Electromotive Mitomycin-C (EMDA-MMC) in Preventing Recurrences in High-risk Non-muscle-invasive Bladder Cancer

Summary

Disease recurrence and progression is a major issue in high risk non-muscle-invasive bladder cancer (NMIBC). The current study compares two adjuvant instillation therapies in the treatment of high risk NMIBC. After resection of the tumour(s), patients will receive either traditional regimen of Bacillus Calmette-Guérin (BCG) instillations or combination treatment consisting of sequential BCG-instillations and mitomycin C instillations administered with electromotive drug administration (EMDA) device.

Timeline

Start

2018-10-26

Primary completion

2025-11-01

Completion

2025-11-01

Outcome

Met primary endpoint

paper Patients assigned sequential BCG and electromotive mitomycin had higher disease-free interval than did those assigned BCG alone PMID 16389183 ↗

paper difference between groups 48 months [42-54], log-rank p=0.0012 PMID 16389183 ↗

Publications

• Background Pasin E, Josephson DY, Mitra AP, Cote RJ, Stein JP. Superficial bladder cancer: an update on etiology, molecular development, classification, and natural history. Rev Urol. 2008 Winter;10(1):31-43.
• Background Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW, Kurth K. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006 Mar;49(3):466-5; discussion 475-7. doi: 10.1016/j.eururo.2005.12.031. Epub 2006 Jan 17.
• Background Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, Hernandez V, Kaasinen E, Palou J, Roupret M, van Rhijn BWG, Shariat SF, Soukup V, Sylvester RJ, Zigeuner R. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 2017 Mar;71(3):447-461. doi: 10.1016/j.eururo.2016.05.041. Epub 2016 Jun 17.
• Background Prescott S, James K, Hargreave TB, Chisholm GD, Smyth JF. Radio-immunoassay detection of interferon-gamma in urine after intravesical Evans BCG therapy. J Urol. 1990 Nov;144(5):1248-51. doi: 10.1016/s0022-5347(17)39713-6.
• Background Luo Y, Knudson MJ. Mycobacterium bovis bacillus Calmette-Guerin-induced macrophage cytotoxicity against bladder cancer cells. Clin Dev Immunol. 2010;2010:357591. doi: 10.1155/2010/357591. Epub 2010 Sep 1.
• Background Brandau S, Riemensberger J, Jacobsen M, Kemp D, Zhao W, Zhao X, Jocham D, Ratliff TL, Bohle A. NK cells are essential for effective BCG immunotherapy. Int J Cancer. 2001 Jun 1;92(5):697-702. doi: 10.1002/1097-0215(20010601)92:53.0.co;2-z.
• Background Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976 Aug;116(2):180-3. doi: 10.1016/s0022-5347(17)58737-6.
• Background Pan J, Liu M, Zhou X. Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with non-muscle invasive bladder cancer? An update and cumulative meta-analysis. Front Med. 2014 Jun;8(2):241-9. doi: 10.1007/s11684-014-0328-0. Epub 2014 May 8.
• Background Malmstrom PU, Sylvester RJ, Crawford DE, Friedrich M, Krege S, Rintala E, Solsona E, Di Stasi SM, Witjes JA. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. Eur Urol. 2009 Aug;56(2):247-56. doi: 10.1016/j.eururo.2009.04.038. Epub 2009 Apr 24.
• Background Chou R, Selph S, Buckley DI, Fu R, Griffin JC, Grusing S, Gore JL. Intravesical Therapy for the Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis. J Urol. 2017 May;197(5):1189-1199. doi: 10.1016/j.juro.2016.12.090. Epub 2016 Dec 24.
• Background Sylvester RJ, van der MEIJDEN AP, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol. 2002 Nov;168(5):1964-70. doi: 10.1016/S0022-5347(05)64273-5.
• Background Bohle A, Bock PR. Intravesical bacille Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology. 2004 Apr;63(4):682-6; discussion 686-7. doi: 10.1016/j.urology.2003.11.049.
• Background Lamm DL, Blumenstein BA, Crissman JD, Montie JE, Gottesman JE, Lowe BA, Sarosdy MF, Bohl RD, Grossman HB, Beck TM, Leimert JT, Crawford ED. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000 Apr;163(4):1124-9.
• Background Di Stasi SM, Giannantoni A, Massoud R, Dolci S, Navarra P, Vespasiani G, Stephen RL. Electromotive versus passive diffusion of mitomycin C into human bladder wall: concentration-depth profiles studies. Cancer Res. 1999 Oct 1;59(19):4912-8.
• Background Rajala P, Kaasinen E, Rintala E, Jauhiainen K, Nurmi M, Alfthan O, Lahde M. Cytostatic effect of different strains of Bacillus Calmette-Guerin on human bladder cancer cells in vitro alone and in combination with mitomycin C and interferon-alpha. Urol Res. 1992;20(3):215-7. doi: 10.1007/BF00299720.
• Background Oosterlinck W, Kirkali Z, Sylvester R, da Silva FC, Busch C, Algaba F, Collette S, Bono A. Sequential intravesical chemoimmunotherapy with mitomycin C and bacillus Calmette-Guerin and with bacillus Calmette-Guerin alone in patients with carcinoma in situ of the urinary bladder: results of an EORTC genito-urinary group randomized phase 2 trial (30993). Eur Urol. 2011 Mar;59(3):438-46. doi: 10.1016/j.eururo.2010.11.038. Epub 2010 Dec 7.
• Background Kaasinen E, Wijkstrom H, Malmstrom PU, Hellsten S, Duchek M, Mestad O, Rintala E; Nordic Urothelial Cancer Group. Alternating mitomycin C and BCG instillations versus BCG alone in treatment of carcinoma in situ of the urinary bladder: a nordic study. Eur Urol. 2003 Jun;43(6):637-45. doi: 10.1016/s0302-2838(03)00140-4.
• Background Solsona E, Madero R, Chantada V, Fernandez JM, Zabala JA, Portillo JA, Alonso JM, Astobieta A, Unda M, Martinez-Pineiro L, Rabadan M, Ojea A, Rodriguez-Molina J, Beardo P, Muntanola P, Gomez M, Montesinos M, Martinez Pineiro JA; Members of Club Urologico Espanol de Tratamiento Oncologico. Sequential combination of mitomycin C plus bacillus Calmette-Guerin (BCG) is more effective but more toxic than BCG alone in patients with non-muscle-invasive bladder cancer in intermediate- and high-risk patients: final outcome of CUETO 93009, a randomized prospective trial. Eur Urol. 2015 Mar;67(3):508-16. doi: 10.1016/j.eururo.2014.09.026. Epub 2014 Oct 6.
• Background Di Stasi SM, Giannantoni A, Stephen RL, Capelli G, Navarra P, Massoud R, Vespasiani G. Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a prospective randomized study. J Urol. 2003 Sep;170(3):777-82. doi: 10.1097/01.ju.0000080568.91703.18.
• Results Di Stasi SM, Giannantoni A, Giurioli A, Valenti M, Zampa G, Storti L, Attisani F, De Carolis A, Capelli G, Vespasiani G, Stephen RL. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol. 2006 Jan;7(1):43-51. doi: 10.1016/S1470-2045(05)70472-1.
• Results Gan C, Amery S, Chatterton K, Khan MS, Thomas K, O'Brien T. Sequential bacillus Calmette-Guerin/Electromotive Drug Administration of Mitomycin C as the Standard Intravesical Regimen in High Risk Nonmuscle Invasive Bladder Cancer: 2-Year Outcomes. J Urol. 2016 Jun;195(6):1697-703. doi: 10.1016/j.juro.2016.01.103. Epub 2016 Feb 2.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	BCG	Other / unclassified	81 mg	—
Subject	BCG	Other / unclassified	2e+08 unknown	—
Subject	BCG	Other / unclassified	8e+08 unknown	—
Subject	BCG	Other / unclassified	3e+09 unknown	—
Subject	Mitomycin C	Other / unclassified	40 mg	Intravenous

Indications