Bacillus Calmette-Guérin Immunotherapy for Bladder Cancer Overview of BCG Immunotherapy

Updated: Dec 13, 2022
  • Author: Kara N Babaian, MD, FACS; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
  • Print
Overview of BCG Immunotherapy

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 replaced 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 (NMIBC). [1]

The classic appearance of carcinoma in situ as a f The classic appearance of carcinoma in situ as a flat, velvety patch. However, using special staining techniques such as 5-aminolevulinic acid, it has been shown that significant areas of carcinoma in situ are easily overlooked by conventional cystoscopy. Courtesy of Abbott and Vysis Inc.

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 typically necessary.

Typically, BCG treatment begins with an induction course (once weekly for 6 weeks). Another 6-week induction course may be administered if a repeat cystoscopy (see image above) reveals tumor persistence or recurrence. Induction therapy followed by maintenance therapy (typically once weekly for 3 weeks, every 3-6 months, for 1-3 years) may provide more lasting results. Periodic bladder biopsies are usually necessary to assess response.

A 2020 guideline from the American Urological Association (AUA) and the Society of Urologic Oncology (SUO) includes the following recommendations for use of BCG in NMIBC. [2]

  • In a patient with suspected or known low- or intermediate-risk bladder cancer, a clinician should consider administration of a single postoperative instillation of intravesical chemotherapy (eg, gemcitabine, mitomycin C) within 24 hours of a transurethral resection for bladder tumor (TURBT). In a patient with a suspected perforation or extensive resection, a clinician should not use postoperative intravesical chemotherapy (moderate recommendation; evidence strength: grade B).
  • In a low-risk patient, a clinician should not administer induction intravesical therapy (moderate recommendation; strength of evidence grade C).
  • In an Intermediate-risk patient, a clinician should consider administration of a 6-week course of induction intravesical chemotherapy or immunotherapy (moderate recommendation; evidence strength: grade C).
  • 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 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).
  • In a patient with persistent or recurrent intermediate- or high-risk NMIBC within 12 months of completion of adequate BCG therapy (two induction courses or one induction course plus one maintenance cycle) who is unwilling or unfit for cystectomy following two courses of BCG, a clinician may recommend clinical trial enrollment or offer alternative intravesical therapy (eg, valrubicin, gemcitabine, docetaxel, combination chemotherapy when clinical trials are unavailable. A clinician may also offer systemic immunotherapy with pembrolizumab to a patient with CIS within 12 months of completion of adequate BCG therapy (expert opinion).

There has been an ongoing shortage of BCG in the United States, so in concert with other groups, the AUA and the SUO have issued a notice outlining strategies to maximize care for patients with NMIBC, including alternatives to BCG. [3] Similarly, National Comprehensive Cancer Network (NCCN) bladder cancer guidelines acknowledge the BCG shortage, offer strategies to prioritize use of intravesical BCG, and identify alternative treatment approaches for some patients with NMIBC. [4]

NCCN recommendations for use of BCG in the context of BCG shortage include the following [4] :

  • In the event of a BCG shortage, BCG should be prioritized for induction of high-risk patients (eg, high-grade T1 and CIS).
  • For induction, the dose of BCG may be split (1/3 or 1/2 dose) so that multiple patients may be treated with a single vial in the event of a shortage.
  • Alternatives to BCG Include mitomycin or gemcitabine. Other options include epirubicin, valrubicin, docetaxel or sequential gemcitabine/docetaxel or gemcitabine/mitomycin.
  • Initial radical cystectomy is another alternative to BCG for patients at high risk of recurrence and at high risk of progression.
  • If supply allows, maintenance BCG should be prioritized for high-risk patients (eg, high-grade T1 and CIS), especially in the early maintenance period (ie, 3- and 6-months post-induction).
  • For maintenance BCG, reduced dosing with 1/2 or 1/3 dose should be used.

For more information, see Bladder Cancer.


Mechanism of Action of BCG

The mechanism of action of bacillus Calmette-Guérin (BCG) therapy is incompletely understood. Some early studies purported that an immune response against 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.

The most likely mechanism of action of BCG immunotherapy involves a combination of its direct effect on tumor cells along with the patient’s immune response to the therapy. These effects are summarized by Kawai et al into three categories: infection of cancer cells, induction of immune response, and antitumor effects. [5]

The infection of cancer cells is mediated by the glycoprotein fibronectin, which allows the internalization of BCG, breakdown of proteins, and cellular changes (antigen expression) that trigger the immune system. This is similar to the immunologic reaction that occurs in patients with tuberculosis. This immune response comprises specific cellular changes including surface receptor changes and release of various cytokines. Interferon (IFN) is considered to be an important part of this process and has been used in the past to determine appropriate response to treatment. The immune response crescendos to antitumor activity in which cells (eg, cytotoxic T lymphocytes, natural killer cells, neutrophils, and macrophages) recognize the cancer cells, target them for destruction, and subsequently decrease cancer burden. [6]

The overall response to BCG is limited if the patient is immunosuppressed.

Dal Moro and colleagues 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 evaluate hypertension as a possible prognostic factor to be used in selecting poor-prognosis BC patients as early candidates for surgical treatment. [7]


Contraindications to BCG

Contraindications to bacillus Calmette-Guérin (BCG) vaccine therapy include the following:

  • Immunosuppression
  • Febrile illness
  • Concurrent antibiotic use
  • Symptomatic urinary tract infection
  • Cancer invading the bladder muscle
  • Large tumor volume

BCG is also contraindicated in active tuberculosis infections; however, a recent study found there was no difference in treatment efficacy in patients with a prior tuberculosis infection. [8]  

Because BCG is a live attenuated organism, it can cause an acute disseminated tuberculosis-like 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 within 7-14 days of any bladder or prostate surgery. [9, 10] Additionally, total bladder incontinence is a contraindication, as those patients cannot retain the BCG solution. Lastly, any previous adverse reactions after receiving BCG treatment is a contraindication to future treatment. [9]


BCG Strains

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. The Tice strain, which is a substrain of the original Pasteur product, is manufactured by Organon Pharmaceuticals-Merck and available in the United States. Other strains such as the Tokyo 172 substrain and the Danish substrain are available in countries other than the United States. Production of TheraCys BCG, which was made from the Connaught strain, was discontinued in 2018.

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 had 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. [11]  This implies that a smaller dose of Tokyo172 is likely to be as effective as a much larger dose of the Connaught strain.

Some researchers are beginning to investigate BCG combination therapy rather than the use of one specific strain. These combinations are still developing, and unfortunately, randomized controlled studies comparing individual strains may be less common due to the current BCG shortage. [12]


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 50 mL of normal saline. [9]  Because this preparation contains live organisms, care should be taken during preparation, administration, and disposal of the supplies. 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. 

The BCG solution must be used within 2 hours and any unused product at that time should be properly disposed of as biohazardous waste. [9]

The prepared solution 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. 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 and be encouraged to drink more water to dilute the urine to avoid exposing other family members to the solution.

BCG induction therapy

To achieve 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. There is a recommended maximum of 2 consecutive cycles of induction therapy. If there is an inadequate response after the first cycle, a second induction cycle can be attempted. [2]

The induction phase is considered complete when the immunologic reaction has occurred. This is evidenced by the following:

  • The patient has irritative bladder symptoms
  • The urine contains white blood cells without evidence of infection
  • Microscopic hematuria is present

BCG maintenance therapy

When induction is completed, a course of immunoprophylaxis or maintenance therapy is begun. Maintenance therapy has been shown to reduce recurrence and progression. The schedule for instillations of BCG has varied from monthly to every 3 months to every 6 months. The only maintenance regimen proven to prevent recurrence and progression is the SWOG protocol, which consists of 3 weekly treatments at months 3, 6, 12, 18, 24, 30, and 36.

Most experts agree that a maintenance program of at least 1 year is necessary for intermediate-risk patients and 3 years for high-risk patients. [4]  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 may not need additional maintenance. [13]

Tolerability of therapy

Patients may 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 be necessary. While studies have shown that one-third the typical dose of BCG is effective for cancer treatment, there is conflicting evidence regarding whether this dose reduction can reduce the associated adverse effects. Currently, full-dose BCG is still recommended unless patients experience extensive local adverse effects. [4]  

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

Common adverse effects include cystitis, dysuria, malaise, fatigue, and a low fever (usually resolves within 24-48 hours). These can be managed by NSAIDS, phenazopyridine, and anticholinergics. If symptoms become intense or last longer than 24 hours, consider either delaying additional instillations until symptoms improve or reducing the dose.

In a review including 2602 patients treated with intravesical BCG instillation (of whom less than 5% had serious complications), the most common  side effects were fever > 103ºF, hematuria, granulomatous prostatitis, pneumonitis and/or hepatitis, arthralgia, epididymitis, sepsis, rash, ureteral obstruction, bladder contracture, renal abscess, and cytopenia. [14]

Early-onset BCG infection (≤3 months of BCG instillation) often presents as systemic manifestations. In contrast, delayed-onset infection (≥3 months of BCG instillation) presents as localized disease. Manifestations are as follows:

  • Systemic manifestations occur when BCG disseminates outside of the genitourinary tract. They include sepsis syndrome, pulmonary issues from dyspnea, granulomatous hepatitis, osteomyelitis, reactive arthritis, monoarthritis, psoas abscess, and vascular complications due to mycotic aneurysms.
  • Localized manifestations include cystitis, bladder contracture, granulomatous prostatitis, prostate abscess, epididymo-orchitis, testicular abscess, pyelonephritis, renal abscess, urethral stricture, and balanitis.

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, epididymo-orchitis, or acute prostatitis should not receive additional BCG vaccine therapy until those complications have resolved. They are indications of a systemic BCG reaction, and further administration is immunosuppressive and potentially lethal.

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.

The AUA has noted the following with regard to BCG [2]

  • Immunosuppression: BCG efficacy is reduced in patients that are immunosuppressed, but evidence suggests that it can be safely administered.
  • Warfarin and statins: BCG may be less effective in patients on warfarin, presumably secondary to inhibitors of the fibronectin binding that is required for BCG entry into the urothelium. Similar observations have been made for statin drugs.
  • Antibiotics: Agents such as quinolones, rifampin, and isoniazid are toxic to BCG bacteria, but do not appreciably reduce BCG adverse effects if given concurrently. Furthermore, isoniazid has been associated with transient liver toxicity and therefore its use for prophylaxis is not recommended.