Timely Recognition of Cardiovascular Toxicity by Anticancer

Cardiovasc Toxicol
DOI 10.1007/s12012-011-9141-z
Timely Recognition of Cardiovascular Toxicity by Anticancer
Agents: A Common Objective of the Pharmacologist, Oncologist
and Cardiologist
Francesca Bonura • Daniela Di Lisi •
Salvatore Novo • Natale D’Alessandro
Springer Science+Business Media, LLC 2011
Abstract Both conventional and new anticancer drugs
can frequently cause adverse cardiovascular effects, which
can span from subclinical abnormalities to serious lifethreatening and sometimes fatal events. This review
examines the principal basic and clinical elements that may
be of profit to identify, prevent and treat such toxicities.
Clearly, the accomplishment of such objectives requires the
strong commitment and cooperation of different professional figures including, but not limited to, pharmacologists, oncologists and cardiologists. The aspect of
anticancer drug cardiotoxicity seems to be somehow
underestimated, mainly due to inadequate reporting of
adverse reactions from oncology drugs in the post-marketing setting. Thus, the implementation of pharmacovigilance is indispensable to rapidly and fully assess the safety
of newer agents in real-life patients.
Keywords Cardiotoxicity Echocardiography Tissue Doppler New anticancer drugs
F. Bonura (&) D. Di Lisi S. Novo
Department of Cardiology, Policlinico P. Giaccone, University
of Palermo, Via del Vespro 129, 90127 Palermo, Italy
e-mail: [email protected]
D. Di Lisi
e-mail: [email protected]
S. Novo
e-mail: [email protected]
N. D’Alessandro
Section of Pharmacology ‘‘P. Benigno’’, Department for Health
Promotion Sciences ‘‘G, D’Alessandro’’, University of Palermo,
Palermo, Italy
e-mail: [email protected]
Introduction
Medical therapy of patients with cancer is a section of
medicine in continuous growth, and in recent years, there
has been an impressive development of new anticancer
drugs. Disappointingly, both the new and conventional
anticancer therapies can result in adverse cardiac and
vascular effects, which can span from subclinical abnormalities to serious life-threatening and sometimes fatal
events. The issue of cardiovascular risk has become of
greater concern than in the past in the light of the increased
use of adjuvant combination therapies along with the
improved life expectancy of cancer patients. This review
wants to examine the principal basic and clinical elements
that may be of profit to identify and reduce the likelihood
of cardiovascular toxicity from both conventional and new
oncology drugs.
Cardiovascular Toxicity of Molecularly Targeted
Anticancer Agents
Several anticancer drugs have been associated with some
form of cardiotoxicity (Table 1). Introduction of targeted
agents has for multiple reasons, not least because of the
economic costs, rendered anticancer therapy even more
complex. In contrast to the limited selective mechanisms of
most conventional drugs, the targeted molecules are
directed to interfere with genetic alterations specific of
cancer cells and thus, in principle, are effective with low
toxicity. They include monoclonal antibodies (mAb) that
selectively target growth factor receptors or their ligands
and small organic molecules which can inhibit a more or
less broad spectrum of receptor or non-receptor tyrosine
kinases (TKs) and, in some cases, of serine/threonine
kinases. Novel agents have also been developed to interact
Cardiovasc Toxicol
Table 1 Cardiovascular toxicities from anticancer agents
Drug(s)
Principal clinical
manifestations
Principal mechanism(s)
Amsacrine
QT prolongation
Interference with cardiac HERG currents
Anthracyclines
and
anthraquinones
LV dysfunction, CHF
Oxidative stress
Notes
Increased risk with cumulative doses
Arsenic trioxide
QT prolongation
Interference with cardiac HERG currents
Bevacizumab
Hypertension,
thromboembolism
Block of VEGF
Bleomycin
Pericarditis, ischaemic
heart disease
Likely related to oxidative stress
Capecitabine,
5-fluorouracil
Ischaemia, infarction,
arrhythmias
Vasospasm (inhibition of endothelial NO
synthase? responsibility of metabolites and
degradation products?)
Cisplatin
Arrhythmias, CHF,
ischaemia/infarction
Hypomagnesaemia, coronary artery fibrosis?
Not firmly established, confounded by
concomitant drugs
Cyclophosphamide
Haemorrhagic
myopericarditis, CHF,
arrhythmias
Endothelial injury
Observed at doses [ 120–170 mg/Kg
Cytarabine
Angina, pericarditis
Unknown
Etoposide
Ischaemia/infarction
Vasospasm
Imatinib
LV dysfunction, CHF,
arrhythmias
Inhibition of Abl kinase
Methotrexate
CHF, arrhythmias,
ischaemia/infarction
Unknown
Case reports only
Mitomycin C
CHF
Oxidative stress
Increased risk with cumulative doses C
30 mg/m2
Multikinase
inhibitors
(sorafenib,
sunitinib)
Hypertension, ischaemia/
infarction, LV
dysfunction, arrhythmias
Anti-angiogenesis, inhibition of relevant
cardiac kinases, hypothyroidism
Tamoxifen
Thromboembolism
Oestrogenic activity
Taxanes
Hypotension, arrhythmias,
CHF
Hypersensitivity reactions (especially to
cremophor EL, vehicle of paclitaxel),
microtubule stabilization
Can aggravate the cardiac toxicity of
doxorubicin
Trastuzumab
LV dysfunction, CHF,
arrhythmias
Inhibition of HER2 signalling in the heart
Concomitant administration aggravates the
cardiac toxicity of other agents such as
the anthracyclines
Vinca alkaloids
Ischaemia/infarction
Vasospasm
Not firmly established
with some other functions, such as those of the proteosome,
the histone deacetylases or the farnesyl transferases, which
are now recognized to be frequently dysregulated in cancer.
The targeted approaches have improved the management
of different neoplastic diseases, with the best results having
been obtained in chronic myeloid leukaemia, gastrointestinal stromal tumours (GIST) and breast cancer. However,
in general, they have not shown to lead to cures or longterm survival for most intractable cancers; whatever the
relevance of the blocked mechanism is, the genetic instability of cancer cells enables them to switch to adaptation
changes and alternative signalling pathways that stimulate
cell proliferation and survival, so that resistance eventually
develops. Reasonably, multi-targeted agents might be less
Not firmly established
likely to run into problems of drug resistance than singletargeted ones; subsequently, many efforts of drug design
are also oriented in this direction. On the whole, it has been
calculated that there are approximately 500 novel anticancer agents under preclinical or clinical development or
already on the market [1].
Importantly, in contrast to initial expectations, targeted
agents have shown to be frequently associated with severe
toxicities. They can affect also the cardiovascular system
with manifestations such as cardiac dysfunction, arrhythmias, hypertension and thromboembolic events. Nonetheless, in many cases, the real dimension of this problem is
not fully defined, owing to various reasons which, as it will
be discussed further, include:
Cardiovasc Toxicol
•
•
•
issues of screening for cardiovascular toxicity through
better predictive preclinical models;
paucity of prospective clinical studies specifically
addressed to monitor cardiovascular events;
need to identify the best clinical approaches and criteria
to evaluate the various types of cardiovascular toxicity.
Last but not least, it should be noted that there exists a
strong inadequacy of reporting adverse reactions from
oncology drugs in the post-marketing setting [2]. However,
the pharmacovigilance detection methods are indispensable
to rapidly and fully assess the safety of newer agents in
real-world patients, as highlighted by the recent experience
with the osteonecrosis of the jaw by bisphosphonates [3].
Cardiac Dysfunction from Targeted Agents
From a mechanistic point of view, it is reasonable that such
toxicity can ensue when the relevant targeted factor in
cancer cells performs an important physiological function
also in cardiomyocytes or other cardiovascular cells [1].
Examples of such ‘‘on-target’’ toxicity are represented by
trastuzumab and, possibly, imatinib with their effects on
HER2 and Abl kinase, respectively. In the case of more
pleiotropic agents, ‘‘off-target’’ toxicities might also be
encountered if their activities include targets not relevant
for anticancer effects but responsible for cardiovascular
functions. The mechanisms of the cardiac toxicity associated with the multikinase inhibitors sunitinib or sorafenib
are not completely understood, but they might reflect
on- and/or off-target effects. Clearly, cardiac toxicity
cannot be considered as a class effect of all the molecularly
targeted approaches, and, for example, there are no major
basic or clinical concerns regarding the inhibitors (like
erlotinib or gefitinib) of epidermal growth factor receptor
(EGFR) TKs as relevant targets frequently adopted in the
new therapies [1].
Trastuzumab and Other HER2 Inhibitors
Trastuzumab, a humanized mAb, blocks activation of the
human epidermal growth factor receptor 2 (HER2); HER2
is over-expressed in about 25–30% of breast cancer
patients, and trastuzumab has clinical efficacy in such
patients both in the metastatic and adjuvant setting. However, the mAb can lead to cardiac toxicity, manifesting as a
reduction in LV systolic function. It can severely aggravate
the cardiac toxicity of other anticancer agents, especially
the anthracyclines [4]. In a pivotal trial in women with
metastatic breast cancer, it was shown that combining
trastuzumab with doxorubicin and cyclophosphamide
caused CHF (NYHA class III or IV) in 16% of patients
compared to the incidence of 3, 2 or 1% in patients
receiving doxorubicin and cyclophosphamide, trastuzumab
and paclitaxel or paclitaxel alone, respectively [5]. The
cardiac toxicity from trastuzumab is mainly related to the
fact that HER2 and its ligand neuregulin activate signals
(like the ERK, PI3 K/AKT and FAK pathways) that promote cardiomyocyte proliferation and anti-apoptosis during
development, as well as contractility in adults [6, 7]. HER2
signalling may also play an important role in the autonomic
regulation of the heart [8].
Disappointingly, preclinical studies in mice could not
detect trastuzumab cardiotoxicity because the mAb does
not recognize ErbB2, the HER2 homologue in mice.
Though trastuzumab binds primate HER2, the preclinical
toxicology studies were done with healthy primates that
had not been treated with anthracyclines [9]. Relevantly to
the clinical situation, it is now clear that mice that have a
targeted deletion of ErbB2 in the heart develop a dilated
cardiomyopathy with advanced age and are particularly
sensitive to hypertensive loads or anthracycline treatments
[10].
As opposed to the anthracycline cardiotoxicity, clinical
trastuzumab-associated cardiac dysfunction does not
appear to be related to cumulative dose; fortunately, it
often recovers with treatment discontinuation, and rechallenge is tolerated. Thus, one may distinguish two types of
anticancer treatment-related cardiac dysfunction: type I and
type II cardiotoxicity. Type I cardiotoxicity is associated
with anthracyclines and results, at least to some degree, in
myocyte destruction and clinical heart failure. Type II
cardiotoxicity is a phenomenon that is not unique to
trastuzumab, but it also occurs with different kinase
inhibitors, and results in a loss of contractility (presumably
a form of stunning or hibernation) that is less likely to be
associated with myocyte death or clinical heart failure and,
in general, is reversible [11, 12]. However, there are still
different uncertainties regarding the trastuzumab cardiotoxicity [13]. In the absence of formal guidelines or consensus statements to predict, prevent and treat trastuzumab
cardiomyopathic effects, proposed recommendations
include a careful assessment of cardiac ejection fraction
(EF) prior to initiating the treatment, avoidance of concurrent administration of trastuzumab with anthracyclines
and regular monitoring of symptoms and cardiac function
during and for several years after therapy. Increased vigilance is needed for higher-risk patients. Interestingly, a
study on a frequent HER2 gene polymorphism (Ile655Val),
though limited in size, has suggested that the Val allele
significantly increases the risk of trastuzumab-induced
cardiotoxicity [14], thus underlining the necessity of
pharmacogenetic research in this particular field.
Lapatinib is a small organic molecule that acts as an
inhibitor of EGFR and HER2 TKs and is currently
approved for treatment of refractory HER2-positive
Cardiovasc Toxicol
advanced breast cancer. Existing clinical evidence indicates that it is less cardiotoxic than trastuzumab, a fact that
might depend on the different selection characteristics of
the patients exposed to trastuzumab or lapatinib thus far,
and, at molecular level, on the inherent differences between
the action mechanisms of the mAb and lapatinib [1]. In
fact, lapatinib would be able to induce cardiac protection
by stimulation of AMP-activated protein kinase (AMPK), a
key regulator of energy metabolism in the heart, while
trastuzumab does not [15].
Imatinib and Other Abelson Kinase (Abl) Inhibitors
Imatinib targets the kinase of the causal fusion protein BcrAbl in chronic myeloid leukaemia and also c-Kit and
PDGFR-a and -b in GIST. Abl kinase inhibits apoptosis,
and studies in mouse models have shown that imatinib
causes a modest, but reproducible, decline in cardiac
contractility along with cardiomyocyte death, due to its
impact on c-Abl kinase in the same cells [1, 16]. A redesigned imatinib, devoid of Bcr-Abl inhibitory capacity, has
demonstrated conserved therapeutic efficacy in a GIST
mouse model with a marked reduction in cardiotoxicity
[17]. However, other authors have suggested that imatinib
may be not cardiotoxic in animals at clinically relevant
concentrations [18]. The clinical cardiac toxicity of
imatinib and of newer Abl inhibitors, like dasatinib and
nilotinib, is under scrutiny. In any case, imatinib appears to
be less cardiotoxic in humans than in mice, though some
clinical cases of imatinib-related CHF have been reported
[19, 20]. So far, dasatinib and nilotinib have been associated mainly with an increased risk of QT interval prolongation [21].
Multikinase Inhibitors: Sunitinib and Sorafenib
Sunitinib and sorafenib are multikinase inhibitors currently
indicated in the treatment of renal cell carcinoma. Sunitinib
is approved for GIST, and sorafenib is now considered a
standard agent for hepatocellular carcinoma. In a phase I/II
trial, eight out of 75 (11%) patients with imatinib-resistant
GIST treated with sunitinib underwent major cardiac
events, such as heart failure (in 8% of patients), myocardial
infarction or cardiovascular death. Decline in left ventricle
ejection fraction (LVEF) of 15% or more occurred in 19%
of the patients and hypertension ([150/100 mm Hg) in
47% [22]. LV dysfunction might be due, in part, to direct
cardiomyocyte toxicity, with mitochondrial impairment,
exacerbated by hypertension. Importantly, CHF and LV
dysfunction generally responded to sunitinib being withheld and institution of medical management, so that
afterwards, the majority of the patients were able to resume
the drug [22].
In clinical trials, sorafenib was associated with acute
coronary syndromes, including myocardial infarction, in
2.9% of patients versus 0.4% of placebo-treated patients
[1]. Detailed cardiovascular monitoring during treatment
with sunitinib or sorafenib may reveal early signs of
myocardial damage. In a study on 74 patients with metastatic renal cell carcinoma treated with either sunitinib or
sorafenib, 11 treated with sunitinib and 14 with sorafenib
experienced a cardiac event; 13 of these 25 event patients
had typical clinical symptoms, which included typical
angina, dyspnoea at exertion and dizziness. Among these,
seven were seriously compromised and required treatment
in intermediate or intensive care units. ECG changes were
found in 12 of the 25 event patients. All patients recovered
after cardiovascular management and were considered
eligible for continuation of the treatment [23]. Close
monitoring is recommended as a prudent approach until
large studies and post-marketing surveillance will clearly
define the nature and rate of sunitinib- or sorafenib-associated cardiovascular effects, especially in patients with
cardiac risk factors, such as advanced age or previous
history of coronary disease [24]. Multikinase inhibitors can
cause also hypothyroidism, which can aggravate their
cardiotoxicity [25].
Sunitinib targets mainly vascular endothelial cell growth
factor receptors (VEGFR) 1–3, platelet-derived growth
factor receptors PDGFR a and b, stem cell factor KIT
receptor, FMS-like tyrosine kinase-3 (FLT-3), colonystimulating factor-1 receptor (CSF-1R) and the product of
the human RET gene. While VEGFR inhibition is
responsible for the anti-angiogenetic as well as the hypertensive effect (see below) of sunitinib, other targets of
sunitinib, such as FLT-3, CSF-1R, KIT and RET, are not
known to be expressed in the adult heart. Possible cardiac
effects of PDGFR inhibition in cancer patients have to be
elucidated. Sunitinib cardiotoxicity does not appear to be
due in a major way to its ability of inhibiting AMPK or also
the ribosomal S6 kinase RSK1 [26]. Sorafenib, alongside
VEGFR, PDGFR, KIT and FLT-3, inhibits the Raf kinases
that trigger the cell proliferation and survival MEK/ERK
pathway and have a protective role in the heart. Interestingly, gain-of-function mutation of Raf-1 and other components of the Raf pathway are causal in some cases of
hypertrophic cardiomyopathy (Noonan and LEOPARD
syndromes) [27]. However, the involvement of RAF-1 and
BRAF in the myocyte toxicity of sorafenib has been
recently questioned [28].
Arterial Hypertension (AH) and Thromboembolic
Events from Anti-Angiogenic Agents
Tumour neo-angiogenesis is a complex process that is
indispensable for cancer growth and involves a
Cardiovasc Toxicol
disequilibrium between pro-angiogenetic factors, such as
the potent VEGF-A (hereinafter referred to as VEGF), and
anti-angiogenetic ones. At present, there are available on
the market the anti-VEGF monoclonal antibody bevacizumab and the small organic molecules sunitinib and
sorafenib, which, as already said, are multikinase inhibitors
targeting also the VEGF receptors. Bevacizumab is indicated for the treatment of advanced colorectal, non-small
cell lung, breast and renal cancers. Other VEGFR inhibitors currently awaiting approval include vatalanib, vandetanib (also an EGFR inhibitor), pazopanib and axitinib, the
latter two being both VEGFR and PDGFR inhibitors [29].
AH, possibly associated with proteinuria, is a very frequent adverse effect of these anti-angiogenetic agents
[30, 31]; it has been proposed that bevacizumab-induced
hypertension might even represent a prognostic factor for
clinical outcome in advanced colorectal cancer patients
receiving first-line treatment with the drug [32]. However,
the incidence of this AH may not be exactly known since
the conventional measurement of arterial pressure in
medical centres does not always permit the diagnosis of
AH, suggesting the usefulness of auto-measurement of
arterial pressure in patients treated with anti-angiogenetic
agents. Further AH incidence has been reported according
to the criteria (grades) of NCI-CTCAE (National Cancer
Institute-Common Terminology Criteria for Adverse
Events) and not according to those commonly accepted by
the international scientific societies (C140 mmHg and/or
90 mmHg or use of an antihypertensive treatment irrespectively of the arterial pressure values) [51]. Nevertheless, in a recent meta-analysis on 12,656 patients, the
incidence of all-grade hypertension in patients receiving
bevacizumab was 23.6% (95% CI: 20.5–27.1) with 7.9%
(95% CI: 6.1–10.2) being high grade (grade 3 or 4). The
risk of high-grade hypertension may vary with tumour
types, with relative risks ranging from 2.49 (95% CI:
0.94–6.59) in patients with mesothelioma to 14.80 (95%
CI: 0.92–238.51) in patients with breast cancer [31].
Though the mechanism of AH is not fully understood, it
clearly involves the blocking of the physiological effects of
VEGF at the level of the vascular walls, through reduction
in the number of terminal arterioles and capillaries
(microvascular rarefaction) as well as inhibition of endothelial NO synthase and of NO release following vasodilatatory stimuli.
An increase in arterial pressure is constant during the
first weeks of treatment in both normotensive and hypertensive patients; it frequently reaches the stage of AH in
normotensive patients and makes controlling of AH in
already hypertensive individuals more difficult. AH from
anti-angiogenetic agents is dose dependent, generally
manageable by antihypertensive agents and rarely compromises the continuation of the anti-angiogenetic
treatment. However, in some cases, serious, short-term
complications, such as malignant or severe refractory AH
and reversible posterior leukoencephalopathy associated
with serious AH, have been reported. The long-term consequences of AH from anti-angiogenetic agents have not
been evaluated. As already noticed, it is conceivable that
elevated arterial pressure can lead to more serious cardiotoxicity if cardiac damage is present. Irrespective of the
mechanism, it is worth noting that bevacizumab aggravated
the cardiotoxicity of doxorubicin in a phase II study on
patients with advanced soft tissue sarcomas [33].
Thromboembolism, especially at arterial sites (Arterial
Thromboembolic Events, ATEs), and haemorrhage have
also emerged as significant toxicities associated with the
use of angiogenesis inhibitors. These events may reflect the
maintenance and protection role of VEGF for endothelial
cells where, independently of angiogenesis and cell proliferation, VEGF regulates the expression of components of
the thrombolytic and coagulation pathways. Loss of these
protective effects may result more crucial when anti-VEGF
agents are associated with chemotherapy, which, per se,
frequently causes haemostatic activation. The risks of
thromboembolic events associated with bevacizumab-,
sunitinib- or sorafenib-based therapies have been recently
reviewed [34]. Overall, the incidence of ATEs due to
bevacizumab, although low (2–3%), is double respect to
that observed in chemotherapy-only-treated patients and
with a significant difference. Since this increased risk of
ATEs in bevacizumab-treated patients seems to be mainly
related to older age, history of previous ATE and ECOG
performance status, these variables should be taken into
account before starting the anti-angiogenic treatment. The
risk of venous thrombotic events (VTEs) from bevacizumab might be comparable [35, 36] or, according to a
recent meta-analysis [37], moderately superior (RR 1.33,
95% CI: 1.13–1.56, P \ 0.001) to that of patients treated
with standard chemotherapy. Some points remain to be
clarified, which might lead to underestimation of such risk.
Considering the yet relatively small numbers of patients
exposed to sunitinib or sorafenib, data on the rates of
thromboembolic events from these molecules are less
mature than those on bevacizumab. Thalidomide and
lenalidomide, two multi-mechanism drugs that can also
inhibit angiogenesis by interfering with VEGF signalling
and by other activities, have been shown to significantly
increase the frequency of VTEs in multiple myeloma
patients [38, 39].
Serious haemorrhagic complications have been
observed in patients with non-small cell lung carcinoma
receiving bevacizumab or other anti-VEGF agents. Risk
factors suggested to be associated with developing haemoptysis include tumour cavitation, squamous cell histology
and central tumour location [40]. Patients with congenital
Cardiovasc Toxicol
bleeding diathesis, acquired coagulopathy or receiving fulldose anticoagulation should receive bevacizumab only
with great caution. The thromboembolic profile has to be
especially estimated also in elderly patients [41].
QT Interval Prolongation and Oncology Therapies
QT interval prolongation is a potentially severe effect
because it may lead to fatal arrhythmias (torsade de pointes
and ventricular fibrillation). It is recognized as a frequent
complication of different conventional anticancer agents,
which include the anthracyclines, 5-fluorouracil, amsacrine, the taxanes, some platinum compounds and arsenic
trioxide [42]. Newer compounds with possible QT prolongation effects include some histone deacetylase inhibitors (such as depsipeptide, the cinnamic acid hydroxamates
panobinostat and LAQ824; however, vorinostat, which is
marketed for the treatment of cutaneous T cell lymphoma,
has no documented QT effects but can cause non-specific
ECG changes), TK inhibitors (such as lapatinib, dasatinib,
nilotinib, sunitinib, vandetanib and XL647), protein kinase
C inhibitors (enzastaurin) and farnesyl protein transferase
inhibitors (L-778123 and lonafarnib). For most of these
agents, the effective clinical significance of these effects
needs to be better assessed. On the basis of preclinical and
early clinical studies, QT effects and other cardiovascular
toxicities are anticipated also for some vascular disrupting
agents, such as combretastatin A4 phosphate and the flavone acetic derivative vadimezan [43–45].
The structural characteristics leading to QT toxicity
have not been fully delineated, though the existence of a
relationship with a given therapeutic class is not likely.
Nevertheless, one of the most frequent mechanisms of QT
prolongation is that, owing to its three-dimensional configuration, an agent may be able to interact with human
ether-a-go-go-related gene potassium ion channels (HERG
K?), which allow for the rapid component of myocardial
repolarization. However, not all drugs that block HERG
K? cause QT prolongation limiting the sensitivity of this
marker. On the other hand, there are several identified
factors that may predispose cancer patients to QT prolongation; they include advanced age, cardiac abnormalities
inherent to cancer population, high prevalence of comorbid
diseases that may independently increase the risk of QT
prolongation, electrolyte disturbances due to severe nausea
or vomiting, starvation, concomitant medications with
other agents that predispose to QT abnormalities (like
5-HT3 receptor antagonists, antipsychotics and antidepressants) and many others [44, 45].
The measurement of QT is affected by variability and
lack of standardization. Biological sources of QT variance
include gender, circadian rhythm, autonomic tone, physical
activity levels, food ingestion and, in particular, heart rate,
as QT interval duration decreases as cardiac frequency
increases. Different formulas have therefore been developed to mathematically correct QT for heart rate variability
(QTc), but they are considered inaccurate, and there is no
consensus on which of them is preferable. In addition, there
is no established threshold below which QT interval prolongation can be considered free of pro-arrhythmic risk.
Overall, emphasis has recently been put on the need of
better preclinical and early clinical criteria and approaches
to evaluate the risk of QT toxicity from novel anticancer
drugs [43, 44].
Principal Diagnostic Investigations to Study
Cardiotoxicity
Guidelines for anthracycline cardiotoxicity monitoring
propose left ventricular ejection fraction (LVEF) measurement as the gold standard parameter for decision-making.
However, its prediction power for late development of
cardiomyopathy is not strictly accurate or timely. Traditionally, the detection of anticancer-induced cardiotoxicity
has been based on the measurement of resting LVEF or LV
fractional shortening (LVFS). In many studies, cardiac
toxicity is assumed if (a) LVEF drops more than 10% from
the baseline to values below 50%, (b) LVEF drops more
than 20% from the baseline despite still having normal
function or (c) LVEF drops below 45% [46].
Another method used is the classification of functional
cardiotoxicity on the basis of both clinical and echocardiographic criteria. Functional cardiotoxicity is defined as
mild (a decrease in LVEF [10% from the baseline with a
final value [50%), moderate (a decrease in LVEF [10%
from the baseline with a final value \ 50% and no symptoms nor signs of heart failure) and severe (a decrease in EF
[10% from the baseline with a final value \50% and
symptoms or signs of heart failure or a decrease in EF of
any percentage leading to a final value \40% irrespective
of symptoms or signs of heart failure) [47].
These parameters are, however, not sensitive enough to
detect the subtle changes in myocardial function which
occur in early cardiotoxicity. A certain proportion of
damaged, dysfunctional myocardium to cause a change in
global systolic function that will exceed the sensitivity
threshold of these parameters is needed. At the point when
changes are detected, functional deterioration already
proceeds rapidly and is mostly irreversible. Therefore, new
methods are needed to reliably detect early myocardial
injury during or shortly after oncological therapies [48].
Currently, multiple tests are available for the monitoring of
anthracycline cardiotoxicity (Table 2). At the moment, it is
difficult to define the best method to assess the cardiotoxicity due to new anticancer drugs.
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Table 2 Principal diagnostic investigations for cardiotoxicity
Electrocardiogram
Benefits
Disadvantages
Easily reproducible
Often non-specific abnormalities
Early electrical alterations
Not invasive
Endomyocardial biopsy
Radionuclide angiocardiography
Echocardiogram
LVEF (Simpson’s rule)
Histological diagnosis
Invasive method
Useful for ‘‘type 1’’ cardiotoxicity
Possibly inapplicable for ‘‘type 2’’
cardiotoxicity
Excellent for evaluation of ejection fraction
Expensive
Easily reproducible
Operator-dependent
Not invasive
Doppler blood flow
Early diagnosis of diastolic dysfunction
Influenced by loading conditions
Easily reproducible
TDI
Very early diagnosis of diastolic an systolic dysfunction
Operator dependent
Not influenced by loading conditions
TEI index
Measure of global (systolic and diastolic) function
without geometrical assumptions
Operator dependent
Strain
Changes in tissue deformation
Need of further validation
Need of further validation
Strain rate
ECHO stress
MRI
Assesses left ventricular function contractile reserve
Published studies appear controversial
Detects changes in ventricular function and toxic effects
Expensive
Of value in patients with limited echocardiographic
imaging windows
Delayed enhancement
Biomarkers
Assessing scar and fibrosis
Need of further validation
Possible value as early disease markers and, in some
cases, also as pathophysiologic determinants
Ability to evaluate cardiotoxicity induced
by non-classical therapeutic agents?
Need of further validation
Electrocardiogram
Endomyocardial Biopsy Examination
Signal-averaged electrocardiography (ECG) is a noninvasive diagnostic technique intensively used to especially
monitor the cardiotoxic effects that can occur during or
shortly (within hours) after administration of chemotherapeutic drugs. These include non-specific ST-T-wave
changes, decreased QRS voltage and prolongation of the
QT interval and rhythm disturbances. Acute cardiac
arrhythmias have been observed in association with the
administration of taxol [49], doxorubicin [50], cisplatin
[51], 5-fluorouracil [52] and other drugs. Atrial fibrillation,
a common finding in elderly patients, may be due to patient
stress but can also be induced by various drugs, including
anticancer agents [53].
In a recent study on anthracycline-induced cardiotoxicity, the ECG changes were compared with the findings on
echocardiography (ECHO). The anthracycline treatment
was associated with changes in electrical activity of the
myocardium, like prolonged QTc interval and decreased
QRS voltage, which could correlate with LV dysfunction in
ECHO [54].
Endomyocardial biopsy examination requires a small
sample of right ventricular myocardium for analysis by a
skilled histopathologist. Although it provides histological
diagnosis along with grading of severity of disease (based
on the Billingham’s score), it has multiple shortcomings
[55]. This method can possibly be used only for type I
cardiotoxicity because type II, exemplified by trastuzumab,
differs from the former in that it may not be associated with
identifiable structural cardiomyocytes changes and appears
to be mostly reversible. Moreover, considering that there
are now a few non-invasive alternative methods, endomyocardial biopsy examinations are increasingly becoming
a scarcely used technique.
Radionuclide Angiocardiography
Scintigraphic parameters of both systolic and diastolic
cardiac function have been recommended to assess cardiac
injury. Equilibrium radionuclide angiocardiography
(ERNA) has shown to be a reliable and reproducible test
Cardiovasc Toxicol
for monitoring and evaluating LV function in patients
undergoing doxorubicin chemotherapy [56]. It is among
the earliest and most widely used methods for this purpose.
Serial monitoring using ERNA allows for the detection of a
predetermined decrease in LVEF that predicts subsequent
cardiac dysfunction [57]. A prospective study on doxorubicin cardiotoxicity using radionuclide angiography found
that patients with normal baseline EF at rest but abnormal
EF under exertion appeared to be at increased risk of cardiac heart failure [58]. Though the number of studies
supporting an additional benefit for the detection of chemotherapy-induced cardiac damage with specific myocardial tracers is limited to date, these techniques appear to be
more sensitive than LVEF measurements. Increased 111Inantimyosin uptake, reflecting myocyte damage, as well as
123
decreased
myocardial
I-metaiodobenzylguanidine
(MIBG) uptake, indicating cardiac adrenergic denervation,
may be useful in identifying both the early and late cardiac
sequelae due to treatment with anthracyclines [59, 60].
Role of Echocardiography (ECHO)
Among non-invasive examinations, ECHO provides a wide
spectrum of information on cardiac morphology and
function. Standard parameters measured in systole and
diastole are LV dimensions, right ventricular anterior wall
(RVAW), interventricular septum (IVS) and LV posterior
wall (LVPW) thickness. LVEF is calculated using the
modified Simpson’s rule with a value of 50% or more
being considered as normal [61]. LV fractional shortening
is calculated from the LV dimensions; a value of [28% is
considered normal. Using the apical four-chamber view,
peak early (E wave) and late (A wave, after atrial contraction) diastolic Doppler blood flow velocities of the
mitral valve can be measured. Accordingly, the E/A ratio is
calculated from these measured peak velocities. However,
although used frequently, the sensitivity of serial measurement of cardiac function by ECHO is limited by
inherent variability [62, 63].
Tissue Doppler imaging (TDI) using ECHO is a technique that allows for measurements of velocity at any point
along the ventricular wall during the cardiac cycle. TDI
allows for the measurement of maximal systolic endocardial velocity and strain rate. When compared with conventional measures of LVEF, TDI-derived parameters are
less influenced by loading conditions, such as the change in
intravascular volume that occurs with chemotherapy in
combination with trastuzumab. Thus, TDI is a feasible
imaging modality that might provide improved sensitivity
in detecting early subclinical LV dysfunction. Recently, the
potential application of TDI for the early detection of
anthracycline- and trastuzumab-mediated cardiac dysfunction was validated in a murine model. It was shown
that TDI was abnormal in mice receiving doxorubicin or
doxorubicin plus trastuzumab as early as 24 h after treatment and that it predicted ensuing LV systolic dysfunction
with increased mortality [64]. TDI may become a regularly
and more widely used non-invasive method to detect subclinical cardiotoxicity emerging after chemotherapy [65].
In addition to traditional parameters of LV systolic and
diastolic function, the Tei index can be calculated, and
TDI-derived longitudinal systolic (Sa) and early diastolic
(Ea) velocities can be measured. The Tei index is calculated as the sum of the isovolumetric contraction time
(ICT) and isovolumetric relaxation time (IRT) divided by
the ejection time (ET) [66]. The longitudinal Sa and Ea
velocities are obtained online using spectral TDI in the
apical 4-chamber view placing a 5 mm pulsed wave sample volume at the level of the lateral mitral annulus [67].
Respiratory manoeuvres (e.g. end expiratory apnoea) are
used where possible to enhance data quality. If used at the
baseline, the manoeuvres are repeated on subsequent
studies to maintain consistency. Each parameter is measured from 3 to 5 consecutive beats and averaged [68].
Overall, the Tei index is a measure of global (systolic and
diastolic) function without geometrical assumptions, correlating well with invasive measurements and has been
validated in the assessment of ventricular function with
higher values conferring poorer prognosis [69]. The Tei
index increases after therapy with anthracyclines in the
majority of the patients (78.8%), indicating that early
myocardial alteration is more frequent than that previously
recognized [70, 71], although this may not predict functional cardiotoxicity in terms of EF and symptoms and
signs of heart failure [47, 72].
New ECHO methods quantifying regional deformation
like strain and strain rate imaging are promising tools,
which have the potential to sensitively monitor cardiac
function and, thus, guide anticancer therapy and preventive
measures to avoid unnecessary myocardial damage
[73, 74]. The aim of a recent study was to investigate
whether changes in tissue deformation, assessed by myocardial strain and strain rate (SR), are able to identify LV
dysfunction earlier than conventional ECHO measures in
patients treated with trastuzumab [75]. There were no
overall changes in 3D-EF, 2D-EF, myocardial E-velocity
or strain. However, significant reductions were seen for
TDI SR, 2D-SR and 2D radial SR. The conclusion was that
myocardial deformation can identify preclinical myocardial dysfunction earlier than conventional measures in
women treated with trastuzumab for breast cancer. TDI,
allowing to measure parameters such as myocardial
velocity, deformation (strain) or deformation rate (strain
rate), can reliably detect early abnormalities in both
regional and global myocardial function. Further validation
in larger prospective studies is needed.
Cardiovasc Toxicol
Stress ECHO
Cardiac Biomarkers
Stress ECHO can assess LV function contractile reserve.
Exercise ECHO is an optimal tool to unmask coronary
artery disease in the general population and may also be of
importance in patients treated with some chemotherapeutic
agents (e.g. 5-fluorouracil or capecitabine) and by radiation
therapy, which is able to provoke accelerated coronary
atherosclerosis. Experiences on exercise ECHO in this
clinical setting are, however, scanty until now [76, 77].
Low-dose dobutamine stress ECHO has been shown to
be useful for the identification of myocardial viability and
the prediction of LV contractile recovery after coronary
revascularization in patients with coronary artery disease
[78]. It has been suggested that abnormalities of myocardial adrenergic neuron activities may occur early in
anthracycline cardiotoxicity before any appreciable systolic dysfunction. The presence of this early adrenergic
derangement might explain the impaired myocardial
responsiveness to dobutamine even when standard ECHO
parameters do not reveal any alteration [79]. Other studies
have shown that dobutamine stress ECHO could detect
subtle changes in LV function due to anthracycline cardiotoxicity [80–84].
Cardiac biomarkers are molecules that are released into the
blood when there is something wrong with the heart.
During an abnormal cardiac event, like a heart attack, or
even angina, the heart muscle is put under great stress and
the heart muscle fibres release molecules that are never
normally produced. These molecules enter into the bloodstream and can be detected in a blood test.
Non-invasive biochemical tests for early detection of
cardiotoxicity are an interesting field addressed by different
papers in the published literature.
Magnetic Resonance Imaging (MRI)
Among other applications, MRI is considered as an ideal
tool to study acute myocardial injuries. One can successfully visualize the site and extent of myocardial infarction
by imaging the necrotic area and associated oedema using
T2- and contrast-enhanced T1-weighted MRI [84]. Furthermore, in a study on MRI in acute myocarditis, myocardial inflammation produced an increase in signal
intensity in contrast-enhanced T1-weighted MRI [85]. Late
contrast enhancement in the myocardium is a reliable
marker of either scar tissue or of the capillary leakage that
occurs early during myocardial damage. This phenomenon
is widely used in cardiology to identify post-infarction scar,
as well as viable myocardium.
MRI may have the potential to image both changes in
ventricular function and toxic effects on the myocardial
tissue. In a study on patients receiving anthracyclines, MRI
could detect early changes in myocardial contrast
enhancement along with slight deterioration in cardiac
function [86]. There is an advantage of MRI in patients
with limited ECHO imaging windows. A comparison of the
wall motion assessment by ECHO and MRI proved the
comparable accuracy of both methods [87]. Recently, it
was demonstrated that delayed contrast enhancement
imaging using cardiac MRI could detect early changes in
the myocardium due to trastuzumab-induced cardiotoxicity
[88]. This finding merits further study.
Natriuretic Peptides
The family of natriuretic peptides includes atrial natriuretic
peptide (ANP), which is dominant in cardiac atria, and
brain natriuretic peptide (BNP), primarily released from the
ventricles. The corresponding pro-hormones split into
inactive N-terminal (NT-pro-ANP and NT-pro-BNP) and
the biologically active ANP and BNP peptides. Increased
quantities of these peptides are released in response to
increased myocardial wall stress induced by volume
overload, as important indicators of severe as well as early
symptomless heart failure. The distinct peptides may possibly reflect different aspects of the process (diastolic
versus systolic dysfunction) [89, 90]. They might also
represent an early sign of cardiotoxicity secondary to
chemotherapy and radiation treatment, although the data
are controversial and their role in this respect has to be
further clarified [91–95]. Combining continuous wave
Doppler ultrasound and NT-pro-BNP monitoring may be
useful to monitor the immediate haemodynamic changes
that occur after trastuzumab therapy [96].
Troponins
Circulating levels of both cardiac troponin T (cTnT) and I
(cTnI) have been correlated in humans to the extent of
myocardial injury from various aetiologies and especially
used as tests for myocardial infarction [97]. Early elevations of serum cardiac troponins have been also reported
after chemotherapy, predicting subsequent subclinical and
clinical cardiac morbidity. On the basis of a significant
body of clinical evidence, troponins can be considered as
well-established markers of myocardial non-ischaemic
damage from drugs. However, their monitoring requires
frequent sampling, as it has not been possible to identify a
single time point for their evaluation [95]. Troponin I
might be superior to troponin C to early detect cardiac
injury associated with anthracycline therapy [98]. A recent
study on 251 breast cancer patients has shown that elevation of troponin I identifies trastuzumab-treated patients
Cardiovasc Toxicol
who are at risk of cardiotoxicity and are unlikely to recover
from cardiac dysfunction despite heart failure therapy [99].
Other Markers
Cardiac endothelial cells contribute to regulate cardiac performance, and endothelin-1 (ET-1) is a central substance in
this mechanism. ET-1, first identified as a vasoconstrictor,
has pleiotropic effects in the heart where it triggers hypertrophic, proliferative and cell survival responses. In an early
small study, progressive elevation of its plasma levels
occurred before deterioration of LVEF in patients who
subsequently developed CHF from doxorubicin [100]. In
contrast, another study on patients with Hodgkin’s or nonHodgkin’s lymphoma has shown that ET-1 levels decreased
significantly after anthracycline therapy and remained low
after 1 year. These findings were accompanied by worsening
of left ventricular function [101]. In studies on mice, block of
ET-1 activities [102, 103] inhibited doxorubicin-induced
cardiomyopathy, suggesting that endothelin may play a role
in mediating the cardiotoxic effects of the anthracycline.
Thus, the pathophysiological and predictive role of ET-1 in
anthracycline cardiomyopathy remains to be better clarified.
Cardiotrophin-1 (CT-1), a member of the interleukin 6
family of cytokines, is capable of promoting both the proliferation and the survival of embryonic or neonatal cardiac
myocytes. It is synthesized in the heart in response to
mechanical stretch and other forms of injury. At first, it may
provide myocardial protection, but in the chronic course, it
induces myocyte hypertrophy and collagen synthesis, thus
participating in the ventricular structural changes that ultimately result in heart failure. Circulating CT-1 levels are
elevated in patients with hypertension, valve diseases, coronary artery diseases and congestive heart failure [104].
However, despite the possible interest in CT-1, both as a
disease marker and a pathophysiological determinant, there
are no systematic studies on the behaviour of CT-1 plasma
levels in the context of clinical toxicity from anticancer drugs
[104, 105].
Other promising markers of cardiomyocyte impairment,
like the heart-type fatty acid-binding protein (H-FABP)
[106], are awaiting validation for their use in cardiooncology. Collectively, however, the clinical value of
biochemical parameters for the early diagnosis and prognostic judgement of cardiotoxicity from anthracyclines
and, possibly, from the newer anticancer drugs remains a
controversial issue.
A New Area of Interest: The Use of Induced Pluripotent
Stem Cells (iPS Cells)
Different studies propose that chemotherapy induces cardiotoxicity by inadvertently interrupting the homoeostasis of
cardiac stem cells and depleting the resident cardiac stem
cells pool. As a result, the heart loses the capability of
regeneration and repair and undergoes cardiotoxic effects.
This hypothesis is supported by several lines of emerging
evidence: the high incidence of cardiotoxicity in paediatric
cancer patients who still have more cardiac stem cells in the
myocardium; the rescue of anthracycline cardiomyopathy by
injection of cardiac stem cells; and the adverse cardiotoxicity
induced by inhibitors of oncogenic kinases or pathways that
target cardiac stem cells besides cancer cells [107].
The recognition that the adult heart in animals and
humans contains a pool of resident primitive cells, which
are self-renewing, clonogenic and multipotent in vitro and
regenerate myocytes and coronary vessels in vivo, raises
the question whether the effects of DOXO on cardiac
homoeostasis and repair are primarily directed to the stem
cell compartment partially ablating the reserve of functionally competent cardiac progenitor cells (CPCs) [108].
In fact, CPCs are particularly sensitive to oxidative stress
and rapidly die by apoptosis. Myocytes are more resistant
to ROS formation than CPCs, strengthening the possibility
that loss of CPCs together with the reduced generation of a
myocyte progeny may be critical in the development of
doxorubicin-mediated cardiomyopathy.
The growing appreciation that cardiac stem cells represent new targets that contribute to chemotherapy-induced
cardiotoxicity opens up novel strategies for overcoming the
problem. How might stem cells play a part in repairing the
heart? To answer this question, researchers are building their
knowledge base about how stem cells are directed to become
specialized cells. The potential capability of both embryonic
and adult stem cells to develop into myocytes, endothelial
and smooth muscle cells is now being explored as part of a
strategy to restore heart function in people who have had
heart attacks or are affected by congestive heart failure.
More evidence for potential stem cell-based therapies
for heart disease is provided by a study that showed that
human adult stem cells taken from bone marrow are
capable of giving rise to vascular endothelial cells when
transplanted into rats [109].
The advent of induced pluripotent stem cell (iPS)
technology, whereby fully differentiated cells are induced
to return to a progenitor state, makes it possible to generate
any cell type from any genetic background, increases the
utility of stem cell-derived experimental models and
negates many of the ethical concerns surrounding embryonic stem cells.
Pluripotent stem cells derived from the inner cell mass
of early stage embryos have provided a prototype for multilineage repair. However, ethical considerations along with
practical limitations have precluded adoption of embryonic
stem cell platforms, thereby driving advances in nuclear
reprogramming to establish viable alternatives [110]. In
Cardiovasc Toxicol
this regard, iPS technology may provide an emerging
innovation that fulfils the unlimited potential of embryonic
stem cells while circumventing the need for embryonic
sources [111].
One of the first studies establishing the real potential for
using iPS cells in cardiac treatment was conducted by a
Mayo Clinic team: It was shown that fibroblasts reprogrammed via a ‘‘stemness-related’’ gene set acquire the
capacity to repair and regenerate infarcted hearts [111].
The ultimate goal is to use iPS cells derived from the
patients themselves, thus eliminating the risk of rejection
and the need of antirejection drugs. In addition, this
regenerative medicine strategy might alleviate the demand
for organ transplantation limited by donor shortage.
Finally, developing iPS cell technology and automated
culturing techniques will enable in vitro testing of pharmaceuticals for both efficacy and toxicity over any individual genetic make-up and truly bring the potential of
personalized medicine to the clinic.
increasingly represents an important challenge for different
professional figures and scientists. Understanding the
mechanisms responsible for such toxicity may possibly help
to design safer drugs or find optimal protective tools.
Pharmacologists are also called to develop adequate animal
models that better predict drug-induced cardiovascular
complications in humans. Such information can offer oncologists the chance to move patients toward less toxic
regimens and allow cardiologists to preserve cardiac
function. In recent years, many groups have studied the
cardiotoxicity and all related issues, because it is an
emerging problem that interested many medical specialists.
A recent review underlines the importance of close collaboration between oncologist and cardiologist with the aim
of balancing the risks of cardiotoxicity with the benefits of
oncologic therapy [115]. All the elements presented in our
article underline the necessity of further interdisciplinary
work in the area of cardio-oncology to improve the survival
and quality of life of cancer patients, with particular regard
of new area of interest: stem cells and pharmacogenomics.
Pharmacogenetics: A New Approach to ‘‘Personalized
Medicine’’
Clearly, pharmacogenetics is another emerging field in
medical science, which aims to improve the treatment of
disease and dramatically reduce the risk of adverse drug
reactions, by incorporating genetic information into the
treatment decision-making process. For example, patients
on doxorubicin show marked interindividual variability in
dose tolerance and toxicity. A recent study examined more
than 200 polymorphisms in 82 genes with a biologically
plausible role in doxorubicin cardiotoxicity. Genetic variants in the ABCC1 and ABCC2 genes (ABC transporters,
which encode multidrug resistance-associated proteins
member 1 [MRP1] and member 2 [MRP2]) and in the
members of the NADPH oxidase complex (genes RAC2
and CYBA) were found to be associated with acute doxorubicin cardiotoxicity [112].
Drug-induced arrhythmias, in particular long QT syndrome and Torsades de Pointes, have been associated with
variants in genes encoding cardiac K? and Na? channels
[113]. While most authors have been concentrating on
mutations in cardiac ion channels, others have also investigated drug metabolizing enzymes on the basis that QT
prolongation is increased at higher drug concentrations
[114]. Genetic biomarkers can be used to identify high-risk
patients and thus prevent serious cardiotoxicity.
Conclusions
The aspect of cardiovascular toxicity from anticancer
agents, including the novel molecularly targeted ones,
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