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NCCN Clinical Practice Guidelines in Oncology™
Cancer- and
Chemotherapy-
Induced Anemia
V.2.2010
www.nccn.org
Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2010
Guidelines Index
Anemia Table of Contents
Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN
®
NCCN Cancer- and Chemotherapy-Induced Anemia Panel Members
George M. Rodgers, III, MD, PhD/Chair
Huntsman Cancer Institute at the
University of Utah
Pamela Sue Becker, MD, PhD
Fred Hutchinson Cancer Research
Center/Seattle Cancer Care Alliance
Charles L. Bennett, MD, PhD, MPP
Robert H. Lurie Comprehensive Cancer
Center of Northwestern University
Peter F. Coccia, MD
UNMC Eppley Cancer Center at The
Nebraska Medical Center
‡
‡ Þ
‡
†
‡
David Cella, PhD
Robert H. Lurie Comprehensive Cancer
Center of Northwestern University
Asher Chanan-Khan, MD
Roswell Park Cancer Institute
Charles Cleeland, PhD
The University of Texas M. D. Anderson
Cancer Center
�
�
€
Joseph Rosenthal, MD
City of Hope
‡
‡
‡
†
‡
€
Comprehensive Cancer
Center
Rowena N. Schwartz, PharmD
The Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
Richard S. Stein, MD
Vanderbilt-Ingram Cancer Center
Ravi Vij, MD
Siteman Cancer Center at Barnes-
Jewish Hospital and Washington
University School of Medicine
Gordana Vlahovic, MD
Duke Comprehensive Cancer Center
Alva B. Weir III, MD
St. Jude Children's Research
Hospital/University of Tennessee
Cancer Institute
б
�
*
‡ Hematology/Hematology oncology
† Medical oncology
Bone marrow transplantation
Þ Internal medicine
# Nursing
Pharmacotherapy
� Psychiatry/Psychology
€ Pediatric oncology
* Writing Committee Member
�
б
Benjamin Djulbegovic, MD, PhD
H. Lee Moffitt Cancer Center & Research
Institute
Jeffrey A. Gilreath, PharmD
Huntsman Cancer Institute at the
University of Utah
Eric H. Kraut, MD
Weei-Chin Lin, MD, PhD
University of Alabama at Birmingham
Comprehensive Cancer Center
Ursula Matulonis, MD
Dana-Farber/Brigham and Women’s
Cancer Center
Michael Millenson, MD
Fox Chase Cancer Center
Denise Reinke, APRN, BC, AOCN #
University of Michigan Comprehensive
Cancer Center
† ‡
‡
† ‡
†
‡ Þ
�
б
The Ohio State University Comprehensive
Cancer Center - James Cancer Hospital
and Solove Research Institute
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*
NCCN Guidelines Panel Disclosures
Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2010
Guidelines Index
Anemia Table of Contents
Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN
®
Table of Contents
NCCN Cancer- and Chemotherapy-Induced Anemia Panel Members
Guidelines Index
Print the Anemia Guideline
Summary of the Guidelines Updates
Screening Evaluation and Risk Assessment (ANEM-1
Cancer-Related Anemia (Non-Treatment Related) (ANEM-2
Symptomatic Treatment and Evaluation (ANEM-6
Comparison of Risks and Benefits of ESA Use Versus Red Blood
Cell Transfusion
� )
)
)
�
�
�
�
Myelosuppressive Chemotherapy-Induced Anemia (ANEM-3
Symptom Assessment (ANEM-3
Evaluation for Symptomatic Anemia Risk (ANEM-4
)
)
)
�
�
�
Asymptomatic Treatment and Evaluation (ANEM-5
Response Assessment (ANEM-7
)
)
Erythropoietic Therapy - Dosing and Titration (ANEM-A
(ANEM-B
Parenteral Iron Preparations (ANEM-C
)
)
)
These guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical
circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no representations or warranties
of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. These guidelines are
copyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in
any form without the express written permission of NCCN. ©2009
For help using these
documents, please click here
Discussion
References
Clinical Trials:
Categories of Evidence and
Consensus:
NCCN
The
believes that the best management
for any cancer patient is in a clinical
trial. Participation in clinical trials is
especially encouraged.
To find clinical trials online at NCCN
member institutions,
All recommendations
are Category 2A unless otherwise
specified.
See
NCCN
click here:
nccn.org/clinical_trials/physician.html
NCCN Categories of Evidence
and Consensus
Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2010
Guidelines Index
Anemia Table of Contents
Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN
®
UPDATES
Summary of the Guidelines Updates
ANEM-3
ANEM-5
ANEM-6
ANEM-A 3 of 5
ANEM-B 1 of 2
ANEM-C 2 of 3
�
�
�
For cancer treatment goals, “curative” was clarified as “chemotherapy
with curative intent” and “non-curative” was clarified as “chemotherapy
with non-curative intent”.
The following footnotes were added to the page.
Footnote ‘f’:
Footnote ‘j’:
“Recommendations for administering parenteral iron products” table
was revised:
For all preparations, the following statement was added, “Examples
of adverse events associated with FDA approved doses of parenteral
iron preparations include: hypotension, hypertension, nausea,
vomiting, diarrhea, pain, fever, dyspnea, pruritis, headaches, and
dizziness.”
Iron dextran, dosage was clarified as “Total dose infusion given over
several hours” and a corresponding statement “Dose = 0.0442
(Desired Hgb - Observed Hgb) X LBW + (0.26X LBW ) LBW = Lean
Body Weight. If dose exceeds 1000 mg, remaining dose may be given
after 4 wks if inadequate hemoglobin response” was added.
Ferric gluconate, dose was clarified as “Maximum dose = 250 mg per
infusion”
Iron sucrose, dose was clarified as “Maximum dose =
300-400 mg per infusion”
�
�
�
�
�
�
An example of therapy with curative intent includes
adjuvant chemotherapy.
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.
For asymptomatic, risk factors present for development of symptomatic
anemia: treatment recommendation for “no iron deficiency” was added.
For absolute iron deficiency, “after 4 weeks” was added to “hemoglobin
increases” and “hemoglobin does not increase”.
For functional iron deficiency, ferritin level was changed from
“< 300 ng/mL” to “ ” and “ IV iron
supplementation” was added to the “erythropoietic therapy” option.
Symptomatic, a statement “Ensure iron studies (iron panel- serum iron,
total iron binding capacity, serum ferritin) do not indicate absolute iron
deficiency” was added to “consider erythropoietic therapy” treatment
option for clarification.
Cancer Patient Survival
Bullet 1 was modified by adding, “One analysis in patients with
cancer not receiving active therapy found decreased survival in ESA
treated patients.”
Bullet 2, two new references of meta-analysis on survival confirming
an increased mortality risk with the use of ESAs were added.
Risks of the use of ESA in the cancer setting: “increased” was added to
“thrombotic events”.
Benefits of the use of ESA in the cancer setting: “avoidance of red
blood cell transfusion” was modified as “transfusion avoidance”
Risks of the use of red blood cell transfusion: “febrile and non-
hemolytic” were added as examples of transfusion reactions.
�
�
�
�
�
�
�
�
� 800 ng/mL Consider
�
�
Changes in the 1.2010 version of the Cancer- and Chemotherapy-Induced Anemia Guidelines from the 3.2009 version include:
Changes in the 2.2010 version of the Cancer- and Chemotherapy-Induced Anemia Guidelines from the 1.2010 version include:
ANEM-3
� Footnote ‘g’ was revised as follows: “For patients receiving chemotherapy for breast, advanced head and neck, lymphoid, non-small cell lung, and
cervical cancers with non-curative intent, ESAs should
”
be used with caution. Some studies have demonstrated an increase in mortality for patients
with these tumor types who are treated with ESAs. See manuscript (MS-6) for detailed discussion and references.
Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2010
Guidelines Index
Anemia Table of Contents
Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN
®
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
aThe NCCN Cancer- and Chemotherapy-Induced Anemia Guidelines were formulated in reference to adult patients.
b
c
d
Transplant-related anemia is not included.
The following studies should have been completed if clinically indicated: reticulocyte count, iron studies, B12/folate, stool guaiac, LDH, fractionated bilirubin, bone
marrow examination, direct Coombs test, Hb electrophoresis, creatinine and/or creatinine clearance. There is no clear evidence that erythropoietin levels are
predictive of response.
Objective physical symptoms may include peripheral edema, sustained tachycardia, and tachypnea and other subjective physical symptoms may include chest pain,
dyspnea on exertion, orthostatic lightheadedness/near syncope or syncope, and fatigue.
PRESENTATIONa,b
Hemoglobin
(Hb) < 11 g/dL
Myelosuppressive
chemotherapy-induced
anemia
Anemia related to
other causes:
�
�
�
�
�
�
�
Bleeding
Hemolysis
Nutritional deficiency
Hereditary
Renal dysfunction
Iron deficiency
Radiation therapy
alone
Treat as
indicated
�
�
CBC with indices
Review of
peripheral smear,
as clinically
indicated
SCREENING EVALUATIONc
ANEM-1
Cancer-related
anemia (non-
treatment related)
See ANEM-2
RISK ASSESSMENT
�
�
�
�
Acuity
Severity
Mild
(Hb 10-11 g/dL)
Moderate
(Hb 8-10 g/dL)
Severe
(Hb < 8 g/dL)
Symptoms-physiological
Cardiac symptoms
Pulmonary symptoms
Comorbidities
Cardiac history/decompensation
Chronic pulmonary disease
Cerebral vascular disease
�
�
�
�
�
�
�
�
d
See Symptom
Assessment
(ANEM-3)
Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2010
Guidelines Index
Anemia Table of Contents
Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN
®
Inadequate data to make
recommendations:
encourage enrollment
in clinical trials
Cancer-related
anemiae (non-
treatment
related) Myelodysplastic
syndromes
See NCCN Myelodysplastic
Syndromes Guidelines
Solid tumors
Hematologic
malignancies
�
�
�
Treat underlying disease per NCCN guideline
Transfuse as indicated based upon symptoms
and institutional or published guidelines
Erythropoiesis-stimulating agents (ESAs) are
not indicated
See NCCN Guidelines Table of Contents
�
�
Treat underlying
hematologic malignancy
per NCCN guideline
Transfuse as indicated
based upon symptoms
and institutional or
published guidelines
See
NCCN Guidelines Table
of Contents
For patients with good
prognosis and
persistent transfusion-
dependent anemia
following response to
treatment
Anemia corrected Observe
Other
hematologic
malignancies
ePatients with terminal cancer who are not receiving chemotherapy should not be treated with ESAs. (See manuscript for detailed discussion and references.)
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
ANEM-2
TREATMENT
CANCER-RELATED ANEMIA (NON-TREATMENT RELATED)
CANCER TYPE
Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2010
Guidelines Index
Anemia Table of Contents
Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN
®
f
j
An example of therapy with curative intent includes adjuvant chemotherapy.
.
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.
gFor patients receiving chemotherapy for breast, advanced head and neck, lymphoid, non-small cell lung, and cervical cancers with non-curative intent, ESAs
should be used with caution. Some studies have demonstrated an increase in mortality for patients with these tumor types who are treated with ESAs. See
manuscript ( ) for detailed discussion and references.
h
iOther anemia-related symptoms include: decreased activity level, and decreased performance status.
MS-6
See Comparison of Risks and Benefits of ESA Use Versus Red Blood Cell Transfusion (ANEM-B)
ANEM-3
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Immediate
correction
not required
Immediate
correction
required
Transfuse as indicated
based on institutional
or published guidelines
Complete symptom
assessment:
Peripheral edema
Sustained tachycardia
Tachypnea
Other subjective physical
symptoms may include:
Chest pain
Dyspnea on exertion
Orthostatic
lightheadedness/near
syncope or syncope
Fatigue
i
�
�
Objective physical
symptoms may include:
�
�
�
�
�
�
�
j
SYMPTOM ASSESSMENT
Symptomatic
Asymptomatic
MYELOSUPPRESSIVE CHEMOTHERAPY-INDUCED ANEMIA
Cancer
treatment
goals
Chemotherapy
with curative
intentf
Chemotherapy
with non-
curative intentg
ESAs are not indicated
Risk/benefit ratio should
be carefully assessed on
an individual basis;
ESAs may be appropriate
based on a thorough
risk/benefit discussion
and patient preference
h
See
Treatment
(ANEM-6)
See
Evaluation
for
Symptomatic
Anemia Risk
(ANEM-4)
NCCN
®
Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2010
Guidelines Index
Anemia Table of Contents
Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN
®
Asymptomatic
EVALUATION FOR SYMPTOMATIC ANEMIA RISK AMONG CANCER PATIENTS
RECEIVING MYELOSUPPRESSIVE CHEMOTHERAPY WITHOUT CURATIVE INTENT
Evaluate risk factors for developing symptomatic anemia:
History of prior myelosuppressive therapy (eg, bone
marrow transplant)
History of radiotherapy > 20% of skeleton
Myelosuppression potential of current therapy
Schedule
Agents
Hemoglobin level
�
�
�
�
�
�
Transfusion in past 6 mo
Duration
Comorbidities
Cardiac history/decompensation
Chronic pulmonary disease
Cerebral vascular disease
�
�
�
�
�
�
Risk factors
present
Risk factors
not present
See Treatment
(ANEM-5)
See Treatment
(ANEM-5)
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
ANEM-4
Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Practice Guidelines
in Oncology – v.2.2010
Guidelines Index
Anemia Table of Contents
Discussion, ReferencesCancer- and Chemotherapy-Induced AnemiaNCCN
®
TREATMENT
Asymptomatic;
Risk factors
present for
development
of symptomatic
anemia
Asymptomatic;
Risk factors
not present for
symptomatic
anemia
development of
Observation
or
Iron studies:
Iron panel (serum
iron, total iron
binding capacity,
serum ferritin)
Observation
ADDITIONAL EVALUATION
Periodic re-evaluation
for symptoms and risk
factors
TREATMENT REGIMEN
See
Response
Assessment
ANEM-7( )
Absolute iron deficiency
(ferritin < 30 ng/mL and
< 15%)transferrin saturation
Functional iron deficiency
f 800( erritin ng/mL and
transferrin saturation < 20%)
�
IV or oral iron
supplementationm
Hemoglobin
increases
after 4 wks
Hemoglobin does
not increase after
4 wks
Observation
See Functional iron
deficiency pathway below
e
h
Patients with terminal cancer who are not receiving chemotherapy should not be treated with ESAs. (See manuscript for detailed discussion and references.)
considering use of ESAs, evaluate the risk factors for
thrombosis: history of thromboembolism, heritable mutation, hypercoagulability, elevated pre-chemotherapy platelet counts, hypertension, steroids, prolonged
immobilization, recent surgery, certain therapies for multiple myeloma, hormonal agents, etc. ( )
IV iron appears to have superior efficacy and should be considered for supplementatio
See manuscript for detailed discussion and references.) .
Five randomized trials which evaluated IV iron with the use of ESA included patients with serum ferritin values ranging from 100 ng/mL to 900 ng/mL.
(See manuscript for references.)
.
Patients with previous risk factors for thrombosis may be at higher risk for thrombosis with the use of ESAs. Ifk
n
l
m n. Oral iron has been more commonly used but is less effective.
(
� �
See Comparison of Risks and Benefits of ESA Use Versus Red Blood Cell Transfusion (ANEM-B
See NCCN Venous Thromboembolic Disease Guidelines
See Parenteral Iron Preparations (ANEM-C
)
)
See Adverse Effects of Erythropoietic Therapy (ANEM-A 3 of 5).
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Periodic re-
evaluation for
symptoms and
risk factors
ANEM-5
CANCER PATIENTS RECEIVING MYELOSUPPRESSIVE CHEMOTHERAPY WITHOUT CURATIVE INTENT
Consider IV iron supplementationm,n
h
+
erythropoietic therapye,k,l
after patient counseling
regarding risks and benefits of ESAs
See
Erythropoietic Therapy - Dosing and
Titration (ANEM-A)
No iron deficiency f( erritin
> 800 ng/mL or transferrin
saturation 20%)�
IV or oral iron
supplementation
is not needed
Consider erythropoietic therapye,k,l
after patient counseling
regarding risks and benefits of ESAsh
See
Erythropoietic Therapy - Dosing and
Titration (ANEM-A)
Version 2.2010, 08/17/09 © 2009 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of N