A Phase III randomised control clinical trial of radiotherapy with radiosensitisation versus intravesical Bacillus Calmette-Guerin therapy for high-risk non-muscle invasive bladder cancer - TRAIN

Research question Can modern radiotherapy with radiosensitisation improve cancer control and bladder preservation compared to intravesical Bacillus Calmette-Guerin (BCG) therapy in high-risk and very high-risk (G3/cis) non-muscle invasive bladder cancer (HR-NMIBC)? Background In the UK 20,000 people develop urothelial bladder cancer each year with 75-80% having NMIBC. Current standard of care for patients with HR-NMIBC (stage T1G3 and/or CIS) is either transurethral resection of bladder tumour (TURBT) followed by intravesical BCG, or radical cystectomy. Induction BCG is given weekly for six weeks followed by maintenance BCG up to 3 years (EAU guidelines). Up to 50% experience recurrence or progression after BCG and 25% stop therapy due to toxicity. Recent global restricted BCG supply has increased HR-NMIBC recurrence rates and costs. Better treatments are required, to prevent recurrence, progression and cystectomy, and mitigate the effects of unpredictable supply. Trimodality treatment (TMT) is maximal TURBT + radiotherapy + a radiosensitiser (gemcitabine, mitomycin C/fluorouracil or carbogen/nicotinamide) and is an equivalent alternative treatment to radical cystectomy for localised muscle-invasive bladder cancer (MIBC). TMT is not routinely used for HR-NMIBC. Meta-analysis of 756 HR-NMIBC patients treated with TMT found a 5-year recurrence-free survival of 54%. Modern radiotherapy is expected to further improve outcomes through hypofractionation and image-guided volumetric modulated arc radiotherapy to minimise side-effects. Radical cystectomy is reserved for BCG failure and rarely used as primary treatment. The BRAVO study could not randomise enough patients between surgery and BCG to compare outcomes. Aims and objectives TRAIN will test if radiotherapy with radiosensitisation improves outcomes for people with HR-NMIBC compared to BCG. Methods 320 patients with HR-NMIBC following maximal TURBT will be randomised 1:1 to BCG or radical radiotherapy (55Gy/20#) with radiosensitisation. The primary outcome will be event free survival (recurrence, progression, metastatic disease, cystectomy, death by any cause). Internal Pilot: formal review of accrual and treatment fidelity 12 months after first site opens with pre-set stop/go criteria. Health Economics: within-trial cost effectiveness analysis of intervention compared to control. Timelines for delivery TRAIN will take 78 months, from May 2025, recruiting from month 10. Trial progress review occurs in month 22. We expect at least 8 sites to be opened by the end of the internal pilot (month 22) with the remainder of sites (up to a total of 12 sites) opening in the months thereafter. If recruitment is RAG-rated amber at the end of the pilot, additional sites (up to 20 sites) will open by month 28. Patient recruitment will continue to month 45, with 24 months follow up and 6 months for data cleaning, analysis and presentation (month 75). Trial close out, publication and dissemination will complete by month 78. Anticipated impact and dissemination If successful, TRAIN will improve event free survival. It may also reduce therapy and major surgery costs. The radiotherapy techniques are routine in the NHS to allow rapid uptake and implementation. Results will be presented across uro-oncology and patient communities, with support from NCRI, BAUS, and our patient partners. Discussion with NHS England would be undertaken to ensure infrastructure and implementation capability.