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Brian M. Alexander, Lorenzo Trippa, Progression-free survival: too much risk, not enough reward?, Neuro-Oncology, Volume 16, Issue 5, May 2014, Pages 615–616, https://doi.org/10.1093/neuonc/nou041
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Given the increasing number of potential therapies for glioblastoma and the slow rate of progress to date, clinical trials must become more efficient while providing clinically relevant answers. In this context, careful selection of clinical trial endpoints is extremely important. Adoption of new therapies requires trials that demonstrate real, clinically meaningful improvements in outcome attributable to the experimental therapy. While survival is undeniably clinically meaningful, there is interest in using other endpoints such as response rate or progression-free survival as more efficient ‘surrogates’ that limit non-treatment related variation and confounding by post-progression therapy.
Han et al. conducted a meta-analysis to determine whether PFS and response rate could be used as surrogates for OS in glioblastoma.1 The most relevant finding was a strong correlation between PFS HR estimates and OS HR estimates (R2 0.92) in non-bevacizumab containing comparative studies. It is important to note, however, that these analyses examine relationships between parameter estimates. If every trial included in the meta-analysis were identical and from the same study population, there would still be variability in summary statistic estimates, which would be strongly correlated but give little information on the value of the proposed surrogate. The analysis should therefore account for the variability and correlation of the study-specific summary statistics and limit comparisons to historical controls to reduce correlations attributable to selection bias. Overall response rate had a poor correlation with OS and point estimates of PFS and OS within groups showed moderate to good correlations. Correlations of PFS and OS estimates within non-comparative groups are less meaningful with respect to the surrogacy question, however.
