Bacille Calmette–Guérin (BCG) vaccine

General information

Bacille Calmette–Guérin (BCG) vaccine is a suspension of living tubercle bacilli of the Calmette–Guérin strain. It is used mainly prophylactically against tuberculosis, but also as a means of stimulating the immune response in malignant disease. There are variations in the characteristics of BCG vaccines, depending on the strain of BCG derived from the original BCG strain and employed for vaccine production. BCG is generally used intradermally, except for instillation in intravesical immunotherapy. The risk of adverse effects after BCG immunization is related to the BCG strain, the dose, the age of the vaccinee, the technique of immunization, and the skill of the vaccinator.

Therapeutic uses of BCG

In addition to its use in preventing tuberculosis, BCG has been used as an immunostimulant or immunomodulator. The degree of safety of this procedure differs with the technique and the purpose for which it is used. In most areas, the use of BCG to counter cancer has proved disappointing, although it is still used to some extent, generally as an adjunct to other forms of treatment [ ]. More encouraging is the use of intravesical instillation of BCG for recurrent superficial transitional cell carcinoma of the bladder, for which it now constitutes the treatment of choice.

BCG immunotherapy in bladder tumors

Intravesical instillation of BCG has been used to treat superficial bladder carcinoma and interstitial cystitis. Many reports have confirmed the efficacy of BCG in the treatment of transitional cell bladder cancers and have delineated its adverse effects. The exact mechanism of its antitumor activity is unknown, but live BCG provokes an inflammatory response that includes activation of macrophages, a delayed hypersensitivity reaction, and stimulation of T and B lymphocytes and natural killer cells.

In general, BCG immunotherapy of bladder cancer is considered to be relatively safe. However, it does have adverse effects, including fever, arthritis/arthralgia, bladder irritability, bladder contracture, cytopenias, cystitis, disseminated intravascular coagulation, respiratory failure, epididymitis, hepatitis, loss of bladder capacity, miliary tuberculosis, pneumonitis, polyarthritis, prostatitis, pyelonephritis, pseudotumoral granulomatous renal mass, rhabdomyolysis, renal granulomas, renal insufficiency, skin abscess, tuberculous aneurysm of the aorta and femoral artery, ureteral obstruction, vertebral osteomyelitis, and psoas abscess. A small number of reports of life-threatening adverse effects after BCG instillation have been published, including disseminated BCG infection [ ], some fatal. These tragic cases illustrate many points of critical importance to all urologists using BCG. BCG should never be given at the same time as tumor resection or transurethral resection of the prostate. The dose of BCG given intravesically corresponds to a potentially lethal intravenous dose. Intravasation as a result of catheterization, tumor resection or biopsy, or cystitis has occurred in two-thirds of the reported cases of systemic BCG infection.

In a review of those observed among 195 patients with bladder cancer treated with various substrains of BCG, there were frequent but mild to moderate local adverse effects, with irritative cystitis leading to frequency and dysuria in 91% of patients and hematuria in 43% [ ]. Low-grade fever (24%), malaise (24%), and nausea (8%) also occurred. These symptoms usually occurred after two or three instillations and lasted for about 2 days. It has been stated that these frequent adverse effects did not seriously affect the quality of life of patients [ ]. Additional information was obtained from a multinational retrospective survey in order to cover the whole scope of severe and/or systemic complications associated with BCG immunotherapy, and to propose guidelines for management [ ]. Among 2602 patients in this survey, more than 95% had no serious adverse effects. Apart from fever higher than 39 °C (2.9%) and major hematuria (1%) serious adverse effects comprised granulomatous prostatitis (0.9%), granulomatous pneumonitis and/or hepatitis (0.7%), arthritis and arthralgia (0.5%), epididymo-orchitis (0.4%), life-threatening BCG sepsis (0.4%), skin rashes (0.3%), ureteric obstruction (0.3%), bladder contracture (0.2%), renal abscesses (0.1%), and cytopenias (0.1%). There was no major difference in incidence among the different substrains used. Lowering the dose of BCG in an attempt to reduce the incidence of adverse effects produced somewhat contrasting results, with a reduced incidence of various adverse effects but no significant difference (or an apparently increased incidence) in the case of pollakiuria, hematuria, fever, and headache [ ].

Other rare complications have been seldom reported, namely cryoglobulinemia with evidence of disseminated BCG infection [ ], ruptured mycotic aneurysm of the abdominal aorta [ ], bladder wall calcification [ ], rhabdomyolysis [ ], iritis or conjunctivitis with arthritis or Reiter’s syndrome [ , ], and severe acute renal insufficiency due to granulomatous interstitial nephritis, which can occur even in the absence of other systemic complications [ ].

In 1990, the US Food and Drug Administration approved the marketing of BCG Live (intravesical) for use in the treatment of primary or relapsed carcinoma in situ of the urinary bladder, with or without associated papillary tumors. BCG is not recommended for treatment of papillary tumors that occur alone. The drug is marketed by Connaught Laboratories as TheraCys and by Organon as TiceBCG. The manufacturers recommend a 6-week induction course of weekly intravesical BCG, usually starting 1–2 weeks after biopsy or after transurethral resection of papillary tumors. Follow-up courses of treatment at 3, 6, 12, and 24 months or monthly for 6–12 months after initial treatment are recommended.

Influence of dosage

The degree of success of different doses of BCG vaccine (100–120 mg, 20–50 mg, or a much smaller dose of 1 mg) in preventing tumor relapse has been described in patients with superficial bladder cancers [ ]. Adverse reactions were dose-related. The authors considered that endovesical instillation of BCG vaccine 1 mg would be the optimal dosage for prevention of relapse.

In 108 patients with bladder cancer, tumor relapse was prevented by the use of BCG vaccine 1 mg [ ]. Inguinal lymphadenitis and dysuria have occurred [ ].

Comparison of BCG strains

In a comparison of 56 patients who received BCG instillations using Berna strain BCG and 32 patients who received Pasteur strain BCG for treatment of superficial bladder cancer, the patients who received Pasteur strain BCG had the highest tumor-free rate but had significantly more toxicity [ ]. The answer to another difficult question connected with the use of intravesical BCG, that is whether the treatment increases the incidence of second primary malignancies, has been sought [ , ]. It was suggested that BCG immunotherapy could accelerate the growth and cause metastatic spread of a growing second primary malignancy that had remained undetected at the start of BCG therapy, and that the time relation between the starting point of second primary tumor development and the starting point of BCG treatment might be crucial in determining whether BCG eradicates the tumor or accelerates its growth. However, in 153 patients there was no evidence that intravesical BCG did increase the incidence of second primary malignancies [ ]. The matter is therefore still unresolved.

Comparison of different regimens for carcinoma in situ of the bladder

The efficacy and adverse effects of various alternative treatment regimens for carcinoma in situ of the bladder have been compared with those of instillation of BCG in 21 patients. All were treated initially with intravesicular instillations of Keyhole-Limpet Hemocyanin (first course: 20 mg weekly for six weeks; second course: 20 mg monthly for 1 year or bimonthly for 2 subsequent years). Patients who did not respond to two courses were treated with regular instillations of BCG Connaught strain 120 mg. Eleven patients were free from tumor tissue after the first or second course of Keyhole-Limpet Hemocyanin. Ten patients had to have a cystectomy because of persistence or progression of carcinoma after hemocyanin or hemocyanin with subsequent BCG. However, instillations of BCG caused severe dysuria in 60% and fever in 40% of patients, whereas hemocyanin treatment had only minor adverse effects [ ]. Combined therapy with mitomycin C and BCG was more effective in 28 patients with carcinoma in situ of the bladder than mitomycin alone [ ]. Compared with BCG monotherapy there were only a few adverse effects. The success rates were comparable.

Two different methods of treating superficial bladder cancer have also been compared in a randomized, multicenter trial, setting transurethral resection only against transurethral resection plus adjuvant mitomycin C and BCG instillation [ ]. The rate of progression was comparable in the two groups; at a medium follow-up of 20 months there was a reduction in recurrence rates with the combination therapy. Adverse effects occurred most often during or after BCG instillation. Other investigators have found the same degree of efficacy of the same regimen in reducing the incidence of recurrence of superficial urothelial cancer after transurethral bladder resection in 99 patients [ ].

Treatment of adverse reactions after intravesical instillation of BCG

The prompt recognition of risk factors for severe complications, namely traumatic catheterization or concurrent cystitis, that increase BCG absorption, and treatment of early adverse effects, is expected to reduce the incidence of severe adverse effects. Severe local and systemic adverse effects can be successfully treated with tuberculostatic drugs for up to 6 months [ ].

Severe local and systemic adverse effects of BCG treatment can be treated successfully with tuberculostatic drugs, to most of which BCG is very susceptible, for up to 6 months [ ]. The effects of isoniazid on the incidence and severity of adverse effects of intravesical BCG therapy have been analysed in patients who received BCG with (n = 289) and without (n = 190) isoniazid [ ]. The authors concluded that prophylactic oral administration of isoniazid (300 mg/day with every BCG instillation) caused no reduction in any adverse effect of BCG. In contrast, transient liver function disturbances occurred slightly more often when isoniazid was used. The polymerase chain reaction has been used to monitor BCG in the blood after intravesical BCG instillation (22 patients) as well as after antituberculosis therapy [ ]. The early and fast diagnosis of BCG in the blood was considered to be potentially valuable in initiating specific early treatment of BCG complications.

Prophylactic BCG immunization

BCG immunization is generally well tolerated. Locally a small papule appears which scales and ultimately leaves a scar; however, abnormal reactions can occur. The most common adverse local reaction, suppurative lymphadenitis, has been reported in 0.1–10% of immunized children under 2 years of age. Faulty immunization technique is the most frequent cause of severe abnormal BCG primary reactions [ ]. The most serious generalized complications of BCG immunization involve disseminated infection with the BCG bacillus and BCG osteitis. Allergic reactions are unusual, but severe anaphylactic reactions can occur, especially when the product is used as an immunostimulant.

Tuberculin

Mammalian tuberculin purified protein derivative (tuberculin PPD) is the active principle of old tuberculin. A small test dose in a healthy individual, given intracutaneously, is likely to produce only a little local pain and pruritus. If tuberculous infection is present, the local reaction is more marked, with vesiculation, ulceration, and even granuloma annulare or necrosis.

If more than a minimal dose is used in cases of tuberculous infection, a severe and even fatal generalized anaphylactic reaction can develop within about 4 hours of the injection [ ].

People who are engaged in manufacturing PPD can easily become sensitized to it, and severe allergic reactions can occur if they later inhale even small quantities [ ].

Lymphangitis after tuberculin testing is rare; twelve such reactions were reported during 1979–83 [ ].

Acute panuveitis has been reported [ ]. The episodes developed after each of two tests carried out at intervals of 8 years and responded well to glucocorticoid therapy.

Organs and systems

Cardiovascular

A mycotic aneurysm, a rare complication of intravesical BCG therapy, has been reported [ ].

A 71-year-old man with bladder carcinoma in situ received six instillations of BCG at weekly intervals followed 3 months later by three booster instillations at weekly intervals. Four months later an inflammatory aortic aneurysm, which had ruptured into a pseudoaneurysm, was diagnosed and excised. Mycobacterium bovis was found. After treatment with isoniazid and rifampicin he recovered. There was no sign of tumor in the bladder at cystocopy 8 months after the last BCG instillation.

Respiratory

There have been two reports of micronodular pulmonary infiltrates (BCG pneumonitis) associated with fever, chills, and night sweats following multiple instillations of intravesical BCG [ ]. Both patients were 71 years old. The reactions, including radiographic infiltrates, resolved spontaneously or after steroid therapy.

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