Radiol Oncol 2018; 52(2): 204-212. doi: 10.2478/raon-2018-0011 204 research article Early cardiotoxicity after adjuvant concomitant treatment with radiotherapy and trastuzumab in patients with breast cancer Tanja Marinko1, Simona Borstnar2, Rok Blagus3, Jure Dolenc4, Cvetka Bilban-Jakopin1 1 Department of Radiation Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 3 Department of Cardiology, University Medical Centre Ljubljana, Ljubljana, Slovenia 4 Institute for biostatistics and medical informatics, University of Ljubljana, Slovenia Radiol Oncol 2018; 52(2): 204-212. Received 4 December 2017 Accepted 12 December 2017 Correspondence to: Assist. Tanja Marinko, M.D., Ph.D., Department of Radiation Oncology, Institute of Oncology Ljubljana; Zaloška 2, 1000 Ljubljana, Slovenia. Phone: +386 1 5879 550; Fax: +386 1 5879 400; Email: tmarinko@onko-i.si Disclosure: No potential conflicts of interest were disclosed Background. The purpose of the study was to find out whether there is a difference in the early parameters of cardio- toxicity (left ventricular ejection fraction [LVEF] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]) between the two groups of patients: the patients treated for left breast cancer (left breast cancer group) and those treated for the right breast cancer (right breast cancer group), after the treatment had been completed. Patients and methods. The study included 175 consecutive patients with human epidermal growth factor recep- tor-2 (HER2) positive early breast cancer, treated concurrently with trastuzumab and radiotherapy (RT), between June 2005 and December 2010. Echocardiography with LVEF measurement was performed before adjuvant RT (LVEF0) and after the completed treatment (LVEF1). After the treatment NT-proBNP measurement was done as well. The difference (Δ) between LVEF0 and LVEF1 was analysed (Δ LVEF = LVEF0 - LVEF1) and compared between the two groups. Results. There were 84 patients in the left and 91 in the right breast cancer group. Median observation time was 57 (37–71) months. Mean Δ LVEF (%) was -1.786% in the left and -2.607% in the right breast cancer group (p = 0.562, CI: -2.004 to 3.648). Median NT-proBNP were 111.0 ng/l in the left and 90.0 ng/l in the right breast cancer group (p = 0.545). Echocardiography showed that the patients in the left breast cancer group did not have significantly worse systolic and diastolic left ventricular function in comparison with the patients in the right breast cancer group, but, they had higher incidence of pericardial effusion (9 [11%] vs. 1 [1%]) (p = 0.007). Conclusions. We did not find any significant differences in the early parameters of cardiotoxicity (LVEF, NT-proBNP) between the observed groups. Patients who received left breast/chest wall irradiation had higher incidence of peri- cardial effusion. Key words: trastuzumab; breast cancer; Radiotherapy; cardiotoxicity; echocardiography Introduction The advent of trastuzumab, a humanized mono- clonal antibody against the extracellular domain of human epidermal growth factor receptor-2 (HER2), represented a major breakthrough in the treatment of patients with HER2-positive breast cancer. Long term follow-up from the initial large adjuvant tri- als with trastuzumab continue to show some re- markably positive results.1 The current standard adjuvant systemic treatment of early HER2-positive breast cancer consists of chemotherapy (CT) plus 12 months of trastuzumab, with or without endo- crine therapy.2-4 The patients treated with adjuvant radiotherapy (RT) of the breast or chest wall receive trastuzumab concurrently with RT. Treatment with Radiol Oncol 2018; 52(2): 204-212. Marinko T et al. / Cardiotoxicity after adjuvant treatment in breast cancer patients 205 trastuzumab results in a small to modest cardiotox- icity risk.5-7 RT could be cardiotoxic as well.8-10 Long- term effects of concomitant treatment with trastu- zumab and RT have not yet been known, the most important of which is the issue of cardiotoxicity. Reduced left ventricular ejection fraction (LVEF) and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels represent early param- eters of cardiotoxicity. LVEF is the golden standard for monitoring cardiac function in patients receiv- ing cardiotoxic therapy.11 Trastuzumab-related cardiotoxicity is most often manifested by an asymptomatic decrease in LVEF, and less often by clinical heart failure.12-14 NT-proBNP represents a sensitive biomarker for both: systolic and diastolic heart failure, not just as a diagnostic tool, but also as a prognostic tool.15 Elevated levels can be detect- ed early in the asymptomatic stage of the disease, or in patients with the preserved ejection fraction.16 Changes in NT-proBNP usually occur earlier than changes in LVEF.17 There are two widely used methods for meas- uring LVEF: radionuclide ventriculography and echocardiography. The first method provides solely the information regarding the LVEF, while the second one provides also the information con- cerning chamber dimensions, heart valves, and pericardium. This data is very important because a reduction in LVEF is not that sensitive and it occurs later than left ventricular diastolic dysfunction. Some patients with heart failure never develop ventricular systolic dysfunction (heart failure with preserved ejection fraction).17-19 The main purpose of this study was to find out whether there is a significant difference in the ear- ly parameters of cardiotoxicity between the two groups of patients: those who received adjuvant trastuzumab and concurrent postoperative RT to the left (left breast cancer group) or to the right (right breast cancer group) breast/chest wall, after the completed treatment. The study was designed as an equivalence study. Our hypothesis was that there were no significant differences between the left breast cancer and the right breast cancer group regarding some early car- diotoxicity parameters (LVEF and NT-proBNP). Materials and methods Patients and treatment In a prospective observational monocentric popu- lation study, we included 175 consecutive patients with HER2-positive breast cancer (stage I-III) with- out disease recurrence, who received adjuvant treatment with trastuzumab and RT to the breast/ chest wall between June 2005 and December 2010 at the Institute of Oncology in Ljubljana. All patients were treated according to the clini- cal guidelines, namely with surgery, CT, endocrine therapy in case of hormone receptor positive dis- ease, trastuzumab, and RT. Trastuzumab treat- ment started before RT or on the first day of RT at the latest. Altogether, 203 consecutive patients with HER2-positive breast cancer were invited to participate in the study, among them 28 patients refused to be involved in the study. Informed con- sent was obtained from all individual participants included in the study. The study was internation- ally registered at ClinicalTrial.gov (identifier NCT 01572883), and it was approved by the Republic of Slovenia National Medical Ethics Committee. In the study framework, between December 2011 and July 2012, after the treatment with trastu- zumab had been completed, we performed clinical examinations, echocardiographic measurements of LVEF, and measurements of NT-proBNP levels in all patients. Baseline LVEF was determined either by means of echocardiography or by radionuclide ventriculography. Before the clinical examination took place patients had fulfilled the question- naires about smoking, concomitant diseases, and problems related to cardio-vascular diseases. All other data were collected from the patients’ re- cords. Patients were classified in New York Heart Association (NYHA) classes, according to the NYHA classification, as well as in World Health Organisation (WHO) performance classes, accord- ing to the WHO classification. Systemic treatment The criteria for the adjuvant treatment with tras- tuzumab regarding tumour, nodal stage and car- diac function were the same as in pivotal adjuvant trials: tumours larger than 2 cm if node negative disease, any tumour size if node positive disease, WHO performance status zero or one, no serious concomitant cardiac disease, and treatment with adjuvant CT.4 Loco regional treatment According to clinical guidelines patients were op- erated with either breast conservation surgery or mastectomy and either sentinel node biopsy or ax- illary dissection. After the operation and CT they were irradiated on the Cobalt machine or on the Radiol Oncol 2018; 52(2): 204-212. Marinko T et al. / Cardiotoxicity after adjuvant treatment in breast cancer patients206 linear accelerator. Two-dimensional RT (2D RT) or three-dimensional conformal RT (3D CRT) were mostly used. Some of the patients received electron- beam chest wall irradiation, sometimes in combi- nation with concomitant photon-beam irradiation of the periclavicular region (regional RT). Whole breast RT was required in all patients who under- went breast cancer surgery. In addition to the irra- diation of the breast/thoracic wall all patients with 4 or more positive axillary lymph nodes also received regional RT. Parasternal lymph nodes were not spe- cifically included in the irradiated area. Patients were irradiated with a total dose (TD) = 25 x 2 Gy, 5 fractions per week. A minority received RT with TD = 17 or 18 x 2.5 Gy, 5 fractions per week. RT was performed 3 or more weeks after CT had been completed and concurrently with trastu- zumab treatment as well as hormonal therapy in case of hormone receptor positive breast cancer. Echocardiography and radionuclide ventriculography At the beginning of the primary systemic therapy baseline echocardiography was performed at dif- ferent clinical institutions according to the short- est waiting time for the examination. Contrary to this, all control echocardiographies were performed in one institution (Department of Cardiology, University Medical Centre Ljubljana) by three cardiologists, and they were carried out on the same device (Aloka SSD-α10, Tokyo, Japan). Conventional and tissue-Doppler echocardiogra- phy was performed on each patient.20,21 Normal range for LVEF was 50% or more. All radionuclide ventriculographs were per- formed at the Institute of Oncology in Ljubljana (Gamma Cam Siemens; erythrocytes were la- belled with in vivo method, activity 740-952 MBq) Normal range for LVEF was 50% or more. LVEF was calculated with the programme Intermedical/ Medicview. NT-proBNP NT-proBNP was determined with the analyser Cobas e 411 (Roche). According to the instructions of the manufacturer, the values of the NT-proBNP below 125 ng/l exclude heart dysfunction. Pathology methods HER2 immuno histochemistry (IHC) expression was scored as follows: 0, no staining or faint mem- brane staining in ≤ 10% of tumour cells; 1+, incom- plete membrane staining that is faint perceptible in >10% of tumour cells,; 2+, incomplete and/or weak to moderate membrane staining in >10% of tumour cells or complete and intense staging in ≤ 10% of tumour cells; and 3+, complete, intense circumfer- ential membrane staining in >10% of tumour cells. HER2 scores of 0 and 1+ were considered negative. All IHC2+ tumours were tested for gene amplifi- cation by fluorescent in situ hybridization (FISH). HER2 IHC 3+ and FISH-amplified tumours were considered positive. Statistical methods The study was designed as an equivalence study. For the purpose of the analysis the patients were divided into two groups: (1) left breast cancer group: patients irradiated on the left side of the chest (breast cancer of the left breast) and (2) right breast cancer group: patients irradiated on the right side of the chest (breast cancer of the right breast). In both group we compared the difference be- tween LVEF, measured at the beginning of the adju- vant systemic therapy (LVEF0), and LVEF measured after the treatment with trastuzumab (LVEF1) had been completed. The difference between the two measurements was marked as Δ LVEF = LVEF0 - LVEF1, and we made comparisons between the two groups. A 95% confidence interval for the difference of means (CI) was estimated. Groups were labelled as equivalent if 95 % CI did not include Δ LVEF of 10 percentage points, but it included the value 0. In calculating the necessary sample size we as- sumed that there were no differences in the popu- lation between the investigated groups, and that the standard deviation of the difference of Δ LVEF would be 10 percentage points. The level of signifi- cance was set to 5% and the desired power to at least 80%. We considered the difference Δ LVEF of 10 percentage points or less as clinically irrelevant. The calculation using PASS (version 12) showed that under these assumptions the equivalence study enrolling 20 patients per group would have 86% power. In addition to the primary objective we, namely, wanted to analyse also echocardio- graphic parameters at the control examination af- ter the completed treatment with trastuzumab and RT. The data is presented as mean (standard devia- tion, SD) or median (interquartile range Q1–Q3) for continuous variables as appropriate, and number (%) for categorical variables. The difference between the groups (the left breast cancer group and the right breast cancer Radiol Oncol 2018; 52(2): 204-212. Marinko T et al. / Cardiotoxicity after adjuvant treatment in breast cancer patients 207 group) for continuous variables was tested with t-test, Welsch t-test, or Mann-Whitney test as appropriate. The assumption of normality was verified with Shapiro-Wilks test, and Bartlett test was used to test the assumption of variance equality. The association between the two groups (left breast cancer and right breast cancer group) and categorical variables was tested with χ2 test, as well as with Yates continuity correction of Fischer exact test as appropriate. A p-value of less than 0.05 was considered as statistically significant. The analysis was per- formed with R language for statistical computing (R version 3.0.1.).22 Results Patient characteristics There were 84 patients (48%) in the left breast can- cer group, and 91 patients (52%) in the right breast cancer group. Median age was 59 (52–67) years in the left breast cancer group, and 55 (46–63) years in the right breast cancer group (p = 0.009). Median observation time was 57 (37–71) months. Patients and tumour characteristics as well as the associated diseases are described in Table 1. Among all the pa- tients, 35 of them (20%) had arterial hypertension, but there were no significant differences between the two groups. Local and systemic treatments All patients received CT. Among all of them 95 patients (54.3% of all the patients) received one of the following CT schemes: doxorubicin, cyclo- phosphamide (AC) / epirubicin, cyclophospha- mide (EC) / 5-FU, doxorubicin, cyclophosphamide (FAC) / 5-FU, epirubicin, and cyclophosphamide (FEC) with a sequence of taxanes, and 69 patients (39.4% of all the patients) received one of the fol- lowing schemes: AC / EC / FAC / FEC without taxanes. Only 11 patients (6.3% of all the patients) did not receive any anthracyclines (6 patients in the left breast cancer group and 5 patients in the right breast cancer group). None of the patients received concomitant anthracyclines and trastuzumab. There were no significant differences found in the CT schemes used, hormone therapies, and in the mean received cumulative doses of anthracyclines, taxanes, cyclophosphamide, and trastuzumab be- tween the two groups. Systemic treatment is de- scribed in detail in Table 2. Among all the patients, 39 patients (79.4% of all the patients) were treated with 2D RT technique, and 25 patients (14.3%) with 3D CRT technique. RT treatment features are presented in Table 3. TABLE 1. Patients and tumour characteristics, concomitant diseases All N = 175 (100%) Left BC group N = 84 (48%) Right BC group N = 91 (52%) p value Age in years (Median [Q1–Q3]) 58 (49–64) 59 (52–67) 55 (46–63) 0.0096 Menopause status Premenopause Pomenopause 90 (51.4%) 85 (48.5%) 38 (45.2%) 46 (54.8%) 52 (57.1%) 39 (42.9%) 0.155 Histological type Ductal invasive Lobular invasive Other 168 (96%) 4 (2.3%) 3 (1.7%) 81 (96.4%) 2 (2.4%) 1 (1.2%) 87 (95.6%) 2 (2.2%) 2 (2.2%) 1 Histo-pathological grade G 1 G 2 G 3 2 (1.1%) 48 (27.4%) 125 (71.5%) 0 21 (25%) 63 (75%) 2 (2.2%) 27 (29.7%) 62 (68.1%) 0.337 Hormonal receptors ER positive PR positive ER in PR negative 97 (55.4%) 82 (46.8%) 73 (41.7%) 53 (63%) 43 (51.2%) 28 (33.3%) 44 (48.3%) 39 (42.8%) 45 (49.4%) 0.851 Concomitant disease Smoking 33 (19%) 13 (15%) 20 (22%) 0.365 Arterial hypertension 35 (20%) 21 (25%) 14 (15.4%) 0.161 Diabetes 3 (1.7%) 3 (3.4%) 0 0.108 Hyperlipidemia 30 (17.1%) 16 (19%) 14 (15.4%) 0,658 Known heart disease* 4 (2.3%) 1 (1.2%) 3 (3.3%) 0.621 BC = breast cancer; ER = estrogens receptor; PR = progesterone receptor; Q1–Q3 = quartiles * All diseases had been already present at diagnosis of breast cancer. Group 1: mild aortic stenosis; Group 2: mitral valve prolapse; compensated hypertonic heart and symptomatic angina pectoris; undefined cardiomyopathy Radiol Oncol 2018; 52(2): 204-212. Marinko T et al. / Cardiotoxicity after adjuvant treatment in breast cancer patients208 Early cardiotoxicity parameters (LVEF and NT-proBNP) The analysis showed no statistically significant dif- ferences between initial and control LVEF in the observed groups. Data is presented in detail in Table 4. The time between the introduction of trastu- zumab and the beginning of RT, the time between LVEF0 measurement and the time beetween LVEF0 and LVEF1 did not differ between the observed groups (p = 0.596, 0.506 and 0.089, respectively). Overall, we found an important reduction of the LVEF (a decrease of LVEF for 10 percent points or TABLE 2. Systemic treatment and surgical characteristics All (N = 175) (%) Left BC Group (N = 84) (%) Right BC Group (N = 91) (%) P value Anthracyclines Cumulative dose- mg/m2 BSA (Median [Q1–Q3]) 350 (292–499) 352 (295–497) 349 (290–499) 0.799 Taxanes Cumulative dose- mg/m2 BSA (Median [Q1–Q3]) 297 (276–594) 297 (281–422) 298 (273–768) 0.783 Cyclophosphamide Cumulative dose- mg/m2 BSA (Median [Q1–Q3]) 2316 (1758–2924) 2344 (1763–2992) 2268 (1758–2829) 0.482 CT Scheme AC/EC/FAC/FEC + taxanes AC/EC/FAC/FEC without taxanes Other 95 (54.3%) 69 (39.4%) 11 (6.3%) 40 (47.6%) 38 (45.3%) 6 (7.1%) 55 (60.4%) 31 (34.1%) 5 (5.5%) 0.235 Endocrine therapy Tamoxifen Aromatase inhibitor Other 39 (22.3%) 45 (25.7%) 10 (5.7%) 21 (25%) 26 (30.9%) 7 (8.3%) 18 (19.8%) 19 (20.8%) 3 (3.3%) 0.652 Trastuzumab Cumulative dose- mg/kg BSA (Median [Q1–Q3]) 105 (97–114) 105 (97–116) 105 (97–112) 0.658 Type of surgery Mastectomy Breast conserving surgery 91 (52%) 84 (48%) 38 (45.2%) 46 (54.8) 53 (58.2%) 38 (41.8%) 0.116 AC = doxorubicin, cyclophosphamide; BC = breast cancer; BSA = body surface area (The Du Bois formula was used for the calculation); CT = chemotherapy; EC = epirubicin, cyclophosphamide; FAC = 5-FU, doxorubicin, cyclophosphamide; FEC = 5-FU, epirubicin, and cyclophosphamide; Q1–Q3 = quartiles TABLE 3. Radiotherapy treatment features All (N = 175) (%) Left BC group (N = 84) (%) Right BC group (N = 91) (%) p value RT field* Breast Breast + scl Thoracic wall Thoracic wall + scl 70 (40%) 17 (9.7%) 17 (9.7%) 71 (40.6%) 38 (45.3%) 9 (10.7%) 8 (9.5%) 29 (34.5%) 32 (35.2%) 8 (8.8%) 9 (9.9%) 42 (46.1%) 0.434 RT technique 2D RT 3D CRT Electrons +/- photons 139 (79.4%) 25 (14.3%) 11 (6.3%) 69 (82.1%) 12 (14.3%) 3 (3.6%) 70 (76.9%) 13 (14.3%) 8 (8.8%) 0.256 RT scheme 25 x 2 Gy 17 or 18 x 2.5 Gy 14 (84.6%) 27 (15.4%) 73 (86.9%) 11 (13.1%) 75 (82.4%) 16 (17.6%) 0.540 BC = breast cancer; RT = radiotherapy; scl = periclavicular nodes; 2D RT = two-dimensional radiotherapy; 3D CRT = three-dimensional conformal radiotherapy * parasternal lymph nodes were not included in the irradiated area Radiol Oncol 2018; 52(2): 204-212. Marinko T et al. / Cardiotoxicity after adjuvant treatment in breast cancer patients 209 more or a final value of LVEF < 50) in 9 patients (6%) (4 patients in the left breast cancer and 5 in the right breast cancer group), of which 8 patients were classified as NYHA class 1. Median NT-proBNP, measured after the com- pleted treatment with trastuzumab, was 111.0 (56.7–182) ng/l in the left breast cancer group, and 90.0 (58-170) ng/l in the right breast cancer group (p = 0.545) Echocardiographic parameters Echocardiographic parameters are presented in Table 5. A comparison of echocardiographic pa- rameters showed that the patients who received RT to the left breast/thoracic wall did not have sig- nificantly worse systolic or diastolic left ventricular function. We found significantly more pericardial effu- sions (9 [11%]) in the left breast cancer group than in the right breast cancer group (1 [1%]) (p = 0.007). The thickness of pericardial effusion was > 1cm in 1 patient in the left breast cancer group, all others were < 1 cm. Discussion Thanks to treatment with trastuzumab, patients with HER2 positive breast cancer nowadays live longer than ever. In the framework of the oncologi- cal treatment they received a very successful ther- apy that in many cases prevents cancer recurrence, but could also have an impact on their health and therefore on the quality of their life a few or many years after the treatment. It is very important to an- alyse such sequels of a treatment, especially if they could be successfully treated at the very beginning, and if the exacerbation could be stopped before it affects the quality of life. Concomitant treatment with trastuzumab and RT has been a part of a standard adjuvant treat- ment of HER2 positive breast cancer at our insti- tution since 2005, which means from the very be- ginning of the “adjuvant trastuzumab era”. In that time 2D RT technique was used at our institution for breast cancer patients, and most patients from our study were irradiated with this technique. Later more accurate 3D CRT technique was availa- ble for adjuvant RT in breast cancer patients. None TABLE 4. Analysis of the difference in left ventricular ejection fractions (Δ LVEF) All (N = 175) Left BC Group (N = 84) Right BC Group (N = 91) P value LVEF0 (%) (Median [Q1–Q3]) 65 (60–69) 65 (61–70) 63 (59.5–67) 0.0208 LVEF1 (%) (Median [Q1–Q3]) 66 (62–70) 67 (64–70) 65 (60–70.5) 0.117 Analysis of Δ LVEF LVEF0 (%)-LVEF1(%) = Δ LVEF (Mean [SD]) (n = 149) -2.22 (8.69) (n = 70) -1.78 (7.85) (n = 79) -2.60 (9.4) 0.562 95% CI: -2.004 – 3.648 BC = breast cancer; CI = confidental interval; LVEF0 = measurement of LVEF before RT; LVEF1- measurement of LVEF after the adjuvant treatment with T; Q1–Q3 = quartiles; SD = standard deviation TABLE 5. Echocardiografic parameters (n = 175) Left BC Group (n = 84) (median [Q1–Q3]) Right BC Group (n = 91) (median [Q1–Q3]) p value LV EDD (cm) 4.6 (4.4–4.9) 4.6 (4.4–4.8) 0.91395% CI (-0.10- 0.10) LV ESD (cm) 2.9 (2.6–3.1) 2.8 (2.5–3.2) 0.541 95% CI (-0.19–0.10) LA tr (cm) 3.4 (3.2–3.8) 3.4 (3.2–3.7) 0.83095% CI (-0.10–0.10) LA long (cm) 4.4 (4.0–4.8) 4.5 (4.2–4.6) 0.97995% CI (-0.10–0.10) RA tr (cm) 3.2 (3.0–3.6) 3.4 (3.0–3.7) 0.298 95% CI (-0.20–0.00) RA long (cm) 4.1 (3.8–4.4) 4.3 (3.9–4.4) 0.226 95% CI (-0.20–0.09) LVEF (%) 68.5 (64–74.2) 68.0 (63.0–72.5) 0.758 95% CI (-2.0–3.00) E/A 1.07 (0.80–1.23) 1.08 (0.87–1.32) 0.11395% CI (-0.18–0.02) E/Em 7.15 (6.27–9.26) 7.40 (6.18–8.68) 0.918 95% CI (-0.52–0.66) s/d 1.368 (1.065–1.600) 1.149 (0.94–1.35) 0.002 95% CI ( 0.07–0.29) TDI Sm (cm/s) 8.0 (7.0–9.1) 8.0 (7.0–9.1) 0.98595% CI (-0.50–0.50) TDI Em (cm/s) 10.0 (7.82–11.37) 10.0 (8.05–11.8) 0.547 95% CI (-0.10–0.50) CI = confidental interval; E/A = mitral valve annulus ratio of early diastolic and atrial flow velocities; E/Em = ratio between the early diastolic blood flow velocitiy on the mitral valve annulus and early diastolic tissue Doppler velocity at the mitral ring; LA long – left atrial longitudinal diameter; LA tr = left atrial transversal diameter; LV EDD = left ventricular end diastolic diameter; LVEF = left ventricular ejection fraction; LV ESD = left ventricular end systolic diameter; Q1–Q3 = quartiles; RA long – right atrial longitudinal diameter; RA tr = right atrial transversal diameter; s/d = ratio of systolic and diastolic blood flow velocities in the pulmonary vein, TDI Sm - systolic tissue Doppler velocity at the mitral ring; TDI Em = early diastolic tissue Doppler velocity at the mitral ring Radiol Oncol 2018; 52(2): 204-212. Marinko T et al. / Cardiotoxicity after adjuvant treatment in breast cancer patients210 of the patients included in the study received RT specifically to the parasternal lymph nodes. This fact is important for the interpretation of the re- sults, because RT in that region may raise the dose received by the heart.23 All the patients included in the study were treated with CT. Only 11 patients did not receive CT with anthracyclines, which is not surprising, especially if taking into account the well-known benefits of the anthracycline treatment.24 There were no significant differences in the CT scheme used, endocrine therapy, and in the mean received cumulative doses of anthracyclines, taxanes, cy- clophosphamide, and trastuzumab between the two groups (p > 0.05). These results suggest that cardiotoxic effect of specific systemic oncological treatment was similar in both groups that were analysed. In the framework of the adjuvant treat- ment received by the patients, the only factor that could affect the difference in cardiotoxic param- eters measured in both groups was the cardiotoxic effect of the adjuvant RT. The prevalence of smoking, hyperlipidemia, and arterial hypertension was approximately the same in both groups (around 20 %). Only 3 pa- tients had diabetes, all of them had breast cancer of the right breast. Among all the patients, 4 patients had already been diagnosed with heart diseases at the time of breast cancer diagnosis (specified in Table 1). One 70-year-old patient acquired atrial fibrillation two years after being diagnosed with breast cancer, but she had had arterial hyperten- sion for 18 years already. According to this data, the influence of cardiovascular disease predispos- ing factors was similar in both groups. The differences in Δ LVEF between the two groups were not statistically significant. The ac- quired data shows that the median value of the LVEF in both groups was slightly lower at the be- ginning of the treatment in comparison with the LVEF value measured after the treatment. This could be explained by the time that passed from the introduction of trastuzumab to the measure- ment of LVEF (mean time 62 days in the left breast cancer group and 66 days in the right breast cancer group. p= 0,591). It was reported that LVEF value could reversibly decrease during treatment with trastuzumab.25 Among all the patients, we found an important reduction of the LVEF (a decrease of LVEF for 10 percent points or more or a final value of LVEF < 50) in 9 patients (6%). There were more such pa- tients in the right breast cancer group (6.3%) than in the left breast cancer group (5.7%); therefore, we concluded that left breast/chest wall irradiation was not the key factor that would significantly af- fect the reduction of LVEF. The analysis showed no statistically signifi- cant differences in NT-proBNP between the two groups. According to the instructions of the di- agnostic test manufacturer, the values of the NT- proBNP below 125 ng/l exclude heart failure, so we decided to mark all the values of NT-proBNP 125 ng/l or higher as an event. There were no sig- nificant differences in the number of such events in both groups. Among all the patients there were 69 patients (39%) with NT-proBNP 125 ng/l or more, 35 patients (41.7%) in the left breast cancer group, 34 patients (37.4%) in the right breast cancer group; p = 0.669. Based on these results we concluded that left breast/chest wall irradiation did not have a con- siderable impact on the measured values of NT- proBNP after the treatment had been completed. Certain parameters of left ventricular diastolic dysfunction, such as mitral valve E/A ratio, E/Em ratio, and pulmonary vein s/d ratio, are more sensi- tive and can be detected before the LVEF reduction. Left ventricular diastolic dysfunction therefore can represent an early sign of cardiotoxicity, and thus, since it is more timely, proves to be more effective than LVEF estimation.26,27 Among patients included in our study 42% had left ventricular diastolic dys- function, mostly mild. One patient in the left breast cancer and 5 patients in the right breast cancer group had moderate diastolic dysfunction, none of the patients had severe diastolic dysfunction. Baseline diastolic function was not determined. We found significantly lower s/d ratio in the right breast cancer group, suggesting worse diastolic function compared to the left breast cancer group. TABLE 6. Pericardial effusion ECHO All (N = 174) (%) Left BC Group (N = 83) (%) Right BC Group (N = 91) (%) p value Pericard NormalEffusion 164 (94.3%) 10 (5.7%) 74 (89%) 9 (11%) 90 (99%) 1 (1%) 0.007 BC = breast cancer; ECHO = echocardiography Radiol Oncol 2018; 52(2): 204-212. Marinko T et al. / Cardiotoxicity after adjuvant treatment in breast cancer patients 211 Since s/d ratio is largely dependent on the hemo- dynamic status it cannot be used as a sole diastolic function predictor. There were no significant dif- ferences in other left ventricular diastolic function parameters between the observed groups. That is why we presumed that RT had no significant influ- ence on the left ventricular diastolic function in the observed time interval. The analysis of echocardiographic parameters showed that patients in both groups had heart cav- ities of normal size and a normal systolic function of the left ventricle. The patients irradiated on the left breast/thoracic wall did not have significantly worse systolic or diastolic function of the left ven- tricle. The data showed that the patients with left breast cancer had significantly higher incidence of pericardial effusion after the stated observation time. It is well known that irradiation could dam- age pericardium and that acute pericarditis is the most common heart damage caused by irradiation. It is rare and most commonly develops in the first year after the RT treatment.28 In conclusion, we did not find any significant differences in the early parameters of cardiotoxic- ity (LVEF, NT-proBNP) between the two observed groups. The patients with the left breast cancer that were irradiated on the left breast/thoracic wall four and a half years after the treatment did not have significantly worse systolic or diastolic function of the left ventricle compared to the patients with the right breast cancer that were irradiated on the right breast/thoracic wall, but, left breast cancer patients had significantly higher incidence of pericardial ef- fusion. RT did not have an important impact on the function of the left ventricle after the stated obser- vation time. 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