|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2006.08.8617 on January 2 2007 © 2007 American Society of Clinical Oncology. Five Years of Letrozole Compared With Tamoxifen As Initial Adjuvant Therapy for Postmenopausal Women With Endocrine-Responsive Early Breast Cancer: Update of Study BIG 1-98
From the International Breast Cancer Study Group (IBCSG); IBCSG Coordinating Center, Bern; Swiss Group for Clinical Cancer Research (SAKK), Senology Center of Eastern Switzerland, Kantonsspital, St Gallen; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; University of Sydney, Sydney; Australian New Zealand Breast Cancer Trials Group, University of Newcastle, Newcastle Mater Hospital, Newcastle, New South Wales; Box Hill and Maroondah Hospitals, Melbourne, Australia; IBCSG Statistical Center, Dana-Farber Cancer Institute; Harvard School of Public Health; Frontier Science and Technology Research Foundation, Boston, MA; Danish Breast Cancer Group, Rigshospitalet, Copenhagen; Vejle Hospital, Vejle, Denmark; French Breast Cancer Group, Institut Bergonié, Bordeaux, France; Department of Medical Oncology, University Hospital Gasthuisberg, Catholic University of Leuven; Jules Bordet Institute; Brussels, Belgium; European Institute of Oncology, Milan; National Cancer Research Institute, Genoa, Italy; National Institute of Oncology, Budapest, Hungary; The Royal Marsden Hospital, London; Christie Hospital National Health Service Trust, South Manchester University Hospital Trust, Manchester, United Kingdom; and the Cancer Center Maria Sklodowska-Curie Memorial Institute of Oncology, Warsaw, Poland Address reprint requests to International Breast Cancer Study Group Coordinating Center, Effingerstrasse 40, CH-3008 Bern, Switzerland; e-mail: alan.coates{at}ibcsg.org
Purpose: Previous analyses of the Breast International Group (BIG) 1-98 four-arm study compared initial therapy with letrozole or tamoxifen including patients randomly assigned to sequential treatment whose information was censored at the time of therapy change. Because this presentation may unduly reflect early events, the present analysis is limited to patients randomly assigned to the continuous therapy arms and includes protocol-defined updated results. Patients and Methods: Four thousand nine hundred twenty-two of the 8,028 postmenopausal women with receptor-positive early breast cancer randomly assigned (double-blind) to the BIG 1-98 trial were assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen; the remainder of women were assigned to receive the agents in sequence. Disease-free survival (DFS) was the primary end point. Results: At a median follow-up time of 51 months, we observed 352 DFS events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen. This reflected an 18% reduction in the risk of an event (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to previous reports. Patients on tamoxifen experienced more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding. Patients on letrozole experienced more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure. Conclusion: The present updated analysis, which was limited to patients on monotherapy arms in BIG 1-98, yields results similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent.
Several large studies attest to the value of third-generation aromatase inhibitors in the adjuvant systemic therapy of postmenopausal women with endocrine-responsive early breast cancer,1-6 and such therapy has been recommended as part of the standard care in this patient group.7-9 The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole with sequences of 2 years of one of these agents followed by 3 years of the other. Previously reported results, called the primary core analysis, compared initial tamoxifen and letrozole and included all available data from patients randomly assigned to the monotherapy arms and data from the sequential therapy arms censored at the time of the therapy switch.3 Such an analysis of all four arms is valid but difficult to compare with other studies because it gives considerable weight to early events. Because prospective meta-analyses of aromatase inhibitor trials are planned (J. Cuzick, J. Bliss, R.D. Gelber, personal communication, September 2006), we present here an analysis of data derived only from patients randomly assigned to continuous tamoxifen or letrozole on the monotherapy arms of study BIG 1-98. The analysis is based on a protocol-specified update.
The design and conduct of the study have been described elsewhere.3 Briefly, BIG 1-98 is a randomized, phase III, double-blind trial comparing the following four options: monotherapy with letrozole or with tamoxifen for 5 years, or sequential administration of tamoxifen for 2 years followed by letrozole for 3 years, or sequential administration of letrozole for 2 years followed by tamoxifen for 3 years. The trial was conducted in postmenopausal women with estrogen receptor–and/or progesterone receptor–positive operable invasive breast cancer. From March 1998 to March 2000, patients were randomly assigned to one of the following two arms: monotherapy with letrozole (2.5 mg daily) or tamoxifen (20 mg daily). From April 1999 to May 2003, patients were randomly assigned to all four arms (Fig 1). Hormone receptor status was based on local assessment.
The scheduled update of the BIG 1-98 trial was defined in the protocol and reviewed by the BIG 1-98 Data and Safety Monitoring Committee. This analysis is restricted to patients who were randomly assigned to the monotherapy arms. The primary end point was disease-free survival (DFS), which was defined as the time from random assignment to the earliest time of invasive recurrence in local, regional, or distant sites; a new invasive breast cancer in the contralateral breast; any second (nonbreast) malignancy; or death from any cause. Protocol-specified secondary end points included overall survival, which was defined as the time from random assignment to death from any cause, and systemic DFS, which was defined as the time from random assignment to systemic recurrence (ignoring local and contralateral breast events, second (nonbreast) malignancy, or death). The following three exploratory end points were analyzed to facilitate comparison with other published studies: DFS as defined earlier but ignoring second (nonbreast) malignancies; time to recurrence ignoring second (nonbreast) malignancies and censoring deaths without recurrence; and time to distant recurrence additionally ignoring local, regional, and contralateral breast recurrence. Death without prior cancer event is a type of DFS event defined as any death that occurs without evidence of breast cancer recurrence or second primary cancer at any time during or after completion of trial treatment. An adverse event by definition occurs or begins during trial treatment or within 28 days of trial treatment completion, regardless of prior recurrence.
Statistical Analysis
Role of Coordinating Group, Trial Steering Committee, and Funding Source Novartis, the manufacturer of letrozole, provided drug distribution and financial support and imposed no restrictions on the investigators with respect to trial data. The article was prepared by the authors, who had full access to the data and who made final decisions on content, and the steering committee (including a minority membership of Novartis employees) reviewed the article and offered changes.
Between March 1998 and May 2003, 8,028 women were randomly assigned to receive 5 years of adjuvant endocrine therapy with letrozole, tamoxifen, or a sequence of these agents. Of these women, 4,933 patients were allocated to continuous therapy with either letrozole or tamoxifen (Fig 1). Eleven patients (seven assigned to letrozole and four assigned to tamoxifen) withdrew consent, declined all therapy, and submitted no follow-up data after random assignment. The results of the remaining 4,922 patients are reported here. Patient characteristics were well-balanced and similar to those reported for the primary core analysis.3 Details are available in Appendix Table A1 (online only). Median follow-up time of the monotherapy arms for this updated analysis was 51 months, which is substantially longer than that of the primary core analysis because of the exclusion of patients on the sequential arms censored at therapy switch. Approximately half of the patients were still receiving study therapy, whereas more than 1,200 had completed 5 years of treatment. More patients in the letrozole group discontinued trial treatment early as a result of an adverse event (12.3% of patients on letrozole and 11.1% of patients on tamoxifen), whereas more patients in the tamoxifen group discontinued treatment early as a result of disease progression (7.9% of patients on letrozole and 11.5% of patients on tamoxifen; Appendix Table A2, online only).
Efficacy
We explored various protocol-defined subgroups to identify whether there was any apparent difference in the relative efficacy of letrozole on DFS compared with the overall benefit observed. No subgroups showed significantly different relative efficacy; in particular, no significant heterogeneity was observed by nodal involvement status or progesterone receptor status (Fig 3B). Cumulative incidence analyses of breast cancer recurrence, second nonbreast cancer, and death without cancer event are shown in Figure 4. Types of second primary cancers included endometrial (letrozole, n = 4; tamoxifen, n = 16), colon (letrozole, n = 10; tamoxifen, n = 13), lung (letrozole, n = 5; tamoxifen, n = 8), ovarian (letrozole, n = 2; tamoxifen, n = 6), renal (letrozole, n = 3; tamoxifen, n = 8), and other (letrozole, n = 39; tamoxifen, n = 31). Causes of death without prior cancer event included cerebrovascular accident (letrozole, n = 8; tamoxifen, n = 3), thromboembolic event (letrozole, n = 3; tamoxifen, n = 3), cardiac (letrozole, n = 12; tamoxifen, n = 7), sudden death of unknown cause (letrozole, n = 7; tamoxifen, n = 11), and other causes (letrozole, n = 30; tamoxifen, n = 24).
Safety Prespecified adverse events, including cholesterol values (90.8% nonfasting), were collected every 6 months while on study.3 The analysis population for safety included 4,895 patients, excluding 27 patients who did not receive any trial treatment. More patients receiving letrozole, compared with patients receiving tamoxifen, reported at least one adverse event of any grade (2,292 patients v 2,165 patients, respectively) and at least one life-threatening or fatal adverse event (113 of 2,448 patients [4.6%] v 92 of 2,447 patients [3.8%], respectively). Table 2 lists the worst grade of adverse events by type. Safety profiles of letrozole and tamoxifen in this updated analysis of monotherapy are generally consistent with the previously reported results of BIG 1-98. Similar to the primary core results,3 patients on tamoxifen experienced significantly more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding. Patients on letrozole experienced significantly more bone fractures, arthralgia, low-grade cholesterol elevation, and cardiovascular events other than ischemic heart disease and cardiac failure. The relatively higher recording of low-grade cholesterol elevation on letrozole may be largely an artifact reflecting a cholesterol-lowering effect of tamoxifen. Although the overall incidence of cardiac adverse events did not differ significantly between the two treatments, a trend for higher grade cardiac events on letrozole compared with tamoxifen was seen (Table 2).
Note that grade 5 adverse events in Table 2 include deaths that occurred within 4 weeks of receiving trial treatment, whereas deaths without prior cancer event (which are summarized in Results, under Efficacy, and Table 1) can occur at any time. The difference in number of deaths without recurrence (60 of 2,463 of patients on letrozole, 2.4%; 48 of 2,459 patients on tamoxifen, 2.0%) was not statistically significant (P = .25).
All reported trials show that modern aromatase inhibitors reduce the risk of relapse of early breast cancer among postmenopausal women with endocrine-responsive early breast cancer, whether in direct comparison to the standard agent tamoxifen or as extended therapy after completion of tamoxifen. Uncertainty persists about the optimal time to introduce aromatase inhibitor therapy (whether initially as in the present analysis of BIG 1-98 and in the Arimidex, Tamoxifen, Alone or in Combination [ATAC] trial1; after approximately 2 years of tamoxifen2,4,5; or after completion of 5 years of tamoxifen6). Models seeking to compare these approaches have been proposed,15 but direct randomized comparisons are as yet lacking. One such comparison will become available when data from the sequential therapy arms of BIG 1-98 mature. Meanwhile, a meta-analysis of aromatase inhibitor trials has been proposed. To present data more directly comparable with other studies, we conducted this updated analysis of BIG 1-98 limited to the patients assigned to 5 years of continuous therapy with either letrozole or tamoxifen. The initial report of BIG 1-98 included patients randomly assigned to the two sequential arms, censoring follow-up at the time of therapy switch. Although this allowed optimal examination of the early efficacy results, as the trial matures, the inclusion of these extra patients progressively biases the overall results by stressing events in the first 2 years of therapy. The present analysis avoids this potential problem and yet provides an adequately powered comparison with more prolonged follow-up of the two continuous therapy arms. Nevertheless, more prolonged follow-up of this and other adjuvant trials of aromatase inhibitors is indicated; at the time of this analysis, more than 1,000 patients remain on therapy on each arm. It will also be important to see whether the early benefits of aromatase inhibitors are maintained with prolonged follow-up. Tamoxifen benefits are known to persist for years after the completion of therapy.16 The conclusions of the present analysis are essentially confirmatory of the primary core analysis,3 but the present data should provide a more easily understood and unbiased basis for comparison with other studies. The most relevant comparison is with the hormone receptor–positive cohort in the first update of the ATAC trial, which compared 5 years of tamoxifen with anastrozole. At a median follow-up time of 47 months, ATAC investigators reported 635 DFS events and a hazard ratio of 0.82 (95% CI, 0.65 to 0.93) favoring anastrozole. Definitions of end points varied slightly between ATAC and BIG 1-98, with ATAC ignoring second (nonbreast) primaries in its definition of DFS and BIG 1-98 ignoring ductal carcinoma in situ in its definition of DFS. In the present analysis of BIG 1-98 at a median follow-up time of 51 months, after ignoring second (nonbreast) primary events, 671 DFS events were reported, with a hazard ratio of 0.83 (95% CI, 0.71 to 0.96) favoring letrozole. The hazard ratio for the exploratory end point of time to recurrence was identical between the present analysis of BIG 1-98 (Fig 3A) and the aforementioned ATAC analysis, and neither study shows a significant difference in overall survival. This analysis adds to the body of data supporting a role for the inclusion of an aromatase inhibitor in the adjuvant therapy of postmenopausal women with receptor-positive early breast cancer.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Henning Mouridsen, Novartis; Louis Mauriac, Novartis; John F. Forbes, Novartis; Robert Paridaens, Novartis; István Láng, Novartis; Lucia Del Mastro, Novartis; Ian Smith, Novartis; Andrew Wardley, Novartis; Aron Goldhirsch, Novartis Stock: Beat Thürlimann, Novartis Honoraria: Henning Mouridsen, Novartis; Louis Mauriac, Novartis; John F. Forbes, Novartis; Robert Paridaens, Novartis; István Láng, Novartis; Lucia Del Mastro, Novartis; Ian Smith, Novartis; Jacquie Chirgwin, Novartis; Andrew Wardley, Novartis; Aron Goldhirsch, Novartis Research Funds: Aparna Keshaviah, Novartis; Louis Mauriac, Novartis; Robert Paridaens, Novartis; Monica Castiglione-Gertsch, Novartis; Richard D. Gelber, Novartis; Jacquie Chirgwin, Novartis; Tadeusz Pienkowski, Novartis; Karen N. Price, Novartis; Aron Goldhirsch, Novartis Testimony: N/A Other: N/A
Conception and design: Alan S. Coates, Aparna Keshaviah, Beat Thürlimann, Henning Mouridsen, John F. Forbes, Monica Castiglione-Gertsch, Richard D. Gelber, Ian Smith, Karen N. Price, Aron Goldhirsch Administrative support: Alan S. Coates, Monica Castiglione-Gertsch, Karen N. Price Provision of study materials or patients: Aparna Keshaviah, Beat Thürlimann, Henning Mouridsen, Louis Mauriac, John F. Forbes, Robert Paridaens, Monica Castiglione-Gertsch, Marco Colleoni, István Láng, Lucia Del Mastro, Ian Smith, Jacquie Chirgwin, Jean-Marie Nogaret, Tadeusz Pienkowski, Andrew Wardley, Erik H. Jakobsen, Karen N. Price, Aron Goldhirsch Collection and assembly of data: Alan S. Coates, Aparna Keshaviah, Beat Thürlimann, Henning Mouridsen, Louis Mauriac, John F. Forbes, Robert Paridaens, Monica Castiglione-Gertsch, Marco Colleoni, István Láng, Lucia Del Mastro, Ian Smith, Jacquie Chirgwin, Jean-Marie Nogaret, Tadeusz Pienkowski, Andrew Wardley, Erik H. Jakobsen, Karen N. Price, Aron Goldhirsch Data analysis and interpretation: Alan S. Coates, Aparna Keshaviah, Henning Mouridsen, Louis Mauriac, John F. Forbes, Monica Castiglione-Gertsch, Richard D. Gelber, Ian Smith, Andrew Wardley, Karen N. Price, Aron Goldhirsch Manuscript writing: Alan S. Coates, Aparna Keshaviah, Richard D. Gelber, Karen N. Price Final approval of manuscript: Alan S. Coates, Aparna Keshaviah, Beat Thürlimann, Henning Mouridsen, Louis Mauriac, John F. Forbes, Robert Paridaens, Monica Castiglione-Gertsch, Richard D. Gelber, Marco Colleoni, István Láng, Lucia Del Mastro, Ian Smith, Jacquie Chirgwin, Jean-Marie Nogaret, Tadeusz Pienkowski, Andrew Wardley, Erik H. Jakobsen, Karen N. Price, Aron Goldhirsch
BIG 1-98 Collaborative Group Participants Steering Committee. B. Thürlimann (Chair), L. Blacher, M. Castiglione, A.S. Coates, T. Cufer, J.F. Forbes, R.D. Gelber, A. Goldhirsch, A. Hiltbrunner, S.B. Holmberg, A. Keshaviah, R. Maibach, A. Martoni, L. Mauriac, H.T. Mouridsen, K.N. Price, M. Rabaglio, A. Santoro, I.E. Smith, C. Straehle, G. Viale. Novartis: H.A. Chaudri-Ross, A. Covelli, D.B. Evans, W. Hackl, E. Raman, M.G. Porro. International Breast Cancer Study Group (IBCSG) Scientific Committee. A. Goldhirsch, A.S. Coates (Co-Chairs), L. Blacher, M. Castiglione, J.F. Forbes, R.D. Gelber, B.A. Gusterson, A. Hiltbrunner, C. Hürny, E. Murray, K.N. Price, M. Rabaglio, R. Studer, G. Viale, A. Wallgren. IBCSG Foundation Council. B. Thürlimann (President), M. Castiglione, A.S. Coates, J.P. Collins, H. Cortés Funes, R.D. Gelber, A. Goldhirsch, M. Green, A. Hiltbrunner, S.B. Holmberg, D.K. Hossfeld, I. Láng, J. Lindtner, F. Paganetti, C.-M. Rudenstam, R. Stahel, H.-J. Senn, A. Veronesi. Coordinating Center (Berne, Switzerland). M. Castiglione (CEO), A. Hiltbrunner (Director), M. Rabaglio, G. Egli, B. Cliffe, S. Ribeli-Hofmann, F. Munarini, R. Kammler, R. Studer, B. Ruepp, R. Maibach, N. Munarini. Statistical Center (Dana-Farber Cancer Institute, Boston, MA). R.D. Gelber (Group Statistician), K.N. Price (Director of Scientific Administration), A. Keshaviah (Trial Statistician), H. Litman, H. Huang, L.J. Somos, B. Timmers, L. Nickerson. Data Management Center (Frontier Science and Technology Research Foundation, Amherst, NY). L. Blacher (Director of Data Management), T. Heckman Scolese (Coordinating Data Manager), M. Belisle, M. Caporale, J. Celano, L. Dalfonso, L. Dooley, S. Fischer, K. Galloway, J. Gould, R. Hinkle, M. Holody, G. Jones, R. Krall, S. Lippert, J. Meshulam, L. Mundy, A. Pavlov-Shapiro, K. Scott, M. Scott, S. Shepard, J. Swick, L. Uhteg, D. Weinbaum, C. Westby, T. Zielinski. Central Pathology Review Office. University of Glasgow, Glasgow, United Kingdom: B.A. Gusterson, E. Mallon; European Institute of Oncology, Division of Pathology, Milano, Italy: G. Viale, P. Dell'Orto, M. Mastropasqua, B. Del Curto. Data and Safety Monitoring Committee. D.F. Hayes, J.E. Garber, S.W. Lagakos, I. Lindgren. Study Support (Novartis Corp, Basel, Switzerland). E. Waldie, I. van Hoomissen, M. De Smet, W. Schmidt, A. Bolton, W. Hackl.
Breast International Group (BIG) International Breast Cancer Study Group (IBCSG) Australia. The Cancer Council Victoria, Melbourne, VIC: F. Abell, R. Basser, R. Bell, B. Brady, D. Blakey, P. Briggs, I. Burns, P. Campbell, M. Chao, J. Chirgwin, B. Chua, K. Clarke, J. Collins, R. De Boer, J.C. Din, R. Doig, A. Dowling, R. Drummond, N. Efe, S.T. Fan, M. Francis, P. Francis, V. Ganju, P. Gibbs, G. Goss, M. Green, P. Gregory, J. Griffiths, I. Haines, M. Henderson, R. Holmes, P. James, J. Kiffler, M. Lehman, M. Leyden, L. Lim, G. Lindeman, R. Lynch, B. Mann, J. McKendrick, S. McLachlan, R. McLennan, G. Mitchell, S. Mitra, C. Murphy, I. Parker, K. Phillips, I. Porter, G. Richardson, J. Scarlet, S. Sewak, J. Shapiro, R. Snyder, R. Stanley, C. Steer, D. Stoney, A. Strickland, G. Toner, C. Underhill, K. White, M. White, A. Wirth, S. Wong; W. P. Holman Clinic, Launceston General Hospital, Launceston, Tasmania: D. Byram, I. Byard; Liverpool Hospital, Sydney, NSW: S. Della-Fiorentina, A. Goldrick, E. Hovey, E. Moylan, E. Segelov; Mount Hospital, Perth, WA: A. Chan, M. Buck, D. Hastrich, D. Ingram, G. Van Hazel, P. Willsher; Nepean Cancer Care Centre, Sydney, NSW: N. Wilcken, C. Crombie; Newcastle Mater Hospital, Newcastle, NSW: J.F. Forbes, F. Abell, S. Ackland, A. Bonaventura, S. Cox, J. Denham, R. Gourlay, D. Jackson, R. Sillar, J. Stewart; Prince of Wales Hospital, Sydney, NSW: C. Lewis, B. Brigham, D. Goldstein, M. Friedlander; Princess Alexandra Hospital, Woollongabba, QLD: E. Walpole, D. Thompson; Royal Adelaide Hospital, Adelaide, SA: P.G. Gill, M. Bochner, J. Coventry, J. Kollias, P. Malycha, I. Olver; Royal Brisbane and Women's Hospital, Brisbane, QLD: M. Colosimo, R. Cheuk, L. Kenny, N. McCarthy, D. Wyld; Royal Hobart Hospital, Hobart, Tasmania: R. Young, R. Harrup, R. Kimber, R. Lowenthal; Royal Perth Hospital, Perth, WA: J. Trotter, E. Bayliss, A. Chan, D. Ransom; Sir Charles Gairdner Hospital, Perth, WA: M. Byrne, M. Buck, J. Dewar, A. Nowak, A. Powell, G. Van Hazel; Toowoomba Hospital, Toowoomba, QLD: E.A. Abdi, R. Brodribb, Z. Volobueva; Westmead Hospital, Sydney, NSW: P. Harnett, V. Ahern, H. Gurney, N. Wilcken. New Zealand. Auckland Hospital, Auckland: V.J. Harvey, B. Evans, W. Jones, M. McCrystal, D. Porter, P. Thompson, M. Vaughan; Christchurch Hospital, Christchurch: D. Gibbs, C. Atkinson, R. Burcombe, B. Fitzharris, B. Hickey, M. Jeffery, B. Robinson; Dunedin Hospital, Dunedin: B. McLaren, S. Costello, J. North, D. Perez; Waikato Hospital, Hamilton: I.D. Campbell, L. Gilbert, R. Gannaway, M. Jameson, I. Kennedy, J. Long, G. Round, L. Spellman, D. Whittle, D. Woolerton. Brazil. Hospital de Clinicas de Porto Alegre, Porto Alegre: C. Menke, J. Biazús, R. Cericatto, J. Cavalheiro, N. Xavier, A. Bittelbrunn, E. Rabin. Chile. Chilean Cooperative Group for Oncologic Research, GOCCHI: J. Gutiérrez (Chairman), R. Arriagada (Scientific Adviser), L. Bronfman (Principal Investigator), M. Zuñiga (Data Manager); Clinica Las Condes, Santiago: J. Gutiérrez, J.C. Acevedo, S. Torres, A. León, E. Salazar; Hospital DIPRECA, Las Condes, Santiago: L. Soto Diaz, R. Duval, N. Oddeshede, M.C. Venti; Hospital San Juan de Dios, Santiago: K. Peña, L. Puente, V. Maidana; IRAM/Instituto de Radiomedicina, Vitacura, Santiago: R. Baeza, R. Arriagada, P. Olfos, J. Solé, E. Vinés, C. Mariani. Hungary. National Institute of Oncology, Budapest: I. Láng, E. Hitre, E. Szabó, Z. Horváth, E. Ganofszky, E. Juhos. Italy. Centro di Riferimento Oncologico, Aviano: A. Veronesi, D. Crivellari, M.D. Magri, A. Buonadonna, F. Coran, E. Borsatti, E. Candiani, S. Massarut, M. Roncadin, M. Arcicasa, A. Carbone, T. Perin, A. Gloghini; Ospedali Riuniti di Bergamo, Bergamo: C. Tondini, R. Labianca, P. Poletti, A. Bettini; Ospedale degli Infermi, Biella: M. Clerico, M. Vincenti, A. Malossi, E. Seles, E. Perfetti, B. Sartorello; Spedali Civili, Brescia: E. Simoncini, G. Marini, P. Marpicati, R. Farfaglia, A.M. Bianchi, P. Grigolato, L. Lucini, P. Frata, A. Huscher, E. Micheletti, C. Fogazzi; U.O. Medicina Oncologica, Ospedale Capri, Ospedale Mirandola: F. Artioli, K. Cagossi, L. Scaltriti, E. Bandieri, L. Botticelli, G. Giovanardi; Ospedale di Cattolica "Cervesi," Cattolica: A. Ravaioli, E. Pasquini, B. Rudnas; Ospedale Civile, Gorizia: L. Foghin; Ospedale "A. Manzoni" Lecco, Lecco: M. Visini, L. Zavallone, G. Ucci; Istituto Europeo di Oncologia, Milano: M. Colleoni, G. Viale, P. Veronesi, G. Peruzzotti, L. Corsetto, R. Ghisini, G. Renne, A. Luini, L. Orlando, R. Torrisi, A. Rocca, T. De Pas, E. Munzone, V. Galimberti, S. Zurrida, M. Intra, F. Nolé, R. Orecchia, G. Martinelli, F. de Braud, A. Goldhirsch; Ospedale Infermi, Rimini: A. Ravaioli, L. Gianni. Peru. Instituto de Enfermedades Neoplásicas, Lima: H. Gome. Slovenia. Institute of Oncology, Ljubljana: T. Cufer, B. Pajk, J. Cervek. South Africa. Groote Schuur Hospital and University of Cape Town, Cape Town: I.D. Werner, E. Murray, D. Govender, S. Dalvie, T. Erasmus, B. Robertson, B. Read, E. Nel, J. Toop, N. Nedeva, E. Panieri; Sandton Oncology Centre, Johannesburg: D. Vorobiof, M. Chasen, G. McMichael, C. Mohammed. Local funding provided by the Cancer Association of South Africa. Sweden. West Swedish Breast Cancer Study Group: S.B. Holmberg; Sahlgrenska U Hospital, Moelndal: S.B. Holmberg, J. Mattsson; Boras Hospital, Boras; Karlstads Hospital, Karlstads: H. Sellström; Kungalvs Hospital, Kungalvs: B. Lindberg. Switzerland. Swiss Group for Clinical Cancer Research (SAKK): A. Goldhirsch (up to January 2004), R. Herrmann (from June 2004): Kantonsspital Aarau, Zentrum f. Onkologie, Aarau: A. Schönenberger, W. Mingrone, Ch. Honegger, E. Bärtschi, M. Neter, M. Rederer, G. Schör; University Hospital Basel, Basel: C. Rochlitz, R. Herrmann, D. Oertli, E. Wight, H. Moch; Institute of Oncology of Southern Switzerland: Ospedale San Giovanni, Bellinzona: J. Bernier, L. Bronz, F. Cavalli, E. Gallerani, A. Richetti, A. Franzetti; Ospedale Regionale di Lugano (Civico & Italiano), Lugano: M. Conti-Beltraminelli, M. Ghielmini, T. Gyr, S. Mauri, P.C. Saletti; Ospedale Regionale Beata Vergine, Mendrisio: A. Goldhirsch, O. Pagani, R. Graffeo, M. Locatelli, S. Longhi, P.C. Rey, M. Ruggeri; Ospedale Regionale La Carità Locarno: E. Zucca, D. Wyss; Istituto Cantonale di Patologia, Locarno: L. Mazzucchelli, E. Pedrinis, T. Rusca; Inselspital, Berne: S. Aebi, M.F. Fey, M. Castiglione, M. Rabaglio; Kantonsspital Olten, Olten: S. Aebi, M.F. Fey, M. Zuber, G. Beck; Bürgerspital, Solothurn: S. Aebi, M.F. Fey, R. Schönenberger; Spital Thun-Simmental AG Thun: J.M. Lüthi, D. Rauch; Hôpital Cantonal Universitaire HCUG, Geneva: H. Bonnefoi; Rätisches Kantons- und Regionalspital, Chur: F. Egli, R. Steiner, P. Fehr; Centre Pluridisciplinaire d'Oncologie, Lausanne: L. Perey, P. de Grandi, W. Jeanneret, S. Leyvraz, J.-F. Delaloye; Kantonsspital St Gallen, St Gallen: B. Thürlimann, D. Köberle, F. Weisser, S., Mattmann, A. Müller, T. Cerny, B. Späti, M. Höfliger, G. Fürstenberger, B. Bolliger, C. Öhlschlegel, U. Lorenz, M. Bamert, J. Kehl-Blank, E. Vogel; Kantonales Spital Herisau, Herisau: B. Thürlimann, D. Hess, I. Senn, D. Köberle, A. Ehrsam, C. Nauer, C. Öhlschlegel, J. Kehl-Blank, E. Vogel; Stadtspital Triemli, Zürich: L. Widmer, M. Häfner; Universitätsspital Zürich, Zürich: B.C. Pestalozzi, M. Fehr, R. Caduff, Z. Varga, R. Trüb, D. Fink. Swiss Private MDs. Private Praxis, Zürich: B.A. Bättig; Sonnenhof-Klinik Engeried, Berne: K. Buser; Frauenklinik Limmattalspital, Schlieren: N. Bürki; Private Praxis, Birsfelden: A. Dieterle; Private Praxis, Biel: L. Hasler; Private Praxis, Baar: M. Mannhart-Harms; Brust-Zentrum, Zürich: C. Rageth; Private Praxis, Berne: J. Richner; Private Praxis, Bellinzona: V. Spataro; Private Praxis, Winterthur: M. Umbricht. United Kingdom. King's College Hospital/Breast Unit, London: P. Ellis, S. Harris, N. Akbar, H. McVicars, C. Lees, R. Raman, G. Crane.
Danish Group (Danish Breast Cancer Cooperative Group)
French Group (Fédération Nationale des Centres de Lutte Contre le Cancer)
North Yorkshire Group
Independent Centers/Groups Australia. Flinders Medical Centre, Adelaide, SA: S. Birrell, M. Eaton, C. Hoffman; Queen Elizabeth Hospital, Adelaide, SA: V. Humeniuk; The Canberra Hospital, Canberra, ACT; P. Craft, R. Stuart-Harris, D. Yip; The Geelong Hospital, Geelong, VIC: R. Bell, F. Abell, M. Francis, J. Kiffer, R. Lynch, R. McLennan, K. White; Royal Melbourne Hospital, Melbourne, VIC: M. Green, R. Basser, J. Collins, R. De Boer, J.C. Din, N. Efe, S.T. Fan, G. Lindeman, S. Wong; Western General Hospital, Melbourne, VIC: M. Green, R. Basser, J. Collins, R. De Boer, J.C. Din, N. Efe, S.T. Fan, G. Lindeman, S. Wong; Newcastle Mater Hospital, Newcastle, NSW: J. Stewart, F. Abell, S. Ackland, A. Bonaventura; Royal Perth Hospital, Perth, WA: J. Trotter, E. Bayliss, A. Chan, D. Ransom, A. Redfern; St George Hospital, Sydney, NSW: P. de Souza, M. Links; St Vincent's Hospital, Sydney, NSW: D. Dalley, J. Grygiel, R. Ward; Murray Valley Private Hospital, Wodonga, VIC: C. Underhill, K. Clarke, C. Steer; Princess Alexandra Hospital, Woolloongabba, QLD: E. Walpole, D. Thompson. Belgium. Institut Jules Bordet, Bruxelles: J.M. Nogaret; University Hospitals Leuven, Leuven: M.R. Christiaens, P. Neven, R. Paridaens, A. Smeets, I. Vergote, C. Weltens, H. Wildiers; Les Cliniques Saint-Joseph ASBL, Liège: C. Focan; Clinique du Parc Léopold, Bruxelles: L. Marcelis; C. H. Etterbeek - Ixelles, Bruxelles: J.P. Kains; Service d'Oncologie Clinique Notre-Dame, Charleroi: J.-L. Canon; CHU André Vèsale, Montigny-Le Tilleul: D. Brohèe. Canada. Cambridge Memorial Hospital, Cambridge: J. Gowing; CHUM Campus Notre-Dame, Montreal: L. Yelle; Hôpital Maisonneuve-Rosemont, Montreal: P. Dubé. Chile. Fundacion Lopez Perez, Santiago: C. Vogel; Hospital Carlos Van Buren, Valparaiso: M. León Prieto. Czech Republic. Institute of Oncology, Brno: K. Petrakova, M. Palacova, R. Demlova; Department of Clinical and Radiation Oncology, Ceske Budejovice: H. Siffnerova, J. Fischer, I. Bustova; Centre of Breast Diseases, Prague: H. Kankova, M. Pintova; Institute of Radiation Oncology, Prague: P. Vitek; University Hospital, Prague: J. Abrahamova, D. Kordikova; University Hospital Prague: L. Petruzelka, E. Sedlackova, H. Honova. Germany. Onkologische Gemeinschaftspraxis, Augsburg: B. Heinrich; Zentralklinikum/Frauenklinik, Augsburg: A. Wischnik; Universitätsklinikum Essen, Essen: C. Oberhoff, A.E. Schindler; Universitäts-Frauenklinik d. JLU Giessen, Giessen: K. Münstedt; Onkologische Gemeinschaftspraxis, Gättingen: D. Meyer; Martin-Luther-Universität Halle-Wittenberg, Halle: R. Grosse, H. Kölbl; Universitätskliniken des Saarlandes, Homburg: W. Schmidt, D. Mink; Universitäts-Frauenklinik und Poliklinik Universitätskrankenhaus Eppendorf, Hamburg: F. Jänicke; Kliniken d. Med. Hochschule, Frauenklinik, Hannover: H.J. Lück; Krankenanstalt Mutterhaus der Borromäerinnen, Trier: W. Dornoff; Gynäkologische Abteilung des St Josefshospital, Wiesbaden: G. Hoffmann; Gynäkologische Abteilung d. Marienhospitals, Universität Witten-Herdecke, Witten: J. Hackmann, W. Bader. Hungary. SZOTE Onkoterápiás Klinika, Szeged: Z. Kahan; BM Központi Kórház, Budapest: G. Pajkos, K. Kristo; SOTE Radiológiaiés Onkoterápiás Klinika, Budapest: M. Dank; Uzsoki Utcai Kórház, Budapest: T. Nagykalnai, L. Landherr; Almási Balogh Pál Kórház, Ózd: E. Kner; Területi Kórház Onkologia, Szentes: M. Kispál; Szent Borbála Kórház, Megyei Onkológiai Gondozó Tatabánya: Á. Dani. Italy. Policlinico S. Orsola-Malpighi, Bologna: A. Martoni, C. Zamagni, S. Giaquinta, E. Piana; Ospedale S. Croce, Fano: R. Mattioli, L. Imperatori; Istituto Clinica Humanitas, Milan/Rozzano: A. Santoro, C. Carnaghi, L. Rimassa; Azienda Ospedaliera San Filippo Neri, Rome: G. Gasparini, G. Sciarretta, A. Morabito; Az. Ospedaliera Treviglio-Caravaggio, Treviglio: S. Barni, M. Cazzaniga, M. Cabiddu; Policlinico Universitario (PUDG), Udine: F. Puglisi; Ospedale di Torrette, Ancona: R. Cellerino, S. Antognoli, F. Freddari; Universitiy of Cagliari, Policlinico Universitario, Cagliari: G. Mantovani, E. Massa, G. Astara; Ospedale Civile Feltre, Feltre: R. Segati; Istituto Nazionali Ricerca Cancro, Genova: R. Rosso, L. Del Mastro, M. Venturini, C. Bighin; Istituto Nazionale dei Tumori, Milano: E. Bajetta, N. Zilembo, D. Paleari, G. Procopio; Azienda Ospedaliera di Parma, Parma: S. Salvagni, M.A. Perrone, V. Franciosi; Azienda Ospedaliera "S. Salvatore," Pesaro: G. Catalano, S. Luzi Fedeli; Azienda Ospedaliera "Ospedale di Circolo e Fondazione Macchi," Varese: G. Pinotti, G. Giardina, I. Vallini; Universitiy of Cagliari, Policlinico Universitario, Cagliari: B. Massidda, M.T. Ionta, M.C. Deidda; Ospedale Maggiore, Lodi: G. Nalli, G. Sita; Policlinico Universitario, Palermo: I. Carreca, S. Cucciarré, D. Burgio; Ospedale Civile dello Spirito Santo, Pescara: M. Lombardo, G. Pandoli, P. Di Stefano; Azienda Ospedaliera Santa Maria Nuova, Reggio Emilia: C. Boni, G. Bisagni, M.C. Banzi, P. Linarello; Azienda Ospedaliera Desenzano del Garda, Manerbio: G. Colosini, A. Spasiano, A. Caldonazzo; Ospedale Civile ASL 20, Tortona: M.G. Pacquola. Netherlands. Ziekenhuis Leyenburg, Den Haag: H.P. Sleeboom; Catharina Ziekenhuis, Eindhoven: H.J.T. Rutten; St Anna Ziekenhuis, Geldrop: E.J. T. Luiten; Tweesteden Ziekenhuis, Tilburg: H.Th.J. Roerdink; Maxima Medisch Centrum, Veldhoven: R.H.M. Roumen. New Zealand. Dunedin Hospital, Dunedin: B. McLaren, S. Costello, J. North, D. Perez, K., Bayston, M. Pfieffer; Waikato Hospital, Hamilton: I. Kennedy, I. D. Campbell, L. Gilbert, R. Gannaway, M. Jameson, J. Long, G. Round, L. Spellman, D. Whittle, D. Woolerton. Poland. Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk: J. Jassem, M. Welnicka-Jaskiewicz, E. Senkus-Konefka, K. Matuszewska; Rydygier's Memorial Hospital, Krakow-Nova Huta: P. Koralewski, J. Pernal; Klinika Nowotworów Piersi i, Chirurgii Rekonstrukcyjnej-Warszawa, Warszawa: T. Pienkowski, E. Brewczynska, B. Bauer-Kosinska, R. Sienkiewicz-Kozlowska, A. Jagiello-Gruszfeld, K. Sudol; Centrum Onkologii w Bydgoszczy, Oddzial Onkologii Klinicznej, Bydgoszcz: J. Tujakowski, B. Zurawski; Collegium Medicum Jagiellonian University, Krakow: J. Pawlega, E. Jablonska, A. Zygulska; Oddzial Kliniczny Onkologiczny, Centralnego Szpitala Klinicznego Wojskowej, Akademii Medycznej-Warszawa, Warszawa: M. Górnasiowa; Dolnoslaskie Centrum Onkologii, Wroclaw: E. Filypczyk-Cisarz, K. Pajak. Portugal. Hospital de S. João, Porto: M. Damasceno; Instituto Português de Oncologia de Coimbra, Coimbra: J.Q. Albano; Hospital de Santa Maria, Lisboa: B. da Costa, L. Costa; Instituto Português de Oncologia de Lisboa, Lisboa: A. Henriques, H. Amaral; Hospital Geral de Santo António, Porto: F. Marques. Russia. Cancer Research Centre, Moscow: D.V. Komov, S.B. Polikarpova; Moscow Municipal Hospital No. 62, Moscow: A.N. Makhson, N.V. Zabaznyi; Moscow Research Institute of Diagnostics and Surgery, Moscow: E.K. Vozny, N.Y. Dobrovolskaya, S. Bolshakova, O.V. Yurgina; N.M. Emmanuel Institute of Biochemical Physics, Moscow: D.B. Korman, I.A. Maslova; N.N. Petrov Research Institute of Oncology, St Petersburg: V. Semiglazov, V. Ivanov; Saint-Petersburg City Oncological Dispensary, St Petersburg: G. Manikhas, G. Dolmatov. South Africa. Mamma Clinic, Tygerberg Hospital, Cape Town: J. Apffelstaedt; Southern Cross Hospital, Cape Town: D. Eedes; Pretoria Academic Hospital, Pretoria: C. Slabber; Pretoria East Hospital, Pretoria: M.A. Coccia-Portugal; Eastern Cape Oncology Centre, Port Elizabeth: K. Maart. Spain. Hospital Ruber Internacional, Madrid: J.E. Alés Martinez, P. Aramburo, R. Sánchez; Hospital Son Dureta, Palma del Mallorca: J. Rifa, J. Martin; Centro Oncológico Integral de Madrid (CONIM), Madrid: R. Pérez-Carrión, J.L. González Larriba, A. Cubillo; Hospital Universitario San Carlos, Madrid: M.M. Jimález, A. Casado; Hospital Central de Asturias, Oviedo: J. Fra, J.M. Vieitez, E. Esteban, A.J. Lacave. Switzerland. Universitätsfrauenklinik, Basel: E. Wight, S. Bartens, R. Decio, U. Güth; Klinik am Park, Zürich: U. Breitenstein. Turkey. Ankara University Ibni Sina Hospital, Ankara: F. Icli, D. Dincol; Hacettepe University Oncology Institute, Ankara: E. Baltali, Y. Ozisik; Istanbul University Oncology Institute, Istanbul: E. Topuz, M. Basaran, A. Aydiner; Ege University Medical School, Izmir: E. Ozdedeli; 9 Eylul University Medical School, Izmir: O. Harmancioglu, A.U. Yilmaz. United Kingdom. The Royal Marsden Hospital, London, Royal Marsden NHS Trust, Surrey: I.E. Smith; University of Dundee, Dundee: A.M. Thompson; Christie Hospital NHS Trust, South Manchester University Hospital Trust, Manchester: A. Wardley; Royal Bournemouth Hospital, Bournemouth: T. Hickish; North Middlesex Hospital, London: F. Neave. Uruguay. Hospital de Clinicas Dr. Manuel Quintela, Montevideo: G. Sabini.
We thank the patients, physicians, nurses, and data managers who participated in this clinical trial; Novartis; and the International Breast Cancer Study Group.
published online ahead of print at www.jco.org on January 2, 2007. Supported by the Swedish Cancer Society, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research, National Cancer Institute Grant No. CA-75362, and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK). Presented in part at the 31st Congress of the European Society for Medical Oncology Conference, September 29-October 3, 2006, Istanbul, Turkey. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Baum M, Buzdar A, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial efficacy and safety update analyses. Cancer 98:1802-1810, 2003[CrossRef][Medline] 2. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004 3. Breast International Group 1-98 Collaborative Group: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005 4. Boccardo F, Rubagotti A, Puntoni M, et al: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: Preliminary results of the Italian Tamoxifen Anastrozole Trial. J Clin Oncol 23:5138-5147, 2005 5. Jakesz R, Jonat W, Gnant M, et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455-462, 2005[CrossRef][Medline] 6. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA. 17. J Natl Cancer Inst 97:1262-1271, 2005 7. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: Status report 2004. J Clin Oncol 23:619-629, 2004[CrossRef][Medline] 8. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International expert consensuson the primary therapy of early breast cancer 2005. Ann Oncol 16:1569-1583, 2005 9. Carlson RW, Brown E, Burstein HJ, et al: NCCN Task Force Report: Adjuvant therapy for breast cancer. J Natl Compr Canc Netw 4:S1-S26, 2006 (suppl 1) 10. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35:1-39, 1977[Medline] 11. Kaplan EL, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457-481, 1958[CrossRef] 12. Cox DR: Regression models and life tables. J R Stat Soc B 34:187-220, 1972 13. Gray RJ: A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988 14. Agresti A: Exact inference for categorical data: Recent advances and continuing controversies. Stat Med 20:2709-2722, 2001[CrossRef][Medline] 15. Cuzick J, Sasieni P, Howell A: Should aromatase inhibitors be used as initial adjuvant treatment or sequenced after tamoxifen? Br J Cancer 94:460-464, 2006[CrossRef][Medline] 16. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] Submitted September 12, 2006; accepted November 20, 2006. This article has been cited by other articles:
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
