乳腺癌辅助治疗规范的解读

乳腺癌辅助治疗规范的解读第1页/共94页2TreatmentGuidelinesareusefulGuidelinesprovideabenchmarkandintegratenewfindingsintoclinicalpracticeTheyaredynamicdocuments,whichneedperiodicupdateTheyaredevelopedtoreduceunder-treatment,over-treatmentandwrongtreatmentCompliancewithguidelineshasbeenshowntoimprovepatientoutcome第2页/共94页3AdjuvantTherapyforBreastCancer

TreatmentGuidelines7883889295980103058085902000GuidelinesSt.GallenNIHNCCN96yearly07如何掌握、使用？第3页/共94页4讨论内容辅助治疗对哪些人有益？如何选择哪种辅助治疗方法？化疗方案的选择分子靶向治疗作用内分泌治疗方法的选择第4页/共94页5AdaptedfromBonadonnaG.CancerRes.1992.AllPatients1 3 5 7 9 11 13 15yearsLOG-RANK:P=0.002WILCOXON:P=0.0001100500%Relapse-freesurvivalCMFSurgery36%26%1 3 5 7 9 11 13 15yearsLOG-RANK:P=0.02WILCOXON:P=0.02100500%OverallsurvivalCMFSurgery51%35%BreastCancer:AdjuvantCMF

(12months)orSurgeryAlonePremenopausal第5页/共94页630year’sfollowupofrandomisedstudiesof

adjuvantCMFinOperablebreastcancer:

cohortstudy

Relapsefreesurvival

Overallsurvival

BonadonnaBMJ330:217,2005复发相对危险降低34%HR0.71(P=0.005)各种死亡降低22%HR0.79(P=0.04)第6页/共94页730year’sfollowupofrandomisedstudiesof

adjuvantCMFinOperablebreastcancer:

cohortstudy

Overallsurvival

BonadonnaBMJ330:217,2005第7页/共94页8ComparativeEfficacyofAdjuvantChemotherapy:EBCTCGMeta-AnalysesTherapyReductionin

AnnualOdds,%RecurrenceDeathPolychemotherapyvs 23.5 15

nochemotherapy(1995) (P<.00001) (P<.00001)Anthracyclinesvs 12 11

CMF(1995) (P=.006) (P=.02)Anthracyclinesvs 10.8 15.7CMF(2000) (P=.0005) (P<.00001) 第8页/共94页92000OxfordOverviewAnalysis

A/E+vsCMF:AllDeaths0.51.52.015.7%(SE3.)

reduction

2p<0.00001 Deaths/Women Allocated Adjusted

A/E+ CMF* A/E+Deaths Logrank Variance

O–E ofO–EYearCode

andStudyNameMonths&Treatment76A4

SECSG26FACv6CMF93/26089/268-2.941.678L2ONCOFRANCE12FACVv12CMF52/13858/113-10.925.080C1SESwedenBCGA8ACv7CMF(+R)8/2113/22-2.25.080MINTMilan8CMF+4Av12CMF-/211-/212(nodata)83ANSABCIsraelBr02832CMF+4AVbCMFv6CMF23/5521/50-1.310.184BNSABPB-15*4AC±3CMFv6CMF(+R)716/15622(374/776)-14.8224.784K1GUN-3Naples3CMFEVv6CMF45/10558/115-5.223.784LICCGCharingCross8/6FECv6CMF20/25632/259-5.511.884Q2AustrianBCSG36CMFVAv6CMF67/12175/124-3.130.885Y1PRONACAM85N+/PreFECMvCMF(nodata)86G2NHGJapan10FACc10CMF(±Tam)(nodata)87D4+5+6GABG3Germany6FECv6CMF(±Tam)52/14260/146-7.523.687Q1PRONACAM874/5CMFEPv6CMF(nodata)88RBrusselsBelgium*8ECv6CMF138/5372(69/267)2.144.188VHSanCarlos,Madrid6FACv6CMF(nodata)89B2SWOG88976FACv6CMF(+R±Tam)173/1461223/1470-25.997.189RNCI-CMA.56FECv6CMF118/356135/360-10.159.189W123456cDenmark-Sweden*9FECV9CMF(+Pmd)150/6010.8(290/781)-31.891.091HNSABPB-23ER-ACvCMF(+Tam)91/1003100/1005-5.546.891QGUNMAM1NaplesZolTaM+(A;CMFvCMF)34/23243/234-3.818.294J1+2+3GOIRCSANG2BItaly6CMFEVv6CMF(+Tam)(nodata)Scottish4E;4CMFv8CMF(nodata)1780/

6850

(26.0%)-128.42019/

6906

(29.2%)752.5Total§*99%or 95%CIA/E+betterCMFbetterTreatmenteffect2p<0.00001Heterogeneitybetween15trials:2=12.9;p>0.1;NS14§1trialwithnodatadoesnotcontributetototal(allocatedA/E+:211;allocatedCMF:212)*Forbalance,controlpatientsin3-waytrialstratacounthalfortwiceinsubtotal(s)andinfinaltotalofevents/women.1.00(?Patients)(100Patients)(322Patients)(158Patients)(<480Patients)(?Patients) Ratioofannualdeathrates

A/E+:CMF第9页/共94页10第10页/共94页11第11页/共94页12HER2predictsbenefitfromadjuvantpaclitaxelafterACinnode-positivebreastcancer:

CALGB9344D.F.HayesASCO2006Abs510ALLER-HER2-2%

(-3,8)8%

(-2,18)-1%

(-8,5)HER2+22%

(12,32)31%

(17,44)9%

(-6,24)ALL7%

(2,12)16%

(8,24)0%

(-6,7)ER+第12页/共94页13BCIRG001StudyDesignDocetaxel 75mg/m2

Doxorubicin 50mg/m2Cyclophosphamide 500mg/m25-FU 500mg/m2

Doxorubicin 50mg/m2Cyclophosphamide 500mg/m2FACTACRDexamethasonepremedication,8mgbid,3daysProphylacticCipro

500mgbid,day5-14Every3weeksx6cyclesStratification:Nodes:

1-3

4+Center第13页/共94页14TACFAC0612182430364248MonthsNumberatRiskTACFAC7457367106786543731522317467296996566053341503105060708090100%AliveandDiseaseFree#EventsRRp-valueTAC1190.680.0011FAC170Total289DiseaseFreeSurvival(ITT)BCIRG001Medianfollow-up:33months82%74%第14页/共94页15NumberatRiskTACFAC745741732718700393171241746738728713678375171331#EventsRRp-valueTAC570.760.11FAC76Total133OverallSurvival(ITT)BCIRG001TACFAC0612182430364248Months5060708090100%Alive92%87%Medianfollow-up:33months第15页/共94页16DiseaseFreeSurvivalby

HormonalStatusTACFAC012243648MonthsNatRiskTACFAC2312171884702282021583405060708090100%AliveandDiseaseFreeTACFAC012243648MonthsNatRiskTACFAC514493466105151849744711605060708090100NegativePositiveRR=0.62p=0.005RR=0.68p=0.02第16页/共94页17第17页/共94页18第18页/共94页19第19页/共94页20EPI120mg/m2D1Q21D×4CCTX600mg/m2D1,8

MTX40mg/m2D1,8Q28D×4C5-FU600mg/m2D1,8R1998,6-2002,7972N+Taxit216multicenterphaseIIItrial

SequentialEpirubicin-Docetaxel-CMFasadjuvanttherapy

ofearlybreastcancer

A(E→CMF)n=486EPI120mg/m2D1Q21D×4CD100mg/m2D1Q21D×4CCTX600mg/m2D1,8

MTX40mg/m2D1,8Q28D×4C5-FU600mg/m2D1,8B(E→T→CMF)n=486A.R.BiancoASCO2006LBA520第20页/共94页21Taxit216multicenterphaseIIItrial

SequentialEpirubicin-Docetaxel-CMFasadjuvanttherapy

ofearlybreastcancer

A.R.BiancoASCO2006LBA520AsofMarch27th2006,medianfollowupwas53monthsDFSat5years:67%inarmAvs74%inarmB

HazardRatio(HR)of0.80(95%CI:0.62-1.03,p=0.079)Afteradjustementbypredefinedbalancingfactors(ER,Nodalandmenopausalstatus)HRwas0.78(95%CIs:0.61-1.00;p=0.05).AsforOS,117deathswereobservedwithHRof0.74(95%CIs:0.51-1.07,p=0.10)Followupupdateisstillongoing第21页/共94页22第22页/共94页23蒽环类+紫杉类可延生存期DFSOSJCO2008,26(1):44第23页/共94页24蒽环类+紫杉类可延生存期JCO2008,26(1):44第24页/共94页25蒽环类+紫杉类可延生存期JCO2008,26(1):44DFSOS第25页/共94页26不同紫杉用法的差异NEnglJMed2008,358(16):1663DFS第26页/共94页27不同紫杉用法的差异OSNEnglJMed2008,358(16):1663第27页/共94页28第28页/共94页29NCCTGN9831BCIRG006FISHN+/-ACPDDCarbo标准方案HERAIHCor

FISH赫赛汀1或2年观察组NSABPB-31IHCor

FISHIHCor

FISHIHC,免疫组织化学;

FISH,荧光原位杂交赫赛汀治疗1年赫赛汀辅助治疗临床试验赫赛汀1年赫赛汀1年(联合或序贯)赫赛汀1年(联合)赫赛汀1年(联合)AC-TAC-TAC-DTCH标准方案第29页/共94页30NSABPB-31NCCTGN9831Arm1Arm2ArmAArmBArmCACq3wk*4=paclitaxelq3wk*4=paclitaxelq1wk*12=trastuzumabq1wHERA(Randomizationafterchemotherapy)ArmANoHerceptinArmBArmC(1yr)(2yr)=trastuzumabq3w第30页/共94页31CombinedanalysisofB31/N9831ControlHerceptinArm1(B31)Arm2(B31)ArmA(N9831)ArmC(N9831)Combined: n=3,351;medianfollow-up2.0yrNSABPB-31: n=1,736;medianfollow-up2.4yr N9831: n=1,615;medianfollow-up1.5yr第31页/共94页3287%85%67%75%

N EventsACT 1679 261ACTH 1672 134%HR=0.48,2P=3x10-12ACTHACTYearsFromRandomizationCombinedAnalysisfor

DFS

ofNSABPB-31/NCCTG–N9831第32页/共94页33HazardRatio0.20.40.60.81.01.21.4ForestPlotForDFS:B31/N9831ProtocolNo.PositiveNodesTumorSizeHormoneReceptorAgeN9831NSABPB-31≥4.1cm2.1-4.0cm<2.0cmPositiveNegative

≥6050-5940-49≤39ALLDATA10+4-91-30第33页/共94页34AnnualHazardofDistantRecurrence01234020406080100120Rateper1000Women/YrYearsFromRandomizationACTHACT第34页/共94页35CombinedAnalysisfor

OS

ofNSABPB-31/NCCTG–N9831

ACTH94%91%87%92%ACT

N DeathsACT 1679 92ACTH 1672 62HR=0.67,2P=0.015YearsFromRandomizationB31/N9831第35页/共94页36Monthsfromrandomization05101520251693142899458028087169414721067629303102Events2-yr

DFS%HR[95%CI]pvalue12785.80.54[0.43,0.67]<0.000122077.4Trastuzumab1yrObservation%aliveanddiseasefree1009080706050403020100No.

atriskDFS:HERATrial第36页/共94页37012AllAny,neo-adjuvantchemotherapyNodalstatus0pos,noneo-adjuvantchemotherapy338735811008722032307n0.540.530.520.770.640.43Hazardratio1-3pos,noneo-adjuvantchemotherapy³4pos,noneo-adjuvantchemotherapyNoanthracyclineortaxaneAdjuvantchemotherapyregimenAnthracycline,notaxaneAnthracycline+taxaneNegativeReceptorstatus/endocrinetherapyPos+noendocrinetherapyPos+endocrinetherapy<35yrs35-49yrs50-59yrs³60yrs9729530.510.5316740.5146712340.490.682510.47149010910.520.535490.70AllAny,neo-adjuvantchemotherapyNodalstatus0pos,noneo-adjuvantchemotherapy338735811008722032307n0.540.530.520.770.640.43Hazardratio1-3pos,noneo-adjuvantchemotherapy³4pos,noneo-adjuvantchemotherapyNoanthracyclineortaxaneAdjuvantchemotherapyregimenAnthracycline,notaxaneAnthracycline+taxaneNegativeReceptorstatus/endocrinetherapyPos+noendocrinetherapyPos+endocrinetherapy<35yrsAgegroup35-49yrs50-59yrs³60yrs9729530.510.5316740.5146712340.490.682510.47149010910.520.535490.70TrastuzumabBetterDFSInPatientSubsets:HERATrialObservationBetter第37页/共94页38赫赛汀可减少三分之一的死亡风险012B-31/N9831ACPH

3HERACTxH1year2Medianfollow-up,yearsOverallsurvivalbenefitBCIRG006ACDH3BCIRG006DCarboH3Favours

HerceptinFavoursno

HerceptinHRSlamonetal2006

Perezetal2007;Smithetal2007H,Herceptin;AC,doxorubicin,cyclophosphamide

P,paclitaxel;D,docetaxel;Carbo,carboplatin

HR,hazardratioSizeofsquarerepresentssamplesize;horizontalbarsindicate95%confidenceintervals第38页/共94页39无论肿瘤大小，赫赛汀均显示DFS获益Slamonetal2006

Perezetal2007;Smithetal2007>2-5cmBCIRG006>2-5cm>5cm0.00.52.51.01.52.00-2cmN9831/B-310-2cm>5cmACDH<2cmDCarboH<2cm≥2cm≥2cmFavoursHerceptinFavoursnoHerceptinHRHERADFS,disease-freesurvival第39页/共94页40无论淋巴结情况，赫赛汀均显示DFS获益N,node1-3+nodesFavoursHerceptinFavoursnoHerceptin0.00.52.51.01.52.01-3+nodes≥4+nodesNotassessedN9831/B-31N-4-9+nodes>10+nodesDCarboHN-N+N+BCIRG006N-ACDHN-HERAHRSlamonetal2006

Perezetal2007;Smithetal2007第40页/共94页41无论年龄大小，赫赛汀均显示DFS获益35-49years0.00.52.51.01.52.0HERA<35years50-59years≥60yearsN9831/B-31<40years≥60years40-49years50-59yearsFavoursHerceptinFavoursnoHerceptinHRPerezetal2007;Smithetal2007第41页/共94页42CardiacMonitoring

~20%ofthepatientsdiscontinuedHerceptinbecauseofsymptomaticorasymptomaticheartproblemsBaseline3mns6mns9mns18mns15mnsAC*4Taxol*4Herceptin*12mns2.1%7.7%10.1%%stoppingHerceptinbytimeperiodLVEFmeasurements~4%ofpatientsnevergotHerceptinbecauseofdevelopingalowLVEFpostAC*4.ThisanalysisfromB31dataalone.第42页/共94页43CardiacSafety

AgeandPostACLVEFwerepredictorsoftheriskofdevelopingCHFRiskofCHF(%)Ageyoungerthan50Age50andolderInitialLVEF50-546.3%19.1%InitialLVEF55-642.2%5.2%InitialLVEF>650.6%1.3%Inbothagegroupsabout10%ofthepatientshadaLVEFof50-54,about50%ofthepatientshadaLVEFof55-64,and35%hadaLVEFof>65%.AverageriskofearlyCHFforpatientyoungerthan50is2%andolderthan50is~5%ThisanalysisfromB31dataalone.第43页/共94页44RiskofCardiacEvents

(nostrongevidenceofanmajordelayedtoxicity)Theonlycardiacdeaththatoccurredduringthisstudyoccurredinacontrolpatient.EndofHerceptintreatmentperiodThisanalysisfromB31dataalone.第44页/共94页45Slamonetal2006

Rastogietal2007

Suteretal2007

Perezetal2008赫赛汀辅助治疗的心脏安全性aDatanotcomparableduetodifferentassessmentcriteria

CHF,congestiveheartfailure;cum,cumulativeincidence

LVEF,leftventricularejectionfraction;NR,notreported3.0NRNR18.08.6Asymptomatic

LVEFdecline,%aH1yearACPHACPHACDHDCarboHArmHERANSABPB-31NCCTGN9831BCIRG0061,6789475701,0681,056nSevereCHF,%0.63.8cum(5yr)3.3cum(3yr)1.90.4Cardiacdeath,n00000第45页/共94页46HER2状态判断

IHC 免疫组化FISH 荧光原位杂交CISH 显色原位杂交SISH 银染原位杂交第46页/共94页47Estimationoftheepidemiologicaleffectoftrastuzumabover20yearsinfiveEuropeancountriesASCO2008,abst,6611第47页/共94页48ASCO2008,abst,6611Estimationoftheepidemiologicaleffectoftrastuzumabover20yearsinfiveEuropeancountries第48页/共94页49HER2阳性乳腺癌治疗原则

使早期乳腺癌患者复发风险降低36%~52%,死亡风险降低33%AC→T→H:(H4mg/kg,与首次T同时使用;然后H2mg/kg维持1年。或T结束后,H6mg/kg维持1年)每3周方案,目前推荐治疗时间为1年在开始治疗的第3、6、9、18个月监测心脏情况H辅助治疗的标准疗程为1年,至少应治疗6个月以保证患者最大获益第49页/共94页50St.Gallen2003第50页/共94页51St.Gallen2003第51页/共94页52St.Gallen2003第52页/共94页53EvolutionofAdjuvantTreatmentofBreastCancer1970’1980’1990’2000’非蒽环类方案含蒽环类方案含紫杉类方案含赫赛丁方案第53页/共94页54第54页/共94页55CHEMOTHERAPYREGIMENS-ST.GALLEN2005

IMPLICATIONSFORPATIENTCAREACx4CMFx6FAC,FECx6CAF,CEFx6A(E)CMFWithoutTaxanesTACACPorDWithTaxanesH第55页/共94页56CHEMOTHERAPYREGIMENS-ST.GALLEN2005

IMPLICATIONSFORPATIENTCAREStandardEfficacySuperiorEfficacyACx4CMFx6FAC,FECx6CAF,CEFx6A(E)CMFWithoutTaxanesTACACPorDWithTaxanesComplexityToxicityEconomiccostButgreaterH第56页/共94页57ChoiceofAdjuvantRegimens第57页/共94页58低危患者：

CMF×6周期或AC、EC×4～6周期

中危患者：

FAC或FEC×6周期

高危患者：

AC→T，FEC×3→T×3，

TAC，A→T→C，密集化疗

乳腺癌按不同危险度治疗第58页/共94页59ChangesinchemotherapyregimensforolderwomenwithbreastcancerwhoreceivedadjuvantchemotherapyforstageItoIIIbreastcancer第59页/共94页60小结CMF有最长的远期疗效结果，至今仍用含蒽环类化疗是目前最基础的标准方案含紫杉类的地位已得到不断证实及巩固

(某些亚组的疗效待进一步观察)赫赛丁可增加化疗的效果剂量密度已开始动摇了传统的三周疗法第60页/共94页61第61页/共94页62100个月的结果：T—21.8%A—17.0%AbsoluteDifference:4.8%第62页/共94页63第63页/共94页64第64页/共94页65MA.17:TrialDesign

Primaryendpoint:DFSSecondaryendpoints:OS/safety/QOL*n=2575(efficacy);2154(safety)intheFEMARAarm.

†n=2582(efficacy);2145(safety)intheplaceboarm.

Gossetal.NEnglJMed.2003;349:TBD.Randomization(Disease-free)TamoxifenPlaceboqd†FEMARA(Letrozole)2.5mgqd*5yearsearlyadjuvant5yearsextendedadjuvant第65页/共94页66MA.17Results:Disease-FreeSurvivalbyTreatmentDuration(cont’d)Gossetal.NEnglJMed.2003;349:TBD.87%93%IncreasingbenefitinestimatedDFSwithtreatmentduration第66页/共94页67第67页/共94页68第68页/共94页69第69页/共94页70第70页/共94页71第71页/共94页72第72页/共94页73第73页/共94页74ATACEXEMBIG1.98(BIGFEMTA)TAMOXIFENAIPLACEBO

ARNO(J)MA-17NSABPB33

EXEM027TEAMEXETrialStrategiesin

AdjuvantTherapy:AIs第74页/共94页75第75页/共94页76第76页/共94页77AI.AdjuvantTrials:DFSTAMATACBIG1-98IESABCSG/ARNOMA-1710.820.810.60.60.5P-values

0.010.0030.00005<0.00180.00008Medianfollow-up(m)332630.62628UPFRONTAIDELAYEDAI第77页/共94页78AI与TAM的随机对照临床试验

HazardratioMedianAromataseDisease-freeTimetodistantFu(m)inhibitorsurvivalmetastasesOS初始治疗：Aromataseinhibitorvs.TAMATAC100Anastrozole0.850.840.97BIG1-98