Clinical trial NCT05820633: Pelvic Nodes Ultra-Hypo vs Conventionally Fractionated IMRT With HDR Boost in Prostate Cancer.
Official title: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Prostate Cancer
Node; Prostate
Radiotherapy Side Effect
Keywords: ultra hypo fractionation
brachytherapy
Lead sponsor: CHU de Quebec-Universite Laval
Sponsor class: OTHER
Collaborators: name: TerSera Therapeutics LLC
First posted: 2023-04-19
Enrollment: 500
Sex: MALE
Minimum age (years): 18
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized phase 3 study
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Non-inferiority analysis of early change in genito-urinary (GU) toxicities induced.
timeFrame: Every 3 months for 1 year.
measure: Non-inferiority analysis of early change in reported Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire.
timeFrame: Every 3 months for 1 year.
measure: Non-inferiority analysis of late change in genito-urinary (GU) toxicities induced.
timeFrame: Every 6 months up to 36 months, then annually up to 10 years.
measure: Non-inferiority analysis of late change in reported Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire.
timeFrame: Every 6 months up to 36 months, then annually up to 10 years.
measure: Non-inferiority analysis of early change in sexual health.
timeFrame: Every 3 months for 1 year.
measure: Non-inferiority analysis of late change in sexual health.
timeFrame: Every 6 months up to 36 months, then annually up to 10 years.
measure: Non-inferiority analysis of early change in toxicities reporte via the Common Terminology Criteria for Adverse Events (CTCAE).
timeFrame: Every 3 months for 1 year.
measure: Non-inferiority analysis of late change in toxicities reporte via the Common Terminology Criteria for Adverse Events (CTCAE).
timeFrame: Every 6 months up to 36 months, then annually up to 10 years.
Secondary outcomes:
measure: Non-inferiority analysis of 5 years biochemical Disease Free Survival.
timeFrame: 5 years (median)
measure: Non-inferiority analysis of 5 years Disease Free Survival.
timeFrame: 5 years (median)
measure: Non-inferiority analysis of 5 years Metastasis Free Survival.
timeFrame: 5 years (median)
measure: Non-inferiority analysis of 5 years Overall Survival.
timeFrame: 5 years (median)
measure: Non-inferiority analysis of 10 years biochemical Disease Free Survival.
timeFrame: 10 years (median)
measure: Non-inferiority analysis of 10 years Disease Free Survival.
timeFrame: 10 years (median)
measure: Non-inferiority analysis of 10 years Metastasis Free Survival.
timeFrame: 10 years (median)
measure: Non-inferiority analysis of 10 years Overall Survival.
timeFrame: 10 years (median)
Other outcomes:
measure: Seric Testosterone change.
timeFrame: From baseline (randomisation), then every 3 months for 3 years, every 6 months for 2 years, and annually up to 10 years.
measure: Complete blood count.
timeFrame: Baseline prior treatment.
measure: Alkaline Phosphatase.
timeFrame: Baseline prior treatment.
measure: Blood urea nitrogen (BUN)
timeFrame: Baseline prior treatment.
measure: Serum creatinine
timeFrame: Baseline prior treatment.
measure: Concomitant added medications list.
timeFrame: Every 3 months for 3 years, every 6 months for 2 years, then annually up to 10 years.
measure: Treatment related loss of income evaluation in dollars estimated through the economic questionnaire.
timeFrame: Baseline and Month 3.
measure: Total body bone scan in order to evaluate if bony metastasis are present or not.
timeFrame: Baseline prior treatment.
measure: Abdomino-Pelvis (thorax not compulsory) CT Scan in order to evaluate if metastasis are present or not.
timeFrame: Baseline prior treatment.
measure: Osteodensitometry.
timeFrame: Baseline within the first year.
measure: Prostate MRI scan in order to evaluate if extra capsular tumor extension are present or not.
timeFrame: Baseline prior treatment.
measure: Total body PET scan in order to evaluate if metastasis are present or not.
timeFrame: Baseline prior treatment.
Locations:
city: Kelowna
country: Canada
facility: BC Cancer Sindi Ahluwalia centre for the Southern Interior
state: British Columbia
city: Mississauga
country: Canada
facility: Carlo Fidani Peel Regional Cancer Centre
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa Cancer centre
state: Ontario
city: Gatineau
country: Canada
facility: CISSS de l'Outaouais, Hôpital de Gatineau
state: Quebec
city: Laval
country: Canada
facility: CISSS de Laval, Hôpital de la Cité-de-la-Santé
state: Quebec
city: Longueuil
country: Canada
facility: CISSS de la Montérégie-Centre, Hôpital Charles-Le Moyne
state: Quebec
city: Montréal-Est
country: Canada
facility: CIUSSS de l'Est-de-l'Île-de-Montréal, Hôpital Maisonneuve-Rosemont
state: Quebec
city: Montréal
country: Canada
facility: CIUSSS du Centre-Ouest-de-l'Île-de-Montréal, Jewish General Hospital
state: Quebec
city: Montréal
country: Canada
facility: Cedars Cancer Centre, McGill University Health Centre (MUHC)
state: Quebec
city: Sherbrooke
country: Canada
facility: CIUSSS de l'Estrie - Centre Hospitalier Universitaire de Sherbrooke (CHUS)
state: Quebec
city: Quebec
country: Canada
facility: CHU de Québec - Université Laval
Study officials:
affiliation: Andre-Guy Martin MD Inc.
name: Andre-Guy Martin, MD MSc FRCPC
role: PRINCIPAL_INVESTIGATOR
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