Background
Recurrence of non–muscle-invasive bladder cancer (NMIBC) is common after transurethral resection of bladder tumor (TURBT). Photodynamic diagnosis (PDD) provides better diagnostic accuracy and more complete tumor resection and may reduce recurrence. However, there is limited evidence on the longer-term clinical effectiveness and cost-effectiveness of PDD-guided resection.
Methods
In this pragmatic, open-label, parallel-group randomized trial conducted in 22 U.K. National Health Service hospitals, we recruited participants with a suspected first diagnosis of NMIBC at intermediate or high risk for recurrence on the basis of routine visual assessment before being listed for TURBT. Participants were assigned (1:1) to PDD-guided TURBT or to standard white light (WL)–guided TURBT. The primary clinical outcome was time to recurrence at 3 years of follow-up, analyzed by modified intention to treat.
Results
A total of 538 participants were enrolled (269 in each group), and 112 participants without histologic confirmation of NMIBC or who had had cystectomy were excluded. After 44 months’ median follow-up, 86 of 209 in the PDD group and 84 of 217 in the WL group had recurrences. The hazard ratio for recurrence was 0.94 (95% confidence interval [CI], 0.69 to 1.28; P=0.70). Three-year recurrence-free rates were 57.8% (95% CI, 50.7 to 64.2) and 61.6% (95% CI, 54.7 to 67.8) in the PDD and WL groups, respectively, with an absolute difference of −3.8 percentage points (95% CI, −13.37 to 5.59) favoring PDD. Adverse events occurred in less than 2% of participants, and rates were similar in both groups, as was health-related quality of life. PDD-guided TURBT was £876 (95% CI, −766 to 2518; P=0.591) more costly than WL-guided TURBT over a 3-year follow-up, with no evidence of a difference in quality-adjusted life years (−0.007; 95% CI, −0.133 to 0.119; P=0.444).
Conclusions
PDD-guided TURBT did not reduce recurrence rates, nor was it cost-effective compared with WL at 3 years. (Funded by the National Institute for Health and Care Research Health Technology Assessment program; ISRCTN number, ISRCTN84013636.)
In the PHOTO trial, Heer et al., performed a randomised trial in which the clinical and cost-effectiveness of photodynamic diagnosis (PDD) resection is compared with conventional white light TURBT for newly diagnosed non-muscle-invasive bladder cancer (NMIBC) with an intermediate and high risk of recurrence. PDD uses an intravesical photosensitiser (intravesical hexaminolevulinate) to cause tumours to fluoresce under blue light and guide transurethral resection of the bladder tumour (TURBT). The idea is that satellite tumours and/or the full tumour extent may be better detected and resected using PDD and therefore subsequent recurrences may be reduced.
In a recent Cochrane review (Maisch et al., 2021) it was described that blue light-enhanced TURBT for NMIBC reduces the risk of recurrence compared to white light TURBT (HR: 0.66 (95% CI, 0.54-0.81). However, the certainty of evidence for these findings was low, because of study limitations and inconsistency. Another recent systematic review (Veeratterapillay et al., EUOS 2021) also found that PDD reduced recurrence rates over 2-year follow up.
For this reason, the present results were eagerly awaited. Heer et al., conducted a phase 3 pragmatic, open-label, parallel-group randomized controlled trial at 22 UK hospitals. Patients with a suspected primary diagnosis of intermediate-risk or high-risk NMIBC were enrolled and randomly assigned to undergo either PDD TURBT or conventional white light TURBT. Further treatment (repeat TURBT, adjuvant instillations) and follow up were in accordance with standard practice. The primary outcome was time to recurrence. Secondary outcomes include adverse events and cost-effectiveness (the incremental cost per QALY gained for PDD relative to white light).
Twenty-two participating sites enrolled 538 participant between 2014 and 2018 (so before the EAU subclassified high risk vs very-high risk tumours); of which 426 (209 PDD vs 217 white light) were included for final analysis. More than 85% of patients was classified as intermediate risk, 13% had CIS and almost one third had a second resection. Almost two thirds received an immediate postoperative intravesical instillation of Mitomycine C (63% PDD, 66% white light). After a median follow up (among survivors) of 44 months, there were 86 bladder recurrences in the PDD group vs 84 in the white light group (HR for recurrence: 0.94 (95% CI, 0.69-1.28). So, no difference in recurrence rate at long-term follow up.
Of note, the authors report that, in patients with recurrence, 30 of the 86 patients (35%) in the PDD arm vs 18 of 84 patients (21%) in the white light arm received BCG induction with or without maintenance. This seems a relatively low subset of patients (given the intermediate and high risk groups and even some of those would have probably been reclassified as very-high risk), although balanced between both groups. Moreover, no further information is provided on the adjuvant instillation schemes that were administered.
Regarding the economic impact, additional equipment cost caused by the cost of PDD was found to be greater. There was no evidence of differences between the groups in health service costs over 36 months, nor a difference between treatment groups in QALYs gained at 3 years.
The authors conclude that there is no difference in bladder cancer recurrence over 3 years by using PDD-guided TURBT vs white light TURBT in newly diagnosed intermediate and high-risk NMIBC patients, and that it was not cost-effective either. Strengths of this study are its randomised controlled fashion (although treating physicians were obviously not blinded) and its practical, pragmatic approach. Remarks can be made about the “pragmatic way” in which the risk classification was estimated (and the recruitment was done) and about the presumably low rate of patients receiving adequate adjuvant therapy. Finally, there is the debate whether long-term survival is the most appropriate endpoint to validate potential surgical improvement.
The major difference between the results of this study and previously reported “positive” studies, is that – although recurrence rates appear to diverge over the first year, supporting many preceding published data – this difference was not borne through to the longer follow-up. All in all, these results show that the long-term quality of NMIBC-management may not be solved by a different TURBT modality alone.