Mini Review
Role of Echocardiography in the Assessment of Cancer Therapeutics–Related Cardiac Dysfunction: An Updated State-of-the-Art Review
Luca Longobardo1, Scipione Carerj1, Concetta Zito1, Giuseppe Caracciolo2 and Bijoy K. Khandheria2*
1Department of Clinical and Experimental Medicine, University of Messina, Italy
2Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke’s Medical Centers, University of Wisconsin School of Medicine and Public Health, USA
*Corresponding author: Bijoy K. Khandheria, Aurora Cardiovascular Services, Aurora St. Luke’s Medical Center, 2801 W. Kinnickinnic River Parkway, Ste. 840 Milwaukee, WI 53215, USA
Published: 17 Oct, 2016
Cite this article as: Longobardo L, Carerj S, Zito C,
Caracciolo G, Khandheria BK. Role of
Echocardiography in the Assessment of
Cancer Therapeutics–Related Cardiac
Dysfunction: An Updated State-of-the-
Art Review. Clin Oncol. 2016; 1: 1112.
Abstract
In the last years, cardiotoxicity in patients treated with chemotherapy became one of the most
urgent issues for cardiologists because cancer has become one of the most common diseases of
this century. The evidence of significant cardiac side effects of anticancer drugs and the awareness
that an early assessment of cardiac damage can substantially reduce the onset of chemotherapyrelated
heart failure motivated several authors to concentrate their efforts in the study of new tools
for sensitive and early detection of Cancer Therapeutics–Related Cardiac Dysfunction (CTRCD).
Echocardiography is widely considered the criterion standard technique for the assessment of
these patients. The aim of this review is to carefully evaluate strengths and weaknesses of the main
echocardiographic parameters commonly used for the detection of CTRCD through a detailed
examination of the most relevant and recent papers in literature, while at the same time providing a
practical approach to evaluate patients with cardiotoxicity.
Keywords: Cardioncology; Cardiotoxicity; Cancer therapeutics–related cardiac dysfunction;
LVEF; 2D speckle tracking strain; Echocardiography
Introduction
In the last century, cancer became one of the most common diseases of the Western world
and chemotherapy one of the most used treatments, with a range of side effects that have been
identified only recently. Cancer Therapeutics–Related Cardiac Dysfunction (CTRCD) is one of the
most common and dangerous side effects of several agents, especially anthracyclines, trastuzumab
and tyrosine-kinase inhibitors [1]. Echocardiography is the most commonly used technique for the
evaluation of CTRCD because of its wide availability, easy repeatability, lack of radiation exposure,
and accuracy in the assessment of cardiac dysfunction. According to the most recent consensus
statements [1,2], CTRCD can be defined as a decrease in the Left Ventricular Ejection Fraction
(LVEF) of more than 10% to a value less than 53%, confirmed by repeated cardiac imaging. However,
the evaluation of cardiac damage is difficult. Indeed, the entity and the timing of cardiac dysfunction
can vary considerably among agents and often is not apparent for several years. Moreover, the
assessment of CTRCD must be accurate and done as early as possible. The evidence of cardiac
impairment can lead to discontinuation of cancer therapy with the loss of the beneficial anti-cancer
effects for the patient, but at the same time, late detection of cardiac injury can lead to irreversible
damage with a high risk of heart failure.
Assessment of LV systolic function: the role of LVEF
LVEF has been historically considered the cornerstone for the quantification of LV systolic
function. Its importance in the assessment of patients potentially affected by cardiotoxicity is well
demonstrated by the definition of CTRCD that the consensus statement from the American Society
of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) [2]
provides. Reduced LVEF after anthracycline-containing therapy [3-6] and an impaired LVEF before
chemotherapy treatment is a good predictor for the onset of heart failure [7]. The main advantages
of LVEF for the quantification of LV systolic function are the ease of the calculation and the huge
amount of data confirming its effectiveness in every clinical setting. According to the current
recommendations [8], LVEF should be quantified using the most accurate echocardiographic technique available in the echolab, i.e., 3D echocardiography or, if it is not available, 2D echocardiography by the biplane Simpson’s
method and associated with the analysis of regional function by wall
motion score index; moreover, for a more accurate evaluation of
changes in patients after chemotherapy, LVEF reduction should be
confirmed by comparing baseline and follow-up studies. However,
the quantification of LVEF by 2D echocardiography is limited by
some technical issues, such as LV geometric assumptions for the
calculation of volumes, the frequent foreshortening of LV apex,
the difficulties in the tracing of endocardial border in patients with
poor image quality, the lack of consideration of subtle regional wall
motion abnormalities, and the high dependence from LV shape
(less effective if LV is dilated) and loading conditions; the latter is
particularly important in patients with cancer because changes in
loading conditions are frequent as a result of side effects associated
with the chemotherapy like nausea, vomiting, and diarrhea. These
limitations could explain the findings of several authors [9-11] who
questioned the real effectiveness of LVEF in patients with potential
cardiotoxicity, especially in the first months after beginning therapy.
Di Lisi et al. [10] reported that inpatients with early breast cancer,
after 6 months from the start of chemotherapy with one or more
between epirubicin, trastuzumab, fluorouracil, cyclophosphamide,
taxotere, and taxolo, significant changes were observed in tissue
Doppler systolic parameters but not in LVEF, whereas Jensen et al.
[11] showed that LVEF changes frequently occur late, when cardiac
damage became irreversible. The issue concerning the timing of LVEF
reduction in patients with CTRCD is crucial, because a late change of
LVEF only in the advanced stages of cardiac damage makes LVEF
poorly effective in the early detection of subtle LV dysfunction and in
the prevention of heart failure. There is not a wide consensus about
the timing of LVEF impairment in patients with CTRCD. Dodos et
al. [4] reported a significant reduction of LVEF immediately after the
completion of therapy in patients treated with anthracycline, whereas
other authors [5,6] did not find significant LVEF changes in the first
months of follow-up, and Cardinale et al. [12] showed that patients
with a late detection of cardiotoxicity had a lower rate of LVEF
recovery after heart failure treatment and a higher risk of mortality.
Finally, LVEF assessment by 2D echocardiography is affected
by important intra- and inter-observer variability. Its effectiveness
has been severely questioned by Thavendiranathan et al. [13]
who demonstrated that the quantification of this parameter by 2D
echocardiography has an inter-observer variability close to 10%; since
the definition of CTRCD is a decrease in LVEF of more than 10% to
a value less than 53%, the reliability of this technique appears to be
debatable.
Assessment of LV systolic function: What can new myocardial deformation measurements add?
In the last years, the role of myocardial deformation parameters
like strain and strain rate in the assessment of LV systolic function
became more and more evident; with great results in several clinical
settings [14]. Myocardial deformation can be quantified by different
techniques, i.e., Doppler strain imaging (DSI) and 2D and 3D Speckle
Tracking Echocardiography (STE). DSI is the first method used,
and, despite the promising results obtained, it was affected by angle
dependency, high intra- and inter-observer variability, limited spatial
resolution, and a high sensitivity to signal noise; all these limitations
were overcome by 2D STE strain, a method that allows a frameby-
frame tracking of natural acoustic markers (speckles), reducing
artifacts due to translational respiration and tethering from the adjacent myocardium and angle-dependency.
Several authors concentrated their efforts in the application
of these new tools for the assessment of patients undergoing
chemotherapy. Most of studies used Global Longitudinal Strain (GLS),
which was more effective than radial and circumferential strains in
the evaluation of these patients; however, a reduced circumferential
strain was demonstrated in some reports [15].
The importance of GLS in the assessment of cardiac damage
was clearly demonstrated. GLS was decreased early in both children
[16,17] and adults [18,19] treated with anthracyclines, often in
patients with normal LVEF. Poterucha et al. [17] studied a cohort
of 19 children treated with anthracycline and found that changes in
GLS preceded decreases in LVEF and that a characteristic pattern of
regional changes, particularly located in mid and apical LV segments,
can be observed (Figure 1). Similarly, Stoodley et al. [19] reported a significant reduction of GLS after one week of anthracyclines therapy in patients with breast cancer, whereas no reduction in LVEF >10%
was registered (Figure 2). According to these data demonstrating the
better sensitivity of myocardial deformation measurements in the
detection of subtle LV systolic dysfunction, the 2016 ESC position
paper on cancer treatments states that the use of strain is preferred,
when available, to serve as the basis for clinical decisions whereas
the ASA/EACVI consensus statement [2] included 2D STE strain
in the protocol for the serial evaluation of these patients, suggesting
a comparison of the measurements during chemotherapy with the
baseline value; indeed, it has been shown that a relative percentage
reduction of GLS of <8% from baseline appears not to be meaningful,
whereas patients with a reduction >15% from baseline are very likely
to be affected by CTRCD [20].
Furthermore, strain showed to have not only a diagnostic but
also a prognostic role in this setting. Data reported by several authors
[21-23] showing that a decrease in longitudinal strain from baseline
predicted the development of cardiotoxicity with high sensitivity
have been recently confirmed by Ali et al. [24] who showed that a low
pre chemotherapy GLS was a strong predictor of cardiac death and
symptomatic heart failure. Interestingly, a GLS <-15.8% quantified at
the time of the diagnosis of CTRCD was associated with subsequent
recovery of LVEF, underlining the role of this parameter in the risk
stratification of these subjects [22]. However, the recovery of LVEF
after the end of the chemotherapy does not always indicate a full
recovery of LV systolic function. Several authors who studied longterm
cancer survivors found that a significant percentage of patients
exposed to chemotherapy between 2 and 30 years before had a
reduced GLS despite a normal LVEF [16,25-28]. Interestingly, the risk
of developing cardiac damage was higher in patients treated with high
doses of anthracyclines compared with other anticancer agents [25]
and in patients exposed to mediastinal radiotherapy [28]. All these
data confirmed the role of myocardial deformation measurements
in the lifelong follow-up of patients who underwent chemotherapy.
However, it is important to keep in mind several limitations that
affect these parameters and the lack of data about its prognostic
role. First, 2D STE strain and strain rate need good image quality to
obtain reliable results, better than what is needed for the calculation
of EF. Moreover, these measurements are very sensitive but poorly
specific; they could be reduced in several clinical conditions, and it
is not possible to distinguish if chemotherapy is the real cause of the
impairment. Furthermore, when doing serial evaluations, similar
vendors and algorithms for calculating strain should be used; intervendor
variability is one of the oldest limitations of strain, and despite
the efforts of the EACVI-ASE-Industry Task Force [29] that recently
found a good reproducibility of GLS, there is a small but statistically
significant variation among vendors that has to be considered. In
addition, currently there are not enough data regarding the prognostic
role of strain and strain rate in this setting. There is a general consensus
that a reduction of LVEF >10% should suggest the discontinuance of
chemotherapy; however, the prognostic relevance of a reduced GLS
with a normal LVEF is not yet established, and currently, the finding
of subnormal strain suggests the need for only closer monitoring of
cardiac function. Moreover, not all subtle reductions in LV function
will progress to heart failure and studies to define criteria for clinically
relevant changes in strain are needed.
Not only the LV systolic function
Echocardiographic evaluation of patients before, during and after
chemotherapy treatment should not be limited to the quantification of LV systolic function, but should include the study of LV diastolic
function, RV systolic function, heart valves and pericardium.
Diastolic function seems to be reduced in a significant percentage
of patients who underwent chemotherapy, but there is little evidence
that parameters for the evaluation of diastolic function could be
considered effective markers of CTRCD. A prolonged isovolumic
relaxation time [30], a reduced E’ or E/E’ ratio [21,31] and an
increased myocardial performance index [32] were indicated as
markers of cardiac damage in small studies, but they were not
confirmed subsequently [33-34]. Moreover, in a recent study, E/E’
ratio at baseline or 3 months after the beginning of the treatment
did not show a significant correlation with subsequent LVEF decline
[31] and its changes can be strongly influenced by changes in loading
conditions due to vomiting and diarrhea, typical side effects of
chemotherapy. Therefore, diastolic function should be assessed for
a general evaluation of patients but not considered closely related to
CTRCD.
On the contrary, the evaluation of RV systolic function is
mandatory in these patients. In the last years, the role of RV
dysfunction became clearly a strong predictor of mortality and
development or worsening of heart failure in several clinical
settings [35]. In patients who underwent chemotherapy, RV
damage can be due to both the harmful effects of anthracyclines on
cardiomyocytes that affect LV and RV myocardium in the same way
and the increased left ventricular filling pressures that could lead to
increased pulmonary artery pressure and affect RV function through
increased after load [36]. RV should be evaluated according to the
recent recommendations [8] (Figure 3). In patients with potential cardiotoxicity, TAPSE [37] and TDI S’ wave [38] were effective tools
for the evaluation of RV systolic function, which were impaired both
in the short-term and long-term follow-up. Interesting results have
been obtained with the use of 2D STE strain for the assessment of
RV systolic function. RV longitudinal strain were reduced in breast
cancer patients after 3 months of anthracycline-based chemotherapy
[39] and in long-term adult survivors of lymphoma and acute
lymphoblastic leukemia, [36] providing important information
for a more accurate risk stratification of these patients. Therefore,
RV function should be routinely assessed in patients with potential
cardiotoxicity to improve the prognostic relevance of the evaluation.
Anticancer drugs do not seem to directly affect cardiac valves,
but valvular diseases can be related to radiation therapy and severe
infection that often affect these patients due to the reduction of
leukocytes as a side effect of chemotherapy. Moreover, the presence
of preexisting valve lesions like mitral prolapse can favor the onset
of endocarditis [40]. Radiation therapy can cause a specific damage
of valves; known as “radiation-induced heart disease” (RIHD) [41]
that usually becomes symptomatic several years after the end of the
therapy. Accordingly, the European Association of Cardiovascular
Imaging and the American Society of Echocardiography (EACVI/
ASE) [41] recommend an echocardiographic evaluation of valves
10 years after the end of radiation therapy and serial exams every
5 years thereafter. In this context, the use of trans-esophageal
echocardiography can add important information for a surgeon if
surgical treatment is required.
Pericardial involvement is very common in patients who
underwent chemotherapy, especially anthracyclines and radiotherapy,
whereas damage due to cancer itself is quite rare. Pericarditis can be
acute or delayed, with the onset of symptoms and pericardial effusion
from 2 months to 15 years after the treatment [1,41] Echocardiography
is the first line tool for the assessment and quantification of pericardial
effusion; more rarely, constrictive pericarditis with the typical signs
of constriction can be found, particularly in patients who underwent
high-doses of radiotherapy. Finally, echocardiography is the
technique of choice to guide pericardiocentesis, when needed.
Advanced assessment of CTRCD: 3D echocardiography and cardiac magnetic resonance
As previously discussed, the quantification of LVEF by 2D
echocardiography is limited by several issues, including the
LV geometric assumptions for the calculation of volumes, the
foreshortening of LV apex, the difficult tracing of endocardial
border in patients with poor image quality, and the high dependence
from LV shape and loading conditions. Most of these limits can be
overcome by 3D echocardiography, which allows an assessment
of LV volumes and EF not based on geometrical assumption,
unaffected by apical foreshortening and improved by the use of an
automated or semi-automated method for the identification of LV
endocardium. Accordingly, 3D echocardiography was the most
reliable echocardiographic technique for the assessment of LV
volumes and EF and should be considered the method of choice,
when available [8]. These recommendations are confirmed by several
studies in patients with potential cardiotoxicity that showed that 3D
echocardiography has the highest sensitivity in identifying subjects
with CMR-derived EF <55% [42,43]. Indeed, Toro-Salazar et al. [42]
reported that in pediatric cancer survivors exposed to high doses
of anthracycline, 3D echocardiographic measurement of EF had
a sensitivity of 68% in identifying subjects with CMR-derived EFs
<55%, compared with 50% and 46% for quantitative analysis of 2D images by the area-length and Simpson’s biplane methods. Moreover,
they found that 3D speckle-tracking echocardiographic peak global
longitudinal strain magnitude <-17.5% best identified subjects with
abnormal longitudinal strain magnitude by CMR. Furthermore, 3D
echocardiography can provide better evaluation of RV function and
allows a better estimation of valve disease severity, giving additional
information for the management of these patients. However, 3D
echocardiography is affected by high cost, need for good image
quality data for analysis, time-consuming processing, inter vendor
software variability, need for a regular cardiac rhythm, and a
relatively low temporal resolution, all of which limited its spread and
use in recent years. When 3D echocardiography is not available and
2D assessment does not provide satisfactory information, Cardiac
Magnetic Resonance (CMR) can be considered for the detection of
CTRCD. CMR is the criterion standard technique for the assessment
of LV and RV systolic function and has a greater accuracy than
echocardiography in the detection of cardiac diseases in all clinical
settings [44]. This evidence has been widely confirmed in patients
with potential cardiotoxicity [45-47]. Ylänen et al. [47] showed that
LV and RV dysfunction were detectable in most of anthracyclineexposed,
long-term survivors of childhood cancer and that both LV
and RV end-systolic and LV end-diastolic volumes were increased
compared with controls, whereas several other authors [48,49] found
that global circumferential and longitudinal strains were reduced in
these patients. However, the high costs, claustrophobia and hazards
associated with ferromagnetic devices limited CMR use in clinical
routine. Accordingly, the current recommendation is to consider the
use of CMR only in situations in which the estimation of LVEF by
echocardiography is thought to be unreliable and discontinuation
of chemotherapeutic regimens secondary to CTRCD is being
entertained [2].
Figure 1
Figure 1
Example of left ventricular (LV) 2D speckle tracking longitudinal
strain in a patient with breast cancer treated with anthracyclines. Note
the typical pattern of regional dysfunction that involves mid and apical LV
segments.
Figure 2
Figure 2
Examples of Left Ventricular (LV) subtle systolic dysfunction in
a patient with breast cancer before and after 6 months of anthracyclines
treatment. A and C: Left Ventricular Ejection Fraction (LVEF) calculated by
the biplane Simpson’s method before and after the treatment, respectively.
B and D: LV 2D speckle tracking longitudinal strain before and after the
treatment, respectively. Note that LV global longitudinal strain is substantially
impaired whereas LVEF is not significantly reduced.
Figure 3
Figure 3
Example of Right Ventricular (RV) systolic dysfunction in a patient
with Hodgkin’s lymphoma treated with high doses of anthracyclines. A:
Tricuspid Annular Plane Systolic Excursion (TAPSE); B: RV 2D speckle
tracking longitudinal strain. Note that both the measurements are reduced
in this patient.
Conclusion
Early assessment for CTRCD is fundamental in patients with potential cardiotoxicity and echocardiography is the diagnostic technique of choice. A comprehensive assessment of LV and RV systolic function, LV diastolic function, heart valves and pericardium is mandatory before the beginning of the therapy, during the treatment, and after the discontinuation, often with a lifelong follow-up. LV systolic function and LVEF should be evaluated by 3D echocardiography and, when it is not available, by 2D. LVEF is considered the benchmark for the detection of CTRCD, but it should be associated with myocardial deformation measurements that appear to be more sensitive and accurate compared with LVEF. LV diastolic function should be assessed but, so far, is not considered closely related with the onset of cardiac damage. RV function must be detected to better stratify the risk of developing heart failure. Heart valve diseases and pericardial effusion should be detected simultaneously.
Acknowledgement
The authors gratefully acknowledge the editorial assistance of Susan Nord and Jennifer Pfaff of Aurora Cardiovascular Services, Milwaukee, Wis., and the figure preparation of Brian Miller and Brian Schurrer of Aurora Research Institute, Milwaukee, Wis.
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