依西美坦的优势重点.docx

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依西美坦的优势重点.docx

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依西美坦的优势重点.docx

依西美坦的优势重点

ARandomizedTrialofExemestaneafterTwotoThreeYears

ofTamoxifenTherapyinPostmenopausalWomen

withPrimaryBreastCancer

R.CharlesCoombes,M.D.,Ph.D.,EmmaHall,Ph.D.,LornaJ.Gibson,M.Phil.,RobertParidaens,M.D.,Ph.D.,

JacekJassem,M.D.,Ph.D.,ThierryDelozier,M.D.,StephenE.Jones,M.D.,IsabelAlvarez,M.D.,

GianfilippoBertelli,M.D.,OlafOrtmann,M.D.,Ph.D.,AlanS.Coates,M.D.,EmilioBajetta,M.D.,DavidDodwell,M.D.,

RobertE.Coleman,M.D.,LesleyJ.Fallowfield,D.Phil.,ElizabethMickiewicz,M.D.,JornAndersen,D.M.Sc.,

PerE.Lønning,M.D.,Ph.D.,GiorgioCocconi,M.D.,Ph.D.,AlanStewart,M.D.,NickStuart,D.M.,

ClaireF.Snowdon,M.Sc.,MarinaCarpentieri,Ph.D.,GiorgioMassimini,M.D.,andJudithM.Bliss,M.Sc.,

background

Tamoxifen,takenforfiveyears,isthestandardadjuvanttreatmentforpostmenopausal

womenwithprimary,estrogen-receptor–positivebreastcancer.Despitethistreatment,

however,somepatientshavearelapse.

methods

Weconductedadouble-blind,randomizedtrialtotestwhether,aftertwotothreeyears

oftamoxifentherapy,switchingtoexemestanewasmoreeffectivethancontinuingta-

moxifentherapyfortheremainderofthefiveyearsoftreatment.Theprimaryendpoint

wasdisease-freesurvival.

results

Ofthe4742patientsenrolled,2362wererandomlyassignedtoswitchtoexemestane,

and2380tocontinuetoreceivetamoxifen.Afteramedianfollow-upof30.6months,

449firstevents（localormetastaticrecurrence,contralateralbreastcancer,ordeath）

werereported—183intheexemestanegroupand266inthetamoxifengroup.Theun-

adjustedhazardratiointheexemestanegroupascomparedwiththetamoxifengroup

was0.68（95percentconfidenceinterval,0.56to0.82;P<0.001bythelog-ranktest）,

representinga32percentreductioninriskandcorrespondingtoanabsolutebenefitin

termsofdisease-freesurvivalof4.7percent（95percentconfidenceinterval,2.6to6.8）

atthreeyearsafterrandomization.Overallsurvivalwasnotsignificantlydifferentinthe

twogroups,with93deathsoccurringintheexemestanegroupand106inthetamoxifen

group.Severetoxiceffectsofexemestanewererare.Contralateralbreastcanceroc-

curredin20patientsinthetamoxifengroupand9intheexemestanegroup（P=0.04）.

conclusions

Exemestanetherapyaftertwotothreeyearsoftamoxifentherapysignificantlyimproved

disease-freesurvivalascomparedwiththestandardfiveyearsoftamoxifentreatment.

nengljmed350;11www.nejm.orgmarch11,2004FromtheDepartmentofCancerMedicine,ImperialCollegeandCharingCrossHospi-tal,London（R.C.C.,L.J.G.,C.F.S.）;InstituteofCancerResearch,Sutton（E.H.,J.M.B.）;SouthWestWalesCancerInstitute,Swan-sea（G.B.）;CookridgeHospital,Leeds（D.D.）;CancerResearchCentre,WestonParkHospital,Sheffield（R.E.C.）;Psycho-socialOncologyGroup,UniversityofSus-sex,Brighton（L.J.F.）;ChristieHospital,Manchester（A.S.）;andYsbytyGwynedd,Bangor,Gwynedd（N.S.）—allintheUnitedKingdom;UniversitairZiekenhuis,Leuven,Belgium（R.P.）;MedicalUniversityofGdansk,Gdansk,Poland（J.J.）;CentreFrançoisBaclesse,Caen,France（T.D.）;U.S.OncologyResearch,Houston（S.E.J.）;Hos-pitalDonostia,SanSebastián,Spain（I.A.）;UniversityofRegensburg,Regensburg,Ger-many（O.O.）;UniversityofSydney,Sydney,Australia（A.S.C.）;IstitutoNazionaleperloStudioelaCuradeiTumori,Milan,Italy（E.B.）;InstitutoAngelRoffo,BuenosAires,Argentina（E.M.）;ÅrhusUniversityHospi-tal,Århus,Denmark（J.A.）;HaukelandHos-pital,UniversityofBergen,Bergen,Norway（P.E.L.）;UniversityHospital,Parma,Italy（G.C.）;andPharmaciaItalia,PfizerGroup,Nerviano,Italy（M.C.,G.M.）.Addressre-printrequeststoDr.CoombesattheDe-partmentofCancerMedicine,ImperialCollegeLondon,6thFl.,CyclotronBldg.,HammersmithHospital,DuCaneRd.,LondonW120NN,UnitedKingdom.NEnglJMed2004;350:

Downloadedfromwww.nejm.orgonMarch10,2004.ThisarticleisbeingprovidedfreeofchargeforuseinChina:

NEJMSponsored.

bThenewenglandjournalofmedicine

reastcancerisestrogen-depen-

dentinmanycases,andreducingtheestro-

genlevelsbymeansofovariectomycan

causeregressionofestablisheddisease,1especially

ifthetumorisrichinestrogenreceptors.2Theselec-

tiveestrogen-receptormodulatortamoxifenblocks

theactionofestrogenbybindingtooneoftheacti-

vatingregionsoftheestrogenreceptor.3,4Whengiv-

entowomenwithestrogen-receptor–positivebreast

cancerforfiveyearsaftersurgery,tamoxifenreduces

theriskofrecurrenceby47percentandtheriskof

deathby26percent.5Therisk–benefitratioofus-

ingtamoxifenforlongerthanfiveyearsremains

unclear,6,7andtrialsaddressingthisquestionare

ongoing.Internationalguidelinesrecommendthat

patientsshouldnotreceiveadjuvanttamoxifenther-

apyformorethanfiveyearsoutsidethecontextof

aclinicaltrial.8

Alternativeendocrinetherapyisofteneffective

afterdiseasehasrelapseddespitetamoxifentreat-

ment,sinceatthatpoint,estrogenreceptorsarestill

presentinmostpatients.9Severaltrialshavecon-

firmedthesuperiorityofaromataseinhibitorsover

progestinsinthissetting.10,11Aromataseisanen-

zymethatcatalyzestheconversionofandrogensto

estrogens.Therearetwoclassesofthird-generation

oralaromataseinhibitors:

irreversiblesteroidalin-

activators,exemplifiedbyexemestane,12,13andre-

versiblenonsteroidalinhibitors,suchasanastro-

zoleandletrozole.14

Exemestaneinhibitsaromatizationinvivoby

about98percent.15Itissuperiortomegestrolace-

tatewithrespecttotimetoprogressioninadvanced

breastcancer14andhasantitumoreffectsinpatients

whohavenoresponsetothird-generationnonste-

roidalaromataseinhibitors.16Preliminaryresults

showthatexemestaneissuperiortotamoxifenas

first-linetherapyformetastaticdisease.17Theo-

retically,exemestaneshouldnotcauseendometri-

althickeningorendometrialcancer,whichareoc-

casionallyobservedaftertamoxifentherapy.18

TheIntergroupExemestaneStudy（IES）wasde-

signedtoinvestigatewhetherexemestane,when

giventopostmenopausalwomenwhoremained

freeofrecurrenceafterreceivingadjuvanttamoxifen

therapyfortwotothreeyearsforprimarybreastcan-

cer,couldprolongdisease-freesurvival,ascom-

paredwithcontinuedtamoxifentherapy.Herewe

reporttheresultsofthesecondplannedinterim

analysis,whichwearereleasinginaccordancewith

therecommendationoftheindependentdataand

safetymonitoringcommittee.Ourstudyisaninternational,intergroup,phase3,randomized,double-blindtrialcomparingtheeffi-cacyandsafetyofcontinuedadjuvanttamoxifentherapywiththeefficacyandsafetyofexemestanetherapyinpostmenopausalwomenwithprimarybreastcancerwhoremainfreeofdiseaseafterre-ceivingadjuvanttamoxifentherapyfortwotothreeyears.Womenwererandomlyassignedtoreceiveoralexemestane（25mg）ortamoxifen（20mg）dai-lyinordertocompleteatotaloffiveyearsofadju-vantendocrinetreatment（Fig.1）.Randomizationwasperformedwiththeuseofpermutedblocksandwasstratifiedaccordingtocenter.Theprimaryendpointwasdisease-freesurvival,definedbythetimefromrandomizationtorecur-renceofbreastcanceratanysite,diagnosisofasec-ondprimarybreastcancer,ordeathfromanycause.Secondaryendpointsincludedoverallsurvival,theincidenceofcontralateralbreastcancer,andlong-termtolerability.Forconsistencyandcomparabilitywithotherreportedtrials,19wealsoreportbreast-cancer–freesurvival,withcensoringofdeathsthatoccurredwithoutarecurrenceofbreastcanceroradiagnosisofcontralateralbreastcancer.Resultsfromsubstudiesassessingthequalityoflife,uterinethickness,bonemetabolism,andbonemineralden-sitywillbereportedseparately.ThestudywascoordinatedbytheInternationalCollaborativeCancerGroup（ICCG）,ImperialCol-legeLondon,andconductedundertheauspicesoftheBreastInternationalGroup（BIG）.Thetrialwasgovernedbyasteeringcommitteecomprisingrep-resentativesfromtheICCG,participatingcoopera-tivegroups,BIG,andthepharmaceutical-industrysponsor.Dataforeachcooperativegroupwerecol-lectedbythegroup’sdatacenterandcollatedcen-trallybytheICCGDataCenter.CentralreviewandqueryingandanalysisofdatawereundertakenbytheICCGDataCenterincollaborationwiththeIn-stituteofCancerResearch,wheretheindependentstatisticianswerebased.Thesponsorhadnoaccesstothetrialdatabaseorinterimanalyses.Thestudywasoverseenbyadataandsafetymonitoringcom-mitteethatwasindependentoftheICCGDataCen-ter,thesteeringcommittee,andthesponsor.Theinstitutionalreviewboardateachpartici-patinginstitutionapprovedthestudyprotocol,andallpatientsgavewritteninformedconsent.Ran-domizationwasperformedbythedatacenterfor

1082nengljmed350;11www.nejm.orgmarch11,2004

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NEJMSponsored.

exemestaneversustamoxifenafterinitialtamoxifentherapyforbreastcancer

eachcooperativegrouporthroughtheICCGDataPatientswererequiredtohaveadequatehematolog-

Center.ic,renal,andliverfunctionatthetimeofrandom-

ization（definedasanormalbloodcount,aserum

eligibilitycriteriacreatinineconcentrationlessthan1.5timestheup-

Patientswereeligibleiftheyhadhistologicallyperlimitofnormal,andaserum

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