Hyperthermia and Mitomycin C, Bacillus Calmette-Guerin, or Standard Therapy as Second-Line Therapy in Treating Patients With Recurrent Bladder Cancer
Hyperthermia and Mitomycin C, Bacillus Calmette-Guerin, or Standard Therapy as Second-Line Therapy in Treating Patients With Recurrent Bladder Cancer
RATIONALE: Hyperthermia therapy kills tumor cells by heating them to several degrees above
 normal body temperature. Drugs used in chemotherapy, such as mitomycin C and epirubicin
 hydrochloride, work in different ways to stop the growth of tumor cells, either by killing
 the cells or by stopping them from dividing. Biological therapies, such as bacillus
 calmette-guerin (BCG) and interferon alfa, may stimulate the immune system in different ways
 and stop tumor cells from growing. It is not yet known whether giving hyperthermia together
 with mitomycin C is more effective than giving BCG or standard therapy as second-line therapy
 in treating patients with recurrent bladder cancer.

 PURPOSE: This randomized phase III trial is studying how well hyperthermia given together
 with mitomycin C works compared with BCG or standard therapy as second-line therapy in
 treating patients with recurrent bladder cancer.
OBJECTIVES:

 Primary

 -  To determine whether hyperthermia in combination with mitomycin C versus bacillus
 Calmette-Guerin (BCG) or standard therapy as second-line therapy is effective in
 patients with recurrent non-muscle invasive bladder cancer following induction or
 maintenance therapy with BCG.

 -  To compare disease-free survival time in all patients.

 -  To compare complete response rate at 3 months in patients with carcinoma in situ.

 Secondary

 -  To compare progression-free survival, overall survival, safety and tolerability of
 treatments, quality of life, cost, and cost-effectiveness in these patients.

 -  To assess biomarkers of response to standard and investigational treatment.

 OUTLINE: This is a multicenter study. Patients are stratified according to presence of
 carcinoma in situ (yes vs no), prior bacillus Calmette-Guérin (BCG) therapy (induction vs
 maintenance), and participating center. Patients are randomized to 1 of 2 treatment arms.

 -  Arm I (experimental): Patients receive intravesical mitomycin C over two 30-minute
 instillations per session, and bladder hyperthermia (42 +/-2°C) is delivered in
 combination with each instillation. The suspension is maintained in the bladder for up
 to 2 hours. Treatment repeats once a week for 6 weeks followed by a 6-week rest period.
 Patients who are disease-free proceed to maintenance therapy consisting of one
 instillation of mitomycin C with bladder hyperthermia every 6 weeks for 1 year and then
 once every 8 weeks for 1 year. Patients who are disease-free at 24 months may continue
 treatment at the discretion of the clinician.

 -  Arm II (control): Patients receive 1 of the following treatment regimens depending on
 prior BCG treatment.

 -  Second course of BCG therapy (patients who failed previous induction BCG): Patients
 receive intravesical BCG (1 instillation) once a week for 6 weeks. The suspension
 is maintained in the bladder for up to 2 hours. Patients then receive maintenance
 therapy consisting of BCG once a week for 3 weeks in months 3, 6, 12, 18, and 24.
 Patients who are disease-free at 24 months may continue treatment at the discretion
 of the clinician.

 -  Standard therapy (patients who failed previous maintenance BCG): Patients receive
 standard therapy for BCG failure as defined by their treating centers. Standard
 therapy may include intravesical BCG alone, intravesical mitomycin C alone,
 intravesical epirubicin hydrochloride alone, or intravesical BCG in combination
 with interferon alpha.

 All patients undergo cystoscopic surveillance with or without a biopsy every 3 months for 2
 years. Urine, blood, and tissue samples are collected periodically for biomarker laboratory
 studies. Patients complete quality of life questionnaires (EORTC QLQ-BLS24, QLQ-C30, and
 EQ5D) at baseline, at 12 weeks, and at 6, 9, and 12 months.

 After completion of study treatment, patients are followed every 3 months for 1 year and then
 every 6 months thereafter.

 Peer Reviewed and Funded or Endorsed by Cancer Research UK
DISEASE CHARACTERISTICS:

 -  Diagnosis of non-muscle invasive bladder cancer

 -  Recurrent disease after undergoing induction or maintenance therapy with bacillus
 Calmette-Guérin (BCG), meeting any 1 of the following criteria:

 -  Stage Ta or T1 disease (grade 2 or 3)

 -  Carcinoma in situ with stage Ta or T1 disease (grade 1, 2, or 3)

 -  Carcinoma in situ alone

 -  Has undergone a second resection of all T1 disease to exclude muscle invasive disease

 -  No urothelial cell carcinoma (UCC) ≥ T2

 -  No recurrence of grade 1 UCC following BCG induction therapy

 -  No UCC involving the prostatic urethra or upper urinary tract

 PATIENT CHARACTERISTICS:

 -  WHO performance status 0-4

 -  WBC ≥ 3.0 x 10^9/L

 -  Absolute neutrophil count ≥ 1.5 x 10^9/L

 -  Hemoglobin ≥ 10 g/dL

 -  Platelet count ≥ 100 x 10^9/L

 -  Serum creatinine < 1.5 times upper limit of normal

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception

 -  Normal kidneys and ureters on imaging CT scan within the past 12 months

 -  Available for long-term follow-up with a life expectancy of the duration of the trial

 -  Must be fit and willing to undergo a full or partial cystectomy

 -  No known or suspected reduced bladder capacity (< 250 mL)

 -  No significant bleeding disorder

 -  No other malignancy within the past 5 years except nonmelanomatous skin cancer cured
 by excision, adequately treated carcinoma in situ of the cervix, or DCIS/LCIS of the
 breast

 -  No known allergy to mitomycin or bacillus Calmette-Guérin (BCG), or previously
 withdrawn from BCG treatment due to a related adverse event (e.g., systemic infection)

 -  No active or intractable urinary tract infection

 -  No urethral stricture or any situation impeding the insertion of a 20F catheter

 -  No bladder diverticula > 1 cm

 -  No significant urinary incontinence

 -  No concurrent implanted electronic devices (e.g., cardiac pacemakers) or metallic
 implants within the pelvis, lower torso, spine, hip, or upper femur

 -  No immunocompromised state for any reason

 PRIOR CONCURRENT THERAPY:

 -  At least 6 months since prior intravesical chemotherapy, except for single
 instillation post-transurethral resection

 -  No prior pelvic irradiation

 -  No prior hyperthermia in combination with intravesical mitomycin

 -  Concurrent participation in other studies allowed

 -  No current or long-term use of corticosteroids

 -  No concurrent chemotherapy