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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
EUROPEAN UROLOGY 64 (2013) 421–430
available at www.sciencedirect.com journal homepage: www.europeanurology.com
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;
c
Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; d Mount Sinai Hospital, Department of Surgery,
b
University of Toronto, Department of Surgery, Division of Urology, Toronto, Ontario, Canada;
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
Article info
Abstract
Article history: Accepted June 7, 2013 Published online ahead of print on June 18, 2013
Context: Non–muscle-invasive bladder cancer (NMIBC) commonly recurs, requiring invasive and costly transurethral resection of bladder tumor (TURBT). A meta-analysis of seven trials published in 2004 demonstrated that intravesical chemotherapy (IVC) following TURBT reduces recurrences. Despite European Association of Urology endorsement, adoption of this practice has been modest. Objective: To investigate whether immediate postoperative IVC prolongs the recurrencefree interval (RFI) and early recurrences (ERs) in light of new trial data and to explore the quality 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 Cochrane databases. Trials examining NMIBC recurrence for adults receiving IVC immediately following TURBT were included. RFI was estimated by hazard ratio (HR), and ER was estimated by absolute risk reduction (ARR) of recurrences within 1 yr of TURBT. Both outcomes were synthesized using random-effects models. Risk of bias was assessed using the Cochrane Collaboration risk-of-bias tool, and quality of evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system. Evidence synthesis: Thirteen studies with 2548 patients were included. IVC prolonged RFI by 38% (HR: 0.62; 95% confidence interval [CI], 0.50–0.77; p < 0.001; I2: 69%), and ERs were 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. Quality of evidence for RFI was very low and low for ERs. Conclusions: Our updated meta-analysis supports that IVC prolongs RFI and reduces ERs of NMIBC when administered immediately after TURBT. However, contemporary methodology suggests low evidence quality for examined outcomes. Thus RCTs with careful randomization and blinding are still warranted to clarify the usefulness of immediate postoperative IVC in this population. # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Bladder cancer Chemotherapy Disease prevention Single instillation Systematic review
* Corresponding author. Division of Urology, Department of Surgical Oncology, Princess Margaret Hospital, 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: [email protected], [email protected] (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
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1.
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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 implantation 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 published 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 metaanalysis 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 methodology for systematic reviews. A detailed search strategy is
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[(Fig._1)TD$IG]
Total citations n = 4929
Duplicate citations n = 1878
Unique citations n = 3051
Full-text review n = 36
Studies included n = 13
Excluded following abstract review n = 3015
Excluded following full-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.
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 crossreferenced to ensure completeness of our literature search. Conference abstracts from the American and European urologic association meetings were also searched.
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.
Data extraction and management
2.4.
2.3.1.
General
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].
Two reviewers (N.P., G.S.K.) performed study selection (k = 0.92) (Fig. 1). Disagreements were resolved by discussion 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
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. Heterogeneity and reporting bias
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 heterogeneity 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.
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Table 1 – Randomized controlled trials included in meta-analysis comparing immediate postoperative intravesical chemotherapy with control Study
Total no. of patients
Tumor risk
399 90 246
Higher risk Higher risk Higher risk
306 121 134
Oosterlinck et al. [22] Fujita [23] Medical Research Council report [24] Tolley et al. [25] Solsona et al. [26] Rajala et al. [27]
Intervention drug and dose
Placebo
CBI
Epirubicin 80 mg Peplomycin 80 mg Thiotepa 30 mg
Water None None
24 h Not specified Discretion of physician
No No No
2 (mean) 2.25 (mean) 8.75
RFI RFI RFI
Higher risk Lower risk Higher risk
MMC 40 mg MMC 30 mg Epirubicin 100 mg
None None None
Discretion of physician No 2h Control only No Not specified Discretion of physician
No No No
7 7.83 6
RFI RFI and ERs RFI
No No Partial
3.4 3.66 (mean) NR
RFI ERs RFI
Discretion of physician 20 h No
No Yes No
3.9 2 1
RFI RFI ERs
12 h
Partial
7.5
RFI and ERs
Okamura et al. [28] El-Ghobashy et al. [29] Berrum-Svennung et al. [30] Gudjo´nsson et al. [8] Bo¨hle et al. [31] Tatar et al. [32]
170 63 307
Higher risk Lower risk Lower risk
THP-doxorubicin 30 mg MMC 30mg Epirubicin 50 mg
None None NS
219 248 43
Higher risk Higher risk Higher risk
Epirubicin 80 mg Gemcitabine 2 g MMC 40 mg
De Nunzio et al. [33]
202
Lower risk
MMC 40 mg
None NS NS or Water None
Blinding
Median follow-up
Primary outcome measure
CBI = continuous bladder irrigation (with saline); ERs = early recurrences; NS = normal saline; RFI = recurrence-free interval.
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 Recommendations, 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 heterogeneity 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 intervention within 24 h of TURBT compared with controls (Fig. 3). Significant ( p < 0.001) statistical between-study heterogeneity 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 improvement for both MMC (three trials; HR: 0.49; 95% CI, 0.28–0.88; p < 0.001; I2: 82%) and epirubicin (four trials;
EUROPEAN UROLOGY 64 (2013) 421–430
[(Fig._2)TD$IG]
425
Fig. 2 – Risk-of-bias graph: reviews of authors’ judgments about each risk-of-bias item presented as percentages across all included studies.
[(Fig._3)TD$IG]
Fig. 3 – Forest plot comparing recurrence-free interval in patients receiving intravesical chemotherapy versus controls. CI = confidence interval; IV = inverse variance; SE = standard error.
HR: 0.65; 95% CI, 0.55–0.77; p < 0.001; I2: 0%). Differences in effect size between subgroups was not statistically significant ( p = 0.38). Stratification by tumor risk category demonstrated RFI improvement for both lower risk tumors (three trials; HR: 0.51; 95% CI, 0.28–0.90; p = 0.003; I2: 83%) and higher risk tumors (eight trials; HR: 0.66; 95% CI, 0.52–0.84; p = 0.006; I2: 64%). Differences in effect size between subgroups was not statistically significant ( p = 0.41). When RFI was stratified by placebo use, trials without placebo demonstrated a 44% reduction in RFI (HR: 0.56; 95% CI, 0.41–0.76; p < 0.001; I2: 75%), whereas those that used placebo demonstrated a 25% reduction in RFI (HR: 0.75; 95% CI, 0.61–0.91; p = 0.004; I2: 4%). Differences in effect size between subgroups was not statistically significant ( p = 0.12). Data regarding CBI use were obtained for 11 of the 13 trials (Table 1). CBI of widely varying duration was used for both intervention and control arms in three trials, only in controls in one trial, according to the discretion of treating physicians in four trials, and not used in three trials. Information on CBI use from two trials could not be obtained despite several attempts to contact authors and institutions. Meaningful calculations of the impact of CBI on recurrence were not possible due to the clinical heterogeneity of the data.
[(Fig._4)TD$IG]
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. 4 – Funnel plot examining the possibility of publication bias. The plot was created by comparing the variance with effect size in publications comparing recurrence-free interval of patients receiving intravesical chemotherapy versus controls. SE = standard error.
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[(Fig._5)TD$IG]
Fig. 5 – Forest plot comparing early recurrences (within 1 yr) between patients receiving immediate intravesical chemotherapy after transurethral resection of bladder tumor versus controls. CI = confidence interval; IV = inverse variance; SE = standard error.
[(Fig._6)TD$IG]
Fig. 6 – Forest plot comparing bladder cancer progression (to muscle invasion) between patients receiving intravesical chemotherapy after transurethral resection of bladder tumor versus controls. CI = confidence interval; IV = inverse variance; SE = standard error.
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
Table 2 – Summary of nonserious adverse events reported in trials examining the effect of immediate postoperative intravesical chemotherapy on non–muscle-invasive bladder cancer recurrences Study
Adverse events reported
Intervention drug and dose
Oosterlinck et al. [22]
Yes
Epirubicin 80 mg
Fujita [23]
Yes
Medical Research Council report [24] Tolley et al. [25] Solsona et al. [26]
Mild cystitis, frequency, urgency
Mild hematuria
Skin irritation, rash
Other
1.0% intervention – 0.5% intervention – –
Nine other nonserious complications (7 intervention, 2 control) ‘‘No patient developed acute bladder irritation or chronic bladder contraction’’ One patient with widespread edema in the thiotepa group – –
– 5.2% overall –
– –
– Only overall adverse events reported
–
–
–
–
– – ‘‘Adverse events possibly attributed to intervention 11/166, placebo 6/162 all nonserious’’ – –
Peplomycin 80 mg
11.7% intervention; 1.9% control –
–
Yes
Thiotepa 30 mg
2.5% intervention
–
Yes Yes
MMC 40 mg MMC 30 mg
– –
Rajala et al. [27] Okamura et al. [28]
No Yes
Epirubicin 100 mg THP 30 mg
0.7% intervention 3.5% intervention; 1.5% control – 10.4% overall
El-Ghobashy et al. [29]
Yes
MMC 30 mg
Berrum-Svennung et al. [30] Gudjo´nsson et al. [8] Bo¨hle et al. [31]
No
Epirubicin 50 mg
6.5% intervention; 3.1% control –
No Yes
Epirubicin 80 mg Gemcitabine 2 g
– –
– –
– –
Tatar et al. [32] De Nunzio et al. [33]
No Yes
MMC 40 mg MMC 40 mg
– 9.3% intervention
– –
– –
MMC = mitomycin C.
–
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 Participants (Studies) Follow-up
Risk of bias
Inconsistency
Indirectness
Imprecision
Summary of findings Publication bias
Overall quality of evidence
Relative effect (95% CI)
Anticipated absolute effects
Risk with control
Reporting bias strongly suspectedc
Early recurrences within 1 yr (assessed with surveillance cystoscopy and confirmed with biopsy) No serious No serious Seriousf Undetected 429 Seriouse inconsistency indirectness (4 studies) 1–7.5 yr Progression to T2 bladder cancer (assessed with surveillance cystoscopy and confirmed with biopsy) No serious Seriousg Seriousf Undetected 831 Seriousa inconsistency (4 studies) 2–7.5 yr
Serious adverse events (assessed with modified Clavien grading classification 2 or as defined in trial protocol) 0 – – – – – (9 studies)
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)
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)
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)
No GRADE applied due to zero events
–
–
–
EUROPEAN UROLOGY 64 (2013) 421–430
Recurrence-free interval (assessed with surveillance cystoscopy and confirmed with biopsy) Seriousb No serious No serious 2442 Seriousa indirectness imprecision (11 studies) 2–8.75 yr
Risk difference with immediate post-TURBT intravesical chemotherapy (95% CI)
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 Bo¨hle 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 instillation 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 qualityof-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 significant 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 postTURBT 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
EUROPEAN UROLOGY 64 (2013) 421–430
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 metaanalysis. For one primary outcome, RFI, between-study heterogeneity accounted for 69% of the overall heterogeneity beyond chance alone. High between-study heterogeneity 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 intermediaterisk 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 confirms, with updated data and contemporary methodology, that IVC reduces NMIBC recurrences when given immediately 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.
429
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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available at www.sciencedirect.com journal homepage: www.europeanurology.com
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;
c
Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; d Mount Sinai Hospital, Department of Surgery,
b
University of Toronto, Department of Surgery, Division of Urology, Toronto, Ontario, Canada;
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
Article info
Abstract
Article history: Accepted June 7, 2013 Published online ahead of print on June 18, 2013
Context: Non–muscle-invasive bladder cancer (NMIBC) commonly recurs, requiring invasive and costly transurethral resection of bladder tumor (TURBT). A meta-analysis of seven trials published in 2004 demonstrated that intravesical chemotherapy (IVC) following TURBT reduces recurrences. Despite European Association of Urology endorsement, adoption of this practice has been modest. Objective: To investigate whether immediate postoperative IVC prolongs the recurrencefree interval (RFI) and early recurrences (ERs) in light of new trial data and to explore the quality 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 Cochrane databases. Trials examining NMIBC recurrence for adults receiving IVC immediately following TURBT were included. RFI was estimated by hazard ratio (HR), and ER was estimated by absolute risk reduction (ARR) of recurrences within 1 yr of TURBT. Both outcomes were synthesized using random-effects models. Risk of bias was assessed using the Cochrane Collaboration risk-of-bias tool, and quality of evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system. Evidence synthesis: Thirteen studies with 2548 patients were included. IVC prolonged RFI by 38% (HR: 0.62; 95% confidence interval [CI], 0.50–0.77; p < 0.001; I2: 69%), and ERs were 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. Quality of evidence for RFI was very low and low for ERs. Conclusions: Our updated meta-analysis supports that IVC prolongs RFI and reduces ERs of NMIBC when administered immediately after TURBT. However, contemporary methodology suggests low evidence quality for examined outcomes. Thus RCTs with careful randomization and blinding are still warranted to clarify the usefulness of immediate postoperative IVC in this population. # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Bladder cancer Chemotherapy Disease prevention Single instillation Systematic review
* Corresponding author. Division of Urology, Department of Surgical Oncology, Princess Margaret Hospital, 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: [email protected], [email protected] (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
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1.
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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 implantation 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 published 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 metaanalysis 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 methodology for systematic reviews. A detailed search strategy is
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[(Fig._1)TD$IG]
Total citations n = 4929
Duplicate citations n = 1878
Unique citations n = 3051
Full-text review n = 36
Studies included n = 13
Excluded following abstract review n = 3015
Excluded following full-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.
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 crossreferenced to ensure completeness of our literature search. Conference abstracts from the American and European urologic association meetings were also searched.
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.
Data extraction and management
2.4.
2.3.1.
General
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].
Two reviewers (N.P., G.S.K.) performed study selection (k = 0.92) (Fig. 1). Disagreements were resolved by discussion 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
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. Heterogeneity and reporting bias
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 heterogeneity 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.
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Table 1 – Randomized controlled trials included in meta-analysis comparing immediate postoperative intravesical chemotherapy with control Study
Total no. of patients
Tumor risk
399 90 246
Higher risk Higher risk Higher risk
306 121 134
Oosterlinck et al. [22] Fujita [23] Medical Research Council report [24] Tolley et al. [25] Solsona et al. [26] Rajala et al. [27]
Intervention drug and dose
Placebo
CBI
Epirubicin 80 mg Peplomycin 80 mg Thiotepa 30 mg
Water None None
24 h Not specified Discretion of physician
No No No
2 (mean) 2.25 (mean) 8.75
RFI RFI RFI
Higher risk Lower risk Higher risk
MMC 40 mg MMC 30 mg Epirubicin 100 mg
None None None
Discretion of physician No 2h Control only No Not specified Discretion of physician
No No No
7 7.83 6
RFI RFI and ERs RFI
No No Partial
3.4 3.66 (mean) NR
RFI ERs RFI
Discretion of physician 20 h No
No Yes No
3.9 2 1
RFI RFI ERs
12 h
Partial
7.5
RFI and ERs
Okamura et al. [28] El-Ghobashy et al. [29] Berrum-Svennung et al. [30] Gudjo´nsson et al. [8] Bo¨hle et al. [31] Tatar et al. [32]
170 63 307
Higher risk Lower risk Lower risk
THP-doxorubicin 30 mg MMC 30mg Epirubicin 50 mg
None None NS
219 248 43
Higher risk Higher risk Higher risk
Epirubicin 80 mg Gemcitabine 2 g MMC 40 mg
De Nunzio et al. [33]
202
Lower risk
MMC 40 mg
None NS NS or Water None
Blinding
Median follow-up
Primary outcome measure
CBI = continuous bladder irrigation (with saline); ERs = early recurrences; NS = normal saline; RFI = recurrence-free interval.
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 Recommendations, 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 heterogeneity 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 intervention within 24 h of TURBT compared with controls (Fig. 3). Significant ( p < 0.001) statistical between-study heterogeneity 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 improvement for both MMC (three trials; HR: 0.49; 95% CI, 0.28–0.88; p < 0.001; I2: 82%) and epirubicin (four trials;
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[(Fig._2)TD$IG]
425
Fig. 2 – Risk-of-bias graph: reviews of authors’ judgments about each risk-of-bias item presented as percentages across all included studies.
[(Fig._3)TD$IG]
Fig. 3 – Forest plot comparing recurrence-free interval in patients receiving intravesical chemotherapy versus controls. CI = confidence interval; IV = inverse variance; SE = standard error.
HR: 0.65; 95% CI, 0.55–0.77; p < 0.001; I2: 0%). Differences in effect size between subgroups was not statistically significant ( p = 0.38). Stratification by tumor risk category demonstrated RFI improvement for both lower risk tumors (three trials; HR: 0.51; 95% CI, 0.28–0.90; p = 0.003; I2: 83%) and higher risk tumors (eight trials; HR: 0.66; 95% CI, 0.52–0.84; p = 0.006; I2: 64%). Differences in effect size between subgroups was not statistically significant ( p = 0.41). When RFI was stratified by placebo use, trials without placebo demonstrated a 44% reduction in RFI (HR: 0.56; 95% CI, 0.41–0.76; p < 0.001; I2: 75%), whereas those that used placebo demonstrated a 25% reduction in RFI (HR: 0.75; 95% CI, 0.61–0.91; p = 0.004; I2: 4%). Differences in effect size between subgroups was not statistically significant ( p = 0.12). Data regarding CBI use were obtained for 11 of the 13 trials (Table 1). CBI of widely varying duration was used for both intervention and control arms in three trials, only in controls in one trial, according to the discretion of treating physicians in four trials, and not used in three trials. Information on CBI use from two trials could not be obtained despite several attempts to contact authors and institutions. Meaningful calculations of the impact of CBI on recurrence were not possible due to the clinical heterogeneity of the data.
[(Fig._4)TD$IG]
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. 4 – Funnel plot examining the possibility of publication bias. The plot was created by comparing the variance with effect size in publications comparing recurrence-free interval of patients receiving intravesical chemotherapy versus controls. SE = standard error.
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[(Fig._5)TD$IG]
Fig. 5 – Forest plot comparing early recurrences (within 1 yr) between patients receiving immediate intravesical chemotherapy after transurethral resection of bladder tumor versus controls. CI = confidence interval; IV = inverse variance; SE = standard error.
[(Fig._6)TD$IG]
Fig. 6 – Forest plot comparing bladder cancer progression (to muscle invasion) between patients receiving intravesical chemotherapy after transurethral resection of bladder tumor versus controls. CI = confidence interval; IV = inverse variance; SE = standard error.
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
Table 2 – Summary of nonserious adverse events reported in trials examining the effect of immediate postoperative intravesical chemotherapy on non–muscle-invasive bladder cancer recurrences Study
Adverse events reported
Intervention drug and dose
Oosterlinck et al. [22]
Yes
Epirubicin 80 mg
Fujita [23]
Yes
Medical Research Council report [24] Tolley et al. [25] Solsona et al. [26]
Mild cystitis, frequency, urgency
Mild hematuria
Skin irritation, rash
Other
1.0% intervention – 0.5% intervention – –
Nine other nonserious complications (7 intervention, 2 control) ‘‘No patient developed acute bladder irritation or chronic bladder contraction’’ One patient with widespread edema in the thiotepa group – –
– 5.2% overall –
– –
– Only overall adverse events reported
–
–
–
–
– – ‘‘Adverse events possibly attributed to intervention 11/166, placebo 6/162 all nonserious’’ – –
Peplomycin 80 mg
11.7% intervention; 1.9% control –
–
Yes
Thiotepa 30 mg
2.5% intervention
–
Yes Yes
MMC 40 mg MMC 30 mg
– –
Rajala et al. [27] Okamura et al. [28]
No Yes
Epirubicin 100 mg THP 30 mg
0.7% intervention 3.5% intervention; 1.5% control – 10.4% overall
El-Ghobashy et al. [29]
Yes
MMC 30 mg
Berrum-Svennung et al. [30] Gudjo´nsson et al. [8] Bo¨hle et al. [31]
No
Epirubicin 50 mg
6.5% intervention; 3.1% control –
No Yes
Epirubicin 80 mg Gemcitabine 2 g
– –
– –
– –
Tatar et al. [32] De Nunzio et al. [33]
No Yes
MMC 40 mg MMC 40 mg
– 9.3% intervention
– –
– –
MMC = mitomycin C.
–
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 Participants (Studies) Follow-up
Risk of bias
Inconsistency
Indirectness
Imprecision
Summary of findings Publication bias
Overall quality of evidence
Relative effect (95% CI)
Anticipated absolute effects
Risk with control
Reporting bias strongly suspectedc
Early recurrences within 1 yr (assessed with surveillance cystoscopy and confirmed with biopsy) No serious No serious Seriousf Undetected 429 Seriouse inconsistency indirectness (4 studies) 1–7.5 yr Progression to T2 bladder cancer (assessed with surveillance cystoscopy and confirmed with biopsy) No serious Seriousg Seriousf Undetected 831 Seriousa inconsistency (4 studies) 2–7.5 yr
Serious adverse events (assessed with modified Clavien grading classification 2 or as defined in trial protocol) 0 – – – – – (9 studies)
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)
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)
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)
No GRADE applied due to zero events
–
–
–
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Recurrence-free interval (assessed with surveillance cystoscopy and confirmed with biopsy) Seriousb No serious No serious 2442 Seriousa indirectness imprecision (11 studies) 2–8.75 yr
Risk difference with immediate post-TURBT intravesical chemotherapy (95% CI)
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 Bo¨hle 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 instillation 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 qualityof-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 significant 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 postTURBT 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
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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 metaanalysis. For one primary outcome, RFI, between-study heterogeneity accounted for 69% of the overall heterogeneity beyond chance alone. High between-study heterogeneity 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 intermediaterisk 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 confirms, with updated data and contemporary methodology, that IVC reduces NMIBC recurrences when given immediately 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.
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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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