《肝癌规范化治疗》ppt.ppt

肝癌,HCC数据,HCC占肝脏原发肿瘤首位:90%1男性肿瘤第五位,女性肿瘤第九位2。恶性肿瘤死亡率第三位3是肝硬化患者死亡的主要原因4年新发病例(560,000)年死亡病例(550,000)5,1.PerzJF,etal.JHepatol.2006;45:529-38.2.JelicS.AnnOncol.2009;Suppl4:iv41-5.3.GarciaM,etal.AmericanCancerSociety.2007.www.cancer.org.AccessedJan2010.4.LlovetJ,JHepatol.2000;33:423-9.5.MarreroCR,MarreroJA.ArchMedRes.2007;38:612-20.,r,HCC流行病学,HCC发病率不同的地域性时间相关性(不同地域有不同的时间相关性)种族差异性性别和社会地位差异性,致癌机理:-无正常肝脏-继发于慢性肝炎,El-SeragHB.ClinLiverDis.2001;5:87-107.,r,El-SeragHB,RudolphKL.Gastro.2007;132:2557-76.,HCC地域死亡率(每100,000人),Annualmortalityperregion:Europe:54,000USA:19,000ChinaKoreaJapan:390,000,r,HCC高危因素和发病率,80%HCC与HBV或HCV相关,LlovetJM,etal.Lancet.2003;362:1907-7.Pisanietal.CancerEpidemiolBiomarkersPrev.1997;6:387-400.,r,肝癌风险合并超重肥胖与正常体重人群对比荟萃分析,回顾性研究:173,463糖尿病病例对比650,620非糖尿病病例.患者无因急性或慢性肝脏疾病近一年内住院治疗,8.,824,263住院治疗美国退伍军人(19851990):肝细胞肝癌:317diabetes(2.39x105person-years)515controls(0.87x105person-years),肝细胞高位因素:糖尿病,肝细胞肝癌:男性多于女性,DatabaseITA.LI.CA,2008.,r,肝细胞肝癌:人种差别(USA),遗传多态性:免疫应答(i.e.HCV)炎症反应酒精代谢,环境致癌胰岛素抗药性治疗反应(IFN),高危因素,ThorgeirssonSS,etal.Hepatology.2006;43(2Suppl1):S145-50.AvilaMA,etal.Oncogene.2006;25:3866-84.,r,2+veforarterialhypervascularizationamong:AngiographyCTMRIDopplerUSor1+veplusAFP400ng/mL,BruixJ,etal.JHepatol.2001;35:421-30.,r,非转移早期肝癌的诊断标准,肝功能分期Child-Pugh分级肿瘤大小分期TNMVauthey(改良的TNM)Izumi(改良的TNM)JS(日本分期)联合分期(肝功能和肿瘤)OkudaCanceroftheLiverItalianProgram(CLIP)ChineseUniversityPrognosticIndex(CUPI)Japaneseintegratedstagingscore(JIS)BarcelonaClinicLiverCancer(BCLC),r,HCC分期,KudoM,etal.JGastroenterol.2003;38:207-15;WildiS,etal.BrJSurg.2004;91:400-8;DohmenK,etal.JGastroenterolHepatol.2004;19:1227-32;MarreroJA,etal.Hepatology.2005;41:707-16.,HCC不同分期包含变量指标(1),肿瘤大小病变数量血管侵犯病变累及程度远处转移肝硬化Child-Pugh分级实验室检查其他(门静脉血栓,AFP,腹水等.),r,KudoM,etal.JGastroenterol.2003;38:207-15;WildiS,etal.BrJSurg.2004;91:400-8;DohmenK,etal.JGastroenterolHepatol.2004;19:1227-32;MarreroJA,etal.Hepatology.2005;41:707-16.,r,HCC不同分期包含变量指标(2),WildiS,etal.BrJSurg.2004;91:400-8.,日本分期(JS),UICC2002TNM分期,r,WildiS,etal.BrJSurg.2004;91:400-8.,T1期评定中的问题(1),定义太宽：符合肿瘤大小1cm肝功能分级Child-PughA(5年无治疗预期生存期50%)，而一个大小11cm肿瘤,肝功能分级Child-PughB(5年无治疗预期生存期5%)两者均属同期肿瘤。,r,TNMstageaccordingtoUICC2002,WildiS,etal.BrJSurg.2004;91:400-8.,Tumorsingle2cmwithoutvascularinvasionEvidenceofStageScore3factorsT1I02factorsT2II11factorT3III20factorsT4orT1T3+N1/M1IV3Liverfunction:Child-PughclassA0B1C2TOTALrangescores:05,JapaneseIntegratedStaging(JIS)systemTNMstageofCancerStudyGroupJapan,r,Child-Pugh评分,PughRN,etal.BrJSurg.1973;60:646-9.,r,HCCChild-Pugh分期与生存,r,CLIP评分系统,总CLIP评分范围06,CLIPInvestigators.Hepatology.1998;28:751-5.,r,早期HCC在多种分期中的判定,早期肝癌诊断在不同分期标准中均不够准确TNM分期(独立病灶,5cm,未限定肝功能状态)Child-Pugh评分(未限定肿瘤大小)OKUDA和CLIP(涉及瘤负荷占肝脏体积50%)JIS分期较好;定义了较早期肝癌(JIS评分=0)较准确判定早期肝细胞肝癌(JIS评分=1）包括了门静脉血栓,或Child-PughB或10cm的大肝癌),最好的确定早期肝癌分期为BCLC分期标准,r,KudoM,etal.JGastroenterol.2003;38:207-15;LlovetJM,etal.SeminLiverDis.1999;19:329-38.,BCLC分期,预后和治疗分配体系,*GriecoA,etal.Gut.2005;54:411-18;LlovetJM,etal.SeminLiverDis.1999;19:329-38.,r,PEI/RFA,Sorafenib,Stage0PST0,Child-PughA,Veryearlystage(0)1HCC2,ChildPughC,Veryearlystage,Single2,Child-PughC,Veryearlystage(0)Single2cmcarcinomainsitu,Earlystage(A)13nodules3cm,PS0,Intermediatestage(B)Multinodular,PS0,Advancedstage(C)Portalinvasion,N1,M1,PS12,Endstage(D),Single,3nodules3cm,Portalpressure/bilirubin,Increased,Associateddiseases,Normal,No,Yes,Resection,Livertransplantation(CLT/LDLT),PEI/RFA,Chemoembolization,Sorafenib,Curativetreatments,Randomizedcontrolledtrials,RFA=radiofrequencyablation;PEI=percutaneousethanolinjection.,LlovetJM,etal.JNatlCancerInst.2008;100:698-711.,r,NCCNGuidelines(2009),NCCNClinicalPracticeGuidelinesinOncology.HepatobiliaryCancer.V2.2009;Availableat:www.nccn.org.AccessedFebruary2010.,r,JapanSocietyofHepatology:consensus-basedtreatmentalgorithmforHCC,KudoM.Oncology.2009;75Suppl1:1-12.,r,ExtrahepaticmetastasisMainportalveintumorthrombus,Resectable,Sorafeniborsystemictherapytrial,Resection/RFA(for3cmHCC),Solitarytumor5cm3tumors3cmNovenousinvasion,Child-PughAChild-PughBChild-PughCChild-PughA/BChild-PughC,Transplantation,TACE,Supportivecare,Localablation,HCC,ConfinedtotheliverMainportalveinpatent,APASLworkingcommitteemeetingconsensusontreatmentguidelinesforHCC,Tumor5cm3tumorsInvasionofhepatic/portalveinbranches,Yes,No,ChildPughA/BChild-PughC,OmataMetal.,APASLworkingcommitteemeetingconsensusonHCC,APASLFebruary1316,2009,HongKong,r,HBVHCV酒精黄曲霉毒素B1,损伤,干细胞增殖停止星形细胞活化,慢性肝病,Livercirrhosis,Abnormallivernodules,Extensivescarring(collagen),染色体不稳定,染色体重度不稳定和P53缺失,Hepatocellularcarcinoma,幼稚细胞结节,Hyperplasticnodule,分化好的,中等分化的,分化差的,增殖,坏死,FaraziPA,DePinhoRA.NatRevCancer.2006;6:674-87.,肝细胞肝癌的组织病理学和分子病理学特征,r,肝硬化,广泛瘢痕形成,肝脏结节形成,结节增生,肝细胞肝癌,肝细胞肝癌的发病机制与多个信号传导通路相关,细胞膜,c-MYC,c-JUN,Wnt受体,BcL-XL,BAD,ERK1/2,MEK1/2,-catenin,GSK3,GBP,DSH,HBx,Akt,mTOR,Raf,PKC,NF-B,Ras,NF-B,PLC,SHC,GrB2,GEF,PI3K,PTEN,p53,生存l转录和翻译,-catenin,HBx,RTK:FGFREGFRIGF-IRc-MET,受体r,AdaptedfromAvilaMA,etal.Oncogene.2006;25:3866-84.,r,肝细胞肝癌的分子学发病机制,肝细胞肝癌的发病机制与多个信号传导通路相关肝细胞恶变是基于炎症、细胞再生、细胞增生、肝硬化、遗传、后天因素等肝细胞肝癌多伴有细胞信号通路失调，主要包括：1,2血管生成信号Ras/Raf/MEK/ERKPI3K/Akt/mTORWnt/-catenin,分子治疗的主要靶点,1.ThorgeirssonS,etal.Hepatology.2006;43:S145-50.2.AvilaMA,etal.Oncogene.2006;25:3866-84.,r,肝细胞肝癌靶向治疗:临床研究,肝细胞肝癌临床研究全面展开Sorafenib的有效性，引发靶向治疗临床研究主要在早期和晚期患者临床研究，一线治疗、二线治疗及辅助治疗方面的研究,LlovetJM,BruixJ.JClinOncol.2009;27:833-35.,r,AdaptedfromTanakaS,AriiS.CancerSci.2009;100:1-8.,临床开发:分子靶向药物和其主要靶点,r,III期临床研究:分子靶向药物和其主要靶点,Sorafenibtargetsbothtumor-cellproliferationandangiogenesisinvitro,KIT/Flt-3/RET,Endothelialcellorpericyte,VEGFR-2,PDGFR-,Tumorcell,WilhelmSM,etal.CancerRes.2004;64:7099-109.,Ras,r,Primaryendpoints:OS,TTSPSecondaryendpoints:TTP,DCR,safety,PhaseIIISHARPandAsiaPacificstudies,EligibilityAdvancedHCC,ECOGPS02,Child-PughA,nopriorsystemictherapyStratificationMVSand/orEHS,ECOGPS(0vs12),geographicregion,RANDOMIZE1:1,SHARP1,AsiaPacific2,RANDOMIZE2:1,Sorafenib400mgbid,Placebo,Sorafenib400mgbid,Placebo,Endpoints:OS,TTSP,TTP,DCR,safety(noprimaryendpointdefined),n=299,n=303,n=150,n=76,1.LlovetJM,etal.NEnglJMed2008;359:378-90.2.ChengA-L,etal.LancetOncol2009;10:25-34.,r,Sorafenibconsistentlyincreasedoverallsurvivalindifferentglobalpatientpopulations,HR=hazardratio;OS=overallsurvival;SHARP=SorafenibHepatocellularCarcinomaAssessmentRandomizedProtocol.,LlovetJMetal.NEnglJMed.2008;359:378-90.ChengA-L,etal.LancetOncol.2009;10:25-34.,Survivalprobability,1.00,0.75,0.50,0.25,Months,0,4,6,8,10,12,14,16,2,0.00,Sorafenib(n=299)MedianOS:10.7months,Placebo(n=303)MedianOS:7.9months,18,HR=0.69,Survivalprobability,1.00,0.75,0.50,0.25,Months,0,4,8,12,22,0.00,Sorafenib(n=150)MedianOS:6.5months,Placebo(n=76)MedianOS:4.2months,2,6,10,14,16,18,20,HR=0.68,SHARP1,AsiaPacific2,r,AsiaPacifictrial1vsSHARP2:baselinepatientcharacteristics,1.ChengA,etal.JClinOncol.2008;26.Abstract4509.UpdatedfromoralpresentationatASCO;Chicago,IL;June2008.2.LlovetJM,etal.NEnglJMed.2008;359:378-90.,r,SHARP:sorafenibprolongsOSby44%andTTPby74%inpatientswithadvancedHCC,LlovetJM,etal.NEnglJMed.2008;359:378-90.,1.00,Survivalprobability,01234567891011121314151617,Sorafenib(n=299)=10.7monthsPlacebo(n=303)=7.9months,Timefromrandomization(months),Probabilityofradiologicprogression,0123456789101112,Sorafenib(n=299)=5.5monthsPlacebo(n=303)=2.8months,Timefromrandomization(months),1.00,0.75,0.50,0.25,0,HR=0.69(95%CI:0.550.87)p0.001,0.75,0.50,0.25,0,HR=0.58(95%CI:0.450.74)p0.001,Overallsurvival,Timetoprogression(independentcentralreview),r,SorafenibprolongsOSby47%andTTPby74%inAsiaPacificpatientswithadvancedHCC,ChengA-L,etal.LancetOncol.2009;10:25-34.,Overallsurvival,Timetoprogression,SorafenibMedian:6.5months(95%CI:5.67.6)PlaceboMedian:4.2months(95%CI:3.75.5,SorafenibMedian:2.8months(95%CI:2.63.6)PlaceboMedian:1.4months(95%CI:1.31.5HR(S/P):0.57(95%CI:0.420.79)p0.001,Sorafenib,Sorafenib,r,AsiaPacificstudy1vsSHARP2:efficacysimilarinbothpatientpopulations,1.ChengA,etal.JClinOncol.2008;26.Abstract4509.UpdatedfromoralpresentationatASCO;Chicago,IL;June2008.2.LlovetJM,etal.NEnglJMed.2008;359:378-90.3.LlovetJMetal.Hepatology.2008;48:1312-27.,r,Sorafenib在晚期肝细胞肝癌为标准治疗,Sorafenib是第一个也是迄今为止唯一延长肝细胞肝癌患者生存的药物在西方和东方不同人种、不同病因中得到验证疗效和安全性得到验证早期肝细胞肝癌的研究在进行中Sorafenib在肝细胞肝癌患者的安全性是在可控范围内的不良反应多为中度可预料和可管理的,LlovetJMetal.NEnglJMed.2008;359:378-90.ChengA-L,etal.LancetOncol.2009;10:25-34.,r,不同靶向药物治疗在实体瘤带来的获益,1.LlovetetalNEnglJMed.2008;359:378-90.2.HurwitzetalNEnglJMed.2004;350:2335-42.3.JonkersetalNEngJMed2007.4.SandleretalNEnglJMed.2006;355:2542-50.5.ShepherdetalNEnglJMed.2005Jul14;353:123-32.6.SlamonetalNEnglJMed.2001;344:783-92.7.MilleretalNEnglJMed.2007;357:2666-76.8.EscudierB,etal.NEnglJMed.2007;356:125-34.9.EscudierB,etal.JClinOncol.2009;27:3312-18.TableadaptedfromLlovetandBruix,Hepatology2008.,r,抗血管生成药物耐药方式,适应性(逃逸)耐药,原发无效,BergersG,HanahanD.NatRevCancer.2008;8:592-603.,r,诱导预血管生成因子替代重建新生血管生成,BergersG,HanahanD.NatRevCancer.2008;8:592-603.,r,BergersG,HanahanD.NatRevCancer.2008;8:592-603.,募集骨髓衍生细胞促使新生血管生成,r,BergersG,HanahanD.NatRevCancer.2008;8:592-603.,肿瘤血管外周防御细胞增加,r,BergersG,HanahanD.NatRevCancer.2008;8:592-603.,营养缺乏和缺氧至肿瘤细胞侵袭增加,r,抗血管生成药物耐药方式,适应性(逃逸)耐药,原发无效,BergersG,HanahanD.NatRevCancer.2008;8:592-603.,r,EACH研究:试验设计,大型、开放、随机对照、多中心的期临床试验，包括中国大陆、台湾，韩国和泰国等38家中心参与,ArmA(FOLFOX4):-OXA85mg/m2iv.h0h2Day1-LV200mg/m2iv.h0h2Day1,2-5FU400mg/m2iv.bolusDay1,2then600mg/m2over22hoursinDay19:143-50.,r,美国肝脏病研究协会（AASLD）肝细胞肝癌临床研究指南,r,LlovetJM,etal.JNatlCancerInst.2008;100:698-711.,贝伐单抗联合厄洛替尼,II期临床,开放,单臂,单中心(MDACC)入选条件进展期HCC既往接受过一线治疗ChildPughABECOG评分012治疗bevacizumab10mg/kg每2周一次erlotinib150mg1次/日主要终点PFS16(16无进展期病例),ThomasMB,etal.JClinOncol.2009;27:843-50.,r,ThomasMB,etal.JClinOncol.2009;27:843-50.,贝伐单抗联合厄洛替尼:结果,r,“II期单臂临床研究结果不能客观反应细胞生长抑制剂疗效”,FreidlinB,SimonR.JClinOncol.2005;23:5094-8.,r,随机对比II期临床研究,60patients,Bevacizumab+erlotinib,60patients,Sorafenib,PatientswithadvancedHCC;noprevioussystemictreatment;ChildPughclassA;ECOGPS02,PrimaryendpointTTPSecondaryendpointsPFSResponserateOverallsurvivalSafetyandtolerability,Studystartdate:March2009Estimatedfinalanalysis:March2011,RANDOMIZATION,r,http:/clinicaltrials.gov/ct2/show/NCT00881751.,III期临床研究:分子靶向药物和其主要靶点,肝细胞肝癌III期临床研究,晚期HCC方案A:Xvssorafenib一线治疗方案B:X+sorafenibvssorafenib一线治疗方案C:Xvs最佳支持治疗(BSC)二线治疗(Sorafenib失败)其他早期肝癌中期肝癌,r,600patients,Sorafenib,600patients,Sunitinibmalate,http:/clinicaltrials.gov/ct2/show/NCT00699374.,PatientswithadvancedHCC;noprevioussystemictreatment;ChildPughclassA;ECOGPS0-1,PrimaryendpointOverallsurvivalSecondaryendpointsPFSTTPSafetyHealthstatus,Studystartdate:July2008Estimatedfinalanalysis:July2012,RANDOMIZATION,方案A:Xvssorafenib一线治疗,r,525patients,Sorafenib,525patients,Brivanib,PatientswithadvancedHCC;noprevioustreatment;ChildPughclassA;ECOGPS0-1,PrimaryendpointOverallsurvivalSecondaryendpointsTTPObjectiveresponseSafetyPKTTSPQoL,Studystartdate:May2009Estimatedfinalanalysis:February2013,+brivanibplacebo,+sorafenibplacebo,RANDOMIZATION,方案A:Xvssorafenib一线治疗,http:/clinicaltrials.gov/ct2/show/NCT00858871.,r,450patients,Sorafenib,450patients,ABT-869,PatientswithadvancedHCC;noprevioustreatment;ChildPughclassA;ECOGPS0-1,PrimaryendpointOverallsurvivalSecondaryendpointsTTPObjectiveresponse,Studystartdate:October2009Estimatedfinalanalysis:February2012,RANDOMIZATION,方案A:Xvssorafenib一线治疗,http:/clinicaltrials.gov/ct2/show/NCT01009593.,r,350patients,Sorafenib+placebo,350patients,Sorafenib+erlotinib,PatientswithadvancedHCC;noprevioustreatment;ChildPughclassA;ECOGPS0-1,PrimaryendpointOverallsurvivalSecondaryendpointsTTPObjectiveresponseSafetyQoL,Studystartdate:May2009Estimatedfinalanalysis:July2011,RANDOMIZATION,方案B：X+sorafenibvssorafenib一线治疗,http:/clinicaltrials.gov/ct2/show/NCT00901901.,r,170patients,Brivanib+BSC,170patients,Placebo+BSC,PatientswithadvancedHCC;sorafenibfailure(orintolerance);ChildPughclassAorB7;ECOGPS02,PrimaryendpointOverallsurvivalSecondaryendpointsTTPObjectiveresponseDiseasecontrolrateSafety,Studystartdate:February2009Estimatedfinalanalysis:January2011,RANDOMIZATION,SettingC:Xvsplacebo/BSCaftersorafenibfailure,http:/clinicaltrials.gov/ct2/show/NCT00825955.,r,RANDOMIZATION,531patients,Everolimus+BSC,Placebo+BSC,PatientswithadvancedHCC;sorafenibfailure(orintolerance)ChildPughclassA;ECOGPS02,PrimaryendpointOverallsurvivalSecondaryendpointsTTPDiseasecontrolrateChangeinECOGPSChangeinQoLSafety,Studystartdate:April2010Estimatedfinalanalysis:November2012,方案C:Xvs最佳支持治疗(BSC)二线治疗(Sorafenib失败),http:/clinicaltrials.gov/ct2/show/NCT01035229.,r,总结,肝细胞肝癌在亚洲人群高发分期多样化，BCLC分期最为准确肝细胞肝癌中常常伴有细胞信号传导通路异常血管生成信号Ras/Raf/MEK/ERKPI3K/Akt/mTORWnt/-cateninSorafenib是目前唯一证实在晚期肝细胞肝癌患者生存的靶向治疗药物1适应性耐药或原发耐药是未来研究重点一些新靶向药物在III期临床研究中，期待结果,r,1.LlovetJMetal.NEnglJMed2008;359:37890,