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

Abstract: 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.

Lay abstract: Aim: To determine whether blue light (photodynamic) surgery is better than conventional surgery in the treatment of bladder cancer and whether its use is worthwhile for the NHS. Background: Bladder cancer is a common disease in the UK, with over 10,500 cases diagnosed each year. The most common form of bladder cancer (8 out of 10 cases) involves the lining of the bladder – this is termed non-muscle invasive bladder cancer (NMIBC). These tumours can be removed in an operation using a telescopic instrument (cystoscope) passed through the urethra into the bladder. Unfortunately NMIBC frequently comes back (recurs) after initial treatment and patients require regular cystoscopies and surgeries. As a consequence, bladder cancer has one of the highest lifetime treatment costs per patient and can be a considerable burden for those affected. In some instances the recurrent tumour can be worse than the first, progressing to become life threatening and requiring treatment with surgery or radiotherapy. It is estimated that one in three patients who suffer a recurrence had disease that was not visible or had been overlooked during the original surgery under standard white light. Photodynamic surgery using a blue light is a treatment that could result in long term reduction of recurrence and progression of NMIBC for patients. Following the introduction of a light-sensitive solution into the bladder, blue light causes tumours to fluoresce, making identification and complete resection easier. A recent review of current evidence suggested surgery guided by photodynamic diagnosis in the short term offered better outcomes for patients who had intermediate or high risk of recurrence. However, the longer-term value of photodynamic-guided surgery in reducing recurrence and progression requires further evaluation and forms the focus of our study. Study design: Potential participants for the trial will be identified at rapid access clinics for people with blood in their urine (haematuria). Usual assessment includes cystoscopy under local anaesthetic and if there is bladder tumour seen then the patient has surgery under a general anaesthetic at a later date. For patients with a new diagnosis of intermediate or high risk NMIBC who agree to join our study, we will randomly allocate treatment to photodynamic or standard white light surgery to test if there is a difference in recurrence rate at three years. Patients will be recruited following informed consent to participate using processes approved by an NHS Research Ethics Committee. Apart from treatment allocation and measurement of study outcomes, participants will have standard NHS follow up. Based on statistical calculations, we aim to recruit 533 participants over two and half years who will be followed up for at least three years across 30 UK hospitals. Outcomes: The main clinical outcome will be the difference in the rates of recurrence between the two study groups at three years. We will also measure the rate of disease progression and changes to participants’ health related quality of life (well being) over the three years. The effect on the quality of life will be particularly important and we will assess this using a specifically designed questionnaire. In addition, we will examine the safety of PDD resection compared with the standard approach. To assess any longer term benefits of photodynamic diagnosis we will use a mathematical model to give a prediction of progression rates, quality of life and freedom from cancer over each participant’s lifetime. We will use the measurements we collect and the model to work out whether use of photodynamic diagnosis is worthwhile to the NHS in terms of balancing any benefit to people’s health against the added costs (cost-effectiveness). Finally we will explore the impact of urologists having to learn the new technique by comparing patient outcomes after surgery by surgeons who are experienced and those who less experienced in the use of photodynamic diagnosis (all surgeons will be experienced at cystoscopic resection). The results of this study will enable patients, clinicians and policy-makers to decide the worth of photodynamic surgery as part of treatment of bladder cancer.

Research activity codes: 6.3 MEDICAL DEVICES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CANCER AND NEOPLASMS