Intravesical Electromotive Mitomycin C Versus Passive Transport Mitomycin C for High Risk Superficial Bladder Cancer: A Prospective Randomized Study

Abstract

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...

Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: a randomised controlled trial

“…As reported elsewhere, 15 intravesical EMDA increases bladder uptake of mitomycin, improving effi cacy in highrisk non-muscle invasive bladder cancer, compared with passive mitomycin transport. Our fi ndings suggest that high mitomycin concentrations in bladder tissue destroyed or inhibited implantation of viable cancer cells that could have been released during TURBT and thus reduced the recurrence rate of non-muscle invasive bladder cancer, with no long-term loss of treatment effi cacy.…”

“…A major concern about the design of our study is not having a group in receipt of intravesical PD mitomycin before TURBT. However, laboratory 15 and clinical 16 studies showed that mitomycin concentrations in the bladder-wall tissues were signifi cantly increased by applying pulsed electric current (EMDA). Higher drug concentrations might have a clinical eff ect since intravesical EMDA mitomycin was associated with a lower recurrence rate than PD mitomycin.…”

“…For immediately pre-TURBT intravesical EMDA mitomycin, about 30 min before spinal or general anaesthesia TURBT patients received 40 mg mitomycin dissolved in 100 mL sterile water, 15,18 infused intravesically through the Foley catheter by gravity and retained in the bladder for 30 min, while 20 mA pulsed electric current for 30 min was given externally. The mitomycin solution was drained and TURBT was done, subsequently continuous intravesical irrigation with saline for 8-18 h, to prevent clot formation or retention and related complications.…”

“…However, disagreement persists despite level 1 evidence supporting its use, [8][9][10][11][12] and it is rarely given by urologists. 13 In laboratory 14 and clinical studies, 15 intravesical electromotive drug administration (EMDA) increased mitomycin bladder uptake, improving clinical effi cacy in high-risk non-muscle invasive bladder cancer. Intravesical EMDA mitomycin is not recommended immediately after TURBT because catheter electrode rigidity might cause additional mechanical trauma and urothelial injury, leading to bladder spasm and leakage of drug solution.…”

An Individual Patient Data Meta-Analysis of the Long-Term Outcome of Randomised Studies Comparing Intravesical Mitomycin C versus Bacillus Calmette-Guérin for Non–Muscle-Invasive Bladder Cancer

“…In total, nine trials were identified, and IPD were obtained from all studies [10][11][12][13][14][15][16][17][18], the main characteristics of which are shown Table 1.…”