ElectroMotive drug administration (EMDA) of Mitomycin C as first-line salvage therapy in high risk “BCG failure” non muscle invasive bladder cancer: 3 years follow-up outcomes

Abstract

BackgroundIn case of high grade non-muscle invasive bladder cancer (HG-NMIBC), intravesical BCG represents the first-line treatment; despite the “gold” standard therapy, up to 50% of patients relapse, needing radical cystectomy. Hence, alternative therapeutic strategies have been developed. The aim of the study was to evaluate a first-line salvage treatment with EMDA®-MMC in patients with HGNMIBC unresponsive to BCG.MethodsWe carried out a prospective, single-center, single-arm Phase II study in order to evaluate the efficacy (in terms of recurrence and progression) and the safety of the EMDA®-MMC treatment in 26 (21 male, 5 female) consecutive patients with “BCG refractory” HGNMIBC on a 3 years follow-up.EMDA®-MMC treatment consisted of 40 mg of MMC diluted in 100 ml of sterile water retained in the bladder for 30 min with 20 mA pulsed electric current.EMDA®-MMC regimen consisted of an induction course of 6 weekly instillations followed by a maintenance course of 6 monthly instillations.Follow-up was performed with systematic mapping biopsies of the bladder (with sampling in the prostatic urethra for men), voiding and washing urinary cytology, radiological study of the upper urinary tract.We performed Survival Kaplan-Meier curves and Log-rank test in order to analyze high grade disease-free survival.ResultsAt the end of follow-up, 16 patients (61.5%) preserved their native bladder; 10 patients (38.4%) underwent radical cystectomy, in 6 patients (23.1%) for recurrent HGNMIBC and in 4 patients (15.4%) for progression to muscle-invasive disease.At the end of follow-up, stratifying patients based on TNM classification (TaG3, T1G3, Cis, TaT1G3 + Cis), disease-free rates were 75, 71.4, 50 and 25%, respectively; survival curves showed statistically significant differences (p value < 0.05).Regarding toxicity, we reported severe adverse systemic event of hypersensitivity to the MMC in 3 patients (11.5%), and local side effects in 6 patients (26.1%).ConclusionsIn the field of alternative strategies to radical cystectomy, the EMDA®-MMC could be considered safe and effective in high-risk NMIBC unresponsive to BCG, as a “bladder sparing” therapy in selected patients. Multicenter studies with a larger number of patients and a longer follow-up might confirm our preliminary results.Trial registrationEudraCT2017-002585-43. 17 June 2017 (retrospectively registered).

<p>Bacillus Calmette-Guérin (BCG) Therapy for Bladder Cancer: An Update</p>

“…79 Another possible solution to improve treatment delivery is electromotive administration to penetrate deeper into the tissue through an electrode while transporting the drug by iontophoresis. Despite encouraging results demonstrating the increased penetration of the drug using this technique, and the confirmation of excellent oncologic efficacy in high-risk BCG-unresponsive NMIBC patients, [80][81][82] tolerability is still a challenge. As in other types of cancer, photodynamic therapy was also tested, [83][84][85][86] but the efficacy of this treatment modality should be explored further in clinical trials.…”

BCG-unresponsive high-grade non-muscle invasive bladder cancer: what does the practicing urologist need to know?

“…An RCT of BCG-naïve NMIBC reported a significantly higher 24-mo recurrence-free survival (RFS) in RITE-treated patients than in those treated with BCG in per-protocol analysis [30]. [35]. At the end of a 3-year follow-up, diseasefree rates of patients with TaG3, T1G3, Cis and TaT1G3 + Cis were 75, 71.4, 50 and 25%, respectively.…”

“…However, its specific role in the BCG-unresponsive setting needs to be elucidated. Racioppi and coworkers published in 2018 the results of a prospective, single-center, single-arm phase II study evaluating a first-line salvage treatment with EMDA ® -MMC in 26 patients with high-grade NMIBC “unresponsive” to BCG [ 35 ]. At the end of a 3-year follow-up, disease-free rates of patients with TaG3, T1G3, Cis and TaT1G3 + Cis were 75, 71.4, 50 and 25%, respectively.…”

Canadian Urological Association guideline on the management of non-muscle invasive bladder cancer

“…c) Device-assisted therapy Device-assisted therapy was also tested in the setting of BCG-unresponsive disease. Racioppi et al recently published the results of a phase II single-arm study on 26 patients using EMDA-MMC (induction and maintenance) for high-risk NMIBC who failed BCG therapy 311 . Median followup was 36 months and HG disease-free rate was 61.5% 311 .…”