Bacillus Calmette-Guérin (BCG) is a widely used immunotherapy for treating non-muscle-invasive bladder cancer (NMIBC). It uses a weakened form of Mycobacterium bovis, the bacterium historically used in the tuberculosis vaccine. When applied directly to the bladder, BCG stimulates a powerful localized immune response against residual cancer cells. Its primary role is to prevent the recurrence and progression of high-risk tumors confined to the inner lining of the bladder. BCG is administered following surgical removal of the tumor to target microscopic disease remaining in the bladder lining.
How BCG Fights Bladder Cancer
BCG is an immunotherapy that harnesses the body’s own defense system, unlike chemotherapy which directly poisons dividing cells. The treatment is delivered as a liquid suspension directly into the bladder, where the bacteria adhere to the bladder wall lining. This attachment is facilitated by molecules on the surface of the BCG organism and the bladder cells.
The presence of the bacteria triggers a rapid, localized inflammatory reaction within the bladder cavity. This immune response recruits a variety of immune cells, including neutrophils, macrophages, and natural killer cells, to the site. The inflammation creates a hostile environment for the cancer cells.
A specific, adaptive immune response follows, mediated by T-cells. The BCG bacteria are internalized by bladder cells, causing them to process and present antigens to T-lymphocytes. This process activates cytotoxic T-cells (CD4+ and CD8+ T-cells), which are the body’s primary cancer-fighting agents.
The activated T-cells and other immune cells release signaling molecules, such as cytokines like Interferon-gamma (IFN-\(\gamma\)). These molecules amplify the anti-tumor activity. The resulting influx of immune cells and inflammatory factors targets and destroys the urothelial cancer cells lining the bladder.
This biological process results in the destruction of residual cancer cells and establishes immunological memory within the bladder. The goal is to eradicate the microscopic disease remaining after surgical removal, reducing the chance of the cancer returning or progressing to a muscle-invasive stage.
The Standard Treatment Schedule
BCG is administered via intravesical instillation, meaning the liquid drug is placed directly into the bladder. A catheter is temporarily inserted through the urethra to deliver the solution, and then immediately removed. The treatment is scheduled in two phases: induction and maintenance.
The initial phase is the Induction course, consisting of six weekly treatments. This period aims to generate the strongest immune reaction and clear the bladder of remaining cancer cells. Before each instillation, patients limit fluid intake for several hours to prevent the BCG solution from being diluted by urine.
After the medication is instilled, the patient must retain the liquid within the bladder for one to two hours. This dwell time ensures sufficient contact between the BCG bacteria and the bladder lining to initiate the immune response. Following this period, the patient voids the solution, and specific precautions must be taken for several hours to safely handle the remaining live bacteria.
If the initial induction course is successful, patients proceed to the Maintenance phase, a schedule of periodic, lower-intensity treatments. Maintenance therapy is recommended for high-risk non-muscle-invasive bladder cancer to sustain anti-tumor immunity and reduce recurrence. A common regimen involves three weekly instillations at months three and six, and then every six months thereafter for up to one to three years.
Expected Side Effects and Adverse Reactions
Since BCG works by intentionally creating a strong inflammatory reaction, patients anticipate common, localized side effects. These symptoms are generally short-lived and represent the immune system actively engaging with the treatment. The most frequent issues relate to bladder irritation, often mimicking a severe urinary tract infection.
Patients commonly experience increased urinary frequency and urgency, along with discomfort or a burning sensation during urination (chemical cystitis). Mild blood in the urine (hematuria) is also frequent following instillation. Many people report flu-like symptoms, such as fatigue, body aches, and a low-grade fever (typically between 99°F and 100°F). These localized effects usually resolve within 24 to 72 hours after the treatment session.
While rare, more serious systemic adverse reactions can occur if the BCG bacteria enter the bloodstream, which is likely if the bladder lining is damaged. One serious concern is BCG sepsis, a life-threatening infection requiring immediate medical attention. Symptoms of a serious reaction include a high-grade fever (above 101.3°F or 38.5°C) that persists beyond 48 hours, or the onset of severe flu-like symptoms like chills, vomiting, or a persistent cough.
Patients must contact their healthcare provider immediately if they experience a sustained high fever or severe, worsening systemic symptoms. Treatment must be withheld if a patient has a urinary tract infection or visible hematuria, as these conditions increase the risk of the bacteria entering the bloodstream.
Treatment Outcomes and Next Steps
BCG immunotherapy is considered the most effective therapy for high-risk non-muscle-invasive bladder cancer, successfully preventing recurrence and progression in many patients. However, the cancer still recurs in approximately 30% to 40% of patients following an adequate course of BCG. Regular monitoring with cystoscopy and biopsies is performed to check for disease return.
A challenging situation arises when the disease persists or returns despite sufficient BCG therapy, termed “BCG-unresponsive” disease. This outcome indicates the cancer is aggressive and has a high risk of progressing to muscle-invasive disease, which is harder to treat. In these scenarios, a patient is unlikely to benefit from further BCG treatments.
For patients with high-risk, BCG-unresponsive disease, the standard of care often involves a radical cystectomy, the surgical removal of the entire bladder. This operation is the most reliable way to prevent the cancer from spreading outside the bladder, improving the chance of long-term survival.
There are bladder-sparing alternatives for patients who are not candidates for surgery or who wish to avoid it. These alternative treatments include intravesical chemotherapy combinations, such as gemcitabine followed by docetaxel, instilled directly into the bladder. Newer immunotherapies, such as checkpoint inhibitors like pembrolizumab, are also used, administered intravenously to unleash the body’s immune response against the cancer.