Doses to the right coronary artery and the left anterior descending coronary artery and death from ischemic heart disease after breast cancer radiotherapy: a case-control study in a population-based cohort.

BACKGROUND AND PURPOSE: Doses to the coronary arteries in breast cancer (BC) radiotherapy (RT) have been suggested to be a risk predictor of long-term cardiac toxicity after BC treatment. We investigated the dose-risk relationships between near maximum doses (Dmax) to the right coronary artery (RCA) and left anterior descending coronary artery (LAD) and ischemic heart disease (IHD) mortality after BC RT. PATIENTS AND METHODS: In a cohort of 2,813 women diagnosed with BC between 1958 and 1992 with a follow-up of at least 10 years, we identified 134 cases of death due to IHD 10-19 years after BC diagnosis. For each case, one control was selected within the cohort matched for age at diagnosis. 3D-volume and 3D-dose reconstructions were obtained from individual RT charts. We estimated the Dmax to the RCA and the LAD and the mean heart dose (MHD). We performed conditional logistic regression analysis comparing piecewise spline transformation and simple linear modeling for best fit. RESULTS: There was a linear dose-risk relationship for both the Dmax to the RCA (odds ratio [OR]/Gray [Gy] 1.03 [1.01-1.05]) and the LAD (OR/Gy 1.04 [1.02-1.06]) in a multivariable model. For MHD there was a linear dose-risk relationship (1,14 OR/Gy [1.08-1.19]. For all relationships, simple linear modelling was superior to spline transformations. INTERPRETATION: Doses to both the RCA and LAD are independent risk predictors of long-term cardiotoxicity after RT for BC In addition to the LAD, the RCA should be regarded as an organ at risk in RT planning.

Distinguish response of low-dose radiation with different dose-rate on gene expression of human coronary artery endothelial cells: a bioinformatic study based on transcriptomic sequencing.

PURPOSE: People are exposed to low-dose radiation in medical diagnosis, occupational, or life circumstances, but the effect of low-dose radiation on human health is still controversial. The biological effects of radiation below 100 mGy are still unproven. In this study, we observed the effects of low-dose radiation (100 mGy) on gene expression in human coronary artery endothelial cells (HCAECs) and its effect on molecular signaling. MATERIALS AND METHODS: HCAECs were exposed to 100 mGy ionizing radiation at 6 mGy/h (low-dose-rate) or 288 mGy/h (high-dose-rate). After 72 h, total RNA was extracted from sham or irradiated cells for Quant-Seq 3'mRNA-Seq, and bioinformatic analyses were performed using Metascape. Gene profiling was validated using qPCR. RESULTS: Compared to the non-irradiated control group, 100 mGy of ionizing radiation at 6 mGy/h altered the expression of 194 genes involved in signaling pathways related to heart contraction, blood circulation, and cardiac myofibril assembly differentially. However, 100 mGy at 288 mGy/h altered expression of 450 genes involved in cell cycle-related signaling pathways, including cell division, nuclear division, and mitosis differentially. Additionally, gene signatures responding to low-dose radiation, including radiation dose-specific gene profiles (HIST1H2AI, RAVER1, and POTEI) and dose-rate-specific gene profiles (MYL2 for the low-dose-rate and DHRS9 and CA14 for the high-dose-rate) were also identified. CONCLUSIONS: We demonstrated that 100 mGy low-dose radiation could alter gene expression and molecular signaling pathways at the low-dose-rate and the high-dose-rate differently. Our findings provide evidence for further research on the potential impact of low-dose radiation on cardiovascular function.

Dose to the Left Anterior Descending Artery Correlates With Cardiac Events After Irradiation for Breast Cancer.

PURPOSE: Although global heart dose has been associated with late cardiac toxic effects in patients who received radiation therapy for breast cancer, data detailing the clinical significance of cardiac substructure dosimetry are limited. We investigated whether dose to the left anterior descending artery (LAD) correlates with adverse cardiac events. METHODS AND MATERIALS: We identified 375 consecutively treated female patients from 2012 to 2018 who received left-sided breast or chest wall irradiation (with or without regional nodal irradiation). Medical records were queried to identify cardiac events after radiation therapy. Mean and maximum LAD and heart doses (LAD Dmean, LAD Dmax, heart Dmean, and heart Dmax) were calculated and converted to 2-Gy equivalent doses (EQD2). Univariate and multivariable Cox regression analyses were performed to determine association with cardiac toxic effects. Potential dose thresholds for each of the 4 dose parameters were identified by receiver operating characteristic (ROC) curve analysis, after which Kaplan-Meier analysis was performed to compare cardiac event-free survival based on these constraints. RESULTS: Median follow-up time was 48 months. Thirty-six patients experienced a cardiac event, and 23 patients experienced a major cardiac event. On univariate and multivariable analyses, increased LAD Dmean, LAD Dmax, and heart Dmean were associated with increased risk of any cardiac event and a major cardiac event. ROC curve analysis identified a threshold LAD Dmean EQD2 of 2.8 Gy (area under the ROC curve, 0.69), above which the risk for any cardiac event was higher (P = .001). Similar results were seen when stratifying by LAD Dmax EQD2 of 6.7 Gy (P = .005) and heart Dmean EQD2 of 0.8 Gy (P = .01). CONCLUSIONS: Dose to the LAD correlated with adverse cardiac events in this cohort. Contouring and minimizing dose to the LAD should be considered for patients receiving radiation therapy for left-sided breast cancer.

Accelerated coronary calcium burden in breast cancer patients after radiotherapy: a comparison with age and race matched healthy women.

BACKGROUND: Radiotherapy (RT) might lead to atherosclerotic plaque buildup and coronary artery stenosis of breast cancer (BC) survivors, and coronary artery calcium (CAC) might be a sign of preclinical atherosclerosis. This study explores possible determinants affecting the acceleration of CAC burden in BC patients after adjuvant RT. METHODS: Female BC patients receiving adjuvant RT from 2002 to 2010 were included. All patients received noncontrast computed tomography (NCCT) of thorax before and after adjuvant RT. Their CAC burden was compared with healthy controls from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. The progression of the CAC burden was manifested by the increment of CAC percentiles (%CACinc). RESULTS: Ninety-four patients, including both left- and right-side BC, were enrolled in this study. From undergoing the first to second NCCT, the %CACinc in BC patients significantly increased rather than non-BC women. In addition, the %CACinc was significantly higher in left-side than right-side BC patients (p < 0.05), and significant differences in most heart outcomes were found between the two groups. Besides, the lower the mean right coronary artery (RCA) dose, the lower the risks of CAC percentiles increase ≥ 50% after adjusting the disease's laterality. CONCLUSIONS: A significantly higher accelerated CAC burden in BC patients than non-BC women represents that BC could affect accelerated CAC. A higher risk of accelerated CAC burden was found in left-side than right-side BC patients after adjuvant RT. A decrease of the mean RCA dose could reduce more than 50% of the risk of accelerated CAC burden in BC patients.

Comparative analysis of the absorbed dose in the heart and anterior descending branch of the left coronary artery (LAD) in patients with left-sided breast cancer who received radiotherapy using 3D-CRT, IMRT and VMAT techniques.

PURPOSE: The purpose of this study was to compare the absorbed dose distributions within the heart and lad in patients with left-sided breast cancer who underwent radiotherapy using 3D-CRT, IMRT and VMAT techniques. METHODS: The treatment plans of 11 patients with left-sided breast cancer were analyzed. All of the patients were irradiated in our facility with DIBH 3D-CRT. For all patients the plans in the IMRT (sliding window) and VMAT (Rapid Arc - Varian) techniques were prepared. Cumulative dose-volume histograms (DVH) were used to compare the dose distributions between the plans for each patient. Statistical analysis was carried out using the one-way ANOVA with repeated measurements and Tukey's post hoc test. RESULTS: The use of IMRT and VMAT techniques allowed for a better coverage of the PTV with 95% isodose and a more homogeneous dose distribution compared to the 3D-CRT technique. The use of dynamic technique (IMRT or VMAT) did not provide significant protection for OARs - only the dose absorbed in LAD was slightly lower. CONCLUSION: The use of 3D-CRT allows better protection of critical organs compared to other techniques, except for the dose in the lad artery which was the lowest in IMRT technique. exposure of large tissue volumes to so-called low radiation doses is undoubtedly a disadvantage of using dynamic techniques.

Cardiac-sparing radiotherapy for locally advanced non-small cell lung cancer.

BACKGROUND: We have carried out a study to determine the scope for reducing heart doses in photon beam radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC). MATERIALS AND METHODS: Baseline VMAT plans were created for 20 LA-NSCLC patients following the IDEAL-CRT isotoxic protocol, and were re-optimized after adding an objective limiting heart mean dose (MDHeart). Reductions in MDHeart achievable without breaching limits on target coverage or normal tissue irradiation were determined. The process was repeated for objectives limiting the heart volume receiving ≥ 50 Gy (VHeart-50-Gy) and left atrial wall volume receiving ≥ 63 Gy (VLAwall-63-Gy). RESULTS: Following re-optimization, mean MDHeart, VHeart-50-Gy and VLAwall-63-Gy values fell by 4.8 Gy and 2.2% and 2.4% absolute respectively. On the basis of associations observed between survival and cardiac irradiation in an independent dataset, the purposefully-achieved reduction in MDHeart is expected to lead to the largest improvement in overall survival. It also led to useful knock-on reductions in many measures of cardiac irradiation including VHeart-50-Gy and VLAwall-63-Gy, providing some insurance against survival being more strongly related to these measures than to MDHeart. The predicted hazard ratio (HR) for death corresponding to the purposefully-achieved mean reduction in MDHeart was 0.806, according to which a randomized trial would require 1140 patients to test improved survival with 0.05 significance and 80% power. In patients whose baseline MDHeart values exceeded the median value in a published series, the average MDHeart reduction was particularly large, 8.8 Gy. The corresponding predicted HR is potentially testable in trials recruiting 359 patients enriched for greater MDHeart values. CONCLUSIONS: Cardiac irradiation in RT of LA-NSCLC can be reduced substantially. Of the measures studied, reduction of MDHeart led to the greatest predicted increase in survival, and to useful knock-on reductions in other cardiac irradiation measures reported to be associated with survival. Potential improvements in survival can be trialled more efficiently in a population enriched for patients with greater baseline MDHeart levels, for whom larger reductions in heart doses can be achieved.

Deep-inspirational breath-hold (DIBH) technique in left-sided breast cancer: various aspects of clinical utility.

BACKGROUND: Studying the clinical utility of deep-inspirational breath-hold (DIBH) in left breast cancer radiotherapy (RT) was aimed at focusing on dosimetry and feasibility aspects. METHODS: In this prospective trial all enrolled patients went through planning CT in supine position under both DIBH and free breathing (FB); in whole breast irradiation (WBI) cases prone CT was also taken. In 3-dimensional conformal radiotherapy (3DCRT) plans heart, left anterior descending coronary artery (LAD), ipsilateral lung and contralateral breast doses were analyzed. The acceptance of DIBH technique as reported by the patients and the staff was analyzed; post-RT side-effects including radiation lung changes (visual scores and lung density measurements) were collected. RESULTS: Among 130 enrolled patients 26 were not suitable for the technique while in 16, heart or LAD dose constraints were not met in the DIBH plans. Among 54 and 34 patients receiving WBI and postmastectomy/nodal RT, respectively with DIBH, mean heart dose (MHD) was reduced to < 50%, the heart V25 Gy to < 20%, the LAD mean dose to < 40% and the LAD maximum dose to about 50% as compared to that under FB; the magnitude of benefit was related to the relative increase of the ipsilateral lung volume at DIBH. Nevertheless, heart and LAD dose differences (DIBH vs. FB) individually varied. Among the WBI cases at least one heart/LAD dose parameter was more favorable in the prone or in the supine FB plan in 15 and 4 cases, respectively; differences were numerically small. All DIBH patients completed the RT, inter-fraction repositioning accuracy and radiation side-effects were similar to that of other breast RT techniques. Both the patients and radiographers were satisfied with the technique. CONCLUSIONS: DIBH is an excellent heart sparing technique in breast RT, but about one-third of the patients do not benefit from that otherwise laborious procedure or benefit less than from an alternative method. TRIAL REGISTRATION: retrospectively registered under ISRCTN14360721 (February 12, 2021).

Prone position versus supine position in postoperative radiotherapy for breast cancer: A meta-analysis.

BACKGROUND: This meta-analysis evaluates the difference of sparing organs at risk (OAR) in different position (Prone position and Supine position) with different breathing patterns (Free breathing, FB/Deep inspiration breath hold, DIBH) for breast cancer patients receiving postoperative radiotherapy and provides a useful reference for clinical practice. METHOD: The relevant controlled trials of prone position versus supine position in postoperative radiotherapy for breast cancer were retrieved from the sources of PubMed, Cochrane Library, Embase, Web of Science and ClinicalTrails.gov. The principal outcome of interest was OAR doses (heart dose, left anterior descending coronary artery dose and ipsilateral lung dose) and target coverage. We mainly compared the effects of P-FB (Prone position FB) and S-FB (Supine position FB) and discussed the effects of DIBH combined with different positions on OAR dose in postoperative radiotherapy. We calculated summary standardized mean difference (SMD) and 95% confidence intervals (CI). The meta-analysis was performed using RevMan 5.4 software. RESULTS: The analysis included 751 patients from 19 observational studies. Compared with the S-FB, the P-FB can have lower heart dose, left anterior descending coronary artery (LADCA) dose, and ipsilateral lung dose (ILL) more effectively, and the difference was statistically significant (heart dose, SMD = - 0.51, 95% CI - 0.66 ∼ - 0.36, P < .00001. LADCA dose, SMD = - 0.58, 95% CI - 0.85 ∼ - 0.31, P < .0001. ILL dose, SMD = - 2.84, 95% CI - 3.2 ∼ - 2.48, P < .00001). And there was no significant difference in target coverage between the S-FB and P-FB groups (SMD = - 0.1, 95% CI - 0.57 ∼ 0.36, P = .66). Moreover, through descriptive analysis, we found that P-DIBH (Prone position DIBH) has better sparing OAR than P-FB and S-DIBH (Supine position DIBH). CONCLUSION: By this meta-analysis, compared with the S-FB we found that implementation of P-FB in postoperative radiotherapy for breast cancer can reduce irradiation of heart dose, LADCA dose and ILL dose, without compromising mean dose of target coverage. Moreover, P-DIBH might become the most promising way for breast cancer patients to undergo radiotherapy.

Variation of heart and lung radiation doses according to setup uncertainty in left breast cancer.

PURPOSE: Breast radiotherapy set-up is often uncertain. Actual dose distribution to normal tissues could be different from planned dose distribution. The objective of this study was to investigate such difference in dose distribution according to the extent of set-up error in breast radiotherapy. MATERIALS AND METHODS: A total of 50 Gy with fraction size of 2 Gy was given to 30 left breasts with different set-ups applying a deep inspiration breath holding (DIBH) or a free breathing (FB) technique. Under the assumption that errors might come from translational axes of deep or caudal directions, the isocenter was shifted from the original tangential alignment every 2.5 mm to simulate uncertainty of deep and caudal tangential set-up in DIBH and FB. Changes were evaluated for dosimetric parameters for the heart, the left ventricle (LV), the left anterior descending coronary artery (LAD), and the ipsilateral lung. RESULTS: On the original plan, mean doses of heart and ipsilateral lung were 2.0 ± 1.1 Gy and 3.7 ± 1.4 Gy in DIBH and 8.4 ± 1.3 Gy and 7.8 ± 1.5 Gy in FB, respectively. The change of dose distribution for the heart in DIBH was milder than that in FB. The deeper the tangential set-up, the worse the heart, LV, LAD, and ipsilateral lung doses, showing as much as 49.4%, 56.4%, 90.3%, and 26.1% shifts, respectively, in 5 mm DIBH setup. The caudal set-up did not show significant dose difference. In multiple comparison of DIBH, differences of mean dose occurred in all 7.5 mm deep set-ups for the heart (p = 0.025), the LV (p = 0.049), and LAD (p = 0.025) in DIBH. CONCLUSIONS: To correct set-up error over indicated limitation for deep tangential set-up in DIBH at 5 mm action level, mean heart and ipsilateral lung doses are expected to increase approximately 50% and 25%, respectively.

Mean Heart Dose Is an Inadequate Surrogate for Left Anterior Descending Coronary Artery Dose and the Risk of Major Adverse Cardiac Events in Lung Cancer Radiation Therapy.

PURPOSE: Mean heart dose (MHD) over 10 Gy and left anterior descending (LAD) coronary artery volume (V) receiving 15 Gy (V15Gy) greater than 10% can significantly increase the risk of major adverse cardiac events (MACE) in patients with non-small cell lung cancer (NSCLC). We sought to characterize the discordance between MHD and LAD dose and the association of this classification on the risk of MACE after radiation therapy. METHODS AND MATERIALS: The coefficient of determination for MHD and LAD V15Gy was calculated in this retrospective analysis of 701 patients with locally advanced NSCLC treated with radiation therapy. Four groups were defined on the basis of high or low MHD (≥10 Gy vs <10 Gy) and LAD V15Gy (≥10% vs <10%). MACE (unstable angina, heart failure, myocardial infarction, coronary revascularization, and cardiac death) cumulative incidence was estimated, and Fine and Gray regressions were performed. RESULTS: The proportion of variance in LAD V15Gy predictable from MHD was only 54.5% (R2 = 0.545). There was discordance (where MHD was high [≥10 Gy] and LAD low [V15Gy < 10%], or vice versa) in 23.1% of patients (n = 162). Two-year MACE estimates were 4.2% (MHDhigh/LADlow), 7.6% (MHDhigh/LADhigh), 1.8% (MHDlow/LADlow), and 13.0% (MHDlow/LADhigh). Adjusting for pre-existing coronary heart disease and other prognostic factors, MHDhigh/LADlow (subdistribution hazard ratio [SHR], 0.34; 95% CI, 0.13-0.93; P = .036) and MHDlow/LADlow (SHR, 0.24; 95% CI, 0.10-0.53; P < .001) were associated with a significantly reduced risk of MACE. CONCLUSIONS: MHD is insufficient to predict LAD V15Gy with confidence. When MHD and LAD V15Gy dose exposure is discordant, isolated low LAD V15Gy significantly reduces the risk of MACE in patients with locally advanced NSCLC after radiation therapy, suggesting that the validity of whole heart metrics for optimally predicting cardiac events should be reassessed.

The Importance of Radiation Dose to the Atherosclerotic Plaque in the Left Anterior Descending Coronary Artery for Radiation-Induced Cardiac Toxicity of Breast Cancer Patients?

PURPOSE: Radiation-induced acute coronary events (ACEs) may occur as a treatment-related late adverse effect of breast cancer (BC) radiation. However, the underlying mechanisms behind this radiation-induced cardiac disease remain to be determined. The objective of this study was to test the hypothesis that radiation dose to calcified atherosclerotic plaques in the left anterior descending coronary artery (LAD) is a better predictor for ACEs than radiation dose to the whole heart or left ventricle in patients with BC treated with radiation therapy. METHODS AND MATERIALS: The study cohort consisted of 910 patients with BC treated with postoperative radiation therapy after breast-conserving surgery. In total, 163 patients had an atherosclerotic plaque in the LAD. The endpoint was the occurrence of an ACE after treatment. For each individual patient, the mean heart dose, volume of the left ventricle receiving ≥5 Gy (LV-V5), mean LAD dose, and mean dose to calcified atherosclerotic plaques in the LAD, if present, were acquired based on planning computed tomography scans. Cox regression analysis was used to analyze the effects on the cumulative incidence of ACEs. RESULTS: The median follow-up time was 9.2 years (range, 0.1-14.3 years). In total, 38 patients (4.2%) developed an ACE during follow-up. For patients with an atherosclerotic plaque (n = 163), the mean dose to the atherosclerotic plaque was the strongest predictor for ACEs, even after correction for cardiovascular risk factors (hazard ratio [HR], 1.269; 95% CI, 1.090-1.477; P = .002). The LV-V5 was associated with ACEs in patients without atherosclerotic plaques in the LAD (n = 680) (HR, 1.021; 95% CI, 1.003-1.039; P = .023). CONCLUSIONS: The results of this study suggest that radiation dose to pre-existing calcified atherosclerotic plaques in the LAD is strongly associated with the development of ACEs in patients with BC.

Cardiac substructures exposure in left-sided breast cancer radiotherapy: Is the mean heart dose a reliable predictor of cardiac toxicity?

PURPOSE: This study aimed to assess radiation dose distribution to cardiac subvolumes in left-sided breast cancer radiotherapy (LBCRT) and to clarify whether the mean heart dose (MHD) reliably reflects cardiac substructures exposure. MATERIALS AND METHODS: Fifty women referred for adjuvant LBCRT were prospectively evaluated. All patients received 3D-conformal hypofractionated radiotherapy (40Gy delivered in 15 fractions of 2.67Gy±boost of 13.35Gy). Cardiac substructures were contoured using the F. Duane's cardiac atlas. Dose distribution to cardiac chambers, left main (LM), left anterior descending (LAD), left circumflex (LCx) and right coronary artery (RCA)) was assessed. Dosimetric associations were analysed. RESULTS: The mean MHD was 3.08Gy (EQD2=3.67Gy). The mean Dmean/Dmax LAD was 11.45Gy (EQD2=13.64Gy)/29.5Gy (EQD2=35.15Gy). Low doses were delivered to LM, LCx, and RCA (Dmean≤1.3Gy). The left ventricle (LV) was the most exposed cardiac chamber with Dmean/Dmax of 4.78Gy/37Gy. The strongest correlation with MHD was found for Dmean LAD (r=0.81). For every 1Gy increase in MHD, Dmean LAD rose by 3.4Gy. However, the proportion of variance in Dmean LAD predictable from MHD was moderate (R2=0.65). For all other cardiac substructures, R2 values were<0.7. CONCLUSION: Our study showed high exposure of LAD and LV in LBCRT. With poor predictive value, MHD may underestimate doses to cardiac substructures. For optimal heart sparing radiotherapy, we recommend to consider LV and LAD as separate organ at risk.

Dosimetric evaluation of left ventricle and left anterior descending artery in left breast radiotherapy.

INTRODUCTION: We evaluated the dosimetric results of the identification of the left ventricle (LV) and left anterior descending artery (LAD) as organs at risk (OARs) in adjuvant radiotherapy (RT) after breast-conserving surgery (BCS). MATERIALS AND METHODS: Twenty-two patients who had previously received RT in our center were evaluated retrospectively. All patients had undergone BCS operation for left breast cancer. LV and LAD were contoured as OARs on the same simulation CTs for these patients whose treatment was previously completed in which LV and LAD were not defined as OARs. Complying with the initial plans, intensity-modulated RT plans with 7-9 fields were made on the computer. Planning target volume (PTV), homogeneity index (HI), conformity index (CI), monitor unit (MU) values, and doses of OARs were compared using the Wilcoxon signed-rank test (p < 0.05). RESULTS: There were no significant differences in PTV 50 (D 50% and D 98%), PTV 60 (D 2% and D 50%), HI, CI, and MU values when treatment plans and control plans were compared (p > 0.05). While it was possible to protect the heart, LAD, and LV better, LAD and LV were not contoured in the treatment plans, and they received higher doses compared to the control plans (p < 0.05). There was no significant difference in the other OARs. CONCLUSION: In conclusion, it is essential to define the lower anatomical regions of the heart as OARs. Otherwise, the doses taken by these regions are ignored and may be maintained less than possible. In our study, it was shown that LV and LAD doses were significantly reduced even in the same center and planning by the same team.

Safety Margins for the Delineation of the Left Anterior Descending Artery in Patients Treated for Breast Cancer.

PURPOSE: Cardiac toxicity after breast cancer (BC) radiation therapy is partly due to the large radiation doses to coronary arteries. The left anterior descending artery (LAD) is particularly exposed. A first step in achieving robust dose constraints to the LAD during treatment planning is homogeneous delineation based on guidelines. LAD delineation can be problematic due to heart movements. The aim of the study was to establish a safety margin for delineation of the LAD in patients with BC. METHODS AND MATERIALS: We studied 45 patients with left-sided BC who had an indication for adjuvant radiation therapy between 2015 and 2018. They all underwent cardiac-gated computed tomography scan, as well as planning computed tomography scans with or without contrast agents, to assess LAD diameter and movements. Cardiac-gated computed tomography scan was performed during monitoring of the cardiac cycle. Acquisition was launched immediately after contrast injection (arterial sequence), with deep-inspiration breath hold and use of a beta-receptor blocking agent. By manually reviewing each scan, the LAD positions and diameter were defined at 20 different phases of the cardiac cycle at 5 different sites: ostium (OS), circumflex bifurcation (bfc), first diagonal bfc, second diagonal (D2) bfc, and apex (right coronary anastomosis). RESULTS: Movement of the LAD is maximal at the ostium and then constant overall even when far from its origin. The diameter decreases with the distance from ostium: 4.9 mm (OS), 3.9 mm (circumflex), 3.5 mm (D2), and 3.1 mm (D2). CONCLUSIONS: We suggest using a safety delineation margin consisting of a cylinder with a diameter of 10 mm surrounding the LAD. These findings must be validated in independent series of patients treated for BC.

Novel Methodology to Investigate the Effect of Radiation Dose to Heart Substructures on Overall Survival.

PURPOSE: For patients with lung cancer treated with radiation therapy, a dose to the heart is associated with excess mortality; however, it is often not feasible to spare the whole heart. Our aim is to define cardiac substructures and dose thresholds that optimally reduce early mortality. METHODS AND MATERIALS: Fourteen cardiac substructures were delineated on 5 template patients with representative anatomies. One thousand one hundred sixty-one patients with non-small cell lung cancer were registered nonrigidly to these 5 template anatomies, and their radiation therapy doses were mapped. Mean and maximum dose to each substructure were extracted, and the means were evaluated as input to prediction models. The cohort was bootstrapped into 2 variable reduction techniques: elastic net least absolute shrinkage and selection operator and the random survival forest model. Each method was optimized to extract variables contributing most to overall survival, and model coefficients were evaluated to select these substructures. The most important variables common to both models were selected and evaluated in multivariable Cox-proportional hazard models. A threshold dose was defined, and Kaplan-Meier survival curves plotted. RESULTS: Nine hundred seventy-eight patients remained after visual quality assurance of the registration. Ranking the model coefficients across the bootstraps selected the maximum dose to the right atrium, right coronary artery, and ascending aorta as the most important factors associated with survival. The maximum dose to the combined cardiac region showed significance in the multivariable model, a hazard ratio of 1.01/Gy, and P = .03 after accounting for tumor volume (P < .001), N stage (P < .01), and performance status (P = .01). The optimal threshold for the maximum dose, equivalent dose in 2-Gy fractions, was 23 Gy. Kaplan-Meier survival curves showed a significant split (log-rank P = .008). CONCLUSIONS: The maximum dose to the combined cardiac region encompassing the right atrium, right coronary artery, and ascending aorta was found to have the greatest effect on patient survival. A maximum equivalent dose in 2-Gy fractions of 23 Gy was identified for consideration as a dose limit in future studies.

Atlas Sampling for Prone Breast Automatic Segmentation of Organs at Risk: The Importance of Patients' Body Mass Index and Breast Cup Size for an Optimized Contouring of the Heart and the Coronary Vessels.

OBJECTIVE: Delineation of organs at risk is a time-consuming task. This study evaluates the benefits of using single-subject atlas-based automatic segmentation of organs at risk in patients with breast cancer treated in prone position, with 2 different criteria for choosing the atlas subject. Together with laterality (left/right), the criteria used were either (1) breast volume or (2) body mass index and breast cup size. METHODS: An atlas supporting different selection criteria for automatic segmentation was generated from contours drawn by a senior radiation oncologist (RO_A). Atlas organs at risk included heart, left anterior descending artery, and right coronary artery. Manual contours drawn by RO_A and automatic segmentation contours of organs at risk and breast clinical target volume were created for 27 nonatlas patients. A second radiation oncologist (RO_B) manually contoured (M_B) the breast clinical target volume and the heart. Contouring times were recorded and the reliability of the automatic segmentation was assessed in the context of 3-D planning. RESULTS: Accounting for body mass index and breast cup size improved automatic segmentation results compared to breast volume-based sampling, especially for the heart (mean similarity indexes >0.9 for automatic segmentation organs at risk and clinical target volume after RO_A editing). Mean similarity indexes for the left anterior descending artery and the right coronary artery edited by RO_A expanded by 1 cm were ≥0.8. Using automatic segmentation reduced contouring time by 40%. For each parameter analyzed (eg, D2%), the difference in dose, averaged over all patients, between automatic segmentation structures edited by RO_A and the same structure manually drawn by RO_A was <1.5% of the prescribed dose. The mean heart dose was reliable for the unedited heart segmentation, and for right-sided treatments, automatic segmentation was adequate for treatment planning with 3-D conformal tangential fields. CONCLUSIONS: Automatic segmentation for prone breast radiotherapy stratified by body mass index and breast cup size improved segmentation accuracy for the heart and coronary vessels compared to breast volume sampling. A significant reduction in contouring time can be achieved by using automatic segmentation.

Effect of radiotherapy on coronary arteries and heart in breast-conserving surgery: a dosimetric analysis.

Background There are certain risks of radiotherapy (RT), especially patients with left-sided breast cancer have a higher tendency to develop cardiac complications than the right-sided cancers. This study aims to perform a dosi-metric analysis the effect of RT on coronary arteries and heart in breast-conserving surgery. Patients and methods A total of 40 patients with early stage right and left-sided breast carcinomas (T1/T2 + N0) were randomly selected. RT was delivered to the entire breast, and tumor beds were boosted in these patients using tangential fields with computed tomography based planning. The doses for Left anterior descending coronary artery (LAD), left circumflex coronary artery (LCx), right ventricle (RV), left ventricle (LV), and heart were recorded and median values compared between groups. Results The highest mean of radiation dose in patients with left-sided breast cancer was to LAD 2402.48 ± 838.39 cGy, while the highest mean dose in right-sided breast cancer patients was to RV 130.18 ± 24.92. The highest maximum dose of radiotherapy was applied to heart at left-sided breast cancer patients as well as at right-sides prients. The mean V5 of the LV was 18.68% (6.89-31.69), mean V25 of the LV was 5.22% (0.45-16.54), mean V5 in bilateral ventricles was 23.73% (2.56-26.89), and mean V25 in bilateral ventricles 6.78% (0.63-13.63). Conclusions Especially in left-sided breast cancer, the most direct and best strategy to reduce and protect radiation-induced cardiac injury is to balance dose constraints between several high-dose regions of cardiac substructures and the mean heart dose.

Meta-analysis of deep inspiration breath hold (DIBH) versus free breathing (FB) in postoperative radiotherapy for left-side breast cancer.

OBJECTIVES: This meta-analysis evaluates the difference in deep inspiration breath hold (DIBH) versus free breathing (FB) for patients receiving postoperative radiotherapy for left breast cancer and provides a useful reference for clinical practice. METHODS: The relevant controlled trials of DIBH versus FB in postoperative radiotherapy for left-side breast cancer were retrieved from the databases of PubMed, Science Direct, Cochrane Library, and Web of Science databases. The principal outcome of interest was heart dose, left anterior descending coronary artery (LADCA) dose, and left lung dose and target coverage. We calculated summary standardized mean difference (SMD) and 95% confidence intervals (CI). The meta-analysis was performed using RevMan 5.3 software. RESULTS: The analysis included 1019 patients from 12 observational studies, of which 576 cases were in the DIBH group and 443 cases in the FB group. Compared with the FB group, the DIBH group can have lower heart dose, left anterior descending coronary artery (LADCA) dose, and left lung dose more effectively, and the difference was statistically significant (heart dose, SMD = - 1.36, 95% CI - 1.64 ~ - 1.09, P < 0.01. LADCA dose, SMD = - 1.45, 95% CI - 1.62 ~ - 1.27, P < 0.01. Left lung dose, SMD = - 0.52, 95% CI - 0.81 ~ - 0.23, P < 0.01). There was no significant difference in target coverage between the two groups (SMD = 0.03, 95% CI - 0.11 ~ 0.18, P = 0.64). CONCLUSION: By this meta-analysis, we found that implementation of DIBH in postoperative radiotherapy for left-side breast cancer can reduce irradiation of heart dose, LADCA dose and left lung dose, without compromising target coverage.

Effects of Radiotherapy in Coronary Artery Disease.

PURPOSE OF REVIEW: This review describes the effects of radiotherapy (RT) on coronary artery disease, its mechanisms, and clinical and laboratory evidence and discusses ways to minimize radiation-induced coronary atherosclerosis. RECENT FINDINGS: Radiation-induced cardiac toxicity is known in patients undergoing thoracic RT. One of the damages occurs in the coronary arteries, with accelerated atherosclerosis manifesting decades later. There is clinical and laboratory evidence of coronary damage in retrospective studies, systematic reviews, and meta-analyses. Clinical studies have shown that RT cardiotoxicity occurs decades after radiation, regardless of chemotherapy, and may occur earlier in patients with pre-existing risk factors or disease. The pathogenesis of radiation-induced coronary artery disease is complex and multifactorial, including endothelial dysfunction, altered vascular tone, hemostatic imbalance, and inflammatory activation. Some factors are responsible, such as mean heart dose, RT chest site, patient position, techniques, and breathing maneuvers. There are approaches to reduce radiation-induced cardiac toxicity. Among them, besides the mentioned factors, metformin and anti-inflammatory agents can minimize coronary damage, with impact on morbidity and mortality.

The relationship between radiation doses to coronary arteries and location of coronary stenosis requiring intervention in breast cancer survivors.

BACKGROUND: To assess the relationship between radiation doses to the coronary arteries (CAs) and location of a coronary stenosis that required intervention after three-dimensional conformal radiotherapy (3DCRT) for breast cancer (BC). METHODS: The study population consisted of 182 women treated for BC in Sweden between 1992 and 2012. All women received 3DCRT and subsequently underwent coronary angiography due to a suspected coronary event. CA segments were delineated in the patient's original planning-CT and radiation doses were recalculated based on the dose distribution of the original radiotherapy (RT) plan. The location of the CA stenosis that required intervention was identified from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Logistic regression analysis was used to assess the relationship between CA radiation doses and risk of a later coronary intervention at this specific location. RESULTS: The odds ratio (OR) varied by radiation dose to the mid left anterior descending artery (LAD) (p = 0.005). Women receiving mean doses of 1-5 Gray (Gy) to the mid LAD had an adjusted OR of 0.90 (95% CI 0.47-1.74) for a later coronary intervention compared to women receiving mean doses of 0-1 Gy to the mid LAD. In women receiving mean doses of 5-20 Gy to the mid LAD, an adjusted OR of 1.24 (95% CI 0.52-2.95) was observed, which increased to an OR of 5.23 (95% CI 2.01-13.6) for mean doses over 20 Gy, when compared to women receiving mean doses of 0-1 Gy to the mid LAD. CONCLUSIONS: In women receiving conventional 3DCRT for BC between 1992 and 2012, radiation doses to the LAD remained high and were associated with an increased requirement of coronary intervention in mid LAD. The results support that the LAD radiation dose should be considered in RT treatment planning and that the dose should be kept as low as possible. Minimising the dose to LAD is expected to diminish the risk of later radiation-induced stenosis.