Introduction
Anemia is the most common hematologic abnormality seen in cancer patients,[1] occurring in approximately 50% of this population.[2] The incidence of anemia is higher in patients with advanced forms of cancer and in those undergoing chemotherapy or radiation.
A nationwide survey of cancer patients found that fatigue, a common symptom of anemia, has profound effects on patients, including their ability to work, meet family needs, and cope with their disease.[3] This survey also concluded that fatigue, not pain, is the most common complaint of cancer patients and the one that is most likely to disrupt their lives.
In addition, studies have shown that cancer patients with anemia have a higher relapse rate and mortality than patients with a similar stage of cancer who are not anemic.[2,4,5] Despite these sequelae and risk factors, cancer-related anemia is frequently overlooked or undertreated.
Since the late 1980s, recombinant human erythropoietin(Drug information on erythropoietin) (rHuEPO, epoetin alfa(Drug information on epoetin alfa) [Epogen, Procrit]) therapy has been proven to be a safe, effective option in addition to, or instead of, red blood cell transfusions for the treatment of cancer-related anemia.[6] However, at rHuEPO doses of 150 to 300 U/kg three times per week, only about 50% of cancer patients fully respond to therapy.[7,8]
The use of rHuEPO in the chronic renal failure population is seen as the best-case scenario for rHuEPO therapy,[9] and functional iron deficiency has been found to be the most common cause of inadequate response to rHuEPO in this population.[10-12] Iron deficiency may also occur in cancer patients receiving rHuEPO therapy and may account for a significant proportion of the 50% of cancer patients who do not respond to rHuEPO. Moreover, functional iron deficiency may not be apparent with the currently available tests of iron status. It is believed that cancer patients may have an improved response to rHuEPO therapy if they were given intravenous (IV) iron supplementation.
This review of cancer-related anemia, iron metabolism, and functional iron deficiency establishes the important role of iron in optimizing red blood cell production. It also reviews how the use of IV iron has improved responses to rHuEPO and has increased hematocrit levels in the chronic renal failure population. These results have led to an ongoing clinical trial aimed at determining whether rHuEPO may have similar beneficial effects in anemic cancer patients.
Causes of Cancer-Related Anemia
The development of anemia in patients with cancer may be attributed to various causes, including the anemia of chronic disease; certain malignancies; chemotherapy and radiation; deficiencies of iron, folic acid, or vitamin B12; malnutrition; infection; inflammation; and blood loss or hemolysis.[6,8] The most common mechanism for the induction of anemia in this population is insufficient bone marrow response to erythropoietin.[8]
Anemia of Chronic Disease
Anemia of chronic disease is common and often accompanies chronic infections, inflammatory disorders, and malignancies. Because this type of anemia results from an underlying illness, correcting the illness will improve the anemia.[6]
The anemia of chronic disease is occasionally a microcytic, hypochromic type of anemia but can be morphologically variable. Changes in iron metabolism also occur, sometimes reflected specifically in a decreased concentration of serum iron, a reduction in total iron-binding capacity (TIBC), and a below-normal transferrin saturation (TSAT).[13] This type of anemia is believed to be mediated by inflammatory cytokines, such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and gamma interferon,[14-16] which have a direct inhibitory effect on erythropoiesis and may also inhibit production of erythropoietin.[17,18]
Cancer Treatments
Radiation and some forms of chemotherapy can have a direct myelosuppressive effect on the bone marrow. Most chemotherapeutic agents suppress rapidly proliferating marrow cells, while certain drugs also directly impair the process of erythropoiesis.[19] For example, when administered over an extended period, cisplatin(Drug information on cisplatin) (Platinol) causes early, progressive dysfunction of renal tubules. Cisplatin-induced renal toxicity is most likely caused by decreased renal production of endogenous erythropoietin, which leads to inadequate production of red blood cells.[20]
Chemotherapy also can impair erythropoiesis over the long term through damage to the stem-cell pool. Stem-cell impairment has been noted as late as 5 years after breast cancer patients received adjuvant therapy with the combination of cyclophosphamide(Drug information on cyclophosphamide), methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on fluorouracil) (CMF).[21] This damage may last much longer in patients treated with more potent stem-cell toxins (eg, nitrosoureas or busulfan(Drug information on busulfan) [Myleran]) or in those who have undergone radiotherapy to the marrow compartment or high-dose chemotherapy with stem-cell support.
Underproduction of Erythropoietin
Inadequate production of erythropoietin is associated with the anemia of cancer. In one study, investigators compared serum erythropoietin concentrations in 74 cancer patients with concentrations in 24 patients with uncomplicated iron-deficiency anemia.[22] None of the cancer patients had hypoxemia or kidney failure.
An inverse linear relationship between hemoglobin and serum erythropoietin concentrations was seen in patients with iron-deficiency anemia but not in those with cancer-related anemia. At any hemoglobin concentration, serum erythropoietin concentrations were lower in the cancer patients than in patients with iron-deficiency anemia. Among patients with cancer-related anemia, serum erythropoietin concentrations were lower in those receiving chemotherapy than in those who had never received chemotherapy or in those who had not received chemotherapy during the previous 6 weeks.[22]
Diagnosing Anemia
Irrespective of cause, anemia results from an imbalance between the production and destruction of red blood cells. The consequence is a reduction in the circulating red blood cell mass, which is reflected in changes in hemoglobin level and, less directly, in hematocrit level. Hemoglobin concentration is a primary parameter that is measured directly and for which there is a recognized international standard.
In the United States, it has become common practice to substitute the direct measure of hemoglobin for an indirect measure, hematocrit. Although the hematocrit level will generally reflect the hemoglobin concentration, the former is not measured directly, and its derivation depends entirely on the validity of the algorithm and counting mechanism of an automated cell counter. Since many different types of cell counters are available, they will not all give the same value for the hematocrit at a given hemoglobin concentration.
Although the hemoglobin level at which a patient is deemed anemic is not exact, it usually ranges from 11 to 12 g/dL. When the hemoglobin concentration is 10 g/dL, a diagnosis of anemia is unequivocal. Red blood cells may initially be normochromic and normocytic but will usually become microcytic (mean corpuscular volume [MCV] < 84 fL; mean corpuscular hemoglobin [MCH] < 27 pg). Patients who are anemic due to iron deficiency usually have a serum ferritin concentration of £12 µg/L, while patients with anemia due to malignancy usually have a serum ferritin concentration > 20 µg/L.
Benefits of Treating Anemia
Anemia can have a substantial negative impact on the quality of life of cancer patients.[23] Conversely, the correction of anemia can result in a dramatic improvement in quality of life, reflected by increased energy and improved ability to perform daily activities. Because of these potential benefits, intervention for the correction of anemia should not be neglected in this patient population.
Furthermore, reversal of cancer-related anemia may enhance the therapeutic response in patients receiving radiation therapy. Adequate oxygenation at the tumor site is necessary for an optimal response to radiation therapy, and, therefore, anemia may prevent a successful therapeutic outcome.[24] In fact, observations in cancer patients receiving radiation therapy have shown a reduced rate of survival in the presence of anemia.[2] Treatment with rHuEPO has been reported to raise hematocrit and hemoglobin levels in anemic cancer patients undergoing radiation therapy.[25-27] However, the impact of the correction of anemia on disease outcome following radiation therapy has yet to be evaluated in a controlled, randomized trial.
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