OverviewCardiac complications of radiation therapy
Introduction
Radiation-induced cardiac damage is common, and can occur to the pericardium, myocardium, conducting mechanism or the coronary vasculature [1]; there can be acute or late side-effects. Cardiac radiation tolerance (TD 5/5) is about 60 Gy if 25% of the heart or less is irradiated, falling to 45 Gy if 65% heart volume or more is irradiated [2]. These tolerances are obtained assuming 2 Gy doses per fraction. The fractionation scheme and field size are vitally important when assessing cardiac tolerance. Radiation-induced cardiac disease has been associated with the radical treatment of lymphomas, breast cancer, oesophagogastric cancer, thymoma or lung cancer.
The pericardium is a double layered mesothelial covering, which has a poor vascular supply. The two layers are lubricated and slide over each other. Acute radiation pericarditis usually appears a few weeks after treatment. Symptoms and signs include fever, tachycardia, chest pain, pericardial friction rub and pericardial effusion. The electrocardiogram (ECG) can show concave ST segment elevation, flattening or inversion of the T-waves, and a decrease in the QRS segment amplitude. Chest X-ray may show cardiomegaly, echocardiography may show an effusion or reduced contractility, and radionuclide studies, such as the multiple uptake gated scan (MUGA), show a reduced ejection fraction. Frustratingly, these tests can often be normal.
Most patients with pericarditis will have received at least 40 Gy over 4 weeks to most of their heart (lymphoma data) [3]. Mediastinal tumours or lung tumours, which can attach themselves to the pericardium, may become necrotic and increase the incidence of acute pericarditis.
About 20% of people with acute pericarditis develop a chronic or constrictive pericarditis 5–10 years after treatment. The risk is much greater if a pericardial effusion was present previously [4]. Chronic pericarditis can occur even if the patient did not suffer acute pericarditis. Chronic pericarditis results in fibrotic change. Symptoms and signs include shortness of breath, chest pain, fever, pleural effusion, raised jugular venous pressure (Kussmaul's sign), and pulsus paradoxus. The ECG changes are similar to those of acute pericarditis.
The pericardium becomes thickened as a result of collagen and fibrin replacement of normal pericardial adipose tissue. The two layers often adhere to each other or to the heart and pleura. The vasculature within the pericardium shows characteristic sub-endothelial connective tissue deposits, which are associated with radiation change, and this leads to increased vascular permeability [5].
Pericarditis is treated with non-steroidal anti-inflammatory agents, and drainage of the pericardial effusion if the patient is significantly compromised. Surgical procedures currently available include pericardial window formation for recurrent effusions, and pericardectomy for constrictive pericarditis.
After ‘mantle’ field radiotherapy for Hodgkin's disease, the incidence of pericardial disease is proportional to dose as well as treatment volume, and greatly decreases with the use of subcarinal shields to the heart after 30 Gy [6].
The slow rate of cell division within the myocardium makes it relatively radiation-resistant. Diffuse interstitial fibrosis occurs after relatively low doses of radiation, and this is distinct from the usual radiation-induced vascular damage. This change alters the compliance of the myocardium, leading to both systolic and diastolic dysfunction [7]. These changes can induce dilated, restrictive or hypertrophic cardiomyopathy. Sub-clinical changes are also very common. A study of 50 patients treated with mean 35 Gy radiation with modern techniques for Hodgkin's disease, and followed for an average of 9 years, showed that 4% had an abnormal left-ventricular ejection fraction and 16% had an abnormal peak filling rate, which is a measure of diastolic function [5].
Direct damage to the cardiac conducting mechanism may occur after high doses, especially large single fractions [8]. Chest radiotherapy is associated with QTc interval prolongation. Other abnormalities, including all levels of heart block and sick sinus syndrome, have been reported 8, 9. Persistent tachycardia and a loss of circadian and respiratory phasic heart rhythms is reported to be common in survivors of childhood cancer treated with chest radiotherapy, and presumably relates to dysfunction within the autonomic nervous system [7].
Radiation can damage blood vessels of all sizes. Following treatment with radiation, there is an increase in capillary wall permeability, with dilatation of vessels leading to the characteristic radiation erythema. This is followed by an inflammatory cell infiltrate, which can be seen after doses as low as 5 Gy. The filtration properties of the endothelium are reduced, and the basement membrane of capillary walls thickens as a result of collagen deposition and fibrosis. Eventually, there is small vessel occlusion. The lesions resemble atheromatous plaques, but differ in their location, as these rarely occur spontaneously in small arteries.
Coronary artery spasm may explain some cases of sudden death occurring in patients after radiation therapy [10].
Changes in large elastic arteries usually occur late, with degeneration of muscular cells, weakening of the vessel walls, fibrosis and changes similar to atherosclerosis. This is due to the classical post-radiation ‘endarteritis obliterans’ in the ‘vasa vasorum’, secondary to collagen deposition after radiotherapy.
Critical coronary artery disease occurs 10–15 years after radiotherapy, and its incidence is increased by the usual risk factors, such as smoking, hypertension or obesity.
Section snippets
Alpha/beta ratios
Alpha/beta ratios for late myocardial and pericardial injury have been determined in experimental animals using morphometric analysis [11]. Alpha/beta ratios of 2.4–2.9 Gy were calculated for myocardial connective tissue, and the ratio was 1.8–2.8 Gy for the capillary component [12]. Analysis of dose–survival curves in rats produced a ratio of 3.4 Gy [13].
Risk factors for cardiac toxicity
See Table 1 for risk factors for cardiac toxicity.
Hodgkin's lymphoma
Cardiovascular complications after mediastinal radiotherapy are the next most frequent cause of treatment-related morbidity after second malignancies in Hodgkin's lymphoma survivors. They account for 25% of the mortality in cured patients [35], which is equal to 2–5% of overall mortality in patients with Hodgkin's disease [36]. Estimates of symptomatic cardiac complications range from 15% to 30% 5–10 years after anterior-weighted radiotherapy for Hodgkin's disease [37]. Myocardial infarction is
Conclusions
The medical literature contains much evidence of cardiac complications resulting from radiotherapy to the mediastinum, oesophagus, gastro-oesophageal junction or breast. Much of this evidence relates to older radiotherapy equipment and techniques, and it is likely that the incidence of complications will fall as late complication data become available from the results of trials utilising modern radiation therapy techniques.
Clinicians should not underestimate the importance of minimising cardiac
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