1、1Comparative Analyses of Hepatocellular Carcinoma between East and West Implication on the design of clinical trials 11th CSCO, Shanghai, 2008Ann-Lii Cheng M.D., Ph.D.Ann-Lii Cheng M.D., Ph.D.Department of Oncology and Department of Internal Medicine, National Taiwan University Hospital; Taipei, Tai
2、wan.Geographic and ethnic factors become important in the era of molecular targeted therapy for cancersAsian (n=342)Non-Asian (n=1350)Proportion survivingTime (months)0.01.00.80.60.40.20246810 12 14 160246810 12 14 16GefitinibPlaceboImportance of Ethnicity for MTA the lessons of ISEL trialEGFR mutat
3、ion rates in each subgroupStudyCentreNo. of patientsAdenoCa(+BAC) (%)M (%)F (%)Smokers (%)n-smokers (%)Taiwan1NTUH624925612956Taiwan2VGH-T3767.452724469Korea3Seoul NU90219331326Japan4NCC Tokyo666153693568Japan5Aichi CCH596444704271HK6Chinese U7232China7Pek UMCH7648.632.334.8Italy8*U Chieti3751063072
4、51. Shih et al, IJC 20052. Chou et al, CCR 20053. Han et al, JCO 20054. Takano et al, JCO 2005*only AdenoCa5. Mitsudomi et al, JCO 20056. Lung et al, PAACR 20057. Mu et al, CCR 20058. Machetti et al, JCO 2005 Liver Cancer in the World Ferlay J et al. IARC Press, 2001.Men (396,364) / Women (165,972)N
5、orth America (%)2.07 / 2.61Central & South America (%)2.09 / 4.33Africa (%)6.90 / 8.69Europe (%)8.21 / 10.45Asia (%)81.54 / 74.13Oceania (%)0.25 / 0.27Geographic differences in the results of clinical trials for advanced HCCSorafenibMedian: 46.3 weeks (10.7 mo)(95% CI: 40.9, 57.9)Survival Probabilit
6、yWeeksHazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88) P=0.00058*PlaceboMedian: 34.4 weeks (7.9 mo) (95% CI: 29.4, 39.4)1.0000.750.500.250808162432404856647202742412051611086738120Patients at risk Sorafenib:027622417912678472572Placebo:299303Phase III SHARP TrialOverall survival (Intention-to-treat)Llo
7、vet J et al, N Engl J Med. 2008 Jul 24;359(4):378-90 (7.9 mo)Comparison of Tx(-) Control ArmsPt NoMedianOSPVTTNMStage IVOkudaStage IIIECOGIII/IVSpain10217M23.5%54.9%0%*0%*HK1063M60.0%90.6%14%13%* Spanish trials excluded “End-stage disease”Llovet JM, Hepatology 1999;29:62-7Yeung YP, Am J Gastroentero
8、l 2005;100:1995-2004EAST VS WESTRandomized trials - octreotide vs placebo Study Schema of SHARP and AP StudiesSorafenib400 mg bidPlaceboEligibility Advanced HCCECOG 0-2Child-Pugh ANo prior systemic therapyStratification Macroscopic vascular invasion (portal vein) and/or extrahepatic spreadECOG PSGeo
9、graphic areaRANDOMIZEPhase III SHARP and Asia-Pacific Overall SurvivalSorafenibMedian: 10.7 months(95% CI: 40.9, 57.9)Survival ProbabilityMonthsHazard ratio (sor/pla): 0.69(95% CI: 0.55, 0.87) P=0.00058*PlaceboMedian: 7.9 months(95% CI: 29.4, 39.4)1.0000.750.500.25020246810 12 14 16 18Survival Proba
10、bilitySorafenibMedian: 6.5 months (95% CI: 5.6-7.6)PlaceboMedian: 4.2 months (95% CI: 3.7-5.5)HR (S/P): 0.68 95% CI: 0.50-0.93P=0.0140.250.500.751.0000Months248 10 12 14 1620 22618Llovet JM, et al. N Engl J Med 2008:359:378-90 Cheng AL, et al. ASCO 2008, Abstract 4509. SHARPSHARPAsia-PacificAsia-Pac
11、ificAsia-Pacific Liver Cancer Study vs SHARP:Baseline Patient CharacteristicsAsia-Pacific(N=226)SHARP1(N=602)Median age (range), years51 (23-86)67 (21-89)Hepatitis virus status (HBV/HCV), %73/818/28Sex (Male), %8587ECOG PS (0/1/2), %26/69/554/38/8Macroscopic vascular invasion, %3538Extrahepatic spre
12、ad, %6951BCLC Stage (B/C), %4/9617/82No. of tumor sites, % 11144 23531 32012 43513Sites of disease, %Lung5021Lymph node32261 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 StageSurgical TreatmentsLocal Ablat
13、ionNew AgentsTACEHCC(30%)Potentially curative treatments5-yr survival: 50-70%(50-60%)Randomized trialsmedian survival if untreated: 6-16 mo(10%)BSC survival 2 or Child CPVT (-)PVT (+)Single2 or 3, 3 cm4, 3 cmICG good*ICG bad*ResectionAblation,Transplan- tationTACEMain PV (-), extra-hepatic spread (-
14、)Main PV (+) or extra-hepatic spread (+)TACEBSCNew agentsBSCBil. 2 mg/dlBil. 2 mg/dlBil. 2 mg/dlBil. 2 mg/dlEarly stage (single or 3 nodules 3 cm, PS 0)Intermediate stage (multi-nodular, PS 0)Advanced stage (portal invasion, N1, M1, PS 1-2Terminal stage (PS 2, Child C)NTUH practiceBCLC guidelineRese
15、ctionAblation, Transplan- tationTACENew agentsBSCSingle, PH (-)Multiple , PH (+)Makuuchi M. et al, Hepatology Research 2007Japan GuidelineEmbolization hepatic arterial infusion chemotherapyGeographic differences in the etiology of HCC implication in the development of MTAsEtiology of HCC Distinct Ge
16、ographic Distribution Risk FactorsHepatitis B virusHepatitis C virusAlcoholTobaccoOral contraceptivesAflatoxinOther 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 - - Est
17、imate 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 ?HB
18、V-related HCCHCC East vs WestLong-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) 74-80Taeck D et al Liver Transplantation 2004;10(suppl 1) 58-63 HBV vs. HCV HCCItalian Liver
19、Cancer groupSurvival 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
20、advanced HCCHBV vs. HCV HCC in NTUHSurvival for patients with advanced ds.927 patients receiving supportive care or chemotherapy. EtiologyMedian survival (M)1 year (%)3 year (%)5 year (%)10 year (%)HBV2.5 12.43.40.80.5HCV3.4 21.78.52.21.1B+C3.410.83.11.50NBNC2.611.23.11.01.0HCV+HCV-HCC patients had
21、better survival than HBV-HCC patientsChen CH et al. Eur J Cancer. 2006 Oct;42(15):2524-9. Epub 2006 Aug 22Is HBV-related HCC a more aggressive tumor ?Is HBV-related HCC associated with molecular changes that will affect molecular therapy ?HBV-related HCCHBV- vs. HCV-associated HCC Genomics and Prote
22、omicsIizuka 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 factorsViral Proteins And Signal Transduction PathwaysHCV
23、 coreHCV coreBy Hsu C, Shen YC, Cheng ALTranscriptome 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 HCCs27Molecular Epidemiology of HBV not all HBVs a
24、re the sameGenotype 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 decompen
25、sated liver cirrhosis than genotype A, C, or D in USA.Chu CJ et al. Gastroenterology 2003;125:444-51.Sorafenib phase II HCC studyHCV- vs. HBV-related HCCPt No.Median age Race (%)CaucasiansClinical benefit (%)PFS (median, M)TTP (median, M)OS (median, M)HCV+337182756.56.512.4HBV+136654533.547.3 Huitzi
26、l-Melendez FD et al: ASCO-2007 GI Symposium Abstract# 173.A retrospective analysisP .27.05.29Sub-group analysis of the SHARP trialHCV1Alcohol2PS3MVI/EHS4(178)(159)0(325)1-2(277)-(421)+(181)OSSorafenib14.0 10.3 13.38.914.5 8.9(m)Placebo7.9 8.0 8.85.610.2 6.7HR0.58 (0.37-0.91)0.76 (0.50-1.16)0.68(0.50
27、-0.95)0.71(0.52-0.96)0.52(0.35-0.85)0.77(0.60-0.99)TTPSorafenib7.6 5.5 5.55.39.6 4.1 (m)Placebo2.83.92.92.84.3 2.7 HR0.44(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; Janu
28、ary 2008. 2. Craxi A, et al. Poster presentation. Chicago. USA3. 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 studyHCV- vs. HBV-related HCCPt No.Median age Objective response+AFP response (%)TTP (median)OS (m
29、edian)HCV+3367.527.314.1 W32.6 WHBV+6153.613.18.3 W21.4 W Hsu C et al: Proc. ASCO 2004: Abs#4198.P61 .001.09.03.08Geographic 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 ad
30、vanced/metastatic hepatocellular carcinomaHsu 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 )ettd_20_2001 Kaplan-Meier plot of Duration of SurvivalProtocol: ML18469Analysis: Intent to Treat PopulationFilter Applied: WHERE ITT=YE
31、S28AUG2007 1:00 Program : $PROD/cdp11999/ml18469/ettd_20.sas / Output : $PROD/cdp11999/ml18469/reports/ettd_20_2001.cgm Median OS: 5.9 M(95% CI: 4.1-9.7)ettpfs_20_2001 Kaplan-Meier plot of Progression Free SurvivalProtocol: ML18469Analysis: Intent to Treat PopulationFilter Applied: WHERE ITT=YES28AU
32、G2007 1:05 Program : $PROD/cdp11999/ml18469/ettpfs_20.sas / Output : $PROD/cdp11999/ml18469/reports/ettpfs_20_2001.cgm For patients without an event will be censored at the date of last assessment Median PFS: 2.7 M(95% CI: 1.5-4.1)Bevacizumab plus capecitabine for advanced HCCOSMedian: 5.9 M (95% CI
33、: 4.1-9.7)PFSMedian: 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 HCCStratifyGeographic RegionPrior TACETumor InvasionRandomize1：1Sunitinib 37.5 mg,qdas long as clinical benefitSorafenib 400mg,bidas long as clinical b
34、enefitSTUDY A6181170 A MULTI-NATIONAL, RANDOMIZED, OPEN-LABEL, PHASE III STUDY OF SUNITINIB VERSUS SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMAConclusion1.Significant geographic differences in clinical practice and etiology are observed in HCC.2.These differences significantly affect
35、 the results of clinical trials, and should be taken into consideration in the design and interpretation of clinical trials for HCC.37Comparative Analyses of Hepatocellular Carcinoma between East and West Implication on the design of clinical trials 11th CSCO, Shanghai, 2008purines and pyrimidinesAn
36、timetabolitesVinca alkaloidsTaxanesMitosisL-asparaginaseDNARNAProteinsActinomycin DAlkylating agentsNitrosoureasCisplatinProcarbazineAntitumor antibioticsChemotherapyMolecular TargetedGenetic Change Molecular ChangeCell Proliferation Geographic Differences in HCCLiver Cancer:1. Garcia M, et al. Amer
37、ican Cancer Society, 2007. www.cancer.org. Accessed March 20, 2008. 2. http:/www.who.int/mediacentre/factsheets/fs297/en/index.html. Accessed June, 2008.196,298226,787230,555200,774314,256330,963529,283559,094711,128782,6471,066,5431,167,0201,301,8671,549,1210200,000400,000600,000800,0001,000,0001,2
38、00,0001,400,0001,600,0001,800,000Non-Hodgkins LymphomaCorpus UteriOvaryOral CavityBladderLeukemiaEsophagusCervix UteriLiverProstateStomachColon/RectalBreastLung Sixth most common cancer worldwide1 Third most common cause of cancer-related death2Incidence of HCC is Increasing1*Primary liver cancer.1.
39、 El-Serag HB et al. Gastroenterology. 2007;132:25572576; 2. Law MG, et al. Med J Aus. 2000;173:403-405; 3. Benhamiche A-M, et al. J Hepatol. 1998;29:802-806; 4. http:/info.cancerresearchuk.org/cancerstats/types/liver/incidence/?a=5441. Accessed January 2008; 5. El-Serag HB, et al. Ann Intern Med. 2003;139:817-823.Year1983-19851995-19961976-19791992-1995197520031975-19771996-1998Australia(men)2France(men)*3UK4US543感恩的心，感谢有你！感恩的心，感谢有你！谢谢你的欣赏！谢谢你的欣赏！全力打造精品课件，教学资料，感谢你的欣赏
