Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA; Google, Mountain View, CA.
University of California, San Francisco, Department of Urology, Center for Digital Health Innovation, San Francisco, CA.
Urol Oncol. 2021 Jul;39(7):435.e17-435.e22. doi: 10.1016/j.urolonc.2020.12.012. Epub 2021 Jan 10.
Neoadjuvant chemotherapy (NAC) is the standard of care for eligible patients with cT2-4a N0 M0 bladder cancer undergoing surgical resection. The extent to which (and if) NAC increases patient survival is not clear as clinical trials and meta-analyses have generated both negative and "borderline" positive results. The novel method of calculating restricted mean survival times (RMST) may provide a more meaningful way to quantify treatment efficacy due to inherent statistical limitations of conventional hazard ratios. In this study we analyzed the survival benefit attributable to NAC in bladder cancer by calculating RMST of previously published clinical trials.
All published randomized controlled clinical trials of bladder cancer with available survival data comparing NAC plus radical cystectomy with cystectomy alone were included. RMSTs were calculated for each cohort at the 5-year and total follow-up time periods, comparing the NAC and radical cystectomy groups. Fixed effect meta-analysis of the 5-year RMSTs was then performed to calculate the net impact of NAC on overall survival.
For 2 among 7 included trails, RMST analysis changed the statistical significance. The SWOG 8,710 trial that had previously suggested a survival benefit associated with NAC (P = 0.06) was found to have a clearer beneficial association by 5-year RMST (6.5 month benefit; P = 0.01) and total follow-up RMST (13.6 month benefit over 168 months; P = 0.04). The International Collaboration of Trialists trial that had previously suggested a survival benefit with NAC (P = 0.04) was found to have a beneficial association by total follow-up RMST (6.7 months benefit over 120 months; P = 0.04) but not 5-year RMST (P = 0.10). The interpretation of other trials did not change. Fixed effect meta-analysis suggested a clinically significant overall survival benefit associated with NAC (3.2 months benefit over 60 months; P < 0.01).
Evaluation of published randomized controlled trials using RMSTs strengthens the association of neoadjuvant chemotherapy with survival benefit in bladder cancer. As RMST may enable improved detection of clinical benefit when compared to conventional statistical methods, consideration should be given to RMST-based endpoints in future clinical trial design.
新辅助化疗（NAC）是接受手术切除的 cT2-4a N0 M0 膀胱癌患者的标准治疗方法。NAC 是否以及在何种程度上增加患者的生存尚不清楚，因为临床试验和荟萃分析得出了阴性和“边缘阳性”的结果。计算受限平均生存时间（RMST）的新方法可能提供了一种更有意义的量化治疗效果的方法，因为它克服了传统风险比的固有统计限制。在这项研究中，我们通过计算先前发表的临床试验的 RMST，分析了 NAC 对膀胱癌患者生存获益的影响。
所有已发表的、具有生存数据的比较 NAC 联合根治性膀胱切除术与单纯膀胱切除术的膀胱癌随机对照临床试验均被纳入。计算了每个队列在 5 年和总随访时间的 RMST，比较了 NAC 和根治性膀胱切除术组。然后对 5 年 RMST 进行固定效应荟萃分析，以计算 NAC 对总生存的净影响。
在纳入的 7 项试验中有 2 项，RMST 分析改变了统计意义。SWOG 8710 试验此前提示 NAC 与生存获益相关（P=0.06），通过 5 年 RMST（6.5 个月获益；P=0.01）和总随访 RMST（168 个月时获益 13.6 个月；P=0.04），发现 NAC 具有更明确的有益关联。先前提示 NAC 有生存获益的国际协作试验（P=0.04），通过总随访 RMST（120 个月时获益 6.7 个月；P=0.04）发现有有益关联，但 5 年 RMST 无关联（P=0.10）。其他试验的解释没有改变。固定效应荟萃分析提示 NAC 与总生存获益有显著的临床关联（60 个月时获益 3.2 个月；P<0.01）。
使用 RMST 评估已发表的随机对照试验，加强了新辅助化疗与膀胱癌生存获益的关联。由于 RMST 可能比传统统计方法更能检测到临床获益，因此在未来的临床试验设计中应考虑基于 RMST 的终点。
