摘要

The rate of observed dose-limiting toxicities (DLT) determines the maximum tolerated dose (MTD) in phase I trials. There are cases in which non-drug-related toxicities or other-cause toxicities (OCT) are flagged as DLTs, or vice versa, due to attribution errors. We aim to assess the impact of such errors on the final estimate of MTD. We compared the impact of attribution errors using 2 trial designs-the "3+3" dose-escalation scheme and the continual reassessment method (CRM). Two attribution errors are considered: when a DLT is classified as an OCT (type A error) and when an OCT is misclassified as a DLT (type B error). The impact of these errors on accuracy, patient safety, sample size, and study duration was evaluated by varying the probability of occurrence of each error through simulated trials. Under no errors, CRM is on average 35% more accurate than 3+3 in finding the true MTD. This improved accuracy is maintained in the presence of errors. At a 15% type B error rate, CRM recommends a dose within 2 levels of the true MTD 68% of the time, compared with 17% of the time using the 3+3 method. A DLT must be attributed as an OCT 30% of the time to increase the accuracy of 3+3; otherwise the method recommends a wrong dose approximately 75% of the time. CRM is more robust to toxicity attribution errors compared with the 3+3 as it uses information from all treated patients, leading to a more accurate MTD estimation at the frequency of attribution errors anticipated in phase I clinical trials.

译文

观察到的剂量限制毒性 (DLT) 的速率决定了 I 期试验中的最大耐受剂量 (MTD)。有些情况下，非药物相关毒性或其他原因毒性 (OCT) 被标记为 dlt，反之亦然，由于归因错误。我们旨在评估此类误差对 MTD 最终估计的影响。我们使用 2 种试验设计 -- “3 3” 剂量递增方案和肿瘤再评估方法 (CRM) 比较了归因错误的影响。考虑两个归因错误: 当 DLT 被归类为 OCT (a 类错误) 时，以及当 OCT 被错误归类为 DLT (B 类错误) 时。通过改变模拟试验中每个错误发生的概率来评估这些错误对准确性、患者安全性、样本量和研究持续时间的影响。在没有错误的情况下，CRM 在寻找真正的 MTD 方面平均比 3 3 高 35%。在存在错误的情况下，这种改进的准确性得以保持。在 15% 的 b型错误率下，CRM 推荐的剂量在真实 MTD 的 2 个水平内，68% 的时间使用 3 3 方法，而 17% 的时间使用 3 3 方法。DLT 必须归因于 30% 的时间，以提高 3 3 的准确性; 否则，该方法推荐大约 75% 的时间使用错误的剂量。与 3 比 3 相比，CRM 对毒性归因错误更稳健，因为它使用来自所有接受治疗的患者的信息, 导致在 I 期临床试验中预期的归因错误频率下更准确的 MTD 估计。