Incorporating Toxicity Grade Information in the Continual Reassessment Method

Abstract

The Continual Reassessment Method (CRM) is a Bayesian method for estimating the Maximum Tolerated Dose (MTD) in Phase I cancer clinical trials. In the standard CRM a parametric model is assumed for the dose-toxicity relationship and prior distributions are chosen for the model parameter(s). Parameter estimates are updated sequentially after each patient using the dichotomized toxicity information obtained at that patient's treatment dose. Subsequent patients are then treated at the estimated MTD from the updated model. This approach to dose escalation has been shown to have significant advantages over standard dose-escalation procedures in that fewer patients are required and fewer patients are given doses that are likely to be ineffective. However, this procedure has been recently criticized because doses that are too toxic may also be recommended. We present a modification to the standard CRM in which ordinal toxicity grade information is incorporated into the estimation of the MTD u..