Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy

Abstract

Background and objectives: Cyclophosphamide treatment improves renal survival in patients with idiopathic membranous nephropathy. However, use of cyclophosphamide is associated with cancer. The incidence of malignancies in patients with idiopathic membranous nephropathy was evaluated, and the cancer risk associated with cyclophosphamide use was estimated.

Design, setting, participants, & measurements: Patients who attended the clinic were included prospectively from 1995 on. A crude incidence ratio for the occurrence of malignancy was calculated. Incidence ratios were subsequently standardized to potential confounders. Latency between cyclophosphamide therapy and the occurrence of cancer was estimated by stratifying for time since the start of treatment. Finally, Poisson regression was used to obtain a multiple adjusted incidence ratio and investigate the dose-response relationship between cyclophosphamide and cancer.

Results: Data were available for 272 patients; the mean age was 51 years, and 70% of the patients were men. Median follow-up was 6.0 years (interquartile range=3.6-9.5), and 127 patients were treated with cyclophosphamide. Cancer incidence was 21.2 per 1000 person-years in treated patients compared with 4.6 per 1000 person-years in patients who did not receive cyclophosphamide, resulting in crude and adjusted incidence ratios of 4.6 (95% confidence interval, 1.5 to 18.8) and 3.2 (95% confidence interval, 1.0 to 9.5), respectively.

Conclusion: Cyclophosphamide therapy in idiopathic membranous nephropathy gives a threefold increase in cancer risk. For the average patient, this finding translates into an increase in annual risk from approximately 0.3% to 1.0%. The increased risk of malignancy must be balanced against the improved renal survival.

Keywords: GN; anti-phospholipase A2 receptor antibodies; cancer incidence; cohort study; cyclophosphamide; dose response relation; latency; malignancy; membranous nephropathy.

Figure 1.

Flowchart for inclusion in the cohort. *The median time between biopsy and start of cyclophosphamide exposure was deducted from the exposure time of controls to adjust for time not at risk. As a result, 11 patients had negative exposure times and therefore, were excluded from the analyses (Materials and Methods). Two cyclophosphamide-treated patients were excluded: one patient was excluded because of a lung carcinoma in situ before treatment, and the other patient was lost to follow-up after the initiation of therapy. iMN, idiopathic membranous nephropathy.

Figure 2.

Cumulative incidence of malignancy for the total cohort of iMN patients. The solid line is the point estimate, and the dashed lines are the 95% confidence interval for the cumulative incidence. Death was considered competing for malignancy risk.

Figure 3.

Unadjusted incidence ratio of malignancy in iMN patients by time since cyclophosphamide exposure in 2-year strata. Vertical lines represent the 95% confidence intervals around the estimated incidence ratio. The horizontal lines signify interquartile range of follow-up time within each 2-year stratum.

Figure 4.

The dose–response relation between cumulative cyclophosphamide exposure in categories (not treated, 1–20, 21–40, 41–60, and >60 g) and the adjusted incidence ratio of malignancy in iMN patients. The untreated group has been chosen as the reference, and thus, the incidence ratio for malignancy is one in that group. The vertical lines represent the 95% confidence intervals around the incidence ratios. The dashed horizontal lines represent the range within the categories for the cumulative cyclophosphamide dose.