title: Joint modeling of progression-free survival and death in advanced cancer clinical trials.
abstract: 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 tau are derived. The model is applied to data from a clinical trial in advanced metastatic ovarian cancer.
authors.affiliation: Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Katholieke Universiteit Leuven and Universiteit Hasselt, Kapucijnenvoer 35, Block D, bus 7001, B3000 Leuven, Belgium. david.dejardin@med.kuleuven.be
authors.forename: David
authors.initials: D
authors.lastname: Dejardin
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lesaffre
authors.forename: Geert
authors.initials: G
authors.lastname: Verbeke
mesh_terms: D000465:Algorithms; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000401:mortality / Q000556:secondary; D002986:Clinical Trials as Topic / Q000379:methods*; D017322:Clinical Trials, Phase II as Topic / Q000379:methods; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D003198:Computer Simulation; D018572:Disease-Free Survival; D015340:Epidemiologic Research Design; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000556:secondary; D015233:Models, Statistical; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000556:secondary; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D016019:Survival Analysis