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Update on Safety of ESAs in Cancer-Induced Anemia

  • Authors: John Glaspy, MD
  • CME Released: 5/7/2012
  • Valid for credit through: 5/7/2013, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for primary care physicians, hematologist/oncologists, and other physicians who care for patients with cancer and anemia.

The goal of this activity is to evaluate the risks and benefits of ESAs in the treatment of cancer-related anemia.

Upon completion of this activity, participants will be able to:

  1. Assess the pathogenesis of anemia in cancer
  2. Analyze the quality of trials of ESAs among patients with cancer
  3. Distinguish the benefits of ESAs among patients with cancer
  4. Evaluate when to use ESAs among patients with cancer


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  • John Glaspy, MD

    Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California


    Disclosure: John Glaspy, MD, has disclosed the following relevant financial relationships:
    The university that employs Dr. Glaspy receives payments to support clinical trials underway from Amgen.


  • Kerrin M. Green, MA

    Assistant Managing Editor, Journal of the National Comprehensive Cancer Network


    Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine


    Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC


    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

  • Sarah Fleischman

    CME Program Manager, Medscape, LLC


    Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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Update on Safety of ESAs in Cancer-Induced Anemia

Authors: John Glaspy, MDFaculty and Disclosures

CME Released: 5/7/2012

Valid for credit through: 5/7/2013, 11:59 PM EST


Abstract and Introduction


Patients with cancer frequently develop a multifactorial anemia. The past decade has seen a dramatic improvement in understanding of the biology of the anemia of chronic disease, which has increased interest in studies of parenteral iron or antihepcidin strategies in these patients. Randomized trials have shown that therapy with erythropoiesis-stimulating agents (ESAs) is associated with a reduction in transfusion rates in patients with cancer undergoing chemotherapy. More recently, some studies have suggested that ESA therapy may increase the risk of tumor progression or reduce survival in patients with cancer. This topic was extensively reviewed previously. This update supplements prior reviews with data generated over the past 4 years. During this interval, interest in thrombosis and its role in cancer biology has increased, and concerns about the thrombotic risks of ESAs has moved to the forefront. Until additional safety data are forthcoming, ESAs should be used only to treat chemotherapy-induced anemia, with the goal of preventing transfusions. Patients and physicians should be aware of the safety data for these products. (JNCCN 2012;10:659-667)


Anemia is frequently encountered in patients with cancer and is often multifactorial, with potential contributing factors, including blood loss from surgery, tumor-associated bleeding, hemolysis or repeated phlebotomy, nutritional deficiencies (iron, B12, or folic acid), hepcidin-mediated disturbances in access to storage iron associated with underlying inflammation (so-called anemia of chronic illness), relative endogenous erythropoietin deficiency, hemolysis, and the myelosuppressive effects of cytotoxic chemotherapy (Figure 1). Cancer-induced anemia can be associated with symptoms and a need for red blood cell transfusions, and it is logical to avoid or minimize it, if possible, through addressing ongoing bleeding, reducing unnecessary blood loss in phlebotomy, and evaluating and treating nutritional deficiencies. Although many patients will remain anemic despite these simple but sometimes overlooked measures, this approach frequently reduces the degree of anemia to a point at which symptoms and/or transfusion requirements diminish.

Figure 1.


The pathogenesis of anemia in patients with cancer. Multiple factors result in 3 mechanisms of anemia: a reduced response of the erythron to erythropoietin, a relative deficiency of endogenous erythropoietin, and a decrease in red cell survival. Iron-restricted erythropoiesis, from either reduced iron stores or a diminished access to storage pools mediated by hepcidin, is frequently present in patients with cancer.
Abbreviations: eEPO, endogenous erythropoietin; ESA, erythropoiesis-stimulating agent; IFN, interferon; IL, interleukin; RE, reticuloendothelial; TNF, tumor necrosis factor.
From Glaspy JA. Erythropoietin in cancer patients. Annu Rev Med 2009;60:187; with permission.

The recent elucidation of the mechanism underlying anemia frequently observed in patients with chronic illnesses, including cancer,[1-5] coupled with the development of parenteral iron preparations that have a more favorable safety profile than the early iron dextran products,[6-8] has increased interest in the role of parenteral iron in managing anemia in patients with cancer. In some patients with inflammatory illnesses, interleukin-6 induces the liver to produce hepcidin,[9,10] a peptide that induces degradation of the iron transport molecule ferroportin,[11] which is required for both the absorption of dietary iron in the gastrointestinal tract and mobilization of storage iron in the reticuloendothelial system. This has raised the question of how frequently iron-restricted erythropoiesis is contributing to the anemia in some patients with cancer, even when sufficient storage iron exists to adequately support red cell production in the absence of inflammation. It also suggests that parenteral iron may be more effective than oral iron in addressing absolute or functional iron deficiency in conditions in which increases in hepcidin levels are suspected.[12-17] Clinical trials are needed that are designed to determine whether parenteral iron has a role in the management of anemia in patients with cancer and, if so, what predictors of response, such as iron saturation, hepcidin levels, or red cell cytometry, can be identified.

Long before the discovery of hepcidin and explication of the disturbances in iron metabolism that can occur in patients with chronic illness, chronic inflammatory conditions, including cancer, were shown to be associated with a blunting of the normal erythropoietin response to a given level of anemia.[18] This suppression of erythropoietin production is mediated by inflammatory cytokines (e.g., tumor necrosis factor, interleukin-1, interferon-gamma) other than interleukin-6, and it is now understood that the pathophysiology of the hypoproliferative anemia of chronic illness includes both iron-restricted erythropoiesis and inappropriately low endogenous erythropoietin levels.

The advent of biotechnology was associated with the cloning and therapeutic application of several human proteins, including erythropoietin. After recombinant human erythropoietin (rEPO) completed its development for the treatment of patients with renal failure, it was logical, given the previously identified blunting of the endogenous erythropoietin response to anemia, to test it for the treatment of anemia in patients with cancer. These early trials showed that rEPO therapy was associated with an increase in hemoglobin levels in patients with cancer-related anemia and, in those who were also receiving chemotherapy, treatment with erythropoiesis-stimulating agents (ESAs) was associated with a reduction in red cell transfusions. In 1989, the FDA approved epoetin alfa, the rEPO used in clinical trials in the United States, for the treatment of patients with cancer-related anemia undergoing chemotherapy based on the reported reduction in red cell transfusions. Subsequently, another cloned erythropoietic protein, darbepoetin alfa, was approved for this indication. For purposes of this update, epoetin alfa, darbepoetin alfa, and an rEPO developed outside the United States—epoetin beta—will be considered together as ESAs.

Although there are many points of contention regarding the efficacy and safety of ESAs in the treatment of patients with cancer, the observation that ESA therapy is associated with a reduction in the rate of red cell transfusions in patients with cancer-related anemia who are receiving chemotherapy has stood the test of time. Although some investigators have reported that these patients also have reduced symptoms or improved functional status or quality of life,[19,20] this has not been a consistent observation and has not been accepted by regulatory authorities as a proven benefit of ESA therapy in this setting. Much of the current controversy and uncertainty regarding ESAs in oncology surrounds their safety in patients with cancer, specifically their effect on tumor progression and survival. The remainder of this update addresses this safety issue. For the sake of brevity, it will focus most on the limited data that have become available since the time of the previous, more-extensive reviews of this topic.