Ultra Hypofractionnated Radiotherapy With HDR Brachytherapy Boost.

Study Overview
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Brief Summary
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Phase 1-2 study, comparing ultra-hypofractionnated (UH) to a moderately hypofractionnated (MH) radiation therapy, with image guided HDR prostate brachytherapy. Using iso-equivalent doses, a non-inferiority analysis will be done in order to prove UH non-inferior to MH, toxicity wise. Acceptability, tolerability, acute and late toxicity will be reported. MRI visible dominant intra-prostatic lesion will be outlines and variability between radiation oncologists and radiologists will be reported. As secondary objective, biochemical and clinical failure free survival will be reported at 5 & 10 years.

Detailed Description
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Phase 1 : consists in a feasibility study (First 28 patients). Phase 2 : monocentric prospective comparative cohort study. Recruitment : Centre intégré de cancérologie du CHU de Québec-Université Laval. Recruitment period: December 2015 to June 2023 Brachytherapy : Implantation under general or spinal anesthesia Foley catheter insertion in bladder. TRUS prostate localisation. Prostate volume measurement. Gold fiducial markers (3) insertion. Prostate brachytherapy catheters (14 à 21) insertion. Cystoscopy for bladder and urethra integrity control. Re-insertion of foley catheter after cystoscopy. Planning imaging: TRUS or CT scan (has needed). Structures delineation by radiation oncologist (brachytherapist). Prostate Seminale vesicles Rectum Colon sigmoïde Bladder Urethra Penile bulb Dosimetric optimisation Oncentra Prostate v. 4.2.2 d'Elekta brachytherapy (Veenendaal, The Netherlands) Oncentra Brachy version 4.6 (if under CT scan). Treatment (brachytherapy dose delivery). 15 Gy in one fraction Direct interstitial dose monitoring (20 patients or more). Fiber-optic dosimeter inserted in prostate brachytherpy catheter for live dose delivery mesurements. Foley ablation under full bladder, same day or day after therapy. Radiotherapy: Via IMRT, VMAT or SBRT technics. Dose : 25 Gy in 5 fractions administered over a 7 days period. 2 to 3 fractions separated by 2 days, weekend break. PTV includes prostate and the first centimeter of seminal vesicle. Simulation one week post brachytherapy standard has described in the department procedure manual. maximal CT scan slice thickness : 2-3mm. uretro-graphy done to identify urogenital sphincter. Multiparametric MRI If no counter-indication and available, a T2 tridimensional sequence for prostate delineation slice thickness : 1 mm. a diffusion weighted sequence will be done. a DTI with tractography can be done optionally. contrast media (gadolinium) is optional. Physique Linac energy (between 6 MV to 18 MV). ARC therapy technique will be used planification softwares: Éclipse, Pinnacle or Raystation. Portal (kV-kV) imagery will be used for marker match. CBCT will be done at each fraction delivered. Clinical and dosimetric data will be collected prior treatment. Primary objectives : Toxicity analysis will be quantitatively evaluated using CTCAE (v5) at 1, 2 and 5 years post-therapy, and has needed at FU visits. Kaplan-Meier statistical analysis will be used to report toxicity evolution through time. median IPSS scores will be reported at 3, 6, 12 months and yearly (1, 2, 3, 4 et 5) post-therapy. IPSS median time to baseline return will be calculated. IPSS urinary scores, sexual function (SHIM) and GI toxicity (CTCAE-v5) and quality of life questionnaires ( EPIC-26) will be given at 3, 6 months and yearly thereafter (1, 2, 3, 4 et 5) post-treatment. Secondary objectives : Biochemical disease-free survival has per Phoenix definition (by American Society of Radiation Oncology - ASTRO) recommendation will be reported using Kaplan-Meier analysis.

Official Title
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ULTRA-HYPO Fractionated (UHF) Compared to Moderate-HYPO Fractionated (MHF) Prostate IGRT With HDR Brachytherapy BOOST : A Phase 1-2 Study.

Conditions
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Prostate Cancer, Radiotherapy Side Effect, Hypofractionation, Brachytherapy, Radiotherapy, Localized Prostate Carcinoma

Intervention / Treatment
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* Radiation: grade and compare reported side effects between groups


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy proven Prostate adenocarcinoma Stage T1c, T2 (Annex 2) Stage Nx or N0 Stage Mx or M0 PSA < 20ng/ml Gleason Score 6 or 7 Having the ability to sing a written consent Exclusion Criteria: Age < 18ans Clinical Stage T3 or T4 Stage N1 Stage M1 PSA > 20 Gleason Score 8 to 10 IPSS Score > 20 alpha-blocking medication. Prior pelvic radiotherapy. History of active collagenosis (Lupus, Sclerodermia, Dermatomyosis) Past history of Inflammatory Bowell Disease Bilateral hip prosthesis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective comparative cohort study with non inferiority analysis UH-IMRT combined to 15 Gy HDR Brachytherapy will considerably reduce the treatment fraction delivered while maintaining b-DFS and Side-effects at comparable levels to our actual reported prostate cancer patient population, without lymph nodes involvement (risk being less than 15%). We believe that this therapeutic regime will show to be non-inferior to our actual standard therapeutic regime
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ultra hypo fractionation radiation therapy<br>comparative PRO's of 25 Gy in 5 daily fractions (Ultra hypo fractionation) administered to prostate and 1st centimeter of proximal seminal vesicle, starting mid week and ending mid following week. | Radiation: grade and compare reported side effects between groups<br>* Compare experimental ultra hypo fractionation (25 Gy in 5 daily fractions administered starting mid week and ending mid following week) to our standard fractionation (either 37,5 Gy given in 15 daily fractions, or 36 Gy in 12 daily fractions). Toxicity analysis will be quantitatively evaluated using CTCAE (v5) at 1, 2 and 5 years post-therapy, and has needed at FU visits. Kaplan-Meier statistical analysis will be used to report toxicity evolution through time. median IPSS scores will be reported at 3, 6, 12 months and yearly (1, 2, 3, 4 et 5) post-therapy. IPSS median time to baseline return will be calculated. IPSS urinary scores, sexual function (SHIM) and GI toxicity (CTCAE-v5) and quality of life questionnaires ( EPIC-26) will be given at 3, 6 months and yearly thereafter (1, 2, 3, 4 et 5) post-treatment.<br>* Other names: report and compare clinical outcomes;|
| Active Comparator: moderate hypo fractionation radiation therapy<br>PRO's of moderate hypo fractionation, 37,5 Gy in 15 or 36 Gy in 12 daily fractions administered 5 days per week. | Radiation: grade and compare reported side effects between groups<br>* Compare experimental ultra hypo fractionation (25 Gy in 5 daily fractions administered starting mid week and ending mid following week) to our standard fractionation (either 37,5 Gy given in 15 daily fractions, or 36 Gy in 12 daily fractions). Toxicity analysis will be quantitatively evaluated using CTCAE (v5) at 1, 2 and 5 years post-therapy, and has needed at FU visits. Kaplan-Meier statistical analysis will be used to report toxicity evolution through time. median IPSS scores will be reported at 3, 6, 12 months and yearly (1, 2, 3, 4 et 5) post-therapy. IPSS median time to baseline return will be calculated. IPSS urinary scores, sexual function (SHIM) and GI toxicity (CTCAE-v5) and quality of life questionnaires ( EPIC-26) will be given at 3, 6 months and yearly thereafter (1, 2, 3, 4 et 5) post-treatment.<br>* Other names: report and compare clinical outcomes;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GU toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at baseline, prior treatment | 
| GU toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 3 months post-therapy | 
| GU toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 6 months post-therapy | 
| GU toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 1 year post-therapy | 
| GU toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 2 years post-therapy | 
| GU toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 3 years post-therapy | 
| GU toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 4 years post-therapy | 
| GU toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 5 years post-therapy | 
| GI toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at baseline, prior treatment | 
| GI toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 3 months post-therapy | 
| GI toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 6 months post-therapy | 
| GI toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 1 year post-therapy | 
| GI toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 2 years post-therapy | 
| GI toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 3 years post-therapy | 
| GI toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 4 years post-therapy | 
| GI toxicity analysis (CTCAE) | quantitatively evaluated using CTCAE (v5) and compare between arms | at 5 years post-therapy | 
| urinary toxicity analysis (IPSS) | median IPSS scores will be reported post-therapy and compare between arms at baseline, prior treatment | at baseline, prior treatment | 
| urinary toxicity analysis (IPSS) | median IPSS scores will be reported post-therapy and compare between arms at 3 months post-therapy | at 3 months | 
| urinary toxicity analysis (IPSS) | median IPSS scores will be reported post-therapy and compare between arms at 6 months post-therapy | at 6 months | 
| urinary toxicity analysis (IPSS) | median IPSS scores will be reported post-therapy and compare between arms at 1 year post-therapy | at 1 year | 
| urinary toxicity analysis (IPSS) | median IPSS scores will be reported post-therapy and compare between arms at 2 years post-therapy | at 2 years | 
| urinary toxicity analysis (IPSS) | median IPSS scores will be reported post-therapy and compare between arms at 3 years post-therapy | at 3 years | 
| urinary toxicity analysis (IPSS) | median IPSS scores will be reported post-therapy and compare between arms at 4 years post-therapy | at 4 years | 
| urinary toxicity analysis (IPSS) | median IPSS scores will be reported post-therapy and compare between arms at 5 years post-therapy | at 5 years | 
| quality of life questionnaires analysis (EPIC26) | median EPIC26 scores will be reported post-therapy and compare between arms at baseline, prior treatment | baseline, prior treatment | 
| quality of life questionnaires analysis (EPIC26) | median EPIC26 scores will be reported post-therapy and compare between arms at 3 months post-treatment | at 3 months | 
| quality of life questionnaires analysis (EPIC26) | median EPIC26 scores will be reported post-therapy and compare between arms at 6 months post-treatment | at 6 months | 
| quality of life questionnaires analysis (EPIC26) | median EPIC26 scores will be reported post-therapy and compare between arms at 1 year post-treatment | at 1 year | 
| quality of life questionnaires analysis (EPIC26) | median EPIC26 scores will be reported post-therapy and compare between arms at 2 years post-treatment | at 2 years | 
| quality of life questionnaires analysis (EPIC26) | median EPIC26 scores will be reported post-therapy and compare between arms at 3 years post-treatment | at 3 years | 
| quality of life questionnaires analysis (EPIC26) | median EPIC26 scores will be reported post-therapy and compare between arms at 4 years post-treatment | at 4 years | 
| quality of life questionnaires analysis (EPIC26) | median EPIC26 scores will be reported post-therapy and compare between arms at 5 years post-treatment | at 5 years | 
| sexual function analysis (SHIM) | median SHIM scores will be reported at baseline prior treatment | baseline, prior treatment | 
| sexual function analysis (SHIM) | median SHIM scores will be reported post-therapy and compare between arms at 3 months post-treatment | at 3 months | 
| sexual function analysis (SHIM) | median SHIM scores will be reported post-therapy and compare between arms at 6 months post-treatment | at 6 months | 
| sexual function analysis (SHIM) | median SHIM scores will be reported post-therapy and compare between arms at 1 year post-treatment | at 1 year | 
| sexual function analysis (SHIM) | median SHIM scores will be reported post-therapy and compare between arms at 2 years post-treatment | at 2 years | 
| sexual function analysis (SHIM) | median SHIM scores will be reported post-therapy and compare between arms at 3 years post-treatment | at 3 years | 
| sexual function analysis (SHIM) | median SHIM scores will be reported post-therapy and compare between arms at 4 years post-treatment | at 4 years | 
| sexual function analysis (SHIM) | median SHIM scores will be reported post-therapy and compare between arms at 5 years post-treatment | at 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical outcomes | Biochemical disease-free survival has per Phoenix definition (by American Society of Radiation Oncology - ASTRO) will be reported using Kaplan-Meier analysis, as well for disease free survival, metastasis free survival and overall survival. | at 5 years | 
| Clinical outcomes | Biochemical disease-free survival has per Phoenix definition (by American Society of Radiation Oncology - ASTRO) will be reported using Kaplan-Meier analysis, as well for disease free survival, metastasis free survival and overall survival. | at 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypo fractionation, brachytherapy, Ultra Hypo fractionation