Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer: methodologic issues.

Abstract

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.99.430 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12202679 Anastrozole Versus Tamoxifen as First-Line Therapy For Advanced Breast Cancer: Methodologic Issues Eric WinquistxEric WinquistSearch for articles by this author , Vivien BramwellxVivien BramwellSearch for articles by this author , Theodore VandenbergxTheodore VandenbergSearch for articles by this author Jacques BonneterrexJacques BonneterreSearch for articles by this author , Jean-Marc NabholtzxJean-Marc NabholtzSearch for articles by this author , Aman BudzarxAman BudzarSearch for articles by this author , John RobertsonxJohn RobertsonSearch for articles by this author , Beat ThürlimannxBeat ThürlimannSearch for articles by this author , Mark SteinbergxMark SteinbergSearch for articles by this author , Alan WebsterxAlan WebsterSearch for articles by this author , Mikael von EulerxMikael von EulerSearch for articles by this author Show More London Regional Cancer Centre, London, Ontario, CanadaCenter Oscar Lambert, Lille, FranceUniversity of California at Los Angeles, Los Angeles, CAM.D. Anderson Cancer Center, Houston, TXCity Hospital, Nottingham, United KingdomMedizinische Klinic C Kantonsspital, San Gallen, SwitzerlandAstraZeneca, Wilmington, DEAstraZeneca, Alderley Park, Cheshire, United KingdomAstraZeneca, Osaka, Japan https://doi.org/10.1200/JCO.2002.99.430 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01092002In Reply:Thank you for giving us the opportunity to respond to the queries of Winquist et al relating to the methodologies used in the anastrozole versus tamoxifen trials1,2 and the combined analysis.3 We agree with the authors that the results of these studies, in which anastrozole was shown to have superior efficacy and safety compared with tamoxifen in patients with hormone receptor–positive metastatic disease, have indeed influenced clinical practice.In regards to the statistical calculations, the sample size of both trials was originally set at 660 patients per trial, based on the time to progression (TTP) end point. This also provided sufficient power to analyze objective response rate, including taking into account the proportion of patients with measurable disease recruited into the trial. As pointed out in the publication3 and noted by Winquist et al, both trials were prospectively planned for combined analysis. With a final recruitment of 1,021 patients across both trials (n = 668, Europe/rest of the world; n = 353, North America), this represents the largest clinical program of any aromatase inhibitor in the first-line treatment of advanced breast cancer in postmenopausal women.The North American trial (0030) halted accrual with less than 660 patients because of difficulty in recruitment resulting from the strict entry criteria. This difficulty in enrolling patients in North America is not unique to the anastrozole versus tamoxifen trials. In the recently published trial of letrozole versus tamozifen,4 of the 907 patients randomized, only 100 (11%) were recruited from North America; the majority of patients were recruited from Europe (n = 580, 64%) and the rest of the world (n = 227, 25%).5The decision to stop trial 0030 was made after consultation between the trial sponsors, the principal investigators of the trial, and the Food and Drug Administration. Subsequently, it was decided that trial 0030 could be stopped, with data still blinded, when the Europe/rest of the world trial reached the target recruitment of 660 patients. Given the superior result of TTP in trial 0030, which showed a much larger treatment difference than previously expected (median TTP was 11.1 months for anastrozole and 5.6 months for tamoxifen), a retrospective power calculation indicated that the power was sufficient based on the current recruitment.The authors are correct in their comment that both trials were designed as noninferiority trials. This was clearly identified in both articles. However, trials designed to prove noninferiority can, in some cases, be used to demonstrate superiority6 based on the nature of the equivalence trial and the larger sample size included in such trials.In summary, we believe the decision to halt accrual to trail 0030 was acceptable. Both trials 0027 and 0030 showed noninferiority to tamoxifen, with trial 0030 showing superiority for TTP and clinical benefit. The combined analysis showed that in receptor-positive patients, anastrozole was superior to tamoxifen in terms of TTP. Combined with the favorable tolerability profile, we feel that these data support anastrozole as a therapeutic option in first-line treatment of postmenopausal women with hormone-responsive advanced breast cancer.Finally, we fully agree with the authors on the importance of large randomized trials. Further support for our data comes from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, which enrolled more than 9,300 patients with early breast cancer who were candidates for adjuvant endocrine therapy. Recently released results from a planned analysis indicate that anastrozole prolonged disease-free survival (P = .013) compared with tamoxifen; in addition, there was a significant reduction (P = .007) in the incidence of contralateral breast cancer.7 Although further follow-up is required, these data suggest that the benefit observed with anastrozole for the treatment of advanced disease may also be seen in early breast cancer.1. Bonneterre J, Thürlimann B, Robertson JFR, et al: Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: Results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability Study. J Clin Oncol 18:: 3748,2000-3757, Link, Google Scholar2. Nabholtz JM, Buzdar A, Pollak M, et al: Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Results of a North American multicenter randomized trial. J Clin Oncol 18:: 3758,2000-3767, Link, Google Scholar3. Bonneterre J, Buzdar A, Nabholtz JM, et al: Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma: Results of two randomized trials designed for combined analysis. Cancer 92:: 2247,2001-2256, Crossref, Medline, Google Scholar4. Mouridsen H, Gershanovich M, Sun Y, et al: Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: Results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 19:: 2596,2001-2606, Link, Google Scholar5. Buzdar AU, Mouridsen H, Chaudri Ross HA: Superior efficacy of letrozole versus tamoxifen as first-line therapy. J Clin Oncol 20:: 876,2002-878, (letter) Link, Google Scholar6. Committee for Proprietary Medicinal Products (Pan European Guideline). London, United Kingdom, Scientific Committee of the European Agency for Evaluation of Medicinal Products, July 2000 Google Scholar7. Tobias JC: The ATAC (‘Arimidex’, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial in postmenopausal (PM) women. Eur J Cancer 38:: S92,,2002 (suppl 3, abstr 202) Crossref, Medline, Google Scholar