Prospective Evaluation of Three-Fraction SBRT with 4D Transperineal Ultrasound Intrafraction Motion Monitoring for Localized Prostate Cancer

Background/Objectives: We aimed to prospectively evaluate the safety, patient-reported quality of life (QoL), and early oncological outcomes of a three-fraction SBRT regimen with real-time transperineal ultrasound guidance in localized prostate cancer. Methods: This prospective single-centre study enrolled patients with localized prostate cancer of all risk groups treated with SBRT (30 Gy in three fractions) between November 2023 and October 2025. Treatment was delivered using VMAT with CBCT-based setup verification and continuous real-time transperineal ultrasound for intrafraction motion monitoring. The primary endpoint was the incidence of acute and late grade ≥ 2 genitourinary (GU) and gastrointestinal (GI) adverse events (AEs) according to CTCAE v5.0. Secondary endpoints included patient-reported QoL (IPSS, EPIC-CP, IIEF-5), biochemical recurrence-free survival (BRFS), PSA kinetics, and factors associated with treatment-related AEs. Results: Seventy-two patients (median age, 78 years; range, 56–87) were enrolled, with a median follow-up of 16 months (range, 6–27). Acute grade ≥ 2 GU and GI AEs occurred in 34.7% and 8.3% of patients, respectively; late grade ≥ 2 GU and GI AEs occurred in 13.9% and 4.2%. One acute and one late grade 3 GU event were observed, with no grade 4–5 AEs. Although several QoL scores changed significantly over time, none exceeded the threshold for clinically meaningful deterioration. Higher baseline IPSS was associated with acute grade ≥ 2 GU Aes (aOR = 1.12, 95% CI: 1.00–1.26; p = 0.045). Median PSA declined from 7.90 to 0.44 ng/mL, and estimated BRFS was 98.2% at 12 months and 96.1% at 24 months. Conclusions: Three-fraction SBRT with real-time transperineal ultrasound guidance was feasible, with severe urinary and bowel AEs remaining uncommon, and associated with preserved clinically meaningful QoL, and encouraging preliminary biochemical control in patients with localized prostate cancer across all risk groups. This regimen may represent a practical intermediate strategy between conventional five-fraction SBRT and ultra-short fractionation, warranting longer follow-up and comparative prospective evaluation.