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  • 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%
  • 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
  • Imaging: CT abdomen: infiltrative right hepatic lobe mass, portal vein thrombosis, no signs of perforation. No interval change since prior CT scan.
  • Portal invasion noted
  • No cirrhosis was identified. IHC: CK-7, CK20, TTF-1, PSA, AFP, hepatocyte negative from OSH
  • Incidence is highest in asian countries because of Hep B and AFB1 Asian countries also have screening programs leading to increased detection of HCC
  • 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.
  • 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 HCC
  • 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.
  • T1 and T2 occurs in less than 20% of patients Relies on pathologic findings and liver function is not taken into account
  • Can not destinguish between early and advanced stages and mostly serves to identify endstage individuals.
  • HBV vaccine for children aged 6 to 9 years in birth cohorts receiving vaccination
  • 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
  • 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
  • 30% Early stage 20% intermediate 40% Advanced stage 10% End stage
  • 5 year survival <5%
  • High rate of expression of drug resistance genes, including p-glycoprotein, glutathione-S-transferase, heat shock proteins, and mutations in p53
  • 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 T138067 sodium A 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
  • 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 2006
  • 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 analysis
  • www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt
  • www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt
  • www.esmo.org/eclu/assets/ESC54/LCT10001261.ppt

Transcript

  • 1. Advanced Hepatocellular Carcinoma After ASCO 2007 Hematology/Oncology Grand Rounds September 14, 2007 Mark A. Schroeder, M.D.
  • 2. Objectives
    • An illustrative case presentation
    • Epidemiology of HCC
    • Pathogenesis of HCC
    • Staging
    • Treatment of HCC
    • Implications for current and future trials
  • 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 31 st and interpreted as HCC
    • Enrolled in the avastin/tarceva clinical trial
    • Course complicated by culture negative fevers and pain
  • 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 ½ PPD, marijuana in the past.
    • Uncle had bone cancer. Brother had colon cancer. Mother had cancer of unknown type
    SH/FH
  • 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
  • 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%)
    Online Calculator: http://homepage.mac.com/sholland/contrivances/childpugh.html Child CG, Turcotte JG. Surgery and portal hypertension. In: The liver and portal hypertension. Edited by CG Child. Philadelphia: Saunders 1964:50-64. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the esophagus in bleeding oesophageal varices. Br J Surg 1973;60:648-52 >3 2-3 <2 Bilirubin Severe (III-IV) Mild (I-II) Absent Encephalopathy Severe / Refractory Mild-Moderate Absent Ascites >2.3 1.7-2.3 <1.7 INR <2.8 3.5-2.8 >3.5 Albumin 3 2 1
  • 8. CT Imaging
  • 9.  
  • 10.  
  • 11.  
  • 12. Pathology “ Hepatocellular carcinoma with cholangiolar features, moderately differentiated”
  • 13. Epidemiology of HCC
    • 6 th 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
    Parkin, D.M., et al., Global cancer statistics, 2002. CA Cancer J Clin, 2005. 55 (2): p. 74-108.
  • 14. Parkin, D. M. et al. CA Cancer J Clin 2005;55:74-108.
    • Estimated Numbers of New Cancer Cases and Deaths in 2002
    • 6% 5 yr survival rate
    #7 #6
  • 15. Parkin, D. M. et al. CA Cancer J Clin 2005;55:74-108. Age-standardized Incidence Rates for Liver Cancer
  • 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
    El-Serag, H.B. and A.C. Mason, Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med, 1999. 340 (10): p. 745-50.
  • 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?
    El-Serag, H.B. and K.L. Rudolph, Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology, 2007. 132 (7): p. 2557-76. Brunetto M.R., O.F., Koehler M., et al., Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study. International Interferon-alpha Hepatocellular Carcinoma Study Group. Lancet, 1998. 351 (9115): p. 1535-9.
  • 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
  • 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
    Thorgeirsson, S.S. and J.W. Grisham, Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet, 2002. 31 (4): p. 339-46 Poon et al. Gastroenterology 2006. 131:1262
  • 20. Pathogenesis Thorgeirsson, S.S. and J.W. Grisham, Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet, 2002. 31 (4): p. 339-46.
  • 21. El-Serag, H.B. Gastroenterology, 2007. 132 (7): p. 2557-76. Loss of cell cycle check points Numerous Oncogenes implicated
  • 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 Prospective validation of the CLIP score: A new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology 2000; 31:840 1 >400 2 Massive or extension >50% 1 Multinodular and extension 50% 0 Tumor morphology Uninodular and extension 50% 2 C 1 B 1 Yes 0 Portal Vein Thrombosis No 0 AFP <400 0 Child-Pugh A
  • 24. Kaplan-Meier estimated survival curves based on the CLIP score (log rank test) Farinati, F, Rinaldi, M, Gianni, S, Naccarato. Cancer 2000; 89:2266.
  • 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
    AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New York, Inc 16% 5 yr survival 37% 5 yr survival 55% 5 yr survival M0 N1 Any T IIIC M0 N0 T4 IIIB M1 Any N Any T Stage IV M0 N0 T3 Stage IIIA M0 N0 T2 Stage II M0 N0 T1 Stage I
  • 26. Okuda staging system for HCC Adapted from Okuda, K, Ohtuiki, T, Obata, H, et al, Cancer 1985; 56:918. <3 >3 Bilirubin >3 <3 Albumin Abscent Clinically detectable Ascites <50% >50% Tumor size Negative Positive Criteria 0.7 mos survival 2 mos survival 8.3 mos survival 3-4 positive Stage III 1-2 positive Stage II No positive Stage I
  • 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
    Thorgeirsson. J Hepatology. 2006. 44:798 Lee Hepatology. 2004. 40(3):667
  • 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
    Chang, M.H., et al., Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med, 1997. 336 (26): p. 1855-9.
  • 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
  • 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
  • 31. Treatment Algorithm Llovt et al. Lancet 362(9399), 6 December 2003, Pages 1907-1917
  • 32. Outcomes for UNTREATED HCC Llovt et al. Lancet 362(9399), 6 December 2003, Pages 1907-1917
  • 33. Outcomes of Palliative Treatments Llovt et al. Lancet 362(9399), 6 December 2003, Pages 1907-1917
    • Absolute Contraindications for TACE:
    • abscence of hepatopetal blood flow (portal vein thrombosis)
    • Encephalopathy, and biliary obstruction
    • Relative Contraindications for TACE
    • 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
    • 2 yr survival 24-63%
  • 34. Intra-arterial Chemotherapy Copyright © 2003 BC Decker Inc. All rights reserved. Holland-Frei Cancer Medicine - 6th Ed. (2003) Patt et al 173 9 60 25 40 dL 10 dL,         q4wk 75 dL 1-5 Doxorubicin   + mitomycin   + FUDR Malik 172 7.1 37 16   6 g/m 2 over 96 h Ifosfamide Kairaluoma et al 171 5 27 11 20, q6wk Mitomycin Kajanti et al 170 20 40 10 50, q4wk CDDP Epirubicin Study 169 - 15 64 60-90, q3wk Epirubicin Doci et al 168 2-6 42 19 15 d 1-8, q4wk   Or 25 d 1-3, q3wk Doxorubicin Nerenstone and Friedman 167 6-15 50 82 - fluorouracil (FU), floxuridine (FUDR) Study Median Survival (mo) Response (%) No. of Patients Evaluated Dose (mg/m 2 ) Drug
  • 35. Holland-Frei Cancer Medicine - 6th Ed. (2003) Study Median Survival (mo) Response (%) No. of Patients Evaluated Dose (mg/m 2 ) Drug   ~ 15 67 23 15 mL    } q8-12wk ethiodized oil   + gel pellets Chang et al 174 ~ 15 68 22 50 mg    }   in         } q8-12wk 15 mL    } Cisplatin   + ethiodized oil   + gel pellets   vs   26 50 185 72 mg     }   in          } q4wk 6.5 mL    } Epirubicin   + ethiodized oil   + gel pellets Kawai et al 180 20 43 180 48 mg    }   in         } q4wk 6.2 mL   } Doxorubicin   + ethiodized oil   + gel pellets   vs Bismuth et al 178 13-20 30 291 50 mg    }   in         } q3wk 15 mL    } Doxorubicin + ethiodized oil   + gel pellets Patt et al 175 15 41 29 60 d 1-4 } 15          } q 5 wk 35 dL      } 100 dL   } FUDR   + leucovorin   + doxorubicin   + cisplatin
  • 36. Meta-analysis of 2 yr survival with chemoembolisation or embolisation Llovt et al. Lancet 362(9399), 6 December 2003, Pages 1907-1917
  • 37. Tamoxifen and HCC Llovt et al. Lancet 362(9399), 6 December 2003, Pages 1907-1917
    • Estrogen receptors are present on 30% of HCCs
    • No proven survival benefit or improved functional status
  • 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
  • 39. Advanced Hepatocellular Carcinoma Phase II trials FMP= 5FU/Mitoxantrone/Cisplatin GEMOX= Gemcytabine/Oxaloplatin ECF= Epirubicin/Cisplatin/5FU GEMOX+B= Gemcytabine/Oxaloplatin + Bevacizumab DCX= Doxorubicin/Cisplatin/Capcitabine 9.2 4.2 2.2 Sorafenib 137 Abou-Alfa 2006 9.6 5.3 20 GEMOX+B 33 Zhu 2006 7.3 6.6 19 DC 42 Lee 2004 6.4 3.2 21 Gem Cis 47 Yang 2003 6.9 2.1 0 Gem 1000 30 Fuchs 2002 4.7 3 18 Gem 1250 28 Yang 2000 11.5 6.3 18 GEMOX 34 Louafi 2007 7.7 3.7 24 DCX 29 Park 2006 10 5.9 14 ECF 21 Boucher 2002 11.6 7.6 27 FMP 51 Ikeda 2005 4.9 2.5 24 FMP 63 Yang 2004 24 5-FU/LV 25 Porta 1995 MS (months) TTP (months) PR (%) Agent n Author, year
  • 40. Phase III randomised trials of systemic therapy for advanced HCC Yeo et al JNCI 2005; Beaugrand et al J Hepatology 2005, Lai et al. 1988 Cancer Gish et al JCO 2007; Posey et al ASCO 2005; Choi et al. 1984 Cancer Quad Rx: 5FU/Mito/Cy/Vin PIAF: Cisplatin, interferon-  2b, doxorubicin, fluorouracil P=0.14 58% 1 yr OS (n=30) IFNa 38% 1 yr OS (n=28) BSC 58 Llovet et al p=0.85 P=0.0068 p=NS p=0.036 p=0.83 p=0.1 p-value 5.7 mos 5.6 mos 9.6 mos 2.7 mos 8.67 mos 1.6 mos Med survival (n=170) (n=222) (n=60) (n=94) (n=19) T-138067 Nolatrexed Seocalcitol Doxorubicin PIAF* Quad Rx Exp arm 5.6 mos 8.1 mos 9.2 mos 1.9 mos 6.83 mos 3.6 mos Median survival (n=169) (n=223) (n=46) (n=94) (n=45) Doxorubicin Doxorubicin Placebo BSC Doxorubicin Doxorubicin Control arm 339 445 746 106 188 64 Total pts Posey et al Gish et al Beaugrand et al Lai et al Yeo et al Choi et al Authors
  • 41. Abstract #LBA1: Sorafenib improves survival in advanced Hepatocellular Carcinoma (HCC): Results of a Phase III randomized placebo-controlled trial (SHARP trial) J. Llovet, S. Ricci, V. Mazzaferro, P. Hilgard, J. Raoul, S. Zeuzem, M. Poulin-Costello, M. Moscovici, D. Voliotis, J. Bruix, For the SHARP Investigators Study Group
  • 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
    Cancer Res 2006; 66: (24). December 15, 2006
  • 43. Llovet ASCO 2007
  • 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
    Llovet ASCO 2007
  • 45. Advanced Hepatocellular Carcinoma Sorafenib vs. Placebo Unresectable / metastatic HCC Child-Pugh A R 1:1 Sorafenib 400mg BID Placebo 2tabs PO BID Primary endpoints : OS, and time to symptomatic progression Secondary endpoint : TTP Stratified by: vascular invasion, extra-hepatic spread, ECOG PS, geographic region Llovet ASCO 2007 N=602 N=299 N=303
  • 46. Balanced Patient Characteristics Llovet ASCO 2007 70% 30% 70% 30% Vascular Invasion/Extrahepatic spread Present Absent 54% 39% 7% 54% 38% 8% ECOG PS: O 1 2 21% 41% 19% 39% Prior Therapies: Surgical resection Loco-regional therapies 98/2 95/5 Child Pugh (A/B %) 27/18 26/29 29/19 26/26 Etiology (HCV/HBV) (Alcohol/Other) 87/10/3 88/9/3 Region (Europe/N. America/Other % 87/13 87/13 Male/Female 66 65 Age Placebo (n=303) Sorafenib (n=299)
  • 47. Phase III SHARP Trial Overall survival (Intention-to-treat) Sorafenib Median: 46.3 weeks (95% CI: 40.9, 57.9) Survival Probability Weeks Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88) P =0.00058* Placebo Median: 34.4 weeks (95% CI: 29.4, 39.4) 1.00 0 0.75 0.50 0.25 0 80 8 16 24 32 40 48 56 64 72 *O’Brien-Fleming threshold for statistical significance was P=0.0077. 0 274 241 205 161 108 67 38 12 0 Patients at risk Sorafenib: 0 276 224 179 126 78 47 25 7 2 Placebo: 299 303 Llovet ASCO 2007
  • 48. Phase III SHARP Trial Time to progression (Independent central review) Probability of Progression Hazard ratio (S/P): 0.58 (95% CI: 0.44, 0.74) P =0.000007 Weeks Patients at risk Sorafenib: Placebo: 299 303 Llovet ASCO 2007 Placebo Median: 12.3 weeks (95% CI: 11.7, 17.1) Sorafenib Median: 24.0 weeks (95% CI: 18.0, 30.0) 0 196 126 80 50 28 14 8 2 0 192 101 57 31 12 8 2 1 54 6 12 18 24 30 36 42 48 0 1.00 0 0.75 0.50 0.25
  • 49. Response Assessment Llovet ASCO 2007 Time to symptomatic progression (additional primary endpoint) – no significant difference (p=0.77) 19 wks 23 wks Duration of treatment 42% 62% Progression free at 4 months 24 18 PD (%) 67 0.7 0 BSC 71 SD (%) 2.3 PR (%) 0 CR (%) Sorafenib
  • 50. Safety Events Llovet ASCO 2007
  • 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 23 GEMOX+cetux 44 II Louafi 2007 13 3.2 8 Erlotinib 150 38 II Phillip 2005 5 Sunitinib 37.5 19 II Zhu 2007 3 (68*) Sunitinib 50 37 II Faivre 2007 9.6 5.3 20 GEMOX+B 33 II Zhu 2006 6.5 8 Bevacizumab 10/5 25 II Schwartz 2007 10.7 v 7.9 OS 5.5 v 2.8 2.3 Sorafenib v placebo 602 III Llovet 2007 9.2 4.2 2.2 Sorafenib 400 137 II Abou-Alfa 2006 MS (months) / OS TTP (months) PR (%) agent n Phase Author year
  • 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 Hepatology. 2007. 46(2):446
  • 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