Open Access from Statistics in Medicine: Dose finding studies for therapies with late-onset toxicities: A comparison study of designs

Every week, we select a recently published Open Access article to feature. This week’s article is from Statistics in Medicine and compares dose finding studies for therapies with late-onset toxicities. 

The article’s abstract is given below, with the full article available to read here.

Barnett, HBoix, OKontos, DJaki, TDose finding studies for therapies with late-onset toxicities: A comparison study of designsStatistics in Medicine20221– 22. doi:10.1002/sim.9593

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 while 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.

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