OBJECTIVES: Tumor necrosis factor (TNF) plays an important role in inflammation and tumor growth control. A previous meta-analysis of randomized controlled trials (RCTs) of anti-TNF antibody therapy in rheumatoid arthritis (RA) associated their use with an increased risk of malignancy [1]. To assess the risk of malignancy with etanercept, a fusion protein that inhibits TNF action, we performed a meta-analysis using individual patient data from RCTs in patients with RA.
METHODS: We conducted a systematic search of four bibliographic databases, abstracts from annual meetings of both EULAR and ACR, and any unpublished studies on file with manufacturers through December 2006. We included only RCTs of etanercept used for 12 weeks or more in patients with RA. Nine trials met our inclusion criteria after review of original study protocols. To adjudicate endpoints, the case narratives of potential cases were reviewed without knowledge of treatment assignment. Patient-level data were extracted from the clinical trials databases.
RESULTS: The 9 trials included 3316 patients, 2244 who received etanercept (contributing 2484 person-years (PY) of follow up) and 1072 who received control therapy (1051 PY). Malignancies were diagnosed in 26 patients in the etanercept group (incidence rate (IR) 10.46/1000 PY) and 7 patients in the control group (IR 6.66/1000 PY). A Cox's proportional hazards, fixed-effect model stratified by trial yielded a hazard ratio of 1.84 (95% CI: 0.79 to 4.28) for the etanercept group compared to the control group. Results were substantially similar in additional analyses that used a random-effects model, excluded non-melanoma skin cancers from the case definition, and truncated follow up at 6 months, 1 year and 2 years. In a secondary analysis based on aggregate study-level data using Mantel-Haenszel methods with a continuity correction designed for sparse data, the pooled odds ratio was 1.93 (95% CI: 0.85 to 4.38).
CONCLUSION: In this meta-analysis the point estimate of malignancy risk was higher in etanercept-treated patients compared to the control group, although the results were not statistically significant. The relative risk estimates for etanercept were not inconsistent with the pooled odds ratio of 2.4 (95% CI: 1.2 to 5.6) from a meta-analysis of RCTs in patients with RA that compared the anti-TNF antibodies adalumimab and infliximab to placebo, although there were some methodological differences between meta-analyses.* The sparse number of events in our study precludes the ability to draw definitive conclusions due to limited power.
