卵巢癌化疗进展

卵巢癌化疗新进展Thestateoftheartinchemotherapyforovariancancers复旦大学附属肿瘤医院妇瘤科女性生殖道肿瘤:全世界统计11.Ferlayetal.GLOBOCAN2000IARC,WHO2001()CancerNewCasesDeathsCervical470,000230,000Endometrial189,00045,000Ovarian192,000114,000Women发病率32%Breast12%Lung&bronchus11%Colon&rectum6%Uterinecorpus4%Ovary4%Non-Hodgkinlymphoma3%Melanomaofskin3%Thyroid2%Pancreas2%Urinarybladder20%AllOtherSites死亡率25%Lung&bronchus15%Breast11%Colon&rectum6%Pancreas5%Ovary4%Non-Hodgkinlymphoma4%Leukemia3%Uterinecorpus2%Brain/ONS2%Multiplemyeloma23%AllothersitesCancerFacts&Figures,ACSO,2003IncidencesofGynecologicalCancersinShanghaiCitizens(1974-2000)4.86.510.511.226.72.54.44.82.54.49.16.30510152025301974199419972000YearIncidences(/100,000)OvarianCancerCervicalCacnerEndometrialCancer上海市居民卵巢癌、宫颈癌、宫体癌发病率（1974-2000，SCDC）内容简介1.早期卵巢癌化疗2.中晚期卵巢癌化疗3.新辅助化疗/中间手术4.复发性卵巢癌化疗5.维持\巩固治疗6.Ca125升高处理卵巢癌的治疗未治患者主要目的是治愈手术分期和细胞减灭术，继而紫杉醇/铂类联合化疗复发患者主要目的是减轻症状和提高生活质量化疗可以延长生存时间最终结果长期存活:25-30%5-年生存率从30%(1970s)提高至50%RiesLAGetal.SEERCancerStatisticsReview,1975-2001,NationalCancerInstitute.Bethesda,MD,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Stagingclassificationsandclinicalpracticeguidelinesofgynaecologiccancers.低危高危(5–10%复发率)(30–40%复发率)StageIAorIBStageICGrade1(or2)Grade3Clearcellcancer高危早期卵巢癌1.YoungSGO20032.YoungRC.SeminOncol27(3):8-10.,20003.ICON-1,EORTC-ACTION:JNatnlCanInst.Vol.95,No.2,January15,20034.Manneletal.GOG-175protocol,–1571,2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&Icon3随机临床试验无立即化疗vs立即化疗结果立即化疗生存率提高8%vs复发时化疗(82%vs74%)FIGOStageIIIandIV定义III盆腔外腹膜种植和/或外阳性腹膜后或腹股沟淋巴结A病灶大致局限于真骨盆;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:Acomprehensivereview.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:远处转移晚期卵巢癌：关键临床实验1GOG1111andOV-102Cisplatin+paclitaxelvscisplatin+cyclophosphamideImprovedsurvivalandprogression-freesurvivalwithcisplatin+paclitaxelGOG1323Cisplatinvspaclitaxelvscisplatin+paclitaxelNostatistaicaldifferenceinoverallsurvivalICON-34Carboplatin+paclitaxelvscarboplatinorCAP(cyclophosphamide+doxorubicin+cisplatin)NostatisticaldifferenceinsurvivalGOG1585;AGO-OVAR6Carboplatin+paclitaxelpreferredcombinationovercisplatin+paclitaxel1.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)NostatisticaldifferenceinsurvivalGOG172（2006）cisplatin+paclitaxeliv/ippreferredcombinationovercisplatin+paclitaxelivJGOG（2009）Carboplatin（d1）+paclitaxel80mgweeklyperferredCarboplatin+paclitaxelArmstrongD,etal.NEnglJMed2006;354:34-43.IsonishiS,etal.theLancet2009;374:1331-38TP方案成为晚期卵巢癌一线化疗的“标准”1919962000GOG111(N=410)Ⅲ-Ⅳ期环磷酰胺750mg/m2顺铂75mg/m2泰素35mg/m2(24h)顺铂75mg/m2VSORR:73%60%p=0.01CR:51%31%p=0.01PFS:18mo13mop=0.001OS:38mo24mop=0.001毒性:泰素/顺铂组有较多的血液学毒性和神经毒性，但毒性可控OV10(N=688)Ⅲ-Ⅳ期环磷酰胺750mg/m2顺铂75mg/m2泰素175mg/m2(3h)顺铂75mg/m2ORR:77%66%p=0.01CR:50%36%p=0.01PFS:16.6mo12mop=0.0005OS:35mo25mop=0.0016毒性:泰素/顺铂组有较多的血液学毒性和神经毒性，但毒性可控VSJNatlCancerInst2000;92:699–708McGuire,etal.NEnglJMed1996334:1-6GOG158:Ovarian(optimalIII)Cisplatin75mg/m2Paclitaxel135mg/m2(24h)CarboplatinAUC7.5Paclitaxel175mg/m2(3h)•EpithelialOvarianCancer•OptimalStageIII•Nopriortherapy•ElectiveSecond-Look•Non-InferiorityDesignOpen:03-Apr-95Closed:26-Jan-98Accrual:792pts(evaluable)IIIOzols,etal.ProcJClinOncol21:3194,20030.00.20.40.60.81.001224364860MonthsonStudyProportionSurviving.GOG158:Ovarian(optimalIII)CDDP-Paclitaxel(24-h)(n=400)median48.8mCarbo-Paclitaxel(3-h)(n=392)median56.7mAdjustedCoxanalysisHR0.86(95%CI0.71–1.04)Ozols,etal.ProcJClinOncol21:3194,200356.7vs48.8m=7.9m晚期卵巢癌的化疗总之:手术和化疗后约75%患者临床完全缓解（CCR），但复发率50%长期生存率20–25%有效率病理完全有效率无进展生存率生存时间OptimalStageIIINA50%21months59monthsSuboptimalIII&IV75%25%18months30months提高疗效的可能对策引入更有效的方案紫杉醇/卡铂+新药腹腔化疗增加剂量强度新的细胞毒性药物分子靶向治疗对复发癌更有效的治疗发明有效的维持治疗Ozols,SeminarsinOncology,vol29;Suppl1(Feb)2002:32-42.提高初治卵巢癌化疗疗效：三药联合化疗标准治疗PC+XGOG0182-ICON5比较五种方案治疗晚期卵巢上皮癌或原发性腹膜癌的III期随机临床试验25MichaelABookman,MDFoxChaseCancerCenterPhiladelphia,PAProcASCO2005:Abstract5002GOG0182-ICON526RANDOMIZEx8CarboplatinAUC5(d1)Paclitaxel175mg/m2(d1)Doxil30mg/m2(d1,everyothercycle)IIIx8CarboplatinAUC6(d1)Paclitaxel175mg/m2(d1)ICarboplatinAUC6(d1)Paclitaxel175mg/m2(d1)x4x4CarboplatinAUC6(d8)Gemcitabine1g/m2(d1,8)Vx4CarboplatinAUC5(d3)Topotecan1.25mg/m2(d1-3)IVx8CarboplatinAUC5(d1)Paclitaxel175mg/m2(d1)Gemcitabine800mg/m2(d1,8)IIGOG0182-ICON5:无进展生