The Impact of Non-Drug-Related Toxicities on the Estimation of the Maximum Tolerated Dose in Phase I Trials
The Impact of Non-Drug-Related Toxicities on the Estimation of the Maximum Tolerated Dose in Phase I Trials
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DOI：
10.1158/1078-0432.ccr-12-0726
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发表时间：
2012-10-01
影响因子：
11.5
通讯作者：
O'Quigley, John
中科院分区：
文献类型：
--
作者：
Iasonos, Alexia;Gounder, Mrinal;O'Quigley, John
在I期试验中，观察到的剂量限制毒性(DLT)率决定了最大耐受量(MTD)。在一些情况下，由于归因错误，非药物相关毒性或其他原因毒性(OCT)被标记为DLT，反之亦然。我们的目标是评估这些误差对MTD最终估计的影响。我们使用2个试验设计--“3+3”剂量递增方案和持续再评估方法(CRM)来比较归因错误的影响。两种归因错误被考虑：当DLT被分类为OCT时(A类型错误)和当OCT被错误分类为DLT时(B类型错误)。通过通过模拟试验改变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。在没有误差的情况下，CRM在找到真正的MTD方面比3+3平均提高35%的准确率。这种改进的准确度在存在错误的情况下保持不变。在B型错误率为15%的情况下，CRM建议的剂量在真实MTD的2个水平以内的比例为68%，而使用3+3方法的比例为17%。DLT必须被归因于30%的OCT时间才能提高3+3的准确度；否则，该方法建议错误剂量的可能性约为75%。与3+3相比，CRM对毒性归因错误的影响更强，因为它使用了来自所有接受治疗的患者的信息，从而在I期临床试验中预期的归因错误频率下更准确地估计MTD。临床癌症资源；18(19)；5179-87。(C)2012年AACR。
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. Clin Cancer Res; 18(19); 5179-87. (C)2012 AACR.