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1. Advanced Hepatocellular Carcinoma After ASCO 2007 Hematology/Oncology Grand Rounds
September 14, 2007
Mark A. Schroeder, M.D.
3. The Case of MV 50 yo AAM with history of HCV
Presented February 2007 c/o chronic worsening back pain and was found to have pneumonia. A CT of the chest was performed at that time and showed hepatic abnormalities. Patient reported an abnormality previously reported in his liver 2.5 years earlier.
U/S guided liver biopsy revealed hepatocellular carcinoma with cholangiolar features. Hepatocyte antigen and alpha-fetoprotein immunostains were negative. Serum AFP was 13,156.
MRI showed extensive involvement of the liver and at least 2 pulmonary nodules with portal vein involvement. Upper and lower endoscopy was negative.
Pathology reviewed at Mayo and thought consistent with HCC but without evidence of cirrhosis.
Repeat biopsy was performed on July 31st and interpreted as HCC
Enrolled in the avastin/tarceva clinical trial
Course complicated by culture negative fevers and pain Patients who develop HCC usually have no symptoms other than those related to their chronic liver disease
Some patients may have mild to moderate upper abdominal pain, weight loss, early satiety, or a palpable mass in the upper abdomen
Fever may develop in association with central tumor necrosis
AFP has a sensitivity of 40-60% and specificity of 80-90%Patients who develop HCC usually have no symptoms other than those related to their chronic liver disease
Some patients may have mild to moderate upper abdominal pain, weight loss, early satiety, or a palpable mass in the upper abdomen
Fever may develop in association with central tumor necrosis
AFP has a sensitivity of 40-60% and specificity of 80-90%
4. PMH HCV with out history of treatment or cirrhosis
Multiple back surgeries
h/o transfusion Married, 2 children, no IV drugs, Prior rare alcohol, moderate smoking PPD, marijuana in the past.
Uncle had bone cancer. Brother had colon cancer. Mother had cancer of unknown type
5. Exam VITAL SIGNS: AF, VSS
GEN: well appearing, muscular AAM
HEENT EXAMINATION: PERRLA, EOMI. Anicteric sclera.
NECK EXAMINATION: No lymphadenopathy, no thyromegaly
LUNGS: CTA
HEART: RRR, no M/R/G
ABDOMEN: RUQ abdominal pain, liver edge 8cm below costal margin and firm
EXTREMITIES: No C/C/E
NEUROLOGIC: Non-focal, no encephalopathy
LYMPH: no cervical, clavicular, axillary or inguinal LAD
6. Labs Lytes normal
BUN 9, creatinine 0.8,
Protein 8.1, albumin 3.9
Total bilirubin 2.9, AST 133, ALT 50, alkaline phosphatase 211
Hemoglobin 14.4, platelets 287, WBC 21.8
INR 1.47
AFP 13,000
Child-Pugh class = A Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. A systematic review and critical analysis. Gupta S; Bent S; Kohlwes J. Ann Intern Med 2003 Jul 1;139(1):46-50.
Sensitivity 41 to 65 percent
Specificity 80 to 94 percent
Positive likelihood ratio 3.1 to 6.8
Negative likelihood ratio 0.4 to 0.6 Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. A systematic review and critical analysis. Gupta S; Bent S; Kohlwes J. Ann Intern Med 2003 Jul 1;139(1):46-50.
Sensitivity 41 to 65 percent
Specificity 80 to 94 percent
Positive likelihood ratio 3.1 to 6.8
Negative likelihood ratio 0.4 to 0.6
7. Child-Pugh Score A=5-6 (2 yr survival 85%)
B=7-9 (2 yr survival 57%)
C=10-15 (2 yr survival 35%)
8. CT Imaging Imaging: CT abdomen: infiltrative right hepatic lobe mass, portal vein
thrombosis, no signs of perforation. No interval change since prior CT scan.Imaging: CT abdomen: infiltrative right hepatic lobe mass, portal vein
thrombosis, no signs of perforation. No interval change since prior CT scan.
11. Portal invasion notedPortal invasion noted
12. Pathology No cirrhosis was identified.
IHC:
CK-7, CK20, TTF-1, PSA, AFP, hepatocyte negative from OSHNo cirrhosis was identified.
IHC:
CK-7, CK20, TTF-1, PSA, AFP, hepatocyte negative from OSH
13. Epidemiology of HCC 6th most common cancer world wide
(626,000 or 5.7% of new cancer cases)
Third most common cause of cancer mortality
Deaths = 598,000
Survival rates 3% - 5% for the US and developing countries
Fastest growing cause of cancer-related death in men in the US
19,160 cases and 16,780 deaths
15. Incidence is highest in asian countries because of Hep B and AFB1
Asian countries also have screening programs leading to increased detection of HCCIncidence is highest in asian countries because of Hep B and AFB1
Asian countries also have screening programs leading to increased detection of HCC
16. Epidemiology In the US HCC rates are Asian>African Americans>Whites
Male>Female (2-4 fold)
Men are more likely to be infected with HBV and HCV, consume EtOH, smoke, have increased iron stores
Peak age >65 in the US
Incidence and death rates are increasing in the US
17. Major Risk Factors HBV
5-15 fold increased risk
70-90% of cases occur in setting of cirrhosis
Treatment does NOT decrease risk
Risk highest in carriers and lower in immune
HCV
1-3% of cirrhotic patients develop HCC
Treatment seems to decrease risk
Co-infection
Aflatoxins (Aspergillus fumigatus)
4 fold increased risk HCC
Alcohol
>50-70g/day
No link to direct carcinogenic effect
Synergistic with HCV and HBV
Nonalcoholic Steatohepatitis? HBV and HCV Increase the risk of liver cancer 20-fold and 75% of cases worldwide (85% of cases in developing countries
70-90% of cases of HCC occur in cirrhosis
HBV is the number one risk factor world wide with 300 million infected persons.
Among HBV infected persons: male sex, older age, Asian or African race, cirrhosis, family history, exposure to aflatoxins, etoh, tobacco or co-infection with HCV or Hep D virus increases risk of HCC
Risk increases with increased HBV levels (HB eAg and HBV DNA levels)
In high risk areas chronic HBV infection is the main risk factor and AFB1 containing food
In Japan the dominate virus is HCV
HCV promotes cirrhosis once cirrhosis develops the annual incidence of HCC is 1-4%.
Cirrhosis from HCV at 25-30 yrs occurs in 15-35% of cases.
Unlike HBV infection host and environment factors are more important than viral load (ie. Older age, male, heavy etoh (>50g/day), DM, obesity and co-infection with HIV or HBV.
EtOH increases cirrhosis no direct carcinogenic effect known
AFB1 is a carcinogen that is metabolized to an intermediate that can bind and damage DNA
Characteristic p53 mutation in ser249 found in 30-60% of cases
Risk is 4 fold alone with AFB1 metabolites detected in the urine, this is increased to 60 fold with active HBV.
Vinyl chloride associated with angiosarcoma of the liver only.HBV and HCV Increase the risk of liver cancer 20-fold and 75% of cases worldwide (85% of cases in developing countries
70-90% of cases of HCC occur in cirrhosis
HBV is the number one risk factor world wide with 300 million infected persons.
Among HBV infected persons: male sex, older age, Asian or African race, cirrhosis, family history, exposure to aflatoxins, etoh, tobacco or co-infection with HCV or Hep D virus increases risk of HCC
Risk increases with increased HBV levels (HB eAg and HBV DNA levels)
In high risk areas chronic HBV infection is the main risk factor and AFB1 containing food
In Japan the dominate virus is HCV
HCV promotes cirrhosis once cirrhosis develops the annual incidence of HCC is 1-4%.
Cirrhosis from HCV at 25-30 yrs occurs in 15-35% of cases.
Unlike HBV infection host and environment factors are more important than viral load (ie. Older age, male, heavy etoh (>50g/day), DM, obesity and co-infection with HIV or HBV.
EtOH increases cirrhosis no direct carcinogenic effect known
AFB1 is a carcinogen that is metabolized to an intermediate that can bind and damage DNA
Characteristic p53 mutation in ser249 found in 30-60% of cases
Risk is 4 fold alone with AFB1 metabolites detected in the urine, this is increased to 60 fold with active HBV.
Vinyl chloride associated with angiosarcoma of the liver only.
18. Other Risk Factors Obesity
Diabetes Mellitus
Hemochromatosis
Alpha-1 antitrypsin deficiency
Autoimmune hepatitis
Porphyrias
15-50% of HCC in the US have no established risk factors Obesity increases risk in large population cohorts by 2-3 fold
Case control studies suggest a association of DM II and HCC
Tobacco use has mixed association with HCC and is not definetively a risk factor
OCPs have no definitive association with HCC
Hemochromatosis has a 1.7 fold increased risk in homozygous carriers of HFE gene mutation (C282Y)
Coffee consumption may decrease risk for HCCObesity increases risk in large population cohorts by 2-3 fold
Case control studies suggest a association of DM II and HCC
Tobacco use has mixed association with HCC and is not definetively a risk factor
OCPs have no definitive association with HCC
Hemochromatosis has a 1.7 fold increased risk in homozygous carriers of HFE gene mutation (C282Y)
Coffee consumption may decrease risk for HCC
19. Pathogenesis Occurs in setting of inflammatory condition (chronic hepatitis) or cirrhosis
HBV, HCV, and AFB1 have molecular marks on hepatocytes
Multiple genomic changes
Copy number
Translocations
add 1q21-23, add 8q22-24 associated with development of HCC in HBV
add 3q23-24 poor prognosis in HBV associate HCC
20. Pathogenesis
22. Clinical Staging Numerous staging systems exist and NO CONSCENSUS
E.g. TNM, Okuda, CLIP, and BCLC
Incorporate 4 determinants of survival
Severity of underlying liver disease
Size of tumor
Extension of the tumor into adjacent structures
Presence of metastases
Primary staging should be clinical staging, and the CLIP is preferred
Secondary staging with the AJCC - TNM staging system for patients undergoing surgery
Staging work up includes Bone Scan and CT chest
23. CLIP Score The Cancer of the Liver Italian Program (CLIP) score has been used to predict survival in patients with hepatocellular carcinoma. The total score is derived by adding each of the subscores. In one study, median survival was 36, 22, 9, 7, and 3 months for patients in CLIP categories 0, 1, 2, 3, 4, and 6, respectively. The Cancer of the Liver Italian Program (CLIP) score has been used to predict survival in patients with hepatocellular carcinoma. The total score is derived by adding each of the subscores. In one study, median survival was 36, 22, 9, 7, and 3 months for patients in CLIP categories 0, 1, 2, 3, 4, and 6, respectively.
25. TNM - AJCC T definitions
T1 solitary nodule without vascular invasion
T2 solitary tumor with vascular invasion or multiple nodules all <5cm
T3 multinodular >5cm, or tumor with major vasculature invasion
T4 Tumor with invasion of adjacent organs T1 and T2 occurs in less than 20% of patients
Relies on pathologic findings and liver function is not taken into account
T1 and T2 occurs in less than 20% of patients
Relies on pathologic findings and liver function is not taken into account
26. Okuda staging system for HCC Can not destinguish between early and advanced stages and mostly serves to identify endstage individuals.Can not destinguish between early and advanced stages and mostly serves to identify endstage individuals.
27. Prognostic Markers Large tumor size, vascular invasion, poor functional status, and nodal metastases
DNA microarrays
Signatures can predict OS, recurrence and change with advanced HCC
Since 2000 over 30 articles have been published
28. Treatment Primary prevention
Taiwan: HBV immunization of newborns introduced in 1984 resulting in decrease in incidence of HCC
0.7 to 0.36 per 100,000 children
Infant vaccination estimated to prevent 84% of HBV related deaths
94% of deaths occur from cirrhosis and HCC HBV vaccine for children aged 6 to 9 years in birth cohorts receiving vaccinationHBV vaccine for children aged 6 to 9 years in birth cohorts receiving vaccination
29. Currative Treatments for Early Stage HCC Liver transplantation / Resection (<5% of cases)
5 yr survival 41-93%
Radiofrequency ablation (RFA) (20-30% of cases)
5 yr survival 33-40%
Solitary tumors, max 3-5cm
Percutaneous ethanol or acetic acid ablation
5 yr survival 29-71%
Solitary tumors, max 3-5cm Milano criteria for resection: solitary tumor <5cm or up to 3 tumors <3cm
Transplantation favored in cirrhotic patients with limited HCC
30% of patients will be eligible for ablation with 5 yr survival rates ~50%
Eligability for ablation: solitary tumors, max 3-5 cm
Milano criteria for resection: solitary tumor <5cm or up to 3 tumors <3cm
Transplantation favored in cirrhotic patients with limited HCC
30% of patients will be eligible for ablation with 5 yr survival rates ~50%
Eligability for ablation: solitary tumors, max 3-5 cm
30. Palliative Treatment for Advanced Stage HCC Transarterial chemoembolization (TACE)
2 yr survival 24-63%
No vascular invasion, preserved liver function, no extrahepatic spread
Radiation therapy
Systemic chemotherapy
>100 trials over the last 30 years
Contraindications for TACE:
Absolute contraindications to this technique include the absence of hepatopetal blood flow (portal vein thrombosis), encephalopathy, and biliary obstruction. Relative contraindications include a variety of other factors including, but not limited to:
Serum bilirubin >2 mg/dL
Lactate dehydrogenase >425 U/L
Aspartate aminotransferase >100 U/L
Tumor burden involving >50 percent of the liver
Cardiac or renal insufficiency
Ascites, recent variceal bleed, or significant thrombocytopenia
Contraindications for TACE:
Absolute contraindications to this technique include the absence of hepatopetal blood flow (portal vein thrombosis), encephalopathy, and biliary obstruction. Relative contraindications include a variety of other factors including, but not limited to:
Serum bilirubin >2 mg/dL
Lactate dehydrogenase >425 U/L
Aspartate aminotransferase >100 U/L
Tumor burden involving >50 percent of the liver
Cardiac or renal insufficiency
Ascites, recent variceal bleed, or significant thrombocytopenia
31. Treatment Algorithm 30% Early stage
20% intermediate
40% Advanced stage
10% End stage30% Early stage
20% intermediate
40% Advanced stage
10% End stage
32. Outcomes for UNTREATED HCC 5 year survival <5%5 year survival <5%
33. Outcomes of Palliative Treatments
34. Intra-arterial Chemotherapy
36. Meta-analysis of 2 yr survival with chemoembolisation or embolisation
37. Tamoxifen and HCC
38. Systemic Chemotherapy for Advanced HCC HCC has been considered to be a relatively chemotherapy refractory tumor
Survival is often determined by degree of hepatic dysfunction
Systemic chemotherapy not well tolerated by patients with significant underlying hepatic dysfunction High rate of expression of drug resistance genes, including p-glycoprotein, glutathione-S-transferase, heat shock proteins, and mutations in p53
High rate of expression of drug resistance genes, including p-glycoprotein, glutathione-S-transferase, heat shock proteins, and mutations in p53
39. Advanced Hepatocellular CarcinomaPhase II trials www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt
Doxorubicin has a 11-32% response rate
Irinotecan and Thalidomide have also been examined in phase II studies with no objective response.www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt
Doxorubicin has a 11-32% response rate
Irinotecan and Thalidomide have also been examined in phase II studies with no objective response.
40. Phase III randomised trials of systemic therapy for advanced HCC www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt
T138067 sodiumA synthetic pentafluorophenylsulfonamide with potential antineoplastic activity. T138067 covalently binds to and selectively modifies the beta 1, beta 2, beta 3, and beta 4 isotypes of beta tubulin at a conserved cysteine residue, resulting in disruption of microtubule polymerization, collapse of the cytoskeleton, an increase in chromosomal ploidy, cell cycle arrest, and tumor cell apoptosis www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt
T138067 sodiumA synthetic pentafluorophenylsulfonamide with potential antineoplastic activity. T138067 covalently binds to and selectively modifies the beta 1, beta 2, beta 3, and beta 4 isotypes of beta tubulin at a conserved cysteine residue, resulting in disruption of microtubule polymerization, collapse of the cytoskeleton, an increase in chromosomal ploidy, cell cycle arrest, and tumor cell apoptosis
41. Abstract #LBA1: Sorafenib improves survival in advanced Hepatocellular Carcinoma (HCC): Results of a Phase III randomized placebo-controlled trial (SHARP trial)
42. Rational for Sorafenib VEGF and Raf kinase is overexpressed and activated in HCC
RAF/MEK/ERK signalling pathway implicated in hepato-carcinogenesis
Sorafenib is a multikinase inhibitor of Raf, VEGF, and other kinases.
Preclinical studies showed activity in HCC cell lines
Sorafenib was active in phase II trials in advanced HCC Hwang et al. Hepatol Res
Calvisi et al. Gastroenterology 2006
Villanueva et al. Sem Liv Dis 2007
Liu et al. Cancer Res 2006
Abou-Alfa et al. JCO 2006Hwang et al. Hepatol Res
Calvisi et al. Gastroenterology 2006
Villanueva et al. Sem Liv Dis 2007
Liu et al. Cancer Res 2006
Abou-Alfa et al. JCO 2006
44. SHARP study design International, multi-center Phase III
Inclusion criteria
Histology-proven HCC
Advanced HCC
At least 1 measurable untreated lesion
ECOG 0-2
Child-Pugh A
No prior treatments
Accrual 3/05-4/06
Intention-to-Treat analysis
45. Advanced Hepatocellular CarcinomaSorafenib vs. Placebo www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt
Sorafenib 400 mg BID continuous dosing until:
Both radiologic progression and FHSI8-TSP were achieved
Any adverse event requiring discontinuation
Stats:
Intention-to-treat analysis
Sample size: N=560 patients (424 OS events)
overall alpha for trial maintained at 0.025 (one-sided)
Overal survival assessment
alpha = 0.02
two interim analyses planned using OBrien-Fleming alpha spending function
90% power to detect a 40% improvement: 7 months 9.7 months
TTSP assessment (FHSI8-TSP)
alpha = 0.005 (one sided)
single analysis performed at time of final survival analysiswww.esmo.org/eclu/assets/ESC54/LCT10001261.ppt
Sorafenib 400 mg BID continuous dosing until:
Both radiologic progression and FHSI8-TSP were achieved
Any adverse event requiring discontinuation
Stats:
Intention-to-treat analysis
Sample size: N=560 patients (424 OS events)
overall alpha for trial maintained at 0.025 (one-sided)
Overal survival assessment
alpha = 0.02
two interim analyses planned using OBrien-Fleming alpha spending function
90% power to detect a 40% improvement: 7 months 9.7 months
TTSP assessment (FHSI8-TSP)
alpha = 0.005 (one sided)
single analysis performed at time of final survival analysis
46. Balanced Patient Characteristics
47. Phase III SHARP TrialOverall survival (Intention-to-treat) www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt
48. Phase III SHARP TrialTime to progression (Independent central review) www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt
49. Response Assessment www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt
50. Safety Events
51. Conclusions Systemic therapy is appropriate for patients with advanced unresectable HCC who are unsuitable for locoregional therapy
Sorafenib prolongs survival in advanced HCC
Median OS 10.7 months vs 7.9 months (HR 0.69)
Sorafenib prolonged time to progression
5.5 months vs 2.8 months (HR 0.58)
52. Molecularly Targeted Therapies in HCC
53. Future Directions Should Sorafenib be the standard of care?
Molecularly targeted therapy combinations?
Phase III trial sorafenib + doxorubicin versus doxorubicin, results expected in late 2007
Correlative science studies to examine the genetic polymorphisms in HCC and response to targeted therapies
54. VEGF Genotypes and Survival in HCC
55. ClinicalTrials.gov FOLFOX4 vs Doxorubicin Phase III
Doxorubicin+Bortezomib Phase II
Oxaliplatin/Capecitabine/Cetuximab Phase II
Dasatinib Phase II
Sirolimu+Bevacizumab Phase I
Sunitinib Phase II
Gefitinib Phase II
Bevacizumab Phase II
Bevacizumab+Erlotinib Phase II
Capecitabine Phase II
Thalidomide Phase III
Etoposide/Oxaliplatin/Capecitabine Phase II