Intravesical bacillus Calmette-Guérin (BCG) therapy is highly effective for managing high-risk non-muscle-invasive urothelial carcinoma of the bladder, with complete response rates at times as high as 83 percent. However, recurrence may occur within a year in up to half of patients with high-risk disease, and within five years in as many as 90 percent of these patients. BCG failure is also associated with an approximately 50 percent chance of disease progression and poor prognosis.
Radical cystectomy is the standard treatment when intravesical BCG therapy fails. However, despite good overall health-related quality of life postoperatively, patients are sometimes reluctant to undergo major surgery for a condition that does not pose an immediate threat. Nor is radical cystectomy suitable for the subset of patients with severe co-morbidities.
Intravesical valrubicin is the only agent approved by the Food and Drug Administration for such patients. It is a modestly active agent in this setting, with a 21 percent complete response rate reported in a phase II study, and a one-year durable complete response of 13 percent.(1) It is infrequently used in the urologic community because of the significant local toxicity and short durability of the response.
At Memorial Sloan Kettering we found the chemotherapy drug gemcitabine given twice weekly to be associated with minimal bladder irritation and tolerable myelosuppression. We proceeded with a phase II study, documenting a complete response rate of 50 percent. However, the one-year durable complete response rate was only 10 percent.(2)
The mTOR inhibitor everolimus (Afinitor®) has been shown to inhibit protein synthesis and growth of bladder cancer cells in vitro and is efficacious in treating bladder cancer cells in vivo. The mTOR inhibitors have also shown synergism with gemcitabine in pancreatic cancer cell lines, supporting the concept of combination therapy using everolimus with intravesical gemcitabine.
Clinical Trial: Gemcitabine plus Everolimus
After completing a phase I study of intravesical gemcitabine in combination with everolimus that indicated minimal toxicity, we proceeded to enroll patients in a phase II study of intravesical gemcitabine given twice weekly for two weeks. This is followed by a week of rest and a second cycle in combination with oral everolimus for 12 consecutive months.
Preliminary data are encouraging, showing activity of this combination in patients with BCG-refractory bladder cancer.