Pediatric Hematology and Oncology, 31:237–252, 2014Copyright C© Informa Healthcare USA, Inc.ISSN: 0888-0018 print / 1521-0669 onlineDOI: 10.3109/08880018.2013.851753

ORIGINAL ARTICLE

Are cardiac Magnetic Resonance Imaging andRadionuclide Ventriculography Good OptionsAgainst Echocardiography for Evaluationof Anthracycline Induced Chronic Cardiotoxicityin Childhood Cancer Survivors?

Evic Zeynep Basar,1 Funda Corapcioglu,1 Kadir Babaoglu,2 Yonca Anik,3

Gozde Gorur Daglioz,4 and Reyhan Dedeoglu5

1Department of Pediatric Oncology, Kocaeli University, Kocaeli, Turkey; 2Department ofPediatric Cardiology, Faculty of Medicine, Kocaeli University, Izmit, Turkey; 3Department ofRadiology, School of Medicine, Kocaeli University, Kocaeli, Turkey; 4Department of NuclearMedicine, Kocaeli University, Kocaeli, Turkey; 5Department of Pediatric Cardiology, Dr.Siyami Ersek hospital, Istanbul, Turkey

Anthracyclines are widely used for the treatment of solid tumors in pediatric oncology. However,their uses may be limited by progressive chronic cardiotoxicity related to the cumulative dosage.The aims of this study are to compare diagnostic techniques and prepare an algorithm for di-agnosis of anthracycline induced chronic cardiotoxicity. The patients were evaluated accordingto age, sex, time elapsed since the last dose of anthracycline treatment, presence of cardiovas-cular symptoms, follow-up duration, type of anthracycline, cumulative anthracycline dose, andconcomitant mediastinal radiation therapy. Late subclinical cardiotoxicity was detected by his-tory, physical examination, electrocardiography (ECG), Holter monitor, echocardiography (ECHO),radionuclide ventriculography (MUGA), and cardiac magnetic resonance imaging (MRI). Thirty-seven male and 19 female patients with a median age of 11.2 ± 4.6 (range, 3.5–22.0) years wereincluded in the study. Patients were grouped according to cumulative anthracycline doses. Sub-clinical cardiac dysfunction was detected in 20 patients by at least one of ECHO, MRI or MUGAafter anthracycline chemotherapy. We revealed that other than ECHO, MRI and MUGA have highclinical importance for evaluating subclinical late cardiac complications in children treated withanthracyclines.

Keywords anthracycline, cardiac magnetic resonance imaging, cardiotoxicity, echocardiogra-phy, radionuclide ventriculography

INTRODUCTION

Survival rates of childhood cancers have increased with intensive chemotherapy pro-tocols and systematic practice of multidisciplinary oncologic treatment modalities.Furthermore, late complications of intensive oncologic treatments have become a ma-jor cause of morbidity in children with longer life expectancy. Studies have shown that,

Received 16 July 2013; accepted 1 October 2013.Address correspondence to Dr Funda Corapcioglu, Department of Pediatric Oncology, KocaeliUniversity, Kocaeli, Turkey. E-mail: fundacorapcioglu@kocaeli.edu.tr

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30 years after the completion of cancer treatment, 73% of patients develop chronichealth issues, and those issues are at life-threatening level in 42% of the patients [1, 2].Cardiotoxicity is a well-known late complication of anticancer treatment. Chemother-apeutic agents and radiation therapy used for the treatment of childhood cancers areknown to have cardiotoxic effects. Among anticancer drugs, the most well-definedgroup of agents for their cardiotoxic effects is anthracycline antibiotics. Anthracyclinecardiotoxicity is classified as either acute, or chronic. Development of cardiotoxicityat least three months after the termination of therapy can be defined as chronic car-diotoxicity [3]. Considering the fact that anthracyclines are widely used for the treat-ment of childhood cancers, assessment of side effects is of vital importance for thefollow-up of patients [4]. Our study employs the usage of traditional diagnostic tests,and additionally cardiac magnetic resonance imaging (MRI), for the evaluation ofanthracycline induced subclinical chronic cardiotoxicity in children with cancer. Weaimed to compare the sensitivities, advantages and disadvantages of these tests at de-tecting subclinical cardiac dysfunction. This study is going to be the first to compare allnoninvasive diagnostic tests by evaluating them all together. At the end of the study,providing a follow-up algorithm, especially in assessing the subclinical cardiac dys-function, is planned.

PATIENTS AND METHODS

This study was performed at Department of Pediatric Oncology, Kocaeli University,Kocaeli, Turkey. Patients diagnosed with cancer (except leukemia) and treated withanthracycline-comprising chemotherapy were enrolled in the study. All patients hadbeen evaluated by echocardiography (ECHO) as a part of routine examination beforethe first course of therapy. These echocardiographic findings were accepted as base-line values. Patients who had baseline echocardiographic measurements of EF >45%and FS >29% and with at least 3 months of post-treatment durations were consideredeligible. Those with primary cardiac disease at the time of cancer diagnosis were ex-cluded from the study. Study group was called in and evaluated by physical exami-nation, electrocardiography (ECG), Holter monitor, ECHO, radionuclide ventriculog-raphy (MUGA), and cardiac MRI, all within one week in Kocaeli University Hospital.All of the data were obtained during the study. The study respected the guidelinesof Helsinki declaration concerning medical research in humans and received localEthics Committee approval. Informed consent was obtained from each patient and/orparents.

Age and sex of patients, type and primary localization of tumor, oncologic treat-ment protocol, type of anthracycline, cumulative anthracycline dose, administrationschema, drug infusion rates, time after completion of last anthracycline-comprisingtherapy at the time of evaluation, condition of oncologic disease at the time of evalu-ation, presence of cardiovascular symptoms at the time of evaluation, total durationof follow-up since the time of diagnosis, presence of concomitant mediastinal radia-tion therapy and dose and site of radiation therapy were evaluated. Doxorubicin wasconsidered equivalent to daunorubicin, 1 mg/m2 of doxorubicin was considered to beequivalent in cardiotoxic potential to 0.2 mg/m2 of idarubicin, 0.25 mg/m2 of mitox-antrone, and 3 mg/m2 of epirubicin [5–7].

Patients were classified into three groups according to cumulative anthracyclinedoses. Cumulative doses were less than 200 mg/m2 in group 1, between 200 and350 mg/m2 in group 2, and more than 350 mg/m2 in group 3. Long-term subclini-cal cardiotoxicity was prospectively evaluated by history, physical examination, ECG,ECHO, MUGA, and MRI.

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Anthracycline Induced Chronic Cardiotoxicity

Standard 12-lead electrocardiogram was performed. All recordings were obtainedby Reynolds Medical digital recorder. Holter monitor recordings were analyzed usingPathfinder Holter Analysis System software (Delmar Reynolds Medical Ltd., Hertford,UK). Ventricular ectopic beats detected by Holter were assessed according to mod-ified Lown-Wolf classification [8]. Grade 2 and above pathologies were accepted asclinically significant.

Echocardiographic examination was performed using two dimensional, M mode,and Doppler techniques. Patients were evaluated in a partial left decubitus positionby Toshiba SSA-390A (Toshiba-Xario, Toshiba Medical Systems Corporation, Tokyo,Japan) powervision system equipped with 2.75–5.5 MHz phased-array transducer.Parasternal long axis, parasternal short axis, apical 4-chamber and apical 5-chamberviews were obtained at rest, accompanied by electrocardiographic monitoring. Leftventricular systolic and diastolic function was evaluated by M mode, pulsed-waveDoppler, and pulsed-wave tissue Doppler techniques. Systolic and diastolic diame-ters, wall thickness values, ejection fraction, fractional shortening, structure of valves,and measurements of diastolic function were obtained. Echocardiographic findingswere evaluated according to standard recommendations of the American Society ofECHO and measurements were compared to standard measurements of healthy chil-dren of the same age [9]. For the comparison of age-dependent diastolic parame-ters; including E, A, E/A ratio, E′, A′, E′/A′; patients were grouped into four age inter-vals: 3 to 5, 6 to 9, 10 to 13, and 14 to 22 years. All echocardiographic examinationswere performed by one experienced pediatric cardiologist (K.B.). Post-treatment EFby echocardiogram of less than 45, or post-treatment FS by echocardiogram of lessthan 29%, or an E/A ratio below 1, and/or any evidence of abnormal hypokinesia ofmyocardium were considered as evidence of cardiac dysfunction [10, 11].

MUGA study was performed after modified in vivo red blood cell labeling with pe-diatric doses of technetium-99m (Tc-99m) calculated from the recommended range ofadult activity [10–20 mCi (370–740 MBq)] and adjusted according to body weight. Dataacquisition was performed with a single-head SPECT system (ADAC, Argus Epic, Mil-pitas, CA, USA) equipped with low-energy, high-resolution collimator. The lower limitof normal LVEF was 45%. Fractional shortening in ECHO is considered as equivalentof radial shortening (RS) in MUGA. RS is calculated using the following formula: (EDline segment−-ES line segment/ED line segment × 100). An RS below 29% was con-sidered evidence of abnormal MUGA scan. For diastolic functional index, the peak-filling rate (PFR) was calculated by taking the first derivative of the time-activity curve.The PFR is typically measured in counts/seconds and normalized end diastolic countsto yield end diastolic volumes/second (EDV/s). The PFR should exceed 2.5 EDV/s[12–14].

All patients were evaluated via cardiac MRI in a 1.5T MR scanner (Philips GyroscanIntera Master; Philips, Eindhoven, The Netherlands) equipped with a 30 mT/m maxi-mum gradient strength and 150 mT/m/ms slew rate. Data were acquired using a syn-ergy body coil with the patient in supine position. Vital signs of patients were moni-tored and recorded during the MR examination.

Imaging was initiated with balanced turbo field echo (B-TFE) sequence pilot im-ages obtained for cardiac orientation in three orthogonal planes. To achieve high res-olution and short imaging times, all images were obtained by the parallel imagingtechnique with a SENSE factor of 2. Twelve phases were evaluated for each cardiaccycle. Four-chamber (horizontal long-axis), vertical long-axis, and short-axis imageswere obtained. Short-axis images were obtained perpendicular to the interventricularseptum. Wall motions were evaluated using an ECG-gated breath-hold balanced fastfield echo (BFFE) sequence (TR/TE 3.1/1.5 ms, flip angle [FA] 60◦) in three slices fromthe apex to the base of the left ventricle. Additionally, single-slice four chamber and

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long-axis images were obtained with the same technique. Magnetic resonance param-eters are given in Table 1.

MRI data were transferred to a dedicated Dell workstation precision 650, softwareViewForum release 3.4 (Philips Medical Systems, Eindhoven, The Netherlands). Car-diac MRI analysis program was used for all assessments. The images were evaluatedaccording to cardiac segmentation used by the American Heart Association (AHA).Left ventricle was evaluated in 17 segments (see Table 2) [15]. For the measurementsof end-diastolic volume (EDV), end-systolic volume (ESV), EF, and LV mass; endocar-dial and epicardial borders were drawn manually on three levels (apex, midventricu-lar, and basal) on the short axis images. Papillary muscles were excluded. ESV, EDV,EF, and LV mass were calculated automatically by the software using the modifiedSimpson’s method. MRI analysis also included assessment of wall motions. LV cineimages were evaluated by visual analysis as normal, hypokinetic (decreased LV wallcontraction at systole), akinetic (absence of LV wall contraction at systole), dyskinetic(paradoxical movement, outward LV wall movement at systole), and aneurysmatic. Allimages were analyzed by one experienced pediatric radiologist (Y.A.).

Statistical AnalysisStatistical analyses were performed using SPSS for Windows R© software. Patient char-acteristics were summarized using descriptive statistics. Mean ± standard deviationvalues were used for the expression of continuous variables. A number of tests wereused to compare results, depending on the data type. For the comparison of quantita-tive values between two groups, Mann-Whitney U test was used. For the comparisonof quantitative values between three groups; Kruskal-Wallis test was used to compareabnormally distributed parameters, and Mann-Whitney U test was used to detect thegroup that caused the difference. For the comparison of parameters within each group;Friedman test was used, and Wilcoxon signed-rank test was used to detect the groupthat caused the difference. Chi-square test was used to compare the sensitivity levelsof ECHO, MUGA, and MRI. The significance threshold in the analyses was P < .05.

RESULTS

Fifty-six patients (37 male, 19 female) were enrolled in the study. Median age was11.2 ± 4.6 years (range, 3.5–22.0). The diagnosis was Hodgkin’s lymphoma in 20, non-Hodgkin’s lymphoma in 16, Wilms’ tumor in 6, primitive neuroectodermal tumor in5, rhabdomyosarcoma in 4, neuroblastoma in 2, osteosarcoma in 2, and pleuropul-monary blastoma in 1 of the patients. Characteristics of treatment protocols are shownin Table 3.

Mean EF and FS values of patients by ECHO at the time of diagnosis were 68.1%± 4.7% (range, 55–77%); 38.0% ± 3.5% (range, 29–46%), respectively. Mean durationafter last anthracycline administration was 21.9 ± 17.8 (range, 3–78) months. Meanfollow-up duration since the time of diagnosis was 28.9 ± 21.0 (range, 5–108) months.Primary tumor was located in the mediastinum in 11 (19.6%) of the patients. At thetime of evaluation, 54 patients were in remission; one out of three patients in relapsehad finished second-line chemotherapy and was in remission; and two patients in re-lapse were in active disease.

With a classification made according to cumulative anthracycline doses; there were24 patients in group 1, 16 in group 2, and 16 in group 3.

Thirty-nine (67.9%) out of 56 patients in the study group had concomitant radiationtherapy. Site of radiation therapy was mediastinum in 9 (16.1%) of the patients. Meanradiation dose of patients with concomitant radiation therapy was 22.0 ± 7.0 (range,15–36) Gy.

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TAB

LE1

Para

met

ers

ofM

RIT

ech

niq

ue∗

Flip

ST/C

SFO

V/R

FOV

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ion

Tim

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reat

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350

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045

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332

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256

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ng-

axis

imag

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ith

bre

ath

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dB

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2.8/

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5010

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753

2925

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6

∗ B-F

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ced

Fast

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cho;

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TABLE 2 Left Ventricular Segmentation

Segment 1 Basal anteriorSegment 2 Basal anteroseptalSegment 3 Basal inferoseptalSegment 4 Basal inferiorSegment 5 Basal inferolateralSegment 6 Basal anterolateralSegment 7 Mid anteriorSegment 8 Mid anteroseptalSegment 9 Mid inferoseptalSegment 10 Mid inferiorSegment 11 Mid inferolateralSegment 12 Mid anterolateralSegment 13 Apical anteriorSegment 14 Apical septalSegment 15 Apical inferiorSegment 16 Apical lateralSegment 17 Apex

All patients, excluding one patient with tachycardia and two patients with arrhyth-mia, were asymptomatic.

Mean heart rates of patients in group 3 measured by ECG and Holter were sig-nificantly higher (P = .045; .009, respectively) and QTc interval measurements ofpatients in group 3 obtained by ECG were significantly longer (P = .021). Electrocar-diographic examination revealed right bundle branch block in one patient, and si-nus tachycardia in another. Twenty-five patients had pathological findings on Holter

TABLE 3 Characteristics of Treatment Protocols of Study Group

Chemotherapy protocolsABVD 18 (32.1%)BFM-NHL 90 protocol 16 (28.6%)IECESS’92 5 (8.9%)IRS-IV treatment protocol 6 (7.1%)TPOG Wilms’ protocol 4 (10.7%)CCG 7921-Osteosarcoma protocol 2 (3.6%)TPOG Neuroblastoma protocol-2003 2 (3.6%)ICE/VAC 1 (1.8%)ABVD-OEPA 1 (1.8%)ABVD-NHL B cell 1 (1.8%)Cumulative dose of anthracycline (mg/m2) (mean ± SD) (range) 244.0 ± 115.7 (60–460)Type of anthracyclineDoxorubicin 49 (87.5%)Doxorubicin + daunorubicin 7 (12.5%)Anthracycline Infusion Rates (mg/m2/hour)20 mg/m2/hour 15 (26.8%)28.75 mg/m2/hour 1 (1.8%)25 mg/m2/hour 33 (58.0%)30 mg/m2/hour 6 (10.7%)60 mg/m2/h 1 (1.8%)

∗ ABVD: adriamycin, bleomycin, vincristine, dacarbazine; BFM NHL protocol: Berlin FrankfurtMunster group non-Hodgkin’s lymphoma treatment protocol; IECESS’92: European IntergroupCooperative Ewing’s Sarcoma Study’92; IRS-IV: Intergroup rhabdomyosarcoma study-IV; TPOGWilms’ protocol: Turkish Pediatric Oncology Group Wilms’ tumor treatment protocol; CCG:Children’s Cancer Group; TPOG Neuroblastoma 2003 protocol: Turkish Pediatric Oncology GroupNeuroblastoma treatment protocol-2003; ICE/VAC: ifosfamide, carboplatin, etoposide,vincristine, adriamycin, cyclophosphamide; OEPA: oncovin, etoposide, prednisone, doxorubicin.

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Anthracycline Induced Chronic Cardiotoxicity

monitor and those findings were clinically insignificant, except for one patient diag-nosed with grade 2 ventricular ectopic beats according to modified Lown-Wolf classi-fication.

Nine patients had systolic dysfunction by echocardiographic examination. EF andFS values of patients in group 3 were lower than values of patients in other groups,though the difference was insignificant (P = .087, .058, respectively). Myocardial per-formance index (MPI) was detected higher than 0.5 in two patients. Interventricularseptum thickness measurements according to body weight and height were belownormal range in 5 patients. In group 3, interventricular septum thickness measure-ments and deceleration time (DT) were significantly decreased (P = .042, .016, respec-tively). E, A, E/A, E′, A′, and E′/A′ values were not significantly different between agegroups (P = .634, .304, .347, .699, .693, .984, respectively). Findings from echocardio-graphic examinations of patients from the study group are shown in Table 4.

Mean heart rate values of patients in the study group obtained by radionuclide ven-triculography (MUGA) were 101.2 ± 24.9 (range, 72–197) bpm. Mean EF values mea-sured by MUGA for evaluating systolic function were 60.2% ± 14.4% (range, 25–87%).Mean PER and time-to-peak ejection rate (TPER) values were measured 3.8 ± 1 (range,0.5–7.3) EDC/second; 147.6 ± 54.3 (range, 10–392) ms; respectively. Mean PFR andTPFR values measured by MUGA for evaluating diastolic dysfunction were 4.3 ± 1.2(range, 0.5–8.9) EDC/second; 105.8 ± 46.3 (range, 19–324) ms; respectively. Heartrates were significantly increased (P = .039), and EF values were significantly de-creased (P = .02) in group 3. MUGA detected systolic dysfunction in six, and diastolicdysfunction in four patients in the entire study group.

Mean EF values obtained by evaluation of systolic function by MRI were 64.8% ±7.4% (range, 48–75%). EF values were significantly decreased in group 3 (P = .019). ESVmeasurements were not significantly different between groups (P = .362). Evaluationof left ventricular wall motions by MRI revealed various pathological findings in 41 pa-tients. In order to evaluate wall motions, 952 segments were analyzed and pathologicalfindings were observed in 119 segments (akinesia in six segments, dyskinesia in onesegment, aneurysm in one segment, and hypokinesia in 111 segments). The most af-fected segments were segment 14 (20 patients), segment 17 (15 patients), and segment9 (12 patients). Segments 6 and 11 were the least affected segments with one patienteach. In the process of evaluating left ventricular wall motions; akinesia, hypokinesia,and aneurysm were accepted as clinically significant findings.

Twenty patients had pathological findings on at least one of ECHO, MRI, or MUGA.Echocardiographic examinations revealed systolic dysfunction in nine patients. Sevenof these patients had decreased FS values, whereas two patients had both decreasedFS and decreased EF values. Radionuclide ventriculography detected systolic dysfunc-tion in two patients, and both systolic and diastolic dysfunction in four patients. Leftventricular segmentation in MRI revealed akinetic myocardial sites in six patients,dyskinetic sites in one patient and aneurysmatic sites in one patient. One patient wasdiagnosed with systolic dysfunction by all three of ECHO, MRI, and MUGA; whereasanother was diagnosed with systolic dysfunction by both ECHO and MRI. Commonparameter evaluated by all three tests (ECHO, MRI, MUGA) was EF value. In the entirestudy group and in groups 2 and 3, with a comparison between all three tests, simi-lar EF values were obtained by MRI and MUGA, whereas EF values by these two testswere significantly lower than values by ECHO. There was not difference between testsin group 1. The assessment of EF values of patient groups by ECHO, MUGA, and MRIis shown on Table 5.

In further analysis of patients with cardiac pathology, one patient diagnosed withsystolic dysfunction and four patients diagnosed with both systolic and diastolic dys-function by MUGA had normal findings on ECHO and MRI. Three patients with

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TAB

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TABLE 5 Evaluation of EF Values of Patient Groups Classified According to CumulativeAnthracycline Doses by ECHO, MRI, and MUGA

Study group Group 1 Group 2 Group 3Parameters∗ (mean + SD) (mean + SD) (mean + SD) (mean + SD)EF (%) (range) (range) (range) (range)

ECHO 67.8 ± 5.4 (56–83) 69 ± 5 (62–81) 63.3 ± 3.8 (63–74) 65.4 ± 6.8 (56–83)MUGA 60.2 ± 14.4 (25–87) 64.3 ± 15.7 (32–87) 58.8 ± 8.6 (36–70) 55.6 ± 16.1 (25–74)MRI 64.8 ± 7.4 (48–75) 66.2 ± 7.0 (48–75) 67.2 ± 6.2 (55–75) 60.2 ± 7.5 (50–70)P .02 .753 0.004 0.029

∗EF: ejection fraction; ECHO: echocardiography; MUGA: radionuclide ventriculography; MRI:magnetic resonance imaging.

abnormal left ventricular wall motions detected by MRI, had normal findings on othertests.

Between patients diagnosed with chronic cardiotoxicity by at least one of ECHO,MUGA, or MRI techniques, and patients without cardiac pathology; there was not sig-nificant difference in terms of age, sex, tumor type, anthracycline infusion rates, cu-mulative dose, and post-treatment follow-up durations (P = .735, .087, .610, .282, .090,.865, respectively).

Patients with concomitant mediastinal radiation therapy had significantly higherMPI values measured by ECHO (P = .008), whereas other parameters were notaffected.

DISCUSSION

Anthracycline class chemotherapy agents, which have been widely used since the1960s, have played an important role in the lately increased survival rates of childhoodcancers. The increased survival rates created a need for more research about the latecardiac complications of chemotherapy in patients with longer life expectancy. One ofthe most important late cardiac complications is anthracycline cardiotoxicity, whichis a cause of mortality and morbidity in children with cancer. Anthracycline cardiotox-icity is classified as either acute, or chronic. Acute cardiotoxicity is less frequently ob-served in children. Development of cardiotoxicity at least 3 months after the termi-nation of therapy can be defined as chronic cardiotoxicity [3]. Several mechanisms,mainly free oxygen radicals, play a role in the pathogenesis of chronic cardiotoxic-ity [6]. Chronic cardiotoxicity develops on the basis of several structural changes in-cluding cytoplasmic vacuolation, myofibrillar distortion, and fibrous degeneration ofmyocardium [16]. All of these structural changes are correlated with the cumulativeanthracycline dose. The risk of cardiotoxicity is significantly increased if the cumula-tive dose is higher than 400–500 mg/ m2. The analysis of retrospective studies showedthat after a mean two-year follow-up, 3% of patients at higher than 400 mg/m2, 7%of patients at higher than 550 mg/m2, and 13% of patients at higher than 700 mg/m2

of cumulative anthracycline dose, developed heart failure [17]. Another factor relatedto the development of heart failure is the duration of post-treatment follow-up. Car-diac dysfunction was diagnosed in 18% of survivors with less than 10-year follow-up durations, and 38% of survivors with longer follow-up durations [3]. In our study,the average post-treatment follow-up duration was 21.9 + 17.8 (range, 3–78) monthsand none of the patients had clinical findings of heart failure. In our study, patientswith various diagnoses received chemotherapy comprising of a mean cumulative an-thracycline dose of 244.0 ± 115.7 (range, 60–460), and 37 male, 19 female patientswith a median age of 11.2 ± 4.6 (range, 3.5–22) years were enrolled. Various cardiac

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pathologies were found in 20 (35.1%) patients. Eighteen (32.1%) patients had systolic,and 4 (7.1%) patients had diastolic dysfunction.

Besides cumulative dosage, there are other factors that establish the cardiotoxicity.Studies emphasize that female sex is a predisposition. In a study of 120 children andadults conducted by Lipshultz et al. [18] in 1995, it was expressed that female sex wasa predisposition to cardiotoxicity. However, in our study; age, sex, tumor type, anthra-cycline infusion rates, cumulative dose, and post-treatment follow-up durations werenot found to be predisposing factors for the development of cardiotoxicity.

Anthracycline induced chronic cardiotoxicity creates a permanent and seriouspathology which leads to heart failure. A multicentered study of more than five-hundred adults showed that 13% of patients developed heart failure after treatment[19]. In our study group, all patients were asymptomatic, excluding two patients withpalpitation complaints in history and one patient with tachycardia and two patientswith arrhythmia in physical examination.

In addition to history and physical examination used for the evaluation of car-diotoxicity, various tests are performed in order to diagnose patients with subclinicaldisease. One of these tests, ECG, frequently shows nonspecific ST and T wave changes,prolonged PR interval and decreased QRS amplitude. Studies support that QT intervalmight be used as an early indicator of ventricular dysfunction [20, 21]. In a study of 52patients, Schwartz et al. [21] showed that two years after completion of treatment, thelength of the QT interval was correlated with the cumulative doxorubicin dose. It wasexpressed that the QT interval was a predictive parameter for the late cardiac decom-pensation and QT measurements could be used as a screening test in patients withnormal echocardiographic findings. In our study, QT interval was significantly longerin patients with a cumulative anthracycline dose of more than 300 mg/m2. Also, pa-tients who received higher doses of anthracycline had significantly increased heartrates. Although studies express that the most common dysrhythmia is sinus tachy-cardia, other arrhythmias can be observed. Praga et al. [22] showed that 14% of pa-tients had pathological ECG findings at the end of the treatment. In our study, onlyone patient (1.8%) had sinus tachycardia by ECG and all other tests of this patientwere normal. It is known that Holter monitor is a reliable technique for evaluatingmean heart rates and dysrhythmias, as it allows 24-hour monitoring in normal dailylife settings. In a study conducted on children treated for acute leukemia with doxoru-bicin, Lipshultz et al. [23] reported that patients diagnosed with ventricular tachycar-dia on Holter monitor developed serious ventricular dysfunction and congestive heartfailure in long-term follow-up. In our study, patients that received higher anthracy-cline doses had significantly increased mean, minimum, and maximum heart rates onHolter monitor. Twenty-five patients had various pathological findings on Holter mon-itor which were rare and clinically insignificant dysrhythmias. Only one patient hadventricular ectopic beats requiring clinical follow-up. For evaluating the cardiotoxic-ity; ECHO, MUGA, MRI, BNP, and myocardial biopsy are other recommended diag-nostic studies. In follow-up protocols published by Steinherz et al. [24], ECHO andMUGA are recommended for monitoring cardiac function. ECHO is widely used infollow-ups because it is noninvasive, easily performed, cheap and does not requirethe use of radioactive substances [24, 25].

Left ventricular systolic function was first evaluated by M mode ECHO. ECHO isuseful for the functional and structural evaluation of left ventricle. In case of left ven-tricular dysfunction, afterload increases and ejection fraction decreases. This decreaseor tendency to decrease is valuable for predicting left ventricular dysfunction and mustbe followed up [2].

M mode technique is appropriate and practical for evaluating normal left ventri-cle, but it has been revealed that it can not correctly measure global left ventricular

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systolic function especially in patients with segmental wall motion abnormality andwall thickness differences. Another factor limiting its use is the interobserver variabil-ity. Additionally, classic echocardiographic studies might be inadequate for evaluatingthe early cardiotoxicity, which influences the course of chronic cardiotoxicity [26].

It is possible to show left ventricular dilatation (increased LVEDd and LVESd) andleft ventricular systolic dysfunction (decreased EF and FS) using two dimensional andM mode ECHO. The most widely used parameters for showing systolic dysfunctionare EF and FS values. Many studies accept EF <45% and FS <29% as systolic dysfunc-tion. However, EF and FS measurements are inadequate for evaluating cardiotoxicityat early stage [24]. In addition to that, EF is influenced by many factors such as preload,afterload, and heart rate [27]. Therefore, additional parameters to ejection fraction areused in order to evaluate left ventricular systolic dysfunction.

With the usage of pulsed-wave Doppler and tissue Doppler imaging (TDI) tech-niques, it is aimed to exceed the limitations of M mode Doppler. The TDI technique,introduced by Isaaz et al. [28] in 1989, made it possible to observe global and regionalmovements of ventricles and quantitatively evaluate systolic and diastolic function.MPI, measured by pulsed-wave Doppler, is a simple parameter for showing globalleft ventricular function. Studies state that, besides offering the possibility of makinga global evaluation, MPI can detect left ventricular dysfunction earlier than conven-tional studies [29, 30]. Reference range of MPI is 0.39 ± 0.05 and values higher than 0.5are accepted as pathological [31]. Everyday more and more studies suggest that MPIhas prognostic value [32].

In a study of 155 patients conducted by Elbl et al. [33] in order to evaluate late car-diac effects of anthracycline treatment; mean EF, FS, MPI, and LVPWd values werefound to be significantly lower in the study group when compared to the control group.In our study, mean EF and FS values measured by ECHO were 67.8% ± 5.4% (range,56–83%), 37.4% ± 4.4% (range, 29–52%), respectively. Among patient groups that wereclassified according to cumulative anthracycline doses, group 3 had lower EF and FSvalues by ECHO, but the difference was insignificant. Two asymptomatic patients hadMPI >0.5. There was not significant difference in MPI values between groups. Five pa-tients had interventricular septum thickness values below normal range. Also, group3 had significantly lower interventricular septum thickness measurements.

Another subject discussed for assessing anthracycline cardiotoxicity is the presenceof diastolic dysfunction in patients with normal ejection fraction as an early predictorof future heart failure [34]. Various measurements can be made by ECHO in order toevaluate diastolic parameters. Isovolumic relaxation time (IVRT), DT, and E/A ratioare among the most common [30, 35–37]. In our study, DT was significantly shorterin group 3. IVRT and E/A ratio values were in normal range in all groups, and therewas not significant difference between groups. Considering the fact that all patients inour study group were asymptomatic, prolonged DT identified in group 3 could be anearly predictor of future heart failure. However, more research is needed on this sub-ject. Although the most widely used diagnostic test for the follow-up of cardiotoxicityis the evaluation of left ventricular function by ECHO; sensitivity, specificity, and re-producibility are strongly influenced by interobserver variability and this brings theneed for a search for alternative tests to include in the algorithm [13].

Previous studies discussed the impact of age on Doppler tissue imaging velocities.It was revealed that reference values for DTI velocities changed with ageing, especiallyin children younger than 12 months [38]. However, in our study, a grouping of patientsinto four age intervals did not reveal statistically significant difference for E, A, E/A, E′,A′, and E′/A′ values between groups.

Radionuclide ventriculography (MUGA) is a noninvasive technique that makes useof intravenously injected radionuclides (Tc-99m) that binds to red blood cells and

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enables the cardiac pool to be visualized by a gamma-camera. It is a perfect toolfor evaluating regional and global function of heart and has great importance in thefollow-up of anthracycline cardiotoxicity [39, 40]. The biggest discussion limiting itsuse is the fact that the test involves ionizing radiation. However, total body irradiationin one scan is equivalent of irradiation by one to two chest X-rays [25]. Besides, thecost of a MUGA scan is nearly twice of that of an echocardiogram [39, 41]. Additionally,there are some technical factors limiting the use of MUGA. RR interval, which repre-sents the duration between two heartbeats, cannot be correctly measured especiallyin patients with arrhythmia and this causes erroneous evaluation results.

In a study of 32 cancer patients treated with 180–200 mg/m2 cumulative anthracy-cline dose, Agarwala et al. [42] reported that 13 (40.6%) patients with systolic dysfunc-tion were detected by MUGA, however, only 3 of these patients had clinical findingsof heart failure. In a study conducted on 21 patients treated with 200–600 mg/ m2 cu-mulative anthracycline, Corapcıoglu et al. [35] reported that 10 patients with cardiacdysfunction were detected by MUGA whereas only three patients with cardiac dys-function were detected by ECHO. In our study, diastolic dysfunction was not detectedby either ECHO or MRI in any of the 4 (7.1%) patients that were diagnosed with dias-tolic dysfunction by MUGA.

MRI is widely used to assess cardiac morphology and function. With recent studies,it has been accepted as the gold standard technique for the assessment of cardiac func-tion [43]. In our study, other than ECG, Holter monitor, ECHO, and MUGA; MRI wasemployed to evaluate cardiotoxicity, and there are only very few studies which focus onthe use of MRI for the evaluation of chronic cardiotoxicity in children. As well as suc-cessfully visualizing functional structure of heart, cardiac MRI has proven itself to be aperfect tool for showing acute and chronic myocardial injury [44]. The reproducibilityof measurements is an important advantage. Early changes in diastolic function can beshown and left ventricular EF, EDV, and ESV can be measured by MRI. Left ventricularwall motions can be evaluated in 17 segments. In a study conducted by Wassmuth et al.[26] in order to assess subclinical cardiotoxic effects of anthracyclines, a significantdecrease in ejection fraction and a significant increase in contrast enhancement wereobserved on the 28th day of the treatment. A different study conducted by Oberholzeret al. [44] aimed to assess chronic cardiotoxicity, and MRI results were compared toechocardiographic findings, and patients diagnosed with cardiac dysfunction by MRIhad normal echocardiographic examination. In our study, EF values by MRI were sig-nificantly lower in group 3 than values in other groups. Unlike other studies, decreasedleft ventricular wall motion was noted. To our knowledge, such results have not beenpublished before. Additionally, pathological findings were observed in 119 segments(akinesia in six segments, dyskinesia in one segment, aneurysm in one segment, andhypokinesia in 111 segments). Only eight of these had clinical importance. Our knowl-edge of future prognosis of patients with hypokinesia is limited. Indisputably, thesepatients require further follow-up. Similar to the data from literature, MRI and MUGAwere shown to be more sensitive than ECHO for the detection of left ventricular dys-function. MRI does not involve the risk of exposure to irradiation, but its use is limitedby factors such as the higher cost of the technique, the need for the availability of anexperienced center for cardiac imaging and the necessity of patient to stay very stillduring the scan for nearly 45 minutes. Also, assessing wall motions by MRI is observer-dependent, and should be performed in an experienced center.

In our study, 20 patients had pathological findings in at least one of ECHO, MUGA,or MRI. One patient was diagnosed with systolic dysfunction by all three of these tech-niques, whereas another patient was diagnosed with systolic dysfunction by ECHOand MUGA. In the entire study group and in groups 2 and 3, with a comparison be-tween all three tests, similar EF values were obtained by MRI and MUGA, whereas

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EF values by these two tests were significantly lower than values by ECHO. There wasno difference between tests in group 1. This result, supporting the data from litera-ture, shows that MRI and MUGA are more sensitive at detecting subclinical cardiacdysfunction. Similar to literature, our study showed the importance of MUGA at de-tecting especially diastolic dysfunction [35]. But, with the help from developing tech-niques such as TDI, ECHO is becoming more and more efficient at detecting subclin-ical cardiotoxicity. The detection of significantly lower DT values in group 3, makesit obligatory to follow-up these patients in terms of future cardiac dysfunction. Like-wise, two patients with MPI >0.5 must be followed up in terms of systolic dysfunction.Additionally, echocardiographic strain imaging, which was not included in our study,has brought innovation in the field of assessing left ventricular wall motions [45, 46].However, there is not enough data about either MRI or recently introduced echocar-diographic evaluations. More research is needed in order to establish reference rangesby age and sex in children for these diagnostic tests.

Another predisposition for the development of cardiotoxicity is the concomitantmediastinal radiation therapy. In a study conducted by Constine et al. [47], among 50patients treated for Hodgkin’s lymphoma with mediastinal radiation therapy (meandose 35.1Gy); 4% had abnormal left ventricular function and 16% had abnormal PFRvalues by MUGA. In a multicentered study of 1273 patients conducted by Praga et al.[22] in 1979, mediastinal radiation therapy was shown to be a significant risk factor forcardiotoxicity. In our study, nine (16.1%) patients had concomitant mediastinal radi-ation therapy. Mean radiation dose of these patients was 22.0 ± 7.0 (range, 15–36) Gy.Left ventricular function of patients with concomitant mediastinal radiation therapywas assessed by ECHO, MUGA, ECG, and MRI. MPI evaluated by ECHO was signifi-cantly increased in this group. This finding supports previous research about the rela-tionship between radiation therapy and cardiotoxicity.

Limitations of the StudyThere are some limitations concerning our study. One of them is the wide age rangeof patients in the study group (range, 3.5–22.0 years). This created difficulties in inter-pretation and comparison of weight-dependent variables. In order to overcome thislimitation, patients were classified into four age groups: 3 to 5, 6 to 9, 10 to 13, and14 to 22 years. Comparisons of diastolic parameters (E, A, E/A ratio, E′, A′, E′/A′) didnot reveal statistically significant difference between age groups. Relatively small studypopulation may be the reason of this. Another limitation of the study is the relativelyshort follow-up duration, the longest being 108 months. This may be responsible forthe fewness of patients diagnosed with chronic cardiotoxicity. Longer follow-up dura-tions will clarify the differences between groups. Lastly, lack of literature and researchon pediatric cardiac MRI made it difficult to interpret and compare MRI findings. Wehope that our study will contribute to future studies on pediatric cardiac MRI.

CONCLUSIONS

The high mortality and morbidity caused by chronic cardiotoxicity, makes it obligatoryto closely monitor the disease. All patients must be evaluated by ECG and ECHO in or-der to determine baseline cardiac function before the beginning of the treatment, andthese tests must be repeated before every course. All three of ECHO, MRI, and MUGAare valuable for evaluating late complications of anthracycline treatment in childrenwith cancer. In the long term, patients must be scanned by ECG and ECHO every twoyears. The reason why ECHO is preferred over MUGA and MRI, is because it is a widelyused and cheap diagnostic technique. Also, its diagnostic value is increasing with theuse of newly introduced echocardiographic methods. However, its use is limited by

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interobserver variability and influence of factors such as preload, afterload, heart rate,etc. on echocardiographic parameters.

Risk of chronic cardiotoxicity increases every year, especially in patients treatedwith high-dose anthracyclines. Our study emphasizes that the use of MRI and MUGAalongside ECHO facilitates the detection of subclinical cardiotoxicity in patientstreated with a cumulative anthracycline dose of more than 200 mg/m2 (groups 2 and3). In addition to ECG and ECHO performed every two years, guidelines recommendscanning of patients by Holter monitor and MUGA with an interval of 5 years [24]. Ourstudy recommends the use of MRI as an alternative to MUGA, because of the fact thatMUGA scans involve exposure to irradiation and results are easily influenced by heartrate changes. Although MRI is a more expensive diagnostic test, it could be accepted ascost-effective when one considers that the cost of the treatment of a patient with heartfailure would be very high. One of the two important factors limiting the use of MRI isthe risk of contrast allergy, and the other one is the necessity of patient to remain verystill for almost 45 minutes during the scan. In older patients without allergy, MRI canbe chosen over MUGA. Disadvantages such as interpretation and performing difficul-ties and the absence of pediatric reference ranges require more study on children andfurther standardization of the technique.

The assessment of long-term clinical importance of cardiac dysfunction findingsdetected by different diagnostic techniques, will only be possible with longtime follow-up of patients.

Declaration of Interest

The authors report no conflicts of interest. The authors alone are responsible for thecontent and writing of the paper.

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