ons carelatedanemia cjon article

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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http://slidepdf.com/reader/full/ons-carelatedanemia-cjon-article 2/11350 June 2007 • Volume 11, Number 3 • Clinical Journal of Oncology Nursing

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



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.



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



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



& 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.



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



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



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 adverse 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

[email protected], with copy to editor at [email protected].

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