What is the role of immunotherapy, including intravesical Bacillus Calmette-Guérin (BCG) therapy and checkpoint inhibitors like pembrolizumab (pembrolizumab) or atezolizumab (atezolizumab), in the perioperative treatment of bladder cancer, particularly for patients at high risk of recurrence?

Immunotherapy in Perioperative Bladder Cancer

For high-risk non-muscle invasive bladder cancer (NMIBC), intravesical BCG with induction and 3-year maintenance therapy using the SWOG schedule remains the standard of care, while checkpoint inhibitors like pembrolizumab are FDA-approved only for BCG-unresponsive disease with limited efficacy. 1, 2

Non-Muscle Invasive Bladder Cancer (NMIBC)

High-Risk Disease: BCG as Standard Immunotherapy

BCG therapy with maintenance is the definitive standard for high-risk NMIBC (any T1, high-grade Ta, or carcinoma in situ). 1

• Administer BCG induction (6 weekly instillations) followed by 3-year maintenance using the SWOG schedule (3 weekly instillations at months 3,6,12,18,24,30, and 36), which provides reproducibly superior efficacy compared to shorter maintenance regimens 1
• BCG with SWOG maintenance demonstrates significant superiority over chemotherapy (epirubicin) for time to first recurrence, time to distant metastases, disease-specific survival, and overall survival 1
• Modified maintenance schedules (such as quarterly instillations) have failed to show benefit and should be avoided 1

Carcinoma In Situ (CIS)

• BCG induction and 3-year maintenance per SWOG schedule is the first-line recommendation 1
• Alternative sequential approaches (mitomycin followed by BCG) showed no significant difference in complete response or disease-free rates but are not widely adopted 1
• The 15-year risk of dying from bladder cancer with appropriate BCG treatment is approximately 28% 1

Intermediate-Risk Disease

• For patients with 1-2 risk factors (multiple tumors, size >3cm, early recurrence <1 year, frequent recurrences >1/year): administer BCG induction with 1-year maintenance 1
• For patients without these risk factors, a single immediate instillation of chemotherapy post-TURBT is sufficient 1

BCG-Unresponsive Disease: Checkpoint Inhibitors

FDA-Approved Pembrolizumab for BCG-Unresponsive NMIBC

Pembrolizumab 200 mg IV every 3 weeks (or 400 mg every 6 weeks) is FDA-approved for BCG-unresponsive, high-risk NMIBC with CIS in patients ineligible for or declining cystectomy. 2

• BCG-unresponsive is defined as persistent disease despite adequate BCG therapy (at least 5 of 6 induction doses plus either 2 of 3 maintenance doses or 2 of 6 second induction doses) 2
• Complete response rate: 41% (95% CI: 31-51%) with median duration of response of 16.2 months 2
• 46% of responders maintained response ≥12 months 2
• Treatment duration: up to 24 months or until persistent/recurrent high-risk NMIBC, disease progression, or unacceptable toxicity 2

Atezolizumab in BCG-Unresponsive Disease

Atezolizumab showed modest efficacy in BCG-unresponsive NMIBC but did not meet prespecified efficacy thresholds and carries significant toxicity risks. 3

• Complete response rate at 6 months: 27% (20 of 74 patients with CIS) with median duration of 17 months 3
• 18-month event-free survival for Ta/T1 disease: 49% (90% CI: 38-60%) 3
• Grade 3-5 treatment-related adverse events occurred in 16% of patients, including three treatment-related deaths 3
• Disease progression to muscle-invasive or metastatic disease occurred in 12 of 129 eligible patients 3

Combination Approaches Under Investigation

Atezolizumab combined with BCG showed preliminary safety and potentially longer duration of response but remains investigational. 4

• The combination was well-tolerated with no grade 4/5 adverse events in the BCG combination cohort 4
• 6-month complete response rate: 42% with median duration not reached (≥12 months) for atezolizumab + BCG versus 33% (median 6.8 months) for atezolizumab alone 4
• Pembrolizumab combined with BCG is being evaluated in the Phase III KEYNOTE-676 trial for persistent/recurrent high-risk NMIBC 5

Intravesical Pembrolizumab: Novel Approach

Intravesical pembrolizumab (1-5 mg/kg for 2 hours) combined with BCG demonstrated safety and immune activation but requires further investigation. 6

• 6-month and 1-year recurrence-free rates: 67% (95% CI: 42-100%) and 22% (95% CI: 6.5-75%), respectively 6
• Pembrolizumab was detected in urine but not in blood, suggesting localized delivery 6
• One death from myasthenia gravis was potentially treatment-related 6

Muscle-Invasive Bladder Cancer (MIBC)

Perioperative Systemic Immunotherapy

Cisplatin-based neoadjuvant chemotherapy before radical cystectomy remains the guideline-recommended standard, with checkpoint inhibitors under active investigation in perioperative settings. 1, 7

• Approximately 50% of MIBC patients develop metastatic disease within 2 years despite radical cystectomy, necessitating systemic treatment 7
• Multiple trials are investigating checkpoint inhibitors with or without chemotherapy in neoadjuvant and adjuvant settings 7
• Adjuvant cisplatin-based chemotherapy is recommended for patients who did not receive neoadjuvant therapy, though definitive survival benefit has not been proven 1

Bladder Preservation with Immunotherapy

Chemoradiotherapy after maximal TURBT remains the evidence-based bladder preservation approach, with immunotherapy combinations under investigation. 8

• 5-year overall survival with chemoradiotherapy: 49-73%, with 80% of long-term survivors maintaining intact bladder 8
• A Phase 1 study combining nivolumab and ipilimumab with chemoradiotherapy showed high metastasis-free and overall survival rates 8
• A Phase 3 trial (NCT03775265) investigating atezolizumab with chemoradiotherapy has completed recruitment 8

Critical Pitfalls and Caveats

BCG Therapy Considerations

• Never use modified BCG maintenance schedules (quarterly dosing)—they lack efficacy 1
• BCG is contraindicated in immunocompromised patients and those requiring immunosuppression 2
• Avoid immediate intravesical chemotherapy if extensive TURBT or bladder perforation is suspected 9

Checkpoint Inhibitor Limitations

• Systemic checkpoint inhibitors for BCG-unresponsive NMIBC carry significant toxicity (16% grade 3-5 adverse events) and risk of disease progression during treatment 3
• Radical cystectomy remains the standard for BCG-unresponsive disease in surgical candidates due to high progression risk 10
• Single biomarker selection (PD-L1 IHC alone) is not justified for post-platinum metastatic disease 1

Disease Progression Risk

• Up to one-third of bladders considered disease-free after chemotherapy may harbor residual disease at cystectomy 8
• Delayed recognition of progression to muscle-invasive disease significantly worsens prognosis 10
• Mandatory surveillance cystoscopy every 3 months for the first 1-2 years is essential for high-risk disease 10

Patient Selection for Bladder Preservation

• Appropriate candidates: solitary tumors <2 cm, minimal muscle invasion, no hydronephrosis, no concomitant CIS, no palpable mass, and good baseline bladder function 8
• TURBT alone is inadequate without additional bladder-directed therapy (chemoradiotherapy) 8