Risk of Secondary Pelvic Cancers Following Radiotherapy for Prostate Cancer

Background/Objectives: Secondary pelvic cancer (SC) risk after radiotherapy (RT) for prostate cancer (PC) remains uncertain; we performed an updated synthesis of observational studies and randomized trials. Methods: We reviewed systematic reviews, meta-analyses, and randomized trials published in 2001-2025 evaluating SC risk after RT for PC. Given potential detection bias from RT-related rectal or bladder bleeding, the primary outcome was relative risk (RR) of death. Results: Across 12 reports-eight systematic reviews/meta-analyses and four randomized trials-comparators were predominantly RP or mixed cohorts; review-level sample sizes were not summed because of potential overlap. In randomized data with >10 years of follow-up, SC occurred in 25.3% of RT-treated patients versus 20.8% in RP/hormone therapy groups, while deaths from other cancers occurred in 8.5% versus 7.2%. The median converted RR of death from SC was 1.05. These estimates may be influenced by unmeasured lifestyle factors such as smoking and baseline comorbidities, which were not accounted for in observational cohorts and are more common among patients receiving RT, who are often less likely to be RP candidates. Conclusions: RT is associated with a small but consistent increase in SC, with a 4.5% absolute excess incidence over >10 years. The observed 1.3% absolute difference in deaths from other cancers was modest and similar in magnitude to the reported perioperative mortality range of approximately 0.2-1.1% after RP, although these risks occur over substantially different time horizons. The smaller excess seen in randomized trials than in retrospective studies suggests that much of the apparent risk in prior reports may reflect confounding and/or detection bias rather than direct radiation effect.