Cancer-And Chemotherapy - Induced Anemia: Clinical Practice Guidelines in Oncology

628
NCCN Richard S. Stein, MD; Gordana Vlahovic, MD; and

Alva B. Weir III, MD
Cancer- and
Chemotherapy- Overview
Anemia is prevalent in 30% to 90% of patients with
Induced Anemia cancer.1 Anemia can be corrected through treating
the underlying cause or providing supportive care
Clinical Practice Guidelines in Oncology through either transfusion with packed red blood
cells (PRBC) or administration of erythropoiesis-
George M. Rodgers III, MD, PhD; Pamela Sue Becker, MD, PhD; stimulating agents (ESAs), with or without iron sup-
Morey Blinder, MD; David Cella, PhD;
plementation. Recent studies showing detrimental
Asher Chanan-Khan, MD; Charles Cleeland, PhD;
Peter F. Coccia, MD; Benjamin Djulbegovic, MD, PhD;
health effects of ESAs sparked a series of FDA label
Jeffrey A. Gilreath, PharmD; Eric H. Kraut, MD; revisions and a sea change in the perception of these
Ursula A. Matulonis, MD; Michael M. Millenson, MD; once commonly used agents. In light of this, these
Denise Reinke, MS, NP; Joseph Rosenthal, MD; guidelines underwent substantial revisions. The pur-
Rowena N. Schwartz, PharmD; Gerald Soff, MD;
pose of these guidelines is 2-fold: 1) to operational-
Abstract Please Note

Anemia is prevalent in 30% to 90% of patients with can- The NCCN Clinical Practice Guidelines in Oncology
cer. Anemia can be corrected through either treating the
(NCCN Guidelines®) are a statement of consensus of the
underlying cause or providing supportive care through
authors regarding their views of currently accepted ap-
transfusion with packed red blood cells or administration
of erythropoiesis-stimulating agents (ESAs), with or without
proaches to treatment. Any clinician seeking to apply or
iron supplementation. Recent studies showing detrimental consult the NCCN Guidelines® is expected to use indepen-
health effects of ESAs sparked a series of FDA label revisions dent medical judgment in the context of individual clinical
and a sea change in the perception of these once com- circumstances to determine any patient’s care or treatment.
monly used agents. In light of this, the NCCN Clinical Practice The National Comprehensive Cancer Network® (NCCN®)
Guidelines in Oncology (NCCN Guidelines) for Cancer- and makes no representation or warranties of any kind regarding
Chemotherapy-Induced Anemia underwent substantial their content, use, or application and disclaims any respon-
revisions this year. The purpose of these NCCN Guidelines is sibility for their applications or use in any way.
twofold: 1) to operationalize the evaluation and treatment of © National Comprehensive Cancer Network, Inc.
anemia in adult cancer patients, with an emphasis on those
2012, All rights reserved. The NCCN Guidelines and the
who are receiving concomitant chemotherapy, and 2) to en-
illustrations herein may not be reproduced in any form
able patients and clinicians to individualize anemia treatment
options based on patient condition. (JNCCN 2012;10:628–653)
without the express written permission of NCCN.
NCCN Categories of Evidence and Consensus Disclosures for the NCCN Cancer- and
Chemotherapy-Induced Anemia Panel
Category 1: Based upon high-level evidence, there is uniform
NCCN consensus that the intervention is appropriate. At the beginning of each NCCN Guidelines panel meeting, panel
Category 2A: Based upon lower-level evidence, there members review all potential conflicts of interest. NCCN, in keep-
ing with its commitment to public transparency, publishes these
is uniform NCCN consensus that the intervention is
disclosures for panel members, staff, and NCCN itself.
appropriate.
Category 2B: Based upon lower-level evidence, there is Individual disclosures for the NCCN Cancer- and Chemo-
NCCN consensus that the intervention is appropriate. therapy-Induced Anemia Panel members can be found on
Category 3: Based upon any level of evidence, there page 653. (The most recent version of these guidelines and
is major NCCN disagreement that the intervention is accompanying disclosures are available on the NCCN Web site
at NCCN.org.)
appropriate.
All recommendations are category 2A unless otherwise These guidelines are also available on the Internet. For the
noted. latest update, visit NCCN.org.
Clinical trials: NCCN believes that the best management for

any cancer patient is in a clinical trial. Participation in clinical
trials is especially encouraged.
© JNCCN–Journal of the National Comprehensive Cancer Network | Volume 10 Number 5 | May 2012
629
NCCN
Guidelines®
Journal of the National Comprehensive Cancer Network Cancer- and Chemotherapy-

Induced Anemia
ize the evaluation and treatment of anemia in adult Etiology

patients with cancer, with an emphasis on those with Causes of anemia in patients with cancer are often
anemia who are receiving concomitant chemother- multifactorial, adding to the complexity of the prob-
apy, and 2) to enable the patient and clinician to lem in evaluation. Anemia may be attributed to un-
assess anemia treatment options based on individual derlying comorbidities, such as bleeding, hemolysis,
patient conditions. hereditary disease, renal insufficiency, nutritional
The pathophysiologic origins of anemia can be deficiencies, anemia of chronic disease, or a combi-
grouped into 3 categories: 1) decreased production of nation.2,3 The malignancy itself can lead to or ex-
acerbate anemia in several ways.4 Cancer cells may
functional red blood cells (RBCs), 2) increased de-
directly suppress hematopoiesis through bone mar-
struction of RBCs, and 3) blood loss. Hence, anemia
row infiltration. They may produce cytokines that
is characterized by a decrease in hemoglobin (Hb) lead to iron sequestration, which decreases RBC
concentration, RBC count, or packed cell volume production and may even shorten survival. Chron-
to subnormal levels. An anemia scale by grade is ic blood loss at tumor sites and organ damage can
provided by the NCI (Table 1); available online, in further exacerbate anemia from cancer. Additional
these guidelines, at NCCN.org [MS-13]). indirect effects may include nutritional deficiencies
Text continues on p. 642
NCCN Cancer- and Chemotherapy-Induced

Anemia Panel Members
*George M. Rodgers III, MD, PhD/Chair‡ Michael M. Millenson, MD‡Þ
Huntsman Cancer Institute at the University of Utah Fox Chase Cancer Center
*Pamela Sue Becker, MD, PhD‡Þ Denise Reinke, MS, NP#
University of Washington/Seattle Cancer Care Alliance University of Michigan Comprehensive Cancer Center
Morey Blinder, MD‡ Joseph Rosenthal, MD‡€
Siteman Cancer Center at Barnes-Jewish Hospital and City of Hope Comprehensive Cancer Center
Washington University School of Medicine Rowena N. Schwartz, PharmD∑
David Cella, PhDθ The Sidney Kimmel Comprehensive Cancer Center at
Robert H. Lurie Comprehensive Cancer Center of Johns Hopkins
Northwestern University Gerald Soff, MD‡
Memorial Sloan-Kettering Cancer Center
Asher Chanan-Khan, MD†
Richard S. Stein, MD‡ξ
Roswell Park Cancer Institute
Vanderbilt-Ingram Cancer Center
Charles Cleeland, PhDθ
Gordana Vlahovic, MD†
The University of Texas MD Anderson Cancer Center
Duke Cancer Institute
Peter F. Coccia, MD‡€
Alva B. Weir III, MD‡
UNMC Eppley Cancer Center at
St. Jude Children’s Research Hospital/
The Nebraska Medical Center
University of Tennessee Cancer Institute
Benjamin Djulbegovic, MD, PhD†‡ξ
H. Lee Moffitt Cancer Center & Research Institute NCCN Staff: Mary Dwyer, MS, and Maria Ho, PhD
*Jeffrey A. Gilreath, PharmD∑ KEY:
Huntsman Cancer Institute at the University of Utah
Eric H. Kraut, MD‡ *Writing Committee Member
The Ohio State University Comprehensive Cancer Center – Specialties: ‡Hematology/Hematology Oncology; ÞInternal
James Cancer Hospital and Solove Research Institute Medicine; θPsychiatry/Psychology; †Medical Oncology;
Ursula A. Matulonis, MD† €Pediatric Oncology; ξBone Marrow Transplantation;
Dana-Farber/Brigham and Women’s Cancer Center ∑Pharmacotherapy; #Nursing
630
Cancer- and Chemotherapy-Induced Anemia Version 2:2012
HEMOGLOBIN EVALUATION OF ANEMIA a,b

CONCENTRATION
TO PROMPT AN
EVALUATION OF
ANEMIA Evaluate anemia for possible cause as
indicated (see Approaches to Evaluation
on page 643): Treat as indicated
First check
➤ Reticulocyte count and MCV
Then consider
Hemoglobin Hemorrhage (stool guaiac,
CBC with
(Hb) 11 g/dL endoscopy)
indices ➤ Hemolysis (Coombs test, DIC panel,
or 2 g/dL Blood smear
below haptoglobin)
morphology ➤ Nutritional (iron, total iron binding
baseline
capacity, ferritin, c B 12, folate)
➤ Inherited (prior history, family
Consider anemia
history)
of inflammation or See
➤ Renal (GFR < 60 mL/min/1.73 m 2, No cause
anemia due to facing
low erythropoietin) identified
➤ Radiation-induced
myelosuppressive page
myelosuppression chemotherapy
See NCCN Clinical Practice Guidelines in Oncology

Myelodysplastic syndromes (NCCN Guidelines) for Myelodysplastic Syndromes
(to view the most recent version of these guidelines,
visit the NCCN Web site at NCCN.org)
Treat underlying disease per NCCN Guideline

(See NCCN GuidelinesTable of Contents at NCCN.org)
Myeloid malignancies or ALL
or
Appropriate therapy for acute lymphoblastic leukemia (ALL)
a These guidelines were formulated in reference to adult patients.

b This is a basic evaluation for possible causes of anemia.
c If absolute iron deficiency is present (ferritin < 30 ng/mL and transferrin saturation < 15%), consider IV or oral iron supplementation. Note, the ferritin value
indicating iron deficiency is laboratory-specific. In general, the lower the level of ferritin, the higher the probability that the patient has true iron deficiency
anemia. However, in the cancer setting, be aware of a chronic inflammatory state, which may falsely elevate the serum ferritin. If hemoglobin increases
after 4 wk, then observe with periodic reevaluation for symptoms and risk factors; if hemoglobin does not increase after 4 wk, see functional iron deficiency
pathway (see page 634).
Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All
recommendations are category 2A unless otherwise indicated.
631
NCCN Clinical Practice Guidelines in Oncology
RISK ASSESSMENT AND INDICATIONS FOR INITIAL TRANSFUSION IN ACUTE SETTING
Asymptomatic without significant comorbidities d Observe Periodic reevaluation
Asymptomatic with comorbidities d or high risk

Comorbidities:
➤ Cardiac including congestive heart failure
Anemia of inflammation and coronary heart disease
or anemia due to ➤ Chronic pulmonary disease
Consider red blood cell transfusion per
myelosuppressive ➤ Cerebral vascular disease
guidelines (See Indications for Red Blood Cell
chemotherapy for
Transfusion in Cancer Patients, page 635)
lymphoid malignancies
and solid tumors High risk:
➤ Progressive decline in hemoglobin with
recent intensive chemotherapy or
radiation
Symptomatic
Physiological:
Red blood cell transfusion per guidelines
➤ Sustained tachycardia, tachypnea, chest
(See Indications for Red Blood Cell
pain, dyspnea on exertion,
Transfusion in Cancer Patients, page 635)
lightheadedness, syncope, severe fatigue e
preventing work and usual activity
See Comparison of Risks and Benefits of ESA Use

Versus Red Blood Cell Transfusion (page 632)
See Special Categories in Considering ESA Use (page 633)
d Degree of severity of comorbidities in combination with the degree of severity of anemia should be taken into consideration when initiating red blood cell
transfusion.
e Fatigue (FACT-F) and Anemia (FACT-An) subscales of the Functional Assessment of Cancer Therapy (FACT) and Brief Fatigue Inventory (BFI) are
examples of standardized measures for assessing patient-reported fatigue.
Version 2.2012, 08-03-11 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be
reproduced in any form without the express written permission of NCCN®.
632
COMPARISON OF RISKS AND BENEFITS OF ESA USE VERSUS RED BLOOD CELL TRANSFUSION f
If anemia is not due to absolute or functional iron deficiency, there are currently only two methods of improving hemoglobin:
ESAs and red blood cell transfusion. Listed below are risks and benefits of each method.
ESA in the Cancer Setting Red Blood Cell Transfusion
Risks • Increased thrombotic events • Transfusion reactions (e.g., hemolytic,

• Decreased survival febrile, nonhemolytic, lung injury)
• Time to tumor progression shortened • Congestive heart failure
• Virus transmission (e.g., hepatitis, HIV)
• Bacterial contamination
• Iron overload
• Increased thrombotic events
Benefits • Transfusion avoidance • Rapid increase of hemoglobin and

• Gradual improvement in fatigue hematocrit levels
• Rapid improvement in fatigue
See REMS: Risk Evaluation and Mitigation Strategy for Erythropoiesis-Stimulating Agents (ESAs) (page 639)
f See the manuscript for detailed information regarding the risks and benefits of ESA use and red blood cell transfusion.
633
SPECIAL CATEGORIES IN CONSIDERING ESA USE
See Management
Consider treatment with ESAs by FDA
of Functional Iron
• Cancer and chronic kidney disease indications/dosing/dosing adjustments for chronic
Deficiency in
(moderate to severe) kidney disease, under REMS guidelines, with
Patients Receiving
informed consent of patient i,j,k,l
ESAs (page 634)
• Myelosuppressive chemotherapy
g
with curative intent
➤ Examples of cancers for which there is
therapy with curative intent include
ESAs not recommended
early-stage breast cancer, Hodgkin
lymphoma, non-Hodgkin’s lymphoma,
testicular cancer, and early-stage non-
small cell lung cancer
See Management
Consider treatment with ESAs by FDA of Functional Iron
indications/dosing/dosing adjustments, under REMS Deficiency in
guidelines, with informed consent of patient i,j,k Patients
• Patient undergoing palliative treatment h or Receiving ESAs
Consider red blood cell transfusion per guidelines (page 634)
(See page 635)
Consider red blood cell transfusion per guidelines

(See page 635)
• Remainder of patients with or
anemia on myelosuppressive Clinical trial See Management
chemotherapy without other or of Functional Iron
identifiable cause of anemia h Consider treatment with ESAs by FDA Deficiency in
indications/dosing/dosing adjustments, under REMS Patients
guidelines, with informed consent of patient i,j,k Receiving ESAs
(page 634)
g A few studies suggest patients with small cell lung cancer on j Health care providers prescribing ESAs need to enroll in the ESA APPRISE
myelosuppressive chemotherapy may not have an increase in mortality program. See REMS: Risk Evaluation and Mitigation Strategy for
when receiving ESAs. Oncologic Drugs Advisory Committee, March Erythropoiesis-Stimulating Agents (ESAs) (page 639).
2008; Pirker R, Ramlau RA, Schuette W, et al. Safety and efficacy of k Patients with previous risk factors for thrombosis may be at higher risk for
darpepoetin alpha in previously untreated extensive-stage small-cell lung thrombosis with the use of ESAs. If considering use of ESAs, evaluate the
cancer treated with platinum plus etoposide. J Clin Oncol 2008;26:2342- risk factors for thrombosis, such as history of thromboembolism, heritable
3249; Grote T, Yeilding AL, Castillo R, et al. Efficacy and safety analysis mutation, hypercoagulability, elevated prechemotherapy platelet counts,
of epoetin alpha in patients with small-cell lung cancer: a randomized, hypertension, steroids, prolonged immobilization, recent surgery, certain
double-blind, placebo-controlled trial. J Clin Oncol 2005;23:9377-9386. therapies for multiple myeloma, and hormonal agents. (See NCCN
h See Comparison of Risks and Benefits of ESA Use Versus Red Blood Guidelines for Venous Thromboembolic Disease; to view the most recent
Cell Transfusion (previous page). version of these guidelines, visit the NCCN Web site at NCCN.org).
i See Erythropoietic Therapy - Dosing, Titration, and Adverse Effects l The hemoglobin threshold for treatment and dosing with ESAs is different for
(pages 636-638). chemotherapy-induced anemia and chronic kidney disease.
634
MANAGEMENT OF FUNCTIONAL IRON DEFICIENCY IN PATIENTS RECEIVING ESAS
Functional iron deficiency

(ferritin 800 ng/mL and Consider IV iron supplementation m,n,o with erythropoietic therapy
transferrin saturation < 20%)
Iron studies:
Iron panel (serum iron,
total iron binding capacity,
serum ferritin)
No iron deficiency (ferritin

> 800 ng/mL or transferrin IV or oral iron supplementation is not needed
saturation 20%)
See Parenteral Iron Preparations (pages 640 and 641)
m IV iron has superior efficacy and should be considered for supplementation. Oral iron has been more commonly used but is less effective.
See Parenteral Iron Preparations (pages 640-641).
n Although all combinations of serum ferritin and TSAT could be found in at least 1 of 6 randomized controlled trials evaluating the use of IV iron with an
ESA, eligibility criteria testing for serum ferritin and TSAT generally ranged from > 10 to < 900 ng/mL, and > 15% to < 60%, respectively.
o Data are insufficient to consider IV iron as monotherapy for the treatment of functional iron-deficiency anemia.
635
INDICATIONS FOR RED BLOOD CELL TRANSFUSION IN CANCER PATIENTS
Goal: Prevent or treat deficit of oxygen-carrying capacity

Asymptomatic
Hemodynamically stable chronic anemia without acute coronary syndrome:
➤ Transfusion goal to maintain hemoglobin 7-9 g/dL
Symptomatic
Acute hemorrhage with evidence of hemodynamic instability or inadequate oxygen delivery:
➤ Transfuse to correct hemodynamic instability and maintain adequate oxygen delivery
Symptomatic (including tachycardia, tachypnea, postural hypotension) anemia (hemoglobin < 10 g/dL):
➤ Transfusion goal to maintain hemoglobin 8-10 g/dL as needed for prevention of symptoms
Anemia in setting of acute coronary syndromes or acute myocardial infarction:

➤ Transfusion goal to maintain hemoglobin 10 g/dL
636
ERYTHROPOIETIC THERAPY - DOSING AND TITRATION 1-4
INITIAL DOSING TITRATION FOR NO RESPONSE TITRATION FOR RESPONSE
PACKAGE INSERT DOSING SCHEDULE • The dose should be adjusted for

each patient to maintain the
Epoetin alfa, 150 units/kg 3 times Increase dose of epoetin alfa to 300 units/kg lowest hemoglobin level sufficient
wk by subcutaneous injection 3 times wk by subcutaneous injection to avoid RBC transfusion.
or
• If Hb reaches a level needed to
avoid transfusion or increases
Epoetin alfa, 40,000 units every Increase dose of epoetin alfa to 60,000 units > 1 g/dL in any 2-wk period,
wk by subcutaneous injection every wk by subcutaneous injection reduce dose by 25% for epoetin
or alfa and by 40% for darbepoetin
alfa.
Darbepoetin alfa, 2.25 mcg/kg every wk Increase darbepoetin alfa to up to 4.5 mcg/kg
by subcutaneous injection every wk by subcutaneous injection
or
Darbepoetin alfa, 500 mcg every 3 wk by subcutaneous injection
ALTERNATIVE REGIMENS
Darbepoetin alfa, 100 mcg fixed dose Increase darbepoetin alfa to up to 150-200 mcg
every wk by subcutaneous injection fixed dose every wk by subcutaneous injection 5
or
Darbepoetin alfa, 200 mcg fixed dose Increase darbepoetin alfa to up to 300 mcg fixed
every 2 wk by subcutaneous injection 7 dose every 2 wk by subcutaneous injectio n 6
or
Darbepoetin alfa, 300 mcg fixed dose Increase darbepoetin alfa to up to 500 mcg fixed See Erythropoietic Therapy-
every 3 wk by subcutaneous injection dose every 3 wk by subcutaneous injectio n 7 Adverse Effects
or (facing page)
Epoetin alfa, 80,000 units every 2 wk by subcutaneous injection 8

or
Epoetin alfa, 120,000 units every 3 wk by subcutaneous injection 9
1 The head to head comparisons of regimens are inconclusive with 5 Vansteenkiste J, Pirker R, Massuti B, et al. Double-blind, placebo-controlled
regard to superiority of one drug over another. Schwartzberg LS, Yee randomized phase III trial of darbepoetin alfa in lung cancer patients receiving
LK, Senecal, FM, et al. A randomized comparison of every-2 week chemotherapy. J Natl Cancer Inst 2002;94:1211-1220.
darbepoetin alfa and weekly epoetin alfa for the treatment of 6 Thames WA, Smith SL, Scheifele AC, et al. Evaluation of the US Oncology
chemotherapy-induced anemia in patients with breast, lung, or Network's recommended guidelines for therapeutic substitution with
gynecologic. Oncologist 2004;9:696-707; and Waltzman R, Croot C, darbepoetin alfa 200 microg every 2 weeks in both naïve patients and patients
Justice G, et al. Randomized comparison of epoetin alfa (40 000 U switched from epoetin alfa. Pharmacotherapy 2004;24:313-323.
weekly) and darbepoetin alfa (200 mcg every 2 weeks) in anemic 7 Canon JL, Vansteenkiste J, Bodoky G, et al. Randomized, double-blind, active-
patients with cancer receiving chemotherapy. Oncologist 2005;10:642- controlled trial of every 3-week darbepoetin alfa for the treatment of
650. chemotherapy-induced anemia. J Natl Cancer Inst 2006;98:273-284.
2 Less frequent dosing regimens could be considered as an alternative 8 Henry DH, Gordan LN, Charu V, et al. Randomized, open-label comparison of
to dose reduction. epoetin alfa extended dosing (80 000 U Q2W) vs weekly dosing (40 000 U
3 The dosages and regimens included in this table have been evaluated
QW) in patients with chemotherapy-induced anemia. Curr Med Res Opin
in patients with cancer receiving chemotherapy. 2006;22:1403-1413.
4 IV iron has superior efficacy and should be considered for 9 Steensma DP, Molina R, Sloan JA, et al. Phase III study of two different dosing
supplementation. Oral iron has been more commonly used but is less schedules of erythropoietin in anemic patients with cancer. J Clin Oncol
effective. (See manuscript for detailed discussion.) See Parenteral 2006;24:1079-1089.
Iron Preparations (pages 640-641).
637
ERYTHROPOIETIC THERAPY - ADVERSE EFFECTS

Cancer Patient Survival
• Studies have reported possible decreased survival in patients with cancer receiving erythropoietic drugs for correction of anemia.
Analyses of 8 studies in patients with cancer found decreased survival in those receiving erythropoietic drugs for correction of
anemia and target hemoglobin levels of > 12 g/dL. 1-8 One analysis in patients with cancer not receiving active therapy found
decreased survival in ESA-treated patients. 6 Please refer to the FDAWeb site for additional information:
http://www.fda.gov/cder/drug/infopage/RHE/default.htm. Unless new evidence shows a change in benefit:risk estimates, physicians
should be advised not to administer ESAs (darbepoetin alfa, epoetin alfa) to patients outside of the treatment period of cancer-
related chemotherapy. A treatment period is defined as anemia after initiation of therapy and continuing approximately 6 weeks after
the completion of treatment.
• Although 3 meta-analysis updates on survival have indicated an increased mortality risk with the use of ESAs, 9-12 2 meta-analyses
have indicated that ESA use did not significantly affect mortality or disease progression. 13,14
• Recent pharmacovigilance trials have reported no adverse effects on survival in cancer patients with chemotherapy-induced anemia
receiving ESAs. 15-17
• The risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to a target hemoglobin of
< 12 g/dL.
• Additional prospective clinical trials designed and powered to measure cancer patient survival are ongoing to provide clinicians with
data to guide optimal use of erythropoietic agents.
• Because of the above issues, providers should inform patients of risks and benefits of ESA therapy versus red blood cell transfusion.
(See Comparison of Risks and Benefits of ESA Use Versus Red Blood Cell Transfusion, page 632)
Thrombosis
• Early trials of recombinant human erythropoietin reported that a high target hematocrit (42 ± 3%) was found to have an increased
number of vascular events (arterial and venous).
• Erythropoietin has a thrombogenic potential independent of hemoglobin levels. 18 Patients with previous risk factors for thrombosis
may be at higher risk for thrombosis with the use of ESAs. If considering use of ESAs, evaluate the risk factors for thrombosis, such
as history of thromboembolism, heritable mutation, hypercoagulability, elevated prechemotherapy platelet counts, hypertension,
steroids, prolonged immobilization, recent surgery, certain therapies for multiple myeloma, and hormonal agents. (See NCCN Guidelines
for Venous Thromboembolic Disease; to view the most recent version of these guidelines, visit the NCCN Web site at NCCN.org)
• Four meta-analyses reported an increase in relative risk of thrombotic events ranging from 48% to 69% with ESA use. 9,12-14
The absolute risk of venous thromboembolism was 7.5% in patients treated with ESAs compared with 4.9% in control patients. 9
• A clinical trial in chronic kidney disease showed a 92% increase in the relative risk of stroke (absolute risk, 5.0% vs. 2.6%) with
darbepoetin alfa. 19
Hypertension/Seizures
• Blood pressure should be controlled in all patients before initiating therapy with erythropoietic drugs and must be monitored regularly
in treated patients.
• Seizures have been reported in chronic renal failure patients receiving erythropoietic drugs.
• Hemoglobin level should be monitored to decrease the risk of hypertension and seizures. (See Titration for Response, previous page.)
ESA Neutralizing Antibodies (Pure Red Cell Aplasia [PRCA])
• Between 1998 and 2004, 197 cases of PRCA were reported in patients treated with erythropoietin. 20 More than 90% of these cases
occurred with Eprex, an epoetin alfa product used outside of the United States. Patients who develop a loss of response to
erythropoietic drugs should be evaluated for possible PRCA, and if present, all erythropoietic drugs should be discontinued. 21
• In 2005, the FDA's interpretation of anemia associated with neutralizing antibodies evolved to include both PRCA and severe
anemia.22 Since 2005, FDA safety databases have included information on 30 new cases of antibody-associated PRCA, primarily
associated with subcutaneous administration of epoetin alfa and darbepoetin alfa. 23 This interpretation resulted in a class label
change for all ESAs. The toxicity has been reported predominantly in patients with chronic renal failure receiving ESAs through
subcutaneous administration. Any patient who develops a sudden loss of response to an ESA, accompanied by a severe anemia and
low reticulocyte count, should be evaluated for the etiology of loss of effect, including the presence of neutralizing antibodies to
erythropoietin. If antierythropoietin antibody-associated anemia is suspected, ESAs should be withheld and plasma should be sent for
evaluation of assays for binding and neutralizing antibodies. ESAs should be permanently discontinued in patients with antibody-
mediated anemia. Patients should not be switched to other ESA products, because antibodies may cross-react.
See References
(page 638)
638
ERYTHROPOIETIC THERAPY - ADVERSE EFFECTS
ADVERSE EFFECTS REFERENCES
1 Leyland-Jones B, BEST Investigators and Study Group. Breast cancer trial 12 Tonelli M, Hemmelgarn B, Reiman T, et al. Benefits and harms of
with erythropoietin terminated unexpectedly. Lancet Oncol 2003;4:459-460. erythropoiesis-stimulating agents for anemia related to cancer: a meta-
2 Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck analysis. CMAJ 2009;180:E62-71.
cancer patients with anaemia undergoing radiotherapy: randomised, 13 Glaspy J, Crawford J, Vansteenkiste J, et al. Erythropoiesis-stimulating
double-blind, placebo-controlled trial. Lancet 2003;362:1255-1260. agents in oncology: a study-level meta-analysis of survival and other
3 Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo- safety outcomes. Br J Cancer 2010;102:301-315.
controlled trial of erythropoietin in non-small-cell lung cancer with disease- 14 Ludwig H, Crawford J, Osterborg A, et al. Pooled analysis of individual
related anemia. J Clin Oncol 2007;25:1027-1032. patient-level data from all randomized, double-blind, placebo-controlled
4 Hedenus M, Adriansson M, San Miguel J, et al. Efficacy and safety of trials of darbepoetin alfa in the treatment of patients with chemotherapy-
darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: induced anemia. J Clin Oncol 2009;27:2838-2847.
a randomized, double-blind, placebo-controlled study. Br J Haematol 15 Engert A, Josting A, Haverkamp H, et al. Epoetin alfa in patients with
2003;122:394-403. advanced-stage Hodgkin’s lymphoma: results of the randomized placebo-
5 Overgaard J, Hoff C, Sand Hansen H, et al. Randomized study of the controlled GHSG HD15EPO trial. J Clin Oncol 2010;28:2239-2245.
importance of novel erythropoiesis stimulating protein (Aranesp) for the 16 Moebus V, Jackisch C, Lueck H, et al. Intense dose-dense sequential
effect of radiotherapy in patients with primary squamous cell carcinoma of chemotherapy with epirubicin, paclitaxel, and cyclophosphamide
head and neck (HNCSS): the Danish Head and Neck Cancer Group compared with conventionally scheduled chemotherapy in high-risk
DAHANCA 10 randomized trial [abstract]. Eur J Cancer Suppl 2007;5: primary breast cancer: mature results of an AGO phase III study. J Clin
Abstract 7. Oncol 2010;28:2874-2880.
6 Smith R, Aapro MS, Ludwig H, et al. Darbepoetin alpha for the treatment of 17 Untch M, Fasching PA, Konecny GE, et al. PREPARE trial: a randomized
anemia in patients with active cancer not receiving chemotherapy or phase III trial comparing preoperative, dose-dense, dose-intensified
radiotherapy: results of a phase III, multicenter, randomized, double-blind, chemotherapy with epirubicin, paclitaxel and CMF versus a standard-
placebo-controlled study. J Clin Oncol 2008;26:1040-1050. dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin
7 Thomas G, Ali S, Hoebers FJ, et al. Phase III trial to evaluate the efficacy of
alfa in primary breast cancer—results at the time of surgery. Ann Oncol
maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 2011;22:1988-1998.
10.0 g/dL without erythropoietin in anemic patients receiving concurrent 18 Singh A, Szczech L, Tang K, et al. Correction of anemia with epoetin alfa
radiation and cisplatin for cervical cancer. Gynecol Oncol 2008;108:317- in chronic kidney disease. N Engl J Med 2006;355:2085-2098.
325. 19 Pfeffer MA, Burdmann EA, Chen C, et al. Trial of darbepoetin alfa in type
8 Untch M, Fasching PA, Bauerfeind I, et al. PREPARE trial. A randomized
2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019-
phase III trial comparing preoperative, dose-dense, dose-intensified 2032.
chemotherapy with epirubicin, paclitaxel and CMF with a standard dosed 20 Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and
epirubicin/ cyclophosphamide followed by paclitaxel ± darbepoetin alfa in epoetin therapy. N Eng J Med 2004;351:1403-1408.
primary breast cancer: a preplanned interim analysis of efficacy at surgery 21 Bennett CL, Cournoyer D, Carson KR, et al. Long-term outcome of
[abstract]. J Clin Oncol 2008;26(Suppl):Abstract 517. individuals with pure red cell aplasia and aniterythropoietin antibodies in
9 Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and
patients treated with recombinant epoetin: a follow-up report from the
mortality associated with recombinant erythropoietin and darbepoetin Research on Adverse Drug Events and Reports (RADAR) project. Blood
administration for the treatment of cancer-associated anemia. JAMA 2005;106:3343-3347.
2008;299:914-924. 22 FDA Patient Safety News.
10 Bennett CL, Henke M, Lai SY. Erythropoiesis-stimulating agents in the
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/printer.cfm?id=430
treatment of cancer-associated anemia reply. JAMA 2008;300:2855-2857. 23 McKoy J, Stonecash R, Cournoyer D, et al. Epoetin-associated pure red
11 Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human erythropoiesis-
cell aplasia: past, present, and future considerations. Transfusion
stimulating agents and mortality in patients with cancer: a meta-analysis of 2008;48:1754-1762.
randomised trials. Lancet 2009;373:1532-1542.
639
REMS: RISK EVALUATION AND MITIGATION STRATEGY FOR ERYTHROPOIESIS-STIMULATING AGENTS (ESAs) 1
• The FDA requires that ESAs be prescribed and used under a risk management program, known as a risk evaluation and mitigation strategy
(REMS), to ensure the safe use of these drugs.
• As part of REMS for ESAs:
A Medication Guide explaining the risks and benefits of ESAs must be provided to all patients receiving ESAs.
See Epoetin Alfa Medication Guide and See Darbepoetin Alfa Medication Guide (available at www.fda.gov.).
Health care providers who prescribe ESAs to patients with cancer are required to enroll in the ESA APPRISE (Assisting Providers and
Cancer Patients with Risk Information for the Safe use of ESAs) Oncology Program
.
• Patients with cancer using ESAs should:
Understand the risks associated with use of ESAs:
ESAs may cause tumors to grow faster
ESAs may cause some patients to die sooner
ESAs may cause some patients to develop blood clots and serious heart problems, such as a heart attack, heart failure, or stroke
Be aware that their health care professional has received special training about the use of ESAs in patients with cancer.
Read the Medication Guide to understand the benefits and risks of using an ESA.
Talk with their health care professional about any questions they may have about using ESAs.
Be aware that they will be asked to sign an acknowledgment form that says they have talked with their health care professional about
the risks of ESAs. This form must be signed before patients begin a course of treatment with an ESA.
Selected safety information for health care providers: 2
•ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast,
non-small cell lung, head and neck, lymphoid, and cervical cancers.
•To decrease these risks, and the risk of serious cardiovascular and thrombovascular events, use the lowest dose needed to avoid red
blood cell transfusion.
•Use ESAs only for treatment of anemia due to concomitant myelosuppressive chemotherapy.
•ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure.
•Discontinue ESA therapy after the completion of a chemotherapy course when anemia resolves (usually 6-8 weeks after the last cycle).
•ESAs are not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy, unless receiving
concomitant myelosuppressive chemotherapy
.
1 Adapted from: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200297.htm

2 Selected safety information adapted from: https://www.esa-apprise.com/ESAAppriseUI/ESAAppriseUI/default.jsp#isi
640
PARENTERAL IRON PREPARATIONS 1-6
• Parenteral iron preparations studied in cancer patients:

➤ Iron dextran
➤ Ferric gluconate
➤ Iron sucrose
• Five 2-6 of six 7 studies have shown parenteral iron products are helpful in treating functional iron deficiency in cancer patients who
are receiving ESAs.
• Test doses are required for iron dextran, but not for ferric gluconate or iron sucrose. Test doses are strongly recommended for ferric
gluconate and iron sucrose if patients have exhibited sensitivities to iron dextran or other IV iron preparations, or who have multiple
drug allergies.
• Most adverse events associated with iron dextran occur with high-molecular-weight iron dextran (Dexferrum).8
• If iron dextran preparation is used, low-molecular-weight iron dextran (INFed) is recommended.9
• Patients with active infection should not receive IV iron therapy.
RECOMMENDATIONS FOR ADMINISTERING PARENTERAL IRON PRODUCTS
Iron Dextran † Ferric Gluconate † Iron Sucrose †
Required MD discretion MD discretion
Test dose 25 mg slow IV push and 25 mg slow IV push or 25 mg slow IV push

wait 1 h before giving infusion
main dose
Dosage 10 100 mg IV over 5 min 125 mg IV over 60 min 200 mg IV over 60 min
• Repeated dosing once • Repeated dosing given • Repeated dosing given
weekly for 10 doses to once weekly for 8 doses every 2-3 wk
achieve total dose of 1 g
or or
• Total dose infusion • Individual doses above 125 mg 200 mg IV over 2-5 min
given over several are not recommended based on • Repeated dosing given
hours* published trial results 7 every 1-4 wk
• Maximum total dose
= 1000 mg • Individual doses above
300 mg are not
recommended 11
• Maximum total dose =
1000 mg
IV infusion
Routes
IV injection/infusion IV injection/infusion
IM (INFed) (not
recommended)
† Examples of adverse events associated with FDA-approved doses of parenteral iron preparations include hypotension,
hypertension, nausea, vomiting, diarrhea, pain, fever, dyspnea, pruritus, headaches, and dizziness.
*Dose = 0.0442 (desired Hgb - observed Hgb) x LBW + (0.26 x LBW ); LBW, lean body weight.
If dose exceeds 1000 mg, remaining dose may be given after 4 wk if inadequate hemoglobin response.
See References (facing page)
641
PARENTERAL IRON PREPARATIONS

REFERENCES
1 Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J Hematol 2004;76:74-78.
2 Henry DH. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients
with cancer receiving chemotherapy. Oncologist 2007;12:231-242.
3 Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer
patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J Clin Oncol 2004;22:1301-1307.
4 Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related
anemia without iron deficiency treated with darbepoetin alpha. J Clin Oncol 2008;26:1619-1625.
5 Hedenus M, Birgegård G, Näsman P, et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases
epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia
2007;21:627-632.
6 Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin
alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol
2008;26:1611-1618.
7 Steensma DP, Sloan JA, Dakhil SR, et al. Phase III, randomized study of the effects of parenteral iron, oral iron, or no iron
supplementation on the erythropoietic response to darbepoetin alfa for patients with chemotherapy-associated anemia. J Clin Oncol
2011;29:97-105.
8 Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on adverse drug events associated with parenteral iron. Nephrol Dial
Transplant 2006;21:378-382.
9 Auerbach M, Ballard H, Glaspy J. Clinical update: intravenous iron for anaemia. Lancet 2007;369:1502-1504.
10 Gilreath JA, Sageser DS, Jorgenson JA, Rodgers GM. Establishing an anemia clinic for optimal erythropoietic-stimulating agent use
in hematology-oncology patients. J Natl Compr Canc Netw 2008;6:577-584.
11Chandler G, Harchowal J, Macdougall IC. Intravenous iron sucrose: establishing a safe dose. Am J Kidney Dis 2001;38:988-991.
642 NCCN Clinical Practice Guidelines in Oncology
Cancer- and Chemotherapy-Induced Anemia

Text continued from p. 629
caused by loss of appetite in patients with cancer, he- the fraction of grades 2 and 3 anemia was also associ-
molysis by immune-mediated antibodies, or changes ated with a greater number of chemotherapy cycles.
in coagulation capability. For these myriad reasons, Other factors to consider when evaluating risk of
anemia is prevalent among patients with cancer at chemotherapy-induced anemia include the nadir Hb
initial presentation. For example, 32% of patients level, time to the nadir Hb level (roughly estimated
with non–Hodgkin’s lymphoma have anemia at di- at 2 weeks, but can vary), and whether an Hb mea-
agnosis,5 whereas 49% are anemic when diagnosed surement is considered to be pre- or post-nadir.4
with gynecologic cancer.6 In addition, the myelo-
suppressive effect of chemotherapy is a significant
contributing factor to anemia in patients undergo- Guideline Overview
ing cytotoxic treatment.7 Radiation therapy to the These revised NCCN Guidelines start with an
skeleton is also associated with hematologic toxicity. evaluation of anemia to delineate the origin, which
In a retrospective analysis, approximately one-third is followed by risk assessment to determine the ini-
of 210 patients undergoing radiotherapy to the cra- tial intervention plan. Special categories are out-
nium and/or spine for treatment of primary tumors of lined in considering the use of ESAs for long-term
the central nervous system developed grades 3 and 4 management. Additional guidelines are provided
hematologic side effects.8 on transfusion, erythropoietic therapy, and iron
Anemia Associated With Myelosuppressive supplementation.
Chemotherapy These NCCN Guidelines focus on patients
Chemotherapeutic agents induce anemia through with solid tumors and chronic lymphoid malignan-
directly impairing hematopoiesis, including synthe- cies. For anemia associated with myelodysplastic
sis of RBC precursors, in the bone marrow.4 In ad- syndromes (MDS), myeloid malignancies, and acute
dition, nephrotoxic effects of particular cytotoxic lymphoblastic leukemia, clinicians are referred to
agents (e.g., platinum-containing agents) can also relevant guidelines in the NCCN Guidelines Table
lead to anemia through decreased renal production of Contents (available at NCCN.org).
of erythropoietin.
Studies have identified patients with lung can-
cer and gynecologic malignancies as having a very Screening Evaluation
high incidence of chemotherapy-induced anemia.6,7 Given the wide variation in Hb level among healthy
Platinum-based regimens, commonly used in lung, subjects, a universal “normal” value remains elusive.
ovarian, and head and neck cancers, are well known For patients with cancer, the panel agrees that an Hb
to induce anemia caused by combined bone mar- level of 11 g/dL or below should prompt evaluation
row and kidney toxicity.7 Selected single agents and for anemia. For patients with a high baseline level, a
regimens frequently associated with anemia for dif- decrease of 2 g/dL or more is also cause for concern
ferent types of cancers are summarized in Table 2 and assessment. A patient with cancer may experi-
(available online, in these guidelines, at NCCN.org ence anemia as the result of a combination of causes,
[MS-13]). Importantly, the hematologic toxicities of some of which may not be directly related to cancer.
newer cytotoxic agents, regimens, and schedules are
The overall goals of evaluation are to characterize
not reflected in this list, and a greater risk for anemia
the anemia and identify any underlying comorbidity
may potentially be associated with some of the more
that can be potentially corrected.
intensive chemotherapy regimens.
The myelosuppressive effects of particular cyto- Initial Assessment
toxic agents are likely to accumulate over the course Initial broad characterization of anemia involves a CBC
of repeated cycles of therapy, resulting in a steady with indices that will show whether other cytopenias are
increase in the rate of anemia with additional che- present. A visual review of the peripheral blood smear is
motherapy cycles. For example, for patients in the critical to confirm the size, shape, and color of RBCs.
European Cancer Anemia Survey (ECAS),6 the rate A detailed history and physical examination must be
of anemia (Hb < 12 g/dL) was found to increase from performed. The history should include the duration
19.5% in cycle 1 to 46.7% by cycle 5. An increase in and time to onset of symptoms; comorbidities; family
NCCN Clinical Practice Guidelines in Oncology 643
history; and exposure to antineoplastic drugs and radia- degree of anemia (reticulocyte index [RI]), a measure-
tion. Common complaints are syncope, exercise dys- ment of the fraction of reticulocytes (immature RBCs)
pnea, headache, vertigo, chest pain, fatigue (disruptive that provides an indication of the RBC production
to work and daily activities), and abnormal menstrua- capacity by the bone marrow. A normal RI ranges be-
tion in female patients; pallor may be apparent. Cancer- tween 1.0 and 2.0.
related fatigue is defined in the NCCN Clinical Practice
• Low RI: indicates decreased RBC production,
Guidelines in Oncology (NCCN Guidelines) for Can-
suggesting iron deficiency, vitamin B12/folate
cer-Related Fatigue as “a distressing persistent subjective
deficiency, aplastic anemia, or bone marrow
sense of tiredness or exhaustion related to cancer or its
dysfunction caused by cancer or cancer-related
treatment that is not proportional to recent activity and
therapy (radiation or myelosuppressive chemo-
interferes with normal functioning” (to view the most
therapy)
recent version of these guidelines, visit the NCCN Web
• High RI: indicates normal or increased RBC
site at NCCN.org). A key characteristic that distin-
guishes fatigue related to cancer from fatigue in healthy production, suggesting blood loss or hemolysis in
individuals is that it is less likely to be ameliorated by patients with anemia
rest.9 The clinical manifestations mentioned are neither A comprehensive review of the follow-up and
sensitive nor specific to the type of anemia. Clinicians treatment of each subtype of anemia related to causes
should be aware of signs of underlying causes, such as independent of myelosuppressive cancer therapy is be-
jaundice, splenic enlargement, neurologic symptoms, yond the scope of these guidelines. Following is a sum-
blood in stool, petechiae, and heart murmur. mary of additional cues or tests for common underlying
Approaches to Evaluation ailments:
There are 2 common approaches to evaluating ane- • Absolute iron deficiency: iron and total iron
mia: morphologic and kinetic. A complete evalua- binding capacity (TIBC) resulting in transferrin
tion often uses both. The morphologic approach saturation less than 15% and ferritin less than
is a characterization of anemia based on the mean 30 ng/mL. The reference interval for serum fer-
corpuscular volume (MCV), or average RBC size, re- ritin depends on the specific laboratory. In gen-
ported in the initial CBC test: eral, the lower the level, the more probable that
• Microcytic (< 80 fL): most commonly caused true iron deficiency is present, although chronic
by iron deficiency; other causes include thalas- inflammation may elevate serum ferritin in pa-
semia, anemia of chronic disease, and sideroblas- tients with cancer. Functional iron deficiency is
tic anemia discussed within the context of ESA therapy in
• Normocytic (80–100 fL): may be caused by hem- a later section
orrhage, hemolysis, bone marrow failure, anemia • Vitamin B12/folate deficiency: low vitamin B12 or
of chronic inflammation, or renal insufficiency. folate levels
The key follow-up test is the reticulocyte count • Hemorrhage: stool guaiac positive, endoscopy
(see following discussion) findings
• Macrocytic (> 100 fL): most is megaloblas- • Hemolysis: Coombs test positive, disseminated
tic, indicating vitamin B12 or folate deficiency intravascular coagulation panel positive, low
caused by insufficient uptake or inadequate ab- haptoglobin levels, elevated indirect bilirubin
sorption through lack of intrinsic factor. Non- • Kidney disease: glomerular filtration rate less
megaloblastic anemia is less common and may than 60 mL/min/1.73 m2, low erythropoietin
be the result of alcoholism. MDS and certain level
drugs, such as hydroxyurea or diphenytoin, can • Inherited anemia: personal and family history
also cause macrocytosis • Sideroblastic anemia: sideroblasts present in
bone marrow biopsy
The kinetic approach focuses on the underlying
mechanism of anemia, distinguishing among the pro- Any cause of anemia that may be rectified
duction, destruction, and loss of RBCs. The main start- independent of cancer therapy should be treated
ing point is the reticulocyte count corrected against the as indicated. When no origin is identified in a
patient with cancer, the effects of cancer-related RBC Transfusion

inflammation or myelosuppressive chemotherapy PRBCs are the preferred blood product for transfu-
(if applicable) should be considered as the cause. sion to correct anemia, and are concentrated from
centrifuged whole blood donations or collected
through apheresis. The component is anticoagu-
Risk Assessment lated and may contain added preservatives. Further
If the likely cause of anemia is cancer-related inflam- enhancements include leukoreductions, irradiation,
mation or myelosuppressive chemotherapy (for solid freezing, and washing. Certain patients may especial-
tumors or lymphoid malignancies), a risk assessment ly need PRBCs that are cytomegalovirus-negative.
of the anemia is necessary to determine the initial One unit of PRBC (300 mL) can have a hematocrit
intervention plan (e.g., if an immediate boost in Hb ranging from 50% to 80%, and typically contains
levels by PRBC transfusion is necessary). Consider- 42.5 g to 80 g of Hb (with 147–278 mg of iron) or
128 mL to 240 mL of pure RBCs.10
ation of ESA therapy is generally a long-term man-
agement decision given its potential risks. Benefits of Transfusion
Importantly, the decision to conduct PRBC The major benefit of transfusion with PRBCs, which
transfusion should not be made strictly based on no other treatment offers, is a rapid increase in Hb
whether the Hb level has reached a certain threshold and hematocrit levels. Hence, PRBC transfusion is
the only intervention option for patients receiving
or “trigger.” The guidelines outline 3 general catego-
myelosuppressive chemotherapy who require im-
ries: 1) asymptomatic without significant comorbidi-
mediate correction of anemia. Transfusion of 1 unit
ties, for which observation and periodic reevaluation
(300 mL) of PRBCs has been estimated to result in
are appropriate; 2) asymptomatic with comorbidities an average increase in Hb level of 1 g/dL or hemato-
or high risk, for which transfusion should be consid- crit by 3% in a normal-size adult who is not experi-
ered; and 3) symptomatic, for which patients should encing a simultaneous loss of blood.10,11
receive transfusion. The clinical manifestations of Results of several studies evaluating the impact
anemia are associated with onset, severity, and du- of transfusion on mortality in critically ill patients
ration of the anemia, and other factors influencing have been conflicting, with some studies showing a
tissue demands for oxygen. When anemia onset is survival benefit in patients receiving transfusion. For
acute, symptoms are likely to be more pronounced, example, in a study of 56 consecutive patients with
because physiologic adjustments to compensate for unresectable esophageal cancer undergoing chemo-
a lower oxygen-carrying capacity of the blood can radiation therapy, blood transfusion was associated
occur with gradual onset. These adaptive measures with an increase in overall survival (hazard ratio
include heightened cardiac output, increased coro- [HR], 0.26; 95% CI, 0.09–0.75; P = .01).12
nary flow, altered blood viscosity, and changes in Risks of Transfusion
oxygen consumption and extraction. The presence Risks associated with PRBC transfusion include
of preexisting cardiovascular, pulmonary, or cerebral transfusion-related reactions, congestive heart fail-
vascular disease may compromise a patient’s abil- ure, bacterial contamination and viral infections,
ity to tolerate anemia. Hence, decisions related to and iron overload.13 Since 1984, the introduction
of numerous safety interventions to screen the US
whether immediate correction of anemia is needed
blood supply for infectious organisms has dramati-
must be based on an assessment of individual pa-
cally decreased the risk of transfusion-transmitted
tient characteristics, degree of severity of anemia, infections.14,15 Prestorage leukoreduction has been
presence and severity of comorbidities, and clinical shown to decrease the incidence of febrile nonhe-
judgment of the physician. For example, even when molytic transfusion reactions, the most common
a patient with anemia has no physiologic symptoms adverse reaction.16,17 However, Khorana et al.18 ana-
or significant comorbidity, transfusion may be appro- lyzed data from discharge summaries of patients with
priate if a progressive decline in Hb level occurs after cancer admitted to 60 US medical centers between
anticancer treatment. 1995 and 2003 and found increased risks (P < .001)
of venous thromboembolism (VTE; odds ratio [OR], Erythropoietic Therapy

1.60; 95% CI, 1.53–1.67), arterial thromboembolism RBC production is normally controlled by erythro-
(OR, 1.53; 95% CI, 1.46–1.61), and mortality (OR, poietin, a cytokine produced in the kidneys. First
1.34; 95% CI, 1.29–1.38) associated with PRBC introduced in 1989, ESAs are a synthetic, recombi-
transfusions. nant human erythropoietin that can stimulate eryth-
The condition of transfusion-related iron over- ropoiesis in patients with low RBC levels. Currently,
load is observed in patients requiring frequent trans- 2 ESAs are available in the United States: epoetin
fusions over several years to manage their anemia alfa and darbepoetin alfa. Unlike transfusion, which
(e.g., patients with MDS).19 However, iron overload almost immediately boosts the Hb level, ESAs can
is unlikely to occur in patients receiving transfusions take weeks to initiate an Hb response, but are effec-
restricted to the period corresponding to chemother- tive at maintaining a target Hb level with repeated
apy treatment (usually < 1 year). Another factor for administration. Popularity of ESAs reached a peak in
possible consideration in the context of full reliance 2003 to 2004, when their use in patients with can-
on PRBC transfusion as a treatment for chemother- cer accounted for 17% of all Medicare Part B spend-
apy-induced anemia relates to the limited supply of ing.23 However, this paradigm is shifting dramatically
blood in the United States. A recent analysis that as evidence of potential detrimental effects recently
modeled the impact of reducing ESA use in this began to emerge.
population indicated that approximately 202,000
additional units of PRBC would be required to treat Benefits of ESA Therapy
anemia in patients undergoing chemotherapy if ESA Avoidance of transfusion is the main benefit of ESAs.
use was reduced by 75%.20 Administration of ESA therapy has been shown to
decrease PRBC transfusion requirements in patients
Transfusion Goals and Basic Principles
with cancer undergoing chemotherapy. In a ran-
Wide variation exists in reported RBC transfusion
domized, placebo-controlled study by Littlewood et
practice,4,14,21 but institutional and clinical practice
al.,24 epoetin alfa was shown to reduce transfusion
guidelines are often “restrictive” in that they are
requirements in patients with anemia receiving che-
based on limiting exposure to allogeneic blood.14 The
motherapy. Transfusion requirements were signifi-
overall goal of transfusion is to treat or prevent a def-
cantly decreased in the epoetin arm compared with
icit of oxygen-carrying capacity in blood to improve
placebo (24.7% vs. 39.5%; P = .0057), and rise in
oxygen delivery to body tissues. Target Hb ranges for
Hb level was increased (2.2 vs. 0.5 g/dL; P < .001).24
specific conditions recommended by the panel are
A double-blind, placebo-controlled, randomized
outlined in the algorithm (see page 635). Transfusion
phase III study enrolled 320 patients (Hb level ≤
is rarely indicated when the Hb level is greater than
11 g/dL) receiving darbepoetin alfa at 2.25 mcg/kg/
10 g/dL. In the multicenter TRICC (Transfusion Re-
wk versus placebo.25 Patients receiving darbepoetin
quirements In Critical Care) trial, 838 critically ill
alfa required fewer transfusions (27% vs. 52%; 95%
patients with no significant in-hospital mortality dif-
CI, 14%–36%; P < .001) than patients receiving
ferences were observed and patients were randomly
placebo. The ability of ESAs to reduce transfusions
assigned to receive transfusions to maintain Hb lev-
was one end point used in a Cochrane review of 42
els of 7 to 9 g/dL (restrictive strategy) versus 10 to 12
randomized controlled clinical trials involving use of
g/dL (liberal strategy).22
ESA therapy that enrolled a total of 6510 patients
Before transfusion, PRBCs must be crossmatched
undergoing treatment for cancer.26 A decreased rela-
to confirm compatibility with ABO and other anti-
tive risk (RR) for transfusion was observed in the pa-
bodies in the recipient. Premedication (acetamino-
tients receiving erythropoietin (RR, 0.64; 95% CI,
phen or antihistamine) is seldom required in patients
for whom long-term transfusion is not planned. If re- 0.60–0.68).
peated transfusions are required, leukocyte-reducing Risks of ESA Therapy
blood and use of premedication can minimize ad- Increased Mortality and Tumor Progression: In
verse transfusion reactions. In most instances, PRBCs 2007, the FDA made substantial revisions to the label
should be transfused by the unit and reassessment information and regulations regarding epoetin alfa
should be conducted after each transfusion. and darbepoetin alfa,27,28 including the addition of a
“Black Box” label warning and implementation of a Overall, results from meta-analyses established
risk management program known as Risk Evaluation a significant association: increased risk of thrombot-
and Mitigation Strategy (REMS; see page 639). The ic events associated with ESA use was reported by
strengthened FDA restrictions were mainly based on Tonelli et al.,39 (RR, 1.69; 95% CI, 1.27–2.24), Ben-
the results of 8 randomized studies that showed a de- nett et al.,37 (RR, 1.57; 95% CI, 1.31–1.87), Ludwig
crease in overall survival and/or locoregional disease et al.,41 (HR, 1.57; 95% CI, 1.10–2.26), and Glaspy
control with ESA use for advanced breast, cervical, et al.42 (OR, 1.48; 95% CI, 1.28–1.72). A combined
head and neck, lymphoid, and non–small cell lung analysis of 6 trials investigating darbepoetin alfa by
cancers.29–36 Of the 8 studies, 3 investigated ESA ef- Glaspy et al.53 also found an increased risk of throm-
fects in patients who underwent chemotherapy. All boembolism for patients with Hb levels greater than
8 trials had an off-label target Hb level of greater 12 g/dL (RR, 1.66; 95% CI, 0.9–3.04) or those expe-
than 12 g/dL. riencing an increase greater than 1 g/dL in 14 days
Worsened health outcomes associated with the (RR, 1.67; 95% CI, 0.96–2.88). In addition, an in-
use of ESAs have been confirmed in 3 recent meta- creased risk for stroke was associated with darbepoet-
analyses of 51 to 53 randomized controlled trials.37–40 in alfa in a clinical trial of patients with chronic kid-
Bohlius et al.,38 Tonelli et al.,39 and Bennett et al.37 ney disease (CKD; HR, 1.92; 95% CI, 1.38–2.68).54
each reported increased mortality in patients receiv- The increased risk of thromboembolism in patients
ing ESAs with RRs/HRs of 1.17 (95% CI, 1.06– with cancer receiving ESA therapy is specified in the
1.30), 1.15 (95% CI, 1.03–1.29), and 1.10 (95% CI, black box warnings included in the updated FDA la-
1.01–1.20), respectively. However, this association bels. The panel cautions physicians to be alert for
has been refuted by 2 other meta-analyses reporting the signs and symptoms of thromboembolism in pa-
no significant effect of ESAs on mortality or pro- tients with cancer receiving ESAs.
gression.41,42 In addition, several recent pharmaco- Risk of Hypertension/Seizures: Seizures have been
vigilance trials reported no decrease in survival with reported in patients with chronic renal failure
ESA use in patients with chemotherapy-related ane- receiving ESAs. A 2.5% incidence of seizure in
mia.43–45 One of these is an update on the PREPARE patients on dialysis is seen during the first 90 days
trial that originally reported increased deaths among of therapy.55 Although whether patients with can-
patients with breast cancer receiving darbepoetin cer receiving ESA therapy are at risk for seizures
compared with no darbepoetin.29 The update found is unclear, Hb levels should be monitored before
no difference in overall survival; a trend was seen and during the use of ESAs to decrease the risk of
toward decreased disease-free survival that failed to these adverse events.
reach statistical significance.45 Data from random- Risk of Pure Red Cell Aplasia: Pure red cell apla-
ized studies also showed no increase in mortality sia (PRCA) is a rare anemia syndrome character-
with ESA use according to the prescribing label spe- ized by a low reticulocyte count, loss of bone mar-
cifically in patients receiving chemotherapy for small row erythroblasts, neutralizing antibodies against
cell lung cancer.46,47 erythropoietin, and resistance to ESA therapy.
Risk of Thromboembolism: Increased thromboem- From 1998 to 2004, however, a marked rise in in-
bolic risks have been associated with ESA treat- cidence (191 cases) was observed, 90% of which
ment in patients with cancer. The cause of VTE is occurred with Eprex, an epoetin alfa product used
complex; a heightened baseline risk is related to the outside of the United States.56,57 Causation was
malignancy itself and to chemotherapy (see NCCN attributed to formulations without human serum
Guidelines for Venous Thromboembolic Disease; albumin, subcutaneous administration, and un-
available on the NCCN Web site at NCCN.org).48–51 coated rubber stoppers.58 Interventions designed
Other risk factors for VTE in patients with cancer accordingly reduced the incidence by 83%. In
include prior history of VTE, heritable mutation, hy- 2005, the FDA interpretation of anemia associat-
percoagulability, elevated prechemotherapy platelet ed with neutralizing antibodies evolved to include
counts, recent surgery, hormonal agents, prolonged both PRCA and severe anemia, with or without
inactivity from hospitalization, steroids, and comor- other cytopenias, associated with neutralizing an-
bidities such as hypertension.52 tibodies.59 PRCA resulted in a class label change
for all ESAs. Toxicity has been reported predomi- cians are advised to use the lowest dose necessary
nantly in patients with chronic renal failure re- to avoid transfusion.
ceiving subcutaneous ESAs. CKD is an independent indication for ESA
The panel recommends that any patient with therapy. Risks of ESA use in these patients seem to
cancer who develops a sudden loss of response to be associated with high doses and/or high target Hb
ESAs, accompanied by severe anemia and low retic- levels, and the FDA label mandates individualized
ulocyte count, should be evaluated for the cause of dosing to maintain Hb levels between 10 and 12 g/
loss of effect. ESAs should be withheld while plasma dL. Because almost one-third of patients with end-
is sent to ESA-producing pharmaceutical companies stage renal disease are also afflicted with cancer, they
for evaluation of assays for binding and neutralizing represent a unique group that requires personalized
antibodies to erythropoietin. ESAs should be perma- use of ESAs based on very careful weighing of risks
nently discontinued in patients with antibody-medi- and benefits (reviewed by Bennett et al.60). For ex-
ated anemia. Patients should not be switched to oth- ample, patients with CKD not undergoing active
er ESA products because antibodies may cross-react. therapy for a malignancy should try to avoid ESAs,
NCCN Recommendations whereas those receiving palliative chemotherapy
To promote safety, the FDA requires that ESAs only may favor ESAs over transfusions to treat severe
be administered with informed patient consent un- anemia through carefully dosing for target Hb be-
der the REMS program that consists of medication tween 10 and 12 g/dL in keeping with the indication
guides for patients and the ESA APPRISE (Assisting for CKD. In patients with CKD who have a curable
Providers and Cancer Patients with Risk Informa- solid tumor, ESAs should not be administered dur-
tion for the Safe Use of ESAs) program for prescribing chemotherapy but may be used with caution after
ing physicians (see page 639). chemotherapy is complete, keeping in mind the pos-
For patients with cancer, the black box warning sibility of residual disease. Risk of thrombosis must
on the revised FDA label states that ESAs should be taken into account in weighing the risk/benefit
only be used to treat chemotherapy-induced ane- ratio.
mia and should be discontinued once the chemo- Most hematopoietic stem cell transplants re-
therapy course is complete.27 Hence, patients not quire transfusion support. Nonetheless, ESA therapy
receiving concomitant myelosuppressive chemo- may be useful in some instances. For example, ESAs
therapy are not eligible. Randomized trial data sug- may be administered posttransplant to increase the
gest that ESAs may promote tumor growth in an hematocrit to allow phlebotomy in cases of transfu-
off-target manner. Therefore, these agents should sional iron overload. ESA efficacy has been reported
not be used when the anticipated treatment out- in patients who refuse blood transfusions while un-
come is cure, including with primary and adjuvant dergoing autologous stem cell transplantation.61–63
chemotherapy for malignancies such as early-stage Posttransplant use of ESAs for patients undergoing
breast cancer, non–small cell lung cancer, lympho- cancer chemotherapy, those with renal insufficiency,
mas, and testicular cancer. An exception to this or those with recurrent/secondary MDS should fol-
may be with small cell lung cancer, for which tri- low NCCN Guidelines for chemotherapy-related
als show no negative impact on survival or disease anemia, CKD, or MDS, respectively (available at
progression (see previous discussion). For patients NCCN.org).
undergoing palliative treatment, ESA therapy can Iron studies, such as serum iron, TIBC, and serum
be considered preferentially over transfusion. ferritin, should accompany ESA therapy to monitor
The panel recognized that whether a chemo- the development of functional iron deficiency (dis-
therapy regimen is considered curative is not al- cussed later).
ways clear. Under these circumstances, given that Dosing Schedules
no other cause of anemia has been identified, the Epoetin alfa and darbepoetin alfa are considered
order of priority for anemia management should equivalent by the panel. Recommended initial dos-
be consideration of RBC transfusion, clinical trial ing schedules for patients receiving chemotherapy
enrollment if available, followed by consideration are summarized in the algorithm. The most common
of ESAs. When ESA use is decided upon, physi- initial dosing schedules for epoetin alfa evaluated in
clinical trials of patients with cancer are 150 U/kg a dose titration with the goal to avoid transfusion.
administered subcutaneously 3 times weekly24,64 and Individuals receiving weekly doses of ESA therapy
40,000 U subcutaneously once weekly.32,35,36,65 Both can be evaluated for subsequent response at 8 or 9
of these initial dose schedules are currently recom- weeks. The same dose-reduction formulas described
mended. Other dosing ranges and schedules of epo- earlier should be followed. ESA therapy should be
etin alfa may be considered, including an extended discontinued in patients showing no response de-
dosing of 80,000 U subcutaneously every 2 weeks66 spite iron supplementation after 8 or 9 weeks of ther-
and a dose of 120,000 U subcutaneously once every apy, and PRBC transfusion should be considered.
3 weeks.62 ESAs should be discontinued when chemotherapy is
Although darbepoetin doses were initially ad- complete and anemia has resolved, usually within 6
ministered at 2.25 mcg/kg subcutaneously every weeks.
week,25,30,68 interest has been shown in using fixed
doses and higher doses at decreased frequency. A
randomized trial compared weekly dosing at 2.25 Iron Monitoring and Supplementation
mcg/kg versus fixed dosing at 500 mcg every 3 weeks “Functional” iron deficiency often arises after con-
in 705 patients with nonmyeloid malignancies with tinued erythropoietin use. As a result, iron supple-
an Hb level less than 11 g/dL. The percentage of pa- mentation will eventually be required in most pa-
tients achieving the target Hb level (≥ 11 g/dL) was tients to maintain optimal erythropoiesis.71,72 This is
77% in the weekly arm and 84% for patients receiv- because rapid ESA-stimulated RBC production in-
ing darbepoetin alfa every 3 weeks.68 Currently the creases the rate of iron mobilization from the usable
panel recommends both schedules. Several studies iron pool in the reticuloendothelial system (RES) to
have shown the safety and efficacy of alternative dos- the bone marrow. Release of iron from the RES can
ing schedules for darbepoetin alfa, including a fixed be further delayed by inflammatory cytokine release
weekly dose of 100 mcg,25 a fixed dose of 200 mcg from tumors, or chemotherapy used to treat cancer.
biweekly,69 and 300 mcg every 3 weeks.70 These inflammatory cytokines lead to the upregula-
Response Assessment and Dose Titration tion of hepcidin, a molecule that blocks the release
Response to ESA therapy is assessed to determine of iron (bound in macrophages within the RES) to
whether the initial dose should be reduced, escalat- its transporter transferrin.72 The overall result is a
ed, or withheld. Decisions related to ESA dose ad- blunted erythropoietic response to anemia. If the pa-
justment are based on the goal of a gradual increase tient is to receive exogenous erythropoietic therapy
in Hb level to avoid transfusion. to overcome the aforementioned response, iron stud-
ESAs require at least 2 weeks of treatment before ies, including serum iron, TIBC, and serum ferritin,
an increase in the number of RBCs is seen. Hb levels should be performed before treatment to rule out ab-
should be measured weekly until they stabilize. Dose solute iron deficiency (transferrin saturation [TSAT]
reduction should be implemented if the Hb level in- < 15%, serum ferritin < 30 ng/mL), which may re-
creases by 1 g/dL or more during a 2-week period, or spond to oral or intravenous iron monotherapy with-
if Hb reaches a level sufficient to avoid transfusion. out an ESA.
Doses of epoetin alfa and darbepoetin alfa should be Iron can be administered in oral or parenteral
decreased by 25% to 40%, although individualized form (low-molecular-weight iron dextran, fer-
dose titrations may be needed. ric gluconate, and iron sucrose).73 Evidence from
Conversely, the ESA dose should be increased 5 published studies using iron in conjunction with
according to the algorithm (see page 636) in patients an ESA suggests that intravenous iron is superior to
receiving chemotherapy who show no response (< oral iron.74–78 Patients participating in these trials
1 g/dL in Hb increase) in Hb level after 4 weeks of had serum ferritin levels ranging from 100 ng/mL to
epoetin alfa or 6 weeks of darbepoetin alfa. Iron sup- 900 ng/mL. A prospective, multicenter, open-label
plementation can be considered to improve response trial randomized 157 patients with chemotherapy-
to ESA therapy (see later discussion). A subsequent induced anemia receiving epoetin alfa to either no
response at 8 or 9 weeks for patients on ESA dos- iron, oral iron, bolus intravenous iron dextran, or
ing schedules of every 2 or 3 weeks may necessitate iron dextran total dose infusion.74 Increases in Hb
concentration were greater with intravenous iron to determine whether iron supplementation can
(groups 3 and 4) than with oral supplementation or allow an ESA dose decrease. Long-term effects of
no iron (P < .02), although no difference was seen intravenous iron supplementation in patients with
between the oral and no iron groups (P = .21). In cancer were not assessed in any of these 5 trials.
a second open-label study by Henry et al.,77 187 pa- In 2011, Steensma et al.79 published findings
tients with cancer-related anemia receiving chemo- from the largest trial to date that challenged results
therapy and epoetin alfa were randomized to no iron, from the studies mentioned earlier. Roughly 500
oral ferrous sulfate 3 times daily, or weekly intrave- patients with cancer-induced anemia were random-
nous ferric gluconate. Intravenous iron produced ized 1:1:1 to intravenous ferric gluconate, oral fer-
a significantly greater Hb response than oral or no rous sulfate, or oral placebo. Intravenous iron failed
iron. The Hb response rate (≥ 2 g/dL increase) was to confer additional benefit in terms of Hb response,
also higher in the intravenous arm (73%) compared transfusion rates, or quality of life. One possibility
with oral (45%) or no iron (41%). A third study was for lack of response may be that the mean baseline
conducted in 67 patients with lymphoproliferative TSAT for patients in the intravenous iron group was
malignancies not undergoing chemotherapy.76 Pa- 22.5%, a value greater than what is considered to be
tients were randomized to weekly epoetin beta with associated with functional iron deficiency.
or without intravenous iron sucrose. Although an A meta-analysis evaluating the role of iron sup-
oral iron arm was not included, intravenous iron re- plementation has been reported in abstract form.80
sulted both in higher mean change in Hb level from This includes 7 randomized controlled trials involv-
baseline (2.76 vs. 1.56 g/dL; P = .0002) and a higher ing 1777 patients with chemotherapy-induced ane-
Hb level response rate (≥ 2 g/dL increase; 87% vs. mia. Oral or intravenous iron supplementation with
53%; P = .0014) compared with the no-iron group. ESAs reduced transfusion rates compared with no
Two additional studies were published in 2008. iron. Intravenous iron but not oral iron was associ-
Bastit et al.75 reported their open-label trial of 396 ated with improved hematopoietic response rates
patients with nonmyeloid malignancies undergo- compared with ESA alone. No difference in adverse
ing chemotherapy (Hb < 11 g/dL). These were events was found.
treated with darbepoetin alfa with or without in- NCCN Recommendations
travenous iron (iron sucrose or ferric gluconate, In these NCCN Guidelines, intravenous iron prod-
proportion of patients receiving each preparation ucts alone (without an ESA) are recommended for
has not been reported), 200 mg every 3 weeks for iron repletion in patients with cancer with absolute
16 weeks. Again, hematopoietic responses and iron deficiency (ferritin < 30 ng/mL, transferrin satu-
time to reach target Hb level were improved in ration < 15%). Intravenous iron monotherapy has
the intravenous iron arm. Most significantly, this not been studied in patients with chemotherapy-
is the first and only study to associate intravenous induced anemia and functional iron deficiency (fer-
iron with fewer RBC transfusions in patients with ritin ≤ 800 ng/mL, transferrin saturation < 20%).
cancer (9% vs. 20%; P = .005). In a study by Pe- Therefore, the currently recommendation is that
drazzoli et al.,78 149 patients with solid tumors and ESAs be used in addition to intravenous iron for pa-
chemotherapy-induced anemia were randomly tients with chemotherapy-induced anemia and func-
assigned to weekly darbepoetin alfa with or with- tional iron deficiency. Common adverse events after
out ferric gluconate. This is the first trial that ex- FDA-approved doses of parenteral iron include hy-
cluded patients with absolute or functional iron potension, nausea, vomiting and/or diarrhea, pain,
deficiency; eligibility requirements included serum hypertension, dyspnea, pruritus, headache, and diz-
ferritin levels greater than 100 ng/mL and TSATs ziness.81–83 Most adverse events associated with iron
greater than 20%. The ESA/intravenous iron dextran occur with high-molecular-weight iron dex-
group showed a higher hematopoietic response tran (Dexferrum).84 The recommended iron dextran
rate (93% vs. 70%; P = .0033) compared with the product is low-molecular-weight iron dextran (IN-
control group. These studies showed that concur- Fed).85 Test doses are required for iron dextran, and
rent intravenous iron enhanced hematologic re- strongly recommended for patients receiving ferric
sponse to ESAs, although evidence is insufficient gluconate or iron sucrose who are sensitive to iron
dextran or have other drug allergies. Dosage details 10. Miller Y, Bachowski G, Benjamin R, et al. Practice guidelines
for blood transfusion: a compilation from recent peer-reviewed
for administering parenteral iron therapy are listed literature, 2nd edition. Washington, DC; American Red Cross;
in the algorithm (see page 640). Although data are 2007. Available at: http://www.redcross.org/www-files/Documents/
conflicting in the literature, concerns exist regarding WorkingWiththeRedCross/practiceguidelinesforbloodtrans.pdf.
intravenous iron possibly promoting inflammation Accessed April 1, 2012.
11. Wiesen AR, Hospenthal DR, Byrd JC, et al. Equilibration of
and bacterial growth.86 Hence, iron supplementa-
hemoglobin concentration after transfusion in medical inpatients
tion is not recommended for patients with active not actively bleeding. Ann Intern Med 1994;121:278–230.
infection. 12. Kader AS, Lim JT, Berthelet E, et al. Prognostic significance of
blood transfusions in patients with esophageal cancer treated with
combined chemoradiotherapy. Am J Clin Oncol 2007;30:492–497.
Future Development 13. Spivak JL, Gascon P, Ludwig H. Anemia management in oncology
and hematology. Oncologist 2009;14(Suppl 1):43–56.
In the face of current controversy in various aspects 14. Hill SR, Carless PA, Henry DA, et al. Transfusion thresholds and
of anemia management, well-designed trials are re- other strategies for guiding allogeneic red blood cell transfusion.
quired to answer questions regarding the safety of Cochrane Database Syst Rev 2002:CD002042.
ESAs for lower target Hb levels, the role of intrave- 15. Blajchman MA, Vamvakas EC. The continuing risk of transfusion-
transmitted infections. N Engl J Med 2006;355:1303–1305.
nous iron in reducing transfusion needs, the optimal
16. King KE, Shirey RS, Thoman SK, et al. Universal leukoreduction
dose and frequency of intravenous iron, and both decreases the incidence of febrile nonhemolytic transfusion
short and long term effects of iron supplementation, reactions to RBCs. Transfusion 2004;44:25–29.
among others. 17. Yazer MH, Podlosky L, Clarke G, Nahirniak SM. The effect of
Several novel intravenous iron agents are cur- prestorage WBC reduction on the rates of febrile nonhemolytic
transfusion reactions to platelet concentrates and RBC. Transfusion
rently being studied as monotherapy (without an 2004;44:10–15.
ESA) in chemotherapy-induced anemia, such as 18. Khorana AA, Francis CW, Blumberg N, et al. Blood transfusions,
iron isomaltoside and ferric carboxymaltose. More thrombosis, and mortality in hospitalized patients with cancer.
information about these agents can be found at Arch Intern Med 2008;168:2377–2381.
ClinicalTrials.gov. 19. Jabbour E, Kantarjian HM, Koller C, Taher A. Red blood cell
transfusions and iron overload in the treatment of patients with
myelodysplastic syndromes. Cancer 2008;112:1089–1095.
20. Vekeman F, Bookhart BK, White J, et al. Impact of limiting
References erythropoiesis-stimulating agent use for chemotherapy-induced
1. Knight K, Wade S, Balducci L. Prevalence and outcomes of anemia on the United States blood supply margin. Transfusion
anemia in cancer: a systematic review of the literature. Am J Med 2009;49:895–902.
2004;116(Suppl 7A):11S–26S. 21. Pawson R, Brunskill S, Murphy MF, et al. Different threshold levels
2. Schwartz RN. Anemia in patients with cancer: incidence, for red blood cell transfusions in patients with haematological
causes, impact, management, and use of treatment guidelines and malignancy (Protocol). Cochrane Database Syst Rev
protocols. Am J Health Syst Pharm 2007;64:S5–13; quiz S28–30. 2006;3:CD006166.
3. Steensma DP. Is anemia of cancer different from chemotherapy- 22. Hebert PC, Wells G, Blajchman MA, et al. A multicenter,
induced anemia? J Clin Oncol 2008;26:1022–1024. randomized, controlled clinical trial of transfusion requirements
4. Wilson J, Yao GL, Raftery J, et al. A systematic review and economic in critical care. Transfusion Requirements in Critical Care
evaluation of epoetin alpha, epoetin beta and darbepoetin alpha Investigators, Canadian Critical Care Trials Group. N Engl J Med
in anaemia associated with cancer, especially that attributable to 1999;340:409–417.
cancer treatment. Health Technol Assess 2007;11:1–202, iii–iv. 23. Steinbrook R. Erythropoietin, the FDA, and oncology. N Engl J
5. Moullet I, Salles G, Ketterer N, et al. Frequency and significance Med 2007;356:2448–2451.
of anemia in non-Hodgkin’s lymphoma patients. Ann Oncol 24. Littlewood TJ, Bajetta E, Nortier JW, et al. Effects of epoetin alfa
1998;9:1109–1115. on hematologic parameters and quality of life in cancer patients
6. Ludwig H, Van Belle S, Barrett-Lee P, et al. The European Cancer receiving nonplatinum chemotherapy: results of a randomized,
Anaemia Survey (ECAS): a large, multinational, prospective double-blind, placebo-controlled trial. J Clin Oncol 2001;19:2865–
survey defining the prevalence, incidence, and treatment of 2874.
anaemia in cancer patients. Eur J Cancer 2004;40:2293–2306. 25. Vansteenkiste J, Pirker R, Massuti B, et al. Double-blind, placebo-
7. Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: controlled, randomized phase III trial of darbepoetin alfa in lung
incidence and treatment. J Natl Cancer Inst 1999;91:1616–1634. cancer patients receiving chemotherapy. J Natl Cancer Inst
8. Jefferies S, Rajan B, Ashley S, et al. Haematological toxicity of 2002;94:1211–1220.
cranio-spinal irradiation. Radiother Oncol 1998;48:23–27. 26. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human
9. Glaus A, Crow R, Hammond S. A qualitative study to explore erythropoietins and cancer patients: updated meta-analysis of 57
the concept of fatigue/tiredness in cancer patients and in healthy studies including 9353 patients. J Natl Cancer Inst 2006;98:708–
individuals. Support Care Cancer 1996;4:82–96. 714.
27. Food and Drug Administration. Epoetin alfa label. Available at: placebo-controlled trials of darbepoetin alfa in the treatment
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103234 of patients with chemotherapy-induced anemia. J Clin Oncol
Orig1s5166_103234Orig1s5266lbl.pdf. Accessed January 25, 2012. 2009;27:2838–2847.
28. Food and Drug Administration. Darbepoetin alfa label. Available 42. Glaspy J, Crawford J, Vansteenkiste J, et al. Erythropoiesis-
at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103 stimulating agents in oncology: a study-level meta-analysis of
951Orig1s5173_103951Orig1s5258lbl.pdf. Accessed January 25, survival and other safety outcomes. Br J Cancer 2010;102:301–315.
2012. 43. Engert A, Josting A, Haverkamp H, et al. Epoetin alfa in
29. Untch M, Fasching PA, Bauerfeind I, et al. PREPARE trial. A patients with advanced-stage Hodgkin’s lymphoma: results of the
randomized phase III trial comparing preoperative, dose-dense, randomized placebo-controlled GHSG HD15EPO trial. J Clin
dose-intensified chemotherapy with epirubicin, paclitaxel and Oncol 2010;28:2239–2245.
CMF with a standard dosed epirubicin/cyclophosphamide followed 44. Moebus V, Jackisch C, Lueck HJ, et al. Intense dose-dense sequential
by paclitaxel {+/-} darbepoetin alfa in primary breast cancer: a chemotherapy with epirubicin, paclitaxel, and cyclophosphamide
preplanned interim analysis of efficacy at surgery [abstract]. J Clin compared with conventionally scheduled chemotherapy in high-
Oncol 2008;26(Suppl 15):Abstract 517. risk primary breast cancer: mature results of an AGO phase III
30. Hedenus M, Adriansson M, San Miguel J, et al. Efficacy and safety study. J Clin Oncol 2010;28:2874–2880.
of darbepoetin alfa in anaemic patients with lymphoproliferative
45. Untch M, Fasching PA, Konecny GE, et al. PREPARE trial: a
malignancies: a randomized, double-blind, placebo-controlled
randomized phase III trial comparing preoperative, dose-dense,
study. Br J Haematol 2003;122:394–403.
dose-intensified chemotherapy with epirubicin, paclitaxel and CMF
31. Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head versus a standard-dosed epirubicin/cyclophosphamide followed by
and neck cancer patients with anaemia undergoing radiotherapy: paclitaxel {+/-} darbepoetin alfa in primary breast cancer: results at
randomised, double-blind, placebo-controlled trial. Lancet the time of surgery. Ann Oncol 2011;22:1988–1998.
2003;362:1255–1260.
46. Pirker R, Ramlau RA, Schuette W, et al. Safety and efficacy of
32. Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining darbepoetin alpha in previously untreated extensive-stage small-
normal hemoglobin levels with epoetin alfa in mainly nonanemic cell lung cancer treated with platinum plus etoposide. J Clin Oncol
patients with metastatic breast cancer receiving first-line 2008;26:2342–2349.
chemotherapy: a survival study. J Clin Oncol 2005;23:5960–5972.
47. Grote T, Yeilding AL, Castillo R, et al. Efficacy and safety analysis of
33. Overgaard J, Hoff CM, Hansen HS, et al. Randomized study epoetin alfa in patients with small-cell lung cancer: a randomized,
of darbepoetin alfa as modifier of radiotherapy in patients with double-blind, placebo-controlled trial. J Clin Oncol 2005;23:9377–
primary squamous cell carcinoma of the head and neck (HNSCC): 9386.
final outcome of the DAHANCA 10 trial [abstract]. J Clin Oncol
48. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep
2009;27(Suppl 15):Abstract 6007.
vein thrombosis and pulmonary embolism: a population-based
34. Smith RE Jr, Aapro MS, Ludwig H, et al. Darbepoetin alfa for the
case-control study. Arch Intern Med 2000;160:809–815.
treatment of anemia in patients with active cancer not receiving
chemotherapy or radiotherapy: results of a phase III, multicenter, 49. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism
randomized, double-blind, placebo-controlled study. J Clin Oncol is a leading cause of death in cancer patients receiving outpatient
2008;26:1040–1050. chemotherapy. J Thromb Haemost 2007;5:632–634.
35. Thomas G, Ali S, Hoebers FJ, et al. Phase III trial to evaluate 50. Levine MN, Gent M, Hirsh J, et al. The thrombogenic effect of
the efficacy of maintaining hemoglobin levels above 12.0 g/dL anticancer drug therapy in women with stage II breast cancer. N
with erythropoietin vs above 10.0 g/dL without erythropoietin in Engl J Med 1988;318:404–407.
anemic patients receiving concurrent radiation and cisplatin for 51. Saphner T, Tormey DC, Gray R. Venous and arterial thrombosis
cervical cancer. Gynecol Oncol 2008;108:317–325. in patients who received adjuvant therapy for breast cancer. J Clin
36. Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, Oncol 1991;9:286–294.
placebo-controlled trial of erythropoietin in non-small-cell lung 52. Lyman GH, Khorana AA, Falanga A, et al. American Society
cancer with disease-related anemia. J Clin Oncol 2007;25:1027– of Clinical Oncology guideline: recommendations for venous
1032. thromboembolism prophylaxis and treatment in patients with
37. Bennett CL, Silver SM, Djulbegovic B, et al. Venous cancer. J Clin Oncol 2007;25:5490–5505.
thromboembolism and mortality associated with recombinant 53. Glaspy J, Osterborg A, Ludwig H, et al. Evaluation of the
erythropoietin and darbepoetin administration for the treatment of association between hemoglobin (Hb) events and safety outcomes
cancer-associated anemia. JAMA 2008;299:914–924. in cancer patients (pts) with chemotherapy-induced anemia (CIA):
38. Bohlius J, Schmidlin K, Brillant C, et al. Recombinant human an integrated analysis of patient-level data from 6 randomized,
erythropoiesis-stimulating agents and mortality in patients with placebo-controlled trials (RCTs) of darbepoetin [abstract]. Eur J
cancer: a meta-analysis of randomised trials. Lancet 2009;373:1532– Cancer Suppl 2007;5:Abstract 147.
1542. 54. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin
39. Tonelli M, Hemmelgarn B, Reiman T, et al. Benefits and harms alfa in type 2 diabetes and chronic kidney disease. N Engl J Med
of erythropoiesis-stimulating agents for anemia related to cancer: a 2009;361:2019–2032.
meta-analysis. CMAJ 2009;180:E62–71. 55. Food and Drug Administration. FDA information on ESAs.
40. Bennett CL, Henke M, Lai SY. Erythropoiesis-stimulating agents 2010. Available at: http://www.fda.gov/cder/drug/infopage/RHE/.
in the treatment of cancer-associated anemia - reply. JAMA Accessed January 25, 2012.
2008;300:2855–2857. 56. Bennett CL, Cournoyer D, Carson KR, et al. Long-term outcome
41. Ludwig H, Crawford J, Osterborg A, et al. Pooled analysis of of individuals with pure red cell aplasia and antierythropoietin
individual patient-level data from all randomized, double-blind, antibodies in patients treated with recombinant epoetin: a follow-
up report from the Research on Adverse Drug Events and Reports 73. Silverstein SB, Gilreath JA, Rodgers GM. Intravenous iron
(RADAR) Project. Blood 2005;106:3343–3347. therapy: a summary of treatment options and review of guidelines.
57. Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia J Pharm Pract 2008;21:431–443.
and epoetin therapy. N Engl J Med 2004;351:1403–1408. 74. Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes
58. McKoy JM, Stonecash RE, Cournoyer D, et al. Epoetin-associated the response to recombinant human erythropoietin in cancer
pure red cell aplasia: past, present, and future considerations. patients with chemotherapy-related anemia: a multicenter, open-
Transfusion 2008;48:1754–1762. label, randomized trial. J Clin Oncol 2004;22:1301–1307.
59. Food and Drug Administration. FDA on ESA-associated PRCA. 75. Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter,
2006. Available at: http://www.accessdata.fda.gov/scripts/cdrh/ controlled trial comparing the efficacy and safety of darbepoetin
cfdocs/psn/printer.cfm?id=430. Accessed January 25, 2012. alpha administered every 3 weeks with or without intravenous
60. Bennett CL, Becker PS, Kraut EH, et al. Intersecting guidelines: iron in patients with chemotherapy-induced anemia. J Clin Oncol
administering erythropoiesis-stimulating agents to chronic kidney 2008;26:1611–1618.
disease patients with cancer. Semin Dial 2009;22:1–4. 76. Hedenus M, Birgegard G, Nasman P, et al. Addition of
61. Ballen KK, Becker PS, Yeap BY, et al. Autologous stem-cell intravenous iron to epoetin beta increases hemoglobin response
transplantation can be performed safely without the use of blood- and decreases epoetin dose requirement in anemic patients with
product support. J Clin Oncol 2004;22:4087–4094. lymphoproliferative malignancies: a randomized multicenter study.
62. Ballen KK, Ford PA, Waitkus H, et al. Successful autologous bone Leukemia 2007;21:627–632.
marrow transplant without the use of blood product support. Bone 77. Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric
Marrow Transplant 2000;26:227–229. gluconate significantly improves response to epoetin alfa versus
63. Brown NM, Kim SY, Ford PA. Autologous stem cell transplants in oral iron or no iron in anemic patients with cancer receiving
Jehovah’s Witnesses. Bone Marrow Transplant 2009;44:391–392. chemotherapy. Oncologist 2007;12:231–242.
64. Glaspy J, Bukowski R, Steinberg D, et al. Impact of therapy with 78. Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of
epoetin alfa on clinical outcomes in patients with nonmyeloid intravenous iron supplementation in patients with chemotherapy-
malignancies during cancer chemotherapy in community oncology related anemia without iron deficiency treated with darbepoetin
practice. Procrit Study Group. J Clin Oncol 1997;15:1218–1234. alpha. J Clin Oncol 2008;26:1619–1625.
65. Gabrilove JL, Cleeland CS, Livingston RB, et al. Clinical 79. Steensma DP, Sloan JA, Dakhil SR, et al. Phase III, randomized
evaluation of once-weekly dosing of epoetin alfa in chemotherapy study of the effects of parenteral iron, oral iron, or no iron
patients: improvements in hemoglobin and quality of life are similar supplementation on the erythropoietic response to darbepoetin alfa
to three-times-weekly dosing. J Clin Oncol 2001;19:2875–2882. for patients with chemotherapy-associated anemia. J Clin Oncol
66. Henry DH, Gordan LN, Charu V, et al. Randomized, open-label 2011;29:97–105.
comparison of epoetin alfa extended dosing (80,000 U Q2W) vs 80. Mhaskar R, Wao H, Kumar A, et al. Role of iron supplementation
weekly dosing (40,000 U QW) in patients with chemotherapy-
to erythropoiesis stimulating agents in the management of
induced anemia. Curr Med Res Opin 2006;22:1403–1413.
chemotherapy-induced anemia in cancer patients: a systematic
67. Steensma DP, Molina R, Sloan JA, et al. Phase III study of two review and meta-analysis [abstract]. Blood 2010;116(Suppl
different dosing schedules of erythropoietin in anemic patients 21):Abstract 2055.
with cancer. J Clin Oncol 2006;24:1079–1089.
81. National Institutes of Health. Ferrlecit package insert. Available at:
68. Canon JL, Vansteenkiste J, Bodoky G, et al. Randomized, double- http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a2f2f298-
blind, active-controlled trial of every-3-week darbepoetin alfa for 2dec-4020-97c8-2aade4b99b2e. Accessed January 25, 2012.
the treatment of chemotherapy-induced anemia. J Natl Cancer
Inst 2006;98:273–284. 82. National Institutes of Health. Venofer package insert.
Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.
69. Thames WA, Smith SL, Scheifele AC, et al. Evaluation of the
cfm?setid=626dc9e5-c6b4-4f9c-9bf4-774fd3ae619a. Accessed
US Oncology Network’s recommended guidelines for therapeutic
January 25, 2012.
substitution with darbepoetin alfa 200 microg every 2 weeks in
both naive patients and patients switched from epoetin alfa. 83. Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J
Pharmacotherapy 2004;24:313–323. Hematol 2004;76:74–78.
70. Boccia R, Malik IA, Raja V, et al. Darbepoetin alfa administered 84. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on
every three weeks is effective for the treatment of chemotherapy- adverse drug events associated with parenteral iron. Nephrol Dial
induced anemia. Oncologist 2006;11:409–417. Transplant 2006;21:378–382.
71. Henry DH. Supplemental iron: a key to optimizing the response of 85. Auerbach M, Ballard H, Glaspy J. Clinical update: intravenous
cancer-related anemia to rHuEPO? Oncologist 1998;3:275–278. iron for anaemia. Lancet 2007;369:1502–1504.
72. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 86. Lapointe M. Iron supplementation in the intensive care unit: when,
2005;352:1011–1023. how much, and by what route? Crit Care 2004;8(Suppl 2):S37–41.
Individual Disclosures for the NCCN Cancer- and Chemotherapy-Induced Anemia Panel
Advisory Boards,
Speakers Bureau,
Clinical Research Expert Witness, or Patent, Equity, Date
Panel Member Support Consultant or Royalty Other Completed
Pamela Sue Becker, MD, PhD None None None None 3/19/12
Morey Blinder, MD None American Regent, None None 5/16/11
Inc.
David Cella, PhD None None None None 3/8/12
Asher Chanan-Khan, MD Millennium Millennium None None 2/25/11
Pharmaceuticals, Pharmaceuticals,
Inc.; and Celgene Inc.; and Celgene
Corporation Corporation
Charles Cleeland, PhD None None None None 7/22/11
Peter F. Coccia, MD None None None None 9/27/11
Benjamin Djulbegovic, MD, PhD Millennium None None None 3/7/12
Pharmaceuticals,
Inc.
Jeffrey A. Gilreath, PharmD None None None None 3/20/12
Eric H. Kraut, MD Pieris pieris None None 3/7/12
Marisa B. Marques, MD None None None None 3/21/12
Ursula A. Matulonis, MD AstraZeneca Eisai Co. Ltd.; and None None 4/19/11
Pharmaceuticals Merck & Co., Inc.
LP; Eli Lilly
and Company;
Genentech,
Inc.;and Merck &
Co., Inc.
Michael M. Millenson, MD, FACP None None None None 4/6/11
Denise Reinke, MS, NP None None None None 3/20/12
George M. Rodgers III, MD, PhD None Amgen Inc. None None 2/15/12
Joseph Rosenthal, MD None None None None 3/21/12
Rowena N. Schwartz, PharmD None Amgen Inc. None None 9/29/11
Gerald Soff, MD Bayer AG None None None 9/28/11
Richard S. Stein, MD None None None None 4/13/11
Carlos E. Vigil, MD None Celgene None None 10/7/11
Corporation
Gordana Vlahovic, MD None None None None 4/18/11
Alva B. Weir III, MD None None None None 3/12/12
The NCCN guidelines staff have no conflicts to disclose.

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NCCN Richard S. Stein, MD; Gordana Vlahovic, MD; and

Abstract Please Note

Clinical trials: NCCN believes that the best management for

Journal of the National Comprehensive Cancer Network Cancer- and Chemotherapy-

ize the evaluation and treatment of anemia in adult Etiology

NCCN Cancer- and Chemotherapy-Induced

Cancer- and Chemotherapy-Induced Anemia Version 2:2012

HEMOGLOBIN EVALUATION OF ANEMIA a,b

See NCCN Clinical Practice Guidelines in Oncology

Treat underlying disease per NCCN Guideline

a These guidelines were formulated in reference to adult patients.

Cancer- and Chemotherapy-Induced Anemia Version 2:2012

RISK ASSESSMENT AND INDICATIONS FOR INITIAL TRANSFUSION IN ACUTE SETTING

Asymptomatic without significant comorbidities d Observe Periodic reevaluation

Asymptomatic with comorbidities d or high risk

See Comparison of Risks and Benefits of ESA Use

See Special Categories in Considering ESA Use (page 633)

Cancer- and Chemotherapy-Induced Anemia Version 2:2012

ESA in the Cancer Setting Red Blood Cell Transfusion

Risks • Increased thrombotic events • Transfusion reactions (e.g., hemolytic,

Benefits • Transfusion avoidance • Rapid increase of hemoglobin and

Cancer- and Chemotherapy-Induced Anemia Version 2:2012

SPECIAL CATEGORIES IN CONSIDERING ESA USE

Consider red blood cell transfusion per guidelines

Cancer- and Chemotherapy-Induced Anemia Version 2:2012

MANAGEMENT OF FUNCTIONAL IRON DEFICIENCY IN PATIENTS RECEIVING ESAS

Functional iron deficiency

No iron deficiency (ferritin

See Parenteral Iron Preparations (pages 640 and 641)

Cancer- and Chemotherapy-Induced Anemia Version 2:2012

INDICATIONS FOR RED BLOOD CELL TRANSFUSION IN CANCER PATIENTS

Goal: Prevent or treat deficit of oxygen-carrying capacity

Anemia in setting of acute coronary syndromes or acute myocardial infarction:

Cancer- and Chemotherapy-Induced Anemia Version 2:2012

ERYTHROPOIETIC THERAPY - DOSING AND TITRATION 1-4

INITIAL DOSING TITRATION FOR NO RESPONSE TITRATION FOR RESPONSE

PACKAGE INSERT DOSING SCHEDULE • The dose should be adjusted for

Darbepoetin alfa, 500 mcg every 3 wk by subcutaneous injection

Epoetin alfa, 80,000 units every 2 wk by subcutaneous injection 8

Cancer- and Chemotherapy-Induced Anemia Version 2:2012

ERYTHROPOIETIC THERAPY - ADVERSE EFFECTS

Cancer- and Chemotherapy-Induced Anemia Version 2:2012

ERYTHROPOIETIC THERAPY - ADVERSE EFFECTS

ADVERSE EFFECTS REFERENCES

Cancer- and Chemotherapy-Induced Anemia Version 2:2012

1 Adapted from: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200297.htm

Cancer- and Chemotherapy-Induced Anemia Version 2:2012

PARENTERAL IRON PREPARATIONS 1-6

• Parenteral iron preparations studied in cancer patients:

Iron Dextran † Ferric Gluconate † Iron Sucrose †

Required MD discretion MD discretion

Test dose 25 mg slow IV push and 25 mg slow IV push or 25 mg slow IV push

See References (facing page)

Cancer- and Chemotherapy-Induced Anemia Version 2:2012

PARENTERAL IRON PREPARATIONS

Cancer- and Chemotherapy-Induced Anemia

Cancer- and Chemotherapy-Induced Anemia

Cancer- and Chemotherapy-Induced Anemia

patient with cancer, the effects of cancer-related RBC Transfusion

Cancer- and Chemotherapy-Induced Anemia

of venous thromboembolism (VTE; odds ratio [OR], Erythropoietic Therapy

Cancer- and Chemotherapy-Induced Anemia