**4. Dose-volume effect of RRHD**

The dose-volume effect of RRHD is highly dependent on the definition of its endpoints. According to the length of its latency, RRHD could be divided into acute injury, which often manifests within a few months and is usually transient, and chronic toxicities, which often manifest as congestive heart failure and ischemic heart disease, among others, and occur with a long latency [33]. RRHD can have subclinical manifestations, such as localized cardiac imaging abnormalities on nuclear magnetic resonance imaging or regional wall motion abnormalities on cardiac ultrasonic examination, but manifestations could also be clinical, such as coronary artery disease or myocardial infarction [33].

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

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

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

The detailed pathogenesis of RRHD has been well reviewed [12, 31]. Overall, the endothelial system of blood vessels, particularly the arteries seem to be the critical target structures. After radiation, early functional alterations might include the pro-inflammatory responses and other changes, followed by slow progression [31, 32]. Although experimental animal models will help to elucidate the possible cellular and molecular mechanisms of RRHD, the results from various animals might be species-specific, and caution should be used in extrapolating to humans. In cancer patients, radiation induces macro- and microvascular injury. The former accelerates age-related atherosclerosis and leads to coronary artery disease after several years or decades due to reduced blood flow to the radiated myocardial territory. On the other hand, the latter reduces capillary density and results in decreased vascular reverse, which usually

may lead to chronic or delayed reemergence of pericarditis with effusion.

196 Radiotherapy

4.0–5.0%) for patients with left- and right-sided cancer, respectively [20].

**3. Pathophysiological mechanisms of RRHD**

**4. Dose-volume effect of RRHD**

individual patients should be well balanced during treatment decision-making.

occurs within several months after RT and has only subclinical manifestations [12].

The dose-volume effect of RRHD is highly dependent on the definition of its endpoints. According to the length of its latency, RRHD could be divided into acute injury, which often manifests within a few months and is usually transient, and chronic toxicities, which often The accurate definition of the heart and its substructures is critical to the estimation of the radiation dose-volume effect on RRHD. However, the imprecise definition of the heart in treatment planning computed tomography (CT) imaging poses a great challenge [33]. Feng et al. [34] developed a heart atlas to study cardiac exposure to radiation in the treatment of breast cancer. Using this consistent atlas for cardiac structure delineation, we could quantify the causative effects of RT on cardiac morbidity and mortality and study the dose-volume constraints on the heart and its substructures [34] (**Figure 2**).

**Figure 2.** Cardiac atlas is illustrated in the CT images with intravenous contrast [34] (with permission).

In all of the published studies about the dose-volume response relationships of RRHD, mortality from pericarditis, ischemic heart disease, and decreased myocardial perfusion were three main clinical endpoints [33]. Gagliardi et al. [33] (**Figure 3**) summarized the dose-volume predictors and normal tissue complication probabilities of pericarditis/pericardial effusion, and the results showed that the mean doses to the pericardium (>30 Gy or >26.1 Gy) or mediastinum (>41 Gy) might be the predictors of radiation-induced pericarditis or pericardial effusion. The incidence of pericarditis was 7% (14/198) with a radiation dose of ≤6 Gy; 12% (5/42) with a dose of 6–15 Gy; 19% (23/123) with a dose of 15–30 Gy; and 50% (7/14) with a dose of >30 Gy. Regarding cardiac mortality from ischemic heart disease or myocardial infarction, radiation dose to the mediastinum >30 Gy; 35% of heart volume receiving a radiation dose > 38 Gy; mean dose to the whole heart volume > 2.5 Gy; and radiation to the internal mammary chain would be the predictive parameters [33]. When taking cardiac perfusion defects as the clinical endpoints, volume of the left ventricle receiving doses higher than 23 (V23Gy) or 33 Gy (V33Gy) could predict myocardial perfusion defects [35].

**Figure 3.** Dose-response curves of radiation-induced cardiac mortality. These data were estimated based on the breast cancer and Hodgkin lymphoma data sets [33] (with permission).

#### **5. Cardiac dose sparing and avoidance techniques**

For curable cancers, such as breast cancer and Hodgkin lymphoma, cardiac dose protection and/or avoidance techniques might be beneficial in minimizing RRHD. For breast cancer, several techniques have been utilized clinically. These techniques include the following: (1) RT delivery with breath control or holding techniques, (2) prone patient positioning, (3) new RT techniques such as intensity-modulated RT (IMRT), proton therapy, or partial breast irradiation techniques, and (4) single-fraction, intraoperative radiation [36] (**Figure 4**).

In all of the published studies about the dose-volume response relationships of RRHD, mortality from pericarditis, ischemic heart disease, and decreased myocardial perfusion were three main clinical endpoints [33]. Gagliardi et al. [33] (**Figure 3**) summarized the dose-volume predictors and normal tissue complication probabilities of pericarditis/pericardial effusion, and the results showed that the mean doses to the pericardium (>30 Gy or >26.1 Gy) or mediastinum (>41 Gy) might be the predictors of radiation-induced pericarditis or pericardial effusion. The incidence of pericarditis was 7% (14/198) with a radiation dose of ≤6 Gy; 12% (5/42) with a dose of 6–15 Gy; 19% (23/123) with a dose of 15–30 Gy; and 50% (7/14) with a dose of >30 Gy. Regarding cardiac mortality from ischemic heart disease or myocardial infarction, radiation dose to the mediastinum >30 Gy; 35% of heart volume receiving a radiation dose > 38 Gy; mean dose to the whole heart volume > 2.5 Gy; and radiation to the internal mammary chain would be the predictive parameters [33]. When taking cardiac perfusion defects as the clinical endpoints, volume of the left ventricle receiving doses higher than 23 (V23Gy) or 33 Gy

(V33Gy) could predict myocardial perfusion defects [35].

198 Radiotherapy

**5. Cardiac dose sparing and avoidance techniques**

cancer and Hodgkin lymphoma data sets [33] (with permission).

For curable cancers, such as breast cancer and Hodgkin lymphoma, cardiac dose protection and/or avoidance techniques might be beneficial in minimizing RRHD. For breast cancer, several techniques have been utilized clinically. These techniques include the following: (1) RT delivery with breath control or holding techniques, (2) prone patient positioning, (3) new RT techniques such as intensity-modulated RT (IMRT), proton therapy, or partial breast irradia-

**Figure 3.** Dose-response curves of radiation-induced cardiac mortality. These data were estimated based on the breast

tion techniques, and (4) single-fraction, intraoperative radiation [36] (**Figure 4**).

**Figure 4.** Cardiac sparing techniques is available nowadays. These techniques included radiation techniques improvement and patient or organ motion management.

With breath holding within inspiration, the distance from the chest wall to the heart will increase and the cardiac volume in the field will decrease, the mean or maximal dose to the heart or left anterior descending artery will be reduced [36], and the probability of cardiac mortality will also be reduced (4.8 vs. 0.1%) [37]. In the delivery of RT, patients are immobilized in the prone position so that the breast falls away from the chest wall and the distance from the heart to the RT beam increases. A few studies showed that with this technique, 75–85% of left-sided breast cancer patients had reduced cardiac volume in the field [38] and the mean cardiac dose decreased [39]. Although the main concerns of the prone position include its reproducibility and the potential increase in radiation to other normal tissues due to the poor setup, recent data showed that this technique could be well reproducible with daily cone-beam CT [40, 41].

For breast cancer patients, IMRT has been proven to have a cardiac dose sparing effect without compromising the dose homogeneity in the breast, especially for those with left-sided lesions [36, 42]. With the IMRT technique, the cardiac dose decreased with improved dose homogeneity in the breast [43]. A series of studies showed that, compared with breath holding in three-dimensional conformal RT and prone position techniques, IMRT has similar benefits and is more reproducible. The advantages of IMRT technique included the improvement of radiation dose homogeneity in target volume, the reduction of high cardiac dose volumes, and the decrease of normal tissue complication probability. In addition, IMRT technique showed its advantages in sparing the high-risk cardiac subregions such as the anterior part of the heart, the coronary arteries, and the left ventricle [16, 17, 44].

Partial breast irradiation, as an alternative method to reduce the cardiac dose, could decrease the irradiated breast volume and increase the distance from the target volume to the heart. Hypofractionation is required by partial breast irradiation, and two recent reviews suggest that hypofractionation has not resulted in increased cardiac morbidity [45, 46]. Dosimetric studies showed that interstitial brachytherapy could reduce cardiac doses with imageguided RT techniques [47, 48]. The mean cardiac dose decreased to 21% of the prescription dose in patients with left-sided breast cancer [48] and the cardiac volume receiving low doses (5 and 10 Gy) decreased significantly. In addition, the advantages of proton therapy including the rapid dose falloff and the Bragg peak make it possible to spare the radiation dose to the surrounding tissues including the heart. Several dosimetric studies showed that proton RT could reduce the maximal dose, V20Gy, V5Gy, etc [49–52]. However, because of the limited availability and high cost, at present, this technique is not advocated for cardiac dose sparing [36].

For Hodgkin lymphoma, the RT field has changed over the past decades. Previously, the majority of patients received mantle field radiation with/without upper abdomen field radiation, and a large volume of the heart had a prescribed dose irradiation. According to the anatomical sites of disease presence, the caudal border of the mantle field individually varied from the bottom border at the 8th–9th thoracic vertebrae (T8–T9) [53] to T10–T11 [54, 55], and the higher caudal border might spare most of the irradiated heart volume [53]. With advanced imaging modalities such as positron emission tomography–CT and improved RT delivery techniques such as IMRT, image-guided RT, and breath control techniques, among others, the previously applied extended field and involved field techniques have now been replaced by techniques using limited target volumes, such as involved node RT (INRT) and involved site RT (ISRT) [56]. With the optimal imaging during the course of treatment, both the INRT and ISRT techniques reduce the treated volume to a safe minimum [56]. In addition, with refinements of Hodgkin lymphoma, the prescription dose decreased to 20–36 Gy [57]. Due to more limited target volume and lower prescribed radiation doses, greater amounts of normal healthy tissues such as lung and heart could be spared.

Theoretically, for RT of non-small cell lung cancer, dose escalation to 74 Gy would be better than the standardized 60 Gy dose. However, the results of a randomized phase 3 study (RTOG 0617) showed that a higher dose did not translate to a better outcome and might even be potentially harmful [58]. One reasonable explanation is that patients receiving doses of 74 Gy usually had worse dose-volume effects on the heart. The dose volume parameters including V5Gy and V30Gy of the heart were the important predictors of patient survival [58]. The dose-volume effects on the heart substructures such as the pericardium, atria, and ventricles will be investigated and their dose-volume limitations will be included in future lung cancer trials. In addition, for early and locally advanced non-small cell lung cancer, proton RT will potentially be used for cardiac sparing [59].

## **6. Radiation for patients with cardiac implantable electronic devices**

The numbers of patients with both cardiac implantable electronic devices (CIEDs) including pacemakers (PMs) and implantable cardiac defibrillators and cancer are expected to rise, and patients in these situations require RT. The potential interactions between high doses of radiation and the function, longevity, and integrity of the CIEDs, as well as the harm to the patients, remain unclear. The results of a recent review [60, 61] showed that the risk of device failure increases with increasing radiation doses, without a clear cutoff point. For patients with pacemakers, the delivered total radiation dose to the device was strongly recommended not to exceed 2 Gy and the dose in patients with implantable cardiac defibrillators should be within 1 Gy. The radiation energy should be less than 6 MV. Because of the potential dangers of device malfunction, the radiation oncologist should have all the measures designed to minimize the risk to patients. Furthermore, it is necessary for the cardiologist, oncologist, radiotherapist, and physicist to collaborate closely.
