REVIEW

ANEMIA AND ERYTHROPOIESIS IN CANCER

Jerry L. Spivak, MD

ABSTRACT
Approximately one third to one half of
patients with cancer are anemic, a condition that
diminishes the ability to engage in daily activities
and undermines the overall quality of life. Although
cancer-related anemia has many causes, one of the
most important is inadequate production and
impaired utilization of erythropoietin. At any given
level of anemia, patients with cancer produce much
less erythropoietin compared with a healthy person and, as a result, are unable to compensate
for the impaired production and shortened lifespan of red blood cells that occur in this situation.
Supplemental recombinant erythropoietin can
stimulate the production of red blood cells, correct anemia, and improve quality of life. New
dosing regimens offer increased convenience to
patients and may hasten drug response.
(Advanced Studies in Medicine. 2002;2(17):612-619)

Address correspondence to Jerry L. Spivak, MD, Johns

Hopkins University School of Medicine, Division of
Hematology, 720 Rutland Avenue, Traylor 924, Baltimore,
MD 21205.

612

he causes of anemia, a common complication of cancer, are varied, ranging from

blood loss to inadequate red blood cell
production. The consequences of anemia,
while equally diverse, all contribute to
undermine quality of life and, perhaps, response to
antineoplastic therapies. Although the causes of cancer-related anemia are many, impaired erythropoietin
production and impaired responsiveness of erythroid
progenitor cells to this hormone are central to its
pathophysiology. Therefore, alleviating the anemia of
cancer requires an understanding of how erythropoietin stimulates red blood cell formation and how the
production of and response to this glycoprotein are
altered in patients with cancer.

ANEMIA AND CANCER

The prevalence of cancer-related anemia, while
not rigorously documented, appears to be substantial. In an audit of more than 2700 patients with a
variety of solid tumors and who were receiving
chemotherapy at 28 oncology centers in the United
Kingdom, 33% of the patients were sufficiently anemic to require blood transfusion.1 The incidence of
transfusion varied widely by tumor type; the incidence was 19% for breast cancer and 43% for lung
cancer. Seven percent of patients with breast cancer
and 22% with lung cancer required more than 1
transfusion. The overall proportion of patients with
a hemoglobin level below 11 g/dL increased from
17% at the start of chemotherapy to 38% by the
sixth cycle, despite transfusion in 33% of the

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patients. Of those patients receiving transfusion,

25% required hospitalization.
Other reports suggest that among patients with
solid tumors, anemia is most common in those with
lung cancer (52%) or ovarian cancer (51%). These
patients are also the most likely to require blood
transfusion (28% and 25%, respectively).2 Patients
treated with platinum-based chemotherapy agents
are at especially high risk for developing anemia.
Reported transfusion rates in these patients range
from 47% to 100%, depending on the cumulative
dose of platinum and other risk factors, particularly a
low baseline hemoglobin level (<11 g/dL) or a reduction in the hemoglobin level of 1 g/dL to 2 g/dL after
the first cycle of chemotherapy. In one study, more
than 50% of 81 patients referred for radiation therapy were anemic.3
THE CONSEQUENCES OF ANEMIA
Although severe anemia has traditionally been treated
with blood transfusion, mild-to-moderate anemia often
goes untreated. This lack of treatment may result from a
desire to avoid unnecessary use of a therapy that, despite
improvements in donor screening, carries definite risks,
including immediate and delayed hemolytic reactions,
alloimmunization, contamination by infectious agents,
iron overload, volume overload, graft-versus-host disease,
and immunosuppression.
An equally valid explanation, however, is that
many physicians consider the clinical consequences of
mild-to-moderate anemia to be minimal.4 This perception is being challenged by new data on the negative influence of anemia on patients performance of
everyday activities and quality of life. Anemic patients
can experience dyspnea, tachycardia, dizziness,
anorexia, hypersensitivity to cold, and, perhaps most
commonly, fatigue (Table 1).5,6 Of the symptoms of
anemia, fatigue is identified by patients as having the
most profound and intrusive effect, limiting their
ability to work and engage in daily activities to a
greater degree than even nausea and pain.6 In addition, anemia impairs tissue oxygenation and organ
function, increases postoperative mortality, increases
the likelihood of transfusion after chemotherapy,
eliminates the possibility of donating blood for autologous transfusion, increases susceptibility to thrombocytopenic bleeding, and, in certain instances,
increases iron absorption.

Advanced Studies in Medicine

There appears to be a link between anemia and

mortality.6 In studies of patients with solid tumors,
those with anemia had worse outcomes after radiation therapy, including reduced overall survival and
less effective locoregional tumor control. Because
hypoxia has been shown to limit the radiosensitivity
of cells, the poorer outcome may be related to
reduced tumor oxygenation in patients with cancerrelated anemia.
An analysis of 60 studies reporting survival of
patients with cancer according to hemoglobin level
showed that anemia was associated with a 65%
increase in the risk of death.7 The relative risk varied by tumor type, from 19% among anemic
patients with lung cancer to 75% among patients
with head and neck cancer. Whether these findings
suggest a causal link or merely reflect the association
between anemia and advanced-stage disease is not
yet clear.
ROLE OF ERYTHROPOIETIN
Many factors cause anemia in patients with solid
tumors (Table 2), including intrinsic or iatrogenic
blood loss; nutritional deficiencies, primarily involving iron or folic acid; autoimmune, traumatic, or
drug-induced hemolysis; and bone marrow failure
due to tumor encroachment, myelofibrosis, or marrow necrosis. Infection, inflammation, and hypersplenism also cause anemia. In some cases, the

Table 1. Consequences of Anemia










Impaired tissue oxygenation

Impaired organ function
Impaired quality of life
Increased postoperative mortality
Increased probability of blood transfusion after chemotherapy
Inability to donate blood for autologous transfusion
Increased susceptibility to thrombocytopenic bleeding
Increased iron absorption (some forms of anemia)

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presence of malignant disease may be the only explanation for anemia.2,8,9

One of the common denominators among the
disparate causes for cancer-related anemia is abnormal production and utilization of erythropoietin,
the glycoprotein hormone that stimulates production of red blood cells and maintains their viability.8,9 Erythropoietin is a 166-amino acid protein
that is heavily glycosylated. The circulating, biologically active form of the protein comprises 165
amino acids glycosylated on 3 N-linked groups and
1 O-linked group. The N-linked carbohydrates
maintain erythropoietin in a biologically active conformation, and their sialic acid residues ensure survival in the circulation.
Erythropoietin is produced primarily in the kidneys by peritubular interstitial cells and, to a lesser
extent, in the liver by fibroblastoid interstitial cells and
hepatocytes.10-12 Normally, plasma erythropoietin levels
are maintained at a constant level by basal production
of the hormone. Plasma levels are characterized by a
diurnal variation, with the highest levels observed in
the morning. Although the normal plasma erythropoietin level is constant in a given individual, the level
varies widely from one person to another (normal
range, 426 mU/mL).11
Erythropoietin production increases in response to
tissue hypoxia. Normally, an inverse relationship
exists between the plasma level of erythropoietin and
hemoglobin or hematocrit, as well as between erythropoietin and arterial oxygen saturation.11 A hypoxiatriggered increase in erythropoietin production
normally causes an increase in red blood cell production; a decrease in the plasma erythropoietin level
occurs with restoration of tissue oxygenation.
Erythropoietin interacts with erythroid progenitor
cells in the bone marrow through specific surface
receptors to promote cell proliferation and differentiation and to maintain cell viability.11-13 The burst-forming unit-erythroid is the earliest erythroid progenitor
cell to express erythropoietin receptors. Because burstforming unit-erythroid cells contain few erythropoietin receptors, an increased concentration of
erythropoietin is required to trigger these dormant
cells into cycle. The colony-forming unit-erythroid
cell, the other target of erythropoietin, expresses a large
number of erythropoietin receptors. Therefore, a
much smaller amount of the hormone is needed to
maintain cell viability.13

614

HOW CANCER INFLUENCES ERYTHROPOIESIS

Erythropoietin production is impaired in several
situations, including renal parenchymal disease,
inflammation, infection, surgery, and blood hyperviscosity.11 In cancer, the causes for reduced production
are multifaceted. At any level of anemia, patients with
cancer produce much less erythropoietin than normal.
As a result, they are unable to compensate for the
impaired production and shortened lifespan of red
blood cells (Table 3).8,9
The release of inflammatory cytokines in response
to malignancy may cause impaired erythropoietin production in patients with cancer.8,9,13 These cytokines
primarily tumor necrosis factor, interferon gamma,
and interleukin 1not only reduce erythropoietin
production, but also suppress the response of erythroid
progenitor cells to the hormone.
Compounding the deleterious effects of inflammatory cytokines are the effects of cancer therapy on
erythropoiesis. Many chemotherapeutic agents not
only impair erythropoietin production, but also
reduce progenitor cell proliferation. Platinum-based
chemotherapeutic agents are reported to cause can-

Table 2. Causes of Anemia in Patients With Cancer
















Blood loss
Nutritional deficiencies
Hemolysis
Hemodilution
Myelofibrosis
Marrow necrosis
Marrow involvement with tumor
Chemotherapy and radiation therapy
Infection
Inflammation
Hypersplenism
Renal failure
Malignancy
Abnormalities in erythropoietin production and utilization

Data from references 2, 8, and 9.

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cer-related anemia through myelosuppression and

damage to the renal tubules where erythropoietin is
produced.2 Irradiation can damage erythroid progenitor cells.
Inflammatory cytokines play an additional,
although probably not central, role in cancer-related
anemia through disordered iron metabolism.9 Iron is
bound to transferrin during transport from the reticuloendothelial system to the bone marrow, where the
complex is internalized by developing erythroid cells.12
The iron molecule is used in the erythroid cells for
hemoglobin synthesis or is stored in the cytoplasm as
ferritin. Serum ferritin provides a measurement of storage iron, with normal values of 20 mcg/L to 100 mcg/L
in women and 30 mcg/L to 300 mcg/L in men.14
Transferrin saturation reflects the iron content of circulating transferrin. Values below 20% are associated with
reduced delivery of iron to the bone marrow.
Normally, tissue iron deficiency is characterized by
low transferrin saturation and a low serum ferritin
level. In cancer, as in many chronic inflammatory disorders, reduced transferrin saturation is usually associated with a normal or elevated serum ferritin level, a
combination characteristic of the so-called anemia of
chronic disease.
The anemia of chronic disease is a hypoproliferative anemia that may be normocytic and normochromic or microcytic and hypochromic. This
disease is characterized by reduced levels of serum iron,
reduced transferrin saturation, increased reticuloendothelial iron stores, normal or elevated serum ferritin
levels, increased erythrocyte free-protoporphyrin, and
reduced gastrointestinal iron absorption.9,15
These observations have supported the belief that
abnormal iron metabolism plays a major role in the anemia of chronic disease. Other evidence, however, refutes
this concept. Although iron absorption is reduced and
reticuloendothelial iron stores are increased, there is no
actual impairment of iron delivery to the bone marrow
and no marked impairment in the utilization of iron by
erythroid cells.16,17 This lack of impairment has been
demonstrated by the ability of recombinant erythropoietin therapy to correct the anemia of chronic disease,
which would not be possible if iron deficiency were an
important element in this form of anemia.18 It is likely,
therefore, that reduced iron absorption, decreased erythroblast transferrin receptor expression, and iron sequestration by the reticuloendothelial system actually
represent the consequences of impaired erythropoietin

Advanced Studies in Medicine

production in this situation, which is caused by the

inflammatory cytokines.
PATIENT OUTCOMES
Treatment with recombinant human erythropoietin is generally recognized as appropriate for
patients with a hemoglobin level below 10 g/dL or
for patients with anemia-related symptoms despite a
higher hemoglobin level.2 Other potential recipients
include patients with a low baseline hemoglobin level
(10 g/dL to 12 g/dL) who are beginning chemotherapy and patients who are receiving platinum-based
chemotherapy and have had a marked decrease
(1 g/dL to 2 g/dL) in hemoglobin from baseline to
the second cycle of treatment. These patients are at
high risk for becoming anemic and requiring blood
transfusion during chemotherapy.
The value of supplemental erythropoietin in patients
with cancer-related anemia is now being judged not only
by its effects on the hemoglobin or hematocrit, but also
by its influence on quality of life. Data from several large
studies, both randomized placebo-controlled trials and
community-based observational studies, indicate that
correcting cancer-related anemia with recombinant
human erythropoietin improves overall quality of life, as
well as participation in physical activity, energy level, and
psychosocial well-being.
Recently, Littlewood et al reported on a randomized,
double-blind, placebo-controlled clinical trial of 375

Table 3. Essential Factors in Erythropoiesis and

the Effect of Anemia of Chronic Disease

Characteristic

Effect of Anemia of Chronic Disease

Intensity of stimulus

Erythropoietin production
suppressed

Functional capacity
of bone marrow

Erythroid progenitor cell

proliferation suppressed

Available nutrients

Iron sequestered and

protein synthesis reduced

Red blood cell survival

Red blood cell survival reduced; blood

loss increased due to diagnostic testing

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patients with cancer-related anemia who were receiving

nonplatinum chemotherapy for solid or nonmyeloid
hematologic malignancies.19 Study participants had a
hemoglobin level of 10.5 g/dL or below, or 12.0 g/dL or
below in conjunction with a decrease of 1.5 g/dL or
more with each cycle of chemotherapy. Patients were
randomized to treatment with either epoetin alfa, 150
IU/kg to 300 IU/kg by subcutaneous injection 3 times
per week for 12 to 24 weeks, or placebo. Compared
with placebo, epoetin alfa significantly reduced the need
for blood transfusion (P = .0057) and increased hemoglobin levels (P < .001). Equally important, all key measures of quality of life, including energy level, the ability
to perform daily activities, and fatigue, were significantly better in patients treated with epoetin alfa (P < .01).
These data support an earlier analysis by Henry and
Abels of 3 randomized, double-blind, placebo-controlled
trials of recombinant erythropoietin for the treatment of
anemia in a total of 413 patients with cancer.20 Those
patients receiving chemotherapy were treated with epoetin alfa (150 U/kg subcutaneously) 3 times per week for
12 weeks. In patients who were not undergoing
chemotherapy, the epoetin dose was 100 U/kg, and the
duration of treatment was 8 weeks. In all cases, epoetin
alfa produced a significantly greater increase in hematocrit compared with placebo (P < .004). When the
results from these 2 chemotherapy trials were considered
together, epoetin therapy was associated with a significant reduction in the need for blood transfusion after the
first month of therapy (P .009). Quality of life
improved significantly among patients who responded
to epoetin therapy with at least a 6percentage point
increase in hematocrit (P < .05).
Community-based studies have also demonstrated
the value of treating cancer-related anemia with epoetin alfa. Gabrilove et al prospectively evaluated data
from 3012 patients with nonmyeloid malignancies
undergoing chemotherapy at 600 community-based
oncology practices in the United States.21 In this nonrandomized open-label study, patients received epoetin alfa 40 000 U once weekly, or 60 000 U once
weekly after 4 weeks if the hemoglobin response was
inadequate. After 16 weeks of therapy, epoetin alfa significantly increased hemoglobin levels, decreased
blood transfusion requirements, and improved functional status and fatigue. The latter 2 characteristics
were assessed by the linear analog scale assessment,
which measures energy level, ability to perform daily
activities, and overall quality of life, and by the anemia

616

subscale of the Functional Assessment of Cancer

TherapyAnemia questionnaire. Improvements in
quality of life were significantly correlated with
increased hemoglobin levels (P < .001).
In an earlier study, Glaspy et al evaluated 2342
patients with a variety of malignancies who were
undergoing cytotoxic chemotherapy.22 Treatment with
epoetin alfa (150 U/kg 3 times per week) was associated with a significant increase in mean hemoglobin levels and a significant decrease in the need for blood
transfusion (P < .001). Patients also reported significant increases in energy level, activity level, and overall
quality of life (Figure). These improvements correlated
with the magnitude of the hemoglobin increase and were
independent of tumor response. Demetri et al reported
similar results in a study of 2370 patients with nonmyeloid malignancies who were being treated with
chemotherapy in 621 community-based oncology practices in the United States.23 Epoetin alfa therapy was associated with an improvement in quality of life that not
only correlated significantly with hemoglobin levels but
also was independent of tumor response.
More recently, Glaspy et al retrospectively analyzed
data from these latter 2 community-based studies to
determine if the selection of chemotherapeutic agent
influenced the effectiveness of epoetin alfa.24 Data
from 4298 of the 4712 patients were included in the

Figure. Effects of Erythropoietin on Quality of Life

Results of linear analog scale assessment scores. Scores are based

on a scale of 1100 mm. P < .001 for all.

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analysis; of these patients, 1601 received a platinumbased chemotherapeutic agent and 2697 received a
nonplatinum-based agent. The investigators found
that in patients receiving erythropoietin, hemoglobin
levels increased from baseline to final evaluation by a
mean of 1.6 g/dL to 2.0 g/dL; the need for blood
transfusion was reduced after 2 months, and quality of
life improved by 20% to 43%. All of these changes
were statistically significant and none was influenced
by the type of chemotherapy the patient received.
Despite their importance in defining the value of
erythropoietin therapy, quality-of-life analyses have
suffered from methodological weaknesses. Recently,
researchers studying outcomes have scrutinized the
available data and, in some cases, found it wanting.
Bottomley et al, of the Quality-of-Life Unit of the
European Organization for Research and Treatment of
Cancer Data Center in Brussels, conducted a critical
review of 13 trials of erythropoietin therapy in patients
with cancer.25 They concluded that, although evidence
showed that erythropoietin therapy had positive
effects on quality of life, methodological limitations
inherent in most of the studies hampered interpretation of the data. They called for new studies of more
robust design to evaluate the quality-of-life benefits of
erythropoietin therapy.
Seidenfeld et al, of the Blue Cross and Blue Shield
Association Technology Evaluation Center, conducted
a meta-analysis of 22 controlled clinical trials of varying quality (all were randomized, but not all were
placebo controlled).26 The researchers concluded that
erythropoietin therapy reduced the need for blood
transfusion in patients with cancer-related anemia but
that lower-quality trials overestimated the magnitude
of this benefit compared with higher-quality trials.
Only those studies whose participants had mean baseline hemoglobin concentrations of 10 g/dL or below
reported statistically significant effects of epoetin treatment on quality of life. The evidence was insufficient
to determine if initiating erythropoietin therapy earlier spared more patients from blood transfusion or
resulted in better quality of life.
Yount et al, from the Center on Outcomes,
Research, and Education at Evanston Northwestern
Healthcare and Northwestern University, Evanston,
Illinois, reviewed literature published between
November 2000 and October 2001.27 The investigators concluded the evidence supported a positive effect
of epoetin therapy on quality of life in patients with

Advanced Studies in Medicine

cancer; however, they also called for future studies

with more rigorous methodological design to clarify
and strengthen the association.
DARBEPOETIN ALFA
The standard dosing schedule for recombinant erythropoietin has been 3 times per week. However,
Gabrilove et al recently reported that once-weekly epoetin alfa therapy appeared to be similarly effective in
increasing hemoglobin levels, decreasing blood transfusion requirements, and improving quality of life in
patients with cancer-related anemia.21 This was a major
advance with respect to patient convenience, and
newer analogs of recombinant erythropoietin, such as
darbepoetin alfa, may offer even more convenient dosing options for patients with cancer-related anemia.
Darbepoetin alfas effects are identical to those of
native erythropoietin. Darbepoetin, however, differs
from native or recombinant erythropoietin in having 2
additional N-linked carbohydrate side chains with
additional sialic acid residues. Darbepoetins structural
differences provide additional metabolic stability in
vivo and markedly extend its half-life.6,28 In patients
with renal failure, darbepoetin alfa has a half-life of
approximately 26 hours following intravenous administrationan estimated 3-fold increase compared with
epoetin alfa.6,28 Subcutaneous administration has been
shown to further extend the half-life of darbepoetin to
49 hours in patients with renal failure. In a study of
patients with nonmyeloid cancers undergoing multiple cycles of chemotherapy, subcutaneous darbepoetin
was found to have a half-life exceeding 40 hours.6
Data are now available from small studies investigating the safety and effectiveness of darbepoetin
administered once per week to treat cancer-related
anemia in patients with solid tumors who are and who
are not undergoing chemotherapy.6,29,30 These studies
show that darbepoetin produced a dose-dependent
increase in hemoglobin levels. In one study focusing
on patients with nonmyeloid malignancies who were
not undergoing chemotherapy, the proportion of
patients responding to darbepoetin ranged from 61%
in the group treated with 1.0 mcg/kg per week to 83%
in the group treated with 4.5 mcg/kg per week.29
Darbepoetins prolonged half-life and greater in
vivo biological activity present the opportunity for
even less frequent dosing. Preliminary evidence from
studies investigating the use of higher doses delivered

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at 2-week or 3-week intervals suggests that an equivalent proportion of patients achieve the target hemoglobin response when darbepoetin is administered
every 2 weeks or 3 weeks compared with weekly dosing. Evidence also shows that darbepoetin alfa administered once every 2 weeks produces a hemoglobin
response equivalent in both magnitude and speed to
that achieved with once-weekly dosing of epoetin alfa6;
response rates of approximately 54% have been reported with 2-week dosing regimens and 50% with 3-week
dosing regimens.
Other approaches being evaluated include a further reduction in dosing frequency to every 4 weeks
and a new 2-part regimen that combines loading
and maintenance phases. In the loading phase, darbepoetin is administered weekly until the target
hemoglobin response is achieved, then every 2
weeks or 3 weeks thereafter. At the 2002 meeting of
the American Society of Clinical Oncology, Glaspy
et al reported the results of a clinical study of 122
patients with solid tumors and a hemoglobin level
of 11 g/dL or below who received darbepoetin alfa
4.5 mcg/kg weekly for 4 weeks, followed by 3.0
mcg/kg every 2 weeks. The researchers observed a
rapid and sustained hemoglobin response and relief
of fatigue in patients receiving this front-loaded
approach to therapy. (See Poster Presentations in
this issue for details.)
CONCLUSION
Clinical understanding of the consequences of cancer-related anemia has been broadened to include its
negative impact on quality of life, most often because
of fatigue. Fortunately, these negative effects can be
corrected with recombinant human erythropoietin
and its newer analogs. Future studies should define the
most efficient means of exploiting these important
biologic agents.

REFERENCES
1. Barrett-Lee PJ, Bailey NP, OBrien ME, Wager E. Largescale UK audit of blood transfusion requirements and
anaemia in patients receiving cytotoxic chemotherapy.
Br J Cancer. 2000;82:93-97.
2. Nowrousian MR. Recombinant human erythropoietin in the
treatment of cancer-related or chemotherapy-induced

618

anaemia in patients with solid tumours. Med Oncol.

1998;15(suppl 1):S19-S28.
3. Reed WR, Hussey DH, DeGowin RL. Implications of the
anemia of chronic disorders in patients anticipating radiotherapy. Am J Med Sci. 1994;308:9-15.
4. Groopman JE, Itri LM. Chemotherapy-induced anemia in
adults: incidence and treatment. J Natl Cancer Inst.
1999;91:1616-1634.
5. Koeller JM. Clinical guidelines for the treatment of cancerrelated anemia. Pharmacotherapy. 1998;18:156-169.
6. Smith R. Applications of darbepoietin alfa, a novel erythropoiesis-stimulating protein, in oncology. Curr Opin Hematol.
2002;9:228-233.
7. Caro JJ, Salas M, Ward A, Goss G. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic quantitative review. Cancer. 2001;91:
2214-2221.
8. Spivak JL. Cancer-related anemia: its causes and characteristics. Semin Oncol. 1994;21(suppl 3):3-8.
9. Bron D, Meuleman N, Mascaux C. Biological basis of anemia. Semin Oncol. 2001;28(suppl 8):1-6.
10. Adamson JW. Erythropoietin: its role in the regulation of erythropoiesis and as therapeutic in humans. In: Goldstein J,
ed. Biotechnology of Blood. Stoneham, Mass: ButterworthHeinemann; 1991.
11. Spivak JL. The biology and clinical applications of recombinant erythropoietin. Semin Oncol. 1998;25(suppl 7):7-11.
12. Adamson JW. Regulation of red blood cell production.
Am J Med. 1996;101(suppl):4S-6S.
13. Mulcahy L. The erythropoietin receptor. Semin Oncol.
2001;28(suppl 8):19-23.
14. Schaefer RM, Schaefer L. Iron monitoring and supplementation: how do we achieve the best results? Nephrol Dial
Transplant. 1998;13(suppl 2):9-12.
15. Ludwig H, Fritz E. Anemia in cancer patients. Semin Oncol.
1998;25(suppl 7):2-6.
16. Raymond FD, Bowie MA, Dugan A. Iron metabolism in
rheumatoid arthritis. Arthritis Rheum. 1965;8: 233-243.
17. Vreugdenhil G, Manger B, Nieuwenhuizen C, Feelders RA,
van Eijk HG, Swaak AJ. Iron stores and serum transferrin
receptor levels during recombinant human erythropoietin
treatment of anemia in rheumatoid arthritis. Ann Hematol.
1992;65:265-268.
18. Andrews NC. Disorders of iron metabolism. N Engl J Med.
1999;341:1986-1995.
19. Littlewood TJ, Bajetta E, Nortier JW, Vercammen E,
Rapoport B. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind,
placebo-controlled trial. J Clin Oncol. 2001;19:2865-2874.
20. Henry DH, Abels RI. Recombinant human erythropoietin in
the treatment of cancer and chemotherapy-induced anemia:
results of double-blind and open-label follow-up studies.
Semin Oncol. 1994;21(suppl 3):21-28.
21. Gabrilove JL, Cleeland CS, Livingston RB, Sarokhan B,
Winer E, Einhorn LH. Clinical evaluation of once-weekly
dosing of epoetin alfa in chemotherapy patients:
improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol. 2001;
19:2875-2882.

Vol. 2, No. 17

October 2002

REVIEW

22. Glaspy J, Bukowski R, Steinberg D, Taylor C, Tchekmedyian S,

Vadhan-Raj S. Impact of therapy with epoetin alfa on clinical
outcomes in patients with nonmyeloid malignancies during
cancer chemotherapy in community oncology practice. Procrit
Study Group. J Clin Oncol. 1997;15:1218-1234.
23. Demetri GD, Kris M, Wade J, Degos L, Cella D. Quality-oflife benefit in chemotherapy patients treated with epoetin
alfa is independent of disease response or tumor type:
results from a prospective community oncology study. Procrit
Study Group. .J Clin Oncol. 1998;16:3412-3425.
24. Glaspy J, Degos L, Dicato M, Demetri GD. Comparable
efficacy of epoetin alfa for anemic cancer patients receiving platinum- and nonplatinum-based chemotherapy: a retrospective subanalysis of two large, community-based trials.
Oncologist. 2002;7:126-135.
25. Bottomley A, Thomas R, van Steel K, Flechtner H,
Djulbegovic B. Human recombinant erythropoietin and quality of life: a wonder drug or something to wonder about?
Lancet Oncol. 2002;3:145-153.

Advanced Studies in Medicine

26. Seidenfeld J, Piper M, Flamm C, et al. Epoetin treatment of

anemia associated with cancer therapy: a systematic
review and meta-analysis of controlled clinical trials. J Natl
Cancer Inst. 2001;93:1204-1214.
27. Yount S, Lai JS, Cella D. Methods and progress in assessing the quality of life effects of supportive care with erythropoietin therapy. Curr Opin Hematol. 2002;9:234-240.
28. Macdougall IC. Darbepoetin alfa: a new therapeutic agent
for renal anemia. Kidney Int. 2002;61(suppl 80):55-61.
29. Smith RE Jr, Jaiyesimi IA, Meza LA, et al. Novel erythropoiesis stimulating protein (NESP) for the treatment of
anaemia of chronic disease associated with cancer. Br J
Cancer. 2001;84(suppl 1):24-30.
30. Glaspy J, Jadeja JS, Justice G, et al. A dose-finding and
safety study of novel erythropoiesis stimulating protein
(NESP) for the treatment of anaemia in patients receiving
multicycle chemotherapy. Br J Cancer. 2001;84(suppl
1):17-23.

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