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Erythropoiesis-stimulating agents increase risk of death in cancer patients with anemia

A new study by Northwestern University's Feinberg School of Medicine has shown that cancer patients take drugs to boost their red blood cells, called erythropoiesis-stimulating agents ( ESAs ), actually raise patients' risk of death, possibly by stimulating the growth of cancer cells.

A meta-analysis of 51 trials with 13,613 patients revealed a 10 percent increased risk of death among cancer patients taking ESAs compared to patients who did not take them.

The study, lead by Charles Bennett, at the Feinberg School, is published in the Journal of the American Medical Association ( JAMA ).

The Northwestern study is the first to demonstrate a quantifiable increased risk of death from EPAs and is based on the largest number of trials ever examined for this purpose.

One of the study's co-authors, Stephen Lai, at the University of Pittsburgh Medical Center, tested the response of cancer cells to an ESA in the laboratory.
Lai saw a significant effect when he added an ESA called Erythropoietin to head and neck cancer cells in tissue culture.

" We saw a dramatic change," Lai said. "Adding Erythropoietin to the cells increased their ability to migrate or invade. Our basic science findings and the clinical trial results suggest that giving cancer patients Erythropoietin for their anemia may actually cause their tumors to progress."

The FDA ( Food and Drug Administration ) approved the Epoetin alpha ( Epogen, Procrit ) and Darbepoetin ( Aranesp ) as a treatment for anemic cancer patients to avoid blood transfusions.
However, evidence linking these drugs to a higher risk of death has been mounting.
In March 2007, the FDA issued a public health advisory on EPAs, warning of an increased risk of serious and life-threatening side effects.

ESAs produced up to $6 billion in cancer-anemia related sales last year for pharmaceutical firms, Bennett said, and represented Medicare's largest pharmaceutical expenditure.

Bennett began investigating these drugs when the study's senior author, Michael Henke, at the University of Freiburg in Germany, first raised an alarm in 2003. For the new study, Bennett and his co-authors updated a 2006 analysis by the Cochrane Collaboration with more recent statistics from 13 additional Phase III trials. The 2006 Cochrane study did not show an increased risk of death, Bennett said.

The Northwestern study also confirmed a previously known 57 percent increased risk of blood clots in the legs or lungs for cancer patients receiving ESAs. But the higher blood clot risk did not explain the 10 percent increased risk of death shown in his study, Bennett said.

" We know that ESA's may prevent a blood transfusion, but if I had cancer and I needed a blood transfusion, I would be much more conservative about taking ESAs," Bennett said. " The current FDA recommendation is these drugs are safe for cancer patients as long their hemoglobin levels aren't raised too high. Our data do not support that."

Lai cautioned that various solid tumors such as breast cancer, colon cancer and melanoma may react differently to ESAs. " The exact effect and size of that effect may be different depending upon the type of tumor. Additional research is clearly necessary, and we have to be careful about generalizing these results before further research is conducted," he said.

Source: Northwestern University, 2008