An objective of phase I dose-finding trials is to find the maximum tolerated dose; the dose with a particular risk of toxicity. Frequently, this risk is assessed across the first cycle of therapy. However, in oncology, a course of treatment frequently consists of multiple cycles of therapy. In many cases, the overall risk of toxicity for a given treatment is not fully encapsulated by observations from the first cycle, and hence it is advantageous to include toxicity outcomes from later cycles in phase I trials. Extending the follow up period in a trial naturally extends the total length of the trial which is undesirable. We present a comparison of eight methods that incorporate late onset toxicities whilst not extensively extending the trial length. We conduct simulation studies over a number of scenarios and in two settings; the first setting with minimal stopping rules and the second setting with a full set of standard stopping rules expected in such a dose finding study. We find that the model-based approaches in general outperform the model-assisted approaches, with an Interval Censored approach and a modified version of the Time-to-Event Continual Reassessment Method giving the most promising overall performance in terms of correct selections and trial length. Further recommendations are made for the implementation of such methods.
翻译:第一阶段剂量调查试验的一个目标是找出最大容许剂量;特别具有毒性风险的剂量; 经常在整个治疗第一阶段评估这一风险; 然而,在肿瘤学方面,治疗过程往往由多种治疗周期组成; 在许多情况下,从第一个试验周期的观察来看,对特定治疗的毒性总体风险没有充分概括,因此,在第一阶段试验中将后期周期的毒性结果纳入试验,是有好处的。 在试验中延长后续期自然延长试验的总长度,这是不可取的。 我们比较了八个方法,这些方法包括晚发毒性,而没有广泛延长试验期。 我们对几种假设和两种情况进行了模拟研究;第一次设定了最低限度停止规则,第二次设定了在这种剂量调查研究中预期的一整套标准停止规则。我们发现,基于模型的方法一般比模型辅助的方法更优于模型辅助的方法,同时采用互见感检查方法,对时间到时间的修改版《持续评估方法》,在正确选择和试验期的执行方面给予最有希望的总体业绩。