A RANDOMIZED STUDY EVALUATING MAINTENANCE SCHEDULE IN EARLY ADJUVANT CHEMOTHERAPY FOR INTERMEDIATE RISK NON-MUSCLE-INVASIVE BLADDER CANCER.

ABSTRACT Introduction and Objective: Adjuvant intravesical chemotherapy or BCG immunotherapy after transurethral resection (TUR) is a standard treatment for non–muscle-invasive transitional cell cancer of the bladder (NMI TCCB) at intermediate risk. Although the clinical value of early intravesical adjuvant chemotherapy is well established, the optimal schedule regimen and the role of maintenance is still debated. Methods: Between May 2002 and August 2003, 577 patients, undergoing TUR for NMI TCCB, were recruited. All patients underwent TUR and early (within 6 hours) intravesical chemotherapy with epirubicin at the dose of 80 mg diluted in 60 ml of saline solution. When histology was available, 95 patients were excluded from the study since they were harbouring T1G3, Tis and single and primary Ta G1-G2 tumors. 482 patients with intermediate risk tumors were randomized according 2 different regimens: arm A: 5 more weekly instillations; arm B: 5 more weekly instillations plus monthly instillations for a total of 16 instillations. All patients were submitted 3-monthly for the first 2-years and then 6-monthly to cytology, cystoscopy and biopsy of every suspicious bladder lesion.. Results: Out of 482 randomized patients, 396 are evaluable for toxicity and 392 for efficacy. The tumours were multiple in 318 patients (66.0%) and recurrent in 192 (39.8%). No difference emerged between the 2 arms in relation to tumors’ characteristics. The median follow-up time was 22 months (range: 3-56). Eighty-two (20.9%) patients recurred at a median time of 9 months from TUR and 4 patients (1%). The incidence of recurrences was 24.4% (47/192) in arm A and 18.5% (35/200) in arm B. No difference emerged between the two arms for recurrence rate at 3 months (p=0.06). Statistical analysis demonstrated an advantage in favour of maintenance in terms of recurrence rate at 6 (p=0.01), 9 (p=0.04) and 12 months (p=0.03) and in terms of recurrence-free interval (p=0.03). No difference for toxicity was detected according to treatment schedule. Conclusions: One-year maintenance significantly reduces the risk of tumour recurrence without enhanced toxicity, in patients with intermediate risk NMI TCCB treated with early epirubicin intravesical chemotherapy followed by 5 weekly instillation.