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1、A Randomized Trial of Exemestane after Two to Three Yearsof Tamoxifen Therapy in Postmenopausal Womenwith Primary Breast CancerR. Charles Coombes, M.D., Ph.D., Emma Hall, Ph.D., Lorna J. Gibson, M.Phil., Robert Paridaens, M.D., Ph.D.,Jacek Jassem, M.D., Ph.D., Thierry Delozier, M.D., Stephen E. Jone

2、s, M.D., Isabel Alvarez, 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 Mickiewicz, M.D., Jorn Andersen, D.M.Sc.,Per E. Lønning, M.D., Ph.D., Giorgio C

3、occoni, M.D., Ph.D., Alan Stewart, M.D., Nick Stuart, D.M.,Claire F. Snowdon, M.Sc., Marina Carpentieri, Ph.D., Giorgio Massimini, M.D., and Judith M. Bliss, M.Sc.,backgroundTamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausalwomen with primary, estrogen-receptorpos

4、itive breast cancer. Despite this treatment,however, some patients have a relapse.methodsWe conducted a double-blind, randomized trial to test whether, after two to three yearsof tamoxifen therapy, switching to exemestane was more effective than continuing ta-moxifen therapy for the remainder of the

5、 five years of treatment. The primary end pointwas disease-free survival.resultsOf the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane,and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months,449 first events (local or metastatic recurrence, cont

6、ralateral breast cancer, or death)were reported 183 in the exemestane group and 266 in the tamoxifen group. The un-adjusted hazard ratio in the exemestane group as compared with the tamoxifen groupwas 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test),representing a

7、 32 percent reduction in risk and corresponding to an absolute benefit interms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8)at three years after randomization. Overall survival was not significantly different in thetwo groups, with 93 deaths occurring in the ex

8、emestane group and 106 in the tamoxifengroup. Severe toxic effects of exemestane were rare. Contralateral breast cancer oc-curred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04).conclusionsExemestane therapy after two to three years of tamoxifen therapy significantly imp

9、roveddisease-free survival as compared with the standard five years of tamoxifen treatment.n engl j med 350;11march 11, 2004From the Department of Cancer Medicine,Imperial College and Charing Cross Hospi-tal, London (R.C.C., L.J.G., C.F.S.); Instituteof Cancer Research, Sutton (E.H., J.M

10、.B.);South West Wales Cancer Institute, Swan-sea (G.B.); Cookridge Hospital, Leeds(D.D.); Cancer Research Centre, WestonPark Hospital, Sheffield (R.E.C.); Psycho-social Oncology Group, University of Sus-sex, Brighton (L.J.F.); Christie Hospital,Manchester (A.S.); and Ysbyty Gwynedd,Bangor, Gwynedd (

11、N.S.) all in the UnitedKingdom; Universitair Ziekenhuis, Leuven,Belgium (R.P.); Medical University ofGdansk, Gdansk, Poland (J.J.); CentreFrançois Baclesse, Caen, France (T.D.); U.S.Oncology Research, Houston (S.E.J.); Hos-pital Donostia, San Sebastián, Spain (I.A.);University of Regensbur

12、g, Regensburg, Ger-many (O.O.); University of Sydney, Sydney,Australia (A.S.C.); Istituto Nazionale perlo Studio e la Cura dei Tumori, Milan, Italy(E.B.); Instituto Angel Roffo, Buenos Aires,Argentina (E.M.); Århus University Hospi-tal, Århus, Denmark (J.A.); Haukeland Hos-pital, Universit

13、y of Bergen, Bergen, Norway(P.E.L.); University Hospital, Parma, Italy(G.C.); and Pharmacia Italia, Pfizer Group,Nerviano, Italy (M.C., G.M.). Address re-print requests to Dr. Coombes at the De-partment of Cancer Medicine, ImperialCollege London, 6th Fl., Cyclotron Bldg.,Hammersmith Hospital, Du Can

14、e Rd.,London W12 0NN, United Kingdom.N Engl J Med 2004;350:1081-92.Copyright © 2004 Massachusetts Medical Society.1081Downloaded from on March 10, 2004. This article is being provided free of charge for use in China:NEJM Sponsored.Copyright © 2004 Massachusetts Medical Society

15、. All rights reserved.bThe new england journal of medicinereast cancer is estrogen-depen-dent in many cases, and reducing the estro-gen levels by means of ovariectomy cancause regression of established disease,1 especiallyif the tumor is rich in estrogen receptors.2 The selec-tive estrogen-receptor

16、modulator tamoxifen blocksthe action of estrogen by binding to one of the acti-vating regions of the estrogen receptor.3,4 When giv-en to women with estrogen-receptorpositive breastcancer for five years after surgery, tamoxifen reducesthe risk of recurrence by 47 percent and the risk ofdeath by 26 p

17、ercent.5 The riskbenefit ratio of us-ing tamoxifen for longer than five years remainsunclear,6,7 and trials addressing this question areongoing. International guidelines recommend thatpatients should not receive adjuvant tamoxifen ther-apy for more than five years outside the context ofa clinical tr

18、ial.8Alternative endocrine therapy is often effectiveafter disease has relapsed despite tamoxifen treat-ment, since at that point, estrogen receptors are stillpresent in most patients.9 Several trials have con-firmed the superiority of aromatase inhibitors overprogestins in this setting.10,11 Aromat

19、ase is an en-zyme that catalyzes the conversion of androgens toestrogens. There are two classes of third-generationoral aromatase inhibitors: irreversible steroidal in-activators, exemplified by exemestane,12,13 and re-versible nonsteroidal inhibitors, such as anastro-zole and letrozole.14Exemestane

20、 inhibits aromatization in vivo byabout 98 percent.15 It is superior to megestrol ace-tate with respect to time to progression in advancedbreast cancer14 and has antitumor effects in patientswho have no response to third-generation nonste-roidal aromatase inhibitors.16 Preliminary resultsshow that e

21、xemestane is superior to tamoxifen asfirst-line therapy for metastatic disease.17 Theo-retically, exemestane should not cause endometri-al thickening or endometrial cancer, which are oc-casionally observed after tamoxifen therapy.18The Intergroup Exemestane Study (IES) was de-signed to investigate w

22、hether exemestane, whengiven to postmenopausal women who remainedfree of recurrence after receiving adjuvant tamoxifentherapy for two to three years for primary breast can-cer, could prolong disease-free survival, as com-pared with continued tamoxifen therapy. Here wereport the results of the second

23、 planned interimanalysis, which we are releasing in accordance withthe recommendation of the independent data andsafety monitoring committee.Our study is an international, intergroup, phase 3,randomized, double-blind trial comparing the effi-cacy and safety of continued adjuvant tamoxifentherapy wit

24、h the efficacy and safety of exemestanetherapy in postmenopausal women with primarybreast cancer who remain free of disease after re-ceiving adjuvant tamoxifen therapy for two to threeyears. Women were randomly assigned to receiveoral exemestane (25 mg) or tamoxifen (20 mg) dai-ly in order to comple

25、te a total of five years of adju-vant endocrine treatment (Fig. 1). Randomizationwas performed with the use of permuted blocksand was stratified according to center.The primary end point was disease-free survival,defined by the time from randomization to recur-rence of breast cancer at any site, dia

26、gnosis of a sec-ond primary breast cancer, or death from any cause.Secondary end points included overall survival, theincidence of contralateral breast cancer, and long-term tolerability. For consistency and comparabilitywith other reported trials,19 we also report breast-cancerfree survival, with c

27、ensoring of deaths thatoccurred without a recurrence of breast cancer or adiagnosis of contralateral breast cancer. Resultsfrom substudies assessing the quality of life, uterinethickness, bone metabolism, and bone mineral den-sity will be reported separately.The study was coordinated by the Internat

28、ionalCollaborative Cancer Group (ICCG), Imperial Col-lege London, and conducted under the auspices ofthe Breast International Group (BIG). The trial wasgoverned by a steering committee comprising rep-resentatives from the ICCG, participating coopera-tive groups, BIG, and the pharmaceutical-industrys

29、ponsor. Data for each cooperative group were col-lected by the groups data center and collated cen-trally by the ICCG Data Center. Central review andquerying and analysis of data were undertaken bythe ICCG Data Center in collaboration with the In-stitute of Cancer Research, where the independentstat

30、isticians were based. The sponsor had no accessto the trial data base or interim analyses. The studywas overseen by a data and safety monitoring com-mittee that was independent of the ICCG Data Cen-ter, the steering committee, and the sponsor.The institutional review board at each partici-pating ins

31、titution approved the study protocol, andall patients gave written informed consent. Ran-domization was performed by the data center for1082n engl j med 350;11march 11, 2004Downloaded from on March 10, 2004. This article is being provided free of charge for use in China:NEJM

32、 Sponsored.Copyright © 2004 Massachusetts Medical Society. All rights reserved.exemestane versus tamoxifen after initial tamoxifen therapy for breast cancereach cooperative group or through the ICCG DataPatients were required to have adequate hematolog-Center.ic, renal, and liver function at th

33、e time of random-ization (defined as a normal blood count, a serumeligibility criteriacreatinine concentration less than 1.5 times the up-Patients were eligible if they had histologicallyper limit of normal, and a serum alanine amino-confirmed, completely resected unilateral invasivetransferase conc

34、entration less than 2.5 times the up-breast carcinoma that was positive for estrogen re-per limit of normal).ceptors (as determined by means of standard immu-The criteria for exclusion included the presencenostaining procedures) or that was of unknown re-of a tumor with known negative estrogen-recep

35、torceptor status. Patients were postmenopausal (55status; evidence of local relapse or a distant metas-years of age or older with amenorrhea for moretasis since the time of diagnosis; a clinically signif-than two years, or amenorrhea for more than oneicant skeletal, cardiac, or endocrine disorder; a

36、ndyear at the time of diagnosis) and had received ad-the use of hormone-replacement therapy within fourjuvant tamoxifen therapy for at least two years butweeks before randomization. Patients were also ex-not more than three years and one month. Most pa-cluded if they had clinical evidence of severe

37、osteo-tients (95 percent) received tamoxifen at a dose ofporosis or a history of a previous neoplasm other20 mg daily, but patients who received 30 mg dailythan carcinoma in situ of the cervix or basal-cell skinwere eligible (and continued to receive the samecarcinoma or if they were taking concomit

38、ant anti-dose if they were assigned to the tamoxifen group).coagulant agents, a selective estrogen-receptor1083n engl j med 350;11march 11, 2004Downloaded from on March 10, 2004. This article is being provided free of charge for use in China:NEJM Sponsored.Copyright © 2

39、004 Massachusetts Medical Society. All rights reserved.The new england journal of medicinemodulator other than tamoxifen, or any other formof hormonal therapy.The protocol required adequate treatment of pri-mary disease, including postoperative radiotherapyin patients who had been treated with breas

40、t-pre-serving surgery. Neoadjuvant chemotherapy waspermitted according to a consistent policy withineach center. Patients were required to have startedchemotherapy within three months after diagnosisand to have begun receiving tamoxifen and radio-therapy within three months after the completionof ch

41、emotherapy.follow-up proceduresMeier time-to-event curves are presented. Thegroups were compared in terms of the incidence ofadverse effects with the use of chi-square tests. Be-cause of the early release of the efficacy results, dataon adverse events are provisional; the validation pro-cess is ongo

42、ing. Here, we emphasize the adverse ef-fects for which there is a difference between groupsSymptoms, side effects, findings on clinical exam-ination, and the level of compliance with treatmentwere recorded at three-month intervals during thefirst year after randomization, every six months dur-ing th

43、e second and third years, and annually there-after. Hematologic and biochemical analyses andmammography (if the local procedure permitted)were performed annually.statistical analysisEnrollment of 4400 patients was required in orderto detect an absolute difference of 3.6 percent indisease-free surviv

44、al three years after randomiza-tion (with 88 percent power and a two-sided levelof significance of 4.3 percent after adjustment forinterim analyses). The a priori expectation was thatthe principal analysis would be conducted after 716end-point events had occurred. Three interim effi-cacy analyses we

45、re to be conducted, with the use ofOBrienFleming stopping boundaries, after onequarter, one half, and three quarters of the plannedtotal number of events. Emerging trial data and in-terim analyses were reviewed by the independentdata and safety monitoring committee, whose termsof reference dictated

46、that their decisions be guided(but not mandated) by the above stopping rules.Analyses were performed according to the in-tention-to-treat principle and included all patientswho underwent randomization. All data were cen-sored on June 30, 2003, but the snapshot of dataused for the analysis of efficac

47、y was updated to in-clude all data received by the ICCG Data Centerthrough December 31, 2003. Log-rank tests wereused to compare the two groups. Two-sided P valuesand 95 percent confidence intervals are reported.Cox proportional-hazards regression was used toadjust for prespecified prognostic factor

48、s.20 Hazardratios of less than 1.0 favor exemestane. Kaplan1084We recruited 4742 women from 37 countries and20 cooperative groups between February 1998 andFebruary 2003. Recruitment continued beyond thetarget enrollment of 4400 in order to complete ac-crual to the substudies on the effects on bone a

49、ndquality of life. The median follow-up was 30.6months (interquartile range, 23.9 to 36.6). The twogroups were balanced with regard to base-line char-acteristics (Table 1). A total of 192 patients were sub-sequently found to be ineligible (16 because of pre-vious breast cancers, 31 because of previo

50、us othercancers, 74 because they had undergone breast-conserving surgery but had not received radiother-apy, 25 because they were of uncertain menopausalstatus, 24 because they had known estrogen-recep-tornegative tumors, 8 because they had used hor-mone-replacement therapy within four weeks be-fore

51、 randomization, and 14 for other reasons); thesepatients are included in all analyses on an intention-to-treat basis.efficacyThe second interim analysis, which was triggeredby the reporting of 358 events, was presented to thedata and safety monitoring committee on Decem-ber 2, 2003, and included all

52、 data that had been re-ceived relating to events and follow-up throughJune 30, 2003. At that meeting, the committeerecommended that key efficacy data be released,because the OBrienFleming stopping boundary(P=0.004) had been exceeded. The steering com-mittee agreed to the release at a meeting on Dece

53、m-ber 3, 2003. This report constitutes a refined analysisof that presented to the data and safety monitoringcommittee.A total of 449 first events were reported: 183 inthe exemestane group and 266 in the tamoxifengroup (Table 2). The unadjusted hazard ratio in theexemestane group as compared with the

54、 tamoxifengroup was 0.68 (95 percent confidence interval, 0.56n engl j med 350;11march 11, 2004Downloaded from on March 10, 2004. This article is being provided free of charge for use in China:NEJM Sponsored.Copyright © 2004 Massachusetts Medical Society. All rights res

55、erved.exemestane versus tamoxifen after initial tamoxifen therapy for breast cancer*Plusminus values are means ±SD. Patients with missing data had no value reported for a given variable; for patients in the “unknown” category, data were reported as unknown.Data for positive and negative estroge

56、n-receptor status include retrospectively ascertained status for some patients whose status was unknown at randomization.n engl j med 350;11march 11, 20041085Downloaded from on March 10, 2004. This article is being provided free of charge for use in China:NEJM Sponsored.Copy

57、right © 2004 Massachusetts Medical Society. All rights reserved.The new england journal of medicine*Data for distant recurrence and primary cancer in the contralateral breast include patients who also reported a local re-lapse. One patient in the exemestane group died of breast cancer after con

58、tralateral breast cancer had been reported andis also included in the analysis of distant-diseasefree survival.to 0.82; P=0.00005 by the log-rank test), which cor-responds to an absolute benefit of 4.7 percent (95percent confidence interval, 2.6 to 6.8) at three years(Fig. 2). Disease-free survival three years after ran-domization was 91.5 percent (95 percent confidenceinterval, 90.0 to 92.7) in the exemestane group and86.8 percent (95 percent confidence interval, 85.1to 88.3) in the tamoxifen group. In a subsidiaryanalysis of breast-cancerfree survival in whi