A Review of the PHOTO Trial Publication

Does use of blue light cystoscopy improve patient outcomes? Researchers from the United Kingdom attempted to investigate this question in a randomized trial recently published online in NEJM Evidence.¹ Non-muscle-invasive bladder cancer (NMIBC) is the most common presentation of bladder cancer. The standard of care for its management includes endoscopic resection of the bladder lesions and use of intravesical bacille Calmette-Guérin (BCG) or an immunotherapeutic agent.

Many patients will experience recurrence, with greater risk of recurrence associated with tumor burden, previous recurrence, T stage, tumor grade, and—importantly—whether or not there is a component of carcinoma in situ (CIS) disease. The authors note that >50% of patients diagnosed with NMIBC are considered to be at intermediate or high risk at the time of diagnosis, portending a 3-year recurrence rate of >60% with a high rate of progression to muscle-invasive disease.²

Because the requirement for both routine surveillance and management of bladder cancer makes treatment costly, researchers make significant efforts to optimize and accomplish a complete resection of tumor burden because it may improve recurrence-free survival (RFS).³ Cystoscopy is generally performed using white light. One strategy has been to enhance the detection of tumor burden to improve endoscopic resection. Photodynamic diagnosis (PDD) using an intravesical photosensitizer can aid in tumor identification and possibly improve recurrence rates by fluorescing the tumor when exposed to blue-light cystoscopy.⁴

Developing the PHOTO Trial

The researchers developed a multicenter phase 3 randomized controlled trial (registered as ISRCTN84013636) to explore use of PDD versus white-light treatment in patients >16 years with a suspicion for intermediate- or high-risk NMIBC. Patients with low-risk disease (defined as a solitary tumor <3 cm), muscle-invasive disease on imaging, upper tract involvement, experience of a life-threatening malignancy in the last 2 years, clinical evidence of metastasis, porphyria/ known porphyrin hypersensitivity, pregnancy, or other contraindication to use of blue or white light were not included in the study.

Patients were randomized to either the white-light arm (WL; control group) or the PDD arm (experimental group). Whether the patient underwent WL or PDD was not blinded but the findings and study personnel were. Patients in the WL cohort underwent a standard transurethral resection of bladder tumor (TURBT) under white light. The patients in the PDD cohort underwent preoperative intravesical instillation of hexaminolevulinate and had a TURBT conducted under blue-light cystoscopy.

Fluoresced lesions were resected. All patients received intravesical mitomycin-C within 6 hours after undergoing TURBT or before discharge. Patients diagnosed with high-risk NMIBC (defined as high-grade or histologic stage pT) underwent a repeat TURBT. In accordance with standard guidelines, adjuvant intravesical therapy and white-light cystoscopy were administered at 3-month intervals for the first year, at 6-month intervals for the following year, and had a final cystoscopy 1 year later.

Patients were monitored throughout the study for adverse events (AEs) and health-related quality of life (HRQOL). The primary outcome was time to recurrence from randomization to pathologically proven recurrence, progression, cystectomy, or death from bladder cancer. Secondary outcomes included self-reported HRQOL related to the surgery or cancer treatment, health care utilization costs over the 36- month trial, and estimated quality-adjusted life-years (QUALYs). The researchers also evaluated AEs and complications within 3 months from the initial or second TURBT, disease progression as evidenced by muscle-invasive disease, development of nodal or distant metastasis or death from bladder cancer, overall survival (OS), and bladder-cancer specific survival.

The authors powered the study based on an assumed 3-year RFS rate of 60% in the control group, supported by the results of previous studies identifying this recurrence rate for patients with intermediate-risk NMIBC.² They set a target for PDD to improve the RFS rate to 72% (hazard ratio [HR], 0.64), which they noted “represents a plausible estimate of the minimal clinically important difference in NMIBC that would be sufficient to change practice guidelines.”¹

A total of 538 patients (269 in each cohort) across 22 centers were enrolled over a 4-year period between 2014 and 2018. After application of exclusion criteria, there were 209 patients in the PDD arm and 217 in the WL arm. Cohorts were well balanced with regard to demographics, 80% of patients were male, and the average age was 70 years. Overall, 85% of patients were identified as having intermediate-risk disease and CIS was present in 13%; 93.7% of patients in the PDD group underwent PDD, 68 patients in each cohort underwent a repeat TURBT, and there was a similar rate of postoperative intravesical chemotherapy instillation between the groups (63.2% in the PDD cohort, 65.9% in the WL cohort).

PHOTO Trial Results

Patients in both cohorts were observed for nearly 44 months and had similar incidences of bladder recurrence (86 in the PDD cohort, 84 in the WL cohort). The HR for recurrence was 0.94 (95% CI, 0.69-1.28; P=0.70). Per-protocol analysis yielded similar findings and was confirmed to “show no evidence that the time ratio differed between groups” using an accelerated failure time model. Similarly, 3-year RFS rates were 57.8% for the PDD cohort versus 61.6% for the WL cohort. In patients who had recurrence, BCG induction with or without maintenance was received by 35% in the PDD cohort versus 21.4% in the WL cohort. No significant difference was appreciated when comparing the number of patients who progressed to invasive disease (PDD cohort, n =19 vs WL cohort, n=12), or with regard to bladder cancer specific survival (deaths: PDD, n=9 vs WL, n=8) or OS (deaths: PDD, n=27 vs WL, n=30).

There were no significant differences in the rates of AEs; 12 patients (<2%) reported in each cohort accounted for 26 serious AEs. Reported HRQOL outcomes were similar between the 2 cohorts. There also were no significant differences in cost regarding length of stay, health service costs, and staff costs between the 2 groups, but there were additional equipment costs for the PDD cohort. Overall, the authors noted that “there was no evidence of a difference between treatment groups in QALYs gained at 3 years. The probability that PDD was cost-effective was never above 30% over the range of society’s cost-effectiveness thresholds considered.”¹

The authors began the discussion by emphasizing that the trial revealed that there was no difference in bladder cancer recurrence at 3 years for patients with intermediate- and high-risk NMIBC, but that PDD was more costly to perform than WL. They noted that the findings of previous studies showing a benefit of PDD to reduce bladder cancer recurrence^4,5,6,7,8 are “difficult to extrapolate” into current practice because they may have used different protocols that did not include immediate postoperative intravesical chemotherapy, repeat resections when indicated, and/or adjuvant intravesical treatments. This longer-term PHOTO trial addresses current practice and does not show differences in recurrence over a longer-term follow-up. Moreover, subgroup analyses considering multiple potential factors, including receipt of BCG or postoperative intravesical chemotherapy, consistently showed no difference in the rates of recurrence.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

References

1. Heer R, Lewis R, Vadiveloo T, et. al. A randomized trial of PHOTOdynamic surgery in non– muscle-invasive bladder cancer. NEJM Evid. 2022;1(10). doi: 10.1056/EVIDoa2200092.
2. Sylvester RJ, van der Meijden APM, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006; 49(3):466-477. doi: 10.1016/j.eururo.2005.12.031.
3. Brausi M, Collette L, Kurth K, et al; for the EORTC Genito-Urinary Tract Cancer Collaborative Group. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol. 2002;41(5):523-531. doi: 10.1016/S0302- 2838(02)00068-4.
4. Mowatt G, N’Dow J, Vale L, et al; for the Aberdeen Technology Assessment Review (TAR) Group. Photodynamic diagnosis of bladder cancer compared with white light cystoscopy: systematic review and meta-analysis. Int J Technol Assess Health Care. 2011;27(1):3-10. doi: 10.1017/S0266462310001364.
5. Kausch I, Sommerauer M, Montorsi F, et al. Photodynamic diagnosis in non–muscle-invasive bladder cancer: a systematic review and cumulative analysis of prospective studies. Eur Urol. 2010;57(4):595-606. doi: 10.1016/j.eururo.2009.11.041.
6. Burger M, Grossman HB, Droller M, et al. Photodynamic diagnosis of non–muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol. 2013;64(5):846-854. doi: 10.1016/j.eururo.2013.03.059.
7. Rink M, Babjuk M, Catto JWF, et al. Hexyl aminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non–muscle-invasive bladder cancer: a critical review of the current literature. Eur Urol. 2013;64(4):624-638. doi: 10.1016/j. eururo.2013.07.007.
8. Veeratterapillay R, Gravestock P, Nambiar A, et al. Time to turn on the blue lights: a systematic review and meta-analysis of photodynamic diagnosis for bladder cancer. Eur Urol Open Sci. 2021;31:17- 27. doi: 10.1016/j.euros.2021.06.011.