Center for Clinical and Research Informatics, NorthShore University HealthSystem, 1001 University Place, Evanston, IL 60201, USA.
J Clin Oncol. 2013 May 10;31(14):1785-91. doi: 10.1200/JCO.2012.45.7903. Epub 2013 Apr 8.
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.
3+3 设计是临床医生在肿瘤学 I 期剂量递增试验中最常选择的方案。在最近的综述中，超过 95%的 I 期试验都是基于 3+3 设计。由于它直观，并且其实施不需要计算机程序，因此临床医生实际上可以在实践中进行 3+3 剂量递增，几乎不需要任何物流成本，而且基于 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。在绝大多数统计学文献中，已经表明 3+3 设计在确定真实最大耐受剂量（MTD）方面表现不佳，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，通过具有匹配样本量的比较模拟研究，我们证明 3+3 设计使患者暴露于 MTD 以上毒性剂量的风险高于新开发的自适应方法——改良毒性概率区间（mTPI）设计。此外，与 mTPI 设计相比，即使在匹配样本量的情况下，3+3 设计也不能提高确定正确 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，并且在实际情况下更灵活，我们强烈鼓励在早期剂量递增研究中采用 mTPI 设计，只要也考虑 3+3 设计。我们提供免费软件，允许在具有匹配样本量的模拟研究中直接比较 3+3 设计与其他基于模型的设计。
