Chemotherapy and Biotherapy Guidelines

FOURTH EDITION
Chemotherapy
and Biotherapy
Guidelines
AND RECOMMENDATIONS
FOR PRACTICE
Edited by
Martha Polovich, PhD, RN, AOCN
MiKaela Olsen, MS, RN, AOCNS
Kristine B. LeFebvre, MSN, RN, AOCN
FOURTH EDITION
Chemotherapy and
Biotherapy Guidelines
and Recommendations
for Practice
Edited by
Oncology Nursing Society

Pittsburgh, Pennsylvania
ONS Publications Department

Executive Director, Professional Practice and Programs and Publisher:
Elizabeth Wertz Evans, PhD, RN, MPM, CPHQ, CPHIMS, FHIMSS, FACMPE
Director of Publications: Bill Tony, BA, CQIA
Managing Editor: Lisa M. George, BA
Technical Content Editor: Angela D. Klimaszewski, RN, MSN
Staff Editor II: Amy Nicoletti, BA
Copy Editor: Laura Pinchot, BA
Graphic Designer: Dany Sjoen
Editorial Assistant: Judy Holmes
Copyright 2014 by the Oncology Nursing Society. All rights reserved. No part of the material protected by this copyright may be reproduced or utilized in any form, electronic or mechanical, including photocopying, recording, or by an information storage and retrieval system,
without written permission from the copyright owner. For information, write to the Oncology Nursing Society, 125 Enterprise Drive, Pittsburgh,
PA 15275-1214, or visit www.ons.org/practice-resources/permissions-reprints.
Cover image of cisplatin crystals courtesy of NCI Visuals Online, Larry Ostby, photographer.
Library of Congress Cataloging-in-Publication Data
Chemotherapy and biotherapy guidelines and recommendations for practice. -- Fourth edition / edited by Martha Polovich, MiKaela Olsen, Kristine B. LeFebvre.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-935864-33-2
ISBN 978-1-935864-49-3 (E-Book)
I. Polovich, Martha, editor of compilation. II. Olsen, MiKaela M., editor of compilation. III. LeFebvre, Kristine B., editor of compilation. IV. Oncology Nursing Society, issuing body.
[DNLM: 1. Neoplasms--drug therapy--Outlines. 2. Neoplasms--drug therapy--Practice Guideline. 3. Antineoplastic Agents--administration & dosage--Outlines. 4. Antineoplastic Agents--administration & dosage--Practice Guideline. 5. Biological Agents--therapeutic use--Outlines. 6. Biological
Agents--therapeutic use--Practice Guideline. 7. Neoplasms--nursing--Outlines. 8. Neoplasms--nursing--Practice Guideline. QV 18.2]
RC266
616.9940231--dc23
2013039836
Publishers Note
This book is published by the Oncology Nursing Society (ONS). ONS neither represents nor guarantees that the practices described herein
will, if followed, ensure safe and effective patient care. The recommendations contained in this book reflect ONSs judgment regarding the
state of general knowledge and practice in the field as of the date of publication. The recommendations may not be appropriate for use in all
circumstances. Those who use this book should make their own determinations regarding specific safe and appropriate patient-care practices,
taking into account the personnel, equipment, and practices available at the hospital or other facility at which they are located. The editors
and publisher cannot be held responsible for any liability incurred as a consequence from the use or application of any of the contents of this
book. Figures and tables are used as examples only. They are not meant to be all-inclusive, nor do they represent endorsement of any particular
institution by ONS. Mention of specific products and opinions related to those products do not indicate or imply endorsement by ONS. Websites
mentioned are provided for information only; the hosts are responsible for their own content and availability. Unless otherwise indicated, dollar
amounts reflect U.S. dollars.
ONS publications are originally published in English. Publishers wishing to translate ONS publications must contact ONS about licensing
arrangements. ONS publications cannot be translated without obtaining written permission from ONS. (Individual tables and figures that are
reprinted or adapted require additional permission from the original source.) Because translations from English may not always be accurate or
precise, ONS disclaims any responsibility for inaccuracies in words or meaning that may occur as a result of the translation. Readers relying on
precise information should check the original English version.
Printed in the United States of America
Integrity Innovation Stewardship Advocacy Excellence Inclusiveness
Contributors
Editors
Oncology Nurse Consultant
Atlanta, Georgia
Chapter 5. Nursing Considerations in Cancer
Treatment; Chapter 8. Infusion-Related Complications
Oncology and Hematology Clinical Nurse Specialist
Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins Hospital
Baltimore, Maryland
Chapter 9. Side Effects of Cancer Therapy

Nurse Planner and Project Manager, Education
Department
Chapter 1. Overview of Cancer and Cancer
Treatment; Chapter 2. Drug Development and
Clinical Trials; Chapter 11. Competence in Chemotherapy Administration
Authors
Carol Stein Blecher, RN, MS, AOCN, APNC,
CBPN-C, CBCN
Advanced Practice Nurse/Clinical Educator
Trinitas Comprehensive Cancer Center
Elizabeth, New Jersey
Chapter 7. Pretreatment Care
Paul F. Davis, MSN, RN
Fourth Floor Manager
Duke Raleigh Hospital
Raleigh, North Carolina
Tracy T. Douglas, RN, MSN
BMT Nurse Manager
Baltimore, Maryland
Cheryl D. Gilbert, RN, MSN, OCN, CBPN-IC
Nurse Navigator
Mercy Womens Center
Oklahoma City, Oklahoma
Catherine E. Jansen, PhD, RN, AOCNS

Oncology Clinical Nurse Specialist
Kaiser Permanente Medical Center
San Francisco, California
Anne Katz, PhD, RN
Clinical Nurse Specialist and Sexuality Counselor
CancerCare Manitoba
Manitoba, Canada
Editor, Oncology Nursing Forum
Alice S. Kerber, MN, APRN, ACNS-BC,
AOCN, APNG
Georgia Center for Oncology Research and
Education
Atlanta, Georgia
Chapter 5. Nursing Considerations in Cancer
Treatment
iii
Copyright 2014 by the Oncology Nursing Society. All rights reserved.
iv
Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (Fourth Edition)
Stephanie Shields, PharmD
Clinical Specialist
McKesson Specialty Health
San Francisco, California
Chapter 3. Principles of Antineoplastic Therapy
Denise Menonna-Quinn, RN-BC, MSN,

AOCNS
Nurse Transplant Insurance Coordinator/
Educator
John Theurer Cancer Center at Hackensack
University Medical Center
Hackensack, New Jersey
Chapter 6. Administration Considerations
Paula M. Muehlbauer, RN, MSN, AOCNS
Clinical Nurse Specialist/Academic Educator
Veterans Affairs San Diego Healthcare System
San Diego, California
Chapter 3. Principles of Antineoplastic Therapy;
Chapter 4. Principles of Biotherapy
Carolene B. Robinson, MA, RN, CNS, CBCN,
AOCN
UnityPoint HealthTrinity
Moline, Illinois
Barbara Barnes Rogers, CRNP, MN, AOCN,
ANP-BC
Adult Hematology-Oncology Nurse Practitioner
Fox Chase Cancer Center
Philadelphia, Pennsylvania
Lisa Schulmeister, MN, RN, ACNS-BC, OCN,
FAAN
Oncology Nursing Consultant
New Orleans, Louisiana
Chapter 8. Infusion-Related Complications
Nonniekaye Shelburne, CRNP, MS, AOCN
Program Director
National Cancer Institute
Bethesda, Maryland
Chapter 3. Principles of Antineoplastic Therapy;
Brenda K. Shelton, MS, RN, CCRN, AOCN
Clinical Nurse Specialist
Baltimore, Maryland
Janice L. Skinner, RN, MS, MSN, CRNP

Nurse Practitioner
Transplant and Oncology Infectious Diseases
Johns Hopkins School of Medicine
Baltimore, Maryland
Michael Smart, RN, BSN, OCN
Oncology Nurse Educator, Charge Nurse
Huntsville Hospital
Huntsville, Alabama
Michael Steinberg, PharmD, BCOP
Associate Professor of Pharmacy Practice
Massachusetts College of Pharmacy and
Health Sciences University
Worcester, Massachusetts
Wendy Stiver, RN, CCM, BSN, MA
Clinical Assessment NurseCase Manager
Alere Health
Atlanta, Georgia
Chapter 1. Overview of Cancer and Cancer
Treatment
Barbara J. Wilson, MS, RN, AOCN, ACNSBC
Director, Oncology Professional Practice
WellStar Kennestone Regional Medical Center
Marietta, Georgia
Laura J. Zitella, MS, RN, ACNP-BC, AOCN
Lead Advanced Practice Provider, Hematology
and Oncology Nurse Practitioner
Stanford University Medical Center
Stanford, California
Chapter 10. Post-Treatment Care
Field Reviewers
Jill Benedeck, BSN, RN, OCN
Oncology Nurse Educator
Centegra Health System
McHenry, Illinois
James Breedon, RN, BSN, OCN, REMT-P
Nurse Educator
Dendreon Corporation
Albuquerque, New Mexico
Amy S. Coghill, MSN, RN, OCN, CNL

Instructional Designer
Health Care Information Services Division
University of North Carolina Health Care System
Chapel Hill, North Carolina
S. Gayle Marble, BSN, RN, OCN
Director, Oncology Service Line Clinical Education
Banner Health Clinical Education
Phoenix, Arizona
Contributors
Disclosure
Editors and authors of books and guidelines provided by the Oncology Nursing Society are expected to disclose to the readers any significant financial interest or other relationships with the
manufacturer(s) of any commercial products.
A vested interest may be considered to exist if a contributor is affiliated with or has a financial interest in commercial organizations that may have a direct or indirect interest in the subject matter.
A financial interest may include, but is not limited to, being a shareholder in the organization; being an employee of the commercial organization; serving on an organizations speakers bureau; or
receiving research from the organization. An affiliation may be holding a position on an advisory
board or some other role of benefit to the commercial organization. Vested interest statements appear in the front matter for each publication.
Contributors are expected to disclose any unlabeled or investigational use of products discussed
in their content. This information is acknowledged solely for the information of the readers.
The contributors provided the following disclosure and vested interest information:
Martha Polovich, PhD, RN, AOCN: BD, ICU Medical, honoraria
Kristine B. LeFebvre, MSN, RN, AOCN: American Nurses Credentialing Center, employment or
leadership position
Alice S. Kerber, MN, APRN, ACNS-BC, AOCN, APNG: Pfizer, honoraria
Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BC: Millennium, Seattle Genetics, Teva, honoraria
Lisa Schulmeister, MN, RN, ACNS-BC, OCN, FAAN: American Society of Clinical Oncology QCP
Program, Intellisphere, consultant
Barbara J. Wilson, MS, RN, AOCN, ACNS-BC: Amgen, honoraria
Table of Contents
Preface........................................................................................................ ix
Abbreviations Used.......................................................................................... xi
Chapter 1. Overview of Cancer and Cancer Treatment..................................................1
A. Definition of cancer...................................................................................................................1
B. Cancer grading and staging......................................................................................................2
C. Cancer treatment modalities ....................................................................................................3
D. Treatment approaches..............................................................................................................5
E. Treatment strategies.................................................................................................................6
F. Goals of cancer therapy: Treatment planning includes discussion with patients about their goals
of therapy and whether those goals are realistic (Skeel, 2011b)...............................................7
G. Measuring response.................................................................................................................7
H. Factors affecting treatment response .....................................................................................10
References.....................................................................................................................................13
Chapter 2. Drug Development and Clinical Trials..................................................... 17
A. Development of new cytotoxic and other therapeutic agents..................................................17
B. Clinical trials involving humans..............................................................................................17
C. Expedited approval..................................................................................................................23
References.....................................................................................................................................23
Chapter 3. Principles of Antineoplastic Therapy....................................................... 25
A. Life cycle of cells....................................................................................................................25
B. Chemotherapeutic agents.......................................................................................................25
References.....................................................................................................................................48
Chapter 4. Principles of Biotherapy...................................................................... 51
A. Immunology...........................................................................................................................51
B. Types of immune response ....................................................................................................51
C. Cells of the immune system....................................................................................................54
D. Tumor escape mechanisms....................................................................................................55
E. Overview of biologic therapies................................................................................................56
F. Categories of biotherapy ........................................................................................................56
G. Radioimmunotherapy.............................................................................................................58
H. Therapeutic uses for biotherapeutic agents............................................................................60
I. Supportive uses for biotherapeutic agents..............................................................................60
J. Biotherapeutic strategies........................................................................................................60
K. Angiogenesis and antiangiogenic agents................................................................................93
References.....................................................................................................................................94
Chapter 5. Nursing Considerations in Cancer Treatment............................................. 97
A. Ethical issues..........................................................................................................................97
B. Legal issues related to cancer therapy....................................................................................99
C. Safety standards for antineoplastic administration...............................................................100
D. Patient safety........................................................................................................................100
E. Safe handling and disposal of hazardous drugs....................................................................102
References...................................................................................................................................115
vii
viii
Chapter 6. Administration Considerations.............................................................121
A. Routes of administration.......................................................................................................121
B. Adherence to therapy............................................................................................................129
C. Pretreatment nursing assessment........................................................................................130
References...................................................................................................................................133
Chapter 7. Pretreatment Care............................................................................137
A. Patient education..................................................................................................................137
B. Verification and maintenance of treatment as planned..........................................................139
References...................................................................................................................................151
Chapter 8. Infusion-Related Complications...........................................................155
A. Types of infusion complications............................................................................................155
B. Extravasation........................................................................................................................155
C. Irritation................................................................................................................................161
D. Flare reaction........................................................................................................................163
E. Acute infusion reactions.......................................................................................................163
F. Patient and caregiver education ...........................................................................................167
References...................................................................................................................................168
Chapter 9. Side Effects of Cancer Therapy.............................................................171
A. Myelosuppression.................................................................................................................171
B. Gastrointestinal and mucosal side effects.............................................................................190
C. Cutaneous toxicity................................................................................................................231
D. Alopecia ...............................................................................................................................250
E. Cardiovascular toxicity..........................................................................................................255
F. Pulmonary toxicity ...............................................................................................................287
G. Hemorrhagic cystitis.............................................................................................................318
H. Hepatotoxicity.......................................................................................................................321
I. Nephrotoxicity.......................................................................................................................329
J. Neurotoxicity.........................................................................................................................337
K. Cognitive impairment............................................................................................................347
L. Ocular toxicity.......................................................................................................................365
M. Pancreatitis...........................................................................................................................375
N. Fatigue..................................................................................................................................377
O. Alterations in sexuality..........................................................................................................383
P. Reproductive alterations.......................................................................................................388
References...................................................................................................................................391
Chapter 10. Post-Treatment Care .......................................................................437
A. Overview...............................................................................................................................437
B. Survivorship care .................................................................................................................437
C. Late effects of cancer treatment............................................................................................438
D. Types of late effects..............................................................................................................440
E. Risk of late effects for patients with select primary cancers.................................................451
F. Collaborative management ...................................................................................................454
G. Nursing assessment ............................................................................................................455
H. Preventive screening recommendations and follow-up care.................................................455
I. Patient and family education ................................................................................................456
J. Professional education..........................................................................................................456
References...................................................................................................................................457
Chapter 11. Competence in Chemotherapy Administration.........................................461
A. Professional education..........................................................................................................461
B. Policies and procedures........................................................................................................463
C. Sample documentation tools................................................................................................463
References...................................................................................................................................464
Appendices.................................................................................................465
Index.........................................................................................................473
Preface
Welcome to the fourth edition of the Oncology Nursing Societys (ONSs) Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. This book comes
more than 30 years after ONS published its first chemotherapy guidelines. Oncology
nursing practice related to pharmacologic cancer treatment has changed significantly over the years. Not only do more patients undergo drug treatment for cancer today compared to patients diagnosed a generation ago, but patients survival time has
increased, making them more likely to receive treatment over extended periods of
time. The need for evidence-based guidelines for nurses administering chemotherapy and biotherapy is greater than ever.
This new edition incorporates a number of significant changes. The content has
been reorganized and is divided into 11 chapters, with references appearing at the
end of each chapter. We hope that this new way of organizing the material will make
it easier to locate information. The section related to nursing considerations now incorporates the American Society of Clinical Oncology/ONS Chemotherapy Administration Safety Standards (Neuss et al., 2013). All nurses who administer antineoplastic agents must familiarize themselves with and adapt their practices to conform to
these standards. Patient education content has been expanded to emphasize its importance to patient care. The cancer treatment section includes information about
sequencing of chemotherapy agents. The chapter on nursing management of treatment side effects has been updated to reflect existing evidence.
Patients expect nurses to possess the knowledge and skills to provide excellent
care. It is difficult for nurses caring for patients receiving chemotherapy, biotherapy,
and targeted agents to keep up with treatment-related information. These guidelines
are as current as possible with respect to approved drugs, standards of practice, and
available evidence. As always, oncology nurses are encouraged to update their knowledge on an ongoing basis.
The editors want to thank all the contributors to this edition and all the previous
editions of the guidelines. This work builds on the expertise of a whole generation
of chemo nurses. We are proud to be a part of this dedicated group of professionals. We hope these guidelines serve as an essential resource for practicing oncology
nurses today.
Neuss, M.N., Polovich, M., McNiff, K., Esper, P., Gilmore, T., LeFebvre, K.B., Jacobson, J. (2013).
2013 updated American Society of Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards including standards for the safe administration and management of oral chemotherapy. Oncology Nursing Forum, 40, 225233. doi:10.1188/13.ONF.40-03AP2
ix
Abbreviations Used
ACEangiotensin-converting enzyme
ADHantidiuretic hormone
AHRQAgency for Healthcare Research and
Quality
AJCCAmerican Joint Committee on Cancer
AKIacute kidney injury
AMLacute myeloid leukemia
ANCabsolute neutrophil count
APHONAssociation of Pediatric Hematology/
Oncology Nurses
APLacute promyelocytic leukemia
ARBangiotensin receptor blocker
ASCOAmerican Society of Clinical Oncology
ASHPAmerican Society of Health-System
Pharmacists
ATIacute tubular injury
ATRAall-trans-retinoic acid
AUCarea under the time-versus-concentration curve
BMTbone marrow transplantation
BSAbody surface area
BSCbiologic safety cabinet
BUNblood urea nitrogen
CACIcompounding aseptic containment isolator
CAMcomplementary and alternative medicine
CBCcomplete blood count
CDcluster of differentiation
CDCCenters for Disease Control and Prevention
CDKcyclin-dependent kinase
CHFcongestive heart failure
CIconfidence interval
CINchemotherapy-induced neutropenia
CINVchemotherapy-induced nausea and
vomiting
CKDchronic kidney disease
CMSCenters for Medicare and Medicaid Services
CNcranial nerve
CNScentral nervous system
COGChildrens Oncology Group
CrClcreatinine clearance
CSFcolony-stimulating factor
CSTDclosed-system transfer device
CTcomputed tomography
CTCAECommon Terminology Criteria for Adverse Events
CTEPCancer Therapy Evaluation Program
(NCI)
CTLA-4cytotoxic T-lymphocyte antigen 4
CTZchemoreceptor trigger zone
CVCcentral venous catheter
CVDcardiovascular disease
DHHSU.S. Department of Health and Human

Services
DICdisseminated intravascular coagulation
DLCOdiffusing capacity of the lung for carbon monoxide
DNAdeoxyribonucleic acid
ECGelectrocardiogram
ECMextracellular matrix
ECOGEastern Cooperative Oncology Group
EGFepidermal growth factor
EGFRepidermal growth factor receptor
EGFRIepidermal growth factor receptor inhibitor
18
F-FDGfluorine-18 fluorodeoxyglucose
EORTCEuropean Organization for Research
and Treatment of Cancer
EPOerythropoietin
ERestrogen receptor
ESAerythropoiesis-stimulating agent
estCrClestimated creatinine clearance
FDAU.S. Food and Drug Administration
5-FU5-fluorouracil
5-HT35-hydroxytryptamine-3 (serotonin)
Ggap phase (G0, G1, G2)
G-CSFgranulocytecolony-stimulating factor
GFRglomerular filtration rate
GIgastrointestinal
GM-CSFgranulocyte macrophagecolonystimulating factor
GVHDgraft-versus-host disease
Gygray (radiation unit)
Hhistamine (H1, H2)
HChemorrhagic cystitis
Hcthematocrit
HDhazardous drug
HEPAhigh-efficiency particulate air
HER2human epidermal growth factor receptor 2
Hgbhemoglobin
HIF-1hypoxia-inducible factor-1
HIVhuman immunodeficiency virus
HLHodgkin lymphoma
HPVhuman papillomavirus
HSChematopoietic stem cell
HSCThematopoietic stem cell transplantation
IARCInternational Agency for Research on
Cancer
ICinformed consent
IFNinterferon
IFRTinvolved-field radiation therapy
Igimmunoglobulin (IgA, IgD, IgE)
ILinterleukin
ILDinterstitial lung disease
IMintramuscular
xi
xii
INRinternational normalized ratio
IPintraperitoneal
IRBinstitutional review board
ITintrathecal
IVintravenous
KPSKarnofsky Performance Status
LFTliver function test
LLNlower limit of normal
LVEFleft ventricular ejection fraction
Mmitosis phase
mAbmonoclonal antibody
MASCCMultinational Association of Supportive Care in Cancer
mclmicroliter
MDAUniversity of Texas MD Anderson Cancer Center (classification system)
MDRmultidrug resistance
MDSmyelodysplastic syndrome
MHCmajor histocompatibility complex
MLLmixed lineage leukemia
MMPmatrix metalloproteinase
MOPPmechlorethamine, vincristine, procarbazine, and prednisone
MRImagnetic resonance imaging
mRNAmessenger ribonucleic acid
mTORmammalian target of rapamycin
MUGAmultigated acquisition
NCCNNational Comprehensive Cancer Network
NCINational Cancer Institute
NF-Bnuclear factor-B
NHLnon-Hodgkin lymphoma
NIHNational Institutes of Health
NIOSHNational Institute for Occupational
Safety and Health
NKnatural killer
NK1neurokinin-1
NKTnature killer T
NPnurse practitioner
NRCU.S. Nuclear Regulatory Commission
NSAIDnonsteroidal anti-inflammatory drug
n/vnausea and vomiting
OHRPOffice for Human Research Protections
ONSOncology Nursing Society
OSHAOccupational Safety and Health Administration
PABApara-aminobenzoic acid
PDE5phosphodiesterase-5
PECprimary engineering control

PEGpolyethylene glycol
PEPPutting Evidence Into Practice (ONS)
PERCISTPositron Emission Tomography Response Criteria in Solid Tumors
PETpositron-emission tomography
P-gpP-glycoprotein
PPEpersonal protective equipment
PRprogesterone receptor
PRESposterior reversible encephalopathy
syndrome
PTprothrombin time
PTTpartial thromboplastin time
QOLquality of life
RBCred blood cell
RDIrelative dose intensity
RECISTResponse Evaluation Criteria in Solid Tumors
RITradioimmunotherapy
RRrelative risk
RSOradiation safety officer
Ssynthesis phase
SCsubcutaneous
SCrserum creatinine
SDSsafety data sheet
SIADHsyndrome of inappropriate antidiuretic hormone
SMNsecond malignant neoplasm
TCcytotoxic T cell
TECtoxic erythema of chemotherapy
THhelper T cell (TH1, TH2)
TLStumor lysis syndrome
TMmemory T cell
TNFtumor necrosis factor
TNMtumor, node, metastasis
Tregregulatory T cell
TSsuppressor T cell
USPU.S. Pharmacopeial Convention
UVultraviolet (UVA, UVB)
VADvascular access device
VCvomiting center
VEGFvascular endothelial growth factor
VEGFRvascular endothelial growth factor receptor
VODveno-occlusive disease
VTEvenous thromboembolism
WBCwhite blood cell
WHOWorld Health Organization
Chapter 1
Overview of Cancer and

Cancer Treatment
A. Definition of cancer
1. Clinically, cancer is a large group of malignant diseases with some or all
of the following characteristics (Eggert, 2010; Merkle, 2011).
a) Abnormal cell proliferation caused by a series of cellular and/or genetic alterations or translocations
b) Lack of controlled growth and cell division that leads to the formation of tumors and invasion of tissues in proximity to tumor cells
c) Ability to spread (metastasize) to distant sites and establish secondary tumors
d) Ability to involve any tissue of the body
e) Evasion of natural cell death (apoptosis)
2. On the cellular and molecular levels, however, cancer is believed to be only
a few diseases (Eggert & Kasse, 2010) that result from faulty or abnormal
genetic expression caused by changes in deoxyribonucleic acid (DNA).
a) The transcription of DNA into a single strand of messenger ribonucleic acid (mRNA) may be changed.
b) When abnormal mRNA exists, the sequence of amino acids is changed,
resulting in abnormal protein synthesis.
3. Multiple factors often interact, leading to the development of cancer. Normal
cells may undergo changes outlined by Eggert and Kasse (2010) because of
a) Spontaneous transformation: No causative agent is identified, but cellular characteristics are typical of cancer cells.
b) Exposure to chemical or physical carcinogens: Environmental factors are continuously being studied. Chronic or occupational exposure to substances such as asbestos, benzene, radiation, tobacco, arsenic, nickel, and some chemotherapeutic agents is implicated in cancer development. The National Institute for Occupational Safety and
Health (NIOSH) and other organizations have identified more than
100 substances as carcinogens, with the listings continually evaluated
and revised (International Agency for Research on Cancer [IARC],
2013; National Toxicology Program, 2011; U.S. Department of Health
and Human Services [DHHS], 2012).
c) Genetic alterations: Mutations are permanent changes in the sequencing of DNA base pairs resulting in a cell with malignant properties.
Some mutations are of no concern, whereas others lead to tumor formation (Eggert & Kasse, 2010; Merkle, 2011).
(1) A small percentage of cancers are caused by mutations inherited between generations in germ cells (sperm and ova).
(2) Most cancers are sporadic and caused by a series of acquired
mutations over time.
d) Exposure to viruses: Genetic changes can occur to cells through viral infections. For example, the human papillomavirus (HPV) is the
primary cause of cervical cancer (Fair, 2011).
4. Figure 1 provides a summary of genetic changes that may result in tumor formation. The properties of transformed cells are changes in the
cytology, cell membrane, and growth and development.
Figure 1. Clonal Evolution in Cancer

Variant 1
Carcinogen
Normal
clone
First mutation
Variant 3
Variant 2
Selective growth
advantage of clone
with first mutation
Second mutation
Selective growth
advantage of clone
with first and second
mutations
Continuing
evolution of
variant
subpopulations
Third mutation
Specific genetic alterations in evolving tumors may range from gene mutations to major chromosomal aberrations. This figure illustrates
a carcinogen-induced genetic change in a progenitor normal cell (P), which produces a cell with selective growth advantage allowing
clonal expansion to begin. In this case, gene mutations produce variant cells. Because they are at a disadvantage metabolically or immunologically, most variant cells are nonviable. If one variant has a selective advantage, its progeny become the predominant subpopulation until another variant appears. The sequential selection of variant subpopulations in each tumor (T) differs because of genetic instability, which positively or negatively affects cell proliferation.
Note. From Biology of Cancer (p. 7), by C.J. Merkle in C.H. Yarbro, D. Wujcik, and B.H. Gobel (Eds.), Cancer Nursing: Principles and Practice (7th ed.),
2011, Burlington, MA: Jones and Bartlett. Copyright 2011 by Jones and Bartlett. Reprinted with permission.
B. Cancer grading and staging

1. Differentiation and grading: Cellular differentiation is based on how
closely tumor cells resemble normal cells in their structure and maturity. Differentiation is graded using the following scale.
a) GXgrade cannot be assessed
b) G1well differentiated (resembles the parent cell)
c) G2moderately well differentiated
d) G3poorly differentiated (bears little resemblance to the parent cell)
e) G4undifferentiated (impossible to tell which cell is the parent)
f) Cells are obtained by biopsy or surgical removal for microscopic examination by a pathologist. Cancer cells appear different from those
of the surrounding normal tissue. Tumor differentiation can vary over
time, and cells with several grades of differentiation can exist within a single tumor. Tumor grade is a prognostic indicator. The higher
the grade, the more aggressive the tumor (American Joint Committee on Cancer [AJCC], 2010; Vogel, 2011).
2. Staging: The purpose of staging is to verify the extent of the disease by
assessing the location and size of the primary tumor and determining
if it has spread to other tissues or organs. Staging assists in determining
prognosis, treatment planning, identification of suitable clinical trials,
and treatment response. Staging provides a common language with which
the healthcare team can communicate about a patients case. Staging criteria are unique for each type of cancer (AJCC, 2010; National Cancer
Institute [NCI], 2013).
a) AJCC (2010) describes three types of staging: clinical (based on physical examination, imaging, and biopsy), pathologic (based on information obtained during surgery), and restaging (completed upon
disease recurrence).
Chapter 1. Overview of Cancer and Cancer Treatment
b) The tumor, node, metastasis (TNM) staging system is maintained

jointly by AJCC and the Union for International Cancer Control. It
is used commonly with solid tumors and classifies cancers by the following three criteria. Additional information about cancer staging is
available online at www.cancerstaging.org (AJCC, 2010; Vogel, 2011).
(1) Ttumor (local involvement, invasion): The primary tumor
is measured to document its size and to determine the depth
of invasion.
(2) Nnode (nodal involvement): Lymph nodes in the area of the
primary tumor are examined for evidence of tumor cells. Lymph
node size, number, and location are documented.
(3) Mmetastasis: Studies are done to determine if the primary tumor has metastasized to a distant location.
c) Lymphomas, leukemias, and multiple myeloma are hematologic malignancies that are staged according to other systems. For example, the
Ann Arbor staging classification is used to stage Hodgkin lymphoma
(HL), and the International Staging System is used for multiple myeloma (Gospodarowicz, 2009; Tariman & Faiman, 2011; Vogel, 2011).
d) Childhood cancers may be staged by the TNM system or by criteria
from the Childrens Oncology Group (COG), which conducts clinical trials in pediatric oncology (NCI, 2013).
e) Some gynecologic cancers are staged using the International Federation of Gynecology and Obstetrics, or FIGO, system.
f) Prognostic information is provided by an increasing number of nonanatomic factors that may predict the effectiveness of specific therapies. Gender, overall health status, and specific biologic properties of
tumor cells are characteristics that may affect patient outcomes and
have been incorporated into some staging algorithms (AJCC, 2010).
C. Cancer treatment modalities
1. Table 1 summarizes the history of cancer therapy. A variety of modalities are used to treat cancer. Treatment may include one or more of the
following interventions.
Table 1. History of Cancer Therapy

Period
Events
Pre-20th century
1500s: Heavy metals are used systemically to treat cancers; however, their effectiveness is limited and their
toxicity is great (Burchenal, 1977).
1890s: William Coley, MD, develops and explores the use of Coley toxins, the first nonspecific immunostimulants used to treat cancer.
World War I
Sulfur-mustard gas is used for chemical warfare; servicemen who are exposed to nitrogen mustard experience bone marrow and lymphoid suppression (Gilman, 1963; Gilman & Philips, 1946).
World War II
Congress passes National Cancer Act in 1937, establishing the National Cancer Institute (NCI).
Alkylating agents are recognized for their antineoplastic effect (Gilman & Philips, 1946).
Thioguanine and mercaptopurine are developed (Guy & Ingram, 1996).
1946: NCI-identified cancer research areas include biology, chemotherapy, epidemiology, and pathology.
1948: Divisions within NCI and external institutions are identified to conduct research (Zubrod, 1984).
Folic acid antagonists are found to be effective against childhood acute leukemia (Farber et al., 1948).
Antitumor antibiotics are discovered.
1950s
1955: The National Chemotherapy Program, developed with Congressional funding, is founded to develop
and test new chemotherapy drugs.
1957: Interferon is discovered.
The Childrens Cancer Group, the first cooperative group dedicated to finding effective treatments for pediatric cancer, is formed.
(Continued on next page)
Table 1. History of Cancer Therapy (Continued)

Period
Events
1960s1970s
Development of platinum compounds begins.

Multidrug therapy improves remission rates without severe toxicity; mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), the first combination chemotherapy, is used and found to be curative against
Hodgkin disease (Noonan, 2007).
Clinical trials of bacillus Calmette-Gurin and Corynebacterium parvum, nonspecific immunostimulants, begin.
Chemotherapy is used with surgery and radiation as cancer treatment.
Development of hybridoma technology begins.
NCI starts its Biological Response Modifiers Program.
Tamoxifen is synthesized in 1962 and first used in 1969.
1970s
The National Cancer Act of 1971 provides funding for cancer research; NCI director is appointed by and reports to the president of the United States.
Doxorubicin phase I trials begin.
Adjuvant chemotherapy begins to be a common cancer treatment (Bonadonna et al., 1985; Fisher et al.,
1986).
1980s
Community Clinical Oncology Programs are developed in 1983 to contribute to NCI chemotherapy clinical trials.
Use of multimodal therapies increases (Eilber et al., 1984; Marcial et al., 1988).
Focus turns to symptom management to alleviate dose-limiting toxicities related to neutropenia, nausea and
vomiting, and cardiotoxicity.
Clinical trials for dexrazoxane (ICRF-187) as a cardioprotectant begin (Speyer et al., 1988).
New chemotherapeutic agents are available.
Scientists begin to investigate recombinant DNA technology.
Trials of monoclonal antibodies and cytokines begin.
Effector cells (lymphokine-activated killer cells and tumor-infiltrating lymphocytes) are grown ex vivo.
1986: U.S. Food and Drug Administration (FDA) approves interferon alfa.
1989: FDA approves erythropoietin.
1990s
New classifications of drugs (e.g., taxanes) are developed.

In clinical trials, paclitaxel is found to be effective against ovarian and breast cancers (Rowinsky et al., 1992).
FDA approves granulocytecolony-stimulating factor and granulocyte macrophagecolony-stimulating factor,
interleukin-2, interleukin-11, rituximab, trastuzumab, and denileukin diftitox.
Clinical trials of gene therapy and antiangiogenic agents begin.
FDA approves filgrastim for use in bone marrow transplantation and chemotherapy-induced neutropenia, severe chronic neutropenia, and peripheral blood stem cell transplantation.
FDA approves ondansetron for prevention of chemotherapy-induced nausea and vomiting; other 5-hydroxytryptamine-3 (5-HT3) receptor antagonists are in clinical trials (Perez, 1995).
As a result of improved symptom management, dose intensity becomes a focus.
FDA approves new analogs (e.g., vinorelbine) (Abeloff, 1995).
Scientists focus on the sequencing of agents (Bonadonna et al., 1995).
The genetic basis of cancers becomes an important factor in cancer risk research (e.g., BRCA1 for breast
cancer, renal cell cancer) (Gnarra et al., 1995; Hoskins et al., 1995; Miki et al., 1994).
Aromatase inhibitors are approved for breast cancer treatment. This marks a step forward for hormonal therapy.
2000present
The Childrens Oncology Group, a cooperative group combining the efforts of several groups, is formed to further the advancement of cancer treatment for children (www.childrensoncologygroup.org).
Scientists complete a working draft of the human genome (American Society of Clinical Oncology [ASCO],
n.d.).
Theory of immune surveillance continues, and biotherapy is used to target and mount a defense against certain antigens on malignant cells (e.g., gemtuzumab ozogamicin binds to CD33 on leukemic cells, rituximab
binds to CD20-positive non-Hodgkin lymphoma cells).
Radioimmunotherapy is used to deliver radioactivity directly to select tumor cells, avoiding damage to healthy
tissue (e.g., ibritumomab tiuxetan, tositumomab I-131).
FDA approves targeted therapies attacking epidermal growth factor receptor for lung cancer (gefitinib and erlotinib) and colon cancer (cetuximab and panitumumab) (ASCO, n.d.).
FDA approves antiangiogenic agents (bevacizumab was the first) (ASCO, n.d.).
Neurokinin-1 antagonist (aprepitant) is used in combination with other antiemetic drugs to prevent chemotherapy-induced nausea and vomiting.
Therapeutic vaccine trials are begun for existing cancers (e.g., OncoVAX, an autologous tumor cell vaccine,
is in phase III studies for stage II colon cancer), and FDA approves a prophylactic vaccine (Gardasil) for the
prevention of human papillomavirus infections that cause cervical cancer (ASCO, n.d.).
2010: Affordable Care Act is signed into law.
2. Surgery (Drake & Lynes, 2010; Gillespie, 2011)

a) Is a precise local treatment
b) May remove all or a portion of the primary tumor
c) Can be used to obtain specimens for cytopathology
d) May be the only treatment a patient requires
e) May be preceded or followed by other modalities
f) May be used in the palliative setting to alleviate or lessen intolerable symptoms
3. Radiation therapy (Gosselin, 2011; Kelvin, 2010)
a) Is a local treatment in which energy is precisely directed at a specific target
b) May follow surgery to prevent recurrence of the primary tumor
c) Is more effective for some diseases than others
d) Is sometimes used after chemotherapy because radiation can permanently damage bone marrow, making it impossible to give chemotherapy in the doses needed for curative therapy
e) Is often given in combination with chemotherapy (chemoradiation)
f) May be given as radioimmunotherapy (RIT), combining a radioisotope and a monoclonal antibody (mAb)
4. Chemotherapy/hormonal therapies (Levine, 2010; Tortorice, 2011)
a) Are systemic therapies, rather than local treatments, as drugs are distributed throughout the body by the bloodstream
b) May be used as single agents or, more commonly, in combination
c) Are limited by toxic effects on normal tissues
d) May have a tumoricidal effect in hormone-sensitive tumors because
of reduction or blockage of the source of the hormone or receptor
site where hormone is active
5. Biotherapy/targeted agents (Lapka & Franson, 2010)
a) Are systemic treatments
b) May modify the patients own immune defenses
c) May be so specific as to target a single receptor on the surface of tumor cells or an enzyme within the cell
d) May cause side effects and toxicities different from those of other antineoplastic agents
e) May be combined with other treatment modalities
f) May promote tumor regression
g) May stimulate hematopoiesis
D. Treatment approaches
1. Neoadjuvant therapy: The use of one or more treatment modalities prior to the primary therapy (e.g., chemotherapy before surgery). Goal is
to shrink the primary tumor to improve the effectiveness of surgery or
decrease the likelihood of micrometastases (Otto, 2007). In cases of locally advanced breast tumors, using neoadjuvant therapy may increase
the possibility for breast conservation.
2. Adjuvant therapy: Therapy following the primary treatment modality
(e.g., chemotherapy or radiation after surgery). The goal of adjuvant
therapy is to target minimal disease or micrometastases for patients at
high risk for recurrence (Otto, 2007).
3. Conditioning or preparative therapy: Administration of chemotherapy,
sometimes with total body irradiation, to eliminate residual disease or
empty the marrow space prior to receiving a stem cell transplant (also
referred to as myeloablation).
a) Myeloablation: Obliteration of bone marrow with chemotherapeutic
agents typically administered in high doses in preparation for peripheral blood stem cell or bone marrow transplantation (BMT). Myeloablative therapy does not allow for spontaneous marrow recovery because
of the lethal doses of agents used; therefore, it must be followed by

stem cell transplantation to prevent death. An example of myeloablative therapy is cyclophosphamide plus total body irradiation or busulfan plus cyclophosphamide (National Marrow Donor Program, 2012).
b) Nonmyeloablative: Reduced-intensity conditioning using doses that
are not lethal to bone marrow (Poliquin, 2007). Use of nonmyeloablative regimens has expanded the number of patients eligible for transplantation (National Marrow Donor Program, 2012).
4. Immunosuppression: Administration of chemotherapy at doses sufficient to blunt a patients immune response. This is done prior to transplantation to prevent graft rejection in allogeneic stem cell transplant
recipients. Agents such as methotrexate are given post-transplantation
to prevent graft-versus-host disease (GVHD). Certain agents are given
for immunosuppression to treat noncancerous conditions, such as autoimmune diseases.
E. Treatment strategies
1. Combination versus single-agent therapy (Tortorice, 2011): A combination of drugs is more effective in producing responses and prolonging life
than the same drugs used sequentially. With combination therapy, more
cancer cells are exposed in a sensitive phase, resulting in higher tumor
cell kill. Moreover, with rare exceptions, . . . single drugs at clinically tolerable doses have been unable to cure cancer (Chu & DeVita, 2013, p. 3).
a) Tumor cell populations are heterogeneous; therefore, a combination
of agents with different mechanisms of action is able to increase the
proportion of cells killed at any one time.
b) Combination agents with different mechanisms of action also reduce
the possibility of drug resistance, theoretically minimizing the chances for outgrowth of resistant clones (Skeel, 2011a).
c) Agents selected for use in combination chemotherapy have proven
efficacy as single agents.
d) Combination chemotherapy may use the principle of drug synergy to
maximize the effects of another drug. Synergy is affected by the rate of
tumor cell proliferation and by timing of drug administration (sequential or simultaneous; for example, leucovorin potentiates the cytotoxicity
of 5-fluorouracil [5-FU]) (Brown, in press). Combinations can be used
to provide access to sanctuary sites for reasons such as drug solubility
or affinity of specific tissues for a particular drug type (Skeel, 2011a).
e) Drugs with similar toxicities generally are avoided, although this is
not always possible. For example, both paclitaxel and cisplatin can
cause peripheral neuropathy as single agents but often are used together (Argyriou et al., 2007).
2. Dosing of chemotherapy
a) Treatment cycles are designed to permit recovery from damage to normal tissues and organs. Because the average white blood cell (WBC)
nadir is 1014 days, many regimens are based upon this time frame.
b) Administering a drug such as 5-FU at a steady concentration over a
period of time increases cell kill (Howland & Mycek, 2006).
c) Dose density refers to the drug dose per unit of time. Higher dose density is achieved by shortening the intervals between treatments (Freter,
2012). Reducing the time between chemotherapy cycles may diminish tumor regrowth. This strategy has resulted in longer survival for
patients with breast, ovarian, and colon cancers and lymphoma (Tortorice, 2011). The prophylactic use of the myeloid growth factor pegfilgrastim has allowed for administration of dose-dense chemotherapy regimens that would otherwise result in unacceptable neutropenia
(Burdette-Radoux et al., 2007; von Minckwitz et al., 2007).
d) Dose intensity is the amount of drug that is delivered over time. Nurses should be aware that dose reduction or delay resulting from chemotherapy side effects, scheduling conflicts, or any other reason reduces dose intensity and may negatively affect patient survival (Tortorice, 2011). Optimal cell kill is achieved by delivering sufficient doses of chemotherapy at planned intervals.
e) Relative dose intensity is calculated by comparing the received dose
to the planned dose of the standard regimen. Proactively managing
symptoms and educating patients on the importance of maintaining
the prescribed dosing schedule are paramount. (See Chapter 7 for
further discussion of dosing concepts.)
F. Goals of cancer therapy: Treatment planning includes discussion with patients about their goals of therapy and whether those goals are realistic
(Skeel, 2011b).
1. Prevention (Mahon, 2010)
a) Primary cancer prevention: Measures taken to avoid carcinogen exposure and promote health. Steps taken to prevent disease development
(e.g., avoidance of tobacco products, immunization against HPV).
(1) Chemoprevention: The use of selected pharmacologic agents
to prevent cancer in high-risk individuals, such as the administration of tamoxifen to women whose personal health history
indicates they are at a statistically increased risk for developing
breast cancer (Brown, in press).
(2) There has been discussion related to the role of nutritional epidemiology in the identification of nutritional or chemopreventive approaches to colon cancer, but that has yet to be confirmed (Marshall, 2009).
b) Secondary cancer prevention: Early detection and treatment of cancer
c) Tertiary cancer prevention: Monitoring for and/or preventing recurrence of the original cancer or secondary malignancies
2. Cure: Defined as the prolonged absence of detectable disease. This is the
desired outcome for all patients but is not always achievable.
3. Control: When cure is not possible, the goal is to allow patients to live
longer than if therapy had not been given (Skeel, 2011b). Treatment
often extends life and may prevent the growth of cancer cells without
complete elimination of disease or may reduce existing disease (Gosselin, 2011).
4. Palliation: Palliative cancer care is the integration of therapies that address the multiple issues that cause suffering in patients with cancer
and their families. In 2009, the American Society of Clinical Oncology
(ASCO) Board of Directors advocated that palliative care be offered to
all patients from the time of diagnosis to death (Ferris et al., 2009). Palliation involves reduction of side effects and symptoms, including pain
(Brown, in press; Gaddis & Gullatte, in press). It may include surgery,
radiation therapy, chemotherapy, or biotherapy, individually or in combination (Otto, 2007).
G. Measuring response
1. Measuring tumor response
a) Objective tumor response is assessed through a quantitative measurement such as surgical examination, imaging studies, or serum
tumor markers. Measurements recorded at the time of diagnosis are
compared to those recorded after treatment completion. In 1981,
the World Health Organization (WHO) first published tumor response criteria with overall assessment of tumor burden. Response
to therapy may be measured by survival, disease-free survival, obCopyright 2014 by the Oncology Nursing Society. All rights reserved.
jective change in tumor size or in tumor product, and subjective

change (Skeel, 2011a). With neoadjuvant therapy, tumor response
and resectability are partial determinants of effectiveness (Skeel,
2011a). The current end point for assessing response to therapy in
solid tumors is measuring change in tumor size (Kumar, Halanaik,
& Dahiya, 2010).
b) Tumor response has historically been classified using the following
system (Wahl, Jacene, Kasamon, & Lodge, 2009).
(1) Complete response: Absence of all signs and symptoms of cancer for at least one month using objective criteria (e.g., quantitative bidimensional tumor measurement)
(2) Partial response: At least a 50% reduction of measurable tumor mass for one month without development of new tumors
(3) Stable disease: A reduction in tumor mass of less than 50% or
less than a 25% increase in tumor growth
(4) Progressive disease: Growth of 25% or more or development of
new tumors. Note that this definition of progressive is negative,
in contrast to the standard English usage of the term.
(5) Relapse: After complete response, a new tumor appears or the
original tumor reappears. Following partial response, a new tumor appears or the original tumor increases in size. See Table
2 for further information.
c) Response Evaluation Criteria in Solid Tumors (RECIST) guidelines
were developed in 1999 by an international task force including
the European Organization for Research and Treatment of Cancer
(EORTC), NCI, and the National Cancer Institute of Canada Clinical Trials Group. The criteria were revised in 2008 and notated as
RECIST 1.1.
(1) Guidelines are intended to facilitate communication between researchers and clinicians (Therasse, Eisenhauer, & Buyse, 2006).
(2) Considerable variation exists between the original RECIST and
WHO criteria for evaluating response (Mazumdar, Smith, &
Schwartz, 2004; Schwartz et al., 2006), as well as subsequent editions of RECIST. These variations create a challenge for evaluating the effectiveness of therapies being studied in clinical trials. For example, RECIST criteria may show tumor progression
more slowly than WHO criteria, and RECIST 1.1 criteria result
in a higher complete response rate than the original RECIST
criteria (Wahl et al., 2009).
2. WHO (Therasse et al., 2000) recognizes that diagnostic technologies
(e.g., computed tomography [CT] scans, magnetic resonance imaging
Table 2. Comparison of WHO and RECIST Criteria for Tumor Response
Response
WHO
RECIST 1.1
Complete response
Absence of all known disease for at least 4

weeks
Disappearance of all target lesions
Partial response
50% reduction of measurable tumor mass for

4 weeks without development of new tumors
30% reduction in the sum of the diameters of target lesions compared to the baseline
Progressive disease
Growth of 25% or more, or development of

new tumors
20% increase in the sum of diameters of target lesions
Stable disease
Unable to meet criteria for either partial response or progressive disease
Unable to meet criteria for either partial response or

progressive disease
RECISTResponse Evaluation Criteria in Solid Tumors; WHOWorld Health Organization

Note. Based on information from Eisenhauer et al., 2009; Wahl et al., 2009.
[MRI]) have led to confusion regarding three-dimensional measurement

of disease. As a result, the reported response criteria vary among research
groups. See Table 2 for a comparison of WHO and RECIST criteria.
3. RECIST 1.1 guidelines
a) Response to a clinical trial is used to decide whether an agent or regimen demonstrated results promising enough to warrant further testing (prospective end point).
b) Baseline lesions are characterized as measurable or nonmeasurable.
At baseline, tumors must be measurable in at least one dimension
(using metrics) by calipers or a ruler. Baseline measurements must
be obtained within four weeks of initiating therapy. Lesions may be
measured using CT or MRI, but CT is preferred in most cases because
of variability in MRI scan parameters. In the original RECIST, nonmeasurable lesions included bone lesions, ascites, pleural or pericardial effusions, leptomeningeal disease, and inflammatory breast cancer. RECIST 1.1 now accepts bone metastases and soft tissue masses measuring 10 mm or larger as target lesions (Costelloe, Chuang,
Madewell, & Ueno, 2010).
c) The same method and technique used at baseline must be used to
evaluate response for reporting and follow-up.
d) If the primary end point is response to treatment, the patient must
have at least one measurable lesion at baseline. If only one measurable lesion is present, it must be confirmed by cytology or histology.
e) Measurable lesions, up to 5 per organ or 10 in total, are identified
as target lesions.
(1) Lesions selected are the longest in diameter and suitable for
follow-up measurement.
(2) The sum of the longest diameters for all target lesions is designated as the baseline sum longest diameter. This sum is used as the
reference to compare response (Skeel, 2011b).
(3) All other nontarget lesions are measured and recorded if possible. Their presence or absence can be noted for follow-up but
is not included in the response evaluation. For example, effusions cannot be measured, nor can lesions with necrotic centers (Skeel, 2011b).
f) Using RECIST criteria: See Table 2.
(1) Time to progression is a valuable indicator in cases when treatment results in disease stability despite failure to produce measurable shrinkage. This can be used as an indicator of disease status
when there is no measurable disease at the start of therapy, given the limitations of current RECIST 1.1 criteria (Skeel, 2011b).
(2) Follow-up should be protocol specific.
(a) Every other cycle (six to eight weeks) is reasonable for follow-up.
(b) Patients who discontinue therapy because of deterioration
of their health condition without evidence of progressive
disease are identified as symptomatically deteriorated and not
included in the partial response, stable disease, or progressive disease groups.
(c) At the conclusion of treatment, follow-up tests and schedules
are based on the goal of the study. If time to a specific event,
such as recurrence or death, is the primary end point of the
study, measurements must be compared to the baseline.
(d) The duration of overall response is measured from when
the measurement criteria were met for complete or partial response until the first date a recurrence or progressive disease was measured.
10
(e) The duration of stable disease is the time from initiation of

therapy until the criteria are met for progressive disease.
g) Reporting using RECIST 1.1 results: All patients in a study are assessed at the end of the study. Patients are assigned to one of the following categories.
(1) Complete response
(2) Partial response
(3) Stable disease
(4) Progressive disease
(5) Early death from disease
(6) Early death from toxicity
4. Glucose analog tracer, fluorine-18 fluorodeoxyglucose (18F-FDG),
positron-emission tomography (PET) scans: Used to assess tumor response both qualitatively and quantitatively (Costelloe et al., 2010)
with PERCIST (Positron Emission Tomography Response Criteria in
Solid Tumors).
a) Used to capture and report fractional change in standardized uptake value at intervals during and after treatment (Wahl et al., 2009)
b) 18F-FDG PET scans have lower sensitivity and specificity for non-small
cell lung cancer than previously published (Levitan, 2012).
5. MDA (University of Texas MD Anderson Cancer Center) classification:
Uses key imaging techniques to stratify patients with breast cancer with
bone-only metastases with respect to progression-free survival, overall
survival, and clinical response. Use of this classification may enable bone
lesions to be considered measurable disease (Hamaoka et al., 2010).
6. Measuring patient response: Performance status scales are used as part
of inclusion and exclusion criteria for clinical trials (Vogel, 2011). Table
3 compares three commonly used performance status scales.
a) Karnofsky Performance Status (KPS) scale: Evaluates adult performance in terms of percentage; a lower score indicates poorer performance (Karnofsky & Burchenal, 1949).
b) Eastern Cooperative Oncology Group (ECOG) and Zubrod scales:
Evaluate adult performance on a 05 scale; a higher score indicates
poorer performance (Oken et al., 1982).
c) WHO scale: Developed by the United Nations and includes performance and toxicity grading.
d) Lansky Performance Scale: Developed specifically for use in children,
as the KPS scale often is not applicable in pediatric populations (Lansky, List, Lansky, Ritter-Sterr, & Miller, 1987).
e) Quality of life (QOL): A partially independent measure of performance determined based on the patients own perceptions. It has
been shown to be an independent predictor of tumor response and
survival in some cancers (Skeel, 2011a).
H. Factors affecting treatment response
1. Pretreatment comorbidities and performance status: Patients with comorbid conditions and those who have been heavily pretreated may be
less able to tolerate the side effects and toxicities of chemotherapy, thus
affecting dose intensity and treatment planning (Camp-Sorrell, 2011).
After tumor type, performance status or activity level is the most important factor to consider when determining appropriate and tolerable
treatment. Patients who have poorer performance scores (e.g., bedridden) may be unable to withstand the rigors of an aggressive treatment
regimen and may experience decreased QOL. Patients who are fully active or have mild symptoms respond more frequently to treatment and
survive longer than those who are less active or experience more symptoms (Skeel, 2011b).
11
2. Tumor burden: The inverse relationship between the number of tumor cells and response implies that the smaller the tumor, the higher
the rate of response (Tortorice, 2011). As tumor mass increases, the
growth rate slows, decreasing the effectiveness of antineoplastic therapy. Additionally, large solid tumors may have inadequate blood flow,
which inhibits the ability of the chemotherapy to reach the entire tumor (Tortorice, 2011).
3. Rate of tumor growth: Tumor doubling time (time for the tumor to double in mass) and growth fraction (proportion of proliferating cells in relation to the total number of tumor cells) are important factors affecting
Table 3. Performance Status Scales

The Karnofsky Performance Status scale has been used in oncology, hospice, case management, and other healthcare settings since
1949. It is a tool for classifying patients on a scale from 0 to 100 according to their level of functional impairment. The Karnofsky scale is
designed for patients age 16 and older.
Rating
Description
100
Normal; no complaints; no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of disease
80
Able to carry on normal activity with effort; some signs or symptoms of disease
70
Cares for self; unable to carry on normal activity or do active work
60
Requires occasional assistance but able to care for most personal needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospital admission indicated although death not imminent
20
Very sick; hospital admission necessary; active supportive treatment necessary
10
Moribund; fatal processes progressing rapidly
Dead
The Eastern Cooperative Oncology Group, World Health Organization, and Zubrod Performance Status scales also are used to classify
patient responses to treatment. These scales are designed for patients age 16 and older.
Grade
Description
Fully active; able to carry on all predisease performance without restriction
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g.,
light housework, office work)
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
Dead
The Lansky Performance Scale is used to classify pediatric patients (younger than 16 years old) according to functionality.
Score
Description
100
Fully active
90
Minor restriction in physically strenuous play
80
Restricted in strenuous play; tires more easily, otherwise active
70
Both greater restrictions of and less time spent in active play
60
Ambulatory up to 50% of time; limited active play with assistance/supervision
50
Considerable assistance required for any active play; fully able to engage in quiet play
40
Able to initiate quiet activities
30
Needs considerable assistance for quiet activity
20
Limited to very passive activity initiated by others (e.g., watching TV)
10
Completely disabled, not even passive play
Note. Based on information from National Marrow Donor Program & Medical College of Wisconsin, 2009; Skeel, 2011b.
12
response. Cytotoxic chemotherapy agents are most effective if given during the growth phase of the tumor, when a high percentage of cells are
susceptible to the effects of that agent (Skeel, 2011a; Tortorice, 2011).
4. Hormone receptor status
a) Presence of estrogen receptors (ERs) and/or progesterone receptors
(PRs) is prognostic for breast cancer. Patients who are ER/PR positive demonstrate better overall survival rates (Yackzan, 2011). Tumors
that grow more rapidly in the presence of a specific hormone may be
suppressed with an antihormonal agent.
b) Hormone receptor status has become increasingly important in cancer therapy.
5. Drug resistance: Many patients experience relapse because tumors become resistant to the drugs used to treat them (McDermott, Downing,
& Stratton, 2011).
a) Genetic instability of tumor cells and the emergence of drug resistance are currently considered the most significant determinants of
tumor response to treatment (Tortorice, 2011).
b) Complex biochemical pathways involving a multitude of receptors
and enzymes are implicated and depend upon the type of cell and
chemotherapy agent (Tortorice, 2011).
c) Research points to a complex interaction among cytotoxic agents,
chemical messengers (transporters that deliver drugs to the tumor),
and the genetic ability of malignant cells to avoid chemotherapyinduced apoptosis because of their high rate of genetic instability
(Gaddis & Gullatte, in press; Tortorice, 2011).
d) Genomic changes, originally presenting in small subclones of cancer cells, often underlie acquired resistance, such as ABL mutation
in chronic myeloid leukemia and MET in non-small cell lung cancer.
Genomic differences have an important role in determining how a
given cancer will respond to treatment (McDermott et al., 2011).
e) Tumor cells may be inherently resistant to antineoplastic agents or develop resistance after drug exposure because of the emergence of resistant clones. Single-agent resistance or multidrug resistance (MDR)
can occur and may be caused by a number of factors.
(1) Insufficient dosing may lead to the development of resistant
cell clones arising from random mutations in cellular DNA.
(2) Chemotherapy may kill sensitive cells while sparing cells resistant to treatment administered (Tortorice, 2011).
(3) MDR occurs when malignant cells are exposed to cytotoxic agents
possessing dissimilar mechanisms of action and appears to be
caused by mutations in the malignant cells regulatory system
(Tortorice, 2011). Several pathways are thought to be responsible for MDR, including alterations in the metabolism of chemotherapy within the tumor, the ability of tumor cells to repair
damaged DNA (thus bypassing apoptosis), and decreased uptake by formerly susceptible cells (Tortorice, 2011). MDR pathways include the following.
(a) Overexpression of the MDR1 gene, which encodes for the
cell membrane efflux pump P-glycoprotein (P-gp), is believed to cause resistance by its ability to remove toxic molecules (e.g., chemotherapy) from inside the cell before the
drug can reach the DNA. The presence of P-gp is a poor
prognostic indicator (Gonzalez-Angulo et al., 2007; Tortorice, 2011).
(b) Resistance to topoisomerase drugs (e.g., doxorubicin) can occur when the tumor develops the ability to change the binding properties of topoisomerase enzymes (Tortorice, 2011).
(c) MDR can occur from increased levels of normally protective enzymes (e.g., glutathione S-transferase), which facilitate the elimination of platinum compounds and alkylating agents from malignant cells (Tortorice, 2011).
(4) Impaired metabolism may result in reduced drug activation or
increased drug deactivation.
(5) Other types of resistance
(a) Acquired resistance is the result of further mutations after exposure to additional drugs and nongenetic mechanisms (Lackner, Wilson, & Settleman, 2012). KRAS mutations contribute to the acquired resistance of colorectal cancers treated with agents targeted against epidermal
growth factor receptor (EGFR). KRAS mutations account
for 40%50% of relapses among patients with colorectal
cancers (Azvolinsky, 2012).
(b) Emergent resistance occurs after the affected cells survive an
exposure to an environmental carcinogen (e.g., tobacco).
(c) Cells may be temporarily less responsive because of changes in environment or stimuli or may have permanent resistance (Freter & Goldie, 2012).
(d) Poor blood supply to the tumor may cause temporary resistance, which prevents delivery of a therapeutic dose of
drug (Tortorice, 2011).
(6) Overcoming drug resistance remains a high priority. Recurrences are presumably attributed to the inability to assess which tumors are resistant to treatment when administering in an adjuvant setting (Dawood et al., 2008). Researchers continue to
look for ways to deactivate P-gp in malignant cells and to identify new agents that alter the apoptotic pathways, increase the
effectiveness of current chemotherapy, and interact with specific characteristics associated with the DNA in malignant cells
(Barton-Burke & Wilkes, 2006).
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Chapter 2
Drug Development and

Clinical Trials
A. Development of new cytotoxic and other therapeutic agents: Although there
is a sense of urgency to develop new and better therapies, protection of the
public is paramount. Steps to develop new anticancer agents are complex,
as well as time and resource consuming. NCI, a division of the National Institutes of Health (NIH), examines thousands of agents each year to discover new ones for testing. Only a small percentage are selected for preclinical testing, and even fewer are tested in phase I clinical trials (see Table 4).
1. Preclinical studies: Laboratory research using animal models often is
conducted collaboratively by NCI and pharmaceutical companies. The
NCI Cancer Therapy Evaluation Program (CTEP) seeks pharmaceutical sponsorship early once an agent is discovered because NCI does not
market new agents. Pharmaceutical companies may seek CTEP codevelopment (Humphrey et al., 2011).
2. Preclinical studies involve laboratory analysis and animal subjects; they
do not involve human subjects (Wong, Bales, & Hurtado, in press).
a) Scientists undertake empirical or rational research to develop a new
agent or a derivative of an existing agent that is more effective, has
fewer side effects, or is less toxic than existing agents.
b) The new agent is tested in vitro in various tumor cell lines. If the agent
is effective, scientists perform in vivo testing using mice or other research animals.
c) The agent is tested for stability, solubility, and dose.
d) Scientists perform studies involving animals to predict the initial dose
for use in human studies.
B. Clinical trials involving humans: The purpose of a clinical trial is to study a
new agent, combination of agents, or device by involving human volunteers
in a scientific experiment. Scientists evaluate the safety, effectiveness, and
toxicities of a new drug or drug combination in humans. Clinical trials are
vital to improving patient care and reducing cancer morbidity and mortality. However, only about 3% of adults with cancer enroll in clinical trials (Institute of Medicine, 2010). Nurses can have a positive impact on this number by being knowledgeable about clinical trials, assisting with patient education, and recording careful documentation of patient symptoms and care
(Deininger, 2010).
1. Regulatory entities relevant to the protection of human research subjects: In addition to strict federal regulation, multiple regulatory groups
oversee the participation of individuals in research (DeLaCruz &
McCabe, 2011).
a) The Office for Human Research Protections (OHRP) operates within the DHHS and oversees the development of informed consent
(IC) documents, the formation and function of institutional review
boards (IRBs), and safeguarding the welfare of research participants.
17
18
Table 4. Overview of Phases of Clinical Trials

Phase
Description
Goals
Subjects
Study Design
Exploratory study using

small doses of investigational agent (i.e., microdosing for a drug or biologic)
Very limited drug exposure
with limited duration of
dosing ( 7 days)
No therapeutic (or diagnostic) intent
Conducted prior to traditional phase 1 study
Conducted under an exploratory Investigational
New Drug application
Provide human pharmacokinetic/pharmacodynamic

data prior to definitive phase
12 testing.
Determine whether mechanism of action defined in preclinical models can be observed in humans.
Refine biomarker assay using human tumor tissue and/
or surrogate tissue.
Enhance efficiency of subsequent development of the
agent.
Increase chance of success
of subsequent development
of the agent.
Limited number (~10

12)
Dose escalation
Open-label
Nonrandomized
Traditional first-in-human
dose-finding study for single agent
Dose-finding study when
using multiple agents or
multiple interventions
(e.g., drug plus radiation)
Evaluate the safety and tolerability.

Determine the maximum tolerated dose.
Single agent
Combination of agents
Combination interventions
Determine dose-limiting toxicity.
Define optimal biologically
active dose.
Evaluate pharmacokinetics/
pharmacodynamics.
Observe preliminary response (e.g., antitumor activity).
Limited number (20

100)
Healthy volunteers
Patient volunteers
Usually includes many
cancer types (e.g., solid tumors)
Refractory to standard
therapy or no remaining
standard therapy
Adequate organ function, specifically bone
marrow, liver, and kidney
Pediatric studies conducted after safety and
toxicity evaluation in
adults
Dose escalation
Traditional 3 + 3
Accelerated titration
Adaptive
Open-label
Randomized (healthy
volunteers)
Nonrandomized (patient
volunteers)
II
Phase IIA: Proof-of-concept

study to provide initial information on activity of intervention to justify conducting a larger study
Phase IIB: Optimal dosing
study to target population
Phase IIA
Demonstrate activity of the
intervention in the intended patient condition/targeted population.
Establish proof of concept.
Phase IIB: Establish optimal
dosing for the intended patient condition/targeted population to be used in phase
III study.
Evaluate for safety.
Moderate number (80

300)
More homogenous population that is deemed
likely to respond based
on
Phase I data
Preclinical models
Mechanisms of action
Requires disease that
can be accurately measured and must be reproducible
May limit number of prior treatments
Open-label or blinded
Nonrandomized or randomized
One-stage, two-stage,
or crossover
Nonstratified or stratified
III
Randomized controlled
study
Compare efficacy of intervention being studied to a control group.

Evaluate for safety.
Large number (hundreds to thousands)

Homogenous population
May be used for initial
treatment
Open-label or blinded
Randomized
Nonstratified or stratified
Multi-institution/multisite

Chapter 2. Drug Development and Clinical Trials
19
Table 4. Overview of Phases of Clinical Trials (Continued)

Phase
IV
Description
Postmarketing
Goals
Subjects
Study Design
Evaluate safety during postmarketing period.

May or may not be required
by the U.S. Food and Drug
Administration.
Compare the drug to another
similar product that is already
being marketed.
Monitor for long-term effects
and additional safety, efficacy, and quality-of-life data.
Assess drug-food interactions.
Assess effect in specific populations (e.g., pregnant women, children), or determine
cost-effectiveness.
Large number of subjects with the labeled indication of the newly

marketed drug/biologic
Open-label
Multi-institution/multisite
Note. Based on information from Doroshow & Kummar, 2009; Kummar et al., 2006; Lertora & Vanevski, 2012.
From Types of Research: Experimental, by E. Ness and G. Cusack in A.D. Klimaszewski, M.A. Bacon, J.A. Eggert, E. Ness, J.G. Westendorp, and K. Willenberg (Eds.), Manual for Clinical Trials Nursing (3rd ed.), in press, Pittsburgh, PA: Oncology Nursing Society. Copyright by the Oncology Nursing Society.
Reprinted with permission.
b) The U.S. Food and Drug Administration (FDA) regulates clinical trials that involve the licensing of a drug or product regardless of the
source of research funding.
c) IRBs are institutionally based and assess clinical trials for risks, benefits, and ethical status and monitor the overall conduct of the clinical trial. NCI sponsors a Central IRB Initiative in consultation with
OHRP. This initiative was designed to decrease the administrative
burden on local IRBs and investigators. Information on the Central
IRB Initiative can be found at www.ncicirb.org.
d) A data monitoring committee is required for all phase III trials. The
purpose of this independent group of experts is to protect the safety of trial participants, the credibility of the study, and the validity of
study results. The committee may recommend termination of a study
if appropriate (Bales & Adams, in press).
2. Drug approval process
a) Research protocols are designed within an academic environment,
through NCI, by pharmaceutical companies, or by cooperative research groups. Funding may originate from public or private sources.
b) If a trial involves a new agent, the FDA reviews and approves the agent
as an Investigational New Drug, or IND.
c) Table 4 presents an overview of the phases of clinical trials (Ness &
Cusack, in press).
d) The FDA approves a new drug for commercial use when studies have
documented its efficacy and safety.
e) The drug is marketed commercially.
f) Postmarketing studies are conducted to define new uses for approved
drugs and monitor for toxicities, long-term safety, and long-term effectiveness (Ness & Cusack, in press).
3. Pediatric patient involvement in clinical trials
a) More than 90% of pediatric patients with cancer receive treatment
at centers affiliated with a multi-institution collaborative research
group, such as the COG. Approximately 60% of children with cancer are treated in a COG protocol (COG, n.d.).
20
b) In general, new drugs are tested in adults before researchers undertake studies involving children.
c) Because childrens size and metabolism differ significantly from those
of adults, drug data derived from adults may not apply to children.
4. Nurses roles in clinical trials: Nurses may
a) Help patients find clinical trials. Useful resources include (Deininger,
2010)
(1) NIHs Clinical Trials website (http://clinicaltrials.gov), which
lists clinical trials and provides education about clinical trials
for consumers
(2) NCIs Cancer Trials Support Unit (www.ctsu.org), which focuses on phase III clinical trials
(3) Coalition of National Cancer Cooperative Groups TrialCheck
(www.trialcheck.org/services), which focuses on cooperative
group oncology trials
(4) Pharmaceutical company registry websites, such as GlaxoSmithKline (www.gsk-clinicalstudyregister.com) and Eli Lilly (www
.lillytrials.com/initiated/initiated.html)
(5) Internationally, nationally, and locally developed and maintained registries.
b) Support prospective participants as they decide whether to enroll.
When patients are considering participation in a clinical trial, they
may be facing other stressors in addition to the enrollment decision,
including a new diagnosis of cancer, disease progression, financial
concerns, psychosocial distress, disruption of career, and role changes at home. Nurses can help by screening for psychological distress at
every visit and referring patients to social work, pastoral care, or mental health services as appropriate (Czaplicki, in press).
c) Ensure IC when patients decide to participate.
(1) IC is a heavily regulated process to protect human rights, of
which the IC document is only a part (Klimaszewski, in press).
Table 5 delineates the steps in the IC process. Nurses are involved in this process by
(a) Ensuring that patients and/or family members understand
the purpose of participation in the clinical trial and allowing adequate time for them to receive answers to all of their
questions. This involves arranging for time with the clinical investigator and/or clinical trials nurse.
(b) Providing educational materials as required. All materials
presented to patients and families must be language specific, developmentally appropriate, and accurate.
(c) Documenting that patients understand the clinical trial,
follow-up and test schedules, and their right to withdraw
at any time (Klimaszewski, in press).
(2) The institutions IRB reviews and revises the IC document for format and appropriateness of reading level for the patient and family. NCI provides a consent form template for adult cancer trials
(see www.cancer.gov/clinicaltrials/conducting/simplification
-of-informed-consent-docs/page3). OHRP and FDA regulations
about the IC document are found in the Code of Federal Regulations and may be viewed at www.hhs.gov/ohrp/humansubjects/
guidance/45cfr46.html#46.116. A basic consent document must
(U.S. DHHS, 2010)
(a) State that the study involves research, provide an explanation of the purpose of the research, identify the possible
duration of the subjects participation, and describe the
procedure(s).
21
Table 5. The Informed Consent Process

Step
Key Elements
Initial meeting
Provide subject and family/friends with the informed consent form (CF).
Discuss the CF logically with subject and one or more members of the research team.
Encourage subject and family to take notes.
Provide adequate time for subject and family members to consider participation and have all questions answered.
Provide subject with a video, audiotape, or interactive computer program to help him or her to understand the information in the CF.
Parents will represent subjects younger than age 18.
If subject is between age 7 and 18, ask for assent to participate, and provide an assent form for signature.
Time to read and

consider participation
Subject is afforded adequate time to review the CF at his or her leisure.

Subject discusses the CF with family, friends, social workers, clergy, a subject representative, or other trusted advisers.
Subject records questions and concerns for discussion at next meeting.
Assessment of
understanding
Discuss subjects questions and concerns that were recorded at home.

Assess subjects understanding with interactive questioning, a written questionnaire, or by having the patient explain specific parts of the CF in his or her own words.
Document assessment of subjects understanding.
Answer subjects questions until the patient states that he or she has enough information to make a decision.
Document subjects statement regarding his or her decision.
Questions
Encourage subject to ask questions until the participant is satisfied with his or her understanding of the CF.
Encourage subject to record questions while away from the clinic and either bring them to the next meeting or
schedule a visit to have the questions discussed.
Verification before
treatment
Ask patient to verify that he or she still consents to the treatment he or she is about to receive immediately prior to
administering the treatment.
New information
Assure subject that any new information available will be shared.

Follow up on assurance.
Provide subject with an updated CF for signature (as required).
Document subjects understanding of new information in the presence of family.
Document subjects signing of the new CF, review of CF, and that all subjects questions were answered.
Provide copy of CF to subject.
Communication
techniques
Videotapes, audiotapes, interactive computer programs, discussions with qualified professional and lay individuals
Supplemental
materials
Videotapes, audiotapes, written materials, interactive computer programs
Note. Based on information from National Cancer Institute, 2013.

From Informed Consent, by A. Klimaszewski in A. Klimaszewski, M. Bacon, J.A. Eggert, E. Ness, J.G. Westendorp, and K. Willenberg (Eds.), Manual for
Clinical Trials Nursing (3rd ed.), in press, Pittsburgh, PA: Oncology Nursing Society. Copyright by the Oncology Nursing Society. Reprinted with permission.
(b) Describe foreseeable risks or discomforts that the participant might encounter.
(c) Describe benefits to the participant or to any others.
(d) Disclose appropriate alternative treatments that may be advantageous to the participant, if applicable.
(e) Describe how confidentiality of records that identify the
participant will be managed.
(f) Explain whether any compensation or other medical
treatments will be made available if injury occurs. If injury does occur, explain what medical treatments will
be available and where the participant can obtain further information.
(g) Clearly document for the participant contact information
for a person who will answer questions about the research
and whom to contact if the participant sustains a researchrelated illness or injury.
22
(h) State that the participant may discontinue involvement

in the trial at any time without penalty or loss of further
treatment(s) and that participation is voluntary.
(3) The nurse should ensure that the parents or a legally authorized representative of pediatric patients understand the concepts of consent, assent, and dissent as they relate to a childs
participation in research. While the parents/legally authorized
representative must provide consent, assent is a minors affirmative agreement to participate in research. Allowing assent
honors a minors autonomy to the extent that he or she has
developed the capacity to make informed choices. If a minor
does not object to participation, assent cannot be presumed
(Klimaszewski, in press). Dissent is a childs active refusal to
participate in research. NCI provides information on the assent process for care providers and parents and guardians (see
www.cancer.gov/clinicaltrials/learningabout/patientsafety/
childrensassent).
d) The Oncology Nursing Society (ONS) defined the role of oncology
clinical trials nurses through competencies (Daugherty, Schmieder,
Good, Leos, & Weiss, 2010) (see Table 6).
e) The oncology nurse caring for a patient on a study protocol has additional responsibilities depending upon the phase of the clinical trial,
such as performance and documentation of the following.
(1) Verify that the patient, parent, or legally authorized representative has given IC, that the original document is in the patients
Table 6. Oncology Clinical Trials Nurse Core Competencies

Competency
Description
I. Protocol
compliance
The oncology clinical trials nurse facilitates compliance with the requirements of the research protocol and
good clinical research practice while remaining cognizant of the needs of diverse patient populations.
II. Clinical trials

related communication
The oncology clinical trials nurse utilizes multiple communication methods to facilitate the effective conduct of
clinical trials.
III. Informed consent

process
The oncology clinical trials nurse demonstrates leadership in ensuring patient comprehension and safety during initial and ongoing clinical trial informed consent discussions.
IV. Management of
clinical trial patients
The oncology clinical trials nurse uses a variety of resources and strategies to manage the care of patients
participating in clinical trials, ensuring compliance with protocol procedures, assessments, and reporting requirements, as well as management of symptoms.
V. Documentation
The oncology clinical trials nurse provides leadership to the research team in ensuring collection of source
data and completion of documentation that validate the integrity of the conduct of the clinical trial.
VI. Patient
recruitment
The oncology clinical trials nurse utilizes a variety of strategies to enhance recruitment while being mindful of
the needs of diverse patient populations.
VII. Ethical issues
The oncology clinical trials nurse demonstrates leadership in ensuring adherence to ethical practices during the
conduct of clinical trials in order to protect the rights and well-being of patients and the collection of quality data.
VIII. Financial
implications
The oncology clinical trials nurse identifies the financial variables that affect research and supports good financial stewardship in clinical trials.
IX. Professional
development
The oncology clinical trials nurse takes responsibility for identifying his or her ongoing professional development needs and seeks resources and opportunities to meet those needs, such as through membership in
nursing, oncology, or research organizations.
Note. From Oncology Clinical Trials Nurse Competencies (pp. 1114), by P. Daugherty, L. Schmieder, M. Good, D. Leos, and P. Weiss, 2010, Pittsburgh, PA:
Oncology Nursing Society. Retrieved from http://www2.ons.org/media/ons/docs/publications/ctncompetencies.pdf. Copyright 2010 by the Oncology Nursing
Society. Reprinted with permission.
medical record, and that the patient has received a copy before any study tests are performed or any study treatments are
administered.
(2) Clarify technical explanations of procedures and treatments.
(3) Obtain pretreatment assessment data.
(4) Measure height and weight, and check dose calculations with
a physician, pharmacist, or another qualified (i.e., chemotherapy-biotherapy trained) nurse.
(5) Have emergency medications and equipment available as appropriate.
(6) Instruct the patient to report changes or symptoms experienced
during and after drug administration.
(7) Assess the patients desire to continue by verbally affirming consent prior to beginning drug infusion (Klimaszewski, in press).
Patients have the right to withdraw at any time.
(8) Administer the drug(s) according to the protocol.
(9) Assess and evaluate drug reactions. Use the NCI Common
Terminology Criteria for Adverse Events (CTCAE), available
online (see http://ctep.cancer.gov/protocolDevelopment/
electronic_applications/ctc.htm) to assess individual toxicities
and identify trends in the study population.
(10) Follow up with telephone calls to assess the patient for delayed or chronic side effects as appropriate (Klimaszewski,
in press).
C. Expedited approval: The FDA may hasten the approval of new drugs to address an unmet medical need, provide a promising therapy to treat a serious condition, improve survival, or decrease toxicity of an accepted treatment. Termed Fast Track, Breakthrough Therapy, Accelerated Approval, and Priority Review, these programs for expedited approval have potential benefits,
including (U.S. FDA, 2013)
1. Improved efficiency by promoting early communication between the
company submitting the drug and the FDA
2. Allowing submission of sections of the new drug application instead of
all components
3. Permitting the evaluation of various studies using surrogate end points
4. Providing priority review and accelerated approval of promising drugs.
References
Bales, C., & Adams, G. (in press). Data and safety monitoring plans. In A.D. Klimaszewski, M. Bacon,
J. Eggert, E. Ness, J.G. Westendorp, & K. Willenberg (Eds.), Manual for clinical trials nursing (3rd
ed.). Pittsburgh, PA: Oncology Nursing Society.
Childrens Oncology Group. (n.d.). What is a clinical trial? Retrieved from http://www
.childrensoncologygroup.org/index.php/what-is-a-clinical-trial
Czaplicki, K. (in press). Psychosocial distress. In A.D. Klimaszewski, M. Bacon, J. Eggert, E. Ness, J.G.
Westendorp, & K. Willenberg (Eds.), Manual for clinical trials nursing (3rd ed.). Pittsburgh, PA: Oncology Nursing Society.
Daugherty, P., Schmieder, L., Good, M., Leos, D., & Weiss, P. (2010). Oncology clinical trials
nurse competencies. Retrieved from http://www2.ons.org/media/ons/docs/publications/
ctncompetencies.pdf
Deininger, H.E. (2010). Clinical trials. In J. Eggert (Ed.), Cancer basics (pp. 287302). Pittsburgh, PA:
DeLaCruz, A., & McCabe, M.S. (2011). Principles of cancer clinical trials. In C.H. Yarbro, D. Wujcik,
& B.H. Gobel (Eds.), Cancer nursing: Principles and practice (7th ed., pp. 219231). Burlington, MA:
Jones and Bartlett.
Doroshow, J.H., & Kummar, S. (2009). Role of phase 0 trials in drug development. Future Medicinal
Chemistry, 1, 13751380. doi:10.4155/fmc.09.117
23
24
Humphrey, R.W., Brockway-Lunardi, L.M., Bonk, D.T., Dohoney, K.M., Doroshow, J.H., Meech, S.J.,
Pardoll, D.M. (2011). Opportunities and challenges in the development of experimental drug combinations for cancer. Journal of the National Cancer Institute, 103, 12221226. doi:10.1093/jnci/djr246
Institute of Medicine. (2010). Transforming clinical research in the United States: Challenges and opportunities: Workshop summary. Washington, DC: National Academies Press. Retrieved from http://www
.ncbi.nlm.nih.gov/books/NBK50892/pdf/TOC.pdf
Klimaszewski, A.D. (in press). Informed consent. In A.D. Klimaszewski, M. Bacon, J. Eggert, E. Ness,
J.G. Westendorp, & K. Willenberg (Eds.), Manual for clinical trials nursing (3rd ed.). Pittsburgh,
PA: Oncology Nursing Society.
Kummar, S., Gutierrez, M., Doroshow, J.H., & Murgo, A.J. (2006). Drug development in oncology:
Classical cytotoxics and molecularly targeted agents. British Journal of Clinical Pharmacology, 62, 15
26. doi:10.1111/j.1365-2125.2006.02713.x
Lertora, J.J.L., & Vanevski, K.M. (2012). Clinical pharmacology and its role in pharmaceutical development. In J.I. Gallin & F.P. Ognibene (Eds.), Principles and practice of clinical research (3rd ed., pp.
627639). Boston, MA: Elsevier Academic Press. doi:10.1016/B978-0-12-382167-6.00043-6
National Cancer Institute. (2013). Simplification of informed consent documents: Appendix 4, communication methods. Retrieved from http://www.cancer.gov/clinicaltrials/conducting/simplification
-of-informed-consent-docs/page5#appendix4
Ness, E., & Cusack, G. (in press). Types of clinical research: Experimental. In A.D. Klimaszewski, M.
Bacon, J. Eggert, E. Ness, J.G. Westendorp, & K. Willenberg (Eds.), Manual for clinical trials nursing (3rd ed.). Pittsburgh, PA: Oncology Nursing Society.
U.S. Department of Health and Human Services. (2010). Title 45: Public welfare, Part 46: Protection
of human subjects, 46.116: General requirements for informed consent (45 C.F.R. 46.116). Retrieved from http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116
U.S. Food and Drug Administration. (2013, June 26). Fast track, breakthrough therapy, accelerated approval and priority review: Expediting availability of new drugs for patients with serious conditions.
Retrieved from http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speeding
accesstoimportantnewtherapies/ucm128291.htm
Wong, S.F., Bales, C., & Hurtado, K. (in press). Investigational agents: Procurement, administration,
and accountability of research study drugs. In A.D. Klimaszewski, M. Bacon, J. Eggert, E. Ness, J.G.
Chapter 3
Principles of Antineoplastic
Therapy
A. Life cycle of cells: The cell life cycle is a five-stage reproductive process occurring in both normal and malignant cells (see Figure 2) and propelled
by cyclincyclin-dependent kinase (CDK) complexes (Brown, in press; Malumbres, 2007; Otto, 2007; Williams & Stoeber, 2012).
1. Gap 0 (G0)
a) Resting or dormant phase
b) Cells are temporarily out of the cycle and not actively proliferating;
however, all other cellular activities occur.
c) Cells continue in G0 until there is a stimulus to enter the cell cycle.
d) Because they are not actively proliferating, cells in this phase have
some protection from exposure to cell cyclespecific chemotherapy agents.
2. Gap 1 (G1)
a) Postmitotic phase
b) Cells begin the first phase of reproduction and growth by synthesizing proteins and RNA necessary for cell division.
3. Synthesis (S): DNA is replicated.
4. Gap 2 (G2)
a) Premitotic (or postsynthetic) phase
b) The second phase of protein and RNA synthesis occurs.
c) Preparation for mitotic spindle formation occurs.
d) The cell is now prepared for division.
5. Mitosis (M)
a) Cell division occurs.
b) Shortest phase of the cell life cycle
c) At the conclusion of mitosis, two daughter cells result with exact copies of the parent cells DNA. Cells either reenter the cell cycle to reproduce or perform the specific functions of the tissue for which
they are programmed.
6. CyclinCDK complexes (Malumbres, 2007; Williams & Stoeber, 2012)
a) Cyclins are cell cycle kinase regulators (e.g., cyclin D).
b) CDKs are cell cycle kinase inhibitors (e.g., CDK4).
c) Cyclins and CDKs unite and create a complex that propels the cell
through each phase of the cell cycle (e.g., cyclin D-CDK4, cyclin DCDK6, and cyclin E-CDK2 drive G1).
d) CDK mutations have been linked to tumor formation (e.g., CDK6
is overexpressed in many hematologic malignancies, glioblastoma,
and lung cancer).
e) Anti-CDK/cyclin inhibitors are being developed and tested in clinical trials as a method to inhibit tumor growth.
B. Chemotherapeutic agents: Drugs are classified according to pharmacologic
action or their effect on cell reproduction (see Table 7).
25
26
1. Cell cyclespecific drugs exert effect within a specific phase of the cell
cycle (Brown, in press; Hande, 2009).
a) These drugs have the greatest tumor cell kill when given in divided but frequent doses or as a continuous infusion with a short cycle time. This allows the maximum number of cells to be exposed to
the drug at the specific time in their life cycle when they are vulnerable to the drug.
b) Classifications include antimetabolites, plant alkaloids (camptothecins, epipodophyllotoxins, taxanes, and vinca alkaloids), and miscellaneous agents.
2. Cell cyclenonspecific drugs exert effect in all phases of the cell cycle,
including the G0 (resting) phase (Brown, in press; Hande, 2009).
Figure 2. Cell Cycle
Growth Factors
G0
CDK
2,4,5,6
Resting Stage
Cyclin D
Active pRb
protein
(master
brake)
EARLY G1
Cell Division
Cyclins A,B
CDK1
G2
p53
p27
p21
Cyclin E CDK2
LATE G1
DNA
damage
TGF-
Proteins
S
Cyclin A
CDK2
Cyclin B
CDK1
DNA Synthesis
Cyclin B
CDK1
The cell cycle consists of 4 phases (G1, S, G2, M) that are controlled by proteins called cyclins. The cyclins (D, E, A, B) are activated when complexed with enzymes called cyclin-dependent kinases (CDKs). Upon activation, the cyclinCDK complex allows the cell
to progress through each specific cell cycle phase. Present throughout the cell cycle, the cyclinCDK complexes serve as checkpoints or monitors of the cell cycle. Inhibitory proteins prevent progression through the cell cycle if DNA damage is present or there
is a lack of nutrients or oxygen to support cellular proliferation. Examples of inhibitory proteins include p21, p27, p53. The inhibitory
proteins in turn are regulated by the presence of inhibitory growth factors and TGF-. Once past R (the restriction point) the cell cycle is turned on and progression through the cell cycle is inevitable. CyclinCDK complexes and pRB (the master brake) tightly
regulate the R point. The stability of the inhibitory proteins and cyclinCDK complexes are altered in cancer, thereby altering control
of the cell cycle, and uncontrolled cellular proliferation prevails.
Note. From Biology of Cancer (p. 14), by C.J. Merkle in C.H. Yarbro, D. Wujcik, and B.H. Gobel (Eds.), Cancer Nursing: Principles and Practice (7th
ed.), 2011, Burlington, MA: Jones and Bartlett. Copyright 2011 by Jones and Bartlett Publishers. Reprinted with permission.
Table 7. Characteristics of Chemotherapeutic Agents

Classification
Alkylating
agents
Mechanism
of Action
Break DNA helix
strand, thereby
interfering with
DNA replication
Drug
Route of
Administration
Indications
Side Effects
Nursing Considerations
PO
Ovarian cancer
Dose-limiting toxicities: Neurotoxicity, peripheral neuropathy, myelosuppression

Nausea, vomiting, skin rash, hypersensitivity, elevation of LFTs, abdominal
cramps, diarrhea
Do not open capsules.

Monitor for progressive neurologic toxicity.
Instruct patients to take after meals and at bedtime.
(Eisai Inc., 2009)
Bendamustine
(Treanda)
IV
CLL, indolent
NHL
Dose-limiting toxicity: Myelosuppression

Pyrexia, nausea, vomiting, skin reactions
Infuse over 3060 min.

Monitor closely for infusion reactions (especially
in second or subsequent cycles).
Dose reduction or discontinuation may be necessary for hematologic toxicities.
Take precautions for TLS in high-risk patients.
Concomitant use of allopurinol may increase risk
of severe skin toxicity.
(Cephalon, Inc., 2012)
Busulfan (IV:
Busulfex;
oral: Myleran)
IV, PO
CML, BMT preparation
Dose-limiting toxicities: Myelosuppression, pulmonary fibrosis

Profound tachycardia, hypertension,
chest pain, hyperpigmentation, alopecia, sperm or ovarian suppression,
confusion, seizures, mucositis, nausea,
vomiting, insomnia, hyperglycemia,
blurred vision, second malignancy
Hepatic sinusoidal obstruction syndrome
(previously known as veno-occlusive
disease) has been reported in patients
receiving doses > 16 mg/kg in conjunction with alkylating agents for stem cell
transplant (Solimando, 2008).
Monitor blood counts closely. If leukocyte count is

< 20,000/mm3, discontinue drug.
Administer seizure prophylaxis.
Instruct patients to take on an empty stomach to
decrease risk of nausea and vomiting.
IV form should be administered through a central
line and has been associated with inflammation
and pain during infusion.
(PDL BioPharma, Inc., 2007)
Carboplatin
(Paraplatin)
IV
Ovarian cancer
Dose-limiting toxicity: Thrombocytopenia

Neutropenia (myelosuppression is
more pronounced with renal impairment), nausea, vomiting, hypersensitivity reaction, mild alopecia, skin
rash
Drug is an irritant.
Carboplatin exhibits much less renal toxicity than
cisplatin, so rigorous hydration is unnecessary
unless renal dysfunction exists.
Monitor blood counts closely, and reduce the
dose per protocol. Specific dosing guidelines
are recommended for carboplatin. See Figures
15, 16, and 17.
Give after taxanes in sequential regimens to limit
myelosuppression and enhance efficacy.
27
Altretamine
(Hexalen)
28
Table 7. Characteristics of Chemotherapeutic Agents (Continued)
Alkylating
agents (cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Carboplatin
(Paraplatin)
(cont.)
Check creatinine level prior to each dose (for
AUC dosing).
Have emergency medications available for hypersensitivity reaction, which usually occurs after the seventh dose.
(Bristol-Myers Squibb Co., 2010a)
Chlorambucil
(Leukeran)
PO
CLL, HL, NHL
Dose-limiting toxicities: Myelosuppression, skin reactions

Ovarian or sperm suppression, nausea, vomiting, secondary malignancy, hyperuricemia, pulmonary fibrosis, seizure (increased risk in children
with nephrotic syndrome)
Use with caution in patients with seizure history

and within one month of radiation and/or cytotoxic therapy.
(GlaxoSmithKline, 2004)
Cisplatin
(Platinol)
IV
Ovarian, testicular, bladder, lung

cancer
Dose-limiting toxicities: Severe nephrotoxicity, myelosuppression

Severe acute and delayed nausea,
vomiting, ototoxicity (tinnitus and/or
high-frequency hearing loss are most
common), hyperuricemia, hypersensitivity reaction, hypomagnesemia and
other electrolyte abnormalities, peripheral neuropathy, SIADH
Cisplatin is an irritant with vesicant potential if >

20 ml of 0.5 mg/ml concentrated solution is extravasated.
Hold the drug if the patients SCr is > 1.5 mg/dl;
otherwise, irreversible renal tubular damage
may occur (Aronoff et al., 2007). Amifostine
may be used as a renal protectant. Rigorous
hydration is necessary to prevent nephrotoxicity. Use mannitol to achieve osmotic diuresis.
Potential exists for delayed nausea and vomiting
up to 6 days after administration.
Consider obtaining a baseline audiogram.
Monitor electrolytes and replace as needed.
(Bristol-Myers Squibb Co., 2010b)
Cyclophosphamide
(Cytoxan)
Intrapleural, IV,
PO
Breast and ovarian cancers, MM,

leukemias, lymphomas, neuroblastoma, retinoblastoma, mycosis fungoides
Dose-limiting toxicity: Hemorrhagic cystitis

Vomiting, myelosuppression, nausea,
alopecia, may cause a temporary
maxillary burning if administered too
quickly, secondary malignancy, testicular or ovarian failure
High-dose: acute cardiomyopathy,
SIADH
Give the dose, whether IV or PO, early in the day.

Ensure adequate hydration. If given PO, have patients drink 23 L/day (Solimando, 2008).
Have patients empty their bladder frequently
and before bed to prevent hemorrhagic cystitis.
Mesna may be considered in conjunction with
IV fluids for prevention of hemorrhagic cystitis.
Pelvic irradiation potentiates hemorrhagic cystitis.
When used with radiation therapy, potential for
radiation recall exists with subsequent doses of
cyclophosphamide.
(Baxter Healthcare Corp., 2013)
Classification

Classification
Alkylating
agents (cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
IV
Malignant melanoma, HL
Dose-limiting toxicities: Severe neutropenia and thrombocytopenia (with

nadir at 23 weeks or more)
Severe nausea and vomiting for up to
12 hours, anorexia, alopecia, rash,
flu-like syndrome (fever, malaise, myalgias), hypotension, hypersensitivity
reaction (uncommon), photosensitivity, hepatic dysfunction
Dacarbazine is an irritant that may cause tissue necrosis if extravasated. Administer by infusion over 3060 min. May cause severe pain
and burning at the injection site and along the
course of the vein. To reduce these effects, increase the diluent, reduce the infusion rate,
and apply cold compresses to the needle insertion site and along the vein.
Protect solution from light (pink solution indicates
decomposition).
Flu-like syndrome may occur up to 7 days after
drug administration; treat symptoms.
Reduce doses for patients with poor renal function.
(Teva Parenteral Medicines, Inc., 2007)
Ifosfamide
(Ifex)
IV
Testicular cancer
Dose-limiting toxicities: Hemorrhagic

cystitis, myelosuppression
Nausea, alopecia, vomiting, neurotoxicity (somnolence, confusion, hallucinations, depressive psychoses, and encephalopathy)
Methylene blue has been used to treat
ifosfamide-induced encephalopathy;
reports have shown that the encephalopathy may spontaneously resolve
(Patel, 2006).
Administer the drug over 30 min or more.

To prevent hemorrhagic cystitis, always administer with mesna. Mesna may be given PO, as a
bolus dose, as a continuous infusion, or mixed
in the bag with the ifosfamide. Mesna dose
should be 60%100% of the ifosfamide dose
(based on weight). Refer to package insert for
specific dosing recommendations.
(Baxter Healthcare Corp., 2012)
Mechlorethamine (nitrogen mustard,

Mustargen)
IV
HL, NHL, CLL,

CML, mycosis
fungoides
Severe nausea, vomiting, alopecia, myelosuppression, pain or phlebitis at

IV site, chills, fever, testicular or ovarian failure
Drug is a vesicant.
Administer the agent over several minutes
through the side arm of a free-flowing IV. Flush
with 125150 ml NS post infusion.
If extravasation occurs, antidote is sodium thiosulfate. Use mechlorethamine as soon after
preparation as possible (1530 min); it is extremely unstable.
Do not mix mechlorethamine with any other drug.
(Baxter Oncology, 2012)
29
Dacarbazine
(DTIC)
30
Alkylating
agents (cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Melphalan
(Alkeran)
IV, PO
MM, ovarian cancer

Nausea, vomiting, mucositis, hypersensitivity reaction
Myelosuppression may be delayed and last 46

weeks; monitor blood counts carefully. Hold or
reduce dose per institutional protocol.
Instruct patients to take on an empty stomach.
Application of ice chips to oral cavity is recommended during high-dose melphalan administration to prevent oral mucositis (Lilleby et al.,
2006).
Drug must be administered within 1 hour of reconstitution. Infuse over 1530 minutes.
(GlaxoSmithKline, 2011a)
Oxaliplatin
(Eloxatin)
IV
Colorectal cancer
Dose-limiting toxicities: Peripheral

neuropathy, myelosuppression
Acute primary transient peripheral sensory neuropathy that presents within
148 hours, resolves within 14 days,
and manifests as paresthesia, dysesthesia, or hypoesthesia in hands,
feet, oral cavity, and throat; can be
aggravated by cold temperatures
Anaphylactic reaction, nausea, vomiting, diarrhea, pulmonary fibrosis, fatigue, fever
Oxaliplatin has been described as an irritant and

a vesicant.
Consider dose reduction in patients with renal
dysfunction.
Monitor for acute, reversible effects and persistent neurotoxicity.
Avoid ice to oral cavity during oxaliplatin infusion.
For 34 days after therapy, patients should avoid
consuming cold drinks and foods and breathing
cold air (cover mouth with scarf).
Do not prepare or infuse in sodium chloride or
other chloride-containing solutions. D5W solution is recommended (Takimoto et al., 2007).
Flush after oxaliplatin with D5W before administering other medications in the same line.
Infuse after taxanes in sequential regimens.
Calcium and magnesium infusions may be used
during oxaliplatin therapy to reduce neurotoxicities (Wen, 2013).
However, in a trial that included 353 patients with
colon cancer undergoing adjuvant therapy with
FOLFOX (5-FU, oxaliplatin, and leucovorin),
patients were randomized to receive IV calcium and magnesium (1 g calcium gluconate, 1 g
magnesium sulfate) or placebo before and calcium and magnesium after oxaliplatin. In a third
arm in the trial, patients received calcium and
magnesium before and placebo after the oxaliplatin. The results showed no differences between the groups in either acute neurotoxicity
Classification

Classification
Alkylating
agents (cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Oxaliplatin
(Eloxatin)
(cont.)
Temozolomide
(Temodar)
or cumulative sensory neurotoxicity, as assessed both by patient and physician questionnaires (Loprinzi et al., 2013).
(sanofi-aventis U.S. LLC, 2011)
PO, IV
Refractory anaplastic astrocytoma, newly diagnosed glioblastoma multiforme

Nausea, vomiting, headache, fatigue,
liver toxicity, rash, alopecia

Administer IV over 90 minutes.
Instruct patients to take on an empty stomach to
decrease risk of nausea and vomiting.
Do not administer if patients have had an allergic
reaction to dacarbazine.
Administer PCP prophylaxis with trimethoprimsulfamethoxazole in patients receiving with radiation therapy for 42-day regimen.
Take oral dose with a full glass of water.
Consider bedtime administration for oral dosing to decrease nausea and vomiting (Solimando, 2008).
(Merck & Co., Inc., 2013)
Thiotepa
(Thioplex)
IV, IT, intravesical, intratumoral

Hypersensitivity reaction, ovarian or
sperm suppression, nausea, vomiting, pain at infusion site, rash, fever, skin burn, mucositis, hemorrhagic cystitis
Thiotepa is primarily excreted in the urine; monitor renal function carefully.

Myelosuppression may be delayed (1428 days).
Thiotepa used in the transplant setting can
cause severe skin irritation. Frequent showering immediately following and during the first
24 hours after administration helps remove
the chemical from the skin. Additionally, avoid
tapes and skin adherents during and immediately following administration.
(Bedford Laboratories, 2001)
31
Bladder, breast,
and ovarian cancers, HL, NHL
32
Antimetabolites
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Azacitidine is believed to cause

hypomethylation
of DNA and direct cytotoxicity
on abnormal hematopoietic cells
in the bone marrow. Abnormal
cells, including
cancer cells, no
longer respond
to normal growth
control mechanisms. The cytotoxic effects of
azacitidine cause
these cells to die,
whereas nonproliferating cells are
relatively insensitive to the medication.
Azacitidine
(Vidaza)
SC, IV
Patients with specific subtypes of

MDS
Dose-limiting toxicities: Myelosuppression, elevated SCr, renal failure

Nausea, vomiting, diarrhea, fatigue, fever, erythema at injection site, hypokalemia, renal tubular acidosis, hepatic coma, constipation
IV: Mix in 50100 ml NS or LR only. Infuse over

1040 min. Administration should be completed
within 1 hour of reconstitution.
SC: Vigorously shake or roll the vial to mix medication immediately prior to administration (solution should be uniformly cloudy).
Divide doses > 4 ml into two syringes and inject into two separate sites. Invert syringe 23
times and roll vigorously between palms prior
to administration. To minimize skin irritation,
ensure that the needle is empty of drug, and do
not expel air in needle before giving the
injection. Do not use ice on injection site, as it
may decrease drug absorption. Rotate sites for
administration among thigh, abdomen, and
upper arm. Administer new injections at least
one inch from old site. Avoid sites that are
tender, bruised, red, or hard.
Monitor CBC and liver and renal function during
therapy.
Drug is contraindicated in patients with hypersensitivity to azacitidine or mannitol and those
with advanced malignant hepatic tumors.
(Celgene Corp., 2012b)
Act in S phase;
inhibit enzyme
production for
DNA synthesis,
leading to strand
breaks or premature chain termination
Capecitabine
(Xeloda)
PO
Breast and metastatic colon cancers
Dose-limiting toxicities: Diarrhea,

palmar-plantar erythrodysesthesia
(hand-foot syndrome)
Mucositis, nausea, vomiting, anemia,
increased bilirubin, fatigue
Patient education regarding importance of reporting toxicity and dose reduction is critical.
Drug is contraindicated in patients with known
hypersensitivity to 5-FU.
Monitor PT and INR closely, as capecitabine increases effect of warfarin.
Administer with food and water.
(Genentech, Inc., 2010)
Cladribine
(Leustatin)
IV
Hairy cell leukemia
Dose-limiting toxicities: Myelosuppression, neurotoxicity

Fever, nausea, vomiting, hypersensitiv
ity reaction, TLS, nephrotoxicity (highdose therapy)
Allopurinol and IV hydration are recommended for patients with high tumor burden to prevent TLS.
Use with caution in patients with liver and renal
dysfunction.
(Centocor Ortho Biotech Products, L.P., 2012)
Classification

Classification
Antimetabolites (cont.)
Mechanism
of Action
A purine nucleoside antimetabolite that incorporates into the
DNA chain inhibiting DNA repair
Drug
Route of
Administration
Indications
Side Effects
IV
Patients ages
121 with relapsed or refractory ALL
Dose-limiting toxicities: Bone marrow

suppression (including anemia, leukopenia, thrombocytopenia, neutropenia, and febrile neutropenia), infection, hepatobiliary toxicity, renal toxicity
Nausea, vomiting, diarrhea, rare cases
of systemic inflammatory response
syndrome/capillary leak syndrome
and cardiac toxicity including tachycardia, pericardial effusion, and left
ventricular systolic dysfunction; TLS,
headache, pruritus, rash
Continuous IV fluid administration during the 5

days of chemotherapy administration is encouraged to reduce risk of TLS and other adverse
effects.
Use prophylactic steroids to help prevent systemic inflammatory response syndrome and capillary leak syndrome.
Give allopurinol if hyperuricemia is expected.
Monitor respiratory status and blood pressure
during infusion.
Monitor renal and hepatic function during the
days of administration.
Monitor hematologic status closely following
treatment.
(Genzyme Corp., 2013)
Cytarabine
(cytosine arabinoside,
ARA-C,
Cytosar-U)
IV, SC, IT
ALL, AML, CML,

CNS leukemia

Nausea, vomiting, anorexia, fever, mucositis, diarrhea, hepatic dysfunction,
rash, pruritus, localized pain and/or
thrombophlebitis at IV site, photophobia
High-dose (13 g/m2): cerebellar toxicity, keratitis (treat with dexamethasone ophthalmic drops), dermatologic toxicities
Determine if ordered dose is standard dose or

high dose; administer according to institutional guidelines.
Note: Toxicities vary depending upon rate of
high-dose cytarabine administration. Continuous-infusion cytarabine is associated with pulmonary toxicity (fluid overload), and bolus administration is associated with cerebellar toxicities. Specific nursing interventions are warranted for each.
For IT administration: Use preservative-free saline.
Allopurinol and IV hydration are recommended
for newly diagnosed patients with AML or patients with high tumor burden to prevent TLS.
(APP Pharmaceuticals, LLC, 2008a)
Cytarabine
liposomal
(DepoCyt)
IT only
Lymphomatous
meningitis
High-dose: mucositis, diarrhea, chemical arachnoiditis (nausea, vomiting,

headache, fever), neurotoxicity, seizure, nausea, vomiting, constipation,
weakness
Do not use in pediatric patients.

Administer IT only.
Patients should lie flat for 1 hour after lumbar
puncture.
Monitor closely for immediate toxic reactions.
Administer dexamethasone 4 mg BID (PO or IV)
for 5 days (start day of cytarabine administration) to decrease symptoms of chemical arachnoiditis.
(Sigma-Tau Pharmaceuticals, Inc., 2011a)
33
Clofarabine
(Clolar)
34
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Decitabine
(Dacogen)
IV
MDS
Myelosuppression, fever, fatigue, nausea, cough, constipation, diarrhea,

hyperglycemia, petechiae, peripheral edema
Delay treatment if SCr 2 mg/dl or total bilirubin

2 ULN until resolved.
Use within 15 min of reconstitution. If this is not
possible, return to pharmacy so solution can be
prepared in cold infusion fluid.
(Eisai Inc., 2010a)
Floxuridine
(FUDR)
Intra-arterial, IV
Adenocarcinoma
of GI tract with
metastasis to liver, gallbladder, or
bile duct
Myelosuppression, nausea, vomiting,

diarrhea, mucositis, alopecia, photosensitivity, darkening of the veins, abdominal pain, gastritis, enteritis, hepatotoxicity, palmar-plantar erythrodysesthesia

Recommendations about dose reduction apply to
patients with compromised liver function. Adjust
dose per institutional protocol and monitor hepatic function carefully.
(APP Pharmaceuticals, LLC, 2008b)
Fludarabine
(Fludara)
IV, PO
CLL

Nausea, vomiting, diarrhea, rash, neurotoxicity, interstitial pneumonitis,
weakness, hemolytic anemia, cough,
infection
Administer as a 30-min infusion.

Monitor PFTs.
Allopurinol and IV hydration are recommended
for newly diagnosed patients with CLL or patients with high tumor burden to prevent TLS.
Do not use in combination with pentostatinmay
cause severe pulmonary toxicity.
Use with caution in patients with renal impairment.
Tablets may be taken with or without food.
Do not chew, break, or crush tablets.
Fluorouracil
(5-FU, Adrucil)
IV, topical
Colorectal,
breast, pancreatic, and stomach
cancers
Dose-limiting toxicities: Mucositis,

myelosuppression
Nausea, anorexia, vomiting, diarrhea,
alopecia, ocular toxicities (e.g., increased lacrimation, photosensitivity),
darkening of the veins, dry skin, cardiac toxicity (rare), neurotoxicity
Ensure that patients take year-round photosensitivity precautions; encourage sunscreen use if
patients must be exposed.
Leucovorin often is given concurrently to enhance 5-FU activity.
Apply ice chips to the oral cavity 1015 min
pre- and post-IV bolus dose of 5-FU to reduce
oral mucositis in patients with GI malignancies. Not recommended in patients receiving
capecitabine or oxaliplatin because of potential
discomfort with exposure to coldness.
Gemcitabine
(Gemzar)
IV
Pancreatic,
breast, and ovarian cancers,
NSCLC
Dose-limiting toxicity: Myelosuppression (especially thrombocytopenia)

Nausea, vomiting, fever, flu-like symptoms, rash, peripheral edema, pulmonary toxicity with increased infusion time

Infuse over 30 min; infusion longer than 60 min or
more than weekly can increase pulmonary toxicity.
(Eli Lilly and Co., 2011)
Classification

Classification
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
PO
ALL

Mucositis, nausea, hyperuricemia, alopecia, hyperpigmentation
Reduce oral dose by 75% when used concurrently with allopurinol.

Patients should take drug on an empty stomach,
1 hour before or 2 hours after meals.
(Gate Pharmaceuticals, 2011)
Methotrexate
IM, IV, IT, PO,

SC
HD, NHL, leukemia; CNS metastasis; lung, breast,

and head and neck
cancers; gestational trophoblastic tumor; osteogenic
sarcoma; rheumatoid arthritis; psoriasis; gestational
choriocarcinoma,
chorioadenoma
destruens, and hydatidiform mole
Dose-limiting toxicities: Hepatotoxicity, renal toxicity

Mucositis, nausea, myelosuppression,
oral or GI ulceration, pneumonitis,
photosensitivity, neurotoxicity associated with high-dose therapy
Drug is yellow in color.

High doses must be followed by timely administration of leucovorin and vigorous hydration.
Follow dosing schedule carefully.
Monitor serum methotrexate levels until 0.1
mmol. Monitor urine pH and maintain at 7 before treatment and until methotrexate levels are
0.1 mmol.
Instruct patients on strict mouth care.
Patients must take photosensitivity precautions.
Ensure that patients avoid taking multivitamins
with folic acid.
Multiple drug interactions (e.g., NSAIDs, alcohol,
aspirin, warfarin, aminoglycosides) are possible.
Methotrexate is contraindicated in patients with
pleural or pericardial effusions and ascites because of severe toxicity from methotrexate accumulation.
Glucarpidase (Voraxaze) is FDA approved for
patients with delayed methotrexate clearance
due to renal impairment. This drug reduces
systemic methotrexate levels by rapidly converting methotrexate to glutamate and 4-deoxy4-amino-N10-methylpteroic acid (DAMPA).
(BTG International Inc., 2013; Hospira, Inc., 2011b)
Nelarabine
(Arranon)
IV
T-cell acute lymphoblastic leukemia and T-cell

lymphoblastic lymphoma
Dose-limiting toxicity: Neurotoxicity

Myelosuppression, headache, nausea, vomiting, diarrhea, constipation,
cough, peripheral edema, fatigue, peripheral neuropathy, dyspnea, neurologic toxicities (somnolence, seizures,
ataxia)
Given as undiluted IV infusion over 2 hours for

adults and 1 hour for pediatrics.
Administer with appropriate supportive care
medications to prevent hyperuricemia and TLS.
Discontinue for grade 2 neurologic events
(severe somnolence, seizure, and peripheral
neuropathy).
Use caution in patients with renal or hepatic dysfunction.
(GlaxoSmithKline, 2011b)
35
Mercaptopurine (6-MP,
Purinethol)
36
Mechanism
of Action
Disrupts folatedependent metabolic processes
essential for cell
replication
Drug
Route of
Administration
Indications
Side Effects
Pemetrexed
(Alimta)
IV
Given in combination with cis

platin for the
treatment of malignant pleural mesothelioma; nonsquamous NSCLC initial treatment in
combination with
cisplatin or as a
single-agent after prior chemotherapy

Side effects with pemetrexed plus cisplatin regimen include myelosuppression, fatigue, nausea, vomiting, chest
pain, and dyspnea. Side effects are
reduced with vitamin supplementation.
Renal and liver toxicity
Infuse over 10 minutes.

To reduce treatment-related hematologic and GI
toxicity, administer folic acid 3501,000 mcg
PO daily starting 1 week prior to the first cycle
and daily for three weeks after final cycle. Give
vitamin B12 injection 1,000 mcg IM 1 week before first cycle and repeat every 9 weeks until
treatment is completed.
Dexamethasone 4 mg BID for 3 days starting the
day before treatment decreases incidence of
skin rash.
Monitor CBC on days 8 and 15. Hold treatment
if absolute neutrophil count < 1,500 cells/mm3,
platelet count < 100,000 cells/mm3, or creatinine clearance < 45 ml/min.
Monitor renal and hepatic function.
The concurrent use of NSAIDs may increase the
risk of renal damage.
(Eli Lilly and Co., 2013)
Pentostatin
(Nipent)
IV
Hairy cell leukemia

Fever, chills, nausea, vomiting, rash,
renal failure, confusion, hepatic enzyme elevation, lymphocytopenia,
heightened infection risk, cough
Administer with 5001,000 ml 5% dextrose in

NS solution prior to the infusion and an additional 500 ml after infusion.
Do not administer with fludarabine, carmustine, etoposide, or high-dose cyclophosphamide.
(Bedford Laboratories, 2010c)
Pralatrexate
(Folotyn)
IV
Peripheral T-cell
lymphoma

Mucositis, dermatologic reactions, TLS,
edema, fatigue, nausea
Must give prophylactic folic acid and vitamin B12

supplements. Supplement patients with vitamin
B12 1 mg IM every 810 weeks and folic acid
11.25 mg PO daily.
Monitor liver and renal function.
Concurrent use with drugs with extensive renal clearance may delay pralatrexate clearance.
(Allos Therapeutics, 2011)
Thioguanine
(Tabloid,
6-TG)
PO
AML

Hyperuricemia, nausea, hepatotoxicity, diarrhea
Monitor hepatic function.

Classification

Classification
Antitumor
antibiotics
Mechanism
of Action
Bind with DNA,
thereby inhibiting
DNA and RNA
synthesis
Drug
Route of
Administration
Indications
Side Effects
IV, SC, IM, intrapleural
Malignant pleural effusion; squamous cell cancer

of head and neck;
cervical, vulvar,
penile, and testicular cancers; HL;
NHL
Dose-limiting toxicities: Hypersensitivity or anaphylactic reaction (rare),

pulmonary toxicity
Hyperpigmentation, alopecia, photosensitivity, renal toxicity, hepatotoxicity, fever, chills, erythema, rash, mucositis
Patients with lymphoma have a higher incidence

of anaphylaxis after receiving bleomycin than
do other patients who receive the drug. Therefore (per institutional protocol), a test dose of
12 units IV, IM, or SC may be administered
before the first dose of bleomycin in patients
with lymphoma.
Patients who have received prior bleomycin are
at risk for pulmonary toxicity when exposed to
oxygen during surgery. Ensure that patients
and family members understand the lifelong
necessity of disclosing previous use of bleomycin when future needs for anesthesia occur to prevent a fatal episode of pulmonary
failure.
Because of the dose-related incidence of pulmonary fibrosis, the cumulative lifetime dose
should not exceed 400 units.
PFTs are recommended at initiation of bleomycin and every 12 months thereafter. Consider stopping drug if a 30%35% decrease from
pretreatment values occurs. Acetaminophen
and an antihistamine may decrease fever and
chills in first 24 hours after administration.
(Bedford Laboratories, 2009)
Dactinomycin
(actinomycin D,
Cosmegen)
IV
Ewing sarcoma,
Wilms tumor, testicular cancer,
gestational trophoblastic disease, rhabdomyosarcoma

Nausea, vomiting, alopecia, mucositis,
diarrhea, ovarian or sperm suppression, radiation recall (hyperpigmentation of previously irradiated areas), sinusoidal obstruction syndrome, hepatic and renal toxicity
Dactinomycin is a vesicant.
This drug may be ordered in micrograms, so
check the dose carefully.
Contraindicated in patients with concurrent or recent chickenpox or herpes zoster.
Avoid within 2 months of radiation therapy for
right-sided Wilms tumor.
(Ovation Pharmaceuticals, 2008)
Mitomycin
(Mutamycin)
IV
Intravesicular
Pancreatic, stomach, and bladder

cancers
Dose-limiting toxicities: Myelosuppression, CHF (doses > 30 mg/m2)

Nausea, vomiting, anorexia, alopecia,
mucositis, renal toxicity, pulmonary
toxicity, fatigue
Drug is purple/blue in color.

Mitomycin is a vesicant.
Nadir occurs 46 weeks after treatment begins.
Acute shortness of breath and bronchospasm
can occur very suddenly when this drug is given with a vinca alkaloid.
37
Bleomycin
(Blenoxane)
38

Mechanism
of Action
Antitumor
antibiotics
(cont.)
Antitumor
antibiotics
(anthracyclines)
Drug
Route of
Administration
Indications
Side Effects
Mitomycin
(Mutamycin)
(cont.)
Bind with DNA,

thereby inhibiting
DNA and RNA
synthesis
Contraindicated in patients with coagulation disorders.
Hemolytic-uremic syndrome has been seen with
single dose 60 mg or cumulative doses 50
mg/m2.
(Bristol-Myers Squibb Co., 2006c)
Mitoxantrone
(Novantrone)
IV
Breast and prostate cancers,

AML, multiple
sclerosis
Dose-limiting toxicities: Myelosuppression, cardiotoxicity

Arrhythmia (if patient was treated with
doxorubicin), nausea, vomiting, mucositis, alopecia, edema, fever, weakness, cardiotoxicity; drug may turn
the urine blue-green and can cause
sclera to turn bluish.
Fatal if given intrathecally.

Mitoxantrone is an irritant with vesicant potential.
Drug is blue in color.
Risk of cardiotoxicity with mitoxantrone is less
than that with doxorubicin, but prior anthracycline use, chest irradiation, or cardiac disease
increases risk.
Prior to beginning therapy, evaluate patients for
cardiac signs/symptoms including obtaining
MUGA scan and baseline LVEF.
(EMD Serono, Inc., 2010)
Daunorubicin (Cerubidine, Daunomycin)
IV
ALL in children,
AML

Nausea, vomiting, alopecia, hyperuricemia, radiation recall, ovarian or
sperm suppression; drug may turn
the urine red.
Daunorubicin is a vesicant.
Drug is red in color.
Test patients cardiac ejection fraction scan before starting therapy.
Use in caution in patients with renal or hepatic
dysfunction.
Total lifetime dose in adults is 550 mg/m2 without
cardiovascular risk factors and 400 mg/m2 in
adults receiving chest irradiation.
(Bedford Laboratories, 2010a)
Daunorubicin
citrate liposomal (DaunoXome)
IV
AIDS-related Kaposi sarcoma

Nausea, vomiting, alopecia, fatigue, fever, diarrhea, hyperuricemia, radiation recall, ovarian or sperm suppression; drug may turn the urine red.

Daunorubicin citrate liposomal is not a vesicant
but should be considered an irritant; take caution to avoid extravasation.
Consider dose reduction in patients with renal or
hepatic dysfunction.
Test patients cardiac ejection fraction before
starting daunorubicin liposomal therapy.
This drug must be mixed in D5W only. Do not use
in-line filters.
(Gilead Sciences, 2011)
Classification

Classification
Antitumor
antibiotics
(anthracyclines) (cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
IV
Breast, prostate,
ovarian, stomach, bladder, thyroid, and small
cell lung cancers;
MM, HL, NHL,
ALL, AML; Wilms
tumor, lymphoma,
sarcoma, neuroblastoma
Dose-limiting toxicities: Myelosuppression, cardiotoxicity, hepatotoxicity

Nausea, vomiting, alopecia, mucositis, radiation recall, arrhythmia, hyperuricemia, photosensitivity; drug may
turn the urine red.
Doxorubicin is a vesicant.
Doxorubicin may cause a flare reaction.
starting therapy.
Do not exceed a lifetime cumulative dose of 550
mg/m2 (450 mg/m2 if the patient has had prior
chest irradiation or concomitant cyclophosphamide treatment).
Consider initiating dexrazoxane (Zinecard) for
patients who have received a cumulative dose
of 300 mg/m2 and are continuing doxorubicin
treatment. In pediatrics, dexrazoxane may be
used concurrently.
(Pfizer Inc., 2010)
Doxorubicin liposomal
(Doxil)
IV
AIDS-related Kaposi sarcoma,

ovarian cancer,
MM

Nausea, vomiting, alopecia, mucositis,
arrhythmia, hyperuricemia, radiation
recall, palmar-plantar erythrodysesthesia, photosensitivity, hypersensitivity reaction, electrolyte imbalance;
drug may turn the urine red.

Doxorubicin liposomal is not a vesicant but
should be considered an irritant; take caution to
avoid extravasation.
The same warnings as with conventional doxorubicin apply regarding cardiovascular complications.
Use only with D5W.
Do not substitute for Adriamycin.
Start infusion at 1 mg/min over at least 30 min to
minimize infusion-related reactions. Do not use
in-line filter.
(Janssen Products, LP, 2013)
Epirubicin
(Ellence)
IV
Breast cancer

Nausea, vomiting, mucositis, diarrhea,
alopecia, amenorrhea, infection, radiation recall; drug may turn the urine
red.
Epirubicin is a vesicant.
Consider dose reduction in patients with liver
dysfunction.
Not recommended in patients with severe hepatic dysfunction.
Reduce dose in patients with SCr > 5 mg/dl.
Cumulative dosing should not exceed 900 mg/
m2.
starting epirubicin therapy.
(Pfizer Inc., 2011)
39
Doxorubicin
(Adriamycin)
40

Mechanism
of Action
Route of
Administration
Indications
Side Effects
Idarubicin
(Idamycin)
IV
ANLL
Dose-limiting toxicities: Myelosuppression, cardiomyopathy

Nausea, vomiting, alopecia, vein itching, radiation recall, rash, mucositis,
diarrhea, GI hemorrhage; drug may
turn the urine red or darker yellow.
Idarubicin is a vesicant. Infuse slowly over 1015

min into free-flowing side-arm infusion.
Drug is red-orange in color.
Cardiotoxicity of idarubicin is less than that of
daunorubicin.
Cumulative doses > 150 mg/m2 idarubicin are associated with decreased ejection fraction.
Local reactions (hives at injection site) may occur.
hepatic impairment.
Do not administer to patients with bilirubin > 5
mg/dl.
(Teva Parenteral Medicines, Inc., 2009a)
Valrubicin
(Valstar)
Intravesical
Intravesical therapy of BCG-refractory in situ bladder cancer
Dysuria, bladder spasm and irritation,

urinary incontinence, leukopenia, hyperglycemia; drug may turn the urine
red.

Valrubicin is administered as an intravesicular
bladder lavage.
Administer through non-PVC tubing.
(Endo Pharmaceuticals Solutions Inc., 2012)
Degrades the
chimeric PML/
RAR-alpha protein; degrades
the NB4 human
promyelocytic
leukemia cells
to cause partial
maturation and
trigger apoptosis;
causes the release of toxic free
radicals inside
the cell that triggers apoptosis of
the APL cell
Arsenic
trioxide
(Trisenox)
IV
APL
Fatigue, prolonged QT interval, APL

differentiation syndrome, leukocytosis, headache, nausea, vomiting, diarrhea, musculoskeletal pain, peripheral neuropathy, tachycardia, edema,
fever, insomnia, dermatitis, cough,
dyspnea
Use with caution with other agents that prolong

QT/QTc interval. Obtain baseline ECG prior to
therapy. Ensure QTc interval < 500 msec prior to infusion. Periodic QTc intervals should be
measured during therapy (e.g., weekly) per institutional guidelines.
Use with caution in patients with renal impairment. Monitor electrolytes during therapy. Maintain serum potassium > 4 mEq/L and magnesium > 1.8 mg/dl.
Inhibits protein
synthesis
Asparaginase
(Elspar)
IV, SC, IM
ALL
Dose-limiting toxicity: Pancreatitis

Nausea, vomiting, hepatotoxicity, fever,
hyperglycemia, anaphylaxis, coagulopathy, hypoalbuminemia, hypersensitivity reaction, renal toxicity, thrombus
Giving the drug IM greatly reduces the incidence

of anaphylaxis.
Keep medications to treat anaphylaxis at bedside.
(Lundbeck, 2013)
Antitumor
antibiotics
(anthracyclines) (cont.)
Miscellaneous
Drug
Classification

Classification
Mechanism
of Action
Miscellaneous
(cont.)
Drug
Route of
Administration
Indications
Side Effects
IM
ALL, for patients

who have developed sensitivity to
E. coli-derived asparaginase
Nausea, vomiting, hepatotoxicity, fever,

hyperglycemia, anaphylaxis, pancreatitis, coagulopathy, hypersensitivity
reaction, renal toxicity, thrombus
Keep medications to treat anaphylaxis at bedside.

Limit the volume of reconstituted Erwinaze at
a single injection site to 2 ml; if reconstituted
dose to be administered is > 2 ml, use multiple
injection sites.
(EUSA Pharma [USA], Inc., 2011)
Pegaspargase
(Oncaspar)
IM, IV
ALL (may be
used upfront or
for those who
have developed
hypersensitivity to
asparaginase)
Hepatotoxicity, coagulopathy, anaphylaxis, hyperglycemia
Longer half-life (56 days) than asparaginase (12

days); therefore, is dosed every 14 days versus
daily or every 3 days. Check dosing carefully.
Risk of anaphylaxis is less than that of asparaginase.
(Sigma-Tau Pharmaceuticals, Inc., 2011b)
Acts in S phase
as antimetabolite
Hydroxyurea
(Hydrea,
Mylocel)
PO
CML, malignant
melanoma, squamous cell cancer
of the head and
neck, metastatic ovarian cancer,
sickle-cell anemia
Dose-limiting toxicities: Myelosuppression, nausea, vomiting, diarrhea,

renal failure, mucositis, fever, hyperuricemia, rash, hepatotoxicity, second
malignancies

Adjust the dose according to WBC counts; monitor WBCs at least every 2 weeks, and stop
treatment until counts recover. Do not change
the dose frequently in older patients because
they may be more sensitive to the medication.
Instruct patients on strict mouth care.
Doses may be divided within the 24-hour period
to decrease nausea and vomiting.
Inhibits adrenal steroid production
Mitotane
(Lysodren)
PO
Adrenocortical
cancer
Nausea, vomiting, mucositis, adrenal

insufficiency, lethargy, rash
Monitor patients on warfarin therapy closely with

PT/INR.
Adrenal steroid replacement is indicated.
hepatic impairment.
May inhibit protein, RNA, and

DNA synthesis
Procarbazine
(Matulane)
PO
HL

Nausea, vomiting, hepatic dysfunction
Patients should avoid foods high in tyramine,

such as aged cheeses, air-dried or cured
meats, fava or broad bean pods, tap/draft beer,
wine (> 120 ml), vermouth, marmite concentrate, sauerkraut, and soy sauce and other soybean condiments because procarbazine inhibits monoamine oxidase.
Patients should avoid alcohol for possible
Antabuse-like reaction.
(Sigma-Tau Pharmaceuticals, Inc., 2012)
41
Asparaginase
Erwinia chrysanthemi (Erwinaze)
42
Miscellaneous
(cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Inhibits growth
phase of microtubules, arresting
cell cycle at G2/M
phase
Eribulin
(Halaven)
IV
Breast cancer
Dose-limiting toxicities: Neutropenia,

neurotoxicity
Peripheral neuropathy, fatigue, alopecia, nausea, constipation, anemia,
QTc prolongation
Monitor electrolytes, ECG, and renal and liver

function tests.
Not compatible with D5W.
(Eisai Inc., 2010b)
Inhibits the enzymatic activity

of HDAC, which
allows for the
accumulation of
acetyl groups on
histone lysine
residue, which
results in cell cycle arrest and/
or apoptosis
of some transformed cells
Romidepsin
(Istodax)
IV
Cutaneous and
peripheral T-cell
lymphoma
Dose-limiting toxicities: Myelosuppression, life-threatening infections

QTc prolongation, fatigue, fever, pruritus, nausea, vomiting, anorexia, constipation, diarrhea, TLS
Obtain baseline and periodic ECG.

Monitor and correct electrolytes.
(Celgene Corp., 2013)
Inhibits the enzymatic activity of

HDAC, which allows for the accumulation of
acetyl groups on
the histone lysine residue,
which results in
cell cycle arrest
and/or apoptosis
of some transformed cells
Vorinostat
(Zolinza)
PO
Cutaneous T-cell
lymphoma
Dose-limiting toxicities: Thrombocytopenia, diarrhea

Anemia, fatigue, nausea, thromboembolism, anorexia, dysgeusia, proteinuria, QTc prolongation
Instruct patients to take once daily with food.

Monitor CBC, electrolytes, glucose, and SCr every 2 weeks during first 2 months and monthly
thereafter because of possible hyperglycemia
and QT prolongation.
Capsules should not be opened or crushed.
Drug may interact with warfarin (Coumadin) (increasing PT/INR) and other HDAC inhibitors
(valproic acid) (severe thrombocytopenia and
GI bleeding).
Classification

Classification
Miscellaneous
(cont.)
Nitrosoureas
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Ixabepilone
(Ixempra)
IV
Metastatic or locally advanced

breast cancer
Dose-limiting toxicities: Peripheral sensory neuropathy, myelosuppression

Fatigue, myalgia, alopecia, nausea,
vomiting, mucositis, diarrhea, musculoskeletal pain
CYP3A4 inhibitors may increase ixabepilone

concentration, and CYP3A4 inducers may decrease ixabepilone concentration. Avoid St.
Johns wort.
Premedicate with diphenhydramine and famotidine or ranitidine 1 hour prior to dose to decrease risk of hypersensitivity reaction.
Mix only in LR in non-PVC bag. Administer
through 0.21.2 micron in-line filter.
(Bristol-Myers Squibb Co., 2011c)
Inhibits protein
synthesis and
is independent
of direct Bcr-Abl
binding
Omacetaxine
(Synribo)
SC
CML in chronic or accelerated

phase with resistance and/or intolerance to 2 or
more TKIs

Thrombocytopenia with bleeding risk,
hyperglycemia, nausea, vomiting, diarrhea, alopecia, skin rash, injectionsite reactions
Monitor patient for bleeding.

Rotate injection sites.
(Teva Pharmaceuticals USA, Inc., 2012)
Break DNA helix,

interfering with
DNA replication;
cross the bloodbrain barrier
Carmustine
(BiCNU)
IV, implantation
(Gliadel wafer)
HL, NHL, CNS tumors, MM

Nausea, vomiting, renal toxicity, hepatotoxicity, pulmonary fibrosis, ovarian
or sperm suppression
Nadir occurs 46 weeks after therapy starts.

Because of delayed toxicity, successive treatments usually are given no more frequently
than once every 68 weeks.
Rapid infusion may cause burning along the vein
and flushing of the skin (infuse over at least 2
hours).
Mix in D5W non-PVC bag.
Long-term therapy can result in irreversible pulmonary fibrosis, which may present as an insidious
cough and dyspnea or sudden respiratory failure.
(Bristol-Myers Squibb Co., 2007)
Lomustine
(CeeNU)
PO
CNS and brain

tumors; HL

Nausea, vomiting, alopecia, renal toxicity, hepatic toxicity, mucositis, anorexia, pulmonary fibrosis
Because of delayed myelosuppression, do not

repeat the dose more than once every 6 weeks.
Administer on an empty stomach.
Monitor PFTs, LFTs, and renal function.
43
Semisynthetic analog of epothilone B; binds

to beta-tubulin
on microtubules,
leading to cell
death by blocking cells in mitotic phase of cell
division cycle
44

Mechanism
of Action
Nitrosoureas
(cont.)
Camptothecins
Plant
alkaloids
(epipodophyllotoxins)
Act in S phase;
inhibit topoisomerase I; cause
double-strand
DNA changes
Induce irreversible blockade of

cells in premitotic phases of
cell cycle (late
G2 and S phases); interfere with
topoisomerase II
enzyme reaction
Drug
Route of
Administration
Indications
Side Effects
Streptozocin
(Zanosar)
IV
Metastatic isletcell pancreatic

carcinoma
Dose-limiting toxicity: Renal toxicity

Myelosuppression, nausea, vomiting,
hypoglycemia, proteinuria, hepatotoxicity
Streptozocin is an irritant.
Nephrotoxicity may be dose limiting.
This drug may alter glucose metabolism in some
patients.
Rapid infusion may cause burning along the vein.
(Sicor Pharmaceuticals, 2006)
Irinotecan
(Camptosar)
IV
Metastatic
colorectal cancer
Dose-limiting toxicity: Diarrhea

Myelosuppression, alopecia, fever,
nausea, vomiting, mucositis, increased bilirubin, weakness

This drug can cause early and late diarrhea,
which can be dose limiting. Early diarrhea can
occur within 24 hours of administration and
generally is cholinergic. Many institutions use
atropine to treat early diarrhea. Refer to institutional protocol regarding dosing and administration of atropine and other antidiarrheals.
(Hospira, Inc., 2011a)
Topotecan
(Hycamtin)
IV, PO
Metastatic ovarian cancer, cervical cancer, SCLC
Dose-limiting toxicity: Diarrhea

Myelosuppression, alopecia, nausea,
vomiting, headache, fatigue, fever, interstitial lung disease

impairment.
Do not crush, chew, or break capsules.
Etoposide
(VP-16,
Toposar,
VePesid)
Etoposide
phosphate
(Etopophos)
IV, PO
Testicular cancer,
SCLC

Nausea, vomiting, alopecia, anorexia, hypotension, hypersensitivity reaction, anaphylaxis
High-dose: Mucositis, diarrhea, myocardial infarction, angina
Do not administer this drug by means of rapid

IV infusion or IV push. Infuse over 3060 min
to avoid hypotension.
Monitor patients blood pressure during infusion.
Prior to use, dilute the drug to a final concentration of 0.20.4 mg/ml to prevent precipitation.
Monitor for crystallization during infusion.
If a patient has an allergic reaction to etoposide, premedicate with diphenhydramine.
Do not administer to patients with bilirubin > 5
mg/dl.
or hepatic impairment.
(Bedford Laboratories, 2010b; Bristol-Myers
Squibb Co., 2011a)
Classification

Classification
Mechanism
of Action
Plant
alkaloids
(epipodophyllotoxins)
(cont.)
Plant
alkaloids
(taxanes)
Stabilize microtubules, inhibiting

cell division; effective in G2 and
M phases
Drug
Route of
Administration
Indications
Side Effects
IV
Childhood ALL

Hypotension, anaphylaxis, nausea,
vomiting, mucositis, alopecia
Drug may cause an allergic reaction.

Do not administer via rapid infusion; infuse over
3060 min; monitor patients blood pressure
during the infusion.
Administer through non-PVC tubing.
hepatic impairment.
(Bristol-Myers Squibb Co., 2011e)
Cabazitaxel
(Jevtana)
IV
Prostate cancer
Hypersensitivity reaction, fatigue, diarrhea, nausea, vomiting, myelosuppression, peripheral neuropathy, abdominal pain, back pain, arthralgia,
asthenia
Premedicate as follows to prevent hypersensitivity reaction, including anaphylaxis, at least 30

min before treatment: IV antihistamine, corticosteroid, and an H2 antagonist.
Administer over 1-hour infusion.
Not recommended in patients with severe hepatic impairment.
Docetaxel
(Taxotere)
IV
NSCLC; breast,
head and neck,
prostate, and
gastric cancers
Myelosuppression, hypersensitivity reaction, fluid retention, alopecia, skin

and nail changes, mucositis, nausea,
vomiting, paresthesia, neurotoxicity

Docetaxel is an irritant. Extravasation may lead
to edema, erythema, and occasional pain
and blister formation.
Premedicate as follows to reduce the severity of hypersensitivity reaction and fluid retention: dexamethasone 8 mg PO BID, beginning
1 day prior to docetaxel treatment and continuing for the day of treatment and 1 day after.
Do not use PVC tubing or bags to administer
docetaxel.
Consider dose reduction in patients with hepatic impairment.
45
Teniposide
(VM-26,
Vumon)
46
Plant
alkaloids
(taxanes)
(cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Paclitaxel
(Taxol)
IV
Metastatic breast,
and ovarian, cancers, NSCLC,
AIDS-related Kaposi sarcoma
Dose-limiting toxicities: Peripheral

neuropathy, hypersensitivity reaction
Myelosuppression, alopecia, facial
flushing, myalgia, fatigue, cardiac arrhythmias, mucositis, diarrhea, nausea, vomiting

Paclitaxel is an irritant and potential vesicant. Extravasation may lead to local pain, edema, and
erythema at the infusion site. There are reports
of necrosis.
Drug is mixed in a mineral oillike solvent that
can cause infusion-related hypersensitivity reactions.
Premedicate as follows to help to prevent hypersensitivity reaction, including anaphylaxis, 30
60 min before treatment: cimetidine 300 mg or
famotidine 20 mg IV, diphenhydramine 50 mg
IV, and (unless contraindicated) dexamethasone 20 mg IV (Solimando, 2008).
Filter paclitaxel with a 0.2 micron in-line filter.
Use glass bottles or non-PVC (polyolefin or polypropylene) bags to administer paclitaxel; do not
use PVC tubing or bags.
hepatic impairment.
To prevent severe myelosuppression, give paclitaxel before platinum-containing drugs.
(Bristol-Myers Squibb Co., 2011d)
Paclitaxel protein-bound
particles; albumin-bound
(Abraxane)
IV
Treatment of metastatic breast

cancer after failure of combination chemotherapy or relapse
within 6 months
of adjuvant therapy and NSCLC

Sensory neuropathy, myalgia, arthralgia, nausea, vomiting, diarrhea, mucositis, alopecia
Drug is free of solvents; therefore, no premedication is required to prevent hypersensitivity reactions.

Consider dose reduction by about 20% for severe sensory neuropathy; resume treatment
with reduced dose when neuropathy improves
to grade 1 or 2 (Solimando, 2008).
Do not use in patients with baseline neutrophil
count < 1,500 cells/mm3.
(Celgene Corp., 2012a)
Classification

Classification
Plant alkaloids (vinca
alkaloids)
Mechanism
of Action
Act in late G2
phase, blocking
DNA production,
and in M phase,
preventing cell
division
Drug
Route of
Administration
Indications
Side Effects
IV
Testicular cancer,
HL, Kaposi sarcoma, histiocytosis, NHL, breast
cancer
Dose-limiting toxicities: Myelosuppression, neurotoxicity

Alopecia, anorexia, jaw pain, peripheral neuropathy, constipation, paralytic ileus
Vinblastine is a vesicant.
Drug is fatal if given intrathecally.
Generally, neurotoxicity occurs less frequently
with vinblastine than with vincristine; however, it
is rare and usually reversible.
(Bedford Laboratories, 2010d)
Vincristine
(Oncovin)
IV
ALL, HL, NHL,

neuroblastoma,
Wilms tumor,
rhabdomyosarcoma
Dose-limiting toxicity: Neurotoxicity

Alopecia, peripheral neuropathy, constipation, paralytic ileus, jaw pain, foot
drop, renal and hepatotoxicity
Vincristine is a vesicant.
Neurotoxicity is cumulative, but often reversible; conduct a neurologic evaluation before
each dose. Withhold dose if severe paresthesia, motor weakness, or other abnormality develops.
Reduce dose in the presence of significant liver disease.
Stool softeners and/or a stimulant laxative may
help to prevent severe constipation.
(Hospira, Inc., 2011c)
Vinorelbine
(Navelbine)
IV
NSCLC

Nausea, vomiting, neurotoxicity, peripheral neuropathy, alopecia, hepatotoxicity

Vinorelbine is a vesicant.
Flush with 75125 ml solution after completion of
vinorelbine administration.
(Teva Parenteral Medicines, Inc., 2009b)
AIDSacquired immunodeficiency syndrome; ALLacute lymphocytic leukemia; AMLacute myeloid leukemia; ANLLacute nonlymphocytic leukemia; APLacute promyelocytic leukemia; AUCarea under the
plasma concentration versus time curve; BCGbacillus Calmette-Gurin; BIDtwice daily; BMTbone marrow transplantation; CBCcomplete blood count; CLLchronic lymphocytic leukemia; CMLchronic myeloid leukemia; CNScentral nervous system; D5W5% dextrose in water; dldeciliter; DNAdeoxyribonucleic acid; ECGelectrocardiogram; FDAU.S. Food and Drug Administration; 5-FU5-fluorouracil; G2
gap 2; GIgastrointestinal; HDAChistone deacetylases; HLHodgkin lymphoma; IMintramuscular; INRinternational normalized ratio; ITintrathecal; IVintravenous; kgkilogram; LFTliver function test;
LRlactated Ringers solution; LVEFleft ventricular ejection fraction; Mmitosis; mcgmicrogram; MDSmyelodysplastic syndrome; mEqmilliequivalent; mgmilligram; minminute; mlmilliliter; MMmultiple myeloma; mmolmillimole; msecmillisecond; MUGAmultigated acquisition; NHLnon-Hodgkin lymphoma; NSnormal saline; NSAIDnonsteroidal anti-inflammatory drug; NSCLCnon-small cell lung cancer; PCPPneumocystis jiroveci pneumonia; PFTpulmonary function test; POby mouth; PTprothrombin time; PVCpolyvinyl chloride; QTcQT interval corrected; RNAribonucleic acid; Ssynthesis; SC
subcutaneous; SCLCsmall cell lung cancer; SCrserum creatinine; SIADHsyndrome of inappropriate antidiuretic hormone; TKItyrosine kinase inhibitor; TLStumor lysis syndrome; ULNupper limit of normal;
WBCwhite blood cell
47
Note. Based on information from Aronoff et al., 2007; Ascherman et al., 2000; Bragalone, 2012; Chu & DeVita, 2010; Elsevier/Gold Standard, 2013; Micromedex, 2013; Solimando, 2008; and manufacturers prescribing
information.
Vinblastine
(Velban)
48
a) Cell cyclenonspecific drugs are effective in treating tumors with

more slowly dividing cells.
b) If the cancer is sensitive to the agent used, the drug is incorporated
into the cell. The cell kill may not be instantaneous but may occur
when the cell attempts to divide.
(1) Destruction of tumor cells is directly proportional to the amount
of drug administered.
(2) These drugs are given intermittently, allowing the individual to
recover from dose-limiting toxicities before the drug is repeated.
(3) The most frequent dose-limiting toxicity is bone marrow suppression.
c) Classifications include alkylating agents, antitumor antibiotics, hormonal therapies, and nitrosoureas.
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Chapter 4
Principles of Biotherapy
A. Immunology: It is essential to understand the immune system in order to understand how biotherapy works. The immune system (see Figure 3) is a highly specialized and adaptive system that protects an individual by providing
1. Defense against foreign organisms
2. Homeostasis: Destruction of aging or damaged cells
3. Surveillance: Identification of foreign, or nonself, substances.
B. Types of immune response (Medzhitov, 2008; Muehlbauer, 2011; Paul, 2008):
An immune response is the reaction of the immune system against a foreign substance, or antigen (e.g., bacteria). Two types of immune responses exist (see Table 8).
1. Innate, or nonspecific, immunity (see Figure 4): Essential for inducing a generic immune response to antigens (Janeway, Travers, Walport,
& Shlomchik, 2005). Innate immunity does not generate immunologic
memory and involves the following (Medzhitov, 2008).
Figure 3. Primary and Secondary Lymphoid Organs
Tonsils and
adenoids
Thymus
Lymph
nodes
Spleen
Appendix
Peyers
patches
Lymph
nodes
Lymphatic
vessels
Bone
marrow
51
a) Physical barriers (skin and mucous membranes)

b) Mechanical barriers (coughing, sneezing, and blinking)
c) Chemical barriers (tears and sweat)
d) Inflammatory responses (production of monocytes, macrophages,
and polymorphonuclear cells)
e) Complement activation
f) Acute-phase protein production (e.g., interleukin [IL]-2)
g) Production of large granular lymphocytes (natural killer [NK] or NK
and natural killer T [NKT] cells)
2. Adaptive, or specific, immunity: Secondary line of defense and involves
immunologic memory, specificity, and collaboration of B cells and T
cells (McHeyzer-Williams, 2008). The three types of adaptive immunity are the following.
Table 8. Innate and Adaptive Immune Responses

Immune
Response
Mechanism of Action
Cells Primarily Involved
Innate
Primary line of defense

Nonspecific
No memory
Neutrophils
Monocytes, macrophages
Large granular lymphocytes (natural killer
cells)
Adaptive
Secondary line of defense

Specific memory
Lymphocytes
T cells (in cell-mediated immunity)
B cells (in humoral immunity)
Note. Based on information from Paul, 2008.
Figure 4. Innate (Nonspecific) Immune Response
gu
lf
Lyse
Natural killer cells
Phagocytes
Tumor cells
En
52
Polymorphonuclear
leukocytes
Monocytes
Macrophages
Eng
ulf
a) Humoral immunity (see Figure 5): B lymphocytes, memory B cells,

and plasma cells mediate humoral immunity. The result is the production of immunoglobulins (Igs).
b) Cell-mediated immunity (see Figure 6): This type of immunity is mediated by T cells and their cytokine products. It does not involve an
antibody but rather cytotoxic T cells (TC) and helper T cells (TH1 or
TH2) (Reiner, 2008).
c) Regulatory T cells (Treg), also known as suppressor T cells (TS)
(1) Limit the activity of other immune effector cells.
Figure 5. Adaptive (Specific) Immune Response: B Cells and Humoral Immunity
Figure 6. Adaptive (Specific) Immune Response: Cell-Mediated Immunity
T-cell activation
Activated cytotoxic T cell kills foreign

cells, virally infected cells, or cells
with new surface antigens.
Activated helper T cell produces

cytokines.
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(2) Their major role is thought to be to prevent the onset of immunity to normal tissues of the body and limit the inflammatory response that can occur with infections.
(3) Animals and people without Treg cells develop a variety of inflammatory disorders primarily involving the bowel, skin, and liver.
C. Cells of the immune system (see Figure 7): The immune response involves the intricate interaction of a number of cells and proteins (PostWhite & Bauer-Wu, 2011). Many cells of the immune system express cluster of differentiation (CD) markers on their surfaces. These CD markers
(e.g., CD4, CD20) are associated with certain immune functions. The science behind biotherapy has capitalized on the use of CD markers to create cell-specific therapy.
1. Antigen-presenting cells: Cells (e.g., macrophages, B cells, dendritic
cells) that efficiently present antigen to T cells; only dendritic cells are
capable of initiating a primary immune response.
2. T cells (Lesterhuis, Haanen, & Punt, 2011; Pardoll, 2012; Paul, 2008;
Reiner, 2008; Restifo, Robbins, & Rosenberg, 2008)
a) TH cells: Cells that coordinate the immune response and cell-mediated immunity; they are required to maintain cytotoxic T cell responses and express CD4.
(1) TH1 cells are necessary for activating macrophages and are involved in production of certain antibody isotypes.
(2) TH2 cells are effective activators of B cells, particularly in primary responses.
b) TC cells: Cells that kill foreign cells, virally infected cells, or cells with
new surface antigens. TC cells express CD8.
c) Treg/TS cells: Cells that interfere with development of immune reaction when recognizing antigen. Their primary role is to modulate the
severity of inflammation produced by infection and prevent autoimmunity; they may be involved in malignancy.
d) Memory T cells (TM cells): Cells that recognize specific antigens and
induce recall responses
e) Cytotoxic T-lymphocyte antigen 4 (CTLA-4): Part of a group of molecules that contribute to activation or inhibition of T-cell immune re-
Figure 7. Cells of the Immune System
sponses (i.e., it is an immune checkpoint). The consequence of CTLA4 ligands binding on antigen-presenting cells is a negative regulation
of T-cell activity. CTLA-4 expression decreases the activation of T cells
as well as sending inhibitory signals to the T cell. CTLA-4 is expressed
by activated CD8+ cells, but the primary role of CTLA-4 is diminishing
TH activity and enhancing Treg immunosuppressive activity.
3. NK cells: Cells that are cytotoxic to tumor cells and virally infected autologous cells by producing substances that can bind to and destroy foreign invaders without having to identify a specific antigen. NK cells identify foreign substances by their lack of identifying surface molecules.
4. NKT cells: Cells that have markers both of NK cells and T cells
5. B lymphocytes: Plasma cell precursors; plasma cells manufacture Ig (an
antibody) specific to an initiating antigen.
6. Antibodies: Protein products of plasma cells; also known as immunoglobulins, they enhance effector cell functions.
a) The majority of peripheral blood antibodies are IgG, which enhances phagocytosis of antigen by macrophages, monocytes, polymorphonuclear cells, and some lymphocytes.
b) IgM is the first antibody produced in response to an antigen.
c) IgA is present in bodily secretions and helps to prevent infections
at sites where the environment interacts with the body, such as the
nose and lungs.
d) IgD is present in small amounts in normal serum. The exact biologic
function is unclear; however, IgD may have some antibody function
for penicillin, diphtheria, and insulin.
e) IgE exists in trace amounts in normal serum and is associated with
immediate hypersensitivity reactions. IgE antibodies are generated
when combined with certain antigens, thus activating the release of
histamine from mast cells.
7. Cytokines: Glycoprotein products of immune cells such as lymphocytes
and macrophages. Cytokines are produced in response to T-cell activation. Cytokines mediate effector defense functions. Cytokines themselves
usually are not cytotoxic (e.g., ILs, interferon [IFN]).
8. Chemokines: Known as chemotactic cytokines, these protein molecules regulate leukocyte migration and are key organizers of cell distribution in
both immune and inflammatory responses.
D. Tumor escape mechanisms: When immune surveillance fails, tumor formation occurs. The theories to explain this process include the following (Agarwal & Busse, 2010; Demaria et al., 2010; Liu, 2011; Muehlbauer, 2011; Topalian, Weiner, & Pardoll, 2011).
1. Altered immunogenicity: Tumors are targeted by the immune system
through cell surface molecules that function as targets for antibody responses or by intracellular molecules that are presented within the context of the major histocompatibility complex (MHC) molecules.
a) Altered antigen expression on the tumor cell surface allows the antigen to go unrecognized by the humoral immune system.
b) Cell-mediated immune response is blunted through loss or alteration
of MHC molecules or loss or mutation of the peptide epitope that
binds to the MHC molecule and is recognized by T cells.
2. Antigen modulation: Antibodies produced as part of the immune response cause antigens to enter the tumor cell or leave it completely.
This further limits the ability of the immune cells to recognize the tumor cell as nonself.
3. Immune suppression: The tumor itself produces substances that alter
or inhibit the bodys immune response. One example is transforming
growth factor-beta, which inhibits T-cell activity.
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4. Acquired deficiencies to immune sensitivity: These include age- and disease-associated alterations such as decreased or increased apoptosis and
signaling defects of T cells.
5. Immunologic aging or immunosenescence: Causes decline in numbers of
nave T cells, generation of TC cells, hematopoietic stem cells, phagocytes,
and NK cells, production of IL-2, signal transduction of lymphocytes, and
humoral immunity. There is also decreased antigen response and proliferation, increased TM cells, and potentially decreased functional Treg cells.
6. Tumors fail to give off inflammatory warning signals to stimulate an immune response.
E. Overview of biologic therapies
1. NCI defines biotherapy as treatment to boost or restore the ability of the
immune system to fight cancer, infections, and other diseases. It also is
used to lessen certain side effects that may be caused by some cancer
treatments. Agents used in biotherapy include mAbs, growth factors, and
vaccines (Biotherapy, n.d.).
2. Theory of immune surveillance
a) The transformation of a cell from normal to malignant involves a
number of genetic mutations over a span of years.
b) As cells differentiate, they produce proteins (antigens) on their surface
that the immune system recognizes as nonself; an immune response
can be mounted in defense. However, cells may not always recognize
cancer cells as foreign (Koon & McDermott, 2011; Restifo et al., 2008).
3. Methods of action: Biotherapeutic agents work by doing one or more of
the following (Koon & McDermott, 2011).
a) Enhancing the patients own immune response
b) Altering the milieu in which cancer cells grow by modifying the actions of normal cells in the area of the tumor
c) Increasing the vulnerability of cancer cells to the bodys own immune system
d) Altering the pathway by which normal cells transform into malignant
cells, which may be more preventive than therapeutic
e) Preventing the metastasis of cancer cells
f) Enhancing the repair of normal cells damaged by treatment
g) Changing cancer cells so they behave like healthy cells
F. Categories of biotherapy (Koon & McDermott, 2011; Muehlbauer, 2011)
1. Cytokines
a) Cytokines are small protein molecules released by diverse cells throughout the body, providing communication between the cells of the immune system.
b) Cytokines generally are activated by a stimulus and induce responses
by binding to specific receptors. Cells expressing receptors for specific cytokines can be activated or inhibited, either of which alters the
immune effector function.
c) Cytokines affect the growth and differentiation of WBCs and regulate immune and inflammatory responses.
d) Cytokines may enhance cytotoxic activity and secrete additional cytokines, resulting in amplification of immune response. This enhanced
immune response stimulates proliferation or activation and recruitment of additional immune effector cells.
e) Cytokines are multifunctional substances having proinflammatory,
anti-inflammatory, and regulatory functions in the immune system.
f) Cytokines include a variety of ILs, IFNs, tumor necrosis factors (TNFs),
and transforming growth factor. Examples include IL-1, -2, -3, -4, -6,
-8, -10, and -15 and IFN- and IFN-.
g) Cytokines regulate antibody production and the functions of B and

T cells, as well as interact with antigen-presenting cells and NK cells.
h) Examples of cytokines used for therapeutic purposes
(1) Hematopoietic growth factors
(2) IFNs
(3) ILs
2. mAbs (see Figure 8 for nomenclature) (Muehlbauer, Cusack, & Morris,
2006; Scheinberg, Rosenblat, Jurcic, Sgouros, & Junghans, 2011; Wujcik, 2011)
a) General
(1) A type of targeted biotherapy derived from human antibodies,
mouse antibodies, or combinations thereof
(a) Murine: Derived from mouse antibody; less effective because they lack the ability to bind to the Fc receptor
(b) Chimeric: Combination of mouse and human antibodies
(c) Humanized: Small part mouse antibodies fused with human antibodies
(d) Human: Only human antibodies
(2) Cell surface proteins can function as targets for binding mAbs.
(3) mAbs target host tissues or proteins that support tumor growth,
such as growth factors and growth factor receptors, or they may
identify targets that are relatively unique to the tumor cell population.
Figure 8. Types of Monoclonal Antibodies
Comparison of monoclonal antibodies (brown: human, gray: nonhuman):

Top row: mouse, chimeric
Bottom row: humanized, chimeric/humanized, human
The substems according to the nomenclature of monoclonal antibodies are shown below each
antibody.
Note. Public domain image from Wikimedia Commons. Retrieved from http://en.wikipedia.org/wiki/
File:Chimeric_and_humanized_antibodies.svg.
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(4) mAbs may inhibit the binding of growth factors to their respective receptors on the cell surface and shut off downstream signaling that stimulates tumor cell growth.
(5) Antibodies recognize and bind to specific antigens.
(a) Depending on its particular class and subtype, an antibody
can interact with other serum proteins, such as the complement system or Fc receptors on cells, to activate normal
immune functions that selectively eliminate the antigen or
the target cell expressing that antigen.
(b) Antibody-dependent cellular cytotoxicity is thought to be
the major mechanism for response to most mAbs. It is believed to involve a three-step process:
i. The antibody binds to the antigen of the tumor cell.
An example is rituximab, which is anti-CD20 and binds
to CD20 receptors on lymphocytes.
ii. NK cells recognize the antibody-covered tumor cells.
iii. Cytotoxic proteins are released to destroy tumor cells.
(c) Alternatively, mAbs can act directly on the tumor cell to induce cell death.
b) Unconjugated antibodies: Antitumor activity results solely from the
actions of the mAb on its targets. These mAbs do not have cytotoxic
agents or radioisotopes attached to them (Muehlbauer et al., 2006;
Scheinberg et al., 2011). Examples include
(1) Rituximab (targets CD20)
(2) Trastuzumab (targets human epidermal growth factor receptor 2 [HER2])
(3) Cetuximab (targets EGFR)
(4) Bevacizumab (targets vascular endothelial growth factor [VEGF])
(5) Ipilimumab (targets anti-CTLA-4)
c) Conjugated antibodies: Antibodies are physically attached to antitumor agents such as radioisotopes (through RIT), chemotherapy
drugs, toxins, or other biologic agents.
(1) After targeting specific antigens, conjugated mAbs release the
attached antitumor agent into the cells or deliver high levels of local radioactive emissions to the site. An example of a
conjugated mAb is brentuximab vedotin, currently FDA approved for the treatment of HL and systemic anaplastic largecell lymphoma.
(2) An advantage of RIT is its ability to kill cells at a distance with
no need to bind to tumor cells directly to have beneficial effects.
(3) Examples of radioisotope conjugates (antibodies labeled with
a radioisotope)
(a) Ibritumomab tiuxetan (Zevalin) (Spectrum Pharmaceuticals, Inc., 2011)
(b) Iodine-131 tositumomab (Bexxar) (GlaxoSmithKline, 2012a)
G. RIT (Iwamoto, Haas, & Gosselin, 2012; Sharkey & Goldenberg, 2011)
1. RIT is a radiopharmaceutical cancer treatment that employs radionuclide-labeled, or radiolabeled, mAbs. These antibodies, which are administered systemically by intravenous (IV) injection, recognize tumor-associated antigens to deliver radioactivity to tumor cells selectively.
2. The goal of RIT is to destroy or inactivate cancer cells while preserving
the integrity of normal tissues.
3. Each radionuclide emits radiation particles and/or rays with energies
that are characteristic of that specific radionuclide. Depending on its
type, a radionuclide can emit one, two, or three types of emissions (Iwamoto et al., 2012; Sharkey & Goldenberg, 2011).
a) Alpha particles
(1) Consist of two protons and two neutrons (the nucleus of a helium atom)
(2) These particles have poor penetrating ability. Alpha particles
cannot penetrate the outermost layers of skin, and they travel
a maximum distance of 5 cm.
(3) A sheet of paper is sufficient to block the radiation source, or
a distance of 5 cm between the radiation source and the point
will shield the radiation.
(4) The skin of an alpha-irradiated patient is adequate to protect
others from radiation exposure; in other words, alpha particles
are not external hazards, but ingestion or inhalation can be lethal or produce secondary malignancies.
(5) Contact with an irradiated patients excreted body fluids may
be hazardous. The use of universal precautions is sufficient.
b) Beta particles
(1) Are electrons
(2) Have greater penetration abilities than do alpha particles and thus
have great potential to cause severe myelosuppression in a patient
(3) Like alpha particles, beta particles are not external hazards.
The patients skin or thick plastic shielding usually is adequate
protection from beta particles.
(4) Yttrium-90 (such as Zevalin) emits beta particles (Spectrum
Pharmaceuticals, Inc., 2011).
(5) After RIT
(a) The patients body fluids are temporarily radioactive.
(b) The patient should receive specific discharge instructions
to limit family exposure.
c) Gamma rays
(1) Are high-energy gamma-emitting radionuclides
(2) Protection from these rays is achieved by maintaining a specific distance from the radioactive source (the distance is specific to the radioisotope used) and using appropriate shielding.
(3) Patients receiving this type of radionuclide may have to be in radiation isolation and behind lead shields (Iwamoto et al., 2012).
(4) Iodine-131 emits high-energy beta particles and gamma rays.
The thyroid gland concentrates iodine and is at risk of damage
if radioactive iodine is ingested.
4. Toxin-conjugated molecules
a) Toxins such as diphtheria or Pseudomonas exotoxin are potent inhibitors
of cell viability. One molecule of diphtheria toxin delivered intracellularly is capable of inhibiting protein synthesis that results in cell death.
b) Antibodies and cytokines deliver these toxic molecules to cancer cells,
and cell death depends upon their uptake of them.
c) The strategy of delivering toxins intracellularly has resulted in FDA
approval of agents for the treatment of malignancy, for example, denileukin diftitox for the treatment of persistent or recurrent CD25+
cutaneous T-cell lymphoma (NCI, 2013).
5. Vaccines
a) The goal of cancer vaccines is to harness the immune system to fight or
destroy the tumor. Theoretically, this can be achieved by the following
methods (Hammerstrom, Cauley, Atkinson, & Sharma, 2011; Liu, 2011).
(1) Protection against pathogens that can cause cancer
(2) Via immunosurveillance, where the body recognizes and destroys cancer cells prior to their multiplying and giving rise to
clinically observable cancer
(3) Immunostimulation
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b) Two vaccines for cancer prevention are FDA approved.

(1) Hepatitis B vaccine: Hepatitis B viral infection can lead to hepatocellular carcinoma. This vaccine prevents hepatitis as well
as hepatocellular carcinoma.
(2) HPV vaccine (Cervarix and Gardasil): Infection with certain
strains of HPV has been associated with development of several cancers including cervical, anal, penile, and head and neck.
Gardasil protects against HPV types 6, 11, 16, and 18 (Merck &
Co., Inc., 2011). Cervarix protects against HPV types 16 and 18
(GlaxoSmithKline, 2011b).
(3) Most vaccines for cancer treatment are experimental, and results
have been disappointing. One vaccine is FDA approved for cancer treatment: sipuleucel-T (Provenge) for advanced prostate
cancer. It is an autologous cellular immunotherapy containing
CD54+ cells designed to induce an immune response against
a common prostate cancer antigen (Dendreon Corp., 2011).
H. Therapeutic uses for biotherapeutic agents (see Table 9): Biotherapeutic
agents have been shown to
1. Cure, when used as a primary or adjuvant therapy
2. Improve overall response or increase disease-free survival when used in
conjunction with conventional therapies (Koon & McDermott, 2011;
Oldham, 2009)
3. Control or stabilize disease
4. Maintain or enhance QOL.
I. Supportive uses for biotherapeutic agents: Biotherapeutic agents can decrease the severity of toxicities associated with other therapeutic modalities (e.g., hematopoietic growth factors can lessen the side effects of chemotherapy).
J. Biotherapeutic strategies: Advances in the knowledge of molecular biology
have led to the development of agents referred to as targeted therapies. These
agents are divided into those that target the extracellular, such as receptors
on the cell surface (e.g., mAbs), and those that target intracellular processes. A growing number of unique molecular targets have been identified within cancer cells, resulting in the discovery of novel agents, many of which are
oral. See Table 10 for a list of targeted therapies.
1. Signal transduction and targeted therapies (Bafico, Grumolato, & Aaronson, 2008; Clark, 2011; Pawson & Jorgensen, 2008; Wilkes, 2006;
Wilkes, Esper, & Muehlbauer, 2006; Wujcik, 2011) (See Figure 9 for common terminology.)
a) Cellular growth, function, and apoptosis are regulated by a complex
network of biochemical and molecular messengers. This process is
referred to as cell signaling.
b) Signal transduction is the generation of a signal from either outside
the cell (growth factors and growth factor receptors) or inside the
cell (tyrosine kinase receptors) that produces a signaling cascade to
the cell nucleus and delivers a signal for the cell to divide.
(1) The nucleus then directs the cell activities. This could include
cell proliferation, induction of angiogenesis, increased growth
factor production, or inhibition of apoptosis.
(2) Receptor tyrosine kinases contain several domains, including an
extracellular ligand-binding domain, a transmembrane domain,
and an intracellular domain containing protein tyrosine kinase.
(3) Activation of receptor tyrosine kinases triggers a biochemical
cascade of cell-signaling events. This signal transduction can
Table 9. Characteristics of Biologic Agents

Classification
Colonystimulating
factors
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Darbepoetin
(Aranesp)
SC
Treatment of anemia associated with

chronic renal failure, whether or not
the patient is receiving dialysis
Treatment of anemia in patients with
nonmyeloid malignancies where anemia is caused by concomitantly administered chemotherapy and at least
two additional months of chemotherapy is planned
Hypertension, skin
rash, urticaria, pure
red cell aplasia, myalgia, infection, fatigue, edema, diarrhea, thrombotic
events
Risk of death, stroke, thrombosis, and serious

cardiovascular events is increased if Hgb >
11 g/dl when administered.
Ensure adequate iron stores in patients prior to and during use.
Drug may be administered every 1, 2, or
3 weeks, but maintain consistent dosing
schedule.
Use lowest effective dose to avoid blood
transfusions.
Do not shake vials or syringes containing drug.
Store in refrigerator.
Do not freeze.
Prescribers and hospitals must enroll in the
ESA APPRISE Oncology Program.
Use is not indicated in patients in whom
cure is the anticipated outcome of chemotherapy treatment.
Discontinue use when treatment with chemotherapy is completed.
(Amgen, Inc., 2012a)
Stimulates erythropoiesis via the same

mechanism as endogenous erythropoietin
Epoetin alfa
(Procrit)
SC

chronic renal failure, whether or not
the patient is receiving dialysis
Treatment of zidovudine-associated
anemia in HIV-infected patients
Treatment of anemia in patients with
nonmyeloid malignancies where anemia is caused by concomitant use of
chemotherapy and at least two additional months of chemotherapy is
planned
To reduce the need for allogeneic red
blood cell transfusions in patients
scheduled to undergo elective noncardiac, nonvascular surgery
Hypertension, skin
rash, urticaria, pure
red cell aplasia, myalgia, infection, fatigue, edema, diarrhea, thrombotic
events
Risk of death, stroke, thrombosis, and serious

cardiovascular events is increased if Hgb >
11 g/dl when administered.
May be given 3 times weekly or as a single
weekly dose.
Use lowest effective dose to avoid blood
transfusions.
Do not freeze.
Prescribers and hospitals must enroll in the
ESA APPRISE Oncology Program.
Use is not indicated in patients in whom
cure is the anticipated outcome of chemotherapy treatment.
Discontinue use when treatment with chemotherapy is completed.
(Janssen Products, LP, 2013)
61
Stimulates erythropoiesis via the same

mechanism as endogenous erythropoietin
62
Table 9. Characteristics of Biologic Agents (Continued)
Colonystimulating
factors (cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Regulates the production of neutrophils within the bone

marrow
Filgrastim (GCSF, Neupogen)
SC, IV
To decrease the incidence of infection

in patients with neutropenic fever associated with myelosuppressive anticancer treatments for nonmyeloid malignancies
To reduce the time to neutrophil recovery and duration of fever following induction or consolidation chemotherapy in patients with AML
To reduce the duration of neutropenia
and associated sequelae in patients
receiving myeloablative chemotherapy prior to BMT
To mobilize hematopoietic progenitor
cells into peripheral blood for collection via leukapheresis
For chronic administration to reduce the
incidence and duration of sequelae of
neutropenia in patients with congenital, cyclic, or idiopathic neutropenia
Allergic reactions including urticaria, rash, and facial edema; rare

risk of splenic rupture; ARDS, alveolar hemorrhage and
hemoptysis, nausea,
vomiting, bone pain,
fever
Do not freeze.
Drug may be diluted with D5W.
Do not dilute with saline solutions.
Do not shake vials or syringes containing
drug.
Avoid use 24 hours before through 24 hours
after administration of chemotherapy; first
dose should be administered at least 24
hours after chemotherapy is administered.
(Amgen, Inc., 2013)
Human G-CSF;
binds to G-CSF receptors and stimulates proliferation of
neutrophils
Tbo-filgrastim
(Granix)
SC
Reduction in the duration of severe

neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia
Allergic reactions, risk

of splenic rupture,
ARDS, bone pain,
may induce severe
sickle-cell crisis in
patients with sicklecell disease
Administer with safety needle guard device.

Inject the entire dose in the prefilled syringe in order to activate the safety needle guard.
Store in refrigerator at 36F46F.
Avoid shaking.
Tbo-filgrastim should be clear without particles; inspect prior to administration.
Classification

Classification
Colonystimulating
factors (cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Pegfilgrastim
(PEG-G-CSF;
Neulasta)
SC
To decrease the incidence of infection

related to neutropenia in patients with
nonmyeloid malignancies receiving
myelosuppressive chemotherapy
Allergic reactions including urticaria,

rash, facial edema;
rare risk of splenic
rupture; ARDS, nausea, vomiting, bone
pain, fever
Pegfilgrastim reduces renal clearance and

prolongs persistence compared to filgrastim.
Do not administer in the period beginning
14 days before until 24 hours after administration of myelosuppressive chemotherapy.
Administer as a single 6 mg injection once
per chemotherapy cycle.
Do not administer the 6 mg fixed dose to
children or adolescents weighing less
than 45 kg.
Do not freeze.
Do not shake vials or syringes containing
drug.
(Amgen, Inc., 2012b)
Stimulates keratinocyte GFR to result

in proliferation, differentiation, and migration of epithelial cells
Palifermin
(rHuKGF,
Kepivance)
IV
To decrease the incidence and duration

of severe oral mucositis in patients
with hematologic malignancies receiving myelosuppressive chemotherapy
prior to BMT
Skin rash, skin erythema, pruritus, fever,

dysesthesia, tongue
discoloration, tongue
thickening, taste alterations, pain, arthralgias, elevated
serum amylase, elevated serum lipase
Do not use within 24 hours before, during,

or after administration of myelosuppressive chemotherapy.
Administer for 3 days before and then 3
days after myelosuppressive chemotherapy.
The third dose should occur 2448 hours
prior to starting chemotherapy; the fourth
dose should be given on the day of hematopoietic stem cell infusion, after the
infusion is complete.
Do not shake reconstituted solution.
Protect reconstituted product from light
and do not use if stored at room temperature for longer than 1 hour.
Do not filter reconstituted solution.
(Amgen, Inc., 2009)
63
Regulates the production of neutrophils within the bone

marrow
64

Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Colonystimulating
factors (cont.)
Induces committed progenitor cells

to divide and differentiate in the GM
pathways, including
neutrophils, monocytes/macrophages,
and myeloid-derived
dendritic cells
Sargramostim
(GM-CSF, Leukine)
SC, IV
Following induction chemotherapy in

patients with AML to shorten neutrophil recovery and reduce incidence of
infection.
For mobilization of hematopoietic progenitor cells for collection via leukapheresis and to speed engraftment
following autologous transplantation
of progenitor cells
To accelerate myeloid recovery following allogeneic BMT
In patients with failure of engraftment
following BMT
Edema, capillary leak

syndrome, pleural or
pericardial effusions,
dyspnea, fever, abdominal pain, headache, chills, diarrhea, bone pain
Dilute in NS solution for IV use.

Do not freeze.
Do not administer through in-line filter.
Interferons
(IFNs)
Mechanisms of activity are not clearly understood but include inhibition of viral replication, direct antiproliferation
of tumor cells, and
modulation of host
immune response.
IFN alfa-2b
(Intron A)
SC, IM, IV
Treatment of hairy cell leukemia, malignant melanoma, follicular lymphoma,

condylomata acuminata, AIDS-related Kaposi sarcoma, chronic hepatitis B and C
Fever, chills, malaise,

myalgia, headache,
anorexia, fatigue,
depression, suicidal ideation, nausea, vomiting, diarrhea, nephrotic syndrome, pancreatitis, psychosis, hallucinations, renal failure, renal insufficiency, leukopenia, anemia, thrombocytopenia, retinopathy, thyroid abnormalities,
hepatotoxicity
Counsel patients on potential for side effects, including but not limited to flu-like
syndrome.
Do not freeze.
Do not shake product.
Protect from light.
Product in multidose vial is stable for 30
days after reconstitution when stored in
refrigerator.
Drug is contraindicated in patients with autoimmune hepatitis or decompensated
liver disease.
Use with caution in patients with a history
of debilitating medical disease such as
pulmonary disease, cardiovascular disease, diabetes mellitus, coagulation disorders, or severe myelosuppression.
Monitor triglycerides.
Classification

Classification
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Immunomodulatory effects including

enhancement of oxidative metabolism
of macrophages,
ADCC, activation
of NK cells, and expression of Fc receptors and cell surface antigens
IFN-gamma
(Actimmune)
SC
To reduce frequency and severity of infections related to chronic granulomatous disease

To delay progression of severe malignant osteoporosis
Fever, headache,
rash, chills, injectionsite tenderness, fatigue, diarrhea, vomiting, nausea, myalgia, arthralgia, myelosuppression, elevated hepatic transaminases, altered
mental status, gait
disturbance, dizziness
Hold therapy or reduce dose by 50% in

cases of severe reactions.
Flu-like syndrome may exacerbate preexisting cardiac conditions, such as CHF.
(InterMune, Inc., 2009)
Interleukins
(ILs)
Promotes proliferation, differentiation,

and recruitment of
T and B cells, NK
cells, LAK cells,
and tumor-infiltrating lymphocytes
that enhance tumorfighting capabilities;
increases production of IFN-gamma,
IL-1, and TNF
Aldesleukin (IL2, Proleukin)
SC, IV
Treatment of renal cell carcinoma and

metastatic melanoma
Fever, rigors, malaise,

headache, myalgia,
arthralgia, tachycardia, hypotension,
cardiomyopathy, arrhythmias, capillary
leak syndrome, dyspnea, nausea, vomiting, diarrhea, stomatitis, dizziness, anemia, thrombocytopenia, leukopenia, elevated transaminases, elevated serum
creatinine and BUN,
neurologic toxicities,
skin rash, pruritus,
hyperbilirubinemia
Do not use with an in-line filter.

Do not mix with NS or bacteriostatic water.
Do not freeze.
Protect from light.
Do not mix with other medications.
Monitor fluid status, vital signs, mental status, and urine output. Hypotension is
dose limiting and mimics septic shock;
use IV boluses carefully; treatment may
require vasopressor support.
Drug is contraindicated in patients with
cardiac disease, abnormal pulmonary
function, or organ allografts.
Assess fall risk during treatment.
May exacerbate or lead to initial presentation of autoimmune diseases or inflammatory disorders such as Crohn disease, scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, and cholecystitis.
(Prometheus Laboratories Inc., 2012)
65
Interferons
(IFNs) (cont.)
66

Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Interleukins
(ILs) (cont.)
Stimulates megakaryocytopoiesis
and thrombopoiesis
Oprelvekin (IL11, Neumega)
SC
To prevent severe thrombocytopenia and reduce the need for platelet

transfusions in patients with nonmyeloid malignancies receiving chemotherapy
Anaphylaxis, dilutional anemia, diarrhea,

dizziness, fever, fluid retention resulting
in peripheral edema,
pulmonary edema,
dyspnea, capillary
leak syndrome, atrial
arrhythmias and exacerbation of preexisting pulmonary effusions, headache,
nausea, vomiting, insomnia, rhinitis
Do not freeze.
Reconstitute with sterile water and use
within 3 hours of reconstitution.
Do not shake or freeze following reconstitution.
Protect from light.
Use with caution in patients with preexisting CHF or other conditions that may be
exacerbated by fluid retention.
Dosing should be initiated 624 hours after
completion of chemotherapy and discontinued at least 2 days before the start of
the next cycle of chemotherapy.
(Wyeth Pharmaceuticals, 2006)
Hematopoietic stem cell

mobilizers
Inhibits the CXCR4

receptor, which
competitively blocks
binding of SDF1-
ligand that anchors
developing hematopoietic stem cells
in the bone marrow,
resulting in release
into the peripheral blood
Plerixafor
(Mozobil)
SC
In combination with filgrastim to mobilize hematopoietic stem cells for collection from peripheral blood of patients with multiple myeloma or nonHodgkin lymphoma who are candidates for autologous stem cell transplantation
Diarrhea, nausea, fatigue, injection-site

reactions, headache,
dizziness, arthralgia,
vomiting
Use actual body weight to calculate dose;

daily dose should not exceed 40 mg.
Store single-use vials at room temperature.
Use reduced dose in patients with creatinine clearance < 50 ml/min.
Four daily morning doses of filgrastim
should be given prior to the first dose of
plerixafor.
Plerixafor may be repeated for up to 4 consecutive days.
Each daily dose of plerixafor should be given approximately 11 hours before any
planned apheresis session.
(Genzyme Corp., 2010)
Classification

Classification
Autologous
cellular immunotherapy
Mechanism
of Action
Autologous CD54+
mononuclear cells
are collected from
the patient and activated in culture with
PAP-GM-CSF for
subsequent infusion.
The activated cells
are designed to induce an immune
response against
prostatic acid phosphatase antigen expressed in patients
with prostate cancer.
Drug
Sipuleucel-T
(Provenge)
Route of
Administration
IV
Side Effects
Treatment of asymptomatic or minimally

symptomatic metastatic castrateresistant prostate cancer
Infusion reactions
such as fever, chills,
dyspnea, hypoxia,
bronchospasm, nausea, vomiting, fatigue, hypertension,
tachycardia, joint
ache, headache
Each dose is cellularly unique and for use

only in one individual patient.
The patients mononuclear cells are collected via apheresis 3 days prior to
planned infusion, shipped to the manufacturer for preparation of the infusion,
and then returned to the administration
site.
Confirmation of product release using patient-specific product disposition forms
must be performed prior to infusion.
Do not administer through a cell filter.
Premedicate patients with acetaminophen
and a histamine antagonist.
Employ universal precautions when handling sipuleucel-T.
Prepared infusion bag must remain within the insulated container until time of infusion.
Do not administer infusion if the storage
bag leaks or clumps remain after gentle mixing.
Once infusion product is removed from insulated storage, it should not remain
at room temperature for longer than 3
hours.
The 60-minute infusion must be completed
prior to expiration date and time.
(Dendreon Corp., 2011)
67
ADCCantibody-dependent cell-mediated cytotoxicity; AIDSacquired immunodeficiency syndrome; AMLacute myeloid leukemia; ARDSadult respiratory distress syndrome; BMTbone marrow transplantation;
BUNblood urea nitrogen; CD54+cluster of differentiation 54 positive; CHFcongestive heart failure; CXCR4chemokine receptor 4; D5W5% dextrose in water; ESAerythropoiesis-stimulating agent; G-CSF
granulocytecolony-stimulating factor; GFRglomerular filtration rate; GMgranulocyte macrophage; GM-CSFgranulocyte macrophagecolony-stimulating factor; Hgbhemoglobin; HIVhuman immunodeficiency
virus; IMintramuscular; IVintravenous; LAKlymphokine-activated killer; NKnatural killer; NSnormal saline; PAP-GM-CSFprostatic acid phosphatase granulocyte macrophagecolony-stimulating factor; rHuKGFrecombinant human keratinocyte growth factor; SCsubcutaneous; SDF1-stromal cellderived factor 1-alpha; TNFtumor necrosis factor
Indications
68
Table 10. Characteristics of Targeted Therapies

Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Immunotoxin
Directs cytotoxic action of diphtheria toxin to

cells that express the IL-2
receptor, resulting in inhibition
of cellular protein synthesis
leading to cell
death
Denileukin diftitox
(Ontak)
IV
Treatment of patients
with persistent or recurrent cutaneous Tcell lymphoma whose
malignant cells express the CD25 component of the IL-2 receptor
Hypersensitivity, vascular leak syndrome, hypotension, edema, hypoalbuminemia, fever, chills,

headache, rash, anorexia, reduced lymphocytes,
increased transaminases,
asthenia, infection, pain,
nausea, vomiting, dyspnea, cough, loss of visual acuity
Confirm that patients malignant cells express CD25 prior to

use of agent.
Discontinue use of agent if patients serum albumin is < 3 g/
dl because of risk of capillary leak syndrome.
Premedicate with acetaminophen and an antihistamine.
Incidence of adverse effects diminishes after first two treatment courses.
Store at or below 10C (14F).
Thaw vials in refrigerator for < 24 hours or at room temperature for 12 hours. Agent cannot be refrozen after thawing and must be brought to room temperature before preparing dose.
Concentration of agent must be 15 mcg/ml during all
steps of product preparation.
Vials should not be heated.
Avoid vigorous agitation.
Use prepared solution within 6 hours.
Do not infuse through a filter.
Protect from light.
(Eisai Inc., 2010)
Miscellaneous
biologic
response
modifiers
Exact antineoplastic mechanism is unclear

but may be related to immunomodulatory, antiangiogenic, or
antineoplastic
properties.
Lenalidomide (Revlimid)
PO
with transfusion-dependent anemia secondary to low- or intermediate-risk MDS associated with the 5q
chromosomal deletion
In combination with
dexamethasone in patients with multiple myeloma who have received at least one prior therapy
Risk of fetal harm, neutropenia, thrombocytopenia, deep vein thrombosis, pulmonary embolism, pruritus, rash, dry
skin, diarrhea, constipation, nausea, nasopharyngitis, cough, dyspnea,
pharyngitis, fatigue, pyrexia, peripheral edema, asthenia, arthralgia, dizziness, headache, muscle
cramps, upper respiratory
tract infections
Women should avoid becoming pregnant during treatment

and within 4 weeks of discontinuing treatment because of
risk of fetal harm. A pregnancy test should be performed
prior to initiating therapy and repeated every 4 weeks in
women of child-bearing age or with regular menses, and
every 2 weeks in women with irregular menses.
Discontinue lenalidomide immediately if pregnancy occurs
during treatment.
Male patients must adhere to strict methods of contraception and be informed of the teratogenic risks of lenalidomide.
Revlimid is only available under the RevAssist program to
ensure patients are properly informed of fetal risks.
Concomitant use with dexamethasone increases the risk of
developing thrombosis; prophylactic anticoagulation may
be warranted.
Capsules should be taken with water.
Capsules should be swallowed whole and not chewed,
crushed, or broken.
Dosage adjustments are recommended in patients with a
creatinine clearance < 60 ml/min.
Classification
Table 10. Characteristics of Targeted Therapies (Continued)

Classification
Miscellaneous
biologic
response
modifiers
(cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Pomalidomide
(Pomalyst)
PO
with multiple myeloma who have received
at least two prior therapies, including lenalidomide and bortezomib, and have evidence of disease progression within 60
days of completion of
the last therapy
Risk of fetal harm, venous

thromboembolism, neutropenia, anemia, dizziness, confusion, neuropathy, second malignancies,
fatigue, asthenia, peripheral edema, constipation,
diarrhea, nausea, vomiting, pneumonia, upper respiratory tract infections,
back pain
Women should avoid becoming pregnant during treatment

and within 4 weeks of discontinuing treatment because of
risk of fetal harm. A pregnancy test should be performed
prior to initiating therapy and repeated every 4 weeks in
women of child-bearing age or with regular menses, and
every 2 weeks in women with irregular menses.
Male patients must adhere to strict methods of contraception and be informed of the teratogenic risks of pomalidomide.
Discontinue pomalidomide immediately if pregnancy occurs
during treatment.
Pomalyst is only available under the Pomalyst REMS
program to ensure patients are properly informed of fetal risks.
Dose adjustments are recommended for patients with neutropenia or thrombocytopenia.

but may be related to immunomodulatory, antiangiogenic, and
anti-inflammatory properties.
Thalidomide (Thalomid)
PO
In combination with
dexamethasone for
treatment in patients
with newly diagnosed
multiple myeloma
Treatment of erythema
nodosum leprosum
Deep vein thrombosis, pulmonary embolism, drowsiness, somnolence, peripheral neuropathy, dizziness,
orthostatic hypotension,
neutropenia, confusion,
anxiety, tremor, insomnia,
depression, fatigue, fever,
anemia, thrombocytopenia, constipation, anorexia, nausea, edema, bone
pain, dyspnea, rash, dry
skin, increased hepatic
enzymes, increased SCr,
muscle weakness
Women should avoid becoming pregnant beginning 4

weeks before treatment, during treatment, and within 4
weeks of discontinuing treatment because of risk of fetal harm.
A pregnancy test should be performed prior to initiating
therapy and repeated every 4 weeks in women of childbearing age or with regular menses, and every 2 weeks in
women with irregular menses.
Thalomid must be dispensed and administered in compliance with the Thalomid REMSTM program.
Male patients must adhere to strict methods of contraception and be informed of the teratogenic risks of thalidomide.
Discontinue thalidomide immediately if pregnancy occurs
during treatment.
Concomitant use with dexamethasone increases the risk of
developing thrombosis; prophylactic anticoagulation may
be warranted.
Because of the potential for significant drowsiness, instruct
patients to avoid situations where impaired mental and/
or physical functioning could put themselves or others at
risk of harm.
69

but may be related to immunomodulatory, antiangiogenic, and
anti-inflammatory properties.
70
Monoclonal
antibodies
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Binds to and inhibits the activity

of human VEGF
to its receptors
(FLT and KDR),
blocking proliferation and formation of new blood
vessels
Bevacizumab
(anti-VEGF
antibody,
Avastin)
IV
In combination with
5-fluorouracilcontaining regimens as firstor second-line treatment for patients with
metastatic carcinoma
of the colon or rectum
In combination with carboplatin and paclitaxel
for first-line treatment
of patients with unresectable, locally advanced, recurrent, or
metastatic nonsquamous NSCLC
Treatment of glioblastoma in patients with
progressive disease
following previous
therapy
In combination with IFN
alfa for treatment of
metastatic renal cell
carcinoma
Hemorrhage, hypertension,
proteinuria, CHF, asthenia, diarrhea, abdominal
pain, headache, neutropenia, hyponatremia, proteinuria, arterial thromboembolic events, GI perforation, wound healing complications, fistula formation
in the GI tract, and/or intra-abdominal abscesses,
infusion reactions
Avoid use for at least 28 days after major surgery; surgical

incision should be fully healed.
Suspend treatment with bevacizumab at least 28 days before elective surgery.
Store agent in refrigerator. Diluted solution may be stored
for up to 8 hours under refrigeration.
Do not freeze.
Do not shake.
Protect from light.
Do not mix or administer with dextrose-containing solutions.
Monitor blood pressure during treatment.
Permanently discontinue medication if patients develop GI
perforation, wound dehiscence requiring medical intervention, serious bleeding, nephrotic syndrome, or hypertensive crisis.
Temporarily suspend if evidence of moderate to severe proteinuria or severe hypertension until evaluation and treatment are provided.
Risk of CHF exists in patients who have previously received
anthracyclines.
(Genentech, Inc., 2011a)
Drug-antibody
conjugate; binds
to CD30+ cells
allowing for internalization of
the antibody
complex and release of MMEA
component that
binds to tubulin
and causes disruption of cell division leading to
apoptosis
Brentuximab vedotin (antiCD30 antibody, Adcetris)
IV
Treatment of Hodgkin
lymphoma in patients
after failure of autologous stem cell transplantation or after failure of 2 multiagent
chemotherapy regimens in patients who
are not candidates for
autologous stem cell
transplantation
Treatment of systemic anaplastic large cell
lymphoma after failure
of 1 multiagent chemotherapy regimen
Peripheral neuropathy, neutropenia, anaphylaxis, infusion reactions, JCV infection resulting in progressive multifocal leukoencephalopathy, StevensJohnson syndrome, fatigue, upper respiratory
tract infection, nausea, diarrhea, vomiting, anemia,
pyrexia, thrombocytopenia, rash, abdominal pain,
cough
Reconstitute vials with 10.5 ml of sterile water. Do not

shake.
Dilute reconstituted solution immediately to a concentration of between 0.41.8 mg/ml and infuse immediately or
store in refrigerator and use within 24 hours.
Concomitant use with bleomycin is contraindicated because of risk of pulmonary toxicity.
Patients can be premedicated with acetaminophen, a histamine antagonist, and a corticosteroid.
Coadministration with CYP3A4 inhibitors, including grapefruit juice, or inducers may increase or decrease concentrations of MMEA component.
(Seattle Genetics, 2012)
Classification

Classification
Monoclonal
antibodies
(cont.)
Mechanism
of Action
Binds to extracellular domain
of EGFR, resulting in inhibition
of cell growth
and induction of
apoptosis, and
decreased matrix metalloproteinase and
VEGF production
Drug
Cetuximab
(antiEGFR
antibody,
Erbitux)
Route of
Administration
IV
Side Effects
In patients with EGFRexpressing metastatic

colorectal cancer after
failure of irinotecanand oxaliplatin-based
regimens
With irinotecan or in patients with metastatic
colorectal cancer who
are intolerant of irinotecan
In combination with radiation therapy to treat
local or regionally advanced squamous cell
carcinoma of the head
and neck
In recurrent or metastatic squamous cell carcinoma of the head
and neck progressing
after platinum-based
therapy
In combination with platinum-based therapy
with 5-fluorouracil for
first-line treatment of
patients with recurrent
locoregional or metastatic squamous cell
carcinoma of the head
and neck
Infusion-related reactions
including bronchospasm,
fever, chills, rigors, angioedema, urticaria, hypotension, and stridor; pulmonary toxicity, acneform
rash, dry skin and fissuring, malaise, asthenia, fever, diarrhea, fatigue, nausea, vomiting, anorexia,
leukopenia, hypomagnesemia, weight loss, pharyngitis, cardiopulmonary
arrest
Serious, potentially fatal infusion reactions may occur.
Cardiopulmonary arrest has occurred in patients when
used in combination with radiation therapy.
Dose modification is recommended following development
of acneform rash.
Instruct patients to wear sunscreen and hats and limit sun
exposure.
Premedicate with an H1 antagonist.
Administer through 0.22-micron in-line filter.
Flush line with NS after infusion.
Store agent in refrigerator.
Do not dilute.
Do not shake.
Do not freeze.
Protect from light.
Discard unused portion after 8 hours at room temperature
or 12 hours under refrigeration.
(Eli Lilly & Co., 2012)
Indications
71
72
Monoclonal
antibodies
(cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Binds to the
transmembrane
protein RANKL
that inhibits osteoclast activity and bone resorption
Denosumab (antiRANKL
antibody,
Prolia,
Xgeva)
SC
Prevention of skeletal
events due to bone
metastases of solid tumors
Treatment to increase
bone mass in men
with nonmetastatic prostate cancer receiving androgen deprivation therapy, and
women with breast
cancer receiving adjuvant aromatase inhibitor therapy at high risk
for bone fractures
Hypocalcemia, osteonecrosis of jaw, fatigue, asthenia, hypophosphatemia,

nausea
Store in refrigerator. Allow 1530 min to warm to room temperature before administration. A 27-gauge needle should
be used to withdraw entire contents from vial for dosing.
Correct and monitor serum calcium, vitamin D, and magnesium before and during treatment.
An oral examination and preventive dentistry should be
performed prior to starting treatment and during therapy.
Good oral hygiene should be practiced during therapy. Invasive dental procedures should be avoided while taking
denosumab.
(Amgen, Inc., 2012b)
Binds to the
complement protein C5, which
inhibits its cleavage to C5a and
C5b; this inhibits
formation of the
terminal components C5b-9,
thus mediating
intravascular hemolysis.
Eculizumab (anti-C5
antibody,
Soliris)
IV
Treatment to reduce hemolysis in patients

with paroxysmal nocturnal hemoglobinuria
with atypical hemolytic
uremic syndrome
Headache, nasopharyngitis, back pain, nausea; increased risk of meningococcal infections
Do not freeze.
Protect from light.
Do not shake.
Do not administer as an IV push or bolus.
Dilute to a final concentration of 5 mg/ml prior to administration.
Allow product to warm to room temperature prior to administration.
Diluted solutions are stable for 24 hours.
Administer by IV infusion over 35 min.
Do not use in patients with unresolved serious Neisseria
meningitides infection or those who are not currently vaccinated against Neisseria meningitides. Vaccinate patients at least 2 weeks prior to the first dose of eculizumab. Revaccinate according to medical guidelines for vaccine use.
Because of the risk of meningococcal infections, eculizumab is only available through a restricted program requiring
enrollment of prescribers and counseling of patients.
(Alexion Pharmaceuticals, Inc., 2011)
Classification

Classification
Monoclonal
antibodies
(cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Ibritumomab
tiuxetan
(anti-CD20
antibody,
Zevalin)
IV
Treatment of relapsed or
refractory low-grade,
follicular, or transformed B-cell NHL
Severe and potentially lifethreatening allergic reactions during infusion; fever, chills, rigors, headache, nausea, bronchospasm, dyspnea, myalgia,
arthralgia, asthenia, prolonged B-cell lymphocytopenia, leukopenia, thrombocytopenia, neutropenia,
anemia, severe cutaneous
and mucocutaneous reactions, secondary leukemia
or MDS
Drug is combined with rituximab.

Premedicate with acetaminophen and diphenhydramine.
Patients with a platelet count < 100,000/mm3 should not be
treated with ibritumomab.
Administer ibritumomab through a 0.22 micron in-line filter.
Administered dose cannot exceed 32 mCi regardless of patients weight.
Drug is not transported with radioisotope; radiolabeling must
be done by appropriate personnel in a specialized facility.
Drug is intended as single-course treatment.
Monitor closely for extravasation.
Do not freeze.
Use of antiplatelet or anticoagulant drugs should be avoided following recent use of ibritumomab.
(Spectrum Pharmaceuticals, Inc., 2011)
Binds CTLA-4
and blocks its
negative regulation of T-cell activation and proliferation, increasing T-cell antitumor immune response
Ipilimumab
(anti-CTLA-4
antibody,
Yervoy)
IV
Treatment of unresectable or metastatic melanoma
Immune-mediated adverse
reactions resulting in enterocolitis, hepatitis, dermatitis, neuropathy, or endocrinopathy
Do not shake.
Diluted product may be stored at room temperature or under refrigeration for up to 24 hours.
Protect from light.
Prior to each dose, evaluate patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and perform laboratory assessment of blood
chemistries, liver function, and thyroid function.
Binds to CD20
on B cells and
B-cell CLL resulting in ADCC
and complement-dependent
cytotoxicity
Ofatumumab
(anti-CD20
antibody,
Arzerra)
IV
Treatment of CLL in patients refractory to

fludarabine and alemtuzumab
Infusion reactions including

bronchospasm, dyspnea,
laryngeal edema, pulmonary edema, flushing, hypertension, hypotension,
syncope, myocardial infarction, back or abdominal pain, fever, rash, urticaria, or angioedema; severe neutropenia or thrombocytopenia, progressive
multifocal leukoencephalopathy, hepatitis B infection/reactivation, intestinal
obstruction, infections
Do not shake.
Do not freeze.
Protect from light.
Administer through in-line filter.
Premedicate with acetaminophen, H1 antagonist, and a
corticosteroid.
Prepare doses in NS.
Store diluted solution under refrigeration.
Infusion should be started within 12 hours of preparation
and discarded after 24 hours.
73
Binds to CD20
on B cells resulting in direct delivery of the radioactive isotope
indium-111 or yttrium-90 that induces cell damage through the
formation of free
radicals
74
Monoclonal
antibodies
(cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Binds to EGFR
and competitively inhibits binding of ligands to
this receptor; this
prevents receptor
autophosphorylation and activation of receptorassociated kinases that results in
inhibition of cell
growth, induction
of apoptosis, decreased production of proinflammatory cytokines
and VGFs, and
internalization of
EGFR
Panitumumab
(antiEGFR
antibody,
Vectibix)
IV
Single-agent treatment
for EGFR-expressing metastatic colorectal carcinoma with disease progression on
or following fluoropyrimidine-, oxaliplatin-,
or irinotecan-containing regimens
Dermatologic toxicity including dermatitis acneform,

pruritus, erythema, rash,
skin exfoliation, paronychia, dry skin, and skin fissures, which may be complicated by abscesses and
sepsis; fatigue, abdominal
pain, hypomagnesemia,
infusion reactions, keratitis
Advise patients to wear sunscreen and a hat to limit sun

exposure.
Dose modification is recommended following infusion-related reactions or dermatologic toxicity.
Drug must be given by IV infusion pump via a 0.22 micron
in-line filter.
Dilute dose with NS.
Do not shake diluted product.
Do not exceed a final concentration of 10 mg/ml.
Do not freeze.
Protect from light.
Use diluted solution within 6 hours at room temperature or
within 24 hours if under refrigeration.
Combination of panitumumab with oxaliplatin-containing
regimens is contraindicated in patients with mutant KRAS
metastatic colorectal cancer or in whom KRAS status is
unknown.
(Amgen, Inc., 2012a)
Targets the extracellular dimerization domain

of HER2 protein
that blocks
ligand-dependent
heterodimerization of HER2 with
other similar proteins. This inhibits
intracellular signaling that results
in slowing cell
growth and triggering apoptosis.
Also triggers antibody-dependent
cell-mediated cytotoxicity.
Pertuzumab
(Perjeta)
IV
In combination with
trastuzumab and
docetaxel for treatment of patients with
HER2+ metastatic
breast cancer
Left ventricular dysfunction,

infusion-related reactions,
fatigue, asthenia, peripheral edema, mucosal inflammation, alopecia, rash,
nail changes, diarrhea,
nausea, vomiting, neutropenia, anemia, peripheral neuropathy, headache,
myalgia, anorexia
Monitor LVEF during treatments and hold doses if ejection

fraction decreases to < 40% or 10% from baseline levels to between 40%45%.
Do not administer mixed with other IV medications.
Store in refrigerator. Keep vials in original container until
time of use to protect from light.
Dilute in 250 ml 0.9% saline only and mix with gentle inversion. Do not shake.
If not used immediately, diluted solutions can be stored under refrigeration for up to 24 hours.
May cause fetal harm when administered to pregnant women. Determine pregnancy status of patients prior to starting treatment with pertuzumab.
Patients must be tested for HER2 status before initiation of
treatment because use has only been studied in patients
who overexpress HER2 protein.
(Genentech, Inc., 2012b)
Classification

Classification
Monoclonal
antibodies
(cont.)
Mechanism
of Action
Binds to CD20
on B cells resulting in activation
of complementdependent cytotoxicity as well
as ADCC
Drug
Rituximab
(anti-CD20
antibody,
Rituxan)
Route of
Administration
IV
Side Effects
Treatment of relapsed
or refractory low-grade
follicular CD20+ B-cell
NHL
First-line treatment of
follicular CD20+ B-cell
NHL in combination
with chemotherapy
and as monotherapy in
patients who have had
a complete or partial
response to rituximab
plus chemotherapy
Treatment of low-grade
CD20+ B-cell NHL in
patients with stable
disease or who have
achieved a partial or
complete response with
CVP chemotherapy
First-line treatment of diffuse large B-cell CD20+
NHL in combination
with CHOP or other anthracycline-based chemotherapy regimen
First-line treatment
in combination with
fludarabine and cyclophosphamide in patients with CD20+ CLL
In combination with methotrexate to treat moderate to severe rheumatoid arthritis in patients
who have not responded to one or more TNFantagonist therapies
In combination with glucocorticoids in patients with Wegener
granulomatosis or microscopic polyangiitis
Severe infusion-related reactions including urticaria, hypotension, angioedema, hypoxia, or bronchospasm; fever, chills, rigors,
headache, dyspnea, myalgia, arthralgia, prolonged
B-cell lymphopenia, leukopenia, infection, asthenia, nausea, rash, hepatitis B reactivation, progressive multifocal leukoencephalopathy, cardiac arrhythmias, bowel obstruction and/or perforation, renal toxicity
Administer only by IV infusion.

Do not freeze.
Protect vials from direct sunlight.
Agent is stable for 24 hours under refrigeration.
Consider premedication with acetaminophen and diphenhydramine.
Infusion-related side effects may resolve with slowing or
suspending infusion.
Incidence of infusion-related side effects is reduced with
subsequent infusions.
Potential exists for development of TLS within 1224 hours
after infusion.
Prophylaxis against Pneumocystis jiroveci pneumonia and
herpesvirus infections in patients with CLL for up to 12
months after treatment.
(Genentech, Inc., 2012c)
Indications
75
76
Monoclonal
antibodies
(cont.)
Mechanism
of Action
Binds to CD20
on pre-B and
mature lymphocytes and B-cell
NHL resulting in
apoptosis, complement-dependent cytotoxicity, and ADCC;
ionizing radiation caused by
iodine-131 (131I)
results in additional cell death.
Drug
Tositumomab 131I
(anti-CD20
antibody,
Bexxar)
Route of
Administration
IV
Indications
Side Effects
with CD20+ relapsed
or refractory, lowgrade, follicular, or
transformed NHL including patients refractory to rituximab
Anaphylaxis, hypothyroidism, severe and prolonged

thrombocytopenia, anemia, neutropenia, allergic reactions, asthenia, fever, infection, chills, rigors,
sweating, nausea, vomiting, hypotension, dyspnea,
bronchospasm, abdominal
pain, rash, secondary leukemia/MDS or nonhematologic malignancies
Agent is not indicated for initial treatment of CD20+ NHL.

Agent should not be administered to patients with platelet
count < 100,000/mm3 or neutrophil count < 1,500/mm3.
Treatment involves two separate steps (dosimetric dose
and therapeutic dose) separated by 714 days.
Thyroid-blocking agents should be given beginning 24
hours prior to tositumomab 131I therapy and continued for
at least 14 days.
Premedicate with acetaminophen and diphenhydramine.
The same IV tubing set must be used throughout the entire
dosimetric or therapeutic steps to prevent loss of drug.
Administer both doses through a 0.22 micron in-line filter.
Instruct patients on how to minimize exposure of other people to radioactivity that will remain in their system for several days.
Only personnel trained in handling radioactive agents
should prepare and administer this agent.
Do not freeze.
Protect from light.
Do not shake.
Classification

Classification
Monoclonal
antibodies
(cont.)
Mechanism
of Action
Binds to the extracellular domain of HER2,
resulting in mediation of ADCC
against cells that
overproduce
HER2
Drug
Trastuzumab (antiHER2 antibody, Herceptin)
Route of
Administration
IV
Side Effects
In combination with
treatment regimens
of doxorubicin, cyclophosphamide, and paclitaxel or docetaxel and carboplatin or
as monotherapy after
anthracycline-based
regimens for adjuvant treatment of patients with HER2-overexpressing node-positive or node-negative
breast cancer
As single-agent therapy for treatment of patients with metastatic
breast cancer whose
tumors overexpress
HER2 and who have
received one or more
chemotherapy regimens for their disease,
or in combination with
paclitaxel for treatment
of patients with metastatic breast cancer
whose tumors overexpress HER2 and who
have not previously received chemotherapy
for their disease
As first-line therapy in
combination with cisplatin and capecitabine
or 5-fluorouracil for
treatment of HER2overexpressing metastatic gastric cancer
or gastroesophageal junction adenocarcinoma
Infusion reactions of chills,

fever, headache, dizziness, dyspnea, hypotension, rash, and asthenia;
pulmonary toxicity related
to infusion; cardiomyopathy, hypersensitivity reactions, diarrhea, leukopenia, anemia, neutropenia,
infection, thrombosis
Administer only by IV infusion.

Do not freeze.
Solution reconstituted with bacteriostatic water is stable for
28 days under refrigeration.
Solution reconstituted with sterile water must be used immediately and not saved.
Dilute dose only with NS. Do not use D5W.
HER2 protein overexpression is seen in 25%30% of primary breast cancers.
Do not administer concurrently with doxorubicin and cyclophosphamide; intended to be administered following completion of doxorubicin and cyclophosphamide.
LVEF must be determined prior to initiation and during
treatment. Cardiomyopathy is increased in patients also
receiving an anthracycline-containing regimen.
Indications
77
78

Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Monoclonal
antibodies
(cont.)
Binds to the extracellular domain of HER2,

resulting in receptor-mediated
internalization
and intracellular
release of emtansine (DM1),
which disrupts
the cells microtubule network,
leading to cell
cycle arrest and
apoptosis
Ado-trastuzumab emtansine
(anti-HER2
antibody
conjugated
with emtansine,
Kadcyla)
IV
with HER2+ metastatic breast cancer who
have previously been
treated with trastuzumab and a taxane
either alone or in combination
Hepatotoxicity, cardiotoxicity, thrombocytopenia, pulmonary toxicity, peripheral

neuropathy, infusionrelated reactions, hypersensitivity, diarrhea, constipation, nausea, fatigue,
musculoskeletal pain, epistaxis
First infusion is administered over 90 min. Patients should

be monitored for infusion-related reactions during and for
at least 90 min following completion of the infusion. If infusion is tolerated, subsequent infusions can be infused
over 30 min with monitoring continuing for at least an additional 30 min.
Dose reductions based on the manufacturers recommendations should occur in the event of certain adverse effects.
Ado-trastuzumab emtansine should be infused using a 0.22
micron inline nonprotein-absorptive polyethersulfone filter.
Do not mix or infuse ado-trastuzumab emtansine with other medications.
Caution should be made not to confuse ado-trastuzumab
emtansine with trastuzumab (Herceptin).
Ado-trastuzumab emtansine should only be diluted with
0.9% saline solution. Do not dilute with D5W.
Prepared diluted solutions can be stored under refrigeration for up to 4 hours.
Do not freeze or shake prepared solutions.
Ado-trastuzumab emtansine can cause fetal harm when
administered to pregnant women. Determine pregnancy
status of patients prior to initiating ado-trastuzumab emtansine and inform patients of fetal risks and the need for
effective contraception during treatment with ado-trastuzumab emtansine.
Concomitant use with CYP3A4 inhibitors should be avoided
because of the risk of increased toxicity. If use of CYP3A4
inhibitors cannot be avoided, use of ado-trastuzumab emtansine may be delayed until the CYP3A4 inhibitor has
cleared from the patients system or if the patient is monitored closely for adverse effects.
Small
molecule
inhibitors
Inhibits VEGF
receptors with
tyrosine kinase
activity that interferes with tumor angiogenesis, growth, and
progression
Axitinib
(Inlyta)
PO
Treatment of advanced
renal cell carcinoma
after failure of previous
therapy
Hypertension, thromboembolism, hemorrhage, GI

perforation, GI fistula formation, hypothyroidism,
PRES, proteinuria, elevated LFTs
Administer doses every 12 hours.

May be taken with or without food.
Concomitant use with CYP3A4/5 inhibitors, including
grapefruit juice, or inducers may alter exposure to axitinib
and should be avoided. If concomitant use cannot be
avoided, dose adjustment of axitinib should be made.
Dosing should be held beginning at least 24 hours before
surgery because of risk of impaired wound healing. Time
to restart therapy is based on clinical judgment.
(Pfizer Inc., 2012b)
Classification

Classification
Small
molecule
inhibitors
(cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Bortezomib (Velcade)
IV, SC
with multiple myeloma or mantle cell lymphoma who have received at least one prior therapy
Peripheral neuropathy, hypotension, cardiomyopathy, pulmonary infiltrates,

nausea, vomiting, diarrhea, constipation, blurred
vision, fatigue, myelosuppression, PRES, hyperbilirubinemia, hepatitis
Use with caution in patients with severe renal or hepatic

disease.
Monitor hydration status and treat as necessary.
Platelet count should be > 70,000/mm3 and neutrophil
count > 1,000/mm3 when bortezomib is combined with
melphalan and prednisone.
Reconstitute only with NS.
Use reconstituted solutions within 8 hours.
Concentrations of SC (2.5 mg/ml) or IV (1 mg/ml) doses are different, and final volume depends on calculated dose.
SC injection site should be rotated in thigh or abdomen. Select new site at least 1 inch from old site, and avoid tender or bruised areas.
Concomitant use with CYP3A4 inhibitors, including grapefruit juice, or inducers may alter exposure to bortezomib.
Fatal if given intrathecally.
(Millennium Pharmaceuticals, Inc., 2012)
Inhibits BCRABL tyrosine kinase created by

the Ph+ genetic
abnormality, inhibiting proliferation, and induces apoptosis in
BCR-ABL+ cell
lines
Bosutinib
(Bosulif)
PO
Treatment of adult patients with chronic, accelerated, or blast

phase Ph+ CML that is
resistant or intolerant
to other therapies
Diarrhea, nausea, vomiting,

abdominal pain, thrombocytopenia, anemia, neutropenia, hepatic toxicity,
fluid retention resulting in
pericardial effusion, pleural effusion, pulmonary or
peripheral edema, fever,
rash, headache
Take with food.

Monitor liver transaminases and hold dose if elevations > 5
ULN occur. Discontinue if bilirubin elevations > 2 ULN
or alkaline phosphatase elevations occur.
Hold dosing and adjust dose if severe or persistent thrombocytopenia or neutropenia occur. Hold dosing if other
clinically significant moderate or severe nonhematologic
or toxicities occur, then restart once symptoms abate.
Concomitant use with CYP3A4 inhibitors, including grapefruit juice, or inducers may alter exposure to bosutinib.
Concomitant use with P-glycoprotein inhibitors such as
verapamil or diltiazem may alter exposure to bosutinib.
Avoid use in pregnant women because of risk of fetal harm.
Use of proton pump inhibitors may reduce bosutinib concentration and is not recommended. Use of antacids or H2
blockers should be separated from bosutinib administration by 2 hours.
(Pfizer Inc., 2012a)
79
Inhibits chymotrypsin-like activity of 26S proteasome resulting in disruption

of cellular homeostatic mechanisms that
can lead to cell
death
80
Small
molecule
inhibitors
(cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Inhibits tyrosine
kinase activity of
multiple receptor
kinases involved
with oncogenesis, metastasis,
tumor angiogenesis, and maintenance of the
tumor microenvironment
Cabozantinib
(Cometriq)
PO
with progressive, metastatic, medullary thyroid cancer
GI perforations and fistulas, hemorrhage, thromboembolism, wound complications, hypertension, osteonecrosis of the jaw, palmar-plantar erythrodysesthesia, proteinuria, PRES,
diarrhea, stomatitis, nausea, oral pain, constipation, abdominal pain, vomiting, fatigue, weight loss,
loss of appetite, dysgeusia, hypocalcemia, hypophosphatemia, hepatotoxicity, lymphopenia, neutropenia, thrombocytopenia
Do not administer with food. Patients should not eat at least

2 hours before and 1 hour after taking cabozantinib.
Capsules should be swallowed whole and not opened.
Missed doses should not be taken within 12 hours of the
next dose.
Concomitant use with CYP3A4 inhibitors, including grapefruit juice, or inducers may alter exposure to cabozantinib.
Dose should be adjusted or discontinued permanently in
the event of certain adverse effects. See manufacturers
prescribing information for full details.
Treatment with cabozantinib should be held at least 28
days prior to elective surgery and resumed based on clinical assessment of wound healing.
(Exelixis, Inc., 2012)
Binds to and inhibits the 20S

proteasome, resulting in anti
proliferative and
antiapoptotic activities
Carfilzomib
(Kyprolis)
IV
with multiple myeloma who have received
at least two previous
therapies and whose
disease has progressed on or within 60 days of the last
treatment
Cardiac arrest, CHF, myocardial ischemia, pulmonary hypertension, dyspnea, infusion reactions
including fever, chills, arthralgia, myalgia, flushing,
hypotension, syncope, or
angina, TLS, thrombocytopenia, anemia, leukopenia, hepatic toxicity, renal
toxicity, fatigue, diarrhea,
headache, peripheral edema, back pain, peripheral neuropathy, herpesvirus
infection
Administer over 210 min on two consecutive days.

Premedicate with dexamethasone 4 mg PO/IV prior to each
dose during the first cycle and in subsequent cycles if infusion reactions occur.
Hold and modify dose if patients develop hematologic, cardiac, renal, or hepatic toxicities, pulmonary hypertension,
pulmonary complications, peripheral neuropathy, or other
grade 34 toxicities.
Do not administer mixed with other IV medications. Infusion
line should be flushed with NS or D5W before and after
administration of carfilzomib.
Store unopened vials in refrigerator. Reconstituted product is stable for 24 hours under refrigeration or 4 hours at
room temperature.
Antiviral prophylaxis should be considered in patients with
a history of herpes zoster infection.
Because of the risk of fatigue, dizziness, fainting, or hypotension, advise patients not to drive or operate heavy machinery if they experience these symptoms.
(Onyx Pharmaceuticals, Inc., 2012)
Classification

Classification
Small
molecule
inhibitors
(cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Crizotinib
(Xalkori)
PO
Treatment of locally advanced or metastatic

ALK+ NSCLC
Hepatotoxicity, pneumonitis, QT prolongation, vision changes, nausea, diarrhea, vomiting, edema,

constipation, neutropenia,
fatigue, anorexia, dizziness, dyspnea
Determination of ALK+ NSCLC is required for treatment.

Capsules should be swallowed whole and not crushed,
chewed, or opened.
Monitor and correct for hypomagnesemia and hypokalemia to
reduce risk of QT prolongation. Do not use in patients with
hypokalemia, hypomagnesemia, or long QT syndrome.
Concomitant use with CYP3A4 inhibitors, including grapefruit juice, or inducers may alter exposure to crizotinib.
(Pfizer Inc., 2013)
Inhibits multiple tyrosine kinases, including BCR-ABL,

SRC family, cKIT, EPHA2, and
PDGFR-beta
Dasatinib
(Sprycel)
PO
Treatment of newly diagnosed Ph+ CML

Treatment of chronic, accelerated, or
myeloid or lymphoid
blast-phase CML with
resistance or intolerance to prior therapy
including imatinib
Treatment of Ph+ ALL
with resistance or intolerance to prior therapy
Myelosuppression, fluid retention including pleural

and pericardial effusion,
prolonged QT interval by
ECG, diarrhea, nausea,
abdominal pain, vomiting,
bleeding, cardiomyopathy,
pulmonary arterial hypertension
Do not crush or cut tablets.

Tablets may be taken with or without food and either in the
morning or evening.
Use with caution if patients are taking anticoagulants.
Concomitant use with CYP3A4 inhibitors, including grapefruit juice, or inducers may alter exposure to dasatinib and
should be avoided. If concomitant use cannot be avoided,
dose adjustment of dasatinib should be made.
Use of proton pump inhibitors or H2 antagonists may reduce dasatinib concentration and is not recommended.
Use of antacids should be separated from administration
of dasatinib by 2 hours.
Elevation of transaminases or bilirubin, hypocalcemia, and
hypophosphatemia may occur. Hypocalcemia may require
oral calcium supplements.
Inhibits the intracellular phosphorylation

of tyrosine kinase associated
with EGFR, expressed on the
surfaces of normal and cancer
cells
Erlotinib
(Tarceva)
PO
Treatment of locally advanced or metastatic

NSCLC after failure of
at least one prior chemotherapy regimen
As monotherapy for
maintenance treatment in patients with
locally advanced or
metastatic NSCLC
who have not progressed after 4 cycles of platinum-based
therapy
Rash, diarrhea, anorexia, fatigue, dyspnea, GI bleeding or perforation, conjunctivitis, nephrotoxicity, hepatotoxicity, myocardial infarction, cerebrovascular
accident, ocular disorders,
elevated INR
Rare reports of serious ILD
(acute onset of new or
progressive pulmonary
symptoms [e.g., dyspnea,
cough, fever]); interrupt
therapy for evaluation if
these symptoms develop.
Patients should take on an empty stomach at least 1 hour

before or 2 hours after food.
Concomitant use with CYP3A4 inhibitors or inducers may
alter exposure to erlotinib.
Monitor LFTs and consider dose reductions.
Monitor INR in patients receiving warfarin.
Monitor for GI bleeding and elevated INR.
Diarrhea can be managed with loperamide. Both diarrhea
and skin reactions may require dose reduction or temporary interruption of therapy.
(Genentech, Inc., 2012d)
81
Inhibits multiple
tyrosine kinases,
including ALK,
which reduces
tumor cell proliferation and survival
82

Mechanism
of Action
Small
molecule
inhibitors
(cont.)
Drug
Route of
Administration
Erlotinib
(Tarceva)
(cont.)
Binds to
FKBP12 intracellular protein and
inhibits mTOR,
which is a serine-threonine
kinase downstream of the
PI3K/AKT pathway, resulting in
reduced cell proliferation and angiogenesis
Everolimus
(Afinitor;
Afinitor
Disperz
tablets for
oral suspension)
Indications
Side Effects
Noninfectious pneumonitis,
infections, oral ulceration,
renal failure, diarrhea, fatigue, nausea, vomiting,
edema, nasopharyngitis, epistaxis, rash, weight
loss, decreased appetite, dysgeusia, headache,
cough, dyspnea, anemia,
leukopenia, thrombocytopenia, hyperglycemia, hypercholesterolemia, elevated hepatic transaminases, hypertriglyceridemia, hypoalbuminemia,
hypokalemia
Patients should take drug at the same time each day and
consistently either with or without food.
Tablets should be swallowed whole with a full glass of water.
Dose adjustment is required in hepatic insufficiency.
Concomitant use with CYP3A4 inhibitors, including grapefruit juice, or inducers may alter exposure to everolimus.
Concomitant use with P-glycoprotein inhibitors such as
verapamil or diltiazem may alter exposure to everolimus.
Everolimus whole blood trough levels should be monitored
routinely using the same assay and laboratory throughout treatment. Measure trough concentrations 2 weeks after starting treatment and with changes in dose, interacting drugs, hepatic function, or dosage form (oral tablets or
tablets for oral suspension).
Titrate dosage to achieve trough levels of 515 ng/ml.
Prepare oral suspension in 25 ml of water only, immediately
prior to use, and discard if not administered within 60 min.
Prepared doses should not exceed 10 mg. If higher doses are required, prepare a second dose. Once tablets are
added to water, allow 3 min for suspension to form, stir
gently, and have patients drink. After administration, add
25 ml additional water to the same glass and stir with the
same spoon to resuspend any remaining particles and
administer to patient.
Oral suspension may be administered using an oral syringe
in doses not to exceed 10 mg per syringe. After dosing
via an oral syringe, rinse the syringe with 5 ml of water
to capture remaining drug particles and administer to patient.
(Novartis Pharmaceuticals Corp., 2012a)
In combination with
gemcitabine for treatment of locally advanced, unresectable,
or metastatic pancreatic cancer
PO
Treatment of postmenopausal women with

advanced hormone
receptorpositive,
HER2-negative breast
cancer in combination
with exemestane after patients have failed
treatment with letrozole or anastrozole
Treatment of adults with
unresectable, locally advanced or metastatic progressive neuroendocrine tumors of
pancreatic origin
Treatment of adult patients with advanced
renal cell carcinoma after failed treatment with sunitinib or
sorafenib
Treatment of subependymal giant cell astrocytoma in patients
with tuberous sclerosis
complex
Classification

Classification
Small
molecule
inhibitors
(cont.)
Mechanism
of Action
Inhibits BCRABL tyrosine kinase created by
the Ph+ genetic
abnormality, inhibiting proliferation and inducing apoptosis in
BCR-ABL+ cell
lines
Drug
Imatinib
mesylate
(Gleevec)
Route of
Administration
PO
Side Effects
with newly diagnosed
Ph+ CML in chronic phase
with Ph+ CML in
blast crisis, accelerated phase, or chronic phase after failure of
IFN alfa therapy
with relapsed or refractory Ph+ ALL
with myelodysplastic/
myeloproliferative disorders associated with
PDGFR gene rearrangements
with systemic mastocytosis without certain
c-KIT mutations
with hypereosinophilic syndrome and/or
chronic eosinophilic
leukemia in the presence of certain mutations
with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans
with unresectable and/
or metastatic GIST
Adjuvant treatment of
resected GIST
Edema and fluid retention,

GI irritation, nausea, vomiting, anemia, neutropenia,
thrombocytopenia, hepatotoxicity, cardiomyopathy,
hemorrhage, dermatologic
toxicity, hypothyroidism
Weigh patients frequently, and monitor for signs and symptoms of fluid retention.
Ensure that patients take imatinib with food and a large
glass of water.
For patients who are unable to swallow tablets, the tablets
may be dispersed in a glass of water or apple juice immediately before administration.
Monitor CBC, differential, and LFTs.
CYP3A4 inducers may decrease levels of imatinib and
should be avoided or a 50% dose increase should be
considered.
CYP3A4 inhibitors, including grapefruit juice, may increase
exposure to imatinib and should be avoided.
Imatinib may increase activity of warfarin, and concomitant
use should be avoided.
Advise women of childbearing age not to become pregnant
while taking imatinib.
(Novartis Pharmaceuticals Corp., 2012b)
Indications
83
84
Small
molecule
inhibitors
(cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
4-Anilinoquinazoline kinase inhibitor of the intracellular tyrosine kinase domains of both

EGFR and
HER2 receptors
Lapatinib
(Tykerb)
PO
In combination with
capecitabine for treatment of patients with
advanced or metastatic breast cancer
whose tumors overexpress HER2 and who
have received prior
therapy including an
anthracycline, a taxane, and trastuzumab
In combination with letrozole in postmenopausal women with
hormone receptor
positive breast cancer that overexpresses HER2
Diarrhea, palmar-plantar
erythrodysesthesia, nausea, rash, vomiting, diarrhea, fatigue, decreased
LVEF, hepatotoxicity, pulmonary toxicity, QT prolongation
Instruct patients to take lapatinib at least 1 hour before or 1

hour after a meal. However, capecitabine should be taken
with food or within 30 min after food.
Lapatinib dose should be taken once daily; do not divide
the daily dose.
Modify the dose in patients with severe hepatic impairment.
Concomitant use with CYP3A4 inhibitors, including grapefruit juice, or inducers may alter exposure to lapatinib and
should be avoided or the dose adjusted if concomitant
use is required.
Confirm normal ejection fraction before beginning drug.
Lapatinib should be discontinued in patients if LVEF
drops below lower limits of normal.
Diarrhea may be managed with antidiarrheal agents; replace fluids and electrolytes if severe.
Lapatinib may cause fetal harm when administered to pregnant women.
Monitor and correct for hypomagnesemia and hypokalemia
to reduce risk of QT prolongation.
(GlaxoSmithKline, 2012b)
Binds to and stabilizes the inactive conformation of BCRABL, the kinase

produced by the
Ph chromosome
Nilotinib
(Tasigna)
PO
newly diagnosed with
Ph+ CML in chronic
phase
Treatment of chronicand accelerated-phase
Ph+ CML in adult patients resistant or intolerant to prior therapy
including imatinib
Rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting,

thrombocytopenia, neutropenia, anemia, elevated lipase, hepatotoxicity, electrolyte abnormalities, prolonged QT interval
Sudden deaths have been
reported.
Instruct patients to swallow capsules whole with water. For

patients unable to swallow capsules, the contents may
be mixed in one teaspoon of applesauce and taken within 15 min.
Twice-daily doses should be taken at 12-hour intervals.
No food should be consumed for at least 2 hours before the
dose and 1 hour after.
Check CBC every 2 weeks for the first 2 months, then
monthly.
Monitor and correct for hypomagnesemia and hypokalemia to
reduce risk of QT prolongation. Do not use in patients with
hypokalemia, hypomagnesemia, or long QT syndrome.
Obtain ECG at baseline, 7 days after initiation, and periodically to monitor QTc.
Avoid concomitant use of drugs known to prolong QT interval.
Concomitant use of CYP3A4 inhibitors, such as grapefruit juice, or inducers may alter exposure to nilotinib and
should be avoided. Dose reduction may be necessary if
inhibitors must be given, and the QTc should be monitored closely.
Classification

Classification
Mechanism
of Action
Small
molecule
inhibitors
(cont.)
Drug
Route of
Administration
Indications
Side Effects
Nilotinib
(Tasigna)
(cont.)
Inhibits VEGF
receptors with
tyrosine kinase
activity, which interferes with tumor angiogenesis, growth, and
progression
Pazopanib
(Votrient)
Do not use in patients who are pregnant or breast-feeding.
Women of childbearing age should use effective contraception during treatment.
Concomitant use of proton pump inhibitors may reduce absorption of nilotinib.
(Novartis Pharmaceuticals Corp., 2011)
PO
Hepatotoxicity, LVEF dysfunction, hemorrhage,

thromboembolism, GI perforation, GI fistula formation, PRES, hypertension,
hypothyroidism, proteinuria, infection, diarrhea,
hair color changes, nausea, anorexia, vomiting,
fatigue, leukopenia, neutropenia, thrombocytopenia, lymphocytopenia, hypophosphatemia, hyperglycemia, hypomagnesemia, headache, myalgia
Doses should be taken once daily at least 1 hour before or

2 hours after a meal.
Do not crush tablets.
Concomitant use of CYP3A4 inhibitors, including grapefruit
juice, and inducers may alter exposure to pazopanib and
should be avoided.
Measure LFTs before start of pazopanib use, and monitor
at least monthly during the first 4 months of treatment and
then periodically thereafter.
Discontinue the drug permanently in patients in whom ALT
> 3 ULN and bilirubin levels increase > 2 ULN while
on pazopanib.
Use with caution in patients with a history of QT prolongation or concomitantly using other drugs that prolong QT
interval.
Stop use of drug at least 7 days prior to planned surgery,
and restart based on clinical judgment.
Concomitant use with simvastatin may increase risk of ALT
elevations.
(GlaxoSmithKline, 2012c)

85
86
Small
molecule
inhibitors
(cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Inhibits multiple membranebound and intracellular kinases

involved in oncogenesis, tumor angiogenesis, and maintenance of tumor
microenvironment
Regorafenib
(Stivarga)
PO
with metastatic
colorectal cancer who
have previously been
treated with other therapies including a fluoropyrimidine, oxaliplatin, irinotecan, antiVEGF therapy, and
anti-EGFR therapy (if
KRAS wild type)
with locally advanced,
unresectable or metastatic GIST following previous treatment
with imatinib and sunitinib
Hepatotoxicity, hemorrhage,
hand-foot skin reactions,
rash, hypertension, cardiac ischemia, myocardial
infarction, PRES, GI perforation or fistula, complications with wound healing,
asthenia, fatigue, pain, fever, anorexia, diarrhea,
mucositis, weight loss, infection, dysphonia, anemia, thrombocytopenia,
lymphopenia, hypocalcemia, hypokalemia, hyponatremia, hypophosphatemia, proteinuria
Patients should take drug at the same time each day.

Tablets should be swallowed whole with a low-fat breakfast.
Reduce dose for grade 2 hand-foot skin reactions, and hold
dose for grade 2 hand-foot skin reactions that recur or do
not improve within 7 days despite dose reduction.
Hold dose for grade 2 hypertension.
Hold dose for any other grade 34 adverse reaction and
then restart at a reduced dose after patient recovers from
the reaction. Restart dosing following grade 4 reactions
only if the potential benefit outweighs the risks.
Hold dose if elevations in hepatic transaminases, and restart only if the potential for benefit outweighs the risk of
hepatotoxicity. Discontinue dosing if transaminase (AST
or ALT) levels are > 20 ULN or > 3 ULN with a bilirubin > 2 ULN or recurrent elevated transaminases > 5
ULN despite dose reduction.
May cause fetal harm when administered to pregnant women.
Concomitant use with CYP3A4 inhibitors, including grapefruit juice, or inducers may alter exposure to regorafenib.
(Bayer Healthcare, 2013)
Inhibits JAK 1
and 2, which
mediate cytokines and growth
factors responsible for hematopoiesis and immune function
Ruxolitinib
(Jakafi)
PO
with intermediate- or
high-risk myelofibrosis,
including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocytopenia myelofibrosis
Thrombocytopenia, anemia,
neutropenia, infections
Store at room temperature.

If patients are unable to swallow the tablets, ruxolitinib may
be mixed to a suspension by adding the tablet to 40 ml of
water and stirring for 10 min before administration via nasogastric tube, followed by a flush with 75 ml of water. Administer the suspension within 6 hours of preparation.
The starting dose is based on a patients current platelet
count, and CBC should be monitored every 24 weeks
until the dose is stabilized, and then as needed.
Hold dose if platelet count is < 50,000 106/L; may restart,
possibly at a reduced dose, after platelet recovery.
Dose may be increased incrementally after at least 4 weeks
of therapy and no more frequently than every 2 weeks
to a maximum of 25 mg twice daily if an inadequate response has been achieved.
When used concomitantly with strong CYP3A4 inhibitors,
the recommended starting dose is 10 mg twice daily in
patients with a platelet count > 100,000 106/L. Avoid use
with strong CYP3A4 inhibitors in patients with a platelet
count < 100,000 106/L.
Classification

Classification
Mechanism
of Action
Small
molecule
inhibitors
(cont.)
Drug
Route of
Administration
Indications
Side Effects
Ruxolitinib
(Jakafi)
(cont.)
Dose adjustment is recommended in patients with creatinine clearance < 60 ml/min or hepatic impairment.
When discontinuing therapy for reasons other than thrombocytopenia, a gradual taper by 5 mg twice daily each
week should occur.
Patients are at an increased risk for herpes zoster infections and should be advised to seek treatment if symptoms present.
(Incyte Corp., 2012)
Sorafenib
(Nexavar)
PO
Treatment of unresectable hepatocellular

carcinoma and advanced renal cell carcinoma
Palmar-plantar erythrodysesthesia, rash, hypertension, myocardial infarction, mucositis, dyspepsia, increased lipase, increased amylase, diarrhea, nausea, vomiting,
decreased appetite, increased risk of bleeding,
peripheral neuropathy, GI
perforation, prolongation
of QT interval, hypophosphatemia, lymphopenia,
neutropenia, anemia
Doses should be taken at least 1 hour before or 2 hours after a meal.

Continue treatment until patients no longer benefit from
therapy or until unacceptable toxicity occurs.
Caution patients to avoid becoming pregnant during treatment and for 2 weeks after treatment has stopped.
Sorafenib has been shown to cause birth defects or fetal loss.
Use with carboplatin and paclitaxel is contraindicated in
patients with squamous cell lung cancer because of increased risk of mortality.
Sorafenib may increase activity of warfarin if taken concomitantly.
(Bayer Healthcare, 2011)
Decreases tumor cell proliferation and reduces tumor angiogenesis through

tyrosine kinase
inhibition
Sunitinib
(Sutent)
PO
Treatment of GIST after

disease progression
while on imatinib or intolerance to imatinib
Treatment of progressive, well-differentiated, unresectable, locally advanced or metastatic pancreatic neuroendocrine tumors
Myelosuppression, hepatotoxicity, left ventricular dysfunction, hypothyroidism, diarrhea, constipation, nausea, vomiting,
mucositis, stomatitis, dyspepsia, skin discoloration,
rash, depigmentation of
hair, palmar-plantar erythrodysesthesia, fatigue, hypertension, bleeding, edema, QT prolongation, impaired wound healing, venous thromboembolism,
pancreatitis
Medication may be taken with or without food.

Obtain baseline ejection fraction prior to initiation of sunitinib.
Concomitant use with CYP3A4 inhibitors, such as grapefruit juice, or inducers may alter exposure to sunitinib.
Monitor and correct for hypomagnesemia and hypokalemia
to reduce risk of QT prolongation.
(Pfizer Inc., 2011)
87
Multikinase inhibitor that is

believed to decrease tumor
cell signaling,
angiogenesis,
and apoptosis
88
Small
molecule
inhibitors
(cont.)
Mechanism
of Action
Binds to the intracellular protein FKBP12, resulting in inhibition of mTOR,
causing an interruption of cell division
Drug
Temsirolimus (Torisel)
Route of
Administration
IV
Indications
Side Effects
Rash, asthenia, mucositis,

nausea, edema, hypersensitivity reactions, anorexia,
myelosuppression, hyperglycemia, hyperlipidemia,
hypercholesterolemia, hypertriglyceridemia, elevated alkaline phosphatase,
elevated SCr, lymphopenia, hypophosphatemia,
elevated AST, ILD, opportunistic infections, bowel
perforation
Preparation requires use of manufacturer-provided diluent

and then additional dilution with NS.
Premedicate with prophylactic IV diphenhydramine 2550
mg (or similar antihistamine) approximately 30 min before
the start of each dose.
Hold dosing if platelet count < 75,000/mm3 or neutrophil
count < 1,000/mm3.
Dose reductions are required in patients with even mild hepatic impairment, and drug is contraindicated in patients
with bilirubin > 1.5 ULN.
Use with CYP3A4 inhibitors, including grapefruit juice, or
inducers may alter exposure to temsirolimus and should
be avoided or the dose adjusted if concomitant use is required.
Protect from light.
Prepare temsirolimus in PVC-free, non-DEHP glass bottles
or infusion bags and tubing.
Protect prepared product from light and administer through
an in-line filter of < 5 microns within 6 hours after dilution
in NS.
Hyperglycemia and hyperlipidemia are likely and may require treatment. Monitor lipid profiles.
Patients receiving additional anticoagulation may be at increased risk for bleeding.
Monitor for symptoms of radiographic changes of ILD.
Because of abnormal wound healing, use with caution in
the perioperative period.
Patients should avoid receiving live vaccines and having
close contact with those who have received live vaccines.
Bowel perforations may occur; promptly evaluate for fever,
abdominal pain, bloody stools, and acute abdomen.
Women of childbearing potential should be advised of the
potential hazard to the fetus and to avoid becoming pregnant during treatment.
Monitor renal function at baseline and throughout treatment.
Classification

Classification
Small
molecule
inhibitors
(cont.)
Mechanism
of Action
Inhibits VEGF
and EGFR tyrosine kinase activity that interferes with endothelial cell migration, proliferation, and new
blood vessel
survival
Drug
Vandetanib
(Caprelsa)
Route of
Administration
PO
Indications
Side Effects
Treatment of symptomatic or progressive, unresectable, locally advanced or metastatic multifocal medullary

thyroid cancer
QT prolongation, skin reactions, skin photosensitivity,

ILD, pneumonitis, ischemic
cardiovascular events,
hemorrhage, heart failure,
diarrhea, hypothyroidism,
hypertension, PRES, rash,
acne, nausea, headache,
fatigue, anorexia, abdominal pain
Caprelsa is available only through a restricted distribution

program requiring certification of prescribers and pharmacies.
Do not crush tablets.
If patients are unable to swallow tablets, the tablets can be
dispersed in 2 oz of noncarbonated water, stirred for approximately 10 min, and then swallowed immediately. Any
residue in the glass should be mixed with 4 oz of additional water and swallowed by patient.
Avoid skin exposure to crushed tablets.
Concomitant use with CYP3A4 inducers may increase exposure to vandetanib and should be avoided.
Use is contraindicated in patients with congenital QT prolongation.
Monitor and correct for hypocalcemia, hypomagnesemia,
and hypokalemia to reduce risk of QT prolongation.
Obtain ECG at baseline and recheck 24 weeks and 812
weeks after starting vandetanib, and then every 3 months
thereafter.
Avoid concomitant use of drugs that prolong QT interval, or
perform more frequent ECG monitoring if use is unavoidable.
Instruct patients to wear sunscreen and protective clothing
when exposed to sun.
(AstraZeneca Pharmaceuticals, 2011)

89
90
Small
molecule
inhibitors
(cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Inhibits the mutated form of

BRAF serine/
threonine kinase
Vemura
fenib
(Zelboraf)
PO
Treatment of unresectable melanoma or

melanoma containing
the BRAF V600E mutation
Hypersensitivity, cutaneous
squamous cell carcinoma,
skin reactions, QT prolongation, hepatotoxicity, photosensitivity, eye irritation,
new malignant melanoma
lesions, alopecia, pruritus,
hyperkeratosis, arthralgia,
fatigue, nausea, diarrhea,
headache
Doses should be taken approximately every 12 hours.

Drug may be taken with or without food.
Tablets should be swallowed whole with a glassful of water.
Do not crush or chew tablets.
Because of the risk of developing cutaneous squamous
cell carcinoma, patients should receive a dermatologic
evaluation prior to starting vemurafenib and then every 2
months thereafter.
Monitor and correct for hypocalcemia, hypomagnesemia,
and hypokalemia to reduce risk of QT prolongation.
ECG should be obtained at baseline, 15 days after the start
of treatment, monthly during the first three months of
treatment, and then at least every 3 months thereafter.
Avoid use in patients with a QTc > 500 ms, and hold therapy if QTc exceeds this time during treatment.
Instruct patients to avoid sun exposure and wear protective
clothing, sunscreen, and lip balm when outdoors.
Vemurafenib is a CYP1A2 and CYP2D6 inhibitor and CYP
3A4 inducer; avoid concomitant use with other medications metabolized by these enzymes because of the potential for altered metabolism.
Concomitant use with CYP3A4 inhibitors, including grapefruit juice, and inducers may alter exposure to vemurafenib.
(Genentech, Inc., 2011b)
Inhibits transmembrane signal transduction

in the Hedgehog
pathway responsible for cell development
Vismodegib (Erivedge)
PO
Treatment of metastatic basal cell carcinoma

or locally advanced
basal cell carcinoma
that has advanced following surgery or in
patients who are not
candidates for surgery
or radiation therapy
Muscle spasm, alopecia,

dysgeusia, weight loss, fatigue, diarrhea, anorexia, constipation, arthralgia,
vomiting
Drug may be taken with or without food.

Patients should swallow capsules whole. Do not crush or
chew.
Because of teratogenicity, determine pregnancy status of
women of childbearing age prior to starting therapy. Inform male patients of fetal risk, and instruct on use of
contraception during treatment.
Patients may not donate blood during treatment or for at
least 7 months after completing treatment.
Concomitant use with agents that reduce stomach acid,
such as a proton pump inhibitor or H2 antagonist, may reduce absorption of vismodegib.
(Genentech, Inc., 2012a)
Classification

Classification
Small
molecule
inhibitors
(cont.)
Mechanism
of Action
Acts as a soluble receptor and
binds to VEGFA, VEGF-B, and
placental growth
factor (known
as PIGF), leading to inhibition
of neovascularization and decreased vascular
permeability
Drug
Ziv-aflibercept (Zaltrap)
Route of
Administration
IV
Indications
Side Effects
In combination with
5-fluorouracil, leucovorin, and irinotecan
in patients with metastatic colorectal cancer that is resistant or
progressing following
treatment with oxaliplatin-based therapy
Hemorrhage, GI perforation, impaired wound healing, fistula formation, hypertension, arterial thromboembolic events including transient ischemic attack, cerebrovascular accident, and angina, proteinuria, nephrotic syndrome,
thrombotic microangiopathy, neutropenia, infection,
thrombocytopenia, diarrhea, dehydration, PRES,
anorexia, stomatitis, abdominal pain, fatigue, elevated hepatic transaminases
Store in refrigerator, and keep vials in original container until time of use to protect from light.
Administer infusions over 1 hour through a 0.2 micron polyethersulfone filter prior to any of the other drugs used in
the chemotherapy regimen. Do not use with filters made
from polyvinylidene fluoride or nylon.
Do not use product if solution is anything other than clear,
colorless to pale yellow in color.
Discard unused product following initial one-time access
into vial.
Dilute in NS or D5W to a concentration of 0.68 mg/ml.
Do not administer mixed with other IV medications.
Diluted solution may be stored under refrigeration for up to
4 hours.
Hold dosing at least 4 weeks prior to elective surgery.
Hold dosing if recurrent or severe hypertension occurs, and
restart once blood pressure is controlled.
Monitor urine protein, and hold dosing if proteinuria > 2
g/24 hours; restart once proteinuria < 2 g/24 hours. Dose
reduction is recommended for recurrent proteinuria > 2
g/24 hours.
(Regeneron Pharmaceuticals, Inc., 2012)

91
ADCCantibody-dependent cellular cytotoxicity; ALKanaplastic lymphoma kinase; ALLacute lymphoblastic leukemia; ALTalanine aminotransferase; ASTaspartate transferase; BCR-ABLbreakpoint cluster region-Abelson; BRAFv-raf murine sarcoma viral oncogene homolog B; CBCcomplete blood count; CDcluster of differentiation; CHFcongestive heart failure; CHOPcyclophosphamide, doxorubicin, vincristine,
prednisone; CLLchronic lymphocytic leukemia; CMLchronic myeloid leukemia; CTLA-4cytotoxic T-lymphocyte antigen 4; CVPcyclophosphamide, vincristine, prednisone; DEHPdi-2-ethylhexyl phthalate; D5W
5% dextrose in water; ECGelectrocardiogram; EGFRepidermal growth factor receptor; EPHA2ephrin A2; FLTFms-related tyrosine kinase; GIgastrointestinal; GISTgastrointestinal stromal tumor; Hhistamine; HER2human epidermal growth factor receptor 2; IFNinterferon; ILinterleukin; ILDinterstitial lung disease; INRinternational normalized ratio; IVintravenous; JAKJanus-associated kinases; JCV
John Cunningham virus; KDRkinase insert domain receptor; KRASKirsten rat sarcoma viral oncogene homolog; LFTliver function test; LVEFleft ventricular ejection fraction; mCimillicurie; MDSmyelodysplastic syndrome; minminutes; MMEAmonomethyl auristatin E; msmillisecond; mTORmammalian target of rapamycin; NHLnon-Hodgkin lymphoma; NSnormal saline; NSCLCnon-small cell lung cancer; oz
ounces; PDGFRplatelet-derived growth factor receptor; Ph+Philadelphia chromosomepositive; POby mouth; PRESposterior reversible encephalopathy syndrome; PVCpolyvinyl chloride; QTcQT interval
corrected; RANKLreceptor activator of nuclear factor B ligand; REMSrisk evaluation and mitigation strategy; SCsubcutaneous; SCrserum creatinine; TLStumor lysis syndrome; TNFtumor necrosis factor;
ULNupper limit of normal; VEGFvascular endothelial growth factor; VGFVaccinia virus growth factor
92
Figure 9. Common Terminology in Cell Signaling

Ligands: Molecules, such as growth factors, that activate receptors, such as growth factor
receptors, on the surface of the cell
Ligand binding: The process by which the ligand attaches to a specific receptor site and
activates the receptor, thereby activating the signaling pathway. This is similar to antigen-antibody binding.
Monomer: Single receptor, inactivated state
Dimerization: Activation of receptor through monomer pairing. Dimerization occurs between
two adjacent receptors that have bound ligands. That is, two monomers that are side by side
on the surface of the cell are paired and activated by the ligand. The joining activates a series
of signals.
Phosphorylation: Activation of a chemical process to initiate signaling, such as with tyrosine kinase
Heterodimerization: The pairing of two different ligand-bound receptors together, such as
Erb1 and Erb2
Homodimerization: The joining of two receptors of the same subtype, such as two Erb1
(HER1) receptors or two Erb2 (HER2), Erb3 (HER3), or Erb4 (HER4) receptors
Note. Based on information from Paul, 2008.
initiate on the ligands of the extracellular domain, sending a

signal through the transmembrane to intracellular tyrosine kinase and on to the nucleus of the cell.
(4) Tyrosine kinases modify themselves as well as other cellular proteins by putting phosphate molecules on the amino acid tyrosine.
(a) This activity is necessary for receptor signaling.
(b) Targeted therapies are directed toward specific molecules
(targets) along a cellular signaling pathway that is involved
in tumor growth, proliferation, and invasion.
(5) Targeted therapies moderate, control, and/or kill cancer cells
and work differently than either chemotherapy or radiation
therapy (see Figure 10).
(6) Therapies targeting intracellular pathways, or tyrosine kinase
receptors, are small molecules and, to date, mostly oral therapies. Because of the need for long-term inhibition of signaling,
chronic oral therapy represents the most rational approach to
dosing. Patients may develop drug resistance with kinase-targeted therapies. Examples:
(a) Erlotinib
(b) Sorafenib
(c) Sunitinib
(d) Imatinib
(7) Mammalian target of rapamycin (mTOR) kinase inhibition:
Temsirolimus
(8) BRAF V600E mutations: Vemurafenib
(9) Anaplastic lymphoma kinasepositive: Crizotinib
(10) Therapies targeting growth factor receptors in the extracellular
pathways are generally mAbs (see previous section).
2. Growth factors
a) Growth factors are produced by cells in all body tissues.
b) They are primarily responsible for initiating the complex cell signaling that is required to maintain cell viability and division.
c) These factors can influence cells in either a positive or negative way
that affects cell survival, apoptosis, and differentiation.
d) Growth factors bind with their specific receptors and initiate a cascade of intracellular signaling.
e) Examples of growth factors
(1) Epidermal growth factor (EGF), which binds to EGFR
(2) VEGF, which binds to the vascular endothelial growth factor

receptor (VEGFR)
f) Redundancies exist in cell signaling. Several extracellular signals may
lead to the activation of the same pathway.
(1) The final response of the cell may differ depending on the response from the nucleus.
(2) Despite this redundancy with stimuli, the kinetics and extent of
activation may vary, leading to vastly different outcomes.
K. Angiogenesis and antiangiogenic agents (Keith & Simon, 2008; Oklu, Walker, Wicky, & Hesketh, 2010; Viale, 2007; Wilkes, 2007; Wisinski & Gradishar,
2011; Wujcik, 2011)
1. Angiogenesis is the development of new blood vessels. It is a complex,
multistep process that is required for a host of normal functions, including wound healing, tissue repair, reproduction, growth, and development.
2. Under normal circumstances, angiogenesis is tightly controlled by a balance of stimulators and inhibitors.
3. In malignant angiogenesis, that balance is upset, leading to irregular molecular and cellular events that contribute to tumor neovascularization.
Figure 10. Cancer Treatments: Mechanisms of Action
Note. Figure courtesy of the Institute for Medical Education & Research, Inc., June 22, 2012. Used with permission.
93
94
4. In the context of tumors, angiogenesis refers to the growth of new vessels

within a tumor. The new vessels develop from the existing vascular network and provide a blood supply for the tumor.
5. Tumors are initially antiangiogenic, so there must be a factor, known as
an angiogenic switch, that makes them proangiogenic. This switch is what
turns on tumor angiogenesis.
a) Hypoxia activates intracellular molecules including the hypoxiainducible factor-1 (HIF-1) complex. HIF-1 activation causes upregulation of proangiogenic factors including VEGF, platelet-derived
growth factor, and nitric oxide synthase. HIF-1 is essential in inducing the angiogenic switch, changing the microenvironment from antiangiogenic to proangiogenic.
b) VEGF and basic fibroblast growth factor are circulating growth factors known to induce angiogenesis. Their presence has been reported to correlate with extent of disease, clinical status, and survival.
c) Endothelial cells line the vasculature of normal tissues. In a resting
state, they provide a homeostatic barrier that prevents the uncontrolled
extravasation of intravascular components and inhibits coagulation.
d) When a tumor begins to grow in normal tissue, tumor cells release
factors that elicit responses from the surrounding endothelium. The
result is vascular growth from normal tissue into the tumor.
e) Neovascularization contributes to tumor invasion and metastasis.
(1) Tumor vasculature is permeable and disorganized with a weak
basement membrane. These conditions facilitate the migration
of endothelial cells.
(2) VEGF can cause accumulation of endothelial cells and stimulate further tumor angiogenesis.
(3) Blood flow in tumors is sluggish, thus inducing hypoxia and
acidosis. Tumor hypoxia further induces tumor angiogenesis.
(4) Hypoxia and acidosis may contribute to chemotherapy and radiotherapy resistance because of lack of oxygen.
6. Other molecular pathways involved in tumor angiogenesis
a) Matrix metalloproteinases (MMPs) are involved in degrading the extracellular matrix components (ECM). In angiogenesis, MMPs invade
the ECM via new vessel formation and lead to proliferation and migration of tumor cells.
b) Tumor angiogenesis also affects the Notch receptor pathway. Notch surface cell receptors are involved in cell fate, cell differentiation, and cell
proliferation. Vascular endothelial cells express certain Notch receptors.
One type is needed for the vascular development of embryos but also is
upregulated in tumor vasculature. This process may be VEGF mediated.
7. Antiangiogenic agents
a) Mechanism of action: Antiangiogenic agents target the neovasculature of tumors to halt their growth, prevent tumor invasion, and preclude metastatic diffusion. Potentially, antiangiogenic agents are ideal for use with other cancer therapy modalities because they maximize the efficacy of the other therapies.
b) Side effects: Table 10 lists some of the side effects of antiangiogenic agents.
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Chapter 5
Nursing Considerations in
Cancer Treatment
A. Ethical issues: The rapidly changing healthcare environment necessitates
that nurses be sensitive to ethical and legal issues. Issues arise in the care
of all patients, but the intensity is often greater in the cancer population
when patients, families, and healthcare professionals face potentially difficult moral choices.
1. Ethical issues related to cancer therapy
a) Healthcare realities that present potential ethical issues
(1) Major advances: Medical technology, increased expectations,
and changing moral attitudes combine to generate complex
ethical and legal problems related to cancer and palliative care
(Butts & Rich, 2012; Pavlish, Brown-Saltzman, Hersh, Shirk, &
Nudelman, 2011; Pendry, 2007; Smith et al., 2011). In particular, the use of life-sustaining measures may raise ethical questions when healthcare professionals
(a) Fail to discuss a patients wishes before a crisis developed
(b) Are reluctant or fail to communicate medical treatment
options with a grief-stricken family
(c) Fail to consider supportive care measures
(d) Experience moral distress related to personal values or biases.
(2) Changing healthcare environment: Staffing shortages, reallocation of resources, consolidation, and corporatization have resulted in growing administrative dominance over clinical practice
(Agency for Healthcare Research and Quality [AHRQ], 2013;
Centers for Medicare and Medicaid Services [CMS], 2013; Institute of Medicine, 2004; Pendry, 2007).
(3) Increasing numbers of underinsured and undocumented individuals: Even for people with health insurance, the need to
make copayments can lead to debt. Children and the working
poor are most affected by poor coverage. Also, some people
with insurance are unable to obtain reimbursement for certain
treatments, such as BMT or off-label use of medications (Brock,
2010; CMS, 2013).
(4) Increases in cultural diversity: Cultural and communication differences present a range of challenges, from discussion of diagnosis and prognosis to decisions about who will provide longterm care (AHRQ, 2013; Butts & Rich, 2012).
(5) Use of alternative therapies: Increasing use of complementary and alternative medicine, either in conjunction with or as a
substitute for conventional treatment, is the result of many factors, including the unpredictable nature of individual response
to cancer and its treatment, the individuals need for a sense
of control, belief in individual rights and determination, and
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cultural and spiritual beliefs (Butts & Rich, 2012; Cooley, 2010;
Fouladbakhsh, 2013).
(6) Expanded use of targeted therapies, discovery of genetic mutations, and increase in molecular testing: As personalized
therapies become more common, healthcare professionals
are expected to apply this knowledge to practice. Reimbursement for testing and services, extensive family history collection, and costs of targeted and biologic therapies offer more
challenges to patients, the healthcare system, and professionals (Bronchud, Foote, Giaccone, Olopade, & Workman, 2008;
Calzone, Masny, & Jenkins, 2010).
b) Ethical issues that oncology nurses face in daily practice (Pendry, 2007)
(1) End-of-life decisions
(2) Informed consent
(3) Patient autonomy and decision-making capacity
(4) The right to refuse treatment
(5) Undertreatment of pain
(6) The healthcare environment and reform
(7) Access to care
(8) Confidentiality
(9) Scientific integrity
(10) Intra-family conflicts
(11) Nurse-family conflicts
(12) Nurse-physician conflicts
(13) Physician-family conflicts
(14) Participation in clinical research
2. The Joint Commission (2011) requires accredited institutions to provide
access to an ethics consultation to assist in evaluating the decision-making capacity of an individual as well as to assist with problem resolution.
3. The ethical principles guiding decision making are summarized in Table 11.
Table 11. Ethical Principles
Principle
Description
Clinical Examples
Autonomy
Independent decision making by an individual in accordance with his or her

own best interest
Respecting an individuals choice even when different from ones

own
Providing supportive services
Nonmaleficence
The duty to do no harm
Providing complete information

Providing survivorship services
Recognizing professional limitations and seeking consultation/collaboration
Adhering to professional standards of care
Beneficence
The duty to act in the best interest of

the involved person
Personalizing care based on individual desires, culture, disease,

and other factors
Providing evidence-based care
Justice
Equitable distribution of available resources
Offering/providing treatment regardless of ability to pay, culture, or

socioeconomic status
Assisting with or referring for financial support
Veracity
Truth telling
Explaining treatment in understandable terms before it is initiated

Providing accurate information and educational materials
Fidelity
Faithfulness to promises made
Following up as promised
Providing survivorship care planning
Fostering collegiality
Note. Based on information from Beauchamp & Childress, 2009.
Chapter 5. Nursing Considerations in Cancer Treatment
B. Legal issues related to cancer therapy: Adhering to national, state, and institutional standards is a fundamental responsibility of all nurses (American
Nurses Association, 2010; Brown, Marcus, & Bales, in press; Sabatino, 2010).
1. The acts and standards guiding nursing practice
a) Nurse practice acts: State laws that define nursing performance in
fundamental terms for each state
b) ONSs Statement on the Scope and Standards of Oncology Nursing Practice:
Generalist and Advanced Practice (Brant & Wickham, 2013) describes the
minimum standard of care to which a patient with cancer is entitled.
c) Infusion Nursing Standards of Practice (Infusion Nurses Society, 2011)
describes the current standards of nursing practice for IV therapy.
d) Sources of institution-specific standards
(1) Standards of practice
(2) Nursing policy and procedure manuals
(3) Job descriptions
(4) IRB decisions
2. Common legal issues
a) Medication errors (see Section D: Patient Safety)
b) Documentation issues: The duty to keep accurate records is a fundamental nursing responsibility. The medical record is scrutinized in the
event of litigious action and is believed to reflect the care rendered
(American Society of Health-System Pharmacists [ASHP], 2011; Anderson & Townsend, 2010; Brock, 2010).
(1) Common documentation errors
(a) Omitting significant observations
(b) Failing to document the patients response to an intervention
(c) Failing to document patient teaching and understanding
(d) Failing to document what was taught and to whom
(2) Nursing actions to include in documentation
(a) Telephone conversations, particularly those in which the
nurse gives the patient instructions or advice
(b) Pertinent conversations with the patient, family, or other
caregivers
(c) Interagency referrals
(d) Cytotoxic drug administration: See Appendices 1 and 2.
(e) Treatment-related documentation including the following,
when applicable
i. Two unique patient identifiers (such as name, medical record number, or date of birth)
ii. Patient-specific measurements used to calculate doses (e.g., body surface area [BSA])
iii. Pertinent laboratory and diagnostic test results
iv. Date and time of therapy
v. Drug name, dose, route of administration, and infusion duration
vi. Volume and type of IV fluids administered
vii. Assessment of the IV site before, during, and after infusion
viii. Information about the infusion device (e.g., vein selection, needle size, type of device, infusion pump)
ix. Verification of IV access device patency, including presence of a blood return before, during, and after IV therapy
(f) Patient assessment and evaluation of the patient response
to and tolerance of treatment
(g) Patient and family education related to drugs received, toxicities, toxicity management, and follow-up care
(h) Post-treatment or discharge instructions
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c) Informed consent
(1) Process: Patients must give IC for treatment, enrollment in a
clinical trial, or participation in nursing research (Beauchamp
& Childress, 2009; Butts & Rich, 2012; Klimaszewski, in press;
Pojman, 2010). With the exception of research, each institution determines its own practice related to how and if a patient
must provide written IC before receiving antineoplastic medications (Jacobson et al., 2012). It is important to maintain consistency between policy and practice throughout the institution.
The following approaches have been used.
(a) The general hospital consent to treat document serves as
the signed permission to provide antineoplastic medications.
(b) The patient signs a consent form designed specifically for
the administration of antineoplastic medications and that
is part of the medical record.
(c) Some centers use a general procedure consent form for
antineoplastic medications.
(d) A specific form is not signed, but consent is documented
within the medical record.
(2) Requirements
(a) The IC document must state the right of the patient to refuse or discontinue treatment at any time.
(b) The IC document and, subsequently, physicians and nurses, must guarantee patients that ongoing support and care
will be provided if they decline or discontinue treatment
connected with the trial or research.
(c) Nurses and physicians have different but complementary
roles in the IC process.
(d) See Chapter 2 for additional information on the IC process and the nurses role.
C. Safety standards for antineoplastic administration
1. ASCO/ONS Chemotherapy Administration Safety Standards: In 2008, ASCO
and ONS began a collaboration to outline safety standards for the administration of chemotherapy (Jacobson et al., 2009).
a) Professionals from disciplines across health care were included in the
development process of this consensus document, which applies to
all practice settings and focuses on patient safety.
b) Standards address staffing-related issues, chemotherapy planning,
documentation, orders, preparation, education, administration, and
monitoring.
c) The standards are included in ASCOs Quality Oncology Practice Initiative (QOPI) program, which certifies hematology/oncology practices based on quality indicators.
d) The original standards and later revisions were published in the
Journal of Clinical Oncology, the Journal of Oncology Practice, and the
Oncology Nursing Forum (Jacobson et al., 2009, 2012; Neuss et al.,
2013).
e) For more information, visit www.ons.org/practice-resources/clinical
-practice/ascoons-chemotherapy-administration-safety-standards.
D. Patient safety: The nurse is the final checkpoint in the medication administration process. Strategies should be implemented to minimize the occurrence of medication errors.
1. Prevalence of medication errors
a) As reported by the Institute of Medicine (2004), 3.7% of inpatients
experienced an adverse event related to a medication error.
b) Preventable adverse drug events have been found to cause one out
of five injuries or deaths to patients in hospitals (AHRQ, 2000; Leape
et al., 1991).
c) Weingart et al. (2010) studied errors related to oral chemotherapy using incident reports from seven comprehensive cancer centers, a literature and Internet search, U.S. Pharmacopeial Convention [USP]
reports, and pharmacy and incident reports from the authors own
center. The majority of errors resulted in a near-miss of a dose; 39.3%
involved inaccurate supply, which resulted in adverse drug events. Incidents derived from the literature and Internet search and the authors hospital incident reporting system showed a greater percentage of adverse drug events (73.1% and 58.8%, respectively) compared
with the other sources (Weingart et al., 2010).
2. Risks associated with the administration of cytotoxic agents (Schwappach & Wernli, 2010)
a) Toxicity
b) Low margin for dosing error (e.g., use of high-dose ablative therapy
leaves essentially no margin for error)
c) Widely varying dosages and administration schedules (doses and
schedules may be patient-specific)
d) Doses often are modified based on patients clinical status and response.
e) Complicated and varying medications, schedules, and regimens
3. Types of chemotherapy medication errors (ASHP, 2011; Schwappach &
Wernli, 2010; Sheridan-Leos, 2007; Weingart et al., 2010)
a) Administration of the wrong dose (under- or overdosing)
b) Schedule and timing errors
c) Use of the wrong drug
d) Infusion rate errors
e) Omission of drugs or hydration
f) Improper drug preparation
g) Route errors (e.g., intrathecal [IT] versus IV)
h) Administration to the wrong patient
i) Administration when laboratory values not appropriate
4. Factors contributing to medication errors in chemotherapy: Most medication errors are system-related and not attributable to individual negligence or misconduct (Schwappach & Wernli, 2010; Sheridan-Leos, 2007;
Weingart et al., 2010).
a) Stress
b) Understaffing
c) Lack of experience in administering chemotherapy
d) Unclear or ambiguous chemotherapy orders
e) Lack of experience in administering the specific chemotherapy drug
with which the error occurred
f) Fatigue
g) Illegible handwriting
h) Inaccessibility of information about chemotherapy drugs
i) Chemotherapy drug packaging or vial difficult to read or understand
j) Increasing number of complicated schedules and new drug combinations
5. Strategies for preventing medication errors (ASHP, 2011; Jacobson et
al., 2012)
a) Verify all pertinent clinical patient information, including patients
measured height and weight, laboratory results, and BSA.
b) Ensure that up-to-date drug information and other resources are readily available to clinicians.
c) Support institutional policy that prohibits verbal orders for chemotherapy.
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d) Use preprinted, standardized forms or computerized physician order entry to order cytotoxic drugs when possible.
e) Avoid the use of abbreviations, acronyms, coined names, and other
ambiguous methods of communicating drug information.
f) Provide ongoing education to patients about their medications, and
encourage them to ask questions and seek clarification before their
drugs are administered.
g) Ensure adherence to institutional policies and procedures.
h) Verify all chemotherapy doses, scheduling, and dosing calculations
(see Chapter 7). Support institutional policy for a systematic method of dose verification.
i) Review orders in an environment with minimal distractions.
j) Limit chemotherapy administration to RNs who are qualified by education and training.
k) Use standardized processes to verify and document the accuracy and
appropriateness of all chemotherapy doses.
6. Inadvertent IT administration: The inadvertent administration of vincristine and other drugs into the subarachnoid space (IT administration) has resulted in a number of tragic deaths around the world (Gilbar & Seger, 2012). Publications from the Joint Commission (2005),
WHO (2007), and the Institute for Safe Medication Practices (2006)
prompted institutions to reevaluate their preparation and delivery of
vinca alkaloids and of IT medications in general. A multidisciplinary
review of the process of drug preparation and administration is advised
in each practice setting.
a) The ASCO/ONS Chemotherapy Administration Safety Standards
(Jacobson et al., 2012) call for organizational policies related to
IT medications. These drugs should not be prepared with any other agents. Once prepared, they should be marked with a uniquely
identifiable medication label and stored in a separate container or
location from other drugs. All IT medications are to be delivered
to the patient only with other medications intended for administration into the CNS.
b) Special procedures should be followed for the administration of IT
medications. See Figure 11 for recommendations.
c) Both the Joint Commission and WHO recommended that vincristine
and other vinca alkaloids be diluted and administered IV via a minibag. Opponents to this approach have cited the risk of extravasation,
as many institutions have policies against the infusion of vesicant chemotherapy into a peripheral vein. Gilbar and Carrington (2006) reported that vinca alkaloids can be safely administered as low-volume,
short-term infusions with minibags. (See recommendations for administration of short-term IV infusions in Chapter 6.)
d) Bortezomib is another drug that is fatal when administered by the IT
route. Bortezomib is administered either by rapid IV push or by subcutaneous (SC) injection. The stability of bortezomib when diluted
in a minibag has not been established (Gilbar & Seger, 2012). Therefore, other processes to prevent the inadvertent IT administration of
bortezomib should be used.
E. Safe handling and disposal of hazardous drugs (HDs): Many drugs used in
the treatment of cancer are hazardous to healthcare workers. The term hazardous describes drugs that require special handling because occupational
exposure may cause adverse health effects. These effects occur because of
the inherent toxicities of the drugs (ASHP, 2006; NIOSH, 2004). According to the Occupational Safety and Health Administration (OSHA, 1999),
a safe level of occupational exposure to HDs is unknown, and no reliable
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Figure 11. Recommendations to Prevent Errors With Intrathecal Chemotherapy Administration

Administer vincristine and other vinca alkaloids IV via a minibag (i.e., IV piggyback). The stability of bortezomib when diluted in a
minibag has not been established.
Vinca alkaloids and bortezomib should include a clear warning label: FOR INTRAVENOUS USE ONLYFATAL IF GIVEN BY OTHER ROUTES.
Vinca alkaloids and bortezomib should never be given in the same treatment room as intrathecal medications. For patients receiving
antineoplastic medications by multiple routes, it is highly recommended that they either receive them in different practice areas or on
different days.
Only healthcare providers who have received specialized educational programs should prescribe, prepare, transport, or administer
intrathecal chemotherapy.
Different connectors should be used, whenever possible, for medicines to be administered via the intrathecal and other parenteral
routes.
Institutions should establish a list of drugs that can and cannot be given intrathecally.
Orders for intrathecal chemotherapy should be written on a separate form than IV chemotherapy. Consider using an intrathecal chemotherapy order form.
Intrathecal chemotherapy should be prepared and delivered as close as possible to the time of administration.
Intrathecal chemotherapy should be packaged, transported, and stored in specifically designated containers separately from IV or
other drugs. Intrathecal drugs should be clearly labeled both on the syringe and outer container For Intrathecal Use.
Intrathecal chemotherapy should not be stored in patient care areas.
Conduct a time-out immediately preceding intrathecal chemotherapy administration, including a formal two-person checking procedure by a chemotherapy-competent nurse and at least one other chemotherapy-trained healthcare professional. Document verification of the right drug, dose, route, patient, and time.
Note. Based on information from Gilbar & Seger, 2012; Institute for Safe Medication Practices, 2006, 2012; Joint Commission, 2005; World Health Organization, 2007.
From Preventing Intrathecal Chemotherapy Errors: One Institutions Experience, by L.H. Smith, 2009, Clinical Journal of Oncology Nursing, 13, p. 345.
doi:10.1188/09.CJON.344-346. Copyright 2009 by the Oncology Nursing Society. Adapted with permission.
method of monitoring work-related exposure exists. Therefore, it is imperative that those who work with HDs adhere to practices designed to minimize occupational exposure.
1. Definition: ASHP (1990) provided the first definition of HDs [a)e)];
NIOSH (2004, 2010, 2012) subsequently refined the definition [f)]. Drugs
are considered hazardous if they demonstrate one or more of the following characteristics in humans or animals.
a) Carcinogenicity
b) Teratogenicity or developmental toxicity
c) Reproductive toxicity
d) Organ toxicity at low doses
e) Genotoxicity
f) New drugs similar in structure or toxicity to drugs classified as hazardous using the above criteria
2. Potential adverse health effects associated with occupational exposure:
Published evidence indicating the increased occurrence of cancer among
occupationally exposed nurses and other healthcare workers (Blair et
al., 2001; Gunnarsdottir, Aspelund, Karlsson, & Rafnsson, 1997; Hansen
& Olsen, 1994; Levin, Holly, & Seward, 1993; Martin, 2005) is limited
because of the failure to connect exposure to health outcomes. IARC
publishes independent assessments of the carcinogenic risks of chemicals and has identified 11 drugs and two combination chemotherapy
regimens used in cancer treatment as known human carcinogens. Other antineoplastic agents are classified as probable or possible carcinogens (see Table 12) (IARC, 2013).
a) Structural defects in a fetus because of occupational exposure during pregnancy (Hemminki, Kyyronen, & Lindbohm, 1985; Peelen,
Roeleveld, Heederik, Kromhout, & de Kort, 1999)
b) Adverse reproductive outcomes, including miscarriage (Lawson et al.,
2012), infertility (Fransman, Roeleveld, et al., 2007; Martin, 2005),
preterm births, and learning disabilities in offspring of nurses exposed to HDs during pregnancy (Martin, 2005)
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Table 12. Antineoplastic Agents Classified as Carcinogens

Exposure Risk
Agents
Arsenic trioxide
Azathioprine
Busulfan
Chlorambucil
Cyclophosphamide
ECB (etoposide, cisplatin, and bleomycin)
Etoposide
Melphalan
MOPP (mechlorethamine hydrochloride, vincristine,
procarbazine, and prednisone)
Semustine
Tamoxifen
Thiotepa
Treosulfan
Group 2A: Probably carcinogenic

to humans
Azacitidine
Carmustine
Cisplatin
Doxorubicin
Lomustine
Mechlorethamine hydrochloride
Procarbazine
Teniposide
Group 2B: Possibly carcinogenic to

humans
Amsacrine
Bleomycin
Dacarbazine
Daunorubicin
Mitomycin
Mitoxantrone
Streptozocin
Group 1: Carcinogenic to humans
Note. Based on information from International Agency for Research on Cancer, 2013.
c) Chromosomal damage in healthcare workers following exposure to

HDs (Bouraoui et al., 2011; El-Ebiary, Abuelfadl, & Sarhan, 2013; McDiarmid, Oliver, Roth, Rogers, & Escalante, 2010; Yoshida, Kosaka,
Tomika, & Kumagai, 2006)
d) Acute symptoms such as hair loss, abdominal pain, fatigue, nausea,
nasal irritation or sores, contact dermatitis, allergic reactions, skin injury, and eye injury (Baykal, Seren, & Sokmen, 2009; Constantinidis
et al., 2011)
3. Potential adverse health outcomes associated with occupational exposure to biotherapy agents: Limited data are available regarding the effects of occupational exposure to biologic agents. It is unclear whether the criteria in the definition of HDs are adequate for protein-based
drugs (Halsen & Krmer, 2011).
a) Most biologic agents do not affect DNA and do not cause genetic
changes.
b) Antiangiogenic agents pose a risk to a fetus (e.g., thalidomide, lenalidomide) (Celgene Corp., 2012).
c) Several targeted agents meet one or more of the criteria in the NIOSH
definition of HDs and should be handled as hazardous (e.g., handled
with personal protective equipment [PPE] and not crushed). These
include dasatinib, imatinib mesylate, nilotinib, pazopanib hydrochloride, sorafenib, sunitinib malate, and vorinostat (NIOSH, 2012).
d) mAbs: Based on mechanism of action, some mAbs may cause developmental toxicity, including alemtuzumab, bevacizumab, cetuximab,
panitumumab, rituximab, and trastuzumab (Halsen & Krmer, 2011);

however, NIOSH does not classify these agents as HDs.
e) Conjugated mAbs are hazardous because of the attached radioactive
isotopes (e.g., tositumomab) or toxins (e.g., brentuximab vedotin).
f) Many drugs used for non-oncology indications meet one or more of
the criteria for HDs and should be handled as HDs. These include
immunosuppressant agents, antivirals, several anticonvulsants, estrogens, progestins, and androgens.
g) A list of HDs is found in NIOSHs List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2012, with periodic updates on the
NIOSH website at www.cdc.gov/niosh/topics/hazdrug.
4. Routes of exposure
a) Absorption through skin or mucous membranes following direct
drug contact or contact with surfaces or objects that are contaminated with HDs
(1) Many studies reported measurable levels of cytotoxic agents in
the urine of healthcare workers (Connor et al., 2010; Fransman,
Peelen, et al., 2007; Sottani, Porro, Comelli, Imbriani, & Minoia, 2010; Sugiura, Asano, Kinoshita, Tanimura, & Nabeshima,
2011; Yoshida et al., 2011), most likely from dermal absorption.
(2) Multiple studies have documented contamination of the environment with HDs in drug preparation areas, drug administration areas, and patient care areas (Konate et al., 2011; Kopp,
Schierl, & Nowak, 2013; Matsumoto et al., 2010; Siderov, Kirsa,
& McLauchlan, 2010; Sottani et al., 2010; Sottani, Porro, Imbriani, & Minoia, 2012; Sugiura et al., 2011; Touzin, Bussieres,
Langlois, & Lefebvre, 2009).
(3) Several researchers have reported drug contamination on the
outside of drug vials when delivered by the manufacturers (Connor et al., 2005; Favier, Gilles, Ardiet, & Latour, 2003; Fischer,
Groebmair, Herwig, Pfaller, & Schierl, 2010; Touzin, Bussires,
Langlois, Lefebvre, & Gallant, 2008; Zock, Soefje, & Rickabaugh, 2011). Cyclophosphamide, 5-FU, ifosfamide, and platinum have all been detected on vial exteriors using various sampling techniques. These findings indicate that nurses are at risk
for skin exposure if they do not wear PPE while handling unopened drug vials.
b) Injection from needlesticks or contaminated sharps (ASHP, 2006;
NIOSH, 2004)
c) Inhalation of drug aerosols, dust, or droplets (Harrison & Schultz,
2000; Kiffmeyer et al., 2002; Mason et al., 2005)
d) Ingestion of contaminated food, beverages, tobacco products, or other hand-to-mouth behavior (NIOSH, 2004)
5. Hierarchy of hazard controls aimed at reducing worker exposure (Connor, 2006)
a) Eliminate the hazard: The best way to protect workers from a hazardous exposure is to eliminate the hazard or substitute a less toxic substance for the hazardous material, but this is not feasible with
drug therapy.
b) Engineering controls: These are machines or equipment used to isolate or contain the hazard to reduce worker exposure.
c) Administrative controls: This third level of protection includes safe
handling policies, procedures, work practices, and education and
training of those responsible for HD handling.
d) PPE: The final level of protection, consisting of protective equipment
and garments designed for worker protection from HDs, places the
primary responsibility for protection on the worker.
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6. Guidelines regarding PPE

a) Apparel
(1) Gloves: Wear two pairs of disposable gloves that are powder free
and have been tested for use with HDs. The FDA requires permeation testing for gloves to be labeled as appropriate for use
with chemotherapy. The ASTM International (2013) standard
involves permeation testing with chemotherapy drugs from several chemical classes. Gloves must prevent HD permeation for
a minimum of 30 minutes. Results are printed on the glove box
or are available from the manufacturer. Several types of materials, such as latex, neoprene, nitrile, and polyurethane, are used
to make chemotherapy gloves. Tested latex gloves provide protection but should be used with caution because of the potential for latex sensitivity. Inspect gloves for physical defects before use. Remove and discard gloves immediately after use, if
a tear, puncture, or drug contact occurs, or after 30 minutes
of wear (ASHP, 2006; NIOSH, 2004; Wallemacq et al., 2006).
Wearing double gloves and removing them carefully reduces
the opportunity for exposure (NIOSH, 2008). Remove outer
gloves first, turning them inside out to prevent the contaminated outer surfaces from touching the inner gloves. Remove the
inner gloves last after discarding all contaminated items and
PPE. Do not reuse gloves.
(2) Gowns: Wear a disposable, lint-free gown made of a low-permeability fabric, such as polyethylene-coated materials (Connor,
2006). The gown should have a solid front, long sleeves, tight
cuffs, and back closure. The inner glove cuff is worn under the
gown cuff; the outer glove cuff extends over the gown cuff to
fully protect the skin. Discard the gown if it is knowingly contaminated, before leaving HD-handling areas, and when finished with HD handling. Gowns are meant for single use. Used
gowns should not be hung up or reapplied after removal. This
prevents transfer of drug contamination to the environment
and the workers clothing (NIOSH, 2008).
(3) Respirators: Wear a NIOSH-approved respirator (such as a nonpowered, air-purifying, particulate-filter respirator) when inhalation exposure is possible. Two examples are when administering an aerosolized HD or cleaning an HD spill. Consult the
safety data sheet (SDS) for the respirator appropriate to the situation (NIOSH, 2005). Surgical masks do not provide respiratory protection from HD aerosols.
(4) Eye and face protection: Wear a face shield or a combination
of mask and face shield that provides splash protection whenever HD splashing is possible.
b) Situations requiring PPE: Wear PPE whenever HDs might be released
into the environment, such as in the following situations (NIOSH,
2004).
(1) Handling any HD vials, ampules, or packaging materials
(2) Introducing or withdrawing needles or dispensing pins from
HD vials
(3) Transferring drugs from HD vials to other containers using needles or dispensing pins and syringes
(4) Opening ampules of HDs
(5) Expelling air from an HD-filled syringe
(6) Administering HDs by any route
(7) Spiking IV bags containing HDs and changing IV tubing
(8) Priming IV tubing with HDs
(9) Handling HD leakage from tubing, syringe, and connection sites

(10) Discontinuing infusions of HDs
(11) Disposing of HDs and items contaminated by HDs
(12) Handling the body fluids of a patient who had received HDs
in the past 48 hours
(13) Cleaning HD spills
(14) Touching any surface that is potentially contaminated with HD
residue
7. Storage and labeling
a) In clinical areas
(1) Store chemotherapy drug containers in a designated location
that limits exposure of healthcare workers and provides appropriate storage conditions (e.g., temperature and light).
(2) Use a distinct label on all HD containers to indicate the hazardous nature of the contents (OSHA, 1999).
(3) Have access to instructions (e.g., SDS) regarding what to do in
the event of accidental HD exposure.
(4) Check HD containers before taking them from the storage area
to ensure that the packaging is intact and to detect any leakage or breakage.
b) In the home (Polovich, 2011) (see Appendix 1)
(1) Keep HDs out of reach of children and pets.
(2) Store HDs in containers that provide protection from puncture or breakage.
(3) Label HD containers to indicate the hazardous nature of their
contents.
(4) Provide instructions listing the procedure for handling a damaged HD container.
(5) Store HDs in an area free of moisture and temperature extremes.
(6) Provide HD spill kits and instructions for their use.
(7) Give verbal and written instructions about handling and storing HDs and HD waste.
8. During compounding: Maintain sterile technique during the preparation
of parenteral drugs. USP (2008) issued standards for sterile products,
including HDs. The environment in which sterile HD preparation takes
place must meet all standards for ventilation, including air exchanges
per hour, particle counts, and negative pressure. For a full explanation
of the standards, refer to the USP document.
a) Chemotherapy drugs
(1) Prepare sterile cytotoxic drugs in a primary engineering control
(PEC) that protects parenteral doses from microbial contamination and the environment from HD contamination (ASHP,
2006; NIOSH, 2004; USP, 2008). The two main types of PECs
are biologic safety cabinets (BSCs) and compounding aseptic
containment isolators (CACIs). A BSC has an open front, inward airflow that creates an air barrier to prevent HD contamination from escaping, and downward high-efficiency particulate air (HEPA)-filtered airflow to minimize bacterial contamination of sterile preparations. A CACI is an enclosed cabinet
that does not allow air exchange with the environment except
through a HEPA filter, with attached sleeves and gloves through
which the operator performs drug manipulations. A PEC must
(a) Be located in an area that is physically separate from other preparation areas and be at negative pressure to an adjacent ante area (USP, 2008)
(b) Eliminate exhaust through a HEPA filter and ideally be vented to the outside (ASHP, 2006; NIOSH, 2004; USP, 2008)
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(c) Be used by individuals trained to employ techniques that

reduce contamination
(d) Be decontaminated at the end of drug preparation or immediately if a spill occurs
(e) Be serviced according to the manufacturers recommendations
(f) Be recertified after relocation, repair, filter replacement,
and/or every six months (National Sanitation Foundation,
2007; OSHA, 1999).
(g) The exhaust fan of a BSC should operate continuously except when the BSC is being repaired or moved. After the fan
has been off, the BSC should be decontaminated before use.
(2) When preparing unsterile HDs, such as oral drugs that require
compounding or crushing, an isolator intended for containment may be used (NIOSH, 2004). Decontaminate the PEC
following use.
(3) Wash hands before donning PPE.
(4) Wear chemotherapy-designated PPE.
(5) If desired, place a sterile, plastic-backed absorbent pad on the
work surface.
(6) Limit items placed in the PEC to avoid interfering with airflow
(ASHP, 2006).
(7) Use safe technique when opening ampules (ASHP, 2006).
(a) Clear fluid from the ampule neck.
(b) Tilt the ampule away from yourself.
(c) Wrap gauze or an alcohol pad around the neck of the ampule.
(d) Break the ampule in the direction away from yourself.
(e) Use a filtered needle to withdraw fluid.
(8) When reconstituting drugs from vials, avoid pressure buildup,
which can result in the release of drug aerosols. Use a closedsystem transfer device (CSTD) if available (NIOSH, 2004). According to NIOSH (2004), a CSTD is a drug transfer device
that mechanically prohibits the transfer of environmental contaminants into the system and the escape of hazardous drug or
vapor concentrations outside the system (p. 44). CSTDs are
supplemental engineering controls and do not eliminate the
need for a PEC or PPE (NIOSH, 2004).
(9) Use tubing and syringes with Luer-lock fittings.
(10) Avoid overfilling syringes. An overfilled syringe may separate
from the plunger end (OSHA, 1999).
(11) Spike IV bags and prime tubing with compatible fluid before
adding cytotoxic drugs (ASHP, 2006; OSHA, 1999) or use a
CSTD to minimize leakage and exposure (Harrison, Peters, &
Bing, 2006; Sessink, Connor, Jorgenson, & Tyler, 2011; Siderov
et al., 2010; Yoshida et al., 2009). Glass IV bottles are discouraged for HDs because of the need for venting and the potential
for breakage, both of which can result in exposure.
(12) Place a label on each HD container that says Cytotoxic Drug
or a similar distinct warning.
(13) Wipe the outside of the HD container (e.g., syringe or IV bag)
with moist gauze before placing it in a sealable bag for transport. Avoid transferring HD contaminants to the outside of the
transport bag.
(14) Dispose of all material that has come into contact with an HD
in a waste container designated for cytotoxic waste.
(15) Remove and discard outer gloves and gown. Then remove inner gloves.
(16) Wash hands with soap and water before touching anything or
leaving the work area.
b) Biotherapy drugs
(1) Use safe handling precautions (e.g., PEC and PPE) for biotherapy agents that are considered hazardous (NIOSH, 2004).
(2) A nuclear pharmacist prepares radiolabeled mAbs for infusion.
Note: Federal and state laws require that radiation safety warning signs designate the areas in which radioisotopes are stored
or used (Iwamoto, Haas, & Gosselin, 2012).
9. Transporting HDs (OSHA, 1999)
a) Transport syringes containing HDs in a sealed container with the Luer-lock end of the syringe capped. Do not transport syringes with attached needles.
b) Select a transport receptacle that can contain HD spillage if dropped
(e.g., a leakproof, zipper-lock bag), and add impervious packing material as necessary to avoid damage during transport.
c) Label the outermost HD receptacle with a distinct label to indicate
that its contents are hazardous.
d) Ensure that whoever transports HDs has access to a spill kit and is
trained in HD spill cleanup.
10. Safe handling precautions during administration (ASHP, 2006; OSHA,
1999; Polovich, 2011)
a) Always wear chemotherapy-designated PPE.
b) Work below eye level.
c) Ensure that a spill kit and chemotherapy waste container are available.
d) Use a CSTD or place a disposable, absorbent, plastic-backed pad on
the work area to absorb droplets of the drug that may spill.
e) Use a CSTD or place a gauze pad under the syringe at injection ports
to catch droplets during administration.
f) Use a CSTD or needles, syringes, and tubing with Luer-lock connectors.
g) If priming occurs at the administration site, prime IV tubing with
a fluid that does not contain the HD or by using the backflow
method.
h) After drug administration, remove the IV container with the tubing
attached (NIOSH, 2004; Polovich, 2011). Do not remove the spike
from IV containers or reuse tubing.
i) Use detergent and water or cleansing wipes to clean surfaces that
come into contact with HDs (Polovich, 2011).
j) Discard all HD-contaminated material and PPE in a designated chemotherapy waste container.
11. Special precautions for RIT: Special precautions are necessary to protect healthcare workers from exposure while caring for patients receiving
RIT. Radiation protection standards and regulations are determined by
the U.S. Nuclear Regulatory Commission (NRC), the FDA (radiopharmaceuticals), and state radiation regulatory agencies.
a) Occupational radiation exposure should be kept as low as reasonably
achievable. This requires close collaboration between the healthcare
team and the radiation safety officer (RSO). Three factors help provide protection (Iwamoto et al., 2012).
(1) Time: Limit the amount of time spent near the radioactive source.
Radiation exposure is directly proportional to the amount of
time spent near the source. After a patient receives RIT, the patient is considered the radioactive source.
(2) Distance: Maximize the amount of space between personnel and
the radioactive source. Radiation exposure decreases as the distance from the radioactive source increases.
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(3) Shielding: Add a protective barrier between the radioactive

source and personnel. The type of shielding used depends on
the type of radiation.
b) Radiation monitoring devices are used to measure occupational exposure.
(1) Monitoring of personnel: Personnel monitoring is required by
law whether a patient is treated as an inpatient or outpatient.
A film badge is the most widely used monitoring device. Each
person caring for a patient receiving radiation therapy should
be assigned a film badge that is only worn within the work environment, is changed according to institutional guidelines, and
is not shared with anyone else (Iwamoto et al., 2012). A dosimeter is another kind of radiation monitoring device. It can be a
personal device or one that is shared after being reset.
(2) Monitoring of the environment: Environmental monitoring is
done with a survey meter that reacts to the presence of ionizing particles. After a course of inpatient RIT is completed and
before the room is cleaned, the RSO surveys the room, linens,
and trash.
12. Handling a patients body fluids
a) After chemotherapy
(1) Wear double chemotherapy-tested gloves and a disposable
gown when handling the blood, emesis, or excreta of a patient
for at least 48 hours after the patient has received chemotherapy. Wear a face shield if splashing is possible (NIOSH, 2004).
(2) For an incontinent patient, clean the patients skin well with
each diaper change. Apply a protective barrier ointment to the
skin of the patients diaper area to decrease the chance of skin
irritation from contact with drug metabolites (Polovich, 2011).
(3) Flush the toilet with the lid down after disposing of excreta from
a patient who has received HDs within the past 48 hours. When
a lid is not present, consider covering the open toilet with a plastic-backed pad to prevent splashing while flushing. Although
there is no research to support the effectiveness of double flushing in reducing contamination, it has been suggested in the past
(Brown et al., 2001; Welch & Silveira, 1997) and may be helpful
with low-volume-per-flush toilets (Polovich, 2011).
b) After RIT (Iwamoto et al., 2012)
(1) Institute standard precautions as previously described when
handling the patients body fluids (e.g., sweat, saliva, urine, feces, blood, semen, vaginal fluid). The duration of precautions
varies depending on the radionuclides half-life.
(2) Consult the RSO or nuclear pharmacist for precautions based
on the specific radioisotope.
13. Handling a patients linens
a) After chemotherapy (Polovich, 2011)
(1) To the extent possible, preclude the need for laundering linens and clothing by using disposable linens or leakproof pads
to contain HD-contaminated body fluids.
(2) If body fluids are present, use standard precautions when handling the linens of a patient who had received chemotherapy
within 48 hours.
(3) Handle HD-contaminated bed linens and clothing as follows.
(a) In the hospital setting
i. Handle linens with PPE and place into a leakproof bag.
ii. In most institutions, all linens are handled as contaminated by laundry personnel before washing.
(b) In the home setting (Polovich, 2011) (see Appendix 1)

i. Wearing gloves, place contaminated linens into a washable pillowcase, separate from other items.
ii. Machine wash linens and cloth diapers twice in hot
water, with regular detergent, separately from other
household items.
iii. Discard disposable diapers in plastic bags to prevent
leakage.
iv. Discard used gloves in a chemotherapy waste container if available.
b) After RIT (Iwamoto et al., 2012)
(1) If body fluids are present, use standard precautions when handling the linens of a patient who has received RIT.
(2) Keep linens in the hospital room until surveyed and cleared by
the RSO or nuclear pharmacist.
14. Disposal of HDs and materials contaminated with HDs
a) In the hospital setting (NIOSH, 2004)
(1) Place soft contaminated materials into a sealable, leakproof bag
or a rigid chemotherapy waste container marked with a brightly
colored label that indicates the hazardous nature of the contents.
(2) Use puncture-proof containers for sharp or breakable items.
Dispose of needles and syringes intact; do not break or recap
needles or crush syringes.
(3) Seal containers when full.
(4) Do not dispose of drug-contaminated items in infectious waste
(red) containers. Some facilities autoclave or microwave these
materials (NIOSH, 2004; Smith, 2002), which does not deactivate HDs.
(5) Follow institutional policy regarding disposal of partial doses
of HDs when administration is interrupted.
(6) Only housekeeping personnel who have received instruction in
safe handling procedures should handle chemotherapy waste
containers. These personnel should wear gowns with cuffs and
a back closure and two pairs of disposable chemical-protective
gloves.
b) In the home setting (Polovich, 2011) (see Appendix 1)
(1) Some agencies that provide HDs arrange for proper disposal
of contaminated equipment.
(2) Follow all the instructions applicable to the hospital setting
except those related to handling the filled waste container (if
provided).
(3) Designate an area away from children and pets where filled containers are placed for pickup.
(4) Follow county and state regulations regarding the disposal of
chemotherapy wastes.
15. Procedures following acute HD exposure: Accidents, improper technique, faulty equipment, or negligence in PEC operation can lead to
exposure (OSHA, 1999).
a) Initial interventions
(1) In the event of skin exposure: Remove any contaminated garments and immediately wash contaminated skin with soap and
water. Refer to the SDS for agent-specific interventions.
(2) In case of eye exposure: Immediately flush the eye with saline
solution or water for at least 15 minutes (OSHA, 1999), then
seek emergency treatment. Ideally, each area where HDs are
handled should contain an eyewash station. An acceptable alternative is a sterile saline IV container connected to IV tubing.
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112
(3) In the event of inhalation exposure, move away from the area
of exposure as quickly as possible. Depending on the severity of
symptoms, seek emergency treatment from an employee health
professional or emergency department. Refer to the SDS for
agent-specific interventions.
(4) For accidental ingestion, do not induce vomiting unless indicated in the SDS. Depending on the severity of symptoms, seek
emergency treatment from an employee health professional or
emergency department. Refer to the SDS for agent-specific interventions.
b) Reporting (Polovich, 2011)
(1) In case of employee exposure: Report HD exposure to the employee health department or as institutional policy requires.
(2) In case of patient exposure: Report the exposure as institutional policy requires. In addition, inform the patients healthcare
providers.
16. Spill management
a) Radioactive spills: In case of a spill of radiolabeled antibody or contamination with the radioactive body fluid of a patient recently treated with RIT (Iwamoto et al., 2012)
(1) Restrict access to the area and contact the RSO immediately. Never try to clean the area or touch the radioactive source.
Adhere to the principles of time, distance, and shielding (discussed previously in paragraph 11).
(2) Follow other applicable NRC guidelines.
b) HD spills: Consider any leak of HDs that is greater than a few drops a
spill. Spill kits must be available wherever HDs are stored, transported, prepared, or administered (see Figure 12). Train everyone who
works with HDs in spill cleanup. Individuals trained in handling hazardous materials (such as a Hazardous Materials Response Team)
should clean up large spills whenever possible (OSHA, 2004b). In
case of a spill involving an HD, follow these procedures.
(1) Assess the spill to determine the need for additional help with
cleanup.
(2) Immediately post signs warning others of the hazardous spill to
prevent them from exposure.
(3) Don two pairs of chemotherapy-designated gloves, a disposable
gown, and a face shield.
(4) Wear a NIOSH-approved respirator (OSHA, 2004c).
(5) Use appropriate items in the spill kit to contain the spill, such
as absorbent pads, cloths, or spill control pillows.
Figure 12. Contents of an Antineoplastic Spill Kit
Two pairs of disposable chemical-protective gloves (optional: a pair of utility gloves)

Low-permeability, disposable protective garments (coveralls or gown and shoe covers)
Face shield
Respirator
Absorbent, plastic-backed sheets or spill pads
Disposable towels (34)
At least two sealable thick plastic hazardous waste disposal bags with an appropriate warning label
A disposable scoop for collecting glass fragments and sharps
A puncture-resistant container for glass fragments
Note. Based on information from American Society of Health-System Pharmacists, 2006.
(6) Clean up the spill according to its location and type. Access the
SDS for the spilled agent to determine if any inactivators are
recommended (Gonzalez & Massoomi, 2010).
(a) To clean up a spill on a hard surface (ASHP, 2006)
i. Wipe up liquids using absorbent pads or spill control pillows. Wipe up solids using wet absorbent pads.
ii. Pick up glass fragments using a small scoop or utility gloves worn over chemotherapy gloves. Do not use
hands to pick up sharps. Place all sharps in a puncture-proof container.
iii. Place puncture-proof container and contaminated materials into a leakproof waste bag. Seal the bag. Place
the sealed bag inside another bag, appropriately labeled as chemotherapy waste. For the moment, leave
the outer bag open.
iv. Clean the spill area thoroughly, from least contaminated to most contaminated areas, using detergent and
sodium hypochlorite solution (bleach) if appropriate, based on the surface. If using bleach, allow contact with the surface for at least 30 seconds and follow with a neutralizer (e.g., 1% sodium thiosulfate).
Rinse twice with clean water.
v. Use fresh detergent solution to wash any reusable
items used to clean up the spill and items located in
the spill area. Use water to rinse the washed items. Repeat the washing and rinsing.
vi. Remove PPE and place disposable items in the unsealed chemotherapy waste disposal bag.
vii. Seal the outer disposal bag and place it in a punctureproof chemotherapy waste container.
viii. Follow institutional or manufacturers guidelines regarding cleaning or maintenance of equipment (e.g.,
an IV pump).
ix. Dispose of all material used in the cleanup process according to institutional policy and federal, state, and
local laws (OSHA, 1999).
(b) To clean up a spill on a carpeted surface (note that carpet is
not recommended in HD administration areas) (ASHP, 2006)
i. Don PPE, including a NIOSH-approved respirator.
ii. Use absorbent powder, not absorbent towels, to absorb the spill.
iii. Use a small vacuum with a HEPA filter (Gonzalez &
Massoomi, 2010), reserved for HD cleanup only, to
remove the powder. Dispose of the collection bag as
chemotherapy waste. Clean the outside of the vacuum before storing.
iv. Clean the carpet as usual.
v. Follow guidelines for a spill on a hard surface to clean
and dispose of other contaminated items.
(c) To clean up a spill in a BSC or CACI (ASHP, 2006; OSHA,
1999)
i. Clean the spill according to the guidelines for a spill
on a hard surface. Complete cleanup by rinsing the
surface with sterile saline for irrigation.
ii. Include the drain spillage trough in washing efforts.
iii. If the spill contaminated the HEPA filter: Seal the
open front of a BSC in plastic. Label any type of PEC
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Chemotherapy Spill Cleanup

Video
To view videos download
ChemoBio4thInteractive.pdf
114
as contaminated equipment. Schedule a PEC service

technician to change the HEPA filter. Ensure that the
PEC is not used before the filter is changed.
(d) To clean up a spill in the home setting: See Figure 13.
(7) Report and document the spill according to institutional policy: For any spill greater than a few drops, complete a report
about the spill and forward it to those specified by institutional policy (ASHP, 2006). Document the following.
(a) Name of the drug
(b) Approximate volume of spill
(c) How the spill occurred
(d) Spill management procedures followed
(e) The names of personnel, patients, and others exposed to
the spill
(f) A list of personnel notified of the spill
17. Requirements for policies regarding the handling of HDs: OSHA (2004a)
requires that employers provide a safe or healthful workplace. Employers must implement policies and procedures related to the safe handling
of HDs. Policies should address all aspects of handling these hazardous
chemicals to protect employees, patients, customers, and the environment from contamination. Such policies must (NIOSH, 2004)
a) Outline procedures to ensure the safe storage, transport, administration, and disposal of hazardous agents
b) Describe the procedure for identifying and updating the list of HDs
used in the facility
c) Require that all employees who handle HDs wear PPE
d) Mandate that HDs be prepared in a BSC, CACI, or containment isolator (USP, 2008)
Figure 13. Spill Kit Procedure for Home Use

(Please review this procedure with your nurse.)
1. Do not touch the spill with unprotected hands.
2. Open the spill kit and put on both pairs of gloves. If the bag or syringe with chemotherapy drugs has been broken or is leaking and
you have a catheter or implanted port in place, before cleaning the spill, disconnect the catheter from the tubing and flush and cap
it.
3. Put on the gown (closes in back), face shield, and respirator.
4. Use spill pillows to contain spillput around puddle to form a V.
5. Use the absorbent sheets to blot up as much of the drug as possible.
6. Put contaminated clean-up materials directly into the plastic bag contained in the kit. Do not lay them on unprotected surfaces.
7. Use the scoop and brush to collect any broken glass, sweeping toward the Vd spill pillows, and dispose of the glass in the box of
the kit.
8. While still wearing the protective gear, wash the area with dishwashing or laundry detergent and warm water, using disposable rags
or paper towels, and put them in the plastic bag with other waste. Rinse the area with clean water and dispose of the towels in the
same plastic bag.
9. Remove gloves, face shield, respirator, and gown and place them in the plastic bag. Put all contaminated materials, including the
spill kit box, into the second large plastic bag, and seal and label the bag with the hazardous waste label in the kit.
10. Wash your hands with soap and water.
11. Call the home health nurse, clinic, or doctors office promptly to report the spill. Plans need to be made to replace the spilled chemotherapy so that treatment can be completed. Arrangements will be made to have the waste material picked up or have you bring it to
the hospital for proper disposal.
12. If the spill occurs on sheets or clothing, wash the items in hot water, separate from other laundry. Wash clothing or bed linen contaminated with body wastes in the same manner.
13. Patients on 24-hour infusions should use a plastic-backed mattress pad to protect the mattress from contamination.
Following these procedures prevents undue exposure and ensures your safety. Call your nurse if you have any questions. Thank you.
Note. Based on information from National Institute for Occupational Safety and Health, 2004.
From Home Chemotherapy Safety Procedures, by C. Blecker, 1989, Oncology Nursing Forum, 16, p. 721. Copyright 1989 by the Oncology Nursing Society. Adapted with permission.
e) Prohibit staff from eating, drinking, smoking, chewing gum, using tobacco, storing food, and applying cosmetics in areas where HDs are
prepared or administered
f) Mandate training for all employees who prepare, transport, or administer HDs or care for patients receiving these drugs. This training must include the risks of exposure and appropriate procedures
for minimizing exposure. The policy should describe how training is
documented (OSHA, 2012).
g) Require that documents such as SDSs are available to healthcare workers who handle HDs
h) State that spills should be managed according to the institutions HD
spill policy and procedure
i) Set forth a plan for medical surveillance of personnel handling HDs
j) Address HD handling around pregnant workers. Even when recommended precautions are used, the potential for accidental exposure cannot be eliminated (Connor et al., 2010; Schierl, Bhlandt,
& Nowak, 2009; Siderov et al., 2010; Turci et al., 2011). Developing
fetuses and newborn infants may be more susceptible to harm from
certain HDs. Therefore, an additional level of protection is suggested for those most vulnerable to the reproductive and developmental
effects of HDs. Employers must allow employees who are actively trying to conceive or are pregnant or breast-feeding to refrain from activities that may expose them and their fetus to reproductive health
hazards such as chemical, physical, or biologic agents. Alternate duty
that does not include HD preparation or administration must be
made available upon request to both men and women in the aforementioned situations or who have other medical reasons for avoiding exposure to HDs. The employee has the responsibility of notifying the employer of the specific situation (e.g., pregnancy, preconception, breast-feeding). The American College of Occupational and
Environmental Medicine (2011) provides guidelines for reproductive hazard management.
k) Define quality improvement programs that monitor compliance with
safe handling policies and procedures.
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Chapter 6
Administration
Considerations
A. Routes of administration
1. Oral: The use of oral antineoplastic agents is more common than in the past
and is likely to double in the next several years (Moody & Jackowski, 2010).
a) Advantages
(1) Convenience of home treatment
(2) Decreased time spent in outpatient or inpatient oncology departments
(3) Increased sense of control and independence for the patient
b) Disadvantages
(1) Can be expensive and may result in reimbursement- and insurance-related issues
(2) Patient difficulty in adhering to treatment regimen due to
(a) Difficulty swallowing medication
(b) Complex dosing and schedules
(3) Inconsistent absorption of agents
c) Potential complications
(1) Food-drug interactions (e.g., grapefruit juice can interfere with
a liver isoenzyme needed to metabolize medications) (Goodin, 2007)
(2) Drug-drug interactions resulting in excess toxicity or decreased
efficacy
(3) Incorrect dosing
(4) Patients continuing medications beyond the planned duration of treatment or despite side effects that necessitate holding treatment
d) Nursing implications (Moody & Jackowski, 2010)
(1) Verify the accurate dosing of oral anticancer therapy using the
same process as for IV chemotherapy.
(2) Wear PPE when administering hazardous oral agents.
(3) Do not crush hazardous oral agents outside of a BSC or other containment device. If a patient has difficulty swallowing or
has a feeding tube, ask the pharmacist to provide the drug in a
ready-to-administer form.
(4) Set up a schedule to monitor patients response to therapy, including follow-up laboratory testing and office visits.
e) Patient education for self-administration of oral therapy
(1) Provide verbal and written information about the drug(s), dose,
schedule, storage, and safe handling.
(2) Explain the scheduled days and times the medication should
be taken and dates of office visits and laboratory tests. A calendar is a useful tool for some patients.
(3) Emphasize side effects that should be reported immediately to
healthcare providers and any that require holding treatment.
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(4) Establish a process to evaluate patient adherence to therapy, including correct dose and schedule. For example,
(a) Make a scheduled phone call with the patient three to five
days after initiation of medication to assess compliance.
(b) Instruct the patient and family members to bring the medication schedule, calendar, and any other tool developed
to all follow-up appointments.
2. Subcutaneous: SC injection allows agents to be administered into the
SC tissue by piercing the epidermal and dermal layers of skin (Joanna
Briggs Institute, 2012).
a) Advantages
(1) Ease of administration
(2) Well tolerated
(3) Decreased side effects for some agents
b) Disadvantages
(1) Inconsistent absorption
(2) Patients with decreased adipose tissue have increased risk of
drug misplacement.
c) Potential complications
(1) Pain at injection site
(2) Infection
(3) Bleeding/bruising
d) Nursing implications
(1) Wear PPE.
(2) Most common site for SC injection is the abdomen; however,
avoid the umbilicus and scars.
(3) Monitor platelet count.
(4) Use the smallest needle possible. Some medications are in prepackaged syringes; follow manufacturers instructions.
(5) Rotate injection sites if multiple injections are needed.
3. Intramuscular (IM): IM injections are used to administer medication
deep into the muscle. The ventrogluteal muscle (anterior gluteal site)
is considered the thickest gluteal muscle, and use of this site has fewer
complications (Joanna Briggs Institute, 2012).
a) Advantage: Rapid absorption of medication
b) Disadvantages and potential complications
(1) Pain
(2) Infection
(3) Peripheral nerve damage/neuropathy
(4) Hematoma
(5) Tissue necrosis
(6) Permanent damage to sciatic nerve
c) Nursing implications (Joanna Briggs Institute, 2012)
(1) Wear PPE.
(2) Use the proper size needle to ensure that medication is delivered
into the muscle and not SC tissue, especially with obese patients.
(3) Choose appropriate site.
(4) Insert at 90 angle and pull back on syringe to ensure injection
is not near a blood vessel.
(5) Avoid massaging the site.
4. Intraperitoneal (IP): IP chemotherapy can be used to treat ovarian cancer, as well as other cancers that cause peritoneal seeding such as lowgrade gastrointestinal (GI) and appendiceal carcinomas (Marin, Oleszewski, & Muehlbauer, 2007). Combining IP chemotherapy with IV therapy may offer a survival benefit over IV therapy alone in select patients
with ovarian cancer (Potter & Held-Warmkessel, 2008). IP chemotherapy may be administered using a catheter or implanted IP port.
a) Advantages (Potter & Held-Warmkessel, 2008)

(1) Chemotherapy agents are delivered directly into the peritoneal cavity, providing higher concentrations of drug to the tumor.
(2) Systemic absorption by diffusion causes prolonged exposure
to the tumor via capillary flow. Lower doses can potentially be
used, decreasing the systemic side effects and allowing for cyclic treatment over time.
(3) IP access devices can be used to remove excess fluid from the
peritoneal cavity, and family members can be taught how to do
this if needed (Camp-Sorrell, 2011).
b) Disadvantages (Potter & Held-Warmkessel, 2008)
(1) Only select patients with minimal disease are candidates for
IP therapy.
(2) Patients require a surgical procedure to place the peritoneal
catheter or IP port.
(3) Potential exists for catheter-related infection or complications
such as bowel obstruction, abdominal pain, or peritonitis.
(4) Frequent postural changes are required following infusion,
which may be difficult for patients with comorbid conditions
such as arthritis, musculoskeletal disorders, or previous surgeries.
c) Potential side effects (Almadrones, 2007; Camp-Sorrell, 2011)
(1) Abdominal pressure and distention related to large amounts of
fluids placed into the peritoneal space
(2) Increased bladder irritation due to abdominal fullness, which
results in increased urinary frequency
(3) Severe nausea and vomiting
(4) Decreased appetite related to the large fluid volume
(5) Dyspnea secondary to abdominal distention
(6) Bleeding
(7) Diarrhea
(8) Ileus
(9) Infection
(10) Intestinal perforation
(11) Anaphylaxis
(1) Utilize PPE.
(2) Place the patient in semi-Fowler position (Camp-Sorrell, 2011;
Hydzik, 2007).
(3) Access the peritoneal port with a 19-gauge noncoring rightangle needle. Depending on the patients size, use a needle
length of 11.5 inches (Hydzik, 2007).
(4) Flush the port according to institutional policy and procedure.
(5) Evidence is lacking to support the warming of IP fluid; therefore,
IP solution can be administered at room temperature (CampSorrell, 2011; Hydzik, 2007). However, if the patient reports being cold, provide warm blankets (Hydzik, 2007).
(6) Rotate the patient side to side every 15 minutes for one hour
after infusion (Hydzik, 2007).
(7) Drain fluid from the peritoneal cavity following dwell time, if
ordered.
5. Intrathecal: IT chemotherapy is used for patients with central nervous
system malignancies, including primary brain tumors, metastasis to the
brain or leptomeninges from solid tumors, lymphoma, and leukemia
(Aiello-Laws & Rutledge, 2008).
a) IT route delivers chemotherapy directly into the cerebrospinal fluid.
b) Cerebrospinal fluid can be accessed by a surgically implanted ventricular reservoir (e.g., Ommaya) or by lumbar puncture.
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c) The most commonly used IT agents are methotrexate and cytarabine

(Aiello-Laws & Rutledge, 2008). Note: Vinca alkaloids, such as vincristine, are lethal if administered via the IT route and should never be
given IT because of severe neurologic toxicity, including coma and
death (Schulmeister, 2006). The majority of chemotherapy agents do
not have IT indications.
d) Advantages
(1) Direct and consistent drug levels in the cerebrospinal fluid
(2) Ability to access the cerebrospinal fluid for testing as well as to
administer opiates and other medications
e) Disadvantages
(1) Requires surgical procedure to place intraventricular device
(2) Lumbar puncture is an invasive procedure.
(3) Requires a physician or specialty-trained RN to administer chemotherapy.
f) Potential side effects
(1) Increased intracranial pressure
(2) Headaches
(3) Confusion
(4) Lethargy
(5) Nausea and vomiting
(6) Seizures
(7) Infection
g) Nursing implications
(1) Utilize PPE.
(2) Ensure that only preservative-free solutions are used for IT chemotherapy (Camp-Sorrell, 2011).
(3) IT chemotherapy must be labeled For Intrathecal Use Only.
Wraps or packages should be removed immediately prior to administration by the person administering the medication (AielloLaws & Rutledge, 2008).
(4) Perform a time-out or other procedure designed to verify that
IT is the intended route for the medication.
(5) Monitor the patient for the potential complications listed previously.
6. Intrapleural: Intrapleural chemotherapy is used to treat malignant pleural effusions, which can be caused by mesothelioma, other solid tumors,
and hematologic disorders that metastasize to the pleura (Polovich, 2011;
Shuey & Payne, 2005). Other treatments include repeated thoracentesis, pleurodesis with sclerosing agent, insertion of pleural catheter, surgical procedures, radiation, and systemic chemotherapy (Shuey & Payne,
2005; Walker & Bryden, 2010).
a) Advantages
(1) May prevent recurrence of malignant pleural effusions
(2) Multiple agents can be used as sclerosing agents, such as chemotherapy agents, antibiotics, talc, and biotherapy agents (Shuey
& Payne, 2005).
b) Disadvantages
(1) Requires insertion of a thoracotomy tube
(2) Must be performed by a physician
c) Potential side effects
(1) Pain
(2) Infection
(3) Pneumothorax
(1) Utilize PPE.
(2) Maintain aseptic technique.
(3) Position the patient in a sitting position, leaning forward over

a sturdy locked tray table with a pillow as a headrest (Shuey &
Payne, 2005).
(4) The effusion fluid must be completely drained from the pleural cavity before instillation of the agent.
(5) Allow the agent to remain for the prescribed dwell time if applicable. If fluid is drained, handle as contaminated fluid (Polovich, 2011).
(6) Observe for signs and symptoms of respiratory distress.
7. Intravesicular: Intravesicular chemotherapy is used to treat urinary bladder cancer (Washburn, 2007). The standard treatment for nonmuscle invasive bladder cancer is transurethral resection followed by intravesical
chemotherapy using bacillus Calmette-Gurin, thiotepa, mitomycin C,
or gemcitabine (Shelley et al., 2012). The urinary bladder is a perfect organ for regional therapy (Shen, Shen, Wientjes, ODonnell, & Au, 2008).
a) Advantages
(1) Delivery of chemotherapy agents directly into the bladder to
eliminate residual disease and prevent recurrence
(2) Avoids side effects of systemic chemotherapy
b) Disadvantage: Requires bladder catheter insertion
c) Potential side effects
(1) Urinary tract infection
(2) Cystitis
(3) Bladder contracture
(4) Urinary urgency
(5) Extravasation with vesicant administration
(1) Utilize PPE including face shield (Washburn, 2007).
(2) Maintain sterile technique during catheter insertion.
(3) Monitor for signs of extravasation, especially pain (Washburn,
2007). If the patient has uncontrolled pain following use of a
vesicant agent, suspect extravasation. Drain the agent and urine,
and notify physician immediately.
(4) Follow physician orders or protocol for schedule and positioning of the patient and drainage of agent after instillation.
8. Intra-arterial: Intra-arterial infusion allows chemotherapy to be delivered
in higher concentrations directly into a tumor site (Matthews, Snell, &
Coats, 2006). According to Camp-Sorrell (2011), several agents can be
delivered via the intra-arterial route: cisplatin, doxorubicin, 5-FU, floxuridine, irinotecan, mitomycin, oxaliplatin, paclitaxel, protein-bound
paclitaxel, tumor necrosis factor, and vinblastine.
a) Common sites (Camp-Sorrell, 2011)
(1) Liver
(2) Head and neck
(3) Bone
b) The three types of arterial access devices are short-term catheters, implanted arterial ports, and implanted arterial pumps (Camp-Sorrell,
2011).
(1) Short-term catheters: A nontunneled percutaneous arterial
catheter is placed during an angiographic procedure. This is
usually done in an interventional radiology department under
local anesthesia (Barber & Fabugais-Nazario, 2003). The most
common sites for insertion are the femoral and brachial artery
(Camp-Sorrell, 2011).
(2) Implanted arterial ports: These are similar to venous ports, with
the catheter surgically implanted into an artery. They are accessed
when needed, using a noncoring needle (Camp-Sorrell, 2011).
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126
(3) Implanted arterial pumps: These are intended for long-term

use. The infusion rate of the pumps can be programmable or
set by the manufacturer (Camp-Sorrell, 2011).
c) Advantages (Camp-Sorrell, 2011)
(1) Higher exposure of the tumor site to the chemotherapy agent,
potentially resulting in greater tumor response and decreased
systemic side effects
(2) Avoidance of extensive surgical procedures and potential complications related to surgery (e.g., liver resection)
(3) Patients with liver metastasis may be surgical candidates after
treatment with intra-arterial chemotherapy.
d) Disadvantages
(1) Requires an invasive procedure performed by physician
(2) Requires specialized nursing care and education
(3) Not all patients are candidates for intra-arterial chemotherapy.
e) Potential side effects (Camp-Sorrell, 2011)
(1) Infection
(2) Catheter migration or dislodgment
(3) Occlusion and thrombosis
(4) Bleeding at catheter insertion site
(5) Device failure
f) Nursing implications
(1) Obtain specialized training to assess and monitor arterial catheters.
(2) Immediately following intra-arterial catheter insertion, assess
the involved limb for peripheral pulses, color, temperature,
numbness and tingling, and bleeding (Camp-Sorrell, 2011).
(3) Utilize PPE.
(4) Monitor for occlusions.
(5) Review and understand the different types of devices.
(6) Review and understand the flushing and dressing change protocols per institutional policy.
(7) Avoid using arterial access devices for routine blood sampling
9. IV: Most chemotherapy is currently administered by the IV route. IV drugs
are delivered by IV push, short-term infusion, or continuous infusion.
a) Advantages
(1) Consistent absorption
(2) Direct route into bloodstream
b) Disadvantages
(1) Increased patient and healthcare provider time, often in a
healthcare setting
(2) Damage to the peripheral veins may necessitate central venous
access.
c) Potential complications (Joanna Briggs Institute, 2012)
(1) Infiltration
(2) Pain
(3) Phlebitis/cellulitis
(4) Infection
(5) Thrombosis
d) Nursing implicationsPeripheral venous access
(1) Avoid the ventral surface of the wrist when starting peripheral
IVs because of increased pain and potential damage to the radial nerve. Use the nondominant arm whenever possible (Infusion Nurses Society, 2011).
(2) Avoid areas of flexion.
(3) Avoid using lower extremities.
(4) Choose veins that are large, smooth, and pliable.

(5) Avoid using the arm of patients who have had axillary lymph
node dissection.
(6) Avoid using an established IV site that is more than 24 hours
old whenever possible. CDC recommendations (OGrady et al.,
2011) allow use of peripheral IVs for up to 96 hours, but that
recommendation is based on risk of catheter-related infection;
use of irritants or vesicants may shorten the useful life of a peripheral IV access device. Thoroughly assess any established IV
site prior to use.
(7) Perform hand hygiene, wear gloves, prepare site with antiseptic, allow skin to dry, and avoid touching the insertion site after applying antiseptic (OGrady et al., 2011).
(8) Use the smallest catheter possible to deliver the planned therapy. IV peripheral catheters range in gauges from 1428 and
lengths from 5/8 to 2 inches (Camp-Sorrell, 2011).
(9) Use a catheter equipped with a safety mechanism to avoid sharps
injury (Infusion Nurses Society, 2011).
(10) Perform venipuncture according to institutional policy and procedure. If unsuccessful, restart IV using a different site on the opposite arm, if possible, or proximal to the previous puncture site.
(11) The chemotherapy agents may be connected directly to the IV
catheter or to a line of compatible maintenance solution. Secure all connections with Luer-lock devices. Administer agents
according to institutional policy.
(12) Check for blood return prior to initiating chemotherapy. Do
not pinch the IV administration tubing to determine blood return because the vein can rupture. Aspirate with a syringe by
the lowest Y-site and clamp off fluid from the bag or use gravity
to check by lowering the IV bag below the patients IV site (Joanna Briggs Institute, 2012).
(13) Observe for swelling, burning, tightness, cool skin, skin color
change, and flow rate (Joanna Briggs Institute, 2012). If infiltration occurs, immediately stop infusion and restart IV using
a different site on the opposite arm, if possible, or proximal to
the previous puncture site.
10. Central venous catheters (CVCs): CVCs include percutaneous subclavian catheters, tunneled subclavian catheters, peripherally inserted central catheters, and implanted ports. Assess for catheter function and
patency prior to use by aspirating for a blood return. Catheter occlusion may occur as a result of extraluminal fibrin deposit or intraluminal thrombosis. Drug precipitate may cause a blockage when the catheter is not flushed adequately between agents (Cummings-Winfield &
Mushani-Kanji, 2008).
a) Implanted ports: Access with a noncoring needle following skin
preparation according to institutional policy. Select the appropriate needle length (0.52 inches) based on the depth of the port
(Camp-Sorrell, 2011). Stabilize the needle as needed, and cover the
insertion site with a transparent semipermeable membrane dressing (Infusion Nurses Society, 2011). Inspect the insertion site for
evidence of needle dislodgment, leakage of IV fluid, drainage, or
edema during infusions.
b) For all CVCs: Verify catheter placement and function either by x-ray
or fluoroscopic dye study prior to initial use per institutional guidelines. Check for blood return by aspiration. DO NOT administer cytotoxic agents in the absence of blood return. The following may help
to establish blood return (Camp-Sorrell, 2011).
127
Chemotherapy Administration
Through an Implanted Port
Video
128
(1) Attempt to flush with normal saline, and gently pull back. Reposition the patient. Ask the patient to cough and take a deep
breath.
(2) Obtain physician order for declotting procedure, and follow
institutional protocol.
(3) Use x-ray or dye study to confirm proper placement of CVC and
to rule out catheter malfunction or migration in the absence of
blood return, according to institutional policy.
11. Special considerations for vesicant administration
a) When administering a vesicant through a peripheral IV site
(1) Avoid using an IV pump or syringe pump to minimize pressure
on the vein (Infusion Nurses Society, 2011).
(2) Remain with the patient during the entire infusion (Sauerland,
Engelking, Wickham, & Corbi, 2006).
(3) Limit administration to IV push or short infusion lasting no longer than 3060 minutes (Sauerland et al., 2006).
(4) Verify blood return every 25 ml for IV push and every 510
minutes during a short infusion (Sauerland et al., 2006).
(5) Closely monitor for signs and symptoms of extravasation, such
as swelling, loss of blood return, and patients report of pain
or burning sensation. Confirming extravasation of vesicants
during chemotherapy administration can be difficult because
manifestations can vary from no immediate signs to pain, swelling, and loss of blood return, as well as differentiating extravasation from flare and recall reactions (Wickham, Engelking,
Sauerland, & Corbi, 2006).
(6) Discontinue vesicant administration at the first sign of extravasation.
b) When administering a vesicant through a central vascular access
device (VAD)
(1) Administer via IV push, short infusion, or continuous infusion,
as ordered.
(2) Verify blood return prior to, during, and after drug administration.
(3) Monitor the IV site throughout the infusion according to institutional policy.
(4) Discontinue vesicant administration at the first sign of extravasation.
c) Piggyback or short-term infusion
(1) Verify blood return and IV patency prior to hanging the infusion.
(2) Attach the secondary tubing to the injection port closest to the
patient using a needleless, Luer-lock connector (Infusion Nurses Society, 2011).
(3) Initiate flow rate according to the physician order, and observe
the patient for any reactions.
(4) Once the short infusion is complete, check vein patency and
flush the line with a compatible solution.
d) Continuous infusions: Used when a constant plasma concentration over
an extended period of time is desired (Joanna Briggs Institute, 2012)
(1) Central VADs are preferred.
(2) Connect directly to the IV access device or by secondary IV set
to a compatible line of maintenance solution, according to institutional policy.
(3) Secure connections with Luer-locking devices.
(4) Monitor the IV site throughout the infusion according to policy.
(5) When patients are discharged with a portable pump for home
infusion, ensure they are instructed on how to manage problems with the pump and infusion and on how and when the
infusion will be discontinued (e.g., in the home or infusion

center).
(6) Flush line at the completion of the infusion.
e) IV push: Refer to physician order or institutional guidelines for suggested IV push rates, diluents, and other drug-specific details.
(1) Free-flow method (side-arm technique) (Infusion Nurses Society, 2011)
(a) Attach the syringe with the drug at the injection port closest to the patient.
(b) Aspirate for blood to verify IV patency.
(c) Allow compatible IV solution to flow freely.
(d) Slowly administer the chemotherapy agent, allowing the
flush solution to dilute the drug. Unless otherwise indicated, administer the agent at a rate of 12 ml/min.
(e) If multiple agents are administered, flush with a compatible fluid between each agent and at the completion of the
infusion.
(2) Direct IV push method: Cytotoxic agents are administered IV
push directly into the IV device. Refer to institutional policy
and procedure.
(a) Establish venous access. Obtain a new access site when administering a vesicant via a peripheral vein (Infusion Nurses Society, 2011).
(b) Flush the line with sterile IV solution in a syringe, and verify blood return.
(c) Detach the flush syringe, and attach the syringe containing the chemotherapy agent.
(d) Slowly administer the agent, aspirating for blood return
every 25 ml.
(e) Upon completion, disconnect the syringe carefully, minimizing blood loss; the blood will contain the cytotoxic agent.
(f) Connect a syringe with sterile flush solution, and gently
flush the catheter.
(g) Cap or disconnect the IV access device, as indicated.
B. Adherence to therapy
1. With the increasing numbers of oral therapies available, adherence to
the prescribed medication regimen is a concern (Weingart et al., 2008).
2. Barriers to adherence (Barefoot, Blecher, & Emery, 2009; Jarvis, 2012;
Moody & Jackowski, 2010)
a) The individuals culturally based health beliefs. Disease causation
may be viewed from a biomedical, naturalistic, or magico-religious
perspective.
b) Cost of the medication, copayment
c) Where to obtain the drug (e.g., local versus specialty pharmacy)
d) Complexity of regimen
e) Health literacy
f) Patients physical condition (e.g., ability to swallow medications)
g) Side effects
h) Poor understanding of the importance of adherence or poor patientprovider relationship
i) Lack of acceptance of illness because of current state of feeling well
(asymptomatic)
j) Inadequate follow-up/missed appointments
3. Optimizing adherence (Anderson & Klemm, 2008; Barefoot et al., 2009;
Jacobson et al., 2012; Winkeljohn, 2010)
a) Provide patient education.
129
130
b) Employ behavior modification for patient and family as necessary.

Engage the patient and family members in the treatment process.
c) Use reminder systems.
(1) Pill boxes
(2) Calendars
(3) Diaries
(4) Follow-up telephone calls
d) Discuss medications at each intervention.
e) Perform pill counts.
f) Include caregivers in all discussions.
C. Pretreatment nursing assessment: Assess and document the following information.
1. Patient history: Identify cancer diagnosis, past and present surgical procedures, radiation therapy, and hormonal agents.
a) Use of complementary and alternative medicine (CAM): Questioning in a nonthreatening manner may encourage patients to disclose the use of these therapies. CAM includes the following (National Center for Complementary and Alternative Medicine, 2013).
(1) Natural products such as vitamins and supplements
(2) Manipulative body-based practices such as chiropractic care
(3) Mind and body medicine such as meditation, yoga, and acupuncture
b) Allergies: Identify food, drug, and environmental allergies, including latex (Infusion Nurses Society, 2011). Document all allergies in
the medical record.
c) Past medical history: Identify underlying health issues, such as hypertension, diabetes, and cardiac and pulmonary disorders. Include any
psychiatric illness. Identify alcohol and substance abuse.
d) Medication review: Obtain an up-to-date list of medications. Include
all prescription, recreational, and over-the-counter medications and
herbal and vitamin supplements. This information is essential to address possible drug-drug and drug-herb interactions (Shelley, Sussman, Williams, Segal, & Crabtree, 2009).
e) Symptom review: Assess symptoms related to the cancer diagnosis,
treatment regimen, comorbidities, and psychological issues (Jakobsson, Ekman, & Ahlberg, 2008).
(1) Poorly controlled symptoms affect QOL (Roiland & Heidrich,
2011) and adherence to the treatment protocol. Use standardized forms or checklists to ensure thorough symptom assessment (Brem & Kumar, 2011; Williams, Williams, LaFaver-Roling, Johnson, & Williams, 2011).
(2) Review nutritional status. Diet affects treatment tolerance (Ralph,
Von Ah, Scheett, Hoverson, & Anderson, 2011). Make the appropriate recommendations and referrals.
f) Distress: Establish the need for interdisciplinary referrals such as social workers, counselors, or religious or spiritual providers.
(1) Assess family structure and dynamics, living conditions, and
caregivers.
(2) Determine practical concerns such as transportation, financial,
or insurance issues.
(3) Assess cultural issues that may influence the treatment plan.
(4) Identify religious beliefs or spiritual concerns that may affect
dietary and other requirements and restrictions.
(5) Screening tools
(a) Assess performance status by using an appropriate scale
(see Table 3).
2.
3.
4.
5.
(b) Assess and document pain using an age-appropriate pain

scale (e.g., FACES Pain Rating Scale, 010 numeric pain
rating scale, McGill Pain Questionnaire [National Initiative on Pain Control, n.d.]).
(c) Assess fatigue using the Brief Fatigue Inventory (Mendoza
et al., 1999), the Piper Fatigue Scale (Piper et al., 1998),
or the Schwartz Cancer Fatigue Scale (Schwartz, 1998).
Patient data
a) Measure and document height and weight. Compare to previous
weight, and address significant changes.
b) Obtain, review, and document current laboratory values that are pertinent to the specific antineoplastic agents (e.g., assessment of kidney
function prior to cisplatin) (Jacobson et al., 2012).
c) Review and document diagnostic tests that are pertinent to the specific antineoplastic agent (e.g., cardiac ejection fraction prior to doxorubicin).
d) Review diagnosis, tumor type, grade, and stage of current disease.
Cancer treatment during pregnancy: The most common malignancies
diagnosed during pregnancy are breast, cervical, thyroid, leukemia, lymphoma, and ovarian (Brewer, Kueck, & Runowicz, 2011).
a) Collaborate with a maternal-fetal medicine team prior to initiation
of treatment.
b) Assist the patient in evaluating the risks and benefits to mother and
unborn child (Rimes, Gano, Hahn, Ramirez, & Milbourne, 2006).
c) Establish accurate gestational age. Cytotoxic chemotherapy is harmful to the fetus during the first trimester. Chemotherapy is not recommended after 35 weeks to avoid delivery during a period of bone
marrow suppression and the lack of drug excretion from immature
fetal organs (Giacalone, Laffargue, & Bnos, 1999; Visco, Meyer, Xi,
& Brown, 2009).
d) Inform the patient that breast-feeding is contraindicated during chemotherapy.
Practices that promote safety during antineoplastic therapy: Using standardized orders, computerized physician order entry, and electronic medication administration records can reduce medication errors.
a) Advantages of electronic systems (Levy et al., 2011; Rogers, 2009)
(1) Provide improved legibility
(2) Provide alerts for missing orders, incorrect doses, and wrong
route, time, and schedule
(3) Promote continuity of care between inpatient and outpatient
departments
(4) Increase communication among healthcare providers
(5) Provide easy access to pertinent patient data related to chemotherapy administration (e.g., laboratory and diagnostic tests)
b) Directly involving the patient and family members in the administration of chemotherapy can serve as a safety mechanism. Future research may identify the best methods for patients and families to be
involved in safe chemotherapy administration (Schwappach, Hochreutener, & Wernli, 2010).
Treatment plan (Jacobson et al., 2012)
a) Review the prescribed treatment plan/protocol. Verify that orders are
written and signed by a qualified licensed independent practitioner.
b) Identify patients participating in a clinical trial, and confirm presence
of a signed IC form. Notify clinical trials nurse for additional information if needed (if applicable).
c) Confirm that IC was obtained for the chemotherapy treatment. Follow institutional policy related to the IC process.
131
132
Pretreatment Preparation for

Chemotherapy Administration
Video
d) Read and scrutinize the entire chemotherapy order to ensure it is

complete. Complete chemotherapy orders include the following elements (Neuss et al., 2013).
(1) Two patient identifiers
(2) Date(s) of administration (schedule, treatment interval)
(3) Diagnosis
(4) Regimen name
(5) Planned duration of treatment
(6) Current cycle number
(7) Criteria to administer the chemotherapy/biotherapy (e.g., laboratory values, toxicity)
(8) Allergies
(9) Method of dose calculation
(10) Height, weight, and other variables used to calculate doses
(11) Name of chemotherapy and biotherapy agents using generic
names rather than brand names
(12) Drug dose
(13) Route and rate of administration
(14) Length of infusion (if applicable)
(15) Supportive care (e.g., premedications, hydration, growth factors)
(16) Sequence of administration, if applicable
e) Confirm the patients current, measured height and weight.
f) Have two individuals recalculate the BSA (or other method of dose
calculation) and dose, and compare with the prescribed dose. Follow
institutional policy regarding which personnel are considered qualified to participate in the double-check process (e.g., two chemotherapy-competent RNs, RN and pharmacist).
g) Determine if the chemotherapy agents have irritant or vesicant potential.
6. Treatment: Patient preparation
a) Inform the patient and family who will be administering the chemotherapy.
b) Verbally review the treatment plan with the patient and/or family
members.
c) Provide a detailed explanation to the patient, family, and/or caregivers of the prescribed chemotherapy agent or protocol, the route of
administration, and short- and long-term side effects and respond to
any questions or concerns.
d) Confirm the patients full name and second identifier, such as date
of birth or medical record number.
e) Notify the prescribing healthcare provider of any symptoms that may
require a change in the treatment plan.
f) Obtain baseline vital signs.
7. Treatment: Staff preparation
a) Assemble the appropriate PPE.
b) Obtain the necessary equipment based on route of administration
(e.g., infusion pump).
c) Ensure that a spill kit and emergency medications and equipment
are available.
d) Ensure that delivered products match the ordered drugs and are labeled appropriately with the following information (Neuss et al., 2013).
(1) Patients full name and second identifier (e.g., date of birth,
medical record number)
(2) Date of administration
(3) Full generic name of the agent
(4) Route of administration
(5) Total dose
(6) Total volume required to administer dose

(7) Date and time the drug was prepared and the expiration date
if not for immediate use. Some agents are unstable and must
be administered within a specific period of time.
8. Chemotherapy administration (Neuss et al., 2013)
a) Confirm the treatment plan with the patient prior to each treatment.
b) Wear PPE.
c) Double-check the drug(s), and document the verification process by
two designated approved healthcare providers.
(1) Confirm two patient identifiers.
(2) Confirm drug name, dose, volume, rate, route, and cycle number.
(3) Obtain two signatures.
(4) Confirm rate setting on infusion pump (when used).
d) Obtain consent from patient to begin treatment as per institutional
policy (Klimaszewski, 2008).
e) Initiate chemotherapy via the appropriate route.
f) Monitor patient during administration for immediate complications.
g) Document the drug administration and the patients response.
h) Provide education and written discharge instructions.
i) Confirm the follow-up plan with patient and/or family member.
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Chapter 7
Pretreatment Care
A. Patient education
1. Definitions
a) Patient education, as defined by the journal Patient Education and
Counseling, is a planned learning experience using a combination
of methods such as teaching, counseling, and behavior modification
techniques, which influence patients knowledge and health and illness behavior. Patient counseling is an individualized process involving guidance and collaborative problem-solving to help the patient
to better manage the health problem. Patient education and counseling involve an interactive process [that] assists patients to participate actively in their health care (Elsevier, n.d., Definitions para.).
b) Bastable, Gramet, Jacobs, and Sopczyk (2011) defined patient education as the process of helping patients learn healthcare behaviors to
incorporate into their lives with the ultimate goal of optimal health
and independence in self-care activities (pp. 1213).
c) Falvo (2011) stated that by definition, one cannot be a teacher unless there is a learner. Therefore, merely giving information to patients does not mean that learning has occurred. To be effective, information must be presented in a way that makes it relevant (p. 38).
2. Factors that affect patient teaching (Bastable et al., 2011; Blecher, 2004;
Rigdon, 2010)
a) The educators expertise regarding the information provided
b) The learners health literacy
c) The educators understanding of differences in individuals learning styles
d) The strategies available to the educator for patient education
e) The educator matching appropriate strategies to specific content
and learners
f) The educators ability to involve the individual in the learning process
3. Short-term outcomes of patient education (Blecher, 2004; Jacobson et
al., 2012)
a) Empowering active participation in health care
b) Explanation of diagnosis and treatment options
c) Verbalization of an understanding of the goals and duration of therapy
d) Identification of both short- and long-term signs and symptoms that
need to be reported
e) Demonstration of the ability to perform self-care and/or adapt to
potential limitations
f) Promotion of adaptive coping skills in a life-threatening condition
g) Autonomous decision making regarding treatment or no treatment
h) Identification and appropriate use of community resources
4. Long-term outcomes of patient education (Joint Commission, 2012a, 2012b)
a) Improved self-care behaviors
b) Improved health-related QOL
c) Decreased healthcare costs
d) Increased customer satisfaction
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e) Better-informed patients, thus lessening the chance of malpractice

claims
5. Methods of patient education (e.g., auditory, visual, return demonstration) should be selected based on patients preferences and abilities.
6. Barriers to patient education
a) Barriers to learning should be assessed on an individual basis. The
following are some common barriers to comprehension (Joint Commission, 2012a, 2012b; Mann, 2011).
(1) Lack of knowledge of diagnosis and treatment plan
(2) Differences in the expectations regarding the purpose of treatment
between the patient/significant other and the healthcare team
(3) Concerns or misconceptions about therapy due to prior experience or the experience of a friend or relative, which may dissuade the patient from undergoing treatment
(4) Language barriers
(5) Educational barriers
(6) Health literacy barriers
(7) Physical barriers: Pain; visual, hearing, and cognitive impairments; and inability to speak can interfere with patients comprehension.
(8) Psychosocial or emotional issues may create barriers to learning.
b) Methods of overcoming barriers
(1) Allow patients to express concerns, and attempt to manage
their anxiety.
(2) Manage physical barriers, such as pain, and ensure that learners have glasses, hearing aids, etc., as needed.
(3) Provide access to translators, either in person or through telecommunications. Note: Significant others are not recommended as translators because of role conflicts or inability to communicate complex medical terminology.
(4) Correct any misconceptions concerning diagnosis, treatment,
and follow-up care.
(5) Tailor teaching to the patients level of understanding.
(6) Assess patients individually, and present information at an appropriate level.
(7) Cancer-related Spanish-language educational literature is available through NCI at www.cancer.gov.
(8) Cancer-related literature for patients with low literacy is available through NCI at www.cancer.gov.
7. Scope of information:
a) Provide verbal information and written material that is easy to read. Encourage patients and family members to ask questions and actively listen.
b) Education should encompass the following (Castiglia, Drummond,
& Purden, 2011; Wilson, Mood, & Nordstrom, 2010).
(1) Names of the prescribed antineoplastic agents and the rationale for the use of each agent.
(2) Potential short- and long-term side effects of therapy
(3) Medications that will be used to alleviate some of the side effects
(4) When to call the physician or nurse
(5) How to contact the multidisciplinary team, including physicians, nurses, emergency department, scheduling office, and
support services
(6) Schedule for laboratory and follow-up visits
8. Documentation: Nurses need to assess and document patients understanding of content after education takes place to meet regulatory (i.e.,
Joint Commission) standards, manage risk, and enhance staff communication (Joint Commission, 2012a, 2012b; Negley, Ness, Fee-Schroeder,
Kokal, & Voll, 2009). Documentation of understanding should include

patients ability to verbalize or demonstrate learning. It also should identify future needs for reinforcement of information. If patients cannot
comprehend the information or they refuse education, this also must
be documented, along with alternative plans. Methods to assess patient
understanding include the following.
a) Patient/significant other is able to verbalize an understanding of the
information presented, including the name(s) of the medication(s)
and the purpose of the therapy.
b) Patient/significant other can identify and verbalize key instructions
for self-care.
c) Patient/significant other can identify and verbalize symptoms/side
effects to report and whom to call.
d) Patient brings new prescriptions on a follow-up visit and correctly verbalizes the instructions for use.
e) Patient is able to perform a return demonstration on items such as
temperature monitoring and hand washing.
f) Patient/significant other is able to accurately verbalize dates and times
of the next follow-up visit.
g) For oral agents, the patient/significant other is able to verbalize the
name of the medication, correct procedure for administration (e.g.,
with or without food), and safe handling and disposal procedures.
B. Verification and maintenance of treatment as planned
1. The treatment plan
a) Maintaining the planned treatment schedule is important because
systemic cancer treatments often have a narrow margin of therapeutic benefit (Levine, 2010).
(1) Minor adjustments below therapeutic doses can result in decreased tumor response, whereas minor adjustments above therapeutic doses can result in increased toxicity without increased
benefit (Levine, 2010).
(2) To ensure optimal patient outcomes, the oncology nurse must
(a) Evaluate the appropriateness of the treatment plan for the
disease being treated. The pathology and stage of cancer
should be clear in the patient record.
i. Goals of therapy should be stated.
ii. The plan should include what cancer drugs are to be
given, at what frequency, and for what duration.
(b) Perform safety checks to ensure that the agents are given
as intended with appropriate premedications and supportive care measures (Jacobson et al., 2012).
(c) Verify that regimen-specific laboratory and other diagnostic measures are performed and evaluated as applicable
(Jacobson et al., 2012).
b) Maintaining a treatment plans dose intensity (total planned dose
over total planned period of time) is associated with improved patient survival, and higher dose intensity may improve tumor response and cure rates (Crivellari, Monfardini, Stragliotto, Marino,
& Aversa, 2007).
(1) Dose reductions and treatment delays often occur because of
toxicities such as febrile neutropenia (Weycker, Barron, Edelsberg, Kartashov, & Lyman, 2012).
(2) Appropriate use of growth factor support (e.g., filgrastim) can
reduce the occurrence of complications related to febrile neutropenia in patients on myelosuppressive chemotherapy (Quirion,
2009).
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(3) When potential toxicities are proactively addressed, dose reductions and delays may be prevented or minimized (Kawashima
et al., 2012).
c) Verification of cancer treatment orders is not as simple as knowing a
single recommended dose or maximum safe dose, as is true for many
non-oncology medications.
(1) Appropriate doses for a given chemotherapy may vary widely
depending on the indication and route.
(2) For example, depending on the condition being treated, doses of methotrexate may range from 2.5 mg orally to 8 g/m2 IV
with a requirement for leucovorin rescue and other supportive measures (Kalb, Strober, Weinstein, & Lebwohl, 2009; Warnick & Auger, 2009).
d) Institutional policies and procedures should detail the process for
regimen and dose verification for cancer treatment orders.
(1) Policies and procedures should clearly define the steps to take
when discrepancies, potentially inappropriate orders, or other
concerns arise (Jacobson et al., 2012).
(2) The oncology nurse evaluates the appropriateness of the treatment regimen considering the indication, route of administration, concomitant treatments, and other factors, including
any premedications and supportive care medications (Jacobson et al., 2012).
e) The oncology nurse works with the patient and the care team to ensure that treatments remain on schedule at planned doses.
(1) Assessment and teaching before, during, and after treatment with
appropriate follow-up regarding identified needs is important.
(2) Developing an education checklist for nurses can ensure standardized approach to patient education (Mueller & Glennon, 2007).
(3) Teaching should include information regarding symptom management strategies.
(4) Education regarding symptom management enables prompt
evaluation and treatment of potentially serious toxicities, such
as neutropenic fever (Hawley, Loney, & Wiece, 2011).
2. Concepts of dose intensity and dose-dense therapy
a) Dose intensity: Dose intensity refers to the amount of drug given over
a period of time (e.g., mg/m2/week) (NCI, n.d.). Maintaining dose
intensity ensures optimal exposure of the tumor to chemotherapy
agents. Treatment delays or dosage reductions decrease dose intensity.
b) Dose-dense therapy: A standard regimen that is given with less time between cycles is referred to as a dose-dense regimen (NCI, n.d.). Dosedense regimens increase dose intensity. The rationale for dose-dense
therapy is to minimize tumor regrowth between cycles (Bayraktar &
Arun, 2012). Myeloid growth factors reduce the severity and duration of neutropenia from myelosuppressive treatments, allowing for
reduced time between treatment cycles (Quirion, 2009).
c) Relative dose intensity (RDI) is a way of expressing the actual dose
intensity compared to the planned dose intensity. It is expressed as a
percentage derived by dividing the actual dose of chemotherapy given over a period of time by the planned dose of chemotherapy over
the planned period of time (Loibl et al., 2011).
(1) Example: The plan calls for 100 mg/m2 of an agent weekly for
four weeks.
(a) The patient receives 100 mg/m2 on weeks 1, 2, and 3, and
75 mg/m2 on week 4.
(b) The planned dose intensity was 400 mg/m2/4 weeks, or
100 mg/m2/week.
(c) The actual dose intensity was 375 mg/m2/4 weeks, or 94

mg/m2/week.
(d) Therefore, the RDI was 94% (375 divided by 400).
(2) A study of patients with metastatic breast cancer (N = 933) found
that an RDI of 85% or greater was an important factor in extending time to disease progression and increasing overall survival in patients receiving first-line anthracycline/taxane-based
therapy (Loibl et al., 2011).
(a) In the same study, dose reductions were primarily related
to toxicity. Dose delays were due to logistics and patient
desires (Loibl et al., 2011). This highlights the necessity of
patient education regarding the importance of maintaining the treatment plan.
(b) Providing supportive care measures as needed to maintain
dose intensity is extremely important to improving longterm survival.
(3) A 20-year study of patients with breast cancer (N = 386) treated with adjuvant chemotherapy found that when RDI fell below 65%, survival rates were similar to not having received chemotherapy at all (Lenhart, 2005).
3. Role of the nurse in verifying the treatment plan and schedule
a) Prior to initiating a cancer treatment regimen, the oncology nurse should
(1) Review the regimen and anticipated side effects.
(2) Verify that the ordered regimen is appropriate for the indication.
(3) If a nonstandard regimen or research protocol is used, ensure that a copy of the nonstandard regimen or research
protocol is available to verify the ordered regimen (Jacobson et al., 2012).
(4) Always verify orders against the known regimen or protocol.
Do not verify doses against a previous treatment that may have
been based on different clinical factors (e.g., renal function).
(5) Obtain clarification orders prior to initiating the cancer treatment regimen if there are aspects of the orders that are unclear
or can be interpreted in more than one way.
b) Verification includes
(1) Checking that prescribed doses are within the normal range
for the indication
(2) Ensuring appropriate time intervals between scheduled treatments
(3) Ensuring that the route, volume, and rate of infusion (as applicable) are clearly stated and appropriate
(4) Reviewing and documenting laboratory values and other factors that may require changes in treatment
(5) Ensuring that all questions regarding orders are addressed prior to preparation of chemotherapy.
c) Institutions must ensure that processes, tools, and technologies (i.e.,
calculators) are in place to enable appropriate verification of treatment regimens by the nurse (Jacobson et al., 2012).
d) The oncology nurse serves a critical role in preventing harm to patients by appropriately ensuring the verification process is completed.
(1) Errors that result in harm to patients may occur during the
ordering process. Factors independently associated with dosing errors include the use of carboplatin (requires complex
AUC [area under time-versus-concentration curve] calculations), regimens with three or more agents, and regimens
requiring modifications (e.g., for renal function) (Ranchon
et al., 2012).
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(2) Use of electronic ordering systems in which prescribers directly enter orders for chemotherapy regimens has the potential
to reduce transcription errors. However, it does not preclude
the need for two independent verifications of dose calculations.
e) Verbal and/or telephone orders for chemotherapy or modifications
to existing orders are not acceptable.
(1) An exception to this rule is an order to hold or stop chemotherapy (Jacobson et al., 2012).
(2) Faxed or electronically signed orders sent via email are acceptable as written orders (Jacobson et al., 2012). This is a safe method for addressing the home medications of a patient hospitalized during off-hours.
4. Verification of patient understanding of the treatment plan
a) See also Patient Education.
(1) Verify patient understanding of and IC for therapy prior to initiating treatment.
(a) IC must be documented in the patients record.
(b) The process for obtaining IC, including who is responsible and allowed to obtain IC, should be specified in institutional policies and procedures (Jacobson et al., 2012).
(2) Provide written information regarding plan of care in language
appropriate for the patient.
(3) Allow opportunities for questions and assessment of understanding.
(4) Ensure patient understanding of therapies to continue at home,
symptom management strategies, follow-up appointments, and
importance of compliance with the treatment plan and schedule.
b) Involving the patient in the plan of care and providing appropriate
education may reduce medication administration errors (Schwappach, Hochreutener, & Wernli, 2010).
(1) Include the patient in the verification process prior to each cycle of chemotherapy (Jacobson et al., 2012).
(2) Verify the prepared drug including the correct drug, dose, volume (as applicable), route, rate (as applicable), and appearance of medication.
(3) Verify the correct patient using two identifiers (e.g., full name
and date of birth) against both the orders and the prepared
drug at the point of administration.
5. Promoting continuity of care: Systems must be in place to ensure accurate and complete reporting of the treatment plan and history when the
patient moves from one healthcare setting to another (Jacobson et al.,
2012). A change of healthcare setting (e.g., if the patient is hospitalized
following a clinic visit) is not in itself a reason to stop or delay treatments,
as this may result in reduced RDI or suboptimal care. Incomplete or inaccurate communication during transition between care settings can lead
to treatment errors. Communication should include
a) Medication reconciliation: Communicating a list of all current medications, which can then be evaluated regarding whether to continue in the new care setting
b) A summary of prior cancer treatments and the current treatment plan
including, as applicable, the cycle number, day of treatment, etc. (Jacobson et al., 2012).
6. Verification of the chemotherapy and biotherapy orders: The nurse
must become familiar with the planned regimen and evaluate the need
for clarification or additional information before initiating treatment.
a) Treating facilities must provide the resources to meet this responsibility (Jacobson et al., 2012). This may be in the form of
(1) Printed drug and regimen references that are updated regularly
(2) Online access to current evidence-based guidelines (e.g., National Comprehensive Cancer Network [NCCN] guidelines, www.
nccn.org) and drug-specific information (e.g., FDA, www.fda
.gov)
b) Use of step-by-step checklists may be helpful in designing doublecheck systems to prevent errors (White et al., 2010).
c) Institutions should consider standardized order sets for commonly
used regimens to reduce the chance of errors during the ordering
process (Jacobson et al., 2012).
d) Order sets should use generic drug names unless there are multiple
brands of the generic drug and a specific brand formulation is desired (Jacobson et al., 2012).
e) Unapproved abbreviations should not be used in order sets (Jacobson
et al., 2012). An example of unapproved abbreviations can be found
at the Joint Commissions Facts About the Official Do Not Use List
at www.jointcommission.org/assets/1/18/Do_Not_Use_List.pdf.
f) Complexity of treatment regimens increases the risk for mistakes and
ambiguity when orders are handwritten. Use of preprinted order sets
and computer ordering systems potentially can decrease the occurrence of ambiguous or incomplete orders (Jacobson et al., 2012).
g) Mechanisms must exist for the reporting, tracking, and analysis of
errors that occur related to cancer treatments. Although individual
practitioner competencies are important, many errors occur related
to system weaknesses (e.g., tolerance of unacceptable abbreviations).
h) Efforts should focus on identifying areas of high risk and designing
systems to reduce human error (Ashley et al., 2011).
7. Standard treatment regimens, research protocols, and tailored protocols
a) Standard treatment regimens: These are treatment regimens determined to be efficacious for a given cancer and patient condition. Specific agents with specified doses, routes, rates, and sequence are identified within the regimen. All of the agents in a regimen constitute
one cycle of treatment. The timing of cycles and planned number of
cycles is included within the standard treatment plan.
b) Investigational regimens: Researchers continue to investigate new
agents and new ways of giving and combining older agents with the
goal of improving tumor response to therapy or reducing the toxicity of therapy.
(1) When a research protocol is used, communication among team
members is imperative to ensure the protocol is followed exactly as written.
(2) Failure to follow the protocol exactly can lead to difficulty in
interpreting the research findings and possibly reduce the validity of findings (Ermete, 2012).
(3) If a research protocol is used at multiple centers, the same version of the protocol must be used at all sites (Mitchell & Smith,
in press).
c) Tailored or individualized protocols: With better understanding of
the interplay of tumor molecular biology, the role of genetics, and
other factors, some regimens are individualized for patients. Patientspecific and tumor-specific data guide the use of agents that are more
likely to have a positive effect while eliminating toxic agents not likely to be of benefit. Some examples include
(1) Testing breast cancer tumors for overexpression of HER2, which
predicts benefit from treatment with anti-HER2 drugs in addition to traditional chemotherapy (Viale & Yamamoto, 2008)
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(2) Testing colon cancer tumors for KRAS mutation, which predicts
benefit from use of anti-EGFR therapy
(3) Using the patients immune system to specifically target the tumor. Sipuleucel-T is prepared by taking a patients own white
cells via apheresis, priming these cells by exposure to a molecule commonly found in prostate cancer, and then reinfusing
the cells (Smart, 2010).
8. High-dose chemotherapy: Some chemotherapy regimens call for very
high doses of chemotherapy to achieve cure or enduring response.
a) Patients receiving these regimens require more supportive care (e.g.,
transfusions, growth factor support) because of severe myelosuppression and other toxicities.
b) Oncology nurses must be familiar with the assessment and supportive care required when giving high doses of chemotherapy (Brown
& Faltus, 2011).
(1) The risk of cardiac toxicity with cyclophosphamide increases significantly when given at high doses (Viale & Yamamoto, 2008).
(2) With administration of high doses of cytarabine, routine neurologic assessments are performed to detect early signs of cerebellar toxicity (Brown, 2010).
(3) High doses of methotrexate can be fatal if leucovorin is not given to help the body to eliminate the methotrexate. This is referred to as a leucovorin rescue.
(4) High-dose chemotherapy sometimes is used with the goal of myeloablation in preparation for hematopoietic progenitor stem
cell transplantation. Administration of myeloablative chemotherapy is highly complex and can be lethal. Nurses should be
prepared with the specialized knowledge and skills required in
caring for these patients before, during, and following transplantation (Brown & Faltus, 2011).
9. Verification of dose modifications: If standard doses are modified, the
rationale should be documented (Jacobson et al., 2012). This allows the
nurse to assess the appropriateness of dosing. Some reasons for dose
modification include comorbid conditions (e.g., renal failure), toxicities
from prior treatment, and other factors such as age and polypharmacy.
a) Older age: Chemotherapy regimens are sometimes modified or reduced in older adults because of presumed inability to tolerate standard doses as renal function declines with age.
(1) Age alone should not exclude consideration of chemotherapy.
(2) Actual comorbid conditions and functional status may be better indicators than age to determine the need for dosage modifications.
(a) Standard doses and combination regimens in older adult
patients with good performance status and without significant comorbidities may be appropriate (Aggarwal & Langer,
2012). Dose reductions, while reducing potential toxicities, may increase the risk for poor response to treatment.
(b) Adjuvant chemotherapy in patients age 7079 with nonsmall cell lung cancer has been well tolerated compared
to younger populations and in associated with improved
survival (Cuffe et al., 2012).
(c) Appropriate myeloid growth factor support may improve the
ability to maintain standard-dose regimens (Quirion, 2009).
b) Children and infants: In pediatric oncology, agents sometimes are
converted from standard BSA dosing (mg/m2) to weight-based dosing (mg/kg) (Levine, 2010).
(1) This may be done using the rule of 30 (30 kg = 1 m2).
(2) The rationale is that BSA dosing may not be accurate or optimal
because of organ development in very young (younger than three
years) and small (less than 10 kg to less than 30 kg) children.
(a) High rates of ototoxicity (15%) with subsequent need for
hearing aids have occurred in infants treated with carboplatin and vincristine (N = 60) for retinoblastoma when
dosing was based on BSA. Previous studies in which mg/
kg dosing strategies were used did not result in significant
hearing loss (Leahey, 2012).
(b) BSA may be preferred at times. A study using weight-based
dosing of busulfan for allogeneic stem cell transplantation
in young children found inadequate tumor responses due
to underdosing. The childrens immune systems had recovered and rejected the transplants (Trigg, 2004).
(3) Safe administration of chemotherapy in a pediatric setting requires a specialized knowledge set. The Association of Pediatric Hematology/Oncology Nurses (APHON) provides resources for pediatric oncology nurses. APHON has developed a Pediatric Chemotherapy and Biotherapy Provider Program, which
standardizes nurses education regarding the administration of
chemotherapy and biotherapy to the pediatric population. For
more information, visit APHONs website at www.aphon.org.
c) Polypharmacy: Sometimes interactions between medications necessitate dosage adjustments or additional monitoring. This can occur
with primary treatment agents as well as supportive care medications.
(1) One example is aprepitant, a supportive care agent given
in combination with other drugs to prevent chemotherapyinduced nausea and vomiting (CINV) (Dunphy & Walker, 2010).
Because of the way aprepitant is metabolized, usage may affect
coadministered medications.
(a) Aprepitant increases the effect of corticosteroids, especially when they are administered orally. It may be advisable to
reduce corticosteroids when they are not part of the cancer treatment itself (Aapro & Walko, 2010).
(b) Aprepitant may affect warfarin sodium several days after
the last dose of aprepitant is given, and international normalized ratio (INR) should be closely monitored (Aapro
& Walko, 2010).
(c) Cisplatin, a highly emetogenic agent that typically calls for
aprepitant use, has been independently associated with elevations in INR (Yano et al., 2011).
(d) Aprepitant may increase the effect of some chemotherapy
agents (Bubalo et al., 2007).
(2) Drug interactions are common and often unavoidable. Nurses
must be cognizant of the possibility of drug interactions that
may alter the efficacy of drugs.
(a) Assess all medications for potential interactions, including
over-the-counter medications and CAM therapies (Jacobson et al., 2012).
(b) Evaluate allergies and prior hypersensitivity reactions (Jacobson et al., 2012).
(c) Consult with an oncology pharmacist if a patient is receiving multiple drugs for cancer therapy or has comorbid conditions such as diabetes or heart failure.
(d) Be aware of common antineoplastic drug-drug interactions
and have access to resources that enable safe nursing practice in medication administration (Daouphars et al., 2012).
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10. Verification of dose calculations

a) Institutional policies and procedures should specify the minimum
components required for order sets to be considered complete and
acceptable. Missing components should be addressed during the verification process and prior to drug preparation (Jacobson et al., 2012).
b) Errors in dose calculations may cause significant patient harm (Levine,
2010).
c) Two chemotherapy-competent individuals (e.g., nurses, pharmacists),
in addition to the ordering prescriber, should perform independent
double checks of dosage calculations and ensure that required components of chemotherapy orders are present (Jacobson et al., 2012).
(1) Independent calculations help to prevent bias errors. Each
person performs calculations independently, and the results
are compared.
(2) If the independent results are not consistent with the ordered
dose, the nurse needs to obtain clarification before preparing
the chemotherapy.
(3) Institutions must ensure that nurses verifying and administering cancer treatments are adequately trained in performing
calculations and other aspects of the verification process. Systems should be in place to confirm that verifications are done
and documented prior to preparation of chemotherapy (Jacobson et al., 2012).
(a) After initial competence (knowledge) and proficiency (ability to use the knowledge) of the nurse has been determined,
institutions must have processes to evaluate and document
continuing competence and proficiency at regular intervals (e.g., annually) (Jacobson et al., 2012).
(b) Development of proficiency checklists may be helpful in
this process (Crannell, 2012).
d) Weights and heights used for dose calculations must be measured
(not stated) values. Institutions may choose to state in policies and
procedures an acceptable time frame for measured values (e.g., up
to 24 hours prior to administration time).
11. How doses are calculated
a) Several methods of dosing may be used depending on the prescribed
agent. Some medications are prescribed with fixed initial doses (mg),
whereas others are dosed based on weight (mg/kg), BSA (mg/m2),
or AUC calculations that account for renal function (Levine, 2010).
b) Fixed doses: This means the prescribed dose does not require calculation based on patient size. Many oral agents are dosed in this manner.
(1) Verification entails ensuring that the ordered dose is appropriate for the condition being treated. The diagnosis and stage of
disease and prior treatments should be clearly documented in
the patient record (Jacobson et al., 2012).
(2) A standard starting dose (typical for the average patient) may
require modification based on comorbid conditions. Package
inserts often describe known conditions requiring dose modifications.
(3) The rationale for any dose modifications should be clearly stated in the patients record (Jacobson et al., 2012).
c) Weight-based dosing: Dosing is expressed as dose of drug per unit of
body weight (e.g., mg/kg). Doses are calculated using an accurately measured weight.
d) BSA-based dosing: Most cytotoxic chemotherapy drugs are dosed based
on BSA, or the estimated total area of a persons skin expressed in
square meters (m2). BSA should be calculated using a current meaCopyright 2014 by the Oncology Nursing Society. All rights reserved.
sured height and weight, not a height and weight stated by the patient (Griggs et al., 2012).
(1) Advantages: The underlying assumption is that by incorporating both height and weight, BSA is a more reliable indicator
than weight alone for predicting pharmacokinetics.
(2) Disadvantages
(a) Increased complexity of dose calculations increases the
chance for medication errors.
(b) BSA dosing does not account for factors other than height
and weight that might influence pharmacokinetics, such
as age and gender (Jger et al., 2012). For example, a man
and woman who both have a BSA of 2.0 m2 may have vastly different renal and hepatic functions.
(c) In addition to the current use of clinical factors in modifying BSA-based doses, future strategies may incorporate
genotype and phenotype markers as well as therapeutic
drug monitoring to achieve optimal doses (Gao, Klumpen,
& Gurney, 2008).
(3) Despite the issues with BSA-based dosing, it remains the most
common method for dosing many chemotherapy agents. Nurses should be aware of drug-specific recommendations for dosage adjustments that account for patient variability such as renal and liver function.
(4) Several different formulas can be used for calculating BSA, each
yielding slightly different results. For this reason, it should be
clear which formula the prescriber used when calculating drug
doses (Jacobson et al., 2012).
(a) In the United States, the most commonly used formula is the Mosteller equation (see Figure 14) (Gaguski &
Karcheski, 2011). However, no evidence has shown that
one BSA formula is more advantageous than another
(Griggs et al., 2012).
(b) An advantage of the Mosteller equation is that it can be carried out with any calculator that has a square root function.
(5) Intentional modifications made to the BSA to obtain adjusted doses should be clearly stated. If an ideal or adjusted body
weight is used instead of actual weight to calculate BSA, this
should be indicated in the order and the rationale should be
clearly documented.
(6) Evidence no longer supports routinely adjusting doses downward for obesity with most chemotherapy agents.
(a) Dose reductions may result in reduced clinical benefit,
while dosing based on actual weight does not typically increase myelotoxicity.
Figure 14. Formulas for Determining Body Surface Area

Mosteller equation (most commonly used in the United States):
height in cm weight in kg
3,600
This formula is converted to inches and pounds as
height in inches weight in pounds

3,131
Note. Based on information from Kouno et al., 2003.
147
148
(b) Obese patients have been observed to experience less profound myelosuppression compared to non-obese patients using actual weight for BSA-based dosing (Griggs et al., 2012).
(7) Institutional policies and procedures should specify acceptable
methods for calculating BSA (e.g., specifying that Mosteller
equation is to be used).
(a) Online calculators, handheld BSA calculators, or any other tools used to obtain BSA should be validated for accuracy prior to use.
(b) The tools used should be based on the same formula used
by the ordering provider.
(8) The nurse should be aware of medication-specific circumstances that affect dosing based on BSA.
(a) For example, vincristine is dosed based on BSA, but prescribers often cap the dose at a maximum of 2 mg regardless of BSA to reduce potential neurologic toxicities.
(b) This capped dose may be further reduced when coadministered with azole antifungal therapies (Harnicar, Adel, &
Jurcic, 2009).
e) Carboplatin and AUC-based dosing: AUC calculations are commonly used to determine carboplatin doses. AUC refers to the amount of
drug exposure over time or the total drug concentration in plasma
over a period of time (Gaguski & Karcheski, 2011).
(1) AUC dosing of carboplatin accounts for age, gender, weight,
and renal function. Carboplatin drug clearance is strongly correlated with renal function (Hiraike et al., 2011).
(2) The Calvert formula is typically used to determine the total dose
of carboplatin in milligrams (see Figure 15). The target AUC is
specified in the order.
(3) In practice, an estimated creatinine clearance (estCrCl) is used
with the Calvert formula rather than an actual glomerular filtration rate (GFR), which requires a 24-hour urine collection.
(4) The estCrCl is related to GFR and is used in calculating carboplatin doses.
(a) Example: The order calls for Carboplatin AUC 6.
(b) The calculated estCrCl is 50 ml/min.
(c) GFR + 25 (estCrCl + 25) = 50 + 25 = 75
(d) Target AUC 75 = 6 75 = 450 mg
(e) Carboplatin dose = 450 mg
(5) Several formulas, each yielding significantly different results,
exist for obtaining the value for estCrCl. Dosing errors can occur when a different formula is used than that intended by the
prescriber.
(6) The Cockcroft-Gault formula (see Figure 16) is the most commonly used in the United States to obtain estCrCl (Gaguski &
Karcheski, 2011).
(7) Generally, the formulas for estCrCl are reliable.
(a) Exceptions include emaciated and/or immobile patients
in whom actual GFR is typically lower than estCrCl.
Figure 15. Calvert Formula

Dose of carboplatin (mg) = (target AUC) (GFR + 25)
Total dose calculated is in mg, not mg/m2.
Note. Based on information from Calvert et al., 1989.
(b) Estimations may be inaccurate in patients with rapidly changing serum creatinine levels (Gaguski & Karcheski, 2011).
(c) For obese patients, evidence shows that use of actual GFR
may be preferred over an estimated value. If an estCrCl is
used in this population, the prescriber may choose to use
an adjusted weight or alternative formula to Cockcroft-Gault
to determine estCrCl (Nelson, Formica, Cooper, Schwartz,
& Rutherford, 2012).
(8) Importantly, changes in how laboratories determine serum
creatinine may result in underestimation of serum creatinine
when it is low.
(a) Use of these values may result in overestimated CrCl and
subsequent overdosing of carboplatin with risk of increased
toxicity without added clinical benefit (Smart, 2011).
(b) For this reason, the FDA has recommended capping estCrCl at 125 ml/min in patients with normal renal function.
See Figure 17 for examples of dose capping. Dose capping
is not required when an actual GFR is used in calculating
the carboplatin dose (Smart, 2011).
(9) Patients with high GFR (measured, not estimated) may require
dose adjustments to minimize toxicity. However, this is an area
where a standardized approach is still controversial (Roy et al.,
2011).
(10) The rationale and choice of any calculation modifications should
always be clearly documented to enable the verification process
(Jacobson et al., 2012).
12. When calculations do not agree
a) Several factors can result in verification calculations yielding results
different from the ordered doses.
(1) A change in the patients weight: Minor weight changes typically are not significant. However, patients should be weighed
Figure 16. Calculation of Glomerular Filtration Rate: Cockcroft-Gault Method
Males:
estCrCl (ml/min) = (140 age) (weight in kg)
72 serum creatinine (mg/dl)
Females:
estCrCl (ml/min) = (140 age) (weight in kg) (0.85)
72 serum creatinine (mg/dl)
estCrClestimated creatinine clearance

Note. Based on information from Cockcroft & Gault, 1976.
Figure 17. Carboplatin Dose Capping Using Estimated Creatinine Clearance

Dose of carboplatin (mg) = (target AUC) (estCrCl + 25)
estCrCl capped at 125 ml/min
Maximum doses for sample target AUCs:
Target AUC 6: Maximum carboplatin dose = 6 (125 + 25) = 900 mg
AUCarea under the concentration-versus-time curve; estCrClestimated creatinine clearance
Note. Based on information from Calvert et al., 1989; Smart, 2011.
149
150
before each treatment cycle and the doses calculated based on

the current weight.
(2) Using different formulas for verifying calculations
(3) An error in calculations during the ordering process
(4) An error in the calculations during the verification process.
The first step when noting discrepancies in doses is to recheck
the calculations.
b) Policy should indicate if rounding of doses is acceptable or expected.
c) Policies and procedures should dictate the acceptable variance between the ordered dose and the recalculated or rounded dose. For
example, a 5% variance rule is common practice (Levine, 2010). With
this, as long as the recalculated or rounded dose is within 5% of the
actual ordered dose, it is acceptable to proceed. Some facilities accept a variance up to 10% (Gaguski & Karcheski, 2011).
(1) When the ordered dose is 100 mg, a 5% variance rule allows
administration of the drug when recalculations fall between
95 mg and 105 mg. With a 10% variance rule and a 100 mg ordered dose, administration is allowed when recalculations fall
between 90 mg and 110 mg.
(2) Without a policy that states an acceptable variance, the nurse
must clarify any dose discrepancy with the prescriber before administering treatment.
(3) It is not in the oncology nurses scope of practice to determine
acceptable variance without policies and procedures guiding
the process.
13. Verification of medication sequence
a) The order in which chemotherapy and biotherapy agents are given may affect the pharmacokinetics and pharmacodynamics of the
agents. However, it is not always known if specific sequences of treatments result in better outcomes.
b) A review of published studies evaluating 35 different chemotherapy combination sequences found only 14 combinations in which
sequence did not seem to have an impact relative to toxicity or
clinical benefit. For the remaining 21 combination regimens, improper sequencing of the chemotherapy agents demonstrated the
potential for increasing toxicity or decreasing the effectiveness of
the regimen (Mancini & Modlin, 2011). The following are some
examples.
(1) Paclitaxel should be given before cisplatin, as the reverse is
known to cause more severe neutropenia without increasing
the effectiveness of the regimen (Mancini & Modlin, 2011).
(2) For the treatment of non-small cell lung cancer, cisplatin should
be given before irinotecan because this sequence has demonstrated more favorable tumor response rates without increased
toxicity (Han et al., 2006).
c) The sequence of administration should be stated in the chemotherapy orders (Jacobson et al., 2012).
d) Some institutions develop algorithms or charts to assist staff in determining administration sequence when no specific direction is given
in the chemotherapy orders.
(1) As new research and medications become available, these tools
should be updated to reflect the most current evidence.
(2) In the absence of specific policy-driven direction, the nurse
should seek clarification of sequence from the ordering provider when the orders are not clear.
14. Verification of oral agents
a) See also Appendix 3.
b) Oral formulations of chemotherapy and biologic agents require the

same processes of verification as other types of systemic cancer treatments. ASCO/ONS have published specific safety standards to address the growing use of oral agents (Neuss et al., 2013).
c) Many oral agents are based on fixed dosing regimens, but some require dose calculations.
d) Ensuring patient/caregiver understanding of the oral treatment regimen is critical when the agents are administered at home.
e) Some patients do not adhere to treatment regimens because of a
lack of understanding or inadequate preparation (Simchowitz et
al., 2010).
f) Retail pharmacists are not always familiar with oral cancer medications and may not have the background to provide adequate patient
education (Simchowitz et al., 2010).
g) Complex treatment schedules may make it difficult for some patients
to maintain adherence. Continuing follow-up (e.g., phone calls) and
providing treatment calendars may be helpful.
h) Failure to adhere to the treatment regimen may result in worse outcomes.
(1) For example, rapid tumor progression and resistance can occur
after only short periods of abstaining from kinase inhibitors such
as imatinib. Patient education should include the importance of
maintaining the regimen as ordered (Barnes & Reinke, 2011).
(2) This highlights the importance of ensuring communication of
the treatment plan between healthcare settings. Cancer therapies should not be stopped solely because of a change in healthcare setting.
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153
Chapter 8
Infusion-Related
Complications
A. Types of infusion complications: The oncology nurse must be alert for immediate complications of cytotoxic therapy. This section covers complications that patients may experience during or shortly after chemotherapy administration. Terms used include
1. Extravasation: A passage or escape into the tissues; passage or escape of
antineoplastic chemotherapeutic drugs into tissue (Mosbys Dictionary of
Medicine, Nursing and Health Professions, 2009)
2. Vesicants (also referred to as blistering agents): A drug or agent capable
of causing tissue necrosis when extravasated (Mosbys, 2009)
3. Flare reaction: Erythema, pruritus, and localized urticaria at or adjacent
to the site of drug administration (Castells & Matulonis, 2012)
4. Irritant: An agent that produces inflammation or irritation (Mosbys, 2009)
B. Extravasation
1. Pathophysiology: Tissue damage secondary to vesicant infiltration or
leakage outside of the vessel that occurs as a result of one of two major
mechanisms
a) The vesicant binds to nucleic acids in the DNA of healthy cells in
the tissue, causing cell death. The dead cells release complexes,
which are taken up by adjacent healthy cells. This process of cellular uptake of extracellular substances sets up a continuing cycle of
tissue damage as the DNA-binding vesicant is retained and recirculated in the tissue for a long period of time (Luedke, Kennedy, &
Rietschel, 1979). Examples of DNA-binding vesicants include anthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin),
dactinomycin, mechlorethamine (nitrogen mustard), mitomycin,
and mitoxantrone.
b) The vesicant does not bind to cellular DNA. The vesicant has an indirect rather than direct effect on the cells in healthy tissue. It is eventually metabolized in the tissue and is more easily neutralized than
DNA-binding vesicants (Ener, Meglathery, & Styler, 2004). Examples
of non-DNA-binding vesicants include plant alkaloids (vinblastine,
vincristine, vindesine, vinorelbine) and taxanes (docetaxel, paclitaxel, paclitaxel protein-bound particles for injectable suspension),
which are mild vesicants.
2. Factors affecting tissue damage severity
a) Type of vesicant extravasated (DNA-binding or nonbinding)
b) Concentration and amount of vesicant in the tissue
c) Location of extravasation
d) Patient factors, such as older age, comorbidity (e.g., diabetes), and
impaired immunocompetence (Ener et al., 2004; Schulmeister, 2011)
3. Risk factors for peripheral extravasation (Goolsby & Lombardo, 2006;
Sauerland, Engelking, Wickham, & Corbi, 2006)
155
156
4.
5.
6.
7.
a) Small, fragile veins

b) Previous multiple venipunctures
c) Prior treatment with irritating or sclerosing drugs, such as chemotherapy
d) Sensory deficits
e) Limited vein selection because of lymph node dissection, lymphedema, or limb removal
f) Impaired cognition, altered mental status (impairs ability to detect
administration site sensation changes), or somnolence
g) Probing during IV catheter insertion
h) Inadequately secured IV catheter
i) Administration site in areas with minimal overlying tissue (e.g., dorsum of the hand, wrist, or antecubital area)
j) Use of rigid IV devices (e.g., steel-winged butterfly needles)
Possible etiologies of peripheral extravasations (Sauerland et al., 2006)
a) Vein wall puncture, piercing, or trauma
b) Dislodgment of the catheter from the vein
c) Administration of a vesicant in a vein below a recent (less than 24
hours) venipuncture site
d) Administration of a vesicant in a vein below a recent or nonhealed
vesicant extravasation site
e) Inadvertent IM or SC vesicant administration
Risk factors for extravasation from central VADs (Sauerland et al., 2006)
a) Difficulty encountered during device insertion (e.g., probing during
venipuncture, inability to advance guidewire or catheter)
b) Inadvertent slicing, piercing, or nicking of catheter prior to or during insertion
c) Device misplacement with catheter tip outside of the venous system
d) Inadequately secured noncoring needles (implanted ports)
e) Deeply implanted ports
f) Presence of a fibrin sheath or thrombus at the catheter tip
g) Catheter migration
h) Long dwell time of catheters inserted using a subclavian approach (increases risk of catheter fracture secondary to compression or pinchoff between the clavicle and first rib)
Possible etiologies of extravasations from central VADs (Goossens, Stas,
Jrme, & Moons, 2011; Sauerland et al., 2006)
a) Vein perforation
b) Catheter leakage, rupture, or fracture
c) Separation of the catheter from a portal body (implanted ports)
d) Incomplete insertion of a noncoring needle into an implanted port
e) Noncoring needle dislodgment from an implanted port
f) Backflow of vesicant along the catheter to the venotomy site secondary to fibrin sheath or thrombus at the catheter tip
Signs and symptoms of vesicant extravasation: Irritation of the vein
and flare reactions may mimic some of the signs and symptoms of
vesicant extravasation (see Table 13 and Appendix 2). Irritation of
the vein and flare reactions are unique to peripheral chemotherapy administration; they do not occur when chemotherapy is administered via central VADs because the chemotherapy is rapidly diluted in large veins (Wickham, Engelking, Sauerland, & Corbi, 2006).
Signs and symptoms of vesicant extravasation are found in Table 13.
Additional signs and symptoms include the following (Ener et al.,
2004).
a) IV flow rate that slows or stops
b) Resistance during IV bolus (push) vesicant administration
c) Leaking around the IV catheter or implanted port needle
157
Table 13. Signs and Symptoms Associated With Vesicant Extravasation, Venous Irritation, and Flare Reaction
Signs and
Symptoms
Vesicant Extravasation
Venous Irritation
Flare Reaction
Pain
Immediate: Pain typically occurs and is described

as burning, stinging, or a sensation of coolness at
and around the vesicant administration site. However, some patients do not experience pain when
a vesicant extravasates.
Delayed: Pain usually increases in intensity over
time.
Aching and tightness along a

peripheral vein, above the administration site, occurs as
the drug infuses.
No pain; the skin overlying the

vein may itch.
Redness
Immediate: Redness in the area of the vesicant administration site commonly occurs but is not always present or may be difficult to detect if the extravasation is occurring deeper in the tissue (e.g.,
as a result of needle dislodgment from implanted port).
Delayed: Redness generally intensifies over time.
The vein may appear reddened or darkened.
Immediate blotches or streaks

develop along the vein, which
usually subside within a few
minutes. Wheals may appear
along the vein.
Swelling
Immediate: Swelling commonly is observed and is

easier to detect when extravasation is superficial
(e.g., from a peripheral vein) rather than deep in
the tissue (e.g., implanted ports).
Delayed: Swelling typically increases over time.
Swelling does not occur.
Swelling does not occur.
Blood return
Immediate: Loss of blood return from IV device occurs.
Blood return should be present. If loss of blood return occurs, suspect infiltration of irritant.
Blood return is present.
Ulceration
Immediate: Skin integrity is intact

Delayed: If vesicant extravasation is not treated,
blistering and sloughing begin within 12 weeks,
followed by tissue necrosis that may require surgical debridement and skin grafting or flap placement.
Ulceration does not occur.
Ulceration does not occur.
Note. Based on information from Goolsby & Lombardo, 2006; Sauerland et al., 2006; Schulmeister, 2011.
8. Possible consequences of untreated vesicant extravasation (Ener et al.,

2004; Goolsby & Lombardo, 2006)
a) Blistering (usually begins within three to five days)
b) Peeling and sloughing of skin (usually begins within two weeks after extravasation)
c) Tissue necrosis (usually evident two to three weeks after extravasation)
(1) DNA-binding vesicants remain in the tissue for long periods of
time. The area of tissue necrosis becomes progressively larger
and deeper over time.
(2) Non-DNA-binding vesicants are more easily metabolized in the tissue. Tissue necrosis is generally localized and improves over time.
d) Damage to tendons, nerves, and joints
e) Functional and sensory impairment of the affected area
f) Disfigurement
g) Loss of limb
9. Vesicant extravasation management: A suspected vesicant extravasation
is best assessed and managed using a systematic and collaborative approach that involves the patient, the nurse administering the vesicant,
and the oncologist treating the patient.
a) Initial management of extravasation: Steps to take when a vesicant
extravasation occurs or is suspected (Goolsby & Lombardo, 2006;
Schulmeister, 2011)
158
(1) Immediately STOP administering the vesicant and IV fluids.

(2) Disconnect the IV tubing from the IV device. Do not remove
the IV device or noncoring port needle.
(3) Attempt to aspirate residual vesicant from the IV device or port
needle using a small (13 ml) syringe.
(4) Remove the peripheral IV device or port needle.
(5) Assess the site of the suspected extravasation.
(6) Assess symptoms experienced by the patient (e.g., pain, impairment in range of motion of extremity).
(7) Notify the physician or advanced practice nurse.
(8) Initiate appropriate management measures in accordance with
Table 14 and institutional policies.
b) Vesicant extravasation antidotes and treatments
(1) Efficacy: The efficacy of extravasation antidotes and treatments
is unknown, with the exception of dexrazoxane for injection,
which has a 98.2% overall efficacy for treating anthracycline
extravasation (Mouridsen et al., 2006). In two European studies, 53 of 54 patients with biopsy-confirmed anthracycline extravasation did not require surgical intervention after receiving
dexrazoxane administered IV daily for three days. The median
baseline extravasation area was 25 cm2 (range 1253 cm2), and
11 patients had extravasation areas exceeding 75 cm2. Thirteen
patients had late sequelae at the extravasation site such as pain,
Table 14. Vesicant Extravasation Management Guidelines
Classification/Drug
Immediate
Topical Therapy
Antidote or Treatment Administration,

Patient Monitoring, and Follow-Up
Antidote or Treatment
Alkylating agent
Mechlorethamine
hydrochloride
(nitrogen mustard,
Mustargen)
Apply ice for

612 hours following sodium
thiosulfate antidote injection
(Lundbeck,
2012).
Antidote: Sodium thiosulfate

Mechanism of action: Neutralizes mechlorethamine to form nontoxic thioesters that
are excreted in the urine
Preparation: Prepare 1/6 molar solution.
If 10% sodium thiosulfate solution: Mix 4
ml with 6 ml sterile water for injection.
If 25% sodium thiosulfate solution: Mix
1.6 ml with 8.4 ml sterile water.
Storage: Store at room temperature between 15C30C (59F86F).
Inject 2 ml of the sodium thiosulfate solution for each milligram of mechlorethamine suspected to have extravasated. Inject the solution SC into the extravasation site using a 25-gauge or smaller needle (change needle with each injection).
Assess the extravasation area for pain,
blister formation, and skin sloughing periodically as needed or in accordance with
institutional policy.
Instruct the patient to monitor the extravasation site and report fever, chills, blistering, skin sloughing, and worsening pain.
Instruct the patient with peripheral extravasations to report arm or hand swelling
and stiffness.
Anthracenedione
Mitoxantrone
(Novantrone)
Apply ice pack

for 1520 minutes at least
four times a
day for the first
24 hours.
No known antidotes or treatments
Extravasation typically causes blue discoloration of the infusion site area and may
require debridement and skin grafting
(EMD Serono, Inc., 2008).
In collaboration with the physician or advanced practice nurse, refer the patient
for specialized care when indicated or
needed (e.g., plastic or hand surgery
consult, physical therapy, pain management, rehabilitation services).
159
Table 14. Vesicant Extravasation Management Guidelines (Continued)

Classification/Drug
Immediate
Topical Therapy

Anthracyclines
Daunorubicin
(Cerubidine)
Doxorubicin
(Adriamycin)
Epirubicin
(Ellence)
Idarubicin
(Idamycin)
Apply ice pack

(but remove at
least 15 minutes prior to
dexrazoxane
treatment).
Treatment: Dexrazoxane for injection (Totect Kit, Biocodex, Inc., 2011)

Note: Totect is the U.S. Food and Drug Administration (FDA)-approved treatment
for anthracycline extravasation, and its
manufacturer maintains a patent for use
on the product. Although Zinecard and
generic dexrazoxane are neither indicated nor FDA-approved for anthracycline
extravasation treatment, their clinical efficacy in treating anthracycline extravasations has been documented in the literature (Arroyo et al., 2010; CondeEstvez et al., 2010; Langer, 2007, 2008;
Uges et al., 2006).
Mechanism of action: Unknown
Dose: The recommended dose of dexrazoxane is based on the patients body surface area:
Day 1: 1,000 mg/m2
Day 2: 1,000 mg/m2
Day 3: 500 mg/m2
The maximum recommended dose is 2,000
mg on days 1 and 2 and 1,000 mg on day
3. The dose should be reduced 50% in patients with creatinine clearance values <
40 ml/min.
Preparation: Each 500 mg vial of dexrazoxane must be mixed with 50 ml diluent. The
patients dose is then added to a 1,000
ml normal saline infusion bag for administration.
Storage: Store at room temperature between 15C30C (59F86F).
The first dexrazoxane infusion should be

initiated as soon as possible and within 6
hours of the anthracycline extravasation.
Dexrazoxane should be infused over 12
hours in a large vein in an area other
than the extravasation area (e.g., opposite arm). The same arm should be
used only when the patients clinical status (e.g., lymphedema, loss of limb) precludes use of the unaffected arm, and a
large vein distal to the extravasation site
should be used for dexrazoxane administration.
Dimethyl sulfoxide should not be applied to
the extravasation area.
Instruct patients with peripheral extravasations to report arm or hand swelling and
stiffness.
Instruct the patient about treatment side
effects (e.g., nausea/vomiting, diarrhea,
stomatitis, bone marrow suppression, elevated liver enzyme levels, infusion-site
burning).
Monitor the patients complete blood count
and liver enzyme levels.
Antitumor antibiotics
Mitomycin
(Mutamycin)
Dactinomycin
(actinomycin D,
Cosmegen)
Apply ice pack

four times a
day for the first
24 hours.
No known antidotes or treatments

In collaboration with the physician or advanced practice nurse, refer the patient
for specialized care when indicated or
needed (e.g., plastic or hand surgery
consult, physical therapy, pain management, rehabilitation services).
Plant alkaloids and

microtubule inhibitors
Vinblastine
(Velban)
Vincristine
(Oncovin)
Vinorelbine
(Navelbine)
Apply warm
pack for 15
20 minutes at
least 4 times
per day for
the first 2448
hours.
Elevate extremity (peripheral extravasations).
Antidote: Hyaluronidase
Mechanism of action: Degrades hyaluronic acid and promotes drug dispersion and
absorption
Preparation: Available hyaluronidase preparations are
Amphadase (bovine, hyaluronidase injection) (Amphastar Pharmaceuticals,
2005): Vial contains 150 units per 1 ml;
use 1 ml of solution. Do not dilute. Use
solution as provided. Store in refrigerator
at 2C8C (36F46F).
Administer 150 units of the hyaluronidase solution as five separate injections,

each containing 0.2 ml of hyaluronidase,
SC into the extravasation site using a
25-gauge or smaller needle (change
needle with each injection).
160
Table 14. Vesicant Extravasation Management Guidelines (Continued)

Classification/Drug
Immediate
Topical Therapy
Plant alkaloids and

microtubule inhibitors (cont.)
Taxanes
Docetaxel
(Taxotere)
Paclitaxel
(Taxol)
Paclitaxel proteinbound particles
for injectable
suspension
(Abraxane)
Apply ice pack

4 times a day
for the first 24
hours.

Hylenex (recombinant, hyaluronidase
human injection) (Halozyme Therapeutics, Inc., 2012): Vial contains 150 units
per 1 ml. Do not dilute. Use solution as
provided. Store in refrigerator at 2C8C
(36F46F).
stiffness.
No known antidote or treatment
Docetaxel extravasation may cause hyperpigmentation, redness, and tenderness

(sanofi-aventis U.S. LLC, 2007).
Paclitaxel is a mild vesicant; extravasation may cause induration, blistering,
and rarely tissue necrosis (Bristol-Myers
Squibb Co., 2011; Stanford & Hardwicke,
2003).
Protein-bound paclitaxel extravasation
has been identified during post-approval use and reported to the manufacturer. It is advisable to monitor the infusion site closely for possible infiltration
during administration (Celgene Corp.,
2012).
Instruct the patient to monitor the extravasation site and to report fever, chills,
blistering, skin sloughing, and worsening pain.
stiffness.
fibrosis, atrophy, and local sensory disturbance; all were judged

as mild (Mouridsen et al., 2006).
(2) Anecdotal reports: No clinical trials have been conducted to determine the efficacy of dimethyl sulfoxide, sodium thiosulfate,
hyaluronidase, growth factors, early surgical intervention, saline
washout or flush-out, or hyperbaric oxygen in treating biopsy-confirmed vesicant extravasations. Information about these antidotes
and treatments is anecdotal and based on case reports (Dougherty & Oakley, 2011; Goolsby & Lombardo, 2006; Schrijvers,
2003; Wickham et al., 2006).
10. Documentation of vesicant extravasation and treatment: Key elements
that may be included in vesicant extravasation documentation are listed in Figure 18. Extravasation treatments/antidotes used should also
be documented.
11. Patient follow-up: Dependent upon individual patient needs and institutional policies
a) Periodically assess the patients response to extravasation treatment.
b) Assessment may include inspection and measurement of the extravasation area, skin integrity, presence of pain or other symptoms, arm/
hand mobility (for peripheral extravasations), and sensation.
c) Obtain follow-up photographs that include the date and time in the
photograph per institutional policy.
d) In collaboration with the physician or advanced practice nurse, refer the patient for specialized care when indicated (e.g., plastic or
hand surgery consultation, physical therapy, pain management, rehabilitation services).
e) Instruct the patient to protect the extravasation area from sunlight,
monitor the site, and report fever, chills, blistering, skin sloughing,
and worsening pain.
C. Irritation
1. Irritants: Chemotherapy agents that may inflame and irritate the peripheral veins include bleomycin, carboplatin, carmustine, dacarbazine, etoposide, floxuridine, gemcitabine, ifosfamide, liposomal daunorubicin,
liposomal doxorubicin, streptozocin, and topotecan (Ener et al., 2004;
Sauerland et al., 2006).
2. Irritants with vesicant properties
a) Oxaliplatin (Eloxatin)
(1) Has been described as both an irritant (de Lemos & Walisser, 2005; Kennedy, Donahue, Hoang, & Boland, 2003) and
a vesicant (Baur, Kienzer, Rath, & Dittrich, 2000). Case reports describe induration, edema, red-brown skin discoloration, hyperpigmentation, and rare instances of tissue necrosis. Kretzschmar et al. (2003) retrospectively reviewed 11 cases of peripheral oxaliplatin extravasation and found that even
with large-volume ( 40 mg) extravasations of oxaliplatin, tissue necrosis did not occur.
(2) Pericay et al. (2009) published a case report of a 165 mg dose
of oxaliplatin that extravasated when a noncoring needle dislodged from an implanted port, resulting in edema and skin
discoloration. They concluded that the effect was that of an irritant rather than a vesicant.
(3) The manufacturer of oxaliplatin states that extravasation
has, in some cases, included necrosis and injection-site reactions such as redness, swelling, and pain (sanofi-aventis
U.S. LLC, 2011).
(4) Because cold packs cause local vasoconstriction, they may precipitate or worsen the cold neuropathy associated with oxaliplatin.
Figure 18. Key Elements of Vesicant Extravasation Documentation

Date and time that extravasation occurred or was suspected
Type and size of peripheral venous access device or type of central venous access device
and gauge/length of noncoring needle (implanted ports)
Location and patency of peripheral or central venous access device
Number and location(s) of venipuncture attempts (for peripheral vesicant administration)
Description and quality of a blood return before and during vesicant administration
Vesicant administration technique (e.g., bolus, infusion)
Concentration and estimated amount of extravasated vesicant
Symptoms reported by patient (e.g., burning, pain)
Description of administration site appearance including measurement of edema and/or redness if present
Photographs of administration site that include date and time in the photograph field
Assessment of extremity (if applicable) for range of motion and discomfort with movement
Immediate nursing interventions (e.g., topical cooling or heating, physician notification)
Follow-up recommendations (e.g., referral to plastic surgery, return appointments)
Patient teaching (e.g., skin assessment, temperature monitoring, reporting pain)
Note. From Extravasation Management: Clinical Update, by L. Schulmeister, 2011, Seminars in Oncology
Nursing, 27, p. 85. doi:10.1016/j.soncn.2010.11.010. Copyright 2011 by Elsevier Inc. Reprinted with permission.
161
162
(5) A warm pack applied to an oxaliplatin extravasation site is

preferable and may reduce local pain and inflammation (Foo,
Michael, Toner, & Zalcberg, 2003).
(6) High-dose dexamethasone (8 mg twice daily for up to 14 days)
has been reported to reduce oxaliplatin extravasation-related
inflammation (Kretzschmar et al., 2003).
b) Vinorelbine (Navelbine)
(1) Has been described as both an irritant (de Lemos, 2005;
Rittenberg, Gralla, & Rehmeyer, 1995) and a vesicant (Ener
et al., 2004; Goolsby & Lombardo, 2006; Hadaway, 2007; Sauerland et al., 2006). Case reports describe skin discoloration,
chemical phlebitis, localized rash, urticaria, blistering, and rarely, skin sloughing.
(2) The manufacturer of vinorelbine states that it is an irritant, and
extravasation may cause local tissue necrosis or thrombophlebitis (Bedford Laboratories, 2005).
(3) Data suggest that rapid IV infusion over 610 minutes followed
by a flush of more than 75124 ml of IV fluid may reduce vinorelbine-induced irritation (de Lemos, 2005).
c) Melphalan (Alkeran)
(1) Information in the literature is conflicting about the risk of extravasation injury associated with melphalan. The drug is listed as neither an irritant nor a vesicant by Dorr, Alberts, and Soble (1986),
as a possible irritant by Schwartz, Rockey, Surati, and Gullatte
(in press), as an irritant by Ener et al. (2004) and Goolsby and
Lombardo (2006), and as a vesicant by Sauerland et al. (2006).
(2) The manufacturer of IV melphalan states that care should be
taken to avoid possible extravasation, and in cases of poor peripheral venous access, use of a central venous line should be
considered (GlaxoSmithKline, 2010).
d) Bendamustine hydrochloride (Treanda): The manufacturer of
bendamustine states that it has received postmarketing reports of
bendamustine extravasation requiring hospitalization for erythema, marked swelling, and pain, and that precautions should be
taken to avoid extravasation (Cephalon, Inc., 2010). Dilution in
500 ml normal saline, which is recommended by the manufacturer, and an infusion time of one to two hours reduced bendamustine-induced venous irritation in a study of 21 patients in Japan
(Watanabe et al., 2013).
e) Irinotecan (Camptosar): The manufacturer of irinotecan states that
care should be taken to avoid extravasation of irinotecan, and should
extravasation occur, topical flushing of the skin with sterile water and
application of ice are recommended (Pfizer Inc., 2010).
3. Risk factors for irritation
a) Small veins
b) Prior treatment with irritating or sclerosing drugs, such as chemotherapy
4. Possible etiologies of venous irritation (Doellman et al., 2009)
a) pH (< 5 or > 9) of infused drugs
b) Hypertonic solutions (e.g., osmolarity > 350 mOsm/L)
c) Concentrated drugs or infusion solutions
5. Signs and symptoms of venous irritation: See Table 13.
6. Management of venous irritation
a) Application of warm pack may reduce local discomfort.
b) Restarting the peripheral IV in a larger vein in another location may
be indicated.
c) Consult a pharmacist to explore diluting irritating medications.
d) Instruct patients to report the development of a hard cord along the

vein, pain, and temperature elevation.
D. Flare reaction: A flare reaction occurs during peripheral administration of
doxorubicin and is thought to be due to local release of histamine from mast
cells or basophils (Curran, Luce, & Page, 1990). It is characterized by transient erythema along the vein proximal to the IV site and may be accompanied by pruritus and urticaria. Flare reactions are distinguishable from extravasation by the lack of pain or swelling and the presence of blood return
(Castells & Matulonis, 2012). In the event of a flare reaction,
1. Verify presence of blood return. If absent, assess for signs and symptoms
of extravasation.
2. Flush the vein slowly with saline and observe for resolution of flare, usually within 45 minutes.
3. If resolution does not occur, obtain an order from an authorized prescriber to administer hydrocortisone or diphenhydramine. For adults,
the diphenhydramine dose is 2550 mg IV followed by a saline flush.
4. Do not resume the infusion through the IV site until the flare reaction
resolves completely. Consider restarting the IV in another site.
5. If the drug is administered again at a later date, premedication with an
antihistamine and/or corticosteroids may prevent flare reaction (Castells & Matulonis, 2012).
6. Document the episode, including all treatment(s) and the patients response, according to institutional policy.
E. Acute infusion reactions: Hypersensitivity, anaphylaxis, and cytokine-release
syndrome
1. Pathophysiology
a) Hypersensitivity and anaphylaxis are mediated by the immune system
and usually are allergic in nature. These reactions may be triggered
by an allergen to which the patient is sensitized. The allergen may be
a chemotherapy or biotherapy agent, its metabolites, or the drug diluent (Lee, Gianos, & Klaustermeyer, 2009). The agents cause direct
or immunoglobulin E (IgE)-mediated mast cell degranulation with
release of histamine. Some reactions may be related to complement
activation. Symptoms range from itching at the injection site to systemic shock caused by smooth muscle contraction, increased vascular
permeability, and vasodilation (Soar, 2009). Reactions usually occur
within 530 minutes of initiating the dose of chemotherapy but may
occur hours later with some agents (Gobel, 2005; Lee et al., 2009).
b) Cytokine-release syndrome, which is commonly referred to as infusion
reaction, is a symptom complex that occurs in association with mAb
infusions. This type of reaction is related to the release of cytokines
such as IL-2, IFN, and TNF from the targeted cells and other recruited immune cells, such as lymphocytes (Breslin, 2007).
2. Risk factors for hypersensitivity and anaphylaxis (Gobel, 2005)
a) Administration of a chemotherapy agent known to cause hypersensitivity reactions (see Figure 19)
b) Preexisting allergies, such as to foods, drugs, bee stings (Grosen, Siitari, Larrison, Tiggelaar, & Roecker, 2000), blood products, or radiographic contrast media
c) Previous exposure to the agent
d) Failure to administer known effective prophylactic premedications
3. Risk factors for cytokine-release syndrome: See Figure 20 (Breslin, 2007;
Gobel, 2007; Lenz, 2007).
a) First infusion of mAbs
b) Chemotherapy-nave patients receiving mAbs
163
164
Figure 19. Immediate Hypersensitivity Reactions:

Predicted Risk of Chemotherapy
High Potential
L-Asparaginase
Taxanes
Paclitaxel
Docetaxel
Platinum compounds
Cisplatin
Carboplatin
Oxaliplatin
Epipodophyllotoxins
Etoposide
Teniposide
Occasional Potential
Anthracyclines
Doxorubicin
Daunorubicin
Idarubicin
Epirubicin
Mercaptopurine
Azathioprine
Rare Potential
Bleomycin
Chlorambucil and melphalan
Cyclophosphamide and
ifosfamide
Cytarabine and fludarabine
Dacarbazine
Dactinomycin
5-Fluorouracil
Hydroxyurea
Methotrexate
Polyethylene glycol-modified E. coli asparaginase
Vincristine and vinblastine
Note. From Chemotherapy-Induced Hypersensitivity Reactions, by B.H. Gobel, 2005, Oncology Nursing Forum, 32, p. 1028. doi:10.1188/05.ONF.1027-1035. Copyright 2005 by Oncology Nursing Society. Reprinted
with permission.
Figure 20. Biotherapy Drugs Associated With Hypersensitivity Reactions

and Cytokine-Release Syndromes
Interferon
Interferon alfa
Interferon beta (1A and 1B)
Interferon gamma
Interleukin
Aldesleukin
Denileukin diftitox
Kinase Inhibitor
Temsirolimus
Monoclonal Antibodies
Murine
Ibritumomab tiuxetan
Tositumomab
Chimeric
Brentuximab
Cetuximab
Rituximab
Humanized
Alemtuzumab
Bevacizumab
Gemtuzumab ozogamicin
Trastuzumab
Fully human
Ipilimumab
Ofatumumab
Panitumumab
Note. Based on information from Bristol-Myers Squibb Co., 2013; GlaxoSmithKline, 2011; Gobel, 2007;
Lenz, 2007; Seattle Genetics, Inc., 2012; Wyeth Pharmaceuticals, 2012.
c) Patients with leukemia or lymphoma, especially those having high

circulating lymphocyte counts (> 25,000/mm3)
4. Preadministration guidelines: Implement the following steps to prevent
and manage hypersensitivity reactions, anaphylaxis, and infusion reactions.
a) Obtain and record baseline vital signs.
b) Review the patients allergy history (e.g., food, medication, environment).
c) Administer premedications as ordered. Common premedications include histamine (H) blockers (e.g., H1 blocker [diphenhydramine], H2
blocker [ranitidine], acetaminophen (for mAbs), and dexamethasone.
d) Ensure emergency equipment and medications are readily available.
e) Obtain physician orders for emergency treatment before drug administration. Written standing orders for management of hypersensitivity and infusion reactions are recommended (Gobel, 2005; Lenz,
2007; Viale, 2009).
f) Instruct the patient to report symptoms of hypersensitivity and infusion reaction.

g) Monitor for reactions with each treatment; hypersensitivity reactions
can occur with a patients repeated exposure to a drug and at any
time during the infusion or the treatment cycle. For example, the incidence of hypersensitivity reactions with platinum-containing agents
increases with multiple doses and can occur after the drug has been
infused (Gobel, 2005; Lee et al., 2009; Winkeljohn & Polovich, 2006).
h) Perform an intradermal skin test or administer a test dose before
the initial dose of the drug to a patient who has a high likelihood
of a hypersensitivity reaction. For a patient receiving repeated doses
of carboplatin, a valid method of predicting a reaction is a skin test
performed after the sixth dose. False-positive and false-negative skin
tests are possible with oxaliplatin and asparaginase (Lee et al., 2009).
(1) Observe the patient for any local or systemic reaction for a minimum of 30 minutes. If no sign of reaction is evident, proceed
with the initial dosing.
(2) When administering an IV drug that is associated with hypersensitivity, observe the patient for signs and symptoms of reaction and be prepared to intervene.
(a) Any patient who has had a severe anaphylactic reaction accompanied by hypotension should not be treated again with
that agent except in special circumstances (Viale, 2009).
(b) Avoid administering subsequent doses if a patient is considered to be sensitized to the drug. If the drug is critical
to the treatment plan, premedication with antihistamines
or corticosteroids (Gobel, 2005; Lenz, 2007) or a desensitization protocol (Cortijo-Cascajares et al., 2013; Lee et
al., 2009; Viale, 2009) may prevent a recurrent hypersensitivity reaction. Discontinuation and drug substitution may
be necessary.
5. Clinical manifestations of anaphylaxis (Soar, 2009) and hypersensitivity
a) Airway compromise, such as tongue or throat swelling, stridor, hoarseness
b) Breathing difficulties, such as shortness of breath, wheezing, cyanosis, or respiratory arrest
c) Circulatory compromise, such as tachycardia, hypotension, myocardial ischemia, or cardiac arrest
d) Neurologic changes, such as confusion, agitation, or loss of consciousness
e) Skin and mucosal changes, such as erythema, urticaria, or periorbital or facial edema
f) Abdominal cramping, diarrhea, nausea, and vomiting (less common)
6. Clinical manifestations of cytokine-release syndrome (severe reactions are
characterized by rapid onset and more severe symptoms) (Breslin, 2007)
a) Fever or chills
b) Nausea
c) Hypotension
d) Tachycardia
e) Asthenia
f) Headache
g) Rash
h) Tongue and throat swelling
i) Dyspnea
7. Emergency management of anaphylaxis: Symptoms of reaction usually
arise within 30 minutes of initial administration or increase in infusion
rate (Gobel, 2005). Immediate action is imperative.
165
166
a) STOP drug infusion immediately.

b) Maintain an IV line with normal saline or another appropriate solution.
c) Stay with the patient. Have another staff member notify the physician
and emergency team, or, if outside the hospital setting, call the local
emergency medical service.
d) Place the patient in a comfortable position: sitting if short of breath
or vomiting, lying flat if hypotensive with elevated legs for shock (systolic blood pressure < 60 mm Hg).
e) Monitor vital signs (pulse, respirations, blood pressure, oxygen saturation) every 2 minutes until the patient is stable, then every 5 minutes for 30 minutes, then every 15 minutes. Monitor electrocardiogram (ECG) for serious reactions.
f) Maintain airway, assessing the patient for increasing edema of the respiratory tract. Administer oxygen if needed. Anticipate the need for
cardiopulmonary resuscitation.
g) Administer emergency medications based on symptoms (Sampson et
al., 2006; Soar, 2009) (see Table 15).
h) Provide emotional support to the patient and family.
i) Document all treatments and the patients response in the medical
record.
Table 15. Emergency Drugs for Use in Case of Hypersensitivity or Anaphylactic Reactions*
Indication
Drug
Dose
Comments
Bronchial constriction
(dyspnea, wheezing,
stridor)
Epinephrine
0.10.5 mg IM into thigh (0.10.5

ml of 1:1,000 solution or EpiPen
0.3 mg automatic device)
IM administration is preferred over IV to minimize adverse cardiac effects. Anterior-lateral

thigh is preferable to deltoid (may also be administered by inhalation or subcutaneously).
May repeat every 510 minutes if needed.
Shortness of breath,
tachypnea (rate > 20
breaths per minute), or
decreased oxygen saturation
Oxygen
610 L/min by face mask
Patients who are hemodynamically unstable

may also benefit from oxygen.
Albuterol
2.5 mg by inhalation (3 ml of
0.083% inhalation solution) by nebulizer
Hold if heart rate is > 110 beats per minute.
Hypotension (> 30%

decrease in systolic
blood pressure from
baseline)
Epinephrine
0.10.5 mg IM into thigh (0.10.5

ml of 1:1,000 solution or EpiPen
0.3 mg automatic device) or 50
100 mcg IV bolus (0.2 mcg/kg) for
hypotension (0.51 ml of 1:10,000
solution)
IM administration is preferred over IV to minimize adverse cardiac effects, except in the

presence of cardiovascular collapse. Cardiac
monitoring is recommended.
Normal saline IV
500 ml fluid bolus
Over 10 minutes 1, then as ordered. Multiple fluid boluses may be required if patient
remains hypotensive despite epinephrine.
Diphenhydramine
2550 mg IVP
Famotidine
OR
20 mg IV
To counteract the multiple effects of histamine release, both H1 and H2 blockers should
be administered.
Ranitidine
50 mg IV
Methylprednisolone
3050 mg IV
Hydrocortisone
injection
100500 mg IV
Dexamethasone
1020 mg IV
Hives, itching, flushing,

swollen lips or tongue
To prevent delayed
reaction
Limited evidence is available to support this

recommendation, although steroids have
been used frequently.
* Additional emergency medications (e.g., sodium bicarbonate, furosemide, lidocaine, naloxone hydrochloride, sublingual nitroglycerine) and emergency
supplies (e.g., oxygen, suction machine with catheters, Ambu bag) should be available in case of medical emergency.
IMintramuscular; IVintravenous; IVPintravenous push
Note. Based on information from Sampson et al., 2006; Soar, 2009.
167
j) Symptoms of anaphylaxis may recur hours after initial intervention; therefore, patients who have experienced a grade 3 or 4 reaction (NCI CTEP, 2010) should be hospitalized and monitored
closely for 24 hours (Sampson et al., 2006). See Table 16 for grading criteria.
8. Clinical management of cytokine-release syndrome (Gobel, 2007; Lenz,
2007)
a) Stop infusion, and observe the patient until symptoms resolve, which
usually occurs within 30 minutes.
b) Administer additional H blockers as ordered.
c) Resume infusion at a slower rate (50%) after resolution of symptoms,
and titrate the rate slowly.
d) For severe reactions (Table 16), administer emergency medications
based on symptoms (see Table 15).
9. Clinical management of localized hypersensitivity (Wilkes, 2010)
a) Observe for and evaluate symptoms (e.g., urticaria).
b) Administer diphenhydramine, ranitidine, or corticosteroids per physician order or according to protocol.
c) Monitor vital signs at least every 15 minutes for 1 hour or as the patients condition requires.
d) Document the episode, including all treatments and the patients response, according to institutional policies.
F. Patient and caregiver education
1. Before cytotoxic therapy, inform the patient and family that chemotherapy and biotherapy agents have the potential for early complications. Instruct them to immediately report signs and symptoms of extravasation,
flare, hypersensitivity, or infusion reactions.
Table 16. Grading Criteria for Allergic Reactions, Anaphylaxis, and Cytokine-Release Syndrome
Grade
Adverse Event
Allergic reaction
Transient
flushing or
rash, drug fever < 38C (<
100.4F); intervention not indicated
Intervention or infusion interruption indicated; responds promptly to

symptomatic treatment
(e.g., antihistamines,
NSAIDs, narcotics); prophylactic medications indicated for 24 hours
Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms
following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates)
Life-threatening
consequences; urgent intervention
indicated
Death
Symptomatic bronchospasm, with

or without urticaria; parenteral intervention indicated; allergy-related
edema/angioedema; hypotension
Life-threatening
consequences; urgent intervention
indicated
Death
Mild reaction;
infusion interruption not indicated; intervention not indicated
Therapy or infusion interruption indicated but

responds promptly to
symptomatic treatment
(e.g., antihistamines,
NSAIDs, narcotics, IV
fluids); prophylactic medications indicated for
24 hours
Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms
following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates)
Life-threatening
consequences;
pressor or ventilatory support indicated
Death
Anaphylaxis
Cytokinerelease
syndrome
IVintravenous; NSAIDsnonsteroidal anti-inflammatory drugs

Note. From Common Terminology Criteria for Adverse Events [v.4.03], by the National Cancer Institute Cancer Therapy Evaluation Program, 2010. Retrieved from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.
168
2. Document all patient teaching. Schulmeister and Camp-Sorrell (2000)

stated that plaintiffs in extravasation lawsuits typically deny being informed of the risk of extravasation or state that they were led to believe
that the risk was minuscule (p. 532).
3. After therapy, instruct the patient and family about the importance of
immediately reporting symptoms of any delayed reaction.
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Chapter 9
Side Effects of Cancer

Therapy
A. Myelosuppression: Neutropenia, anemia, and thrombocytopenia
1. Myelosuppression is a condition manifested by a significant decrease in
the number of neutrophils, megakaryocytes, and erythrocytes within the
bone marrow (NCI, n.d.). Myelosuppression is a dose-limiting toxicity
of systemic chemotherapy (Camp-Sorrell, 2011). Terms used in this section include the following.
a) Neutropenia: A significant reduction in the absolute number of circulating neutrophils in the blood. The absolute neutrophil count (ANC)
is the basis for neutropenia classification and is generally defined as
an ANC < 1,500 neutrophils/microliter (mcl) (Watts, 2009). NCCN
(2013f) and the Infectious Diseases Society of America (Freifeld et
al., 2011) define neutropenia as < 500 neutrophils/mcl or < 1,000
neutrophils/mcl with the expectation that the neutrophil count will
decline to < 500 neutrophils/mcl over 48 hours. NCI CTEP (2010)
outlines the grading of neutropenia.
(1) Mild: ANC < lower limit of normal (LLN)1,500 neutrophils/mcl
(2) Moderate: ANC < 1,5001,000 neutrophils/mcl
(3) Severe: ANC < 1,000500 neutrophils/mcl
(4) Life-threatening: ANC < 500 neutrophils/mcl
b) Anemia: In adults, anemia is defined as a hemoglobin (Hgb) < 11 g/
dl or > 2 g/dl below baseline (NCCN, 2013c). Other references for
adults in industrialized nations identify 14 g/dl for men and 12 g/dl
for women as lower limits for normal Hgb. A decrease in the hematocrit (Hct) level or number of red blood cells (RBCs) can be used
to define anemia, but Hgb is the value used most often because it reflects physiologic consequences of anemia (Means & Glader, 2009).
NCI CTEP (2010) outlines the grading of anemia.
(1) Grade 1: 10 g/dl to < LLN
(2) Grade 2: 8.09.9 g/dl
(3) Grade 3: 6.57.9 g/dl
(4) Life-threatening: < 6.5 g/dl
c) Thrombocytopenia: Platelet count below the LLN, 400150 109/L
(Liles & Knupp, 2009). NCI CTEP (2010) outlines the grading of decreased platelet count.
(1) Mild: < LLN75,000/mcl
(2) Moderate: < 75,00050,000/mcl
(3) Severe: < 50,00025,000/mcl
(4) Life-threatening: < 25,000/mcl
d) Cytopenia: The lack of cellular elements in circulating blood
e) Pancytopenia: A depression of the normal bone marrow elements; white
cells, red cells, and platelets in the peripheral blood (Harmening, 2009)
f) Nadir: Following cytotoxic therapy, the time or level at which the
lowest blood cell count is reached (OLeary, 2010). The nadir varies
171
172
with individual agents but usually occurs 710 days after treatment
g) Hematopoiesis
(1) The processes involved in the production of all blood cells
from hematopoietic stem cells (HSCs). In adults, most hematopoiesis occurs in the bone marrow in myeloid tissue (see
Figure 21).
(2) The process begins with HSCs, also called pluripotent stem cells
(Bell, Harmening & Hughes, 2009; Koury, Mahmud, & Rhodes,
2009). These are the most primitive type of blood cell and the
source of all hematopoietic cells. Pluripotent stem cells are able
to self-renew and maintain their numbers because they have the
capacity to proliferate, differentiate, and mature into all cell lines.
With each stem cell division, one daughter cell stays in the stem
cell pool while the other daughter cell leaves the stem cell pool
and becomes committed to a distinct cell line. These committed progenitor cells differentiate and mature in the bone marrow. Whether HSCs proliferate or differentiate is determined
by the bodys needs in response to exogenous (e.g., high altitude) or endogenous (e.g., stress, infection, hemorrhage, drug
therapy) influences. Once released into the bloodstream, mature cells have a varied life span (see Table 17).
2. Most chemotherapy agents cause some degree of myelosuppression. The
degree and duration of chemotherapy-related myelosuppression is related to the agents mechanism of action (e.g., cell cyclespecific drugs
are associated with rapid cytopenias).
3. Neutropenia: Chemotherapy-induced neutropenia (CIN) is the primary dose-limiting toxicity associated with systemic chemotherapy (Harmening, Marty, & Strauss, 2009). It has significant negative clinical consequences for patients with cancer, including life-threatening infections,
prolonged hospital stays, dose reductions, and dose delays.
a) Normal physiology of neutrophils (see Figure 21): Neutrophils and
monocytes stem from the colony-forming unitgranulocyte-macrophage progenitor cell. The earliest identifiable cell of the neutrophil
lineage is the myeloblast. Differentiation from a myeloblast to a segmented neutrophil takes 711 days. Normal adult bone marrow produces approximately 1 1011 neutrophils each day (Harmening, Marty, et al., 2009). The major steps of development follow (Bell et al.,
2009).
(1) The pluripotent stem cell gives rise to the myeloblast, the earliest form of the neutrophil. During this phase, the nucleus is
round. At the end of this phase, granules are evident as the cell
transitions to a promyelocyte.
(2) Promyelocytes have a large nucleus, averaging three to five
times larger than the cytoplasm of the cell. During this phase,
the granules begin to fade.
(3) During the myelocyte phase, primary granules decrease and secondary neutrophilic granules appear. Myelocytes may have nuclei that are round, oval, or flattened on one side.
(4) Metamyelocytes are observed with indented nuclei that make
them appear bean-shaped.
(5) Band neutrophils evolve when the indentation of the nucleus
is more than half the width of the nucleus. At this point, the
cell is approximately 24 hours from maturation into a segmented neutrophil. In the presence of acute infection or inflammation, bands are released early from the marrow and complete
maturation in circulation.
Figure 21. Hematopoiesis

173
174
Table 17. Life Spans of Blood Components

Blood Component
Typical Life Span
Red blood cell
90120 days
Platelet
810 days
Neutrophil
< 1 day to approximately 5.4 days
Monocyte
5 days, but dependent on many factors
Macrophage
Dependent on many factors
Eosinophil
818 hours in blood and 25 days in tissue
Basophil
12 days
Tissue mast cell
Cutaneous: 1 year; mucosal: 12 weeks
B lymphocyte
Depends on type and subtype
T lymphocyte
Depends on type and subtype
Natural killer cell
Approximately 10 days
Note. Based on information from Kitamura, 1989; Milot & Filep, 2011; Min et al., 2012; Nayak et al., 2013;
Park & Bochner, 2010; Pillay et al., 2010; Whitelaw, 1966; Zhang, Wallace, et al., 2007.
(6) In the segmented neutrophil phase, the nucleus has two to five
lobes connected to each other by fine strands.
b) Locations of neutrophils (Bell et al., 2009).
(1) The bone marrow of a healthy adult contains both mature segmented neutrophils and immature neutrophils in various stages of development. Neutrophils leave the bone marrow for the
blood through pores that form between the marrow parenchyma and venous blood vessels.
(2) Once in the bloodstream, these cells join the functional
pool by circulating or lining blood vessel walls as marginated cells, meaning they are adhering to endothelial cells lining the blood vessel. Neutrophils exist in the bloodstream
as mature and immature cells. These cells perform a critical
role in the bodys defense by generating chemotactic agents
(e.g., endotoxin-activated serum [Anderson, Glover, & Robinson, 1978]) in response to infection. The result is activation of neutrophil defense and movement of neutrophils to
the site of infection.
(3) Neutrophils leave the blood for tissue by migrating through endothelial cells, a process called diapedesis. After neutrophils enter
the tissue, they do not return to circulation or the bone marrow.
c) Pathophysiology
(1) The bone marrow must constantly produce neutrophils because
the life span of a neutrophil is estimated to be only 712 hours
(see Table 17). Chemotherapeutic agents suppress bone marrow activity and damage stem cells, preventing them from continuing the maturation process. Therefore, chemotherapy decreases the neutrophil count as mature neutrophils die and are
not replaced (Camp-Sorrell, 2011).
(2) The WBC nadir depends on the specific drugs and dosages
used. A prolonged nadir may occur if stem cells fail to repopulate quickly following high-dose chemotherapy (OLeary,
2010). Neutropenia occurs 812 days following chemotherapy and resolves 2128 days after chemotherapy.
(a) Cell cyclespecific agents (e.g., antimetabolites) are generally less damaging because they primarily affect cells in
a specific phase of the cell cycle. Severe neutropenia can
develop when cell cyclespecific drugs are used in doseintensification and combination chemotherapy regimens
(b) Cell cyclenonspecific agents (e.g., alkylating agents, nitrosoureas) are damaging to cells in all phases of the cell
cycle, thereby causing more damage to stem cells. The extent of neutropenia with these agents is dependent on dose,
schedule, and agent. For example, oxaliplatin as a single
agent is expected to cause mild neutropenia, but in regimens with 5-FU and leucovorin, toxicity can be much higher (Camp-Sorrell, 2011).
(c) Some cell cyclenonspecific agents (e.g., nitrosoureas) produce a delayed and prolonged neutropenia.
i. In adults, nadir occurs at 2146 days, with recovery at
3560 days (Wilkes & Barton-Burke, 2012).
ii. In children, nadir with BCNU (carmustine) occurs
at 2135 days, with recovery at 4250 days (Hennessy
& Scott, 2008).
d) Risk factors for developing neutropenia: Risk assessment for CIN
should be done prior to each cycle of therapy, including initial therapy (see Figure 22) (NCCN, 2013d; OLeary, 2010).
e) Fever and febrile neutropenia: Fever is defined as a one-time oral
temperature > 101F (38.3C) or oral temperature of 100.4F
Figure 22. Risk Factors for Developing Febrile Neutropenia

Patient Related
Older than 65 years
Female
Poor performance status
Poor nutritional status
Low neutrophil count at the beginning of a treatment cycle
Renal dysfunction
Liver dysfunction, especially elevated bilirubin
Cardiovascular disease
Recent surgery
Preexisting infection
Open wounds
Disease Related
Advanced disease stage
Tumor involvement of the bone marrow
Type of malignancy: hematologic (leukemia, myelodysplastic syndromes), breast, lung,
colorectal, ovarian, and lymphoma
Preexisting, prolonged, or previous episode of neutropenia
Treatment Related
Previous myelosuppressive chemotherapy or radiation
Treatment intent (curative intent rather than palliative)
Planned relative dose intensity ( 85%)
Use of specific medications (e.g., immunosuppressive drugs)
Chemotherapy intensity (i.e., dose dense, high dose, myeloablative)
Note. From Putting Evidence Into Practice: Improving Oncology Patient Outcomes; Prevention of Infection (p.
7), by M. Irwin, C. Erb, C. Williams, B.J. Wilson, and L.J. Zitella, 2013, Pittsburgh, PA: Oncology Nursing Society. Copyright 2013 by the Oncology Nursing Society. Reprinted with permission.
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176
(38C) lasting one hour. Febrile neutropenia occurs when the ANC
is < 500/mcl or < 1,000/mcl with anticipated decline to < 500/mcl
over the next 48 hours and fever as defined previously (NCCN,
2013f).
f) Risk assessment
(1) Assess for febrile neutropenia risk prior to each treatment cycle (Irwin, Erb, Williams, Wilson, & Zitella, 2013). Increased
infection risk is present in patients with fever in the presence
of neutropenia.
(2) Risk factors for developing febrile neutropenia (NCCN, 2013f)
(a) Advanced age
(b) Low neutrophil count at the beginning of chemotherapy cycle
(c) Tumor involvement of bone marrow
(d) Poor performance status
(e) Renal dysfunction
(f) Liver dysfunction, especially elevated bilirubin
(g) Previous myelosuppressive chemotherapy or radiation
(h) Preexisting infection, open wounds, or recent surgery
(i) Chemotherapy regimens (e.g., high-dose therapy, dosedense therapy)
(j) Use of specific medications including but not limited to
phenothiazines, diuretics, and immunosuppressive drugs
g) Clinical manifestation of infection in patients with neutropenia
(Camp-Sorrell, 2011; Freifeld et al., 2011; NCCN, 2013f; OLeary,
2010; Shelton, 2011)
(1) A fever > 100.4F (38C) is the most reliable, and often the
only, sign of infection in patients with neutropenia. Normally, WBCs cause the classic signs of infection (e.g., redness,
edema, pus). Extremely neutropenic patients, however, may
not be able to manifest the usual signs of infection (NCCN,
2013f).
(2) Common sites of infection and corresponding signs and symptoms in neutropenic patients
(a) GI tract: Fever, abdominal pain, alimentary mucositis (mucositis at any level of the digestive tract), diarrhea
(b) Respiratory tract: Fever, cough, dyspnea on exertion, adventitious breath sounds, chest discomfort, asymmetric chest
wall movement, nasal flaring
(c) Genitourinary tract: Fever, dysuria, frequency, urgency, hematuria, cloudy urine, flank pain, perineal itching, vaginal discharge
(d) Head and neck: Swelling, itching, redness or drainage of
eyes, pain or discharge of ears, nasal congestion or drainage, oral ulcerations, difficulty swallowing, fever
(e) Indwelling devices (e.g., VADs, ventricular peritoneal shunts): Fever, erythema, pain or tenderness, edema,
drainage, induration at site
(f) Dermatologic and mucous membranes: Erythema, tenderness, warm skin, edema (especially in axilla, mouth, sinuses
and perineal or rectal areas), rashes, itching, skin lesions,
fever, draining open wounds
(g) Central nervous system (CNS): Change in mental status,
headache, seizure, vision changes, photosensitivity, fever,
nausea, lethargy
(h) Hematologic/immunologic: Decrease in diastolic blood
pressure, headache, oliguria, fever, flushed appearance
(3) Septic shock associated with neutropenia has a high mortality

rate (Vusirikala, 2009).
h) ANC calculation: Use laboratory data to assess neutropenia by calculating the ANC. Note that neutropenia can occur when the total WBC
count is within a normal range (4,00010,000/mcl) (Camp-Sorrell,
2011). Consequently, calculating the ANC is essential to achieving a
correct assessment of neutrophil status. To calculate ANC, ANC = %
(polys + bands) WBC.
(1) Obtain complete WBC count including differential. The differential will include mature neutrophils, also referred to as segs
for segmented neutrophils or PMNs/polys for polymorphonuclear neutrophils. In addition, less mature neutrophils will be
present; these are known as bands.
(2) Add the total number of mature polys and less mature neutrophil bands.
(3) Convert sum from (2) to a percentage.
(4) Multiply total WBC count by total neutrophil percentage (polys + bands). ANC calculation example: WBC = 1,500, polys =
30; bands = 5.
(a) Add polys and bands: 30 + 5 = 35.
(b) Convert sum to percentage: 35 100 = 0.35 = 35%.
(c) Multiply WBC count by percentage to find ANC: 1,500;
0.35 = 525/mcl.
i) Collaborative management
(1) Nurses play an important role in preventing infection in patients
with neutropenia and cancer through evidence-based nursing
practice, research, and patient education (Irwin et al., 2013).
(a) Hand hygiene: Proper hand hygiene is the most effective
measure to prevent the spread of infection. It reduces the
risk of healthcare-associated infections by decreasing person-to-person transmission of pathogens (CDC, 2012; Freifeld et al., 2011; Irwin et al., 2013).
(b) Diet: No recent studies have linked neutropenic diets (restricting fresh fruits and vegetables) with a lower risk of
infection for neutropenic patients with cancer. Dietary
precautions regarding the omission of fresh fruit and vegetables remain unsupported (Gardner et al., 2008). Uncooked fruits and vegetables should be thoroughly washed
(Freifeld et al., 2011; Irwin et al., 2013). Basic safe food
handling practices, such as avoiding uncooked and undercooked meats, seafood, and eggs and unwashed fruits
and vegetables, should be employed (Freifeld et al., 2011;
Wilson, 2002).
(c) Environment: Protective or strict isolation studies reveal
no significant differences in documented infections, febrile episodes, or antibiotic use for patients with CIN.
Protective isolation has no effect on the hosts endogenous flora and no impact on organisms transmitted by
water or food (Freifeld et al., 2011).
i. In general, patients with CIN do not require specific
room ventilation.
ii. Allogeneic hematopoietic stem cell transplantation
(HSCT) recipients are recommended to be placed in
rooms with HEPA filtration with > 12 air exchanges
per hour. Air pressure in these rooms should be positive when compared to surrounding areas, such as
hallways, toilets, and anterooms.
177
178
(d) Plants and flowers: No research studies are available that

evaluate the potential harm of plants and flowers to patients with CIN (Irwin et al., 2013).
i. Because fresh or dried flowers could expose patients
with cancer to Aspergillus and Fusarium, they should be
kept out of patient rooms (Freifeld et al., 2011).
ii. If plants must be present, plant care should be done
by staff not directly caring for patients (Sehulster &
Chinn, 2003).
iii. If caregivers are unable to avoid plant care, they should
wear gloves and perform hand hygiene after removing gloves.
(e) Treatment with colony-stimulating factors (CSFs) (see Table 9)
i. Granulocyte macrophagecolony-stimulating factor
(GM-CSF) (sargramostim) (Genzyme Corp., 2009b)
ii. Granulocytecolony-stimulating factor (G-CSF) (filgrastim, pegfilgrastim [Amgen, 2012c, 2013a]). NCCN
(2013d) recommends use of these drugs when the risk
of febrile neutropenia is > 20%.
iii. The manufacturer recommends initiation of G-CSF
no earlier than 24 hours following chemotherapy.
iv. The manufacturer of G-CSF warns that safety of administration simultaneously with chemotherapy has
not been established. Rationale is the potential sensitivity of rapidly dividing myeloid cells to cytotoxic
agents (Amgen, 2012c, 2013a).
(f) Preventing trauma to the patients skin and mucous membranes (Freifeld et al., 2011; OLeary, 2010; Shelton,
2011)
i. Provide meticulous care for all indwelling devices.
ii. Prevent pressure sores and constipation.
iii. Change water in pitchers, denture cups, and nebulizers at least daily.
iv. Consider risk-benefit ratio for invasive procedures (e.g., thoracentesis, paracentesis, VAD placement).
v. Use only an electric razor for shaving.
vi. Protect skin from cuts and burns. Immediately cleanse
and treat any wound that breaks the skin.
vii. Use a soft toothbrush for frequent (minimum of three
to four times daily) oral care. Allow toothbrush to dry
before storing (Brown, 2010).
(g) Protective measures that patients can follow (Brown, 2010;
OLeary, 2010; Shelton, 2011)
i. Report fever, chills, and other signs and symptoms of
infection at onset.
ii. Personal hygiene
Wash hands frequently with soap and water or an
antiseptic hand rub. Hands may remain colonized
with microorganisms if they are not dried properly after washing.
Bathe daily.
Avoid activities that may compromise skin integrity.
Wear gloves when working in the garden.
Perform frequent (three to four times per day) oral
assessment and care.
Cleanse the perineal area from front to back after

toileting.
Avoid exposure to pathogens or people who are experiencing signs and symptoms of contagious conditions.
iii. Protective measures
Do not share eating utensils.
Do not eat meat or produce that has not been either cooked or washed.
Adhere to safe food handling practices, and avoid
consuming food when safety of preparation, storage, or serving is not guaranteed.
Do not provide direct care for pets or farm animals;
avoid contact with animal excreta.
Refrain from direct or indirect contact with reptiles, fish, and birds.
Avoid exposure to fresh or dried plants and flowers because of risk of Aspergillus infection. Plant care
may be done by staff not directly providing care to
the patient.
Do not enter, travel through, or stay in an area of
construction or renovation or where construction
material or debris has been placed or where fields
have recently been plowed.
Consider vaccination for influenza and pneumonia (CDC, 2011).
Avoid contact with people who have been vaccinated with a live vaccine within the past 30
days.
(2) Management of neutropenic fever: Use of CSFs after a patient
is diagnosed with febrile neutropenia is not recommended (de
Naurois et al., 2010; Freifeld et al., 2011). To manage neutropenic fever, the clinician should take the following steps.
(a) Obtain cultures (NCCN, 2013f).
i. Urine: If symptomatic, with catheter, or if urinalysis
is abnormal
ii. Blood: Two sets (one set includes two bottles). If patient has a central VAD, options include
One peripheral and one central VAD, which may
assist in identifying central VAD as the source of
bloodstream infection
Both peripheral
Both from central VAD.
iii. Stool: For diarrhea, obtain Clostridium difficile assay
and enteric pathogen screen.
iv. Skin: Aspirate/biopsy skin lesions. Vesicular or ulcerated skin lesions require viral cultures.
v. VAD cutaneous site: Consider routine fungal/Mycobacterium culture if inflammation is present.
vi. Throat/nasopharynx: When respiratory viral symptoms are present, especially during seasonal outbreaks
(b) Conduct site-specific history and physical examination with
attention to identifying the source of infection (NCCN,
2013f).
i. Assess VADs, skin, lungs, sinus, mouth, pharynx, esophagus, bowel, rectum, and perivaginal and perirectal areas for signs and symptoms of infection.
179
180
ii. Obtain historical data including comorbidities, date

and regimen of last chemotherapy, previous infections,
recent antibiotic therapy/prophylaxis, medications,
and human immunodeficiency virus (HIV) status. Explore exposure risks, including anyone at home with
similar symptoms, pets, travel, recent blood product
transfusion, or exposure to tuberculosis.
(c) Obtain a chest x-ray if respiratory symptoms are present.
(d) Once initial cultures have been obtained, administer empiric broad-spectrum antibiotics as ordered until organism
source is identified.
(e) Monitor blood culture reports daily and anticipate antibiotic therapy based on findings.
4. Anemia
a) Erythropoiesis: The process of erythrocyte (RBC) production in the
bone marrow (Bell et al., 2009; Dessypris & Sawyer, 2009)
(1) The kidneys are the primary producers of erythropoietin (EPO),
the growth factor that stimulates pluripotent stem cells to produce RBCs.
(2) RBC production is regulated by oxygen levels. When oxygen
levels are low, the kidney releases EPO to stimulate pluripotent
stem cells to produce more RBCs.
b) Normal physiology of erythrocytes (see Figure 21) (Bell et al.,
2009)
(1) In the bone marrow, the pluripotent stem cell becomes an
erythrocyte via a series of maturation phases that takes about
five days. The five major stages follow.
(a) The earliest identifiable stage is the pronormoblast (rubricyte). These cells take about 12 hours to divide into basophilic normoblast daughter cells.
(b) In approximately 20 hours, the normoblast cells continue maturation marked by accumulation of more RNA and
Hgb. When they divide, they become polychromatophilic normoblasts.
(c) Polychromatophilic normoblasts are smaller than their
precursor cells, and nucleoli are no longer visible. Proliferation is apparent in this phase (about 30 hours) as polychromatophilic normoblasts outnumber cells in earlier
development by 3:1. Under normal circumstances, polychromatophilic normoblasts are absent in adult peripheral blood. Small numbers are normal in the peripheral
blood of newborns.
(d) Orthochromatic normoblasts are derived in about 48 hours
from polychromatophilic normoblasts. In this phase, the
nucleus is unable to synthesize DNA, thereby ending cell
division.
(e) In the polychromatophilic erythrocyte (reticulocyte)
phase, the nucleus is phagocytized after being pushed
out of the cell. The reticulocyte either remains in the
bone marrow for several days to mature or is released
and matures in the spleen for one to two days. At this
point, the erythrocyte holds approximately two-thirds of
its Hgb content.
(2) Without a nucleus, mature erythrocytes cannot synthesize Hgb.
They are able to transport oxygen from the lungs to tissue and,
because of their flexible form, move easily through microcirculation to do so.
(3) Iron is essential for RBC production. Iron reaches the precursor cells bound to transferrin, where it is used for heme synthesis and stored as ferritin in bone marrow reticuloendothelial cells, liver, and spleen. Dietary sources provide and maintain iron stores.
(4) RBC mass and volume: Homeostasis of erythropoiesis is a continuous process driven by oxygen levels and EPO response. The
average number of circulating RBCs in adults ranges from 4.7
6.1/mm3 in men and 4.25.4/mm3 in women but can vary by
up to 10% (Hughes, 2009).
(5) EPO is a hormone primarily (90%) produced by the peritubular cells of the kidneys and to a lesser extent in the liver. The
plasma half-life of EPO is six to nine hours. Levels vary as they
respond to internal (e.g., decreased Hgb level) and external
(e.g., high altitude) signals of low oxygen tension within kidney tissue. During anemia or hypoxemia, EPO is secreted into
the plasma and stimulates activity of erythrocyte precursor cells.
As a result, the reticulocyte count is elevated by an early and
increased number of polychromatophilic cells released from
the bone marrow.
(6) RBC life span: A typical RBC has a life span of approximately
120 days in peripheral circulation (see Table 17). It travels 200
300 miles before being removed in a systematic process by macrophages. The turnover is generally 1% per day. The duration
of RBC life span, time for maturation in the bone marrow, and
low turnover explain why anemia occurs later than neutropenia and thrombocytopenia following myelosuppressive therapy (Camp-Sorrell, 2011).
c) Pathophysiology
(1) Many causes for anemia exist in patients with cancer. Myelosuppressive therapy, bone marrow involvement, inadequate EPO
levels, and RBC destruction all may contribute to the diagnosis
of anemia (Camp-Sorrell, 2011; Miller, 2010).
(2) Classification of anemia based on RBC size: Mean corpuscular
volume, which reflects the size of RBCs, is used in the differential diagnosis of microcytic, normocytic, or macrocytic anemia (see Table 18) (Glassman, 2009; Means & Glader, 2009;
Miller, 2010).
d) Incidence
(1) Many patients (40%70%) experience some degree of anemia during or following systemic chemotherapy (Calabrich
& Katz, 2011). Severity may increase with comorbidities, concurrent radiation therapy, and insufficient nutritional intake. The incidence of anemia in patients with hematologic
malignancies has been reported as three times higher than
in those with solid tumors (Birgegrd, Gascn, & Ludwig,
2006).
(2) Cancer diagnosis, frequency of treatments, regimen, and dosing schedule all may contribute to onset, severity, and duration
of anemia (Glassman, 2009).
e) Risk factors
(1) Medications that suppress bone marrow function, interfere with
erythrocyte development and function, or suppress EPO production (Bottomley, 2009)
(a) Platinum drugs are known to be nephrotoxic (Calabrich
& Katz, 2011).
(b) Biotherapies (e.g., alemtuzumab [Genzyme Corp., 2009a])
181
182
Table 18. Classifications of Common Cancer-Related Anemias

Anemia Type
Description
Differential Diagnosis
Microcytic
Decreased MCV (< 80 fL)

RBCs small in size
Iron deficiency
Anemia of chronic disease
Thalassemia minor
Sideroblastic anemia
Normocytic
Normal MCV (80100 fL)

RBCs normal in size

Hemolytic anemia
Aplastic anemia
Renal failure
Macrocytic
Increased MCV (> 100 fL)

RBCs large in size
B12 deficiency
Folate deficiency
Myelodysplastic syndromes
Low reticulocyte
count
Decreased RBC production

< 0.5%1.5% of erythrocytes

Aplastic anemia
Iron deficiency
Vitamin B12 deficiency
Folate deficiency
Bone marrow suppression or infiltration
High reticulocyte
count
Increased RBC destruction

> 0.5%1.5% of erythrocytes
Hemolysis
Chemotherapy-induced
Autoimmune
fLfemtoliters; MCVmean corpuscular volume; RBCred blood cell

Note. Based on information from Loney & Chernecky, 2000; Lynch, 2006.
From Cancer-Related Anemia: Clinical Review and Management Update, by B. Hurter and N.J. Bush,
2007, Clinical Journal of Oncology Nursing, 11, p. 350. doi:10.1188/07.CJON.349-359. Copyright 2007 by
Oncology Nursing Society. Reprinted with permission.
(c) Antituberculosis agents: Isonicotinylhydrazine (isoniazid),

pyrazinamide, and cycloserine (Bottomley, 2009)
(d) High-dose chemotherapy for HSCT
(2) Malignancies that originate or metastasize to the bone marrow
and suppress RBC precursors
(3) Radiation therapy to areas of the skeleton involved with hematopoiesis (NCCN, 2013c)
(4) Acute or chronic blood loss directly related to tumor invasion
(5) Advanced age: Places patients at risk for anemia of malignancy (Mayden, 2011)
(6) Poor nutrition: Anorexia, nausea, vomiting, stomatitis, early
satiety, and diarrhea may contribute to decreased oral intake
and absorption of nutrients. Lack of calorie, protein, vitamin,
and mineral intake, reflected in weight loss or weakness, compromises cellular functions, including erythrocyte production
(Cunningham & Huhmann, 2011; Miller, 2010).
(7) Comorbidities
(a) Renal insufficiency: Chemotherapy agents known to have
nephrotoxic properties (e.g., cisplatin, carboplatin) place
patients at risk because kidney function is essential for
EPO production. When EPO levels are low, more hypoxia is required to stimulate EPO response (Dessypris &
Sawyer, 2009).
(b) Alcohol abuse and liver dysfunction (Bottomley, 2009)
(c) Cardiopulmonary disease (Means & Glader, 2009; NCCN,
2013c)
(8) Female gender (Spivak, Gascn, & Ludwig, 2009)

f) Clinical manifestations (Means & Glader, 2009)
(1) Cardiopulmonary
(a) Dyspnea, hypoxia
(b) Tachycardia, heart murmurs
(c) Orthostatic hypotension
(2) Integumentary
(a) Pallor of oral mucous membranes, conjunctivae, lips, nail
beds, and palms of hands or soles of feet
(b) Hair loss, thinning, and early graying
(c) Brittle fingernails and toenails
(d) Cyanosis
(e) Hypothermia
(3) Neuromuscular
(a) Headache, dizziness
(b) Drowsiness, restlessness, inability to concentrate
(c) Paresthesias
(d) Fatigue, weakness
(4) Decreased urine output
g) Adverse outcomes (Calabrich & Katz, 2011; Spivak et al., 2009)
(1) Because low tissue oxygenation is related to reduced sensitivity of tumors to radiation therapy and some chemotherapy, hypoxia may adversely affect treatment outcomes.
(2) Low oxygen levels are directly associated with fatigue and weakness and may adversely affect QOL.
(3) Hypoxic tissue promotes angiogenic factors that may contribute to tumor growth.
(4) Postoperative mortality is increased in the presence of anemia.
(5) Survival times of anemic patients are shorter compared to those
without anemia for most tumor types.
h) Management (Mitchell, 2010a)
(1) Fatigue is an early and frequent symptom of anemia with significant negative impact on QOL. Interventions should be aimed
at identifying and managing fatigue.
(a) Encourage frequent rest periods to conserve energy.
(b) Use exercise when benefits outweigh risks.
(c) Explore complementary therapies (e.g., relaxation, massage, healing touch [Mitchell, Beck, Hood, Moore, & Tanner, 2009]) with potential to minimize fatigue.
(d) Assess nutritional intake for adequate content and quantity.
(e) Teach patients and significant others the importance of
hydration.
(2) Monitor laboratory results related to anemia (see Table 19)
and take appropriate action when abnormal (e.g., B12 and iron
deficiencies).
(3) Interventions for hypoxia
(a) Provide supplemental oxygen.
(b) Teach energy conservation.
(c) Consider measures to increase Hgb (Lemoine & Gobel,
2011).
i. Blood transfusions
ii. Erythropoiesis-stimulating agents (ESAs) (see Table 20)
iii. The manufacturers black box warning is supported
by eight randomized studies that each demonstrated decreased overall survival and locoregional conCopyright 2014 by the Oncology Nursing Society. All rights reserved.
183
184
Table 19. Laboratory Assessment of Anemia: Normal Values (Adults)

Laboratory Test
Normal Value
Red blood cell count
Male: 4.76 million cells/mcl; female: 4.25.4 million cells/mcl
Hemoglobin
Male: 13.518 g/dl; female: 1216 g/dl
Hematocrit
Male: 42%52%; female: 37%47%
Mean corpuscular volume
78100 fL
Mean corpuscular hemoglobin
2731 pg/cell
Red cell distribution width
11.5%14%
Reticulocyte count
0.5%1.85% of erythrocytes
Ferritin
Male: 20300 ng/ml; female: 15120 ng/ml
Serum iron
Male: 75175 mcg/dl; female: 65165 mcg/dl
Total iron-binding capacity
250450 mcg/dl
Serum erythropoietin level
Male: 17.2 mU/ml; female: 18.8 mU/ml
Coombs test (direct and

indirect)
Negative
Serum B12
190900 pg/ml
Serum folate
> 3.5 mcg/L
Note. Based on information from Cullis, 2011; Knovich et al., 2009; Van Vranken, 2010.
From Anemia of Chronic Disease, by B. Faiman in D. Camp-Sorrell and R.A. Hawkins (Eds.), Clinical Manual for the Oncology Advanced Practice Nurse (3rd ed.), in press, Pittsburgh, PA: Oncology Nursing Society.
Copyright 2014 by the Oncology Nursing Society. Reprinted with permission.
trol when ESAs were used in patients diagnosed with

advanced breast, cervical, head and neck, lymphoid,
and non-small cell lung cancer. The FDA implemented a risk management program (known as a risk evaluation and mitigation strategy, or REMS), requiring prescribers of ESAs to enroll patients in the ESA
APPRISE (Assisting Providers and Cancer Patients
with Risk Information for the Safe Use of ESAs) Oncology Program. This program has prescriber and
patient requirements aimed at ensuring safe use of
these agents (Amgen Inc., 2012a; NCCN, 2013c).
5. Thrombocytopenia
a) Normal physiology of platelets (see Figure 21) (Bell et al., 2009)
(1) The thrombocyte (platelet) precursor megakaryocyte is the largest hematopoietic cell descending from the pluripotent stem
cell. The goal of thrombopoiesis is to produce and release mature platelets so that a normal level (150,000400,000/mcl) is
circulating at any given time.
(2) The major steps in thrombopoiesis
(a) Maturation begins with megakaryoblasts that increase in
amounts of cytoplasm and nuclear components as they become promegakaryocytes.
(b) During the promegakaryocyte phase, the nucleus continues to enlarge and becomes lobulated in preparation for
the megakaryocyte phase.
Table 20. Growth Factors

Classification
Colonystimulating
factor
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Darbepoetin
(Aranesp)
SC, IV

chronic renal failure whether or not the
patient is receiving dialysis
Treatment of anemia in patients where
anemia is caused by concomitantly administered chemotherapy and, upon initiation, there is a minimum of two additional months of planned chemotherapy
Shortness of breath, cough,

low blood pressure during
dialysis, abdominal pain,
edema of arms and legs,
hypertension, skin rash,
urticaria, pure red cell
aplasia, myalgia, infection,
fatigue edema, diarrhea,
thrombotic events
Increased risk of death and serious

cardiovascular events exists if administered when hemoglobin is >
12 g/dl.
Agent may be administered every 1,
2, or 3 weeks, but dosing schedule
should be consistent.
Use lowest effective dose.
Do not freeze.
(Amgen Inc., 2012a)
Stimulates erythropoiesis via the

same mechanism as endogenous erythropoietin
Epoetin alfa
(Procrit,
Epogen)
SC
Treatment of anemia associated with renal

failure whether or not the patient is receiving dialysis
Treatment of anemia associated with treatment using zidovudine in HIV-infected
patients
Treatment of anemia in patients with nonmyeloid malignancies where anemia is
caused by concomitant use of chemotherapy for minimum of two months
Treatment of anemia in patients scheduled
to undergo elective noncardiac, nonvascular surgery to reduce the need for allogeneic red blood cell transfusions
Contraindicated when goal of chemotherapy is curative
Hypertension, skin rash, urticaria, pure red cell aplasia, myalgia, infection, fatigue, edema, diarrhea,
thrombotic events
Increased risk of death and serious

cardiovascular events exists if administered when hemoglobin is >
12 g/dl.
Agent may be given three times
weekly or once weekly.
Use lowest effective dose.
Do not freeze.
(Amgen Inc., 2012b; Janssen Products, LP, 2012)
185
Stimulates erythropoiesis via the

same mechanism as endogenous erythropoietin
186
Table 20. Growth Factors (Continued)
Colonystimulating
factor (cont.)
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Regulates the
production of
neutrophils within the bone marrow
Filgrastim
(G-CSF,
Neupogen)
SC, IV
To decrease the incidence of infection in

patients with nonmyeloid malignancies
who are receiving myelosuppressive
cancer therapies associated with severe
neutropenic fever
To reduce the time to neutrophil recovery
and duration of fever following induction
or consolidation chemotherapy in patients with AML
To reduce the duration of neutropenia and
associated sequelae in patients receiving myeloablative chemotherapy prior to
marrow transplant
To mobilize hematopoietic progenitor cells
into peripheral blood for collection via
leukapheresis
For chronic administration to reduce the
incidence and duration of sequelae of
neutropenia in patients with congenital,
cyclic, or idiopathic neutropenia
Allergic reactions including

urticaria, rash, and facial
edema; acute respiratory distress syndrome, nausea, vomiting, bone pain
secondary to rapid growth
of myeloid cells in the
bone marrow, fever, severe sickle-cell crisis in patients with sickle-cell disorder; risk of rare splenic rupture
Do not freeze.
Agent may be diluted with 5% dextrose in water.
Do not dilute with saline solutions.
Do not shake.
Filgrastim is not to be administered in
the 24 hours prior to chemotherapy
through 24 hours after chemotherapy completion. SC dosing continues
daily up to 14 days, until postnadir
ANC > 10,000/mm3 is achieved.
(Amgen Inc., 2013a)
Regulates the
production of
neutrophils within the bone marrow
Pegfilgrastim
(Neulasta)
SC
To decrease the incidence of infection related to neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy
Allergic reactions including urticaria, rash, and facial edema; acute respiratory distress syndrome,
nausea, vomiting, bone
pain secondary to rapid growth of myeloid cells
in the bone marrow, fever,
sickle-cell crisis in patients
with sickle-cell disorder; injection-site reaction; risk of
rare splenic rupture
Pegfilgrastim is cleared by neutrophil

receptor binding with serum clearance directly related to number of
neutrophils. Do not administer in
the period beginning 14 days before
until 24 hours after administration of
cytotoxic chemotherapy.
Administer as a single 6 mg injection
once per chemotherapy cycle.
The 6 mg fixed dose should not be
administered to children or adolescents weighing < 45 kg.
Do not freeze.
Do not shake.
(Amgen Inc., 2012c)
Classification
Table 20. Growth Factors (Continued)

Classification
Mechanism
of Action
Drug
Route of
Administration
Indications
Side Effects
Induces committed progenitor cells to divide

and differentiate in the granulocyte-macrophage pathways
including neutrophils, monocytes/macrophages, and myeloid-derived
dendritic cells
Sargramostim (GMCSF, Leukine)
SC, IV
Following induction chemotherapy in patients with AML to shorten neutrophil recovery and reduce incidence of infection
In patients for the mobilization of hematopoietic progenitor cells for collection via
leukapheresis and to speed engraftment
following autologous transplantation of
progenitor cells
To accelerate myeloid recovery following
allogeneic BMT
In patients with failure of engraftment following BMT
Edema, capillary leak syndrome, pleural or pericardial effusions, dyspnea, fever, abdominal pain, headache, chills, diarrhea, occasional transient supraventricular arrhythmia,
bone pain secondary to
rapid growth of myeloid
cells in the bone marrow
Dilute in NS solution for IV use.

Do not freeze.
Do not shake.
Do not administer through in-line filter.
Monitor CBC for elevated WBC and
platelet count.
Safety and effectiveness have not
been established for pediatric patients.
(Genzyme Corp., 2009b)
Leukocyte
growth factor
(short acting)
Binds to G-CSF
receptors and
stimulates proliferation of neutrophils
Tbo-filgrastim
SC
To reduce duration of severe neutropenia

in patients with nonmyeloid malignancies
receiving myelosuppressive anticancer
drugs associated with a clinically significant incidence of febrile neutropenia
Bone pain; allergic reactions including angioneurotic edema, dermatitis,

drug hypersensitivity, hypersensitivity, rash, pruritic rash, and urticaria; sickle-cell crisis; acute respiratory distress syndrome;
splenic rupture
Safety and effectiveness has not

been established in patients younger than age 18.
Administer first dose no sooner than
24 hours following chemotherapy
or within 24 hours prior to chemotherapy.
(Teva Pharmaceuticals USA, 2012d)
Thrombopoietic growth
factor
Stimulation of
megakaryocytopoiesis and
thrombopoiesis
Oprelvekin
(IL-11, Neumega)
SC
To prevent severe thrombocytopenia and

reduce the need for platelet transfusions
in patients with nonmyeloid malignancies
receiving chemotherapy with high risk of
severe thrombocytopenia
Anaphylaxis; dilutional anemia; diarrhea; dizziness;

fever; fluid retention resulting in peripheral edema,
pulmonary edema, dyspnea, capillary leak syndrome, atrial arrhythmias,
and exacerbation of preexisting pulmonary effusions; headache; nausea,
vomiting; insomnia; rhinitis; cough; injection-site reactions
Do not freeze.
Reconstitute with sterile water.
Should be used within 3 hours of reconstitution.
Do not shake or freeze following reconstitution.
Protect from light.
Dosing should begin 624 hours after completion of chemotherapy.
Discontinue when postchemotherapy platelet nadir > 50,000/mcl and
2 days before next chemotherapy cycle.
187
AMLacute myeloid leukemia; ANCabsolute neutrophil count; BMTbone marrow transplantation; CBCcomplete blood count; G-CSFgranulocytecolony-stimulating factor; GM-CSFgranulocyte macrophage
colony-stimulating factor; HIVhuman immunodeficiency virus; ILinterleukin; IVintravenous; mclmicroliter; NSnormal saline; SCsubcutaneous; WBCwhite blood cell
Colonystimulating
factor (cont.)
188
(c) When the cell reaches the megakaryocyte phase, invagination of the cytoplasm occurs to begin delineation of individual platelets.
(d) When the megakaryocyte completes maturation, its membrane ruptures and all of the cytoplasm separates into
platelets. One megakaryocyte is able to release thousands
of platelets.
(e) Platelets are released into circulation as the cytoplasm
extends through a basement membrane of the bone
marrow. Continued separation of the platelet-forming cytoplasm may occur after the cells reach the sinus.
The life span of circulating platelets is seven to eight
days (see Table 17). There is no reserve in the bone
marrow.
(3) When blood vessel wall integrity is damaged, platelets are
incorporated into the vessel wall and assist the endothelial cells in regaining vessel integrity by releasing platelet-derived growth factor (Harmening, Escobar, & McGlasson,
2009).
(4) Platelet plug formation involves adhesion and aggregation of
platelets in response to vascular damage. Platelets are able to
fulfill this vital role in hemostasis only when normal in number and function.
(5) Aggregation is a platelet-to-platelet interaction usually occurring 1020 seconds after loss of vascular integrity and platelet
adhesion.
(6) Secondary hemostasis is accomplished by fibrin clot formation.
If this process is flawed, decreased fibrin production and instability of the formed clot result.
b) Pathophysiology (Camp-Sorrell, 2011)
(1) Thrombocytopenia after chemotherapy is evident in approximately 814 days and is directly related to bone marrow suppression.
(2) Severity varies with drug, dose, and schedule.
(3) For some agents (e.g., gemcitabine, carboplatin, dacarbazine,
5-FU, lomustine, mitomycin C, thiotepa, trimetrexate), it is a
dose-limiting toxicity.
c) Risks and incidence: The following are known to cause thrombocytopenia (Kobos & Bussel, 2008).
(1) Myelosuppressive chemotherapy (e.g., carboplatin, gemcitabine)
or radiation therapy to marrow-producing skeletal sites
(2) Biotherapy (e.g., IFN)
(3) Comorbidities (e.g., liver disease)
(4) Destruction of platelets in the presence of autoimmune disease
(e.g., immune thrombocytopenic purpura) or disseminated intravascular coagulation (DIC)
(5) Bone marrow infiltration of primary or metastatic malignancies
(6) Drug therapy affecting platelet function (Rodriguez & Gobel,
2011)
(a) Aspirin
(b) Nonsteroidal anti-inflammatory drugs (NSAIDs)
(c) Quinine and quinidine
(d) Thiazide diuretics (e.g., furosemide)
(e) Benzene and benzene derivatives
(f) Tricyclic antidepressants
(g) Antibiotics
i. High-dose beta-lactam antibiotics (e.g., piperacillin,

ampicillin)
ii. Cephalosporins and moxalactam
(h) Heparin
(7) Herbal agents (e.g., ginkgo, garlic, ginger, turmeric)
d) Clinical manifestations (Camp-Sorrell, 2011; Rodriguez & Gobel, 2011)
(1) Cardiopulmonary
(a) Adverse changes in peripheral pulses, tachycardia, hypotension, orthopnea
(b) Dyspnea, tachypnea, adventitious breath sounds, hemoptysis
(2) Head and neck
(a) Petechiae of oral or nasal membranes
(b) Epistaxis
(c) Periorbital edema, subconjunctival hemorrhage, eye pain,
blurred or double vision
(3) Integumentary system
(a) Petechia, bruising, pallor, or acrocyanosis anywhere on skin
or mucous membranes
(b) Bleeding from surgical, device, or wound sites
(4) Neurologic
(a) Change in mental status, confusion, restlessness, lethargy
(b) Widening pulse pressure, abnormal change in pupil
size, diminished reflexes, loss of motor strength or coordination
(c) Headache or seizures
(5) Gastrointestinal
(a) Abdominal pain or distention
(b) Rectal bleeding, tarry stools, hematemesis
(c) Enlarged, palpable spleen
(6) Genitourinary
(a) Menorrhagia
(b) Hematuria, dysuria, low urine output
e) Management
(1) Monitor laboratory findings and take appropriate action.
(a) Obtain platelet count, prothrombin time, partial thromboplastin time, Hgb, Hct, D-dimer, fibrinogen, and fibrin.
(b) Test stool, urine, and emesis for occult blood.
(2) Maintain safe environment.
(a) Instruct patients to avoid activities that may cause injury.
(b) Assess the home environment and promote the use of nonskid rugs, nightlights, and ambulatory assistive devices to
prevent falls.
(3) Educate patients and families on ways to maintain skin integrity by (Camp-Sorrell, 2011; Rodriguez & Gobel, 2011)
(a) Using soft toothbrush
(b) Blowing nose gently
(c) Using electric razor versus straight blade razor
(d) Using emery board versus metal nail files
(e) Using water-soluble lubricants for sexual intercourse
(f) Avoiding any sexual activity that may compromise skin or
mucous membrane integrity
(g) Avoiding use of tampons
(h) Using laxatives or stool softeners to avoid constipation
(i) Refraining from using mechanical oral irrigation or aggressive dental flossing
(j) Avoiding dental and other invasive procedures.
(4) Medications and treatments (Rodriguez & Gobel, 2011)
189
190
(a) Administer platelet transfusions.

(b) Consider administering IL-11 (oprelvekin) (see Table
20).
B. GI and mucosal side effects
1. Nausea and vomiting: Nausea and vomiting (n/v) are two of the
most feared side effects of cancer treatment (NCI, 2011a). Healthcare providers underestimate the incidence of nausea (Grunberg,
2012). Emesis is better controlled than nausea (Basch et al., 2011).
Oncology nurses must be knowledgeable and proactive when treating
CINV.
a) Definitions
(1) Nausea is an unpleasant subjective experience that is described as a wavelike feeling occurring in the stomach and/
or back of the throat that may be accompanied by vomiting
(NCI, n.d.).
(2) The autonomic nervous system is involved in the development
of n/v. Physical manifestations include tachycardia, diaphoresis,
light-headedness, dizziness, pallor, excess salivation, and weakness (Camp-Sorrell, 2011).
(3) Retching is a rhythmic contraction involving the esophagus, diaphragm, and abdominal muscles in an attempt to eject stomach contents. Retching in the absence of vomiting is known as
dry heaves (Camp-Sorrell, 2011).
(4) Vomiting is the forceful expulsion of gastric, duodenum, or jejunum contents through the mouth (NCI, n.d.).
b) Pathophysiology
(1) Mechanisms of emesis (see Figure 23): Nausea, retching, and
vomiting are independent phenomena that can occur sequentially or as separate entities. The subjective nature of nausea
prevents a clear understanding of it; however, mechanisms of
vomiting related to chemotherapy administration are becoming better understood.
(a) Vomiting results from the stimulation of a complex process
that involves the activation of various pathways and neurotransmitter receptors (see Figures 23 and 24).
(b) Vomiting occurs when certain neural structures in the
brain stem, collectively called the vomiting center (VC),
are stimulated. The VC is activated by the visceral and
vagal afferent pathways from the GI tract, the chemoreceptor trigger zone (CTZ), the vestibular apparatus,
and the cerebral cortex. Decreased motility and reverse
motility occur when the VC is stimulated (Camp-Sorrell,
2011).
(c) Chemotherapy stimulates enterochromaffin cells, causing them to release serotonin (5-hydroxytryptamine-3
[5-HT3]). The vagus nerve plays a key role in emesis caused
by chemotherapy, radiation therapy to the epigastrium,
and abdominal distention or obstruction. Serotonin release causes the activation of the vagus nerve, which stimulates vomiting through either the CTZ or the VC (CampSorrell, 2011). Serotonin is primarily involved in acute n/v
(Rojas & Slusher, 2012).
(d) The CTZ, a highly vascular area, lies at the surface of
the fourth ventricle, close to the VC. The CTZ is not
confined within the blood-brain barrier. Therefore, it
can detect chemical stimuli in the cerebrospinal fluid
191
Figure 23. Mechanics of Emesis
Sensory input (pain, smell, sight)
Higher cortical
centers
Histamine antagonists
Muscarinic antagonists
Dopamine antagonists
Cannabinoids
Neurokinin-1 receptor antagonists
Chemotherapy
Anesthetics
Opioids
Sphincter
modulators
Chemotherapy
Chemoreceptor
trigger zone
(area postrema, 4th
ventricle)
Benzodiazepines
Vomiting center
(medulla)
Neurokinin-1 receptor
antagonists
5-HT3-antagonists
Stomach
Small intestine
Surgery
Memory, fear, anticipation
Labyrinths
Surgery
Radiotherapy
Gastroprokinetic
agents
Neuronal pathways
Sites of action of drugs
Factors that can cause
nausea and vomiting
and the blood. The CTZ plays a role in CINV as well as

in emesis associated with other causes such as anesthetics and opioids.
(e) Substance P is found in vagal afferent neurons and binds
to neurokinin-1 (NK1) receptors, causing vomiting. Stimulation of the NK1 receptor by substance P is believed to be
the main trigger for delayed n/v, which led to the discovery of aprepitant, an NK1 receptor antagonist.
(f) Motion sickness and labyrinthitis are the most common
stimuli to the vestibular apparatus of the inner ear that induce n/v. The vestibular apparatus may play a minor role
in CINV. Surgery can induce vomiting through stimulation
of the vestibular system.
(g) Memory, fear, anticipation, pain, and an unpleasant smell
can trigger n/v at the cerebral cortex.
(h) Factors that can cause n/v include chemotherapy, biotherapy, targeted therapy, radiation therapy, surgery, opioids,
and other medications.
(i) Other potential causes of n/v (Rangwala, Zafar, & Abernethy, 2012)
i. Psychophysiologic (e.g., anxiety, anticipatory n/v)
ii. Bowel obstruction (partial or complete)
iii. Vestibular disturbance
iv. Brain metastasis
v. Hypercalcemia, hyperglycemia, or hyponatremia
192
Figure 24. Neuroreceptors
Corticosteroid
Dopamine-2
Histamine
Neurokinin-1
Chemoreceptor Trigger Zone,

Vomiting and Vestibular Centers,
and GI Tract
Serotonin
(5-HT3)
Muscarinic
Cannabinoid
Opioid
Acetylcholine
Note. Based on information from National Comprehensive Cancer Network, 2013b.
vi. Uremia
vii. Gastroparesis
(2) Patterns of therapy-related emesis (NCCN, 2013b)
(a) Anticipatory n/v: A conditioned response that occurs most
commonly before treatment and can be triggered by a particular smell, taste, or sight
i. Anticipatory n/v can occur during treatment and
may last one to two days after therapy. This usually
is a result of a previous unpleasant experience with
uncontrolled n/v, and it may be worse in patients
with high levels of anxiety. Anticipatory nausea usually occurs after two or three cycles of chemotherapy. To minimize the risk of this side effect, adequate
antiemetic control with initial treatments is essential. Infants and young children usually do not experience anticipatory n/v.
ii. Incidence: Anticipatory n/v occurs in 18%57% of patients as a result of classical conditioning from stimuli associated with chemotherapy (e.g., odors, tastes
of drugs, visual cues). Nausea is more common than
vomiting (NCCN, 2013b).
iii. Risk factors that may increase susceptibility to anticipatory n/v (NCI, 2011a)
Having a history of poorly controlled CINV with

previous encounters
Being young or middle-aged (e.g., patients younger than age 50)
Being of female gender
Having high levels of anxiety prior to and during
treatment
Feeling warm, hot, dizzy, or sweaty after chemotherapy
Having a susceptibility to motion sickness
Having a history of pregnancy-induced n/v
Feeling generalized weakness after chemotherapy
(b) Acute n/v: Starts within minutes to hours after chemotherapy administration and may last up to 24 hours depending
upon the agent (NCCN, 2013b)
i. The type, dose, route, and administration schedule of
chemotherapy influence the severity and risk of acute
n/v (Roila et al., 2010).
ii. Combination chemotherapy may cause more n/v than
single-agent therapy. Antiemetics for combination
chemotherapy should be administered based on the
agent with the highest emetogenic potential (Basch
et al., 2011).
iii. Incidence is determined by the emetogenicity of
the chemotherapy agents (see Tables 21 and 22)
and whether pretreatment with an antiemetic agent
occurred (Basch et al., 2011; Camp-Sorrell, 2011;
NCCN, 2013b).
iv. Current treatment guidelines published by NCCN
and ASCO are based on four categories of emetogenic potential for IV antineoplastics: high, > 90%; moderate, 30%90%; low, 10%30%; and minimal, < 10%
(Grunberg et al., 2011; NCCN, 2013b).
v. Risk factors that increase susceptibility to acute n/v
(NCI, 2011a; NCCN, 2013b)
Type and dose of antitumor treatment used (see Tables 21 and 22)
Gender: Women experience more acute n/v
than men.
Age: Patients older than age 50 experience less
n/v than patients younger than 50.
Alcohol use: Patients with a history of chronic
or high alcohol intake generally have less severe
nausea than those without such a history (intake
less than four drinks per week) (Irwin, Lee, Rodgers, Starr, & Webber, 2012).
Advanced-stage disease
Fatigue
Pain
Tumor burden
Concomitant medical conditions (e.g., obstruction, pancreatitis, hepatic metastases)
Presence of strong taste disturbances during chemotherapy
High level of pretreatment anxiety
Susceptibility to GI distress
Poor performance status
193
194
Table 21. Emetogenic Potential of Intravenous Antineoplastic Drugs

Incidence
High (90%100%)
Agent
Onset (hours)
Duration (hours)
Cisplatin (> 50 mg/m2)
16
2448+
Dacarbazine
13
112
Mechlorethamine
0.52
824
Melphalan: high dose
0.36
612
16
1224
14
1248
Cyclophosphamide (> 1,500 mg/m )
AC combination (doxorubicin or epirubicin + cyclophosphamide)
24
424
412
1224
Clofarabine
Arsenic trioxide
Aldesleukin (> 1215 MIU/m2)
Azacitidine
2427
Variable
46
24+
Carboplatin
Busulfan
Bendamustine
Lomustine
46
1224
Dactinomycin
25
24
Daunorubicin
Plicamycin
16
1224
Actinomycin D
112
2448
Cytarabine (> 200 mg/m2)
112
2448
Doxorubicin ( 60 mg/m2)
46
6+
612
24+
Ifosfamide (< 10 g/m2)
Interferon alfa ( 10 MIU/m2)
Irinotecan
112
2472
Ifosfamide ( 10 g/m )
2
Epirubicin (> 90 mg/m )

2
Doxorubicin (> 60 mg/m )

2
Streptozocin
Cytarabine: high dose (> 1 g/m )
2
Carmustine (> 250 mg/m )

2
Moderate (30%90%)
Carmustine ( 250 mg/m2)

Cisplatin (< 50 mg/m2)
Cyclophosphamide (< 1,500 mg/m2)
Procarbazine
Etoposide: high dose
Epirubicin ( 90 mg/m2)
Idarubicin
Melphalan
Methotrexate ( 250 mg/m )
2
195
Table 21. Emetogenic Potential of Intravenous Antineoplastic Drugs (Continued)

Incidence
Moderate (cont.)
Agent
Temozolomide
Oxaliplatin
Low (10%30%)
Duration (hours)
16
24
Aldesleukin ( 12 MIU/m2)
Cabazitaxel
Cytarabine (100200 mg/m2)
46
6+
Docetaxel
Doxorubicin (liposomal)
Eribulin
5-Fluorouracil
36
24+
Mitomycin C
14
4872
Etoposide
Gemcitabine
Interferon alfa (> 510 MIU/m2)
Topotecan
612
2472
Ixabepilone
Methotrexate (> 50 mg/m2 but < 250 mg/m2)
Paclitaxel, albumin bound
Pemetrexed
Pentostatin
Pralatrexate
Romidepsin
Thiotepa
Paclitaxel
Bleomycin
36
2-Chlorodeoxyadenosine
Alemtuzumab
Asparaginase
Bevacizumab
Bortezomib
Cetuximab
Cytarabine (< 100 mg/m )
612
312
Decitabine (< 100 mg/m )
Mitoxantrone
Minimal (< 10%)
Onset (hours)
Cladribine
2
Denileukin diftitox
Interferon alfa ( 5 MIU/m )
Ipilimumab
48
6-Mercaptopurine
196
Table 21. Emetogenic Potential of Intravenous Antineoplastic Drugs (Continued)

Incidence
Minimal (cont.)
Agent
Onset (hours)
Duration (hours)
412
312
Nelarabine
Ofatumumab
Pegasparaginase
Peginterferon
48
Hydroxyurea
Teniposide
Vincristine
Vinorelbine
Fludarabine
Rituximab
Trastuzumab
Temsirolimus
Valrubicin
Methotrexate (< 50 mg/m2)
Vinblastine
ACanthracycline + cyclophosphamide; MIUmillion international units

Note. Based on information from Basch et al., 2011; Grunberg et al., 2011; National Comprehensive Cancer Network, 2013b.
From Chemotherapy Toxicities and Management (p. 473), by D. Camp-Sorrell in C.H. Yarbro, D. Wujcik, and B.H. Gobel (Eds.), Cancer Nursing: Principles
and Practice (7th ed.), 2011, Burlington, MA: Jones and Bartlett. Copyright 2011 by Jones and Bartlett. Adapted with permission.
History of hyperemesis during pregnancy or morning sickness throughout pregnancy

(c) Delayed n/v: Occurs at least 24 hours after chemotherapy
administration (NCCN, 2013b).
i. Chemotherapy metabolites may cause increased delayed n/v because of an ongoing effect on the CNS
and/or GI tract (Camp-Sorrell, 2011).
ii. Occurs commonly with cisplatin, carboplatin, cyclophosphamide, and doxorubicin
iii. Cisplatin is associated with the highest incidence of
delayed n/v and may last for up to 6 days.
iv. Patients who experience acute n/v are more likely to
have delayed n/v (Roila et al., 2010).
c) Risk factors
(1) Cisplatin-containing regimens (60%90% of patients) (Roila
et al., 2010)
(2) High-dose chemotherapy
(3) Cyclophosphamide, ifosfamide, doxorubicin
(4) Poorly controlled n/v with prior chemotherapy cycles
d) Assessment: Determine the potential causes of n/v, the specific type(s),
and the level of emetogenicity (see Tables 21 and 22). Refer to Table 23 for assessment of n/v.
(1) Chemotherapy (NCCN, 2013b)
(a) Evaluate the emetogenic potential of all chemotherapy
agents the patient will be taking and ensure the patient has
prescriptions for antiemetics.
(b) Use of oral antineoplastic therapy is increasing. It is important to consider the emetogenic potential of these
Table 22. Emetogenic Potential of Oral Antineoplastic Drugs

Level
Agent
High
Hexamethylmelamine
Procarbazine
Moderate
Cyclophosphamide
Temozolomide
Vinorelbine
Imatinib
Low
Capecitabine
Tegafur-uracil
Etoposide
Sunitinib
Fludarabine
Everolimus
Lapatinib
Lenalidomide
Thalidomide
Minimal
Chlorambucil
Hydroxyurea
Melphalan
Methotrexate
6-Thioguanine
Gefitinib
Sorafenib
Erlotinib
L-Phenylalanine mustard
Note. From MASCC/ESMO Antiemetic Guideline 2013 (Slide 16), by Multinational Association of Supportive
Care in Cancer, 2013. Retrieved from http://www.mascc.org/antiemetic-guidelines. Copyright 2013 by Multinational Association of Supportive Care in Cancer. All rights reserved worldwide. Reprinted with permission.
drugs and treat as appropriate (NCCN, 2013b) (see Table 22).

(2) Biotherapy (IFN or IL-2)
(a) Patients receiving biologic agents may experience n/v as
part of a flu-like syndrome (see Table 9 in Chapter 4).
(b) Biotherapy involving the infusion of mAbs may be associated with n/v during the infusion.
(3) Targeted therapies: Many targeted drugs, which are primarily
administered orally, have emerged in the past decade. Each one
is unique in terms of mechanism of action and side effects. The
majority of currently FDA-approved targeted drugs are associated with minimal to low n/v risk (Roila et al., 2010).
(4) Physical causes: Tumor obstruction, gastroparesis, constipation,
increased intracranial pressure, brain metastasis, vestibular dysfunction, uncontrolled pain
(5) Metabolic causes: Hypercalcemia, hyponatremia, hyperglycemia, uremia, increased creatinine
(6) Other medications (e.g., opioids, antibiotics)
(7) Psychological causes: Anxiety, fear, emotional distress
e) Potential complications of n/v
(1) Discomfort
(2) Delay of treatment
(3) Interference with QOL (e.g., impaired mobility, fatigue)
(4) Dehydration
(5) Metabolic disturbances
(6) Anorexia and weight loss
197
198
Table 23. National Cancer Institutes Common Terminology Criteria for

Adverse Events: Nausea and Vomiting
Adverse Event
Nausea
Vomiting
Grade
Description
Loss of appetite without alteration in eating habits
Oral intake decreased without significant weight loss, dehydration, or malnutrition
Inadequate oral caloric or fluid intake; tube feeding, parenteral

nutrition, or hospitalization indicated
12 episodes (separated by 5 minutes) in 24 hours
35 episodes (separated by 5 minutes) in 24 hours
6 episodes (separated by 5 minutes) in 24 hours; tube feeding, total parenteral nutrition, or hospitalization indicated
Life-threatening consequences; urgent intervention indicated
Death
Note. From Common Terminology Criteria for Adverse Events [v.4.03], by the National Cancer Institute
Cancer Therapy Evaluation Program, 2010. Retrieved from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03
_2010-06-14_QuickReference_8.5x11.pdf.
(7) Physical debilitation from malnutrition

(8) Straining of abdominal muscles
(9) Increased intracranial pressure
(10) Aspiration
f) Collaborative managementPharmacologic actions: See Table 24.
(1) The goal of antiemetic therapy is complete control of CINV
(NCCN, 2013b).
(a) Choose antiemetics appropriate to the chemotherapeutic regimen.
(b) Consider level of emetogenicity based on route of administration and dose administered. Choose antiemetic regimen based on the drug with the highest emetogenicity
along with patient-specific risk factors (Roila et al., 2010).
(c) Patient response to pharmacologic interventions for n/v
may change over time and requires frequent assessment
and modification as appropriate (Basch et al., 2011).
(d) Administer antiemetics to cover the expected emetogenic
period of the chemotherapy agent, considering the duration and pattern of emesis. Antiemetics should be administered each day of chemotherapy and for two days after
the completion of chemotherapy as appropriate (Basch et
al., 2011).
(e) Note: Steroids may be contraindicated for patients receiving biotherapy agents because of their immunosuppressive
effects. This is agent-specific and should be considered prior to use. The benefit of steroids for minimizing hypersensitivity reactions or treating n/v may outweigh the risks related to immunosuppression. Glucocorticoids are contraindicated with IL-2 and IFN therapy (NCCN, 2013b).
(2) To manage acute n/v (NCCN, 2013b)
(a) For patients receiving IV agents categorized as high risk
(> 90% frequency) of emesis: Use a three-drug combination of a 5-HT3 antagonist, an NK1 antagonist, and a corticosteroid before chemotherapy. Alternatively, an olanzapine-containing regimen may be used consisting of olanzapCopyright 2014 by the Oncology Nursing Society. All rights reserved.
Table 24. Commonly Used Agents for the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting
Classification
Mechanism
of Action
Drug
Route, Dose, and Schedule
Indications
Side Effects
Action in multiple CINV receptor sites
Olanzapine
2.55 mg PO BID
Breakthrough n/v
Dry mouth, weight gain,

dizziness, sedation
Drug is contraindicated in older adult patients with dementia.
Anxiolytic
CNS depressant,
interferes with
afferent nerves
from cerebral
cortex causing
sedation
Alprazolam
0.52 mg PO TID beginning

the night before treatment
Prevention of anticipatory n/v
Sedation, confusion,
hyperactivity, agitation, dizziness, lightheadedness, hallucinations
Decrease starting dose to 0.25 mg PO BID

or TID in older adult patients, patients with
advanced liver disease, or patients with
other pertinent comorbidities.
CNS depressant,
interferes with
afferent nerves
from cerebral
cortex causing
sedation
Lorazepam
0.52 mg PO, sublingual or IV;

every 46 hours
For anticipatory n/v: 0.52 mg
PO beginning the night before to treatment and the
morning of treatment
Prevention of anticipatory n/v

In combination with other
antiemetics as needed
for acute or delayed n/v
Sedation, confusion,
hyperactivity, agitation, dizziness, lightheadedness, hallucinations
Use with caution in older adult patients or

those with hepatic or renal dysfunction.
Give first dose the night before treatment
and the morning of chemotherapy for anticipatory n/v.
Interacts with
cannabinoid receptors
Dronabinol
510 mg PO every 3 or 6
hours.
Treatment of CINV after standard antiemetics

have failed
Sedation, vertigo, euphoria, dysphoria, dry

mouth, tachycardia,
orthostasis
Incidence of paranoid reactions or abnormal thinking increases with maximum

doses.
Use with caution in patients with history of
psychiatric illness.
Nabilone
12 mg PO BID
Maximum recommended dose
is 6 mg given in divided doses TID.
Treatment of CINV after standard antiemetics

have failed
Sedation, vertigo, euphoria, dysphoria, dry

mouth, tachycardia,
orthostasis
Incidence of paranoid reactions or abnormal thinking increases with maximum

doses.
Use with caution in patients with history of
psychiatric illness.
Cannabinoid
Corticosteroid
Antiprostaglandin synthesis activity
Dexamethasone
12 mg IV or PO day 1 of chemotherapy; 8 mg IV or PO
days 24 of chemotherapy
Prevention of n/v caused

by highly and moderately emetogenic chemotherapy
Prevention of delayed n/v
Administer slowly over

at least 10 minutes
to prevent perianal
or vaginal burning or
itching.
Insomnia, anxiety, acne
Adding a corticosteroid increases the efficacy of antiemetic regimens by 15%

25%. Add dexamethasone to 5-HT3 regimens.
Dopamine
antagonist
Blocks dopamine
receptors
Haloperidol
0.52 mg PO or IV every 46
hours

or treatment of breakthrough n/v
Sedation, extrapyramidal symptoms, dystonia, dizziness, orthostasis
Administering haloperidol with diphenhydra

mine 2550 mg PO or IV prevents extrapyramidal symptoms; occurs more commonly in younger patients.
Drug is highly sedating.
199
Antipsychotic
Mechanism
of Action
Dopamine
antagonist
(cont.)
Neurokinin-1
antagonist
Neurokinin-1 receptor antagonist
Drug
Indications
Side Effects
Metoclopramide
1040 mg PO or IV every 46
hours
Prevention of n/v caused

by moderately emetogenic chemotherapy
Incidence of drowsiness is greater with high

doses.
Drug may cause diarrhea.
Prochlorperazine
Doses vary: 10 mg PO or IV
every 46 hours
Also available: 25 mg suppositories every 12 hours

Drug is not used for pediatric patients.

Drug is highly sedating.
Aprepitant
Capsules: 125 mg PO day 1 of

chemotherapy, then 80 mg
PO days 2 and 3
Prevention of acute and

delayed CINV in combination with other antiemetics
Constipation, hiccups,
loss of appetite, diarrhea, fatigue
Drug is given in combination with a corticosteroid and 5-HT3 antagonist on day 1

and a corticosteroid on days 2 and 3.
Consider a 50% dose reduction of oral
methylprednisolone and dexamethasone
and a 25% dose reduction of IV methylprednisolone. (Aprepitant increases the
AUC of steroids 13-fold.)
Use with caution in patients receiving chemotherapy that is primarily metabolized
through CYP3A4.
Efficacy of oral and hormonal contraceptives during administration of aprepitant
may be compromised; use alternative or
backup contraception method.
Coadministration with warfarin may decrease INR; monitor closely.
Consider drug interactions prior to administration.
Fosaprepitant
dimeglumine
150 mg IV day 1 or 115 mg

day 1 followed by aprepitant 80 mg PO daily on days
2 and 3
Prevention of acute and

delayed CINV
Infusion-site reactions
(e.g., pruritus, induration, erythema3%),
hypersensitivity, constipation, hiccups,
loss of appetite, diarrhea, fatigue
Drug is given in combination with a corticosteroid and 5-HT3 antagonist on day 1.

Administer over 2030 minutes in a 150 ml
normal saline minibag (contraindicated
with lactated Ringers solution).
Consider a 50% dose reduction of oral
methylprednisolone and dexamethasone
and a 25% dose reduction of IV methylprednisolone. (Fosaprepitant increases
the AUC of steroids 13-fold.)
Classification
200
Table 24. Commonly Used Agents for the Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting (Continued)
Mechanism
of Action
Drug
Neurokinin-1
antagonist
(cont.)
Neurokinin-1 receptor antagonist

(cont.)
Fosaprepitant
dimeglumine
(cont.)
Serotonin
antagonist
Serotonin receptor antagonist
Dolasetron
100 mg PO or 100 mg IV 30
minutes before chemotherapy
Prevention of acute CINV
Headache, diarrhea,
dizziness, fatigue, abnormal LFTs
Dolasetron precipitates with dexamethasone in D5W.

Dolasetron can be administered as a rapid IV bolus.
Granisetron
2 mg PO or 1 mg PO BID up to
1 hour before chemotherapy;
0.01 mg/kg (max 1 mg) IV 30
minutes before chemotherapy
Prevention of acute CINV
Headache, asthenia, diarrhea, constipation,

fever, somnolence,
QTc prolongation
Granisetron can be administered by rapid IV bolus.

Instruct patients to take oral formulation
with milk or food.
Granisetron
transdermal
(Sancuso)
Transdermal patch containing

34.3 mg of granisetron; one
patch delivers 3.1 mg per 24
hours. Apply a single patch
to the upper outer arm a
minimum of 2448 hours before chemotherapy.
Patch can be worn for up to 7
days (depending upon the
duration of the regimen). Remove patch a minimum of
24 hours after completion of
chemotherapy.
Prevention of n/v in patients receiving moderately and/or highly

emetogenic chemotherapy for up to 5 consecutive days
Constipation; may
mask a progressive
ileus and/or gastric
distention caused by
the underlying condition; headache, skin
rash, QTc prolongation
Drug is contraindicated in patients with

known hypersensitivity to granisetron or
any of the components of the patch.
Remove patch if severe skin reactions occur (allergic, erythematous, macular, or
papular rash or pruritus). Avoid direct exposure of application site to natural and
artificial light while wearing the patch and
for 10 days after removing it.
Ondansetron
1624 mg PO or 812 mg IV
(maximum 32 mg/day); infuse IV dose over 15 minutes; give 30 minutes before
chemotherapy.
Orally disintegrating tablet formulation: 8 mg
Prevention of n/v associated with single-day

highly and moderately
emetogenic chemotherapy in adults
Headache, diarrhea,
fever, constipation,
transient increase in
SGOT, SGPT, hypotension, QTc prolongation
Ondansetron and dexamethasone are compatible.
Classification
Indications
Side Effects
Use with caution in patients receiving chemotherapy that is primarily metabolized
through CYP3A4.
Efficacy of oral and hormonal contraceptives during administration of fosaprepitant may be compromised; use alternative
or backup contraception method.
Coadministration with warfarin may decrease INR; monitor closely.
Consider drug interactions prior to use.

201
Serotonin
antagonist
(cont.)
Mechanism
of Action
Drug
Indications
Side Effects
Palonosetron
0.25 mg fixed IV dose; infuse

over 30 seconds; give 30
minutes prior to chemotherapy on day 1.
0.5 mg PO; give once, 30 minutes prior to chemotherapy
on day 1.
Prevention of acute n/v

associated with initial
and repeated courses
of moderately and highly emetogenic chemotherapy and the prevention of delayed n/v associated with initial and repeat courses of moderately emetogenic chemotherapy
Headache, constipation
Mean terminal elimination half-life is approximately 40 hours.

Palonosetron is the first 5-HT3 receptor antangonist approved for delayed n/v.
Repeat dosing within a 7-day interval is not
recommended until further evaluated.
Drug is not currently used for pediatric patients.
AUCarea under the time-versus-concentration curve; BIDtwice daily; CINVchemotherapy-induced nausea and vomiting; CNScentral nervous system; D5W5% dextrose in water; 5-HT35-hydroxytryptamine-3; INRinternational normalized ratio; IVintravenous; LFTliver function test; n/vnausea and vomiting; POby mouth; QTcQT interval corrected; SGOTserum glutamic-oxaloacetic transaminase;
SGPTserum glutamic-pyruvic transaminase; TIDthree times daily
Note. Based on information from Camp-Sorrell, 2011; Irwin et al., 2012; Merck & Co., Inc., 2009; National Comprehensive Cancer Network, 2013b.
Classification
202
ine, palonosetron, and a corticosteroid. Lorazepam may be

used in combination with the aforementioned antiemetics
to improve control in high-risk regimens. Consider adding
an H2 blocker or proton pump inhibitor.
i. Administration of a corticosteroid with a 5-HT3 antagonist has been found to improve the control of
n/v when compared to a 5-HT3 antagonist alone and
is recommended for acute nausea in highly emetogenic regimens by NCCN (2013b), ASCO (Basch et
al., 2011), and the Multinational Association of Supportive Care in Cancer (MASCC) (Roila et al., 2010).
ii. If the antitumor regimen contains steroids (e.g., CHOP),
additional steroids are not needed (NCCN, 2013b).
iii. There is no difference in efficacy between IV and PO
5-HT3 antagonists (Basch et al., 2011).
iv. Anthracycline and cyclophosphamide regimens are
classified as highly emetogenic and should be treated
as such (Basch et al., 2011; NCCN, 2013b).
v. Oral aprepitant (days 13) and IV fosaprepitant (day
1 only) have equal efficacy (Basch et al., 2011).
vi. For patients receiving high-dose chemotherapy with
HSCT, a 5-HT3 antagonist combined with a corticosteroid is recommended (Basch et al., 2011).
(b) For patients receiving IV agents classified as moderate risk:
Use a two-drug combination of a 5-HT3 antagonist and a
corticosteroid. An NK1 antagonist and lorazepam may be
considered for select patients. Consider adding an H2 blocker or proton pump inhibitor.
i. NCCN (2013b) guidelines recommend palonosetron as
the preferred 5-HT3 antagonist. If it is not available, another 5-HT3 is acceptable. Alternatively, an olanzapinecontaining regimen may be used consisting of olanzapine, palonosetron, and a corticosteroid.
ii. Consider adding an NK1 antagonist for patients in
whom corticosteroids are contraindicated (Basch et
al., 2011).
(c) For patients receiving IV agents classified as low risk: Use
an agent such as a corticosteroid daily, metoclopramide,
prochlorperazine, or an oral 5-HT3 antagonist. Lorazepam
may be added. An H2 blocker or proton pump inhibitor
may be considered (NCCN, 2013b).
(d) For patients receiving IVs agents classified as minimal risk:
No routine prophylaxis is necessary. Ongoing assessment
for the occurrence of n/v should be performed. If n/v occurs, treat per low-risk guidelines (NCCN, 2013b).
(e) For patients receiving oral agents with high to moderate
risk: Use an oral 5-HT3 antagonist daily. Consider lorazepam oral or sublingual PRN and an H2 blocker or proton
pump inhibitor (NCCN, 2013b).
(f) For patients receiving oral agents with low to minimal risk:
Administer PRN antiemetics (e.g., metoclopramide, prochlorperazine, haloperidol), and if n/v occurs, add a 5-HT3
antagonist. Consider lorazepam and an H2 blocker or proton pump inhibitor if appropriate (NCCN, 2013b).
(g) For patients undergoing multiple consecutive days of chemotherapy: Each day, use antiemetics appropriate to the risk
category of the chemotherapy to be administered that day.
203
204
(3) To manage delayed n/v (NCCN, 2013b)

(a) Delayed n/v is a significant problem for patients with cancer who are receiving chemotherapy; prevention is the primary goal. NK1 antagonists and longer-acting 5-HT3 antagonists can help improve management of n/v in this setting.
(b) For patients at risk for delayed n/v (e.g., patients receiving
cisplatin) (NCCN, 2013b)
i. Use an NK1 antagonist in combination with a corticosteroid beginning on day 1 for delayed n/v.
ii. Use a single agent such as a corticosteroid, a 5-HT3
antagonist, or a dopamine antagonist.
iii. Consider adding lorazepam and an H2 blocker or proton pump inhibitor.
iv. Use a combination of the previously listed antiemetics
based on patient-specific needs (see Table 24).
v. Note: Metoclopramide is rarely used for pediatric patients.
(4) To manage anticipatory n/v: Use the most active antiemetic regimen appropriate to the chemotherapy being given. Such regimens must be used with the initial chemotherapy rather than
after assessment of the patients emetic response to less-effective treatment.
(a) Benzodiazepines (lorazepam or alprazolam) are the primary drugs used for the treatment of anticipatory n/v. Administer beginning the night before treatment (see Table
24) (NCCN, 2013b).
(b) Consider the addition of nonpharmacologic interventions
(e.g., relaxation, music therapy, hypnosis), which can be
helpful in this type of nausea [see g later in this section])
(NCCN, 2013b).
(5) For patients experiencing breakthrough n/v despite optimal
prophylaxis in current or prior cycles, ascertain that the best
regimen is being given based on the emetogenic potential of
the regimen (NCCN, 2013b).
(a) Conduct a careful evaluation of risk, antiemetic agents, disease, concurrent conditions, and medication factors.
(b) Consider adding an antianxiety agent to the regimen.
(c) Consider adding other antiemetic agents from different
drug classifications, using caution to avoid overlapping side
effects (see Table 24).
(d) Multiple agents used in combination may be required to
control n/v.
(e) Around-the-clock scheduling is suggested (NCCN, 2013b).
(f) Consider adding nonpharmacologic interventions in conjunction with antiemetics per patient preference.
g) Collaborative management: Nonpharmacologic interventions should
be used in conjunction with antiemetics.
(1) Music therapy is the controlled use of music to influence physiologic, psychological, and emotional responses. Music therapy may be beneficial to some patients at risk for CINV (Irwin
et al., 2012). It is often combined with other nonpharmacologic interventions. If music therapy is used, it should be in conjunction with antiemetics.
(2) The effectiveness of exercise as an intervention for n/v has not
been established. Further study is warranted (Irwin et al., 2012).
(3) Acupressure wristbands have been used with some success. Acupressure is a form of massage using pressure to localized areas
to reduce symptoms such as n/v (NCI, 2011a). In a Cochrane

Database systematic review (Ezzo et al., 2006), acupressure was
found to have no significant benefit for delayed n/v. This review found acupressure to have some benefit in acute nausea
but not vomiting.
(4) Acupuncture and electroacupuncture currently are being studied for the treatment of CINV.
(a) Acupuncture is the insertion of fine-gauge needles at specific points.
(b) Electroacupuncture is the use of electric pulses with acupuncture needles to increase stimulation.
(c) Research is needed to determine which of these treatments
may be more beneficial. Based on the results of studies to
date, acupuncture is likely to be effective for treatment of
CINV when combined with antiemetics. Further study is
needed to determine effectiveness in acute versus delayed
n/v when combined with currently recommended antiemetics (Ezzo et al., 2006).
(5) Behavioral interventions such as progressive muscle relaxation and guided imagery have been studied either alone or in
combination with pharmacologic agents to prevent or control
CINV. These behavioral methods have shown success and may
be used as adjunct therapies with pharmacologic interventions
(Irwin et al., 2012).
(6) Dietary interventions (NCI, 2011a)
(a) Encourage patients to eat small, frequent meals.
(b) Encourage patients to choose healthful foods.
(c) Encourage patients to avoid overeating.
(d) Medicate patients prior to meals so that the antiemetic effect is active during and immediately after eating.
(e) Consider medicating with an H2 blocker or proton pump
inhibitor to prevent dyspepsia, as it may mimic nausea.
(f) Encourage patients to avoid fatty, spicy, and highly salted
foods and foods with strong odors.
(g) Determine and repeat past measures that have been effective in controlling n/v.
(h) Encourage patients to eat cold or room-temperature foods
because these emit fewer odors than hot foods.
(i) Suggest that patients cook meals between chemotherapy regimens, when they are not nauseated, and freeze the
meals for later use, or suggest that another family member cook meals.
(j) Encourage patients to eat favorite foods when not experiencing n/v to prevent permanent dislike of these foods.
(k) Use ginger for CINV only per patient preference. Ginger is
thought to function as a 5-HT3 antagonist, NK1 antagonist,
antihistamine, and prokinetic (Haniadka, Rajeev, Palatty,
Arora, & Baliga, 2012). Effectiveness of ginger for CINV
has not been established and requires further study (Irwin
et al., 2012). Additional randomized controlled clinical trials using ginger with patients receiving chemotherapy are
needed to prove safety and benefit (Haniadka et al., 2012).
(l) Initiate dietary consult as needed.
h) Patient and family education
(1) Instruct adult patients to notify the staff if n/v persists for > 24
hours or if they are unable to maintain fluid intake. Ensure that
parents of pediatric patients know to notify staff if vomiting perCopyright 2014 by the Oncology Nursing Society. All rights reserved.
205
206
sists for more than two hours. In children, just a few hours of
vomiting can cause dehydration.
(2) Remind patients as necessary to take antiemetics before arriving for treatment. Ensure that antiemetics have been taken prior to administration of chemotherapy.
(3) Follow up 2448 hours after outpatient treatment to ensure adherence to and effectiveness of the antiemetic regimen (CampSorrell, 2011).
(4) Refer patient to educational resources such as NCIs Eating
Hints: Before, During, and After Cancer Treatment (NCI, 2009).
2. Diarrhea
a) Definition: Diarrhea is defined as loose or watery stools. Diarrhea resulting from administration of chemotherapy or specific biotherapy
agents is a frequent problem. Left untreated or inadequately treated,
diarrhea can lead to severe dehydration, hospitalization, treatment delays, dose reductions, and even death (Stein, Voigt, & Jordan, 2010).
b) Pathophysiology: The pathophysiology and etiology of diarrhea in
patients with cancer can be multifaceted. All possible causes of diarrhea need to be considered to treat the patient appropriately. The
most common mechanisms of chemotherapy-induced diarrhea are
osmotic, secretory, and exudative (NCI, 2012a).
(1) Osmotic diarrhea: Osmotic diarrhea usually is related to injury
to the gut, dietary factors, or problems with digestion. Water is
drawn into the intestinal lumen, resulting in increased stool volume and weight. Lactose intolerance is an example of this type
of diarrhea. New-onset lactose intolerance can occur in patients
undergoing cancer treatment (Andreyev, Davidson, Gillespie, Allum, & Swarbrick, 2012; Roy, Komanapalli, Shojamanesh, Bashir,
& Choudhary, 2013). Osmotic diarrhea is associated with large
stool volumes and sometimes is improved with fasting or elimination of the causative factor (e.g., lactose, sorbitol).
(2) Secretory diarrhea: The small and large intestines secrete more
fluids and electrolytes than can be absorbed. Infection and inflammation of the gut; damage to the gut caused by chemotherapy, radiation, or GVHD; and certain endocrine tumors
can cause secretory diarrhea. The imbalance between absorption and secretion leads to production of a large volume of fluid and electrolytes in the small bowel. This type of diarrhea is
associated with large volumes and may require a period of bowel rest with parenteral nutrition following by slow diet progression as tolerated (Muehlbauer, 2014).
(3) Exudative diarrhea: This type is caused by alterations in mucosal integrity, epithelial loss, enzyme destruction, and defective
absorption of the colon. Mucosal inflammation and ulceration
caused by inflammatory diseases, cancers, and cancer treatment
may result in the outpouring of plasma, proteins, mucus, and
blood into the stool, all of which can result in exudative diarrhea. This type of diarrhea is characterized by more than six
stools per day (Field, 2003).
c) Chemotherapy agents presenting the highest risk of diarrhea (Stein
et al., 2010)
(1) Irinotecan
(2) 5-FU
(3) Paclitaxel
(4) Dactinomycin
(5) Capecitabine
d) Examples of chemotherapy agents that may cause diarrhea
(1) Fludarabine
(2) Cytarabine
(3) Idarubicin
(4) Mitoxantrone
(5) Pentostatin
(6) Floxuridine
(7) Topotecan
(8) Cisplatin
(9) Oxaliplatin
(10) Docetaxel
(11) Pemetrexed
(12) Hydroxyurea
e) Biotherapy agents that may cause diarrhea
(1) IL-2
(2) IFNs
f) Targeted agents that may cause diarrhea
(1) mAbs: Ipilimumab is associated with diarrhea (32%, all grades),
abdominal pain, mucus or blood in stool, and immune-mediated enterocolitis. Loperamide and corticosteroids are used for
treatment. Discontinuation of ipilimumab may be necessary.
Evaluate abdominal pain with diarrhea for perforation or peritonitis, which has been reported with ipilimumab (Bristol-Myers
Squibb Co., 2013; Rubin, 2012) (see Table 10 in Chapter 4).
(2) Bortezomib
(3) Dasatinib
(4) Erlotinib
(5) Gefitinib
(6) Imatinib mesylate
(7) Lapatinib
(8) Lenalidomide
(9) Sunitinib
(10) Temsirolimus
(11) Thalidomide
(12) Vorinostat
g) Incidence of diarrhea following cytotoxic therapy
(1) The incidence of diarrhea varies greatly depending upon the
agent(s) used.
(2) The specific agent, dose, schedule, and combination with other
anticancer therapies all influence the severity of chemotherapyinduced diarrhea.
h) Clinical manifestations and consequences: If manifestations are severe, the course of action may be to modify or hold the causative
agent, which could compromise the benefit of the regimen. The clinical manifestations of diarrhea include the following (NCI, 2012a).
(1) Dehydration: Diarrhea dehydrates pediatric patients very quickly.
(2) Orthostasis
(3) Life-threatening hypokalemia, metabolic acidosis, hypercalcemia, malnutrition
(4) Cardiovascular or renal compromise
(5) Impaired immune function following frequent episodes of chemotherapy-induced diarrhea
(6) Perianal skin breakdown, discomfort, or infection
(7) Reduced absorption of oral medications
(8) Pain (abdominal cramping)
(9) Anxiety
(10) Exhaustion
(11) Decreased QOL
207
208
i) Risk factors
(1) Radiation therapy to the pelvis, abdomen, or lower thoracic and
lumbar spine can lead to destruction of the cells of the lumen
of the bowel and can be an acute or chronic toxicity.
(2) 5-FU in combination with high-dose leucovorin (500 mg/m2)
or 5-FU administered as a weekly bolus (versus continuous infusion) (Goldberg et al., 2004)
(3) Irinotecan is associated with both acute and delayed diarrhea.
Irinotecan combined with bolus 5-FU and leucovorin is associated with increased morbidity and mortality related to diarrhea
(Pfizer Inc., 2012a; Stein et al., 2010).
(4) EGFR-targeted therapies (Stein et al., 2010)
(a) Grade 3 and 4 CTCAE (NCI CTEP, 2010) is < 10%.
(b) Cetuximab or panitumumab: Grade 2 is approximately 21%
and grade 3 is 1%2%.
(c) Small molecule EGFR tyrosine kinase inhibitors (e.g., erlotinib, gefitinib, lapatinib): All grades of diarrhea may occur in up to 60% of patients.
(5) Multitargeted tyrosine kinase inhibitors (Stein et al., 2010)
(a) Sorafenib and sunitinib: 30%50% incidence (all grades)
(b) Imatinib, a Bcr-Abl protein tyrosine kinase inhibitor: 30%
incidence although severe diarrhea is rare
(6) Immunosuppression
(7) Intestinal resection or gastrectomy
(8) Manipulation of bowel during surgery, which may cause diarrhea or ileus
(9) Intestinal infection secondary to mucositis and neutropenia
(e.g., infection with Rotavirus, Escherichia coli, Shigella, Salmonella, Giardia, or Clostridium difficile)
(10) GVHD
(11) Dietary causes (e.g., lactose intolerance; ingestion of caffeine, alcohol, or spicy or fatty foods; use of hyperosmotic dietary supplements)
(12) Inflammatory conditions, such as diverticulitis, irritable bowel
syndrome, or ulcerative colitis
(13) Malabsorption, partial bowel obstruction, bowel edema, motility disruption
(14) Anxiety and stress
j) Assessment: Accurate assessment is vital in determining the cause
and type of diarrhea; knowing the cause and type can be crucial to
proper treatment.
(1) Mistakenly using an antidiarrheal to treat diarrhea caused by
infection can intensify diarrhea severity and infectious complications (Curry, 2013).
(2) Irinotecan causes two distinct forms of diarrhea (early and late
onset), and each requires a different management strategy (see
Table 7 in Chapter 3).
(3) Fluoropyrimidine-induced diarrhea (e.g., 5-FU) risk factors
(Stein et al., 2010)
(a) Female gender
(b) Caucasian race
(c) Presence of diabetes
(4) Assess stool.
(a) Assess the pattern of elimination and stool character in relation to treatments (e.g., onset, duration, frequency, consistency, amount, odor, color).
(b) Assess for presence of nocturnal diarrhea, which can be
associated with diabetic autonomic neuropathy or infecCopyright 2014 by the Oncology Nursing Society. All rights reserved.
tions. Loss of sleep or interrupted sleep during the night

may increase fatigue.
(c) Grade diarrhea according to CTCAE criteria (NCI CTEP,
2010). See Table 25.
(d) Check for presence of blood or mucus in the stools.
(e) Monitor the patient for incontinence.
(5) Conduct a physical examination: The presence of fever, blood in
the stool, abdominal pain, weakness, or dizziness warrants medical
attention to rule out infection, bowel obstruction, and dehydration
(Benson et al., 2004). The steps of a physical examination follow.
(a) Auscultate for bowel sounds.
(b) Palpate and assess the abdomen.
(c) Assess for fecal impaction. Avoid manual rectal assessment
in patients who are thrombocytopenic or neutropenic.
(d) Look for signs of malnutrition, dehydration, electrolyte imbalance, and infectious process.
(e) Ask about pain experienced during or after defecation.
(f) Assess for fever, weakness, and dizziness.
(g) Determine if blood has been present in the stool (occult
or gross).
(h) Assess perianal area for skin breakdown and signs and symptoms of infection.
(6) Take a diet history (Engelking, 2008).
(a) Determine if dietary habits have changed. Be especially
aware of clues that indicate rapidly increased amount of
fiber in the diet.
(b) Assess for intake that could contribute to diarrhea (e.g., irritating foods, alcohol, coffee, fiber, fruit, lactose-containing foods/fluids, sorbitol-based gum, candy, herbal teas
that may contain laxatives).
(c) Assess for food or lactose intolerance or allergies.
(7) Take a medication history: Assess for use of the following (Micromedex, 2013; Muehlbauer, 2014).
(a) Antacids (especially those containing magnesium)
(b) Antibiotics
(c) Antihypertensives
Table 25. National Cancer Institutes Common Terminology Criteria
for Adverse Events: Diarrhea
Grade
Description
Increase of < 4 stools/day over baseline; mild increase in ostomy output compared
to baseline
Increase of 46 stools/day over baseline; moderate increase in ostomy output compared to baseline
Increase of 7 stools/day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care ADL*
Death
* Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications,
and not bedridden.
ADLactivities of daily living
209
210
(d) Potassium or calcium supplements

(e) Diuretics
(f) Caffeine
(g) Theophylline
(h) NSAIDs
(i) Antiarrhythmic drugs
(j) Laxatives or stool softeners
(k) Promotility agents (metoclopramide)
(l) Magnesium oxide
(8) Assess for other possible contributing factors.
(a) Travel history (outside the United States)
(b) Use of alternative therapies (e.g., dietary supplements,
herbal remedies)
(c) Opioid withdrawal
(9) Take objective measurements (Engelking, 2008).
(a) Monitor intake and output.
(b) Monitor weight.
(c) Monitor laboratory data.
i. Check stool culture results for presence of infection.
ii. Check serum chemistries for electrolyte imbalance,
specifically potassium. Albumin may be decreased
with diarrhea.
iii. Assess complete blood count (CBC) to determine if
neutropenia or infection is present.
(d) Check skin turgor.
(e) Check vital signs.
k) Collaborative management
(1) Monitor number, amount, and consistency of bowel movements. For patients with colostomies, an increase in the number of loose stools daily should be monitored to assess for chemotherapy-induced diarrhea.
(2) Replace fluid and electrolytes, including potassium. Electrolytes
and fluids are absorbed in the small intestine. When diarrhea
occurs, these substances quickly pass through the small intestine without being absorbed. This can cause severe fluid and
electrolyte disturbances.
(3) Administer antidiarrheal medication as appropriate once infection has been ruled out. This will reduce stool frequency,
volume, and peristalsis. Reassess the severity of chemotherapyinduced diarrhea at the appropriate interval after antidiarrheal
medication. Table 26 lists antidiarrheal medications.
(a) NCCN currently does not have a guideline for management
of chemotherapy-induced diarrhea.
(b) Loperamide and octreotide are the only drugs that have established efficacy in chemotherapy-induced diarrhea. Further study is warranted to define the role of other pharmacologic interventions (Muehlbauer et al., 2009).
(4) Consider the use of antibiotics for patients with persistent diarrhea and signs of infection (Benson et al., 2004).
(5) Probiotics: The role of probiotics in chemotherapy-induced
diarrhea is an area of investigation. The appropriate strain(s),
dosage, and administration schedules need to be determined
(Guandalini, 2011; Muehlbauer et al., 2009).
(6) See Figure 25 for an example of chemotherapy-induced diarrhea treatment guidelines.
l) Patient and family education (Muehlbauer, 2014; NCI, 2012a): Provide the following instructions.
Table 26. Common Antidiarrheal Medications

Classification
Mechanism of Action
Drug
Route, Dose, and Schedule*
Side Effects*
Nursing Considerations*
Antimotility
agents
Slows GI transit time

and promotes reabsorption of water from
bowel; antiperistaltic
Diphenoxylate HCl
with atropine sulfate (Lomotil)
Adults: Individualize dosage. Initial

dose is 10 mg followed by 5 mg PO
QID; maximum dose is 20 mg/day.
Dry mouth, urinary retention, confusion, sedation, restlessness
Invasive bacterial diarrhea, pseudomembranous

colitis
In patients with advanced liver disease, drug may
precipitate hepatic coma.
Do not use in children younger than age 2.
Loperamide
(Imodium A-D)
Adults: 4 mg PO initially, followed by

2 mg PO after each unformed stool;
do not exceed 16 mg/day. Exception:
Doses are higher for late-onset irinotecan-induced diarrhea (2 mg every
2 hours).
Constipation, fatigue,
urinary retention,
drowsiness, dizziness
Invasive bacterial diarrhea

Do not use in children younger than age 2.
Inhibits growth hormone, glucagon, and

insulin; prolongs intestinal transit time; increases sodium and
water absorption
Octreotide (Sandostatin)
Adults: 100150 mcg SC or IV TID.

Doses may be escalated to 500 mcg
SC or IV TID or by continuous IV infusion 2550 mcg/hr.
Abdominal discomfort,
flatulence, constipation,
diarrhea, nausea, dizziness, headache, cardiac dysrhythmias, bradycardia
Drug may interact with insulin, oral hypoglycemic

medications, beta-blockers, or calcium channel
blockers. Insulin requirements may be decreased.
Observe for hyperglycemia/hypoglycemia.
Drug may decrease levels of cyclosporine when
given concurrently.
Drug may increase risk of developing gallstones.
Recommended after failure of Imodium or in patients with complicated diarrhea. Complicated diarrhea is defined as involving abdominal cramping, nausea and vomiting, fever, sepsis, neutropenia, or bleeding.
Sandostatin LAR Depot is under investigation for
the treatment of chemotherapy-induced diarrhea.
Anticholinergic
Antagonist of acetylcholine
Atropine
Adults: Used for early-onset cholinergic diarrhea (e.g., irinotecan induced),

0.251 mg PO or SC
Dry mouth, blurred vision, photophobia, constipation, xerostomia,

tachyarrhythmia
Antacids interfere with absorption of atropine.

Drug is contraindicated in patients with closedangle glaucoma.
Somatostatin
analog
* Consult product information for complete list of contraindications, drug interactions, and dosage ranges.
GIgastrointestinal; IVintravenous; POoral; QIDfour times daily; SCsubcutaneous; TIDthree times a daily
211
Note. Based on information from Benson et al., 2004; Engelking, 2008; Gibson & Stringer, 2009; Micromedex, 2013; Stein et al., 2010; and manufacturers prescribing information.
212
Figure 25. Proposed Algorithm for the Assessment and Management of Treatment-Induced Diarrhea
EVALUATE
Obtain history of onset and duration of diarrhea
Describe number of stools and stool composition (e.g., watery, blood in stool, nocturnal)
Assess patient for fever, dizziness, abdominal pain/cramping, or weakness (i.e., rule out
risk for sepsis, bowel obstruction, dehydration)
Medication profile (i.e., to identify diarrheogenic agents)
Dietary profile (i.e., to identify diarrhea-enhancing foods)
UNCOMPLICATED
CTC grade 12 diarrhea
with no complicating
signs or symptoms
ADDED RISK FACTORS
MANAGEMENT
Stop all lactose-containing products, alcohol, and high-osmolar supplements
Drink 810 large glasses of clear liquids a day (e.g., Gatorade or broth)
Eat frequent small meals (e.g., bananas, rice, applesauce, toast, plain pasta)
Instruct patient to record the number of stools and report symptoms of life-threatening sequelae
(e.g., fever or dizziness upon standing)
For grade 2 diarrhea, hold cytotoxic chemotherapy until symptoms resolve and consider dose
reduction
COMPLICATED
CTC grade 3 or 4 diarrhea or grade
1 or 2 with one or more of the following signs or symptoms
Cramping
Nausea/vomiting ( grade 2)
Decreased performance status
Fever
Sepsis
Neutropenia
Frank bleeding
Dehydration
TREATMENT
Administer standard dose of loperamide: initial dose of 4 mg followed by 2 mg every 4 hours or
after every unformed stool
Consider clinical trial
Reassess 1224 hours later
Diarrhea resolving
Continue instruction for dietary modification
Gradually add solid foods to diet
Discontinue loperamide after 12-hour diarrheafree interval
RT-induced: Continue loperamide
Diarrhea unresolved
Progression to severe diarrhea

(NCI grades 34 with or without
fever, dehydration, neutropenia,
and/or blood in stool)
Persistent diarrhea (NCI grades 12)

Administer loperamide 2 mg every 2 hours
Start oral antibiotics
Observe patient for response
RT-induced: Oral antibiotics not generally recommended
Reassess 1224 hours later

Diarrhea resolved
Continue instructions for dietary modification
Gradually add solid foods to diet
Discontinue loperamide after 12-hour diarrheafree interval
RT-induced: Continue loperamide
Progression to severe diarrhea

(NCI grades 34 with or without
fever, dehydration, neutropenia,
Diarrhea unresolved
Persistent diarrhea (NCI

grades 12) (no fever, dehydration, neutropenia,
EVALUATE IN OFFICE/OUTPATIENT CENTER

Check stool workup (blood, fecal leukocytes, Clostridium difficile, Salmonella, Escherichia coli,
Campylobacter, infectious colitis)
Check CBC and electrolytes
Perform abdominal exam
Replace fluids and electrolytes as appropriate
Discontinue loperamide and begin second-line agent
Octreotide (100150 mcg SC TID with dose escalation up to 500 mcg TID)
Other second-line agent (e.g., tincture of opium)
RT-induced: Continue loperamide or other oral agent; no workup required
ADMIT TO HOSPITAL*
Administer octreotide (100150 mcg SC
TID or IV [2550 mcg/hr] if dehydration
is severe with dose escalation up to 500
mcg TID)
Start IV fluids and antibiotics as needed
(e.g., fluoroquinolone)
Stool workup, CBC, and electrolyte profile
Discontinue cytotoxic chemotherapy until
all symptoms resolve; restart chemotherapy at reduced dose
* For radiation-induced cases and select patients with chemotherapy-induced diarrhea consider intensive outpatient management, unless the patient has
sepsis, fever, or neutropenia.
CBCcomplete blood count; CTCCommon Toxicity Criteria; NCINational Cancer Institute; RTradiotherapy; SCsubcutaneous; TIDthree times
daily
Note. Based on information from Benson et al., 2004.
From Management of Cancer TreatmentRelated Diarrhea Issues and Therapeutic Strategies, by S. Kornblau, A.B. Benson III, R. Catalano, R.E. Champlin, C. Engelking, M. Field, S. Wadler, 2000, Journal of Pain and Symptom Management, 19, p. 125. Copyright 2000 by U.S. Cancer Pain Relief Committee. Adapted with permission.
(1) Start antidiarrheal medications at the specified time. With

certain chemotherapeutic agents, antidiarrheal medication
should be provided so that patients can self-administer at
the onset.
(2) Avoid foods high in insoluble fiber (e.g., raw fruits and vegetables), greasy or fried foods, lactose, skins, seeds, legumes, caffeine, alcohol, and hyperosmotic liquids (Muehlbauer et al.,
2009). These may be stimulating or irritating to the GI tract.
(3) Include foods high in soluble fiber or pectin in their diets and
low insoluble fiber foods such as rice noodles, bananas, white
toast, skinned turkey or chicken, fish, and mashed potatoes
(Muehlbauer et al., 2009).
(4) Maintain fluid intake by drinking 810 large glasses each day of
clear fluids (e.g., bouillon; weak, tepid decaffeinated tea; gelatin; sports drinks). Water alone lacks the needed electrolytes
and vitamins. Carbonated and caffeinated drinks contain relatively few electrolytes and may worsen diarrhea. Fluids with glucose are useful because glucose absorption drives sodium and
water back into the body.
(5) Limit the use of sugar-free candies or gum made with sugar alcohol (sorbitol) (NCI, 2012a).
(6) Eat food at room temperature if not tolerated otherwise. Hot
and cold foods may aggravate diarrhea.
(7) Limit or avoid milk and dairy products.
(8) Avoid hyperosmotic supplements (e.g., Ensure), which can contribute to the production of loose, high-volume stools (Muehlbauer et al., 2009).
(9) Clean the rectal area with mild soap and water after each bowel
movement, rinsing well, and patting dry with a soft towel. Cleaning decreases the risk of infection and skin irritation.
(10) Apply moisture-barrier ointment to protect perianal skin.
(11) Take warm sitz baths to relieve pain related to perianal inflammation. Anesthetic creams or sprays may help to relieve pain
related to inflammation.
(12) Understand when diarrhea can be self-managed and when to
seek help.
(13) Report excessive thirst, fever, dizziness or light-headedness, palpitations, rectal spasms, excessive cramping, watery or bloody
stools, and continued diarrhea despite antidiarrheal treatment.
These symptoms can be life threatening.
3. Mucositis: Mucositis is a common complication of both systemic cytotoxic therapy and radiation therapy. Severe mucositis is reported in > 90%
of patients with head and neck cancer who are receiving concurrent chemotherapy and radiation (Sonis, 2011) and in the majority of patients
undergoing HSCT (Raber-Durlacher, Elad, & Barasch, 2010). It is associated with decreased QOL and increased risk of infections, hospitalizations, opioid use, parenteral nutrition, and dose reductions and delays
(Murphy, 2007; Rosenthal, 2007).
a) Definitions
(1) Mucositis: A general term referring to inflammation of any mucosal membranes, including the oral cavity
(2) Stomatitis or oral mucositis: Any inflammatory condition of oral
tissue including mucosa, dentition, periapices, and periodontium (Eilers & Million, 2011). Stomatitis includes oral infections.
(3) Alimentary tract mucositis: Inflammation and mucosal damage
occurring in the mouth (stomatitis) and extending the entire
length of the alimentary tract
213
214
b) Pathophysiology: Oral mucositis traditionally has been attributed to

the direct effects of cytotoxic drugs or radiation on epithelial stem
cells. More recently, evidence has suggested that microvascular injury and connective tissue damage in the submucosa precede epithelial damage. Oral mucositis is now described as having five phases
(Sonis, 2011).
(1) Initiation: Stomatotoxic drugs and radiation therapy generate
reactive oxygen species that damage DNA, resulting in cell, tissue, and blood vessel damage in the mucosa.
(2) Upregulation and generation of messenger signals: Chemotherapy and radiation therapy activate nuclear factor-B
(NF-B). This results in upregulation of a large number of genes
and release of proinflammatory cytokines, such as TNF-alpha
(TNF-), IL-1 beta (IL-1), and IL-6. These and other cytokines
are responsible for tissue injury and apoptosis.
(3) Signaling and amplification: In addition to causing direct tissue damage, proinflammatory cytokines activate the production
of tissue-damaging TNF-, IL-1, and IL-6, and other cytokines
that alter mucosal tissues.
(4) Ulceration: Tissue injury in the oral mucosa appears as ulcers
that penetrate through the epithelium to the submucosa. Bacteria penetrate the submucosa and stimulate macrophage activity, which increases the release of proinflammatory cytokines.
Angiogenesis also is stimulated.
(5) Healing: Signals from extracellular tissues stimulate epithelial
proliferation until the mucosa returns to its normal thickness.
Tissues do not return completely to normal, however, placing
them at increased risk for future injury.
c) Incidence of oral mucositis
(1) Incidence varies based on type of chemotherapy, dose, and schedule. Radiation therapy directed at mucosa increases the risk,
and incidence varies depending on the dose, field, and whether chemotherapy is used concurrently. Overall, 30%100% of
patients treated for cancer will develop some degree of mucositis (Brown, 2011).
(2) HSCT recipients
(a) Up to a 100% risk
(b) Factors such as intensity of treatment regimen, transplant
type, and use of total body irradiation can affect incidence
(Raber-Durlacher et al., 2010).
(3) Incidence in patients undergoing head and neck radiation therapy is 65%90% (Sonis, 2011).
d) Risk factors
(1) Mucosal cells have a rapid mitotic rate and are susceptible to
chemotherapy and radiation (Raber-Durlacher et al., 2010).
The following classes of chemotherapy agents are associated
with mucositis.
(a) Antimetabolites: Increased risk noted with bolus delivery
of 5-FU
(b) Antitumor antibiotics
(c) Alkylating agents: Increased risk noted with high-dose melphalan
(d) Plant alkaloids
(e) Rapamycin (mTOR) inhibitors
(2) Biologic agents, particularly IL-2 and IFN
(3) Neutropenia
(4) Drugs or therapies that alter mucous membranes (Wujcik, 2014)
(a) Oxygen therapy: Dries out the mucosal lining

(b) Anticholinergics: Decrease salivary flow
(c) Phenytoin: Causes gingival hyperplasia
(d) Steroids: Can result in fungal overgrowth
(5) Total body irradiation or radiation therapy to the head or neck
(6) Dental disease and poor oral hygiene (Brown, 2011)
(7) Ill-fitting dentures: Irritate the mucosa and break integrity
(8) Advanced age and youth (Brown, 2011)
(a) Older adult patients may be at risk because of degenerative changes, decreased salivary flow, diminished keratinization of mucosa, and increased prevalence of gingivitis.
(b) Younger patients are prone to develop oral mucositis more
frequently than older patients because of their increased
rate of basal cell turnover (Treister & Woo, 2013).
(9) History of alcohol and tobacco use: Alcohol and tobacco irritate the mucosa. Tobacco affects microcirculation, which may
delay healing (Eilers & Million, 2011).
(10) Poor nutrition: Reduced nutritional intake delays healing.
(11) Consumption of irritating foods: Acidic or spicy foods may inflame and traumatize mucosa (Wujcik, 2014).
(12) Dehydration alters mucosal integrity.
(13) Patients with head and neck cancer are at especially high risk if
they have surgery followed by radiation therapy. Patients with
cancers of the mouth and oropharynx are at highest risk (>
90%) (Sonis, 2011).
(14) Leukemia, lymphoma, and HSCT put patients at risk because
treatment involves drugs with a great potential to produce oral
mucositis and cause prolonged neutropenia.
(15) Methotrexate for prophylaxis of GVHD following HSCT (Brennan, von Bltzingslwen, Schubert, & Keefe, 2006; Cutler et
al., 2005)
(16) Hepatic or renal impairment: Inadequate metabolism or excretion of certain mucotoxic cytotoxic agents
(17) Combined chemotherapy and radiation is associated with a
greater risk of mucositis (Eilers & Million, 2011).
e) Clinical manifestations
(1) The pattern of mucositis varies both by drug regimen and
by individual. Intensity and duration vary by type of drug,
dose, and frequency of administration (Raber-Durlacher et
al., 2010).
(a) Chemotherapy-induced oral mucositis develops most often four to seven days following standard-dose chemotherapy and peaks within two weeks (Raber-Durlacher et al.,
2010).
(b) HSCT recipients experience mucositis three to five days
following the conditioning regimen.
(c) Patients receiving head and neck radiation therapy experience mucositis during week two of therapy, and it can last
for weeks to months (Raber-Durlacher et al., 2010).
(2) Intensity increases with higher doses of cytotoxic drugs. Drugs
that are not usually stomatotoxic at standard doses (e.g., cyclophosphamide) can cause cellular damage to the mucosa at high
doses (Keefe et al., 2007).
(3) Signs and symptoms (Eilers & Million, 2011)
(a) Changes in taste and ability to swallow
(b) Hoarseness or decreased voice strength
(c) Pain when swallowing or talking
215
216
(d) Changes in the color of the oral mucosa (e.g., pallor, erythema of varying degrees, white patches, discolored lesions or ulcers)
(e) Changes in oral moisture (e.g., amount of saliva, quality
of secretions)
(f) Edema of oral mucosa and tongue
(g) Mucosal ulcerations
f) Assessment
(1) Use a standardized assessment tool or scale when performing a
physical examination. Scales designed for clinical use take into
account symptoms, signs, and functional disturbances associated with oral mucositis and assign an overall score. The following are three common tools.
(a) Oral Assessment Guide: This tool contains eight categories
that reflect oral health and function (Eilers, Berger, & Peterson, 1988) (see Table 27).
(b) WHO (1979)
(c) CTCAE: This tool consists of a 15 grading index that is associated with descriptions of oral mucosal changes (see Table 28) (NCI CTEP, 2010).
(2) After removing dental appliances, examine the outer lips, teeth,
gums, tongue, soft and hard palate, and buccal mucosa for color, moisture, integrity, and cleanliness (Brown, 2011).
(3) Assess for changes in taste, voice, ability to swallow, pain, and
discomfort.
(4) Examine the saliva for amount and quality.
g) Collaborative management: Currently, no standard of care exists for
the prevention and treatment of oral mucositis. MASCC, in collaboration with the International Society for Oral Oncology, issued clinical
practice guidelines in 2004 with suggestions and recommendations
based on literature published between 1966 and 2001. The guidelines
were revised in 2005 and again in 2007 (Keefe et al., 2007). ASCO has
published guidelines as well (Hensley et al., 2009).
(1) Oral care protocols, including patient education, should be instituted to reduce the severity of oral mucositis from chemotherapy and radiation therapy (Brown, 2011). Patient education may improve compliance with oral care, frequency, and
ability to cope with mucositis.
(a) Provide patient education, which is essential in promoting
good oral hygiene (Dodd, 2004).
(b) Benefits of oral care may include decreased risk of infection, decreased pain, and elevated microbial flora
(Brown, 2011).
(c) Conduct a pretreatment dental evaluation with attention
to potentially irritating teeth surfaces, underlying gingivitis, periodontal infection, and ill-fitting dentures. Crucial
dental work should be done before chemotherapy begins.
Removing braces may be necessary in adult and pediatric
patients if they are to undergo transplantation or if prolonged periods of neutropenia are anticipated.
(d) Emphasize intake of high-protein foods and increased fluid intake (> 1,500 ml/day).
(2) Prevention of oral mucositis (Keefe et al., 2007; Peterson et
al., 2012)
(a) Oral cryotherapy (ice chewing) is recommended for patients receiving bolus 5-FU for GI malignancies, bolus edatrexate, or high-dose melphalan.
217
Table 27. Oral Assessment Guide

Numeric and Descriptive Ratings
Category
Tools for
Assessment
Voice
Auditory
Converse with patient.
Normal
Deeper or raspy
Difficulty talking or
painful
Swallow
Observation
Ask patient to swallow.

To test gag reflex, gently place
blade on back of tongue and
depress.
Observe result.
Normal swallow
Some pain on swallowing
Unable to swallow
Lips
Visual/palpatory
Observe and feel tissue.
Smooth and pink

and moist
Dry or cracked
Ulcerated or bleeding
Tongue
Visual and/or
palpation
Feel and observe appearance

of tissue.
Pink and moist

and papillae
present
Coated or loss of papillae with a shiny

appearance with or
without redness
Blistered or cracked
Saliva
Tongue
blade
Insert blade into mouth, touching the center of the tongue

and the floor of the mouth.
Watery
Thick or ropy
Absent
Mucous
membranes
Visual
Observe appearance of tissue.
Pink and moist
Reddened or coated
(increased whiteness) without ulcerations
Ulcerations with or
without bleeding
Gingiva
Tongue
blade and visual
Gently press tissue with tip of

blade.
Pink, stippled,
and firm
Edematous with or
without redness
Spontaneous bleeding or bleeding with

pressure
Teeth or
dentures (or
denturebearing area)
Visual
Observe appearance of teeth

or denture-bearing area.
Clean and no debris
Plaque or debris in
localized areas
(between teeth if
present)
Plaque or debris
generalized along
gum line or denture-bearing area
Methods of Measurement
Note. Table courtesy of June Eilers, PhD, APRN-CNS, BC, The Nebraska Medical Center. Used with permission.
(b) Chlorhexidine is not recommended for treatment of mucositis (Harris, Eilers, Harriman, Cashavelly, & Maxwell, 2008;
Keefe et al., 2007; Worthington et al., 2011).
(c) Consider use of a keratinocyte growth factor to reduce the
severity and duration of oral mucositis in patients with hematologic malignancies undergoing high-dose chemotherapy and total body irradiation for autologous HSCT (Keefe
et al., 2007; Raber-Durlacher et al., 2013).
(3) Prevention of GI mucositis (Keefe et al., 2007)
(a) Either ranitidine or omeprazole is recommended for the
prevention of epigastric pain after treatment with cyclophosphamide, methotrexate and 5-FU, or 5-FU with or
without levcovorin.
(b) Amifostine has been suggested for reducing the severity
of esophagitis caused by the combination of chemotherapy and radiation therapy for non-small cell lung cancer (Keefe et al., 2007). However, ASCO does not recommend the routine use of amifostine for the prevention of
esophagitis in patients receiving concurrent chemotherapy because of insufficient evidence (Hensley et al., 2009).
In a 2011 Cochrane review, amifostine was found to have
218

for Adverse Events: Oral Mucositis
Grade
Description
Asymptomatic or mild symptoms; intervention not indicated
Moderate pain, not interfering with oral intake; modified diet indicated
Severe pain, interfering with oral intake
Life-threatening consequences; urgent intervention required
Death
Note. From Common Terminology Criteria for Adverse Events [v.4.03], by the National Cancer Institute Cancer
Therapy Evaluation Program, 2010. Retrieved from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010
-06-14_QuickReference_8.5x11.pdf.
weak evidence of benefit for prevention of any mucositis

(Worthington et al., 2011).
(c) Other agents that have been studied include sucralfate,
aloe vera, glutamine, G-CSF, honey, and antibiotic lozenges
containing polymyxin, tobramycin, and amphotericin. Evidence of benefit was weak in small studies that included these
agents. Further study is required (Worthington et al., 2011).
(d) Low-level laser therapy is recommended for the prevention
of oral mucositis in adult patients receiving HSCT conditioned with high-dose chemotherapy with or without total
body irradiation. It is also recommended for patients with
head and neck cancer undergoing radiation without concurrent chemotherapy (Migliorati et al., 2013).
(4) Treatment: Currently, no evidence-based recommendations exist for the treatment of established oral mucositis. Interventions
are aimed at symptom relief and preventing further tissue damage. These interventions may include the following (Harris et
al., 2008; Keefe et al., 2007).
(a) Encourage the use of oral agents to promote cleansing,
moisture, and comfort (see Table 29).
(b) Encourage patients to brush, floss, and rinse to maintain
mucosal health.
(c) Administer systemic pain medications for mucositis pain.
MASCC guidelines recommend the use of patient-controlled
analgesia in HSCT recipients experiencing oral mucositis
pain (Keefe et al., 2007).
(d) Culture mucosal lesions so that appropriate antimicrobial
agents can be prescribed. Candidal lesions look like whitish or cream-colored plaques on the mucosa and often are
treated while cultures are pending.
h) Patient and family education: Stress the goals of keeping the oral cavity clean, moist, and intact to prevent further damage to the mucosa during mucotoxic therapy (Harris et al., 2008; Keefe et al., 2007).
To do this, patients should
(1) Perform a daily oral self-examination, and report signs and
symptoms of mucositis.
(2) Comply with an oral hygiene program. Oral hygiene should be
performed after every meal and at bedtime. If mild to moderate
dysfunction is present, the frequency of oral hygiene should be
increased to every two to four hours. If the condition progresses to a more severe dysfunction, hourly care may be indicated.
The program should include the following.
219
Table 29. Commonly Used Agents for Mucositis Management

Agent
Efficacy
Comments
Bland rinses
0.9% saline
solution
Formal evaluation is lacking.
Inexpensive rinsing solution
Sodium bicarbonate
Creates an alkaline environment that promotes bacterial microflora

Unpleasant taste may affect adherence.
Recommended by NCI
0.9% saline/sodium bicarbonate
Inexpensive rinsing solution

teaspoon salt mixed with 2 tablespoons sodium bicarbonate with 32 ounces of water
Unpleasant taste may affect adherence.
Recommended by NCI
Rinse, multiagent
Data demonstrating efficacy are lacking for prevention

and treatment of mucositis.
Various agents include antihistamines, lidocaine, and

Mylanta.
Agents may be useful for pain or discomfort only.
Patients may experience numbness, which can cause
potential injury.
Alcohol-based elixirs should be avoided.
Discontinue if patient experiences discomfort related
to rinse (e.g., nausea and vomiting)
Coating agents, mucosal protectants

Sucralfate
suspension
Most data demonstrate no statistically significant difference in oral mucositis severity, pain intensity scores,
and other subjective symptoms (e.g., taste alteration, dry mouth). Not recommended for practice (Harris et al., 2008). A Cochrane review published in 2011
found that some benefit may exist for the reduction of
oral mucositis. Further studies are needed (Worthington et al., 2011).
Mucosal coating agent

Poor tolerability and potential for GI side effects (e.g.,
nausea and rectal bleeding) (Harris et al., 2008)
Gelclair
Bioadherant oral gel forms a coating to make a barrier.

Provides moisture and is flavorful
Not recommended for prevention or treatment of oral
mucositis
May be helpful for improvement of swallowing and

pain scores
MuGard
Mucoadhesive oral wound rinse that forms a protective coating over the oral mucosa. Indicated for the
management of mucositis/stomatitis (which may be
caused by radiation therapy or chemotherapy) and all
types of oral wounds.
Dose is 5 ml. Rinse in mouth for at least 1 minute.

Coat entire oral cavity. If necessary, up to 10 ml may
be used to coat entire oral cavity.
Recommended for reduction of esophagitis induced by

simultaneous chemotherapy and radiation therapy in
patients with non-small cell lung cancer (Keefe et al.,
2007). However, ASCO does not recommend the routine use of amifostine for the prevention of esophagitis in patients receiving concurrent chemotherapy because of insufficient evidence (Hensley et al., 2009).
Tissue protector
Studies needed to determine role in prevention of oral
mucositis
Overall, data demonstrate no significant change in

oral mucositis severity or suppression of any type of
oral microflora. A 2011 Cochrane review found no
benefit over placebo for the prevention of mucositis
(Worthington et al., 2011).
Contains alcohol
Reports of rinse-induced discomfort, taste alteration
Not recommended for oral mucositis (Keefe et al.,
2007)
Can turn teeth brown
Tissue protectants
Amifostine
Antiseptic agents
Chlorhexidine
220
Table 29. Commonly Used Agents for Mucositis Management (Continued)

Agent
Efficacy
Comments
Hydrogen
peroxide
Mixed results: Linked to exacerbation or dryness, stinging, pain, and nausea; some reports of intensification
of symptoms as a result of glossodynia (burning sensation)
Repeated use as a rinse is not recommended; longterm use is discouraged.

At full potency, it may break down new granulation tissue and disrupt normal oral flora due to damage of
fibroblasts and keratinocytes.
Povidone-iodine
Possesses antiviral, antibacterial, and antifungal efficacy; less tolerable than normal saline
No evidence that this agent is more effective than placebo (Worthington et al., 2011)
Potency limits use in patients with new granulation tissue. Swallowing is contraindicated.
Antimicrobial agents
Acyclovir (and its
analogs)
Antiviral
Not recommended for prevention of oral mucositis
Antimicrobial
lozenges
Not recommended for prevention of radiation-induced

oral mucositis
More research is needed.
Anti-inflammatory agents
Kamillosan liquid
rinse
Unfavorable results in clinical trials
Most patients appear to develop mucositis despite

treatment.
Chamomile
Lacks data demonstrating its efficacy
Anti-inflammatory, antipeptic properties reported

Inexpensive, readily available, and innocuous
Oral corticosteroids
No significant difference in degree of mucositis compared to placebo
Data are limited; definitive conclusions cannot be

drawn.
Benzydamine
Nonsteroidal anti-inflammatory analgesic

Antitumor necrosis factor activity
Only recommended for the prevention of oral mucositis in patients with solid tumors of the head and
neck receiving radiation therapy (Keefe et al., 2007).
In a 2011 Cochrane review, this agent was found to
have weak, unreliable evidence for the reduction of
mucositis (Worthington et al., 2011).
Topical lidocaine
Limited data; may provide significant relief of limited duration
Requires frequent application; may lead to decreased

sensitivity and additional trauma and impair taste
perception
Prophylaxis is not recommended.
Topical capsaicin
Pilot data demonstrated marked reduction in oral pain.
Clinical potential possibly linked to reepithelialization

and elevation of pain threshold
Further study is warranted.
Morphine
Topical morphine has limited utility. Patient-controlled

analgesia using morphine is recommended for patients undergoing HSCT.
Oral alcohol-based formulations may cause burning.

Comprehensive pain assessments should be performed to adequately treat pain associated with mucositis.
Analgesics
Antiproliferative, mucosal protectant, cytokine-like agents and growth factors

GM-CSF
Some data indicate reduction in oral mucositis severity

and pain; others do not.
No evidence of benefit with duration or severity of oral
mucositis (Worthington et al., 2011)
Oral mouthwashes are not recommended.

High rate of drug discontinuation because of intolerable side effects, including local skin reaction, fever,
bone pain, and nausea when administered subcutaneously.
G-CSF
Weak, unreliable evidence of benefit for prevention of

mucositis (Worthington et al., 2011)
Further study is needed to draw any conclusion.
221
Table 29. Commonly Used Agents for Mucositis Management (Continued)

Agent
Keratinocyte
growth factor-1:
Palifermin
Efficacy
Comments
Approved for prevention of oral mucositis in patients undergoing autologous HSCT receiving high-dose chemotherapy or total body irradiation
60 mcg/kg/day IV for 3 days prior to the preparatory

regimen and for 3 days post-transplant
Further study is needed in other patient populations.
Cryotherapy (ice
chips)
Demonstrates consistent reduction in incidence and severity of oral mucositis among patients receiving bolus 5-FU
Also recommended for bolus edatrexate chemotherapy
infusion and high-dose melphalan infusions in HSCT
Not recommended in patients with head and neck

cancers
Apply ice chips to mouth 5 minutes before bolus 5-FU
therapy and continue for 30 minutes after (Peterson
et al., 2012).
Not recommended in patients receiving capecitabine
or oxaliplatin because of potential discomfort with
exposure to coldness (Harris et al., 2008)
L-Glutamine
Essential amino acid, poorly absorbed

Not recommended systemically for prevention of GI mucositis
Has not been shown to prevent mucositis

IV formulation under investigation
Other
ASCOAmerican Society of Clinical Oncology; 5-FU5-fluorouracil; G-CSFgranulocytecolony-stimulating factor; GIgastrointestinal; GM-CSFgranulocyte macrophagecolony-stimulating factor; HSCThematopoietic stem cell transplantation; IVintravenous; NCINational Cancer Institute
Note. Based on information from Bensinger et al., 2008; Brown, 2011; Harris et al., 2008; National Cancer Institute, 2012b; Peterson et al., 2013; RaberDurlacher et al., 2013; Worthington et al., 2011.
From Nursing Interventions and Supportive Care for the Prevention and Treatment of Oral Mucositis Associated With Cancer Treatment, by J. Eilers, 2004,
Oncology Nursing Forum, 31(Suppl. 4), pp. 1920. Copyright 2004 by the Oncology Nursing Society. Adapted with permission.
(a) Floss the teeth with dental tape at least once daily or as advised by the clinician (Harris et al., 2008). However, patients
who do not regularly floss should not do so while immunosuppressed (Eilers & Million, 2011).
(b) Brush all tooth surfaces with a soft toothbrush for at least
90 seconds at least twice daily. Allow toothbrush to air dry
before storing, and replace toothbrush frequently (Harris et al., 2008). Sponge swabs are not as effective as toothbrushes and should be avoided when cleaning the teeth except in patients who cannot tolerate a toothbrush because
of severe pain with mucositis. However, sponge swabs may
be beneficial for cleaning the mucous membranes of the
oral cavity (Eilers & Million, 2011).
(c) Cleanse the oral cavity after meals, at bedtime, and at other times by vigorously swishing the mouth with an appropriate cleansing rinse (see Table 29). Oral rinsing should
be done to remove excess debris, hydrate the oral mucosa,
and aid in the removal of organisms (Eilers & Million, 2011;
Harris et al., 2008). Patients should use one tablespoon of
rinse to swish in the oral cavity for 30 seconds and then expectorate (Harris et al., 2008).
(d) Apply water-based moisturizers to lips.
(e) Maintain hydration
(f) Consider the use of oral moisturizers to promote comfort
if xerostomia exists (Eilers & Million, 2011).
(g) Avoid irritating agents, including commercial mouthwashes containing phenol, astringents, or alcohol; highly abrasive toothpastes; acidic, hot, or spicy foods and beverages; rough foods; alcohol; tobacco; poorly fitting dentures;
braces; and lemon-glycerin swabs and solutions (Harris
et al., 2008).
222
(h) Recommendations for patients with dentures (NCI,

2012b)
i. Clean dentures twice a day and rinse them well.
ii. Soak dentures in an antibacterial solution when they
are not being worn.
iii. Clean denture soaking cups and change soaking solution daily.
iv. Remove dentures and other oral devices when cleaning the mouth. If mouth sores are present, or if the
mouth is inflamed or painful, avoid using removable
oral devices to prevent further irritation.
(i) Instruct patients to report pain associated with mucositis.
Treat pain with oral topical agents or systemic opioids or
nonopioids. Avoid oral topical agents that contain alcohol
(Eilers & Million, 2011).
4. Anorexia
a) Definitions
(1) Anorexia: Loss of a desire to eat (NCI, n.d.) (see Table 30)
(2) Cachexia: Cancer cachexia is defined as a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass
(with or without loss of fat mass) that cannot be fully reversed
by conventional nutritional support and leads to progressive
functional impairment. The pathophysiology is characterized
by a negative protein and energy balance driven by a variable
combination of reduced food intake and abnormal metabolism (Fearon et al., 2011, p. 490) (see Figure 26).
b) Pathophysiology
(1) The two entities are interrelated. Lack of food intake is only
one factor that contributes to weight loss, muscle wasting, and
malnutrition.
(2) Anorexia/cachexia results from a complicated process involving numerous physiologic and psychological factors.
(a) Tumor effect (Inui, 2002)
i. Obstruction of the GI tract can lead to nutrient malabsorption, nausea, vomiting, and pain.
ii. Proinflammatory cytokines such as IL-6, IL-1, TNF-,
and IFN alfa may be released by the tumor and cause
satiety and metabolic abnormalities. These agents may
serve as tumor promoters and contribute to a negative
prognosis (MacDonald, 2007; Tisdale, 2010).
for Adverse Events: Anorexia
Grade
Description
Loss of appetite without alteration in eating habits
Oral intake altered without significant weight loss or malnutrition; oral nutritional
supplements indicated
Associated with significant weight loss or malnutrition (e.g., inadequate oral caloric
and/or fluid intake); tube feeding or total parenteral nutrition indicated
Death
Figure 26. Cancer Cachexia

Diagnostic Criteria
Weight loss > 5% over the past 6 months; or
Body mass index < 20 and any degree of weight loss > 2%
Appendicular skeletal muscle index consistent with sarcopenia (another wasting syndrome)
and weight loss of > 2%
Stages of Cancer Cachexia
Precachexia: Weight loss of < 5%, along with other symptoms such as impaired glucose tolerance or anorexia
Cachexia: Weight loss > 5% or other symptoms and conditions consistent with the diagnostic criteria for cachexia
Refractory cachexia: Patients experiencing cachexia who are no longer responsive to cancer
treatment, have a low performance score, and have a life expectancy of < 3 months
Note. Based on information from Fearon et al., 2011.
iii. Metabolic abnormalities may lead to elevated blood

glucose, amino acid, and free fatty acid levels, resulting in early satiety and appetite suppression.
iv. Neurohormonal abnormalities may directly affect the
hypothalamic appetite center.
v. Hypercalcemia secondary to bony involvement or
paraneoplastic syndrome may lead to nausea, vomiting, and anorexia.
(b) Treatment effects (Cunningham & Huhmann, 2011)
i. Surgery may result in malabsorption, obstruction, and
fluid and electrolyte abnormalities.
ii. Chemotherapy and radiation therapy side effects include nausea, vomiting, mucositis, taste changes, xerostomia, constipation, and diarrhea.
iii. Combination therapy results in a greater number of
adverse effects.
(c) Psychosocial effects
i. Cancer-related depression often coexists with anorexia and cachexia, especially with patients who
are at a late stage or have multiple symptoms (Jimnez et al., 2011).
ii. The prevalence of depression among patients with
cancer is estimated to be 10%30%, compared to
5%10% in the general medical population (Illman
et al., 2005).
iii. Anxiety, fear, grief, fatigue, pain, and the patients
reaction to body image changes may contribute to
anorexia.
(3) Cachexia results in decreased survival and adherence to chemotherapy and increased treatment toxicity (Blum & Strasser, 2011).
c) Incidence: Historical data demonstrated an overall incidence of anorexia/cachexia in patients with cancer of 50%, increasing to 80%
before death (Inui, 2002).
d) Risk factors (Cunningham & Huhmann, 2011; Del Fabbro, Dalal, &
Bruera, 2006)
(1) Advanced cancer
(2) Solid tumor: Most common types are head and neck, GI, and lung.
(3) Chronic illness such as pulmonary disease and congestive heart
failure
(4) Increased prevalence in the very young and older adults
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224
(5) Surgery, radiation, chemotherapy, biotherapy, and targeted

therapies
(6) Multimodal therapies
e) Clinical manifestations (Cunningham & Huhmann, 2011; Strasser
& Bruera, 2002)
(1) Involuntary weight loss of > 5% of usual weight
(2) Changes in appetite
(a) Changes in taste and smell
(b) Early satiety
(3) Changes in GI tract function
(a) Dysmotility
(b) Inactivation of bile salts or pancreatic enzymes
(c) Partial or complete obstruction
(4) Loss of muscle mass
(5) Loss of adipose tissue
(6) Fatigue and weakness
(7) Immune system impairment
(8) Metabolic dysfunction
(9) Hypoalbuminemia
f) Assessment
(1) Monitor weight: Compare with pretreatment weight.
(2) Obtain a diet history or have patient complete a food diary for
several days.
(3) Measure body composition.
(a) Triceps skinfold thickness estimates body fat.
(b) Mid-arm muscle circumference estimates muscle mass.
(4) Laboratory results
(a) Laboratory tests generally are nonspecific for malnutrition
(Cunningham & Huhmann, 2011). The practitioner will
evaluate patient labs for the presence of contributing factors that may be corrected.
(b) Assess for endocrine abnormalities (e.g., thyroid dysfunction, metabolic abnormalities, hypogonadism) (NCCN,
2013e).
(5) Assess functional status (Chang, Xia, & Kasimis, 2005; Ottery,
1994).
(a) The Patient-Generated Subjective Global Assessment and
the Functional Assessment of Anorexia/Cachexia Therapy are easy-to-use tools that patients complete in the clinical setting.
(b) Functional status tools include symptom distress and QOL
questions.
(c) Validated cachexia assessment tools based on updated definitions are being investigated (Blum & Strasser, 2011).
g) Collaborative management: The extent of nutrition intervention depends on the cause of weight loss and overall goals of the patient,
family, and healthcare team.
(1) Treatment of the cancer is the primary objective.
(2) Symptom management: Management of symptoms such as n/v,
mucositis, oral candidiasis, diarrhea, constipation, taste changes, dysphagia, xerostomia, fatigue, pain, and depression may
improve anorexia. (See the discussion of management in the
specific sections of this publication.)
(3) Pharmacologic intervention: Progestins and corticosteroids are
the only two classes of drugs to have demonstrated effectiveness as appetite stimulants (Adams et al., 2009; NCCN, 2013e).
(a) Progestins (Berenstein & Ortiz, 2012; Dy & Apostol, 2010)
i. Megestrol acetate is most commonly used.

ii. Improves appetite and weight gain in patients with
cancer; however, it does not improve QOL.
iii. Mechanism of action is not well established.
iv. Optimal dose is not defined but ranges from 100
1,600 mg/day.
v. Side effects include deep vein thrombosis, edema, impotence in men, and GI disturbances.
(b) Corticosteroids (Adams et al., 2009; NCCN, 2013e)
i. Mechanism of action is unknown but may be related
to euphoric and anti-inflammatory effects.
ii. Effects are short-lived.
iii. Many side effects, both short and long term, can occur, including immunosuppression, hyperglycemia,
and muscle wasting.
(4) Nonpharmacologic interventions (Adams et al., 2009; NCCN,
2013e)
(a) Interventions may not increase weight or length of survival but may improve QOL.
(b) Refer to a dietitian for nutritional counseling. This has been
shown to improve dietary intake.
(c) Provide high-calorie/high-protein oral supplements as
needed and tolerated.
(d) Enteral or parenteral nutrition: Consider if the disease or
treatment interferes with the patients ability to eat or to
absorb nutrients (NCCN, 2013e).
i. Enteral: Patients must have a functioning bowel. Complications include aspiration pneumonia, electrolyte
abnormalities, diarrhea, and infection.
ii. Parenteral: Includes central parenteral nutrition,
which requires a central VAD, and peripheral parenteral nutrition. Complications include high infection rate.
h) Patient education
(1) Provide written handouts, stressing high-calorie/high-protein
foods.
(2) Monitor and record weight weekly, using the same scale at the
same time of the day.
(3) Encourage small, frequent meals.
(4) Provide an attractive setting for meals.
(5) Encourage physical activity.
(6) Use measures to control n/v, mucositis, dry mouth, taste changes, and other side effects of treatment.
(7) Include patients in family activities to avoid isolation, even if patients have no appetite. Do not force patients to eat.
(8) Remind families that patients lack of appetite is caused by the
effects of the disease and treatment and is not their fault.
(9) Refer to community resources as needed, such as home care
and Meals on Wheels.
(10) Refer patients for psychosocial interventions and emotional
support.
5. Constipation
a) Definition: Excessively hard, dry bowel movements that are infrequent and a result of decreased rectal emptying or filling (CampSorrell, 2011). Constipation may be a presenting symptom of the
cancer diagnosis, a side effect of therapy, the result of tumor progression, or unrelated to the cancer or therapy. Depression and
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226
anxiety caused by cancer treatment or pain can lead to constipation, either alone or with other functional and physiologic disorders. The most common causes are inadequate fluid intake and use
of pain medications.
b) Pathophysiology: Infrequent and difficult bowel evacuation, which
can be associated with abdominal bloating, pain, and discomfort. Decreases in fluid and fiber intake and in exercise/activity contribute to
the severity of constipation (Connolly & Larkin, 2012).
(1) Common contributing factors include advanced age, autonomic nervous system dysfunction, spinal cord compression from
tumor, metabolic effects, dehydration, immobility, cancer treatment, and medications such as opioids and tricyclic antidepressants (Woolery et al., 2008).
(2) Certain chemotherapy agents that cause n/v may contribute
to constipation, as n/v may result in decreased oral intake or
slowed peristaltic movement in the GI tract. In the absence of
food intake, fewer stools are produced, transit time increases,
and the stool becomes hard and difficult to eliminate.
(a) Agents that decrease motility include vinca alkaloids. Autonomic nervous system dysfunction can result in upper
colon impaction, colicky abdominal pain, and paralytic ileus. Rectal emptying is decreased when nonfunctional afferent and efferent pathways from the sacral cord are interrupted (Camp-Sorrell, 2011).
(b) Vincristine, vinorelbine, and vinblastine can cause neurotoxicity that affects the smooth muscles of the GI tract, leading to decreased peristalsis or paralytic ileus.
(c) Vincristine may damage the mesenteric plexus of the colon.
(3) Opioids profoundly affect the bowels ability to maintain appropriate motility. They are the primary cause of medicationinduced constipation (Bohnenkamp & LeBaron, 2010).
c) Incidence
(1) Clinically, constipation is a common problem for patients with
cancer occuring in 50%95% of patients. Patients receiving opioids are at highest risk (Woolery et al., 2008).
(2) Constipation has been reported in 20%35% of patients receiving vinblastine, especially in high doses or after prolonged
treatment (Engelking, 2008).
(3) Constipation, abdominal pain, and paralytic ileus are common
side effects of vincristine (Chu & DeVita, 2012).
(4) Vinorelbine may cause severe constipation, with an overall incidence of all grades of 35% (Sagent Pharmaceuticals, 2009).
(5) Constipation occurs in up to 55% of patients receiving thalidomide (Celgene Corp., 2013b) and approximately 38% of patients receiving lenalidomide (Celgene Corp., 2013a).
(6) Bortezomib causes constipation in 42% of patients (Millennium Pharmaceuticals, 2012).
d) Clinical consequences
(1) Abdominal or rectal discomfort or pain
(2) Nausea and/or vomiting
(3) Anorexia
(4) Impaction/obstruction
(5) Ileus
(6) Anal fissures
(7) Hemorrhoids
(8) Ruptured bowel and life-threatening sepsis
e) Risk factors (Woolery et al., 2008)
(1) Advanced age

(2) Mechanical pressure on the bowel (e.g., bowel obstruction secondary to tumor in the GI tract, pressure from ascites)
(3) Damage to the spinal cord from T8 to L3, which causes compression of nerves that innervate the bowel
(4) Decreased mobility
(5) Dehydration
(6) Poor nutritional intake
(7) Low dietary fiber intake
(8) Metabolic and endocrine disorders
(a) Hypercalcemia
(b) Hypothyroidism
(c) Hypokalemia
(d) Diabetes mellitus
(9) Use of certain medications (Woolery et al., 2008)
(a) Neurotoxic chemotherapy drugs
(b) Anticholinergic medications
(c) Diuretics
(d) Opioids
(e) Aluminum- and calcium-based antacids
(f) Calcium and iron supplements
(g) Tricyclic antidepressants
(h) Antihypertensives
(i) Antispasmodics
(j) 5-HT3 antagonists
(k) NSAIDs
(l) Barbiturates
(10) Overuse of laxatives
f) Assessment
(1) Assess patterns of elimination, including the amount and frequency of elimination and the urge to defecate, character and
volume of the stool, and use of laxatives, stool softeners, or
other measures to enhance bowel function. Note that small
amounts of loose stool may indicate constipation as the liquid
stool passes around a stool mass. Small, pellet-like stool indicates slow colonic transit time, and long, thin pieces of stool
may indicate stenosis or hemorrhoids (Bohnenkamp & LeBaron, 2010).
(2) Assess patients usual dietary patterns, focusing on fluid and fiber intake.
(3) Assess mobility, activity level, and functional status.
(4) Assess for abdominal pain, distention, and presence or absence
of bowel sounds.
(5) Assess for the presence of straining, rectal pressure, excessive
flatulence, or cramping.
(6) Determine facts about the patients last bowel movement (e.g.,
when it occurred, amount, consistency, color, presence of blood).
(7) Determine current medication usage.
(8) Use laboratory results to assist in metabolic evaluation.
(9) Perform abdominal palpation and rectal examination if appropriate. A rectal examination is not routinely performed in pediatric patients. Rectal or stoma manipulation for examinations,
enemas, or suppositories should be avoided in myelosuppressed
patients because of the risk for bleeding, fissures, or abscesses
(NCI, 2012a; Woolery et al., 2008).
(10) Use radiographic imaging to differentiate between mechanical
obstruction and decreased motility from an ileus.
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228
g) Collaborative management: No evidence has shown any one laxative to be more efficacious than another (Woolery et al., 2008). The
cause of the constipation should be considered prior to beginning
treatment. NCCN (2013e) palliative care guidelines offer guidance
for the treatment of constipation.
(1) Pharmacologic interventions
(a) Bulk-forming laxatives (e.g., methylcellulose, psyllium,
calcium polycarbophil): Cause water to be retained in the
stool. Must be taken with at least 200300 ml of water to
avoid intestinal obstruction and are of limited use in patients who cannot tolerate fluids (Bohnenkamp & LeBaron, 2010; Woolery et al., 2008). Side effects include flatulence, abdominal distention and bloating, mechanical obstruction, and anaphylactic reactions (Woolery et al., 2008).
(b) Lubricant laxatives (e.g., mineral oil, glycerin suppositories): Coat and soften the stool. Excessive doses can lead
to malabsorption of fat-soluble vitamins and rectal seepage with perianal irritation (Bohnenkamp & LeBaron,
2010).
(c) Saline laxatives (e.g., magnesium salts, sodium phosphate):
Contain magnesium or sulfate ions. Act by drawing water
into the gut. Are of little use in a daily prevention program
and are used most often for acute evacuation of the bowel. Hypermagnesemia or hyperphosphatemia can occur
with renal insufficiency (Bohnenkamp & LeBaron, 2010).
(d) Osmotic laxatives (e.g., lactulose, sorbitol, polyethylene glycol [PEG]): Attract and retain water in the bowel, resulting
in softer stool. Side effects include abdominal pain, distention, and gas (Bohnenkamp & LeBaron, 2010).
(e) PEG with or without electrolytes is considered a hyperosmotic laxative and increases the water content of stool.
NCCN (2013e) recommends PEG for persistent constipation. Woolery et al. (2008) recommended that electrolytes not be administered with PEG when kidney function
is compromised.
(f) Detergent laxatives (e.g., docusate sodium): Have a direct
action on the intestines by allowing water and fats to penetrate into dry stool and decreasing electrolyte and water
absorption from the colon. Appropriate for short-term use
when straining is to be avoided.
(g) Stimulant laxatives (e.g., bisacodyl, senna): Act directly on
the colon to stimulate motility and are activated by bacterial degradation in the intestine. Most commonly used in a
prophylactic plan. Side effects include abdominal discomfort, electrolyte abnormalities, and hepatotoxicity (Woolery et al., 2008).
(h) Suppositories: Stimulate the intestinal nerve plexus and
cause rectal emptying. Not indicated for long-term bowel management.
(i) Prokinetic agents (e.g., metoclopramide, 1020 mg by
mouth every six hours): Promotes motility in the upper
GI tract and hastens gastric emptying and intestinal transit time. Exhibits antiemetic properties, which are the result of central and peripheral dopamine receptor inhibition. Doses are higher when used for CINV (Micromedex,
2013). Consider adding a prokinetic agent for constipation that is not associated with obstruction (NCCN, 2013e).
(j) Methylnaltrexone is approved for opioid-induced constipation in patients with advanced illness who are receiving
palliative care. It is a peripherally acting opioid receptor
antagonist that has shown efficacy in preventing opioidinduced constipation without diminishing pain, palliation,
or precipitating opioid withdrawal. Dosing is 0.15 mg/kg SC
every other day, not more often than once a day (NCCN,
2013e). Most common adverse effects reported were flatulence, abdominal pain, dizziness, diarrhea, nausea, and
hyperhidrosis. This drug is contraindicated with known or
suspected mechanical GI obstruction (Salix Pharmaceuticals, Inc., 2012).
(k) Use a combination laxative-stool softener prophylactically for patients receiving vinca alkaloids (Engelking, 2008).
(2) Other
(a) Include increased physical activity or passive exercise as appropriate in a bowel retraining regimen. This promotes the
urge to defecate by helping to move feces into the rectum.
(b) Help patients to maintain usual bowel habits during hospitalization. Provide privacy and comfort. Avoid use of a bedpan when constipation exists.
(c) Increase fluid and fiber intake and obtain a nutritional consult (Woolery et al., 2008).
(d) Begin management with oral medications.
(e) Rotating opioids may decrease constipation (e.g., switching
from a long-acting oral morphine to a transdermal fentanyl patch) (Woolery et al., 2008).
(f) Patient and family education
i. Increase fluid intake: Encourage patients to drink at
least eight 8-oz glasses of fluid daily unless medically contraindicated. Drinking warm or hot liquids before a defecation attempt may help to stimulate bowel movement (Woolery et al., 2008).
ii. Increase fiber in diet: Fiber causes feces to pass through
intestines more rapidly and decreases the occurrence
of fecal impaction.
High-fiber foods include 100% whole-grain cereals, breads, and bran; fruits such as prunes, peaches, apples, raisins, and dates; and vegetables such as
squash, broccoli, carrots, and celery (NCI, 2012a).
Advise patients that they may experience abdominal
discomfort, flatulence, or a change in bowel habits
in the first few weeks after increasing fiber intake.
Fiber tolerance will develop, and such effects can
be minimized by slowly titrating fiber consumption.
Adults should consume 2530 g/day total if tolerated (NCI, 2012a). This approach is contraindicated in patients who are at risk for bowel obstruction
(NCI, 2012a).
Fiber should not be recommended in patients with
cancer who have inadequate fluid intake (NCI,
2012a).
(3) Encourage patients to exercise regularly. Regular exercise stimulates GI motility.
(4) Teach diaphragmatic breathing and abdominal muscle exercises; these help to increase muscle tone, which assists with defecation (Engelking, 2008).
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(5) Help patients to develop a regular bowel program.

(6) Instruct patients to report constipation and to be aware of the
complications associated with constipation, such as fecal impaction.
(7) Stress that patients should call a physician to initiate a bowel
program if three days pass without a bowel movement.
(8) Ensure that all patients who are prescribed opioids are started
on pharmacologic and nonpharmacologic interventions to prevent constipation and maintain bowel program until opioids are
discontinued (Bohnenkamp & LeBaron, 2010).
6. Perirectal cellulitis
a) Definition: Inflammation and edema of the perineal and rectal area
b) Pathophysiology
(1) Minimal tears of the anorectal mucosa allow infection. The
most common anaerobic organisms include Bacteroides fragilis,
Peptostreptococcus, Prevotella, Fusobacterium, Porphyromonas, and
Clostridium. The most common aerobic bacteria include Staphylococcus aureus, Streptococcus, and Escherichia coli. Communityacquired methicillin-resistant Staphylococcus aureus (known as
MRSA) has been implicated in rectal abscess infections (Valesky
& Kifaieh, 2012).
(2) Infection starting as a local abscess can lead to systemic sepsis.
c) Incidence: Overall incidence has decreased in the past decade, presumably because of the early use of empiric antibiotics in febrile neutropenic patients. Perirectal abscesses are more common in patients
with anorectal cancer or hematologic malignancies and may be present at initial diagnosis (Valesky & Kifaieh, 2012).
d) Risk factors
(1) Chronic neutropenia or thrombocytopenia
(2) Constipation: The passage of hard stool causes trauma to the
rectal mucosa.
(3) Diarrhea: Caustic fluid irritates and breaks down perirectal tissue.
(4) Perirectal mucositis caused by chemotherapy and/or radiation therapy
(5) Any rectal trauma, such as rectal stimulation or the use of rectal thermometers, enemas, or suppositories
(6) Hemorrhoids or anal fissures/abscesses
e) Assessment
(1) Ask patients if they are experiencing perineal and/or rectal discomfort. Fear of defecation related to pain may not be reported and may increase risk of constipation. A large majority of patients with anal abscess will complain of dull, aching, or throbbing pain, which may worsen when sitting or before defecation.
(2) Monitor for the presence of fever.
(3) Perform a physical examination of the perineal area. The entrance site for the infective agent may be a small tear that shows
minimal irritation. Conversely, localized tenderness, gross swelling, fluctuance, erythema, and drainage may be observed if an
abscess is present. An abscess of the perirectal area may produce bloody, purulent, or mucoid drainage. Obtain a culture,
if possible, for identification of infectious organisms (Valesky
& Kifaieh, 2012).
(4) Consider abdominal/pelvic CT (NCCN, 2013f) if an abscess
is suspected. MRI and ultrasound are also used for diagnosis
of an abscess. Look for and document tissue sloughing and
necrosis.
f) Collaborative management (NCCN, 2013f)
(1) Ensure that antibiotic coverage includes a specific antianaerobic

agent in addition to broad-spectrum aerobic coverage. Consider
Enterococcus or Candida coverage if appropriate (NCCN, 2013f).
(2) Administer antipyretic medications to relieve fever.
(3) Teach and encourage patients to take sitz baths or use gentle
external perineal irrigation.
(4) Administer stool softeners, and encourage patients to eat a lowbulk diet. Consult a dietitian as needed.
(5) Inspect the perirectal mucosa frequently for any signs of irritation or skin breakdown.
g) Patient and family education
(1) Teach patients and significant others to
(a) Maintain meticulous perineal hygiene, especially in the
presence of neutropenia.
(b) Apply appropriate barrier creams and medicated creams.
(c) Monitor carefully for any signs of infection or worsening
of tissue integrity.
(2) Ensure that patients and significant others are able to
(a) Identify the risk factors for perirectal cellulitis.
(b) Implement measures that minimize the risk of developing
perirectal cellulitis.
(c) Identify situations that require prompt professional intervention.
i. Pain, redness, or swelling in the affected area
ii. Body temperature > 100.4F (38C)
C. Cutaneous toxicity: Chemotherapy and its cutaneous side effects are an increasingly common source of injury to the skin, hair, and nails. For years,
the cutaneous side effects from conventional cytotoxic chemotherapeutic
agents have been observed and described in detail. More recently, the emergence of targeted chemotherapy drugs has widened the spectrum of adverse
cutaneous side effects seen in patients with cancer (Choi, 2011). See Table
31 for cutaneous reactions and management of toxicities from chemotherapy, biotherapy, and targeted agents.
1. Over the past decade, cancer therapy has increasingly shifted toward targeting specific pathways involved in the pathogenesis of malignancy. The
EGFR inhibitors (EGFRIs) are one of the best known examples of targeted therapy that are used both as first-line and adjuvant chemotherapy for solid organ cancers. These agents are less likely than traditional
cytotoxic chemotherapeutics to cause myelosuppression, infection, nausea, vomiting, and diarrhea. However, dermatologic adverse events from
EGFRIs, small molecule inhibitors, and mAbs such as gefitinib, erlotinib,
cetuximab, lapatinib, and panitumumab are significantly more common
than with cytotoxic agents, are symptomatic, and manifest in cosmetically sensitive areas (Wu, Balagula, Lacouture, & Anadkat, 2011). As the
number of agents and uses for targeted therapies increase, so does the
need to recognize and treat the dermatologic side effects of these agents.
2. Pathophysiology
a) EGFR is normally expressed in the epidermis, sebaceous glands, and
hair follicular epithelium, where it plays a number of important roles
in the maintenance of normal skin health, including control of differentiation, protection against damage induced by ultraviolet radiation, inhibition of inflammation, and acceleration of wound healing (Melosky et al., 2009).
b) Although not fully understood, inhibition of EGFR is believed to
cause follicular occlusion and rupture because of premature epithelial differentiation and an increase in the expression of genes that
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Table 31. Cutaneous Reactions to Antineoplastic Agents

General Comments
Chemotherapy
Biotherapy and Targeted Therapy
A number of chemotherapy drugs can cause hair changes and

Hair changes:
hair loss. Dose, route of administration, combination of drugs,
Alopecia, hirand other individual characteristics will influence occurrence as
sutism, hypertriwell as degree of hair loss.
chosis
Hair changes may occur 23 months after initiation of EGFRI
therapy, with hair thinning and developing a dry, brittle, or curly
texture (Segaert & Van Cutsem, 2005).
Hirsutism is characterized by excess hair growth in women in anatomic sites where growth is typically a male characteristic (beard,
mustache, chest, and abdomen) (Lacouture et al., 2010).
Hypertrichosis is characterized by hair density or length beyond
the accepted limits of normal in a particular body region or a
particular age or race (Lacouture et al., 2010).
Hair changes: Bexarotene, carboplatin,

cisplatin, cyclophosphamide, dactinomycin, doxorubicin, etoposide, hexamethylmelamine, ifosfamide, paclitaxel, vincristine
Alopecia: Carboplatin, cisplatin, cyclophosphamide, Ara-C, dacarbazine,
dactinomycin, daunorubicin, doxorubicin, etoposide, 5-FU, hydroxyurea, ifosfamide, methotrexate, vinblastine, vincristine (Kamil et al., 2010)
Alopecia: Axitinib, eltrombopag, eribulin, pazopanib, pegylated IFN alfa-2b, vemurafenib (Wolters Kluwer
Health, Inc., 2012); cetuximab (Bristol-Myers Squibb
Co. & ImClone Systems, 2012); gefitinib (AstraZeneca Pharmaceuticals, 2010); panitumumab (Amgen Inc.,
2013b); sorafenib (Bayer HealthCare Pharmaceuticals
Inc., 2011)
Alopecia, hirsutism, hypertrichosis: everolimus (Wolters
Kluwer Health, Inc., 2012)
Hair color changes and alopecia: sunitinib (Pfizer Inc.,
2012c)
Trichomegaly
Increased hair growth of the eyelashes and eyebrows is rare but

can occur (Segaert & Van Cutsem, 2005).
Trichomegaly is associated with patient discomfort and can lead to
corneal abrasions and further ocular complications. Ocular changes may occur within 12 weeks of treatment (Boucher et al., 2011).
Trichomegaly can be treated with lash clipping every 24 weeks.
Referral to an ophthalmologist is indicated for patients with irritation or persistent discomfort. Topical eflornithine cream has
been well tolerated (Lacouture et al., 2011).
Waxing or electrolysis may be recommended (Braiteh et al., 2008;
Segaert & Van Cutsem, 2005).
Cyclosporine, gemcitabine (Bouch et

al., 2005)
Cetuximab (Bristol-Myers Squibb Co. & ImClone Systems, 2012); gefitinib, IFN alfa-2b (Bouch et al., 2005);
panitumumab (Amgen Inc., 2013b)
Paronychia
Paronychia is characterized by tender, edematous, often purulent

inflammation of the nail fold. Fingernails and toenails may be affected, with the first digits the most commonly affected (Lacouture
et al., 2011).
It is often delayed, developing 48 weeks after start of therapy
and occurring in 12%58% of patients (Potthoff et al., 2011;
Segaert & Van Cutsem, 2005).
Encourage preventive measures, such as keeping hands dry and
out of water if possible, wearing gloves while cleaning (e.g.,
household, dishes), avoiding friction and pressure on the nail
fold or manipulation of the nail, and wearing comfortable shoes
(Lacouture et al., 2011; Potthoff et al., 2011).
Treatment may include white vinegar (1:10) or bleach soaks (1/4
cup bleach in 3 gallons of water) or topical agents (Wu et al.,
2011). Oral antibiotics or surgical intervention may be indicated
(Lacouture et al., 2010).
Bleomycin, cyclophosphamide, docetaxel, doxorubicin, hydroxyurea, methotrexate
Cetuximab (Bristol-Myers Squibb Co. & ImClone Systems, 2012); gefitinib (AstraZeneca Pharmaceuticals,
2010); panitumumab (Amgen Inc., 2013b)
Cutaneous
Reaction
Table 31. Cutaneous Reactions to Antineoplastic Agents (Continued)

Cutaneous
Reaction
Nail changes
General Comments
Chemotherapy
Cyclophosphamide, daunorubicin, doxorubicin, ifosfamide (Kamil et al., 2010)
Cetuximab (Bristol-Myers Squibb Co. & ImClone Systems, 2012); gefitinib (AstraZeneca Pharmaceuticals,
2010); panitumumab (Amgen Inc., 2013b); temsirolimus
Nail shedding
(onycholysis)
Loss of all or a portion of the nail (Lacouture et al., 2010)
Bleomycin, cisplatin, docetaxel, doxorubicin, melphalan, mitoxantrone, topical

5-FU, vincristine, weekly paclitaxel administration (Huang & Anadkat, 2011;
Hussain et al., 2000)
Everolimus (Wolters Kluwer Health, Inc., 2012)
Dystrophy
Transverse midline linear groove in the nail plate
Bleomycin, hydroxyurea
Dystrophy and nail changes are common with EGFRIs.
Beau lines
Transverse ridges across the nail plate. These findings are benign, dose related, and resolve with cessation of chemotherapy
(Huang & Anadkat, 2011).
Bleomycin, cisplatin, docetaxel (taxanes), doxorubicin, melphalan, vincristine (Huang & Anadkat, 2011);
capecitabine, hydroxyurea
Beau lines and nail changes are common with EFGRIs.
Hyperpigmentation
Hyperpigmentation is the darkening of an area of skin or nails

caused by increased melanin.
Cutaneous hyperpigmentation associated with chemotherapeutics can present in localized or generalized patterns affecting the
skin, teeth, or nails (Huang & Anadkat, 2011).
Patients should avoid sun exposure or use effective sun barrier
preparations to minimize the risk of hyperpigmentation. Sun exposure aggravates hyperpigmentation.
Bleaching creams are not helpful; the hyperpigmentation will fade
spontaneously with time (months) (Segaert & Van Cutsem,
2005).
It occurs most commonly in people of Mediterranean descent.
Darkening may occur within 23 weeks of chemotherapy/biotherapy and persist for months following the completion of therapy.
Postinflammatory hyperpigmentation is seen following acneform
eruption or other causes of skin inflammation such as eczema
or an inflamed sebaceous cyst (Segaert & Van Cutsem, 2005).
Alkylating agents are most commonly associated with mucocutaneous hyperpigmentation (Huang & Anadkat,
2011).
Bleomycin, busulfan, cyclophosphamide,
dacarbazine, daunorubicin, docetaxel,
doxorubicin, etoposide, 5-FU, hydroxyurea, melphalan, methotrexate, nitrogen mustard, nitrosoureas, paclitaxel
(Vassallo et al., 2001); dactinomycin, ifosfamide, prednisolone, 6-mercaptopurine (Kamil et al., 2010)
Flagellate streaks of hyperpigmentation
caused by nail scratching the skin have
been reported with parenteral and intrapleural administration of bleomycin

233
234
Rash
General Comments
Chemotherapy
Manifestation of mAb-induced skin rash: Rash appears to be dose

related and generally evolves within 13 weeks of the start of
treatment. No association has been observed between mAbmediated skin rash and past or preexisting skin abnormalities
such as acne or rosacea (Melosky et al., 2009).
Docetaxel, paclitaxel (Hetherington et

al., 2007); bendamustine HCI (Cephalon, Inc., 2012); Ara-C, asparaginase,
carboplatin, cyclophosphamide, dacarbazine, 5-FU, hydroxyurea, ifosfamide,
lomustine, methotrexate, vinblastine,
vincristine (Kamil et al., 2010)
Ara-C can cause skin peeling (Kamil et
al., 2010).
Axitinibrash: all grades, 13%; grades 34, < 1% (Wolters Kluwer Health, Inc., 2012)
Cetuximabrash: grades 14, 89%; grades 34, 12%
(Bristol-Myers Squibb Co. & ImClone Systems, 2012)
Crizotinibrash: 10% (Wolters Kluwer Health, Inc., 2012)
Denosumabrash: 3%11%; dermatitis: 11%; eczema:
11% (Wolters Kluwer Health, Inc., 2012)
Eltrombopagrash: 3% (Wolters Kluwer Health, Inc., 2012)
Erlotinibrash: any grade, 75%; grade 3, 8%; grade 4, <
1% (Astellas Pharma US, Inc., & Genentech, Inc., 2012)
Everolimusrash: 18%59% (Wolters Kluwer Health, Inc.,
2012)
Ipilimumabrash: all grades, 19%29%; grade 35, 2%;
dermatitis: grade 2, 12%; grades 35, 2%3% (Wolters
Lapatinibrash: all grades, 28%; grade 3, 2%; grade 4,
0% when given in combination with capecitabine (Genentech, Inc., 2011); dry skin: all grades, 10%; grades
34, 0% when given in combination with capecitabine
Ofatumumabrash: 14% (Wolters Kluwer Health, Inc.,
2012)
Panitumumabskin rash: all grades, 22%; grades 34,
1% (Amgen Inc., 2013b)
Pazopanibrash: 8% (Wolters Kluwer Health, Inc., 2012)
Pegylated IFN alfa-2brash: 6%36% (Wolters Kluwer
Health, Inc., 2012)
Pertuzumabrash: 34% (Wolters Kluwer Health, Inc., 2012)
Pralatrexaterash: all grades, 15%; grades 34, 0%
(Wolters Kluwer Health, Inc., 2012)
Romidepsindermatitis/exfoliative dermatitis: 4%27%
Sorafenibrash/desquamation: all grades, 19%, grade 3,
1% (Bayer HealthCare Pharmaceuticals Inc., 2011)
Sunitinibrash: all grades, 29%; grades 34, 2% (Pfizer
Inc., 2012c)
Trastuzumabrash: 18%; herpes simplex: 2%; acne: 2%;
trastuzumab + paclitaxelrash: 38% (Genentech, Inc.,
2012b)
Vemurafenibrash: 37%54%; grade 3, 7%8% (Wolters
Vandetanibrash: all grades, 53%; grades 34, 9%
Cutaneous
Reaction

Cutaneous
Reaction
Chemotherapy
Acneform
eruptions or
papulopustular
rash
An EGFRI-mediated rash generally follows a well-characterized clinical course. Within the first week of treatment, patients experience sensory disturbance with erythema and
edema; from weeks 13, the papulopustular eruption manifests, followed by crusting at week 4. Despite successful
treatment, erythema and dry skin may persist in the areas
previously affected by skin rash through weeks 46 (Melosky
et al., 2009).
It generally presents as a diffuse erythema over the face and
body, progressing to follicular papules and pustules resembling
acne.
Causative chemotherapy agents should be discontinued. Causative EGFRIs may not need to be discontinued.
The disorder is characterized by an eruption consisting of papules
(a small, raised pimple) and pustules (a small pus-filled blister), typically appearing on the face, scalp, and upper chest and
back. Unlike acne, this rash does not present with whiteheads or
blackheads and can be symptomatic, with itchy or tender lesions
See text for grading and management of papulopustular rash.
Cetuximabacneform rash: grades 14, 87%; grades

34, 17% (Bristol-Myers Squibb Co. & ImClone Systems, 2012)
Erlotinibrash: all grades, 75%; grade 3, 8%; grade 4, <
1% (Astellas Pharma US, Inc., & Genentech, Inc., 2012)
Everolimusacne: 3%25% (Wolters Kluwer Health, Inc.,
2012)
Gefitinibacne: all grades, 10.9%25%; grade 1, 19%;
grade 2, 6%; grades 34, 0%; dermatitis acneform:
5.8%; rash/acne: 65.6% (AstraZeneca Pharmaceuticals, 2010)
Lapatinibdermatitis acneform: all grades, 44%; grade 3,
< 1%; grade 4, 0% (GlaxoSmithKline, 2012)
Panitumumabacne dermatitis: all grades, 57%; grades
34, 7%; acne: all grades, 13%; grades 34, 1% (Amgen Inc., 2013b)
Temsirolimusacne: all grades, 10%; grades 34, 0%
Vandetanibdermatitis acneform/acne: grades 34,
1%. Withhold treatment for grade 3 or higher. Consider
dose reduction or permanent discontinuation upon improvement of symptoms (Wolters Kluwer Health, Inc.,
2012).
Erythema
multiforme
Condition generally presents as a macular-papular erythematous

lesion that may progress to vesicles and also can progress to
Stevens-Johnson syndrome and toxic epidermal necrolysis.
Record description, presentation, and severity (use a grading
scale). Consult with physician regarding possible etiology. Consider discontinuing offending chemotherapy agent. Causative
EGFRIs may not need to be discontinued.
Examine areas of tissue breakdown, and attend to comfort measures with skin care and pain management strategies (see
guidelines in text).
Infrequently associated with chemotherapy. High-dose combination chemotherapy produces highest risk. Characterized by lesions over the extremities and often involving mucous membranes. Busulfan, etoposide, procarbazine, hydroxyurea, bleomycin, methotrexate, and cytarabine are associated with these lesions, which sometimes progress to generalized blistering
Can occur with allopurinol, carba
mazepine, phenytoin sodium, sulfa
drugs, and various antibiotics, anticonvulsants, and antituberculoid agents
(Plaza et al., 2013)
Vemurafenibmaculopapular rash: 9%21%; papular

rash: 5%13%; skin papilloma: 21%30%; hyperkeratosis: 24%28%; cutaneous squamous cell carcinoma:
all grades, 24%; grade 3, 22%24% (Wolters Kluwer
Health, Inc., 2012)
235
General Comments
236

General Comments
Erythema
multiforme
(cont.)
Blistering of the
skin
Chemotherapy
Daunorubicin, doxorubicin, 5-FU,

ifosfamide, vinblastine (Kamil et al.,
2010); amifostine, cladribine, cyclophosphamide, docetaxel,
gefitinib, mechlorethamine, mitomycin
C, mitotane, paclitaxel, tamoxifen
Bexarotene (Targretin)maculopapular rash: 6% (Ligand Pharmaceuticals,
2011)
5-FU, vinblastine (White & Cox, 20011)
IL-2 (White & Cox, 2006)
Xerosis
Abnormal dryness of the skin, mucous membranes, or conjunctiva (Segaert & Van Cutsem, 2005)
Treatment of mild or moderate xerosis consists of thick moisturizing creams without fragrances or potential irritants. Moisturizers should be occlusive, emollient creams that are generally
packaged in a jar or tub rather than a lotion that can be pumped
or poured. Specific creams can include urea, colloidal oatmeal,
and petroleum-based creams.
For scaly areas of xerosis, ammonium lactate or lactic acid
creams can be used. Greasy creams may be used on the limbs
for better control of xerosis but are cautioned on the face and
chest, along with extremely hairy sites, because of the risk for
folliculitis secondary to occlusion.
For more severe xerosis causing inflammation with or without eczema, topical steroid creams may be necessary. Topical retinoids and benzoyl peroxide gels are not recommended because
of their drying effect (Lacouture et al., 2011).
Bexarotenedry skin: 9.4%10.7%;

rash: 16.7%, severe, 2%; exfoliative dermatitis: 9.5%, moderate to severe, 1%3% (Ligand Pharmaceuticals, 2011)
Axitinibdry skin: 10% (Wolters Kluwer Health, Inc., 2012)

Cetuximabdry skin: 49%; pruritus: 40% (Bristol-Myers
Squibb Co. & ImClone Systems, 2012)
Erlotinibrash: all grades, 75%; grade 3, 8%; grade 4, <
1%; dry skin: all grades, 12%; grades 34, 0% (Wolters
Gefitinibdry skin: all grades, 13%; grade 1, 12%; grade
2, 1%; grades 34, 0% (AstraZeneca Pharmaceuticals,
2010)
Pegylated IFN alfa-2bdry skin: 11% (Wolters Kluwer
Health, Inc., 2012)
Sorafenibpruritus: all grades, 14%; grade 3, < 1%; dry
skin: 10% (Bayer HealthCare Pharmaceuticals Inc., 2011)
Sunitinibdry skin: all grades, 15%; grades 34, < 1%
(Pfizer Inc., 2012c)
Temsirolimusdry skin: all grades, 11%; grades 34, 1%;
rash: all grades, 47%; grades 34, 10% (Wyeth Pharmaceuticals, 2012)
Vandetanibdry skin: 15% (Wolters Kluwer Health, Inc.,
2012)
Vemurafenibdry skin: 16%19%; seborrheic keratosis:
10%14% (Wolters Kluwer Health, Inc., 2012)
Painful fissures
Skin fissures and deep cracks in the skin can form as a result of
significant xerosis and often occur in the fingertips, palms or
knuckles, and the soles. Fissures are a late side effect of EGFRI
therapy, occurring around 3060 days into therapy. They can be
very painful and create risk for infection (Lacouture et al., 2011).
Cyanoacrylate glue (liquid bandage formulations) may be helpful
in protecting the fissures (Segaert & Van Cutsem, 2005).
EGFRI therapy can lead to painful fissures.

Panitumumaball grades, 20%; grades 34, 1% (Amgen
Inc., 2013b)
Cutaneous
Reaction

Cutaneous
Reaction
General Comments
Chemotherapy
Treat topically with propylene glycol 50% in water for 30 minutes

under plastic occlusion every night, followed by application of
hydrocolloid dressing, antiseptic baths, or topical application of
silver nitrate (Potthoff et al., 2011).
Painful fissures on toes: Use protective footwear and a topical
corticosteroid, thick moisturizer, or barrier cream (petroleum jelly, zinc oxide) (Wu et al., 2011).
Telangiectasia
Disorder is characterized by local dilation of small vessels resulting in red discoloration of the skin or mucous membranes
Early during the development of acneform eruption or with subsequent flares of the rash, scattered telangiectasia may appear on
the face, on and behind the ears, and on the chest, back, and
limbs, usually in the vicinity of a follicular pustule. Unlike other telangiectasia, the lesions tend to fade over months, usually
leaving some hyperpigmentation (Lacouture et al., 2010).
Telangiectasia caused by treatment with EGFRIs, unlike spontaneous telangiectasia, will gradually disappear over months. In select
cases, electrocoagulation or pulsed dye laser therapy can be applied to accelerate disappearance (Segaert & Van Cutsem, 2005).
Radiation may cause telangiectasia, which is thought to be related to the destruction of the capillary bed. It generally is considered a permanent change in the vessel (Haas, M.L., 2011).
Topical carmustine and mechlorethamine

(nitrogen mustard) cause vessel fragility
and destruction (Camp-Sorrell, 2011).
Scattered telangiectasia can be seen with the development of any acneform eruption caused by EGFRIs.
Stevens-Johnson syndrome
Stevens-Johnson Syndrome is a rare, serious disorder in which

the skin and mucous membranes react severely to a medication
or infection. It often begins with flu-like symptoms, followed by a
painful red or purplish rash that spreads and blisters, eventually
causing the top layer of the skin to die and shed.
Stevens-Johnson Syndrome presents a medical emergency that
usually requires hospitalization. Treatment focuses on eliminating the underlying cause, controlling symptoms, and minimizing
complications (Mayo Clinic Staff, 2011).
Cases of Stevens-Johnson Syndrome and

toxic epidermal necrolysis, some fatal,
have been reported when bendamustine HCI (Treanda) was administered
concomitantly with allopurinol and other
medications known to cause these syndromes. The relationship to Treanda cannot be determined (Cephalon, Inc., 2012).
Stevens-Johnson Syndrome has been reported with allopurinol, amifostine, asparaginase, bleomycin, bortezomib,
capecitabine, cetuximab, chlorambucil, cladribine, cyclophosphamide, cytarabine, docetaxel, doxorubicin, etoposide, 5-FU, gefitinib, imatinib, lenalidomide, letrozole, levamisole, methotrexate, paclitaxel, procarbazine, rituximab,
and thalidomide.
Gefitinib0.04% (AstraZeneca Pharmaceuticals, 2010)

Ipilimumab2%3% (Wolters Kluwer Health, Inc., 2012)
VemurafenibStevens-Johnson syndrome has been observed. Discontinue drug permanently (Wolters Kluwer
Health, Inc., 2012).
237
Painful fissures
(cont.)
238
General Comments
Chemotherapy
Toxic epidermal
necrolysis
Toxic epidermal necrolysis is most commonly drug induced. However, the disorder has other potential etiologies, including infection, malignancy, and vaccinations. toxic epidermal necrolysis is
idiosyncratic, and its occurrence is not easily predicted.
Some authors believe that Stevens-Johnson syndrome (also
known as erythema multiforme major) is a manifestation of the
same process involved in toxic epidermal necrolysis, with the latter involving more extensive necrotic epidermal detachment.
toxic epidermal necrolysis involves > 30% of the body surface,
whereas Stevens-Johnson syndrome involves < 10% (Cohen et
al., 2013).
Bendamustine HCIin combination with

rituximab, one case of toxic epidermal
necrolysis occurred. Toxic epidermal
necrolysis has been reported with rituximab. Report and withhold bendamustine
and/or rituximab (Cephalon, Inc., 2012).
Toxic epidermal necrolysis has been reported with allopurinol, amifostine, asparaginase, bleomycin, bortezomib,
capecitabine, cetuximab, chlorambucil, cladribine, cyclophosphamide, cytarabine, docetaxel, doxorubicin, etoposide, 5-FU, gefitinib, imatinib, lenalidomide, letrozole, levamisole, methotrexate, paclitaxel, procarbazine, rituximab,
and thalidomide.
Gefitinib0.04% (AstraZeneca Pharmaceuticals, 2010)

Ipilimumabdermal ulceration, necrotic, bullous, or hemorrhagic dermatitis: 2%3% (Wolters Kluwer Health,
Inc., 2012)
Vemurafenibtoxic epidermal necrolysis has been observed. Discontinue drug permanently (Wolters Kluwer
Health, Inc., 2012).
Acral erythema
Generally presents as dysesthesia (altered sensation of the skin)

with tingling in the hands and feet progressing to pain
After 4 or 5 days of intense edematous erythema and even fissures of the palms, soles, and digital joints, progression to desquamation and reepithelialization occurs. It resolves 57 days
after therapy is discontinued. The etiology is not clear but may
be related to drug concentration in eccrine glands of the palms
and soles.
Applying cold compresses and elevating hands and feet during
drug administration may minimize incidence and degree of toxicity.
Skin care and comfort measures are instituted as soon as symptoms are evident. Supportive care may include wound dressings, analgesia (pain relief), and cold compresses.
High-dose cytarabine, capecitabine,

docetaxel, doxorubicin, 5-FU, floxuridine, liposomal doxorubicin, methotrexate, paclitaxel (Camp-Sorrell, 2011)
Axitinib2% (Wolters Kluwer Health, Inc., 2012)

Everolimus4% (Wolters Kluwer Health, Inc., 2012)
Cutaneous
Reaction

Cutaneous
Reaction
Palmar-plantar
erythrodysesthesia (handfoot syndrome)
Photosensitivity
General Comments
Chemotherapy
It first appears as mild redness on the palms and soles with tingling sensations in the hands, usually at the fingertips; symptoms progress to a more intense burning pain and tenderness.
Palms and soles appear edematous, and patients may have difficulty walking or grasping objects. Ulceration may occur if therapy is not stopped.
Incidence and severity of symptoms are related to protracted exposure of cells to the drug. Symptoms usually develop 212
days after administration of chemotherapy. Early recognition and
cessation of drug administration are critical to symptom management (Morse, 2014).
Symptoms may include flaking, swelling, small blisters, or small
sores.
Prevention and treatment include reducing exposure of hands and
feet to friction and heat by having patients avoid
Hot water (washing dishes, long showers, hot baths)
Impact on their feet (jogging, aerobics, walking, jumping)
Use of tools that require them to squeeze their hand on a hard
surface (garden tools, household tools, kitchen knives)
Rubbing (applying lotion, massaging).
Dose reduction may minimize the risk of recurrence (Huang &
Anadkat, 2011).
Bleomycin, capecitabine, cisplatin, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, etoposide, 5-FU (given in prolonged infusion), floxuridine, fludarabine, gemcitabine, hydroxyurea, idarubicin, ixabepilone, liposomal encapsulated doxorubicin, methotrexate, mitotane, thiotepa, vinorelbine (Degen et
al., 2010; Huang & Anadkat, 2011; Kamil et al., 2010; Morse, 2014; Wolters
Incidence of 50% (though reports vary)
in patients receiving liposome-encapsulated doxorubicin. Incidence correlates with higher doses and increased
number of cycles (Morse, 2014).
Hand-foot skin reaction is common with multikinase inhibitors, shown to occur in 9%62% of patients, and develops within the first 24 weeks of treatment (Eaby-Sandy et al., 2012).
Axitiniball grades, 27%; grades 34, 5% (Wolters Kluwer Health, Inc., 2012)
Everolimus5% (Wolters Kluwer Health, Inc., 2012)
Lapatinibpalmar-plantar erythrodysesthesia when given
with capecitabine: all grades, 53%; grade 3, 12%; grade
4, 0% (GlaxoSmithKline, 2012)
Pazopanib6% (Wolters Kluwer Health, Inc., 2012)
Sorafenib34%48% (Degen et al., 2010)
Sorafeniball grades, 21%; grade 3, 1% (Bayer HealthCare Pharmaceuticals Inc., 2011)
Sorafenib + bevacizumaball grades, 79%; grades 23,
57% (Degen et al., 2010)
Sunitiniball grades, 19%36%; grade > 3, 6%23%
(Degen et al., 2010)
Sunburn occurring after minimal sun exposure

Appears as an erythematous response to UV radiation; skin appears red with erythema, edema, and possibly vesicles.
Patients are instructed to wear protective clothing and a hat when
in the sun, avoid direct sunlight when possible, especially during
peak hours of 10 am and 3 pm, and avoid tanning beds. They
should wear a sunscreen with an SPF higher than 15 (CampSorrell, 2011).
In addition to measures take to avoid sun exposure, patients treated with EGFRIs are advised to wear sunscreen with an SPF of
30 or higher (Potthoff et al., 2011).
High-dose methotrexate, dacarbazine,

5-FU, trans-retinoic acid, vinblastine
(Camp-Sorrell, 2011)
Combination therapy:
Docetaxel + capecitabine
56%63% (Degen et al., 2010)
Doxorubicin + continuous 5-FU
89% (Degen et al., 2010)
239
Patients treated with EGFRIs may develop photosensitivity characterized by erythema from UV-induced damage. Erythema may be painful and associated with desquamation. In severe cases, photosensitivity and erythema may be disabling or life threatening (Boucher et
al., 2011).
Cetuximab (Bristol-Myers Squibb Co. & ImClone Systems, 2012); panitumumab (Amgen Inc., 2013b); vandetanib, vemurafenib (Wolters Kluwer Health, Inc., 2012)
240
Transient
erythema or
urticaria
Skin
depigmentation
General Comments
Chemotherapy
Urticaria is characterized as multiple swollen, raised areas on the

skin that are intensely itchy and appear primarily on the chest,
back, extremities, face, and scalp. It usually occurs within hours
of chemotherapy and disappears within a few hours. It may be
generalized or local at the site of chemotherapy or along the
vein.
Aldesleukin can cause erythema and

pruritus that may progress into a pruritic papular rash (Prometheus Laboratories Inc., 2012).
Asparaginase can cause urticaria, fever,
chills, and hypotension (skin testing is
advised).
Bleomycin can cause erythema over
pressure points and hyperpigmentation
Chlorambucil, methotrexate, melphalan,
and thiotepa can cause urticaria and
angioedema.
Arsenic trioxide can cause urticaria
Cytarabine can cause transient erythema.
Ara-C, asparaginase, carboplatin, daunorubicin, and prednisolone can cause
urticaria (Kamil et al., 2010).
Doxorubicin can cause an erythematous
flare with pruritus at the IV site and
along the vein.
Oxaliplatin can cause delayed urticaria
(Ville et al., 2010).
The offending agent may need to be discontinued if the

reaction is severe or associated with systemic reactions
such as a generalized rash (Morse, 2014).
IFN alfa-2a and IFN alfa-2b can cause dry, scaling, itchy
skin or a pruritic maculopapular reaction (Hoffmann-La
Roche Inc., 2008; Merck Sharp & Dohme Corp., 2013a).
Panitumumaberythema: all grades, 65%; grades 34,
5% (Amgen Inc., 2013b)
Sunitiniberythema: all grades, 12%; grade 3, < 1%
(Pfizer Inc., 2012c)
Vemurafeniberythema: 8%14% (Wolters Kluwer
Health, Inc., 2012)
Pazopanib3% (Wolters Kluwer Health, Inc., 2012)
Cutaneous
Reaction

Cutaneous
Reaction
Pruritus or
itching
Chemotherapy
May be localized or generalized; symptoms may worsen with dehydration. Encourage patients to drink 810 glasses of fluid per
day and minimize salt and alcohol intake.
Recommended skin care includes the use of medicated baths,
anesthetic creams, and emollient creams. Mild soap designed
for sensitive skin should be used, and perfumes, deodorants,
cosmetics, and starch-based powders avoided. Massage, pressure, or rubbing with a soft cloth should be suggested instead of
scratching (Camp-Sorrell, 2011).
Wearing loose-fitting clothing and clothing made of cotton or other soft fabrics can alleviate pruritus. Use antibiotics if pruritus is
secondary to infection. Use oral antihistamines, with increased
doses at bedtime. Sedatives, tranquilizers, and antidepressants
may be useful treatments. Aspirin seems to reduce itching in
some patients but increases it for others. Aspirin combined with
cimetidine may be effective for patients with Hodgkin lymphoma or polycythemia vera. Use of distraction, relaxation, positive
imagery, or cutaneous stimulation is encouraged. A cool, humid
environment may prevent skin from itching (National Cancer Institute, 2011b).
Skin moisturizer and urea- or polidocanol-containing lotions are
suitable to soothe pruritus. Systemic treatment with oral H1-antihistamines such as cetirizine, loratadine, or fexofenadine, as
well as clemastine, may provide relief of itching for patients with
grade 23 pruritus (Potthoff et al., 2011).
Alkylating agents, antimetabolites, antibiotics, plant alkaloids, and nitrosoureas

The agents most associated with hypersensitivities include doxorubicin, daunorubicin, cytarabine, L-asparaginase,
paclitaxel, and cisplatin (National Cancer Institute, 2011b).
Asparaginase, cisplatin, carboplatin, cytarabine, daunorubicin, doxorubicin,
etoposide, IFN alfa-2a and IFN alfa2b, melphalan, and teniposide can all
cause a rash.
Temsirolimuspruritus: all grades, 19%;
grades 34, 1% (Wyeth Pharmaceuticals, 2012)
Bendamustine HCIpruritus: 8% (Cephalon, Inc., 2012)
Actinic keratosestopical 5-FU, cisplatin, cytarabine, dacarbazine, dactinomycin, docetaxel, doxorubicin, pentostatin, 6-thioguanine, vincristine
(Huang & Anadkat, 2011)
Axitinibpruritus: 7% (Wolters Kluwer Health, Inc., 2012)

Cetuximabpruritus: grades 14, 16%; grades 34, <
1%; skin disorders: grades 14, 4%; grades 34, 0%
(Bristol-Myers Squibb Co. & ImClone Systems, 2012)
Erlotinibdry skin: 12%; pruritus: all grades, 7.4%13%;
grade 3, < 1% (Astellas Pharma US, Inc., & Genentech,
Inc., 2012)
Gefitinibpruritus: all grades, 17.6%; grade 1, 7%; grade
2, 1%; grades 34, 0% (AstraZeneca Pharmaceuticals,
2010)
Panitumumabpruritus: all grades, 57%, grades 34,
2%; skin exfoliation: all grades, 25%; grades 34, 2%
(Amgen Inc., 2013b)
Pegylated IFN alfa-2bpruritus: 12% (Wolters Kluwer
Health, Inc., 2012)
Pralatrexatepruritus: all grades, 14%; grade 3, 2%;
grade 4, 0% (Wolters Kluwer Health, Inc., 2012)
Sorafenibpruritus: all grades, 14%; grade 3, < 1% (Bayer HealthCare Pharmaceuticals Inc., 2011)
Sunitinibpruritus: 12%; dry skin: all grades, 23%; grade
3, < 1% (Pfizer Inc., 2012c)
Vandetanibpruritus: 11% (Wolters Kluwer Health, Inc.,
2012)
Vemurafenibpruritus: 23%30%; actinic keratosis: 8%
17%, seborrheic keratosis: 10%14% (Wolters Kluwer
Health, Inc., 2012)
241
ARA-Ccytosine arabinoside; EGFRIepidermal growth factor receptor inhibitor; 5-FU5-fluorouracil; GVHDgraft-versus-host disease; IFNinterferon; ILinterleukin; IVintravenous; mAbmonoclonal antibody;
SPFsun protection factor; UVultraviolet
General Comments
242
stimulate inflammation, apoptosis, and cell attachment. This altered

permeability barrier may allow for the promotion of bacterial overgrowth, further exacerbating cutaneous injury and development of
the characteristic skin rash (Melosky et al., 2009).
c) EGFRI treatment induces a complex pattern of tissue injury and inflammatory cell recruitment, damaging the basal epidermis, the sweat
and sebaceous glands, and hair follicles (Potthoff et al., 2011).
d) Skin toxicities include rash (papulopustular), xerosis, painful cracks
and fissures on the palms and soles, paronychia, pruritus, and abnormal hair and eyelash growth (Mittmann & Seung, 2011).
e) Rash presentation: The presentation can be divided into four stages
beginning with sensory disturbance accompanied by edema and erythema. The characteristic rash of papules and pustules, which is predominantly but not exclusively folliculocentric in distribution, appears subsequently. This is followed by a postinflammatory phase of
erythema and telangiectasias. For patients with darker skin tone, a
fourth phase of postinflammatory hyperpigmentation may be present and can be long lasting (Wu et al., 2011).
f) The pathology and etiology of rash associated with HER1/EGFR-targeted agents are distinct from acne vulgaris. Histopathology confirms
a sterile eruption consisting of follicular papules and pustules in an
acneform distribution.
g) Noninflammatory comedones (blackheads and whiteheads) have
not been described as part of the EGFRI rash (Pomerantz, Mirvish,
& Geskin, 2010).
h) Rash associated with HER1/EGFR-targeted agents is dominated by pustules that can develop an impetiginous, honey-combed crust in serious
cases. Yellowish-brown crust overlying inflammatory eruptions with
oozing of fluid from lesions may be indicative of a secondary bacterial infection (Mitchell, Perez-Soler, Van Cutsem, & Lacouture, 2007).
i) Pustules show an intrafollicular collection of neutrophilsthe hallmark of infectious folliculitis. Pustules often contain pus and are accompanied by dry skin and pruritus (Prez-Soler et al., 2005).
j) Differentiation of rash etiology and characteristics: HER1/EGFR-targeted agentassociated rash should not be confused with acne vulgaris, steroid-induced rash, or cellulitis; the rashes are separate entities and vary in their characteristics.
(1) Acne vulgaris has a unique pathology. Acne is characterized clinically by both noninflammatory lesions known as comedones,
as well as inflammatory papules, pustules, and nodules (PrezSoler et al., 2005).
(2) Patients taking steroids for cancer therapy may develop steroidinduced acne, a monomorphous eruption with widespread, 23
mm, firm, erythematous papules primarily on the trunk. Culture
will not reveal any purulent material (Prez-Soler et al., 2005).
(3) EGFRI rash differs from cellulitis. Cellulitis typically presents
with a localized area of warmth, erythema, and tenderness and
can be associated with fever (Prez-Soler et al., 2005).
k) Rash terminology
(1) Described in phenotypic (observable traits) terms related to its
appearance and location (Prez-Soler et al., 2005)
(2) Terms pustular/papular rash, pustular eruption, or follicular and
intrafollicular pustular eruptions are preferred to the commonly
used terms acneform and acne-like for description (Pomerantz et al., 2010).
(3) Accurate rash description is essential for proper treatment. See
Figure 27.
243
Figure 27. Pustular/Papular Rash Presentations
Papular Lesions on the Chest
V-Shaped Papulopustular Eruption
Follicular Pustules
Confluent Pustules
Note. From Clinical Signs, Pathophysiology and Management of Skin Toxicity During Therapy With Epidermal Growth Factor Receptor Inhibitors, by S.
Segaert and E. Van Cutsem, 2005, Annals of Oncology, 16, p. 1427. doi:10.1093/annonc/mdi279. Copyright 2005 by the European Society for Medical Oncology. Reprinted with permission.
3. Incidence
a) Pustular/papular rash, the most frequent EGFRI-induced skin toxicity, occurs in 45%100% of patients (Potthoff et al., 2011). The rash
usually develops in cosmetically sensitive areas. Pruritic and tender
erythematous papules and pustules develop in skin with a high density of sebaceous glands (scalp, face, upper chest, and back) (Lacouture et al., 2011). The rash generally appears 810 days after the start
of therapy and peaks approximately two weeks after initiation, diminishing after four to six weeks of EGFRI therapy (Eaby-Sandy, Grande,
& Viale, 2012; Lynch et al., 2007). Time to first rash appearance may
be related to the agent and dose (Prez-Soler et al., 2005). The rash
may change in intensity throughout the course of treatment and usually resolves within one to three months after treatment is stopped
(Lynch et al., 2007).
(1) Papulopustular rash (45%100%)
(2) Xerosis (7%35%)
(3) Periungual inflammation (12%16%)
(4) Alopecia (12%14%)
244
(5) Ocular reactions (4%12%) are characteristic of EGFRIs, resulting in significant ocular discomfort and potential visual blur
(Lacouture, 2007).
(a) Trichomegaly
(b) Conjunctivitis
(c) Keratoconjunctivitis sicca
(d) Lacrimation
b) Factors associated with an increased risk of developing rash with erlotinib include nonsmokers, fair skin, and age older than 70. Men taking cetuximab and those younger than 70 are at increased risk. Severe rash is more frequent with mAbs (10%17%) than with low-molecular-weight tyrosine kinase inhibitors (5%9%).
4. Grading rash severity: Accurate grading of dermatologic adverse events
due to EGFRIs is necessary for drug toxicity determination, integrant
comparisons, and supportive grading scale. The CTCAE version 4.0 (NCI
CTEP, 2009) is widely accepted throughout the oncology community as
the standard classification and severity grading scale for adverse events
in cancer therapy clinical trials and other oncology settings. However, it
was not designed specifically for this class of agents and may result in underreporting and poor grading of distinctive adverse events (Lacouture
et al., 2010). The standard grading of dermatologic toxicity employs the
NCI CTCAE version 4.03 (NCI CTEP, 2010) (see Table 32). The MASCC
Study Group has proposed a new grading scale for EGFRI-induced dermatologic adverse events. The group believes a class-specific grading scale
is needed to help standardize assessment and improve reporting of these
dermatologic adverse events (Lacouture et al., 2010).
5. Skin reactions are associated with significant morbidity and can lead to dose
reductions or premature discontinuation of chemotherapy. The adverse
effect of cutaneous reactions on patients QOL is only beginning to be
understood (Wu et al., 2011). EGFRIs frequently induce a variety of skin
effects that are predictive and often severe enough to warrant delaying
treatment or even permanent discontinuation (Cotliar, 2011).
6. Collaborative management
a) Treatment of rash is largely dependent on the patients symptoms.
EGFRI-induced skin reactions can be effectively treated at all stages
and all grades, and dermatologic effects induced by EGFRIs are believed to be reversible (Potthoff et al., 2011). Skin care recommendations while receiving EGFRI treatment include the following (Potthoff et al., 2011, unless otherwise cited).
(1) Instruct patients to use gentle soaps and shampoos for personal hygiene (i.e., pH-5 neutral bath and shower formulations)
and tepid water. Avoid alcohol-containing lotions or gels in favor of oil-in-water creams or ointments. Clean, smooth towels
are recommended to reduce potential risk of infection. Pat skin
to dry; avoid rubbing. Avoid hot blow-drying the hair.
(2) A dermatologist-approved makeup (e.g., Dermablend) can
be used, although any type of foundation may be useful. Remove makeup with a hypoallergenic liquid cleanser (e.g., Neutrogena, Cetaphil, Dove, Ivory Skin Cleansing Liquid Gel)
(Prez-Soler et al., 2005). Avoid manipulation of the skin because of risk of infection.
(3) Instruct patients to shave with caution and avoid excessive beard
growth. Use regular shaving razor with sharp multiblades and
shaving cream emollients and moisturizing aftershave. Avoid using an electric shaver and aftershave containing alcohol (Pinto
et al., 2011).
(4) Smooth-cotton clothes should be worn instead of synthetic fabrics.
245
Table 32. National Cancer Institute Common Terminology Criteria for Adverse Events Categories
Relevant to EGFRI-Associated Dermatologic Toxicity
Toxicity
Grade
Description
Dry skin
Covering < 10% BSA and no associated erythema or pruritus
Covering 10%30% BSA and associated with erythema or pruritus; limiting instrumental ADL
Covering > 30% BSA and associated with pruritus; limiting self-care ADL
Definition: A disorder characterized by flaky and dull skin; the pores are generally fine, and the texture is a papery thin texture.
Papulopustular rash
Papules and/or pustules covering < 10% BSA, which may or may not be associated with symptoms of pruritus or tenderness
Papules and/or pustules covering 10%30% BSA, which may or may not be associated with symptoms of
pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL
Papules and/or pustules covering > 30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; limiting self-care ADL; associated with local superinfection with oral antibiotics indicated
Papules and/or pustules covering any percent BSA, which may or may not be associated with symptoms
of pruritus or tenderness and are associated with extensive superinfection with IV antibiotics indicated; lifethreatening consequences
Death
Definition: A disorder characterized by an eruption consisting of papules (small, raised pimples) and pustules (small pus-filled blisters),
typically appearing on the face, scalp, and upper chest and back. Unlike acne, this rash does not present with whiteheads or blackheads
and can be symptomatic, with itchy or tender lesions.
Paronychia
Nail fold edema or erythema; disruption of the cuticle
Localized intervention indicated; oral intervention indicated (e.g., antibiotic, antifungal, antiviral); nail fold edema or erythema with pain; associated with discharge or nail plate separation; limiting instrumental ADL
Surgical intervention or IV antibiotics indicated; limiting self-care ADL
Definition: A disorder characterized by an infectious process involving the soft tissues around the nail.
Pruritus
Mild or localized; topical intervention indicated
Intense or widespread; intermittent; skin changes from scratching (e.g., edema, papulation, excoriations, lichenification, oozing/crusts); oral intervention indicated; limiting instrumental ADL
Intense or widespread; constant; limiting self-care ADL or sleep; oral corticosteroid or immunosuppressive
therapy indicated
Definition: A disorder characterized by an intense itching sensation.
ADLactivities of daily living; BSAbody surface area; EGFRIepidermal growth factor receptor inhibitor; IVintravenous
Note. From Common Terminology Criteria for Adverse Events [v.4.03], by National Cancer Institute Cancer Therapy Evaluation Program, 2010. Retrieved
from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
246
(5) Instruct patient to avoid skincare products that contain alcohol or other harsh additives and detergents or other household
cleaning products (Eaby, Culkin, & Lacouture, 2008).
(6) Nails should be cut straight across until the nails no longer extend over the fingers or toes. Cuticles should not be trimmed
because of an increased risk of nail bed infection (Potthoff et
al., 2011). Advise patients to avoid pushing back cuticles or biting fingernails and to avoid wearing tight-fitting shoes, which
can exacerbate toenail changes. Instruct patients to wear rubber or cotton-lined gloves while washing dishes, gardening, or
cleaning (Eaby et al., 2008).
(7) Instruct patients to avoid sun exposure. Sunscreen should be
applied daily to exposed skin areas regardless of the season.
Hypoallergenic sunscreens with high sun protection factor (at
least 30), para-aminobenzoic acid (PABA)-free, ultraviolet A
and B (UVA/UVB) protection, preferably broad spectrum and
containing zinc oxide or titanium dioxide are recommended.
Recommend that patients wear a hat and protective clothing
for sun protection.
(8) Moisturize the skin when EGFRI therapy is started, with emollients
free of perfume, alcohol, and petroleum jelly (e.g., Neutrogena
Norwegian Formula hand cream, Vaseline Intensive Care Advanced Healing Lotion) to prevent dryness (OncUView, 2011a).
Hypoallergenic moisturizing creams, ointments, and emollient
should be used once daily to smooth the skin and to prevent and
alleviate skin dryness; greasy creams should be avoided for basic care (e.g., pure petroleum). Such creams might facilitate the
development of folliculitis because of their occlusive properties.
(9) Instruct patient not to use topical acne medications, (e.g., retinoids, alpha hydroxy acid, benzoyl peroxide gel or cream)
which may irritate and worsen EGFRI-induced rash because of
their drying effects (Potthoff et al., 2011).
b) Recommendations for management of EGFRI-associated rash are
available from MASCC and NCCN (see Figure 28).
c) Patients should be referred to a dermatologist if lesions have an uncharacteristic appearance or distribution or if necrosis, blistering, or
petechial purpuric lesions are present (Segaert & Van Cutsem, 2005).
7. Secondary infection: Signs of secondary infection can be subtle, especially in patients who are neutropenic or taking systemic steroids (PrezSoler et al., 2005).
a) The pustules associated with HER1/EGFR inhibitors are notably sterile with negative cultures or staining for bacteria, fungi, and yeast
(Segaert & Van Cutsem, 2005).
b) Inflammatory-based pustules should be sterile, but experience shows
that secondary infections are common.
(1) Most common presentation of a secondary infection is an increase in pustules.
(2) Significant oozing of fluid from lesions or an abrupt change in
their appearance may be present.
(3) Secondary infection of skin rash may occur at later stages, which
includes impetiginization, an important complication caused by
staphylococci or streptococci. Staphylococcus aureus is the most
frequently detected infectious agent; less frequent infections
include herpes simplex, herpes zoster, and dermatophytes. Abscesses may require incision and drainage to prevent sepsis. Bacterial swabs should be taken and anti-infective treatment started (Potthoff et al., 2011).
247
Figure 28. Recommendations for Prevention and Management of EGFRI Rash

MASCC
Preventive/Prophylactic
Systemic
Minocycline 100 mg dailya or doxycycline 100 mg BIDb
Topical
Hydrocortisone 1% cream with moisturizer and sunscreen
BID
Treatment
Topical
Alclometasone 0.05% cream
Fluocinonide 0.05% cream BID
Clindamycin 1%
Systemic
Doxycycline 100 mg BID
Minocycline 100 mg daily
Isotretinoin at low doses of 2030 mg/day
NCCN
Preventive/Prophylactic
Systemic
Oral semisynthetic tetracycline agents (doxycycline or minocycline)
Doxycycline 100 mg BID in combination with
Topical
Hydrocortisone 1%, skin moisturizer, and sunscreen.
Treatment
Topical
Topical steroids and antibiotics, such as clindamycin and
erythromycin, may be useful.
Systemic
Oral antibiotics include doxycycline or minocycline.
Systemic steroids are not typically used, but published case
reports have suggested their use in specific settings.
Administer isotretinoin reactively (based on anecdotal or
nonrandomized studies).
Not Recommended
Pimecrolimus 1% cream, tazarotene 0.05% cream, sunscreen as a single agent, tetracycline 500 mg BID, vitamin K1 cream, acitretin,
oil-in-water topical trolamine emulsion
a
Minocycline is less photosensitizing.
Doxycycline should be used in patients with renal impairment.
BIDtwice daily; EGFRIepidermal growth factor receptor inhibitor; MASCCMultinational Association of Supportive Care in Cancer; NCCNNational
Comprehensive Cancer Network
Note. Based on information from Burtness et al., 2009; Eaby-Sandy et al., 2012; Lacouture et al., 2011.
(4) Inspect rash regularly, culturing pustules in early-onset rash to

determine if Staphylococcus aureus is present.
(5) Frequent culturing enables assessment of the extent of secondary infection, the type of colonizing bacteria, and effectiveness
of treatments.
(6) If antibiotic resistance is suspected, culture the pustules to determine bacterial strain before treating.
8. Rash and response/survival
a) Incidence and severity of papulopustular rashes are associated with
a better prognosis and therefore are considered to predict response
of a tumor to the EGFRI (Gutzmer et al., 2012). Studies addressing
EGFRI-induced rash suggest that its severity is a surrogate marker for
efficacy of the therapy (Potthoff et al., 2011).
b) Data suggest a correlation of rash incidence and severity with clinical
response and increased survival time, leading investigators to implement dose-to-rash strategies, in which a patients EGFRI dose is progressively escalated until rash of a specified grade appears. A consistent
relationship between rash and response has not been observed with
all EGFRIs studied in clinical trials to date (Pomerantz et al., 2010).
9. Psychosocial issues
a) Skin toxicities from EGFRIs can have a significant impact on patients
physical, emotional, and social function. These side effects may interfere with treatment adherence, but patients may accept them as
part of their experience with cancer or as a sign of response to therapy (Romito et al., 2010; Wagner & Lacouture, 2007).
b) The majority of cases do not require withdrawal of EGFRI treatment.
Suspension of EGFRI treatment should only be temporary, allowing
for diminution of the rash (Lynch et al., 2007).
248
c) Most significant skin toxicities and health-related QOL factors (Wagner & Lacouture, 2007)
(1) Inability to work
(2) Sleep disturbances
(3) Interference with activities of daily living
(4) Disruption of hobbies
(5) Skin pain, burning, itching, and irritation
(6) Increased facial hair
(7) Depression, frustration, anxiety, and worry
(8) Disruption of social life
10. Patient and family education
a) Instruct patients about the potential EGFRI-related symptoms of dermatologic toxicities as part of supportive measures (Boucher, Olson,
& Piperdi, 2011).
(1) Include information about potential toxicities including rash,
pruritus, xerosis, photosensitivity, and erythema.
(2) Provide information on preventive and management measures.
b) Ensure that family and other support systems (friends, clergy, visiting nurses, homecare personnel) can provide encouragement to
patients to help rebuild their self-esteem and self-belief. Discuss the
potential for anxiety or depression (Boucher et al., 2011; Eaby et
al., 2008; Lacouture, 2007; Oishi, 2008; Wagner & Lacouture, 2007).
c) Follow-up phone calls promote communication with patients regarding their treatment experience. It is an opportunity for nurses to educate and give supportive care (Boucher et al., 2011).
11. Combination radiation and EGFRI therapy
a) Significant in-field toxicity can occur when radiation therapy and
EGFRIs are given concomitantly (Bernier et al., 2008).
b) Most people experience grade 1 (using version 2.0 of NCI CTEPs
Common Toxicity Criteria) or mild toxicities, but 20%25% of people experience severe dermatitis with the combination of radiation
and EGFRI therapy (Wu et al., 2011).
c) Management guidelines for radiation dermatitis in the setting of
EGFRI papulopustular rash include minimizing the radiation dose
exposure of the epidermis, keeping the treated area clean and dry,
and applying topical medications such as hydrocortisone for a limited time (Bernier et al., 2008; Miller et al., 2011; Wu et al., 2011).
d) The ONS Putting Evidence Into Practice (PEP) (Baney et al., 2011)
resource on radiation dermatitis addresses the management of radiation dermatitis and coexisting EGFRI rash. Information is available
at www.ons.org/practice-resources/PEP/radiodermatitis.
12. Chemotherapy agents associated with radiation enhancement and radiation recall
a) Radiation enhancement: Bleomycin, dactinomycin, doxorubicin, 5-FU
with and without cisplatin, hydroxyurea, 6-mercaptopurine, methotrexate, paclitaxel, gemcitabine, chlorambucil, and capecitabine
b) Radiation recall: Arsenic trioxide, bleomycin, capecitabine, cyclophosphamide, cytarabine, dactinomycin, daunorubicin, docetaxel,
doxorubicin (free and liposomal), etoposide, 5-FU, gemcitabine,
hydroxyurea, idarubicin, lomustine, melphalan, methotrexate, paclitaxel, pemetrexed, tamoxifen, and vinblastine (Wolters Kluwer
Health, Inc., 2012)
13. Multiple drugs are in development, including anti-EGFR mAb therapies
that inhibit dimerization of EGFR/HER receptors on the external surface of the cell and small molecules that inhibit pathways such as RAS
(K-ras), BRAF (B-raf), and tyrosine kinase.
14. Toxic erythema of chemotherapy (TEC) is chemotherapy-induced iatrogenic injury of the skin (Choi, 2011).
a) Numerous cutaneous side effects have been reported from traditional
chemotherapy drugs, including cytarabine, anthracyclines (including
doxorubicin), 5-FU, capecitabine (5-FU prodrug), taxanes (including docetaxel), and methotrexate. Reports include clinical and histologic findings that have significant overlap. The clinically descriptive term toxic erythema of chemotherapy has been introduced as an easily understood clinical name for numerous entities (see Figure 29).
b) Clinical findings of TEC include areas of erythema that may be accompanied by edema, most often involving the hands, feet, and intertriginous zones, such as the axillae and inguinal folds. Less frequently, the elbows, knees, and ears are involved.
c) Patches or plaques typically develop within two days to three weeks following drug administration. Associated symptoms of pain, burning, paresthesia, and pruritus are frequently present. Areas of intense erythema
can be accompanied by development of a dusky discoloration, petechiae, or sterile bullae, which can be followed by erosions. Typically, spontaneous resolution and desquamation occur without specific therapy,
and if the chemotherapeutic agent is given again at the same or higher dose, recurrences are possible and may be more intense with higher doses. In certain cases, a delayed onset of 210 months can be seen,
particularly in patients receiving lower-dose, continuous IV infusions.
d) Treatment options have been of variable success and include bland
emollients, analgesics, cool compresses, topical corticosteroids, and
topical antibiotics for erosions. It is important for oncologists and dermatologists to recognize TEC, understanding that the reaction is not
allergic or infectious in nature and thus avoiding unnecessary labeling of drug allergies or use of antimicrobials (Choi, 2011).
15. See Figures 3035 for examples of specific cutaneous manifestations of
EGFRI- and chemotherapy-induced toxicities.
Figure 29. Entities Included in Toxic Erythema of Chemotherapy

Ara-C (cytarabine) ears

Burgdorf reaction
Chemotherapy-associated eccrine reactions
Eccrine squamous syringometaplasia, chemotherapy induced
Epidermal dysmaturation, chemotherapy induced
Epidermal dystrophy
Erythrodysesthesia
Acral erythema
Acral erythrodysesthesia
Chemotherapy-induced acral erythema (CIAE or CAE)
Hand-foot syndrome
Palmar-plantar erythema
Palmar-plantar (palmoplantar) erythrodysesthesia
Toxic acral erythema
Toxic erythema of the palms and soles
Intertriginous eruption associated with chemotherapy
Intertrigo-like eruption, chemotherapy-induced
Flexural erythematous eruption
Intertrigo dermatitis
Neutrophilic eccrine hidradenitis, chemotherapy-associated
Chemotherapy-induced hidradenitis
Drug-induced hidradenitis
Note. Based on information from Choi, 2011.
From Toxic Erythema of Chemotherapy: A Useful Clinical Term, by J.L. Bolognia, D.L. Cooper, and E.J.
Glusac, 2008, Journal of the American Academy of Dermatology, 59, p. 525. Copyright 2008 by American
Academy of Dermatology, Inc. Adapted with permission.
249
250
Figure 30. Trichomegaly
Figure 31. Paronychia of the Nail
Note. From Clinical Signs, Pathophysiology and

Management of Skin Toxicity During Therapy With
Epidermal Growth Factor Receptor Inhibitors, by
S. Segaert and E. Van Cutsem, 2005, Annals of
Oncology, 16, p. 1428. Copyright 2005 by the European Society for Medical Oncology. Reprinted
with permission.

with permission.
Figure 32. Hyperpigmentation
Figure 33. Fissure

Management of Skin Toxicity During Therapy
With Epidermal Growth Factor Receptor Inhibitors, by S. Segaert and E. Van Cutsem, 2005,
Annals of Oncology, 16, p. 1428. Copyright 2005
by the European Society for Medical Oncology.
Reprinted with permission.

with permission.
D. Alopecia
1. Overview: Alopecia is one of the most common and distressing side effects of chemotherapy. Hair loss was identified as the most traumatic
aspect of chemotherapy by 47% of female patients in a study by McGarvey, Baum, Pinkerton, and Rogers (2001). A portion of these patients
may choose not to receive chemotherapy because of an intense fear of
this side effect (McGarvey et al., 2001; Mnstedt, Manthey, Sachsse, &
Vahrson, 1997). In young adults age 1838, men and women reported
equally negative experiences related to chemotherapy-induced alopecia (Hilton, Hunt, Emslie, Salinas, & Ziebland, 2008). Chemotherapyinduced alopecia most commonly occurs on the scalp; however, it can
occur anywhere on the body including facial (beards, eyebrows, eyelashes), axillary, and pubic hair. Chemotherapy-induced alopecia negatively
affects an individuals perFigure 34. Acral Erythema

ceptions of body image,
sexuality, and self-esteem.
2. Pathophysiology: The
pathobiology of the response of human hair follicles to chemotherapy remains largely unknown.
Cells responsible for hair
growth have high mitotic
and metabolic rates. Certain cytotoxic agents disrupt the proliferative phase
of hair growth. Approximately 90% of hair folliNote. From Painful Blistered Hands and Feet, by C.
cles on the scalp are in the
Coyle and V. Wenhold, 2001, Clinical Journal of Oncology Nursing, 5, p. 230. Copyright 2001 by the Onanagen (growth) phase of
cology Nursing Society. Reprinted with permission.
the hair cycle at any given
time (Treb, 2010). The
two major types of chemotherapy-induced alopecia exist: telogen effluvium and anagen effluvium.
a) Telogen effluvium involves < 50% of the scalp and results in hair thinning. Hair enters the telogen, or resting, phase and results in shedding three to four months after drug administration. Cytotoxic drugs
that can cause this type of alopecia are methotrexate, 5-FU, and retinoids (Yeager & Olsen, 2011).
b) Anagen effluvium is the most common form of chemotherapy-induced
alopecia. Because most hair follicles are in the anagen (growth) phase,
chemotherapy damages these rapidly growing cells, leading to damage
of the inner root sheath cells or the hair shaft integrity. The hair shaft is
no longer anchored and falls out easily or breaks off at the scalp. Hair
falls out spontaneously or during washing or combing. Chemotherapeutic agents such as cyclophosphamide, daunorubicin, doxorubicin, etoposide, ifosfamide, and paclitaxel are associated with this type of damage. The hairs remain in the telogen phase after damage occurs until
the chemotherapy is completed, at which time they can enter the anagen phase again and hair regrowth resumes (Yeager & Olsen, 2011).
3. Incidence
a) As many as 65% of patients undergoing chemotherapy will experience alopecia to some degree (Treb, 2010).
b) The extent of alopecia depends on the mechanism of action of the
drug, administration route, drug dose, serum half-life, duration (e.g.,
bolus versus continuous infusion), the response of the patient, the use
of combination chemotherapy, and the condition of the hair prior to
treatment (Chon, Champion, Geddes, & Rashid, 2011).
4. Risk factors
a) Type of cytotoxic drug(s) administered
(1) The drugs that present the highest risk of alopecia are cyclophosphamide, daunorubicin, epirubicin, doxorubicin, etoposide, ifosfamide, docetaxel, paclitaxel, camptothecins, and
vinorelbine (Treb, 2010) (see Table 33).
(2) Combination chemotherapy is associated with a higher incidence of alopecia than single-agent therapy.
(3) Molecularly targeted agents such as mAbs, which target EGFR,
and small molecular inhibitors of EGFR have been associated
with diffuse alopecia that is generally reversible (Chon et al.,
2011; Donovan, Ghazarian, & Shaw, 2008).
251
252
Figure 35. Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome)*

Grade 1
Minimal skin changes or dermatitis (e.g., erythema, edema, hyperkeratosis), swelling, tingling, and/or discomfort of hands or feet not
disrupting normal activities
Grade 2
Painful skin changes (e.g., peeling, blisters,
bleeding, edema, hyperkeratosis), erythema
and swelling of hands or feet and/or discomfort limiting instrumental activities of daily living (ADLs)
Grade 3
Severe skin changes (e.g., peeling, blisters,
bleeding, edema, hyperkeratosis, moist desquamation, ulceration) with pain, or severe discomfort limiting self-care ADLs
* Grading criteria based on information from National Cancer Institute Cancer Therapy Evaluation Program, 2010.
Note. Photos courtesy of Susan Moore, RN, MSN, ANP, Chicago, IL. Used with permission.
Table 33. Risk of Chemotherapy-Induced Alopecia for Antineoplastic Agents

Classification
Alkylating agents
Antimetabolites
High Risk
Cyclophosphamide
Ifosfamide
Moderate Risk
Mild Risk
Mechlorethamine
Methotrexate
Carboplatin
Cisplatin
Amsacrine
Busulfan
Cytarabine
Gemcitabine
Capecitabine
5-Fluorouracil
Fludarabine
Hydroxyurea
Thiotepa
Antitumor antibiotics
Daunorubicin
Doxorubicin
Epirubicin
Camptothecins
Irinotecan
Topotecan
Epipodophyllotoxins
Etoposide
Tyrosine kinase inhibitors
Targeted therapies
Taxanes
Docetaxel
Paclitaxel
Vinca alkaloids
Vinorelbine
Bleomycin
Mitoxantrone
Vinblastine
Vincristine
Note. Based on information from Chon et al., 2011; Treb, 2009.
(4) Multitargeted tyrosine kinase inhibitors (e.g., sorafenib, sunitinib) have been associated with alopecia (Chon et al., 2011).
b) High-dose chemotherapy: Busulfan-containing regimens used for BMT
or HSCT have been linked to permanent hair loss, although this is rare
(Machado, Moreb, & Khan, 2007; Tosti, Piraccini, Vincenzi, & Misciali,
2005; Vowels, Chan, Giri, Russell, & Lam-Po-Tang, 1993).
c) Certain noncytotoxic medications (e.g., propranolol hydrochloride,
heparin sodium, lithium carbonate, prednisone, vitamin A, androgen preparations)
d) Certain medical conditions (e.g., hypothyroidism, aging)
e) Poor hair condition before cytotoxic treatment
f) Concomitant or previous radiation therapy to the head (local effect)
5. Clinical manifestations: Scalp dryness, soreness, pruritus, and rash can
occur before, during, or after hair loss.
a) Degrees of alopecia (NCI CTEP, 2010)
(1) Grade 1: Hair loss of < 50% of normal for that individual that
is not obvious from a distance but only on close inspection; a
different hair style may be required to cover the hair loss, but
it does not require a wig or hairpiece to camouflage.
(2) Grade 2: Hair loss of 50% or greater compared to normal for
that individual that is readily apparent to others; a wig or hairpiece is necessary if the patient desires to completely camouflage the hair loss; associated with psychosocial impact.
b) Expected time frame and pattern (Chon et al., 2011)
(1) Hair shedding begins approximately one to three weeks after
administration of the drug and may last one to two months after initiation of therapy.
(2) Pattern: Hair loss tends to occur first on the crown and sides of
head above the ears.
253
254
(3) Chemotherapy-induced alopecia is generally reversible.

(4) Hair regrowth begins one to three months after discontinuation of chemotherapy.
(5) Regrown hair may demonstrate changes in color, structure, or
texture and, in some patients, hair density may continue to be
reduced after treatment.
(6) Permanent alopecia following chemotherapy, although rare, can
occur with high-dose busulfan and cyclophosphamide following
HSCT, long-term use of EGFR inhibitors, and after treatment
with taxanes (Donovan et al., 2008; Machado et al., 2007; Miteva
et al., 2011; Tallon, Blanchard, & Goldberg, 2010).
6. Collaborative management: Alopecia is a constant reminder of disease
and greatly affects patients sense of self. Patients may experience privacy issues because alopecia is often associated with having cancer. Currently, no approved pharmacologic treatment is available for prevention
of alopecia caused by cytotoxic therapy. Multiple pharmacologic and biologic therapies are being studied, such as epidermal growth factor, keratinocyte growth factor, cytokines, antioxidants, and apoptosis inhibitors (Yeager & Olsen, 2011).
a) Scalp hypothermia, although used in the past with mixed results, is
not currently recommended in patients with hematologic malignancies and remains controversial in patients with nonhematologic malignancies. Patients should only consider this therapy if enrolled in
a clinical trial and/or with approval from their primary oncologist.
Patients may experience headaches, excessive coldness, or feelings
of claustrophobia (Treb, 2010).
(1) There is long-standing concern that reducing circulation to the
scalp through vasoconstriction may create a sanctuary site for
malignant cells, resulting in scalp metastasis.
(2) In six of seven randomized controlled trials published prior to
2004, investigators demonstrated a reduction in alopecia when
scalp hypothermia was used. However, these studies were small
and did not characterize the exact methods for cooling and effect on long-term survival (Grevelman & Breed, 2005).
(3) Randomized clinical trials are needed to determine the proper technique for application, efficacy, and safety of scalp cooling in preventing chemotherapy-induced alopecia (Grevelman
& Breed, 2005).
b) Topical minoxidil prolongs the anagen phase and may increase hair
follicle size. It appears to be most effective if used while hair still exists. Minoxidil has been associated with decreased severity and duration but does not eliminate chemotherapy-induced alopecia (Chon
et al., 2011).
7. Patient and family education: Ask patients to verbalize feelings related to
hair loss. Increasing patients knowledge may give them a sense of control as their appearance changes (Borsellino & Young, 2011). Advise patients and caregivers about the following (Batchelor, 2001; Chon et al.,
2011; Hesketh et al., 2004).
a) The cause of alopecia and the time frame of hair loss and regrowth
b) Strategies to manage hair loss and regrowth
(1) Most strategies are literature-based and have not been tested in
randomized controlled clinical trials.
(2) Use shampoos without detergents, menthol, salicylic acid, alcohol, or heavy perfumes.
(3) Avoid using permanent waves, bleach, and coloring agents on
hair, as well as vigorous brushing, hot rollers, and excessive heat
with hair dryer use.
(4) Avoid excessive brushing or combing. Use a soft brush.

(5) Consider cutting hair in a short style or shaving the head.
(6) Protect the scalp from the cold and sun with hats, scarves, wigs,
and sunscreen. Consider cotton head coverings because they
will not slip off.
(7) Protect the eyes with sunglasses or clear-glass glasses if lashes
become thin or fall out completely; dust or particles can enter
the eye more easily and cause irritation.
(8) Instruct patients that new hair that grows after completion of
therapy may differ from the original hair in color or texture.
c) Local resources for support (e.g., wig salons, scarf and turban catalogs, support groups)
(1) Look Good Feel Better is a program offered by the Personal Care Products Council Foundation through community organizations such as the American Cancer Society to provide
guidance and support regarding wigs and other head coverings, makeup, and skin care (Personal Care Products Council
Foundation, 2012).
(2) Computerized imaging programs to simulate baldness and the
look of various types and colors of wigs may be useful and can
decrease distress related to hair loss (McGarvey et al., 2010).
d) A wig may be covered by the patients insurance, which will help to defray costs. A prescription written for hair prosthesis may be required.
(1) Wigs can be synthetic or made of actual human hair, with
the latter being more costly. Salons or stores that specialize
in wigs can provide a discussion of the pros and cons of each
type of wig with the client. Synthetic wigs may be damaged
by excessive heat during styling. Manufacturers care guidelines should be followed.
(2) Wig specialists may have an easier time matching a wig to the
patients usual style if the patient consults the stylist before hair
loss begins or provides pictures. It may be helpful to preserve a
portion of normal hair prior to complete hair loss to allow for
color and texture matching.
(3) If a wig is purchased prior to hair loss, it should be adjustable
so that the size can be decreased as the hair loss occurs (Personal Care Products Council Foundation, 2012).
(4) A variety of scarves and turbans are available and assist with protection of the scalp and prevention of heat loss.
E. Cardiovascular toxicity
1. Cardiovascular toxicity includes changes in conduction pathways (dysrhythmias), vasculature (hypotension, hypertension, Raynaud phenomenon), coronary arteries (unstable angina, acute myocardial infarction),
cardiac myocytes (cardiomyopathy), and pericardial fluid accumulation
(Anderson & Sawyer, 2008; Broder, Gottlieb, & Lepor, 2008; Chen, 2009;
Fadol & Lech, 2011; Sereno et al., 2008; Viale & Yamamoto, 2008). In
some cases, cardiac dysfunction cannot be linked to a specific therapeutic agent but reflects the effects of a combination of agents and comorbid risk factors (Chung et al., 2008; Fadol & Lech, 2011). These cardiovascular toxicities are described in greater detail by chemotherapeutic
drug category in Table 34.
2. Conduction pathway disorders
a) Defined as disturbance in the regular excitation of the heart (Chummun, 2009; Mottram & Svenson, 2011)
b) Pathophysiology (Collins, 2010; Guglin, Aljayeh, Saiyad, Ali, & Curtis, 2009; Palatnik, 2011; Sharam, 2007)
255
256
Table 34. Cardiotoxicity of Chemotherapeutic Agents

Classification
Incidence
Characteristic Effects
Cisplatin
Oxygen radicals released with antineoplastic activity can produce acidosis, ischemia, and arterial vasospasm. It is cumulative, worsening
with long-term exposure, but is reversible as
long as neuropathies resolve.
Raynaud phenomenon has been reported, but no coronary artery disease

(Bristol-Myers Squibb Co., 2011d).
Hypomagnesemia induced by cisplatin has
been associated with QT prolongation that
subsequently results in bradycardia and
with atrial or ventricular dysrhythmias (Slovacek et al., 2008).
Maintain magnesium levels > 2 mEq/L (Slovacek

et al., 2008).
Cyclophosphamide (high-dose)
Toxicity is rare with cumulative or standard doses.

There have been some reports of increased frequency with high-dose therapy > 180200 mg/
kg/day for 4 days (Bristol-Myers Squibb Co.,
2005; Shaikh & Shih, 2012).
Pediatric patients with thalassemia have been
shown to have a potential for cardiac tamponade when cyclophosphamide is given with busulfan (Bristol-Myers Squibb Co., 2005).
ECG may show diminished QRS complex.

Cardiomegaly, pulmonary congestion, and
cardiac tamponade in children often are
preceded by complaints of abdominal pain
and vomiting (Bristol-Myers Squibb Co.,
2005).
Acute lethal pericarditis, pericardial effusion, cardiac tamponade, and hemorrhagic myocardial necrosis may result in rare circumstances (Shaikh
& Shih, 2012).
Cardiotoxicity usually is related to high doses for
short intervals prior to BMT (Viale & Yamamoto, 2008).
Cases of cardiomyopathy with subsequent death
have been reported following experimental
high-dose therapy with cytarabine in combination with cyclophosphamide when used for BMT
preparation (Bristol-Myers Squibb Co., 2005).
Estramustine (estradiol and nitrogen mustard)
CHF occurs in 3% of patients; MI in 3% of patients (Pfizer Inc., 2011c).
General fluid retention and exacerbation of

preexisting or incipient peripheral edema
or CHF have occurred in some patients.
Men receiving estrogens for prostate cancer are at increased risk for thrombosis,
including fatal and nonfatal MI (Pfizer Inc.,
2011c).
Estramustine should be used with caution in patients with a history of cerebral vascular or coronary artery disease.
Because hypertension may occur, blood pressure
should be monitored periodically (Pfizer Inc.,
2011c).
Ifosfamide
Cardiotoxicity occurs in < 1% of patients (Baxter

Healthcare Corp., 2009a). Hypotension during
infusion is possible.
Rare cardiac effects such as infusional hypotension, dysrhythmias, late hypertension, and acute heart failure have been reported.
Establish baseline cardiac status and monitor for

acute changes.
Melphalan
Dose-related adverse effects are seen in < 5%

of cases (GlaxoSmithKline, 2003a).
Raynaud phenomenon is dose dependent,

occurring only during active therapy and
resolving after completion of the cycle.
Teach patients to avoid cold exposure and tobacco smoking, both of which will exacerbate pain.
Alkylating
agents
Drug
Table 34. Cardiotoxicity of Chemotherapeutic Agents (Continued)

Classification
Drug
Incidence
Abiraterone acetate
All grades of hypertension occurred at a rate of

8.5%, and 1.3% with grade 3 or 4 toxicity in
registration trials (Janssen Biotech, Inc., 2012).
Fluid retention with resultant hypertension

and dysrhythmias can occur.
Use with caution in patients with known heart or

vascular disease known to be compromised by
hypertension, hypokalemia, or fluid retention
(Janssen Biotech, Inc., 2012).
Safety of this agent has not been established in
patients with LVEF < 50% or having New York
Heart Association class III or IV heart failure
(Janssen Biotech, Inc., 2012).
Monitor blood pressure and fluid balance at least
monthly during therapy (Janssen Biotech, Inc.,
2012).
Anthracycline
antitumor
antibiotics
Daunorubicin
If total dose < 600 mg/m2, incidence is 0%4.1%

(Camp-Sorrell, 2011; Teva Pharmaceuticals
USA, 2012a).
If total dose is 1,000 mg/m2, incidence is 12%
(Teva Pharmaceuticals, 2012a).
Nonspecific arrhythmia, tachycardia, cardiomyopathy, pericardial effusion, and/or

CHF may occur. Acute left ventricular failure can occur with high doses. CHF may
be unresponsive to treatment (Teva Pharmaceuticals USA, 2012a).
Acute toxicity unrelated to dose may occur
within hours.
Although rare, myocarditis-pericarditis syndrome may be fatal (Barry et al., 2007).
Chronic effects are similar to those of doxorubicin, but higher cumulative doses may be tolerated (Camp-Sorrell, 2011).
Periodic monitoring with echocardiogram or
MUGA scan is recommended.
Daunorubicin citrate liposomal
Chronic therapy > 300 mg/m2 has increased the

incidence of cardiomyopathy and CHF.
In a phase III study, 13.8% of patients reported a
triad of back pain, flushing, and chest tightness
(Galen US Inc., 2011).
Cardiomyopathy associated with a decrease

in LVEF may occur, especially in patients
with prior anthracycline experience or preexisting cardiac disease (Galen US Inc.,
2011).
Ensure that the patient undergoes a physical examination and cardiac evaluation with MUGA
scan or echocardiogram before each course
and at total cumulative doses of 320 mg/m2 (160
mg/m2 for higher-risk patients) and at every 160
mg/m2 thereafter.
MUGA scans is recommended.
Triad usually occurs during the first five minutes
of infusion, subsides with infusion interruption,
and generally does not recur if the infusion is resumed at a slower rate (Galen US Inc., 2011).
257
Androgen
inhibitor
258

Classification
Incidence
Doxorubicin
If total dose is < 550 mg/m2, incidence is 0.1%

1.2% (Camp-Sorrell, 2011; Pfizer Inc., 2011a).
If total dose is > 550 mg/m2, incidence rises exponentially (Camp-Sorrell, 2011; Pfizer Inc.,
2011a).
If total dose is 1,000 mg/m2, incidence is nearly
50% (Camp-Sorrell, 2011; Pfizer Inc., 2011a).
Incidence may manifest during therapy and
last for months to years afterward (Pfizer Inc.,
2011a).
Late effects for pediatric patients: In one study,
some relevant cardiac impairments (12% of
129 patients) occurred, 3 of which required
cardiac drug therapy (Bryant et al., 2007).
ECG changes; nonspecific ST-T wave

changes; premature ventricular and atrial contraction; low-voltage QRS changes;
and sinus tachycardia may occur acutely
during administration (Pfizer Inc., 2011a).
Decreased ejection fraction, sinus tachycardia, and cardiomyopathy with symptoms
of CHF occur later, with peak incidence 7
years after exposure (Barry et al., 2007).
It was once believed that continuous infusion caused more cardiotoxicity than intermittent delivery, but this has not been supported by systematic review (van Dalen et
al., 2008).
Pericardial effusion may be small and
asymptomatic or may be hemorrhagic and
produce acute symptoms.
Chronic effects seen with cumulative doses may

result in CHF.
Concomitant administration of other antineoplastics
(e.g., cyclophosphamide, taxanes, trastuzumab)
has been implicated as a risk factor, although exact synergism is unclear (Camp-Sorrell, 2011).
Cardiotoxicity at lower doses may occur in patients
who received mediastinal radiation and/or patients
with preexisting heart disease (Barry et al., 2007).
Perform periodic monitoring of cardiac function
with echocardiogram or MUGA scan throughout therapy and at least yearly after completion
of treatment.
Monitoring of troponin or BNP may be used to
monitor for early changes (Anderson, 2008;
Lenihan et al., 2007).
Protect against cardiac toxicity with dexrazoxane
in 10:1 ratio of dexrazoxane to doxorubicin. Protective agent is administered by IV push or rapid infusion 30 minutes prior to doxorubicin (Ng &
Green, 2007; Pfizer Inc., 2011a, 2012d).
Coadministration of coenzyme Q10 has shown
some potential benefit in minimizing cardiotoxicity (Brown & Giampa, 2010; Bryant et al., 2007;
van Dalen et al., 2011).
Doxorubicin liposomal; pegylated

liposomal doxorubicin
Effects on the myocardium have not been confirmed.

In studies of patients with AIDS-related Kaposi sarcoma, < 5% experienced cardiac-related adverse effects possibly related to the drug
(Janssen Products, LP, 2013).
Irreversible toxicity may occur as the total dose
nears 550 mg/m2; patients who have received
mediastinal radiation or concomitant cardiotoxic therapy may experience heart failure at 400
mg/m2 (Janssen Products, LP, 2013).
Nonspecific arrhythmia, tachycardia, cardiomyopathy, and/or CHF may occur.

Acute cardiac toxicity in the form of selflimiting atrial or ventricular dysrhythmias
may occur with any dose and at any time
during the treatment cycle. Second-degree atrioventricular heart block has been
reported (Janssen Products, LP, 2013).
Acute left ventricular failure can occur with
isolated high doses (Janssen Products,
LP, 2013).
Delayed-onset, dose-related cardiomyopathy is the most common and well-known
cardiotoxicity and is likely to be irreversible and unresponsive to treatment. Ten
patients treated with pegylated doxorubicin developed protocol-defined cardiac events, compared with 48 doxorubicintreated patients (Rahman et al., 2007).
Pegylated liposomal doxorubicin is believed to be

associated with less risk of cardiotoxicity than
the other anthracyclines (Camp-Sorrell, 2011).
Experience with large cumulative doses is limited; consider the cardiac risk to be comparable to that of conventional doxorubicin formulation and calculate dosages of liposomal doxorubicin with any previous anthracyclines (Shaikh &
Shih, 2012).
Irreversible cardiac damage is dose limiting. Longterm cardiac safety is unknown (Camp-Sorrell,
2011).
MUGA scans is recommended.
Anthracycline
antitumor
antibiotics
(cont.)
Drug

Drug
Incidence
Anthracycline
antitumor
antibiotics
(cont.)
Epirubicin hydrochloride
The probability of developing clinically evident

CHF is estimated at approximately 0.9% at a
cumulative dose of 550 mg/m2, 1.6% at 700
mg/m2, and 3.3% at 900 mg/m2 (Sagent Pharmaceuticals, 2011; Shaikh & Shih, 2012).
The risk of developing CHF rises rapidly with increasing total cumulative doses in excess of
900 mg/m2; cumulative dose only should be exceeded with extreme caution (Sagent Pharmaceuticals, 2011).
High single doses have been associated with
acute myocardial ischemia.
Myocardial toxicity, manifested in its most

severe form by potentially fatal CHF, may
occur either during therapy with epirubicin or months to years after termination of
therapy (Sagent Pharmaceuticals, 2011).
Dysrhythmias include premature ventricular
contractions, sinus tachycardia, bradycardia, and heart block.
Cardiomyopathy is notably late in onset, occurring 6 months to years after therapy.
Active or dormant cardiovascular disease, prior or

concomitant radiation to the mediastinal or pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant
use of other cardiotoxic drugs may increase the
risk of cardiac toxicity.
In the adjuvant treatment of breast cancer, the
maximum cumulative dose used in clinical trials
was 720 mg/m2.
Cardiotoxicity may occur at lower cumulative doses whether or not cardiac risk factors are present (Sagent Pharmaceuticals, 2011).
Idarubicin
Reported to have lower incidence of CHF than

other anthracyclines, but rate is 1.2% at 150
mg/m2 (Pfizer Inc., 2006).
High-risk populations may have increased incidence of cardiotoxicity up to 18% (Shaikh &
Shih, 2012).
Myocardial toxicity, manifested in its most

severe form by potentially fatal CHF, may
occur either during therapy with idarubicin or months to years after termination of
therapy (Pfizer Inc., 2006).
Drug is approved for use with children (Pfizer Inc.,

2006).
Mitoxantrone
Estimated risk is approximately 2.6% in doses of

140 mg/m2.
Maximum dose is considered 160 mg/m2 (CampSorrell, 2011).
Risk increases with cumulative dose (EMD Serono, Inc., 2012).
Rare, but potentially fatal, CHF may occur

during therapy or years after therapy completion (Shaikh & Shih, 2012).
Establish baseline cardiac function.

Monitor for cardiotoxicity beyond doses of 100
mg/m2.
Risk is increased by other cardiotoxic medications, mediastinal radiation, or concomitant cardiovascular disease.
5-Azacitidine
Capillary permeability is dose-related.

Rare hypotension and dysrhythmias have been
reported (Celgene Corp., 2012).
Drug can exacerbate heart failure and QT prolongation of other agents (Celgene Corp.,
2012).
Pericardial effusion, hypotension, and dysrhythmias related to compensatory response to hypotension may occur.
Toxicity usually is self-limiting and responds to a

drug holiday.
Monitor coadministration with other cardiotoxic
medications (Celgene Corp., 2012).
Antimetabolites
259
Classification
260

Classification
Incidence
5-FU
Incidence of 5-FU cardiotoxicity is dependent

upon dose and schedule.
Incidence of 10% has been associated with doses > 800 mg/m2/day (Yusuf et al., 2008).
The addition of other antineoplastic agents such
as irinotecan or cisplatin may influence the incidence of cardiotoxicity. Incidence is 1.6%
3% with bolus regimens but 7.6%18% with
prolonged infusion (45 days) (Fadol & Lech,
2011; Yeh & Bickford, 2009). One report with
two-day infusional 5-FU (de Gramont regimen)
was 3.9% (Fadol & Lech, 2011).
Deaths have been reported from myocardial
ischemia, and other severe coronary artery
events have been noted (Akhtar et al., 2011).
Literature suggests the incidence is highest in
the first and second cycles of therapy. In the de
Gramont regimen, symptoms begin at night, a
few hours after the bolus part of the infusion
(Talapatra et al., 2007).
Angina, palpitations, sweating, and/or syncope may occur (Sorrentino et al., 2012).
Angina-like chest pain with or without MI,
dysrhythmias, or cardiogenic shock occurs due to coronary vasospasm. Sudden
death has been reported and is presumed
to be due to acute myocardial ischemia
or infarction (Meydan et al., 2005; Paiva
et al., 2009). ECG changes without symptoms are unusual but have been reported.
Transient symptomatic bradycardia was reported in a small group of patients receiving infusional 5-FU (Talapatra et al., 2007).
Patients at higher risk for developing cardiotoxicity include those with heart disease, electrolyte
disturbances, or radiation exposure to the heart
(Singh et al., 2004; Sorrentino et al., 2012; Yusuf
et al., 2008). It may be treated prophylactically or therapeutically with long-acting nitrates or
calcium channel blockers (Fadol & Lech, 2011).
5-FU most commonly is discontinued with cardiotoxicity, but careful rechallenge with the agent
has been successfully achieved without exacerbation of previous cardiotoxicity (Fadol & Lech,
2011).
Capecitabine
Cardiotoxicity is rare; 1%18% is associated

with fluorinated pyrimidine therapy (Roche
Pharmaceuticals, 2011). In a retrospective
analysis of two randomized phase III clinical
trials of capecitabine as a single agent administered at 1,250 mg/m2 twice daily for days
114 followed by 7 days of rest, the incidence
noted was 3% of patients. Incidence of cardiotoxicity of capecitabine has been reported as
3%5% when administered alone or in combination with irinotecan, oxaliplatin, and taxanes
(Shah et al., 2012; Tsiamis et al., 2011).
Angina-like chest pain with or without MI,

dysrhythmias, or cardiogenic shock occurs
because of coronary vasospasm. Sudden
death has been reported and is presumed
to be associated with acute myocardial
ischemia or infarction (Roche Pharmaceuticals, 2011).
ECG changes without symptoms are unusual but have been reported. At least one
case report of Raynaud phenomenon has
been published (Coward et al., 2005).
These adverse events may be more common in

patients with a prior history of coronary artery
disease.
Interrupt drug if grade 2 or 3 adverse reactions
occur; discontinue drug for grade 4 toxicity
(Roche Pharmaceuticals, 2011).
Antimetabolites
(cont.)
Drug

Classification
Cladribine
Incidence of edema and tachycardia is 6%.

Chest pain has been reported (Pfizer Inc.,
2011b).
Transient decreased LVEF has been reported in
up to 27% of patients (Shaikh & Shih, 2012).
Tachycardia; edema, generalized and not

dependent; and chest pain not associated
with ischemic ECG changes may occur.
Drug has limited effects on QT interval but
may exacerbate QT prolongation from
other more potent inhibitors (Pfizer Inc.,
2011b).
Most events occurred in patients with a history of

cardiovascular disease or chest tumors.
Gemcitabine hydrochloride
CHF and MI have been reported rarely with the

use of gemcitabine.
Arrhythmias, predominantly supraventricular in
nature, have been reported very rarely.
Incidence of hypotension is 11% when given
with cisplatin. A study of doses above 1,000
mg/m2 on a daily 5 dose schedule showed
that patients developed significant hypotension
(Eli Lilly & Co., 2013).
Hypotension, MI, arrhythmia, and hypotension may occur (Eli Lilly & Co., 2013).
Age, gender, and infusion time factors: Lower clearance in women and older adults results
in higher concentrations of gemcitabine for any
given dose.
Toxicity is increased when administered more frequently than once weekly or with infusions longer than 60 minutes (Eli Lilly & Co., 2013).
Antitumor
antibiotic
Bleomycin
Maximum lifetime dose is 400 units, but lower

doses are recommended when administered
with other cardiotoxic agents or chest irradiation involving the heart. Pulmonary fibrosis is
its more common dose-limiting toxicity. Cardiomyopathy has been reported at similar doses
(Bristol-Myers Squibb Co., 2012a).
Little is known about the incidence or risk factors for Raynaud phenomenon. It is believed
that oxygen radical release causes localized
ischemia in poorly perfused areas (Gayraud,
2007).
Gangrenous digits have been reported. This
seems to be idiosyncratic, not dose-related,
and related to rate of infusion (Grnwald et al.,
2005).
Raynaud phenomenon is infusion-related

and will resolve with discontinuation or
completion of the agent.
Raynaud phenomenon presents initially as
pain and heaviness of the digits.
Cardiomyopathy presents as progressive
decline in ejection fraction with dyspnea
as the usual first presenting symptom.
Perform routine monitoring of echocardiogram

once close to maximum tolerated dose.
Cytokine
IFN alfa
Raynaud symptoms are rare but potentially severe. Peak incidence is 3 weeks to 3 years after beginning therapy of 3,000,000 units daily. Concomitant administration of hydroxyurea
may increase risk in some patients (Schering
Corp., 2012a).
Raynaud phenomenon with superficial skin

ulceration or gangrene can occur (Schering Corp., 2012a).
Teach patients to report Raynaud symptoms.

Symptoms resolve with discontinuation of medication.
261
Incidence
Antimetabolites
(cont.)
Drug
262

Classification
Incidence
Immune
conjugates
Denileukin diftitox
Vascular leak syndrome, also known as CLS,

with vasodilation, hypotension, and compensatory tachycardia occurred in 27% of patients
on registration trials, with 6% requiring hospitalization, and rare deaths reported. Onset may
be delayed up to 2 weeks after infusion and
may persist or worsen after discontinuing the
agent (Eisai Inc., 2011a; McCann et al., 2012).
Hypotension can occur, likely related to capillary permeability and vasodilation from
immediate inflammatory responses of the
vasculature (Eisai Inc., 2011a).
Dysrhythmias may occur and seem to be related to vasodilation and volume status.
Accurate intake and output, weight measurements, and central venous pressure readings
may help to determine total fluid volume and
vascular space volume status.
Interleukin
IL-2
Side effects appear to be dose related (Shelton,

2012). Risk increases with doses > 100,000 IU/
kg (Shelton, 2012). Average dose is 600,000
IU/kg (Prometheus Laboratories Inc., 2012).
Most adverse reactions are self-limiting and usually, but not invariably, reverse or improve within 23 days of discontinuing therapy.
Hypotension of all grades occurs in 71% of patients, but severe grade 4 toxicity occurs in only
3% (Prometheus Laboratories Inc., 2012).
The rate of drug-related deaths in 255 patients
with metastatic renal cell carcinoma who received single-agent IL-2 was 4% (11/255); the
rate of drug-related deaths in 270 patients with
metastatic melanoma who received singleagent IL-2 was 2% (6/270) (Prometheus Laboratories Inc., 2012).
CLS results in hypotension and reduced organ perfusion, which may be severe and
can result in death. CLS may be associated with cardiac arrhythmias (supraventricular and ventricular), CHF, angina, pleural
and pericardial effusion, myocarditis, chest
pain, and (rarely) MI (Prometheus Laboratories Inc., 2012).
CLS begins immediately after aldesleukin
treatment starts. In most patients, a concomitant drop in mean arterial blood pressure occurs within 212 hours after the
start of treatment.
With continued therapy, clinically significant
hypotension (systolic blood pressure 90
mm Hg or a 20 mm Hg drop from baseline systolic pressure) and hypoperfusion
will develop (Prometheus Laboratories
Inc., 2012).
Electrical changes caused by cytokine biotherapy usually relate to cellular swelling or
inflammatory cytokine release causing disruption of conduction pathways. Capillary
permeability and hypovolemia enhance the
risk of supraventricular tachycardia.
IL-2 should be withheld in patients developing

ventricular dysrhythmias until cardiac ischemia
and wall motion can be assessed.
Should adverse events occur, dosage should be
withheld, not reduced.
Patients should have normal cardiac, pulmonary,
hepatic, and CNS function at the start of therapy.
Cardiac toxicities are worse when administered in
conjunction with IFN alfa (Prometheus Laboratories Inc., 2012).
Medical management of CLS begins with careful
monitoring of the patients fluid and organ perfusion status; this is achieved by frequent determination of blood pressure and pulse and assessment of mental status and urine output. Hypovolemia is assessed by catheterization and central
pressure monitoring.
Electrical changes associated with biotherapeutic
agents generally necessitate temporary discontinuation of the drug. Once inflammatory effects
have resolved, rechallenge is possible (Shelton, 2012).
HER2 receptor
agonist
Pertuzumab
Decreased LVEF, which included some patients

with symptomatic heart failure, occurred in
4.4% of treated patients (Genentech, Inc.,
2012c).
Assess LVEF prior to initiation of pertuzumab and

at regular intervals (e.g., every 3 months) during
therapy to ensure that ventricular function is not
impaired (Genentech, Inc., 2012c).
Withhold both pertuzumab and trastuzumab if significant decrease in LVEF, then reassess within
3 weeks. If it continues to be decreased, discontinue both pertuzumab and trastuzumab (Genentech, Inc., 2012c).
Drug

Classification
Drug
Incidence
Tamoxifen
Rare cases of QT prolongation with dysrhythmia

or heart failure (Teva Pharmaceuticals USA,
2012c)
QT prolongation with bradycardia or ventricular dysrhythmias occurs infrequently and without clear risk factors such as
dose or longevity of therapy (Slovacek et
al., 2008).
Rare cases of myocardial ischemia and infarction have occurred from unclear mechanisms but may be a component of hypercoagulability (Teva Pharmaceuticals USA,
2012c).
Monitor ECG for QT prolongation.

Avoid other medications known to prolong the QT
interval.
Miscellaneous
Arsenic trioxide
QT prolongation occurs in 40% of patients treated with arsenic trioxide at usual therapeutic
doses (Cephalon, Inc., 2010).
Dysrhythmias related to prolongation of the QT
have occurred in approximately 10% of cases.
It is usually asymptomatic but can induce ventricular tachycardia. Drug should not be administered unless the QTc is < 500 msec. Therapy
can be resumed once the QTc returns to < 460
msec (Cephalon, Inc., 2010).
QT prolongation with dysrhythmias

Usual onset of QT prolongation > 0.50 msec
was 14 weeks after treatment.
QT prolongation effects may persist up to
8 weeks after therapy (Cephalon, Inc.,
2010).
Complete atrioventricular block has been reported with arsenic trioxide (Cephalon,
Inc., 2010).
Check 12-lead ECG prior to therapy and hold if

QTc is > 500 msec (Cephalon, Inc., 2010).
Check all electrolytes prior to administration of
medication and replenish prior to therapy. Potassium should be kept > 4 mEq/L, and magnesium
> 1.8 mEq/L (Cephalon, Inc., 2010).
Assess for other causes of dysrhythmias prior to
administering drug.
Eribulin
Asymptomatic QT prolongation was present in

all patients in a small sample (Eisai Inc., 2013).
QT prolongation was noted on day 8 of therapy.

QT prolongation is independent of eribulin
concentration.
Monitor QT interval while on therapy.

Increase vigilance of monitoring for patients with
heart failure, bradyarrhythmias, and concomitant
administration of QT-prolonging drugs.
Correct hypokalemia and hypomagnesemia during therapy.
Romidepsin
T-wave and ST changes (grade 1): 71%, but few

progressed to severe medical consequences
ECG changes are not linked to clinical decompensation and are of uncertain clinical
significance (Glass & Viale, 2013).
Monitor 12-lead ECG periodically (Glass & Viale, 2013).
Vorinostat
VTE with pulmonary embolism occurred in 5%

of patients in registration trials (Olsen et al.,
2007).
Teach patients methods to reduce risk of VTE:

drink fluids and maintain mobility (Glass & Viale, 2013).
Consider thromboprophylaxis for patients with additional risks for VTE.
Ziv-aflibercept
Hypertension
Monitor blood pressure every two weeks or more

frequently as indicated.
Treat with appropriate antihypertensive therapy
(Regeneron Pharmaceuticals, Inc., 2013).
263
Hormone
264

Classification
Incidence
Alemtuzumab
Cardiac toxicities are uncommon, although incidence is higher when this agent is used in
lymphoproliferative malignancies, especially
Szary syndrome.
In an 8-patient case series, 4 developed newonset CHF caused by left ventricular dysfunction (Lenihan et al., 2004).
CHF may present even after one dose, but

most symptoms present 611 weeks after
starting therapy at doses of 30 mg 3 times/
week (Genzyme Corp., 2009a).
No clear cardiac pathology was detectable on
endomyocardial biopsy despite permanent
reduction in ejection fraction.
Dysrhythmias: Atrial fibrillation has been reported, but it is unclear if they are related to
capillary leak and hypotension.
The proposed mechanism of all cardiotoxicity
associated with alemtuzumab is that of cytokine release.
Use with caution in patients who have received

prior antitumor antibiotics that may exacerbate
risk of cardiac failure (Genzyme Corp., 2009a).
Bevacizumab
Significant hypertension occurred in 5%18% of

patients receiving bevacizumab. It can occur
as early as two weeks after the start of therapy, and peak incidence is the second month of
therapy (Genentech, Inc., 2012a).
CHF was reported in 1.7% of patients overall,
but the incidence was as high as 14% in patients who received prior anthracyclines (Genentech, Inc., 2012a).
Hypertension and thrombosis or hemorrhage

may occur.
Hypertension may persist for several weeks
after discontinuation of bevacizumab (Genentech, Inc., 2012a).
CHF occurs more frequently in patients
who have received prior anthracyclines or
left chest wall radiation (Genentech, Inc.,
2012a).
Check baseline vital signs, and monitor with each

clinic visit or at least every 23 weeks during
therapy (Genentech, Inc., 2012a).
Establish home routine of twice-daily blood pressue monitoring while adjusting medications to
treat hypertension.
Temporarily suspend treatment if urine shows 3+
urine dipstick reading, particularly if accompanied by hypertension.
No clear antihypertensive treatment has been
identified.
Cetuximab
Cardiac arrest occurred with 0.2% incidence in

patients receiving cetuximab for head and neck
cancer but was not evident in patients receiving
for metastatic colorectal cancer (Bristol-Myers
Squibb Co. & ImClone Systems, 2012).
Cardiac arrest of unclear etiology, but clear

hypomagnesemia with this agent could
cause dysrhythmias related to QT prolongation.
Maintain magnesium level of 2 mEq/L.

Monitor magnesium level throughout treatment
and up to 8 weeks after conclusion of therapy
(Bristol-Myers Squibb Co. & ImClone Systems,
2012).
Ipilimumab
Hypotension, immune-mediated vasculitis, temporal arteritis, myocarditis, and pericarditis

can occur (Bristol-Myers Squibb Co., 2013).
Rituximab
Cardiotoxicity when used as a single agent is

unknown.
Infusion-related deaths have occurred within 24
hours of infusion (Biogen Idec, Inc., & Genentech, Inc., 2013).
Incidence of mild to moderate hypotension requiring treatment interruption was 10% (Biogen
Idec, Inc., & Genentech, Inc., 2013).
Case reports of dysrhythmias exist.
Hypotension and angioedema can occur.

Infusion-related complex includes MI, ventricular fibrillation, and cardiogenic shock (Biogen
Idec, Inc., & Genentech, Inc., 2013).
Although tachydysrhythmias are more common, case reports of bradycardia and heart
block exist and may be related to prolongation of the QTc (Grau et al., 2008).
Nearly all fatalities have occurred on first infusion.

Discontinue and medically treat patients who develop clinically significant cardiopulmonary reactions.
After symptoms resolve, resume treatment by reducing the infusion rate by 50% (Biogen Idec,
Inc., & Genentech, Inc., 2013).
Monoclonal
antibodies
Drug

Classification
Drug
Incidence
Trastuzumab
Incidence of cardiac dysfunction as a single

agent is 7%.
Incidence with paclitaxel is 11%.
When the drug is combined with anthracycline
and cyclophosphamide, incidence is 28%.
Advanced age may increase the probability of
cardiac dysfunction (Bird & Swain, 2008; Frankel, 2010; Genentech, Inc., 2012b).
Signs and symptoms of cardiac dysfunction

observed in patients treated with trastuzumab include dyspnea, cough, paroxysmal nocturnal dyspnea, peripheral edema,
S3 gallop, or reduced ejection fraction (Genentech, Inc., 2012b).
Prolonging the infusion rate decreases infusion-related events for first infusion by
80% and 40% for subsequent infusions
(Genentech, Inc., 2012b).
CHF has been associated with disabling cardiac failure, death, and mural thrombosis leading to stroke.
Discontinuing therapy is strongly suggested for
those with significant CHF or asymptomatic
ejection fraction decreases.
Exercise extreme caution in treating patients with
preexisting cardiac dysfunction.
Patients should undergo frequent monitoring for deteriorating cardiac function (Genentech, Inc., 2012b).
Avoid anthracyclines within 24 weeks of trastuzumab due to long half-life of drug.
Multikinase
inhibitors
Bosutinib
Among patients with fluid retention in registration

trials, only 3 patients (< 1%) experienced grade
3 or 4 pericardial effusion (Pfizer Inc., 2013a).
Cause of pericardial effusion is thought

to be fluid retention common with agent
(Pfizer Inc., 2013a).
Consider dose reductions or temporary interruptions of therapy for symptomatic pericardial effusions (Pfizer Inc., 2013a).
Lapatinib
Grade 4 heart failure with systolic dysfunction

occurred in 1.6% of patients pooled from multiple studies; 88% developed reversible disease
(Perez et al., 2008).
Incidence is dependent on lapatinib concentration (GlaxoSmithKline, 2012).
QT interval may be prolonged and increase

the risk for dysrhythmias (GlaxoSmithKline, 2012).
The QT prolongation most often occurred in
individuals who had received prior anthracyclines.
Onset averages 13 weeks after start of therapy and lasts approximately 7 weeks (Perez et al., 2008).
QT prolongation most often leads to bradycardia but can cause life-threatening tor
sades de pointes (Shelton, in press-a).
Obtain baseline cardiac evaluation with echocardiogram or MUGA scan (GlaxoSmithKline, 2012).
If the ejection fraction drops below the lower limit of normal, lapatinib is stopped for at least 2
weeks, and when ejection fraction is returned to
normal and the patient remains asymptomatic,
the dose is reduced and resumed at 1,000 mg/
day (GlaxoSmithKline, 2012).
Monitor for subtle signs of heart failure.
Agent will prolong effects of digitalis (GlaxoSmithKline, 2012).
Sorafenib
Cardiac failure or asymptomatic left ventricular

end-diastolic dysfunction with reduced ejection fraction is reported infrequently (< 1%)
(Force et al., 2007).
No clear incidence rate has been identified
(Kamba & McDonald, 2007; Patel et al., 2008;
Porta et al., 2007).
Cardiac ischemia with MI has been reported
rarely (< 1%) (Bayer Healthcare Pharmaceuticals Inc., 2011).
Hypertension occurred in 16.9% of patients with
renal cell cancer and 9.4% of patients with hepatic carcinoma (Bayer Healthcare Pharmaceuticals Inc., 2011).
Cardiac failure, chest pain with myocardial ischemia, and asymptomatic decreased
left ventricular end-diastolic function with
reduced ejection fraction may occur.
Vasculitis with hypertension can develop
(Shaikh & Shih, 2012).
Asymptomatic myocardial ischemia and
acute MI have been reported (Bayer
Healthcare Pharmaceuticals Inc., 2011).
Monitor blood pressure weekly for the first 6

weeks, then periodically throughout therapy.
Standard antihypertensive agents are recommended for management of hypertension.
Therapy breaks have been effective for resolution
of hypertension.
Hypertension seems to be related to presence
of proteinuria, and both usually are present prior to cardiac failure (Force et al., 2007; Porta et
al., 2007).
Halt all therapy if symptomatic myocardial ischemia occurs temporally related to drug administration (Bayer Healthcare Pharmaceuticals Inc.,
2011).
265
Monoclonal
antibodies
(cont.)
266

Classification
Drug
Incidence
Sunitinib
Incidence of cardiotoxicities was evaluated in

phase I and II studies. Hypertension was reported in 35 of 75 patients with an incidence
rate of 47% (Chu et al., 2007; Pfizer Inc.,
2012c). This frequency has persisted through
registration trials and current clinical practice.
There are well-established reports of both asymptomatic left ventricular end-diastolic dysfunction
(> 15% reduction in ejection fraction) and cardiac failure; incidence is 28% and 8%, respectively (Chu et al., 2007). Class effect (symptom occurring in most drugs in same category) involves
mitochondrial injury and cardiomyocyte apoptosis, suggesting that there is risk for cardiac toxicities, but incidence rate is unclear (Chu et al.,
2007; Force et al., 2007; Shaikh & Shih, 2012).
Hypertension, cardiac failure, and asymptomatic decreased left ventricular end-diastolic function with reduced ejection fraction can occur.
See sorafenib.
Plant alkaloids
Vinblastine
Idiosyncratic response to medication can develop that is not dose-related but does not resolve
until the medication is discontinued (APP Pharmaceuticals, LLC, 2011).
Raynaud phenomenon can occur.
Teach patients to avoid cold exposure and tobacco smoking, which will exacerbate pain.
Vincristine
There have been isolated reports of Raynaud

phenomenon with vincristine in adults and adolescents. It seems to be dose-related and does
not resolve until the medication is discontinued
(Hospira, Inc., 2013).
One study of children associated symptomatic
respiratory-phase heart rate variation with use
of vincristine (Steinherz & Steinherz, 1995).
Raynaud phenomenon has occurred even

with single doses.
Advise patients to avoid cold exposure and tobacco smoking, which will exacerbate pain.
Vinorelbine
tartrate
There have been rare reports of MI (Pierre Fabre Pharmaceuticals USA, 2007).
Chest pain was reported in 5% of patients
(Pierre Fabre Pharmaceuticals USA, 2007).
Hypertension, hypotension, vasodilation, tachycardia, and pulmonary edema have been reported (Pierre Fabre Pharmaceuticals USA,
2007).
Rare incidence with variable symptoms that

may be mistaken for evolving acute cardiac event.
Most reports of chest pain were in patients who

had either a history of cardiovascular disease
or tumor within the chest (Pierre Fabre Pharmaceuticals USA, 2007).
There is a high level of suspicion for an acute cardiac event with symptoms.
Temporarily discontinue vinorelbine and perform
cardiac diagnostic tests when patients report
cardiac symptoms. Therapy may be resumed after resolution of symptoms (Pierre Fabre Pharmaceuticals USA, 2007).
Multikinase
inhibitors (cont.)

Classification
Taxanes
Tyrosine
kinase
inhibitors
Drug
Docetaxel
Hypotension incidence is 2.8% (1.2% required

treatment). Incidence related to high-dose
treatment is unknown (sanofi-aventis U.S. LLC,
2013).
Drug can cause cardiac adverse effects

similar to other microtubule-inhibiting
agents (Salvatorelli et al., 2006).
Hypotension may develop during infusion
that resolves with slowing of infusion rate.
CHF occurred in patients also treated with
doxorubicin (> 360 mg/m2).
Sinus tachycardia, atrial flutter, dysrhythmia,
unstable angina, and/or hypertension may
occur (sanofi-aventis U.S. LLC, 2013).
Drug is well tolerated in older adult patients with

non-small cell lung cancer (Hainsworth et al.,
2000).
Paclitaxel
Asymptomatic bradycardia occurred in almost

30% of patients with ovarian cancer; cardiac
ischemia occurred in 5% (Bristol-Myers Squibb
Co., 2011f).
Significant cardiac events occurred in 3% of all
cases (Bristol-Myers Squibb Co., 2011f).
Rare reports exist of cardiac ischemia or MI (Yusuf et al., 2008).
CHF has been reported in patients receiving other chemotherapy agents (Bristol-Myers Squibb
Co., 2011f).
Asymptomatic bradycardia (4060 bpm), hypotension, and asymptomatic ventricular

tachycardia have been reported at all doses (Fadol & Lech, 2011).
Atypical chest pain with and without cardiac ischemia occurs occasionally and originally was thought to be related to the
agents diluent, polyoxyl 40 hydrogenated castor oil (Kolliphor EL, formerly Cremophor EL), but this is now less clear
(Bristol-Myers Squibb Co., 2011f).
Pericardial effusion can occur.
Obtain a baseline ECG, history and physical, and

cardiac assessment before treatment. However,
routine cardiac monitoring during infusion is not
recommended (Fadol & Lech, 2011).
Axitinib
In a controlled clinical trial of patients with renal cell cancer, 40% (145/359) developed hypertension. Grade 3 or 4 hypertension was observed in only 16% (56/359). Hypertensive crisis was reported in < 1% of patients (Pfizer
Inc., 2012b).
Median onset of systolic BP > 150 mm Hg

or diastolic BP > 100 mm Hg was within the first month of therapy (Pfizer Inc.,
2012b). BP increases were observed as
early as 4 days after the first dose (Pfizer
Inc., 2012b).
BP should be well controlled prior to start of therapy (Tyler, 2012). Elevated BP should be managed with standard antihypertensive strategies
and medications. Dose reduction is permitted if
refractory hypertension is present. Discontinuation of axitinib is recommended if hypertension
is severe and persistent despite therapeutic interventions.
267
Incidence
268

Classification
Incidence
Crizotinib
QT prolongation with dysrhythmias has been observed infrequently. Bradycardia grade 1 or 2

has been observed in 5% of patients (Kwon &
Meagher, 2012).
Dysrhythmias, particularly bradycardia, can

occur.
Use with caution in patients with higher risk of developing prolonged QT interval or with baseline
cardiac disease. Consider periodic monitoring
with ECG in patients with risk factors for QT prolongation.
Perform baseline and periodic monitoring of electrolytes with potassium goal 4 mEq/L and magnesium goal 2 mEq/L.
Permanently discontinue the drug for grade 4 QT
prolongation, and hold for grade 3 QT prolongation until recovery to grade 1 toxicity. Discontinue if grade 3 QT prolongation recurs (Pfizer
Inc., 2013c).
Dasatinib
QTc prolongation: < 1%

Heart failure: 3%
Toxicity may be enhanced for patients who

previously received anthracyclines (Galinsky & Buchanan, 2009).
Administer with caution to patients who have or

are at risk for QT prolongation.
If QT prolongation occurs, stop therapy with dasatinib until the QT interval returns to normal.
Replenish electrolytes to prevent hypokalemia
and hypomagnesemia.
The decision to resume dasatinib at reduced dose
after cardiotoxicity is an individual clinician decision (Galinsky & Buchanan, 2009).
Pazopanib
QT prolongation occurred in < 1% of patients

on registration trials, but the risk is still present because of its class effect (GlaxoSmithKline, 2013).
Hypertension occurred in 40% of patients with
renal cell cancer who received pazopanib
(GlaxoSmithKline, 2013). It was observed early
in the course of treatment. Approximately 39%
experienced hypertension within the first 9
days and 90% experienced it during the first 18
weeks of treatment. Only 4%7% were grade 3
or 4 (GlaxoSmithKline, 2013).
Myocardial dysfunction in the form of decreased
LVEF was only 0.6% with renal cell carcinoma
but 11% with soft tissue sarcoma, possibly attributable to collective toxicity with other antineoplastic agents (GlaxoSmithKline, 2013).
VTE occurred in 5% of patients in registration trials (GlaxoSmithKline, 2013).
QT prolongation with dysrhythmias, including torsades de pointes, has been reported in patients receiving pazopanib (GlaxoSmithKline, 2013).
Hypertension is extremely common during
therapy.
Use with caution in patients with higher risk of developing prolonged QT interval or with baseline
cardiac disease. Consider periodic monitoring
with ECG in patients with risk factors for QT prolongation.
Perform baseline and periodic monitoring of electrolytes with potassium goal of 4 mEq/L and
magnesium goal of 2 mEq/L (Nguyen & Shayahi, 2012).
Control preexisting blood pressure before beginning pazopanib therapy (Nguyen & Shayahi, 2012).
Dose reduction is permitted if hypertension persists despite supportive antihypertensive therapies (GlaxoSmithKline, 2013).
Tyrosine
kinase
inhibitors (cont.)
Drug

Classification
VEGF
inhibitors
Drug
Lenalidomide
Chest pain was reported in 8.2% of patients during registration trials, but it is not clear if it was
related to cardiotoxicities or pulmonary embolism (Celgene Corp., 2013a).
Hypertension (all grades) occurred in 7.1% of
patients receiving lenalidomide during registration trials.
VTE occurred in 9.3% of patients receiving lenalidomide with dexamethasone, a rate double that of patients receiving dexamethasone
alone (Celgene Corp., 2013a).
Bradycardia has been reported infrequently,

and less often than with thalidomide. Atrial
fibrillation has been reported with unidentified frequency (Celgene Corp., 2013a).
Hypertension (primarily systolic) has been
reported with lenalidomide administration
and is more frequent when the drug is given with dexamethasone.
Rare instances of cardiac ischemia are noted in prescribing information (Celgene
Corp., 2013a).
Thromboembolism displays no established
pattern of lower or upper extremities or
specific timing during treatment. It is associated with patients who are also receiving high-dose corticosteroids (Elice et al.,
2008).
Establish baseline blood pressure, heart rate and

regularity, and ECG findings to identify drugrelated changes.
Monitor heart rate, rhythm, and blood pressure
frequently during therapy or with new cardiac
symptoms.
Strongly consider appropriate antithrombotic prophylaxis while receiving lenalidomide.
Thalidomide
In a small phase I study, grade 3 dysrhythmias

occurred in 2% of patients (Sharma et al.,
2006).
Registration trial reported dysrhythmias, most
commonly bradycardia not requiring clinical intervention (Celgene Corp., 2013b).
Incidence of thromboembolism is increased (up
to 23%), but it is unclear whether this is related to this agent or the cancer (Celgene Corp.,
2013b).
Bradycardia is the most common dysrhythmia reported.

Thromboembolism displays no established
pattern of lower or upper extremities or
specific timing during treatment. It is associated with patients who are also receiving high-dose corticosteroids (Elice et al.,
2008).
Assess patients for dizziness, palpitations, or other symptoms of dysrhythmias.

Initiate thromboprophylaxis when not contraindicated.
Lenalidomide is an additional immune modulator with similar actions and cardiotoxicities (Celgene Corp., 2013b; Menon et al., 2008).
269
AIDSacquired immunodeficiency syndrome; BMTbone marrow transplantation; BNPbrain natriuretic peptide; BPblood pressure; bpmbeats per minute; CHFcongestive heart failure; CLScapillary leak syndrome; CNScentral nervous system; ECGelectrocardiogram; 5-FU5-fluorouracil; HER2human epidermal growth factor receptor 2; IFNinterferon; ILinterleukin; IUinternational units; kgkilogram; LVEF
left ventricular ejection fraction; mEq/Lmilliequivalent per liter; MImyocardial infarction; mm Hgmillimeters of mercury; msecmillisecond; MUGAmultigated acquisition; QTcQT interval corrected; VEGFvascular endothelial growth factor; VTEvenous thromboembolism
Incidence
270
(1) Conduction disturbances are classified according to their origin (e.g., atrial, ventricular, heart blocks) or their degree of lifethreatening symptoms.
(2) Life-threatening dysrhythmias such as ventricular tachycardia,
ventricular fibrillation, or advanced heart blocks are less common but may warrant permanent discontinuation of therapy.
Other exacerbating factors such as comorbidities, electrolyte
and acid-base disturbances, or tumor compression often are involved and make it difficult to determine if the disorder is truly triggered by the chemotherapeutic or biologic agent (Shelton, in press-b)
(a) Electrolyte disturbances (e.g., hypokalemia, hyperkalemia,
hypocalcemia, hypomagnesemia) (Bashir et al., 2007; Pepin & Shields, 2012)
(b) Comorbid health conditions (e.g., chronic obstructive lung
disease, heart disease) (Yusuf, Razeghi, & Yeh, 2008).
(c) Prolonged QT interval (Sauer & Newton-Cheh, 2012;
Scheibly & Tsiperfal, 2009)
(3) Mechanisms of arrhythmogenesis (Guglin et al., 2009; Shelton, in press-b)
(a) Fluid volume loss
(b) Oxygen free radicals released by ischemic cardiomyocytes
(c) Inflammatory capillary permeability within the myocytes
(d) Prolongation of the refractory period and interference
with the action potential of myocytes (Drew et al., 2010;
Scheibly & Tsiperfal, 2009)
(4) Potential negative consequences of dysrhythmias (Desai &
Giugliano, 2012; Hazinski, Samson, & Schexnayder, 2010)
(a) Decreased cardiac output
(b) Thrombus formation within the heart
(c) Cardiac ischemia
(d) Uncomfortable symptoms such as chest tightness, difficulty breathing, or light-headedness.
c) Incidence: The incidence of dysrhythmias specifically associated with
cancer treatments is largely underestimated because of the probable
attribution to other causes (Fadol & Lech, 2011; Guglin et al., 2009;
Sereno et al., 2008). In well-defined cases, the incidence can still only
be imperfectly quantified because preventive measures are always employed when possible. Incidence rates reported with specific therapies include the following.
(1) Asymptomatic bradycardia occurs in 3%30% of patients receiving paclitaxel. More profound cardiac events (e.g., ventricular tachycardia, left-bundle branch block) have been observed
in rare instances (Fadol & Lech, 2011; Yeh & Bickford, 2009).
(2) Bradycardia from thalidomide has been reported with a variable frequency from < 1% to up to 55% of patients treated. The
proposed mechanisms include therapy-related hypothyroidism,
sedative effects, and increased vagal sensitivity (Fadol & Lech,
2011; Guglin et al., 2009).
(3) 10%20% of dysrhythmias associated with cytokine therapies
such as IL-2 are linked to fluid and electrolyte imbalances (Guglin et al., 2009).
(4) Lower incidence rates of < 5% occur with agents that cause
myocarditis or QT prolongation (Force & Kerkel, 2008; Guglin et al., 2009).
d) Risk factors (Fadol & Lech, 2011; Guglin et al., 2009; Viale & Yamamoto, 2008)
(1) Capillary permeability syndrome due to vascular depletion (Guglin et al., 2009; Shelton, 2012)
(2) Myocarditis, pericarditis, or pericardial effusion (Shelton, in
press-c)
(3) Agents with direct cardiotoxicity, including anthracyclines,
fluoropyrimidines (e.g., 5-FU, capecitabine), and trastuzumab (Floyd & Perry, 2008; Gianni, Salvatorelli, & Minotti, 2007)
(4) Medications and conditions known to prolong the QTc, including 5-FU, arsenic trioxide, dasatinib, lapatinib, nilotinib,
pazopanib, sunitinib, tamoxifen, temsirolimus, and vorinostat
(Cahoon, 2009; Drew et al., 2010; Fadol & Lech, 2011; Guglin
et al., 2011)
(5) Personal history of heart disease, diabetes mellitus, hypertension, pulmonary hypertension, or electrolyte disturbances (Viale
& Yamamoto, 2008)
e) Clinical manifestations
(1) Most patients with dysrhythmias report subjective symptoms
such as palpitations, chest discomfort, dyspnea, or dizziness
(Carey & Pelter, 2009a).
(2) Syncope as the first presenting symptom is more common with
ventricular dysrhythmias (Hazinski et al., 2010).
(3) Most patients report diminished functional capacity with atrial
fibrillation. Dyspnea and fatigue are common, and loss of atrial contribution to cardiac output (approximately one-third of
cardiac output) leads to worsening of all other cardiac disease
symptoms (Bontempo & Goralnick, 2011).
f) Assessment
(1) Assess patient history for known medical conditions or medications that may precipitate dysrhythmias. Elimination of preventable risks may reduce incidence or severity (Jolobe, 2010).
(2) Compare apical and peripheral heart rate (Carey & Pelter,
2009b; Shelton, in press-b).
(3) Auscultate for abnormal heart sounds demonstrating pericardial effusion (muffled) or heart failure (gallops or murmurs)
(Shelton, in press-b).
(4) Perform follow-up assessments of vital signs and symptoms of
dyspnea, hypoxemia (shown as low oxygen saturation), hypotension, or chest discomfort (Hazinski et al., 2010).
(5) Obtain 12-lead ECG.
(6) Maintain ongoing monitoring (continuous or intermittent) of
rhythm (Drew et al., 2010; Shelton, in press-b).
(7) Assess contributing causes of QT prolongation.
g) Collaborative management (Chopra, 2011)
(1) Correct contributing factors such as hypoxemia, anemia, fluid imbalance, and electrolyte abnormalities. Administer electrolyte replacement to a goal potassium value > 4 mEq/L and
magnesium value > 2 mEq/L (Hinkle, 2011; Pepin & Shields,
2012; Shelton, in press-b). Optimal calcium levels are not established, but ionized calcium levels > 1.1 mEq/L are the usual goal.
(2) Determine if antidysrhythmic agents are warranted (Hazinski et al., 2010).
(a) Antidysrhythmic medications (Carey, Pelter, Cao, & Pillow,
2010; Hazinski et al., 2010; Shelton, in press-a)
(b) Implantable defibrillator, such as pacers, synchronous cardioversion, atrial pacing, or ablation (Chatterjee et al.,
2012; Edgerton, 2012; Jackson, Daubert, & Thomas, 2012)
h) Patient and family education (Chopra, 2011; Nair & Asirvatham, 2011)
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(1) Teach patients and families the symptoms of dysrhythmia and

the potential urgency of treatment.
(2) Advise patients when to call or come to the clinic and, more importantly, to call emergency medical services if they feel short
of breath or dizzy.
(3) Once dysrhythmias are identified in a patient, teach preventive strategies such as hydration or electrolyte replacement.
Emphasize that vomiting or diarrhea may disrupt fluid or electrolyte balance.
(4) If supraventricular tachycardia has occurred, teach patients
to induce vagal maneuvers via coughing or bearing down as if
defecating.
(5) Patients with ventricular dysrhythmias are at risk for sudden
death, and if indicated, family members may be advised to learn
basic life support skills.
(6) Emphasize importance of periodic evaluation of laboratory values and ECG when at risk for dysrhythmias.
3. Vascular abnormalities
a) Capillary leak syndrome, a condition associated with the use of IL-2,
involves extravasation of fluids and albumin into body issues. The results are decreased peripheral vascular resistance, hypotension, and
decreased intravascular volume (Xie et al., 2012).
b) Raynaud phenomenon: This syndrome may occur with high-dose cytarabine arabinoside, docetaxel, oprelvekin, suramin, and temsirolimus. Noncardiac arterial vasospasm and insufficiency may present as
Raynaud phenomenon, whereby small distal arterial vessels constrict
and prevent digit circulation (Viale & Yamamoto, 2008). Vasospasm
causes immediate circulatory compromise that leads to local symptoms of pain and discoloration of the digits (Boin & Wigley, 2005;
Daher & Yeh, 2008; Kamba & McDonald, 2007; Pope, 2007).
(1) Pathophysiology: Abnormal nerve conduction and vascular diameter contribute to the pathophysiology of vasculitis (Boin &
Wigley, 2005). Endothelial injury with inflammatory mediators
(e.g., taxanes, antiangiogenesis agents) can explain this process
(Gayraud, 2007; Herrick, 2013).
(2) Incidence: Raynaud phenomenon is infrequent. Only case reports are evident with any given therapy regimen (Brydy et
al., 2009; Gayraud, 2007; Steingart et al., 2012; Ting, Fukshansky, & Burton, 2007).
(3) Risk factors
(a) Certain drug therapy: Cisplatin, gemcitabine, tyrosine kinase inhibitors, IFN, vincristine, and bleomycin (Boin &
Wigley, 2005; Pope, 2007)
(b) Preexisting vascular insufficiency or hypertension (Boin &
Wigley, 2005; Pope, 2007)
(c) Certain malignancies (lymphoma, sarcoma), autoimmune
disorders (rheumatoid arthritis, scleroderma, systemic lupus erythematosus), or hormone imbalance (hypothyroidism, estrogen therapy) (Herrick, 2013)
(d) Exacerbated by extreme hot or cold temperatures or emotional stress (Boin & Wigley, 2005; Gayraud, 2007)
(4) Clinical manifestations
(a) Cool, pale, and painful digits with an area of demarcation
between perfused and nonperfused tissue (Boin & Wigley,
2005; Gayraud, 2007; Pope, 2007)
(b) Onset of symptoms is usually rapid, lasting a few minutes
to several hours, and most often involves the fingers and
is unilateral. Vascular spasm with low blood flow first leads

to pale-white and painful digits. This is followed by cyanosis, reduced pain, and, lastly, flushing with return of circulation accompanied by pain.
(5) Assessment: Obtain health history and examine distal extremities at every clinic or hospital visit. Raynaud phenomenon is
diagnosed by signs and symptoms in conjunction with a known
risk factor. Raynaud phenomenon is visible and easily confirmed.
Patient report is highly reliable because of the visibility of the
condition and associated pain.
(6) Collaborative management: Advise patients to avoid exposure
to cold and to quit smoking (Pope, 2007). Mild forms are managed with supportive interventions such as wearing gloves when
performing tasks such as removing items from the refrigerator
or placing hand warmers in gloves or pockets in cold weather.
When the condition is severe, initial treatment is calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors,
or angiotensin receptor blockers (ARBs) (Herrick, 2013; Pope,
2007; Yusuf et al., 2008).
c) Hypertension: Defined as a systolic blood pressure 140 mm Hg or a
diastolic blood pressure 90 mm Hg (Cushman, 2007; U.S. Department of Health and Human Services, National Institutes of Health,
National Heart, Lung, and Blood Institute, 2004)
(1) Pathophysiology
(a) Multikinase inhibition results in antiangiogenesis by blocking the Bcr-Abl receptor and the actions of VEGF, which
decreases cellular nitric oxide (Daher & Yeh, 2008; Force,
Krause, & Van Etten, 2007; Yusuf et al., 2008). Hypertension is thought to be related to the loss of VEGF effect on
the vascular endothelial wall, leading to diminished nitric
oxide synthase and loss of vasodilatory effects of nitric oxide
(Kamba & McDonald, 2007; Kurtin, 2009; Subbiah, Lenihan, & Tsimberidou, 2011; Yusuf et al., 2008).
(b) Lower nitric oxide levels are associated with sodium and water retention (Chen & Cleck, 2009; Kajdaniuk, Marek, MarekBorgiel, & Kos-Kuda, 2011; Kamba & McDonald, 2007).
(c) Vasoconstriction (Mourad, des Guetz, Debbabi, & Levy,
2008; Sereno et al., 2008; Zeb, Ali, & Rohra, 2007)
(2) Incidence: Hypertension associated with antiangiogenic therapies and multikinase inhibitors occurs with high frequency,
ranging from 4%67% of cases (Chu et al., 2007; Fadol & Lech,
2011; Floyd & Perry, 2008; Kamba & McDonald, 2007; Mourad et
al., 2008; Patel et al., 2008; Porta, Paglino, Imarisio, & Bonomi,
2007; Viale & Yamamoto, 2008; Yusuf et al., 2008). About 11%
16% of patients receiving bevacizumab have significant enough
hypertension to require addition or adjustment of antihypertensive medications (Subbiah et al., 2011; Yusuf et al., 2008).
(3) Risk factors
(a) Preexisting hypertension or cardiovascular disease (CVD)
(Kajdaniuk et al., 2011; Steingart et al., 2012; Subbiah et
al., 2011)
(b) Treatment with bevacizumab, pazopanib, sorafenib, sunitinib, or vandetanib (Fadol & Lech, 2011). Proteinuria usually precedes hypertension with bevacizumab therapy (Gerber, 2008; Patel et al., 2008).
(c) Renal insufficiency, hyperthyroidism, Cushing syndrome,
increased intracranial pressure, and hypomagnesemia indeCopyright 2014 by the Oncology Nursing Society. All rights reserved.
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274
pendent of chemotherapy toxicity (Costa, Tejpar, Prenen,

& Van Cutsem, 2011; Houston, 2011)
(4) Clinical manifestations
(a) Blood pressure rises with multikinase inhibitors and antiangiogenic agents may be asymptomatic or accompanied
by headache, visual disturbances, fatigue, tachycardia, or
heart failure.
(b) There does not seem to be a specific pattern of primary systolic or diastolic hypertension; it appears to be reversible
with a therapy break.
(c) Refractoriness to traditional therapy is an important indicator that anticancer therapies are the cause (Force et
al., 2007).
(5) Assessment: Obtain health history and blood pressure measurement at every clinic or hospital visit. Assess for medications (e.g.,
sinus or cold remedies) or clinical conditions that may contribute to altered blood pressure. The onset of treatment-related
hypertension may occur as early as two weeks into therapy and
peaks by the second month of treatment (Mourad et al., 2008).
Angiogenesis inhibitor therapyassociated hypertension usually is preceded by proteinuria.
(6) Collaborative management: Vascular constrictioninduced hypertension is treated with ACE inhibitors, ARBs, or direct vasodilators (e.g., calcium channel blockers) (Higgins & Williams,
2007; Jurcut et al., 2008; Kolasinska-Malkowska, Filipiak, Gwizdala, & Tykarski, 2008). Diuretics reduce VEGF inhibitorassociated hypertension by reducing circulating blood volume
(Mourad et al., 2008). Nationally accepted guidelines for management of hypertension recommend thiazide diuretics as a
first-line measure (Cushman, 2007; Higgins & Williams, 2007;
Kolasinska-Malkowska et al., 2008). Beta-blockers also are an
option for some patients (London, 2008).
d) Venous thromboembolism (VTE)
(1) Endothelial wall damage is thought to have a direct relationship to atherosclerotic events such as VTE, supported by the fact
that VTE occurs with higher incidence in patients treated with
VEGF inhibitors (Force et al., 2007; Kamba & McDonald, 2007).
(2) Incidence: The risk of VTE in patients with cancer ranges from
1.9%11% based on a variety of risk factors. The addition of
thalidomide increases this risk to as high as 30%, and antiangiogenic agents increase the risk up to 30%, even in lower-risk
individuals (Yusuf et al., 2008).
(3) Risk factors
(a) Treatment with chemotherapy and biotherapy agents, including bevacizumab, cisplatin, erlotinib, lenalidomide,
tamoxifen, thalidomide, and vorinostat (Fadol & Lech,
2011; Zangari, Berno, Zhan, Tricot, & Fink, 2012)
(b) Edema, immobility, dehydration, congestive heart failure,
and ESAs (Connolly, Dalal, Lin, & Khorana, 2012)
(4) Clinical manifestations: Unilateral pain, redness, and swelling
of affected extremity
(5) Assessment: Obtain health history at every clinic or hospital visit. Assess patients for signs and symptoms of VTE, such
as pain, redness, and swelling of extremities, especially unilaterally.
(6) Collaborative management: Refer patients for diagnostic testing (e.g., venous Doppler study). Initiate anticoagulant theraCopyright 2014 by the Oncology Nursing Society. All rights reserved.
py when indicated, and monitor therapeutic levels when necessary. Discontinue medications thought to contribute to VTE.
e) Patient and family education (Viale & Yamamoto, 2008)
(1) Teach patients the signs and symptoms of vascular complications.
(2) Teach lifestyle changes, such as smoking cessation, low-fat diet,
moderate exercise, and stress management, that may reduce incidence and severity of vascular complications.
(3) Advise patients to report symptoms to care provider so that assessment and preventive strategies can be implemented early.
(4) Hypertension can be life threatening and cause stroke, so patients should be prepared to recognize signs of a hypertensive
crisis or stroke.
(a) Memory lapses
(b) Blackouts or near syncope
(c) Visual abnormalities
(d) Persistent headache
(e) Slurred words
(f) Numbness or tingling of an extremity
(g) Facial droop
(5) Patients may require guidance with self-administration of antihypertensive agents.
(6) Many antihypertensive agents can cause immediate orthostasis,
dizziness, nausea, and risk of falling.
4. Coronary artery disease: The most common identified is coronary artery
spasm (Prinzmetal or variant angina).
a) Pathophysiology: Ischemic heart disease may be related to atherosclerosis, inflammatory platelet aggregation, anemia, or capillary permeability. Myocarditis-induced edema of myocytes creates increased automaticity and impaired perfusion. Increased workload and myocardial stress is thought to be the mechanism for myocardial ischemia
and infarction. Thromboses occurring as a result of increased propensity for clotting may involve coronary arteries (Kusama et al., 2011).
b) Incidence: Coronary vasospasm or occlusion occurs rarely, with an incidence of < 1% for most therapies (Yeh & Bickford, 2009).
c) Risk factors: With the use of some drugs, coronary artery spasm leads
to ischemia and possibly infarction (Arima et al., 2009; Floyd & Perry, 2008; Porto et al., 2010; Saif, Shah, & Shah, 2009; Yeh & Bickford,
2009; Yusuf et al., 2008).
(1) Anticancer therapies associated with myocardial ischemia include bevacizumab, bortezomib, capecitabine, docetaxel, doxorubicin, erlotinib, 5-FU, hydroxyurea, paclitaxel, pazopanib,
rituximab, and sorafenib (Arima et al., 2009; Arunprasath,
Gobu, Dubashi, Satheesh, & Balachander, 2011; Cerny, Hassan, Smith, & Piperdi, 2009; Kalsch, Wieneke, & Erbel, 2010;
Molteni et al., 2010; Saif et al., 2009; Subbiah et al., 2011;
Takamatsu et al., 2010; Tunio, Hashmi, & Shoaib, 2012; Winchester & Bavry, 2010).
(2) Androgen deprivation (Saylor & Smith, 2009)
(3) Cetuximab used for locally advanced squamous cell head and
neck cancer (Bristol-Myers Squibb Co. & ImClone Systems,
2012). Similar events did not occur with cetuximab when used
for treatment of metastatic colorectal cancer.
(4) IL-2 resulting in capillary permeability with myocarditis (Jones
& Ewer, 2006; Muehlbauer, 2011)
(5) Taxane therapy (Londhey & Parikh, 2009): Few patients suffer
coronary artery disease with now-established drug monitoring
and dose attenuation plans.
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(6) Agents enhancing hypercoagulability, although no relationship

to any specific chemotherapy or biotherapy agent has been demonstrated (Floyd & Perry, 2008; Yusuf et al., 2008).
(7) High-dose chemotherapy. Rare unexplained chest pain with ischemic ECG changes that spontaneously resolve (Fadol & Lech,
2011; Yusuf et al., 2008).
(8) Aromatase inhibitors (Bird & Swain, 2008; Towns, Bedard, &
Verma, 2008)
(9) Transarterial chemoembolization, with unclear etiology (Lai
et al., 2010)
d) Clinical manifestations (Hazinski et al., 2010; Jugdutt, 2011; Leeper,
Cyr, Lambert, & Martin, 2011)
(1) Chest pain is the most common manifestation of coronary ischemia. Severity may be diminished in patients with chronic anemia. Chest pain may be pressure-like and radiate to the back
or neck.
(2) Unexplained dyspnea
(3) Signs/symptoms of reduced cardiac output: Hypotension, oliguria, diminished bowel sounds, weak and thready pulses, cool
extremities
(4) Signs/symptoms of cardiac irritability: Irregular pulse, palpitations, dysrhythmias
e) Assessment: Rapid diagnostic test performance (12-lead ECG, serum
cardiac enzymes) with suspicious symptoms to facilitate appropriate
management
(1) Assessment of chest discomfort
(2) Heart rate and rhythm
(3) Central and distal pulse strength and equality
(4) Blood pressure
(5) Heart sounds
(6) Breath sounds, respiratory rate
(7) Jugular venous distention
(8) ECG rhythm by continuous cardiac monitoring: Dysrhythmias
are common; life-threatening ventricular tachycardia or ventricular fibrillation is most common in the first two hours.
(9) Cardiac enzymes (creatine phosphokinase-MB, troponin I, or
troponin T) measured in the serum are elevated when myocardial injury occurs (Gaze, 2011).
(10) Echocardiogram or multigated acquisition (MUGA) scan
(11) Diagnostic right heart catheterization
f) Collaborative management (Daga, Kaul, & Mansoor, 2011; Hazinski
et al., 2010; Jugdutt, 2011)
(1) Administer O2 at a rate sufficient to maintain O2 saturation
above 90% unless otherwise contraindicated.
(2) Implement cardiac monitoring: Observe for dysrhythmias and
ischemic changes, low oxygen saturation, or extremes in blood
pressure.
(3) Obtain order for aspirin 325 mg to be chewed as soon as 12-lead
ECG is performed and ST changes are present.
(4) Consider patient candidacy for reperfusion strategies such as
cardiac catheterization with angioplasty, stent placement, or intracoronary/IV thrombolysis (Iyengar & Godbole, 2011).
(5) Consider ischemia-reducing or myocardial preservation strategies such as administration of nitrates, beta-blockers, or statins
(Ferreira & Mochly-Rosen, 2012; Gerczuk & Kloner, 2012).
(6) Maintain potassium > 4 mEq/L, magnesium > 2 mEq/L, and
ionized calcium > 1 mEq/L (Akhtar, Ullah, & Hamid, 2011).
(7) Consider discontinuation of antineoplastic agents such as fluoropyrimidines, oxaliplatin, sorafenib, or tamoxifen that are
thought to cause cardiac ischemia or infarction (Basselin et
al., 2011; Chang, Hung, Yeh, Yang, & Wang, 2011; Shah, Shah,
& Rather, 2012).
(8) Determine need for follow-up assessment of coronary arteries
and myocardial function with exercise stress testing, cardiac
catheterization, echocardiogram, or MUGA scan (Al-Zaiti, Pelter, & Carey, 2011; Arrighi & Dilsizian, 2012).
g) Patient and family education (Brown, Clark, Dalal, Welch, & Taylor,
2011; Crumlish & Magel, 2011)
(1) Specific risks for this complication based on personal risk factors and cancer treatment regimen
(2) Reportable symptoms: Chest discomfort, left arm or neck pain,
dyspnea
(3) Activation of emergency medical system
(4) Management of risks for cardiac ischemia that are specific to
oncology (e.g., anemia, cardiac demands of infection, electrolyte disturbances)
(5) Cardiac medications and unique considerations in oncology
care (e.g., risk for low blood pressure increased when febrile;
electrolyte disturbances with nausea and vomiting may contribute to cardiac dysrhythmias)
(6) Referral and education regarding cardiac rehabilitation programs (Heran et al., 2011)
5. Cardiac failure/cardiomyopathy: Cardiac failure is defined as inadequate
contractile force to eject the required amount of blood for perfusion of
the body (Heart Failure Society of America, 2010; Hunt et al., 2009). It
is classified as primary or secondary based on the primary etiology and
has three types: acute, chronic early, or chronic late.
a) Pathophysiology (Barry, Alvarez, Scully, Miller, & Lipshultz, 2007;
Ewer & Ewer, 2008; Yusuf et al., 2008)
(1) May be confined to the heart or part of a generalized systemic
disease such as anemia or thyrotoxicosis (Fadol & Lech, 2011)
(2) Myocardial muscle dysfunction leads to hyperplasia of cardiac
myocytes and ventricular hypertrophy.
(3) Ventricular dilation occurs as a compensatory mechanism to
permit the heart to fill with more blood and attempt to enhance
cardiac output (Fadol & Lech, 2011; Maitland et al., 2010).
(4) Cancer treatmentrelated heart failure is usually nonischemic
in nature and the result of direct toxicity to the myocytes (Martinelli, Carleo, Girelli, & Olivieri, 2011).
(5) Physiologic mechanisms that contribute to heart failure include
available oxygen content (e.g., reduced RBC count with decreased oxygen-carrying capacity), myocyte strength, ventricular hypertrophy, ventricular dilation, and circulating blood volume (Yusuf et al., 2008).
(a) Anemia results in decreased available oxygen. Reduced oxygen saturation with decreased oxygen delivery causes the
heart to contract stronger and more frequently to deliver
oxygen to tissues. With extended increased workload, the
heart will fail. This is called high-output failure. The consequences are the same as with other etiologic mechanisms.
(b) The etiology of IL-2 cardiac failure is capillary permeability with interstitial fluid collection around the myocytes
and eosinophilic infiltration of the heart muscle (Viale &
Yamamoto, 2008).
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278
(c) Renal retention of sodium associated with IL-11 leads to

fluid retention and functional cardiomyositis.
(6) Anthracycline-induced cardiomyopathy is the most-documented etiology of chemotherapy-induced cardiomyopathy associated with myocyte atrophy. These agents act by DNA intercalation (Barrett-Lee et al., 2009; Barry et al., 2007; Frankel, 2010).
(a) Oxidative stress in the presence of increased free radicals
and decreased antioxidants results in myocyte injury or
death (Viale & Yamamoto, 2008; Yusuf et al., 2008).
(b) Immune-mediated actions cause injury to the plasma membranes of cardiomyocytes.
(7) Cyclophosphamide toxicity is thought to be related to direct endothelial injury (Fadol & Lech, 2011; Viale & Yamamoto, 2008;
Yeh & Bickford, 2009).
(a) May lead to interstitial hemorrhage within the myocytes
(b) Left ventricular wall thickening with hemorrhagic necrosis has been reported.
(c) Most closely related to individual doses > 1.5 mg/m2 rather than cumulative dosing
(8) Regardless of etiology, irreversible myocyte damage may occur prior to changes in ejection fraction or left ventricular wall
thickness (Ewer & Lenihan, 2008).
b) Types of anthracycline toxicity (Barry et al., 2007; Yusuf et al., 2008)
(1) Early-onset anthracycline toxicity (type I)
(a) Occurs during or within one year of completion of anthracycline therapy (Gianni et al., 2007)
i. Severity varies.
ii. Some cases involve stable, asymptomatic abnormalities in left ventricular function.
iii. Other cases are progressive and involve ECG changes, associated signs of cardiomyopathy, changes in exercise-stress capacity, and overt congestive heart failure (CHF).
(b) Dose-related: Toxicity increases with higher cumulative
doses and higher maximal doses (Floyd & Perry, 2008; Yusuf et al., 2008).
(2) Late-onset anthracycline toxicity (type II) (Barry et al., 2007;
Ganz et al., 2008)
(a) Occurs one year or more after completion of anthracycline therapy
(b) Presumably caused by decreased left ventricular contractility and inappropriately thin left ventricular wall, elevated
wall stress, and progressive ventricular dysfunction (Ewer
& Lenihan, 2008)
(c) Dose-related: Incidence increases with higher cumulative
doses as well as higher maximal dose.
(d) More common than early-onset anthracycline toxicity
c) Types of nonanthracycline cardiomyopathy (Chen, 2009; Ewer & Ewer,
2008; Ewer & Lenihan, 2008; Yeh & Bickford, 2009; Yusuf et al., 2008)
(1) Acute
(a) Occurs within 24 hours of drug administration
(b) Self-limiting
(c) Not dose related (Camp-Sorrell, 2011)
(d) May cause electrical changes in the heart that an ECG may
reflect
(e) Electrical changes caused by chemotherapy: The most frequent electrical change is decreased voltage.
(f) Chemotherapy can lead to cardiac decompensation and

collapse; however, transient changes usually do not call
for discontinuation of therapy (Ewer & Ewer, 2008; Ewer
& Lenihan, 2008; Ewer & Tan-Chiu, 2007).
(g) Indications to discontinue therapy (Viale & Yamamoto,
2008; Yeh & Bickford, 2009; Yusuf et al., 2008)
i. Acute changes associated with 5-FU (Georgieva et al.,
2007; Sorrentino, Kim, Foderaro, & Truesdell, 2012)
ii. Endothelial damage leading to myocardial necrosis
with use of high-dose cyclophosphamide (Chung et
al., 2008)
iii. Serious arrhythmias resulting from any drug
iv. Acute myocardial infarction after treatment with an
EGFR inhibitor (Bristol-Myers Squibb Co. & ImClone
Systems, 2012)
(2) Subacute
(a) Symptoms appear four to five weeks following therapy.
(b) Fibrinous pericarditis and myocardial dysfunction, which
may be diagnosed with a radionuclide cardiac MUGA scan
(c) Usually reversible
(d) Chemotherapy may or may not be stopped, depending on
the patients condition.
(e) Biotherapy usually is discontinued if symptoms of subacute
cardiac toxicity appear.
(3) Chronic
(a) Nonreversible cardiomyopathy may occur weeks or months
after drug administration (Camp-Sorrell, 2011; Floyd & Perry, 2008; Yusuf et al., 2008).
(b) Seen with cumulative doses of cardiotoxic drugs that cause
myocardial weakening because of direct damage to myocytes
(c) Enhanced if radiation therapy has been given to the left
chest, thorax, or mediastinum (Fadol & Lech, 2011; Viale
& Yamamoto, 2008; Yusuf et al., 2008)
(d) Cardiotoxic chemotherapy is stopped if chronic toxicity
occurs.
(e) HER2 receptor blockers such as trastuzumab and lapatinib
may cause cardiomyopathy via inhibition of mitochondrial function and the tyrosine kinase pathway (a major metabolic pathway) shared by cardiac myocytes (Ewer & Ewer,
2008; Fadol & Lech, 2011; Fiza, 2009; Gianni et al., 2007;
Perez et al., 2008; Senkus & Jassem, 2011).
i. Inhibition of cardiac tyrosine kinase results in atrophy and death of myocytes.
ii. HER2 signaling may be important in protecting cardiomyocytes from cardiac injury by anthracyclines.
iii. HER2 inhibition (e.g., lapatinib, trastuzumab) may exacerbate cardiotoxic effects of anthracyclines.
(f) Probably reversible (Frankel, 2010; Telli, Hunt, Carlson, &
Guardino, 2007)
(g) Timing: As early as 48 hours after administration and as late
as 89 days (Perez et al., 2008; Suter et al., 2007)
(h) Some multikinase inhibitors (e.g., sunitinib) and antiangiogenic agents (e.g., bevacizumab) are less direct in inhibiting tyrosine kinase with similar potential for myocyte dysfunction (Chen, 2009; Chu et al., 2007; Force et al., 2007;
Gerber, 2008; Senkus & Jassem, 2011).
(i) Longevity ranges from two to eight weeks (Perez et al., 2008).
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280
(j) Average left ventricular ejection fraction (LVEF) decrease

is 10%15%; mean value is 40%43% (Ewer, Lenihan, &
Khakoo, 2007; Frankel, 2010; Perez et al., 2008).
d) Incidence
(1) Anthracyclines produce some degree of cardiac dysfunction
in 50% of patients over a 1020-year period after exposure.
Approximately 3%5% develop overt heart failure (Fadol &
Lech, 2011).
(2) Early-onset anthracycline toxicity occurs in 1.6% of children
with cancer treated with anthracycline chemotherapy according to Pediatric Oncology Group protocols (Bryant et al., 2007;
Scully & Lipshultz, 2007).
(3) Acute and subacute toxicity occurs infrequently; approximately 10% of acute toxicities consist of transient electrical changes in the heart (Camp-Sorrell, 2011).
(4) Chronic toxicity is related to cumulative dose.
(5) Some antitumor antibiotics (e.g., epirubicin, idarubicin, mitoxantrone) produce less cardiac toxicity than do other anthracyclines.
(6) Data suggest that even lower levels of anthracyclines that do
not alter ejection fraction may compromise the hearts ability
to handle other stressors, thereby increasing the risk of adverse
cardiac events (Ewer & Lenihan, 2008).
(7) Cardiotoxicity incidence with anthracyclines, taxanes, and trastuzumab in adjuvant and therapeutic breast cancer treatment has
led to studies to assess best drug order and combinations (Barry
et al., 2007; Ewer & OShaughnessy, 2007; Frankel, 2010; Ganz
et al., 2008; Gianni et al., 2007; Perez et al., 2008; Seidman et
al., 2008; Suter et al., 2007).
(a) The HERA (HERceptin Adjuvant) trial showed higher incidence of heart failure with trastuzumab (3.64%) as compared to lapatinib (1.6%). Preexisting CVD was an exclusion to receive these drugs, so the incidence is thought to
be less than what may occur in the general population.
(b) Prior anthracyclines and cyclophosphamide with concomitant trastuzumab caused a 27% incidence of cardiotoxicity as compared to doxorubicin and cyclophosphamide alone.
(c) Paclitaxel with trastuzumab caused 13% incidence of cardiotoxicity as compared to 1% with paclitaxel alone.
(d) Greatest decrease in left ventricular function is at six- and
nine-month assessments during concomitant therapy (Frankel, 2010).
(8) Chemotherapy-related cardiotoxicity carries a poorer prognosis than heart failure from other causes. The two-year mortality can be > 50% in some populations with severe toxicity (Fadol & Lech, 2011).
e) Risk factors
(1) Direct insult of myofibrils by drugs such as the anthracyclines
doxorubicin, daunorubicin, epirubicin, and idarubicin
(2) Cardiotoxicity can be potentiated when taxanes are given
with other cardiotoxic drugs such as doxorubicin. Paclitaxel (but not docetaxel) appears to interfere with the pharmacokinetic elimination of doxorubicin (Bird & Swain, 2008;
DIncalci, Schller, Colombo, Zucchetti, & Riva, 1998; Ewer &
OShaughnessy, 2007; Mackey et al., 2008; Perez et al., 2008;
Towns et al., 2008).
(3) Occasional cases of hemorrhagic myocarditis have been reported in adults who received very high doses of cyclophosphamide,
such as patients who are being prepared for BMT (Satti et al.,
2007). High-dose cyclophosphamide is considered potentially
cardiotoxic for children (Bryant et al., 2007; van Dalen, Caron,
Dickinson, & Kremer, 2011). The effects may be additive with
those of anthracyclines.
(4) Anthracycline-induced cardiotoxicity (Rahman, Yusuf, & Ewer,
2007)
(a) Chemotherapy-induced cardiac toxicity in pediatric patients
is almost always attributable to anthracyclines.
(b) In children and adults, cardiac toxicity has been associated
with all anthracyclines in clinical use (Floyd & Perry, 2008;
van Dalen et al., 2001).
(c) The cumulative dose at which cardiac toxicity occurs varies from drug to drug.
(d) Doxorubicin is the most widely used anthracycline and the
most extensively studied (Fadol & Lech, 2011). It serves as
a model for identifying anthracycline-related cardiomyopathies (Yusuf et al., 2008).
(5) Exposure to other agents may potentiate anthracycline-induced
cardiac toxicity.
(a) Mitoxantrone: Reports indicate that it potentiates cardiotoxicity when administered following anthracyclines or mediastinal radiation.
(b) Dactinomycin
(c) Mitomycin C
(d) Bleomycin
(e) Amsacrine
(f) Very-high-dose cyclophosphamide (usually > 100 mg/kg)
(g) Dacarbazine
(h) Vincristine
(i) Diethylstilbestrol diphosphate
(j) Tamoxifen is rarely associated with reduced left ventricular function (Barr Laboratories, 2007).
(k) Taxanes (e.g., paclitaxel, docetaxel) added to standard anthracycline regimens increase cardiotoxicity (Gianni et al., 2007).
(l) Trastuzumab has been shown to escalate severity of cardiotoxicity when used simultaneously with anthracyclines or
taxanes (Ewer & Ewer, 2008; Ewer & OShaughnessy, 2007;
Gianni et al., 2007; Suter et al., 2007).
i. Does not cause structural myocyte damage like anthracyclines
ii. Average reduction in ejection fraction is 10%15%,
with overt heart failure symptoms occurring in 0%
3.9% of patients.
iii. Reversible in 88% of cases and permanent drug discontinuation not required
(6) High-dose therapy
(a) Administration schedule: Higher doses of cardiotoxic drugs
given over a shorter period demonstrate increased toxicity
(Camp-Sorrell, 2011). Dividing doses into smaller boluses
has been shown to decrease toxicity.
(b) Thoracic irradiation of the lungs or mediastinum: Cardiac
toxicity may occur at lower radiation doses when patients
receive anthracyclines and mediastinal radiation (Yeh &
Bickford, 2009; Yusuf et al., 2008).
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(c) High-dose chemotherapy associated with HSCT may cause

a spectrum of subacute to life-threatening cardiomyopathy
peaking in incidence 616 days after administration of the
preparative regimen (Chung et al., 2008).
(7) Age
(a) Malnutrition may increase cardiotoxicity. In cases of preexisting malnutrition, children are at higher risk than adults
because of biologic and metabolic differences, the high
tissue sensitivity of children, and the intensity of pediatric chemotherapy regimens (Fulbright, Huh, Anderson,
& Chandra, 2010).
(b) Conflicting evidence exists regarding older adults. Older
adults may be at higher risk because of the aging process and
limitations in DNA self-repair, but the incidence of cardiotoxicity is not clearly increased in older adults unless CVD
is present. Studies of older women receiving adjuvant chemotherapy with anthracyclines have showed an increased
risk of cardiomyopathy (Gianni et al., 2007).
(8) Preexisting cardiac disease, such as cardiac abnormalities or tumors in the chest, increases risk of cardiomyopathy (Fadol &
Lech, 2011; Yusuf et al., 2008).
(9) Smoking is associated with cardiac changes such as vasoconstriction, hypertension, and atherosclerosis (Fadol & Lech, 2011).
(10) Mediastinal radiotherapy increases risk of cardiomyopathy.
f) Clinical manifestations (Fares, 2008; Heart Failure Society of America, 2010; Hunt et al., 2009)
(1) Dyspnea is most common clinical finding.
(2) Heart failure usually presents with symptoms of increased work
of the heart, such as tachycardia; full, bounding pulses; gallops;
or murmurs.
(3) Compensatory symptoms that reflect the bodys attempt to improve tissue perfusion of major organs in the face of inadequate
contractile force include tachypnea, distended neck veins, cool
and pale or cyanotic extremities, decreased bowel sounds with
nausea or poor digestion, and decreased urine output.
(4) When the blood cannot enter the heart for a prolonged period of time, venous congestion occurs. Peripheral and dependent edema is accompanied by hepatosplenomegaly; crackles
are detected on lung auscultation; and pleural or pericardial
effusions may occur.
(5) Late effects of compromised peripheral circulation may be detected by poor distal extremity wound healing.
g) Assessment
(1) Assess daily weights in high-risk patients whether inpatient
or at home. Patient weight gain is a highly sensitive and specific predictor for decompensating heart failure (Hunt et
al., 2009).
(2) When patients call with symptoms, the ability to determine the
degree of heart failure is dependent upon the patients report
of dyspnea, weight gain, or edema.
(3) Assess breath sounds and heart sounds of patients at risk for
cardiomyopathy at every visit.
(4) Anthracycline toxicity diagnosis (Jannazzo, 2007; Jurcut et al.,
2008; Shelton, 2009a)
(a) Cardiac toxicity associated with anthracycline therapy is best
diagnosed by serial endocardial biopsy (Ewer & Lenihan,
2008). The means for doing such a biopsy are not available
in all institutions, and obtaining the tissue needed for the

biopsy is an invasive procedure. Serial endocardial biopsy
seldom is used in pediatric patients.
(b) MUGA scans are widely used to detect early-onset anthracycline cardiotoxicity. They are reliable indicators of cardiac damage but may not reflect early reversible changes
(Ewer & Lenihan, 2008; Yusuf et al., 2008).
(5) Three-dimensional color Doppler echocardiography is widely
used to diagnose all types of cardiomyopathy. It is noninvasive
and can measure LVEF, fractional shortening, and left ventricular wall thickness (Ewer & Lenihan, 2008; Jurcut et al., 2008;
Yusuf et al., 2008).
(6) Blood levels of cardiac troponin can detect early myocardiocyte
injury caused by anthracycline toxicity (Anderson, 2008; Ewer
& Lenihan, 2008; Jurcut et al., 2008).
(7) Brain natriuretic peptide levels are used to monitor left ventricular heart failure. They may be elevated postoperatively or
in patients with anemia, atrial fibrillation, cor pulmonale, ventricular hypertrophy, pulmonary embolism, or lung cancer (Anderson, 2008).
(8) ECG can detect abnormalities in cardiac electrophysiology
caused by cardiotoxicity. The most common abnormal findings are low QRS voltage or tachycardia. Ischemic ST changes
may be present or accompanied by left ventricular strain seen
as ischemia on anterior chest leads 4, 5, and 6.
(9) Assessment before biotherapy (Prometheus Laboratories Inc.,
2012; Shelton, 2009a)
(a) Before treatment with IL-2, obtain baseline evaluation of left
ventricular function to determine eligibility for treatment.
(b) Before treatment with certain mAbs (e.g., trastuzumab)
and chemotherapy agents, establish baseline cardiac function by MUGA scan and ECG.
(10) Assessment throughout therapy, especially for high-risk patients
(a) Check the results of baseline cardiac studies (e.g., ejection
fraction) before administering the drug. Ejection fraction
may not be the most sensitive indicator and should not be
the only parameter used to assess cardiotoxicity (Ewer &
Lenihan, 2008). Other clinical assessments may include
ventricular dilation, ventricular wall thickness, or wall motion abnormalities.
(b) Observe for clinical manifestations of CHF (e.g., tachycardia, shortness of breath, nonproductive cough, neck-vein
distention, ankle edema, displaced point of maximal impulse crackles, hepatomegaly).
(11) Calculate and assess the cumulative dose of the applicable drug
(e.g., doxorubicin) and document it in the patients record. Cardiotoxic levels of common anthracyclines are
(a) Doxorubicin 400450 mg/m2 (Swain, Whaley, & Ewer, 2003)
(b) Daunorubicin 400 mg/m2 (Jannazzo, 2007)
(c) Epirubicin 900 mg/m2 (Ryberg et al., 1998)
(d) Idarubicin 150 mg/m2 (Anderlini et al., 1995).
(12) Assess heart rate, rhythm, and regularity, including murmurs,
split sounds, and extra sounds; a gallop or third heart sound
may indicate insufficiency.
(13) Assess electrolytes (e.g., potassium, calcium); abnormal electrolyte levels can interfere with cardiac function.
h) Collaborative management (Fares, 2008; Yusuf et al., 2008)
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(1) Administer, if part of the protocol in the institution, the cardioprotective iron-chelating agent dexrazoxane (Zinecard) during
or prior to the administration of doxorubicin to prevent cardiotoxicity in some patients (e.g., those with metastatic breast cancer who have received > 300 mg/m2 doxorubicin) (Barry et al.,
2007; van Dalen et al., 2011). Iron-chelating agents inhibit the
generation of free radicals. The administration of dexrazoxane
significantly decreased cardiac toxicity in pediatric trials (Bryant et al., 2007). Dexrazoxane is FDA-approved to reduce cardiac toxicity in adults (Pfizer Inc., 2012d).
(2) Administer liposomal formulation of anthracyclines (liposomal doxorubicin [Doxil] or liposomal daunorubicin [DaunoXome]) when indicated. They have demonstrated less cardiotoxicity, permitting higher dose delivery (Rahman et al., 2007).
(3) Administration over longer periods of time (e.g., 4872 hours)
is thought to reduce the incidence or severity of cardiac toxicity (Fulbright et al., 2010; Scully & Lipshultz, 2007; van Dalen
et al., 2011).
(4) Administer medications as prescribed to treat CHF and support cardiac output (e.g., diuretics, inotropic cardiac medications, vasodilators, oxygen) (Anderson & Sawyer, 2008; Fulbright et al., 2010).
(a) ACE inhibitors have been administered to prevent cardiomyopathy in patients receiving radiation therapy to the left
breast and children receiving total body irradiation (Heart
Failure Society of America, 2010).
(b) Metoprolol tartrate, a beta-blocker, has been used effectively
to treat pediatric patients with severe CHF following doxorubicin therapy (Heart Failure Society of America, 2010).
(c) Develop an activity or exercise plan.
(d) Institute dietary modifications (e.g., a low-salt diet) as necessary for patients with CHF. Omega-3 fatty acids have been
reported to both enhance and abrogate doxorubicin toxicities, but no clinical effects have been proved.
(5) Expect to discontinue or reduce the dose of the cardiotoxic
agent if the patients ejection fraction is less than 40% to 45%
(Ewer & Lenihan, 2008; Ewer & Tan-Chiu, 2007).
(6) Monitor results of ECGs; for patients receiving chemotherapy, an ECG is recommended at three months, six months, and
one year after anthracycline therapy (Barry et al., 2007; Ng &
Green, 2007).
(7) Manufacturer recommendations for monitoring during arsenic trioxide therapy (Cephalon, Inc., 2010)
(a) Monitor serum electrolytes twice weekly during induction
and at least weekly during the consolidation phase.
(b) Monitor ECG baseline and weekly during both induction
and consolidation.
(c) Monitor for drugs that prolong QT.
(d) Hold until QTc < 0.46 s (460 msec).
(8) Cardiac troponins I and T and brain natriuretic peptide levels
have been suggested as effective methods of monitoring for immediate and ongoing cardiotoxicity. Elevated levels prior to anthracycline administration are thought to imply higher risk for
cardiotoxicity, and levels that rise during therapy may predict
early cardiotoxicity prior to changes in ejection fraction (Lenihan et al., 2007; Pandey, Gupta, & Wander, 2011; Urbanova, Urban, Danova, & Simkova, 2008).
(9) Monitor results of MUGA scans (Genentech, Inc., 2012b).

(10) Before initiation of any agent that is reported as causing heart
failure and at least every three months for the first year, evaluate cardiac function by MUGA scan or ECG. Adjuvant breast
cancer therapies that include anthracyclines, cyclophosphamide, taxanes, and trastuzumab have special monitoring recommendations as follows (Frankel, 2010; Rahman et al., 2007;
Yusuf et al., 2008).
(a) Three months after anthracycline and cyclophosphamide
and prior to start of taxanes
(b) After completion of taxanes and before start of trastuzumab; LVEF must be above lower limits of normal and not
> 15% below baseline
(c) At 3, 6, and 15 months after start of trastuzumab
(d) Thereafter, a scan is recommended every five years.
(11) Treat asymptomatic decreases in LVEF associated with trastuzumab as follows (Barry et al., 2007; Frankel, 2010; Genentech,
Inc., 2012b; Rahman et al., 2007) (see Table 35).
(a) Resume trastuzumab in four to eight weeks if LVEF returns
to normal and absolute decrease from baseline is 15%
(Genentech, Inc., 2012b).
(b) Permanently discontinue trastuzumab if decline in LVEF
lasts longer than eight weeks or if trastuzumab was held
more than three times previously (Genentech, Inc., 2012b).
i) Patient and family education (Ewer et al., 2007; Fadol & Lech, 2011;
Frankel, 2010; van Dalen et al., 2011)
(1) Teach patients that cardiotoxicity is a possible side effect of the
drug(s) (e.g., doxorubicin, daunorubicin and liposomal daunorubicin, mitoxantrone, high-dose 5-FU, high-dose cyclophosphamide, ILs, IFNs, some mAbs) (see Table 34).
(2) Instruct patients about the signs and symptoms of CHF and
when to report to a nurse or physician. Explain that close monitoring for possible late effects may be required even after treatment has ended.
(3) Instruct patients to avoid tobacco and alcohol use because these
agents stimulate the cardiac muscle.
(4) Instruct patients that chronic cardiotoxicity usually is doserelated and possibly irreversible.
(5) Inform patients and caregivers about strategies to manage symptoms at home.
(6) Ensure that patients are familiar with the ongoing protocol for
follow-up care, including the following (Fares, 2008).
(a) A yearly standard physical and history
(b) MUGA scans, echocardiogram, and/or ECG every two to
five years. The number of risk factors determines the inTable 35. Trastuzumab Administration for Asymptomatic Decreases in
Left Ventricular Ejection Fraction (LVEF)
Relationship of LVEF
and Lower Limit of
Normal
< 10% Absolute

Decrease From
Baseline
10%15% Absolute
Decrease From
Baseline
16% Absolute
Decrease From
Baseline
Within normal limits
Continue.
Continue.
Hold 4 weeks.
Below lower limits of

normal
Continue.
Hold 4 weeks.
Hold 4 weeks.
Note. Based on information from Frankel, 2010; Genentech, Inc., 2012b.

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terval between such tests. Patients with preexisting CVD

or risk factors or receiving multiple agents with potential
cardiotoxicity will have more frequent monitoring of cardiac function.
(c) 24-hour Holter monitoring every three years
(7) Instruct the patient to obtain a cardiology consult before pregnancy, general anesthesia, or the start of a vigorous exercise
program.
(8) Encourage maintenance of a healthful lifestyle that eliminates
tobacco and alcohol and includes exercising regularly and maintaining an appropriate weight and nutritious diet (Heart Failure Society of America, 2010).
(9) Stress the importance of lifelong follow-up care with a healthcare provider familiar with the patients cancer history, treatment, and risk of late effects.
6. Pericardial effusions
a) Pathophysiology (Bodson, Bouferrache, & Vieillard-Baron, 2011;
Shelton, in press-c)
(1) The space between the visceral and parietal pericardium is
characterized by a negative pressure gradient and is filled with
a small amount of fluid.
(2) The spaces negativity allows for filling and expansion of the
atria and ventricles during the cardiac cycle.
(3) Accumulation of excessive amounts of pericardial fluid causes
a more positive pressure within the space, impeding venous return into the heart.
(4) Several antineoplastic therapies increase capillary permeability
and enhance the risk of increased pericardial fluid.
(5) Cytarabine has been hypothesized to trigger a hypersensitivity reaction, with pericardial fluid extravasation occurring 328
days after treatment (Fadol & Lech, 2011).
(6) Anthracyclines are thought to produce an acute fibrinous pericardial syndrome that can be early or delayed in onset (Fadol
& Lech, 2011).
b) Incidence
(1) The incidence of pericardial effusion is < 5% across all therapies (Shelton, in press-c).
(2) Prognosis for full recovery when therapy-related is excellent.
c) Risk factors (Bouzas-Mosquera et al., 2008; Fadol & Lech, 2011; Floyd
& Perry, 2008; Yusuf et al., 2008)
(1) Antineoplastic therapies that have clearly been associated with
pericardial effusion include cytosine arabinoside and IL-2.
(2) Other antineoplastic therapies with rare instances of pericardial
fluid accumulation include bleomycin, cyclophosphamide, daunomycin, docetaxel, doxorubicin, imatinib, and methotrexate.
(3) Comorbid health conditions such as hypothyroidism, heart failure, autoimmune disease, and uremia may increase the incidence of pericardial effusion (Wang et al., 2010).
d) Clinical manifestations
(1) Chest pain, cough, and dyspnea (Gandhi et al., 2008; Shelton,
2009a)
(2) Signs/symptoms of right heart failure are more common with
slowly developing effusions: Edema, weak and thready pulses,
low-voltage QRS on ECG rhythm
e) Assessment (Bodson et al., 2011; Shelton, in press-c; Sisson, 2010)
(1) Vital signs assessment: Assess for weak, thready, or irregular pulses
and hypotension with narrow pulse pressure. Pulsus paradoxus
is a clinical finding where there are two audible systolic pressures indicative of inefficient contractility.
(2) Heart sounds assessment: Muffled heart sounds indicate significant fluid accumulation, although pericardial rub may be present.
(3) Jugular venous pulsations/distention: Elevated bilaterally with
significant pericardial effusion
(4) Signs/symptoms of poor perfusion: Cool or clammy skin, poor
capillary refill, oliguria, diminished bowel sounds, confusion
(5) Diagnostic test data
(a) Chest x-ray: Nonspecific screening tool that usually shows
enlarged cardiac silhouette (Gandhi et al., 2008; Shelton,
in press-c)
(b) Echocardiogram: Can show collapsed right ventricle, excess fluid in pericardial space, and poor wall motion (Lestuzzi, 2010; Lestuzzi et al., 2010; Sagrista-Sauleda, Merce,
& Soler-Soler, 2011)
(c) ECG: Electrical alternans is uncommon but specific; lowvoltage of the QRS; ST-segment elevation in all the precordial leads (Gandhi et al., 2008; Jung, Seung, & Madias,
2010; Shelton, in press-c)
f) Collaborative management (Bodson et al., 2011; Shelton, 2009a;
Sparano & Ward, 2011)
(1) The majority of effusions are not clinically significant and do
not require active interventions.
(2) Watchful waiting with treatment of the etiologic factor or discontinuation of the therapy causing effusion usually is sufficient treatment for drug-related pericardial effusions (Yusuf
et al., 2008).
(3) Immediate emergency management of impending tamponade
is administration of large-volume IV fluids. This will raise the venous pressure above the pericardial pressure and allow for better ventricular filling and improved cardiac output.
(4) On rare occasions, emergency evacuation of pericardial fluid may be necessary. When time permits, a planned catheter
drainage in an operative or procedural area is preferred (Inglis, King, Gleave, Bradlow, & Adlam, 2011; Tam et al., 2009).
g) Patient and family education (Shelton, in press-c)
(1) Teach importance of reporting changes in fatigue, dyspnea,
and edema.
(2) Advise patients to weigh themselves and check for fluid retention (e.g., weight gain, tight rings, swollen ankles).
(3) Ensure that patients and caregivers understand the importance of
keeping appointments for regular follow-up and diagnostic tests.
F. Pulmonary toxicity
1. Pulmonary toxicity ranges from reversible short-term reactive airway disease to diffuse permanent fibrosis and structural destruction. Most side
effects are rare, occurring in < 1% of low-risk patients and up to 8% in
high-risk groups (Barber & Ganti, 2011; Chernecky, 2009; Schwaiblmair
et al., 2012). On rare occasions, these toxicities are fatal (Boeck, Hausmann, Reibke, Schulz, & Heinemann, 2007; Chikura, Sathi, Lane, & Dawson, 2008; Giusti, Shastri, Cohen, Keegan, & Pazdur, 2007; Gupta & Mahipal, 2007; Keijzer & Kuenen, 2007; Leimgruber et al., 2006; Makris et
al., 2007; Vahid & Marik, 2008). As patients survive increasingly aggressive and multimodal therapy and the use of multitargeted therapies becomes more commonplace, additional pulmonary toxicities are emerging. As in the case of acute promyelocytic leukemia (APL) differentiaCopyright 2014 by the Oncology Nursing Society. All rights reserved.
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tion syndrome (Lamour & Bergeron, 2011; Luesink & Jansen, 2010) or
pulmonary veno-occlusive disease (VOD) (Huertas et al., 2011; Solh,
Arat, Cao, Majhail, & Weisdorf, 2011), it is unclear whether pulmonary
changes are related to the disease, rejection phenomena, chemotherapy agents, or the combined effects of chemoradiotherapy.
2. Chemotherapy-induced pulmonary toxicities are divided into acute, undefined, and chronic disorders (American Thoracic Society & European Respiratory Society, 2002; Charpidou et al., 2009; Schwaiblmair et al., 2012).
a) Acute disorders occur within minutes to a few months after exposure
to the offending agent. Toxicities usually have a direct effect on the
lungs. Many are believed to be at least partially reversible yet may still
be fatal in their most acute forms. Examples of acute disorders include
bronchospasm, hypersensitivity pneumonitis, alveolar hemorrhage,
retinoic acid syndrome, noncardiogenic pulmonary edema, pulmonary alveolar proteinosis, and interstitial pneumonitis.
b) Chronic disorders occur months to years after exposure. Most chronic disorders cause irreversible lung injury and may be progressive in
nature, leading to severe disability or death. Examples of chronic
lung toxicities include progressive interstitial pneumonitis, organizing pneumonia, pulmonary VOD, and pulmonary fibrosis.
c) Indeterminate lung toxicities are those conditions that are undefined
or have an unclear trajectory. They may begin with features of both
acute and chronic disorders and are ultimately defined when the degree of alveolar damage is identified.
3. Determining the etiology of pulmonary signs and symptoms in patients
with cancer can be challenging because toxicity can mimic a broad spectrum of pathogenic causes, including infectious and neoplastic (Barber
& Ganti, 2011; Charpidou et al., 2009; Meadors, Floyd, & Perry, 2006;
Schwaiblmair et al., 2012). Consequently, it is imperative to understand the
potential for toxicity and to detect pulmonary toxicity as early as possible.
a) Common symptoms of pulmonary toxicities include dyspnea, tachypnea, exercise intolerance, and increased work of breathing. Some
disorders also cause fever, substernal discomfort, and hypoxemia
(Charpidou et al., 2009; Parshall et al., 2012; Schwaiblmair et al.,
2012; Vahid & Marik, 2008).
b) The primary diagnostic test used to differentiate specific conditions
is the CT scan. Although unique findings indicate some disorders,
histologic sampling may be necessary to determine the precise pathology (Torrisi et al., 2011).
4. Interstitial lung disease (ILD) is a heterogeneous group of lung disorders involving damage to the alveoli and surrounding interstitium. ILD
includes acute chemotherapy-induced pneumonitis, pulmonary capillary permeability syndrome, chemotherapy-related adult respiratory distress syndrome, hypersensitivity/eosinophilic pneumonitis, cryptogenic (of unknown cause) organizing pneumonia, pulmonary fibrosis, and
pulmonary alveolar proteinosis (American Thoracic Society & European Respiratory Society, 2002; Charpidou et al., 2009; NCI CTEP, 2010;
Schwaiblmair et al., 2012).
a) Pathophysiology
(1) Postulated pathologic changes (American Thoracic Society &
European Respiratory Society, 2002; Charpidou et al., 2009;
Chernecky, 2009; Schwaiblmair et al., 2012; Silva & Mller, 2009;
Specks, 2012; Vahid & Marik, 2008)
(a) Injury to lung parenchyma
(b) Inflammation of alveoli, alveolar cell walls, interstitial spaces, and terminal bronchioles
(c) Release of ILs and transforming growth factors
(d) Destruction of the alveolar-capillary endothelium leading

to changes in interstitial fibroblasts
(e) Activation of fibroblasts and microfibroblasts, which cause
collagen deposition in the alveolar interstitium
(2) Disease results predominantly from inflammatory features.
(a) Fluid or bloody exudates in alveoli
(b) Fluid between alveoli (interstitial spaces) from degradation of the alveolar wall
(c) Fibrosis and stiffening of vascular, airway, and alveolar walls
(3) Resolution results in scarring and fibrosis of tissue, beginning
in the interstitium and later involving the alveolar sacs. Pulmonary fibrosis is the chronic continuation of some acute pneumonitis syndromes.
(4) Stiff, noncompliant lungs have poor elasticity and cause increased work of breathing.
(5) Chronic exposure to chemotherapy agents may result in changes in lung connective tissue, obliteration of alveoli, and dilation of air spaces leading to a honeycomb appearance on xrays and scans.
(6) Increased pulmonary pressure from connective tissue and fibrotic banding leads to pulmonary hypertension, cor pulmonale, and heart failure.
(7) Cellular mechanisms of injury (American Thoracic Society &
European Respiratory Society, 2002)
(a) Direct damage: Some chemotherapy agents cause direct
damage to the alveoli and capillary endothelium (e.g., highdose cytarabine or mitomycin C) (Chan & King, 2012c;
Forghieri, Luppi, Morselli, & Potenza, 2007; Morgensztern
& Govidan, 2008).
(b) Metabolic damage: Cyclophosphamide metabolism in the
lung leads to the formation of alkylating metabolites and
acrolein, which may cause toxicity (Bein & Leikauf, 2011;
Gupta & Mahipal, 2007; Specks, 2012; Vahid & Marik, 2008).
(c) Multikinase inhibitors (e.g., sorafenib [Ide et al., 2010]), including tyrosine kinase inhibitors (e.g., imatinib, dasatinib),
and EGFR inhibitors (e.g., cetuximab, panitumumab) can
cause injury (Barber & Ganti, 2011; Min et al., 2011; Vahid
& Marik, 2008). Inhibition of the tyrosine kinase pathway
may affect the alveoli and pneumocytes.
(d) Acute onset of pulmonary edema (noncardiogenic) is related to cytokine-induced capillary leak syndrome (Binder,
Hbner, Temmesfeld-Wollbrck, & Schlattmann, 2011; Disel, Paydas, Yavuz, & Karakoc, 2010; Forghieri et al., 2007;
Maldonado, Limper, & Jett, 2012).
(e) Hemorrhagic pneumonitis is parenchymal injury and microvascular bleeding similar to alveolar hemorrhage but
occurs in both alveolar and interstitial spaces (Balk, 2012).
(f) Hypersensitivity pneumonitis is characterized by an acute
and rapid-onset immunologic alveolar reaction that leads
to capillary permeability, fluid extravasation, and lymphocytic or eosinophilic infiltration of the alveoli and
interstitium, impeding gas exchange (Balk, 2012; Kim,
Mishima, & Yoshizawa, 2010; Kim, Song, & Ryu, 2009;
King & Jett, 2013; Lerch, Gyorik, Feilchenfeldt, Mazzucchelli, & Quadri, 2010; Lobera et al., 2008; Maldonado
et al., 2012; Maldonado, Limper, & Jett, 2013a; Zappasodi et al., 2007)
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290
(g) Cryptogenic organizing pneumonia, previously called bronchiolitis obliterans organizing pneumonia, is characterized by
development of fibrous connective tissue between and involving alveolar and bronchiolar spaces; inflammation activation of autoimmune collagen deposition; and obstruction of the ventilating airways. This disorder may be associated with immune disorders (e.g., autoimmune diseases, post-transplant), infectious diseases, hematologic malignancies, and some antineoplastic medications (Cottin,
& Cordier, 2011; Vasu et al., 2009).
(h) Pulmonary alveolar proteinosis is a syndrome of phospholipidosis and frothy exudates of the distal airways. Although
the triggering mechanisms are not well understood, autoimmune activation is suspected. It is characterized by
GM-CSF deficiency. It has most commonly been reported
after HSCT, but it is unclear if it is triggered by medication
exposure or immune deficits (Khan & Agarwal, 2011; Pidala, Khalil, & Fernandez, 2011).
b) Incidence varies based upon host and medication-related factors.
Pneumonitis syndromes are infrequent.
(1) Incidence increases when pulmonary toxic agents are administered concomitantly with thoracic radiation.
(2) Incidence is influenced by cumulative dose with some agents.
c) Risk factors (Maldonado et al., 2012, 2013a, 2013b; Reck, Mok, Wolf,
Heigener, & Wu, 2011; Vahid & Marik, 2008; Zayen et al., 2011)
(1) The chemotherapy and targeted therapy drugs most commonly associated with pulmonary toxicity are all-trans-retinoic acid
(ATRA), bleomycin, busulfan, carmustine, cyclophosphamide,
cytosine arabinoside, everolimus, gemcitabine, methotrexate,
mitomycin, oxaliplatin, rituximab, and tamoxifen (Gemma,
2009; Mizuno et al., 2012).
(a) Agents associated with bronchospasm include asparaginase,
cetuximab, etoposide, gemcitabine, oxaliplatin, rituximab, taxanes, trastuzumab, and vinorelbine (Goli, Osman, Koduri, Byrd,
& Roy, 2011; Lee, Gianos, & Klaustermeyer, 2009; Kuntzsch &
Voge, 2009; Syrigou et al., 2011; Vahid & Marik, 2008).
(b) Agents associated with noncardiogenic pulmonary edema
include cytarabine, gemcitabine, interleukins, and vinca alkaloids (Binder et al., 2011; Disel et al., 2010; Forghieri et
al., 2007; Maldonado et al., 2012).
(c) Agents associated with hypersensitivity pneumonitis include bortezomib, imatinib, lenalidomide, methotrexate, oxaliplatin, paclitaxel, procarbazine, and thalidomide
(Balk, 2012; Kim et al., 2009, 2010; King & Jett, 2013; Lerch et al., 2010; Lobera et al., 2008; Maldonado et al.,
2012, 2013a; Zappasodi et al., 2007).
(d) Antineoplastic therapies associated with cryptogenic organizing pneumonia include radiofrequency ablation, radiation therapy, bleomycin, busulfan, everolimus, IFN alfa,
methotrexate, platinum agents, rituximab, sirolimus, tacrolimus, temozolomide, thalidomide, and trastuzumab.
(2) Agents associated with nonspecific dyspnea include ATRA, azathioprine, cetuximab, chlorambucil, chlorozotocin, crizotinib,
dasatinib, docetaxel, doxorubicin, erlotinib, etoposide, fludarabine, gemcitabine, ifosfamide, imatinib, irinotecan, lenalidomide, lomustine, melphalan, mercaptopurine, mitoxantrone,
nilotinib, panitumumab, pemetrexed, procarbazine, semustine,
temozolomide, temsirolimus, thalidomide, trastuzumab, vinblastine, and vindesine.

(3) General host risk factors for ILD (Amin et al., 2011; Arrieta et
al., 2009; Takeda et al., 2012)
(a) Age: Because the effectiveness of the antioxidant defense
system decreases with age, susceptibility to pulmonary toxicity from certain cytotoxic drugs increases significantly after age 70 (Wagner, Mehta, & Laber, 2007).
(b) Tobacco smoking (Chernecky, 2009)
(c) Deteriorating creatinine clearance affecting drug clearance has been implicated in increased risk for pneumonitis and pulmonary fibrosis (Vahid & Marik, 2008; Yahalom
& Portlock, 2008).
(d) High oxygen concentrations (about 60% fraction of inspired oxygen), such as those used during administration
of general anesthesia, can enhance the pulmonary toxicity of bleomycin (Chernecky, 2009; Mazeron et al., 2010).
(e) Prior lung disease (e.g., chronic obstructive lung disease)
or reduced lung reserve (Chernecky, 2009; Xu et al., 2012)
(f) Autoimmune disease enhances release of inflammatory
mediators that increase drug-related pulmonary toxicity
(Chernecky, 2009; Hadjinicolaou et al., 2011; Silva & Mller, 2009; Varga, 2007).
(4) Treatment-related factors (see Table 36)
(a) Thoracic radiation therapy (Chernecky, 2009; Hadjinicolaou et al., 2011; Merrill, 2013)
(b) Multidrug regimens such as those including bleomycin, mitomycin, cyclophosphamide, methotrexate, or BCNU (Binder et al., 2011; Boeck et al., 2007; Czarnecki & Voss, 2006;
Leo et al., 2010; Lim, Kim, Choi, & Lee, 2010; Usman, Faruqui, ud Din, & Zahid, 2010). It has not been determined
whether any single drug is the causative agent or if the interaction of these antineoplastics results in enhanced toxicity (Boeck et al., 2007).
(c) Concurrent chemotherapy and radiation therapy, especially with bleomycin, carmustine, cyclophosphamide, or
doxorubicin, has been associated with interstitial pulmonary pneumonitis (Amin et al., 2011; Chernecky, 2009).
(d) Cumulative dose: Increasing toxicity with increasing dose
is believed to be a result of drug accumulation in the lung
itself. Two patterns of dose-related pulmonary toxicity are
clinically observed.
i. A threshold effect: A definite increase in risk for pulmonary toxicity occurs when a cumulative dose is reached.
Total lifetime dose of bleomycin exceeding 400 units
(Bristol-Myers Squibb Co., 2012a; Gilligan, 2012)
Busulfan, in the absence of other predisposing factors, total dose > 500 mg (GlaxoSmithKline, 2008b)
Mitomycin maximum dose of 30 mg/m2 (Chan &
King, 2012c)
Lomustine dose > 1,100 mg/m2 (Bristol-Myers
Squibb Co., 2010a)
ii. A linear effect: Risk for the development of pulmonary toxicity constantly increases as more drug is
administered (e.g., carmustine [Bristol-Myers Squibb
Co., 2011a]).
(e) Long-term treatment (e.g., busulfan, imatinib treatment)
291
292
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents

Classification
Incidence
Comments
Busulfan
Incidence is rare but serious.

Busulfan is associated with pulmonary damage and
pneumonitis. It occurs in 2.5%11.5% of patients,
usually those on long-term treatment, although it can
occur more acutely.
Mean time from exposure to interstitial pneumonitis
toxicity is 4 years, (range = 8 months to 10 years)
(Bunte et al., 2008).
Risk increases with total doses > 500 mg, concurrent
pulmonary toxic medications, and preexisting lung
disease (Bunte et al., 2008).
Types of toxicity: Interstitial pneumonitis, pulmonary fibrosis, organizing pneumonia, pulmonary VOD (Bunte et al., 2008; Maldonado et al., 2013a)
Insidious-onset cough, dyspnea, and low-grade fever; bronchopulmonary dysplasia progressing to interstitial pulmonary fibrosis (busulfan lung)
Bronchopulmonary dysplasia with pulmonary fibrosis is a rare
but serious complication following chronic busulfan therapy.
The average onset of symptoms is 4 years after therapy; delayed onsets have occurred (range = 8 months to 10 years)
(Bunte et al., 2008; GlaxoSmithKline, 2008b).
Chest x-rays show diffuse linear densities, sometimes with reticular
nodular or nodular infiltrates or consolidation. Pleural effusions
have occurred (GlaxoSmithKline, 2008b; Smalley & Wall, 1966).
Establish baseline pulmonary function.

Assess x-rays, PFTs, and
CT scans as indicated.
Chlorambucil
Incidence is low. Respiratory dysfunction is usually reported at high dose but occurs at total doses of 540
834 mg (Dweik, 2013; GlaxoSmithKline, 2003b).
Occurs 6 months to 3 years after initiation of therapy
(Dweik, 2013).
Types of toxicity: Interstitial pneumonitis, organizing pneumonia,

pulmonary fibrosis (Dweik, 2013; Maldonado et al., 2012b)
Pulmonary fibrosis and bronchopulmonary dysplasia in patients
receiving long-term therapy (GlaxoSmithKline, 2003b)
Biopsy findings may include T-cell infiltration and alveolitis.
Periodic monitoring of PFTs shows decreased lung volumes and
reduced DLCO before clinical symptoms.
Steroid responsive in < 10% of cases (Dweik, 2013)
Cyclophosphamide
Incidence is rare. Diffuse alveolar damage is the most

common manifestation of cyclophosphamideinduced lung disease (Specks, 2012).
In early-onset toxicity occurring within the first 48
days, no relationship exists among development
of lung injury, dose, and duration of administration
(Specks, 2012).
Incidence of pulmonary toxicity has been reportedly increased in patients who have received concomitant methotrexate or amiodarone and in chronic
graft-versus-host disease (Gupta & Mahipal, 2007;
Specks, 2012).
Types of toxicity: Interstitial pneumonitis, pulmonary fibrosis, alveolar hemorrhage

Edema, fibrosis, alveolar hemorrhage, and fibrin deposition are
thought to be due to accumulation of the alkylating agent metabolite acrolein. The metabolite causes lipid peroxidation normally cleared by pulmonary antioxidant mechanisms, but when
accumulated, it erodes the lipid layer and causes microvascular damage (Bein & Leikauf, 2011; Specks, 2012).
Onset of chronic fibrosis can be 15 weeks to 6 years after medication administration.
Interstitial pulmonary fibrosis has been reported in patients receiving high doses of cyclophosphamide over a prolonged period (Gupta & Mahipal, 2007).
Anaphylactic reactions are associated with death. Possible
cross-sensitivity with other alkylating agents has been reported (Bristol-Myers Squibb Co., 2005).
One clinical change in PFTs that has been proved significantly predictive for cyclophosphamide pulmonary toxicity is reduction of DLCO.
Concomitant oxygen delivery

> 60% FiO2 may exacerbate incidence and severity
(Specks, 2012).
Treatment involves discontinuing the agent and administering steroids, which
have good to variable response in early-onset toxicity (Bristol-Myers Squibb
Co., 2005; Specks, 2012).
Delayed-onset interstitial fibrosis with pleural thickening is less responsive to
corticosteroids.
Alkylating
agents
Drug
Table 36. Pulmonary Toxicity of Chemotherapeutic Agents (Continued)

Classification
Alkylating
agents (cont.)
Drug
Incidence
Comments
Interstitial pneumonitis with pulmonary fibrosis occurs

with variable incidence, with the highest incidence
of 6% in non-small cell lung cancer (Vahid & Marik,
2008).
Acute dyspnea with hypoxemia may occur in some patients due to transient methemoglobinemia (Maldonado et al., 2013a; Vahid & Marik, 2008).
Types of toxicity: Interstitial pneumonitis

Dyspnea, tachypnea, and cough warrant investigation of possible pulmonary toxicity (Baxter Healthcare Corp., 2009a).
Methemoglobinemia occurs
due to reactions between
4-thioifosfamide and glutathione to deplete antioxidant reserves (Maldonado et al., 2013a; Vahid &
Marik, 2008).
Melphalan
Reports of bronchopulmonary dysplasia (GlaxoSmithKline, 2003a)

Acute hypersensitivity reactions including anaphylaxis
were reported in 2.4% of 425 patients receiving the
injected drug for myeloma (GlaxoSmithKline, 2003a).
Types of toxicity: Bronchospasm, interstitial pneumonitis (Maldonado et al., 2013a)

Pulmonary fibrosis, interstitial pneumonia, bronchospasm, and
dyspnea can signal rare hypersensitivity, not pulmonary toxicity. These patients responded to antihistamine and corticosteroid therapy (GlaxoSmithKline, 2003a).
If a hypersensitivity reaction
occurs, IV or PO melphalan should not be readministered because hypersensitivity reactions have been
reported with PO melphalan (GlaxoSmithKline,
2003a).
Oxaliplatin
Associated with pulmonary fibrosis (< 1% of study patients), which may be fatal (Lobera et al., 2008; Maldonado et al., 2013a; Pasetto & Monfardini, 2006).
Peak incidence of interstitial lung disease is > 36
months after start of therapy, but not clearly cumulative doserelated (Lim et al., 2010).
Incidence of events increases with combined therapy
(Chan et al., 2011). An acute syndrome of grade 3
or 4 pharyngolaryngeal dysesthesia is seen in 1%
2% of patients previously untreated for advanced
colorectal cancer.
The combined incidence of cough, dyspnea, and hypoxia was 43% (any grade) and 7% (grades 3 and 4)
in the oxaliplatin plus 5-FU/LV arm compared to 32%
(any grade) and 5% (grades 3 and 4) in the irinotecan
plus 5-FU/LV arm for patients with previously untreated colorectal cancer (sanofi-aventis U.S. LLC, 2011b).
Types of toxicity: Dyspnea of uncertain significance, bronchospasm, hypersensitivity pneumonitis, interstitial pneumonitis, pulmonary fibrosis, diffuse alveolar hemorrhage, organizing pneumonia (Chan et al., 2011; Fekrazad et al., 2010; Garrido et al., 2007; Lobera et al., 2008; Shogbon et al., 2013; Watkins et al., 2011)
Anaphylactic-like reactions, thought to be related to eosinophilic
infiltration of the lungs, are treatable with epinephrine, corticosteroids, and antihistamines (Vahid & Marik, 2008).
Corticosteroids are of uncertain benefit for interstitial pneumonitis, pulmonary fibrosis, or organizing pneumonia (Chan et al.,
2011; Shogbon et al., 2013).
Rare cases of diffuse alveolar hemorrhage have been fatal
(Lobera et al., 2008; Watkins et al., 2011).
Previously treated patients experienced subjective sensations of
dysphagia or dyspnea, without laryngospasm or bronchospasm
(no stridor or wheezing) (sanofi-aventis U.S. LLC, 2011b).
In cases of unexplained respiratory symptoms such

as nonproductive cough,
dyspnea, crackles, or radiologic pulmonary infiltrates, oxaliplatin should be
discontinued until further
pulmonary investigation excludes ILD or pulmonary fibrosis (sanofi-aventis U.S.
LLC, 2011b).
Temozolomide
Dyspnea: 5%8%; sinusitis: 6%; coughing: 5% (Merck

Sharp & Dohme Corp., 2013b)
Interstitial pneumonitis occurs in up to 4.8% of patients receiving doses exceeding 150200 mg/m2
(Maldonado et al., 2007; Vahid & Marik, 2008).
Types of toxicity: Dyspnea of uncertain significance, bronchospasm, interstitial pneumonitis, organizing pneumonia (Kim et
al., 2012; Maldonado et al., 2007)
Allergic reactions, including rare cases of anaphylaxis, when
used with nitrosoureas and procarbazine (Maldonado et al.,
2007; Merck Sharp & Dohme Corp., 2013b)
Pneumonitis with high doses
Organizing pneumonia has been treated with methylprednisolone 1 mg/kg/day with moderate success (Kim et al., 2012).
Establish baseline pulmonary function and reassess

with any respiratory symptoms.
293
Ifosfamide
294

Classification
Antimetabolites
Incidence
Comments
Aldesleukin
(IL-2)
Life-threatening grade 4 respiratory disorders: 3%

(ARDS, respiratory failure, intubation); 1% (apnea)
(Prometheus Laboratories Inc., 2012)
Adverse events occurred in 10% of patients (N = 525)
(Prometheus Laboratories Inc., 2012).
Dyspnea: 43%
Lung disorder: 24% (physical findings associated with
pulmonary congestion, rales, rhonchi)
Respiratory disorder: 11% (ARDS, chest x-ray infiltrates, unspecified pulmonary changes)
Increased cough: 11% (Prometheus Laboratories Inc.,
2012)
Types of toxicity: Noncardiogenic pulmonary edema, dyspnea,

respiratory failure, tachypnea, pleural effusion, wheezing, apnea, pneumothorax, hemoptysis (Kai-Feng et al., 2011; Prometheus Laboratories Inc., 2012)
Toxicities may worsen with continued exposure or occur more
quickly with each subsequent therapy cycle (Schwartzentruber, 2005).
Establish baseline pulmonary function, and assess

abnormalities that indicate
ineligibility for high-dose
aldesleukin (Prometheus
Laboratories Inc., 2012).
Consider fluid limitations
with respiratory symptoms
if blood pressure tolerates
(Letizia & Conway, 1996).
Consider holding or discontinuing dose with refractory symptoms (Prometheus
Laboratories Inc., 2012;
Siegel & Puri, 1991).
IFN alfa-2b
Rare (Merck Sharp & Dohme Corp., 2013a)
Types of toxicity: Fever, cough, dyspnea, nonspecific pulmonary infiltrates, pneumonitis, pulmonary alveolar proteinosis,
organizing pneumonia (Kai-Feng et al., 2011; Merck Sharp &
Dohme Corp., 2013a)
Consider holding drug while

evaluating symptoms.
Oprelvekin
(IL-11)
Dyspnea: 48%; increased cough: 29%; pleural effusions: 10% (Kai-Feng et al., 2011; Wyeth Pharmaceuticals, 2011)
Types of toxicity: Noncardiogenic pulmonary edema, pleural effusions, dyspnea of uncertain significance
Peripheral edema, dyspnea; preexisting fluid collections, including pleural and pericardial effusions or ascites, should be monitored.
Patients should be advised to immediately seek medical attention if any of the following signs or symptoms develop: swelling of the face, tongue, or throat; difficulty breathing, swallowing, or talking; shortness of breath; or wheezing (Wyeth Pharmaceuticals, 2011).
Fluid retention is reversible

within several days of discontinuing oprelvekin (Vahid & Marik, 2008).
Fluid balance should be
monitored, and appropriate medical management
is advised. Closely monitor
fluid and electrolyte status
in patients receiving chronic diuretic therapy (KaiFeng et al., 2011; Wyeth
Pharmaceuticals, 2011).
Capecitabine
Dyspnea: 14% (Genentech, Inc., 2011)

Not considered a major toxicity but has demonstrated
these side effects: 0.1% cough; 0.1% epistaxis, hemoptysis, respiratory distress; 0.2% asthma (Genentech, Inc., 2011)
Most reported cases have been in combination with
another pulmonary toxic agent such as oxaliplatin
(Chan et al., 2011; Lim et al., 2010).
Types of toxicity: Interstitial pneumonitis

Dyspnea, cough, respiratory distress; manage toxicities with
symptomatic treatment, dose interruptions, and dose adjustment.
Once dose has been adjusted, it should not be increased at a later time (Genentech, Inc., 2011).
Anticancer
cytokines
Drug

Classification
Drug
Comments
Cytarabine
Noncardiogenic pulmonary edema in doses > 5 g/m2

(612 hours after dose) (Mayne Pharma, 2011)
Incidence is approximately 14% of patients, with most
(approximately 75%) reversible (Breccia et al., 2008,
2012)
Cytarabine liposomal: No pulmonary data (Sigma-Tau
Pharmaceuticals, Inc., 2011)
Types of toxicity: Noncardiogenic pulmonary edema (previously

known as cytarabine syndrome) (Luesink & Jansen, 2010)
A syndrome of sudden respiratory distress, rapidly progressing
to pulmonary edema, capillary leak syndrome, respiratory failure, and ARDS (Jeddi et al., 2008)
High-resolution CT will show

diffuse bilateral patchy infiltrates (Forghieri et al.,
2007).
May be reduced with fluid restrictions.
Fludarabine
phosphate
Cough: 10%*; 44%**

Pneumonia: 16%*; 22%**
Dyspnea: 9%*; 22%**
Allergic pneumonitis: 0%*; 6%**
*N = 101; **N = 32 (Berlex Laboratories, 2006)
Rare cases of progression to debilitating or fatal pulmonary fibrosis have occurred (Disel et al., 2010).
Types of toxicity: Alveolitis, noncardiogenic pulmonary edema,

hypersensitivity pneumonitis, pulmonary fibrosis
Pulmonary hypersensitivity reactions such as dyspnea, cough,
and interstitial pulmonary infiltrate have been observed.
A clinical investigation using fludarabine phosphate injection in
combination with pentostatin for the treatment of refractory
chronic lymphocytic leukemia in adults showed an unacceptably high incidence of fatal pulmonary toxicity. Therefore, this
combination is not recommended (Berlex Laboratories, 2006).
Corticosteroids are of uncertain benefit (Disel et al., 2010).
Rechallenge after suspected

toxicity is contraindicated.
Gemcitabine
hydrochloride
Pulmonary toxicity is reported in 0.2%13% of patients (Shaib et al., 2008; Vahid & Marik, 2008).
Dyspnea: 23% (severe dyspnea in 3%) (Eli Lilly & Co.,
2013)
Bronchospasm incidence currently is reported as
0.6% (Shaib et al., 2008).
Parenchymal lung toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and
ARDS, has been reported rarely (Eli Lilly & Co.,
2013).
Severe pulmonary toxicities likely to be related to
bronchospastic events, capillary permeabilityinduced pulmonary edema, or diffuse alveolar hemorrhage have been reported (Vahid & Marik, 2008).
These have led to death in approximately 0.3% of
cases (Binder et al., 2011; Boeck et al., 2007; Vahid
& Marik, 2008).
Late pulmonary fibrosis has been reported in < 1% of
patients (Binder et al., 2011). Incidence increased to
2.7% when administered with other pulmonary toxic agents (Binder et al., 2011; Boeck et al., 2007;
Grande et al., 2007; Maldonado et al., 2013a; Vahid
& Marik, 2008).
Types of toxicity: Dyspnea of uncertain significance, bronchospasm, noncardiogenic pulmonary edema, ILD, pulmonary fibrosis, alveolar hemorrhage, pleural effusion, pulmonary VOD,
radiation recall (Boeck et al., 2007; Kido et al., 2012; Shaib et
al., 2008; Vahid & Marik, 2008)
Dyspnea, cough, bronchospasm, and parenchymal lung toxicity
(rare) may occur. If such effects develop, gemcitabine should
be discontinued. Early use of supportive care measures may
help to ameliorate these conditions (Eli Lilly & Co., 2013).
Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy (Czarnecki & Voss,
2006).
Some patients experienced onset of pulmonary symptoms up to
two weeks after the last dose (Eli Lilly & Co., 2013).
Prolonged infusion time beyond 60 minutes and doses more than once weekly
increase toxicities (Vahid &
Marik, 2008).
Risk is increased when administered with other pulmonary-toxic medications
(Boeck et al., 2007; Vahid
& Marik, 2008).
Bronchospasm can be treated and resolved with corticosteroids. Rechallenge
may require premedication
with corticosteroids (Vahid
& Marik, 2008).
295
Incidence
296

Classification
Antitumor
antibiotics
Incidence
Comments
Gemcitabine
hydrochloride
(cont.)
Pulmonary hemorrhage has been associated with a

20% mortality rate (Vahid & Marik, 2008).
Radiation recall after thoracic irradiation has been reported rarely in patients with lung cancer (Ding et
al., 2011).
Methotrexate
The incidence of allergic pneumonitis is 5%10%

(Chikura et al., 2008). Toxicity is not dose related,
but patients who receive treatment more frequently may be more susceptible to lung injury (Chikura et
al., 2008; Kim et al., 2009).
Types of toxicity: Hypersensitivity pneumonitis, pulmonary fibrosis, organizing pneumonia (Balk, 2012)
Fever, dyspnea, cough (especially dry nonproductive), nonspecific pneumonitis, or chronic interstitial obstructive pulmonary
disease (deaths have been reported); pulmonary infiltrates
(Balk, 2012; Chikura et al., 2008; Kim et al., 2009; Teva Pharmaceuticals USA, 2012b)
Neutrophil-predominant histology is more likely to progress to
pulmonary fibrosis (Kim et al., 2009).
Readministration with a desensitization protocol has

been successfully implemented (Balk, 2012).
Pemetrexed
Postmarketing data show low incidence of ILD with

variable severity.
Both ILD and pleural effusions have been reported (Breuer &
Nechushtan, 2012; Dickgreber et al., 2010). ILD presents initially as dyspnea without pulmonary infiltrates (Hochstrasser et
al., 2012). Pulmonary infiltrates are diffuse with ground-glass
opacities (Hochstrasser et al., 2012). Pleural effusions occur
in 7%12% of patients and are more common if premedication with corticosteroids is not performed (Breuer & Nechushtan, 2012).
Establish baseline pulmonary function and imaging

to have for comparison if
respiratory symptoms develop.
Discontinue medication with
respiratory symptoms until etiology can be established.
Corticosteroids have been
used with anecdotal evidence of benefit.
Bleomycin
sulfate
Average incidence: 10% of treated patients

Dose-related incidence (Gilligan, 2012):
< 270 units: 0%2%
> 360 units: 6%18%
Nonspecific pneumonitis progresses to pulmonary fibrosis and death in approximately 1% of patients
(Keijzer & Kuenen, 2007; Specks, 2012).
More common in patients older than age 70 receiving total dose > 400 units, concomitant pulmonarytoxic agents, renal dysfunction, concomitant radiation therapy, or oxygen therapy (Bristol-Myers
Squibb Co., 2012a; Fyfe & McKay, 2010; Usman et
al., 2010).
Types of toxicity: Hypersensitivity pneumonitis, pulmonary fibrosis, pulmonary VOD, organizing pneumonia, spontaneous
pneumothorax
The characteristics of bleomycin-induced pneumonitis include
dyspnea and fine rales.
Bleomycin-induced pneumonitis produces patchy x-ray opacities
usually of the lower lung fields that look the same as infectious
bronchopneumonia or even lung metastases in some patients
(Fyfe & McKay, 2010; Gilligan, 2012).
DLCO may be abnormal before other symptoms appear (Fyfe &
McKay, 2010).
Early toxicity may be self-resolving. Monitor for early

warning signs of toxicity to
avoid irreversible pulmonary damage.
Chest x-rays should be taken every one to two weeks.
If pulmonary changes are
noted, treatment should be
discontinued.
Drug

Classification
Antitumor
antibiotics
(cont.)
Drug
Incidence
Comments
Toxicity may be lower if drug is not given as IV bolus

(Bristol-Myers Squibb Co., 2012a; Specks, 2012).
Exposure to increasing concentrations of oxygen-increasing toxicity warrants prudently maintaining oxygen levels at room
air (25%) (Bristol-Myers
Squibb Co., 2012a; Chernecky, 2009; van Gorselen
& Gerding, 2011).
Oral carnosine to abrogate
bleomycin pulmonary toxicity has anecdotal reports
of success (Cuzzocrea et
al., 2007).
Mitomycin
Pulmonary toxicity has been reported with singleagent therapy and combination chemotherapy, 3%
36%, 612 months after therapy (Chan & King,
2012c).
Prior treatment with mitomycin, cumulative doses > 30
mg/m2, and other anticancer drugs may increase risk
of toxicity (Bristol-Myers Squibb Co., 2012b; Chan &
King, 2012c).
Types of toxicity: Bronchospasm, noncardiogenic pulmonary

edema, ILD, pulmonary VOD
Dyspnea, nonproductive cough, crackles, capillary leak, with
progressive respiratory dysfunction indicative of ILD (Charpidou et al., 2009)
Severe bronchospasm has been reported following administration of vinca alkaloids in patients who previously or simultaneously received mitomycin. Acute respiratory distress occurred
within minutes to hours after the vinca alkaloid injection. The
total doses for each drug varied considerably (Bristol-Myers
Squibb Co., 2012b).
Pulmonary VOD occurs later after exposure (up to 10 years) and
leads to symptoms of pulmonary hypertension (Chan & King,
2012c).
Signs and symptoms of

pneumonitis may be reversed if therapy is instituted early. Drug may be discontinued if dyspnea occurs even with normal
chest radiograph. Caution
should be exercised when
using oxygen because oxygen toxic injury occurs
even the absence of other medication etiologic precipitators (Schwaiblmair et
al., 2012).
Pay careful attention to fluid balance, and avoid overhydration (Bristol-Myers
Squibb Co., 2012b).
Mitoxantrone
Hypersensitivity-like acute pneumonitis occurs variably when given in combination with other chemotherapeutic agents (Vahid & Marik, 2008).
Types of toxicity: Hypersensitivity pneumonitis, ILD, organizing

pneumonia (Chan & King, 2012a)
Sudden-onset dyspnea and tachypnea with hypoxemia
Patchy infiltrates on x-ray or CT scan
Usually only occurs when given with other potentially pulmonary
toxic medications
Organizing pneumonia detectable on bronchial biopsy or open lung biopsy usually is responsive to
corticosteroid treatment
(Vahid & Marik, 2008).
297
Bleomycin
sulfate (cont.)
298

Classification
Drug
Incidence
Comments
ATRA
Incidence of acute differentiation syndrome in patients

receiving ATRA is 14%25% with an associated
mortality of approximately 2% (Patatanian & Thompson, 2008; Weinberger & Larson, 2012). Severe and
moderate disease occur with equal frequency.
Types of toxicity: Retinoic acid differentiation syndrome

Pulmonary infiltration of differentiating leukemic cells and their
associated chemokines cause inflammatory capillary permeability with sudden and severe hypoxemia (Luesink et al., 2009).
Differentiation syndrome is present with ATRA or arsenic individually or in combination therapies (Breccia et al., 2008; Luesink
et al., 2009).
Occurs in a bimodal pattern, with 46% developing symptoms in
the first week of therapy and an additional 36% having symptoms between the third and fourth weeks (Weinberger & Larson, 2012).
Characteristic features of this syndrome include fever, myalgias,
arthralgias, weight gain, peripheral edema, respiratory distress
with pulmonary infiltrates, hypotension, hepatic and renal dysfunction, rash, and effusions (Weinberger & Larson, 2012).
Respiratory findings usually include an increased cardiothoracic ratio, peribronchial cuffing, and ground-glass opacities. Consolidation and pleural effusions are common. Approximately
40% may have a clear radiograph, although this is uncommon
in severe disease (Montesinos et al., 2009).
Pulmonary hemorrhage has occurred in severe cases of differentiation syndrome but may be difficult to differentiate from coagulopathies common in acute progranulocytic leukemia.
Close monitoring of intake

and output, weight, vital
signs, and breath sounds
may assist early detection.
Monitor oxygen saturation for
early signs of hypoxemia
on exertion.
Monitor chest x-ray for pulmonary infiltrates that may
precede clinical symptoms.
Monitor labs for evidence of
renal dysfunction.
Miscellaneous
Arsenic trioxide
Respiratory events (all grades, N = 40):

Cough: 65%
Dyspnea: 53%
Hypoxia: 23%
Pleural effusion: 20%
Wheezing: 13%
Grades 3 and 4:
Dyspnea: 10%
Hypoxia: 10%
Pleural effusion: 3%
Types of toxicity: Differentiation syndrome (Jeddi et al., 2008;

Weinberger & Larson, 2012)
These adverse effects usually are not permanent or irreversible and usually do not require interruption of therapy (Cephalon, Inc., 2010).
Risk increases with high WBC count, high percentage blasts,
and preexisting lung disease (Luesink & Jansen, 2010).

Monitor WBC counts and
blast percentages.
Differentiating
agent
Classification
Drug
Incidence
Comments
Miscellaneous
(cont.)
Brentuximab
Concomitant use with bleomycin is contraindicated

because of pulmonary toxicity. In a clinical trial that
studied brentoximab with
bleomycin as part of a
combination regimen, noninfectious pulmonary toxicity was greater than with
ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). Cough and
dyspnea were reported,
and imaging showed Interstitial infiltration and inflammation. Most patients responded to corticosteroids
(Seattle Genetics, Inc.,
2012).
Lenalidomide
Dyspnea of uncertain significance in 15%23%, but

only 4% severe (Barber & Ganti, 2011; Lerch et al.,
2010)
Hypersensitivity reactions are rare (< 1%) but can be
severe and progress to irreversible pulmonary fibrosis (Lerch et al., 2010).
Types of toxicity: Dyspnea of uncertain significance, hypersensitivity pneumonitis, interstitial pneumonitis, organizing pneumonia (Lerch et al., 2010; Thornburg et al., 2007)
Immediately discontinue
medication if pulmonary
toxicity is suspected (Celgene Corp., 2013a).
Thalidomide
Dyspnea of uncertain significance in 50%, but only 4%

severe (Barber & Ganti, 2011).
Other acute pulmonary toxicities are rare and have no
reported incidence rate (Celgene Corp., 2013b).
Types of toxicity: Dyspnea of uncertain significance, hypersensitivity pneumonitis, alveolar hemorrhage, pulmonary fibrosis,
organizing pneumonitis, pulmonary VOD with pulmonary hypertension
Sudden-onset ground-glass opacities have been noted with thalidomide. Case reports reflect multiple different etiologies: infection, interstitial lung toxicity, organizing pneumonia, and alveolar hemorrhage. It is believed that antiangiogenic properties have been temporally associated with alveolar hemorrhage in patients receiving thalidomide (Barber & Ganti, 2011;
Charpidou et al., 2009; Khalsa et al., 2007; Schwaiblmair et
al., 2012).
Consider infectious etiology as higher risk for pulmonary symptoms than drug
toxicity.
Other bleeding symptoms
may support suspicion for
alveolar hemorrhage in patients with respiratory distress temporally related to
thalidomide administration
(Khalsa et al., 2007).
299
300

Drug
Incidence
Comments
Miscellaneous:
Antiangiogenesis agent
Bevacizumab
Hemoptysis is more common with squamous cell lung

cancer (31%) than with nonsquamous cell lung cancer (2%3%) (Vahid & Marik, 2008).
Interstitial pneumonitis and organizing pneumonia incidence is difficult to quantify because it usually is
associated with thoracic radiation.
Types of toxicity: Hemoptysis, interstitial pneumonia, pleural effusion, organizing pneumonia (Barber & Ganti, 2011; Vahid &
Marik, 2008).
All toxicities are more common in patients with squamous cell
carcinoma of the lung (Vahid & Marik, 2008). Most common
clinical presentation is hemoptysis (Vahid & Marik, 2008).
Use of bevacizumab clearly increases risk of radiation pneumonitis syndromes (Lind et al., 2012).
Mechanism of toxicity is unclear but thought to be related to
blocking of VEGF (Hollebecque et al., 2012).
This medication is always

discontinued when pulmonary bleeding of any type
is noted (Genentech, Inc.,
2012a).
Miscellaneous:
Proteasome
inhibitor
Bortezomib
Acute pneumonitis syndrome has been reported rarely in case reports of Japanese patients treated after
HSCT and an African American patient without history of transplantation (Ohri & Arena, 2006).
Types of toxicity: Differentiation syndrome, hypersensitivity pneumonitis (Barber & Ganti, 2011)
Sudden respiratory distress with accompanying pulmonary infiltrates
Proposed pathophysiology is acute vasculitis (Pitini et al., 2007).
Inconsistent reversibility or responsiveness to corticosteroids
(Barber & Ganti, 2011)
Immediate discontinuation
of this drug is recommended when pulmonary symptoms occur (Millennium
Pharmaceuticals, 2012).
Monoclonal
antibodies
Alemtuzumab
Infusion raterelated dyspnea: 17%

Acute infusion-related events were most common during the first week of therapy.
Incidence (N = 149):
Dyspnea: 26%
Cough: 25%
Bronchitis/pneumonitis: 21%
Pneumonia: 16%
Bronchospasm: 9%
(Genzyme Corp., 2009a)
Types of toxicity: Dyspnea of uncertain significance, bronchospasm, interstitial pneumonitis

Alemtuzumab has been associated with infusion-related events
including hypotension, rigors, fever, shortness of breath, bronchospasm, chills, and/or rash.
Side effects include asthma, bronchitis, chronic obstructive pulmonary disease, hemoptysis, hypoxia, pleural effusion, pleurisy, pulmonary edema, pulmonary fibrosis, pulmonary infiltration, respiratory depression, respiratory insufficiency, sinusitis,
stridor, and throat tightness (Genzyme Corp., 2009a).
To ameliorate or avoid infusion-related events, premedicate patients with an

oral antihistamine and acetaminophen prior to dosing and monitor closely for
infusion-related adverse
events.
Cetuximab
Bronchospasm with hypersensitivity reaction is generally uncommon (2.5%), but frequent severe reactions (20%) have a geographic propensity (southeast United States through southern Midwest states
such as Oklahoma, Arkansas, and Texas) (Chua et
al., 2009)
ILD < 1% is idiosyncratic in nature (Bristol-Myers
Squibb Co. & ImClone Systems, 2012).
Types of toxicity: Bronchospasm, interstitial pneumonitis, organizing pneumonia (Barber & Ganti, 2011; Chua et al., 2009)
ILD has been reported as serious and potentially fatal
(Bristol-Myers Squibb Co. & ImClone Systems, 2012).
Onset of pneumonitis syndromes 26 months after start of drug
(Chua et al., 2009). May worsen after discontinuation of medication.
Characterized by dyspnea, tachypnea, and activity intolerance.
Symptoms can progressively worsen even after initial discontinuation of medication.
All dyspnea noted between

cycles warrants evaluation
of PFTs.
Hold medication until ILD
is ruled out. If drug is resumed, administer at
50% of previous rate
(Bristol-Myers Squibb Co.
& ImClone Systems, 2012).
Classification

Classification
Monoclonal
antibodies
(cont.)
Drug
Incidence
Comments
Bronchospasm: Infusion reactions occur in 4% of patients, but severe reactions with bronchospasm occur in 1%2% (Amgen Inc., 2013b; Giusti et al.,
2007)
ILD: < 1% (Amgen Inc., 2013b; Giusti et al., 2007)
Types of toxicity: Bronchospasm, ILD

ILD is characterized by dyspnea, cough, and pulmonary infiltrates that occur 24 months into therapy and worsen even after drug discontinuation (Amgen Inc., 2013b; Cohenuram &
Saif, 2007).
Monitor for infusion reactions

(Giusti et al., 2007).
Evidence of interstitial pneumonitis via PFTs and
high-resolution CT scan
prompts permanent discontinuation of the drug
(Cohenuram & Saif, 2007).
Rituximab
38% (N = 135) experienced pulmonary events in clinical trials. Infusion-related deaths involving pulmonary function occurred in 0.04%0.07%.
Bronchospasm: 8% (Biogen Idec, Inc., & Genentech,
Inc., 2013)
ILD incidence was approximately 2%, but up to 4.8%
with low lymphocyte counts (Zayen et al., 2011).
Types of toxicity: Bronchospasm, hypersensitivity pneumonitis,

ILD, alveolar hemorrhage, pulmonary alveolar proteinosis, organizing pneumonia
Most common adverse events were increased cough, rhinitis,
bronchospasm, dyspnea, and sinusitis.
Infusion-related symptom complex includes pulmonary effects:
hypoxia, bronchospasm, dyspnea, pulmonary infiltrates, and
ARDS (Biogen Idec, Inc., & Genentech, Inc., 2013).
Increased pulmonary toxicities are seen in patients with low absolute lymphocyte count (Huang, Liu, et al., 2011).
Pulmonary toxicities are more frequent in patients with cancer
than in patients with autoimmune disease (Hadjinicolaou et al.,
2011; Subramanian et al., 2010).
Hypersensitivity pneumonitis onsets within days to weeks of exposure and shows eosinophilic infiltration on bronchoscopy
(Tonelli et al., 2009).
Alveolar hemorrhage can be acute in onset and fatal (Ikpeama
& Bailes, 2012).
Pulmonary alveolar proteinosis occurs more often in patients
with immature lymphocyte cell types and has not been reported in patients with multiple myeloma treated with rituximab
(Borie et al., 2009).
There have been reports of organizing pneumonia presenting up
to 6 months post-infusion and a limited number of reports of
pneumonitis (including interstitial pneumonitis) presenting up
to 3 months post-infusion, some of which resulted in fatal outcomes (Barber & Ganti, 2011; Borie et al., 2009; Urun et al.,
2012; Wagner et al., 2007).
Treatment with corticosteroids is standard for most toxicity but
is not clearly helpful. Most substantiated with alveolar hemorrhage and organizing pneumonia (Maldonado et al., 2013b).
Interrupt treatment for severe

reactions and resume at
50% reduced infusion rate
when symptoms resolve.
The safety of resuming or
continuing administration
of rituximab in patients with
ILD or organizing pneumonitis is unknown (Biogen
Idec, Inc., & Genentech,
Inc., 2013).
Panitumumab
301
302

Classification
Incidence
Comments
Trastuzumab
As a single agent:
Increased cough: 26%
Dyspnea: 22%
In the postmarketing setting, severe hypersensitivity
reactions (including anaphylaxis), infusion reactions,
and pulmonary adverse events have been reported. Severe pulmonary events leading to death have
been reported rarely (Genentech, Inc., 2012b).
Interstitial pneumonitis occurred in 1%2% and was
severe in only 0.3% (Barber & Ganti, 2011).
Incidence of chronic organizing pneumonia was < 1%
(Vahid & Marik, 2008).
Types of toxicity: Dyspnea of uncertain significance, bronchospasm, interstitial pneumonitis, organizing pneumonia, increased cough, dyspnea, rhinitis, pharyngitis, pulmonary infiltrates, pleural effusions, noncardiac edema, pulmonary insufficiency, hypoxia, and ARDS (Genentech, Inc., 2012b)
Other severe events reported rarely in the postmarketing setting include pneumonitis and pulmonary fibrosis (Genentech,
Inc., 2012b).
Corticosteroids may be helpful (Vahid & Marik, 2008).
Patients with symptomatic intrinsic lung disease or extensive tumor involvement

of the lungs, resulting in
dyspnea at rest, may be at
greater risk for severe reactions. Adverse effects increase with combined drug
therapy (Genentech, Inc.,
2012b).
Rechallenge with this agent
is not recommended.
Carmustine
Although rare, cases of fatal pulmonary toxicity have

been reported. Most of these patients were receiving prolonged therapy with total doses of carmustine > 1,400 mg/m2. However, reports exist of pulmonary fibrosis in patients receiving lower total doses
In a long-term study of carmustine, all participants initially treated before age 5 died of delayed pulmonary
fibrosis (Bristol-Myers Squibb Co., 2011a). In another report, 40% of those experiencing delayed toxicity
after childhood treatment died of pulmonary fibrosis
(Huang, Hudson, et al., 2011).
Types of toxicity: ILD, pulmonary VOD

Pulmonary infiltrates and fibrosis have been reported to occur from 9 days to 43 months after treatment and appear to be dose related. Fibrosis may be slowly progressive
When used in high doses (300600 mg/m2) prior to HSCT, pulmonary toxicity may occur and may be dose limiting. The pulmonary toxicity of high-dose carmustine may manifest as severe interstitial pneumonitis, which occurs most frequently in
patients who have had recent mediastinal irradiation.
A linear relationship exists between total dose and pulmonary
toxicity at doses > 1,000 mg/m2, with 50% of patients developing pulmonary toxicity at total cumulative doses of 1,500
mg/m2. Risk factors include preexisting lung disease, smoking, cyclophosphamide therapy, and recent (within months)
thoracic irradiation. Patients with baseline forced vital capacity and/or DLCO < 70% of the predicted value are at high risk
Delayed toxicity after childhood treatment has increased mortality compared to toxicities from other causes (Huang, Hudson,
et al., 2011).
Other risks for increased pulmonary toxicity with carmustine include history of lung disease and treatment duration (Charpidou et al., 2009).
Perform baseline and regular PFTs, especially in patients with risk factors or
those who have received >
800 mg/m2 (Bristol-Myers
Squibb Co., 2011a).
CT abnormalities with carmustine occur in the upper
zones of the lungs (Huang,
Hudson, et al., 2011).
Nitrosoureas
Drug

Classification
Drug
Incidence
Comments
Lomustine
Rare; usually occurs with doses > 1,100 mg/

m2 (one reported case at a dose of 600 mg/m2)
(Bristol-Myers Squibb Co., 2010a). There appeared
to be some late reduction of pulmonary function in
all long-term survivors.
This form of lung fibrosis may be slowly progressive and has resulted in death in some cases
Incidence is increased in childhood survivors treated before age 5 (Bristol-Myers Squibb Co.,
2010a).
Types of toxicity: ILD, pulmonary fibrosis

Pulmonary toxicity onset is characterized by an interval of 6
months or longer from the start of therapy with cumulative doses of lomustine usually > 1,100 mg/m2 (Bristol-Myers Squibb
Co., 2010a).
Delayed-onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received nitrosoureas in childhood and early adolescence (116 years)
combined with cranial irradiation for intracranial tumors

Monitor high-risk patients
with PFTs.
Plant
alkaloids
Docetaxel
Nondose-related interstitial pneumonitis with pulmonary fibrosis occurs in approximately 3%5% of cases, most often manifesting 48 weeks after exposure
(Leimgruber et al., 2006; sanofi-aventis U.S. LLC,
2013; Tamiya et al., 2012).
Progression to pulmonary fibrosis occurs in < 1% of
patients (Lee et al., 2009).
Incidence of ILD is higher (up to 47%) when drug is
given with gemcitabine (King & Jett, 2013).
Pleural effusion is more common after cumulative
dose of 400 mg/m2 if no steroid premedications
were given. Incidence is reduced from 20% to 6%
with steroid premedications (Binder et al., 2011).

ILD, pleural effusion, noncardiogenic pulmonary edema (King
& Jett, 2013)
Usual steroid dose to prevent pleural effusions is dexamethasone 48 mg the day prior or same day as docetaxel administration (King & Jett, 2013).
Bronchoalveolar lavage in early lung toxicity showed lymphocytosis in cases of reported hypersensitivity pneumonitis (Syrigou et al., 2011).
Pleural effusions may be

reversible with diuretics
(sanofi-aventis U.S. LLC,
2013).
Pulmonary fibrosis is not
consistently responsive
to corticosteroids (sanofiaventis U.S. LLC, 2013).
Etoposide
Cases of pulmonary events have been reported infrequently: pneumonitis/pulmonary fibrosis, pulmonary hypertension in < 1% of patients (Bristol-Myers
Squibb Co., 2011b).
Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea, and/or
hypotension have occurred in 0.7%4% of patients
receiving IV etoposide and in < 1% of patients treated with oral capsules (Bristol-Myers Squibb Co.,
2011b; Post et al., 2007).
Incidence of ILD is as high as 24% when drug is given
with methotrexate and cyclophosphamide.
Types of toxicity: Bronchospasm, interstitial pneumonitis, pulmonary fibrosis, pulmonary hypertension

Anaphylactic-like reactions have occurred during the initial infusion of etoposide. Facial/tongue swelling, coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm, back pain,
and/or loss of consciousness have occurred with aforementioned reactions. An apparent hypersensitivity-associated apnea has been reported rarely.
Toxicity is increased with low serum albumin and impaired renal
function (Bristol-Myers Squibb Co., 2011b).
Increased methotrexate blood levels when given concomitantly,
but unclear whether this is due to etoposide interaction or decreased clearance (Charpidou et al., 2009).
Higher rates of anaphylactic-like reactions have been

reported in children who
received infusions at concentrations higher than
those recommended. The
role of concentration of infusion (or rate of infusion)
in the development of anaphylactic-like reactions is
uncertain.
Treatment is symptomatic
(Bristol-Myers Squibb Co.,
2011b).
303
Nitrosoureas
(cont.)
304

Classification
Targeted
therapies:
mTOR
inhibitors
Incidence
Etoposide
(cont.)
Comments
PET scintigraphy may demonstrate clear ventilation
abnormalities with etoposide pulmonary toxicity
(Post et al., 2007).
Rechallenge with agent has
been done with premedications without repeat of
bronchospasm (Collier et
al., 2008).
Paclitaxel
Rare for single agent: 2% dyspnea

Rare reports of interstitial pneumonia, lung fibrosis,
and pulmonary embolism (Bristol-Myers Squibb Co.,
2011f): 8.5%9% with combined therapy
Events usually occur with high doses or in combined
therapy (Bristol-Myers Squibb Co., 2011f).

pulmonary fibrosis, radiation recall (King & Jett, 2013)
Rare reports exist of radiation pneumonitis recall phenomenon
in patients receiving concurrent radiation (Bristol-Myers Squibb
Co., 2011f; Ding et al., 2011).
Incidence may be higher in weekly rather than every-three-week
dosing (King & Jett, 2013).
Incidence is higher when administered with gemcitabine or radiation (King & Jett, 2013).
Bronchoalveolar lavage in early lung toxicity showed lymphocytosis in cases of reported hypersensitivity pneumonitis (Syrigou et al., 2011).
Toxicity is rarely severe or

fatal and often responds
to corticosteroids (King &
Jett, 2013).
Vinorelbine
tartrate
Shortness of breath was reported in 3% of patients receiving vinorelbine and was severe in 2% (Goli et
al., 2011).
Rare but severe cases of ILD, most of which were fatal, occurred in patients treated with single-agent
vinorelbine (Mayne Pharma, 2002).
Types of toxicity: Bronchospasm, ILD

Acute shortness of breath and severe bronchospasm occurred,
most commonly when vinorelbine was used in combination
with mitomycin; these adverse events may require treatment
with supplemental oxygen, bronchodilators, or corticosteroids,
particularly when there is preexisting pulmonary dysfunction.
The mean time to onset of these symptoms after vinorelbine administration was 1 week (range = 38 days) (Mayne Pharma, 2002).
Patients with alterations in

their baseline pulmonary
function or with new onset of dyspnea, cough,
hypoxia, or other symptoms should be evaluated promptly (Mayne Pharma, 2002).
Everolimus
Up to 20% of patients experience a cough of unknown

clinical significance while receiving everolimus (Novartis Pharmaceuticals Corp., 2012).
The most common significant respiratory toxicity is
ILD, occurring in 14%19% of patients, of which 4%
were grade 3 and 0.2% were grade 4 (Dabydeen et
al., 2012; Novartis Pharmaceuticals Corp., 2012).
Pleural effusions occur in 7% of patients receiving
everolimus (Novartis Pharmaceuticals Corp., 2012).
Rare reports (< 0.2%) exist of alveolar hemorrhage
associated with everolimus therapy (Depuydt et al.,
2012; Mizuno et al., 2012; Vandewiele et al., 2010).
Types of toxicity: Cough, ILD, diffuse alveolar hemorrhage, organizing pneumonia
Acute onset of respiratory

distress warrants immediate discontinuation of medication with diagnostic testing.
Plant
alkaloids
(cont.)
Drug

Classification
Incidence
Comments
Targeted
therapies:
mTOR
inhibitors
(cont.)
Temsirolimus
Incidence is 1%36% of patients treated for renal cell

cancer (Duran et al., 2006; Mizuno et al., 2012; Vahid & Marik, 2008).
Cases of ILD, some resulting in death, have occurred. Some patients with ILD were asymptomatic and others presented with
symptoms (Dabydeen et al., 2012; Wyeth Pharmaceuticals,
2012).
Some patients with ILD required discontinuation of

temsirolimus and treatment
with corticosteroids or antibiotics.
Targeted
therapies:
Multitargeted
kinase
inhibitor
Crizotinib
ILD is rare, occurring in approximately 1.6% during registration trials, but potentially life threatening
(Pfizer Inc., 2013c).
Type of toxicity: ILD

ILD presents as dyspnea with pulmonary infiltrates. All cases
of ILD presented within the first two months of crizotinib therapy (Pfizer Inc., 2013c). Reports of dyspnea warrant temporary discontinuation of agent until ILD can be ruled out (Kwon
& Meagher, 2012).
Coadministration of other
pulmonary toxic agents or
lung irradiation warrants
frequent physical assessment and diagnostic tests
such as imaging or PFTs.
If treatment-related ILD is
strongly suspected, permanent discontinuation of
crizotinib is recommended.
Targeted
therapies:
Tyrosine
kinase
inhibitors
Dasatinib
Pleural effusion occurred in approximately 35% of patients across multiple studies (Bristol-Myers Squibb
Co., 2011e; Quints-Cardama et al., 2007).
ILD and pulmonary VOD are rare but can be fatal (Min
et al., 2011; Montani et al., 2012).
Types of toxicity: ILD, pleural effusion, pulmonary VOD (Barber &

Ganti, 2011; Montani et al., 2012)
Most effusions are exudative and characterized by lymphocytic infiltration of the pleura (Bergeron et al., 2007; Bristol-Myers
Squibb Co., 2011e).
Most patients who develop grades 3 and 4 pleural effusions
have accelerated- or blast-phase chronic myeloid leukemia
(Quints-Cardama et al., 2007).
Pleural effusion is more prevalent in twice-daily dosing (QuintsCardama et al., 2007).
Symptoms include dyspnea, cough, and chest pain (Bergeron et
al., 2007; Bristol-Myers Squibb Co., 2011e).
Most pleural effusions are reversible but may recur with

future treatment (Barber &
Ganti, 2011; Bergeron et
al., 2007).
Treatment may include interruption of medication
and administration of diuretics or corticosteroids
(Bergeron et al., 2007;
Quints-Cardama et al.,
2007).
Erlotinib
Incidence is rare (< 1%) except when the drug is given in combination with gemcitabine, where incidence
is approximately 2.5% (Astellas Pharma US, Inc., &
Genentech, Inc., 2012; Vahid & Marik, 2008).
Types of toxicity: ILD, pulmonary fibrosis, organizing pneumonia

Fatal ILD has been associated with oral erlotinib therapy for
lung cancer (Hotta et al., 2010; Liu et al., 2007; Vahid & Marik,
2008). Can occur days to months after exposure.
Some patients have shown

clinical improvement with
corticosteroid treatment
(De Sanctis et al., 2011;
Vahid & Marik, 2008).
Strong suspicion of erlotinibinduced lung injury warrants discontinuation of the
drug (Astellas Pharma US,
Inc., & Genentech, Inc.,
2012).
305
Drug
306

Classification
Topoisomerase inhibitor
Incidence
Comments
Gefitinib
Cases of ILD have been observed in patients at an

overall incidence of 1%3%, the highest incidence of
all tyrosine kinase inhibitors (Hotta et al., 2010).
Approximately one-third of the ILD cases have been
fatal (Min et al., 2011).
Reports indicate that ILD has occurred in patients
who have received prior radiation therapy (31%), prior chemotherapy (57%), and no previous therapy
(12%) (AstraZeneca Pharmaceuticals, 2010).
Incidence of ILD with gefitinib is increased among
smokers, older adults, and those with chronic lung
disease, poor performance status, or concurrent cardiac disease (Barber & Ganti, 2011).
Types of toxicity: ILD, diffuse alveolar hemorrhage, pulmonary fibrosis, organizing pneumonia
Patients often present with acute-onset dyspnea, sometimes associated with cough or low-grade fever and often becoming severe quickly and requiring hospitalization.
Increased mortality has been observed in patients with concurrent idiopathic pulmonary fibrosis whose condition worsens
while receiving gefitinib (AstraZeneca Pharmaceuticals, 2010).
Alveolar hemorrhage presents within 2442 days after administration (Barber & Ganti, 2011).
If acute onset or worsening

of pulmonary symptoms
(dyspnea, cough, and fever) occurs, therapy should
be interrupted and symptoms promptly investigated. If ILD is confirmed, discontinue.
Corticosteroids are of uncertain benefit with ILD but are
routinely administered.
Imatinib
mesylate
Severe superficial edema and severe fluid retention

(pleural effusion, pulmonary edema, and ascites)
were reported in 1%6% of patients taking imatinib
for gastrointestinal stromal tumors (Vahid & Marik,
2008).
Dyspnea was reported in 14%15% of patients.
Interstitial pneumonitis and pulmonary fibrosis are rare
(Novartis Pharmaceuticals Corp., 2013).
Types of toxicity: Dyspnea of uncertain significance, hypersensitivity pneumonitis, noncardiogenic pulmonary edema, ILD, pulmonary alveolar proteinosis, pleural effusions
Fluid retention events include pleural effusion, ascites, pulmonary edema, pericardial effusion, and anasarca. Differentiation
of these as complications of disease or therapy was difficult to
ascertain (Ishii et al., 2006).
Fluid extravasation and pleural effusions appear to be dose related, were more common in the blast crisis and acceleratedphase studies (where the dose was 600 mg/day), and were
more common in older adults (Vahid & Marik, 2008). However,
a few of these events may be serious or life threatening, and
one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure (Deininger et al., 2003; Novartis Pharmaceuticals Corp., 2013).
These events usually were

managed by interrupting
imatinib mesylate treatment
and using diuretics or other
appropriate supportive care
measures. Symptoms often
resurface when rechallenging with this agent (Vahid &
Marik, 2008).
The overall safety profile in
pediatric patients (39 children studied) was similar to that found in studies of adult patients treated with imatinib; however,
no peripheral edema has
been reported in children
(Novartis Pharmaceuticals
Corp., 2013).
Topotecan
hydrochloride
The incidence of grade 3 or 4 dyspnea was 4% in patients with ovarian cancer and 12% in patients with
small cell lung cancer (GlaxoSmithKline, 2008a).
Pulmonary fibrosis may occur, but there is only one
documented pathologic confirmation of this complication (Maitland et al., 2006).
Dyspnea, all grades: 22% (GlaxoSmithKline, 2008a)
Dyspnea, coughing, and pneumonia are the main pulmonary

side effects (GlaxoSmithKline, 2008a).
ARDSadult respiratory distress syndrome; ATRAall-trans-retinoic acid; CTcomputed tomography; DLCOdiffusing capacity of the lung for carbon monoxide; FiO2fraction of inspired oxygen; 5-FU/LV5-fluorouracil/leucovorin; HSCThematopoietic stem cell transplantation; IFNinterferon; ILinterleukin; ILDinterstitial lung disease; IVintravenous; mTORmammalian target of rapamycin; PETpositron-emission tomography; PFTpulmonary function test; POby mouth; VEGFvascular endothelial growth factor; VODveno-occlusive disease; WBCwhite blood cell
Targeted
therapies:
Tyrosine
kinase
inhibitors
(cont.)
Drug
(5) Risk factors for direct injury

(a) Rare reports of interstitial pulmonary infiltrates and acute
alveolitis with hydroxyurea
(b) Metabolic injury
i. Metabolites of cyclophosphamide cause acute pneumonitis that may be hemorrhagic in nature. The mortality rate associated with this syndrome is approximately 50% (Specks, 2012).
ii. Renal dysfunction may cause delayed drug excretion
and increase pulmonary toxicity of cyclophosphamide
and bleomycin (Specks, 2012).
(c) Disruption of intracellular kinases
i. Tyrosine kinase inhibitors (e.g., gefitinib, erlotinib)
(Endo, Johkoh, Kimura, & Yamamoto, 2006; Ieki,
Saitoh, & Shibuya, 2003; Vahid & Marik, 2008)
ii. EGFR inhibitors (e.g., cetuximab)
iii. mTOR inhibitors (e.g., temsirolimus) (Barber & Ganti,
2011; Dabydeen et al., 2012; Duran et al., 2006; Klastersky, 2006; Novartis Oncology U.S., n.d.)
(d) Pulmonary edema
i. Biologic agents cause this toxicity (Antoniou, Ferdoutsis, & Bouros, 2003; Schwartzentruber, 2005). IL-2 is
associated with a high incidence of capillary leak syndrome. Pulmonary edema is a dose-limiting toxicity
of high-dose IL-2 therapy (Prometheus Laboratories,
Inc., 2012). Severity depends on the route, dose, and
administration schedule (Schwartzentruber, 2005). It
resolves quickly after therapy ends and diuresis begins.
ii. Docetaxel is associated with fluid retention, alveolar
permeability, and pulmonary infiltrates. This may be
prevented with corticosteroid premedication and is
treated with diuretics (King & Jett, 2013).
iii. Cytosine arabinoside (Forghieri et al., 2007)
iv. Leuprolide acetate (Ferrari, Pezzuto, & Coppola, 2007)
v. Tyrosine kinase inhibitors (e.g., bortezomib, gefitinib,
dasatinib, imatinib mesylate) cause capillary permeability, pulmonary edema, and effusions (Miyakoshi et
al., 2006; Vahid & Marik, 2008).
(e) Hypersensitivity pneumonitis
i. Paclitaxel can cause acute pneumonitis, which no longer appears to be a hypersensitivity reaction to polyoxyl 40 hydrogenated castor oil (Kolliphor EL, formerly Cremophor EL) emulsifier as originally postulated (King & Jett, 2013).
ii. Docetaxel: Hypersensitivity pneumonitis occurs in
7%47% depending on total dose, chemotherapy
schedule, and concurrent administration with gemcitabine or radiation (Grande, Villanueva, Huidobro,
& Casal, 2007).
iii. Acute methotrexate reaction is likely allergic in origin (Balk, 2012; Davis, Williams, & Walker, 2003; Lateef, Shakoor, & Balk, 2005).
iv. Pathologically confirmed hypersensitivity pneumonitis has occurred with bortezomib, imatinib, lenalidomide, oxaliplatin, procarbazine, and thalidomide, but no clear etiologic mechanisms have been
identified.
307
308
d) Clinical manifestations: May be difficult to detect when clinical manifestations are subtle
(1) Signs and symptoms
(a) Dyspnea
(b) Tachypnea
(c) Increased work of breathing
(d) Dry, nonproductive cough
(e) Fever occurs in some types of ILD
(f) Hypoxemia: Cyanosis, low oxygen saturation
(g) Anxiety, uneasiness
(h) Weight loss
(i) Fatigue
(2) Timing of signs and symptoms
(a) Hypersensitivity reactions may occur as early as hours after exposure.
(b) Hypersensitivity pneumonitis occurs 710 days after exposure.
(c) Methotrexate hypersensitivity reactions occur 1218 hours
after first dose (Balk, 2012).
(d) Delayed toxicity may occur 8 months to 10 years after therapy.
e) Assessment
(1) Past medical history
(a) Chemotherapy and biotherapy drug exposure
(b) Other medications known to cause pulmonary toxicity (e.g.,
amiodarone, nitrofurantoin, penicillamine, phenytoin, procainamide, propranolol, statins, sulfonamides) (Chernecky,
2009; Merrill, 2013; Vahid & Marik, 2008; Xu et al., 2012)
(c) Recent or chronic pulmonary conditions (Klastersky, 2006)
(d) Recent viral illness that predispose to hemorrhagic airway disease
(e) Autoimmune or connective tissue disease (Chernecky, 2009;
King, 2012; Varga, 2007)
(f) Occupational exposures such as silica, dusts, coal, and cotton
(Chernecky, 2009; Daba, El-Tahir, Al-Arifi, & Gubara, 2004)
(g) Environmental exposures such as asbestos, gases, and dusts
(Chernecky, 2009; Daba et al., 2004)
(2) Physical examination
(a) Vital signstachypnea, tachycardia
(b) Crackles on auscultation
(c) Cough and sputum production; hemoptysis
(d) Pleuritic pain may accompany some disorders (e.g., erlotinib-induced reactions)
(e) Accessory muscle use for breathing
(f) Evidence of poor tissue oxygenationcyanosis, oliguria,
decreased bowel sounds, altered mentation
(3) Diagnostic tests
(a) Arterial blood gases usually show hypoxemia with respiratory alkalosis.
(b) Changes suggesting pulmonary edema were observed in radiographs of patients receiving high-dose IL-2 during initial registration trials, but the incidence of this toxicity
has been minimized with careful assessment and management of hypotension and cardiac dysfunction (Berthiaume
et al., 1995; Prometheus Laboratories Inc., 2012; Siegel &
Puri, 1991).
(c) Chest x-ray showed ground-glass opacities/infiltrates and
interstitial or alveolar thickening of interlobular septum
(Endo et al., 2006; Stark, 2012). Nodular patterns indicated fibrosis (Stark, 2012).
(d) Chest CT is highly sensitive and able to differentiate pneumonitis from pulmonary embolism or fibrosis that may occur in patients with cancer experiencing respiratory distress
(Endo et al., 2006; Forghieri et al., 2007).
(e) A sensitive test of pulmonary function is the carbon monoxide diffusing capacity, which is reduced prior to symptoms
in many patients (Bahhady & Unterborn, 2003).
(f) Serum markers KL-6, SP-A, and SP-D have been used as
indicators of ILD for some agents (e.g., gefitinib) (Kitajima et al., 2006).
(g) PET scintigraphy has been helpful for early diagnosis of pulmonary fibrosis related to etoposide (Post, Grutters, Verzijlbergen, & Biesma, 2007).
(h) Open lung biopsy provides definitive diagnosis.
f) Collaborative management
(1) Pulmonary function testing is a prerequisite for the following
patients being evaluated for biotherapy, particularly for treatment with IL-2 (Letizia & Conway, 1996; Prometheus Laboratories Inc., 2012).
(a) Heavy smokers (> 10 cigarettes/day) (Fernander, Schu
macher, Wei, Crooks, & Wedlund, 2008)
(b) Patients with extensive pulmonary disease
(c) Patients with symptoms suggesting decreased pulmonary reserve such as exercise intolerance, new cough, or tachypnea
(2) Avoid exceeding maximum recommended doses.
(a) Bleomycin: 400 units total lifetime dose (Bristol-Myers
Squibb Co., 2012a; Gilligan, 2012)
(b) Mitomycin C: 30 mg/m2 (Chan & King, 2012c)
(3) If pulmonary toxicity is suspected, hold chemotherapy and notify prescriber.
(4) Administer oxygen cautiously and only if patient is hypoxemic
(Chernecky, 2009).
(a) Some lung-toxic medications have produced increased toxicity (diffuse alveolar damage) with oxygen therapy (e.g.,
bleomycin).
(b) Oxygen can cause absorption atelectasis and loss of surfactant that may exacerbate toxicity risk.
(5) Establish fluid balance goals.
(a) Carefully record intake and output.
(b) Determine if fluid boluses or fluid restrictions are warranted.
(c) Consider using goal dry weight to target diuretic therapy. Weigh patient on a regular basis.
(d) Diuretics decrease parenchymal edema, drawing fluid from
interstitial spaces. This is not always effective when capillary permeability is impaired and cell and vessel boundaries have been compromised.
(6) Supportive care
(a) Oxygen therapy: When using bleomycin, be alert for oxygen-induced lung damage (Fyfe & McKay, 2010; Gilligan, 2012).
(b) Bronchodilators: Metered dose inhaler provides better delivery than nebulizer.
(c) Position for best breathing: Head of bed elevated, tripod
position (arms elevated and extended with knees separated while leaning forward), legs over side of bed
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(7) Treatment of possible etiologies of ILD

(a) Administer corticosteroids as ordered. Corticosteroids usually are contraindicated for patients receiving biotherapy.
(b) Initiate antimicrobial therapy when infection superimposed
upon other lung toxicity is suspected.
(c) Oral carnosine has been reported as suggestive of reduced
incidence or severity of bleomycin toxicity based upon an
animal study (Cuzzocrea et al., 2007).
(8) Follow-up evaluation of patients at risk
(a) Monitor x-rays and CT scans routinely with disorders that
can produce hypersensitivity, idiopathic, or nondoserelated toxicities.
i. For targeted therapies (erlotinib, cetuximab, rituximab) recommend at least monthly (Gemma, 2009).
ii. Frequency is based on risk for ILD and may increase
with cumulative dose or added risk factors.
iii. A chest x-ray may be recommended every one to two
weeks to monitor for bleomycin toxicity (Bristol-Myers
Squibb Co., 2012a).
(b) Periodic monitoring of pulmonary function tests for patients at risk for ILD (baseline and every three months during active therapy; often performed years after HSCT) (AlAshkar, Mehra, & Mazzone, 2003; Chernecky, 2009; McCormack, 2013). Most ILD produces restrictive disease. The ratio of forced expiratory volume in one second to forced vital capacity is most sensitive to detect restrictive disease. Ratios greater than the lower limit of normal indicate restrictive
lung disease. Low forced vital capacity with normal forced expiratory volume in one second and total lung capacity below
the lower limit of normal suggests restrictive lung disease.
(c) Low diffusing capacity of the lung for carbon monoxide
(DLCO) corrected for Hgb and lung volume indicates parenchymal restrictive disease. DLCO may differentiate parenchymal restrictive disease associated with chemotherapy agents from other physical causes (e.g., obesity, pleural effusions). It is used more frequently to detect pulmonary fibrosis.
(d) In patients with acute-onset symptomatic disorders such
as alveolar hemorrhage or acute hypersensitivity reaction, screening is not performed given the usual acute
presentation.
(e) Late or delayed onset of lung toxicity may occur and be related to treatment and host factors, but plans for follow-up
care are not clearly defined (Tashiro et al., 2008).
g) Patient and family education (Camp-Sorrell, 2011)
(1) Provide education regarding symptoms associated with pulmonary toxicity (e.g., cough, dyspnea, chest pain, shallow breathing, chest wall discomfort). Make sure all patients know to seek
medical assistance immediately if symptoms occur.
(2) Inform patients that treatment may be delayed or held until
pulmonary symptoms resolve.
(3) Explore with patients their wishes regarding intubation and resuscitation status; establish advance directives.
(4) Teach patients that raising the head of the bed may facilitate
breathing.
(5) Instruct patients to conserve energy by performing daily activities when their energy level is highest.
(6) Teach patients and significant others methods to decrease symptoms of dyspnea (e.g., exercising to tolerance, practicing pursedlip breathing, refraining from smoking, using a small fan).
(7) Teach patients to take an opioid (e.g., morphine) as prescribed
by their physician to relieve discomfort caused by air hunger.
(8) Review the safety issues (e.g., flammability) related to oxygen
administration.
5. Alveolar hemorrhage
a) Pathophysiology
(1) Unlike tumor invasion of the upper airways, alveolar hemorrhage as a toxicity of antineoplastic therapy occurs in the microvasculature of small airways. Three types exist (Ikpeama &
Bailes, 2012).
(a) Bland pulmonary hemorrhage occurs due to hydrostatic pressure changes and is most common with coagulopathies, anticoagulant therapy, heart failure, or renal failure.
(b) Diffuse alveolar hemorrhage occurs as a result of direct
lung injury causing alveolar edema and development of
hyaline membranes. Toxic metabolites from cyclophosphamide and gemcitabine produce lung toxicity by this
mechanism.
(c) Pulmonary/capillary vasculitis is an autoimmune process resulting in the fibrinous destruction of alveolar basement
membranes. It is caused by agents that trigger immunologic mechanisms (e.g., rituximab).
(2) Vascular endothelial wall destruction by chemotherapy or chemoradiotherapy causes microcapillary bleeding.
(3) Repeated episodes of alveolar hemorrhage may lead to pulmonary fibrosis.
b) Incidence: Alveolar hemorrhage incidence rates are 1.9% in patients receiving nonmyeloablative transplant regimens (Wanko,
Broadwater, Foltz, & Chao, 2006), as high as 10.3% in those undergoing myeloablative HSCT (Majhail, Parks, DeFor, & Weisdorf,
2006; Wanko et al., 2006), and < 5% in pediatric transplant recipients (Heggen et al., 2002). More current data are limited given
the heterogeneity of transplant preparative regimens and rejection
protection practices.
c) Risk factors
(1) Alveolar hemorrhage is most well-documented in the setting
of HSCT, although some acute pneumonitis syndromes may
be hemorrhagic in nature (Alexandrescu et al., 2004; Carron
et al., 2001; Lin et al., 2005).
(2) Alveolar hemorrhage has been rarely associated with normal
doses of bevacizumab, cyclophosphamide, etoposide, everolimus, gefitinib, gemcitabine, oxaliplatin, and sirolimus (Depuydt
et al., 2012; Lara & Schwarz, 2010; Patel et al., 2010; Vahid &
Marik, 2008; Vandewiele, Vandecasteele, Vanwalleghem, & De
Vriese, 2010).
(3) Concomitant pulmonary infection may be present with adenovirus, cytomegalovirus, dengue fever, Epstein-Barr virus, and
Strongyloides (parasite) (Lara & Schwarz, 2010).
(4) Non-oncologic drugs can cause alveolar hemorrhage (e.g., amiodarone, crack cocaine, nitrofurantoin, propylthiouracil, valproate) (Ikpeama & Bailes, 2012; Lara & Schwarz, 2010).
(5) Unlike other bleeding syndromes, pulmonary hemorrhage is
not always related to platelet counts or coagulation values.
d) Clinical manifestations (Ikpeama & Bailes, 2012; Lara & Schwarz, 2010)
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(1) Onset of bleeding is often sudden, over a single day. It usually begins within the first two weeks after the preparative regimen of HSCT.
(2) Symptoms include dyspnea, fever, cough, chest discomfort, and
profound hypoxemia.
(3) Hemoptysis occurs in up to one-third of patients. Pink, frothy
sputum and blood in bronchoalveolar specimens may be found
(Lara & Schwarz, 2010).
(4) Hypoxemia-related symptoms include agitation, confusion, air
hunger, cyanosis, tachycardia, and bradycardia.
e) Assessment
(1) Breath sounds (early crackles and diminished breath sounds as
the airways become filled with bloody exudate)
(2) Oxygen saturation (decreased)
(3) Sputum (increase in quantity and change in quality)
(4) Hgb, platelet count, and coagulation parameters: Hgb may not
fall until bleeding is life threatening.
(5) Nonspecific findings of inflammation: Increased erythrocyte
sedimentation rate, leukocytosis (if not marrow suppressed)
(6) Pulmonary function tests (increased DLCO with hypoxemia) if
patient is able to participate
(7) Chest x-ray or CT scan: Bilateral patchy, irregular interstitial
infiltrates
(8) Bronchoalveolar lavage: Bloody returns, higher yield than instilled, and positive hemosiderin-laden macrophages in the sputum (Lara & Schwarz, 2010; Vahid & Marik, 2008).
(1) Corticosteroids are standard treatment, although they have not
been proved effective in treatment of medication-induced alveolar hemorrhage (Grigoriyan, Rishi, Molina, Homer, & Manthous, 2007; Lara & Schwarz, 2010).
(a) Methylprednisolone at doses of 5002,000 mg IV daily for
approximately five days
(b) No standard tapering regimen is recommended. Close observation for rebleeding during steroid tapering is recommended to guide practice.
(2) Coagulation factors can be administered, although no one therapy has been proved effective (Grigoriyan et al., 2007). Unproven coagulation therapies include IV aminocaproic acid and coagulation factor VII (Heslet, Nielson, & Nepper-Christensen,
2012; Lara & Schwarz, 2010).
(3) Consider noninvasive or invasive mechanical ventilation with
positive pressure to produce intra-alveolar pressure and reduce bleeding.
(4) Experimental therapies are based upon suspected etiologic
factor and include plasma exchange and IV immunoglobulin
(Lara & Schwarz, 2010).
(5) Ensure adequate airway clearance with bronchodilator therapy, adequate hydration, and deep endotracheal suctioning as
needed. Retained blood can cause secondary infection and
worsened hypoxemia.
(6) Provide supportive management of dyspnea.
6. APL differentiation syndrome/retinoic acid syndrome
a) Pathophysiology
(1) Occurs with APL (M3 leukemia), previously known as retinoic
acid syndrome because of its association with administration of
ATRA, but the name was changed as it was realized that the synCopyright 2014 by the Oncology Nursing Society. All rights reserved.
drome occurs with any effective initial treatment for APL (Au
& Kwong, 2008; Fenaux, Wang, & Degos, 2007).
(2) Caused by rapid proliferation and differentiation of WBCs.
This results in immunologic stimulation by vasoactive cytokines,
thus creating inflammatory capillary permeability of the lungs
and a widespread erythematous rash (Ahmed et al., 2007; Bi &
Jiang, 2006; Weinberger & Larson, 2012).
(3) It is more a condition of tumor responsiveness to therapy than
a toxicity.
b) Incidence
(1) It occurs in approximately 25% of patients with APL receiving
induction therapy (Weinberger & Larson, 2012). It also has occurred in other settings of retinoid administration, emphasizing the need for monitoring when administering any retinoid
or differentiating agent (DiNardo et al., 2008).
(2) It has been reported to occur in 10%15% of patients receiving combination retinoid and chemotherapy and is more prevalent in patients with high WBC counts (Fenaux et al., 2007;
Luesink et al., 2009).
c) Risk factors (Au & Kwong, 2008; Breccia et al., 2012; Fenaux et al.,
2007; Jeddi et al., 2008; Luesink et al., 2009; Montesinos et al., 2009;
Montesinos & Sanz, 2011; Weinberger & Larson, 2012)
(1) Increased body mass index; only validated risk factor that predicts
for presence of syndrome (Breccia et al., 2012; Jeddi et al., 2008)
(2) Induction therapy with active disease; does not occur during
consolidation therapy when there is no active leukemia
(3) High WBC count may or may not be associated with increased
risk, but it is clear that rapid rise of WBC count, or large percentage of immature cells, is related to the presence of retinoic acid syndrome (Weinberger & Larson, 2012).
(4) Acute leukemia, M3 subtype, expression of CD13 on APL blast
cells
(5) ATRA treatment
(6) Arsenic trioxide
(7) Bortezomib
d) Clinical manifestations (Montesinos et al., 2009; Montesinos & Sanz,
2011; Weinberger & Larson, 2012)
(1) Fever, dyspnea, cough, hypotension, crackles, hypoxemia, musculoskeletal pain (e.g., arthralgias, myalgias), effusions, edema,
weight gain > 5 kg from baseline
(2) Rash can be diffuse, erythematous, and nonpruritic and is more
common in severe cases (Weinberger & Larson, 2012).
(3) Renal dysfunction may occur but is often slower in onset than
other symptoms, so may be noted after recognition of the syndrome.
(4) About one-half of patients have symptoms within one week, and
the rest develop symptoms between the third and fourth week
of induction therapy (Montesinos et al., 2009).
(5) NCI toxicity scale labels weight gain < 3 kg without respiratory
distress as grade 1, weight gain with mild-moderate respiratory
symptoms grade 2, severe symptoms requiring hospitalization
as grade 3, symptoms requiring ventilatory support as grade 4,
and death as grade 5 (NCI CTEP, 2010).
e) Assessment
(1) Breath sounds and oxygen saturation
(2) Intake and output, weight; monitor for overhydration, which
may worsen respiratory symptoms.
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(3) Laboratory
(a) WBC count with differential daily; assessment of blast percentage
(b) Periodic assessment of Hgb, Hct, and platelet count, as anemia and thrombocytopenia are common
(c) Periodic evaluation of coagulation parameters and platelet count; DIC may be present.
(d) Renal function tests to monitor for impairment; it is unclear if dysfunction is related to hypotension or thrombosis (Weinberger & Larson, 2012).
(4) Chest x-ray or CT: Nodular or ground-glass opacities with patchy
bilateral distribution, consolidation, air bronchograms, prominent septal lines, and possible pleural effusions, although up to
40% of patients will have no initial x-ray findings of peribronchial cuffing and increased cardiothoracic ratio (Luesink &
Jansen, 2010; Montesinos, 2009; Weinberger & Larson, 2012).
(1) Prevention
(a) Immediate administration of chemotherapy when WBC
count rises
(b) Platelet goal 50,000/mcl
(c) Fluid management (strict intake and output)
(2) Although the clinical benefit is still unclear, immediate treatment with corticosteroids (Tallman & Altman, 2009) and conventional chemotherapy are still believed by some to improve
outcomes.
(a) Dexamethasone, which usually inhibits inflammatory chemokines, does not appear to be effective in reduction of this
syndromes clinical manifestations (Luesink et al., 2009).
(b) If treatment with steroids is selected, the usual treatment is
dexamethasone 10 mg IV twice daily for at least three days
(Patatanian & Thompson, 2008).
(c) Even with steroid treatment, the syndrome carries an approximate 10% mortality rate (Ahmed et al., 2007; Fenaux
et al., 2007).
(3) Noninvasive or invasive mechanical ventilation with positive
pressure
(4) Removal of pleural or pericardial effusions
7. Pleural effusions: Defined as accumulation of excess fluid in the pleural space that impairs lung expansion. Four to six liters of pleural fluid
usually pass daily through the potential space between the visceral and
parietal pleura (Light, 2011).
a) Pathophysiology: Excess fluid is retained in the pleural space, which
restricts full alveolar expansion (Light, 2011; Muzumdar, 2012).
(1) Major causes of pleural effusion are obstruction to fluid outflow and pleural irritation leading to exudative capillary permeability into the space (Muzumdar, 2012).
(2) Transudative effusions are produced by passive capillary permeability and characteristic of fluid overload, heart failure, or
hypothyroidism.
b) Incidence of drug-related pleural effusions (Alagha, Tummino, Sofalvi, & Chanez, 2011; Light, 2011)
(1) Incidence varies and is dependent upon agent, dose, schedule,
and comorbid conditions.
(2) Pleural effusions can be detected radiographically in 42%52%
of patients receiving IL-2. In general, no intervention is required,
and effusions resolve after IL-2 is discontinued (Shelton, 2009b).
(3) Incidence can be as high as 54% with some agents (Kim, Goh, Kim,
Cho, & Kim, 2011; Quints-Cardama et al., 2007; Valent, 2011).
c) Risk factors
(1) Pleural effusions are a common complication of cancer and other medical disorders, such as cirrhosis, gout, heart failure, infections, pneumonia, pulmonary embolism, renal failure, rheumatoid conditions, or hypothyroidism, and medications such as
valproate and clozapine (Findik, 2012; Light, 2011).
(2) When associated with chemotherapy and biologic therapies,
pleural effusions are the result of capillary permeability that
is temporally related to administration of the offending agent.
Chemotherapy and biotherapy agents that have been associated with development of pleural effusions include (Alagha et al.,
2011; Krenke & Light, 2011)
(a) Bortezomib (Oudart et al., 2012; Pitini, Arrigio, Altavilla,
& Naro, 2007)
(b) Cytosine arabinoside
(c) Cyclophosphamide (high-dose)
(d) Dasatinib (Bergeron et al., 2007; Ishii, Shoji, Kimura, & Ohyashiki, 2006; Kim et al., 2011; Quints-Cardama et al., 2007)
i. Onset 155 days, average 35 days
ii. Increased incidence with twice-daily dosing and higher daily dose (> 100 mg/day)
(e) Docetaxel (Toh et al., 2007)
(f) Erlotinib (Toh et al., 2007)
(g) Imatinib (2%6%) (Bergeron et al., 2007; Ishii et al., 2006;
Kantarjian et al., 2012)
(h) Oprelvekin (Kai-Feng, Hong-Ming, Hai-Zhou, Li-Rong, &
Xi-Yan, 2011; Wyeth Pharmaceuticals, 2011)
d) Clinical manifestations and assessment (Alagha et al., 2011; Light,
2011; Muzumdar, 2012)
(1) Patients present with tachypnea, dyspnea, increased work of
breathing, abnormal chest excursion, and fatigue.
(2) Large pleural effusions are easily documented by an upright
chest x-ray.
(3) Smaller effusions are seen on chest CT.
(4) Tyrosine kinase inhibitorinduced pleural effusions are characterized by exudative features and lymphocytic infiltration of
the pleura.
e) Collaborative management (Kaifi et al., 2012)
(1) In most cases, pleural effusions are uncomplicated and spontaneously resolve upon discontinuing the causative agent (Alagha
et al., 2011; Light, 2011; Quints-Cardama et al., 2007).
(2) Dose reduction has been successful at eliminating pleural effusion related to dasatinib (Bergeron et al., 2007; Galinsky &
Buchanan, 2009).
(3) Concomitant corticosteroids have been effective at reducing
the severity of pleural effusions related to docetaxel.
(4) Other treatment strategies have included albumin supplementation, fluid restrictions, diuretics, and corticosteroids,
but these interventions do not have a body of evidence to support use (Alagha et al., 2011; Bergeron et al., 2007; QuintsCardama et al., 2007).
(5) Medical or surgical pleurodesis is rarely required to treat druginduced pleural effusion.
(a) On rare occasions, thoracentesis has been performed as a
temporary measure or to rule out other causes of the effusion.
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(b) Tunneled or temporary pleural catheters have been used

with persistent drug-related pleural effusion (Chalhoub,
Harris, Castellano, Maroun, & Bourjeily, 2011).
8. Pulmonary alveolar proteinosis/pulmonary alveolar phospholipoproteinosis
a) Pathophysiology
(1) Distal airway disorder characterized by accumulation of lipoproteinaceous exudate with surfactant components and cell
fragments that stain positive for periodic acid-Schiff protein
(Chan & King, 2012a).
(2) The thick proteinaceous exudate causes bronchiolar occlusion,
poor respiratory compliance, and hypoxemia (Pedroso et al., 2007).
(3) Primary pathologic mechanism is likely related to GM-CSF deficiency (Doerschuk, 2007; Uchida et al., 2009). In adults, it is
thought to be due to antiGM-CSF antibodies (Bonella et al.,
2011; Carey & Trapnell, 2010).
b) Incidence: Rare
c) Risk factors (Inaba et al., 2008; Miyoshi, Daibata, Takemoto, Machida, & Taguchi, 2005; Pamuk et al., 2003; Shoji et al., 2002)
(1) After HSCT (Ansari et al., 2012; Borie et al., 2011)
(2) Autoimmune disease or concomitant autoimmune pathologic
process (e.g., autoimmune hemolytic anemia, immune thrombocytopenia) is associated with > 90% of cases (Edwards, Primhak, & Cohen, 2010; Inoue et al., 2008).
(3) Hematologic malignancies
(4) Myelodysplastic syndromes
(5) Profound neutropenia at the onset of the disorder
(6) Unclear whether disorder is caused by antineoplastic agents,
such as alkylating agents (Inaba et al., 2008) or imatinib, or
the underlying disease
(7) Infection with Acinetobacter, Pneumocystis, Nocardia, or Mycobacterium (Chan & King, 2012a; Edwards et al., 2010; Shattuck &
Bean, 2013)
d) Clinical manifestations
(1) Dyspnea, tachypnea, cough, and increased work of breathing
(2) Occurs over a few days with progressive worsening
(3) CT scan shows widespread air-space consolidation with crazypaving patterns, appearing like octagonal pavement stones
pieced together, with even bilateral distribution centrally located and sparing the apices and costophrenic angle (Bonella
et al., 2011; Chan & King, 2012b; Guan et al., 2011; Shattuck
& Bean, 2013).
(4) 75% are diagnosed by bronchoscopy (Ishii et al., 2009).
(a) Lung biopsy specimens are positive for periodic acid-schiff
stain.
(b) Lavage specimens are cloudy, with alveolar macrophages
and eosinophils.
(c) A recent study showed the presence of myelin-like lamellar bodies (Yi et al., 2012).
(5) Other markers include increased lactate dehydrogenase, carcinoembryonic antigen, and CA 19-9 (Chan & King, 2012a).
(6) The syndrome usually corrects itself when patients go into remission or recover normal WBC counts.
(7) It may be fatal in patients with persistent disease or those who
fail to recover counts (Inaba et al., 2008).
e) Collaborative management (Inaba et al., 2008; Kim, Kim, & Kim,
2004; Pamuk et al., 2003)
(1) Whole lung lavage: An operative procedure where single lung

ventilation is performed during warmed saline flushing of the
other lung; may require multiple procedures (Cai, Ye, Xu, &
Li, 2012; Luisetti et al., 2010)
(2) Antibiotics to treat causative organisms or prevent secondary
infections (Khan & Agarwal, 2011)
(3) Chest percussion
(4) Investigational use of GM-CSF subcutaneously or by inhalation
over 812 weeks (Khan & Agarwal, 2011; Khan, Agarwal, & Aggarwal, 2012; Satoh et al., 2012)
(5) Rituximab (Kavuru et al., 2011; Malur et al., 2012)
(6) Corticosteroids have been used to treat this disorder and have
a strong scientific basis validated by the inflammatory nature
of this disorder. Despite their extensive use, some authors believe them to be ineffective in altering the disease course (Chan
& King, 2012b).
(7) Hydration, sputum expectoration, and bronchodilators
9. Pulmonary VOD
a) Pathophysiology
(1) Endothelial wall damage is the proposed mechanism of injury
(Bunte, Patnaik, Pritzker, & Burns, 2008).
(2) Postcapillary pulmonary venular obstruction occurs with fibrous
tissue that becomes dense and sclerotic (Bunte et al., 2008).
(a) Calcium deposits in elastic fibers of venule walls
(b) Engorgement of alveolar capillaries
(c) Dilated lymphatics with interstitial edema
(d) Venous fibrosis
(3) The clinical result of this process is pulmonary hypertension
with right heart failure.
(4) Pulmonary VOD presents 4060 days after HSCT as hypoxemia, volume-dependent hypotension, atrial arrhythmias,
right bundle branch block, or hepatic congestion (Bunte
et al., 2008).
b) Incidence
(1) Infrequent manifestation of endothelial injury in < 2% of HSCT
recipients
(2) Likely underestimated because symptoms mimic other adverse
effects
(3) Possibly accounts for 5%10% all cases of idiopathic pulmonary hypertension (Montani, Price, et al., 2009; Palazzini &
Manes, 2008)
c) Risk factors (Bishop, Mauro, & Khouri, 2012; Bunte et al., 2008; Mandel & Clardy, 2012; McKoy et al., 2007)
(1) HSCT: Especially matched unrelated transplant recipients and
those with GVHD
(2) High-dose alkylating agents: Busulfan, carmustine, other alkylating agents used for the preparative regimen for HSCT
(3) Other agents: Dasatinib, mitomycin
(4) Prior lung injury; familial pulmonary hypertension
(5) Viral illnesses (e.g., cytomegalovirus, Epstein-Barr virus)
(6) Thrombotic disorders
d) Clinical manifestations and assessment
(1) Subtle and vague symptoms: Dyspnea, fatigue
(2) Heart failure symptoms (Mandel & Clardy, 2012; Montani,
Kemp, et al., 2009)
(a) Right heart failure early: Elevated jugular venous pressure,
hepatomegaly, edema
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318
(b) Left heart failure later: Crackles, heart murmurs and gallops, subxiphoid retraction, oliguria
(3) Definitive diagnosis requires a right heart catheterization, but
risk of bleeding is high. Elevated right heart pressures on echocardiogram may be suggestive of this disorder.
(4) CT demonstrates patchy, ground-glass, or nodular infiltrates
with perihilar distribution and engorgement of major central
pulmonary veins that are unique to pulmonary VOD, differentiating pulmonary hypertension from other causes (Bunte et
al., 2008; Huertas et al., 2011).
(5) Bronchoscopic exam shows hyperemia of lobar and segmental bronchi with vascular engorgement (Huertas et al., 2011).
e) Collaborative management
(1) Correct etiologic factors (e.g., viral infections, DIC, offending
medications).
(2) Avoid calcium channel blockers and prostacyclins (usual treatments
for pulmonary hypertension), which can cause pulmonary edema in pulmonary VOD (Bishop et al., 2012; Huertas et al., 2011).
(3) Nitric oxide, prostanoids, endothelin-1 receptor antagonists,
and phosphodiesterase inhibitors have been used with limited success (Bishop et al., 2012; Huertas et al., 2011; Montani,
OCallaghan, et al., 2009).
(4) If there is an autoimmune component (e.g., GVHD), corticosteroids may be beneficial (Bunte et al., 2008).
(5) Anticoagulant, antiplatelet, and fibrinolytic agents used with
hepatic VOD have not been proved effective and may increase
bleeding risk (Mandel & Clardy, 2012).
(6) Most documented cases have been fatal (Bunte et al., 2008).
(7) Differential diagnosis between pulmonary VOD and other etiologies of pulmonary hypertension is essential to ensure appropriate treatment with minimization of adverse effects.
G. Hemorrhagic cystitis (HC) is the inflammation of the mucosal surface of the
bladder and/or ureters with the presence of sustained hematuria and lower urinary tract symptoms in the absence of other conditions such as infection and vaginal bleeding (Decker, Karam, & Wilcox, 2009).
1. Pathophysiology
a) Damage to the bladder wall can occur from toxins, drugs, disease, radiation, and infection (Basler & Stanley, 2012).
(1) Chemotherapy-induced cystitis can arise from agents that are
directly instilled into the bladder or from toxic metabolites that
come in contact with the bladder.
(2) Radiation cystitis can occur when the bladder is within the radiation port.
(3) Infectious cystitis can occur from bacterial, fungal, or parasitic urinary infections.
(4) Gross hematuria can occur rarely from arteriovenous malformations, stones, primary bladder cancer, adjacent cancers (prostate, uterus, cervix, or rectum), or metastatic disease that affects the bladder.
b) Acrolein is a liver metabolite of cyclophosphamide and ifosfamide.
Eliminated through the urine, acrolein binds to the bladder mucosa,
resulting in ulceration, inflammation, necrosis, and hemorrhage. Although the entire urinary tract can be affected, the bladder is more
likely to be affected because of prolonged contact (Basler & Stanley,
2012; Gerson, Bulgar, Weeks, & Chabner, 2011; Hassan, 2011; Lima,
Ferreira, Macedo, de Castro Brito, & Ribeiro, 2007).
2. Incidence
a) HC is reported more frequently following ifosfamide than cyclophosphamide. The incidence of HC after ifosfamide ranges from 18%
40% (Lima et al., 2007).
b) When cyclophosphamide was used to treat non-Hodgkin lymphoma (NHL), the cumulative five-year incidence of HC was 12% (Le
Guenno, Mahr, Pagnoux, Dhote, & Guillevin, 2011).
c) HC occurs in about 2%40% of patients treated with high-dose cyclophosphamide (Levine & Ritchie, 1989; Marshall et al., 2012).
d) In the pediatric population following allogeneic stem cell transplantation, the incidence of HC ranges from 10%70% (Decker et al.,
2009; Hassan, 2011).
e) Severe cases are rare, but HC can be fatal up to 6% of cases (Marshall et al., 2012).
3. Risk factors
a) HC can develop following treatment with oxazaphosphorines (cyclophosphamide and ifosfamide). Cases have been reported with busulfan, cabazitaxel, high-dose therapy, and biologics such as gefitinib and
bevacizumab (Arakawa et al., 2010; Hassan, 2011).
b) Most patients who develop cyclophosphamide-induced HC have received doses of approximately 150200 g. HC is rarely seen after lowdose cyclophosphamide (Marshall et al., 2012; Fairchild, Spence, Soloman, & Gangai, 1979; Forni, Koss, & Geller, 1964).
c) HC is unlikely to occur with cumulative doses of oral cyclophosphamide lower than 100 g. Typical cumulative doses that can cause chronic
cystitis are 18206 g over 10 months to 9 years (Hu et al., 2008; Marshall et al., 2012).
d) Risk factors in the HSCT setting include male gender, age, allogeneic or myeloablative transplant, unrelated donor, presence of GVHD,
infection, and use of steroids (Hassan, 2011; Nadir & Brenner, 2007).
4. Clinical manifestations of HC
a) Usually occurs 2448 hours after a single dose of high-dose cyclophosphamide and typically lasts four to five days (Marshall et al., 2012; Spiers, 1963). Can occur at any time after repeated doses of ifosfamide
or lower-dose cyclophosphamide.
b) Symptoms may include dysuria, frequency, urgency, and lower abdominal or suprapubic pain. In men, bladder spasms can produce severe referred pain in the glans penis (Basler & Stanley, 2012; CampSorrell, 2011).
c) Clinical symptoms vary from asymptomatic microscopic hematuria
to frank hematuria with clot formation and urinary tract obstruction and may lead to acute renal failure (Basler & Stanley, 2012;
Hassan, 2011).
d) Rare adverse effects include bladder wall necrosis, bladder fibrosis
with loss of compliance, contracture or shrinkage of the bladder reservoir volume, and vesicoureteral reflux (Basler & Stanley, 2012). Potential exists for lifelong fibrosis, contracture of the bladder, and bladder cancer (Decker et al., 2009; Gerson et al., 2011).
e) Can deteriorate QOL and cause prolonged hospitalization (Hassan,
2011)
5. Assessment
a) Monitor for red-tinged urine or screen for hematuria with urine dipstick. Diagnosis is based on detection of microscopic or macroscopic hematuria with or without symptoms of discomfort in the urinary
tract (Hassan, 2011).
b) Obtain history of past and present medications, as chemotherapy
agents can produce cystitis years after exposure.
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320
c) Laboratory analysis (Basler & Stanley, 2012; Decker et al., 2009; Hassan, 2011)
(1) Obtain a baseline urinalysis and monitor as needed.
(2) Urine culture to screen for bacterial and viral infection. In grade
3 or 4 HC, it may be beneficial to follow the BK polyomavirus
titer because there is evidence linking BK virus and HC (Decker et al., 2009; Hassan, 2011).
(3) CBC: Hgb is rarely below normal except in patients with chronic HC. WBC count may be elevated with concurrent infections
or due to treatment of the underlying malignancy.
(4) Obtain basic metabolic panel to evaluate blood urea nitrogen
(BUN)/creatinine for renal failure.
(5) Assess coagulation parameters (prothrombin time [PT] and
partial thromboplastin time [PTT]).
d) Ultrasound of kidneys and bladder to characterize clotting within the
bladder and evaluate upper tract dilation
e) Cystoscopy to confirm diagnosis or for clot evacuation
f) Grading system (Decker et al., 2009; Droller, Saral, & Santos, 1982)
(1) Grade 0: No symptoms of bladder irritability or hemorrhage
(2) Grade I: Microscopic hematuria
(3) Grade II: Macroscopic hematuria
(4) Grade III: Macroscopic hematuria with small clots
(5) Grade IV: Gross hematuria with clots causing urinary tract obstruction requiring instrumentation for clot evacuation
6. Prevention strategies
a) Protective measures (Basler & Stanley, 2012; Camp-Sorrell, 2011;
Decker et al., 2009)
(1) Encourage increased fluid intake. Provide vigorous hydration
and diuresis as needed.
(2) Administer cyclophosphamide early in the day when feasible
to allow patients to drink fluids and void frequently without interruption of sleep.
(3) Encourage patients to empty bladder frequently, including before sleeping at night.
(4) Monitor intake and output. Instruct patients and caregivers in
this process.
(5) Perform continuous bladder irrigation.
b) Mesna (2-mercaptoethane sulfonate) is the most effective agent for
preventing oxazaphosphorine-induced cystitis. By binding to acrolein, mesna neutralizes acrolein acid and serves as a uroprotectant
(Basler & Stanley, 2012; Decker et al., 2009; Gerson et al., 2011; Hassan, 2011; Hensley et al., 2009). It usually is given in divided doses every four hours (Gerson et al., 2011).
(1) Ifosfamide dose < 2.5 g/m2/day administered as a short infusion: Mesna should be administered as three bolus doses given 15 minutes before and 4 and 8 hours after each dose of
ifosfamide.
(2) Ifosfamide dose over 2.5 g/m2/day: Insufficient evidence exists
on which to base a recommendation for use of mesna. ASCO
guidelines (Hensley et al., 2008) indicate that the efficacy of
mesna for urothelial protection with very-high-dose ifosfamide
has not been established.
(3) Ifosfamide as continuous infusion: Mesna may be administered
as a bolus dose equal to 20% of the total ifosfamide dose followed by a continuous infusion of mesna equal to 40% of the
ifosfamide dose. Continue for 1224 hours after completion of
ifosfamide infusion.
(4) Mesna tablets: Administer IV mesna at a dose equal to 20% of the

ifosfamide dose at the time of ifosfamide administration. Then,
the oral dose of mesna is administered at 40% of the ifosfamide
dose at two and six hours after each dose of ifosfamide with the
total daily dose of mesna equaling 100% of the ifosfamide dose.
If the patient vomits within two hours after taking the oral mesna, repeat the dose or give the mesna IV. This same dosing schedule should be followed each day the patient receives ifosfamide.
(5) Mesna with cyclophosphamide: In patients receiving high-dose
cyclophosphamide in the setting of HSCT, mesna plus saline
diuresis or forced saline diuresis is recommended to decrease
the incidence of urothelial toxicity.
a) Management depends on etiology and severity of symptoms. No single standardized, evidence-based approach to managing HC has
been adopted, and multiple therapeutic modalities often are necessary (Decker et al., 2009).
b) Hematuria will subside in most patients if chemotherapy agents are
discontinued.
c) Microscopic hematuria with few or no clinical symptoms usually resolves spontaneously and does not require treatment other than hydration (Hassan, 2011).
d) Early grade (grade 13): Interventions include intensive IV hydration,
forced diuresis, analgesia, and spasmolytic drugs (Decker et al., 2009).
e) Bladder irrigation: Continuous bladder irrigation through a threeway Foley catheter is often the mainstay of management of HC in order to prevent clot retention and renal insufficiency/failure (Decker et al., 2009; Hassan, 2011).
f) Cystoscopy with clot evacuation is necessary when clot formation or
clot organization results in hydronephrosis and/or urinary bladder
tamponade (Decker et al., 2009; Hassan, 2011).
g) Intravesicular instillation of chemicals such as formalin, aluminum
potassium sulfate, prostaglandin, aminocaproic acid, or cidofovir may
be performed (Basler & Stanley, 2012; Decker et al., 2009; Hassan,
2011; Nadir & Brenner, 2007).
h) Administration of IV or oral aminocaproic acid can decrease clotting (Hu et al., 2008).
i) Potential treatments include hyperbaric oxygen (Basler & Stanley,
2012; Nadir & Brenner, 2007), embolization or ligation of internal
iliac arteries, and endoscopic laser coagulation (Hu et al., 2008).
8. Patient education (Camp-Sorrell, 2011)
a) Teach patients and caregivers about the potential for HC following
administration of potential offending agents.
b) Instruct patients to drink plenty of fluids following treatment and to
void frequently.
c) Ensure that patients know how to identify and report urinary symptoms.
H. Hepatotoxicity
1. Pathophysiology (Aloia & Fahy, 2010; Camp-Sorrell, 2011; Floyd & Kerr,
2013; Medlin & Perry, 2008)
a) Hepatotoxicity can occur through the following mechanisms.
(1) Idiosyncratic hypersensitivity immune reactions
(2) Hepatocellular injury, necrosis; hepatocytes are at increased
risk if steatosis is present; some chemotherapy causes steatosis.
(3) Ductal injury with cholestasis
(4) Hepatic vascular lesions leading to thrombosis and occasionally VOD
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322
(5) Reactivation of dormant viruses such as hepatitis

b) Pediatric considerations (Chordas & Graham, 2010)
(1) Liver toxicity is commonly reported among children with the
use of antimetabolites.
(2) Hepatotoxicity from chemotherapy among pediatric patients is variable, and incidence and severity are increased
by concomitant supportive care medications such as anti-inflammatory agents, antimicrobials, and anticonvulsants. Frequent monitoring of liver function tests (LFTs) is necessary
with the consideration of decreasing doses or discontinuing
drugs. Total parenteral nutrition should be avoided to decrease the potential for additional liver damage.
2. Incidence: See Table 37.
3. Risk factors
a) Child-Pugh class B or C score (Floyd & Kerr, 2013): Child-Pugh is a
grading system for cirrhosis that considers total bilirubin, albumin,
INR, ascites, and encephalopathy. Scores range from AC, with a higher score indicating more hepatic dysfunction. It may be used for dose
modifications for chemotherapy, although it was originally designed
for predicting surgical mortality (Verbeeck, 2008).
b) Prior liver infection, damage, or disorder (e.g., cirrhosis, hepatitis,
Budd-Chiari syndrome)
c) Hepatotoxic chemotherapy drugs (risk increases with higher dosing)
d) Liposomal chemotherapy does not necessarily decrease hepatotoxicity in children (Sieswerda, Kremer, Caron, & van Dalen, 2011).
e) Family history of hereditary liver diseases (e.g., alpha-1 antitrypsin
deficiency, hemochromatosis, Wilson disease)
f) Prior tumor involvement of the liver
g) Past medical history of transplantation (e.g., liver, kidney, bone marrow, peripheral blood stem cell): Cholestasis is present in 80% of patients with chronic GVHD; chronic hepatitis is seen in the majority
of HSCT survivors who experienced acute hepatitis.
h) Comorbidities such as HIV, diabetes mellitus, underlying liver disease, and obesity (Verma & Kaplowitz, 2009)
i) Prior radiation therapy to the liver or right side of abdomen
j) History of alcohol and illicit drug abuse, especially if liver is cirrhotic
k) Concurrent administration of noncytotoxic hepatotoxic drugs or
herbal products
l) Intrahepatic chemotherapy administration
m) Advancing age
n) Genetic factors, which may be different for each drug, leading to variable reactions (de Beaumais et al., 2011; Verma & Kaplowitz, 2009)
4. Clinical manifestations (Roesser, in press)
a) Varying degrees of jaundice, from mild seen in the sclera to severe
seen in the tissue
b) Hyperpigmentation of the skin
c) Ascites and edema
d) Fatigue, malaise, and other flu-like symptoms
e) Anorexia and weight loss
f) Mild to severe nausea with varying degrees of emesis
g) Diarrhea, weight loss, dehydration, cachectic appearance
h) Right upper quadrant pain
i) Hepatosplenomegaly
j) Dark-orange urine, clay-colored stools
k) Pruritus
l) Elevated transaminases (aspartate aminotransferase, alanine aminotransferase), prolonged PTT
Table 37. Hepatotoxicity of Antineoplastic Agents

Classification
Alkylating
agents
Anthracycline
antibiotics
Drug
Route of
Administration
Side Effects
PO, IV
Increased ALT, hyperbilirubinemia, VOD (SCT: 11%

42%) (GlaxoSmithKline, 2008b; Otsuka America Pharmaceutical, Inc., 2011)
Hepatic VOD: High busulfan AUC values (> 1,500 mcMmin)
and baseline LFT elevations are associated with increased risk of hepatic VOD during conditioning for allogeneic BMT (Krivoy et al., 2008). Incidence of hepatic VOD reported in the literature from randomized controlled trials was 7.7%12% (Otsuka America Pharmaceutical, Inc., 2011).
Monitor baseline LFTs, bilirubin, and alkaline phosphatase, and

then every other day after BMT.
Monitor for signs of VOD using Jones criteria: RUQ pain, weight
gain, and increased bilirubin. If VOD is diagnosed, monitor LFTs
daily (Jones et al., 1987).
Dacarbazine
IV
Rare hepatic necrosis associated with venous thrombosis

has been reported (Teva Pharmaceuticals USA, 2007).
Increased LFTs
Monitor LFTs as clinically indicated.
Procarbazine
PO
Hepatic dysfunction (Sigma-Tau Pharmaceuticals, Inc.,

2008)
Monitor LFTs prior to each cycle (Fesler et al., 2010).
Daunorubicin
IV
LFT elevations (Teva Pharmaceuticals USA, 2012a)
Doses need to be modified for elevated LFTs.

Monitor LFTs.
Doxorubicin
IV, intravesicular,
intraperitoneal
Increased bilirubin levels, hepatitis
Hepatic impairment [U.S. Boxed Warning]: Use with caution in patients with hepatic impairment; dosage adjustment is recommended. Use with caution in patients with hepatobiliary dysfunction (Pfizer Inc., 2011a).
Drug is extensively metabolized in liver; reduce dose for T. bili >
1.23 mg/dl (Pfizer Inc., 2011a). Contraindicated in marked liver
function impairment.
Doxorubicin liposomal injection
IV
LFT elevations
Monitor LFTs. Dose reduce for hepatic dysfunction (50% if T. bili

1.23 mg/dl; 75% if T. bili > 3 mg/dl) (Janssen Products, LP,
2013).
Epirubicin
IV
Mitoxantrone
IV
Transient elevation of liver enzymes, jaundice
Dose reductions are recommended in patients with mild-to-moderate hepatic impairment. Do not use in patients with severe hepatic dysfunction (Pfizer Inc., 2013b). Monitor LFTs.
Consider dose adjustments in patients with severe hepatic dysfunction (T. bili > 3.4 mg/dl) (EMD Serono, Inc., 2012). Monitor
LFTs.
323
Busulfan
324
Table 37. Hepatotoxicity of Antineoplastic Agents (Continued)

Drug
Route of
Administration
Side Effects
Antibiotic
Dactinomycin
IV
Ascites, hepatic failure, hepatitis, hepatomegaly, LFT abnormality (Recordati Rare Diseases Inc., 2013)
May cause hepatic VOD (increased risk in children < 4
years of age); use with caution in patients with hepatobiliary dysfunction (Recordati Rare Diseases Inc.,
2013).
Avoid dactinomycin use within 2 months of radiation treatment for

right-sided Wilms tumor, as it may increase the risk of hepatotoxicity (Recordati Rare Diseases Inc., 2013).
Antimetabolites
Eribulin mesylate
IV
Reversible elevations of ALT (Eisai Inc., 2013)
Institute dose modifications and a lower starting dose for patients

with Child-Pugh A and Child-Pugh B hepatic impairment. Patients with Child-Pugh C hepatic impairment were not studied
(Eisai Inc., 2013).
Monitor LFTs at baseline and during treatment.
Among patients with grade 0 or 1 ALT levels at baseline, 18%
had grade 2 or greater elevations in ALT with eribulin mesylate,
which resolved and did not recur with re-exposure to the drug
(Eisai Inc., 2013).
6-Mercaptopurine
PO
Intrahepatic centrilobular necrosis can occur. Hyperbilirubinemia, increased alkaline phosphatase and AST,
jaundice, ascites, and encephalopathy; hepatotoxicity is
more common at doses > 2.5 mg/kg/day (Gate Pharmaceuticals, 2011).
Clinically detectable jaundice usually occurs within 2 months

of therapy, but may occur within 1 week or be delayed up to 8
years (Gate Pharmaceuticals, 2011). The majority of children
who have developed portal hypertension continue to have it 10
years later (Rawat et al., 2011).
Methotrexate
IM, IV, SC, intrathecal
U.S. boxed warning: Methotrexate has been associated

with acute (elevated transaminases) and potentially fatal chronic (fibrosis, cirrhosis) hepatotoxicity. Risk is related to cumulative dose and prolonged exposure (Teva
Pharmaceuticals USA, 2012b).
Ethanol abuse, obesity, advanced age, and diabetes may
increase the risk of hepatotoxic reactions (Teva Pharmaceuticals USA, 2012b).
Use caution in patients with preexisting liver impairment;
may require dosage reduction.
Monitor closely (with LFTs, including serum albumin) for liver toxicities.
Use caution when drug is used with proton pump inhibitor therapy
and other hepatotoxic agents (e.g., azathioprine, retinoids, sulfasalazine).
Liver toxicity usually is transient and higher in patients treated on
a daily schedule (Camp-Sorrell, 2011).
Pralatrexate
IV
13% had elevated LFTs after treatment (Allos Therapeutics, Inc., 2012).
Monitor LFTs at baseline and prior to the start of the first and
fourth dose of each cycle. Dose reductions are recommended
for elevated LFTs (Allos Therapeutics, Inc., 2012).
Antimetabolite:
Antifolates
Classification

Classification
Drug
Route of
Administration
Side Effects
Cytarabine
IV, SC
Transient elevations of liver enzymes, jaundice

High-dose cytarabine can cause intrahepatic cholestasis
Dose adjustment may be needed in patients with liver failure because cytarabine is partially detoxified in the liver (Bedford Laboratories, 2008).
There is no FDA-approved hepatic dosing adjustment guideline; the
following guideline has been used by some clinicians (dose level
not specified): If bilirubin > 2 mg/dl, administer 50% of dose and
elevate subsequent doses with lack of toxicity (Koren et al., 1992).
Hepatic changes with cytarabine are usually reversible.
Antimetabolite:
Pyrimidine
antagonists
Capecitabine
PO
Increased bilirubin (22%48%; grades 34: 11%23%);

hepatic failure, hepatic fibrosis, hepatitis: < 1% (Genentech, Inc., 2011)
Use with caution in patients with hepatic impairment.

Institute dose modifications if T. bili > 1.5 ULN (Genentech, Inc.,
2011).
Clofarabine
IV
Severe and fatal hepatotoxicity has occurred with clofarabine. Most often are transient in the first 15 days. Rare
cases of VOD have been reported (Genzyme Corp.,
2013; Hijiya et al., 2011).
Monitor LFTs at baseline and during treatment 23 times a week.

Educate patients to avoid other hepatotoxic drugs during the
five-day course (Dressel et al., 2011). Has not been studied in
patients with baseline hepatic dysfunction. VOD has been reported in patients who had a previous blood and marrow transplant (Genzyme Corp., 2013).
Floxuridine
Intra-arterial, IV
Hepatocellular injury with increased aminotransferases,

alkaline phosphatase, and serum bilirubin (hepatitis pattern); stricture of the intrahepatic or extrahepatic bile
ducts (sclerosing cholangitis) accompanied by elevated
alkaline phosphatase and serum bilirubin (Bedford Laboratories, 2000; Chang et al., 1987; Hohn et al., 1989)
Use with caution in patients with hepatic impairment (Bedford

Laboratories, 2000).
Gemcitabine
IV
When used as a single agent: Increased transaminases

(67%68%; grades 34: 8%10%), increased alkaline
phosphatase (55%; grades 34: 9%), increased bilirubin
(13%; grades 34: < 1%2%) (Eli Lilly & Co., 2013)
Serious hepatotoxicity has been reported. Use caution in patients

with hepatic impairment (history of cirrhosis, hepatitis, or alcoholism) or hepatic metastases; may lead to exacerbation of hepatic impairment. Monitor LFTs prior to initiation and periodically (Eli Lilly & Co., 2013).
IL-2; aldesleukin
IV, SC
Increased transaminases and alkaline phosphatase; jaundice

Signs of hepatic failure: encephalopathy, ascites, liver
pain, hypoglycemia (Wilkes & Barton-Burke, 2012)
Not recommended for patients with preexisting liver dysfunction;

dosing is typically delayed until resolution of hepatic dysfunction.
Monitor LFTs.
Pegylated interferon alfa-2b
SC
Increased risk of hepatic decompensation and death in

patients with cirrhosis (Schering Corp., 2012b)
Contraindicated and must be discontinued in patients with moderate or severe hepatic dysfunction or history of autoimmune hepatitis. Monitor LFTs and LDH at baseline and at weeks 2, 4, 8,
and 12 and then at 6-week intervals following the initiation of
therapy (Schering Corp., 2012b).
Biotherapy
agents
325
Antimetabolite:
Purine
antagonist
326

Drug
Route of
Administration
Side Effects
Camptothecin
Irinotecan
IV
Increased bilirubin (84%), increased alkaline phosphatase (13%), increased AST (10%), ascites and/or jaundice (grades 34: 9%) (Pfizer Inc., 2012a)
Use with caution in patients with hepatic impairment.

Hyperbilirubinemia: Patients with even modest elevations in total serum bilirubin levels (12 mg/dl) have a significantly greater
likelihood of experiencing first-course grade 3 or 4 neutropenia
than those with bilirubin levels < 1 mg/dl (Pfizer Inc., 2012a). Patients with abnormal glucuronidation of bilirubin, such as those
with Gilbert syndrome, may be at greater risk of myelosuppression when receiving therapy with irinotecan. Use caution when
treating patients with known hepatic dysfunction or hyperbilirubinemia; dose adjustments should be considered (Venook et al.,
2003).
Miscellaneous
Abiraterone acetate
PO
Monitor LFTs at baseline and every week for the first month, every 2 weeks for the following 2 months, and monthly thereafter.
Reduce doses for Child-Pugh B at baseline and hold if T. bili > 3
ULN or AST and/or ALT > 5 ULN. Do not use in patients with
severe hepatic impairment (Janssen Biotech, Inc., 2012).
Asparaginase
IM, IV, SC
Increased transaminases, bilirubin, and alkaline phosphatase (transient) (Lundbeck, 2013)
Use with caution in patients with preexisting hepatic impairment;

may alter function.
Asparaginase Erwinia chrysanthemi
IM
Elevated LFTs in 4%; rare hyperammonemia (1%) (EUSA

Pharma [USA], Inc., 2011)
Monitor LFTs, fibrinogen, PT, and PTT. Monitor ammonia level if

signs and symptoms of encephalopathy develop.
Bexarotene
Topical, PO
Increased LDH and hepatic failure (with oral formulation)

(Eisai Inc., 2011b)
Extensive hepatic elimination

Monitor LFTs; consider stopping if values are > 3 ULN (Eisai
Inc., 2011b; Floyd & Kerr, 2013).
Denileukin diftitox
IV
Increase in ALT/AST from baseline occurred in 84% of

patients, mostly occurring during either the first or second cycle and resolving without medical intervention or
interruption of denileukin diftitox (Eisai Inc., 2011a).
Monitor LFTs.
Ipilimumab
IV
T-cell activation and proliferation leading to immune-mediated organ failure (Bristol-Myers Squibb Co., 2013)
Monitor LFTs prior to each dose. Stop drug and treat immune reaction with steroids for AST/ALT > 5 ULN or T. bili > 3 ULN
(Bristol-Myers Squibb Co., 2013).
Ofatumumab
IV
Hepatitis B reactivation (GlaxoSmithKline, 2011)
Screen high-risk patients (GlaxoSmithKline, 2011).
Rituximab
IV
Hepatitis B reactivation with possible fulminant hepatitis,

sometimes fatal (Biogen Idec, Inc., & Genentech, Inc.,
2013)
Screen high-risk patients and monitor hepatitis B carriers during

and several months after therapy (Biogen Idec, Inc., & Genentech, Inc., 2013).
Monoclonal
antibodies
Classification

Classification
Drug
Route of
Administration
Side Effects
Carmustine
IV, wafer
Reversible increases in bilirubin, alkaline phosphatase, and AST occur in a small percentage of patients
Monitor LFTs (Bristol-Myers Squibb Co., 2011a).

Dose adjustment may be required in hepatic impairment, but no
guidelines are available.
Tyrosine kinase
inhibitors
Axitinib
PO
22% had ALT elevations of all grades; < 1% had severe

elevations (Pfizer Inc., 2012b).
Monitor LFTs at baseline and periodically. Dose adjust for patients with prior Child-Pugh B hepatic impairment. Has not been
studied in patients with severe hepatic impairment (Pfizer Inc.,
2012b).
Crizotinib
PO
< 1% fatal hepatotoxicity has occurred (Pfizer Inc.,

2013c). Elevations in ALT/AST and T. bili can occur.
Monitor LFTs at baseline and monthly; increase frequency if elevation occurs. Hold drug for elevated AST/ALT; discontinue if
concurrent rise in T. bili > 2 ULN.
Imatinib mesylate
PO
Mild elevations in serum AST and ALT levels are very

common and may be a hypersensitivity reaction (Novartis Pharmaceuticals Corp., 2013).
Use with caution in patients with hepatic impairment. Drug interruption is recommended for patients with AST/ALT > 5 ULN
or bilirubin > 3 ULN. Steroids have been used to treat severe
hepatotoxicity. Advise patients to avoid alcohol and other hepatoxic drugs (Joensuu et al., 2011).
Pazopanib
PO
U.S. boxed warning: Severe fatal hepatotoxicity has been

observed. LFT elevations can occur, usually in the first
18 weeks (GlaxoSmithKline, 2013).
Monitor LFTs at baseline and once a week for the first 4 months
and then periodically. Institute dose modifications for patients
with moderate hepatic impairment. Drug is not recommended in
patients with severe impairment.
Sunitinib
PO
U.S. boxed warning: Fatal hepatotoxicity has occurred.

Signs include jaundice, elevated transaminases and/or
hyperbilirubinemia, coagulopathy, encephalopathy, and/
or renal failure (Pfizer Inc., 2012c).
Monitor LFTs at baseline, during each cycle, and as clinically indicated. Drug interruption is instituted for patients with AST/ALT
> 5 ULN.
Vincristine
IV
Vinca alkaloid;
natural source
(plant)
derivative
Metabolized extensively in the liver. Use with caution in patients

with hepatic impairment; dose modification required (Hospira,
Inc., 2013).
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ALTalanine aminotransferase; ASTaspartate aminotransferase; AUCarea under the time-versus-concentration curve; BMTbone marrow transplantation; FDAU.S. Food and Drug Administration; IL-2interleukin-2; IMintramuscular; IVintravenous; LDHlactate dehydrogenase; LFTliver function test; POby mouth; PTprothrombin time; PTTpartial thromboplastin time; RUQright upper quadrant; SCsubcutaneous; SCTstem cell transplantation; T. bilitotal bilirubin; ULNupper limit of normal; VODveno-occlusive disease
Nitrosourea
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m) Bruising and/or bleeding

n) Portal hypertension
o) Encephalopathy: Mental status changes ranging from subtle, such
as decrease in memory, mental fogginess, and mild confusion, to severe, such as coma
p) Arthralgia/myalgia
5. Assessment (Khalili, Liao, & Nguyen, 2010; Roesser, in press)
a) Vital signs: Fever may suggest hepatitis.
b) Physical examination to find and document the preceding clinical
manifestations
(1) Integument: Assess for presence of jaundice, skin rash, ecchymosis, and petechiae.
(2) Head, eyes, ears, nose, and throat examination: Assess for icteric sclera.
(3) Neurologic examination: Assess level of orientation, mental status, asterixis, and behavioral changes.
(4) Abdominal examination: Assess bowel sounds, liver/spleen, ascites, and venous distention.
(5) Assess for Charcot triad: jaundice, fever, and upper abdominal
pain, indicating gallstones.
(6) Cardiac and pulmonary exam: Assess for signs of CHF (e.g., peripheral edema, extra heart sounds, rales, jugular venous distentionmay suggest hepatic congestion).
c) Baseline LFTs prior to initiation of therapy
d) History of hepatotoxic drug use
e) Past medical history: Organ transplant, hepatitis, exposure to infected individuals, comorbidities, drug and alcohol use, family history
of liver disease
6. Collaborative management: Few guidelines exist for the dosing of drugs
based on elevated LFTs.
a) Avoid using hepatotoxic drugs during the administration of hepatotoxic chemotherapy and if LFT results are abnormal.
b) Consider adjusting the dose of chemotherapy in the presence of impaired hepatic function (Wilkes & Barton-Burke, 2012).
c) Monitor serum chemistries, CBC, and clotting factors. Institute bleeding precautions if clotting factors are abnormal.
d) Instruct and assist patients in following a low-fat, high-glucose diet
containing vitamin B and C additives. Consult a dietitian and consider decreasing dietary protein in patients with signs of liver dysfunction (Fisher & Brown, 2010).
e) Assess patients level of consciousness. If altered, monitor ammonia
levels and consider lactulose (McKinley, 2009).
f) Monitor for weakness, fatigue, and malaise. Encourage rest. If patients are confined to bed rest, elevate the head of the bed and promote deep breathing to prevent pneumonia. Assess and monitor fall
risk (McKinley, 2009).
g) Monitor subsequent LFT results. Consult a hepatologist for liver failure (Fleming & Abbass, 2010).
h) Rule out other causes of liver injury including infections, iron overload, and autoimmune hepatitis, and treat as indicated (Verma &
Kaplowitz, 2009).
i) Consider treating prolonged cholestasis with ursodeoxycholic acid
(Verma & Kaplowitz, 2009).
j) Monitor renal function and other electrolytes. Prevent hepatorenal
syndrome by optimizing fluid and sodium balance and avoiding nephrotoxic medications (Fleming & Abbass, 2010).
a) If appropriate, inform patients and significant others that hepatotoxicity is a possible side effect of the chemotherapy agent.
b) Instruct patients to avoid all alcoholic beverages if hepatotoxicity is
present.
c) Provide instruction on the signs and symptoms of liver failure (e.g.,
jaundice, liver tenderness, changes in color of urine or stool).
d) Promote rest.
e) Encourage use of soothing lotions and tepid showers to promote skin
comfort. Remind patients not to scratch.
f) Suggest that patients wear lightweight, loose clothing.
g) Encourage patients to continue eating a light (low-fat), high-glucose diet.
h) Reinforce the importance of having lifelong annual follow-up assessments performed by a healthcare provider familiar with their cancer
history, treatment, and risk of developing late effects (Rawat, Gillett,
Devadason, Wilson, & McKiernan, 2011).
i) Encourage patients to have periodic LFTs and to plan appropriate
follow-up.
j) For patients with signs of liver failure, provide education about infection prevention, bleeding precautions, and safety.
I. Nephrotoxicity
1. Pathophysiology: The kidneys clear metabolic waste products, control
fluid volume status, maintain electrolyte and acid-base balance, and assist with endocrine function. Each kidney contains about 1 million nephrons, the functional unit of the kidney. The nephron includes the glomerulus, proximal tubule, loop of Henle, distal tubule, and collecting
duct (Trombetta & Foote, 2009). Chemotherapy can damage the proximal tubule epithelial cells, leading to acute tubular necrosis. Renal impairment often is reversible if the offending drug is discontinued early
(Naughton, 2008).
a) Tubulopathies: Drugs can cause injury to one or more segments of
the renal tubules, leading to salt wasting, magnesium wasting, syndrome of inappropriate antidiuretic hormone (SIADH), and Fanconi syndrome (Perazella & Moeckel, 2010).
(1) SIADH is a disorder of water intoxication. The release of anti
diuretic hormone (ADH) causes the kidneys to reabsorb water,
leading to hyponatremia (Fairclough & Brown, 2010). Chemotherapy agents that can contribute to SIADH include cyclophosphamide, vincristine, cisplatin, docetaxel, melphalan, and ifosfamide and regimens that require vigorous hydration (Kelly, Billemont, & Rixe, 2009; Perazella & Moeckel, 2010).
(a) ADH acts in the kidneys to conserve water by binding to
receptors in the distal or collecting renal tubules. This action promotes reabsorption of water and excretion of a
lesser amount of concentrated urine. The reabsorbed water dilutes the blood and reduces the serum osmolality toward normal, with an increase in urine osmolarity causing
hyposmolality and dilutional hyponatremia (Fairclough &
Brown, 2010).
(b) Symptoms of SIADH depend on the absolute concentration of sodium in the serum (Fairclough & Brown, 2010;
Keenan, 2011).
i. Mild hyponatremia (serum sodium concentration of
125135 mEq/L): Symptoms may be absent or nonspecific, such as thirst, anorexia, nausea, fatigue, weakness, muscle cramps, or headache.
329
330
ii. Moderate hyponatremia (serum sodium concentration

of 115124 mEq/L): Symptoms include weight gain,
oliguria, and progressive neurologic deficits.
iii. Severe hyponatremia (serum sodium concentration
< 115 mEq/L): Considered an oncologic emergency. Symptoms of cerebral edema include papilledema, delirium, hypoactive reflexes, ataxia, gait disturbance, seizures, coma, and death. Initiate seizure precautions for sodium levels < 120 mEq/L.
(c) Management of presenting symptoms may include fluid restriction, diuresis, demeclocycline, and hypertonic saline.
(2) Fanconi syndrome is characterized by urinary wasting of potassium, phosphate, bicarbonate, uric acid, and glucose.
b) Acute kidney injury (AKI) has replaced the term acute renal failure and
is characterized by a rapid reduction in kidney function that results
in a failure to maintain fluid, electrolyte, and acid-base homeostasis
(Lewington & Kanagasundaram, 2011). Chemotherapy agents are a
common cause of AKI (Perazella & Moecke, 2010). Types of AKI include the following.
(1) Prerenal AKI occurs less commonly than the other types and
causes capillary leak syndrome. May be seen with IL-2 and denileukin (Perazella & Moecke, 2010).
(2) Acute tubular injury (ATI) is the most common cause of AKI.
Proximal tubule cells are exposed to high levels of circulating
toxins, making them more vulnerable to the toxic effects of
drugs. ATI is dose related. Various tubulopathies may be permanent in 25%44% of patients (Naughton, 2008; Perazella &
Moecke, 2010).
(3) Crystal nephropathy occurs when the insoluble crystals produced
by drugs precipitate, usually within the distal tubular lumen, obstructing urine flow. The likelihood of crystal precipitation depends on drug concentration and the urinary pH. Patients at
highest risk are those with volume depletion and underlying renal insufficiency (Naughton, 2008; Perazella & Moecke, 2010).
(a) Methotrexate is associated with production of crystals. The
parent drug and its metabolites precipitate within tubular lumens.
(b) Tumor lysis syndrome (TLS) is the massive and sudden release of cellular contents into the bloodstream following
the rapid lysis of tumor cells in large numbers. This release
results in abnormally high levels of potassium, phosphorus, and uric acid. Phosphorus binds to calcium, resulting
in hypocalcemia. Uric acid and calcium phosphate crystal
deposition occurs and leads to renal failure. Symptoms of
TLS include hypocalcemia, hyperkalemia, hyperuricemia,
and hyperphosphatemia. Because of the risk of life-threatening complications, TLS is considered an oncologic emergency (Fairclough & Brown, 2010; Givens & Crandall, 2010;
Lydon, 2011; Mackiewicz, 2012; Muslimani et al., 2011).
i. The incidence of TLS is unknown. Although it occurs
more frequently in aggressive hematologic malignancies including Burkitt and other high-grade lymphomas, acute lymphoblastic leukemia, acute myeloid
leukemia, and multiple myeloma, TLS has been reported in solid tumors including breast cancer, small
cell and non-small cell lung cancers, sarcoma, bladder cancer, and ovarian cancer. TLS can occur sponCopyright 2014 by the Oncology Nursing Society. All rights reserved.
taneously but usually develops after the start of cytotoxic therapy, primarily chemotherapy.
ii. AKI may result from crystal formation due to hyperuricemia and hyperphosphatemia. Oliguria can lead
to volume overload, hypertension, and pulmonary
edema, and elevated BUN can result in pericarditis,
platelet dysfunction, and impaired cellular immunity. Cardiac arrhythmias can occur as a result of electrolyte imbalances.
iii. Prevention is the goal of TLS management. Vigorous
hydration with 23 L of normal saline or 5% dextrose
solution is necessary to stimulate diuresis. Allopurinol
administration should begin one to three days before
chemotherapy and continue for three to seven days
after chemotherapy.
iv. For patients at high risk for TLS, including those
with a uric acid level > 7.5 mg/dl (Coiffier, Altman,
Pui, Younes, & Cairo, 2008), WBC count higher than
50,000/mcl, elevated lactate dehydrogenase or serum
creatinine (SCr), CHF, pulmonary edema, and those
unable to take oral medication, rasburicase is recommended to decrease uric acid levels within four hours
of administration (sanofi-aventis U.S. LLC, 2011a).
Although the FDA-approved dose is 0.150.2 mg/kg
IV daily for five days (Coiffier et al., 2008), several
studies demonstrated that a single, 6 mg fixed dose
was effective and may be repeated if necessary, but
this is rarely required (Giraldez & Puto, 2010; Vines,
Shanholtz, & Thompson, 2010). Rasburicase should
not be administered to patients with glucose-6-phosphate dehydrogenase deficiency (sanofi-aventis U.S.
LLC, 2011a).
v. Urinary alkalinization is no longer recommended for
all patients at risk for TLS. Use should be individualized and is recommended only in patients with metabolic acidosis.
vi. Nursing care involves monitoring for signs and symptoms of fluid and electrolyte abnormality and management of altered electrolyte levels as appropriate.
Monitor intake and output, and involve patients and
caregivers in prevention, early detection, and interventions.
(4) Thrombotic microangiopathy is damage with occlusion that occurs in small vessels, most commonly within the kidneys, and
presents with hematuria and proteinuria or with isolated proteinuria (Perazella & Moeckel, 2010).
c) Nephritic/nephrotic syndromes: Nephritic syndrome includes hematuria with the presence of RBC casts in the urine. It often includes
mild to moderate proteinuria, edema, hypertension, elevated SCr,
and oliguria. Nephrotic syndrome is characterized by proteinuria, hypoalbuminemia, hyperlipidemia, lipiduria, and hypercoagulability (Firman, 2010). Drugs can cause inflammatory changes in the
glomerulus, renal tubular cells, and the surrounding interstitium,
which can lead to fibrosis and renal scarring (Kelly et al., 2009;
Naughton, 2008).
(1) Glomerulonephritis is an inflammatory condition primarily
caused by immune mechanisms and is often associated with
331
332
proteinuria, which may be mild and detected by dipstick. Immune modulators associated with this mechanism of kidney
injury include IFN alfa, beta, and gamma.
(2) Acute interstitial nephritis can result from an allergic response
to a suspected drug, which may be individual and unrelated
to dose. Typical symptoms of hypersensitivity reaction such as
fever, rash, and eosinophilia are not always present. It can occur from numerous drugs, including allopurinol and acyclovir. Chronic interstitial nephritis can progress to end-stage renal disease.
d) Chronic kidney disease (CKD) may be associated with irreversible renal injury, higher cumulative drug dose, combined treatment with
other nephrotoxins, and host risk factors such as diabetes and hypertension. CKD includes chronic interstitial nephritis and glomerulosclerosis (Perazella & Moeckel, 2010).
2. Incidence: See Table 38.
Table 38. Nephrotoxicity of Antineoplastic Agents

Drug
Incidence of Nephrotoxicity
Comments
Axitinib
Proteinuria: 23%70%
Hypertension: 50%100%
Azacitidine
Transient elevation of SCr: 20%
Magnesium wasting and sodium wasting
Bevacizumab
Nephrotic-range proteinuria: 1%2%

Proteinuria, any grade: 4%36%
Hematuria: 6%; 6% with grade 3 cystitis
Associated with TMA with associated side effects such as hypertension,

proteinuria, and arterial thrombotic events
Bevacizumab administration may be associated with damage to the glomerular endothelium.
Renal damage induced by bevacizumab is a direct reduction of glomerular VEGF production.
Cetuximab
Severe hypomagnesemia: 10%15%

Renal failure in patients with colon
cancer: 1%
Causes isolated urinary magnesium wasting
Cisplatin
One-third of patients receiving cis

platin develop AKI after one dose of
therapy.
Risk of AKI increases with higher cumulative dose.
Overall reported nephrotoxicity: 28%
36%
Associated with chronic interstitial nephritis

Causes tubulopathies with FS, sodium and magnesium wasting
Chronic interstitial nephritis
Nephrogenic diabetes insipidus
Associated with SIADH
Causes acute tubular necrosis: Usually causes proximal tubular injury caused by the pathway of renal excretion of cisplatin, and can cause
CKD
Conversion of cisplatin to toxic molecules is an important step in the induction of nephrotoxicity.
Cisplatin is more nephrotoxic than carboplatin and oxaliplatin.
Cyclophosphamide
Hemorrhagic cystitis: 15%
Cyclosporine
Nephrotoxicity: 25%38%
Denileukin
diftitox
Capillary leak: 11.1%32.5%
Can cause prerenal AKI (capillary leak syndrome)
Diaziquone
Causes acute tubular necrosis
Docetaxel
Gefitinib
Promotes renal phosphate wasting and hypophosphatemia due to a partial FS

Hemorrhagic cystitis has been reported.
333
Table 38. Nephrotoxicity of Antineoplastic Agents (Continued)

Drug
Comments
Gemcitabine
Hematuria: 13%35%
Proteinuria: 10%45%
Elevated SCr: 2%38%
TMA
Ifosfamide
Hematuria without mesna: 44.1%;

hematuria with mesna: 21.3%

Can cause CKD
Can cause nephrogenic diabetes insipidus
Imatinib
Acute renal failure: 0.1%1%
Promotes renal phosphate wasting and hypophosphatemia due to a partial FS

Interferon
Interleukin-2
Melphalan
Methotrexate
Oliguria: 63%
Elevated SCr: 33%
Overall incidence of AKI: 1.8%
Associated with minimal change disease

Associated with collapsing and noncollapsing focal segmental glomerulosclerosis
Associated with membranoproliferative glomerulonephritis with proteinuria
that is often mild and reversible
Can cause prerenal AKI (capillary leak syndrome)
Causes crystal nephropathy when administered in high doses
Precipitation of the parent drug and its metabolites can occur within the
tubular lumens.
Initially an asymptomatic SCr increase develops with nonoliguria followed
by more severe AKI.
True or effective volume depletion and acidic urine are two major risk factors for AKI.
Drug-drug interaction may play a role in high-dose methotrexateinduced
AKI (e.g., methotrexate and piperacillin-tazobactam).
Another mechanism of methotrexate-mediated nephrotoxicity is hyperhomocysteinemia in patients with deficient folate metabolism.
Drug is retained in ascites and pleural effusions.
Avoid concurrent administration with NSAIDs.
Mithramycin
Mitomycin C
Approximately 10% of patients develop renal effects after 57 months of

mitomycin C.
Hemolytic uremic syndrome: < 10%
Leads to TMA
Higher cumulative dose ( 60 mg) increases risk for TMA.
Nitrosoureas
Kidney disease develops in approximately 10% of patients who receive

carmustine and lomustine.
Streptozocin and semustine are the
most nephrotoxic drugs, affecting >
75% of patients.
Associated with chronic interstitial nephritis and glomerulosclerosis

Nitrosoureas can cause slow, progressive CKD that occurs over a period
of 35 years.
Streptozocin causes AKI.
Can cause kidney injury that is manifested by an asymptomatic increase
in SCr, but tubular insufficiency can occur, resulting in clinically evident
FS.
In the majority of patients receiving 6 courses of nitrosoureas, irreversible
kidney damage that is chronic and progressive can occur.
Pamidronate
Deteriorating renal function: 8.2%
Associated with minimal change disease

Associated with focal segmental glomerulosclerosis, which is at least partially reversible after discontinuation of pamidronate
Mechanism is at least partially related to podocyte apoptosis.
334
Table 38. Nephrotoxicity of Antineoplastic Agents (Continued)

Drug
Comments
Panitumumab
Hypomagnesemia: 36%; 3% with severe symptomatic hypomagnesemia
Associated with magnesium wasting
Pemetrexed
Mild, transient renal dysfunction is reported in up to 20% of patients. Occasionally AKI is reported.
Decreased GFR may occur.

Drug is retained in pleural effusions and ascites, leading to prolonged
drug exposure.
Pentostatin
Renal failure: < 3%
Sorafenib
Acute renal failure: < 1%
Proteinuria has been reported in patients who have received sorafenib.

Other renal effects reported include hypophosphatemia, hyponatremia,
and hypocalcemia.
Sunitinib
Creatinine elevation is reported in approximately 14% of patients

Increased uric acid: 46%
Grade IIIII hypertension has been reported.

TMA has been reported.
Tacrolimus
Associated with interstitial nephritis
Vincristine
Zoledronic acid
Elevated SCr: 1%2.1%

Acute renal failure
AKIacute kidney injury; CKDchronic kidney disease; FSFanconi syndrome; GFRglomerular filtration rate; NSAIDnonsteroidal anti-inflammatory drug; SCrserum creatinine; SIADHsyndrome of inappropriate antidiuretic hormone; TMAthrombotic microangiopathy; VEGFvascular endothelial growth factor
Note. Based on information from Flombaum, 2011; Kelly et al., 2009; Launay-Vacher, 2011; Micromedex, 2013; Perazella & Moeckel, 2010.
3. Risk factors for chemotherapy-induced renal toxicity (Bhadauria & Agrawal, 2012; Camp-Sorrell, 2011; Naughton, 2008; Perazella & Moeckel, 2010;
Trombetta & Foote, 2009)
a) Older age
b) Female
c) History of nephrotic syndrome, acute or chronic kidney disease, nephrectomy, ileal conduits
d) Cirrhosis or obstructive jaundice
e) Metabolic disturbances including diabetes mellitus, alkaline or acidic urine pH, hypokalemia, hypomagnesemia, hypocalcemia, hypercalcemia.
f) History of hypertension, congestive heart failure
g) Hypovolemia
h) Administration of nephrotoxic drugs (e.g., aminoglycoside therapy,
amphotericin B, cyclosporine, NSAIDs)
i) Dehydration, poor nutritional status
j) Duration of cancer therapy
k) Malignancies associated with nephrotoxicity: Multiple myeloma, renal infiltration by tumor, and urinary obstruction from malignancy
4. Clinical manifestations: See signs and symptoms listed previously for specific syndromes of SIADH and TLS. Signs and symptoms associated with
renal dysfunction that require attention include the following (CampSorrell, 2011; Perazella & Moeckel, 2010).
a) Oliguria
b) Azotemia
c) Increasing SCr
d) Declining creatinine clearance (CrCl)
e) Elevated BUN
f) Hypomagnesemia
g) Proteinuria
h) Hematuria
i) Weight gain from fluid retention or edema
a) Prior to therapy, assess for risk factors of nephrotoxicity. Evaluate for
comorbidities (e.g., diabetes, hypertension, nephrectomy) and prior therapies that may contribute to renal toxicity (Kelly et al., 2009;
Naughton, 2008).
b) Physical assessment data (Camp-Sorrell, 2011; Kelly et al., 2009)
(1) Monitor vital signs.
(2) Monitor weight daily or as clinically indicated, especially in the
case of weight gain and edema.
(3) Monitor intake and output.
(4) Monitor for changes in mental status, level of consciousness,
or behavior.
c) Laboratory data
(1) SCr
(a) A rise in SCr usually indicates decreased GFR (Trombetta & Foote, 2009).
(b) Monitor creatinine and discontinue offending agent if rise
is noted (Camp-Sorrell, 2011).
(c) Criteria that have been used for AKI include a 50% rise in
SCr over baseline, an increase of 0.5 mg/dl or more when
baseline SCr is < 2 mg/dl, or an increase of 1 mg/dl if
baseline SCr is > 2 mg/dl (Naughton, 2008).
(2) BUN (Trombetta & Foote, 2009)
(a) Provides an estimate of renal function
(b) Level may vary and should be used with other studies to
evaluate renal function.
(3) CrCl
(a) Most common method used to estimate GFR
(b) Level may be determined from a 24-hour urine collection,
the Cockcroft-Gault equation, or the Modification of Diet
in Renal Disease formula (Flombaum, 2011; Trombetta &
Foote, 2009).
(c) Most drugs that are renally excreted do not require dose
reduction until GFR is below 50 ml/min/1.73 m2 (Naughton, 2008).
(4) Urine protein: Proteinuria indicates damage to the tubular and
glomerular systems (Trombetta & Foote, 2009).
(5) Urine pH, osmolarity, and uric acid (Trombetta & Foote, 2009)
(6) Chemistry panel: Calcium, phosphorus, and magnesium (Givens & Crandall, 2010; Trombetta & Foote, 2009)
d) Preventive measures
(1) Correct metabolic abnormalities prior to treatment (e.g., hypokalemia, hypomagnesemia) (Bhadauria & Agrawal, 2012).
(2) Hydrate patients with saline, approximately 3 L/day to prevent
or minimize renal damage, primarily with cisplatin and highdose methotrexate regimens (Camp-Sorrell, 2011).
(3) Assess for evidence of volume depletion such as orthostatic hypotension, blood pressure < 90/60 mm Hg, or decreased skin
turgor accompanied by a loss of > 5% of baseline body weight
(Launay-Vacher, Rey, Isnard-Bagnis, Deray, & Daouphars, 2008;
Naughton, 2008; Perazella & Moeckel, 2010).
(4) Adjust dose of medications for renal function. Most drugs that
are renally excreted do not require dose reduction until GFR
is below 50 ml/min/1.73 m2. Avoid nephrotoxic drug combinations (Naughton, 2008).
335
336
e) Early intervention
(1) At the first sign of renal dysfunction, review patients medications to determine any potential agents that could be causing
the altered renal function. If more than one agent is renal toxic and the patient is stable, discontinue the most recently added agent first (Naughton, 2008).
(2) Renal function generally returns to baseline if the impairment
is recognized early and the offending drug is discontinued
(Naughton, 2008).
(3) Treat hypertension. Encourage patients to monitor blood pressure at home (Kelly et al., 2009).
f) Drug-specific measures
(1) Cisplatin administration may result in acute declines in renal
function, salt-wasting and magnesium-wasting nephropathy,
and SIADH. The nephrotoxicity can be cumulative and may
occur after intraperitoneal and regional intra-arterial delivery
(Flombaum, 2011).
(a) Assess renal function studies prior to administration (check
BUN, SCr, and 24-hour CrCl), and discuss abnormal results
with physician (Wilkes & Barton-Burke, 2012).
(b) Institute vigorous saline hydration before and after therapy. Urine output should be at least 100150 ml/hr (CampSorrell, 2011; Wilkes & Barton-Burke, 2012).
(c) Mannitol may prevent renal damage from cisplatin. Loop
diuretics (furosemide) should be used with caution (Flombaum, 2011).
(d) Notify physician if CrCl < 50 mg/ml or if SCr is elevated.
Drug may be held until renal function improves (Flombaum, 2011).
(e) Monitor serum electrolytes and replace as ordered. Add
magnesium and potassium to IV hydration before and after cisplatin administration as ordered (Wilkes & BartonBurke, 2012).
(f) ASCO guidelines include the use of amifostine as a potential agent for the prevention of nephrotoxicity in patients
receiving cisplatin-based therapy (Hensley et al., 2009).
i. Amifostine is used to reduce the cumulative renal
toxicity experienced with multiple doses of cisplatin.
ii. Dose is 910 mg/m2 IV infused over 515 minutes after
antiemetics have been administered and the patient
has been hydrated with at least 1 L of fluid. Cisplatin
is administered 15 minutes after the amifostine is given (MedImmune Pharma B.V., 2013).
iii. Most common side effects are hypotension, nausea,
vomiting, flushing, chills, and dizziness (Vallerand &
Sanoski, 2012).
iv. Monitor blood pressure every five minutes throughout infusion and then as clinically indicated. Treat
systolic hypotension with fluid administration and
Trendelenburg position (MedImmune Pharma
B.V., 2013).
(2) Methotrexate: Both the parent drug and its metabolite are highly insoluble, especially in acidic and concentrated urine, leading to intratubular precipitation of the drug with large doses
(Flombaum, 2011).
(a) Check BUN and creatinine before, during, and after each
dose (Wilkes & Barton-Burke, 2012).
(b) Proper hydration (to ensure adequate urine volume) with

bicarbonate administration is needed to alkalinize the urine
before and after administration of high-dose (17.5 g/m2)
methotrexate to prevent urine crystallization.
(c) Monitor urine pH and maintain at > 7. Record intake and
output (Wilkes & Barton-Burke, 2012).
(d) Monitor methotrexate levels. To minimize systemic toxicity, leucovorin must be administered on time (usually beginning 24 hours after the start of methotrexate) and continued until serum methotrexate levels decrease below 0.05
0.1 mcmol/L (Camp-Sorrell, 2011; Flombaum, 2011). Administer oral leucovorin with antacids, milk, or juice (Wilkes
& Barton-Burke, 2012).
(e) Ensure that patients do not take oral folic acid during methotrexate therapy (Wilkes & Barton-Burke, 2012).
(f) Drugs that are protein-bound (e.g., aspirin, sulfonamides,
phenytoin) may increase toxicity and must be used
cautiously. Monitor patients closely (Wilkes & BartonBurke, 2012).
(g) Do not administer NSAIDs concurrently with methotrexate. Drug levels may be increased and prolonged (Wilkes
& Barton-Burke, 2012).
(h) Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients necessitate especially careful monitoring for toxicity
and require dose reduction or discontinuation of methotrexate (Flombaum, 2011).
6. Patient and family education (Camp-Sorrell, 2011; Fairclough & Brown,
2010; Wilkes & Barton-Burke, 2012)
a) Educate patients about the risk of nephrotoxicity with certain cytotoxic agents.
b) Provide patients with a list of drugs to avoid that can lead to renal
dysfunction.
c) Teach patients and family members the need for increased oral fluids on discharge. Intake should be up to 3 L or more for five days after therapy.
d) Ensure that patients understand the reasons for changes in urine output, electrolyte depletion, and increasing SCr and BUN.
e) Reinforce the importance of complying with preventive measures including alkalinization of urine, allopurinol or amifostine treatment,
and the need to take leucovorin rescue as prescribed.
f) Instruct patients on when and how to notify the healthcare team, including if
(1) Unable to make urine for more than 12 hours
(2) Only very small amounts of urine are produced
(3) Urine is dark, concentrated, pink, bloody, or cloudy
(4) Edema or weight gain occurs.
J. Neurotoxicity: Cancer therapy uses a combination of treatment modalities
such as surgery, radiation, and chemotherapy that may improve patient outcomes (Butowski & Chang, 2005). However, combination therapy and extended survival often are associated with potential acute or delayed neurotoxicity. Neurotoxicity can arise as direct or indirect damage to the CNS, peripheral nervous system, cranial nerves (CNs), or any combination of the
three (Gilbert, 2008). Some drugs cause neurotoxicity at low doses, whereas others cause neurotoxicity only during intensive therapy. Neurologic toxicity is a dose-limiting factor in several cancer treatments, such as radiation
337
338
therapy. Patients may suffer more from the toxicities than from the cancer
itself (Quasthoff & Hartung, 2002).
1. Pathophysiology
a) CN deficits: These deficits result from damage to one of the 12 CNs
arising from the brain stem. The result depends on which nerve is damaged (Barker, 2008). Examples of CN deficits include the following.
(1) Olfactory (CN I): Loss or decrease of smell
(2) Optic (CN II): Loss of visual acuity, optic atrophy, altered visual field
(3) Oculomotor (CN III): Ptosis, dilated pupils, altered ocular muscle function, nystagmus
(4) Trochlear (CN IV): Altered ocular muscle function causing
nystagmus
(5) Trigeminal (CN V): Numbness, poor blink reflex, weakened
chewing
(6) Abducens (CN VI): Altered ocular muscle function causing
nystagmus
(7) Facial (CN VII): Facial paralysis, drooping mouth, sagging lower eyelid, flat nasolabial fold
(8) Acoustic (CN VIII): Sensory neuronal hearing loss, vertigo, ataxia, nausea and/or vomiting
(9) Glossopharyngeal (CN IX): Altered sense of taste, altered throat
sensation
(10) Vagus (CN X): Hoarseness, altered gag reflex, altered swallowing function
(11) Spinal accessory (CN XI): Tilting of head, weakness of shoulder muscles
(12) Hypoglossal (CN XII): Abnormal tongue movement
b) Peripheral nervous system deficits are a result of damage to sensory
and motor nerves outside the CNS, including the autonomic nerves.
Peripheral neuropathy is estimated to occur in 10%20% of patients
with cancer. It is commonly associated with the use of platinum drugs,
taxanes, epothilones, vinca alkaloids, bortezomib, and lenalidomide
(Fernndez-de-Las-Peas et al., 2010). Peripheral neuropathy is caused
by chemotherapy injuring the sensory and motor axons. This results
in demyelination, which reduces nerve conduction velocity and leads
to loss of deep tendon reflexes. Disorders of one or more peripheral nerves cause signs and symptoms that correspond to the anatomic distribution and normal function of the nerve. The distal branches are most affected by axonal transport flow disruption, causing the
stocking-and-glove pattern of sensory loss (Stillman & Cata, 2006).
Signs and symptoms of a peripheral nerve disorder may include sensory, motor, or autonomic disturbances (Hickey, 2009). The CTCAE
(NCI CTEP, 2010) is used to identify the severity of the neuropathy.
Grades range from 1 (mild symptoms) to 5 (death). See Table 39.
(1) Sensory nerve fibers: Decrease or loss of light touch and pinprick sensation along the involved dermatome. Tingling, numbness, paresthesias, and dysesthesias are common. Paresthesias are
unusual sensations such as pins and needles; dysesthesias are
unpleasant sensations such as burning (Hickey, 2009). Cisplatin causes an axonal neuropathy that primarily affects large myelinated sensory fibers.
(2) Motor nerve fibers: Symmetric generalized motor weakness that
may cause decreased balance, strength, and activity level, foot
or wrist drop, myalgias, and muscle cramping (Armstrong, Almadrones, & Gilbert, 2005). Paclitaxel causes a motor neuropathy, which predominantly affects proximal muscles. A pacliCopyright 2014 by the Oncology Nursing Society. All rights reserved.
339
Table 39. National Cancer Institutes Common Terminology Criteria for Adverse Events: Neuropathies
Grade
Adverse Event
Cranial nerve disorder

(cranial nerve specific)
Asymptomatic; clinical
or diagnostic observations only; intervention
not indicated
Moderate symptoms; limiting instrumental ADL
Severe symptoms; limiting

self-care ADL
Death
Peripheral motor neuropathy
Asymptomatic; clinical
or diagnostic observations only; intervention
not indicated

self-care ADL;
assistive device
indicated
Death
Peripheral sensory neuropathy
Asymptomatic; loss of
deep tendon reflexes
or paresthesia

self-care ADL
Death
ADLactivities of daily living

Note. From Common Terminology Criteria for Adverse Events [v.4.03], by National Cancer Institute Cancer Therapy Evaluation Program, 2010, Bethesda,
MD: National Cancer Institute.
taxel-associated pain syndrome can develop, which is characterized by severe arthralgias and myalgias (Loprinzi et al., 2011).
(3) Decreased or absent deep tendon reflexes are the two most common and earliest symptoms of peripheral neuropathy caused
by vincristine. The incidence of vincristine-induced areflexia is
57% (Armstrong et al., 2005).
(4) Autonomic nerves: Constipation, paralytic ileus (rare), urinary
retention, incontinence, erectile dysfunction, and orthostatic
hypotension. Autonomic symptoms commonly seen with bortezomib include constipation and orthostatic hypotension; with
thalidomide, constipation, impotence, and bradycardia are common (Tariman, Love, McCullagh, & Sandifer, 2008).
c) CNS deficits: These deficits have multiple causes (e.g., metabolic imbalances, intracranial hemorrhage, infection related to chemotherapy-induced coagulopathy or myelosuppression, IT or intra-arterial
chemotherapy, high-dose therapy). Deficits depend on the area of
brain or brain stem affected (Gilbert, 2008).
(1) Acute or chronic encephalopathy: Symptoms of acute highdose methotrexate neurotoxicity include somnolence, lethargy, and confusion within 24 hours (Dietrich & Wen, 2008).
Methotrexate at a high dose in the CNS causes encephalopathy or posterior reversible encephalopathy syndrome (PRES).
The main symptoms associated with PRES are encephalopathy
(92%), seizures (87%), headache (53%), and visual symptoms
(39%) (Hodnett, Coyle, ORegan, Maher, & Fanning, 2009).
The pathogenesis of PRES is unclear, but it appears to be related to disordered autoregulation and endothelial dysfunction.
This has become an increasingly recognized neurologic disorder (Hodnett et al., 2009). PRES has been associated with the
use of cisplatin, rituximab, bevacizumab, and immunosuppressive therapy such as tacrolimus or cyclosporine (Seet & Rabinstein, 2012). PRES is a reversible condition that warrants either
dose reduction or withholding the causative agent, which results in a complete recovery for most patients (Aranas, Prabhakaran, & Lee, 2009).
340
(2) Seizures: Can occur as a result of structural abnormalities of

the brain (brain metastasis), cerebrovascular disease, PRES,
and radiation toxicity (Pulzova, Bhide, & Andrej, 2009). The
following chemotherapy agents are known to cause seizures:
asparaginase, BCNU (carmustine), busulfan, cisplatin, cyclophosphamide, dacarbazine, docetaxel, etoposide, 5-FU, gemcitabine, IFN, ifosfamide, IL-2, suramin, temozolomide, teniposide, thalidomide, and vinca alkaloids (Glantz & Batten, 2008).
(3) Cerebellar dysfunction: Truncal, limb, and gait ataxia; dysarthria (staggered gait and postural imbalance); difficulty speaking; slow or irregular speech; nystagmus
(4) The blood-brain barrier contributes to the immune privilege of
the CNS; however, significant cross talk and bidirectional communication occur between the CNS and the immune system
(Maier & Watkins, 2003). The release of proinflammatory cytokines (e.g., IL-1, IL-6, TNF-) in the peripheral blood leads
to penetration of the blood-brain barrier and production of
proinflammatory cytokines in the CNS (Myers, Pierce, & Pazdernik, 2008). The proinflammatory cytokines are associated
with a syndrome of behaviors and symptoms known as sickness behavior (Kronfol & Remick, 2000). Sickness behavior includes fever, fatigue, lethargy, muscle aches, decreased ability to concentrate, and decreased social interaction (Parnet, Kelley, Bluth,
& Dantzer, 2002)
(5) Ifosfamide and some of its metabolites can cross the blood-brain
barrier (Verstappen, Heimans, Hoekman, & Postma, 2003). Nitrosoureas are alkylating agents that can cross the blood-brain
barrier and are used to treat brain tumors, melanoma, and
lymphomas. Concomitant administration of dexamethasone
or mannitol may reduce side effects of cerebral edema as a result of penetration of the blood-brain barrier (Wilkes & BartonBurke, 2013).
2. Incidence: Exact incidence is unknown, but as newer agents and targeted
therapies are being developed, the number and range of neurotoxicities
are increasing (Dropcho, 2010). Incidence is also increasing with greater use of high-dose chemotherapy, the use of more than one neurotoxic agent at a time or sequentially, and with increased detection because
of objective and subjective assessment (Dropcho, 2010) (see Table 40).
3. Risk factors
a) Regimens that include high-dose chemotherapy are associated with
blood-brain barrier penetration; most chemotherapeutic agents do
not cross the blood-brain barrier in standard doses (Saykin, Ahles, &
McDonald, 2003). Some exceptions are methotrexate, cisplatin, cytarabine, ifosfamide, procarbazine, temozolomide, carmustine, lomustine (Wilkes & Barton-Burke, 2013), and topotecan (Wong &
Berkenblit, 2004).
b) Route of administration: IT methotrexate and liposomal cytarabine
may be used to treat meningeal leukemia or lymphoma. Although
rare, toxicity to the spinal cord, which can be severe, can result from
IT drug administration (Schlegel, 2011). Methotrexate and liposomal cytarabine can cause irritation of the spinal cord; patients can
experience transient pain that may progress to spinal cord dysfunction (Schlegel, 2011). High peripheral doses can cause neurotoxicity
(e.g., lethargy, somnolence) and cerebellar toxicity (e.g., nystagmus,
dysarthria, ataxia, slurred speech, decreased ability to make fine coordinated movements) (Wilkes & Barton-Burke, 2013).
341
Table 40. Neurotoxicity of Antineoplastic Agents

Classification
Alkylating
agents
Antimetabolites
Drug
Incidence of Neurotoxicity
Characteristic Effects and Comments
Busulfan
Low at conventional dosing; high dosing can

cause seizures (Otsuka America Pharmaceutical, Inc., 2011).
Administer seizure prophylaxis (e.g., phenytoin). Use caution when administering the recommended dose of busulfan to patients with
a history of a seizure disorder or head trauma
or who are receiving other potentially epileptogenic drugs (Otsuka America Pharmaceutical, Inc., 2011).
Cisplatin
Occurs with cumulative doses beyond 400 mg/

m2 (van der Hoop et al., 1990)
Symptomatic hearing loss affects 15%20% of
patients, and hearing impairment in more than
three-fourths of the patients (Oldenburg et al.,
2007).
Genetic polymorphisms responsible for cisplatin
metabolism may contribute to individual hearing loss (Oldenburg, 2007).
Numbness, paresthesia, and pain in toes and

fingers spreading proximally to the arms and
legs; proprioception is impaired and reflexes
are lost, but power is almost always spared
(Hilkens et al., 1995).
Radiation therapy to the normal cochlea or cranial nerve VIII with concurrent administration
of cisplatin results in ototoxicity (Low et al.,
2006). Ototoxicity can be severe in children
(Li et al., 2004).
Lhermitte sign is a shock-like, nonpainful paresthesia radiating from the back to the feet
during neck flexion (Dietrich & Wen, 2008).
Ifosfamide
Encephalopathy develops in 10%20% of patients (David & Picus, 2005).

Rare toxicities are seizures, ataxia, weakness,
and neuropathies (Posner, 2001).
Symptoms can occur during drug administration and usually resolve within several days
(David & Picus, 2005).
Patients at risk for toxicities include those with
a prior history of ifosfamide-related encephalopathy, renal dysfunction, or low serum albumin prior to treatment (Posner, 2001).
Oxaliplatin
Acute symptoms were observed more frequently with doses > 130 mg/m2 than with doses <
85 mg/m2 and are dependent on infusion rate
(Gamelin et al., 2002). However, a trial found
increasing neurotoxicity with a dose of 680
mg/m2 (Green et al., 2005).
Symptoms consist of striking paresthesias and

dysesthesias of the hands, feet, and perioral
region with jaw tightness. Symptoms are often induced or aggravated by the cold (Lehky et al., 2004).
Capecitabine
Paresthesias were common for less than 10% of

patients treated (Renouf & Gill, 2006).
Paresthesias, headaches, dizziness, or insomnia can occur. Cerebellar toxicity has been reported (Renouf & Gill, 2006). Symptoms resolved after stopping the drug (Videnovic et
al., 2005).
Cytarabine
Conventional doses cause little toxicity. Highdose, 3 g/m2, every 12 hours for 6 doses can
cause an acute cerebellar syndrome in 10%
25% of patients (Smith et al., 1997).
Patients older than age 50 with abnormal liver
or renal function or who received a total dose
> 30 g are likely to develop cerebellar toxicity
(Smith et al., 1997).
Symptoms begin with somnolence and occasionally encephalopathy. Immediately thereafter, cerebellar signs are noted. Symptoms
range from mild ataxia to an inability to sit or
walk.
No specific treatment, but cytarabine should be
stopped immediately. In some, the syndrome
resolves immediately, but it is permanent in
others (Friedman & Shetty, 2001).
5-Fluorouracil
Rare side effects including encephalopathy, optic neuropathy, or seizures have been recorded (Pirzada et al., 2000).
Symptoms of an acute onset of ataxia, dysmetria, and dysarthria can develop weeks to
months after beginning treatment. Stop 5-fluorouracil in any patient with cerebellar toxicity; with time, symptoms will resolve (Pirzada
et al., 2000).
342
Table 40. Neurotoxicity of Antineoplastic Agents (Continued)

Classification
Drug
Antimetabolites
(cont.)
Gemcitabine
Up to 10% of patients experience mild paresthesias during treatment, but severe peripheral
and autonomic neuropathies can occur (Dormann et al., 1998).
Acute inflammatory myopathy and asymmetric,

painful, proximal muscle weakness can occur
(Ardavanis et al., 2005).
Myositis can occur when gemcitabine is given
during or after radiation (radiation recall phenomenon) (Friedlander et al., 2004).
Methotrexate
Generalized or focal seizures have been reported among pediatric patients with acute lymphocytic leukemia treated with intermediatedose IV methotrexate (1 g/m2) (Teva Pharmaceuticals USA, 2012b).
Acute chemical arachnoiditis can occur after
intrathecal methotrexate and presents with
symptoms such as headache, back pain, nuchal rigidity, and fever (Teva Pharmaceuticals
USA, 2012b).
Acute neurotoxicity is most frequently seen after
high-dose methotrexate and may develop in
the second or third week of therapy (Schmiegelow, 2009).
Symptomatic patients were commonly noted to

have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging
studies (Teva Pharmaceuticals USA, 2012b).
Symptoms such as somnolence, confusion,
hemiparesis, transient blindness, seizures,
and coma may occur (Teva Pharmaceuticals USA, 2012b); leucovorin administration
should begin as promptly as possible. Monitoring of serum methotrexate concentration is
essential in determining optimal dose and duration of leucovorin treatment (Teva Pharmaceuticals USA, 2012b).
Epothilone
Ixabepilone
Neurotoxicity is cumulative. Median time to onset of grade 34 neuropathy was 4 cycles.
Dose reduction of 20% is recommended for

patients with grade 2 (moderate) neuropathy persisting 7 days (Bristol-Myers Squibb
Co., 2011c).
Interferons
(IFNs)
IFN alfa
Low-dose toxicity causes tremors. High-dose

toxicity is rare and includes oculomotor palsy and sensory motor neuropathies (Rutkove,
1997).
Neurotoxicity tends to be dose related. High

doses can cause confusion, lethargy, hallucinations, and seizures (Meyers et al., 1991).
IFN alfa-2a,
IFN alfa-2b
Incidence of neuropsychiatric depression and

suicidal behavior was > 15% (Hensley et al.,
2000).
Depression, anxiety, or emotional lability was
seen in 4%40% of patients (Hensley et al.,
2000).
Motor weakness can be seen at high doses (>

100 million units) and reverses within days
(Hensley et al., 2000).
All patients recovered upon withdrawal of drug.
Those with psychiatric history were more likely to develop neuropsychiatric toxicity (Hensley et al., 2000).
Interleukin (IL)
IL-2
Neuropsychiatric complications occur in 30%

50% of patients (Denicoff et al., 1987).
Toxicity is dose dependent. Confusion may be

a dose-limiting effect of high-dose IL-2 (Petrella et al., 2007).
Monoclonal
antibody
Bevacizumab
Posterior reverse encephalopathy syndrome

(PRES) occurs infrequently (Seet & Rabinstein, 2012).
Headache, seizure, lethargy, confusion, and

blindness can occur. PRES associated with
mild to moderate hypertension has been reported. Symptoms can occur up to 1 year after therapy. Symptoms usually resolve after
stopping the bevacizumab and controlling hypertension (Allen et al., 2006).
Protease
inhibitors
Bortezomib
Peripheral neuropathy is the main dose-limiting toxicity, and grade 1 or 2 peripheral neuropathies affect 33% of patients (Richardson
et al., 2003).
Peripheral neuropathy is length dependent and

sensory rather than motor (Cata et al., 2007).
Symptoms include reduced ankle reflexes,
decreased vibration sensation, and impaired
heel-to-toe gait (Gidal, 2006). Symptoms can
improve or stabilize after patient stops or decreases the dose of the drug (Jagganath et
al., 2004).

343
Table 40. Neurotoxicity of Antineoplastic Agents (Continued)

Classification
Plant alkaloids
Purine analog
Drug
Thalidomide
Peripheral neuropathy develops in approximately 75% of patients who receive a prolonged

course of thalidomide (Cavaletti et al., 2004;
Mileshkin et al., 2006; Tosi et al., 2005).
Somnolence can occur and stops after a few
weeks on therapy.
The neuropathy is partially reversible, and dose

reduction or cessation of treatment is required in up to 60% of patients (Mileshkin et
al., 2006; Tosi et al., 2005).
Examine patients at monthly intervals for the
first 3 months to detect early signs of neuropathy, which include numbness, tingling,
and pain in hands and feet (Celgene Corp.,
2013b).
Lenalidomide is less neurotoxic but still can
produce peripheral grade 23 neuropathy.
Docetaxel
Sensory and motor neuropathies can occur.

Grade 3 or 4 (National Cancer Institute Cancer Therapy Evaluation Program, 2006) neuropathies occur in less than 5% of patients
Treatment with docetaxel has been associated with the development of Lhermitte sign
Paclitaxel
Sensory and motor neuropathies are common

with paclitaxel. The incidence of grade 3 or 4
neuropathy occurs in patients receiving 250
mg/m2 every 3 weeks compared to 5%12%
with dosing of < 200 mg/m2 every 3 weeks
(Lee & Swain, 2006).
Neuropathy with burning paresthesias of the

hands and feet can occur (Lee & Swain,
2006). Paresthesias are dose dependent and
can be profound with numbness and a decrease in deep tendon reflexes (Postma &
Heimans, 2000).
Vincristine
Vincristine causes some degree of neuropathy.

The toxicity is severe in adults, dose dependent,
and more prominent with hepatic dysfunction
(Donelli et al., 1998).
Autonomic neuropathy such as colicky abdominal pain and constipation occurs in almost
50% of patients; paralytic ileus may result
(Verstappen et al., 2005).
Symptoms include paresthesias of the fingertips and feet. Symptoms can occur with the
first dose, may appear after the drug has been
stopped, and can progress before improving.
Weakness can be mild, such as inability to walk
on heels or decreased strength in wrists, or
more severe, such as foot drop and foot slapping when walking (Verstappen et al., 2005).
Nelarabine
In phase 2 studies, 40%75% of patients had

neurotoxicity of any grade; 15%20% were
grade 3 (Cohen et al., 2006).
Peripheral neuropathy can mimic Guillain-Barr

syndrome (Schiff et al., 2009). Seizures have
been reported.
c) Concomitant cranial or spinal cord radiation therapy causes cells in

the CNS to replicate slowly or not at all. The brain and spinal cord,
and to a lesser degree the peripheral nerves, are susceptible to damage by ionizing radiation that usually causes symptoms months or
years after completion of radiation treatment (Belka, Budach, Kortmann, & Bamberg, 2001). Radiation myelopathy may present as early as four to six months or as late as one to two years after treatment.
Delayed radiation myopathy can occur even if the radiation dose is
considered safe or standard (Dropcho, 2010).
d) Age
(1) Cerebellar neurotoxicity of cytarabine and vincristine increases
with age. However, neurotoxicity varies with dose and route of
administration for both agents (Voss & Wilkes, 1999).
(2) Children are at higher risk than adults for ototoxicity because
childrens inner ears are not fully developed. Although children may have a slightly greater capacity for improvement once
treatment is discontinued, profound hearing impairment can
interfere with subsequent speech and language development
(Knight, Kraemer, & Neuwelt, 2005).
(3) Older adults and pediatric patients receiving biologic agents
are at increased risk for neurotoxicity (Muehlbauer, 2011). The
344
risk and severity of chemotherapy-induced peripheral neuropathy appear to increase with age, and neuroprotective pharmacologic agents have had limited success (Visovsky, Collins, Abbott, Aschenbrenner, & Hart, 2007). The drugs used to treat the
most common cancers (breast and lung) in older adults result in
neuropathy. This includes the taxanes, vinca alkaloids, platinum
complexes, thalidomide, and suramin (Malik & Stillman, 2008).
e) Acute renal injury or renal impairment can occur with high-dose
methotrexate and may be altered by drug excretion, which is related
to hydration and urinary alkalinization (Schmiegelow, 2009).
f) Steroids can lead to a variety of systemic and neurologic complications. Myopathy, which presents as skeletal muscle weakness and tenderness, is a common side effect associated with steroid therapy. Myopathy may be so severe that it can impair mobility by causing inability to lift arms and legs and preventing ambulation. Treatment is
dose reduction or taper with discontinuation (Owczarek, Jasiska, &
Orszulak-Michalak, 2005).
g) Preexisting neuropathy can be caused by concomitant medical conditions (e.g., diabetes, vitamin B12 deficiency, thyroid dysfunction, cachexia, Charcot-Marie-Tooth disease, hearing loss) (Armstrong & Gilbert, 2002). Peripheral neuropathy can have other etiologies including alcoholism, HIV and other immunosuppressive illnesses, congenital neuropathy, other neurotoxic medications, and exposure to certain toxins and metals (Hughes, 2002).
4. Assessment
a) Neurologic assessment enables determination of changes in the CNS,
peripheral nervous system, and CNs. The hallmark for optimal care
begins with assessment followed by documentation of findings (Barker, 2008). Patient-reported symptoms as well as careful physical assessment are critical in the detection of neurotoxicity.
b) Identify patients who are at increased risk for neurotoxicity based
on risk factors.
c) Perform a neurologic examination prior to each chemotherapy/biotherapy treatment and subsequent medical visits that includes evaluation of level of consciousness, sensory and motor function, gait, range
of motion, CN function, and reflexes. Evaluation includes
(1) Peripheral neuropathy grading criteria scale (NCI CTEP, 2010)
(2) CNS deficits as described in Section 1.c
(3) CN assessment (see Table 41).
d) Assess pain. Despite a plethora of research and publications, pain continues to be common in adults with cancer (American Pain Society,
2005; NCCN, 2013a). A pathophysiologic approach to pain management is required in patients with cancer. Such an approach includes
a patient history, physical examination, and dedicated testing to determine whether pain is visceral, somatic, or neuropathic (de LeonCasasola & Lema, 2003). Patients describe visceral pain as gnawing,
cramping, aching, or sharp (NCCN, 2013a). Visceral pain is diffuse,
and many patients use a whole hand to describe where it hurts. With
somatic pain, patients can describe where it hurts with one finger.
Neuropathic pain usually is described as sharp, tingling, burning, or
shooting (NCCN, 2013a). Neuropathic pain caused by chemotherapy is often distinguished by a cluster of symptoms: spontaneous pain
that is both constant and intermittent, loss of sensation, and motor
symptoms (Tofthagen, 2010). Pain is a nursing-sensitive outcome.
Nursing-sensitive outcomes are those that are attainable through or significantly affected by interventions that are within the scope of nursing practice (Gobel, Beck, & OLeary, 2006).
345
Table 41. Neurologic Assessment of the Cranial Nerves

Cranial Nerve
Test
Dysfunction
Olfactory I
Check first for obstruction, mucus, and inflammation. Test one nostril at a time.
Anosmia
Optic II
Determine if patient wears glasses. Have patient read held-up fingers.
Blind eye
Oculomotor III
Test one eye at a time. Shine flashlight in eye; note brisk constriction.
Lids should not dip below top of iris (ptosis).
Ask patient to follow your finger/light as you move it up, down, and medially.
Nonreactive pupil, ptosis
Trochlear IV
Ability to move eyes down and in
Inability to move eyes down

and in
Trigeminal V
Patient closes eyes. Stroke three zones of face, comparing right to left.
If awake, stroke cornea gently with cotton. Normal response is lid closure.
Blink reflex decreased or absent
Abducens VI
Ability to look out (abduct)
Inability to look out
Facial VII
Test all three zones; ask patient to close eyelids, wrinkle brow, raise eyebrows,
wiggle nose, pucker, show teeth, smile, and puff out cheek.
Inability to close eyelids, raise

eyebrows, wiggle nose, or
puff out cheeks
Acoustic VIII
Ask patient to open eyelids and turn head side to side. Eyes will move to opposite direction.
Have patient close eyes, and test for sounds (tick of watch, rubbing fingers,
faint whisper).
Eyes will not move when turning head side to side.
Glossopharyngeal/
vagus IX and X
Assess patients gag, palate, swallow, and speech. Look for midline uvula.
Note ability to give healthy cough.
Palate sags on weak side.

Uvula swings to strong side.
Decreased cough.
Spinal accessory XI
Have patient turn chin against resisting examiners hand. Push down on both
shoulders as patient elevates them.
Weakness
Hypoglossal XII
Ask patient to stick out tongue; note position and symmetry.
Tongue deviates to weak side.
Ask patient to put tongue in cheek and push.
Weakness
Note. From The Clinical Practice of Neurological and Neurosurgical Nursing (6th ed., p. 164), by J.V. Hickey, 2009, Philadelphia, PA: Lippincott Williams &
Wilkins. Copyright 2009 by Lippincott Williams & Wilkins. Adapted with permission.
e) Administer self-report questionnaires that assess neurologic function

and QOL at baseline and subsequent visits (Almadrones, McGuire,
Walczak, Florio, & Tian, 2004).
f) Assess hearing with audiogram prior to ototoxic chemotherapy (e.g.,
cisplatin, carboplatin) to establish baseline.
g) Older adults require different examination considerations.
(1) Use a quiet area and reduce background noise.
(2) Use a low-pitched, soft voice and address patients by surnames.
(3) Review medicines at every encounter.
(4) Always ask about pain.
(5) Do not expect a typical presentation of chronic or acute diseases (Barker, 2008).
h) Assess patients environment to ensure safety with impaired function.
i) Assess patient and family coping.
a) Use assessment guidelines for early detection and treatment.
b) Reduce drug dose, discontinue drug, or switch to a less neurotoxic drug
as ordered when neurologic deficits occur (Rose & Smrekar, 2003).
c) No proven pharmacologic intervention is currently available for neurotoxicity prevention. Clinical trials using amifostine and glutamine
have been equivocal (Moore et al., 2003).
d) Manage concomitant medical conditions known to cause and increase
chemotherapy-related neurotoxicity (e.g., diabetes, vitamin B12 caCopyright 2014 by the Oncology Nursing Society. All rights reserved.
346
chexia, Charcot-Marie-Tooth disease) (Armstrong & Gilbert, 2002).

Chemotherapy-induced peripheral neuropathy is more likely to occur in individuals with baseline peripheral neuropathy (Chaudhry,
Chaudhry, Crawford, Simmons-OBrien, & Griffin, 2003).
e) Use of vitamins and minerals to treat neurotoxic side effects
(1) Vitamin E is an antioxidant believed to protect against cellular
oxidative damage and side effects such as numbness, tingling,
burning, and pain in peripheral extremities produced by cisplatin and other cytotoxic drugs (Visovsky, Collins, Abbott, Aschenbrenner, & Hart, 2007).
(2) Calcium and magnesium infusions were used in patients receiving oxaliplatin. Oxalate, an oxaliplatin metabolite, seeks and
binds to calcium and magnesium, which is responsible for the
neurotoxic effects of oxaliplatin therapy. Following infusion of
calcium and magnesium, patients experienced improvements
in pseudolaryngospasm and other clinical manifestations of
acute neurotoxicity (Gamelin et al., 2004).
(3) These studies were done with small samples and will need to
be tested further in larger randomized controlled clinical trials. Other agents that are being investigated but need substantiation include glutathione, N-acetylcysteine, oxcarbazepine,
and xaliproden (Fernndez-de-Las-Peas et al., 2010). More recently, however, a trial was conducted in 353 patients with colon cancer undergoing adjuvant therapy with FOLFOX (5-FU,
oxaliplatin, and leucovorin) who were randomized to receive
IV calcium and magnesium (1 g calcium gluconate, 1 g magnesium sulfate) or placebo before and after oxaliplatin (Loprinzi
et al., 2013). In a third arm in the trial, patients received calcium and magnesium before and placebo after the oxaliplatin.
The results showed no differences between the groups in either
acute neurotoxicity or cumulative sensory neurotoxicity, as assessed both by patient and physician questionnaires.
f) Administer analgesic medications. The three most commonly used
are NSAIDs, opioids, and adjuvant agents such as tricyclic antidepressants and corticosteroids (de Leon-Casasola & Lema, 2003).
g) Administer analgesics with coanalgesic medications. The effectiveness of analgesics is variable, so drugs and dosing must be individualized. Coanalgesics were previously referred to as adjuvants. Individualized categories of coanalgesics include anticonvulsants, antidepressants, and topical anesthetics. With many coanalgesics, the onset
of pain relief is delayed and analgesia may take weeks (Aiello-Laws et
al., 2009). Coanalgesics should be administered as a single agent for
management of neuropathic pain. First-line therapies include antidepressants, tricyclic antidepressants, selective serotonin-norepinephrine reuptake inhibitors, gabapentin, pregabalin, topical lidocaine,
and opioid analgesics (Dworkin et al., 2007).
h) Consider consultation with a neurologist; occupational, physical, or
speech therapist; or audiologist. Consider nerve function and mobility
tests over the course of the cancer treatment and refer patients to prevent or rehabilitate nerve deficits (Hile, Fitzgerald, & Studenski, 2010).
i) Consider nonpharmacologic management (e.g., exercise, relaxation
techniques such as yoga, meditation, acupuncture, deep breathing,
and guided imagery) (Richardson, Sandman, & Vela, 2001). Neuropathic pain usually does not respond to analgesics alone. In these patients, mind-body techniques may be especially worthwhile, as they may
alter the perception of pain (Deng & Cassileth, 2005). Physical activity and exercise interventions have not been studied in the prevention
or treatment of peripheral neuropathy in patients with cancer. Studies

with small sample sizes have examined progressive resistance exercise,
aerobic exercise, and stretching exercises in the treatment of diabetic neuropathy and myotonic dystrophy. All three found significant improvements in outcomes such as stance and functional reach (Balducci et al., 2006). It has been demonstrated that acupuncture activates
both myelinated and unmyelinated nerve fibers (Zhao, 2008). Studies
of the use of acupuncture to help alleviate symptoms related to peripheral neuropathy have been conducted in patients with diabetes. Zhang,
Ma, and Yan (2010) reported effective treatment in both the treatment
and control group in a population of 65 patients with diabetic neuropathy treated with acupuncture. The study size was small, and further
randomized controlled clinical trials are needed in patients with cancer. Most studies to date have focused on outcomes at the impairment
level, but physical performance measures could be useful in determining functional limitations and restricted participation in response
to side effects such as neuropathy and fatigue (Gilchrist et al., 2009).
a) Instruct patients and significant others that neurotoxicity is a possible side effect of selected cytotoxic agents. Teach strategies to manage
symptoms of autonomic dysfunction (postural hypotension, constipation, and urinary retention), such as dangling legs prior to standing,
increasing oral intake, and adding dietary fiber (Visovsky et al., 2007).
b) Emphasize patient safety issues and provide educational materials.
Teach clients strategies for managing personal safety, such as using visual input to compensate for loss of lower-extremity sensation in navigating changing terrains, such as removing throw rugs and clearing
walkways of clutter (Visovsky et al., 2007). Currently, the only interventions that can be recommended for nursing practice are education and support to preserve safety (Paice, 2007).
c) Provide information regarding signs and symptoms of neurotoxicity,
and instruct patients to report these symptoms to the physician and/
or nurse as soon as they or their families notice them.
d) Instruct patients about the risk for ischemic and thermal injuries resulting from loss of sensation in the extremities. Patients should protect body parts from cold and hot temperature extremes (Visovsky et
al., 2007). Educate patients regarding foot care, including inspection
of the feet and importance of wearing properly fitted shoes.
e) Provide information about the potential side effects of medications that
can cause or change neurologic symptoms. Any changes in thinking or
behavior should be evaluated if they begin to affect the patients lifestyle.
f) Educate patients and significant others regarding any needed referrals, support organizations, adaptations, and rehabilitative strategies.
Instruct patients to keep a notepad or diary and write down everything that is important, keep a detailed calendar of events, and take
a friend or family member to doctors appointments.
g) Educate patients and families about seizures. Teach family members
to not restrain the person during a seizure, to turn the persons head
to the side if vomiting with a seizure, and to avoid putting anything
in the persons mouth during the seizure. Instruct patients to wear a
medical alert bracelet at all times. If patients have had a seizure, instruct them not to drive a car or operate any type of heavy machinery.
K. Cognitive impairment: Studies suggest that cancer and its treatments (i.e., surgery, radiation therapy, chemotherapy, hormonal therapy, immunotherapy)
can cause changes in cognitive functioning (Joly, Rigal, Noal, & Giffard, 2011;
Khasraw & Posner, 2010; Wefel & Schagen, 2012). Cognitive function is a mulCopyright 2014 by the Oncology Nursing Society. All rights reserved.
347
348
tidimensional concept that encompasses multiple domains (i.e., attention and

concentration, executive function, information processing speed, language,
motor function, visuospatial skill, learning, and memory) that are regulated
by the brain (Jansen, 2010). Cognitive impairment is a decline in function in
either one or multiple domains of cognitive function and may represent a single highly specific deficit or a cluster of related deficits (Lezak, Howieson, Bigler, & Tranel, 2012; Von Ah, Jansen, Allen, Schiavone, & Wulff, 2011). Despite
heightened interest in cancer treatmentrelated cognitive impairment, it remains the least understood toxicity. Identifying cognitive changes associated
with cancer treatments is challenging, as even patients with cancers outside of
the CNS may present with cognitive impairment prior to treatment (Jansen,
2010; Wefel & Schagen, 2012). Cognitive functioning is influenced by risk factors and confounding variables that are independent of cancer and/or cancerrelated treatment. The science defining the phenomena, potential mechanisms,
sensitive neuropsychological measures, and potential interventions is ongoing.
1. Pathophysiology: Although cancer therapies that have been associated
with cognitive changes include surgery, radiation therapy, chemotherapy, hormonal therapy, and immunotherapy, the use of multimodal therapy makes it difficult to determine the underlying mechanism for cognitive impairment. In fact, the presence of cancer and tumor burden may
attribute to cognitive impairment prior to the initiation of treatment
(Wefel & Schagen, 2012). The mechanisms of cancer treatmentrelated cognitive changes are thought to be multifactorial, and although animal studies have elucidated many hypotheses, the actual mechanisms
for individual and multimodal treatments are still not fully understood
(Walker, 2010; Walker, Drew, Antoon, Kalueff, & Beckman, 2012). Suggested mechanisms include the following.
a) Structural damage of the brain due to surgical removal of CNS tumors (Jansen, 2010)
b) DNA damage due to chemotherapy or ionizing irradiation (Ahles &
Saykin, 2007; Aluise et al., 2010; Jansen, 2010)
c) Direct injury to neurons or other brain structures (including oligodendrocytes, glial cells, and white matter tracts) may occur with chemotherapy or radiation therapy (Jansen, 2010; Walker et al., 2012).
Neurotoxic effects can result in disruption of neural stem and progenitor cells within the CNS, which appear to be more sensitive than
cancer cells to various chemotherapy agents (Dietrich, 2010; Dietrich, Monje, Wefel, & Meyers, 2008; Vardy, Wefel, Ahles, Tannock, &
Schagen, 2008). Chemotherapy drugs shown to target neural progenitor cells in experimental studies include alkylating agents, carmustine, cisplatin, cytarabine, 5-FU, ifosfamide, methotrexate, and thiotepa (Dietrich, 2010). Neural precursor cells are also sensitive to radiation therapy (Fike, Rosi, & Limoli, 2009).
d) Oxidative damage: Various chemotherapy drugs, such as doxorubicin,
signal a cascade of oxidative stress that triggers cell membrane damage
and produces large amounts of free radicals (Aluise et al., 2010; Cardoso
et al., 2008; Joshi et al., 2007; Qin, He, Hai, Liang, & Liu, 2008). Oxidative damage or inflammatory responses can occur with radiation therapy, are dose dependent, and may last weeks to months (Fike et al., 2009).
e) Telomeres are regions of repetitive nucleotide sequences at the end
of a chromosome. They are important for supporting chromosomal
stability and for cell division, such that increased telomere shortening due to oxidative stress can lead to cell death (Walker et al., 2012).
f) Hormone-mediated effects: Estrogen is thought to play a neuroprotective role in the brain by relieving oxidative stress (Ahles & Saykin,
2007). Chemotherapy often induces menopause and lowers estrogen levels, and aromatase inhibitors can decrease synthesis of estroCopyright 2014 by the Oncology Nursing Society. All rights reserved.
gen in the peripheral tissues (Walker et al., 2012). Androgen receptors are also present in the brain; therefore, the use of androgen deprivation therapy can affect cognitive functioning (Grunfeld, Halliday, Martin, & Drudge-Coates, 2012; Jansen, 2010).
g) Cytokine dysregulation: Cytokines are proteins that have a role in neural function and repair and the metabolism of neurotransmitters. Increased levels of cytokines may activate a stress cascade that can affect
cognition (Myers, 2010). Although many chemotherapeutic agents are
not able to cross the blood-brain barrier, they can stimulate a release
of proinflammatory cytokines in response to cell injury. This release
leads to an elevation in circulating TNF- that can cross the bloodbrain barrier and cause excessive levels of CNS cytokines, resulting in
cognitive impairment (Aluise et al., 2010; Konat, Kraszpulski, James,
Zhang, & Abraham, 2008; Raffa, 2011). One study found higher levels of IL-6, IL-8, and monocyte chemotactic protein-1 in patients on
regimens containing doxorubicin with cyclophosphamide or cyclophosphamide plus 5-FU compared to patients receiving cyclophosphamide, methotrexate, and 5-FU treatment (Janelsins et al., 2012).
h) Leukoencephalopathy: Structural alterations in cerebral white matter can occur with cranial irradiation (Ricard, Taillia, & Renard,
2009). White matter changes have also been reported with various
chemotherapy and targeted agents such as bevacizumab, bortezomib,
capecitabine, carmustine, cisplatin, cytarabine, docetaxel, erlotinib,
etoposide, 5-FU, fludarabine, gemcitabine, IFNs, L-asparaginase, levamisole, melphalan, methotrexate, paclitaxel, procarbazine, rituximab, sorafenib, sunitinib, thalidomide, and vincristine (Rinne, Lee,
& Wen, 2012; Wefel & Schagen, 2012).
i) Anemia: Insufficient brain oxygenation is associated with cognitive
problems in multiple domains such as attention and concentration,
executive functioning, motor function, and memory (Lezak et al.,
2012). In one study of patients with hematologic cancers who had
not received any previous or current treatment, an Hgb level 10
g/dl was associated with cognitive impairment, especially in the domains of attention, motor function, and verbal memory (Wood et al.,
2011). Patients with cancer may experience anemia as a result of primary or metastatic cancer involvement of the bone marrow or bones
or because of cancer treatments such as chemotherapy and radiation
therapy (Jansen, 2010).
2. Incidence: The incidence of treatment-related cognitive changes is difficult to determine because many factors influence cognition. Many of the
earlier studies were limited by their cross-sectional study design, which
lacked baseline neuropsychological testing and consisted of small sample sizes. There is a growing evidence base for cancer and cancer treatmentrelated cognitive changes that incorporates objective and subjective measures, as well as genetic and radiologic tests (see Table 42). It is
important to include predisposing factors and to evaluate for presence
of impairment prior to treatment, use of combination therapies, and differences in sample characteristics to attempt to differentiate what cognitive changes are truly treatment related.
a) Chemotherapy-related cognitive changes have been predominantly studied in patients with breast cancer. Evidence to support whether chemotherapy-induced cognitive changes exist or are due solely
to chemotherapy is inconclusive. However, it is estimated that up to
75% of patients with cancer experience cognitive impairment during or after cancer treatment (Janelsins et al., 2011).
b) Evidence of cognitive impairment prior to treatment has been found
(Wefel & Schagen, 2012).
349
350
Table 42. Evidence of Cancer TreatmentRelated Cognitive Changes
Breast
Author
and Year
Published
Treatment Specifics
Sample Characteristics
and Study Designs
Cognitive
Domains
Assessed
Results and Conclusions
Abraham et
al., 2008
Chemotherapy: AC, AC plus a

taxane
Hormonal therapy: Anastrozole,
tamoxifen
N = 19; 10 with breast cancer, 9 healthy controls

Mean age (standard deviation): 49.8 (8.0)
breast cancer patients, 46.8 (6.8) controls
Cognitive testing done at one time (an average of 22 months since completion of chemotherapy)
IPS
There was a significant difference between groups

in IPS (p = 0.005), with patients with poorer performance. Of note, patients had significantly more
anxiety (p = 0.36), which was correlated with IPS
(p < 0.05). Diffusion tensor imaging results of decreased cerebral white matter were also correlated
with decreased IPS (p < 0.05). Findings are limited
in this pilot study because of a small sample, lack
of baseline data, and lack of a comparison group
that contained patients with breast cancer who did
not receive chemotherapy.
Ahles et al.,
2010
Chemotherapy: AC, AC-T, CAF,

CMF, FEC, TAC
Hormonal therapy: Anastrozole,
raloxifene, tamoxifen
N = 177; 60 chemotherapy patients, 72

breast cancer controls, 45 healthy controls
chemotherapy patients, 56.6 (8.3) breast
cancer controls, 52.9 (10) healthy controls
Cognitive testing completed prior to the start
of chemotherapy and repeated at 1, 6, and
18 months after treatment
AC, EF, IPS,

L, VerM,
VisM, and
a subjective
measure
Significant difference was found in L (p = 0.01) as

the control groups improved over time but the chemotherapy group did not. Patients treated with
tamoxifen performed worse than healthy controls in
IPS (p = 0.16), L (p = 0.023), and VerM (p = 0.018).
There was a significant increase in cognitive complaints by chemotherapy patients compared to the
two control groups (p < 0.05). Although there were
significant differences in anxiety (p = 0.002), depression (p < 0.001), and fatigue (p = 0.011) between groups, these were not correlated with neuropsychological test outcomes. There was a significant difference in age (p = 0.003) between groups.
Of note, older patients with lower baseline cognitive reserve who received chemotherapy had poorer performances in IPS than patients with breast
cancer (p = 0.003) and healthy controls (p < 0.001).
Study findings are limited by the focus on age and
cognitive reserve.
Breckenridge
et al., 2012
Hormonal therapy: Tamoxifen,

aromatase inhibitor, combination of both, or other not defined
N = 133; 77 exposed to endocrine therapy,

56 controls
endocrine group, 44.80 (8.88) controls
Cognitive testing done at one time; time since
primary treatment ranged from 110 years
for participants in both groups
AC, EF, MF,

and a subjective measure
of AC, EF, M,
and VS
No differences were seen between the groups in

objective measures. However, patients who received hormonal therapy reported significantly
more perceived cognitive impairments (p < 0.05).
Anxiety, depression, and fatigue significantly affected perceptions of cognitive impairment but not objective measures. Study results are difficult to interpret because > 80% of patients in both groups had
received chemotherapy (regimens not defined).
Type of
Cancer
Table 42. Evidence of Cancer TreatmentRelated Cognitive Changes (Continued)

Type of
Cancer
Breast (cont.)
Author
and Year
Published
Treatment Specifics
and Study Designs
Cognitive
Domains
Assessed
Chemotherapy: Various regimens including AC, AC-T, AP,

CEF, EC-T, FAC, FEC
Hormonal therapy including
tamoxifen, anastrozole, letrozole
N = 93; 53 receiving chemotherapy, 40 controls on hormonal therapy

chemotherapy patients, 57.6 (4.0) controls
Cognitive testing before chemotherapy and 1
month and 1 year after completion of chemotherapy
AC, EF, IPS,

L, MF, VerM,
VisM, VS
Significant decline was noted in patients on chemotherapy compared to controls 1 month after chemotherapy (p = 0.02). However, no differences in
cognitive decline were found between groups at
the final testing. Of note, those who received chemotherapy and hormonal therapy had significantly decreased scores in IPS (p = 0.01) and VerM
(p = 0.01) than those who received chemotherapy
alone. Results are difficult to interpret because of
multiple chemotherapy regimens and attrition. Hormonal therapy may contribute to cognitive impairments.
Collins et al.,
2009b
Hormonal therapy: Anastrozole

or tamoxifen
N = 73; 14 on anastrozole, 31 on tamoxifen,

28 healthy controls
Mean age (standard deviation): 57.8 (4.4) anastrozole patients, 57.5 (4.0) tamoxifen patients, 59.3 (4.2) controls
Cognitive testing done after surgery and
around the time of the initiation of hormonal
therapy and repeated in 56 months
AC, EF, IPS,

L, MF, VerM,
VisM, VS
Patients on hormonal therapy were more likely to

show declines in cognitive functioning over time
with deficits present in 64% in patients on anastrozole, 39% in those taking tamoxifen, and only 7% in
healthy controls. Significant differences existed between healthy controls and all patients on hormonal
therapy in IPS (p = 0.02) and VerM (p = 0.003) for
patients on anastrozole. Results may be skewed as
some patients had already started hormonal therapy prior to baseline testing.
Debess et
al., 2010
Chemotherapy: CEF
Hormonal therapy: Tamoxifen
N = 238; 120 patients with breast cancer (75

who received chemotherapy, 26 hormonal
therapy, 19 with no treatment), 208 controls
Mean age: 47.2 chemotherapy patients, 56.2
hormonal therapy patients, 49.7 breast cancer controls, 48.1 healthy controls
Cognitive testing done prior to chemotherapy
and after 6 months
AC, EF, IPS,

VerM, VisM,
of AC, mental
burden, vitality, M, and CF
No differences were found in either objective or

perceived cognitive functioning between groups.
Study is limited by significant differences in age,
educational level, and menopausal status between
groups. All of these factors are known to affect performance on cognitive tests.
351
Collins et al.,
2009a
352
Breast (cont.)
Author
and Year
Published
Treatment Specifics
and Study Designs
Cognitive
Domains
Assessed
Deprez et al.,
2011
Chemotherapy: FEC or FEC-T

N = 39; 14 post-chemotherapy patients, 10

breast cancer controls, 15 healthy controls
cancer controls, 45.1 (4.0) healthy controls
Cognitive testing done in chemotherapy patients after completion of therapy (range
80160 days) as well as in healthy controls
Magnetic resonance diffusion tensor imaging
done in all three groups to evaluate cerebral white matter integrity
AC, EF, IPS,

L, MF, VerM,
VisM, and
a subjective measure
of CF
Patients who had received chemotherapy performed significantly worse in AC, IPS, and MF
(p < 0.001) than healthy controls. They also reported cognitive problems with distraction (p = 0.02).
Neuropsychological testing was not done for breast
cancer controls. Significant decreases in white matter integrity were found in chemotherapy patients
compared to either control group (p < 0.05). In contrast, no differences were found between the two
control groups. Of note, self-reports of cognitive impairment were significantly correlated with changes in white matter integrity (p < 0.005). One limitation of this study is the use of tamoxifen by patients in the chemotherapy and breast cancer control groups, which may have an effect on cognition.
In addition, the lack of baseline testing makes it difficult to ascertain whether cognitive impairments
can be directly attributed to treatment (either chemotherapy or hormonal therapy).
Deprez et al.,
2012
Chemotherapy: FEC or FEC-T

N = 69; 34 chemotherapy patients, 16 breast

cancer controls, 19 healthy controls
Cognitive testing done after surgery but prior
to the start of chemotherapy as well as 35
months after the completion of treatment
Magnetic resonance diffusion tensor imaging
done in all three groups to evaluate cerebral white matter integrity
AC, EF, IPS,

L, MF, VerM,
VisM, and
a subjective measure
of CF
Patients treated with chemotherapy performed significantly worse in AC, IPS, and VerM in contrast to
control groups, which performed better over time
(p < 0.05). Significant decreases in white matter integrity were found over time in frontal, parietal, and
occipital white matter tracts of patients who received chemotherapy (p < 0.05) but were not found
in either control group. Of note, significant correlations were found between cognitive complaints and
impairments in attention (p 0.05), verbal memory
(p = 0.026), and language (p = 0.02). One limitation of this study is the use of tamoxifen by patients
in the chemotherapy and breast cancer control
groups, which may have an effect on cognition.
Type of
Cancer

Type of
Cancer
Breast (cont.)
Author
and Year
Published
Treatment Specifics
Jansen et al.,
2011
Chemotherapy: AC with or without a taxane
N = 71
Cognitive testing done prior to chemotherapy and approximately 1 week after 4 cycles
of AC, 1 week after completing taxane, and
6 months after completing all chemotherapy
AC, EF, L,
M, MF, VS,
of CF
23% of patients had cognitive impairment prior to

initiation of chemotherapy in L, VS, MF, immediate
M, and/or AC. No cognitive changes were found for
immediate M, L, or EF over time. However, a significant effect of time was found for AC (p = 0.022), VS
(p < 0.001), delayed M (p = 0.006), MF (p = 0.043),
and the total cognitive score (p < 0.001). The trajectory for most tests showed a general decline during
treatment followed by improvement within 6 months
after chemotherapy. However, VS did not improve to
baseline at that time. Cognitive changes were not
related to anemia, anxiety, depression, fatigue, or
patient perception of cognitive functioning. However, self-reported cognitive problems were associated with anxiety, depression, and fatigue. Study is
limited by lack of a control group.
Kesler et al.,
2011
Chemotherapy: Regimens included AC, AC-D, AC-T, CAF,

CEF-D, CMF, carboplatin +
docetaxel, or cyclophosphamide and either paclitaxel or
docetaxel
Hormonal therapy: 56% of chemotherapy patients and 53%
of breast cancer controls on
tamoxifen
N = 62; 25 chemotherapy patients, 19 breast

cancer controls, 18 healthy controls
Cognitive testing done at one time
EF, IPS, L,
of EF
Significant reductions in prefrontal and premotor

cortex activity were found in patients with breast
cancer compared to healthy controls (p = 0.001).
Patients who received chemotherapy had significantly poorer performances in EF than controls
(p = 0.02). Chemotherapy patients reported more
difficulty with executive functioning (p = 0.001).
Findings are limited by lack of baseline testing and
small sample size.
Koppelmans
et al., 2012
Chemotherapy: CMF
N = 1,705; 196 on chemotherapy, 1,509 controls

chemotherapy patients, 57.9 (5.4) controls
Cognitive testing done at one time (average
time since treatment = 21 years)
EF, IPS, L,
MF, VerM, VS
Women who received chemotherapy had significantly poorer performance in EF (p = 0.013), IPS
(p < 0.001), and motor speed (p = 0.001), as well
as immediate (p = 0.015) and delayed VerM (p =
0.002). A limitation of this study is the lack of baseline testing prior to chemotherapy and a significant difference in age (p < 0.001) between groups,
which may influence neuropsychological testing results.
and Study Designs
Cognitive
Domains
Assessed

353
354
Breast (cont.)
Author
and Year
Published
Treatment Specifics
Legault et al.,
2009
Hormonal therapy: Tamoxifen or

raloxifene
N = 1,498; 733 on tamoxifen, 765 on raloxifene

tamoxifen patients, 69.7 (4.2) raloxifene patients
Cognitive testing started after initiation of
therapy for most patients, then repeated 1
and 2 years later
AC, L, MF,
VerM, VisM,
VS
There were no differences between treatment

groups. However, there were significant differences over time in VS (p < 0.0001), VerM (p < 0.0001),
VisM (p < 0.0001), and some measures of L
(p < 0.0001). A limitation of the study is the lack of
a control group. In addition, only 273 patients had
baseline testing done prior to the start of therapy.
Mehlsen et
al., 2009
Chemotherapy: CEF
Hormonal therapy: tamoxifen
(19 patients with cancer)
N = 58; 34 chemotherapy patients, 12 cardiac

patients, 12 healthy controls
Mean age (standard deviation): 48.6 (8.0) patients with cancer, 50.4 (9.1) cardiac patients, 39.3 (11.7) controls
and approximately 46 weeks after the last
cycle of treatment
EF, IPS, L,
VerM, VisM,
VS and a
subjective
measure of
AC, M
No differences in cognitive functioning over time

were found. Additionally, there was no difference
in reliable decline or improvement in cognition between groups. However, patients with cancer reported significantly more negative changes in
memory and concentration (p < 0.01). Findings are
limited by small sample size.
Noal et al.,
2010
Chemotherapy: FEC, FEC-D,

other not specified
Radiation therapy
aromatase inhibitor, or tamoxifen with luteinizing hormonereleasing hormone
N = 302; 161 receiving chemotherapy plus

radiation, 141 receiving radiation therapy
Median age: 53 chemotherapy patients, 58
radiation therapyonly patients
Cognitive testing done prior to the start of radiation therapy, at 3 weeks, at the end of
treatment, and at 4 and 12 months after the
completion of radiation therapy
AC, EF, IPS,

VerM
Cognitive impairment was found prior to the start of

radiation therapy in both groups. Interpretation of
results is difficult because of limited data reported
and lack of a control group. Hormonal therapy may
have affected results.
Phillips et al.,
2010

letrozole
N = 120; 55 tamoxifen, 65 letrozole

tamoxifen patients, 63.25 (6.67) letrozole
patients
Cognitive testing done after completion of 5
years of treatment with hormonal therapy
AC, L, MF,
VerM, VisM
There was a significant difference with patients on

letrozole with better overall cognitive function
(p = 0.04). Findings are difficult to interpret because of lack of baseline testing prior to the start of
therapy. Some of the participants were in arms that
crossed over to the alternate hormonal agent after
two years.
and Study Designs
Cognitive
Domains
Assessed
Type of
Cancer

Type of
Cancer
Breast (cont.)
Author
and Year
Published
Treatment Specifics
and Study Designs
Cognitive
Domains
Assessed
Chemotherapy regimens: AC,

AC-D, AC-T, AD, CMF, FEC,
FEC-T
Hormonal therapy (48% of chemotherapy plus radiation therapy and 76% of radiation therapyonly groups): Tamoxifen,
anastrozole, toremifene, or letrozole
N = 449; 96 receiving chemotherapy plus radiation therapy, 113 receiving radiation therapy only, 240 controls
chemotherapy plus radiation therapy group,
57.30 (8.57) radiation therapyonly group,
56.58 (8.60) healthy controls
Cognitive testing done 6 months after completing radiation therapy and 36 months later
AC, EF, IPS,

VerM, VisM
There was a significant difference in the groups

over time for IPS (p = 0.009) with controls improving over time. At each testing, controls performed
better than patients who received treatment in EF
(p = 0.006). No differences were found between patients who received hormonal therapy versus those
who did not.
Quesnel et
al., 2009

FEC, TAC
Hormonal therapy: Tamoxifen in
87.1% of chemotherapy and
80.7% of radiation therapy patients; anastrozole in 12.9% of
chemotherapy and 19.3% of
radiation therapy patients
N = 126; 41 receiving chemotherapy, 40 receiving radiation therapy only, 45 controls

chemotherapy patients, 57.7 (4.9) radiation
therapyonly controls
Cognitive testing done in patients prior to
therapy, immediately after their first treatment, and 3 months after completion of all
chemotherapy
AC, EF, IPS,

L, VerM,
VisM, and
subjective
measures of
CF
Significant effects of time were found in VerM (p <

0.01) for both patient groups. In contrast, a significant group-by-time interaction was found only in
patients receiving chemotherapy, signifying a decline in L (p < 0.01). A significant effect of time was
found in chemotherapy patients for reported cognitive problems (p = 0.02). One limitation of this study
is the use of hormonal therapy in several patients,
which might have influenced cognitive scores.
Reid-Arndt et
al., 2010

AC-D, AC-T
Hormonal therapy: 41% received tamoxifen
N = 46
Cognitive testing done 1, 6, and 12 months
after chemotherapy
EF, IPS, L,
VerM
As a group, there were no differences over time.

Results must be interpreted with caution because
improvement may have been due to practice effects. Study findings are limited by the lack of baseline testing prior to the initiation of chemotherapy
and small sample size (especially with 28% dropout
rate). A control group would have been beneficial to
determine whether patients improved as much as
either healthy or nontreated controls.
Ribi et al.,
2012
Hormonal therapy: Tamoxifen, letrozole, or sequence of

tamoxifen and letrozole
Chemotherapy: Unclear how
many patients received chemotherapy prior to hormonal therapy
N = 100
Mean age not reported
Cognitive testing done after completion of 5
years of hormonal therapy and repeated 1
year later
AC, EF, IPS,

VerM, VisM,
of CF
No differences were found either between treatment groups or over time for subjective cognitive
measures. Objective and subjective measures of
cognitive functioning were not correlated. A limitation of this study is the lack of baseline testing prior
to the initiation of hormonal therapy as well the lack
of a non-treatment control group.
355
Phillips et al.,
2012
356
Breast (cont.)
Author
and Year
Published
Treatment Specifics
and Study Designs
Cognitive
Domains
Assessed
Scherling et
al., 2012
Chemotherapy: AC, FEC-D, TC
N = 46; 23 on chemotherapy, 23 healthy controls

Mean age (standard deviation): 51 (8.5) chemotherapy patients, 50 (9) controls
Cognitive testing done prior to the start of
chemotherapy
AC, EF, IPS,

L, VerM,
VisM, and
magnetic resonance imaging
A significant decrease in white matter volume was

found in patients with cancer compared to controls
prior to initiation of chemotherapy. Neuropsychological test results were not reported. Whether these
findings are of importance would be determined
with follow-up after initiation of chemotherapy.
Schilder et
al., 2010

and exemestane
N = 330; 92 patients with breast cancer on

tamoxifen, 114 receiving exemestane, 124
controls
Age not reported
Cognitive testing done after surgery but prior to start of hormonal therapy and repeated 1 year later
AC, EF, IPS,

L, MF, VerM,
VisM
At baseline, patients had significantly lower cognitive scores (p = 0.03). Review of specific domains
revealed significantly lower performance only in L
(p < 0.01). Although differences were not found between patients on exemestane and controls, patients receiving tamoxifen had significant deficits
on EF (p = 0.01) and VerM (p < 0.01) over time. In
addition, patients on tamoxifen scored lower than
those on exemestane on IPS (p = 0.02). A limitation
of this study is the short-term follow-up because
hormonal therapy is generally given for 5 years.
Schilder et
al., 2012

and exemestane
N = 299; 80 on tamoxifen, 99 on exemestane,

120 healthy controls
Age (standard deviation): 68.7 (7.6) tamoxifen patients, 68.3 (6.8) exemestane patients, 66.2 (7.9) healthy controls
Subjective cognitive measures done after
surgery but prior to start of hormonal therapy and repeated 1 year later
Subjective
measures of
CF
At baseline, healthy controls reported significantly more cognitive problems on subjective measures
(p = 0.004). However, there were no differences between groups on prevalence of self-reported cognitive complaints as measured by the interview questions. One year after baseline, healthy controls continued to report the highest frequency of cognitive
problems (p = 0.003). A limitation of this study is
the short-term follow-up because hormonal therapy
is generally given for 5 years. Objective measures
reported in another publication (see Schilder et al.,
2010 in previous row).
Small et al.,
2011
Chemotherapy: AC, AC-D, AC-T,

CMF, CAF, CEF
N = 334; 72 receiving chemotherapy, 58 receiving radiation therapy, 204 healthy controls

chemotherapy patients, 56.93 (9.01) radiation therapy patients, 57.07 (9.52) healthy
controls
Cognitive testing done approximately 6
months after completion of chemotherapy
AC, EF, L,
MF, VerM,
VisM
Although differences were not found between cancer survivors and healthy controls, significant differences was found related to genotype, with catechol-O-methyltransferase (COMT)-Met homozygote
carriers outperforming COMT-Val carriers
(p = 0.002).
Type of
Cancer

Type of
Cancer
Breast (cont.)
Author
and Year
Published
Treatment Specifics
and Study Designs
Cognitive
Domains
Assessed

AC-T, CMF
Hormonal therapies: Tamoxifen,
anastrozole
N = 61; 30 on chemotherapy, 31 controls

Mean age: 60.7
Cognitive testing done prior to start of chemotherapy and 6 and 12 months after treatment
AC, EF, L,
MF, VerM,
VisM, VS
of CF
A significant time-by-treatment interaction was

found for MF (p = 0.007), revealing poorer performance in those who received chemotherapy. However, these results may have been influenced by
peripheral neuropathy in those who received taxanes. Although women reported memory problems at all time periods, these were related to anxiety and depression and not correlated with objective measures. A limitation of the study is the inclusion of multiple chemotherapy regimens; some patients were also taking hormonal therapy at later
testing periods.
Vearncombe
et al., 2009

AC-D, AC-T, CAF, CD, CMF,
FEA, FEC, FEC-D
N = 159; 138 chemotherapy patients, 21

breast cancer controls
chemotherapy group, 53.98 (8.24) control
group
Cognitive testing done initially after surgery
but prior to start of chemotherapy and repeated approximately 4 weeks after completion of chemotherapy
AC, EF, IPS,

L, MF, VerM,
VisM
A significant effect of time was found for AC (p <

0.001), IPS (p < 0.001), VerM (p < 0.001), and VisM
(p < 0.01) only in the chemotherapy group. Significant differences between the two groups in menopausal status (p < 0.001) and time between testing
intervals (p < 0.001) may have affected results.
Vearncombe
et al., 2011

FEC
Hormonal therapy: Not specified
N = 121; 23 premenopausal patients, 43 patients with chemotherapy-induced menopause, 55 postmenopausal patients

premenopausal, 46.78 (3.68) chemotherapy-induced menopause, 55.77 (5.42) postmenopausal
Cognitive testing done at baseline after surgery but prior to chemotherapy and approximately 1, 6, and 18 months after completion of chemotherapy
AC, EF, IPS,

L, MF, VerM,
VisM
A significant effect of time was found for AC (p <

0.001), one measure of EF (p < 0.001), and IPS
(p < 0.001), L (p = 0.002), VerM (p < 0.001), and
VisM (p 0.001). These findings revealed a decline
in cognitive functioning immediately after treatment
with subsequent improvement in performance over
time. A significant difference was found in EF over
time (p = 0.14) with improvement in pre- and postmenopausal groups; however, there was no change
in the chemotherapy-induced menopause group.
Because estrogen levels were not measured, it is
difficult to determine definitively if patients had chemotherapy-induced menopause.
357
Tager et al.,
2010
358

Author
and Year
Published
Treatment Specifics
and Study Designs
Cognitive
Domains
Assessed
Breast (cont.)
Weis et al.,
2009

AC-D, AC-T, CMF, CMF + either doxorubicin or epirubicin,
EC, EC-D, EC-T
N = 90
Cognitive testing done at the start of inpatient
rehabilitation (shortly after conclusion of
acute therapy), at the end of rehabilitation
(average 26 days), and 6 months later
AC, IPS,
VerM, VisM,
of CF
At the final testing, 21% of patients met the authors criteria for clinically relevant cognitive deficits;
however, this was based on objective or subjective
measures, or a combination of both. This study is
limited by the lack of baseline testing prior to initiation of treatment, lack of a control group, and high
percentage of patients on hormonal therapy (72%),
which may contribute to test results. It is not clear
whether the rehabilitation program may have contributed to improvement in cognitive functioning.
Central
nervous
system tumors
Correa et al.,
2012
Chemotherapy: High-dose methotrexate plus a variety of other agents that included procarbazine, vincristine, and highdose cytarabine
Radiation therapy: WBRT
N = 50; 24 received chemotherapy with

WBRT, 26 received chemotherapy alone
chemotherapy with WBRT group, 70.6 (8.2)
chemotherapy-only group
Cognitive testing done after completion of
treatment (50.3 [39.5] months for chemotherapy plus WBRT group, 14.9 [12.5]
months for chemotherapy-only group), and
additional follow-up assessment in 33 patients (16.2 [18.3] months for the combinedmodality group, 14.1 [12.0] months for
those on chemotherapy alone)
AC, EF, L,
MF, VerM,
of CF
The chemotherapy plus WBRT group was significantly younger (p 0.001) and tested at a later date after completion of treatment (p < 0.0001).
However, when controlling for age and time since
treatment, patients receiving chemotherapy alone
were found to perform significantly better in some
measures of attention (p < 0.04) and VerM (p <
0.02). Follow-up testing revealed that patients who
received chemotherapy alone still performed significantly better on tests of attention (p = 0.04). Results are limited by small sample size, especially at
the follow-up testing. Another limitation is the lack
of baseline testing prior to initiation of therapy.
Hahn et al.,
2009
Radiation therapy: Partial brain

irradiation
N = 11 (only 6 patients completed all testing)

Mean age: 48
Cognitive testing done prior to the initiation of
radiation therapy, then repeated at 3 weeks
and 6 months. This was compared to central nervous system metabolism measured
by positron-emission tomography.
AC, EF, VerM,

VisM and a
subjective
measure of
CF
Results indicated increases in relative blood flow

with increasing doses at 3 weeks (p = 0.037) and 6
months (p = 0.072). No changes were found in AC,
VerM, or VisM. However, decreased fluorodeoxyglucose uptake was correlated with EF (p = 0.037)
and increased symptoms on the subjective measure (p < 0.0001). Interpretation of results is difficult
because of the small sample size, especially at follow-up. In addition, tumor location may have an impact on testing deficits.
Type of
Cancer

Type of
Cancer
Author
and Year
Published
Treatment Specifics
and Study Designs
Cognitive
Domains
Assessed
Hilverda et
al., 2010
Chemotherapy: Temozolomide
Radiation therapy
N = 13
Cognitive testing done initially after surgery
but before radiation therapy or chemotherapy, and repeated after 6 weeks of radiation
therapy with chemotherapy and after three
cycles of adjuvant chemotherapy that was
given after radiation therapy
AC, EF, IPS,

MF, VerM
Eleven patients had cognitive impairment prior to

the start of treatment. Although changes did occur
in individuals, overall cognitive impairment was stable over time. However, it is difficult to make any
conclusions because of the small sample size and
lack of a control group.
Colorectal
Galica et al.,
2012
Chemotherapy: 5-FU alone, or

with oxaliplatin or radiation, or
capecitabine alone or with oxaliplatin
N = 74 (those who completed cognitive testing); 16 prechemotherapy patients, 13 postsurgery controls, 20 after completion of
chemotherapy, 15 six-months postsurgery
controls
Cognitive testing was done at the time based
on group assignment, then repeated at 6,
12, and 24 months. However, only baseline
data were presented in this publication.
AC, EF, IPS,

MF, VisM
Although cognitive function was not the primary outcome, no group differences were found. This
study is limited by lack of baseline testing in all
groups, which may have affected results.
Head and neck
Gan et al.,
2011
Radiation therapy alone or with

chemotherapy (cisplatin)
N = 10; 5 underwent radiation therapy alone,

5 received chemotherapy and radiation
Mean age: 58.1
Cognitive testing done at one time only with a
mean time from the end of treatment of 20
months (range 941)
AC, EF, IPS,

L, MF, VerM,
VisM, and a
subjective
measure of
CF
Based on individual intelligence, cognitive performance was lower than expected for all cognitive domains with the exception of language. However, patients did not report cognitive problems. Interpretation of results is difficult because of the small sample size, lack of baseline testing, and multiple covariates.
Hematologic
Chang et al.,
2009
Chemotherapy: Patients with

chronic myeloid leukemia
(CML) treated with either imatinib mesylate, hydroxyurea,
or interferon; patients with myelodysplastic syndrome (MDS)
treated with hydroxyurea,
5-azacitidine, or no chemotherapy
HSCT: Regimen not reported;
94% underwent TBI
N = 106; 91 with CML, 15 with MDS

CML group, 64.8 (9.3) MDS group
Cognitive testing done at baseline and repeated 12 and 18 months after initial assessment
AC, EF, MF,

VerM
Overall, significant time effects were found in VerM

(p < 0.0016) with improved scores at the final assessment regardless of treatment. Patients who underwent HSCT had worse MF than those who received other treatments (p = 0.05). Difficult to compare groups by diagnosis because of the small
number of patients with MDS.
359
Central
nervous
system tumors
(cont.)
360
Hematologic
(cont.)
Lung
Mixed cancer
diagnoses
Author
and Year
Published
Treatment Specifics
and Study Designs
Cognitive
Domains
Assessed
Jim et al.,
2012
HSCT: Regimen not reported

Chemotherapy treatment prior
to HSCT was variable (range
of 07 regimens). In addition,
2% of patients received cranial
irradiation, 5% TBI, and 6% intrathecal chemotherapy.
N = 278; 78% in group A, 13% in group B,

9% in group C
Cognitive testing was done prior to HSCT
and at 6 and 12 months after completion
of HSCT. Patients in group A were tested
at all three time periods, group B at 6 and
12 months after HSCT, and group C at 12
months after HSCT.
AC, EF, MF,

VerM, VisM
Patients with a greater number of risk factors had

poorer total cognitive functioning at baseline and at
6 months post HSCT, as well as less recovery over
time (p < 0.05). Study results may be skewed by
the high attrition rate (73%).
Syrjala et al.,
2011
HSCT: Allogeneic regimens included cyclophosphamide with

TBI (52%), cyclophosphamide
and busulfan (40%), other
chemotherapy (type not specified) with TBI (7%), or other
chemotherapy (type not specified) alone (1%)
Chemotherapy treatment prior
to HSCT was not reported.
N = 158; 92 patients, 66 case-matched controls

survivors, 46.6 (9.7) controls
Cognitive testing was done prior to HSCT
and 80 days, 1 year, and 5 years after
HSCT. Controls were tested at only one
time.
AC, EF, IPS,

L, MF, VerM
Overall survivors had improved cognitive functioning over time (p < 0.001). Patients who had undergone HSCT showed persistent deficits in MF (p =
0.017). A significant difference between survivors
and controls was found for MF (p < 0.001) only. Because controls were tested at only one time period
as compared to survivors, some of the results may
be due to practice effects.
Pesce et al.,
2012
Radiation: WBRT
Chemotherapy: Gefitinib or temozolomide
N = 59; 16 on gefitinib, 43 on temozolomide

Median age: 61
Cognitive testing done prior to start of treatment and on day 1 of cycles 2, 3, and 5
EF and a
subjective
measure of
CF
No differences were found between groups. Study

results are limited by inability to meet accrual goal,
significant attrition (90%) over time, small sample
size, and lack of controlling for previous chemotherapy.
Sun et al.,
2011
Radiation: PCI
N = 340; 163 received PCI, 177 observation

Age not reported
Cognitive testing done at baseline after definitive treatment (not defined), prior to PCI,
and repeated at 3, 6, and 12 months from
the original testing
VerM and a
subjective
measure of
CF
Compared to patients who underwent observation,

patients who received PCI showed significant declines in VerM at all time periods. Study results are
limited by inability to meet accrual goal and significant attrition (72%) over time.
Kvale et al.,
2010
Chemotherapy: Regimens not

reported; unclear if patients
with cancer received any other
treatments
N = 76; 39 chemotherapy patients, 37 controls without cancer

Mean age: 76.0 patients with cancer, 75.8
controls
Cognitive testing done prior to treatment and
repeated annually for 4 years
EF, IPS, VerM
No differences were found; however, the study is

likely underpowered. Another limitation of the study
is the inclusion of multiple cancer diagnoses with
potentially variable chemotherapy regimens.
Type of
Cancer

Type of
Cancer
Ovarian
Prostate
Treatment Specifics
and Study Designs
Cognitive
Domains
Assessed
Correa et al.,
2010
Chemotherapy: Various regimens including paclitaxel, carboplatin, cisplatin, and others

not specified
Concurrent hormonal therapy for
five patients
N = 48; 22 disease-free survivors, 26 survivors who had at least one recurrence and
receiving active treatment
Mean age for entire group: 61
Cognitive testing done at one time; all participants were 510 years from their original diagnosis
AC, EF, M
Although no significant differences were seen between the groups, 28% of those tested met criteria for cognitive impairment. Cognitive scores were
not significantly correlated with depression or age.
No baseline cognitive testing was done for either
group.
Hess et al.,
2010
Chemotherapy: Specified only

as platinum-based regimens
N = 27
Mean age: 59.3
and repeated at cycles 3 and 6
AC, IPS, and

a subjective
measure of
AC, EF, VS,
and M
There was a significant group difference over time

in some measures of IPS (p < 0.0001). The authors
reported that almost half of the participants had impairment compared to baseline. However, many of
the participants experienced neurotoxicity, which
may have been responsible for the decline in cognitive measures.
Alibhai et al.,
2010
ADT: Actual medications not

stated
N = 241; 77 receiving ADT, 82 prostate cancer controls, 82 healthy controls

Mean age: 68.9
ADT and at 6 and 12 months after baseline testing
AC, EF, IPS,

L, VerM,
VisM, VS
Although significant differences were found in a single test for AC (p = 0.029), VS (p = 0.34), and EF
(p = 0.31), most measures did not show any differences between groups. The proportion of participants in each group who scored worse on any cognitive domain was similar, indicating that ADT does
not adversely affect cognitive function.
Cherrier et
al., 2009
ADT: Intermittent therapy with

leuprolide and flutamide
N = 38; 19 receiving ADT, 19 controls

patients, 65.47 (7.99) controls
ADT and at 3, 9, and 12 months after baseline testing
AC, EF, L,
VerM, VisM,
VS
A significant group-by-time interaction (p < 0.05)

was found for cognitive function. Although declines
in EF (p < 0.05) and VS (p < 0.05) were found three
months after initiation of ADT, these changes were
not sustained and scores returned to baseline by
subsequent testing.
Pedersen et
al., 2009
Chemotherapy: BEP
N = 72; 36 receiving chemotherapy, 36 undergoing surgery with or without radiation

therapy
chemotherapy group, 42.0 (9.8) controls
Cognitive testing done 27 years after completion of treatment
EF, IPS, L,
VerM, VisM,
VS
No differences were found between groups. The

study may be underpowered but more importantly is limited by lack of baseline cognitive testing prior to treatment.
361
Testicular
Author
and Year
Published
362
Testicular
(cont.)
Author
and Year
Published
Treatment Specifics
and Study Designs
Cognitive
Domains
Assessed
Skoogh et
al., 2012
Chemotherapy: Platinum-based
regimens including BEP, BEPif, CVB, PEI
N = 960; 692 patients who received at least

one cycle of chemotherapy, 268 controls
Mean age for all participants: 41
Cognitive functioning evaluated by a single
study-specific questionnaire at a mean of
11 years after diagnosis
Subjective
measure of
CF based on
earlier qualitative results
Patients who received 5 cycles of chemotherapy reported a greater incidence of language difficulties. Multiple limitations of the study, including
the lack of an objective measure and cross-sectional design, make it difficult to determine the validity
of the results.
Wefel, Vidrine, et al.,

2011
Surgery only
N = 69
Mean age (standard deviation): 31 (7.5)
Cognitive testing performed after orchiectomy and prior to starting chemotherapy
AC, EF, IPS,

L, MF, VerM
Prior to the initiation of chemotherapy, cognitive impairment was found in 46% of patients, especially in VerM, EF, and MF (p < 0.001). Depression was
associated with EF (p < 0.01), IPS (p < 0.01), and
VerM (p < 0.05). VerM was also associated with
anxiety (p < 0.05). Interpretation of results is difficult because of the lack of a control group and the
cross-sectional design.
Therapy: ACdoxorubicin and cyclophosphamide; AC-Ddoxorubicin and cyclophosphamide followed by docetaxel; AC-Tdoxorubicin and cyclophosphamide followed by paclitaxel; ADdoxorubicin and docetaxel; ADTandrogen-deprivation therapy; APdoxorubicin and cisplatin; BEPbleomycin, etoposide, and cisplatin; BEP-ifbleomycin, etoposide, cisplatin, ifosfamide, and mesna; CAFcyclophosphamide, doxorubicin, and 5-FU; CDcyclophosphamide and docetaxel; CEFcyclophosphamide, epirubicin, and 5-FU; CEF-Dcyclophosphamide, epirubicin, and 5-FU followed by docetaxel; CMFcyclophosphamide, methotrexate,
and 5-FU; CVBcisplatin, vinblastine, and bleomycin; ECepirubicin and cyclophosphamide; EC-Depirubicin and cyclophosphamide followed by docetaxel; EC-Tepirubicin and cyclophosphamide followed by paclitaxel; FACFU, doxorubicin, and cyclophosphamide; FEA5-FU, epirubicin, and doxorubicin; FEC5-FU, epirubicin, and cyclophosphamide; FEC-D5-FU, epirubicin, and cyclophosphamide followed by docetaxel; FEC-T5-FU, epirubicin, and cyclophosphamide followed by paclitaxel; 5-FU5-fluorouracil; HSCThematopoietic stem cell transplantation; PCIprophylactic cranial irradiation; PEIcisplatin, etoposide, ifosfamide, and mesna; TACdocetaxel, doxorubicin, and cyclophosphamide; TBItotal body irradiation; TCdocetaxel and cyclophosphamide; WBRTwhole brain radiation therapy
Cognitive domains: ACattention/concentration; CFcognitive function; EFexecutive function; IPSinformation processing speed; Llanguage; Mmemory; MFmotor function; VerMverbal memory; VisM
visual memory; VSvisuospatial skill
Type of
Cancer
c) Whether cognitive impairment starts before or after the cancer treatment, cognitive problems are estimated to persist for months or years
following the completion of treatment in up to 35% of survivors
(Janelsins et al., 2011).
d) The duration of chemotherapy-related cognitive impairment remains
unknown. In one study of survivors, cognitive problems were the most
troublesome post-treatment symptom (Boykoff, Moieni, & Subramanian, 2009). In other studies, survivors confirmed that cognitive issues
continued to have a negative impact on their workplace for at least
one if not many years after treatment (Calvio, Peugeot, Bruns, Todd,
& Feuerstein, 2010; Munir, Burrows, Yarker, Kalawsky, & Bains, 2010).
3. Risk factors
a) Predisposing factors that influence cognitive function are not consistent; however, the following have been suggested.
(1) Gender: Women excel in language, information processing
speed, and motor function, whereas men perform better in visuospatial skills and mathematics (Lezak et al., 2012).
(2) Age: Cognitive decline occurs with aging. However, normative
data for neuropsychological tests are based on age.
(3) Intelligence and educational levels: Intelligence and educational levels have strong, positive relationships with neuropsychological test performances and have been found to be protective against cognitive impairments associated with brain trauma (Lezak et al., 2012).
(4) Genetics: Similar to other side effects, not all patients are
equally affected by the same regimen. Consequently, several genetic mutations are being evaluated to determine those
that might influence an individuals risk of cognitive changes during cancer and cancer treatments (Argyriou, Assimakopoulous, Iconomou, Giannakopoulou, & Kalofonos, 2011).
For example, the presence of the apolipoprotein E (APOE)
gene e4 variant has been associated with decreased cognitive
function, and several other candidate genes are being studied for their potential role in chemotherapy-induced cognitive changes (Ahles & Saykin, 2007). In a study of breast cancer
survivors, participants who were catechol-O-methyltransferaseVal carriers performed more poorly on tests of attention, verbal fluency, and motor speed (Small et al., 2011). Other polymorphisms that have been proposed are those that influence
the efficiency of DNA repair mechanisms and drug efflux pump
systems (Fishel, Vasko, & Kelley, 2007).
(5) Psychological factors such as stress, anxiety, and depression can
affect performance on neuropsychological testing (Lezak et al.,
2012). However, in general, these psychological factors are not
correlated with objective measures in studies of patients with
cancer. In contrast, anxiety and depression often are correlated with subjective measures of cognitive functioning.
(a) Increased anxiety was found to predict overall cognitive
decline in one study (Vearncombe et al., 2009). Although
anxiety has not been consistently related to objective measures, it has been found to be significantly correlated to
perceived cognitive functioning (p < 0.05) in some studies
(Breckenridge, Bruns, Todd, & Feuerstein, 2012; Jansen,
Cooper, Dodd, & Miaskowski, 2011). In one study of employed survivors, anxiety was directly related to attention
and concentration (p < 0.01), executive functioning (p <
0.05), and memory (p < 0.05) (Breckenridge et al., 2012).
363
364
(b) Depression has been found to influence specific cognitive

domains such as attention (Vearncombe et al., 2009). One
study of employed survivors found depression to be correlated with attention and concentration (p < 0.01), executive functioning (p < 0.05), and memory (p < 0.05) (Breckenridge et al., 2012).
(6) Fatigue can negatively affect cognitive function and was found
in several studies to cause impairments in specific domains, such
as attention, concentration, and executive function (Collins,
Mackenzie, Stewart, Bielajew, & Verma 2009a; Mehlsen, Pedersen, Jensen, & Zacharieae, 2009; Vearncombe et al., 2009).
Fatigue is also related to subjective measures of cognitive functioning (Breckenridge et al., 2012).
b) Factors related to cancer treatments
(1) Regimens: Because most patients receive multimodal therapy, it
is difficult to determine if specific drugs or regimens promote
higher incidences of cognitive changes.
(2) Dose intensity and cumulative effects: Cognitive changes in patients who receive cranial irradiation are related to the total
dose received (Khasraw & Posner, 2010; Rinne et al., 2012). Exposure to higher doses of chemotherapy (or higher concentrations due to impaired clearance), as well as the additive or synergistic effects of multiagent regimens, also may increase risk
(Wefel & Schagen, 2012).
c) Concomitant medications such as analgesics, antidepressants, antiepileptics, anxiolytics, antipsychotics, immunosuppressants, and steroids (Allen et al., 2011)
4. Clinical manifestations: Although cognitive changes may be subtle, patients report that they impair their ability to concentrate, think clearly, retain or learn new information, be efficient, manage responsibility, and cope with problems (Boykoff et al., 2009; Calvio et al., 2010; Munir et al., 2010).
5. Assessment: Many neuropsychological tests are available to measure cognitive function. Imaging (e.g., MRI, PET) has been used to study structural and electrophysiologic outcomes related to cognitive impairment
(Raffa, 2010).
a) Factors in neuropsychological test selection (Lezak et al., 2012)
(1) Specific cognitive domain to be measured
(2) Appropriateness of test for the domain being studied
(3) Reliability and validity of the test and availability of normative data
(4) Sensitivity and specificity to measure cancer treatmentrelated
cognitive changes (Jansen, Miaskowski, Dodd, & Dowling, 2007)
(5) Availability of parallel forms or resistance to practice effects for
use with repeated measures
(6) Feasibility of instrument for clinical use (such as length of time
and ease of administration)
(7) Specific tests recommended by the International Cognition and
Cancer Task Force include the Hopkins Verbal Learning Test
Revised, the Trail Making Test, and the Controlled Oral Word
Association Test to evaluate learning and memory, processing
speed, and executive function, which appear to be the most
vulnerable cognitive domains in patients with cancer (Wefel,
Vardy, Ahles, & Schagen, 2011).
b) Baseline neuropsychological assessment prior to the initiation of
treatment is necessary to determine if changes occur after treatment. Changes may be difficult to assess because they may be subtle (e.g., patients test within normal limits, but lower than nonCopyright 2014 by the Oncology Nursing Society. All rights reserved.
chemotherapy-treated patients), or preexisting risk factors may

influence results.
c) Although objective neuropsychological tests are the gold standard for
evaluating cognition, subjective measures may add valuable information regarding patient complaints (e.g., inability to focus on tasks or
follow instructions; problems with concentration or memory).
d) Assess coexisting medical conditions (e.g., CVD, diabetes, neurologic conditions, psychiatric illness), current medications, and any potential influencing factors such as anxiety, depression, fatigue, or
menopausal status.
6. Collaborative management: Currently, no evidence-based recommendations exist for the prevention or treatment of cognitive impairment. Although the mechanisms of cancer treatmentrelated cognitive changes
are still unclear, several pharmacologic and nonpharmacologic interventions have been studied. Many of these focus on preventing cognitive impairment by targeting the potential mechanisms discussed earlier. Erythropoietin, although evaluated in several studies with mixed outcomes,
is not recommended because of FDA warnings regarding risks associated with its use (Allen et al., 2011). The effectiveness of other pharmacologic (i.e., dexmethylphenidate methylphenidate, donepezil) and nonpharmacologic (i.e., vitamin E, natural restorative environments, cognitive training programs) interventions has not been established (Allen et
al., 2011; Von Ah et al., 2011). Further research is needed to determine
potential interventions for patients experiencing cognitive impairments.
7. Patient and family education: Patients should be informed that cognitive
changes are a possible side effect of treatment, but little information is
known. Studies elucidating this phenomenon, its mechanisms, and subsequent interventions are ongoing.
a) Acknowledge, validate, and record patient reports of cognitive changes.
b) Advise patients that although studies have been done for various interventions, not enough evidence is available to make treatment recommendations.
c) Although studies supporting the effectiveness of practical solutions
are lacking, patients have reported the following as helpful (Cheung
et al., 2012).
(1) Healthy lifestyle practices
(a) Ensure adequate sleep and rest.
(b) Eat a well-balanced diet.
(c) Engage in physical exercise.
(2) Intellectual activities (e.g., reading, learning new skills, solving
puzzles, working out math problems)
(3) Social activities (e.g., support groups)
(4) Practical management
(a) Use technology (e.g., smartphones, voice recorders).
(b) Keep a daily planner.
(c) Write reminders and use notes.
L. Ocular toxicity
1. Pathophysiology
a) The causes of ocular toxicity are not fully understood and may include the following.
(1) Damage to the eye or eye structures related directly to treatment
(e.g., distribution of cytotoxic drugs in tears, direct vascular injury
during intracarotid administration, direct nerve injury from chemotherapy or radiation therapy, or the solubility characteristics
of the drug and its ability to gain access through barriers such as
the blood-ocular barrier) (DeAngelis, 2010; Palmer et al., 2008).
365
366
(2) EGFRIs: EGFR is a normal part of epidermal cells. EGFR is

widely distributed on the eye surface in the conjunctival and
corneal epithelium, as well as in the eyelid skin, lash follicles, tear glands, and sebaceous and sweat glands (Burtness
et al., 2009). Inhibiting EGFR can lead to damage to the epidermal cells found in the ocular region (eye and surrounding skin) (Garibaldi & Adler, 2007). Examples of EGFRIinduced effects are tear film dysfunction and unusual hyper- or hypopigmentation (Zhang, Basti, & Jampol, 2007).
EGFRIs have led to dry eyes, inflammation of the lid margin (blepharitis), dysfunction of the sebaceous glands of the
eyelid (meibomitis), corneal erosion, and inversion or eversion of the eyelid margin (Burtness et al., 2009). EGFR also
has a crucial role in the regulation of the hair growth cycle.
An EGFRI can hinder this cycle, leading to loss of eyelashes
and eyebrows (Robert et al., 2005; Zhang, Basti, et al., 2007)
or an accelerated growth and curling of the eyelashes, leading to tortuous eyelashes or eyelash trichomegaly (Robert et
al., 2005). Most ocular side effects are not vision threatening but should be followed by an ophthalmologist to quickly treat the discomfort and prevent ocular injury (Burtness
et al., 2009). For symptom management for ocular toxicity
related to EGFRI medications, see Table 43.
(3) A secondary process related to treatment (e.g., eye irritation
caused by loss of eyelashes in the presence of neutropenia)
(4) A secondary process related to concurrent disease (e.g., diabetes or Graves disease leading to diplopia or ptosis) (DeAngelis,
2010)
(5) Metastases to the eyes or CNS resulting in increased intracranial pressure
(6) Factors unrelated to cytotoxic therapy (e.g., head trauma or
drug toxicity from narcotics or anticonvulsants leading to diplopia) (DeAngelis, 2010)
b) A broad spectrum of disorders has been documented, including inflammatory conditions (e.g., uveitis, conjunctivitis, keratitis, blepharitis, iritis), development of retinal opacities, cataract formation, lid
and lacrimation disorders, optic neuritis, and other neurologic injuries (Fraunfelder, Fraunfelder, & Chambers, 2008). For site-specific
disorders, see Table 44.
c) With frequent use of combination therapy, determining which specific drug is causing complications may be difficult (Fraunfelder et
al., 2008).
d) Patients may experience toxicity-related visual impairment during
chemotherapy and up to two weeks after chemotherapy (Kende, Sirkin, Thomas, & Freeman, 1979). Neurologic damage to the eye has
occurred up to 43 days following chemotherapy (Warrell & Berman,
1986).
e) The toxic effect of certain drugs may be cumulative and dose dependent (Palmer et al., 2008).
f) Ocular changes may go unnoticed until damage is irreversible.
g) Ocular signs and symptoms may precede the development of peripheral neuropathies and thus may be an important marker of neurologic status (Bobba & Klein, 2012).
h) The presence of ocular signs or symptoms may predict development
of GVHD in patients who have received allogeneic BMT (Kim et al.,
2002).
i) Ocular changes may be incorrectly attributed to the aging process.
367
Table 43. Ocular Toxicity Symptom Management Related to EGFR Inhibitors

Adverse Event
Symptoms
Management Strategy
Corneal epithelial
defect
Significant eye pain, sensitivity to light
Refer to an ophthalmologist.
Eyelid skin
changes (i.e.,
squamous blepharitis)
Hyperemia, papulopustular rash, crusting

Eyelids become sore and irritated, with discomfort described as severe. The eyelid margins
may have mild redness to significant edema and soreness of the eyelid margin. Small
pustules at the base of the eyelashes may be
seen (Burtness et al., 2009).
Acute reactions: Warm compresses with a moist washcloth,

regular cleaning of the eyelid, artificial tears (Ouwerkerk &
Boers-Doets, 2010)
Apply fluorometholone (0.1%) ointment to eyelid (both skin and
lid margin) for 1 week. Do not use for > 2 weeks. An ophthalmologist must examine patient within 4 weeks.
Chronic reactions: Apply tacrolimus 0.03% ointment or
pimecrolimus cream BID to skin of eyelid only. If treatment is
minimally effective or not effective at all, try tacrolimus 0.1%.
This treatment should not be used for > 6 months.
Iridocyclitis
Sensitivity to light, sustained eye pain, decrease in vision
Refer to an ophthalmologist.
Treatment involves use of anti-inflammatory medications.
Meibomitis (meibomian gland

dysfunction)
Fluctuations in vision (varying degrees), burning sensation in the eye, some mucus discharge, eye redness (may occur only on
awakening)
Perform lid scrubs and apply warm compresses to the eyelid for
at least 5 minutes BID.
If lid scrubs and warm compresses are ineffective, give doxycycline 50 mg PO BID for 2 weeks followed by 50 mg every day
for 4 weeks.
Tear film changes (dysfunctional

tear syndrome)
Fluctuating or mild decrease in vision, transient

eye pain, burning or foreign body sensation in
the eye, eye fatigue
Mild symptoms: Apply supplemental tears 46 times a day.

Severe symptoms or no relief: Refer to an ophthalmologist
(treatment may consist of punctal plugs and/or anti-inflammatory medications).
Trichomegaly
Lengthening of the eyelashes or eyebrows,

patchy lashes, misdirected lashes
Elongated or patchy lashes: No specific treatment. Will return

to normal after EGFR inhibitor is completed. While many researchers (Braiteh et al., 2008; Eaby et al., 2008; Esper et
al., 2007) agree that for patients experiencing trichomegaly,
an ophthalmologist should be seen if eye irritations occur and
eyelashes may be carefully and safely trimmed, Basti (2007)
advises patients to not cut their lashes or have them cut.
Waxing or electrolysis may be recommended (Braiteh et al.,
2008; Segaert & Van Cutsem, 2005).
Misdirected lashes: This is infrequent. Refer to an ophthalmologist. Do not remove misdirected lashes.
BIDtwice a daily; EGFRepidermal growth factor receptor; POby mouth

Note. From Ocular Toxicities of Epidermal Growth Factor Receptor Inhibitors and Their Management, by S. Basti, 2007, Cancer Nursing, 30(Suppl. 4), p.
S14. Copyright 2007 by Lippincott Williams & Wilkins. Adapted with permission.
2. Incidence
a) Incidence varies according to drug classification, dose, and route of
administration (see Table 45).
b) Ophthalmologic effects of chemotherapy occur less frequently and
tend to be less severe than other chemotherapy-related side effects.
Most ocular side effects tend to improve or even resolve completely
upon discontinuation of the drug. Sequelae are often minimized by
early detection (Teitelbaum, 2011)
3. Risk factors: Causal relationships between agents and ocular toxicities
are difficult to establish. Risk factors are equally difficult to establish.
4. Clinical manifestations: See Table 45.
5. Assessment: Ask patients about a history of any eye disturbance. In addition, assess the following (Bickley, 2013).
a) Visual acuity: Use a Snellen eye chart if possible. Position the patient
20 feet from the chart. Have the patient wear glasses or contacts for
the examination if the corrective lenses are normally used other than
368
Table 44. Specific Ocular Toxicities by Anatomic Site

Site
Ocular Toxicity
Orbit
Arteriovenous shunts, cavernous sinus syndrome, edema, exo

phthalmos, pallor, pain
Lids
Cicatricial ectropion, ankyloblepharon, increased lid necrosis

after cryotherapy, hyperpigmentation
Lacrimal drainage
Tear duct fibrosis and punctal occlusion
Lacrimal gland
Keratoconjunctivitis sicca
Conjunctiva
Conjunctivitis
Sclera
Discoloration
Cornea
Keratopathy, keratitis
Pupil
Pinpoint pupils, internal ophthalmoplegia
Uvea
Uveitis
Trabecular meshwork and/

or ciliary body
Increased intraocular pressure
Lens
Cataract
Retina
Toxic retinopathy
Vitreous
Opacification
Optic nerve
Disc edema, optic neuritis, optic atrophy
Cranial nerves III, IV, V, VI
Ptosis, paresis with or without diplopia, corneal hypesthesia
Extraocular muscles
Fibrosis
Central nervous system
Cortical blindness, internuclear ophthalmoplegia, blepharospasm
Note. Based on information from Palmer et al., 2008.
for reading. Ask the patient to cover one eye with a card and to read
the smallest line possible. Have the patient repeat with the other eye.
Acuity can be assessed using a near-vision card held at arms length;
patients who wear glasses or contact lenses should remove them. Record any visual disturbances.
b) Visual fields: Sit or stand in front of the patient and have the patient
look with both eyes into your eyes. While the patient gazes into your
eyes, place your hands two feet apart, lateral to the patients ears. Instruct the patient to point to your fingers as soon as they are seen.
Slowly move your fingers along an imaginary bowl and toward the
line of gaze until the patient identifies them. Repeat this pattern in
upper and lower temporal quadrants.
c) Position of eyes, eyebrows, and eyelids: While standing or sitting in
front of the patient, observe the eyes for position and alignment with
each other. Inspect the eyebrows, noting their quantity and distribution and any flaking of the underlying skin. Survey the eyelids, observing and palpating for signs of erythema and edema. Assess for
signs of exudates, crusting, and presence of ptosis. Observe condition of lashes.
d) Lacrimation: Note dryness, foreign-body sensation, excessive tearing,
or swelling of the lacrimal sac.
Table 45. Ocular Toxicities of Antineoplastic Agents

Classification
Alkylating agents
Ocular Toxicity
Comments
Busulfan
Long-standing reports of cataract formation and blurred vision (Bobba & Klein, 2012;
Palmer et al., 2008; Singh & Singh, 2012); rare cases of keratoconjunctivitis sicca
(Palmer et al., 2008; Sidi et al., 1977; Singh & Singh, 2012)
Toxic effects are believed to act on proliferating lens epithelial

cells (Bobba & Klein, 2012).
Carboplatin
IV: Rare cases of blurred vision, eye pain (Al-Tweigeri et al., 1996); reports of maculopathy and optic neuropathy with transient cortical blindness when given to patients with renal dysfunction (OBrien et al., 1992; Singh & Singh, 2012)
Intracarotid: Reports of severe ocular and orbital toxicity in ipsilateral eye following intracarotid injection (Watanabe et al., 2002)
Chlorambucil
Keratitis, diplopia, bilateral papilledema, retinal hemorrhages (Bobba & Klein, 2012);
oculomotor disturbance, disc edema, retinopathy (Palmer et al., 2008)
Cisplatin
IV: Blurred vision, altered color perception, papilledema, decreased visual acuity, retrobulbar neuritis, transient cortical blindness, disc edema, retinopathy, electroretinogram abnormalities, cavernous sinus syndrome, color blindness (Becher et al.,
1980; Palmer et al., 2008; Prager et al., 1998)
Intracarotid: Ipsilateral visual loss (15%60%) from retinal or optic nerve ischemia, possibly prevented by infusion distal to ophthalmic artery (Palmer et al., 2008); optic neuropathy, unilateral vision loss (Bobba & Klein, 2012); retinal pigment disturbances, altered color perception, cotton wool spots, intraretinal hemorrhages (Kwan et al., 2006)
Cyclophosphamide
Blurred vision (reversible), keratoconjunctivitis sicca, pinpoint pupils (Jack & Hicks,
1981; Kende et al., 1979; Palmer et al., 2008; Singh & Singh, 2012)
Ifosfamide
Blurred vision (reversible), conjunctivitis (Bobba & Klein, 2012; Choonara et al., 1987;
Singh & Singh, 2012)
Mechlorethamine
Intracarotid: Rare reports of ipsilateral necrotizing uveitis and necrotizing vasculitis of

choroids (Bobba & Klein, 2012)
No reports exist of ocular toxicity with IV administration (Bobba & Klein, 2012).
Oxaliplatin
Mild changes: Dry eyes, excessive tearing, severe ocular irritation, conjunctivitis, abnormal lacrimation (Mesquida et al., 2010; OncUView, 2011b; Singh & Singh, 2012)
Severe changes: Retinal damages, visual field cuts (Mesquida et al., 2010; Singh &
Singh, 2012)
Look for patients complaining of blurred vision, visual loss,

tunnel vision, or altered color vision. Most changes are
transient and reversible once treatment is stopped (Mesquida et al., 2010).
Capecitabine
Ocular irritation, decreased vision, corneal deposits (Singh & Singh, 2012; Walkhom
et al., 2000)
Cytarabine
IV: Keratitis and conjunctivitis most common (Haddadin & Perry, 2012); blurred vision
with evidence of bilateral conjunctival hyperemia, ocular pain, photophobia, and foreign body sensation at high doses (Al-Tweigeri et al., 1996; Bobba & Klein, 2012);
case reports of corneal toxicity with low dose of cytarabine (Lochhead et al., 2003)
Intrathecal: Optic neuropathy leading to severe visual loss (may be potentiated by
cranial radiation therapy) (Hopen et al., 1981; Margileth et al., 1977)
Ocular toxicity is rare (Bobba & Klein, 2012).
Hydrocortisone or dexamethasone eye drops may prevent

keratitis. It is recommended to start eye drops the evening
before therapy begins (Cleri & Haywood, 2002; Higa et al.,
1991).
369
Antimetabolites
Drug
370
Table 45. Ocular Toxicities of Antineoplastic Agents (Continued)

Classification
Antitumor
antibiotics
Biotherapy
agents
Ocular Toxicity
Comments
5-Fluorouracil
Conjunctivitis (Christophidis et al., 1979; Singh & Singh, 2012), excessive lacrimation (Hamersley et al., 1973; Singh & Singh, 2012), tear duct fibrosis (Haidak et
al., 1978), and blepharitis (Fraunfelder et al., 2008). Other ocular toxicities include
keratoconjunctivitis, cicatricial ectropion, ankyloblepharon, blepharospasm, punctal occlusion, oculomotor disturbances, blurred vision, photophobia, nystagmus, increased lid necrosis after cryotherapy, ocular pain, circumorbital edemas (Jansman
et al., 2001; Palmer et al., 2008; Singh & Singh, 2012), dry eyes, and excessive
tearing (OncUView, 2011b)
Loprinzi et al. (1994) studied the use of ice packs to decrease ocular irritation; effectiveness was reinforced by
North Central Cancer Treatment Group (ice applied for
30 minutes, starting 5 minutes before infusion). The use
of dexamethasone eye drops decreased ocular toxicities
(Jansman et al., 2001).
Fludarabine
Decreased visual acuity (most common presenting sign before development of progressive encephalopathy); rare cases of diplopia, photophobia, and optic neuritis (Al-Tweigeri et al., 1996; Chun et al., 1986; Palmer et al., 2008; Singh & Singh,
2012; Warrell & Berman, 1986)
Effects are dose dependent (Bobba & Klein, 2012).
Methotrexate
IV: Blepharitis, conjunctival hyperemia, increased lacrimation, periorbital edema, photophobia, optic pain (Palmer et al., 2008; Singh & Singh, 2012)
Intrathecal: With concurrent radiation, case reports of bilateral ophthalmoplegia with
exotropia; optic nerve atrophy (Bobba & Klein, 2012)
Intra-arterial: Retinal changes in ipsilateral eye (Fraunfelder et al., 2008; Singh &
Singh, 2012)
Up to 25% of patients may develop ocular toxicity (Palmer et

al., 2008). Toxicity is more common with higher doses (Bobba & Klein, 2012).
Drug is found in tears (Fraunfelder et al., 2008).
Pentostatin
Conjunctivitis, photophobia, diplopia (Haddadin & Perry, 2012); abnormal vision, amblyopia, conjunctivitis, dry eye, problems with lacrimation, photophobia, retinopathy,
watery eyes (Singh & Singh, 2012)
Doxorubicin
Conjunctivitis, increased lacrimation (Bobba & Klein, 2012; Curran & Luce, 1989;
Singh & Singh, 2012); increased lacrimation in up to 25% of patients receiving
doxorubicin (Blum, 1975; Singh & Singh, 2012)
Serious ocular side effects are rare (Bobba & Klein, 2012).
Mitomycin C
IV: Blurred vision (Al-Tweigeri et al., 1996; Palmer et al., 2008; Singh & Singh, 2012)
Topical: Keratoconjunctivitis (Bobba & Klein, 2012)
Other than blurred vision, keratoconjunctivitis was reported after topical use in ophthalmologic surgeries (Bobba &
Klein, 2012; Singh & Singh, 2012).
Mitoxantrone
Conjunctivitis, discoloration of sclera (Karch, 2014)
Drug is secreted in tears.
BCG live vaccine
Uveitis, conjunctivitis, iritis, keratitis, granulomatous chorioretinitis (Palmer et al.,

2008; Sanofi Pasteur Inc., 2012)
Ocular side effects rare and are more common in patients

who are positive for HLA-B27 (Sanofi Pasteur Inc., 2012).
G-CSF,
GM-CSF
Case report of acute iritis in healthy stem cell donor taking G-CSF (Parkkali et al.,
1996); marginal keratitis and mild uveitis in healthy stem cell donor following both
G-CSF and GM-CSF (Esmaeli et al., 2002)
Antimetabolites
(cont.)
Drug

Classification
Biotherapy
agents (cont.)
Miscellaneous
Drug
Ocular Toxicity
Comments
IFN alfa,
IFN beta,
IFN gamma
Retinopathy, primarily retinal hemorrhages; cotton wool spots (Esmaeli, Koller, et al.,
2001; Wilson, 2004); disc edema (Palmer et al., 2008)
Changes in vision, nonspecific conjunctivitis, and ocular pain are most frequent reported ocular side effects (Teitelbaum, 2011).
Risk is increased in patients with hypertension or diabetes and those receiving higher doses. Effects may occur
as soon as 15 minutes after initial exposure or take many
months to be seen. Less than 1% of patients receiving IFN
develop ocular toxicities (Teitelbaum, 2011).
IL-2
Neuro-ophthalmic effects including scotoma, diplopia, transient blindness, and visual

hallucinations (Teitelbaum, 2011)
Retinoid
Blepharoconjunctivitis, corneal opacities, papilledema, pseudotumor cerebri, night

blindness (Al-Tweigeri et al., 1996)
Avoid concurrent use of tetracyclines and drugs causing intracranial hypertension (Fraunfelder et al., 2008).
Bisphosphonates
Conjunctivitis, uveitis, scleritis (Fraunfelder et al., 2008), episcleritis, eyelid edema,

optic neuritis, periorbital edema (Renouf et al., 2012)
Bisphosphonates must be discontinued for symptoms to resolve (Fraunfelder et al., 2008).

Most reports describe the onset of symptoms within 48 hours
of the initial infusion along with symptoms such as flu-like,
fever, or myalgia (Renouf et al., 2012).
Corticosteroids
Posterior subcapsular cataracts, glaucoma, retinal hemorrhage (Loredo et al., 1972);

opportunistic eye infections, visual field defects, blurred vision, diplopia, exophthalmos, scleral discoloration (Palmer et al., 2008)
Increased intraocular pressure and subsequent glaucoma have been noted with
long-term use (Teitelbaum, 2011).
Cyclosporine A
Optic neuropathy (Mejico et al., 2000); blurred vision, retinopathy, case reports of cortical blindness (Palmer et al., 2008)
Combination of cyclosporine A and TBI may increase susceptibility to develop radiation-induced optic neuropathy;
patients symptoms improved to some extent when cyclosporine was discontinued (Mejico et al., 2000).
Deferoxamine
mesylate/
desferrioxamine
Night blindness, visual field constriction, cataracts, pigmentary retinopathy, optic neuropathy (Arora et al., 2004); blurring vision, decreased visual acuity, vision loss, visual defects, scotoma, impaired peripheral, color, and night vision, optic neuritis,
corneal opacities (Novartis Pharmaceuticals Corp., 2011)
Ocular side effects occurred related to prolonged use and

high doses or in patients with low ferritin levels; ocular disturbances were reversible upon cessation of treatment
(Arora et al., 2004; Novartis Pharmaceuticals Corp., 2011).
Ethambutol
hydrochloride
Decreased visual acuity, color blindness, visual defect, possible irreversible blindness, optic neuritis (STI Pharma, LLC, 2012)
Ocular toxicity can happen at any dose but is increased at

doses > 50 mg/kg (Donald et al., 2006); change in visual
acuity can be unilateral or bilateral. Testing for visual acuity
should be performed before treatment begins and periodically during treatment, unless dose is > 15 mg/kg/day, then
monthly testing is needed (STI Pharma, LLC, 2012).

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372

Classification
Nitrosoureas
Ocular Toxicity
Comments
Mannitol
Blurred vision (Baxter Healthcare Corp., 2009b)
Because of fluid and electrolyte shift, side effects can be prevented with close monitoring and test dose to evaluate degree of renal failure when indicated (Baxter Healthcare
Corp., 2009b).
Mitotane
Visual blurring, diplopia, lens opacity, toxic retinopathy (Bristol-Myers Squibb Co.,
2010b; Palmer et al., 2008)
Ocular side effects are infrequent (Bristol-Myers Squibb Co.,

2010b).
Procarbazine
hydrochloride
Retinal hemorrhage, papilledema, photophobia, diplopia, inability to focus (SigmaTau Pharmaceuticals, Inc., 2008)
Ophthalmic side effects are rare (Cleri & Haywood, 2002).
Radiation therapy
Xerophthalmia, keratoconjunctivitis (dry eye syndrome), pain, sensation of a foreign

body in the eye, corneal ulceration (Brigden & McKenzie, 2000)
Xerophthalmia is caused by the radiation effect on the lacrimal and other adnexal glands that contribute to tear production. Lubricants and an ophthalmologic consultation are
helpful (Brigden & McKenzie, 2000).
Tacrolimus
(FK506)
Optic neuropathy (Mejico et al., 2000)
Tamoxifen
Cataracts and decreased color vision; increased risk with doses > 20 mg/day (Singh
& Singh, 2012); retinal toxicity (small refractile or crystalline dot-like yellowish deposits in the area surrounding the macula, in the nerve, and in plexiform layers)
(Gianni et al., 2006; Lazzaroni et al., 1998; Singh & Singh, 2012; Tsai et al., 2003);
corneal opacities, retinopathy (Palmer et al., 2008; Singh & Singh, 2012)
A baseline ophthalmic examination is recommended within the first year (Gorin et al., 1998). Visual acuity along with
macular edema may improve with tamoxifen withdrawal, but
retinal deposits often do not (Gianni et al., 2006).
Carmustine,
lomustine
Optic neuritis and atrophy, hyperemia, orbital pain, retinopathy, corneal opacities and
edema, orbital IV shunts, secondary glaucoma, internal ophthalmoplegia, blurred
vision, vitreous opacification, extraocular muscle fibrosis, diplopia (Palmer et al.,
2008; Singh & Singh, 2012)
IV: Rare reports of delayed blurred vision and loss of depth perception (Bobba &
Klein, 2012; Singh & Singh, 2012)
Intracarotid: Severe, ipsilateral occurrences including arterial narrowing, disc edema,
and intraretinal hemorrhages (Greenberg et al., 1984; Shingleton et al., 1982; Singh
& Singh, 2012)
Miscellaneous
(cont.)
Drug

Classification
Targeted
therapies
Ocular Toxicity
Comments
Cetuximab
Blurred vision, eye pain, visual field cuts (OncUView, 2011b); blepharitis (RamrezSoria et al., 2008); eyelid dermatitis, conjunctivitis, poliosis (whitening of the eyelashes), corneal erosions, punctate keratitis (Renouf et al., 2012)
Relatively common: Loss of eyelashes/eyebrows (madarosis) and/or cicatricial ectropion, loss of color of the skin around the eye with weekly infusions (Garibaldi &
Adler, 2007), trichomegaly (Basti, 2007; Robert et al., 2005)
Very rare: Bilateral ocular discomfort with itchiness around both eyelids, foreign body
sensation, tearing associated with exfoliated skin, oil secretions, crusty scaling (Tonini et al., 2005)
Ocular side effects occured in < 20% of patients and resolved

after treatment was discontinued (OncUView, 2011b).
Blepharitis was treated with oxytetracycline cream TID for 20
days (Ramrez-Soria et al., 2008)
Madarosis and cicatricial ectropion resolved after discontinuation of cetuximab (Garibaldi & Adler, 2007).
Ocular discomfort cleared up with topical antibiotics and
holding therapy (Tonini et al., 2005). While many researchers (Braiteh et al., 2008; Eaby et al., 2008; Esper et al.,
2007) agree that for patients experiencing trichomegaly,
an ophthalmologist should be seen if eye irritations occur
and eyelashes may be carefully and safely trimmed, Basti
(2007) advises patients to not cut their lashes or have them
cut. Waxing or electrolysis may be recommended (Braiteh
et al., 2008; Segaert & Van Cutsem, 2005).
Erlotinib
Periorbital rash, conjunctivitis, eyelid ectropion (Methvin & Gausas, 2007; Singh &
Singh, 2012); eyelash trichomegaly (Robert et al., 2005)
Episcleritis and corneal abrasion related to infectious keratitis (Renouf et al., 2012)
Side effects resolved within 6 weeks after treatment was

stopped (Methvin & Gausas, 2007; Renouf et al., 2012).
See cetuximab for comments regarding trichomegaly.
Imatinib
Periorbital edema (Robert et al., 2005), dry eyes, visual disorders such as blurred vision, reduced visual acuity, and visual disturbances (Singh & Singh, 2012), epiphora, optic neuritis, cystoid macular edema (Renouf et al., 2012)
Symptoms resolve after EGFR inhibitor treatment is stopped.

Periorbital edema is the most common side effect, occurring
in 30% (Renouf et al., 2012).
Ipilimumab
Uveitis, iritis, papillitis; rare (< 1%) conjunctivitis, scleritis, episcleritis, blepharitis, and
temporal arteritis (Renouf et al., 2012)
Uveitis, iritis, and papillitis were successfully treated with topical corticosteroid drops (Renouf et al., 2012).
Panitumumab
Keratitis and ulcerative keratitis, conjunctivitis, ocular hyperemia, increased lacrimation, eye/eyelid irritation, growth of eyelashes (Amgen Inc., 2013b; OncUView,
2011b; Singh & Singh, 2012)
Onset of ocular symptoms is 1415 days after first dose of

panitumumab. Symptoms resolve after panitumumab is
stopped. Median time of resolution is 84 days (Amgen Inc.,
2013b).
Rituximab
Conjunctivitis, transient ocular edema, burning sensation, transient visual changes or

permanent and severe loss of visual acuity (Singh & Singh, 2012)
Sunitinib
Periorbital edema (Robert et al., 2005), neurosensory retinal detachment (Renouf et

al., 2012)
Effects resolve after EGFR inhibitor treatment is stopped

(Renouf et al., 2012; Robert et al., 2005).
Docetaxel
Epiphora, canalicular stenosis (Esmaeli, Valero, et al., 2001); conjunctivitis, punctal

stenosis (Singh & Singh, 2012)
Drug is secreted in tears (Esmaeli et al., 2002).

Successful treatment is achieved with bicanalicular silicone
intubation (Ahmadi & Esmaeli, 2001).
373
Taxanes
Drug
374

Classification
Drug
Ocular Toxicity
Comments
Paclitaxel
Scintillating scotomas or shooting lights in 20% of cases, which resolved spontaneously (Bobba & Klein, 2012); transient scintillating scotoma, visual impairment, photopsia, possible ischemic optic neuropathy (Singh & Singh, 2012)
Scotomas usually occur toward the end of the 3-hour infusion

(Bobba & Klein, 2012).
Vinca alkaloids
Etoposide
Intracarotid: Optic neuritis, transient cortical blindness (Lauer et al., 1999)
Effects occur when etoposide is given in combination with

carboplatin (Lauer et al., 1999).
Vinblastine
Extraocular muscle palsies (Fraunfelder & Fraunfelder, 2004), cranial nerve palsies,
optic neuropathy, optic atrophy, cortical blindness, night blindness (Singh & Singh,
2012)
Vincristine
Cranial nerve palsies, optic neuropathy, optic atrophy, case reports of transient cortical blindness, night blindness (Bobba & Klein, 2012; Palmer et al., 2008; Singh &
Singh, 2012)
Effects usually are reversible after discontinuation of vincristine (Bobba & Klein, 2012).
BCGbacillus Calmette-Gurin; EGFRepidermal growth factor receptor; G-CSFgranulocytecolony-stimulating factor; GM-CSFgranulocyte macrophagecolony-stimulating factor; HLAhuman leukocyte antigen; IFNinterferon; ILinterleukin; IVintravenous; TBItotal body irradiation; TIDthree times daily
Taxanes (cont.)
e) Conjunctiva and sclera: Ask the patient to look up as you depress

both lower lids with your thumbs, exposing the sclera and conjunctiva. Inspect both for color, vascular pattern, discharge, and any nodules or swelling.
f) Cornea, lens, iris, and pupils: Observe the cornea and lens for smooth
appearance, clarity, and any opacities in the lens. Test corneal reflex
by gently touching a cotton swab to corneal surface. Observe iris and
pupils. Margins should be clearly identified. Observe the pupils for
size, shape, and symmetry. If the pupils are > 5 mm or < 3 mm, then
measure the pupils with a pupil guide (a card or pen light with black
circles of varying sizes). Test the pupils for light reaction, observing
for direct reaction (pupillary constriction in the same eye) and consensual reaction (pupillary constriction in the opposite eye). Note
pain and photophobia.
g) Extraocular muscles (CNs): Observe for light reflex (shining a
light in the patients eyes and inspecting the reflections in the corneas) and extraocular movement by having the patient follow finger movements in six planes and convergence. Note any unilateral
movement, lack of movement, nystagmus, lid lag, or other abnormal movements.
a) Refer to an ophthalmologist for further evaluation and treatment.
b) Symptoms that necessitate a referral (Ouwerkerk & Boers-Doets, 2010)
(1) Persistent ocular pain, significant loss of vision, or decreased
acuity of vision
(2) Severe redness of the eye or light sensitivity
(3) Trichomegaly
(4) Failure to respond to treatment within one week of initiation
of treatment for squamous blepharitis, meibomitis, or dysfunctional tear syndrome
c) Instruct patients to use pharmacologic management as appropriate
(e.g., antibiotics, steroids, artificial tears).
d) Prevent further damage: Discontinue causative agent and promote
symptom management.
e) Surgical interventions may be necessary (e.g., cataract surgery, dilation for punctal stenosis, enucleation).
a) Teach patients self-examination techniques, emphasizing the importance of close monitoring and prompt reporting of any structural
changes in eyelids or eyelashes or changes in vision.
b) Emphasize the importance of careful hygiene and hand-washing techniques to minimize cross-contamination.
c) Demonstrate the proper use of eye drops and lubricants.
d) Encourage patients to schedule regular eye examinations.
M. Pancreatitis: Inflammation of the pancreas
1. Pathophysiology (Andris, 2010; Hruban & Iacobuzio-Donahue, 2010)
a) Inflammation that can lead to parenchymal necrosis and alteration
of pancreatic exocrine cells that produce digestive enzymes such as
amylase and lipase and endocrine cells that produce insulin, glucagon, and somatostatin, secondary infection with gram-negative bacteria commonly occurs.
b) Secondary to ductal obstruction, possible ductal rupture, and premature activation of pancreatic enzymes leading to pancreatic autodigestion
2. Risk factors (Andris, 2010; Hruban & Iacobuzio-Donahue, 2010; Stock
et al., 2011)
375
376
a) Pegylated and natural asparaginase: Causes pancreatitis in 5%18%

of patients (5% in adults), with a 2% incidence of grade 3 or 4 acute
pancreatitis (per CTCAE version 4.0). Pancreatitis associated with asparaginase usually occurs with the first three to five doses.
b) Other agents: Mercaptopurine, ATRA in case reports (Hoshino, Hatsumi, Takada, Sakura, & Miyawaki, 2008), arsenic in case reports (Connelly, Zancosky, & Farah, 2011), cytosine arabinoside, and tamoxifen
c) Obstructions of the duct system including periampullary neoplasms,
cholelithiasis, and congenital alterations in the ductal system such as
pancreas divisum
d) Hypertriglyceridemia, hypercalcemia
e) Diabetes
f) TLS
g) Postendoscopic retrograde cholangiopancreatography
h) Alcohol abuse
i) Illicit drug use
j) Pediatrics: Post-BMT
k) Infection
l) Genetic mutations of cationic trypsinogen (PRSS1) and trypsin inhibitor (SPINK1) genes
3. Three main clinical manifestations (Brenner & Krenzer, 2010)
a) Sudden onset of severe epigastric, periumbilical, or left or right
upper abdominal pain that radiates to the back: Pain lasts > 72
hours and usually is exacerbated by sitting up and alleviated by
fetal position.
b) Increased serum levels of pancreatic enzymes: Amylase rises within
two hours of symptoms to two or more times the upper limit of normal and decreases within 36 hours. Serum lipase is elevated within
48 hours of symptoms and decreases after 14 days.
c) CT positive for signs of pancreatic inflammation
4. Other clinical findings
a) Fever
b) Tachycardia and hypovolemia
c) Hypoxemia in 40%70% of patients (Werner, Feuerbach, Uhl, &
Bchler, 2005)
d) Anorexia and severe nausea and vomiting
e) Jaundice
f) Hypoactive bowel sounds, ileus
g) Elevated LFTs
h) Hyperglycemia, especially related to steroids
i) Frequently elevated WBC count
j) Hemorrhagic pancreatitis manifested by a bluish discoloration around
the umbilicus (Cullen sign) or a reddish-brown discoloration along
the flanks (Grey Turner sign)
k) Later complications include hemorrhage, sepsis, and multiple system organ failure.
5. Assessment
a) Perform physical examination to find and document the preceding
clinical manifestations.
b) Anticipate orders for diagnostic imaging of the abdomen (e.g., abdominal flat plate and upright to detect ileus and rule out other etiologies such as bowel perforation or obstruction; ultrasound to visualize gallbladder and biliary tree for stones, edema, and dilation; CT
scan to image pancreas).
6. Collaborative management (Andris, 2010; Forsmark & Baillie, 2007):
Treatment is aimed at correcting underlying predisposing conditions,
managing complications, and decreasing pancreatic inflammation.
a) Holding or discontinuing any agent that may be the cause of the condition is the primary treatment. Pancreatitis associated with asparaginase tends to respond after the drug is discontinued and aggressive treatment is initiated (Stock et al., 2011; Treepongkaruna et al.,
2009) and will most likely recur if the drug is used again (Kearney et
al., 2009; Stock et al., 2011; Tokimasa & Yamato, 2012). Because reduced asparaginase exposure is related to a decreased cure rate in
acute lymphoblastic leukemia, the drug should not be stopped unless
pancreatitis is diagnosed. Asparaginase is contraindicated in patients
with a history of severe pancreatitis (EUSA Pharma [USA], Inc., 2011).
b) Insert a nasogastric tube if patients have nausea and vomiting or ileus to rest the gut and the pancreas during the acute phase.
c) If patients are unable to eat, consider enteral nutrition through a
feeding tube to prevent malnutrition (McClave et al., 2009).
d) Administer vigorous hydration with electrolyte monitoring and replacement (e.g., calcium, potassium, magnesium) as indicated.
e) Monitor serum lipase, amylase, glucose, electrolytes, and LFTs.
f) Treat hyperglycemia as indicated.
g) Provide effective pain control and monitor for increasing pain, which
may indicate progression of pancreatitis.
h) Administer antibiotic therapy.
i) Some studies show severe pancreatitis can be managed with protease inhibitors, such as nafamostat mesylate, or octreotide therapy
(Stock et al., 2011).
j) Monitor patients vital signs, oxygen saturation, level of consciousness, and condition carefully for signs of hypovolemic shock. Hypotension occurs because of sequestration of protein-rich fluids in
the pancreas, retroperitoneal space, and abdominal cavity in severe
acute pancreatitis.
k) When food is reintroduced, provide a lipid-restricted diet.
a) Instruct patients to use analgesics for pain control.
b) Implement oral and nasal care while patients are NPO (nothing by
mouth) with a nasogastric tube.
c) Ensure that patients know the importance of adherence to dietary,
pharmacologic, and lifestyle recommendations.
d) Ensure that patients and significant others can recognize the early
symptoms of pancreatitis such as abdominal pain, especially associated with vomiting, and instruct them to seek medical intervention
when these occur.
N. Fatigue: Cancer-related fatigue is a distressing, persistent, subjective
sense of physical, emotional, or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning (NCCN, 2012, p. FT-1). Multiple factors contribute to this complex syndrome in patients with cancer, making it difficult to identify a clear underlying cause (Johnson Armin, & Matzo, 2012). Fatigue is underreported, underdiagnosed, and
undertreated. Cancer-related fatigue is the most common and distressing side effect of cancer treatment and has a profound effect on individuals ability to carry out usual functions of daily living (Berger, Gerber,
& Mayer, 2012). NCCN (2012) guidelines recommend that all patients
be screened for fatigue at their initial visit and at regular intervals during the cancer treatment continuum and that fatigue should be treated
promptly in both children and adults.
1. Pathophysiology: Exact mechanisms are unknown. Clinical studies have
focused on understanding the factors that contribute to cancer-related
377
378
fatigue. Factors include the tumor itself, treatments, and comorbid conditions (Wang, 2008) (see Figure 36).
a) Underlying causes of cancer-related fatigue are believed to involve
several physiologic and biochemical systems (Wang, 2008).
(1) 5-HT neurotransmitter dysregulation
(2) Vagal afferent activation
(3) Alterations in muscle and ATP metabolism
(4) Anemia
(5) Proinflammatory cytokines
(a) Hypothalamic-pituitary-adrenal axis and cortisol dysfunction
(b) Circadian rhythm disruption
(c) Cytokine dysregulation
(d) Growth factor modulation
(e) Depression
(f) Cachexia
b) Treatment-related causes: Direct effects of chemotherapy, hormone
therapy, radiation therapy, and combined-modality therapies have
Figure 36. Proposed Potential Causes of Cancer-Related Fatigue
EGFRepidermal growth factor receptor; 5-HT5-hydroxytryptamine; HPAhypothalamic-pituitary-adrenal; VEGFvascular endothelial growth factor
Note. From Pathophysiology of Cancer-Related Fatigue, by X.S. Wang, 2008, Clinical Journal of Oncology Nursing, 12(Suppl. 5), p. 12. doi:10.1188/08.
CJON.S2.11-20. Copyright 2008 by the Oncology Nursing Society. Reprinted with permission.
all been implicated as contributors to the intensity of fatigue in patients with cancer (Bruera & Yennurajalingam, 2010). Travel to and
from a clinic for treatment adds to a patients fatigue, as well as the
therapy itself.
c) Disease process and comorbid conditions including metabolic disorders
(1) Hypothyroidism
(2) Electrolyte imbalances
(3) Infection
(4) Insulin sensitivity: Insulin resistance causes abnormal uptake of
glucose by muscle and increases body fat, contributing to cancer-related fatigue (Berger et al., 2012).
d) Uncontrolled pain, nausea, and vomiting
e) Anxiety and stress
f) Sleep disturbances (NCCN, 2012)
(1) Obstructive sleep apnea
(2) Restless legs syndrome
(3) Narcolepsy
(4) Insomnia
(5) Hypersomnia
g) Mood disturbances
h) Anemia: A relationship clearly exists between Hgb and fatigue. A decrease in RBCs increases hypoxia-related compromise in organ function, which contributes to fatigue (Wang, 2008).
i) Nutritional deficiencies: Reduced caloric intake and imbalances in serum levels of sodium, potassium, calcium, and magnesium may contribute to fatigue and affect QOL (NCCN, 2012; Sauer & Voss, 2012).
j) Physical deconditioning and activity level: Direct effects of the tumor
or side effects of the treatment regimen often contribute to fatigue
through reduced physical activity, debilitation, and reduced muscle
strength (Winters-Stone, Bennett, Nail, & Schwartz, 2008).
k) Stress
l) Depression: Depression may occur concurrently or independently of
fatigue and has a different pattern of expression over time. Depression often decreases over the course of treatment, whereas fatigue
increases (NCCN, 2012).
m) Phenotypes/genotypes: Underlying genetic variants and pathways may
produce a cancer-related fatigue phenotype (Piper & Cella, 2010).
2. Incidence: Fatigue is one of the most commonly reported symptoms
experienced by patients receiving treatment for cancer, and it often
persists beyond the conclusion of active treatment. Depending upon
how cancer-related fatigue is defined and measured, prevalence estimates across the disease trajectory range from 25%99% (Mitchell, 2010b).
3. Assessment: Oncology nurses can ensure that cancer-related fatigue is
routinely assessed, managed, and documented. Multiple cancer-related
fatigue assessment and screening tools are available (Piper et al., 2008).
a) Single-item, single-dimension measures are easy to administer. These
include a 010 scale, a visual analog scale, or Likert scales (Piper et
al., 2008).
(1) On a 010 scale (0 = no fatigue, and 10 = worst fatigue imaginable), mild fatigue is given a score of 13; moderate fatigue,
46; and severe fatigue, 710.
(2) Fatigue measurement in children is simplified. Young children
(age < 6) may just be asked if they are tired or not tired. Valid and reliable instruments are available to measure fatigue in
children and adolescents (NCCN, 2012).
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(3) If mild levels (13) are determined, patients and family members should receive education about fatigue and common strategies for management.
(4) When fatigue is rated as moderate to severe (410), a more focused history and physical examination should be conducted as
part of the primary evaluation phase. Multi-item, single-dimension measures, multidimensional measures, and fatigue measures embedded in other scales are available with limitations.
Most have been validated as reliable but have not been tested
in practice settings. More studies are needed to evaluate whether these scales are useful for treatment planning.
b) Disease status
c) Disease recurrence or progression
d) Current medications or medication changes that may contribute to
fatigue
(1) Polypharmacy is common in patients with cancer. Many drugs
alone (e.g., antihistamines, beta-blockers) or in combination
can contribute to fatigue (Breitbart & Alici, 2008).
(2) Tricyclic antidepressants, opioids, antiemetic medications, and
sleep aids all can cause sedation. Combined use of these agents
can cause prolonged sedation, leading to limited activity and
overall fatigue.
e) Complete review of systems
f) Onset, pattern, and duration of fatigue
g) Nutritional and metabolic evaluation: Improving dietary intake, with
appropriate caloric intake, often can improve fatigue symptoms.
(1) A dietitian can design a patient-specific plan to improve nutritional status. Fluids and electrolytes should be assessed. Specifically, imbalances in sodium, potassium, calcium, and magnesium can be reversed with appropriate supplementation, which
may improve fatigue (NCCN, 2012).
(2) Nausea and vomiting, taste changes, and bowel changes (e.g.,
obstruction, constipation, diarrhea) will interfere with nutritional intake and affect fatigue level.
h) Activity level
i) Associated or alleviating factors (e.g., rest, energy conservation, balancing activities with rest periods)
a) General
(1) Energy conservation: The goal of energy conservation as defined by NCCN (2012) is to maintain a balance between rest
and activity during times of high fatigue so that valued activities can be maintained (p. MS-16). This is a learned process for
each patient and is dictated by the patients disease experience.
(2) Instruct patients to delegate activities, pace themselves, take extra rest periods, plan high-energy activities at times of peak energy, and conserve energy for valued activities (NCCN, 2012).
(3) Recommend energy-saving devices (e.g., raised toilet seats, grabber tools, seated walkers, wheelchairs).
b) Pharmacologic: Because the exact pathophysiology of cancer-related
fatigue is obscure, pharmacotherapy is empiric or geared toward reversing possible contributing factors such as anemia, poor nutrition,
or depression (Minton, Richardson, Sharpe, Hotopf, & Stone, 2008).
(1) ESAs (Epogen, Procrit, and Aranesp) have been under intense scrutiny. These agents, when used appropriately, reduce
transfusion requirements and improve anemia. However, safety concerns, including increased risk of thrombotic events, hyCopyright 2014 by the Oncology Nursing Society. All rights reserved.
pertension, red cell aplasia, and decreased locoregional disease

control and survival outcomes, limit their use in clinical practice. Current recommendations for use are for treatment of anemia related to myelosuppressive chemotherapy without curative intent (Mitchell, 2010b; Minton et al., 2008; NCCN, 2012).
(2) Antidepressants have been recommended as treatment for fatigue because depression was suggested as a causal factor. In
particular, paroxetine, bupropion, and venlafaxine are used.
(a) Although these drugs are helpful in alleviating depression,
studies have not demonstrated a benefit compared to placebo in cancer-related fatigue, and they are not recommended to lessen fatigue (Mitchell, 2010b; Minton, Richardson,
Sharpe, Hotopf, & Stone, 2010; NCCN, 2012).
(b) Antidepressants might have a greater effect on cancer survivors, in whom fatigue and depression are prevalent and
often coexist (Johnson et al., 2012).
(3) Psychostimulants
(a) Methylphenidate: Studies have reported mixed results using methylphenidate to reduce fatigue (Portela, Rubiales,
& Centeno, 2011). Side effects of headache, insomnia, agitation, anorexia, nausea, vomiting, and dry mouth are common (Minton et al., 2008; Mitchell, 2010b; NCCN, 2012).
The most recent randomized controlled trial conducted
by the North Central Cancer Treatment Group was unable
to demonstrate that the chosen long-acting methylphenidate product would decrease cancer-related fatigue (Moraska et al., 2010).
(b) Dexmethylphenidate has a longer duration of action compared to methylphenidate. Trials have demonstrated improvement in fatigue outcomes in patients with breast and
ovarian cancers but no improvement in those with primary
or metastatic brain tumors (Breitbart & Alici, 2008; Mitchell, 2010b).
(c) Modafinil is a wakefulness-promoting agent. It is indicated
for narcolepsy. Data from a large randomized controlled
trial observed improvement in fatigue in patients with severe fatigue but not in those with mild or moderate fatigue
(NCCN, 2012).
(4) Glucocorticoids
(a) Corticosteroids (prednisone and dexamethasone) have
been used in providing short-term relief for cancer-related
fatigue. Given the detrimental side effects of muscle wasting with long-term use, steroids are restricted to the terminally ill (Breitbart & Alici, 2008; NCCN, 2012).
(b) Megestrol acetate is widely used for appetite improvement,
and its safety and efficacy have been confirmed in treating
cancer cachexia. However, meta-analysis of the four trials
that compared progestational steroids with placebo found
no difference in the two arms for reducing cancer-related
fatigue (Breitbart & Alici, 2008; Chan, 2011; NCCN, 2012).
(5) The supplement L-carnitine has been examined in several openlabel studies and has shown improvement in cancer-related fatigue. Carnitine is a micronutrient important in the processing
of long-chain fatty acids and energy production in mammalian
cells. Carnitine supplements may prove beneficial for fatigue
management (Breitbart & Alici, 2008; Mitchell, 2010b).
(6) CAM therapies
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(a) Limited studies of herbal supplements have been conducted with regard to fatigue in patients with cancer. A trend
toward improvement in fatigue was seen with ginseng at
greater dose levels (Homeber, Fischer, Dimeo, Rffer, &
Weis, 2012; Mitchell, 2010b). Current data are insufficient
to warrant recommendation of many of these substances.
(b) Mistletoe extract demonstrated some positive effect on
cancer-related fatigue in an observational cohort analysis
(Mitchell, 2010b).
(7) Nonpharmacologic interventions
(a) Exercise (activity enhancement): Cumulative evidence is
strong in support of exercise as an intervention to manage
cancer-related fatigue (NCCN, 2012). All patients with cancer should be encouraged to maintain an optimum level of
physical activity during and following cancer treatment. Exercise improves aerobic capacity, prevents muscle loss and
deconditioning, and helps to manage cancer-related fatigue
during and after treatment even in older cancer survivors
(Brown, Huedo-Medina, et al., 2011; Mishra et al., 2012;
Mitchell, 2010b; Puetz & Herring, 2012).
i. Exercise intensity, frequency, and type of activity need
further study to determine the most beneficial program for each individual and stage of disease. Referral for exercise rehabilitation can be helpful (Mitchell, 2010b; NCCN, 2012).
ii. Exercise programs must be undertaken with caution
for patients with bone metastasis, immunosuppression
or neutropenia, fever, thrombocytopenia, anemia, or
other treatment complications.
iii. Programs should be initiated slowly to assess the patients tolerance and can be modified as the patients
condition changes (NCCN, 2012). Walking, cycling,
swimming, resistance training, and a combination of
these have been evaluated and are reasonable modalities for patients to choose.
(b) Complementary therapies: In cases in which exercise or
medication is prohibited, evidence is emerging in support of complementary therapies. Yoga, progressive muscle relaxation, polarity therapy, hypnosis, medical Qigong,
healing touch, Reiki, and massage have demonstrated improvement in cancer-related fatigue in small trials (Mitchell, 2010b; NCCN, 2012). Boehm, Ostermann, Milazzo, and
Bssing (2012), in a meta-analysis of the effects of yoga on
fatigue in patients with cancer, found the intervention to
be limited. However, the authors concluded that the studies
were not well designed and that the treatment benefit from
this generally safe, therapeutic intervention may be more
powerful than reported. Although patients frequently use
complementary therapies to reduce distress from cancer
treatment side effects, efficacy related to benefit for cancerrelated fatigue needs to be confirmed in further randomized controlled studies (Wanchai, Armer, & Stewart, 2011).
Psychosocial and educational interventions that teach patients to recognize cancer-related fatigue and manage it
through energy conservation activities have demonstrated
some benefit (Bennett et al., 2009; Goedendorp, Gielissen,
Verhagen, & Bleijenberg, 2009).
(c) Sleep therapy: Cognitive-behavioral therapies to optimize

sleep quality have been shown to decrease cancer-related
fatigue (NCCN, 2012; Wanchai et al., 2011).
i. Stimulus control: Maintain a consistent bedtime ritual and wake time.
ii. Sleep restriction: Limit the amount of time in bed,
including naps.
iii. Sleep hygiene: Avoid caffeine late in the day and provide a comfortable sleep environment to promote a
good nights sleep.
a) Management of fatigue originates with the primary oncology team with
assessment of fatigue as a symptom related to treatment and disease status. This begins with the initial screening and then expands to a more focused evaluation for moderate to higher levels of fatigue (NCCN, 2012).
b) Inform patients and family members that fatigue is a major symptom
related to the disease and treatment process and that patterns are variable and not necessarily an indication of treatment failure or disease
progression. Daily self-monitoring of fatigue levels in a log or diary
can be helpful (NCCN, 2012). Verbal encouragement from healthcare providers and other patients with cancer to maintain physical activity may enhance self-efficacy and mediate the effect of cancer-related fatigue on activity enhancement (Haas, B.K., 2011).
c) Supportive expressive therapies, including in-person or online support groups, counseling, and journal writing, may serve as an emotional outlet as well as an avenue for support and encouragement
(NCCN, 2012). Oncology nurses frequently provide this one-on-one
education for the patient.
d) Nutritional consults with a registered dietitian will identify nutritional deficits and inform patients and caregivers of the best strategies to
improve dietary intake. Maintaining adequate hydration and electrolyte balance is essential in preventing and managing cancer-related
fatigue (NCCN, 2012; Sauer & Voss, 2012).
O. Alterations in sexuality
1. Pathophysiology
a) Female: Ovarian function is affected by chemotherapy.
(1) Altered production of female sex hormones (estrogen, progesterone, and testosterone) (Nappi, Albani, Strada, & Jannini, 2011)
(2) Varying effects on sexuality (Krebs, 2012)
(3) No association found between specific androgen levels and low
sexual function (Davis, Davison, Donath, & Bell, 2005)
b) Male
(1) Testosterone is involved in
(a) Development of secondary sex characteristics
(b) Development of sperm
(c) Secretion of fluid from the prostate gland, seminal vesicles,
and Cowper glands.
(2) Prolactin is secreted by the pituitary gland.
(a) Maintains the production of testosterone
(b) At high levels, suppresses production in a negative feedback loop (Deneris & Huether, 2010)
2. Incidence: Almost all cancer survivors report ongoing problems with sexual functioning. These issues are global and reflect changes in body image, sexual self-image, and reentering life as a cancer survivor and may
persist for many years after completion of treatment (Harrington, Hansen, Moskowitz, Todd, & Feuerstein, 2010).
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a) Females
(1) Desire: Decrease in desire ranges from 31%56%, although
this may be underreported (Rellini, Farmer, & Golden, 2011).
(2) Dyspareunia: Painful intercourse is a common complaint caused
by vaginal dryness as a result of reduced estrogen levels or radiation damage to the pelvis (Goldfinger & Pukall, 2011).
(3) Arousal and orgasm: 36% of women report problems with arousal and pleasure, and 46% report decreased lubrication following cancer diagnosis and treatment (Huyghe, Sui, Odensky, &
Schover, 2009).
b) Males
(1) 90% of men experience profound loss of sexual desire while on
androgen deprivation therapy (DiBlasio et al., 2008).
(2) Up to 80% of men experience permanent erectile problems after any treatment for prostate cancer (Hoffman et al., 2006).
3. Chemotherapy agents that affect sexual function: There is very little information in the literature directly related to the effects of chemotherapy on sexual functioning beyond agents that are known to target the
gonads. Much of what is known comes from anecdotal evidence from
qualitative studies where participants may mention alterations in sexual functioning while on chemotherapy. All of the following agents are
used in various combinations; thus, the side effects may be cumulative
(Lubejko & Ashley, 1998).
a) Alkylating agents (e.g., busulfan, cyclophosphamide, ifosfamide, nitrogen mustard) cause nausea and vomiting, which significantly decreases desire.
b) Antimetabolites (e.g., cladribine, cytarabine, hydroxyurea, methotrexate) cause general malaise, mucositis, nausea, and vomiting.
c) Antitumor antibiotics (e.g., daunorubicin, doxorubicin, mitoxantrone) cause nausea, vomiting, and mucositis.
d) Plant alkaloids (e.g., vincristine) cause peripheral neuropathy, which may
affect sensation in the hands and fingers (Schwartz & Plawecki, 2002).
e) Hair loss is a common side effect of chemotherapy. The loss of hair
makes both men and women feel less attractive.
4. Biologic agents: Many of these agents cause fatigue, flu-like symptoms,
and changes to body image (Rothaermel & Baum, 2009).
5. Targeted therapies: There is no evidence about direct sexual effects, but
these agents cause fatigue, diarrhea, and rash with the potential to affect
body image (Remer, 2009).
6. Contributing factors
a) Chemotherapy-induced menopause: Symptoms of chemically induced
menopause are dramatic.
(1) Menstrual cycle changes with eventual cessation
(2) Hot flashes, insomnia
(3) Vaginal dryness
(4) Dyspareunia
(5) Weight gain (Deniz et al., 2007)
b) Severity
(1) Symptoms may be worse for women who are premenopausal
when diagnosed (Rogers & Kristjanson, 2002).
(2) Postmenopausal women also suffer severe symptoms (Crandall,
Petersen, Ganz, & Greendale, 2004).
c) Treatment: Women experiencing chemotherapy-induced menopause
benefit from a coordinated, multidisciplinary approach to managing symptoms.
(1) Hormonal: No consensus exists on the safety of hormone therapy for women with breast cancer, especially if it is estrogen
receptorpositive (Hickey, Saunders, & Stuckey, 2005, 2007;

Ponzone et al., 2005). Those with hormone-dependent cancer
should make a decision based on consultation with an oncologist (North American Menopause Society, 2007).
(a) Local estrogen therapy for vaginal atrophy
i. The use of vaginal estrogen creams, pessaries, or rings
can significantly reduce vaginal dryness.
ii. Systemic absorption is minimal (Ponzone et al., 2005).
(b) Systemic therapy: Three to five years of hormone replacement therapy may be considered if menopausal symptoms
are refractory to other treatments (Xydakis, Sakkas, & Mastorakos, 2006).
(2) Nonhormonal
(a) Clonidine (an antihypertensive) and gabapentin (an anticonvulsant) may reduce the severity and frequency of hot
flashes (Molina, Barton, & Loprinzi, 2005).
(b) Selective serotonin reuptake inhibitors
i. These agents have been effective in reducing the frequency and severity of hot flashes (Hickey et al., 2007).
ii. Venlafaxine and paroxetine have been suggested as
the most effective nonhormonal treatments for women with breast cancer (Bordeleau, Pritchard, Goodwin, & Loprinzi, 2007).
iii. Safety of selective serotonin reuptake inhibitors in
women with cancer is not yet established. Recent evidence suggests that these drugs may decrease the effectiveness of tamoxifen (Antoine, Liebens, Carly, Pastijn, & Rozenberg, 2007).
(c) Vitamin E may be effective in reducing hot flashes (Hickey et al., 2007).
(d) Vaginal moisturizers such as Replens may help women
who are experiencing vaginal dryness (Davis, Zinkand, &
Fitch, 2000).
(3) Complementary therapies
(a) Phytoestrogens: Long-term effectiveness has not been established (Hickey et al., 2007).
(b) Acupuncture may reduce the severity but not the frequency
of hot flashes (Nir, Huang, Schnyer, Chen, & Manber, 2007).
(c) Relaxation exercises are effective in reducing hot flashes
(Zaborowska et al., 2007).
d) Endocrine manipulation
(1) Tamoxifen
(a) Side effects appear to be most severe in premenopausal
women.
(b) Postmenopausal women experience negative side effects
of this drug to a lesser degree (Ganz, Rowland, Desmond,
Meyerowitz, & Wyatt, 1998).
(c) Decrease in libido has been reported.
(d) Tamoxifen produces mildly estrogenic effects on the vagina. Some women find relief from the vaginal dryness experienced as a result of chemotherapy-induced atrophy (Rogers & Kristjanson, 2002), whereas others think that the dryness has resulted from tamoxifen use (Hunter et al., 2004).
(2) Aromatase inhibitors cause vaginal dryness leading to dyspareunia (Mok, Juraskova, & Friedlander, 2008)
e) Body image changes related to ability to engage in sexually pleasurable activities: A womans comfort with her body after treatment; the
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reaction of her sexual partner to her body and weight gain (Garrusi & Faezee, 2008).
7. Clinical manifestations
a) Females: Alterations in sexual functioning can occur at all stages
of the sexual response cycle for women treated for cancer. Fatigue,
weight gain, and altered sexuality occur as a cluster of symptoms,
which magnifies the impact of each more than if they occurred individually (Wilmoth, Coleman, Smith, & Davis, 2004).
(1) Dyspareunia leading to vaginismus (Goldfinger & Pukall, 2011)
(2) Urinary tract infections after attempts at sexual intercourse
(Ponzone et al., 2005); this can create a negative feedback loop
with decreased interest in sex if the result is a painful infection.
(3) Mucositis manifested as vaginal irritation or vaginitis, vulvar irritation, itching, discharge, soreness, bleeding, and odor; this
usually occurs 35 days after chemotherapy administration and
lasts for up to 10 days.
(4) Other factors contributing to decreased sexual desire
(a) Depressed mood, fatigue, and nausea (Taylor, BasenEngquist, Shinn, & Bodurka, 2004)
(b) Loss of hair, particularly pubic hair (Fitch, 2003)
(c) Distress at role inadequacy (Lammers, Schaefer, Ladd, &
Echenberg, 2000)
(d) Fear that lack of sexual activity may cause problems in the
relationship (Sun et al., 2005)
b) Males
(1) Effects of androgen deprivation therapy
(a) Absence of sexual dreams; cessation of fantasies
(b) Lack of interest in anything sexual
(c) Cessation of any sexual pleasure (Navon & Morag, 2003)
(d) Changes in body image and perception of masculinity
(e) Alterations in spousal/partner relationships (Wittmann
et al., 2009)
(f) Erectile dysfunction
(g) Feminization
(h) Gynecomastia (increase in volume of breast tissue) (Anderson, 2001)
(i) Genital shrinkage, which is very distressing (Higano, 2003)
(2) Treatment for testicular cancer: More than one-third of men
experience loss of libido, orgasmic and ejaculatory problems,
and a subsequent decrease in sexual activity (Dahl et al., 2007).
These problems may persist for two years after completion of
treatment (Wiechno, Demkow, Kubiak, Sadowska, & Kamiska,
2007). Inability to perform sexually can affect the mans confidence in himself as a sexual partner and may have psychological consequences that last for a significant period of time.
a) Females
(1) Provision of anticipatory guidance at all stages of the disease
trajectory (Rusten & Begnum, 2000)
(a) 68% of women with breast cancer wanted information
about all aspects of sexual functioning (Ussher, Perz, &
Gilbert, 2013).
(b) A great deal of information is given at the time of diagnosis, when patients cannot assimilate and integrate the new
information (Koinberg, Holmberg, & Fridlund, 2001).
(c) Only a small proportion of women with breast cancer discussed
sexual issues with their physician (Barni & Mondin, 1997).
(d) Most women have never been asked if sexual problems occurred as a result of treatment (Young-McCaughan, 1996).
(e) Less than half of women were satisfied with their discussion with their oncologist or family physician compared to
almost 60% who were satisfied with their discussion with a
breast care nurse (Ussher et al., 2013)
(f) Women have reported that their physicians were not understanding or helpful when sexual dysfunction was identified as a problem (Wilmoth & Ross, 1997).
(g) Older women may be more reluctant than younger women to state their needs for information (Gray, Goel, Fitch,
Franssen, & Labrecque, 2002).
(2) A modified form of sensate focus exercises can help the woman
and her partner to learn a new way of dealing with the changes
from treatment. Refer patients to a sexuality counselor or sex
therapist for assistance.
(3) Instruct patients to prevent or manage vaginitis or vulvar irritation.
(a) Focus on prevention, including avoidance of tight-fitting
pants and pantyhose.
(b) Wear cotton underwear.
(c) Employ fastidious personal hygiene; use a mild soap with
water for cleansing.
(d) Avoid bubble baths, douching, and chemical irritants such
as genital deodorant sprays.
(e) Use cool sitz baths and warm compresses to provide local relief.
(f) Treat concomitant bacterial infections such as Candida albicans or Trichomonas vaginitis, if present.
(4) Lubricants are available to help women feel more comfortable
with sexual activity.
(a) Water- and glycerin- or silicone-based lubricants are the
safest to use.
(b) Lubricants that are dye and perfume free are less irritating.
(c) Instruct patients to avoid the use of oil-based products or
anything that is colored, scented, or not designed specifically for sexual activity, such as hand lotion.
b) Males: A thorough assessment of prediagnosis and pretreatment sexual functioning is important to establish the mans current level of
functioning.
(1) It is common for men age 75 and older who have prostate cancer to have diminished levels of sexual interest and functioning before treatment begins.
(2) Other men may have erectile difficulties before the diagnosis
of cancer as a result of cardiac disease, diabetes, and medications (Clayton & Ramamurthy, 2008).
(3) Obtaining an accurate description of pretreatment erectile functioning and sexual activity is crucial so that the patient has realistic expectations of what treatment can do.
(4) Treatment of erectile dysfunction includes oral therapies (phosphodiesterase-5 [PDE5] inhibitors), vacuum devices, alprostadil
intraurethral pellets (MUSE), alprostadil intracorporeal injections (Caverject), and penile implants. Each has benefits and
disadvantages. All require a prescription, extensive patient education, and varied degrees of motivation on the part of both
the man and his partner. Only 10% of men who used erectile
aids after surgery (PDE5 inhibitors such as sildenafil, tadalafil,
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or vardenafil, or vacuum devices) reported satisfaction with

their sex lives (Miller et al., 2006).
9. Patient/couple education: A number of models are helpful in communicating with patients about sexuality. The most frequently used model
is the PLISSIT model (Annon, 1974). A more recent model specifically designed for the oncology population is the BETTER model (Mick,
Hughes, & Cohen, 2003).
a) PLISSIT
(1) The first level in this model involves giving the patient or client
permission to talk about sexual issues.
(2) The second level, limited information, refers to factual information
given to the patient in response to a question or observation.
(3) The third level involves making a specific suggestion to the client or patient.
(4) The fourth level refers to intensive therapy needed for severe or
more long-standing sexual problems.
b) BETTER
(1) The first level of intervention involves bringing up the topic.
(2) The second level involves explaining that sexuality is part of
QOL, and patients should be aware that they can talk about
this with the nurse.
(3) Care providers should then tell patients that appropriate resources will be found to address their concerns.
(4) Care providers should state that while the timing may not be
appropriate now, patients can ask for information at any time.
(5) Patients should be educated about the sexual side effects of their
treatment.
(6) Finally, a record should be made in the patients medical record
to report that this topic has been discussed.
c) Sexual intercourse is not always the end goal of sexual touch. Encourage patients and their partners to find other ways of sexual pleasuring
that are not fatigue- or nausea-provoking for patients and that satisfy
both individuals needs and desires for intimate touch.
d) Patients should avoid intercourse when neutrophil and platelet counts
are low (Vachani, 2011). Recommend use of condoms to prevent transmission of infection and exposure of the partner to chemotherapeutic
agents in the body fluids of the patient. Caution should be used in the
type of condom chosen, as those that are lubricated usually contain nonoxynol-9, which can be irritating to vaginal tissue (Burke et al., 2010).
P. Reproductive alterations
1. Pathophysiology
a) Females (Knobf, 2006)
(1) Effects of chemotherapy
(a) Damage to ovarian follicles
(b) Decreased ovarian volume
(c) Ovarian fibrosis
(2) Manifestations
(a) Amenorrhea (permanent or reversible)
(b) Menopausal symptoms
(c) Eventual bone loss
(3) Associated factors
(a) Age
(b) Dosage and duration of treatment
b) Males: Effects of chemotherapy (Maltaris et al., 2006)
(1) Primary or secondary hormonal changes from damage to the
hypothalamic-pituitary axis
(2) Damage to germinal stem cells in the testes

2. Incidence
a) Females
(1) Women older than age 30: Risk of permanent amenorrhea increases.
(2) Breast cancer: 15% of premenopausal women treated with an
alkylating agent developed long-term amenorrhea (Fornier,
Modi, Panageas, Norton, & Hudis, 2005).
(3) Childhood cancer survivors: Less than 20% will develop premature ovarian failure (Larsen, Mller, Schmiegelow, Rechnitzer,
& Andersen, 2006).
b) Males: Testicular cancer
(1) Decreased sperm production is present at the time of diagnosis (Rives et al., 2012).
(2) 70% of patients who have retroperitoneal lymph node dissection will be unable to ejaculate and will notice a decrease in semen volume or experience a dry ejaculate (Arai, Kawakita,
Okada, & Yoshida, 1997).
3. Agents
a) Alkylating agents (e.g., cyclophosphamide, cisplatin, chlorambucil,
melphalan, busulfan, nitrogen mustard, dacarbazine, ifosfamide, procarbazine) (Marhhom & Cohen, 2007) have the greatest effect on
both female and male fertility (Maltaris et al., 2006).
b) Nitrosoureas (e.g., carmustine, lomustine) affect the ovaries (Blatt, 1999).
c) Anthracycline antibiotics affect fertility.
d) Vinca alkaloids affect fertility (Maltaris et al., 2007).
e) Taxanes increase the risk of chemotherapy-induced amenorrhea
(Tham et al., 2007).
4. Contributing factors
a) Age
(1) Older women are more likely to experience complete ovarian
failure and permanent infertility (Maltaris et al., 2007).
(2) The adult testis is more susceptible than the testis of the prepubescent boy (Tomao, Miele, Spinelli, & Tomao, 2006).
b) Combination therapy: The addition of radiation to the treatment
regimen significantly increases the risk of permanent infertility (Davis, V.J., 2006).
c) Preexisting disease: Men with cancer commonly have reduced
fertility before diagnosis and treatment. This reduced fertility is
thought to be a result of anatomic or endocrine changes (Maltaris et al., 2006).
d) Treatment effect: Lymph node or tumor resection results in retrograde ejaculation, which affects fertility (Spermon et al., 2003).
5. Clinical manifestations
a) Females
(1) Amenorrhea (permanent or temporary)
(2) Signs of premature menopause in younger women: These may
be more severe than in naturally menopausal women.
(a) Hot flashes
(b) Urogenital atrophy
(c) Osteoporosis (late-stage symptom)
(3) Psychosocial distress: 57% of young women in one study identified significant concerns about infertility (Partridge et al., 2004).
b) Males: Alterations in spermatogenesis (Maltaris et al., 2006)
(1) Low sperm counts
(2) Poor sperm motility
(3) Altered morphology
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a) Females
(1) Cryopreservation of embryos
(a) Most effective intervention in terms of successful pregnancies
(b) May result in a delay of two to six weeks in starting chemotherapy (Oktay, 2005)
(c) Requires ovarian stimulation; may be contraindicated with
estrogen-sensitive cancers (Marhhom & Cohen, 2007)
(d) Tamoxifen and letrozole may be used to stimulate ovaries
with estrogen-sensitive tumors. Tamoxifen cannot be used for
women with endometrial cancer (Marhhom & Cohen, 2007).
(2) Oocyte cryopreservation (surgical)
(a) Regarded as experimental
(b) May be offered to single women with no male partner
(c) Low pregnancy rates (Marhhom & Cohen, 2007).
(3) Cryopreservation of ovarian tissue (surgical)
(a) New experimental technique that may offer some hope to
women who do not have the time for ovarian stimulation
(b) Concerns about introducing malignant cells when the preserved ovarian tissue is transplanted back into the woman
(4) Nonsurgical: Monthly injections of gonadotropin analogs (e.g.,
leuprolide) to reduce the rate of ovarian follicle atresia (Davis, M., 2006)
(5) The return of menstrual periods does not necessarily indicate
good ovarian function, and in turn, lack of menstruation does
not mean that ovarian function has ceased (Del Mastro, Catzeddu, & Venturini, 2006).
b) Males
(1) Cryopreservation: Sperm cryopreservation before treatment is
highly effective, as sperm remain viable after freezing and can
be used to fertilize ovum.
(2) New reproductive technologies may be useful in causing pregnancy (Stensvold, Magelssen, & Oskam, 2011).
(a) Testicular sperm extraction
(b) In vitro fertilization
(c) Intracytoplasmic sperm injection
7. Patient and family education: Decisions about treatments that affect fertility have to be made when the patient is trying to cope with the diagnosis of cancer; priorities may change over time. It is important to educate patients honestly and directly, as they may assume that modern reproductive technologies will result in a future pregnancy.
a) Parents of a child with cancer may have to make decisions about treatment for their child and may not be capable of discussing sperm banking or ovarian preservation with their child or healthcare providers,
as their priority is to save the life of their child.
b) Males: Because of the average young age of those affected with testicular cancer, many will not be in a relationship at the time of diagnosis, and thoughts of parenthood may be remote and not a priority.
(1) Men who are young, unmarried, and childless experience more
infertility-related distress than those who have fathered children and are in a supportive relationship. This needs to be taken into consideration when informing patients of the consequences of treatment.
(2) Sperm samples can be obtained with 2448 hours between collections (Brown, 2003), which allows for minimal delay of chemotherapy treatment.
(3) Men should be counseled honestly and directly that cryopreservation does not guarantee success despite advances in technique
(Schmidt et al., 2004).
c) Females: Women older than age 18 want information about fertility and are frustrated by their lack of choice or control over fertility
(Gorman, Bailey, Pierce, & Su, 2012).
(1) Many do not recall being told about the potential for alterations
to reproductive health (Duffy, Allen, & Clark, 2005).
(2) Women who have been treated for cancer have lower live birth
rates with in vitro fertilization than women without cancer undergoing in vitro fertilization (Barton, Missmer, Berry, & Ginsburg, 2012).
8. Access to fertility services
a) A multidisciplinary approach is regarded as optimal to address the
complex ethical and psychological issues (Treves, Grynberg, Hesters,
& Frydman, 2011).
b) Disparity in access to fertility services is related to age (older than
35), previous children, ethnicity, and sexual orientation (Letourneau et al., 2012).
9. Ethical issues
a) Concerns exist about whether teens can make decisions about fertility; however, they are interested in future fertility and want to be involved in decisions (Quinn et al., 2011).
b) Patients have concerns about insurance coverage, even though threat
to future fertility is iatrogenic (Shah, Goldman, & Fisseha, 2011).
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Chapter 10
Post-Treatment Care
A. Overview: Over the past 30 years, the number of cancer survivors in the United States has increased from 3 million to 13 million (NCI, 2011). Early diagnosis and advances in cancer treatment have led to improved five-year relative
survival rates for all cancers from 50% in the 1970s to 68% during 20072008
(Siegel, Naishadham, & Jemal, 2013). Childhood cancers are now often cured;
83% of children and adolescents survive a cancer diagnosis (Siegel et al., 2013).
However, long-term cancer survivors are at risk for adverse effects from their
lifesaving treatment. Research suggests that more than 60% of survivors of
childhood cancers have one or more treatment- or disease-related long-term
effects (Oeffinger et al., 2006). Late treatment effects include impairment in
the function of specific organs, second malignant neoplasms (SMNs), cognitive
impairments, and psychosocial concerns. COG (2008) developed long-term
follow-up guidelines for screening and management of late effects in survivors of childhood cancer. These guidelines are available at www.survivorship
guidelines.org. The Childhood Cancer Survivor Study has followed more
than 14,000 childhood cancer survivors to observe the type and incidence
of the late effects of cancer treatment. This study provides important information about late effects of cancer treatment in childhood cancer survivors
and can be accessed at http://ccss.stjude.org.
1. Because more than 60% of cancer survivors are older than age 60, research efforts are under way to better understand the long-term effects
of cancer treatment for adult cancers (COG, 2008).
2. Nurses have an important role in the continuing care of survivors, including monitoring, assessing, and treating children and adult survivors
for the effects of treatment that emerge long after completion of therapy. Nurses are vital in teaching survivors about leading a healthy lifestyle
to minimize the potential effects of cancer treatment.
B. Survivorship care
1. Cancer survivor: An individual is considered a cancer survivor from the
time of cancer diagnosis, through the balance of his or her life, regardless of the ultimate cause of death. This definition was first published
by Fitzhugh Mullan in his seminal 1985 article and has been adopted by
the National Coalition for Cancer Survivorship, NCI, and other survivorship organizations (Mullan, 1985; NCI, 2012).
2. Cancer survivors require follow-up care annually for life.
3. Early follow-up care may be more frequent and emphasizes surveillance
and detection of disease recurrence. Long-term follow-up care transitions to a focus on identifying and anticipating chronic or late effects
of the disease or treatment, as well as continued surveillance for disease
recurrence.
4. Essential components of survivorship care (Hewitt, Greenfield, & Stovall,
2005)
a) Prevention of recurrent and new cancers and of other late effects
b) Surveillance for cancer recurrence, metastasis, or second cancers
c) Assessment of medical and psychosocial late effects
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d) Intervention for consequences of cancer and its treatment, including medical problems such as lymphedema and sexual dysfunction;
symptoms including pain and fatigue; psychosocial distress experienced by cancer survivors and their caregivers; and concerns related
to employment, insurance, and disability
e) Coordination among specialists and primary care providers to ensure
that all of the survivors health needs are met
C. Late effects of cancer treatment: SMNs and CVD are among the most serious and life-threatening late adverse effects of cancer treatment.
1. Incidence
a) Cancer survivors have a 14% greater risk of developing another malignancy than the general population with 25 years of follow-up (Curtis et al., 2006).
b) The 30-year cumulative incidence of SMNs among survivors of childhood malignancies is 20.5% including nonmelanoma skin cancer and
7.9%, excluding nonmelanoma skin cancer (Friedman et al., 2010).
2. Therapy-related risk factors
a) Chemotherapy
(1) Chemotherapy is associated with a risk of SMN, primarily treatment-related leukemia, and to a lesser extent, solid tumors
(Cowell & Austin, 2012; Ng & Travis, 2008; Travis et al., 2010).
(2) Type of chemotherapy: Alkylating agents are associated with the
greatest incidence of late effects.
(3) Dose
(a) Higher cumulative dose increases the risk of treatmentrelated leukemia (Leone, Fianchi, & Voso, 2011; Travis et
al., 2010).
(b) Higher cumulative doses of alkylating agents are associated with an increased risk of multiple health conditions
(Oeffinger et al., 2006).
(4) Agents with known carcinogenic potential (see Table 12)
(a) Alkylating agents
(b) Heavy metals
i. Cisplatin
ii. Carboplatin
(c) Topoisomerase II inhibitors
i. Epipodophyllotoxins (etoposide, teniposide)
ii. Anthracyclines
(d) Nonclassical alkylating agents
i. Dacarbazine
ii. Temozolomide
b) Radiation-associated solid tumors: The most common type of SMN
(Ng, Kenney, Gilbert, & Travis, 2010)
(1) Radiation is associated with a risk of solid tumors that develop
within or near the radiation fields and have a latency period of
510 years (Ng & Travis, 2008; Travis et al., 2012).
(2) The risk of an SMN from radiation increases with the dose of radiation and the extent of the radiation field (Travis et al., 2012).
(a) Advances in imaging have resulted in three-dimensional views of the tumor to accurately identify tumor volume, allowing reduction of the radiation field (Travis
et al., 2012).
(b) Advances in radiation technology allow for more precise
delivery of radiation to the tumor so that increased doses
can be delivered to the tumor while sparing healthy tissue
(Travis et al., 2012).
(c) Treatment with 35 gray (Gy) involved-field radiation therapy (IFRT): Compared to 35 Gy mantle radiation therapy,
35 Gy IFRT is estimated to reduce the risk for female breast
and lung cancer by approximately 65% and the risk for male
lung cancer by approximately 35%. Reducing the dose of
IFRT from 35 Gy to 20 Gy is estimated to reduce the risk
approximately 40% more (Koh et al., 2007).
(3) Combination chemotherapy and radiation
(a) The combination of radiation and alkylating agents is associated with increased risk of secondary malignancies (Allan & Travis, 2005; Oeffinger et al., 2006).
(b) Exposure to one of five specific combinations is associated with a risk of having a severe health condition that is at
least 10 times the expected risk (Oeffinger et al., 2006).
i. Chest irradiation plus bleomycin
ii. Chest irradiation plus an anthracycline
iii. Chest irradiation plus abdominal or pelvic irradiation
iv. Anthracycline plus an alkylating agent
v. Abdominal or pelvic irradiation plus an alkylating agent
c) Patient-related risk factors
(1) Age
(a) Younger age at cancer diagnosis increases the risk of developing an SMN (van den Belt-Dusebout et al., 2007). The
risk of developing a subsequent cancer is sixfold in childhood cancer survivors, two- to threefold in patients diagnosed at ages 1839, and 1.21.6-fold in patients diagnosed
at ages 4059 (Curtis et al., 2006).
(b) Developing organs in younger patients may be especially
vulnerable to the effects of medication and radiation (Ng,
Kenney, et al., 2010). Older patients who experience adverse effects from their disease or its treatment may be unable to compensate for lost function.
(c) The cumulative incidence of a chronic health condition
in childhood cancer survivors is more than 70% within 30
years of the cancer diagnosis, and more than 40% of these
conditions will be severe, disabling, or fatal (Oeffinger et
al., 2006).
(2) Gender
(a) Female childhood cancer survivors are more likely than
male survivors to have one or more chronic health conditions (Oeffinger et al., 2006).
(b) Overall, women have a slightly higher risk of secondary
malignancies than men (Curtis et al., 2006; Friedman et
al., 2010).
(3) Exposures
(a) Tobacco and alcohol exposure increase the risk of developing a secondary malignancy in all cancer survivors to approximately 35% (Curtis et al., 2006).
(b) Infections such as HPV, HIV, human herpes virus-8, EpsteinBarr virus, hepatitis B and C, and Helicobacter pylori may increase the risk of SMNs (Ng & Travis, 2008).
(c) Sun exposure (Ng & Travis, 2008)
(4) Diet and exercise: Caloric excess, a diet low in fruits and vegetables, obesity, and physical inactivity contribute to the risk of
SMNs involving the upper aerodigestive tract, colon cancer,
breast cancer, and cancers of the female reproductive organs
(Curtis et al., 2006; Ng & Travis, 2008).
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440
(5) Immunodeficiency increases the risk of secondary malignancies. Immune dysregulation may be associated with primary
cancers such as leukemia and lymphoma or with immunosuppressive treatment.
(6) Genetic predisposition: Patients with genetic phenotypes that
contributed to the development of their original cancer are
at increased risk for a secondary cancer. Examples of genetic
cancer syndromes that increase the susceptibility to a primary or secondary cancer include Fanconi anemia, Cowden disease, BRCA1- or BRCA2-related cancer, hereditary nonpolyposis
colorectal cancer, Bloom syndrome, xeroderma pigmentosum,
and Li-Fraumeni syndrome (Ng & Travis, 2008).
D. Types of late effects
1. Nonmalignant physical effects (Miller & Triano, 2008): See Table 46.
a) Cardiac: Cardiomyopathy, subclinical left ventricular dysfunction,
coronary artery disease, valvular heart disease, pericardial disease,
and arrhythmias
(1) The risk of developing anthracycline-associated cardiotoxicity
increases with the total cumulative dose of doxorubicin: 1%
5% up to 550 mg/m2; 30% at 600 mg/m2; and 50% at 1,000
mg/m2 (Carver et al., 2007).
(2) Approximately 60% of children treated for childhood cancers
received an anthracycline; subsequently, there is a 0%16% risk
of heart failure and 0%57% risk of subclinical cardiomyopathy (Dickerman, 2007).
(3) Cardiac toxicity may have a latency period of 25 years, and the
risk increases with time (Carver et al., 2007).
(4) Cisplatin is associated with an increased risk of cardiovascular
risk factors such as obesity, lipid abnormalities (decreased highdensity lipoprotein and elevated low-density lipoprotein), and
hypertension (Carver et al., 2007).
b) Pulmonary: Pulmonary fibrosis, restrictive/obstructive lung disease,
and delayed ILD
c) Renal: Nephropathy, CKD
d) Musculoskeletal: Osteopenia, osteoporosis, avascular necrosis
e) Endocrine: Hypothyroidism, growth hormone deficiency, gonadal
failure, panhypopituitarism, adrenal insufficiency, diabetes mellitus
f) CNS: Cognitive impairment, peripheral neuropathy, leukoencephalopathy, cataracts, hearing loss, visual changes
2. SMNs (see Table 47)
a) Definition: A second malignant neoplasm is a new cancer that is distinct
from the original malignancy and does not represent metastatic disease from the primary tumor (Allan & Travis, 2005).
b) Pathophysiology
(1) Chemotherapy and radiation therapy cause DNA damage, which is
the mechanism that leads to cell death. However, if nonlethal DNA
damage occurs, DNA repair is critical to prevent the development
of a secondary cancer (Allan & Travis, 2005; Cowell & Austin, 2012).
(2) Alkylating agents transfer an alkyl group to DNA, causing
DNA mismatch and inhibition of DNA replication and transcription. A DNA mismatch repair mechanism is responsible
for repairing this cell damage; otherwise, apoptosis occurs. If
cells survive with a dysfunctional DNA mismatch repair or genomic instability, this may lead to malignancy (Allan & Travis, 2005; Cowell & Austin, 2012; Tward, Glenn, Pulsipher, Barnette, & Gaffney, 2007).
Table 46. Potential Late Effects of Selected Cancer Treatments by Organ System With Associated Monitoring
Therapeutic Exposures
Organ System
Chemotherapy
Radiation
Therapy
Surgery
HSCT
Potential Late Effect(s)
Screening
Any
Any
Any
Any
Depression, anxiety, post-traumatic stress disorder,

limitations in health care access, alterations in body
image
Psychosocial assessment
Ocular
Corticosteroids
Busulfan
Tamoxifen
Head/brain
TBI
Neurosurgery
Chronic GVHD
Cataracts, glaucoma
Crystal deposition of the retinatamoxifen
Retinopathy, optic nerve injury/atrophy
Ocular nerve palsy (surgery)
Xerophthalmia (radiation, GVHD)
Ophthalmology
evaluation
Auditory
Platinum chemotherapy
Head/brain
Tinnitus
Sensorineural hearing loss
Conductive hearing loss
Eustachian tube dysfunction
Vestibular dysfunction/balance problems
Audiological evaluation
Head/brain
Neck
Xerostomia
Periodontal disease
Dental caries
Dental exams
Congestive cardiomyopathy
Congestive heart failure
Electrical/conductive system disease
Pericardial disease/restrictive cardiomyopathy
Coronary artery disease
Valvular heart disease
Dyslipidemia (related to platinum agents)
ECG
Echocardiogram
MUGA scan
Upper airway sequelae

Pulmonary fibrosis
Interstitial pneumonitis
Restrictive/obstructive lung disease
Fatigue
PFT
CXR
Radiation-induced breast cancer
Mammogram
Breast MRI
Dental
Cardiovascular
Anthracyclines
Trastuzumab
High-dose cyclophosphamide
Mitomycin
Platinum agents
Thorax
Respiratory
Bleomycin
Busulfan
Nitrosoureas
Head/neck
Thorax
TBI
Breast
Thorax
Axilla
TBI
Head/neck surgery
Pulmonary lobectomy
Chronic GVHD
Chronic GVHD
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Psychosocial
442
Table 46. Potential Late Effects of Selected Cancer Treatments by Organ System With Associated Monitoring (Continued)
Chemotherapy
Gastrointestinal
Radiation
Therapy
Surgery
HSCT
Head/neck
Abdominal
Pelvic
Head/neck surgery
Laparotomy
Colorectal surgery
Ostomy
Pelvic/spinal surgery
HSCT with
chronic GVHD
Chronic enterocolitis
Diarrhea
GI tract strictures/fibrosis/vasculitis
Adhesions/fistulae/obstruction/perforation/hernia
Impaired swallowing
Anorexia
Impaired nutritional intake
Impaired gastrointestinal motility
Vomiting
Constipation
Impaired absorption of nutrients
Fecal incontinence
Subsequent malignancy (e.g., colon)
Colonoscopy
HSCT
Hepatic dysfunction
VOD
Hepatic fibrosis, cirrhosis
Cholelithiasis
Iron overload (HSCT)
Hepatitis (related to blood product transfusions)
Liver function tests

Ferritin
Hepatitis serologies
HSCT with
GVHD
Glomerular toxicity
Tubular dysfunction
Acute kidney injury
Hypertension
Radiation nephritis
Chronic kidney disease
Renal function tests

Urinalysis
Hemorrhagic cystitis
Bladder fibrosis
Dysfunctional voiding
Incontinence
Neurogenic bladder
Bladder malignancy
Urinalysis
Hepatic
Antimetabolites
Abdominal
Renal
Platinum agents
Ifosfamide
Methotrexate
Bisphosphonates
Nitrosoureas
Calcineurin inhibitors
(for GVHD)
Abdominal (including kidney)

TBI
Nephrectomy
Bladder
Cyclophosphamide
Pelvic (including
prostate and
bladder)
Lumbar-sacral
spine
Spinal surgery
Cystectomy
Prostatectomy
Screening
Organ System
Organ System
Chemotherapy
Radiation
Therapy
Surgery
Alkylating agents
Androgen deprivation
(hormonal) therapy
Hypothalamicpituitary
Pelvic
Prostate
Testicular
TBI
Pelvic/spinal surgery
Orchiectomy
Prostatectomy
Sexual/reproductive (females)
Alkylating agents
Tamoxifen
Aromatase inhibitors
Lupron
Pelvic
Ovarian
Lumbar-sacral
spine
TBI
Oophorectomy
Endocrine/
metabolic
Corticosteroids
Neck (thyroid)
Pancreas
Thyroidectomy
Surgery involving
the hypothalamus
or pituitary
Surgery involving
the pancreas
Neurocognitive
Methotrexate (highdose IV, IT)

Cytarabine (high-dose
IV)
Adjuvant chemotherapy
for breast cancer
Head/brain
TBI
Central nervous
system
Methotrexate (highdose IV, IT)

Cytarabine (high-dose
IV)
High radiation
doses to head/
brain/neck
Screening
Hypogonadism
Infertility
Erectile/ejaculatory dysfunction
FSH, LH
Testosterone
Semen analysis
Premature menopause
Infertility
Uterine vascular insufficiency
Vaginal fibrosis/stenosis
Sexual dysfunction
FSH, LH
Estradiol
Hypothyroidism
Adrenal insufficiency
Growth hormone deficiency
Impaired glucose tolerance
Thyroid nodules/cancer
High radiation doses
Hyperprolactinemia
Central adrenal insufficiency
Gonadotropin deficiency
Hyperthyroidism
Free T4
TSH
8 am serum cortisol
Neurosurgery
Neurocognitive deficits (executive function, attention, memory, processing speed, visual motor integration)
Neurocognitive
testing
Neurosurgery
Leukoencephalopathy
Motor and sensory deficits
Cerebrovascular complications (stroke, moyamoya
disease [certain arteries in the brain are constricted], occlusive cerebral vasculopathy)
Radiation-induced brain tumor
Seizures
Chronic GVHD
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Sexual/reproductive (males)
HSCT
444
Peripheral
nervous system
Lymphatic
Musculoskeletal
Radiation
Therapy
Chemotherapy
Vincristine
Vinblastine
Platinum agents
Taxanes
Bortezomib
Thalidomide
Oxaliplatin
Corticosteroids
Methotrexate
Androgen deprivation
therapy
Aromatase inhibitors
Surgery
HSCT
High-dose radiation to brachial

or lumbosacral
plexus
Spinal surgery
Peripheral sensory neuropathy (e.g., paresthesias,

dysesthesias, sensory loss)
Peripheral motor neuropathy (e.g., weakness, foot
drop)
Plexopathies
Radiation involving lymphatic

channels
Breast cancer surgery

Melanoma excision
Pelvic lymph node
dissection
Axillary lymph
node dissection
Lymphedema
Pelvic/gonadal
Surgical castration
Bilateral oophorectomy
Gastrectomy
HSCT
Amputation
Limb-sparing procedures
Osteopenia/osteoporosis
Corticosteroids
Bisphosphonates
High-dose radiation to jaw
Chemotherapy for
breast and ovarian
cancers
Post-chemotherapy rheumatism syndrome
All fields
Atrophy, deformity, fibrosis, fractures

Secondary benign or malignant neoplasms
Screening
DEXA scan
Functional changes
Postsurgical phantom pain
HSCT with
chronic GVHD
Joint contractures
HSCT
Osteonecrosis
Myopathy (proximal muscle weakness)
MRI of affected
area
X-ray of affected
area
Organ System
Organ System
Dermatologic
Hematologic
Immunologic
Chemotherapy
Anthracyclines
Epipodophyllotoxins
Alkylating agents
Stem cell priming with
etoposide
Radiation
Therapy
All areas
Abdomen, left
upper quadrant,
spleen (high
doses)
Surgery
HSCT
Chronic GVHD
Dysplastic nevi
Vitiligo
Scleroderma
Nail dysplasia
Alopecia
Skin cancer
Autologous
HSCT for nonHodgkin lymphoma
Acute myeloid leukemia

Myelodysplastic syndrome (associated with alkylating agents)
Chronic active
GVHD
Life-threatening infection related to functional or anatomic asplenia
Splenectomy
Screening
CBC with differential
CBCcomplete blood count; CXRchest x-ray; DEXAdual energy x-ray absorptiometry; ECGelectrocardiogram; FSHfollicle-stimulating hormone; GIgastrointestinal; GVHDgraft-versus-host disease;
HSCThematopoietic stem cell transplant; ITintrathecal; IVintravenous; LHluteinizing hormone; MRImagnetic resonance imaging; MUGAmultigated acquisition; PFTpulmonary function testing; TBItotal
body irradiation; T4thyroxine; TSHthyroid-stimulating hormone; VODveno-occlusive disease
Note. Based on information from Aziz, 2007; Childrens Oncology Group, 2008; Ganz, 2006; Miller & Triano, 2008; Stricker & Jacobs, 2008; Tichelli & Soci, 2005.
445
From Late Effects of Cancer Treatment (pp. 17571761), by W. Landier and S. Smith in C.H. Yarbro, D. Wujcik, and B.H. Gobel (Eds.), Cancer Nursing: Principles and Practice (7th ed.), 2011, Burlington, MA: Jones
and Bartlett. Copyright 2011 by Jones and Bartlett. Reprinted with permission.
446
(3) Topoisomerase II inhibitors cause double-stranded DNA breaks,

which lead to apoptosis. If the cell survives, these DNA breaks
may cause chromosomal translocations of the mixed lineage
leukemia (MLL) gene or other crucial transforming genes that
can lead to leukemia (Allan & Travis, 2005; Cowell & Austin,
2012; Tward et al., 2007).
(4) Radiation therapy deposits energy in or near DNA, which results
in genetic or epigenetic changes that cause cell death. If radiation induces mutations in the DNA and the cells do not die,
the DNA mutations are passed on to cellular progeny and over
time may lead to malignant transformation (Travis et al., 2012).
(5) Chemotherapy and radiation therapy interact with other factors such as tobacco exposure, genetic makeup, hormonal status, and immune function, which may contribute to the risk
of developing a secondary cancer (Allan & Travis, 2005; Travis et al., 2012).
c) Types of SMNs: The two major types of SMNs are acute myeloid neoplasms and solid neoplasms. The relative risk of treatment-related
leukemia is generally greatest during the first five years after therapy, whereas solid tumors occur at least 510 years after treatment with
the risk tending to increase over time (Ng & Travis, 2008). The overall risk of developing an SMN is small compared to the risk of dying
from the primary malignancy.
(1) Treatment-related acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) generally presents within five years of chemotherapy and is most commonly associated with the use of alkylating agents or topoisomerase inhibitors.
Table 47. Second Malignant Neoplasms

Primary
Malignancy
ALL
Breast cancer
Second Malignant Neoplasm
Risk Factors
CNS malignancy
Risk is 17-fold after 5 years.
Melanoma
Cumulative incidence: 0.43%
Thyroid cancer
Cranial irradiation at doses of 1824 Gy
Any SMN
Elevated risk for women diagnosed at younger
than age 40 (SIR: 1.81) but not for women diagnosed after age 40
Increased risk of salivary gland, esophagus,
stomach, colon, breast, uterine corpus, ovary, thyroid, soft tissues, melanoma, and acute
nonlymphocytic leukemia
Age < 40 at diagnosis

Risk of leukemia associated with alkylating agents
Risk of solid tumors associated with radiation therapy
> 10 years old (p < 0.001)

Family history of cancer (p = 0.01)
RT
Leukemia
Cumulative incidence: < 0.5% at 810 years
after anthracycline-cyclophosphamide chemotherapy
Cervical cancer
Endometrial
Associated with 35% increased risk
Sarcoma
SIR: 36
Latency: 510 years
Tamoxifen
Urogenital cancer
10 to > 40 years after treatment
RT
RT
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Table 47. Second Malignant Neoplasms (Continued)

Primary
Malignancy
CLL/SLL

HL
SIR: 15.11
Lung cancer
SIR: 1.44
Melanoma
SIR: 1.92
Risk Factors
Age < 70 at time of CLL/SLL diagnosis
Chemotherapy
Risk higher in CLL than SLL
Patients diagnosed before age 55 had higher SIR: 2.32.
CML
Breast cancer (in CML Ph+)

SIR: 0.24
Endocrine cancer (in CML Ph+)
SIR: 3.0
Gastrointestinal cancer (in CML Ph+)
SIR: 0.38
Stomach cancer
SIR: 2.76
Colorectal cancer
SIR: 1.12
Head and neck cancer
Buccal cavity, SIR: 1.27
Lymphoid leukemia
SIR: 5.53
Myeloid leukemia
SIR: 12.32
Melanoma
SIR: 1.4
SIR: 3.0 (CML Ph+)
NHL
SIR: 2.17
Prostate cancer
SIR: 1.38
Renal cancer
SIR: 1.5 (CML Ph+)
Skin (nonmelanoma)
SIR: 5.36
Urogenital cancer
SIR: 1.61
HL
Breast
20-year cumulative risk after mantle RT: 23%
(median dose 40 Gy)
RR: 6.1 for patients diagnosed at age 30 and
survived to 40
Occurs 1015 years after chest irradiation

Highest risk occurs in women treated with chest irradiation
at age 35 or younger; risk increases with younger age.
Risk increases with dose of radiation.
Risk increases with TBI use pretransplantation.
RT-related premature menopause is associated with decreased risk.
Leukemia
Peaks 37 years after treatment
Up to 10% risk
MOPP
Risk is 7 times greater in patients who received > 20 Gy irradiation to bone marrow than in those who received a lesser dose.
HCT
448

Primary
Malignancy
Risk Factors
Lung cancer
RR: 7.0
Chemotherapy-associated lung cancer occurs
14 years after therapy up to 15 years.
Radiation-associated lung cancer risk is elevated for 59 years after therapy and can last
for more than 20 years.
Pleura
RR: 19.5
Thoracic irradiation
Alkylating agents
Radiation dose and therapy with alkylating agents has a
combined additive risk.
RT and smoking significantly increases risk (p < 0.001)
Melanoma
14 years after treatment
RR: 5.5
NHL
Within 5 years of treatment, then risk remains
constant or increases over lifetime
25-year cumulative risk: 3.5%
RR: 21.5
Thyroid cancer
RR: 15.2
May be related to immunosuppression associated with HL
Colorectal cancer
Mesothelioma
RR is 20-fold for patients diagnosed at age 30
and survived to age 40.
Multiple
myeloma
17% at 50 months
Alkylating agents
NHL
Bladder cancer
Cyclophosphamide:
** 2049 g, RR: 6.0
** > 50 g, RR: 14.5
Leukemia
Overall RR: 8.8
Occurs within 15 years
Male, RR: 5.65
Female, RR: 19.89
Cyclophosphamide > 20 g
Risk increases with RT use.
Lung cancer
SIR: 1.62.45
Melanoma
Cumulative incidence: 0.55%
Mesothelioma
DLBCL
AML
SIR: 4.96
HL
SIR: 9.02
Immunosuppression associated with the HL or with combined chemoradiation treatment
RT
CHOP (RR: 14.2)

ACVBP
Carmustine
Procarbazine
Mechlorethamine (RR: 13.0)
Chlorambucil > 1,300 mg (RR: 6.5)
Risk of acute leukemia increases with RT use, especially
TBI pretransplantation.
Male gender
Smoking is dose-related with higher risk in those who
smoked at diagnosis and continue to smoke after therapy.
Alkylating agents
> 10 years old (p < 0.001)
Family history of cancer (p = 0.01)
Risk increases with RT use.
Chemotherapy
Age < 55
Female
449

Primary
Malignancy
Follicular lymphoma
Risk Factors
AML
SIR: 5.96
HL
SIR: 6.78
Lung cancer
SIR: 1.28
Melanoma
SIR: 1.6
Chemotherapy
Age < 55
Lung cancer
Leukemia
Small cell, SIR: 6.57
Non-small cell, SIR: 1.47
Increased risk due to use of alkylating agents
Mycosis fungoides/Szary
syndrome
Bladder cancer
SIR: 1.71
HL
SIR: 1.71
Lung cancer
SIR: 1.42
Melanoma
SIR: 2.60
NHL
SIR: 5.08
Renal cancer
SIR: 1.71
Ovarian cancer
Leukemia
Occurs up to 10 years after therapy
Polycythemia
vera
CML
SIR: 1.6
Myeloid leukemia:
SIR: 8.5 at 12 years
Lung cancer
SIR: 1.8
NHL
SIR: 1.8
Testicular cancer
Leukemia
SIR: 1.66.7
Median time to occurrence: 4.5 years
Gastrointestinal cancer
SIR: 1.272.1
Bladder cancer
SIR: 3.9
Median time to occurrence: 20 years
Patients diagnosed before age 55 had higher SIR: 2.01.
Alkylating agents, including cyclophosphamide and melphalan

Platinum-containing regimens
Etoposide (Risk appears to be increasing since PEB chemotherapy became standard in the 1990s.)
RT
RT including the iliac lymph nodes (This risk will likely decrease because from the mid-1980s, RT has been directed
to the para-aortic lymph nodes only.)
No study noted increased risk of bladder cancer after chemotherapy alone; however, because PEB is carcinogenic to humans, and platinum is excreted in urine up to 20
years after treatment with PEB chemotherapy, prolonged
platinum exposure may play a role in bladder cancer development.
450

Primary
Malignancy
Waldenstrm
macroglobulinemia
Risk Factors
AML
SIR: 5.3
Colorectal cancer
SIR: 2.2
Lung cancer
SIR: 1.6
Melanoma
SIR: 1.6
Multiple myeloma
SIR: 4.4
NHL
SIR: 4.9
Prostate cancer
SIR: 1.2
Renal cancer
SIR: 1.4
Uterine cancer
SIR: 2.2
SIR: Standardized incidence ratio or relative risk (observed cases/expected cases) compares actual cases observed with the number of expected cases in
the general population to determine increased (> 1.0) or decreased (< 1.0) risk (Curtis et al., 2006; Ojha & Thertulien, 2012; Verma et al., 2011).
ACVBPdoxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone; ALLacute lymphocytic leukemia; AMLacute myeloid leukemia; CHOPcyclophosphamide, doxorubicin, vincristine, prednisone; CLLchronic lymphocytic leukemia; CMLchronic myeloid leukemia; CNScentral nervous system;
DLBCLdiffuse large B-cell lymphoma; Gygray; HCThematopoietic cell transplantation; HLHodgkin lymphoma; MOPPmechlorethamine, vincristine,
procarbazine, prednisone; NHLnon-Hodgkin lymphoma; PEBcisplatin, etoposide, bleomycin; Ph+Philadelphia chromosome positive; RRrelative risk;
RTradiation therapy; SIRstandardized incidence ratio; SLLsmall lymphocytic lymphoma; SMNsecond malignant neoplasm; TBItotal body irradiation
Note. Based on information from Andr et al., 2004; Chaturvedi et al., 2007; Curtis et al., 2006; Forman & Nakamura, 2011; Frederiksen et al., 2011; Hodgson, 2011; Hodgson et al., 2007; Huang et al., 2007; International Agency for Research on Cancer, 2012a, 2012b; Morton et al., 2010; Ng et al., 2011; Ojha
& Thertulien, 2012; Rebora et al., 2010; Richiardi et al., 2007; Travis et al., 2012; Tward et al., 2007; van den Belt-Dusebout et al., 2007; van Leeuwen et al.,
2000; van Leeuwen & Travis, 2001; Verma et al., 2011.
From Management of the Complications of Hematologic Malignancy and Treatment, by C.H. Erb and W.H. Vogel in M. Olsen and L.J. Zitella (Eds.), Hematologic Malignancies in Adults (pp. 629633), 2013, Pittsburgh: PA: Oncology Nursing Society. Copyright 2013 by the Oncology Nursing Society. Adapted
with permission.
(2) Two types of treatment-related leukemia (Cowell & Austin, 2012)

(a) Classic alkylating agentinduced AML (Cowell & Austin, 2012)
i. Associated with alkylating agents such as cyclophosphamide, melphalan, chlorambucil, and nitrosoureas
ii. Usually occurs two to eight years after treatment
iii. More than half present as MDS, which typically progresses to AML within a year.
iv. Development is associated with chromosome 5 and
7 aberrations.
(b) Topoisomerase II inhibitorinduced acute leukemia (Cowell & Austin, 2012)
i. Associated with topoisomerase II inhibitors such as etoposide, teniposide, mitoxantrone, and anthracyclines
ii. Risk begins shortly after completion of therapy, and
disease usually occurs within two years of treatment.
iii. It is not associated with preceding MDS.
iv. Development is associated with chromosomal translocations 11q23 (MLL gene), t(15;17) (PML-RARA),
and t(8;21) (AML-ETO).
d) Radiation-induced solid tumors, such as sarcomas, breast, lung, skin,
and thyroid, are observed at least 510 years after treatment, and the
risk persists for decades (Ng & Travis, 2008; Travis et al., 2012). Radiation-induced SMNs tend to occur within or at the margins of the
radiation field, and the risk increases with the volume of tissue irradiated and the dose of radiation (Ng & Travis, 2008).
3. Psychosocial effects (Hewitt et al., 2005; Stein, Syrjala, & Andrykowski,
2008)
a) Psychosocial disorders: Social withdrawal, educational problems, and
relationship, body image, and sexuality issues
b) Mental health disorders: Depression, anxiety, post-traumatic stress
c) Political and vocational issues: Employment, access to health care, insurance, and educational assistance
E. Risk of late effects for patients with select primary cancers
1. HL
a) The leading causes of death in HL survivors are SMNs and CVD (Ng,
LaCasce, & Travis, 2011).
(1) Patients treated with radiation are at greater risk of SMNs and CVD
than those treated with chemotherapy alone (Ng et al., 2011).
(2) SMNs: HL survivors are at risk for leukemia and solid tumors,
particularly lung and breast cancer (Ng et al., 2011).
(a) Solid tumors account for 70%80% of all SMNs following
treatment for HL, and the risk is greatly increased with radiation (Ng, Costine, et al., 2010).
i. Cumulative risk of SMN following treatment with 40
45 Gy of extended-field or mantle radiation therapy
is approximately 30% at 30 years (Hodgson, 2011).
ii. Modern radiation therapy for HL uses IFRT, which
treats only the lymph node regions that are initially
involved. Prescribed radiation doses range from 20
30 Gy. This reduces the volume of healthy tissue exposed to radiation and significantly decreases the risk
of SMNs (Hodgson, 2011).
(b) Breast cancer: Risk of breast cancer in HL survivors is significantly increased, particularly for women who were treated
with chest irradiation before age 35 (Hodgson, 2011; Ng et
al., 2011). The latency period is 1015 years following treatment (Ng, Costine, et al., 2010). The risk of breast cancer
appears to be decreased in patients who experienced treatment-related premature menopause (Hodgson, 2011; Ng,
Costine, et al., 2010).
(c) Lung cancer: The risk of lung cancer is associated with radiation therapy, alkylating agents, and smoking (Hodgson, 2011).
(3) CVD: HL survivors have a three- to fivefold increased risk of
CVD, which generally manifests 10 years after therapy and persists more than 25 years after therapy (Ng et al., 2011)
(a) Coronary artery disease is the most common form of cardiovascular toxicity among HL survivors, accounting for approximately 40%50% of adverse cardiac events (Hodgson, 2011).
(b) Valvular disease is less common, typically has a late onset
(10 years after radiation therapy), and is related to higher
doses (30 Gy) or young age at treatment (Hodgson, 2011).
(c) Acute pericarditis is uncommon but may occur following radiation that includes a large cardiac volume (Hodgson, 2011).
(d) HL survivors treated with mantle radiation therapy at doses of 3545 Gy are estimated to have a two- to fourfold increased risk of cardiac morbidity. The cumulative risks of
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significant heart disease among survivors of adult HL are

approximately 5%10% at 15 years, 16% at 20 years, and
34% at 30 years (Hodgson, 2011).
b) Pulmonary toxicity: HL survivors have a risk of treatment-related pulmonary toxicity including radiation pneumonitis and bleomycin toxicity (Ng et al., 2011)
2. NHL
a) Relative risk of a secondary cancer in NHL survivors is increased 1.14
1.47 over the general population (Tward et al., 2007).
b) Patients are at increased risk for AML, sarcomas, bladder cancer, cancers of the head and neck, melanoma, lung cancer, GI cancer, kidney
cancer, HL, and thyroid cancer (Tward et al., 2007).
(1) Chemotherapy increases the risk of AML, lung cancer, and bladder cancer (Tward et al., 2007).
(2) Radiation therapy increases the risk of sarcomas, breast cancer,
and mesothelioma (Tward et al., 2007).
c) Survivors of NHL have an overall significantly decreased risk of breast
cancer, prostate cancer, and myeloma (Tward et al., 2007).
3. Breast cancer: Breast cancer survivors are at risk for SMNs, cardiac toxicity from anthracyclines and/or trastuzumab, chemotherapy-induced premature menopause, osteoporosis, chemotherapy-induced cognitive impairment, sexual dysfunction, and taxane-related neuropathy (Azim, de
Azambuja, Colozza, Bines, & Piccart, 2011; Ganz & Hahn, 2008).
a) SMNs: Breast cancer survivors are at increased risk for sarcoma,
melanoma, AML, and cancers of the salivary gland, esophagus,
stomach, colon, breast, uterine corpus, ovary, and thyroid (Curtis et al., 2006).
b) Risk of SMN is greater in breast cancer survivors who carry a genetic predisposition (e.g., BRCA2 and TP53), were treated with radiation therapy (e.g., risk for secondary lung and esophageal cancer),
or were treated with hormonal therapy (e.g., risk for uterine cancer
secondary to tamoxifen) (Azim et al., 2011).
c) Radiation to the breast increases the risk of lung cancer, esophageal
cancer, and sarcoma in all patients, as well as the risk of the contralateral breast cancer in patients younger than 4045 years of age (Ng,
Kenney, et al., 2010; Travis et al., 2012).
4. Prostate cancer: Prostate cancer survivors are at increased risk for subsequent melanoma, small intestine, soft tissue, bladder, thyroid, and thymus cancer (Curtis et al., 2006; Ng, Kenney, et al., 2010).
5. Testicular cancer
a) Testicular cancer survivors are at risk for SMNs, CVD, neurotoxicity,
nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility,
psychosocial disorders, and cognitive impairment (Travis et al., 2010).
b) SMNs
(1) Among 10-year testicular cancer survivors, there are statistically
significant increased risks of malignant melanoma and cancers
of the lung (relative risk [RR] = 1.5, 95% confidence interval
[CI] [1.2, 1.7]); thyroid, esophagus, pleura, and stomach (RR
= 4.0, 95% CI [3.2, 4.8]); and pancreas, colon, rectum, kidney,
bladder, and connective tissue (RR = 4.0, 95% CI [2.3, 6.3])
(Travis et al., 2005, 2012).
(2) Chemotherapy increases the risk of radiation-associated SMNs
(van den Belt-Dusebout et al., 2007).
(3) The risk of SMN increases with younger age at time of treatment (van den Belt-Dusebout et al., 2007).
(4) The median time to occurrence of SMN is 20 years (van den
Belt-Dusebout et al., 2007).
(5) Etoposide and cisplatin chemotherapy increase the risk of treatment-related leukemia in a dose-related fashion (Travis et al.,
2010).
c) Cardiac toxicity: Increased risk of cardiac toxicity, including
myocardial infarction, coronary artery disease, hyperlipidemia,
and metabolic syndrome (Carver et al., 2007; Ng, 2011; Travis
et al., 2010)
d) Neurotoxicity: Increased risk of sensory peripheral neuropathy and
cisplatin-induced ototoxicity (Travis et al., 2010)
e) Nephrotoxicity: Increased risk of cisplatin-induced chronic renal dysfunction (Travis et al., 2010)
f) Pulmonary toxicity: Increased risk of bleomycin-induced pneumonitis and increased risk of mortality related to respiratory disease (Travis et al., 2010)
6. Cervical cancer (Chaturvedi et al., 2007)
a) Cervical cancer survivors have an increased risk for HPV-related cancers (of the pharynx, genital sites, and rectum/anus) and smokingrelated cancers (of the pharynx, trachea/bronchus/lung, pancreas,
and urinary bladder).
b) Patients with cervical cancer treated with radiation were at increased
risk for all SMNs at heavily irradiated sites (colon, rectum/anus, urinary bladder, ovary, and genital sites) beyond 40 years of follow-up
compared with women in the general population (Curtis et al., 2006;
Travis et al., 2012).
c) The 40-year cumulative risk of any secondary cancer was 22% among
women diagnosed with cervical cancer before age 50 and 16% for
those diagnosed after age 50.
7. Pediatric malignancies
a) The cumulative incidence of SMNs in five-year survivors of childhood
cancer treated from 19701986 at 30 years after diagnosis was 20.5%
(95% CI [19.1%, 21.8%]) and was higher for patients who received
radiation therapy than for those who did not (approximately 25%
versus 10%) (Friedman et al., 2010).
b) The most frequent SMNs were nonmelanoma skin cancer and breast
cancer, with 30-year cumulative incidences of 9.1% and 5%, respectively (Friedman et al., 2010). SMNs with a 30-year cumulative incidence < 1% included bone cancer, soft tissue sarcoma, leukemia, lymphoma, CNS tumors, head and neck cancer, GI cancer, lung cancer,
and thyroid cancer (Friedman et al., 2010).
c) The risk of SMNs among childhood cancer survivors is associated
with radiation therapy, chemotherapy, and genetic predisposition
(Travis et al., 2012).
d) The median latency period for development of an SMN was 17.8 years
(range 535.2 years) (Friedman et al., 2010).
8. HSCT recipients: HSCT recipients are at risk for secondary solid tumors,
treatment-related leukemia/MDS, and post-transplant lymphoproliferative disorders
a) In patients who underwent autologous HSCT for lymphoma, the cumulative incidence of secondary myelodysplasia/acute leukemia was
3.09% at 5 years and 4.52% at 10 years. The cumulative incidence of
solid tumors was 2.54% at 5 years and 6.79% at 10 years. The risk of
solid tumors was associated with advanced age and radiation therapy (Tarella et al., 2011).
b) Allogeneic HCT recipients were twice as likely to develop a solid tumor than the general population. Risk was related to younger age
at the time of transplantation (age < 30) and exposure to radiation
(Rizzo et al., 2009).
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454
c) The risk of a post-transplant malignancy increases with younger age

at time of transplant, especially for those younger than 10 years (Baker et al., 2003; Bhatia et al., 2001).
d) Relative risk of thyroid carcinoma is 3.26 overall, with a significantly
increased risk associated with age < 10 years, radiation, female gender, and chronic GVHD (Cohen et al., 2007).
F. Collaborative management
1. Elements of comprehensive survivorship care (Hewitt et al., 2005; Rechis, Beckjord, Arvey, Reynold, & McGoldrick, 2011)
a) Essential elements
(1) Survivorship care plan, psychosocial care plan, and treatment
summary
(2) Screening for new cancers and surveillance for recurrence
(3) Care coordination strategy, which addresses care coordination
with primary care physicians and primary oncologists
(4) Health promotion education
(5) Symptom management and palliative care
b) Highly recommended elements
(1) Late effects education
(2) Psychosocial assessment and care
(3) Comprehensive medical assessment
(4) Nutrition services, physical activity services, and weight management
(5) Transition visit and cancer-specific transition visit
(6) Rehabilitation for late effects
(7) Family and caregiver support
(8) Patient navigation
(9) Educational information about survivorship and program offerings
c) Other services
(1) Self-advocacy skills training
(2) Counseling for practical issues
(3) Ongoing quality improvement activities
(4) Referral to specialty care
(5) Continuing medical education for healthcare providers
2. Survivorship care plan: Patients completing primary treatment should
be provided with a comprehensive care summary and follow-up plan that
is clearly and effectively explained. This survivorship care plan should
be written by the principal provider(s) who coordinated oncology treatment. The plan should summarize critical information needed for the
survivors long-term care (Hewitt et al., 2005).
a) Summary of cancer treatment
(1) Date of diagnosis
(2) Survivors age at diagnosis
(3) Names of all chemotherapy agents and doses received
(4) All radiation field(s) and total radiation dose (in Gy) to each
field (For chest, thoracic spine, and upper abdominal radiation, include age at first dose.)
(5) Names of all relevant surgical procedures
(6) Names of all other therapeutic modalities
(7) Complications related to cancer treatment
b) Potential long-term effects of cancer treatment
c) Specific information about the timing and content of recommended follow-up
d) Recommendations regarding preventive practices and how to maintain health and well-being
e) Information on legal protections regarding employment and access

to health insurance
f) Availability of psychosocial services in the community
3. Models of survivorship care (Oeffinger & McCabe, 2006)
a) Consultative model: Primary oncology team refers survivor for a onetime visit in long-term follow-up clinic, where a comprehensive survivorship care plan is developed.
b) Nurse practitioner (NP)-led survivor clinic: Survivors are transitioned
to the care of an NP who shares care of the survivor with the primary care physician. The NP and primary care physician communicate
regularly, and the NP provides details of the patients cancer history
and patient-specific recommendations for follow-up care.
c) Specialty multidisciplinary clinic: Modeled after pediatric long-term
follow-up clinics, these clinics employ a team consisting of physicians,
oncology NPs, social workers, psychologists, administrators, and a
network of consulting physicians trained in the care of cancer survivors. NPs play a central role in the coordination and delivery of care.
G. Nursing assessment
1. Obtain history.
a) Chemotherapy, surgery, and radiation received
b) Toxicities experienced during therapy
c) Physical and psychosocial systems
d) Preexisting diseases that may exacerbate effects or contribute to synergistic effects of long-term effects or secondary malignancies
2. Perform physical examination.
3. Review results of laboratory tests including CBC, blood chemistry panel, and urinalysis.
4. Review results of imaging studies as indicated (e.g., chest x-ray, bone
densitometry).
5. Review results of pulmonary function tests, echocardiogram, and ECG
as indicated.
H. Preventive screening recommendations and follow-up care
1. Survivors should follow adult cancer screening recommendations. This
is especially important for childhood cancer survivors who have additional risk for premature development of adult cancers.
2. Irradiated skin and soft tissues should be thoroughly evaluated and reassessed for the life of the patient.
3. Women who have been treated with mantle-field irradiation should perform breast self-examination on a monthly basis beginning at the time
of puberty, and medical breast examination should be performed annually. Annual mammograms should begin eight years after irradiation
(Ng, Costine, et al., 2010).
4. Discuss weight management and exercise regimens with all cancer survivors. Physical activity and a healthy diet reduce the risk of cancer recurrences and decrease overall mortality in multiple cancer survivor
groups, including breast, colorectal, prostate, and ovarian cancer (American Cancer Society, 2013).
a) Eating a diet high in fruits, vegetables, and whole grains and low in
red and processed meat appears to protect against cancer progression, risk of recurrence, and overall mortality for a variety of cancers.
b) Regular exercise appears to be associated with a lower risk for recurrence and improved survival following treatment for breast, prostate,
ovarian, and colorectal cancers.
c) Cancer survivors who are overweight or obese may benefit from intentional weight loss following treatment.
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456
d) Cancer survivors should obtain the nutrients they need from foods
instead of supplements or vitamins because preliminary evidence has
shown that supplements may do more harm than good.
5. Patients should be counseled regarding smoking cessation (Curtis et
al., 2006).
6. Bone density studies are indicated for breast cancer survivors age 65 or
older, age 6064 with risk factors (family history, prior nontraumatic fracture), postmenopausal patients on an aromatase inhibitor, and patients
with chemotherapy-induced early menopause (Ganz & Hahn, 2008).
I. Patient and family education
1. Provide information about the treatment and potential late effects related to disease and treatment received (see Table 48).
2. Explain the risks of SMNs, the typical time to onset, cancer screening
recommendations, and the importance of follow-up visits.
3. Promote healthy lifestyle practices.
a) Diet
(1) A diet high in fruits, vegetables, and whole grains is associated
with a lower risk of death than one that contains a high intake
of processed and red meat, refined grains, sugar, and high-fat
dairy products.
(2) Avoid vitamin supplements, and obtain nutrients from food.
b) Regular physical activity
c) Smoking cessation
d) Sun safety practices
J. Professional education
1. Educate primary care professionals who may be working with survivors
after the survivors are no longer followed by an oncologist. A survivor-
Table 48. Key Resources for Cancer Survivorship Information

Organization and Website
Description
Centers for Disease Control and Prevention:

Cancer Survivorship
www.cdc.gov/cancer/survivorship
Comprehensive cancer survivorship information for patients and caregivers
National Coalition for Cancer Survivorship

www.canceradvocacy.org
http://journeyforward.org
Comprehensive cancer survivorship information for patients, caregivers, and

healthcare professionals
Resources include
Patient education
Cancer Survivor Toolbox, a free, self-learning audio program to help patients/
survivors acquire knowledge and skills to face common issues during the cancer journey.
Downloadable software
Medical History Builder (http://journeyforward.org/patients/medical-historybuilder)
Journey Forwards Survivorship Care Plan Builder (http://journeyforward.org/
professionals/survivorship-care-plan-builder)
Designed for oncology professionals to create custom Survivorship Care
Plans for patients with cancer and their physicians.
Includes forms that expedite the preparation of treatment summaries and follow-up care plans
Contains utilities such as a built-in regimen library, body surface area and
body mass index calculators, and various checklists
Provides support for breast cancer, colon cancer, lymphoma, and other
types of cancer
Ability to customize survivorship care plans with custom practice logo
Ability to expand care plans with information on symptoms to watch for, effects of treatment, support resources, and more
ship plan that includes potential long-term effects of treatment and recommended follow-up is helpful for primary providers who may be unfamiliar with cancer and its treatments.
2. Ensure that healthcare providers have the same information about SMNs
as do patients and that they are aware of recommended follow-up (see
Table 48).
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459
Chapter 11
Competence in
Chemotherapy
Administration
A. Professional education: To ensure a safe level of care for individuals receiving chemotherapy and biotherapy agents, each institution or supporting
agency ensures that RNs receive specialized education and preparation consisting of didactic learning followed by successful completion of a clinical
practicum (ONS, 2011).
1. Didactic content is comprehensive, current, and evidence-based. At
the conclusion of the didactic course, the nurse demonstrates an understanding of the following as identified in the ONS (2011) position Education of the Nurse Who Administers Chemotherapy and Biotherapy.
a) Principles of cancer chemotherapy and biotherapy
b) Types, classifications, and routes of administration of chemotherapy
and biotherapy agents
c) Pharmacology of cytotoxic and immunologic agents in cancer care
d) Chemotherapy and biotherapy indications in cancer care
e) Molecular biomarkers pertinent to chemotherapy and biotherapy
f) Chemotherapy and radiotherapy protectants
g) Principles of safe preparation, administration, storage, labeling, transportation, and disposal of chemotherapy and biology agents
h) Appropriate use and disposal of PPE
i) Administration procedures, including administration schedule, dose,
and route; patient consent; and appropriate documentation in the
medical record
j) Process to ensure patient safety
k) Assessment, monitoring, and management of patients receiving chemotherapy and biotherapy in all care settings
l) Patient and family education on chemotherapy and biotherapy side
effects and related symptom management and appropriate documentation in the medical record
m) Assessment of, education about, and management of post-treatment care, including urgent follow-up care procedures, late or longterm side effects, and physical and psychosocial aspects of survivorship
2. The clinical practicum allows the nurse to apply the knowledge gained
in the didactic component to direct patient care situations. Emphasis is
placed on the clinical skills that a nurse must demonstrate prior to being considered competent to administer chemotherapy and biotherapy
(see Appendices 3 and 4). At the completion of the clinical practicum,
the nurse will be able to
a) Demonstrate proficiency regarding the safe preparation, storage,
transport, handling, spill management, administration, and disposal
of chemotherapy drugs and equipment.
461
462
b) Identify appropriate physical and laboratory assessments for specific chemotherapy agents.
c) Demonstrate skill in venipuncture, including vein selection and sterile
technique and care of the site during and after drug administration.
d) Demonstrate skill in the care and use of various VADs.
e) Identify patient and family education needs in relation to specific
chemotherapy agents.
f) Identify acute local or systemic reactions as a result of extravasation
or anaphylaxis in association with specific chemotherapy drugs, and
identify appropriate interventions.
g) Demonstrate proficiency in the safe administration of chemotherapy
and disposal of chemotherapy waste and equipment.
h) Verbalize knowledge of institutional policies and procedures regarding chemotherapy administration.
i) Document pertinent information in the medical record.
3. Clinical activities
a) The nurse should be supervised by a qualified preceptor to ensure
safe practice.
b) The preceptor and the nurse should establish specific objectives at
the beginning of the clinical practicum. Ideally, the nurse and preceptor should select a specific population of patients, and the nurse
should assume responsibility for planning the care for these patients
with supervision by the preceptor.
c) The length of time spent in the supervised clinical practicum should
be individualized depending on the nurses ability and skill in meeting the specific objectives and institutional standards.
d) After the nurse becomes proficient and independent in administering nonvesicants, progression to vesicant administration can occur.
e) The nurse should verbalize to the preceptor potential adverse reactions, side effects, toxicities, and measures to prevent and/or manage these reactions.
f) Various clinical settings can be used for the nurse to demonstrate
competence in chemotherapy administration. It may not be realistic
for all settings or agencies to provide on-site chemotherapy education
and training. Alternative methods should be used, such as
(1) Contracting with larger institutions to credential nurses for specific needs (e.g., vesicant, nonvesicant, IV push, short infusion,
continuous infusion)
(2) Creating a simulated laboratory to substitute for the clinical
component when patients are not available.
4. Evaluation: An evaluation tool based on the course objectives should be
used to determine
a) The nurses knowledge of chemotherapy drugs and the associated
nursing implications
b) The nurses knowledge of the necessary technical skills required for
the administration of chemotherapy agents (e.g., venipuncture, VAD
access and management, indwelling catheter management)
c) The nurses knowledge of patient and family education, which should
be initiated based on the chemotherapy administered
d) The nurses knowledge of steps to be taken in the event of an unto
ward response following chemotherapy administration (e.g., anaphylaxis, hypersensitivity reaction, extravasation).
5. Following successful completion of the clinical practicum, the nurse
should complete a skills inventory to demonstrate his or her ability to
perform the four criteria described herein. This can be done in a simulated setting (e.g., skills laboratory) or as a precepted experience in the
clinical setting. It is recommended that the learner administer at least
Chapter 11. Competence in Chemotherapy Administration
three chemotherapy agents under the supervision of trained personnel.

Two should be administered by IV pushthe first should be a nonvesicant agent, the second should be a vesicant agent.
6. Annual education and competency evaluation is recommended. Educational content should, at a minimum, emphasize any new information available. Methods for evaluation may include but are not limited to clinical
observation, quality improvement studies, chart audits, competency checklist, attendance at an educational program, literature review, and testing.
B. Policies and procedures
1. Policies help to promote standardization of practice within an institution. They provide an operational framework for organizational goals
and objectives and may be required by regulatory or accrediting agencies. Procedures commonly outline the steps needed to accomplish a
task (Scott & Harris, 2011).
2. Once a policy is implemented, it is imperative that it is enforced and followed by staff. Individuals can be held liable if patient harm results from
failure to follow a policy; institutions are liable if a policy is not followed
by their staff. Consider staff in units outside of hematology/oncology.
Are nurses administering HDs in obstetrics/gynecology or rheumatology? How is this addressed in institutional policy?
3. Interdisciplinary staff involvement is recommended when creating antineoplastic policies and procedures. Input from pharmacy, medicine, nursing, and other departments will result in a more comprehensive policy.
4. Topics that may be included in an antineoplastic policy are drug administration, safety checks, disposal, home care, medical surveillance
for staff, mixing, medication orders (e.g., who can write them, rounding volumes, format), PPE, linen handling, spill management, staff exposure to HDs, staff education, extravasation, documentation, storage,
and transportation.
5. To maintain safety, it is important to accurately identify the patient prior
to antineoplastic administration. Unique patient identifiers to be used
are frequently standardized by the institution and may include the individuals name; date of birth; medical record number; account, visit, or
admission number; photograph; and social security number. Many institutions incorporate this data on a wristband that may be read or scanned
electronically. Caution should be used when verifying patient identification with an identifier that can be easily changed, such as bed or chair
number or a phone number.
6. Antineoplastic medications administered outside the oncology areas: It
is the position of ONS that all RNs who administer and/or care for patients receiving chemotherapy receive specialized education, including
a didactic component and a practicum. Refer to the ONS position titled
Education of the Nurse Who Administers Chemotherapy and Biotherapy, available at www.ons.org/about-ons/ons-position-statements. This position
applies to antineoplastic drugs regardless of route, indication, or setting.
a) All nurses should be knowledgeable about the drugs they administer:
the mode of action, side effects, and toxicity; dosage range, rate, and
route of excretion; potential responses; and interactions with other
medications and foods.
b) Institutional policy should address the antineoplastic medication educational plan for nurses working within the facility. Some staff may
require drug- or disease-specific education, whereas others will require comprehensive education for all antineoplastic medications.
C. Sample documentation tools
1. Consent document (see Appendix 5)
463
464
2. Extravasation flow sheet (see Appendix 6)

3. Competency checklist (see Appendices 3 and 4)
References
Oncology Nursing Society. (2011). Oncology Nursing Society position on the education of the nurse
who administers chemotherapy and biotherapy. Retrieved from http://www.ons.org/about-ons/
ons-position-statements/education-certification-and-role-delineation/education-rn-who
Scott, M.L., & Harris, J.Y. (2011). Organizational design and structure. In M.M. Gullatte (Ed.), Nursing management: Principles and practice (2nd ed., pp. 97113). Pittsburgh, PA: Oncology Nursing Society.
Appendices
465
466
Appendix 1. Safe Management of Chemotherapy in the Home

You are getting medicine used to treat cancer (chemotherapy, or chemo). You must be careful to make sure other people do not accidentally touch the drugs or your body waste for a time after treatment. This form teaches you and your family how to protect others from
the chemo and how to handle the waste from the chemo in your home.
Chemo Drugs Are Dangerous
Chemo drugs are strong chemicals. Only patients who need chemo for treatment should take or touch the drugs. Items that touch the
medicines (such as syringes and needles) are contaminated with chemo. Regardless of how you take the medicines, chemo remains in
your body for many hours and sometimes days after your treatment. Your body will get rid of the drugs in your urine or stool. Traces of
chemo also may be present in vomit.
Disposal of Chemo
Dispose of items contaminated with chemo separately from other trash. If required, the company supplying your medicines and equipment will give you a hard plastic container labeled with Chemotherapy Waste or a similar warning. Place equipment and gloves that
have touched chemo into this container after use. If the waste is too large to fit in the plastic container, place it in a separate plastic bag
and seal it tightly with rubber bands. Place sharp objects in the hard plastic container. The company will tell you who will pick up the disposal container.
Body Waste
You may use the toilet (septic tank or sewer) as usual. Flush twice with the lid closed for 48 hours after receiving chemo. Wash your
hands well with soap and water afterward, and wash your skin if urine or stool gets on it. Pregnant women, children, and pets should
avoid touching chemo or contaminated waste.
Laundry
Wash your clothing or linen normally unless they become soiled with chemo. If that happens, put on disposable gloves and handle the
laundry carefully to avoid getting chemo on your skin. If you do not have a washer, place soiled items in a plastic bag until they can be
washed.
Skin Care
Chemo spilled on skin may be irritating. If this happens, thoroughly wash the area with soap and water, then dry. If redness lasts for
more than one hour or if a rash occurs, call your doctor. To prevent chemo from being absorbed through the skin, wear gloves when
working with chemo, chemo-soiled equipment, or waste.
Eye Care
If any chemo splashes into your eyes, flush them with water for 1015 minutes and notify your doctor.
Questions and Answers
Is it safe for family members to have contact with me during my chemo treatment?
Yes. Eating together, enjoying favorite activities, hugging, and kissing are all safe.
Is it safe for my family to use the same toilet as I do?
Yes. As long as you clean any chemo waste from the toilet seat, sharing is safe.
What should I do if I do not have control of my bladder or bowels?
Use a disposable, plastic-backed pad, diaper, or sheet to soak up urine or stool. Change immediately when soiled, and wash skin with
soap and water. If you have an ostomy, your caregiver should wear gloves when emptying or changing the bags. Discard disposable ostomy supplies in the chemo waste container.
What if I use a bedpan, urinal, or commode?
Your caregiver should wear gloves when emptying body wastes. Rinse the container with water after each use, and wash it with soap
and water at least once a day.
What if I vomit?
Your caregiver should wear gloves when emptying the basin. Rinse the container with water after each use, and wash it with soap and
water at least once a day.
Is it safe to be sexually active during my treatment?
Ask your doctor or your nurse this question. Traces of chemo may be present in vaginal fluid and semen for up to 48 hours after treatment. Special precautions may be necessary.
How should I store chemo at home?
You should store chemo and equipment in a safe place, out of reach of children and pets. Do not store chemo in the bathroom, as high
humidity may damage the drugs. Check medicine labels to see if your chemo should be kept in the refrigerator or away from light. Be
sure all medicines have complete labels.
Appendices
467
Appendix 1. Safe Management of Chemotherapy in the Home (Continued)

Is it safe to dispose of chemo in the trash?
No. Chemo waste is dangerous and requires separate handling. If you are receiving IV chemo at home, you should have a special
waste container for the chemo and equipment. This includes used syringes, needles, tubing, bags, cassettes, and vials. This container
should be hard plastic and labeled with Chemotherapy Waste or a similar warning.
Can I travel with my chemo?
Yes. Usually, traveling is no problem. Some chemo requires special storage (such as refrigeration), so you may need to make special arrangements. Check with your nurse, doctor, or medicine supplier for further instructions. Regardless of your means of travel (airplane,
car, or other), always seal your chemo drugs in a plastic bag.
What should I do if I spill some chemotherapy?
You will have a spill kit if you are receiving IV chemo at home. In the event of a chemo spill, open the spill kit and put on two pairs of
gloves, the mask, gown, and goggles. Absorb the spill with the disposable sponge. Clean the area with soap and water. Dispose of all
the materialsincluding gloves, mask, gown, and gogglesin the chemo waste container.
468
Appendix 2. Extravasation
Photo 1. Erythema of site of port extravasation of doxorubicin

(February 14)
Photo 2. Skin necrosis begins (February 28).
Photo 3. Area of extravasation following debridement (March 18)
Photo 4. Outer areas of debrided area are granulating (June 5).
Photo 5. Ten months following extravasation, the area has healed

and scars have formed (December 10).
Photo 6. Severe tissue necrosis secondary to vesicant extravasation
Note. Photos 15 from Chemotherapy Extravasation From Implanted Ports, by L. Schulmeister and D. Camp-Sorrell, 2000, Oncology Nursing Forum, 27,
p. 534. Copyright 2000 by the Oncology Nursing Society. Reprinted with permission. Photo 6 courtesy of Rita Wickham, RN, PhD, AOCN. Used with permission.
Appendices
Appendix 3. Clinical Practicum Evaluation: Part I

Chemotherapy Administration Competency Record
Employee Name _______________________________________________________________________________
Chemotherapy-competent RN evaluators must observe practice and validate that the nurse meets all of the following criteria. Administer at least one vesicant under supervision.
RN Evaluators
Date
Drugs Administered
PRIOR TO ADMINISTRATION
1. Coordinates time of administration with pharmacy and others as needed.
2. Verifies signed consent for treatment.
3. Verifies laboratory values are within acceptable parameters and reports results to provider as
needed.
4. Performs independent double check of original orders with a second RN for accuracy of
Protocol or regimen
Agents
Recalculated body surface area
Patient dose
Schedule
Route
5. Verifies that patient education, premedication, prehydration, and other preparations are completed.
ADMINISTRATION
1. Compares original order to dispensed drug label at the bedside or chairside with another RN.
2. Verifies patient identification.
3. Applies gloves and gown and uses safe handling precautions.
4. Verifies adequacy of venous access and appropriate IV site selection.
5. Checks IV patency and flushes line with 510 ml normal saline.
6. Demonstrates safe administration:
Pushes through side arm or at hub closest to patient; checks patency every 25 ml (every 23
ml for pediatric patients).
Verifies appropriate rate of administration.
7. Demonstrates appropriate monitoring/observation for specific acute drug effects.
8. Verbalizes appropriate action in the event of extravasation.
9. Verbalizes appropriate action in the event of hypersensitivity reaction.
AFTER ADMINISTRATION
1. Flushes line with enough fluid to clear IV tubing of drug.
2. Removes peripheral IV device or flushes/maintains vascular access device.
3. Disposes of chemotherapy waste according to policy.
4. Documents medications, education, and patient response.
5. Communicates post-treatment considerations to the patient, caregivers, and appropriate personnel.
Initials
469
470
Appendix 4. Clinical Practicum Evaluation: Part II

Check the appropriate column to indicate whether the nurse performs the listed activities satisfactorily. If the nurse has not had the opportunity to perform an activity, check the N/A (not applicable) column. Under Comments, provide examples of how the nurse met each
objective or performed each activity. Include plans for remediation for all activities for which No is indicated.
Yes
No
N/A
1. Participates in interdisciplinary care planning with physicians, nurses, and other healthcare professionals
(e.g., home care or dietary workers).
Comments:
2. Anticipates complications of chemotherapy and takes action to prevent or minimize the complications.
Comments:
3. Involves patients and caregivers in care planning and provides interventions specific to individual patient
needs.
Comments:
4. Instructs patients about hair, scalp, and skin care and takes measures to preserve body image.
Comments:
5. Reviews laboratory values and provides patients with information about myelosuppression, prevention of infection, fatigue, and prevention of bleeding according to ONS Putting Evidence Into Practice (PEP) evidence.
Comments:
6. Identifies patients at risk for oral mucositis and provides education regarding oral hygiene according to ONS
PEP evidence.
Comments:
7. Demonstrates knowledge of interventions (drug therapy and nonpharmacologic) for prevention and management of nausea and vomiting according to ONS PEP evidence.
Comments:
8. Instructs patients about the prevention and management of gastrointestinal complications (e.g., constipation, diarrhea, anorexia) according to ONS PEP evidence.
Comments:
9. Identifies and takes nursing action to prevent or manage potential or actual hypersensitivity and anaphylactic reactions.
Comments:
10. Uses appropriate safe handling precautions in the preparation, handling, and disposal of hazardous drugs.
Comments:
11. Demonstrates knowledge and skill in the assessment, management, and follow-up care of extravasations.
Comments:
12. Assesses patients for the most appropriate type of venous access device (peripheral or central) based on
type and duration of intended therapy.
Comments:
13. Demonstrates knowledge of research trials by participating in data collection, drug administration, patient
education, and follow-up.
Comments:
Appendices
471
Appendix 5. Consent for Chemotherapy Treatment

Patient Name:
Date:
Diagnosis:
Medications:
Possible side effects may include any of the following or a combination of the following:
Allergic and allergic-like reactions
Anemia
Fatigue
Constipation
Diarrhea
Loss of appetite
Mouth sores
Nausea or vomiting
Weight gain or loss
Liver damage
Hair loss
Skin and nail darkening

Skin ulceration at injection site
Skin rash
Light and temperature sensitivity
Numbness or tingling
Hearing loss
Heart damage
Kidney damage
Low platelet count causing bleeding
Low white blood cell count
Risk of infection
Menopausal symptoms
Menstrual irregularities
Sterility
Dizziness
Forgetfulness
Cognitive impairments
Secondary malignancy
Muscle aching or weakness
Unexpected side effects may occur in addition to those noted above. In rare instances, cancer treatment can cause life-threatening complications and death.
Chemotherapy can be harmful to an unborn child. It is important to tell the doctor if I think I may be pregnant. It is important for both
men and women who are being treated with chemotherapy and who are sexually active and fertile and who have a fertile partner to use
a reliable form of birth control (birth control pills, a reliable barrier method, or a hormonal implant as recommended by your physician). I
have discussed possible ways of preserving my fertility with my doctor, if applicable.
_________ (Patient Initials) A healthcare professional has provided and reviewed with me written information on the drugs I
will receive. I HAVE HAD THE CHANCE TO ASK ANY QUESTIONS ABOUT THE DRUGS I WILL RECEIVE AND AM SATISFIED
WITH THE INFORMATION PROVIDED.
My healthcare team has explained my treatment plan in detail. My doctor has discussed with me other methods of treating this disease
and the risks and benefits of treatment. There is no guarantee that this treatment will give me the same results that other patients have
received. If I change my mind and decide to stop treatment at any time, my doctor will continue to provide for my care in the future.
I have read the above information. I understand the possible risks and benefits of the recommended treatment plan. I agree to
accept the treatment and authorize Dr. _______________________ and his/her healthcare team to carry out the treatment plan.
Patient signature:
Date:
I have explained the expected response, side effects, and possibility of risks of the listed drugs to the above named patient.
Physician signature:
Witness:
472
Appendix 6. Extravasation Record

Vesicant Drug Extravasation Record
Patient:
Date of infiltration:
Time:
Todays date:
Drug:
Dilution (mg/ml):
Estimated amount infiltrated:

Vascular access
Infusion method
Peripheral IV
Location:
PICC
Implanted port
Needle size and length:
Tunneled catheter
Other
IV push via side-arm of free-flowing IV

Direct IV push
Minibag infusion
Continuous infusion
Infusion pump used?
Yes
No
Pretreatment assessment
Location:
Type and size of needle/catheter:

Description and quality of blood return:

Comments:

**Attach timed and dated photograph of site, if requested**
Description
Include topical cooling/heating applied, treatments, antidotes used, measurements of site, edema, and/or redness.
Assess extremity for range of motion and discomfort with movement.
Situation:
Background:

Assessment (include photos):

Recommendations:

Physician notified:
Patient/Caregiver Instructions:

Comments:

Consultations:
Plastic Surgery
Physical Therapy
Other:

Follow-up:
Date:
Date:
Include return appointments, patient instructions on

skin assessment, temperature monitoring, and reporting of pain.

Notes:

Signature:
Date:
Index
The letter f after a page number indicates that relevant content appears in a figure; the letter t, in a table.
A
abiraterone acetate
cardiotoxicity of, 257t
hepatotoxicity of, 326t
absolute neutrophil count
(ANC), 171
calculation of, 177
ACE inhibitors, for cardiomyopathy, 284
acneform eruptions, 235t, 243f
acquired drug resistance, 13
acral erythema, 238t, 251f
actinomycin, nausea/vomiting
from, 194t
acupressure wristbands, for
nausea/vomiting, 204
205
acupuncture, for nausea/vomiting, 205
acute infusion reactions, 163
167
pathophysiology of, 163
preadministration guidelines, 164165
risk factors for, 163164,
164f
acute kidney injury (AKI),
330331
acute nausea/vomiting, 193
196, 198203
acute renal failure. See acute
kidney injury
acute tubular injury (ATI), 330
acyclovir, for mucositis, 220t
adaptive immunity, 52t, 52
54, 53f
adherence, to therapy, 129
130
adjuvant therapy, 5
adotrastuzumab emtansine,
78t
aldesleukin (IL-2), 65t
nausea/vomiting from,
194t195t
nephrotoxicity of, 333t
neurotoxicity of, 342t
ocular toxicity of, 371t
pulmonary toxicity of, 294t
alemtuzumab
nausea/vomiting from, 195t
alimentary tract mucositis,
213, 217218
alkylating agents, 27t31t, 158t.
See also specific drugs
affecting sexuality, 384
293t
allergies, 130. See also hypersensitivity
alopecia, 232t, 244, 250251,
384
clinical manifestations of,
253254
grading of, 253
incidence of, 251
management of, 256
253t
support/resources for, 255
time frame/pattern of, 253
254
alpha particles, 5859
alprazolam, for nausea/vomiting, 199t
altered immunogenicity, 55
alternative therapies. See complementary and alternative medicine
altretamine, 27t
alveolar hemorrhage, 311312
amifostine, for GI mucositis,
217218, 219t
anagen effluvium, 251. See also
alopecia
anaphylaxis, 163. See also acute
infusion reactions
165
emergency treatment of,
165167, 166t
grading of, 167t
androgen inhibitors, cardiotoxicity of, 257t

anemia
adverse outcomes of, 183,
277, 349
classification of, 182t
183, 184t
definition of, 171
and fatigue, 379
incidence of, 181
lab assessment of, 184t
management of, 183184,
184t187t
risk factors for, 181183
angiogenesis, 9394
angiogenic switch, 94
anorexia, 222
assessment of, 222t, 224
224
incidence of, 223
management of, 224225
anthracyclines, 38t40t. See also
specific drugs
cardiotoxicity of, 257t259t,
278, 280281
extravasation of, 159t
antiangiogenic agents, 9394.
See also biotherapeutic
agents
antibodies, 55
anticipatory nausea/vomiting,
192193, 204
antidepressants, for fatigue
management, 381
antidiarrheal medications,
211t
antiemetic therapy, 198, 199t
202t
antigen modulation, 55
antigen-presenting cells, 54
antimetabolites, 32t36t. See
also specific drugs
cardiotoxicity of, 260t261t
473
474

neurotoxicity of, 341t342t
ocular toxicity of, 369t370t
296t
antitumor antibiotics, 37t40t.
cardiotoxicity of, 257t259t,
261t
discovery of, 3t
297t
APL differentiation syndrome,
287288, 312314
aprepitant, 191
drug interactions with, 145
for nausea/vomiting, 200t,
203
arsenic trioxide, 40t
arterial access devices, 125126
ASCO/ONS Chemotherapy
Administration Safety
Standards, 100
asparaginase, 40t
asparaginase Erwinia chrysanthemi, 41t
assessment, pretreatment, 130
133
ATRA, pulmonary toxicity of,
298t, 312314
atropine, for diarrhea, 211t
AUC calculations, 148149
autologous cellular immunotherapy, 67t
autonomic nerve deficits, 339
axitinib, 78t
azacitidine, 32t
B
band neutrophils, 172, 177
BCG live vaccine, ocular toxicity of, 370t
BCNU. See carmustine
Beau lines, 233t
bendamustine, 27t
as irritant, 162
benzodiazepines, for anticipatory nausea/vomiting, 204
benzydamine, for mucositis,
220t
beta particles, 59
BETTER model, of communication on sexuality, 388
bevacizumab, 58, 70t
bexarotene, hepatotoxicity of,
326t
biologic response modifiers,
68t69t
biologic safety cabinets (BSCs),
107108, 113114
biotherapeutic agents, 5. See also
specific drugs
accidental exposure to, 104
105
characteristics/therapeutic
uses of, 60, 61t67t, 93f
supportive uses for, 60
biotherapy
cardiac assessment before,
283
categories of, 5660
definition/overview of, 56
strategies of, 6093, 68t91t,
92f
bisphosphonates, ocular toxicity of, 371t
bleomycin, 37t
pulmonary toxicity of, 290
291, 296t297t
blistering, 236t
blistering agents. See vesicants
blood-brain barrier, 340
blood components, life spans of,
174t, 181
B lymphocytes, 55
body fluids, safe handling of,
110
body surface area (BSA) dosing,
144148, 147f
bone marrow, 174
bortezomib, 79t
inadvertent IT administration
of, 102, 103f
bosutinib, 79t
bradycardia. See conduction
pathway disorders
brain natriuretic peptide levels,
283284
breakthrough nausea/vomiting, 204
breast cancer
cognitive impairment with,
350t358t
as late effect, 441t
secondary malignancies following, 452
brentuximab vedotin, 58, 70t

bronchospasm, 290
bulk-forming laxatives, 228
busulfan, 27t
291, 292t
C
cabazitaxel, 45t
cabozantinib, 80t
cachexia. See anorexia
Calvert formula, 148, 148f
camptothecins, 44t
cancer
definition of, 12
factors causing, 12
genetic alterations in, 1, 2f
grading/staging of, 23
history of therapy, 3t4t, 35
therapy goals, 127
treatment approaches, 56
treatment strategies, 6
cancer cachexia, 222, 223f. See
also anorexia
cancer-related fatigue. See fatigue
capecitabine, 32t
capillary leak syndrome, 272
carboplatin, 27t28t
AUC-based dosing of, 148
149, 149f
cardiac failure/cardiomyopathy, 277
assessment of, 282283
282
incidence of, 280
types of, 278280
cardiovascular toxicity, 255,
256t269t. See also specific
disorders
carfilzomib, 80t
carmustine, 43t
pulmonary toxicity of, 290,
302t
catheters, 125, 127128
cell cycle, 25, 26f

cell cyclenonspecific drugs,
26, 48
cell cyclespecific drugs, 26
cell-mediated immunity, 53, 53f
cell signaling, 60, 9293
central nervous system (CNS)
deficits, 339340
as late effects, 443t
central nervous system (CNS)
tumors, cognitive impairment with, 358t359t
central venous catheters (CVCs),
127128
cerebellar dysfunction, 340
cervical cancer, secondary malignancies following, 453
cetuximab, 58, 71t
diarrhea from, 208
rash from, 244. See also rash
chemokines, 55
chemoprevention, 7
chemoreceptor trigger zone
(CTZ), 190191, 191f
chemotactic cytokines, 55
chemotherapeutic agents. See
also specific drugs
cell cyclenonspecific, 26, 48
cell cyclespecific, 26
characteristics of, 27t47t
history of, 3t4t
chemotherapy
for cancer treatment, 5
dosing of, 67
chemotherapy-induced nausea
and vomiting (CINV), 190.
See also nausea/vomiting
chemotherapy-induced neutropenia (CIN), 172. See also
neutropenia
chest CT, 309
chest x-ray, 287, 308309
Childrens Cancer Group, 3t
Childrens Oncology Group
(COG), 4t, 19
chimeric mAbs, 57, 57f
chlorambucil, 28t
chlorhexidine, for oral mucositis, 217, 219t
chronic kidney disease (CKD),
332
cisplatin, 28t
nephrotoxicity of, 332t, 336
cladribine, 32t
clinical trials, 1723
Index
nurses role in, 2023
nursing core competencies
for, 22, 22t
pediatric patient involvement
in, 1920
phases of, 18t19t
regulation of, 1719
resources for, 20
clofarabine, 33t
clonidine, for hot flashes, 385
clot formation, 184188. See also
thrombocytopenia
cluster of differentiation (CD)
markers, 54
Cockcroft-Gault formula, 148,
149f
cognitive impairment, 347348
by cancer site, 350t362t
clinical manifestations of, 364
incidence of, 349, 363
management of, 365
Coley, William, 3t
colony-stimulating factors
(CSFs), 61t64t. See also filgrastim; pegfilgrastim; sargramostim
for anemia, 185t187t
for neutropenia, 178
colorectal cancer, cognitive impairment with, 359t
combination chemotherapy
first used, 4t
vs. single-agent, 6
Common Terminology Criteria
for Adverse Events
(CTCAE)
for diarrhea, 209
for nausea/vomiting, 198t
for neuropathies, 339t
for oral mucositis, 216, 218t
for skin toxicities, 245t
competence
for chemotherapy administration, 461464, 469470
for clinical trial nursing, 22, 22t
complementary and alternative
medicine (CAM), 9798
assessment of, 130
for fatigue management, 381
382
for sexuality alterations, 385
complete response (CR), 8, 8t
compounding aseptic containment isolators (CACIs),
107108, 113114
conditioning therapy, 56
conduction pathway disorders,
255
assessment of, 271
incidence of, 270
management of, 271
pathophysiology of, 255, 270

congestive heart failure (CHF),
284
conjugated antibodies, 58
conjunctivitis, 244
constipation, 225226
assessment of, 227
consequences of, 226
incidence of, 226
continuity of care, 142
continuous IV infusion, 128129
control, as treatment goal, 7
coronary artery disease, 275277
corticosteroids
for anorexia, 224225
for mucositis, 220t
for nausea/vomiting, 199t,
2023
cranial nerve deficits, 338, 339t,
345t
crizotinib, 81t, 92
cryotherapy, oral (ice chips),
216, 221t
cryptogenic organizing pneumonia, 290
crystal nephropathy, 330331
cure, as treatment goal, 7
cutaneous effects. See skin toxicities
cyclincyclin-dependent kinase
(CDK) complexes, 25
cyclophosphamide, 28t
cardiotoxicity of, 256t, 278,
281
nausea/vomiting from, 194t,
197t
292t, 307
cyclosporine
cytarabine, 33t
195t
cytarabine liposomal, 33t
cytokine-release syndrome, 163
165, 164f, 167, 167t
cytokines, 5557
cytopenia, definition of, 171
cytosine arabinoside, pulmonary
toxicity of, 290, 307
cytotoxic T-lymphoctye antigen
4 (CTLA-4), 5455
D
dacarbazine, 29t
dactinomycin, 37t
darbepoetin, 61t
dasatinib, 81t
daunorubicin, 38t
cardiotoxicity of, 257t, 283
daunorubicin citrate liposomal, 38t
decitabine, 34t
deep tendon reflexes, 339
deferoxamine, ocular toxicity
of, 371t
delayed nausea/vomiting, 191,
196, 204
denileukin diftitox, 68t
denosumab, 72t
depigmentation, 240t
detergent laxatives, 228
dexamethasone, for nausea/
vomiting, 199t
dexmethylphenidate, for fatigue
management, 381
dexrazoxane, 284
diapedesis, 174
diarrhea, 206
assessment of, 208210, 209t
chemotherapeutic/biotherapy
agents causing, 206207
clinical manifestations/consequences of, 207
incidence of, 207
management of, 210, 211t,
212f
patient education on, 210213
diaziquone, nephrotoxicity of,
332t
dietary interventions
for constipation, 229
for nausea/vomiting, 205
diffusing capacity of lung
for carbon monoxide
(DLCO), 310
diphenoxylate, for diarrhea,
211t
distress, 130131
docetaxel, 45t
475

pulmonary toxicity of, 303t,
307
documentation, 99100, 112
of extravasation, 160, 161f,
472
of patient education, 138139
dolasetron, for nausea/vomiting, 201t
dose calculation, 146149
verification of, 146, 150151
dose capping, 149, 149f
dose density, 6, 140141
dose intensity, 7, 140141
dose modifications, verification
of, 144145
dosimeters, 110
dosing, of chemotherapy, 67
doxorubicin, 39t
flare reaction with, 163
195t
doxorubicin liposomal, 39t
dronabinol, for nausea/vomiting, 199t
drug interactions, 145
drug resistance, 1213, 92
dysesthesias, 338
dyspnea, 290. See also pulmonary
toxicities
dysrhythmias. See conduction
pathway disorders
dystrophy (nail), 233t
E
Eastern Cooperative Oncology
Group (ECOG) scale, 10,
11t
echocardiography, 283, 287
eculizumab, 72t
electroacupuncture, for nausea/
vomiting, 205
electrocardiogram (ECG), 283,
287
electrolyte replacement, 210
emergent drug resistance, 13
emesis. See nausea/vomiting
emetogenicity, of antineoplastic
drugs, 194t197t
encephalopathy, 339
energy conservation, 380
enteral nutrition, for anorexia, 225
epidermal growth factor (EGF),
93
epidermal growth factor receptor inhibitors (EGFRIs)
ocular toxicity of, 366, 367t
476

rash with, 231, 242246, 247f.
See also rash
epidermal growth factor receptors (EGFRs), 93, 231
epipodophyllotoxins, 44t45t
epirubicin, 39t
epoetin alfa, 61t
eribulin, 42t
erlotinib, 81t82t, 92
rash from, 244. See also rash
erythema multiforme, 235t236t
erythema, transient, 240t
erythrocytes, normal physiology
of, 180181
erythropoiesis, 180
erythropoiesis-stimulating
agents (ESAs), 184, 185t
187t
381
erythropoietin (EPO), 180181
ESA APPRISE Oncology
Program, 61t, 184
esophagitis. See GI mucositis
estramustine, cardiotoxicity of,
256t
estrogen receptors (ERs), 12
estrogen therapy, 385
ethambutol, ocular toxicity of,
371t
ethical issues
in cancer therapy, 9798
with reproductive changes, 391
ethical principles, 98t
etoposide, 44t
195t, 197t
304t
everolimus, 81t82t
304t
exercise
expedited approval programs,
for new drugs, 23
extracellular matrix components
(ECM), 94
extravasation, 155
documentation of, 160, 161f,
472
factors affecting, 155
follow-up after, 160161

158t160t
signs/symptoms of, 156157,
157t, 470
exudative diarrhea, 206
eye damage. See ocular toxicity
eye exposure, to hazardous
drugs, 111
eye protection, 106
F
face protection, 106
fatigue, 377
incidence of, 379
nonpharmacologic interventions, 382383
pathophysiology of, 377379,
378f
febrile neutropenia, 175f, 175
176, 178. See also neutropenia
fertility services, 391. See also reproductive alterations
fever, 175176, 178180. See also
neutropenia
fiber intake, for constipation, 229
filgrastim (G-CSF), 62t
for anemia, 186t
development of, 4t
film badges, 110
fissures, in skin, 236t237t, 250f
5-HT3 receptor antagonists
development of, 4t
202t, 203
fixed dosing, 146
flare reaction, 155, 157t, 163
floxuridine, 34t
fludarabine, 34t
197t
fluid replacement
for diarrhea, 210
fluorine-18 fluorodeoxyglucose
(18F-FDG), 10
fluorouracil (5-FU), 34t
diarrhea from, 208
forced expiratory volume in one
second (FEV1), 310
forced vital capacity (FVC), 310
fosaprepitant dimeglumine, for
nausea/vomiting, 200t
201t, 203
G
gabapentin, for hot flashes, 385
gamma rays, 59
gefitinib
gemcitabine, 34t
295t296t
genetic alterations, 1, 2f
GI mucositis, 213, 217218
glomerular filtration rate (GFR),
148149, 149f
glomerulonephritis, 331332
gloves, 106
glucose analog tracer, 10
goals of cancer therapy, 7
gowns, 106
grading
of alopecia, 253
of anaphylaxis, 167t
of cancer, 23
of rash, 244, 245t
granisetron, for nausea/vomiting, 201t
granulocytecolony-stimulating
factor (G-CSF). See also filgrastim; pegfilgrastim
for mucositis, 220t
granulocyte macrophagecolony-stimulating factor (GMCSF). See also sargramostim
for mucositis, 220t
growth factors, 60, 9293
growth fraction, of tumor, 1112
guided imagery, for nausea/
vomiting, 205
H
hair changes, 232t
haloperidol, for nausea/vomiting, 199t
hand-foot syndrome, 239t, 252f
hand hygiene, 177, 179
hazardous drugs
definition of, 102103
disposal of, 111
occupational exposure to,
103105, 104t, 111112
policy requirements for, 114
115
routes of exposure to, 105
safe administration of, 109,
128129, 131133, 142
143, 145, 466467
safe compounding of, 107

109
spill management of, 112f,
112114, 114f
storage/labeling of, 107
transporting, 109
head and neck cancer, cognitive
impairment with, 359t
hematologic cancer
359t360t
secondary, 445t
hematopoiesis, 172, 173f
hematopoietic stem cell mobilizers, 66t
hematopoietic stem cells
(HSCs), 172
hemorrhagic cystitis (HC)
incidence/risk factors of, 319
management of, 321
prevention of, 320321
hemorrhagic pneumonitis, 289
hepatitis B vaccine, 60
hepatotoxicity
assessment of, 328
322328
management of, 328
HERA (HERceptin Adjuvant)
clinical trial, 280
hexamethylmelamine, nausea/
vomiting from, 197t
high-dose chemotherapy, 144,
194t
282
high-output failure, 277
hirsutism, 232t
Hodgkin lymphoma (HL), 451
452
hormone receptor status, 12
HPV vaccine, 60
HSCT, secondary malignancies
following, 453454
humanized mAbs, 57, 57f
human mAbs, 57, 57f
humoral immunity, 53, 53f
hydrogen peroxide, for mucositis, 220t
hydroxyurea, 41t
197t
hyperpigmentation, 233t, 250f
hypersensitivity, 163165, 164f,
166t, 167, 167t. See also
acute infusion reactions
hypersensitivity pneumonitis,
289290, 307
hypertension, 273274
hypertrichosis, 232t
hypoxia, 183184
hypoxia-inducible factor-1
(HIF-1) complex, 94
Index
I
ibritumomab tiuxetan, 58, 73t
idarubicin, 40t
IFN alfa-2b, 64t
IFN gamma, 65t
ifosfamide, 29t
neurotoxicity of, 340, 341t
imatinib, 83t, 92
diarrhea from, 208
immune response, types of, 51
54, 52t, 52f53f
immune suppression, 55
immune system, 51, 51f
cells of, 54f, 5455
immunoglobulins, 55
immunosenescence, 56
immunosuppressive therapy, 6
immunosurveillance, 56, 60
immunotoxins, 68t
implanted arterial ports, 125
implanted arterial pumps, 126
individualized protocols, 143
144
informed consent (IC), 2022,
21t, 100, 131, 471
infusion complications, 155. See
also acute infusion reactions; extravasation; flare
reaction; venous irritation
Infusion Nursing Standards of
Practice, 99
infusion reaction, 163167
inhalation exposure, to hazardous drugs, 112
innate immunity, 5152, 52f, 52t
institutional review boards
(IRBs), 19
interferon alfa
195t
interferons (IFNs), 64t65t
discovery of, 3t
interleukins (ILs), 65t66t. See
also aldesleukin
interstitial lung disease (ILD),

288
incidence of, 290
292t306t
intra-arterial infusion, 125126
intramuscular (IM) injection,
122
intraperitoneal (IP) chemotherapy, 122123
intrapleural administration,
124125
intrathecal (IT) administration,
123124
inadvertent, 102, 103f, 124
intravenous (IV) administration,
126127
intravesicular administration,
125
investigational regimens, 143
involved-field radiation therapy
(IFRT), 439
iodine-131 tositumomab, 58
ipilimumab, 58, 73t
irinotecan, 44t
diarrhea from, 208
iron-chelating agents, 284
iron, for RBC production, 181
irritants, 161. See also venous irritation
with vesicant properties, 161
162
itching, 241t
IV push, 129
ixabepilone, 43t
K
Karnofsky Performance Status
(KPS) scale, 10, 11t
keratinocyte growth factors, for
oral mucositis, 217
keratoconjunctivitis sicca, 244
L
labyrinthitis, 191
lacrimation, 244, 368. See also ocular toxicity
Lansky Performance Scale, 10,
11t
lapatinib, 84t
late effects
of cancer treatment, 438440

nonmalignant, 440, 441t445t
types of, 440451, 441t450t
laxatives, 228
L-carnitine, for fatigue management, 381
legal issues, in cancer therapy,
99100
lenalidomide, 68t
leucovorin, diarrhea from, 208
leucovorin rescue, 144
leukocyte growth factor, for anemia, 187t
leukoencephalopathy, 349
linens, safe handling of, 110
111
liver toxicity. See hepatotoxicity
lomustine, 43t
303t
Look Good Feel Better program, 255
loperamide, for diarrhea, 210,
211t
lorazepam, for nausea/vomiting, 199t
low-level laser therapy, for oral
mucositis, 218
L-phenylalanine, nausea/vomiting from, 197t
lubricant laxatives, 228
lung cancer, cognitive impairment with, 360t
M
macrocytic anemia, 182t
major histocompatibility complex (MHC), 55
malnutrition, and cardiotoxicity, 282
mammalian target of rapamycin
(mTOR) kinase, 92
mannitol, ocular toxicity of, 372t
marginated cells, 174
matrix metalloproteinases
(MMPs), 94
MDA classification, of tumor response, 10
mechlorethamine, 29t
medical records, 99100
medication errors, 100102,
103f
medication sequence, verification of, 150
megakaryocytes, 188
megestrol acetate
for anorexia, 225
melphalan, 30t
477

as irritant, 162
197t
memory T cells (TM cells), 54
menopause, chemotherapy-induced, 384385
mercaptopurine (6-MP), 3t, 35t
mesna, for cystitis prevention,
320321
metamyelocytes, 172
methotrexate, 35t
197t
nephrotoxicity of, 333t, 336
337
296t, 307
methylnaltrexone, for constipation, 229
methylphenidate, for fatigue
management, 381
metoclopramide, for nausea/
vomiting, 200t
metoprolol, for cardiomyopathy, 284
microcytic anemia, 182t
minoxidil, for alopecia, 254
mithramycin, nephrotoxicity
of, 333t
mitomycin, 37t 38t
291, 297t
mitotane, 41t
mitoxantrone, 38t
modafinil, for fatigue management, 381
monoclonal antibodies (mAbs),
57f, 5758. See also specific drugs
characteristics of, 70t78t, 93f
302t
MOPP chemotherapy, first
used, 4t
Mosteller equation, 147f
motion sickness, 191
motor neuropathy, 338, 339t
478
mTOR inhibitors, pulmonary

toxicity of, 304t305t, 307
mucositis, 213222. See also oral
mucositis
MUGA scans, 283, 285
multidrug resistance (MDR),
1213
murine mAbs, 57, 57f
music therapy, for nausea/vomiting, 204
myeloablation, 56
myeloblasts, 172
myelocytes, 172
myelosuppression, 171190. See
also anemia; neutropenia;
thrombocytopenia
myocardial muscle dysfunction, 277
N
nabilone, for nausea/vomiting, 199t
nadir
in children, 175
definition of, 171172
WBC, 174175
nail changes, 233t
National Cancer Act (1937), 3t
National Cancer Act (1971), 4t
National Cancer Institute (NCI),
3t
Cancer Therapy Evaluation
Program (CTEP), 17
Common Terminology
Criteria for Adverse
Events (CTCAE). See
Common Terminology
Criteria for Adverse
Events
National Chemotherapy
Program, 3t
natural killer (NK) cells, 52, 55
natural killer T (NKT) cells,
52, 55
nausea, definition of, 190
nausea/vomiting, 190
acute, 193196, 198203
anticipatory, 192193, 204
antineoplastic drugs causing,
194t196t
assessment of, 196197, 198t
breakthrough, 204
complications of, 197198
delayed, 191, 196, 204
199t202t
nonpharmalogic interventions for, 204205
pathophysiology of, 190196,
191f192f
patient education on, 205
206
nelarabine, 35t
neoadjuvant therapy, 5, 8
neovascularization, 94. See also

angiogenesis
nephritic/nephrotic syndromes,
331332
nephrotoxicity, 332t334t
334335
neuropathic pain, 344
neuroreceptors, 192f
neurotoxicity, 337338
incidence of, 340
pain with, 344345
neutropenia, 171172
176177
prevention of, 179
risk factors for, 175f, 175176
neutropenic diet, 177
neutrophils
locations of, 174
normal physiology of, 172
174
pathophysiology of, 174175.
See also neutropenia
nilotinib, 84t85t
nitrogen mustard. See mechlorethamine
nitrosoureas, 43t44t
303t
NK1 antagonists, for nausea/
vomiting, 200t201t, 203
NK1 receptors, 191
non-Hodgkin lymphoma
(NHL), 452
nonmyeloablative therapy, 6
nonspecific immunity, 5152,
52f, 52t
normocytic anemia, 182t
Notch receptor pathway, 94
nurse practice acts, 99
nursing-sensitive outcomes, 344
O
occupational exposure
hazard controls hierarchy,
105
to hazardous drugs, 103110,
104t
octreotide, for diarrhea, 210,
211t
ocular toxicity, 244, 367t368t
incidence/risk factors, 367

management of, 375
ofatumumab, 73t
Office for Human Research
Protections (OHRP), 17
olanzapine, for nausea/vomiting, 199t
older adults
cardiotoxicity in, 282
neurotoxicity in, 344
omacetaxine, 43t
omeprazole, for GI mucositis, 217
(ONS)
on nursing scope and standards, 99
on role of clinical trials nurses, 22
ondansetron
development of, 4t
onycholysis, 233t
oprelvekin, 66t
for anemia, 187t
Oral Assessment Guide, 216,
217t
oral care, 216, 218222
oral cryotherapy (ice chips),
216, 221t
oral mucositis, 213
assessment of, 216
215216
incidence of, 214
phases of, 214
prevention of, 216217
treatment for, 218, 219t221t
oral route of administration,
121122
order sets, 143
orthochromatic normoblasts,
181
osmotic diarrhea, 206
osmotic laxatives, 228
ovarian cancer, cognitive impairment with, 361t
oxaliplatin, 30t 31t
as irritant, 161162
293t
oxidative damage, cognitive impairment from, 348
P
paclitaxel, 46t
development of, 4t

pulmonary toxicity of, 304t,
307
paclitaxel protein-bound/albumin-bound, 46t
pain, with neuropathies, 344
345
palifermin, 63t
palliative cancer care, 7
palmar-plantar erythrodysesthesia, 239t, 252f
palonosetron, for nausea/vomiting, 201t, 203
pamidronate, nephrotoxicity
of, 333t
pancreatitis, 375377
pancytopenia, definition of, 171
panitumumab, 74t
diarrhea from, 208
papulopustular rash, 235t, 242
244, 245t, 246
parenteral nutrition, for anorexia, 225
paresthesias, 338
paronychia of nail, 232t, 245t,
250f
paroxetine, 385
partial response (PR), 8, 8t
patient education
on alopecia, 254255
on anorexia, 225
barriers to, 138
on cardiomyopathy, 285286
on cognitive impairment, 365
on constipation, 229
on coronary artery disease,
277
on cystitis, 321
definition of, 137
documentation of, 138139
on dysrhythmias, 271272
on fatigue management, 383
on hepatotoxicities, 328
on infusion reactions, 167
168
on mucositis, 218222
on nausea/vomiting, 205206
on nephrotoxicities, 337
on neurotoxicities, 347
on ocular toxicities, 375
outcomes of, 137138
on perirectal cellulitis, 231
on pulmonary toxicities, 310
on reproductive changes,
380381
for self-administration of oral
therapy, 121122
on sexuality alterations, 388
on skin toxicities, 248
during survivorship care, 456
on thrombocytopenia, 189
Index
patient safety, 100102, 103f,
131133, 142143, 145,
466467. See also hazardous drugs
pazopanib, 85t
pediatric cancers, secondary malignancies following, 453
pediatric patients
in clinical trials, 1920
dose modifications for, 144
145
neurotoxicity in, 343
safe administration to, 145
pegaspargase, 41t
pegfilgrastim (PEG-G-CSF), 63t
for anemia, 186t
and dose-dense chemotherapy, 6
peginterferon, nausea/vomiting
from, 196t
pemetrexed, 36t
pentostatin, 36t
pericardial effusions, 286287
peripheral nervous system deficits, 338339, 339t
peripheral venous access, 126127
perirectal cellulitis, 230231
personal protective equipment
(PPE), 104107
pertuzumab, 74t
photosensitivity, 239t
physical activity. See exercise
plant alkaloids, 44t47t
extravasation of, 159t160t
304t
plants/flowers, neutropenic patients and, 178
platelets, normal physiology of,
184188
plerixafor, 66t
pleural effusions, 314316
plicamycin, nausea/vomiting
from, 194t
PLISSIT model, of communication on sexuality, 388
pluripotent stem cells, 172
polychromatophilic erythrocytes, 181
polychromatophilic normoblasts, 180
polyethylene glycol (PEG), for
constipation, 228
polymorphonuclear neutrophils, 177

polypharmacy, 145
pomalidomide, 69t
Positron Emission Tomography
Response Criteria in Solid
Tumors (PERCIST), 10
positron-emission tomography
(PET) scans, 10, 309
posterior reversible encephalopathy syndrome (PRES), 339
pralatrexate, 36t
preclinical studies, 17
pregnancy, cancer treatment
during, 131. See also reproductive alterations
primary cancer prevention, 7
primary engineering control
(PEC), 107108
probiotics, for diarrhea, 210
procarbazine, 41t
197t
prochlorperazine, for nausea/
vomiting, 200t
professional education, 456
457, 461464
progesterone receptors (PRs), 12
progestins, for anorexia, 224
225
progressive disease (PD), 8, 8t
progressive muscle relaxation,
prokinetic agents, for constipation, 228
promegakaryocytes, 188
promyelocytes, 172
pronormoblasts, 180
prostate cancer
361t
pruritus, 241t, 245t
psychosocial issues
with skin toxicities, 247248
psychostimulants, for fatigue
management, 381
pulmonary alveolar proteinosis/
phospholipoproteinosis,
316317
pulmonary edema, 289290,
307
pulmonary function tests, 309
310
pulmonary toxicities, 287288,
292t306t. See also alveolar hemorrhage; interstitial lung disease; pleural
effusions
pulmonary veno-occlusive disease (VOD), 288, 317
318
Q
quality of life (QOL), measurement of, 10
R
radiation enhancement, 248
radiation monitoring devices, 110
radiation recall, 248
radiation safety officer (RSO),
109
radiation therapy
for cancer treatment, 5
late effects of, 438439, 446
pulmonary toxicities from,
291
skin toxicities from, 248
radioisotope (RIT) treatment,
5860
safety precautions for, 109
111
ranitidine, for GI mucositis, 217
rasburicase, 331
rash, 232t241t, 242, 243f
grading of, 244, 245t
incidence of, 243244
Raynaud phenomenon, 272273
RBC production, 180181. See
also anemia
record keeping. See documentation
regorafenib, 86t
regulatory T cells (Treg), 5354
relapse, 8
relative dose intensity (RDI), 7,
140141
reproductive alterations, 388
391, 443t
respirators, 106
Response Evaluation Criteria in
Solid Tumors (RECIST)
guidelines, 8, 8t, 910
retching. See also nausea/vomiting
definition of, 190
reticulocytes, 181, 182t
retinoic acid syndrome, 287
288, 312314
risk evaluation and mitigation
strategy (REMS), 184
rituximab, 58, 75t
301t
romidepsin, 42t
routes of administration, 121
129
and neurotoxicity, 340
rubricytes, 180
ruxolitinib, 86t87t
479
S
safe handling/disposal, of hazardous drugs, 102115
safety standards, for antineoplastic administration, 100,
103f. See also patient safety
saline laxatives, 228
sargramostim (GM-CSF), 64t
for anemia, 187t
scalp hypothermia, for alopecia, 254
Scope and Standards of Oncology
Nursing Practice (ONS), 99
secondary cancers, 437440,
446t450t, 451
prevention of, 7
types of, 446450, 446t450t
secondary infections, with skin
toxicities, 246247
secretory diarrhea, 206
segmented neutrophils, 177
seizures, 340
selective serotonin reuptake inhibitors, 385
sensory neuropathy, 338, 339t
septic shock, 177. See also neutropenia
serotonin antagonists, for nausea/vomiting, 201t202t
sexuality, alterations in
agents causing, 384
386
short-term infusion, 125, 128
signal transduction, and targeted therapies, 60, 92f,
9293
sipuleucel-T, 60, 67t
skin exposure, to hazardous
drugs, 111
skin toxicities, 231, 232t241t,
250f252f. See also rash;
toxic erythema of chemotherapy
from chemoradiation, 248
grading of, 244, 245t
management of, 232t241t,
245246
nursing interventions, 244
246
psychosocial issues with, 247
248
and response/survival, 247
and secondary infections,
246247
small molecule inhibitors, 78t
91t
somatic pain, 344
sorafenib, 87t, 92
480

diarrhea from, 208
specific immunity, 52t, 5254,
53f
spill management, 112f, 112
114, 114f
stable disease (SD), 8, 8t
staging, of cancer, 23
standards of practice, 99
standard treatment regimens,
143
Stevens-Johnson syndrome
(SJS), 237t
stimulant laxatives, 228
stomatitis, 213
streptozocin, 44t
subcutaneous (SC) injection,
122
substance P, 191
sun exposure, 246
sunitinib, 87t, 92
diarrhea from, 208
suppositories, for constipation,
228
suppressor T cells (Ts), 5354
surgery, for cancer treatment, 5
survivorship care, 437438
elements of, 454
follow-ups during, 455456
models of, 455
nursing assessment in, 455
plan for, 454
resources for, 456t
syndrome of inappropriate
antidiuretic hormone
(SIADH), 329330
T
tacrolimus
tamoxifen
first used, 4t
sexuality alterations with, 385
targeted therapies. See also biotherapeutic agents; biotherapy
characteristics of, 60, 68t
91t, 93f
306t
taxanes, 45t46t. See also specific drugs

tbo-filgrastim, 62t
for anemia, 187t
T cells, 5455
tegafur-uracil, nausea/vomiting
from, 197t
telangiectasia, 237t
telogen effluvium, 251. See also
alopecia
telomeres, 348
temozolomide, 31t
197t
temsirolimus, 88t, 92
teniposide, 45t
tertiary cancer prevention, 7
testicular cancer
361t362t
thalidomide, 69t
thioguanine, 3t, 36t
thiotepa, 31t
thrombocytopenia
definition of, 171
thrombopoiesis, 184188
thrombopoietic growth factor,
for anemia, 187t
thrombotic microangiopathy,
331
topotecan, 44t
tositumomab, 76t
toxic epidermal necrolysis
(TEN), 238t
toxic erythema of chemotherapy
(TEC), 249, 249f
toxin-conjugated molecules, 59
transient erythema/urticaria, 240t
trastuzumab, 58, 77t
cardiotoxicity of, 265t, 280,
285, 285t
treatment plan, 7, 131132,

139140
nurses role in, 141142
patient understanding of, 142
trichomegaly, 232t, 244, 250f
tubulopathies, 329
tumor burden, 11
tumor doubling time, 1112
tumor escape mechanisms, 55
56
tumor lysis syndrome (TLS),
330331
tumor, node, metastasis (TNM)
staging system, 3
tumor response
measurement of, 710, 8t
2-chlorodeoxyadenosine, nausea/vomiting from, 195t
tyrosine kinase inhibitors, 93f.
diarrhea from, 208
tyrosine kinase receptors, 60, 92
U
unconjugated antibodies, 58
urinary alkalinization, 331
urticaria, transient, 240t
U.S. Food and Drug
Administration (FDA),
19, 23
V
vaccines, 5960
vagus nerve, 190
valrubicin, 40t
vandetanib, 89t
vascular abnormalities, 272275
vascular access devices (VADs),
infection from, 176177,
179180. See also neutropenia
vascular endothelial growth factor (VEGF), 9394
vascular endothelial growth factor (VEGF) inhibitors. See
also specific drugs
vascular endothelial growth factor receptor (VEGFR), 93
vemurafenib, 90t, 92
venlafaxine, 385
venous irritation, 155163, 157t
venous thromboembolism
(VTE), 274275
ventricular dilation, 277
verification of orders, 142143

vesicants. See also extravasation
IV administration of, 128
129, 155
vinblastine, 47t
vinca alkaloids, 47t. See also plant
alkaloids; specific drugs
vincristine, 47t
inadvertent IT administration
of, 102, 103f
vindesine, extravasation of, 159t
vinorelbine, 47t
as irritant, 162
197t
visceral pain, 344
vismodegib, 90t
vomiting. See also nausea/vomiting
definition of, 190
vomiting center (VC), 190, 191f
vorinostat, 42t
W
weight-based dosing, 146
wigs, 255
World Health Organization
(WHO)
oral assessment guide, 216
patient response scale, 10, 11t
tumor response criteria,
79, 8t
X
xerosis, 236t, 245t
Z
ziv-aflibercept, 91t
zoledronic acid, nephrotoxicity of, 334t
Zubrod scale, 10, 11t

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FOURTH EDITION

Oncology Nursing Society

ONS Publications Department

Printed in the United States of America

Integrity Innovation Stewardship Advocacy Excellence Inclusiveness

Kristine B. LeFebvre, MSN, RN, AOCN

Catherine E. Jansen, PhD, RN, AOCNS

Denise Menonna-Quinn, RN-BC, MSN,

Janice L. Skinner, RN, MS, MSN, CRNP

Amy S. Coghill, MSN, RN, OCN, CNL

Copyright 2014 by the Oncology Nursing Society. All rights reserved.

Copyright 2014 by the Oncology Nursing Society. All rights reserved.

DHHSU.S. Department of Health and Human

Copyright 2014 by the Oncology Nursing Society. All rights reserved.

PECprimary engineering control

Copyright 2014 by the Oncology Nursing Society. All rights reserved.

Overview of Cancer and

Figure 1. Clonal Evolution in Cancer

B. Cancer grading and staging

Chapter 1. Overview of Cancer and Cancer Treatment

b) The tumor, node, metastasis (TNM) staging system is maintained

Table 1. History of Cancer Therapy

Copyright 2014 by the Oncology Nursing Society. All rights reserved.

Table 1. History of Cancer Therapy (Continued)

Development of platinum compounds begins.

New classifications of drugs (e.g., taxanes) are developed.

Copyright 2014 by the Oncology Nursing Society. All rights reserved.

Chapter 1. Overview of Cancer and Cancer Treatment

2. Surgery (Drake & Lynes, 2010; Gillespie, 2011)

of the lethal doses of agents used; therefore, it must be followed by

Chapter 1. Overview of Cancer and Cancer Treatment

jective change in tumor size or in tumor product, and subjective

Absence of all known disease for at least 4

Disappearance of all target lesions

50% reduction of measurable tumor mass for

Growth of 25% or more, or development of

20% increase in the sum of diameters of target lesions

Unable to meet criteria for either partial response or progressive disease

Unable to meet criteria for either partial response or

RECISTResponse Evaluation Criteria in Solid Tumors; WHOWorld Health Organization

Chapter 1. Overview of Cancer and Cancer Treatment

[MRI]) have led to confusion regarding three-dimensional measurement

(e) The duration of stable disease is the time from initiation of

Chapter 1. Overview of Cancer and Cancer Treatment

Table 3. Performance Status Scales

Normal; no complaints; no evidence of disease

Able to carry on normal activity; minor signs or symptoms of disease

Cares for self; unable to carry on normal activity or do active work

Requires considerable assistance and frequent medical care

Disabled; requires special care and assistance

Severely disabled; hospital admission indicated although death not imminent

Very sick; hospital admission necessary; active supportive treatment necessary

Moribund; fatal processes progressing rapidly

Fully active; able to carry on all predisease performance without restriction

Minor restriction in physically strenuous play

Restricted in strenuous play; tires more easily, otherwise active

Both greater restrictions of and less time spent in active play

Ambulatory up to 50% of time; limited active play with assistance/supervision

Able to initiate quiet activities

Needs considerable assistance for quiet activity

Limited to very passive activity initiated by others (e.g., watching TV)

Completely disabled, not even passive play

Copyright 2014 by the Oncology Nursing Society. All rights reserved.

Chapter 1. Overview of Cancer and Cancer Treatment