CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))

See Non-Muscle Invasive Bladder Cancer Chapter Notes

• More recent guidelines from AUA available

Background

• See Risk factors in Bladder cancer: Epidemiology and Pathogenesis Chapter Notes for further details

• See Bladder cancer: Diagnosis & Evaluation Chapter Notes for further details
• See Prognostic factors in Bladder cancer: Non-muscle invasive bladder cancer Chapter Notes for further details

Risk Stratification

	CUA	AUA
Low risk	Primary, solitary, TaLG, and <3cm OR PUNLMP	Primary, solitary, TaLG, and <3cm OR PUNLMP
Intermediate risk	Solitary, TaLG and ≥3cm OR Multifocal (TaLG <3cm) OR Multi-recurrent TaLG Substratification based on number of risk factors (4): multiple tumours, ≥3cm, time to recurrence (<1 year), and frequency of recurrence (>1 / year) Low-intermediate-risk: 0 factors – consider treating as low-risk patients Intermediate-risk: 1-2 factors High-intermediate-risk: ≥3 factors – consider treating as high-risk patients Primary, solitary, TaHG, and <3 cm Consider treating as high-risk patients	Solitary TaLG >3cm OR Multifocal TaLG OR TaLG recurrence within 1 year TaHG ≤3cm T1LG
High risk	T1 OR CIS OR Recurrent, or multiple, or ≥3cm TaHG Very high-risk: T1HG + any of (4): Multiple and ≥ 3cm Presence of concurrent CIS (in the bladder or prostatic urethra) Presence of LVI Variant histology (e.g., micropapillary, plasmacytoid, sarcomatoid, neuroendocrine)	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:
  • AUA: blue light cystoscopy should be offered at the time of TURBT, if available, to increase detection and decrease recurrence
  • CUA: can increase tumour detection at first TURBT and reduce recurrence risk.
• Guideline perspective on role of narrow band imaging (NBI) cystoscopy:
  • AUA: consider the use of NBI to increase detection and decrease recurrence
  • CUA: can increase tumour detection at first TURBT and reduce recurrence risk.

NMIBC with variant histology

• Pathological review by an experienced GU pathologist is recommended in cases of (3):
  1. Variant or suspected variant histology (e.g., micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid), extensive squamous or glandular differentiation (AUA and CUA)
  2. LVI (AUA)
  3. Atyipcal tumors are seen during TURBT (CUA)
  • 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

• Advantages of re-TURBT (4):

1. 1. More accurate staging (identification of occult muscle-invasive disease)
      • Re-TURBT results in upstaging rates of
      1. • pTa: 0.4%
         • pT1: 8%
   2. Improves patient selection (and thus response) to BCG therapy
   3. Improves outcomes
      1. pTa: lower rates of recurrence, but not progression
      2. pT1: lower rates of progression and overall mortality, with additional trend for lower cancer-specific mortality

• CUA
  • Absolute indications (2)
    1. Initial TUR incomplete, when repeat resection technically feasible
    2. All T1
  • Consider for (1)
    1. Select TaHG (e.g. large and/or multiple tumours)
       • TaHG without muscle is not an absolute indication for re-staging TURBT
• 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 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 post-operative instillation (with MMC, epirubicin, doxorubicin, pirarubicin or gemcitabine)
      • Recommended in patients with presumed (3):
        1. Low-risk NMIBC
        2. Intermediate-risk NMIBC
        3. Patients with ≤ 1 recurrence/year and EORTC recurrence score < 5
        • Benefit unclear in high risk patients when BCG is planned as adjuvant treatment
      • Should be administered within 24 hours after endoscopic resection
    • Should be discussed even when further adjuvant intravesical chemotherapy is planned
  • 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:
      • Intermediate-risk patients can be substratified (see Risk Stratification table above)
        • Low-intermediate risk may be treated similarly to low risk patients, with post-operative instillation only and no additional intravesical treatment
        • True-intermediate risk may be treated with adjuvant intravesical chemotherapy (induction followed by monthly maintenance for 1-year) or BCG (induction followed by that maintenance for 1 year with 3 weekly instillations at 3, 6 and 12 months)
        • High-intermediate risk may be treated as high risk patients, with full BCG schedule (induction followed by maintenance for 3 years with 3 weeks instillations at 3, 6, 12, 18 and 36 months)
        • Intermediate risk patients with primary, small, and solitary HG Ta may be treated as high risk patients, with full BCG schedule (induction followed by maintenance for 3 years with 3 weeks instillations at 3, 6, 12, 18 and 36 months)
      • Recurrence during intravesical chemotherapy may be treated with induction and maintainence BCG
    • 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: 2021 guidelines recommend full dose in high-risk disease, unless there is a shortage (see below); 2016 guidelines suggested that 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 and management

• See Table 6 from 2021 CUA NMIBC Guidelines

BCG failure classification

• See Non-Muscle Invasive Bladder Cancer Chapter Notes

Management of BCG-unresponsive NMIBC

• CUA
  • Standard of care (in surgically fit patients): radical cystectomy with pelvic lymph node dissection
    • BCG-unresponsive with CIS or HG Ta: a second-line intravesical therapy might be considered before radical cystectomy
      • Studies suggest that these patients can be managed conservatively for up to one year after initial TURBT without an impact on cancer-specific mortality
    • BCG-unresponsive with CIS who are unfit for or refuse to undergo radical cystectomy, consider (4):
      1. Intravenous pembrolizumab
      2. Intravesical oportuzumab monatox (pending Health Canada approval)
      3. Intravesical nadofaragene firadenovec (pending Health Canada approval)
      4. BCG plus N-803 (pending Health Canada approval)
      • Chemoradiation should not be recommended for patients with BCG-unresponsive CIS
    • BCG-unresponsive who are unfit for or refuse to undergo radical cystectomy, consider (4):
      1. Clinical trial
      2. Sequential intravesical gemcitabine/docetaxel (induction plus maintenance)
      3. Other combination intravesical therapy (e.g., sequential gemcitabine/MMC, BCG + interferon if available)
      4. Single-agent intravesical therapy (MMC, epirubicin, docetaxel, gemcitabine)
         • Valrubicin is approved but rarely used due to limited efficacy
         • For BCG-unresponsive patients undergoing intravesical chemotherapy, sequential combination of drugs is favoured instead of single-agent regimens

• AUA
  • 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.
      • 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
      • >2 BCG induction courses is not recommended due to high failure rate
  • Intermediate- or high-risk patient with persistent or recurrent Ta or CIS disease after a single course of induction intravesical BCG: second course of BCG can be considered
    • 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
  • In patients with BCG relapse who are not suitable for or refuse radical cystectomy, alternative options include:
    • Intravesical chemotherapy (gemcitabine, valrubicin, docetaxel)
    • Clinical trial

Treatment adjustments only if BCG shortage (2021 CUA NMIBC Guidelines)

• Intermediate risk NMIBC
  • Intravesical chemotherapy is recommended as the first-line option.
  • If BCG is planned as a second-line therapy, induction might be administered with reduced dose (1/2 or 1/3 dose) and maintenance can be omitted
• High risk NMIBC:
  • Full BCG schedule (induction followed by 3- year maintenance) is recommended. Only during BCG shortage, when full dose is not possible due to limited supply, dose reduction to 1/2 or 1/3 might be considered, while maintenance can be reduced to one year.
• When BCG is unavailable, single agent chemotherapy (e.g., MMC, gemcitabine) or sequential combination of intravesical chemotherapy (e.g., gemcitabine/docetaxel) is recommended with induction followed by monthly maintenance for up to one year.

Indications for cystectomy in NMIBC

• CUA (7):
  • Large volume, diffuse, endoscopically unresectable NMIBC
  • HG recurrent NMIBC despite adequate BCG therapy i.e. BCG-unresponsive NMIBC
  • T1HG with (5):
    1. variant histology(micropapillary, sarcomatoid, plasmacytoid)
    2. LVI
    3. concomitant bladder/prostatic CIS
    4. Multiple and/or large (≥3cm) tumours
    5. Persistent T1HG on restaging TURBT
• 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
    • Low-risk:
      • Cystoscopy at 1 year and then yearly for 5 years; urine cytology is not necessary
      • PUNLMP is associated with recurrence rates comparable to LG Ta tumours and progression is rare. Therefore, these patients should be follow-up similarly to LG tumours
      • Fulguration under local anesthesia might be considered for small (<5mm) papillary tumours and negative cytology in patients with a prior history of PUNLMP or LG Ta tumours
    • Intermediate risk
      • Cystoscopy + cytology: q3-6mo x 2 years, q6mo years 3, yearly thereafter
        • Cytology should be obtained at initial 3 month cytoscopy
    • High risk
      • Cystoscopy + cytology: q3-4mo x 2 years, q6mo years 3-4, yearly thereafter
        • Cytology should be obtained at initial 3 month cytoscopy
  • 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:
    • Intermediate- or high-risk NMIBC: life-long surveillance required
    • If low-risk disease and no recurrence x 5 years, consider discontinuing surveillance
  • AUA
    • Surveillance continuation/frequency after 5 years is based on shared-decision making in low-, intermediate-, and high-risk
• Upper tract imaging surveillance:
  • CUA: recommended within 12 months of diagnosis and then every 2 years thereafter in high-risk NMIBC
  • AUA: every 1-2 years in intermediate or high-risk NMIBC
    • 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

Random bladder biopsies (2021 CUA NMIBC Guidelines)

• Indication:
  • Presence of (3):
    1. Positive urine cytology
    2. Normal appearing bladder
    3. Normal upper urinary tract imaging
    • Presence of all 3 is associated with high risk of harbouring occult CIS
• Alternative to random bladder biopsy is blue-light cystoscopy with directed biopsies

Prostatic urethral involvement (2021 CUA NMIBC Guidelines)

• See Urothelial Carcinoma of the Prostate Chapter Notes
• CIS present in the prostatic urethra associated with higher rates of NMIBC recurrence, progression, and disease-specific mortality.
• Prostatic urethral biopsies advised in the presence of (4):
  1. Extensive bladder CIS
  2. Bladder neck tumour
  3. Positive cytology with normal appearing bladder and normal upper urinary tract imaging (should be taken at same time as bladder biopsies)
  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.
    • Re-biopsy of prostatic urethra is recommended after BCG to detect recurrences early
    • RC can be discussed as an alternative option.
  • pTis pd (CIS involving the prostatic ducts) or T1HG: treatment controversial, consider RC
    • TURP followed by intravesical BCG is an alternative option
      • Despite good response to BCG, prostatic ductal involvement has potential for invasion, and if invasion occurs there is a high risk of metastasis.
        • The prostatic urethra is less exposed to intravesical therapy, allowing CIS and high-risk papillary disease to advance through the prostatic ducts into the prostatic stroma.
      • Close followup with repeat prostatic urethral biopsies after induction BCG should be considered
  • 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): neoadjuvant cisplatin-based chemotherapy followed byradical cystectomy +/- urethrectomy

Positive cytology (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