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Combined-Modality Therapy With Gemcitabine and Radiotherapy As a Bladder Preservation Strategy: Results of a Phase I Trial

From the Departments of Internal Medicine, Radiation Oncology, and Urology of the University of Michigan School of Medicine and the University of Michigan, Comprehensive Cancer Center

Address reprint requests to David C. Smith, MD, 7302 CCGC 0946, 1500 E Medical Center Dr, Ann Arbor, MI 48109; e-mail: dcsmith{at}umich.edu

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.

Supported in part by 2P30 CA 46592-14 from the National Cancer Institute and the National Institutes of Health and a grant from Eli Lilly and Company.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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