Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover.

Abstract

PURPOSE:

The interim analysis of the National Cancer Institute of Canada Clinical Trials Group MA.17 trial showed that letrozole was significantly better than placebo in disease-free survival (DFS) for postmenopausal women with hormone receptor-positive breast cancer following about 5 years of tamoxifen therapy. When patients were unblinded, those on placebo were offered letrozole. Longer-term efficacy of letrozole, especially survival, was of particular interest because the median follow-up of the first interim analysis was only 2.5 years. Efficacy was difficult to assess because more than 60% of placebo patients crossed over to letrozole after being unblinded.

PATIENTS AND METHODS:

Two statistical approaches were used to adjust for the potential effects of treatment crossover: one was based on the inverse probability of censoring weighted (IPCW) Cox model and the other on a Cox model with time-dependent covariates.

RESULTS:

With a median follow-up of 64 months, the hazard ratios (HRs) of letrozole and placebo from the IPCW analyses were HR of 0.52 (95% CI, 0.45 to 0.61; P < .001) for DFS, HR of 0.51 (95% CI, 0.42 to 0.61; P < .001) for distant disease-free survival (DDFS), and HR of 0.61 (95% CI, 0.52 to 0.71; P < .001) for overall survival (OS). The results from the analyses based on the Cox model with time-dependent covariates were similar for letrozole and placebo: HR of 0.58 (95% CI, 0.47 to 0.72; P < .001) for DFS, HR of 0.68 (95% CI, 0.52 to 0.88; P = .004) for DDFS, and HR of 0.76 (95% CI, 0.60 to 0.96; P = .02) for OS.

CONCLUSION:

Exploratory analyses based on longer follow-up and adjusting for treatment crossover suggest that extended adjuvant letrozole was superior to placebo in DFS, DDFS, and OS.

• Authors: Huan Jin, Dongsheng Tu, Naiqing Zhao, Lois E Shepherd, Paul E Goss
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 30 Issue 7 Pg. 718-21 (Mar 01 2012) ISSN: 1527-7755 [Electronic] United States
• PMID: 22042967 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Aromatase Inhibitors
• Nitriles
• Placebos
• Triazoles
• Tamoxifen
• Letrozole

Topics

• Aromatase Inhibitors (adverse effects, therapeutic use)
• Breast Neoplasms (drug therapy)
• Disease-Free Survival
• Double-Blind Method
• Drug Administration Schedule
• Female
• Humans
• Letrozole
• Middle Aged
• Nitriles (adverse effects, therapeutic use)
• Placebos
• Postmenopause
• Tamoxifen (adverse effects, therapeutic use)
• Treatment Outcome
• Triazoles (adverse effects, therapeutic use)