Introduction: Recent reports suggest that early salvage radiation (esRT) is non-inferior to adjuvant radiation (aRT) for adverse pathological features at radical prostatectomy. However, aRT was accepted as a standard treatment primarily based on effects on biochemical progression-free survival (bPFS). In order to understand the merits of esRT, the objective was to reassess if aRT vs. observation is associated with improved overall survival (OS). Methods: A systematic review and meta-analysis of published randomized trials evaluating aRT was performed. The primary outcome was OS. Secondary outcomes were metastasis-free survival (MFS), loco-regional recurrence-free survival (RFS), bPFS, and adverse events. We performed a random-effects meta-analysis. Results: Four randomized trials including 2068 patients with a median followup of 8.7-12.6 years were identified. While all trials reported a bPFS benefit, only one reported an OS benefit. Upon meta-analysis, no significant OS benefit was detected with aRT vs. observation (hazard ratio [HR] 0.90; 95% confidence interval [CI] 0.61-1.33), although consistent bPFS (HR 0.47; 95% CI 0.41-0.54) and local-RFS (HR 0.54; 95% CI 0.39-0.73) benefits were noted. There is an uncertain MFS benefit with aRT (HR 0.79; 95% CI 0.62-1.01), and the effect is largely driven by one trial with a notable risk of bias. There was also a risk of overtreatment, with 35-60% of patients being biochemical recurrence-free with observation alone. Adverse events risk was greater with aRT vs. observation. Conclusions: Although aRT vs. observation provides a bPFS benefit related to local control, there is no clear OS or MFS benefit, a greater risk of adverse events, and a risk of overtreatment. By extension, these data have implications for patient selection and counselling for esRT.
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