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Emerging Approaches to Diagnosis and Treatment of Non–Muscle-Invasive Bladder Cancer
Comparative Effectiveness Reviews, No. 153
Investigators: Roger Chou, MD, FACP, David Buckley, MD, MPH, Rochelle Fu, PhD, John L Gore, MD, Katie Gustafson, MD, Jessica Griffin, MS, Sara Grusing, BA, and Shelley Selph, MD.
Author Information and AffiliationsStructured Abstract
Objectives:
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.
Results:
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.
Conclusions:
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.
Contents
- Preface
- Acknowledgments
- Key Informants
- Technical Expert Panel
- Peer Reviewers
- Executive Summary
- Introduction
- Methods
- Results
- Results of Literature Searches
- Key Question 1. What is the diagnostic accuracy of various urinary biomarkers compared with other urinary biomarkers or standard diagnostic methods (cystoscopy, cytology, and imaging) in (1) people with signs or symptoms warranting evaluation for possible bladder cancer or (2) people undergoing surveillance for previously treated bladder cancer?
- Key Question 1a. Does the diagnostic accuracy differ according to patient characteristics (e.g., age, sex, race/ethnicity) or according to the nature of the presenting signs or symptoms?
- Key Question 2. For patients with non–muscle-invasive bladder cancer, does the use of a formal risk-adapted assessment approach to treatment decisions (e.g., based on Guidelines of the European Association of Urology or on urinary biomarker tests) decrease mortality or improve other outcomes (e.g., recurrence, progression, need for cystectomy, quality of life) compared with treatment not guided by a formal assessed risk-adapted approach?
- Key Question 3. For patients with non–muscle-invasive bladder cancer treated with transurethral resection of bladder tumor, what is the effectiveness of various intravesical chemotherapeutic or immunotherapeutic agents for decreasing mortality or improving other outcomes (e.g., recurrence, progression, need for cystectomy, quality of life) compared with TURBT alone?
- Key Question 3a. What is the comparative effectiveness of various chemotherapeutic or immunotherapeutic agents, as monotherapy or in combination?
- Key Question 3b. Does the comparative effectiveness differ according to tumor characteristics, such as stage, grade, size, multiplicity, whether the tumor is primary or recurrent, or molecular/genetic markers?
- Key Question 3c. Does the comparative effectiveness differ according to patient characteristics, such as age, sex, race/ethnicity, performance status, or medical comorbidities?
- Key Question 3d. Does the comparative effectiveness of various chemotherapeutic or immunotherapeutic agents differ according to dosing frequency, duration of treatment, and/or the timing of administration relative to TURBT?
- Key Question 4. For patients with high-risk non–muscle-invasive bladder cancer treated with TURBT, what is the effectiveness of external beam radiation therapy (either alone or with systemic chemotherapy/immunotherapy) for decreasing mortality or improving other outcomes compared with intravesical chemotherapy/immunotherapy alone or cystectomy?
- Key Question 5. In surveillance of patients treated for non–muscle-invasive bladder cancer, what is the effectiveness of various urinary biomarkers to decrease mortality or improve other outcomes compared with other urinary biomarkers or standard diagnostic methods (cystoscopy, cytology, and imaging)?
- Key Question 5a. Does the comparative effectiveness differ according to tumor characteristics, such as histology, stage, grade, size, or molecular/genetic markers?
- Key Question 5b. Does the comparative effectiveness differ according to the treatment used (i.e., specific chemotherapeutic or immunotherapeutic agents and/or TURBT)?
- Key Question 5c. Does the comparative effectiveness differ according to the length of surveillance intervals?
- Key Question 5d. Does the comparative effectiveness differ according to patient characteristics, such as age, sex, or race/ethnicity?
- Key Question 6. For initial diagnosis or surveillance of patients treated for non–muscle-invasive bladder cancer, what is the effectiveness of blue light or other methods of augmented cystoscopy compared with standard cystoscopy for recurrence rates, progression of bladder cancer, mortality, or other clinical outcomes?
- Key Question 7. What are the comparative adverse effects of various tests for diagnosis and post-treatment surveillance of bladder cancer, including urinary biomarkers, cytology, and cystoscopy?
- Key Question 8. What are the comparative adverse effects of various treatments for non–muscle-invasive bladder cancer, including intravesical chemotherapeutic or immunotherapeutic agents and TURBT?
- Key Question 8a. How do adverse effects of treatment vary by patient characteristics, such as age, sex, race/ethnicity, performance status, or medical comorbidities such as chronic kidney disease?
- Discussion
- Conclusions
- References
- Abbreviations
- Addendum
- Appendix A. Search Strategies
- Appendix B. PICOTS
- Appendix C. Included Studies
- Appendix D. Excluded Studies
- Appendix E. Data Abstraction of Included Studies
- Appendix F. Risk of Bias
- Appendix G. Strength of Evidence
- Appendix H. Abbreviations Used in the Appendixes
Addendum November 2016
Suggested citation:
Chou R, Buckley D, Fu R, Gore JL, Gustafson K, Griffin J, Grusing S, Selph S. Emerging Approaches to Diagnosis and Treatment of Non–Muscle-Invasive Bladder Cancer. Comparative Effectiveness Review No. 153. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2012-00014-I.) AHRQ Publication No. 15(16)-EHC017-EF. Rockville, MD: Agency for Healthcare Research and Quality. October 2015. Addendum November 2016. www.effectivehealthcare.ahrq.gov/reports/final.cfm.
This report is based on research conducted by the Pacific Northwest Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2012-00014-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.
The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients.
AHRQ or U.S. Department of Health and Human Services endorsement of any derivative products that may be developed from this report, such as clinical practice guidelines, other quality enhancement tools, or reimbursement or coverage policies, may not be stated or implied.
This report may periodically be assessed for the currency of conclusions. If an assessment is done, the resulting surveillance report describing the methodology and findings will be found on the Effective Health Care Program Web site at www.effectivehealthcare.ahrq.gov. Search on the title of the report.
None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report.
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