Incidence and predictors of urotoxic adverse events in cyclophosphamide‐treated patients with systemic necrotizing vasculitides

Abstract

Objective. To assess hemorrhagic cystitis and urinary tract cancer incidence and predictors in cyclophosphamide (CYC)-treated patients with systemic necrotizing vasculitis (SNV).Methods. The French Vasculitis Study Group database, which contains longitudinal data on SNV patients, was searched for urinary tract cancer and/or hemorrhagic cystitis occurrences in patients diagnosed as having Wegener's granulomatosis (WG), microscopic polyangiitis, Churg-Strauss syndrome, or polyarteritis nodosa. The observed incidence of urinary tract cancer was compared to the expected incidence in the general population by calculating standardized incidence ratios (SIRs). Relationships between urinary tract cancer and/or hemorrhagic cystitis and 10 variables, including CYC dosage and administration route, were investigated by survival analyses for a nested subgroup of patients for whom detailed information on CYC exposure was available.Results. Among the 805 patients observed over 4,230 patient-years (mean followup 5.3 years), 22 cases of hemorrhagic cystitis and 7 of urinary tract cancer were identified in 27 patients. The SIRs for urinary tract cancer were 5.00 for all patients with SNV (P ‫؍‬ 0.001) and 5.96 for patients with WG (P ‫؍‬ 0.03). Based on 467 patients with detailed CYC information, cumulative CYC dose (hazard ratio [HR] for 10-gm increments 1.09; P ‫؍‬ 0.03), ever-oral CYC administration (HR 5.50; P ‫؍‬ 0.001), and WG (HR 2.96; P ‫؍‬ 0.01) independently predicted urinary tract cancer and/or hemorrhagic cystitis. According to univariate analyses, smoking (ever) (HR 8.20; P ‫؍‬ 0.02) and a prior hemorrhagic cystitis episode (HR 5.20; P ‫؍‬ 0.046) significantly predicted urinary tract cancer. Conclusion. Our findings indicate that CYC treatment of SNV is associated with a 5-fold higher risk of developing urinary tract cancer. Urotoxicity risk in SNV is associated with the cumulative CYC dose and its oral administration, and might be higher in WG.The alkylating agent cyclophosphamide (CYC) is a cytotoxic drug widely given, by either intravenous (IV) or oral routes of administration, to treat solid and hematologic malignancies (1) and rheumatic diseases, e.g., systemic lupus erythematosus, systemic sclerosis, or systemic necrotizing vasculitis (SNV) (2). It has long been recognized that CYC has substantial adverse effects, such as infections, secondary hematologic cancers, and urotoxicity. CYC-related urotoxicity includes hemorrhagic cystitis (3-5) and urinary tract cancers of the bladder (6,7) and, less commonly, the ureter and renal pelvis (8-10) that may occur long after the first CYC exposure (2). When CYC was used to treat nonHodgkin's lymphoma, cumulative 5-year hemorrhagic cystitis incidence rates of 12% and 12-year bladder cancer incidence rates of 11% (11) were reported, and the close link between cumulative CYC dose and secondary bladder cancer risk was established (12).In the setting of SNV, CYC-related urotoxicity has also raised concerns (13,14). In Wegener's granulomatosis (WG), an SNV frequently character...

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