卵巢癌化疗进展ppt课件

卵巢癌化疗进展,1,卵巢癌化疗新进展Thestateoftheartinchemotherapyforovariancancers,卵巢癌化疗进展,2,女性生殖道肿瘤:全世界统计1,Ferlayetal.GLOBOCAN2000IARC,WHO2001(www.dep.iarc.fr),卵巢癌化疗进展,3,卵巢癌化疗进展,4,Women,发病率32%Breast12%Lung2001/,2004.,卵巢癌可认为是一种慢性疾病,早期卵巢癌:FIGOIandII,全面的分期剖腹探查术经腹全子宫/双侧卵巢输卵管切除(TAH/BSO)大网膜切除淋巴结切除术（dissection）腹膜和膈膜活检（biopsies）细胞学检查高危vs低危早期卵巢癌,S,早期卵巢癌,MedicalOncology:Atextbook,低危,高危,(510%复发率),(3040%复发率),StageIAorIB,StageIC,Grade1(or2),Grade3Clearcellcancer,高危早期卵巢癌,YoungSGO20032.YoungRC.SeminOncol27(3):8-10.,20003.ICON-1,EORTC-ACTION:JNatnlCanInst.Vol.95,No.2,January15,20034.Manneletal.GOG-175protocol,,GOG1571,2,辅助化疗的随机临床试验:3vs6疗程紫杉醇+卡铂,结果6个疗程进展危险性降低了33%生存率无改善,Action淋巴结阴性;镜下腹腔种植B腹腔种植灶2cm;淋巴结阴性C腹腔种植灶2cm和/或阳性腹膜后淋巴结或腹股沟IV远处转移,MedicalOncology:Atextbook,准确全面分期依据手术探查和病理组织学、细胞学检查根据腹腔内转移灶的大小对III期再分为IIIa、IIIb、IIIc腹膜后淋巴结转移影响分期肝表面和肝实质转移分属III期和IV期,StageI:局限于卵巢StageII:局限于盆腔StageIII:局限于腹腔StageIV:远处转移,卵巢癌化疗进展,16,晚期卵巢癌：关键临床实验1,GOG1111andOV-102Cisplatin+paclitaxelvscisplatin+cyclophosphamideImprovedsurvivalandprogression-freesurvivalwithcisplatin+paclitaxelGOG1323Cisplatinvspaclitaxelvscisplatin+paclitaxelNostatistaicaldifferenceinoverallsurvivalICON-34Carboplatin+paclitaxelvscarboplatinorCAP(cyclophosphamide+doxorubicin+cisplatin)NostatisticaldifferenceinsurvivalGOG1585;AGO-OVAR6Carboplatin+paclitaxelpreferredcombinationovercisplatin+paclitaxel,1.McGuireWPetal.NEnglJMed1996,334:1-84.ICONGroup.Lancet2002,360:505-5152.PiccartMetal.IntJGynCancer2003,13(suppl2),144-1485.OzolsRFetal.JClinOncol2003;21:3194-32003.MuggiaFetal.JClinOncol2000,18:106-1156.duBoisetal.JNatlCancerInst.2003Sep3;95(17):1320-9,晚期卵巢癌:关键临床实验2,ICON-5-GOG182（2006）Carboplatin+paclitaxelvsGemcitabintripletvsDoxilTripletvsTopotecanduble+TPvsGemcitabindublet+TP(cyclophosphamide+doxorubicin+cisplatin)NostatisticaldifferenceinsurvivalGOG172（2006）cisplatin+paclitaxeliv/ippreferredcombinationovercisplatin+paclitaxelivJGOG（2009）Carboplatin（d1）+paclitaxel80mgweeklyperferredCarboplatin+paclitaxel,ArmstrongD,etal.NEnglJMed2006;354:34-43.IsonishiS,etal.theLancet2009;374:1331-38,TP方案成为晚期卵巢癌一线化疗的“标准”,19,1996,2000,GOG111(N=410)-期,环磷酰胺750mg/m2顺铂75mg/m2,泰素35mg/m2(24h)顺铂75mg/m2,VS,ORR:73%60%p=0.01,CR:51%31%p=0.01,PFS:18mo13mo12个月复发,存在的相关问题大多数(55%)晚期患者将会出现铂类敏感性复发,无治疗间期,06,712,1318,18,0,20,40,60,80,100,距前次治疗的时间（月）,有效率(%),Blackledge,etal.BrJCancer.1989;59:650-653.,二线化疗的目标,分类目标治疗无效缓解(6,12个月)治愈?,对铂类敏感的卵巢癌,两药联合化疗能否成为对铂类敏感的复发性卵巢癌患者的治疗标准？,对铂类敏感的复发性卵巢癌单药有效率累积总有效率（OR）,duBoisAetal.2000GeburtshFrauenheilk2000;60:41-58,但是,这个问题在一个RCT即可解决!,Pfistereretal.JClinOncol2006;24(29):4699-4707.,健择/卡铂治疗复发卵巢癌的III期临床试验,健择/卡铂治疗复发卵巢癌的III期临床试验:PFS,卡铂组178例162例进展事件；健择/卡铂组178例163例进展事件,Pfistereretal.JClinOncol2006;24(29):4699-4707.,铂类敏感的复发卵巢癌患者健择联合卡铂方案显著延长PFS，提高缓解率，且未降低生活质量1健择联合卡铂快速缓解症状，并明显改善生活质量2,1Pfistereretal.JClinOncol2006;24(29):4699.2Pfistereretal.IntJGynecolCancer2005;15(Suppl1):36-41.,健择/卡铂治疗复发卵巢癌的III期临床试验,各个方案的毒副作用不同：卡铂-紫杉醇：神经毒性卡铂-多西紫杉醇：血液性毒性卡铂-吉西他滨：血液性毒性顺铂-吉西他滨：血液性毒性,铂类耐药复发性卵巢癌治疗模式:,手术fewselectedpts.(e.g.bowelobstruction),内分泌TXSelectedpts.,rather3rd/4thline?,支持治疗everypt.asneeded,放疗fewselectedpts.,心理-社会支持everypt.asneeded,“新药“onlyinclinicaltrials,非铂单药Tx,非铂联合Tx,铂类为主治疗mainlypt-sensitiveROC,FromDr.AndreasduBois,对铂类耐药卵巢癌,选择哪种非铂类？单药联合或改变用药途径？或改变用药方案？,有效率随机临床试验，06个月,紫杉醇1,4n=90,拓泊替康1,2,4n=259,楷莱3n=130,奥沙利铂4n=132,1tenBokkelJCO19972GoreEJC20023GordonJCO20014PiccartJCO2000,%,有效率随机临床试验，6个月,紫杉醇1,4n=90,拓泊替康1,2,4n=259,楷莱3n=109,奥沙利铂4n=132,1tenBokkelJCO19972GoreEJC20023GordonJCO20014PiccartJCO2000,%,WhatistheEvidence?,RandomisedStudiesinRecurrentOC:StudiesPts.mono-vs.monochemotherapy102.195mono:schedule/dose/application71.614mono-vs.endocrinetherapy2303endocrinevs.endocrinetherapy2bination2bination*143.499all:377.924*Including1trialwithmultipleregimensaccordingtotesting;mostothertrialsinpts.withplatinumsensitiverelapse,R,Paclitaxel175mg/m3hq21,Paclitaxel175mg/mEpirubicin80mg/mq21,BudaA2004,BrJCancer,106pts.12mos.,106pts.,results:OR47%vs.37%(combi),PFS6vs.6mos.OS14vs.12mos.(n.s.),R,Topotecan1.25mg/md1-5q21,Topotecan1.0mg/md1-5Etoposid50mgpod6-12q21,SehouliJ2008,JCO,178pts.,177pts.,results:OR36%(TE)vs.32%(TG)vs.28%(Topo)meanPFS15vs.13vs.13months(n.s.)meanOS23vs.18vs.24months(n.s.),Topotecan0.5-0.75mg/md1-5Gemcitabine800mg/md1+600mg/md8q21,app.20%refractory41%12Mon.,147pts.,binationchemotherapyinrefractoryrecurrentOC,Trabectedin+PLD4.0mos,PLD3.7mos,PFSevents:163HR:0.95(0.70-1.30)P=0.7540bycourtesyofBJMonketal(Email:),binationchemotherapyinrefractoryrecurrentOC,R,Doxil/Caelyx(PLD)50mg/mq28,Trabectedin1.1mg/mq21+Doxil/Caelyx(PLD)30mg/mq28,BJMonketall,ESMO2008,118pts.,113pts.,results:OR12,2%vs13,4%(combi;n.s.),PFS/OSn.s.,铂类耐药复发性卵巢癌治疗模式:,手术fewselectedpts.(e.g.bowelobstruction),内分泌TXSelectedpts.,rather3rd/4thline?,支持治疗everypt.asneeded,放疗fewselectedpts.,心理-社会支持everypt.asneeded,“新药“onlyinclinicaltrials,非铂单药Tx,目前尚无足够证据支持非铂联合Tx,铂类为主治疗mainlypt-sensitiveROC,FromDr.AndreasduBois,WhatistheEvidence?,RandomisedStudiesinRecurrentOC:StudiesPts.mono-vs.monochemotherapy102.195mono:schedule/dose/application71.614mono-vs.endocrinetherapy2303endocrinevs.endocrinetherapy2bination2bination*143.499all:377.924*Including1trialwithmultipleregimensaccordingtotesting;mostothertrialsinpts.withplatinumsensitiverelapse,WeeklyPaclitaxel,65,复发或耐药的卵巢癌癌患者,泰素80mg/m2,每周给药，连续3周，休息一周，至少两周期。,WeeklyPaclitaxel（80mg/m2/周）,用于对TP方案无反应或耐药的病例RRMarkman25%Kaern56%Kita25-56%毒性主要为可耐受的神经毒性_JClinOncol20:2365,2002EurJGynecolOncol23:383,2002GynecolOncol92:813,2004,66,R,Topotecan1,5mg/mivd1-5q21,Caelyx50mg/mivq28,Gordon2001,JClinOncol2004,GynecolOncol,235pts.55%Pt.-refractory,70%priortaxans,239pts.,Resultsplatinumrefractorysubgroup:Caelyx(130)Topotecan(124)p-valuePFS(weeks,median)9,113,10.733OS(weeks,median)36410.455G3/4toxicity(allpts.;%)Neutropenia12770.001Anemia5280.001Thrombocytopenia1340.001Leukopenia10500.001Treatment-relatedsepsis040.001Alopecia(allgrades)16490.007Hand-Foot-Syndrom2300.001Stomatitis80.40.001,monovs.monochemotherapyinrecurrent(mostly)refractoryOC-RCTs,R,Gemcitabine1000mg/md1+8q21,Caelyx50mg/md1q28,Mutch,JCO2007,99pts.,96pts.,Results:,monovs.monochemotherapyinrecurrent(mostly)refractoryOC-RCTs,66pts.,64pts.,*Statisticallysignificant.,健择vs.聚乙二醇脂质体阿霉素治疗铂类耐药的卵巢癌的III期临床试验,研究结论：健择可替代聚乙二醇脂质体阿霉素治疗铂类耐药的卵巢癌患者,MutchDG,etal.JClinOncol2007;25(19):2811-2819.,Results:OR16%vs.18%(Gem),ORduration18vs.17(Gem)weeks;n.s.QoLadvantageforcaelyxin2of4timepoints(p0.05),R,Gemcitabine1000mg/md1,8,15q28,Caelyx40mg/md1q28,Mito-3GFerrandinaetalJCO2008,77pts.100%platinum-taxan,TFI12mos.(57%6mos.),76pts.,monovs.monochemotherapyinrecurrent(mostly)refractoryOC-RCTs,铂类耐药复发性卵巢癌治疗模式:,手术fewselectedpts.(e.g.bowelobstruction),内分泌TXSelectedpts.,rather3rd/4thline?,支持治疗everypt.asneeded,放疗fewselectedpts.,心理-社会支持everypt.asneeded,“新药“onlyinclinicaltrials,首选非铂单药：CaelyxTopotecanGemcitabine,目前尚无足够证据支持非铂联合Tx,铂类为主治疗mainlypt-sensitiveROC,FromDr.AndreasduBois,二线治疗,一线治疗,一线治疗,三线治疗,12个月,3个月,3个月,STOP,STOP,二线治疗,3个月,3个月,卵巢癌终止治疗：LondonRoyalMarsdenHospital指南,卵巢癌化疗进展,74,Maintenance（维持）Prolongedadministrationoftreatment延长治疗Treatmentuntilprogression治疗至进展Consolidation（巩固）Adefinedtherapyfollowingaresponsetoinitialtreatment首次治疗有效后，接着同样的治疗,定义：Definitions,巩固/维持治疗随机临床试验（RCT）（i.v.）,1.ScarfoneASCO2002abstractbook:2.ShroederIGCS2004Abstr567:3.MITO-1JClinOncol.2004Jul1;22(13):263542:4.CureJofClinOncol,2004ASCOVol22,No14S(July15Supplement),2004;5006:5.MarkmanJCO,Vol21,No13(July1)2003;24602465,巩固化疗,Markman的期临床研究：两组PFS相差7个月，OS无差异,277例卵巢癌患者经过手术后及TP联合化疗达到完全缓解,R,Taxol175mg/m23小时滴注，每月1次，共3个月,Taxol175mg/m23小时滴注，每月1次，共12个月,MarkmanMetal.GynecolOncol2002;84(3):79,卵巢癌:生物靶向治疗,独特腹腔上皮和Mllerian上皮Specializedrelationship;spreadviaimplantationFrequentproductionofascites,associatedwithVEGFNegativeimmunoregulation(VEGF,IL-10,IL-6,IL-12,APC)生长因子受体EGF-Rfrequentlyexpressed,mutationsuncommon,frequencyofoverexp