Decision making in adjuvant trials in breast cancer: the NCIC CTG MA.17 trial as an example

Abstract

Decision-making regarding early closure and reporting of clinical trial results became a topic of intense debate following the reporting of the MA.17 adjuvant endocrine therapy trial. This trial was terminated at the first planned interim analysis when a highly significant improvement in disease free survival (DFS) was found. It has been suggested that the criterion for early stopping be made stricter when DFS is the primary study endpoint by ensuring that the targeted effect size is excluded. Our purpose is to examine this approach and to determine whether applying such a criterion would have affected the decision to terminate MA17. The sample size assumptions and the interim analysis of MA17 were reviewed and an appropriate method employed to convert hazard ratios (HR) to absolute differences. Expressed in relative terms, the effect size of MA17 was an HR of 0.78, and the upper boundary (0.75) of the confidence limits around the observed HR (0.57) excluded this value. In absolute terms, the lower confidence limit (3.1%) of best estimate of the 4 year difference in DFS (5.4%) excludes the difference (2.5%) used in the calculation of the targeted HR. We conclude that although the decision to release the results of the interim analysis of MA17 and allow patients on placebo to take letrozole was justified, methods for analyzing and interpreting interim results can be improved.

Polymorphisms ofESR1, UGT1A1, HCN1, MAP3K1andCYP2B6are associated with the prognosis of hormone receptor-positive early breast cancer

“…Whether new treatment, such as the GnRh analogue plus aromatase inhibitor, improves the survival of the SNP-poor prognostic group compared to treatment with tamoxifen deserves further study. In addition, several studies have revealed that a longer duration of adjuvant hormonal therapy improves the survival of HR+ patients [19–21], and host factors may be helpful in the selection of patients who may benefit more from longer duration of hormonal therapy.…”

Increasing protection after tamoxifen: insights from the extended adjuvant aromatase inhibitor trials

“…From a statistical standpoint, the MA.17 trial was designed with the assumption of a 4-year DFS rate of 88% in the placebo arm and for the detection of a 2.5% diVerence in this parameter with 80% power; this necessitated the enrollment of 4,800 women over 4 years with 2 years of follow-up and 515 events . Considering these predeWned parameters, it is important that the results of the Wrst interim analysis far exceeded these expectations, with a 6% diVerence in DFS between the groups (93 vs. 87%) after only 2.4 years, a highly signiWcant result (P = 0.00008) that clearly necessitated the early unblinding of the trial (Pater et al 2007). Letrozole is the Wrst and only AI thus far to demonstrate a signiWcant diVerence in DFS with acceptable tolerability as an extended adjuvant therapy for postmenopausal women with ER-positive early breast cancer in a randomized, appropriately designed, placebocontrolled trial.…”