Combining tumour response and progression free survival as surrogate endpoints for overall survival in advanced colorectal cancer

Background:Progression free survival (PFS) and tumour response (TR) have been investigated as surrogateendpoints for overall survival (OS) in advanced colorectal cancer (aCRC), however their validity has been shownto be suboptimal. In recent years, meta-analytic methods allowing for use of multiple surrogate endpoints jointlyhave been proposed. Our aim was to assess if PFS and TR used jointly as surrogate endpoints to OS improve theirpredictive value.Methods:Data were obtained from a systematic review of randomised controlled trials investigating effective-ness of pharmacological therapies in aCRC, including systemic chemotherapies, anti-epidermal growth factorreceptor therapies and anti-angiogenic agents. Multivariate meta-analysis was used to model the associationpatterns between treatment effects on the surrogate endpoints (TR, PFS) and thefinal outcome (OS).Results:Analysis of 33 trials reporting treatment effects on all three outcomes showed reasonably strong asso-ciation between treatment effects on PFS and OS, however the association parameters were obtained with a largeuncertainty. A weak surrogate relationship was noted between the treatment effects on TR and OS. Modelling thetwo surrogate endpoints, TR and PFS, jointly as predictors of treatment effect on OS gave no marked im-provement to surrogate association patterns. Modest improvement in the precision of the predicted treatmenteffects on thefinal outcome was noted in studies investigating anti-angiogenic therapy, however it was likelydue to chance.Conclusion:The joint use of two surrogate endpoints did not lead to marked improvement in the associationbetween treatment effects on surrogate andfinal endpoints in advanced colorectal cancer