東西方肝癌的分析比較ppt課件

1、Geographic and ethnic factors become important in the era of molecular targeted therapy for cancersAsian (n=342)Non-Asian (n=0)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 mutation rat

2、es in each subgroupStudyCentreNo. of patientsAdenoCa(+BAC) (%)M (%)F (%)Smokers (%)n-smokers (%)Taiwan1NTUH624925612956Taiwan2VGH-T3767.452724469Korea3Seoul NU90219331326Japan4NCC Tokyo666153693568Japan5Aichi CCH596444704271HK6Chinese U7232China7Pek UMCH7648.632.334.8Italy8*U Chieti37510630725Shih e

3、t al, IJC 2005Chou et al, CCR 2005Han et al, JCO 2005Takano et al, JCO 2005*only AdenoCaMitsudomi et al, JCO 2005Lung et al, PAACR 2005Mu et al, CCR 2005Machetti 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 / 2.61Cent

4、ral & 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 ProbabilityWeeksHazard ratio (S/P): 0

5、.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)Llovet J et al, N Engl J Med.

6、2021 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 Gastroenterol 2005;100:1995-2004EAST VS

7、 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 PSGeographic areaRANDOMIZEPhase

8、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 ProbabilitySorafenibMedian: 6.5

9、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 2021:359:378-90 Cheng AL, et al. ASCO 2021, Abstract 4509. SHARPSHARPAsia-PacificAsia-PacificAsia-Pacific Liver Canc

10、er 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 spread, %6951BCLC Stage (B/C),

11、%4/9617/82No. of tumor sites, % 11144 23531 32012 43513Sites of disease, %Lung5021Lymph node32261 Llovet J, et al. N Engl J Med 2021:359:378-90 . Llovet JM et al. Lancet. 2003; 362:1907-1917.End StageAdvanced StageIntermediate StageEarly StageSurgical TreatmentsLocal AblationNew AgentsTACEHCC(30%)Po

12、tentially 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 (-)Main PV (+) or extra-hepat

13、ic 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 guidelineResectionAblation, Transplan- t

14、ationTACENew 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 Geographic Distribution Risk

15、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 - - Estimate Range 60 4090 20 956

16、- 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 HCCHCC East vs We

17、stLong-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 Cancer groupSurvival in pat

18、ients 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 HCCHBV vs. HCV HCC

19、 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 better survival than HBV-HC

20、C 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 ProteomicsIizuka N et al. Cancer

21、 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 coreHCV coreBy Hsu C, Shen

22、 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 HCCs26Molecular Epidemiology of HBV not all HBVs are the sameGenotype C is as

23、sociated 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

24、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 Huitzil-Melendez FD et al: ASCO-2

25、007 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(0.50-0.95)0.71(0.52-0.96)0.52(0

26、.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; January 2008. 2. Craxi A, et al

27、. 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 (median)HCV+3367.527.314.1 W3

28、2.6 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 advanced/metastatic hepatocel

29、lular 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 2021:26; #4603 )ettd_20_2001 Kaplan-Meier plot of Duration of SurvivalProtocol: ML18469Analysis: Intent to Treat PopulationFilter Applied: WHERE ITT=YES28AUG2007 1:00 Program : $

30、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=YES28AUG2007 1:05 Program : $PROD/

31、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: 4.1-9.7)PFSMedian: 2.7 M

32、(95% CI: 1.5-4.1) Hsu CH et al: Proc ASCO 2021: 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 benefitSTUDY A6181170 A MULT

33、I-NATIONAL, RANDOMIZED, OPEN-LABEL, PHASE III STUDY OF SUNITINIB VERSUS SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMAConclusionSignificant geographic differences in clinical practice and etiology are observed in HCC.These differences significantly affect the results of clinical trials

34、, and should be taken into consideration in the design and interpretation of clinical trials for HCC.36Comparative Analyses of Hepatocellular Carcinoma between East and West Implication on the design of clinical trials 11th CSCO, Shanghai, 2021purines and pyrimidinesAntimetabolitesVinca alkaloidsTaxanesMitosisL-asparaginaseDNARNAProteinsActinomycin DAlkylating agentsNitrosoureasCisplatinProcarbazineAntitumor ant