Basar - Are Cardiac Magnetic

Pediatric Hematology and Oncology, 31:237–252, 2014
Copyright C Informa Healthcare USA, Inc.

ISSN: 0888-0018 print / 1521-0669 online
DOI: 10.3109/08880018.2013.851753
ORIGINAL ARTICLE
Are cardiac Magnetic Resonance Imaging and

Radionuclide Ventriculography Good Options
Against Echocardiography for Evaluation
of Anthracycline Induced Chronic Cardiotoxicity
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Thammasat University on 10/04/14
in Childhood Cancer Survivors?
Evic Zeynep Basar,1 Funda Corapcioglu,1 Kadir Babaoglu,2 Yonca Anik,3

Gozde Gorur Daglioz,4 and Reyhan Dedeoglu5
1
Department of Pediatric Oncology, Kocaeli University, Kocaeli, Turkey; 2 Department of
Pediatric Cardiology, Faculty of Medicine, Kocaeli University, Izmit, Turkey; 3 Department of
Radiology, School of Medicine, Kocaeli University, Kocaeli, Turkey; 4 Department of Nuclear
Medicine, Kocaeli University, Kocaeli, Turkey; 5 Department of Pediatric Cardiology, Dr.
Siyami Ersek hospital, Istanbul, Turkey
For personal use only.
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 according
to 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, and
concomitant 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 were
included 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 MUGA
after anthracycline chemotherapy. We revealed that other than ECHO, MRI and MUGA have high
clinical importance for evaluating subclinical late cardiac complications in children treated with
anthracyclines.
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, Kocaeli
University, Kocaeli, Turkey. E-mail: fundacorapcioglu@kocaeli.edu.tr

 E. Z. Basar et al.
30 years after the completion of cancer treatment, 73% of patients develop chronic
health 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 are
known to have cardiotoxic effects. Among anticancer drugs, the most well-defined
group of agents for their cardiotoxic effects is anthracycline antibiotics. Anthracycline
cardiotoxicity is classified as either acute, or chronic. Development of cardiotoxicity
at 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 the
follow-up of patients [4]. Our study employs the usage of traditional diagnostic tests,
and additionally cardiac magnetic resonance imaging (MRI), for the evaluation of
anthracycline induced subclinical chronic cardiotoxicity in children with cancer. We

aimed 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 all
noninvasive 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 with
anthracycline-comprising chemotherapy were enrolled in the study. All patients had
been evaluated by echocardiography (ECHO) as a part of routine examination before
the 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 considered
eligible. 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 guidelines
of Helsinki declaration concerning medical research in humans and received local
Ethics Committee approval. Informed consent was obtained from each patient and/or
parents.
Age and sex of patients, type and primary localization of tumor, oncologic treat-
ment protocol, type of anthracycline, cumulative anthracycline dose, administration
schema, drug infusion rates, time after completion of last anthracycline-comprising
therapy 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 duration
of follow-up since the time of diagnosis, presence of concomitant mediastinal radia-
tion therapy and dose and site of radiation therapy were evaluated. Doxorubicin was
considered equivalent to daunorubicin, 1 mg/m2 of doxorubicin was considered to be
equivalent 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 anthracycline
doses. Cumulative doses were less than 200 mg/m2 in group 1, between 200 and
350 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.
Pediatric Hematology and Oncology

Anthracycline Induced Chronic Cardiotoxicity 
Standard 12-lead electrocardiogram was performed. All recordings were obtained

by Reynolds Medical digital recorder. Holter monitor recordings were analyzed using
Pathfinder 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 as
clinically significant.
Echocardiographic examination was performed using two dimensional, M mode,
and Doppler techniques. Patients were evaluated in a partial left decubitus position
by 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-chamber
views were obtained at rest, accompanied by electrocardiographic monitoring. Left
ventricular systolic and diastolic function was evaluated by M mode, pulsed-wave

Doppler, 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 findings
were evaluated according to standard recommendations of the American Society of
ECHO 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 examinations
were performed by one experienced pediatric cardiologist (K.B.). Post-treatment EF
by echocardiogram of less than 45, or post-treatment FS by echocardiogram of less
than 29%, or an E/A ratio below 1, and/or any evidence of abnormal hypokinesia of
myocardium 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 of
adult activity [10–20 mCi (370–740 MBq)] and adjusted according to body weight. Data
acquisition was performed with a single-head SPECT system (ADAC, Argus Epic, Mil-
pitas, CA, USA) equipped with low-energy, high-resolution collimator. The lower limit
of normal LVEF was 45%. Fractional shortening in ECHO is considered as equivalent
of radial shortening (RS) in MUGA. RS is calculated using the following formula: (ED
line 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 counts
to 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 Gyroscan
Intera 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 imaging
technique with a SENSE factor of 2. Twelve phases were evaluated for each cardiac
cycle. Four-chamber (horizontal long-axis), vertical long-axis, and short-axis images
were obtained. Short-axis images were obtained perpendicular to the interventricular
septum. Wall motions were evaluated using an ECG-gated breath-hold balanced fast
field echo (BFFE) sequence (TR/TE 3.1/1.5 ms, flip angle [FA] 60◦ ) in three slices from
the apex to the base of the left ventricle. Additionally, single-slice four chamber and
Copyright
C Informa Healthcare USA, Inc.
 E. Z. Basar et al.
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, software
ViewForum release 3.4 (Philips Medical Systems, Eindhoven, The Netherlands). Car-
diac MRI analysis program was used for all assessments. The images were evaluated
according to cardiac segmentation used by the American Heart Association (AHA).
Left ventricle was evaluated in 17 segments (see Table 2) [15]. For the measurements
of 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 modified
Simpson’s method. MRI analysis also included assessment of wall motions. LV cine
images were evaluated by visual analysis as normal, hypokinetic (decreased LV wall

contraction at systole), akinetic (absence of LV wall contraction at systole), dyskinetic
(paradoxical movement, outward LV wall movement at systole), and aneurysmatic. All
images were analyzed by one experienced pediatric radiologist (Y.A.).
Statistical Analysis
Statistical analyses were performed using SPSS for Windows R
software. Patient char-
acteristics were summarized using descriptive statistics. Mean ± standard deviation
values were used for the expression of continuous variables. A number of tests were
used 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 comparison
of quantitative values between three groups; Kruskal-Wallis test was used to compare
abnormally distributed parameters, and Mann-Whitney U test was used to detect the
group 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 group
that caused the difference. Chi-square test was used to compare the sensitivity levels
of 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 was
11.2 ± 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 in
5, rhabdomyosarcoma in 4, neuroblastoma in 2, osteosarcoma in 2, and pleuropul-
monary blastoma in 1 of the patients. Characteristics of treatment protocols are shown
in 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 duration
after last anthracycline administration was 21.9 ± 17.8 (range, 3–78) months. Mean
follow-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 the
time of evaluation, 54 patients were in remission; one out of three patients in relapse
had 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 were
24 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 radiation
therapy. Site of radiation therapy was mediastinum in 9 (16.1%) of the patients. Mean
radiation dose of patients with concomitant radiation therapy was 22.0 ± 7.0 (range,
15–36) Gy.

TABLE 1 Parameters of MRI Technique∗

Flip ST/CS FOV/RFOV Section Time
Examination Sequence TR/TE angle Mm % number seconds Matrix
Scanning corona-sagittal-transverse B-TFE 3.1/1.5 60 4/1 450–500/100 15 20–24 224–256
Four-chamber with breath-hold B-FFE 2.7/1.3 50 10/10 450–480/70 3 32 256/256
Left ventricle long-axis images with breath-hold B-FFE 2.8/1.4 50 10/10 500/75 3 29 256/256
∗
B-FFE: Balanced Fast Field Echo; B-TFE: Balanced Turbo Field Echo; TR/TE: Repetition Time/Echo Time; ST: Slice Thickness; CS: Cross Sectional; FOV/RFOV: Field of
view/region Field of view

 E. Z. Basar et al.
TABLE 2 Left Ventricular Segmentation

Segment 1 Basal anterior
Segment 2 Basal anteroseptal
Segment 3 Basal inferoseptal
Segment 4 Basal inferior
Segment 5 Basal inferolateral
Segment 6 Basal anterolateral
Segment 7 Mid anterior
Segment 8 Mid anteroseptal
Segment 9 Mid inferoseptal
Segment 10 Mid inferior
Segment 11 Mid inferolateral
Segment 12 Mid anterolateral
Segment 13 Apical anterior
Segment 14 Apical septal

Segment 15 Apical inferior
Segment 16 Apical lateral
Segment 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 of
patients 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 protocols
ABVD 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 anthracycline
Doxorubicin 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 Frankfurt
Munster group non-Hodgkin’s lymphoma treatment protocol; IECESS’92: European Intergroup
Cooperative Ewing’s Sarcoma Study’92; IRS-IV: Intergroup rhabdomyosarcoma study-IV; TPOG
Wilms’ protocol: Turkish Pediatric Oncology Group Wilms’ tumor treatment protocol; CCG:
Children’s Cancer Group; TPOG Neuroblastoma 2003 protocol: Turkish Pediatric Oncology Group
Neuroblastoma treatment protocol-2003; ICE/VAC: ifosfamide, carboplatin, etoposide,
vincristine, adriamycin, cyclophosphamide; OEPA: oncovin, etoposide, prednisone, doxorubicin.

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 and
FS 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. Interventricular
septum thickness measurements according to body weight and height were below
normal 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 age
groups (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 and
TPFR 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. Heart
rates were significantly increased (P = .039), and EF values were significantly de-
creased (P = .02) in group 3. MUGA detected systolic dysfunction in six, and diastolic
dysfunction 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). ESV
measurements were not significantly different between groups (P = .362). Evaluation
of 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 pathological
findings were observed in 119 segments (akinesia in six segments, dyskinesia in one
segment, aneurysm in one segment, and hypokinesia in 111 segments). The most af-
fected segments were segment 14 (20 patients), segment 17 (15 patients), and segment
9 (12 patients). Segments 6 and 11 were the least affected segments with one patient
each. 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. Seven
of these patients had decreased FS values, whereas two patients had both decreased
FS and decreased EF values. Radionuclide ventriculography detected systolic dysfunc-
tion in two patients, and both systolic and diastolic dysfunction in four patients. Left
ventricular segmentation in MRI revealed akinetic myocardial sites in six patients,
dyskinetic sites in one patient and aneurysmatic sites in one patient. One patient was
diagnosed with systolic dysfunction by all three of ECHO, MRI, and MUGA; whereas
another was diagnosed with systolic dysfunction by both ECHO and MRI. Common
parameter evaluated by all three tests (ECHO, MRI, MUGA) was EF value. In the entire
study 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 tests
were significantly lower than values by ECHO. There was not difference between tests
in group 1. The assessment of EF values of patient groups by ECHO, MUGA, and MRI
is shown on Table 5.
In further analysis of patients with cardiac pathology, one patient diagnosed with
systolic 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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
TABLE 4 Evaluation of Left Ventricular Systolic and Diastolic Function of Study Group
Parameters (mean ± Study group (mean + Group 1 (mean + Group 2 (mean + Group 3 (mean
SD) (range) SD) (range) SD) (range) SD) (range) + SD) (range) P
Systolic
Fractional shortening (FS) (%) 37.4 ± 4.4 (29–52) 38.5 ± 4.1 (33–50) 37.6 ± 3.0 (33–42) 35.8 ± 5.7 (29–52) .058
Ejection fraction (EF) (%) 67.8 ± 5.4 (56–83) 69 ± 5 (62–81) 63.3 ± 3.8 (63–74) 65.4 ± 6.8 (56–83) .087
Peak systolic velocity (S) (mL) 10.8 ± 2.6 (7–17) 11.3 ± 2.8 (8–17) 10.2 ± 2.0 (7.0–13.6) 10.6 ± 2.9 (7–15) .601
Myocardial performance index (tei) 0.5 ± 0.1 (0.18–0.89) 0.4 ± 0.1 (0.4–0.6) 0.5 ± 0.1 (0.2–0.6) 0.5 ± 0.1 (0.3–0.9) .718
Isovolumic contraction time (ICT) (ms) 58.2 ± 9.4 (40–80) 59.8 ± 8.5 (40–74) 59.1 ± 11.9 (44–80) 54.9 ± 7.5 (44–70) .234
Diastolic
Early filling velocity (E) (cm/second) 95.0 ± 15.6 (65–126) 97.1 ± 16.6 (65–126) 90.6 ± 13.5 (72–114) 96.3 ± 16.0 (79–125) .390
Late filling velocity (A) (cm/second) 59.7 ± 12.6 (39–98) 59.5 ± 10.6 (39–78) 54.6 ± 9.2 (41–80) 65.1 ± 16.3 (42–98) .102
Ratio of the early to late filling velocity (E/A) 1.7 ± 0.5 (1.0–4.4) 1.7 ± 0.4 (1.1–2.6) 1.9 ± 0.8 (1.3–4.5) 1.5 ± 0.3 (1.1–2.1) .271
Early filling velocity by tissue Doppler (E ) 18.3 ± 3.3 (10.2–25.0) 18.8 ± 3.6 (0.2–25.0) 18.1 ± 3.0 (14.0–22.4) 17.8 ± 3.4 (13–25) .602
Late Filling Velocity by tissue Doppler (A ) 7.5 ± 1.9 (4–13) 7.4 ± 2.0 (4.0–13.0) 7.8 ± 2.0 (4–13) 7.3 ± 1.9 (5–12) .617
Ratio of the early to late filling velocity by 2.5 ± 0.64 (1.5–3.9) 2.6 ± 0.6 (1.6–3.8) 2.5 ± 0.8 (1.6–3.9) 2.5 ± 0.6 (1.7–3.9) .540
tissue Doppler (E /A )
Deceleration time Dt (seconds) 130.9 ± 29.1 (77–193) 142.0 ± 23.6 (107–183) 128.2 ± 30.6 (82–193) 117.2 ± 30.2 (77–177) .016
Isovolumic relaxation time (IRS) (ms) 58.1 ± 12.3 (34–81.0) 57.7 ± 13.6 (34–80) 60.7 ± 11.5 (44–81) 56.2 ± 11.3 (37–70) .513
Anthracycline Induced Chronic Cardiotoxicity 
TABLE 5 Evaluation of EF Values of Patient Groups Classified According to Cumulative

Anthracycline Doses by ECHO, MRI, and MUGA
Study group Group 1 Group 2 Group 3
Parameters∗ (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 other
tests.
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 higher
MPI values measured by ECHO (P = .008), whereas other parameters were not
affected.
DISCUSSION
Anthracycline class chemotherapy agents, which have been widely used since the
1960s, have played an important role in the lately increased survival rates of childhood
cancers. The increased survival rates created a need for more research about the late
cardiac complications of chemotherapy in patients with longer life expectancy. One of
the most important late cardiac complications is anthracycline cardiotoxicity, which
is 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 of
myocardium [16]. All of these structural changes are correlated with the cumulative
anthracycline 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 showed
that 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 related
to 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) months
and none of the patients had clinical findings of heart failure. In our study, patients
with 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 patients
with a median age of 11.2 ± 4.6 (range, 3.5–22) years were enrolled. Various cardiac
Copyright
 E. Z. Basar et al.
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 and
adults conducted by Lipshultz et al. [18] in 1995, it was expressed that female sex was
a predisposition to cardiotoxicity. However, in our study; age, sex, tumor type, anthra-
cycline infusion rates, cumulative dose, and post-treatment follow-up durations were
not found to be predisposing factors for the development of cardiotoxicity.
Anthracycline induced chronic cardiotoxicity creates a permanent and serious
pathology 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 with
palpitation complaints in history and one patient with tachycardia and two patients
with 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 subclinical
disease. One of these tests, ECG, frequently shows nonspecific ST and T wave changes,
prolonged PR interval and decreased QRS amplitude. Studies support that QT interval
might be used as an early indicator of ventricular dysfunction [20, 21]. In a study of 52
patients, Schwartz et al. [21] showed that two years after completion of treatment, the
length of the QT interval was correlated with the cumulative doxorubicin dose. It was
expressed 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 with
normal echocardiographic findings. In our study, QT interval was significantly longer

in patients with a cumulative anthracycline dose of more than 300 mg/m2 . Also, pa-
tients who received higher doses of anthracycline had significantly increased heart
rates. 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, only
one patient (1.8%) had sinus tachycardia by ECG and all other tests of this patient
were normal. It is known that Holter monitor is a reliable technique for evaluating
mean heart rates and dysrhythmias, as it allows 24-hour monitoring in normal daily
life 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 heart
failure in long-term follow-up. In our study, patients that received higher anthracy-
cline doses had significantly increased mean, minimum, and maximum heart rates on
Holter monitor. Twenty-five patients had various pathological findings on Holter mon-
itor which were rare and clinically insignificant dysrhythmias. Only one patient had
ventricular 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 and
MUGA are recommended for monitoring cardiac function. ECHO is widely used in
follow-ups because it is noninvasive, easily performed, cheap and does not require
the use of radioactive substances [24, 25].
Left ventricular systolic function was first evaluated by M mode ECHO. ECHO is
useful for the functional and structural evaluation of left ventricle. In case of left ven-
tricular dysfunction, afterload increases and ejection fraction decreases. This decrease
or tendency to decrease is valuable for predicting left ventricular dysfunction and must
be 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

Anthracycline Induced Chronic Cardiotoxicity 
systolic function especially in patients with segmental wall motion abnormality and
wall thickness differences. Another factor limiting its use is the interobserver variabil-
ity. Additionally, classic echocardiographic studies might be inadequate for evaluating
the early cardiotoxicity, which influences the course of chronic cardiotoxicity [26].
It is possible to show left ventricular dilatation (increased LVEDd and LVESd) and
left ventricular systolic dysfunction (decreased EF and FS) using two dimensional and
M mode ECHO. The most widely used parameters for showing systolic dysfunction
are 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 cardiotoxicity
at 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 are
used 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 regional
movements of ventricles and quantitatively evaluate systolic and diastolic function.
MPI, measured by pulsed-wave Doppler, is a simple parameter for showing global
left ventricular function. Studies state that, besides offering the possibility of making
a 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 0.5
are accepted as pathological [31]. Everyday more and more studies suggest that MPI
has 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 were
found 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 were
classified according to cumulative anthracycline doses, group 3 had lower EF and FS
values by ECHO, but the difference was insignificant. Two asymptomatic patients had
MPI >0.5. There was not significant difference in MPI values between groups. Five pa-
tients had interventricular septum thickness values below normal range. Also, group
3 had significantly lower interventricular septum thickness measurements.
Another subject discussed for assessing anthracycline cardiotoxicity is the presence
of diastolic dysfunction in patients with normal ejection fraction as an early predictor
of future heart failure [34]. Various measurements can be made by ECHO in order to
evaluate diastolic parameters. Isovolumic relaxation time (IVRT), DT, and E/A ratio
are among the most common [30, 35–37]. In our study, DT was significantly shorter
in group 3. IVRT and E/A ratio values were in normal range in all groups, and there
was not significant difference between groups. Considering the fact that all patients in
our study group were asymptomatic, prolonged DT identified in group 3 could be an
early 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 cardiotoxicity
is the evaluation of left ventricular function by ECHO; sensitivity, specificity, and re-
producibility are strongly influenced by interobserver variability and this brings the
need 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, especially
in children younger than 12 months [38]. However, in our study, a grouping of patients
into 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 use
of intravenously injected radionuclides (Tc-99m) that binds to red blood cells and
Copyright
 E. Z. Basar et al.
enables the cardiac pool to be visualized by a gamma-camera. It is a perfect tool

for evaluating regional and global function of heart and has great importance in the
follow-up of anthracycline cardiotoxicity [39, 40]. The biggest discussion limiting its
use is the fact that the test involves ionizing radiation. However, total body irradiation
in one scan is equivalent of irradiation by one to two chest X-rays [25]. Besides, the
cost 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 especially
in 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 findings
of heart failure. In a study conducted on 21 patients treated with 200–600 mg/ m2 cu-
mulative anthracycline, Çorapçıoğlu et al. [35] reported that 10 patients with cardiac
dysfunction were detected by MUGA whereas only three patients with cardiac dys-
function were detected by ECHO. In our study, diastolic dysfunction was not detected
by 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 was
employed to evaluate cardiotoxicity, and there are only very few studies which focus on
the 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 a
perfect tool for showing acute and chronic myocardial injury [44]. The reproducibility
of measurements is an important advantage. Early changes in diastolic function can be
shown and left ventricular EF, EDV, and ESV can be measured by MRI. Left ventricular
wall 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 significant
decrease in ejection fraction and a significant increase in contrast enhancement were
observed on the 28th day of the treatment. A different study conducted by Oberholzer
et al. [44] aimed to assess chronic cardiotoxicity, and MRI results were compared to
echocardiographic findings, and patients diagnosed with cardiac dysfunction by MRI
had 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, decreased
left ventricular wall motion was noted. To our knowledge, such results have not been
published before. Additionally, pathological findings were observed in 119 segments
(akinesia in six segments, dyskinesia in one segment, aneurysm in one segment, and
hypokinesia in 111 segments). Only eight of these had clinical importance. Our knowl-
edge of future prognosis of patients with hypokinesia is limited. Indisputably, these
patients require further follow-up. Similar to the data from literature, MRI and MUGA
were 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 limited
by factors such as the higher cost of the technique, the need for the availability of an
experienced center for cardiac imaging and the necessity of patient to stay very still
during 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 ECHO
and 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

Anthracycline Induced Chronic Cardiotoxicity 
EF values by these two tests were significantly lower than values by ECHO. There was
no 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 cardiac
dysfunction. 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, makes
it 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 ranges

by age and sex in children for these diagnostic tests.
Another predisposition for the development of cardiotoxicity is the concomitant
mediastinal radiation therapy. In a study conducted by Constine et al. [47], among 50
patients treated for Hodgkin’s lymphoma with mediastinal radiation therapy (mean
dose 35.1Gy); 4% had abnormal left ventricular function and 16% had abnormal PFR
values 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 for
cardiotoxicity. 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 therapy
was 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 Study

There are some limitations concerning our study. One of them is the wide age range
of 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 this
limitation, patients were classified into four age groups: 3 to 5, 6 to 9, 10 to 13, and
14 to 22 years. Comparisons of diastolic parameters (E, A, E/A ratio, E , A , E /A ) did
not reveal statistically significant difference between age groups. Relatively small study
population may be the reason of this. Another limitation of the study is the relatively
short follow-up duration, the longest being 108 months. This may be responsible for
the fewness of patients diagnosed with chronic cardiotoxicity. Longer follow-up dura-
tions will clarify the differences between groups. Lastly, lack of literature and research
on pediatric cardiac MRI made it difficult to interpret and compare MRI findings. We
hope that our study will contribute to future studies on pediatric cardiac MRI.
CONCLUSIONS
The high mortality and morbidity caused by chronic cardiotoxicity, makes it obligatory
to 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, and
these tests must be repeated before every course. All three of ECHO, MRI, and MUGA
are valuable for evaluating late complications of anthracycline treatment in children
with cancer. In the long term, patients must be scanned by ECG and ECHO every two
years. The reason why ECHO is preferred over MUGA and MRI, is because it is a widely
used and cheap diagnostic technique. Also, its diagnostic value is increasing with the
use of newly introduced echocardiographic methods. However, its use is limited by
Copyright
 E. Z. Basar et al.
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 treated
with high-dose anthracyclines. Our study emphasizes that the use of MRI and MUGA
alongside ECHO facilitates the detection of subclinical cardiotoxicity in patients
treated with a cumulative anthracycline dose of more than 200 mg/m2 (groups 2 and
3). In addition to ECG and ECHO performed every two years, guidelines recommend
scanning of patients by Holter monitor and MUGA with an interval of 5 years [24]. Our
study recommends the use of MRI as an alternative to MUGA, because of the fact that
MUGA scans involve exposure to irradiation and results are easily influenced by heart
rate changes. Although MRI is a more expensive diagnostic test, it could be accepted as
cost-effective when one considers that the cost of the treatment of a patient with heart
failure would be very high. One of the two important factors limiting the use of MRI is
the risk of contrast allergy, and the other one is the necessity of patient to remain very
still for almost 45 minutes during the scan. In older patients without allergy, MRI can
be chosen over MUGA. Disadvantages such as interpretation and performing difficul-
ties and the absence of pediatric reference ranges require more study on children and
further standardization of the technique.
The assessment of long-term clinical importance of cardiac dysfunction findings
detected 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 the
content and writing of the paper.
REFERENCES
[1] Hale JP, Lewis IJ. Anthracyclines: cardiotoxicity and its prevention. Arch Dis Child. 1994;71:457–462.
[2] Lipshultz SE, Alvarez JA, Scully RE. Anthracycline associated cardiotoxicity in survivors of childhood
cancer. Heart. 2008;94:525–533.
[3] Grenier MA, Lipshultz SE. Epidemiology of anthracycline cardiotoxicity in children and adults.
Semin Oncol. 1998;25:72–85.
[4] Hitchcock-Bryan S, Gelber RD, Cassady Jr, Sallan SE. The impact of induction anthracycline on
long-term failure-free survival in childhood acute lymphoblastic leukemia. Med Pediatr Oncol.
1986;14:211–215.
[5] Dreyer ZE, Blatt J, Bleyer A. Late effects of childhood cancer and its treatment. In: Pizzo PA,
Poplack DG, eds. Principles and Practice of Pediatric Oncology. Philadelphia, PA: Lippincott
Williams&Wilkins; 2002:1431–1461.
[6] Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents. Drug Saf. 2000;22:263–302.
[7] Pui CH, Schrappe M, Ribeiro RC, Niemeyer CM. Childhood and adolescent lymphoid and myeloid
leukemia. Hematology (Am Soc Hematol Educ Program). 2004;118–145.
[8] Lown B, Wolf M. Approaches of sudden death from coronary heart disease. Circulation.
1971;46:130–142.
[9] Sahn DJ, DeMaria A, Kisslo J, Weyman A. The committee on M-Mode standardisation of the American
Society of Echocardiography: recommendations regarding quantitation in M-Mode echocardiogra-
phy: result of a survey of echocardiographic measurements. Circulation. 1978;58:1072–1083.
[10] Mirsky I, Pasipoularides A. Clinical assessment of diastolic function. Prog Cardiovasc Dis.
1990;32:291–318.
[11] Bu’Lock FA, Mott MG, Martin RP. Left ventricular diastolic dysfunction in children measured by-
Doppler echocardiography: normal values and relation with growth. Br Heart J. 1995;73:334–339.
[12] Ganz WI, Sridhar KS, Ganz SS, et al. Review of test for monitoring doxorubicin-induced cardiomy-
opathy. Oncology. 1996;53:461–470.
[13] Meinardi MT, van der Graaf WTA, van Veldhuisen DJ, et al. Detection of anthracycline-induced car-
diotoxicity. Cancer Treat Rev. 1999;25:237–224

Anthracycline Induced Chronic Cardiotoxicity 
[14] Murphy PB, Port SC. Radionuclide evaluation of left ventricular function. In: Sandler MP, Coleman
RE, Patton JA, Wackers FJTH, Gottschalk A, eds. Diagnostic Nuclear Medicine. Philadelphia, PA: Lip-
pincott Williams & Wilkins; 2003:239–271.
[15] Cerqueira MD, Weissman NJ, Dilsizian V. Standardized myocardial segmentation and nomencla-
ture for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac
Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circu-
lation. 2002;105:539–542.
[16] Billingham ME, Masek MA. The pathology of anthracycline cardiotoxicity in children, adolescents
and adults. In: Bricker JT, Green DM, D’Angio G, eds. Cardiac Toxicity After Treatment for Childhood
Cancer. New York: Wiley-Liss, 1993;17–24.
[17] Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure.
Ann Intern Med. 1979;91:710–717.
[18] Lipshultz SE, Lipsitz SR, Mone SM, et al. Female sex and drug dose as risk factors for late cardiotoxic
effects of doxorubicin therapy for childhood cancer. N Engl J Med. 1995;332:1738–1743.
[19] Swain SM. Adult multicenter trials using dexrazoxane to protect against cardiac toxicity. Semin Oncol.
1998;25:43–47.
[20] Iarussi D, Indolfi P, Galderisi M, Bossone E. Cardiac toxicity after anthracycline chemotherapy in
childhood. Herz. 2000;25:676–688.
[21] Schwartz CL, Hobbie WL, Truesdell S, et al. Corrected QT interval prolongation in anthracycline-
treated survivors of childhood cancer. J Clin Oncol. 1993;11:1906–1910.
[22] Praga C, Beretta G, Vigo PL, et al. Adriamycin cardiotoxicity: a survey of 1273 patients. Cancer Treat
Rep. 1979;63:827–834.
[23] Lipshultz SE, Colan SD, Gelber RD, et al. Late cardiac effects of doxorubicin therapy for acute lym-
phoblastic leukemia in childhood. N Engl J Med. 1991;324:808–815.
[24] Steinherz LJ, Graham T, Hurwitz R, et al. Guidelines for cardiac monitoring of children during and af-
ter anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group.
Pediatrics. 1992;89:942–949.
[25] Bu’Lock FA, Mott MG, Oakhill A, Martin RP. Early identification of anthracycline cardiomyopathy:
possibilities and implications. Arch Dis Child. 1996;75:416–422.

[26] Wassmuth R, Lentzsch S, Erdbruegger U, et al. Subclinical cardiotoxic effects of anthracyclines as
assessed by magnetic resonance imaging-a pilot study. Am Heart J. 2001;141:1007–1013.
[27] Mahler F, Ross J Jr, O’Rourke RA, Covell JW. Effects of changes in preload, afterload and inotropic
state on ejection and isovolumic phase measures of contractility in the conscious dog. Am J Cardiol.
1975;35:626–634.
[28] Isaaz K, Thompson A, Ethevenot G, Cloez JL. Doppler electrocardiografic mesurement of low velocity
motıon of the left ventricular posterior wall. Am J Cardiol. 1989;64:66–75.
[29] Oğuzhan A, Abacı A, Çetin S. Doku Doppler ekokardiyografi. Türk J Echocardiography. 2000;2:35–41.
[30] Kantar M, Levent E, Çetingül N, et al. Plasma natriuretic peptides levels and echocardiographic find-
ings in late subclinical anthracycline toxicity. Pediatr Hematol Oncol. 2008;25:723–733.
[31] Eidem BW, Sapp BG, Suarez CR, Cetta F. Usefulness of the myocardial performance index for early
detection of anthracycline-induced cardiotoxicity in children. Am J Cardiol. 2001;87:1120–1122.
[32] Feigenbaum H, Armstrong WF, Ryan T. Feigenbaum’s Echocardiography (6th ed.). Philadelphia, PA:
Lippincott Williams-Wilkins; 2005:437–486.
[33] Elbl L, Hrstkova H, Chaloupka V. The late consequences of anthracycline treatment on left ventricu-
lar function after treatment for childhood cancer. Eur J Pediatr. 2003;162:690–696.
[34] Mj, Thomas JD, Klein AL. New Doppler echocardiographic applications for the study of diastolic
function. J Am Coll Cardiol. 1998;32:865–875.
[35] Çorapcıoğlu F, Sarper N, Berk F, et al. Evaluation of anthracycline-induced early left ventricular dys-
function in children with cancer: a comparative study with echocardiography and multigated ra-
dionuclide angiography. Pediatr Hematol Oncol. 2006;23:71–80.
[36] Leong DP, De Pasquale CG, Selvanayagam JB. Heart failure with normal ejectıon fraction: the com-
plementary roles of echocardiography and CMR ımagıng. JACC Cardiovasc Imaging. 2010;3:409–420.
[37] Marchandise B, Schroeder E, Bosly A, et al. Early detection of doxorubicine cardiotoxicity: interest of
Doppler echocardiographic analysis of left ventricular filling dynamics. Am Heart J. 1989;118:92–98.
[38] Eidem BW, McMahon CJ, Cohen RR, et al. Impact of cardiac growth on Doppler tissue imaging ve-
locities: a study in healthy children. J Am Soc Echocardiogr. 2004;17(3):212–221.
[39] Ganz WI, Sridhar KS, Ganz SS, et al. Review of test for monitoring doxorubicin-induced cardiomy-
opathy. Oncology. 1996;53:461–470.
[40] Steinberg JS, Wasserman AG. Radionuclide ventriculography for evaluation and prevention of dox-
orubicin cardiotoxicity. Clin Ther. 1985;7:660–667.
[41] Shureiqi I, Cantor SB, Lippman SM, et al. Clinical and economic impact of multiple gated acquisition
scan monitoring during anthracycline therapy. Br J Cancer. 2002;86:226–232.
Copyright
 E. Z. Basar et al.
[42] Agarwala S, Kumar R, Bhatnagar V, et al. High incidence of adriamycin cardiotoxicity in children even
at low cumulative doses: role of radionuclide cardiac angiography. J Pediatr Surg. 2000;35:1786–1789.
[43] Higgins CB. Which standard has the gold? J Amer Coll Cardiol. 1992;19:1608–1609.
[44] Oberholzer K, Kunz RP, Dittrich M, Thelen M. Anthracycline-induced cardiotoxicity: cardiac MRI
after treatment for childhood cancer. [Article in German]. Rofo. 2004;176:1245–1250.
[45] Stoodley PW, Richards DA, Meikle SR, et al. The potential role of echocardiographic strain imaging
for evaluating cardiotoxicity due to cancer therapy. Heart Lung Circ. 2011;20:3–9.
[46] Stoodley PW, Richards DAB, Hui R, Boyd A, Harnett PR, Meikle SR. Two-dimensional myocardial
strain imaging detects changes in left ventricular systolic function immediately after anthracycline
chemotherapy. Eur J Echocardiogr. 2011;12:945–952.
[47] Constine LS, Schwartz RG, Savage DE, et al. Cardiac function, perfusion, and morbidity in irradiated
long-term survivors of Hodgkin’s disease. Int J Radiat Oncol Biol Phys. 1997;39:897–906.

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Pediatric Hematology and Oncology, 31:237–252, 2014

Copyright C Informa Healthcare USA, Inc.

Are cardiac Magnetic Resonance Imaging and

in Childhood Cancer Survivors?

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

Received 16 July 2013; accepted 1 October 2013.

anthracycline induced subclinical chronic cardiotoxicity in children with cancer. We

PATIENTS AND METHODS

Pediatric Hematology and Oncology

Standard 12-lead electrocardiogram was performed. All recordings were obtained

ventricular systolic and diastolic function was evaluated by M mode, pulsed-wave

images were evaluated by visual analysis as normal, hypokinetic (decreased LV wall

Pediatric Hematology and Oncology

TABLE 1 Parameters of MRI Technique∗

TABLE 2 Left Ventricular Segmentation

Segment 14 Apical septal

TABLE 3 Characteristics of Treatment Protocols of Study Group

Pediatric Hematology and Oncology

Mean EF values obtained by evaluation of systolic function by MRI were 64.8% ±

TABLE 5 Evaluation of EF Values of Patient Groups Classified According to Cumulative

normal echocardiographic findings. In our study, QT interval was significantly longer

Pediatric Hematology and Oncology

enables the cardiac pool to be visualized by a gamma-camera. It is a perfect tool

Pediatric Hematology and Oncology

diographic evaluations. More research is needed in order to establish reference ranges

Limitations of the Study

Pediatric Hematology and Oncology

possibilities and implications. Arch Dis Child. 1996;75:416–422.

Pediatric Hematology and Oncology

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