Author's Accepted Manuscript

Comparative effectiveness of fluorescent versus white light cystoscopy for initial

diagnosis or surveillance of bladder cancer on clinical outcomes: Systematic review
and meta-analysis

Roger Chou , Shelley Selph , David I. Buckley , Rongwei Fu , Jessica C. Griffin ,

Sara Grusing , John L. Gore

PII: S0022-5347(16)31585-3
DOI: 10.1016/j.juro.2016.10.061
Reference: JURO 14111

To appear in: The Journal of Urology

Please cite this article as: Chou R, Selph S, Buckley DI, Fu R, Griffin JC, Grusing S, Gore JL,
Comparative effectiveness of fluorescent versus white light cystoscopy for initial diagnosis or
surveillance of bladder cancer on clinical outcomes: Systematic review and meta-analysis, The Journal
of Urology® (2016), doi: 10.1016/j.juro.2016.10.061.

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 ACCEPTED MANUSCRIPT

Comparative effectiveness of fluorescent versus white light cystoscopy for initial diagnosis
or surveillance of bladder cancer on clinical outcomes: Systematic review and meta-
analysis

Authors:
Roger Chou, MD1
Shelley Selph, MD, MPH1

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David I. Buckley, MD, MPH1
Rongwei Fu, PhD1
Jessica C. Griffin, MS1

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Sara Grusing, BA1
John L. Gore, MD, MS2

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Author Affiliations:
1. The Pacific Northwest Evidence-based Practice Center, Department of Medical
Informatics and Clinical Epidemiology, Oregon Health & Science University
2. The Pacific Northwest Evidence-based Practice Center, The Department of Urology,

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University of Washington
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Corresponding Author: Roger Chou, MD, FACP; 3181 SW Sam Jackson Park Road, Mail
Code: BICC, Portland, OR 97239; Email: chour@ohsu.edu; Phone 503-494-6550; Fax 503-346-
6815
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Conflict of interest: There are no conflict of interest disclosures from any authors.

Running Title: Fluorescent cystoscopy for bladder cancer

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Key Words: Fluorescent cystoscopy, 5-aminolevulinic acid, hexaminolevulinic acid, bladder

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cancer

Funding: Agency for Healthcare Research and Quality, Contract No. HHSA290-2012-00014-I
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Text word count:3,833; Figures: 7; Tables: 2; Tables in Supplement: 2

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Abstract

Purpose: To systematically review the comparative effectiveness of fluorescent versus white

light cystoscopy on bladder cancer clinical outcomes.

Methods: Systematic literature searches of Ovid MEDLINE (January 1990 through September
2015), Cochrane databases, and reference lists were performed. Fourteen randomized trials of

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fluorescent cystoscopy using 5-amimolevulinic acid (5-ALA) or hexaminolevulinic acid (HAL)
versus white light cystoscopy for diagnosis of initial or recurrent bladder cancer that reported
bladder cancer recurrence, progression, mortality, and harms were selected for review.

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Results: Fluorescent cystoscopy was associated with decreased risk of bladder cancer recurrence
versus white light cystoscopy at short-term (<3 months, ten trials, RR 0.59, 95% CI 0.40 to 0.88,

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I2=69%), intermediate-term (3 months to <1 year, six trials, RR 0.70, 95% CI 0.56 to 0.88,
I2=19%), and long-term followup (≥1 year, 12 trials, RR 0.81, 95% CI 0.70 to 0.93, I2=49%).
However, findings were inconsistent and potentially susceptible to performance and publication
bias (strength of evidence [SOE]: low). There were no differences between cystoscopic methods

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in risk of mortality (3 trials, RR 1.28, 95% CI 0.55 to 2.95, I2=41%) (SOE: low) or progression
(9 trials, RR 0.74, 95% CI 0.52 to 1.03, I2=0%) (SOE: moderate). Estimates for short-term
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recurrence (6 trials, RR 0.62, 95% CI 0.38 to 1.00), long-term recurrence (7 trials, RR 0.75, 95%
CI 0.62 to 0.92) and progression (4 trials, RR 0.51, 95% CI 0.28 to 0.96) were statistically
significant in the subgroup of trials that used HAL, but there were no statistically significant
interactions based on the photosensitizer used. Fluorescent cystoscopy was not associated with
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decreased risk of long-term recurrence in three trials that utilized methods to reduce performance
bias with initial cystoscopy (RR 0.96, 95% CI 0.79 to 1.18; I2=36%). Data on harms were
sparse.
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Conclusions: Fluorescent cystoscopy was associated with reduced risk of bladder cancer
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recurrence versus white light cystoscopy; however, additional trials that adequately guard against
performance bias are needed to confirm these findings. Fluorescent cystoscopy with HAL may
be associated with decreased risk of progression, but more studies with long-term followup are
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needed to better understand effects of the photosensitizer used on progression.

Funding Source: Agency for Healthcare Research and Quality, Contract No. 290-2012-00014-I
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Introduction

Bladder cancer is common in the United States.1 At diagnosis, bladder cancer is non-muscle-

invasive (NMIBC) in about 70% of cases. Initial treatment for NMIBC typically includes

transurethral resection of the bladder tumor (TURBT) and adjuvant intravesical therapy, but

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recurrence is frequent.2 Some apparent early recurrences may represent missed tumors or

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inadequate initial resection due to suboptimal visualization, rather than true recurrences3 of

completely resected tumors. Therefore, alternative cystoscopy methods have been developed to

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improve bladder cancer visual detection.

Nonpapillary bladder cancers such as carcinoma in situ and smaller or satellite tumors may

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be difficult to visualize during standard white light cystoscopy.4 Fluorescent cystoscopy involves
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the preoperative intravesical instillation of a photoactive agent that is preferentially taken up by

bladder cancer cells.5 After removal of the instillate, cystoscopy is performed under fluorescent
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light, highlighting cells that have taken up the photodynamic agent. The photodynamic agents
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studied for fluorescent cystoscopy are 5-aminolevulinic acid (5-ALA) and its derivative,
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hexaminolevulinic acid (HAL). Compared with 5-ALA, HAL is more lipophilic and is taken up

throughout the urothelial cell layer, rather than only the superficial layers, resulting in greater
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fluorescence at lower concentrations and shorter instillation times. Only HAL has been FDA-

approved for use in bladder cancer detection and is commercially available in the United States
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and Europe, though initial fluorescent cystoscopy studies were performed using 5-ALA.
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Studies indicate that fluorescent cystoscopy is associated with higher cancer detection rates

than white light cystoscopy, and appears to reduce recurrence.6-9 However, the effects of

fluorescent cystoscopy on more clinical outcomes such as progression and mortality are less

clear. The purpose of this study is to systematically review the current evidence on the effects of

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fluorescent versus white light cystoscopy on bladder cancer recurrence, progression, and

mortality. This review was conducted as part of a larger review on the evaluation and treatment

of NMIBC.10

Materials and Methods

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Detailed methods and data for this review, including the analytic framework, key questions,

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search strategies, inclusion criteria, study data extraction, and quality ratings, are available in the

full report,10 which also addressed narrow band imaging,11 the diagnostic accuracy of urinary

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biomarkers, and benefits and harms of bladder cancer treatments. The topic was nominated to the

Agency for Healthcare Research and Quality (AHRQ) and the protocol was developed using a

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standardized process12 with input from experts and the public. The protocol was registered in the
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PROSPERO database prior to conducting the review.13 This article focuses on the following

question: for the initial diagnosis or surveillance of NMIBC, what is the comparative
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effectiveness of fluorescent cystoscopy versus standard white light cystoscopy for bladder cancer
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recurrence, progression to muscle-invasive bladder cancer, mortality, and harms?

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Data Sources and Searches

For the original report,10 a research librarian searched multiple electronic databases including
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Ovid MEDLINE (January 1990 – October 2014), the Cochrane Central Register of Controlled

Trials, and the Cochrane Database of Systematic Reviews (through September 2014). An update
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search was conducted in September 2015. We also reviewed reference lists and searched
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ClinicalTrials.gov.

Study Selection

Two investigators independently reviewed abstracts and full-text articles against pre-

specified criteria. We included randomized trials of fluorescent versus white light cystoscopy for

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initial or recurrent bladder cancer that reported recurrence, progression, all-cause or bladder

cancer-specific mortality, or local or systemic harms. We included studies that used either 5-

ALA or HAL as the photosensitizing agent. We excluded studies that only reported initial

bladder cancer detection rates, used a non-randomized design, evaluated other types of

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augmented cystoscopy (e.g., narrow band imaging), or were published only as conference

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abstracts.

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Data Extraction and Quality Assessment

One investigator extracted details about the setting, study design, inclusion criteria,

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population characteristics, cystoscopic methods, bladder cancer stage and grade, treatments,
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followup methods, and results. We calculated relative risks for recurrence, progression, and

mortality based on the raw (uncensored) event rates in each group.

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Two investigators independently assessed the risk of bias for each study as low, moderate, or

high using criteria adapted from the U.S. Preventive Services Task Force.14 Discrepancies were
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resolved through discussion and consensus.

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Data Synthesis and Analysis

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We conducted meta-analyses using the Dersimonian-Laird random effects method in Stata

Version 10.0 (StataCorp LP, College Station, TX).15 We assessed statistical heterogeneity using
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the p value for the Q test and the I2 test.16 When the I2 was >20%, we also pooled studies using
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the profile likelihood method.17 All analyses were stratified by the photosensitizing agent used.

For recurrence, we stratified analyses according to duration of followup after initial cystoscopy

as short-term (<3 months), intermediate-term (3 months to <1 year), or long-term (≥1 year)

followup We performed sensitivity and subgroup analyses based on risk of bias ratings, use of

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methods to reduce potential bias in performance of initial cystoscopy (e.g., blinded

administration of photosensitizer or randomization to fluorescent cystoscopy after performing

white light cystoscopy), masking of followup cystoscopy to initial cystoscopic methods,

inclusion of high-risk NMIBC patients, followup cystoscopy methods (e.g., use of fluorescent or

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white light cystoscopy), and tumor characteristics (stage, grade, initial or recurrent, and

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multifocality). For progression and mortality, analyses were also stratified by duration of

followup (less or greater than 24 months). The main analysis was restricted to fully published

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trials, but we performed a sensitivity analysis that included trials only published as conference

abstracts. We constructed funnel plots and performed the Egger test for small sample effects for

analyses with at least 10 trials.18

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We assessed the strength of evidence for each body of evidence as high, moderate, low, or

insufficient based on aggregate study quality, precision, consistency, and directness.19

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Role of the Funding Source

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This project was funded under Contract No. 290-2012-00014-I from the Agency for
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Healthcare Research and Quality (AHRQ), U.S. Department of Health and Human Services
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(DHHS). The authors of this report are responsible for its content. Statements in the report

should not be construed as endorsement by AHRQ or DHHS.

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Results

The search and selection of articles are summarized in Figure 1. We identified 4,444 potentially

relevant articles. After dual review of abstracts and titles, 68 articles were selected for full-text

dual review. From these, fifteen trials (reported in 20 publications) of fluorescent versus white

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light cystoscopy met inclusion criteria (Table 1 in supplement).20-38 Six trials evaluated

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fluorescent cystoscopy using 5-ALA20, 25, 32, 35, 36, 38 and nine trials used HAL.24, 26-28, 30, 31, 33, 34, 37

Sample sizes ranged from 44 to 551 patients (total n=2906) and duration of followup ranged

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from 4 weeks to 60 months. Participants’ mean age ranged from 60 to 74 years and were

predominantly male. One trial was conducted in the United States, Canada, and Europe;29, 37 the

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remainder were conducted in Europe. Two trials restricted enrollment to new diagnoses of
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bladder cancer33, 34 and two trials focused on high-risk bladder cancer;26, 33 the other trials
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evaluated mixed populations or did not specify these characteristics. Intravesical therapy

protocols varied (Table 1 in supplement). Followup analyses were restricted to patients with
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NMIBC (Ta, T1, and in some cases CIS) on initial cystoscopy. Followup was performed with
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fluorescent light cystoscopy in three trials;28, 33, 35 in the other trials, followup was performed

with white light cystoscopy or the method was not reported.

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Four trials were rated high risk of bias20, 32, 33, 37 and the other eleven trials medium risk of

bias. Two trials described adequate randomization methods,28, 33 five trials reported adequate
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allocation concealment,26, 27, 33, 34, 36 and four trials reported followup cystoscopic examinations
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blinded to initial cystoscopy method;26, 27, 36, 38 in one trial an intention-to-treat population was

not clearly defined.33 Three trials utilized methods to reduce potential performance bias in

performance of initial white light cystoscopy (blinded administration of photosensitizer or

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randomization to fluorescent cystoscopy after performing white light cystoscopy).28, 37, 38 Four

trials reported high attrition,32, 36-38 and one trial20 did not report attrition.

Recurrence

Fluorescent cystoscopy was associated with decreased risk of bladder cancer recurrence

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versus white light cystoscopy at short-term (<3 months, ten trials, RR 0.59, 95% CI 0.40 to 0.88,

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I2=69%, Figure 2),20, 24, 26, 27, 31-35, 38 intermediate-term (3 months to <1 year, six trials, RR 0.70,

95% CI 0.56 to 0.88, I2=19%, Figure 3),24, 27, 28, 30, 35, 37 and long-term followup (≥1 year, 12

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trials, RR 0.81, 95% CI 0.70 to 0.93, I2=49%, Figure 4) (Table 2 in supplement).20, 24, 25, 27, 28, 30,
31, 34-38
Estimates were similar when analyses were performed using the profile likelihood method

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or when three high risk of bias trials20, 32, 33 were excluded. Effects on short- and long-term
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recurrence were statistically significant in trials that evaluated HAL (6 trials, RR 0.62, 95% CI

0.38 to 1.00, I2=51% for short-term recurrence24, 26, 27, 31, 34 and 7 trials, RR 0.75, 95% CI 0.62 to
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0.92, I2=41% for long-term recurrence)24, 27, 28, 30, 31, 34, 37 and not statistically significant in trials
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that evaluated 5-ALA (4 trials, RR 0.57, 95% CI 0.28 to 1.16, I2=84%20, 32, 35, 38 and 5 trials, RR
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0.86, 95% CI 0.68 to 1.08, I2=65%,20, 25, 35, 36, 38 respectively), but point estimates were similar,

there were no statistically significant subgroup effects (p for interaction 0.97 and 0.41,
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respectively), and statistical heterogeneity remained present in both subgroups.

For long-term recurrence, effects were somewhat stronger among trials with followup >12
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months (7 trials, RR 0.76, 95% CI 0.64 to 0.90, I2=50%)20, 25, 27, 28, 31, 35, 37 than trials with 12
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month followup (5 trials, RR 0.90, 95% CI 0.69 to 1.17, I2=51%).24, 30, 34, 36, 38 Fluorescent

cystoscopy was not associated with decreased risk of long-term recurrence in the trials that

utilized methods to reduce performance bias with initial cystoscopy (3 trials, RR 0.96, 95% CI

0.79 to 1.18; I2=36%),28, 37, 38 or that masked followup cystoscopy to the initial cystoscopy

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method (3 trials, RR 0.95, 95% CI 0.69 to 1.29; I2=68%),27, 36, 38 Statistical heterogeneity was not

reduced and estimates were similar when results were stratified according to risk of bias

(medium or high). Results were also similar when one trial that used fluorescent cystoscopy for

followup was excluded.35

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Analyses of short-term recurrence stratified according to baseline tumor risk category,

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multiplicity, or whether the tumors were primary or recurrent showed no clear differences (Table

1), but most trials did not contribute to stratified analyses and estimates were imprecise. For

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intermediate- and long-term recurrence, there were also no clear differences in analyses stratified

according to tumor risk group, but evidence was even more sparse.

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For short-term recurrence, two outlier trials reported point estimates that favored white light
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cystoscopy.34, 38 In one of the trials, fluorescent cystoscopy was blinded to instillation of a

photosensitizer or placebo into the bladder (RR 1.37, 95% CI 0.90 to 2.09).38 In this trial, effects
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on long-term recurrence also favored white-light cystoscopy (RR 1.20, 95% 0.94 to 1.52). The
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other trial restricted inclusion to newly diagnosed bladder cancer (RR 1.16, 95% CI 0.61 to
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2.19).34 Although all patients in this trial—including those with low-risk NMIBC—received

single-dose post-TURBT intravesical mitomycin C, other trials that found fluorescent cystoscopy
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associated with lower likelihood of recurrence also administered intravesical therapy for lower-

risk cancers.20, 24-26, 35

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For short-term recurrence, a funnel plot (Figure 5) and Egger’s test (p=0.04) suggested
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potential publication bias. One trial that (n=604) did not meet inclusion criteria because it was

published only as an abstract. found no differences between fluorescent versus white light

cystoscopy in risk for recurrence at short-term (29% vs. 29%) or long-term (24-month) followup

(18% vs. 19%).39 Including this trial resulted in a slightly attenuated pooled estimate (RR 0.65,

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95% CI 0.47 to 0.91, I2=70%) but the Egger’s test remained statistically significant. For long-

term recurrence, there was no evidence of publication bias.

Progression

There was no difference between fluorescent and white light cystoscopy in risk of

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progression to muscle-invasive bladder cancer, though the estimate favored fluorescent

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cystoscopy (9 trials, RR 0.74, 95% CI 0.52 to 1.03, I2=0%, Figure 6).20, 24, 25, 27, 31, 35-38 Effects

were statistically significant and stronger in trials that used HAL (4 trials, RR 0.51, 95% CI 0.28

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to 0.96, I2=0%)24, 27, 31, 37 than 5-ALA (5 trials, RR 0.86, 95% CI 0.57 to 1.28, I2=0%),20, 25, 35, 36,
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but the subgroup effect was not statistically significant (p for interaction=0.18). Estimates

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were somewhat stronger in 4 trials25, 27, 35, 37 with followup for at least 24 months (range 24 to 89
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months) than in 5 trials20, 24, 31, 36, 38 with followup of less than 24 months (RR 0.60, 95% CI 0.36

to 1.02, I2=0% vs. RR 0.85, 95% CI 0.54 to 1.32, I2=0%) , but there was no statistically
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significant interaction with followup duration. There were no clear differences in estimates when
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trials were stratified by risk of bias, or masking of followup cystoscopy to the initial cystoscopy
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method. Results were also similar when one trial that performed followup using fluorescent

cystoscopy was excluded.35

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Mortality

There was no difference between fluorescent and white light cystoscopy in risk of mortality,
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based on three trials with an imprecise estimate (RR 1.28, 95% CI 0.55 to 2.95, I2=43%, Figure
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7).34, 36, 37 Duration of followup for assessment of mortality was 54 months in one trial29, 37 and

12 months in the other two trials. The largest trial, which accounted for 83 of the 100 mortality

events, evaluated HAL and reported results consistent with the pooled estimate (RR 0.92, 95%

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0.29 to 12.22).37 Results were similar when trials were pooled using the profile likelihood

method.

Harms

Local adverse events such as hematuria, dysuria, urinary frequency or urgency, and bladder

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spasms occurred frequently following cystoscopy, with no clear differences between fluorescent

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cystoscopy and white light cystoscopy, but only three trials reported comparative harms.36-38

Discussion

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The key findings of this review are summarized in Table 2. Most trials found fluorescent

cystoscopy associated with decreased risk of bladder cancer recurrence versus white light

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cystoscopy, but there were methodological shortcomings in the studies and some inconsistency
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(strength of evidence [SOE]: low). A factor that complicates interpretation of short-term
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recurrence is that bladder cancers identified early after initial cystoscopy may represent missed

or incompletely treated tumors, rather than true recurrence. However, findings were similar
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when we evaluated short-term (≤3 months), intermediate-term (3 months to <1 year), and long-
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term (≥1 year) recurrence risk. Effects on short- and long-term recurrence were statistically

significant in trials that used HAL, which has been approved for diagnosis of bladder cancer in
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the United States and Europe, and not statistically significant in trials that used 5-ALA, which is

not commercially available. However, there was no statistically significant interaction effect
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based on the photosensitizer used, the subgroup estimates were similar, and stratifying by
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photosensitizer did not account for statistical heterogeneity. Factors such as differences in the

populations evaluated and intravesical therapies used also did not account for the observed

inconsistencies, with findings generally robust in sensitivity and subgroup analyses.

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Performance bias could have impacted some of the findings. In most trials, administration of

the photosensitizer was not masked, cystoscopists knew which patients had been randomized to

fluorescent cystoscopy at the time that initial white light cystoscopy was performed, and

followup cystoscopy was not blinded to the initial cystoscopic method. This could have resulted

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in performance bias, if initial cystoscopy was more thorough in persons known to have been

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randomized to fluorescent cystoscopy (potentially resulting in more complete treatment of

tumors) or outcomes assessment bias, if followup cystoscopy was more thorough in persons who

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did not undergo initial fluorescent cystoscopy (potentially resulting in more complete

identification of recurrence) There was no difference between fluorescent versus white light

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cystoscopy in risk of long-term recurrence in three trials that utilized methods to reduce
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susceptibility to potential performance bias, such as blinded instillation of a photosensitizer or

randomization to fluorescent cystoscopy after performing white light cystoscopy.28, 37, 38 In

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addition, a subgroup of three trials in which followup cystoscopy was blinded to the initial
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cystoscopic method found no effect on long-term recurrence.27, 36, 38

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There were no differences between fluorescent versus white light cystoscopy in risk of

progression (SOE: moderate) or mortality (SOE: low). Although findings were relatively
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consistent, evidence was sparse, as most trials did not report these outcomes, and there were

relatively few events. Effects on progression were statistically significant and stronger in trials
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that used HAL, but there was no statistically significant interaction effect based on the
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photosensitizer used. Followup duration was short in most trials, relative to the time frame over

which progression and mortality are likely to occur. For progression, only four trials evaluated

outcomes 2 or more years after initial cystoscopy, and two of three trials evaluated mortality at 1

year. Fluorescent cystoscopy could reduce recurrence rates without having an impact on

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progression or mortality if longer-term followup is needed to evaluated effects, if delayed

diagnosis of tumors missed on white light cystoscopy does not impact the success of treatment of

these tumors,40 if the primary determinant of progression or mortality is the underlying tumor

biology rather than risk of recurrence, or if surveillance and treatment strategies are effective in

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patients with an early recurrence.

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A network meta-analysis also found no clear difference between fluorescent cystoscopy with

5-ALA versus HAL in risk of progression (OR 1.37, 95% CI 0.48 to 3.20), but found 5-ALA

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associated with lower risk of recurrence (OR 0.48, 95% CI 0.26 to 0.95).41 However, no study in

the network meta-analysis directly compared 5-ALA versus HAL, so findings were entirely

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based on indirect comparisons, and the network meta-analysis did not stratify recurrence
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outcomes according to followup duration followup or use long-term recurrence data from some

studies.
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Strengths of our review are that we included additional, recently published trials, stratified
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analyses by use of 5-ALA and HAL, stratified recurrence data by followup duration, assessed
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more distal clinical outcomes (progression and mortality), and performed sensitivity and

subgroup analysis based on cystoscopic methods, followup methods, risk of bias, tumor
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characteristics, and other factors. Our findings are consistent with prior reviews that found

fluorescent cystoscopy associated with decreased risk of recurrence versus white light
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cystoscopy, with no overall effect on risk of progression or mortality.6-9 Prior reviews also found
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that fluorescent cystoscopy detected more bladder cancers on initial cystoscopy. One review that

found no differences between fluorescent cystoscopy and white light cystoscopy in bladder

cancer detection rates or risk of recurrence included a retrospective trial, considered multiple

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publications from the same trial as separate studies for meta-analysis, and appeared to have

errors in data extraction.42

Our review had limitations. Statistical heterogeneity was present in some pooled analyses.

To address anticipated statistical heterogeneity, we used the Dersimonian-Laird random effects

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model to pool studies. The Dersimonian-Laird random effects model may result in confidence

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intervals that are too narrow when heterogeneity is present, particularly when the number of

studies is small.17 Therefore, we repeated analyses using an alternative random effects model, the

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profile likelihood method, when heterogeneity was present, which resulted in similar findings.

We also performed sensitivity and subgroup analyses to explore sources of heterogeneity. Some

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analyses were based on small numbers of trials, which can result in underestimation of statistical
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heterogeneity and should be interpreted with caution.17 Because only 2 of the 14 trials reported

hazards ratios,24, 25 our analyses were based on relative risks, which are based on the cumulative
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number of events and do not take into account the time to events. However, we stratified
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analyses by followup intervals, to account for potential time varying effects. In addition,
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estimates from trials that reported both hazards ratios and relative risks were similar. We

excluded non-English language articles and were limited in our ability to formally assess for
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publication bias because of the relatively small numbers of trials. However, we found one

relatively large (n=604) randomized trial that found no difference between fluorescent versus
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white light cystoscopy in risk of recurrence, suggesting that publication bias could have impacted
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results.39 We did not have access to individual patient data. One review with access to individual

patient data found no clear differences by tumor stage, risk category, or primary versus recurrent

cancer.7 We did not address other factors that might impact decisions to use fluorescent

cystoscopy, such as cost.

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There were also important limitations in the evidence. All trials had methodological

shortcomings. In addition to the previously discussed susceptibility to performance bias, we

could not assess how patient factors or indication for cystoscopy (i.e., for initial diagnosis or for

surveillance) impacted estimates, and limited evidence showed no clear effects of tumor

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characteristics (risk category, multiplicity, or primary or recurrent tumor). There was insufficient

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evidence to understand effects of factors such as differences in treatment regimens and followup

methods on findings. Theoretically, fluorescent cystoscopy could be of greater benefit in patients

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with high-risk NMIBCs at baseline due to greater risk of progression. Similarly, fluorescent

cystoscopy might be of greater benefit in persons with carcinoma in situ given its flat

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appearance, which could be missed on white light cystoscopy. However, more evidence is
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needed to verify these hypotheses. Additional research is needed to determine whether

fluorescent cystoscopy with HAL is truly associated with better outcomes than with 5-ALA. Few
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trials reported harms.

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Conclusions
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Fluorescent cystoscopy was associated with reduced risk of recurrence versus white light

cystoscopy, though there were inconsistencies and our findings may have been affected by
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performance or publication bias. Fluorescent cystoscopy with HAL may be associated with

decreased risk of progression, but more studies with long-term followup are needed to better
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understand effects of the photosensitizer used on progression. Evidence on effects of fluorescent

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cystoscopy on mortality are too sparse too reach strong conclusions. Additional randomized

trials that use HAL as the photosensitizing agent and utilize blinded study designs and other

methods for reducing performance bias are needed. In the meantime, our findings can help

inform decisions regarding the dissemination of fluorescent cystoscopy.

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7. Burger, M., Grossman, H. B., Droller, M. et al.: Photodynamic diagnosis of non-muscle-
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9. Kausch, I., Sommerauer, M., Montorsi, F. et al.: Photodynamic diagnosis in non-muscle-

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Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF. Rockville,

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16. Higgins, J. P., Thompson, S. G., Deeks, J. J. et al.: Measuring inconsistency in meta-
analyses. BMJ, 327: 557, 2003
17. Cornell, J. E., Mulrow, C. D., Localio, R. et al.: Random-effects meta-analysis of
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Rockville MD: Agency for Healthcare Research and Quality 2013.

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20. Babjuk, M., Soukup, V., Petrík, R. et al.: 5-aminolaevulinic acid-induced fluorescence
cystoscopy during transurethral resection reduces the risk of recurrence in stage Ta/T1
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21. Daniltchenko, D. I., Riedl, C. R., Sachs, M. D. et al.: Long-term benefit of 5-aminolevulinic

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acid fluorescence assisted transurethral resection of superficial bladder cancer: 5-year results
of a prospective randomized study. J Urol, 174: 2129, 2005
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22. Denzinger, S., Burger, M., Walter, B. et al.: Clinically relevant reduction in risk of
recurrence of superficial bladder cancer using 5-aminolevulinic acid-induced fluorescence
diagnosis: 8-year results of prospective randomized study. Urology, 69: 675, 2007
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23. Denzinger, S., Wieland, W. F., Otto, W. et al.: Does photodynamic transurethral resection of
bladder tumour improve the outcome of initial T1 high-grade bladder cancer? A long-term
follow-up of a randomized study. BJU International, 101: 566, 2008
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24. Drăgoescu O, Tomescu P, Pănuş A et al: Photodynamic diagnosis of non-muscle invasive

bladder cancer using hexaminolevulinic acid. Rom J Morphol Embryol, 52: 123, 2011
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25. Filbeck, T., Pichlmeier, U., Knuechel, R. et al.: Clinically relevant improvement of
recurrence-free survival with 5-aminolevulinic acid induced fluorescence diagnosis in
patients with superficial bladder tumors. J Urol, 168: 67, 2002
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26. Geavlete, B., Jecu, M., Multescu, R. et al.: HAL blue-light cystoscopy in high-risk
nonmuscle-invasive bladder cancer--re-TURBT recurrence rates in a prospective,
randomized study. Urology, 76: 664, 2010
27. Geavlete, B., Multescu, R., Georgescu, D. et al.: Treatment changes and long-term
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recurrence rates after hexaminolevulinate (HAL) fluorescence cystoscopy: does it really

make a difference in patients with non-muscle-invasive bladder cancer (NMIBC)? BJU
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International, 109: 549, 2012

28. Gkritsios, P., Hatzimouratidis, K., Kazantzidis, S. et al.: Hexaminolevulinate-guided
transurethral resection of non-muscle-invasive bladder cancer does not reduce the recurrence
rates after a 2-year follow-up: a prospective randomized trial. Int Urol Nephrol, 46: 927,
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29. Grossman, H. B., Stenzl, A., Fradet, Y. et al.: Long-term decrease in bladder cancer
recurrence with hexaminolevulinate enabled fluorescence cystoscopy. J Urol, 188: 58, 2012

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30. Hermann, G. G., Mogensen, K., Carlsson, S. et al.: Fluorescence-guided transurethral

resection of bladder tumours reduces bladder tumour recurrence due to less residual tumour
tissue in Ta/T1 patients: a randomized two-centre study. BJU International, 108: E297, 2011
31. Karaolides, T., Skolarikos, A., Bourdoumis, A. et al.: Hexaminolevulinate-induced
fluorescence versus white light during transurethral resection of noninvasive bladder tumor:
does it reduce recurrences? Urology, 80: 354, 2012

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32. Kriegmair, M., Zaak, D., Rothenberger, K. H. et al.: Transurethral resection for bladder
cancer using 5-aminolevulinic acid induced fluorescence endoscopy versus white light
endoscopy. J Urol, 168: 475, 2002
33. Neuzillet, Y., Methorst, C., Schneider, M. et al.: Assessment of diagnostic gain with

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hexaminolevulinate (HAL) in the setting of newly diagnosed non-muscle-invasive bladder
cancer with positive results on urine cytology. Urol Oncol, 32: 1135, 2014

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34. O'Brien, T., Ray, E., Chatterton, K. et al.: Prospective randomized trial of
hexylaminolevulinate photodynamic-assisted transurethral resection of bladder tumour
(TURBT) plus single-shot intravesical mitomycin C vs conventional white-light TURBT plus
mitomycin C in newly presenting non-muscle-invasive bladder cancer. BJU International,

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112: 1096, 2013
35. Riedl, C. R., Daniltchenko, D., Koenig, F. et al.: Fluorescence endoscopy with 5-
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36. Schumacher, M. C., Holmäng, S., Davidsson, T. et al.: Transurethral resection of non-
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under visible and fluorescent light: results of a prospective, randomised, multicentre study.
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37. Stenzl, A., Burger, M., Fradet, Y. et al.: Hexaminolevulinate guided fluorescence cystoscopy
reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol, 184: 1907,
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38. Stenzl, A., Penkoff, H., Dajc-Sommerer, E. et al.: Detection and clinical outcome of urinary
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39. Alken, P., Siegsmund, M., Gromoll-Bergmann K. et al.: A randomised controlled multicentre
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Suppl, 6: 171, 2007

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intermediate risk nonmuscle invasive bladder cancer. J Urol, 192: 305, 2014
41. Lee, J. Y., Cho, K. S., Kang, D. H. et al.: A network meta-analysis of therapeutic outcomes
after new image technology-assisted transurethral resection for non-muscle invasive bladder
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band imaging. BMC Cancer, 15: 566, 2015
42. Shen, P., Yang, J., Wei, W. et al.: Effects of fluorescent light-guided transurethral resection
on non-muscle-invasive bladder cancer: a systematic review and meta-analysis. BJU
International, 110: E209, 2012

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Comparative effectiveness of fluorescent versus white light cystoscopy for initial diagnosis
or surveillance of bladder cancer on clinical outcomes: Systematic review and meta-
analysis

Tables
Table 1. Short-term (<3 months) recurrence, stratified by tumor characteristics

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Subgroup Number of Relative risk (95% I2
trials CI)
Low risk tumors 420,25,34,35 0.48 (0.16 to 1.42) 71%

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High risk tumors 520,25,26,34,35 0.37 (0.22 to 0.63) 18%
Primary tumors 320,34,35 0.63 (0.24 to 1.66) 54%
Recurrent tumors 220,35 1.16 (0.08 to 16.0) 93%

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Solitary tumors 220,34 0.89 (0.42 to 1.89) 0%
Multiple tumors 220,34 0.45 (0.04 to 4.84) 90%

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Table 2. Strength of Evidence

Strength of
Outcome
Study Reporting Evidence
Number of

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Studies Limitations Consistency Directness Precision Bias Grade Conclusions

Fluorescent cystoscopy with 5-ALA or

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HAL was associated with decreased
risk of bladder cancer recurrence vs.

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white light cystoscopy at short-term (<3
months; 10 trials; RR, 0.59; 95% CI,
2
0.40 to 0.88; I = 69%), intermediate-

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term (3 months to <1 year; 6 trials; RR,
2
0.70; 95% CI, 0.56 to 0.88; I = 19%),

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and long-term followup (≥1 year; 12
2
Recurrence trials; RR, 0.81, 95% CI, 0.70 to 0.93; I
Moderate Inconsistent Direct Precise Suspected Low = 49%), but findings were inconsistent

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14 RCTs and potentially susceptible to
performance and publication bias.
Estimates for short- and long-term

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recurrence were statistically significant
in trials that used HAL and not

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statistically significant in trials that
used 5-ALA, but estimates were
similar and there were no statistically
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significant subgroup effects based on
the photosensitizer used.
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There was no difference between fluorescent

and white light cystoscopy in risk of
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progression to muscle-invasive bladder

Progression
Moderate Consistent Direct Precise Not detected Moderate cancer (9 trials; RR, 0.74; 95% CI, 0.52 to
2
6 RCTs 1.03; I = 0%). Fluorescent cystoscopy was
associated with decreased risk of progression
in trials that used HAL (4 trials; RR, 0.51,
2
95% CI 0.28 to 0.96, I =0%), but there was
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no statistically significant subgroup effect.

There was no difference between fluorescent

Mortality and white light cystoscopy in risk of mortality
Moderate Consistent Direct Imprecise Not detected Low

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3 RCTs (3 trials; RR, 1.28; 95% CI, 0.55 to 2.95; I2 =
43%).

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5-ALA = 5-aminolevulinic acid; CI = confidence interval; HAL = hexaminolevulinate; RR = risk ratio

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Comparative effectiveness of fluorescent versus white light cystoscopy for initial diagnosis
or surveillance of bladder cancer on clinical outcomes: Systematic review and meta-
analysis

Figures
Figure 1. Literature Flow Diagram

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Abstracts of potentially relevant articles identified through Ovid MEDLINE,
Cochrane databases*, Health Technology Assessment, National Health
Sciences Economic Evaluation Database, Database of Abstracts of Reviews
of Effects and other sources† (N=4,443)

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Excluded abstracts and

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background articles (n=4,376)

Full text articles reviewed for relevance

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to the key questions (n=67)
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Excluded Publications: 47
Wrong intervention: 3
Wrong outcome(s): 1
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Wrong study design for Key Question: 18

Wrong publication type (letter, editorial,
nonsystematic review article): 2
Non-English language, but possibly
relevant: 5
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Systematic review or meta-analysis, used

as a source document only to identify
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individual studies: 5
Case control design: 1
Included in full AHRQ evidence review, but
not relevant for this report: 12
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Included Studies
14 studies (in 20 publications)
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*Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of
Systematic Reviews.
†Other sources include prior reports, reference lists of relevant articles, systematic reviews, etc.
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Figure 2. Meta-analysis of fluorescent cystoscopy versus white light cystoscopy: Risk of bladder cancer
recurrence at short-term (<3 months) follow-up.

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Figure 3. Meta-analysis of fluorescent cystoscopy versus white light cystoscopy: Risk of bladder cancer
recurrence at intermediate term (3 months to <1 year) follow-up.

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5-ALA: 5-amimolevulinic acid; HAL: hexaminolevulinic acid

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Figure 4. Meta-analysis of fluorescent cystoscopy versus white light cystoscopy: Risk of bladder
cancer recurrence at long term (≥1 year) follow-up.

Recurrence

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Long-term
Study Relative Events, Events,

ID Risk (95% CI) Treatment Control

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ALA

Babjuk, 2005 0.83 (0.64, 1.07) 36/60 45/62

Filbeck, 2002 0.49 (0.31, 0.78) 18/88 43/103

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Schumacher, 2010 1.01 (0.78, 1.31) 63/141 61/138

Stenzl, 2011 1.22 (0.87, 1.70) 57/183 45/176

Riedl, 2001 0.79 (0.60, 1.04) 30/51 38/51

D+L Subtotal (I-squared = 65.3%, p = 0.021) 0.86 (0.68, 1.08) 204/523 232/530

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.

HAL

Dragoescu, 2011 0.40 (0.15, 1.08) 4/22 10/22

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Geavlete, 2011 0.68 (0.49, 0.95) 39/125 52/114

Hermann, 2011 0.65 (0.41, 1.02) 18/59 35/74

Karaolides, 2012 0.43 (0.20, 0.92) 7/41 18/45

O'Brien, 2013 0.89 (0.58, 1.36) 27/86 29/82

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Stenzl, 2010 0.91 (0.80, 1.03) 158/255 178/261

Gkritsios, 2014 0.82 (0.49, 1.35) 18/48 17/37

D+L Subtotal (I-squared = 41.3%, p = 0.115) 0.75 (0.62, 0.92) 271/636 339/635

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D+L Overall (I-squared = 48.9%, p = 0.028) 0.81 (0.70, 0.93) 475/1159 571/1165

Profile Likelihood, I-squared=38% Overall 0.82 (0.68, 0.93)

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NOTE: Weights are from random effects analysis

.15 1 2

Favors Flourescent Favors White Light

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5-ALA: 5-amimolevulinic acid; HAL: hexaminolevulinic acid

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Figure 5. Funnel plot for trials of fluorescent versus white light cystoscopy, short-term recurrence

Recurrence: Short-term
Funnel plot with pseudo 95% confidence limits
0

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s.e. of logRR
.5

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1

-2 -1

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logRR
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Figure 6. Meta-analysis of fluorescent cystoscopy versus white light cystoscopy: Risk of

progression to muscle invasive bladder cancer

Progression
Study Relative Events, Events,

ID Risk (95% CI) Treatment Control

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ALA

Stenzl, 2011 0.90 (0.45, 1.80) 14/183 15/176

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Riedl, 2001 0.44 (0.15, 1.35) 4/51 9/51

Babjuk, 2005 1.03 (0.32, 3.39) 5/60 5/62

Filbeck, 2002 1.59 (0.40, 6.31) 4/21 3/25

Schumacher, 2010 0.85 (0.42, 1.72) 13/141 15/138

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Subtotal (I-squared = 0.0%, p = 0.695) 0.86 (0.57, 1.28) 40/456 47/452

HAL

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Dragoescu, 2011 0.50 (0.05, 5.12) 1/22 2/22

Geavlete, 2011 0.57 (0.19, 1.69) 5/125 8/114

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Karaolides, 2012 0.22 (0.01, 4.43) 0/41 2/45

Stenzl, 2010 0.52 (0.22, 1.19) 8/271 16/280

Subtotal (I-squared = 0.0%, p = 0.951) 0.51 (0.28, 0.96) 14/459 28/461

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Overall (I-squared = 0.0%, p = 0.818) 0.74 (0.52, 1.03) 54/915 75/913

NOTE: Weights are from random effects analysis

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Favors Flourescent Favors White Light

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Figure 7. Meta-analysis of fluorescent cystoscopy versus white light cystoscopy: Risk of mortality

Study Relative Events, Events,

ID Risk (95% CI) Treatment Control

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ALA

Schumacher, 2010 1.22 (0.34, 4.46) 5/141 4/138

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D+L Subtotal (I-squared = .%, p = .) 1.22 (0.34, 4.46) 5/141 4/138

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HAL

O'Brien, 2013 6.51 (0.81, 52.15) 7/129 1/120

Stenzl, 2010 0.92 (0.62, 1.36) 39/271 44/280

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D+L Subtotal (I-squared = 70.6%, p = 0.065) 1.87 (0.29, 12.22) 46/400 45/400

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D+L Overall (I-squared = 42.8%, p = 0.174) 1.28 (0.55, 2.95) 51/541 49/538

Profile Likelihood, I-squared=Fixed Effects Overall 1.00 (0.66, 3.01)

NOTE: Weights are from random effects analysis

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Favors Fluorescent Favors White Light
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Comparative effectiveness of fluorescent versus white light cystoscopy for initial diagnosis or
surveillance of bladder cancer on clinical outcomes: Systematic review and meta-analysis

Key of Definitions for Abbreviations

Abbreviation Definition
NMIBC Non-muscle-invasive bladder cancer

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TURBT Transurethral resection of the bladder tumor
5-ALA 5-aminolevulinic acid
HAL Hexaminolevulinic acid

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SOE Strength of evidence

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Supplemental Table 1. Fluorescent cystoscopy study characteristics

Duration of
Followup and

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Setting and Study Interventions (number analyzed for Cystoscopic Population Characteristics
Author, Year Years recurrence) Followup Method by Treatment Group
Babjuk, 20051 Czech Republic A: White light and 5-ALA fluorescent Duration: 24 months Age (mean): 68 vs. 70 years

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Single center cystoscopy with TURBT (n=60) Male: 72% vs. 63%
2001-2003 Method: White light Stage: 63% vs. 60% Ta, 37%

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B: White light cystoscopy with TURBT cystoscopy vs. 40% T1
(n=62) Grade: 50% vs. 53% G1, 40%
vs. 35% G2, 10% vs. 11% G3

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All patients with G1 or G2 tumors
received adjuvant intravesical therapy;

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all patients with G3 tumors received
intravesical BCG
Dragoescu, Romania A: White light and HAL fluorescent Duration: 12 months Age (mean): 59 vs. 62 years

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20112 Single center cystoscopy with TURBT (n=22) Male: 78%
2009 Method not reported Stage: 22% vs. 18% Ta, 78%
B: White light cystoscopy with TURBT vs. 82% T1

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(n=22) Grade: 32% vs. 27% G1, 55%
vs. 64% G2, 14% vs. 9.1% G3

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All patients received postoperative
intravesical epirubicin (Farmorubicin)
and additional therapy based on risk
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group
Filbeck, 20023 Germany A: White light and 5-ALA fluorescent Duration, mean: 21 Age (median): 68 vs. 70 years
(also Denzinger Single center cystoscopy with TURBT (n=88) months Sex: Not reported
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2007a4, 1997-2000 Stage: 42% vs. 41% pTaG1,

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Denzinger B: White light cystoscopy with TURBT
2007b5) (n=103)
All patients received intravesical
prophylaxis based on AUA guidelines
according to number of tumors, stage,
and grade
Method not reported 31% vs. 28% pTaG2, 2.3%
vs. 1.0% pTaG3, 7.9% vs.
13% pT1G2, 11.4% vs. 11.7%
pT1G3, 5.7% vs. 4.9% CIS
Risk group: 35% vs. 48% low,
46% vs. 34% intermediate,
19% vs. 18% high

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Duration of
Followup and
Setting and Study Interventions (number analyzed for Cystoscopic Population Characteristics
Author, Year Years recurrence) Followup Method by Treatment Group

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Geavlete, Romania A: White light and HAL fluorescent Duration: 6 weeks Age (mean): 64 years
20106 Single center cystoscopy with TURBT (n=223) (overall)
2007-2009 Method: White light Male: 73% (overall)

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B: White light cystoscopy (n=223) cystoscopy Stage: 10% vs. 8.1% CIS,
51% vs. 47% pTa, 17% vs.
All patients received single, immediate 17% pT1, 14% vs. 15% MIBC

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postoperative MMC instillation Grade (for Ta and T1 tumors):
40% vs. 40% G1, 41% vs.
41% G2, 19% vs. 19% G3

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Geavlete, Romania A: White light and HAL fluorescent Duration: 2 years Age (mean): 67 years
20117 Single center cystoscopy with TURBT (n=125) (overall)

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Study years not Method: White light Male: 74% (overall)
reported B: White light cystoscopy and TURBT cystoscopy Stage: 11% vs. 8.3% CIS,
(n=114) 45% vs. 41% pTa, 19% vs.

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18% pT1
All patients received single, immediate Grade: Not reported

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postoperative MMC instillation
Gkritsios, 20148 Greece A: White light and HAL fluorescent Duration: up to 40 Age (mean): 66 vs. 68 years

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Single center cystoscopy with TURBT (n=48) months (mean not Male: 80% vs. 73%
Study years not reported) Stage: 76% vs. 70% Ta, 24%
reported B: White light cystoscopy (n=37) vs. 30% T1 and CIS
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Method: White light Grade: 85% vs. 73% low
All patients received single instillation of cystoscopy grade, 15% vs. 27% high
epirubicin 50 mg immediately following grade and CIS
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Duration of
Followup and
Setting and Study Interventions (number analyzed for Cystoscopic Population Characteristics
Author, Year Years recurrence) Followup Method by Treatment Group

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Hermann, Denmark A: White light and HAL fluorescent Duration: 12 months Age (mean): 71 vs. 69 years
20119 Multicenter cystoscopy with TURBT (n=59) Male: 75%
Study years not Method: White light Stage and grade: 84% vs.

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reported B: White light cystoscopy (n=74) cystoscopy 90% Ta low grade, 12% vs.
6% Ta high grade, 0% T1 low
No patient received intravesical therapy grade, 2% vs. 4% T1 high

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immediately after TURBT, 3 patients in grade
each arm had previously received MMC
and 21 patients BCG (10 in arm A and

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11 in arm B)
Karaolides, Greece A: White light and HAL fluorescent Duration: 18 months Age (mean): 66 vs. 64 years

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201210 Single center cystoscopy with TURBT (n=41) Male: 80% vs. 89%
2008-2010 Method: White light Stage and grade: 12% vs.
B: White light cystoscopy with TURBT cystoscopy 6.7% CIS, 22% vs. 31% high

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(n=45) grade, 63% vs. 60% low
grade, 2.4% vs. 2.2% low

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Patients with moderate and high risk malignant potential
tumors received epirubicin 6 weeks

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after TURBT, or BCG
Kriegmair, Austria A: White light and 5-ALA fluorescent Duration: 10 to 14 Age (mean): 69 vs. 70 years
200211 Multicenter cystoscopy with TURBT (n=52) days Male: 82% vs. 70%
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1997-1998 Stage: 4.6% vs. 6.2% CIS,
B: White light cystoscopy with TURBT Method: Not 55% vs. 47% Ta, 18% vs.
(n=49) reported 20% T1, 7.7% vs. 16% T2
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Grade: 32% vs. 12% G1, 32%

Additional treatments not reported vs. 42% G2, 9.2% vs. 12% G3
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Duration of
Followup and
Setting and Study Interventions (number analyzed for Cystoscopic Population Characteristics
Author, Year Years recurrence) Followup Method by Treatment Group

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Neuzillet, France A: White light and 5-ALA fluorescent Duration: 4 to 6 Age (mean): 74 vs. 74 years
201412 Two centers cystoscopy with TURBT (n=43) weeks Male: 89% vs. 87%
Study years not Stage and grade (based on

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reported B: White light cystoscopy with Method: White Ta, Ta, and Tis only): 14%
TURBT (n=50) light and HAL vs. 5.4% Tia, 69% vs. 86%
fluorescent Ta-T1 high-grade, 17% vs.

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Additional treatments not reported cystoscopy 18% with associated CIS
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O'Brien, 2013 UK A: HAL fluorescent cystoscopy with Duration: 12 months Age (mean): 68 vs. 68 years
Single center TURBT (n=86) Male: 74% vs. 73%

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2005-2010 Method: Not Stage and grade: 57% vs.
B: White light cystoscopy with TURBT reported 50% G1pTa or G2 (low grade)

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(n=82) pTa/pT1; 17% vs. 13% G2
(high grade) pTa or G3pTa;
All patients received single shot 25% vs. 36% G2 (high grade)

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intravesical MMC, BCG for grade pTa or G3pT1; 14% vs. 26%
tumors or CIS secondary CIS

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Riedl, 200114 Germany A: 5-ALA fluorescent cystoscopy with Duration: 60 months Age (mean): 70 vs. 67 years
(also Multicenter TURBT (n=51) (median 42 vs. 39 Male: 71% vs. 73%

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Daniltchenko, 1998-2000 months) Stage: 78% vs. 78% Ta, 22%
200515) B: White light cystoscopy with TURBT vs. 22% T1
(n=51) Method: ALA Grade: 18% vs. 14% G1, 69%
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fluorescent vs. 76% G2, 14% vs. 9.8% G3
MMC for pTa and pT1G1-2, BCG for cystoscopy
pT1G3, CIS, and failed MMC
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Duration of
Followup and
Setting and Study Interventions (number analyzed for Cystoscopic Population Characteristics
Author, Year Years recurrence) Followup Method by Treatment Group

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Schumacher, Sweden A: White light and 5-ALA fluorescent Duration: 12 months Age (mean): 70 vs. 69 years
201016 Multicenter cystoscopy with TURBT (n=141) Male: 73% vs. 75%
2002-2005 Method: White light Stage and grade: 0.7% vs.

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B: White light cystoscopy with TURBT cystoscopy 4.3% CIS, 55% vs. 48%
(n=138) pTaG1-2, 12% vs. 10%
pTaG3 or pT1G1-2, 4.3% vs.

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Patients received BCG for CIS, pTaG3, 5.1% pT1G3, 0.7% vs. 3.6%
and pT1G2-3 starting 4 weeks after pT2
TURBT

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Stenzl, 201017 USA, Canada, and A: White light cystoscopy following Duration: 9 months, Age (mean): 68 vs. 70 years
(also Grossman Europe instillation of HAL, followed by second additional followup Male: 78% vs. 79%

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201218) Multicenter randomization: to median of 53-55 Stage: 72% vs. not reported
Study years not a: Fluorescent cystoscopy and TURBT months Ta, 17% vs. not reported T1,
reported (n=271) 11% vs. not reported CIS

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b: TURBT without fluorescent Method: White light Grade: Not reported
cystoscopy (excluded from recurrence cystoscopy

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analysis, n unclear)

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B: White light cystoscopy and TURBT
(n=280)
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Intravesical BCG for high grade T1 or
CIS
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Duration of
Followup and
Setting and Study Interventions (number analyzed for Cystoscopic Population Characteristics
Author, Year Years recurrence) Followup Method by Treatment Group
Stenzl, 201119

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Italy A: White light and fluorescent Duration: 12 months Age (mean): 66 years
Multicenter cystoscopy with TURBT following (overall)
2009-2010 instillation of 5-ALA (n=183) Method: White light Male: 72% (overall)

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cystoscopy Stage and grade: 33% vs.
B: White light and fluorescent 28% pTaG1, 19% vs. 20%
cystoscopy with TURBT following pTaG2, 1.1% vs. 0% pTaG3,

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instillation of placebo (n=176) 1.1% vs. 0.6% pT1G1, 8.7%
vs. 8.5% pT1G2, 10% vs.
CIS, pTaG3, or pT1G2-3 received BCG 31% pT1G3, 5.5% vs. 4.5%

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4 weeks after TURBT pT2, 1.6% vs. 1.7% isolated
CIS

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5-ALA = 5-aminolevulinic acid; AUA = American Urological Association; BCG = bacillus Calmette-Guérin; CIS = carcinoma in situ; G1 = Grade 1; G2 = Grade 2; G3 = Grade 3;
HAL = hexaminolevulinate; MMC = Mitomycin C; pT1 = Tumor stage 1 determined by pathology; pTa = Tumor stage a determined by pathology; T1 = Tumor stage 1; Ta =
Tumor stage a; TURBT = transurethral resection of the bladder tumor

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Supplemental Table 2. Fluorescent cystoscopy results summary

Interventions (number
Author, Year analyzed for recurrence) Recurrence Progression Mortality
5-ALA fluorescent cystoscopy

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Babjuk, 20051 A: White light and 5-ALA Short-term: 8.3% (5/60) vs. 8.3% (5/60) vs. 8.1% Not reported
fluorescent cystoscopy 37% (23/62) (5/62)
with TURBT (n=60) Long-term: 60% (36/60) vs.

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B: White light cystoscopy 73% (45/62)
with TURBT (n=62)

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Filbeck, 20023 A: White light and 5-ALA Long-term: 20% (18/88) vs. 19% (4/21) vs. 12% (3/25) Not reported
(also Denzinger fluorescent cystoscopy 42% (43/103)
2007a4, with TURBT (n=88)

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Denzinger B: White light cystoscopy
2007b5) with TURBT (n=103)

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Progression analysis
restricted to patients with

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T1 high grade lesions on
initial cystoscopy
Kriegmair, A: White light and 5-ALA Short-term: 52% (27/52) vs. Not reported Not reported

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200211 fluorescent cystoscopy 54% (26/49)

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with TURBT (n=52)
B: White light cystoscopy
with TURBT (n=49)
Riedl, 200114
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A: 5-ALA fluorescent Short-term: 20% (10/51) vs. 7.8% (4/51) vs. 18% (9/51) Not reported
(also cystoscopy with TURBT 47% (24/51)
Daniltchenko, (n=51) Intermediate term: 29%
200515)
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B: White light cystoscopy (15/51) vs. 53% (27/51)

with TURBT (n=51) Long-term: 59% (30/51) vs.
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75% (38/51)
Schumacher, A: White light and 5-ALA Long-term: 45% (63/141) 9.2% (13/141) vs. 11% 3.5% (5/141) vs. 2.9%
201016 fluorescent cystoscopy vs. 44% (61/138) (15/138) (4/138)
with TURBT (n=141)
B: White light cystoscopy
with TURBT (n=138)

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Interventions (number
Author, Year analyzed for recurrence) Recurrence Progression Mortality
Stenzl, 201119 A: White light and Short-term: 65% (24/37) vs. 7.7% (14/183) vs. 8.5% Not reported
fluorescent cystoscopy 47% (17/36) (15/176)

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with TURBT following Long-term: 31% (57/183)
instillation of 5-ALA vs. 26% (45/176)
(n=183)

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B: White light and
fluorescent cystoscopy
with TURBT following

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instillation of placebo
(n=176)
HAL fluorescent cystoscopy

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Dragoescu, A: White light and HAL Short-term: 4.5% (1/22) vs. 4.5% (1/22) vs. 9.1% Not reported
20112

fluorescent cystoscopy
with TURBT (n=22)
B: White light cystoscopy
with TURBT (n=22)
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14% (3/22) (2/22)
Intermediate-term: 9.1%
(2/22) vs. 23% (5/22)
Long-term: 18% (4/22) vs.

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45% (10/22)
Geavlete, 20106 A: White light and HAL Short-term: 11% (8/72) vs. Not reported Not reported

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fluorescent cystoscopy 31% (20/64)
with TURBT (n=223)

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B: White light cystoscopy
(n=223)
Geavlete, 20117 A: White light and HAL Short-term: 7.2% (9/125) 2.4% (3/125) vs. 4.4% Not reported
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fluorescent cystoscopy vs. 16% (18/114) (5/114) at 1 year, 4%
with TURBT (n=125) Intermediate term: 12% (5/125) vs. 7% (8/114) at 2
B: White light cystoscopy (15/125) vs. 22% (25/114) years
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and TURBT (n=114) Long-term: 31% (39/125)

vs. 46% (52/114)
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Gkritsios, 20148 A: White light and HAL Intermediate-term: 8.3% Not reported Not reported
fluorescent cystoscopy (4/48) vs. 11% (4/37)
with TURBT (n=48) Long-term: 38% (18/48) vs.
B: White light cystoscopy 46% (17/37)
(n=37)

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Interventions (number
Author, Year analyzed for recurrence) Recurrence Progression Mortality
Hermann, 20119 A: White light and HAL Intermediate-term: 17% Not reported Not reported
fluorescent cystoscopy (10/59) vs. 31% (23/74)

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with TURBT (n=59) Long-term: 31% (18/59) vs.
B: White light cystoscopy 47% (35/74)
(n=74)

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Karaolides, A: White light and HAL Short-term: 2.4% (1/41) vs. 0% (0/41) vs. 4.4% (2/45) Not reported
201210 fluorescent cystoscopy 13% (6/45)
with TURBT (n=41) Long-term: 17% (7/41) vs.

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B: White light cystoscopy 40% (18/45)
with TURBT (n=45)
Neuzillet, 201412 A: White light and HAL Short-term: 47% (20/43) Not reported Not reported

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fluorescent cystoscopy vs. 52% (26/50)
with TURBT (n=43)

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B: White light
cystoscopy with TURBT
(n=50)

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O'Brien, 2013 A: HAL fluorescent Short-term: 20% (17/86) vs. Not reported 5.4% (7/129) vs. 0.8%
cystoscopy with TURBT 17% (14/82) (1/120)

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(n=86) Long-term: 31% (27/86) vs.
B: White light cystoscopy 35% (29/82)

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with TURBT (n=82)
Stenzl, 201020 A: White light cystoscopy Intermediate-term: 47% 1.8% (5/271) vs. 2.5% Mortality: 1.4% (5/365)
(also Grossman following instillation of (128/271) vs. 56% (7/280) vs. 1.4% (5/361) at 9
EP
201218) HAL, followed by second (157/280) months, 14% (39/271)
US, Canada, and randomization: a: Long-term: 38% (97/255) vs. 16% (44/280) at
Europe Fluorescent cystoscopy vs. 32% (83/261) median 53 to 55 months
C

and TURBT (n=271) b: Bladder cancer

TURBT without mortality: 2.2% (6/271)
AC

fluorescent cystoscopy vs. 2.9% (8/280)

(excluded from recurrence
analysis, n unclear)
B: White light cystoscopy
and TURBT (n=280)
5-ALA = 5-aminolevulinic acid; HAL = hexaminolevulinate; TURBT = transurethral resection of the bladder tumor

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Supplemental Table References

1. Babjuk, M., Soukup, V., Petrik, R. et al.: 5-aminolaevulinic acid-induced fluorescence

cystoscopy during transurethral resection reduces the risk of recurrence in stage Ta/T1
bladder cancer. BJU International, 96: 798, 2005
2. Dragoescu, O., Tomescu, P., Panus, A. et al.: Photodynamic diagnosis of non-muscle
invasive bladder cancer using hexaminolevulinic acid. Rom J Morphol Embryol, 52: 123,

PT
2011
3. Filbeck, T., Pichlmeier, U., Knuechel, R. et al.: Clinically relevant improvement of
recurrence-free survival with 5-aminolevulinic acid induced fluorescence diagnosis in

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patients with superficial bladder tumors. J Urol, 168: 67, 2002
4. Denzinger, S., Burger, M., Walter, B. et al.: Clinically relevant reduction in risk of
recurrence of superficial bladder cancer using 5-aminolevulinic acid-induced

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fluorescence diagnosis: 8-year results of prospective randomized study. Urology, 69:
675, 2007
5. Denzinger, S., Wieland, W. F., Otto, W. et al.: Does photodynamic transurethral resection

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of bladder tumour improve the outcome of initial T1 high-grade bladder cancer? A long-
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6. Geavlete, B., Jecu, M., Multescu, R. et al.: HAL blue-light cystoscopy in high-risk
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M

7. Geavlete, B., Multescu, R., Georgescu, D. et al.: Treatment changes and long-term
recurrence rates after hexaminolevulinate (HAL) fluorescence cystoscopy: does it really
make a difference in patients with non-muscle-invasive bladder cancer (NMIBC)? BJU
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International, 109: 549, 2011

8. Gkritsios, P., Hatzimouratidis, K., Kazantzidis, S. et al.: Hexaminolevulinate-guided
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transurethral resection of non-muscle-invasive bladder cancer does not reduce the

recurrence rates after a 2-year follow-up: a prospective randomized trial. Int Urol
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9. Hermann, G. G., Mogensen, K., Carlsson, S. et al.: Fluorescence-guided transurethral
EP

resection of bladder tumours reduces bladder tumour recurrence due to less residual
tumour tissue in Ta/T1 patients: a randomized two-centre study. BJU International, 108:
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C

10. Karaolides, T., Skolarikos, A., Bourdoumis, A. et al.: Hexaminolevulinate-induced

fluorescence versus white light during transurethral resection of noninvasive bladder
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tumor: does it reduce recurrences? Urology, 80: 354, 2012

11. Kriegmair, M., Zaak, D., Rothenberger, K. H. et al.: Transurethral resection for bladder
cancer using 5-aminolevulinic acid induced fluorescence endoscopy versus white light
endoscopy. J Urol, 168: 475, 2002
12. Neuzillet, Y., Methorst, C., Schneider, M. et al.: Assessment of diagnostic gain with
hexaminolevulinate (HAL) in the setting of newly diagnosed non-muscle-invasive
bladder cancer with positive results on urine cytology. Urol Oncol, 32: 1135, 2014
13. O'Brien, T., Ray, E., Chatterton, K. et al.: Prospective randomized trial of
hexylaminolevulinate photodynamic-assisted transurethral resection of bladder tumour

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(TURBT) plus single-shot intravesical mitomycin C vs conventional white-light TURBT

plus mitomycin C in newly presenting non-muscle-invasive bladder cancer. BJU
International, 112: 1096, 2013
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aminolevulinic acid reduces early recurrence rate in superficial bladder cancer. J Urol,
165: 1121, 2001

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15. Daniltchenko, D. I., Riedl, C. R., Sachs, M. D. et al.: Long-term benefit of 5-
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16. Schumacher, M. C., Holmang, S., Davidsson, T. et al.: Transurethral resection of non-

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muscle-invasive bladder transitional cell cancers with or without 5-aminolevulinic Acid
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study. Eur Urol, 57: 293, 2010

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17. Stenzl, A., Burger, M., Fradet, Y. et al.: Hexaminolevulinate guided fluorescence
cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J
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18. Grossman, H. B., Stenzl, A., Fradet, Y. et al.: Long-term decrease in bladder cancer
recurrence with hexaminolevulinate enabled fluorescence cystoscopy. J Urol, 188: 58,
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19. Stenzl, A., Penkoff, H., Dajc-Sommerer, E. et al.: Detection and clinical outcome of
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multicenter randomized, double-blind, placebo-controlled trial. Cancer, 117: 938, 2011

20. Stenzl, A., Burger, M., Fradet, Y. et al.: Hexaminolevulinate guided fluorescence
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Urol, 184: 1907, 2010

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