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

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