New Study Probes Safety of Erythropoiesis-Stimulating Agents

Allison Gandey

June 10, 2008

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Investigators and industry discuss ESAs

June 10, 2008 (Chicago, Illinois) — A provocative new study has shown that erythropoiesis-stimulating agents (ESAs) might have an effect not only on red blood cells but on tumor blood vessels as well. The findings were presented here at the American Society of Clinical Oncology (ASCO) 44th Annual Meeting, where investigators emphasized that the work is preliminary and will require further study.

The finding comes in the wake of a recent US Food and Drug Administration (FDA) advisory-committee meeting exploring safety concerns about the drugs. As reported by Medscape Oncology in March, the committee reviewed the growing number of trials showing that cancer patients who receive ESAs have worse outcomes than those who do not.

Anthony Blau, MD, from the University of Washington, in Seattle, and his team investigated this question and explored whether erythropoietin-receptor messenger (m)RNA levels could identify patients susceptible to erythropoietin-induced tumor growth.

His group studied 101 tumors from patients enrolled in the ENHANCE trial. The controversial phase 3 randomized, double-blind, placebo-controlled trial showed that epoetin beta corrects anemia in head and neck cancer patients undergoing radiotherapy but does not improve cancer control or survival (Lancet. 2003;362:1255-1260). The authors of the trial, led by Michael Henke, MD, from University Clinics in Freiburg, Germany, suggested that disease control might even be impaired.

Dr. Henke worked on this new study with Dr. Blau, and they found that ESA-treated patients with unresected tumors that expressed erythropoietin-receptor mRNA levels above the median experienced a reduction in locoregional progression-free survival, compared with the placebo group (P = .02; n = 14).

They found a similar effect in patients with tumors that had high mRNA levels of Jak2. This is the primary transmitter of erythropoietin-receptor signals in red blood cells.

The investigators did not observe this effect in patients who had unresected tumors that expressed erythropoietin-receptor mRNA levels below the median (P = .80; n = 14). They observed no effect in patients with completely or partially resected tumors.

Molecular Test May Soon Predict Patient Response to ESAs

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Dr. Anthony Blau addresses the controversy over ESAs

At a news conference about the findings, Dr. Blau emphasized to reporters that these results are preliminary and will have to be confirmed with larger studies. "If this holds up, it will allow us to predict which patients should be treated with erythropoietin and which patients are more likely to have poor outcomes."

It is a prospect that news-conference moderator Julie Gralow, MD, ASCO's cancer communications committee chair and associate professor of medicine at the University of Washington, said is very exciting.

"ESAs offer many benefits, including decreasing anemia levels and decreasing transfusion rates, but several large trials have suggested that in cancer, there might also be some stimulatory effect." Dr. Gralow noted that any test that could confirm who would be able to take ESAs safely and who should avoid treatment would be beneficial.

Dr. Blau said the definitive answer to this question remains hidden in the file cabinets of pathologists. And he expressed frustration at not being able to access tumor blocks. "We are dependent on sponsors of phase 3 trials to assist us, and they need to come through here," he said at the news conference. "The answers can be known in a relatively short period of time."

To Investigators: Make Tumor Blocks Available

During the discussion period after Dr. Blau's presentation, David Steensma, MD, from the Mayo Clinic, in Rochester, Minnesota, encouraged investigators to make their tumor blocks available. "Erythropoietin does not operate in a vacuum, and this is a provocative association and 1 potential mechanism," he said.

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: Epogen and Procrit. Amgen distributes Epogen, and Ortho Biotech, a subsidiary of Johnson & Johnson, distributes Procrit.

Responding to Dr. Blau's study in a written statement, representatives from Amgen told Medscape Oncology that the company "believes 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."

The Amgen statement said that independent investigators have reached similar conclusions and added: "The potential for using Epo-receptor mRNA levels to predict tumor progression with ESAs is a hypothesis that has not been rigorously tested or validated."

ASCO Ethics Committee Presents Panel

This has been a hot topic of debate at the meeting. The ASCO ethics committee put together a panel to discuss the issue, and the question period following that session was peppered with strong opinions on both sides.

Deborah Schrag, MD, from the Dana-Farber Cancer Institute, in Boston, Massachusetts, was part of the panel that explored many controversial questions: Were ESAs approved too quickly on the basis of inadequate data? Were oncologists too eager to believe company claims that they were a safe and convenient fix for this important clinical problem? Did direct-to-consumer advertising fuel widespread enthusiasm for the products? Did this eagerness encourage inappropriate prescribing for asymptomatic patients and off-label uses?

The products were rapidly adopted by clinicians and quickly became among the most widely used in the United States. Fadlo Raja Khuri, MD, from Emory University School of Medicine, in Atlanta, Georgia, was also part of the panel. He pointed out that ESAs have been on the market for nearly 20 years, and he criticized the amount of low-level and largely inadequate data.

"I think it is a very intelligent drug and a very intelligent compound," Dr. Henke told Medscape Oncology. "People were excited to use it because anemia definitely is a problem in cancer patients. The problem is that it took too long to see eventual safety problems."

Dr. Henke said that more studies should have been conducted. And he suggested that for the studies that were undertaken, researchers were not asking the right questions. There were end-point problems with work that focused on hemoglobin levels instead of overall survival or other long-term safety issues.

Now many sponsored trials are focusing on transfusion rates and outcomes — arguably a new variation on the same end-point problem. Panelist Jennifer Malin, MD, from the Veterans Affairs Greater Los Angeles Healthcare System, in California, said she would like to see new trials comparing ESAs with transfusions.

Dr. Henke said the recent FDA committee finally asked the right questions and, in his opinion, gave the right answers.

New product labeling for ESAs includes a boxed warning — the strongest warning for an FDA-approved product — and modifications to the dosing instructions.

Summary of Label Changes for ESAs

The agency recommends that prescribers use the lowest dose of ESAs that will gradually increase the hemoglobin concentration to the lowest level sufficient to eliminate the need for red-blood-cell transfusion.
The label 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 agency reports that the use of ESAs shorten the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy.
The label states that ESAs were linked to shortened overall survival and increased deaths attributed to disease progression in patients with metastatic breast cancer receiving chemotherapy.
ESAs also increased the risk for death in patients with active malignant disease not undergoing treatment with chemotherapy or radiation therapy and are not indicated for this patient population.
The boxed warning also notes that patients treated before surgery with ESAs to reduce allogeneic red-blood-cell transfusions had a higher incidence of deep venous thrombosis.


Craig Tendler, MD, vice president of medical affairs at Ortho Biotech, told Medscape Oncology that he concurs with the new more conservative approach to ESA prescribing. "We now know there are specific patients at risk that either shouldn't be exposed to the drug or should be managed very carefully," he said. The company is working to educate clinicians to minimize risk and encourage appropriate product use.

"This will have an enormous impact on the practice of oncology," Dr. Blau said. "It is way less convenient to give transfused blood than to give shots of ESAs."

Dr. Blau's research team reports having financial ties to Hoffman-La Roche.

American Society of Clinical Oncology (ASCO) 44th Annual Meeting: Abstract 11007. Presented June 2, 2008.


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