Solid malignancies among patients in the Wegener's granulomatosis etanercept trial

Abstract

Objective. Etanercept is a soluble fusion protein designed to inhibit tumor necrosis factor (TNF). During the Wegener's Granulomatosis Etanercept Trial (WGET), a placebo-controlled trial of etanercept given in addition to standard therapy for remission induction and maintenance, more solid malignancies were observed in the etanercept group than in the group treated with standard therapy alone. This study was undertaken to further explore the potential association between anti-TNF therapy and the development of malignancy in these patients.Methods. One hundred eighty patients with active WG were enrolled and followed up for a median of 27 months. At enrollment, disease characteristics, treatment history, specific medical history items, and information about previous WG treatments and risk factors for malignancy were recorded. During the trial, the occurrence of malignancies and other adverse events was recorded prospectively.Results. All 6 solid malignancies observed during the WGET occurred in the etanercept group (P ‫؍‬ 0.01 versus placebo group); based on a comparison of ageand sex-specific incidence rates, 1.92 solid malignancies would have been expected in this group. The solid malignancies included 2 cases of mucinous adenocarcinoma of the colon, 1 each of metastatic cholangiocarcinoma, renal cell carcinoma, and breast carcinoma, and 1 recurrent liposarcoma. There were no differences between the 2 treatment groups in sex distribution, disease severity, personal or family history of cancer, or tobacco and alcohol use. The etanercept group was older at baseline and less likely to be newly diagnosed with WG at the time of randomization. Patients who developed solid tumors were older than patients who did not. All etanercept-treated patients who developed solid tumors were also treated with cyclophosphamide during the trial. However, there were no differences between the groups in the amount of cyclophosphamide received during the trial or the percentage who had received cyclophosphamide before enrollment. There were also no differences in the mean duration of daily cyclophosphamide therapy or the maximum daily cyclophosphamide dosage before enrollment.Conclusion.

Cytokines

“…Subsequently, anti-TNF-a strategies were successfully applied to other related rheumatologic diseases (12) and then to inflammatory bowel disease (IBD) (13). However, anti-TNF-a therapy was not effective in ANCA vasculitis (14) and multiple sclerosis (MS) (15). A number of different strategies have been used to achieve therapeutic outcomes by cytokine manipulation.…”

TNFα blockade in human diseases: An overview of efficacy and safety

“…Studies in specific populations, however, have suggested some increased risk. For example, a study of ETA in patients with Wegener's granulomatosis, all of whom had previously received treatment with cyclophosphamide, reported an excess of solid tumors [103].…”

Natural Killer Cell Cytotoxicity in Rheumatoid Arthritis Patients Treated with TNF Inhibitors

“…[33][34][35][36] Particularly, the risk of solid tumor development is further increased in patients who concurrently use cyclophosphamide and anti-TNF agents. 37 Imai et al has shown that patients with low NK activity have a higher risk of cancer development during a follow-up period of 11 years. 38 The interactions between proliferating tumor cells, human leukocyte antigen system and NK-receptors have also been postulated to be responsible for tumor survival and progression.…”