A retrospective evaluation was performed on survivors of childhood cancer treated with anthracyclines at the Pediatric Hematology-Oncology Unit of the S.Orsola-Malpighi Clinic. All children were evaluated with standard echocardiography and Tissue Doppler Imaging (TDI) using iE 33 xMatrixs Echo system (Philips, Eindhoven, The Netherlands). The results were compared with those obtained from a population of healthy age-matched and sex-matched controls.
The patients cohort includes 50 children (32 males, 18 females), mean age of 11,7 (±4,7 SD) years, with mean body surface area (BSA) of 1,35 (±0,32 SD) m2. They were treated for leukemia (n = 31), lymphoma (n = 15), and other solid tumors (n = 4), with a median cumulative dose of 219,6 (range 83–780) mg/m2 of anthracyclines. The mean age at the start of chemotherapy was (7,7 ± 4,7 SD) years, with a median follow-up period of 24 months (4–127 months) after the anthracycline treatment was completed. Among these, 14 children (8 male, 6 females) underwent haematopoietic stem cell transplantation and 11 children received mediastinal irradiation (7 males, 4 females). The control population includes 50 subjects (30 males, 20 females) with a mean age of 11,5 (± 5,4 SD) years and mean body surface area of 1,31 (±0,39 SD).
The cumulative doses of anthracyclines were converted into Doxorubicin (DOX) equivalents, using conversion factors of 0,83 (Daunorubicin), 5,0 (Idarubicin) and 4,0 (Mitoxantrone) [5].
An expert pediatric cardiologist and a trained pediatrician performed the transthoracic echocardiographies. All measurements were performed on 3 consecutive cardiac cycles. The pediatric cardiologist reviewed all the images acquired. The analysis included standard left ventricle chamber measurements (two-dimensional M-mode), blood flow velocity through the mitral valve (pulsed-wave doppler) and tissue peak velocities for the interventricular septum and left ventricle parietal wall (pulsed-wave TDI).
The variables measured on 2D M-mode ultrasonography were: interventricular septum thickness in diastole (IVSd) and systole (IVSs), left ventricle end-diastolic diameter (LVEDD or LVIDd), left ventricle end-systolic diameter (LVESD or LVIDs), left ventricle posterior wall in diastole (LVPWd) and systole (LVPWs). Shortening fraction (SF) and ejection fraction (EF) were calculated from M-mode measurements of LV dimensions at the level of mitral valve leaflet using parasternal long axis view. The EF was considered normal when ≥55% and mildly abnormal between 54 and 45% [6]. LVFS was considered normal when ≥28%. LVEF and LVSF are good surrogate measure of systolic performance, while ventricular (LVIDd/LVIDs and LVPWd/LVPWs) and septal (IVSd and IVSs) dimensions were used to monitor the impact of the treatment on the ventricular structure [5]. Z-scores were calculated for M-mode parameters (IVSs, LVIDs, LVIDd, LVPWd). Despite susceptible of both inter- and intra-rater variability, these measures are easily reproducible, can be monitored over time and was found to be reliable in pediatric patients [7].
Pulsed-wave Doppler was used to evaluate the diastolic function: mitral inflow wave velocity in the early diastole (E) and in the late diastole (A), left ventricle isovolumic relaxation time (IVRT) and E deceleration time (DT) were measured. Sample volume was placed between the leaflets of the mitral valve. The Diastolic function was considered normal when E/A ratio ranged between 0.9 and 1.5, abnormal with delayed relaxation pattern if E/A ratio < 0.9 and with restrictive pattern if E/A ratio > 2. Pulsed-wave Tissue Doppler Imaging (TDI) was used to add information on both systolic and diastolic performance. The apical four chamber view was used to assess peak myocardial velocities of the LV during systole (S′), early diastole (E’) and late diastole (A’). E’/A’ index and E/E’ index were calculated. The sample volume was placed at the basal and median segments of the interventricular septum (IVSb, IVSm) and left ventricular posterior wall (LVPWb, LVPWm). We did not include the evaluation of LV apical segments because myocardial velocities decreases toward the apex of the heart, resulting in unreliable and less significant measurements in this segment [8]. The same measurements were recorded from the lateral segment of the mitral annulus to evaluate the mitral annular displacement (MAD), as suggested from the American Society of Echocardiography [9] (Fig. 1). We chose to evaluate these three segments to detect potential regional wall motion abnormalities [10].
The patient’s cohort was divided into sub-groups according to risk factors for anthracycline cardiomyopathy [1, 4]: A) Total cumulative dose of anthracyclines the patients’ cohort was divided into 3 subgroups according to the literature [11]: 1)low-risk: < 150 mg/m2; 2)medium-risk: 150–300 mg/m2; 3)high-risk: > 300 mg/m2. We compared the low-risk class with patients at medium- and high-risk, and the high-risk class with patients at low- and medium-risk. B) Gender C) Medistinic Irradiation D) Haematopoietic stem cell transplantation (HSCT): the results obtained from the children who underwent HSCT at the Pediatric Hematology-Oncology Unit of the S.Orsola-Malpighi Clinic were compared with those who didn’t receive such procedure during their therapy. E) Oncologic diagnosis. F) Follow-up duration at the time of the evaluation: we compared the patients evaluated within 12 months after the end of therapy with those evaluated after 12 months after the end of therapy. The same comparison was carried out using also a 24 months cut-off.
Analysis of variance was used to assess differences in the mean value of the normally distributed variables between groups, while the Student Test was used for within-group post-hoc analysis. A p value < 0.05 was considered to be statistically significant.
The statistically significant measurements of the case-control analysis were analyzed by linear regression analysis; multivariate analysis was also performed to determine the influence of the risk factors on each parameters. The independent variables considered were 1) time from end of therapy to TDI evaluation, 2) time from diagnosis to TDI evaluation, 3) gender, 4) BSA (body surface area), 5) anthracycline equivalent dose, 6) Hematopoietic Stem Cell Transplantation procedure, 7) Tumor Type. A p value < 0.05 was considered to be statistically significant. The clinical and echocardiographic data between the two groups were compared by the independent-samples t-test. All data were expressed as mean ± standard deviation. A two-tailed P-value < 0.05 was considered statistically significant. Statistical analysis was performed using STATA 7.0.