Physician- and Patient-Reported Outcomes Following Contemporary Image-Guided Intensity-Modulated Proton Therapy for Prostate Cancer: Results from the Prospective PRO-Cube (PRO3) Study. Registry can be omitted

Abstract Purpose : Multiple prospective studies have established the safety of proton therapy for localized prostate cancer. However, prospective data defining physician-reported adverse events (AEs) and patient-reported outcomes (PROs) with contemporary image-guided intensity-modulated proton therapy (IG-IMPT) in high-risk and node-positive disease treated with hypofractionation, including extreme hypofractionation (SBPT) and pelvic nodal irradiation (PNI), remain limited. We report prospectively collected clinical outcomes from the PRO-Cube registry. Methods and Materials : PRO-Cube is a prospective, single-centre registry enrolling men with prostate cancer treated with IG-IMPT across all risk groups using hypofractionation schedules with or without PNI. This analysis included 155 consecutive patients treated definitively using daily cone-beam CT–guided robustly optimized IMPT. Physician-reported GU and GI AEs were graded using CTCAEv5.0, and PROs were analysed longitudinally using EORTC QLQ-PR25 with mixed-effects linear models to characterize temporal symptom trajectories and minimal clinically important difference (MCID). Results : Median age was 70 years (IQR, 62–75); 73.6% had high- or very-high-risk disease, including 24.5% node-positive. SBPT was used in 46.5%, PNI in 60%, and androgen deprivation therapy in 87.1% of patients. With a median follow-up of 35.8 months (IQR, 24–52), acute grade ≥2 GU AEs occurred in 23.9%, driven primarily by transient irritative urinary symptoms, while no acute grade ≥2 GI AEs were observed. Cumulative late grade ≥2 GU and GI AEs were infrequent, occurring in 5% and 4.3%, respectively. Severe late AEs (grade ≥3) were rare (<1%). PRO trajectories demonstrated early post-treatment worsening in urinary and bowel symptoms followed by gradual improvement over time concordant with physician-reported AEs. No patient, tumor, or treatment-related factors were associated with higher AEs or adverse PROs. Conclusion : IG-IMPT demonstrated low rates of physician-reported AEs and favorable PRO trajectories, despite frequent use of hypofractionation and PNI in a predominantly high-risk and node-positive cohort. These findings establish a benchmark for modern IMPT practice and provide a rationale for prospective comparison with contemporary IMRT.