多西他赛联用卡培他宾治疗her2阴性乳腺癌.docx

多西他赛联用卡培他宾治疗her2阴性乳腺癌.docx

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多西他赛联用卡培他宾治疗her2阴性乳腺癌

FinalResultsfromPhaseIITrialofNeoadjuvantDocetaxelandCapecitabineGivenSequentiallyorConcurrentlyforHER2-NegativeBreastCancers

AmeliaB.Zelnak1,

ToncredM.Styblo2,MonicaRizzo2,SherylG.Gabram2,WilliamC.Wood2,SeemaHarichand-Herdt3,SungjinKim4,YuanLiu4,RuthM.O'Regan1,

GeorgiaCenterforOncologyResearchandEducation

1DepartmentofHematologyandMedicalOncology,WinshipCancerInstitute,EmoryUniversity,SchoolofMedicine,Atlanta,GA

2DepartmentofSurgery,WinshipCancerInstitute,EmoryUniversity,SchoolofMedicine,Atlanta,GA

3FloridaHospitalMemorialMedicalCenterCancerInstitute,OrmondBeach,FL

4DepartmentofBiostatisticsandBioinformatics,WinshipCancerInstitute,EmoryUniversity,SchoolofMedicine,Atlanta,GA

Abstract

Background

Thecombinationofdocetaxelandcapecitabinehasbeendemonstratedtoimproveprogression-freesurvival（PFS）andoverallsurvival（OS）inpatientswithmetastaticbreastcancercomparedwithdocetaxelalone.Wehypothesizedthatthecombinationofdocetaxelandcapecitabine,givenconcomitantlyorsequentially,wouldpresentanonanthracycline-basedtreatmentoptionforpatientswithearlystageandlocallyadvancedbreastcancer.

PatientsandMethods

PatientswithstageItostageIIIC,humanepidermalgrowthfactorreceptor2–negative（HER2−）breastcancerwererandomlyassignedtoreceiveeitherdocetaxelfollowedbycapecitabine（D→C）ordocetaxeladministeredconcomitantlywithcapecitabine（DC）.

Results

BetweenApril2007andJuly2009,51patientswereaccruedtothetrialatanacademiccenter,acountyhospital,andcommunitysites.Mediantumorsizewas3.8cmand>70%ofpatientshadaxillarylymphnodeinvolvement.Fifty-sevenpercentofpatientsaccruedwereAfricanAmerican.Twenty-oneofthe51subjectshadtriple-negativebreastcancer.Thepathologiccompleteresponse（pCR）ratewas8%intheD→Carm;12%intheDCarm.ThepCRrateamongpatientswithtriple-negativebreastcancerwas19%.

Conclusion

Thecombinationofdocetaxelandcapecitabinehasmodestactivityintheneoadjuvantsetting.Theseresultsareconsistentwithothertrialsusingthiscombinationintheneoadjuvantsetting.

Keywords

Breastcancer;Capecitabine;Docetaxel;Neoadjuvantchemotherapy

Introduction

Neoadjuvantchemotherapyforbreastcancerresultsinhigherratesofbreastconservationwithsimilaroverallsurvival（OS）ratescomparedwithpostoperativeadjuvanttherapy.1Additionally,neoadjuvantchemotherapyprovidesanopportunitytoassesstheinvivochemosensitivityofatumor.Neoadjuvantchemotherapyisthestandardofcareforpatientswithinoperable,locallyadvanced,orinflammatorybreastcancerandiswidelyacceptedasatreatmentoptionforpatientswithearlierstagebreastcancerforwhomadjuvantchemotherapyisrecommended.2

Achievementofapathologiccompleteresponse（pCR）,definedasabsenceofinvasivediseaseatthetimeofsurgicalresection,isastrongprognosticfactorforimproveddisease-freesurvival（DFS）andOSinsomebutnotallsubtypesofbreastcancer.3and4IntheNationalSurgicalAdjuvantBreastandBowelProject（NSABP）B-18clinicaltrial,4cyclesofdoxorubicinandcyclophosphamide（AC）resultedinapCRrateof13%.5InNSABPB-27,theadditionof4cyclesofdocetaxelto4cyclesofACdoubledthepCRrateto26%.6InbothtrialspCRwasassociatedwithanimprovedlong-termoutcomecomparedwiththatinpatientswhodidnotachieveapCR.Theoptimalcombinationofneoadjuvantchemotherapyhasnotbeendetermined.pCRhasbeenusedastheprimaryendpointinearlierstageclinicaltrialsasasurrogateforDFSandOSbecauseitmaypredictlong-termclinicalbenefit.7Responsetoneoadjuvantchemotherapyvariesbetweenintrinsicsubtypesofbreastcancer.CareyetalanalyzedpCRratesforanthracycline-basedchemotherapyandshowedthatpatientswithbasalorHER2-enrichedsubtypesweremorelikelytoachieveapCRthanwerepatientswithluminalAorBtumors.4LiedtkeetalevaluatedpCRratesin>1100patientstreatedatasingleinstitution:

ThepCRrateamongpatientswithtriple-negativebreastcancerwas22%comparedwith11%inpatientswithouttriple-negativebreastcancer.8pCRratesbymolecularphenotypewerealsoassessedintheI-SPYtrialacrossmultipleinstitutions,confirmingthatluminalAandBbreastcancershavealowerpCRratecomparedwithbasal-likeandHER2-positive（HER2+）cancers.9

Capecitabineisanorallybioavailablefluoropyrimidinethatispreferentiallyconvertedto5-fluorouracilintumorsthrougha3-stepprocessrequiringtheenzymethymidinephosphorylase（TP）.Preclinicalstudieshavedemonstratedsynergisticinhibitionofgrowthbetweencapecitabineanddocetaxel,possiblyresultingfromaninductionofTPexpressionbydocetaxel.10Inalargerandomizedtrialofpatientswithmetastaticbreastcancer,thecombinationofcapecitabineanddocetaxelresultedinasignificantprogression-freesurvival（PFS）andOSadvantagecomparedwithsingle-agentdocetaxel.11Thisstudyinthemetastaticsettingwasnotdesignedtodetermineifcombinationtherapywasmoreeffectivethansequentialtherapywithbothagents.Single-agentcapecitabineisapprovedinpatientswithmetastaticbreastcancerwhohavereceivedpreviousanthracyclineandtaxane-basedtherapy.12

Basedonthedatainthemetastaticsetting,weevaluatedthecombinationofdocetaxelandcapecitabineinpatientswithHER2−,early-stage,orlocallyadvancedbreastcancer.Sinceitwasnotclearwhetherconcurrentorsequentialcombinationsoftheseagentswasoptimal,werandomizedpatientstoreceiveeitherbothagentsgivenconcomitantlyordocetaxelfollowedbycapecitabine,withequaldosesandcyclesineacharm.OverallthepCRratewasrelativelymodestbutconsistentwithotherstudies,andtherewerenounexpectedtoxicities.

PatientsandMethods

PatientEligibility

Patientswithpreviouslyuntreatedunilateralprimarybreastcarcinomawereenrolledinthestudyafterprovidingwritteninformedconsent.Abreastcancerdiagnosishadtobehistologicallyconfirmed.Patientshadmeasurabledisease,definedasapalpablelesionmeasuring≥1cmin2dimensionsusingacaliperoranabnormalmammogramorultrasonogramwithatleast1dimension≥1cm.Patientscouldnothaveevidenceofdiseaseoutsidethebreastorchestwall,exceptipsilateralaxillaryorinternalmammarylymphnodes.PatientswithclinicalstagesI,II,orIII,includinginflammatorybreastcancer,wereeligible.Patientshadtobeatleast18yearsofage,haveanEasternCooperativeOncologyGroupperformancestatusof0to2andnormalbloodcountandnormalrenalandhepaticfunction.HormonereceptorstatusandHER2statusweredeterminedaccordingtostandardmethodsattheenrollinginstitutions.

Patientswereexcludediftheyhadreceivedanyprevioustherapyfortheircurrentbreastcancerorwerepregnantorlactating.Theywerealsoexcludediftheyhadanyofthefollowing:

preexistingperipheralorsensoryneuropathy;uncontrolledcoagulopathy;malabsorptionsyndromeorinabilitytoswallowpills;clinicallysignificantcardiacdisease（eg,congestiveheartfailure,symptomaticcoronaryarterydisease,cardiacarrhythmiasnotwellcontrolledwithmedications）;historyofmyocardialinfarctionwithin12months;majorsurgerywithin28daysofstudyentry;evidenceofcentralnervoussystemmetastases;medical,psychological,orsurgicalconditionsthatmightcompromisestudyparticipation;seriousuncontrolledconcurrentinfection;knownhypersensitivitytodocetaxelorotherdrugsformulatedwithpolysorbate80;unanticipatedseverereactiontofluoropyrimidinetherapyorhypersensitivityto5-fluorouracil.Patientswithahistoryofpreviousorcurrentmalignancyatothersites,withtheexceptionofadequatelytreatedcarcinomainsituofthecervixorbasalorsquamouscellcarcinomaoftheskin,wereexcluded.Patientswithahistoryofothermalignancieswhohadremaineddiseasefreefor>5yearswereeligible.

StudyDesignandTreatment

ThiswasaphaseIIclinicaltrialevaluatingthesequentialadministrationofdocetaxelandcapecitabine（D→C）andtheirconcomitantadministration（DC）inpatientswithprimarybreastcancerintheneoadjuvantsetting.ThestudyprotocolwasreviewedandapprovedbytheEmoryUniversitySchoolofMedicineInstitutionalReviewBoard（IRB）andbytheWesternIRBforthecommunitysites.Eachstudyparticipantsignedanapprovedinformedconsentdocumentbeforeanystudy-specificprocedures.TheprimaryendpointofthestudywastodeterminethepCRratetopreoperativeD→CandtothecombinationofDC.ThestudywassponsoredbytheGeorgiaCenterforOncologyResearchandEducation（GeorgiaCORE）,astatewidenetworkofacademicandcommunityoncologists.

Patientswererandomlyassignedtoreceiveeither4cyclesofdocetaxel100mg/m2onday1every3weeksfollowedbycapecitabine1000mg/m2bymouthtwicedailyondays1to14every3weeksfor4cycles（total24weeks）ordocetaxel50mg/m2onday1concomitantwithcapecitabine1000mg/m2bymouthtwicedailyondays1to7every2weeksfor8cycles（total16weeks）.Thetotalplanneddoseofeachagent（400mg/m2docetaxeland112,000mg/m2capecitabine）andnumberofcycleswereequalineacharm.Incaseoftumorprogressioninthesequentialarm,patientscouldproceedwithcapecitabineordiscontinuestudytreatment（investigator'schoice）.Incaseoftumorprogressionintheconcomitantarm,studytreatmentwasdiscontinuedandadditionaltherapywasatthediscretionoftheinvestigator.Growthfactorsupportwaspermitted.Incaseofexcesstoxicity,dosemodificationguidelineswerefollowed.

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