Cyclophosphamide-Induced Cystitis and Bladder Cancer in Patients with Wegener Granulomatosis

OBJECTIVE: To describe the incidence of, clinical manifestations of, and risk factors for cyclophosphamide-induced urinary bladder toxicity in patients treated for nonmalignant disease. DESIGN: Retrospective analysis of patients followed at the National Institutes of Allergy and Infectious Diseases from 1967 to 1993. SETTING: The Warren G. Magnuson Clinical Center of the National Institutes of Health (NIH). PATIENTS: 145 patients who received cyclophosphamide for the treatment of Wegener granulomatosis and were followed for 0.5 to 27 years (median, 8.5 years), for a total of 1333 patient-years. MEASUREMENTS: Clinical characteristics, cystoscopic findings, results of cytologic examination of urine, surgical pathology, and total dose and duration of cyclophosphamide therapy were recorded and analyzed using a computer-based information retrieval system. RESULTS: Nonglomerular hematuria occurred in 73 of 145 patients treated with cyclophosphamide (50%). Sixty of the 73 patients with nonglomerular hematuria (82%) had cystoscopy at the NIH. Forty-two of the 60 patients (70%) who had cystoscopy had macroscopic changes consistent with cyclophosphamide-induced bladder injury. Seven patients (5%) developed transitional-cell carcinoma of the urinary bladder. In 6 of these 7 patients, the total cumulative cyclophosphamide dose exceeded 100 g, and the cumulative duration of cyclophosphamide therapy exceeded 2.7 years. Before they were given a diagnosis of bladder cancer, all 7 patients had had one or more episodes of microscopic or gross nonglomerular hematuria. In contrast, none of the 72 patients who had never had nonglomerular hematuria developed bladder cancer. Cox proportional hazards regression analysis showed that only microscopic nonglomerular hematuria was a significant risk factor for the development of bladder cancer (P < 0.01). CONCLUSION: Long-term oral cyclophosphamide therapy is associated with substantial urotoxicity, including the development of transitional-cell carcinoma of the urinary bladder. In this cohort of patients, the estimated incidence of bladder cancer after the first exposure to cyclophosphamide was 5% at 10 years and 16% at 15 years. Nonglomerular hematuria was a frequent manifestation of cyclophosphamide-induced cystitis, and it identified a subgroup of patients at high risk for the development of bladder cancer.