Zhong Zihang, Yang Min, Ni Senmiao, Cai Lixin, Wu Jingwei, Bai Jianling, Yu Hao
Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China.
Department of Epidemiology and Biostatistics, College of Public Health, Temple University, Philadelphia, PA, USA.
J Appl Stat. 2022 Nov 14;51(4):646-663. doi: 10.1080/02664763.2022.2145272. eCollection 2024.
Progression-free survival (PFS) is an increasingly important surrogate endpoint in cancer clinical trials. However, the true time of progression is typically unknown if the evaluation of progression status is only scheduled at given surveillance intervals. In addition, comparison between treatment arms under different surveillance schema is not uncommon. Our aim is to explore whether the heterogeneity of the surveillance intervals may interfere with the validity of the conclusion of efficacy based on PFS, and the extent to which the variation would bias the results. We conduct comprehensive simulation studies to explore the aforementioned goals in a two-arm randomized control trial. We introduce three steps to simulate survival data with predefined surveillance intervals under different censoring rate considerations. We report the estimated hazard ratios and examine false positive rate, power and bias under different surveillance intervals, given different baseline median PFS, hazard ratio and censoring rate settings. Results show that larger heterogeneous lengths of surveillance intervals lead to higher false positive rate and overestimate the power, and the effect of the heterogeneous surveillance intervals may depend upon both the life expectancy of the tumor prognoses and the censoring proportion of the survival data. We also demonstrate such heterogeneity effect of surveillance intervals on PFS in a phase III metastatic colorectal cancer trial. In our opinions, adherence to consistent surveillance intervals should be favored in designing the comparative trials. Otherwise, it needs to be appropriately taken into account when analyzing data.
无进展生存期（PFS）在癌症临床试验中是一个日益重要的替代终点。然而，如果仅在给定的监测间隔安排进展状态评估，通常无法得知真正的进展时间。此外，不同监测方案下治疗组之间的比较并不罕见。我们的目的是探讨监测间隔的异质性是否会干扰基于PFS的疗效结论的有效性，以及这种变化会在多大程度上使结果产生偏差。我们进行了全面的模拟研究，以在双臂随机对照试验中探讨上述目标。我们引入三个步骤，在不同删失率考虑下，用预定义的监测间隔模拟生存数据。我们报告估计的风险比，并在不同的监测间隔下，给定不同的基线中位PFS、风险比和删失率设置，检查假阳性率、检验效能和偏差。结果表明，监测间隔的异质性长度越大，假阳性率越高，且高估检验效能，监测间隔的异质性影响可能取决于肿瘤预后的预期寿命和生存数据的删失比例。我们还在一项III期转移性结直肠癌试验中证明了监测间隔对PFS的这种异质性影响。我们认为，在设计比较试验时应倾向于坚持一致的监测间隔。否则，在分析数据时需要适当考虑。
