Radiation-induced Cardiac Toxicity Research Articles

Convolution Neural Network-Based Automatic Scoring of Coronary Artery Calcification and Its Value to Identify the Risk of Radiation-Induced Cardiac Toxicity on Radiotherapy Planning CT Scans in Breast Cancer Patients

To develop an automatic scoring of coronary artery calcification (CAC) on breast cancer radiotherapy (RT) planning computed tomography (CT) scans, and to explore its predictive value of CAC for radiation-induced cardiac toxicity. Planning CT scans of 668 breast cancer patients from two prospective clinical trials (NCT02942615, NCT03829553) were retrospectively reviewed. In total, 34 CTs containing CAC were identified. The training and test samples were 29 and 5, respectively. We proposed a two-stage model for CAC segmentation task with nnU-Net as backbone. The segmentation results were processed by threshold extraction and region growth algorithm. We also employed transfer learning to automatically identify calcification of left anterior descending artery (LAD), right coronary artery (RCA), left circumflex artery (LCX), and left main coronary artery (LM) based on a public dataset of 430 cases from Stanford University. The data of cardiac examination of these 34 patients before and during the follow-up after RT were collected. The cardiac event was any symptomatic heart disease or new-onset abnormality in the cardiac examination after RT. The mean dice coefficients (DSC) and 95% Harsdorf distance (95HD) of test samples were 0.992 and 0.599 mm, respectively. The mean absolute error (MAE) of CAC Angaston score between ground truth (GT) and predictions was 0.532. The detailed consistency parameters of 5 test samples were shown in Table 1. After 1:2 propensity score matching (PSM), 21 patients had CAC and 42 patients had no CAC were selected. The number of patients with CAC scores of 1 to 10, 11 to 100, and greater than 100 was 10, 9 and 2, respectively. During median follow-up of 9.2 months (range, 1-42.7), 90.5% and 38.1% of patients in CAC cohort and no CAC cohort developed cardiac event (p<0.001). Patients with CAC had significantly increased cardiac events (HR = 2.4; 95% CI, 1.22-4.75; p = 0.0117). The risk of cardiac events increased with CAC scores ([HR]1-10 = 2.1, 95% CI 0.9-4.9; [HR]11-100 = 2.5, 95% CI 1.0-5.9; [HR]>100 = 4.0, 95% CI 0.9-17.4). Our primary results showed that this two-stage segmentation model is capable of achieving automatic CAC scoring which might assist to predict the risk of post-RT cardiac events in breast cancer patients.

Correlation of Mean Heart Dose and Cardiac Biomarkers with Electrocardiographic Changes in Patients Receiving Thoracic Radiation Therapy.

Cardiotoxicity is a well-recognized, serious adverse effect of thoracic radiation therapy. This study aimed to evaluate longitudinal electrocardiogram (ECG) changes in patients receiving thoracic radiation therapy and identify correlating factors that can predict the risk of cardiotoxicity. This retrospective study included 202 patients treated with thoracic radiation therapy, and chemotherapy and targeted therapy were allowed. Mean heart dose (MHD) was evaluated on dose-volume histograms. ECG, high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal B-type natriuretic peptide (NT-proBNP) analyses were conducted before irradiation and during the follow-up period of 6-12 months (average 8 months). Chi square test and logistic regression analysis were applied to identify risk factors associated with ECG changes. At a median time of 3 months postirradiation, 46.5% of patients showed ECG changes, and 33.0% of patients achieved baseline ECG levels during the follow-up period at a median of 5 months postirradiation. Logistic regression analysis identified MHD, hs-cTnT and NT-pro BNP as significant factors associated with ECG changes (P < 0.05). Hs-cTnT and NT-proBNP were increased significantly after radiation therapy compared with baseline levels (P < 0.05), and these increases were observed as a median time of 2 months postirradiation, which was earlier than ECG changes. Higher MHD and elevated hs-cTnT and NT-proBNP levels correlated with an increased risk of ECG changes in patients receiving thoracic radiation therapy. Early identification of patients at high risk of cardiotoxicity and timely intervention might reduce the incidence of radiation-induced cardiac toxicity.

Mitigating, monitoring, and managing long-term chemotherapy- and radiation-induced cardiac toxicity

Five-year survival for childhood cancer now exceeds 85%. However, for many patients, treatment requires the use of intensive anthracycline-based chemotherapy and radiotherapy, both of which are associated with significant long-term cardiovascular toxicity. As such, late cardiovascular disease is now one of the leading causes of premature morbidity and mortality among childhood cancer survivors. Recent advances over the past decade have refined the cardiotoxic potential of various chemotherapeutics, and ongoing work seeks to determine the efficacy of various cardioprotective strategies in children receiving active cancer therapy. The development of risk prediction models offers an additional strategy to define risk for both newly treated and long-term survivors. Current screening strategies are primarily based on echocardiography, although there is active research investigating methods to further optimize screening through myocardial strain, cardiac magnetic resonance imaging, blood biomarkers, and genetics, along with the cost-effectiveness of different screening strategies. Active research is also underway investigating the efficacy of prevention strategies for childhood cancer survivors who have completed cancer therapy. This ranges from the use of medications to mitigate potential pathologic ventricular remodeling to reducing adverse and modifiable cardiovascular risk factors (eg, hypertension, dyslipidemia, insulin resistance, physical inactivity, tobacco exposure), many of which may be more common in cancer survivors vs the general population and are often underrecognized and undertreated in relatively young adult-aged survivors of childhood cancer.

Baseline cardiac risk profile determines radiation-induced cardiac toxicity in patients with mid-lower esophageal cancer

Abstract Background: The radiotherapy techniques are evolving. Besides optimal tumour coverage, considering organs at risk (OAR) is pertinent to radiation oncologists. In mid-lower esophageal cancer (MLEC) radiotherapy, heart is the main OAR. Studies on excess absolute risk (EAR) of cardiovascular disease (CVD) in MLEC radiotherapy are limited in the main literature. Therefore, this study was conducted to estimate the EAR of CVD in patients with MLEC treated with the intensity-modulated radiation therapy (IMRT) technique. Results: Family history of heart disease and smoking increased the EAR of CVD significantly compared to the cholesterol and high-sensitivity C-reactive protein. The 10-year EAR of the high-risk group was more than four times of the low-risk group at all ages. In the low-risk group, EAR of CVD after radiotherapy of esophageal cancer can increase by up to 9·1%, while in the high-risk group, EAR increased by 34·89%. Conclusions: Adding the baseline CVD risk factors improved the estimation of EAR of heart disease after MLEC radiotherapy with the IMRT technique.

On the feasibility of cardiac substructure sparing in magnetic resonance imaging guided stereotactic lung radiotherapy.

Lung stereotactic body radiotherapy (SBRT) has proven an effective treatment for medically inoperable lung tumors, even for (ultra-)central tumors. Recently, there has been growing interest in radiation-induced cardiac toxicity in lung radiotherapy. More specifically, dose to cardiac (sub-)structures (CS) was found to correlate with survival afterradiotherapy. Our goal is first, to investigate the percentage of patients who require CS sparing in an magnetic resonance imaging guided lung SBRT workflow, and second, to quantify how successful implementation of cardiac sparing would be. The patient cohort consists of 34 patients with stage II-IV lung cancer who were treated with SBRT between 2017 and 2020. A mid-position computed tomography (CT) image was used to create treatment plans for the 1.5 T Unity MR-linac (Elekta AB, Stockholm, Sweden) following clinical templates. Under guidance of a cardio-thoracic radiologist, 11 CS were contoured manually for each patient. Dose constraints for five CS were extracted from the literature. Patients were stratified according to their need for cardiac sparing depending on the CS dose in their non-CS constrained MR-linac treatment plans. Cardiac sparing treatment plans (CSPs) were then created and dosimetrically compared with their non-CS constrained treatment plan counterparts. CSPs complied with the departmental constraints and were considered successful when fulfilling all CS constraints, and partially successful if some CS constraints could be fulfilled. Predictors for the need for and feasibility of cardiac sparing were explored, specifically planning target volume (PTV) size, cranio-caudal (CC) distance, 3D distance, and in-field overlap volume histograms (iOVH). 47% of the patients (16 out of 34) were in need of cardiac sparing. A successful CSP could be created for 62.5% (10 out of 16) of these patients. Partially successful CSPs still complied with two to four CS constraints. No significant difference in dose to organs at risk (OARs) or targets was identified between CSPs and the corresponding non-CS constrained MR-linac plans. The need for cardiac sparing was found to correlate with distance in the CC direction between target and all of the individual CS (Mann-Whitney U-test p-values <10-6 ). iOVHs revealed that complying with dose constraints for CS is primarily determined by in-plane distance and secondarily by PTVsize. We demonstrated that CS can be successfully spared in lung SBRT on the MR-linac for most of this patient cohort, without compromising doses to the tumor or to other OARs. CC distance between the target and CS can be used to predict the need for cardiac sparing. iOVHs, in combination with PTV size, can be used to predict if cardiac sparing will be successful for all constrained CS except the leftventricle.

Preclinical models of radiation-induced cardiac toxicity: Potential mechanisms and biomarkers.

Radiation therapy (RT) is an important modality in cancer treatment with >50% of cancer patients undergoing RT for curative or palliative intent. In patients with breast, lung, and esophageal cancer, as well as mediastinal malignancies, incidental RT dose to heart or vascular structures has been linked to the development of Radiation-Induced Heart Disease (RIHD) which manifests as ischemic heart disease, cardiomyopathy, cardiac dysfunction, and heart failure. Despite the remarkable progress in the delivery of radiotherapy treatment, off-target cardiac toxicities are unavoidable. One of the best-studied pathological consequences of incidental exposure of the heart to RT is collagen deposition and fibrosis, leading to the development of radiation-induced myocardial fibrosis (RIMF). However, the pathogenesis of RIMF is still largely unknown. Moreover, there are no available clinical approaches to reverse RIMF once it occurs and it continues to impair the quality of life of long-term cancer survivors. Hence, there is an increasing need for more clinically relevant preclinical models to elucidate the molecular and cellular mechanisms involved in the development of RIMF. This review offers an insight into the existing preclinical models to study RIHD and the suggested mechanisms of RIMF, as well as available multi-modality treatments and outcomes. Moreover, we summarize the valuable detection methods of RIHD/RIMF, and the clinical use of sensitive radiographic and circulating biomarkers.

Dosimetric Planning Comparison for Left-Sided Breast Cancer Radiotherapy: The Clinical Feasibility of Four-Dimensional-Computed Tomography-Based Treatment Planning Optimization.

Background: Adjuvant whole-breast radiotherapy (RT) is a significant part of the standard of care treatment after breast cancer (BC) conserving surgery. Modern techniques including intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) have constituted to better target coverage and critical organs sparing. However, BC survivors are at risk of developing radiation-induced cardiac toxicity. Hence, deep-inspiration breath-hold (DIBH) techniques have been implemented at many centers to further reduce cardiac exposure but require compliance. 4D-CT robust optimization can account for heart intrafractional motion per breathing phase. The optimization has been explored in cardiac sparing of breast IMRT compared to DIBH in a small sample size but has not been evaluated in substructures sparing, nor in VMAT. To provide patients who are not compliant to breath-hold with an optimal treatment approach, various heart sparing techniques need to be evaluated for statistical significance and clinical feasibility.Aim: This retrospective study aimed to provide an extensive dosimetric heart sparing comparison of free-breathing, 4D-CT-based treatment planning, including robust optimization with DIBH-based treatment planning. Combinations of forward and inverse IMRT and VMAT are also considered.Methods: Fifteen early stage left-sided BC standard treatment plans were selected. Breast, lung, left anterior descending artery (LAD), left ventricle (LV), and the whole heart were contoured on each 4D-CT phase and DIBH CT dataset. Each treatment plan was optimized using forward/inverse IMRT and VMAT on the following CT datasets: DIBH, average 4D-CT, and the complete 4D-CT dataset needed for robust optimization. Dose-volume histograms were used to compare V5GyHeart, mean heart dose, mean and max LAD dose, mean LV dose, and V50%Lung.Results: All RT techniques assessed including 4D robust optimization were clinically feasible. Statistically significant differences in mean heart, LAD and LV dose, max LAD dose, and V5GyHeart (p < 0.01) but no difference in V50%Lung (p = 0.29) were found between different techniques. IMRT DIBH achieved the optimal cardiac and substructure sparing among treatment plans. 4D robust IMRT had significantly greater mean heart and LV dose than DIBH IMRT (p ≤ 0.01), except LAD dose. Among free-breathing methods, no difference in all cardiac and substructure dose parameters was observed (p > 0.2) in comparing forward and inverse IMRT with average 4D-CT, inverse average 4D-CT, and 4D robust with IMRT, and between average 4D-CT VMAT and 4D robust VMAT. Only V5GyHeart and mean LV dose were significantly greater in 4D robust VMAT (p < 0.01) compared to DIBH VMAT. Mean heart and LV doses were significantly reduced (p < 0.01) in DIBH IMRT compared to DIBH VMAT. Moreover, mean heart and LV dose, V5GyHeart were significantly reduced in inverse IMRT average 4D-CT compared to average 4D-CT VMAT (p < 0.02) and in 4D robust IMRT compared to 4D robust VMAT (p < 0.04).Conclusion: This study demonstrated the clinical feasibility of 4D robust optimization in limiting the cardiac and substructures dose during free-breathing RT with both IMRT/VMAT for patients who are not compliant with breath-hold RT. However, this study also presents that 4D robust optimization can reduce LAD dose but not fully outperform DIBH or conventional 4D-CT-based planning with IMRT/VMAT in heart sparing in treating early staged left-sided BC patients.

Dosimetric comparison between three-dimensional conformal radiotherapy followed by electron beam boost and volumetric modulated arc therapy using concomitant boost for the heart and cardiac segments in patients with left-sided breast cancer at risk for radiation-induced cardiac toxicity

PurposeWe aimed to compare dosimetric parameters between three-dimensional conformal radiation therapy followed by electron beam boost (3D-CRT + EB) and volumetric modulated arc therapy using simultaneous integrated boost (SIB-VMAT) in left-sided breast cancer patients. MethodsThis study included 57 patients with left-sided breast cancer who underwent SIB-VMAT. All patients had a computed tomography-based maximum heart distance of ≥ 1 cm and were prescribed a dose of 42.56 Gy/16 fractions to the planning target volume and a concomitant-boosted target dose of 53.2 Gy or 51.2 Gy. The 3D-CRT + EB plan was retrospectively created for the purpose of comparison using tangential fields with field-in-field technique followed by electron beam irradiation. ResultsThe doses to the clinical target volume significantly improved in the SIB-VMAT plans. All dosimetric parameters for the left anterior descending coronary artery (LAD) and LAD middle position (LAD mid) in the SIB-VMAT plans were significantly lower than those for 3D-CRT + EB plans (P < 0.01), while the doses to the heart, lung, contralateral breast and non-target tissue were decreased in the 3D-CRT + EB plans compared with those in the SIB-VMAT plans (e.g., 1.9 Gy vs. 2.9 Gy; P < 0.001 for the mean dose of heart). ConclusionsSIB-VMAT significantly improved the dose to the target while reducing the doses to the LAD and LAD mid, whereas 3D-CRT + EB significantly decreased the doses to the heart and other organs at risk in patients with left-sided breast cancer at risk for radiation-induced coronary artery disease.

Is Radiation-Induced Cardiac Toxicity Reversible? Prospective Evaluation of Patients With Breast Cancer Enrolled in a Phase 3 Randomized Controlled Trial

Myocardial perfusion defects after breast radiation therapy (RT) correlate with volume of irradiated left ventricle (LV). We aimed to determine the relationship between myocardial perfusion, LV dosimetry, and grade ≥2 late cardiac events in patients with breast cancer undergoing adjuvant RT. A randomized study evaluated the benefit of inverse-planned intensity modulated radiation therapy over forward-planned intensity modulated radiation therapy for radiation toxicity in breast cancer. A secondary endpoint was evaluating cardiac perfusion by single-photon emission computed tomography done at baseline, 6 months, 1 year, 2 years, and 5 years post-RT. We used receiver operating curve and regression analysis to identify association between perfusion, radiation dose-volumes, and the risk of late cardiac events. Of 181 patients who received adjuvant RT, 102 were patients with cancer in the left breast (called in this study the left-sided group) and 79 were patients with cancer in the right breast (called in this study the right-sided group). Median follow-up was 127 months (range, 19-160 months). A significant worsening of perfusion defects occurred after RT in the left-sided group, which improved by 1 year. Late cardiac events were found among 16 patients (17.2%) in the left-sided group and 4 patients (5.5%) in the right-sided group. Perfusion changes did not correlate with late cardiac events, but LV dose-volumes correlated with late cardiac events. Maintaining the LV volume receiving 5 Gy and 10 Gy to <42 cc and <38cc, respectively, can reduce the risk of radiation-related late cardiac events at 10 years to <5% over baseline. RT was associated with short-term perfusion defects that improved within 1 year and was not correlated with late cardiac events. The ventricular volumes receiving 5 Gy and 10 Gy were correlated with late cardiac events.

MicroRNA-223-3p Protect Against Radiation-Induced Cardiac Toxicity by Alleviating Myocardial Oxidative Stress and Programmed Cell Death via Targeting the AMPK Pathway.

Objectives: Radiotherapy improves the survival rate of cancer patients, yet it also involves some inevitable complications. Radiation-induced heart disease (RIHD) is one of the most serious complications, especially the radiotherapy of thoracic tumors, which is characterized by cardiac oxidative stress disorder and programmed cell death. At present, there is no effective treatment strategy for RIHD; in addition, it cannot be reversed when it progresses. This study aims to explore the role and potential mechanism of microRNA-223-3p (miR-223-3p) in RIHD. Methods: Mice were injected with miR-223-3p mimic, inhibitor, or their respective controls in the tail vein and received a single dose of 20 Gy whole-heart irradiation (WHI) for 16 weeks after 3 days to construct a RIHD mouse model. To inhibit adenosine monophosphate activated protein kinase (AMPK) or phosphodiesterase 4D (PDE4D), compound C (CompC) and AAV9-shPDE4D were used. Results: WHI treatment significantly inhibited the expression of miR-223-3p in the hearts; furthermore, the levels of miR-223-3p decreased in a radiation time-dependent manner. miR-223-3p mimic significantly relieved, while miR-223-3p inhibitor aggravated apoptosis, oxidative damage, and cardiac dysfunction in RIHD mice. In addition, we found that miR-223-3p mimic improves WHI-induced myocardial injury by activating AMPK and that the inhibition of AMPK by CompC completely blocks these protective effects of miR-223-3p mimic. Further studies found that miR-223-3p lowers the protein levels of PDE4D and inhibiting PDE4D by AAV9-shPDE4D blocks the WHI-induced myocardial injury mediated by miR-223-3p inhibitor. Conclusion: miR-223-3p ameliorates WHI-induced RIHD through anti-oxidant and anti-programmed cell death mechanisms via activating AMPK by PDE4D regulation. miR-223-3p mimic exhibits potential value in the treatment of RIHD.

Activation of PPARα by Fenofibrate Attenuates the Effect of Local Heart High Dose Irradiation on the Mouse Cardiac Proteome.

Radiation-induced cardiovascular disease is associated with metabolic remodeling in the heart, mainly due to the inactivation of the transcription factor peroxisome proliferator-activated receptor alpha (PPARα), thereby inhibiting lipid metabolic enzymes. The objective of the present study was to investigate the potential protective effect of fenofibrate, a known agonist of PPARα on radiation-induced cardiac toxicity. To this end, we compared, for the first time, the cardiac proteome of fenofibrate- and placebo-treated mice 20 weeks after local heart irradiation (16 Gy) using label-free proteomics. The observations were further validated using immunoblotting, enzyme activity assays, and ELISA. The analysis showed that fenofibrate restored signalling pathways that were negatively affected by irradiation, including lipid metabolism, mitochondrial respiratory chain, redox response, tissue homeostasis, endothelial NO signalling and the inflammatory status. The results presented here indicate that PPARα activation by fenofibrate attenuates the cardiac proteome alterations induced by irradiation. These findings suggest a potential benefit of fenofibrate administration in the prevention of cardiovascular diseases, following radiation exposure.

Cardiac Substructure Delineation Based on Synthetic Contrast-Enhanced CT Generation Using Deep Convolutional Neural Network in Breast Cancer Radiation Therapy

Although radiation-induced cardiac toxicity is an important issue in breast radiation therapy (RT), the dose relationship between cardiac structures and its toxicity has not been fully elucidated, partially because many centers do not routinely administer intravenous (IV) contrast for breast RT, which preclude substructure delineation and detection of potential correlations. In this study, we attempted to generate the synthetic contrast-enhanced CT (CECTsyn) from the non-contrast CT (NCTreal) using deep convolutional neural network (DCNN) and to investigate whether CECTsyn can take a supportive role in case the studies for the cardiac toxicity induced by radiation is needed for the patient whose CECTreal cannot be obtained.For this study, 22 NCTreal-CECTreal cardiac scan-pairs have been prepared of which the volume size was ∼512 × 512 × 400 and the resolution was ∼0.75 × 0.75 × 1 mm3 on average. Of the 22 datasets, 13/2/7 were used for training, validation, and testing, respectively. After matching the structure of paired scans using the deformable image registration (DIR), the area near the heart was cropped and used for training the deep learning model. We adopted the modified 2D fully convolution DenseNet (FC-DenseNet) as our backbone and trained it in the conditional generative adversarial network (cGAN) framework. The similarity between CECTsyn and CECTreal was evaluated first, and all NCTreal,CECTsyn, and CECTreal were applied to pre-trained cardiac auto-segmentation models to obtain the substructures of the heart, which is used for dose assessments in each of them. Finally, dose evaluations were conducted on CECTsyn and CECTreal with the dose distributions which are from clinical treatment plans and the manually modified contours of cardiac substructures.Firstly, the peak signal-to-noise ratio (PSNR) and the structural similarity index measure (SSIM) between CECTsyn and CECTreal were 23.96 and 0.772, whereas those of NCTreal and CECTreal were 22.25and 0.748, respectively. Secondly, the results of applying the pre-trained cardiac auto-segmentation model were obtained, and the dice similarity coefficient (DSC) of CECTsyn was 0.762 on average which is superior to 0.267 of NCTreal and comparable to 0.843 of CECTreal. We could distinguish the L/R ventricles, L/R atriums, left anterior descending artery (LAD), and right coronary artery (RCA) clearly on CECTsyn. Finally, the dose differences between CECTsyn and CECTreal were on average 0.4/2.0 Gy in Dmean and Dmax, and 2.1/1.3/0.6/0.4/0.3/0.1/0.0% in V5 Gy, V10 Gy, V20 Gy, V30 Gy, V40 Gy, V50 Gy, and V60 Gy, respectively.DCNN model proposed here showed the feasibility of CECTsyn generation from NCTreal and potential for cardiac substructure delineation such as ventricles, atriums, LAD, and RCA on NCTreal for breast RT. Furthermore, it is shown that CECTsyn can play a supportive role when the studies for the radiation-induced cardiac toxicity is needed.

Machine Learning Based Analysis of Heart and Cardiac Substructures for Radiation-Induced Cardiac Toxicity From Breast Cancer Radiotherapy

Radiation-induced cardiac toxicity is an importantissue of breast RT. Although a relationship between mean heart dose and acute coronary event (ACE) risk was reported in previous study, the specific relationships between doses to cardiac structures or their sub-regions and subsequent toxicity have not been well defined. In this study, we studied the effect of radiation on specific heart segments on subsequent cardiac toxicity.From the 1294 patients with breast cancer where previously demonstrated a relationship between mean heart dose and ACE, 21 patients who developed HF following breast RT and 39 with ACE were identified after an independent review by cardiologists. The study included 21 and 39 controls for respective toxicity who were matched according to age, comorbidities, and physical activity. For each patient who received radiotherapy, substructures were manually drawn, and then dose-distribution parameters of heart and substructures (Mean, Maximum (Max) dose, Relative volume at least given dose from 5-50 Gy in 5 Gy increments) were collected from CT planning data. To specify most critical regions for developing ACE, analysis using High-dimensional Cox regression model (SNet) was performed to reveal the effect of radiation on specific heart segments on subsequent cardiac toxicity.In HF (n = 42) and ACE (n = 78) cohorts, characteristics between case and control were well matched. Mean time to develop heart failure, acute coronary events were 40.0 months and 42.2 months, respectively. In HF cohort, there was no significant difference not only in the mean heart dose (3.7 Gy vs 3.1 Gy, P = 0.652), but also in the mean left ventricle (LV) (5.0 Gy vs 4.1 Gy, P = 0.587), mean right ventricle (RV) (4.8 Gy vs 3.6 Gy, P = 0.473). On the other hand, in ACE cohort, there was significant difference in mean dose of heart (2.9 Gy vs 1.3 Gy, P = 0.015), left atrium (LA) (1.0 Gy vs 0.5 Gy, P = 0.008), LV (3.7 Gy vs 1.5 Gy, P = 0.028), left anterior descending artery (LAD) (6.6 Gy vs 2.4 Gy, P = 0.028) and right atrium (RA) (1.5 Gy vs 0.9 Gy, P = 0.025). In univariate analysis, mean dose of heart, LA, LV, LAD and RA was significant factors for acute coronary event free survival. ((Heart; P = 0.006, Hazard ratio (HR) 1.139, 95% Confidence Interval (CI) 1.035-1.253) (LA; P = 0.002, HR 1.735, 95% CI 1.209-2.490), (LV; P = 0.018, HR 1.079, 95% CI 1.012-1.150), (LAD; P = 0.031, HR 1.032, 95% CI 1.002-1.064), (RA; P = 0.008, HR = 1.307, 95% CI 1.068-1.598)). For predicting ACE risk for breast cancer patients, SNet model suggested nomogram based on mean and max LA dose, LAD V10, 15, 20, mean heart dose, mean RA dose and RV V35 in the order of higher predicted point variation. Based on this risk stratification model, event free survival significantly showed difference (P = 0.013).There was significant difference between cardiac substructure dose parameters in ACE cohort, but not in HF cohort. Further analysis using convolution neural network will be performed to specify most critical region to be spared.

Dosimetric Comparison Between 3D Conformal Radiation Therapy Plus Electron Boost and Simultaneous Integrated Boost Volumetric Modulated Arc Therapy for Left-Sided Breast Cancer Patients With a Potential Risk of Radiation-Induced Cardiac Toxicity

Reducing radiation doses to the heart and/or cardiac segments are crucial to decrease the risk of radiation-induced coronary artery diseases (RICAD) for patients with left-sided breast cancer. However, dosimetric advantages for these structures between three-dimensional conformal radiation therapy plus electron boost (3D-CRT+EB) and simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) remain unclear, especially in the patients with a potential risk of RICAD. The aim of this study was to compare some dosimetric parameters between the 3D-CRT + EB and SIB-VMAT in left-sided breast cancer patients with a potential risk of RICAD.A total of 57 patients with left-sided breast cancer treated with SIB-VMAT between 2018 and 2020 were enrolled. All patients were identified as the potential risk of RICAD by radiation oncologists using maximum heart distance (MHD), and met the MHD ≧ 1 cm. All patients were prescribed a dose of 42.56 Gy/ 16 fractions to planning target volume and a total dose of 53.2 Gy (N = 21) or 51.2 Gy (N = 36) for a concomitant-boosted target. The 3D-CRT + EB plans were retrospectively created for a comparison purpose, using field-in-field technique followed by electron beam irradiations. Some dosimetric parameters for clinical target volume (CTV), heart, left anterior descending coronary artery (LAD), middle LAD (mLAD), lungs, and contralateral breast were compared using the Wilcoxon signed rank test.The Dmean, Dmax and D98% for CTV were significantly improved in the SIB-VMAT plans. For cardiac-related structures, the median doses of SIB-VMAT versus 3D-CRT + EB were as follows: Dmean for heart, 2.9 Gy vs. 1.9 Gy (P < 0.001); Dmean, V20 and V30 for LAD, 12.6 Gy vs. 15.4 Gy (P < 0.001), 23.0% vs. 33.3% (P = 0.0049) and 2.0% vs. 24.7% (P < 0.001); Dmean, V20 and V30 for mLAD, 16.0 Gy vs. 21.1 Gy (P = 0.0014), 29.9% vs. 51.4% (P = 0.0040) and 0.5% vs. 31.1% (P < 0.001), respectively. The Dmean, V5 and V20 for the lungs and the Dmean for contralateral breast were significantly reduced in the 3D-CRT + EB plans (P < 0.001, for all). The doses to the LAD and mLAD tended to be higher in lateral cohort (upper outer and lower outer quadrants of breast) than in medial cohort (upper inner and lower inner quadrants of breast), while these doses were significantly reduced by the SIB-VMAT.Although 3D-CRT + EB technique can reduce the mean dose to the heart, the doses to LAD and mLAD can be significantly decreased by SIB-VMAT, which could be a benchmark for selecting the most appropriate irradiation technique in the patients with a potential risk of RICAD.

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?

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. 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. 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). 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.

Abstract SP069: Strategies to reduce cardiac toxicity

Abstract Approximately 60-70% of breast cancer (BC) patients receive radiation therapy (RT) as part of their care. Breast or chest wall RT improves locoregional control for BC and also improves BC survival in select populations. However, RT to the cardiac silhouette can be cardiotoxic and radiation induced cardiac toxicity (RIC) affects many breast cancer survivors. The likelihood of RIC is radiation dose dependent and can manifest in multiple forms including cardiovascular disease, heart failure, and/or pericarditis. The risk of cardiovascular disease among patients receiving RT for breast cancer increases linearly with mean heart dose exposure, with no minimum safe threshold. Prior studies have shown an increased risk of both major coronary events and heart failure within 5 years of RT among women with breast cancer, though the latency can be pronounced (10-20 years from exposure) and is further influenced by patient age at treatment as well as pre-existing cardiac risk factors. Therefore, the purpose of this talk is to: 1) discuss the nature and timing of RIC, including those patients most at risk of developing RIC, 2) review national and international cardiology-based guidelines for patient management after chest radiotherapy and 3) detail advances in cardiac sparing radiation techniques intended to reduce the risk of RIC. Ongoing research regarding novel detection and prevention strategies will be highlighted. Citation Format: R Jimenez. Strategies to reduce cardiac toxicity [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP069.

Radiation-Induced Myocardial Fibrosis in Long-Term Esophageal Cancer Survivors.

Radiation-induced cardiac toxicity is a potential lethal complication. The aim of this study was to assess whether there is a dose-dependent relationship between radiation dose and myocardial fibrosis in patients who received neoadjuvant chemoradiation (nCRT) for esophageal cancer (EC). Forty patients with EC treated with a transthoracic esophagectomy with (n = 20) or without (n = 20) nCRT (CROSS study regimen) were included. Cardiovascular magnetic resonance imaging (1.5 Tesla) for left ventricular (LV) function, late gadolinium enhancement, and T1 mapping were performed. Extracellular volume (ECV), as a surrogate for collagen burden, was measured for all LV segments separately. The dose-response relationship between ECV and mean radiation dose per LV myocardial segment was evaluated using a mixed-model analysis. Seventeen nCRT and 16 control patients were suitable for analysis. The mean time after treatment was 67.6 ± 8.1 (nCRT) and 122 ± 35 (controls) months (P = .02). In nCRT patients, we found a significantly higher mean global ECV of 28.2% compared with 24.0% in the controls (P < .001). After nCRT, LV myocardial segments with elevated ECV had received significantly higher radiation doses. In addition, a linear dose-effect relation was found with a 0.136% point increase of ECV for each Gy (P < .001). There were no differences in LV function measures and late gadolinium enhancement between both groups. Myocardial ECV was significantly higher in long-term EC survivors after nCRT compared with surgery only. Moreover, this ECV increase was linear with the radiation dose per LV segment, indicating radiation-induced myocardial fibrosis.

Dose-Weighted CT Radiomics Associated with Radiation-Induced Cardiac Toxicity in Women Treated for Localized Breast Cancer

Breast cancer continues to be the most commonly occurring non-skin cancer in women. Survivorship is of increased importance as women are living longer after treatment. Cardiac toxicity after radiotherapy (RT) is a concern for such patients who otherwise have excellent life expectancy. We hypothesize via this exploratory analysis that dose-weighted texture features from pre-treatment CT may predict for cardiac toxicity post-RT for women with breast cancer. We retrospectively analyzed 17 patients treated with standard RT for localized breast cancer between 2011-2016 at a single institution. Patients had no known heart disease pre-RT. Eight patients with cardiac disease post-RT, diagnosed via echocardiogram or cardiac catheterization, were compared to 9 patients without cardiac disease post-RT. Using published contouring guidelines, each treatment planning CT was used for delineation of the heart, cardiac chambers, left main coronary artery, left anterior descending coronary artery, left circumflex artery (LCX), right coronary artery, atrioventricular (AV) node, ascending aorta and pulmonary artery. Ninety-two geometric, first-, second-, and third-order conventional texture features were extracted for each structure. An in-house developed software modified the features by dose weighting on a voxel-by-voxel basis, resulting in an additional 65 dose-weighted textures. Random forest was used for analyses. A univariate logistic regression model was used to estimate odds ratio (OR) and p-value for each imaging feature – with and without dose weighting. Eight patients were diagnosed with pericarditis (n = 1), arrhythmia (n = 1), coronary artery disease (n = 2), or heart failure (n = 4) a median of 3 years after completion of RT (mean: 3.5 years). RT was delivered to the left breast (n = 4), left chest wall (CW, n = 2), and right CW (n = 2) with mean heart dose of 2.1 Gy (range: 0.4-5.25 Gy). The 9 reference patients without cardiac sequelae were treated with RT to the left chest wall with mean heart dose of 2.7 Gy (range: 1.4-6.8 Gy). On univariate analysis, left atrium volume (OR: 39.89, p = 0.04) and a dose-weighted feature of the right ventricle (OR: 0.15, p = 0.03) were significantly associated with cardiac disease. Several dose-weighted texture features approached significance including those of the AV node (OR: 42.37, p = 0.08), left atrium (OR 0.10, p = 0.07), LCX (OR:8.5, p 0.09), and right atrium (OR:8.5, p = 0.09). Area under the receiver operating characteristic curve (AUC) ranged between 0.75 and 0.88. Dose-weighted texture features of the right ventricle and left atrium volume were significantly associated with development of cardiac disease post-RT. Multiple dose-weighted features approached significance, suggesting that distribution of dose amongst subsites may affect cardiac outcomes. Future directions include expansion of the database by cardiac disease type with covariate analysis including systemic therapy and comorbidities.

Dosimetric Comparison of 3D-CRT, IMRT, IMAT and Helical Tomotherapy for Thoracic Esophageal Carcinoma

In this study, we compared the dose-volume parameters for treatment of thoracic esophageal cancer with treatment plans for 3D-CRT, IMRT, IMAT and HT. 15 thoracic esophagus patients who were treated in our clinic between 2017-2018 years were selected. PTV volumes were between 205 and 445.4 cc with an average of 355.2 cc. 3D-CRT, IMRT, IMAT and HT radiotherapy plans were created for each patient using the same contours and the same dose planning prescription. Total dose of 50.4 Gy for all patients was planed with 180 cGy dose per a fraction in total 28 fractions. For PTV; when the four treatment techniques were compared, HI values were 3D-CRT 0.84 ± 0.0, IMRT 0.57 ± 0.05, IMAT 0.06 ± 0.013, HT 0.08 ± 0.03 (p &amp;lt;0.05). CI values were found for 3D-CRT as 1.84 ± 0.2, for IMRT as 1.25 ± 0.05, for IMAT as 1.19 ± 0.04, for HT as 1.2 ± 0.06 (p &amp;lt;0.05). IMRT and IMAT techniques provided better OAR protection compared to other techniques in all lung and heart comparisons. The lowest doses for Dmax and D1% of Spinal Cord were provided by HT technique. We found that IMRT, IMAT and HT techniques have lower critical organ doses than 3D-CRT technique for treating torasic esophageal cancer. Considering the current evidence of the relationship between radiation-induced cardiac toxicity in the literature and the dose-volume parameters after treatment for esophageal cancer in our study, we can say that dose plans are better for IMRT and IMAT plans than 3D-CRT and HT in terms of lung and heart doses.

Plasma metabolite biomarkers predictive of radiation induced cardiotoxicity

PurposeAlthough advancements in cancer treatments using radiation therapy (RT) have led to improved outcomes, radiation-induced heart disease (RIHD) remains a significant source of morbidity and mortality in survivors of cancers in the chest. Currently, there are no diagnostic tests in clinical use due to a lack of understanding of the natural history and mechanisms of RIHD development. Few studies have examined the utility of using metabolomics to prospectively identify cancer survivors who are at risk of developing cardiotoxicity. MethodsWe analyzed plasma and left ventricle heart tissue samples collected from a cohort of male Sprague Dawley (SD) rats that were either sham irradiated or received fractionated doses (9 Gy per day × 5 days) of targeted X-ray radiation to the heart. Metabolomic and lipidomic analyses were utilized as a correlative approach for delineation of novel biomarkers associated with radiation-induced cardiac toxicity. Additionally, we used high-resolution mass spectrometry to examine the metabolomic profiles of plasma samples obtained from patients receiving high dose thoracic RT for esophageal cancer. ResultsMetabolic alterations in the rat model and patient plasma profiles, showed commonalities of radiation response that included steroid hormone biosynthesis and vitamin E metabolism. Alterations in patient plasma profiles were used to develop classification algorithms predictive of patients at risk of developing RIHD. ConclusionHerein, we report the feasibility of developing a metabolomics-based biomarker panel that is associated with adverse outcomes of cardiac function in patients who received RT for the treatment of esophageal cancer.