European Regulators Say Transfusions Safer Than ESAs in Cancer

Allison Gandey

June 30, 2008

June 30, 2008 — In a startling recommendation, the European Medicines Agency is urging oncologists to favor transfusions over erythropoiesis-stimulating agents (ESAs). The popular drugs have been used to treat cancer-related anemia for close to 20 years and have become a mainstay of therapy. The new recommendation is encouraging clinicians to reverse this common practice.

Studies suggesting worse outcomes for patients taking ESAs are mounting. Researchers are questioning whether the drugs have an off-target effect and whether they might even be fueling tumor progression. More study is needed, but the data available so far have prompted safety concerns among regulators around the world.

The European agency's committee has reviewed new data from studies that showed an increased risk for tumor progression, venous thromboembolism, and shorter overall survival in patients who received ESAs.

"In cancer patients with a reasonably long life expectancy, the benefit of using epoetins does not outweigh the risk of tumor progression and shorter overall survival," the committee noted in a statement.

Risk for Tumor Progression and Shorter Overall Survival

In March, a US Food and Drug Administration advisory committee also explored safety concerns related to ESAs, but the regulators did not go as far as recommending blood transfusions over ESAs.

In the United States, regulators and industry changed the product labeling for the drugs to include a boxed warning — the strongest warning for an FDA-approved product — and made modifications to the dosing instructions.

The agency recommends that prescribers use the lowest dose of ESAs that will gradually increase the hemoglobin concentration. The label also warns that the products increase the risk for death and serious cardiovascular events when administered to target a hemoglobin of greater than 12 g/dL.

The FDA first approved epoetin alfa in 1989 for the treatment of anemia associated with chronic renal failure. Manufactured by Amgen, the products are marketed under 2 different brand names: Amgen distributes Epogen, and Ortho Biotech, a subsidiary of Johnson & Johnson, distributes Procrit.

Amgen was not available to comment on the new European recommendation, but in a June statement, company representatives told Medscape Oncology that "there is no definitive evidence of Epo-receptor involvement in tumor progression and no reliable evidence that the Epo-receptor is present in cancer cells."

Amgen has recently been studying transfusion rates and outcomes, but critics say that research in this area has been laden with end-point problems. Earlier this month, Michael Henke, MD, from University Clinics in Freiburg, Germany, said in an interview that researchers haven't been asking the right questions. Work has focused on hemoglobin levels and now transfusion rates, not overall survival, he noted.

It was Dr. Henke and his team that first sounded the alarm about safety in their paper published in 2003 (Lancet. 2003; 362:1255-1260). Dr. Henke said it has taken too long to see safety problems with these drugs. "More ESA studies should have been ongoing."

Safety Problem Took Too Long to Identify

Fadlo Raja Khuri, MD, from the Emory University School of Medicine in Atlanta, Georgia, said he agrees. At the annual meeting of the American Society of Clinical Oncology earlier this month, Dr. Khuri, as part of a discussion panel, criticized the amount of low-level and largely inadequate data on ESAs.

Panelist Deborah Schrag, MD, from the Dana-Farber Cancer Institute, in Boston, Massachusetts, shared many of these concerns and urged caution moving forward.

For now, the European Medicines Agency has this advice: "Doctors and patients are advised that the decision to administer epoetin-containing medicines should be based on an informed assessment of the benefits against the risks on an individual basis, taking into account the type and stage of tumor, the degree of anemia, the patient's life expectancy, the environment in which the patient is being treated, and patient preference."

The new recommendation will not affect patients taking the drugs for chronic kidney failure.


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