Cardiac Radiation Dose Research Articles

Cardiotoxicity following thoracic radiotherapy for lung cancer.

Radiotherapy is the standard of care treatment for unresectable NSCLC, combined with concurrent chemotherapy and adjuvant immunotherapy. Despite technological advances in radiotherapy planning and delivery, the risk of damage to surrounding thoracic tissues remains high. Cardiac problems, including arrhythmia, heart failure and ischaemic events, occur in 20% of patients with lung cancer who undergo radiotherapy. As survival rates improve incrementally for this cohort, minimising the cardiovascular morbidity of RT is increasingly important. Problematically, the reporting of cardiac endpoints has been poor in thoracic radiotherapy clinical trials, and retrospective studies have been limited by the lack of standardisation of nomenclature and endpoints. How baseline cardiovascular profile and cardiac substructure radiation dose distribution impact the risk of cardiotoxicity is incompletely understood. As Thoracic Oncology departments seek to expand the indications for radiotherapy, and as the patient cohort becomes older and more comorbid, there is a pressing need for cardiotoxicity to be comprehensively characterised with sophisticated oncology, physics and cardio-oncology evaluations. This review synthesises the evidence base for cardiotoxicity in conventional radiotherapy, focusing on lung cancer, including current data, unmet clinical needs, and future scientific directions.

How Effective is Deep Inspiration Breath Hold in Minimizing Cardiac Doses During Hybrid Radiotherapy Treatment for Left-Sided Breast Cancer with Comprehensive Regional Nodes?

In the context of left breast cancer radiotherapy, long term cardiopulmonary toxicity has been well-documented, significant efforts have been undertaken to mitigate such toxicity by using 4D gating, deep inspiration breath-hold(DIBH) and active breath control(ABC) techniques. To evaluate and compare the cardio-pulmonary radiation doses incurred during postmastectomy radiotherapy (PMRT) in two distinct breathing conditions such as DIBH and Free Breathing (FB), with a specific focus on the left chest wall with comprehensive regional nodal irradiation. A prospective dosimetric study was conducted on 15 patients who received adjuvant loco-regional radiotherapy of chest-wall (CW), supraclavicular fossa(SCF), and internal mammary region(IMC), with or without axilla. Two sets of planning CT scans were taken in DIBH and FB conditions. The dosimetric difference between DIBH CT and FB CT plans analyzed using Wilcoxon signed-rank test, employing SPSS software version 21.0. Comparison of DIBH and FB parameters for target coverage revealed a statistically significant advantage with DIBH in SCF(D95, V90, p<0.017) and IMC(D98, V90 & V95, p<0.03). Dosimetric characteristics of heart and LAD exhibited statistically significant lower doses with DIBH (V20, V25, and Dmean, p<0.001) compared to FB plans. Lung doses were similar with no discernible advantage of one technique over the other. Other OARs such as contralateral breast (p=0.027) and esophagus (p=0.001) received lower doses with the DIBH technique while the spinal cord (p=0.691) and thyroid(p=0.496) showed no significant difference. Maximum heart distance (p= 0.001), central lung distance (p= 0.011) and Haller index (p= 0.001) exhibited statistical significance between the two techniques, whereas chest wall separation showed no significant statistical difference (p=0.629). DIBH demonstrates a substantial reduction in cardiac and LAD doses compared to the FB technique. This study underscores the efficacy of DIBH as a viable strategy for mitigating cardiac and LAD radiation doses in left-sided breast cancer patients undergoing PMRT of chest wall with comprehensive regional nodes.

Cancer therapy-related cardiac dysfunction after radiation therapy for breast cancer: results from the BACCARAT cohort study

BackgroundRadiation therapy (RT) for breast cancer (BC) can result in subtle cardiac dysfunction that can occur early after treatment. In 2022, the European Society of Cardiology (ESC) published the first guidelines in cardio-oncology with a harmonized definition of cancer therapy-related cardiac dysfunction (CTRCD). The aim of this study was to evaluate CTRCD occurrence over 24 months of follow-up after RT in BC patients and to analyze the association with cardiac radiation exposure.MethodsThe prospective monocentric BACCARAT study included BC patients treated with RT without chemotherapy, aged 40–75 years, with conventional and 2D Speckle tracking echocardiography performed before RT, 6 and 24 months after RT. Based on ESC cardio-oncology guidelines, CTRCD and corresponding severity were defined with left ventricle ejection fraction and global longitudinal strain decrease, occurring at 6 or 24 months after RT. Dosimetry for whole heart, left ventricle (LV) and left coronary artery (left anterior descending and circumflex arteries (CX)) was considered to evaluate the association with CTRCD, based on logistic regressions (Odds Ratio – OR and 95% confidence interval – 95%CI). Youden index based on receiver operating characteristic curve analysis was used to identify the optimal threshold of dose-volume parameters for predicting CTRCD.ResultsThe study included 72 BC patients with a mean age of 58 ± 8.2 years. A total of 32 (44%) patients developed CTRCD during follow-up: 20 (28%) mild CTRCD, 7 (9%) moderate CTRCD, and 5 (7%) severe CTRCD. Cardiac radiation doses were generally higher among patients with CTRCD rather than non-CTRCD. Dose-response relationships were significant for mean CX dose (OR = 2.48, 95%CI (1.12–5.51), p = 0.02) and marginally significant for V2 of LV (OR = 1.03 95%CI (1.00-1.06), p = 0.05). V2 of LV ≥ 36% and mean CX dose ≥ 1.40 Gy thresholds were determined to be optimal for predicting CTRCD.ConclusionFor BC patients treated with RT without chemotherapy, CTRCD can be observed in an important proportion of the population over 24 months after treatment. Left ventricle and circumflex coronary artery exposure were found to be associated with CTRCD and could be used for the prediction of such cardiotoxicity. Further research remains needed to confirm these results.Trial RegistrationClinicalTrials.gov Identifier- NCT02605512.

Cardiac Substructure Radiation Dose and Associations With Tachyarrhythmia and Bradyarrhythmia After Lung Cancer Radiotherapy

BackgroundArrhythmias are common following radiotherapy for non–small cell lung cancer. ObjectivesThe aim of this study was to analyze the association of distinct arrhythmia classes with cardiac substructure radiotherapy dose. MethodsA retrospective analysis was conducted of 748 patients with locally advanced non–small cell lung cancer treated with radiotherapy. Cardiac substructure dose parameters were calculated. Receiver-operating characteristic curve analyses for predictors of Common Terminology Criteria for Adverse Events grade ≥3 atrial fibrillation (AF), atrial flutter, non-AF and non–atrial flutter supraventricular tachyarrhythmia (SVT), bradyarrhythmia, and ventricular tachyarrhythmia (VT) or asystole were calculated. Fine-Gray regression models were performed (with noncardiac death as a competing risk). ResultsOf 748 patients, 128 (17.1%) experienced at least 1 grade ≥3 arrhythmia, with a median time to first arrhythmia of 2.0 years (Q1-Q3: 0.9-4.2 years). The 2-year cumulative incidences of each arrhythmia group were 8.0% for AF, 2.7% for atrial flutter, 1.8% for other SVT, 1.4% for bradyarrhythmia, and 1.1% for VT or asystole. Adjusting for baseline cardiovascular risk, pulmonary vein (PV) volume receiving 5 Gy was associated with AF (subdistribution HR [sHR]: 1.04/mL; 95% CI: 1.01-1.08; P = 0.016), left circumflex coronary artery volume receiving 35 Gy with atrial flutter (sHR: 1.10/mL; 95% CI: 1.01-1.19; P = 0.028), PV volume receiving 55 Gy with SVT (sHR: 1.03 per 1%; 95% CI: 1.02-1.05; P < 0.001), right coronary artery volume receiving 25 Gy with bradyarrhythmia (sHR: 1.14/mL; 95% CI: 1.00-1.30; P = 0.042), and left main coronary artery volume receiving 5 Gy with VT or asystole (sHR: 2.45/mL; 95% CI: 1.21-4.97; P = 0.013). ConclusionsThis study revealed pathophysiologically distinct arrhythmia classes associated with radiotherapy dose to discrete cardiac substructures, including PV dose with AF and SVT, left circumflex coronary artery dose with atrial flutter, right coronary artery dose with bradyarrhythmia, and left main coronary artery dose with VT or asystole, guiding potential risk mitigation approaches.

Uncovering the connection between Ly6ChiCD103+ myeloid cells and radiation-induced cardiac fibrosis by CyTOF

Several immune cell populations participate in the development of radiation-induced cardiac fibrosis. However, the underlying mechanism remains to be elucidated. Male C57BL/6 mice (8–12 weeks old) were anesthetized and exposed to a single cardiac radiation dose of 20 Gy using the small-animal radiation research platform. We conducted echocardiography and histological analysis to identify cardiac fibrosis from a functional and pathological perspective. Time-of-flight mass cytometry (CyTOF) was used to describe the compositional changes of immune cells 1, 4, and 8 weeks after cardiac irradiation in mouse peripheral blood and cardiac tissue samples. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to measure CD14 and CD105 mRNA levels from peripheral blood cells in eight patients who received thoracic radiotherapy 6 months ago. We observed reduced cardiac systolic function and increased collagen deposition in cardiac tissue after irradiation. Transforming growth factor-β, tumor necrosis factor-α, and interleukin-6 expression significantly elevated in the plasma. We identified a significant increase in CD45+ immune cell levels four weeks after cardiac irradiation using CyTOF, and neutrophil, monocyte, and macrophage levels elevated in blood samples after cardiac irradiation (four weeks). In cardiac tissue samples, monocyte and macrophage levels increased after cardiac irradiation (four weeks) compared with control group. Macrophages and monocytes were further analyzed, and the proportion of Ly6ChiCD103+ myeloid cells increased after cardiac irradiation in tissue samples (four weeks). RT-qPCR revealed that CD14 expression was higher in patients with cardiac injured group than in the control group (Previous studies reported that Ly6Chi monocytes in mice are similar to CD14 + CD16− monocytes in humans). We found that Ly6ChiCD103+ myeloid cells are critical subsets in radiation-induced cardiac fibrosis and might play protective roles in the process. Ly6ChiCD103+ myeloid cells may be considered an early biomarker for detecting radiation-induced cardiac fibrosis.

Cardiac substructure radiation dose study of conventional radiotherapy for stage N2-3 non-small cell lung cancer.

e20071 Background: There has been widespread reporting on predictive dose parameters for cardiac substructures in radiotherapy for non-small cell lung cancer (NSCLC). However, most advanced NSCLC patients are staged as N2-3, and there is a lack of research on the dose distribution, dose contribution and prognosis of the heart in conventional radiotherapy for N2-3 stage NSCLC. Methods: Retrospective analysis of 274 patients of stage N2-3 NSCLC treated with radiotherapy (RT) of prescription dose from 60Gy to 70Gy. Experienced radiation oncologists delineated the cardiac substructures. All patients were categorized according to different lymph node irradiation and tumor spatial locations. Spearman and linear regression were used for variation of dose-volume parameters, as well as the impact of different primary tumor locations and irradiated lymph nodes on the parameters of the entire heart and substructures. Receiver operating characteristic (ROC) curves, Kaplan-Meier, and Cox regression were performed on the influencing factors of adverse cardiac events after radiotherapy and prognosis analysis. Results: There are significant differences in the dose-volume parameters of the whole heart and its substructures. Mean heart doses (MHD),and the mean doses (Dmean) for the left atrium, right atrium, right ventricle, left ventricle and the left anterior descending coronary artery (LAD) were 15.7Gy (range 0.2-30.0Gy), 19.7Gy (range 0.3-55.0Gy), 9.7Gy (range 0.3-59.8Gy), 7.9Gy (range 0.1-48.2Gy), 6.4Gy (range 0.1-52.6Gy) and 5.2Gy (range 0.1-45.0Gy), respectively. The left atrium Dmean has the most significant impact on MHD compared to other substructures (B = 0.418, P &lt; 0.05). Dose-volume parameters of the whole heart and the left atrium were positively correlated with the irradiation of the 7th lymph node region (P &lt; 0.05). MHD and left atrium Dmean for tumors located in the lower region were significantly higher than those in the upper region (P &lt; 0.001). Patients with LAD V30 ≥ 26.9% had a significantly higher risk of mortality compared to those with LAD V30 &lt; 26.9% (P = 0.003, HR = 2.883, 95% CI = 1.436-5.788). Conclusions: With the dose distribution differences among the whole heart and its substructures. We observed the base of the heart received the highest dose, the dose to the left atrium is particularly required attention. The irradiation of different lymph nodes and different primary lesions has an impact on the dose variations of different cardiac structures. LAD V30 is an independent influencing factor of overall survival (OS) for N2-3 stage NSCLC. This study provides considerable information for the dose optimization of cardiac substructure in radiotherapy planning for N2-3 stage NSCLC.

1489: Impact of Cardiac Radiation Dose on Subclinical and Clinical Cardiotoxicity HER2+ Breast Cancer

1489: Impact of Cardiac Radiation Dose on Subclinical and Clinical Cardiotoxicity HER2+ Breast Cancer

Cardiac radiation dose is associated with inferior survival but not cardiac events in patients with locally advanced non-small cell lung cancer in the era of immune checkpoint inhibitor consolidation

PurposeWe assessed the association of cardiac radiation dose with cardiac events and survival post-chemoradiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) after adoption of modern radiation therapy (RT) techniques, stricter cardiac dose constraints, and immune checkpoint inhibitor (ICI) consolidation. Methods and MaterialsThis single-institution, multi-site retrospective study included 335 patients with LA-NSCLC treated with definitive, concurrent CRT between October 2017 and December 2021. All patients were evaluated for ICI consolidation. Planning dose constraints included heart mean dose < 20 Gy (<10 Gy if feasible) and heart volume receiving ≥ 50 Gy (V50Gy) < 25 %. Twenty-one dosimetric parameters for three different cardiac structures (heart, left anterior descending coronary artery [LAD], and left ventricle) were extracted. Primary endpoint was any major adverse cardiac event (MACE) post-CRT, defined as acute coronary syndrome, heart failure, coronary revascularization, or cardiac-related death. Secondary endpoints were: grade ≥ 3 cardiac events (per CTCAE v5.0), overall survival (OS), lung cancer-specific mortality (LCSM), and other-cause mortality (OCM). ResultsMedian age was 68 years, 139 (41 %) had baseline coronary heart disease, and 225 (67 %) received ICI consolidation. Proton therapy was used in 117 (35 %) and intensity-modulated RT in 199 (59 %). Median LAD V15Gy was 1.4 % (IQR 0–22) and median heart mean dose was 8.7 Gy (IQR 4.6–14.4). Median follow-up was 3.3 years. Two-year cumulative incidence of MACE was 9.5 % for all patients and 14.3 % for those with baseline coronary heart disease. Two-year cumulative incidence of grade ≥ 3 cardiac events was 20.4 %. No cardiac dosimetric parameter was associated with an increased risk of MACE or grade ≥ 3 cardiac events. On multivariable analysis, cardiac dose (LAD V15Gy and heart mean dose) was associated with worse OS, driven by an association with LCSM but not OCM. ConclusionsWith modern RT techniques, stricter cardiac dose constraints, and ICI consolidation, cardiac dose was associated with LCSM but not OCM or cardiac events in patients with LA-NSCLC.

Correlation of High-Sensitivity Cardiac Troponin I Values and Cardiac Radiation Doses in Patients with Left-Sided Breast Cancer Undergoing Hypofractionated Adjuvant Radiotherapy with Concurrent Anti-HER2 Therapy.

Anti HER2 therapy and left breast adjuvant radiation therapy (RT) can both result in cardiotoxicity. The aim of this study was to evaluate the influence of radiation dose on cardiac structures on the values of the early cardiotoxicity marker high-sensitivity cardiac troponin I (hscTnI) in patients with HER2-positive left breast cancer undergoing adjuvant concomitant antiHER2 therapy and radiotherapy, and to establish a correlation between the hscTnI values and cardiac radiation doses. Sixty-one patients underwent left breast hypofractionated radiotherapy in parallel with anti-HER2 therapy: trastuzumab, combined trastuzumab-pertuzumab or trastuzumab emtansine (T-DM1). The hscTnI values were measured prior to and upon completion of radiotherapy. A significant increase in hscTnI was defined as >30% from baseline, with the second value being 4 ng/L or higher. Dose volume histograms (DVH) were generated for the heart, left ventricle (LV) and left anterior descending artery (LAD). The hscTnI levels were corelated with radiation doses on cardiac structures. An increase in hscTnI values was observed in 17 patients (Group 1). These patients had significantly higher mean radiation doses for the heart (p = 0.02), LV (p = 0.03) and LAD (p = 0.04), and AUC for heart and LV (p = 0.01), than patients without hscTnI increase (Group 2). The patients in Group 1 also had larger volumes of heart and LV receiving 2 Gy (p = 0.01 for both) and 4 Gy (p = 0.02 for both). LAD differences were observed in volumes receiving 2 Gy (p = 0.03), 4 Gy (p = 0.02) and 5 Gy (p = 0.02). The increase in hscTnI observed in patients receiving anti-HER2 therapy after adjuvant RT was positively associated with radiation doses on the heart, LV and LAD.

Factors Associated With Cardiac Radiation Dose Reduction After Hypofractionated Radiation Therapy for Localized, Left-Sided Breast Cancer in a Large Statewide Quality Consortium

Limiting cardiac radiation dose is important for minimizing long-term cardiac toxicity in patients with left-sided early-stage breast cancer. Prospectively collected dosimetric data were analyzed for patients undergoing moderately hypofractionated radiation therapy to the left breast within the Michigan Radiation Oncology Quality Consortium from 2016 to 2022. The mean heart dose (MHD) goal was progressively tightened from ≤2 Gy in 2016 to MHD ≤ 1.2 Gy in 2018. In 2021, a planning target volume (PTV) coverage goal was added, and the goal MHD was reduced to ≤1 Gy. Multivariate logistic regression models were developed to assess for covariates associated with meeting the MHD goals in 2016 to 2020 and the combined MHD/PTV coverage goal in 2021 to 2022. In total, 4165 patients were analyzed with a median age of 64 years. Overall average cardiac metric compliance was 91.7%. Utilization of motion management increased from 41.8% in 2016 to 2020 to 46.5% in 2021 to 2022. Similarly, use of prone positioning increased from 12.2% to 22.2% in these periods. On multivariate analysis in the 2016 to 2020 cohort, treatment with motion management (odds ratio [OR], 5.20; 95% CI, 3.59-7.54; P < .0001) or prone positioning (OR, 3.21; 95% CI, 1.85-5.57; P < .0001) was associated with meeting the MHD goal, while receipt of boost (OR, 0.25; 95% CI, 0.17-0.39; P < .0001) and omission of hormone therapy (OR, 0.65; 95% CI, 0.49-0.88; P=.0047) were associated with not meeting the MHD goal. From 2021 to 2022, treatment with motion management (OR, 1.89; 95% CI, 1.12-3.21; P=.018) or prone positioning (OR, 3.71; 95% CI, 1.73-7.95; P=.0008) was associated with meeting the combined MHD/PTV goal, while larger breast volume (≥1440 cc; OR, 0.34; 95% CI, 0.13-0.91; P=.031) was associated with not meeting the combined goal. In our statewide consortium, high rates of compliance with aggressive targets for limiting cardiac dose were achievable without sacrificing target coverage.

Factors Associated with Cardiac Radiation Dose Reduction Following Hypofractionated Radiation Therapy for Localized, Left-Sided Breast Cancer in a Large Statewide Quality Consortium

Limiting radiation dose to the heart is important for minimizing the risk of long-term cardiac toxicity in patients with left-sided early-stage breast cancer. Prospectively collected dosimetric data were analyzed for patients undergoing hypofractionated radiation therapy to the left breast for localized node-negative breast cancer within the Michigan Radiation Oncology Quality Consortium (MROQC) from 2016-2022. Goals for limiting cardiac dose were adjusted over time. From 2016-2020, the cardiac quality metric focused on total mean heart dose (MHD) from the composite whole breast and boost plans, tightening from a goal of MHD ≤2 Gy to MHD ≤1.2 Gy by 2020. In 2021-2022, the cardiac metric transitioned to a combined goal of MHD ≤1.0 Gy from the whole breast plan and ≥95% lumpectomy cavity planning target volume (PTV) receiving 95% of the prescription dose. Separate multivariate logistic regression models were developed to assess for covariates associated with meeting the MHD goal in 2016-2020 and combined MHD/PTV coverage goal in 2021-2022. In total, 4,165 patients were analyzed with a median age of 64 years. Most patients (86%) had either Tis or T1 disease, and 66% received hormone therapy. Baseline demographic and disease characteristics did not change substantially between treatment periods. Use of breath-hold or motion gating increased from 42% in 2016-2020 to 46% in 2021-2022. Similarly, use of prone positioning increased from 12% to 20%. From 2016-2020, 90.9% of plans achieved the MHD goal, compared to 93.6% of plans achieving the composite MHD/PTV goal from 2021-2022. On multivariate analysis in the 2016-2020 cohort, treatment with motion management (OR 5.20, 95% CI [3.59-7.54], p<0.0001) or prone positioning (OR 3.21, 95% CI [1.85-5.57], p < 0.0001) were associated with meeting the MHD goal, while receipt of boost (OR 0.25, 95% CI [0.17-0.39], p<0.0001) and omission of hormone therapy (OR 0.65, 95% CI [0.49-0.88], p = 0.0047), were associated with not meeting the MHD goal. During the era including composite heart dose and PTV coverage goals (2021-2022), treatment with motion management (OR 1.89, 95% CI [1.12-3.21], p = 0.018) or prone positioning (OR 3.71, 95% CI [1.73-7.95], p = 0.0008) were associated with meeting the combined goal, while larger breast volume (≥1440 cc, OR 0.34, 95% CI [0.13 - 0.91], p = 0.031) and treatment at an academic center (OR 0.36, 95% CI [0.22-0.67], p = 0.0009) were associated with not meeting the combined goal. In our statewide consortium, rates of compliance with aggressive targets for limiting cardiac dose remain high, despite tightening of these goals to include lower mean heart doses and inclusion of a concurrent PTV coverage goal. Treatment using motion management or prone positioning is associated with achieving the cardiac dose goals.

Assessment of Cardiac Radiation Dose in the Co-60 Prone Based Stereotactic Partial Breast Irradiation (CP-sPBI) Using the Distance from the Heart to the Planning Treatment Volume as a Surrogate Marker

Irradiation of the breast has shown to provide sharp dose gradients using Co-60 prone based stereotactic partial breast irradiation (CP-sPBI), a contemporary device for stereotactic radiotherapy for breast cancer (BC) for accelerated partial breast irradiation (APBI). In addition, the precise setup of CP-sPBI permits a small planning treatment volume (PTV) margin of 3 mm creating a greater distance from PTV to organs at risk. However, to date the factors that influence dose gradients and subsequent cardiac doses of ionizing radiation using CP-sPBI have not been well-studied. Here we evaluate distance of the heart to the lumpectomy PTV cavity and how this effects cardiac dose. A retrospective database of 113 consecutive patients treated by CP-sPBI for APBI from March 2019 to February 2023 who were treated with 30 Gy in 5 fractions were queried for analysis. The minimum distance from the heart to the PTV (hP) was measured in either the axial or sagittal view. A group of 28 patient cases were randomly selected to achieve an even distribution of 28 cases with hP < 2.75 cm and hP ≥ 2.75 cm to compare cardiac toxicities based on hP. Descriptive analyses were performed to evaluate various cardiac dosimetric parameters based on laterality of BC and hP, using the student's t test. The mean (range) hP was 4.58 cm (0.80-12.23) for all cases. The subgroup analyses of 28 patient cases with cardiac parameters showed the heart mean (range) dose of 1.20 Gy (0.01-2.11). The mean and max heart dose to the left-sided BC were similar to those to the right-sided BC (mean dose: 1.20 vs. 1.19 Gy; P = 0.97 and max dose: 10.47 vs. 5.66 Gy; P = 0.06). An inverse correlation between hP and mean heart dose was shown with the correlation coefficient of -0.81. Using a cutoff of 2.75 cm hP, the differences between hP < 2.75 and hP ≥ 2.75 cm for all cardiac dosimetric evaluations were all statistically significant, including mean (1.67 vs. 0.79 Gy; p<0.01) and maximal heart dose (14.48 vs. 4.11 Gy; p<0.01) CONCLUSION: CP-sPBI treatment delivery system was able to achieve acceptable clinically relevant heart dosimetric parameters when delivering 5 fraction APBI with a mean heart dose of 1.20 Gy for all locations of PTV cavity volume in the breast. Due to CP-sPBIs excellent dose fall-off characteristics, APBI using CP-SPBI showed clinically acceptable cardiac dosimetric parameters, particularly for PTVs located > 2.75 cm from the heart.

Association between statin therapy dose intensity and radiation cardiotoxicity in non-small cell lung cancer: Results from the NI-HEART study

IntroductionRadiation cardiotoxicity is a dose-limiting toxicity and major survivorship issue for patients with non-small cell lung cancer (NSCLC) completing curative-intent radiotherapy, however patients’ cardiovascular baseline is not routinely optimised prior to treatment. In this study we examined the impact of statin therapy on overall survival and post-radiotherapy cardiac events. MethodsPatients treated between 2015–2020 at a regional center were identified. Clinical notes were interrogated for baseline patient, tumor and cardiac details, and both follow-up cancer control and cardiac events. Three cardiologists verified cardiac events. Radiotherapy planning scans were retrieved for application of validated deep learning-based autosegmentation. Pre-specified Cox regression analyses were generated with varying degrees of adjustment for overall survival. Fine and Gray regression for the risk of cardiac events, accounting for the competing risk of death and cardiac covariables was undertaken. ResultsStatin therapy was prescribed to 59% of the 478 included patients. The majority (88%) of patients not prescribed a statin had at least one indication for statin therapy according to cardiovascular guidelines. In total, 340 patients (71%) died and 79 patients (17%) experienced a cardiac event. High-intensity (HR 0.68, 95%CI 0.50–0.91, p = 0.012) and medium-intensity (HR 0.70, 95%CI 0.51–0.97, p = 0.033) statin therapy were associated with improved overall survival after adjustment for patient, cancer, treatment, response and cardiovascular clinical factors. There were no consistent differences in the rate or grade of cardiac events according to statin intensity. ConclusionsStatin therapy is associated with improved overall survival in patients receiving curative-intent radiotherapy for NSCLC, and there is evidence of a dose–response relationship. This study highlights the importance of a pre-treatment cardiovascular risk assessment in this cohort. Further studies are needed to examine if statin therapy is cardioprotective in patients undergoing treatment for NSCLC with considerable incidental cardiac radiation dose and a low baseline cardiac risk.

Cardiac Substructure Radiation Dose and Risk of Late Cardiac Disease in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.

Radiation-associated cardiac disease is a major cause of morbidity/mortality among childhood cancer survivors. Radiation dose-response relationships for cardiac substructures and cardiac diseases remain unestablished. Using the 25,481 5-year survivors of childhood cancer treated from 1970 to 1999 in the Childhood Cancer Survivor Study, we evaluated coronary artery disease (CAD), heart failure (HF), valvular disease (VD), and arrhythmia. We reconstructed radiation doses for each survivor to the coronary arteries, chambers, valves, and whole heart. Excess relative rate (ERR) models and piecewise exponential models evaluated dose-response relationships. The cumulative incidence 35 years from diagnosis was 3.9% (95% CI, 3.4 to 4.3) for CAD, 3.8% (95% CI, 3.4 to 4.2) for HF, 1.2% (95% CI, 1.0 to 1.5) for VD, and 1.4% (95% CI, 1.1 to 1.6) for arrhythmia. A total of 12,288 survivors (48.2%) were exposed to radiotherapy. Quadratic ERR models improved fit compared with linear ERR models for the dose-response relationship between mean whole heart and CAD, HF, and arrhythmia, suggesting a potential threshold dose; however, such departure from linearity was not observed for most cardiac substructure end point dose-response relationships. Mean doses of 5-9.9 Gy to the whole heart did not increase the risk of any cardiac diseases. Mean doses of 5-9.9 Gy to the right coronary artery (rate ratio [RR], 2.6 [95% CI, 1.6 to 4.1]) and left ventricle (RR, 2.2 [95% CI, 1.3 to 3.7]) increased risk of CAD, and to the tricuspid valve (RR, 5.5 [95% CI, 2.0 to 15.1]) and right ventricle (RR, 8.4 [95% CI, 3.7 to 19.0]) increased risk of VD. Among children with cancer, there may be no threshold dose below which radiation to the cardiac substructures does not increase the risk of cardiac diseases. This emphasizes their importance in modern treatment planning.

V5 and High Sensitivity Cardiac Troponin T for Early Detection of Cardiac Toxicity During Left Breast Cancer Irradiation.

The high sensitivity cardiac troponin T (Hs-cTnT) is a myocardial damage biomarker that could have a predictive value in patients who undergo radiotherapy for left sided breast cancer. The aim of this study was to evaluate the early effect of left whole breast radiotherapy (WB-RT) on serum Hs-cTnT levels and its correlation with pre-existing factors. The study was conducted from December 2017 to May 2018. Forty-five patients with early stage left-sided breast cancer who received adjuvant breast hypofractionated RT without prior chemotherapy were included. Serum levels of Hs-cTnT were obtained before, weekly during RT, and within one week after the end of treatment. Considering the physiological variations of serum levels, an increase in Hs-cTnT (∆Hs-cTnT) of more than 30% from the baseline value was chosen as a threshold. The main cardiovascular risk factors were recorded. Dose volume histograms (DVHs) were used to provide a quantitative analysis for the whole heart, left ventricle, and left anterior descending artery (LAD). Twelve of 45 patients (26.6%) showed a ∆Hs-cTnT ≥30%. The maximum Hs-cTnT level was recorded in the last week of treatment. ∆Hs-cTnT was strongly associated with heart V5 (p=0.05) and hypertension (p=0.05). Multivariate analysis confirmed the importance of the heart V5 and correlated with ∆Hs-cTnT. The increase in Hs-cTnT serum levels during adjuvant WB-RT suggested a correlation with the cardiac radiation dose in chemotherapy-naive breast cancer patients. A longer follow-up is needed to correlate Hs-cTnT values with cardiac events.

Cardiac Disease in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review

Radiation therapy (RT) is an essential component in the treatment of many pediatric malignancies. Thoracic RT may expose the heart to radiation dose and thereby increase the risk of late cardiac disease. This comprehensive review from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative focused on late cardiac disease in survivors of childhood cancer treated with RT. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. We identified 1496 articles; 4 were included for dose-response modeling between mean cardiac radiation dose and risk of late coronary artery disease, heart failure (HF), valvular disease, and any cardiac disease. For each 10-Gy increase in corrected mean cardiac radiation dose in 1.8- to 2.0-Gy fractions, we estimated a hazard ratio of 2.01 (95% confidence interval [CI], 1.79-2.25) for coronary artery disease, of 1.87 (95% CI, 1.70-2.06) for HF, of 1.87 (95% CI, 1.78-1.96) for valvular disease, and of 1.88 (95% CI, 1.75-2.03) for any cardiac disease. From the same model, for each 100-mg/m2 increase in cumulative anthracycline dose, the hazard ratio for the development of HF was 1.93 (95% CI, 1.58-2.36), equivalent to an increase in mean heart dose of approximately 10.5 Gy. Other nontreatment factors were inconsistently reported in the analyzed articles. Radiation dose to the heart increases the risk of late cardiac disease, but survivors of childhood cancer who receive a mean dose <10 Gy at standard fractionation are at low absolute risk (<∼2% approximately 30 years after exposure) of late cardiac disease in the absence of anthracycline exposure. Minimizing cardiac radiation dose is especially relevant in children receiving anthracyclines. When cardiac sparing is not possible, we recommend prioritizing target coverage. It is likely that individual cardiac substructure doses will be a better predictor of specific cardiac diseases than mean dose, and we urge the pediatric oncology community to further study these relationships.

Association of Cardiac Sub-Structure Radiation Dose with Bradyarrhythmias and Tachyarrhythmias after Lung Cancer Radiotherapy

<h3>Purpose/Objective(s)</h3> Arrhythmias are the most common cardiac events following radiotherapy (RT) for non-small cell lung cancer (NSCLC). However, data detailing types of arrhythmias and associated cardiac sub-structure dose-volume predictors is limited. <h3>Materials/Methods</h3> Retrospective analysis of 748 patients with locally advanced NSCLC treated with RT. Cardiac chambers and coronary arteries were manually segmented and dose-volume histogram (DVH) parameters (mean, max, and volume [V] receiving X Gy [in 5 Gy increments]) were calculated. 15 Common Terminology Criteria for Adverse Events (CTCAE) arrhythmia types were assessed. Receiver operating curve and cut-point analyses estimating grade ≥3 bradyarrhythmias, atrial flutter/fibrillation (AF), non-AF supraventricular tachyarrhythmias (other SVT), and ventricular tachyarrhythmias (VT) were performed. Cox and Fine and Gray regressions were performed (non-cardiac death as a competing risk). <h3>Results</h3> The median age was 65 years, 128/748 patients experienced ≥1 Grade ≥3 CTCAE arrhythmia (median onset, 1.6 years). The 2-year cumulative incidences were: 11.9% overall, 9.0% AF, 1.8% other SVT, 1.0% VT, 1.7% bradyarrhythmias. DVH parameters with highest AUC predicting each arrhythmia group are in Table 1. Adjusting for pre-existing arrhythmia and coronary heart disease: 1) left atrium (LA) V5 Gy ≥60 cc was associated with an increased risk of AF (subdistribution hazard ratio [SHR] 2.06, 95% CI 1.29-3.28; p=.002); 2) right atrium (RA) V60 Gy ≥0.03 cc was associated with an increased risk of other SVT (SHR 4.72, 95% CI 1.65-13.50; p=.004); 3) left main (LM) coronary artery V5 Gy ≥1 cc was associated with an increased risk of VT (SHR 7.4, 95% CI 1.72-31.71; p=.007); and 4) LM V10 Gy ≥1 cc was associated with an increased risk of bradyarrhythmias (SHR 2.27, 95% CI 1.04-4.96; p=.04). The 2-year estimates of AF for LA V5 Gy ≥ 60 cc vs. <60cc were 14.1% vs 5.5% (p<.001), respectively. On all-cause mortality (ACM) analysis, adjusting for lung cancer and cardiac prognostic factors, LA V5 Gy ≥60 cc was associated with an increased risk of ACM (HR 1.22, 95% CI 1.00-1.49; p=.046), while the other DVH variables were not (P>0.05). The 2-year ACM for LA V5Gy ≥60 cc vs <60 cc was 54% vs 46% (p=.010), respectively. <h3>Conclusion</h3> To our knowledge, this is the first report describing functionally distinct arrhythmia classes being associated with RT dose to discrete atrial and coronary sub-structures. Specifically, LA V5 Gy ≥60 cc is associated with an increased risk of AF and mortality. These observations build on our growing knowledge of sub-structure dose leading to localized cardiac dysfunction and guide potential mitigation approaches.

Regional Nodal Irradiation for Breast Cancer Using Volumetric Modulated Arc Therapy: Echocardiographic Functional Outcomes

<h3>Purpose/Objective(s)</h3> Regional nodal irradiation (RNI) for breast cancer yields improvements in disease outcomes, yet comprehensive target coverage often increases cardiac radiation (RT) dose. Volumetric modulated arc therapy (VMAT) may mitigate high-dose cardiac exposure, although often increases the volume of low-dose exposure. The cardiac implications of this dosimetric configuration (in contrast to historic 3D conformal techniques) remains uncertain. <h3>Materials/Methods</h3> Eligible patients receiving adjuvant RNI using VMAT for locoregional breast cancer were prospectively enrolled on an IRB-approved study. Echocardiograms were performed prior to RT, at the conclusion of RT, and 6-months following RT. Echocardiographic parameters were measured by a single reader (AY) and measures were compared pre- and post-RT via the Wilcoxon signed rank test. Changes in echocardiographic parameters over time were compared to mean and max heart doses via the Spearman correlation test. <h3>Results</h3> Among 19 evaluable patients (median age 38), 89% (n=17) received doxorubicin and 37% (n=7) received trastuzumab/pertuzumab combination therapy. All patients received VMAT-based whole-breast/chest-wall and regional nodal irradiation. Average mean heart dose was 456cGy (range 187–697cGy) and average max heart dose was 3001cGy (1560-4793cGy). Among salient echocardiographic parameters, no significant decrement in cardiac function was observed when comparing pre-RT to 6-months post-RT: mean left ventricular ejection fraction (LVEF) was 61.8 (SD 4.4) pre-RT and 62.7 (SD 3.8) 6-months post-RT (p=0.493); mean global longitudinal strain (GLS) was -19.3 (SD 2.2) pre-RT and -19.6 (SD 1.8) 6-months post-RT (p=0.627). No correlations were observed for changes in LVEF or GLS when compared to mean or maximum heart doses (p>0.1 for all). <h3>Conclusion</h3> VMAT for left-sided RNI yielded no significant early decrement in echocardiographic parameters of cardiac function including LVEF and GLS. VMAT appears safe for patients requiring RNI, including those receiving anthracyclines and HER2-directed therapy. Larger cohorts with longer follow-up will be needed to validate these findings.

Heart dose and cardiac comorbidities influence death with a cardiac cause following hypofractionated radiotherapy for lung cancer.

BackgroundThere is increasing evidence of cardiac toxicity of thoracic radiotherapy however, it is difficult to draw conclusions on cardiac dose constraints due to the heterogeneity of published studies. Moreover, few studies record data on cause of death. The aim of this paper is to investigate the relationship between conventional cardiac dosimetric parameters and death with cardiac causes using data from the UK national cause of death registry.MethodsData on cancer diagnosis, treatment and cause of death following radical lung cancer radiotherapy were obtained from Public Health England for all patients treated at the Christie NHS Foundation Trust between 1/1/10 and 31/12/16. Individuals with metastatic disease and those who received multiple courses of thoracic radiotherapy where excluded. All patients who received > 45Gy in 20 fractions were included. Cardiac cause of death was defined as the following ICD-10 codes on death certificate: I20-I25; I30-I32; I34-I37; I40-I52. Cardiac V5Gy, V30Gy, V50Gy and mean heart dose (MHD) were extracted. Cumulative incidence of death with cardiac causes were plotted for each cardiac dosimetric parameter. Multi-variable Fine and Gray competing risk analysis was used to model predictors for cardiac death with non-cardiac death as a competing risk.ResultsCardiac dosimetric parameters were available for 967 individuals, 110 died with a cardiac cause (11.4%). Patients with a cardiac comorbidity had an increased risk of death with a cardiac cause compared with those without a cardiac comorbidity (2-year cumulative incidence 21.3% v 6.2%, p<0.001). In patients with a pre-existing cardiac comorbidity, heart V30Gy ≥ 15% was associated with higher cumulative incidence of death with a cardiac cause compared to patients with heart V30Gy <15% (2-year rate 25.8% v 17.3%, p=0.05). In patients without a cardiac comorbidity, after adjusting for tumour and cardiac risk factors, MHD (aHR 1.07, 1.01-1.13, p=0.021), heart V5Gy (aHR 1.01, 1-1.13, p=0.05) and heart V30Gy (aHR 1.04, 1-1.07, p=0.039) were associated with cardiac death.ConclusionThe effect of cardiac radiation dose on cardiac-related death following thoracic radiotherapy is different in patients with and without cardiac comorbidities. Therefore patients’ cardiovascular risk factors should be identified and managed alongside radiotherapy for lung cancer.

EP05.01-012 Avoiding Cardiac Toxicity in Lung Cancer Radiotherapy (ACcoLade) Trial - Initial Results

Increasing cardiac radiation dose is associated with worse survival and cardiac events following thoracic radiotherapy however, the mechanism of injury is unknown. High sensitivity cardiac troponin I (hsTnI) and N-terminal pro-B-type natriuretic peptide (NT pro-BNP) are established blood biomarkers of cardiac injury. Cardiac CT (CCT) is a non-invasive method of assessing coronary artery disease and echocardiography assesses cardiac structure and function. We present initial results of a prospective cohort study of cardiac blood and imaging biomarkers in patients undergoing lung cancer radiotherapy.