Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

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Urinary Bladder Neoplasms

Non-Muscle Invasive Bladder Neoplasms

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Female Urogenital Diseases and Pregnancy Complications

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Mitomycins

Mitomycin

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Patients with non-muscle invasive bladder cancer who underwent transurethral resection alone;

Patients with non-muscle invasive bladder cancer who underwent one intravesical instillation of mitomycin-C immediately after transurethral resection

Patients with non-muscle invasive bladder cancer who underwent single immediate intravesical instillation of electromotive mitomycin-C immediately before transurethral resection

Mitomycin-C 40 mg

Savino M Di Stasi, MD, PhD

Early single instillation of chemotherapy after TUR is recommended in the European Association of Urology Guidelines. Nevertheless, the procedure is suboptimal for patients with multiple tumors, sometimes is not tolerated and it can results in severe complications. In both laboratory and clinical studies, intravesical electromotive drug administration (EMDA) increases mitomycin-C (MMC) bladder uptake, resulting in an improved clinical efficacy in non-muscle invasive bladder cancer (NMIBC). The investigators will compare the effects of one immediate pre-TUR intravesical EMDA/MMC instillation with one immediate post-TUR intravesical passive diffusion MMC (PD/MMC) instillation and TUR alone in patients with NMIBC.

All eligible patients with primary NMIBC will be randomized into 3 groups who will undergo transurethral resection alone (TUR/alone); TUR plus single immediate postoperative instillation (immediately after TUR) of 40 mg PD/MMC with a dwell time of 60 minutes; or single immediate preoperative instillation (immediately before TUR) of 40 mg EMDA/MMC with 20 mA electric current for 30 minutes. Patients with intermediate and high risk NMIBC will undergo adjuvant intravesical therapy. The primary end points will be the recurrence rate and disease-free interval. All clinical analyses will be performed on an intent to treat basis.

Preoperative Intravesical Electromotive Mitomycin-c for Primary Non-muscle Invasive Bladder Cancer

Single Preoperative Intravesical Instillation of Electromotive Mitomycin-c for Primary Non-muscle Invasive Bladder Cancer: a Prospective Randomized Trial.

University of Rome Tor Vergata

Professor

Carcinoma in Situ

Pharmaceutical Solutions

BCG Vaccine

Vaccines

Adjuvants, Immunologic

Immunologic Factors

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

bacillus Calmette-Guerin

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).

electromotive mitomycin

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.

All patients with histologically proven stage pT1 urothelial carcinoma of the bladder, whether papillary or solid, are regarded as being at high risk for tumour recurrence and at moderate to high risk for progression because of: multifocal pT1, primary or recurrent, grade 2 transitional-cell carcinoma; primary or recurrent pT1, multifocal or solitary, grade 3 transitional-cell carcinoma; or pT1 with carcinoma in situ. Inclusion criteria are: age 18 years or older; adequate bone-marrow reserve; normal renal function; normal liver function; and Karnofsky performance status between 50 and 100. Exclusion criteria are: previous treatment with BCG or electromotive mitomycin; treatment with any other intravesical cytostatic agent within the past 6 months; concomitant urothelial tumours of the upper urinary tract; previous muscle-invasive (ie, stage T2 or higher) transitional-cell carcinoma of the bladder; bladder capacity less than 2 L; untreated urinary-tract infection; severe systemic infection (ie, sepsis); urethral strictures that would prevent endoscopic procedures and repeated catheterisation; disease of upper urinary tract (eg, vesicoureteral reflux or urinary-tract stones) that would make multiple transurethral procedures a risk; previous radiotherapy to the pelvis; other concurrent chemotherapy; treatment with radiotherapy-response or biological-response modifiers; history of tuberculosis; other malignant diseases within 5 years of trial registration (except for basal-cell carcinoma); pregnancy or nursing; and psychological, familial, sociological, or geographical factors that would preclude study participation.

Study design The institutional review boards of every participating centre approved the study design. Every patient enrolled signed an informed-consent form approved by the institutional review boards. All patients underwent: urinary cytology of the bladder and upper urinary tract; random cold-cup biopsies of the bladder and prostatic urethra-ie, sampling of seemingly healthy urothelium and of suspicious areas; and complete transurethral resection of all bladder tumour visible on endoscopy, ensuring muscle is included in resected samples. Patients with positive or suspect cytology, carcinoma in situ, multifocal tumours, or grade 3 tumours underwent restaging transurethral resection 4-5 weeks later. All clinical assessors are adequately trained in the above procedures, and no methods are used to enhance the quality of measurements. All biopsy samples of tumour and bladder are reviewed by a pathologist for stage and grade. Tumour stage is classified according to the 1997 TNM classification of the International Union Against Cancer, and tumour grade is defined in accordance with the 1973 WHO classification. Patients are randomised within 10 days of the first or restaging transurethral resection. Randomisation and data collection are done by use of a central computer. Patients are allocated to BCG alone or to BCG and electromotive mitomycin by use stratified, blocked randomisation cross 14 strata as a result of four factors: primary versus recurrent tumours; multifocal versus unifocal tumours; grade 3 versus grade 2 tumours; and presence versus absence of carcinoma in situ. MV generated and coordinated the randomisation process. This study is not blinded because of differences in treatment schedules and drug appearance.

Treatment schedules All patients are scheduled to receive their allocated intervention about 3 weeks after transurethral resection and multiple, random biopsy sampling. The BCG instillation consisted of 81 mg wet weight 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. Patients randomly allocated to BCG and mitomycin, are placed on fluid restriction and 2 g ingested sodium bicarbonate the night before treatment, the morning of treatment, and 2 h before treatment with mitomycin. A Foley catheter is inserted and postvoid residual volume is reduced to less than 10mL. 40 mg mitomycin (Mitomycin, Kyowa Italiana Farmaceutici, Srl, Milan, Italy) dissolved in 100 mL water is infused intravesically through the Foley catheter by gravity and retained in the bladder for 30 min, while 40-60 mA per s to a maximum of 20 mA or 30 min pulsed electric current is given externally.13 Two dispersive cathode electrodes are placed on lower abdominal skin that had been degreased with alcohol and a 2-5-mm layer of conductive gel applied. The bladder is then emptied and the catheter removed. The BCG-alone group is assigned one course of intravesical treatment per week for 6 weeks; patients assigned sequential BCG and electromotive mitomycin are assigned one course of treatment per week for 9 weeks, for whom one cycle consisted of two BCG infusions and one mitomycin infusion (three cycles in total). 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. 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 mitomycin and three infusions of BCG.

Maintenance treatment for both groups is given to the same dose and methods of infusion as initial allocated treatment.

Role of the funding source The sponsor of the study has no role in study design; in the collection, analysis, or interpretation of data; or in the writing of the report.

Sequential Bacillus Calmette-Guérin (BCG) and Electromotive Mitomycin-C Versus Bacillus Calmette-Guérin (BCG) Alone for High Risk Superficial Bladder Cancer

Sequential Bacillus Calmette-Guérin and Electromotive Mitomycin-C Versus Bacillus Calmette-Guérin Alone for High Risk Superficial Bladder Cancer: a Prospective Randomised Study

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 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 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 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.

University of L'Aquila

Symptoms and General Pathology

Recurrence

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.

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

Induction period of six weekly instillations of BCG followed by maintenance period of ten monthly instillations of BCG

BCG instillation therapy

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)

Sequential BCG and EMDA mitomycin C

Pertti T Nurminen, MD

Riikka Järvinen, MD, PhD

Heikki Seikkula, MD, PhD

Taina Isotalo, MD, PhD

Taina Isotalo, Md, PhD

Niilo Hendolin, MD

Timo Marttila, MD

Dimitri Pogodin-Hannolainen, MD

Peter J Boström, MD, PhD

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.

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.

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

Intravesical Instillation Therapy With Bacillus Calmette-Guérin (BCG) and Sequential BCG and Electromotive Mitomycin-C (EMDA-MCC) in Patients With High-risk Non-muscle-invasive Bladder Carcinoma

Progression of bladder cancer in terms of T-category compared to the last resected tumour prior to randomisation

Death due bladder cancer or other reasons

Side-effects related to the treatment measured with EORTC QLQ-NMIBC24

Complications or adverse events related to bladder cancer or the treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Preoperative Intravesical Electromotive Mitomycin-c for Primary Non-muscle Invasive Bladder Cancer	NCT01149174	Superficial Bla...	Mitomycin-C 40 ...	18 Years - 90 Years	University of Rome Tor Vergata
Sequential Bacillus Calmette-Guérin (BCG) and Electromotive Mitomycin-C Versus Bacillus Calmette-Guérin (BCG) Alone for High Risk Superficial Bladder Cancer	NCT01442519	Bladder Cancer	bacillus Calmet... electromotive m...	18 Years - 90 Years	University of Rome Tor Vergata
Electromotive Mitomycin-C (EMDA-MMC) in Preventing Recurrences in High-risk Non-muscle-invasive Bladder Cancer	NCT03664869	Bladder Cancer	BCG instillatio... Sequential BCG ...	18 Years -	Turku University Hospital
Sequential Bacillus Calmette-Guérin (BCG) and Electromotive Mitomycin-C Versus Bacillus Calmette-Guérin (BCG) Alone for High Risk Superficial Bladder Cancer	NCT01442519	Bladder Cancer	bacillus Calmet... electromotive m...	18 Years - 90 Years	University of Rome Tor Vergata

Spots Global Cancer Trial Database for electromotive drug administration