Drs. Baselli and Greenberg have produced a comprehensive review of the literature concerning current maintenance regimens in the therapy of superficial transitional cell carcinoma of the bladder, the most effective intravesical agents, and the relative merits of bacillus Calmette-Guérin (BCG) and chemotherapy.
This is a very complex and confusing topic, and there are a multitude of studies that suggest the benefits and potential complications of each treatment. The majority of these studies include relatively few patients, a variety of tumor stages and grades, and often insufficient follow-up. The authors have done a commendable job in their article; however, it is debatable whether adjuvant intravesical chemotherapy offers any long-term benefit or alters the natural history of bladder cancer.
Large Studies of Intravesical Chemotherapy
In 1994, Traynelis and Lamm analyzed data from 23 controlled clinical trials involving more than 4,000 patients and confirmed that the average net benefit from intravesical chemotherapy, compared to transurethral resection alone, was only 14% at 1 to 3 years. Furthermore, the therapeutic arms (thiotepa [Thioplex], doxorubicin(Drug information on doxorubicin), and mitomycin(Drug information on mitomycin) [Mutamycin]) reported a 5-year recurrence rate that equaled or exceeded that of the control arms. These findings were supported by the Medical Research Council and the European Organization for Research and Treatment of Cancer (EORTC) when they performed an analysis of randomized clinical trials for a variety of chemotherapeutic agents. No clear advantage concerning progression, time to metastases, progression-free survival, and survival was noted at a median of 7.8 years. Only the disease-free survival duration was better in the treatment arms.
Finally, the Southwest Oncology Group (SWOG) study comparing mitomycin to intravesical BCG was closed at the first interim analysis because the BCG regimen was clearly superior in terms of recurrence rate and prolongation of time to recurrence. The findings of these very large reviews would not support Baselli and Greenberg’s views concerning chemotherapy.
Pros and Cons of BCG Maintenance Therapy
This article makes a good case for the benefits of BCG maintenance therapy. However, it should be emphasized that the role of maintenance chemotherapy is controversial. Similar results have been reported from either early single-dose chemotherapy or maintenance chemotherapy protocols; but no enhancement has been evident when both are combined. Clearly, the large cost issues underlying these findings need to be considered when long-term treatment strategies are planned.
As Baselli and Greenberg expound, BCG has a clearly established role as a maintenance therapy protocol. However, they offer little discussion of options for patients in whom either induction or maintenance therapy fails. Clearly, radical cystectomy remains a definite option, yet among those in whom an initial induction course fails, a further 39% of patients will become disease free after a second 6-week course. The value of a second induction course for relapsing patients on maintenance BCG has not been reported.
The tolerability of BCG also deserves further consideration. Rather than placing an intolerant patient on mitomycin, it would perhaps be preferable to initiate a reduced-dose or slow-rate regimen of BCG, as has recently been reported by Bassi et al.
Interferon Alfa-2b/BCG for Bladder Cancer
I do not feel a review of this topic is complete without a discussion of interferon alfa-2b(Drug information on interferon alfa-2b) (Intron A) and the impressive results being reported for its combination with BCG in high-risk primary and relapsing patients. This regimen has been developed due to reported evidence of synergistic activity between these two agentsthe fact that they are biocompatible and can be instilled simultaneously, and that by combining interferon alfa-2b with a markedly reduced dose of BCG, toxicity can be reduced while anticancer efficacy is maintained. This regimen is an effective alternative for patients at high risk of disease recurrence and/or progression in whom BCG therapy has previously failed. With this regimen, a 56% disease-free survival has been reported at 24 months.
Currently, a multiphase 11-registry trial and at least two randomized trials are ongoing. They will hopefully support these initial results and establish this regimen as an option for both induction and maintenance therapy of primary and recurrent superficial bladder cancer.