Photodynamic versus white-light-guided resection of first-diagnosis non-muscle-invasive bladder cancer: PHOTO RCT

Rakesh Heer, Rebecca Lewis, Anne Duncan, Steven Penegar, Thenmalar Vadiveloo, Emma Clark, Ge Yu, Paramananthan Mariappan, Joanne Cresswell, John McGrath, James N'Dow, Ghulam Nabi, Hugh Mostafid, John Kelly, Craig Ramsay, Henry Lazarowicz, Angela Allan, Matthew Breckons, Karen Campbell, Louise CampbellAndy Feber, Alison McDonald, John Norrie, Giovany Orozco-Leal, Stephen Rice, Zafer Tandogdu, Ernest Taylor, Laura Wilson, Luke Vale, Graeme MacLennan, Emma Hall

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Abstract

BACKGROUND: Around 7500 people are diagnosed with non-muscle-invasive bladder cancer in the UK annually. Recurrence following transurethral resection of bladder tumour is common, and the intensive monitoring schedule required after initial treatment has associated costs for patients and the NHS. In photodynamic diagnosis, before transurethral resection of bladder tumour, a photosensitiser that is preferentially absorbed by tumour cells is instilled intravesically. Transurethral resection of bladder tumour is then conducted under blue light, causing the photosensitiser to fluoresce. Photodynamic diagnosis-guided transurethral resection of bladder tumour offers better diagnostic accuracy than standard white-light-guided transurethral resection of bladder tumour, potentially reducing the chance of subsequent recurrence. OBJECTIVE: The objective was to assess the clinical effectiveness and cost-effectiveness of photodynamic diagnosis-guided transurethral resection of bladder tumour. DESIGN: This was a multicentre, pragmatic, open-label, parallel-group, non-masked, superiority randomised controlled trial. Allocation was by remote web-based service, using a 1 : 1 ratio and a minimisation algorithm balanced by centre and sex. SETTING: The setting was 22 NHS hospitals. PARTICIPANTS: Patients aged ≥ 16 years with a suspected first diagnosis of high-risk non-muscle-invasive bladder cancer, no contraindications to photodynamic diagnosis and written informed consent were eligible. INTERVENTIONS: Photodynamic diagnosis-guided transurethral resection of bladder tumour and standard white-light cystoscopy transurethral resection of bladder tumour. MAIN OUTCOME MEASURES: The primary clinical outcome measure was the time to recurrence from the date of randomisation to the date of pathologically proven first recurrence (or intercurrent bladder cancer death). The primary health economic outcome was the incremental cost per quality-adjusted life-year gained at 3 years. RESULTS: We enrolled 538 participants from 22 UK hospitals between 11 November 2014 and 6 February 2018. Of these, 269 were allocated to photodynamic diagnosis and 269 were allocated to white light. A total of 112 participants were excluded from the analysis because of ineligibility (n = 5), lack of non-muscle-invasive bladder cancer diagnosis following transurethral resection of bladder tumour (n = 89) or early cystectomy (n = 18). In total, 209 photodynamic diagnosis and 217 white-light participants were included in the clinical end-point analysis population. All randomised participants were included in the cost-effectiveness analysis. Over a median follow-up period of 21 months for the photodynamic diagnosis group and 22 months for the white-light group, there were 86 recurrences (3-year recurrence-free survival rate 57.8%, 95% confidence interval 50.7% to 64.2%) in the photodynamic diagnosis group and 84 recurrences (3-year recurrence-free survival rate 61.6%, 95% confidence interval 54.7% to 67.8%) in the white-light group (hazard ratio 0.94, 95% confidence interval 0.69 to 1.28; p = 0.70). Adverse event frequency was low and similar in both groups [12 (5.7%) in the photodynamic diagnosis group vs. 12 (5.5%) in the white-light group]. At 3 years, the total cost was £12,881 for photodynamic diagnosis-guided transurethral resection of bladder tumour and £12,005 for white light. There was no evidence of differences in the use of health services or total cost at 3 years. At 3 years, the quality-adjusted life-years gain was 2.094 in the photodynamic diagnosis transurethral resection of bladder tumour group and 2.087 in the white light group. The probability that photodynamic diagnosis-guided transurethral resection of bladder tumour was cost-effective was never > 30% over the range of society's cost-effectiveness thresholds. LIMITATIONS: Fewer patients than anticipated were correctly diagnosed with intermediate- to high-risk non-muscle-invasive bladder cancer before transurethral resection of bladder tumour and the ratio of intermediate- to high-risk non-muscle-invasive bladder cancer was higher than expected, reducing the number of observed recurrences and the statistical power. CONCLUSIONS: Photodynamic diagnosis-guided transurethral resection of bladder tumour did not reduce recurrences, nor was it likely to be cost-effective compared with white light at 3 years. Photodynamic diagnosis-guided transurethral resection of bladder tumour is not supported in the management of primary intermediate- to high-risk non-muscle-invasive bladder cancer. FUTURE WORK: Further work should include the modelling of appropriate surveillance schedules and exploring predictive and prognostic biomarkers. TRIAL REGISTRATION: This trial is registered as ISRCTN84013636. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 40. See the NIHR Journals Library website for further project information.

Original languageEnglish
Pages (from-to)1-144
Number of pages144
JournalHealth technology assessment (Winchester, England)
Volume26
Issue number40
DOIs
Publication statusPublished - 1 Oct 2022

Bibliographical note

Funding Information:
The research reported in this issue of the journal was funded by the HTA programme as project number 11/142/02. The contractual start date was in June 2014. The draft report began editorial review in February 2021 and was accepted for publication in July 2021. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Funding Information:
This report presents independent research funded by the National Institute for Health and Care Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care.

Funding Information:
Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 40. See the NIHR Journals Library website for further project information.

Funding Information:
The Newcastle & North Tyneside 2 ethics committee [Research Ethics Committee (REC) reference number 14/NE/1062] provided a favourable ethics opinion for this research in July 2014. The trial was sponsored by The Newcastle upon Tyne Hospitals NHS Foundation Trust and is registered as ISRCTN84013636.

Funding Information:
This project is funded by a NIHR BRC Doctor of Philosophy studentship (Newcastle Award).

Funding Information:
The authors wish to thank the patients who participated in the PHOTO trial. We particularly acknowledge the late Rob Pickard for his contribution to the inception and design of the trial. We also wish to thank: • Helen Green (ICR-CTSU) for her secretarial support • the CHaRT programming team, led by Gladys McPherson (until 2016) and Mark Forrest (2016-present) • Lorna Henderson (CHaRT), who was involved in the statistical analysis of the trial until 2018 • Jing Shen (Newcastle), who was involved in the health economic analysis until 2019 • Laura Wilson for supporting the PHOTO-T study (2019 to present) • other staff in the CHaRT/Health Services Research Unit for their assistance with the trial (Lorna Aucott, Maria Ntessalen and Rebecca Bruce) • members of the TMG for their ongoing advice and support of the trial • the independent members of the TSC and DMC • the staff at the recruitment centres who facilitated the recruitment, treatment and follow-up of trial participants. Finally, we would like to thank NIHR and the HTA programme for funding the PHOTO trial. This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 40. See the NIHR Journals Library website for further project information.

Funding Information:
This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme and will be published in full in Health Technology Assessment; Vol. 26, No. 40. See the NIHR Journals Library website for further project information.

Publisher Copyright:
© 2022 Heer et al.

Keywords

  • BLADDER CANCER
  • NON-MUSCLE-INVASIVE BLADDER CANCER
  • PHASE III: TRANSURETHRAL RESECTION
  • PHOTODYNAMIC DETECTION
  • RANDOMISED TRIAL
  • SURGERY
  • TRANSURETHRAL RESECTION OF BLADDER TUMOUR
  • URINARY BLADDER NEOPLASMS

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