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Practitioners’ Practical Model for Managing Cancer-Related Anemia

Practitioners’ Practical Model for Managing Cancer-Related Anemia

ABSTRACT: 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.[10] 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.[11]

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.

Defining Anemia in Cancer

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
).[10]

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.[12] 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.[3]

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.[3]

The Regulation of
Red Blood Cell Production

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).[13]

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.[14] 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[15]; 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.[16] Tissue
hypoxia triggers increased erythropoietin production when hemoglobin falls below
12 g/dL.[17] 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.[18] 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).[12] 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.[19]

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.[22]

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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