Pelvic Nodes Ultra-Hypo vs Conventionally Fractionated IMRT With HDR Boost in Prostate Cancer.

Study Overview
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Brief Summary
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Randomized Phase III study, comparing pelvic ultra-hypo fractionated radiotherapy (UHF: 5Gy/fraction) to a standard or moderate hypo-fractionation (1.8-2.15Gy/fraction), both associated to an HDR prostate +/- adjacent seminal vesicles brachytherapy boost (HDR-BT)+ ADT according to NCCN guidelines. Considering that the calculated bio-equivalent doses to the tumor are similar for all treatment options, the UHF technique is deemed to be non-inferior to the standard approach. Treatment acceptability, tolerance and adverse events will be reported and compared for non-inferiority as the primary objective. Secondary objectives are biochemical control, metastasis-free, disease specific and overall survival.

Detailed Description
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Prostate cancer is the most common non-skin cancer in North American men. In 2020, an estimated 23 300 Canadian men will be diagnosed with prostate cancer of which, 4200 will die. Fortunately, with an early screening, most will have a localized disease at diagnosis. Despite this, high risk disease affects a growing portion of the population and this according to age (29.3%, 39.1%, 60.4%, et 90.6% respectively at 55-59, 65-69, 75-79, & 85-89 years of age). Gleason score 8 to 10 tumors follow the same pattern (16.5%, 23.4%, 37.2%, and 59.9% at respective ages). Those patients are at risk for harboring lymph nodes metastasis. Multiple therapeutic options, with similar biochemical disease-free survival (bDFS) are available: surgery +/- salvage radiotherapy +/- androgen deprivation therapy (ADT) or radiotherapy (RT) +/- HDR-BT +/- ADT. For men with high-risk disease, the combined approach of RT + HDR-BT + ADT might even offer higher cancer specific survival (CSS) rates when compared to surgery. HDR-BT allows for the delivery of a very high (ablative) dose of radiation while giving a lower dose to the nearby organs at risk (OARs). Recently published literature showed that pelvic RT plus HDR-BT significantly increased bDFS (84 vs 77%). Pelvic RT is generally given on a daily basis (5 days/week) over a period of 4-5 weeks, with 1,8-2,15Gy per fraction. This requires a substantial time investment from patients undergoing treatment. Many studies have shown that prostate cancer offers a radiation cell kill ratio (α/β) of 0.9-1.5 Gy. Furthermore, the most commonly used α/β value for prostate cancer is 1,5 Gy (range 0,8 - 2,2). This low α/β ratio offers a more efficient cell kill with hypo-fractionated doses, offering a better tumor control with a lower cumulative dose, given in a shorter time span. Recently, a multicentric randomized phase III study has shown similar late toxicity and oncologic control outcomes between UHF (>/= 5 Gy/fraction) and conventionally fractionated RT. However, until now, no phase III study has compared combined UHF pelvic RT to standard fractionation combined with an HDR-BT in this population. The proposed experimental fractionation scheme for whole pelvic RT in this study will be 5Gy administered every other day over 2 weeks (UHF). It will be compared to standard pelvic RT (1.8-2.15Gy/working day) given over 4 to 5 weeks. Both will be combined with a single 15 Gy fraction of HDR-BT and ADT (goserelin). The UHF treatment modality significantly reduces the overall treatment time, freeing machine-time and allowing more patients to be treated. Given its low α/β ratio, prostate cancer is readily amenable to UHF fractionation. The bio-equivalent dose calculations were done based on published litterature. Neo-adjuvant and adjuvant ADT (goserelin) will be administered for a duration according to NCCN guidelines. In these COVID-19 pandemic times, a reduction in the number of patients' visits to the clinic is highly desirable in order to limit the risk of virus transmission. UHF would also lower the socio-economic burden incurred by the patients and their families. It also increases the therapeutic efficiency reducing costs for both, patients and health services. The proposed study aims to demonstrate the non-inferiority of UHF treatment compared to standard of care. If this hypothesis is confirmed, all future patients could benefit from it. In order to improve the quality of life of men diagnosed with prostate cancer this study aim to demonstrate that combined UHF pelvic RT plus HDR-BT (+ ADT according to NCCN guidelines) is safe and non-inferior to standard fractionation regimens in regard to toxicities and tumor control for prostate cancer patients with risk of nodal involvement. Therefore, 500 men will be recruited, in order to confirm the hypothesis.

Official Title
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Pelvic Nodes Ultra-Hypo Fractionated Versus Conventionally Fractionated IMRT With HDR Brachytherapy Boost in Prostate Cancer: A Collaborative Multi-institutional Non-inferiority Phase 3 Trial. (PCS-XI)

Conditions
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Prostate Cancer, Node; Prostate, Radiotherapy Side Effect

Intervention / Treatment
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* Radiation: Report and compare changes in a non-inferiority analysis of the International Prostate Symptom Score (I-PSS)
* Radiation: Report and compare changes in a non-inferiority analysis of the expanded prostate cancer index composite (EPIC-26):
* Radiation: Report and compare changes in a non-inferiority analysis of the Sexual Health Inventory for Men (SHIM)
* Radiation: Report and compare changes in a non-inferiority analysis of the toxicities reported according to the Common Terminology Criteria for Adverse Events (CTCAE)
* Radiation: Report and compare the biochemical disease free survival (bDFS)
* Radiation: Report and compare the disease free survival (DFS)
* Radiation: Report and compare the metastase free survival (MFS)
* Radiation: Report and compare the overall survival (OS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologically confirmed adenocarcinoma of the prostate. All clinical stages with lymph node involvement risk needing pelvis RT. Stage Mx or M0. Unfavorable Intermediate, high or very high-risk disease according to NCCN guidelines. Having the ability to give free and informed consent. Exclusion Criteria: Clinical stage M1. IPSS Score > 20 with alpha-blocking medication. Prior pelvic radiotherapy, History of active collagenosis (Lupus, Scleroderma, Dermatomyositis). 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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized phase 3 study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ultra hypo fractionation radiation therapy (UHF)<br>5 radiation treatments (5 Gy per fraction) to the prostate, seminal vesicle and pelvic nodes given every other day over 2 weeks for a total of 25 Gy. | Radiation: Report and compare changes in a non-inferiority analysis of the International Prostate Symptom Score (I-PSS)<br>* Assess early and late genito-urinary (GU) toxicities induced assessed via the International Prostate Symptom Score (I-PSS) in the experimental UHF group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).<br>Radiation: Report and compare changes in a non-inferiority analysis of the expanded prostate cancer index composite (EPIC-26):<br>* Assess early and late genito-urinary (GU) and gastro-intestinal (GI) toxicities induced and quality of life assessed via expanded prostate cancer index composite (EPIC-26) in the experimental UHF group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).<br>Radiation: Report and compare changes in a non-inferiority analysis of the Sexual Health Inventory for Men (SHIM)<br>* Assess early and late sexual health in the experimental UHF group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).<br>Radiation: Report and compare changes in a non-inferiority analysis of the toxicities reported according to the Common Terminology Criteria for Adverse Events (CTCAE)<br>* Assess early and late toxicities reported according to the Common Terminology Criteria for Adverse Events (CTCAE) in the experimental UHF group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).<br>Radiation: Report and compare the biochemical disease free survival (bDFS)<br>* Assess the 5 and 10 years biochemical disease-free survival (bDFS) in the UHF group and compare them for non-inferiority to those of the control group.<br>Radiation: Report and compare the disease free survival (DFS)<br>* Assess the 5 and 10 years disease-free survival (DFS) in the UHF group and compare them for non-inferiority to those of the control group.<br>Radiation: Report and compare the metastase free survival (MFS)<br>* Assess the 5 and 10 years metastasis-free survival (MFS) in the UHF group and compare them for non-inferiority to those of the control group.<br>Radiation: Report and compare the overall survival (OS)<br>* Assess the 5 and 10 years overall survival (OS) in the UHF group and compare them for non-inferiority to those of the control group.<br>|
| Active Comparator: standard of care fractionation (SOC)<br>20-25 radiation treatments (range: 1,8 to 2,15 Gy per fraction) to the prostate, seminal vesicle and pelvic nodes given in 20-25 working day treatments over 4-5 weeks for a total of 43 Gy to 46 Gy. | Radiation: Report and compare changes in a non-inferiority analysis of the International Prostate Symptom Score (I-PSS)<br>* Assess early and late genito-urinary (GU) toxicities induced assessed via the International Prostate Symptom Score (I-PSS) in the experimental UHF group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).<br>Radiation: Report and compare changes in a non-inferiority analysis of the expanded prostate cancer index composite (EPIC-26):<br>* Assess early and late genito-urinary (GU) and gastro-intestinal (GI) toxicities induced and quality of life assessed via expanded prostate cancer index composite (EPIC-26) in the experimental UHF group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).<br>Radiation: Report and compare changes in a non-inferiority analysis of the Sexual Health Inventory for Men (SHIM)<br>* Assess early and late sexual health in the experimental UHF group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).<br>Radiation: Report and compare changes in a non-inferiority analysis of the toxicities reported according to the Common Terminology Criteria for Adverse Events (CTCAE)<br>* Assess early and late toxicities reported according to the Common Terminology Criteria for Adverse Events (CTCAE) in the experimental UHF group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group).<br>Radiation: Report and compare the biochemical disease free survival (bDFS)<br>* Assess the 5 and 10 years biochemical disease-free survival (bDFS) in the UHF group and compare them for non-inferiority to those of the control group.<br>Radiation: Report and compare the disease free survival (DFS)<br>* Assess the 5 and 10 years disease-free survival (DFS) in the UHF group and compare them for non-inferiority to those of the control group.<br>Radiation: Report and compare the metastase free survival (MFS)<br>* Assess the 5 and 10 years metastasis-free survival (MFS) in the UHF group and compare them for non-inferiority to those of the control group.<br>Radiation: Report and compare the overall survival (OS)<br>* Assess the 5 and 10 years overall survival (OS) in the UHF group and compare them for non-inferiority to those of the control group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-inferiority analysis of early change in genito-urinary (GU) toxicities induced. | Assess early genito-urinary (GU) toxicities induced opposed to baseline assessed via the International Prostate Symptom Score (I-PSS) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group). | Every 3 months for 1 year. | 
| Non-inferiority analysis of early change in reported Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire. | Assess early health-related quality of life opposed to baseline assessed via the Expanded Prostate Cancer Index Composite (EPIC-26) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group) every 3 months for 1 year. | Every 3 months for 1 year. | 
| Non-inferiority analysis of late change in genito-urinary (GU) toxicities induced. | Assess late genito-urinary (GU) toxicities induced opposed to baseline evaluated by the International Prostate Symptom Score (I-PSS) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group). | Every 6 months up to 36 months, then annually up to 10 years. | 
| Non-inferiority analysis of late change in reported Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire. | Assess late health-related quality of life opposed to baseline assessed via the Expanded Prostate Cancer Index Composite (EPIC-26) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group) every 6 months up to 36 months, then annually. | Every 6 months up to 36 months, then annually up to 10 years. | 
| Non-inferiority analysis of early change in sexual health. | Assess early quality of life opposed to baseline assessed via the Sexual Health Inventory for Men (SHIM) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group) every 3 months for 1 year. | Every 3 months for 1 year. | 
| Non-inferiority analysis of late change in sexual health. | Assess early sexual health status opposed to baseline assessed via the Sexual Health Inventory for Men (SHIM) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group) every 6 months up to 36 months, then annually. | Every 6 months up to 36 months, then annually up to 10 years. | 
| Non-inferiority analysis of early change in toxicities reporte via the Common Terminology Criteria for Adverse Events (CTCAE). | Assess early reported toxicities opposed to baseline assessed via the Common Terminology Criteria for Adverse Events (CTCAE) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group) every 3 months for 1 year, every 6 months up to 36 months, then annually. | Every 3 months for 1 year. | 
| Non-inferiority analysis of late change in toxicities reporte via the Common Terminology Criteria for Adverse Events (CTCAE). | Assess early reported toxicities opposed to baseline assessed via the Common Terminology Criteria for Adverse Events (CTCAE) in the experimental UH group has compared in a non-inferiority analysis to those of patients who received a standard treatment (control group) every 3 months for 1 year, every 6 months up to 36 months, then annually. | Every 6 months up to 36 months, then annually up to 10 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-inferiority analysis of 5 years biochemical Disease Free Survival. | Assess the 5 years the biochemical disease-free survival (bDFS) in the UH group and compare them for non-inferiority to those of the control group. | 5 years (median) | 
| Non-inferiority analysis of 5 years Disease Free Survival. | Assess the 5 years the disease-free survival (DFS) in the UH group and compare them for non-inferiority to those of the control group. | 5 years (median) | 
| Non-inferiority analysis of 5 years Metastasis Free Survival. | Assess the 5 years the Metastasis Free Survival (MFS) in the UH group and compare them for non-inferiority to those of the control group. | 5 years (median) | 
| Non-inferiority analysis of 5 years Overall Survival. | Assess the 5 years the Overall Survival (OS) in the UH group and compare them for non-inferiority to those of the control group. | 5 years (median) | 
| Non-inferiority analysis of 10 years biochemical Disease Free Survival. | Assess the 10 years the biochemical disease-free survival (bDFS) in the UH group and compare them for non-inferiority to those of the control group. | 10 years (median) | 
| Non-inferiority analysis of 10 years Disease Free Survival. | Assess the 10 years the disease-free survival (DFS) in the UH group and compare them for non-inferiority to those of the control group. | 10 years (median) | 
| Non-inferiority analysis of 10 years Metastasis Free Survival. | Assess the 10 years the Metastasis Free Survival (MFS) in the UH group and compare them for non-inferiority to those of the control group. | 10 years (median) | 
| Non-inferiority analysis of 10 years Overall Survival. | Assess the 10 years the Overall Survival (OS) in the UH group and compare them for non-inferiority to those of the control group. | 10 years (median) | 

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