Enhanced Visualization Methods for First Transurethral Resection of Bladder Tumour in Suspected Non-muscle-invasive Bladder Cancer: A Health Technology Assessment.

Background: Bladder cancer begins in the innermost lining of the bladder wall and, on histological examination, is classified as one of two types: non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer. Transurethral resection of bladder tumour (TURBT) is the standard treatment for people with NMIBC, but the high rate of cancer recurrence after first TURBT is a challenge that physicians and patients face. Tumours seen during follow-up may have been missed or incompletely resected during first TURBT. TURBT is conventionally performed using white light to see the tumours. However, small papillary or flat tumours may be missed with the use of white light alone. With the emergence of new technologies to improve visualization during TURBT, better diagnostic and patient outcomes may be expected. We conducted a health technology assessment of two enhanced visualization methods, both as an adjunct to white light to guide first TURBT for people with suspected NMIBC-hexaminolevulinate hydrochloride (HAL), a solution that is instilled into the bladder to make tumours fluoresce under blue-violet light, and narrow band imaging (NBI), a technology that filters light into wavelengths that can be absorbed by hemoglobin in the tumours, making them appear darker. Our assessment included an evaluation of effectiveness, safety, cost-effectiveness, and the budget impact of publicly funding these new technologies to improve patient outcomes following first TURBT. The use of NBI in diagnostic cystoscopy was out of scope for this health technology assessment.

Methods: We performed a systematic literature search of the clinical evidence from inception to April 15, 2020. We searched for randomized controlled trials (RCTs) that compared the outcomes of first TURBT with the use of HAL or NBI, both as an adjunct to white light, with the outcomes of first TURBT using white light alone, or studies that made such comparison between HAL and NBI. We conducted pairwise meta-analyses using a fixed effects model where head-to-head comparisons were available. In the absence of any published RCT for comparison between HAL and NBI, we indirectly compared the two technologies through indirect treatment comparison (ITC) analysis. We assessed the risk of bias of each included study using the Cochrane risk-of-bias tool. We assessed the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and conducted a cost-utility analysis with a 15-year time horizon from a public payer perspective. We also analyzed the budget impact of publicly funding HAL and NBI as an adjunct to white light in people undergoing their first TURBT for suspected non-muscle-invasive bladder cancer in Ontario.

Results: In the clinical evidence review, we identified 8 RCTs that used HAL or NBI as an adjunct to white light during first TURBT. Pairwise meta-analysis of HAL studies showed that HAL-guided TURBT as an adjunct to white light significantly reduces recurrence rate at 12 months compared with TURBT using white light alone (risk ratio 0.70, 95% confidence interval [CI] 0.51-0.95) (GRADE: Moderate). Five-year recurrence-free survival was significantly higher when HAL was used as an adjunct to white light than when white light was used alone (GRADE: Moderate). There was little to no difference in the tumour progression rate (GRADE: Moderate).Meta-analysis of NBI studies did not show a significant difference between NBI-guided TURBT as an adjunct to white light and TURBT using white light alone in reducing the rate of recurrence at 12 months (risk ratio 0.94, 95% CI 0.75-1.19) (GRADE: Moderate). No evidence on the effect on recurrence-free survival or tumour progression rate was identified for NBI-guided TURBT. The indirect estimate from the network analysis showed a trend toward a lower rate of recurrence after HAL-guided TURBT than after NBI-guided TURBT but the difference was not statistically significant (risk ratio 0.76, 95% CI 0.51-1.11) (GRADE: Low). Studies showed that use of HAL or NBI during TURBT was generally safe.The incremental cost-effectiveness ratio of HAL-guided TURBT compared with NBI-guided TURBT, both as an adjunct to white light, is $12,618 per quality-adjusted life-year (QALY) gained. Compared with TURBT using white light alone and using adjunct NBI, the probability of HAL-guided TURBT being cost-effective is 69.1% at a willingness-to-pay value of $50,000 per QALY gained and 74.6% at a willingness-to-pay of $100,000 per QALY gained. The annual budget impact of publicly funding HAL-guided TURBT in Ontario over the next 5 years ranges from an additional $0.6 million in year 1 to $2.5 million in year 5.

Conclusions: First TURBT guided by HAL as an adjunct to white light likely reduces the rate of recurrence at 12 months and increases 5-year recurrence-free survival when compared with first TURBT using white light alone. There is likely little to no difference in the tumour progression rate. First TURBT guided by NBI as an adjunct to white light likely results in little to no difference in the rate of recurrence at 12 months when compared with first TURBT using white light alone. Based on an indirect comparison, there may be little to no difference in cancer recurrence rate between HAL-guided and NBI-guided first TURBT. Use of HAL or NBI during first TURBT is generally safe. For people undergoing their first TURBT for suspected non-muscle-invasive bladder cancer, using HAL as an adjunct to white light is likely to be cost-effective compared with using white light alone or with using NBI as an adjunct to white light. We estimate that publicly funding HAL as an adjunct to white light to guide first TURBT for people in Ontario with suspected NMIBC would result in additional costs of between $0.6 million and $2.5 million per year over the next 5 years.