Hypofractionated radiotherapy is a standard treatment for localized prostate cancer, supported by phase III trials showing non-inferiority versus conventional fractionation. However, most trials excluded elective pelvic lymph node irradiation, so evidence remains limited when pelvic nodes are treated. The primary objective of this study was to compare clinical outcomes and toxicity profiles between normofractionated radiotherapy and moderately hypofractionated radiotherapy.

We performed a narrative review of phase III trials evaluating moderate or ultra-hypofractionated radiotherapy, then conducted a retrospective single-institution analysis comparing conventional fractionation (delivering 80 Gy in 40 fractions) with moderate hypofractionation (delivering 72.5 Gy in 29 fractions), with or without elective pelvic lymph node irradiation. The primary endpoint was disease-free survival. Secondary endpoints were overall survival and acute and late genitourinary and gastrointestinal toxicity.

Eleven phase III trials were identified, confirming non-inferiority of moderate hypofractionation for prostate-only irradiation. In our cohort of 156 patients (76 treated with conventional fractionation and 80 with moderate hypofractionation), half received elective pelvic lymph node irradiation, and three quarters received androgen deprivation therapy. After a median follow-up of 69 months, 5-year disease-free survival was 85 % with conventional fractionation and 84 % with moderate hypofractionation, with similar five-year overall survival (88 % and 84 %). Grade 2 or higher acute genitourinary toxicity was more frequent with moderate hypofractionation, whereas late genitourinary and gastrointestinal toxicities were comparable.

Moderate hypofractionation achieved disease control similar to conventional fractionation with acceptable toxicity, including in patients receiving elective pelvic lymph node irradiation. These findings support extension of moderate hypofractionation to patients requiring pelvic treatment and the need for prospective validation and integration with androgen deprivation therapy and stereotactic radiotherapy.