Bacillus Calmette-Guérin Immunotherapy for Bladder cancer.
Currently, bacillus Calmette-Guérin (BCG) is a live attenuated strain of Mycobacterium bovis and is the only agent approved by the US Food and Drug Administration as the primary therapy of carcinoma in situ of the bladder.
BCG supplanted cystectomy as the treatment of choice for carcinoma in situ of the bladder.
Carcinoma in situ appears as a flat, velvety patch, yet significant areas of carcinoma in situ are easily overlooked by conventional cystoscopy.
To be effective, the host should be immunocompetent, the tumor burden small, direct contact with the tumor should occur, and the dose should be adequate to incite a reaction.
Intravesical BCG treatment can eradicate cancer-in-situ cancer in 70% of patients with these criteria.
Long-term maintenance therapy following the induction phase may be necessary to prevent recurrence of cancer.
Intravesicle BCG is administered in either an induction weekly for 6 weeks or as maintenance, once weekly for 3 weeks.
If there is persistence or recurrence of tumor an additional 6 week course of treatment may be administered.
Induction therapy combined with maintenance therapy every 3-6 months for 1-3 years may provide more lasting results.
Action of BCG is purported that an immune response against bacillus Calmette-Guérin (BCG) surface antigens cross-reacted with putative bladder tumor antigens, but multiple subsequent studies refute this claim.
Live BCG organisms enter macrophages, where they induce the same type of histologic and immunologic reaction as found in patients with tuberculosis.
The response to BCG is limited if the patient is immunosuppressed.
Contraindications to bacillus Calmette-Guérin (BCG) vaccine therapy include immunosuppression, cancer invading the bladder muscle, and large bladder tumor volume.
As BCG is a live attenuated organism, it can result in an acute disseminated tuberculosislike illness if it enters the bloodstream.
Its use of BCG is contraindicated in patients with gross hematuria, traumatic catheterization, and recent bladder tumor resection.
Total bladder incontinence is a contraindication, if patients cannot retain the BCG solution.
BCG viability must be adequate for the vaccine to be effective.
The BCG solution is prepared by dissolving the freeze-dried powder with the diluent and saline with the preparation so that the total volume is approximately 30 mL
The BCG solution is used within 2-3 hours, and is instilled into the bladder via a small catheter by gravity or a slow drip.
The BCG solution is not forced into the bladder.
The solution must be retained for 1.5-2 hours, after which time the patient voids, and is encouraged to move positions every 30-45 minutes to allow the BCG solution to contact all portions of the bladder lumen.
The bladder is not fully emptied and the patient’s bladder retains more than 60 mL of urine, the bladder may need to be drained after the BCG solution is retained for 2 hours.
Antibiotics should not be given at the time of the instillation, as they can kill the live organisms and negate the effect of the treatment.
The toilet is washed with bleach following the next 3 urinations to avoid exposing other family members to the vaccine.
Typically, 6 weekly instillations constitute the induction therapy.
Some patients respond with fewer instillations and some require more, indicating that the patient’s response should be assessed each time the patient comes for treatment.
Antigenic stimulation increases with consecutive instillations but decreases dramatically when the stimulation is excessive.
BCG induces is systemic nonspecific immunostimulatory response leading to the secretion of pro-inflammatory cytokines.
Patients may experience flu like symptoms that may last 48 to 72 hours.
When the immunologic reaction has incurred and includes irritative bladder symptoms, the urine contains white blood cells without evidence of infection, and micro scopic hematuria is present the induction phase is considered complete.
Installation of BCG into the bladder, mimics a UTI, and may produce intense local discomfort:60% of patients report dysuria.
Following induction, a course of maintenance therapy is begun.
Maintenance therapy reduces the frequency of recurrence and progression of the disease and intervals of treatment vary from monthly to every three months or every six months.
The optimum frequency and duration of this therapy in a Southwest Oncology study found that 2-3 instillations every 3 months was effective.
A maintenance program of at least one year is required.
Some patients have significant irritative adverse affects, and in such cases the intervals between instillation should be lengthened or the dose decreased.
The dose depends on the potency of the product and the patient’s reaction.
The first 1-3 instillations of bacillus Calmette-Guérin (BCG) vaccine usually cause very few adverse effects.
Subsequently, after the third instillation, patients usually begin experiencing irritative bladder symptoms and/or flulike symptoms that last 24-72 hours.
Nearly 80% of patients can expect to experience this type of reaction, which arevfairly mild and can be controlled with and to histamine’s, nonsteroidal anti-inflammatory drugs, and bladder anti-spasmodic agents.
If the patient develops fever of higher than 102.2°F, or have a gross hematuria, or severe irritative symptoms within 24 hours, a UTI, elevated liver functions, arthritis, prostatitis or epididymitis should have the BCG vaccine therapy stopped until these problems have resolved.
The presence of severe symptoms such as the systemic reaction to BCG and further administration of the drug is immunosuppressive and potentially lethal.
BCG induces a systemic non-specific immunostimulatorr response leading to secretion of pro inflammatory cytokines causing patients to experience flu like symptoms that may last 48 to 72 hours.
Intravesical BCG also mimics UTI and may produce intense local discomfort: Dysuria is reported in up to 60% of patients.
Severe reactions to BCG vaccine, including high-grade fevers 104°F, hepatotoxicity, respiratory distress, chills, hemodynamic instability, and mental status changes, suggest life-threatening septicemia.
Many cases of septicemia following BCG vaccine instillation are caused by more common uropathogens, rather than the organisms in the BCG vaccine.
With severe reactions patient should be started on broad-spectrum antibiotics without waiting for culture results.
Symptom management with a single dose, short term quinolones and/or anticholinergics reduce adverse events from BCG.
In addition, patients with severe systemic reactions should be starting on antituberculosis therapy including rifampin, isoniazid and cycloserine.
Corticosteroids are also recommended in some patients.