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 hematuria9. 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


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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 genito-urinary group randomized phase III trial. J Urol, 166: 476, 2001


15. 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