AUA/SUO Joint Guideline: Published 2016

Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline provides a risk-stratified clinical framework for the management of non-muscle invasive bladder cancer. Diagnosis and use of urine markers is discussed in addition to variant histologies, resection, intravesical therapy, BCG therapy, cystectomy, enhanced cystoscopy, and patient follow up.

Unabridged version of this Guideline [pdf]
Algorithm associated with this Guideline [pdf]

Sam S. Chang, MD, MBA; Stephen A. Boorjian, MD; Roger Chou, MD; Peter E. Clark, MD; Siamak Daneshmand, MD; Badrinath R. Konety, MD, FACS, MBA; Raj Pruthi, MD, FACS; Diane Z. Quale; Chad R. Ritch, MD, MBA; John D. Seigne, MD; Eila Curlee Skinner, MD; Norm D. Smith, MD; James M. McKiernan, MD

Purpose

The survival rate for the majority of patients with non-muscle invasive bladder cancer (NMIBC) is favorable; however, the rates of recurrence and progression to muscle-invasive bladder cancer (MIBC) are important surrogate endpoints for overall prognosis, as these are major determinants of long-term outcome. The recurrence and progression probability rates depend on several clinical and pathologic factors. Therefore, the ability to predict risk of recurrence and progression and treat the disease appropriately is important. This guideline provides a risk-stratified clinical framework for the management of NMIBC. Please also refer to the associated Non-Muscle Invasive Bladder Cancer Treatment Algorithm.

Methodology

The systematic review utilized in the creation of this guideline was completed in part through the Agency for Healthcare Research and Quality (AHRQ) and through additional supplementation that further addressed additional key questions and more recently published literature. A research librarian experienced in conducting literature searches for comparative effectiveness reviews searched in 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 3rd Quarter, 2014), National Health Sciences Economic Evaluation Database (through 3rd Quarter, 2014), and Database of Abstracts of Reviews of Effects (through 3rd Quarter, 2014) to capture both published and grey literature. Database searches resulted in 3,740 potentially relevant articles. After dual review of abstracts and titles, 643 articles were selected for full-text dual review, and 149 studies (in 192 publications) were determined to meet inclusion criteria and were included in this review. The AHRQ review was then updated by a consultant methodologist though September 2, 2015. Reference lists and previous systematic reviews were also reviewed for additional studies. This supplementation added 29 studies to the completed systematic review used in the creation of guideline statements. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate) or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. The 38 statements created vary in level of evidence, but none include Level A evidence, and a majority are Level C evidence.

Guideline Statements

Diagnosis

1. At the time of resection of suspected bladder cancer, a clinician should perform a thorough cystoscopic examination of a patient’s entire urethra and bladder that evaluates and documents tumor size, location, configuration, number, and mucosal abnormalities. (Clinical Principle)
2. At initial diagnosis of a patient with bladder cancer, a clinician should perform complete visual resection of the bladder tumor(s), when technically feasible. (Clinical Principle)
3. A clinician should perform upper urinary tract imaging as a component of the initial evaluation of a patient with bladder cancer. (Clinical Principle)
4. In a patient with a history of NMIBC with normal cystoscopy and positive cytology, a clinician should consider prostatic urethral biopsies and upper tract imaging, as well as enhanced cystoscopic techniques (blue light cystoscopy, when available), ureteroscopy, or random bladder biopsies. (Expert Opinion)

Risk Stratification

5. At the time of each occurrence/recurrence, a clinician should assign a clinical stage and classify a patient accordingly as “low-,” “intermediate-,” or “high-risk.” (Moderate Recommendation; Evidence Strength: Grade C)

Variant Histologies

6. An experienced genitourinary pathologist should review the pathology of a patient with any doubt in regards to variant or suspected variant histology (e.g., micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid), extensive squamous or glandular differentiation, or the presence/absence of LVI. (Moderate Recommendation; Evidence Strength: Grade C)
7. If a bladder sparing approach is being considered in a patient with variant histology, then a clinician should perform a restaging TURBT within four to six weeks of the initial TURBT. (Expert Opinion)
8. Due to the high rate of upstaging associated with variant histology, a clinician should consider offering initial radical cystectomy. (Expert Opinion)

Urine Markers after Diagnosis of Bladder Cancer

9. In surveillance of NMIBC, a clinician should not use urinary biomarkers in place of cystoscopic evaluation. (Strong Recommendation; Evidence Strength: Grade B)
10. In a patient with a history of low-risk cancer and a normal cystoscopy, a clinician should not routinely use a urinary biomarker or cytology during surveillance. (Expert Opinion)
11. In a patient with NMIBC, a clinician may use biomarkers to assess response to intravesical BCG (UroVysion® FISH) and adjudicate equivocal cytology (UroVysion® FISH and ImmunoCyt™). (Expert Opinion)

TURBT/Repeat Resection: Timing, Technique, Goal, Indication

12. In a patient with non-muscle invasive disease who underwent an incomplete initial resection (not all visible tumor treated), a clinician should perform repeat transurethral resection or endoscopic treatment of all remaining tumor if technically feasible. (Strong Recommendation; Evidence Strength: Grade B)
13. In a patient with high-risk, high-grade Ta tumors, a clinician should consider performing repeat transurethral resection of the primary tumor site within six weeks of the initial TURBT. (Moderate Recommendation; Evidence Strength: Grade C)
14. In a patient with T1 disease, a clinician should perform repeat transurethral resection of the primary tumor site to include muscularis propria within six weeks of the initial TURBT. (Strong Recommendation; Evidence Strength: Grade B)

Intravesical Therapy; BCG/Maintenance; Chemotherapy/BCG Combinations

15. In a patient with suspected or known low- or intermediate-risk bladder cancer, a clinician should consider administration of a single postoperative instillation of intravesical chemotherapy (e.g., mitomycin C or epirubicin) within 24 hours of TURBT. In a patient with a suspected perforation or extensive resection, a clinician should not use postoperative chemotherapy. (Moderate Recommendation; Evidence Strength: Grade B)
16. In a low-risk patient, a clinician should not administer induction intravesical therapy. (Moderate Recommendation; Evidence Strength: Grade C)
17. In an intermediate-risk patient a clinician should consider administration of a six week course of induction intravesical chemotherapy or immunotherapy. (Moderate Recommendation; Evidence Strength: Grade B)
18. In a high-risk patient with newly diagnosed CIS, high-grade T1, or high-risk Ta urothelial carcinoma, a clinician should administer a six-week induction course of BCG. (Strong Recommendation; Evidence Strength: Grade B)
19. In an intermediate-risk patient who completely responds to an induction course of intravesical chemotherapy, a clinician may utilize maintenance therapy. (Conditional Recommendation; Evidence Strength: Grade C)
20. In an intermediate-risk patient who completely responds to induction BCG, a clinician should consider maintenance BCG for one year, as tolerated. (Moderate Recommendation; Evidence Strength: Grade C)
21. In a high-risk patient who completely responds to induction BCG, a clinician should continue maintenance BCG for three years, as tolerated. (Moderate Recommendation; Evidence Strength: Grade B)

BCG Relapse and Salvage Regimens

22. In an intermediate- or high-risk patient with persistent or recurrent disease or positive cytology following intravesical therapy, a clinician should consider performing prostatic urethral biopsy and an upper tract evaluation prior to administration of additional intravesical therapy. (Conditional Recommendation; Evidence Strength: Grade C)
23. In an intermediate- or high-risk patient with persistent or recurrent Ta or CIS disease after a single course of induction intravesical BCG, a clinician should offer a second course of BCG. (Moderate Recommendation; Evidence Strength: Grade C)
24. In a patient fit for surgery with high-grade T1 disease after a single course of induction intravesical BCG, a clinician should offer radical cystectomy. (Moderate Recommendation; Evidence Strength: Grade C)
25. A clinician should not prescribe additional BCG to a patient who is intolerant of BCG or has documented recurrence on TURBT of high-grade, non-muscle-invasive disease and/or CIS within six months of two induction courses of BCG or induction BCG plus maintenance. (Moderate Recommendation; Evidence Strength: Grade C)
26. In a patient with persistent or recurrent intermediate- or high-risk NMIBC who is unwilling or unfit for cystectomy following two courses of BCG, a clinician may recommend clinical trial enrollment. A clinician may offer this patient intravesical chemotherapy when clinical trials are unavailable. (Expert Opinion)

Role of Cystectomy in NMIBC

27. In a patient with Ta low- or intermediate-risk disease, a clinician should not perform radical cystectomy until bladder-sparing modalities (staged TURBT, intravesical therapies) have failed. (Clinical Principle)
28. In a high-risk patient who is fit for surgery with persistent high-grade T1 disease on repeat resection, or T1 tumors with associated CIS, LVI, or variant histologies, a clinician should consider offering initial radical cystectomy. (Moderate Recommendation; Evidence Strength: Grade C)
29. In a high-risk patient with persistent or recurrent disease within one year following treatment with two induction cycles of BCG or BCG maintenance, a clinician should offer radical cystectomy. (Moderate Recommendation; Evidence Strength: Grade C)

Enhanced Cystoscopy

30. In a patient with NMIBC, a clinician should offer blue light cystoscopy at the time of TURBT, if available, to increase detection and decrease recurrence. (Moderate Recommendation; Evidence Strength: Grade B)
31. In a patient with NMIBC, a clinician may consider use of NBI to increase detection and decrease recurrence. (Conditional Recommendation; Evidence Strength: Grade C)

Risk Adjusted Surveillance and Follow-up Strategies

32. After completion of the initial evaluation and treatment of a patient with NMIBC, a clinician should perform the first surveillance cystoscopy within three to four months. (Expert Opinion)
33. For a low-risk patient whose first surveillance cystoscopy is negative for tumor, a clinician should perform subsequent surveillance cystoscopy six to nine months later, and then annually thereafter; surveillance after five years in the absence of recurrence should be based on shared-decision making between the patient and clinician. (Moderate Recommendation; Evidence Strength: Grade C)
34. In an asymptomatic patient with a history of low-risk NMIBC, a clinician should not perform routine surveillance upper tract imaging. (Expert Opinion)
35. In a patient with a history of low-grade Ta disease and a noted sub-centimeter papillary tumor(s), a clinician may consider in-office fulguration as an alternative to resection under anesthesia. (Expert Opinion)
36. For an intermediate-risk patient whose first surveillance cystoscopy is negative for tumor, a clinician should perform subsequent cystoscopy with cytology every 3-6 months for 2 years, then 6-12 months for years 3 and 4, and then annually thereafter. (Expert Opinion)
37. For a high-risk patient whose first surveillance cystoscopy is negative for tumor, a clinician should perform subsequent cystoscopy with cytology every three to four months for two years, then six months for years three and four, and then annually thereafter. (Expert Opinion)
38. For an intermediate- or high-risk patient, a clinician should consider performing surveillance upper tract imaging at one to two year intervals. (Expert Opinion)

Purpose

The survival rate for the majority of patients with non-muscle invasive bladder cancer (NMIBC) is favorable; however, the rates of recurrence and progression to muscle-invasive bladder cancer (MIBC) are important surrogate endpoints for overall prognosis, as these are major determinants of long-term outcome. The recurrence and progression probability rates depend on several clinical and pathologic factors. Therefore, the ability to predict risk of recurrence and progression and treat the disease appropriately is important. This guideline provides a risk-stratified clinical framework for the management of NMIBC.

Methodology

Systematic Review. The systematic review utilized in the creation of this guideline was completed in part through the Agency for Healthcare Research and Quality (AHRQ) and through additional supplementation that further addressed additional key questions and more recently published literature. A research librarian experienced in conducting literature searches for comparative effectiveness reviews searched in 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 3rd Quarter, 2014), National Health Sciences Economic Evaluation Database (through 3rd Quarter, 2014), and Database of Abstracts of Reviews of Effects (through 3rd Quarter, 2014) to capture both published and grey literature. Database searches resulted in 3,740 potentially relevant articles. After dual review of abstracts and titles, 643 articles were selected for full-text dual review, and 149 studies (in 192 publications) were determined to meet inclusion criteria and were included in this review. The AHRQ review was then updated by a consultant methodologist though September 2, 2015. Reference lists and previous systematic reviews were also reviewed for additional studies. This supplementation added 29 studies to the completed systematic review used in the creation of guideline statements.

Data Extraction and Data Management. For treatment studies, the following information was extracted into evidence tables: study design, setting, inclusion and exclusion criteria, dose and duration of treatment for experimental and control groups, duration of follow-up, number of subjects screened, eligible and enrolled population characteristics (including age, race, sex, stage of disease, and functional status), results, adverse events, withdrawals due to adverse events, and sources of funding. Relative risks and associated 95 percent confidence intervals (CI) were calculated based on the information provided (sample sizes and incidence of outcomes in each intervention group). Discrepancies between calculated and reported results were noted when present.

For diagnostic accuracy studies, the following information was abstracted: setting, screening test or tests, method of data collection, reference standard, inclusion criteria, population characteristics (including age, sex, race, smoking status, signs or symptoms, and prior bladder cancer stage or grade), proportion of individuals with bladder cancer, bladder cancer stage and grade, definition of a positive screening exam, proportion of individuals unexaminable by the screening test, proportion who did not undergo reference standard, results, and sources of funding. When possible, two-by-two tables were created from information provided (sample size, prevalence, sensitivity, and specificity) and compared to calculated measures of diagnostic accuracy based on the two-by-two tables with reported results. Discrepancies between calculated and reported results were noted when present. Data extraction for each study was completed by one investigator and independently reviewed for accuracy and completeness by a second investigator.

Assessment of the Risk of Bias of Individual Studies. Risk of bias was assessed for randomized trials and observational studies using criteria adapted from those developed by the U.S. Preventive Services Task Force.¹ Studies of diagnostic accuracy were rated using criteria adapted from QUADAS-2.² These criteria were applied in conjunction with the approaches recommended in the AHRQ Methods Guide³ for medical interventions and the AHRQ Methods Guide for Medical Test Reviews.⁴ Two investigators independently assessed the risk of bias of each study. Discrepancies were resolved through discussion and consensus. Each study was rated as "low," "medium," or "high" risk of bias.³

Determination of Evidence Strength. The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and includes not only individual study quality but consideration of study design, consistency of findings across studies, adequacy of sample sizes, and generalizability of samples, settings, and treatments for the purposes of the guideline. The AUA categorizes body of evidence strength as Grade A (well-conducted and highly-generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data). By definition, Grade A evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is evidence about which the Panel has a moderate level of certainty, and Grade C evidence is evidence about which the Panel has a low level of certainty.⁵ The 38 statements created vary in level of evidence, but none include Level A evidence, and a majority are Level C evidence.

AUA Nomenclature: Linking Statement Type to Evidence Strength. The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, magnitude of benefit or risk/burdens, and the Panel’s judgment regarding the balance between benefits and risks/burdens (Table 1). Strong Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is substantial. Moderate Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is moderate.

Conditional Recommendations are non-directive statements used when the evidence indicates that there is no apparent net benefit or harm or when the balance between benefits and risks/burden is unclear. All three statement types may be supported by any body of evidence strength grade. Body of evidence strength Grade A in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances and that future research is unlikely to change confidence. Body of evidence strength Grade B in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence could change confidence. Body of evidence strength Grade C in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence is likely to change confidence. Body of evidence strength Grade C is only rarely used in support of a Strong Recommendation. Conditional Recommendations also can be supported by any evidence strength. When body of evidence strength is Grade A, the statement indicates that benefits and risks/burdens appear balanced, the best action depends on patient circumstances, and future research is unlikely to change confidence. When body of evidence strength Grade B is used, benefits and risks/burdens appear balanced, the best action also depends on individual patient circumstances and better evidence could change confidence. When body of evidence strength Grade C is used, there is uncertainty regarding the balance between benefits and risks/burdens, alternative strategies may be equally reasonable, and better evidence is likely to change confidence.

Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinion with consensus achieved using a modified Delphi technique if differences of opinion emerged.⁶ A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence.

Process. The Non-Muscle-Invasive Bladder Cancer Panel was created in 2014 by the American Urological Association Education and Research, Inc. (AUA). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Chair who in turn appointed the Vice Chair. In a collaborative process, additional Panel members, including additional members of the Society of Urologic Oncology (SUO) with specific expertise in this area, where then nominated and approved by the PGC. The AUA conducted a thorough peer review process. The draft guidelines document was distributed to 128 peer reviewers, 66 of which submitted comments. The Panel reviewed and discussed all submitted comments and revised the draft as needed. Once finalized, the guideline was submitted for approval to the PGC and Science and Quality Council (S&Q). Then it was submitted to the AUA Board of Directors for final approval. Funding of the Panel was provided by the AUA; Panel members received no remuneration for their work.

Background

Epidemiology

NMIBC represents approximately 75% of the 74,000 estimated new bladder cancer cases diagnosed in the United States in 2015.^7,8 Bladder cancer is more common in males than females with a ratio of approximately 3:1, and it is the fourth most common solid malignancy in men. There are 16,000 estimated deaths for 2015, predominantly affecting males.^7,9 Bladder cancer primarily affects Caucasian Americans and those older than 65 years with relatively stable mortality rates since 1975.⁹

National registry data from the U.S. Surveillance Epidemiology and End Results (SEER) program demonstrates that the incidence of all stages of NMIBC has been relatively stable from 1988-2006; however, the adjusted incidence of stage Ta has significantly increased, while stages Tis and T1 have slightly decreased.¹⁰

Etiology

Risk factors. Multiple factors are associated with bladder carcinogenesis; however, tobacco smoking is the most significant and most common risk factor.¹¹ Although smoking cessation may somewhat decrease carcinogenesis risk, former smokers still have a higher risk of bladder cancer than those who never smoked.¹¹ With respect to NMIBC, current tobacco use and cumulative lifetime exposure may be associated with recurrence and progression.^12,13 Although an incomplete list, the Panel has identified other more common risk factors. Occupational exposure to chemical carcinogens, such as aromatic amines, polycyclic aromatic hydrocarbons, and arsenic, is another reported risk factor.^14,15 Patients with other malignancies, such as lymphomas and leukemias, who receive treatment with cyclophosphamide may be at increased risk for bladder cancer.^16,17 Patients with Lynch Syndrome may also be at increased risk of urothelial carcinoma of the bladder, as well as, the upper urinary tract.^18,19 Infection also increases the risk of bladder cancer; in particular, Schistosoma hematobium, the pathogen responsible for schistosomiasis, is a risk factor for squamous cell carcinoma of the bladder in certain regions of the world.²⁰ In looking at squamous cell carcinoma of the bladder, chronic catheter use also serves as a risk factor. Additionally, aristolochic acid, a natural compound found in a number of plants of the Aristolochia genus, has been linked to upper-tract urothelial carcinoma.²¹ Another known risk factor includes external beam radiation to the pelvis.²²

Molecular Mechanism and Genetics. There is no currently accepted genetic or inheritable cause of bladder cancer; however, studies suggest that genomic instability and genetic pathway mutations/alterations may play a role in bladder carcinogenesis. Studies suggest that polymorphisms in two carcinogen-detoxifying genes GSTM-1 and NAT-2 may be responsible for increased susceptibility to developing bladder cancer in certain patients.²³ Chromosome 9 deletion is a common genetic alteration found in NMIBC, with loss of heterozygosity (LOH) of 9p, homozygous deletion of CDKN2A, and loss of expression of p16 in NMIBC predicting recurrence free survival.^24-26 Mutations in tumor suppressor genes can lead to disruption of cell cycle regulation and predispose to carcinogenesis. Carcinoma in situ (CIS) frequently demonstrates mutations in the tumor suppressor genes TP53, RB1 (retinoblastoma), and PTEN.²⁷ Oncogenes that promote tumor cell development and alterations in FGFR3, PIK3CA, and RAS are common in NMIBC.^27,28

Presentation and Diagnosis

The most common presenting symptom is painless hematuria (gross or microscopic). According to the AUA Guideline on the diagnosis, evaluation, and follow-up of patients with asymptomatic microhematuria (AMH), the rate of urinary tract malignancy in AMH is approximately 2.6%.²⁹ Irritative voiding symptoms (e.g., frequency, urgency, dysuria) may also be associated with CIS in patients with no sign of urinary tract infection. Physical exam rarely reveals significant findings in patients with NMIBC. However, a bimanual exam may be performed under anesthesia at the time of transurethral resection of bladder tumor (TURBT) and should be performed at that time if the tumor appears invasive. Although not indicated for routine screening and evaluation of AMH, urinary cytology (voided or barbotage) may be used in the surveillance of bladder cancer for certain patients as it possesses a high sensitivity and positive predictive value for high-grade tumors and CIS.^30,31 Contrast-based axial imaging, such as computed tomography (CT) or magnetic resonance imaging (MRI) is the recommended imaging modality during the work-up for bladder cancer. Retrograde pyelogram and intravenous urography may also be used when CT or MRI are unavailable. Abdomino-pelvic sonography alone may not provide sufficient anatomic detail for upper urinary tract imaging during the work-up of bladder cancer.³²

The diagnosis of bladder cancer is confirmed by direct visualization of the tumor and other mucosal abnormalities with endoscopic excision using cystoscopy and TURBT. An adequate TURBT requires complete resection of all visible tumor with adequate sampling of the bladder to assess the depth of invasion.

Staging and Grading

Staging for bladder cancer is separated into clinical and pathologic stage, as outlined by the American Joint Committee on Cancer (AJCC), also known as the Tumor-Node-Metastases (TNM) classification.³³ Clinical stage reflects the histologic findings at TURBT; the clinician's physical exam, including bimanual exam under anesthesia; and findings on radiologic imaging. The pathologic report of the TURBT should indicate whether lamina propria and muscularis propria are present as well as the degree of involvement, if present. In addition, effort should be made by the pathologist to examine the specimen for lymphovascular invasion (LVI), when applicable, as this is associated with worse prognosis.^34-37 Pathological staging, also known as surgical staging, is based on the extent of disease following surgical resection of the bladder (partial versus radical cystectomy) and of the adjacent pelvic lymph nodes. Under the AJCC staging system, NMIBC includes the following: (1) papillary tumors confined to the epithelial mucosa (stage Ta), (2) tumors invading the subepithelial tissue (i.e., lamina propria; T1), and (3) Tis. (Table 2)

Tumor grade is an important prognostic factor for determining risk of recurrence and progression in bladder cancer. Prior to the 2004 revised classification, the 1973 World Health Organization (WHO) classification was the widely accepted format for grading bladder neoplasia.^38,39 The 1973 version designated tumors as either papilloma, grade 1, 2, or 3, whereas the 2004 revision designated tumors as 'low' or 'high' grade. The 1973 grade 2 or 'intermediate' grade tumors are now re-classified as either 'low' or 'high' grade depending on cellular morphology.^38,39 In addition, the 2004 classification introduced the new category of papillary urothelial neoplasm of low malignant potential to describe lesions with an increased number of urothelial layers when compared with papilloma but without cytologic features of malignancy. The WHO/International Society of Urological Pathology (ISUP) 2004 grading system is now the most widely accepted and utilized system in the United States. (Table 3)

Prognosis

The survival prognosis for patients with NMIBC is relatively favorable, with the cancer-specific survival (CSS) in high-grade disease ranging from approximately 70-85% at 10 years and a much higher rate for low-grade disease.^40,41 The rates of recurrence and progression to MIBC are important surrogate endpoints for prognosis in NMIBC, as these are major determinants of long-term outcome. However, NMIBC is a clinically heterogeneous group of cancers with a wide range of recurrence and progression probabilities that depend on several clinical and pathologic factors. For example, long-term follow up of low-grade Ta lesions demonstrates a recurrence rate of approximately 55%, but with a much lower percentage (6%) experiencing stage progression.⁴² In contrast, high-grade T1 lesions have both a significant risk of recurrence (45%) and increased chance of progression (17%) in single institution series.⁴⁰ Therefore, the ability to predict recurrence and progression risk in NMIBC, based on patient-specific disease characteristics, holds prognostic significance. Risk stratification in NMIBC aids personalized treatment decisions and surveillance strategies as opposed to a generalized 'one-size fits all' approach.

Risk Stratification

Significant effort has been put forth to develop tools for risk stratification and prognostication. A widely published system is the European Organization for Research and Treatment of Cancer (EORTC) risk calculator, based on the combined data from seven trials involving patients with NMIBC.⁴³ Using clinical and pathologic variables in a scoring system, the EORTC calculator provides a probability of recurrence and progression at one and five years. Important factors for recurrence identified by the EORTC study include prior recurrence rate, number of tumors, and tumor size.⁴³ With respect to progression, important factors include T-stage, presence of CIS, and grade. A second risk stratification tool is that developed by the Spanish Urological Club for Oncological Treatment/Club Urologico Espanol de Tratamiento Oncologico (CUETO).⁴⁴ These models are examples of carefully constructed risk stratification systems; however, they have limitations. Both tools are limited by lack of applicability to current patient populations because few patients from the development cohort received BCG maintenance, underwent re-staging transurethral-resection, or received single-dose post-operative mitomycin C. A recent update of the EORTC nomogram for risk stratification attempted to address the lack of BCG maintenance in prior studies, by analyzing a cohort of patients treated with one to three years of BCG. This updated study cohort lacked patients with CIS and again was limited by absence of routine re-resection.⁴⁵ Additionally, the EORTC risk calculator utilizes the 1973 WHO grading system to generate risk probabilities as opposed to the 2004 version. As previously mentioned, the 2004 revision is the currently accepted classification for tumor grade; therefore, the EORTC risk tables are commonly not considered in the U.S.

Risk groupings are evaluated by their ability to predict the outcome of patients who are felt to be similar to one another. The most commonly used tool to assess the accuracy of risk groupings is the concordance index (C-index). The C-index is a measure of the ability of a risk assessment tool to separate those patients with the outcome of interest from those without the outcome of interest (e.g. recurrence or progression).⁴⁶ A C-index of 0.5 implies that the ability to predict outcome is no better than random chance. For the original EORTC study, the C-indices for recurrence and progression were 0.66 and 0.75, respectively and 0.64 and 0.7, respectively, for the CUETO study.^43,44 A further important limitation of the existing risk stratification models is that neither reported formal measures of calibration (the degree to which predicted and observed risk estimates agree). Several studies have retrospectively evaluated the ability of the EORTC and CUETO models to predict the risk of recurrence and progression in other patient populations.^47-52 These attempts at external validation using other patient populations have yielded variable C-index results and underscore the fact that both instruments are limited by suboptimal calibration and inherent biases based on their designs. Evaluation of these studies investigating the utility of risk stratification in multiple populations demonstrate that they have a poor to fair ability to discriminate risk of recurrence (C-index 0.52 to 0.66) and good to fair (C-index 0.62 to 0.81) ability to discriminate risk of progression.

The Panel acknowledges that Level A evidence does not support stratification as affecting disease recurrence, progression, or survival However, despite the lack of evidence confirming a positive influence on clinical outcome, the Panel agrees that there is value to creating fundamental categories that broadly estimate the likelihood of recurrence and progression. The Panel set out to create such a system, with categories summarized as 'low,' 'intermediate,' and 'high' risk for recurrence and/or progression. (Table 4) This risk grouping system is a simple tool, intended for use in clinical practice as a general framework for guiding patient counseling and aiding in treatment and surveillance decisions based on prognosis. While there are similarities between the current risk categories outlined in the Guideline and the EORTC stratification, it should be noted that they are not based on a meta-analysis or original studies and represent the Panel's consensus regarding the likelihood of recurrence and progression. To develop the current risk groupings, the Panel set forth defining first those at lowest and highest risk for recurrence and/or progression. Numerous clinical scenarios based on disease characteristics were then incorporated into the grouping system, and each one was placed into a category based on unanimous expert consensus and available published data. The Panel also recognizes that the intermediate group is somewhat heterogeneous, and the outcome of patients within this group may still exhibit some variation along the spectrum of risk of recurrence and progression.

Unique to the AUA/SUO Guideline Risk Stratification System is the incorporation of prior BCG intravesical therapy on prognosis. There are limited data that demonstrate that patients who have persistent or recurrent disease at six months following BCG therapy are at increased risk of disease progression.^53,54 As such, the Panel reasons that patients who are intermediate risk and demonstrate BCG failure should be re-stratified to the high risk group. The rationale for this approach is that those patients who do not respond to standard intravesical therapy likely harbor more aggressive disease than implied by clinical or pathologic features; therefore, a lack of response serves as a surrogate marker for increased risk of recurrence and/or progression. The Panel also understands and appreciates that within each of these risk strata that an individual patient may have more or less concerning features that can influence care.

The Panel acknowledges the need for validation of these risk groups in large, contemporary patient cohorts in order to assess the model's performance for predicting disease recurrence and progression.

1. At the time of resection of suspected bladder cancer, a clinician should perform a thorough cystoscopic examination of a patient's entire urethra and bladder that evaluates and documents tumor size, location, configuration, number, and mucosal abnormalities. (Clinical Principle)

2. At initial diagnosis of a patient with bladder cancer, a clinician should perform complete visual resection of the bladder tumor(s), when technically feasible. (Clinical Principle)

3. A clinician should perform upper urinary tract imaging as a component of the initial evaluation of a patient with bladder cancer. (Clinical Principle)

4. In a patient with a history of NMIBC with normal cystoscopy and positive cytology, a clinician should consider prostatic urethral biopsies and upper tract imaging, as well as enhanced cystoscopic techniques (blue light cystoscopy, when available), ureteroscopy, or random bladder biopsies. (Expert Opinion)

5. At the time of each occurrence/recurrence, a clinician should assign a clinical stage and classify a patient accordingly as "low-," "intermediate-," or "high-risk." (Moderate Recommendation; Evidence Strength: Grade C)

6. An experienced genitourinary pathologist should review the pathology of a patient with any doubt in regards to variant or suspected variant histology (e.g., micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid), extensive squamous or glandular differentiation, or the presence/absence of LVI. (Moderate Recommendation; Evidence Strength: Grade C)

7. If a bladder sparing approach is being considered in a patient with variant histology, then a clinician should perform a restaging TURBT within four to six weeks of the initial TURBT. (Expert Opinion)

8. Due to the high rate of upstaging associated with variant histology, a clinician should consider offering initial radical cystectomy. (Expert Opinion)

9. In surveillance of NMIBC, a clinician should not use urinary biomarkers in place of cystoscopic evaluation. (Strong Recommendation; Evidence Strength: Grade B)

10. In a patient with a history of low-risk cancer and a normal cystoscopy, a clinician should not routinely use a urinary biomarker or cytology during surveillance. (Expert Opinion)

11. In a patient with NMIBC, a clinician may use biomarkers to assess response to intravesical BCG (UroVysion® FISH) and adjudicate equivocal cytology (UroVysion® FISH and ImmunoCyt™). (Expert Opinion)

12. In a patient with non-muscle invasive disease who underwent an incomplete initial resection (not all visible tumor treated), a clinician should perform repeat transurethral resection or endoscopic treatment of all remaining tumor if technically feasible. (Strong Recommendation; Evidence Strength: Grade B)

13. In a patient with high-risk, high-grade Ta tumors, a clinician should consider performing repeat transurethral resection of the primary tumor site within six weeks of the initial TURBT. (Moderate Recommendation; Evidence Strength: Grade C)

14. In a patient with T1 disease, a clinician should perform repeat transurethral resection of the primary tumor site to include muscularis propria within six weeks of the initial TURBT. (Strong Recommendation; Evidence Strength: Grade B)

15. In a patient with suspected or known low- or intermediate-risk bladder cancer, a clinician should consider administration of a single postoperative instillation of intravesical chemotherapy (e.g., mitomycin C or epirubicin) within 24 hours of TURBT. In a patient with a suspected perforation or extensive resection, a clinician should not use postoperative chemotherapy. (Moderate Recommendation; Evidence Strength: Grade B)

16. In a low-risk patient, a clinician should not administer induction intravesical therapy. (Moderate Recommendation; Evidence Strength: Grade C)

17. In an intermediate-risk patient a clinician should consider administration of a six week course of induction intravesical chemotherapy or immunotherapy. (Moderate Recommendation; Evidence Strength: Grade B)

18. In a high-risk patient with newly diagnosed CIS, high-grade T1, or high-risk Ta urothelial carcinoma, a clinician should administer a six-week induction course of BCG. (Strong Recommendation; Evidence Strength: Grade B)

19. In an intermediate-risk patient who completely responds to an induction course of intravesical chemotherapy, a clinician may utilize maintenance therapy. (Conditional Recommendation; Evidence Strength: Grade C)

20. In an intermediate-risk patient who completely responds to induction BCG, a clinician should consider maintenance BCG for one year, as tolerated. (Moderate Recommendation; Evidence Strength: Grade C)

21. In a high-risk patient who completely responds to induction BCG, a clinician should continue maintenance BCG for three years, as tolerated. (Moderate Recommendation; Evidence Strength: Grade B)

22. In an intermediate- or high-risk patient with persistent or recurrent disease or positive cytology following intravesical therapy, a clinician should consider performing prostatic urethral biopsy and an upper tract evaluation prior to administration of additional intravesical therapy. (Conditional Recommendation; Evidence Strength: Grade C)

23. In an intermediate- or high-risk patient with persistent or recurrent Ta or CIS disease after a single course of induction intravesical BCG, a clinician should offer a second course of BCG. (Moderate Recommendation; Evidence Strength: Grade C)

24. In a patient fit for surgery with high-grade T1 disease after a single course of induction intravesical BCG, a clinician should offer radical cystectomy. (Moderate Recommendation; Evidence Strength: Grade C)

25. A clinician should not prescribe additional BCG to a patient who is intolerant of BCG or has documented recurrence on TURBT of high-grade, non-muscle-invasive disease and/or CIS within six months of two induction courses of BCG or induction BCG plus maintenance. (Moderate Recommendation; Evidence Strength: Grade C)

26. In a patient with persistent or recurrent intermediate- or high-risk NMIBC who is unwilling or unfit for cystectomy following two courses of BCG, a clinician may recommend clinical trial enrollment. A clinician may offer this patient intravesical chemotherapy when clinical trials are unavailable. (Expert Opinion)

27. In a patient with Ta low- or intermediate-risk disease, a clinician should not perform radical cystectomy until bladder-sparing modalities (staged TURBT, intravesical therapies) have failed. (Clinical Principle)

28. In a high-risk patient who is fit for surgery with persistent high-grade T1 disease on repeat resection, or T1 tumors with associated CIS, LVI, or variant histologies, a clinician should consider offering initial radical cystectomy. (Moderate Recommendation; Evidence Strength: Grade C)

29. In a high-risk patient with persistent or recurrent disease within one year following treatment with two induction cycles of BCG or BCG maintenance, a clinician should offer radical cystectomy. (Moderate Recommendation; Evidence Strength: Grade C)

30. In a patient with NMIBC, a clinician should offer blue light cystoscopy at the time of TURBT, if available, to increase detection and decrease recurrence. (Moderate Recommendation; Evidence Strength: Grade B)

31. In a patient with NMIBC, a clinician may consider use of NBI to increase detection and decrease recurrence. (Conditional Recommendation; Evidence Strength: Grade C)

32. After completion of the initial evaluation and treatment of a patient with NMIBC, a clinician should perform the first surveillance cystoscopy within three to four months. (Expert Opinion)

33. For a low-risk patient whose first surveillance cystoscopy is negative for tumor, a clinician should perform subsequent surveillance cystoscopy six to nine months later, and then annually thereafter; surveillance after five years in the absence of recurrence should be based on shared-decision making between the patient and clinician. (Moderate Recommendation; Evidence Strength: Grade C)

34. In an asymptomatic patient with a history of low-risk NMIBC, a clinician should not perform routine surveillance upper tract imaging. (Expert Opinion)

35. In a patient with a history of low-grade Ta disease and a noted sub-centimeter papillary tumor(s), a clinician may consider in-office fulguration as an alternative to resection under anesthesia. (Expert Opinion)

36. For an intermediate-risk patient whose first surveillance cystoscopy is negative for tumor, a clinician should perform subsequent cystoscopy with cytology every 3-6 months for 2 years, then 6-12 months for years 3 and 4, and then annually thereafter. (Expert Opinion)

37. For a high-risk patient whose first surveillance cystoscopy is negative for tumor, a clinician should perform subsequent cystoscopy with cytology every three to four months for two years, then six months for years three and four, and then annually thereafter. (Expert Opinion)

38. For an intermediate- or high-risk patient, a clinician should consider performing surveillance upper tract imaging at one to two year intervals. (Expert Opinion)

The future of NMIBC will likely be driven forward by basic science, novel technologies, new therapeutics and clinical trials. The bladder cancer genome atlas project²⁵¹ provided analysis of 131 muscle-invasive urothelial carcinomas in an effort to describe molecular alterations and, ideally, provide insight into use of molecularly targeted agents for both muscle-invasive and NMIBC. The NMIBC community is fortunate to have a multitude of clinical trials currently in this disease space, the vast majority of which are studying novel agents to improve outcomes of BCG or treat BCG failures, but there are also several trials investigating new technology, surgical techniques, radiation, and surveillance schedules.

Novel agents to improve BCG efficacy or manage BCG failures. Management of patients with intermediate- or high-risk bladder cancer recurrences after two induction courses of BCG unwilling or unfit for radical cystectomy remains uncertain. Although many different salvage intravesical therapies have been evaluated, these studies are generally limited by small patient numbers, modest improvements in recurrence-free survival with respective intravesical agent(s), and no significant effects on progression or survival. These limitations highlight the dire need for novel agents in this disease setting. For instance, immune checkpoint inhibitors have been a resounding success in metastatic bladder cancer with trials already underway moving these agents into earlier stages of bladder cancer, including adjuvant, neoadjuvant and NMIBC settings.²⁵² There are multiple current open clinical trials evaluating novel agents for BCG failures, including an oncolytic virus regimen (BOND 2), recombinant fusion proteins (Vicinium), immune modulation (ALT-801, HS-410, ALT-803, PANVAC), cytotoxic therapies (nanoparticle encapsulated rapamycin [ABI-009], genistein, cabazitaxel, gemcitabine, cisplatin,) and targeted small molecule kinase inhibitors (sunitinib, dovitinib, erlotinib).

New technologies. Enhanced cystoscopy, including BLC at time of TURBT, has been demonstrated in multiple studies to decrease bladder tumor recurrence and seems particularly valuable in evaluation of positive urinary cytology in the setting of negative white light cystoscopy.⁷³ A current Phase III study (NCT02560584) is enrolling patients to determine if BLC improves detection of tumors in patients with bladder cancer during surveillance cystoscopy, with secondary endpoints of safety and efficacy with repeated use. Further studies of new technologies in management of patients with NMIBC include a current phase IV trial (NCT01567462) underway to evaluate TURBT using a PK button vaporization electrode compared to standard monopolar loop electrocautery. Investigators hypothesize TURBT using PK button vaporization may be less invasive with fewer side effects and improved patient recovery.

Therapeutic Trials in Surgery/Radiation. RAZOR is a multi-institutional, non-inferiority trial evaluating cancer outcomes, surgical complications and quality of life measures of open versus robotic cystectomy with a primary endpoint of two-year progression-free survival. The RAZOR trial is closed to accrual, but full data from the study are expected in 2016-2017.²⁵³ If the trial shows oncological non-inferiority and improved quality of life measures, perhaps radical cystectomy and urinary diversion will be more accepted in management of high-risk NMIBC from a patient perspective. Wider acceptance of intracorporeal urinary diversion in the urologic community could potentially have similar effects. An upcoming clinical trial (NCT02252393) will randomize patients undergoing robotic radical cystectomy to intracorporeal versus extracorporeal urinary diversion with primary objectives to compare perioperative outcomes and complications.

There are minimal data to support chemoradiation in the management of high-risk NMIBC,²³⁷ but current trials are underway evaluating the role of radiation therapy in patients with recurrent high-grade T1 disease after intravesical BCG. RTOG 0926 (NCT00981656) is a Phase II trial evaluating chemoradiation (cisplatin or mitomycin/fluorouracil with three-dimensional conformal radiation therapy) with a primary endpoint of three-year freedom from radical cystectomy and several secondary endpoints, including progression-free, disease-specific and overall survival.

Surveillance. Finally, a randomized pilot clinical trial (NCT02298998) evaluating common surveillance schedules could significantly impact follow-up in patients with NMIBC. Patients will be randomized to either cystoscopy at 3 months, 12 months and then annually for 5 years versus cystoscopy every 3 months for 2 years, every 6 months for 2 years and annually thereafter. The primary objectives of this study include development of methodology to assess both patient satisfaction and costs associated with cystoscopy for bladder cancer surveillance with secondary objectives of cost, number of overall procedures and proportion of patients with disease recurrence and progression at two years. Monitoring patients with NMIBC less frequently may potentially decrease costs and improve patient satisfaction without increased risk of progression to muscle-invasive disease.

Related Content: AUA/SUNA Joint Statement on Intravesical Administration of Therapeutic Medication

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