Adjusting for Selective Crossover in Analyses of Letrozole (Let) Versus Tamoxifen (Tam) in the BIG 1-98 Trial.
Authors: M. Regan, M. Colleoni, A. Giobbie-Hurder, B. Thuerlimann, H. Mouridsen, L. Mauriac, R. Paridaens, J. Forbes, A. Wardley, I. Smith, K. Price, A. Goldhirsch, A. Coates, R. Gelber
Journal: Cancer Research (2009)

Abstract Background: BIG 1-98 is a double-blind randomized trial comparing 5yrs of Let (Letx5), Tam (Tamx5) and sequences of Let and Tam as adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer. Initial results (presented Jan05) demonstrated superiority of Let over Tam in significantly prolonging disease-free survival (DFS) and reducing risk of relapse in distant sites. Following these results, investigators were informed of the treatment allocation for patients (pts) randomized to Tamx5 and 25% of pts selectively crossed over to Let. Selective crossover has occurred in other clinical trials (eg trastuzumab trials).At SABCS 2008 the protocol-specified 8yr update of the monotherapy comparison (Tamx5 vs. Letx5; median follow-up 76 mo) was presented, as randomized (ITT) and with follow-up of the pts who selectively crossed over artificially censored at the time of the crossover. As with the earlier results, Let significantly improved DFS; a trend for improved overall survival (OS) was seen in the ITT, and was significant in the artificially censored analysis (Table). Treatment effect estimates of both analyses are affected by the selective crossover.Methods: The goal of this analysis is to estimate the true magnitude of the Letx5 : Tamx5 treatment effect had pts randomized to Tam not selectively crossed over to Let. Pts assigned Tamx5 who took Let after Jan05 were identified as selective crossover pts (619/2459 pts; 25%); post-crossover follow-up was 7% of the total, and median duration of post-crossover Let was 18 months. 21 DFS and 5 OS events occurred among these 619 pts. Inverse probability of censor weighting (IPCW), to handle induced selection bias by artificial censoring at crossover, is used to estimate the treatment effect. IPCW assigns a weight to each pt who remains on Tam so that she accounts in the analysis not only for herself but also for those with similar characteristics who are artificially censored at crossover to Let.Results: Several baseline factors, including age, prior local therapy, nodal status, ER/PgR status, and tumor grade were associated both with outcome and with selective crossover. Also performance status (PS) over time was associated with OS and crossover. For DFS, the IPCW estimate of treatment effect (HR=0.84) was larger than the ITT and artificially-censored estimates, and more similar to the ITT estimates reported earlier in follow-up. For OS, the IPCW estimate (HR=0.83) was larger than the ITT estimate but suggested the artificially-censored estimate over-estimated the OS treatment effect. HR[Letx5:Tamx5] (95% CI)Analysis (mo/yr presented) [median follow up]DFSOSITT (3/05) [26 months].81 (.70-.93).86 (.70-1.06)ITT (12/08) [76 months].88 (.78-.99).87 (.75-1.02)Artificially censor Tam pts at selective crossover (12/08) [76 months].85 (.75-.96).82 (.70-.96)IPCW (new analysis) [76 months].84 (.75-.95).83 (.71-.97) Conclusion: The selective crossover affects efficacy results of the ITT analysis of the BIG 1-98 monotherapy comparison. Additional IPCW analysis accounting for the selective crossover indicates that the benefit of Let over Tam is greater than that reflected by the ITT estimate. Let for 5yrs is significantly better than Tam for DFS and OS. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 16.