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8/10/2019 CCO HepatocellularCarcinoma SlidesetModule
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Forging Partnerships in theManagement of HepatocellularCarcinoma: Multidisciplinary Strategies
to Provide Continuity of Care
Jointly sponsored by Postgraduate Institute for Medicine
and Clinical Care Options, LLC
This program is supported by educational grants from
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Forging Partnerships in the Management of Hepatocellular Carcinoma:
Multidisciplinary Strategies to Provide Continuity of Care
clinicaloptions.com/oncology
Disclaimer
The materials published on the Clinical Care Options Web site reflect the views of the authors, not those of
Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The
materials may discuss uses and dosages for therapeutic products that have not been approved by the
United States Food and Drug Administration. A qualified healthcare professional should be consulted
before using any therapeutic product discussed. Readers should verify all information and data before
treating patients or using any therapies described in these materials.
About These Slides Users are encouraged to include these slides in their own presentations, but
we ask that content and attribution not be changed. Users are asked to honorthis intent.
These slides may not be published or posted online or used for any othercommercial purpose without written permission from Clinical Care Options.
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 inthe preparation of this slideset.
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Forging Partnerships in the Management of Hepatocellular Carcinoma:
Multidisciplinary Strategies to Provide Continuity of Care
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Overview Introduction: Current Trends in the Treatment of Patients
With Advanced HCC
Managing Liver Dysfunction in Patients WithHepatocellular Carcinoma
Systemic Therapy and Supportive Care in Patients WithAdvanced Hepatocellular Carcinoma
Medical Management of Patients Undergoing RegionalTherapy for Hepatocellular Carcinoma
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Introduction: Current Trends in theTreatment of Patients With
Advanced HCC
Luigi Bolondi, MDProfessor of Medicine
ChairmanDepartment of Digestive Diseases
and Internal Medicine
University of Bologna
Policlinico S. Orsola Malpighi
Bologna, Italy
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Staging Strategy and Treatment for
Patients With HCC
Liver transplant PEI/RF
Curative treatments
TACE
HCC
Single
Increased Associated
diseases
Normal No Yes No Yes
Terminalstage
PST 0-2, Child-Pugh A-B
Multinodular, PST 0
Portal invasion,N1, M1
Sorafenib
Portal pressure/bilirubin
3 nodules 3 cm
Intermediate stage
PST > 2, Child-Pugh C
Very early stageSingle < 2 cm
Early stageSingle or 3 nodules
3 cm, PST 0
Advanced stagePortal invasion,
N1, M1, PST 1-2
PST 0, Child-Pugh A
Resection
Symptomatic(unless LT)
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.Bruix J, et al. Hepatology. 2005;42:1208-1236.
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Surgical treatments: applicable overall to
10% to 15% of HCC at first diagnosis and2% to 5% of recurrent HCC
Staging Strategy and Treatment for
Patients With HCC
Liver transplant PEI/RF TACE
HCC
Single
Increased Associated
diseases
Normal No Yes No Yes
Terminalstage
PST 0-2, Child-Pugh A-B
Multinodular, PST 0
Portal invasion,N1, M1
Sorafenib
Portal pressure/bilirubin
3 nodules 3 cm
Intermediate stage
PST > 2, Child-Pugh C
Very early stageSingle < 2 cm
Early stageSingle or 3 nodules
3 cm, PST 0
Advanced stagePortal invasion,
N1, M1, PST 1-2
PST 0, Child-Pugh A
Resection
Symptomatic(unless LT)Nonsurgical treatments: applicable
overall to 65% to 75% of HCC at
first diagnosis and 50% to 70% of
recurrent HCC
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Approved Curative Treatments for
Unresectable HCC: Percutaneous Ablation Local ablation: safe and effective therapy for patients who
cannot undergo resection or as a bridgeto transplantation(level II)
Alcohol injection and radiofrequency areequally effectivefor tumors< 2 cm
However, necrotic effect of radiofrequency is more
predictable inall tumor sizes
In addition, efficacy is clearlysuperior to that of alcoholinjection in larger tumors(level I)
Bruix J, et al. Hepatology. 2005;42:1208-1236.
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Approved & Investigational Noncurative
Agents for Unresectable HCC AASLD 2005 recommendations
Chemoembolization (TACE)(with doxorubicin, cisplatin, ormitomycin) is recommendedas first-line, noncurativetherapy for nonsurgical patients with large/multifocal HCCwho 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); otheroptions such as drug-eluting beads, radiolabelled yttriumglass beads, radiolabelled lipiodol, or immunotherapy cannotbe recommendedas standard therapy for advanced HCCoutside clinical trials
Bruix J, et al. Hepatology. 2005;42:1208-1236.
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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 thestandard 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.
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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
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Sorafenib: Ongoing Studies in HCC
Europe
10 studies approved
4 TACE + sorafenib (1 phase I,1 phase II, 2 phase III)
Sorafenib + tegafur
Sorafenib + erlotinib
Sorafenib + temsirolimus
Sorafenib dose escalation
Sorafenib + gemcitabine/oxaliplatin
Biomarkers
Asia-Pacific
4 studies approved
Sorafenib + tegafur
Sorafenib + capecitabine/oxaliplatin
Sorafenib + bevacizumab
Sorafenib + gemcitabine
United States
4 studies (nonactivated)
2 TACE + sorafenib
Sorafenib + erlotinib
Sorafenib + lapatinib
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Managing Liver Dysfunction inPatients With Hepatocellular
Carcinoma
Jorge A. Marrero, MD, MScAssociate Professor of Medicine
Director, Multidisciplinary LiverTumor Program
University of Michigan Health System
Ann Arbor, Michigan
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Forging Partnerships in the Management of Hepatocellular Carcinoma:
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Malignant TransformationMultistep
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
Liver cirrhosis
Hepatitis C
Hepatitis B
Ethanol
NASH
Epigenetic alterations
Genetic alterations
HCC[2]
Dysplastic nodules[1]
1. Tornillo L, et al. Lab Invest. 2002;82:547-553.2. Verslype C, et al. AASLD 2007. Abstract 24.
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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
Prothrombin time (sec) 1.0-3.0 4.0-6.0 > 6.0
Ascites None Slight Moderate
Encephalopathy (grade) None I-II III-IV
Grade Total Points Surgical Risk
A 5-6 Good
B 7-9 Moderate
C 10-15 Poor
Pugh RN, et al. Br J Surg.1973;60:646-649.
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MELD Score Predicts Severity of Liver
Disease and Cirrhosis-Related MortalityMELD 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.
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Survival of Cirrhotic Patients
Markedly longer survival in patients with compensatedcirrhosis 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.
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Survival of Cirrhotic Patients
Child-Pugh classification also important
Child-Pugh class A disease had better 1- and 2-yearsurvival
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.
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Portal Hypertension
Portal hypertension
Cirrhosis
Increased intrahepaticvascular resistance
Decreased nitric oxide
Portal hypertension
Hyperdynamic circulation
Increased splanchnic bloodflow
Increased total blood volume
Increased cardiac output
Systemic vasodilation(decreased systemic vascular
resistance)
Increased renin-angiotensin,vasopressin, sympatheticsystems
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Diagnosis
The gold standard is biopsy because it is the only way toascertain 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)
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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
f C
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Complications of Cirrhosis
Cirrhosis
Variceal bleeding
Ascites/hepatorenalsyndrome
Hepatic encephalopathy
HCC
F i P t hi i th M t f H t ll l C i
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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.
F i P t hi i th M t f H t ll l C i
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Variceal Hemorrhage
Courtesy of Jorge A. Marrero, MD.
F i P t hi i th M t f H t ll l C i
http://www.gastrointestinalatlas.com/Varixstds6.mpghttp://www.gastrointestinalatlas.com/Varixstds10.mpghttp://www.gastrointestinalatlas.com/Varixstds.mpg8/10/2019 CCO HepatocellularCarcinoma SlidesetModule
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Treatment of Variceal Bleeding
Resuscitative measures
Hematocrit replaced to 25% to 30%
Prophylactic antibiotics because of development ofinfections
First Line Second Line Third Line
Endoscopy + TIPS/shunt surgery Balloonsomatostatin tamponade
Garcia-Tsao G. Gastroenterology. 2001;120:726-748.
Forging Partnerships in the Management of Hepatocell lar Carcinoma
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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 preventspontaneous bacterial peritonitis and hepatorenalsyndrome
Gines P, et al. Semin Liver Dis. 2008;28:43-58.
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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
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Management of Ascites
2 g sodium diet
Promote natriuresis with a combination of K-sparing andloop diuretics
Large volume paracentesis (> 5 L) is safe
Albumin infusion concomitantly prevents circulatorydysfunction
TIPS
Importantly, patients who develop hepatorenal syndromehave a poor prognosis
Garcia-Tsao G. Gastroenterology. 2001;120:726-748.
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Hepatic Encephalopathy
Type A is related to acute liver failure
Type B occurs in the setting of normal liver histology andthe presence of a hepatic vascular bypass
Type C, due to cirrhosis, involves the majority of cases
Incidence in cirrhotics: ~ 10%
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Management of Hepatic
Encephalopathy First line
Lactulose, a nonabsorbable disaccharide, should be initiatedand titrated to approximately 4 bowel movements per day
Second line
Enteric flora modification with antibiotics, such asmetronidazole or neomycin
Third line
L-ornithine-L-aspartate administration
Marrero J, et al. Am J Respir Crit Care Med. 2003;168:1421-1426.
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Conclusions
The incidence of chronic liver disease is rising
The improved survival of patients with cirrhosis will likelyincrease the number of patients with HCC
Because most patients with HCC have underlying cirrhosisof the liver, attention in managing these complications isimportant
HCC is best managed in a multidisciplinary setting
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Systemic Therapy and SupportiveCare in Patients With Advanced
Hepatocellular CarcinomaAdrian M. Di Bisceglie, MD, FACPProfessor 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
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Management of HCC
Liver transplantation
Resection
Tumor ablation Radiofrequency thermal ablation
Alcohol injection
Chemoembolization
Targeted molecular therapy
Chemotherapy
Regional/systemic
Potentially
curative
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Evidence of Benefit in Treatment
of HCCTreatment Benefit Evidence
Surgical treatments
Resection Increased survival Case series
Adjuvant therapies Uncertain Randomized trial,
meta-analysis, nonblinded
Liver transplantation Increased survival Case series
Neoadjuvant therapies Treatment response Nonrandomized trials
Locoregional treatment
Percutaneous treatment Increased survival Case series
RFA vs PEI Better local control Randomized trial,meta-analysis, nonblinded
Chemoembolization Increased survivalRandomized trial,
meta-analysis, nonblinded
Arterial chemotherapy Treatment response Case series
Internal radiation Treatment response Case series
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
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Evidence of Benefit in Treatment
of HCC (contd)Treatment Benefit Evidence
Systemic therapies
Sorafenib Increased survivalRandomized trial, meta-
analysis, double blinded
Tamoxifen No benefitRandomized trial, meta-
analysis, double blinded
Chemotherapy No benefitRandomized trial, meta-
analysis, nonblinded
IFN No benefit Randomized trial, meta-analysis, nonblinded
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
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Staging Strategy and Treatment for
Patients With HCC
Liver transplant PEI/RF
Curative treatments
TACE
HCC
Single
Increased Associated
diseases
Normal No Yes No Yes
Terminalstage
PST 0-2, Child-Pugh A-B
Multinodular, PST 0
Portal invasion,N1, M1
Sorafenib
Portal pressure/bilirubin
3 nodules 3 cm
Intermediate stage
PST > 2, Child-Pugh C
Very early stageSingle < 2 cm
Early stageSingle or 3 nodules
3 cm, PST 0
Advanced stagePortal invasion,
N1, M1, PST 1-2
PST 0, Child-Pugh A
Resection
Symptomatic(unless LT)
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
Bruix J, et al. Hepatology. 2005;42:1208-1236.
RCTs (50%)
Median survival: 11-20 mos
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o g g a e s ps e a age e o epa oce u a Ca c o a
Multidisciplinary Strategies to Provide Continuity of Care
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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.
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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.
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226 discontinued sorafenib
86 had an adverse event61 had radiologic and
systematic progression28 withdrew consent
1 had ECOG score of 4
3 died
47 had other reason
297 received sorafenib
(safety population)
71 included in the ongoing study
1 had an adverse event1 had a protocol violation
299 were assigned to receive sorafenib(intent-to-treat population)
602 underwent randomization
902 patients were screened
300 were excluded
244 had protocol exclusioncriteria
24 withdrew consent15 had an adverse event
11 died
6 were lost to follow-up
303 were assigned to receive placebo(intent-to-treat population)
1 had a protocol violation
302 received placebo
(safety population)
242 discontinued placebo
90 had an adverse event62 had radiologic and
systematic progression25 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.
Sorafenib in Advanced HCC:
The SHARP Trial
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SHARP Trial: Baseline Characteristics
Characteristic Sorafenib(n = 299)
Placebo
(n = 303)
Median age, yrs 64.9 66.3
Male, % 87 87BCLC stage, %
B (intermediate) 18 17
C (advanced) 82 83
Vascular invasion, % 70 70
Llovet JM, et al. N Engl J Med. 2008;359:378-390.
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Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med.
2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.
Median OS
Sorafenib: 10.7 mos
Placebo: 7.9 mos
Median TTSP
Sorafenib: 4.1 mos
Placebo: 4.9 mos
Median TTRP
Sorafenib: 5.5 mos
Placebo: 2.8 mos
The SHARP Trial: OS and Time to
Progression
Months Since Randomization
Pr
obabilityof
Survival
0.000.25
0.50
0.75
1.00
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
P < .001
A OS
Months Since Randomization
Prob
abilityofNo
Sy
mptomatic
Progression
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
P - 0.77
B Time to Symptomatic Progression
180.00
0.25
0.50
0.75
1.00
Months Since Randomization
Probabilityof
Radiologic
Progression
0 1 2 3 4 5 6 7 8 9 10 11
Placebo
SorafenibP < 0.001
C Time to Radiologic Progression
0.00
0.25
0.50
0.75
1.00
12
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Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med.
2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.
The SHARP Trial: OS and Baseline
Prognostic Factors
0.0 0.5 1.0 1.5
Sorafenib
Better
Placebo
Better
Subgroup
ECOG score
0
1-2
Extrahepatic spread
No
Yes
Macroscopic vascular invasion
No
Yes
Macroscopic vascular invasion,
extrahepatic spread, or both
NoYes
Hazard Ratio (95% CI)
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)
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Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med.
2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.
AEs, % Sorafenib (N = 297) Placebo (N = 302) PValue
AnyGrade
Grade 3 Grade 4 AnyGrade
Grade 3 Grade4
AnyGrade
Grade 3or 4
Overall incidence 80 52
Constitutional
symptoms
Fatigue 22 3 1 16 3 < 1 .07 1.00
Weight Loss 9 2 0 1 0 0 < .001 .03
Dermatologic events
Alopecia 14 0 0 2 0 0 < .001 NA
Dry skin 8 0 0 4 0 0 .04 NA
Hand-foot skinreaction 21 8 0 3 < 1 0 < .001 < .001
Pruritus 8 0 0 7 < 1 0 .65 1.00
Rash ordesquamation
16 1 0 11 0 0 .12 .12
Other 5 1 0 1 0 0 < .001 .12
The SHARP Trial: Drug-Related AEs
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The SHARP Trial: Drug-Related AEs
(Contd)AEs, % Sorafenib (N = 297) Placebo (N = 302) PValue
AnyGrade
Grade 3 Grade 4 AnyGrade
Grade 3 Grade4
AnyGrade
Grade 3or 4
Gastrointestinal events
Anorexia 14 < 1 0 3 1 0 < .001 1.0
Diarrhea 39 8 0 11 2 0 < .001 < .001
Nausea 11 < 1 0 8 1 0 .16 .62
Vomiting 5 1 0 3 1 0 .14 .68
Voice changes 6 0 0 1 0 0 < .001 NA
Hypertension 5 2 0 2 1 0 .05 .28
Liver dysfunction < 1 < 1 0 0 0 0 .50 .50
Abdominal pain nototherwise specified
8 2 0 3 1 0 .007 .17
Bleeding 7 1 0 4 1 < 1 .07 1.00
Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med.
2008;359:378-390. 2008, Massachusetts Medical Society. All rights reserved.
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clinicaloptions.com/oncologyScheithauer W, et al. Oncology (Williston Park) 2004; 18:1161.
Hand-Foot Syndrome
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Grading of Hand-Foot Syndrome
Grade Symptom
1 Minimal skin changes or dermatitis (eg, erythema) without pain
2Skin changes (eg, peeling, blisters, bleeding, edema) or pain,
not interfering with function3 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.
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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
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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.
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Possible Future Studies in HCC
New targeted molecular agents
Small molecules in combination
With each other
With local ablation
With conventional chemotherapy
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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.
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Targeted Molecular Therapies:
Mechanisms of Action VEGF antagonists
Cediranib
ABT-869
NF-B antagonists
Perifosine
Proteasome inhibitors Bortezomib
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Targeted Molecular Therapies:
Mechanisms of Action (contd) EGFR tyrosine kinase inhibitors
Lapatinib
Sunitinib
Erlotinib
TRAIL receptor antibodies
Mapatumumab BCR-ABL inhibitors
Dasatinib
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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
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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
Approved Targeted Molecular Therapies
With Possible Efficacy in HCC
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Endpoints in Clinical Trials of HCC
Primary and secondaryendpoints
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 symptomaticprogression
DFS
PFS
Response rate
Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.
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Summary and Conclusion
The demonstration that sorafenib improves survival inHCC 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
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Transcatheter Intra-arterialTherapies for Hepatocellular
Carcinoma
Jean-Francois Geschwind, MDProfessor, Radiology, Surgery, and
Oncology
Director, Vascular and Interventional
Radiology
Johns Hopkins University School of
Medicine
Baltimore, Maryland
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Intra-arterial Locoregional Therapy
Established
TACE
Radioembolization: yttrium-90 radioactive microspheres
Undergoing clinical trials
Drug-eluting beads
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Primary Treatment Modality Used in
Korea
TACE48.2%
RFA
1.5%
Surgery11.2%
Chemotherapy
7.5%
Radiotherapy
2.1%
Conservativetreatment
29.5%
N = 1078
Joong-Won Park, MD, National Cancer Center. Adapted with permission.
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Chemoembolization: Randomized
Trials (Nearly Identical Techniques)
TechniqueSurvival, %
Year 1 Year 2 Year 3
TACE 57 31 26
Supportive care 32 11 3
Technique Survival, %Year 1 Year 2
TACE 82 63
Supportive care 63 27
Llovet et al[2]: N = 112 with unresectable HCC, 80% to 90% HCV positive,
5-cm tumors (~ 70% multifocal)
Lo et al[1]: N = 80 with newly diagnosed unresectable HCC, 80% HBV positive,
7-cm tumors (60% multifocal)
1. Lo CM, et al. Hepatology. 2002;35:1164-1171.
2. Llovet JM, et al. Lancet. 2002;359:1734-1739.
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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.
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p y g y
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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.
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TACE vs Surgical Resection: A Case-
Control Prospective Study
TechniqueSurvival, %
Year 1 Year 2 Year 3 Year 5
TACE 96 80 56 30
Surgical resection 90 80 70 52
N = 182, ~ 70% HBV positive, 99% Okuda stage I, 76% with tumors < 3 cm
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.
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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 ofhepatic 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.
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Can TACE Be Used as a Determinant
of Tumor Biology?
96 consecutivepatients treatedwith TACE
62 exceeded Milancriteria
34 meeting Milan criterialisted immediately
50 patients
transplanted
27 exceeded Milancriteria
Otto G, et al. Liver Transpl. 2006;12:1260-1267.
Functional
Decompensation (n = 1)
Patients with HCC;
age 65 years without
contraindication against LT
(n = 96)
Milan criteria fulfilled
(n = 34)
Listing
TACE
Milan criteria exceeded
(n = 62)
6 weeks
6 weeks
6 weeks
TACE
Listing (n = 34)
WL (n = 4) WL (n = 1)
Progress (n = 6)
Functional
decompensation (n = 5)
Functional
decompensation (n = 1)
Extrahepatic
disease (n = 5)
Stable 18
Progress* 927 LT
Stable 21
Progress 223 LT
TACE
Regress Stable or progress (n = 23)
Restaging
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clinicaloptions.com/oncologyOtto G, et al. Liver Transpl. 2006;12:1260-1267.
Transplanted
All
patients
TACE
nonresponders
Overall 5-year survival:51.9%
Highly significant difference in
5-year survival betweendownstaged (transplanted)patients and patients notresponding to TACE(P< .0001)
Survival calculated from the
beginning of TACE treatment
Surv
iva
l
0
0.2
0.4
0.6
0.8
1.0
0 365 730 1095 1460 1825
Days
80.9%
51.9%
0%
Response to TACE as a Biological
Selection Criterion for LT in HCC
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TACE nonresponders
TACE responders
Otto G, et al. Liver Transpl. 2006;12:1260-1267.
Response to TACE as a Biological
Selection Criterion for LT in HCC
0
Free
dom
From
Rec
urrence
0
0.2
0.4
0.6
0.8
1.0
365 730 1095 1460 1825
Days
35.4%
94.5%
P= .0017
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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
Chemoembolization: Ineligibility
Criteria
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32 patients with HCC and PVT
Median OS: 10 months
Child-Pugh score: best prognostic factor (ie, most stronglyrelated to survival)
30-day mortality: 0%
No evidence of TACE-related hepatic infarction or acute
liver failure
Safety & Efficacy of TACE in Patients
With Unresectable HCC & PVT
Georgiades CS, et al. J Vasc Interv Radiol. 2005;16:1653-1659.
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Radioembolization: Use of intra-arterially delivered yttrium-90 microspheres emitting high-dose radiation for thetreatment 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)
Intra-arterial Radioembolization With
Yttrium-90: Rationale and History
Murthy R, et al. Biomed Imaging Interv J. 2006;3:e43.
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Clinical Response to Yttrium-90
MicrospheresOutcome Dancey
et al[1]
(N = 20)
Carr et al[2]
(N = 65)
Geschwind
et al[3]
(N = 80)
Salem
et al[4]
(N = 43)
Response rate, % 39 47
Median survival 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.
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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 andcirrhosis
Median survival, main PVT: 260 days
Branch PVT: 370 days
No PVT: 460 days
Yttrium-90 Radiotherapy for HCC
Patients With and Without PVT
Kulik LM, et al. Hepatology. 2008;47:5-7.
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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 forfirst-line treatment of HCC?
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27 patients with Child-Pugh A stage disease
Response rate (assessed
by CT) at 6 months: 75%
1- and 2-year survivalrates: 92% and 89%
Median follow-up:28 months
Varela M, et al. J Hepatol. 2007;46:474-481.
Doxorub
icina
t
Serum
(ng
/mL)
Do
xoru
bicina
t
Se
rum
(ng
/mL)
DEB-TACE
Conventional TACE
Time Postprocedure
Time Postprocedure
0
200
400
600
800
1000
0
200
400600
800
1000
TACE With Doxorubicin-Eluting Beads:
Efficacy and Pharmacokinetics
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clinicaloptions.com/oncologyCourtesy Jean-Francois Geschwind, MD.
65-Year-Old Woman, Child-Pugh B Disease,
and Large HCC: First Treatment
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Posttreatment 1: Residual Viable Tumor
Pretreatment
Pretreatment and Posttreatment 1
Courtesy Jean-Francois Geschwind, MD.
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Second Treatment
Courtesy Jean-Francois Geschwind, MD.
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Underwent successful resection Tumor free 16 months after initial treatment
MRI Posttreatment 2
Courtesy Jean-Francois Geschwind, MD.
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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, pendingoutcome of clinical trials
Conclusions
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