Intravesical Electromotive Mitomycin After Bacillus Calmette-Guérin Failure
Condition: Bladder Cancer
MeSH terms: Urinary Bladder Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      Patients with urothelial high risk non-muscle invasive bladder cancer patients will be
      treated with intravesical electromotive drug administration/mitomycin (EMDA/MMC) after
      bacillus Calmette-Guerin (BCG) failure. Patients are scheduled for an initial 6 weekly
      treatments, a further 6 weekly treatments for non-responders and a followup 10 monthly
      treatments for responders. Complete response will be defined as histological disappearance of
      malignancy on bladder biopsy and resolution of abnormal cytological findings after treatment.
      Time to first recurrence, time to progression, overall survival, and disease-specific
      survival wil be estimated by use of the Kaplan-Meier method.
    

Detailed description: 
      Partecipants

      Inclusion criteria:

        -  Patients with urothelial high risk NMIBC (high grade stage Ta, T1 and/or carcinoma in
           situ) after intravesical BCG failure;

        -  adequate bone marrow reserve;

        -  normal renal function;

        -  normal liver function;

        -  Karnofsky performance score of 50 to 100.

      Exclusion criteria:

        -  non-urothelial carcinomas of the bladder;

        -  known allergy to MMC;

        -  previous or concomitant urothelial carcinoma of the upper urinary tract and urethra, or
           both;

        -  bladder capacity less than 200 mL;

        -  untreated urinary-tract infection;

        -  severe systemic infection (ie, sepsis);

        -  urethral strictures that would prevent endoscopic procedures and catheterisation;

        -  other concurrent chemotherapy, radiotherapy, and treatment with biological response
           modifiers;

        -  other malignant diseases within 5 years of start of EMDA MMC (except for adequately
           treated basal-cell or squamous-cell skin cancer, in situ cervical cancer);

        -  pregnancy;

        -  psychological, familial, sociological, or geographical factors that would preclude study
           participation.

      The institutional review boards of each participating centre approved the study design. all
      enrolled patients will sign an informed consent form, approved by the institutional review
      boards, providing details of treatments.

      BCG Failure

      The definition of BCG failure in patients has been proposed as follows:

        1. BCG-refractory disease when there is failure to achieve a disease-free state at 6 months
           following initial BCG therapy with either maintenance or retreatment at 3 months because
           of persistent or rapidly recurrent tumor;

        2. BCG-resistant disease when there is recurrence or persistence at 3 months following an
           induction cycle;

        3. BCG-relapsing disease when the disease recurs after the patient is disease-free for 6
           months;

        4. BCG-intolerant disease when the disease recurs following administration of a less than
           adequate course of therapy because of a serious adverse event or symptomatic intolerance
           that requires discontinuation of further BCG therapy.13 Study design Patients will
           underwent: upper urinary tract imaging, 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 (TUR) of all bladder tumour visible on endoscopy, ensuring
           muscle was included in resected samples. All patients will underwent re-staging TUR 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 will be reviewed by a pathologist for stage and grade. Tumour stage are
           classified according to the 1997 TNM classification of the International Union Against
           Cancer, and tumour grade was defined in accordance with the 1973 WHO classification.

      Treatment schedule All patients will start induction EMDA/MMC of 6 intravesical treatments at
      weekly intervals commencing 2-3 weeks after re-staging TUR. Intravesical EMDA MMC is given by
      a battery-powered generator delivering a controlled electric current that passes between the
      active intravesical electrode integrated into a specific transurethral catheter and
      dispersive ground electrodes on skin of the lower abdomen (Physion srl, Mirandola, Italy).
      Patients 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. The bladder is
      emptied through the electrode-transurethral-catheter and 40 mg mitomycin dissolved in 100 mL
      water was infused intravesically by gravity and retained in the bladder for 30 min, while 20
      mA for 30 min pulsed electric current was given externally. Two dispersive cathode electrodes
      were placed on lower abdominal skin that had been degreased with alcohol. The bladder was
      then emptied and the catheter removed.

      Patients who were disease-free 3 months after treatment were scheduled to receive monthly
      infusions of BCG for 10 months. Maintenance treatment was given to the same dose and methods
      of infusion as initial allocated treatment. Response to treatment was assessed with abdominal
      ultrasonography, cystoscopy, and urinary cytology. In patients who were free of disease 3
      months after treatment, these assessments were done every 3 months during the first 3 years
      and every 6 months thereafter. Patients with carcinoma in situ underwent abdominal
      ultrasonography, cystoscopy, urinary cytology, and random bladder biopsies at 3 months and 6
      months. If bladder cytology was positive for cancer cells but no lesions were visible on
      cystoscopy, cytology of the upper urinary tract and random biopsies of the bladder and
      prostatic urethra were done. If, at 3 months' follow-up, carcinoma in situ persisted or a
      superficial tumour recurred (ie, stage pTa tumour confined to the urothelium or stage pT1
      with invasion of the lamina propria), the patient underwent multiple, random biopsy sampling
      and TUR of all bladder tumour visible on endoscopy and received a second course of
      intervention treatment.

      Cystoscopy, biopsies, and urinary cytology were repeated 3 months after the start of the
      second course. Patients who were disease-free after the second course of treatment received
      the full course of monthly maintenance instillations (ie, one infusion of electromotive
      mitomycin for 10).

      Patients were suspended from the trial on a second recurrence, on persistence of carcinoma in
      situ, on development of carcinoma in the upper-urinary tract or prostatic urethra, on
      progression to muscle-invasive disease (ie, stage pT2 or more advanced), or on development of
      metastases. Further treatment was left to the discretion of the local investigator.

      Toxicity Side effects were classified as local, systemic or allergic. Local toxicity was
      defined as culture proven bacterial cystitis, drug induced (chemical) cystitis and other
      localized effects. Systemic side effects were defined as fever exceeding 38C, general malaise
      and fatigue. Skin rash was regarded as allergic reaction. The severity of side effects were
      classified by the treating physician, with subsequent decision to continue, delay or abandon
      treatment.

      Patient follow-up. Response to treatment was assessed with cystoscopy, urinary cytology and
      /or biopsy only if indicated by suspicious cytological findings or on cystoscopy. In
      disease-free cases, cystoscopy and urinary cytology were repeated at 3-month intervals for 2
      years, 6-month intervals for 3 years and yearly thereafter.

      Patient evaluation Patients with stage pTa and pT1 tumour without carcinoma in situ are
      classified as disease-free and therefore treated prophylactically; those with carcinoma in
      situ are treated therapeutically, and response is scored as no response or as complete
      response. Complete response is defined as complete disappearance of carcinoma in situ, as
      documented by a normal cytology, cystoscopy, and random bladder biopsies.

      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 enrollment
      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. The secondary endpoints are time to progression, overall survival, and disease
      specific survival. Time to progression is defined as time from randomisation until the onset
      of muscle invasive disease as recorded by pathological assessment of TUR samples or biopsy
      samples. Overall survival is defined as time from enrollment until death from any cause;
      disease specific survival as time from enrollment until death from bladder cancer. Patients
      without recurrence or progression are censored at the last cystoscopy, and those lost to
      follow-up were censored at the last known day of survival.

      Statistical Analysis All analyses are done by intention to treat. Time to first recurrence,
      time to progression, overall survival, and disease-specific survival are estimated by use of
      the Kaplan-Meier method. Comparisons are estimated by use of log-rank test. All tests are
      two-sided, and p<0·05 was regarded as significant. The investigators will calculated hazard
      ratios with 95% CI by use of proportional-hazards regression.
    

Intervention name(s): intravesical electromotive administration of mitomycin
Intervention type(s): Combination Product
Intervention MeSH terms: Mitomycins; Mitomycin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: non-muscle invasive bladder cancer