Efficacy and tolerability of hypofractionated and dose-boosted radiotherapy for localised prostate cancer: a systematic review and meta-analysis

In this systematic review and meta-analysis (PROSPERO: CRD42024601045), we evaluated the efficacy and safety of hypofractionated and dose-boosted radiotherapy fractionation schedules in patients with clinically localised prostate cancer. We searched MEDLINE, Embase, Web of Science, CENTRAL, and Google Scholar on 2025–06-15 for randomised controlled trials (RCT) using equivalent doses in 2 Gy fractions (EQD2) ≥ 70 Gy in both arms, with outcomes including biochemical recurrence-free survival (BRFS), metastasis-free survival (MFS), overall survival (OS), and rates of grade ≥ 2/≥3 adverse events (AEs). Data were pooled using random-effects meta-analyses and presented in forest plots. Risk-of-bias (RoB) was assessed using the Cochrane RoB 2 tool. We identified 25 RCTs involving 12,479 patients. Combining external beam radiotherapy with brachytherapy or with focal boost was associated with significant MFS improvement (n = 1468, hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.6–0.95, p = 0.016) compared to standard radiotherapy. A sensitivity analysis including two studies with extended follow-up suggested possible OS benefit (n = 897, HR: 0.75, 95% CI: 0.6–0.95, p = 0.016). BRFS was evaluated in 15 trials testing hypofractionation (n = 10220). We found a small numerical improvement (HR 0.88, 95% CI 0.76–1, p = 0.058), though not well explained by the EQD2 model, and no significant differences in MFS or OS. Acute grade ≥ 2 gastrointestinal AEs were modestly increased with moderate hypofractionation, and acute grade ≥ 3 genitourinary AEs were increased with ultra-hypofractionation, without significant differences in late AEs. Primary limitations included concerns regarding RoB associated with patient allocation in dose-boost analysis, and impact of open-label study designs on AE reporting. These findings support the use of dose-boosting as a means to improve survival in high-risk patients, and hypofractionation as a method to reduce treatment time associated with a potential improvement in disease control.