Sequential Bacillus Calmette-Guérin (BCG) and Electromotive Mitomycin-C Versus Bacillus Calmette-Guérin (BCG) Alone for High Risk Superficial Bladder Cancer
Condition: Bladder Cancer
MeSH terms: Urinary Bladder Neoplasms
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): bacillus Calmette-Guerin; electromotive mitomycin
Intervention type(s): Biological; Drug
Intervention description(s): 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; 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).
Other intervention name(s): IMMUCYST, Alpha Wassermann, Bologna, Italy; IMMUCYST, Alpha Wassermann, Bologna, Italy; MITOMYCIN C 40 mg, Kyowa Italiana Farmaceutici
Intervention MeSH terms: Mitomycins; Mitomycin; BCG Vaccine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: non-muscle invasive urothelial bladder cancer; intravesical therapy; BCG; mitomycin; electromotive drug administration; Bladder Cancer Stage 0, Without Cancer in Situ