Chemotherapy-Induced Cardiotoxicity in Children

Abstract

Introduction: With advances in clinical oncology, the burden of morbidity and mortality for cancer survivors due to the cardiac side effects of the chemotherapy is steadily increasing. Treatment-related cardiac damage is progressive and often irreversible. Primary prevention of cardiotoxicity during treatment is possible with strategies like limiting the cumulative anthracycline dose, the use of anthracycline structural analogs, and especially cardioprotective agents.
Areas Covered: This review covers the various cardiotoxic chemotherapeutic agents, the pathophysiology of cardiotoxicity due to anthracyclines, and the clinical and subclinical presentations and progression of childhood anthracycline cardiotoxicity. We also discuss preventive measures and strategies, especially the cardioprotectant agent dexrazoxane where there is strong evidence-based support for its use with anthracycline chemotherapy. However, there is a paucity of evidence-based recommendations for diagnosing and treating cancer therapy-induced cardiovascular complications. Finally, we discuss the potential of cardio-oncology.
Expert Opinion: There is no “safe” anthracycline dose if the goal is normal long-term cardiovascular status but higher lifetime cumulative doses of anthracyclines, higher dose rates, female sex, longer follow-up, younger age at anthracycline treatment, pre-existing cardiovascular disease, and cardiac irradiation are associated with more severe cardiotoxicity. With deeper understanding of the mechanisms of the adverse cardiac effects and identification of driver mutations causing these effects, personalized cancer therapy to limit cardiotoxic effects can be achieved, such as with the cardioprotectant dexrazoxane.

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Chemotherapy-induced cardiotoxicity in children
Neha Bansal, Shahnawaz Amdani, Emma R. Lipshultz & Steven E. Lipshultz
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Toxicology, DOI: 10.1080/17425255.2017.1351547
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REVIEW
Chemotherapy-induced cardiotoxicity in children
Neha Bansal
a
, Shahnawaz Amdani
a
, Emma R. Lipshultz
c
and Steven E. Lipshultz
a,b
a
Department of Pediatrics, Wayne State University School of Medicine and Children’s Hospital of Michigan, Detroit, MI, USA;
b
Karmanos Cancer
Institute, Detroit, MI, USA;
c
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
ABSTRACT
Introduction: With advances in clinical oncology, the burden of morbidity and mortality for cancer
survivors due to the cardiac side effects of the chemotherapy is steadily increasing. Treatment-related
cardiac damage is progressive and often irreversible. Primary prevention of cardiotoxicity during
treatment is possible with strategies like limiting the cumulative anthracycline dose, the use of
anthracycline structural analogs, and especially cardioprotective agents.
Areas covered: This review covers the various cardiotoxic chemotherapeutic agents, the pathophysiol-
ogy of cardiotoxicity due to anthracyclines, and the clinical and subclinical presentations and progres-
sion of childhood anthracycline cardiotoxicity. We also discuss preventive measures and strategies,
especially the cardioprotectant agent dexrazoxane where there is strong evidence-based support for its
use with anthracycline chemotherapy. However, there is a paucity of evidence-based recommendations
for diagnosing and treating cancer therapy-induced cardiovascular complications. Finally, we discuss
the potential of cardio-oncology.
Expert opinion: There is no ‘safe’anthracycline dose if the goal is normal long-term cardiovascular
status but higher lifetime cumulative doses of anthracyclines, higher dose rates, female sex, longer
follow-up, younger age at anthracycline treatment, pre-existing cardiovascular disease, and cardiac
irradiation are associated with more severe cardiotoxicity. With deeper understanding of the mechan-
isms of the adverse cardiac effects and identification of driver mutations causing these effects,
personalized cancer therapy to limit cardiotoxic effects can be achieved, such as with the cardiopro-
tectant dexrazoxane.
ARTICLE HISTORY
Received 28 March 2017
Accepted 3 July 2017
KEYWORDS
Childhood cancer;
anthracycline;
cardiotoxicity; survivorship;
cardio-oncology
1. Introduction
The burden of childhood cancer is large. Recent estimates
have revealed that >15,000 children are diagnosed with can-
cer every year in the United States [1]. With the advances in
management over the years, there has been a rise in the rate
of childhood cancer survivors from ~50% to ~80% from 1970
to 2010 [2,3]. As of 2005, nearly one-fourth of the almost
330,000 survivors of childhood cancer have survived longer
than 30 years since diagnosis [4]. The focus of care for these
survivors of childhood cancers has now shifted from not just
the early survival, but also toward the long-term outcomes
including chronic health conditions and health-related quality
of life in adult survivors of childhood malignancies [5,6].
Unfortunately, the same treatments that cure cancer also
increase the risk of adverse effects in other organ systems,
especially the cardiovascular system [7].
The onset of these cardiotoxic effects is categorized as
acute, or early or late chronic, depending on the time since
anthracycline administration [8–10]. It was reported as
early as the 1970s that patients receiving >500 mg/m
2
of
the anthracyclines doxorubicin or daunorubicin experi-
enced severe cardiotoxicity either during or shortly after
treatment [11]. Moreover, it has been noted that anthracy-
clines result in cardiotoxicity (decreased left ventricular
(LV) contractility and increased LV afterload) in a dose-
related fashion [12,13]. Newer treatment protocols with
limited chemotherapy dosing and accurate radiation tar-
geting have reduced the acute symptomatic cardiovascular
complications on frontline cancer treatment protocols sig-
nificantly to less than 1% [13]. However, it is now clear that
the cardiotoxicity of treatment is not limited to acute
complications and that long-term survivors are at risk for
progressive cardiovascular complications for the rest of
their lives (Table 1)[12,14–18]. An in-depth understanding
of the early and long-term sequela of antineoplastic drugs
and their effects on the cardiovascular system is essential
for not only the health-care professionals taking care of
these patients but also, for the professionals from the
pharmaceutical industry who will be instrumental in devel-
oping future drugs used for treatment.
2. Cardiotoxic therapies
Certain treatments of childhood cancer are cardiotoxic,
especially anthracyclines and tyrosine kinase inhibitors
(Table 2)[20]. Anthracyclines, such as doxorubicin, daunor-
ubicin, and epirubicin, are among the chemotherapeutic
agents commonly used to treat both hematologic
CONTACT Steven E. Lipshultz slipshultz@med.wayne.edu Department of Pediatrics, Wayne State University School of Medicine, Children’s Hospital of
Michigan, 3901 Beaubien Boulevard, Pediatric Administration-T121A, Detroit, MI 48201, USA
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, 2017
https://doi.org/10.1080/17425255.2017.1351547
© 2017 Informa UK Limited, trading as Taylor & Francis Group

malignancies and solid tumors, and they have improved
outcomes in patients with cancers such as acute lympho-
blastic leukemia (ALL) and sarcomas [21–25]. Anthracycline
therapy, however, is also a cardiotoxic cancer therapy and
is often dose limiting when clinically significant cardiotoxi-
city develops [24,26]. Anthracyclines cause several adverse
outcomes, which have been known and studied for dec-
ades. A study by Ewer et al. in doxorubicin-treated adult
oncology patients showed a correlation between the
cumulative doxorubicin dose and the grade of cardiotoxi-
city found on their endomyocardial biopsies by electron
microscopy [27]. More than 50% of childhood cancer sur-
vivors have been treated with anthracyclines and show
progressive cardiotoxicity [8]. The most important side
effect of this class of medications is long-term cardiotoxi-
city, which has been well established [28], and is a major
limitation of this class of medications [29,30]. The expres-
sion of heart failure (HF) in survivors treated with anthra-
cyclines ranges from 1% to 16% according to some studies,
but the true rate may be even greater with extended
follow-up [16,31].
3. Pathophysiology of cardiotoxicity
As Andreas Moritz has written in his 2005 book entitled
‘Cancer is Not a Disease –It’s a Survival Mechanism’:‘The
Article highlights
●The number of survivors of childhood cancers has increased expo-
nentially; survivors are at substantially increased long-term risk of
morbidity and mortality from treatment-related cardiotoxicity
●There is no ‘safe’dose of anthracycline but higher lifetime cumulative
doses of anthracyclines, higher dose rates, younger age at treatment,
longer follow-up after treatment, female sex, and cardiac irradiation
are associated with more severe cardiotoxicity.
●There is a paucity of evidence-based recommendations for diagnosing
and treating cancer therapy-induced cardiovascular complications.
●Treatment-related cardiac damage is progressive and often difficult
to reverse.
●The key points in management of these toxicities are: mitigation by
primary prevention and then effective management of the toxicity,
which has already occurred, in order to minimize ongoing morbidity.
●With deeper understanding of the mechanisms of the adverse cardiac
effects and identifications of driver mutations causing these effects,
personalized cancer therapy to limit cardiotoxic effects may be
achieved.
This box summarizes key points contained in the article.
Table 1. Characteristics of different types of anthracycline-associated cardiotoxicity.
Characteristic Acute cardiotoxicity
Early onset, chronic progressive
cardiotoxicity
Late-onset, chronic progressive
cardiotoxicity
Onset Within the first week of anthracycline treatment <1 year after completing anthracycline
therapy
>1 year after completing anthracycline
therapy
Risk factor
dependence
Unknown Yes Yes
Clinical features
in adults
Transient depression of myocardial contractility;
myocardial necrosis (cTnT elevation); arrhythmia
Dilated cardiomyopathy; arrhythmia Dilated cardiomyopathy; arrhythmia
Clinical features
in children
Transient depression of myocardial contractility;
myocardial necrosis (cTnT elevation); arrhythmia
Restrictive cardiomyopathy and/or
dilated cardiomyopathy; arrhythmia
Restrictive cardiomyopathy and/or
dilated cardiomyopathy; arrhythmia
Course Usually reversible on discontinuation of anthracycline Can be progressive Can be progressive
Reproduced with permission from [8].
Table 2. Cardiotoxic effects of selected cytotoxic agents.
Treatment Cardiotoxic effect
Anthracyclines:
Daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone
Arrhythmias, pericarditis, myocarditis, HF, LV dysfunction
Liposomal anthracyclines:
Pegylated liposomal doxorubicin hydrochloride (DOXIL®, CAELYX®)
HF, LV dysfunction, arrhythmias
Antimetabolites:
Capecitabine, carmustine, clofarabine, cytarabine, 5-fluorouracil,
methotrexate
Ischemia, chest pain, MI, HF, arrhythmias, pericardial effusions, pericarditis,
hemodynamic abnormalities
Antimicrotubule agents:
Paclitaxel, vinca alkaloids
Hypotension or hypertension, ischemia, angina, MI, bradycardia, arrhythmias,
conduction abnormalities, HF
Alkylating agents:
Busulfan, chlormethine, cisplatin, cyclophosphamide, ifosfamide,
mitomycin
Endomyocardial fibrosis, pericarditis, tamponade, ischemia, MI, hypertension,
myocarditis, HF, arrhythmias
Small-molecule tyrosine kinase inhibitors:
Dasatinib, gefitinib, imatinib mesylate, lapatinib, erlotinib, sorafenib,
sunitinib
HF, edema, pericardial effusion, pericarditis, hypertension, arrhythmias, prolonged QT
interval, ischemia, chest pain
Monoclonal antibodies:
Alemtuzumab, bevacizumab, cetuximab, rituximab, trastuzumab
Hemodynamic abnormalities, LV dysfunction, HF, thromboembolism, angioedema,
arrhythmias
Interleukins:
Denileukin, IL-2
Hypotension, capillary leak syndrome, arrhythmias, coronary artery thrombosis,
ischemia, LV dysfunction
Miscellaneous agents:
All-trans-retinoic acid, arsenic trioxide, asparaginase, etoposide, IFN-α,
lenalidomide, 6-mercaptopurine, pentostatin, teniposide, thalidomide
Electrocardiographic changes, QT prolongation, torsades de pointes, other
arrhythmias, ischemia, angina, MI, HF, edema, hypotension, bradycardia,
thromboembolism, and retinoid acid syndrome that includes fever, hypotension,
respiratory distress, weight gain, peripheral edema, pleural-pericardial effusions
HF: heart failure; LV: left ventricular; MI: myocardial infarction. Reproduced with permission from [19].
2N. BANSAL ET AL.

standard treatments for cancer are not meant to heal, but to
destroy.’As a result, antineoplastic agents by design work
most effectively on rapidly dividing malignant cells. But as a
consequence they also damage normal body cells with high
division rates thereby causing toxicity. Cardiomyocytes, unlike
bone marrow and other cells, are often terminally differen-
tiated cells that have a limited capacity to regenerate; hence,
they are particularly vulnerable to long-term damage from
these medications. Also, children are different from adults in
drug utilization rates and their subsequent effects. Children
have differences in drug metabolism (drug absorption, meta-
bolism, and excretion) and drug effects are more likely to have
long-term consequences following drug administration. With
continuously improving medical management, most survivors
of childhood cancer live for at least a decade after successful
treatment of their cancer [32]. The small, subclinical changes
due to the side effects of toxic chemotherapeutic medications
become more severe over a long period of time and cause
marked disability for childhood cancer survivors that may
often not be experienced by their adult malignancy survivor
counterparts.
A recent study showed that the mitochondria from adults
are ‘apoptosis refractory’[33]. In contrast, the mitochondria
from the heart and brain tissues in young mice and humans
are primed for apoptosis, predisposing them to undergo cell
death in response to genotoxic damage. This supports the
hypothesis that young pediatric cancer patients may be
more predisposed to the severe side effects of toxic
chemotherapy than adult cancer patients in whom this apop-
totic machinery is almost absent [33].
Various antineoplastic medications like cyclophosphamide,
cytosine arabinoside, cisplatin, ifosfamide, paclitaxel, 5-fluor-
ouracil, and amsacrine have been known to cause cardiomyo-
cyte damage. These groups of antineoplastic medications
express their effects in several ways including: (A) by their
inhibition of topoisomerase II activity thereby preventing
uncoiling of DNA and (B) by their intercalation into base
pairs of DNA. By doing this they, in turn, inhibit replication
and transcription of neoplastic cells [20,34].
The mechanism of anthracycline-induced cardiotoxicity
is complex but one of the acknowledged mechanisms is
the ‘oxidative stress hypothesis’(Figure 1)[36–39].
Cardiolipins, found abundantly on the inner cell mem-
brane of mitochondria have an increased affinity for
anthracyclines allowing for their increased entry [40,41].
Anthracyclines enter cells by passive diffusion and can
reach intracellular concentrations much higher than in
the extracellular compartments. By forming complexes
with iron intracellularly, anthracyclines lead to the produc-
tion of free radicals and reactive oxygen species, which
lead to cellular damage and death. They also cause cell
membrane damage by lipid peroxidation. Cardiomyocytes
have an abundance of mitochondria. Moreover, anthracy-
clines cause depletion of glutathione peroxidase (antiox-
idant) thus explaining the vulnerability of cardiomyocytes
to anthracycline-induced damage [42,43]. Several other
Figure 1. Potential opportunities for cardioprotection. Doxorubicin chemotherapy has a range of effects on cardiomyocytes. It induces lipid peroxidation at
the cell and mitochondrial membranes by way of complexing with Fe
2+
and induces apoptosis, mitochondrial DNA damage and energy depletion through its
production of ROS. Furthermore, it impairs Ca
2+
processing in the sarcoplasmic reticulum and inhibits the transcription of important muscle elements, weakening
the heart muscle. It also down-regulates adrenergic receptors and interrupts cell signaling. (1) Administration of dexrazoxane can prevent Fe
2+
complex formation.
(2) Intravenous immunoglobulin therapy can reduce inflammatory cytokines. (3) L-carnitine can bolster mitochondrial function. (4) Anti-HF therapies, such as
angiotensin-converting-enzyme inhibitors and β-blockers, can prevent further damage. Abbreviations: cTn, cardiac troponin; MLC2, myosin light chain 2; MM-CK,
myofibrillar isoform of the CK enzyme; ROS, reactive oxygen species; TOPII, topoisomerase 2. [Reproduced with permission from Nature Publishing Group [35].
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 3

mechanisms of cardiotoxicity include the upregulation of
nitricoxidesynthetaseandthealterationofgeneexpres-
sion, causing impaired creatine kinase activity and func-
tion in mitochondria [44,45]. By impairing mitochondrial
calcium regulation, they also cause instability of the mito-
chondrial membrane, decrease ATP synthesis, and ulti-
mately may cause cell death. Many of these subcellular
sequelae progress for weeks after exposure to anthracy-
clines providing insight into mechanisms of chronic cardi-
omyopathy [46].
Topoisomerase-II β(Top2β) alterations have also been
documented as a mechanism of doxorubicin-mediated car-
diotoxicity [47,48]. Top2βis an upstream target for anthra-
cyclines. It is found in terminally differentiated
cardiomyocytes. An animal study [49] comparing dexrazox-
ane and inorganic nitrates to prevent anthracycline cardi-
otoxicity revealed that while inorganic nitrates were
ineffective, dexrazoxane prevented all investigated mole-
cular, cellular, and functional perturbations that were
induced by daunorubicin. In that study, dexrazoxane con-
sistently and significantly depleted the Top2βprotein in
both primary neonatal cardiomyocytes and H9c2 cells as
well as in rabbit hearts. Studies by Ichikawa et al. [50], and
Zhang et al. [47], suggest that targeting both mitochon-
drial iron and topoisomerases is protective against the
cardiotoxicity of doxorubicin. A study by Martin et al. [51]
demonstrated that topoisomerase II-inactive 3-carbon lin-
ker bisdioxopiperazine, an analog of dexrazoxane, does
chelate iron and protect against doxorubicin-induced LDH
release from primary rat cardiomyocytes in vitro.Thissup-
ports the theory of Top2βmodulation by dexrazoxane as a
mechanism behind its cardioprotection. In a recent study,
the peripheral blood leukocytes’Top2βexpression was
higher in anthracycline-sensitive patients (patients who
demonstrated a decrease LV ejection fraction (LVEF) ≥
10% from baseline and who also showed an LVEF < 50%,
despite receiving a cumulative doxorubicin dose of
≤250 mg/m
2
) than in anthracycline-resistant patients
(who received a cumulative doxorubicin dosee of
≥450 mg/m
2
and who maintained an LVEF ≥50%) [52]. In
a mouse model, deleting cardiomyocyte Top2βprevented
anthracycline-induced cardiotoxicity [53]. This provides
new strategies for preventing anthracycline-induced cardi-
otoxicity and possible uses of Top2βas a surrogate marker
for assessing the susceptibility to anthracycline-induced
cardiotoxicity.
The susceptibility of cardiomyocytes to anthracyclines is
manifold and not hinged on a single theory. Cardiomyocytes
have a limited regenerative potential and hence once
damaged by chemotherapeutic agents, they may never
recover.
In addition to myocardial structural damage, antineoplastic
therapies may also affect the conduction tissue within the
heart that may lead to bradycardia (paclitaxel and thalido-
mide); arrhythmias and QT interval prolongation (amsacrine
and anthracyclines); myocardial ischemia via coronary vasos-
pasm (antimetabolites and 5-fluorouracil); LV dysfunction/HF
(anthracyclines, tyrosine kinase inhibitors, alkylating agents,
and cisplatin) (Table 3).
4. Progression of cardiotoxicity
Anthracycline cardiotoxicity can be categorized at the time of
presentation as either acute or chronic, with chronic toxicity
further categorized as early- or late-onset (Table 1)[55]. Acute
symptomatic cardiotoxicity presents in less than 1% of pedia-
tric patients being treated on frontline cancer protocols. It
may present within a few hours of infusion or during the
course of the treatment [8,13,55], and often manifests as
arrhythmias and electrocardiographic abnormalities.
Sometimes, at very high doses, it can present as HF or as a
myocarditis-pericarditis syndrome [8,13,55,56]. It generally
resolves on discontinuation of the treatment [8,56]. In a fol-
low-up study of survivors treated with anthracyclines and with
acute HF, all recovered temporarily, although nearly half later
had recurrent HF [12].
Early onset cardiomyopathy may show LV dysfunction, elec-
trocardiographic changes, or clinical HF [8,9,13,29,55,57].
According to our 2005 study, these anthracycline-treated pedia-
tric ALL patients initially developed a dilated cardiomyopathy
with reduced LV fractional shortening (LVFS) and LV contractility
along with LV dilation. Slowly, with time, it changed to a pattern
found in patients with a restrictive cardiomyopathy with normal
to reduced LV dimensions along with significantly reduced LV
wall thickness, LVFS, and LV contractility [58]. In 115 survivors of
ALL or osteosarcoma treated with the doxorubicin, 6 years after
treatment, LV wall thickness was decreased relative to body-
surface area which impaired LV systolic function, limited LV
contractility, and reduced cardiac output [12,15,16]. At 8 years
after treatment, we found that younger age at diagnosis and an
increased follow-up time were associated with decreased LV wall
thickness for body-surface area and female sex. We also observed
that an increased cumulative anthracycline dose was associated
with reduced LV contractility, indicating unhealthy heart muscle
(Figure 2)[15]. At the 12-year follow-up mark, we found that LV
mass for body-surface area, as well as LV contractility, progres-
sively declined, indicating that the health and growth of cardiac
muscle cells in the LV worsened (Figure 3)[16]. This study also
reported that even survivors who received low cumulative doses
of anthracyclines were still at risk for chronic cardiotoxicity years
after therapy, indicating that there is no safe dose of anthracy-
clines that leaves a long-term survivor completely free of asso-
ciated cardiovascular abnormalities. At a mean of 17.3-years
follow-up, these 115 survivors had a mean LV dimension
Table 3. Examples of pediatric chemotherapeutics agents associated with
cardiotoxicity.
Adverse effect Class/compound Pathogenesis
Bradycardia Taxanes/paclitaxel Hypersensitivity
Arrhythmias/QT
prolongation
Amsacrine
Anthracyclines
(doxorubicin)
Sunitinib
Anthracyclines
(doxorubicin)
Interference with HERG
currents
Inhibition of cardiac
kinases
Interference of ion
channels
Myocardial ischemia Antimetabolites/5-
fluorouracil
Coronary vasospasm
Left ventricular
dysfunction/HF
Anthracyclines
(doxorubicin), Cisplatin
Oxidative
Coronary artery fibrosis
HF: heart failure; HERG: human ether-a-go-go related.
Reproduced with permission from the American Heart Association [54].
4N. BANSAL ET AL.

z-score adjusted for body-surface area that decreased and the LV
posterior wall thickness z-score adjusted for body-surface area
subsequently increased, resulting in an abnormally reduced LV
thickness-to-dimension ratio, indicating pathologic LV remodel-
ing (Figure 4). This shrinking myocardial cavity for body-surface
area (which we have called‘Grinch Syndrome’), indicating a heart
too small for body size, is a chronic cardiomyopathy, which may
result in HF, heart transplantation, or premature death in long-
term survivors [61]. Abnormal LV structure and function, as well
as a restrictive-like cardiomyopathy pattern, are also found in
other long-term follow-up studies of other anthracycline-treated
survivors [62–64]. Endomyocardial biopsies from survivors with
chronic anthracycline cardiotoxicity display both individual car-
diomyocyte hypertrophy and cytoplasmic and nuclear enlarge-
ment [12,14]. There is evidence of late deterioration and death
>10 years after anthracycline therapy due to the replacement of
degenerated cardiomyocytes by fibrosis. Early acute toxicity pre-
sents with vacuolization and long-standing damage presents
with fibrosis. However, hemorrhage and edema have also been
reported in the biopsy. Endomyocardial biopsy has the advan-
tage of identifying the etiology of deterioration (e.g. infectious
myocarditis or monitoring the degree of anthracycline damage)
[65]. The LV faces the increasing afterload of the systemic circula-
tion and hence is likely more susceptible to or likely to demon-
strate anthracycline damage leading to systolic and diastolic
dysfunction than the right ventricle (RV). A study in rabbits
evaluated how the RV and the LV were affected in rabbits
exposed to daunorubicin [66]. They found that the RV was less
affected than the LV. Daunorubicin altered various sarcomeric
proteins in the LV, affected calcium regulation in the LV cardio-
myocytes, and caused extensive remodeling of the extracellular
matrix in the LV with lesser changes found in the RV. The RV
however is also affected. Historically, RV mechanics were more
difficult to assess with 2D echocardiographic imaging. Newer
studies have found that the RV is also affected by anthracycline
cardiotoxicity [67–69]. Treatment-related damage likely results in
both cardiac cell death and permanent injury to many of the
remaining cardiac cells, especially stem cell populations.
5. Cardiac monitoring
Given the increased prevalence of cardiotoxicity and cardiovas-
cular complications in anthracycline-treated childhood cancer
survivors, it is prudent to assess cardiac structure and function
on a periodic basis. Methods of assessing cardiac function (echo-
cardiography, cardiac MRI, and radionuclide ventriculography)
often detect abnormalities only after a certain degree of cardio-
myocyte damage has occurred. Hence, detecting myocardial
injury before irreversible damage has occurred can be challen-
ging. The guidelines published by Steinherz et al. [70]inthe
1990s for monitoring children during chemotherapy (utilizing
LVFS and LVEF, radionuclide angiography and endomyocardial
biopsy) were questioned by Lipshultz et al. as no evidence was
provided that such screening predicted early or late cardiac
adverse events, or improved overall quality of life for a patient
and their family over a lifespan [71]. For long-term monitoring,
the Children’s Oncology Group guidelines recommend life-long
echocardiographic screening every 3–5 years in survivors treated
with anthracyclines or cardiac radiation [72,73], which have been
further refined [74,75]. Although these guidelines may reduce
risk for HF in survivors, they are still not evidence based [74].
Echocardiography is a commonly used modality for monitor-
ing childhood cancer survivors. Modifying chemotherapeutic
dosage during oncologic therapy based on changes in echocar-
diographic measurements in anthracycline-treated childhood
cancer patients without symptomatic cardiovascular disease
should require evidence that withholding potentially lifesaving
chemotherapy will improve overall survival and quality of life.
Figure 2. Factors associated with cardiac abnormalities and progression to
left ventricular dysfunction in childhood cancer survivors who received
anthracyclines. [Reproduced by permission [59].
Figure 3. Changes in left ventricular structure and function over time,
reported as Z-scores, from a study of 115 survivors of childhood acute
lymphoblastic leukemia. The solid line is the overall group mean, and dashed
lines are the upper and lower bounds for the 95
t
% confidence interval for left
ventricular contractility (LV stress-velocity index). Dox, doxorubicin; CDM, dilated
cardiomyopathy; RCM, restrictive cardiomyopathy [Reproduced with permission
from [16].
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 5

With the current monitoring protocols the probability of HF is
low and hence utilizing traditional measures of evaluating car-
diac function (LVEF) as a monitoring tool has an unacceptably
low predictive value. Moreover, withholding chemotherapy in an
asymptomatic individual because of changes in LVEF is more
likely to cause oncologic treatment failure than decreasing the
likelihood of irreversible cardiac injury [76]. Other echocardiogra-
phy techniques are being utilized to evaluate LV systolic dysfunc-
tion (LV stress velocity index), LV diastolic function, global
ventricular function (myocardial performance index), and LV
mechanics (2-dimensional strain and strain rate) [77–81], but
they may have limited specificity to detect cardiomyocyte injury
[76]. More formal studies are needed to assess the impact of such
monitoring for long-term management.
Cardiac MRI may be beneficial to assess myocardial function,
ventricular mass, and subendocardial damage more accurately,
particularly when acoustic windows are limited. Although MRI
was able to detect acute as well as chronic subclinical signs of
cardiac involvement [82], how it correlates with subsequent
clinically significant endpoints is yet to be evaluated. Cardiac
MRI is also time consuming, has limited availability, and is costly,
thus, limiting the utility of this modality.
More recently, serum biomarkers of cardiotoxicity (cTnT, car-
diac troponin I [cTnI] and N-terminal pro-brain natriuretic pep-
tide [NT-proBNP]) are increasingly being used to monitor
childhood cancer patients for cardiotoxicity. Serum cTnT and
NT-proBNP have been validated as serum biomarkers for predict-
ing during anthracycline therapy which patients may subse-
quently experience years later cardiotoxicity as long-term
cancer survivors [18]. Lipshultz et al. evaluated the use of cardiac
biomarkers during anthracycline treatment in childhood cancer
patients [83]. We randomized 205 patients with high-risk ALL to
receive doxorubicin or doxorubicin with the cardioprotectant
dexrazoxane. Serum cTnT levels and NT-proBNP levels were
detectable or elevated for some children during the first
90 days of therapy. Measureable serum cTnT levels were signifi-
cantly associated with lower LV mass Z-scores and LV end-dia-
stolic posterior wall thickness Z-scores. They were also marginally
associated with a reduced LV thickness-to-dimension ratio
4 years later (Figure 5). Also, higher serum NT-proBNP levels
were associated with an abnormally reduced LV thickness-to-
Figure 5. Model-based estimated probability of having (a) an increased
cardiac troponin T (cTnT) concentration or (b) an elevated N-terminal pro-
brain natriuretic peptide (NT-proBNP) concentration in patients treated
with doxorubicin, with or without dexrazoxane. The doxorubicin-dexrazox-
ane group is indicated by the blue line, the doxorubicin group by the gold line.
Vertical bars show 95% confidence intervals. Increased cTnT is defined as a
value >0.01 ng/mL. *Pvs. dexrazoxane group ≤0.05; †Pvs. dexrazoxane group
≤0.001. An overall test for dexrazoxane effect during treatment was significant
(P< 0.001). Increased NT-proBNP is defined as a value ≥150 pg/mL for children
<1 year old and ≥100 pg/mL for children aged ≥1 year. *Pvs. dexrazoxane
group ≤0.05; †Pvs. dexrazoxane group ≤0.001. An overall test for dexrazoxane
effect during treatment was significant (P< 0.001) and after treatment was not
significant (P= 0.24). [Permission from American Society of Clinical Oncology ©
Lipshultz SE, et al. Lipshultz SE, Miller TL, Scully RE, et al. Changes in cardiac
biomarkers during doxorubicin treatment of pediatric patients with high-risk
acute lymphoblastic leukemia: associations with long-term echocardiographic
outcomes. Reproduced with permission from [83].
Figure 4. Stages in the development of pediatric ventricular dysfunction. Stages in the course of pediatric ventricular dysfunction. (1) Primary prevention is
possible at this stage by reducing risk factors in high-risk populations (such as those receiving anticancer therapy). (2) Secondary prevention is possible at this stage
to reduce the effects of the treatment-induced injury. (3) Secondary prevention is also possible at this stage. (4) Clinically significant conduction and rhythm
abnormalities might be observed. (5) Radical therapies might be required at this stage (such as heart transplant) if there is failure of medical management.
Preventive strategies are progressively less effective as the toxicity increases. Treatment strategies have a greater impact when used to treat the more-diseased
heart, but have longer effects if initiated early. Biomarkers and surrogate end points are potentially useful at early stages to alter the course with interventions, and
are potentially useful at later stages to aid decisions about transplantation [Reproduced with permission from Nature Publishing Group [60].
6N. BANSAL ET AL.

dimension ratio, suggesting pathologic LV remodeling by echo-
cardiography performed 4 years later. In addition, before, during,
and after treatment, a higher percentage of children had
increased levels of NT-proBNP (indicating increased myocardial
stress) than had abnormal cTnT levels (indicating cardiomyocyte
injury or death), suggesting that NT-proBNP may detect cardiac
stress before irreversible cardiomyocyte damage or cell death
[83]. Another study by Lipshultz et al. studied the cardiovascular
status of 156 childhood cancer survivors exposed and 45 unex-
posed to cardiotoxic therapy compared with 76 sibling controls
[18]. One of the important findings of this study was that both
exposed and unexposed survivors, compared to siblings, had
higher serum NT-proBNP levels (81.7 and 69.0 pg/ml, respec-
tively, vs. 39.4 pg/ml) suggesting increased myocardial stress in
both groups. In this study, we also showed that both exposed
and unexposed survivors had a higher age-adjusted, predicted-
to-ideal 30-year risk of myocardial infarction, stroke, or coronary
death [18]. This suggests that even childhood cancer survivors
not receiving cardiotoxic treatments have cardiovascular
abnormalities. Further research is needed in this area to evaluate
the utility of cardiac biomarkers in tailoring cancer chemother-
apy and improving long-term outcomes in these patients.
The optimal timing and frequency of cardiovascular monitor-
ing in cancer survivors remains controversial as the available
guidelines are not consistent in their recommendations and are
based on limited evidence. A comprehensive AHA scientific
statement summarizing a large amount of evidence in the field
of cardiotoxicity after treatment of cancer in children, adoles-
cents, and young adults was published by Lipshultz et al. which
may be valuable to clinicians in providing available evidence
related to the clinical care and monitoring of these patients [54].
6. Risk factors
There are several risk factors that contribute to late-onset
anthracycline-induced cardiotoxicity, including younger age
at treatment, increasing time since treatment, female sex,
higher cumulative doses, higher dose rates, elevations of
serum cTnT or NT-proBNP measurements before or during
anthracycline therapy, and HF during anthracycline therapy
[84](Table 4).
A comprehensive study by Lipshultz et al. [15] reviewing
120 children and adults treated with anthracyclines for ALL
and osteosarcoma revealed that female sex was an indepen-
dent risk factor cardiac abnormalities along with a higher dose
rate of doxorubicin administration. This has been confirmed in
other pediatric studies [87,88]. Anthracycline-induced cardio-
myopathy may be acute or subacute, occurring within 1 year
of treatment, or late, occurring several years post administra-
tion [55,57]. As mentioned, dilated cardiomyopathy may be
observed immediately after high-dose anthracycline treat-
ment. However, a restrictive cardiomyopathy (LV diastolic dys-
function) develops in many survivors over time, placing them
at risk for HF with preserved LV systolic function [84].
Many long-term follow-up studies have documented the
cardiac effects of anthracyclines. For example, among 755
patients with localized osteosarcoma treated with doxorubicin
(median age, 15 years; range, 3–40 years) the incidence of HF
(New York Heart Association Functional Heart Failure
Classification System’s moderate to severe HF classes II–IV)
was 1.7% (13/755) at a median follow-up of 8.5 years. Of
these 13 patients, 6 died and 3 needed a heart transplant
[23]. The incidence was higher in females and in those treated
with a higher cumulative anthracycline dose. Another retro-
spective longitudinal study of children less than 17 years old
with Ewing sarcoma found a high incidence of cardiotoxicity
as detected by echocardiography [89]. Of the 71 patients, LV
function, as assessed by LVEF, declined in 17 after completing
therapy. The strong association between the cumulative
anthracycline dose and cardiotoxicity appears to become
more important with time from treatment, as shown in a
study of nearly 5000 survivors treated with anthracyclines
who described their cardiac health at up to 30 years after
treatment [90]. A longitudinal study of 22 survivors with
Table 4. Risk factors for anthracycline-related cardiotoxicity.
Risk factor Notes References
Cumulative anthracycline
dose
Cumulative doses >500 mg/m
2
associated with significantly elevated long-term risk [12,13,15,16]
Length of post-therapy
interval
Incidence of clinically relevant cardiotoxicity increases progressively post-therapy [12,15,16]
Rate of anthracycline
administration
Prolonged administration to minimize circulating dose volume may decrease toxicity; results are mixed [85]
Individual anthracycline
dose
Higher individual anthracycline doses are associated with increased late cardiotoxicity, even when cumulative doses
are limited
[15,16]
Type of anthracycline Liposomal encapsulated preparations may reduce cardiotoxicity. Results for anthracycline analogs and cardiotoxicity
differences are conflicting
[29,59,86]
Radiation therapy Cumulative radiation dose >30 Gy; before or concomitant anthracycline treatment [9,55]
Concomitant therapy Trastuzumab, cyclophosphamide, bleomycin, vincristine, amsacrine, mitoxantrone may increase susceptibility/toxicity.
Others agents have also been implicated
[28,55]
Preexisting cardiac risk
factors
Hypertension; ischemic, myocardial, and valvular heart disease; prior cardiotoxic treatment [28]
Comorbidities Diabetes, obesity, renal dysfunction, pulmonary disease, sepsis, infection, endocrinopathies, electrolyte and metabolic
abnormalities, and pregnancy
[28]
Age Both young and advanced age at treatment are associated with elevated risk [12,15]
Sex Females are at greater risk than males [15]
Additional factors Trisomy 21; African American ancestry [13]
Reproduced with permission from [8].
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 7

malignant bone tumors treated with anthracyclines found that
adverse cardiac structural changes resulted in marked and
progressive cardiac dysfunction [91]. The risk of HF, valvar
disease, and pericardial disease in survivors is five times as
high as that of healthy siblings, and cardiac dysfunction will
develop in up to half of survivors within 20 years after anthra-
cycline treatment [90]. Despite the vast amount of data doc-
umenting the adverse cardiac effects of doxorubicin and other
anthracyclines, these drugs have remained critical compo-
nents of therapy for many years, particularly for patients
with hematologic malignancies and solid tumors.
Because cardiac abnormalities do not develop in all chil-
dren exposed to anthracyclines, and because the clinical
severity of such abnormalities varies greatly, determining the
factors that may increase their likelihood is greatly important.
As stated, higher cumulative doses of anthracyclines, higher
anthracycline dose rates, the use of concomitant cardiotoxic
therapies (such as mediastinal radiation), younger age at treat-
ment, increasing time since treatment, female sex, preexisting
cardiovascular disease including elevations in serum cTnT or
NT-proBNP concentrations measured before and during
anthracycline therapy, and HF during anthracycline therapy,
are risk factors for anthracycline cardiotoxicity [62,84].
Genetic factors can identify individuals at higher risk of
anthracycline cardiotoxicity and so may be useful in prevent-
ing cardiotoxicity [92]. This hypothesis is supported by the
greater cardiac susceptibility of patients with trisomy 21 and
black race [13,92,93]. Genetic variations and polymorphism of
the NAD(P)H oxidase and doxorubicin efflux transporters have
been shown to modulate and contribute to acute and chronic
cardiotoxicity associated with anthracycline [94].
Krajinovic et al. confirmed clinically relevant associations
between NOS3 and ABCC5 gene variants and their contribu-
tion to chronic cardiotoxicity following doxorubicin treatment
[95]. Patients with an A-1629 T genotype variant in the ABCC5
gene showed significantly more impaired LV function with
decreases in LVEF and shortening fractions. Another genotype
variant of the NOS3 gene, G-894 T, demonstrated a more
protective effect by showing a relative increase in the LVEF.
Given the importance of iron, and its potential genetic
involvement in anthracycline-induced cardiac injury, Lipshultz
et al. studied mutations of the hemochromatosis gene (HFE),
which is associated with hereditary hemochromatosis [96]. We
found that in 184 survivors of childhood ALL, 10% carried a
mutation in the HFE C282Y allele. Heterozygosity for C282Y
was associated with multiple elevations in cTnT concentra-
tions, indicating myocardial injury, after doxorubicin therapy,
when controlling for dexrazoxane treatment. The presence of
the C282Y mutation resulted in nearly a ninefold increased risk
of myocardial injury when these children with ALL were trea-
ted with doxorubicin when compared to similar children with-
out the C282Y allele. We also found that patients with the
C282Y and/or H63D allelic variants had significantly lower LV
function, LV mass, and wall thickness 2 years after diagnosis,
when compared to the normal population [96].
These studies, along with others [97], have shown that a
genetic predisposition exists for anthracycline-induced cardio-
toxicity. Genetic screening for these mutations may help guide
us in the future toward developing individual treatments for
susceptible patients and thus, limit the long-term incidence of
cardiotoxicity.
Despite these population-based risk factors, determining the
individual risk for a specific patient is still limited. Thus, at
present, all children who receive anthracycline therapy should
be followed closely during and after treatment for cardiotoxicity,
including long-term follow-up into adulthood. The above risk
factors are currently used to guide the frequency of follow-up
exams and may also help increase our understanding of the
underlying pathophysiologic mechanisms.
7. Treatment of anthracycline-induced
cardiotoxicity
Treating and curing cancer, in most cases, involves a multi-
modality approach. Children and adolescents with cancer are
at significant risk of cardiotoxicity and several additional
adverse effects that often have delayed onset from surgical
resection, chemotherapy, radiation, and newer biologic and
targeted therapies. Common drugs used in treating anthracy-
cline-induced cardiotoxicity are angiotensin-converting
enzyme inhibitors (ACEI), beta-blockers, and growth hormone
replacement therapy. However, despite these options, there
has been no established standard-of-care therapy for che-
motherapy-induced cardiac disease. Beta-blockers and ACEI
are standard-of-care medications for treating and managing
HF, but their effects on progression-free or overall survival
have not been established [54]. The benefial effect of enalapril,
an ACEI, in children or adolescents with cancer who developed
either asymptomatic LV dysfunction or HF delayed but did not
prevent progression of disease [85,98]. The goal of therapy is
to prevent or slow LV remodeling rather than to treat the
cause of cardiomyopathy [99]. This emphasizes the need for
new and specific strategies to treat anthracycline-related car-
diotoxicity and that methods of preventing these complica-
tions would be of great clinical utility.
ACEI were hypothesized to reduce LV afterload to compen-
sate for decreased LV wall thickness and to ease progression
of HF. However, ACEI did not provide a sustained benefit in
treating survivors with anthracycline-related cardiotoxicity,
raising concerns that the risks of these drugs may outweigh
their benefit in this population [85,98]. In our study that
examined 18 survivors who had received enalapril after treat-
ment with doxorubicin at Boston Children’s Hospital from
1984 to 1989, 6 of whom were in HF at the beginning of
therapy, during the first few years of enalapril therapy, mean
LV afterload and diastolic blood pressure were significantly
reduced [85]. Mean LVFS also improved, although LV wall
thickness did not. After 6–10 years on enalapril, these
improvements were no longer evident. Mean LV wall thickness
for body-surface area steadily declined. All 6 patients in HF
when enalapril therapy began had died or undergone heart
transplant, and 7 of the 12 originally asymptomatic patients
had progressed to HF. This study indicates that, although ACEI
may have had some short-term benefit, they did not prevent
the progression of disease nor have sustained effects.
In this survivor population, enalapril-induced improvement
in LV structure and function was transient. Enalapril did not
prevent, but merely delayed, progression, for a 6- to 10-year
8N. BANSAL ET AL.

benefit for patients with asymptomatic LV dysfunction before
returning to baseline. For enalapril-treated HF patients on this
study there was only a 2- to 6-year benefit. All HF patients
progressed to cardiac transplantation or cardiac death within
2–6 years [85,98]. Enalapril did not prevent progressive LV wall
thinning for body-surface area, the primary defect that results
in increased LV afterload and decreased LVFS. Limiting hyper-
trophic growth in a developing child may have detrimental
consequences over a lifespan related to the long-term exacer-
bation of inadequate hypertrophy for body-surface area
related to doxorubicin and then to enalapril. Enalapril did
not address the primary defect of an inappropriately thin LV
wall for body-surface area. Enalapril reduced LV afterload by a
short-term lowering of diastolic blood pressure and LV dilation
[85,98].
The ‘AAA’(ACEI After Anthracycline) randomized, double-
blind, placebo-controlled trial of enalapril of 146 childhood
cancer survivors showed that the only significant cardiac find-
ing was that there was a fall in LV end-systolic stress in the first
year of enalapril therapy based on a fall in blood pressure due
to ACEI (P= .036) [100].
It is important to understand the differences between
anthracycline cardiomyopathy (ACM) and dilated cardiomyo-
pathy (DCM). ACM differs from ischemic, postinfectious, and
idiopathic DCM. In both the AAA study [100] and our study
[54] there was a notable absence of ventricular remodeling in
response to the fall in LV wall stress. In most DCM patients,
ACEIs induce reverse ventricular remodeling with a reduction
in ventricular volume and an improved mass-to-volume ratio,
which further reduces wall stress and improves cardiac func-
tion. In both studies, despite a marked fall in wall stress,
ventricular size and thickness did not change. In contrast to
other forms of DCM, the natural history of ACM is character-
ized by minimal, nonprogressive dilation. The natural history
of ACM and the response to ACEI therapy is unlike that of
DCM, but is more characteristic of a restrictive cardiomyopa-
thy, a disease class that does not benefit from ACEI therapy.
Further, many AAA study participants also received cardiac
irradiation, a therapy also associated with the development
of a late restrictive cardiomyopathy.
It is important to note that the available data does not
address whether the risk of ACEI therapy in patients with
ACM exceeds those in other forms of DCM. Therefore, the
wisdom of recommending ACEI use based on the applicability
of trials conducted in other patient groups should be ques-
tioned. The clinical pattern of a dominantly restrictive cardio-
myopathy predicts a reduced likelihood of benefit. Current
data are also inadequate to address the risk associated with
ACEI therapy of asymptomatic LV dysfunction in this popula-
tion. Any adverse effects of long-term therapy clearly increase
the risks for these patients, purely on the basis of markedly
longer exposure. Further, these patients may be at increased
risk for potential adverse events. Therefore, these findings
argue against the routine use of ACEI therapy in patients
with asymptomatic LV dysfunction secondary to ACM.
There are a few theoretical ACEI concerns in this popula-
tion, using enalapril as an example. The first is that an excess
rate of gastrointestinal cancers relative to placebo has been
observed in several large trials of non-oncology adult patients
receiving pronged ACEI therapy [85,98]. This may be more of a
concern to younger cancer survivors already at increased risk
for relapsed primary or secondary malignancies. Second, sur-
vivors are at increased global risk for premature atherosclero-
tic heart disease, a risk that may also be affected by ACEI
therapy. As well, the unknown effects of chronic neurohormo-
nal suppression or other side effects of long-term enalapril
therapy in this population are a concern. Dizziness, hypoten-
sion, and fatigue were common problems for enalapril-treated
AAA participants [85,98]. The considerable cost of an unpro-
ven potentially life-long therapy in a young patient population
with large past medical expenses and lifetime insurance limits
is a risk in ACEI therapy. As well, there are compliance issues
for daily potentially lifelong ACEI use for asymptomatic
patients. The effects do not appear to last forever raising
other concerns. Understanding of other potentially adverse
drug interactions with this therapy for this population is
unknown. For females of childbearing age, ACEI use may
cause fetal kidney abnormalities if taken during pregnancy.
Finally, the potential for healthy, asymptomatic survivors to
feel or be treated differently from their peers for taking
chronic medications, may increase the likelihood of these
children feeling like ‘cardiac cripples.’[85,98]
The efficacy of ACEI therapy in anthracycline-treated, long-
term survivors of childhood cancer remains an unanswered,
but is an important question. No study has shown any bene-
ficial effects of ACEI in childhood survivors on improving
quality of life, long-term benefit, or reducing progression to
HF or death. The potential adverse effects of this therapy in
patients with ACM argue against using this therapy, especially
without convincing evidence of efficacy [85,98].
Beta-blockers, which are beta-adrenergic receptor antago-
nists, block sympathetic stimulation to the heart, among other
effects, and reduce cardiac demand, which is hypothesized to
slow the progression of anthracycline-related cardiotoxicity
[29]. Carvedilol is a frequently used beta-blocker as it simulta-
neously reduces cardiac demand as a nonselective beta-
blocker and reduces LV afterload as an alpha-1-blocker
through systemic vasodilation. In a randomized trial of 50
children with newly diagnosed ALL treated with doxorubicin,
with or without carvedilol pretreatment, treatment reduced LV
systolic function and increased plasma troponin I and lactate
dehydrogenase concentrations. Pretreatment with carvedilol
significantly increased LV systolic function and inhibited dox-
orubicin-induced increases in plasma troponin I and lactate
dehydrogenase concentrations. However, the follow-up was
short, so a sustained effect must still be examined [101]. A
more recent randomized controlled placebo-based trial in 91
women with breast cancer showed that the prophylactic use
of carvedilol inhibited anthracycline-induced cardiotoxi-
city [102].
8. Preventing cardiotoxicity
In addition to monitoring and treating cardiotoxicity among
survivors, preventing cardiotoxicity is now a priority.
Preventive medications given concurrently with chemother-
apy regimens, such as dexrazoxane and liposomal formula-
tions of doxorubicin, can reduce anthracycline-induced
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 9

cardiotoxicity, as can addressing the life-style risk factors for
anthracycline-induced cardiotoxicity [18]. The potential for
developing new and improved mechanisms to treat individual
patients based on their specific genetic traits and risk factors
should be considered when possible [95,96]. Cardioprotective
medications have been a primary focus for preventing anthra-
cycline-induced cardiotoxicity.
Dexrazoxane, first studied in beagles in the early 1980s
[103], prevents cardiotoxicity among women with advanced
breast cancer and has been approved by the US Food and
Drug Administration for this indication [104–107].
Dexrazoxane is believed to act in part by chelating iron and
ultimately interfering with iron-mediated free radicals
(Figure 1)[35,54,60,108]. Lyu et al. showed that dexrazoxane
shifts Top2’s configuration to a close-clamp form by tight
binding to Top2’s ATP-binding sites, preventing anthracyclines
from binding to the Top2 complex [109,110].
Since these initial studies in adults, several studies have
been conducted in children and adolescents with cancer trea-
ted with anthracyclines. In an open-label, randomized trial of
children and adolescents with sarcomas treated with doxoru-
bicin-containing chemotherapy, with or without dexrazoxane,
those receiving dexrazoxane had less subclinical cardiotoxicity,
smaller decreases in LVEF, and received higher cumulative
doses of doxorubicin with no difference in event-free or over-
all survival rates [22]. The Dana-Farber Cancer Institute’s
Childhood ALL Consortium Protocol 95–01 determined that
dexrazoxane was associated with decreased myocardial injury
among children with ALL treated with doxorubicin and also
determined that event-free survival was unchanged after a
median follow-up of 8.7 years [111–113]. Additionally, the
Children’s Oncology Group trials for localized and metastatic
osteosarcoma whose patients received both doxorubicin and
dexrazoxane showed no clinical evidence of cardiotoxicity
[114,115].
One concern about dexrazoxane has been whether or not it
reduces the oncologic efficacy of anthracycline therapy. To
date, no definitive studies suggest that dexrazoxane decreases
survival. In fact, a study of children and adolescents with
nonmetastatic osteosarcoma who were treated with both
dexrazoxane and doxorubicin showed that dexrazoxane did
not compromise response to induction chemotherapy [116].
As well, in comparing 5-year event-free survival in patients on
Pediatric Oncology Group Protocol POG 9404, there was no
difference in survival between patients randomly assigned to
treatment with or without dexrazoxane [112,113].
Another concern has been whether dexrazoxane is asso-
ciated with or a cause of secondary malignant neoplasms
(SMNs). Tebbi et al. reported in 2007 that dexrazoxane might
have increased the risk of SMNs among children with
Hodgkin’s disease treated with doxorubicin, bleomycin, vin-
cristine, and etoposide, with or without prednisone and cyclo-
phosphamide [117]. Their findings ultimately led the European
Medicines Agency in 2011 not to approve the use of dexra-
zoxane among children with cancer treated with anthracy-
clines [99]. Posted recommendations to the European
Medicines Agency in 2017 recommended amending the
2011 decision, which is likely to occur. Tebbi’s conclusion has
been disputed, however, particularly because the study was
not intended to determine whether SMNs were associated
with dexrazoxane [118]. Since then, multiple studies have
found that dexrazoxane is not associated with an increased
risk of SMNs and has no adverse effect on overall long-term
survival [110,119,120]. In fact, dexrazoxane may even help
protect against SMNs associated with doxorubicin [121]. With
very long-term follow-up of patients receiving dexrazoxane,
dexrazoxane cardioprotection was maintained [122].
In a recent meta-analysis of randomized trials and nonran-
domized observational studies with a pooled sample of 4639
children with cancer treated with an anthracycline, with or
without dexrazoxane, dexrazoxane was associated with a sta-
tistically significant reduction in most cardiotoxic outcomes
[123]. The authors also noted that the slightly higher risk of
SMNs in patients receiving dexrazoxane was more likely to be
related to the concurrent therapies than to dexrazoxane.
Among the five randomized trials analyzed, SMNs occurred
in 17 of 635 patients receiving dexrazoxane and 7 of 619
patients not receiving it. Importantly, only the two trials that
treated patients with both etoposide and dexrazoxane found
an increased rate of acute myelogenous leukemia. Only the
one trial using cranial radiation reported an increased risk of
secondary brain tumors among patients also receiving dexra-
zoxane. When these excess SMNs were removed from the
analysis, there was no difference between groups [123].
Thus, much evidence supports the conclusion that dexrazox-
ane prevents cardiotoxicity without adverse outcomes in a
wide range of cancers. The American Heart Association and
the American Academy of Pediatrics have endorsed dexrazox-
ane for use as a cardioprotectant among children and adoles-
cents undergoing anthracycline-containing protocols [54]. This
has been used as the standard of good clinical care on all DFCI
Childhood ALL Consortium protocols involving anthracycline
therapy since 2000 and has been required to be written into
all new COG protocols involving treatment with ≥150 mg/m
2
doxorubicin or anthracycline administration at any dose with
planned radiation treatment portals that may impact the heart
since 2015 [124].
There are certain other methods to prevent the cardiotoxi-
city caused by anthracyclines like analogs of anthracycline or
changes to the anthracycline delivery system [55], which can
be used, and are already approved in the adult population.
These include:
(1) Liposomal anthracyclines: Liposomal encapsulation of
doxorubicin helps to concentrate the drug in the
tumor cells and hence reduces their concentration in
blood [125,126]. The study by O’Brien et al. in adult
patients with metastatic breast cancer revealed that
treatment with liposomal formulation decreased the
incidence of cardiotoxicity by fivefold while having
comparable efficacy [127]. Another adult study on
patients with breast cancer revealed similar results
[128]. However, studies in pediatric patients are limited
[129,130].
(2) Anthracycline analogs: Extensive pediatric studies com-
paring head-to-head efficacy of analogs versus
10 N. BANSAL ET AL.

conventional anthracyclines have not been performed.
However, they may be beneficial in reducing anthracy-
cline cardiotoxicity, and further studies in this regard
may be helpful. Analogs include:
(a) Epirubicin: An epimer of anthracycline that was intro-
duced in the 1970s may be less cardiotoxic. However,
a randomized clinical trial in pediatric soft tissue
sarcoma patients involving 172 patients revealed no
difference in the cardiotoxicity in both groups at a
follow-up of 27.7 months (0% for epirubicin treated
vs. 0.9% for doxorubicin treated) [131].
(b) Idarubicin: Another analog that was studied in a
phase III trial revealed no difference in the incidence
of heart failure between groups treated with idaru-
bicin vs. daunorubicin [132].
(c) Mitoxantrone: This analog has a large volume of dis-
tribution and hence acts efficiently at the tissue level.
A systemic review of published literature by van Dalen
et al. [86]revealedthat0–6.7% patients had sympto-
matic mitoxantrone-induced cardiotoxicity and
0–80% had asymptomatic mitoxantrone-induced car-
diotoxicity. They concluded that in order to confirm
that mitoxantrone is less cardiotoxic than anthracy-
clines, a well-designed study should be undertaken.
However, the analogs and changes to the anthracycline deliv-
ery system’s effectiveness in preventing toxicity in children
have not been determined. Medications, such as ACEIs and
beta-blockers, both used to treat HF and hypertension, among
other disorders, can improve LV function in adults, but have
not provided long-term improvements in children.
9. Expert opinion
The pediatric drugs are often known as ‘therapeutic orphans’
in the drug market [133]. Pediatric clinical trials are plagued
with issues of recruitment, ethical considerations as well as
low profitability, which mar their success [134]. The number of
clinical trials enrolling children is far lower than for adults
[135]. There is a serious dearth of pediatric drug development,
and this has been acknowledged in the literature [136].
Breaking down silos across different disciplines is important,
as there is a current need to improve pediatric pharmacother-
apy and encourage collaborations between the community,
industry, and the United States government.
The number of cancer survivors in the United States in 2012
was 12 million and this number is expected to double by the
next decade [137]. Despite surviving their initial cancer, these
survivors face considerable morbidity and mortality as adults
due in part to the side effects of the chemotherapy they have
received. Doxorubicin has been a widely used effective ther-
apy in treating childhood cancers but it is now known to cause
a myriad of complications like arrhythmias, cardiomyopathy
and HF. Thus, it becomes important for physicians to detect
these cardiotoxic effects of these medications with close mon-
itoring and timely testing. Subclinical cardiac damage not
evident on echocardiography can be detected by biomarkers
like serum cTnT and NT-proBNP. Both the American Society of
Echocardiography and European Society of Medical Oncology
endorse the use of troponin for early recognition of the car-
diotoxicity during chemotherapy [138]. Surveillance should
begin early for these patients. The guidelines for the exact
method, duration, and the frequency of the surveillance are
currently controversial. So, further studies are needed to help
delineate the best and uniform recommendations, which can
then be used by clinicians in their daily practice. However,
short of acute myocardial infarction levels of serum cTnT, it is
not possible to make evidence-based decisions about with-
holding potentially lifesaving chemotherapy if there are eleva-
tions of serum levels of these cardiac biomarkers. No trial has
been performed that compares conventional management
versus cardiac biomarker guided management to see if the
overall outcomes of morbidity, mortality, and quality of life are
improved with cardiac biomarker-guided management.
Higher lifetime cumulative doses of anthracycline and
higher dose rates are risk factors for late cardiotoxicity [139].
However, even doses as low as 250 mg/m
2
have been shown
to cause cardiac damage, proving that there is not a cumula-
tive dose of anthracycline that is free of late echocardio-
graphic abnormalities in long-term survivors [58].
Unfortunately, no evidence-based specific therapy has been
established as the standard-of-care for cardiac disease second-
ary to chemotherapy or radiation. Beta-blockers and ACEIs, for
example, are standard-of-care medications for preventing and
treating HF, but their effects on progression-free or overall
survival, or even quality of life among survivors, have not
been established [54], and the benefial effect of the ACEI
enalapril in this population with either asymptomatic LV dys-
function or HF was transient, delaying but not preventing
progression [85,98]. Their use in some survivors with restrictive
cardiomyopathy may be detrimental and the fact that they
exaccerbated inadequate LV hypertrophy may be concerning
in their future [85,98]. Growth hormone replacement therapy
increases LV wall thickness closer to normal but does not
delay or prevent cardiomyopathy in survivors [84]. Thus, pri-
mary prevention of anthracycline cardiomyopathy is essential.
Less cardiotoxic analogs like epirubicin, as well as liposomal
encapsulation of doxorubicin, which help to concentrate the
drug in the tumor cells and decrease overall side effects, have
shown some promise in treatment of the childhood cancers
but have not been well studied. Cardioprotective medications
have been a primary focus for preventing anthracycline-
induced cardiotoxicity. Administering dexrazoxane with
anthracycline chemotherapy, beginning before the first dose
of anthracycline therapy, provides the best cardioprotection.
In a recent long-term study, dexrazoxane proved to be very
effective as a cardioprotectant and did not compromise anti-
tumor efficacy or increase second malignancies [113].
There is often a building pressure on the pharmaceutical
industry and the US FDA to expedite the approval of new
drugs for faster improvement in clinical outcomes. However,
if that is done, there should be a requirement for patients who
received these drugs to participate in phase 4 confirmatory
trials to establish their long-term safety and efficacy. When the
US FDA grants an early approval to these drugs, there is often
much less known about the long-term, multiorgan toxicity of
these agents, especially when used in combination therapy.
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 11

For example, in adults, newer medications like immune check-
point inhibitors have proven to improve clinical outcomes in
various cancers like melanoma [140]. However, recent reports
of fulminant myocarditis even with these new medications
show that clinicians need to be extremely vigilant for cardio-
vascular toxicities even with these newer therapeutic agents
[141]. Although these medications are currently used in adults,
they will soon be utilized in the pediatric population. Reports
like these, along with symptoms and functional surveys, may
help to capture late toxicities from therapeutic agents in long-
term survivors of childhood cancer.
According to the current estimates, the number of survivors
of cancer is predicted to be about 20 million in the next
decade [142]. This significant number warrants better under-
standing of the development of toxicities, effects of chronic
toxicities by the various cancer therapeutic agents as well as
‘tolerability’of these late toxic effects by the survivors. We
need to learn the effects of possible treatment holidays, which
may affect both toxicity and efficacy of cancer management.
Often, patients with significant comorbidities or those who are
heavily pretreated as high-risk patients in treatment regimens
are often neglected or excluded in clinical trials. However,
these are the patients who often develop severe toxicity. We
need to add our patients as partners in our fight against
cancer and engage them to grasp what is tolerable and
acceptable by these survivors. Educating and engaging our
patients will also help with treatment decisions and treatment
adherence, which in turn improves outcomes. It is important
to account for patient-reported outcomes or effects as the
creation of this new feedback mechanism is critical and a
potential opportunity for us to develop a better understand-
ing of toxicity development.
There is a growing need for improving the preventive
strategies for other side effects like HF in the treatment of
childhood cancer. The National Institutes of Health has con-
ducted a workshop, published a white paper, and established
a funding mechanism (PA-16–035, PA-16–036) for the study of
basic clinical research relevant to cardio-oncology [143]. The
US National Cancer Institute’s Provocative Questions initiative
(PQ 9 specifically) and innovative seed funding programs such
as the HESI-Pardee THRIVE Initiative provide funding to con-
duct research [144]. Using these resources, a huge network of
expertise is developing to prevent, predict, and further man-
age treatment-related toxicities. There is a need to create new
implementation initiatives, which include: (1) Sponsor studies
and post-market surveillance. (2) New non-label adverse event
reporting to the US FDA. (3) Label changes and usage
changes. (4) Acute/chronic effects that impact adherence,
morbidity, mortality, and quality of life.
With the recent advances in oncology, identification of
driver mutations like Top2β, and deeper understanding of
the mechanisms of the cardiotoxicities secondary to cancer
therapy, we may be able to rapidly develop personalized
cancer therapies based on the identification of these driver
mutations [145]. These driver mutations may help predict
sensitivities of certain patients to toxicities and thus help
make decisions on the choice of therapy. This would enable
the clinicians to be more proactive with symptom mitiga-
tion, and aid in considering alternative approaches or dosing
schedules. Current research should focus on known knowl-
edge, identifying remaining gaps, potential limitations of
cancer therapy, and appropriate management of the toxici-
ties. The available resources should focus on the scope of
needed future research potential in the field of cardio-oncol-
ogy and acknowledge the balance in managing and treating
the adverse effects in this population in the absence of
novel action and roles. This research has the potential to
predict and recognize important mechanistic reasons of
these toxicities, which may further lead to novel therapeutic
mitigation strategies. There are exciting future opportunities
in drug development and clinical medicine in the field of
cardio-oncology as there is attainable room to improve
long-term follow-up care to help survivors thrive post
treatment.
Funding
The contents in this review chapter were supported in part by grants from
the National Institutes of Health (HL072705, HL078522, HL053392,
CA127642, CA068484, HD052104, AI50274, HD52102, HL087708,
HL079233, HL004537, HL087000, HL007188, HL094100, HL095127, and
HD80002), the National Heart, Lung, and Blood Institute (R01 HL53392,
R01 HL111459, R01 HL109090), the Children’s Cardiomyopathy
Foundation, the Women’s Cancer Association, the Lance Armstrong
Foundation, the STOP Children’s Cancer Foundation, the Parker Family
Foundation, the Scott Howard Fund, the Michael Garil Fund, Sofia’s Hope,
the Kyle John Rymiszewski Foundation.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
References
Papers of special note have been highlighted as either of interest (•)orof
considerable interest (••) to readers.
1. Ward E, DeSantis C, Robbins A, et al. Childhood and adolescent
cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):83–103.
2. Ries LAG, Smith MA, Gurney JG, et al., editors. Cancer incidence and
survival among children and adolescents: United States SEER pro-
gram 1975–1995, National Cancer Institute, SEER Program. NIH
Pub; Bethesda, MD; 1999. No. 99-4649.
3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J
Clin. 2015;65(1):5–29.
4. Mariotto AB, Rowland JH, Yabroff KR, et al. Long-term survivors of
childhood cancers in the United States. Cancer Epidemiol
Biomarkers Prev. 2009;18(4):1033–1040.
5. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions
in adult survivors of childhood cancer. N Engl J Med. 2006;355
(15):1572–1582.
6. Hudson MM, Mertens AC, Yasui Y, et al. Health status of adult long-
term survivors of childhood cancer: a report from the childhood
cancer survivor study. JAMA. 2003;290(12):1583–1592.
7. Armstrong GT, Kawashima T, Leisenring W, et al. Aging and risk of
severe, disabling, life-threatening and fatal events in the childhood
cancer survivor study. J Clin Oncol. 2014;32(12):1218–1227.
8. Lipshultz SE, Alvarez JA, Scully RE. Anthracycline associated cardi-
otoxicity in survivors of childhood cancer. Heart. 2008;94(4):525–
533.
12 N. BANSAL ET AL.

9. Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and
radiation-associated cardiomyopathies: implications for screening
and prevention. Pediatr Blood Cancer. 2005;44(7):600–606.
10. Franco VI, Henkel JM, Miller TL, et al. Cardiovascular effects in
childhood cancer survivors treated with anthracyclines. Cardiol
Res Pract. 2011;2011:134679.
11. Gilladoga AC, Manuel C, Tan CT, et al. The cardiotoxicity of adria-
mycin and daunomycin in children. Cancer. 1976;37(2 Suppl):1070–
1078.
12. Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac effects of
doxorubicin therapy for acute lymphoblastic leukemia in child-
hood. N Engl J Med. 1991;324(12):808–815.
13. Krischer JP, Epstein S, Cuthbertson DD, et al. Clinical cardiotoxicity
following anthracycline treatment for childhood cancer: the
Pediatric Oncology Group experience. J Clin Oncol. 1997;15
(4):1544–1552.
14. Goorin AM, Chauvenet AR, Perez-Atayde AR, et al. Initial congestive
heart failure, six to ten years after doxorubicin chemotherapy for
childhood cancer. J Pediatr. 1990;116(1):144–147.
15. Lipshultz SE, Lipsitz SR, Mone SM, et al. Female sex and higher drug
dose as risk factors for late cardiotoxic effects of doxorubicin
therapy for childhood cancer. N Engl J Med. 1995;332(26):1738–
1743.
16. Lipshultz SE, Lipsitz SR, Sallan SE, et al. Chronic progressive cardiac
dysfunction years after doxorubicin therapy for childhood acute
lymphoblastic leukemia. J Clin Oncol. 2005;23(12):2629–2636.
•• A longitudinal prospective study examining the course of LV
structure and function. This study found that after 11.8 years
abnormalities of cardiac structure and function were persistent
and progressive in children diagnosed with ALL treated with
any amount of doxorubicin, but were particularly worse in
children who received >300 mg/m
2
.
17. Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascular status in long-
term survivors of Hodgkin’s disease treated with chest radiother-
apy. J Clin Oncol. 2004;22(15):3139–3148.
18. Lipshultz SE, Landy DC, Lopez-Mitnik G, et al. Cardiovascular status
of childhood cancer survivors exposed and unexposed to cardio-
toxic therapy. J Clin Oncol. 2012;30(10):1050–1057.
•• A prospective cohort study of children with high-risk ALL
examining the association between changes in cardiac biomar-
kers during treatment and late LV structure and function. This
study found that increased serum levels of cardiac biomarkers,
cTnT, and NT-proBNP, during the first 90 days of anthracycline
treatment were associated with worse cardiac function and
structure 4 years later. These findings suggest the potential
use of cardiac biomarkers for the early detection of cardiotoxi-
city in children with high-risk ALL.
19. Zerra P, Cochran TR, Franco VI, et al. An expert opinion on phar-
macologic approaches to reducing the cardiotoxicity of childhood
acute lymphoblastic leukemia therapies. Expert Opin
Pharmacother. 2013;14(11):1497–1513.
20. Simbre VC, Duffy SA, Dadlani GH, et al. Cardiotoxicity of cancer
chemotherapy: implications for children. Paediatr Drugs. 2005;7
(3):187–202.
21. Steinherz LJ, Steinherz PG, Tan CT, et al. Cardiac toxicity 4 to 20
years after completing anthracycline therapy. JAMA. 1991;266
(12):1672–1677.
22. Wexler LH, Andrich MP, Venzon D, et al. Randomized trial of the
cardioprotective agent ICRF-187 in pediatric sarcoma patients trea-
ted with doxorubicin. J Clin Oncol. 1996;14(2):362–372.
23. Longhi A, Ferrari S, Bacci G, et al. Long-term follow-up of patients
with doxorubicin-induced cardiac toxicity after chemotherapy for
osteosarcoma. Anticancer Drugs. 2007;18(6):737–744.
24. Dolci A, Dominici R, Cardinale D, et al. Biochemical markers for
prediction of chemotherapy-induced cardiotoxicity: systematic
review of the literature and recommendations for use. Am J Clin
Pathol. 2008;130(5):688–695.
25. Lipshultz ER, Holt GE, Ramasamy R, et al. Fertility, cardiac, and
orthopedic challenges in survivors of adult and childhood sarcoma.
Am Soc Clin Oncol Educ Book. 2017;37:799–806.
26. Elbl L, Hrstkova H, Tomaskova I, et al. Long-term serial echocardio-
graphic examination of late anthracycline cardiotoxicity and its
prevention by dexrazoxane in paediatric patients. Eur J Pediatr.
2005;164(11):678–684.
27. Ewer MS, Ali MK, Mackay B, et al. A comparison of cardiac biopsy
grades and ejection fraction estimations in patients receiving adria-
mycin. J Clin Oncol. 1984 Feb;2(2):112–117.
28. Levitt G, Anazodo A, Burch M, et al. Cardiac or cardiopulmonary
transplantation in childhood cancer survivors: an increasing need?
Eur J Cancer. 2009;45(17):3027–3034.
29. Barry E, Alvarez JA, Scully RE, et al. Anthracycline-induced cardio-
toxicity: course, pathophysiology, prevention and management.
Expert Opin Pharmacother. 2007;8(8):1039–1058.
30. Nysom K, Holm K, Lipsitz SR, et al. Relationship between cumula-
tive anthracycline dose and late cardiotoxicity in childhood acute
lymphoblastic leukemia. J Clin Oncol. 1998;16(2):545–550.
31. Kremer LC, van Dalen EC, Offringa M, et al. Frequency and risk
factors of anthracycline-induced clinical heart failure in children: a
systematic review. Ann Oncol. 2002;13(4):503–512.
32. Silverman LB, Stevenson KE, O’Brien JE, et al. Long-term results of
Dana-Farber Cancer Institute ALL Consortium protocols for children
with newly diagnosed acute lymphoblastic leukemia (1985–2000).
Leukemia. 2010;24(2):320–334.
33. Sarosiek KA, Fraser C, Muthalagu N, et al. Developmental regulation of
mitochondrial apoptosis by c-myc governs age- and tissue-specific
sensitivity to cancer therapeutics. Cancer Cell. 2017;31(1):142–156.
34. Fulbright JM. Review of cardiotoxicity in pediatric cancer patients:
during and after therapy. Cardiol Res Pract. 2011;2011:1–9.
35. Hutchins KK, Siddeek H, Franco VI, et al. Prevention of cardiotoxi-
city among survivors of childhood cancer. Br J Clin Pharmacol.
2017;83(3):455–465.
36. Lebrecht D, Setzer B, Ketelsen UP, et al. Time-dependent and
tissue-specific accumulation of mtDNA and respiratory chain
defects in chronic doxorubicin cardiomyopathy. Circulation.
2003;108(19):2423–2429.
37. Minotti G, Menna P, Salvatorelli E, et al. Anthracyclines: molecular
advances and pharmacologic developments in antitumor activity
and cardiotoxicity. Pharmacol Rev. 2004;56(2):185–229.
38. Horenstein MS, Vander Heide RS, L’Ecuyer TJ. Molecular basis of
anthracycline-induced cardiotoxicity and its prevention. Mol Genet
Metab. 2000;71(1–2):436–444.
39. Gianni L, Herman EH, Lipshultz SE, et al. Anthracycline cardiotoxi-
city: from bench to bedside. J Clin Oncol. 2008;26(22):3777–3784.
40. Nicolay K, van der Neut R, Fok JJ, et al. Effects of adriamycin on
lipid polymorphism in cardiolipin-containing model and mitochon-
drial membranes. Biochim Biophys Acta. 1985;819(1):55–65.
41. Leonard RC, Williams S, Tulpule A, et al. Improving the therapeutic
index of anthracycline chemotherapy: focus on liposomal doxoru-
bicin (Myocet). Breast. 2009;18(4):218–224.
42. Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of the
mouse heart against reactive oxygen metabolites: alterations pro-
duced by doxorubicin. J Clin Invest. 1980;65(1):128–135.
43. Simunek T, Sterba M, Popelova O, et al. Anthracycline-induced
cardiotoxicity: overview of studies examining the roles of oxidative
stress and free cellular iron. Pharmacol Rep. 2009;61(1):154–171.
44. Chen B, Peng X, Pentassuglia L, et al. Molecular and cellular
mechanisms of anthracycline cardiotoxicity. Cardiovasc Toxicol.
2007;7(2):114–121.
45. Ito H, Miller SC, Billingham ME, et al. Doxorubicin selectively inhi-
bits muscle gene expression in cardiac muscle cells in vivo and in
vitro. Proc Natl Acad Sci USA. 1990;87(11):4275–4279.
46. Tokarska-Schlattner M, Zaugg M, Zuppinger C, et al. New insights
into doxorubicin-induced cardiotoxicity: the critical role of cellular
energetics. J Mol Cell Cardiol. 2006;41(3):389–405.
47. Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the molecular
basis of doxorubicin-induced cardiotoxicity. Nat Med. 2012;18
(11):1639–1642.
48. Khiati S, Dalla Rosa I, Sourbier C, et al. Mitochondrial topoisomerase
I (top1mt) is a novel limiting factor of doxorubicin cardiotoxicity.
Clin Cancer Res. 2014;20(18):4873–4881.
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 13

49. Lenčová-Popelová O, Jirkovský E, Jansová H, et al. Cardioprotective
effects of inorganic nitrate/nitrite in chronic anthracycline cardio-
toxicity: comparison with dexrazoxane. J Mol Cell Cardiol. 2016
Feb;29(91):92–103.
50. Ichikawa Y, Ghanefar M, Bayeva M, et al. Cardiotoxicity of doxor-
ubicin is mediated through mitochondrial iron accumulation. J Clin
Invest. 2014 Feb 3;124(2):617–630.
51. Martin E, Thougaard AV, Grauslund M, et al. Evaluation of the
topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protec-
tant against doxorubicin-induced cardiomyopathy. Toxicology.
2009 Jan 8;255(1–2):72–79.
52. Ong DS, Aertker RA, Clark AN, et al. Radiation-associated valvular
heart disease. J Heart Valve Dis. 2013;22(6):883–892.
53. Vejpongsa P, Yeh ET. Topoisomerase 2beta: a promising molecular
target for primary prevention of anthracycline-induced cardiotoxi-
city. Clin Pharmacol Ther. 2014;95(1):45–52.
54. Lipshultz SE, Adams MJ, Colan SD, et al. Long-term cardiovascular
toxicity in children, adolescents, and young adults who receive
cancer therapy: pathophysiology, course, monitoring, manage-
ment, prevention, and research directions: a scientific statement
from the American Heart Association. Circulation. 2013;128
(17):1927–1995.
•• A scientific statement endorsed by the American Heart
Association and the American Academy of Pediatrics regarding
cardiotoxicity in survivors of childhood cancer.
55. Giantris A, Abdurrahman L, Hinkle A, et al. Anthracycline-induced
cardiotoxicity in children and young adults. Crit Rev Oncol
Hematol. 1998;27(1):53–68.
56. Bristow MR, Mason JW, Billingham ME, et al. Doxorubicin cardio-
myopathy: evaluation by phonocardiography, endomyocardial
biopsy, and cardiac catheterization. Ann Intern Med. 1978;88
(2):168–175.
57. Grenier MA, Lipshultz SE. Epidemiology of anthracycline cardiotoxi-
city in children and adults. Semin Oncol. 1998;25(4 Suppl 10):72–
85.
58. Trachtenberg BH, Landy DC, Franco VI, et al. Anthracycline-asso-
ciated cardiotoxicity in survivors of childhood cancer. Pediatr
Cardiol. 2011;32(3):342–353.
59. Wouters KA, Kremer LC, Miller TL, et al. Protecting against anthra-
cycline-induced myocardial damage: a review of the most promis-
ing strategies. Br J Haematol. 2005;131:561–578.
60. Lipshultz SE, Cochran TR, Franco VI, et al. Treatment-related cardi-
otoxicity in survivors of childhood cancer. Nat Rev Clin Oncol.
2013;10(12):697–710.
61. Lipshultz SE, Scully RE, Stevenson KE, et al. Hearts too small for
body size after doxorubicin for childhood leukemia: Grinch syn-
drome. J Clin Oncol. 2014;32:10021(abstract).
62. Armenian SH, Gelehrter SK, Vase T, et al. Screening for cardiac
dysfunction in anthracycline-exposed childhood cancer survivors.
Clin Cancer Res. 2014;20(24):6314–6323.
63. Sorensen K, Levitt GA, Bull C, et al. Late anthracycline cardiotoxicity
after childhood cancer: a prospective longitudinal study. Cancer.
2003;97(8):1991–1998.
64. Ganame J, Claus P, Uyttebroeck A, et al. Myocardial dysfunction
late after low-dose anthracycline treatment in asymptomatic pedia-
tric patients. J Am Soc Echocardiogr. 2007;20(12):1351–1358.
65. Pegelow CH, Popper RW, DeWit SA, et al. Endomyocardial biopsy to
monitor anthracycline therapy in children. J Clin Oncol. 1984;2:443–
446.
66. Lenčová-Popelová O, Jirkovský E, Mazurová Y, et al. Molecular
remodeling of left and right ventricular myocardium in chronic
anthracycline cardiotoxicity and post-treatment follow up. PloS
One. 2014 May 7;9(5):e96055.
67. Calleja A, Poulin F, Khorolsky C, et al. Right ventricular dysfunction
in patients experiencing cardiotoxicity during breast cancer ther-
apy. J Oncol. 2015 Aug 3;2015:1–10.
68. Boczar KE, Aseyev O, Sulpher J, et al. Right heart function deterio-
rates in breast cancer patients undergoing anthracycline-based
chemotherapy. Echo Res Pract. 2016 Sep 1;3(3):79–84.
69. Tadic M, Cuspidi C, Hering D, et al. The influence of chemotherapy
on the right ventricle: did we forget something? Clin Cardiol. 2017;
doi: 10.1002/clc.22672.
70. Steinherz LJ, Graham T, Hurwitz R, et al. Guidelines for cardiac
monitoring of children during and after anthracycline therapy:
report of the Cardiology Committee of the Childrens Cancer
Study Group. Pediatrics. 1992;89(5 Pt 1):942–949.
71. Lipshultz SE, Sanders SP, Goorin AM, et al. Monitoring for anthra-
cycline cardiotoxicity. Pediatrics. 1994;93(3):433–437.
72. Shankar SM, Marina N, Hudson MM, et al. Monitoring for cardio-
vascular disease in survivors of childhood cancer: report from the
Cardiovascular Disease Task Force of the Children’s Oncology
Group. Pediatrics. 2008;121(2):e387–396.
73. Landier W, Bhatia S, Eshelman DA, et al. Development of risk-based
guidelines for pediatric cancer survivors: the Children’s Oncology
Group long-term follow-up guidelines from the Children’s
Oncology Group late effects committee and nursing discipline. J
Clin Oncol. 2004;22(24):4979–4990.
74. Wong FL, Bhatia S, Landier W, et al. Cost-effectiveness of the
Children’s Oncology Group long-term follow-up screening guide-
lines for childhood cancer survivors at risk for treatment-related
heart failure. Ann Intern Med. 2014;160(10):672–683.
75. Steingart RM, Liu JE, Oeffinger KC. Cost-effectiveness of screening
for asymptomatic left ventricular dysfunction in childhood cancer
survivors. Ann Intern Med. 2014;160(10):731–732.
76. Colan SD, Lipshultz SE, Sallan SE. Balancing the oncologic effec-
tiveness versus the cardiotoxicity of anthracycline chemotherapy in
childhood cancer. Prog Pediatr Cardiol. 2014;36(1):7–10.
77. Pudil R, Horacek JM, Strasova A, et al. Monitoring of the very early
changes of left ventricular diastolic function in patients with acute
leukemia treated with anthracyclines. Exp Oncol. 2008;30(2):160–162.
78. Burdick J, Berridge B, Coatney R. Strain echocardiography com-
bined with pharmacological stress test for early detection of
anthracycline induced cardiomyopathy. J Pharmacol Toxicol
Methods. 2015;73:15–20.
79. Mavinkurve-Groothuis AM, Marcus KA, Pourier M, et al. Myocardial
2D strain echocardiography and cardiac biomarkers in children
during and shortly after anthracycline therapy for acute lympho-
blastic leukaemia (ALL): a prospective study. Eur Heart J Cardiovasc
Imaging. 2013;14(6):562–569.
80. Moon TJ, Miyamoto SD, Younoszai AK, et al. Left ventricular strain
and strain rates are decreased in children with normal fractional
shortening after exposure to anthracycline chemotherapy. Cardiol
Young. 2014;24(5):854–865.
81. Leger K, Slone T, Lemler M, et al. Subclinical cardiotoxicity in child-
hood cancer survivors exposed to very low dose anthracycline
therapy. Pediatr Blood Cancer. 2015;62(1):123–127.
82. Armstrong GT, Plana JC, Zhang N, et al. Screening adult survivors of
childhood cancer for cardiomyopathy: comparison of echocardio-
graphy and cardiac magnetic resonance imaging. J Clin Oncol.
2012;30(23):2876–2884.
83. Lipshultz SE, Miller TL, Scully RE, et al. Changes in cardiac biomar-
kers during doxorubicin treatment of pediatric patients with high-
risk acute lymphoblastic leukemia: associations with long-term
echocardiographic outcomes. J Clin Oncol. 2012;30(10):1042–1049.
84. Lipshultz SE, Adams MJ. Cardiotoxicity after childhood cancer:
beginning with the end in mind. J Clin Oncol. 2010;28(8):1276–
1281.
85. Lipshultz SE, Lipsitz SR, Sallan SE, et al. Long-term enalapril therapy
for left ventricular dysfunction in doxorubicin-treated survivors of
childhood cancer. J Clin Oncol. 2002;20(23):4517–4522.
86. Van Dalen EC, Van Der Pal HJ, Bakker PJ, et al. Cumulative inci-
dence and risk factors of mitoxantrone-induced cardiotoxicity in
children: a systematic review. Eur J Cancer. 2004;40(5):643–652.
87. Silber JH, Jakacki RI, Larsen RL, et al. Increased risk of cardiac
dysfunction after anthracyclines in girls. Med Pediatr Oncol.
1993;21:477–479.
88. Lanzarini L, Bossi G, Laudisa ML, et al. Lack of clinically significant
cardiac dysfunction during intermediate dobutamine doses in
14 N. BANSAL ET AL.

long-term childhood cancer survivors exposed to anthracyclines.
Am Heart J. 2000;140(2):315–323.
89. Brown TR, Vijarnsorn C, Potts J, et al. Anthracycline induced cardiac
toxicity in pediatric Ewing sarcoma: a longitudinal study. Pediatr
Blood Cancer. 2013;60(5):842–848.
90. Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in
a cohort of adult survivors of childhood and adolescent cancer:
retrospective analysis of the Childhood Cancer Survivor Study
cohort. BMJ. 2009;339:b4606.
•This study found that adult survivors of childhood cancer were
more likely than healthy siblings to report HF, myocardial
infarction, pericardial disease, or valvar abnormalities.
Additionally, survivors exposed to 250 mg/m
2
or more of
anthracyclines were found to have two to five times higher
risks of HF, pericardial disease, and valvar abnormalities com-
pared with survivors unexposed to anthracyclines.
91. Brouwer CA, Gietema JA, van den Berg MP, et al. Long-term cardiac
follow-up in survivors of a malignant bone tumour. Ann Oncol.
2006;17(10):1586–1591.
92. Aminkeng F, Ross CJ, Rassekh SR, et al. Recommendations for
genetic testing to reduce the incidence of anthracycline-induced
cardiotoxicity. Br J Clin Pharmacol. 2016;82(3):683–695.
93. Krischer JP, Cuthbertson DD, Epstein, S, et al. Risk factors for early
anthracycline cardiotoxicity in children: the Pediatric Oncology
Group experience. Prog Pediatr Cardiol. 1998;8:83–90.
94. Wojnowski L, Kulle B, Schirmer M, et al. NAD(P)H oxidase and
multidrug resistance protein genetic polymorphisms are associated
with doxorubicin-induced cardiotoxicity. Circulation. 2005;112
(24):3754–3762.
95. Krajinovic M, Elbared J, Drouin S, et al. Polymorphisms of ABCC5
and NOS3 genes influence doxorubicin cardiotoxicity in survivors
of childhood acute lymphoblastic leukemia. Pharmacogenomics J.
2016;16(6):530–535.
•• This study confirmed clinically relevant associations between
NOS3 and ABCC5 gene variants and their contribution to
chronic cardiotoxicity following doxorubicin treatment.
96. Lipshultz SE, Lipsitz SR, Kutok JL, et al. Impact of hemochromatosis
gene mutations on cardiac status in doxorubicin-treated survivors
of childhood high-risk leukemia. Cancer. 2013;119(19):3555–3562.
•• A prospective cohort study that found that 10% of children
newly diagnosed with ALL carried a mutation in the HFE C282Y
allele. Heterozygosity for C282Y was associated with a nearly
ninefold increased amount of doxorubicin-associated myocar-
dial injury as measured by cTnT compared with newly diag-
nosed children without this HFE mutation. Children with HFE
mutations had significantly more echocardiographic abnorm-
alities of LV structure and function 2 years later than those
without HFE mutations.
97. Blanco JG, Leisenring WM, Gonzalez-Covarrubias VM, et al. Genetic
polymorphisms in the carbonyl reductase 3 gene CBR3 and the
NAD(P)H: quinoneoxidoreductase 1 gene NQO1 in patients who
developed anthracycline-related congestive heart failure after
childhood cancer. Cancer. 2008;112(12):2789–2795.
98. Lipshultz SE, Colan SD. Cardiovascular trials in long-term survivors
of childhood cancer. J Clin Oncol. 2004;22(5):769–773.
99. Akam-Venkata J, Franco VI, Lipshultz SE. Late cardiotoxicity: issues
for childhood cancer survivors. Curr Treat Options Cardiovasc Med.
2016;18(7):47.
100. Silber JH, Cnaan A, Clark BJ, et al. Enalapril to prevent cardiac
function decline in long-term survivors of pediatric cancer exposed
to anthracyclines. J Clin Oncol. 2004;22:820–828.
101. El-Shitany NA, Tolba OA, El-Shanshory MR, et al. Protective effect of
carvedilol on adriamycin-induced left ventricular dysfunction in
children with acute lymphoblastic leukemia. J Card Fail. 2012;18
(8):607–613.
102. Nabati M, Janbabai G, Baghyari S, et al. Cardioprotective effects of
carvedilol in inhibiting doxorubicin-induced cardiotoxicity. J
Cardiovasc Pharmacol. 2017 Jan 30;69:279–285. [Epub ahead of
print].
103. Herman EH, Ferrans VJ, Myers CE, et al. Comparison of the effec-
tiveness of (±)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187)
and N-acetylcysteine in preventing chronic doxorubicin cardiotoxi-
city in beagles. Cancer Res. 1985;45(1):276–281.
104. Speyer JL, Green MD, Kramer E, et al. Protective effect of the
bispiperazinedione ICRF-187 against doxorubicin-induced cardiac
toxicity in women with advanced breast cancer. N Engl J Med.
1988;319(12):745–752.
105. Speyer JL, Green MD, Zeleniuch-Jacquotte A, et al. ICRF-187 per-
mits longer treatment with doxorubicin in women with breast
cancer. J Clin Oncol. 1992;10(1):117–127.
106. Tonkin K, Bates M, Lieu D, et al. Dexrazoxane cardioprotection for
patients receiving FAC chemotherapy: a pharmacoeconomic eva-
luation. Can J Oncol. 1996;6(2):458–473.
107. Swain SM, Whaley FS, Gerber MC, et al. Delayed administration of
dexrazoxane provides cardioprotection for patients with advanced
breast cancer treated with doxorubicin-containing therapy. J Clin
Oncol. 1997;15(4):1333–1340.
108. Hochster HS. Clinical pharmacology of dexrazoxane. Semin Oncol.
1998;25(4 Suppl 10):37–42.
109. Lyu YL, Kerrigan JE, Lin CP, et al. Topoisomerase IIbeta mediated
DNA double-strand breaks: implications in doxorubicin cardiotoxi-
city and prevention by dexrazoxane. Cancer Res. 2007;67(18):8839–
8846.
110. Vrooman LM, Neuberg DS, Stevenson KE, et al. The low incidence
of secondary acute myelogenous leukaemia in children and ado-
lescents treated with dexrazoxane for acute lymphoblastic leukae-
mia: a report from the Dana-Farber Cancer Institute ALL
Consortium. Eur J Cancer. 2011;47(9):1373–1379.
111. Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on
myocardial injury in doxorubicin-treated children with acute lym-
phoblastic leukemia. N Engl J Med. 2004;351(2):145–153.
112. Lipshultz SE, Scully RE, Lipsitz SR, et al. Assessment of dexrazoxane
as a cardioprotectant in doxorubicin-treated children with high-risk
acute lymphoblastic leukaemia: long-term follow-up of a prospec-
tive, randomised, multicentre trial. Lancet Oncol. 2010;11(10):950–
961.
•• A randomized clinical trial comparing the cardioprotective
benefits of the administration of doxorubicin alone versus
doxorubicin plus dexrazoxane. Found worse than normal car-
diac abnormalities in the doxorubicin-only group, but not for
the doxorubicin plus dexrazoxane. In addition to the cardio-
protective effects of dexrazoxane, event-free survival was simi-
lar for both groups after 8.7 years of median follow-up.
113. Asselin BL, Devidas M, Chen L, et al. Cardioprotection and safety of
dexrazoxane in patients treated for newly diagnosed T-cell acute
lymphoblastic leukemia or advanced-stage lymphoblastic non-
Hodgkin lymphoma: a report of the Children’s Oncology Group
Randomized Trial Pediatric Oncology Group 9404. J Clin Oncol.
2016;34(8):854–862.
114. Kopp LM, Bernstein ML, Schwartz CL, et al. The effects of dexrazox-
ane on cardiac status and second malignant neoplasms (SMN) in
doxorubicin-treated patients with osteosarcoma (OS). J Clin Oncol.
2012;30:15_suppl, 9503-9503
115. Lipshultz SE, Anderson LM, Miller TL, et al. Impaired mitochondrial
function is abrogated by dexrazoxane in doxorubicin-treated child-
hood acute lymphoblastic leukemia survivors. Cancer. 2016;122
(6):946–953.
116. Schwartz CL, Wexler LH, Krailo MD, et al. Intensified chemotherapy
with dexrazoxane cardioprotection in newly diagnosed nonmeta-
static osteosarcoma: a report from the Children’sOncology Group.
Pediatr Blood Cancer. 2016;63(1):54–61.
117. Tebbi CK, London WB, Friedman D, et al. Dexrazoxane-associated
risk for acute myeloid leukemia/myelodysplastic syndrome and
other secondary malignancies in pediatric Hodgkin’s disease. J
Clin Oncol. 2007;25(5):493–500.
118. Lipshultz SE, Lipsitz SR, Orav EJ. Dexrazoxane-associated risk for
secondary malignancies in pediatric Hodgkin’s disease: a claim
without compelling evidence. J Clin Oncol. 2007;25(21):3179.
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 15

119. Lipshultz SE, Stevenson KE, Franco VI, et al. Hearts too small for
body size after doxorubicin for childhood ALL: Grinch syndrome. J
Clin Oncol. 2014;32:10021.
120. Chow EJ, Asselin BL, Schwartz CL, et al. Late mortality after dexra-
zoxane treatment: a report from the Children’s Oncology Group. J
Clin Oncol. 2015;33(24):2639–2645.
121. Attia SM, Ahmad SF, Bakheet SA. Impact of dexrazoxane on dox-
orubicin-induced aneuploidy in somatic and germinal cells of male
mice. Cancer Chemother Pharmacol. 2016;77(1):27–33.
122. Chow EJ, Doody RD, Armenian SH, et al. Effect of dexrazoxane on
heart function among long-term survivors of childhood leukemia
and lymphoma: a report from the Children’s Oncology Group. ASH
58th Annual Meeting and Exposition. December 3-6, 2016; San
Diego, CA; No. 696 (abstract).
123. Shaikh F, Dupuis LL, Alexander S, et al. Cardioprotection and
second malignant neoplasms associated with dexrazoxane in chil-
dren receiving anthracycline chemotherapy: a systematic review
and meta-analysis. J Natl Cancer Inst. 2016;108(4):djv357.
124. Lipshultz SE, Franco VI, Sallan SE, et al. Dexrazoxane for reducing
anthracycline-related cardiotoxicity in children with cancer: an
update of the evidence. Prog Pediatr Cardiol. 2014;36(1):39–49.
125. Fulbright JM, Huh W, Anderson P, et al. Can anthracycline therapy
for pediatric malignancies be less cardiotoxic? Curr Oncol Rep.
2010;12:411–419.
126. Safra T. Cardiac safety of liposomal anthracyclines. Oncologist.
2003;8(suppl 2):17–24.
127. O’Brien ME, Wigler N, Inbar M, et al. CAELYX Breast Cancer Study
Group. Reduced cardiotoxicity and comparable efficacy in a phase
III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil)
versus conventional doxorubicin for first-line treatment of meta-
static breast cancer. Ann Oncol. 2004;15:440–449.
128. Batist G, Ramakrishnan G, Rao CS, et al. Reduced cardiotoxicity and
preserved antitumor efficacy of liposome-encapsulated doxorubi-
cin and cyclophosphamide compared with conventional doxorubi-
cin and cyclophosphamide in a randomized, multicenter trial of
metastatic breast cancer. J Clin Oncol. 2001;19:1444–1454.
129. Marina NM, Cochrane D, Harney E, et al. Dose escalation and
pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in
children with solid tumors. Clin Cancer Res. 2002 Feb 1;8(2):413–
418.
130. Munoz A, Maldonado M, Pardo N, et al. Pegylated liposomal dox-
orubicin hydrochloride (PLD) for advanced sarcomas in children:
preliminary results. Pediatr Blood Cancer. 2004;43(2):152–155.
131. Stöhr W, Paulides M, Brecht I, et al. Comparison of epirubicin and
doxorubicin cardiotoxicity in children and adolescents treated
within the German Cooperative Soft Tissue Sarcoma Study (CWS).
J Cancer Res Clin Oncol. 2006;132(1):35–40.
132. Vogler WR, Velez-Garcia E, Weiner RS, et al. A phase III trial compar-
ing idarubicin and daunorubicin in combination with cytarabine in
acute myelogenous leukemia: a Southeastern Cancer Study Group
Study. J Clin Oncol. 1992;10(7):1103–1111.
133. Shirkey H. Therapeutic orphans. J Pediatr. 1968;72(1):119–120.
134. Milne CP, Davis J. The pediatric studies initiative: after 15 years
have we reached the limits of the law? Clin Ther. 2014;36(2):156–
162.
135. Pasquali SK, Lam WK, Chiswell K, et al. Status of the pediatric
clinical trials enterprise: an analysis of the US ClinicalTrials.gov
registry. Pediatrics. 2012;130(5):e1269–1277.
136. Tsukamoto K, Carroll KA, Onishi T, et al. Improvement of pediatric
drug development: regulatory and practical frameworks. Clin Ther.
2016;38(3):574–581.
137. Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivor-
ship statistics, 2012. CA Cancer J Clin. 2012;62(4):220–241.
138. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity
induced by chemotherapy, targeted agents and radiotherapy:
ESMO Clinical Practice Guidelines. Ann Oncol. 2012;23(Suppl 7):
vii155–166.
139. Lipshultz SE, Miller TL, Lipsitz SR, et al. Continuous versus bolus
infusion of doxorubicin in children with ALL: long-term cardiac
outcomes. Pediatrics. 2012;130(6):1003–1011.
•• A randomized clinical trial comparing cardioprotective effects
of continuous versus bolus infusion of doxorubicin in children
with high-risk ALL. This study found no cardioprotective ben-
efit in using continuous infusion of doxorubicin.
140. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with
ipilimumab in patients with metastatic melanoma. N Engl J Med.
2010;363(8):711–723.
141. Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis
with combination immune checkpoint blockade. N Engl J Med.
2016;375(18):1749–1755.
142. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J
Clin. 2016;66(1):7–30.
143. Shelburne N, Adhikari B, Brell J, et al. Cancer treatment-related
cardiotoxicity: current state of knowledge and future research
priorities. J Natl Cancer Inst. 2014;106(9):dju232.
144. Pettit SD, Lipshultz SE, Cleeland CS, et al. Enhancing quality of life
as a goal for anticancer therapeutics. Sci Transl Med. 2016;8
(344):344ed9.
145. Yeh ET, Chang HM. Oncocardiology-past, present, and future: a
review. JAMA Cardiol. 2016;1(9):1066–1072.
16 N. BANSAL ET AL.