Biologics Do Not Raise Cancer Risk More Than DMARDs in RA

Janis C. Kelly

September 13, 2012

September 13, 2012 — Patients with rheumatoid arthritis (RA) who were treated with biologic response modifiers (BRMs) appear to be at no greater risk for cancer than similar patients treated with conventional drugs, according to a meta-analysis published in the September 5 issue of JAMA. The researchers, led by Maria A. Lopez-Olivo, MD, PhD, from the University of Texas M.D. Anderson Cancer Center, Houston, stress that patients with RA, regardless of treatment, have a higher cancer risk than patients without RA because of factors associated with the underlying autoimmune disease.

The new analysis complements data from previous studies in juvenile arthritis and provides additional reassurance for both clinicians and patients with RA regarding the safety of BRM treatments in RA. Data about possible associations between BRMs (primarily tumor necrosis factor [TNF] inhibitors) and cancer led the US Food and Drug Administration (FDA) in 2009 to require that a black box warning about cancer risk be added to the labelling for TNF inhibitors.

Senior author Maria E. Suarez-Almazor, MD, PhD, Barnts Family Distinguished Professor, chief of the Section of Rheumatology, and deputy chair of the Department of General Internal Medicine, University of Texas M.D. Anderson Cancer Center, told Medscape Medical News that the researchers' major conclusion is that malignancy risk is no greater in patients with RA treated with BRMs than in patients receiving other disease-modifying antirheumatic drugs (DMARDs) or placebo.

Dr. Suarez-Almazor said, "I think the data are reassuring for patients and clinicians. Many patients have been concerned because of the warnings related to anti-TNF agents with respect to malignancies. While we cannot say that there is no risk whatsoever, since a null hypothesis cannot be proven, we show that if any risk were present it would be very small, and minor with respect to the benefits that patients with rheumatoid arthritis can achieve with these agents. A caveat once again is that clinical trials have a relatively short duration and many patients will require these drugs for many years. Therefore, ongoing monitoring with observational studies of longer follow-up is required to ensure safety in the long term."

The meta-analysis was based on pooled results from 63 randomized controlled trials (RCTs) that included 29,423 patients treated with abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, or tocilizumab. Studies were selected that compared the safety of any BRM used in patients with RA with placebo and/or any traditional DMARDs with a minimum of 24 weeks of follow-up.

No statistically significant increased risk of developing malignancy was observed. Of the 29,423 patients, 211 (0.72%; 95% confidence interval [CI], 0.63% - 0.82%) developed a malignancy during the study period. This included 23 of 3615 patients in the BRM monotherapy group (0.64%; 95% CI, 0.42% - 0.95%), 123 of 15,989 patients in the BRM combination therapy group (0.77%; 95% CI, 0.65% - 0.92%), and 65 of 9819 patients in the control group (0.66%; 95% CI, 0.52% - 0.84%).

The 211 malignancies included 118 solid tumors, 48 skin cancers, 14 lymphomas, 26 unspecified tumor types, and 5 hematologic nonlymphomas. Although the risk for lymphoma with TNF inhibitors was doubled compared with in control patients (Peto odds ratio [OR], 2.1; 95% CI, 0.55 - 8.4), this difference did not reach statistical significance. In fact, no statistically significant risk was observed for specific cancer types.

Anakinra plus methotrexate decreased cancer risk more than methotrexate alone (Peto OR, 0.11; 95% CI, 0.03 - 0.45). Dr. Suarez-Almazor said, "[T]he results were not consistent, and given the number of comparisons performed in the subgroup analyses, this could be happening by chance. In a study such as this one, with so many comparisons and subgroup analyses, we look for consistency across results, which was not the case. This appeared to be an isolated finding. This said, most of the trials included in the analysis had 1 year of follow-up. It will be important to continue to examine long-term effects of these agents beyond 1 or 2 years with observational studies."

"Overall, our findings do not support an increased risk of malignancy for patients with RA receiving BRMs in RCTs of at least 24 weeks' duration," the authors conclude. "Additional systematic reviews of observational studies are needed to establish risk in the longer term. Although the findings suggest that BRMs 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."

Study limitations include a dependence on quality of data in the original trials; the inability to assess risk of bias; the use of only English, French, and Spanish articles and other possible publication biases; lack of blinding of data extraction; pharmaceutical funding of many of the trials included in the analysis; and possible confounding bias and lack of generalizability.

Dr. Suarez-Almazor added, "We know that patients with RA are at increased risk of lymphoma, but because of the lack of a strong association with any of the biologic therapies, we can't really infer that any of the pathways affected by these drugs are related to immune alterations leading to lymphoma. With respect to other cancers, we know that patients with RA have an increased risk for lung cancer, but this appears to be related to smoking as a risk factor for both RA and lung cancer. On the other hand, the incidence of colorectal cancer is reduced in patients with [RA], possibly because of a protective effect of [nonsteroidal anti-inflammatories]."

She concluded, "Bottom line, patients with RA may have different malignancies compared to the population at large because the prevalence of well-recognized risk factors for cancer may differ in patients with RA, as seen for lung and colorectal cancer."

Outside Experts Concur: Long-Term Risks Remain Uncertain

Pierre Le Blay, MD, from the Départment Thérapeutique et Médecine Physique Ostéoarticulaire, Unité Génétique Clinique at CHU Montpellier in France, reviewed the study for Medscape Medical News. Dr. Le Blay was lead author on a recent meta-analysis and systematic review of malignancy risk associated with TNF inhibitor treatment in patients with RA.

Dr. Le Blay said, "This meta-analysis appears to be very complete, with a large number of papers selected, and the distinction of having taken into account all BRMs. So far the risk of malignancy in RA was studied mainly with anti-TNF agents. This analysis is more reassuring and takes into account all BRMs encountered in more everyday practice. However, this association may lead to some confusion about the side effects of these treatments that do not have the same mechanism of action. The risk of malignancy with rituximab and its anti-CD 20 action, for example, cannot be compared to the risk with anti-TNF drugs; TNF alpha has a very complex action in carcinogenesis."

According to Dr. Le Blay, the main question unanswered now concerns risks associated with long-term use of BRMs.

"Indeed, the action of these treatments on carcinogenesis is poorly understood, and we cannot exclude a dose-cumulative effect after many years of treatment. The main challenge for studies and especially registries will therefore be to have long-term monitoring and an 'early warning' system," Dr. Le Blay said.

Frederick Wolfe, MD, director of the National Data Bank for Rheumatic Diseases in Wichita, Kansas, also reviewed the study for Medscape Medical News. Dr. Wolfe said, "I am convinced by the data. The researchers didn't overlook anything. There are always limitations, but this is a good view of the area. The biggest limitation is the inherent short-term look assessments. Observational studies will provide further answers in the future. Also, [the data do not indicate] whether treatments are safe in those with existing or past malignancies. But this study should provide a degree of assurance to physicians and patients."

The work of Dr. Suarez-Almazor is supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Disease. The authors, Dr. Le Bay, and Dr. Wolfe have disclosed no relevant financial relationships.

JAMA. 2012;308:898-908. Abstract