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Role of Iron in Optimizing Responses of Anemic Cancer Patients to Erythropoietin

Role of Iron in Optimizing Responses of Anemic Cancer Patients to Erythropoietin

ABSTRACT: Approximately 50% of cancer patients develop anemia. In the past, the only available treatment option for these patients was transfusion. Since the late 1980s, recombinant human erythropoietin (rHuEPO, epoetin alfa [Epogen, Procrit]) has provided a treatment alternative. Controlled clinical trials have shown that rHuEPO increases hemoglobin and hematocrit levels and reduces the need for transfusions in patients with cancer-related anemia. These controlled trials have suggested (as have larger, uncontrolled studies) that the improvements in hemoglobin are associated with increases in energy level, functional status, and overall quality of life. However, only about 50% of patients respond adequately to usual doses of rHuEPO. In the chronic renal failure population, functional iron deficiency is the most common cause of inadequate response to rHuEPO. It has been hypothesized that functional iron deficiency may also occur in cancer patients receiving rHuEPO and may account for the lack of response in up to half of those patients. Studies in renal failure patients have shown that administration of intravenous iron can correct functional iron deficiency more effectively than oral iron and may improve response to rHuEPO. Intravenous iron also reduces the total amount of rHuEPO needed to normalize hematocrit and hemoglobin levels, thereby reducing treatment costs. Ongoing clinical trials are evaluating whether IV iron can also improve rHuEPO responsiveness in patients with cancer-related anemia. [ONCOLOGY 13(4):461-483, 1999]

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 (rHuEPO,
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
(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,
methotrexate, and fluorouracil (CMF).[21] This damage may last much
longer in patients treated with more potent stem-cell toxins (eg,
nitrosoureas or 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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