Anemia in Cancer Patients-1

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.

Table 1. Anemia of Cancer: Direct Effects of the Neoplasm

Exogenous blood loss (acute or chronic)

Gastrointestnal malignancies
Head and neck cancer
Genitourinary cancers
Cervical and vaginal cancers

Intratumor
bleeding

Sarcomas
Bulky melanomas
Hepatoma
Ovarian cancer
Adrenocortical tumors

Anemia due to erthrophagocytosis

Histiocytic medullary reticulosis
Histiocytic lymphomas
Other histiocyctic neoplasms

Bone marrow replacement

Leukemias
Lymphomas
Myelomas
Carcinomas (breast, prostate)

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:

Table 2.Anemia Due to Known Products of Cancer
Substance Mechanism Neoplasm
Amyloid Marrow replacement Plasma cell dyscrasia
Antibodies Immune hemolytic anemia Chronic lymphocytic leukemia, lymphoma, adenocarcinom
Procoagulant proteins Microangiopathic hemolytic anemia Gastrointestinal malignancies (mucin), prostate cancer

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.

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