Modified Toxicity Probability Interval Design: A Safer and More Reliable Method Than the 3+3 Design for Practical Phase I Trials
Modified Toxicity Probability Interval Design: A Safer and More Reliable Method Than the 3+3 Design for Practical Phase I Trials
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DOI：
10.1200/jco.2012.45.7903
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发表时间：
2013-05-10
影响因子：
45.3
通讯作者：
Wang, Sue-Jane
中科院分区：
文献类型：
--
作者：
Ji, Yuan;Wang, Sue-Jane
3 + 3 设计是临床医生进行 I 期剂量递增肿瘤试验最常见的选择。在最近的审查中，超过 95% 的 I 期试验都是基于 3 + 3 设计。鉴于其直观且实施不需要计算机程序，临床医生可以在实践中进行 3 + 3 剂量升级，几乎不需要任何后勤成本，并且基于 3 + 3 设计的试验方案可以快速通过机构审查委员会和生物统计学审查。然而，在具有匹配样本量的模拟研究中，3+3设计的性能很少与基于模型的设计进行比较。在绝大多数统计文献中，3 + 3 设计已被证明在确定真正的最大耐受剂量 (MTD) 方面较差，尽管 3 + 3 设计所需的样本量通常比基于模型的设计小几个数量级。在本文中，通过匹配样本量的比较模拟研究，我们证明3 + 3设计比新开发的自适应方法修正毒性概率区间（mTPI）设计具有更高的使患者暴露于高于MTD的毒性剂量的风险。此外，与 mTPI 设计相比，即使样本量匹配，3 + 3 设计也不会产生更高的识别正确 MTD 的概率。鉴于 mTPI 设计同样透明，使用免费软件实施无需成本，并且在实际情况中更加灵活，因此每当考虑 3 + 3 设计时，我们强烈鼓励在早期剂量递增研究中采用它。我们提供免费软件，允许在具有匹配样本量的模拟研究中将 3 + 3 设计与其他基于模型的设计进行直接比较。 (C) 2013 年美国临床肿瘤学会
The 3 + 3 design is the most common choice among clinicians for phase I dose-escalation oncology trials. In recent reviews, more than 95% of phase I trials have been based on the 3 + 3 design. Given that it is intuitive and its implementation does not require a computer program, clinicians can conduct 3 + 3 dose escalations in practice with virtually no logistic cost, and trial protocols based on the 3 + 3 design pass institutional review board and biostatistics reviews quickly. However, the performance of the 3 + 3 design has rarely been compared with model-based designs in simulation studies with matched sample sizes. In the vast majority of statistical literature, the 3 + 3 design has been shown to be inferior in identifying true maximum-tolerated doses (MTDs), although the sample size required by the 3 + 3 design is often orders-of-magnitude smaller than model-based designs. In this article, through comparative simulation studies with matched sample sizes, we demonstrate that the 3 + 3 design has higher risks of exposing patients to toxic doses above the MTD than the modified toxicity probability interval (mTPI) design, a newly developed adaptive method. In addition, compared with the mTPI design, the 3 + 3 design does not yield higher probabilities in identifying the correct MTD, even when the sample size is matched. Given that the mTPI design is equally transparent, costless to implement with free software, and more flexible in practical situations, we highly encourage its adoption in early dose-escalation studies whenever the 3 + 3 design is also considered. We provide free software to allow direct comparisons of the 3 + 3 design with other model-based designs in simulation studies with matched sample sizes. (C) 2013 by American Society of Clinical Oncology