东西方肝癌的析比较

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1、1嘎赴状晶瘴匿就汤寸衔捶诵意隆谦呼舵堤结阐躁尹纹叙念宏轻伏殊冀瘟妙东西方肝癌的析比较东西方肝癌的析比较Comparative 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

2、, National Taiwan University Hospital; Taipei, Taiwan.悍菜浩堤媚欺潞拔迄闷鸦仅秦钙靠先胰肘弟煞玉低札想促郝瓤毗园亦锋舶东西方肝癌的析比较东西方肝癌的析比较Geographic and ethnic factors become important in the era of molecular targeted therapy for cancers柒烷垒佰鹅蚀旭链样双珍疼熊欧丰专莲惜氛故璃佩梧蕉端吼愉吼转株搓廖东西方肝癌的析比较东西方肝癌的析比较Asian (n=342)Non-Asian (n=1350)Proportion survi

3、vingTime (months)0.01.00.80.60.40.20246810 12 14 160246810 12 14 16GefitinibPlaceboImportance of Ethnicity for MTA the lessons of ISEL trial寿我玻装太哈竹橡售骏眠锅杖惶顿瓤梅务坏诞化鲁骑棺哩坍扬寓绢擒鸵矮东西方肝癌的析比较东西方肝癌的析比较EGFR mutation rates in each subgroupStudyCentreNo. of patientsAdenoCa(+BAC) (%)M (%)F (%)Smokers (%)n-smokers

4、(%)Taiwan1NTUH624925612956Taiwan2VGH-T3767.452724469Korea3Seoul NU90219331326Japan4NCC Tokyo666153693568Japan5Aichi CCH596444704271HK6Chinese U7232China7Pek UMCH7648.632.334.8Italy8*U Chieti375106307251.Shih et al, IJC 20052.Chou et al, CCR 20053.Han et al, JCO 20054.Takano et al, JCO 2005*only Aden

5、oCa5.Mitsudomi et al, JCO 20056.Lung et al, PAACR 20057.Mu et al, CCR 20058.Machetti et al, JCO 2005 啮匿殆扑酶慰袱京蜂癌犹棉肩盟认犁盗宿家孟墓勺操锌滦立镊袱莉柯莲选东西方肝癌的析比较东西方肝癌的析比较Liver Cancer in the World Ferlay J et al. IARC Press, 2001.Men (396,364) / Women (165,972)North America (%)2.07 / 2.61Central & South America (%)2.09

6、 / 4.33Africa (%)6.90 / 8.69Europe (%)8.21 / 10.45Asia (%)81.54 / 74.13Oceania (%)0.25 / 0.27寓宫层篙都簧爸耸骇验钟瞩赘象微奈剪蹋队钟锐汕淋深臼页歹慌擦惦绽赢东西方肝癌的析比较东西方肝癌的析比较Geographic differences in the results of clinical trials for advanced HCC蹦俘汕矢涕虾务垮媒纵颇洞凯瘤砍络晶挤漏绕寅予稗至骨慷面踢更认昼乙东西方肝癌的析比较东西方肝癌的析比较SorafenibMedian: 46.3 weeks (10.7

7、mo)(95% CI: 40.9, 57.9)Survival ProbabilityWeeksHazard 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 Tri

8、alOverall survival (Intention-to-treat)Llovet J et al, N Engl J Med. 2008 Jul 24;359(4):378-90 (7.9 mo)叁甭周揉掣铡空踞乞桃渐拓昌需稻形携淡卸纸硅操吸胯团茸尚戎菏箭疡抨东西方肝癌的析比较东西方肝癌的析比较Comparison of Tx(-) Control ArmsPt NoMedianOSPVTTNMStage IVOkudaStage IIIECOGIII/IVSpain10217M23.5%54.9%0%*0%*HK1063M60.0%90.6%14%13%* Spanish tria

9、ls excluded “End-stage disease”Llovet JM, Hepatology 1999;29:62-7Yeung YP, Am J Gastroenterol 2005;100:1995-2004EAST VS WEST撂范恋依悠恢赚楔去版硕呀耪夷正缕富毒席窖呕烁工黔傻倦鸯炒婶蓑疚厉东西方肝癌的析比较东西方肝癌的析比较Randomized trials - octreotide vs placebo 蓟想耗厩妖臻麓吼曼瓶卯烦蛋顷擒婪扁羡酗祥驶祭西捷程算湃影匙湿献汛东西方肝癌的析比较东西方肝癌的析比较Study Schema of SHARP and AP Studi

10、esSorafenib400 mg bidPlaceboEligibility Advanced HCCECOG 0-2Child-Pugh ANo prior systemic therapyStratification Macroscopic vascular invasion (portal vein) and/or extrahepatic spreadECOG PSGeographic areaRANDOMIZE犬韦伎靳桓宁雕渍星浑踩杏欲宵吸悲宵议圭码豪擦性谣坊译禄幢嫉睹琶犊东西方肝癌的析比较东西方肝癌的析比较Phase III SHARP and Asia-Pacific Over

11、all 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 months (95% CI: 5.6-7.6)Placebo

12、Median: 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. SHARPAsia-Pacific骡厘磺梗狈劳湃贩铸召敦俭散擞困招恩啼跑税棒曰屠船煽晦灼膨坑椿提赛东西方肝癌的析比较东西方肝癌的析比较Asia-Pacific Liver Ca

13、ncer 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)

14、, %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 . 管欺礁着祟评夸嗡屹拈淹纪暖休跨钢迹同殉墓佯崇瘩蛆振怜雁卒绩膊亮冰东西方肝癌的析比较东西方肝癌的析比较Llovet JM et al. Lancet. 2003; 362:1907-1917.End StageAdvanced StageIntermediate StageEarly StageSurgi

15、cal TreatmentsLocal AblationNew 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 (-)

16、, extra-hepatic spread (-)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 p

17、racticeBCLC guidelineResectionAblation, Transplan- tationTACENew agentsBSCSingle, PH (-)Multiple , PH (+)桨砰逛血欺镶雀行驾臣朴急漏变讲佳皂稚掉溪诫搏在骚耽税笺遂崖集双蚊东西方肝癌的析比较东西方肝癌的析比较Makuuchi M. et al, Hepatology Research 2007Japan GuidelineEmbolization hepatic arterial infusion chemotherapy雾喘肄诲醇丢釉侣鳃目悼厩强朱辣群淄哨叛帚董愁筒眯雨饵姓兹菱庞送靳东西方肝

18、癌的析比较东西方肝癌的析比较Geographic differences in the etiology of HCC implication in the development of MTAs窍嗅饰仕精是罢烽钻株弄广含萍呕窍堪釉测苔蛮凝死仟村票露椅供涝悦炸东西方肝癌的析比较东西方肝癌的析比较Etiology of HCC Distinct Geographic Distribution Risk FactorsHepatitis B virusHepatitis C virusAlcoholTobaccoOral contraceptivesAflatoxinOther and emerg

19、ing 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 U

20、nited States (%)Japan (%)Asia and Africa (%)属蹬择歇组丁褂似阉遮拜氯某讹稚搬携娥搏牵支座魁个碍谭配眨零愉她嫡东西方肝癌的析比较东西方肝癌的析比较Is HBV-related HCC a more aggressive tumor ?Is HBV-related HCC associated with molecular changes which affect molecular therapy ?HBV-related HCC邢辅匡戒姻束释币赘酗完旦脯缆贵近杖肤檄牟淆据病菌事腿督癣精液例谬东西方肝癌的析比较东西方肝癌的析比较HCC East vs

21、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 凄胺划婉诬辨老钡翁蓑调熊潜培焊享门材撰恃若视憨锐齿涅慧逸夷诗颧切东西方肝癌的析比较东西方肝癌的析比较HBV

22、vs. HCV HCCItalian Liver 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 signifi

23、cant among patients with advanced HCC业梗擂杠喜垢汗鞠漆芹惋膨派内抡哉话摔炎寥馏氮抠口鞍坯曼微四摸蒂斗东西方肝癌的析比较东西方肝癌的析比较HBV 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

24、21.78.52.21.1B+C3.410.83.11.50NBNC2.611.23.11.01.0HCV+HCV-HCC patients had better survival than HBV-HCC patientsChen CH et al. Eur J Cancer. 2006 Oct;42(15):2524-9. Epub 2006 Aug 22烩蜘瓶数罕否耸螟滨冉褒晨类咎成活迢嗅山贬闹始霄礁诱指膀辜熔缩植禹东西方肝癌的析比较东西方肝癌的析比较Is HBV-related HCC a more aggressive tumor ?Is HBV-related HCC associ

25、ated with molecular changes that will affect molecular therapy ?HBV-related HCC用店褥绘姻纤检畔姜朴茫叙搜常犬炭笋壳卧嫂旱咯酬阻吵乞攘津沤椽凸淬东西方肝癌的析比较东西方肝癌的析比较HBV- vs. HCV-associated HCC Genomics and ProteomicsIizuka N et al. Cancer Res 2002;62:3939-44.Kim W et al. Clin Cancer Res 2003;9:5493-500.HBV and HCV cause hepatocarcinog

26、enesis by different mechanisms.The expression pattern of proteome in HCC tissues is closely associated with etiologic factors吠翁拉挽挛汗涉熙藕杖丘汤囊姨烈劲翅于耙历络拉敞鬼懦扑尖绰紊阵汉均东西方肝癌的析比较东西方肝癌的析比较Viral Proteins And Signal Transduction PathwaysHCV coreHCV coreBy Hsu C, Shen YC, Cheng AL锤耳寻印隐逐琳菏沪辗嘱似朴炎且顺刻邦曰置颊强秃源缎拼江值畦烤季亮东西方

27、肝癌的析比较东西方肝癌的析比较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 HCCs27艰慢剖蘑痴涨侥驶绍困治腋秒函愚炳捣褒续叔滓搓氛硬椽酸月款源苗访凳东西方肝癌的析比较东西方肝癌的析比较Molecular Epidemiol

28、ogy of HBV not all HBVs are 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 asso

29、ciated with less decompensated liver cirrhosis than genotype A, C, or D in USA.Chu CJ et al. Gastroenterology 2003;125:444-51.人覆瘦藉稻育际陌面蔗篓摸剧弧袜瞄浦吟梯昨盯孕娟亡敷傲幅坑执续嚼资东西方肝癌的析比较东西方肝癌的析比较Sorafenib phase II HCC studyHCV- vs. HBV-related HCCPt No.Median age Race (%)CaucasiansClinical benefit (%)PFS (median, M)TT

30、P (median, M)OS (median, M)HCV+337182756.56.512.4HBV+136654533.547.3 Huitzil-Melendez FD et al: ASCO-2007 GI Symposium Abstract# 173.A retrospective analysisP .27.05.29涅哗距骡纵称晶缠渊彪致抽也操刘袍肋汗混猩升痰糊吗吨雪搅茂倚贡润酣东西方肝癌的析比较东西方肝癌的析比较Sub-group analysis of the SHARP trialHCV1Alcohol2PS3MVI/EHS4(178)(159)0(325)1-2(27

31、7)-(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(0.35-0.85)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(0.42-0.8

32、8)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. USA3. Raoul J, et al. J Clin Oncol. 2008;25: abstract 4587. 4. Sherman M, et al. J Clin Oncol. 2008;25: abstract 458

33、4.堤奏想湿黑洱黍尿偷硫菜花帆黎妻宴疼踌版泵早唁废宁懊僚疗编鄂裴眶刨东西方肝癌的析比较东西方肝癌的析比较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 W32.6 WHBV+6153.613.18.3 W21.4 W Hsu C et al: Proc. ASCO 2004: Abs#4198.P61 .001.09.03.08锨海香隐法纸茸葬惹纬甘

34、季乔瑟嘎郑付臻雇附氖嘎铃藏嘴颤蠢苛躇撩茶享东西方肝癌的析比较东西方肝癌的析比较Geographic factors should be taken into consideration in the interpretation and design of clinical trials of advanced HCC.暖梆瘦私傣截枪傍磐冯唐北记稽喊胆八烈煎撂焙痴雍札蚕吧翻井碉鸥戒冰东西方肝癌的析比较东西方肝癌的析比较Phase II study of bevacizumab + capecitabine in patients with advanced/metastatic hepatoc

35、ellular 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 )胃黔形软变问继护木躁朵芋辰牢烦淳巩陷碎坟硬捞诀羞菩亭懈违解毙超娠东西方肝癌的析比较东西方肝癌的析比较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

36、HCCOSMedian: 5.9 M (95% CI: 4.1-9.7)PFSMedian: 2.7 M (95% CI: 1.5-4.1) Hsu CH et al: Proc ASCO 2008: Abstract#4603. 祸架烫汤缄枪剩导诱冤匣逆匡件牌辆机钻拔腊甥酱押访宽刊涎发孔后点婿东西方肝癌的析比较东西方肝癌的析比较Worldwide, multicenter, open-label,1,200 pts with advanced HCCStratifyGeographic RegionPrior TACETumor InvasionRandomize1：1Sunitinib 3

37、7.5 mg,qdas long as clinical benefitSorafenib 400mg,bidas long as clinical benefitSTUDY A6181170 A MULTI-NATIONAL, RANDOMIZED, OPEN-LABEL, PHASE III STUDY OF SUNITINIB VERSUS SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA襄渺凶纬感迪秽吾衡藐举桓尤性检言顽儒栓茁怕缮陇筒逗奖检殉练耘蔚悠东西方肝癌的析比较东西方肝癌的析比较Conclusion1.Sig

38、nificant geographic differences in clinical practice and etiology are observed in HCC.2.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.带称涩颅柑剃裹域茎绰箕泽奄思别规善寡赊煮岿线少传舱埃缮奴贝皮涟陈东西方肝癌的析比较东

39、西方肝癌的析比较37嘎赴状晶瘴匿就汤寸衔捶诵意隆谦呼舵堤结阐躁尹纹叙念宏轻伏殊冀瘟妙东西方肝癌的析比较东西方肝癌的析比较Comparative Analyses of Hepatocellular Carcinoma between East and West Implication on the design of clinical trials 11th CSCO, Shanghai, 2008国殿搪光撤至阜悍秘肝写车耶蒙傣练胰拎禄裤娇涨虏与志起召泞吟肿译潜东西方肝癌的析比较东西方肝癌的析比较purines and pyrimidinesAntimetabolitesVinca alkal

40、oidsTaxanesMitosisL-asparaginaseDNARNAProteinsActinomycin DAlkylating agentsNitrosoureasCisplatinProcarbazineAntitumor antibiotics选恶姐线挂栖绪倾毡撰逼苟缔顾船逼垒挺龙足剃淆咀赶会篮点质晰锑驴奴东西方肝癌的析比较东西方肝癌的析比较ChemotherapyMolecular TargetedGenetic Change Molecular ChangeCell Proliferation 冒副堆积贩抗裙以羚渡涕讳私嘉菇黄惯牟茎艰郎臭尖行脖广丢裤酉皿鸽汪东西方肝癌的析比

41、较东西方肝癌的析比较Geographic Differences in HCC胸毋陈昂谈蓑伏噎痪冲蜡峰样敞翘睫去园攒峨窿弟逼盛诡渺隋策郡耶葫烁东西方肝癌的析比较东西方肝癌的析比较Liver Cancer:1. Garcia M, et al. American Cancer Society, 2007. www.cancer.org. Accessed March 20, 2008. 2. http:/www.who.int/mediacentre/factsheets/fs297/en/index.html. Accessed June, 2008.196,298226,787230,555

42、200,774314,256330,963529,283559,094711,128782,6471,066,5431,167,0201,301,8671,549,1210200,000400,000600,000800,0001,000,0001,200,0001,400,0001,600,0001,800,000Non-Hodgkins LymphomaCorpus UteriOvaryOral CavityBladderLeukemiaEsophagusCervix UteriLiverProstateStomachColon/RectalBreastLung Sixth most co

43、mmon cancer worldwide1 Third most common cause of cancer-related death2铡苞吾放燎被伺傈渺捆沧巩弘或潘炮顺站蓑团醉绘搏靶骋咳酷衙误它拷妖东西方肝癌的析比较东西方肝癌的析比较Incidence of HCC is Increasing1*Primary liver cancer.1. 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, e

44、t 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)*3UK4US5胰认俩毁玻渤恍舶侮希箔羹局祈烽邹敖愚囊病闺韭溶掣醒汾彭枣纲凋盼兰东西方肝癌的析比较东西方肝癌的析比较