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American Urological Association (AUA)/

Society of Urologic Oncology (SUO)

A PPROVED BY THE AUA DIAGNOSIS AND TREATMENT OF NON-MUSCLE

B OARD OF D IRECTORS
J ANUARY 2024 INVASIVE BLADDER CANCER: AUA/SUO GUIDELINE
Authors’ disclosure of
potential conflicts of interest
and author/staff contributions
appear at the end of the (Published 2016; Amended 2020, 2024)
article.

© 2024 by the American

Urological Association Guideline Panel
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

2020 Amendment Panel

James M. McKiernan, MD; Sam S. Chang, MD, MBA; Christopher Anderson, MD, MPH;
John Gore, MD; Jeffrey Holzbeierlein, MD

2024 Amendment Panel

Jeffrey Holzbeierlein, MD; Sam S. Chang, MD, MBA; Andrew C. James, MD; James M.
McKiernan, MD; Anne K. Schuckman, MD

Staff and Consultants

Brooke R. Bixler, MPH; Erin Kirkby, MS; David I. Buckley, MD, MPH; Rebecca Holmes,
MD, MS

SUMMARY
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 NMIBC Treatment Algorithm.

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Non-Muscle Invasive Bladder Cancer (NMIBC)

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. The
guideline underwent review in 2019. The updated search (June 1, 2015 to November 22, 2019) identified 1,626 abstracts,
of which 76 met inclusion criteria. An additional review was performed in 2023. The updated search (July 2019 to May 2023)
identified 1918 abstracts, of which 75 met inclusion criteria. 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.

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 [BLC], 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 regard to variant
or suspected variant histology (e.g., micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid), extensive

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Non-Muscle Invasive Bladder Cancer (NMIBC)

squamous or glandular differentiation, or the presence/absence of lymphovascular invasion (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 transurethral resection of bladder tumor (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., gemcitabine, mitomycin C)
within 24 hours of TURBT. In a patient with a suspected perforation or extensive resection, a clinician should not
use postoperative intravesical 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)

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Non-Muscle Invasive Bladder Cancer (NMIBC)

18. In a high-risk patient with newly diagnosed carcinoma in situ (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,
based on availability, 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 high-grade NMIBC within 12 months of completion of adequate BCG therapy
(two induction courses or one induction course plus one maintenance cycle) who is unwilling or unfit for cystectomy,
a clinician may recommend clinical trial enrollment, an alternative intravesical therapy (i.e., nadofaragene
[firadenovec-vncg]) or alternative intravesical chemotherapies (gemcitabine/docetaxel). A clinician may also offer
systemic immunotherapy with pembrolizumab to a patient with CIS within 12 months of completion of adequate
BCG therapy. (Conditional Recommendation; Evidence Strength: Grade C)

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)

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Non-Muscle Invasive Bladder Cancer (NMIBC)

ENHANCED CYSTOSCOPY
30. In a patient with NMIBC, a clinician should offer BLC 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 narrow-band imaging (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)

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Non-Muscle Invasive Bladder Cancer (NMIBC)

In 2020, the NMIBC guideline was updated through the

INTRODUCTION AUA amendment process in which newly published
literature is reviewed and integrated into previously
PURPOSE published guidelines in an effort to maintain currency. The
amendment allowed for the incorporation of additional
The survival rate for the majority of patients with NMIBC literature released since the initial publication of this
is favorable; however, the rates of recurrence and guideline in 2016. For this updated literature review the
progression to muscle-invasive bladder cancer (MIBC) methodology team searched Ovid MEDLINEI ALL from
are important surrogate endpoints for overall prognosis, June 1, 2015 to November 22, 2019, and eliminated
as these are major determinants of long-term outcome. duplicate abstracts reviewed for earlier reports. Following
The recurrence and progression probability rates depend initial report review, the Panel suggested additional
on several clinical and pathologic factors. Therefore, the abstracts that were assessed for inclusion as well. In total,
ability to predict risk of recurrence and progression and the updated literature search identified 1,626 abstracts, of
treat the disease appropriately is important. This guideline which 76 met inclusion criteria.
provides a risk-stratified clinical framework for the
management of NMIBC. An additional update was performed in 2023. The updated
search gathered literature from July 2019 to May 2023.
METHODOLOGY This review identified 1,918 abstracts, of which 75 met
inclusion criteria.
Systematic Review
Data Extraction and Data Management
The systematic review utilized in the creation of this
guideline was completed in part through AHRQ and For treatment studies, the following information was
through additional supplementation that further extracted into evidence tables: study design, setting,
addressed additional key questions and more recently inclusion and exclusion criteria, dose and duration of
published literature. A research librarian experienced in treatment for experimental and control groups, duration of
conducting literature searches for comparative follow-up, number of subjects screened, eligible and
effectiveness reviews searched in Ovid MEDLINE enrolled population characteristics (including age, race,
(January 1990 – October 2014), Cochrane Central sex, stage of disease, and functional status), results,
Register of Controlled Trials (through September 2014), adverse events, withdrawals due to adverse events, and
Cochrane Database of Systematic Reviews (through sources of funding. Relative risks and associated 95
September 2014), Health Technology Assessment percent confidence intervals (CI) were calculated based
(through 3rd Quarter, 2014), National Health Sciences on the information provided (sample sizes and incidence
Economic Evaluation Database (through 3rd Quarter, of outcomes in each intervention group). Discrepancies
2014), and Database of Abstracts of Reviews of Effects between calculated and reported results were noted when
(through 3rd Quarter, 2014) to capture both published and present.
grey literature. Database searches resulted in 3,740 For diagnostic accuracy studies, the following information
potentially relevant articles. After dual review of abstracts was abstracted: setting, screening test or tests, method of
and titles, 643 articles were selected for full-text dual data collection, reference standard, inclusion criteria,
review, and 149 studies (in 192 publications) were population characteristics (including age, sex, race,
determined to meet inclusion criteria and were included in smoking status, signs or symptoms, and prior bladder
this review. The AHRQ review was then updated by a cancer stage or grade), proportion of individuals with
consultant methodologist though September 2, 2015. bladder cancer, bladder cancer stage and grade,
Reference lists and previous systematic reviews were definition of a positive screening exam, proportion of
also reviewed for additional studies. This individuals unexaminable by the screening test,
supplementation added 29 studies to the completed proportion who did not undergo reference standard,
systematic review used in the creation of guideline results, and sources of funding. When possible, two-by-
statements. two tables were created from information provided
(sample size, prevalence, sensitivity, and specificity) and

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compared to calculated measures of diagnostic accuracy The categorization of evidence strength is conceptually
based on the two-by-two tables with reported results. distinct from the quality of individual studies. Evidence
Discrepancies between calculated and reported results strength refers to the body of evidence available for a
were noted when present. Data extraction for each study particular question and includes not only individual study
was completed by one investigator and independently quality but consideration of study design, consistency of
reviewed for accuracy and completeness by a second findings across studies, adequacy of sample sizes, and
investigator. generalizability of samples, settings, and treatments for the
purposes of the guideline. The AUA categorizes body of
Assessment of the Risk of Bias of Individual evidence strength as Grade A (well-conducted and highly-
Studies generalizable RCTs or exceptionally strong observational
Risk of bias was assessed for randomized trials and studies with consistent findings), Grade B (RCTs with some
observational studies using criteria adapted from those weaknesses of procedure or generalizability or moderately
developed by the U.S. Preventive Services Task Force.1 strong observational studies with consistent findings), or
Studies of diagnostic accuracy were rated using criteria Grade C (RCTs with serious deficiencies of procedure or
adapted from QUADAS-2.2 These criteria were applied in generalizability or extremely small sample sizes or
conjunction with the approaches recommended in the observational studies that are inconsistent, have small
AHRQ Methods Guide3 for medical interventions and the sample sizes, or have other problems that potentially
AHRQ Methods Guide for Medical Test Reviews.4 Two confound interpretation of data). By definition, Grade A
investigators independently assessed the risk of bias of evidence is evidence about which the Panel has a high
each study. Discrepancies were resolved through level of certainty, Grade B evidence is evidence about
discussion and consensus. Each study was rated as which the Panel has a moderate level of certainty, and
“low,” “medium,” or “high” risk of bias.3 Grade C evidence is evidence about which the Panel has
a low level of certainty (Table 1).5 The 38 statements
Determination of Evidence Strength created vary in level of evidence, but none include Level A
evidence, and a majority are Level C evidence.

TABLE 1: Strength of Evidence Definitions

AUA Strength of GRADE Certainty Rating Definition

Evidence Category
A High • Very confident that the true effect lies close
to that of the estimate of the effect

B Moderate • Moderately confident in the effect estimate

• The true effect is likely to be close to the
estimate of the effect, but there is a
possibility that it is substantially different

C Low • Confidence in the effect estimate is limited

• The true effect may be substantially
different from the estimate of the effect

Very Low • Very little confidence in the effect estimate

• The true effect is likely to be substantially
different from the estimate of effect

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Non-Muscle Invasive Bladder Cancer (NMIBC)

AUA Nomenclature: Linking Statement Type Where gaps in the evidence existed, the Panel provides
to Evidence Strength guidance in the form of Clinical Principles or Expert
Opinion with consensus achieved using a modified Delphi
The AUA nomenclature system explicitly links statement technique if differences of opinion emerged.6 A Clinical
type to body of evidence strength, level of certainty, Principle is a statement about a component of clinical care
magnitude of benefit or risk/burdens, and the Panel’s that is widely agreed upon by urologists or other clinicians
judgment regarding the balance between benefits and for which there may or may not be evidence in the medical
risks/burdens (Table 2). Strong Recommendations are literature. Expert Opinion refers to a statement, achieved
directive statements that an action should (benefits by consensus of the Panel, which is based on members’
outweigh risks/burdens) or should not (risks/burdens clinical training, experience, knowledge, and judgment for
outweigh benefits) be undertaken because net benefit or which there is no evidence.
net harm is substantial. Moderate Recommendations are
Process
directive statements that an action should (benefits
outweigh risks/burdens) or should not (risks/burdens The NMIBC Panel was created in 2014 by the American
outweigh benefits) be undertaken because net benefit or Urological Association Education and Research, Inc.
net harm is moderate. Conditional Recommendations (AUA). The Practice Guidelines Committee (PGC) of the
are non-directive statements used when the evidence AUA selected the Panel Chair who in turn appointed the
indicates that there is no apparent net benefit or harm or Vice Chair. In a collaborative process, additional Panel
when the balance between benefits and risks/burden is members, including additional members of the Society of
unclear. All three statement types may be supported by any Urologic Oncology (SUO) with specific expertise in this
body of evidence strength grade. Body of evidence area, where then nominated and approved by the PGC.
strength Grade A in support of a Strong or Moderate The AUA conducted a thorough peer review process. The
Recommendation indicates that the statement can be draft guidelines document was distributed to 128 peer
applied to most patients in most circumstances and that reviewers, 66 of which submitted comments. The panel
future research is unlikely to change confidence. Body of reviewed and discussed all submitted comments and
evidence strength Grade B in support of a Strong or revised the draft as needed. Once finalized, the guideline
Moderate Recommendation indicates that the statement was submitted for approval to the PGC and Science and
can be applied to most patients in most circumstances but Quality Council (S&Q). Then it was submitted to the AUA
that better evidence could change confidence. Body of Board of Directors for final approval.
evidence strength Grade C in support of a Strong or
Moderate Recommendation indicates that the statement The 2020 amendment also underwent peer review. The
can be applied to most patients in most circumstances but draft amendment was distributed to 77 peer reviewers, 21
that better evidence is likely to change confidence. Body of of whom submitted 57 comments. The Panel reviewed
evidence strength Grade C is only rarely used in support of and discussed all submitted comments and revised the
a Strong Recommendation. Conditional Recommendations draft as needed. Once finalized, the amendment was
also can be supported by any evidence strength. When submitted for approval in the same manner as with the full
body of evidence strength is Grade A, the statement guideline.
indicates that benefits and risks/burdens appear balanced,
the best action depends on patient circumstances, and Additionally, the 2024 amendment underwent peer
future research is unlikely to change confidence. When review. The draft amendment was distributed to 83 peer
body of evidence strength Grade B is used, benefits and reviewers, 18 of whom submitted 80 comments. The
risks/burdens appear balanced, the best action also Panel reviewed and discussed all submitted comments
depends on individual patient circumstances and better and revised the draft as needed. Once finalized, the
evidence could change confidence. When body of amendment was submitted for approval in the same
evidence strength Grade C is used, there is uncertainty manner as with the full guideline.
regarding the balance between benefits and risks/burdens,
Funding of the Panel was provided by the AUA; Panel
alternative strategies may be equally reasonable, and
members received no remuneration for their work.
better evidence is likely to change confidence.

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Non-Muscle Invasive Bladder Cancer (NMIBC)

TABLE 2: AUA Nomenclature Linking Statement Type to Level of Certainty, Magnitude of Benefit or
Risk/Burden, and Body of Evidence Strength

Evidence Grade Evidence Strength A Evidence Strength B Evidence Strength C

(High Certainty) (Moderate Certainty) (Low Certainty)

Strong -Benefits > Risks/Burdens (or -Benefits > Risks/Burdens (or -Benefits > Risks/Burdens (or vice
Recommendation vice versa) vice versa) versa)

(Net benefit or -Net benefit (or net harm) is -Net benefit (or net harm) is -Net benefit (or net harm) appears
harm substantial) substantial
substantial substantial
-Applies to most patients in most
-Applies to most patients in -Applies to most patients in circumstances but better evidence
most circumstances and most circumstances but better is likely to change confidence
future research is unlikely to evidence could change (rarely used to support a Strong
change confidence confidence Recommendation)

Moderate -Benefits > Risks/Burdens (or -Benefits > Risks/Burdens (or -Benefits > Risks/Burdens (or vice
Recommendation vice versa) vice versa) versa)

(Net benefit or -Net benefit (or net harm) is -Net benefit (or net harm) is -Net benefit (or net harm) appears
harm moderate) moderate
moderate moderate
-Applies to most patients in most
-Applies to most patients in -Applies to most patients in circumstances but better evidence
most circumstances and most circumstances but better is likely to change confidence
future research is unlikely to evidence could change
change confidence confidence

Conditional -Benefits = Risks/Burdens -Benefits = Risks/Burdens -Balance between Benefits &

Recommendation
-Best action depends on -Best action appears to Risks/Burdens unclear
(Net benefit or individual patient depend on individual patient
harm comparable circumstances circumstances -Net benefit (or net harm)
to other options) comparable to other options
-Future Research is unlikely -Better evidence could change
to change confidence confidence -Alternative strategies may be
equally reasonable

-Better evidence likely to change

confidence

Clinical Principle 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 a statement, achieved by consensus of the Panel, that is based on members' clinical training,
experience, knowledge, and judgment for which there may or may not be evidence in the medical
literature

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Non-Muscle Invasive Bladder Cancer (NMIBC)

BACKGROUND chronic catheter use also serves as a risk factor.

Additionally, aristolochic acid, a natural compound found
Epidemiology in a number of plants of the Aristolochia genus, has been
linked to upper-tract urothelial carcinoma.21 Another
NMIBC represents approximately 75% of the 74,000 known risk factor includes external beam radiation to the
estimated new bladder cancer cases diagnosed in the pelvis.22
United States in 2015.7, 8 Bladder cancer is more common
in males than females with a ratio of approximately 3:1, M OLECULAR M ECHANISM AND G ENETICS
and it is the fourth most common solid malignancy in men. There is no currently accepted genetic or inheritable
There are 16,000 estimated deaths for 2015, cause of bladder cancer; however, studies suggest that
predominantly affecting males.7, 9 Bladder cancer genomic instability and genetic pathway
primarily affects Caucasian Americans and those older mutations/alterations may play a role in bladder
than 65 years with relatively stable mortality rates since carcinogenesis. Studies suggest that polymorphisms in
1975.9 two carcinogen-detoxifying genes GSTM-1 and NAT-2
may be responsible for increased susceptibility to
National registry data from the U.S. Surveillance
developing bladder cancer in certain patients.23
Epidemiology and End Results program demonstrates
Chromosome 9 deletion is a common genetic alteration
that the incidence of all stages of NMIBC has been
found in NMIBC, with loss of heterozygosity (LOH) of 9p,
relatively stable from 1988-2006; however, the adjusted
homozygous deletion of CDKN2A, and loss of expression
incidence of stage Ta has significantly increased, while
of p16 in NMIBC predicting recurrence free survival.24-26
stages Tis and T1 have slightly decreased.10
Mutations in tumor suppressor genes can lead to
Etiology disruption of cell cycle regulation and predispose to
carcinogenesis. CIS frequently demonstrates mutations
R ISK FACTORS in the tumor suppressor genes TP53, RB1
Multiple factors are associated with bladder (retinoblastoma), and PTEN.27 Oncogenes that promote
carcinogenesis; however, tobacco smoking is the most tumor cell development and alterations in FGFR3,
significant and most common risk factor.11 Although PIK3CA, and RAS are common in NMIBC.27, 28
smoking cessation may somewhat decrease
Presentation and Diagnosis
carcinogenesis risk, former smokers still have a higher
risk of bladder cancer than those who never smoked.11 The most common presenting symptom is painless
With respect to NMIBC, current tobacco use and hematuria (gross or microscopic). According to the AUA
cumulative lifetime exposure may be associated with Guideline on the diagnosis, evaluation, and follow-up of
recurrence and progression.12, 13 Although an incomplete patients with asymptomatic microhematuria (AMH), the
list, the Panel has identified other more common risk rate of urinary tract malignancy in AMH is approximately
factors. Occupational exposure to chemical carcinogens, 2.6%.29 Irritative voiding symptoms (e.g., frequency,
such as aromatic amines, polycyclic aromatic urgency, dysuria) may also be associated with CIS in
hydrocarbons, and arsenic, is another reported risk patients with no sign of urinary tract infection (UTI).
factor.14, 15 Patients with other malignancies, such as Physical exam rarely reveals significant findings in
lymphomas and leukemias, who receive treatment with patients with NMIBC. However, a bimanual exam may be
cyclophosphamide may be at increased risk for bladder performed under anesthesia at the time of TURBT and
cancer.16, 17 Patients with Lynch Syndrome may also be at should be performed at that time if the tumor appears
increased risk of urothelial carcinoma of the bladder, as invasive. Although not indicated for routine screening and
well as, the upper urinary tract.18, 19 Infection also evaluation of AMH, urinary cytology (voided or barbotage)
increases the risk of bladder cancer; in particular, may be used in the surveillance of bladder cancer for
Schistosoma hematobium, the pathogen responsible for certain patients as it possesses a high sensitivity and
schistosomiasis, is a risk factor for squamous cell positive predictive value for high-grade tumors and CIS.30,
carcinoma of the bladder in certain regions of the world.20 31 Contrast-based axial imaging, such as computed

In looking at squamous cell carcinoma of the bladder, tomography (CT) or magnetic resonance imaging (MRI) is
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Non-Muscle Invasive Bladder Cancer (NMIBC)

the recommended imaging modality during the work-up Node-Metastases (TNM) classification.33 Clinical stage
for bladder cancer. Retrograde pyelogram and reflects the histologic findings at TURBT; the clinician’s
intravenous urography may also be used when CT or MRI physical exam, including bimanual exam under
are unavailable. Abdomino-pelvic sonography alone may anesthesia; and findings on radiologic imaging. The
not provide sufficient anatomic detail for upper urinary pathologic report of the TURBT should indicate whether
tract imaging during the work-up of bladder cancer.32 lamina propria and muscularis propria are present as well
as the degree of involvement, if present. In addition, effort
The diagnosis of bladder cancer is confirmed by direct
should be made by the pathologist to examine the
visualization of the tumor and other mucosal
specimen for lymphovascular invasion (LVI), when
abnormalities with endoscopic excision using cystoscopy
applicable, as this is associated with worse prognosis. 34-
and TURBT. An adequate TURBT requires complete 37 Pathological staging, also known as surgical staging, is
resection of all visible tumor with adequate sampling of
based on the extent of disease following surgical
the bladder to assess the depth of invasion.
resection of the bladder (partial versus radical
Staging and Grading cystectomy) and of the adjacent pelvic lymph nodes.
Under the AJCC staging system, NMIBC includes the
Staging for bladder cancer is separated into clinical and following: (1) papillary tumors confined to the epithelial
pathologic stage, as outlined by the American Joint mucosa (stage Ta), (2) tumors invading the subepithelial
Committee on Cancer (AJCC), also known as the Tumor- tissue (i.e., lamina propria; T1), and (3) Tis. (Table 3)

TABLE 3: Staging of primary tumors (T) in bladder cancer33

TX Primary tumor cannot be assessed
Ta Noninvasive papillary carcinoma
Tis Carcinoma in situ (CIS)
T1 Tumor invades lamina propria
T2 Tumor invades muscularis propria
T2a Tumor invades superficial muscularis propria (inner
half)
T2b Tumor invades deep muscularis propria (outer half)
T3 Tumor invades perivesical tissue/fat
T3a Tumor invades perivesical tissue/fat microscopically
T3b Tumor invades perivesical tissue fat macroscopically
(extravesical mass)
T4 Tumor invades prostate, uterus, vagina, pelvic wall, or
abdominal wall
T4a Tumor invades adjacent organs (uterus, ovaries,
prostate stoma)
T4b Tumor invades pelvic wall and/or abdominal wall

Tumor grade is an important prognostic factor for World Health Organization (WHO) classification was the
determining risk of recurrence and progression in bladder widely accepted format for grading bladder neoplasia. 38,
cancer. Prior to the 2004 revised classification, the 1973 39 The 1973 version designated tumors as either

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Non-Muscle Invasive Bladder Cancer (NMIBC)

papilloma, grade 1, 2, or 3, whereas the 2004 revision of approximately 55%, but with a much lower percentage
designated tumors as ‘low’ or ‘high’ grade. The 1973 (6%) experiencing stage progression.42 In contrast, high-
grade 2 or ‘intermediate’ grade tumors are now re- grade T1 lesions have both a significant risk of recurrence
classified as either ‘low’ or ‘high’ grade depending on (45%) and increased chance of progression (17%) in
cellular morphology.38, 39 In addition, the 2004 single institution series.40 Therefore, the ability to predict
classification introduced the new category of papillary recurrence and progression risk in NMIBC, based on
urothelial neoplasm of low malignant potential to describe patient-specific disease characteristics, holds prognostic
lesions with an increased number of urothelial layers significance. Risk stratification in NMIBC aids
when compared with papilloma but without cytologic personalized treatment decisions and surveillance
features of malignancy. The WHO/International Society of strategies as opposed to a generalized ‘one-size fits all’
Urological Pathology 2004 grading system is now the approach.
most widely accepted and utilized system in the United
States. (Table 4)
Risk Stratification

TABLE 4: 2004 WHO/ International Society of Significant effort has been put forth to develop tools for
Urologic Pathologists: Classification of Non- risk stratification and prognostication. A widely published
muscle Invasive Urothelial Neoplasia38 system is the European Organization for Research and
Treatment of Cancer (EORTC) risk calculator, based on
Hyperplasia (flat and papillary)
the combined data from seven trials involving patients
Reactive atypia with NMIBC.43 Using clinical and pathologic variables in a
scoring system, the EORTC calculator provides a
Atypia of unknown significance
probability of recurrence and progression at one and five
Urothelial dysplasia years. Important factors for recurrence identified by the
Urothelial CIS EORTC study include prior recurrence rate, number of
tumors, and tumor size.43 With respect to progression,
Urothelial papilloma important factors include T-stage, presence of CIS, and
Papillary urothelial neoplasm of low malignant grade. A second risk stratification tool is that developed
potential by the Spanish Urological Club for Oncological
Treatment/Club Urologico Espanol de Tratamiento
Non-muscle invasive low-grade papillary Oncologico (CUETO).44 These models are examples of
urothelial carcinoma
carefully constructed risk stratification systems; however,
Non-muscle invasive high-grade papillary they have limitations. Both tools are limited by lack of
urothelial carcinoma applicability to current patient populations because few
patients from the development cohort received BCG
maintenance, underwent re-staging transurethral-
Prognosis resection, or received single-dose post-operative
mitomycin C. A recent update of the EORTC nomogram
The survival prognosis for patients with NMIBC is for risk stratification attempted to address the lack of BCG
relatively favorable, with the cancer-specific survival maintenance in prior studies, by analyzing a cohort of
(CSS) in high-grade disease ranging from approximately patients treated with one to three years of BCG. This
70-85% at 10 years and a much higher rate for low-grade updated study cohort lacked patients with CIS and again
disease.40, 41 The rates of recurrence and progression to was limited by absence of routine re-resection.45
MIBC are important surrogate endpoints for prognosis in Additionally, the EORTC risk calculator utilizes the 1973
NMIBC, as these are major determinants of long-term WHO grading system to generate risk probabilities as
outcome. However, NMIBC is a clinically heterogeneous opposed to the 2004 version. As previously mentioned,
group of cancers with a wide range of recurrence and the 2004 revision is the currently accepted classification
progression probabilities that depend on several clinical for tumor grade; therefore, the EORTC risk tables are
and pathologic factors. For example, long-term follow up commonly not considered in the U.S.
of low-grade Ta lesions demonstrates a recurrence rate

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Risk groupings are evaluated by their ability to predict the groupings, the Panel set forth defining first those at lowest
outcome of patients who are felt to be similar to one and highest risk for recurrence and/or progression.
another. The most commonly used tool to assess the Numerous clinical scenarios based on disease
accuracy of risk groupings is the concordance index (C- characteristics were then incorporated into the grouping
index). The C-index is a measure of the ability of a risk system, and each one was placed into a category based
assessment tool to separate those patients with the on unanimous expert consensus and available published
outcome of interest from those without the outcome of data. The Panel also recognizes that the intermediate
interest (e.g., recurrence or progression).46 A C-index of group is somewhat heterogeneous, and the outcome of
0.5 implies that the ability to predict outcome is no better patients within this group may still exhibit some variation
than random chance. For the original EORTC study, the along the spectrum of risk of recurrence and progression.
C-indices for recurrence and progression were 0.66 and
Unique to the AUA/SUO Guideline Risk Stratification
0.75, respectively and 0.64 and 0.7, respectively, for the
System is the incorporation of prior BCG intravesical
CUETO study.43, 44 A further important limitation of the
therapy on prognosis. There are limited data that
existing risk stratification models is that neither reported
demonstrate that patients who have persistent or
formal measures of calibration (the degree to which
recurrent disease at six months following BCG therapy
predicted and observed risk estimates agree). Several
are at increased risk of disease progression.53, 54 As such,
studies have retrospectively evaluated the ability of the
the Panel reasons that patients who are intermediate risk
EORTC and CUETO models to predict the risk of
and demonstrate BCG failure should be re-stratified to the
recurrence and progression in other patient
47-52
high-risk group. The rationale for this approach is that
populations. These attempts at external validation
those patients who do not respond to standard
using other patient populations have yielded variable C-
intravesical therapy likely harbor more aggressive
index results and underscore the fact that both
disease than implied by clinical or pathologic features;
instruments are limited by suboptimal calibration and
therefore, a lack of response serves as a surrogate
inherent biases based on their designs. Evaluation of
marker for increased risk of recurrence and/or
these studies investigating the utility of risk stratification in
progression. The Panel also understands and
multiple populations demonstrate that they have a poor to
appreciates that within each of these risk strata that an
fair ability to discriminate risk of recurrence (C-index 0.52
individual patient may have more or less concerning
to 0.66) and good to fair (C-index 0.62 to 0.81) ability to
features that can influence care.
discriminate risk of progression.
The Panel acknowledges the need for validation of these
The Panel acknowledges that Level A evidence does not
risk groups in large, contemporary patient cohorts in order
support stratification as affecting disease recurrence,
to assess the model’s performance for predicting disease
progression, or survival. However, despite the lack of
recurrence and progression.
evidence confirming a positive influence on clinical
outcome, the Panel agrees that there is value to creating Relevance of the International BCG Shortage
fundamental categories that broadly estimate the to the AUA Guidelines
likelihood of recurrence and progression. The Panel set
out to create such a system, with categories summarized The global shortages in TICE BCG that occurred in 2014
as ‘low,’ ‘intermediate,’ and ‘high’ risk for recurrence and 2019 led the AUA to recommend several
and/or progression. (Table 5) This risk grouping system management strategies to maintain high quality care for
is a simple tool, intended for use in clinical practice as a patients with NMIBC. These recommendations may
general framework for guiding patient counseling and supersede the guideline statements below. In particular,
aiding in treatment and surveillance decisions based on the BCG shortage impacts guideline statements 17, 20,
prognosis. While there are similarities between the and 21. The AUA Statement on the BCG Shortage is
current risk categories outlined in the Guideline and the available at https://www.auanet.org/about-us/bcg-
EORTC stratification, it should be noted that they are not shortage-info.
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
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Non-Muscle Invasive Bladder Cancer (NMIBC)

TABLE 5: AUA Risk Stratification for NMIBC

Low Risk Intermediate Risk High Risk

LGa solitary Ta ≤ 3cm Recurrence within 1 year, LG Ta HG T1

PUNLMPb Solitary LG Ta > 3cm Any recurrent, HG Ta

LG Ta, multifocal HG Ta, >3cm (or multifocal)

HGc Ta, ≤ 3cm Any CISd

LG T1 Any BCG failure in HG patient

Any variant histology

Any LVIe

Any HG prostatic urethral

involvement

a
LG = low grade; bPUNLMP = papillary urothelial neoplasm of low malignant potential; cHG = high
grade; dCIS=carcinoma in situ; eLVI = lymphovascular invasion

with topical intraurethral anesthetic lubricant decreases

GUIDELINE STATEMENTS patient discomfort during the procedure, particularly in
men.55 Most cases of NMIBC are initially treated with
Diagnosis transurethral resection, but careful cystoscopic
examination of the entire urethra and bladder should
1. At the time of resection of suspected bladder precede resection.56 However, surgeons may proceed
cancer, a clinician should perform a thorough directly to TURBT should CT or MRI reveal a bladder
cystoscopic examination of a patient’s entire lesion during the evaluation of hematuria. During
urethra and bladder that evaluates and resection, tumors of significant size should be resected
documents tumor size, location, configuration, and labeled. The anatomic location of tumors with respect
number, and mucosal abnormalities. (Clinical to the bladder neck and ureteral orifices, tumor
Principle) configuration (papillary or sessile), as well as both the size
The diagnosis of NMIBC relies upon cystoscopy and and number of tumors should be documented in some
tissue sampling. Initial cystoscopic evaluation is often consistent manner (e.g., diagram, text description) to
performed in the office setting with or without biopsies of inform future follow-up and evaluate treatment response.
visualized tumor(s). Flexible cystoscopy in conjunction

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Non-Muscle Invasive Bladder Cancer (NMIBC)

2. At initial diagnosis of a patient with bladder one to two years in a high-risk patient.
cancer, a clinician should perform complete
4. In a patient with a history of NMIBC with normal
visual resection of the bladder tumor(s), when
cystoscopy and positive cytology, a clinician
technically feasible. (Clinical Principle)
should consider prostatic urethral biopsies and
Incomplete TURBT is likely a significant contributing upper tract imaging, as well as enhanced
factor to early bladder cancer recurrences, as tumors are cystoscopic techniques (blue light cystoscopy
seen at first surveillance cystoscopy in up to 45% of [BLC], when available), ureteroscopy, or random
patients.57 Thus, complete TURBT is critical in bladder biopsies. (Expert Opinion)
management of NMIBC for accurate tumor type, staging,
The likelihood of detecting CIS on random bladder
grading, and optimization of patient outcomes.57-59 A lack
biopsies in patients with low-risk disease is exceedingly
of detrusor muscle in the resection specimens is
small but increases significantly in patients with high-risk
associated with increased risk of understaging, residual
disease or positive cytology.70, 71 Similarly, involvement of
disease on repeat TURBT, and early tumor recurrence. 59,
60 In addition to complete resection, bimanual examination
the prostatic urethra is very uncommon in men with low-
risk disease but increases substantially in the presence of
under anesthesia after TURBT can also assist with clinical
CIS, multifocal disease, and tumors of the bladder neck
staging. Enhanced cystoscopy methods and newer
and trigone.40, 72 Furthermore, enhanced cystoscopic
resection techniques, such as bipolar electrocautery, may
techniques, including BLC and NBI, seem particularly
serve to enhance complete resection and reduce
valuable for diagnosis of urothelial carcinoma in the
complications from TURBT.61-63 For patients with a history
setting of positive cytology but negative white light
of small, low-grade Ta tumors, however, office-based
cystoscopy (WLC).73, 74
cystoscopy and fulguration of small recurrences or even
cystoscopic surveillance are treatment options and may Risk Stratification
reduce overall therapeutic burden.64-67 Emerging larger
clinical experiences and confirmatory trials are needed to 5. At the time of each occurrence/recurrence, a
validate these conservative approaches. clinician should assign a clinical stage and
classify a patient accordingly as “low-,”
3. A clinician should perform upper urinary tract
“intermediate-,” or “high-risk.” (Moderate
imaging as a component of the initial evaluation
Recommendation; Evidence Strength: Grade C)
of a patient with bladder cancer. (Clinical
Principle) In creating the AUA/SUO Guideline Risk Stratification
System (see Table 5), the Panel chose to adhere to the
In patients with a known history of bladder cancer, upper
general principles of the EORTC and CUETO models by
tract tumors occur in less than 5% of patients and can be
including factors that have been found to have a
evaluated with common imaging techniques, including
significant impact on risk of recurrence and progression,
retrograde pyelography, CT, MRI, as well as
such as tumor size, tumor focality, grade, and stage. In
transabdominal ultrasonography (US), in select cases.
addition, however, the Panel incorporated evidence from
CT urogram or MR urogram have advantages over US,
other studies that has demonstrated that LVI, prostatic
showing not only potential hydronephrosis, but also filling
urethral involvement, variant histology, and poor
defects, as well as regional lymph nodes and adjacent
response to BCG also confer high-risk for progression to
organs. US and retrograde pyelography are typically
muscle invasion.53, 54, 75-77
reserved for patients with renal function non-supportive of
contrast-enhanced CT or MRI. The overall incidence of Risk stratification for each patient is a dynamic and
significant findings with imaging of the upper tracts in iterative process. Patients may recur multiple times during
patients with newly diagnosed bladder cancer is low but the continuum of their care and may face repetitive
increases with tumors of the trigone, CIS, and high-risk therapeutic interventions, such as intravesical therapy.
disease.68, 69 The timing of initial upper tract imaging for Those patients who recur following optimal standard
bladder cancer is not clear, but it should likely be risk intravesical therapy likely harbor more aggressive
stratified and generally within six months of initial disease than implied by clinical or pathologic features; as
diagnosis. Repeat upper tract imaging should occur every such, continued risk evaluation and classification is
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Non-Muscle Invasive Bladder Cancer (NMIBC)

necessary for the optimal care of patients prior to each 7. If a bladder sparing approach is being
treatment decision. considered in a patient with variant histology,
then a clinician should perform a restaging
Variant Histologies transurethral resection of bladder tumor
(TURBT) within four to six weeks of the initial
6. An experienced genitourinary pathologist should
TURBT. (Expert Opinion)
review the pathology of a patient with any doubt
in regard to variant or suspected variant Historically, the variant histologies have been under-
histology (e.g., micropapillary, nested, appreciated and under-reported, but data is accumulating
plasmacytoid, neuroendocrine, sarcomatoid), in regard to their aggressiveness. With their potential risk,
extensive squamous or glandular differentiation, the committee believes that if a clinician is considering
or the presence/absence of lymphovascular any treatment that would preserve the bladder, that at a
invasion (LVI). (Moderate Recommendation; minimum, a repeat TURBT should be done to evaluate
Evidence Strength: Grade C) clinical stage for these tumor types.

The pathology report should specify the presence and The presence of variant histology within the TURBT
percentage of variant histology (e.g., squamous and/or specimen is uniformly associated with high-grade disease
glandular differentiation, micropapillary, nested, and almost always invasive. In one study, 86% of patients
plasmacytoid, neuroendocrine, sarcomatoid) as well as with variant histology presented with muscle-invasive
the presence or absence of LVI. These currently disease at TURBT compared with 53% of those with high-
recognized histologic variants are less common and can grade pure urothelial carcinoma. At cystectomy, 64% of
influence disease prognosis and treatment choices. The the patients with variant histology were found to have T3-
Panel recognizes that future pathologic and molecular T4 disease compared to 34% of those with pure high-
subtypes will continue to be elucidated and that these grade urothelial carcinoma.83 In 2021, Iida and colleagues
may require secondary review. In cases of non-muscle reported on a cohort of 94 patients with BCG-
invasive disease, re-resection is mandatory to rule out unresponsive NMIBC treated without radical cystectomy.
muscle-invasive disease given the high rate of upstaging They found that the presence of variant histology was an
with variant histology. Several studies suggest that variant independent predictor of poor overall survival. Although
differentiation may affect survival; however, there is a this study did not evaluate the role of re-TURBT in this
paucity of data due to the rarity of most variants. Some of population, it does support the high-risk nature of variant
the variants, such as micropapillary, have been described histology.84 As such, patients with mixed histologic
fairly recently (1994), and others are under-recognized or features are generally not ideal candidates for bladder
understaged.78 In one study from the Mayo Clinic, sparing protocols and are best served with an aggressive
pathological re-review of cystectomy specimens identified treatment modality.85
variant histologies in up to one third of patients initially 8. Due to the high rate of upstaging associated with
classified with pure urothelial carcinoma.79 Compared to variant histology, a clinician should consider
patients with pure urothelial carcinoma, those with variant offering initial radical cystectomy. (Expert
histology have a greater incidence of locally advanced Opinion)
disease and worse survival.80-82
There is a lack of evidence regarding the efficacy of
The diagnosis of LVI is defined by the presence of tumor intravesical therapy for patients with non-muscle invasive
within endothelium-lined spaces. Numerous studies have urothelial carcinoma with variant histology. Given the high
documented the clinical importance of LVI as an important rate of upstaging associated with variant histology and the
prognostic marker of upstaging, lymph node involvement, presence of LVI, surgeons should consider offering
recurrence, and decreased overall survival.34-37 Thus, the patients early cystectomy.83, 85, 86 The Iida and colleagues
committee believes that the reporting of the presence or study cited previously supports the rationale for radical
absence of LVI is important. cystectomy when variant histology is present in patients
with NMIBC unresponsive to BCG.84

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Non-Muscle Invasive Bladder Cancer (NMIBC)

Urine Markers after Diagnosis of ImmunoCyt™ test identifies three cell surface
glycoproteins that are present on the membrane of cancer
Bladder Cancer cells and can be used in conjunction with cytology to
enhance the sensitivity of cytology. The Cxbladder™ test
9. In surveillance of NMIBC, a clinician should not
identifies the presence of five mRNA fragments in the
use urinary biomarkers in place of cystoscopic
urine that are expressed at high levels in patients with
evaluation. (Strong Recommendation; Evidence
bladder cancer.90 One such fragment, CXCR2, is an
Strength: Grade B)
inflammatory marker that helps discriminate false positive
For many years, researchers have attempted to identify cases. This test appears to be able to distinguish between
and utilize urinary markers for bladder cancer detection. low- and high-grade tumors and may perform better than
Voided urine cytology has been the mainstay of urine- protein-based markers, such as NMP22® and BTA®.
based diagnosis of bladder cancer since the original Although not a complete listing, given the lower specificity
description by Papanicolou and Marshall.87 Urine of all of the other currently available urinary markers to
cytology, however, has several drawbacks, including a urine cytology as well as other concerns, the use of these
poor sensitivity for low-grade/stage tumors, a lack of markers has not been widely adopted.
interobserver consistency, a range of readings (e.g.,
Direct comparisons of protein markers, such as NMP22®
atypical, atypical-suspicious, non-diagnostic), a need to
and BTA®, suggest that there is little difference in
send the specimen to an external laboratory, and a delay
sensitivity or specificity between them.92 Comparing
in obtaining results.88 These shortcomings have inspired
ImmunoCyt™ to UroVysion® FISH suggests that
the search for a more sensitive urinary bladder cancer
ImmunoCyt™ has a higher sensitivity but a lower
marker.
specificity than UroVysion® FISH. Most of the studies
Several markers have been investigated and developed evaluating these markers utilized cystoscopy as a gold
over the past three decades, with five of these markers standard for detecting tumors, while some utilized a
approved by the FDA and/or are commercially available pathologic evaluation of the biopsy specimen as the final
in the US.89, 90 The NMP22® and BTA® tests are protein- reference. Direct comparisons between markers are
based, while UroVysion® FISH, ImmunoCyt™ and difficult, and given the uncertainty in sensitivity, these
CxBladder™ are cell-based. The pooled sensitivity, tests cannot be used to replace cystoscopy.
specificity, positive and negative likelihood ratios are
The update review identified six new observational
shown in Table 6.91
studies (in seven publications) including 1,604
The NMP22® test is available as a point of care test participants and one systematic review relevant to this
(NMP22BladderChek®) or in a more quantitative format. guideline statement. Since the guideline’s initial
This test identifies a nuclear matrix protein that is involved publication in 2016, several new urinary biomarkers have
in the mitotic apparatus. The BTA® test identifies a been developed to detect recurrent bladder cancer in
basement membrane antigen that is related to NMIBC patients on surveillance.93-95 One such marker is
complement factor H and is present within urine at higher CxBladder Monitor. It was designed as a high sensitivity
levels in patients with bladder cancer. Like NMP22®, the rule-out test such that a negative result can be used to
BTA® test is also available in qualitative and quantitative defer cystoscopy or confirm negative cystoscopy. In a
formats. Both tests are FDA-approved for initial evaluation cohort of 763 NMIBC patients on surveillance, CxBladder
and surveillance of bladder cancer; however, these Monitor had a 93% sensitivity and 97% negative
protein-based urine markers have a tendency to be falsely predictive value for recurrent NMIBC; however, the test
positive in the presence of inflammation, resulting in lower specificity was not reported. Approximately one-third of
specificity than urine cytology. This can result in patients had a negative test and could potentially avoid
subjecting patients to unnecessary diagnostic cystoscopy. The test performed well for both low- and
evaluations. high-grade recurrences93 and outperformed urine
cytology, NMP22, and UroVysion® FISH.96 While a
The UroVysion® (FISH) test identifies altered copy
patient with a negative test is unlikely to have recurrent
numbers of four specific chromosomes or loss of regions
NMIBC, a non-negative test requires continued
of chromosome 9p using fluorescent probes. The
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Non-Muscle Invasive Bladder Cancer (NMIBC)

cystoscopic surveillance and is not necessarily diagnostic needed to determine if a negative test is sufficient to defer
of a recurrence. Although the early data on CxBladder surveillance cystoscopy and what the clinical implications
Monitor are promising, further validation studies are are of a non-negative test.

TABLE 6: Performance Characteristics of Commonly Used and FDA Approved Urinary Markers91

Marker Sensitivity Specificity Pos. likelihood Neg. likelihood

ratio (95% CI) ratio (95% CI)

1. NMP22® quantitative 4. 7. 3.05 (2.28-4.10) 0.40 (0.32-0.50)

2. Overall 5. 69% 8. 77%
3. Diagnosis 6. 67% 9. 84%
Surveillance 61% 71%

10. NMP22® qualitative 13. 16. 4.89 (3.23-7.40) 0.48 (0.33-0.71)

11. Overall 14. 58% 17. 88%
12. Diagnosis 15. 47% 18. 93%
Surveillance 70% 83%

19. BTA® quantitative 21. 24. 2.52 (1.86-3.41) 0.47 (0.37-0.61)

Overall 22. 65% 25. 74%
20. Diagnosis 23. 76% 26. 53%
Surveillance 58% 79%

27. BTA® qualitative 30. 33. 2.80 (2.31-3.39) 0.47 (0.30-0.55)

28. Overall 31. 64% 34. 77%
29. Diagnosis 32. 76% 35. 78%
Surveillance 60% 76%

36. UroVysion® FISH 39. 42. 5.02 (2.93-8.60) 0.42 (0.30-0.59)

37. Overall 40. 63% 43. 87%
38. Diagnosis 41. 73% 44. 95%
Surveillance 55% 80%

45. ImmunoCyt™ 48. 51. 3.49 (2.82-4.32) 0.29 (0.20-0.41)

46. Overall 49. 78% 52. 78%
47. Diagnosis 50. 85% 53. 83%
Surveillance 75% 76%

CxBladder™ 82% 85% 5.53 (4.28-7.15) 0.21 (0.13-0.36)

CxBladder Monitor™*93 93%

*Additional data outside sensitivity not reported

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The role of markers as adjuncts to cystoscopy in select recurrent bladder cancer in NMIBC patients on
instances along with urine cytology continues to be surveillance. Although this biomarker performed well for
evaluated. Comprehensive literature analysis showed intermediate- and high-risk NMIBC patients in a large
that urinary markers have an increased sensitivity and cohort study, its sensitivity was only 53% in a small subset
specificity as tumor grade and stage increase. Urinary of patients with an EORTC risk score of 0, which is
marker sensitivity is improved in patients with larger equivalent to AUA low-risk.93 As such, there is currently
tumors. Several studies have examined markers for insufficient evidence to recommend CxBladder Monitor
bladder cancer screening in high-risk populations.97, 98 during surveillance for low-risk patients. With the overall
Utilization of urine markers could potentially reduce the lack of combined effective specificity and sensitivity for
frequency of cystoscopy in screening.99 While this is an low-risk patients, the Panel believes that current urinary
intriguing idea, the prevalence of bladder cancer even in biomarkers and cytology should not be routinely used for
high-risk individuals is not high enough to justify routine surveillance in these patients.
screening at this time. Further, the point of care protein
11. In a patient with NMIBC, a clinician may use
markers used in screening do not appear helpful in
biomarkers to assess response to intravesical
identifying the screen-detectable cancers;99, 100 therefore,
BCG (UroVysion® FISH) and adjudicate
this approach cannot be endorsed.
equivocal cytology (UroVysion® FISH and
10. In a patient with a history of low-risk cancer and ImmunoCyt™). (Expert Opinion)
a normal cystoscopy, a clinician should not
The presence of significant inflammation immediately
routinely use a urinary biomarker or cytology
post BCG instillation can affect the accuracy of urine
during surveillance. (Expert Opinion)
cytology. Urinary markers may be used to assess
Many urine markers have been evaluated and even FDA- response to intravesical BCG therapy. In examining the
approved in the context of surveillance for recurrent change in UroVysion® FISH results before and after an
bladder cancer. However, while they exhibit excellent induction or induction + maintenance course of BCG,
sensitivity, particularly for lower-grade tumors, their several studies have noted a correlation between
specificity is still lower than that of urine cytology, and response to BCG and likelihood of disease
although cytology’s sensitivity for intermediate and high- progression.104-108 Based on these studies, it appears that
risk cancer may approach 80%, its level is low in detecting the presence of a persistently positive UroVysion® FISH
low-risk cancer (approximately 20%).88, 101 Thus, this low following completion of induction BCG predicts a poor
sensitivity renders cytology as little use in this context. 102 response to BCG therapy with a higher likelihood of
While ImmunoCyt™ appears to have the highest recurrence and progression. Additionally an observational
sensitivity and specificity in the context of surveillance, the study utilizing a novel scoring system based upon
specificity still falls short of urine cytology. Since recurrent UroVysion® (FISH) in patients who had a history of
bladder tumors detected during surveillance tend to be NMIBC identified an association between a positive FISH
smaller than primary tumors, the amount of protein and the development of MIBC.109 Based on these data,
expressed by these small tumors is also less. This has led clinicians can use UroVysion® FISH as an early guide to
to the suggestion that lower cutoff levels need to be predict response to intravesical BCG therapy. The utility
utilized for protein-based markers, such as NMP22®, in of protein-based markers in this setting has not been well
order to enhance sensitivity for detecting small recurrent tested, but as with cytology, inflammation may also
bladder tumors. Although at least one prospective negatively impact their ability to predict response.
randomized study reported that when a clinician knows
Equivocal urine cytology can occur in as high as 21% of
the marker result, he/she detects and biopsies more
patients being evaluated for hematuria.110 Performance of
tumors,103 it remains unknown if this results in any clinical
a complete diagnostic workup to rule out cancer is
benefit or harm. Among other things, the new urine
typically the default approach in many of these patients
markers were aimed at specifically overcoming the low
with atypical cytology readings and is one reason why its
detection rate of urine cytology for low-grade tumors, but
routine use is no longer advocated for hematuria
this came at the expense of specificity. The previously
evaluations. Even in patients with high-grade cancers,
discussed CxBladder Monitor was designed to detect
cytology may be read as suspicious or atypical. 111, 112
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Non-Muscle Invasive Bladder Cancer (NMIBC)

Thus, utilization of another test to arbitrate an atypical or patients with incompletely resected non-muscle invasive
equivocal cytology reading may be helpful in reducing the disease. Examples of such patients include those with
need for unnecessary diagnostic evaluations in large-volume, high-grade tumors not amenable to
intermediate- and high-risk bladder cancer patients. While complete endoscopic resection for whom immediate
a smaller observational study suggests diagnostic radical cystectomy is planned. An additional example
accuracy of UroVysion® FISH to be inferior to urine includes those patients with a tumor diagnosed within a
cytology, studies have used UroVysion® FISH in this bladder diverticulum and for whom subsequent surgical
context, and found that these urine markers may help resection (e.g., partial or radical cystectomy) is planned.
distinguish between patients with recurrence versus no However, for the majority of patients, complete resection
recurrence.109 In more recent observational studies, is essential for adequate staging and optimal clinical
Bladder Epicheck had improved sensitivity but decreased management.
specificity as compared to urine cytology, indicating
Although surgeons may utilize BLC for this situation, of
potential utility in conjunction with cystoscopy for
note, there is insufficient evidence in this repeat
surveillance of recurrent disease.113-115
transurethral resection setting to support the routine use
Some patients may present with a positive urinary marker of enhanced or BLC versus standard WLC, particularly in
while the bladder appears cystoscopically tumor-free. A light of the noted increase in false positive diagnosis with
proportion but not all of such patients subsequently BLC following recent TURBT.119-121
develop cystoscopically-identifiable tumors. In these 13. In a patient with high-risk, high-grade Ta tumors,
instances, the urinary marker is able to identify a tumor a clinician should consider performing repeat
before it manifests, resulting in an “anticipatory positive” transurethral resection of the primary tumor site
test. Among the newer markers, UroVysion® FISH has within six weeks of the initial TURBT. (Moderate
been found to yield an “anticipatory positive” test in Recommendation; Evidence Strength: Grade C)
approximately 30-40% of patients.116, 117 A recent study
Residual tumor can be found at the time of repeat
suggests that patients with atypical cytology and positive
resection in up to 50% of patients with high-grade Ta
UroVysion® FISH may develop recurrent identifiable
disease, with up to 15% of such tumors being
tumors earlier than a patients with a negative UroVysion®
upstaged.122-125 Larger and multifocal tumors (i.e., high-
FISH.118 In light of these data, these patients should
risk tumors) are at a particularly increased risk for
continue close surveillance but do not all develop
incomplete initial resection, and it this incomplete
identifiable tumors.
resection that is likely a significant contributing factor to
TURBT/ Repeat Resection: Timing, inadequately treated tumors that are then diagnosed as
early recurrences.126 Nevertheless, the Panel
Technique, Goal, Indication acknowledges the paucity of data demonstrating an
absolute therapeutic benefit to repeat resection for high-
12. In a patient with non-muscle invasive disease
grade Ta tumors, and recognizes that in select cases, for
who underwent an incomplete initial resection
example small high-grade Ta lesions in which a visually
(not all visible tumor treated), a clinician should
complete initial resection was performed, repeat resection
perform repeat transurethral resection or
may not be necessary. Thus, the Panel advocates careful
endoscopic treatment of all remaining tumor if
consideration for repeat resection for these patients.
technically feasible. (Strong Recommendation;
Evidence Strength: Grade B) 14. In a patient with T1 disease, a clinician should
perform repeat transurethral resection of the
Incomplete resection is likely a significant contributing
primary tumor site to include muscularis propria
factor to what have been described and diagnosed as
within six weeks of the initial TURBT. (Strong
early recurrences, as tumors have been noted at the first
Recommendation; Evidence Strength: Grade B)
follow-up cystoscopic evaluation in up to 45% of
patients.57 The Panel recognizes specific, albeit rare, Repeat transurethral resection for patients with T1 tumors
circumstances in which transurethral resection is not likely achieves diagnostic, prognostic, and therapeutic benefit.
to impact clinical management and may be omitted for From a diagnostic standpoint, disease understaging is
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Non-Muscle Invasive Bladder Cancer (NMIBC)

common for these patients; therefore, a second resection should be individualized, with consideration given to the
provides a more thorough interrogation for the presence specific tumor histology as well as patient comorbidity and
of muscle-invasive disease. Upstaging at repeat resection renal function status.
to muscle-invasive disease has been reported in
approximately 30% of patients with T1 tumors.122 The risk Intravesical Therapy;
of upstaging is related to the presence or absence of BCG/Maintenance;
muscularis propria on the initial resection specimen, with
rates of upstaging varying from 40-50% among patients
Chemotherapy/BCG Combinations
without muscle present on the first TURBT specimen to
15. In a patient with suspected or known low- or
15-20% in patients with muscle present at the first
intermediate-risk bladder cancer, a clinician
TURBT.122 Repeat resection is recommended even when
should consider administration of a single
the initial TURBT demonstrates the presence of
postoperative instillation of intravesical
muscularis propria given the noted risk of upstaging in
chemotherapy (e.g., gemcitabine, mitomycin C)
that setting. Additionally, the pathology at repeat resection
within 24 hours of TURBT. In a patient with a
contains prognostic value that may guide subsequent
suspected perforation or extensive resection, a
clinical management. Patients found to have muscle-
clinician should not use postoperative
invasive disease may be offered neoadjuvant
intravesical chemotherapy. (Moderate
chemotherapy and radical cystectomy as well as tri-
Recommendation; Evidence Strength: Grade B)
modality definitive local treatment. The presence of
residual T1 disease at the time of repeat resection is The rationale for postoperative instillation of intravesical
associated with subsequent progression risk approaching chemotherapy includes both destruction of residual
80%. As such, these patients should be counseled microscopic tumor at the site of TURBT and of tumor cells
regarding the potential benefit of early cystectomy.127 dispersed within the bladder.132-134 A single postoperative
Alternatively, patients with non-invasive disease at repeat instillation of intravesical chemotherapy after TURBT has
resection may be considered for initial bladder been demonstrated in multiple studies to decrease tumor
preservation with intravesical therapy. recurrence without effects on progression or survival.
SWOG 0337, which was a randomized, controlled double-
In terms of a therapeutic benefit, approximately 50-70%
blind trial of a single dose of intravesical gemcitabine (2g
of patients with T1 tumors have been reported from prior
in 100mL of saline) versus normal saline reduced
white-light cystoscopy series to have residual disease at
recurrences of low-grade Ta bladder cancer with a
the time of repeat TURBT.122-125 In addition, repeat
relative risk reduction of 35% and an absolute risk
resection is associated with improved response rates to
reduction of 10-15% at 4 years.135 In addition, there were
intravesical BCG therapy, specifically with a decreased
no Grade 4-5 adverse events in any patient in the trial,
risk of subsequent tumor recurrence and progression.128-
130 Moreover, a prospective, randomized trial of patients
and the incidence of Grade 3 adverse events between
gemcitabine and saline were equal, emphasizing the
with T1 tumors treated with intravesical mitomycin C
safety of gemcitabine. Three separate meta-analyses
demonstrated that repeat TURBT significantly decreased
have reported that a single postoperative instillation of
recurrence and progression rates.131
chemotherapy significantly decreases tumor recurrence
The Panel recognizes that for select patients, repeat between 10-15% compared to TURBT, although a recent
transurethral resection is not likely to impact clinical randomized 3-arm trial in 82 patients of a single dose of
management and may, therefore, be omitted. Such mitomycin C, gemcitabine or saline failed to demonstrate
patients include those with high-risk non-muscle invasive an improvement in recurrence.135-138 Intravesical
disease who would not be eligible to receive neoadjuvant mitomycin C and epirubicin are additional agents that
chemotherapy even if muscle-invasive disease is have been studied as a single perioperative dose of
documented and for whom immediate radical cystectomy chemotherapy.139 In the trials, the agents had a dwell time
is planned. In addition, the role of repeat transurethral of one to two hours and both decrease recurrence in this
resection for patients with pure non-urothelial histology is setting, but there have been no direct head to head
not well defined; therefore, management of these patients comparison trials between these two agents to date.
Recently, a trial demonstrating the efficacy of using these
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two agents (epirubicin and mitomycin C) together was 17. In an intermediate-risk patient a clinician should
published showing a 31% relative-risk reduction.140 Single consider administration of a six-week course of
instillation postoperative intravesical chemotherapy induction intravesical chemotherapy or
seems to have the greatest effect in patients with single, immunotherapy. (Moderate Recommendation;
small, low-grade tumors141, 142 and may decrease Evidence Strength: Grade B)
recurrences even when additional adjuvant intravesical
The patient group with intermediate-risk bladder cancer is
therapy is given.143-146 However, in patients with quickly
heterogeneous and primarily at risk of recurrence rather
recurrent tumors and multiple, larger tumors, this
than progression. As discussed previously, there are tools
postoperative instillation may not be as helpful.146 Single
that a clinician can use, albeit with uncertain accuracy, to
instillation studies have given the drug within 24 hours,
estimate if a patient in this group has a higher or lower
and physiologic rationale exists for this early treatment, as
recurrence risk.43 Therefore, the decision to administer or
tumor cells implant and are covered by extracellular
not administer additional intravesical therapy (distinct
matrix within a few hours in various in vitro and murine
from the immediate postoperative dose) and the type of
studies.147-149 The most common side effects of single
additional intravesical therapy can be based on a
instillation postoperative chemotherapy are irritative lower
clinician’s assessment of recurrence risk, morbidity of
urinary tract symptoms, but severe complications have
subsequent TURBT’s, patient symptomatology and
been reported in patients with drug extravasation. 150, 151
history, and toxicity of therapy.
Thus, immediate intravesical chemotherapy should be
avoided when TURBT is extensive, perforation is Meta-analyses have demonstrated that BCG (3 trials, RR:
suspected, significant bleeding requires bladder 0.56; 95% CI: 0.43 to 0.71: I2=0%), mitomycin C (8 trials,
irrigations, or the tumor appears invasive. RR: 0.71; 95% CI: 0.57 to 0.89: I2=72%), doxorubicin (10
trials, RR: 0.80; 95% CI: 0.72 to 0.88; I2=46%) and
Given the low toxicity of gemcitabine and case reports of
epirubicin (9 trials, RR: 0.63; 95% CI: 0.53 to 0.75;
adverse events with mitomycin C, careful consideration
I2=64%) all decrease the risk of recurrence as compared
should be given to the selection of the best agent for
to no intravesical therapy.91 As previously noted, BCG has
perioperative single dose chemotherapy.
been shown to be superior to doxorubicin or epirubicin
16. In a low-risk patient, a clinician should not and similar to mitomycin with regard to preventing
administer induction intravesical therapy. recurrence.91 However, BCG does have a greater risk of
(Moderate Recommendation; Evidence Strength: adverse events, both local (granulomatous cystitis,
Grade C) dysuria, hematuria) and systemic (fever), as compared to
most intravesical chemotherapies.91 Thus, when the
Patients with low-risk NMIBC have a risk of recurrence of
recurrence risk is moderate and intravesical therapy is felt
approximately 30-40% at 5 years.43 As noted previously,
appropriate, a better-tolerated intravesical chemotherapy
a single post-operative dose of intravesical chemotherapy
may have a better risk to benefit ratio than BCG when the
has been shown in multiple studies and meta-analyses to
primary goal is to prevent recurrence.
decrease the risk of recurrence, with a number needed to
treat of approximately 8.5.146 Subsequent studies have If mitomycin C is the chosen agent, there is evidence from
found that the patients most likely to benefit from a single one randomized trial that treatment efficacy can be
post-operative dose are those with low-risk NMIBC.146 A enhanced by using an optimized administration program
number of trials have examined the addition of various that consists of a period of dehydration (no fluids for 8
combinations of intravesical chemotherapy following the hours prior to treatment), urinary alkalinization (1.3 g
single post-operative dose with a goal of further NaHCO3 by mouth, the night prior, the morning of, and 30
decreasing the risk of recurrence. Trials of additional minutes prior to the intravesical therapy), confirmed
mitomycin C152 and epirubicin153-155 have demonstrated complete bladder drainage prior to intravesical therapy
no benefit of additional chemotherapy courses as (post-void residual <10 mL by US bladder scanner), and
compared to a single post-operative dose and in most a higher mitomycin C concentration (40 mg in 20 mL of
cases demonstrate an increased risk of side effects. sterile water).156

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18. In a high-risk patient with newly diagnosed compared to a reduced dose (HR=1.162; 95% CI: 1.051-
carcinoma in situ (CIS), high-grade T1, or high- 1.285; P=0.003), but no difference in progression free
risk Ta urothelial carcinoma, a clinician should survival (HR: 1.151; 95% CI: 0.853 to 1.554; P=0.356).163
administer a six-week induction course of BCG. The largest individual study of 1,355 patients (EORTC
(Strong Recommendation; Evidence Strength: 30962) compared different BCG strengths (full dose
Grade B) versus 1/3 dose) and different BCG maintenance
schedules (1 year versus 3 years) and found no difference
Patients with newly diagnosed high-risk NMIBC have a
in recurrence free survival between 1/3 dose and full dose
60-70% chance of recurrence and a 10-45% chance of
administered for either 1 year or 3 years. However, in
progression to muscle-invasive or metastatic bladder
high-risk patients (patients with high-grade, T1 tumors),
cancer within 5 years.43 Multiple studies and meta-
the 3-year full dose schedule had an improved recurrence
analyses have shown that a six-week induction course of
free survival (HR: 1.61; 95% CI: 1.13 to 2.30; p = 0.009)
BCG decreases the risk of recurrence.157-160 In further
as compared to the 1-year 1/3 dose schedule, leading the
analysis performed for this systematic review, BCG was
authors to recommend full dose BCG in this patient
shown to be superior in the prevention of recurrence (3
subgroup (although EORTC 30962 was not formally
trials, RR: 0.56; 95% CI: 0.43 to 0.71; I2=0%) and
powered to test this hypothesis).164 In most studies, dose
progression (4 trials, RR: 0.39; 95% CI: 0.24 to 0.64;
reduction was associated with a decreased risk of local
I2=40%) compared to no intravesical therapy.91 BCG was
and systemic side effects.91 However, in this study there
superior to doxorubicin (2 trials RR: 0.31; 95% CI: 0.16 to
was no difference in the risk of local or systemic side
0.61; and RR: 0.75; 95% CI: 0.64 to 0.88), epirubicin (5
effects or in the discontinuation rate between full dose and
trials, RR: 0.54; 95% CI: 0.40 to 0.74; I2=76%) and
1/3 dose BCG.164 Importantly, it should be noted, EORTC
mitomycin (when BCG maintenance is added to induction
30962 did not include patients with CIS.
[5 trials, RR: 0.79; 95% CI: 0.71 to 0.87; I2=0%]) in the
prevention of recurrence.91 There is insufficient evidence to recommend using
BCG in combination with other intravesical agents:
There is insufficient evidence to recommend one
There is significant interest in developing synergistic
particular strain of BCG: Bacillus Calmette-Guerin is a
combinations that enhance the efficacy of BCG in
heterogeneous organism with at least eight different
preventing recurrence and progression of bladder cancer.
strains being used for intravesical therapy worldwide. 161
BCG has been combined with intravesical chemotherapy
Although there is insufficient evidence to recommend one
to test the concept that the inflammatory reaction caused
strain over another, several small studies suggest that
by chemotherapy increases exposure of fibronectin. As
different strains may have different efficacies. For
BCG binds to the urothelium and tumor cells through
instance, one study of patients with NMIBC comparing the
fibronectin, enhanced exposure of fibronectin should
two most commonly used strains in the US (BCG Tice
improve the immunological response. Unfortunately, trials
versus BCG Connaught) reported that a 6-week course of
to date have not consistently demonstrated a decreased
BCG Connaught resulted in a significantly better
recurrence or progression with such combinations. A
recurrence free survival (74.0%; 95% CI: 62.8 to 87.2)
meta-analysis performed in 2013 found that adjuvant
compared to BCG Tice (48.0%; 95% CI: 35.5 to 65.1; p =
BCG followed by maintenance therapy is the appropriate
0.0108). However, there was no difference in progression
standard of care when compared with combination
free survival.162
therapy.165 More recently CUETO 93009, a randomized
There is insufficient evidence to prescribe a particular trial of sequential mitomycin followed by BCG versus BCG
strength of BCG: Seven trials have compared standard alone in patients with intermediate- or high-risk bladder
dose BCG to reduced dose BCG given as a variety of cancer found an improved 5-year disease free interval
different strains, in various combinations and (HR: 0.57; 95% CI: 0.39 to 0.83; p = 0.003) at the cost of
permutations. Most trials found no clear difference increased toxicity in the sequential arm. The clinical
between standard dose and reduced dose BCG in terms relevance of the decrease in recurrence is uncertain as
of recurrence and other outcomes.91 In favor of standard no maintenance therapy was used.166
dose BCG, a meta-analysis by Zhu et al. demonstrated
improved recurrence free survival with standard dose as
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Non-Muscle Invasive Bladder Cancer (NMIBC)

An alternative strategy to enhance the immune response recurrence rate in half (RR: 2.5; 95% CI: 1.5 to 4.2)
is to add cytokines or other agents to BCG. In a 670- without any clear difference in adverse events.169
patient study Nepple compared BCG + maintenance to Conversely, for epirubicin two studies that compared
BCG with Interferon α2B + maintenance +/- megadose induction therapy with and without a maintenance
vitamins. No difference was found in two-year disease regimen failed to find any significant improvement in
free survival for any of these combination therapies.167 recurrence rates.170, 171 A study of 395 patients by Serretta
et al. found no significant difference in the four year
Despite these disappointing results of combination
recurrence rate when they compared an induction course
therapy to date, there remains considerable interest in
of six weekly instillations of epirubicin (80 mg) to the same
developing new synergistic combinations with several
induction course plus monthly maintenance for one year
ongoing clinical trials examining different drug
(recurrence rate of 46% versus 50%, p=0.26).171 Similarly,
combinations as well as surgical techniques not currently
a study of 148 patients by Okamura et al. compared a six
available in the U.S. One such therapy includes chemo-
week induction course of epirubicin (40 mg) to the same
hyperthermia, which may be an effective treatment but
induction course plus once monthly maintenance for one
requires additional study and is not currently available in
year and reported no difference in recurrence free survival
the U.S.168
at three years (75% versus 77%, p=0.62).170 In both trials,
Patients with higher-risk features, such as persistent high- there was no significant difference in the rate of adverse
grade T1 disease on repeat resection, T1 tumors with events between the two study arms. Importantly,
associated CIS, LVI presence, or variant histologies, however, there are five trials that compared differing
should be offered radical cystectomy as an alternative to induction plus maintenance regimens and demonstrated
BCG. a benefit of increased dosing intensity of epirubicin on
19. In an intermediate-risk patient who completely disease recurrence.172-176 While these trials varied
responds to an induction course of intravesical considerably in their patient inclusion criteria and dosing
chemotherapy, a clinician may utilize regimens, the analysis conducted for this review91 found
maintenance therapy. (Conditional that, in general, more intensive exposure to intravesical
Recommendation; Evidence Strength: Grade C) epirubicin was associated with decreased risk of
recurrence. For doxorubicin, two trials that compared
As discussed previously, the available data supports the induction intravesical therapy to induction plus
use of mitomycin C, doxorubicin, and epirubicin as maintenance therapy for either one year177 or two years178
choices for induction intravesical therapy in patients with demonstrated that maintenance was not associated with
intermediate-risk NMIBC. Relatively few studies directly any significant improvement in recurrence rates. For all
test the benefit of maintenance therapy for those patients three of these agents, there was no evidence to suggest
who completely respond (defined as a normal cystoscopy that, where it was analyzed, maintenance therapy
and cytology, with no evidence of cancer on pathology if decreased disease progression or cancer related
a bladder biopsy is performed) to an induction course of mortality in NMIBC. Therefore, the Panel felt that,
intravesical chemotherapy.145 If a bladder biopsy or although there was some evidence to support the use of
TURBT is performed, to meet a complete response maintenance intravesical chemotherapy in those with a
definition, no evidence of cancer is detected. Although the complete response after induction therapy, its routine use
specific best maintenance regimen is unknown, common could not be supported, and more trials are needed to
maintenance regimens include full dose chemotherapy assess this question.
given at monthly intervals for a 6–12-month time period.
Available studies are difficult to generalize due to 20. In an intermediate-risk patient who completely
variability of the tumor characteristics in the populations responds to induction BCG, a clinician should
treated and the dosing regimens chosen for each trial. For consider maintenance BCG for one year, as
mitomycin C there is a single trial that focused on patients tolerated. (Moderate Recommendation; Evidence
with higher-risk disease (T1, higher-grade, multifocality, Strength: Grade C)
or recurrent) that reported that the addition of three years Approximately 70% of patients receiving BCG complain
of maintenance therapy compared to a 6-week induction of side effects with 8% of these being severe enough to
only course of mitomycin C (20 mg) reduced the
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Non-Muscle Invasive Bladder Cancer (NMIBC)

discontinue treatment.179 The toxicity of long term BCG Relapse and Salvage Regimens
maintenance and the lack of high-quality studies to
support the value of more prolonged maintenance over a 22. In an intermediate- or high-risk patient with
re-induction course at the time of relapse have led some persistent or recurrent disease or positive
to question the routine use of a three-year maintenance cytology following intravesical therapy, a
program,180 especially in lower risk patients. In a sub- clinician should consider performing prostatic
group analyses of EORTC 30962, three years of full dose urethral biopsy and an upper tract evaluation
maintenance was not superior to one year of full dose prior to administration of additional intravesical
maintenance (HR: 0.88; 95% CI: 0.64 to 1.21; p = therapy. (Conditional Recommendation;
0.4380)164 in an intermediate-risk group (as defined by a Evidence Strength: Grade C)
progression risk score of ≤6 and a recurrence score of ≤9
Urothelial carcinoma, particularly CIS, is considered a
using the EORTC risk calculator).43 Given the data from
field-change disease with the entire urothelium at risk in
meta-analyses supporting the need for maintenance
affected individuals. Clinicians should remain aware of
therapy with the data from EORTC 30962 suggesting that
sites outside the bladder as potential sources for
a more prolonged maintenance is not necessary, the
metachronous tumors. While the initial diagnostic
Panel supports one year of maintenance therapy in the
evaluation includes radiographic/endoscopic visualization
patient with intermediate-risk NMIBC who has responded
of the entire urinary tract, the extra-vesical urothelium
to an induction course of BCG.
remains at long-term risk for subsequent tumor
21. In a high-risk patient who completely responds development. Moreover, these sites may harbor disease
to induction BCG, a clinician should continue and contribute to cancer recurrence within the bladder.
maintenance BCG, based on availability, for
Indeed, tumor recurrence involves the prostatic urethra in
three years, as tolerated. (Moderate
24-39% of patients with NMIBC.184, 185 In addition,
Recommendation; Evidence Strength: Grade B)
approximately 20% of patients with a positive cytology but
Several meta-analyses have reported that the superiority no visible bladder tumors after a complete BCG response
of BCG compared to intravesical chemotherapy to have urethral recurrence.186 Meanwhile, metachronous
prevent recurrence and progression of high-risk NMIBC is upper tract tumors are discovered in up to 25% of patients
restricted to those patients who receive maintenance with NMIBC,185 and patients with more frequent bladder
therapy.145, 181, 182 The optimal schedule and duration of recurrences have an increased risk for upper tract tumor
maintenance therapy is unknown. A three-year diagnosis.187 Further, a recent study of patients with high-
maintenance schedule for those who can tolerate risk non-muscle invasive disease failing two or more
maintenance is supported by data from SWOG 8507 183 courses of BCG demonstrated upper tract and/or urethral
and EORTC 30962.164 SWOG 8507 showed that carcinoma in over half of the cases during follow-up.188
maintenance BCG given as a weekly instillation for 3 Important to note, however, is that the overall risk for
weeks at months 3,6,12,18,24,30, and 36 as compared to patients with bladder cancer to develop upper tract
induction BCG alone increased the 5-year recurrence free carcinoma is low (0.8% to 10%).189-191
survival from 41% to 60% (P<0.0001).183 EORTC 30692,
Upper urinary tract imaging and prostatic urethral biopsy
using a similar regimen, showed that high-risk patients
are warranted to assess potential tumor sites that may
(high-grade, T1) receiving three years of full dose
serve as a source for bladder recurrence in patients with
maintenance had an increased likelihood of remaining
persistent or recurrent disease after intravesical therapy.
disease free at five years compared to those receiving
The technique for prostate urethra evaluation is at the
one year of maintenance (HR: 1.61; 95%CI: 1.13 to 2.30;
discretion of the surgeon, with acceptable approaches
P=0.009).164
including transurethral loop resection and cold-cup biopsy
of the prostatic urethra at the 5- and 7-O’clock
positions.186, 192 It is the Panel’s consensus that upper
tract evaluation be performed with contrast-based
imaging (i.e., CT or MR urography, intravenous
pyelogram [IVP], or retrograde pyelogram). In addition, at
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the time of cystoscopic evaluation, bilateral selective effectively represent the first of the patient’s maintenance
ureteral cytology via washing may be obtained. Further therapy.202, 203
diagnostic evaluation may then be undertaken pending
While the use of interferon alpha 2b (IFN-α2B) in
the findings of these initial studies.
combination with BCG has been reported in patients
Although bladder cancer represents the most common previously treated with BCG,204-207 this regimen has not
source for a positive voided urine cytology,193 both the been directly compared with a second course of BCG
upper urinary tract and the prostatic urethra should be alone, and, therefore, the incremental additive value of
evaluated for tumor recurrence in patients with a BCG with IFN-α2B over BCG alone in this setting remains
persistently positive cytology after intravesical therapy in unknown. In addition, when compared to BCG induction
the absence of demonstrated disease in the bladder. In and maintenance in a BCG-naïve population, the group
particular, the Panel supports investigation of the upper that received combination BCG and IFN-α2B had no
tract and urethra prior to further bladder-directed improvement in tumor recurrence rates and had more
therapies for patients with a positive cytology and no side effects.167 The Panel believes that this combination
evidence of concurrent disease in the bladder. For such should not be used as a primary initial therapy. In addition,
patients with a positive cytology and negative cystoscopy, one phase II randomized trial demonstrated that
surgeons should consider use of fluorescence-guided intravesical gemcitabine was associated with a superior
cystoscopy to evaluate the bladder. Indeed, BLC has 2-year recurrence-free survival compared to BCG (19%
been demonstrated to increase the detection of CIS by versus 3%; p<0.008) among patients with high-risk non-
20-40%61, 121, 194 and has been demonstrated to be of muscle invasive recurrence after a single course of BCG,
benefit in additional tumor detection, specifically among albeit with no significant difference in progression. 208
patients with a positive cytology and negative white-light However, the small sample size of the study (n=80), the
cystoscopy.195, 196 Nevertheless, the Panel acknowledges high rate of disease recurrence noted in the BCG arm,
that the value of BLC has not been directly tested to date and lack of robust subsequent validation raise questions
versus random bladder biopsies in this setting and that about the study’s generalizability.
the false positive rate of BLC may be increased in patients
24. In a patient fit for surgery with high-grade T1
recently treated with BCG.121, 194, 197
disease after a single course of induction
Of note, the Panel recognizes that evaluation of the upper intravesical BCG, a clinician should offer radical
urinary tract and urethra may be withheld in select cystectomy. (Moderate Recommendation;
patients who have received a single induction course of Evidence Strength: Grade C)
intravesical BCG and subsequently have persistent
The Panel recognizes the adverse prognostic significance
evidence of disease and are to undergo a second course
of high-grade T1 disease in patients treated with induction
of BCG.
BCG.209 Data have demonstrated adverse cancer-specific
23. In an intermediate- or high-risk patient with survival among patients with NMIBC recurrence after
persistent or recurrent Ta or CIS disease after a BCG who undergo delayed versus early cystectomy. 210
single course of induction intravesical BCG, a Patients initially with NMIBC who progress to muscle
clinician should offer a second course of BCG. invasion have been found to have a worse prognosis than
(Moderate Recommendation; Evidence Strength: patients initially presenting with muscle-invasive
Grade C) disease.211-213 Further, in a retrospective comparative
analysis, patients with T1 recurrence after BCG treated
Approximately 50% of patients who have persistent or
with radical cystectomy were noted to have a decreased
recurrent NMIBC following a single induction course of
5-year cumulative incidence of death from disease (31%)
BCG respond to a second induction course of BCG.198-201
compared to patients with T1 recurrence after BCG
Patients, particularly those with Ta or CIS after a single
treated with repeat resection and BCG (48%).214 Thus,
induction course of BCG, should be offered re-treatment
the Panel recommends that patients with high-grade T1
with BCG, provided that the patient tolerated the initial
disease after a single course of induction BCG who are fit
induction course of BCG. Retreatment may consist of a
for surgery be offered radical cystectomy. The timing of
second six-week induction course or, particularly for
tumor recurrence following BCG may be incorporated into
patients with CIS, three weekly treatments, which would
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Non-Muscle Invasive Bladder Cancer (NMIBC)

the decision process for treatment as well as the time months of completion of adequate BCG therapy.
between BCG treatment and tumor detection has been (Conditional Recommendation; Evidence
identified as an additional prognostic feature.53, 207, 215 Strength: Grade C)
25. A clinician should not prescribe additional BCG The optimal management for patients with persistent or
to a patient who is intolerant of BCG or has recurrent high-grade NMIBC after two courses of BCG
documented recurrence on TURBT of high- (e.g., two induction six-week courses or an induction six-
grade, non-muscle-invasive disease and/or CIS week course and maintenance three-week course) who
within six months of two induction courses of are unwilling to undergo or unfit for cystectomy remains
BCG or induction BCG plus maintenance. to be established.
(Moderate Recommendation; Evidence Strength:
Continued investigation through clinical trials of novel
Grade C)
therapeutic approaches for such patients remains
Clinicians should avoid prescribing additional BCG paramount, and clinicians should seek trials and enroll
instillations to patients who are not likely to benefit from patients.
further BCG therapy. Various definitions have been put
The Panel recognizes that clinical trials may not be
forth to more specifically classify patients in which disease
available in all such cases, and certain patients might not
continues or recurs quickly after BCG.202, 215-217 Historical
meet trial eligibility criteria. When clinical trial enrollment
evidence has demonstrated the lack of clinical benefit of
is not available for such patients, several options for
additional BCG in patients who have continued disease
intravesical chemotherapy exist and may be offered,215
after two prior BCG induction courses,200, 204 while a short
but the existing supportive data is limited. As such, the
time interval between completion of BCG treatment and
Panel cannot advocate a single preferred therapy.
subsequent tumor detection has been identified as an
adverse prognostic feature.53, 207, 215 Recently, separate Possible therapies include intravesical valrubicin,
consensus panels have put forth similar defining administered weekly for six weeks. This regimen is an
characteristics of patients not likely to benefit from FDA-approved intravesical treatment for BCG-refractory
additional BCG; specifically, patients with high-grade non- CIS in patients who are unfit or unwilling to undergo
muscle invasive disease who have received two induction cystectomy. The complete response rate after valrubicin
courses of BCG or induction plus maintenance within six treatment is only 18%, and only 10% of patients have
months, as well as those who are intolerant of BCG.218, 219 been found to be disease-free at one year following
The intention of such a definition as put forth in the therapy.220
statement here is to avoid patients receiving treatments In December 2022, the FDA approved nadofaragene
from which they are unlikely to benefit, as well as to aid in (firadenovec-vncg) for patients with high-risk BCG-
future clinical trial design by establishing appropriate unresponsive NMIBC with CIS with or without papillary
eligibility criteria for studies of novel therapies for patients tumors.221 This intravesical medication instilled every 3
with persistent or recurrent tumor despite BCG treatment. months is a suspension of adenoviral-vector based gene
26. In a patient with persistent or recurrent high- therapy for intravesical instillation. The active ingredient is
grade NMIBC within 12 months of completion of recombinant, non-replicating adenovirus serotype 5 (Ad5)
adequate BCG therapy (two induction courses or vector containing a transgene encoding the human
one induction course plus one maintenance interferon alfa-2b (IFNα2b). Phase III data reported a
cycle) who is unwilling or unfit for cystectomy 53.4% complete response rate at 3 months after the first
following two courses of BCG, a clinician may dose and 45.5% of the complete responders continue to
recommend clinical trial enrollment, an have a complete response at 12 months.222
alternative intravesical therapy (i.e., Gemcitabine, frequently used as a component of systemic
nadofaragene [firadenovec-vncg]) or alternative chemotherapy for advanced bladder cancer, has also
intravesical chemotherapies been given intravesically for patients with recurrent non-
(gemcitabine/docetaxel). A clinician may also muscle invasive disease. A Phase II trial of 30 patients
offer systemic immunotherapy with noted a 1-year recurrence free survival of 21%, with 37%
pembrolizumab to a patient with CIS within 12 of patients subsequently undergoing cystectomy. 223
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Non-Muscle Invasive Bladder Cancer (NMIBC)

Furthermore, a randomized Phase III trial inclusive of 109 The number of clinical trials for patients who continue to
patients with recurrent NMIBC, of whom 83% had have disease or have disease-recurrence soon after any
received prior BCG, demonstrated that intravesical exposure to BCG continue to increase. These include
gemcitabine was associated with a greater disease-free novel intravesical agents as well systemic therapies. The
survival and a lower rate of chemical cystitis than avoidance of radical cystectomy, the oncologic standard,
intravesical mitomycin.224 Sequential intravesical has become a secondary endpoint for many of these
gemcitabine and mitomycin C for recurrent non-muscle trials.
invasive disease has been studied.225 In a retrospective
study of 27 patients, the median disease-free survival was Role of Cystectomy in NMIBC
15.2 months, with 37% of patients without evidence of
27. In a patient with Ta low- or intermediate-risk
disease at last follow-up.225 Also, docetaxel, a microtubule
disease, a clinician should not perform radical
depolymerization inhibitor, has been evaluated as an
cystectomy until bladder-sparing modalities
intravesical therapy for patients with recurrent non-
(staged TURBT, intravesical therapies) have
muscle invasive disease. A Phase I study of 18 patients
failed. (Clinical Principle)
treated with 6 weekly instillations demonstrated that the
agent was well-tolerated and that 56% of patients had no Low-grade, noninvasive tumors very rarely metastasize,
evidence of disease at posttreatment evaluation.226 A and even large-volume, multifocal cancers can usually be
subsequent report from the same group of investigators, managed with techniques such as staged resection.
including 33 treated patients, noted a 2-year recurrence- Patients with low-grade recurrences can be successfully
free survival of 32%.227 managed with intravesical chemotherapy231 or BCG.181,
232, 233 In addition, small, multifocal recurrences despite
Currently being examined in the BCG-naïve patient
intravesical therapy can usually be treated effectively with
group, sequential intravesical gemcitabine and docetaxel
office fulguration, repeat TURBT or even surveillance, in
has demonstrated efficacy. A multi-institutional review of
select cases.64-67
276 patients with NMIBC who received at least an
induction course (once weekly for 6 weeks) reported 1- 28. In a high-risk patient who is fit for surgery with
year recurrence-free rates of 65% and a 2-year persistent high-grade T1 disease on repeat
recurrence-free rate of 52%.228 Sequential intravesical resection, or T1 tumors with associated CIS, LVI,
gemcitabine and docetaxel are currently being examined or variant histologies, a clinician should
in the BCG-naïve patient group. consider offering initial radical cystectomy.
(Moderate Recommendation; Evidence Strength:
Meanwhile, intravesical nanoparticle albumin-bound
Grade C)
paclitaxel represents another taxane-based intravesical
treatment option that attempts.229 In a Phase II trial of 28 Although randomized trials comparing initial radical
patients treated with induction plus maintenance, 35% cystectomy versus intravesical therapy for high-grade T1
were found to have no evidence of disease at one year. bladder cancer are lacking, numerous studies
demonstrate poor oncological outcomes with intravesical
As of January 2020, intravenous pembrolizumab became
therapy in patients with the aforementioned “highest-risk”
FDA approved for the treatment of patients with BCG-
features. The potential benefits of timely, upfront radical
unresponsive, high-risk, NMIBC with CIS with or without
cystectomy need to be weighed against the risks
papillary tumors who are ineligible for or have elected not
associated with cystectomy, such as complications,
to undergo cystectomy. The approval is based on findings
morbidity, and decreased quality of life for any given
from the multicenter, open-label, single-arm, multicohort,
patient. Several factors support early radical cystectomy
phase II KEYNOTE-057 trial. The study enrolled 148
in patients with highest risk NMIBC, including significant
patients with high-risk NMIBC, 96 of whom had BCG-
understaging of high-grade T1 tumors and increased risk
unresponsive, high-risk NMIBC with CIS with or without
of progression to muscle-invasive disease despite
papillary tumors. Of those 96 patients, the initial response
appropriate intravesical therapy. Up to 50% of T1 tumors
rate was 41%; however, the durable response rate at data
are upstaged to T2 or greater at time of radical
cutoff was 28%.230
cystectomy.76, 234-237 Factors associated with high risk of

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progression to muscle-invasion are high-grade T1 tumors repeat intravesical therapy seems most appropriate in
with large tumor size, multifocality, associated CIS, LVI or patients with late recurrences (> 1 year) after previous
prostatic urethral involvement, as well as presence of complete response to intravesical therapy.183, 200, 201
variant histologies, diffuse disease or tumor location in a Recurrent, high-grade T1 tumors in patients after adjuvant
site not amenable to complete resection.40, 43, 44, 86, 238-240 induction BCG carry a poor prognosis.209 When radical
It is not clear if intravesical therapy alters the risk of cystectomy is performed for pathologic NMIBC, 5-year
progression in these highest-risk patients with NMIBC, cancer-specific survival is greater than 80%.246-249
and excellent oncological outcomes are reported with However, there is substantial risk of progression to
immediate radical cystectomy.241, 242 Thus, despite the muscle-invasion in these patients with reported adverse
recognized morbidity of radical cystectomy, the Panel consequences of further intravesical therapy and delayed
supports considering timely, initial radical cystectomy in cystectomy.210 Similarly, patients with T1 recurrence after
this patient population. BCG treated with radical cystectomy had improved five-
year cancer-specific survival compared to patients with T1
However, radical cystectomy with urinary diversion has
recurrence after BCG managed with second-look TUR
considerable morbidity, including gastrointestinal,
and further intravesical therapy.214 Interestingly, radical
genitourinary, infectious and wound-related complications
cystectomy patients who progress to muscle-invasive
totaling over 60% within 90 days of surgery, even in high-
disease after initial management of NMIBC have
volume centers of excellence and regardless of open
decreased cancer-specific survival compared to patients
versus robotic approaches.243, 244 Mortality after radical
with de novo muscle-invasive disease.211-213 Only minimal
cystectomy is typically < 5%,243 but may increase
data examines chemoradiation in management of high-
substantially in the elderly with 90-day mortality rates over
risk NMIBC,250 but current trials are underway evaluating
10% in patients > 75 years of age and almost 20% in
the role of radiation therapy in patients with recurrent,
octagenarians.245 Thus, the risks of radical cystectomy
high-grade T1 disease after intravesical BCG.
and urinary diversion must be weighed and balanced
carefully against the risks of disease progression and Enhanced Cystoscopy
potential loss of the opportunity for cure in high-risk
patients. 30. In a patient with NMIBC, a clinician should offer
29. In a high-risk patient with persistent or recurrent BLC at the time of TURBT, if available, to
disease within one year following treatment with increase detection and decrease recurrence.
two induction cycles of BCG or BCG (Moderate Recommendation; Evidence Strength:
maintenance, a clinician should offer radical Grade B)
cystectomy. (Moderate Recommendation; Standard bladder cancer surveillance utilizes WLC;
Evidence Strength: Grade C) however, bladder tumors can display various gross
All guidelines and substantial literature recommend morphological features, and CIS in particular can appear
radical cystectomy for patients who are fit for surgery with as normal urothelium under WLC. Use of fluorescent
high-risk urothelial cancer that persists or recurs despite cystoscopy improves the detection of urothelial
adequate intravesical BCG therapy. Patients with early, carcinoma, especially CIS.194, 251 A recent meta-analysis
high-risk recurrences after BCG therapy are at significant of 13 trials concluded that the risk of bladder cancer
risk of progression, and salvage intravesical therapies recurrence is decreased with fluorescent cystoscopy
have poor success rates. These patients should be versus WLC at short-term (<3 months, 9 trials, RR: 0.58;
offered radical cystectomy. In addition, a recent study 95% CI: 0.36 to 0.94; I2=75%), intermediate-term (3
demonstrated that patients with a low GFR, variant months to <1 year, six trials, RR: 0.70; 95% CI: 0.56 to
histology, and tumor size greater than 3 cm may have 0.88, I2=19%), and long-term follow-up (≥1 year, 12 trials,
particularly poor outcomes if they do not respond to BCG RR: 0.81; 95% CI: 0.70 to 0.93; I2=49%).91 Although
and should be prioritized for consideration of 5-aminolevulinic acid (5-ALA) was used in some of the
cystectomy.84 aforementioned clinical studies, it is not approved by the
FDA, and Hexaminolevulinate (HAL) is currently the only
Limited studies support that select patients will respond to agent approved in the US and Europe for use with BLC.
second induction regimens, particularly with BCG, and
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Non-Muscle Invasive Bladder Cancer (NMIBC)

Focusing on studies that used HAL only, fluorescent Importantly, however, researchers have reported higher
cystoscopy was associated with a decreased risk in false-positive results for HAL–BLC compared to WLC,
bladder cancer recurrence at long-term follow-up (≥1 particularly in patients who have undergone recent
year, 7 trials, RR: 0.75; 95% CI: 0.62 to 0.92; I2=41%). In TURBT, who have concurrent UTI or inflammation, or who
a large RCT of HAL–BLC performed in patients with have recently received intravesical BCG or
NMIBC, there was a statistically significant reduction in chemotherapy. This over-detection may be improved if
recurrence rates at 9 months (47% for patients who BLC is delayed for greater than or equal to three months
received HAL–BLC and WLC compared with 56% for after intravesical therapy.252 The reported false-positive
those who underwent WLC alone; p = 0.026), and a non- rates of BLC also seem decrease over time with
significant reduction in the rate of recurrent ‘worrisome’ experience.74
tumors (defined as CIS, recurrent T1 or muscle-invasive
31. In a patient with NMIBC, a clinician may consider
disease; 16% versus 24%; p = 0.17).252 With a median
use of narrow-band imaging (NBI) to increase
follow-up of 53 months for patients who underwent WLC
detection and decrease recurrence. (Conditional
alone and 55 months for those who received HAL–BLC in
Recommendation; Evidence Strength: Grade C)
addition to WLC, a large international RCT reported that
the HAL–BLC group experienced a significant delay in One trial evaluating outcomes following use of NBI versus
median time to recurrence (16.4 months) compared with WLC found that NBI was associated with a lower risk of
the WLC group (9.4 months; p = 0.04). A meta-analysis bladder cancer recurrence at 3 months (3.9% versus
using pooled data from nine prospective trials that 17%; OR: 0.62; 95% CI: 0.41 to 0.92) and at 12 months
included only HAL using actual raw data demonstrated (OR: 0.24; 95% CI: 0.07 to 0.81).260 Another trial (n=179)
that HAL–BLC was associated with lower recurrence found NBI plus WLC to be associated with a non-
rates at 12 months compared with WLC (35% versus statistically significant decreased risk of recurrence at 1
45%; RR: 0.761; p = 0.006). The benefits were year versus WLC in patients with multiple tumors >3 cm
independent of the baseline risk of recurrence and were in diameter (7.9% versus 18%; RR: 0.44; 95% CI: 0.19 to
demonstrated in patients with primary or recurrent Ta, T1 1.02).261 Another randomized trial of 600 patients
or CIS lesions.253 undergoing either white light/white light or white light/ NBI
cystoscopy for previously diagnosed high-risk NMIBC
In contrast, the PHOTO trial, a randomized prospective
showed no benefit with regards to recurrence for patients
trial, did not find a difference in recurrence or progression
undergoing second look with NBI (26% [78/300] versus
rates over 44 months in intermediate and high-risk NMIBC
23% [70/300]; p = 0.507) There was also no difference in
patients undergoing initial TURBT with BLC versus
time to recurrence between groups.262 Four recent
WLC.254 538 patients with an initial clinical diagnosis of
systematic reviews have examined WLC versus white
intermediate-/high-risk NMIBC were randomized to
light + NBI.256, 263-265 In a combined analysis of six RCT’s,
undergo either white light or blue light resection at several
one systematic review found improved recurrence for NBI
UK centers. At 44 months, the HR for recurrence was 0.94
plus white light versus white light alone in patients with
(95% CI: 0.69 to 1.28; P=0.70). There was no difference
suspected or confirmed NMIBC (6 RCTs, 1244 patients,
in progression detected between groups (HR: 1.41; 95%
HR: 0.63; 95% CI: 0.45 to 0.89; I2=53%).264 The other
CI: 0.67 to 2.96). CIS was present in only 13% of the
three systematic reviews found no difference in
resection specimens of patients enrolled in the trial; thus,
recurrence with white light versus white light +NBI
a key group in which blue light detects the most “missed”
cystoscopy.256, 257, 266
tumors was under-represented in the study. Additionally,
the trial was published prior to enrolling the full number of The Panel acknowledges that NBI technology is readily
patients for adequate power to detect a difference available to many clinicians whereas blue-light might not
between groups and is also underpowered in the efficacy be. While not proven to decrease recurrence, there is no
of high-risk patients. Five other systematic reviews have evidence of additional risk incurred by patients with its
shown decreased recurrence rates with the use of BLC use.
compared to WLC.255-259

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Risk Adjusted Surveillance and Follow- patients who are low-risk can be surveyed at a less
stringent interval while maintaining a similar risk of
up Strategies recurrence and/or progression. Less stringent endoscopic
surveillance may reduce a patient’s exposure to the
32. After completion of the initial evaluation and anxiety, discomfort, and modest infection risks associated
treatment of a patient with NMIBC, a clinician with cystoscopy without unduly compromising a patient’s
should perform the first surveillance cystoscopy risk.
within three to four months. (Expert Opinion)
There is relatively little data on the ongoing rates of
The natural history of NMIBC is often characterized by recurrence for patients with NMIBC who remain disease
recurrence, even for solitary, small, low-grade papillary free for a prolonged period of time. Two retrospective
tumors. At the time of first evaluation and treatment, none studies reported a recurrence rate of 10-15% in patients
of the existent risk stratification tools or urinary who had been free of disease for 5 or more years, with
biomarkers is sufficiently sensitive and specific to predict about 3% of patients having muscle invasive disease.268,
which patient will have an early tumor recurrence. 269 The initial stage and grade of tumor did not appear to
Therefore, the only reliable way to know in a particular determine the risk of recurrence268 and it is unclear if
patient whether they are at risk for early recurrence is by routine annual cystoscopic as opposed to symptom based
cystoscopic visualization of the urothelium at a relatively evaluation would have resulted in a significant change in
early interval after the first treatment/resection. In clinical outcome. Life-long surveillance in the absence of
addition, visualization at a relatively early interval allows documented recurrence subjects a patient to repeated
the treating urologist to verify that the initial resection was anxiety, discomfort, and the small risk of infection or
complete. The Panel, therefore, felt that the first repeat bleeding associated with cystoscopic surveillance of the
cystoscopic evaluation should occur three to four months bladder. Given these competing risks and a relative
after the initial treatment and evaluation, regardless of the paucity of data to drive decision-making, the Panel feels
patient’s overall risk. that ongoing surveillance after five years in the absence
33. For a low-risk patient whose first surveillance of recurrence should be based on shared-decision
cystoscopy is negative for tumor, a clinician making between the patient and their clinician.
should perform subsequent surveillance 34. In an asymptomatic patient with a history of low-
cystoscopy six to nine months later, and then risk NMIBC, a clinician should not perform routine
annually thereafter; surveillance after five years surveillance upper tract imaging. (Expert
in the absence of recurrence should be based on Opinion)
shared-decision making between the patient and
clinician. (Moderate Recommendation; Evidence There are no studies that directly test whether differing
Strength: Grade C) follow up regimens for upper tract imaging impact
oncologic outcomes among NMIBC patients. However,
The data comparing different surveillance regimens for there are several retrospective single cohort series that
NMIBC and associated oncologic outcomes are very suggest that patients with “lower-risk” bladder cancer
limited. One study by Olsen and Genster randomized 97 have a low incidence of subsequent upper tract urothelial
patients with papillary grade 1-2 tumors who remained carcinoma on the order of 0.6-0.9%.69, 190 Furthermore, a
tumor free three months after the first TURBT between more recent cohort study suggests that even among
two follow up regimens.267 A more frequent follow up those patients who do develop upper tract recurrence
regimen (every three months for two years, every six after a diagnosis of NMIBC, only 29% are incidentally
months in year three, then annually thereafter) was found on routine surveillance imaging.270 The remaining
compared to a less frequent regimen (every six months recurrences were found only after the patient developed
for year one, then annually thereafter). While the study is symptoms prompting an evaluation. Optimal upper tract
small and likely underpowered, there was no difference in imaging currently utilizes CT with the administration of
the risk of recurrence (RR: 1.2; 95% CI: 0.87 to 1.8) or intravenous contrast. Therefore, the Panel felt that in
progression (RR: 3.5; 95% CI: 0.37 to 32.0) with a median asymptomatic, low-risk patients, routine use of upper tract
follow up of 27 to 31 months. This suggests that those imaging for surveillance unnecessarily subjects patients
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to the risks associated with intravenous contrast reagents, repeated recurrences of small papillary lesions in the
including nephrotoxicity, anaphylaxis, and repeated bladder.
radiation exposure, with only a small chance of detecting
36. For an intermediate-risk patient whose first
upper tract urothelial carcinoma.
surveillance cystoscopy is negative for tumor, a
35. In a patient with a history of low-grade Ta disease clinician should perform subsequent cystoscopy
and a noted sub-centimeter papillary tumor(s), a with cytology every 3-6 months for 2 years, then
clinician may consider in-office fulguration as an 6-12 months for years 3 and 4, and then annually
alternative to resection under anesthesia. (Expert thereafter. (Expert Opinion)
Opinion)
Unlike the case for low-risk patients, there are no
Prospective, randomized trials comparing office-based prospective studies that compare outcomes among
fulguration to operating room-based resection for small, differing cystoscopic surveillance regimens for
papillary bladder tumors in low-risk NMIBC patients have intermediate-risk NMIBC patients. The risk of
not been completed. Several centers have reported on progression, however, among these patients is higher,
retrospective cohort series of office-based endoscopic and in the absence of data to demonstrate otherwise, the
fulguration of small bladder masses with acceptable Panel felt a slightly more intensive cystoscopic
oncologic outcomes.66, 271-273 While these cohort series surveillance regimen was warranted. Panel consensus
varied in their inclusion criteria, in general office-based and historic precedence support surveillance cystoscopy
fulguration was restricted to patients with known low- and urinary cytology every three to six months for two
grade Ta disease in which the size of the tumor was small years, then every six to twelve months for years three and
(typically defined at less than 0.5 to 1.0 cm). This four, and then annually thereafter. The Panel felt that the
suggests that selected patients with low-risk NMIBC and gaps in the literature should permit clinicians more
isolated, small, papillary recurrences may be effectively flexibility and clinical judgement in determining the
managed with office-based, endoscopic fulguration with surveillance cystoscopic regimen in the intermediate-
local anesthesia and sedation. This has the potential to compared to the high-risk group (see below). Future
spare a patient the risks associated with anesthesia research is needed to determine if less stringent follow up
required for a more invasive resection in an operating regimens can be employed without significantly affecting
room setting. For highly selected patients, clinicians may oncologic outcomes in both intermediate-and higher-risk
opt for watchful waiting or conservative management in patients, especially as the time to recurrences increases
those patients for whom the risks of fulguration may beyond five years. As with low-risk tumors, shared
outweigh the risks of disease progression. This might decision-making is imperative beyond five years if the
include those cases where in-office fulguration is not patient remains disease-free.
readily available or patients who required ongoing anti-
37. For a high-risk patient whose first surveillance
coagulation. This should include careful shared decision
cystoscopy is negative for tumor, a clinician
making with the patient.
should perform subsequent cystoscopy with
However, the Panel felt several important caveats should cytology every three to four months for two years,
be kept in mind. A fulguration approach that does not then six months for years three and four, and then
obtain tissue for pathologic evaluation should not be annually thereafter. (Expert Opinion)
utilized unless a diagnosis of low-grade Ta disease or
As with intermediate-risk patients, there are no
PUNLMP has been previously established. A fulguration
prospective studies that compare outcomes among
approach should be restricted to those patients in whom
differing cystoscopic surveillance regimens for high-risk
the lesion is papillary in appearance, rather than sessile
NMIBC patients. Given the risk of progression among
or flat, and is no more than 1 cm in size. Furthermore,
high-risk patients is higher than any other group, the
patients in whom a urinary cytology is suspicious for
Panel felt a more intensive cystoscopic surveillance
urothelial carcinoma are at higher risk for harboring occult
regimen was warranted. Panel consensus and historic
high-grade disease and warrant pathologic evaluation of
precedence support surveillance cystoscopy and urinary
any visible lesion. Upper tract imaging to assess occult
cytology every three months for two years, then every six
disease also may be considered in patients who develop
months for years three and four, and then annually
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thereafter. As with intermediate-risk disease, there is an community is fortunate to have a multitude of clinical trials
urgent need for studies to determine if less stringent currently in this disease space, the vast majority of which
follow up regimens can be employed without significantly are studying novel agents to improve outcomes of BCG
affecting oncologic outcomes in these patients. As the risk or treat BCG failures with both intravesical and systemic
of recurrence decreases and the time to recurrences agents. There are also several trials investigating new
increases beyond five years, a decision to decrease the technology, surgical techniques, radiation therapy, and
frequency of cystoscopy or stop routine follow up variable surveillance schedules.
cystoscopy after five years should only be made after a
As new treatment alternatives for NMIBC are being
shared decision-making conversation with the patient.
examined, research should continue in optimizing the
38. For an intermediate- or high-risk patient, a dosing, scheduling, and administration of currently used
clinician should consider performing surveillance medications that have already shown efficacy.
upper tract imaging at one- to two- year intervals.
Novel urinary biomarkers. Although the current
(Expert Opinion)
consensus of the guideline panel describes a limited role
As is the case with low-risk patients, there are no studies for urinary biomarkers to replace cystoscopic surveillance
that directly compare varying upper tract imaging in NMIBC, the future directions in this field hold promise.
surveillance regimens on oncologic outcomes in NMIBC Advances in sensitivity for detection of high-grade
patients. Retrospective cohort studies have suggested, disease in a surveillance population of high-grade NMIBC
however, that in a “higher-” risk cohort of patients, patients using the CX Bladder platform have been
including those with higher-grade, multiple recurrences, significant. In addition the recent review article by Rose
or stage T1 disease, the subsequent rate of upper tract and colleagues has outlined the future applications of
recurrence is as high as 10%69, 190 of which almost half will urinary cell free DNA in both detection and molecular risk
have at least stage T1 disease. As such, these stratification of patients with NMIBC and the Panel
recurrences, which are often high-stage and/or high- believes that this technology holds promise for future
grade, are potentially life threatening. Whether routine clinical application.274
imaging in asymptomatic patients is likely to diagnose
Novel agents to improve BCG efficacy or manage
such recurrences in a manner that actually improves
BCG failures. Management of patients with intermediate-
oncologic outcomes or therapeutic options is
or high-risk bladder cancer recurrences after two
controversial.270 Nevertheless, the Panel believes that
induction courses of BCG unwilling or unfit for radical
periodic upper tract surveillance imaging offers potential
cystectomy remains uncertain. Although many different
benefit in this patient population. While optimally upper
salvage intravesical therapies have been evaluated,
tract surveillance would be through the use of CT-
these studies are generally limited by small patient
Urography, the Panel acknowledges that not all patients
numbers, modest improvements in recurrence-free
can undergo this study. Alternative options can include
survival with respective intravesical agent(s), and no
MR urography, retrograde pyelography, renal ultrasound,
significant effects on progression or survival. These
or foregoing upper tract imaging depending on the
limitations highlight the dire need for novel agents in this
patient’s co-morbidities and shared decision-making
disease setting. For instance, immune checkpoint
regarding the risks of alternative imaging approaches.
inhibitors have been a resounding success in metastatic
bladder cancer with trials already underway moving these
FUTURE DIRECTIONS agents into earlier stages of bladder cancer, including
adjuvant, neoadjuvant and NMIBC settings.275 There are
The future of NMIBC will likely be driven forward by basic
multiple current open clinical trials evaluating novel
science, novel technologies, new therapeutics and clinical
agents for BCG failures, including an oncolytic virus
trials. The bladder cancer genome atlas project provided
regimen (BOND 2), recombinant fusion proteins
analysis of 131 muscle-invasive urothelial carcinomas in
(Vicinium), immune modulation (ALT-801, HS-410, ALT-
an effort to describe molecular alterations and, ideally,
803, PANVAC), cytotoxic therapies (cabazitaxel,
provide insight into use of molecularly targeted agents for
gemcitabine, cisplatin,) and targeted small molecule
both muscle-invasive and NMIBC. The NMIBC
kinase inhibitors (sunitinib, dovitinib, erlotinib). In an open-
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label, multicenter, parallel-arm, phase II study, 43 patients this form of imaging may lead to a decrease in the burden
with HG BCG-unresponsive or relapsed NMIBC received of re-TURBT and improved selection of patients with
intravesical nadofaragene (firadenovec-vncg).276 MIBC for more appropriate therapy.278
Fourteen patients remained free of HG recurrence 12
Surveillance. Finally, a randomized pilot clinical trial
months after initial treatment. These results lead to the
(NCT02298998) evaluating common surveillance
FDA approval of this agent in 2022. More recently in the
schedules could significantly impact follow-up in patients
Quilt -3.0-32 trial, Suderman and colleagues reported
with NMIBC. Patients will be randomized to either
their results using a combination of BCG and
cystoscopy at 3 months, 12 months and then annually for
nogapendekin alfa inbakicept, an IL-15 superagonist.277
5 years versus cystoscopy every 3 months for 2 years,
This combination therapy achieved a one-year disease
every 6 months for 2 years and annually thereafter. The
free survival of 45% in BCG-unresponsive CIS and
primary objectives of this study include development of
papillary bladder cancer with limited toxicity.
methodology to assess both patient satisfaction and costs
As research continues in this space, we are likely to see associated with cystoscopy for bladder cancer
an increase in the number of available treatment options surveillance with secondary objectives of cost, number of
for such patients. overall procedures and proportion of patients with disease
recurrence and progression at two years. Monitoring
New technologies. Enhanced cystoscopy, including BLC patients with NMIBC less frequently may potentially
at time of TURBT, has been demonstrated in multiple decrease costs and improve patient satisfaction without
studies to decrease bladder tumor recurrence and seems increased risk of progression to muscle-invasive disease.
particularly valuable in evaluation of positive urinary
cytology in the setting of negative WLC.73 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. There are
minimal data to support chemoradiation in the
management of high-risk NMIBC,250 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.
Imaging. The advent of multiparametric MRI imaging has
led to advances in the accuracy of staging both NMIBC
and MIBC. In centers of expertise, the use of the vesical
imaging reporting and data system (VI-RADS) coupled
with state of the art 3 Tesla MR systems, has reported
outstanding sensitivity and specificity for detection of
MIBC in the setting of high-risk NMIBC.278 If reproducible,

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Non-Muscle Invasive Bladder Cancer (NMIBC)

Abbreviations
AHRQ Agency for Healthcare Research and Quality

AJCC American Joint Committee on Cancer

AMH Asymptomatic Microhematuria

BLC Blue light cystoscopy

CSS Cancer-specific survival

CIS Carcinoma in situ

CT Computed tomography

CUETO Club Urologico Español de Tratamiento

Oncologico

EORTC European Organization for Research and

Treatment of Cancer

LVI Lymphovascular invasion

MRI Magnetic resonance imaging

NBI Narrow band imaging

NMIBC Non-muscle invasive bladder cancer

US Ultrasonography

TURBT Transurethral resection of bladder tumor

UTI Urinary tract infection

WHO World Health Organization

WLC White light cystoscopy

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Non-Muscle Invasive Bladder Cancer (NMIBC)

NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) PANEL,

CONSULTANTS, AND STAFF
Non-Muscle Invasive Bladder Cancer Panel 2016 Non-Muscle Invasive Bladder Cancer Amendment
Panel 2020
Sam S. Chang, MD, MBA, Chair James M. McKiernan, MD, Chair
Vanderbilt University Medical Center Columbia University Medical Center
Nashville, TN New York, NY

James M. McKiernan, MD, Vice Chair Sam S. Chang, MD, MBA, Chair
Columbia University Medical Center Vanderbilt University Medical Center
New York, NY Nashville, TN

Stephen A. Boorjian, MD Jeffrey M. Holzbeierlein, MD, FACS

Mayo Clinic The University of Kansas Health System
Rochester, MN Kansas City, KS

Peter E. Clark, MD Christopher B. Anderson, MD, MPH

Vanderbilt University Medical Center Columbia University Medical Center
Nashville, TN New York, NY

Siamak Daneshmand, MD John L. Gore, MD, MS, FACS

USC Institute of Urology University of Washington
Los Angeles, CA Seattle, WA

Badrinath R. Konety, MD, FACS, MBA Non-Muscle Invasive Bladder Cancer Amendment
University of Minnesota Panel 2024
Minneapolis, MN Jeffrey M. Holzbeierlein, MD, FACS
The University of Kansas Health System
Raj Pruthi, MD, FACS Kansas City, KS
UNC School of Medicine
Chapel Hill, NC Sam S. Chang, MD, MBA, Chair
Diane Z. Quale (Patient Advocate) Bladder Cancer Vanderbilt University Medical Center
Advocacy Network Bethesda, MD Nashville, TN
Chad R. Ritch, MD, MBA
Andrew C. James, MD
University of Miami Health System Miami, FL Texas Urology Group
John D. Seigne, MD San Antonio, TX
Dartmouth Hitchcock Medical Center Lebanon, NH
James M. McKiernan, MD, Chair
Eila Curlee Skinner, MD Columbia University Medical Center
Stanford University New York, NY
Stanford, CA
Anne K. Schuckman, MD
Norm D. Smith, MD USC Urological Oncology
University of Chicago Medical Center Chicago, IL Los Angeles, CA

Consultants Staff
Roger Chou, MD Erin Kirkby, MS
Jessica Griffin, MS Leila Rahimi, MHS
Brooke Bixler, MPH

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Non-Muscle Invasive Bladder Cancer (NMIBC)

Sennett K. Kim PEER REVIEWERS

Lauren Pak, MHS, MS
We are grateful to the persons listed below who
contributed to the Guideline by providing comments
CONFLICT OF INTEREST DISCLOSURES during the peer review process. Their reviews do not
necessarily imply endorsement of the Guideline.
All panel members completed COI disclosures.
Disclosures listed include both topic– and non -topic- Peer Review 2016
related relationships. Panel members not listed below
have nothing to disclose. Peter C. Albertsen, MD
Christopher Anderson, MD
Consultant/Advisor: Sam S. Chang, Astellas, GLG, Peter C. Black, MD
Bayer, Tolmar; Peter E. Clark, Galil Medical; Siamak Stephen Boorjian, MD
Daneshmand, Photocure; Badrinath R. Konety, Axogen Rodney H. Breau, M.D
Inc., Takeda Inc. Steven C. Campbell, MD, Ph.D.
Karim Chamie, MD
Meeting Participant or Lecturer: Siamak Arnold Chin, MD
Daneshmand, Photocure Muhammad S. Choudhury, MD
Peter E. Clark, MD
Scientific Study or Trial: Sam S. Chang, NIH, Cold Michael S. Cookson, MD, MMHC
Genesys, Inc.; Siamak Daneshmand, Photocure; David Darling
Badrinath R. Konety, Photocure, Myriad Genetics, John Denstedt, MD
Genomic Health; James M. McKiernan, Sanofi Scott E. Delacroix Jr., MD
Jordan Dimitrakoff, MD
Colin P. N. Dinney, MD
Amendment Panel Disclosures 2020 Sherri Machele Donat, MD
Robert Dreicer, MD
Consultant/Advisor: Sam S. Chang, Astellas, GLG, Robert C. Flanigan, MD
Janssen, Want, BMS, Pfizer, Urovant, Urogen, Uro Pat Fox Fulgham, MD
Today; John L. Gore, Genome DX Biosciences, Inc. William H. Gans, MD
David A. Ginsberg, MD
Scientific Study or Trial: Sam S. Chang, NIH; Jeffrey Leonard G. Gomella, MD
M. Holzbeierlein MDx Health; John L. Gore, Ferring Mark Gonzalgo, MD
Pharmaceutical, Inc. John L. Gore, MD
H. Barton Grossman, MD
Amendment Panel Disclosures 2024 Thomas J. Guzzo, MD
Subramanian Hariharan
Consultant/Advisor: Jeffrey M. Holzbeierlein, Janssen Richard E. Hautmann, MD
Oncology; Sam S. Chang, GLG, Janssenn, BMS, Pfizer, William C. Huang, MD
Urogen, Virtuoso Surgical, mIR, Prokarium, KDx Brant Inman, MD
Diagnostics, Tu Therapeutics, Lantheus, Merck, Pacific Ashish M. Kamat, MD
Edge, Nonagen; James M. McKiernan, mIR Scientific; Lawrence Karsh, MD
Anne K. Schuckman, vyriad Wes Kassouf, MD
Melissa R. Kaufman, MD
Meeting Participant or Lecturer: Anne K. Schuckman, Badrinath Konety, MD
Photocure, Fergene Seth P. Lerner, MD, FACS
Deborah J. Lightner, MD
Scientific Study or Trial: Jeffrey M. Holzbeierlein, MDx Yair Lotan, MD
Health, Astellas Medivation; Sam S. Chang, NIH, William T. Lowrance, MD
NantBio; Anne K. Schuckman, Urogen Joshua J. Meeks, MD, PhD
Maxwell V. Meng, MD
Health Publishing: Sam S. Chang, Uro Today James E. Montie, MD
Todd M. Morgan, MD
John Mulhall, MD
Alan M. Nieder, MD

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Non-Muscle Invasive Bladder Cancer (NMIBC)

Matthew E. Nielsen, MD John D. Seigne

Jeffrey W. Nix, MD
Dipen J. Parekh, MD Public Commenters (Via public notice on AUA
Manish I. Patel, MD website)
Sanjay Patel, MD Ved Desai
Craig A. Peters, MD Yuri Jo
Phillip M. Pierorazio, MD Mark Schoenberg
Sima P. Porten, MD Kirill Shiranov
Badrinath R. Konety, MD Guobing Xiong
Hassan Razvi, MD
Matthew J. Resnick, MD
Mark P. Schoenberg, MD DISCLAIMER
Florian R. Schroeck, MD
Anne K. Schuckman, MD This document was written by the NMIBC Panel of the
John Seigne, MD American Urological Association Education and
Wade J. Sexton, MD
Research, Inc., which was created in 2016. The Practice
Kirill Shiranov, MD
Angela M. Smith, MD, MS Guidelines Committee (PGC) of the AUA selected the
Anthony Y. Smith, MD Panel Chair. Panel members were selected by the Panel
Mark S. Soloway, MD and PGC Chair.
Preston C. Sprenkle, MD
Lambros Stamatakis, MD Membership of the panel included specialists with specific
Gary D. Steinberg, MD expertise on this disorder. The mission of the panel was
Kelly L. Stratton, MD to develop recommendations that are analysis-based or
Thomas F. Stringer, MD
consensus-based, depending on panel processes and
Seth A. Strope, MD
Stephen E. Strup, MD available data, for optimal clinical practices in the early
Chandru P. Sundaram, MD detection of prostate cancer setting.
Richard J Sylvester, MD
John A. Taylor III, MD, MS Funding of the panel was provided by the AUA. Panel
J. Brantley Thrasher, MD members received no remuneration for their work. Each
Alon Z. Weizer, MD member of the panel provides an ongoing conflict of
J. Alfred Witjes, MD interest disclosure to the AUA.
J. Stuart Wolf, Jr., MD
Guo-bing Xiong, MD While these guidelines do not necessarily establish the
Alexandre R. Zlotta, MD standard of care, AUA seeks to recommend and to
encourage compliance by practitioners with current best
Peer Review 2024
practices related to the condition being treated. As
AUA (Board of Directors, Science and Quality medical knowledge expands and technology advances,
Council, Practice Guidelines Committee, Journal of the guidelines will change. Today these evidence-based
Urology) guidelines statements represent not absolute mandates
Erin Bird but provisional proposals for treatment under the specific
Stephen Boorjian
conditions described in each document. For all these
David Ginsberg
Philip Pierorazio reasons, the guidelines do not pre-empt physician
Suzanne Merrill judgment in individual cases.
Matthew Nielsen
Christopher Porter Treating physicians must take into account variations in
Angela Smith resources, and patient tolerances, needs, and
preferences. Conformance with any clinical guideline
External Reviewers (Non-AUA Affiliates) does not guarantee a successful outcome. The guideline
Christopher Anderson text may include information or recommendations about
Kelly Bree
certain drug uses (“off label”) that are not approved by the
Peter E. Clark
Chad R. Ritch Food and Drug Administration (FDA), or about
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Non-Muscle Invasive Bladder Cancer (NMIBC)

medications or substances not subject to the FDA

approval process. AUA urges strict compliance with all
government regulations and protocols for prescription and
use of these substances. The physician is encouraged to
carefully follow all available prescribing information about
indications, contraindications, precautions and warnings.
These guidelines and best practice statements are not in-
tended to provide legal advice about use and misuse of
these substances.

Although guidelines are intended to encourage best

practices and potentially encompass available
technologies with sufficient data as of close of the
literature review, they are necessarily time-limited.
Guidelines cannot include evaluation of all data on
emerging technologies or management, including those
that are FDA-approved, which may immediately come to
represent accepted clinical practices.

For this reason, the AUA does not regard technologies or

management that are too new to be addressed by this
guideline as necessarily experimental or investigational.

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