Figure. Advancements in technology for nonmuscle-invasive bladder cancer surveillance.

Nonmuscle-invasive bladder cancer (NMIBC) accounts for 75% of initial bladder cancer diagnoses with stages high grade T1 and carcinoma in situ (CIS) diagnosed in 20% and 10%, respectively, of cases. AUA guidelines risk stratify T1 and CIS disease as high-risk disease given the 78% recurrence rate and 45% progression rate to muscle invasive disease at 5 years.¹

Intravesical Bacillus Calmette-Guérin (BCG) remains the standard treatment option for high-risk NMIBC, with induction and maintenance treatment associated with lower long-term recurrence rate and increased complete response rate for CIS. However, detection of recurrent tumors after BCG treatment presents unique challenges given the potential to miss CIS changes and possible inflammatory reactive changes of the bladder mucosa. The treatment discussion for BCG-unresponsive disease changes to escalated therapy options, including second-line intravesical therapy, immunotherapy (eg, pembrolizumab), radical cystectomy, or clinical trials.¹ Therefore, accurate detection is critical at these junctions after BCG treatment.

In the acute post-BCG setting, urothelial cells undergo morphologic alteration (eg, prominent nucleoli, reactive atypia, increase in granulocytes) due to complex interactions between BCG and local microenvironment and, therefore, recent BCG treatment impacts the sensitivity of urine cytology as a diagnostic test.² In patients with high-grade tumors and subsequent BCG instillations, the sensitivity of cytology and flexible white light cystoscopy (WLC) to detect high-grade disease is modest (56% and 87.5%, respectively). Nonetheless, negative WLC and normal urine cytology provide reassurance of local disease response to BCG and potentially can avoid unnecessary procedures such as bladder biopsy.³

Utilizing next generation sequencing technology in clinical practice may mitigate excessive invasive testing and avoid diagnosis delays in high-risk NMIBC. Several urinary biomarkers, including bladder tumor antigen, ImmunoCyt, UroVysion (fluorescence in situ hybridization), Bladder Cancer Test, and nuclear matrix protein 22, have been introduced with varying sensitivity and specificity for surveillance of NMIBC.⁴ The recent validation of Cxbladder, which combines urinary genomic biomarkers with phenotypic and clinical data to classify hematuria patients into low-/high-risk probability of urothelial carcinoma, has a high sensitivity (92.4%) and specificity (93.8%) for identifying high-risk tumors.⁵ Ultimately, data remain limited for wide utilization of urinary biomarkers in NMIBC monitoring and these tests cannot replace the value of cystoscopy and tissue biopsy.

Enhanced cystoscopy technologies can further improve detection of high-grade tumors and CIS lesions, and several options are now available in the ambulatory clinic and operating room settings.

Narrow band imaging (NBI) is an optical filter that restricts the wavelength of light to blue and green to improve visualization of red colored structures, which in turn highlights neoplastic and hypervascular processes. Approved by the Food and Drug Administration in 2014, NBI is readily available in flexible and rigid cystoscopy equipment from Olympus. In a Cochrane review, NBI in addition to WLC reduced risk of recurrence compared to standard WLC (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.45-0.89) with an anticipated absolute effect of 163 fewer per 1,000 cases (95% CI 43-265) in patients with high-risk NMIBC.⁶ In our experience, it can be especially useful for detecting early papillary changes, which may be present with CIS, and users may be able to differentiate inflammatory changes from suspected neoplastic changes.

The Food and Drug Administration approved blue light cystoscopy (BLC) with hexaminolevulinate hydrochloride (Cysview), also known as photodynamic diagnosis, in 2010 as an adjunct to WLC for patients with known or suspected NMIBC. Based on a systematic Cochrane review, blue light–guided bladder tumor resection reduces the risk of disease recurrence over a 12-month follow-up period compared to WLC (HR 0.66, 95% CI 0.54-0.81). For cases with intermediate- and high-risk NMIBC, the risk of progression with BLC was reduced by 17 and 56 cases per 1,000 participants, respectively, compared to WLC.⁷

To understand the clinical utility of BLC for post-BCG patients, Chappidi et al reported among 282 cystoscopies after BCG in a prospective multi-institutional BLC registry, the overall recurrence rate was 45.0% (127 cases) with 88% of recurrences being CIS positive. With only WLC, 16 of the 127 (13%) high-grade early recurrence cases would have been missed. Although the adverse events reported between BLC and WLC were equivocal, false-positive rates for BLC are notable given the anesthetic risk for operating room lesion biopsies—50% and 5% false-positive rates at the lesion-specific and cystoscopy levels, respectively.^7,8

A recently published randomized trial called into question the magnitude of the clinical utility of BLC to reduce disease recurrence. Heer et al reported an open-labeled, multi-institutional randomized clinical trial of 538 intermediate- and high-risk NMIBC patients undergoing either blue light or white light guided transurethral resection of bladder tumor with 3 years of follow-up. In the study, patients were randomized to transurethral resection of bladder tumor with or without photodynamic diagnosis and monitored for recurrence (median follow-up 44 months). Of the cohort, 41.1% and 38.7% of patients had recurrences in the BLC and WLC arms, respectively (HR 0.94, 95% CI 0.69-1.28, P = .70). Additionally, the cost of performing BLC was markedly higher than the cost of WLC due to the need for intravesical instillation and compatible equipment.⁹ One plausible hypothesis for the negligible difference in recurrence rates may be the improved visualization with digital cystoscopes and potential for better detection.¹⁰ Further, only 8% of the cohort had high-risk disease by EORTC (European Organization for Research and Treatment of Cancer) risk groups with 13% with a history of CIS.⁹ Although the stratification-based use of intravesical BCG was not reported in the trial, further investigation is warranted to determine the difference in recurrence after BCG as well as the cost-effectiveness of early detection and escalated therapy with BLC in this high-risk population.

Costs of adjunctive technology and novel diagnostic testing are not minimal to the health care burden, particularly when false-positive results occur. In the high-stakes setting after BCG, applying new approaches can change the course. Improved digital endoscopic tools, enhanced technologies such as NBI and BLC, and judicious application of additional tests may improve cancer detection, identify the need for escalated intervention, and direct BCG-unresponsive patients to clinical trials earlier.