24 Gy in One Fraction Urethral-sparing "HDR Like" SBRT for Prostate Cancer (PRO-FAST)

24 Gy in One Fraction Urethral-sparing "High-Dose-Rate Like" Stereotactic Body RadioTherapy for Prostate Cancer: a Single-center Non-randomized Prospective Clinical Study (PRO-FAST)

Patients with prostate cancer who are candidates for stereotactic radiotherapy to the prostate and seminal vesicles will undergo staging exams which will include prostate specific memrane antigen (PSMA) positron emission tomography-computed tomography (PET-CT). If the PET scan is negative and the uroflowmetry is acceptable, the patients will perform the treatment, after fiducial implantation, simulation CT and magnetic resonance (MR), in a single fraction, delivered with an high-dose-rate (HDR)-like urethral sparing technique. In 70 patients acute and late toxicity, biochemical control, overall, cancer specific survival and quality of life with specific questionnaires will be evaluated.

This is an interventional prospective non-randomised single-center trial, that will enroll, according to the optimal design of Simon, 13 patients for the first phase of the study. The hypothesis is that the proportion of patients free from acute cumulative G3-G4 toxicity (Common Terminology Criteria for Adverse Events-CTCAE v5.0 scale) 1 month after the end of treatment must be < 85% to suspend treatment and > 95% to consider the treatment as safe. The treatment will be interrupted if G3-G4 toxicities and/or biochemical recurrences are recorded within a month in 2 or more patients, otherwise the study will continue with the second phase. Another 52 patients will be added, for a total of 65 patients The treatment consist in a single fraction of 24 Gy with the "urethral sparing HDR like" technique. Assuming a minimal if any drop-out, given that the primary objective is toxicity one month after treatment, we will enroll 5 more patients in total, thus reaching a total number of 70 patients (65 necessary + 5 for any drop-outs). In the absence of successively worse toxicity and with comparable biochemical control with literature data and historical treatments in our Radiation Oncology, the scheme will be considered safe and the enrollment will continue open label. Patients with negative lymph nodes and without distant metastases will be enrolled and treated on the prostate/prostate and tumor vesicles (depending on the stage) at a total dose of 24 Gy delivered in a single fraction, sparing the urethra and witha a dose distribution similar to high dose rate brachytherapy. Androgen Deprivation Therapy (ADT) will be prescribed according to the guidelines for the stages of the disease. Short-term cortisone and alpha lytics will be prescribed, for prophylactic purposes. Follow-up visits will be performed at 1, 3, 6,12,18, 24, 36, 38, 60 months with blood tests including prostate specific antigen (PSA) and testosterone (performed every 3 months in the first two years, every 6 months in the next 3 years), imaging, when needed, and quality of life questionnaires European Organization for Research and Treatment of cancer (EORTC) quality of life questionnaire (QLQ) C30 and QLQ-PR25, International Prostate symptoms score (IPSS), International Index of Erectile Function (IIEF)-5, Expanded Prostate Cancer Index Composite (EPIC)- 26. .

one fraction SBRT, Urethral sparing HDR like, PSMA PET CT for intermediate and high risk prostate cancer

According to the optimal design of Simon, 13 pts will be enrolled for the first phase of the study. Hypothesis: the proportion of pts free from acute cumulative G ≥3 toxicity (CTCAE v5.0 scale) 1 month after the end of treatment must be < 85% to suspend treatment and > 95% to consider the treatment as safe. The treatment will be interrupted if G3-G4 toxicities and/or biochemical recurrences are recorded within a month in 2 or more pts, otherwise the study will continue with the second phase enrolling another 52 pts for a total of 65 pts. A single fraction SBRT of 24 Gy with the "urethral sparing HDR like" technique will be delivered. Assuming a minimal if any drop-out, 5 more pts will be enrolled, thus reaching a total number of 70 pts (65 necessary + 5 for any drop-outs). In the absence of successively worse toxicity and with a biochemical control comparable to the literature and to historical treatments of our department, the scheme will be considered as safe and effective.

Patients with localized prostate cancer - negative PSMA PET CT +/- standard staging exams (bone scan, CT, MRI)-enrolled in this study, will be treated to prostate/prostate seminal vesicles (according to the risk group) to a total dose of 24 Gy delivered in 1 fraction, with an urethral sparing HDR like technique. For unfavorable intermediate and high-risk pts, Androgen Deprivation Therapy (ADT) will be prescribed for 6 and 24 months, respectively.

Patients with prostate cancer will be treated with high-dose SBRT to prostate and seminal vesicles, delivered in one fraction, sparing the urethra and generating a dose distribution similar to HDR brachytherapy

Incidence of acute toxicity of grade 3 or 4 as maximum toxicity value during the radiation treatment or in any case within a month of the end of SBRT, using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 scale (toxicity from 0- patients without toxicity to 5-death from toxicity)

Biochemical control rate at 1,3 and 5 years by measuring Prostate Specific Antigen-PSA- value which must be below (2+nadir) ng/ml

Survey with the questionnaire of European Organisation for Research and Treatment of Cancer (EORTC) Quality of life of cancer patients (QLQ C30) which contains 30 questions on patients' quality of life with answers from 1, lowest grade, to 4, highest grade

Survey with the questionnaire of European Organisation for Research and Treatment of Cancer (EORTC) Quality of life of prostate cancer patients (QLQ PR25) which contains 25 questions on patients' quality of life with answers from 1, lowest grade, to 4, highest grade

Survey with the questionnaire International Prostatic Symptoms Score (IPSS) which has 8 questions with answers rom never (0) to almost every time (5). The score is obtained by summing the answers

Survey with the questionnaire IIEF-5 (International Index of Erectile Function). The IIEF-5 score is the sum of the ordinal responses to the 5 items, with higher scores indicating no erectile dysfunction and lower scors indicating severe erectile dysfunction.

Survey with the questionnaire EPIC-26 (The Expanded Prostate Cancer Index Composite) a questionnaire designed to measure Quality of Life issues in patients with Prostate cancer, through 13 questions with answers from 1 to 5, with 1 indicating the absence of the problem and 5 indicating an important problem. Lower scores indicate a better outcome

Modeling of organ movements during treatment: Movements of the target and neighboring organs between the treatment fractions and during the treatment will be quantified in millimeters, the median value will be recorded with the range and mean with the standard deviation, and the contributing factors will be identified to find a useful solution

Evaluation of radiomic characteristics: Mathematical extraction of the spatial distribution of signal intensities and pixel interrelationships of medical images of the patients, to quantify textural information resampled according to International Biomarker Standardization Initiative (IBSI).

Inclusion Criteria: Histological diagnosis of prostate adenocarcinoma, International Society of Urological Pathology (ISUP) grade groups 1-5 Patients over 18 years of age Signed informed consent Negative lymph nodes confirmed by imaging (PSMA PET/CT and/or pelvic MRI with and without contrast medium) where recommended by guidelines (intermediate and high risk patients, according to National Comprehensive Cancer Network (NCCN) guidelines) in the previous 3 months Clinical M0 (PSMA PET/CT and/or bone scan and/or pelvic MRI with and without contrast medium in suspected patients and all patients with poor intermediate and high risk, according to NCCN guidelines), in the previous 3 months Acceptable uroflowmetry: peak urine flow index (peak flow preferably ≥ 15 ml/s), post voiding residue (PVR) ≤50 cc. If lower, acceptable if by carrying out 3 months of neoadjuvant hormone therapy + alpha-lytic for the reduction of prostate volume the uroflowmetry is reset to at least ≥ 12 ml/s. PS (ECOG) ≤2 No previous pelvic radiotherapy Other conditions necessary for the correct execution of the proposed treatment (ability to fill in the questionnaires for the evaluation of the Quality of Life EORTC QLQ-C30, EORTC QLQ-PR25, IPSS, IIEF-5, EPIC 26) Exclusion Criteria: Serious systemic diseases Psychic or other disorders that may prevent the patient from signing the informed consent Previous invasive cancer, except skin cancer (excluding melanoma) unless patient free of disease for at least 3 years (e.g. carcinoma in situ of the oral cavity or bladder) Lymph node disease (N1) Evidence of distant metastases (M1) IPSS questionnaire data > 20 points Uroflowmetry with maximum basal flow ≤ 11 ml/sec and/or PVR >100 ml Concomitant urinary/gastrointestinal inflammatory diseases (e.g. ulcerative colitis, Crohn's disease) Overactive bladder Impossibility of implantation of fiducials Inability or refusal to place bladder catheter for simulation CT and MR Inability to perform simulation MRI Contraindication to hormonal treatment for patients with poor intermediate, high or very high risk disease Non-compliance with dose limits established in the treatment plan

The data that support the findings of this study (anonymized individual participant data) are available on request from the corresponding author to researchers who provide a methodologically sound proposal. Requests made to the corresponding author will be evaluated by the IRCCS San Raffaele Scientific Institute Ethics Committee.

Request made to PI prof. Nadia Di Muzio or co-PI Dr. Andrei Fodor, approved by Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) San Raffaele Ethics Committee

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