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

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.