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Emerging Approaches to Diagnosis and Treatment of Non–Muscle-Invasive Bladder Cancer

Systematic Review ARCHIVED Oct 27, 2015
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Notice: An addendum was added to this report in November 2016. The addendum is located at the end of the main report, before the appendixes.

Structured Abstract


Non–muscle-invasive bladder cancer (NMIBC) frequently recurs and can progress to muscle-invasive disease. This report reviews the current evidence on emerging approaches to diagnosing and treating bladder cancer.

Data sources

Electronic databases (Ovid MEDLINE®, January 1990–October 2014, Cochrane Central Register of Controlled Trials through September 2014, Cochrane Database of Systematic Reviews through September 2014, Health Technology Assessment through Third Quarter 2014, National Health Sciences Economic Evaluation Database through Third Quarter 2014, and Database of Abstracts of Reviews of Effects through Third Quarter 2014); reference lists; and clinical trials registries.

Review methods

Using predefined criteria, we selected studies on diagnostic accuracy of urinary biomarkers versus cystoscopy, and trials of fluorescent cystoscopy, intravesical therapy, and radiation therapy for NMIBC that evaluated bladder cancer recurrence, progression, mortality, or harms. The quality of included studies was assessed, data were extracted, and results were summarized qualitatively and using meta-analysis.


Urinary biomarkers were associated with sensitivity for bladder cancer that ranged from 0.57 to 0.82 and specificity from 0.74 to 0.88, for positive likelihood ratios from 2.52 to 5.53 and negative likelihood ratios from 0.21 to 0.48 (strength of evidence [SOE]: moderate for quantitative nuclear matrix protein 22 [NMP22], qualitative bladder tumor antigen [BTA], fluorescence in situ hybridization [FISH], and ImmunoCyt™; low for other biomarkers). Sensitivity increased for higher stage and grade tumors. Studies that directly compared the accuracy of quantitative NMP22 and qualitative BTA found no differences in diagnostic accuracy (SOE: moderate).

Most trials found fluorescent cystoscopy to be associated with decreased risk of subsequent bladder recurrence versus white light cystoscopy, but results were inconsistent, and there was no difference in risk of progression or mortality (SOE: low).

Intravesical therapy was more effective than no intravesical therapy for reducing risk of bladder cancer recurrence (for bacillus Calmette-Guérin [BCG], relative risk [RR], 0.56; 95% confidence interval [CI]. 0.43 to 0.71; SOE: moderate; for mitomycin C [MMC], doxorubicin, and epirubicin, RR, 0.66 to 0.72; SOE: moderate). BCG was also associated with decreased risk of bladder cancer progression, but no intravesical agent was associated with decreased risk of all-cause or bladder cancer mortality. Intravesical therapy appeared to be effective across subgroups defined by tumor stage, grade, multiplicity, recurrence status, and size (SOE: low). Evidence was too limited to draw strong conclusions regarding effects of dose or duration of therapy on effectiveness. Compared with no intravesical therapy, BCG was associated with a higher rate of local and systemic adverse events (granulomatous cystitis or irritative symptoms in 27% to 84% of patients, macroscopic hematuria in 21% to 72%, and fever in 27% to 44%) (SOE: low). Compared with MMC, BCG was also associated with an increased risk of local adverse events and fever (SOE: low). One randomized trial found no difference between radiation therapy and no radiation therapy in clinical outcomes in patients with T1G3 cancers.


Urinary biomarkers miss a substantial proportion of patients with bladder cancer, and additional research is needed to clarify advantages of fluorescent cystoscopy over white light cystoscopy. Intravesical therapy reduces risk of bladder cancer recurrence versus no intravesical therapy. BCG is the only intravesical therapy shown to be associated with decreased risk of bladder cancer progression, but it is associated with a high rate of adverse events. More research is needed to define optimal doses and regimens of intravesical therapy.

Journal Publications

Chou R, Gore JL, Buckley D, Fu R, Gustafson K, Griffin JC, et al. Urinary Biomarkers for Diagnosis of Bladder Cancer: A Systematic Review and Meta-analysis. Ann Intern Med. [Epub ahead of print 27 October 2015] doi:10.7326/M15-0997

Project Timeline

Emerging Approaches to Diagnosis and Treatment of Non-Muscle-Invasive Bladder Cancer

Feb 5, 2014
Jul 21, 2014
Oct 27, 2015
Systematic Review Archived
Page last reviewed December 2019
Page originally created November 2017

Internet Citation: Systematic Review: Emerging Approaches to Diagnosis and Treatment of Non–Muscle-Invasive Bladder Cancer. Content last reviewed December 2019. Effective Health Care Program, Agency for Healthcare Research and Quality, Rockville, MD.

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