东西方肝癌的分析比较

1 Comparative Analyses of Hepatocellular Carcinoma between East and West Implication on the design of clinical trials 11th CSCO, Shanghai, 2008 Ann-Lii Cheng M.D., Ph.D. Department of Oncology and Department of Internal Medicine, National Taiwan University Hospital; Taipei, Taiwan. Geographic and ethnic factors become important in the era of molecular targeted therapy for cancers Asian (n=342) Non-Asian (n=1350) Proportion surviving Time (months) 0.0 1.0 0.8 0.6 0.4 0.2 0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16 Gefitinib Placebo Importance of Ethnicity for MTA the lessons of ISEL trial EGFR mutation rates in each subgroup Study Centre No. of patients AdenoCa (+BAC) (%) M (%) F (%) Smokers (%) n-smokers (%) Taiwan1 NTUH 62 49 25 61 29 56 Taiwan2 VGH-T 37 67.4 52 72 44 69 Korea3 Seoul NU 90 21 9 33 13 26 Japan4 NCC Tokyo 66 61 53 69 35 68 Japan5 Aichi CCH 59 64 44 70 42 71 HK6 Chinese U 72 32 China7 Pek UMCH 76 48.6 32.3 34.8 Italy8* U Chieti 375 10 6 30 7 25 1.Shih et al, IJC 2005 2.Chou et al, CCR 2005 3.Han et al, JCO 2005 4.Takano et al, JCO 2005 *only AdenoCa 5.Mitsudomi et al, JCO 2005 6.Lung et al, PAACR 2005 7.Mu et al, CCR 2005 8.Machetti et al, JCO 2005 Liver Cancer in the World Ferlay J et al. IARC Press, 2001. Men (396,364) / Women (165,972) North America (%) 2.07 / 2.61 Central 359(4):378-90 (7.9 mo) Comparison of Tx(-) Control Arms Pt No Median OS PVT TNM Stage IV Okuda Stage III ECOG III/IV Spain 102 17M 23.5% 54.9% 0%* 0%* HK 106 3M 60.0% 90.6% 14% 13% * Spanish trials excluded “End-stage disease” Llovet JM, Hepatology 1999;29:62-7 Yeung YP, Am J Gastroenterol 2005;100:1995-2004 EAST VS WEST Randomized trials - octreotide vs placebo Study Schema of SHARP and AP Studies Sorafenib 400 mg bid Placebo Eligibility Advanced HCC ECOG 0-2 Child-Pugh A No prior systemic therapy Stratification Macroscopic vascular invasion (portal vein) and/or extrahepatic spread ECOG PS Geographic area R A N D O M I Z E Phase III SHARP and Asia- Pacific Overall Survival Sorafenib Median: 10.7 months (95% CI: 40.9, 57.9) Survival Probability Months Hazard ratio (sor/pla): 0.69 (95% CI: 0.55, 0.87) P=0.00058* Placebo Median: 7.9 months (95% CI: 29.4, 39.4) 1.00 0 0.75 0.50 0.25 0 202 4 6 8 10 12 14 16 18 Survival Probability Sorafenib Median: 6.5 months (95% CI: 5.6-7.6) Placebo Median: 4.2 months (95% CI: 3.7-5.5) HR (S/P): 0.68 95% CI: 0.50-0.93 P=0.014 0.25 0.50 0.75 1.00 0 0 Months 2 4 8 10 1214 16 20226 18 Llovet JM, et al. N Engl J Med 2008:359:378-90 Cheng AL, et al. ASCO 2008, Abstract 4509. SHARP Asia-Pacific Asia-Pacific Liver Cancer Study vs SHARP: Baseline Patient Characteristics Asia-Pacific (N=226) SHARP1 (N=602) Median age (range), years 51 (23-86) 67 (21-89) Hepatitis virus status (HBV/HCV), % 73/8 18/28 Sex (Male), % 85 87 ECOG PS (0/1/2), % 26/69/5 54/38/8Macroscopic vascular invasion, % 35 38 Extrahepatic spread, % 69 51 BCLC Stage (B/C), % 4/96 17/82No. of tumor sites, % 1 11 44 2 35 31 3 20 12 4 35 13 Sites of disease, % Lung 50 21 Lymph node 32 26 1 Llovet J, et al. N Engl J Med 2008:359:378-90 . Llovet JM et al. Lancet. 2003; 362:1907-1917. End StageAdvanced StageIntermediate StageEarly Stage Surgical Treatments Local Ablation New AgentsTACE HCC (30%) Potentially curative treatments 5-yr survival: 50-70% (50-60%) Randomized trials median survival if untreated: 6-16 mo (10%) BSC survival 2 or Child C PVT (-) PVT (+) Single 2 or 3, 3 cm 4, 3 cm ICG good* ICG bad* Resection Ablation,Transplan - tation TACE Main PV (-), extra- hepatic spread (-) Main PV (+) or extra -hepatic spread (+) TACE BSC New agents BSC Bil. 2 mg/dl Bil. 2 mg/dl Bil. 2 mg/dl Bil. 2 mg/dl Early stage (single or 3 nodules 3 cm, PS 0) Intermediate stage (multi- nodular, PS 0) Advanced stage (portal invasion, N1, M1, PS 1-2 Terminal stage (PS 2, Child C) NTUH practice BCLC guideline Resection Ablation, Transplan - tation TACE New agents BSC Single, PH (-) Multiple , PH (+) Makuuchi M. et al, Hepatology Research 2007 Japan Guideline Embolization hepatic arterial infusion chemotherapy Geographic differences in the etiology of HCC implication in the development of MTAs Etiology of HCC Distinct Geographic Distribution Risk Factors Hepatitis B virus Hepatitis C virus Alcohol Tobacco Oral contraceptives Aflatoxin Other and emerging risk factors/cofactors Estimate Range 22 4-58 60 1272 45 857 12 014 - 1050 Limited exposure 5 - Estimate Range 20 18-44 63 4894 20 1533 40 951 - - Limited exposure - - Estimate Range 60 4090 20 956 - 1141 22 - 8 - Important exposure 5 - Bosch FX et al. Gastroenterology 2004;127:S5-16. Europe and United States (%) Japan (%) Asia and Africa (%) Is HBV-related HCC a more aggressive tumor ? Is HBV-related HCC associated with molecular changes which affect molecular therapy ? HBV-related HCC HCC East vs West Long-term results after surgical treatment were similar in West and East when clinicopatnologic factors were accounted for. Pawlik TM et al Liver Transplantation 2004;10(suppl 1) 74-80 Taeck D et al Liver Transplantation 2004;10(suppl 1) 58-63 HBV vs. HCV HCC Italian Liver Cancer group Survival in patients with advanced HCC. HBV- HCC patients had a lower survival than HCV- HCC patients (p=0.025) Patients with HBV-HCC tended to have poor prognosis; Cantarini MC et al: Am J Gastroenterol 2006;101:91-8. and the difference became statistically significant among patients with advanced HCC HBV vs. HCV HCC in NTUH Survival for patients with advanced ds. 927 patients receiving supportive care or chemotherapy. Etiology Median survival (M) 1 year (%) 3 year (%) 5 year (%) 10 year (%) HBV 2.5 12.4 3.4 0.8 0.5 HCV 3.4 21.7 8.5 2.2 1.1 B+C 3.4 10.8 3.1 1.5 0 NBNC 2.6 11.2 3.1 1.0 1.0 HCV+ HCV-HCC patients had better survival than HBV-HCC patients Chen CH et al. Eur J Cancer. 2006 Oct;42(15):2524-9. Epub 2006 Aug 22 Is HBV-related HCC a more aggressive tumor ? Is HBV-related HCC associated with molecular changes that will affect molecular therapy ? HBV-related HCC HBV- vs. HCV-associated HCC Genomics and Proteomics Iizuka N et al. Cancer Res 2002;62:3939-44. Kim W et al. Clin Cancer Res 2003;9:5493-500. HBV and HCV cause hepatocarcinogenesis by different mechanisms. The expression pattern of proteome in HCC tissues is closely associated with etiologic factors Viral Proteins And Signal Transduction Pathways HCV core HCV core By Hsu C, Shen YC, Cheng AL Transcriptome classification of HCC Boyault S et al: Hepatol 2007;45:42. based on120 surgically resected HCC, including transcriptome analysis on 57 HCCs and 3 adenomas, and qRT-PCR validation in additional 63 HCCs 27 Molecular Epidemiology of HBV not all HBVs are the same Genotype C is associated with an increased risk of HCC in Taiwan. (OR=5.11) Yu MW et al. J Natl Cancer Inst 2005;97:265-72. Genotype A HBV has a greater hepatocarcinogenic potential in sub-saharan Africans. Kew MC et al. J Med Virol 2005;75:513-21. Genotype B is associated with less decompensated liver cirrhosis than genotype A, C, or D in USA. Chu CJ et al. Gastroenterology 2003;125:444-51. Sorafenib phase II HCC study HCV- vs. HBV-related HCC Pt No. Median age Race (%) Caucasians Clinical benefit (%) PFS (median, M) TTP (median, M) OS (median, M) HCV+ 33 71 82 75 6.5 6.5 12.4 HBV+ 13 66 54 53 3.5 4 7.3 Huitzil-Melendez FD et al: ASCO-2007 GI Symposium Abstract# 173. A retrospective analysis P .27 .05 .29 Sub-group analysis of the SHARP trial HCV1 Alcohol2 PS3 MVI/EHS4 (178) (159) 0 (325) 1-2 (277) - (421) + (181) OS Sorafenib 14.0 10.3 13.3 8.9 14.5 8.9 (m) Placebo 7.9 8.0 8.8 5.6 10.2 6.7 HR 0.58 (0.37-0.91) 0.76 (0.50-1.16) 0.68(0.50-0.95) 0.71 (0.52- 0.96) 0.52 (0.35- 0.85) 0.77 (0.60- 0.99) TTP Sorafenib 7.6 5.5 5.5 5.3 9.6 4.1 (m) Placebo 2.8 3.9 2.9 2.8 4.3 2.7 HR 0.44 (0.25-0.76) 0.64 (0.40-1.03) 0.55 (0.40-0.77) 0.61 (0.42- 0.88) 0.40 (0.23- 0.70) 0.64 (0.48- 0.84) 1. Bolondi L, et al. Abstract 129. Poster and oral presentation at ASCO-GI; Orlando, FL; January 2008. 2. Craxi A, et al. Poster presentation. Chicago. USA 3. Raoul J, et al. J Clin Oncol. 2008;25: abstract 4587. 4. Sherman M, et al. J Clin Oncol. 2008;25: abstract 4584. Thalidomide phase II HCC study HCV- vs. HBV-related HCC Pt No. Median age Objective response+ AFP response (%) TTP (median) OS (median) HCV+ 33 67.5 27.3 14.1 W 32.6 W HBV+ 61 53.6 13.1 8.3 W 21.4 W Hsu C et al: Proc. ASCO 2004: Abs#4198. P 61 .001 .09 .03 .08 Geographic factors should be taken into consideration in the interpretation and design of clinical trials of advanced HCC. Phase II study of bevacizumab + capecitabine in patients with advanced/metastatic hepatocellular carcinoma Hsu C-H1, Yang T-S2, Hsu C1, Toh HC3, Epstein R4, Hsiao L-T5, Lin Z-Z1, Cheng A-L1 (Proc Am Soc Clin Oncol 2008:26; #4603 ) Median OS: 5.9 M (95% CI: 4.1-9.7) Median PFS: 2.7 M (95% CI: 1.5-4.1) Bevacizumab plus capecitabine for advanced HCC OS Median: 5.9 M (95% CI: 4.1-9.7) PFS Median: 2.7 M (95% CI: 1.5-4.1) Hsu CH et al: Proc ASCO 2008: Abstract#4603. Worldwide, multicenter, open-label, 1,200 pts with advanced HCC Stratify Geographic Region Prior TACE Tumor Invasion Randomize 1： 1 Sunitinib 37.5 mg,qd as long as clinical benefit Sorafenib 400mg,bid as long as clinical benefit STUDY A6181170 A MULTI-NATIONAL, RANDOMIZED, OPEN-LABEL, PHASE III STUDY OF SUNITINIB VERSUS SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA Conclusion Significant geographic differences in clinical practice and etiology are observed in HCC. These differences significantly affect the results of clinical trials, and should be taken into consideration in the design and interpretation of clinical trials for HCC. 37 Comparative Analyses of Hepatocellular Carcinoma between East and West Implication on the design of clinical trials 11th CSCO, Shanghai, 2008 purines and pyrimidines Antimetabolites Vinca alkaloids Taxanes Mitosis L-asparaginase DNA RNA Proteins Actinomycin D Alkylating agents Nitrosoureas Cisplatin Procarbazine Antitumor antibiotics ChemotherapyMolecular Targeted Genetic Change Molecular Change Cell Proliferation Geographic Differences i