Comparative Health Research Outcomes of NOvel Surgery in Prostate Cancer

AIM:

CHRONOS-A

Pilot: To determine if men will agree to participate in a randomised controlled trial that randomly assigns them to focal therapy alone or radical therapy (radiotherapy or prostatectomy).

Main: To determine if focal therapy alone is non-inferior when compared to radical therapy (radiotherapy or surgery) in terms of progression-free survival at 5 years in men with clinically significant non-metastatic cancer.

CHRONOS-B

Pilot: To determine if men expressing a preference for focal therapy will agree to participate in a multi-arm, multi-stage Randomised Controlled Trial that randomly assigns them to focal therapy alone or focal therapy in combination with neoadjuvant and/or adjuvant agents.

Main: To determine if focal therapy combined with neoadjuvant and/or adjuvant agents, compared to focal therapy alone, will improve failure-free survival at 5 years, in men with clinically significant non-metastatic cancer.

OBJECTIVES To deliver a trials framework that fits with existing patient and physician equipoise so that the investigators can answer the next generation of research questions to evaluate medium-term outcomes following minimally invasive focal therapy in the treatment of clinically significant, non-metastatic prostate cancer.

Embedded internal pilot objectives:

• Determine patient acceptance to randomisation.
• Conduct an embedded qualitative study of patient and clinician acceptance and experience of the linked randomised controlled trial CHRONOS design.
• Establish the feasibility of an economic evaluation alongside the main trial.
• Determine acceptability and completeness of resource use and utility measures.
• Identify the relevant NHS and non-NHS resource use to be collected alongside the main trial.
• Identify the relevant items to populate the Cost and Consequences framework.
• Perform preliminary analysis of pattern of missing data.

MAIN STUDY PRIMARY OBJECTIVES

CHRONOS-A:

To evaluate progression-free survival rates of focal therapy alone compared to radical therapy (radiotherapy or surgery) in the treatment of non-metastatic clinically significant prostate cancer. Progression-free survival is defined as time from randomisation to salvage whole-gland or systemic therapy, prostate cancer metastases or prostate cancer-specific mortality.

CHRONOS-B:

To evaluate Failure-Free-Survival rates of focal therapy alone compared to focal therapy combined with other therapies as a neoadjuvant strategy. Failure-Free-Survival is defined as time from randomisation to further focal therapy session or salvage whole-gland or systemic therapy or prostate cancer metastases or prostate cancer-specific mortality.

MAIN STUDY SECONDARY OBJECTIVES

Disease control:

Determine the histological, biochemical and oncological disease control for men undergoing radical therapy, focal therapy or focal therapy with neo/adjuvant treatments.

Adverse events and Functional Outcomes:

Determine the adverse events and functional outcomes after radical therapy, focal therapy or focal therapy with neo/adjuvant treatments

Health economics:

• Establish the NHS costs of the different interventions.
• Determine the Cost per QALYs (CUA), cost per PFS/FFS (CEA) and cost and consequences (CCA).
• Determine acceptability and completeness of resource use and utility measures.

Qualitative:

• Patient experience of consent and recruitment, including reasons for declining participation.
• Participants' motivation to accept randomisation to and compliance with an intervention, which may or may not include neoadjuvant and adjuvant treatments.
• Patients' understanding and experience of each trial arm.
• Patients' experience of toxicities, focusing on erectile dysfunction and urinary symptoms.
• Patients' attitudes to the predicted survival rate.
• Potential improvements to recruitment processes.
• Healthcare professionals' attitudes to intervention arms and trial design and whether this might impact on recruitment.

Imaging and Histology:

• Compare MRI outcomes with histology at time-points in which both are mandated.

Biobank and databank objectives:

• Evaluate cancer infiltrating immune cells and immune gene signatures following ablation.
• Build a biobank and databank of matched imaging, blood, serum, plasma and pre-digital rectal examination urine as well as FFPE biopsy samples.

DURATION :

Pilot: Recruitment 12 months. Minimum 3 months follow-up. Main study: Recruitment further 48 months. Total including follow-up = 96 months

SAMPLE SIZE :

Pilot Study - CHRONOS-A \& B - 60 patients each over 12-months. Main study - CHRONOS-A - 1190 patients / CHRONOS-B - 1260 patients. PATIENT POPULATION: Men with non-metastatic prostate cancer who are suitable for focal therapy and radiotherapy.

PRIMARY ENDPOINTS (Main Stage) CHRONOS-A: Progression-Free survival (PFS) defined as biochemical failure (radical therapies only) or salvage therapy (local or systemic) or prostate cancer metastases or prostate cancer specific mortality.

CHRONOS-B: Failure-Free survival (FFS) defined as more than one focal therapy session or salvage therapy (local or systemic) or prostate cancer metastases or prostate cancer specific mortality.

SECONDARY ENDPOINTS (Main Stage)

Disease control:

• Rates of positive biopsy for any prostate cancer and significant cancer defined by a number of different thresholds on biopsy following focal therapy (treated and untreated side).
• Rates of second or third focal therapy sessions, in-field or out-of-field.
• Rates of radiotherapy as adjuvant or salvage therapy following surgery or focal therapy.
• Rates of prostatectomy as adjuvant or salvage therapy following radiotherapy or focal therapy.
• Rates of systemic therapy as adjuvant or salvage therapy following surgery, radiotherapy or focal therapy.
• Rates of prostate cancer-specific mortality.
• Rates of all-cause mortality.
• Long-term health outcomes of those participants consenting to longitudinal follow-up will be reported in subsequent studies pending further funding.

Adverse events and functional outcomes:

• Rates of cystoscopic interventions following treatment.
• Rates of implant insertion for treatment of incontinence and erectile dysfunction.
• Rates of medication and/or pump devices used for erectile dysfunction following treatment.
• Rates of endoscopic investigations of the lower bowel following treatment.
• Rates of pad-use and quantity per day for urinary incontinence following treatment.
• Rates of pad-use and quantity per day for faecal incontinence following treatment.
• Rates of adverse event rates and complications.
• Genito-urinary and rectal side-effects using patient-reported outcome measures using validated questionnaires including evaluation of return to baseline function for erectile and urinary function and various minimum decreases in PROMS scores.

Health economics:

• To establish the NHS costs of the different interventions.
• To determine the incremental cost per quality adjusted life year (QALYs)gained over the estimated lifetime of participants for focal therapy versus radical therapy.
• To determine the incremental cost per quality adjusted life year (QALYs) gained over the estimated lifetime of participants for focal therapy versus focal therapy with neoadjuvant and/or adjuvant strategies.

Qualitative:

• The impact on participants' overall health-related quality-of-life including adverse events and impact on genito-urinary and rectal functional status using validated patient reported outcome measures.
• Descriptive analyses of the questionnaire data, and use of questionnaire and qualitative interview datasets in a multi-methods analysis to look for overarching themes in barriers and facilitators to participation in CHRONOS-A and CHRONOS-B.

Imaging and Pathology

• Accuracy and variability of multi-parametric MRI (mpMRI) in detecting disease at baseline prior to focal therapy and absence or presence of recurrence of cancer based on histology outcomes on biopsy. Target definition for recurrence will be defined as significant prostate cancer as per inclusion criteria.

Translational, Biobank and Databank:

• Analysis on the localisation and nature of cancer-infiltrating immune cells and the immune-relevant gene expression within the cancer tissue.
• The creation of a biobank and databank of matched blood, serum, plasma and pre-digital rectal examination urine as well as imaging as well as FFPE biopsy samples.