A desirable property of any dose-escalation strategy for phase I oncology trials is coherence: if the previous patient experienced a toxicity, a higher dose is not recommended for the next patient; similarly, if the previous patient did not experience a toxicity, a lower dose is not recommended for the next patient. The escalation with overdose control (EWOC) approach is a model-based design that has been applied in practice, under which the dose assigned to the next patient is the one that, given all available data, has a posterior probability of exceeding the maximum tolerated dose equal to a pre-specified value known as the feasibility bound. Several methodological and applied publications have considered the EWOC approach with both feasibility bounds fixed and increasing throughout the trial. Whilst the EWOC approach with fixed feasibility bound has been proven to be coherent, some proposed methods of increasing the feasibility bound regardless of toxicity outcomes of patients can lead to incoherent dose-escalation. This paper formalises a proof that incoherent dose-escalation can occur if the feasibility bound is increased without consideration of preceding toxicity outcomes, and shows via simulation studies that only small increases in the feasibility bound are required for incoherent dose-escalations to occur.

中文翻译：

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使用过量控制方法递增的 I 期试验中不连贯的剂量递增

I 期肿瘤学试验的任何剂量递增策略的一个理想特性是一致性：如果前一个患者出现毒性，则不建议下一个患者使用更高的剂量；同样，如果前一位患者没有出现毒性，则不建议下一位患者使用较低的剂量。药物过量控制递增 (EWOC) 方法是一种基于模型的设计，已在实践中应用，根据所有可用数据，分配给下一位患者的剂量是具有超过最大耐受量的后验概率剂量等于预先指定的值，称为可行性界限。一些方法论和应用出版物已经考虑了 EWOC 方法，在整个试验过程中，其可行性界限是固定的并且不断增加。虽然具有固定可行性界限的 EWOC 方法已被证明是连贯的，但一些增加可行性界限而不管患者的毒性结果如何的提议方法可能导致不连贯的剂量递增。本文正式证明，如果在不考虑之前的毒性结果的情况下增加可行性界限，就会发生不连贯的剂量递增，并通过模拟研究表明，不连贯的剂量递增只需要在可行性界限上小幅增加。