卵巢癌化療進展

.,卵巢癌化療新進展Thestateoftheartinchemotherapyforovariancancers,復旦大學附屬腫瘤醫(yī)院婦瘤科,.,女性生殖道腫瘤:全世界統(tǒng)計1,Ferlayetal.GLOBOCAN2000IARC,WHO2001(www.dep.iarc.fr),.,.,Women,發(fā)病率32%Breast12%Lung2001/,2004.,卵巢癌可認為是一種慢性疾病,早期卵巢癌:FIGOIandII,全面的分期剖腹探查術經腹全子宮/雙側卵巢輸卵管切除(TAH/BSO)大網膜切除淋巴結切除術（dissection）腹膜和膈膜活檢（biopsies）細胞學檢查高危vs低危早期卵巢癌,S,早期卵巢癌,MedicalOncology:Atextbook,低危,高危,(510%復發(fā)率),(3040%復發(fā)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,輔助化療的隨機臨床試驗:3vs6療程紫杉醇+卡鉑,結果6個療程進展危險性降低了33%生存率無改善,Action淋巴結陰性;鏡下腹腔種植B腹腔種植灶2cm;淋巴結陰性C腹腔種植灶2cm和/或陽性腹膜后淋巴結或腹股溝IV遠處轉移,MedicalOncology:Atextbook,準確全面分期依據(jù)手術探查和病理組織學、細胞學檢查根據(jù)腹腔內轉移灶的大小對III期再分為IIIa、IIIb、IIIc腹膜后淋巴結轉移影響分期肝表面和肝實質轉移分屬III期和IV期,StageI:局限于卵巢StageII:局限于盆腔StageIII:局限于腹腔StageIV:遠處轉移,.,晚期卵巢癌：關鍵臨床實驗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:關鍵臨床實驗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方案成為晚期卵巢癌一線化療的“標準”,19,1996,2000,GOG111(N=410)-期,環(huán)磷酰胺750mg/m2順鉑75mg/m2,泰素35mg/m2(24h)順鉑75mg/m2,VS,ORR:73%60%p=0.01,CR:51%31%p=0.01,PFS:18mo13mo12個月復發(fā),存在的相關問題大多數(shù)(55%)晚期患者將會出現(xiàn)鉑類敏感性復發(fā),無治療間期,06,712,1318,18,0,20,40,60,80,100,距前次治療的時間（月）,有效率(%),Blackledge,etal.BrJCancer.1989;59:650-653.,二線化療的目標,分類目標治療無效緩解(6,12個月)治愈?,對鉑類敏感的卵巢癌,兩藥聯(lián)合化療能否成為對鉑類敏感的復發(fā)性卵巢癌患者的治療標準？,對鉑類敏感的復發(fā)性卵巢癌單藥有效率累積總有效率（OR）,duBoisAetal.2000GeburtshFrauenheilk2000;60:41-58,但是,這個問題在一個RCT即可解決!,Pfistereretal.JClinOncol2006;24(29):4699-4707.,健擇/卡鉑治療復發(fā)卵巢癌的III期臨床試驗,健擇/卡鉑治療復發(fā)卵巢癌的III期臨床試驗:PFS,卡鉑組178例162例進展事件；健擇/卡鉑組178例163例進展事件,Pfistereretal.JClinOncol2006;24(29):4699-4707.,鉑類敏感的復發(fā)卵巢癌患者健擇聯(lián)合卡鉑方案顯著延長PFS，提高緩解率，且未降低生活質量1健擇聯(lián)合卡鉑快速緩解癥狀，并明顯改善生活質量2,1Pfistereretal.JClinOncol2006;24(29):4699.2Pfistereretal.IntJGynecolCancer2005;15(Suppl1):36-41.,健擇/卡鉑治療復發(fā)卵巢癌的III期臨床試驗,各個方案的毒副作用不同：卡鉑-紫杉醇：神經毒性卡鉑-多西紫杉醇：血液性毒性卡鉑-吉西他濱：血液性毒性順鉑-吉西他濱：血液性毒性,鉑類耐藥復發(fā)性卵巢癌治療模式:,手術fewselectedpts.(e.g.bowelobstruction),內分泌TXSelectedpts.,rather3rd/4thline?,支持治療everypt.asneeded,放療fewselectedpts.,心理-社會支持everypt.asneeded,“新藥“onlyinclinicaltrials,非鉑單藥Tx,非鉑聯(lián)合Tx,鉑類為主治療mainlypt-sensitiveROC,FromDr.AndreasduBois,對鉑類耐藥卵巢癌,選擇哪種非鉑類？單藥聯(lián)合或改變用藥途徑？或改變用藥方案？,有效率隨機臨床試驗，06個月,紫杉醇1,4n=90,拓泊替康1,2,4n=259,楷萊3n=130,奧沙利鉑4n=132,1tenBokkelJCO19972GoreEJC20023GordonJCO20014PiccartJCO2000,%,有效率隨機臨床試驗，6個月,紫杉醇1,4n=90,拓泊替康1,2,4n=259,楷萊3n=109,奧沙利鉑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.,鉑類耐藥復發(fā)性卵巢癌治療模式:,手術fewselectedpts.(e.g.bowelobstruction),內分泌TXSelectedpts.,rather3rd/4thline?,支持治療everypt.asneeded,放療fewselectedpts.,心理-社會支持everypt.asneeded,“新藥“onlyinclinicaltrials,非鉑單藥Tx,目前尚無足夠證據(jù)支持非鉑聯(lián)合Tx,鉑類為主治療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,復發(fā)或耐藥的卵巢癌癌患者,泰素80mg/m2,每周給藥，連續(xù)3周，休息一周，至少兩周期。,WeeklyPaclitaxel（80mg/m2/周）,用于對TP方案無反應或耐藥的病例RRMarkman25%Kaern56%Kita25-56%毒性主要為可耐受的神經毒性_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.,健擇vs.聚乙二醇脂質體阿霉素治療鉑類耐藥的卵巢癌的III期臨床試驗,研究結論：健擇可替代聚乙二醇脂質體阿霉素治療鉑類耐藥的卵巢癌患者,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,鉑類耐藥復發(fā)性卵巢癌治療模式:,手術fewselectedpts.(e.g.bowelobstruction),內分泌TXSelectedpts.,rather3rd/4thline?,支持治療everypt.asneeded,放療fewselectedpts.,心理-社會支持everypt.asneeded,“新藥“onlyinclinicaltrials,首選非鉑單藥：CaelyxTopotecanGemcitabine,目前尚無足夠證據(jù)支持非鉑聯(lián)合Tx,鉑類為主治療mainlypt-sensitiveROC,FromDr.AndreasduBois,二線治療,一線治療,一線治療,三線治療,12個月,3個月,3個月,STOP,STOP,二線治療,3個月,3個月,卵巢癌終止治療：LondonRoyalMarsdenHospital指南,.,Maintenance（維持）Prolongedadministrationoftreatment延長治療Treatmentuntilprogression治療至進展Consolidation（鞏固）Adefinedtherapyfollowingaresponsetoinitialtreatment首次治療有效后，接著同樣的治療,定義：Definitions,鞏固/維持治療隨機臨床試驗（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,鞏固化療,Markman的期臨床研究：兩組PFS相差7個月，OS無差異,277例卵巢癌患者經過手術后及TP聯(lián)合化療達到完全緩解,R,Taxol175mg/m23小時滴注，每月1次，共3個月,Taxol175mg/m23小時滴注，每月1次，共12個月,MarkmanMetal.GynecolOncol2002;84(3):79,卵巢癌:生物靶向治療,獨特腹腔上皮和Mllerian上皮Specializedrelationship;spreadviaimplantationFrequentproductionofascites,associatedwithVEGFNegativeimmunoregulation(VEGF,IL-10,IL-6,IL-12,APC)生長因子受體EGF-Rfrequentlyexpressed,mutationsuncommon,frequencyofoverexpress