Plexiform neurofibromas, trial design, and the definitions of 'progression' and 'treatment failure'

摘要

The article by Widermann et al is timely. In the context of this study and recently reported trials in newly diagnosed Glioblast-oma, the question of appropriate endpoints and outcome measures, along with trial design, has resurfaced as a critical discussion point, particularly as it relates to decisions concerning drug development. In the current trial children and young adults with progressive plexiform neurofibromas were treated with tipifarnib, a farnesyl-transferase inhibitor, or placebo, and allowed a cross-over at progression to either treatment in a second stage. There are a number of unique aspects to the study, starting with the understanding that this is a disease with a poorly understood and studied natural history. These tumors grow slowly and variably over time, are difficult to measure, occur in multiple regions of the body, have a complex biology related to RAS signaling, and there is no effective treatment other than surgery done as an attempt to minimize morbidity. Besides the difficult choice of drug selection, the type(s) of endpoint needed to evaluate efficacy becomes problematic without good historical control studies. The authors chose to use progression as the primary endpoint rather than objective response, and added the placebo control arm because of the uncertain natural history of these tumors.