CCO HepatocellularCarcinoma SlidesetModule

Jointly sponsored by Postgraduate Institute for Medicine
and Clinical Care Options, LLC
Forging Partnerships in the

Management of Hepatocellular
Carcinoma: Multidisciplinary Strategies
to Provide Continuity of Care
This program is supported by educational grants from
Forging Partnerships in the Management of Hepatocellular Carcinoma:

Multidisciplinary Strategies to Provide Continuity of Care
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We are grateful to Luigi Bolondi, MD; Adrian M. Di Bisceglie, MD, FACP;

Jean-Francois Geschwind, MD; and Jorge A. Marrero, MD, MS, who aided in
the preparation of this slideset.
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clinicaloptions.com/oncology

Overview
Introduction: Current Trends in the Treatment of Patients
With Advanced HCC
Managing Liver Dysfunction in Patients With
Hepatocellular Carcinoma
Systemic Therapy and Supportive Care in Patients With
Advanced Hepatocellular Carcinoma
Medical Management of Patients Undergoing Regional
Therapy for Hepatocellular Carcinoma
Introduction: Current Trends in the

Treatment of Patients With
Advanced HCC
Luigi Bolondi, MD
Professor of Medicine
Chairman
Department of Digestive Diseases
and Internal Medicine
University of Bologna
Policlinico S. Orsola Malpighi
Bologna, Italy

Background
In the United States and Europe, the majority of HCC develops
on an underlying liver cirrhosis
Treatment strategies for HCC should avoid worsening liver
function to such an extent that would offset their possible
benefit
Staging systems for treatment allocation, therefore, must
concurrently consider tumor extension and severity of the
underlying liver function impairment
There is no universally accepted staging system for HCC

The BCLC staging system for HCC is the most widely used in
Western countries, particularly for treatment allocation

Staging Strategy and Treatment for

Patients With HCC
HCC
PST 0, Child-Pugh A
PST 0-2, Child-Pugh A-B
Very early stage

Early stage
Single < 2 cm Single or 3 nodules
3 cm, PST 0
Portal pressure/bilirubin
Increased
Resection
Advanced stage
Portal invasion,
N1, M1, PST 1-2
Terminal
stage
3 nodules 3 cm
Single
Normal
Intermediate stage
Multinodular, PST 0
PST > 2, Child-Pugh C
No
Liver transplant
Portal invasion,
N1, M1
Associated
diseases
Yes
PEI/RF
No
TACE
Curative treatments
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.

Bruix J, et al. Hepatology. 2005;42:1208-1236.
Yes
Sorafenib
Symptomatic
(unless LT)


Patients With HCC
HCC
PST 0, Child-Pugh A
Very early stage

Early stage
3 cm, PST 0
Increased
Resection
Advanced stage
Portal invasion,
N1, M1, PST 1-2
Terminal
stage
3 nodules 3 cm
Single
Normal
Intermediate stage
Multinodular, PST 0
No
Liver transplant
Portal invasion,
N1, M1
Associated
diseases
Yes
PEI/RF
Surgical treatments: applicable overall to

10% to 15% of HCC at first diagnosis and
2% to 5% of recurrent HCC
No
TACE
Yes
Sorafenib
Symptomatic
Nonsurgical treatments: applicable (unless LT)
overall to 65% to 75% of HCC at
first diagnosis and 50% to 70% of clinicaloptions.com/oncology
recurrent HCC

Approved Curative Treatments for

Unresectable HCC: Percutaneous Ablation
Local ablation: safe and effective therapy for patients who
cannot undergo resection or as a bridge to transplantation
(level II)
Alcohol injection and radiofrequency are equally effective
for tumors < 2 cm
However, necrotic effect of radiofrequency is more
predictable in all tumor sizes
In addition, efcacy is clearly superior to that of alcohol

injection in larger tumors (level I)

Approved & Investigational Noncurative

Agents for Unresectable HCC
AASLD 2005 recommendations
Chemoembolization (TACE) (with doxorubicin, cisplatin, or
mitomycin) is recommended as first-line, noncurative
therapy for nonsurgical patients with large/multifocal HCC
who do not have vascular invasion or extrahepatic spread
(and are not eligible for percutaneous ablation) (level I)
Tamoxifen, octreotide, antiandrogens, and hepatic artery
ligation/embolization are not recommended (level I); other
options such as drug-eluting beads, radiolabelled yttrium
glass beads, radiolabelled lipiodol, or immunotherapy cannot
be recommended as standard therapy for advanced HCC
outside clinical trials

Treatment of Advanced HCC

(BCLC Stage C)
AASLD 2005 recommendation: no standard therapy;
patients should enroll in a randomized clinical trial[1]
2008 recommendation: sorafenib has become the
standard of care for advanced HCC[2]
Prolongs OS by 3 months[3]
1-year survival: 44%[4]
1. Bruix J, et al. Hepatology. 2005;42:1208-1236.

2. Llovet JM, et al. J Hepatol. 2008;48:S20-S37.
3. Llovet J, et al. ASCO 2007. Abstract LBA 1.
4. Llovet J, et al. N Engl J Med. 2008;359:378-390.

Intermediate/Advanced HCC:
Future Directions
499 trials registered at clinicaltrials.gov for HCC as of
August 21, 2008, including
Improving efficacy of RF and TACE (drug-eluting beads)
Exploring alternative treatments for intermediate HCC (yttrium-90)
Molecularly targeted agents in combination regimens (advanced HCC)
Molecularly targeted agents in combination with current modalities

(early/intermediate HCC)
Improving tumor targeting of chemotherapeutic agents
New molecular targets and new molecularly targeted agents

Sorafenib: Ongoing Studies in HCC

Europe
Asia-Pacific
10 studies approved
4 TACE + sorafenib (1 phase I,

1 phase II, 2 phase III)
Sorafenib + tegafur
Sorafenib + capecitabine/oxaliplatin
Sorafenib + bevacizumab
Sorafenib + gemcitabine
Sorafenib + erlotinib
Sorafenib + temsirolimus
Sorafenib dose escalation
Sorafenib + tegafur
4 studies approved
United States
4 studies (nonactivated)
Sorafenib + gemcitabine/oxaliplatin
2 TACE + sorafenib
Sorafenib + erlotinib
Sorafenib + lapatinib
Biomarkers
Managing Liver Dysfunction in

Patients With Hepatocellular
Carcinoma
Jorge A. Marrero, MD, MSc
Associate Professor of Medicine
Director, Multidisciplinary Liver
Tumor Program
University of Michigan Health System
Ann Arbor, Michigan

Malignant Transformation
HCC[2]
Multistep
Epigenetic alterations
Genetic alterations
Dysplastic nodules[1]
Liver cirrhosis
Hepatitis C
Hepatitis B
Ethanol
NASH
Potential Targets
Oxidative stress and
inflammation
Viral oncogenes
Carcinogens
Growth factors
Telomere
shortening
Cancer stem
cells
Loss of cell cycle

checkpoints
Antiapoptosis
Angiogenesis
Normal liver
1. Tornillo L, et al. Lab Invest. 2002;82:547-553.

2. Verslype C, et al. AASLD 2007. Abstract 24.

Child-Pugh Score
Measure
1 Point
Each
2 Points
Each
3 Points
Each
Bilirubin (mg/dL)
< 2.0
2.0-3.0
> 3.0
Albumin (g/dL)
> 3.5
2.8-3.5
< 2.8
1.0-3.0
4.0-6.0
> 6.0
Ascites
None
Slight
Moderate
Encephalopathy (grade)
None
I-II
III-IV
Prothrombin time (sec)
Grade
A
B
C
Total Points
5-6
7-9
10-15
Pugh RN, et al. Br J Surg. 1973;60:646-649.
Surgical Risk
Good
Moderate
Poor

MELD Score Predicts Severity of Liver

Disease and Cirrhosis-Related Mortality
MELD score: (0.957 x Ln[creatinine] + 0.378 x Ln[bilirubin] +
1.12 x Ln[INR] + 0.643) x 10
Mortality by MELD score
< 9: 2.9% (n = 12)
10-19: 7.7% (n = 180)
20-29: 23.5% (n = 1038)
30-39: 60.0% (n = 295)

> 40: 81.0% (n = 126)
Wiesner RH, et al. Gastroenterology. 2003;124:91-96.

Survival of Cirrhotic Patients

Markedly longer survival in patients with compensated
cirrhosis vs those with decompensated cirrhosis
Median survival
Compensated cirrhosis: > 12 years
Decompensated cirrhosis: ~ 2 years
DAmico G, et al. J Hepatology. 2006;44:217-231.

Survival of Cirrhotic Patients

Child-Pugh classification also important
Child-Pugh class A disease had better 1- and 2-year
survival
Median 1- and 2-year survival by Child-Pugh class

Class A: 95% and 90%, respectively
Class B: 80% and 70%, respectively
Class C: 45% and 38%, respectively
DAmico G, et al. J Hepatology. 2006;44:217-231.

Portal Hypertension
Portal hypertension
Cirrhosis
Increased intrahepatic
vascular resistance
Hyperdynamic circulation
Increased splanchnic blood
flow
Increased total blood volume
Decreased nitric oxide
Increased cardiac output
Portal hypertension
Systemic vasodilation
(decreased systemic vascular
resistance)
Increased renin-angiotensin,
vasopressin, sympathetic
systems

Diagnosis
The gold standard is biopsy because it is the only way to
ascertain the degree of fibrosis
Noninvasive diagnosis
Physical exam indicating stigmata of liver disease
Evidence of splenomegaly
Thrombocytopenia
Cirrhotic-appearing liver on ultrasound or CT
Presence of chronic liver disease
Evidence of portal hypertension (ie, presence of varices, caput)

Treatment of Liver Disease
Hepatitis C: IFN + RBV
Hepatitis B: IFN, lamivudine, adefovir, entecavir
Alcohol: Abstinence
Primary biliary cirrhosis: Ursodeoxycholic acid
Hemochromatosis: Phlebotomy
Alpha-1 ATD: None
Nonalcoholic fatty liver: Diet and exercise
Wilsons disease: Zinc, trientene
Sclerosing cholangitis: Ursodeoxycholic acid, biliary stents
Autoimmune hepatitis: Immunosuppression


Complications of Cirrhosis
Variceal bleeding
Cirrhosis
Ascites/hepatorenal
syndrome
Hepatic encephalopathy
HCC

Gastroesophageal Varices
Present in approximately 50% of cirrhotics
Correlates with hepatic function
Child-Pugh class A: 40% prevalence
Child-Pugh class C: 85% prevalence
Hemorrhage rate: 10% to 30% per year

Threshold portal pressure: 12 mm Hg
Mortality: 30% to 50%
Garcia-Tsao G. Gastroenterology. 2001;120:726-748.

Variceal Hemorrhage
Courtesy of Jorge A. Marrero, MD.

Treatment of Variceal Bleeding

Resuscitative measures
Hematocrit replaced to 25% to 30%
Prophylactic antibiotics because of development of
infections
First Line
Endoscopy +
somatostatin
Second Line
Third Line
TIPS/shunt surgery
Balloon
tamponade

Ascites
The second most frequent complication of cirrhosis
5-year cumulative rate: 30%
Once ascites develops, the 1-year survival is ~ 50%
Treatment will improve quality of life and prevent

spontaneous bacterial peritonitis and hepatorenal
syndrome
Gines P, et al. Semin Liver Dis. 2008;28:43-58.

Diagnostic Paracentesis
Tests to be ordered (20-50 mL samples)
Cell count + differential
Albumin
Total protein
Culture in blood culture bottle
Glucose, LDH, amylase
Serum-ascites albumin gradient

> 1.1: portal hypertension
< 1.1: infection, cancer, renal

Management of Ascites
2 g sodium diet
Promote natriuresis with a combination of K-sparing and
loop diuretics
Large volume paracentesis (> 5 L) is safe
Albumin infusion concomitantly prevents circulatory
dysfunction
TIPS
Importantly, patients who develop hepatorenal syndrome
have a poor prognosis

Hepatic Encephalopathy
Type A is related to acute liver failure
Type B occurs in the setting of normal liver histology and
the presence of a hepatic vascular bypass
Type C, due to cirrhosis, involves the majority of cases

Incidence in cirrhotics: ~ 10%

Management of Hepatic
Encephalopathy
First line
Lactulose, a nonabsorbable disaccharide, should be initiated
and titrated to approximately 4 bowel movements per day
Second line
Enteric flora modification with antibiotics, such as
metronidazole or neomycin
Third line
L-ornithine-L-aspartate administration
Marrero J, et al. Am J Respir Crit Care Med. 2003;168:1421-1426.

Conclusions
The incidence of chronic liver disease is rising
The improved survival of patients with cirrhosis will likely
increase the number of patients with HCC
Because most patients with HCC have underlying cirrhosis

of the liver, attention in managing these complications is
important
HCC is best managed in a multidisciplinary setting
Systemic Therapy and Supportive

Care in Patients With Advanced
Hepatocellular Carcinoma
Adrian M. Di Bisceglie, MD, FACP
Professor of Internal Medicine
Acting Chairman
Department of Internal Medicine
Saint Louis University School of Medicine
Chief, Hepatology
Division of Gastroenterology and
Hepatology
Saint Louis University Hospital
St Louis, Missouri

Management of HCC
Liver transplantation
Resection
Tumor ablation
Potentially
curative
Radiofrequency thermal ablation

Alcohol injection
Chemoembolization
Targeted molecular therapy

Chemotherapy
Regional/systemic

Evidence of Benefit in Treatment

of HCC
Treatment
Benefit
Evidence
Increased survival
Case series
Adjuvant therapies
Uncertain
Randomized trial,
meta-analysis, nonblinded
Liver transplantation
Increased survival
Case series
Treatment response
Nonrandomized trials
Percutaneous treatment
Increased survival
Case series
RFA vs PEI
Better local control
Randomized trial,
Chemoembolization
Increased survival
Randomized trial,
Arterial chemotherapy
Treatment response
Case series
Internal radiation
Treatment response
Case series
Surgical treatments
Resection
Neoadjuvant therapies
Locoregional treatment

Evidence of Benefit in Treatment

of HCC (contd)
Treatment
Benefit
Evidence
Sorafenib
Increased survival
Randomized trial, metaanalysis, double blinded
Tamoxifen
No benefit
Randomized trial, metaanalysis, double blinded
Chemotherapy
No benefit
Randomized trial, metaanalysis, nonblinded
IFN
No benefit
Randomized trial, metaanalysis, nonblinded
Systemic therapies


Patients With HCC
HCC
PST 0, Child-Pugh A
Very early stage

Early stage
3 cm, PST 0
Increased
Resection
Advanced stage
Portal invasion,
N1, M1, PST 1-2
Terminal
stage
3 nodules 3 cm
Single
Normal
Intermediate stage
Multinodular, PST 0
No
Liver transplant
Portal invasion,
N1, M1
Associated
diseases
Yes
PEI/RF
Curative treatments
No
TACE
Yes
Sorafenib
RCTs (50%)
Median survival: 11-20 mos
Symptomatic
(unless LT)

Key Pathways in Hepatocarcinogenesis:

Possible Targets for Novel Therapies
Growth factor-stimulated receptor tyrosine kinase signaling
Wnt/beta-catenin pathway
p13Kinase/AKT/mTOR
JAK/STAT signaling
Angiogenic signaling pathways
p53 and cell cycle regulatory pathways
Ubiquitin-proteasome pathway
Epigenetic promoter methylation and histone acetylation pathways
Ras-Raf-MEK-MAPK pathway
Roberts LR, et al. Semin Liver Dis. 2005;25:212-225.

Sorafenib in Advanced HCC:

The SHARP Trial
Entry criteria
Advanced HCC
Not eligible for or failed surgical or locoregional therapies
Child-Pugh class A disease

At least 1 untreated target lesion
Exclusions
Previous chemotherapy
Previous molecularly targeted therapy
Llovet JM, et al. N Engl J Med. 2008;359:378-390.

Sorafenib in Advanced HCC:

The SHARP Trial
902 patients were screened
602 underwent randomization
299 were assigned to receive sorafenib

(intent-to-treat population)
303 were assigned to receive placebo

(intent-to-treat population)
1 had an adverse event

1 had a protocol violation
297 received sorafenib
(safety population)
1 had a protocol violation

302 received placebo
(safety population)
226 discontinued sorafenib

61 had radiologic and
systematic progression
28 withdrew consent
1 had ECOG score of 4
3 died
47 had other reason
71 included in the ongoing study
300 were excluded

244 had protocol exclusion
criteria
24 withdrew consent
11 died
6 were lost to follow-up
242 discontinued placebo

62 had radiologic and
systematic progression
25 withdrew consent
7 had ECOG score of 4
6 died
52 had other reason
60 included in the ongoing study
Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med.

2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.

SHARP Trial: Baseline Characteristics

Characteristic
Sorafenib
(n = 299)
Placebo
(n = 303)
Median age, yrs
64.9
66.3
Male, %
BCLC stage, %
87
87
B (intermediate)
18
17
C (advanced)
82
83
Vascular invasion, %
70
70
Llovet JM, et al. N Engl J Med. 2008;359:378-390.

The SHARP Trial: OS and Time to

Progression
OS
Median OS
Sorafenib: 10.7 mos
Placebo: 7.9 mos
1.00
0.75
0.50
0.25
0.00
Time to Symptomatic Progression
Probability of No
Symptomatic
Progression
Probability of
Survival
P < .001
Median TTSP
Sorafenib: 4.1 mos
Placebo: 4.9 mos
1.00
0.75
0.50
0.25
P - 0.77
0.00
0 1 2 3 4 5 6 7 8 9 10 11 12 13 1415 16 1718
0 1 2 3 4 5 6 7 8 9 10 11 12 13 1415 16 17
Months Since Randomization
Probability of
Radiologic
Progression
Time to Radiologic Progression

1.00
P < 0.001
0.75
Placebo
Sorafenib
Median TTRP
Sorafenib: 5.5 mos
Placebo: 2.8 mos
0.50
0.25
0.00
0
9 10 11 12
3


The SHARP Trial: OS and Baseline

Prognostic Factors
Subgroup
Hazard Ratio (95% CI)
ECOG score
0
1-2
Extrahepatic spread
No
Yes
Macroscopic vascular invasion
No
Yes
Macroscopic vascular invasion,
extrahepatic spread, or both
No
Yes
0.0
0.5
Sorafenib
Better
0
0.68 (0.50-0.95)
0.71 (0.52-0.96)
0.55 (0.39-0.77)
0.85 (0.64-1.14)
0.74 (0.54-1.00)
0.68 (0.49-0.93)
0.52 (0.32-0.85)
0.77 (0.60-0.99)
1.0
1.5
Placebo
Better


The SHARP Trial: Drug-Related AEs

AEs, %
Sorafenib (N = 297)
Any
Grade
Overall incidence
Grade 3
Placebo (N = 302)
Grade 4
80
Any
Grade
P Value
Grade 3
Grade
4
Any
Grade
Grade 3
or 4
52
Constitutional
symptoms
Fatigue
22
16
<1
.07
1.00
Weight Loss
< .001
.03
Alopecia
14
< .001
NA
Dry skin
.04
NA
Hand-foot skin
reaction
21
<1
< .001
< .001
Pruritus
<1
.65
1.00
Rash or
desquamation
16
11
.12
.12
Other
< .001
.12
Dermatologic events


The SHARP Trial: Drug-Related AEs

(Contd)
AEs, %
Sorafenib (N = 297)
Placebo (N = 302)
P Value
Any
Grade
Grade 3
Grade 4
Any
Grade
Grade 3
Grade
4
Any
Grade
Grade 3
or 4
Anorexia
14
<1
< .001
1.0
Diarrhea
39
11
< .001
< .001
Nausea
11
<1
.16
.62
Vomiting
.14
.68
Voice changes
< .001
NA
Hypertension
.05
.28
<1
<1
.50
.50
Abdominal pain not

otherwise specified
.007
.17
Bleeding
<1
.07
1.00
Gastrointestinal events
Liver dysfunction


Hand-Foot Syndrome
Scheithauer W, et al. Oncology (Williston Park) 2004; 18:1161.

Grading of Hand-Foot Syndrome

Grade
Symptom
Minimal skin changes or dermatitis (eg, erythema) without pain
Skin changes (eg, peeling, blisters, bleeding, edema) or pain,

not interfering with function
Skin changes with pain, interfering with function
Common Terminology Criteria for Adverse Events, Version 3.0. Available

at: http://ctep.cancer.gov. Accessed October 13, 2008.

Strategies for Managing AEs

Hand-foot syndrome
Creams and lotions
Avoid tight footwear
May require dose reduction
Diarrhea
Antidiarrheal agents if severe
Fatigue
Consider modafinil or methylphenidate if severe
Hypertension
Start or adjust antihypertensives

Erlotinib in HCC: EGFR Inhibitor

Phase II study in patients with unresectable HCC (N = 40)
Oral erlotinib 150 mg/day, 28-day cycles
No CRs or PRs
PFS rate at 16 weeks: 43%

Drug-related adverse events: diarrhea, folliculitis, fatigue,
pruritus, dry skin, xerostomia, epistaxis
Thomas MB, et al. Cancer. 2007;110:1059-1067.

Possible Future Studies in HCC

New targeted molecular agents
Small molecules in combination
With each other
With local ablation

With conventional chemotherapy

Ongoing HCC Trials in the US

117 studies registered at ClinicalTrials.gov
Radiation: 21
Targeted molecular therapies: 18
Chemotherapy: 26
Local ablative therapy: 8
Other
ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov.

Accessed October 13, 2008.

Targeted Molecular Therapies:

Mechanisms of Action
VEGF antagonists
Cediranib
ABT-869
NF-B antagonists
Perifosine
Proteasome inhibitors
Bortezomib

Targeted Molecular Therapies:

Mechanisms of Action (contd)
EGFR tyrosine kinase inhibitors
Lapatinib
Sunitinib
Erlotinib
TRAIL receptor antibodies

Mapatumumab
BCR-ABL inhibitors
Dasatinib

Targeted Molecular Therapies

Mechanisms of Action (contd)
Multiple pathways
Sorafenib
RAF/MEK/ERK signaling
VEGFR-2
PDGF-
Brivanib
VEGFR-2
FGFR-1 kinase
Pazopanib
VEGFR-1, -2, -3
PDGF-, -
c-KIT

Approved Targeted Molecular Therapies

With Possible Efficacy in HCC
Dasatinib: CML
Bevacizumab: breast cancer, NSCLC, CRC
Erlotinib: NSCLC, pancreatic cancer
Sunitinib: RCC, GIST

Lapatinib: breast cancer
Bortezomib: myeloma, mantle cell lymphoma
Sorafenib: RCC, HCC
Temsirolimus: RCC

Endpoints in Clinical Trials of HCC

Primary and secondary
endpoints
Survival (phase III)
Time to recurrence
(phase II/III)
Time to progression
(phase II)
Time to local recurrence

(locoregional treatment)
Tertiary endpoints
Cancer-specific death
Time to symptomatic
progression
DFS
PFS
Response rate

Summary and Conclusion

The demonstration that sorafenib improves survival in
HCC is a major milestone
Other agents are available or being developed that target
known molecular pathways in HCC
AASLD has outlined endpoints for study of new agents
Transcatheter Intra-arterial
Therapies for Hepatocellular
Carcinoma
Jean-Francois Geschwind, MD
Professor, Radiology, Surgery, and
Oncology
Director, Vascular and Interventional
Radiology
Johns Hopkins University School of
Medicine
Baltimore, Maryland

Intra-arterial Locoregional Therapy

Established
TACE
Radioembolization: yttrium-90 radioactive microspheres
Undergoing clinical trials

Drug-eluting beads

Primary Treatment Modality Used in

Korea
Conservative
treatment
29.5%
TACE
48.2%
Surgery
11.2%
Radiotherapy
2.1%
Chemotherapy
7.5%
RFA
1.5%
Joong-Won Park, MD, National Cancer Center. Adapted with permission.
N = 1078

Chemoembolization: Randomized
Trials (Nearly Identical Techniques)
Lo et al[1]: N = 80 with newly diagnosed unresectable HCC, 80% HBV positive,
7-cm tumors (60% multifocal)
Technique
TACE
Supportive care
Year 1
57
32
Survival, %
Year 2
31
11
Year 3
26
3
Llovet et al[2]: N = 112 with unresectable HCC, 80% to 90% HCV positive,
5-cm tumors (~ 70% multifocal)
Technique
TACE
Supportive care
Survival, %
Year 1
82
63
1. Lo CM, et al. Hepatology. 2002;35:1164-1171.

2. Llovet JM, et al. Lancet. 2002;359:1734-1739.
Year 2
63
27

Chemoembolization: Predictors of
Survival
Lo et al[1]
Absence of presenting symptoms (ECOG PS < 2)
Absence of portal vein obstruction
Tumor size ( vs > 5 cm)
Okuda stage (I vs II)
Llovet et al[2]
Absence of constitutional syndrome (ECOG PS < 2)
Low serum bilirubin

Treatment response (modified WHO criteria, > 6 months)
1. Lo CM, et al. Hepatology. 2002;35:1164-1171.
2. Llovet JM, et al. Lancet. 2002;359:1734-1739.

Largest Prospective Study of TACE for

Unresectable HCC to Date
N = 8510 patients
Primary endpoint: OS
Multivariate analysis conducted of factors affecting survival
OS
Year 1: 82%; Year 3: 47%; Year 5: 26%; Year 7: 16%
OS better with lesser degree of liver damage
Factors affecting survival

Child-Pugh stage
TNM stage (OS better with stage I, increasingly worse progressing toward stage IV)
Alpha-fetoprotein level
Takayasu K, et al. Gastroenterology. 2006;131:461-469.

TACE vs Surgical Resection: A CaseControl Prospective Study

N = 182, ~ 70% HBV positive, 99% Okuda stage I, 76% with tumors < 3 cm
Technique
Survival, %
Year 1
Year 2
Year 3
Year 5
TACE
96
80
56
30
Surgical resection
90
80
70
52
Surgery superior to TACE for tumors smaller than 2 cm and/or CLIP stage 0
BUT for tumors > 3 cm and/or CLIP stage 1-2, 5-year survival identical for both
groups (27%)
Median OS (P = .1529)
Resection: 65.1 months
TACE: 50.4 months
Lee HS, et al. J Clin Oncol. 2002;20:4459-4465.

Chemoembolization: Efficacy Before

Transplantation
Major issue: dropout rate (~ 20%)
Lower in US since adoption of MELD criteria
Role of TACE
Control tumor and prevent progression
Should be considered if waiting time > 6 months
Complications from TACE: rare (no increased rate of

hepatic artery complications)
Richard HM 3rd, et al. Radiology. 2000;214:775-779.
Graziadei IW, et al. Liver Transpl. 2003;9:557-563.
Alba E, et al. Am J Roentgenol. 2008;190:1341-1348.

Can TACE Be Used as a Determinant

of Tumor Biology?
Patients with HCC;
age 65 years without
contraindication against LT
(n = 96)
Milan criteria fulfilled

(n = 34)
Milan criteria exceeded

(n = 62)
TACE
96 consecutive
patients treated
with TACE
6 weeks
Functional
decompensation (n = 5)
Listing
Restaging
TACE
Regress
Stable or progress (n = 23)
Listing (n = 34)
Progress (n = 6)
Functional
Decompensation (n = 1)
Stable
21
Progress 2
WL (n = 4)
6 weeks
TACE
Functional
decompensation (n = 1)
6 weeks
Extrahepatic
disease (n = 5)
23 LT
WL (n = 1)
Stable
18
Progress* 9
Otto G, et al. Liver Transpl. 2006;12:1260-1267.
62 exceeded Milan
criteria
34 meeting Milan criteria
listed immediately
50 patients
transplanted
27 exceeded Milan
criteria
27 LT

Response to TACE as a Biological

Selection Criterion for LT in HCC
Transplanted
1.0
80.9%
Survival
0.8
All
patients
51.9%
0.6
0.4
TACE
nonresponders
0.2
0%
Overall 5-year survival:

51.9%
Highly significant difference in
5-year survival between
downstaged (transplanted)
patients and patients not
responding to TACE
(P < .0001)
Survival calculated from the

beginning of TACE treatment
0
0
365
730
1095
1460 1825
Days

Response to TACE as a Biological

Selection Criterion for LT in HCC
94.5%
Freedom From Recurrence
1.0
0.8
P = .0017
TACE responders
TACE nonresponders
0.6
0.4
35.4%
0.2
0
0
365
730 1095
Days
1460
1825

Chemoembolization: Ineligibility
Criteria
Absolute contraindications
Child-Pugh class C disease
Poor performance status (ECOG PS > 2)
Relative contraindication
Extrahepatic disease (benefit unclear)
Former contraindication
PVT
Minimize embolization and be more selective

Safety & Efficacy of TACE in Patients

With Unresectable HCC & PVT
32 patients with HCC and PVT
Median OS: 10 months
Child-Pugh score: best prognostic factor (ie, most strongly
related to survival)
30-day mortality: 0%
No evidence of TACE-related hepatic infarction or acute
liver failure
Georgiades CS, et al. J Vasc Interv Radiol. 2005;16:1653-1659.

Intra-arterial Radioembolization With

Yttrium-90: Rationale and History
Radioembolization: Use of intra-arterially delivered yttrium90 microspheres emitting high-dose radiation for the
treatment of liver tumors
Yttrium-90 microspheres
Average diameter: 20-30 m
100% pure beta emitter (0.9367 MeV)
Physical half-life: 64.2 hours
Irradiates tissue with average path length of 2.5 mm
(maximum: 11 mm)
Murthy R, et al. Biomed Imaging Interv J. 2006;3:e43.

Clinical Response to Yttrium-90

Microspheres
Outcome
Dancey
et al[1]
(N = 20)
Response rate, %
Median survival
Carr et al[2]
(N = 65)
Geschwind
et al[3]
(N = 80)
39
Salem
et al[4]
(N = 43)
47
378 days
(> 104 Gy)
Okuda stage I
649 days
628 days
24.4 mos
Okuda stage II
302 days
384 days
12.5 mos
1. Dancey JE, et al. J Nucl Med. 2000;41:1673-1681.

2. Carr BI. Liver Transpl. 2004;10(2 suppl 1):S107-S110.
3. Geschwind JF, et al. Gastroenterology. 2004;127(5 suppl 1):S194-S205.
4. Salem R, et al. J Vasc Interv Radiol. 2005;16:1627-1639.

Yttrium-90 Radiotherapy for HCC

Patients With and Without PVT
Phase II study: N = 108 (37 with PVT, 71 without PVT)
Stratified by toxicity: Child-Pugh score (in cirrhotics), dose,
location of PVT
Median dose: 134 Gy
Partial response rate: 42% (WHO), 70% (EASL)
Adverse event rate highest in patients with main PVT and
cirrhosis
Median survival, main PVT: 260 days

Branch PVT: 370 days
No PVT: 460 days
Kulik LM, et al. Hepatology. 2008;47:5-7.

Lessons Learned
Patient selection
Good performance status (ECOG PS < 2)
Total bilirubin < 2.0 mg/dL (possibly < 1.4 mg/dL)
Tumor burden < 50%
90Y
or TACE: Which is best for

first-line treatment of HCC?

Response rate (assessed

by CT) at 6 months: 75%
1- and 2-year survival
rates: 92% and 89%
Median follow-up:
28 months
1000
800
600
400
200
0
DEB-TACE
Time Postprocedure
Doxorubicin at
Serum (ng/mL)
27 patients with ChildPugh A stage disease
Doxorubicin at
Serum (ng/mL)
TACE With Doxorubicin-Eluting Beads:

Efficacy and Pharmacokinetics
1000
800
600
400
200
0
Conventional TACE
Time Postprocedure
Varela M, et al. J Hepatol. 2007;46:474-481.

65-Year-Old Woman, Child-Pugh B Disease,

and Large HCC: First Treatment
Courtesy Jean-Francois Geschwind, MD.

Pretreatment and Posttreatment 1
Pretreatment
Posttreatment 1: Residual Viable Tumor


Second Treatment

MRI Posttreatment 2
Underwent successful resection

Tumor free 16 months after initial treatment

Conclusions
TACE accepted as treatment of choice for unresectable
(nonablatable?) HCC
Prolonged survival established through randomized trials
and prospective studies
Best vs good performance status, Child-Pugh class A-B

Role for yttrium-90 microspheres
Growing role for doxorubicin-loaded beads, pending
outcome of clinical trials

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About These Slides

We are grateful to Luigi Bolondi, MD; Adrian M. Di Bisceglie, MD, FACP;

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Introduction: Current Trends in the

Forging Partnerships in the Management of Hepatocellular Carcinoma:

There is no universally accepted staging system for HCC

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Staging Strategy and Treatment for

PST 0-2, Child-Pugh A-B

Very early stage

PST > 2, Child-Pugh C

Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Staging Strategy and Treatment for

PST 0-2, Child-Pugh A-B

Very early stage

PST > 2, Child-Pugh C

Surgical treatments: applicable overall to

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Approved Curative Treatments for

In addition, efcacy is clearly superior to that of alcohol

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Approved & Investigational Noncurative

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Treatment of Advanced HCC

1. Bruix J, et al. Hepatology. 2005;42:1208-1236.

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Improving efficacy of RF and TACE (drug-eluting beads)

Exploring alternative treatments for intermediate HCC (yttrium-90)

Molecularly targeted agents in combination regimens (advanced HCC)

Molecularly targeted agents in combination with current modalities

Improving tumor targeting of chemotherapeutic agents

New molecular targets and new molecularly targeted agents

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Sorafenib: Ongoing Studies in HCC

4 TACE + sorafenib (1 phase I,

Sorafenib dose escalation

Managing Liver Dysfunction in

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Loss of cell cycle

1. Tornillo L, et al. Lab Invest. 2002;82:547-553.

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Prothrombin time (sec)

Pugh RN, et al. Br J Surg. 1973;60:646-649.

Forging Partnerships in the Management of Hepatocellular Carcinoma:

MELD Score Predicts Severity of Liver

30-39: 60.0% (n = 295)

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Survival of Cirrhotic Patients

DAmico G, et al. J Hepatology. 2006;44:217-231.

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Survival of Cirrhotic Patients

Median 1- and 2-year survival by Child-Pugh class

Class C: 45% and 38%, respectively

DAmico G, et al. J Hepatology. 2006;44:217-231.

Forging Partnerships in the Management of Hepatocellular Carcinoma:

Decreased nitric oxide

Increased cardiac output

Forging Partnerships in the Management of Hepatocellular Carcinoma: