To the Editor In their randomized clinical trial among older and frail patients with advanced gastroesophageal cancer, Hall and colleagues1 compared 3 dosing strategies: oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m2 on day 1, capecitabine 625 mg/m2 twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), and Level C (0.6 times A). The goal was to assess whether Levels B and C were noninferior to Level A for progression-free survival (PFS). The study was designed to exclude 34 days or greater reduction in median PFS for each pairwise noninferiority assessment (B vs A and C vs A). Presumably, one could estimate the study size using such an assumed difference in median PFS directly and analyze observed PFS data accordingly. Instead of using this direct and clinically interpretable approach, the investigators converted this difference in median to a hazard ratio (HR) of 1.34 for each pairwise comparison as the noninferiority margin. It was not clear why the investigators took a detour for designing the trial. With the PFS survival observations, the HR for B vs A was 1.09 (95% CI, 0.89 to 1.32), and the HR for C vs A was 1.10 (95% CI, 0.90 to 1.33). Because the upper bound of the CI for either comparison was below 1.34, the authors claimed that the reduced-intensity chemotherapy was acceptable with respect to cancer control. However, with reconstructed PFS data from Figure 2 of the article,1,2 the median PFS difference for A vs B is 21.5 days (95% CI, −11.5 to 54.5), and the difference for A vs C is 15.5 days (95% CI, −24.1 to 55.2). Both upper bounds of CIs were substantially larger than the prespecified margin of 34 days. With this margin, the noninferiority for the reduced-intensity chemotherapy is not justifiable.
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Wang X, Kim DH, Wei L. Quantifying and Interpreting Efficacy of Reduced-Intensity Chemotherapy With Oxaliplatin and Capecitabine on Cancer Control for Advanced Gastroesophageal Cancer Among an Older Population. JAMA Oncol. 2021;7(11):1723–1724. doi:10.1001/jamaoncol.2021.4004
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