BCG Immunotherapy for Bladder Cancer
BCG (Bacillus Calmette-Guérin) immunotherapy is the standard of care treatment for high-grade non-muscle invasive bladder cancer (NMIBC) and carcinoma in situ (CIS), which works by activating the immune system to recognize and destroy malignant cells. 1
What is BCG?
BCG is a live, attenuated strain of Mycobacterium bovis that was originally developed as a tuberculosis vaccine. When used as immunotherapy for bladder cancer, it is administered directly into the bladder through intravesical instillation.
Mechanism of Action
BCG immunotherapy works through several immunological mechanisms:
- Initial immune response: After instillation, BCG bacilli are internalized by urothelial cells, triggering a local inflammatory response 2
- Immune cell recruitment: This leads to cytokine and chemokine release that recruits neutrophils, monocytes, macrophages, T cells, B cells, and natural killer cells 2
- Tumor-specific immunity: Animal studies suggest BCG induces specific anti-tumor immunity 2
- Trained immunity: BCG also provides non-specific protective effects through a process called trained immunity 2
Clinical Application
BCG immunotherapy is primarily used for:
- High-grade Ta tumors
- All T1 tumors
- Carcinoma in situ (Tis) 1
Treatment Protocol
The standard BCG treatment protocol includes:
- Timing: Typically administered after transurethral resection of bladder tumor (TURBT)
- Induction: Six weekly instillations
- Maintenance: Three-week maintenance schedule for 3 years has been shown in randomized trials to be the current optimal treatment 3
Efficacy
BCG immunotherapy has demonstrated significant clinical benefits:
- Reduces recurrence: Multiple studies show BCG significantly lowers tumor recurrence rates 1, 3
- Prevents progression: BCG therapy can reduce disease progression when properly administered 1
- Long-term protection: A single 6-week course can provide protection for up to 10 years, though maintenance therapy is recommended for optimal outcomes 3
Side Effects and Complications
BCG immunotherapy can cause various side effects:
- Common mild effects: Dysuria and flu-like symptoms 2
- Serious complications: Systemic BCG infection occurs in approximately 4.3% of patients, with miliary tuberculosis being the most common form 4
- Presentation of infection: Disseminated (34.4%), genitourinary (23.4%), and osteomuscular (19.9%) infections are the most common presentations 4
Risk Factors and Management
While specific risk factors for BCG infection are not clearly established, certain considerations are important:
- Age: Patients ≥65 years have higher attributable mortality (7.4% vs 2.1%) 4
- Infection type: Disseminated infections have higher mortality (9.9% vs 3.0%) 4
- Treatment: Most BCG infections are treated with a 3-drug antituberculosis regimen for approximately 6 months 4
Potential Optimization of BCG Therapy
Recent research suggests several ways to potentially improve BCG therapy:
- Timing: Minimizing the duration between resection and first BCG instillation may improve outcomes 5
- Dosing: Higher BCG doses may improve probability of tumor extinction 5
- Indwelling time: Longer indwelling times could improve treatment efficacy 5
- Treatment interval: Interestingly, an inter-instillation interval twice as long as the standard seven-day interval might substantially improve outcomes 5
Important Clinical Considerations
- Patient selection: BCG is most effective for high-risk NMIBC patients compared to other treatments like mitomycin C 1
- Dose adjustment: Logarithmic dose reduction can help manage increasing side effects without escalating toxicity 3
- Contraindications: Understanding treatment contraindications is crucial for safe administration 3
- Resumption after infection: Resuming BCG after a systemic infection is rare (only 5.6% of cases) and requires careful risk-benefit assessment 4
BCG immunotherapy represents one of the most successful applications of immunotherapy in cancer treatment, with decades of clinical evidence supporting its use in bladder cancer management.