Major Finding: The standardized incidence ratio for cancers at all sites indicated a 58% increased risk, compared with the general population (SIR 1.58; P = .003).
Data Source: Long-term follow-up of 493 patients with ANCA-associated vasculitis.
Disclosures: Dr. Heijl and her coauthors report no conflicts of interest.
An extensive range of cancers was found in long-term follow-up of patients with antineutrophil cytoplasm antibody–associated vasculitis, although the findings also suggest that the use of cyclophosphamide-sparing regimens could be paying off.
Among 493 evaluable patients in four randomized clinical trials, the standardized incidence ratio for all cancers indicated a 58% increased risk, compared with the general population (standardized incidence ratio, 1.58; P value = .003).
The only site-specific cancer that was significantly increased, however, was nonmelanoma skin cancer (NMSC), with an SIR of 2.78 (P = .001), reported Dr. Caroline Heijl on behalf of the European Vasculitis Study Group (EUVAS)
The SIR was 1.30 for cancers at all sites, excluding NMSC (P = .16), 2.41 for bladder cancer (P = .17), 3.25 for leukemia (P = .26), and 1.11 for non-Hodgkin's lymphoma (P = 1.0).
For the past 2 decades, researchers have been working to limit the use of cyclophosphamide in the treatment of patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) because of the increased incidence of cancer in AAV patients, reported to be 1.6-2.4 times higher than that of the general public.
Particularly worrisome have been cancer type–specific analyses showing an increased risk of bladder cancer and leukemia in AAV patients because of the known urothelial and hematologic toxicities of cyclophosphamide, and higher incidence of lymphoma and NMSC, Dr. Heijl wrote.
Three of the four trials that formed the basis of the analysis helped to advance cyclophosphamide-sparing regimens, demonstrating that cyclophosphamide use could be limited to the remission-induction phase, given as periodic intravenous pulses, or replaced by methotrexate.
“Although the lower cyclophosphamide exposure achieved by these treatment regimens remains difficult to quantify, the lower standardized incidence ratios for cancers in any site, particularly for bladder cancer and leukemia in our study population as compared with findings obtained earlier, could indicate that the more contained use of this drug might have started to show a benefit,” Dr. Heijl wrote (Ann. Rheum. Dis. 2011;70:1415-21).
The researchers analyzed long-term data from 535 patients with newly diagnosed AAV who had been enrolled in four trials organized by the EUVAS between March 1995 and September 2002. Follow-up ran from 2004 to 2007, with a mean of 4.85 years.
Among the 493 patients with detailed treatment data available, 53 definitive cancers were identified. They included 13 basal and 5 squamous cell carcinomas in 15 patients, and 35 non-NMSCs in 34 patients.
All 15 patients with NMSC had received cyclophosphamide, and 13 of those had also taken azathioprine. All four patients identified with bladder cancer had received cyclophosphamide for 6-36 months, with 2.1 to 6.6 years elapsing from the time of trial enrollment to bladder cancer diagnosis.
Three of the bladder cancers were observed in patients with granulomatosis with polyangiitis (GPA) and one in a patient with microscopic polyangiitis (MPA). Higher SIR was observed for cancers at all sites in GPA vs. MPA patients (SIR, 1.92 vs. 1.20), but their 95% confidence intervals overlapped. The corresponding relative risk was 1.60, reported Dr. Heijl of the nephrology department at Skåne University Hospital in Lund, Sweden.
A further analysis of three follow-up periods (less than 3 years, 3-5 years, and longer than 5 years) did not indicate a clear cancer incidence trend over time. Nevertheless, longer follow-up data are warranted to appraise the risk of developing cancers later during the course of AAV, the authors noted.