Sequential Bacillus Calmette-Guérin (BCG) and Electromotive Mitomycin-C Versus Bacillus Calmette-Guérin (BCG) Alone for High Risk Superficial Bladder Cancer (BCG/EMDA-MMC)
|ClinicalTrials.gov Identifier: NCT01442519|
Recruitment Status : Completed
First Posted : September 28, 2011
Last Update Posted : September 28, 2011
Intravesical treatment for superficial bladder cancer has been used for the past 4-5 decades. Intravesical chemotherapy is beneficial in terms of recurrence and time to recurrence in grade 1-2 stage Ta tumours, usually non-invasive. Intravesical chemotherapy has negligible effect on disease progression in high-risk superficial bladder cancer—ie, grade 3, stage T1, and carcinoma in situ. However, BCG as induction and maintenance treatment effectively delays progression. Electromotive mitomycin increases tissue uptake compared with that of passive diffusion. Electromotive mitomycin has emerged as an alternative or complementary treatment to BCG. The rationale for combining anticancer drugs is based on the need to increase efficacy and reduce emergence of resistant malignant cells. This approach is not frequently applied to use of intravesical agents for treatment of superficial bladder cancer, for which immunotherapeutic BCG and chemotherapeutic mitomycin seem to be a potentially effective combination. Studies have addressed concurrent use of mitomycin and BCG, and assigned two roles to mitomycin: antitumor action and tissue-scarifying (ie, surface-modifying) effect that enables BCG to attach more efficiently to the urothelium. The investigators therefore aimed to assess whether induction of inflammation by use of BCG before mitomycin treatment makes the bladder mucosa more permeable and thus enables mitomycin to reach the target more easily. This randomised trial to compare the efficacy of sequential BCG and electromotive mitomycin with that of the current standard of BCG alone for patients with high-risk superficial bladder cancer.
After transurethral resection and multiple biopsies patients with stage pT1 bladder cancer are randomly assigned to: 81 mg BCG infused over 120 min once a week for 6 weeks; or to 81 mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical electric current 20 mA for 30 min) once a week as one cycle for three cycles (n=107). Complete responders underwent maintenance treatment: those assigned BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG and mitomycin had 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles. The primary endpoint was disease-free interval; secondary endpoints were time to progression; overall survival; and disease-specific survival. Analyses were intention to treat.
|Condition or disease||Intervention/treatment||Phase|
|Bladder Cancer||Biological: bacillus Calmette-Guerin Drug: electromotive mitomycin||Phase 3|
Show Detailed Description
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||212 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Sequential Bacillus Calmette-Guérin and Electromotive Mitomycin-C Versus Bacillus Calmette-Guérin Alone for High Risk Superficial Bladder Cancer: a Prospective Randomised Study|
|Study Start Date :||January 1994|
|Actual Primary Completion Date :||June 2002|
|Actual Study Completion Date :||June 2002|
|Active Comparator: Intravesical BCG alone||
Biological: bacillus Calmette-Guerin
The BCG instillation consisted of 81 mg wet weight (10•2±9•0_108 colony-forming units) BCG Connaught substrain (ImmuCyst®, Alfa Wassermann SpA, Bologna, Italy). Lyophilised (ie, freeze-dried) BCG is suspended in 50 mL bacteriostatic-free solution of 0•9% sodium chloride. After draining of the bladder, the suspension is infused intravesically through a Foley catheter. The solution is retained in the bladder for 120 min, followed by emptying of the bladder and removal of the catheter. The BCG-alone group is assigned one course of intravesical treatment per week for 6 weeks. Patients in the BCG-alone group who are disease-free 3 months after treatment are scheduled to receive monthly infusions of BCG for 10 months
Other Name: IMMUCYST, Alpha Wassermann, Bologna, Italy
|Experimental: Intravesical sequential BCG and EMDA MMC||
Drug: electromotive mitomycin
BCG instillation of 81 mg BCG Connaught-substrain, suspended in 50 mL bacteriostatic-free saline solution, retained for 120 min. Electromotive instillation: 40 mg mitomycin in 100 mL water infused intravesically and retained in the bladder for 30 min, while 20 mA for 30 min pulsed electric current is given externally. Patients assigned sequential BCG and EMDA MMC are assigned 1 course of treatment/week for 9 weeks: one cycle consisted of two BCG infusions and one mitomycin infusion (three cycles in total). Patients in the BCG-and-mitomycin group who are disease-free 3 months after treatment are scheduled to receive one infusion a month for 9 months: three cycles of mitomycin, mitomycin, and BCG (ie, six infusions of MMC and three of BCG).
- Disease-free interval [ Time Frame: From date of randomization until the date of first documented recurrence, assessed up to 120 months ]The primary endpoint is disease-free interval for patients without carcinoma in situ and for patients with carcinoma in situ who are disease-free after treatment—ie, time from randomisation to first cystoscopy noting recurrence. Patients with carcinoma in situ who did not have complete response after 3 months of treatment are regarded as having recurrence with no follow-up.
- Time to progression [ Time Frame: From date of randomization until the date of documented progression, assessed up to 120 months. ]Time to progression is defined as time from randomisation until the onset of muscle-invasive disease as recorded by pathological assessment of transurethral-resection samples or biopsy samples. Patients without recurrence or progression are censored at the last cystoscopy, and those lost to follow-up are censored at the last known day of survival.
- Overall survival [ Time Frame: From date of randomization until the date of death for any cause, assessed up to 120 months. ]Overall survival is defined as time from randomisation until death from any cause. Patients without recurrence or progression are censored at the last cystoscopy, and those lost to follow-up are censored at the last known day of survival.
- Disease-specific survival [ Time Frame: From date of randomization until the date of death for bladder cancer, assessed up to 120 months. ]Disease-specific survival as time from randomisation until death from bladder cancer. Patients without recurrence or progression are censored at the last cystoscopy, and those lost to follow-up are censored at the last known day of survival.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01442519
|Dept. of Surgery/Urology, Tor Vergata University|
|Rome, RM, Italy, 00133|
|Principal Investigator:||Savino M Di Stasi, MD, PhD||Tor Vergata University, Rome, Italy|