Radiotherapy: Clinical Aspects and Cardiotoxicity

Abstract

Radiation therapy (RT) causes inflammation, activation of pro-fibrotic cytokines, and endothelial and microvascular damage. Radiation increases oxidative stress through free radical production and results in recruitment of matrix metalloproteinases and pro-inflammatory mediators. These changes may lead to acute toxicity (evident during or shortly after radiotherapy) and start a chronic process leading to delayed dysfunction that is evident several years later. Acute changes largely result from direct radiation damage and the immediate inflammatory response, while long-term changes are due to stem cell loss and late and persistent tissue fibrosis. Thus, chronic radiation-induced damage is irreversible and can affect multiple cardiac structures including the coronary arteries, myocardium, pericardium, cardiac valves, and the conduction system. The incidence of acute pericarditis has decreased over time from 20 % to 2.5 % with modern radiation techniques; therapy is the same as for acute viral or idiopathic pericarditis. Ventricular dysfunction is a rare event. It is more frequent when an anthracycline or high-dose chemotherapy is administered concurrently, or shortly before RT, since radiation interacts synergistically to induce myocardial damage.Delayed radiation-induced heart disease (RIHD) is a significant problem, especially in long-term survivors of lymphoma and breast cancer. The median time from RT to appearance of clinically significant RIHD is 15 years, with the incidence increasing progressively over time. All the patients treated with mediastinal or chest radiotherapy more than 10 years ago should be object of an active program of prevention and follow-up. The follow-up should last lifelong. Many cancer patients who achieved complete remission are dismissed by the oncological follow-up after 5–10 years. Few patients have the opportunity to be included in a cancer survivor clinic for long-term follow-up of treatment-related disease. The general practitioners and the cardiologists should take care of this problem. The group at highest risk is represented by childhood cancer survivors, and this problem has been addressed in Chap. 16. Coronary Artery Disease (CAD) is the most frequent and relevant form of RIHD. The risk of death due to acute myocardial infarction (AMI) is two- to fourfold higher in patients treated for Hodgkin lymphoma compared with age-matched controls, but can be increased sevenfold or higher in some subgroups. The mechanism involved in plaque formation is thought to mirror spontaneous atherosclerosis; however, plaques in irradiated patients have been found to be more fibrous with decreased lipid content, and the lesions are consistently more proximal, smoother, concentric, tubular, and longer. Left ventricular (LV) dysfunction is a frequent complication of chest RT, and may be due to: macroscopic CAD leading to chronic ischemia; decrease in capillary density resulting in myocyte hypoxia; direct myocyte damage and necrosis, more evident in synergy with anthracycline cardiotoxicity, with progressive fibrosis replacing viable myocardial tissue; increase in type I collagen rather than type III collagen, leading to reduced myocardial distensibility. Valvular heart disease (VHD) ranges from sclerosis to severe, often calcific, valvular stenosis and/or regurgitation. It is more common after mediastinal RT in comparison to chest wall RT for breast cancer. Among breast cancer patients, it is more common after left-sided RT in comparison to right-sided RT. Chronic pericarditis may develop as a consequence of acute pericarditis seen during or shortly after RT and as a delayed complication. Most patients have a combination of restrictive and constrictive disease and pericardial stripping does not afford similar benefits in RT patients compared to those with constriction due to other causes. Arrhythmias can be seen as a consequence of RT, and may be both hyperkinetic and hypokinetic. Inappropriate sinus tachycardia, both at rest and during effort, is common after thoracic RT and is felt to be a consequence of autonomic dysfunction. Bundle branch and atrio-ventricular blocks may also be observed. Radiation-induced carotid disease produces carotid lesions that are more extensive than the traditional bifurcation stenosis and often involves atypical areas such as long segments of the carotid artery. The global risk of cerebrovascular events is increased and the common atherosclerosis risk factors and preexisting atherosclerotic lesions are exacerbating factors In patients presenting with symptoms of dyspnea, fatigue, and reduced exercise tolerance, it is important to consider other organs that may be affected by RT or chemotherapy in the differential diagnosis: acute, chronic and recall radiation pneumonitis should be ruled out; chemotherapyinduced lung disease may be observed with several agents, mostly with bleomycin; radiation fields including the neck (such as mantle field used for HL) may cause thyroid dysfunction, most frequently hypothyroidism..