Review – Bladder Cancer

Immediate Post–Transurethral Resection of Bladder Tumor

Intravesical Chemotherapy Prevents Non–Muscle-invasive

Bladder Cancer Recurrences: An Updated Meta-analysis on

2548 Patients and Quality-of-Evidence Review

Nathan Perlis a,b,c,*, Alexandre R. Zlotta a,b,d, Joseph Beyene c,e, Antonio Finelli a,b,f,Neil E. Fleshner a,b,f, Girish S. Kulkarni a,b,g

a University Health Network, Toronto, Ontario, Canada; b University of Toronto, Department of Surgery, Division of Urology, Toronto, Ontario, Canada;c Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; d Mount Sinai Hospital, Department of Surgery,

Division of Urology, Toronto, Ontario, Canada; e Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada;f Institute of Medical Science, University of Toronto, Ontario, Canada; g Institute for Clinical Evaluative Sciences, University of Toronto, Ontario, Canada

E U R O P E A N U R O L O G Y 6 4 ( 2 0 1 3 ) 4 2 1 – 4 3 0

ava i lable at www.sciencedirect .com

journal homepage: www.europeanurology.com

Article info

Article history:

Accepted June 7, 2013Published online ahead ofprint on June 18, 2013

Keywords:

Bladder cancer

Chemotherapy

Disease prevention

Single instillation

Systematic review

Abstract

Context: Non–muscle-invasive bladder cancer (NMIBC) commonly recurs, requiringinvasive and costly transurethral resection of bladder tumor (TURBT). A meta-analysisof seven trials published in 2004 demonstrated that intravesical chemotherapy (IVC)following TURBT reduces recurrences. Despite European Association of Urology en-dorsement, adoption of this practice has been modest.Objective: To investigate whether immediate postoperative IVC prolongs the recurrence-free interval (RFI) and early recurrences (ERs) in light of new trial data and to explore thequality of evidence supporting its use.Evidence acquisition: A systematic literature review of random controlled trials (RCTs)published before March 2013 was performed using the Medline, Embase, and Cochranedatabases. Trials examining NMIBC recurrence for adults receiving IVC immediatelyfollowing TURBT were included. RFI was estimated by hazard ratio (HR), and ER wasestimated by absolute risk reduction (ARR) of recurrences within 1 yr of TURBT. Bothoutcomes were synthesized using random-effects models. Risk of bias was assessedusing the Cochrane Collaboration risk-of-bias tool, and quality of evidence for eachoutcome was assessed using the Grading of Recommendations, Assessment, Develop-ment, and Evaluation system.Evidence synthesis: Thirteen studies with 2548 patients were included. IVC prolongedRFI by 38% (HR: 0.62; 95% confidence interval [CI], 0.50–0.77; p < 0.001; I2: 69%), and ERswere 12% less likely in the intervention population (ARR: 0.12; 95% CI, �0.18 to �0.06;p < 0.001, I2: 0%). The number needed to treat to prevent one ER was 9 (95% CI,6–17 patients). There was high risk of bias present in 12 of 13 publications. Qualityof evidence for RFI was very low and low for ERs.Conclusions: Our updated meta-analysis supports that IVC prolongs RFI and reduces ERsof NMIBC when administered immediately after TURBT. However, contemporary meth-odology suggests low evidence quality for examined outcomes. Thus RCTs with carefulrandomization and blinding are still warranted to clarify the usefulness of immediatepostoperative IVC in this population.

# 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Division of Urology, Department of Surgical Oncology, Princess MargaretHospital, University Health Network, 610 University Avenue, M5G 2M9, Toronto, Ontario, Canada.Tel. +1 416 946 4501, ext. 3698; Fax: +1 416 598 9997.E-mail addresses: Nathan.perlis@utoronto.ca, nathan.perlis@gmail.com (N. Perlis).

0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.eururo.2013.06.009

1. Introduction

Bladder cancer (BCa) is the most expensive solid tumor to

treat mainly due to the high recurrence rate of its non–

muscle-invasive form (confined to the urothelium [Ta] or

lamina propria [T1]) [1]. Many non–muscle-invasive BCas

(NMIBCs) are amenable to treatment with transurethral

resection of bladder tumor (TURBT) alone. However,

despite the therapeutic impact of TURBT, BCa recurrence

rates can be as high as 80% [2]. Attempts have been made

to decrease these high recurrence rates and consequently

their associated costs.

It is hypothesized that one of the mechanisms for

early recurrence of NMIBC following TURBT is implanta-

tion of floating cancers cells into the bladder urothelium

following resection [3]. To address this so-called

seeding phenomenon, many investigators have utilized

an immediate postoperative instillation of intravesical

chemotherapy (IVC) to eradicate any free-floating cancer

cells after a complete TURBT [4]. Evidence supporting

such a practice was strengthened in 2004 by Sylvester

et al., who performed a meta-analysis incorporating all

immediate postoperative chemoprophylaxis trials pub-

lished to date [5]. They demonstrated a significant

improvement in the likelihood of recurrence for NMIBC

patients who received IVC after TURBT. The number

needed to treat (NNT) to prevent one NMIBC recurrence

was 8.5.

Despite the published evidence favoring postoperative

chemoprophylaxis, its adoption has been modest

because many urologists are reluctant to use it [6]. Cited

reasons for nonadherence include burden of extra

postoperative nursing care and coordination difficulties

between operating room, pharmacy, and recovery room

[6]. Critics of IVC believe that NMIBC recurrences can be

managed with simple office-based fulguration [7]. Some

trials suggest that the benefit of IVC may be limited

to a select subset of patients with small tumors [8]. A

more current review without meta-analysis from

2009 estimates that IVC chemotherapy may have a

NNT closer to 20 for NMIBC recurrence prevention [9].

Both the American Urological Association and the

European Association of Urology guidelines continue to

recommend immediate post-TURBT IVC for suspected

NMIBC [10,11].

Due to the ongoing conflict between the available

synthesized data and the practices of urologists and the

large number of studies performed since the first meta-

analysis in 2004, we believed an updated meta-analysis

with robust methodology was required. Our primary

objective was to synthesize current evidence-based

data regarding the use of immediate post-TURBT IVC in

NMIBC by (1) investigating the impact of postoperative IVC

on recurrence-free interval (RFI) and early recurrences

(ERs) in light of newly published clinical trial data, and

(2) exploring the quality of evidence available in the

included studies.

2. Evidence acquisition

2.1. Criteria for study inclusion/exclusion

2.1.1. Studies

Randomized controlled trials (RCTs) published in any

language were eligible for inclusion. Abstracts from RCTs

were eligible for inclusion only if adequate data (as defined

by inclusion criteria below) were available.

2.1.2. Participants

Patient-level inclusion criteria included age (adults �18 yr),

and histology showing pathologically confirmed urothelial or

transitional cell carcinoma. Other histologic subtypes of BCa

(eg, squamous, adenocarcinoma) were excluded because

they are rare, portend worse outcomes, and are not typically

managed with IVC [12]. Tumor characteristics included

pathologically confirmed low-grade (previously G1 or G2)

and low-stage BCa (Ta or T1). Patients with any component of

carcinoma in situ (CIS), muscle invasion, or metastatic

disease were not eligible.

2.1.3. Interventions

Intervention-level inclusion criteria were determined based

on the following categories:

� Chemotherapy: Trials using any IVC were included. Those

trials examining alternative routes of administration

(ie, intravenous, oral, intramuscular injection) were

excluded.

� Timing: IVC administration within 24 h following TURBT.

� Other interventions: Trial arms with any mandated

additional interventions aside from placebo IVC were

excluded.

2.1.4. Outcomes

Studies were only included if they contained at least one of

the following primary outcome measures: RFI following

randomization as measured by hazard ratio (HR) and/or ER

within 1 yr of randomization as measured by absolute risk

reduction (ARR; also termed risk difference). Recurrences

were identified by cystoscopy and biopsy.

Data on the these secondary outcomes were also

collected: ARR of progression to muscle-invasive BCa

during follow-up, and relative risk of severe adverse events

defined by either a modified Clavien grading classification

�2 or as defined in the trial protocol [13]. Summary data

on nonsevere adverse events were also collected and

tabulated.

2.2. Search methods for identification of studies

Electronic searches were carried out using the Medline,

Embase, and Cochrane databases for trials published before

March 2013. The search was assisted by a professional

librarian with extensive experience in searching methodol-

ogy for systematic reviews. A detailed search strategy is

E U R O P E A N U R O L O G Y 6 4 ( 2 0 1 3 ) 4 2 1 – 4 3 0422

presented in Appendix A where the following four concepts

were combined: BCa or therapeutic irrigation, cancer

recurrences or prevention or prophylaxis, antineoplastic

agents, and controlled clinical trials or meta-analysis or

observational.

References from review articles, meta-analyses, and

trials relating to our study topic were reviewed and cross-

referenced to ensure completeness of our literature search.

Conference abstracts from the American and European

urologic association meetings were also searched.

2.3. Data extraction and management

2.3.1. General

Two reviewers (N.P., G.S.K.) performed study selection

(k = 0.92) (Fig. 1). Disagreements were resolved by discus-

sion and consensus. Titles and abstracts were used to screen

for initial study inclusion. Full-text review was carried out

on the remaining papers that matched inclusion/exclusion

criteria. The same reviewers performed all data extraction

including evaluating study characteristics and outcome

data. Disagreements were resolved by consensus. A data

collection form was designed and pilot-tested to ensure

completeness and agreement for the first three studies. If

trials had multiple publications, publications with the

longest follow-up were used and older publications were

accessed to clarify methods if required.

2.3.2. Assessment of risk of bias in included studies

The Cochrane Collaboration’s tool for assessing risk of bias,

which includes selection, performance, attrition, detection,

and reporting bias, was used to assess risk of bias for each

included study [14]. It is specifically designed for assessing

bias in RCTs and addresses sequence generation, allocation

concealment, blinding, handling of incomplete data, and

selective reporting. As per Cochrane guidelines, for a study

to achieve a global low risk score, all key domains (in our

study sequence generation, allocation concealment, and

blinding) must be low risk. If any single domain was

high risk, the study was automatically graded high risk on

the global scale [15].

2.3.3. Measures of treatment effect

Treatment effect was measured using RFI time-to-event

data from Kaplan-Meier curves. Where HR and 95%

confidence intervals (CIs) were not available, they were

approximated using the method of Parmar et al. [16]. ARR

was used to evaluate ERs and disease progression.

2.4. Heterogeneity and reporting bias

The Q test was used to evaluate statistical heterogeneity

( p < 0.10). The I2 statistic was used to assess between-study

heterogeneity’s contribution to overall heterogeneity [17].

Funnel plots were generated to assess the possibility of

publication bias using established methods [18].

2.5. Data synthesis

2.5.1. Primary outcomes

Meta-analysis was performed for prespecified outcomes

and stratified data when sufficient data were available. The

Cochrane Collaboration RevMan (v.5) software was used for

statistical analyses. Acknowledging the clinical heteroge-

neity inherent in our sample with several different study

medications, random-effects models were used for all

meta-analyzed data. Weighting was performed using the

inverse variance method except for one secondary outcome,

disease progression, where Mantel-Haenszel weighting was

used because of its superior ability to handle rare events

[19].

2.5.2. Subgroup analysis

Four a priori subgroups were planned for data stratification

by intervention drug, tumor risk, placebo use in control

group, and continuous bladder irrigation (CBI) use in trial.

[(Fig._1)TD$FIG]

Total citationsn = 4929

Studiesincludedn = 13

Duplicate citationsn = 1878

Full-text reviewn = 36

Unique citationsn = 3051

Excluded followingabstract reviewn = 3015

Excluded followingfull-text review

n = 23

761 – Basic science 680 – Nontrial/review 658 – Non-BCa focused 576 – MIBC 239 – Long-term course IVC 101 – Irrigation nontrial

12 – No control group 4 – Long-term IVC 3 – Oral chemotherapy 2 – Non-RCT 1 – Non-chemotherapy 1 – No early recurrences or RFI outcome available

Fig. 1 – Flow diagram outlining search results and final included and excluded studies. BCa = bladder cancer; MIBC = muscle-invasive bladder cancer;IVC = intravesical chemotherapy; RCT = randomized controlled trial; RFI = recurrence-free interval.

E U R O P E A N U R O L O G Y 6 4 ( 2 0 1 3 ) 4 2 1 – 4 3 0 423

Tumor risk was defined by inclusion criteria where studies

enrolling patients with more than two high-risk inclusion

criteria (high-grade, multiple, recurrent, or tumors >3 cm)

[10] were deemed higher risk. The remaining studies were

deemed lower risk. The presence of CIS was not included in

this definition because CIS was an exclusion criterion for

study involvement, and tumor stage was not included

because no trials included T2 tumors. Because CBI was not

typically described in the papers or RCT protocols, authors

and institutions were contacted via e-mail and telephone to

clarify its use in each trial.

2.6. Quality-of-evidence assessment

Evidence quality was judged using the Grading of Recom-

mendations, Assessment, Development, and Evaluation

(GRADE) system [20]. In this approach, scores for evidence

quality are generated separately for each outcome. For

systematic reviews of RCTs, evidence is initially assumed to

be of high quality. However, scores can be downgraded to

moderate, low, or very low based on the presence of biased

study design, indirectness of evidence, unexplained het-

erogeneity or inconsistency, imprecision, and publication

bias in included studies [21]. GRADEpro v.3.6 software was

used to generate GRADE evidence profiles and tables

summarizing findings.

3. Evidence synthesis

3.1. Literature search

A total of 3051 unique citations were obtained from our

literature search (Fig. 1). After the title and abstract review,

36 studies were examined in detail. Of the 13 included

studies, 9 contained RFI data only, 2 contained ER data only,

and 2 contained both (Table 1). One study was published in

Turkish [32], which was translated with the help of

language translation software. Twenty-three full-text

reviewed publications did not meet the inclusion criteria

(Appendix B).

Appendix C presents the details of quality assessment,

as measured by the Cochrane Collaboration risk-of-bias

tool. Overall, although most trials were free of selective

reporting, few adequately detailed randomization, and only

one trial had adequate blinding of key study personnel and

patients (Fig. 2). Only one trial, Bohle et al. [31], met the

criteria for low overall risk of bias. The remaining trials were

assessed as exhibiting high risk of bias.

A combined 2548 patients were included in all trials

(mean: 196). Six different study drugs were used across the

trials, although 9 of 13 trials (69%) used mitomycin C (MMC)

or epirubicin, both of which are DNA-targeting antitumor

antibiotics. Only four trials (31%) used placebo, and only

three (23%) explicitly detailed CBI use. Although there were

differences in study drugs between trials, patient factors,

tumor characteristics, and study design were similar

enough to justify aggregating data for meta-analysis.

3.2. Effects of interventions

3.2.1. Primary outcome: recurrence-free interval

IVC instillation prolonged RFI by 38% (HR: 0.62; 95% CI,

0.50–0.77; p < 0.001) in those patients receiving interven-

tion within 24 h of TURBT compared with controls (Fig. 3).

Significant ( p < 0.001) statistical between-study heteroge-

neity was present, with 69% of variance secondary to

between-study differences (I2: 69%). The overall RFI

improvement with IVC did not significantly change in a

sensitivity analysis where studies whose HRs were attained

with the Parmar method (HR: 0.58; 95% CI, 0.40–0.83;

p < 0.001) were removed.

Stratification by study drug demonstrated RFI improve-

ment for both MMC (three trials; HR: 0.49; 95% CI,

0.28–0.88; p < 0.001; I2: 82%) and epirubicin (four trials;

Table 1 – Randomized controlled trials included in meta-analysis comparing immediate postoperative intravesical chemotherapy withcontrol

Study Totalno. of

patients

Tumorrisk

Interventiondrug and dose

Placebo CBI Blinding Medianfollow-up

Primaryoutcomemeasure

Oosterlinck et al. [22] 399 Higher risk Epirubicin 80 mg Water 24 h No 2 (mean) RFI

Fujita [23] 90 Higher risk Peplomycin 80 mg None Not specified No 2.25 (mean) RFI

Medical Research

Council report [24]

246 Higher risk Thiotepa 30 mg None Discretion of physician No 8.75 RFI

Tolley et al. [25] 306 Higher risk MMC 40 mg None Discretion of physician No 7 RFI

Solsona et al. [26] 121 Lower risk MMC 30 mg None No No 7.83 RFI and ERs

Rajala et al. [27] 134 Higher risk Epirubicin 100 mg None 2 h

Control only

No 6 RFI

Okamura et al. [28] 170 Higher risk THP-doxorubicin 30 mg None No No 3.4 RFI

El-Ghobashy et al. [29] 63 Lower risk MMC 30mg None Not specified No 3.66 (mean) ERs

Berrum-Svennung

et al. [30]

307 Lower risk Epirubicin 50 mg NS Discretion of physician Partial NR RFI

Gudjonsson et al. [8] 219 Higher risk Epirubicin 80 mg None Discretion of physician No 3.9 RFI

Bohle et al. [31] 248 Higher risk Gemcitabine 2 g NS 20 h Yes 2 RFI

Tatar et al. [32] 43 Higher risk MMC 40 mg NS or

Water

No No 1 ERs

De Nunzio et al. [33] 202 Lower risk MMC 40 mg None 12 h Partial 7.5 RFI and ERs

CBI = continuous bladder irrigation (with saline); ERs = early recurrences; NS = normal saline; RFI = recurrence-free interval.

E U R O P E A N U R O L O G Y 6 4 ( 2 0 1 3 ) 4 2 1 – 4 3 0424

HR: 0.65; 95% CI, 0.55–0.77; p < 0.001; I2: 0%). Differences

in effect size between subgroups was not statistically

significant ( p = 0.38).

Stratification by tumor risk category demonstrated RFI

improvement for both lower risk tumors (three trials; HR:

0.51; 95% CI, 0.28–0.90; p = 0.003; I2: 83%) and higher risk

tumors (eight trials; HR: 0.66; 95% CI, 0.52–0.84; p = 0.006;

I2: 64%). Differences in effect size between subgroups was

not statistically significant ( p = 0.41).

When RFI was stratified by placebo use, trials without

placebo demonstrated a 44% reduction in RFI (HR: 0.56; 95%

CI, 0.41–0.76; p < 0.001; I2: 75%), whereas those that

used placebo demonstrated a 25% reduction in RFI (HR:

0.75; 95% CI, 0.61–0.91; p = 0.004; I2: 4%). Differences in

effect size between subgroups was not statistically signifi-

cant ( p = 0.12).

Data regarding CBI use were obtained for 11 of the

13 trials (Table 1). CBI of widely varying duration was used

for both intervention and control arms in three trials, only in

controls in one trial, according to the discretion of treating

physicians in four trials, and not used in three trials.

Information on CBI use from two trials could not be

obtained despite several attempts to contact authors and

institutions. Meaningful calculations of the impact of CBI on

recurrence were not possible due to the clinical heteroge-

neity of the data.

All studies with RFI outcome data were plotted on a

funnel plot comparing effect size and measure of precision

of the effect size (Fig. 4). Four studies with small sample size

and large positive effect were published. There was a

theoretical absence of studies published with small sample

size and large negative effect, suggesting the possibility of

publication bias.

[(Fig._3)TD$FIG]

Fig. 3 – Forest plot comparing recurrence-free interval in patients receiving intravesical chemotherapy versus controls. CI = confidence interval;IV = inverse variance; SE = standard error.

[(Fig._2)TD$FIG]

Fig. 2 – Risk-of-bias graph: reviews of authors’ judgments about each risk-of-bias item presented as percentages across all included studies.

[(Fig._4)TD$FIG]

Fig. 4 – Funnel plot examining the possibility of publication bias. The plotwas created by comparing the variance with effect size in publicationscomparing recurrence-free interval of patients receiving intravesicalchemotherapy versus controls. SE = standard error.

E U R O P E A N U R O L O G Y 6 4 ( 2 0 1 3 ) 4 2 1 – 4 3 0 425

3.2.2. Primary outcome: early recurrences

ERs were 12% less likely in the intervention population

(ARR: 0.12; 95% CI, �0.18 to �0.06; p < 0.001; I2: 0%)

(Fig. 5). Thus nine patients would need to be treated with

IVC to prevent one BCa recurrence within the first year

following treatment (NNT: 9; 95% CI, 6–17 patients). Due to

the small number of trials reporting ERs, subgroup analysis

and publication bias assessment were not possible.

3.2.3. Secondary outcome: bladder cancer progression

Only four studies reported BCa progression (Fig. 6). This was

a rare event, occurring in only 3.0% of patients receiving

[(Fig._5)TD$FIG]

Fig. 5 – Forest plot comparing early recurrences (within 1 yr) between patients receiving immediate intravesical chemotherapy after transurethralresection of bladder tumor versus controls. CI = confidence interval; IV = inverse variance; SE = standard error.

[(Fig._6)TD$FIG]

Fig. 6 – Forest plot comparing bladder cancer progression (to muscle invasion) between patients receiving intravesical chemotherapy after transurethralresection of bladder tumor versus controls. CI = confidence interval; IV = inverse variance; SE = standard error.

Table 2 – Summary of nonserious adverse events reported in trials examining the effect of immediate postoperative intravesicalchemotherapy on non–muscle-invasive bladder cancer recurrences

Study Adverseevents

reported

Interventiondrug and dose

Mild cystitis,frequency,

urgency

Mildhematuria

Skinirritation,

rash

Other

Oosterlinck et al. [22] Yes Epirubicin 80 mg 11.7% intervention;

1.9% control

– 1.0%

intervention

Nine other nonserious complications

(7 intervention, 2 control)

Fujita [23] Yes Peplomycin 80 mg – – – ‘‘No patient developed acute bladder

irritation or chronic bladder contraction’’

Medical Research

Council report [24]

Yes Thiotepa 30 mg 2.5% intervention – 0.5%

intervention

One patient with widespread edema in

the thiotepa group

Tolley et al. [25] Yes MMC 40 mg 0.7% intervention – – –

Solsona et al. [26] Yes MMC 30 mg 3.5% intervention;

1.5% control

– – –

Rajala et al. [27] No Epirubicin 100 mg – – – –

Okamura et al. [28] Yes THP 30 mg 10.4% overall 5.2%

overall

– Only overall adverse events reported

El-Ghobashy et al. [29] Yes MMC 30 mg 6.5% intervention;

3.1% control

– – –

Berrum-Svennung

et al. [30]

No Epirubicin 50 mg – – – –

Gudjonsson et al. [8] No Epirubicin 80 mg – – – –

Bohle et al. [31] Yes Gemcitabine 2 g – – – ‘‘Adverse events possibly attributed to

intervention 11/166, placebo 6/162 all

nonserious’’

Tatar et al. [32] No MMC 40 mg – – – –

De Nunzio et al. [33] Yes MMC 40 mg 9.3% intervention – – –

MMC = mitomycin C.

E U R O P E A N U R O L O G Y 6 4 ( 2 0 1 3 ) 4 2 1 – 4 3 0426

Table 3 – Quality of evidence assessment and summary of findings using the GRADE system

Question: Should immediate post-TURBT intravesical chemotherapy be used for non–muscle-invasive bladder cancer?

Quality assessment Summary of findings

Participants(Studies)Follow-up

Risk of bias Inconsistency Indirectness Imprecision Publication bias Overall qualityof evidence

Relative effect(95% CI)

Anticipated absolute effects

Risk withcontrol

Risk differencewith immediate

post-TURBT intravesicalchemotherapy (95% CI)

Recurrence-free interval (assessed with surveillance cystoscopy and confirmed with biopsy)

2442

(11 studies)

2–8.75 yr

Seriousa Seriousb No serious

indirectness

No serious

imprecision

Reporting bias

strongly suspectedc

�O O O

VERY LOWa,b,c

due to risk of bias,

inconsistency,

publication bias

HR: 0.62

(0.5–0.77)

599 RFIs/1000d 166 fewer RFIs/1000

(from 94 fewer to

232 fewer)

Early recurrences within 1 yr (assessed with surveillance cystoscopy and confirmed with biopsy)

429

(4 studies)

1–7.5 yr

Seriouse No serious

inconsistency

No serious

indirectness

Seriousf Undetected ��O O

LOWe,f

due to risk of

bias, imprecision

See commenth 211 ERs/1000 124 fewer ERs/1000

(from 59 fewer to

179 fewer)

Progression to T2 bladder cancer (assessed with surveillance cystoscopy and confirmed with biopsy)

831

(4 studies)

2–7.5 yr

Seriousa No serious

inconsistency

Seriousg Seriousf Undetected �O O O

VERY LOWa,f,g

due to risk of bias,

indirectness,

imprecision

See commenth 19/1000 11 more/1000

(from 10 fewer to

30 more)

Serious adverse events (assessed with modified Clavien grading classification �2 or as defined in trial protocol)

0

(9 studies)

– – – – – No GRADE applied

due to zero events

– – –

CI = confidence interval; ERs = early recurrences; GRADE = Grading of Recommendations, Assessment, Development, and Evaluation; HR = hazard ratio; RFIs = recurrence-free intervals; TURBT = transurethral resection of

bladder tumor.a Risk of bias in all trials except Bohle et al. [31] was ‘‘high’’ due to lack of blinding and unclear randomization.b Significant statistical heterogeneity and high I2 (69%).c See publication bias plot (Fig. 4). Concern that studies with large negative effect were not published.d Assumed baseline event rate for control group is approximated using data from Tolley et al. [25] (59.9%) because it approximates the average across trials and is from a trial with a large sample size using a common

intravesical chemotherapy (mitomycin C).e Risk of bias for all included studies was ‘‘high’’ according to Cochrane risk of bias tool. Studies lacked blinding and had unclear randomization.f Small sample size and number of events.g Progression to T2 bladder cancer outcome was not the primary outcome measure for any of the included studies.h Risks were calculated from pooled absolute risk reductions.

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chemotherapy (12 of 406) and 1.9% of controls (8 of 425)

with no statistically significant difference ( p = 0.28).

3.2.4. Secondary outcome: adverse events

Adverse event data were reported in nine studies. There

were no documented serious adverse events in any

study. Table 2 summarizes the nonserious adverse event

data.

3.3. Quality-of-evidence review

Results of the GRADE system quality-of-evidence review are

presented in Table 3 for all primary and secondary outcome

measures. No grade was assigned to serious adverse events

because none were reported.

4. Conclusions

This systematic review and meta-analysis with 13 studies

and 2548 patients expands on the previous meta-analysis in

2004 [5] composed of 7 studies and 1476 patients, and it

differs in several ways.

First, we performed a thorough risk-of-bias evaluation

for all included studies. Second, random-effects models

were used because trials with multiple different study

drugs were combined, and there was unlikely one true

effect to be identified. Third, the GRADE system, adopted by

the Cochrane Collaboration [21] and the suggested manner

in which to generate more transparent and structured

reviews [34], was used to grade the quality of evidence in

this systematic review. Interestingly, our findings are

similar to the previous meta-analysis [5]. This systematic

review suggests that immediate postoperative IVC instilla-

tion in patients with NMIBC increases RFI and reduces ERs

with minimal morbidity.

The methods of our study differ from a very recent

meta-analysis by Abern et al. also supporting the benefit of

postoperative IVC instillation [35] where 18 trials were

synthesized and the effects of tumor risk factors were

calculated using meta-regression. Risk-of-bias and quality-

of-evidence assessment were important additions in our

analysis. We also deliberately elected to use a time-to-event

end point (RFI) as a main outcome measure because it

addresses the temporal sequence of recurrences. For patients

with NMIBC, extending the time from TURBT to recurrence is

vital. Using a time-to-event metric is particularly important in

this question because the RCTs available had vastly different

median durations of follow-up. Indeed, by simply combining

all events from all trials (as would be the case if an aggregated

odds ratio were calculated), a recurrence at 6 mo after

TURBT would be treated identically to a recurrence 6 yr after

TURBT.

We performed several a priori subgroup analyses to

examine whether the effect of IVC differed in various

clinical situations. The RFI-reducing effect of IVC persisted

regardless of tumor risk (lower or higher) or drug used (only

MMC and epirubicin were examined in enough studies to be

included in subgroup analysis) without statistically signifi-

cant differences between effects.

The final subgroup analysis examined whether studies

using water or saline placebo intravesical instillation had an

impact on RFI. We suspected that placebo instillation could

reduce recurrences via several mechanisms. The placebo

effect has been well documented in sham procedures [36].

Also, the instillation of any agent into the bladder may

theoretically decrease tumor recurrence via mechanical

lavage of circulating tumor cells, or if the agent is hypotonic,

tumor cell lysis may ensue [37]. There is observational

study data demonstrating equal recurrence rates between

patients treated with MMC versus CBI with saline [38].

Finally placebo use may simply reflect better quality studies

that have been shown to be associated with reduced effect

size [39]. However, the use of placebo did not demonstrate a

statistically significant difference in subgroup analysis.

We also attempted to evaluate whether CBI after TURBT

could affect tumor recurrence. We hypothesized that CBI

may play a role in reducing tumor recurrence by providing

an extended period of mechanical lavage of tumor cells after

resection. CBI is sometimes used after transurethral

operations to prevent blood clotting and allow for adequate

hemostasis and catheter drainage. One unpublished study

in which 866 patients were randomized to CBI versus no CBI

following TURBT demonstrated an improved RFI for

patients in the CBI arm [40]. Of the 13 trials included in

this review, only 3 trials mandated CBI after TURBT, and

each was for a varying duration from 2 to 24 h. None of the

other publications described whether CBI was used or not.

By contacting authors and institutions, we learned that CBI

use varied, and it was often left to the discretion of the

treating urologist. Thus the high degree of clinical

heterogeneity in CBI use prohibited meta-analysis of the

data.

Despite the evidence that IVC reduces recurrences,

which is reinforced by our study, many practitioners do

not use this intervention for their patients. In a recent

survey of 259 practicing urologists, 66% did not use

postoperative chemotherapy for their patients [41]. The

most commonly cited reasons for limited use were

increased cost, challenge of administering chemotherapy

in the operating or recovery room, possibility of serious side

effects, and the belief that decreasing small superficial BCa

recurrences is not clinically important. Additionally, the

strength of the primary studies has been questioned,

particularly because it has been demonstrated that the

benefit from IVC was driven by RCTs with small sample size

and large effect [9]. However, despite these criticisms, both

the American and European urologic societies support post-

TURBT IVC for all suspected NMIBC [10,11].

IVC administration appears safe and relatively nontoxic.

There were no serious adverse events reported in the

studies included in our meta-analysis. However, in a study

using 50 mg epirubicin, not included here because it did not

contain time-to-event data or data on ERs, one patient

experienced permanent bladder contraction secondary to

IVC [42].

The quality of evidence for each outcome in this study as

judged using the GRADE system ranged from low to very

low. Quality scores for all outcomes were downgraded

E U R O P E A N U R O L O G Y 6 4 ( 2 0 1 3 ) 4 2 1 – 4 3 0428

because data for this meta-analysis were extracted from

studies at high risk of bias. In most of the studies, the

urologist and patients were not blinded and placebo was

not used, which may cause bias toward improved outcomes

in patients receiving the study drug. The RFI outcome was

further downgraded due to inconsistent results (significant

heterogeneity) and potential for publication bias illustrated

by the lack of studies published with small sample size

and negative effect. Further downgrading of the ERs and

progression to T2 outcomes was secondary to imprecision

caused by small sample size. Finally, the progression to T2

outcome suffered from indirectness because it was not a

primary outcome in most included studies. Due to the low

evidence quality, it may not be suitable to rely on these

results to guide clinical decisions.

The report by Bohle et al. [31] was the only study

identified with a low overall risk of bias. Interestingly, in

their trial, IVC using gemcitabine did not reduce NMIBC

recurrences.

This study has several limitations. There was a high

degree of heterogeneity in the studies included in this meta-

analysis. For one primary outcome, RFI, between-study

heterogeneity accounted for 69% of the overall heterogene-

ity beyond chance alone. High between-study heterogene-

ity persisted despite stratification and subgroup analyses.

Unmeasured items that could not be accounted for,

including variation in surgical technique between sites,

patient comorbidities, and age, may be driving the

heterogeneity. Additional limitations of this study include

the lack of individual patient data and the likely variation in

surgical quality across studies. Jancke et al. described the

association between incomplete tumor resection and local

NMIBC recurrences [43], which may be the case for some

studies included in the meta-analysis. However, despite

these limitations, we believe this study carefully evaluates

and fairly represents the most current evidence for

immediate postoperative IVC for low- and intermediate-

risk NMIBC.

In summary, the practice of immediate postoperative

IVC in NMIBC has polarized health care providers due to

challenges in drug administration and conflicting primary

data [6,8]. The implications of our study are relevant to both

patients and health systems worldwide given the high costs

associated with this disease [1]. This meta-analysis con-

firms, with updated data and contemporary methodology,

that IVC reduces NMIBC recurrences when given immedi-

ately following TURBT with minimal adverse events.

Subgroup analyses suggest that this effect persists for

several study drugs, risk groups, and whether or not placebo

was used in each trial. However, due to the low quality of

evidence, we still suggest that a well-designed RCT with

proper blinding and placebo be performed with one of the

more commonly used agents.

Author contributions: Nathan Perlis had full access to all the data in the

study and takes responsibility for the integrity of the data and the

accuracy of the data analysis.

Study concept and design: Perlis, Kulkarni, Finelli, Fleshner, Zlotta.

Acquisition of data: Perlis, Kulkarni.

Analysis and interpretation of data: Perlis, Kulkarni, Beyene.

Drafting of the manuscript: Perlis, Kulkarni,

Critical revision of the manuscript for important intellectual content:

Kulkarni, Beyene, Zlotta.

Statistical analysis: Perlis, Beyene.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Kulkarni, Zlotta.

Other (specify): None.

Financial disclosures: Nathan Perlis certifies that all conflicts of interest,

including specific financial interests and relationships and affiliations

relevant to the subject matter or materials discussed in the manuscript

(eg, employment/affiliation, grants or funding, consultancies, honoraria,

stock ownership or options, expert testimony, royalties, or patents filed,

received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

Appendix A. Supplementary data

Supplementary data associated with this article can be

found, in the online version, at http://dx.doi.org/10.1016/

j.eururo.2013.06.009.

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