WASHINGTON, DC–A large observational study reported at the American College of Rheumatology 2006 meeting challenges meta-analysis data that showed greatly increased cancer risk associated with TNF inhibitor therapy.^1,2 Frederick Wolfe, MD, from the National Data Bank for Rheumatic Diseases, Wichita, Kansas,  reported data on 14,869 rheumatoid arthritis (RA) patients, 6507 of whom had been treated with biologics. All had at least 1 year of follow-up, and the total included over 49,000 patient-years of observation.

"Our conclusions are that melanoma and nonmelanoma skin cancer rates are increased in RA patients treated with biologics and that there is no increase in solid tumors. Therefore, at least two large observational studies are in substantial disagreement with the meta-analysis," Dr. Wolfe said.

Study analyzed new cancer cases in RA patients

The investigators studied incident cases of cancer among the subjects participating in a study of RA outcomes.  Dr. Wolfe said that cancer reports were validated by hospital, physician, and death records, except for nonmelanomatous skin cancers, which were based on self-report and follow-up interview. Biologic therapy use was classified as ever or never, by duration of individual biologic use, and by duration of total biologic use.

The US National Cancer Institute SEER data bank was used to estimate general population cancer rates for comparative purposes. The cancer types examined included breast, colon, lung, lymphoma, melanoma, and nonmelanomatous skin cancer. Biologic therapy was associated with increased rates of melanoma and other skin cancers (primarily basal cell) but not any of the other cancers, including lung cancer and lymphoma.

"This report confirms the results of European studies and shows an overall increase in lymphoma and lung cancer and decrease in breast and colon cancer in persons with RA, as well as non-increase when all cancers are considered simultaneously," Dr. Wolfe said. "There was no association between either infliximab or etanercept and all cancers, lung cancers, and lymphomas. Rates of melanomas and skin cancers were approximately equal for infliximab and etanercept." He cautioned that longer follow-up may be needed for definitive answers regarding the association of TNF inhibitors with cancer types other than melanomas and other skin cancers.

Why do observational studies and meta-analyses of RCTs show different outcomes?

During the discussion period, Dr. Wolfe said that the conflicting outcomes of the observational studies and the meta-analysis of randomized clinical trial data are hard to reconcile.

"I posed that question to [a doctor from the FDA]," Dr. Wolfe said, acknowledging his own puzzlement. "I said, 'Look, we study thousands and thousands of patients, and we don't see an effect, but the clinical trial studies do show an effect. How do you explain that?'" One possibility suggested was that anti-TNF therapy might unmask ongoing cancer processes that would show up in relatively short-term clinical trials data, but fade into the background over time and not be apparent in longitudinal studies of RA patients treated with TNF inhibitors or other biologics as compared with patients who were treated with other drugs.

Table 1: Association of Biologic Therapy and Subsequent Malignancy*

Malignancy	Odds Ratio	P
All cancers	1.0	.858
Melanoma	2.3	.070
Nonmelanomatous skin cancers	1.5	<.001

*14,869 subjects, including 6507 who used biologics, principally etanercept or infliximab.

Source: Wolfe F, et al. ¹