9-前列腺癌争议话题讨论

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UrolRes19851986年Klotzetal报告间歇性应用乙烯雌酚治疗20例前列腺癌患者Cancer19861995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.reportedaphaseIIIstudyon636patientswithT3–4M0andM1disease,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/mlPSA4.0ng/mlPSA下降至治疗前的90%在最低点维持3~6个月各家报道极不统一停止治疗的指征ThemedianPSAnadirwas0.1,1.1,0.8,2.0and3.3ng/mLafterthefirst,second,third,fourth,andfifthcycles,respectively(Fig.1).(AmJClinOncol2003;26:e119–e123)恢复治疗的指征PSA4ng/mlPSA升至10-20ng/mlPSA升至20ng/mlPSA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：PSA≤0.2ng/ml，维持3-6月重新开始治疗的标准：PSA＞4ng/mlCUA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,TX2012ASCO(FundedbytheNationalCancerInstituteandothers;ClinicalTrials.govnumber,NCT00002651.)NEnglJMed2013;368:1314-25.Thestudywasdesignedin1993bythefirstauthorandbytheleadersofthegenitourinarycancerandquality-of-lifecommitteesoftheSouthwestOncologyGroup(SWOG).Patientswereenr