symposium article Annals of Oncology 21 (Supplement 7): vii173–vii179, 2010

doi:10.1093/annonc/mdq295

Cardiotoxicity
I. Brana & J. Tabernero*
Medical Oncology Department. Vall d’Hebron University Hospital, Barcelona, Spain

Cancer treatment has improved extraordinarily in recent years. The development of targeted therapies has widened
the cardiotoxic spectrum of antineoplastic drugs. Optimum management of cardiovascular disease before and during
antineoplastic treatment is essential to reduce morbidity and mortality in cancer patients. This article reviews the
incidence and characteristics of cardiotoxic effects of antineoplastic drugs with special focus on the
pathophysiological mechanisms. It also emphasizes the importance of early detection and correction of cardiovascular
risk factors and the relevance of close cardiac monitoring during antineoplastic treatment in order to reduce
cardiotoxicity.
Key words: adverse effects, antineoplastic agents, arrhythmia, chemically induced heart diseases, heart failure, QTc
prolongation

introduction The main hypothesis for the underlying mechanism of AAC

is the generation of reactive free radical species that interact and
Cardiotoxicity is defined by the National Cancer Institute as the damage cellular membranes. Other possible mechanisms are

symposium
‘toxicity that affects the heart’. This definition includes a direct the induction of apoptosis, mitochondrial DNA damage,

article
effect of the drug on the heart but also an indirect effect due to changes in ATP production, downregulation of mRNA
enhancement of haemodynamic flow alterations or due to expression for sarcoplasmic reticulum calcium ATPase [5].
thrombotic events [1]. Cardiotoxicity has a rising relevance as Early interventional treatment with angiotensin-converting
a consequence of the global improvement in cancer enzyme (ACE) inhibitors and b-adrenergic blocking drugs has
management, which leads to better survival and, therefore, shown a clear benefit in adult patients with decreased left
adverse effects of treatments have significant consequences on ventricle ejection function (LVEF) not specifically caused by
patient outcome [2–4]. New targeted therapies have widened anthracycine therapy [4]. The potential role of preventive
the cardiotoxic spectrum of antineoplastic drugs. interventions, such as dexrazoxane treatment, will be discussed
The aim of this article is to describe the incidence and the later in this article.
underlying mechanisms of cardiotoxicity induced by
antineoplastic drugs focusing on targeted therapies, as well as
targeted therapies
strategies to prevent and treat this spectrum of toxic effects.
Drugs will be classified based on their main cardiotoxic effect: trastuzumab. Trastuzumab is a humanized monoclonal
left ventricle dysfunction, rhythm disturbances and ischaemia. antibody against the HER2 tyrosine kinase receptor. The
incidence of LVEF decrease or asymptomatic heart failure (HF)
is 7% (Table 1), but it can rise to 13% when trastuzumab is
left ventricle dysfunction administered with concurrent paclitaxel and to 27% with
anthracyclines concurrent anthracyclines [6, 7].
The risk factors described for the development of
Anthracycline-associated cardiotoxicity (AAC) can be divided
trastuzumab-induced cardiotoxicity include age >50 years,
into three forms: immediate pericarditis–myocarditis
borderline LVEF before trastuzumab treatment, history of
syndrome, an early-onset chronic progressive form and a late-
cardiovascular disease, cardiovascular risk factors such as
onset chronic progressive form. The latter two forms are the
diabetes, dislipidemia or elevated body mass index (>30),
most frequently observed [4, 5].
sequence in which chemotherapy is administered and prior
The main risk factor for AAC is the cumulative dose [5].
treatment with anthracyclines (cumulative doses >300 mg/m2)
Other described factors include administration schedule,
[4, 7–10]. Possibly, genetic background and immune status
mediastinal radiotherapy, combination therapy, old age or age
may also have an influence in patient susceptibility to
<4 years, female gender, ethnicity, hypertension, previous
trastuzumab-induced cardiotoxicity [10].
cardiovascular disease, chromosomal abnormalities and liver
Some differences can be established between anthracycline-
disease [5].
and trastuzumab-induced cardiotoxicity: trastuzumab-induced
cardiotoxicity is at least reversible while anthracycline-induced
*Correspondence to: Dr J. Tabernero. Email: jtabernero@vhebron.net is not; there are no ultrastructural changes in cardiomyocytes in

ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
symposium article Annals of Oncology

Table 1. Safety with trastuzumab in the HERA trial study [6]. its phosphorylation and therefore inactivating it. Nilotinib has
a similar inhibition spectrum but its potency at inhibiting BCR-
Adverse events Trastuzumab, Observation, P ABL is 20-fold greater. Dasatinib also inhibits Src family kinases
n (%) n (%) and can inhibit phosphorylated and unphosphorylated ABL,
(N = 1677) (N = 1710) which gives it a greater potency (100-fold greater) [10].
Patients with grade 3/4 AEs 132 (7.9) 75 (4.4) <0.001 Kerkela et al. [3] initially described 10 cases of congestive
Fatal AEs 6 (0.4) 3 (0.2) 0.34 heart failure in patients with chronic myelogenous leukaemia
Cardiac events treated with imatinib. Later on, a retrospective review of the six
Death 9 (0.5) 1 (0.06) 1.0 registration trials was conducted and the incidence of HF was
Severe CHF 29 (1.7) 0 0.002 established as 0.5% out of 2327 patients [18]. The major
Symptomatic CHF 113 (7.1) 1 (0.06) <0.001 limitation of this study is the absence of pre-planned cardiac
Decrease in LVEF (>10%) 32 (2.2) <0.001 monitoring. During a phase III dose-optimization study with
dasatinib in patients with chronic myeloid leukaemia the
AE, adverse event; CHF, cardiac heart failure.
incidence of HF was 4% [4].
The proposed mechanism of cardiotoxicity [3] of these
trastuzumab-induced cardiotoxicity while in anthracycline compounds is related to the activation of the endoplasmic
cardiotoxicity changes such as vacuolization on cardiomyocytes reticulum (ER) stress response, a mechanism that protects cells
or loss of cardiomyocytes are present [10, 11]. by shutting down general protein translation while
pathophysiology. HER2 has a relevant role in embryonic upregulating the expression of specific protective stress
heart development. It forms heterodimers with HER4 after the response genes. This phenomenon is mediated by PKR like ER
union of neuregulin 1 with HER4 (neuregulins are peptide kinase (PERK), which phosphorylates the transcription factor
ligands of HER3 and HER4 expressed only in cardiac tissue). eIF2a and activates the IRE1 signalling pathway. Imatinib also
HER2–HER4 heterodimerization leads to its leads to an increase in PKCd expression. Ultimately, prolonged
autophosphorylation, which activates several signalling ER stress response and PKCd expression lead to apoptosis. It
pathways such as Src–FAK, which increases cell–cell contacts has been recently indicated that ER stress response and
and mechanical coupling [12], or phosphatidylinositol 3-kinase apoptosis induced by imatinib may occur at concentrations
(PI3K)–Akt and mitogen-activated protein kinase (MAPK), higher than the therapeutic concentration [19].
which promote cardiomyocite proliferation, survival and sunitinib. Sunitinib is an oral inhibitor of vascular endothelial
contractile function [13]. HER2, HER4 and neuregulin 1 have growth factor recptor (VEGFR) 1–3, PDGFRa/b, KIT, FMS-
been shown to be indispensable for heart development as related tyrosine kinase 3 (FLT3), colony-stimulating factor 1
deletion of one of them is lethal in mice embryos [10]. receptor (CSF1R) and rearranged during transfection (RET).
Lapatinib, an oral dual kinase inhibitor of epidermal growth The incidence of HF related to sunitinib in clinical trials ranges
factor receptor (EGFR) and HER2, has been shown to produce from 4% to 11% [20, 21], but the incidence in the general
a low rate of cardiotoxicity (1.6%) [14]. Several mechanisms population may be higher (up to 33.8% in renal cancer
have been described to explain the difference in cardiotoxicity patients) [22, 23]. The main cause of these discrepant rates may
rates between trastuzumab and lapatinib [10]. First, an be related to the higher number of co-morbidities in the general
immune-mediating effect can be raised as trastuzumab has population (higher rate of hypertension and previous cardiac
been shown to stimulate antibody-dependent cell-mediated ischaemia).
toxicity against HER2 tumour cells in vitro [15]. Second, the The mechanism of sunitinib-induced cardiotoxicity is an off-
pharmacokinetic difference in the duration or extent of target effect due to ribosomal S6kinase inhibition producing
inhibition of HER2 by trastuzumab or lapatinib could partially ATP depletion that activates the intrinsic apoptotic pathway. It
explain these differences, although some studies indicate that is also known that VEGF signalling is necessary to obtain an
the kinetics of HER2-signalling inhibition is similar after adequate response of cardiomyocytes to pressure load in those
a single dose of either agent [10]. A third mechanism has been patients with hypertension, which may explain the higher rate
studied with various anti-HER2 antibodies in rat of HF in this population [10].
cardiomyocyte models. The binding of anti-HER2 antibodies to
HER2 also triggers BCL-XL downregulation and BCL-XS
activation, which leads to loss of mitochondrial membrane other targeted therapies
potential, reduction in ATP levels, cytochrome C release and bortezomib. The incidence of HF with bortezomib, a
caspase activation. The intrinsic resistance of cardiomyocytes to proteasome inhibitor, is 5%. The underlying mechanism
apoptosis induced by the BCL pathway may explain the lack of of HF is the induction of ER stress after proteasome inhibition
ultrastructural changes in trastuzumab-induced cardiotoxicity. [4, 24, 25].
In this way downregulation of BCL-XL and activation of BCL- bevacizumab. The incidence of HF related to bevacizumab-
XS would lead to ATP depletion and contractile dysfunction containing treatment is 2.2% in phase III studies. Uncontrolled
[16, 17]. hypertension and inhibition of VEGF signalling that impairs the
ABL inhibitors: imatinib, dasatinib, nilotinib. Imatinib is a adaptive response of the heart to pressure overload have been
tyrosine kinase inhibitor of ABL, ABL-related gene (ARG), raised as potential mechanisms to explain this toxicity [26, 27].
platelet-derived growth factor receptor (PDGFR) a and b and Other kinases have been shown to present a role in survival
KIT. It binds to the unphosphorylated form of ABL preventing or adaptation of cardiomyocytes to different injuries, and for

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Annals of Oncology symposium article
this reason the inhibition of these kinases could have a potential Of note, cancer patients may be prone to QT prolongation as
cardiotoxic role that should be taken into account in drug many of them have electrolyte disturbances, take concomitant
development. This group of kinases includes PDGFR, KIT, RAF medications that could enlarge QT interval such as antiemetics,
and JAK2. PDGFR is expressed in cardiomyocytes and antifungals or antibiotics (Table 3), or have baseline
overexpression of PDGFR is known to induce cardiomyocyte electrocardiogram abnormalities (up to 32% of patients) (Table 4)
survival [28, 10]. KIT has been shown to be necessary to recruit [29, 30].
endothelial progenitor cells to injured areas in the heart. RAF1 arsenic trioxide. The incidence of QT prolongation with arsenic
has been shown to contribute in cardiac adaptation to pressure. trioxide treatment in clinical trials ranges from 26% to 93% [4].
JAK–STAT signalling seems to be protective in the heart at least
maintaining cardiac capillary density, and its downregulation in
mouse models increases the susceptibility to cardiac injury after Table 3. Drugs producing prolonged QT interval
myocardial ischaemia or anthracycline treatment [10].
Antidepressants Amitryptiline, clomipramine,
rhythm disturbances desipramine, imipramine
Antibiotics Clarithromycin,
Paclitaxel can be considered as a prototypic pro-arrythmogenic erythromycin,
cytotoxic drug. Paclitaxel has a chronotropic effect either sparfloxacin, pentamidine
directly on the Purkinje system or indirectly through histamine Antifungals Ketoconazole, miconazole,
release mediated by its vehicle Cremophor EL that ultimately itraconazole
would lead to bradycardia [4]. Serotonin agonist/antagonist Cisapride, ketaserin,
The development of new drugs in the past decade has zimeldine
revealed a new spectrum of pro-arrythmogenic effects of Antipsychotics Phenothiazine, droperidol,
anticancer drugs, the most important one consisting in QT haloperidol
interval prolongation [29, 30]. Antiarrhythmic drugs IA: procainamide, quinidine,
amaline, disopyramide
QT interval prolongation IB: flecaine, propafenone
III: amiodarone, sotalol,
QT interval is a measure of the total duration of ventricular
dofetilide, ibutilide
activation and recovery (depolarization and repolarization).
Vasodilators Bepridil, perhexiline
During depolarization the main event in cardiomyocytes is Other Methadone
a sodium and calcium inflow that exceeds potassium outflow.
When potassium outflow exceeds sodium and calcium inflow,
repolarization occurs. In the electrocardiogram QT is measured
from the beginning of the QRS complex to the end of the T Table 4. Risk factors for drug-induced QT interval prolongation and
wave. The QT interval is influenced by heart rate. There are torsade des pointes
several methods to correct QT for heart rate variation (Table 2).
The definition of QTc prolongation varies in the literature, but Gender Female
most authors consider normal QTc £ 400 ms, and prolonged Baseline ECG alteration Baseline QT prolongation
QTc > 450 ms in men and >470 ms in women. Ventricular Subclinical long QT
arrhythmias, particularly torsades des pointes are correlated with syndrome
QTc ‡ 550 ms, but there is no threshold below which Previous cardiovascular disease Myocardial ischaemia
prolongation QT interval is considered free of pro-arrhythmic Congestive heart failure
risk [29, 30]. Cardiac hypertrophy
The most accepted hypothesis about the aetiology of QT Myocarditis
prolongation is an interaction with HERG K channels. HERG K Bradycardia
channels allow the rapid component of myocardial Atrioventricular block
repolarization; when a drug interferes with their function, the Electrolyte disturbances Hypokalaemia,
potassium inflow decreases leading to prolongation of hypomagnesaemia,
repolarization [29]. hypocalcaemia
Endocrine disorders Hypothyroidism,
hyperparathyroidism,
Table 2. QT heart rate corrections
hyperaldosteronism
Neurological disorders Subarachnoid haemorrhage
Reference Formula Stroke
Bazett QTc = QT/RR½ Intracranial trauma
Fridericia QTF = QT/RR1/3 Other diseases Diabetes, cirrhosis
Framingham (Sagie) QTLC = QT + 0.154 (1–RR) Related to drug administration High drug concentration
Hodges QTcH = QT + 105 (1/RR21) Rapid rate of intravenous
infusion with a QT-
RR, interval from the onset of one QRS complex to the onset of the next prolonging drug
QRS complex.

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In a multicentre study in acute promyelocytic leukaemia cases of cardiac ischaemia. In another phase I trial evaluating
40% of patients developed QT prolongation that returned to the combination of combrestatin with radiotherapy the QTc
baseline 8 weeks after the end of treatment [31]. was increased by a mean of 13 ms, in all patients without
histone deacetylase inhibitors. Histone deacetylase (HDAC) related symptoms [36].
inhibitors target an epigenetic mechanism of acetylation that
modulates transcription. Depsipeptide (FK228) is a cyclic protein kinase C inhibitors
peptide HDAC inhibitor. In a retrospective analysis of 500 Enzastaurin is a protein kinase C inhibitor that suppresses the
patients who had received depsipeptide, five sudden deaths PI3K/Akt pathway, leading to anti-angiogenic effects,
were reported. All these patients had risk factors for sudden impairment of tumour growth and induction of tumour death.
death such as electrolyte abnormalities, concomitant therapy In a phase I trial 3 out of 47 enrolled patients developed
with a QTc-prolonging agent or hypertrophic cardiomyopathy. asymptomatic grade 3 QTc prolongation. In the combination
Documentation of increased QT was not obtained before phase I trial of enzastaurin with gemcitabine one patient had
sudden death. In other patients ST and T wave changes and QT a grade 2 QTc interval prolongation [29]. Finally, a phase II
prolongation were described as a class effect due to HDAC trial of enzastaurin 500 mg daily as second- or third-line
inhibition [29, 30, 32]. The incidence of QT prolongation treatment in patients with non-small-cell lung cancer showed 1
associated with vorinostat, a phenylbutyrate-derived HDAC asymptomatic grade 1 QTc prolongation out of 55 patients
inhibitor, is 3.5%–6% [29]. [37].
Scr/Abl kinase inhibitors. QT prolongation was reported to Hdm2 inhibitors. Serdemetan, a novel inhibitor of the
occur in 2%–3% of patients treated with dasatinib, but <1% Hdm2–p53 complex, has shown prolongation of the QTc
experienced a QTc interval of >500 ms [4]. interval in the preliminary presentation of a phase I study [38].
multitargeted tyrosine kinase inhibitors. Sunitinib has been
shown to prolong the QT interval, the PR interval, causing
bradycardia, and to induce ST and T wave changes [22]. ischaemia
Torsade de pointes has been observed in <0.1% of patients
receiving sunitinib. The effect of sunitinib on QT interval is Several cancer treatments, including not only cytotoxic drugs
dose dependent [23]. but also radiotherapy and targeted therapies, are associated
Vandetanib is an oral selective inhibitor of VEGFR, epidermal with an increased risk of coronary artery disease with or
growth factor receptor (EGFR) and RET tyrosine kinases. without coronary syndrome.
Preclinical studies showed an interaction of vandetanib with
cardiac ion channels leading to repolarization abnormalities. In fluoropyrimidines
a phase I trial of vandetanib in solid tumours 9% of patients fluorouracil. The incidence of cardiotoxicity with 5-fluorouracil
developed asymptomatic QTc prolongation, while in a Japanese (5FU) in the literature varies from 1% to 68% [4] with a mean
phase I trial the incidence rose to 61% [29]. A study carried out onset of 72 h after the initiation of administration. The most
in healthy volunteers showed that the effect on QT interval was common cardiac symptom is angina-like chest pain, but some
increased by the combination of vandetanib with ondansetron. cases developed myocardial infarction (MI), arrhythmias, HF,
In phase II trials the incidence of asymptomatic QT prolongation cardiogenic shock and sudden death [4, 11]. Risk factors are
was 15%, all events grade 1–2 [30]. not well defined but one of the most associated risk factors is
Nilotinib, a multitargeted tyrosine kinase inhibitor against a previous history of coronary artery disease. Other described
the Bcr–Abl fusion protein, KIT and PDGFR, has shown risk factors are previous mediastinal radiotherapy and
a mean QT prolongation in healthy volunteers of 18 ms [30]. In concomitant cisplatin therapy. The toxicity is described to be
phase II trials the incidence of grade 2 QT prolongation has dose and rate dependent, as high doses (>800 mg/m2) and
been 1%–4% [4]. In a phase I/II study five sudden deaths continuous infusion administration have been associated with
(0.6%) were reported considered probably or potentially higher rates of toxicity [4, 39].
related to nilotinib [34]. capecitabine. The incidence of cardiotoxicity related to
farnesyl protein transferase inhibitors. Farnesyl protein capecitabine ranges from 3% to 9%. The onset of angina
transferase inhibitors selectively inhibit post-translational symptoms ranges from 3 h to 4 days after treatment has been
farnesylation of Ras and other proteins from other signalling initiated [4]. The main risk factor described is previous
pathways. In a phase II trial of lonafarnib (SCH66336) in coronary artery disease.
patients with refractory head and neck squamous cell pathophysiology. The aetiology of fluoropyrimidine-related
carcinoma 1 out of 15 patients developed grade 3 QTc cardiotoxicity is still unknown. Several hypotheses have been
prolongation and another patient presented syncope without raised including vasospasm PKC mediated, direct toxicity on
previously documented QTc prolongation [29]. Asymptomatic the myocardium, coronary artery thrombus, activation of the
QT prolongation was observed in two phase I trials with coagulation system or autoimmune response [4, 11, 39]. The
L-778123 and also in the phase I trial of the combination of induction of vasospasm is the most likely mechanism as some
L-778123 with paclitaxel [29]. studies have shown a contraction in the brachial artery or an
vascular disruption agents. Combrestatin A4 phosphate (CA4P) increased level of endothelin-1 after 5FU infusion. In contrast,
is a targeted natural tubulin inhibitor with a vascular the co-administration of ergotamine to elicit vasospasm or the
disruption effect. In a phase I trial Dowlati et al. [35] described administration of vasodilating drugs as a preventive treatment
7 cases of QTc prolongation out of 25 enrolled patients and two has shown lack of benefit.

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Annals of Oncology symposium article
taxanes potentially lead to QT prolongation should be evaluated by
Although the main cardiotoxicity of taxanes is bradycardia, a cardiologist [30].
ischaemia has also been described. The incidence reported with
paclitaxel ranges from 0.5% to 5%, and with docetaxel is 1.7% monitoring cardiac function
[4]. The underlying mechanism of taxane-induced ischaemia is Despite the lack of consensus about the strategy to evaluate
not well defined. It is also not known whether this is a direct cardiotoxicity [44], periodic evaluation of LVEF should be
effect of paclitaxel or is mediated by Cremophor EL vehicle carried out before, during and after treatment with cytotoxic or
through histamine release [4]. targeted agents known to induce HF in order to detect
subclinical cardiac damage [1, 30].
bevacizumab For QTc monitoring, periodic electrocardiograms should be
In a pooled analysis of 1745 patients enrolled in five obtained, especially in patients at risk. A recommended
randomized trials in colorectal, non-small-cell lung cancer and schedule for cardiac monitoring could be to carry out a baseline
metastatic breast cancer the incidence of angina and MI was ECG, another 7 days after initiation and periodically following
1.5% in the bevacizumab group [40]. In the observational any dose adjustments [30].
BRiTE study in patients with colorectal cancer the incidence of The development of better biomarkers to identify patients at
MI was 0.6% [41]. Proposed risk factors include age >65 years high risk of cardiotoxicity [1] and the integration of different
and a previous history of arterial thrombotic event. These methods for cardiologic monitoring constitute a field of major
events can occur at any time during therapy but the median research interest [44].
time to the event is 3 months. This toxicity does not seem to be
dose related. A decrease in the regeneration process of development of cardioprotective drugs
endothelial cells after incidental trauma during anti-VEGF Most of the randomized trials with cardioprotective agents in
treatment has been proposed as a mechanism of development patients receiving anthracyclines harbour methodological
of arterial thrombotic events. This would allow the exposure of limitations. A meta-analysis of six randomized controlled trials
subendothelial collagen, which would activate tissue factor, with dexrazoxane, an ethylenediaminetetraacetic-acid-like iron
increasing the risk of thrombotic events [43]. chelator, showed a statistically significant benefit in favour of
dexrazoxane for the occurrence of HF, without a difference in
sorafenib response rate or survival between the dexrazoxane and control
Sorafenib is a multi-kinase inhibitor that targets VEGFR2, groups [45]. The American Society for Clinical Oncology
VEGFR3, FLT3, KIT, PDGFR, RAF1 and BRAF. The incidence (ASCO) guidelines recommend that dexrazoxane treatment
of myocardial ischaemia in clinical trials with sorafenib is 3% should be considered only in patients with metastatic breast
[4, 10]. In considering the pathophysiology of cardiotoxicity cancer who have received a minimum of 300 mg/m2 of
induced by sorafenib the inhibition of VEGFR could have anthracycline and would benefit from continued anthracycline-
a similar role in maintenance of vascular integrity but also the based therapy [46].
inhibition of RAF activates two pro-apoptotic kinases, ACE inhibitors have been tested in a randomized trial in
apoptosis signal-regulating kinase (ASK1) and mammalian patients receiving high-dose chemotherapy with high serum
sterile 20 kinase 2 (MST2), which have an important role in troponin I levels. None of the 56 patients receiving the ACE
oxidant stress-induced injury in cardiomyocytes [10]. inhibitor developed HF while 24% of the control patients
developed it [47].
The identification of other endothelial or cardiomyocyte
prevention and treatment protective agents to prevent cardiotoxicity of anticancer drugs
Several review articles have been recently published in order to without decreasing their antitumoral effect continues to be
clarify the underlying mechanism of anticancer drug a priority.
cardiotoxicity and to improve the cardiologic follow-up of
patients with cancer [1, 4, 30, 39, 44]. The appropriate cardiotoxicity assessment in drug development
management should include better detection of those patients Following FDA and EMEA regulations, all phase I clinical trials
at risk, the development of preventive strategies and the early have a rigorous cardiac monitoring plan. The identification of
treatment of cardiotoxicity when it does appear. We will off-target toxic effects of kinase inhibitors and the development
highlight the main goals to achieve. of new drugs that elicit those off-target kinases is also a goal. An
example is the successful redesign of imatinib to reduce its
identification of the high-risk population cardiotoxic effects for the treatment of GIST [48].
Schmidinger et al. [23] have shown that the pre-existing cardiac
disease is underestimated in patients with cancer, as the early management of cardiotoxicity
incidence reported in the study was 9.3%. Many of the Antineoplastic drug should be discontinued in the case of
cardiovascular risk factors such as hypertension, diabetes, a cardiovascular event such as significant decrease in LVEF or
dyslipidemia or electrolyte disturbances can be treated and the occurrence of a QTc prolongation of >500 ms [1, 30]. Other
corrected before the anticancer treatment is started and causes that could collaborate in this cardiovascular event, such
thereafter closely monitored during therapy [1, 4, 30, 44]. as electrolyte disturbances or coronary disease, should be
Patients with pre-existing cardiac disease or taking drugs that studied and treated.

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