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8/9/2019 ONS CaRelatedAnemia CJON Article
http://slidepdf.com/reader/full/ons-carelatedanemia-cjon-article 1/11Clinical Journal of Oncology Nursing • Volume 11, Number 3 • Cancer-Related Anemia 349
Beth Hurter, RN, MSN, CNP, OCN, and Nancy Jo Bush, RN, MN, MA, AOCN®
CJON WRITING MENTORSHIP PROGRAM ARTICLE
Anemia is a decrease in circulating red blood cells that contributes to a complex group of symptoms. Anemia may be pres-
ent in more than half of all patients with cancer but often is assessed, documented, prevented, and treated inadequately.
Individuals with cancer are living longer, and the number of cancer treatment options provided at various points in the
cancer continuum is growing; however, many treatments contribute to anemia. Because anemia can develop from multiple
causes, treatment must be tailored to the underlying etiology. Cancer-related anemia can significantly affect therapeutic
outcomes and patients’ quality of life. Therapeutic interventions may include blood transfusions, administration of recom-
binant human erythropoietin, and interventions to support patient symptoms, most significantly, fatigue. Oncology nursesplay a central role in risk assessment, symptom management, treatment planning, and evaluation and therefore must
understand the etiology and physiology of cancer-related anemic states as well as evidence-based interventions to ensure
optimal outcomes.
Cancer-Related Anemia:
Clinical Review and Management Update
At a Glance
✦ Anemia often is assessed, documented, prevented, and
treated inadequately.
✦ Cancer-related anemia can significantly affect therapeuticoutcomes and patients’ quality of life.
✦ Oncology nurses play a central role along the continuum of
care of patients experiencing cancer-related anemia.
Beth Hurter, RN, MSN, CNP, OCN®
, is an acute care nurse practitionerof stem cell transplant at the University of Illinois Medical Center inChicago, and Nancy Jo Bush, RN, MN, MA, AOCN®, is an oncologynurse practitioner and assistant clinical professor in the School ofNursing at the University of California, Los Angeles. The authors wereparticipants in the 2005 CJON Writing Mentorship Program, which wasunderwritten through an unrestricted educational grant by Amgen, Inc.No financial relationships to disclose. Mention of specific products andopinions related to those products do not indicate or imply endorse-ment by the Clinical Journal of Oncology Nursing or the OncologyNursing Society. (Submitted February 2006. Accepted for publicationSeptember 22, 2006.)
Digital Object Identifier: 10.1188/07.CJON.349-359
In patients with cancer, anemia can result from secondary
blood loss, displacement of normal bone marrow cells by
malignant cells, myelotoxic therapy, or a tumor, yet the
condition may not become evident unless it represents a
source of significant symptoms or patient distress. Risk factors
for anemia development include platinum-based treatment
regimens, specific tumor types, and low baseline hemoglobin
levels. Anemia has the potential to impact patient performance
status, quality of life, clinical symptoms, therapeutic efficacy,
and survival. Treatment interventions directed toward the
underlying etiology of anemia involve iron supplementation,
blood transfusion, and administration of recombinant human
erythropoietin (rHuEPO). Novel approaches that may add to
the complement of strategies designed to address anemia in
patients with cancer are being developed (Cella, Dobrez, &
Glaspy, 2003; Gillespie, 2003; Groopman & Itri, 1999; Mer-
cadante, Gebbia, Marrazzo, & Filosto, 2000).
Although considerable progress has been made in prevent-
ing or alleviating many of the common toxicities associated
with cancer and its therapy, anemia continues to be frequently
overlooked and undertreated (Loney & Chernecky, 2000). Ane-
mia contributes to fatigue, a symptom that adversely affects
functional status and causes considerable distress to patients
and their fami lies (Stovall & Young, 2006; Von Gunten, 1999).
In addition, the lack of a standard definition regarding symp-
tomatic anemia requiring intervention and the availability of
suboptimal assessment tools further complicate the problem
of anemia in patients with cancer (Gillespie, 2003; Groop-
man & Itri, 1999). Oncology nurses are pivotal to the care of
patients with cancer-related anemia (CRA) because they are
a constant presence along the continuum of care; therefore,
oncology nurses must be able to identify pert inent assessment
criteria, identify patients at risk, carry out evidence-based
interventions, and evaluate therapeutic outcomes.
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Causes of Cancer-Related Anemia
Anemia is defined as a decrease in the volume of circulating
red blood cells (RBCs) or the concentration of hemoglobin
resulting in the body’s diminished ability to carry oxygen to
tissues (Lynch, 2006d). The causes of anemia may be multi-
factorial, especially in patients with cancer undergoing mul-
tiple and prolonged treatment regimens. Anemia may result
from decreased RBC production, increased RBC destruction,decreased circulating RBCs, or a combination of those fac-
tors, as well as other compounding reasons (e.g., poor dietary
intake of iron), which often is the case in patients with cancer
(Loney & Chernecky, 2000). Inadequate production of RBCs
may result from defects in erythropoietin-producing cells,
DNA synthesis, hemoglobin synthesis, bone marrow sup-
pression, or renal failure (Lynch, 2006d). RBC destruction is
caused by many factors such as intrinsic factors (e.g., enzyme
deficiencies) or cancer-related extrinsic destruction by che-
motherapeutic agents (e.g., antimetabolites), the malignancy
itself stimulating an autoimmune hemolysis (e.g., chronic
lymphocytic leukemia), or inflammatory cytokines produced
by the malignancy destroying RBCs (e.g., tumor necrosis fac-tor) (Loney & Chernecky; Lynch, 2006d; Worrall, Tompkins,
& Rust, 1999). Decreased circulating RBCs can result from
acute hemorrhage or cancer-related coagulopathies as in dis-
seminated intravascular coagulation. In patients with cancer,
compounding factors such as deficiencies in iron, vitamin B12
,
and folate present risks for decreased production and loss of
circulating RBCs (Loney & Chernecky).
The etiology of anemia often is classified according to the
size of the RBC, which is determined by evaluation of the mean
corpuscular volume laboratory data. Anemia may be classified
as microcytic, normocytic, and macrocytic (Lynch, 2006d)
(see Table 1). Other classifications may be based on RBC mor-
phology, including the amount of pigment, noted by the mean
corpuscular hemoglobin (e.g., hypochromic, normochromic),
or by the reticulocyte count, which delineates the productive
capacity of the bone marrow to meet the RBC requirements
of the body. A low reticulocyte count demonstrates decreased
RBC production, whereas a high reticulocyte count indicates
increased RBC destruction (Lynch, 2006d).
Microcytic Anemia
Two common causes of microcytic anemia in patients with
cancer are iron deficiency or comorbid chronic disease states. In
microcytic anemia, the RBC is small in size (i.e., mean corpuscu-
lar volume < 80 fl). In patients with iron deficiency, microcytic
anemia is caused by insufficient iron for hemoglobin synthesis.
Iron deficiency anemia is the most common cause of anemia
worldwide, occurring frequently in young chi ldren, pregnant
women, and older adults (Lynch, 2006c; Worrall et al., 1999). In
patients with cancer, the most frequent causes of iron deficiency
are inadequate absorption (e.g., gastrectomy), excessive loss
of iron because of blood loss (i.e., uterine, gastrointestinal, or
genitourinary tract bleeding) (Lynch, 2006c), or other cancer-
related effects such as anorexia resulting in poor dietary intake
of iron (Loney & Chernecky, 2000). Differential diagnoses for
iron deficiency microcytic anemia in patients with cancer in-
clude other hematologic disorders such as thalassemia minor
and sideroblastic anemia (Lynch, 2006c).
Malignancies and other conditions such as chronic in fection,
inflammatory conditions, and congestive heart failure contrib-
ute to a common set of factors resulting in anemia and are re-
ferred to as anemia of chronic disease (ACD). ACD is triggered
by immune and inflammatory cytokines that are common to
those conditions, specifically tumor necrosis factor, interleukin-
1, and interferon (Cella et al., 2003). Reduced erythropoietin
production results from inhibition of RBC precursors in the
bone marrow, impaired iron uptake by developing RBCs, or
erythropoietin inadequately released from the kidneys (Lynch,
2006a). Chronic infections decrease the stem cell pool in addi-
tion to reducing the body’s response to erythropoietin stimula-
tion (Loney & Chernecky, 2000).
The reticulocyte count is the productive capacity of the bonemarrow to meet the RBC requirements of the body. Patients
with ACD have a low reticulocyte count, indicating a hypo-
proliferative state. Differential diagnoses for microcytic ACD in
patients with cancer include other hematologic disorders such
as aplastic anemia, bone marrow suppression caused by myelo-
dysplasia or chemotherapy, and anemia resulting from chronic
renal failure (Lynch, 2006a).
Normocytic Anemia
In its early stages, ACD may present as normocytic anemia,
a state in which RBCs are normal in size. Classification by RBC
Table 1. Classifications of Common
Cancer-Related Anemias
Note . Based on information from Loney & Chernecky, 2000; Lynch, 2006d.
DIFFERENTIAL DIAGNOSIS
Iron deficiencyAnemia of chronic diseaseThalassemia minorSideroblastic anemia
Anemia of chronic diseaseHemolytic anemiaAplastic anemiaRenal failure
B12 deficiencyFolate deficiencyMyelodysplastic syndromes
Anemia of chronic diseaseAplastic anemiaIron deficiencyVitamin B12 deficiency
Folate deficiencyBone marrow suppressionor infiltration
HemolysisChemotherapy-inducedAutoimmune
ANEMIA TYPE
Microcytic
Normocytic
Macrocytic
Low reticulo-cyte count
High reticulo-cyte count
DESCRIPTION
Decreased meancorpuscular volume(MCV) (< 80 fl)
Red blood cells
(RBCs) small in size
Normal MCV (80–100fl)
RBCs normal in size
Increased MCV(> 100 fl)
RBCs large in size
Decreased RBC pro-duction
< 0.5%–1.5% oferythrocytes
Increased RBC de-struction
> 0.5%–1.5% oferythrocytes
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size is dependent on the type and stage of the anemia. Patients
with cancer often present with ACD and chemotherapy-induced
anemia or iron deficiency depending on the disease stage and
treatment. Hemolytic anemias are normocytic and most com-
monly are drug induced or result from renal failure. Chemother-
apy or radiation therapy may directly decrease RBC production
because of treatment-induced bone marrow suppression caus-
ing depletion of pluripotent stem cells. The metabol ic effects of
destroying RBCs may be compounded by physical factors suchas displacement of bone marrow by tumor metastases or fibrosis
or, rarely, damage by bone marrow necrosis (Smith & Tchekme-
dyian, 2002). Severe catabolism associated with cancer also may
impair protein production, rendering the bone marrow unable
to effectively produce an adequate number of RBCs (Smith &
Tchekmedyian) yet those present remain normal in size.
The processes of erythropoietin production and erythro-
poiesis are essential in stimulating the bone marrow for RBC
production and maturation. A normal feedback loop occurs
when hypoxia in the renal cells triggers release of erythropoi-
etin from the bone marrow (Loney & Chernecky, 2000). As
a result, decreased RBC production can be caused by kidney
damage related to a tumor or nephrotoxic chemotherapy or,rarely, radiation renal injury, as well as other coexisting causes
of renal insufficiency such as end-stage renal disease (Worrall
et al., 1999).
Other causes of hemolytic anemia in patients with cancer may
include autoimmune hemolysis (e.g., cold agglutinin antibod-
ies), enzyme deficiencies (e.g., glucose-6-phosphate genase),
or RBC destruction by tumor (e.g., non-Hodgkin lymphoma),
chemotherapeutic agents (e.g., cisplatin), total body irradiation
(e.g., bone marrow transplant), or risks associated with cancer
and its treatment (e.g., disseminated intravascular coagulation).
In addition, nonchemotherapeutic medications common to can-
cer protocols can contribute to anemia (e.g., lorazepam) (Loney
& Chernecky, 2000; Lynch, 2006d; Worrall et al., 1999).
Macrocytic Anemia
Abnormal maturation of RBCs contributes to macrocytic or
large cells (> 100 fl), such as in vitamin B12
and folic acid defi-
ciencies which interfere with DNA synthesis necessary for RBC
precursors (Worrall et al., 1999). Impaired absorption of vitamin
B12
(cobalamin) may be related to deficiency of intrinsic factor
secreted by the parietal cells of the stomach (e.g., total gastrec-
tomy). Pernicious anemia is an autoimmune reaction that causes
atrophy of the gastric mucosa and failure of intrinsic factor se-
cretion (Lynch, 2006b; Worrall et al.) (see Figure 1). Vitamin B12
or intr insic factor deficiency causes megaloblastic, macrocytic,
normochromic anemia and occurs more commonly in the sixth
decade of life. It is insidious in nature because of bodily stores
of vitamin B12
, yet deficiencies may occur in patients who are
strict vegetarians (e.g., no dairy or meat), in those with bacterial
infections of the gastrointestinal tract, or when precipitated by
certain medications (e.g., cimetidine) (Lynch, 2006b; Worrall et
al.). Vitamin B12
is necessary for the metabolism of folate. Bodily
stores of folate are not abundant; therefore, dietary intake (e.g.,
green leafy vegetables) is important. Deficiencies in folic acid
may occur because of alcoholism, liver disease, malabsorption
syndromes, and anorexia. In patients with cancer, medications
may lead to folic acid deficiencies such as anticonvulsants (e.g.,
phenytoin) and folic acid antagonists (e.g., hydroxurea, metho-
trexate, pemetrexed) (Worrall et al.). Differential diagnoses for
macrocytic anemia include vitamin B12
or intrinsic factor defi-
ciency, folate deficiency, ACD, and myelodysplastic syndromes
(Lynch, 2006b).
The causes and risks for CRA include iron, vitamin B12
, and
folate deficiencies; the malignancy itself; treatment; inflam-
mation; infection; comorbid disease (e.g., renal failure); andhemolysis (Worra ll et al., 1999). The causes of CRA are multiple
and complex and therefore require astute clinical evaluation
to determine patient risk factors and the underlying etiology.
A clinica l guide for delineating the causes of anemia can be
found in Figure 2.
Impact of Cancer-Related Anemia
Despite the difficulties in assessing anemia and its related
symptoms, trends in the prevalence of anemia in patients with
cancer have been identified. Some tumor types reportedly cor-
relate with high rates of anemia, such as lung cancer (52%) and
ovarian cancer (51%). The high incidence probably is related
to the advanced age of many patients with lung cancer and the
frequent use of platinum-based therapies for tumors at both sites
(Gillespie, 2002). The options for multiple chemotherapy proto-
cols are increasing and individuals with cancer are l iving longer
after treatment; therefore, the effect of anemia on patients’
quality of life and their response to treatment will continue
to present challenges for healthcare professionals (Hudis, Van
Belle, Chang, & Muenstedt, 2004).
Physical and Psychosocial Impact
The physical and psychosocial impact of undetected CRA can
be profound (Loney & Chernecky, 2000). A major complica-
tion of anemia is fatigue. Anemia results in decreased oxygen
delivery to tissues and, when untreated, eventually leads to a
negative energy balance (Gutstein, 2001). According to patient
Figure 1. Photomicrograph of Pernicious Anemia
in Bone Marrow CellsNote. Copyright C. James Webb/Phototake. All rights reserved. Reprint-
ed with permission.
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Pancytopenia
Bone marrow aspiration
and biopsy to rule out
disease, suppression,or replacement
Serum
erythropoietin
If low
Serum creatinine
to rule out
renal disease
Macrocytic
Folate
If low
Folate deficiency
If history
of paresthesias
Vitamin B12
If low
Vitamin B12
deficiency
Positive history Positive physical examination
Complete blood count
If low hemoglobin (Hgb)
or hematocrit
Mean corpuscular volume
Normocytic
If Hgb is less than 10 g/d
Rule out anemia of chronic disease
Diet/intake
Upper gastrointestinal (GI)
Barium enema
Hemoccult test
If positive
GI bleeding
No pancytopenia
Hypoproliferative (microcytic)
Reticulocytes
If low
Ferritin
If low
Source
for iron
deficiency
If high
Rule out
acutebleeding
Rule out
splenomegaly
Lactate
dehydrogenase
and bilirubin
If high—
hemolysis
If negative
Colonoscopy
If lesion
Biopsy to rule out
cancer
If positive
Immune-
mediated
Peripheral
smear
If schistocytes
Warm antibody
hemolysis
If negative
Nonimmune-
mediated
Rule out
microangiopathic
hemolysis
If positive RBC
clumping
Cold agglutinin
hemolysis
Coomb’s test
Figure 2. Algorithm for Identifying the Causes of Cancer-Related AnemiaNote. From “Anemia,” by M. Loney and C. Chernecky, 2000, Oncology Nursing Forum , 27, p. 957. Copyright 2000 by the Oncology Nursing Society.
Reprinted with permission.
RBC—red blood cell
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reports, fatigue is the most distressing symptom associated with
cancer and its treatment (Mock, 2001). As cancer treatment
protocols have become more dose dense and dose intensive,
the risk of anemia has increased, as well as the likelihood that
cancer-related fatigue will become more distressing for patients,
adversely affecting their quality of li fe (Mock).
Fatigue is difficult to assess objectively because it is a multifac-
torial and multidimensional symptom with physical, emotional,
and cognitive effects (Escalante et al., 2001; Von Gunten, 1999).Fatigue has been defined as “a subjective state of overwhelming
sustained exhaustion and decreased capacity for physical and
mental work that is unrelieved by rest” (Escalante et al., p. 1708).
The significant loss of energy associated with even mild anemic
states can limit patients’ ability to perform everyday activities,
including work, social, and leisure activities. Fatigue also has
been correlated with loss of self-esteem, anxiety, depression,
and emotional stress (Escalante et al.). Severe fatigue may dimin-
ish patients’ ability to cope with cancer and its treatment. In a
literature review, Von Gunten reported that correcting anemia-
related fatigue correlated with at least a modest improvement
in overall quality of life and energy levels.
Other disturbing symptoms that occur with anemia arecaused by increased cardiac output, shunting of blood to vital
organs, and peripheral vascular dilation (Cella et al., 2003; Hudis
et al., 2004). Mild anemia can cause tachycardia, palpitations,
and dyspnea on exertion (Loney & Chernecky, 2000). Severe
anemia results in disabling fatigue states, compounds tachy-
cardia and dyspnea, and may precipitate headaches, dizziness,
mood changes, and difficulty concentrating, whereas prolonged
anemia may cause insomnia, anorexia, indigestion, menstrual
irregularities, and sexual dysfunction (Loney & Chernecky).
Anemia’s Impact on Treatment and Survival
Hypoxia, a characteristic feature of locally advanced solid
tumors, has been recognized as a critical factor in promoting
tumor resistance to radiotherapy, chemoradiation, and some
chemotherapeutic agents (Littlewood, 2001; Shasha, 2001). In
a systematic review to determine whether anemia was an inde-
pendent prognostic factor for cancer survival, the overall risk
of death increased by 65%, adjusting for variables, in anemic
patients with cancer relative to those without anemia (Caro, Salas,
Ward, & Goss, 2001).
Severe anemia may have an impact on therapies used to
manage cancer. Anemia may delay surgical interventions when
treatment requires preoperative correction through RBC trans-
fusion. Similarly, low levels of hemoglobin before or during
chemotherapy cycles may require dose reductions or delays in
administration, resulting in a decrease in the overall treatment
intensity. Tumor hypoxia also may limit the effectiveness of
oxygen-dependent chemotherapy (Cella et al., 2003; Kelleher,
Mattheinsen, Thews, & Vaupel, 1996).
Hemoglobin levels are reported to be a strong independent
prognostic factor for tumor control by radiation therapy, with
the hemoglobin level at the conclusion of therapy believed to
be more important than the baseline level (Finney & Allison,
2005; Lavey, 1998). Cells that are not fully oxygenated are sub-
stantially less sensitive to the effects of ionizing radiation. The
proportion of cells killed by a given dose of radiation under
well-oxygenated conditions is termed oxygen enhancement
ratio. Radiation biologists have hypothesized that minimally
oxygenated tumor cells most distant from the capillary are rela-
tively resistant to radiotherapy and are the most likely source of
local treatment failure. In addition, anemia may increase local
failure rates by exacerbating local tumor hypoxia (Caro et al.,
2001; Harrison, Shasha, White, & Ramdeen, 2000). Although
the link among treatment of preexisting mild anemia, local
control, and cure rates for radiation therapy has not been suf-ficiently confirmed in randomized clinical trials, most clinicians
accept the premise that anemia compromises radiotherapy and
that it merits careful attention when cure or improved survival
is a potential therapeutic outcome (Finney & Allison; Glaspy,
2002). Hemoglobin levels have been strongly correlated with
tumor size, which may explain the poorer outcomes reported
for patients with anemia receiving radiation therapy in earlier
published studies (Gillespie, 2003).
Assessment Criteria Assessment begins with a thorough history that identifies
patients who are at risk for developing anemia or symptomsthat may be changing over time such as fatigue-related lifestyle
changes (Loney & Chernecky, 2000) (see Figure 3). Physical ex-
amination must include all organ systems and may reveal pallor,
tachycardia, systolic ejection murmur (S3 extra heart sound),
shortness of breath on activity, and pedal edema (Loney & Cher-
necky). Careful assessment of anemia and its related symptoms
is made more difficult by the lack of a standard definition of the
condition, the absence of gender-specific differences in normal
hemoglobin levels, and variable trigger points leading to transfu-
sion (Gillespie, 2003). Individual assessments should evaluate
current blood counts and other pertinent laboratory values (see
Figure 4). Physical symptoms (e.g., pulmonary, cardiac) should
be ascertained as well as changes in trends related to the find-
ings over time. Patients who become more symptomatic, as com-
pared with baseline values, may be experiencing an increase
in the severity of anemia, even if the hemoglobin level has not
decreased to very low levels.
Complicating the assessment, objective findings in symptom-
atic patients with a given hemoglobin value cannot be general-
ized to others with similar values (Gillespie, 2003). Laboratory
data play a pertinent role in the assessment of anemia, and nurs-
es should be familiar with normal ranges for the complete blood
count with indexes (see Table 2). When indicated, standards of
practice recommend that anemia assessment should include
examination of the peripheral smear, bone marrow aspiration
and biopsy (e.g., hypocellular marrow found in aplastic anemia),
and serum creatinine to evaluate renal function (Earles, 2004;
Lynch, 2006c).
Astute patient assessment is vital to differentiate anemia-related
symptoms such as fatigue and mood changes from other major
diagnoses (e.g., depression, chemotherapy-induced cognitive
changes). The underlying cause of anemia must be determined
for the optimal intervention to be designed. Concomitant pro-
cesses, such as nutritional deficiencies, inflammation, infection,
hemolysis, blood loss, and other diagnoses in the context of can-
cer, should be evaluated as well as information about the impact
of current or previous myelosuppressive therapy (Groopman
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& Itri, 1999). Multiple causes of anemia exist, and treatment is
tailored to the cause. The degree of anemia is not always reflec-
tive of the severity of the causative disorder; therefore, careful
and thorough assessment, including attention to patterns that
patients experience, is critical in anemia treatment (Gillespie,
2003; Groopman & Itri; Tavio, Milan, & Tirelli, 2002). Quan-
titative assessment scales such as the Anemia Subscale of the
Functional Assessment of Cancer Therapy and the Brief Fatigue
Inventory can be used to assess the impact of fatigue on patients’
daily activities. Nurses also can incorporate a 0–10 numeric rat-
ing scale or a descriptive scale (e.g., mild, medium, severe) into
their patient assessments (Earles, 2004).
Symptom ManagementCorrection or management of the underlying etiology in
patients with documented anemia is the optimal outcome (Gil-
lespie, 2003; Tavio et al., 2002). Once the source of anemia
has been determined, treatment can be initiated. Supportive
interventions include transfusion therapy, erythropoiesis-stimu-
lating therapies, iron supplementation, nutrition, and patient
education (see Figure 5). Because multiple causes of anemia
may be present in an individual, more than one therapy often
is necessary.
Evidence-based guidelines for the treatment of anemia in
patients with cancer have been established (Earles, 2004). Joint
practice guidelines were adopted by the American Society ofClinical Oncology and the American Society of Hematology
in 2002 (Rizzo et al., 2002), and the National Comprehensive
Cancer Network (NCCN) published an updated version of
guidelines in 2007. The standards of care for CRA must be incor-
porated into clinical practice to ensure consistency and benefit
for patients (Berger, 2005).
Transfusion Therapy
The NCCN (2007) guidelines defined levels of hemoglobin
to guide interventions—mild anemia (10–11 g/dl), moder-
ate anemia (8–10 g/dl), and severe anemia (< 8 g/dl). When
clinical symptoms warrant immediate correction, transfusion
therapy is appropriate (Earles, 2004). Packed RBCs usually are
administered for a hemoglobin level less than 8 g/dl, raising
the level of hemoglobin quickly to ensure adequate oxygen-
carrying capacity to vital organs and improving overall clinical
status (Von Gunten, 1999). Symptoms of anemia generally are
relieved and quality-of-life data support that optimal improve-
ment occurs when the hemoglobin level ranges from 11–12
g/dl (Earles). Although the blood supply in the United States
is considered extremely safe, RBC transfusion is not without
accompanying risk and patients often are concerned about the
hazards (Gillespie, 2002, 2003). The potential for transfusion
reactions (e.g., allergic, febrile, hemolytic), as well as other
possible risks (e.g., alloimmunization, immunosuppression,
Risk Factors
• History of blood transfusion in previous six months
• Decreased hemoglobin
• Nutritional deficiency
• Iron deficiency
• Myelosuppressive chemotherapy
• Radiation therapy to more than 20% of the skeleton
• Bleeding
• Hemolysis
• Advanced age
Characteristics
• Onset, duration, pattern, and course
• Severity
• Lifestyle or activity changes over time
• Emotional distress and impact
• Exacerbating and palliative factors
Signs and Symptoms
• Integument: pallor or hypersensitivity to cold
• Central nervous system: dizziness, headaches, or mood changes
• Cardiovascular: tachycardia, palpitations, or S3 systolic murmur
• Pulmonary: shortness of breath or dyspnea on exertion or at rest
• Gastrointestinal: anorexia or indigestion
• Genitourinary: menstrual irregularities or loss of libido
Manifestations of Fatigue
• Lack of energy
• Weakness
• Difficulty concentrating
• Mood changes or irritability
• Sleep disturbances
Related Constructs
• Symptom distress
• Impact of myelosuppressive therapy
• Goals of treatment
• Subjective quality of life
Figure 3. Assessment Criteria for Cancer-Related
AnemiaNote. Based on information from Earles, 2004; Loney & Chernecky, 2000;
Portenoy & Itri, 1999.
Figure 4. Various Forms of Anemia and the Blood
Tests Used for DiagnosisNote. Copyright Bedell Communications, Inc./Phototake. All rights re-
served. Reprinted with permission.
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iron or circulatory overload, transfusion-related acute lung
injury, transfusion-transmitted infectious agents), should be
considered prior to initiation of transfusion therapy (Gillespie,
2002, 2003; Perrotta & Snyder, 2001). Some patients may have
religious beliefs prohibiting the use of blood or blood products
(Gillespie, 2003).
Not only does transfusion therapy rapidly correct anemia and
related symptoms, it reduces delays in cancer treatment because
of anemia. However, quantifiable disadvantages must be consid-
ered, including supply issues, expenses associated with blood
products and their administration, and the inconvenience for
patients undergoing several hours of administration. The risks
and benefits of transfusion therapy must be weighed carefullyin each situation (Buchsel, Murphy, & Newton, 2002; Groopman
& Itri, 1999) and transfusion of RBCs should be initiated only
if anemia is so severe that inadequate time exists to permit the
use of an erythropoiesis-stimulating therapy (Gillespie, 2003)
or in cases of anemia that are not responsive to iron, vitamin
B12
, folate, or dietary supplementation.
Erythropoiesis-Stimulating Therapies
Erythropoietin is a naturally occurring hormone produced
by the kidneys to regulate RBC production and specifically
acts at the colony-forming unit–erythroid of the bone marrow
to promote erythroid stem cell development into mature cir-
culating erythrocytes (Buchsel et al., 2002). The production
of erythropoietin is regulated by a feedback loop in which the
kidney senses decreased oxygen or t issue hypoxia, decreased
arterial oxygen, anemia, or increased hemoglobin affinity and
releases erythropoietin (Buchsel et al.; Groopman & Itr i, 1999;
Tong & Nissenson, 2001).
With advances in recombinant DNA technology and the ability
to manufacture hematopoietic growth factors, the introductionof rHuEPO (epoetin alfa) in the 1990s represented a significantly
new approach to treatment and potential reduction in CRA and
other conditions, such as chronic renal failure, zidovudine-treated
patients with HIV, and patients with anemia undergoing elective,
noncardiac, nonvascular surgery (Buchsel et al., 2002). Epoetin’s
mechanism of action and its immunologic and hematologic
properties are equivalent to those of endogenous erythropoietin
(Amgen Inc., 2006b; Faulds & Sorkin, 1989).
In patients whose endogenous erythropoietin levels are ab-
normally low considering the degree of anemia experienced, the
administration of exogenous erythropoietin may be beneficial.
Conversely, if endogenous levels of erythropoietin are adequate,
the addition of exogenously administered erythropoietin maybe of little help in a lleviating the anemia (Gillespie, 2003). For
example, in patients with myelodysplasia, erythropoietin levels
less than 200 mu/ml are predictive of insensitivity to epoetin
(Earles, 2004). Other causes of low response include vitamin
deficiencies, decreased iron stores, or infectious processes
(Buchsel et al., 2002).
Prior to starting any patient on an erythropoietin-stimulating
therapy, NCCN (2007) has recommended a thorough evaluation
of CRA to rule out nutritional deficiencies of vitamin B12
, iron,
and folate, in addition to assessing for hemolysis (e.g., hemoglo-
bin electropheresis) and evidence of gastrointestinal bleeding
(e.g., guaic testing). Other pertinent laboratory testing must
be carried out to identify a noncancer- or nontreatment-related
cause of anemia because the underlying cause must become
the initial focus of treatment (e.g., normocytic anemia caused
by hypothyroidism).
Epoetin alfa: Epoetin alfa (Procrit, Ortho Biotech Prod-
ucts, LP; Epogen, Amgen Inc.) was approved by the U.S. Food
and Drug Administration (FDA) in 1993 for the treatment of
anemia in patients with nonmyeloid malignancies (Earles,
2004). Epoetin alfa stimulates the division and differentiation
a Range of normal laboratory values is dependent on institutional guide-
lines.b The National Comprehensive Cancer Network (2007) guidelines have
suggested iron studies prior to erythropoietic therapy to ensure adequate
iron stores.
Note. Based on information from Loney & Chernecky, 2000; Portenoy &
Itri, 1999.
Table 2. Evaluation of Laboratory Data
for Cancer-Related Anemias
LABORATORY TEST
Red blood cell count
Hemoglobin
Hematocrit
Mean corpuscular volumeMean corpuscular hemoglobinMean corpuscular hemoglobin
concentrationRed cell distribution widthReticulocyte countFerritinb
Serum ironb
Total iron-binding capacityb Serum erythropoietin level
Serum transferrinCoomb’s test (direct or indirect)Serum B12
Serum folateSedimentation rate
NORMATIVE VALUESa
Men: 4.7–6 million/mclWomen: 4.2–5.4 million/mclMen: 13.5–18 g/dlWomen: 12–16 g/dl
Men: 42%–52%Women: 37%–47%80–100 fl27–31 pg/cell30%–37%
11.5%–14%0.5%–1.5% of erythrocytesMen: 20–300 ng/mlWomen: 15–120 ng/mlMen: 75–175 ug/dlWomen: 65–165 ug/dl250–450 ug/dlMen: 17.2 mu/mlWomen: 18.8 mu/ml
200–400 mg/dlNegative190–1,100 pg/ml> 3.5 ng/ml41%–54%
• Differential diagnosis of causative factor(s)
• Treatment aimed at underlying cause(s)• Replacement of hematologic component(s) necessary for DNA synthe-
sis for red blood cell production (e.g., vitamin B12
, folate)
• Transfusion therapy for hemoglobin less than 8 g/dl or symptomatic
• Erythropoiesis-stimulating agents as prescribed
• Iron supplementation as appropriate
• Evidence-based interventions (physical and psychosocial)
• Symptom management (e.g., fatigue)
• Patient education regarding goals of treatment(s)
• Documentation of assessment, treatment, and patient outcomes
• Repeated assessment and evaluation across continuum of care
Figure 5. Management of Cancer-Related Anemia
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of erythrocyte stem cells in the bone marrow, resulting in the
release of reticulocytes into the blood stream in 7–10 days where
they mature into erythrocytes. The process of increasing the
hemoglobin takes two to six weeks (Wilkes & Barton-Burke,
2005).
NCCN (2007) recommended beginning treatment with
epoetin alfa using either 150 U/kg subcutaneously three times
weekly or 40,000 units weekly. Doses are titrated up to 300
units/kg three times weekly or 60,000 units every week if thehemoglobin has not risen by at least 1–2 g/dl after four weeks
(Amgen Inc., 2006b; Ortho Biotech Products, LP, 2006). Doses
are reduced by 25% if the hemoglobin increases by more than
1 g/dl in a two-week period, and therapy is held if hemoglobin
exceeds 12 g/dl (NCCN).
Erythropoietin has been shown to raise the mean hematocrit
in patients with chemotherapy and CRA, independent of tumor
type or disease response, significantly improving energy levels
and quality of life (Demetri, Kr is, Wade, Degos, & Cella, 1998;
Gabri love et al., 2001; Glaspy et al., 1997). NCCN (2007) guide-
lines also recommended that prophylactic rHuEPO be admin-
istered in asymptomatic patients with known risk factors (e.g.,
history of blood transfusions) or in any symptomatic patients(e.g., fatigue). Administration of epoetin alfa early in cancer
therapies with known myelosuppressive risk may prevent ad-
verse effects on clinica l outcomes, but continued research is
needed to identify the role of prophylactic use of erythropoietin
therapy across different tumor types and treatment modalities
(Earles, 2004; Gi llespie, 2003; Mercadante et al., 2000).
Darbepoetin alfa: A novel erythropoiesis-st imulating
agent for CRA is darbepoetin alfa (Aranesp, Amgen Inc.). Dar-
bepoetin alfa has a mechanism of action similar to rHuEPO, but
it is biochemically distinct with a half-life two to three times
longer than that of rHuEPO, as demonstrated in patients with
chronic renal failure (Gillespie, 2003; Vanrenterghem, Barany,
& Mann, 1999). The agent has demonstrated equivalent efficacy
in maintaining hemoglobin levels when administered as a single
weekly injection instead of the two to three weekly injections
required for rHuEPO (Macdougall, 2000). Darbepoetin alfa
given every two weeks also has been shown to be as effective
as weekly dosing of the drug (Vanrenterghem et al.).
The FDA approved darbepoetin alfa in 2002 for chemother-
apy-induced anemia in patients with nonmyeloid malignancies
(Gillespie, 2003). Current NCCN (2007) recommendations
include initiating therapy at 2.25 mcg/kg every week or a fixed
dose of 500 mcg every three weeks. Alternative fixed dosing of
100 mcg every week, 200 mcg every two weeks, or 300 mcg
every three weeks are noted as well with suggested titrations
for poor response (Amgen Inc., 2006a; NCCN).
The dose of 200 mcg every two weeks has been compared
to epoetin alfa 40,000 units every week. At those doses, darbe-
poetin alfa and epoetin al fa appeared to have similar effective-
ness in terms of hematopoietic response and decrease the need
for blood transfusions (Herrington et al., 2005). Less frequent
dosing of darbepoetin al fa has cost-effective and quality-of-life
advantages. Administration every three to four weeks reduces
drug costs as well as the nursing time needed to prepare, admin-
ister, and monitor the medication’s effects. The long half-life of
darbepoetin alfa may al low the medication to be synchronized
with chemotherapy cycles, reduce patient office visits, enhance
patient compliance (Demetri, 2001; Earles, 2004; Gillespie,
2003), and decrease patient and caregiver burden (Koopman &
Iakiri, 2005; Longfield, Gebhart, & Hayward, 2005).
Risks Associated With Erythropoiesis-Stimulating Therapies
The companies producing erythropoietin (Ortho BiotechProducts, LP, and Amgen Inc.) and darbepoetin alfa (Amgen
Inc.) released revised prescribing information in December
2005 based on the FDA (2005) MedWatch Safety Program.
Two recommendations directly a ffect nursing assessment and
monitoring of patient response to erythropoiesis-stimulating
therapies.
First, the revised package inserts recommended dosing
interruption and/or modification based on hemoglobin levels
for patients receiving growth factor support related to cancer
chemotherapy. Hemoglobin levels should not exceed 12 g/dl
for either therapy. The recommendations resulted from investi-
gational studies conducted outside of the United States, where
patients with cancer were treated to high hemoglobin targetlevels, beyond the correction of anemia. The studies permit-
ted or required dosing with either erythropoiesis-stimulating
therapy to achieve hemoglobin levels more than 12 g/dl. An
increased frequency of adverse patient outcomes, including in-
creased mortality and thrombotic vascular events, was reported
in the studies (Amgen Inc., 2006b; Ortho Biotech Products, LP,
2006).
Second, the FDA warned that, although rare, the presence of
neutralizing antibodies to erythropoietin have caused serious
adverse reactions, including pure red cell aplasia and severe ane-
mia compounded by other cytopenias (Amgen Inc., 2005). Pa-
tients with chronic renal fai lure are most susceptible to the reac-
tions; however, oncology nurses must be aware of the risks and
monitor for signs and symptoms indicative of increasing anemia
(e.g., increasing fatigue, pallor). Because of the rapid prolifera-
tion of stem cells with the therapies, oncology nurses should be
aware of other possible adverse reactions. Both medications are
contraindicated in patients with uncontrolled hypertension or
any patient with a known hypersensitivity to substances in the
product (e.g., mammalian cell-derived products, human albu-
min) (Buchsel et al., 2002; Gillespie, 2003). Finally, additional
adverse reactions seen in patients treated with darbepoetin alfa
have included pulmonary embolism, deep vein thrombosis, and
edema (Amgen Inc., 2006a; Gillespie, 2003).
Iron supplementation: Iron supplementation may be
required in combination with erythropoiesis-stimulating thera-
pies to treat anemia effectively (NCCN, 2007), and supplemen-
tation also may reduce the total amount of rHuEPO needed to
correct hemoglobin levels. The transport of iron is necessary for
the process of erythropoiesis. Inadequate use and transport of
iron, termed functional iron deficiency, are the most common
causes of an inadequate response to rHuEPO among patients
with chronic renal fai lure (Feelders et al., 1998; Gil lespie,
2002), and functional iron deficiency also may be an important
factor in chronic anemia in cancer. NCCN, the American Society
of Clinical Oncology, and the American Society of Hematology
guidelines advised that iron studies be carried out periodically
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for all patients receiving erythropoietic therapy (Rizzo et al.,
2002), and Medicare guidelines require that all patients re-
ceiving chemotherapy have iron studies carried out prior to
treatment initiation (Gaits, Shaftic, & Terlizzi, 2005; Miskin &
Hoechner, 2005). Iron supplementation may be given orally
or via IV, although significant gastrointestinal discomfort and
potential noncompliance can result from oral administration
(Glaspy & Cavill, 1999). IV iron supplementation, however, can
be inconvenient and costly and is associated with significant ad- verse events such as anaphylaxis. Standardization of laboratory
monitoring and documentation of iron and folate supplementa-
tion, as well as patient outcomes, continue to be challenges in
clinical settings (Gaits et al.).
Patient EducationEducating patients with CRA complements adjuvant therapy
and is a necessary component of a comprehensive protocol. Edu-
cation will promote patient compliance, give patients a sense of
control, and improve treatment outcomes. Prior to the initiation
of cancer treatment, patients should be instructed about pos-
sible side effects, including anemia and its related symptoms,especially fatigue. Providing patients with the appropriate
knowledge to understand diagnosis and treatment enables them
to become active partners in the plan of care and equips them
to recognize any physical or lifestyle changes over time and
notify the healthcare team for immediate intervention. Fatigue
is the cardinal symptom of anemia (Gillespie, 2002), and oncol-
ogy nurses play a pivotal role in educating patients about self-
care skills to minimize the negative effects of fatigue on daily
activities and quality of l ife (Mock, 2001; Ream & Richardson,
1999; Stovall & Young, 2006). Fatigue management includes
identifying personal limitations, conserving energy, planning
ahead for the efficient use of energy, alternating rest and activity
periods, keeping regular sleep schedules, and exercising safely
within capabilities (Portenoy & Itri, 1999). Education regarding
nutrition is important to combat fatigue and vitamin deficien-
cies. If iron supplementation is required, patients should be
advised regarding appropriate medication requirements (e.g.,
bowel regimen to prevent constipation). Integrating stress
management techniques and cognitive therapies can minimize
the impact of symptoms related to fatigue (Portenoy & Itri).
Personal treatment diaries can provide subjective assessments
on activity levels and actual nutrition and hydration intake, in
addition to giving patients a sense of control and the means to
identify changes over time.
ConclusionOncology nurses play a central role in risk assessment, symp-
tom evaluation, evidence-based interventions, and determina-
tion of treatment options for their patients with CRA, making
a significant contribution to improving patients’ quality of life
and positively influencing clinical outcomes. Anemia tradition-
ally has been a symptom that rarely was assessed carefully,
perceived as producing little or no change in cancer outcomes
(Gillespie, 2003). With the advent of erythropoiesis-stimulat-
ing therapies and the recognition of the debilitating impact
of fatigue, the symptom clusters caused by CRA can no longer
be ignored. Implementation of standards of care, essential
laboratory studies, necessary iron and folate supplementation,
pertinent documentation, and clinical monitoring of patient
status have been widely inconsistent (Berger, 2005). Oncology
nurses are in a key position to rectify clinical discrepancies
and contribute to the research that is needed to determine the
most effective interventions for patients (Berger). The impact
of erythropoietic therapy on treatment response and survival
outcomes and the role of prophylactic treatment with theseagents still must be determined. Clinical management of anemia
requires a comprehensive and holistic approach (Loney & Cher-
necky, 2000) across all patient care settings—goals inherent in
the role of oncology nurses.
Author Contact: Beth Hurter, RN, MSN, CNP, OCN®, can be reached at
ehurter@uic.edu, with copy to editor at CJONEditor@ons.org.
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