The use of chemotherapy has largely improved the prognosis of cancer patients in recent decades. However, chemotherapy-induced cardiotoxicity (CTX) shows an increased incidence1 and represents a significant determinant of quality of life and mortality during on-going treatment and in long-term survivors of cancer. Thus, the prediction of CTX in this setting is highly desirable, such that alternative therapeutic strategies can be explored and/or potentially preventive cardio-active treatment can be instituted.
However, a universally accepted definition of CTX is not available to date. The recent joint consensus document of the European Association of Cardiovascular Imaging and American Society of Echocardiography redefined CTX as a drop in the left ventricular ejection fraction (LVEF) more than 10% below the value of 53%, as assessed by two-dimensional echocardiography (2DE).2 Accordingly, LVEF still represents the parameter most used in the follow-up of oncologic patients.
In addition, 2DE is the most exploited diagnostic tool because of its feasibility, repeatability, availability, safety and low cost. However, 2DE-calculated LVEF suffers from suboptimal reproducibility and depends on the acoustic window; furthermore, the use of contrast imaging can only partially improve inter-observer variability.3 Three-dimensional echocardiography (3DE) demonstrates better reproducibility4; however, it is not yet widely implemented in current practice (the role of echocardiography in the diagnosis and monitoring of CTX is extensively addressed in a dedicated article within this Special Issue).
Moreover, a decrease of LVEF occurs only after a relevant ultrastructural injury, and thus it does not represent a marker of early CTX and cannot predict the development of future heart failure.5,6 Therefore, the need for a reliable and accurate detection method for early CTX has encouraged the introduction of second-line advanced imaging modalities into the evaluation of chemotherapy-treated patients, including cardiac magnetic resonance (CMR) and nuclear techniques.
Cardiac magnetic resonance and chemotherapy-induced cardiotoxicity
Standard and new function parameters
CMR is a ionizing radiation free imaging method accepted as the gold standard for quantifying bi-ventricular parameters because of the lack of acoustic window limits and the need for geometric model assumption, high contrast to noise ratio and good temporal resolution.7 The excellent reproducibility of this approach has been confirmed in multicentre observational studies8 and is valuable for detecting an early cardiac injury, monitoring patients over time and significantly reducing sample size in the research setting.
These characteristics can be very useful in chemotherapy-treated patients, whose management depends on minimal variations in systolic function. CMR has demonstrated a good correlation with echocardiography and radionuclide ventriculography. However, the absolute cut-off values are different,9 and when monitoring CTX, it is strongly recommended that the same patients be followed with the same technique over time.
The standard CMR approach for quantifying biventricular function parameters uses contiguous short-axis slices covering the entire ventricles acquired from a cine steady-state free precession (SSFP) sequence (Fig. 1).
CMR demonstrates higher sensitivity compared with 2DE and 3DE in detecting values of LVEF less than 50%,10 suggesting a preferential use of CMR in cases of ventricular dysfunction by echocardiography.
Two small CMR studies have demonstrated a significant early decrease in LVEF at 3–6 months after chemotherapy.11 With regard to late CTX, Ylanen studied 62 subjects and found an overly decreased LVEF (<45%) in 18% and a suboptimal LVEF (45–55%) in 61% at a mean follow-up time of 7.8 years.12 Unfortunately, none of these studies reported prognostic data.
CTX may also involve the right ventricle, and CMR is the most accurate method for the determination of its morphological and functional parameters because the irregular shape of the right ventricle cannot be derived by geometrical formulas and requires 3D acquisition. Regrettably, few and small studies in the literature have investigated right ventricle parameters in oncologic patients, and no prognostic data are available.13
A decrease in myocardial mass has been identified in many long-term survivors of childhood cancer, suggesting that it could be considered as a late CTX manifestation.10,14 In particular, a study by Neilan highlighted that indexed left ventricular mass is the strongest predictor of major cardiovascular events.14 Conversely, echocardiography failed to detect functional and structural alterations in most patients in this group.10
The fact that LVEF does not take into account the relationship between mass and chamber dimensions may partly explain its limited sensitivity.15,16 The LV global function index is a new CMR parameter that combines left ventricular stroke volume, end-systolic and end-diastolic volumes, and mass, and a value less than 37% has been shown to be associated with the occurrence of cardiovascular events in a more powerful way.16 However, no data are available on this promising index in monitoring CTX.
Contrasting opinions have been reported on the predictive value of diastolic dysfunction in chemotherapy-treated patients.
In general, 2DE and Doppler represent the most useful instruments for detecting diastolic function. However, in oncologic patients, diastolic dysfunction is not specific and in large studies, has failed to predict a late decrease in LVEF less than 50% within 3 years.17 Additionally, the use of the E/e′ ratio remains questionable, as fluctuation in E and e′ velocities could be significantly influenced by changes in loading conditions associated with chemotherapy. Although diastolic parameters can be derived by CMR using the variation rate of the atrial volume18 and phase contrast sequences to evaluate mitral inflow,19 these techniques are typically time-consuming, and a clear advantage over Doppler has not been demonstrated. Consequently, diastolic function by CMR is not usually recommended in current practice.2
Early changes in LV mechanical deformation typically precede a drop in LVEF in patients undergoing chemotherapy, representing an early marker of myocardial damage.20,21 CMR is able to provide an accurate and reliable evaluation of myocardial deformation by tagging techniques and, more recently, by using phase contrast imaging and CMR feature tracking. In the technique most frequently used, the myocardium is tagged with a grid of magnetic saturation lines at end diastole, allowing the analysis of deformation by tracking the distortion of the grid during systole.
Only few and small studies evaluating myocardial deformation parameters by tagging in the monitoring of early CTX have demonstrated a significant decrease in longitudinal and circumferential deformation compared with controls.11,21 However, deformation analysis did not demonstrate an incremental value versus the LVEF in early CTX detection. Indeed, only Toro-Salazar, in a study including 46 long-term childhood cancer survivors treated with anthracycline doses of 200 mg/m2 or more, was able to show a significant decrease in circumferential and longitudinal strain and regional peak circumferential strain, despite a normal LVEF by 2DE and CMR. Unfortunately, the study did not report a predictive role.22 Although tagging CMR is promising, larger studies including long-term follow-up data are needed to clarify the real predictive value of this method. The suboptimal sequence efficiency for creating the tag lines and the time-consuming image analysis limit the introduction of the method into current practice and make tagging CMR a focus of research.
Stress cardiac magnetic resonance
Some chemotherapeutic agents such as 5-fluorouracil and tyrosine kinase inhibitors show an association with myocardial ischaemia.23 Some studies performed with echocardiography reported an additional role of stress imaging, revealing that patients treated with chemotherapy have reduced contractile reserve in comparison to healthy subjects.24,25 However, none of these studies demonstrated a prognostic value, whereas other studies did not report an incremental value of stress imaging in patients without suspicion of myocardial ischaemia.26,27 Therefore, when myocardial ischaemia secondary to chemotherapy is clinically suspected, CMR can be used, as indicated by the current Guidelines of the European Society of Cardiology on stable coronary artery disease.28 In patients with an intermediate pre-test probability of stable coronary artery disease, stress imaging testing is preferred to exercise ECG.29 Specifically, the advantages of CMR include the absence of radiation exposure, higher spatial resolution and higher diagnostic performance compared with SPECT,30,31 as well as independence from the acoustic window and the opportunity to evaluate wall motion abnormalities, myocardial perfusion and necrosis/fibrosis in the same test. In addition to the classical contraindications of performing a basal CMR exam, the main limitations for stress CMR to date are local expertise and availability.
In the evaluation of CTX, the additive and incremental value of CMR is the unique possibility of providing information on tissue characterization. As expected, chemotherapeutic agents can cause oedema and hyperaemia, and even cellular necrosis and subsequent fibrosis.
Myocardial oedema leads to an overall increase in the water burden of the affected tissue, resulting in elongation of T2 relaxation times. In the clinical setting, the most common approach for the evaluation of myocardial oedema is the qualitative analysis of T2-weighted short tau inversion recovery fast spin echo (FSE) sequences, in which oedema appears hyper-intense (Fig. 2a). However, the disadvantages of the qualitative approach are a coil sensitivity and the inability to monitor serial progress. Moreover, oedema may be global and thus not recognizable to the naked eye. Consequently, semi-quantitative analysis by normalizing the signal intensity of the myocardium to that of skeletal muscle, using a cut-off of more than 1.9, is strongly recommended.31
Only two small studies have demonstrated the early presence of myocardial oedema by CMR in patients treated with cardiotoxic chemotherapy.13,32 Specifically, Grover et al. found a significant relationship between the presence of oedema (myocardium/skeletal ratio ≥2) and a lower RVEF at 12 months. Conversely, Jordan et al.33 did not find differences in myocardial oedema during 3 months of chemotherapy; however these authors only evaluated a mid-short axis view, and this could have influenced the negative result. Regardless, no prognostic data are available regarding the detection of oedema by CMR after chemotherapy.
Several groups are promoting quantitative T2 mapping as being more sensitive than qualitative and semi-quantitative analyses.34 Indeed, T2 mapping allows monitoring the inflammatory state regionally and serially as well as across subjects. However, we are still in the research phase, and no data have been published in cardiac oncology; due to technical challenges, translation to the clinical area is pending.
The increased blood volume in an inflamed area leads to higher uptake of contrast agent during the early vascular phase. Myocardial hyperaemia is usually assessed using T1 FSE pulse sequences, acquired before and shortly after gadolinium-based contrast administration, by the demonstration of an increased signal intensity ratio between the myocardium and skeletal muscle.
In a small study on 22 patients, early enhancement of the myocardium increased significantly at the end of doxorubicin; this was negatively correlated with the LVEF and returned to the same value of the skeletal muscle within 6 months.35
T1 FSE sequences are time-consuming and vulnerable to inconsistent image quality. Conversely, cine SSFP images used to quantify biventricular parameters acquired shortly after gadolinium-based contrast administration may provide a valid and rapid alternative for the evaluation of myocardial hyperaemia.36 Regrettably, no data for oncologic patients are available in the literature.
CMR is a unique non-invasive technique validated for the detection of myocardial necrosis/fibrosis by acquiring T1 inversion recovery sequences after approximately 10 min following gadolinium-based contrast injection. Using this approach, which is called late gadolinium enhancement (LGE), the necrotic/fibrotic areas that retain the contrast appear hyper-intense (Fig. 2b), and their presence is strongly correlated with prognosis in all cardiomyopathies.37
Although many gadolinium-based contrasts for the heart are at present designated as off-label use by the U.S. Food and Drug Administration and in many European countries, the incidence of adverse reactions in the off-label setting of CMR was found to not be different from the incidence in the FDA-approved general radiology setting.38 The use of these agents was proved to be relatively safe39 and should be limited only in patients with severe renal insufficiency due to the potential risk of nephrogenic systemic fibrosis and in patients with previous severe allergic reactions to gadolinium.40
Two small studies failed to detect the presence of LGE11,12 in chemotherapy-treated patients. Conversely, other relatively small studies have reported the presence of non-ischaemic areas of LGE with a prevalence between 6 and 100%.41,42 The potential prognostic value of LGE was weakly shown in two retrospective studies, in which approximately 40% of patients with LGE had no improvement or further decline in LVEF.42,43 Moreover, in a single, small prognostic study, the presence of LGE was not an independent predictor of adverse cardiovascular outcomes, though the incidence of the events was low.14
The amount of fibrosis depends on many variables, such as cumulative dose, individual response, age and presence of comorbidities. Thus, larger studies with longer follow-up are needed for an understanding of the prevalence and prognostic impact of LGE in monitoring CTX.
Finally, when using the LGE technique, it is also possible to evaluate pericardial enhancement as a sign of pericardial inflammation, with the imposition of aggressive anti-inflammatory therapy to prevent late constrictive pericarditis.44
Diffuse myocardial fibrosis
LGE is able to detect only macroscopic fibrosis. However, chemotherapy-treated patients can develop mild diffuse myocardial fibrosis that can be detected by T1 mapping with the evaluation of the extracellular volume (ECV).
T1 values of the myocardium and blood pool before and after the 15-min administration of gadolinium-based contrast are necessary to estimate the myocardial ECV according to the formula ECV = [1/T1(myocardiumpost) − 1/T1(myocardiumpre)]/[1/T1(bloodpost) − 1/T1(bloodpre)] (1-Hct), where Hct is the blood haematocrit.45,46
Some small studies have reported encouraging results on the use of T1 mapping in chemotherapy-induced heart damage. Toro-Salazar et al.22 measured the mean T1 values of 46 long-term survivors in comparison with volunteers and found that T1 values after contrast administration were significantly lower in the study subjects, revealing mild diffuse fibrosis. Tham et al.47 studied 30 paediatric patients at least 2 years after anthracycline administration, showing that increased ECV correlated with a decreased mass/volume ratio, decreased LV wall thickness/height ratio, lower peak VO(2), and higher cumulative dose.
In addition, Neilan et al.48 showed that the ECV of 42 patients previously treated with anthracyclines was significantly higher in comparison to age-matched controls, with the ECV being positively correlated with the left atrial volume and negatively correlated with diastolic function.
T1 mapping represents a very useful technique that is able to detect changes in the molecular features of the myocardium prior to the occurrence of functional alterations. Nevertheless, its role in the detection of the early CTX should be further investigated to provide a prognostic role for these findings and to ascertain whether this technique can improve the management of patients.
The emerging role of iron
Cardiac damage induced by anthracyclines appears to be partially dependent on the alteration of intracellular iron metabolism. Recent evidence has revealed that CTX is mitigated by iron chelators and not by antioxidants, suggesting that anthracycline iron-mediated damage relies on complicated alterations of the intracellular metabolic pathways involved in the inhibition of iron regulatory proteins.49 Cascales et al.50 demonstrated that the post-mortem iron concentration in patients with genetic haemochromatosis is strongly related to the cumulative doxorubicin dose, independently from liver iron overload and transfusion therapy. Miranda et al.51 found that mice affected by genetic haemochromatosis were more susceptible to anthracycline-mediated myocardial damage and burdened with a poor survival in comparison to wild-type subjects. CMR is a unique approach for quantifying non-invasive myocardial iron overload (MIO) by exploiting the paramagnetic properties of iron, which shortens the T2* relaxation time.52 The multi-slice multi-echo T2* technique (Fig. 3) is a validated method for detecting global and segmental MIO in haemochromatosis,53,54 allowing the identification of different MIO patterns and correlating with an increased risk of heart failure and biventricular dysfunction.55 Although evaluations of MIO in patients treated with anthracyclines has not yet been performed, patients at risk of increased MIO (primary and secondary haemocromatosis also due to multiple blood transfusions) should be screened for MIO before starting anthracyclines and in the follow-up. In fact, new oral iron chelation agents56 could have a potential role in cardio-protection strategies.
Nuclear imaging techniques and cardiotoxicity
Although echocardiography and CMR are the two most commonly used imaging techniques for non-invasive CTX, nuclear imaging may still have a role in the evaluation and monitoring of cancer patients treated with cardiotoxic drugs. In fact, nuclear imaging techniques employing specific radiotracer molecules represent an emerging tool for the non-invasive detection of biological processes preceding anatomical involvement and physiological consequences of myocardial damage induced by antineoplastic drugs.
The role of nuclear techniques for evaluating LVEF is limited and principally based on 99m Technetium (Tc)-erythrocyte multi-gated radionuclide angiography (MUGA), a non-invasive technique using 99mTc to visualize the cardiac blood pool through a γ camera with gated acquisition.57 Although MUGA provides accurate and highly reproducible quantification of LV volumes and LVEF during cancer therapy,58 it can be hampered by soft tissue attenuation artefacts and also exposes the patient to ionizing radiation.59 As a consequence, in clinical practice, this technique is preferred when echocardiography as a first-line or CMR as a second-line approach are not feasible or available. However, the capability of MUGA to accurately assess diastolic dysfunction in patients with breast cancer treated with trastuzumab (Tz) has been documented,60 suggesting the potential role of a diastolic parameter, the diastolic time to peak filling rate, in the early screening of CTX.
Moreover, new cadmium-zinc-telluride camera allows obtaining 3D MUGA with low dose (dose < 2mSv) and thus the possibility to achieve information with high safety, about right and left ventricular function (ejection fraction, systolic and diastolic volumes), intra-ventricular and inter-ventricular dyssynchrony (Fig. 4). Nevertheless, further clarification about the additive predictive value of this parameter is needed.
Very promising results were been obtained with 123Iodio (123I)-metaiodobenzylguanidine (123I-MIBG) single-photon emission computed tomography (SPECT). 123I-MIBG is a 123I-labelled norepinephrine analogue used in the non-invasive assessment of sympathetic myocardial innervation. Because 123I-MIBG is not metabolized, it reflects neuronal integrity and cardiac status.61 Studies conducted in asymptomatic patients treated with anthracyclines have revealed that assessment of myocardial adrenergic derangement with 123I-MIBG SPECT was able to identify patients at risk of developing CTX62,63 and that the degree of myocardial adrenergic impairment was related to anthracycline dose.62 These findings suggest new potential applications of nuclear cardiac innervation assessment in the early detection of CTX. However, such evidence requires confirmation in larger studies.
Interesting results have also been obtained using specific radiotracer molecules, such as 111indium (In)-antimyosin, 99mTc-annexin V, 123I-15-(P-iodophenyl)-3-(R,S)-methylpentadecanoic and 111In-Tz.
The immunoscintigraphic agent 111In-antimyosin is a specific marker of myocardial cell injury and necrosis, and its role in assessing subclinical impairment of LV function in patients treated with anthracyclines was already well documented approximately 20 years ago.64–66 In patients affected by breast cancer without cardiovascular risk factors, it has been demonstrated that the uptake of 111In-antimyosin increases after anthracycline chemotherapy and that the degree of uptake is correlated with changes in LVEF65 and anthracycline dosage.64 Moreover, in some patients, the radiotracer uptake was found to be independent of a significant reduction in LVEF, suggesting that this technique may be used to recognize cellular damage prior to the onset of LV functional impairment.64 In addition, 111In-antimyosin could also be useful in discriminating between patients with transient and persistent LV dysfunction and in guiding clinical decisions about the discontinuation of anthracycline therapy.66
Annexin V shows high affinity for the phosphatidylserine molecules exposed on the outer surface of the myocardial cell membrane at the early stages of anthracycline-induced cardiomyopathy. In in-vivo studies, annexin V labelled with 99mTc has been used to assess acute and chronic doxorubicin-induced cardiomyopathy.67,68 However, studies in humans are needed to clarify the role of 99mTc-annexin V scintigraphy in the nuclear imaging of CTX.
Taxanes, antineoplastic drugs used in the treatment of several tumours, can induce CTX, impairing myocardial microtubular transport system and producing a significant perturbation in the free fatty acid oxidation system.69 One free fatty acid, 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid, labelled with 123I (123I-BMIPP) has been used to assess taxane-induced cardiomyopathy.70,71 In these studies, the BMIPP uptake score was reduced after chemotherapy compared with that measured before treatment,70 and the degree of reduction was related to the administered dose of the drug and was also directly associated with the development of LV dysfunction.71
Attractive results were also obtained with 111In-labelled Tz in patients with metastatic breast cancer. Tz, a chemotherapeutic agent with a direct effect on human epidermal growth 70factor receptor 2 (HER2) is often used as second-line therapy.72 It has been demonstrated that anthracyclines can increase the levels of HER2 expressed by myocytes; as a consequence, such patients with high myocyte expression of HER2 as candidates for receiving Tz have a high risk of developing CTX, likely as a result of the inhibition of cardiac HER2, which activates the apoptotic pathways and amplifies anthracycline oxidative stress.72
111In-Tz SPECT was been used to identify patients with high myocardial levels of HER2 receptors and at an elevated risk of developing LV dysfunction.73,74 However, contrasting results have been obtained in studies of 111In-Tz SPECT. In a small preliminary study, Behr et al.73 investigated 111In-Tz scintigraphy in 20 metastatic breast cancer patients expressing the HER2/neu receptor, pre-treated with anthracyclines, and scheduled for Tz administration as second-line therapy. These authors documented myocardial 111In-Tz uptake in seven patients; of these, six developed clinical heart failure, whereas none of 13 patients without uptake had adverse cardiac events, suggesting that pre-treatment scanning with 111In-Tz could predict CTX. Opposite results were obtained by Perik et al.74 These authors enrolled 15 breast cancer patients that were candidates for receiving Tz as second-line therapy and performed 111In-Tz SPECT scintigraphy within 24 h after the first Tz infusion and again after 12 h; the results showed myocardial uptake at the start of Tz in only one patient who had received extensive anthracycline pre-treatment and had cardiac ventricular arrhythmias before the Tz treatment. However, no myocardial uptake was observed in the three patients who developed severe symptomatic left ventricular dysfunction during Tz and paclitaxel treatment. It should be noted that these data are from single-centre studies of limited sample size. Indeed, there could be mechanisms not yet elucidated that in addition to HER2 receptor inhibition, are involved in Tz-CTX, which might explain these conflicting results.
PET is the gold standard technique for assessing myocardial metabolism and perfusion. However, the role of PET in the early detection of CTX is still debated.75 Nony et al.76 showed a significant decrease in LVEF assessed by radionuclide angiography after treatment with doxorubicin, but no significant effect was observed in myocardial blood flow evaluated with PET in six female cancer patients without heart disease. Recently, Borde et al.77 analysed changes in myocardial glucose metabolism using FDG-PET and suggested that a greater utilization of this substrate constitutes evidence of a cellular alteration preceding the CTX cascade in patients treated with adriamycin. Similarly to SPECT, PET imaging can play a key role in the evaluation of cardiac autonomic dysfunction associated with heart failure,78 providing several advantages over SPECT, with higher spatial and temporal resolution and routinely available attenuation correction. In addition, PET radiotracers more closely resemble endogenous neurotransmitters than the 123MIBG used for SPECT imaging, and the variety of available tracers may allow more detailed analysis of neuronal signalling.79 Regardless, studies are needed to validate these new radiotracers in the field of cardio-oncology, in addition to the complexity of radiolabeling ligands, requirements of labour and specific knowledge, the high cost and the low availability limit the clinical use of PET.80
Based on the recent joint consensus document of the European Association of Cardiovascular Imaging and American Society of Echocardiography, the use of CMR is recommended for the quantification of LVEF when the quality of echocardiogram is suboptimal. Furthermore, CMR is suggested for confirming a LVEF less than 53%. In follow-up assessments, CMR is recommended for the quantification of LVEF in cases of possible discontinuation of chemotherapeutic regimens as a result of CTX or when LVEF estimation by echocardiography is controversial or unreliable due to technical constrains.2
Nonetheless, in the evaluation of CTX, the additive and incremental value of CMR is represented by its unique competence for providing information on tissue characterization, such as oedema, iron overload, hyperaemia and diffuse fibrosis, which have all been associated with early CTX. The early appreciation of these findings can play a crucial role in the management of patients treated with chemotherapy because it may allow the implementation of a timely and optimal cardioprotective regimen, thereby justifying the relatively higher cost of CMR compared with echocardiography. Future studies should explore the role of CMR upstream to the diagnostic algorithm for the management of CTX using as gatekeepers either biomarkers, a high-risk profile for CTX or a borderline dysfunction by 2DE.
Standard safety precautions for CMR must be observed, taking into account the electromagnetic interference, among others. A major limitation is the restricted availability of CMR laboratories with standardized quality criteria.81
Finally, larger and prospective studies are necessary to definitively introduce CMR into current clinical practice and to define its role in the management of CTX based on a cost/effectiveness balance.
MUGA, though also providing highly reproducible quantification of LVEF during cancer therapy, retains its principal limitation: radiation exposure. Therefore, this technique should be considered only when echocardiography as the front line or CMR as the second line are not feasible or available.2 However, owing to the use of new molecular tracers, nuclear imaging offers interesting future perspectives in the early detection of myocardial damage and deserves further evaluation in larger studies and in prospective clinical trials.
The manuscript was edited by Elsevier Language Editing Services.
We would like to thank Prof. Giuseppe Mercuro as promoter of the manuscript in quality of coordinator of the Working Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology.
There are no conflicts of interest.
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