**2. Epidemiological data for radiation-related heart disease**

Following the use of mantle field radiation for Hodgkin lymphoma in the 1960s, RRHD was recognized because substantial cardiac damage was observed to occur after the whole heart received doses of radiation higher than 30 Gy [12]. Traditionally, RRHD mainly included radiation-related pericarditis, pericardial and myocardial fibrosis, and coronary artery disease, as well as conduction system abnormalities. However, with improvements in RT techniques and refinements in RT delivery, radiation doses to the heart have decreased in the past three decades. For example, in lung and esophageal cancer, the mean heart dose might be >20 Gy [15], while in postoperative RT for breast cancer, it might be <10 Gy [16, 17]. As a reference point, the survivors of the atomic bombings of Japan received up to 4 Gy [18]. The endpoints of RRHD could be categorized as radiation-induced death from heart disease (mortality), clinical manifestations (clinical disease), and imaging or laboratory abnormalities (subclinical disease) [14] as shown in **Figure 1**.

Breast cancer is a curable disease. Therefore, minimization of anticancer therapy-induced toxicity is an important concern during treatment decision-making. In a study of breast cancer, mortality due to heart disease was increased by 27% (2p = 0.0001) in women who received surgery plus RT compared to the rate in those who did not receive postoperative RT. The proportional excess of vascular deaths was similar in the first decade and the period thereafter (ratio 1·32 vs. 1·27). However, the absolute rates were about three times higher in the second decade and the latter period for the patients with left-sided breast cancer [5]. Exposure to cardiac radiation in the treatment of breast cancer will increase the subsequent rate of ischemic heart disease for more than 10 years after completion of the therapy. In addition, women with cardiac risk factors experience greater increases in risk after thoracic RT. Darby et al. quantified the dose effect of ischemic heart disease in patients with breast cancer who received adjuvant thoracic RT. They found that the rate of major coronary events increased by 7.4% per Gy without an apparent threshold, and the major coronary events included myocardial infarction, coronary revascularization, and death from ischemic heart disease [13, 19]. Even in the era of modern RT, in comparison with patients with right-sided breast cancer, those with left-sided breast cancer experienced a small increase in the risk of percutaneous coronary intervention (PCI) following RT, and the 10-year cumulative incidences in patients with leftsided and right-sided disease were 5.5 and 4.5%, respectively [20].

occurred [2]. Lung cancer is the most common incident cancer and the leading cause of cancer death in China, and esophageal cancer is also commonly diagnosed. Worldwide, lung, esophageal, and breast cancer account for approximately 27% of new cancer cases which means that more than 20% of patients will receive thoracic radiation therapy (RT). Many studies have proven that local RT improves local control and prolongs overall survival [3–11]. However, thoracic RT might inadvertently result in various forms of cardiac toxicity and manifest as clinical and subclinical cardiac disease, termed radiation-related heart disease (RRHD) [12, 13]. In this chapter, we will present the epidemiological data and discuss the possible pathophysiological mechanisms in brief. We will also address the cardiac avoidance techniques and the dose-volume-effect relationship. Although many cytotoxic and molecularly targeted drugs also result in various cardiac toxicities [14], consideration of these is outside the scope

Following the use of mantle field radiation for Hodgkin lymphoma in the 1960s, RRHD was recognized because substantial cardiac damage was observed to occur after the whole heart received doses of radiation higher than 30 Gy [12]. Traditionally, RRHD mainly included radiation-related pericarditis, pericardial and myocardial fibrosis, and coronary artery disease, as well as conduction system abnormalities. However, with improvements in RT techniques and refinements in RT delivery, radiation doses to the heart have decreased in the past three decades. For example, in lung and esophageal cancer, the mean heart dose might be >20 Gy [15], while in postoperative RT for breast cancer, it might be <10 Gy [16, 17]. As a reference point, the survivors of the atomic bombings of Japan received up to 4 Gy [18]. The endpoints of RRHD could be categorized as radiation-induced death from heart disease (mortality), clinical manifestations (clinical disease), and imaging or laboratory abnormalities (subclinical disease) [14] as shown in **Figure 1**. Breast cancer is a curable disease. Therefore, minimization of anticancer therapy-induced toxicity is an important concern during treatment decision-making. In a study of breast cancer, mortality due to heart disease was increased by 27% (2p = 0.0001) in women who received surgery plus RT compared to the rate in those who did not receive postoperative RT. The proportional excess of vascular deaths was similar in the first decade and the period thereafter (ratio 1·32 vs. 1·27). However, the absolute rates were about three times higher in the second decade and the latter period for the patients with left-sided breast cancer [5]. Exposure to cardiac radiation in the treatment of breast cancer will increase the subsequent rate of ischemic heart disease for more than 10 years after completion of the therapy. In addition, women with cardiac risk factors experience greater increases in risk after thoracic RT. Darby et al. quantified the dose effect of ischemic heart disease in patients with breast cancer who received adjuvant thoracic RT. They found that the rate of major coronary events increased by 7.4% per Gy without an apparent threshold, and the major coronary events included myocardial infarction, coronary revascularization, and death from ischemic heart disease [13, 19]. Even in the era of modern RT, in comparison with patients with right-sided breast cancer, those with left-sided breast cancer experienced a small increase in the risk of percutaneous coronary

**2. Epidemiological data for radiation-related heart disease**

of this chapter.

194 Radiotherapy

**Figure 1.** Radiation-related heart disease usually occurs with a certain latency from a few hours to several decades after the heart and its substructures receive direct or indirect irradiation. The endpoints of RRHD included its mortality and morbidity. According the occurrence timing of cardiac radiation response, RRHD includes acute and late cardiac toxicities. Generally, the probability of RRHD is positively related to the radiation dose that the heart received.

Hodgkin lymphoma usually occurs in young patients and is also one of the most curable cancers. Cytotoxic treatment with anthracyclines and vinca alkaloids and RT are the cornerstone choices for therapy of this cancer, and both are associated with the risk of cardiovascular disease. The cardiovascular risks after chemotherapy and RT have been well established [21, 22]. According to data from old cohort studies, Hodgkin lymphoma was usually treated with radiation doses of 35–45 Gy using extended field treatment such as mantle field radiation. The cumulative risks of heart disease among survivors of adult Hodgkin lymphoma are approximately 5–10% at 15 years, 16% at 20 years, and 34% at 30 years, and coronary artery disease, as the most common form, accounts for approximately 40–50% of adverse cardiac events [23]. A recent systemic analysis showed that among 6039 patients with a median length of follow-up of 9 years, 703 patients were recorded to have 1238 first cardiovascular events, which mostly included ischemic heart disease (19%), congestive heart failure (12%), arrhythmia (16%), and valvular disease (11%). The predictors of cardiovascular disease were the mean heart radiation dose per 1 Gy increase (HR 1015) and the dose of anthracyclines per 50 mg/m<sup>2</sup> increase in cumulative dose (HR 1077) [24]. In a Dutch study conducted to examine the relative and absolute excess risk of cardiovascular disease incidence, 1713 cardiovascular events were detected in 797 patients after a median follow-up of 20 years. Furthermore, 20% of patients with a cardiovascular disease developed multiple events. Mediastinal RT, anthracycline-containing chemotherapy, and smoking are appeared to be additive factors [25]. In addition, the data from both individuals exposed to radiation during a medical career [26, 27] and survivors of the atomic bombings in Japan [28] proved that radiation was the source of the risk for RRHD.

Cardiac valvular disease is less common, typically has a late onset (10 years after RT), and is related to higher doses (30 Gy) or young age at treatment. Treatment of a large cardiac volume with high doses can produce acute pericarditis, although this is uncommon. At times, this may lead to chronic or delayed reemergence of pericarditis with effusion.

Furthermore, due to the wide use of advanced imaging techniques, more subclinical manifestations are detected. With repeat nuclear imaging to assess changes in regional and global cardiac function after RT for left-sided breast cancer, a prospective clinical study found that volume-dependent perfusion defects occurred in approximately 40% of patients within the first 2 years after RT for left-sided breast cancer, and these perfusion defects were associated with cardiac wall motion abnormalities [29]. In addition, new perfusion defects usually occurred in the anterior left ventricle within 6 months after radiation [30]. The data from the Surveillance, Epidemiology, and End Results Medicare database showed that patients with left-sided breast cancer who had a history of cardiac disease had an increased risk of PCI after thoracic RT, and there was a lower survival rate in those who received PCI. The 10-year cumulative PCI incidence was 5.5% [95% confidence interval (CI) 4.9–6.2%] and 4.5% (95% CI 4.0–5.0%) for patients with left- and right-sided cancer, respectively [20].

For curable cancer types, such as breast cancer and Hodgkin lymphoma, both the radiation dose to the heart and its substructures and the risks and benefits of different regimens for individual patients should be well balanced during treatment decision-making.
