What is the recommended treatment regimen for intravesical (directly into the bladder) BCG (Bacillus Calmette-Guérin) therapy for high-risk non-muscle-invasive bladder cancer?

Intravesical BCG Therapy for High-Risk Non-Muscle-Invasive Bladder Cancer

For high-risk non-muscle-invasive bladder cancer, intravesical BCG therapy should consist of a 6-week induction course (weekly instillations) starting 2-3 weeks after TURBT, followed by mandatory maintenance therapy for 1-3 years using the Southwest Oncology Group regimen: 3 weekly instillations at months 3,6,12,18,24,30, and 36. 1

Standard BCG Regimen

Induction Phase

• Begin BCG instillations 2-3 weeks after TURBT to allow adequate healing of the bladder mucosa 1
• Administer 6 weekly instillations (once per week for 6 consecutive weeks) 1
• Use full-dose BCG (not reduced dose) as standard therapy, as one-third dose showed inferior disease-free intervals (58.5% vs 61.7% at 5 years, HR 1.15, P=0.045) 1

Maintenance Phase

Maintenance BCG is essential and non-negotiable for high-risk disease, as it provides superior outcomes compared to induction alone 1, 2. The evidence-based maintenance schedule is:

• 3 weekly instillations at months 3,6, and 12 after starting induction 1, 2
• Continue with 3 weekly instillations at months 18,24,30, and 36 for high-risk patients 1
• Total duration: 1-3 years, with 3-year maintenance significantly reducing recurrence risk compared to 1-year (HR 1.61,95% CI 1.13-2.30, P=0.01) in high-risk tumors 1

Risk-Stratified Approach

High-Risk Disease (Primary Indication)

BCG with full maintenance is the gold standard for patients with: 1

• Carcinoma in situ (CIS)
• High-grade T1 tumors
• High-grade Ta tumors with adverse features
• Multiple or large high-grade tumors

BCG significantly reduces 72-month recurrence rates (RR=0.70,95% CI 0.56-0.89) and 143-month recurrence rates (RR=0.18,95% CI 0.05-0.72) compared to intravesical chemotherapy in CIS patients 1

Intermediate-Risk Disease

Either 12 months of BCG or intravesical chemotherapy can be used, though BCG with maintenance shows superior recurrence prevention (32% risk reduction, P<0.0001) 1, 3

Low-Risk Disease

BCG is not recommended due to side effects without proportional benefit; single immediate chemotherapy instillation is sufficient 1, 3

Critical Management Considerations

Repeat TURBT Requirements

Perform repeat TURBT within 4-6 weeks in the following scenarios before initiating BCG: 1, 2

• All T1 tumors
• All high-grade tumors (except primary CIS)
• Incomplete initial resection
• Absence of detrusor muscle in initial specimen

BCG Failure Definitions and Management

Stop BCG and proceed to radical cystectomy for: 1, 2, 3

• BCG-refractory disease: Persistent high-grade disease at 6 months despite adequate BCG
• High-grade recurrence within 6 months of two induction courses or induction plus maintenance
• Persistent or recurrent high-grade T1 after TURBT following BCG

Do not give additional BCG to patients meeting these criteria, as they have BCG-unresponsive disease with high progression risk 2, 3

BCG Shortage Protocols

During shortages, prioritize as follows: 1

1. First priority: High-risk NMIBC (T1 high-grade or CIS) for induction BCG
2. Second priority: Maintenance BCG for high-risk patients
3. Consider one-half or one-third dose for induction during shortages only
4. Alternative: Intravesical gemcitabine or mitomycin C if BCG unavailable

Common Pitfalls to Avoid

Never administer immediate postoperative BCG if bladder perforation is suspected, extensive resection occurred with extravasation concern, or muscle-invasive disease is visually apparent 3

Never skip maintenance therapy in high-risk patients, as induction alone is insufficient—maintenance provides the critical long-term benefit 1, 2

Never delay cystectomy in BCG-unresponsive patients, as early cystectomy (within 2 years of BCG failure) improves 15-year disease-specific survival compared to delayed cystectomy 1, 2

Never use combination BCG plus chemotherapy in non-BCG-unresponsive patients, as this is not recommended due to increased toxicity without proven benefit 1

Alternative Therapies for BCG-Unresponsive Disease

For patients who fail BCG and refuse or cannot undergo cystectomy: 1, 3, 4

• Nadofaragene firadenovec (FDA-approved): 53.4% complete response at 3 months, 45.5% sustained at 12 months
• Pembrolizumab: 41% complete response rate in BCG-unresponsive CIS
• Intravesical gemcitabine or mitomycin C: Lower efficacy but acceptable for select patients