依西美坦的優(yōu)勢重點

1、The NEW ENGLANDJOURNAL of MEDICINEi It IanMARCH 11, 2004WL. |! MO. 11A Ran domized Trial of Exemesta ne after Two to Three Yearsof Tamoxife n Therapy in Postme nopausal Wome nwith Primary Breast Can cerR. Charles Coombes, M.D., Ph.D., Emma Hall, Ph.D., Lorna J. Gibson, M.Phil., Robert Paridae ns, M.

2、D., Ph.D.,Jacek Jassem, M.D., Ph.D., Thierry Delozier, M.D., Stephen E. Jon es, M.D., Isabel Alvare z, M.D.,Gianfilippo Bertelli, M.D., Olaf Ortmann, M.D., Ph.D., Alan S. Coates, M.D., Emilio Bajetta, M.D., David Dodwell, M.D.,Robert E. Coleman, M.D., Lesley J. Fallowfield, D.Phil., Elizabeth Mickie

3、wicz, M.D.,Jorn An derse n, D.M.Sc.,Per E. L?nning, M.D., Ph.D., Giorgio Cocconi, M.D., Ph.D., Alan Stewart, M.D., Nick Stuart, D.M.,Claire F. Snowdon, M.Sc., Marina Carpe ntieri, Ph.D., Giorgio Massimi ni, M.D., and Judith M. Bliss, M.Sc.,AB&T JL ACTbackgro undTamoxife n, take n for five years, is

4、the sta ndard adjuva nt treatme nt for postme nopausal wome n with primary, estroge n-receptopositive breast can cer. Despite this treatme nt, however, some patie nts have a relapse.methodsWe con ducted a double-bli nd, ra ndomized trial to test whether, after two to three years of tamoxife n therap

5、y, switchi ng to exemesta ne was more effective tha n con ti nuing tamoxife n therapy for the rema in der of the five years of treatme nt. The primary end point was disease-free survival.resultsOf the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to con ti nue

6、 to receive tamoxife n. After a media n follow-up of 30.6 mon ths,449 first eve nts (local or metastatic recurre nee, con tralateral breast can cer, or death) were reported 183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemesta ne group as compared wi

7、th the tamoxife n group was 0.68 (95 perce nt con fide nce in terval, 0.56 to 0.82; P r#i-v h4dU/iwntItl Foe *xMt1.4 fe el pll-rerls. Cl!9lihhkKIq* tr護Ji麗pWtr JiftcfMitdfEj rr：ciLia.fH矣rcWill Schema.IK? peKenwpp of pitiprrti wboconimw to fKfsve irtatni： reprentt lhe perce口費 who ire nal unown to haw-

8、drwon dhuhI ctwir ramtofruzed ncitment ard who begin mitui EimoMjfen therapy l5 five years before Owmber 11,2001exemesta ne versus tamoxife n after in itial tamoxife n therapy for breast can cer each cooperative group or through the ICCG DataPatie nts were required to have adequate hematolog-Center.

9、ic, renal, and liver function at the time of randomization (defined as a normal blood count, a serumeligibility criteriacreatinine concentration less than 1.5 times the up-Patie nts were eligible if they had histologicallyper limit of no rmal, and a serum ala nine aminocon firmed, completely resecte

10、d un ilateral inv asivetra nsferase concen tratio n less tha n2.5 times the up-breast carc inoma that was positive for estroge n re-per limit of no rmal).ceptors (as determ ined by means of sta ndard immu-The criteria for exclusi on in cluded the prese neeno sta ining procedures) or that was of unkn

11、own re-of a tumor with known n egative estroge n-receptorceptor status. Patie nts were postme nopausal (55status; evide nee of local relapse or a dista nt metas-years of age or older with ame no rrhea for moretasis since the time of diag no sis; a cli nically sig nif-than two years, or ame no rrhea

12、for more tha n on eica nt skeletal, cardiac, or en docri ne disorder; andyear at the time of diag no sis) and had received ad-the use of horm on e-replaceme nt therapy with in fourjuva nt tamoxife n therapy for at least two years butweeks before ran domizati on. Patie nts were also ex- not more tha

13、n three years and one mon th. Most pa-cluded if they had cli ni cal evide nee of severe osteo- tie nts (95 perce nt) received tamoxife n at a dose ofporosis or a history of a previous n eoplasm other20 mg daily, but patie nts who received 30 mg dailytha n carci noma in situ of the cervix or basal-ce

14、ll skin were eligible (and con ti nued to receive the samecarc inoma or if they were tak ing con comita nt an ti-dose if they were assig ned to the tamoxife n group).coagula nt age nts, a selective estroge n-receptor1083n engl j med 350;11www. march 11,2004Downl oaded from on Ma

15、rch 10, 2004. This article is being provided free of charge for use in Chi na:NEJM Spon sored.Copyright ? 2004 Massachusetts Medical Society. All rights reserved.The new en gla nd journal of medic ine modulator other tha n tamoxife n, or any other form of horm onal therapy.The protocol required adeq

16、uate treatme nt of primary disease, including postoperative radiotherapy in patie nts who had bee n treated with breast-pre- serv ing surgery. Neoadjuva nt chemotherapy was permitted accordi ng to a con siste nt policy within each cen ter. Patie nts were required to have started chemotherapy within

17、three mon ths after diag no sis and to have beg un recei ving tamoxife n and radiotherapy within three mon ths after the completi on of chemotherapy.follow-up proceduresMeier time-to-eve nt curves are prese nted. Thegroups were compared in terms of the in cide nee ofadverse effects with the use of c

18、hi-square tests. Be-cause of the early release of the efficacy results, data on adverse eve nts are provisi on al; the validati on pro-cess is ongoing. Here, we emphasize the adverse ef-fects for which there is a differe nee betwee n groupsRESULTSSymptoms, side effects, findings on cli ni cal examin

19、 atio n, and the level of complia nee with treatme nt were recorded at three-m on th in tervals duri ng the first year after ran domizati on, every six mon ths during the sec ond and third years, and annu ally thereafter. Hematologic and biochemical an alyses and mammography (if the local procedure

20、permitted) were performed annu ally.statistical an alysisEn rollme nt of 4400 patie nts was required in order to detect an absolute differe nee of 3.6 perce nt in disease-free survival three years after ran domiza- tion (with 88 percent power and a two-sided level of sig ni fica nee of 4.3 perce nt

21、after adjustme nt for interim analyses). The a priori expectation was that the prin cipal an alysis would be eon ducted after 716 en d-po int eve nts had occurred. Three in terim efficacy an alyses were to be eon ducted, with the use of O BrienFming stopping boundaries, after one quarter, one half,

22、and three quarters of the planned total nu mber of eve nts. Emergi ng trial data and interim an alyses were reviewed by the in depe ndent data and safety mon itori ng committee, whose terms of refere nee dictated that their decisi ons be guided (but not man dated) by the above stopp ing rules. An al

23、yses were performed accord ing to the infen tio n-to-treat prin ciple and in eluded all patie ntswho un derwe nt ran domizati on. All data were censored on June 30, 2003, but the sn apshot of data used for the an alysis of efficacy was updated to include all data received by the ICCG Data Center thr

24、ough December 31,2003. Log-ra nk tests were used to compare the two groups. Two-sided P values and 95 perce nt con fide nee in tervals are reported. Cox proporti on al-hazards regressi on was used to adjust for prespecified prog no stic factors.20 Hazard ratios of less than 1.0 favor exemestane. Kap

25、lan 1084We recruited 4742 wome n from 37 coun tries an d20 cooperative groups betwee n February 1998 an dFebruary 2003. Recruitme nt continued bey ond thetarget en rollme nt of 4400 in order to complete ac-crual to the substudies on the effects on bone andquality of life. The media n follow-up was 3

26、0.6m on ths (in terquartile ran ge, 23.9 to 36.6). The twogroups were bala need with regard to base-li ne char-acteristics (Table 1). A total of 192 patie nts were sub-seque ntly found to be in eligible (16 because of pre-vious breast can cers, 31 because of previous otherca ncers, 74 because they h

27、ad un derg one breast- con serv ing surgery but had not received radiother-apy, 25 because they were of un certa in men opausalstatus, 24 because they had known estroge n-recep-torgative tumors, 8 because they had used hor-mon e-replaceme nt therapy withi n four weeks before randomization, and 14 fo

28、r other reasons); thesepatients are included in all analyses on an inten tio n-to-treat basis.efficacyThe sec ond in terim an alysis, which was triggeredby the report ing of 358 eve nts, was prese nted to thedata and safety mon itori ng committee on Decem-ber 2, 2003, and in cluded all data that had

29、 bee n re-ceived relat ing to eve nts and follow-up throughJ une 30, 2003. At that meet ing, the committeerecommended that key efficacy data be released,because the Oien - BrFlemi ng stopp ing boun dary(P=0.004) had bee n exceeded. The steeri ng com-mittee agreed to the release at a meeting on Decem

30、-ber 3, 2003. This report constitutes a refined an alysisof that prese nted to the data and safety mon itori ngcommittee.A total of 449 first eve nts were reported: 183 in the exemesta ne group and 266 in the tamoxife ngroup (Table 2). The un adjusted hazard ratio in theexemesta ne group as compared

31、 with the tamoxife ngroup was 0.68 (95 perce nt con fide nee in terval, 0.56 n engl j med 350;11www. march 11,2004Downl oaded from on March 10, 2004. This article is being provided free of charge for use in Chi na:NEJM Spon sored.Copyright ? 2004 Massachusetts Medical Society. All rights reserved.Tiihk L ELase-Urteof t