转移性乳腺癌的化疗进展ppt课件.ppt

1,转移性乳腺癌的化疗进展,.,2,乳腺癌的流行病学,乳腺癌是女性最常见的肿瘤，女性肿瘤死因第二位。发达国家乳癌发生率是发展中国家的176%。在美国85岁以下女性一生中每9人中1人患乳腺癌，8%与家族遗传有关并与生殖细胞的BRCA1和BRCA2突变相关。男性乳癌发生率1%。60%乳癌存在常染色体基因突变，一些综合征：Li-Fraumennisymdrome生殖细胞P53抑癌基因突变，Cowdensdiseas的PTEN基因突变月经早潮，停经迟，晚育或不生育，增加乳腺癌风险。不典型小叶或导管增生也有可能增加乳癌患病风险。青春期离子化射线暴露，绝经后长期激素替代和酒精摄入也是乳癌患病危险因素。提高对乳腺癌患病的意识，定期普查，早期细胞学诊断，提高乳癌早诊早治，但是仍然有1/4（甚至1/3）患者死于转移性乳腺癌。尽管现代辅助治疗的标准化减少乳腺癌复发和死亡，仍然会有复发和转移性乳癌患者需要进一步治疗。,3,乳腺癌的内科治疗,乳腺癌是一种全身性疾病，在乳腺癌早期可能存在着微小转移灶，除0或1期较早的病人以外，几乎各期病人都在一定时期需要内科治疗。早期乳腺癌的术后辅助化疗和内分泌治疗。转移性乳腺癌的姑息性治疗。2年无内脏转移转移器官数少,高危激素受体阴性HER2阳性无复发生存2年内脏转移转移器官数多,首选内分泌治疗,选择化疗，HER2+/-Herceptin,8,其他影响治疗选择的因素,病人的考虑：患者的年龄，身体条件，患者对治疗方案的主观看法。病史：过去治疗，无病间隔，合并疾病：心、肝、肾功能，糖尿病等。治疗药物和方案的效果和毒性，以及费用。,9,化疗方案的选择,用什么药剂量方案时间顺序干细胞移植,10,复发或转性乳腺癌的一线化疗,11,HER2阴性转移性乳腺癌的一线治疗,Anthracyclines（？）TaxanesPaclitaxel/AdriamicineXeloda/Taxotere(XT)Paclitaxel/GemcitabineXelodaCMFOther,fitterpatientswithgoodperformancestatusandrapidlyprogressingdiseaseorvisceralmetastasesmightderivemostbenefitfrommoreintensivecombinationswhereaslessfitpatientsorthosewithmoreindolentdiseasemightderivemorebenefitfromsingle-agents.,12,蒽环类和紫杉类是主要化疗方案蒽环类单药疗效40%左右。紫杉类单药疗效33%-50%。蒽环类与紫杉类联合疗效优于蒽环类为主的联合化疗。首选的联合治疗方案CAF/FAC/FEC/CMFAC/ECPaclitaxel+ADRDocetaxel+XelodaPaclitaxel+Gemcitabine首选的单药和其他有效的药物蒽环类、紫杉类、希罗达、NVB和健择。铂类VP-16(po)、VLB、5-FU(civ),13,紫杉类治疗MBC临床研究,14,紫杉类单药一线治疗MBC,作者方案NORR%m-TTF(m)m-OS(m)ChanDoce100mg/m28250615ADR75mg/m270364.814,作者方案NORR%m-TTF(m)m-OS(m)ParidaensPacli200mg/m2166253.915.6SledgePacli200mg/m2739335.922.2ADR60mg/m2346.220.1Pacli150mg/m2468.022.4+ADR50mg/m2BishopPacli200mg/m2107295.317.3CMF(口服)102356.413.9,15,蒽环类+紫杉类与联合化疗一线治疗MBC的随机对照临床研究,作者方案NORR%m-TTF(m)m-OS(m)CHF%BonneterreE75+D7565637.8NR1F500+E75+C50067345.9NR0NabholtzA50+D75215608.621.62.8A60+C600214477.419.33.8NabholtzD75+A50+C50023855NANA2F500+A50+C50023742NANA0.4,Docetaxel,16,蒽环类+紫杉醇与联合化疗随机对照一线治疗MBC的临床研究,作者方案NORR%m-TTF(m)m-OS(m)CHF%BiganzoliA60+P175138585.9NR3A60+C600137546.0NR0JassemA50+P220134688.3232F500+A50+C500133556.218.31LuckE60+P175204469.016.81.4E60+C600197407.420.30CarmichaelE75+P200705406.513.71E75+C600(total)376.813.80,Paclitaxel,17,泰索帝/蒽环类与蒽环类方案的比较,RRTAX306ADAC60%47%TAX307TACFAC55%42%P=.008,18,紫杉类对MBC的研究结果,单药一线治疗疗效25-50%，中位TTF3.5-6月。与蒽环类联合一线疗效：55-63%，中位TTF7.8月。与蒽环类合理联合应用，心脏毒性没有增加。紫杉类单药或与蒽环类联合是转移性乳腺癌的标准一线化疗方案。,19,紫杉类每周给药优于每3周方案,20,泰素每周方案治疗转移性乳腺癌的疗效,NR=notreported;ORR=overallresponserate;OS=overallsurvival;TTP=timetotumorprogression.,21,泰素每周方案1小时静滴治疗转移性乳腺癌:耐受性,Seidmanetal.,JClinOncol1998;16:335361,22,WeeklyPaclitaxelSuperiortoStandardEvery-Three-WeekScheduleforMBCPrinterFriendly,CALGB9840(asco2004abstract#512).AndrewD.Seidman,MD,thestudysprincipalinvestigator,ofMemorialSloan-KetteringCancerCenter,23,研究方案,MBC根据一线或二线治疗以及HER2状态，随机分4组,standardpaclitaxel(q3w),weeklypaclitaxel,standardpaclitaxel=trastuzu-mab,weeklypaclitaxel+trastuzumab,R,24,0,20,40,60,80,100,泰素每周组,泰素三周组,联用曲妥珠单抗,不用曲妥珠单抗,40%,28%,35%,29%,所有病人(HR=1.61,p=0.017),HER2阴性病人(p=0.34),344,373,112,111,百分率,CALGB9840肿瘤缓解率,25,CALGB9840研究两组间疾病进展时间曲线,泰素三周组N=385事件数=324中位值=0.44年Chi-square=26.2865泰素每周组N=350事件数=221中位值=0.73年p=0.0008,YearsFromStudyEntry,ProportionProgression-Free,0,1,2,3,4,5,6,0.0,0.2,0.4,0.6,0.8,1.0,TimetoProgression,q3w,q1w,q1w,q3w,26,CALGB9840研究两组间总生存期曲线,泰素三周组N=385事件数=285中位值=1.29年Chi-square=19.1292泰素每周组N=350事件数=190中位值=1.99年p=0.17,YearsFromStudyEntry,ProportionSurviving,0,1,2,3,4,5,6,0.0,0.2,0.4,0.6,0.8,1.0,OverallSurvival,q3w,q1w,q1w,q3w,27,粒细胞减少,感染,贫血,血小板减少,15%,4%,3%,2%,5%,3%,5%,1%,p=0.013,泰素三周治疗组,泰素每周治疗组,3-4级毒性,CALGB9840研究:血液学毒性,28,感觉神经病变,运动神经病变,关节痛/肌痛,呼吸困难,12%,4%,5%,4%,23%,8%,1%,7%,p=0.001,泰素三周治疗组,泰素每周治疗组,3-4级毒性,CALGB9840研究:非血液学毒性,29,结果,RR明显以weeklypaclitaxel优于3weekly,分别为40%和28%(p=0.017;oddsratio,1.61)。增加trastuzumab对HER2-negative患者不增加疗效。WeeklypaclitaxelTTP更长，(p=0.0008;adjustedhazardratio,1.45).trastuzumab同样对HER2-negative没有明显作用。但是OS没有明显差别。,患者对WeeklyPaclitaxel耐受性更好，血液毒性轻，神经毒性高。,30,每周凯素治疗紫杉类耐药MBC两个PhaseIITrial,OShaughnessyJA,凯素是纳米白蛋白紫杉醇,是第一个通过受体介导通道(gp60),使肿瘤细胞紫杉醇浓度更高。,紫杉类耐药MBC，n=106,凯素100mg/m2/W3doses,1weekofrest,ORR15%PFS12ms13%1yrSR38%,凯素125mg/m2/W3doses,1weekofrest,紫杉类耐药MBC，n=75,安全性：G3/4：中粒减少，感觉神经异常，血小板减少，黏膜炎,.,31,OR:31.8%(14of44;95%CI17.5-46.1),noCR.7/14docetaxel抗药者有效。M-DR6.1months(2.1-12.7).M-TTP5.0months临床SAE(3/4):neutropenia(27.2%),leukopenia(25.0%),neuropathy-sensory(13.6%),febrileneutropenia(6.8%),anemia(2.2%),constipation(2.2%),andedema(2.2%).,Weeklypaclitaxel对docetaxel-resistant转移性乳腺癌是有效的，研究显示部分交叉抗药。没有毒性累积的证据。,每周Paclitaxel治疗docetaxel抗药MBC:asingle-centerstudy.,研究设计:Paclitaxel(80mg/m2)每周方案，44例docetaxel治疗进展的转移性乳腺癌。,JapanSawakiM.Tumori2004Jan-Feb;90(1):36-9,32,ACCOGBR0201Opened2003,局部晚期或转移性乳腺癌一线或二线治疗N=600,泰素175mg/m2over3hq3wk,泰素90mg/m2over1hqwk,R,33,在MBC维持治疗的作用,Paclitaxel(200mg/m2）Epirubicin(90mg/m2),every3weeks8cycleN=550(215),CR/PR/SD,R,Paclitaxel(175mg/m2）,nofurtherchemotherapy,every3weeks8cycle,*HR+HT,Table:ResultsofMaintenanceTherapy,34,联合和单药序贯化疗,35,ADR和Doce序贯和同时给药一线治疗MBC:(GEICAM-9903)PhaseIIIStudy,AT：ADR50mg/m2+Docetaxel75mg/m2,每21天.,EmilioAlba,Spain2003ASCO(Abstract27).,A-T：ADR75mg/m23Docetaxel100mg/m23q21d,N=144例MBC,过去用过ADR:2疗程ADR,再给4疗程docetaxel(A-T),或3程AT,再用docetaxel100mg/m2.,R,36,疗效和安全性分析,中粒减少：A-TarmATarmP29.3%47.8%=.02（Asthenia,diarrhea,andfevermoreintheATarm）ORR:61%51%M-DR8.7m7.6mM-TTPs10.5m9.2mM-OS22.3m21.8mNS,结论：序贯AT较同时AT减少中粒下降，可作为MBC治疗选择。,37,单药序贯与联合化疗PhaseIIIJCOG9802,AC40/500mg/m26,Doce60mg/m26,AC/Doce交替6,R,MBCN=441,AC或Doce组PD后交换到对侧方案治疗,AC/D组PD后继续原方案再次治疗.,38,JCOG9802临床研究结果,2005ASCOUpdatedOS,初始Doce优于初始AC组,P=.04,39,单药序贯与联合化疗比较,显示相同的ORR和TTP,以及OS。单药序贯组不良反应发生率较低，耐受性更好。,40,紫杉醇和紫杉特尔直接对照临床研究,41,PhaseIIIComparisonofDocetaxelandPaclitaxelinPatientsWithMetastaticBreastCancer(TAX311)RavdinP,EurJCancer2003;1(Suppl5):s201.Abstract670Presentedat:ECCO12Sep24.2003,.,42,43,ObjectiveResponseinITTpopulation,DocetaxelPaclitaxelPvalue-ORR(CR+PR)32%25%0.10SD38.2%39.7%M-Duration(m)7.54.60.0195%C.I.5.8-9.13.9-6.0M-TTP(m)5.73.6.000195%C.I.4.6-6.93.1-4.2OS(m)15.412.70.0395%C.I.13.3-18.610.6-14.8,ObjectiveResponseinEvaluablePopulationDocePacliPvalueORR37.0%25.9%0.02SD42.9%42.9%,44,紫杉类对蒽环类治疗后的MBC:ORR在可评价病例中，Doci组高于Pacli,但ITT没有达到统计学显著性差异（32%vs25%,P值=0.10）。TTP明显优于Pacli组（5.7mvs3.6m,P=65岁，m-年龄74岁（6589）标准剂量：1250mg/m2，每日两次14天，21天重复（n30）1000mg/m2，每日两次14天，21天重复（n10）ORR36，ORR+SD80低起始剂量可以改善老年患者耐受性,G3/4治疗相关毒性8人，1人死亡，低剂量G3/41/0肾功减退者应用低起始剂量，(如950/m2),ASCO2004,55,希罗达和泰索帝联合与泰索帝单药对照治疗蒽环类失败的MBCalargephaseIIItrial,Xeloda1250mg/m2bidd1-14Taxotere75mg/m2,day1q3w,Taxotere100mg/m2,day1q3w,Primaryendpoint:TTP,(n=255),(n=256),OShaughnessyJetal.JClinOncol2002;20:281223,随机分组,56,XT与Taxotere对照研究结果,所有病人用过蒽环类，80%内脏转移，2/3接受过2/3线研究药物治疗。,单Doce更多中粒减少性发热，联合组更多3/4级腹泻、胃炎和HFS.住院和SAE发生率相当。,FDA2001.09批准泰素帝/希罗达联合治疗转移性乳腺癌,XTTPvalueHazardRatioORR42%30%.006TTP6.1m4.2m.0001OS14.5m11.5m.0130.77,OShaughnessyJetal.JClinOncol2002;20:281223,57,XT与Taxotere比较明显改善RR(32versus22%),TTP(186versus128days)。XT较Taxotere延长生存（442versus352days），是蒽环类治疗过MBC患者的标准治疗。XT不损害QoL。方便的剂量调整可以用于XT副作用的处理。,XT与Taxotere对照研究结论,OShaughnessyJetal.JClinOncol2002;20:281223,58,Vinorelbine诺维本,半合成长春碱类药物，主要用于NSCLC的治疗，也用于宫颈癌，卡波氏肉瘤，转移性乳腺癌，SCLC的化疗。是临床常用广谱抗肿瘤药物。,59,Vinorelbine诺维本治疗MBC,一线单药ORR44%(range:3552%),中位有效时间和中位治疗失败时间分别为8.5(range:4.39)和5(range:4.46)月。中位生存时间16(range:9.924)月。一年生存率近80%。二线单药ORR28%(range:1637%)，中位有效时间、中位治疗失败时间和生存时间分别为5(range:3.58.5)，3.8(range:34.5)和11.7(range:724)月。一年生存率近65%。与其他药物联合时，一线和二线ORR分别为70%(range:5489%)和38.5%,(range:1858%)。,60,诺维本治疗难治性MBC,1stline,2nd+line,61,诺维本与其他化疗联合,NVB+GEM一线疗效55.5%，二线疗效40%。NVB+XELO：6项，251例，ORR33-67%.与蒽环类联合：一线74-80%，CR19-21%，RD12ms,OS22.7-27ms,Spielmann(1994)J.Clin.Oncol.,12,1764R.HeggCurrMedResOpin16(4):225-234,2001,62,诺维本联合化疗一线治疗MBCIII期临床研究,63,Gemcitabine健择,嘧啶类抗癌药物，早期批准用于NSCLC和胰腺癌的治疗，04年5月批准用于MBC的一线救援治疗。单药有效率25%-42%，胃肠反应，神经毒性和脱发均较蒽环类和紫杉类轻。可与多种抗癌药物联合使用。,64,健择单药治疗MBC,N=381from5phaseIItrialsandonephaseIII,MostpatientshadreceivedprioranthracyclineortaxaneResponse1stline:14-37%;2ndline:21-28%;3rdline:13-33%CRrate:0-10%MedianTTP:2-5monthsMediansurvival:11.5to21monthsToxicityHematologictoxicitywithminimalclinicalconsequencesGrade3/4neutropenia30%,thrombocytopenia20%Non-hematologictoxicityminimalOccasionalflu-likesymptoms,nausea/vomiting,dyspnea,elevatedLFTs,alopeciarare,65,紫杉类和健择联合,Taxane可以是gem的活性代谢产物累积浓度提高，因而有协同作用,66,健择与其他药物联合,GEMZAR+Paclitaxel:1st,2nd,or3rdlinemetastaticdisease,Responserates44%to69%,Mediansurvival12monthsGEMZAR+Docetaxel:Mostpatientshadreceivedprioranthracyclineand/orataxane,Responseratesfrom36%to79%GEMZAR+Cisplatin:Mostpatientshadreceivedpriorchemotherapywithanthracyclineortaxane,Responserates26%to81%GEMZAR+Vinorelbine:1st,2nd,3rdlinemetastaticdisease,ResponseRates:22%to54%,67,GEMZAR+Paclitaxelvs.PaclitaxelinPatientsasfrontlinetherapyforMBC,InterimOveralSurvivalReport(aglobalphaseIIIstudy),KS.Albainetal.ASCO2004,.,68,StudyDesignandTreatment,TreatuntildocumentedPDAllsitesofdiseaseassessedevery8weeks,Paclitaxel175mg/m2(3hr)Gemcitabine1250mg/m2,Paclitaxel175mg/m2(3hr),GTarm(21-daycycle),Tarm(21-daycycle),Day1:,Day1:,Gemcitabine1250mg/m2,Day8:,RANDOMIZE,Standardpaclitaxelpremedications,KS.Albainetal.ASCO2004,69,Interimanalysis,EndopointGTTP-valueRR(95%C.I.)40.8%22.1%.0001(34.9,46.7)(17.2,27.2)M-TTP(95%C.I.)5.22.9.0001(4.2,8.6)(2.6,3.7)6-month37%23%.0027(progressionfree),KS.Albainetal.ASCO2004,70,Interimoveralsurvival,Deaths160183Censored40.1%30.2%M-OS(m)18.515.8(95%C.I.)(16.5,21.2)(14.4,17.4)12-monsurvival70.7%60.9%18-monsurvival50.7%41.9%,KS.Albainetal.ASCO2004,LogrankP=.018Hazardratio0.78(0.63,0.69),EndopointGT(267)T(262),FDA2004/5,71,TEGCombinationsPhaseIIstudy,FirstlineforMBC,n=36Epirubicin90mg/m2d1Paclitaxel175mg/m2d1Gemzar1000mg/m2d1,4q21d,6cycle60yrCR,PR,SD_HDCT,ORR92%,11CR,ORR96%inHDCTM-PFS21mToxicity(G3/4)Neutropenia37%Dosedelaysin34%Dosereductions14%,BeingtestedinphaseIIItrial,72,PhaseIIIstudyGETVSFEC一线治疗MBC,ZielinskiCentralEuropeCooprativeOncologyGroupProcASCO2003;22:7abstr26,.,73,Arm1GETGem1000mg/m2EPI90mg/m2Pacli175mg/m2Arm2FEC5-FU500mg/m2EPI90mg/m2CTX500mg/m2,方案：,每3周重复，最大8个疗程或至肿瘤进展。,74,结果,总259例入组:GET和FEC分别为124和135例GETFECP-valueTTP(M)9.19.0NSRR(%)62.351.2.09M-survi(M)29.524.9.61,血液毒性、黏膜炎更多见于GET组。是否值得在辅助化疗中评价应该进一步讨论,75,蒽环类和紫杉类方案失败后的治疗选择，XeloNVBGEM的疗效大致相当，但是毒性不同。三种药物之间没有直接对照的研究，选择时更注重避免毒性重叠。,76,Her2过表达的MBC的治疗,77,人类表皮生长因子(HER2),也称做c-erbB-2和HER2/neu,能促进细胞生长和肿瘤发生。在原发性乳腺癌患者中25%to30%有HER2蛋白过度表达，这些患者通常具有早期复发和生存期较短的临床特征。Trastuzumab是一种人源化的重组DNA单克隆抗体，能够选择性与细胞表面HER2决定簇结合。有HER2过度表达的转移性乳腺癌患者，赫赛丁单药治疗具有抗肿瘤疗效。与单纯化疗比较，与化疗联合应用时能提高疗效、并且能延长生存。,78,赫赛丁单药治疗的客观疗效StudyH0649g,79,赫赛丁单药一线治疗MBCStudyH0650ResponseRate,N=114patients2mg/kgVs4mg/kgCompleteresponses7ptPartialresponses23ptOverallresponserate30pt(26%)Timetoresponse1.8moResponseduration11-22mo,80,赫赛丁与化疗联合一线治疗MBCORR(HO648g),Designandenrolment,Noprioranthracyclines,Prioranthracyclines,Paclitaxel(n=96),Herceptin+paclitaxel(n=92),AC(n=138),Herceptin+AC(n=143),Eligiblepatients(n=469),81,ComparativeStudyHO648gOverallORR,P-value0.10380.0001,82,ComparativeStudyHO648gTime-to-DiseaseProgression,H+P(n=92)median=6.9moP(n=96)median=3.0mo,H+AC(n=143)median=8.1moAC(n=138)median=6.1mo,p=0.0003,p=0.0001,83,Overallsurvival,CTpatientstreatedwithHerceptinafterdisease24%62%65%progression,1.00.80.60.40.20,0515253545,H+CTCT,Probabilityofsurvival,25.4months(25%),20.3months,RR=0.76p=0.025,Time(months),84,Meancombinationindexvaluesforchemotherapeuticdrug/Herceptincombinationsinvitro,*5-dFUrdisametaboliteofXeloda;HerceptinplusXelodademonstratesadditiveactivityinvivo3,1KonecnyG,etal.BreastCancerResTreat1999;57:114(Abstract467)2PegramM,etal.Oncogene1999;18:2241513Fujimoto-OuchiK,etal.CancerChemotherPharmacol2002;49:21116,85,Herceptin与每周paclitaxel(n=95),PhaseIItrialofHerceptinplusweeklypaclitaxel(90mg/m2)RRsin7080%rangeinHER2-positivepatients169%(DAKO)67%(PAb1)76%(CB11)81%(TAB250)75%(FISH)UsedbyIntergrouptodevelopadjuvantdesignWidelyusedintheclinicalsettingintheUSAandAustralia,1SeidmanAD,etal.JClinOncol2001;19:258795,86,Herceptin联合docetaxelPhaseIItrials,Herceptinwasadministeredasa4mg/kginitialdosefollowedby2mg/kgweeklyuntilprogression,87,Herceptin与vinorelbine联合,1BursteinH,etal.JClinOncol2001;19:2722302JahanzebM,etal.BreastCancerResTreat2001;69:284(Abstract429),88,Herceptin与gemcitabine联合,PhaseIIstudy(n=59)ofHerceptinplusgemcitabine(1,200mg/m2day1and8q3-weekly)RR=33%(22/59)InpatientswithIHC3+disease,RR=45%(17/38),OShaughnessyJA,etal.BreastCancerResTreat2001;69:302(Abstract523),89,Herceptin与docetaxel和platinum联合（First-line）,Herceptinincombinationwithdocetaxelandcisplatin(BCIRG101)RR=79%(49/62)Herceptinincombinationwithdocetaxelandcarboplatin(BCIRG102)RR=56%(31/55)ThisregimenisbeinginvestigatedinphaseIIItrialsintheadjuvant(006)andmetastatic(007)settings,NabholtzJ-M,etal.EurJCancer2001;37:S190(Abstract695),90,Herceptin与Xeloda联合,InpatientspretreatedformetastaticbreastcancerRR=62%(8/13)whenXelodawasadministeredatadoseof1,125mg/m2b.i.d.1RR=53%(9/17)whenXelodawasadministeredatadoseof1,000mg/m2b.i.d.2ThecombinationwaswelltoleratedAdditionaltrialstofurtherexaminethiscombinationincludearandomisedphaseIItrialofHerceptinplusdocetaxelXeloda,1BangemannN,etal.AnnOncol2000;11:143(Abstract653P)2BangemannN,etal.BreastCancerResTreat2000;64:123(Abstract530),91,Herceptin与化疗联合小结,SeveralHerceptincombinationregimensareactivehighRRsfavourablesafetyprofilesTodate,nodirectcomparisonhasbeenmadetoestablishthebestfirst-linecombinationstrategyOptimaltherapymaydifferdependingonpatientandtumourcharacteristics,92,Herceptininmetastaticbreastcancer,EvidencesupportsHerceptintherapyinHER-2overexpressingmetastaticbreastcancer1.Herceptinwithchemotherapyinfirstlineimprovedtimetotreatmentfailureincreasedresponseratesimprovedsurvival2.Herceptinmonotherapyactiveinfirstlineandinsecond/thirdlinefavourablesafetyprofilesurvivaldatainfirstlinenotinferiortocombinationtherapy,93,NCCTG98-32-52,KendrithM.Rowland,VeraJ.Suman,JamesN.Ingle,CharlesL.Loprinzi,PatrickJ.Flynn,JamesE.Krook,MuhammadSalim,JamesA.Mailliard,CarlG.Kardinal,EdithA.PerezPI:EdithA.Perez,RandomizedPhaseIITrialofWeeklyVersusEvery3-weekAdministrationofPaclitaxel,CarboplatinandTrastuzumabinWomenwithHER2PositiveMetastaticBreastCancer,94,NCCTG98-32-52,Evaluatetherapeuticratioofweeklyorq3wcarboplatin,paclitaxel,andtrastuzumabinHER2+metastaticbreastcancerAccrualgoal:92patientsPlannedinterimanalysisafter36patientsperarmefficacydata:18patientsperarmtolerability:70patients(enrolledbeforeOct.2002),95,Pacli/CBP/HerceptininHer2OverexpressMBCWeeklyVS3weekly-NCCTG,Chemotherapy+Trastuzumabx6moTrastuzumabq3w,1stLineHER2+MBC,PI:PerezEA,96,ResponsetoTherapy(InterimAnalysis),50%,OverallResponse,56%,27%,1-yearPFS,13.4mo,8.8mo,MedianPFS,61%,39%,PartialResponse,78%,11%,CompleteResponse,weekly(n=18),q3w(n=18),97,Survival(InterimAnalysis),81%,50%,2-yearOS,100%,89%,1-yearOS,weekly(n=18),q3w(n=18),98,AdverseEvents:Hematologic(70EvaluablePatients),-,-,3%,15%,FebrileNeutropenia,-,6%,-,29%,RBCTransfusion,-,3%,-,18%,Anemia,-,3%,-,35%,Thrombocytopenia,11%,44%,71%,18%,Neutropenia,4,3,4,3,NCIGrade,weekly(n=36),q3w(n=34),p*,0.003,0.01,0.005,0.05,0.01,*p-valuefromFishersExacttest;post-hocanalysis,99,AdverseEvents:Non-Hematologic(70EvaluablePatients),-,-,-,9%,-,3%,-,24%,-,47%,-,68%,Alopecia(grade2),Neuropathy,-,3%,-,18%,Myalgia,-,8%,6%,6%,Hypersensitivity,-,11%,-,12%,Fatigue,-,8%,-,15%,Arthralgia,4,3,4,3,NCIGrade,weekly(n=36),q3w(n=34),p*,0.47,1.0,0.71,0.05,0.11,0.012,0.10,*p-valuefromFishersExacttest;post-hocanalysis,Motor,Sensory,100,Conclusions,Bothq3wandweeklyregimenofcarboplatin,paclitaxel,andtrastuzumabarehighlyactiveinHER2+MBCWeeklyregimenisbettertoleratedTherapeuticratioofcarboplatin,paclitaxel,andtrastuzumabinHER2+MBCisimprovedwithweeklyregimen,101,CerbB2Over-expressedMBCHerceptin联合化疗的首选方案,Paclitaxel+/-CarboplatinDocetaxel+/-CarboplatinVinorebine,NCCN2004,102,Milleretal.ASCO2005.Oralpresentationduringsymposium,AdvancesinMonoclonalAntibodyTherapyforBreastCancer.,Bevacizumab10mg/kgDays1,15+Paclitaxel90mg/m2Days1,8,15(n=365),Paclitaxel90mg/m2Days1,8,15(n=350),Patientswithlocallyrecurrentormetastaticbreastcancer,ECOGperformancestatusscore0-1(N=715),Stratifiedbydisease-freeinterval,numberofmetastaticsites,adjuvantchemotherapy,andestrogenreceptorstatus,BevacizumabPaclitaxel1stlineforLocallyRecurrentorMetastaticDisease,EasternCooperativeOncologyGroup(ECOG)2100trialFirstplannedinterimanalysisofrandomized,first-line,phase3trial,103,Milleretal.ASCO2005.Oralpresentationduringsymposium,AdvancesinMonoclonalAntibodyTherapyforBreastCancer.,BevacizumabPaclitaxelforLocallyRecurrentorMetastaticDisease,PFSsignificantlylongerwithcombinationtherapy10.97monthsvs6.11monthsHR=0.498(95%CI,0.401-0.618),P.001Overallsurvivalsignificantlyhigherforpatientsreceivingbevaciz