Thall P F, Lee J J, Tseng C H, Estey E H
Department of Biomathematics, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Stat Med. 1999 May 30;18(10):1155-69. doi: 10.1002/(sici)1097-0258(19990530)18:10<1155::aid-sim114>3.0.co;2-h.
Phase I dose-finding trials typically are conducted using adaptive rules that select dose levels for successive patient cohorts based on the outcomes of patients treated previously in the trial. When patient outcome cannot be observed immediately after treatment, the problem arises of how to deal with new patients while waiting to observe the current patient cohort's outcomes. We consider two alternative approaches to this problem in the context of a phase I trial conducted using the continual reassessment method. With the first approach, a patient requiring treatment before the next cohort opens is treated off protocol with standard therapy, and otherwise waits until the next cohort opens. The second approach treats each patient immediately upon arrival at the dose recommended based on currently available data. We compare these two approaches by simulation under varying dose--toxicity curves, accrual rates, cohort sizes and early stopping rules. We evaluate patient waiting time, trial duration, number of patients treated off protocol and the probabilities of toxicity and of selecting the correct dose. We also study three strategies for assigning patients to trials when two or more phase I trials may be ongoing simultaneously. Based on our results, we provide practical guidelines for deciding among these approaches and strategies in a given clinical setting.
I期剂量探索试验通常采用适应性规则进行，该规则根据试验中先前治疗患者的结果为连续的患者队列选择剂量水平。当治疗后不能立即观察到患者的结果时，就会出现如何在等待观察当前患者队列结果的同时处理新患者的问题。在使用连续重新评估方法进行的I期试验背景下，我们考虑解决这个问题的两种替代方法。第一种方法是，在下一个队列开放之前需要治疗的患者采用标准治疗进行非方案治疗，否则等待直到下一个队列开放。第二种方法是，每个患者在到达基于当前可用数据推荐的剂量时立即接受治疗。我们通过在不同的剂量-毒性曲线、入组率、队列大小和早期终止规则下进行模拟来比较这两种方法。我们评估患者等待时间、试验持续时间、非方案治疗的患者数量以及毒性概率和选择正确剂量的概率。我们还研究了在两个或多个I期试验可能同时进行时将患者分配到试验的三种策略。根据我们的结果，我们提供了在给定临床环境中在这些方法和策略之间进行决策的实用指南。
