The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

DanL. Longo, M.D., Editor

Cardiovascular Toxic Effects of Targeted

Cancer Therapies
JavidJ. Moslehi, M.D.

T
he field of cardio-oncology represents the intersection of From the Division of Cardiovascular
cancer and cardiovascular disease. This clinical specialty is focused on Medicine and the Cardio-Oncology Pro-
gram, Vanderbilt School of Medicine,
the cardiovascular care of patients with cancer and has expanded owing and the VanderbiltIngram Cancer Cen-
to the emergence of new targeted oncology therapies. Although these treatments ter both in Nashville. Address reprint
have dramatically changed the natural course of many cancers, they may result in requests to Dr. Moslehi at the Cardio-
Oncology Program, Vanderbilt University
cardiovascular, thrombotic, or metabolic complications, which can be manifested Medical Center, 2220 Pierce Ave., Nash-
either during the course of therapy or after completion of treatment. This article ville, TN 37232, or at javid
.
moslehi@
focuses on the cardiovascular toxic effects that may be associated with these new vanderbilt.edu.
targeted cancer therapies and provides a broad overview of this emerging field. N Engl J Med 2016;375:1457-67.
Where possible, preventive and treatment strategies that are relevant to patient DOI: 10.1056/NEJMra1100265
Copyright 2016 Massachusetts Medical Society.
care are recommended, although the paucity of data reflects the need for further
research.

His t or y of C a r diova scul a r C ompl ic at ions

in C a ncer Ther a py

Traditional cancer therapies, such as treatment with anthracyclines and radiation,

are known to cause cardiovascular complications. Forty years ago, anthracyclines
were associated with cardiotoxicity, including heart-failure symptoms, in a dose-
dependent manner.1 Radiation therapy (especially targeting the chest) was associ-
ated with myocardial, valvular, pericardial, and vascular toxic effects.2,3 In the case
of anthracyclines, investigators have elucidated mechanistic insights into such
cardiotoxicity.4 In addition, collaborative studies, especially in children, have pro-
vided preventive and therapeutic strategies for cardiotoxicity in these patients.5,6
Several recent articles have summarized cardiac outcomes in adult survivors of
childhood cancer who were exposed to cardiotoxic therapies.7-9
During the past two decades, a better understanding of the molecular pathways
that are involved in tumor progression has led to the introduction of more selec-
tive, mechanism-based therapies. For example, aberrant activation of kinases plays
a critical role in the pathogenesis of a number of cancers, a factor that has stimu-
lated efforts to develop kinase inhibitors for therapy.10 Kinase inhibition is
achieved by several means, including the use of monoclonal antibodies or soluble
decoy receptors (so-called ligand traps) that bind the receptor kinase or its ligand.
Alternatively, small-molecule inhibitors interfere with the binding of the kinase to
ATP or substrates (Fig.1A).10 Kinases also play a critical role in cardiovascular
homeostasis, including vascular, metabolic, and myocardial regulation.11 There-
fore, in principle, it is not surprising that kinase inhibition may result in cardio-
vascular sequelae. More unexpected have been instances in which the specific
kinase that was inhibited was not known to have a biologic role in the cardiovas-
cular system, resulting in on-target toxicity. In addition, multitargeted small-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A mAb targeting
Receptor ligand Monoclonal Antibody (mAb)
ligand 2 or Ligand Trap
Ligand cannot
bind to receptors
mAb targeting Given as an infusion
receptor dimerization Binds ligand or receptor kinase
mAb
and downstream Can be covalently attached to
targeting
activation other chemotherapy for more
receptor
potency

Receptor
cannot dimerize

Dimerization and Inactive Dimerization and Inactive CYTOPLASM

activation of receptor receptor kinase 1 activation of receptor receptor kinase 2
kinase 1 kinase 2
Multitargeted Tyrosine Kinase Inhibitor
(small-molecule inhibitors)

Taken orally
Cell survival Can bind more than one kinase
Angiogenesis receptor, resulting in off-target
Cell growth Nonreceptor effects
kinase

B HIF
Activation and
stabilization
VEGFA VEGF Signaling Pathway Inhibitors
PDGF VEGFA
PDGF VEGFA Bevacizumab (anti-VEGF)
PDGF VEGFA Aflibercept (VEGF trap)
Ramucirumab (Anti-VEGFR2)

KIT
PDGFR VEGFR1 VEGFR3 VEGFR2

Tyrosine Kinase Inhibitors with Anti-VEGF Activity

FDA Approved
Sunitinib, sorafenib, pazopanib, axitinib,
regorafenib, vandetanib, ponatinib,
CYTOPLASM cabozantinib, lenvatinib
Cell survival
Angiogenesis Under Investigation
Prostaglandin production Cediranib, tivozanib, toceranib, lucitanib
Nitric oxide production

Figure 1. Targeting of Kinases and VEGF Signaling Pathways for Cancer Therapy.
Aberrant activation of kinases plays a critical role in the pathogenesis of cancer and has stimulated efforts to develop kinase inhibitors for
therapy (Panel A). Kinase inhibition can be achieved by targeting the ligand or the receptor kinase, usually by means of a monoclonal anti-
body (mAb) that is given as an intravenous infusion. Alternatively, small-molecule inhibitors, which are taken orally, work intracellularly and
can inhibit one or more kinases, including receptor kinases and nonreceptor kinases (usually serinethreonine kinases). Monoclonal anti-
bodies can also be covalently attached to other chemotherapy or radionuclides. Tumor hypoxia, which is usually achieved through the stabi-
lization and activation of master transcription factor (hypoxia-inducible factor [HIF] in the tumor) leads to the transcription and secretion
of several secreted factors that include vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) that promote
angiogenesis (Panel B). The mammalian family of VEGF genes consists of five glycoproteins that bind and activate three structurally related
receptor tyrosine kinases and has been a major focus of kinase-directed therapy in cancer. VEGF-targeted therapies include a monoclonal
antibody or ligand trap that binds circulating VEGFA, a monoclonal antibody that targets VEGF receptor 2 (VEGFR2), and multitargeted tyro-
sine kinase inhibitors that target VEGF receptors, along with receptor tyrosine kinases, such as KIT and PDGFR.

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 Cardiovascular Effects of Targeted Cancer Ther apies

molecule inhibitors, by virtue of inhibiting mul- 9.4% of the patients who were randomly assigned
tiple kinases, can result in off-target effects.10,11 to a regimen that included paclitaxel, cyclophos-
Both these scenarios have played out in practice. phamide, and trastuzumab had cardiac dysfunc-
tion, as compared with 19.2% of the patients
HER 2 Inhibi t or s whose regimen also included anthracyclines.13
On the other hand, a number of newer HER2-
Trastuzumab, a humanized monoclonal antibody targeted therapies have been approved and can be
targeting human epidermal growth factor recep- used in combination with trastuzumab.19,20 The
tor 2 (HER2), a receptor kinase that is overex- cardiotoxic effects of such combination therapies
pressed in a subgroup of breast cancers, dramati- are less clear, although early studies have sug-
cally improved the prognosis of women with gested a reasonable safety signal.19,21 Another con-
HER2-positive breast cancer. However, in the founding factor is that clinical trials of trastuzu
first pivotal study, either symptomatic heart fail- mab largely excluded patients with a history of
ure or asymptomatic cardiac dysfunction devel- cardiac disease or heart failure; such exclusions do
oped in an alarming 27% of patients who re- not apply once a drug is approved. As such, several
ceived trastuzumab with traditional chemotherapy retrospective analyses with the use of publicly
(doxorubicin and cyclophosphamide).12 Initial available databases have suggested a higher rate of
regulatory approval of trastuzumab for meta- trastuzumab-associated cardiotoxicity than what
static breast cancer was accompanied by caveats is reported in the breast-cancer clinical trials.22-24
addressing cardiac safety. All patients were re- The incorporation of noninvasive cardiac mon-
quired to undergo periodic monitoring of car- itoring into clinical practice in patients with
diac function during trastuzumab treatment. In breast cancer has allowed the recognition of
addition, trastuzumab would be administered subclinical cardiomyopathy (systolic cardiac dys-
sequentially after treatment with other therapies, function without heart-failure symptoms) in a
especially anthracyclines, with the presumption large number of patients exposed to anthracy-
that concomitant treatment would result in syn- clines, trastuzumab, or both. For example, up to
ergistic cardiotoxicity. Subsequent trials and 8% of the patients in one breast-cancer trial
clinical experience with trastuzumab showed a were found to have cardiac dysfunction immedi-
lower incidence of cardiomyopathy, perhaps in ately after anthracycline therapy but before treat-
part owing to closer cardiac monitoring and ment with trastuzumab.25 One recent study sug-
recognition of cardiac toxicity. In breast-cancer gested that the initiation of standard heart-failure
trials, the incidence of symptomatic heart failure medications was associated with at least partial
in trastuzumab-treated patients was 2 to 4%, recovery of cardiac function after treatment with
and the incidence of cardiac dysfunction was anthracyclines; however, this single-institution
3to 19%.13-15 Basic studies showed a critical, study did not include a placebo group, so it is
unexpected role for HER2 in cardiac biologic possible that the cardiac recovery would have
features, which suggested on-target toxicity.16 occurred regardless of the initiation of heart-
In the future, the cardiomyopathy associated failure therapy.26 In the case of trastuzumab,
with existing breast-cancer therapies may be a most patients in whom cardiomyopathy devel-
moving target for several reasons. With decreas- oped have improvement in their clinical or car-
ing use of anthracyclines for HER2-positive breast diac function, although approximately one third
cancer, the degree of cardiac dysfunction associ- of the patients have some degree of persistent
ated with trastuzumab may be less than that re- cardiac dysfunction.13,15,25
ported in earlier studies, in which all the patients An important unanswered question is the
were also treated with anthracycline-based chemo- long-term clinical sequelae of such subclinical
therapy.17 In a recent clinical trial involving 406 cardiomyopathies. In 2016, the survivorship
patients with HER2-positive breast cancer who guidelines of the National Comprehensive Can-
were treated with paclitaxel and trastuzumab, cer Network emphasized early recognition and
clinical heart failure developed in only 2 patients prevention of heart failure in patients who had
(0.5%) and substantial systolic dysfunction in 13 received anthracyclines. They also advised that
(3.2%).18 In the 10-year follow-up of a trial by the high-risk survivors should undergo a thorough
Breast Cancer International Research Group in- clinical screening for heart failure within 1 year
volving women with HER2-positive breast cancer, after completion of anthracycline therapy.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Inhibi t ion of V EGF Signa l ing
Path wa y
Vascular endothelial growth factor A (VEGFA),
which is secreted by tumors, plays a critical role
in angiogenesis through binding VEGF receptors
and activating the VEGF signaling pathway.27
VEGF signaling inhibitors have been approved
for a number of different cancers, with more
than 10 therapies that have been approved by the
Food and Drug Administration (FDA) (Fig.1B).27
From a cardio-oncology perspective, VEGF sig-
naling inhibitors have been associated with a
vast array of cardiovascular issues, including
hypertension, vascular toxic effects, and cardio-
myopathy.28 Nearly all the patients who have been
treated with VEGF signaling inhibitors have
anincrease in blood pressure, often in a dose-
dependent and transient manner, within 1 week
after treatment. The overall incidence of hyper-
tension ranges from 20 to 25% with bevacizu
mab and sunitinib (the initially approved drugs
in this class) to more than 50% with newer ap-
proved agents.29 Both systolic and diastolic blood-
pressure levels have been affected.
Several mechanisms for the association be-
tween the use of VEGF signaling inhibitors and
hypertension have been proposed.29,30 VEGF in-
duces the production of two vasodilators, nitric
oxide and prostacyclin, and decreases the produc-
tion of endothelin-1, a potent vasoconstrictor. In
addition, VEGF is expressed in endothelial cells
and in the kidney and plays an important role in
cellular proliferation and homeostasis in the two
sites. Thus, VEGF signaling inhibitors may lead
to an imbalance between vasodilators and vaso-
constrictors, loss of capillary circulation, and
alteration in glomerular function, all of which
contribute to hypertension.29,30
VEGF signaling inhibitors further increase the
risk of vascular events (presumed to be throm-
bosis) and cardiomyopathy.31,32 In a clinical trial
comparing two VEGF signaling inhibitors, pazo-
panib and sunitinib, prospective surveillance of
cardiac function showed that 9% of the patients
in each group had a significant decrease in car-
diac function, although only approximately 1% Mult i ta rge ted T y rosine K ina se
had symptomatic heart failure.33 Retrospective
analyses suggest a higher incidence of cardiovas-
cular toxic effects. One single-institution study The advent of small-molecule inhibitors that can
showed that 27% of the patients who were re- block multiple tyrosine kinases has expanded the
ceiving single-agent VEGF signaling inhibitors
had various cardiovascular toxic effects. When
hypertension was included in the definition of
toxic effects, the proportion increased to 64%.34
In another retrospective study in which sunitinib
was used as single-agent therapy, 28% of the
patients had a clinically significant decrease in
cardiac function, with the development of con-
gestive heart failure in 8% of the patients.35
There are striking similarities between car-
diovascular toxic effects that are associated with
VEGF signaling inhibitors and cardiovascular
issues that arise during pregnancy.11 Proteinuria
frequently accompanies hypertension associated
with the use of VEGF signaling inhibitors in a
manner similar to that in women with preeclamp-
sia. A preeclampsia-like syndrome has been de-
scribed in patients receiving VEGF signaling in-
hibitors. In these patients, features of thrombotic
microangiopathy on renal biopsy are similar to
those of severe preeclampsia.36,37 Renal-biopsy
procedures that have been performed on sam-
ples obtained from 22 patients who received vari-
ous VEGF signaling inhibitors showed throm-
botic microangiopathy in 21 patients.38 There is
biologic plausibility for these similarities. Soluble
fms-related tyrosine kinase 1 (FLT1) plays a
causal role in preeclampsia and peripartum car-
diomyopathy, another cardiovascular complica-
tion that can arise late in pregnancy or early
after delivery.39,40 FLT1, also known as soluble
VEGFR1, abrogates VEGF signaling in a manner
that is similar to those of other VEGF signaling
inhibitors. These observations may have rele-
vance to patient care. For example, patients with
preeclampsia are at increased risk for subsequent
cardiovascular issues, including peripartum car-
diomyopathy.40 Similarly, patients who have pro-
teinuria and hypertension immediately after start-
ing VEGF signaling inhibitors may be at increased
risk for subsequent cardiac issues, including car-
diomyopathy. Such observations may also warrant
a multidisciplinary approach to the cardiovascu-
lar and renal care of patients receiving VEGF
signaling inhibitors.
Inhibi t or s

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 Cardiovascular Effects of Targeted Cancer Ther apies
arsenal of targeted cancer therapies. Imatinib
was the first such multitargeted tyrosine kinase
inhibitor. By virtue of inhibiting the ABL1 kinase,
a tyrosine kinase that is activated in chronic
myeloid leukemia (CML), as well as proto-onco-
gene receptor tyrosine kinase (KIT) and platelet-
derived growth factor receptor alpha (PDGFRA),
which are mutationally activated kinases in
gastrointestinal stromal tumor, imatinib dramati-
cally changed the natural course of these can-
cers and turned fatal diseases into manageable
chronic conditions.41,42
Later-generation tyrosine kinase inhibitors
were initially developed to overcome imatinib
resistance, but these drugs were soon tested as
front-line treatment on the basis of more rapid
and profound molecular responses.43,44 Four such
drugs dasatinib, nilotinib, bosutinib, and
ponatinib serve as such examples in CML,
with dasatinib and nilotinib having been ap-
proved for front-line use. From a cardio-oncology
perspective, a broad spectrum of cardiovascular
toxic effects was observed with these tyrosine
kinase inhibitors.45 Whereas imatinib showed
minimal cardiovascular complications, dasatinib
was associated with cardiopulmonary issues,
especially pulmonary hypertension; both nilo-
tinib and ponatinib were associated with vascu-
lar events.45 Ponatinib, a unique drug owing to
its potent activity against ABL1 kinase mutations
that remain resistant against other tyrosine ki-
nase inhibitors, was even briefly removed from
the market in the United States because of sub-
stantial vascular events. In a trial testing the
efficacy of ponatinib in patients with CML in
whom treatment with other tyrosine kinase in-
hibitors had failed, the cumulative rates of vas-
cular events at a median follow-up of 15 months
were 7.1% for cardiac events, 3.6% for cerebro-
vascular events, and 4.9% for peripheral-artery
vascular events.45,46 These toxic effects occurred
despite treatment efficacy. A post hoc analysis of
this trial suggested that traditional atheroscle-
rotic risk factors, such as age, hypertension, and
diabetes, are important predictors of cardiovas-
cular adverse events.45
With the advent of tyrosine kinase inhibitors,
CML has become a chronic disease, with a pre-
dicted 5-year survival rate of more than 90%.
Given the multiple treatment options, cardiovas-
cular considerations may have to play a part in
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selecting a specific tyrosine kinase inhibitor for
treatment, especially for front-line use. It may
also be relevant for primary care physicians and
cardiologists to be involved in the care of these
patients, especially when later-generation tyro-
sine kinase inhibitors are used in therapy. In
addition, the involvement of cardiologists in the
design of future trials involving patients with
CML may improve the definition of cardiovascu-
lar end points and provide insights into the
pathophysiologic features of vascular events as-
sociated with nilotinib and ponatinib or of pul-
monary vascular events associated with dasatinib.
More complete phenotyping of adverse events
for example, if vascular events that are associ-
ated with ponatinib represent thrombosis, athero-
sclerosis, or some other vascular process, such
as vasospasm will provide superior strategies
for cardiovascular prevention and treatment.47
Increasingly, newer generations of tyrosine
kinase inhibitors are tested for various types of
cancer. Although many tyrosine kinase inhibi-
tors appear to have cardiovascular sequelae, it is
unclear whether such events are clinically sig-
nificant (Table1). For example, ibrutinib, which
inhibits Brutons tyrosine kinase, has shown
considerable efficacy in certain types of B-cell
cancers.48 In a recent trial, 3% of the patients
who received ibrutinib had grade 3 or higher
atrial fibrillation requiring hospitalization or
invasive intervention, as compared with none of
the control patients who received an alternative
agent.49 Since the trial did not specifically screen
for cardiac toxic effects, it is unclear whether a
higher percentage of patients had other arrhyth-
mias or asymptomatic atrial fibrillation. Similar-
ly, trametinib, a MEK inhibitor, was associated
with cardiac dysfunction in 7% of patients, which
prompted a recommendation by the FDA for
cardiac monitoring during treatment.50 The clin-
ical significance of this cardiac dysfunction is
not clear.
Ta rge t ing Ne w Path wa ys
for C a ncer T r e atmen t
In the coming decade, the explosion of cancer
therapies will involve new mechanisms that ex-
tend beyond kinase inhibition.51 The introduction
of immunomodulatory drugs and proteasome
inhibitors has improved the prognosis of patients
1461
 Table 1. Cancer Therapies, Cellular Targets, and Associated Cardiovascular Toxic Effects.*

1462
Class Drug Cellular Target Common Cardiovascular Toxic Effects
Traditional cancer therapies
Radiation NA NA Myocardial ischemia, pericarditis, myocarditis,
valvular heart disease, arrhythmia
Anthracyclines Doxorubicin, daunorubicin, idarubicin, Type II topoisomerase, DNA and RNA Cardiomyopathy, arrhythmia, acute myocarditis
epirubicin, mitoxantrone synthesis or pericarditis
Platinum Cisplatin, carboplatin, oxaliplatin Cross-link DNA Hypertension, myocardial ischemia
Antimetabolites Fluorouracil Thymidylate synthase Myocardial ischemia
Capecitabine Thymidylate synthase Myocardial ischemia, arrhythmias
Alkylating agents Cyclophosphamide Cross-link DNA Congestive heart failure, myocarditis, pericarditis
Antimicrotubule agents Paclitaxel Microtubule Arrhythmias (including bradycardia, heart block,
premature ventricular contractions, and ven-
tricular tachycardia), thrombosis
The

Vinca alkaloids Microtubule Myocardial ischemia, coronary spasm

Targeted cancer therapies
HER2 inhibitors
HER2 monoclonal antibody Trastuzumab HER2 Decline in LVEF, congestive heart failure
Newer HER2 inhibitors Pertuzumab, trastuzumab emtansine, HER2 Decline in LVEF, congestive heart failure
lapatinib
VEGF signaling pathway inhibitors VEGF signaling pathway Hypertension, venous or arterial thromboembolic
events, proteinuria, cardiomyopathy
VEGFA monoclonal antibody Bevacizumab
n e w e ng l a n d j o u r na l

VEGF trap Aflibercept

The New England Journal of Medicine

of

VEGFR2 monoclonal antibody Ramucirumab

Tyrosine kinase inhibitor with anti-VEGF activity Sunitinib, sorafenib, pazopanib, VEGF receptors (mainly VEGFR2) and
axitinib, vandetanib, regorafenib, other kinases; PDGFR

n engl j med 375;15nejm.org October 13, 2016

cabozantinib, lenvatinib

Copyright 2016 Massachusetts Medical Society. All rights reserved.

Multitargeted tyrosine kinase inhibitors Dasatinib ABL, ABL mutants (except T315I), and Pulmonary hypertension, vascular events, prolon-
m e dic i n e

other kinases; SRC, KIT, PDGFR, gation of QT interval corrected for heart rate
EGFR, BRAF, DDR1, DDR2, ephrin
receptors
Nilotinib ABL, ABL mutants (except T315I), and Coronary, cerebral, and peripheral vascular events,
other kinases; ABL2 (also called hyperglycemia, prolongation of QT interval cor-
ARG), KIT, DDR1, NQO2 rected for heart rate
Ponatinib ABL, ABL mutants (including T315I), Coronary, cerebral, and peripheral vascular events
and other kinases; FGFR, VEGFR,
PDGFR, ephrin receptors, SRC, KIT,
RET, TEK (also called TIE2), FLT3

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 Cardiovascular Effects of Targeted Cancer Ther apies

with multiple myeloma.52 Immunomodulatory

* CTLA4 denotes cytotoxic T-lymphocyteassociated protein 4, DDR discoidin domain receptor tyrosine kinase, FGFR fibroblast growth factor receptor, FLT3 fms-related tyrosine kinase 3,
HER2 human epidermal growth factor receptor 2, IKZF IKAROS family zinc finger, LVEF left ventricular ejection fraction, MEK mitogen-activated protein kinase, mTOR mammalian (or
Cardiomyopathy, hypertension, venous or arterial
Bradycardia, prolongation of QT interval corrected
drugs have been shown to promote the degrada-

cholesterolemia, hypertriglyceridemia, hyper-

mechanistic) target of rapamycin, NA not applicable, NQO2 NAD(P)H quinone dehydrogenase 2, PDGFR platelet-derived growth factor receptor, PI3K phosphatidylinositol 3-kinase,
Cardiometabolic toxic effects, including hyper

Only two drugs targeting the PI3KAKTmTOR signaling pathway, everolimus and temsirolimus, which are mTOR complex 1 inhibitors, have been approved by the Food and Drug
tion of two B-cell transcription factors, which
Common Cardiovascular Toxic Effects

Venous or arterial thromboembolic events

has introduced selective protein degradation as

thromboembolic events, arrhythmia

a new approach to drug activity.51,53,54 These drugs

Atrial fibrillation, other arrhythmias

have been associated with a number of cardio-
vascular toxic effects (Table1). Initial clinical
trials involving two immunomodulatory drugs,
thalidomide and lenalidomide, showed a high
risk of venous thromboembolic disease, espe-
for heart rate

Cardiomyopathy

cially when the drugs were combined with high-

glycemia

dose dexamethasone, which led to a protocol

Myocarditis
Myocarditis
modification requiring mandatory thrombopro-
phylaxis with aspirin or anticoagulation.55 Im-
munomodulatory drugs are also associated with
an increased risk of arterial events, which has
Lymphoid transcription factors IKZF1
PI3KAKTmTOR signaling pathway

led to a black-box warning of an increased risk

of myocardial infarction and stroke in patients
Ubiquitinproteasome system
Anaplastic lymphoma kinase

with multiple myeloma who are receiving lena

Cellular Target

Programmed cell death 1

Brutons tyrosine kinase

lidomide and dexamethasone. For these reasons,

the International Myeloma Working Group issued
a consensus statement that recommended throm-
and IZKF3
MEK1, MEK2

boprophylaxis for high-risk patients with multi-

ple myeloma.56 Carfilzomib, an irreversible pro-
Administration. Many other inhibitors targeting this signaling pathway are currently in clinical trials.
CTLA4

teasome inhibitor, has been associated with a

high risk of various cardiovascular complica-
tions, despite considerable efficacy in patients
with multiple myeloma.57,58 In a recent trial com-
Thalidomide, lenalidomide, poma

paring the efficacy of a combination of carfilzo-

mib, lenalidomide, and dexamethasone with that
Pembrolizumab, nivolumab
Everolimus, temsirolimus

of lenalidomide and dexamethasone, the carfil-

Bortezomib, carfilzomib
Drug

zomib group had a higher incidence of a spec-

Crizotinib, ceritinib

trum of cardiovascular toxic events than the

group not receiving carfilzomib; these events
lidomide

Ipilimumab
Trametinib

included heart failure (6.4% vs. 4.1%), ischemic

Ibrutinib

heart disease (5.9% vs. 4.6%), venous thrombo-

embolism (10.2% vs. 6.2%), and hypertension
(14.3% vs. 6.9%).58
Cancer immunotherapies, such as immune
Other multitargeted tyrosine kinase inhibitors

and VEGF vascular endothelial growth factor.

checkpoint inhibitors (e.g., inhibitors of pro-

Anaplastic lymphoma kinase inhibitors

grammed cell death 1 [PD-1]), have shown

Brutons tyrosine kinase inhibitors

unprecedented activity and even long-term re-

missions in a subgroup of cancers, including
PI3KAKTmTOR inhibitors

metastatic melanomas.59 The cardiovascular tox-

Immune checkpoint inhibitors

icity profile is unclear at this point, given the

Immunomodulatory drugs

novelty of this class. At least one case of autoim-

Proteasome inhibitors

mune myocarditis has been documented after

MEK inhibitors

treatment with a PD-1 inhibitor.60 The disruption

of PD-1 in mice has led to cardiomyopathy and
sudden death.61 The cardiovascular safety profile
Class

is even less clear when immunotherapies are used

in combination.62

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 The n e w e ng l a n d j o u r na l
Gener a l C onsider at ions
The current experience with cardiovascular toxic
effects associated with cancer therapies intro-
duces several important concepts that are per-
tinent to future oncology trials. First, given the
high prevalence of cardiovascular disease in
the general population, it is imperative to de-
fine drug-related toxic effects versus cardiovas-
cular events that are not related to these drugs.
Second, cardiovascular toxic effects that are
identified with new cancer therapies must also
be juxtaposed against the prognosis of the can-
cer, existing therapies in the same class, and the
net benefit of therapy. The threshold for toxicity
may be different for a first-in-class therapy for a
cancer type that has a poor prognosis and has
few existing treatment possibilities versus a
later-generation drug in a cancer with multiple
existing therapies and a generally good progno-
sis. Similarly, cardiovascular considerations may
play a part in the specific therapy that is selected
in a cancer that has an overall good prognosis
and that has a number of approved therapies.
Third, cancer clinical trials often exclude pa-
tients with a previous cardiovascular history. In
addition, most oncology clinical trials do not
prospectively evaluate cardiac measurements,
such as left ventricular dysfunction. As a result,
cardiovascular events may be higher in the real-
world population. In this regard, once a therapy
is approved, it is important to establish multi-
center registries in which cardiovascular events
can be monitored. Fourth, a closer collaboration
between cardiologists and oncologists is neces-
sary, both in clinical trial design and in adjudi-
cating cardiovascular end points. The National
Cancer Institute Common Terminology Criteria
for Adverse Events (CTCAE) were developed to
standardize reporting of adverse reactions in
oncology clinical trials. However, these criteria
often differ from methods that are actually used
in cardiovascular drug trials, which compromis-
es the ability to correctly classify the nature of
the cardiovascular toxicity.47 In addition, even
within the CTCAE, there are various definitions
for a specific adverse cardiovascular effect. For
example, cardiomyopathy can be categorized
and graded under either heart failure or left ven-
tricular dysfunction. Fifth, when a drug-associ-
1464 n engl j med 375;15nejm.org October 13, 2016
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of m e dic i n e
ated toxicity is identified, it is imperative to
understand the precise mechanisms of cardio-
vascular toxicity and to identify patients at risk
for cardiovascular events. Just as so-called preci-
sion medicine has revolutionized cancer treat-
ment, a similar personalized approach must be
incorporated in toxicity assessment in drug se-
lection. Finally, more rigorous preclinical car-
diovascular platforms are necessary to detect
potential cardiovascular toxicity and to elucidate
mechanisms of toxicity.
Cardio-oncology has evolved in the past
decade because of the explosion of cancer treat-
ments and related cardiovascular toxicity. How-
ever, the intersection between cancer and car-
diovascular disease extends beyond toxicology
(Fig.2). Tumors themselves may adversely affect
the cardiovascular and metabolic systems or may
arise from cardiovascular tissue.63 In addition,
emerging data suggest that common genetic and
traditional risk factors may predispose patients
to both cancer and cardiovascular and meta-
bolic diseases. For example, somatic or inherited
mutations in select genes not only may predis-
pose patients to various cancers but also may
lead to an increased risk of cardiovascular dis-
ease or cardiovascular risk factors, such as in-
sulin sensitivity.64,65 Obesity and hyperlipidemia,
which are established risk factors for cardio-
vascular disease, may also predispose patients
to certain cancers, such as estrogen-receptor
positive breast cancer.66,67 The recent discovery
of a cholesterol metabolite that activates the es-
trogen receptor and stimulates tumor growth
lends biologic plausibility to these observa-
tions.68 Lowering cholesterol levels through life-
style modifications, pharmacologic intervention,
or exercise all factors that have been known
to be cardioprotective may also reduce the
risk of breast cancer or slow tumor growth.69,70
If true, this concept would have enormous pub-
lic health implications and directly affect the
care of patients with cancer and subsequent sur-
vivors.
Cancer survivors, who today number nearly
15 million in the United States alone, face many
challenges, including the risk of cancer recur-
rence and cardiovascular perils during survivor-
ship.71 A simple ABCDE approach has been
proposed to prevent cardiovascular disease in
 Cardiovascular Effects of Targeted Cancer Ther apies

Shared Common Risk Factors

Genetic Cigarette Obesity Hyperlipidemia Sedentary Diabetes Aging

predispositions smoking lifestyle

Cancer Treatment
Cardiovascular
Radiation Involvement from Tumor Cardiac Tumors
Traditional
chemotherapies Cardiac amyloidosis from Myxoma
Cardio-oncology Development Targeted cancer plasma-cell dyscrasia Lipoma
(intersection of cancer and therapies Cardiac metastasis Papillary fibroelastoma
between cardiovascular Other new cancer Carcinoid heart disease Rhabdomyoma,
cancer and disease therapies from carcinoid tumors sarcoma
cardiovascular
disease)

Vascular Toxic Effects

Hypertension
Venous and arterial
thromboembolic events
Cancer-cell Peripheral-artery disease
death Pulmonary hypertension
Vasospasm
Proteinuria
Accelerated atherosclerosis Cardiovascular
Metabolic derangements disease

Cardiac Toxic Effects

Decline in left ventricular

ejection fraction
Congestive heart failure
Arrhythmia
Myocarditis
Pericardial disease
Pericardial effusion

Prevention Strategies (ABCDE Approach)

A B C D E
Awareness Blood-pressure Cholesterol lowering Diet Exercise
Assessment control Cigarette cessation Dose of chemotherapy Echocardiography
Aspirin Diabetes management

Figure 2. The World of Cardio-oncology Where Cancer and Cardiovascular Disease Meet.
The intersection between cancer and cardiovascular disease extends beyond cardiovascular and cardiometabolic
toxic effects that are associated with cancer treatment. Cancers themselves may arise from cardiac tissue or directly
cause cardiovascular diseases. In addition, there is a growing appreciation of common risk factors that predispose
patients to both cancer and cardiovascular disease, which are by far the two most common causes of death and com-
plications in industrialized countries. This latter concept may have major implications for public health, including
the health of more than 15 million cancer survivors in the United States alone. A simple ABCDE approach, which
has been proposed to prevent cardiovascular disease in cancer survivors, may have the added benefit of protecting
patients from the recurrence of cancer.

n engl j med 375;15 nejm.org October 13, 2016 1465

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 The n e w e ng l a n d j o u r na l of m e dic i n e

cancer survivors (Fig.2). This approach may leading causes of death and complications in
have the added benefit of protecting patients industrialized countries.
from the recurrence of cancer.45,72,73 In light of Dr. Moslehi reports receiving consulting fees from Pfizer,
these intriguing emerging data, additional re- Takeda/Millennium, Ariad, Bristol-Myers Squibb, Acceleron,
search is needed to further understand and tar- Vertex, Incyte, and Verastem. No other potential conflict of in-
terest relevant to this article was reported.
get the common pathways that lead to cancer Disclosure forms provided by the author are available with the
and to cardiovascular disease, still by far the two full text of this article at NEJM.org.

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