PHOTOdynamic versus white light-guided treatment of non-muscle invasive bladder cancer: A randomised trial of clinical and cost-effectiveness (The PHOTO Trial)

DESIGN: A pragmatic patient-randomised controlled, non-blinded, parallel group study, stratified 1:1 according to centre's photodynamic experience. Trial treatments will be followed by routine management protocols. SETTING: The trial will be undertaken in around 30 UK NHS secondary care sites and will include established and current non-users of photodynamic resection and low and high volume sites. Patients will be identified from rapid access haematuria clinics following cystoscopy for suspected non-muscle invasive bladder cancer (NMIBC). TARGET POPULATION: Adults with newly diagnosed presumed intermediate or high risk NMIBC will be recruited. HEALTH TECHNOLOGY BEING ASSESSED: Photodynamic cystoscopic resection under blue light (380-450 nm) following the instillation of photosensitiser (hexaminolevulinate; 85 mg/50 ml) into the bladder through a urethral catheter. The control group will undergo standard resection using white light (400-800 nm), without photosensitiser. Patients in both groups will receive a single post-operative instillation of mitomycin C (MMC). OUTCOME MEASURES: Primary objectives: (1) Clinical effectiveness: compare time to recurrence, for each of the two treatment strategies, with a principal point of interest at 3 years. (2) Cost-effectiveness: Evaluate cost-effectiveness by the incremental cost for recurrence avoided and cost-utility as the incremental cost per quality-adjusted life year (QALY) gained at three years. Secondary objectives: (1) Clinical effectiveness: (a) Measure relative rate of disease progression at 3 years (b) Measure relative harms and safety (c) Measure Health Related Quality of Life (HRQoL) and cancer specific survival. (2) Economic evaluation: Model costs and health state changes over a patient lifetime to estimate the incremental cost per recurrence avoided, costs to the NHS, and incremental cost per QALY. Additional objectives: (a) Model the safest and most cost-effective cystoscopic follow-up surveillance schedule (b) Evaluate the learning curve for the procedure and account for its effects on outcomes of both PDD-guided and standard white light resections (c) Establish a well-characterised cohort of patients with intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) including clinical data, urine, blood and tumour specimens that would be available for separately funded research of basic science and translational studies. SAMPLE SIZE: We aim to detect a relative reduction in recurrence of 30% based on an absolute reduction in recurrence of 12% at 3 years from 40% (weighted average for intermediate and high risk disease) to 28% (similar effect sizes of photodynamic therapy are reported in both intermediate and high risk groups). Recruitment of 533 participants will detect a hazard ratio of 0.64 with a log-rank test (90% power, 2-sided 5% significance) and assumes 2.5 years staggered recruitment, a minimum of 3 years follow-up and 6.4% follow-up attrition at year 3. PROJECT TIMETABLE INCLUDING RECRUITMENT RATE: We will recruit for 30 months an average 0.9 cases per site month and follow-up all cases for at least 36 months. Months 0-26: staggered set up of trial sites (4 sites every 3 months). Months 3-33: recruitment. An internal pilot study at 18 months of recruitment, reviewed by the Trial Steering Committee, will report feasibility to the NIHR based on numbers of active sites and accrual rates. Months 3-69: Follow-up. Months 3-75: data checking, preparation, modelling and reporting of analysis.