Single-Dose Image-Guided Radiotherapy With Urethral Sparing and DIL Boost for Intermediate-Risk Prostate Cancer (PROSINT II)

This prospective phase II study evaluates the safety, feasibility, quality-of-life effects, prostate-specific antigen kinetics, imaging response, and clinical outcomes of definitive ultra-high-dose single-fraction external beam radiotherapy in patients with biopsy-proven NCCN intermediate-risk localized adenocarcinoma of the prostate.

The study investigates single-dose image-guided radiotherapy using image-guided volumetric modulated arc therapy with urethral sparing, organ-motion mitigation, and online target tracking. All eligible participants receive single-fraction radiotherapy to the prostate gland and proximal seminal vesicles. The whole-gland prescription dose is 24 Gy delivered in one treatment session. Participants with NCCN unfavorable intermediate-risk disease and an imaging-defined dominant intraprostatic lesion may also receive a prostate-specific membrane antigen PET/CT-guided simultaneous integrated boost to the dominant intraprostatic lesion. The boost is delivered in sequential dose-escalation cohorts up to a target dose of 30 Gy, while maintaining protocol-defined organ-at-risk dose constraints.

The rationale for the study is based on the radiobiological sensitivity of prostate cancer to large radiation fraction sizes, the clinical experience with extreme hypofractionation in localized prostate cancer, and prior institutional experience with prostate image-guided radiotherapy using target immobilization, urethral localization, and online tracking. Prior studies at the study institution have suggested that ultra-hypofractionated and single-fraction prostate radiotherapy can be delivered with acceptable toxicity when careful target stabilization, urethral sparing, and treatment-planning quality assurance procedures are used. In unfavorable intermediate-risk disease, intraprostatic recurrence may occur preferentially at the site of the dominant lesion, supporting the investigation of dose escalation to the dominant intraprostatic lesion while preserving strict normal tissue constraints.

Participants undergo pretreatment evaluation including history and physical examination, pathology confirmation, serum PSA assessment, laboratory testing, and multiparametric MRI of the prostate. PSMA PET/CT is required for participants being considered for PSMA-guided dominant intraprostatic lesion boost and may also be used when clinically indicated for staging. Imaging datasets are used for treatment planning and, when applicable, dominant intraprostatic lesion definition.

Radiotherapy is delivered using image-guided volumetric modulated arc therapy. A rectal balloon filled with air is used to improve prostate immobilization and anatomical reproducibility. A Foley catheter loaded with beacon transponders is used to identify the urethra, support urethral-sparing treatment planning, and enable setup reproducibility and online target tracking. Treatment planning includes delineation of the prostate, proximal seminal vesicles, urethra, rectal wall, bladder wall, bowel, urogenital diaphragm, penile bulb, neurovascular bundles, femoral heads, and other protocol-specified organs at risk. Urethral sparing is incorporated using an avoidance structure around the catheter-defined urethra. Erectile-related structures are contoured and recorded for quality-of-life and dosimetric analyses when compatible with target coverage and disease anatomy.

For participants receiving a dominant intraprostatic lesion boost, the lesion is defined using PSMA PET uptake co-localized with multiparametric MRI abnormality. Sequential boost cohorts may include 24 Gy whole-gland treatment without boost, followed by dominant intraprostatic lesion boost dose levels of 26.4 Gy, 28.8 Gy, and 30 Gy. Organ-at-risk constraints remain unchanged across dose levels. Escalation to the next boost dose level occurs only after review of acute toxicity, patient-reported outcomes, protocol deviations, and treatment-plan constraint adherence in the preceding cohort. Dose-limiting toxicity for escalation monitoring is defined as CTCAE v4.0 grade 3 or higher acute genitourinary or gastrointestinal toxicity occurring within 90 days after treatment.

The primary clinical endpoint is the incidence of acute physician-assessed CTCAE v4.0 grade 2 or higher genitourinary and/or gastrointestinal toxicity occurring within 90 days after treatment. Key patient-reported safety endpoints include clinically meaningful changes from baseline in urinary and bowel function within 90 days, assessed using the International Prostate Symptom Score and EPIC-26 questionnaires. Secondary endpoints include late genitourinary and gastrointestinal toxicity, longitudinal patient-reported urinary, bowel, and sexual quality-of-life outcomes, sexual-function outcomes assessed using IIEF and the EPIC-26 sexual domain, PSA kinetics, biochemical relapse-free survival using the Phoenix definition, MRI-based imaging response, and patterns of local, regional, nodal, and distant failure assessed by clinically indicated imaging, including PSMA PET/CT.

Participants are followed after treatment at approximately 1 month, every 3 months through 12 months, every 6 months through 60 months, and annually thereafter. Follow-up evaluations include toxicity assessment, patient-reported quality-of-life questionnaires, serum PSA measurements, and clinical assessment of urinary, rectal, and sexual function. Multiparametric MRI is performed at baseline and at 12 and 24 months after treatment. Participants are monitored for a minimum of 5 years. Biochemical relapses are evaluated with imaging, including MRI and PSMA PET/CT when clinically indicated, to characterize recurrence as local, nodal/regional, distant, or combined.

Inclusion criteria

Participants must meet all of the following criteria:

Signed study-specific informed consent form Histologic confirmation of adenocarcinoma of the prostate by biopsy Biopsy ISUP grade 1-3 Biopsy-proven localized intermediate-risk prostate cancer according to NCCN criteria No previous hormonal therapy PSA ≤20 ng/mL Staging multiparametric MRI confirmation of AJCC cT1c-cT2c disease, with no radiographic evidence of cT3, cT4, or N1 disease No direct evidence of regional or distant metastases after appropriate staging studies Age ≥18 years Performance status 0-2 IPSS score ≤15; alpha-blockers allowed CT- or ultrasound-based prostate gland volume estimate ≤100 grams

Exclusion criteria

Participants with any of the following are ineligible:

Positive lymph nodes or metastatic disease from prostate cancer on imaging studies MRI evidence of radiographic T3, T4, or N1 disease Biopsy ISUP grade ≥4 Previous pelvic radiotherapy Previous surgery for prostate cancer Previous transurethral resection of the prostate within 3 months Contraindication to protocol-required Foley catheter placement, rectal-balloon placement, MRI, PSMA PET/CT where required, or treatment immobilization/tracking procedures Active urinary tract infection, unresolved acute prostatitis, or other acute condition judged by the investigator to make simulation or SDRT unsafe until resolved Previous hormonal therapy History of Crohn's disease or ulcerative colitis Previous significant obstructive symptoms Significant psychiatric illness CT- or ultrasound-estimated prostate volume >100 grams Severe active comorbidity judged by the investigator to preclude protocol treatment