REVIEW
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Cancer-related anemia and recombinant human
erythropoietin—an updated overview
Julia Bohlius, Olaf Weingart, Sven Trelle and Andreas Engert*
INTRODUCTION
Anemia is defined as a deficiency in red blood cells
(RBCs) and is a widely prevalent complication
among cancer patients.1 The prevalence of anemia
varies according to the type of neoplasia.2,3 About
50% of patients with solid tumors present with
anemia at diagnosis. Hematologic malignancies
increase the likelihood of developing anemia; for
example, 60–70% of patients with non-Hodgkin’s
lymphoma are anemic at the time of diagnosis.2
The National Cancer Institute suggested a classi-
fication for anemia based on hemoglobin (Hb)
values (Table 1).3
The pathophysiology of tumor anemia is
multifactorial (Figure 1).4 Tumor-associated
factors such as tumor bleeding, hemolysis, and
deficiency in folic acid and vitamin B12, can be
acute or chronic. In the advanced stages of hema-
tologic malignancies, bone marrow involvement
often leads to progressive anemia. In addition,
interaction between tumor cell populations and
the immune system can lead to the release of
cytokines, especially interferon-γ, interleukin-
1 and tumor-necrosis factor-α. This release
disrupts endogenous erythropoietin synthesis
in the kidney and suppresses differentiation of
erythroid precursor cells in the bone marrow.
As a result, patients with tumor anemia can have
relatively low levels of erythropoietin for the
grade of anemia observed.5 Moreover, activation
of macrophages can lead to a shorter erythro-
cyte half-life and a decrease in iron utilization.
Cytostatic therapy and radiation further aggra-
vates anemia in cancer patients. Platinum-based
chemotherapy regimens might diminish endo-
genous erythropoietin production by damaging
renal tubular cells,6 and myelotoxic anticancer
drugs can compromise erythroid precursor cells.
As a consequence, dose-intensified treatment
regimens or shortened treatment intervals, as
well as multimodal therapies, are associated with
a higher degree of anemia. Mild or moderate
(grade 1 and 2) anemia in patients with solid
cancers could affect about 60% of patients after
platinum-based chemotherapy.3 Severe (grade 3)
For cancer patients, anemia can be a debilitating problem that negatively
influences their overall quality of life and worsens their prognosis. The
condition is caused either by the cancer itself or by cytotoxic treatment.
Anemia is the primary indication for transfusion of red blood cells, but the
development of recombinant human erythropoietins (epoetins) provides
an alternative to red blood cell transfusions. Treatment with epoetins has
been shown to reduce transfusion rates and increase hemoglobin response.
There is some evidence that epoetins improve quality of life. It remains
unclear, however, whether erythropoietin affects tumor growth and
survival, and this area requires further investigation. Data from clinical
trials suggest that erythropoietin increases the risk of thromboembolic
complications. In the management of anemic patients, physicians should
follow closely the dosing recommendations in products’ package inserts
or the ASCO/American Society of Hematology guidelines. Treatment of
patients beyond the correction of anemia, however, has to be regarded as
experimental and is potentially harmful, so should only be conducted in
clinical trials.
KEYWORDS anemia, cancer, darbepoetin, erythropoietin, thromboembolic
J Bohlius is a research fellow at the Cochrane Haematological Malignancies
Group, O Weingart is a research fellow at the Cochrane Haematological
Malignancies Group, and A Engert is Senior Consultant in Department I
of Internal Medicine, at the University of Cologne, Cologne, Germany.
S Trelle is a research fellow at the Division of Epidemiology and Biostatistics,
University of Berne, Berne, Switzerland.
Correspondence
*Department I of Internal Medicine, University Hospital of Cologne, Kerpener Strasse 62,
D-50924 Cologne, Germany
a.engert@uni-koeln.de
Received 22 August 2005 Accepted 15 January 2006
www.nature.com/clinicalpractice
doi:10.1038/ncponc0451
REVIEW CRITERIA
Data for this review were obtained by searching the MEDLINE and EMBASE
databases for articles using combinatorial search terms that included
“erythropoietin”, “epoetin alfa”, “epoetin beta”, and “darbepoetin alfa”, as well
as “recombinant”, “myelodysplasia” and “neoplasms”. In addition, conference
proceedings from ASCO, ASH and ESMO were reviewed, and the largest studies
from this search together with reference lists from other systematic reviews and
guidelines were assessed. The abstracts of retrieved citations were reviewed and
prioritized by study size and relative clinical and preclinical data. Full articles
were obtained and references checked for additional material when appropriate.
SUMMARY
152 NATURE CLINICAL PRACTICE ONCOLOGY MARCH 2006 VOL 3 NO 3
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REVIEW
MARCH 2006 VOL 3 NO 3 BOHLIUS ET AL. NATURE CLINICAL PRACTICE ONCOLOGY 153
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anemia in elderly patients with hemato-
logic malignancies can occur in up to 74% of
patients with non-Hodgkin’s lymphoma after
standard CHOP (cyclophosphamide/doxorubicin/
vincristine/ prednisolone) treatment.3 In addi-
tion, some of the newer chemotherapeutic agents,
such as taxanes or vinorelbine, are strongly
myelosuppressive and can cause high degrees
of anemia.3
SIGNS AND SYMPTOMS OF ANEMIA
The clinical manifestation and severity of
anemia vary considerably among individual
patients. Moderate anemia can typically cause
signs and symptoms such as headache, palpi-
tations, tachycardia and shortness of breath.
Chronic anemia can result in severe organ
damage affecting the cardiovascular system,
immune system, lungs, kidneys, and the central
nervous system.7 In addition to physical symp-
toms, the subjective impact of cancer-related
anemia on quality of life (QOL), mental health
and social activities may be substantial. Clinical
studies have reported correlations between Hb
levels and QOL.8–10 A common anemia-related
problem is fatigue, which impairs the patient’s
ability to perform normal daily activities.7,11
As fatigue is a multifactorial syndrome not
only caused by anemia, trying to correlate the
relative contribution of anemia to fatigue is
complex. Even when anemia is improved, the
full symptoms of fatigue might not be relieved,
because fatigue can be present independent of
anemia.12,13
Tumor hypoxia and survival
Another aspect of anemia in patients with
malignant disease is the effect on the tumor
itself. For several cancers, including cervical
carcinoma, head and neck, prostate, bladder
and lung cancer, as well as lymphoma, anemia is
known to be associated with a poor prognosis.14
This association is partly the result of
confounding factors, because advanced cancers
usually present with lower Hb levels at diag-
nosis compared with early-stage cancers, and
also have poorer survival outcomes. An addi-
tional, causal, explanation might be the reduced
oxygenation of tumor tissue at lower Hb levels.
Tumor cells can become resistant to radio-
therapy and chemotherapy because of hypoxia;
this is because the decreased oxygen transport
capacity as a result of tumor- associated anemia
can contribute to the development of hypoxia.
Because of an abnormal micro environment,
solid tumor tissue is often hypoxic. Hypoxia
might be more prevalent in anemic patients
than in patients with normal Hb levels.15
Tumor hypoxia can impair the effectiveness of
radiotherapy and oxygen-dependent chemo-
therapies.15,16 For example, a study in cervical
cancer demonstrated that increased hypoxia
(defined as partial pressure of oxygen below
10 mm Hg) was associated with decreased local
tumor control and lower rates of disease-free
survival and overall survival.17 These obser-
vations generated the hypothesis that strate-
gies to diminish cancer-related anemia might
not only alleviate anemia-related symptoms
but also improve tumor response and overall
survival. Such an effect was partly demonstrated
in animal models, where the augmentation
of Hb levels with erythropoietin led to better
tumor control following treatment with either
radiotherapy or chemotherapy with cisplatin or
cyclophosphamide.18–22
TREATMENT OPTIONS
Red blood cell transfusions
Before erythropoietin was available, blood
transfusion was the only treatment option for
severe cancer-related anemia. Homologous
blood transfusion is the fastest method by
which to alleviate symptoms; however, short-
term and long-term risks exist with this
pro cedure.23 Potential complications associ-
ated with blood transfusion are transmission of
infectious diseases, transfusion reactions, allo-
immunization, lung injury, over-transfusion
and immune modulation with possible adverse
effects on tumor growth.23–25 In the US, the
Table 1 Grading of anemia according to the
National Cancer Institute classification.
Grade Symptom
severity
Hemoglobin
values
0 Within normal
limits
12.0–16.0 g/dl
for women
and 14.0–18.0 g/ dl
for men
1 Mild 10 g/dl to levels
within normal limits
2 Moderate 8.0–10.0 g/dl
3 Serious/severe 6.5–7.9 g/dl
4 Life
threatening
<6.5 g/dl
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