Anemia is the most common hematologic abnormality seen in patients with cancer. Anemia is associated with debilitating symptoms and poorer health-related quality of life and may result in less than optimal disease/treatment outcomes. The high prevalence of anemia and the potential clinical and prognostic impact make it important to have a systematic approach to the diagnosis and treatment of cancer-related anemia. A rigorous diagnostic evaluation should be undertaken to identify the cause of anemia and guide appropriate treatment. Treatment of anemia with erythropoiesis stimulating proteins offers an alternative treatment to red blood cell transfusions and has been shown to improve quality of life for patients being treated for cancer. In addition, recent studies suggest improved cancer treatment outcomes. Data indicate that treatment with darbepoetin alfa, a novel erythropoiesis stimulating protein, improves hemoglobin levels and quality of life in anemic patients with cancer who are not receiving chemotherapy or radiotherapy. Symptoms of anemia, when searched for properly, are identified often at hemoglobin levels less than 12 g/dL. As the understanding of the importance of anemia grows, and more convenient methods of therapy become available, patients will benefit with a more proactive approach to early treatment or prevention of this complication of cancer and its treatment. [ONCOLOGY 16(Suppl 10):55-63, 2002]
While granulocytopenia and thrombocytopenia frequently receive greater attention in cancer management as a consequence of their potential life-threatening risks, anemia is the most common hematologic abnormality seen with malignancies. Anemia occurs in more than 50% of patients with cancer[1,2] and is itself associated with debilitating symptoms, lower health-related quality of life (QOL) and potentially poorer disease/treatment outcomes.[3-9]
Wide variability exists in the incidence and severity of anemia in different malignant conditions. A review of the incidence of severe anemia requiring red blood cell (RBC) transfusion found the highest incidence (50%-60%) in patients with lung cancer, lymphoma, gynecologic (ovarian), and genitourinary tumors. In a study of a single oncology practice, 31% of patients (103 of 331) required transfusion on at least one occasion during a 1-year period of cancer treatment.
Owing to the high prevalence of clinically significant anemia and its potential impact on quality of life and patient outcomes, it is important to have a systematic approach to cancer-related anemia with regard to diagnosis, evaluation, and treatment. Such an approach could prove beneficial not only for medical oncologists, but also for other caregivers involved in managing patients with malignant conditions.
Anemia is normally defined as a reduction in hemoglobin or hematocrit below well-defined gender-based levels. Several systems are used for defining and grading the severity of anemia (see Table 1).
For the care of an individual patient, however, it is more relevant to have a functional definition of anemia, namely that there are insufficient RBCs to provide adequate tissue oxygenation. The hemoglobin level at which this state is reached depends on the clinical circumstances of the individual patient. For example, a patient with lung cancer and coexistent chronic obstructive lung disease might be "anemic," with all the associated symptoms, despite hemoglobin levels falling within the accepted normal ranges.
Patients with anemia may experience a variety of symptoms, again depending on their underlying condition and general clinical state. Symptoms may result directly from the oxygen deprivation of tissues, or as a result of the body’s efforts to compensate for this, such as increased cardiac output, increased respiratory rate, and preferential shunting of blood to oxygen-sensitive organs. Common symptoms include fatigue, irritability, insomnia, depression, impaired cognitive function, tachycardia and palpitations, dyspnea, pallor, fluid retention, irregular bowel movements, and reduced sexual desire.
Varying symptoms may manifest with different degrees of anemia. For example, impaired cognitive function, gastrointestinal disturbance, and reduced sexual function may start to appear at higher hemoglobin levels than do the cardiovascular symptoms, which become apparent only when a patient is severely anemic. The severity of symptoms experienced by the individual patient also varies; for example, elderly patients with comorbid conditions may experience more severe symptoms than younger patients.
To optimally approach anemia in any clinical situation, an understanding of the erythropoietin system that regulates RBC production by the bone marrow is important. This is especially true for the patient with cancer-related anemia, which can be complex in its etiology. A remarkable process for regulating red blood cell production has evolved in humans. The process is a classic hormonal system with a feedback loop, the stimulus for increased RBC production being tissue hypoxia, with down-regulation of RBC production being controlled by increasing red cell mass, and therefore increased oxygen delivery to tissues (as reviewed by Spivak).
Erythropoietin is a glycoprotein, composed of a 165-amino-acid polypeptide chain with three sialic-acid-containing carbohydrate side chains N-linked to asparagine, and one side-chain O-linked to serine. Although classified as a hematopoietic growth factor, erythropoietin acts as a hormone. Erythropoietin is primarily produced by dedicated peritubular cells in the renal cortex, although the liver is also capable of producing a small "maintenance" amount of erythropoietin. Recently, erythropoietin receptors and production have even been recognized in neural tissues; however, their role and function remain to be fully clarified.
Since the human spleen does not act as a storage organ, it cannot (as can spleens in canine and other species) release additional RBCs into the circulation in response to situations requiring a rapid increase in oxygen delivery. Sufficient erythropoietin is produced by the dedicated peritubular cells of the kidneys to maintain hemoglobin at levels of approximately 14 to 18 g/dL for an adult male, and 12 to 16 g/dL for an adult female. Tissue hypoxia triggers increased erythropoietin production when hemoglobin falls below 12 g/dL. Thus, the normal basal production of erythropoietin by the kidney is more than sufficient to keep hemoglobin levels well above this "trigger" point, allowing the body to compensate in acute or emergency situations when additional oxygen-carrying capacity is suddenly needed.
There is a wide variation in plasma erythropoietin levels between individuals, so an unequivocal increase in plasma erythropoietin in response to tissue hypoxia is not generally measurable until hemoglobin levels are < 10.5 g/dL. This increased erythropoietin production is achieved by up-regulation of the gene expressing erythropoietin, thus recruiting additional renal cells for production, and also through stimulation of hepatic cells already producing the factor at lower levels.
Once produced, erythropoietin acts on the erythroid progenitor cells in the bone marrow (as reviewed by Spivak). The earliest progenitor form that can be identified is the erythroid burst-forming unit (BFU-E). These units evolve into erythroid colony-forming units (CFU-E), and erythropoietin acts primarily on these cells by stimulating cell division and maturation and reducing apoptosis.
Due to the potential for exponential increases in erythropoietin production and its exponential effect on bone marrow, the RBC production process must be tightly regulated to avoid large variations in red cell mass in a given individual over time.[20,21] Precise regulation does indeed seem to occur, as both hemoglobin and erythropoietin levels remain remarkably constant in a given individual, with fluctuations of erythropoietin primarily due to diurnal variation.
Between individuals, however, there may be wide variations in erythropoietin and hemoglobin levels, and therefore, the normal ranges for these parameters are large. The precise control of RBC production appears to be accomplished by rapid down-regulation of the erythropoietin gene, and by the fact that receptors for erythropoietin are seen only in late BFU-E and CFU-E.[23,24] In these cells, clonal expansion is much more limited than in early BFU-E, which are regulated in part by cytokines such as interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine), and insulin-like growth factor 1 (IGF-1).[25,26] In patients with cancer, this efficient and conservative system for regulating RBC production can be substantially disturbed.
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