前列腺癌争议话题讨论总结.ppt

前列腺癌争议话题讨论,1.游离PSA/总PSA比值的意义2.寡转移前列腺癌是否可行前列腺根治术3.前列腺癌间歇内分泌是否可行,前列腺癌的间歇性内分泌治疗是否可行？SWOG9346结果解读,北京大学第一医院泌尿外科北京大学泌尿外科研究所何志嵩,为什么开展间歇性内分泌治疗？,1941年以后内分泌治疗成为晚期前列腺癌的标准治疗内分泌治疗可以改善生存质量内分泌治疗是否可以延长生存期？内分泌治疗有不良反应内分泌治疗应早期开始还是延缓进行？动物试验研究发现中等程度地降低激素水平可以减慢激素依赖性肿瘤细胞的生长并延缓其转变为自主细胞（autonomy）去势可以加速细胞向激素非依赖性自主细胞的转化是否可以周期性进行？,间歇性内分泌治疗的历史,1985年Vahlensiecketal报告比较间歇性与连续性应用雌醇氮芥治疗前列腺癌的结果UrolRes19851986年Klotzetal报告间歇性应用乙烯雌酚治疗20例前列腺癌患者Cancer19861995年Goldenbergetal报告间歇性应用CAB治疗43例患者Urology1995,间歇性内分泌治疗的目的,延长内分泌治疗的时间，进而达到延长生存期的目的减少内分泌治疗的副作用减少治疗费用,间歇性内分泌治疗的理论基础,克隆选择学说适应学说突变学说多肽生长因子及其受体的作用,延长内分泌治疗时间？,延长内分泌治疗时间？,AkakuraK,etal.Cancer1993，21:2782.,延长内分泌治疗时间？,LNCap肿瘤发展到AI的时间，IHT组用77天，而CHT组用27天去势后，IHT组的血清PSA水平在70天时只有75%高于去势前，而CHT组则在28天时均高于去势前SatoN,etal.SteroidBiochemMolecBiol1996,58:139.,68例患者前瞻性随机化期临床研究3年疾病进展率间歇组显著低于持续组(P0.01).6.7(4.6)%37.5(10.8)%在20例明显骨转移患者两组3年疾病进展率上无差异(P=0.3).,WaltregnyD,BocaP,NicolasHetal.Urol2002;168(Suppl):A701,欧洲43个研究中心，193名患者随机分组:IHT(n=97)orCHT(n=96)T2-4N1-3M0(n=37),T2-4N0-3M1(n=156)平均随访66个月总生存期相近,J.F.Langenhuijsen,etal:EuropeanUrologySupplements,2008;7(3):205,延长内分泌治疗时间？,尚无临床试验研究证实期待SWOG研究结果,减少内分泌治疗的副作用？,内分泌治疗的副作用,潮热乏力性欲下降体重增加肌肉无力贫血骨质疏松,减少内分泌治疗的副作用？,21例IAT，停药3个月后100%潮热消失93%性欲提高90%恢复勃起功能80%感到有精神13%体重恢复HiganoetalUrology1996,改善性功能,Calaisetal.reportedaphaseIIIstudyon636patientswithT34M0andM1disease,showinganimprovementinsexualactivityontheintermittentarm.,CalaisF,BonoA,WhelanPetal：.EurUrol2002;41；(Suppl):A531,减少骨质疏松,IHT组平均骨密度显著高于CHT组(0.920g/cm2vs.0.84g/cm2,p0.05)After9months,themeanBMDinthesepatientshaddecreasedby4.5%atthelumbarspine(P=0.0007)andby2.5%atthehip(P=0.00013).Afteramedianoff-treatmentperiodof7.9months,themeanchangeinBMDofthelumbarspineandhiprelativetothepost-ASvalueswas1.5%(P=0.06)and0.01%(P=0.09),respectively.,Y.Takezawa,etal:Urology,Volume70,Issue3,Supplement1,September2007,Page306,改善生活质量,49患者(26withT3N0M0,8withT2-T3N1M0,2withT4N0M0,and13withT2-T3N0M1)平均随访136.5周comparedwiththoseintheon-treatmentperiod.QOL评分中的potency(11.4versus2.4)social/familywell-being(20.3versus16.1),NAOHIDESATO,etal:UROLOGY64(2),2004:341-45,降低费用？,是的！？,是否与药物去势的方法有关？,单纯药物去势LHRH-A抗雄激素制剂？雌激素最大雄激素阻断,适应症是什么？,标准内分泌治疗的适应症新辅助治疗？辅助治疗？,如何进行？,停止治疗的指征,PSA0.2ng/mlPSA4ng/mlPSA升至10-20ng/mlPSA升至20ng/mlPSA升至治疗前的1/2对于PSA下降80%而未达到正常值者,当PSA上升了最低值的20,间歇内分泌治疗(IHT)推荐：适应症：局限不适应手术；T3-T4；切缘阳性；根治术或放疗后复发IHT的治疗模式：多用MAB，也可单用LHRHa停药标准：PSA0.2ng/ml，维持3-6月重新开始治疗的标准：PSA4ng/ml,CUA前列腺癌诊断治疗指南2011,IADisbasedonintermittentcastration.Thus,onlydrugsleadingtocastrationshouldbeconsideredforuseinIAD.ItisunclearifanLHRHagonistmaybeusedalone,aspublishedexperiencesarebasedonCAB.AnLHRHantagonistmightbeavalidalternative,providedclearresultsareobtainedfromrandomisedtrials.Theinitial(induction)cyclemustlastbetween6and9months,otherwisetestosteronerecoveryisunlikely.,Inconclusion,IADiscurrentlywidelyofferedtopatientswithPCainvariousclinicalsettings,anditsstatusshouldnolongerberegardedasinvestigational(LE:2).,存在什么问题？,是否回加速疾病进展？PSA是否是合适的判断指标？缺乏大样本的随机对照研究,间歇性内分泌治疗临床研究,Overall,eightrandomisedtrialsareunderway,onlysomeofwhichhavepublishedfindings.Mostofthetrialsincludedamixedpatientpopulation,i.e.bothlocallyadvancedandmetastaticdisease.Onlythreetrialsincludedonlymetastaticpatients,andtwotrialsonlyrelapsingpatients.Thetwolargesttrialseachcontainedmorethan1,300patients,withonetrialfocusedonlyonmetastaticpatients(SWOG9346)andtheotheronrelapsingpatientsafterradiotherapy(SWOGJPR7),间歇雄激素去除与持续雄激素去除治疗激素敏感性转移性前列腺癌:国际III期临床研究SWOG9346(INT-0162)结果,HussainM,TangenCM,HiganoCS,CrawfordED,LiuG,WildingG,PrescottS,AkdasA,SmallEJ,DawsonNA,DonnellyBJ,VennerP,VaishampayanUN,SchellhammerPF,QuinnDI,RaghavanD,VogelzangNJ,ThompsonJr,IMUniv.ofMichigan,AnnArbor,MI;SWOGStatisticalCenter,Seattle,WA;FredHutchinsonCancerResearchCenter,Seattle,WA;UniversityofColoradoHealthScienceCenter,Aurora,CO;UniversityofWisconsinCarboneCancerCenter,Madison,WI;St.JamesUniversityHopsital,Leeds,UK;MarmaraUniversity,Istanbul,Turkey;UniversityofCalifornia,SanFrancisco,SanFrancisco,CA;GeorgetownUniversityHospitalLombardiComprehensiveCancerCenter,Washington,DC;ProstateCancerInstitute,Calgary,Alberta,Canada,Calgary,AB;CrossCancerInstitute,Edmonton,AB;KarmanosCancerInstitute,WayneStateUniversity,Detroit,MI;UrologyofVirginia,Norfolk,VA;UniversityofSouthernCaliforniaNorrisComprehensiveCancerCenter,LosAngeles,CA;LevineCancerInstitute,CarolinasHealthCareSystem,CharlotteNC;USOncologyResearch,LLC,McKessonSpecialtyHealth,TheWoodlands,TX,andComprehensiveCancerCentersofNevada,LasVegas,NV;UniversityofTexasHealthScienceCenteratSanAntonio,SanAntonio,TX,2012ASCO,(FundedbytheNationalCancerInstituteandothers;ClinicalTnumber,NCT00002651.),NEnglJMed2013;368:1314-25.,Thestudywasdesignedin1993bythefirstauthorandbytheleadersofthegenitourinarycancerandquality-of-lifecommitteesoftheSouthwestOncologyGroup(SWOG).PatientswereenrolledbytheSWOG,theEasternCooperativeOncologyGroup(ECOG),theCancerandLeukemiaGroupB(CALGB),theNationalCancerInstituteofCanadaClinicalTrialsGroup(NCIC-CTG),andtheEORTC.Patientswhohadreceivedpriorneoadjuvantoradjuvantandrogen-deprivationtherapywereeligibleiftheyhadreceivedthetherapyfor4monthsorless.Patientswhohadreceivedpriorfinasteridetherapyforprostatecancerwereeligibleiftheyhadreceivedthedrugfor9monthsorless.,PRESENTEDBY:MahaHussain,MD,FACP,SWOG9346(INT-0162):研究目的,主要间歇性内分泌治疗的生存期isNotInferiorto持续性内分泌治疗生活质量*:比较三项治疗特异性症状（勃起功能、性欲、体能）次要-MoregeneralQOLmeasures-PSAdynamicsbetweenarms,andcorrelationswithotherendpoints,*Moinpouret-al,Abstract#4571describesresultsforQOL,2012ASCO,PRESENTEDBY:MahaHussain,MD,FACP,主要入选标准,新诊断的转移性前列腺癌.开始内分泌治疗前PSA5ng/mlPriorneoadjuvantoradjuvanthormonetherapyorpriorfinasteridewasallowedwithsomerestrictions.SWOGperformancestatusof0-2.SignedIRBapprovedinformedconsent.,2012ASCO,亚组分层:,体质状态评分:0-1vs.2疾病严重程度:轻微:脊柱、骨盆24(24):3984-90,IAD组:治疗流程,当PSA上升至20ng/ml(如初始治疗时PSA20ng/ml，则当PSA上升至初始治疗水平)or出现症状时：恢复内分泌治疗如果恢复内分泌治疗7个月后的PSA水平再次满足正常标准，患者开始进入另一个间歇期.如果在在第6和第7月时PSA均大于4ng/ml，则患者转为接受出现内分泌治疗.,PRESENTEDBY:MahaHussain,MD,FACP,2012ASCO,PRESENTEDBY:MahaHussain,MD,FACP,统计学方法,主要目的:随机后生存期假设:“IADisNOTinferiortoCAD”Designspecifications:SurvivalwithIADisnotinferiorifthe95%confidenceintervalforthehazardratio(IADvs.CAD)excludes1.2,=0.05,power=90%,adjustingforstratificationfactorsinproportionalhazardsmodel.假设:随机后中位生存期CAD=3years:样本量:1500eligible,randomizedpatients计划:6.25yrs.+2additionalyrs.offollow-up.,2012ASCO,SWOG9346,启动:5/15/1995结束:9/1/2008,CAD765eligiblepatients,PRESENTEDBY:MahaHussain,MD,FACP,2012ASCO,S9346StudyInformationN=3040,PRESENTEDBY:MahaHussain,MD,FACP,Black,2012ASCO,PRESENTEDBY:MahaHussain,MD,FACP,随机时（步骤二）患者特征,2012ASCO,AdverseEventswithaGrade4Reported*,*Treatmentattribution:possible,probable,ordefinite,NoGrade5reported,PRESENTEDBY:MahaHussain,MD,FACP,2012ASCO,HR:1.0995%CI(0.95,1.24),7yrSurvival,42%38%,AtriskIntermittent26747Continuous30153,OverallSurvival:IntermittentTherapyisInferiorComparedtoContinuousTherapy,PRESENTEDBY:MahaHussain,MD,FACP,2012ASCO,PRESENTEDBY:MahaHussain,MD,FACP,EvaluatingHomogeneityofTreatmentEffectAcrossSubsetsofPatients,favorsfavorsintermittentcontinuous,1.0,1.2,p=0.08*,p=0.26*,p=0.94*,Extensivedisease,Minimaldisease,Bonepain,Nobonepain,PSAatRandomization0.2ng/ml,PSAatRandomization0.3-4.0ng/ml,Overall,*testoffactorxtreatmentinteraction,2012ASCO,HR:0.9695%CI(0.80,1.16),7YearSurvival,33%,33%,AtriskIntermittent11911Continuous10622,OverallSurvivalforPatientswithExtensiveDiseasebyTreatmentArm,PRESENTEDBY:MahaHussain,MD,FACP,2012ASCO,7yr.Survival,HR:1.23,95%CI(1.02,1.49)p=0.034,50%42%,AtriskIntermittent14335Continuous19430,OverallSurvivalforPatientswithMinimalDiseasebyTreatmentArm,PRESENTEDBY:MahaHussain,MD,FACP,2012ASCO,结论,根据SWOG9346研究预设的标准，IAD的生存期wasinferiortoCADHR:1.09,95%CI(0.95,1.24).因此CAD仍应为标准治疗.Inasecondaryanalysis:对于转移程度严重的患者，IADwasnot-inferiortoCADHR:0.9695%CI(0.80,1.16).对于转移程度轻微的患者，IADwasinferior，统计学有显著性差异HR:1.23,95%CI(1.02,1.49),p=0.034.Theseobservationss