This Article Full Text Full Text (PDF) eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Blackwell, K. Articles by Jolliffe, L. Search for Related Content PubMed PubMed Citation Articles by Blackwell, K. Articles by Jolliffe, L.

rHuEPO and Improved Treatment Outcomes: Potential Modes of Action

^a Duke University Medical Center, Durham, North Carolina, USA; ^b Servei d’Oncologia Medica, Barcelona, Spain; ^c ECU Brody School of Medicine, Greenville, North Carolina, USA; ^d Ortho Biotech, Raritan, New Jersey, USA

Correspondence: Kimberly L. Blackwell, M.D., Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA. Telephone: 919-668-1748; Fax: 919-684-4221; e-mail: black034{at}mc.duke.edu

Within the past decade, clinical trials have shown that the presence of anemia can diminish the physical status, functional abilities, and overall quality of life (QOL) of cancer patients and can negatively influence the outcome of their treatment. However, recent preclinical and clinical studies have also shown that increasing hemoglobin levels by administering recombinant human erythropoietin (rHuEPO, epoetin alfa) may ameliorate anemia and, in doing so, improve QOL and possibly result in better treatment outcomes following radiotherapy, chemotherapy, or a combination of these modalities. Several mechanisms by which rHuEPO may improve treatment outcome have been proposed, including correction of tumor hypoxia, increased sensitivity of tumor cells to radiotherapy and chemotherapy, correction of anemia and its associated symptoms (particularly fatigue), and immune-modulated effects of rHuEPO on tumor growth. Improvement of tumor oxygenation by rHuEPO could affect treatment outcome in two ways. First, correction of hypoxia results in the downregulation of hypoxia-inducible factor 1 (HIF-1), a key regulator of cellular adaptive responses to hypoxia (e.g., angiogenesis), including many pathways that are important for tumor growth and metastasis. Interruption of the HIF-1 pathway not only limits growth of the primary tumor but also reduces the potential for the development of more aggressive tumors and metastatic spread, which could ultimately improve treatment outcome. Second, within the tumor, it is the hypoxic cells that are resistant to oxygen-dependent radiotherapy and chemotherapy, and improvement in their oxygenation would increase their sensitivity to the cytotoxic effects of such treatment.

Correction of anemia and its associated symptoms, particularly fatigue, can have a beneficial effect on patient QOL, and this in turn may translate into greater tolerance of radiotherapy and chemotherapy, allowing patients to receive full doses and on-schedule dosing, and thus have an increased likelihood of a therapeutic response. Lastly, results of a study using a murine model of multiple myeloma have indicated that rHuEPO may induce an immune-mediated antitumor effect. Therefore, additional research is warranted to further explore the biologic actions of rHuEPO and to determine their relevance to therapeutic outcome.

Key Words. Anemia • Cancer • Epoetin alfa • Hemoglobin • Mechanism of action • Outcomes • Quality of life • rHuEPO • Survival • Tumor hypoxia

This article has been cited by other articles:

				R. D. Lester, M. Jo, W. M. Campana, and S. L. Gonias Erythropoietin Promotes MCF-7 Breast Cancer Cell Migration by an ERK/Mitogen-activated Protein Kinase-dependent Pathway and Is Primarily Responsible for the Increase in Migration Observed in Hypoxia J. Biol. Chem., November 25, 2005; 280(47): 39273 - 39277. [Abstract] [Full Text] [PDF]

				C. A. Hudis and S. Van Belle Introduction: Examining the Potential Impact of Anemia Treatment on Clinical Outcomes in Anemic Cancer Patients Oncologist, November 1, 2004; 9(suppl_5): 1 - 3. [Full Text] [PDF]

				F. Farrell and A. Lee The Erythropoietin Receptor and Its Expression in Tumor Cells and Other Tissues Oncologist, November 1, 2004; 9(suppl_5): 18 - 30. [Abstract] [Full Text] [PDF]

				H. Ludwig rHuEPO and Treatment Outcomes: The Preclinical Experience Oncologist, November 1, 2004; 9(suppl_5): 48 - 54. [Abstract] [Full Text] [PDF]

				H. Ludwig, C. A. Hudis, G. Goss, and B. Leyland-Jones Epoetin Alfa: Future Directions and Future Research Oncologist, November 1, 2004; 9(suppl_5): 70 - 73. [Full Text] [PDF]