Background and Objectives for the Systematic Review

Nature and burden of non-metastatic muscle-invasive bladder cancer

Bladder cancer is the fourth most commonly diagnosed cancer in men and tenth most commonly diagnosed cancer in women in the U.S.¹ The American Cancer Society estimates there will be 72,570 new cases of bladder cancer in the United States. in 2013 (about 54,610 men and 17,960 women), and about 15,210 deaths due to bladder cancer (about 10,820 men and 4,390 women).¹ The lifetime probability of developing bladder cancer in the U.S. is approximately 3.8 percent in men and 1.2 percent in women, although the incidence of bladder cancer is increasing in women. Bladder cancer occurs primarily in men older than 60 and roughly twice as frequently in white compared with black men,² though mortality is similar, presumably due to delayed diagnosis in black men.

Bladder cancer remains an important health problem, with no improvement in associated mortality since 1975.³ Economic analyses have shown bladder cancer to be the costliest cancer to treat in the U.S. on a per capita basis, taking into account diagnostic testing, management, and long term follow up.⁴ The most common risk factor for bladder cancer is smoking, though other risk factors include occupational exposures and family history. The most common symptom of bladder cancer is painless hematuria (blood in the urine).

Bladder cancer is staged based on the extent of penetration or invasion into the bladder wall and adjacent structures.⁵ Bladder cancers that have not invaded the bladder smooth muscle layer (stage classifications Tis, Ta and T1) are grouped as non-muscle-invasive bladder cancers. Stage 2 cancers are muscle-invasive, and higher stage cancers invade beyond the muscle layer into surrounding fat (stage classification T3 bladder cancer). Stage T4a cancers, which go beyond the fat into the prostate, vaginal wall, or uterus, are also still considered localized because the bladder is contiguous with these structures. Stage T4b cancer, in which the tumor has spread to the pelvis or abdominal wall, bladder cancer involving the lymph nodes (N>0), and metastatic bladder cancer (M1) are not amenable to potentially curative treatments and are outside the scope of this review. Approximately 25 percent of newly diagnosed bladder cancers present as stage 2 or higher tumors.⁶ Once bladder cancer invades muscle, it can quickly progress and metastasize, and is associated with a poor prognosis.

Interventions and outcomes for muscle-invasive bladder cancer

Once bladder cancer has been diagnosed, a number of factors affect prognosis and treatment options. These include the stage of the cancer, tumor grade, whether the tumor is an initial tumor or a recurrence, the patient’s age and general health, and other factors. A variety of molecular and other biomarkers, including p53, mTOR pathway genes, MRE11, BRCA1, ERCC1, MDR1, ET-1, and others, have also been evaluated for their prognostic value and to inform selection of treatments.⁷ For non-metastatic muscle-invasive bladder cancer, the gold standard treatment option is cystectomy combined with neoadjuvant systemic chemotherapy with combination gemcitabine and cisplatin. Other commonly used chemotherapeutic regimens are methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); cisplatin, methotrexate, and vinblastine (CMV); and gemcitabine plus carboplatin.⁸ Patients with bladder cancer are often elderly and have multiple medical comorbidities. Factors such as performance status and renal function must be considered in relation to treatment effectiveness and adverse effects. Medically frail patients may not be good candidates for cisplatin because of potential renal toxicity. These treatments are FDA approved and clinically available in the U.S. Regional lymph node dissection is important to diagnosis of lymph node metastases and may be associated with improved cancer-specific survival.^9-11 Thus, lymph node dissection in conjunction with cystectomy or partial cystectomy is recommended.⁸ Yet reviews of population-based data suggest heterogeneity¹¹ in performance of lymph node dissection, possibly due to provider uncertainty about its benefit. Similarly, because removal of the urinary bladder necessitates reconstruction with a urinary diversion, cystectomy appears to be underused for non-metastatic muscle-invasive bladder cancer.¹² Alternative bladder-sparing options combining maximal transurethral resection of bladder tumor (TURBT), chemotherapy, and/or radiation have been investigated. Maximal TURBT denotes resection of all visible tumor into deep muscle or perivesical fat with at least 1 cm resected margin of normal mucosa.¹³ Several modalities of radiation therapy have been evaluated, including external beam radiation therapy and interstitial radiation therapy (brachytherapy). These alternative treatments are generally only recommended for carefully selected, well-informed patients due to the need for continued surveillance and invasive diagnostic procedures, and the risk of eventual cystectomy.⁸ The comparative effectiveness of these treatments or their combinations is uncertain. A systematic evidence review that includes recently published research may provide a better understanding of the comparative effectiveness of these treatments for muscle-invasive bladder cancer.

Rationale for evidence review

There do not appear to be many, if any, systematic reviews of the comparative effectiveness of treatment options for muscle-invasive bladder cancer. A systematic review of this topic may be used to develop a comprehensive clinical guideline for muscle-invasive bladder cancer. Existing recommendations are several years old and current guidelines may not represent the current landscape for treatment of muscle-invasive bladder cancer.

Key Questions

The Agency for Healthcare Research and Quality (AHRQ) initially received this topic as a nomination via the Effective Health Care Web site. The Scientific Resource Center (SRC) developed preliminary Key Questions (KQs) based on input from the topic nominator. The Evidence-based Practice Center (EPC) revised the KQs and developed eligibility criteria to identify the populations, interventions, comparators, outcomes, timing, and study designs (PICOTS) of interest. The EPC further refined the KQs and PICOTS based on input from interviews with the Key Informants. The KQs and PICOTS were then posted for public comment from February 6, 2014 through February 26, 2014, and comments were received from four individuals. In response to public comments, the EPC added “functional status” as an outcome of interest to KQ1, KQ2, and KQ3. Based on additional input from a Technical Expert Panel convened for this report (see Technical Experts, below), we restricted systemic chemotherapeutic regimens to combination regimens currently in use.

Key Question 1

For patients with non-metastatic muscle-invasive bladder cancer, what is the effectiveness of bladder-preserving treatments (chemotherapy, external beam or interstitial radiation therapy, partial cystectomy, and/or maximal transurethral resection of bladder tumor) for decreasing mortality or improving other outcomes (e.g., recurrence, metastasis, quality of life, functional status) compared with cystectomy alone or cystectomy in combination with chemotherapy?

1. Does the comparative effectiveness differ according to tumor characteristics, such as histology, stage, grade, size, or molecular/genetic markers?
2. Does the comparative effectiveness differ according to patient characteristics, such as age, sex, ethnicity, performance status, or medical comorbidities such as chronic kidney disease?
3. What is the comparative effectiveness of various combinations of agents and/or radiation therapy used for bladder-preserving chemotherapy?
4. What is the effectiveness of different bladder-preserving treatments (chemotherapy, external beam or interstitial radiation therapy, partial cystectomy and/or maximal transurethral resection of bladder tumor) compared with one another?

Key Question 2

For patients with clinically non-metastatic muscle-invasive bladder cancer that is treated with cystectomy, does regional lymph node dissection improve outcomes compared with cystectomy alone?

1. Does the comparative effectiveness differ according to tumor characteristics, such as histology, stage, grade, size, or molecular/genetic markers?
2. Does the comparative effectiveness differ according to the extent of the regional lymph node dissection (e.g., as measured by the number of lymph nodes removed)?

Key Question 3

For patients with non-metastatic muscle-invasive bladder cancer that is treated with cystectomy, does neo-adjuvant or adjuvant chemotherapy improve outcomes compared with cystectomy alone?

1. What is the comparative effectiveness of various combinations of agents used for neo-adjuvant or adjuvant chemotherapy?
2. Does the comparative effectiveness of various combinations of agents used for neo-adjuvant or adjuvant chemotherapy differ according to tumor characteristics, such as histology, stage, grade, size, or molecular/genetic markers?
3. Does the comparative effectiveness differ according to patient characteristics, such as age, sex, ethnicity, performance status, or medical comorbidities such as chronic kidney disease?
4. Does the comparative effectiveness of neo-adjuvant or adjuvant chemotherapy differ according to dosing frequency and/or the timing of its administration relative to cystectomy?

Key Question 4

What are the comparative adverse effects of treatments for non-metastatic muscle-invasive bladder cancer?

1. How do adverse effects of treatment vary by patient characteristics, such as age, sex, ethnicity, performance status, or medical comorbidities such as chronic kidney disease?

PICOTS

Population

Adults with node-negative, non-metastatic muscle-invasive bladder cancer (stages T2, T3, T4a)

Interventions

• For KQ 1, KQ 4: Bladder-preserving chemotherapy,* radiation therapy (external beam or interstitial radiation therapy), partial cystectomy, or maximal transurethral resection of bladder tumor
• For KQ 2: Regional lymph node dissection in conjunction with cystectomy or partial cystectomy
• For KQ 3, KQ 4: Cystectomy plus neo-adjuvant and/or adjuvant chemotherapy*

Comparators

• For KQ 1, KQ 3, and KQ 4: Cystectomy alone
• For KQ 1 and KQ 4: Cystectomy in combination with chemotherapy
• For KQ 1: Bladder-preserving chemotherapy, radiation therapy (external beam or interstitial radiation therapy), partial cystectomy, and/or maximal transurethral resection of bladder tumor
• For KQ 2: Cystectomy without lymph node dissection

Outcomes

• For KQ 1, KQ 2, KQ 3: Mortality, disease-specific and all-cause (primary outcome)
• For KQ 1, KQ 2, KQ 3: Recurrence of bladder cancer
• For KQ 1, KQ 2, KQ 3: Progression or metastasis of bladder cancer
• For KQ 1, KQ 2, KQ 3: Quality of life
• For KQ 1, KQ 2, KQ 3: Functional status
• For KQ 4: Complications or adverse effects related to treatment with chemotherapy (e.g, myelosuppression, neuropathy, acute kidney injury, venous thromboembolic events), radiation therapy (e.g., cystitis, hematuria, pain, proctitis), and cystectomy with or without lymph node dissection (e.g., operative mortality, bowel fistula, urinary obstruction, surgical site infections, hernia).

Timing

Any duration of follow-up

Setting

Any setting in which treatment for non-metastatic muscle-invasive bladder cancer occurs

* Chemotherapeutic regimens of interest are: carboplatin and gemcitabine; cisplatin and gemcitabine; “CMV” (cisplatin, methotrexate, and vinblastine); and “MVAC” (methotrexate, vinblastine, doxorubicin, and cisplatin).

Analytic Framework

Figure 1. Provisional analytic framework for Treatment of Non-metastatic Muscle-invasive Bladder Cancer

^a Questions on diagnostic testing and identification of patients with muscle-invasive bladder cancer are addressed in a complementary review of non-muscle-invasive bladder cancer
^b Treatments include: bladder-preserving chemotherapy and/or radiation therapy, partial cystectomy, maximal transurethral resection of bladder tumor [KQ 1]; regional lymph node dissection [KQ 2]; neo-adjuvant or adjuvant chemotherapy [KQ 3]

Methods

A. Criteria for Inclusion/Exclusion of Studies in the Review

The criteria for inclusion and exclusion of studies will be based on the Key Questions and discussion with TEP members, and are described in the previous PICOTS section.

Below are additional details on the scope of this project:

Study Designs

We will include randomized controlled trials (RCTs), and cohort studies with comparators when RCTs are not available, for all KQs. Additionally, we will exclude uncontrolled observational studies, case-control studies, case series, and case reports, as these studies are less informative than studies with a control group.

Systematic reviews will be used as primary sources of evidence if they address a key question and are assessed as being at low risk of bias, according to the AMSTAR quality assessment tool.^14,15 If systematic reviews are included, we will update findings with any new primary studies identified in our searches, update meta-analyses if appropriate, and re-assess SOE based on the totality of evidence. If multiple systematic reviews are relevant and low risk of bias, we will focus on the findings from the most recent reviews and evaluate areas of consistency across the reviews.^16,17

Non-English Language Studies

We will restrict to English-language articles, but will review English language abstracts of non-English language articles to identify studies that would otherwise meet inclusion criteria, in order to assess for the likelihood of language bias.

B. Searching for the Evidence: Literature Search Strategies for Identification of Relevant Studies to Answer the Key Questions

Publication Date Range

Searches will begin in January 1990, a date early enough to capture all relevant published studies of current treatments for bladder cancer.

Library searches will be updated while the draft report is posted for public comment and peer review to capture any new publications. Literature identified during the update search will be assessed by following the same process of dual review as all other studies considered for inclusion in the report. If any pertinent new literature is identified for inclusion in the report, it will be incorporated before the final submission of the report.

Literature Databases

Ovid MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Health Technology Assessment, National Health Sciences Economic Evaluation Database, and Database of Abstracts of Reviews of Effects will be searched to capture both published and grey literature. See Appendix A for the primary Ovid MEDLINE search strategy.

Scientific Information Packets

Scientific information packets (SIPs) will be requested from drug and device manufacturers and a notice inviting submission of relevant scientific information will be published in the Federal Register in an effort to identify any relevant unpublished literature that may contribute to the body of evidence. All interested parties will have the opportunity to submit data for this review during a four-week period, using the AHRQ Effective Health Care Web site publicly accessible online SIP portal (https://effectivehealthcare.ahrq.gov/get-involved/submit-sead/).

Manufacturers of currently available and FDA approved treatments for MIBC will be invited to provide SIPs.

Hand Searching

Reference lists of included articles will also be reviewed for includable literature. Searches will also be supplemented by suggestions from the TEP.

Contacting Authors

In the event that information regarding methods or results appears to be omitted from the published results of a study, or if we are aware of unpublished data, we will query the authors to obtain this information.

Process for Selecting Studies

The KQs and PICOTS described above will be used to determine eligibility for inclusion and exclusion of abstracts in accordance with the AHRQ Methods Guide. To ensure accuracy, all excluded abstracts will be dual reviewed. All citations deemed appropriate for inclusion by at least one of the reviewers will be retrieved. Each full-text article will be independently reviewed for eligibility by two team members, including any articles suggested by peer reviewers or that arise from the public posting process. Any disagreements will be resolved by consensus.

C. Data Abstraction and Data Management

After studies are selected for inclusion, data will be abstracted into categories that include but are not limited to: study design, year, setting, country, sample size, eligibility criteria, population and clinical characteristics (age, sex, bladder cancer stage, performance status), intervention characteristics (drugs, dosage, duration), and results relevant to each key question as outlined in the previous PICOTS section. Information that will be abstracted that is relevant for assessing applicability will include the number of patients randomized relative to the number of patients enrolled, and characteristics of the population, intervention, and care settings. Sources of funding for all studies will also be recorded. All study data will be verified for accuracy and completeness by a second team member. A record of studies excluded at the full-text level with reasons for exclusion will be maintained.

D. Assessment of Methodological Risk of Bias of Individual Studies

Predefined criteria will be used to assess the risk of bias for individual controlled trials, systematic reviews, and observational studies by using clearly defined templates and criteria as appropriate. Studies will be evaluated using appropriate criteria developed by the U.S. Preventive Services Task Force.¹⁸ Systematic reviews will be assessed using the AMSTAR quality rating instrument.¹⁵ These criteria and methods will be used in conjunction with the approach recommended in the chapter, Assessing the Risk of Bias of Individual Studies When Comparing Medical Interventions in the AHRQ Methods Guide developed by the Agency for Healthcare Research and Quality.¹⁴ Studies will be rated as “low risk of bias,” “medium risk of bias,” or “high risk of bias.”^17,19

Studies rated “low risk of bias” will be considered to have the least risk of bias, and their results will be considered valid. “Low risk of bias” studies include clear descriptions of the population, setting, interventions, and comparison groups; a valid method for allocation of patients to treatment; low dropout rates and clear reporting of dropouts; appropriate means for preventing bias; and appropriate measurement of outcomes.

Studies rated “medium risk of bias” will be susceptible to some bias, though not enough to invalidate the results. These studies may not meet all the criteria for a rating of low risk of bias, but no flaw likely to cause major bias. The study may be missing information, making it difficult to assess limitations and potential problems. The “medium risk of bias” category is broad, and studies with this rating will vary in their strengths and weaknesses. The results of some medium risk of bias studies are likely to be valid, while others may be only possibly valid.

Studies rated “high risk of bias” will have significant flaws that imply biases of various types that may invalidate the results. They will have a serious or “fatal” flaw or flaws in design, analysis, or reporting; large amounts of missing information; discrepancies in reporting; or serious problems in the delivery of the intervention. Studies with fatal flaws have one or more serious issues that introduce a high risk of bias as identified during assessment using the criteria outlined above.^18,20 An example of a study with a fatal flaw would be a study with very high loss to follow up (e.g., >60%), failure to perform appropriate intention-to-treat analyses, and/or use of inadequate randomization procedures (e.g., alternating allocation). The results of these studies will be at least as likely to reflect flaws in the study design as the true difference between the compared interventions. We will not exclude studies rated as being high risk of bias a priori, but high risk of bias studies will be considered to be less reliable than low or medium risk of bias studies when synthesizing the evidence, particularly if discrepancies between studies are present.

Each study evaluated will be independently reviewed for risk of bias by two team members. Any disagreements will be resolved by consensus.

E. Data Synthesis

We will review and highlight studies by using a hierarchy-of-evidence approach, where the best evidence is the focus of our synthesis for each key question.

We will construct summary tables to highlight the main findings. Qualitative data will be summarized in summary tables and as ranges and descriptive analysis and interpretation of the results will be provided.

Meta-analyses will be conducted to summarize data and obtain more precise estimates on outcomes for which studies are similar enough to provide a meaningful combined estimate. The feasibility of a quantitative synthesis will depend on the number and completeness of reported outcomes and a lack of heterogeneity among the reported results. To determine whether meta-analysis could be meaningfully performed, we will consider the risk of bias for each of the studies and the heterogeneity among studies in design, patient population, interventions, and outcomes, and may conduct sensitivity analyses. Meta-regression may be conducted to explore statistical heterogeneity using additional variables on methodological or other characteristics (e.g., risk of bias, randomization or blinding, outcome definition and ascertainment) given enough number of studies.

Results will be presented as structured by the key questions, and any prioritized outcomes will be presented first.

F. Grading the Strength of Evidence (SOE) for Major Comparisons and Outcomes

The strength of evidence for each key question will be initially assessed by one researcher for each clinical outcome (see PICOTS) by using the approach described in the AHRQ Methods Guide.¹⁴ To ensure consistency and validity of the evaluation, the grades will be reviewed by the entire team of investigators for:

• Risk of bias (low, medium, or high risk of bias)
• Consistency (consistent, inconsistent, or unknown/not applicable)
• Directness (direct or indirect)
• Precision (precise or imprecise)
• Reporting bias (suspected or undetected)

Assessments of reporting bias will be based on whether studies defined and reported primary outcomes, and when available, by comparing published results to results reported in trial registries. The strength of evidence will be assigned an overall grade of high, moderate, low, or insufficient according to a four-level scale by evaluating and weighing the combined results of the above domains:

• High — We are very confident that the estimate of effect lies close to the true effect for this outcome. The body of evidence has few or no deficiencies. We believe that the findings are stable, i.e., another study would not change the conclusions.
• Moderate — We are moderately confident that the estimate of effect lies close to the true effect for this outcome. The body of evidence has some deficiencies. We believe that the findings are likely to be stable, but some doubt remains.
• Low — We have limited confidence that the estimate of effect lies close to the true effect for this outcome. The body of evidence has major or numerous deficiencies (or both). We believe that additional evidence is needed before concluding either that the findings are stable or that the estimate of effect is close to the true effect.
• Insufficient — We have no evidence, we are unable to estimate an effect, or we have no confidence in the estimate of effect for this outcome. No evidence is available or the body of evidence has unacceptable deficiencies, precluding reaching a conclusion

G. Assessing Applicability

Applicability will be estimated by examining the characteristics of the patient populations (e.g., demographic characteristics; stage of disease; performance status); interventions; and settings (e.g., patients in developing countries) in which the studies are performed. Issues with applicability may limit the ability to generalize the results to other populations and settings.

References

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30. PMID: 23335087.
2. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2009 Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute;2013.
3. National Cancer Institute Surveillance Research Program. Surveillance Epidemiology and End Results. Browse the SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). https://seer.cancer.gov/csr/1975_2009_pops09/browse_csr.php?section=27&page=sect_27_table.01.html. Accessed October 16th, 2013.
4. James AC, Gore JL. The costs of non-muscle invasive bladder cancer. Urol Clin North Am. 2013;40(2):261-9. PMID: 23540783.
5. American Cancer Society. Bladder Cancer; Early Detection, Diagnosis, and Staging Topics. http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-staging. Accessed October 16th, 2013.
6. Konety BR, Joyce GF, F. W. Bladder and upper tract urothelial cancer. Vol 07-5512. Washington, DC: US Government Printing Office; 2007. PMID: 17437776.
7. Ru Y, Dancik GM, Theodorescu D. Biomarkers for prognosis and treatment selection in advanced bladder cancer patients. Curr Opin Urol. 2011;21(5):420-7. PMID: 21814055.
8. Stenzl A, Witjes JA, Compérat E. Guidelines on Bladder Cancer Muscle-invasive and Metastatic. 2012.
9. Bruins HM, Huang GJ, Cai J, et al. Clinical outcomes and recurrence predictors of lymph node positive urothelial cancer after cystectomy. J Urol. 2009;182(5):2182-7. PMID: 19758623.
10. Stein JP, Cai J, Groshen S, et al. Risk factors for patients with pelvic lymph node metastases following radical cystectomy with en bloc pelvic lymphadenectomy: concept of lymph node density. J Urol. 2003;170(1):35-41. PMID: 12796639.
11. Wright JL, Lin DW, Porter MP. The association between extent of lymphadenectomy and survival among patients with lymph node metastases undergoing radical cystectomy. Cancer. 2008;112(11):2401-8. PMID: 18383515.
12. Gore JL, Litwin MS, Lai J, et al. Use of radical cystectomy for patients with invasive bladder cancer. J Natl Cancer Inst. 2010;102(11):802-11. PMID: 20400716.
13. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol. 2001;19(1):89-93. PMID: 11134199.
14. Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. 2013; https://effectivehealthcare.ahrq.gov/products/cer-methods-guide/overview/. Accessed April 4th, 2014.
15. Shea BJ, Hamel C, Wells GA, et al. AMSTAR is a reliable and valid measurement tool to assess the methodological quality of systematic reviews. J Clin Epidemiol. 2009;62(10):1013-20. PMID: 19230606.
16. White CM, Ip S, McPheeters M, et al. Using Existing Systematic Reviews to Replace De Novo Processes in Conducing Comparative Effectiveness Reviews.: Agency for Healthcare Research and Quality. Methods Guide for Comparative Effectiveness Reviews [posted September 2009]. Available at: https://effectivehealthcare.ahrq.gov/products/methods-guidance-de-novo-processes/methods/. PMID: 21433402.
17. Whitlock EP, Lin JS, Chou R, et al. Using existing systematic reviews in complex systematic reviews. Ann Intern Med. 2008;148(10):776-82. PMID: 18490690.
18. U.S. Preventive Services Task Force. U.S. Preventive Services Task Force Procedure Manual. [Web Page]. 2008; https://www.uspreventiveservicestaskforce.org/uspstf08/methods/procmanual.htm. Accessed April 4th, 2014.
19. Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med. 2001;20(3 Suppl):21-35. PMID: 11306229.
20. McDonagh MS, Jonas DE, Gartlehner G, et al. Methods for the drug effectiveness review project. BMC Med Res Methodol. 2012;12:140. PMID: 22970848.

Definition of Terms

• Bladder Cancer: Cancer that starts in the bladder, the part of the body that holds and releases urine.
• Cystectomy: Surgical removal of all or part of the urinary bladder.
• Hematuria: Blood in the urine.
• Immunotherapy: Treatment that induces, enhances, or suppresses the immune response in order to treat a disease (e.g., cancer).
• Intravesical Therapy: A drug (chemotherapy or immunotherapy) directly into the bladder through a catheter rather than giving it by mouth or injecting it into a vein.

Summary of Protocol Amendments

If we need to amend this protocol, we will give the date of each amendment, describe the change and give the rationale in this section. Changes will not be incorporated into the protocol.

Review of Key Questions

AHRQ posted the key questions on the Effective Health Care Website for public comment. The EPC refined and finalized the key questions after review of the public comments, and input from Key Informants and the Technical Expert Panel (TEP). This input is intended to ensure that the key questions are specific and relevant.

Key Informants

Key informants are the end users of research, including patients and caregivers, practicing clinicians, relevant professional and consumer organizations, purchasers of health care, and others with experience in making health care decisions. Within the EPC program, the key informant role is to provide input into identifying the Key Questions for research that will inform healthcare decisions. The EPC solicits input from key informants when developing questions for systematic review or when identifying high priority research gaps and needed new research. Key informants are not involved in analyzing the evidence or writing the report and have not reviewed the report, except as given the opportunity to do so through the peer or public review mechanism.

Key informants must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their role as end-users, individuals are invited to serve as key informants and those who present with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.

Technical Experts

Technical experts constitute a multi-disciplinary group of clinical, content, and methodological experts who provide input in defining populations, interventions, comparisons, or outcomes and identify particular studies or databases to search. They are selected to provide broad expertise and perspectives specific to the topic under development. Divergent and conflicting opinions are common and perceived as health scientific discourse that results in a thoughtful, relevant systematic review. Therefore study questions, design, and methodological approaches do not necessarily represent the views of individual technical and content experts. Technical experts provide information to the EPC to identify literature search strategies and recommend approaches to specific issues as requested by the EPC. Technical experts do not do analysis of any kind nor do they contribute to the writing of the report. They have not reviewed the report, except as given the opportunity to do so through the peer or public review mechanism.

Technical experts must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals are invited to serve as technical experts and those who present with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.

Peer Reviewers

Peer reviewers are invited to provide written comments on the draft report based on their clinical, content, or methodological expertise. The EPC considers all peer review comments on the draft report in preparation of the final report. Peer reviewers do not participate in writing or editing of the final report or other products. The final report does not necessarily represent the views of individual reviewers. The EPC will complete a disposition of all peer review comments. The disposition of comments for systematic reviews and technical briefs will be published three months after the publication of the evidence report.

Potential peer reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Invited peer reviewers may not have any financial conflict of interest greater than $10,000. Peer reviewers who disclose potential business or professional conflicts of interest may submit comments on draft reports through the public comment mechanism.

EPC Team Disclosures

EPC core team members must disclose any financial conflicts of interest greater than $1,000 and any other relevant business or professional conflicts of interest. Related financial conflicts of interest that cumulatively total greater than $1,000 will usually disqualify EPC core team investigators.

Role of the Funder

This project was funded under Contract No. xxx-xxx from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The Task Order Officer reviewed contract deliverables for adherence to contract requirements and quality. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Appendix

Appendix A: Search Strategy

Primary Search Strategy (Ovid MEDLINE) for Emerging Approaches to Diagnosis and Treatment of Non-Muscle-Invasive Bladder Cancer and Treatment of Non-metastatic Muscle-invasive Bladder Cancer

1. exp Urinary Bladder Neoplasms/ (42649)
2. ((((non or "not") adj (invas$ or invad$ or infiltrat$)) or noninvas$ or noninvad$ or noninfiltrat$) adj5 muscle$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (560)
3. (cis or Tis or ta or t1$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (171383)
4. 2 or 3 (171904)
5. ((sign or signs or symptom$ or possib$ or suspect$ or potential$) adj5 (bladder$ adj3 (cancer$ or tumor$ or tumour$ or neoplas$ or carcino$ or malig$ or adenocarcin$))).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (1411)
6. 4 or 5 (173181)
7. 1 and 6 (4066)
8. exp Biological Markers/ (599845)
9. 7 and 8 (577)
10. ((urin$ adj3 biomark$) or bladder tumor associated antigen$ or nuclear matrix protein or nmp22 or fluorescence in situ hybrid$ or (fish adj assay$) or fibroblast growth factor receptor 3 or fgfr3 or cxbladder or immunocyt or cytokeratin fragment$ or cyfra 21-1 or (cytokerat$ adj3 (tpa or tps)) or survivin or telomeras$ or vascular endothelial growth factor$ or vegf or metalloproteinas$ or mmp-2 or mmp-9 or twist homolog$ or twist1 or nidogen-2 or nid2).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (135002)
11. 7 and 10 (290)
12. ((assess$ or analyz$ or judg$ or consider$ or quantif$ or predict$ or identif$ or adapt$) adj7 risk$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (348853)
13. exp Surgical Procedures, Operative/ (2324899)
14. exp Drug Therapy/ (1046457)
15. exp Antineoplastic Agents/ (806939)
16. exp Radiotherapy/ (134644)
17. (th or su or rt or dh or dt).fs. (4403551)
18. 13 or 14 or 15 or 16 or 17 (6203229)
19. 12 and 18 (143282)
20. 7 and 19 (165)
21. (mitomycin$ or apaziquone or paclitaxel or gemcitabine or thiotepa or valrubicin or doxorubicin or bacillus calmette guerin or bcg or interferon$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (260287)
22. 7 and 21 (1034)
23. (electromotiv$ or emda).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (438)
24. 1 and 23 (29)
25. (blue adj5 cystoscop$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (40)
26. 1 and 25 (30)
27. exp Radiotherapy/ (134644)
28. rt.fs. (153801)
29. 27 or 28 (215263)
30. 7 and 29 (231)
31. 9 or 11 or 20 or 22 or 24 or 26 or 30 (2005)
32. exp Urinary Bladder Neoplasms/ (42649)
33. ((invas$ or invad$ or infiltrat$) adj5 muscl$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (5934)
34. (t2$ or t3$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (92421)
35. 33 or 34 (97810)
36. 32 and 35 (4517)
37. cystectom$.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (10382)
38. ((excis$ or remov$ or ((cut or cutting or cuts) adj3 (out or away))) adj5 bladder$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (1540)
39. 37 or 38 (11727)
40. (bladder$ adj5 (spare or sparing or spares or spared or preserv$)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (1201)
41. (avoid$ adj7 cystectom$).mp. (51)
42. 40 or 41 (1247)
43. exp Lymph Node Excision/ (34323)
44. ((excis$ or remov$ or ((cut or cutting or cuts) adj3 (out or away))) adj5 (lymph$ or node or nodes)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (29000)
45. 43 or 44 (38668)
46. (adjuvant$ or neoadjuvant$).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (146279)
47. (abraxane or carboplatin$ or cisplatin$ or docetaxel or doxorubicin or epirubicin or 5-fluorouracil or gemcitabine or methotrexate or mitomycin or paclitaxel or valrubicin or vinblastin).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] (181085)
48. 46 or 47 (308733)
49. 39 or 42 or 45 or 48 (350734)
50. 36 and 49 (2242)
51. 31 or 50 (3863)
52. limit 51 to yr="1990 -Current" (3413)
53. limit 52 to english language (2874)
54. limit 52 to abstracts (3288)
55. 53 or 54 (34)