Risk Of Radiation-induced Heart Disease Research Articles

Deep learning–based automatic segmentation of cardiac substructures for lung cancers

PurposeAccurate and comprehensive segmentation of cardiac substructures is crucial for minimizing the risk of radiation-induced heart disease in lung cancer radiotherapy. We sought to develop and validate deep learning–based auto-segmentation models for cardiac substructures. Materials and MethodsNineteen cardiac substructures (whole heart, 4 heart chambers, 6 great vessels, 4 valves, and 4 coronary arteries) in 100 patients treated for non-small cell lung cancer were manually delineated by two radiation oncologists. The valves and coronary arteries were delineated as planning risk volumes. An nnU-Net auto-segmentation model was trained, validated, and tested on this dataset with a split ratio of 75:5:20. The auto-segmented contours were evaluated by comparing them with manually drawn contours in terms of Dice similarity coefficient (DSC) and dose metrics extracted from clinical plans. An independent dataset of 42 patients was used for subjective evaluation of the auto-segmentation model by 4 physicians. ResultsThe average DSCs were 0.95 (+/– 0.01) for the whole heart, 0.91 (+/– 0.02) for 4 chambers, 0.86 (+/– 0.09) for 6 great vessels, 0.81 (+/– 0.09) for 4 valves, and 0.60 (+/– 0.14) for 4 coronary arteries. The average absolute errors in mean/max doses to all substructures were 1.04 (+/– 1.99) Gy and 2.20 (+/– 4.37) Gy. The subjective evaluation revealed that 94% of the auto-segmented contours were clinically acceptable. ConclusionWe demonstrated the effectiveness of our nnU-Net model for delineating cardiac substructures, including coronary arteries. Our results indicate that this model has promise for studies regarding radiation dose to cardiac substructures.

Internal Mammary Node Irradiation in Patients With Node-Positive Early Breast Cancer: Fifteen-Year Results From the Danish Breast Cancer Group Internal Mammary Node Study.

The Danish Breast Cancer Group Internal Mammary Node study demonstrated improved 8-year overall survival (OS) with internal mammary node irradiation (IMNI) in patients with node-positive early breast cancer. Here, we present long-term results from the Danish Breast Cancer Group Internal Mammary Node study cohort. This nationwide, prospective cohort study allocated patients with node-positive early breast cancer to adjuvant radiotherapy with or without IMNI depending on cancer laterality. Patients with right-sided cancer received IMNI. Patients with left-sided cancer were treated without IMNI because of risk of radiation-induced heart disease. Other treatment was independent of laterality. The primary study end point was OS. Secondary end points were distant recurrence and breast cancer mortality. Analyses were by intention to treat. During 2003-2007, 3,089 women were allocated to IMNI (right-sided, n = 1,491) or no IMNI (left-sided, n = 1,598). With a median follow-up of 14.8 years, 589 patients with and 701 patients without IMNI had died. The corresponding 15-year OS rates were 60.1% and 55.4%. The adjusted hazard ratio (HR) for death was 0.86 (95% CI, 0.77 to 0.96; P = .007) in favor of IMNI. The 15-year risk of developing distant recurrence was 35.6% (523 recurrences) and 38.6% (602 recurrences) with vs. without IMNI (adjusted HR, 0.88 [95% CI, 0.79 to 0.99; P = .04]). The 15-year breast cancer mortality with IMNI was 31.7% (467 deaths) compared with 33.9% (537 deaths) without IMNI (adjusted HR, 0.88 [95% CI, 0.78 to 1.00; P = .05]). The distribution of other deaths was similar across groups. In patients with node-positive early breast cancer treated with IMNI or without IMNI depending on breast cancer laterality, IMNI reduced the risk of distant recurrence and death from breast cancer, thereby improving long-term survival.

Experimental study of 18F-FDG PET/CT imaging and cardiac MRI in diagnosis of radiation-induced myocardial injury in Beagle dogs

Objective To investigate the value of 18F-fluorodeoxyglucose (FDG) PET/CT imaging and cardiac MRI (CMR) in the diagnosis of radiation-induced heart disease (RIHD) in Beagle models. Methods Twenty-four normal male Beagle dogs (1-year old) were randomly divided into control group and irradiated groups (3-month, 6-month and 12-month after radiation). The left anterior myocardium of Beagle dogs in irradiated groups was irradiated locally with a single dose of 20 Gy X-ray. Cardiac 18F-FDG PET/CT imaging and CMR were performed on all dogs, and the mean standardized uptake value (SUVmean) and the area of lesions with increased 18F-FDG uptake were obtained. After imaging examinations were finished, dogs were sacrificed and their hearts were taken out to perform Masson staining and electron microcopy. One-way analysis of variance was used for data analysis. Results There was basically no uptake in myocardium in control group. The myocardium showed increased uptake of 18F-FDG in the irradiated groups. The SUVmean of myocardium in 3-month, 6-month and 12-month after radiation groups and control group were 5.90±1.31, 4.66±2.21, 3.21±0.82 and 1.13±0.21, respectively (F=11.81, P<0.05). The area with increased 18F-FDG uptake in the irradiated groups decreased progressively with the prolongation of irradiation time (F=195.74, P<0.01). The reduction in myocardial perfusion and myocardial fibrosis were observed by CMR early at 6-month after irradiation. Compared with the control group, the 6-month and 12-month after radiation groups had increased end diastolic volume (EDV) and end systolic volume (ESV; F=15.479 and 16.908, both P<0.01), and decreased left ventricular ejection fraction (LVEF; F=63.715, P<0.01). The progressive aggravation of myocardial fibrosis was displayed in irradiated groups by Masson staining. The mitochondria degeneration, swelling and the count reduction in irradiated groups were observed by electron microscopy. Conclusions The increased 18F-FDG uptake in the irradiated myocardium may predict the risk of RIHD. 18F-FDG PET/CT imaging can detect RIHD earlier than CMR. Key words: Heart; Radiation injuries, experimental; Positron emission tomography; Tomography, X-ray computed; Deoxyglucose; Magnetic resonance imaging; Dogs

DBCG-IMN: A Population-Based Cohort Study on the Effect of Internal Mammary Node Irradiation in Early Node-Positive Breast Cancer.

It is unknown whether irradiation of the internal mammary lymph nodes improves survival in patients with early-stage breast cancer. A possible survival benefit might be offset by radiation-induced heart disease. We assessed the effect of internal mammary node irradiation (IMNI) in patients with early-stage node-positive breast cancer. In this nationwide, prospective population-based cohort study, we included patients who underwent operation for unilateral early-stage node-positive breast cancer. Patients with right-sided disease were allocated to IMNI, whereas patients with left-sided disease were allocated to no IMNI because of the risk of radiation-induced heart disease. The primary end point was overall survival. Secondary end points were breast cancer mortality and distant recurrence. Analyses were by intention to treat. A total of 3,089 patients were included. Of these, 1,492 patients were allocated to IMNI, whereas 1,597 patients were allocated to no IMNI. With a median of 8.9 years of follow-up time, the 8-year overall survival rates were 75.9% with IMNI versus 72.2% without IMNI. The adjusted hazard ratio (HR) for death was 0.82 (95% CI, 0.72 to 0.94; P = .005). Breast cancer mortality was 20.9% with IMNI versus 23.4% without IMNI (adjusted HR, 0.85; 95% CI, 0.73 to 0.98; P = .03). The risk of distant recurrence at 8 years was 27.4% with IMNI versus 29.7% without IMNI (adjusted HR, 0.89; 95% CI, 0.78 to 1.01; P = .07). The effect of IMNI was more pronounced in patients at high risk of internal mammary node metastasis. Equal numbers in each group died of ischemic heart disease. In this naturally allocated, population-based cohort study, IMNI increased overall survival in patients with early-stage node-positive breast cancer.

Thalidomide is not able to inhibit radiation-induced heart disease

Purpose: Radiotherapy to the thorax increases the risk of radiation-induced heart disease. We and others have shown that local irradiation to the murine heart results in inflammatory and fibrotic responses and decreased microvascular density. In the present study we tested whether thalidomide is able to inhibit radiation-induced heart disease.Methods: Single doses of 16 Gy or 0 Gy (sham treatment) were delivered to the hearts of mice. At 16 weeks after irradiation the mice were allocated to receive a thalidomide-containing chow (100 mg/kg body weight/day) or control chow until the end of the experiment. At 40 weeks after irradiation, functional imaging was performed and the hearts were examined for histological damage.Results: Irradiation led to an increase in epicardial thickness and infiltrating inflammatory cells in the epicardium as well as an increase in interstitial collagen content. The microvasculature had a decreased alkaline phosphatase activity and reduced pericyte coverage. Thalidomide had no protective role in any of these processes. There were no differences in heart function measured between the treatment groups.Conclusions: Although others have shown protective effects of thalidomide in disease models involving inflammation, fibrosis and blood vessel maturation, thalidomide was not able to reduce radiation-induced heart damage.

Ionising radiation induces persistent alterations in the cardiac mitochondrial function of C57BL/6 mice 40 weeks after local heart exposure

Background and purposeRadiotherapy of thoracic and chest-wall tumours increases the long-term risk of radiation-induced heart disease. The aim of this study was to investigate the long-term effect of local heart irradiation on cardiac mitochondria. MethodsC57BL/6 and atherosclerosis-prone ApoE−/− mice received local heart irradiation with a single X-ray dose of 2Gy. To investigate the low-dose effect, C57BL/6 mice also received a single heart dose of 0.2Gy. Functional and proteomic alterations of cardiac mitochondria were evaluated after 40weeks, compared to age-matched controls. ResultsThe respiratory capacity of irradiated C57BL/6 cardiac mitochondria was significantly reduced at 40weeks. In parallel, protein carbonylation was increased, suggesting enhanced oxidative stress. Considerable alterations were found in the levels of proteins of mitochondria-associated cytoskeleton, respiratory chain, ion transport and lipid metabolism. Radiation induced similar but less pronounced effects in the mitochondrial proteome of ApoE−/− mice. In ApoE−/−, no significant change was observed in mitochondrial respiration or protein carbonylation. The dose of 0.2Gy had no significant effects on cardiac mitochondria. ConclusionThis study suggests that ionising radiation causes non-transient alterations in cardiac mitochondria, resulting in oxidative stress that may ultimately lead to malfunctioning of the heart muscle.

Local heart irradiation of ApoE−/− mice induces microvascular and endocardial damage and accelerates coronary atherosclerosis

Background and purposeRadiotherapy of thoracic and chest-wall tumors increases the long-term risk of radiation-induced heart disease, like a myocardial infarct. Cancer patients commonly have additional risk factors for cardiovascular disease, such as hypercholesterolemia. The goal of this study is to define the interaction of irradiation with such cardiovascular risk factors in radiation-induced damage to the heart and coronary arteries. Material and methodsHypercholesterolemic and atherosclerosis-prone ApoE−/− mice received local heart irradiation with a single dose of 0, 2, 8 or 16Gy. Histopathological changes, microvascular damage and functional alterations were assessed after 20 and 40weeks. ResultsInflammatory cells were significantly increased in the left ventricular myocardium at 20 and 40weeks after 8 and 16Gy. Microvascular density decreased at both follow-up time-points after 8 and 16Gy. Remaining vessels had decreased alkaline phosphatase activity (2–16Gy) and increased von Willebrand Factor expression (16Gy), indicative of endothelial cell damage. The endocardium was extensively damaged after 16Gy, with foam cell accumulations at 20weeks, and fibrosis and protein leakage at 40weeks. Despite an accelerated coronary atherosclerotic lesion development at 20weeks after 16Gy, gated SPECT and ultrasound measurements showed only minor changes in functional cardiac parameters at 20weeks. ConclusionsThe combination of hypercholesterolemia and local cardiac irradiation induced an inflammatory response, microvascular and endocardial damage, and accelerated the development of coronary atherosclerosis. Despite these pronounced effects, cardiac function of ApoE−/− mice was maintained.

Can cutaneous telangiectasiae as late normal-tissue injury predict cardiovascular disease in women receiving radiotherapy for breast cancer?

Background:Overall, ∼5% of patients show late normal-tissue damage after radiotherapy with a smaller number having a risk of radiation-induced heart disease. Although the data are conflicting, large studies have shown increased risks of cardiovascular disease (CVD) for irradiated patients compared with non-irradiated ones, or for those treated to the left breast or chest wall compared with those treated to the right. Cutaneous telangiectasiae as late normal-tissue injury have so far only been regarded as a cosmetic burden.Methods:The relationship between late normal-tissue radiation injury phenotypes in 149 irradiated breast cancer patients and the presence of cardiovascular disease were examined.Results:A statistically significant association between the presence of skin telangiectasiae and the long-term risk of CVD was shown in these patients (P=0.017; Fisher's exact test).Interpretation:This association may represent initial evidence that telangiectasiae can be used as a marker of future radiation-induced cardiac complications. It could also suggest a common biological pathway for the development of both telangiectasiae and CVD on the basis of a genetically predisposed endothelium. To our knowledge this is the first reported study looking at this association.

Cardiac doses from Swedish breast cancer radiotherapy since the 1950s

Purpose To estimate cardiac doses from breast cancer radiotherapy in Sweden from the 1950s to the 1990s. These doses will contribute to deriving dose–response relationships for the risk of radiation-induced heart disease. Materials and methods The Swedish nationwide cancer register was used to identify women irradiated for breast cancer in the Stockholm area. Virtual simulation, computed tomography planning, and manual planning were used to reconstruct radiotherapy regimens. Estimates of heart and coronary artery dose were derived for each woman. Results Cardiac doses were assessed in 358 women. Mean heart dose varied from <0.1 to 23.6 Gy and mean left anterior descending coronary artery dose varied from 0.1 to 46.3 Gy. Mean heart doses averaged across women irradiated in each decade for left-sided and right-sided breast cancers, respectively, were 5.1 and 1.8 Gy in the 1950s, 10.5 and 4.7 Gy in the 1970s and 3.0 and 1.9 Gy in the 1990s. Conclusions Cardiac doses from Swedish breast cancer radiotherapy increased from the 1950s to the 1970s, and then reduced substantially in the 1980s and 1990s. The wide range of doses observed should provide substantial statistical power for the estimation of dose–response relationships for radiation-induced heart disease.