The ELIPSE Study - a randomised controlled trial comparing the clinical and cost-effectiveness of lymph node removal in patients undergoing curative surgery for localised high-risk prostate cancer.

Research Question

Does Pelvic Lymph Node Dissection (PLND) provide better cancer control compared to no PLND in patients undergoing surgery (radical prostatectomy, RP) for localised high-risk prostate cancer (PCa_? Aims and Objectives

To determine the clinical and cost effectiveness of RP + PLND versus RP alone in patients undergoing surgery for localised high-risk Pca. 1. Primary objectives: Compare RP+ PLND and RP alone in terms of cancer recurrence and cost-effectiveness at 3-years.

2. Secondary objectives: Compare the treatments in terms of harms (complications and re-intervention rates), complete excision of primary prostate tumour, metastasis free survival (MFS), and health related quality of life (HRQoL; generic and prostate-cancer specific), time to return to normal activities (post-surgery), indirect costs due to productivity losses and cost to participants; and model cost-effectiveness over the lifetime of participants, based on extrapolation of the trial data and linkage with published evidence to capture the full impact of recurrence.

Methods: Design: Two-arm multicentre pragmatic superiority RCT.

Health technologies being assessed: Radical prostatectomy (RP) with and without PLND. PLND involves excision of lymph glands from standard pre-defined anatomical locations in the pelvis – external iliac and obturator fossae territories. Target population: 25 NHS centres routinely offering surgery for localised high-risk PCa.

Inclusion Criteria: Adults =18-years; biopsy proven clinically localised high-risk PCa; local multi-disciplinary review identifying those cases thought be suitable for RP; with negative staging imaging (as per local standard of care); able and willing to give informed consent to participate and to participate in study procedures.

Exclusion Criteria: Hormone therapy within the 3 months prior to consent; previous radical treatment for PCa; unsuitable for surgical treatment; people without capacity. Outcome measures:

1. Primary outcome: Time to cancer recurrence, defined as: PSA recurrence/persistence with two consecutive measures =0.2ng/ml (American & European Urology guidance) AND/OR disease progression (e.g. metastatic disease) AND/OR need for further PCa treatment AND/OR PCa specific death. 2. Secondary measures:

- incremental cost per QALY gained with RP+ PLND versus RP alone, modelled over the estimated lifetime of patients using trial data, health care resource use and HRQoL - harms - positive surgical margins, - cancer outcomes (progression free survival, metastasis free survival, PCa-specific mortality)

- HRQoL using a prostate specific questionnaire, EPIC 26 (15), and EQ-5D-5L collected at baseline, then 3, 12, 24, and 36 months post-surgery. - Time to return to normal activities - Indirect costs - Costs to participants

3. Longer-term follow-up: We will obtain consent from participants to allow future follow-up through efficient means (such as routine data) as part of a separately funded study.

Sample size: We will recruit 1080 participants to detect a 10% or more difference in RP + PLND vs RP alone at three years with 90% power and 5% significance assuming 10% loss to follow-up.

Timelines for delivery: Start date: 1 February 2024; Study duration: 72 months; 6 months for study set up, 24-month recruitment, 36-month follow-up for all participants, and 6 months for site close-down and analysis and writing up.

Impact and dissemination : Having carefully identified clinician and patient equipoise, outcomes from this study targeting these specific areas of clinical uncertainty will be impactful in informing day-to-day practice. Clinical and cost-effectiveness results will be presented in high-impact journals and conferences. With our PPI team we will produce lay summaries and disseminate through patient organisations (PCUK and The Urology Foundation (TUF) websites), and social media.

We will inform policy makers shaping NHS practice, such as NICE, NHS England and international guideline writing committees.