More than 81,000 individuals are diagnosed with bladder cancer in the United States every year, of whom 75% have non-muscle invasive disease.1,2 Unfortunately, half these cases recur despite transurethral resection of bladder tumor (TURBT), and from 5% to 25% of repeated recurrences progress to muscle-invasive disease.3,4,5
Reliable visualization of bladder tumors is crucial to the success of TURBT, but carcinoma in situ (CIS) and other low-grade flat lesions are difficult to detect under standard white light cystoscopy. 6,7,8 In a recent meta-analysis of raw data from six prospective studies, white light cystoscopy missed 24.9% of Ta and T1 tumors and 26.7% of CIS tumors. 9 Other studies have associated white light cystoscopy with miss rates of 10% to 45%, depending on patient subgroups.10
Evidence consistently indicates that the addition of blue light cystoscopy to white light cystoscopy improves the detection and resection of non-muscle invasive bladder malignancies over white light cystoscopy alone.11,12 Blue light cystoscopy is used in conjunction with a photoactive porphyrin, either 5-aminolevulinic acid (ALA) or hexaminolevulinate hydrochloride (HAL), which accrues preferentially in neoplastic tissue and fluoresces when exposed to blue light between 375 and 440 nm in wavelength.13,14 In a large real-world study, HAL-assisted blue light cystoscopy detected bladder carcinoma in situ (CIS) with a sensitivity of 75%, compared with 52.8% for white light cystoscopy (P=.02).12 In the previously cited meta-analysis of raw data, HAL-assisted blue light cystoscopy detected significantly more Ta tumors and CIS lesions compared with white light alone (P < .001 for each comparison).9 Importantly, this result spanned subgroups of intermediate and high-risk patients and patients with both primary and recurrent tumors.9
Based on such findings, joint guidelines from the American Urological Association (AUA) and the Society of Urologic Oncology (SUO) now recommend offering blue light cystoscopy to all patients with non-muscle invasive bladder cancer and considering blue light cystoscopy for patients with a history of non-muscle invasive bladder cancer and positive cytology.15
It is important to emphasize that blue light cystoscopy should be used in conjunction with white light cystoscopy, not as a replacement. In a multicenter study of 311 patients with known or suspected bladder cancer, HAL-assisted blue light cystoscopy missed 9% of tumors visualized by white light cystoscopy, including 5% of T1 tumors.16 In the same study, HAL-assisted blue light cystoscopy detected at least one additional tumor compared with white light cystoscopy in 29% of patients and detected at least one additional T1 tumor in 15% of patients.16 Thus, both white light and blue light must be used in the same patient to obtain maximum benefit.
Hexaminolevulinate was approved by the U.S. Food and Drug Administration (FDA) in 2010 for the cystoscopic detection of non-muscle invasive bladder cancer in patients with known or suspected lesions based on prior cystoscopy.17 Because the procedure has required a rigid cystoscope, it generally has been performed under anesthesia.
However, in February 2018, the FDA approved a supplemental new drug application for the use of a HAL in conjunction with a flexible cystoscope, the Karl Storz D-Light C Photodynamic Diagnostic system.17,18 This approval effectively expanded the use of blue light cystoscopy into outpatient settings. Understanding the advantages and caveats of blue light cystoscopy can help us better care for our hospitalized patients and outpatients with suspected or confirmed bladder cancer.
BLUE LIGHT CYSTOSCOPY REDUCES RISK OF RECURRENCE
Blue light cystoscopy has been used for approximately 20 years in Europe, and multiple studies there have associated this enhanced technique with significantly prolonged recurrence-free survival that is potentially maintained for years following TURBT.
In one such randomized study, 115 patients with non-muscle invasive bladder cancer underwent TURBT with either conventional white light cystoscopy or ALA-assisted blue light cystoscopy.19 Cancer recurred after a median of 5 months in the white-light group compared with 12 months in the ALA blue light group.19 After 36 months, rates of recurrence were 73% in the white-light group versus 59% in the blue-light group.19 Centers elsewhere in Europe reported similar results. In a single-center randomized trial in Romania, blue light cystoscopy identified 25.8% more non-muscle invasive bladder tumors than did white light cystoscopy, leading to a 27% reduction in the rate of 12-month recurrence.20
Particularly compelling are the results of a phase III, randomized, prospective study of 814 patients in Germany with suspected bladder cancer at increased risk for recurrence.6 All patients underwent white light cystoscopy and TURBT with or without intravesical HAL-assisted blue light cystoscopy before and after resection.6 Among 286 patients with at least one Ta or T1 bladder tumor detected, blue light cystoscopy was associated with a 16% decrease in recurrence at 9 months.6 This effect persisted at a median of 54 months of follow-up, when 38% of patients in the blue light group remained tumor-free versus 31.8% of the white light group (median time to recurrence, 16.4 months vs. 9.6 months, respectively; P = .04).21 Furthermore, there was a trend toward a decreased risk of cystectomy in the blue light group.
The meta-analysis of raw data also linked HAL-assisted blue light cystoscopy and resection with a 24% lower risk of recurrence at 12 months compared with white light cystoscopy alone (risk ratio, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P = .006).9 In a separate single-center prospective study, researchers in the United Kingdom evaluated the effects of switching from standard white light cystoscopy to white light plus HAL-assisted blue light cystoscopy.22 A total of 345 patients with non-muscle invasive bladder cancer underwent one of these modalities in conjunction with high-quality TURBT, followed by intravesical mitomycin C administered within 24 hours post-surgery.22 One-year rates of recurrence were 38.9% when the hospital used only white light cystoscopy versus 21.5% after the addition of blue light cystoscopy (P < .001). This finding spanned risk-based subgroups and patients matched by age, multifocality, length of follow-up, and tumor grade, stage, and size. Furthermore, the reduction in risk of recurrence remained statistically significant at 3-year follow-up (39.0% vs. 53.3%, respectively; P=.02) (P < .001).22
Several other studies have compared longer-term rates of recurrence between blue light and white light cystoscopy. In a single-center medical database analysis of 159 cases of recurrent non-muscle invasive bladder cancer treated by a single surgeon performing TURBT, 44 cases involved HAL-assisted blue light cystoscopy and 115 cases were performed with white light cystoscopy alone.23 In the multivariate analysis, blue light cystoscopy was associated with a significant reduction in 3-year risk of recurrence (adjusted hazard ratio, 0.42; 95% CI, 0.25 to 0.70; P = .001).23 Three years after TURBT, 53.7% of blue light patients remained recurrence-free versus 27.4% of white light patients.23
Looking beyond TURBT, blue light cystoscopy also is useful for the surveillance of patients who are considered at high risk for bladder cancer recurrence. In a multicenter phase III study, 304 such patients received intravesical HAL (Hexvix® or Cysview®) and white light flexible cystoscopy, after which they were randomly assigned to undergo either blue light flexible cystoscopy or no additional evaluation.8 Among 63 patients with confirmed recurrent malignancies, 20.6% (95% CI, 11.5% to 32.7%) were detected only by blue light cystoscopy.
BLUE LIGHT CYSTOSCOPY AND PROGRESSION
Disease progression is one of the most important clinical sequelae of non-muscle invasive bladder cancer, as it signifies worsening of disease and is an independent predictor of cancer-related mortality. 24,25,26,27 The effects of blue light cystoscopy on progression are less clear; early studies documented reductions in recurrence that did not appear to translate to an impact progression. 28,29 For example, in a prospective, randomized, double-blind study, 370 patients with non-muscle invasive bladder cancer received either intravesical 5-ALA or placebo before undergoing cystoscopy under white and blue light.29 Twelve months after tumor resection, rates of progression-free survival were identical (89%) between study arms.
In another 12-month, randomized, multicenter trial, 5-ALAassisted blue light cystoscopy detected more lesions than white light cystoscopy alone but did not confer significant improvements in progression-free survival.30
These results reflect at least two shortcomings in research on cystoscopy and progression. The first is the indolent nature of some early-stage bladder tumors; they may recur and progress over years, rather than months. We need longer-term prospective studies to assess the effects of enhanced tumor detection on the progression of non-muscle invasive bladder cancer.
The second limitation is that older studies tended to define progression inconsistently, imprecisely, and often too strictly to detect clinically important events. It has been only four years since the International Bladder Cancer Group (IBCG) called for a uniform, more sensitive definition of progression in order to facilitate earlier-stage diagnosis as well as cross-study comparisons.31 In this paper, the IBCG suggested defining progression as any one of the following: an increase in T stage leading to invasion of the lamina propria (T1 disease), the development of muscle-invasive disease (stage T2 or greater), progression to lymph node (N+) or distant metastasis (M1), or an increase in grade from low to high.31
Based on this new definition, does the addition of blue light cystoscopy to standard white light cystoscopy appear to affect progression? In the phase III study in Germany, which was published prior to the proposed IBCG definition, researchers defined progression as non-muscle-invasive tumors becoming muscle-invasive. Based on this definition, the researchers reported a non-significant trend toward lower risk of progression among patients who underwent HAL-assisted blue light cystoscopy instead of white light cystoscopy only.6 After 9 months, progression to muscle-invasive disease had occurred among nine patients in the white light group and seven patients in the blue light group. After a median of 4.5 years, eight and 16 patients, respectively, had progressed to stage T2-T4 disease.21
Recently, my colleagues and I re-analyzed the German data based on the IBCG definition.24 We identified more progressors in both groups: 31 (12.2%) patients in the blue-light group and 46 (17.6%) patients in the white-light group. Progression from Ta to CIS tumors occurred in four (1.6%) blue-light patients and 11 (4.2%) white-light patients.24 The difference in rates of progression trended toward statistical significance, favoring the blue-light group (P = .085).24 Median time to progression also was longer in the blue light group (P = .05), possibly because of better detection and resection of earlier-stage disease.24 Furthermore, blue light cystoscopy was associated with a trend toward improved progression-free survival (P=.05).24
The authors of a recent systematic review and meta-analysis also concluded that the use of HAL-assisted blue light cystoscopy in combination with white light cystoscopy reduced the likelihood of progression following TURBT.32 This meta-analysis, which specifically focused on progression, included four randomized studies and one retrospective study published between 2000 and 2016. Among 1,301 patients who underwent TURBT, approximately half received blue light cystoscopy in addition to white light cystoscopy while the rest were evaluated with white light alone.32 After a median follow-up period of approximately 38 months, 10.7% of white-light patients had progressed, compared with only 6.8% of blue-light patients. As a result, the odds of progression were 64% higher among patients who underwent TURBT without blue light cystoscopy (median odds ratio, 1.64, 95% CI, 1.10 to 2.45; P=.01).32
In summary, while more research is needed, we have limited data suggesting that blue light cystoscopy can delay progression by facilitating earlier detection and resection of bladder tumors.
IMPACT ON PATIENT MANAGEMENT
vSeveral studies also indicate that improved detection of bladder tumors with blue light cystoscopy leads to important improvements in management, including the use of intravesical therapy, earlier cystectomy, and closer surveillance.
In one prospective, randomized study of 362 patients with suspected non-muscle invasive bladder cancer, the use of HALassisted blue light cystoscopy detected more tumors in 35% of patients compared with white light cystoscopy alone.33 Respective rates of recurrence were 7.2% versus 15.8% at 3 months, 21.6% versus 32.5% at 1 year, and 31.2% versus 45.6% at 2 years.33 Although progression rates at 1 and 2 years did not significantly differ (2.4% vs. 4.4%; P=.2, and 4% vs. 7%, respectively; P=.12), the study authors reported that by detecting additional lesions, blue light cystoscopy led to meaningful changes in treatment, such as the use of intravesical BCG or chemotherapy instead of forgoing postoperative therapy.33
In another randomized study of 146 patients, an independently blinded urologist reviewed two sets of records, one of which only described the results of white light cystoscopy and the other of which also included the results of HAL-assisted blue light cystoscopy.11 The addition of blue light cystoscopy findings improved the management of 21.7% of patients, including more extensive resections in 10 patients and additional postoperative procedures in 15 patients.11 In a third small study of 39 patients, 38% had additional papillary and flat lesions detected by HAL-assisted blue light cystoscopy.34 The use of blue light cystoscopy led to changes in management, including the use of BCG instead of mitomycin C, in 13% of patients.34
Table 1. Blue light cystoscopy: Randomized controlled trials
BC: bladder cancer
CIS: carcinoma in situ
HAL-BLC: hexaminolevulinate blue light cystoscopy
IBCG: International Bladder Cancer Group
NMIBC: non-muscle invasive bladder cancer
PDD: photodynamic diagnosis
WLC: white light cystoscopy
Blue light cystoscopy also is useful after TURBT to confirm treatment efficacy. By improving the accuracy of post-TURBT assessments, blue light cystoscopy can spare patients the pain, risks, and cost of unnecessary treatment.35 This is because residual tumor that persists after TURBT and instillation therapy can be misinterpreted as treatment failure, leading to more radical treatment.35
SAFETY AND QUALITY OF LIFE
Blue light cystoscopy generally is well tolerated.17,36 The main cause of adverse events is catheterization. In randomized trials of fluorescence cystoscopy and TURBT with up to 2 years of follow-up, the most common adverse events were hematuria, dysuria, and bladder spasm, which were equally likely with blue and white light cystoscopy and were concluded to be related to resection.36 In another study of post-marketing data from more than 200,000 patients, there were no serious adverse events definitively attributed to HAL-assisted blue light cystoscopy and its repeated use did not appear to increase the risk of toxicities.37
Earlier and more accurate detection of non-muscle invasive disease can reduce and delay the need for more invasive procedures, such as repeat TURBT and cystectomy. As a result, several studies have found that the use of blue light cystoscopy led to significant reductions in health care costs and improvements in patient quality of life.38,39,40 Perhaps the most robust of these studies was a prospective, multicenter, phase III trial published in July 2018.41 For the study, researchers used HAL-assisted blue light flexible cystoscopy for the office-based surveillance of non-muscle invasive bladder cancer in patients at high risk of recurrence.41
Among 304 enrolled patients, 103 individuals were referred for surgical examination, and 63 had histologically confirmed malignancies.41 After patients underwent blue light cystoscopy, their scores on the anxiety instrument of the Patient-Reported Outcomes Measurement Information System (PROMIS) decreased by 2.6 points, an effect that was independent of patient gender, test performance, or cystoscopy result.41 Furthermore, 94% of patients reported that blue light cystoscopy was worthwhile and that they would undergo it again, while 91% stated that they would recommend blue light cystoscopy to other patients.41 Finally, three-quarters of patients said that they would be willing to pay for blue light cystoscopy out-of-pocket.41 These findings suggest that blue light cystoscopy is acceptable to and valued by high-risk patients in outpatient settings.
ALTERNATIVES TO BLUE LIGHT CYSTOSCOPY
Fluorescence is not our only available option for enhanced cystoscopy. An alternative is narrow band imaging (NBI), a technology that excludes the red spectrum of light in order to increase the contrast between mucosal vasculature and superficial tissue structures of the bladder.42 Narrowband imaging does not require instillation of agents into the bladder, and the technology is already present on many cystoscopes used in clinics and hospitals.
Several studies have found that narrow band imaging detected CIS and other non-muscle invasive bladder tumors with greater sensitivity than white light cystoscopy alone.42,43 In a randomized prospective trial, rates of 1-year post-TURBT recurrence rates were approximately 33% with narrow band imaging versus 51% with white light cystoscopy alone (P = .01).44
In another recent meta-analysis of 25 studies, narrow band imaging detected lesions in 10% more patients (95% CI, 5% to 14%) than white light cystoscopy and detected 19% more lesions per patient (95% CI, 15% to 25%).43 Narrow band imaging also was associated with a significantly reduced rate of recurrence compared with white light cystoscopy. Pooled risk ratios were 0.43 (95% CI, 0.23 to 0.79) at 3 months and 0.81 (95% CI, 0.69 to 0.95) at 12 months.43
In another network meta-analysis of 15 randomized controlled trials, narrow band imaging and blue light cystoscopy were associated with a statistically similar risk of recurrence after TURBT (OR = 1.11, 95% CI, 0.55 to 2.1), and both modalities significantly outperformed white light cystoscopy alone.42 To date, however, we have no randomized head-to-head studies of blue light cystoscopy versus narrow band imaging in the setting of either resection or surveillance.
Enhanced cystoscopy techniques are an essential addition to our armamentarium for the detection and treatment of bladder cancer. Two recently developed technologies are currently in clinical use – narrow band imaging (NBI) and blue light cystoscopy. Among the two, blue light cystoscopy has been studied more extensively and has been shown to significantly improve the detection of initial and recurrent non-muscle invasive bladder tumors, particularly CIS and other low-grade flat lesions that are difficult to detect with white light cystoscopy alone. Results from multiple studies indicate that blue light cystoscopy significantly improves recurrence-free survival and also is useful to confirm the efficacy of TURBT and guide post-operative decision-making. Emerging data also suggest that improved tumor detection – and resection - with blue light cystoscopy reduces the risk of progression. However, it must be emphasized that blue light cystoscopy is not a stand-alone technique and must be performed in conjunction with white light cystoscopy.
Written By: Ashish M. Kamat, MD, MBBS
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