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

Cheryl Talar-Williams, MPH, PA-C; Yasmine M. Hijazi, MD; McClellan M. Walther, MD; W. Marston Linehan, MD; Claire W. Hallahan, MS; Irina Lubensky, MD; Gail S. Kerr, MD; Gary S. Hoffman, MD; Anthony S. Fauci, MD; and Michael C. Sneller, MD
[+] Article and Author Information

From the National Institutes of Health, Bethesda, Maryland. Note: Since the manuscript for this article was submitted, an additional study patient has been given a diagnosis of a grade II to III transitional-cell carcinoma of the bladder. The tumor developed after a lag time of 3 years and a latency period of 17 years. The patient is a 41-year-old nonsmoking white man whose cumulative cyclophosphamide dose was 264 g administered over 7 years. The indication for cystoscopy was routine follow-up for a history of cyclophosphamide-induced cystitis (presenting with microscopic nonglomerular hematuria). The results of the cytologic examination of voided urine obtained the day before cystoscopy showed changes consistent with therapeutic or viral effect and no evidence of atypia, dysplasia, or malignancy. Requests for Reprints: Michael C. Sneller, MD, National Institute of Allergy and Infectious Diseases, Building 10, Room 11B-13/10, Center Drive, MSC 1876, Bethesda, MD 20892-1876. Current Author Addresses: Ms. Talar-Williams, Ms. Hallahan, and Drs. Sneller and Fauci: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11B-13, 9000 Rockville Pike, Bethesda, MD 20892.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1996;124(5):477-484. doi:10.7326/0003-4819-124-5-199603010-00003
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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.

Figures

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Figure 1.
Cumulative risk for developing nonglomerular hematuria. Top.Bottom.

As a function of time receiving cyclophosphamide therapy. As a function of total cyclophosphamide dose.

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Figure 2.
Cumulative risk for developing nonglomerular hematuria as a function of time receiving cyclophosphamide therapy for smokers compared with nonsmokers.
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Figure 3.
Cumulative risk for bladder cancer in 145 patients treated with cyclophosphamide who had Wegener granulomatosis; time from first cyclophosphamide dose to development of bladder cancer.

Dashed lines represent 95% Cls.

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