Nonmuscle invasive bladder cancer (NMIBC) comprises a group of tumors—including pathological stages Ta, T1, and carcinoma in situ (CIS)—that constitutes approximately 75% of new bladder cancer diagnoses.1,2 Variations in clinical and pathologic features of these tumors are associated with increasing risks of recurrence and progression, which are major determinants of prognosis and the development of more advanced disease, namely muscle invasive bladder cancer (MIBC). For example, evidence suggests that the risks of recurrence and progression for low-grade Ta tumors are approximately 55% and 6%, respectively, whereas the risks of recurrence and progression for high-grade T1 tumors are approximately 45% and 17%, respectively.2-4 Similarly, in a long-term study of patients with NMIBC, the estimated 15-year progression-free survival (PFS) of patients with low-grade Ta disease was 95%, with no patients dying from bladder cancer during the study period, whereas the 15-year PFS of patients with T1 disease was 44% and the disease-specific survival was 62%.5 The presence of CIS and persistent or recurrent disease after intravesical Bacillus Calmette-Guérin therapy also is associated with an increased risk of progression, as reflected in the American Urological Association (AUA) risk stratification categories for NMIBC.2,6 Therefore, performance of accurate cystoscopy and transurethral resection of bladder tumor (TURBT) for proper diagnosis, staging, and surveillance of tumors is critical.
Conventional white light cystoscopy (WLC) is known to inadequately visualize and detect all tumors, especially in cases of CIS and multifocal disease; therefore, enhanced cystoscopy techniques have been developed. There are currently 2 enhanced cystoscopy techniques included in the 2016 AUA guidelines on NMIBC and TURBT: blue light cystoscopy (BLC® with Cysview) and narrow band imaging (NBI).2 BLC involves the intravesical instillation of hexaminolevulinate (HAL, Cysview), a photosensitizing agent that accumulates in neoplastic cells and emits a red/pink light upon exposure to blue light; currently, HAL is the only FDA-approved photosensitizing agent for this use.1 Several studies have demonstrated the benefit of BLC with HAL. A multicenter, prospective randomized study of patients who underwent BLC with HAL in addition to WLC vs WLC demonstrated a significantly reduced recurrence rate at 9 months (47% vs. 56%, p=0.026) in patients who underwent TURBT using BLC. Similarly, a meta-analysis demonstrated that patients who underwent BLC with HAL had a significantly reduced overall recurrence rate at 12 months compared with patients who underwent WLC only (34.5% vs 45.4%, p=0.006).7,8 Recently published data from the multicenter prospective BLC with Cysview Registry demonstrated that adding BLC to standard WLC increased the detection rate of any papillary lesion by 12% and CIS by 43%. Furthermore, among patients who had negative WLC, use of BLC resulted in the detection of additional lesions in 25% of patients.9 This improved detection was clinically significant. In fact, 8% of cystectomies in this cohort were performed due to lesions detected only on BLC.9 There were also no serious adverse reactions with HAL, even with multiple instillations.9 Therefore, the 2016 AUA guidelines on NMIBC provide a moderate recommendation that clinicians should offer BLC to patients with NMIBC at the time of TURBT, if available, to increase detection and decrease recurrence based on grade B evidence.2
NBI has been used to detect NMIBC—including CIS—among patients with known or suspected bladder tumors. NBI filters out the red spectrum from white light, thereby enhancing the contrast between normal and hypervascular tissue to improve detection of areas of neoangiogenesis in the bladder mucosa associated with bladder tumors. The advantage of NBI is the lack of intravesical instillation of photosensitizing agents. A recent meta-analysis of single-center studies demonstrated that the pooled additional detection rate of NBI for NMIBC was 9.9% (95% CI: 0.05-0.14) per patient compared with WLC, and the pooled additional detection rate of NBI for CIS was 25.1% (95% CI: 0.09-0.42) per patient.10 However, 2 recent prospective randomized studies did not show any significant difference in 1-year recurrence-free rates overall between patients who underwent NBI in addition to WLC versus WLC only, although 1 of the studies (Naito et al., 2016) did demonstrate a significant difference between NBI and WLC among patients who were at low risk for recurrence (1-year recurrence rate WLC: 27.3% vs 1-year recurrence rate NBI: 5.6%, p=0.002).11,12 Therefore, since NBI does not appear to be as effective as BLC in preventing recurrence, especially in higher risk patients, the 2016 AUA guidelines on NMIBC provide a conditional recommendation that clinicians may consider NBI in patients with NMIBC to increase detection and decrease recurrence based on grade C evidence.2
Earlier this year, it was announced that the FDA approved an expanded indication for Cysview for use with blue light flexible cystoscopes for surveillance of patients with NMIBC.13 A recently published multicenter, randomized prospective phase III trial supports the use of BLC with HAL in the surveillance setting and highlights the utility of BLFC in detecting CIS. It also demonstrated that repeat instillation of HALwas safe. In this study, 304 patients with NMIBC at high risk for recurrence all received Cysview instillations and were randomized to either BLC in addition to WLC or WLC only for surveillance via flexible cystoscopy.14 Patients with suspicious lesions on surveillance cystoscopy were referred to the operating room for TURBT, which resulted in 63 patients with confirmed malignancy.14 Approximately 40% of recurrences were CIS, and 20% of recurrences were only seen with BLC with Cysview. In addition, 40% of recurrences seen only with BLC with Cysview were CIS.14 Patient-reported outcomes related to this study further support the use of BLC with Cysview in the outpatient setting. Despite the additional catheterization required for BLC with Cysview, most patients reported stable or improved quality of life after BLC with Cysview and did not report increased pain.15 On average, patients’ anxiety decreased after surveillance cystoscopy, and most patients reported that they considered BLC “worthwhile” and were willing to pay out of pocket for it.15
The use of enhanced cystoscopy both in the operating room at the time of TURBT and now in the outpatient surveillance setting shows increased detection of high-grade NMIBC. Given the new FDA approval and encouraging evidence in support of its use, BLC with Cysview will likely increasingly be used in the outpatient setting to improve the detection of tumors in patients with NMIBC undergoing surveillance, especially those with high-risk NMIBC following intravesical treatments and CIS. Prospective registries using enhanced cystoscopy (especially BLC) are ongoing. Guidelines are being proposed for use of enhanced cystoscopy for managing NMIBC, which will help guide urologists managing this difficult to treat population of patients.
Dr. Gupta and Dr. Bivalacqua are from the James Buchanan Brady Urologic Institute, Johns Hopkins Hospital, Baltimore, Maryland.
1. Pearce S, Daneshmand S. Enhanced endoscopy in bladder cancer. Curr Urol Rep. 2018;19:84.
2. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO Guideline. J Urol. 2016;196:1021-1029.
3. Leblanc B, Duclos AJ, Benard F, et al. Long-term followup of initial Ta grade 1 transitional cell carcinoma of the bladder. J Urol. 1999;162:1946-1950.
4. Palou J, Sylvester RJ, Faba OR, et al. Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with bacillus Calmette-Guérin. Eur Urol. 2012;62:118-125.
5. Herr HW. Tumor progression and survival of patients with high grade, noninvasive papillary (TaG3) bladder tumors: 15-year outcome. J Urol. 2000;163:60-61. discussion 61-62.
6. Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J, et al. Multivariate analysis of the prognostic factors of primary superficial bladder cancer. J Urol. 2000;163:73-78. Review.
7. Stenzl A, Burger M, Fradet Y, et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol. 2010;184:1907-1913.
8. 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;64:846-854.
9. Daneshmand S, Bazargani ST, Bivalacqua TJ, et al. Blue Light Cystoscopy with Cysview Registry G: Blue light cystoscopy for the diagnosis of bladder cancer: Results from the US prospective multicenter registry. Urol Oncol. 2018;36:361.e1-361.e6.
10. Xiong Y, Li J, Ma S, et al. A meta-analysis of narrow band imaging for the diagnosis and therapeutic outcome of non-muscle invasive bladder cancer. PloS One. 2017; e0170819.
11. Naito S, Algaba F, Babjuk M, et al. The Clinical Research Office of the Endourological Society (CROES) Multicentre Randomised Trial of Narrow Band Imaging-Assisted Transurethral Resection of Bladder Tumour (TURBT) Versus Conventional White Light Imaging-Assisted TURBT in Primary Non-Muscle-invasive Bladder Cancer Patients: Trial Protocol and 1-year Results. Eur Urol. 2016;70:506-515.
12. Kim SB, Yoon SG, Tae J, et al. Detection and recurrence rate of transurethral resection of bladder tumors by narrow-band imaging: Prospective, randomized comparison with white light cystoscopy. Investig Clin Urol. 2018;59:98-105.
13. Katz A. FDA approves expanded indication for blue light cytoscopy with cysview for bladder cancer detection. Targeted Oncology. 2018 https://www.targetedonc.com/news/fda-approves-expanded-indication-for-blue-light-cytoscopy-with-cysview-for-bladder-cancer-detection
14. Daneshmand S, Patel S, Lotan Y, et al; Flexible Blue Light Study Group C. Efficacy and safety of blue light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: A Phase III, comparative, multicenter study. J Urol. 2018;199:1158-1165.
15. Smith AB, Daneshmand S, Patel S, et al; Flexible Blue Light Study Group C. Patient-reported outcomes of blue-light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: results from a prospective multicentre study. BJU Int. 2018; published online ahead of print.