Immunotherapy
Bacille Calmette-Guerin
Morales et al. first reported the benefits of intravesical Bacille Calmette-Guerin using six weekly installations of approximately 10 cultures. This six-dose installation became the standard regimen although it appears chance alone gave Morales the opportunity to use six installations. A 60% response rate in papillary disease was reported and this has been consistently confirmed. Although useful in papillary disease, its greatest benefit is in the treatment of primary carcinoma in situ, an uncommon disease in this form although appearing much more commonly associated with aggressive papillary tumours as secondary carcinoma in situ. In the pure disease, as reported by Herr et al., in excess of 70% response rates are achieved but longer follow-ups have shown that there is a late relapse rate and lifelong follow-up in patients who have achieved a response is mandatory.
Although effective Bacille Calmette-Guerin is associated with a high incidence of both local and systemic side-effects including mortality, much of this appeared to be in the early days of its usage when it was instilled early into bladders in which resections had occurred and undoubtedly there was a systemic absorption that gave rise to BCGosis. After enforcement of a policy of requiring a minimum 2-week delay between resection and the initiation of intravesical Bacille Calmette-Guerin therapy, the rate of side-effects and especially the serious systemic side-effects have significantly reduced, although local toxic side-effects remain.
The second innovation has been the suggestion that maintenance, i.e. continuing top-up Bacille Calmette-Guerin advocated by Lamm, has a better overall efficiency than just a single course. In Lamm’s original discussion two to three additional top-up doses of Bacille Calmette-Guerin are used every 3-6 months over an 18/24-month period and there is some evidence that this regimen although difficult and susceptible to a high dropout rate of patients does seem to have some effect in limiting progression of the disease to invasive disease. The comparative benefits of Bacille Calmette-Guerin versus intravesical chemotherapeutic agents have been the subject of several studies and are discussed below.
Interferon-alpha
It is a naturally occurring biological protein with both antiviral and antiprlific properties. Toxicity appears to be limited to mild flu-like symptoms and most studies of interferon have been with interferon-alpha in phase I and II, mostly in carcinoma in situ. Although its use as a prophylactic agent has been reported with some benefits, its utility has not been demonstrated almost certainly because of the difficulty in obtaining it as an agent and the ready accessibility and utility of Bacille Calmette-Guerin. The use of interferon alpha in combination with Bacille Calmette-Guerin and also with mitomycin C has been explored with benefit in small phase II studies.
Keyhole limpet haemocyanin
Keyhole limpet haemocyanin is a protein of the mollusc Megathura crenulata and is a highly immunogenic protein. It was used for many years as an experimental antigen in the study of delayed hypersensitivity Olsson first noted a marked reduction in papillary tumour recurrence among patients that had been immunized with subcutaneous Keyhole limpet haemocyanin and he then performed a small prospective trial confirming the apparent anti-tumour effect of Keyhole limpet haemocyanin in 1972 and 1974, and in 1988 Jurinic showed its benefits in a small randomized trial, with a recurrence rate of only 14% in the Keyhole limpet haemocyanin arm compared with 39% in the mitomycin C arm.
It has been this author’s frustrating experience that this agent has been virtually unobtainable for further studies in intravesical chemotherapy. Concluding from both the original work of Olsson et al. and the one small trial it is at least equivalent to Bacille Calmette-Guerin and probably more effective with less side-effects and yet remains frustratingly unavailable. It is an agent about which future comparative studies should and must be made.