Research Article|Articles in Press

Sequential treatment with Bacillus Calmette-Güerin (BCG) and mitomycin C administered with Electromotive Drug Administration (EMDA) in patients with high-risk non-muscle invasive bladder cancer after BCG failure

Published:March 16, 2023DOI:
      • What is already known about this subject?



      Nowadays, there is no standard non-surgical treatment for patients with non-muscle invasive bladder cancer (NMIBC) in whom Bacillus Calmette-Güerin (BCG) therapy has failed.


      to assess the clinical and oncological outcomes of sequential treatment with BCG and Mitomycin C (MMC) administered with Electromotive Drug Administration (EMDA) in patients with high-risk NMIBC who fail BCG inmunotherapy.

      Material and methods

      We retrospectively studied patients with NMIBC who failed BCG and received alternating BCG and Mitomycin C with EMDA between 2010 and 2020. Treatment schedule consisted in an induction therapy with 6 instillations (BCG, BCG, MMC + EMDA, BCG, BCG, MMC + EMDA) and a 1-year maintenance.
      Complete response (CR) was defined as the absence of high-grade recurrences (HG) during follow-up, and progression was defined as the occurrence of muscle invasive or metastatic disease. CR rate was estimated at 3, 6, 12 and 24 months. Progression rate and toxicity were also assessed.


      Twenty-two patients were included with a median age of 73 years. Fifty percent of tumors were single, 90% were smaller than 1.5cm, 40% were GII (HG) and 40% were Ta. Complete response rate was 95.5%, 81% and 70% at 3 and 6 months, 12 months and 24 months, respectively.
      With a median follow-up of 28.8 months, 6 patients (27%) presented HG recurrence and only 1 patient (4.5%) progressed and ended in cystectomy. This patient died due to metastatic disease. Treatment was well tolerated and 22% of the patients presented adverse effects, being dysuria the most frequent one.


      Sequential treatment with BCG and Mitomycin C with EMDA achieved good responses and low toxicity in selected patients who did not respond to BCG. Only one patient ended in cystectomy and died due to metastatic disease, therefore, cystectomy was avoided in most cases.


      We evaluated the result of bladder preservation in patients with nonmuscle invasive bladder cancer in whom Bacillus Calmette-Guerin (BCG) therapy had failed. They received BCG and Mitomycin C instillations administered with Electromotive Drug Agministration (EMDA) and we evaluated the response and tolerability. They seem to be safe and to provide good responses in these patients, without a high progression rate.


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        • Chehroudi AC
        • Black PC.
        Emerging intravesical therapies for the management of bacillus Calmette–Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer: Charting a path forward.
        Canadian Urological Association Journal. 2020; 14
        • Martin FM
        • Kamat AM.
        Definition and management of patients with bladder cancer who fail BCG therapy.
        Expert Review of Anticancer Therapy. 2009; 9: 815-820
        • Kamat AM
        • Colombel M
        • Sundi D
        • Lamm D
        • Boehle A
        • Brausi M
        • et al.
        BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG.
        Nature Reviews Urology. 2017; 14: 244-255
        • DeCastro GJ
        • Sui W
        • Pak JS
        • Lee SM
        • Holder D
        • Kates MM
        • et al.
        A Phase I Trial of Intravesical Cabazitaxel, Gemcitabine and Cisplatin for the Treatment of Nonmuscle Invasive bacillus Calmette-Guérin Unresponsive or Recurrent/Relapsing Urothelial Carcinoma of the Bladder.
        Journal of Urology. 2020; 204: 247-253
        • Juvet T
        • Mari A
        • Lajkosz K
        • Wallis CJ
        • Kuk C
        • Erlich A
        • et al.
        Sequential administration of Bacillus Calmette-Guerin (BCG) and Electromotive Drug Administration (EMDA) of mitomycin C (MMC) for the treatment of high-grade nonmuscle invasive bladder cancer after BCG failure.
        Urologic Oncology: Seminars and Original Investigations. 2020; 38 (e15): e9-850
        • Racioppi M
        • di Gianfrancesco L
        • Ragonese M
        • Palermo G
        • Sacco E
        • Bassi PF.
        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.
        BMC Cancer. 2018; 18
        • Brausi M
        • Campo B
        • Pizzocaro G
        • Rigatti P
        • Parma A
        • Mazza G
        • et al.
        Intravesical electromotive administration of drugs for treatment of superficial bladder cancer: a comparative phase II study.
        Urology. 1998; 51: 506-509
        • Chien YW
        • Banga AK.
        Iontophoretic (Transdermal) Delivery of Drugs: Overview of Historical Development.
        Journal of Pharmaceutical Sciences. 1989; 78: 353-354
        • di Stasi SM
        • Giannantoni A
        • Giurioli A
        • Valenti M
        • Zampa G
        • Storti L
        • et al.
        Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial.
        The Lancet Oncology. 2006; 7: 43-51
      1. Compérat E, Gontero P, Liedberg F, Masson-Lecomte A, Mostafid AH, Palou J, et al. Non-muscle-invasive Bladder Cancer (TaT1 and CIS) EAU Guidelines on. 2022.

        • Kamat AM
        • Sylvester RJ
        • Böhle A
        • Palou J
        • Lamm DL
        • Brausi M
        • et al.
        Definitions, End Points, and Clinical Trial Designs for Non–Muscle-Invasive Bladder Cancer: Recommendations From the International Bladder Cancer Group.
        Journal of Clinical Oncology. 2016; 34: 1935-1944
        • Steinberg G
        • Bahnson R
        • Brosman S
        • Middleton R
        • Wajsman Z
        • Wehle M.
        Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group.
        J Urol. 2000; 163: 761-767
        • v Balar A
        • AM Kamat
        • Kulkarni GS
        • Uchio EM
        • Boormans JL
        • Roumiguié M
        • et al.
        Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study.
        The Lancet Oncology. 2021; 22: 919-930
        • Boorjian SA
        • Alemozaffar M
        • Konety BR
        • Shore ND
        • Gomella LG
        • Kamat AM
        • et al.
        Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.
        The Lancet Oncology. 2021; 22: 107-117
        • Kowalski M
        • Guindon J
        • Brazas L
        • Moore C
        • Entwistle J
        • Cizeau J
        • et al.
        A Phase II Study of Oportuzumab Monatox: An Immunotoxin Therapy for Patients with Noninvasive Urothelial Carcinoma In Situ Previously Treated with Bacillus Calmette-Guérin.
        Journal of Urology. 2012; 188: 1712-1718
        • Steinberg RL
        • Thomas LJ
        • Brooks N
        • Mott SL
        • Vitale A
        • Crump T
        • et al.
        Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer.
        Journal of Urology. 2020; 203: 902-909
        • Pijpers OM
        • Hendricksen K
        • Mostafid H
        • de Jong FC
        • Rosier M
        • Mayor N
        • et al.
        Long-term efficacy of hyperthermic intravesical chemotherapy for BCG-unresponsive non-muscle invasive bladder cancer.
        Urologic Oncology: Seminars and Original Investigations. 2022; 40 (e20): e13-e62