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AHRQ--Agency for Healthcare Research and Quality: Advancing Excellence in Health Care

Topic Suggestion Description

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Date submitted: October 03, 2012

Briefly describe a specific question, or set of related questions, about a health care test or treatment that this program should consider.
Diagnosis and Treatment of Non-muscle Invasive Bladder Cancer

1. How do the accuracies of imaging tests, cystoscopy, urine cytology, urine-based biomarkers, transurethral resection of bladder tumor (TURBT) and new cystoscopic techniques compare to one another in the screening, diagnosis and staging of non-muscle invasive (clinically localized) bladder cancer?

2. How can physicians and patients manage side effects and complications associated with the available non-muscle invasive (clinically localized) bladder cancer treatment options?

3. Do peri-operative chemotherapy, intravesical chemotherapy or intravesical immunotherapy decrease the recurrence and progression of non-muscle invasive (clinically localized) bladder cancer when administered alone or in association with other available treatment options?

4. How can a physician best monitor a patient for cancer recurrence or progression following initial treatment for non-muscle invasive (clinically localized) bladder cancer?

5. How do tumor characteristics (stage, grade, multiplicity, size, molecular and genetic alterations) predict oncologic outcome following treatment of both initial and recurrent non-muscle invasive (clinically localized) bladder cancer?
Does your question include a comparison of different health care approaches? (If no, your topic will still be considered.)
If yes, explain the specific technologies, devices, drugs, or interventions you would like to see compared:
In recent years, there has been an intense search for non-invasive, adjunctive urine-based markers that could improve or perhaps replace cytology and cystoscopy in the diagnosis and surveillance of patients with urothelial cancers. The superiority of one test over another and the ideal clinical scenario for employing these tests remain unclear and confusing to the practicing physician.
The evidence report should compare the effectiveness of the various diagnostic methods for detection of bladder cancer:
- Cystoscopy
- Urine cytology
- Urine-based biomarkers (see below)
- Imaging tests

Controversy surrounds the use of the previously mentioned urine-based biomarkers in the diagnosis of bladder cancer. The evidence report should include information on the performance characteristics of these tests (listed in alphabetical order, no hierarchy implied) as well as additional biomarkers currently under investigation:
- BTA stat
- Cytokeratin
- NMP22
- Survivin
- Telomerase

The evidence report should include analysis and comparisons of treatment options for non-muscle invasive (clinically localized) bladder cancer, including information on oncologic outcomes, functional outcomes and quality of life for each management strategy. These treatment options include the following:
- Intravesical chemotherapy and immunotherapy (see below)
- Laser ablation therapy
- Conservative management (e.g., office fulguration or cystoscopic surveillance)
- Photodynamic therapy
- Definitive chemo-radiation therapy
- Cystectomy (partial and radical)

There are many intravesical and systemic therapies for the treatment of non-muscle invasive bladder cancer, used alone, in combination or adjunctive to surgical treatment. These therapies should be assessed for efficacy as a monotherapy and in combination, and include the following (listed in alphabetical order, no hierarchy implied):
- Paclitaxol
- Apaziquone
What patients or group(s) of patients does your question apply to? (Please include specific details such as age range, gender, coexisting diagnoses, and indications for therapy.)
• Adult men and women
As of January 1, 2009, there were approximately 554,347 men and women alive who had a history of bladder cancer. This includes 411,234 men and 143,113 women. Based on rates from 2007-2009, it is estimated that 1 in 42 men and women born today will be diagnosed with bladder cancer at some point during their lifetime. (Howlander 2012) This topic nomination is specifically looking at those patients diagnosed with localized, non-muscle invasive bladder cancer (stages Ta, T1 and Tis).
Are there subgroups of patients that your question might apply to? (For example, an ethnic group, stage or severity of a disease.)
• Elderly
• Women
• African Americans

Genetic and epidemiological evidence indicates that African Americans may have a more aggressive form of malignancy, and when diagnosed, bladder cancer may manifest itself at a more advanced stage. (Bladder Cancer Facts 2012) According to the Surveillance Epidemiology and End Results (SEER) program, from 1975 – 2005, African Americans had the poorest disease-specific survival (DSS) rate of any ethnicity. Five-year DSS was also consistently worse for African Americans than for any other ethnicity, even when stratified by stage and grade and adjusted for other patient characteristics and primary therapy. These findings remain consistent with a recent study conducted by SEER that reported an excess hazard of death from bladder cancer among African Americans despite adjustment of age, stage and grade. (Yee 2011)
Survival of the disease is higher in men than women with survival rates of women lagging behind that of men at all disease stages. (Bladder Cancer Advocacy Network 2012) For women over 65 years of age diagnosed between 1995 and 2000, the five-year survival rate was approximately 73%, while that of males was 82%.
Bladder cancer is diagnosed most often in the elderly population, with about 9 out of 10 bladder cancer patients over age 55; the average age at diagnosis is 73. (American Cancer Society 2006)

1. Howlander N, Noone AM, Krapcho M et al: SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). National Cancer Institute 2012; <>.
2. Bladder Cancer Facts. Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, UW Medicine. Seattle Cancer Care Alliance 2012; .
3. Yee D, Ishill M, Lowrance W et al: Ethnic differences in bladder cancer survival. Urology 2011; 78: 544.
4. Bladder Cancer Advocacy Network. BCAN 2012; <>.
5. Cancer Facts and Figures
Describe the health-related benefits you are interested in. (For example, improvements in patient symptoms or problems from treatment or diagnosis.)
• Improvement in early detection
• Reduction in the number of invasive procedures
• Improvement in treatment and follow-up
• Improved treatment alternatives for those unable to undergo traditional therapy
• Improvement in quality of life

There is currently a tremendous amount of research looking into genetic variants that predispose one to bladder cancer in hopes of earlier detection. Additionally, research is also looking into newer tests for substances in the urine that might indicate that a person has bladder cancer. While these tests currently look for recurrence in patients who have already been treated, researchers are now studying such tests to determine if they may help in the screening of patients before they begin to develop symptoms of the disease.

Currently, certain patients with low risk and recurrent non-muscle invasive bladder tumors may be managed conservatively with office fulguration of the lesions or even cystoscopic surveillance. (Soloway 2003, Donat 2004, Gofrit 2006) However, only those patients with a well-documented history of low grade Ta tumors have been considered for such an approach, in that the surgical and anesthetic risks of multiple repeated TURBT in these patients may exceed the low risk of disease progression. The evidence may indicate a broader group of patients who can be managed conservatively, thus reducing the cost of overutilization, unnecessary invasive procedures and possible complications.

There is an ever-expanding body of literature looking into the available surgical, chemotherapy and immunotherapy treatment options for patients once bladder cancer is diagnosed. For those patients unable to undergo surgery, there is a growing focus on alternative treatment options.

With so many options available in terms of diagnosis and treatment, a guideline such as that which will be created from the AHRQ evidence report will be able to provide physicians with the information necessary to make important decisio
Describe any health-related risks, side effects, or harms that you are concerned about.
• Risk of missed diagnosis
• Side-effects associated with chemo- and immunotherapy options
• Risks of intraoperative complications

While physicians continue to look for non-invasive diagnostic tools, the risk of a missed diagnosis is a constant concern. Additionally, there are multiple options for both chemotherapy and immunotherapy in addition to surgery following a diagnosis of bladder cancer; however, all options are associated with various side effects. Given that a majority of diagnoses are in the elderly population, such side effects have a tremendous impact on overall health. In addition, there is little consensus on proper follow-up procedures. Without a post-treatment strategy in place, recurrence and progression into a muscle-invasive stage is a concern, especially given that 75% of bladder transitional cell carcinomas (TCCs) have a proclivity for local recurrence. (Messing 2002)

1. Messing EM: Urothelial tumors of the urinary tract. Campbells Urology 8th edition 2002; 2732

Appropriateness for EHC Program

Does your question include a health care drug, intervention, device, or technology available (or likely to be available) in the U.S.?
Which priority area(s) and population(s) does this topic apply to? (check all that apply)
EHC Priority Conditions (updated in 2008)
  • Cancer
AHRQ Priority Populations
  • Low income groups
  • Minority groups
  • Women
  • Elderly
Federal Health Care Program
  • Medicaid
  • Medicare


Describe why this topic is important.
Malignant bladder cancer typically manifests in one of three forms: transitional cell carcinoma (TCC), squamous cell carcinoma (SCC) or adenocarcinoma. TCC occurs in the cells that line the bladder and is the most common form of bladder cancer, which accounts for 90% of all malignant tumors. (Messing 2002) This population of non-muscle invasive bladder tumors is highly heterogeneous and includes tumors that are papillary in nature and limited to the mucosa (Ta), high-grade and flat and confined to the epithelium (Tis) and those that invade into the submucosa or lamina propria (T1). Nearly 80% of patients who initially present with TCC have tumors confined to the mucosa or submucosa. (Pasin 2008)
In 2011 alone, it was anticipated that 69,250 new cases of bladder cancer would be diagnosed. Of those, 52,020 were anticipated to be men, 17,230 were anticipated to be women and 14,990 people would die from bladder cancer. While bladder cancer can be diagnosed at any age, it is more prevalent after the age of 65. (National Cancer Institute 2010)
The single most important risk factor for bladder cancer is smoking, which is accountable for approximately half of all female cases of bladder cancer. (National Cancer Institute 2010, Konety 2007) Former smokers are two times more likely to develop bladder cancer compared to those who have never smoked, and current smokers are four times more likely to develop the disease compared to non-smokers. (National Cancer Institute 2010) Other factors that can increase the risk of developing bladder cancer include aniline dyes used in coloring, printing and rubber industries; a history of radiation or cyclophosphamide chemotherapy; an overuse of analgesic phenacetin; increasing age; chronic bladder inflammation and a family history of the disease.
The most common symptom of bladder cancer is hematuria, most often gross, episodic and not associated with any type of pain. Other symptoms include frequent urination, painful urination
What specifically motivated you to ask this question? (For example, you are developing a clinical guideline, working with a policy with large uncertainty about the appropriate approach, costly intervention, new research you have read, items in the media you may have seen, a clinical practice dilemma you know of, etc.)
The AUA intends to use this systematic report developed by AHRQ as the basis for evidence-based guidelines. The creation of an evidence report on this topic would allow the AUA to create a clinical practice guideline in a relatively short timeframe as the data collection, extraction and analysis would have already been completed in adherence with the highest standards of systematic review. AUA guidelines are scientifically rigorous and evidence-based, and with a staff of six full-time professionals as well as extensive consultant support, the AUA Guidelines Department is well positioned to develop high-quality guidelines in a timely, efficient and effective manner.
The AUA Guidelines Department works closely with the AUA Foundation, committed to patient education and advocacy, to develop patient guides from its clinical practice guidelines. Following the 2007 publication of the AUA's most recent update to the bladder cancer guideline, the AUA continued its dedication to providing quality, evidence-based education through the dissemination of pocket guides to both urologic specialists and primary care physicians in addition to patients. The development of a newly-updated clinical practice guideline on bladder cancer would enable the AUA to develop additional material with a strong focus on the importance of patient counseling and education.
The AUA has previously partnered with AHRQ in the development of evidence reports on the Management of Female Overactive Bladder (OAB), Urinary Retention, Medical Recurrent Nephrolithiasis and Cryptorchidism. Following the publication of the OAB guideline in Spring of 2012, the AUA increased its previous dissemination efforts by producing a high-quality video for the purposes of continuing medical education (CME) with the help of additional support from Astellas. Additional patient and medical provider trifolds and spaced education tools were also produced. The AUA is pleased to have recently partnered with an organization to en
Does your question represent uncertainty for clinicians and/or policy-makers? (For example, variations in clinical care, controversy in what constitutes appropriate clinical care, or a policy decision.)
If yes, please explain:
There is currently extraordinary individual variability of both observational and randomized controlled trials, which makes it very difficult to consolidate data in a meaningful fashion to allow for robust conclusions to aid in the diagnosis, treatment and outcome prediction of non-muscle-invasive bladder cancer. Decision-making by urologist oftentimes is empirically-based, although more evidence is being published rapidly.
Progression is an important outcome with lethal implications, but the reduction of progression to muscle invasion and beyond the bladder remains unproven. Additionally, there is wide variation in the use of neoadjuvant/adjuvant therapy and extended lymph node dissection procedures.
Significant differences in practice patterns reflect the availability of a wide variety of drugs and delivery regimens. Many newer treatments and combinations of treatments have not yet been assessed. The clinician who is faced with a patient who presents with a specific clinical picture is often uncertain as to which treatment to recommend; a guideline such as that proposed for this evidence report would aid in the decision of treatment approach for such complex patients.
In a disturbing study of guideline compliance by physicians treating patients with bladder cancer, Chamie et al. (2011) found that there is tremendous variation in the delivery of care. In analyzing over 4,000 subjects, it was found that only a single patient received all of the recommended measures. This critical study points to the need for future studies that identify barriers to adoption of guidelines critical to improving care for a potentially curable cohort of patients.

1. Chamie K, Saigal CS, Lai J et al: Compliance with guidelines for patients with bladder cancer: variation in the delivery of care. Cancer 2011; 117:5392.

Potential Impact

How will an answer to your research question be used or help inform decisions for you or your group?
The AUA has a dynamic guideline development and dissemination process. The AUA Board of Directors has mandated that the AUA increase its number of guidelines as well as periodically update existing guidelines; as such, the AUA Guidelines team develops and updates a minimum of three new guidelines per year and assesses existing guidelines every two years.
The AUA publishes guidelines on its website as well as on the G-I-N website, and these are often accompanied by pocket guides for physicians as well as patient education materials. Following a guideline's publication, a summary manuscript is published in the Journal of Urology, which has extensive readership spanning both national and international clinical communities. Additionally, the AUA widely disseminates information about its guidelines through its annual meeting, the AUA Health Policy Brief, AUA News and through its Board of Directors and members. In addition, AUA is utilizing informaticists to help make guideline statements more actionable and relevant for electronic health records (EHRs). The creation of an AHRQ evidence report on bladder cancer will enable the AUA to develop a guideline to enhance physician knowledge and reduce treatment inequalities among both the urologic and primary care medical communities.
Describe the timeframe in which an answer to your question is needed.
The AUA is flexible. If it is possible to develop a guideline from the evidence report, development will begin the year in which the evidence report is issued. If, because of competing priorities to revise existing AUA guidelines, a guideline cannot begin, the evidence report will be posted on the web site immediately.
Describe any health disparities, inequities, or impact on vulnerable populations your question applies to.
While the prevalence of Caucasians developing bladder cancer is higher than African Americans, the mortality rates are similar, speculated to be because of a late diagnosis in African Americans. (National Cancer Institute 2010)

Additionally, the number of women diagnosed with bladder cancer is continually increasing. While significant findings are not confirmed, it has been suggested that overall survival rates are significantly lower due to the higher risk of being diagnosed with TCC, particularly in African American women, because of underreporting of urothelial cancers, delayed diagnosis and/or more frequent occurrence of more aggressive variants of TCC. (Jones 2012)

Medicare and Medicaid beneficiaries are certainly affected by bladder cancer. The elderly are typically insured by Medicare, and those individuals with a low income can be covered by both Medicare and Medicaid. Expenditures for lower tract TCC in Medicare enrollees over the age of 65 were $643 million in 2001, an increase of 33% since 1992. (Konety 2007)

1. National Cancer Institute: What You Need to Know About Bladder Cancer. National Institute of Health 2010; .

2. Jones J and Larchian W: Campbell-Walsh Urology 10th ed. Elsevier Saunders 2012.
3. Konety B, Joyce G and Wise M: Bladder and upper tract urothelial cancer. Urologic Diseases in America. National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health 2007; 225.

Nominator Information

Other Information About You: (optional)
Please choose a description that best describes your role or perspective: (you may select more than one category if appropriate)
  • Professional Society
Are you making a suggestion as an individual or on behalf of an organization?
Organization - AUA
Please tell us how you heard about the Effective Health Care Program
The AUA has previously partnered with AHRQ in the development of evidence reports on the Management of Female Overactive Bladder (OAB), Urinary Retention, Medical Recurrent Nephrolithiasis and Cryptorchidism.