Anemia in Cancer Patients:
Introduction and Overview

Hussain I. Saba, MD, PhD

Introduction

    Anemia is a common complication of malignancies.  Because its causes and mechanisms are complex, the term “multifactorial” has been applied.  Cancer-related anemia may occur as a direct effect of the neoplasm, it may be due to products of the cancer, or it may develop as a result of the cancer treatment itself.  In the past, anemia occurring in cancer patients was often referred to as “chronic anemia” or “anemia of chronic disease.”  These effects may be reflective of a paraneoplastic syndrome.

Anemia Occurring as a Direct Effect of the Neoplasm

    Direct-acting factors due to the effects of the cancer are summarized in Table 1.  Notable among these are solid tumor malignancies, such as breast and prostate cancer, that invade the marrow.  Often overlooked as factors in inducing anemia, these malignancies produce a desmoid or fibrotic reaction, with increased marrow fibrosis that results in alteration of marrow space and sinusoidal matrix.  This can affect the orderly release of mature blood cells from bone marrow and can produce a leukoerythroblastic picture with immature red cells and early myeloid white cells seen in peripheral blood.
 

    Direct causes of anemia in malignancy include known substances or proteins produced by the cancer (Table 2).  The deposits of amyloid in myelomas and amyloidosis can be extensive enough to replace the bone marrow.  The development of antibodies in chronic lymphocytic leukemia, lymphoma, and sometimes solid tumor malignancies can lead to immune hemolytic anemias.  Furthermore, development of microangiopathic hemolytic anemia, which is seen in some solid tumor malignancies, may result from procoagulants released from cancers.
 

Anemia of Cancer:  Anemia of Chronic Disease or a Cytokine-Associated Syndrome?

    In many cancer patients, the causative mechanism of anemia is incompletely defined; thus, the term “anemia of chronic disease” is used.  Defective iron utilization, the hallmark of anemia of chronic disease, is common among patients suffering from anemia of malignancy.

    The concept of anemia of chronic disease was reported 150 years ago by German investigators Andral and Cavarret.  Despite extensive studies by William Cartwright after World War II, its pathophysiologic mechanism remains unclear.  However, in 1966, Dr Cartwright suggested a conceptual mechanism for the anemia of chronic disease that could easily be applied to the anemia of malignancy.  Cartwright’s three mechanisms include shortened red cell survival, failure of the bone marrow to increase erythropoiesis to meet the demand and to repair the deficiency (ie, a hypoproliferative state), and failure of bone marrow to release iron from the senescent red cells phagocytosed by the bone marrow macrophages (ie, defective iron reutilization).  Each of these mechanisms pertains to the development of the anemia of malignancy.

    New lines of evidence suggest that abnormalities in the production of erythropoietin (EPO) are involved.  The hypoproliferative state in anemia of cancer appears to be related to either decreased EPO production or impaired bone marrow response to EPO.

    Recent evidence has indicated that recombinant EPO can correct the anemia of malignancy in many patients.  This finding has rekindled interest in decreased EPO production as an important factor in the anemia of cancer.  One concept states that inappropriate secretion of EPO is related to increased cytokine production by the tumor.  In vitro studies have shown that tumor necrosis factor (TNF) and interleukin-1 (IL-1) inhibit EPO mRNA synthesis.  This indicates that hypoproliferative response of the marrow in cancer patients could be a cytokine-mediated phenomenon.  Cytokines liberated in cancer patients could cause inhibition of EPO secretion and possibly EPO responsiveness of the marrow erythroid progenitors.
 

Impaired Iron Utilization in the Anemia of Cancer

    Impairment of iron metabolism and depressed erythropoiesis constitute primary hallmarks as well as the basis for anemia in cancer patients.  Although most studies were conducted in chronic inflammatory states such as rheumatoid arthritis rather than the anemia of cancer, it is now clear that several cytokines produced in cancer patients (eg, TNF, IL-1, IL-6, transforming growth factor-beta, interferon-gamma, and EPO) are responsible for suppressed erythropoiesis and impaired iron metabolism.

    It is not yet known whether different cytokines or different sequences of cytokine release are critical to specific lesions.  TNF increases in patients with cancer.  In the animal model, TNF administration has resulted in changes of iron metabolism characteristic of the anemia of malignancy.  Furthermore, injection of TNF in human patients with metastatic cancer has resulted in the expression of all of the features of impaired iron utilization.  IL-1 has been implicated in suppression of erythropoiesis in inflammatory lesions, like rheumatoid arthritis, but its role in anemia of malignancy in humans has not yet been delineated.  Other cytokines such as IL-6 and transforming growth factor-beta also suppress erythropoiesis and iron metabolism, but their exact roles have not yet been determined.

    Thus, it appears that anemia in cancer patients can be defined as a “cytokine-associated syndrome” in which multiple cytokines interact to produce suppression of erythropoiesis and derangement of iron metabolism.  Some scientists have suggested that the term “anemia of malignancy” should be replaced with the term “cytokine associated anemia” and the primary involved cytokine should be delineated by an appropriate subscript.  More studies are underway to understand the critical interaction of these cytokines, their production, their release, and their temporal relationship with each other in cancer patients.  It is not known whether specific cytokines are related to specific neoplasms.  With this information, the true mechanism of anemia in cancer patients will be clearly understood and appropriate management strategies can be developed.

Therapy of Anemia of Malignancy

    Although therapy for the anemia of malignancy has been focused on treating the underlying malignancy, there have been reports of improved red cell mass with EPO administration in cancer patients undergoing radiation therapy and chemotherapy, such as cisplatin and carboplatin.  Investigators have also reported improvements in the quality of life associated with EPO administration.  The Ludwig group reported experience with EPO in 63 patients with myelodysplastic syndrome and multiple myeloma.  Response, as measured by raising hemoglobin to 2 g/dL above the baseline, was seen in 43% of patients.  Experience with patients with nonmyeloid malignancies receiving cancer chemotherapy in community oncology practice in the United States demonstrates that responses occur in 50% to 60% of EPO-treated patients, and the response rate is over 75% in patients with > or = to 1 g/dL decrease in hemoglobin.

    In a Japanese study, head and neck cancer patients undergoing radiation therapy exhibited increased hemoglobin levels with successive EPO injections. Two sequential trials in ovarian cancer patients treated with carboplatin and etoposide, with and without EPO, showed improvement in hemoglobin levels in the EPO-treated group.  Preliminary analyses of randomized open-label trials of EPO with radiation therapy in patients with lung, breast, and prostate cancer also have shown increases in mean hemoglobin levels during treatment.  Additional randomized, controlled studies are needed to clearly define the efficacy of EPO in the management of anemia in cancer patients.

Conclusions

    Anemia, a common occurrence in malignant disease, can be the first diagnostic clue to suggest a malignant disease.  It also can create a disabling burden for patients already coping with cancer.  Because a number of underlying mechanisms may contribute to the anemia of cancer, it is important to define causes that are treatable.  As our understanding of this phenomenon increases, researchers are beginning to appreciate the role played by tumor-associated cytokine production in the development of anemia of malignancy.

    The availability of recombinant EPO is a significant addition to the therapeutic armamentarium.  Many of these issues are further described in this supplement, which distills the proceedings of a roundtable discussion of experts held in Key West, Florida, in October 1997.

Suggested Readings

Glaspy J, Bukowski R, Steinberg D, et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice: Procrit Study Group. J Clin Oncol. 1997;15:1218-1234.

Moliterno AR, Spivak JL.  Anemia of cancer.  Hematol Oncol Clin North Am.  1996;10:345-363.

Frenkel EP, Bick RL, Rutherford CJ.  Anemia of malignancy.  Hematol Oncol Clin North Am. 1996;10:861-873.

Spivak JL.  Cancer-related anemia:  its causes and characteristics.  Semin Oncol.  1994;21(suppl 3):3-8.

Henry D.  Recombinant human erythropoietin for treatment of anemia in patients with advanced cancer.  Semin Hematol.  1993;30 (suppl 6):12-16.

Hyman GA.  Studies of anemia of disseminated malignant neoplastic disease.  1.  The hemolytic factor.  Blood.  1954;9:911.

From the Department of Medical Oncology/Hematology at the H. Lee Moffitt Cancer Center Research Institute, University of South Florida School of Medicine, Tampa, Fla.

Address reprint requests to Hussain I. Saba, MD, PhD, Hematologic Malignancy Program, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Dr, Tampa, FL 33612

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