The NEW ENGLAND JOURNAL of MEDICINE ESTABLISHED IN 1812 NOVEMBER 6, 2003 VOL. 349 NO. 19 A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer Paul E. Goss, M.D., Ph.D., James N. Ingle, M.D., Silvana Martino, D.O., Nicholas J. Robert, M.D., Hyman B. Muss, M.D., Martine J. Piccart, M.D., Ph.D., Monica Castiglione, M.D., Dongsheng Tu, Ph.D., Lois E. Shepherd, M.D., Kathleen I. Pritchard, M.D., Robert B. Livingston, M.D., Nancy E. Davidson, M.D., Larry Norton, M.D., Edith A. Perez, M.D., Jeffrey S. Abrams, M.D., Patrick Therasse, M.D., Michael J. Palmer, M.Sc., and Joseph L. Pater, M.D. ABSTRACT BACKGROUND In hormone-dependent breast cancer, five years of postoperative tamoxifen therapy - From the Division of Hematology-Oncol- but not tamoxifen therapy of longer duration - prolongs disease-free and overall sur- ogy, Princess Margaret Hospital, Toronto vival. The aromatase inhibitor letrozole, by suppressing estrogen production, might (P.E.G.); the Mayo Clinic, Rochester, Minn. ().N.1.); the John Wayne Cancer Institute, improve the outcome after the discontinuation of tamoxifen therapy. Santa Monica, Calif. (S.M.); the Inova Fair- fax Hospital, Falls Church, Va. (N.J.R.); the METHODS University of Vermont, Burlington (H.B.M); Institut Jules Bordet, Brussels, Belgium We conducted a double-blind, placebo-controlled trial to test the effectiveness of five (M.J. Piccart); the International Breast Can- years of letrozole therapy in postmenopausal women with breast cancer who have com- cer Study Group Coordinating Center, Bern pleted five years of tamoxifen therapy. The primary end point was disease-free survival. Switzerland (M.C.); the National Cancer Institute of Canada, Clinical Trials Group, Kingston, Ont. (D.T., L.E.S., M.J. Palmer, RESULTS J.L.P.); the Toronto-Sunnybrook Regional A total of 5187 women were enrolled (median follow-up, 2.4 years). At the first interim Cancer Centre, Toronto (K.I.P.); the Uni- versity of Washington, Seattle (R.B.L.); the analysis, there were 207 local or metastatic recurrences of breast cancer or new primary Sidney Kimmel Comprehensive Cancer cancers in the contralateral breast - 75 in the letrozole group and 132 in the placebo Center at Johns Hopkins University, Balti- group -with estimated four-year disease-free survival rates of 93 percent and 87 per- more (N.E.D.); the Memorial Sloan-Ketter- ing Cancer Center, New York (L.N.); the cent, respectively, in the two groups (P50.001 for the comparison of disease-free surviv- Mayo Clinic, Jacksonville, Fla. (E.A.P); the al). A total of 42 women in the placebo group and 31 women in the letrozole group died Cancer Therapy Evaluation Program, Clini- (P=0.25 for the comparison of overall survival). Low-grade hot flashes, arthritis, arthral- cal Investigations Branch, National Cancer Institute, Rockville, Md. (J.S.A.); and the gia, and myalgia were more frequent in the letrozole group, butvaginal bleeding was less European Organization for Research and frequent. There were new diagnoses of osteoporosis in 5.8 percent of the women in the Treatment of Cancer Data Center, Brussels, letrozole group and 4.5 percent of the women in the placebo group (P=0.07); the rates Belgium (P.T.). Address reprint requests to Dr. Goss at the Division of Hematology- of fracture were similar. After the first interim analysis, the independent data and safety Oncology, Princess Margaret Hospital, 610 monitoring committee recommended termination of the trial and prompt communi- University Ave., Toronto, ON MSG 2M9, cation of the results to the participants. Canada, or at pegoss @interlog.com. This article was published at www.nejm.org CONCLUSIONS on October 9, 2003. As compared with placebo, letrozole therapy after the completion of standard tamoxifen N Engl J Med 2003;349:1793-802. treatment significantly improves disease-free survival. Copyright @ 2003 Massachusetts Medical Society.Q6. In the methods section, the authors describe how they conducted their sample size calculations. In trials with a failure time endpoint, the key quantity is the total number of observed events (here, recurrences of breast cancer) as this directly impacts power. They determined that they needed 515 events and 4800 women to have 80% power to detect a 2.5% difference in four-year disease-free survival, with Type 1 error of 0.05. They assumed that the four-year disease-free survival rate in the placebo population was 88%. For each of the following scenarios, specify whether the required sample size would increase or decrease. Highlight or circle the appropriate answer for each scenario. Increase sample size / Decrease sample size: Increase power to 90% Increase sample size I Decrease sample size: Increase Type 1 error to 0.10. Increase sample size I Decrease sample size: Detect a 5% difference in four-year disease-free survival Increase sample size / Decrease sample size: Detect a 1% difference in four-year disease-free survival