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CUA & AUA GUIDELINE: NON-MUSCLE INVASIVE BLADDER CANCER (2015 CUA, 2016 AUA)

See Non-Muscle Invasive Bladder Cancer Chapter Notes

Risk Stratification

 

	CUA	AUA
Low risk	Solitary, TaLG, and <3cm	Solitary, TaLG, and <3cm OR PUNLMP
Intermediate risk	Solitary, TaLG and >3cm OR Multifocal (TaLG <3cm) OR Multi-recurrent TaLG	Solitary TaLG >3cm OR Multifocal TaLG OR TaLG recurrence within 1 year TaHG ≤3cm T1LG
High risk	T1 OR CIS OR HG OR >3cm AND multifocal AND multi-recurrent TaLG	T1HG Any recurrent TaHG TaHG >3cm or multifocal Any CIS Any BCG failure in HG patient Any variant histology Any LVI Any HG prostatic urethral involvement

• 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.”

Enhanced cystoscopy

• See Bladder Cancer Diagnosis and Evaluation Chapter Notes
• Guideline perspective on role of fluorescent (blue light) cystoscopy in NMIBC:
• CUA: not explicitly stated, interpreted as unknown benefit
• AUA: blue light cystoscopy should be offered at the time of TURBT, if available, to increase detection and decrease recurrence
• Guideline perspective on role of narrow band imaging (NBI) cystoscopy:
• CUA: NBI improves tumour detection, but the impact on prognosis remains unknown
• AUA: consider the use of NBI to increase detection and decrease recurrence

NMIBC with variant histology (2016 AUA NMIBC guidelines)

• An experienced GU pathologist should review any doubt in regards to variant or suspected variant histology (e.g., micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid), extensive squamous or glandular differentiation, or the presence of LVI
• Compared to patients with pure urothelial carcinoma in TURBT pathology, those with variant histology have a greater incidence of high-grade, invasive, locally advanced disease and worse survival
• Numerous studies have documented the importance of LVI as an important prognostic marker of upstaging, lymph node involvement, recurrence, and decreased overall survival
• Due to the high rate of upstaging associated with variant histology, consider offering initial radical cystectomy (see below for indications of “early” cystectomy).
• There is a lack of evidence regarding the efficacy of intravesical therapy for patient with non-muscle invasive urothelial carcinoma with variant histology
• If a bladder sparing approach is being considered in a patient with variant histology, a restaging TURBT should be performed within 4-6 weeks of the initial TURBT (Note that CUA Guidelines do not have this as an indication for re-resection)

Restaging TURBT

• CUA
• Absolute indications (2)
  1. Initial TUR incomplete, when repeat resection technically feasible
     • Removing all residual tumours in a second therapeutic TURBT allows for (4):
     1. More accurate staging
     2. Improves patient selection (and thus response) to BCG therapy
     3. Reduces risk of recurrence
     4. Potentially delays tumour progression
  2. T1 in absence of muscle
• Recommended for (2)
  1. Any HG
  2. T1 with benign muscle
• AUA
• Recommended for (2):
  1. Initial TUR incomplete, when repeat resection technically feasible
  • In specific, albeit rare, circumstances in which repeat TURBT is not likely to impact clinical management (e.g. immediate radical cystectomy is planned), repeat resection may be omitted
  2. T1 (with or without muscle)
• Upstaging at repeat resection to muscle-invasive disease has been reported in ≈30% of patients with T1 tumors
• The risk of upstaging is related to the presence or absence of muscularis propria on the initial resection specimen, with rates of upstaging varying from 40-50% among patients without muscle present on the first TURBT specimen to 15-20% in patients with muscle present at the first TURBT
• Repeat resection is recommended even when the initial TURBT demonstrates the presence of muscularis propria given the noted risk of upstaging in that setting.
• The presence of residual T1 disease at the time of repeat resection is associated with subsequent progression risk ≈80%. As such, these patients should be counseled regarding the potential benefit of early cystectomy
• For select patients, repeat transurethral resection is not likely to impact clinical management (e.g. immediate radical cystectomy is planned) and may, therefore, be omitted.
• Consider for (2):
  1. High-risk disease
  • Larger and multifocal tumors (i.e. high-risk tumors) are at a particularly increased risk for incomplete initial resection, and it is this incomplete resection that is likely a significant contributing factor to inadequately treated tumors that are then diagnosed as early recurrences
  2. TaHG
• Residual tumor can be found at the time of repeat resection in up to 50% of patients with high-grade Ta disease, with up to 15% of such tumors being upstaged.
• Timing:
• CUA: within 2-6 weeks from initial TURBT
• AUA: within 6 weeks from initial TURBT

Post-operative instillation of intravesical chemotherapy

• See Non-Muscle Invasive Bladder Cancer Chapter Notes
• Indications:
• CUA:
• Immediate postop instillation recommended in all patients with NMIBC, unless extensive resection or suspected perforation
• For patients with planned BCG, benefit of immediate chemotherapy instillation is less clear
• AUA:
• Immediate post-operative instillation recommended in low- or intermediate-risk (suspected or known), NMIBC unless extensive resection, suspected perforation, or significant bleeding requires bladder irrigations
• Should be avoided if tumour appears invasive

Adjuvant treatment (beyond immediate instillation of intravesical chemotherapy)

• Indications (based on risk stratification)
  • Low-risk:
    • No adjuvant treatment (both CUA and AUA)
  • Intermediate-risk:
    • CUA: 6-week induction chemotherapy followed by 1-year maintenance is recommended if complete response to induction
    • AUA: 6-week induction chemotherapy is recommended; 1-year maintenance is optional
      • AUA: “although there was some evidence to support the use of maintenance intravesical chemotherapy in those with a complete response after induction therapy, its routine use could not be supported, and more trials are needed to assess this question”
    • No published trials comparing an induction MMC to MMC induction + maintenance therapy; however a meta-analysis suggests that long-term maintenance therapy enhances the effectiveness of MMC induction in preventing recurrences
    • CUA only discusses MMC; AUA describes potential use of doxorubicin and epirubicin, in addition to MMC, as options for adjuvant intravesical chemotherapy
    • Although monthly instillations are commonly used, the optimal maintenance dose, schedule and duration remain unclear
      • AUA describes monthly intervals for a 6-12 month time period
    • In intermediate risk, intravesical chemotherapy is preferred, but can also use BCG induction and maintenance
      • AUA guidelines state that maintenance BCG for 1 year should be considered in patients who completely respond to induction BCG (whereas wording for maintenance chemotherapy for 1 year was “may utilize”)
        • In a sub-group analyses of EORTC 30962, 3 years of full dose maintenance was not superior to 1 year of full dose maintenance [in these patients]
    • Intermediate-risk patients that fail intravesical chemotherapy may benefit from BCG, and vice-versa
  • High-risk
    • Induction BCG and 3-year maintenance is recommended (both CUA and AUA)
      • 3-year maintenance schedule is based on SWOG (Lamm) protocol: induction (weekly x 6) followed by maintenance (3 weekly cycles at 3 and 6mo, then every 6 mo up to 36 mo
        • 5-year 19% ARR in RFS; 60% with maintenance vs. 41% without
      • BCG dose
        • CUA: Full dose preferred for patients with high-risk NMIBC who can tolerate intravesical therapy, with dose reduction reserved for cases of BCG intolerance
        • AUA: There is insufficient evidence to prescribe a particular dose

BCG toxicity

• See Table 1 from Original Guideline
  

BCG failure classification (as per 2015 CUA NMIBC Guidelines)

1. BCG intolerant

• Tumour recurs due to inadequate course of BCG owing to adverse effects

2. BCG resistant
   • Recurrence or persistence of disease at 3 months after induction cycle but of lesser stage or grade which subsequently is no longer present at 6 months
3. BCG relapsing
   • Recurrence of tumour after being disease-free at the 6-month evaluation:
     • Early relapse (<1 year), intermediate (1–2 years), and late (>2 years)
4. BCG refractory
   • Persistent HG disease at 6 months despite BCG therapy [after induction and 1 maintenance course] (or at 3 months [after induction] if initial tumour is T1HG).
   • Progression in stage, grade, or disease extent by 3 months after induction BCG [prior to maintenance cycle]

• Among patients with BCG failure, BCG intolerance has the best prognosis, whereas BCG refractory disease portrays the worst prognosis.

• In patients with NMIBC treated with an induction course of BCG (without maintenance) who later develop recurrence of disease (BCG relapse), a second induction course may achieve 30-50% response rates. The impact of re-induction on patients receiving maintenance is unknown
• Limited studies demonstrate that select patients will respond to second induction regimens, particularly with BCG, and repeat intravesical therapy seems most appropriate in patients with late recurrences (> 1 year) after previous complete response to intravesical therapy

 

• For patients with high-risk NMIBC who fail BCG, the option of radical cystectomy should be recommended and discussed with the patient
• NOTE AUA states that a second course of BCG can be offered to intermediate- or high-risk patient with persistent or recurrent Ta or CIS disease; however, 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
• Patients initially with NMIBC who progress to muscle invasion have been found to have a worse prognosis than patients initially presenting with muscle-invasive disease
• CUA treatment options in patients with BCG relapse who are not suitable for or refuse radical cystectomy (4):
  1. Clinical trial
  2. BCG plus interferon (mentioned in CUA, not AUA)
  3. Intravesical gemcitabine (valrubicin, docetaxel mentioned in AUA, not CUA)
     • A phase II randomized trial found that intravesical gemcitabine was associated with an improved 2-year RFS compared to BCG (19% versus 3%; p<0.008) among patients with high-risk non-muscle invasive recurrence after a single course of BCG, but no significant difference in progression
  4. Re-induction with BCG; more than 2 BCG induction courses is not recommended
• AUA treatment options in patients with BCG relapse
  1. Recurrent Ta or CIS disease after a single course of induction intravesical BCG: second course of BCG
  2. High-grade T1 disease after a single course of induction intravesical BCG: radical cystectomy
  • Additional BCG should not be given 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 6 months of two induction courses of BCG or induction BCG plus maintenance.
  3. In patients with BCG relapse who are not suitable for or refuse radical cystectomy, alternative options include clinical trial or intravesical chemotherapy (see above)

Indications for cystectomy in NMIBC

• CUA (7):
• T1HG with:
  1. variant histology (micropapillary, sarcomatoid, plasmacytoid, or small cell)
  2. LVI
  3. concomitant bladder/prostatic CIS
• Multiple and/or large T1HG
• Invasive tumours involving bladder diverticula
• Persistent T1HG on restaging TUR
• HG recurrence at 3 months
• AUA (5):
• T1HG with:
• variant histology (micropapillary, sarcomatoid, plasmacytoid, or small cell)
• LVI
• concomitant bladder/prostatic CIS
• Up to 50% of T1 tumors are upstaged to T2 or greater at time of radical cystectomy. In addition to CIS, LVI, and variant histology, other factors associated with high risk of progression to muscle-invasion are high-grade T1 tumors with large tumor size, multifocality, prostatic urethral involvement, diffuse disease or tumor location in a site not amenable to complete resection [though AUA does not explicitly describe these as indications for “early” cystectomy
• Persistent T1HG on restaging TUR
• High-risk patient with persistent or recurrent disease within 1 year following treatment with 2 induction cycles of BCG or BCG maintenance
• This is not considered an early/timely cystectomy
• Should not be performed in Ta low- or intermediate-risk disease, until bladder-sparing modalities (staged TURBT, intravesical therapies) have failed.

Follow-up

• First surveillance cystoscopy following TURBT:
• CUA: 3 mo
• AUA 3-4 mo
• Follow-up after first surveillance cystoscopy
  • CUA:
    • All patients:
      • Cysto and cytology (or another urinary marker) q3-4mo x 2 years, q6mo years 3-4, yearly thereafter
        • Primary, solitary, TaLG: less frequent cysto with cysto at 3 and 12mo then yearly thereafter
  • AUA:
    • Low-risk:
      • Cysto at 6-9mo after initial surveillance cystoscopy, then annually, no urine cytology in surveillance of low-risk
        • In a patient with a history of low-risk cancer and a normal cystoscopy, urinary biomarker or cytology during surveillance should not be used routinely
          • Sensitivity for cytology in intermediate and high-risk cancer may approach 80%, however, sensitivity is low in detecting low-risk cancer (≈20%)
    • Intermediate-risk:
      • Cysto and cytology q3-6mo x 2 years, q6-12mo years 3-4, yearly thereafter
    • High-risk:
      • Cysto and cytology q3-4mo x 2 years, q6mo years 3-4, yearly thereafter
    • In NMIBC surveillance, urinary biomarkers should not be used in place of cystoscopic evaluation
      • Several markers have been investigated, with 5 of these markers approved by the FDA and/or are commercially available in the US.
        • NMP22® and BTA® tests are protein-based
        • UroVysion® FISH, ImmunoCyt™ and Cxbladder™ are cell-based
  • Any recurrence resets schedule

• Discontinuing surveillance
• CUA:
• Patients with high-risk NMIBC require lifelong cystoscopic surveillance
• If LG disease and no recurrence x 10 years, consider discontinuing cysto and monitor with cytology
• AUA
• Surveillance continuation/frequency after 5 years is based on shared-decision making in low-, intermediate-, and high-risk
• Upper tract imaging surveillance:
• CUA: every 1-2 years in high-risk NMIBC
• AUA: every 1-2 years in intermediate or high-risk NMIBC
• Both CUA and AUA: not needed in asymptomatic patient with history of low-risk NMIBC
• Evaluating response to BCG (2016 AUA NMIBC guidelines)
• The presence of significant inflammation immediately post BCG instillation can affect the accuracy of urine cytology. Urinary markers may be used to assess response to intravesical BCG therapy (UroVysion® FISH) and adjudicate equivocal cytology (UroVysion® FISH and ImmunoCyt™).
• Clinicians can use UroVysion® FISH as an early guide to predict response to intravesical BCG therapy. The utility of protein-based markers in this setting has not been well tested, but as with cytology, inflammation may also negatively impact their ability to predict response
• Utilization of another test to arbitrate an atypical or equivocal cytology reading may be helpful in reducing the need for unnecessary diagnostic evaluations in intermediate- and high-risk bladder cancer patients.
• Equivocal urine cytology can occur in as high as 21% of patients being evaluated for hematuria. Performance of a complete diagnostic workup to rule out cancer is typically the default approach in many of these patients with atypical cytology readings and is one reason why its routine use is no longer advocated for hematuria evaluations.
• Some patients may present with a positive urinary marker while the bladder appears cystoscopically tumor-free. A proportion but not all of such patients subsequently develop cystoscopically-identifiable tumors. In these instances, the urinary marker is able to identify a tumor before it manifests, resulting in an “anticipatory positive” test.

Special scenarios
Prostatic urethral involvement (CUA NMIBC Guidelines)

• See Urothelial Carcinoma of the Prostate Chapter Notes
• Prostatic urethral biopsies advised in the presence of (4):
  1. Extensive bladder CIS
  2. Bladder neck tumour
  3. Positive cytology without bladder tumour
  4. Suspicious areas in the prostatic urethra
• Management of prostatic urethral carcinoma
• pTis pu (CIS of the prostatic urethra) or visible prostatic urethra tumour concomitant with NMIBC of the bladder: TURP then BCG.
• BCG is given after TURP for accurate staging and increasing efficacy by increasing surface area
• pTis pd (CIS involving the prostatic ducts): treatment controversial, consider TURP + BCG
• Despite good response to BCG, prostatic ductal involvement has potential for invasion, and if invasion occurs there is a high risk of metastasis.
• Re-biopsy of prostatic urethra recommended after BCG to detect recurrences early
• Recurrence of any HG lesion in prostatic urethra after TURP + BCG: consider radical cystectomy plus urethrectomy; if patient prefers bladder-sparing approach, consider repeat BCG or intra-vesical gemcitabine
• pT2 (prostatic stromal invasion (pT2): radical cystectomy +/- urethrectomy

Positive cytology (from 2016 AUA NMIBC Guidelines)

• In a patient with a history of NMIBC with normal cystoscopy and positive cytology, consider (5):
  1. Prostatic urethral biopsies
  2. Upper tract imaging
  3. Enhanced cystoscopic techniques (blue light cystoscopy, when available)
  4. Ureteroscopy
  5. Random bladder biopsies
• 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
• Metachronous upper tract tumors are discovered in up to 25% of patients with NMIBC
• Urothelial carcinoma, particularly CIS, is considered a field-change disease with the entire urothelium at risk in affected individuals. Clinicians should remain aware of sites outside the bladder as potential sources for metachronous tumors.
• Although bladder cancer represents the most common source for a positive voided urine cytology, both the upper urinary tract and the prostatic urethra should be evaluated to assess potential tumor sites that may serve as a source for bladder recurrence in patients with persistent or recurrent disease after intravesical therapy.
•  ≈20% of patients with a positive cytology but no visible bladder tumors after a complete BCG response have urethral recurrence
• The technique for prostate urethra evaluation is at the discretion of the surgeon, with acceptable approaches including TURP and cold-cup biopsy of the prostatic urethra at the 5- and 7-O’clock positions; upper tract evaluation be performed with contrast-based imaging
• In particular, the Panel supports investigation of the upper tract and urethra prior to further bladder-directed therapies for patients with a positive cytology and no evidence of concurrent disease in the bladder. For such patients with a positive cytology and negative cystoscopy, consider use of fluorescence-guided cystoscopy to evaluate the bladder.

 

Questions (includes 2016 AUA NMIBC Guidelines and NMIBC Chapter Notes content)

1. What is the CUA risk classification of NMIBC?
2. What proportion of patients with bladder cancer present with NMIBC?
3. What is the stage breakdown in patients presenting with NMIBC?
4. What proportion of patients with NMIBC progress to MIBC?
5. What methods of enhanced cystoscopy are used in NMIBC
6. What are the indications for re-staging TUR?
7. Which patients should receive post-operative intravesical mitomycin C?
8. What are the contraindications to post-operative intravesical mitomycin C?
9. When should adjuvant treatment be given in NMIBC? Describe the treatment regimen.
10. What are the treatment options in a patient with NMIBC that has BCG relapse?
11. What are the indications for timely cystectomy in NMIBC?
12. When is prostatic urethral biopsy recommended?
13. Which genetic abnormalities are associated with low vs. high-malignant potential of NMIBC
14. What techniques can be used to reduce the risk of an obturator reflex during TURBT?
15. Which methods can optimize MMC administration?

 

Answers

1. What is the CUA risk classification of NMIBC?
1. Low-risk:
   • Solitary, TaLG, and <3cm
2. Intermediate-risk:
   • Solitary, TaLG and >3cm OR
   • Multifocal (TaLG <3cm) OR
   • Multi-recurrent TaLG
3. High-risk:
   • T1 OR
   • CIS OR
   • HG OR
   • >3cm AND multifocal AND multi-recurrent TaLG
2. What proportion of patients with bladder cancer present with NMIBC?
   • ≈80%
3. What is the stage breakdown in patients presenting with NMIBC?
   • Ta: 60%
   • T1: 30%
   • CIS: 10%
4. What proportion of patients with NMIBC progress to MIBC?
   • ≈20%
5. What methods of enhanced cystoscopy are used in NMIBC
1. Blue light
2. Narrow bang
6. What are the indications for re-staging TUR?
   • CUA absolute: incomplete resection and T1 without muscle
   • CUA relative: any HG lesion and T1 with benign muscle
7. Which patients should receive post-operative intravesical mitomycin C?
   • All patients unless contraindicated
8. What are the contraindications to post-operative intravesical mitomycin C?
1. Extensive resection
2. Suspected perforation
3. Significant bleeding requiring bladder irrigation
9. When should adjuvant treatment be given in NMIBC? Describe the treatment regimen.
10. What are the treatment options in a patient with NMIBC that has BCG relapse?
1. Clinical trial
2. Radical cystectomy
3. BCG plus interferon
4. Intravesical gemcitabine
5. Re-induction with BCG (more than 2 BCG induction courses is not recommended)
6. Intravesical valrubicin, docetaxel
11. What are the indications for timely cystectomy in NMIBC?
1. T1HG with:
1. variant histology (micropapillary, sarcomatoid, plasmacytoid, or small cell)
2. LVI
3. concomitant bladder/prostatic CIS
2. Persistent T1HG on restaging TUR
3. Multiple and/or large T1HG
4. HG recurrence at 3 months
5. Invasive tumours involving bladder diverticula
12. When is prostatic urethral biopsy recommended?
1. Tumour in bladder neck
2. Extensive bladder CIS
3. Tumour visible in prostatic urethra
4. Positive cytology with normal bladder
13. Which genetic abnormalities are associated with low vs. high-malignant potential of NMIBC
    • Low: chromosome-9, FGFR-3
    • High: TP53, RB
14. What techniques can be used to reduce the risk of an obturator reflex during TURBT?
15. Which methods can optimize MMC administration?
1. Dehydration prior to administration
2. Emptying bladder prior to administration
3. Increasing concentration
4. Alkalinizing urine