Cardiovascular disease and cancer are the top two causes of global mortality, accounting for 46% of deaths worldwide. To complicate matters further, cancer treatment has led to a significant increase in the global incidence of cardiovascular disease. A mainstay of cancer treatment is radiation therapy (RT). Its success with and without systemic therapy as an effective modality in Hodgkin’s and non-Hodgkin’s lymphomas, breast cancer, and lung cancer, for example, has led to improved survival rates. There were an estimated 16.9 million American cancer survivors in 2019 and this number is expected to grow to 26 million by 2040. This increase in survivorship will continue to lead to an increase in manifestations of various cardiovascular toxicities.
Compared with nonirradiated patients, patients who have received mediastinal radiation have a 2% higher absolute risk of cardiac toxicity and death at 5 years and 23% increased absolute risk after 20 years. Cardiovascular disease associated with RT presents via a spectrum of disorders. This is thought to reflect the differing radiosensitivities of involved cells and tissues. Coronary artery atherosclerosis, valvular disease, pericardial disease, cardiomyopathy, and autonomic dysfunction represent the main clinical manifestations of radiation-induced cardiovascular disease (RICD).
Late cardiac toxicity has been notably described in pediatric patients receiving mediastinal radiation for lymphomas. Given that these patients have curable cancers and live for decades after initial treatment with radiation with or without chemotherapy, they have a greater potential for the development of RICD. Although not as prevalent, cardiovascular toxicity has also been described in women with breast cancer receiving adjuvant RT. As cure rates are high, women live long enough for cardiac toxicity to be exhibited.
Advances in modern chest radiotherapy techniques have led to the development of newer considerations in radiation oncology. Beyond the initial radiation course with or without systemic therapy, the implementation of reirradiation as well as stereotactic body RT have led to unique clinical situations requiring careful thought. Although the clinical manifestations of cardiotoxicity may remain similar, the nuances provided by possible cardiac cell regeneration and hypofractionation serve to make an already complex situation even more challenging in terms of safely delivering therapies.
In this chapter, we will review the clinical manifestations of cardiovascular toxicity and the mechanistic changes associated with such toxicities. We will then review preventative methods including published dose constraints for the major cardiovascular organs and discuss management options and considerations.
Radiation-induced cardiovascular toxicity has become an important issue as outcomes have improved with advances in thoracic RT. Risk factors for the development of toxicity include younger age at time of RT (<50), higher cumulative dose of RT (>30 Gy), volume of heart irradiated, higher dose per fraction (>2 Gy/day), anterior or left chest irradiation, presence of tumor in the mediastinum, concurrent cardiotoxic systemic therapy, and preexisting cardiovascular disease as well as cardiovascular risk factors.
Cardiotoxicity manifests itself in a number of ways. The tissues affected include the pericardium, coronary arteries, the myocardium, the valves, the cardiac electrical conduction system, and the great vessels of the chest. Whereas acute effects can manifest themselves during RT or weeks to months after RT, long-term effects are demonstrated years to decades later. Table 29.1 shows the various toxicities and associated early and late effects. Although pericarditis is the most common manifestation of RICD, ischemic heart disease is the most common cause of cardiac death in patients who have undergone RT. The risk of RICD relates to both the dose and duration of RT.
PericarditisAcute exudative pericarditis, rare—occurs during RT—reaction to necrosis/inflammation of tumor adjacent to the heartDelayed acute pericarditis—within weeks—manifests as asymptomatic pericardial effusion or symptomatic pericarditis. Cardiac tamponade, rare. Spontaneous clearance of effusion can take up to 2 years
PericarditisDelayed chronic pericarditis—weeks to years after RT—extensive fibrous thickening, adhesions, chronic constriction, and chronic pericardial effusion—observed in up to 20% of patients within 2 yearsConstrictive pericarditis seen in 4%–20% of patients and is dose-dependent and related to presence of pericardial effusion in delayed acute phase
CardiomyopathyAcute myocarditis—radiation-induced inflammation with transient repolarization abnormalities and mild myocardial dysfunction
CardiomyopathyDiffuse myocardial fibrosis (after >30 Gy) with systolic/diastolic dysfunction, conduction abnormalities, and autonomic dysfunctionRestrictive cardiomyopathy—advanced myocardial damage due to fibrosis with severe diastolic dysfunction and heart failure signs and symptoms
Valvular DiseaseNo immediate effects
Valvular DiseaseValve apparatus and leaflet thickening, fibrosis, shortening, and calcification on mostly left-sided valvesValve regurgitation > valve stenosisStenosis more commonly affects aortic valveValve disease increases significantly after 20 years
Conduction System DiseaseNo immediate effects
Conduction System DiseaseRight bundle branch block most commonProlongation of the corrected QT intervalAtrioventricular nodal bradycardia, heart block, sick sinus syndrome
Coronary Artery DiseaseNo immediate effects—perfusion defects can be seen in ∼50% of patients 6 months after RT, sometimes a/w wall-motion abnormalities and chest pain
Coronary Artery DiseaseAccelerated CAD appearing at younger agePatients <50 tend to develop CAD in first 10 years, patients >50 have longer latencyCoronary ostia and proximal segments typically involvedCAD doubles risk of death via myocardial infarction
Carotid Artery DiseaseNo immediate effects
Carotid Artery DiseaseRT–induced lesions more extensive, involve longer segments, and atypical areas of carotid segments
Vascular DiseaseNo immediate effects
Vascular DiseaseAtherosclerotic calcifications of ascending aorta and aortic arch
The clinical presentation of RICD is similar to that of cardiac disease unrelated to RT, which makes it difficult to differentiate the two. It is important to assess the risk factors and the timeframe for development in diagnosing radiation-induced cardiotoxicity.
|Acute pericarditis||Chest pain, fever, pericardial rub|
|Chronic pericarditis||Dyspnea, hypotension, thready pulse|
|Cardiomyopathy||Dyspnea, fatigue, weakness, edema, pulmonary edema|
|Valvular disease||Dyspnea, symptoms of valvular regurgitation/stenosis|
|Coronary artery disease||Chest pain/tightness/heaviness, dyspnea, fatigue|
|Conduction abnormalities||Palpitations, dizziness, dyspnea, chest discomfort|
Screening and Diagnostic Workup
The initial evaluation of the patient involves a complete history and physical examination, together with a history of prior RT and prior systemic therapy, with close attention to cumulative cardiovascular radiation dose and volume of cardiac tissue irradiated in addition to cumulative dose of systemic therapy received. Subsequent workup depends on the symptoms and history but all include an electrocardiogram (ECG) with echocardiography with or without the following (depending on scenario): chest X-ray, cardiac enzymes, chest computed tomography (CT), cardiac magnetic resonance imaging (MRI), angiography, and Holter monitoring.
The most common screening tool for detection and monitoring of RICD is echocardiography. The European Association of Cardiovascular Imaging and the American Society of Echocardiography recommends comprehensive screening and risk-factor modification for patients, in addition to baseline transthoracic echocardiography (TTE) to detect cardiac abnormalities prior to RT. They recommend careful annual symptom screening and an annual TTE if a murmur is detected. At 5 years, a TTE is recommended for high-risk asymptomatic patients, stress echocardiography or stress cardiac MRI, and repeat TTE at 5-year intervals. At 10 years, TTE is recommended for non–high-risk patients with repeat TTE at 5-year intervals.
Echocardiography : Features of RICD on echo include biventricular systolic and diastolic dysfunction, multivalvular involvement with mixed valvular dysfunction, prominent calcification (pericardial, valvular, annular, aortomitral curtain, and aortic), wall motion abnormalities associated with coronary artery disease, and pericardial constriction. Valvular regurgitation is more common than stenosis.
Coronary computed tomographic angiography (CTA) : This can be useful for its negative predictive value in that no coronary calcification is indicative of a very low chance of coronary artery disease (CAD). CTA can be used for the evaluation of aortic, valvular, myocardial, and pericardial calcification and for preoperative assessment in patients undergoing cardiac surgery. CT can provide information regarding mediastinal and pulmonary fibrosis, and single photon emission CT, as well as positron emission tomography, have been utilized to assess myocardial ischemia.
Cardiac magnetic resonance (CMR) : CMR allows for the simultaneous analysis of functional and structural data, enabling detection of RICD involving the coronary arteries, the valves, and the myocardium, as well as the pericardium. Cine imaging allows assessment of ventricular volumes and regional wall motion abnormalities, whereas late gadolinium enhancement allows for visualization of scar and viable tissue as well as regional nonischemic fibrosis.
Cardiac catherization: Invasive catheterization allows for confirmation of findings seen in noninvasive imaging. Left-heart catheterization evaluates coronary artery stenosis severity and disease extent, whereas right-heart catheterization allows for calculation of intracardiac and pulmonary pressures.
Evaluation for pulmonary disease: Patients with RICD should also be evaluated for concurrent pulmonary disease via clinical evaluation, chest X-ray, pulmonary function tests, and dedicated high-resolution chest CT. This is because concurrent pulmonary disease is independently associated with reduced survival in RICD.
The grading of RICD can be performed with the use of Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. This grading system is described in detail elsewhere in this book. Each component of RICD is analyzed individually and graded accordingly.
Mechanisms of Action
RICD occurs via differing mechanisms based on the sequelae in question. The major mediator of RICD is the formation of fibrosis in both acute and chronic settings, which can affect all cardiac tissues including the pericardium, the myocardium, the coronary arteries, and conductive tissue, as well as the great vessels.
Acute phase: In the acute phase, radiation to cardiac tissues results in acute inflammation via tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, and IL-8 leading to vasodilation and vascular permeability. This results in neutrophil infiltration and the release of profibrotic cytokines such as platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β, fibroblast growth factor (FGF), insulin-like growth factor (IGF), and connective tissue growth factor (CTGF). Subsequently, the coagulation cascade is initiated and degradation of the endothelial basement membrane begins, allowing for the clearance of injured tissue. The acute phase spans minutes to several days.
Late phase: In the late phase, radiation-induced upregulation of c-Myc, c-Jun, TGF-β, IL-4, and IL-13 lead to further development of fibrosis. , Radiation additionally can induce premature differentiation of fibroblasts, leading to the development of fibrocytes that in turn produce higher levels of collagen. This results in chronic collagen deposition within cardiac tissue leading to fibrotic scar tissue and reducing the heart’s elasticity and, eventually, function. In radiation-induced vascular disease, NF- κ β plays a large role by upregulating proinflammatory cytokines and adhesion molecules in the endothelium, leading to the recruitment of inflammatory cells to the site of vascular injury.
DNA damage response, chronic oxidative stress/hypoxia, epigenetic regulation, and telomere extension have also been found to be involved in the formation of radiation-induced fibrosis and RICD. , , Other chronic changes include microvascular injury and neovascularization, which affect conductive tissue and the pericardium, as well as atherosclerosis, which affects the coronary arteries as well as the great vessels. Table 29.2 describes the mechanisms related to various components of RICD.