TNF Blockers Not Seen To Boost Cancer Risk In RA Patients Tracked In Large Spanish Registry

The only elevated cancer type in patients taking the biologic drugs was non-melanoma skin cancer, investigator reports at rheumatology scientific conference.

SAN FRANCISCO - Tumor necrosis factor antagonists do not appear to increase the risk of cancer among rheumatoid arthritis patients tracked by Spanish medical registries over the past several years, according to data presented at the American College of Rheumatology/Association of Rheumatology Health Professionals' annual scientific conference.

The study, presented Oct. 27, addresses concern that anti-TNF therapy could make patients more susceptible to malignancies because any agent that would deplete tumor necrosis factors might also then enable malignancies to develop and proliferate.

A widely publicized meta-analysis conducted by Mayo Clinic researchers had suggested a possible increase in solid tumor malignancies. Other studies of possible cancer risk have produced mixed results, but smaller registries have failed to document a link.

The Mayo study, published in the May 17, 2006, Journal of the American Medical Association, found "evidence of an increased risk of serious infections and a dose-dependent increased risk of malignancies in patients with rheumatoid arthritis treated with anti-TNF antibody therapy."

Subgroup analysis of nine randomized clinical trials "that used high- and low-dose groups of anti-TNF treatment revealed a consistent and significant difference of the pooled estimate between dose groups," the article said. But it also advised that the adverse event risk "has to be interpreted in the light of the high effectiveness of anti-TNF therapy" (¹ (Also see "Remicade “Black Box” Warning On Risk Of Lymphoma Added To Label" - Pink Sheet, 19 May, 2006.)).

FDA is in the midst of an investigation into a link between tumor necrosis factor blockers and lymphoma and other cancers in children who take the products for juvenile idiopathic arthritis and Crohn's disease (² (Also see "Anti-TNFs’ Link To Cancer In Children Under Investigation By FDA" - Pink Sheet, 4 Jun, 2008.)).

Labeling for the four TNF blockers approved in the U.S. -Johnson & Johnson's Remicade , Amgen/Wyeth's Enbrel , Abbott's Humira and UCB's Cimzia - includes a warning on the risk of cancer.

Labeling for Enbrel and Humira carries a warning on malignancies, while Remicade's prescribing information includes a black box warning on rare cases of hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease.

Cimzia, the first pegylated anti-TNF, was approved for Crohn's disease in April (³ (Also see "Three’s A Crowd: Cimzia Joins Humira, Remicade For Crohn’s Disease" - Pink Sheet, 5 May, 2008.)). The approval includes a Risk Evaluation and Management Strategy requiring UCB to conduct a 10-year study assessing long-term risk of the product, including lymphoma and other cancers.

Study encompassed 40 percent of RA patients in Spain

In the Spanish study, rates of cancer were compared in two rheumatoid arthritis cohorts reflecting approximately 40 percent of all rheumatoid arthritis patients in Spain.

The first was the BIOBADASER registry, a safety database that has followed 4,529 patients receiving anti-TNF-a agents since 2001. For comparison, the researchers examined data from 2,243 patients enrolled in the Spanish EMECAR study from 1999 to 2005 who did not receive anti-TNF-a biologics.

Patients receiving the biologic agents were, on average, 7 years younger than were those in the control group, and had more severe disease, as measured by their higher mean Disease Activity Score. Disease duration was similar in both groups, at nine to 10 years.

A total of 99 incident cancer cases were found in the cohort of 6,772 patients: 70 in the larger anti-TNF-a group, and 29 in the control group, Loreto Carmona Ortells, director of the research unit of the Spanish Foundation of Rheumatology in Madrid, said at a press conference at the ACR conference.

The crude incidence risk ratio (IRR) for developing cancer was halved in the anti-TNF-a group, at 0.46. After adjustment for age, sex, disease duration, and disease activity, however, the IRR was nearly identical for patients who had received biologic therapy as it was for those who had not, at 0.92.

Cancers in the study were mostly common malignancies, such as breast cancer, Ortells said. The only elevated cancer type in patients taking biologic drugs was non-melanoma skin cancer. Patients with rheumatoid arthritis face a heightened risk of certain cancers, especially hematologic malignancies and lung cancer.

Patients' lung cancer risk may be caused by smoking, as in the general population, but their apparent vulnerability to hematologic cancer is thought to be related to prolonged inflammation associated with the disease.

Products could reduce risk of inflammation-associated cancers

Rather than being a cancer driver, then, some researchers say they believe long-term biologic therapy may have the opposite effect.

"I think in the long term, the inflammation is going down, so the risk of [inflammation-associated] cancer is also going down," Ortells said.

The large Spanish registry study was composed of 14,001 person-years of data, and its detailing of cancer incidence is "very encouraging, very reassuring," said Michael Weinblatt, professor of rheumatology, immunology, and allergy at Harvard Medical School and Brigham and Women's Hospital, in an interview at the scientific conference.

Weinblatt, who was not involved in the study, said he was not surprised by the results. But he said the size and power of the study may ease patients' and physicians' concerns about long-term safety.

In an interview, Ortells addressed what she believes may have produced an apparent rise in malignancies in the Mayo Clinic study and other nonregistry investigations.

Cancer risk may seem elevated in the early months of biologic therapy because previously undetected cancers emerge quickly in the face of TNF-a antagonists, she explained.

In the first six months of exposure, patients in the BIOBADASER registry had a cancer incidence rate of 7/10,000, while after five years of exposure, that rate was 59/10,000.

- Betsy Bates and Denise Peterson ([email protected])

[Editor's note: This story contains reporting from the staff of Elsevier Global Medical News. For more information on those publications, please contact Michael Magoulias at 240-221-4530.]