Progression-related endpoints (such as time to progression or progression-free survival) and time to death are common endpoints in cancer clinical trials. It is of interest to study the link between progression-related endpoints and time to death (e.g. to evaluate the degree of surrogacy). However, current methods ignore some aspects of the definitions of progression-related endpoints. We review those definitions and investigate their impact on modeling the joint distribution. Further, we propose a multi-state model in which the association between the endpoints is modeled through a frailty term. We also argue that interval-censoring needs to be taken into account to more closely match the latent disease evolution. The joint distribution and an expression for Kendall's s are derived. The model is applied to data from a clinical trial in advanced metastatic ovarian cancer.

Frailty models, Interval censoring, Progressive multi-state models, Survival, Time to progression,
Statistics in Medicine
Erasmus MC: University Medical Center Rotterdam

Dejardin, D, Lesaffre, E.M.E.H, & Verbeke, G. (2010). Joint modeling of progression-free survival and death in advanced cancer clinical trials. Statistics in Medicine, 29(16), 1724–1734. doi:10.1002/sim.3918