Balancing efficacy and cancer risk of cyclophosphamide for patients with Wegener's granulomatosis

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SYNOPSISBACKGROUNDCyclophosphamide is a standard immunosuppressive therapy for Wegener's granulomatosis (WG), but is also a known carcinogen. The effect of cumulative cyclophosphamide dose on cancer risk in patients with WG is unclear.OBJECTIVESTo determine the risk of malignancy associated with cumulative cyclophosphamide dose in patients with WG.DESIGN AND INTERVENTIONPatients discharged from Danish hospitals with a diagnosis of WG were identified from national records. Patients who met the classification criteria for WG and who had complete medical records were included in the study. Cancer incidence in the study population was compared with that in the general population by using information from the Danish Cancer Registry. The standardized incidence ratio (SIR)-the observed number of cancers divided by the expected number-was calculated for all cancer types. The analysis was stratified by time since WG diagnosis and by cyclophosphamide dose. A dose of 36 g, roughly equal to treatment with 100 mg daily for 1 year, was taken as the cutoff between low and high cumulative doses of cyclophosphamide.OUTCOME MEASURESThe main outcome measure was the incidence of cancer in patients treated with low and high doses of cyclophosphamide compared with the general population. Whether the risk of cancer was influenced by treatment with a DMARD after initiation of treatment with cyclophosphamide was also examined.RESULTSThe search identified 293 patients with WG, who had a median age at diagnosis of 59 years. Median length of follow-up was 6 years. Forty-one patients received no cyclophosphamide, 129 received cumulative doses of 1-36 g, 76 received >36 g, and 47 received an unknown dose. Fifty cancers occurred in the study cohort over 2,121 person -years of follow-up; the SIR compared with the general population was 2.1 (95% CI 1.5-2.7). Particularly high rates were noted for bladder cancer (SIR 3.6, 95% CI 1.2-8.3), nonmelanoma skin cancer (SIR 4.7, 95% CI 2.8-7.3), and acute myeloid leukemia (AML; SIR 19.6, 95% CI 4.0-57). Median latency time for bladder cancer was 11.7 years, and the observed cases of AML occurred between 7 and 16 years after treatment. In patients who never received cyclophosphamide, no excess cancers were found. The SIRs associated with low and high doses of cyclophosphamide were 1.8 (95% CI 1.1-2.9) and 2.4 (95% CI 1.4-3.7), respectively. The risk of nonmelanoma skin cancer was significantly increased in both cyclophosphamide-treated groups, whereas the risks of bladder cancer and AML were significantly increased only in the high-dose group. Maintenance therapy with methotrexate or azathioprine after cyclophosphamide treatment was associated with higher rates of bladder and skin cancers; however, patient numbers for this analysis were small.CONCLUSIONCyclophosphamide treatment leads to an increased incidence of cancer in patients with WG, especially for cumulative doses >36 g; the risk of late-occurring bladder cancer or AML is particularly high.

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