Physician- and Patient-Reported Outcomes Following Contemporary Image Guided Intensity Modulated Proton Therapy for Prostate Cancer: Results From the Prospective PRO-Cube Study.

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 (stereotactic body proton therapy) 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-center 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 computed tomography-guided robustly optimized intensity modulated proton therapy. Physician-reported genitourinary (GU) and gastrointestinal (GI) AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and PROs were analyzed longitudinally usingEuropean Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Prostate Cancer Module - 25 items (EORTC QLQ-PR25) with mixed-effects linear models to characterize temporal symptom trajectories and minimal clinically important difference. Results: Median age was 70 years (IQR, 62-75); 73.6% had high or very high-risk disease, including 24.5% node-positive. Stereotactic body proton therapy 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 posttreatment 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. Conclusions: 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 intensity modulated proton therapy practice and provide a rationale for prospective comparison with contemporary intensity modulated radiation therapy.