FB10: Electromotive Mitomycin-C (EMDA-MMC) in Preventing Recurrences in High-risk Non-muscle-invasive Bladder Cancer
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Phase 3 |
Detailed Description
Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease. The patients with NMIBC may be categorized in three risk groups according to the risk of recurrence and progression characterized by the disease. The treatment of high risk NMIBC includes a transurethral resection of the tumour(s), which is followed by an adjuvant instillation therapy, aiming to reduce the risk of recurrence and progression. Intravesical bacillus Calmette-Guérin (BCG) treatment is been the most effective single agent against NMIBC, and it is referred to as the gold standard in the treatment of high risk disease.
BCG is a solution of live, attenuated mycobacterium bovis bacteria, which is administered intravesically in an outpatient clinic. BCG activates an immunological reaction in the bladder wall, which leads to antitumour effect by activation of macrophages, T-cells, and natural killer (NK) cells. BCG treatment comprises an induction period, which includes six weekly instillations. This is followed by maintenance period including monthly or repeated series of three weekly instillations up to 1-3 years.
Other instillation therapies include intravesically administered chemotherapy. Mitomycin C (MMC) is the most used chemotherapeutic agent. MMC provides a better tolerated side effect profile, but is less effective against high risk NMIBC than BCG, when MMC is used as a single agent. Combinations of BCG- and MMC treatment has also been described with various results. The rationale for combining BCG and MMC is to enhance the absorption of BCG as MMC might cause disruption of bladder mucosa, which makes the mucosa more permeable thus enhancing the absorption of BCG. However, it is also hypothesized, that BCG may also work synergistic in favor of MMC.
The absorption and effect of MMC may be enhanced with electromotive drug administration (EMDA) device. After instillation of MMC, an electric field is conducted in the bladder with EMDA device via catheter and electrodes, which are placed in the bladder and lower abdomen skin. Electric field creates movement of sodium ions and water into the bladder wall, which creates electro-osmotic drag of MMC molecules. In a laboratory setting, EMDA-MMC instillation results in 4-7 times greater concentration of MMC in the deeper layers of the bladder wall than passively administered MMC instillation. EMDA-MMC treatment may also be combined with BCG treatment administering BCG and EMDA-MMC instillations sequentially. Results from a prospective randomized trial suggested, that sequential EMDA-MMC and BCG treatment might be even more effective against NMIBC than BCG therapy alone in terms of recurrence, progression and overall survival.
The current study is a prospective, open label, phase III randomized study allocating patients with high risk NMIBC to receive adjuvant instillation therapy either as traditional BCG treatment, or sequential BCG- and EMDA-MMC treatment. The aim of the study is to compare effectiveness and tolerability of the two treatment regimens in preventing recurrence and progression of high risk NMIBC.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Group A BCG instillation therapy with induction period of six weekly instillations of BCG followed by maintenance period of ten monthly instillations of BCG Dosage of Bacillus of Calmette-Guerin (BCG) is dependent on the preferred brand of BCG by the participating institution. Either 2 x 10^8 - 3 x 10^9 for BCG-MEDAC, 2-8 x 10^8 colony forming unit for OncoTICE or, 81mg for ImmuCYST and TheraCys. The investigators will nominate which BCG brand is used. |
Drug: BCG instillation therapy
Induction period of six weekly instillations of BCG followed by maintenance period of ten monthly instillations of BCG
Other Names:
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| Experimental: Group B Sequential BCG and EMDA mitomycin C treatment with nine weekly instillations of BCG, BCG, EMDA-MMC x3 followed by nine monthly instillations of EMDA-MMC, EMDA-MMC, BCG x3 Dosage of Bacillus of Calmette-Guerin (BCG) is dependent on the preferred brand of BCG by the participating institution. Either 2 x 10^8 - 3 x 10^9 for BCG-MEDAC, 2-8 x 10^8 colony forming unit for OncoTICE or, 81mg for ImmuCYST and TheraCys. The investigators will nominate which BCG brand is used. Mitomycin C dosage is 40 mg of MMC with 960 mg of excipient sodium chloride dissolved in 100 ml sterile water |
Drug: Sequential BCG and EMDA mitomycin C
Induction period includes nine weekly instillations of sequential BCG and EMDA-MMC instillations applied as three cycles of BCG, BCG and EMDA-MMC. Induction period is followed by maintenance period of nine monthly instillations of sequential EMDA-MMC and BCG applied with three cycles of EMDA-MMC, EMDA-MMC and BCG.
BCG instillation is performed as a standard instillation.
Mitomycin C is administered with electromotive drug administration (EMDA) device (Instillation: 40 mg mitomycin C with 960 mg of excipient sodium chloride dissolved in 100 ml sterile water, EMDA settings: current rise rate 30-50 microamperes per second, max 25 milliamperes, treatment duration 30 min)
Other Names:
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Outcome Measures
Primary Outcome Measures
- Bladder cancer recurrence rate [2 years]
Any bladder cancer recurrence at 2 years
Secondary Outcome Measures
- Progression of bladder cancer [2 years]
Progression of bladder cancer in terms of T-category compared to the last resected tumour prior to randomisation
- Mortality [2 years]
Death due bladder cancer or other reasons
- NMIBC24 quality of life questionnaire (QLQ) score [2 years]
Side-effects related to the treatment measured with EORTC QLQ-NMIBC24
- Adverse effects [2 years]
Complications or adverse events related to bladder cancer or the treatment
Eligibility Criteria
Criteria
Inclusion Criteria:
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Histologically proven non-muscle-invasive tumour types confined to the urinary bladder
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Carcinoma in situ with or without a papillary tumour(s)
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Ta tumour(s) of high-grade
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Any T1 tumour(s)
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Written informed consent is required from every eligible patient
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Second resection performed in case of T1 tumour
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Adequate physical and mental condition to participate in the study (as judged by treating physician
Exclusion Criteria:
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Ta low grade tumour(s)
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Muscle invasive (pT≥2) tumors
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Urothelial cancer involving the prostatic urethra or upper urinary tract
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Non-urothelial bladder cancer.
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Prior BCG failure (If the patient has previously been successfully treated with BCG, and duration from the last instillation is >12 months, participation may be considered, if bladder preserving is chosen)
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Prior or concurrent immunotherapy
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Any medication or condition considered as contraindication to BCG or MMC (as judged by the treating physician)
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Urethral stricture, stone disease, chronic urinary tract infection or any other urological condition that may comprise study participation (as judged by the treating physician)
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Known allergy to MMC or BCG
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Age < 18 years
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Pregnancy or lactating patient
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Other untreated or unstable malignancy in risk of recurrence/progression (as judged by the treating physician)
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Cardiac pacemaker
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Expected survival time less than one year
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Expected poor compliance
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | HYKS Peijas Hospital | Helsinki | Finland | 00029 | |
| 2 | Jyväskylä Central Hospital | Jyväskylä | Finland | 40620 | |
| 3 | Päijät-Häme Central hospital | Lahti | Finland | 15850 | |
| 4 | Mikkeli Central Hospital | Mikkeli | Finland | 50100 | |
| 5 | Seinäjoki Central Hospital | Seinäjoki | Finland | 60220 | |
| 6 | Tampere University Hospital | Tampere | Finland | 33521 | |
| 7 | Turku University Hospital | Turku | Finland | 20521 |
Sponsors and Collaborators
- Turku University Hospital
- Finnbladder
Investigators
- Study Director: Peter J Boström, MD, PhD, Turku University Hospital, Hospital District of Southwest Finland
Study Documents (Full-Text)
None provided.More Information
Publications
- Babjuk M, Böhle A, Burger M, Capoun O, Cohen D, Compérat EM, Hernández V, Kaasinen E, Palou J, Rouprêt 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.
- Böhle A, Bock PR. Intravesical bacille Calmette-Guérin 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.
- Brandau S, Riemensberger J, Jacobsen M, Kemp D, Zhao W, Zhao X, Jocham D, Ratliff TL, Böhle A. NK cells are essential for effective BCG immunotherapy. Int J Cancer. 2001 Jun 1;92(5):697-702.
- 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.
- 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.
- 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.
- Kaasinen E, Wijkström H, Malmström 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.
- 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.
- Luo Y, Knudson MJ. Mycobacterium bovis bacillus Calmette-Guérin-induced macrophage cytotoxicity against bladder cancer cells. Clin Dev Immunol. 2010;2010:357591. doi: 10.1155/2010/357591. Epub 2010 Sep 1. Review.
- Malmström 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-Guérin 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.
- 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.
- 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-Guérin and with bacillus Calmette-Guérin 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.
- Pan J, Liu M, Zhou X. Can intravesical bacillus Calmette-Guérin 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.
- 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.
- 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.
- Rajala P, Kaasinen E, Rintala E, Jauhiainen K, Nurmi M, Alfthan O, Lähde M. Cytostatic effect of different strains of Bacillus Calmette-Guérin on human bladder cancer cells in vitro alone and in combination with mitomycin C and interferon-alpha. Urol Res. 1992;20(3):215-7.
- Solsona E, Madero R, Chantada V, Fernandez JM, Zabala JA, Portillo JA, Alonso JM, Astobieta A, Unda M, Martinez-Piñeiro L, Rabadan M, Ojea A, Rodriguez-Molina J, Beardo P, Muntañola P, Gomez M, Montesinos M, Martinez Piñeiro JA; Members of Club Urológico Español de Tratamiento Oncológico. Sequential combination of mitomycin C plus bacillus Calmette-Guérin (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.
- 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.
- 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. Epub 2006 Jan 17.
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