A Trial of 5 Fraction Prostate SBRT Versus 5 Fraction Prostate and Pelvic Nodal SBRT

Study Overview
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Brief Summary
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This study will compare the safety and efficacy of curative radiotherapy to the prostate and lymph glands given in 5 visits to that of prostate alone radiotherapy given in 5 visits, in men with high risk localised prostate cancer.

Detailed Description
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This study will look at the safety of curative radiotherapy to the prostate and lymph glands given in 5 visits, in men with high risk localised prostate cancer. The purpose of the research is to test an advanced type of external beam radiotherapy called stereotactic body radiotherapy (also known as SBRT) in 536 participants with high risk localised prostate cancer (that is, prostate cancer that has not spread beyond the prostate gland but is at high risk of growing quickly or spreading). Importantly, this treatment delivers a potentially curative dose of radiotherapy in only 5 treatments over two weeks. Half the participants in the trial will receive radiotherapy to the prostate, the other half will have radiotherapy to the prostate as well as the surrounding lymph nodes. The investigators will follow patients in the trial for at least three and half years to see which treatment is best. The investigators will be looking at whether it is safe to give this treatment by reviewing any side-effects that occur and also assessing whether giving SBRT to the lymph nodes as well as the prostate reduces the chance of prostate cancer returning. The treatment will take place at NHS radiotherapy centres that are experienced in giving SBRT and radiotherapy to the pelvic nodes, and have been quality assured to deliver these treatments

Official Title
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PACE-NODES. A Phase III Randomised Trial of 5 Fraction Prostate SBRT Versus 5 Fraction Prostate and Pelvic Nodal SBRT

Conditions
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Prostate Cancer

Intervention / Treatment
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* Radiation: SBRT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥ 18 years at randomisation Histopathological confirmation of prostate adenocarcinoma with Gleason/ISUP grade group scoring within twelve months of randomisation (unless otherwise discussed with the CI or co-Clinical Leads) Patients planned for 12-36 months androgen deprivation therapy High risk localised prostate cancer as defined by Gleason 8-10 (grade groups 4 and 5) and/or Stage T3a/b or T4 and/or PSA > 20ng/ml (or >10 ng/ml for patients on 5-alpha reductase inhibitors) Multi-parametric MRI of the pelvis- to include at least one functional MRI sequence in addition to T2W imaging within twelve months of randomisation Radiological staging to exclude metastatic disease, prior to starting ADT, with one of the following: PSMA PET-CT, fluciclovine/choline PET-CT, whole-body MRI, bone scan, CT of chest, abdomen and pelvis (imaging method as per local practice/standard of care). WHO performance status 0-2 Ability of research subject to give written informed consent Exclusion Criteria: N1 or M1 disease PSA >50ng/ml (or >25ng/ml for patients on 5-alpha reductase inhibitors), unless PET-CT imaging has been performed to confirm N0M0 disease Previous active treatment for prostate cancer Patients where SBRT is contraindicated: prior pelvic radiotherapy, inflammatory bowel disease, significant lower urinary tract symptoms N.B. where patient has repeated imaging showing bowel in close apposition to target volumes that would make pelvic radiotherapy highly unlikely to be deliverable should be excluded. Contraindications to fiducial marker insertion, where used- including clotting disorders, or patients at high risk when stopping anticoagulation or antiplatelet medications Bilateral hip prostheses or any other implants/hardware that would introduce substantial CT artefacts and would make pelvic node planning more difficult. Patients who have had chemotherapy within 6 weeks of the start of radiotherapy. Life expectancy < 5 years

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: P-SBRT<br>Participants allocated P-SBRT will receive 36.25Gy in 5 fractions to the prostate and seminal vesicles on alternate days (40Gy to prostate CTV). | Radiation: SBRT<br>* Stereotactic Body Radiotherapy<br>* Other names: SABR;|
| Experimental: PPN-SBRT<br>Participants allocated PPN-SBRT will receive 36.25Gy in 5 fractions to the prostate and seminal vesicles on alternate days (40Gy to prostate clinical target volume (CTV)) and 25Gy in 5 fractions to pelvic nodes on alternate days. | Radiation: SBRT<br>* Stereotactic Body Radiotherapy<br>* Other names: SABR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to biochemical or clinical failure | Time to biochemical or clinical failure as defined by time from randomisation to the first progression event (either biochemical failure, local recurrence, lymph node/pelvic recurrence, distant metastases, recommencement of androgen deprivation therapy or death due to prostate cancer). | minimum of 3.5 years follow up post-randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical reported acute toxicity | Clinical reported acute and late toxicity using CTCAE version 5.0 and RTOG criteria. Focus will be given to GU and GI Grade 2 or higher (G2+) toxicities | 12 weeks post-randomisation | 
| Clinical reported late toxicity | Clinical reported acute and late toxicity using CTCAE version 5.0 and RTOG criteria. Focus will be given to GU and GI Grade 2 or higher (G2+) toxicities | up to 5 years post-randomisation | 
| Metastatic relapse-free survival | Time from randomisation to distant metastases or death from prostate cancer | up to 5 years post-randomisation | 
| Prostate cancer-specific survival | Time from randomisation to death due to prostate cancer | up to 5 years post-randomisation | 
| Overall survival | Time from randomisation to death from any cause | up to 5 years post-randomisation | 
| Patient Reported Outcome Measures | Quality of life will be evaluated using combined data from the following questionnaires. IPSS questionnaire: a validated diagnostic tool used to assess urinary & bowel incontinence. IIEF-5: validated diagnostic tool for erectile dysfunction. EPIC questionnaire: to assess typical symptoms after radiotherapy in prostate cancer patients. EQ-5D: a commonly used generic questionnaire to measure health-related QoL used to asess mobility, self-care, usual activities, pain/discomfort, anxiety/depression & the subject's perceptions of their own current overall health. A QoL analysis plan will be developed in consultation with the TMG with key endpoints for each questionnaire. Standard algorithms will be used to derive scores and handle missing data. Changes from baseline at each time point will be compared within groups as well as between treatment groups (by means of ordinal logistic regressions or ANCOVA models). Analyses to account for the longitudinal nature of the data may be used. | up to 5 years post-randomisation | 
| Adherence to radiotherapy protocol | Qualitative analysis of adherence to pre-specified radiotherapy dose constraints with radiotherapy quality assurance to demonstrate feasibility in a muliticentre setting. | after completion of treatment |