转移性乳腺癌的内科治疗(squip) ppt课件

转移性乳腺癌的化疗 中山医科大学肿瘤医院内科刘冬耕 NCCN2006 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 HER2阴性转移性乳腺癌的一线治疗 Anthracyclines TaxanesPaclitaxel AdriamicineXeloda Taxotere XT Paclitaxel Gemcitabine GP XelodaCMFOther fitterpatientswithgoodperformancestatusandrapidlyprogressingdiseaseorvisceralmetastasesmightderivemostbenefitfrommoreintensivecombinationswhereaslessfitpatientsorthosewithmoreindolentdiseasemightderivemorebenefitfromsingle agents 卡培他滨Capecitabine Xeloda长春花碱酰胺Vinorebine吉西他滨Gemcitabine铂类 Cisplatin Carpoplatin 蒽环类与紫杉类失败后的化疗选择 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 O ShaughnessyJetal JClinOncol2002 20 2812 23 随机分组 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 O ShaughnessyJetal JClinOncol2002 20 2812 23 CapecitabineinTaxane pretreatedMetastaticBreastCancer 1 BlumJLetal EurJCancer2001 37 S190 Abstract693 2 BlumJLetal Cancer2001 92 1759 1768 3 ReichardtPetal AnnOncol 2003 14 1227 1233 4 FumoleauPetal EurJCancer 2004 40 536 542 GemcitabineinAnthracycline Taxane RefractoryMBC 1 ValerioMRetal ProcAmSocClinOncol 2001 Abstract1953 2 RhaSYetal BreastCancerResTreat 2005 90 215 221 3 ModiSetal ClinBreastCancer 2005 6 55 60 Days1 8 and15every21days VinorelbineinRefractoryMBC MultiplephaseIIstudies ORR 16 34 Degardinetal 1 N 100 CR PR 16 Mediandurationofresponse 5mos range 3 18 Livingstonetal 2 N 40 CR PR 25 MedianTTP 13weeksMediansurvival 33weeks 1 Degardinetal AnnOncol 1994 5 423 426 2 LivingstonRBetal JClinOncol 1997 15 1395 1400 蒽环类和紫杉类方案失败后的治疗选择 Xelo NVB GEM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 AfterAnthracyclinesandTaxanes MultipleOptions CapecitabineVinorelbineGemcitabineIrinotecanVinflunineXRP9881Ixabepilonenab paclitaxel Abraxane ABI 007 楷素 1 IbrahimNKetal JClinOncol 2005 23 6019 26 2 BlumJLetal ProcAmSocClinOncol 2004 Abstract543 Albumin boundpaclitaxel nanoparticleformulationPhaseIItrial taxane refractoryMBC N 106 中国注册研究已经完成II III期临床FDA已经批准用于MBC治疗 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 Vinflunine 长春富宁 AfterAnthracyclineandTaxaneFailureinMBC Fumoleauetal ProcAmSocClinOncol 2004 Abstract542 Novelsemi syntheticvincaalkaloidInhibitstubulinassemblyNostabilizingeffectonassembledmicrotubulesPhaseIIstudy N 60 PR30 0 diseasecontrol PR SD 63 3 PR36 8 diseasecontrol57 9 intaxane refractory PFI 3mo patientsGrade3 4neutropeniain63 5 ofpatients neutropenicinfectionin5 8 Ixabepilone BMS 247550 埃坡霉素 EpothiloneBisanaturalmacrolideproducedbythemyxobacteriumSorangiumcellulosumIxabepiloneisasemisyntheticanalogofepothiloneB aza epothiloneB EpothiloneB Ixabepilone AntitumorActivityinTaxane ResistantPAT 21BreastCancerXenografts PAT 21breastcancerxenograftsarederivedfromapatientwithMBCwhoreceived10cyclesofCMF then4cyclesofpaclitaxel MTD maximumtolerateddose Mediantumorwt mg 10 100 1000 40 70 100 130 160 Daysposttumorimplantation Control Ixabepilone 10mg kg MTD Paclitaxel 36mg kg MTD Control Ixabepilone 13mg kg MTD Docetaxel 20mg kg MTD Vinorelbine 9mg kg MTD Daysposttumorimplantation 10 100 1000 40 50 60 70 80 90 Mediantumorwt mg Dataonfile Bristol MyersSquibbCompany ClinicalResponsetoIxabepiloneNCI 0229 Low JClinOncol 2005 23 2726 34 PhaseIIIClinicalTrialsofIxabepilonePlusCapecitabine Ixabepilone40mg m2q3wkplusCapecitabine1000mg m2bidx14days Capecitabine1250mg m2bidx14days Randomized Conclusion IxabepiloneveryactiveinbreastcancerAdvantagesNosteroidpremedicationMinimalhypersensitivityreactionsandnausea vomiting3 5 Grade3peripheralneuropathyCombinationsinprogress 分子靶点药物临床研究 HercecptininHer2 MBCBevazcizumabinMBC TargetingDysregulatedPathwaysWithNovelAgents HERtyrosinekinaseinhibitors Apoptosis Rassignaling VEGFsignaling HERsignaling TP Apoptoticagents Kinaseinhibitors Anti HERMAbs Tumor activatedchemotherapy Anti VEGFMAbsandothermolecules StrategiesforErbBReceptorInhibition Monoclonalantibodies MAbs againsterbBreceptorsSmall moleculetyrosinekinaseinhibitors SMTKIs Her2过表达的MBC的治疗 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 赫赛丁单药治疗的客观疗效StudyH0649g 赫赛丁单药一线治疗MBCStudyH0650ResponseRate N 114patients2mg kgVs4mg kgCompleteresponses7ptPartialresponses23ptOverallresponserate30pt 26 Timetoresponse1 8moResponseduration11 22mo 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 ComparativeStudyHO648gOverallORR P value0 10380 0001 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 Overallsurvival CTpatientstreatedwithHerceptin afterdisease24 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 Meancombinationindexvaluesforchemotherapeuticdrug Herceptin combinationsinvitro 5 dFUrdisametaboliteofXeloda Herceptin plusXeloda demonstratesadditiveactivityinvivo3 1KonecnyG etal BreastCancerResTreat1999 57 114 Abstract467 2PegramM etal Oncogene1999 18 2241 513Fujimoto OuchiK etal CancerChemotherPharmacol2002 49 211 16 Herceptin与每周paclitaxel n 95 PhaseIItrialofHerceptin plusweeklypaclitaxel 90mg m2 RRsin70 80 rangeinHER2 positivepatients169 DAKO 67 PAb1 76 CB11 81 TAB250 75 FISH UsedbyIntergrouptodevelopadjuvantdesignWidelyusedintheclinicalsettingintheUSAandAustralia 1SeidmanAD etal JClinOncol2001 19 2587 95 Herceptin联合docetaxelPhaseIItrials Herceptin wasadministeredasa4mg kginitialdosefollowedby2mg kgweeklyuntilprogression Herceptin与vinorelbine联合 1BursteinH etal JClinOncol2001 19 2722 302JahanzebM etal BreastCancerResTreat2001 69 284 Abstract429 Herceptin与gemcitabine联合 PhaseIIstudy n 59 ofHerceptin plusgemcitabine 1 200mg m2day1and8q3 weekly RR 33 22 59 InpatientswithIHC3 disease RR 45 17 38 O ShaughnessyJA etal BreastCancerResTreat2001 69 302 Abstract523 Herceptin与docetaxel和platinum联合 First line Herceptin incombinationwithdocetaxelandcisplatin BCIRG101 RR 79 49 62 Herceptin incombinationwithdocetaxelandcarboplatin BCIRG102 RR 56 31 55 ThisregimenisbeinginvestigatedinphaseIIItrialsintheadjuvant 006 andmetastatic 007 settings NabholtzJ M etal EurJCancer2001 37 S190 Abstract695 Herceptin与Xeloda联合 InpatientspretreatedformetastaticbreastcancerRR 62 8 13 whenXeloda wasadministeredatadoseof1 125mg m2b i d 1RR 53 9 17 whenXeloda wasadministeredatadoseof1 000mg m2b i d 2ThecombinationwaswelltoleratedAdditionaltrialstofurtherexaminethiscombinationincludearandomisedphaseIItrialofHerceptin plusdocetaxel Xeloda 1BangemannN etal AnnOncol2000 11 143 Abstract653P 2BangemannN etal BreastCancerResTreat2000 64 123 Abstract530 M77001 trialdesign HER2 positiveMBC IHC3 and orFISH n 188 Docetaxel 100mg m2q3wx6 Docetaxel100mg m2q3wx6 Herceptin 4mg kgloading 2mg kgweeklyuntilPD PatientsprogressingondocetaxelalonecouldcrossovertoreceiveHerceptin Twopatientsdidnotreceivestudymedicationn 92 n 94 M77001 efficacysummary Kaplan Meierestimate Intent to treatpopulation 12 monthcut off Herceptininmetastaticbreastcancer EvidencesupportsHerceptintherapyinHER 2overexpressingmetastaticbreastcancer1 Herceptinwithchemotherapyinfirstlineimprovedtimetotreatmentfailureincreasedresponseratesimprovedsurvival2 Herceptinmonotherapyactiveinfirstlineandinsecond thirdlinefavourablesafetyprofilesurvivaldatainfirstlinenotinferiortocombinationtherapy 3药联合治疗Her2OverexpressMBCWeeklyVS3weekly NCCTG Chemotherapy Trastuzumabx6mo Trastuzumabq3w 1stLineHER2 MBC PI PerezEA 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 Survival InterimAnalysis 81 50 2 yearOS 100 89 1 yearOS weekly n 18 q3w n 18 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 valuefromFisher sExacttest post hocanalysis 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 valuefromFisher sExacttest post hocanalysis Motor Sensory Conclusions Bothq3wandweeklyregimenofcarboplatin paclitaxel andtrastuzumabarehighlyactiveinHER2 MBCWeeklyregimenisbettertoleratedTherapeuticratioofcarboplatin paclitaxel andtrastuzumabinHER2 MBCisimprovedwithweeklyregimen ForbesJF etal ASCO2006 Abstract516 BCIRG007 First LineTrastuzumab Docetaxel CarboplatinHER2 MBC BCIRG007 First LineTrastuzumab Docetaxel CarboplatinHER2 MBC Medianfollow up 27 6monthsTimetoprogressionequivalentbetweenarms P 57 TH 11 07monthsTCH 10 35monthsSimilaroverallresponseTH 72 5 TCH 72 7 Mediansurvival 40months ForbesJF etal ASCO2006 Abstract516 BCIRG007 First LineTrastuzumab Docetaxel CarboplatinHER2 MBC DifferenttoxicityprofilesnotedwitheachtreatmentTH neuropathy myalgia rash nailchanges neutropeniaTCH thrombocytopenia nausea vomiting ForbesJF etal ASCO2006 Abstract516 CerbB2Over expressedMBCHerceptin联合化疗的首选方案 Paclitaxel CarboplatinDocetaxel CarboplatinVinorebine NCCN2004 Tykerb lapatinib ADualReceptorTyrosineKinaseInhibitor Potent oral reversibledualtyrosinekinaseinhibitorBindstoATPsiteoferbB 1anderbB 2receptorkinases blockingkinaseactivityanddownstreamsignaling StrategiesforErbBReceptorInhibition Monoclonalantibodies MAbs againsterbBreceptorsSmall moleculetyrosinekinaseinhibitors SMTKIs Lapatinib TargetingEGFRandHER2 LapatiniboraltyrosinekinaseinhibitorofErbB1andErbB2BlockssignalingthroughEGFRandHER2homodimersandheterodimersMayalsopreventsignalingbetweenErbB1 ErbB2andotherErbBfamilymembers RusnakDW etal MolCancerTher 2001 1 85 94 XiaW etal Oncogene 2002 21 6255 6263 EGF100151 Lapatinib CapecitabineinAdvancedBreastCancer GeyerCE etal ASCO2006 ClinicalScienceSymposium EGF100151 Lapatinib CapecitabineinAdvancedBreastCancer cont d Additionoflapatinibtocapecitabineinwomenwithtreatment refractory advancedmetastaticbreastcancerassociatedwithLongertimetoprogression36 9vs19 7wks P 00016 Longerprogression freesurvival36 9vs17 9wks P 000045 Fewerprogressionsordeaths38 vs48 Response independentreview Overall 22 5 vs14 3 P 113 GeyerCE etal ASCO2006 ClinicalScienceSymposium EGF100151 Lapatinib CapecitabineinAdvancedBreastCancer cont d GeyerCE etal ASCO2006 ClinicalScienceSymposium EGF103009 LapatinibMonotherapyinRelapsed RefractoryIBC 58womenwithrelapsedorrefractoryinflammatorybreastcancergivenlapatinib1500mg dayinphaseIIstudyMedianpriorchemotherapyregimens 4 5 range 0 21 ResponseratesinErbB2overexpressers 62 AllclinicalrespondersErbB2 IHC3 FISH p ErbB2 ResponseratesinErbB1overexpressers 8 3 SpectorNL etal ASCO2006 Abstract502 TargetingHER2viaHSP 90 Heatshockprotein 90 HSP 90 isachaperoneproteinforavarietyofoncogenicproteins includingHER2 ER PR AKT MET andRafkinase17 AAG KOS 953 aninhibitorofHSP 90 suppressestumorgrowthinmousexenograftmodelsofHER2 humanbreastcancers ModiS etal ASCO2006 Abstract501 17 AAG Trastuzumab Partialresponse 159 inlungmetastasisTumorregression 4AllHER2 MBCwhoprogressedontrastuzumabDecreasesinlung nodal breastmetastasesnotedStabledisease 4 4months PhaseIItrialof17 AAG 450mg m2 trastuzumabinHER2 metastaticbreastcancerongoing DatafromphaseItrialof17 AAG trastuzumabreportedWeekly17 AAG variousdoses standardweeklytrastuzumab25patientswithvarioussolidtumortypesevaluatedLargestproportionhadHER2 overexpressingbreastcancerMaximum450mg m2dosewelltolerated1grade2thrombocytopenia ModiS etal ASCO2006 Abstract501 单药紫杉醇vslapatinib 紫杉醇一线治疗Her2过表达MBCPhaseIII 首次复发的转移性乳腺癌有可测量病灶Her2过渡表达 IHC orFISH 抗血管生成因子治疗 TargetingDysregulatedPathwaysWithNovelAgents HERtyrosinekinaseinhibitors Apoptosis Rassignaling VEGFsignaling HERsignaling TP Apoptoticagents Kinaseinhibitors Anti HERMAbs Tumor activatedchemotherapy Anti VEGFMAbsandothermolecules AgentsTargetingtheVEGFPathway PodarandAnderson Blood 2005 105 1383 VEGFR 2 VEGFR 1 Endothelialcell Small moleculeVEGFRinhibitors PTK787 SU11248 ZD6474 BAY43 9006 Anti VEGFRantibodies IMC 1121b VEGF Anti VEGFantibodies bevacizumab SolubleVEGFRs VEGF TRAP Capecitabine BevacizumabforMBC Significantlyincreasedresponseincombinationarm19 8 vs9 1 P 001NosignificantdifferenceinPFSorOS combinationvssingleagentPFS 4 86vs4 17mos HR 0 98 OS15 1vs14 5mos MillerKDetal JClinOncol 2005 23 792 799 Capecitabine n 230 Capecitabine Bevacizumab n 232 PatientswithMBCPreviouslytreatedwithA T Capecitabine BevacizumabforMBC MillerKDetal JClinOncol 2005 23 792 799 Eligiblepatientshadreceivedanthracyclineandtaxanetreatment1or2priorchemotherapyregimensforMBC orRelapsewithin12monthsofcompletinganthracycline andtaxane containingadjuvanttherapyStudyregimenincludedbevacizumab15mg kgIVq3w capecitabine1250mg m2poBIDx14dq3w Bevacizumab的其他研究 Millerandcolleagues 2 比较capecitabinewithandwithoutbevacizumabIn462patients一线MBCcapecitabine2500mg m2 day 14dq21dayalonecapecitabine2500mg m2 day bevacizumab15mg kgd1虽然RR在XB组较高 19 8 vsXalone 9 1 但是PFS XB4 86mvs4 17msXalone 或OS XB15 1msvsX14 5ms 都没有改善 与Herceptin Paclitaxel在改善PFSvsOS的疗效十分相似 是以往细胞毒方案所不能比拟的 显示十分重要的前景 有可能成为Her2阴性乳癌的一线治疗 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 Bevaciz