Reducing adverse effects in hypofractionated radiotherapy for prostate cancer: Clinical evidence and emerging mitigation strategies.

BACKGROUND

The technical advances allowed to take the leap towards hypofractionated schedules, as well as dose-escalated schedules, for prostate cancer (PCa) radiotherapy (RT). The aim of this systematic review is to describe RT techniques and toxicity outcomes within trials investigating hypofractionation, and to discuss current or future strategies to mitigate treatment-related toxicity.

METHODS

We searched Pubmed database until June, 2025. Studies deemed eligible were phase III trials randomizing different type of fractionation (with at least one arm using hypofractionation) for PCa RT.

RESULTS

Thirty-two articles were included. Rates of late grade≥2 genitourinary (GU) toxicity ranged between 12-46% and 15-45% for patients receiving isodose and dose-escalated moderately hypofractionated radiotherapy (MHRT). A flare of grade≥2 GU toxicity was observed 12 to 24 months following stereotactic body radiotherapy (SBRT), translating into a higher cumulative incidence of grade≥2 GU toxicity at 5 years. Higher IPSS at baseline was suggested to be predictive of late grade≥2 GU toxicity following both MHRT and SBRT. Overall, MHRT does not seem to negatively impact late gastrointestinal (GI) toxicity, with rates of late grade≥2 toxicity ranging between 8.9-25% and 12.7-23.8% for isodose and dose-escalated MHRT. Current mitigation strategies include minimizing the dose delivered to organs at risk (OARs), prolonging overall treatment time, and personalizing treatments based on individual radiosensitivity. Among the strategies allowing for a reduction of the dose to adjacent OARs, margin reduction achieved through motion management strategies halved the rates of grade≥2 toxicity following PCa SBRT.

CONCLUSIONS

Grade≥2 GU toxicity remains frequent in trials testing hypofractionation. Mitigation strategies are therefore critical to the continued evolution of intensified RT regimens. Motion management and margin reduction are particularly promising approaches to reduce severe toxicity after PCa SBRT, warranting their incorporation into clinical practice and future clinical trial designs.