KEY POINTS
- The review included 12 reports published between 2001 and 2025: eight systematic reviews or meta-analyses and four randomized trials. Because primary cohorts overlapped substantially, review-level patient totals were not combined.
- Across randomized trials with more than ten years of follow-up, second cancers occurred in 25.3% of radiotherapy-treated patients versus 20.8% of patients treated with prostatectomy or hormone therapy, an absolute difference of 4.5 percentage points.
- Deaths from other cancers occurred in 8.5% after radiotherapy versus 7.2% after prostatectomy or hormone therapy, an absolute difference of approximately 1.3 percentage points. The median converted relative risk for death from a secondary cancer or other cancer was 1.05.
- Observational syntheses consistently suggested greater bladder-cancer incidence after prostate radiotherapy, with a median converted relative risk of 1.83, ranging from 1.63 to 2.54. Rectal and colorectal estimates were lower, with a median of 1.46 and a range of 0.81–1.79.
- In EORTC 22911, second cancers occurred in 13.5% after immediate postoperative radiotherapy and 13.7% with observation after prostatectomy (RR 0.99, 95% CI 0.72–1.35). This contrasts with several surgery-controlled observational analyses reporting substantially larger excess risks.
- In ProtecT at 15 years, deaths from other cancers occurred in 9.9% after radiotherapy, 9.4% after prostatectomy, and 10.6% with active monitoring. None of the pairwise comparisons showed a statistically clear difference.
- Interpretation is limited by overlapping source populations, heterogeneous endpoints, historical radiotherapy techniques, absent formal risk-of-bias assessment, and poor adjustment for smoking, obesity, comorbidity, socioeconomic status, and surveillance intensity. Modern-technique risks remain uncertain because sufficiently mature follow-up is unavailable.
CLINICAL TAKEAWAY
Patients considering prostate radiotherapy should be told that second bladder or rectal cancers may be slightly more common after long follow-up, but the absolute excess and associated mortality appear modest. Observational comparisons with surgical cohorts probably overestimate causality because prostatectomy patients are generally healthier and differently surveilled.