What is the management approach for a patient with non-muscle-invasive bladder cancer (NMIBC)?

Management of Non-Muscle-Invasive Bladder Cancer (NMIBC)

Complete transurethral resection of bladder tumor (TURBT) with deep resection into detrusor muscle is the cornerstone of NMIBC management, followed by risk-stratified intravesical therapy and surveillance protocols tailored to recurrence and progression risk. 1, 2

Step 1: Initial Diagnostic Workup and Complete TURBT

Cystoscopic Evaluation

• Perform thorough cystoscopic examination documenting tumor size, location, configuration, number, and all mucosal abnormalities throughout the entire urethra and bladder 1
• Conduct bimanual examination under anesthesia, particularly if the tumor appears invasive 1

Upper Tract Imaging

• Obtain contrast-based axial imaging (CT urography preferred, or MRI urography) as part of initial evaluation to assess for synchronous upper tract urothelial carcinoma, hydronephrosis, and lymph node involvement 1, 3

TURBT Technique

• For tumors <1 cm: Resect en bloc with underlying bladder wall, ensuring the specimen contains complete tumor plus part of the bladder wall 1, 2
• For larger tumors: Perform fractional resection in separate portions—first the exophytic component, then the underlying bladder wall with detrusor muscle, then the resection edges—sending each fraction in separate containers to pathology 1
• Critical requirement: The pathology specimen MUST include detrusor muscle tissue for accurate staging; absence of muscle necessitates staging as Tx 1, 4
• Minimize cauterization to prevent tissue destruction that impairs pathological assessment 1

Step 2: Repeat TURBT (Mandatory in Specific Situations)

Perform repeat TURBT within 2-6 weeks for the following indications: 1, 2, 3

• Incomplete initial resection 1
• No muscle tissue present in the initial specimen (except for TaG1/low-grade tumors where it's optional) 1
• All T1 tumors 1, 5
• All G3/high-grade tumors (except isolated CIS) 1
• Referred patients where initial pathology may be unreliable 1

Rationale: Residual tumor is found in 17-67% of Ta cases and 20-71% of T1 cases at repeat TURBT, with upstaging to muscle-invasive disease occurring in up to 10-32% of T1 cases 1, 5. For T1 tumors, repeat TURBT reduces progression rates and may slightly reduce overall mortality (22-30% vs 26-36% without repeat TURBT) 1, 5.

Step 3: Risk Stratification

Classify patients into risk categories at each occurrence/recurrence: 1, 2

Low Risk

• Solitary, primary, low-grade Ta tumor 1
• Progression rate approximately 6% 1

Intermediate Risk

• Multiple or recurrent low-grade Ta tumors 1

High Risk (Any of the following)

• Any T1 tumor 1
• Any G3/high-grade tumor 1
• Carcinoma in situ (CIS) 1
• Progression rate approximately 17% for high-grade T1 lesions 1

Very High Risk (Consider immediate cystectomy)

• T1 high-grade with concurrent CIS 3
• Multiple and/or large (≥3 cm) T1 high-grade tumors 3
• T1 high-grade with lymphovascular invasion 3
• Variant histology (micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid) 3

Use EORTC risk calculator to quantify individual recurrence and progression probabilities at 1 and 5 years based on prior recurrence rate, number of tumors, tumor size, T-stage, grade, and presence of CIS. 1, 3

Step 4: Risk-Stratified Adjuvant Intravesical Therapy

Low-Risk Disease

• Single immediate postoperative intravesical chemotherapy instillation within 24 hours of TURBT (reduces 5-year recurrence from 59% to 45%) 1, 2, 6
• Use mitomycin C or epirubicin 2, 6
• Contraindications: Obvious or suspected bladder perforation, extensive resection 1
• No further intravesical therapy required after single dose 1, 2

Intermediate-Risk Disease

• Single immediate postoperative chemotherapy instillation within 24 hours 2, 6
• Followed by either:
  • Intravesical chemotherapy (mitomycin C or epirubicin) for up to 1 year 2, 6, OR
  • BCG induction (6 weekly instillations) with consideration for maintenance 2, 6

High-Risk Disease

• Full-dose BCG with induction (6 weekly instillations) PLUS maintenance therapy for 1-3 years is the standard of care 2, 3, 6, 4
• Maintenance BCG significantly improves outcomes compared to induction alone 4
• Do NOT use reduced-dose BCG (1/3 dose) for high-risk patients—this is suboptimal treatment 4
• One-year full-dose BCG is also suboptimal; three-year maintenance is preferred 4

Common pitfall: Recent evidence suggests no statistically significant benefit from early postoperative chemotherapy in patients with large, recurrent (intermediate-risk), or high-risk NMIBC—these patients should proceed directly to BCG therapy rather than receiving immediate chemotherapy 1.

Step 5: Surveillance Protocol

Cystoscopy Schedule (Risk-Adapted)

• High-risk patients: Cystoscopy and cytology at 3 months, then every 3 months for 2 years, then every 6 months until 5 years, then annually 4
• Intermediate/low-risk patients: Less frequent intervals based on individual risk 1, 6

Additional Surveillance

• Upper tract imaging (CT urography) especially in patients with CIS or high-risk features 1, 3, 6
• Urinary cytology in high-risk cases 1, 6

Step 6: Management of BCG Failure

Define BCG failure status: 2

• BCG-refractory: Persistent high-grade disease at 6 months despite adequate BCG
• BCG-relapsing: Recurrence after initial complete response to BCG
• BCG-intolerant: Unable to complete therapy due to toxicity

Treatment Options for BCG Failure

Radical cystectomy is the gold standard for BCG-unresponsive high-risk disease in patients fit for surgery. 2, 3, 4

Immediate radical cystectomy should be strongly considered for: 3, 4

• Young patients with high-grade T1 tumors plus additional poor prognostic factors (multifocality, associated CIS, prostatic involvement, lymphovascular invasion) 4
• Patients who recur as T1 high-grade at 3 months after BCG induction 4
• Any variant histology due to high upstaging rates 3

For patients unfit for or refusing cystectomy: 4

• Additional course of BCG may be considered for low/intermediate-grade disease or those who failed before completing maintenance 4
• Device-assisted chemotherapy (EMDA, Synergo with mitomycin C) may have a role 4

Critical warning: Postponing radical cystectomy until progression to muscle-invasive disease may negatively impact survival 4. For very high-risk patients, early cystectomy should be discussed upfront rather than waiting for BCG failure 3, 4.

Special Considerations

Elderly or Frail Patients

• Evaluate comorbidities affecting surgical candidacy and tolerance of intravesical therapy 2
• Consider performance status and life expectancy when deciding between aggressive treatment versus surveillance 2
• For patients unable to tolerate lithotomy position (skeletal/muscle disease, severe urethral stricture), TURBT is not feasible; office fulguration may be an alternative 1, 2

Enhanced Cystoscopic Techniques

• Consider fluorescence cystoscopy (blue light) or narrow-band imaging for patients with suspected multiple tumors, CIS, high-grade tumors, or positive cytology with negative white-light cystoscopy 1

Multidisciplinary Assessment for Very High-Risk Disease

• Convene team including urologic oncology, medical oncology, and radiation oncology to discuss immediate cystectomy versus BCG, fertility preservation (sperm banking before any systemic therapy), and impact on quality of life (sexual function, continence, body image) 3