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
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:
1081-92.Copyright©2004MassachusettsMedicalSociety.1081
Downloadedfromwww.nejm.orgonMarch10,2004.ThisarticleisbeingprovidedfreeofchargeforuseinChina:
NEJMSponsored.
Copyright©2004MassachusettsMedicalSociety.Allrightsreserved.
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
Downloadedfromwww.nejm.orgonMarch10,2004.ThisarticleisbeingprovidedfreeofchargeforuseinChina:
NEJMSponsored.
Copyright©2004MassachusettsMedicalSociety.Allrightsreserved.
exemestaneversustamoxifenafterinitialtamoxifentherapyforbreastcancer
eachcooperativegrouporthroughtheICCGDataPatientswererequiredtohaveadequatehematolog-
Center.ic,renal,andliverfunctionatthetimeofrandom-
ization(definedasanormalbloodcount,aserum
eligibilitycriteriacreatinineconcentrationlessthan1.5timestheup-
Patientswereeligibleiftheyhadhistologicallyperlimitofnormal,andaserum
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