A statistical model for the dependence between progression-free survival and overall survival.
Among the surrogate endpoints for overall survival (OS) in oncology trials, progression-free survival (PFS) is more and more taking the leading role. Although there have been some empirical investigations on the dependence structure between OS and PFS (in particular between the median OS and the median PFS), statistical models are almost non-existing. This paper aims at filling this gap by introducing an easy-to-handle model based on exponential time-to-event distributions that describe the dependence structure between OS and PFS. Based on this model, explicit formulae for individual correlations are derived together with a lower bound for the correlation of OS and PFS, which is given by the fraction of the two medians for OS and PFS. Two methods on how to estimate the parameter of the model from real data are discussed. One method is based on a maximum-likelihood estimator whereas the other method uses a plug-in approach. Three examples from non-small cell lung cancer are considered. In the first example, the parameters of the model are determined and the estimated survival curce is compared with the observed one. The second example explains how to obtain sample size estimates for OS based on assumptions on median PFS and OS. Finally, the third example provides a way of modelling and quantifying confounding effects that might explain a levelling of differences in OS although a difference in PFS is observed.
Fleischer
Frank
F
Boehringer-Ingelheim Pharma GmbH and Co., KG, Biberach/Riss, Germany. frank.fleischer@boehringer-ingelheim.com
Gaschler-Markefski
Birgit
B
Bluhmki
Erich
E
D015415:Biomarkers; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy*; D018572:Disease-Free Survival; D006801:Humans; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data
D015415:Biomarkers