PT  - JOURNAL ARTICLE
AU  - Mann, Bhupinder S.
AU  - Johnson, John R.
AU  - Kelly, Roswitha
AU  - Sridhara, Rajeshwari
AU  - Williams, Grant
AU  - Pazdur, Richard
TI  - Letrozole in the Extended Adjuvant Treatment of Postmenopausal Women with History of Early-Stage Breast Cancer Who Have Completed 5 Years of Adjuvant Tamoxifen
AID  - 10.1158/1078-0432.CCR-05-0354
DP  - 2005 Aug 15
TA  - Clinical Cancer Research
PG  - 5671--5677
VI  - 11
IP  - 16
4099  - http://clincancerres.aacrjournals.org/content/11/16/5671.short
4100  - http://clincancerres.aacrjournals.org/content/11/16/5671.full
SO  - Clin Cancer Res2005 Aug 15; 11
AB  - Purpose: To present the basis of the decision of the Food and Drug Administration to grant accelerated approval for letrozole for extended adjuvant treatment of early-stage breast cancer in postmenopausal women after completion of adjuvant tamoxifen. Experimental Design: The Food and Drug Administration reviewed the data from the MA17 trial, a single, multinational, randomized, double-blind, and placebo-controlled trial, submitted by the applicant to support the proposed new indication. Results: MA17 consisted of a core study and Lipid and Bone Mineral Density safety substudies. It enrolled 5,187 patients. In the core study, median treatment duration was 24 months and median follow-up duration was 27.4 months. Using a conventional definition of disease-free survival, 122 events on letrozole and 193 events on placebo were observed (hazard ratio, 0.62; 95% confidence interval, 0.49-0.78; P = 0.00003). Distant disease-free survival also improved with letrozole, 55 versus 92 events (hazard ratio, 0.61; 95% confidence interval, 0.44-0.84; P = 0.003). No statistically significant improvement in overall survival was observed. Hot flushes, arthralgia/arthritis, myalgia, and new diagnosis of osteoporosis were more common on letrozole. Frequency of fractures and cardiovascular ischemic events was not significantly different. A statistically significant mean decrease in bone mineral density in the hip occurred at 24 months on letrozole. Conclusions: Letrozole administration led to a statistically significant prolongation in disease-free survival. Fractures and cardiovascular events were similar to placebo; however, new diagnoses of osteoporosis were more frequent. Short duration of treatment and follow-up precluded assessment of long-term safety and efficacy. Thus, accelerated approval was granted instead of regular approval.