Dose-finding clinical trials in oncology aim to estimate the maximum tolerated dose (MTD), based on safety traditionally obtained from the clinician's perspective. While the collection of patient-reported outcomes (PROs) has been advocated to better inform treatment tolerability, there is a lack of guidance and methods on how to use PROs for dose assignments and recommendations. The PRO continual reassessment method (PRO-CRM) has been proposed to formally incorporate PROs to estimate the MTD, requiring complete follow-up of both clinician and patient toxicity information per dose cohort to assign the next cohort of patients. In this paper, we propose two extensions of the PRO-CRM, allowing continuous enrollment of patients and handling longer toxicity observation windows to capture late-onset or cumulative toxicities. The first method, the TITE-PRO-CRM, uses a weighted likelihood to include the partial follow-up information from PRO in estimating the MTD during and at the end of the trial. The second method, the TITE-CRM+PRO, uses clinician's information solely to inform dose assignments during the trial and incorporates PRO at the end of the trial for dose recommendation. Simulation studies show that the TITE-PRO-CRM performs similarly to the PRO-CRM in terms of dose recommendation and assignments during the trial while reducing trial duration. The TITE-CRM + PRO slightly underperforms compared to the TITE-PRO-CRM, but similar performance can be attained by requiring larger sample sizes. We also show that the proposed methods have similar performance under higher accrual rates, different toxicity hazards, and correlated time-to-clinician toxicity and time-to-patient toxicity data.

翻译：肿瘤学剂量探索临床试验旨在基于传统上从临床医生视角获取的安全性数据，估计最大耐受剂量（MTD）。尽管已倡导收集患者报告结局（PRO）以更全面地评估治疗耐受性，但目前缺乏关于如何利用PRO进行剂量分配与推荐的指导原则及方法。PRO连续重新评估方法（PRO-CRM）已被提出，用于正式整合PRO以估计MTD，但该方法要求每个剂量队列中患者需完成临床医生与患者双方毒性信息的完整随访，方可分配下一队列患者。本文提出PRO-CRM的两种扩展方法，允许患者连续入组，并处理更长的毒性观察窗口以捕捉迟发性或累积性毒性。第一种方法TITE-PRO-CRM采用加权似然法，在试验期间及结束时将PRO的部分随访信息纳入MTD估计。第二种方法TITE-CRM+PRO在试验期间仅依据临床医生信息进行剂量分配，而在试验结束时结合PRO进行剂量推荐。模拟研究表明：TITE-PRO-CRM在剂量推荐与试验期间分配方面与PRO-CRM表现相近，同时缩短了试验周期；TITE-CRM+PRO相较TITE-PRO-CRM略逊色，但通过增加样本量可达到相似性能。此外，在更高入组率、不同毒性风险函数以及临床医生毒性发生时间与患者毒性发生时间存在相关性的情形下，所提方法均表现出相近性能。