet 2002 112
Overall 503
Median survival: ~ 20 mos
0.01 0.1 0.5 1 2 10 100
Z = -2.3
P = .017
Favors Treatment Favors Control
Contraindications to TACE
Extrahepatic tumor spread
Lack of portal blood flow
Portal vein thrombosis, portosystemic anastomoses or
hepatofugal flow
Advanced liver disease (Child-Pugh Class B or C)
Clinical symptoms of end-stage cancer
Bruix J, et al. AASLD HCC guidelines. July 2010.
Lammer J, et al. Cardiovasc Intervent Radiol. 2010;33:41-52.
Randomized Study of Conventional TACE vs
DEB TACE
Patients, % Child-Pugh B ECOG 1 Bilobar Recurrent Disease
DEB
TACE
cTACE DEB
TACE
cTACE DEB
TACE
cTACE DEB
TACE
cTACE
Disease
control
63 32 0 32 59 49 73 54
Objective
response
44 21 63 29 49 40 55 31
Complete
response
25 16 37 14 17 13 27 15
Treatment of Advanced HCC
Liver transplantation RFA/PEI
Curative treatments (30%); 5-yr survival: 40%-70%
TACE
Single
Increased
Associated
diseases
Normal
No Yes
Sorafenib
Portal pressure/bilirubin
3 nodules 3 cm
Resection
Symptomatic
(20%); survival <
3 mos
RCTs (50%); 3-yr survival: 10%-40%
Terminal
stage (D)
Okuda 1-2, PS 0-2, Child-Pugh A-B
Multinodular, PS 0
N1, M1, PS 1-2
< 3 cm, PS 0
Intermediate
stage (B)
Okuda 3, PS > 2,
Child-Pugh C
Very early stage (0)
Single < 2 cm
Carcinoma in situ
Early stage (A)
Single or 3 nodules
Advanced stage (C)
Portal invasion,
PS 0, Child-Pugh A
HCC
BCLC Staging and Treatment Strategy
Llovet JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. Journal of the National Cancer
Institute. 2008;100(10):698-711, by permission of Oxford University Press.
Llovet JM, et al. N Engl J Med. 2008;359:378-390.
Patients with
advanced,
measurable HCC,
ECOG PS 0-2

(N = 602)
Sorafenib 400 mg BID PO
(n = 299)
Placebo
(n = 303)
Stratification by macroscopic vascular
invasion and/or extrahepatic spread,
ECOG PS, geographical region
Primary endpoints: OS, time to symptomatic progression
Secondary endpoints: progression (radiologic, clinical), adverse events
Phase III SHARP Trial: Sorafenib vs Placebo
in Advanced HCC
Llovet JM, et al. N Engl J Med. 2008;359:378-390. Copyright 2008 Massachusetts Medical Society. All rights
reserved.
Phase III SHARP Trial: OS (ITT)
Sorafenib (n = 299)
Median: 10.7 mos (95% CI: 9.4-13.3)
Placebo (n = 303)
Median: 7.9 mos (95% CI: 6.8-9.1)
1.00
0.75
0.50
0.25
0
S
u
r
v
i
v
a
l

P
r
o
b
a
b
i
l
i
t
y

HR (S/P): 0.69 (95% CI: 0.55-0.88;
P = .00058)
0 80 8 16 24 32 40 48 56 64 72
Wks
Pts at Risk, n
Sorafenib
Placebo
299
303
274
276
241
224
205
179
161
126
108
78
67
47
38
25
12
7
0
2
0
0
1. Llovet JM, et al. N Engl J Med. 2008;359:378-390. 2. Galle P, et al. EASL 2008. 3. Bolondi L, et al. ASCO-GI 2008.
Abstract 129. 4. Craxi A, et al. ASCO 2008. Abstract 15591. 5. Raoul J, et al. ASCO 2008. Abstract 4587. 6. Sherman
M, et al. ASCO 2008. Abstract 4584.
Exploratory Subgroup Analyses
Sorafenib
Placebo
Phase III SHARP Trial: Subgroup Analysis
M
e
d
i
a
n

O
S

(
M
o
s
)

16
14
12
10
8
6
4
2
0
10.7
7.9
11.9
8.8
9.9
11.9
14.0
7.0
10.3
8.0
13.3
8.8 8.9
5.6
8.9
6.7
14.5
10.2
Overall
Population
[1]
N = 602
Prior
Curative
Therapy
[2]
n = 158
Prior
TACE
[2]
n = 176
HCV
[3]
n = 178
Alcoholic
Cirrhosis
[4]
n = 159
ECOG
PS 0
[5]
n = 325
ECOG
PS 1-2
[5]
n = 277
MVI
and/or
EHS
[6]
n = 421
No MVI
and/or
EHS
[6]
n = 181
HR: 0.69
(95% CI:
0.55-0.87;
P < .001) HR: 0.79
HR: 0.75
HR: 0.58
HR: 0.76 HR: 0.71
HR: 0.77
HR: 0.52
HR: 0.68
Llovet JM, et al. N Engl J Med. 2008;359:378-390.
Conclusions From Phase III SHARP Trial
Sorafenib is first systemic therapy to prolong survival
in HCC patients
Survival: HR: 0.69; 31% decrease in risk of death
Time to radiologic progression: 5.5 mos with sorafenib
vs
2.8 mos with placebo (P < .001)
Sorafenib is the new reference standard for systemic
therapy of HCC patients
Molecular Therapies Under Evaluation for
HCC in Phase III (2011)
Targeted Population Phase III Comparison
Adjuvant Prevent recurrences 1. Sorafenib vs placebo
2. Retinoids vs placebo
Intermediate HCC Improve TACE 1. TACE sorafenib
2. TACE brivanib
Advanced HCC First line:






Second line:
1. Sorafenib erlotinib
2. Sorafenib vs brivanib
3. Sorafenib vs sunitinib
4. Sorafenib vs lifitinib
5. Sorafenib Y90
6. Sorafenib doxorubicin

1. Brivanib vs placebo
2. Everolimus vs placebo
3. Ramucirumab vs placebo
NEGATIVE:
ASCO 2010
HALTED:
2010
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis.
2010;30:52-60 (reprinted by permission).
AASLD-JNCI Guidelines in HCC:Trial Design
Endpoints
Survival or time to recurrence (phase III)
Time to progression (phase II)
Trial strategy: Test in the setting of randomized phase II before moving to
phase III
HCC classification: BCLC staging system recommended for selection of
target population, stratification
Assessment of response and TTP: Follow the AASLD-JNCI amendments
HCC Subclass (Standard of Care) Testing of Novel Drugs
First-line Treatment
Second-line
Treatment*
BCLC 0/A (resection, transplantation, local ablation) Adjuvant: drug vs placebo ---
BCLC B (chemoembolization, TACE) TACE vs TACE + drug
TACE vs drug or device

---
BCLC C (sorafenib) Sorafenib vs sorafenib + drug
Sorafenib vs drug

Drug vs placebo
*In case of failure to standard of care.

Head to head comparisons with standard of care are only justified if phase II data are very promising.
Understanding Survival Outcomes in HCC
Patients
HCC
Stage 0
PS 0, Child-Pugh A
Stage D
Okuda 3, PS > 2, Child-Pugh C
Stage A-C
Okuda 1-2, PS 0-2, Child-Pugh A-B
Very early
stage (0)
Single < 2 cm
Carcinoma in situ
Early stage (A)
Single or 3 nodules
< 3 cm, PS 0
Intermediate stage (B)
Multinodular, PS 0
Advanced stage (C)
Portal invasion,
N1, M1, PS 1-2
Terminal
stage (D)
2010
2020 60% 20% 20%
Median OS > 36 mos
Median OS
16 mos
Median OS
6 mos (4-8 mos)
Curative therapies
OS > 60 mos
Sorafenib: 10.7 mos
TACE:
OS 20 mos
40% 20% 40%
Natural
History
With
Therapy
2011 Stage at
Diagnosis
Courtesy of Josep M. Llovet, MD.
Role of Radiation Therapy
3D-CRT
a Mornex F, Girard N, Beziat C et al (2006) French Phase II RTF-1 trial. Int J Radiat Oncol Biol Phys 66:11521158
b Chung YL, Jian JJ-M, Cheng SH et al (2006) Clin Cancer Res 12:27062715
c Chia-Hsien Cheng J, Chuang VP, Cheng SH et al (2001). Int J Cancer 96:243252
d Zeng ZC, Fan J, Tang ZY et al (2008). Cancer Sci 99:25102517
e Seong J, Keum KC, Han KH et al (1999). Int J Radiat Oncol Biol Phys 43:393397
SBRT
a Mndez Romero A, Wunderink W, Hussain SM et al (2006). Acta Oncol 45:831837
b Henderson MA, Azzous F, Breen T et al (2007). Poster presentation, ASTRO 2007. Int J Radiat Oncol Biol Phys 69:S297; Wulf
J, Hdinger U, Oppitz U et al (2001). Strahlenther Onkol 177:645655
c Henderson MA, Azzous F, Breen T et al (2007). Poster presentation, ASTRO 2007. Int J Radiat Oncol Biol Phys 69:S297
d Choi BO, Choi IB, Jang HS et al (2008). BMC Cancer 8:351
Radiation Therapy
Conclusions
Burden of HCC is increasing
Requirements for diagnosis depends on patient
characteristics and tumor characteristics
BCLC staging system recommended by US and European
guidelines
BCLC system provides framework for selection of
treatment
Many studies ongoing for treatment of HCC
Multidisciplinary HCC Management
HCC is the intersection of 2 diseases
Liver disease and cancer
Skilled pathologists needed for diagnosis
Specialists required to deliver treatment options
Surgeons for resection or transplantation
Radiologists for ablation and chemoembolization
Hepatologists and oncologists follow treatment strategy
and labs
Midlevel providers bring support, particularly for oral
therapy