Combined-modality therapy with gemcitabine and radiotherapy as a bladder preservation strategy: Results of a phase I trial

Purpose: We conducted a phase I trial of gemcitabine given twice weekly with concurrent radiotherapy in patients with muscle-invasive bladder cancer. Patients and Methods: Eligible patients underwent maximal transurethral resection of their bladder tumors followed by twice-weekly infusion of gemcitabine with 2 Gy/d concurrent radiotherapy to the bladder, for a total of 60 Gy over 6 weeks. The starting dose of gemcitabine was 10 mg/m² with subsequent dose levels of 20, 27, 30, and 33 mg/m². The primary end point was the determination of the maximum-tolerated dose (MTD) of twice weekly gemcitabine with concurrent radiotherapy. Secondary end points included assessment of toxicity associated with combined-modality therapy and initial assessment of the rate of bladder preservation. Results: Twenty-four patients were enrolled and 23 were assessable for toxicity and response. No significant toxicity was demonstrated at the 10 or 20 mg/m² twice-weekly doses. Dose-limiting toxicity (DLT) occurred in two of three patients treated at 33 mg/m². Intermediate dose levels of 27 and 30 mg/m² were then evaluated. The MTD of gemcitabine was 27 mg/m². The DLT was systemic, manifested as an elevation in liver function tests, malaise, and edema. Fifteen of 23 patients (65%) are alive with bladders intact and no evidence of recurrent disease at a median follow-up of 43 months. Conclusion: Twice-weekly gemcitabine with concurrent radiotherapy at 2 Gy/d to a total dose of 60 Gy is well-tolerated. The MTD of gemcitabine is 27 mg/m². There is a high rate of bladder preservation in this selected group of patients.