Radiation, chemotherapy, and biological agents, independently and in combination, increase the risk of CVD in cancer survivors. For survivors of some cancers, radiotherapy-related CVD is the leading noncancer cause of mortality (93
). Radiation-related CVD includes pericardial disease, coronary artery disease, valvular dysfunction, conduction abnormalities, and cerebrovascular disease. However, the risk of pericarditis is rare with modern techniques of irradiation and dose fractionation. When at least 60% of the heart is irradiated at doses of 40 Gy or less, the risk for mild pericarditis is less than 5%, and severe pericarditis is rare (176
Coronary artery disease results from injury and replacement of damaged cells by myofibroblasts and the deposition of platelets, followed by a cascade of events that result in atherosclerosis (102
). Myocardial infarction is one of the most common types of CVD in long-term Hodgkin lymphoma survivors. High-dose (ie, >30–35 Gy) mediastinal radiation, particularly in younger Hodgkin lymphoma patients, increases the risk of coronary artery disease (177
). The resulting high rate of complications and/or death most frequently occurs in Hodgkin lymphoma patients who have diastolic dysfunction (179
). Among 2232 consecutive Hodgkin lymphoma patients treated from 1960 through 1991, irradiated children and adolescents had a markedly increased risk of death due to heart disease (RR = 28–37), and all of these deaths were in patients who received doses of 42–45 Gy (180
). When this analysis was extended to include all Hodgkin lymphoma patients, the overall relative risk of death from acute myocardial infarction was 3.2 (180
). The increased risks of death from myocardial infarction were statistically significant within 5 years after radiotherapy, the average time from completion of radiotherapy to myocardial infarction was 10.3 years, and the risk of death from myocardial infarction remained elevated throughout the follow-up period (>20 years).
Many studies of breast cancer survivors have reported a statistically significant increase in coronary artery disease and/or nonfatal myocardial infarction associated with left-sided radiotherapy compared with right-sided radiotherapy or no radiotherapy (181
). Breast cancer patients treated with internal mammary node radiotherapy may also be at increased risk for coronary artery disease (129
Radiotherapy is associated with an increased risk of valvular dysfunction (189
). Hull et al. (191
) reported that valvular dysfunction developed in 25 of 415 Hodgkin lymphoma survivors at a median of 22 years after radiotherapy. In a large Dutch study of breast cancer survivors (184
), the hazard ratio of valvular dysfunction for internal mammary node radiotherapy vs no radiotherapy was 3.17 (95% CI = 1.90 to 5.29). The 2009 CCSS survey (9
) showed that the cumulative incidence of self-reported valvular disease increased with increasing cardiac radiation dose.
Radiation may cause fibrosis of cardiac conduction pathways, which can lead to life-threatening arrhythmias or other conduction defects. Serious post-radiation abnormalities include atrioventricular nodal bradycardia, all levels of heart block including complete heart block, and sick sinus syndrome (192
). The frequency of one type of cardiac conduction damage (ie, QTc > 0.44 seconds) in 134 childhood cancer survivors was 12.5% after chest radiotherapy alone and 18.9% after radiotherapy and anthracyclines (192
). Persistent fixed-rate tachycardia and loss of circadian variability in the heart rate have also been documented following chest radiotherapy that resulted in cardiac exposure. In one study (193
), 74.5% of long-term survivors of Hodgkin lymphoma treated with chest radiotherapy had a cardiac conduction defect or arrhythmia, 31% had sustained tachycardia, and 57% had a monotonous heart rate. Autonomic nervous system dysfunction could lead to the decreased perception of angina observed by some patients.
Myocardial infarction due to radiotherapy can also lead to congestive heart failure. When myocardial dysfunction develops after standard-dose mediastinal irradiation, it is typically mild or subclinical (194
) and involves diastolic and systolic left ventricular dysfunction (195
). Restrictive cardiomyopathy is more common in cancer survivors treated with radiotherapy who have not received an anthracycline (196
). Subtle left ventricular dysfunction has been detected by echocardiography and radionuclide angiography in Hodgkin lymphoma patients evaluated a few years after mediastinal irradiation (197
). Two retrospective studies (184
) of congestive heart failure among irradiated breast cancer patients yielded conflicting results. A multi-institutional study with a median follow-up of 18 years found an increased risk of congestive heart failure with radiotherapy compared with no radiotherapy (184
), whereas another investigation (188
) found no increased incidence of congestive heart failure associated with radiotherapy laterality or internal mammary node radiotherapy.
Few analytic data describe the relationship between radiation dose to the heart and adverse outcomes. The 2009 CCSS survey (9
) is thus noteworthy for the detailed dose–response evaluations conducted following radiotherapy and anthracycline treatments and the risks (albeit self-reported) of congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities (). Compared with siblings, childhood cancer survivors were statistically significantly more likely to report congestive heart failure (HR = 5.9, 95% CI = 3.4 to 9.6), myocardial infarction (HR = 5.0, 95% CI = 2.3 to 10.4), pericardial disease (HR = 6.3, 95% CI = 3.3 to 11.9), and valvular abnormalities (HR = 4.8, 95% CI = 3.0 to 7.6). Cardiac radiation exposure of at least 15 Gy increased the risk of congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities by two- to sixfold compared with nonirradiated survivors. There was no evidence for increased risks of any of these conditions following exposure to less than 5 Gy, and the slight elevations in these risks were not statistically significant at exposures between 5 and 15 Gy. The hazard ratios for the four cardiac conditions ranged from 3.6 to 5.5 for cardiac doses greater than 35 Gy. The cumulative incidence of adverse cardiac outcomes in childhood cancer survivors continued to increase up to 30 years after diagnosis and ranged from approximately 2% to slightly more than 4% overall, but to much higher levels for those who received the highest cardiac radiation doses () and the highest cumulative dose of anthracyclines. Recent data from the German–Austrian DAL-HD (German Association for Childhood Leukemia Research and Treatment and Hodgkin’s disease) studies show a dose–response relationship for cardiac diseases in children treated for Hodgkin lymphoma with combined anthracycline-based chemotherapy (cumulative doxorubicin dose was uniformly 160 mg/m2
) and radiation (198
). The 25-year cumulative incidence of cardiac disease was 3% with no radiotherapy, 5% after 20 Gy, 6% after 25 Gy, 10% after 30 Gy, and 21% after 36 Gy (198
Figure 2 Cumulative incidence of cardiac disorders among childhood cancer survivors by average cardiac radiation dose. From Mulrooney et al. (9), with permission from BMJ Publishing Group Ltd. cGy = centigray.
Patients treated for head and neck cancer with radiation doses of 40–70 Gy, and particularly with doses greater than 60 Gy, have an elevated risk for stroke and occlusive carotid artery disease (199
). In one study (201
), the median time from radiotherapy to stroke diagnosis was 10.9 years (range = 1.3–21 years). Another study (199
) reported 66 cerebrovascular events among 2567 head and neck cancer patients who were treated with 30–66 Gy radiotherapy compared with only 12 events among 4119 nonirradiated patients (odds ratio = 9.0; P
In a 2009 study of 2201 5-year survivors of Hodgkin lymphoma (201
), 96 patients developed cerebrovascular disease (55 had a stroke, 31 had a transient ischemic attack, and 10 had both) at a median age of 52 years. The standardized incidence ratio was 2.2 for stroke and 3.1 for transient ischemic attack. Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (HR = 2.5, 95% CI = 1.1 to 5.6 compared with no radiotherapy).
The incidence of stroke in the CCSS cohort was almost 10-fold higher than in the sibling comparison group (202
). Leukemia survivors were six times more likely to suffer a stroke compared with the siblings, and brain tumor survivors were 29 times more likely. Of the brain tumor cohort, 69 (4.9%) of 1411 patients who had a history of radiotherapy reported a stroke, and the cumulative incidence of stroke at 25 years after radiation therapy was 6.9% (95% CI = 4.5% to 9.3%). Cancer survivors who were exposed to cranial radiotherapy at a dose of 30 Gy or higher had an increased risk for stroke, with the highest risk among those treated with a dose of 50 Gy or higher (202
). Adult survivors of childhood Hodgkin lymphoma who were treated with thoracic radiotherapy (median dose = 40 Gy), which included mediastinal and neck radiotherapy, had a 5.6-fold increased risk of stroke compared with the siblings.