Overview of BCG Immunotherapy
Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, is currently the only agent approved by the US Food and Drug Administration for primary therapy of carcinoma in situ (CIS; see image below) of the bladder. BCG supplanted cystectomy as the treatment of choice for CIS in the mid-1980s. BCG therapy also reduces the risk of recurrence, and ongoing maintenance therapy with BCG reduces the risk of progression in patients with high-grade non–muscle invasive bladder cancer. 
Bladder cancer is the only cancer in which BCG is commonly used. Other agents have been used in bladder cancer, but none has surpassed the effectiveness of BCG.
For BCG to be effective, all the following criteria should be met:
The patient is immunocompetent
The tumor burden is small
BCG makes direct contact with the tumor
The dose is adequate to incite a reaction
Studies have consistently shown that BCG treatment can eradicate this cancer in 70% of patients with CIS who meet these criteria. To prevent cancer recurrence, long-term maintenance therapy following the induction phase is necessary.
Typically, BCG is administered in either an induction (once weekly for 6 weeks) or maintenance (once weekly for 3 weeks) course. Another 6-week course may be administered if a repeat cystoscopy (see image above) reveals tumor persistence or recurrence. Induction therapy combined with maintenance therapy every 3-6 months for 1-3 years may provide more lasting results. Periodic bladder biopsies are usually necessary to assess response.
A 2016 guideline from the American Urological Association (AUA) and the Society of Urologic Oncology (SUO) includes the following recommendations for use of BCG in non–muscle invasive bladder cancer 
In a high-risk patient with newly diagnosed CIS, high-grade T1, or high-risk Ta urothelial carcinoma, administer a 6-week induction course of BCG (strong recommendation; evidence strength, grade B)
In an intermediate-risk patient who completely responds to an induction course of intravesical chemotherapy, maintenance BCG therapy may be used (conditional recommendation; evidence strength, grade C)
In an intermediate-risk patient who completely responds to induction BCG, consider maintenance BCG for 1 year, as tolerated (moderate recommendation; evidence strength, grade C)
In a high-risk patient who completely responds to induction BCG, maintenance BCG should be continued for 3 years, as tolerated (moderate recommendation; evidence strength, grade B)
In an intermediate- or high-risk patient with persistent or recurrent disease or positive cytology following intravesical therapy, consider performing prostatic urethral biopsy and an upper tract evaluation prior to administering additional intravesical therapy (conditional recommendation, evidence strength, grade C)
In an intermediate- or high-risk patient with persistent or recurrent Ta or CIS disease after a single course of induction intravesical BCG, a second course of BCG should be offered (moderate recommendation, evidence strength, grade C)
In a patient fit for surgery with high-grade T1 disease after a single course of induction intravesical BCG, radical cystectomy should be offered (moderate recommendation, evidence strength, grade C)
Additional BCG should not be prescribed to a patient who is intolerant of BCG or has documented recurrence on transurethral resection of bladder tumor (TURBT) of high-grade, non–muscle-invasive disease and/or CIS within 6 months of two induction courses of BCG or induction BCG plus maintenance (moderate recommendation, evidence strength, grade C)
If intermediate- or high-risk non–muscle-invasive bladder cancer persists or recurs after two courses of BCG and the patient is unwilling to undergo cystectomy or is unfit for it, clinical trial enrollment may be recommended; if a trial is unavailable, the patient may be offered intravesical chemotherapy (expert opinion)
In a high-risk patient with persistent or recurrent disease within 1 year following treatment with two induction cycles of BCG or BCG maintenance, radical cystectomy should be offered (moderate recommendation, evidence strength, grade C)
For more information, see Bladder Cancer.
Mechanism of Action of BCG
The mechanism of action of BCG therapy is incompletely understood. Some early studies purported that an immune response against bacillus Calmette-Guérin (BCG) surface antigens cross-reacted with putative bladder tumor antigens, and this was proposed as the mechanism for the therapeutic effect of BCG; however, multiple subsequent studies refute this claim.
Once in the bladder, the live organisms enter macrophages, where they induce the same type of histologic and immunologic reaction as found in patients with tuberculosis. BCG vaccine also has been shown to have a predilection for entering bladder cancer cells, where the proteins are broken down and fragments are combined with histocompatibility antigens and displayed on the cell surface. This induces a cytokine and direct cell-to-cell cytotoxicity response, which targets these cells for destruction.
The overall response to BCG is limited if the patient is immunosuppressed.
Dal Moro and collegues evaluated the influence of hypertension on the outcome of patients with noninvasive bladder cancer treated with BCG. In both univariate and multivariate analyses of 343 high-risk bladder cancer patients undergoing BCG with a median follow-up of 116 months, hypertension was a statistically significant parameter prognostic for recurrence after BCG treatment. Further study is needed to both evaluate hypertension as a possible prognostic factor to be used in selecting poor-prognosis BC patients as early candidates for surgical treatment. 
Contraindications to BCG
Contraindications to bacillus Calmette-Guérin (BCG) vaccine therapy include immunosuppression, cancer invading the bladder muscle, and large tumor volume. Because BCG is a live attenuated organism, it can cause an acute disseminated tuberculosislike illness if it enters the bloodstream (BCG sepsis), possibly resulting in death. Reports have described BCG vaccine organisms identified on vascular grafts in patients who have died following BCG vaccine sepsis. Therefore, the use of BCG is contraindicated in patients with gross hematuria, traumatic catheterization, and recent bladder tumor resection. Additionally, total bladder incontinence is a contraindication, as patients cannot retain the BCG solution.
The original bacillus Calmette-Guérin (BCG) strain was developed at the Pasteur Institute from an attenuated strain of Mycobacterium bovis. Subcultures were made and sent to other parts of the world. Two BCG products are commercially available in the United States. The Tice strain, which is a substrain of the original Pasteur product, is manufactured by Organon Pharmaceuticals. The TheraCys strain is made by Aventis/Pasteur. These products, in addition to the Tokyo 172 substrain and the Danish substrain, are available in countries other than the United States.
No one product has been shown to have consistent clinical superiority. BCG viability is an important consideration for the vaccine to be effective. This viability is measured in colony-forming units (CFUs). A vaccine that contains no or very few live organisms would be clinically ineffective. One dose, either an ampule or vial, may vary in weight from one product to another, but the CFU should be similar. Tice BCG has 1-8×10-8 CFUs. TheraCys has 10.5 +/-8.7×10-8 CFUs.
In a study that compared Tokyo172 with the Connaught vaccines, Ikeda et al found that the Tokyo172 vaccine had 48.77 +/-5.43 CFUs per dose, while the Connaught strain had 3.77 +/-1.45 CFUs.  This implies that a smaller dose of Tokyo172 is likely to be as effective as a much larger dose of the Connaught strain.
BCG Immunotherapy Technique
The BCG solution is prepared by initially dissolving the freeze-dried powder with the diluent that comes with the preparation. This solution is diluted further with saline, so that the total volume is approximately 30 mL
The individuals who prepare and administer BCG should wear gloves and avoid spilling or touching the vaccine. BCG may cause a strong local reaction in a sore or a cut. If the vaccine is splashed into an eye, it should immediately be washed. This is a preparation that contains live organisms; care should be taken during preparation, administration, and disposal of the supplies.
The BCG solution should be used within 2-3 hours. It is instilled into the bladder via a small catheter by gravity or a slow drip (not forced into the bladder).
The solution should be retained for 1.5-2 hours, after which time the patient voids. The patient is encouraged to move positions every 30-45 minutes to allow the BCG solution to contact all portions of the bladder lumen. If the patient’s bladder ordinarily retains more than 60 mL of urine, the bladder may need to be drained after the BCG solution is retained for 2 hours.
Patients do not have to remain in the office during the retention time. Patients should not be given antibiotics at the time of the instillation. These medications can kill the live organisms and negate the effect of the treatment.
The patient should wash out the toilet with bleach following the next 3 urinations to avoid exposing other family members to the vaccine.
BCG induction therapy
To a BCG reaction, multiple instillations of BCG are required. Typically, 6 weekly instillations constitute the induction phase, although some patients respond with fewer instillations and some require more. Each patient's response should be assessed each time the patient comes for an instillation.
The induction phase is considered complete when the immunologic reaction has occurred. This is evident when the patient has irritative bladder symptoms, the urine contains WBCs without evidence of infection, and microscopic hematuria is present. Once the patient has been induced or vaccinated, this phase of therapy has been completed.
BCG maintenance therapy
When induction is completed, a course of immunoprophylaxis or maintenance therapy is begun. Prolonging the course of therapy has been shown to reduce the frequency of recurrence and progression. These intervals have varied from instillations administered monthly to every 3 months or every 6 months. The optimum frequency and duration of this therapy seems to vary, but a Southwest Oncology study found that 2-3 instillations every 3 months is effective. 
Most experts agree that a maintenance program of at least 1 year is necessary. From the immunologic point of view, establishing this interval is difficult because patient variability is great and this is a biologic product whose dose may differ slightly with each instillation. The products also vary. Antigenic stimulation becomes greater with consecutive instillations but decreases dramatically when the stimulation is excessive.
Data from a small study conducted by Palou et al indicated that patients who are tumor-free after 6 months of therapy are likely to remain so indefinitely and do not need additional maintenance.  Most studies have shown the benefit of using maintenance therapy for at least one year.
Tolerability of therapy
Patients often have difficulty completing long-term therapy because of irritative adverse effects in the bladder. In such cases, the intervals between instillations should be lengthened; in addition, dose modification may also be necessary. Generally, a full ampule is administered, but some patients respond just as well to half or even one third of a dose and seem to have fewer adverse effects. The dose selection depends on the degree of reaction in the patient. Patients treated with the Tokyo172 substrain need only a 25% dose because of the potency of this product. The intent of the treatment is to elicit an immune response without overwhelming the immune system.
Adverse Effects of BCG
Usually, the first 1-3 instillations of bacillus Calmette-Guérin (BCG) vaccine cause very few adverse effects, unless the patient has been previously vaccinated with BCG vaccine or has a history of tuberculosis. After the third instillation, patients usually begin experiencing irritative bladder symptoms and/or flulike symptoms that last 24-72 hours. These symptoms are usually mild and can be controlled with bladder antispasmodics, NSAIDs, and antihistamines, and they are often perceived as favorable immunological responses to the therapy. Nearly 80% of patients can expect to experience this type of reaction.
In a randomized controlled study of 166 patients, the complete response rate for low dose BCG was 79% compared to 85% for standard dose BCG. However, low dose BCG was associated with significantly less fever and micturition pain and significantly higher quality of life scores. There were no significant differences between the groups in terms of recurrence, progression and overall survival. 
A study by Rosevear et al found that a poor response to BCG plus interferon-α therapy in patients with carcinoma in situ were associated with prior tumor stage, 2 or more prior BCG failures, and a BCG failure pattern. 
Patients who develop a fever of higher than 39°C (102.2°F) and those who have gross hematuria, severe irritative symptoms lasting more than 72 hours, a urinary tract infection, elevated liver enzyme levels, arthritis, epididymoorchitis, or acute prostatitis should not receive additional BCG vaccine therapy until these findings have resolved. These are symptoms of a systemic BCG reaction, and further administration is unnecessary, immunosuppressive, and potentially lethal. BCG therapy should be administered at reduced doses half or a quarter dose can be administered.
Severe reactions to BCG vaccine, including high-grade fevers (ie, temperature >40°C [104°F]), hepatotoxicity, respiratory distress, chills, hemodynamic instability, and mental status changes, suggest life-threatening septicemia. These are emergencies, and patients should be hospitalized.
A urine culture should be obtained because many cases of septicemia following BCG vaccine instillation are caused by more common uropathogens, rather than the organisms in the BCG vaccine. Tuberculosis organisms from the urine or tissues are usually difficult to culture.
Treatment should be initiated without waiting for culture results. Broad-spectrum antibiotics should be administered intravenously, and the patient should be started on antituberculosis therapy, including rifampin, isoniazid, and cycloserine, which is the only antituberculosis drug to reach bactericidal levels within 24 hours of administration. Corticosteroids are also recommended in some patients.
When BCG vaccine therapy was introduced, several deaths were reported, all of which could be attributed to improper use of this agent. At present, a death is extraordinary because clinicians have learned how to administer this agent and to stop therapy before a patient becomes ill.