Advanced Hepatocellular Carcinoma After ASCO 2007

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 O�Brien-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 O�Brien-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