Commentary (Morales): BCG Immunotherapy for Transitional-Cell Carcinoma in Situ of the Bladder

Very few people have the level of expertise Dr. Lamm does with the use of bacillus Calmette-Guérin (BCG) for the treatment of superficial bladder cancer. His enthusiasm is based on a large, solid experience with the vaccine. He has pushed the therapeutic effectiveness of BCG to new levels and has reviewed the world literature on the subject frequently and conscientiously. The current review covers most areas of interest in depth. A few key points deserve emphasis, however.

Is BCG Really the Best Available Option?

There is little controversy that BCG is the best therapeutic option for a bladder harboring carcinoma in situ (CIS). The accepted wisdom is that BCG is the first line of treatment for CIS. However, once past initial treatment, a different view has been and is being vigorously presented by proponents of cytotoxic chemotherapy, who believe that several other agents are equally effective in the treatment of residual disease and the prevention of recurrence and cause less toxicity than BCG.

Although the arguments from both camps are credible and well supported, a number of factors must be considered when evaluating these two very different therapies. Treatment implies that a tumor is present at the time of drug administration, as is the case with CIS, for which BCG is clearly superior to other available therapies. But how about the other major problem with this disease, namely, prophylaxis against recurrence after adequate resection of a superficial papillary lesion? Both thiotepa (Thiotepa) and doxorubicin exhibit antitumor activity, but they appear to be inferior to mitomycin (Mutamycin). This leaves only mitomycin and BCG as contenders for first-line therapy.

With regard to the relative effectiveness of these two agents, the opinions are divergent: An American trial [1] clearly demonstrated the superiority of BCG, whereas a Dutch study [2] showed equivalent effectiveness of the two agents for prophylaxis against recurrent papillary tumors. After reviewing the literature, one can conclude that, in patients with a high risk of recurrence and in treating CIS, the newer regimens of BCG therapy (ie, the "6 plus 3" schedule devised by Dr. Lamm) achieve superior responses [3]. Among the chemotherapeutic agents, mitomycin is the most effective drug, and it has less toxicity than full doses of BCG. In North America, cost represents a significant disadvantage for mitomycin.

Induction Alone vs Maintenance Regimens

The concept that a 6-week treatment period of BCG is suboptimal is now widely accepted. What remains to be established is the most appropriate course of maintenance. Dr. Lamm deserves credit for the "6 plus 3" schedule, which has significantly improved the effectiveness of BCG therapy. He has developed this schedule based on sound immunologic grounds.

Searching for the Most Appropriate Dose

Sporadic attempts have been made to determine the most appropriate dose of BCG. Preliminary evidence suggests that the doses currently used may not be necessary in most cases and that much lower amounts (one-half to one-third) may be equally effective with a significant decrease in toxicity. Full doses may be required only for the more anaplastic tumors. Further study is needed to confirm these views.

On the Toxicity of BCG

As with most antineoplastic agents, careful administration of BCG is essential to avoid serious toxicity. Most side effects of the vaccine are mild and self-limiting. Serious toxicity is rare, and its occurrence is frequently associated with traumatic catheterization or the presence of a disrupted urothelium leading to intravascular dissemination. Physicians using BCG must be familiar with the regimen described by Dr. Lamm since these serious toxic reactions may occur rapidly and demand prompt, vigorous treatment.

Alternative Forms of Immunotherapy

Dr. Lamm discusses those biologic-response modifiers that have at least reached the level of clinical investigation. Although bropirimine and interferon-alfa have shown significant antitumor activity in preventing recurrence and in treating CIS, they have not achieved the degree of efficacy seen with BCG.

A burning issue is the synergism that these and other compounds may exhibit at reduced doses. The observation that failure to respond to BCG does not preclude a good response to cytotoxic chemotherapy, and vice versa, is expected since their mechanisms of antineoplastic activity are completely different. On the other hand, it is surprising that complete responses to interferon are observed after failure of BCG treatment. Trials aimed at determining whether or not synergism exists between BCG and other biologic-response modifiers would be of significant clinical consequence.

On the Mechanism of Action of BCG

A great deal has been learned about the effector mechanisms of the vaccine in the treatment of bladder cancer. There is no doubt that intravesical administration of BCG elicits a true immunologic response. Much less is known, however, about the components of the mycobacteria responsible for its activity. For instance, is the waxy capsule the fundamental inducer? If so, why are live bacteria needed? Will the therapeutic effect be preserved with the simultaneous administration of the vaccine and antituberculous medication (given in an effort to diminish toxicity)? Answers to these questions are relevant not only because they would improve our current approach to bladder cancer but also because they may allow for the use of BCG in other malignancies.

Megadoses of Vitamins and Bladder Cancer

Dr. Lamm has strenuously advocated the use of megadoses of certain vitamins in the prevention of recurrence and as enhancers of immunotherapy. Although the concept is not new, the beneficial effects of this therapy remain purely speculative. Dr. Lamm and others have argued that the inherent risks of taking large doses of vitamins are few and most are not serious. While this view is sensible, megadose vitamin therapy needs to be tested further before accepting it simply on the basis that if it does not help it does not cause harm either.

References:

1. Lamm DL, Crawford ED, Blumenstein B, et al: SWOG 8795: A randomized comparison of bacillus Calmette-Guerin and mitomycin C prophylaxis in stage Ta and T1 transitional cell carcinoma of the bladder (abstract). J Urol 149:282A, 1993.

2. Vegt PDJ, Witjes JA, Wim PJ, et al: A randomized study of intravesical mitomycin C, bacillus Calmette-Guerin Tice and bacillus Calmette Guerin RIVM treatment in pTa-pT1 papillary carcinoma and carcinoma in situ of the bladder. J Urol 153:929-933, 1995.

3. Lamm DL: Bladder cancer: Improving patient selection and treatment. J Urol 153:942-943, 1995.