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

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.

Blue light transurethral resection and biopsy of bladder cancer with hexaminolevulinate: Histopathological characteristics and recurrence rates in a single UK centre study

“…A recently published ‘PHOTO’ trial randomised patients with suspected first diagnosis of bladder cancer with intermediate or high risk of recurrence based on routine visual assessment to either PDD‐TURBT or WLC‐TURBT. This study reported no benefit of PDD‐TURBT on reducing recurrence rates at 3 years 14 . However, there were several shortcomings in the study.…”

Impact on Japanese healthcare economics of photodynamic diagnosis‐assisted transurethral resection of bladder tumor for non‐muscle invasive bladder cancer: A multicenter retrospective cohort study

“…However, this study evaluated hospitalization and surgical procedures only and did not consider second transurethral resection (TUR), adjuvant intravesical therapies, or follow‐up and salvage treatments. In the United Kingdom and Sweden healthcare systems, comparisons of total costs, including exhaustive information, were made, and PDD‐TURBT is likely to be more cost‐effective than WL‐TURBT 11,12 . However, the impact of PDD‐TURBT on the Japanese healthcare economy remains unclear.…”

“…In the United Kingdom and Sweden healthcare systems, comparisons of total costs, including exhaustive information, were made, and PDD-TURBT is likely to be more cost-effective than WL-TURBT. 11,12 However, the impact of PDD-TURBT on the Japanese healthcare economy remains unclear. We evaluated the comprehensive medical costs of NMIBC treatment and cost-effectiveness of PDD-TURBT, including postTURBT information.…”

Wider indications and more efficient drug delivery: A bibliometric analysis and visualization of photodynamic therapy in skin cancer

“…4,5 Clinical studies revealed that PDT can be curative in the early stage of tumors or prolong survival in patients with inoperable cancers as well as significantly improve patients' quality of life. [6][7][8][9][10] Moreover, negligible non-malignant tissue toxicity and systemic effects, lower incidence of intrinsic or acquired resistance and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic alternative. 1 Lesions of skin cancers is conspicuous, therefore a treatment with less invasiveness and comparable efficacy will be appreciated.…”

“…Activated photosensitizer conducted the anti‐tumor effect through multiple approaches including oxidative stress at first and eventually inducing cell death and launching anti‐tumor immunity 4,5 . Clinical studies revealed that PDT can be curative in the early stage of tumors or prolong survival in patients with inoperable cancers as well as significantly improve patients' quality of life 6–10 . Moreover, negligible non‐malignant tissue toxicity and systemic effects, lower incidence of intrinsic or acquired resistance and excellent cosmetic as well as organ function‐sparing effects of this treatment make it a valuable therapeutic alternative 1 …”