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Administration of BCG with Modifications to Minimize
Local and Systemic Toxicity
Marc C. Smaldone
Fellow in Urologic Oncology, Fox Chase Cancer Center
for
Introduction
BCG, an attenuated mycobacterium developed as a vaccine for tuberculosis, has
been shown to have significant anti-tumor activity in patients with non-muscle invasive
bladder cancer, and is the most effective intravesical agent at reducing recurrence and
disease progression for patients with non-muscle invasive bladder cancer with high risk
features (high grade disease, lamina propria involvement, carcinoma in situ)1-5. BCG is
stored in refrigeration and reconstituted from a lyophilized powder. The Connaught,
Tice, Armand Frappier, Pasteur, Tokyo, and RIVM strains all arise from a common
original strain developed at the Pasteur Institute. Despite differing dosages, a recent
meta-analysis suggests similar efficacy with all commercially available strains4.
Duration of Induction and Maintenance Therapy
Initiation of induction BCG therapy is usually delayed for two to three weeks
following transurethral resection (TUR) to allow for healing of the urothelium and to
reduce the risk of systemic side effects from translocation of live vaccinia. Dosing varies
between strains, but recent evidence suggests that a three fold reduction in dose may
be equally efficacious with significantly reduced toxicity6. Absolute contraindications to
therapy are primarily due to risk of systemic dissemination and include
immunosuppressed/compromised patients, immediate treatment following TUR,
personal history of BCG sepsis, gross hematuria, traumatic catheterization, and total
incontinence due to inability to retain the agent. Relative contraindications include
urinary tract infection, liver disease, history of tuberculosis, advanced age, and poor
overall performance status7.
The optimal treatment schedule and dose for BCG have not been established.
Traditionally per Morales original description8, induction therapy consists of 6 weekly
instillations, although there is little contemporary evidence to support this dosing
schedule. In the event of a traumatic catheterization, therapy should be delayed for an
additional 4-7 days. The vaccine is reconstituted with 50 mL of saline and should be
administered through a urethral catheter under gravity drainage, with a standard dwell
time (duration of retention) of 1-2 hours. Reducing dwell time to less than 30 minutes
has been described as an alternative to dose reduction in patients with severe local
toxicity9. Some clinicians have advocated the patient turn from side to side increase
total urothelial contact time, but there is currently no evidence to suggest that this
increased efficacy. Fluid, diuretic, and caffeine restriction has been recommended to
increase agent concentration and to facilitate retention of the agent for up to 2 hours.
Oral desmopressin given prior to administration has also been suggested, although this
also lacks convincing evidence7.
Maintenance therapy has been described as a crucial adjunct to induction
therapy to most effectively reduce risk of recurrence and progression4. The most
commonly utilized maintenance regimen (SWOG protocol) consists of three weekly
treatments administered at 3 months and 6 months post induction therapy, and then
every 6 months for up to 3 years10. However, prolonged BCG treatment can increase the
risk of BCG toxicity, particularly in older and immunocompromised patients, and of the
243 patients in the SWOG study only 16% tolerated the full dose schedule. It is currently
unclear at which point the maximum effect is obtained, and shorter regimens may
ultimately achieve similar results with less toxicity.
Managing Local and Systemic Toxicity of BCG
Local and systemic side effects following the administration of BCG can lead to
treatment cessation in 20-30% of patients, and can lead to the reduction in the number
of treatments or delay in therapy in as many as 50-80% of patients11. According to a
recent EORTC trial, the risks of local and systemic adverse events are highest during the
six months of treatment12. Although considerable variation in reporting of adverse
events exists in the contemporary body of literature, strain virulence, allergic reactions,
and concomitant urinary tract infection have been associated with increased risk of
toxicity, the most common of which is flu-like symptoms and low grade fevers. Should
fever and malaise continue for greater than 48 hours despite anti-pyretic therapy,
intravesical therapy should be discontinued and the patient should be evaluated for a
bacterial urinary tract infections or signs of systemic BCG sepsis. While diagnostic tests
such as chest radiograph, liver function tests, and urine/blood cultures are pending,
treatment should be initiated with antimicrobial agents (most commonly
flouroquinolones) and/or anti-tuberculosis agents (isoniazid and rifampicin) until
symptoms resolve. If symptoms resolve quickly, a dose reduction can be considered
when therapy is resumed7. Should a more severe infection be suspected, adding
Ethambutol and steroids in select cases as adjuncts to prompt admission and supportive
resuscitation may be necessary. Infectious disease consultation with a physician
experienced in management of mycobacterial infections/complications should be
considered as well. Although not as efficacious at preventing recurrence or progression,
in select patients intolerant of BCG, intravesical chemotherapeutic agents such as
Mitomycin C (MMC) may be attractive alternatives due to reduced side effect profiles in
large meta-analyses 13.
Maneuvers to Reduce BCG Toxicity
To summarize, several attempts to reduce the toxicity of BCG without
compromising its efficacy have been investigated. These include the concomitant
treatment with a fluoroquinolone or single anti-tuberculosis therapy, reducing the
treatment BCG dosage, reducing the individual treatment dwell time, and addition of
other immunomodulating agents or anti-pyretic therapy11. Although simultaneous
treatment with isoniazid was initially received with enthusiasm, it was not shown to
effectively reduce local toxicity in a prospective trial14. Antibiotic therapy may have a
beneficial effect in treating or preventing systemic side effects of BCG therapy, yet it
may also inhibit the effectiveness of BCG therapy if it is given routinely for urinary tract
prophylaxis during a course of BCG therapy. In a recent clinical trial, the administration
of Ofloxacin, a fluoroquinolone with tuberculostatic properties, was successful in
improving compliance with BCG therapy without impairing effectiveness up to two
years15. Reducing the dosage of individual BCG strains, summarized nicely in a recent
review article (Table I) by Gontero et al., can be applied in select cases without an
appreciable reduction in effectiveness11. As an alternative to dose reduction, a recent
study demonstrated that a reduction in dwell time to less than 30 minutes resulted in a
reduction in chills, fever, and dysuria but no change in frequency or hematuria 9. Other
methods such as prolonging the interval between dosing or number of doses per cycle
have been less rigorously evaluated in the literature. In the significant proportion of
patients who cannot tolerate BCG (up to one third), these maneuvers may prove useful
prior to stopping therapy outright or choosing an alternative chemotherapeutic agent.
References
1.
Bohle, A., Bock, P. R.: Intravesical bacille Calmette-Guerin versus
mitomycin C in superficial bladder cancer: formal meta-analysis of comparative
studies on tumor progression. Urology, 63: 682, 2004
2.
Shelley, M. D., Court, J. B., Kynaston, H. et al.: Intravesical bacillus
Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer. Cochrane
Database Syst Rev: CD003231, 2003
3.
Shelley, M. D., Court, J. B., Kynaston, H. et al.: Intravesical Bacillus
Calmette-Guerin in Ta and T1 Bladder Cancer. Cochrane Database Syst Rev:
CD001986, 2000
4.
Sylvester, R. J., van der, M. A., Lamm, D. L.: Intravesical bacillus CalmetteGuerin reduces the risk of progression in patients with superficial bladder
cancer: a meta-analysis of the published results of randomized clinical trials. J
Urol, 168: 1964, 2002
5.
Sylvester, R. J., van der Meijden, A. P., Witjes, J. A. et al.: Bacillus
calmette-guerin versus chemotherapy for the intravesical treatment of patients
with carcinoma in situ of the bladder: a meta-analysis of the published results of
randomized clinical trials. J Urol, 174: 86, 2005
6.
Martinez-Pineiro, J. A., Martinez-Pineiro, L., Solsona, E. et al.: Has a 3-fold
decreased dose of bacillus Calmette-Guerin the same efficacy against
recurrences and progression of T1G3 and Tis bladder tumors than the standard
dose? Results of a prospective randomized trial. J Urol, 174: 1242, 2005
7.
Jones, S. J., Campbell, S. C.: Non-Muscle Invasive Bladder Cancer (Ta,T1,
and CIS). In: Campbell-Walsh Urology, 9th edition. Edited by A. J. Wein, L. R.
Kavoussi, A. C. Novick et al.: Saunders, pp. 2447-2467, 2006
8.
Herr, H. W., Morales, A.: History of bacillus Calmette-Guerin and bladder
cancer: an immunotherapy success story. J Urol, 179: 53, 2008
9.
Andius, P., Fehrling, M., Holmang, S.: Intravesical bacillus CalmetteGuerin therapy: experience with a reduced dwell-time in patients with
pronounced side-effects. BJU Int, 96: 1290, 2005
10.
Lamm, D. L., Blumenstein, B. A., Crissman, J. D. et al.: Maintenance
bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in
situ transitional cell carcinoma of the bladder: a randomized Southwest
Oncology Group Study. J Urol, 163: 1124, 2000
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Gontero, P., Bohle, A., Malmstrom, P. U. et al.: The role of bacillus
Calmette-Guerin in the treatment of non-muscle-invasive bladder cancer. Eur
Urol, 57: 410, 2009
12.
Sylvester, R. J., van der Meijden, A. P., Oosterlinck, W. et al.: The side
effects of Bacillus Calmette-Guerin in the treatment of Ta T1 bladder cancer do
not predict its efficacy: results from a European Organisation for Research and
Treatment of Cancer Genito-Urinary Group Phase III Trial. Eur Urol, 44: 423, 2003
13.
Shelley, M. D., Wilt, T. J., Court, J. et al.: Intravesical bacillus CalmetteGuerin is superior to mitomycin C in reducing tumour recurrence in high-risk
superficial bladder cancer: a meta-analysis of randomized trials. BJU Int, 93: 485,
2004
14.
van der Meijden, A. P., Brausi, M., Zambon, V. et al.: Intravesical
instillation of epirubicin, bacillus Calmette-Guerin and bacillus Calmette-Guerin
plus isoniazid for intermediate and high risk Ta, T1 papillary carcinoma of the
bladder: a European Organization for Research and Treatment of Cancer genitourinary group randomized phase III trial. J Urol, 166: 476, 2001
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Colombel, M., Saint, F., Chopin, D. et al.: The effect of ofloxacin on
bacillus calmette-guerin induced toxicity in patients with superficial bladder
cancer: results of a randomized, prospective, double-blind, placebo controlled,
multicenter study. J Urol, 176: 935, 2006
Marc C. Smaldone, MD
Fellow in Urologic Oncology, Fox Chase Cancer Center