Online Continuing Education Activity: Cardiotoxicity of Anticancer Treatments: Epidemiology, Detection, and Management

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ARTICLE TITLE: Cardiotoxicity of Anticancer Treatments: Epidemiology, Detection, and Management CME CNE
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After reading the article “Cardiotoxicity of Anticancer Treatments: Epidemiology, Detection and Management,” the learner should be able to:
1. Review the most common and most serious types of cardiotoxicity associated with treatment of cancer.
2. Describe options for prevention, diagnosis, and treatment of cardiovascular disease associated with anticancer systemic therapies and radiotherapy.
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NURSING ADVISORY BOARD DISCLOSURES:
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Susan Jackson, RN, MPH, has no financial relationships or interests to disclose.
Barbara Lesser, BSN, MSN, has no financial relationships or interests to disclose.
AUTHOR DISCLOSURES:
Susan Dent, MD, reports consulting fees from Hoffman-La Roche, Novartis, and Amgen outside the submitted work. Daniel Lenihan, MD, reports grants from Takeda and
Acorda; personal fees from Roche (Data Safety and Monitoring Board), and consultant fees from Bristol Myers Squibb and Onyx. Giuseppe Curigliano, MD, PhD;
Daniela Cardinale, MD, PhD; Carmen Criscitiello, MD, PhD; Olexiy Aseyev, MD, PhD; and Carlo Maria Cipolla, MD, have no financial relationships or interests to disclose.
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SPONSORED BY THE AMERICAN CANCER SOCIETY, INC. VOLUME 66 | NUMBER 4 | JULY/AUGUST 2016 309
Cardiotoxicity of Anticancer Treatments
Cardiotoxicity of Anticancer Treatments: Epidemiology,

Detection, and Management
Giuseppe Curigliano, MD, PhD1; Daniela Cardinale, MD, PhD2; Susan Dent, MD3; Carmen Criscitiello, MD, PhD1;
Olexiy Aseyev, MD, PhD3; Daniel Lenihan, MD4; Carlo Maria Cipolla, MD2
Cancer and heart disease are the leading causes of morbidity and mortality in the industrialized world. Modern treatment strat-
egies have led to an improvement in the chances of surviving a diagnosis of cancer; however, these gains can come at a cost.
Patients may experience adverse cardiovascular events related to their cancer treatment or as a result of an exacerbation of
underlying cardiovascular disease. With longer periods of survival, late effects of cancer treatment may become clinically evi-
dent years or decades after completion of therapy. Current cancer therapy incorporates multiple agents whose deleterious car-
diac effects may be additive or synergistic. Cardiac dysfunction may result from agents that can result in myocyte destruction,
such as with anthracycline use, or from agents that appear to transiently affect left ventricular contractility. In addition, cancer
treatment may be associated with other cardiac events, such as severe treatment-induced hypertension and vasospastic and
thromboembolic ischemia, as well as rhythm disturbances, including QTc prolongation, that may be rarely life-threatening. Early
and late effects of chest radiation can lead to radiation-induced heart disease, including pericardial disease, myocardial fibrosis,
cardiomyopathy, coronary artery disease, valvular disease, and arrhythmias, in the setting of myocardial fibrosis. The discipline
of cardio-oncology has developed in response to the combined decision making necessary to optimize the care of cancer
patients, whether they are receiving active treatment or are long-term survivors. Strategies to prevent or mitigate cardiovascular
damage from cancer treatment are needed to provide the best cancer care. This review will focus on the common cardiovascu-
lar issues that may arise during or after cancer therapy, the detection and monitoring of cardiovascular injury, and the best
management principles to protect against or minimize cardiotoxicity during the spectrum of cancer treatment strategies. CA
Cancer J Clin 2016;66:309-325. V C 2016 American Cancer Society.
Keywords: cancer treatment, cardiac dysfunction, cardio-oncology, cardiotoxicity, hypertension, rhythm disturbances, vascu-
lar events
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Introduction
Mortality rates from cancer have declined over the past 30 years largely because of early detection strategies, improved surgi-
cal approaches, as well as advances in cancer therapeutics.1-3 Improvement in survivorship, however, can be associated with
other organ injuries, including impact on cardiovascular health.4 Cardiovascular (CV) disease (CVD) is now the second
leading cause of long-term morbidity and mortality among cancer survivors.1-3,5,6 Conventional chemotherapy and targeted
therapies are associated with an increased risk of cardiac damage, including left ventricular (LV) dysfunction (LVD) and
heart failure (HF),7,8 treatment-induced hypertension, vasospastic and thromboembolic ischemia, as well as rhythm distur-
bances, including conduction system damage and potentially QTc prolongation, that may be rarely life-threatening.
Although some of these cardiac adverse effects are irreversible and cause progressive CVD, others induce only temporary
dysfunction with no apparent long-term sequelae.9 Early and late effects of chest radiation can lead to radiation-induced
heart disease (RIHD), which may involve a spectrum of cardiac conditions, such as pericardial disease, myocardial fibrosis,
1
Director, Division of Experimental Therapeutics, Division of Medical Oncology, European Institute of Oncology, Milan, Italy; 2Director, Division of Cardi-
ology, Cardio-Oncology Program, International Cardio-Oncology Society (ICOS), European Institute of Oncology, Milan, Italy; 3Associate Professor and
Postdoctoral fellow, The Ottawa Hospital Cancer Center, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; 4Director, Division of
Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN
Corresponding author: Giuseppe Curigliano, MD, PhD, Istituto Europeo di Oncologia, Division of Experimental Therapeutics, Via Ripamonti 435, 20133 Milano,
Italy; giuseppe.curigliano@ieo.it
DISCLOSURES: Susan Dent reports consulting fees from Hoffman-La Roche, Novartis, and Amgen outside the submitted work. Daniel Lenihan reports grants
from Takeda and Acorda; personal fees from Roche (Data Safety and Monitoring Board), and consultant fees from Bristol Myers Squibb and Onyx. The remaining
authors report no conflicts of interest.
We thank Dr. Lucia Gelao for the editorial support.
doi: 10.3322/caac.21341. Available online at cacancerjournal.com
310 CA: A Cancer Journal for Clinicians

CA CANCER J CLIN 2016;66:309–325
cardiomyopathy, coronary artery disease (CAD), valvular average.18,19 Compared with controls, long-term childhood
disease, and arrhythmias in the setting of myocardial fibro- cancer survivors had 15-fold increased rates of congestive
sis.10 Oncologists face the challenge of treating patients with HF, 10-fold higher rates of CVD, and 9-fold higher rates
the best cancer therapies available without adversely impact- of stroke.20 These results have significant implications for
ing CV health. The discipline of cardio-oncology has devel- adult cancer survivors who face the CV effects of aging
oped in response to the combined decision making necessary compounded by the potential detrimental impact of cancer
to optimize the care of patients with cancer, whether they therapy. Recognition of the importance of CV health in
are receiving active treatment or are long-term survivors after adult cancer patients is paramount if we are to sustain the
successful treatment. This review will focus on the common survival gains achieved with modern cancer therapies.
CV issues that may arise during or after cancer therapy, the
detection and monitoring of CV injury, and the best man- Common CV Adverse Events
agement principles to protect or minimize the impact of CV LVD and HF
issues during the spectrum of cancer therapies.
Cardiac dysfunction and HF are among the most serious CV
consequences of systemic cancer treatment.9 Conventional
Epidemiology of Cancer Therapy-Induced chemotherapeutics, such as anthracyclines, antimetabolites,
Cardiotoxicity and cyclophosphamide, can induce permanent myocardial cell
Cancer and heart disease are the leading causes of morbid- injury, leading to acute or chronic LVD.21,22 Anthracyclines,
ity and mortality in the industrialized world. However, commonly used in the treatment of solid tumors (ie, breast
there is cause for optimism. Modern treatment strategies cancer, osteosarcoma, etc) and hematologic malignancies
have led to an improvement in the chances of surviving a (Hodgkin/non-Hodgkin lymphoma, acute lymphoblastic
diagnosis of cancer; the 5-year survival for early stage breast leukemia, etc), can trigger significant LVD. Anthracycline-
cancer increased from 79% in 1990 to 88% in 2012,2,3,6,11 related LVD has historically been considered to be dose-
and similar improvements have been seen with some other dependent, cumulative, and progressive,22,23 which manifest
solid and hematological cancers, including non-Hodgkin as decreased LV ejection fraction (LVEF) and, ultimately,
lymphoma and testicular cancer.1 Long-term cancer survi- symptomatic HF in up to 5% of patients.24 The mechanism
vors are expected to increase by approximately 30% in the of anthracycline-induced cardiac injury has been studied
next decade to an estimated 18 million by 2022 in the extensively and is still not clearly understood.15 Structural
United States alone.12 These improvements in survivorship cardiomyocyte alterations and cell death induced by anthra-
can come at a cost.4 Current anticancer therapies are associ- cyclines are mediated in part by reactive oxygen species (ROS)
ated with unique and various degrees of direct (eg, myocar- generated in iron-dependent chemical reactions. ROS lead to
dial toxicity, ischemia, hypertension, arrhythmias)13-17 as the peroxidation of myocyte membranes and, after calcium
well as indirect CV insults (eg, unfavorable lifestyle influx, into the intracellular space, which can ultimately lead
changes). The incidence of cancer treatment-induced CV to permanent myocyte damage. In addition, mechanisms have
injury varies widely, depending on the specific cancer ther- been identified, including disturbances in DNA topoisomerase
apy used, duration of therapy, and underlying patient 2-b (Top2b) metabolism.25 The risk of doxorubicin-induced
comorbidities. In a recent comprehensive review of breast HF (which can occur within hours, weeks, or years after expo-
cancer survivors in the United States, women were noted to sure) increases with cumulative dose of anthracycline: 3% to
be at significantly increased risk of death caused by CVD, 5% with 400 mg/m2, 7% to 26% at 550 mg/m2, and 18% to
exceeding their risk of death from the initial cancer itself or 48% at 700 mg/m2.24,26,27 High-risk patients include those at
from recurrent disease.5,6,11 CVD is the predominant cause the extremes of age (<5 or >65 years), those who received
of mortality in breast cancer patients over 50 years of age18 prior or concurrent chest radiation, and those with preexisting
and is a more common contributor than cancer to mortality cardiac disease or established CV risk factors.22
among older cancer survivors.5,6,11,18 CVD is not always In a Surveillance, Epidemiology, and End Results
caused by toxicity from cancer therapy exposures, and it can (SEER) database review of elderly breast cancer patients, the
be a normal disease process in older adults. However, the adjusted hazard ratio (HR) for HF was 1.26 (95% confidence
impact of cancer therapies on CVD in the general adult interval [CI], 1.12-1.42) for those who received adjuvant
cancer survivor population is largely unknown. We can gain anthracyclines compared with those who received nonan-
some insight from longitudinal studies in the pediatric pop- thracycline adjuvant regimens.18 The cumulative incidence
ulation. The Childhood Cancer Survivor Study showed of HF at 10 years was 38% after anthracyclines, 32.5% with
that, 15 to 25 years after diagnosis, survivors of childhood nonanthracycline chemotherapy regimens, and 29% with no
cancer have an 8.2-fold higher rate of cardiac death com- chemotherapy.18,28 The likelihood of anthracycline-induced
pared with the age-matched and sex-matched national HF almost doubles with each 10-year increase in age.
VOLUME 66 _ NUMBER 4 _ JULY/AUGUST 2016 311

TABLE 1. Potential Cardiac Toxicity Induced by Anticancer Chemotherapeutic Agents

FREQUENCY OF
DRUG STUDY TOXIC DOSE RANGE CARDIAC TOXICITY OCCURRENCEa
Doxorubicin Chlebowski 197930 > 450 mg/m2 Left ventricular dysfunction Common
Epirubicin Tjuljandin 199031 > 900 mg/m2 Common
Idarubicin Anderlini 199532 150-290 mg/m2 Intermediate
Paclitaxel Perez 199833 Conventional dose Left ventricular dysfunction Intermediate
Docetaxel Kenmotsu & Tanigawara 201534 Intermediate
Cyclophosphamide Gottdiener 1981,35 Goldberg 198636 >100-120 mg/kg Left ventricular dysfunction Intermediate
Ifosfamide Kandylis 1989,37 Tascilar 2007,38 Cancer Care Ontario39 >10 mg/m2 Uncommon
Capecitabine Sent€urk 200940 Conventional dose Cardiac ischemia Intermediate
Fluorouracil Sent€urk 2009,40 Schimmel 2004,41 Chanan-Khan 200442 Intermediate
Paclitaxel Perez 199833 Conventional dose Cardiac ischemia Uncommon
Docetaxel Kenmotsu & Tanigawara 201534 Intermediate
Trabectedin Lebedinsky 201143 Conventional dose Cardiac ischemia Intermediate
Arsenic trioxide Brana & Taberno 201044 Conventional dose QTc prolongation Common
Paclitaxel Perez 199833 Conventional dose QTc prolongation Uncommon
a
Common indicates that more than 5% reported incidence; intermediate, between 1% and 5% reported incidence; uncommon, less than 1% reported incidence.
Peripheral and coronary artery disease (CAD) (HR, 1.31 tion in response to pressure overload compared with
and 1.58, respectively), diabetes (HR, 1.74), hypertension normal mice.15 Therefore, it would appear that ErbB2
(HR, 1.45), as well as emphysema and chronic bronchitis receptor signaling is important in the maintenance of myo-
(HR, 1.68), represent additional predictors of increased cardial function.15 In contrast to anthracycline-induced car-
risk for cardiac dysfunction.29 The risk of HF remains diotoxicity, trastuzumab exposure can result in LVD and
higher for patients who receive anthracyclines compared HF that appears mostly reversible.45 At highest risk for car-
with those who receive other agents, even after excluding diotoxicity from trastuzumab exposure are those aged >50
elderly patients and those with relevant comorbidities.18,29 years, patients with underlying heart disease or hyperten-
Cancer treatment-induced HF occurs with several other sion, those with baseline LVEF between 50% and 55% or
traditional chemotherapeutic agents, including cyclophos- lower, and those who have also received anthracycline ther-
phamide (7%-28%)21and docetaxel (2.3%-8%)26 apy. The introduction of adjuvant trastuzumab for patients
30-44
(Table 1). The potential for permanent cardiac dam- with HER2-positive, early stage breast cancer has reduced
age with exposure to anthracyclines has led to the adop- the risk of breast cancer recurrence by 50% and mortality by
tion, in some clinical settings (ie, early stage breast 33%.46 However, in the 5 major adjuvant trastuzumab trials
cancer), of chemotherapy regimens with lower cumulative (summarized in Table 2),47-50 symptomatic, severe HF/car-
anthracycline exposure. diac events, ranging from 0% to 3.9%, were observed with
Many targeted therapies, particularly monoclonal anti- the addition of trastuzumab to traditional chemother-
bodies and tyrosine kinase inhibitors (TKIs), targeting apy.51-53 Long-term follow-up of the pivotal adjuvant trials
human epidermal growth factor receptor 2 (HER-2) (ie, have demonstrated the cardiac safety of trastuzumab with
trastuzumab, pertuzumab, etc), vascular endothelial growth no substantial increase in CV events over 8 to 10 years,
factor (VEGF), and VEGF receptors (ie, bevacizumab, even with longer term trastuzumab therapy.49,54 However,
sunitinib, sorafenib, etc), and Abl kinase activity (ie, imati- it is difficult to generally define cardiac toxicity across stud-
nib, nilotinib, dasatinib, etc), have been demonstrated to ies, as criteria vary by trial. Current clinical trials in early
interfere with molecular pathways crucial to CV health.12,13 breast cancer are taking advantage of the role of dual
LVD associated with targeted therapies has been most HER2 blockade, including the synergistic activity of pertu-
extensively evaluated in the breast cancer population treated zumab and trastuzumab. To date, there has not been any
with trastuzumab. Trastuzumab binds to the extracellular additional cardiac safety concern when those agents were
domain of the erb-b2 receptor tyrosine kinase 2 (ErbB2)/ combined55,56; however, we await the results of a large, pro-
HER2 and leads to reduced ErbB2 signaling via several spective, randomized trial (Aphinity trial) exploring this
mechanisms. It has been speculated that the cardiac dys- combination in the adjuvant setting.57 Two neoadjuvant
function associated with trastuzumab is a direct conse- studies (Neosphere, Tryphaena) demonstrated higher path-
quence of ErbB2 inhibition in cardiomyocytes.15 Mice with ological complete response rates in women with breast can-
cardiac-specific deletion of ErbB2 develop dilated cardio- cer treated with chemotherapy and dual HER2 blockade
myopathy and demonstrate exaggerated systolic dysfunc- (pertuzumab, trastuzumab) compared with chemotherapy

TABLE 2. Cardiotoxicity in the Major Adjuvant Trastuzumab Trials for HER2-Positive Patients
SEVERE CHF/CARDIAC DISCONTINUED H
ASYMPTOMATIC SYMPTOMATIC EVENTS (CHF OR FOR CARDIAC
TRIAL DESIGN DROP IN LVEF, % DROP IN LVEF, % DEATH), % REASONS, %
NSABP B31 (Perez 201147), AC 3 4 1 T vs 34 vs 17 3.9 vs 1.3 18a

n 5 2043 AC 3 4 1 TH 1 H
NCCTG N9831 (Perez 201147), AC 3 4 1 T vs 3.3 vs 2.8 vs 0.3 5b
n 5 2766 AC 1 T 1 H vs
AC 3 4 1 TH 1 H
BCIRG 006 (Samon 201148), AC 3 4 1 T vs 18 vs 10 vs 8.6 1.87 vs 0.38 vs 0.38
n 5 3222; update with SABCS 2009 AC 3 4 1 TH 1
H vs TCaHc
HERA (Goldhirsch 2013,49 Adj CT ! H vs 3.04 vs 0.53 OR 1.7 vs 0.06 0.6 vs 0 4.3
Baselga 200650), n 5 5102 Adj chemo aloned 7.03 vs 2.05
FinHer (Baselga 200650), V or T 6 H ! 3.5 vs 6.0 0
n 5 232 FEC 3 3e
6, with or without; A, anthracycline; AC, anthracycline plus cyclophosphamide; Adj, adjuvant; BCIRG, Breast Cancer International Research Group; C, cyclo-
phosphamide; Ca, carboplatin; chemo, chemotherapy; CHF, cardiac heart failure; E, epirubicin; F, 5-flouroracil; FEC, 5-fluorouracil, epidoxorubicin, plus cyclo-
phosphamide; FinHer, Finland Herceptin trial; H, trastuzumab; HERA, Herceptin Adjuvant trial; LVEF, left ventricular ejection fraction; NCCTG, North Central
Cancer Treatment Group; NSABP, National Surgical Adjuvant Breast and Bowel Project; SABCS, San Antonio Breast Cancer Symposium; T, taxane; TCaH, tax-
ane, carboplatin, plus trastuzumab; V, vinorelbine. aBecause of unacceptable drops in LVEF, 3.23% did not receive H after A. bBecause of unacceptable drops
in LVEF, 5.0% did not receive H after A. cThe study included an A-free arm. dNinety-six percent of chemotherapy was A-containing. eThere were no patients
who had prior A exposure before H exposure; H exposure was limited to 9 weeks.
and trastuzumab therapy alone. In the Tryphanea study, Hypertension

the primary endpoint of cardiac safety was met, with a low The TKIs, which include certain VEGF signaling path-
incidence of symptomatic and asymptomatic LV systolic way (VSP) inhibitors, such as sorafenib and sunitinib,
dysfunction across all arms.58 commonly cause hypertension.64 Although these are
Cardiac dysfunction has also been reported with angio- effective anticancer agents, their clinical use may be lim-
genesis inhibitors, including bevacizumab (1.7%-3%) and ited by their potential negative impact on CV health.
sunitinib (4%-11%).59 Inhibitors of VEGF receptors, such as Hypertension is the most frequent cardiotoxicity
sunitinib and sorafenib, block several tyrosine kinase recep- observed with VSP inhibitors, with a reported incidence
tors,52 thus making it difficult to identify which targets of 19% to 47% (see Table 3).60,65-76 The mechanisms of
mediate cardiotoxicity.59 Preclinical studies have associated hypertension induced by VSP inhibitors have recently
sunitinib therapy with LV systolic dysfunction related to the
been reviewed15 and include: reduced nitric oxide pro-
inhibition of 50 adenosine monophosphate-activated protein
duction in the wall of arterioles, increased endothelin-1
kinase (AMPK), a regulator of cardiomyocyte response to
production, and capillary rarefaction that results in the
stress.60 This inhibition leads to a condition of energy deple-
reduction of effective capillary beds.12,77 In addition,
tion and consequent cardiomyocyte dysfunction. Mitochon-
VSP inhibitor-induced hypertension is perhaps related to
drial dysfunction may explain the transient episodes of LV
VEGF-mediated suppression of nephrin, a transmem-
systolic dysfunction observed in clinical practice. A marked
brane protein that is important for the maintenance of
increase in systemic vasoconstriction, increasing the afterload
the glomerular slit diaphragm, which may contribute to
on a susceptible LV, provides another plausible explanation
proteinuria seen with this class of drugs. Strategies to
for LV systolic dysfunction.61
attenuate or prevent VSP inhibitor-induced hypertension
The hypothesis of reversibility for cardiac damage is not
are necessary to prevent cardiac dysfunction and early
unique to toxic exposure from chemotherapy or targeted
agents, because the features of stunning or hibernation of termination of effective anticancer therapy.
the myocardium are well established in cardiac physiol-
ogy.62 Myocyte injury may also be reversible if the extent of Vascular Thrombosis and Ischemia
damage has not met a threshold of irreversibility; if cell Several of the newer TKIs (dasatinib, nilotinib, and ponati-
death exceeds this threshold, then it will result in potential nib) that have revolutionized the treatment of some hemato-
permanent LV contractile dysfunction. The distinction logic cancers appear to be associated with important vascular
between reversible and irreversible cardiac dysfunction, events.78,79 There is also an increased rate of thrombotic
however, is somewhat arbitrary. In fact, if LVD is detected adverse events in patients treated with combination therapy
early and appropriate HF-based treatment is instituted, for multiple myeloma that includes dexamethasone, revlimid,
even anthracycline cardiac damage may be reversible.63 and proteasome inhibitors like carfilzomib.80,81 The nature

TABLE 3. Rates of Hypertension With Selected Angiogenesis Inhibitors
GRADE 3/4 HYPERTENSION

RATES, %
DISEASE DRUG STUDY ANTIANGIOGENIC CONTROL

65 66
Colon cancer Bevacizumab Dewdney 2012, Mir 2011 11 2.3
Renal cell cancer Bevacizumab Fraeman 201367 36 NA
Lung cancer Bevacizumab Mir 2011,66 Chen 201568 7 0.7
Breast cancer Bevacizumab Fraeman 2013,67 Gampenrieder 201469 14.8 14.6
Ovarian cancer Bevacizumab Fraeman 201367 26.4 16.7
Renal cell cancer Sunitinib Larochelle 201271 8 1
GIST Sunitinib George 201272 3 0
Breast cancer Sunitinib Sungyub & Chamberlain 201573 6 NA
Breast cancer Sorafenib Funakoshi 201374 17 12
Lung cancer Cediranib Langenberg 200975 35 NA
Breast cancer Cediranib Langenberg 200975 42 NA
Phase 1 Sorafenib and bevacizumab Castellano 2013,76 Azad 200870 33 NA
GIST, gastrointestinal stromal tumor; NA, not available.
of these events varies, depending on the exact agent used and Radiotherapy-Induced CV Damage
the severity of the hematologic malignancy being treated. The association of radiotherapy (RT) and cardiac dysfunc-
The range of vascular problems is related to the vascular beds tion is well recognized. Radiation-associated cardiac inju-
affected. For instance, dasatinib rarely induces pleural effu- ries are especially important in young patients with curable
sions or pulmonary hypertension,82 although the vascular malignancies, in whom the risk of developing clinically sig-
issues noted with nilotinib are completely different and likely nificant late cardiotoxicity is high. The development of CV
represent progressive atherosclerosis.83,84 In addition, combi- damage after RT may be progressive and can include coro-
nation therapies used in myeloma may increase the risk of nary artery disease, valvular disease, myocardium damage,
venous and arterial thrombotic events.85 Overall, it is fair defects in the conduction system, and diastolic dysfunc-
to say that these myriad vascular complications are impor- tion.89 The relative risk of fatal CV events after mediastinal
tant and ultimately require specific strategies to manage irradiation for Hodgkin disease and for left-sided breast
them effectively. cancer, which are the two most common reasons for RT in
young patients, is between 2.0 and 7.0 and between 1.0 and
2.2, respectively.89-91 In addition, it is worth highlighting
that these data may not reflect contemporary radiation
Rhythm Disturbances and QTc Prolongation
treatment protocols, because RT methods have significantly
Cancer therapies may be associated with a variety of
changed over time. Damage to the arterial endothelium can
rhythm disturbances but most notably can prolong the QT induce premature atherosclerosis in the coronary circula-
interval, potentially leading to ventricular arrhythmias. The tion, particularly in the left anterior descending and right
use of some medications used in supportive care during coronary arteries.90 This usually occurs 10 to 15 years after
cancer therapy (eg, antiemetics, antidepressants) in combi- RT. Acute pericarditis and either symptomatic or asymp-
nation with cancer treatments can lead to QT prolongation. tomatic chronic pericardial effusion may appear 6 to 12
A careful review of drug interactions should be considered months after RT. Stenosis and regurgitation of mitral and
the standard of care for all patients receiving cancer treat- aortic valves have been reported. Fibrosis of the conduction
ment.86 There are specific therapies that have been associ- system with disturbed heart rate and heart block (either
ated with certain rhythm disturbances, but the mechanism complete or incomplete) may also occur. These late
for this association is frequently related to electrolyte radiation-induced cardiac effects have been seen with doses
abnormalities or concomitant medications that occur in a from 30 to 40 grays.91 Newer RT techniques, including
particular population. Potential QT interval changes may 3-dimensional (3D) treatment planning with dose-volume
be related to the pharmacologic targets, but this association histograms to precisely calculate both heart volume and
is difficult to prove.86-88 In general, electrolyte abnormal- dose, should decrease the risk of direct cardiac damage.89-91
ities should be carefully managed, and concomitant medica- The prone position and deep inspiration breath hold are
tions should be chosen that have minimal impact on also commonly used as techniques. Models to predict the
rhythm disturbances. risk of radiation damage include the normal tissue

complication probability (NTCP) method, which takes effective than therapy interventions aimed at counteracting
into account the dose and the volume of normal tissues that existing damage, which can be progressive and irreversible
are subject to radiation exposure.92 The NTCP model pre- in many cases.
dicts the correlation between the given dose and the risk of Diastolic dysfunction may precede LVEF reduction
cardiac mortality within 15 years after RT.93 in patients with chemotherapy-induced cardiotoxicity.101
Accordingly, abnormal diastolic filling without evidence of
Detection of Cardiac Dysfunction and LVEF decrease has been demonstrated in chemotherapy-
Evidence for Cardiotoxicity treated patients.102 However, no diastolic parameters have
Echocardiographic Imaging been proven to definitively predict cardiotoxicity, and the role
of diastolic dysfunction in screening for the detection of early
Echocardiography, particularly 2-dimensional imaging
subclinical cardiotoxicity currently remains controversial.
(2D-Echo), is the most commonly used imaging technique
to monitor cardiac function during and after chemotherapy. Myocardial strain
It is a widely available, reproducible, noninvasive modality Newer technology has emerged that allows for an improve-
that permits safe, serial assessment of cardiac function. ment in the accuracy of calculating LVEF. One of the most
There are many technical limitations to any technique, and promising is strain-echocardiography. Strain is a measure-
2D-Echo is no exception. Recent reviews have detailed ment of myocardial deformation. As the ventricle contracts,
these considerations.94 Common parameters that are muscle shortens in the longitudinal and circumferential
followed include LVEF and myocardial strain. dimensions and thickens and lengthens in the radial direc-
LVEF tion. Strain imaging can provide an assessment of global
and regional cardiac function and can be measured using
LVEF is the most commonly accepted parameter of cardiac
either tissue Doppler or 2D-based methods.103 Several
function that independently predicts short-term and long-
small studies evaluating tissue Doppler and LV strain rate
term mortality from CV events, including myocardial
imaging have detected early subclinical changes in cardiac
infarction, ischemic and idiopathic cardiomyopathy, as well
function that preceded a decrease in LVEF.104-106 By using
as anthracycline-induced cardiomyopathy.95-99 However,
tissue Doppler-based strain imaging, a common measure-
the measurement of LVEF presents several challenges
ment known as the peak systolic longitudinal strain rate can
related to image quality, assumption of LV geometry, load
be used to reliably recognize most early myocardial defor-
dependency, and expertise. Moreover, LVEF measurement
mation variations during anticancer therapy; whereas, with
remains a relatively insensitive tool for detecting cardiotox-
speckle tracking echocardiography, an advancement of
icity at an early stage.100 This is largely because a decrease
strain imaging, peak systolic global longitudinal strain
in LVEF does not occur until a critical amount of myocar-
(GLS) would appear to be the most accurate measure. A
dial damage has taken place and cardiac compensatory
10% to 15% early decrease in GLS by speckle tracking
mechanisms are exhausted. Interestingly, in a recent study
echocardiography during therapy seems to be the most use-
involving a large, predominantly breast cancer population
ful parameter for the early detection of cardiotoxicity,
treated with anthracyclines, prospective and close monitor-
defined as a drop in LVEF or HF.103 However, currently,
ing of LVEF with standard 2D-Echo during the first 12
long-term data on large populations confirming the clinical
months after the completion of chemotherapy allowed early
significance of such changes are not available. Moreover,
detection of almost all cases of cardiotoxicity (98%), and
there are currently important limitations of these techni-
prompt treatment led to normalization of cardiac function
ques: data analysis is currently offline, time-consuming, and
in most cases (82%). In this study, candidate variables were
still depends on the quality of the acoustic windows. In
age, sex, CV risk factors, cumulative anthracycline dose,
addition, different echo machines and software packages
mediastinal RT, left chest RT, body mass index, and year
may yield different strain results, making them difficult to
of recruitment; and baseline and final (at the end of chemo-
compare. Consequently, these new echo imaging techni-
therapy) LVEF measurements were collected. LVEF at the
ques are not typically included in a routine assessment of
end of chemotherapy was an independent predictor of fur-
cardiac function during chemotherapy.94
ther development of cardiotoxicity.101
However, only 11% of patients had a full recovery—ie, The role of other imaging techniques
showed an LVEF value equal to or better than the baseline Multiple-gated acquisition (MUGA) scans can limit inter-
value (before chemotherapy initiation); in the remaining observer variability in assessing LVEF, but it has the disad-
89% of patients, cardiac function was below the baseline vantages of exposing the patient to radiation and provides
value. This evidence suggests that strategies aimed at pre- limited information on cardiac structure and diastolic func-
venting the development of LVD appear strategically more tion. Magnetic resonance imaging is considered to be the

TABLE 4. Studies Demonstrating Troponins as Predictor of Antitumor Drug-Induced Left Ventricular Dysfunction
NO. OF TROPONIN
STUDY PATIENTS CANCER TYPE DRUGS TYPE CUTOFF, ng/mL TIMING OF ASSESSMENT
Lipshultz 1997113 15a ALL AC T 0.03 Before CT; 1–3 d after each dose
Cardinale 2000114 201 Various HD CT I 0.04 0, 12, 24, 36, and 72 h after CT
Cardinale 2002115 232 Breast cancer HD CT I 0.04 0, 12, 24, 36, and 72 h after CT
Auner 2002116 30 Hematological HD CTX T 0.03 Before CT; 1-14 d after CT
Sandri 2003117 179 Various HD CT I 0.04 0, 12, 24, 36, and 72 h after CT
Cardinale 2004110 703 Various HD CT I 0.04 0, 12, 24, 36, and 72 h after CT
Specchia 2005118 79 Hematological AC I 0.15 Before CT; weekly 3 4
Kilickap 2005119 41 Various AC T 0.10 Before CT; 3-5 d after first
and last dose
Lee 2008120 86 Hematological AC I 0.20 Before each dose
Schmidinger 2008121 74 Renal carcinoma Sunitinib/sorafenib I 0.03 Before CT; bimonthly during CT
Cardinale 2010122 251 Breast cancer TRZ I 0.04 Before and after each cycle
Morris 2011123 95 Breast cancer AC 1 taxanes 1 TRZ/LAP I 0.30 Every 2 wk during CT
Sawaya 2011124 43 Breast cancer AC 1 taxanes 1 TRZ HS-I 0.015 Before CT; after 3 and 6 mo
during CT
Lipshultz 2012125 205a ALL AC/AC 1 dexrazoxane I/T Any detectable Before CT; 1-7 d after each
amount dose; end CT
Sawaya 2012126 81 Breast cancer AC 1 taxane1 TRZ HS-I 30 pg/mL Before CT; after 3 and
6 mo during CT
127
Geiger 2012 50 Various AC T NA Before CT; after 6 h,7 d, 3 mo
Drafts 2013104 53 Various AC I 0.06 Before CT; after 1, 3, and 6 mo
Mornos & Petrescu 2013128 74 Various AC HS-T NA Before CT; after 6, 12, 24,
and 52 wk
Mavinkurve-Groothuis 2013129 60a ALL AC HS-T 0.01 Before CT; after 3 and 12 mo
Ky 2014108 78 Breast cancer AC 1 taxanes 1 TRZ HS-I NA Before CT; after 3 and
6 mo during CT
Mornos 2014130 92 Various AC HS-T NA Before CT; after 12 and 36 wk
Abbreviations: AC indicates anthracycline-containing chemotherapy; ALL, acute lymphoblastic leukemia; CT, chemotherapy; CTX, cyclophosphamide; HD, high-
dose; HS-I, high-sensitivity troponin 1; HS-T, high-sensitivity troponin; I, troponin I; LAP, lapatinib; NA, not available; T, troponin T; TRZ, trastuzumab. aThis was
a pediatric population.
gold standard for the evaluation of cardiac volumes, mass, before any reduction in LVEF has occurred, in patients
and both systolic and diastolic function. However, because treated with antitumor drugs (Table 4).104,108,110,113-130
of high cost and lack of availability, this imaging modality Measurement of troponins may provide additional infor-
is not routinely used.103,105 mation, including:
1. Prediction of the severity of future LVD, because the
Cardiac Biomarkers peak value of troponin after chemotherapy is closely
A strategy based on the use of biochemical markers, in par- correlated to the extent of LVEF reduction;
ticular cardiac troponins, has developed in the last 15 years 2. Stratification of cardiac risk after chemotherapy, which
for early real-time identification, assessment, and monitoring allows for the personalization of the intensity of post-
of antitumor drug-induced cardiotoxicity. This approach chemotherapy monitoring of cardiac function;
negates the interobserver variability reported with strategies 3. Selection of patients more prone to develop cardiotox-
using imaging; but, unfortunately, the exact timing of bio- icity, in whom a cardioprotective therapy can be con-
marker measurement and the variability in techniques have sidered; and
not been adequately determined.103,107,108 4. Exclusion of most patients from prolonged cardiologic
monitoring.
Troponins In a study of 703 predominantly breast cancer patients,
Cardiac troponins are regulatory proteins within the myo- troponin I (TnI) was assessed before chemotherapy, during
cardium that are released into the circulation when damage the 3 days after the end of chemotherapy (early evaluation),
to the myocyte has occurred.109 Troponins are the first and after 1 month (late evaluation).110 Three different tro-
blood biomarkers identified to detect cardiac damage. They ponin release patterns were identified. TnI was regularly
are medium-sized proteins regulating the contractile ele- within the normal range in 70% of patients, increased only
ments actin and myosin. Although they are normally unde- at early evaluation in 21%, and increased at both early and
tectable, troponins may increase within 2 or 3 hours after late evaluations in 9%. Patients without a TnI increase after
cardiac damage occurs.110-112 Studies have shown that tro- chemotherapy showed no significant reduction in LVEF
ponins may detect cardiotoxicity at a preclinical phase, long and had a low incidence of cardiac events (1%) during the

>3-year follow-up. In contrast, TnI-positive patients had a nins, NT-pro-BNP, ST2 (interleukin 1 receptor-like 1),
greater incidence of major adverse cardiac events. In partic- LVEF, and echocardiographic parameters of myocardial
ular, among TnI-positive patients, the persistence of the deformation were used to detect LVD in patients receiving
TnI rise 1 month after chemotherapy was associated with a anthracyclines, taxanes, and trastuzumab. Decreases in peak
greater LVEF reduction and a higher incidence of cardiac longitudinal strain and increases in HS TnI concentrations at
events compared with patients who had only a transient the completion of the anthracycline treatment were predictive
increase in the marker (84% vs 37%; P < .001). An addi- of subsequent LVD. The combined assessment of the two
tional study in leukemia patients suggested that a troponin endpoints showed an improved specificity (93%) compared
elevation may identify those at risk for LVD.131 with either parameter alone (both 73%).124 However, this
High-sensitivity troponins result was associated with a reduction in sensitivity to 35%.126
Recent improvements in assay technology have led to more
Other Proposed Biomarkers
sensitive and precise troponin assays. These new high-
Other potential markers of cardiotoxicity have been investi-
sensitivity (HS) assays can now reliably measure small
gated in small studies. These include markers of endothelial
increases that are undetectable by using other troponin
dysfunction (tissue-type plasminogen activator, plasmino-
assays.132 The most recent study in which HS troponin was
gen activator inhibitor type 1, soluble intercellular adhesion
assessed was that by Ky et al,108 who investigated the associ-
molecule-1, and circulating endothelial cells), markers of
ation between multiple biomarker increases and successive
myocardial ischemia (fatty acid binding protein), as well as
development of cardiotoxicity in breast cancer patients being
markers of oxidative stress and inflammation (glutathione
treated with anthracyclines, taxanes, and trastuzumab.108 In
peroxidase, high-sensitivity C-reactive protein, interleu-
that study, however, the most important risk of cardiotoxic-
kins).132,133 Although many of these proposed biomarkers
ity was associated with HS TnI change in absolute values at
have shown significant changes during chemotherapy, the
the end of anthracycline treatments as well an increase in
impact of these changes on cardiac function are unknown;
myeloperoxidase, a marker of oxidative stress.
thus, further research is needed.136
Natriuretic peptides In summary, a novel approach based on the use of cardiac
Increased natriuretic peptide (NP) levels can detect biomarkers has emerged in the last decade, resulting in a
chemotherapy-induced LVD in both adult and pediatric promising, cost-effective diagnostic tool for early, real-time
populations.133,134 Unfortunately, many studies failed to identification, assessment, and monitoring of cardiotoxicity.
find a correlation between the increase in NP and the devel- Further trials are necessary to confirm their use in clinical prac-
opment of cardiac dysfunction, probably because significant tice. Standardization of the use of routine biomarkers in this
volume changes can occur in patients who are receiving clinical setting is a current unmet need, and future larger, pro-
chemotherapy without any significant change in LVEF. It spective, multicenter studies should provide clear indications
is noteworthy that, when considering only the two most of the appropriate use of these biomarkers in clinical practice.
used NPs—B-type NP (BNP) and N-terminal pro-BNP
(NT-proBNP)—the significant differences in analytical Management of Anticancer Drug-Related
characteristics and measured values among the most widely Cardiotoxicity
used commercial methods underline that clinicians must be The Role of Cardioprotective Therapy for
careful and cautious when comparing results obtained by Prevention
laboratories that use different methods. Understanding the The cardioprotective effects of many pharmacologic agents
utility of NP as an adjunct to clinical care in patients being have been demonstrated during cancer therapy in a laboratory
treated with potential cardiotoxic therapy is necessary.135 setting; however, most of these agents have not been proven
New prospective and multicenter studies that include large to be cardioprotective for cancer treatment-related cardiotox-
populations, using well standardized methods for dosage, icity. Several agents—dexrazozane, beta-blockers, angiotensin
and with well defined timing of sampling and cardiac end- antagonists, statins, and aldosterone antagonists—have been
points are paramount to clarify the appropriate use of NP shown to be potentially cardioprotective in patients exposed
and to interpret the results in the clinical context.
to anthracyclines or trastuzumab (Table 5).137-146
An Integrated Approach of Markers and Dexrazoxane
Cardiac Imaging Dexrazoxane significantly reduces anthracycline-related car-
An integrated approach combining biomarkers as well as diotoxicity in adults with different solid tumors and in
imaging data may yield progressive utility in predicting subse- children with acute lymphoblastic leukemia and Ewing sar-
quent cardiotoxicity. In a recent multicenter study, HS tropo- coma.147-149 There is a large amount of evidence that

TABLE 5. Cardiovascular Drugs Showing a Prophylactic Effect Against Anthracycline/Trastuzumab-Induced

Cardiotoxicity in Adult Cancer Populations
STUDY DESIGN/ NO. OF
STUDY FOLLOW-UP PATIENTS CANCER TYPE DRUGS INTERVENTION RESULTS
ACEI
Cardinale 2006137 RCT/12 mo 114 Various HD CT Enalapril No LVEF#; MACE incidence#
ARB
Nakamae 2005138 RCT/7 d 40 NHL AC Valsartan No LVEDD"; no BNP and ANP"; no QT"
Cadeddu 2010139 RCT/18 mo 49 Various AC Telmisartan No peak strain rate#; no interleukin 6"
Aldosterone antagonists
Akpek 2015140 RCT/6 mo 83 Breast cancer AC Spironolactone No LVEF#; no TNI and BNP"
Beta-blockers
Kalay 2006141 RCT/6 mo 50 Various AC Carvedilol No LVEF#
Kaya 2013142 RCT/6 mo 45 Breast cancer AC Nebivolol No LVEF and NT-proBNP"
Seicean 2013143 Retrospective/5 y 318 Breast cancer AC, TRZ Beta-blockers HF#
ACEI 1 beta-blockers
Bosch 2013144 RCT/6 mo 90 Hematological AC Enalapril 1 carvedilol No LVEF#; death#; HF#
Statin
Acar 2011145 RCT/6 mo 40 Hematological AC Atorvastatin No LVEF#
Seicean 2012146 Retrospective/5 y 67 Breast cancer AC Statins HF#
#, decrease; ", increase; ACEI, angiotensin-converting enzyme inhibitor; ANP, atrial natriuretic peptide; ARB, angiotensin receptor blocker; BNP, brain natriuretic
peptide; HD CT, high-dose chemotherapy; LVEF, left ventricular ejection fraction; LVEDD, left ventricular end-diastolic diameter; HF, heart failure; MACE, major
adverse cardiac events; NHL, non-Hodgkin lymphoma; NT-proBNP, N-terminal-probrain natriuretic peptide; QT, QT interval; RCT, randomized controlled trial;
TNI, troponin I; TRZ, trastuzumab.
patients who received dexrazoxane had a decreased incidence cin was evaluated by Cadeddu et al139 in a randomized trial
of HF compared with those who did not receive the drug. that included 49 patients with a variety of solid cancers.139
Despite these consistent positive findings, the use of dexra- Twenty-five patients who started telmisartan 1 week before
zoxane has not been widely adopted, and it is recommended chemotherapy showed no significant reductions in myocar-
as a cardioprotectant by the American Society of Clinical dial deformation parameters (peak strain rate), as evaluated
Oncology (ASCO) only in patients with metastatic breast using a tissue Doppler echo technique, and no significant rise
cancer who have already received more than 300 mg/m2 of in ROS or interleukin-6, as found in 24 control patients.139
doxorubicin.150 This might be explained by the suspicion— These results suggest that telmisartan might protect against
never confirmed—of interference with the efficacy of anthra- epirubicin-induced ROS production and inhibit the genera-
cyclines, by the occurrence of secondary malignancies, or by tion of inflammation, thus preventing the development of
its possible additive effects of myelosuppression. early myocardial impairment.139 The cardioprotective effects
of enalapril, an angiotensin-converting enzyme inhibitor
Beta-blockers
(ACE-I), were studied in a randomized, controlled trial that
Carvedilol, a nonselective beta-blocker with antioxidant
included 473 patients (53% had breast cancer) treated with
activity that is considered crucial in the treatment of
high-dose anthracyclines.137 One-hundred fourteen patients
patients with HF and LVD, is an effective cardioprotective
(24%) showed an early troponin increase and were random-
agent during doxorubicin treatment.151 This effect was
ized to receive enalapril or no treatment. Enalapril was
confirmed in a randomized study in which prophylactic
started 1 month after the end of chemotherapy and contin-
use of the drug protected both systolic and diastolic LV
ued for 1 year. In the enalapril-treated group, LVEF did not
function in a small population of anthracycline-treated change during the follow-up period. Conversely, in patients
patients.141 The protective effect of nebivolol, a beta-selective who did not receive enalapril, a progressive decrease in
beta-blocker with a nitric oxide donor capacity, has also been LVEF and an increase in end-diastolic and end-systolic vol-
demonstrated to be beneficial in a recent randomized study of umes were observed. Moreover, enalapril-treated patients
47 breast cancer patients receiving anthracycline-therapy142; had a significantly lower incidence of adverse cardiac events
notably, LVEF and NT-proBNP remained unchanged after 6 compared with controls at 1-year follow-up (2% vs 52%;
months in patients who received nebivolol. Conversely, in the P < .001).137
placebo group, a significant decrease in LVEF and an increase The preventive effects of combined enalapril and carvedilol
in NT-proBNP were observed.142 recently were tested in a randomized trial of 90 patients with
Angiotensin-converting enzyme inhibitors and hematologic malignancies who were treated with anthracy-
angiotensin receptor blockers clines.144 After 6 months, LVEF did not change in the inter-
The possible role of telmisartan, an angiotensin receptor vention group; conversely, LVEF significantly decreased in
blocker, in preventing myocardial injury induced by epirubi- controls (P 5 .035). Importantly, compared with controls,

patients in the intervention group had a lower incidence of The PRADA (Prevention of Cardiac Dysfunction Dur-
the combined event of death or HF (6.7% vs 22%; P 5 .036) ing Adjuvant Breast Cancer Therapy) trial is assessing
or of death, HF, and a final LVEF below 45% (7% vs 24%; whether the use of candesartan, metoprolol, or their combi-
P 5 .02).144 nation can prevent the development of LVD in patients on
Statins adjuvant epirubicin-containing chemotherapy with or with-
out trastuzumab.155 The results demonstrated that cande-
Statins exert antioxidative, anti-inflammatory, and other
sartan—but not metoprolol—concomitantly administrated
pleiotropic effects in addition to reducing low-density lipo-
with adjuvant chemotherapy, including epirubicin with or
protein (LDL) cholesterol. In an animal model, it was
without trastuzumab, can protect against early decline in
demonstrated that pretreatment with fluvastatin blunted
LVEF, assessed with cardiac magnetic resonance.
anthracycline-induced toxicity, reducing oxidative stress,
The International Cardioncology Society (ICOS)-ONE
enhancing the expression of antioxidative enzyme mito-
trial is the only randomized study that is designed to com-
chondrial superoxide-dismutase-2, and limiting cardiac
pare the use of enalapril administration concomitantly with
inflammation.153 In a retrospective case-control study, 67
anthracycline-containing chemotherapy (primary prevention)
women with breast cancer treated with anthracyclines who
versus enalapril administration after preclinical cardiotoxic-
also were receiving a statin drug were compared with 134
ity detection, as revealed by the increase in troponins (sec-
matched controls.146 Women treated with statins showed a ondary prevention; national clinical trial NCT01968200;
lower incidence of HF at a mean of 2.5 years of follow- clinicaltrials.gov).
up.146 Finally, in a small clinical trial of 40 patients who In the NCT01708798 study (clinicaltrials.gov), the
had normal LVEF before undergoing chemotherapy potential ability of the aldosterone antagonist eplerenone to
(which included anthracyclines), the 6-month LVEF value prevent doxorubicin-induced cardiotoxicity will be explored
was unchanged among patients treated with atorvastatin in a randomized controlled trial of breast cancer patients.
compared with an 8% absolute decrease in controls.145 Finally, at Memorial Sloan Kettering Cancer Center, an
Aldosterone antagonists ongoing randomized trial (NCT02177175; clinicaltrials.gov)
Aldosterone antagonism has been evaluated in a very recent is assessing the use of carvedilol for the prevention of anthra-
trial that included 83 patients with breast cancer who were cycline/trastuzumab therapy-associated cardiotoxicity among
randomized to spironolactone or placebo and a concomitant women with HER2-positive breast cancer using myocardial
anthracycline-containing chemotherapy control groups.140 strain for early risk stratification. In this trial, carvedilol is
During at least 24 weeks of treatment, including 3 weeks started in women who show an absolute decrease in GLS
after completing anthracycline-containing chemotherapy, below 19% or in those who have a decrease 11% from base-
spironolactone prevented a decrease in LVEF, blunted the line. It is hoped that the findings from these trials will pro-
increase in TnI and NT-proBNP, and preserved diastolic vide important insights into the best strategy for managing
function.140 cardiotoxicity induced by anticancer drugs.
Ongoing Studies Treatment

Currently, several studies are ongoing to evaluate CV drugs The Role of ACE-I and Beta-Blockers
as cardioprotectant agents. The MANTICORE-101 (Mul- Limited data exist regarding the treatment of patients with
tidisciplinary Approach to Novel Therapies in Cardiology antitumor drug-associated cardiomyopathy. Typically, these
Oncology Research) trial is evaluating the use of perindo- patients have been excluded from large randomized trials
pril versus bisoprolol in patients with HER2-positive breast evaluating the effectiveness of HF therapies. The use of
cancer who are undergoing treatment with trastuzumab in ACE-I and beta-blocking agents in this particular clinical
the prevention of LVD as assessed by cardiac magnetic setting were first evaluated in a very few retrospective studies,
resonance imaging.154 At the end of trastuzumab therapy, which involved small populations (Table 6).45,63,99,101,156-163
neither drug had an impact on LV end-diastolic volume More recently, the effectiveness of ACE-I and beta-blockers
(the primary outcome of change from baseline in the study). were prospectively assessed in this setting. In 201 consecutive
In univariate analysis, only bisoprolol was associated with patients with anthracycline-induced LVD, enalapril (com-
preservation of baseline function (from 62% to 61%; sec- bined with carvedilol when possible) was initiated at the time
ondary outcome). However, in multivariate analysis, the use of LVEF impairment detection and was up-titrated to the
of both cardiac drugs significantly predicted preserved maximal tolerated dose.63 The investigators found that the
LV function (for perindopril, P 5 .013; for bisoprolol, P < time elapsed from the end of chemotherapy to the start of
.001). These data were presented during the 2015 San HF therapy was a crucial variable for the recovery of cardiac
Antonio Breast Cancer Symposium. function. Indeed, among patients who were treated within

TABLE 6. Clinical Studies Evaluating Angiotensin-Converting Enzyme Inhibitors and Beta-Blockers in Anticancer Drug-
Induced Cardiomyopathy
NO. OF MEAN FOLLOW-UP, B-LVEF, F-LVEF,
TREATMENT AUTHOR (YEAR) PATIENTS AGE, Y STUDY DRUGS MO % % REPORTED EVENT
156
Dig 1 Diur 1 ACEI Saini 1987 3 49 CR AC 12-16 20 48 Relief of symptoms, LVEF"
Dig 1 Diur; Dig 1 Jensen 1996157 9 58 P AC 26 27 47 CD, HF
Diur 1 ACEI
Dig 1 Diur 1 ACEI; BB Fazio 1998158 1 35 CR AC 12 14 45 Relief of symptoms
BB; BB 1 ACEI Noori 2000159 2; 6 51 R AC 32 28 41 LVEF"
Dig 1 Diur; Dig 1 Jensen 200299 10 54 P AC 30 27 41 HF
Diur 1 ACEI
BB; BB 1 ACEI Mukai 2004160 3; 2 53 CR AC 27 37 53 LVEF", NYHA#
ACEI; ACEI 1 BB Tallaj 2005161 10; 15 47 R AC 70 25 34 CD, TXS
ACEI; ACEI 1 BB Ewer 200545 38 52 R AC, TRZ 10 43 56 LVEF"
ACEI 1 BB Tabet 2006162 1 52 CR AC 8 NA 30 HF
ACEI 1 BB Cardinale 201063 201 53 P AC 12-96 38 46 LVEF" up to 50%
ACEI; ACEI 1 BB Thakur & Witteles 2014134 79 52 R AC, TRZ, TKI NA 41 53 LVEF "
ACEI 1 BB Cardinale 2015101 226 50 P AC 4-228 40 52 LVEF" of 5 points 1 50%
#, decrease; ", increase; AC, anthracycline-containing chemotherapy; ACEI, angiotensin-converting enzyme inhibitor; BB, beta-blockers; B-LVEF, baseline left
ventricular ejection fraction; CD, cardiac death; CS, case report; Dig, digoxin; Diur, diuretics; F-LVEF, final left ventricular ejection fraction; HF, heart failure;
LVEF, left ventricular ejection fraction; NA, not available; NYHA, New York Heart Association; P, prospective; R, retrospective; TKI, tyrosine kinase inhibitor;
TRZ, trastuzumab; TXS, cardiac transplantation.
2 months after the end of chemotherapy, 64% had a com- Periodic monitoring with on-treatment electrocardiograms
plete recovery of LVEF. Conversely, after 2 months, the per- and electrolytes should be considered.163,164
centage of patients who recovered progressively decreased,
with no complete recovery seen after 6 months.63 Consistent Hypertension Treatment and Management
with these findings, a greater improvement in cardiac func- A collaboration between oncologists, a primary care health
tion was observed in a large population of patients with care provider, and cardiologists is essential to properly
anthracycline-induced LVD who were receiving a combina- monitor and manage hypertension, which is an unwanted
tion of enalapril and carvedilol or bisoprolol. Initiation of adverse effect of many antiangiogenic agents associated
HF medications promptly after the detection of symptomatic with VSP inhibition. Aggressive management of hyperten-
and asymptomatic anthracycline-induced cardiomyopathy sion beginning from the initiation of therapy is important
was associated with recovery in 82% of patients over a mean to avoid cardiac dysfunction; and, again, an understanding
period of 8 6 5 months. Long-term studies are needed to of the potential cardiac toxicities of the chemotherapeutic
determine if therapy with ACE-I and beta-blockers should regimen used is essential, giving further support to the con-
be prolonged lifelong, or discontinued after achievement of cept of a multidisciplinary strategy for management.
complete recovery of LVEF. Patients who are candidates for treatment with VEGF/
TKI inhibitors should be considered at higher risk for CV
QTc Prolongation Management complications if they have systolic blood pressure (BP)
Prolongation of the QT interval can lead to life- 160 mm Hg or diastolic BP 100 mm Hg; diabetes mel-
threatening cardiac arrhythmias, including “torsade de litus; established CV disease, including any history of ische-
pointes.” Although prolongation of the QT interval is not mic stroke, cerebral hemorrhage, or transient ischemic
the best predictor of proarrhythmic risk, it represents the attack; myocardial infarction, angina, coronary revasculari-
principal clinical surrogate marker by which to evaluate the zation, or HF; peripheral artery disease; subclinical organ
arrhythmic risk of a drug and has led to withdrawal of sev- damage previously documented by electrocardiogram or
eral anticancer drugs from the market. Although drugs 2D-Echo revealing LV hypertrophy; cigarette smoking;
leading to prolonged QT may possess significant risks of and dyslipidemia. Repeated BP measurements and aggres-
serious adverse events, the clinical benefit of therapy in the sive management of BP elevations are recommended to
oncologic setting, including the possibility of cure for a prevent clinically limiting complications.79,164,165
cancer patient, may outweigh the potential risks of QTc
prolongation, even when the prolongation is significant. Anticoagulation in Cancer Patients
Patients with a history of QT interval prolongation; Venous thromboembolism (VTE) is an important cause of
patients who are taking antiarrhythmics; or patients with morbidity and mortality in cancer patients. Patients receiving
relevant CVD, bradycardia, thyroid dysfunction, or electro- chemotherapy or antiangiogenic agents have a 7-fold higher
lyte disturbances should be screened and monitored. risk of developing VTE compared with patients

The prophylactic use of LMWH may be considered for

TABLE 7. Predictive Model for Chemotherapy-
Associated Venous Thromboembolism highly selected, high-risk patients only, according to the
RISK risk-assessment model validated by Khorana et al167 (Table
VARIABLE SCOREa 7), ie, in patients with scores 3 and a low bleeding
Site of cancer risk.167,168 Data about the new oral anticoagulants (dabiga-
Very high risk (stomach, pancreas) 2
High risk (lung, lymphoma, gynecologic, bladder, testicular) 1
tran, apixaban, rivaroxaban) for either prophylaxis or treat-
Prechemotherapy platelet count 350 3 109/L 1 ment of VTE in patients with cancer are still limited, and
Hemoglobin level <10 g/dL or use of red cell growth factors 1
Prechemotherapy leukocyte count >11 3 109/L 1
their use is currently not recommended (ASCO).168
Body mass index 35 kg/m2 1
a
Risk categories included low risk (score 0), intermediate risk (score 1–2), Conclusions
and high risk (score 3). Modified from Khorana AA, Kuderer NM, Culakova
E, Lyman GH, Francis CW. Development and validation of a predictive model Modern cancer treatment strategies have led to a significant
for chemotherapy-associated thrombosis. Blood. 2008;111:4902–4907.167
improvement in the chances of surviving a diagnosis of can-
cer for many years. These gains in overall outcome may be
offset by the potential negative impact of cancer therapy on
without cancer. Several randomized trials have demon- CV health. Cancer therapies may have short-term and
strated a significant thromboprophylactic effect of low- long-term side effects involving the heart and circulation,
molecular-weight heparins (LMWH) in ambulatory cancer as well as exacerbating and/or unmasking existing heart dis-
patients who are receiving chemotherapy.166,167 However, ease. The development of CV disease during the course of
routine thromboprophylaxis is currently not recommended cancer treatment can adversely impact the management of
for ambulatory cancer patients by ASCO because of the the underlying malignancy by interfering with the optimal
limited absolute risk reduction demonstrated with doses and timing of lifesaving cancer therapy. In addition,
LMWH and the concern with bleeding complications. the development of a potentially important cancer therapy
FIGURE 1. Cardiotoxicity Diagnosis and Management. AMPK, 50 adenosine monophosphate-activated protein kinase; CV, cardiovascular; BNP, B-type
natriuretic peptide; LV, left ventricle; LVD, left ventricular dysfunction; LVEF, left ventricular ejection fraction; MUGA, multiple-gated acquisition; NT-
proBNP, N-terminal pro-B-type natriuretic peptide; ROS, reactive oxygen species.

may be halted or abandoned because of a perceived will provide important guidance for clinicians on best prac-
increased CV risk. The discipline of cardio-oncology has tices for patients today, many questions remain unan-
developed in response to the combined decision making swered: How can we predict who will develop
necessary to optimize the care of patients with cancer, cardiotoxicity, what is the best prevention strategy, how
whether they are receiving active treatment or are long- should we monitor those at risk of cardiotoxicity, and what
term survivors after successful treatment (Fig. 1). Cardiol- are the best management strategies? There is an urgent
ogy and oncology organizations around the world (ie, need for collaborative research to address these questions.
European Society for Medical Oncology, American Col- Vibrant collaborative partnerships between oncologists, car-
lege of Cardiology, ASCO, European Society of Cardiol- diologists, and other allied health care professionals will
ogy, Canadian Cardiovascular Society) are now recognizing play an important role in the development and promotion
the importance of this collaboration, resulting in the of clinical care models, educational programs (for patients
ongoing development of several clinical practice guidelines and health care providers), and evidence-based research to
and position statements.94,164,165 Although these initiatives improve the care of patients being treated for cancer. 䊏
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Online Continuing Education Activity: Cardiotoxicity of Anticancer Treatments: Epidemiology, Detection, and Management

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CME INSTRUCTIONS ON RECEIVING CME CREDIT:

Cardiotoxicity of Anticancer Treatments: Epidemiology,

We thank Dr. Lucia Gelao for the editorial support.

doi: 10.3322/caac.21341. Available online at cacancerjournal.com

310 CA: A Cancer Journal for Clinicians

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TABLE 1. Potential Cardiac Toxicity Induced by Anticancer Chemotherapeutic Agents

312 CA: A Cancer Journal for Clinicians

NSABP B31 (Perez 201147), AC 3 4 1 T vs 34 vs 17 3.9 vs 1.3 18a

and trastuzumab therapy alone. In the Tryphanea study, Hypertension

VOLUME 66 _ NUMBER 4 _ JULY/AUGUST 2016 313

TABLE 3. Rates of Hypertension With Selected Angiogenesis Inhibitors

GRADE 3/4 HYPERTENSION

DISEASE DRUG STUDY ANTIANGIOGENIC CONTROL

314 CA: A Cancer Journal for Clinicians

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316 CA: A Cancer Journal for Clinicians

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TABLE 5. Cardiovascular Drugs Showing a Prophylactic Effect Against Anthracycline/Trastuzumab-Induced

318 CA: A Cancer Journal for Clinicians

Ongoing Studies Treatment

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320 CA: A Cancer Journal for Clinicians

The prophylactic use of LMWH may be considered for

VOLUME 66 _ NUMBER 4 _ JULY/AUGUST 2016 321

322 CA: A Cancer Journal for Clinicians

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324 CA: A Cancer Journal for Clinicians

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