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Examining the Involvement of Erythropoiesis-Stimulating Agents in Tumor Proliferation (Erythropoietin Receptors, Receptor Binding, Signal Transduction), Angiogenesis, and Venous Thromboembolic Events

^aInstitut für Physiologie, Universität Duisburg-Essen, Essen, Germany; ^bHematology-Oncology Service, Luxembourg Medical Centre, Luxembourg

Key Words. Erythropoietin receptor • Erythropoiesis-stimulating agents • Epoetin • Angiogenesis • Hypoxia • Thromboembolism • Venous thromboembolic events

Correspondence: Joachim Fandrey, M.D., Institut für Physiologie, Universität Duisburg-Essen, Hufelandstr 55, D-45147 Essen, Germany. Telephone: 49-201-723-4600; Fax: 49-201-723-4648; e-mail: joachim.fandrey{at}uni-due.de

Received February 25, 2009; accepted for publication June 30, 2009.

Disclosures: Joachim Fandrey: Honoraria: Janssen-Cilag, Ortho Biotech; Mario Dicato: Honoraria: Amgen, Janssen-Cilag.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.

Safety concerns have arisen about the possibility of erythropoiesis-stimulating agents (ESAs) promoting tumor growth and increasing the incidence of venous thromboembolic events (VTEs). Because of the reported presence of erythropoietin receptors (EPORs) on tumor cells, it was questioned if ESAs had the potential for promoting tumor growth through stimulation of EPORs and tumor vessels and/or enhanced tumor oxygenation. Studies have shown that EPOR mRNA can be isolated from tumor cells, but the presence of EPOR protein has not yet been proven because of a lack of specific antibodies against EPORs. It is questionable whether EPORs on tumor cells are functional and there is no evidence that ESAs (within the approved indication in patients receiving chemotherapy) can stimulate EPORs on tumor cells in vivo. VTEs are frequent in cancer patients, resulting from the effects of malignant disease, cancer treatments, and comorbidities. VTEs are a leading cause of death in cancer patients. There are concerns about ESAs and a possible higher risk for VTEs and shorter survival in cancer patients. The higher risk for VTEs associated with ESAs appears to be a class effect, but the risk may be particularly pronounced when ESAs are used off label, as seen in clinical trials that targeted hemoglobin levels higher than those recommended by current ESA labeling and trials that enrolled patients who were not anemic at baseline. ESA treatment should be used within labeling confines.

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