Meta-analysis for the evaluation of surrogate endpoints in cancer clinical trials

The identification and validation of putative surrogate endpoints in oncology is a great challenge to medical investigators, statisticians, and regulators. A putative surrogate endpoint must be validated at both individual-level and trial-level before it can be used to replace the clinical endpoint in a future clinical trial. Recently, meta-analytic methods for evaluating potential surrogates have become widely accepted in cancer clinical trials. In this review, after addressing multiple complications and general issues surrounding surrogate endpoints, we review various proposed and adopted meta-analytic methodologies pertaining to the application of these methods to oncology clinical trials with different tumor types. In oncology, several applications have successfully identified useful surrogates. For example, disease-free survival and progression-free survival have been validated through meta-analyses as acceptable surrogates for overall survival in adjuvant colon cancer and advanced colorectal cancer, respectively. We also discuss several limitations of surrogate endpoints, including the critical issues that the extrapolation of the validity of a surrogate is always context-dependent and that such extrapolation should be exercised with caution.