The effects of radiation therapy on the heart: implications for management.

Chemotherapy, radiotherapy, and surgery constitute the three primary modalities employed in the treatment of patients with cancer. Radiotherapy, in particular, is a mainstay of treatment for patients with cancers of the breast, esophagus, lung, and lymph nodes. Prior studies have shown, however, that radiotherapy can impact the heart. Radiation exposure, in fact, can lead to pathophysiological changes that may result in short- and long-term radiation-induced cardiac toxicities. Such toxicities can cause substantial morbidity and may manifest clinically in the weeks to years after the completion of treatment. As a result, in both modern clinical practice and clinical trials, the heart has been recognized as an organ-at-risk, and radiotherapy treatment plans seek to minimize the dose that it receives. In this review, we focus on the impacts of radiotherapy on underlying cardiac risk factors, the pathophysiology of radiotherapy-induced cardiac changes, and the clinical impacts of radiotherapy on the heart. Due to the location of the heart, we focus primarily on patients who have received radiotherapy for cancers of the breast, esophagus, lung, and lymph nodes, and those who have received cardiac-directed therapy. We then elaborate on the ongoing attempts to further lower the doses delivered to the heart during therapeutic courses of radiation.

Dose-dependent changes in cardiac function, strain and remodelling in a preclinical model of heart base irradiation.

BACKGROUND AND PURPOSE: Radiation induced cardiotoxicity (RICT) is as an important sequela of radiotherapy to the thorax for patients. In this study, we aim to investigate the dose and fractionation response of RICT. We propose global longitudinal strain (GLS) as an early indicator of RICT and investigate myocardial deformation following irradiation. METHODS: RICT was investigated in female C57BL/6J mice in which the base of the heart was irradiated under image-guidance using a small animal radiation research platform (SARRP). Mice were randomly assigned to a treatment group: single-fraction dose of 16 Gy or 20 Gy, 3 consecutive fractions of 8.66 Gy, or sham irradiation; biological effective doses (BED) used were 101.3 Gy, 153.3 Gy and 101.3 Gy respectively. Longitudinal transthoracic echocardiography (TTE) was performed from baseline up to 50 weeks post-irradiation to detect structural and functional effects. RESULTS: Irradiation of the heart base leads to BED-dependent changes in systolic and diastolic function 50 weeks post-irradiation. GLS showed significant decreases in a BED-dependent manner for all irradiated animals, as early as 10 weeks after irradiation. Early changes in GLS indicate late changes in cardiac function. BED-independent increases were observed in the left ventricle (LV) mass and volume and myocardial fibrosis. CONCLUSIONS: Functional features of RICT displayed a BED dependence in this study. GLS showed an early change at 10 weeks post-irradiation. Cardiac remodelling was observed as increases in mass and volume of the LV, further supporting our hypothesis that dose to the base of the heart drives the global heart toxicity.

Deep inspiration breath hold real-time tumor-tracking radiation therapy (DBRT) as a novel stereotactic body radiation therapy approach for lung tumors.

Radiotherapy with deep inspiration breath hold (DIBH) reduces doses to the lungs and organs at risk. The stability of breath holding and reproducibility of tumor location are higher during expiration than during inspiration; therefore, we developed an irradiation method combining DIBH and real-time tumor-tracking radiotherapy (RTRT) (DBRT). Nine patients were enrolled in this study. Fiducial markers were placed near tumors using bronchoscopy. Treatment planning computed tomography (CT) was performed thrice during DIBH, assisted by spirometer-based device. Each CT scan was fused using fiducial markers. Gross tumor volume (GTV) was contoured for each dataset and summed to create GTVsum; adding a 5-mm margin around GTVsum generated the planning target volume. The prescribed dose was mainly 42 Gy in four fractions. The treatment plan was created using DIBH CT (DBRT-plan), with a similar treatment plan created for expiratory CT for cases for which DBRT could not be performed (conv-plan). Vx defined as the volume of the lung received x Gy, and the mean lung dose, V20, V10, and V5 were evaluated. DBRT was completed in all patients. Mean dose, V20, and V10 were significantly lower in the DBRT-plan than in the conv-plan (all p = 0.003). Mean rates of decrease for mean dose, V20, and V10 were 14.0%, 27.6%, and 19.1%, respectively. No significant difference was observed in V5. We developed DBRT, a stereotactic body radiation therapy performed with the DIBH technique; it combines a spirometer-based breath-hold support system with an RTRT system. All patients who underwent DBRT completed the procedure without any technical or mechanical complications. This is a promising methodology that may significantly reduce lung doses.

Impact of breath hold on regional nodal irradiation and heart volume in field in left breast cancer adjuvant irradiation.

PURPOSE: Compared to the free-breathing technique, adjuvant left breast irradiation after breast-conserving surgery or mastectomy using the breath-hold method significantly reduces the heart mean dose, Left anterior descending artery, and ipsilateral lung doses. Movement with deep inspiration may also reduce heart volume in the field and regional node doses. MATERIALS AND METHODS: Pre-radiotherapy planning CT was performed in the free-breathing, and breath-hold techniques using RPM, demographic information, clinicopathological data, heart volume in the field, heart mean dose, LAD mean dose, and regional nodal doses were calculated in both free breathing and DIBH. Fifty patients with left breast cancer receiving left breast adjuvant radiation were enrolled. RESULTS: There was no significant difference in axillary LN coverage between the two techniques, except for SCL maximum dose, Axilla I node maximum dose, and Axilla II minimum dose in favor of the breath hold technique. The mean age was 47.54 years, 78% had GII IDC, 66% had positive LVSI results, and 74% of patients had T2. The breath hold strategy resulted in considerably decreased mean heart dose (p = 0.000), LAD dose (p = 0.000), ipsilateral lung mean dose (p = 0.012), and heart volume if the field (p = 0.013). The mean cardiac dosage and the dose of the LAD were significantly correlated (p = 0.000, R = 0.673). Heart volume in the field and heart mean dosage was not significantly correlated (p = 0.285, r = - 0.108). CONCLUSION: When compared to free breathing scans, DIBH procedures result in considerably reduced dosage to the OAR and no appreciable changes in dose exposure to regional lymph node stations in patients with left-sided breast cancer.

A multimodality assessment of the protective capacity of statin therapy in a mouse model of radiation cardiotoxicity.

PURPOSE: Despite technological advances in radiotherapy (RT), cardiotoxicity remains a common complication in patients with lung, oesophageal and breast cancers. Statin therapy has been shown to have pleiotropic properties beyond its lipid-lowering effects. Previous murine models have shown statin therapy can reduce short-term functional effects of whole-heart irradiation. In this study, we assessed the efficacy of atorvastatin in protecting against the late effects of radiation exposure on systolic function, cardiac conduction, and atrial natriuretic peptide (ANP) following a clinically relevant partial-heart radiation exposure. MATERIALS AND METHODS: Female, 12-week old, C57BL/6j mice received an image-guided 16 Gy X-ray field to the base of the heart using a small animal radiotherapy research platform (SARRP), with or without atorvastatin from 1 week prior to irradiation until the end of the experiment. The animals were followed for 50 weeks with longitudinal transthoracic echocardiography (TTE) and electrocardiography (ECG) every 10 weeks, and plasma ANP every 20 weeks. RESULTS: At 30-50 weeks, mild left ventricular systolic function impairment observed in the RT control group was less apparent in animals receiving atorvastatin. ECG analysis demonstrated prolongation of components of cardiac conduction related to the heart base at 10 and 30 weeks in the RT control group but not in animals treated with atorvastatin. In contrast to systolic function, conduction disturbances resolved at later time-points with radiation alone. ANP reductions were lower in irradiated animals receiving atorvastatin at 30 and 50 weeks. CONCLUSIONS: Atorvastatin prevents left ventricular systolic dysfunction, and the perturbation of cardiac conduction following partial heart irradiation. If confirmed in clinical studies, these data would support the use of statin therapy for cardioprotection during thoracic radiotherapy.

A Framework for Assessing the Effect of Cardiac and Respiratory Motion for Stereotactic Arrhythmia Radioablation Using a Digital Phantom With a 17-Segment Model: A STOPSTORM.eu Consortium Study.

PURPOSE: The optimal motion management strategy for patients receiving stereotactic arrhythmia radioablation (STAR) for the treatment of ventricular tachycardia (VT) is not fully known. We developed a framework using a digital phantom to simulate cardiorespiratory motion in combination with different motion management strategies to gain insight into the effect of cardiorespiratory motion on STAR. METHODS AND MATERIALS: The 4-dimensional (4D) extended cardiac-torso (XCAT) phantom was expanded with the 17-segment left ventricular (LV) model, which allowed placement of STAR targets in standardized ventricular regions. Cardiac- and respiratory-binned 4D computed tomography (CT) scans were simulated for free-breathing, reduced free-breathing, respiratory-gating, and breath-hold scenarios. Respiratory motion of the heart was set to population-averaged values of patients with VT: 6, 2, and 1 mm in the superior-inferior, posterior-anterior, and left-right direction, respectively. Cardiac contraction was adjusted by reducing LV ejection fraction to 35%. Target displacement was evaluated for all segments using envelopes encompassing the cardiorespiratory motion. Envelopes incorporating only the diastole plus respiratory motion were created to simulate the scenario where cardiac motion is not fully captured on 4D respiratory CT scans used for radiation therapy planning. RESULTS: The average volume of the 17 segments was 6 cm3 (1-9 cm3). Cardiac contraction-relaxation resulted in maximum segment (centroid) motion of 4, 6, and 3.5 mm in the superior-inferior, posterior-anterior, and left-right direction, respectively. Cardiac contraction-relaxation resulted in a motion envelope increase of 49% (24%-79%) compared with individual segment volumes, whereas envelopes increased by 126% (79%-167%) if respiratory motion also was considered. Envelopes incorporating only the diastole and respiration motion covered on average 68% to 75% of the motion envelope. CONCLUSIONS: The developed LV-segmental XCAT framework showed that free-wall regions display the most cardiorespiratory displacement. Our framework supports the optimization of STAR by evaluating the effect of (cardio)respiratory motion and motion management strategies for patients with VT.

A pooled analysis of nine studies in one institution to assess effects of whole heart irradiation in rat models.

PURPOSE: Over the years, animal models of local heart irradiation have provided insight into mechanisms of and treatments for radiation-induced heart disease in human populations. However, it is not completely clear which manifestations of radiation injury are most commonly seen after whole heart irradiation, and whether certain biological factors impact experimental results. Combining 9 homogeneous studies in rat models of whole heart irradiation from one laboratory, we sought to identify experimental and/or biological factors that impact heart outcomes. We evaluated the usefulness of including (1) heart rate and (2) bodyweight as covariates when analyzing biological parameters, and (3) we determined which echocardiography, histological, and immunohistochemistry parameters are most susceptible to radiation effects. Finally, (4) as an educational example, we illustrate a hypothetical sample size calculation for a study design commonly used in evaluating radiation modifiers, using the pooled estimates from the 9 rat studies only for context. The results may assist investigators in the design and analyses of pre-clinical studies of whole heart irradiation. MATERIALS AND METHODS: We made use of data from 9 rat studies from our labs, 8 published elsewhere in 2008-2017, and one unpublished study. Echocardiography, histological, and immunohistochemical parameters were collected from these studies. Using mixed effects analysis of covariance models, we estimated slopes for heart rate and bodyweight and estimated the radiation effect on each of the parameters. RESULTS: Bodyweight was related to most echocardiography parameters, and heart rate had an effect on echocardiography parameters related to the diameter of the left ventricle. For some parameters, there was evidence that heart rate and bodyweight relationships with the parameter depended on whether the rats were irradiated. Radiation effects were found in systolic measures of echocardiography parameters related to the diameter of the left ventricle, with ejection fraction and fractional shortening, with atrial wall thickness, and with histological measures of capillary density, collagen deposition, and mast cells infiltration in the heart. CONCLUSION: Accounting for bodyweight, as well as heart rate, in analyses of echocardiography parameters should reduce variability in estimated radiation effects. Several echocardiography and histological parameters were particularly susceptible to whole heart irradiation, showing robust effects compared to sham-irradiation. Lastly, we provide an example approach for a sample size calculation that will contribute to a rigorous study design and reproducibility in experiments studying radiation modifiers.

An open source auto-segmentation algorithm for delineating heart and substructures - Development and validation within a multicenter lung cancer cohort.

BACKGROUND AND PURPOSE: Irradiation of the heart in thoracic cancers raises toxicity concerns. For accurate dose estimation, automated heart and substructure segmentation is potentially useful. In this study, a hybrid automatic segmentation is developed. The accuracy of delineation and dose predictions were evaluated, testing the method's potential within heart toxicity studies. MATERIALS AND METHODS: The hybrid segmentation method delineated the heart, four chambers, three large vessels, and the coronary arteries. The method consisted of a nnU-net heart segmentation and partly atlas- and model-based segmentation of the substructures. The nnU-net training and atlas segmentation was based on lung cancer patients and was validated against a national consensus dataset of 12 patients with breast cancer. The accuracy of dose predictions between manual and auto-segmented heart and substructures was evaluated by transferring the dose distribution of 240 previously treated lung cancer patients to the consensus data set. RESULTS: The hybrid auto-segmentation method performed well with a heart dice similarity coefficient (DSC) of 0.95, with no statistically significant difference between the automatic and manual delineations. The DSC for the chambers varied from 0.78-0.86 for the automatic segmentation and was comparable with the inter-observer variability. Most importantly, the automatic segmentation was as precise as the clinical experts in predicting the dose distribution to the heart and all substructures. CONCLUSION: The hybrid segmentation method performed well in delineating the heart and substructures. The prediction of dose by the automatic segmentation was aligned with the manual delineations, enabling measurement of heart and substructure dose in large cohorts. The delineation algorithm will be available for download.

Comparing breath hold versus free breathing irradiation for left-sided breast radiotherapy by PlanIQ™.

BACKGROUND: Breast cancer is the most widespread cancer in women and young women worldwide. Moving towards customised radiotherapy, balancing the use of the available technology with the best treatment modality may not be an easy task in the daily routine. This study aims to evaluate the effectiveness of introducing IQ-feasibility into clinical practice to support the decision of free-breathing (FB) versus breath-hold (BH) left-sided breast irradiations, in order to optimise the technology available and the effectiveness of the treatment. METHODS: Thirty-five patients who received 3D radiotherapy treatment of the left breast in deep-inspiration BH were included in this retrospective study. Computed tomography scans in FB and BH were acquired for each patient; targets contoured in both imaging datasets by an experienced radiation oncologist, and organs at risk delineated using automatic segmentation software were exported to PlanIQ™ (Sun Nuclear Corp.) to generate feasibility dose volume histogram (FDVHs). The dosimetric parameter of BH versus FB FDVH, and BH clinical dataset versus BH FDVH were compared. RESULTS: A total of 30 patients out of 35 patients analysed, presented for the BH treatments a significant reduction (p < 0.05) in the heart mean dose ([Formula: see text]), volume receiving 5 Gy ([Formula: see text]) and 20 Gy ([Formula: see text]), of 35.7%, 54.5%, and 2.1%, respectively; for the left lung, a lower reduction was registered and significant only for [Formula: see text] (21.4%, p = 0.046). For the remaining five patients, the FDVH cut-off points of heart and lung were superimposable with differences of less than 1%. Heart and left lung dosimetric parameters of the BH clinical plans are located in the difficult zone of the FDVH and differ significantly (p < 0.05) from the corresponding parameters of the FDVH curves delimiting this buffer area between the impossible and feasible zones, respectively. CONCLUSION: The use of PlanIQTM as a decision-support tool for the FB versus BH treatment delivery modality allows customisation of the treatment technique using the most appropriate technology for each patient enabling accurate management of available technologies.

Active Breathing Coordinator reduces radiation dose to the stomach in patients with left breast cancer.

BACKGROUND/PURPOSE: Gastric dose parameters comparison for deep inspiration breath-hold (DIBH) or free breathing (FB) mode during radiotherapy (RT) for left-sided breast cancer patients (LSBCPs) has not been investigated before. This study aimed to analyze the impact of Active Breath Coordinator (ABC)-DIBH technique on the dose received by the stomach during RT for LSBCPs and to provide organ-specific dosimetric parameters. MATERIALS AND METHODS: The study included 73 LSBCPs. The dosimetric parameters of the stomach were compared between FB and DIBH mode. The correlation between the stomach volume and dosimetric parameters was analyzed. RESULTS: Compared to FB mode, statistically significant reductions were observed in gastric dose parameters in ABC-DIBH mode, including Dmax (46.60 vs 17.25, p < 0.001), D1cc (38.42 vs 9.60, p < 0.001), Dmean (4.10 vs 0.80, p < 0.001), V40Gy (0.50 vs 0.00, p < 0.001), V30Gy (6.30 vs 0.00, p < 0.001), V20Gy (20.80 vs 0.00, p < 0.001), V10Gy (51.10 vs 0.77, p < 0.001), and V5Gy (93.20 vs 9.60, p < 0.001). ABC-DIBH increased the distance between the stomach and the breast PTV when compared to FB, from 1.3 cm to 2.8 cm (p < 0.001). Physiologic decrease in stomach volume was not found from FB to ABC-DIBH (415.54 cm3 vs 411.61 cm3, p = 0.260). The stomach volume showed a positive correlation with V40Gy (r2 = 0.289; p < 0.05), V30Gy (r2 = 0.287; p < 0.05), V20Gy (r2 = 0.343; p < 0.05), V10Gy (r2 = 0.039; p < 0.001), V5Gy (r2 = 0.439; p < 0.001), Dmax (r2 = 0.269; p < 0.05) and D1cc (r2 = 0.278; p < 0.05) in FB mode. While in ABC-DIBH mode, most stomach dosimetric parameters were not correlated with gastric volume. CONCLUSIONS: The implementation of ABC-DIBH in LSBCPs radiotherapy resulted in lower irradiation of the stomach. Larger stomach volume was associated with statistically significantly higher dose irradiation in FB mode. To reduce radiotherapy related side effects in FB mode, patients should be fast for at least 2 hours before the CT simulation and treatment.

Radiation therapy in the thoracic region: Radio-induced cardiovascular disease, cardiac delineation and sparing, cardiac dose constraints, and cardiac implantable electronic devices.

Radiation therapy in the thoracic region may deliver incidental ionizing radiation to the surrounding healthy structures, including the heart. Radio-induced heart toxicity has long been a concern in breast cancer and Hodgkin's lymphoma and was deemed a long-term event. However, recent data highlight the need to limit the dose to the heart in less favorable thoracic cancers too, such as lung and esophageal cancers in which incidental irradiation led to increased mortality. This article will summarize available cardiac dose constraints in various clinical settings and the types of radio-induced cardiovascular diseases encountered as well as delineation of cardiac subheadings and management of cardiac devices. Although still not completely deciphered, heart dose constraints remain intensively investigated and the mean dose to the heart is no longer the only dosimetric parameter to consider since the left anterior descending artery as well as the left ventricle should also be part of dosimetry constraints.

Regional nodal irradiation in breast cancer patients: Effects of deep inspiration breath hold on the internal mammary chain location.

The purpose of this study was to investigate the impact of deep inspiration breath hold (DIBH) on the positioning of thoracic structures and provide treatment planning recommendations for internal mammary chain (IMC) irradiation in breast cancer patients. Thirty-two breast cancer patients from our database underwent both DIBH and free breathing (FB) treatment planning. Contouring of the axillary lymph node clinical target volumes (CTVs: level I, II, III, IV, and IMC according to ESTRO), the internal mammary artery (IMA), the heart, and the left anterior descending artery (LAD) was performed. The following were then analyzed: the distance between the IMA and the heart, the craniocaudal distance in which IMC-CTV and heart coexist, the craniocaudal distance between the lower end of the of level III and IV and the upper end of the heart. Several significant geometric differences were observed between DIBH and FB that explain the efficacy of the DIBH for regional nodal irradiation. In >80% of patients the cranial origin of the LAD lies below the lower edge of the IMC-CTV in DIBH. In addition the slices in which the heart/LAD and IMC-CTV coexist decrease during DIBH. The IMA-heart distance is significantly larger in DIBH. Also the craniocaudal distance between the lower border of the CTV level III and IV and the upper border of the heart is larger in DIBH. The observed mechanisms during DIBH contribute significantly to the dose reduction in regional nodal irradiation. To further enhance the benefits of DIBH for the irradiation of the IMC-CTV, it is recommended to implement steep dose gradients in the caudal plane.

Can we predict the cardiac benefit of deep inspiration breath hold for left breast and regional nodal irradiation?

PURPOSE: Deep inspiration breath hold (DIBH) is used to decrease the dose of radiotherapy delivered to the heart. There is a need to define criteria to select patients with the potential to derive a real clinical benefit from DIBH treatment. Our study's main goal was to investigate whether two CT-scan cardiac anatomical parameters, cardiac contact distance in the parasagittal plane (CCDps) and lateral heart-to-chest distance (HCD), were predictive of unmet dosimetric cardiac constraints for left breast and regional nodal irradiation (RNI). MATERIALS AND METHODS: This retrospective single-institution dosimetric study included 62 planning CT scans of women with left-sided breast cancer (BC) from 2016 to 2021. Two independent radiation oncologists measured HCD and CCDps twice to assess inter- and intra-observer reproducibility. Dosimetric constraints to be respected were defined, and dosimetric parameters of interest were collected for each patient. RESULTS: Mean heart dose was 7.9Gy. Inter-rater reproducibility between the two readers was considered excellent. The mean heart dose constraint<8Gy was not achieved in 25 patients (40%) and was achieved in 37 patients (60%). There was a significant correlation between mean heart dose and HCD (rs=-0.25, P=0.050) and between mean heart dose and CCDps (rs=0.25, P=0.047). The correlation between HCD and CCDps and unmet cardiac dosimetric constraints was not statistically significant. CONCLUSION: Our dosimetric analysis did not find that the cardiac anatomical parameters HCD and CCDps were predictive of unmet dosimetric cardiac constraints, nor that they were good predictors for cardiac exposure in left-sided BC radiotherapy comprising RNI.

Effects of proton and oxygen ion irradiation on cardiovascular function and structure in a rabbit model.

PURPOSE: Astronauts on missions beyond low Earth orbit will be exposed to galactic cosmic radiation, and there is concern about potential adverse cardiovascular effects. Most of the research to identify cardiovascular risk of space radiation has been performed in rodent models. To aid in the translation of research results to humans, the current study identified long-term effects of high-energy charged particle irradiation on cardiovascular function and structure in a larger non-rodent animal model. MATERIALS AND METHODS: At the age of 12 months, male New Zealand white rabbits were exposed to whole-body protons (250 MeV) or oxygen ions (16O, 600 MeV/n) at a dose of 0 or 0.5 Gy and were followed for 12 months after irradiation. Ultrasonography was used to measure in vivo cardiac function and blood flow parameters at 10- and 12-months post-irradiation. At 12 months after irradiation, blood cell counts and blood chemistry values were assessed, and cardiac tissue and aorta were collected for histological as well as molecular and biochemical analyses. Plasma was used for metabolomic analysis and to quantify common markers of cardiac injury. RESULTS: A small but significant decrease in the percentage of circulating lymphocytes and an increase in neutrophil percentage was seen 12 months after 0.5 Gy protons, while 16O exposure resulted in an increase in monocyte percentage. Markers of cardiac injury, cardiac troponin I (cTnI) and N-Terminal pro-B-type Natriuretic Peptide were modestly increased in the proton group, and cTnI was also increased after 16O. On the other hand, metabolomics on plasma at 12 months revealed no changes. Both types of irradiation demonstrated alterations in cardiac mitochondrial morphology and an increase in left ventricular protein levels of inflammatory cell marker CD68. However, changes in cardiac function were only mild. CONCLUSION: Low dose charged particle irradiation caused mild long-term changes in inflammatory markers, cardiac function, and structure in the rabbit heart, in line with previous studies in mouse and rat models.

SGRT-based DIBH radiotherapy practice for right-sided breast cancer combined with RNI: A retrospective study on dosimetry and setup accuracy.

BACKGROUND: We retrospectively studied the dosimetry and setup accuracy of deep inspiration breath-hold (DIBH) radiotherapy in right-sided breast cancer patients with regional nodal irradiation (RNI) who had completed treatment based on surface-guided radiotherapy (SGRT) technology by Sentinel/Catalyst system, aiming to clarify the clinical application value and related issues. METHODS: Dosimetric indicators of four organs at risk (OARs), namely the heart, right coronary artery (RCA), right lung, and liver, were compared on the premise that the planning target volume met dose-volume prescription requirements. Meanwhile, the patients were divided into the edge of the xiphoid process (EXP), sternum middle (SM), and left breast wall (LBW) groups according to different positions of respiratory gating primary points. The CBCT setup error data of the three groups were contrasted for the treatment accuracy study, and the effects of different gating window heights on the right lung volume increases were compared among the three groups. RESULTS: Compared with free breath (FB), DIBH reduced the maximum dose of heart and RCA by 739.3 ± 571.2 cGy and 509.8 ± 403.8 cGy, respectively (p < 0.05). The liver changed the most in terms of the mean dose (916.9 ± 318.9 cGy to 281.2 ± 150.3 cGy, p < 0.05). The setup error of the EXP group in the anterior-posterior (AP) direction was 3.6 ± 4.5 mm, which is the highest among the three groups. The right lung volume increases in the EXP, SM, and LBW groups were 72.3%, 69.9%, and 67.2%, respectively (p = 0.08), and the corresponding breath-holding heights were 13.5 ± 3.7 mm, 10.3 ± 2.4 mm, and 9.6 ± 2.8 mm, respectively (p < 0.05). CONCLUSIONS: SGRT-based DIBH radiotherapy can better protect the four OARs of right-sided breast cancer patients with RNI. Different respiratory gating primary points have different setup accuracy and breath-hold height.

Radiation Treatment Mechanisms of Cardiotoxicity: A Systematic Review.

Radiotherapy may be used alone or in combination with chemotherapy for cancer treatment. There are many mechanisms of radiation treatment exposure to toxicities. Our aim was to summarize the literature about known mechanisms of radiation-induced cardiac toxicities. We performed a systematic review of the literature on the PubMed database until October 2022 about cardiovascular toxicities and radiation therapy exposure. Only systematic reviews, meta-analyses, and reviews were selected. Out of 1429 publications screened, 43 papers met inclusion criteria and were selected for the umbrella review process. Microvascular and macrovascular complications could lead to adverse cardiac effects. Many radiotherapy-associated risk factors were responsible, such as the site of radiation treatment, beam proximity to heart tissues, total dosage, the number of radiotherapy sessions, adjuvant chemotherapeutic agents used, and patient traditional cardiovascular risk factors, patient age, and gender. Moreover, important dosage cutoff values could increase the incidence of cardiac toxicities. Finally, the time from radiation exposure to cardiac side effects was assessed. Our report highlighted mechanisms, radiation dosage values, and the timeline of cardiovascular toxicities after radiation therapy. All of the above may be used for the assessment of cardiovascular risk factors and the development of screening programs for cancer patients.

Cardiac impacts of postoperative radiotherapy for breast cancer in Japanese patients.

Radiotherapy for breast cancer has attracted attention in Western countries because radiation to the heart can cause cardiac events. The purposes of this study were to evaluate the relationship between radiotherapy after breast-conserving surgery and the frequency of cardiac events in Japanese patients and to investigate the risk factors of cardiac events after postoperative radiotherapy in those patients. Female patients who received postoperative radiotherapy following breast-conserving surgery between 2007 and 2012 at our hospital were evaluated. In this study, we estimated the cumulative incidence of cardiac events including angina pectoris, myocardial infarction, ischemic heart disease, heart failure and cardiomyopathy after radiotherapy. Of 311 eligible patients, 7.1% of the patients had a smoking history, 20.3% of the patients were obese and 22.2% of the patients had hypertension. The median follow-up period was 118 months (interquartile range, 102-132 months). Twelve patients (3.9%) experienced cardiac events after treatment. The mean time to cardiac events was 126 months. The 10-year cumulative incidences of cardiac events after treatment were 4.2% and 4.3% for patients with left-sided and right-sided breast cancer, respectively, without a significant difference. Multivariate analysis showed that only hypertension was a risk factor for cardiac events (hazard ratio = 16.67, P = 0.0003). In conclusion, postoperative radiotherapy for breast cancer did not increase the incidence of cardiac events. Since at least 2007, postoperative radiotherapy for breast cancer has been safely performed without effects on the heart.

Acute coronary event (ACE) prediction following breast radiotherapy by features extracted from 3D CT, dose, and cardiac structures.

PURPOSE: Heart toxicity, such as major acute coronary events (ACE), following breast radiation therapy (RT) is of utmost concern. Thus, many studies have been investigating the effect of mean heart dose (MHD) and dose received in heart sub-structures on toxicity. Most studies focused on the dose thresholds in the heart and its sub-structures, while few studies adopted such computational methods as deep neural networks (DNN) and radiomics. This work aims to construct a feature-driven predictive model for ACE after breast RT. METHODS: A recently proposed two-step predictive model that extracts a number of features from a deep auto-segmentation network and processes the selected features for prediction was adopted. This work refined the auto-segmenting network and feature processing algorithms to enhance performance in cardiac toxicity prediction. In the predictive model, the deep convolutional neural network (CNN) extracted features from 3D computed tomography (CT) images and dose distributions in three automatically segmented heart sub-structures, including the left anterior descending artery (LAD), right coronary artery (RCA), and left ventricle (LV). The optimal feature processing workflow for the extracted features was explored to enhance the prediction accuracy. The regions associated with toxicity were visualized using a class activation map (CAM)-based technique. Our proposed model was validated against a conventional DNN (convolutional and fully connected layers) and radiomics with a patient cohort of 84 cases, including 29 and 55 patient cases with and without ACE. Of the entire 84 cases, 12 randomly chosen cases (5 toxicity and 7 non-toxicity cases) were set aside for independent test, and the remaining 72 cases were applied to 4-fold stratified cross-validation. RESULTS: Our predictive model outperformed the conventional DNN by 38% and 10% and radiomics-based predictive models by 9% and 10% in AUC for 4-fold cross-validations and independent test, respectively. The degree of enhancement was greater when incorporating dose information and heart sub-structures into feature extraction. The model whose inputs were CT, dose, and three sub-structures (LV, LAD, and RCA) reached 96% prediction accuracy on average and 0.94 area under the curve (AUC) on average in the cross-validation, and also achieved prediction accuracy of 83% and AUC of 0.83 in the independent test. On 10 correctly predicted cases out of 12 for the independent test, the activation maps implied that for cases of ACE toxicity, the higher intensity was more likely to be observed inside the LV. CONCLUSIONS: The proposed model characterized by modifications in model input with dose distributions and cardiac sub-structures, and serial processing of feature extraction and feature selection techniques can improve the predictive performance in ACE following breast RT.

Differences in radiation-induced heart dysfunction in male versus female rats.

PURPOSE: Radiation therapy remains part of the standard of care for breast, lung, and esophageal cancers. While radiotherapy improves local control and survival, radiation-induced heart dysfunction is a common side effect of thoracic radiotherapy. Cardiovascular dysfunction can also result from non-therapeutic total body radiation exposures. Numerous studies have evaluated the relationship between radiation dose to the heart and cardiotoxicity, but relatively little is known about whether there are differences based on biological sex in radiation-induced heart dysfunction (RIHD). MATERIALS AND METHODS: We evaluated whether male and female inbred Dahl SS rats display differences in RIHD following delivery of 24 Gy in a single fraction to the whole heart using a 1.5 cm beam size (collimater). We also compared the 2.0 cm vs. 1.5 cm collimator in males. Pleural and pericardial effusions and normalized heart weights were measured, and echocardiograms were performed. RESULTS: Female SS rats displayed more severe RIHD relative to age-matched SS male rats. Normalized heart weight was significantly increased in females, but not in males. A total of 94% (15/16) of males and 55% (6/11) of females survived 5 months after completion of radiotherapy (p < .01). Among surviving rats, 100% of females and 14% of males developed moderate-to-severe pericardial effusions at 5 months. Females demonstrated increased pleural effusions, with the mean normalized pleural fluid volume for females and males being 56.6 mL/kg ± 12.1 and 10.96 mL/kg ± 6.4 in males (p = .001), respectively. Echocardiogram findings showed evidence of heart failure, which was more pronounced in females. Because age-matched female rats have smaller lungs, a higher percentage of the total lung was treated with radiation in females than males using the same beam size. After using a larger 2 cm beam in males which results in higher lung exposure, there was not a significant difference between males and females in terms of the development of moderate-to-severe pericardial effusions or pleural effusions. Treatment of males with a 2 cm beam resulted in comparable increases in LV mass and reductions in stroke volume to female rats treated with a 1.5 cm beam. CONCLUSION: Together, these results illustrate that there are differences in radiation-induced cardiotoxicity between male and female SS rats and add to the data that lung radiation doses, in addition to other factors, may play an important role in cardiac dysfunction following heart radiation exposure. These factors may be important to factor into future mitigation studies of radiation-induced cardiotoxicity.

Voluntary versus mechanically-induced deep inspiration breath-hold for left breast cancer: A randomized controlled trial.

BACKGROUND AND PURPOSE: Deep inspiration breath-hold (DIBH) protects critical organs-at-risk (OARs) for adjuvant breast radiotherapy. Guidance systems e.g. surface guided radiation therapy (SGRT) improve the positional breast reproducibility and stability during DIBH. In parallel, OARs sparing with DIBH is enhanced through different techniques e.g. prone position, continuous positive airway pressure (CPAP). By inducing repeated DIBH with the same level of positive pressure, mechanically-assisted and non-invasive ventilation (MANIV) could potentially combine these DIBH optimizations. MATERIALS AND METHODS: We conducted a randomized, open-label, multicenter and single-institution non-inferiority trial. Sixty-six patients eligible for adjuvant left whole-breast radiotherapy in supine position were equally assigned between mechanically-induced DIBH (MANIV-DIBH) and voluntary DIBH guided by SGRT (sDIBH). The co-primary endpoints were positional breast stability and reproducibility with a non-inferiority margin of 1 mm. Secondary endpoints were tolerance assessed daily via validated scales, treatment time, dose to OARs and their inter-fraction positional reproducibility. RESULTS: Differences between both arms for positional breast reproducibility and stability occurred at a sub-millimetric level (p < 0.001 for non-inferiority). The left anterior descending artery near-max dose (14,6 ± 12,0 Gy vs. 7,7 ± 7,1 Gy, p = 0,018) and mean dose (5,0 ± 3,5 Gy vs. 3,0 ± 2,0 Gy, p = 0,009) were improved with MANIV-DIBH. The same applied for the V5Gy of the left ventricle (2,4 ± 4,1 % vs. 0,8 ± 1,6 %, p = 0,001) as well as for the left lung V20Gy (11,4 ± 2,8 % vs. 9,7 ± 2,7 %, p = 0,019) and V30Gy (8,0 ± 2,6 % vs. 6,5 ± 2,3 %, p = 0,0018). Better heart's inter-fraction positional reproducibility was observed with MANIV-DIBH. Tolerance and treatment time were similar. CONCLUSION: Mechanical ventilation provides the same target irradiation accuracy as with SGRT while better protecting and repositioning OARs.