Treatment with biologic response modifiers did not predispose patients with rheumatoid arthritis (RA) to an increased risk of cancer, according to an analysis of clinical trials involving almost 30,000 patients.

Patients treated with biologic agents, either alone or in combination with methotrexate, had cancer rates similar to the 0.66 percent observed among patients in the control groups.

The only notable variation was a nonsignificantly higher risk of lymphoma in patients treated with tumor necrosis factor (TNF) inhibitors, as reported in the Sept. 5 issue of JAMA.

"Overall, our findings do not support an increased risk of malignancy for patients with RA receiving biologic response modifiers in randomized controlled trials of at least 24 weeks' duration," Maria Suarez-Almazor, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and co-authors wrote in conclusion.

"Although the findings suggest that biologic response modifiers may be generally safe with respect to risk of malignancy in the short term, the risk of recurrence in patients with RA with history of cancer or cancer risk factors remains unknown," they added.

Use of biologic response modifiers to treat RA has increased dramatically since the first agents were introduced in the 1990s. A recent analysis of U.S. and European registry data suggested that as many as 56 percent of patients with RA receive biologic agents (Semin Arthritis Rheum 2010; 40: 2-14).

The current spectrum of biologic agents encompasses TNF inhibitors, an interleukin (IL)-1 receptor antagonist, anti-CD20 antibodies, a T-cell-activation inhibitor, and an IL-6 inhibitor. Although the drugs differ mechanistically and structurally, they have in common the therapeutic strategy of immunomodulation, posing at least a theoretical risk of malignancy.

Studies of malignancy risk in patients treated with TNF inhibitors have yielded conflicting data, the authors wrote in their introduction. Observational studies have produced relative risks as low as 0.7 to as high as 5.0, depending on the type of malignancy evaluated.

Almost a dozen meta-analyses have examined cancer risk among RA patients treated with TNF inhibitors. Suarez-Almazor and colleagues extended the analysis to cancer risk to RA patients treated with any of the nine approved biologic response modifiers for a minimum of 6 months.

From a review of electronic databases, conference proceedings, and regulatory-agency websites, they identified 63 randomized controlled trials involving 29,423 patients with RA, of whom 15,989 received biologic response modifiers.

The investigators documented 211 malignancies in the 29,423 patients, resulting in an overall rate of 0.72 percent. The malignancies consisted of 118 solid tumors, 48 skin cancers (four cases of melanoma), 14 cases of lymphoma, five nonlymphoma hematologic malignancies, and 26 unspecified malignancies.

The malignancies occurred in 23 of 3,615 patients who received monotherapy with a biologic response modifier (0.42 percent), in 123 of 15,989 patients who received a biologic as a component of combination therapy (0.77 percent), and in 65 of 9,819 patients in control groups (0.66 percent).

The authors calculated the Peto odds ratios and continuity correction for 0-total-event trials, in addition to the relative risk of malignancy, for each of the biologic agents. They focused on the Peto odds ratios, which they described as most appropriate for analysis of low-frequency events.

The only statistically significant risk of malignancy occurred in the comparison of patients who received TNF inhibitor-methotrexate combination therapy versus control groups, resulting in an odds ratio of 2.1. However, random effects decreased the risk to a nonsignificant level.

No other analyses produced significant differences in malignancy risk, including TNF inhibitors versus control groups treated with methotrexate or nonbiologic disease-modifying drugs, individual TNF inhibitors, and non-TNF inhibitors. The combination of anakinra (Kineret) and methotrexate significantly reduced the odds of malignancy compared with methotrexate alone.

Patients treated with anakinra also had a lower odds for nonmelanoma skin cancer versus control groups.

The risk of lymphoma was doubled among patients treated with TNF inhibitors, but the difference did not achieve statistical significance.

"There was no statistically significant increased risk of any type of cancer with use of biologic response modifiers versus controls," the authors wrote in their comments about the findings.

Limitations of the study included: lack of data in some studies to assess risk of bias, use of trials only in English, Spanish, and French, lack of blinding for data abstraction, pharmaceutical industry funding of most of the trials, and lack of generalizability for data from randomized clinical trials.

Source: Biologics for RA Pose No Early Cancer Risk