Surrogate endpoints for overall survival in randomised controlled trials of localised osteosarcoma: A meta-analytic evaluation

Event-free survival (EFS) is considered the most reliable surrogate endpoint for overall survival (OS) in randomised controlled trials (RCTs) of adjuvant therapies for malignant tumours. However, the surrogacy of intermediate endpoints such as EFS for OS in trials of patients with osteosarcoma has not been investigated to date. In this study, we investigated the correlation between OS and intermediate endpoints in RCTs of localised osteosarcoma. A systematic search identified 20 relevant RCTs. The correlations between the surrogate endpoints and OS were evaluated using weighted linear regression analyses and by calculating the Spearman rank correlation coefficients (ρ). The strength of the correlation was determined by calculating the coefficient of determination (R(2)). A total of 5,620 patients were randomly assigned to 45 treatment arms in the eligible 20 RCTs. The correlation between the hazard ratios for EFS and OS was moderate (R(2) = 0.456, ρ = 0.440); this correlation tended to be weaker for patients with localised osteosarcoma excluding the patients with metastases. Overall, the trial-level correlation between the surrogate endpoints and OS was not robust in RCTs of osteosarcoma published to date. Hence, the suitability of the intermediate endpoints as surrogates for OS could not be confirmed.