What are the treatment alternatives for a patient with BCG (Bacillus Calmette-Guérin) refractory non-muscle invasive bladder cancer?

Treatment Alternatives for BCG-Refractory Non-Muscle Invasive Bladder Cancer

Radical cystectomy remains the gold standard treatment for BCG-refractory non-muscle invasive bladder cancer and should be offered to all surgical candidates, as it provides the best oncologic outcomes with long-term survival rates exceeding 90%. 1

Defining BCG-Refractory Disease

BCG-refractory disease encompasses several distinct patterns that guide treatment decisions 1:

• BCG-unresponsive: Persistent high-grade disease at 6 months despite adequate BCG treatment, OR stage progression at 3 months after adequate BCG induction 1
• BCG-relapsing: Recurrence of high-grade disease after achieving disease-free state at 6 months following adequate BCG 1
• BCG-intolerant: Disease persistence due to inability to receive adequate BCG because of toxicity 1

Patients with persistent or recurrent high-grade disease within one year following two induction cycles of BCG or BCG maintenance should be offered radical cystectomy as the primary treatment. 1

Treatment Algorithm for BCG-Refractory Disease

First-Line Option: Radical Cystectomy

Radical cystectomy with pelvic lymph node dissection is strongly recommended for BCG-unresponsive NMIBC, particularly in patients with high-risk features including high-grade T1 with concomitant CIS, lymphovascular invasion, prostatic urethral involvement, or variant histology. 1

• Patients with low GFR, variant histology, and tumor size >3 cm have particularly poor outcomes without cystectomy and should be prioritized for surgical intervention 1
• Cystectomy achieves long-term survival rates exceeding 90% with ongoing improvements in morbidity 2

Second-Line Options: Bladder-Sparing Therapies

For patients who are unfit for or refuse radical cystectomy, the following alternatives are available in descending order of evidence quality:

FDA-Approved Systemic Immunotherapy

Pembrolizumab (intravenous PD-1 inhibitor) is FDA-approved for BCG-unresponsive, high-risk NMIBC with CIS (with or without papillary tumors) in patients ineligible for or refusing cystectomy. 3

• The KEYNOTE-057 trial demonstrated 41% complete response rate at 3 months (95% CI 31%-51%) in 96 patients 1
• Median duration of response was 16.2 months (range 0.0-30.4 months) 1
• This represents the highest level of evidence for systemic therapy in this population 1

FDA-Approved Intravesical Gene Therapy

Nadofaragene firadenovec (intravesical adenoviral vector-based gene therapy) is FDA-approved for BCG-unresponsive high-risk NMIBC with CIS (with or without papillary tumors). 1

• Administered every 3 months as intravesical instillation 1
• Phase III data showed 53.4% complete response rate at 3 months and 45.5% maintained complete response at 12 months 1
• Recommended with the same strength as pembrolizumab for this population 1

Alternative Intravesical Chemotherapy Regimens

When the above options are unavailable or contraindicated, consider the following intravesical therapies 1:

Sequential gemcitabine/docetaxel is the most extensively studied combination:

• Weighted mean 12-month RFS of 60% and 24-month RFS of 42% in BCG-failure setting 4
• Multi-institutional data shows 1-year recurrence-free rate of 65% and 2-year rate of 52% 1
• Treatment success of 66% at first surveillance, 54% at 1 year, and 34% at 2 years 5
• Grade III toxicity reported in <1% of patients 4
• Administered as 1 gram gemcitabine in 50 mL sterile water followed immediately by 37.5 mg docetaxel in 50 mL saline, weekly for 6 weeks 5

Gemcitabine/mitomycin C combination:

• Weighted mean 12-month RFS of 63% and 24-month RFS of 40% in BCG-failure setting 4
• Well-tolerated with similar safety profile to gemcitabine/docetaxel 4

Single-agent intravesical chemotherapy (in order of guideline preference) 1:

• Intravesical gemcitabine (first choice)
• Intravesical mitomycin C
• Epirubicin
• Valrubicin
• Docetaxel

Device-Based Therapy

Thermo-chemotherapy can achieve 2-year disease-free survival in 47% of patients and showed similar disease control to BCG re-induction in randomized trials 1. This option should only be offered to patients unwilling or unable to undergo radical cystectomy 1.

Critical Management Considerations

Patients without BCG exposure and papillary disease only benefit most from gemcitabine/docetaxel, though reasonable efficacy exists even in BCG-refractory disease with CIS. 4

Ten patients who underwent cystectomy after failed salvage intravesical therapy (median 5.6 months from starting induction) had no positive margins or lymph nodes on final pathology, suggesting that delayed cystectomy after failed salvage therapy does not compromise oncologic outcomes. 5

Common Pitfalls to Avoid

• Do not delay cystectomy in high-risk patients with BCG-refractory disease who are surgical candidates, as progression risk is substantial 1
• Do not use single-agent intravesical chemotherapy when combination regimens are available, as efficacy is inferior 4
• Do not continue BCG therapy beyond two induction courses or one induction plus maintenance course in patients with persistent high-grade disease 1
• Ensure adequate operative staging to identify treatment failures early when using salvage intravesical therapy 6