Radiol Oncol 2020; 54(4): 470-479. doi: 10.2478/raon-2020-0050 470 research article Breast size and dose to cardiac substructures in adjuvant three-dimensional conformal radiotherapy compared to tangential intensity modulated radiotherapy Ivica Ratosa1,2, Aljasa Jenko1, Zeljko Sljivic1,3, Maja Pirnat4, Irena Oblak1,2 1 Department of Radiotherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Faculty of Health Sciences, University of Ljubljana, Ljubljana, Slovenia 4 Department of Radiology, University Medical Centre Maribor, Maribor, Slovenia Radiol Oncol 2020; 54(4): 470-479. Received 18 March 2020 Accepted 10 May 2020 Correspondence to: Assist. Ivica Ratoša, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška cesta 2, SI-1000 Ljubljana, Slovenia. E-mail: iratosa@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Background. The aim of the study was to quantify planned doses to the heart and specific cardiac substructures in free-breathing adjuvant three-dimensional radiation therapy (3D-CRT) and tangential intensity modulated radio- therapy (t-IMRT) for left-sided node-negative breast cancer, and to assess the differences in planned doses to organs at risk according to patients’ individual anatomy, including breast volume. Patients and methods. In the study, the whole heart and cardiac substructures were delineated for 60 patients using cardiac atlas. For each patient, 3D-CRT and t-IMRT plans were generated. The prescribed dose was 42.72 Gy in 16 fractions. Patients were divided into groups with small, medium, and large clinical target volume (CTV). Calculated dose distributions were compared amongst the two techniques and the three different groups of CTV. Results. Mean absorbed dose to the whole heart (MWHD) (1.9 vs. 2.1 Gy, P < 0.005), left anterior descending coro- nary artery mean dose (8.2 vs. 8.4 Gy, P < 0.005) and left ventricle (LV) mean dose (3.0 vs. 3.2, P < 0.005) were all significantly lower with 3D-CRT technique compared to t-IMRT. Apical (8.5 vs. 9.0, P < 0.005) and anterior LV walls (5.0 vs. 5.4 Gy, P < 0.005) received the highest mean dose (Dmean). MWHD and LV-Dmean increased with increasing CTV size regardless of the technique. Low MWHD values (< 2.5 Gy) were achieved in 44 (73.3%) and 41 (68.3%) patients for 3D-CRT and t-IMRT techniques, correspondingly. Conclusions. Our study confirms a considerable range of the planned doses within the heart for adjuvant 3D-CRT or t-IMRT in node-negative breast cancer. We observed differences in heart dosimetric metrics between the three groups of CTV size, regardless of the radiotherapy planning technique. Key words: breast cancer; breast size; 3D-CRT; IMRT; heart dose; left anterior descending coronary artery Introduction Cardiovascular diseases are becoming the most critical competing mortality risk in women with early breast cancer treated with present-day ra- diotherapy (RT).1,2 The relative risk of radiation- induced heart failure increases with rising cardiac radiation exposure, typically reported as mean ab- sorbed dose to the whole heart (MWHD).3-5 MWHD values reflect local radiation therapy practices, and with the help of modern RT approaches, now ranging from 1.7–5.4 Gy6-8 and 1.22–1.65 Gy9, for mean and median values, respectively. However, even very low cardiac exposure does not eliminate the risk of radiotherapy-mediated cardiotoxicity, which has been demonstrated in recent studies.3,5,10 Radiol Oncol 2020; 54(4): 470-479. Ratosa I et al. / Dose to cardiac substructures in breast cancer adjuvant radiotherapy 471 In many recent publications, authors favor the use of intensity modulated techniques over three- dimensional conformal radiotherapy (3D-CRT) in node negative breast cancer adjuvant RT, argu- ing for lower MWHD, decreased skin toxicity and more homogeneous dose distribution in the target volume.11-13 Besides the RT technique used, MWHD depends on the position of the patient’s heart rela- tive to the irradiated breast and the shape of their chest wall.14 Different simple anatomical measures were evaluated to predict increased MWHD and subsequently for the need to use one of the heart- sparing techniques, namely deep inspiration breath hold technique (DIBH). Useful anatomical meas- ures are increased chest wall separation (CWS)9, maximum heart distance (the distance between the anterior cardiac contour crossing over the posterior edge of the tangential fields)15, multidimensional assessment of the presence of the heart in contact with the chest wall14 and linear heart contact dis- tance from the left sternal to the beginning of the lung parenchyma edges at the 4th costal arch in the axial axis.16 It has also been shown that the shape and size of the clinical target volume (CTV) result in increased mean and/or maximum point heart doses.9,17,18 If a cohort of breast cancer patients with similar breast volume is defined, specific problems and resolutions can be proposed, because breast contours according to breast size and shape may be associated with the variations in the target vol- ume coverage and calculated dose to organs at risk.19 Three-dimensional treatment planning al- lows target volume to be measured and CTVs of ≤ 500–975 cm3, 975–1.600 cm3 and ≥ 1.600 cm3 have been typically, but not consistently, defined as small, medium and large breasts, respectively.20,21 Additionally, quite a few clinical studies have re- ported a comparison of the clinical adverse events in regard to the three groups of breast sizes.22 Although observed average MWHD in a popu- lation of breast cancer survivors is low, smaller fragments of the heart might have received doses exceeding 25–40 Gy.4,10,23,24 Subclinical cardiac dysfunction was observed early after adjuvant ra- diotherapy for breast cancer with molecular bio- markers25,26, radionuclide myocardial perfusion imaging27–29, echocardiography30–32, and functional magnetic resonance imaging.31 Limited data exist regarding the range of doses received by individu- al heart substructures with adjuvant free-breathing 3D-CRT or tangential intensity modulated radio- therapy (t-IMRT) for left-sided breast cancer. It has been shown that MWHD does not necessarily cor- relate to mean radiation doses, absorbed by cardiac chambers or coronary arteries in adjuvant breast cancer radiotherapy.33–36 Lately, detailed studies of the specific cardiac structures’ absorbed radiation dose in thoracic radiation therapy24,36,37, and the ef- forts to understand the specific radiation dose-vol- ume effects in the heart have emerged. 4,38–41 With expanding knowledge in this field, German Society of Radiation Oncology (DEGRO) recommends new stringent dose constraints for the heart and its substructures: MWHD < 2.5 Gy, left ventricle (LV) Dmean < 3 Gy (LV mean dose), LV V5 < 17% (volume of LV receiving ≤ 5 Gy), LV V23 < 5% (volume of LV receiving ≤ 23 Gy), left anterior descending coro- nary (LADCA) Dmean < 10 Gy (LADCA mean dose), LADCA V30 < 2% (volume of LADCA receiving ≤ 30 Gy), and LADCA V40 < 1% (volume of LADCA receiving ≤ 40 Gy).42 To standardize the reporting of cardiac imag- ing regardless of diagnostic modality, both The American Society of Echocardiography and the European Association of Cardiovascular Imaging recommend using a segmentation model of the LV to assess regional LV function.42,44 The LV segmen- tation model reflects coronary arteries’ territories and permits to compare echocardiography with other imaging modalities.43 Five main LV seg- ments, defined in a cardiac atlas by Duane et al.24 are based on a previously described 17-segmenta- tion model.44 In this work, we hypothesized that in the set- ting of the node-negative left-sided breast cancer adjuvant radiotherapy, the lowest median MWHD and doses to the cardiac substructures would be achieved with the t-IMRT, compared to 3D-CRT. In addition, we assumed that individual patient characteristics, which include chest wall separation and breast volume, would contribute to the differ- ences in absorbed doses to the heart and cardiac substructures, regardless of the treatment plan- ning technique. To test our hypothesis, we aimed to quantify doses to the heart and cardiac sub- structures in present-day free-breathing adjuvant 3D-CRT and t-IMRT and to analyze the differences in dosimetric metrics to organs at risk between three different groups of CTV according to breast size and other individual anatomical information. Patients and methods Patient selection and CT simulation The study was approved by the ethics review board committee (approval number KME 78/07/15). Based on the size of the CTV, we randomly selected Radiol Oncol 2020; 54(4): 470-479. Ratosa I et al. / Dose to cardiac substructures in breast cancer adjuvant radiotherapy472 patients with early left-sided node-negative breast cancer. The definitions of the small, medium, and large breast volumes were like those made avail- able elsewhere.22 The patients were referred to ad- juvant radiotherapy between the years 2014 and 2015. All patients underwent a free-breathing non- enhanced simulation computed tomography (CT) scan with a 3 mm slice thickness. The treatment position for all women was supine, on an inclined simulation table using a breast board, with both arms positioned above the head. Delineation, treatment planning, and data collection Whole heart, LV with its anterior, apical, inferior, lateral, and septal walls, right ventricle (RV), left atrium (LA), right atrium (RA), LADCA with proxi- mal, middle and distal segments, right coronary ar- tery (RCA), left circumflex coronary artery (LCX), and left main coronary artery (LMCA) were de- lineated by one radiation oncologist. We followed identification of the individual structure segments by the instructions proposed by Duane et al.24 in a recently published heart atlas. We used a 6 mm di- ameter for all coronary arteries’ segments, as previ- ously proposed.23 The thickness of the LV wall was set to 10 mm. An experienced cardiac radiologist reviewed the contoured cardiac segments. We de- lineated CTV to include total glandular breast tis- sue according to published guidelines.45 Planning target volume (PTV) was generated by adding a 5 mm uniform margin to the CTV, and the planning target volume for evaluation (PTVeval) was created similarly, with a modification that excludes 5 mm below the skin surface. Additionally, we collected anatomically based distance metrics, such as chest wall separation (CWS) and a previously described “4th arch” metric.16 We used Monaco (Elekta AB®, Stockholm, Sweden) as a contouring and treatment planning platform. The prescribed dose was 42.72 Gy in 16 fractions, 5 days per week. For the 3D-CRT treat- ment planning, we used 6MV photon tangential beam arrangement with wedge filters and addition- al 6MV or 15MV small beams in tangential or non- tangential beam direction where needed to achieve a homogeneous dose distribution. The “Collapsed Cone” algorithm was used to calculate the dose. For t-IMRT plans we used the same isocenter posi- tion as with 3D-CRT planning and two tangential 6 MV photon beams positioned in the same direction as for 3D-CRT plans. The plans were calculated us- ing inverse dose optimization with “Monte-Carlo” algorithm. Dynamic Multileaf Collimator (dMLC) technique was used with minimum segment size 1 cm and 30 control points, which generated 25–30 segments per beam. Although “the dose-to-water” reporting is typically used in clinical routine for the inverse optimization treatment plans and since “Collapsed Cone” algorithm does not have that option for calculation, we used “the dose-to-medi- um” reporting in our study for both 3D-CRT and t- IMRT planning in order to improve treatment plan comparability. In the planning optimization procedure, we used institutional target goals for both treatment plans (Table 1). Dose constraints for the specific cardiac substructures were not incorporated into the optimization process but we strived to keep the dose to the whole heart as low as possible without compromising the target coverage for both tech- niques. Each plan was thoroughly evaluated for target coverage and OAR. We reported nominal median absolute doses, without EQD2 (equivalent dose in 2 Gy per fraction) conversion. All treatment plans were created by one dosimetrist and one medical physicist. Statistical analyses Calculated dose distributions were compared amongst the two techniques and the three different groups of CTV. Due to mostly non-parametrically distributed data, dose distributions data between the groups were compared using the Kruskal- Wallis and Mann-Whitney tests. Friedman ANOVA and Wilcoxon signed-rank test were also used to compare values between the two techniques. All TABLE 1. Target goals used in the planning process Structure Target goals PTV D2% < 108% PTVeval V95% > 95% Whole Body Contour Global Dmax < V110% Heart Dmean < 3.2 Gy V17 Gy < 10% V35 Gy < 5% Ipsilateral Lung Dmean < 10 Gy V17 Gy < 25% V26 Gy < 20% Bilateral lung Dmean < 3.2 Gy Dmax = maximum dose; Dmean = mean dose; Dx % = absorbed dose, received by x % of the PTV; PTV = planning target volume; PTVeval = planning target volume for evaluation; Vx % = fractional volume, receiving x % of the prescribed dose; Vx Gy = fractional volume receiving x Gy Radiol Oncol 2020; 54(4): 470-479. Ratosa I et al. / Dose to cardiac substructures in breast cancer adjuvant radiotherapy 473 numbers are presented as median values with a range. Statistical analyses were performed with IBM® SPSS® version 24.0 (SPSS Inc., Armonk: NY, IBM corporation). We considered a p-value ≤ 0.05 as statistically significant. Results Patient population and treatment plans Sixty patients with left-sided breast cancer were included in this analysis, divided into groups of small (N = 22, 36.6%), medium (N = 21, 35.0%) and large (N = 17, 28.4%) CTV size. Target volumes’ and OAR’s metrics are presented in Table 2. There was a statistically significant difference between the three groups for all measured target volumes, OAR volumes, and anatomically based simple distance metrics. Regarding target cover- age, all except two dosimetric parameters (PTVeval V107%, PTVeval D2%), were superior in the 3D-CRT group (Tables 3 and 4). Nevertheless, the t-IM- RT approach resulted in lower high-dose areas (PTVeval V105%) across all three CTV groups. Whole heart For the whole group of evaluated patients, 3D-CRT technique showed significant lower MWHD com- pared to t-IMRT (Table 5) with an absolute differ- ence of 0.2 Gy. Absolute difference in MWHD between the two techniques ranged from 0.06, 0.46 and 0.7 for the groups of medium-, large- and small-sized CTVs, respectively (Table 6). CTV size had an impact on MWHD regardless of the RT technique, while oth- er parameters were not statistically different except for heart-V5 Gy in 3D-CRT technique. In 3D-CRT, MWHD correlated with increased CWS relative to 18.0 cm (0.09 Gy/1 cm, p = 0.0022) and with CTV size (0.06 Gy/100 cm3, p = 0.0015). Low MWHD values (< 2.5 Gy) were achieved in 44 (73.3%) and 41 (68.3%) patients for 3D-CRT and t-IMRT tech- niques, correspondingly (Figure 1). Heart chambers Selected dose-volume parameters for the LV are presented in Table 5 and 6. For the whole group, 3D-CRT showed lower dosimetric metrics for the TABLE 2. Target volumes’ and organs at risk’s metrics Target volume/ Organ at risk The whole group N = 60 Small CTV N = 22 Medium CTV N = 21 Large CTV N = 17 p value CTV [cm3] 800.6 (124.8–2970.9) 425.7 (124.8–545.5) 867.0 (652.1–1295.1) 1586.8 (1348.9–2970.9) 0.021 PTVeval [cm3] 990.7 (233.5–3336.1) 583.0 (233.5–711.1) 1035.9 (834.3–1576.5) 1874.3 (1605.8–3336.1) < 0.005 PTV [cm3] 1163.3 (340.1–3792.2) 730.7 (340.1–856.6) 1212.3 (985.1–1805) 2134.8 (1826.4–3792.2) < 0.005 CWS [cm] 23.1 (17.9–33.2) 19.5 (17.9–23.2) 24.0 (19.9–28.5) 27.5 (22.9–33.2) < 0.005 4th arch metrics [cm] 4.4 (0–11.6) 1.6 (0–9.6) 5.5 (0–11.6) 7.1 (0–10.7) 0.008 Heart [cm3] 677.7 (432.9–1192.7) 625.2 (432.9–912.8) 671.1 (563.5–872.4) 817.9 (620.1–1192.7) < 0.005 Left Ventricle [cm3] 173.8 (116–277.4) 161.3 (116–251.7) 173.8 (120.8–229.8) 188.7 (147.4–277.4) 0.018 Left Lung [cm3] 1245.1 (809.3–2127.9) 1458.9 (824.5–2127.9) 1123.8 (944.2–1619.2) 1230.6 (809.3–1541.7) 0.003 Right Lung [cm3] 1563.4 (855–2560.1) 1721.9 (992.9–2560.1) 1466.4 (855.1–1838.2) 1493.2 (1089.6–1925.6) 0.002 Lungs [cm3] 2879.7 (1504.6–4789.2) 3241.3 (1877.5–4789.2) 2634.4 (1504.6–3513.6) 2799.8 (1960.2–3479.2) 0.001 CTV = clinical target volume; CWS = chest wall separation distance at isocenter; PTV = planning target volume; PTVeval = planning target volume for evaluation TABLE 3. Target volume dosimetric metrics Target volume 3D-CRT t-IMRT p value PTVeval D98% [Gy] 40.6 (39.8–41.4) 40.3 (38.7–41.6) 0.002 PTVeval D2% [Gy] 44.7 (44.4–45.5) 43.8 (43.8–47.1) NS PTVeval D50% [Gy] 43.3 (42.7–43.7) 42.9 (42.2–43.9) < 0.005 PTVeval V95% [%] 98.1 (95.3–99.6) 96.8 (79.9–99.9) 0.001 PTVeval V105% [%] 1.3 (0.1–10.3) 4.3 (0.01–85.9) < 0.005 PTVeval V105% [cm3] 11.7 (0.08–656.7) 5.4 (0.06–68.0) 0.014 PTVeval V107% [%] 0 (0–1.4) 0.1 (0–9.6) < 0.005 PTVeval V107% [cm3] 0 (0–321.4) 0 (0–7.2) NS PTVeval V110% [%] 0 (0–0) 0 (0–0) NS Dmax [Gy] 45.7 (45.1–46.9) 46.9 (45.3–51) < 0.005 3D-CRT = three-dimensional conformal radiotherapy; D2% = near maximum dose, D50% = median dose; D98% = near minumum dose, Dmax = maximal absorbed dose, NS = not significant; PTVeval = planning target volume for evaluation; t-IMRT = tangential intensity modulated radiation therapy; Vx% = fractional volume, receiving x % of the prescribed dose Radiol Oncol 2020; 54(4): 470-479. Ratosa I et al. / Dose to cardiac substructures in breast cancer adjuvant radiotherapy474 LV contour, except for LV apical-Dmean and LV-V23 Gy. The lowest Dmean values of the dosimetric met- rics for LV, including anterior, lateral, septal, and inferior LV wall, were obtained in the small CTV group, regardless of treatment technique. In 3D-CRT, apical and anterior LV walls received the highest Dmean (Table 5), while lateral, septal, and inferior regions, received 1.9, 1.6, and only 0.6 Gy, respectively. The Dmean of RV, RA, and LA were 1.41 Gy (range, 0.5–4.8), 0.5 Gy (0.3–1.2), and 0.6 Gy (0.4–1.5), respectively and were not statistically sig- nificantly different among different groups of the CTV size. Likewise, with IMRT, apical and anterior LV walls received similarly high mean radiation doses. The Dmean varied from 8.5 Gy (range, 1.64– 22.16), 5.4 Gy (1.94–19.18), 2.33 Gy (1.18–7.59), 2.18 Gy (1.01–4.46), and 1.11 Gy (0.77–1.98) for apical, anterior, lateral, septal and inferior LV walls, corre- spondingly. Seventeen-segmental LV models, rep- resented as a Bull’s eye diagram, with respective Dmean dose distributions, are presented in Figure 2. Low LV-Dmean ( < 3 Gy), LV-V5 (< 17%), and LV-V23 (< 5%) values were achieved in 51.6%, 88.3%, and 73.3% of treatment plans in 3D-CRT and in 41.6%, 88.3%, and 85.0% of treatment plans in t-IMRT, re- spectively. Coronary arteries Planned median Dmean values for LADCA and its segments are presented in Table 5. Median mean doses to other coronary arteries, namely RCA, LCX, and LMCA were 0.7 Gy (range, 0.3–4.7), 0.7 Gy (0.3–2.0), and 0.8 Gy (0.5–2.0), in the 3D-CRT group and 1.14 Gy (0.77–1.86), 1.10 Gy (0.79–2.18) and 1.31 Gy (0.96–2.17) in the t-IMRT group, re- spectively. For the entire group, only parameter LADCA-V30 Gy was found to be lower with t-IMRT compared to 3D-CRT technique, but the reduction TABLE 4. Target volume dosimetric metrics and CTV size Target volume Small CTV Medium CTV Large CTV p value (S vs. M vs. L) 3D-CRT PTVeval V95% [%] 97.7 (95.3–99.6) 98.3 (96.2–99.5) 98.8 (97.5–99.4) 0.022 (S vs. M, S vs. L) t-IMRT PTVeval V95% [%] 97.9 (96.3–99.2) 97.3 (95.3–99.0) 96.8 (79.9–99.9) NS p value (3D-CRT vs. T-IMRT) NS p = 0.003 p = 0.013 3D-CRT PTVeval V105% [cm3] 8.1 (0.5–17.5) 12.5 (0.08–91.3) 87.3 (9.5–656.6) < 0.005 (S vs. M, S vs. L, M vs. L) t-IMRT PTVeval V105% [cm3] 7.4 (0.1–61.5) 5.9 (0.09–54) 4.2 (0.06–68.2) NS p value (3D-CRT vs. T-IMRT) NS NS p = 0.012 3D-CRT = three-dimensional conformal radiotherapy; L = large; M = medium; NS = not significant; PTVeval = planning target volume for evaluation; S = small; t-IMRT = tangential intensity modulated radiation therapy; Vx% = fractional volume, receiving x % of the prescribed dose TABLE 5. Radiotherapy technique and selected dose-volume parameters for the whole heart and selected cardiac substructures Parameter 3D-CRT t-IMRT p value* MWHD [Gy] 1.90 (0.61–4.14) 2.13 (1.06–4.4) < 0.005 LV-Dmean [Gy] 2.98 (0.78–8.03) 3.22 (1.31–7.25) < 0.005 LV-V5 Gy [%] 8.67 (0–26.3) 9.21 (0–26.02) 0.455 LV-V23 Gy [%] 2.46 (0–14.32) 1.86 (0–10.58) 0.003 LV anterior-Dmean [Gy] 5.00 (1.27–20.17) 5.42 (1.94–19.18) < 0.005 LV apical-Dmean [Gy] 8.97 (1.22–24.89) 8.47 (1.64–22.16) < 0.005 LADCA-Dmean [Gy] 8.20 (1.23–27.92) 8.39 (1.8–27.62) < 0.005 LADCA-V30 Gy [%] 5.39 (0–66.34) 2.01 (0–84.20) < 0.005 LADCA-V40 Gy [%] 0 (0–37.8) 0 (0–43.09) < 0.005 LADCA-prox-Dmean [Gy] 2.17 (0.62–8.68) 2.66 (1.22–12.43) < 0.005 LADCA-mid-Dmean [Gy] 9.63 (1.67–40.07) 11.05 (2.26–39.63) 0.956 LADCA-dist-Dmean [Gy] 13.73 (1.44–41.11) 15.93 (2.03–3.89) 0.132 *Wilcoxon signed-rank test; 3D-CRT = three-dimensional conformal radiotherapy; dist = distal; Dmean = mean dose; Gy = Gray; LADCA = left anterior descending artery; LV = left ventricle; mid = middle; MWHD = whole heart mean dose; prox = proximal; t-IMRT = tangential intensity modulated radiation therapy; Vx Gy = fractional volume receiving x Gy 19 3 18 4 15 6 16 5 10 7 7 10 < 2.5 Gy .5 Gy < 2.5 Gy .5 Gy 3D-CRT t-IMRT 0 2 4 6 8 10 12 14 16 18 20 Small CTV Medium CTV Large CTV FIGURE 1. Mean whole heart dose and number of plans within each CTV groups, concerning optimal mean dose value. 3D-CRT = three-dimensional conformal radiotherapy; CTV = clinical target volume; Gy = Gray; t-IMRT = tangential intensity modulated radiation therapy Radiol Oncol 2020; 54(4): 470-479. Ratosa I et al. / Dose to cardiac substructures in breast cancer adjuvant radiotherapy 475 was seen only in the medium and large CTV-size groups. Compared to t-IMRT, 3D-CRT technique showed advantages in terms of lower planned Dmean values of proximal, middle and distal LADCA segments (Table 5). However, dose to the proximal LADCA segment increased with the CTV size, regardless of the planning method. The highest Dmean values of the middle and distal LADCA segments were achieved in patients with the medium or large tar- get volumes. Low LADCA-Dmean (< 10 Gy), LADCA-V30 Gy (< 2%), and LADCA-V30 Gy (< 1%) values were achieved in 55.0%, 48.3%, and 71.6% of treatment plans in 3D-CRT and in 56.6%, 51.6%, and 86.6% of treatment plans in t-IMRT, respectively. Figure 2 represents Bull’s eye diagrams of the LV and seg- ment models of the coronary arteries with reported median Dmean distributions for 3D-CRT technique. Discussion By tradition and its contouring pragmatism, MWHD is the most frequently reported surrogate for the assessment of the potential subsequent car- diotoxic effects after radiation therapy for breast cancer. In the present study, we aimed to compare doses to the individual cardiac structures in the circumstances that represent everyday practice in free-breathing node-negative left-sided breast can- cer adjuvant 3D-CRT or t-IMRT. Herein, we report reasonably low median MWHD values achieved with both techniques, 1.9 Gy with 3D-CRT and 2.1 Gy with t-IMRT. In the contemporary series, measured mean or median MWHD values in free- breathing node-negative left-sided breast cancer adjuvant RT are in the range of 2.6–3.6 Gy for 3D-CRT6,33,35,36 and 1.8–4.8 for the intensity modu- lated techniques.11,46,47 In both evalu ated techniques, we observed statistically significant differences between the groups of small, medium, and large CTV sizes for the following dose-volume parameters: MWHD, mean doses for proximal LADCA segment, ante- rior, lateral, inferior, and septal LV walls. In me- dium and large-sized CTV, we observed reduction of LADCA-Dmean with t-IMRT technique, which was not statistically different. Our results are con- sistent with previously published studies showing increased CWS, relative to 22 cm, to be one of the predictors for a higher MWHD, in both normo- and hypofractionation.9 Other studies have also demonstrated the correlation between the calcu- lated heart dose and increasing breast size, espe- cially when PTV exceeds 1500 cm3.17,18 Compared to small-sized CTV, MWHD increased with medium- and large- sized CTVs in our study, although the absolute differences between the groups were rela- tively small, ranging from 0.73 Gy and 0.97 Gy for the t-IMRT and 3D-CRT, respectively. Our results imply that patients’ anatomy, including CWS and/ or CTV/PTV volume, should be also considered when choosing the appropriate radiotherapy tech- nique (3D-CRT vs. modulated approaches), patient setup (prone or lateral vs. supine), and breathing adaptation techniques. As previously mentioned, breast size grouping could be useful in this context, helping to tailor whole breast irradiation.19 FIGURE 2. Bull’s eye diagrams of the left ventricle and segment models of the coronary arteries with reported median Dmean distributions in three-dimensional conformal radiotherapy plans, divided in groups according to clinical target volume size. Contouring segments of left ventricle consisted of anterior (segments 1 and 7), apical (segments 13–17), inferior (segments 4 and 10), lateral (segments 5, 6, 11, 12) and septal regions (segments 2, 3, 8, 9). CTV = clinical target volume; Gy = Gray; LADCA = left anterior descending artery; LCX = left circumflex artery; LMCA = left main coronary artery; RCA = right coronary artery Radiol Oncol 2020; 54(4): 470-479. Ratosa I et al. / Dose to cardiac substructures in breast cancer adjuvant radiotherapy476 Despite the low MWHD for the whole group, our study confirms that apical and anterior parts of LV and mid or distal LADCA segments in both 3D-CRT and t-IMRT techniques receive dispropor- tionately higher Dmean radiation doses. Likewise, in the study by Tang et al., segments corresponding to anterior and apical LV wall absorbed the high- est doses, 9.2 Gy and 14.9 Gy, respectively. Patients were treated with tangential breast RT, with or without regional nodal irradiation and with or without DIBH.36 Corresponding values in our study were lower in both evaluated techniques, 3D-CRT vs. t-IMRT for anterior and apical LV walls were 5.0 vs. 5.4 Gy and 8.5 vs. 8.9 Gy, respectively. Lower numbers might reflect a difference in con- toured thickness of the LV wall, 6-9 mm in the study of Tang et al. compared to 10 mm used in our study, as suggested by Duane et al.24 In our work, the LADCA-Dmean was 8.2 Gy (range, 1.2–27.9) in 3D-CRT and 8.4 Gy (range, 1.8– 27.6) in t-IMRT, respectively. Drost et al. in their systematic review of heart doses reported vary- ing dose-volume measurements for the LADCA. The LADCA-Dmean ranged from 1.9–40.8 Gy (aver- age 12.4 Gy)6, which is similar to our data. In our series of treatment plans, we have demonstrated the highest Dmean for the middle LADCA segment in the group of women with medium-sized CTVs (17.9 Gy) but was not significantly different com- pared to the smallest or the largest CTV groups. With t-IMRT, it was possible to lower LADCA high-dose areas (V30 Gy), but not low-dose areas or mean doses to the coronary arteries. Carosi et al. observed no difference in MWHD when t-IM- RT was compared to 3D-CRT (2.0 vs. 1.9 Gy) in 24 patients with a median breast volume of 645 cm3. TABLE 6. Breast size and selected dose-volume parameters for the whole heart and cardiac substructures Parameter Small CTV Medium CTV Large CTV p value 3D-CRT t-IMRT 3D-CRT t-IMRT 3D-CRT t-IMRT MWHD [Gy] 1.29 (0.61–3.75) 1.99 (1.06–3.98) 2.05 (1.06–3.84) 2.11 (1.62–3.54) 2.26 (1.04–4.14) 2.72 (1.46–4.4) < 0.005*; 0.047† Heart-V5 Gy [%] 2.56 (0.02–10.84) 3.77 (0.1–11.01) 4.99 (0.59–10.87) 4.34 (1.19–9.58) 5.29 (0–12.81) 6.19 (0.04–12.83) 0.043* Heart-V10 Gy [%] 1.28 (0–7.91) 2.01 (0–7.59) 2.71 (0.01–7.73) 2.24 (0.12–68.14) 3.09 (0–8.24) 3.17 (0–8.54) NS Heart-V17 Gy [%] 0.76 (0–6.61) 1.22 (0–6.08) 2.03 (0–6.52) 1.36 (0–4.79) 2.37 (0–6.92) 3.36 (0–6.42) NS Heart-V20 Gy [%] 0.62 (0–6.22) 1 (0–5.63) 1.83 (0–6.16) 1.17 (0–4.38) 2.15 (0–6.51) 2.01 (0–5.81) NS Heart-V35 Gy [%] 0.15 (0–4.12) 0.2 (0–3.4) 0.93 (0–4.15) 0.31 (0–2.3) 1.06 (0–4.32) 0.63 (0–2.91) NS Heart-V40 Gy [%] 0.02 (0–1.41) 0.01 (0–1.65) 0.24 (0–1.45) 0.03 (0–0.42) 0.03 (0–1.93) 0.04 (0–1.69) NS LV-Dmean [Gy] 2.3 (0.7–5.7) 2.9 (1.31–5.84) 3.2 (1.1–6.9) 3.15 (1.78–5.97) 3.5 (1.3–8.0) 3.92 (1.83–7.25) 0.019* LV-V5 Gy [%] 6.8 (0–17.4) 8.27 (0–17.39) 9.7 (0–22.0) 8.47 (0.46–19.87) 10.8 (0–26.3) 12 (0–26.02) 0.052* LV-V23 Gy [%] 1.4 (0–9.5) 1.73 (0–8.47) 2.8 (0–12.0) 1.81 (0–8.18) 3.3 (0–14.3) 3.1 (0–10.58) NS LV anterior-Dmean [Gy] 3.6 (1.2–12.8) 4.86 (1.94–12.35) 6.8 (2.0–15.9) 5.71 (2.69–14.48) 6.8 (1.9–20.1) 6.94 (2.58–19.18) 0.017* LV lateral-Dmean [Gy] 1.6 (0.7–2.8) 2.16 (1.18–3.38) 1.8 (0.9–6.3) 2.24 (1.55–5.12) 2.5 (1.2–8.7) 2.98 (1.73–7.59) < 0.001*, < 0.001† LV inferior-Dmean [Gy] 0.5 (0.3–3.3) 0.96 (0.77–1.17) 0.6 (0.5–0.9) 1.07 (0.9–1.32) 0.8 (0.6–2.0) 1.33 (0.96–1.98) < 0.005*, < 0.005† LV septal-Dmean [Gy] 1.2 (0.4–3.4) 1.8 (1.01–3.71) 1.6 (1.1–3.4) 2.19 (1.77–3.74) 1.9 (1.2–3.9) 2.56 (1.72–4.46) < 0.005*, < 0.005† LV apical-Dmean [Gy] 6.9 (1.2–19.6) 8.54 (1.64–19.79) 9.0 (1.7–21.9) 8.42 (2.46–19.68) 9.5 (1.2–24.8) 8.91 (1.76–22.16) NS LADCA-Dmean [Gy] 5.2 (1.2–27.9) 6.84 (1.8–27.62) 13.8 (2.6–25.2) 10.76 (3.01–20.73) 11.1 (2.2–21.2) 8.24 (2.84–21.22) NS LADCA-V30 Gy [%] 0.2 (0–66.3) 0.36 (0–63.48) 17.8 (0–59.0) 7.39 (0–84.2) 8.9 (0–43.3) 2.13 (0–46.34) NS LADCA-V40 Gy [%] 0 (0–37.8) 0 (0–43.09) 0.5 (0–32.9) 0 (0–3.22) 0 (0–19.2) 0 (0–7.26) NS LADCA-prox-Dmean [Gy] 1.6 (0.6–8.6) 2.22 (1.22–7.95) 2.9 (0.6–7.2) 2.96 (1.96–5.19) 2.5 (1.4–7.2) 2.84 (2.07–12.43) < 0.001*, 0.002† LADCA-mid-Dmean [Gy] 7.9 (1.6–40.0) 9.12 (2.26–39.63) 17.9 (2.0–38.7) 13.81 (4.22–30.95) 10.4 (2.5–29.8) 11.14 (3.23–36.01) NS LADCA-dist-Dmean [Gy] 5.5 (1.4–41.1) 8.58 (2.03–40.65) 26.9 (3.5–39.4) 17.46 (3.98–35.39) 14.0 (2.4–39.7) 16.32 (2.87–34.95) NS *intergroup comparison within 3D-CRT technique, using Kruskal-Wallis test; † intergroup comparison within t-IMRT technique using Kruskal-Wallis test; 3D-CRT = three-dimensional conformal radiotherapy; CTV = clinical target volume; Dmean = mean dose; dist = distal; Gy = Gray; LADCA = left anterior descending artery; LV = left ventricle; mid = middle; MWHD = whole heart mean dose; NS = not significant; prox = proximal; t-IMRT = tangential intensity modulated radiation therapy; Vx Gy = fractional volume receiving x Gy Radiol Oncol 2020; 54(4): 470-479. Ratosa I et al. / Dose to cardiac substructures in breast cancer adjuvant radiotherapy 477 However, the authors showed a statistically mean- ingful difference in LADCA Dmean (10.3 vs. 11.9 Gy, p=0.0003), LADCA-Dmax and LADCA-V17 Gy pa- rameters using t-IMRT compared to 3D-CRT.48 There are many possible explanations for the dissimilar reported heart and heart substructures’ absorbed doses in free-breathing left-breast only RT. The differences may arise from the discrep- ancy in the total dose prescription and the size of the radiation field, CTV definition and size, OAR contouring, including diameter of the coronary ar- teries and LV thickness, the lack of detailed heart contouring atlases, individual coronary topology, heart size, body mass index, CWS distance, and finally radiotherapy technique used.9,33,49–52 The use of contrast agent53 or automatic substructures’ segmentation without54 or with cardiac magnetic resonance imaging55 could improve contouring consistency, but these technical solutions are un- likely to be widely adopted in the near future. Non-automatic contouring is feasible as showed in a study by Francolini et al. Authors made multiple comparisons of delineated cardiac chambers and 5 left LV wall segments according to aforementioned cardiac atlas24 and confirmed high interobserver delineation consistency.56 Spatial variation in contouring has been shown to result in less than 1 Gy dose variation for most segments and in most regimens in adjuvant breast cancer RT, but higher dose variations up to 21.8 Gy were seen for segments close to the radiation field edge.24 Substantial variation in the estimated dose was observed for LADCA, regardless of which par- ticular delineation guidelines were used.57 Except for proximal LADCA (2.6 Gy vs. 2.5 Gy), absorbed mean Dmean values of LADCA segments and LV were lower in our study compared to the partially wide tangential technique used in Duane and co- workers’ research; 15.1 Gy vs. 25.1 Gy for middle LADCA segment, 17.6 Gy vs. 35.8 Gy for distal LADCA segment, and 3.2 vs. 6.7 Gy for LV. In the study of Wennstig et al., three radiation oncolo- gists, using the heart atlas of Feng et al., achieved substantial spatial agreement in delineating coro- nary arteries on 32 CT study sets. The agreement was the highest for LMCA and LADCA, and less for RCA.23,58 In our study, the coronary vessel di- ameter was set to 6 mm considering both cardiac and respiratory motion, similar to Wennstig and colleagues’ work.23 Based on recent clinical reports, the DEGRO group proposed stringent dose constraints for the heart and its substructures in adjuvant breast can- cer radiation treatment.42 We surpassed at least one of the proposed optimal dose constraints for LV (Dmean < 3 Gy, V5 < 17%, and V23 < 5%) or LADCA (Dmean < 10 Gy, V30 < 2%, and V40 < 1%) in 11.7–51.7% of all evaluated plans. In our plan optimization process, we did not use specific dose-volume con- straints for cardiac substructures. However, it has been shown that additional LADCA or LV con- straints in breast cancer adjuvant 3D-CRT or IMRT treatment planning might help to optimize heart dosimetric metrics further.23,59 In our study, the evaluation of the planned dose to the heart and specific cardiac substructures was performed in a free-breathing simulation CT scan and in the supine position. Ideally, the dose to car- diac substructures should also be evaluated for pa- tients treated using alternative treatment positions (lateral decubitus or prone) or with DIBH. Due to various reasons, most patients are still treated in the conventional free-breathing supine position, whereas prone positioning or DIBH is in the best- case scenario offered to only 28–83% of breast can- cer patients.15,60 All delineations were performed on a non-enhanced CT scan, an approach that may impact the visibility of the small cardiac segments. Additional drawback of our study is not including patients receiving peri-clavicular regional nodal irradiation with or without internal mammary lymph chain irradiation. Strengths of this study include careful contouring of individual cardiac substructures and using a cardiac atlas based on individual anatomy. An experienced cardiac radi- ologist thoroughly evaluated the contours. Conclusions This is the first study to evaluate the cardiac con- touring atlas for radiotherapy by Duane et al.24 si- multaneously considering different CTV size. We confirmed that regardless of very low Dmean val- ues for the whole heart achieved using a 3D-CRT or t-IMRT free-breathing adjuvant RT technique for breast cancer, a small volume of the heart may receive disproportionate Dmean or Dmax values ex- ceeding 40 Gy. We observed differences in heart dosimetric metrics between the small, medium, and large CTV sizes for both evaluated techniques, which may disappear with DIBH technique. With t-IMRT technique, only few dosimetric metrics were improved compared to 3D-CRT. The ob- served results in our study suggest that anatomic differences, especially breast volume and CWS, should be considered in clinical practice as well as in the dosimetric studies of various treatment plan- Radiol Oncol 2020; 54(4): 470-479. Ratosa I et al. / Dose to cardiac substructures in breast cancer adjuvant radiotherapy478 ning techniques. Subdividing breast target volume into similar cohorts could be helpful in this context and further research is warranted. The quantifica- tion of the radiation dose variability of individual cardiac substructures is an important first step to understand the unique cardiac structures’ dose- volume predictors for cardiotoxicity in adjuvant, free-breathing breast cancer radiation therapy. In the future, reported absorbed doses may be paired with cardiac imaging and help to choose patients for whom more intense cardiac function monitor- ing is warranted. 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