The use of biologic agents to treat rheumatoid arthritis doesn’t appear to be associated with an increased risk of malignancy, compared with either placebo or with other disease-modifying drugs, according to a report in the Sept. 5 issue of JAMA.
In a meta-analysis of 63 randomized clinical trials of at least 24 weeks’ duration involving 29,423 adults with RA, there was no increase in the risk of cancer in general or in the risk of specific cancers. "Additional systematic reviews of observational studies are needed to establish risk in the longer term," said Dr. Maria A. Lopez-Olivo of the University of Texas M.D. Anderson Cancer Center, Houston, and her associates.
They described their study as the first systematic review and meta-analysis to assess the risk of any type of malignancy solely in RA patients who were taking any of the nine biologic agents approved for such use: abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, or tocilizumab.
There has been concern that these agents could raise cancer risk because they interfere with the immune system. Some data have implicated tumor necrosis factor (TNF) inhibitors in particular, prompting the Food and Drug Administration to recommend adding a warning label citing an excess of cases of spontaneous lymphoma among children and adolescents taking TNF inhibitors.
"While trials in RA are relatively short and cannot evaluate the risk over longer-term exposure as observational studies do, we thought there was a need to conduct an updated meta-analysis of RCTs [randomized controlled trials] because of the older reports of the possible increase in malignancies and the more recent FDA advisory for TNF inhibitors, mostly based on studies in children," the researchers noted.
In the RCTs included in this meta-analysis, sample sizes ranged from 20 to 1,399 subjects. Most study subjects (79%) were white, and 76% were women. The mean duration of RA ranged from less than 1 year to 13 years.
Pharmaceutical companies sponsored 56 of the 63 trials, and another 3 did not disclose their funding sources. The remaining four trials were funded by national organizations, but the agents they used were provided free of charge by manufacturers. "There is evidence that industry-sponsored trials may overestimate the treatment effect and could possibly also overestimate safety," acacording to Dr. Lopez-Olivo and her associates.
A total of 15,989 study subjects were assigned to take biologic agents plus methotrexate and/or other disease-modifying antirheumatic drugs, while 3,615 were assigned to take the biologic agents alone and 9,819 served as control subjects who were given placebos.
A total of 211 malignancies developed during the trials, in 0.77% of the combination-therapy group, 0.64% of the monotherapy group, and 0.66% of the control group. These differences were not significant, the investigators said (JAMA 2012;308:898-908).
Skin cancers accounted for 48 of the malignancies (which included 4 melanomas), 14 were lymphomas, 26 were not specified, and 5 were hematologic nonlymphomas. The remaining 118 malignancies were solid tumors affecting a wide variety of organs including the adrenal glands, bladder, breast, GI system, liver, lung, ovary, pancreas, prostate, kidney, testes, thyroid, tongue, and uterus.
Thus there was no pattern involving a specific type of cancer.
Similarly, there was no pattern involving any of the individual biologic agents, Dr. Lopez-Olivo and her associates said.
"The only increased risk of malignancy we observed was in patients with RA treated with TNF inhibitors plus methotrexate at 52 weeks, for all cancers combined." However, this effect was not consistent across the three separate analytical methods the researchers used, did not occur in patients taking TNF inhibitors as monotherapy, and did not occur at any of the other three time points assessed.
The study findings "suggest that biologic, disease-modifying agents may be generally safe with respect to risk of malignancy in the short term," but their safety in RA patients who have concomitant cancer or risk factors for cancer remains unknown, the researchers said.
No sponsors were involved with this study, and no financial conflicts of interest were reported.