Subsequent treatments can result in a difficulty in interpretation of the overall survival results in confirmatory oncology clinical trials. To complement the intention-to-treat (ITT) analysis affected by subsequent treatment patterns unintentional in the trial protocol, several causal methods targeting the per-protocol effect have been proposed. When two or more types of subsequent treatments are allowed in the trial protocol, however, these methods cannot answer clinical questions such as how sensitive the ITT analysis result is to higher or lower proportions of each subsequent treatment allowed in the trial protocol than observed, and to what extent ITT analysis result is generalizable to subsequent treatment patterns other than observed one. To answer these clinical questions, we propose a sensitivity analysis method for subsequent treatments using the inverse probability of treatment weighting method for stochastic dynamic treatment regimes (DTRs). We formulate oncology clinical trials with subsequent treatments as two-stage designs in which initial treatments are randomized but subsequent treatments are observational. In this formulation, we use stochastic DTRs to simulate specific proportions of each subsequent treatment and compare an initial experimental treatment with an initial control treatment under various proportions of each subsequent treatment. We applied our proposed method to a motivating randomized non-inferiority trial for metastatic breast cancer. Simulation results are also reported to show the usefulness of the proposed method. This article is protected by copyright. All rights reserved.

中文翻译：

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确认性肿瘤临床试验中后续治疗的敏感性分析：两阶段随机动态治疗方案方法

随后的治疗可能导致难以解释确认性肿瘤临床试验中的总生存结果。为了补充受试验方案中无意的后续治疗模式影响的意向治疗 (ITT) 分析，已经提出了几种针对符合方案效应的因果方法。然而，当试验方案中允许两种或两种以上的后续治疗时，这些方法无法回答临床问题，例如 ITT 分析结果对试验方案中允许的每种后续治疗的比例比观察到的更高或更低的敏感度，以及ITT 分析结果在多大程度上可推广到除观察到的治疗模式以外的后续治疗模式。为了回答这些临床问题，我们使用随机动态治疗方案（DTR）的治疗加权方法的逆概率为后续治疗提出了一种敏感性分析方法。我们将肿瘤学临床试验和后续治疗制定为两阶段设计，其中初始治疗是随机的，但后续治疗是观察性的。在这个公式中，我们使用随机 DTR 来模拟每个后续处理的特定比例，并在每个后续处理的不同比例下比较初始实验处理与初始对照处理。我们将我们提出的方法应用于转移性乳腺癌的随机非劣效性试验。还报告了仿真结果以显示所提出方法的有用性。本文受版权保护。版权所有。