Synthesizing studies for comparing different treatment sequences in clinical trials

Abstract

With advances in cancer treatments and improved patient survival, more patients may go through multiple lines of treatment. It is of clinical importance to choose a sequence of effective treatments (eg, lines of treatment) for individual patients with the goal of optimizing their long-term clinical outcome (eg, survival). Several important issues arise in cancer studies. First, cancer clinical trials are usually conducted by each line of treatment. For a treatment sequence, we may have first line and second line treatment data from two different studies. Second, there is typically a treatment initiation period varying from patient to patient between progression of disease and the start of the second line treatment due to administrative reasons. Additionally, the choice of the second line treatment for patients with progression of disease may depend on their characteristics. We address all these issues and develop semiparametric methods under the potential outcome framework for the estimation of the overall survival probability for a treatment sequence and for comparing different treatment sequences. We establish the large sample properties of the proposed inferential procedures. Simulation studies and an application to a colorectal clinical trial are provided.