Patients who failed ZVADFMK therapy immediately, failed in less than 12 months, or had 2 or more failures have an intermediate response to BCG and interferon. Those patients who failed BCG therapy more than once and within a short period fare poorly

with this treatment and should consider an alternative therapy. Newer Agents: Gemcitabine and Valrubicin Gemcitabine Gemcitabine (2′,2′-difluorodeoxycytidine) is a novel deoxycytidine analogue with a broad spectrum of antitumor activity. After transport into the cell, it is phosphorylated and incorporated into RNA and DNA, causing inhibition of cell growth and triggering Inhibitors,research,lifescience,medical apoptosis. Gemcitabine has shown efficacy when used systemically against advanced

bladder cancers with single-agent responses in the range of 27% to 38%. Gemcitabine appears to be relatively safe at concentrations of 40 mg/ Inhibitors,research,lifescience,medical mL (2000 mg/50 mL) and can be held in the bladder for up to 2 hours with minimal transient systemic absorption and low detectible levels of active metabolites. Early single intravesical instillation appears feasible, with the caveat of avoiding instillation if there is a bladder perforation. In an open-label trial examining prophylactic use of intravesical gemcitabine, Inhibitors,research,lifescience,medical Bartoletti and colleagues8 followed 116 patients with noninvasive intermediate-risk and high-risk Inhibitors,research,lifescience,medical bladder cancer (Ta, T1, and CIS) given 2000 mg/50 mL in weekly instillations for

6 weeks. Based on the European Organization on the Research and Treatment of Cancer (EORTC) risk stratification, intermediate-risk patients had about a 26% recurrence rate (21/81 recurred, 2 progressed), and high-risk patients had about 77% (27/35 recurred, 5 progressed). This regimen worked better in lower-risk patients, patients with first-time tumors (P = .04), and patients who had no prior therapy (P = .03). Toxicity was relatively low. The most frequently reported toxicity was urgency (14/116, 12%), followed by dizziness and slight fever (6/116, 5%). Inhibitors,research,lifescience,medical Gemcitabine has also been studied in BCG-refractory patients. In the Bartoletti study cited earlier, 18 out of 24 (75%) intermediate-risk and 7 out of 16 (43.7%) high-risk BCG-refractory patients achieved CR.8 Dalbagni STK38 and colleagues conducted a phase II study using a more intensive, twice-weekly administration in 30 BCG-refractory patients.9 With median follow- up of 19 months (range, 0-35), 15 of the 30 (50%) had an initial CR. However, 12 out of 15 (80%) had recurrence, with a median recurrence-free survival of 3.6 months. Eleven of the 30 (37%) eventually went on to cystectomy. Valrubicin Valrubicin is US Food and Drug Administration (FDA)-approved for intravesical treatment of BCG-refractory CIS of the bladder.