Malignancies and cyclophosphamide exposure in Wegener's granulomatosis.

Wegener’s granulomatosis (WG) is characterized by necrotizing small-vessel vasculitis and granulomatous inflammation. Although it classically involves the upper and/or lower respiratory tracts (being the most common form of vasculitis to involve the lungs) as well as the kidneys, it can occur in virtually any organ1. Standard therapy for remission induction conventionally involves high-dose corticosteroids along with oral cyclophosphamide (CYC, 1–2 mg/kg/day). The high relapse rate of WG means repeated and prolonged courses of CYC in some patients. Such a regimen, while efficacious, is fraught with risks, as Faurschou and colleagues highlight in this issue of The Journal2. Their work in a large cohort of patients with WG demonstrates tremendously high cancer risk related to cumulative CYC therapy. Early studies assessing malignancy risk in WG have largely focused on CYC-related bladder cancers3. This is believed to be mediated by the toxic metabolite acrolein, which is excreted into the urine. Subsequent studies in WG have brought to light important increased risks (compared to the general population) for leukemia, lymphoma, and nonmelanoma skin cancer, in addition to bladder cancer4. These more recent reports are consistent with observations in other populations (specifically, rheumatoid arthritis, RA), where CYC exposure was also shown to be associated with an increased risk of cancer, notably non-melanoma skin and hematological malignancies5,6. Although CYC has long been thought to drive the increased risk of all of these malignancies in WG, the hypothesis was somewhat difficult to establish because of the almost ubiquitous exposure of patients to this agent. Talar-Williams, et al have previously demonstrated that the risk for bladder cancer was associated with both dosage and duration of treatment with CYC3. In the most recent assessment of cancer risk in WG, Faurschou and colleagues2 extend the previous study’s results by demonstrating very high risks of acute myeloid leukemia [AML; standardized incidence ratio (SIR) 59.0, 95% confidence interval 12–72] and bladder cancer (SIR 9.5, 95% CI 2.6–24) in patients treated with cumulative CYC doses > 36 grams. The risk of these malignancies was not shown to be increased for patients who never received CYC or for patients treated with cumulative doses ≤ 36 grams. It is important to note that these huge cumulative doses are related to the oral route of administration, which exposes the patient to up to 2 mg per kg of CYC a day. In contrast, cumulative doses are lower when CYC is given by intermittent pulse therapy. One limitation of the work by Faurschou, et al is that disease activity, which may potentially confound the association between cancer risk and medication exposure, was not controlled for. The risk-to-benefit ratio of pulse therapy, as an alternative to oral CYC, has been evaluated in several studies in the past decade. In one study, patients with newly diagnosed systemic WG were enrolled in a prospective, randomized trial (n = 50) of intravenous versus oral CYC for induction therapy. CYC was given for at least 1 year and then tapered. This study showed not only that pulse therapy was as effective as oral treatment for initial remission, but also that there were fewer adverse events, including mortality. However, in the long term, relapses occurred more often in the pulse therapy group (59.2%) than the oral CYC group (13%)7. In another study (of similar sample size, design, and duration) on vasculitis associated with antineutrophil cytoplasmic antibody (ANCA) and renal involvement, the cumulative CYC dose was halved in the pulse treatment group compared to the daily oral therapy group, and patient remission, relapse rate, progression to renal failure, and mortality appeared similar, with less toxicity in the pulse therapy group8. On the basis of such data, some have concluded that intravenous administration of CYC is more desirable than oral administration, in spite of the possibility of increased relapse rates with pulse therapy. To those who consider pulse CYC as a more optimal alternative to oral therapy, the study by Faurschou and colleagues may seem less relevant. However, as indicated