SummaryBackground The rationale for combining anticancer drugs has not been applied consistently to use of intravesical agents for treatment of superficial bladder cancer, for which immunotherapeutic BCG and chemotherapeutic mitomycin seem to be a potentially effective combination. We aimed to do a prospective, randomised comparison of BCG alone with that of sequential BCG and electromotive mitomycin in patients with stage pT1 bladder cancer.Methods After transurethral resection and multiple biopsies, 212 patients with stage pT1 bladder cancer were randomly assigned to: 81 mg BCG infused over 120 min once a week for 6 weeks (n=105); or to 81 mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical electric current 20 mA for 30 min) once a week as one cycle for three cycles (n=107). Complete responders underwent maintenance treatment: those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG and mitomycin had 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles. The primary endpoint was disease-free interval; secondary endpoints were time to progression; overall survival; and disease-specific survival. Analyses were done by intention to treat. This trial has been submitted for registration at the US National Cancer Institute website http://clinicaltrials.gov. Findings

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Purpose: In laboratory studies electromotive mitomycin C (MMC) demonstrated markedly increased transport rates compared with passive transport. We performed a prospective study in patients with high risk superficial bladder cancer to assess the efficacy of intravesical electromotive vs passive MMC using bacillus Calmette-Guerin (BCG) as a comparative treatment.Materials and Methods: Following transurethral resection and multiple biopsies 108 patients with multifocal Tis, including 98 with T1 tumors, were randomized into 3 equal groups of 36 each who underwent 40 mg electromotive MMC instillation with 20 mA electric current for 30 minutes, 40 mg passive MMC with a dwell time of 60 minutes or 81 mg BCG with a dwell time of 120 minutes. Patients were scheduled for an initial 6 weekly treatments, a further 6 weekly treatments for nonresponders and a followup 10 monthly treatments for responders. Primary end points were the complete response rate at 3 and 6 months. MMC pharmacokinetics were assessed.Results: The complete response for electromotive vs passive MMC at 3 and 6 months was 53% versus 28% (p ϭ 0.036) and 58% versus 31% (p ϭ 0.012). For BCG the responses were 56% and 64%. Median time to recurrence was 35 vs 19.5 months (p ϭ 0.013) and for BCG it was 26 months. Peak plasma MMC was significantly higher following electromotive MMC than after MMC ((43 vs 8 ng/ml), consistent with bladder content absorption.Conclusions: Intravesical electromotive administration increases bladder uptake of MMC, resulting in an improved response rate in cases of high risk superficial bladder cancer. Intravesical anticancer therapy is appropriate treatment for high risk superficial bladder cancer even if the ultimate long-term benefits are in doubt. 4 Investigators have described superior results with intravesical bacillus CalmetteGuerin (BCG) compared with chemotherapeutic drugs and they also attributed more numerous and more severe side effects to BCG. 5A chemotherapeutic agent that has withstood the test of time is mitomycin C (MMC) but evaluation of its clinical efficacy is difficult because so many investigators have used widely varying MMC doses, concentrations, instillation volumes and residence times, usually in heterogeneous patient populations. However, as early as 1993 Wientjes et al combined data from laboratory, animal and human studies with computer simulations to describe a compelling MMC regimen primarily based on optimizing diffusion down concentration gradients (Fick's first law). 6 The same group followed up with a study showing the advantages of increased concentration gradients in animals and humans 7 and then reported a phase III trial, in which the optimized regimen proved superior to a standard MMC regimen in patients with Ta grade I/II bladder cancers.8 However, results in subgroups with Tis, grade III and T1 disease were less definitive, although trends toward improvement were discernible. Therefore, it must be assumed that there are several reasons for the many failures that occur using intravesica...

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