Version July 2025
INTRODUCTION —
Radiation therapy (RT) improves survival and is standardly used for breast cancer, Hodgkin lymphoma (HL), lung cancer, esophageal cancer, and other thoracic malignancies (See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma" and "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer" and "Management of stage I and stage II non-small cell lung cancer" and "Management of stage III non-small cell lung cancer".)
Successes with thoracic RT (used alone or with chemotherapy and surgery) have resulted in large cohorts of cancer survivors who are at risk for treatment-related toxicity from incidental radiation dose to the heart. Analyses have shown that the therapeutic benefits from RT may be offset to some extent by delayed (or for certain populations, acute/subacute) cardiotoxicity.
Irradiation of a substantial volume of the heart to a sufficiently high dose can damage virtually any cardiac substructure, including pericardium, myocardium, valves, coronary arteries, capillaries, and conducting system. Pericarditis and effusion are the typical acute manifestation of radiation injury, while chronic pericardial disease, coronary artery disease, cardiomyopathy, valvular disease, and conduction abnormalities can manifest years or decades after the original treatment.
Data on late cardiovascular toxicity of RT originated from survivors of breast cancer and HL, both generally favorable prognosis malignancies occurring in young and/or healthy patient populations. In the past decade, increasing evidence has established cardiac dose effects of radiation for lung and esophageal cancer, where smoking is a shared risk factor for both cancer and pre-existing heart disease, and cardiotoxicity may present earlier. An awareness of the potential cardiotoxicity of RT has led to improved RT techniques (eg, intensity-modulated RT, deep inspiration breath hold) and modalities (eg, proton, carbon ion therapy) that minimize heart dose. These advances decrease the incidence of complications but do not eliminate risk.
The pathophysiology of RT-induced cardiac injury and the clinical data on the magnitude of risk are presented here. The study of cardiac injury is a key component of survivorship and the evolving discipline of cardio-oncology (see "Cancer survivorship: Cardiovascular and respiratory issues"), and is also consistent with ASCO guidelines that call for thoughtful assessment of treatment-related risks along with baseline cardiovascular health assessment in at-risk adult populations [1].
RT-induced cardiotoxicity associated with Hodgkin lymphoma and pediatric malignancies is discussed separately. (See "Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies".)
PATHOPHYSIOLOGY —
Radiation injury to the heart and other organs are sequelae of deoxyribonucleic acid (DNA) alterations either from direct ionization or indirect (via reactive oxygen species) damage. The most studied mechanism is accelerated fibrosis and vascular atherosclerosis, predisposing to tissue ischemia and subsequent (usually late) ischemic cardiac disease. Other mechanisms include pericardial inflammation leading to acute/subacute pericarditis and pericardial effusion, along with effects on nervous conduction pathways associated with arrhythmia. Cardiotoxicity is related to both the volume of heart (and cardiac substructures) irradiated and the radiation dose delivered to that volume.
Histologic hallmarks of cardiotoxicity include diffuse fibrosis in myocardial interstitium with normal-appearing myocytes but capillary and arterial narrowing [2]. Irregularities of the endothelial cell membranes, cytoplasmic swelling, thrombosis, and rupture of the walls are present. The ratio of capillaries to myocytes is reduced by approximately 50 percent, and this leads to myocardial cell death, ischemia, and fibrosis.
These changes can have several consequences:
●Coronary artery disease (CAD) results from injury to the intima of the coronary arteries. This initiates a cascade of events that is typical of atherosclerosis, including replacement of damaged cells by myofibroblasts and deposition of platelets [2]. Doses to both small and large vessels increase risk, with recent data supporting a specific contribution from left anterior descending doses [3-6].
●The cusp and/or leaflets of valves may undergo fibrotic changes with or without calcification. Changes to valves on the left side are more common than those on the right, regardless of the relative dose distribution of RT [7]. This suggests that the higher pressures in the systemic circulation contribute to the pathogenesis of these lesions.
●Myocardial fibrosis can compromise cardiac compliance, leading to diastolic dysfunction [8].
●Dense collagen and fibrin may replace the normal adipose tissue of the outer layer of the heart, leading to late pericardial fibrosis and rarely tamponade [9].
●Fibrosis of cells in the conduction system can predispose to dysrhythmia [10,11].
A number of risk factors for the development of RT-induced cardiac toxicity have been identified, including the total radiation dose, dose per fraction, volume of heart irradiated, and the concomitant administration of cardiotoxic systemic agents (eg, anthracyclines, trastuzumab). The risk of radiation-induced cardiotoxicity is also increased by presence of baseline cardiac risk (eg, due to hypertension, smoking, and other medical comorbidities). Whereas younger patients may be predisposed to late toxicity, older patients with lower baseline reserve may present with earlier cardiac effects.
BREAST CANCER
Cardiovascular toxicity with modified RT techniques — Although early evidence suggested increase in cardiovascular mortality with radiation [2-4], treatment techniques were modified to minimize incidental cardiac irradiation. (See "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer".)
Although data from more recent studies suggest a decreased incidence of cardiotoxicity with lower cardiac doses [12], the evidence indicates that there is at least some residual risk.
Approaches to assessing the relative risk of cardiotoxicity in breast cancer patients treated with modified RT techniques have included:
●Comparison of the incidence of cardiac morbidity and/or mortality in those treated with RT (breast or chest wall) with those not receiving RT following surgery.
●Analyses of the effect of radiation dose to the heart on the incidence of cardiac morbidity and/or mortality. These have included case control studies comparing those who did and did not develop coronary events after RT for breast cancer, as well as studies comparing females with left-sided versus right-sided breast cancers. (See 'Effect of radiation dose to the heart' below.)
●Radiographic assessment of cardiac injury following RT. (See 'Surrogate endpoints of myocardial injury' below.)
Data have shown that radiation exposure of the heart increases the risk of ischemic heart disease and cardiac mortality, though the absolute risks are small, and less than the risk of omitting radiation for appropriately selected patients.
In a meta-analysis of 39 studies involving almost 1.2 million patients with breast cancer, those receiving radiotherapy experienced an increased risk of coronary artery disease (relative risk [RR] 1.3, 95% CI 1.13-1.49) and cardiac death (RR 1.38, 95% CI 1.18-1.62) [13]. However, the absolute risk increase for coronary artery disease and cardiac death was only 76 and 126 cases, respectively, per 100,000 person-years. For coronary artery disease, the risk increased within the first decade, and for cardiac mortality, it increased in the second decade.
Although previous randomized trials have not suggested a difference between irradiated patients and controls in regards to cardiac morbidity or death, this may be due, in part, to a relatively shorter follow-up. For example, in randomized trials conducted by the Danish Breast Cancer Cooperative Group (DBCG 82b and 82c), among 3083 patients with high-risk stage II or III primary breast cancer randomly assigned to adjuvant systemic treatment with or without RT following mastectomy, there were no significant differences between irradiated patients and controls with respect to either death or morbidity from ischemic heart disease or acute myocardial infarction at a median follow-up of 10 years [14].
Importantly, in these studies, postmastectomy chest wall irradiation improved survival in high-risk females with breast cancer, and the benefit of chest wall irradiation more than outweighed any increase in cardiac morbidity and mortality. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Patients treated with breast-conserving surgery'.)
Effect of radiation dose to the heart — There does not appear to be any minimum radiation dose that is entirely safe, and the effects of radiation on the heart increase with increasing doses of radiation and volume of heart exposed [15]. The increased risk can be seen within the first five years and remains elevated for at least 20 years. Females with significant cardiac risk factors may be at a particularly increased risk.
This effect of RT was demonstrated in a population-based case-control study that included 2168 females who were treated for breast cancer with surgery and RT in Sweden and Denmark between 1958 and 2001. The study included 963 females who experienced a significant coronary event (myocardial infarction, revascularization, or death from ischemic heart disease) following their treatment for breast cancer. These females were compared with 1205 matched controls who did not have coronary events. RT records were reviewed for all patients, and the dose of radiation to the heart estimated for each patient.
Results included the following [16]:
●There was increased risk of major coronary events following RT for all time periods from the period less than five years through greater than 20 years.
●The estimated mean dose of radiation to the heart was 4.9 Gy (calculated by averaging a high radiation dose to a small cardiac volume across the entire heart); the dose of radiation to the heart was greater in those with a left-sided breast cancer (6.6 versus 2.9 Gy). The risk of a coronary event increased progressively with the radiation dose, with a relative increase of 7.4 percent for each 1 Gy of radiation to the heart.
●A history of ischemic heart disease before cancer therapy was associated with an increased risk of a cardiac event after treatment for breast cancer (ratio 6.67, p <0.001). Other factors associated with a significantly increased risk included other circulatory disease, diabetes, or a left-sided breast cancer (risk ratios 1.88, 3.23, and 1.32, respectively).
Only a very limited number of patients received potentially cardiotoxic medications (eg, anthracyclines, trastuzumab), which might substantially increase the risk associated with RT. However, this analysis did not take into account other cardiac complications of radiation (cardiomyopathy, valvular heart disease, arrhythmias).
The impact of radiation dose on the risk of ischemic heart disease was confirmed in a smaller study that analyzed cardiac outcomes in a population treated with a consistent RT technique [17]. In this particular study, mean heart dose was validated as predictive of toxicity, but the greatest association was with doses received by the left ventricle (LV) specifically. (See 'Impact of dose to cardiac substructures' below.)
Additional evidence comes from observational studies that have analyzed the rate of cardiac complications in breast cancer survivors [18-28]. These studies have yielded conflicting results but suggest that there is an increase in cardiac events in females with left-sided breast tumors compared with right-sided cancers. Three of the larger registry studies illustrate the potential impact of RT based upon the laterality of the tumor:
●In one report, outcomes were analyzed from 115,000 females in the Surveillance, Epidemiology, and End Results (SEER) database who received adjuvant RT in the United States between 1973 and 2001 [20]. For patients irradiated between 1973 and 1982, cardiac mortality was significantly higher in females with left-sided cancers and the difference was more pronounced with longer follow-up (cardiac mortality ratio [CMR] for left-sided versus right-sided cancers 1.20, 1.42, and 1.58, at <10, 10-14, and >15 years, respectively). However, for females treated from 1983 to 1992, the differences were less pronounced and not statistically significant. This decrease in excess mortality may reflect improvements in RT techniques, shorter follow-up, or other unknown factors.
●In a second SEER study, the risk of death from ischemic heart disease was analyzed in 27,283 females whose treatment included adjuvant RT during the period 1973 to 1989 [18]. For females diagnosed between 1973 and 1979, there was a significantly higher 15-year mortality rate from ischemic heart disease for females with left-sided versus right-sided tumors (13.1 versus 10.2 percent). For those diagnosed from 1980 to 1984, and from 1985 to 1989, the differences in 15-year mortality rates for females with left-sided versus right-sided tumors were not significant (9.4 versus 8.7 percent and 5.8 versus 5.2 percent, respectively). The overall incidence of death from cardiac disease decreased substantially with the later cohorts.
●A large Danish registry-based study of patients treated from 1970 to 2009 suggested that both irradiation of the internal mammary nodes (IMN) and anthracycline-based chemotherapy can increase the risk of cardiotoxicity (in at least an additive manner, and perhaps synergistically). For example, overall, the hazard ratio for cardiovascular disease among those receiving radiation to the internal mammary chain without anthracyclines was 1.54 (95% CI 1.4-1.8) relative to those receiving neither internal mammary chain radiation nor anthracyclines, and 2.1 if anthracyclines were also administered (95% CI 1.6 -2.7) [29]. Absolute risk rates were increased over time and in patients with pre-existing cardiac risk factors. The authors of the study suggest that patients treated with these techniques might warrant more careful surveillance for cardiac disease.
The applicability of these studies to more recently treated patients is unclear since the cardiac radiation doses seen in the era studied were typically much higher than those seen in contemporary series using more modern techniques. Nevertheless, about 29 percent of the patients in the third study received radiation after 1999 (ie, with relatively modern techniques). This study highlights the ongoing controversy surrounding IMN RT as several contemporary prospective trials suggest that IMN RT can improve overall outcomes [30-32], but their follow-up is not as long as in this large population-based study.
The absolute increase in risk of a major coronary event or death from ischemic heart disease is small. In the case control study comparing females given RT who had a major coronary event with those did not have a coronary event [16], the authors calculated that the risk that a 50-year-old female with no other coronary risk factors would die of ischemic heart disease prior to age 80 years would increase from 1.9 to 2.4 percent if she received a mean dose of radiation of 3 Gy to her heart; the risk of having at least one major coronary event would increase from 4.5 to 5.4 percent. If the mean dose to the heart were 10 Gy, the risk of dying would increase from 1.9 to 3.4 percent, and the risk of having at least one acute coronary event would increase from 4.5 to 7.7 percent.
Data suggest that the cardiac risk associated with breast cancer radiation is higher for smokers than for nonsmokers, though still low for both groups. In a patient data meta-analysis including approximately 41,000 breast cancer patients randomly assigned to receive or not receive adjuvant radiation in 75 trials, those receiving radiation had an increased cardiac mortality (relative risk [RR] 1.3, 95% CI 1.15-1.46) [33]. The risk of radiation-associated cardiac mortality was higher for smokers, translating to an absolute increase of 1.0 percent, versus 0.3 percent for nonsmokers.
Numerous other studies, using either overall morbidity and mortality frequencies or less detailed individual patient data, confirm that the effect of radiation on the heart is small compared with the benefit potentially derived from such treatment in appropriately selected patients [34-40].
Surrogate endpoints of myocardial injury — Changes in the incidence of cardiac morbidity and mortality represent the "gold standard" endpoints for evaluating the risk of RT-induced cardiotoxicity. However, there are several drawbacks to this approach:
●Cardiac injury is typically a "late effect" that may only become apparent many years or even decades after RT. Without prolonged follow-up, cardiac events attributable to RT are unlikely to be observed.
●Coronary artery disease is frequent in North America and Europe. Thus, analysis of large numbers of patients is required to detect a statistically significant difference in the ratio of observed to expected events in females who have or have not received RT for breast cancer.
●Competing causes of death (breast cancer itself, other noncardiac causes, age-related illnesses) are likely to obscure any increase in cardiac mortality observed following RT unless a cohort of relatively young, favorable-prognosis breast cancer patients is studied.
To provide an early assessment of possible myocardial injury, studies have used radionuclide myocardial perfusion imaging to look for RT-induced cardiac changes. In the largest prospective series, 160 females were treated with tangential photons to the left breast or chest. Patients underwent serial single-photon emission computed tomography (SPECT)-gated cardiac myocardial perfusion scans for up to six years [41].
The following findings were noted:
●The incidence of new perfusion defects was related to the volume of myocardium included in the radiation field. When greater than 5 percent of the LV was included in the RT field, the incidence of perfusion defects was significantly higher (approximately 55 percent in the first two years versus 25 percent in those with less than 5 percent of the LV in the RT field).
●Among patients who develop a perfusion defect 6 to 24 months after RT, those defects largely persist at longer follow-up intervals.
●The patients with perfusion defects were slightly more likely to have an abnormality in wall motion, but there were no evident reductions in ejection fraction. Thus, the clinical significance of these perfusion defects remains unclear.
Smaller retrospective studies from other groups have generated conflicting results, with some showing a similarly high incidence of RT-associated perfusion defects, and others not identifying such an association [42-45]. A systematic review of six SPECT perfusion studies performed between 6 and 12 months post RT for left-sided breast cancer concluded that perfusion defects were dose dependent [46]. Additional research will be required to establish the long-term clinical and functional significance of these perfusion defects, but the defects and their increase in frequency from time since therapy (over different studies) correlate with the increase in frequency of events in survivors over time.
Effect of radiation after lumpectomy versus mastectomy — Any associations of RT with cardiotoxicity are not dependent on the presence or absence of a breast, but on the radiation volume. Thus, cardiotoxicities associated with RT should be very similar in the postlumpectomy and postmastectomy settings, if the irradiated volumes are similar. However, this is usually not the case; in the postmastectomy setting, the RT field often includes the nodal tissues, and these nodes are not always targeted in the post-lumpectomy setting. Thus, postmastectomy RT is more often associated with cardiac disease (compared with postlumpectomy RT), but this is likely a result of the usually-larger irradiated volumes in the former. Details of adjuvant radiation therapy are discussed elsewhere. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer".)
Time course and risk factors — The key factors that appear to influence the risk of delayed cardiovascular toxicity include:
●The RT field and dose – This determines the amount of incidental irradiation to the heart. As an example, studies that separately analyzed the risk in patients who received internal mammary lymph node irradiation partially or entirely with anterior photon fields found an increased risk of cardiovascular complications compared with those in whom the internal mammary lymph nodes were not included in the field [34]. (See 'Effect of radiation dose to the heart' above.)
The controversy surrounding whether the internal mammary nodes should be included in the radiation field is discussed elsewhere. (See "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer", section on 'Regional field'.)
●The time interval between RT and cardiac events – Most studies in patients irradiated for breast cancer have suggested that latency is generally long (eg >10 years). For example, most of the studies that have not found an increased risk of cardiovascular disease were characterized by a follow-up of approximately 10 years [14,21,23,35-37]. By contrast, those analyses that looked at cohorts with longer follow-up have observed an increase in toxicity [9,18,20,34,37].
●As an example, one pooled analysis of randomized trials evaluated overall survival in patients treated with mastectomy with or without RT [47], and found equivalent outcomes in the 10 years post-RT, but decreased overall survival (attributed to cardiac disease) seen only at later follow-up durations.
However, there are several lines of evidence suggesting that RT-associated cardiac injury can be clinically pertinent at earlier time points, including the following:
●A large case control study suggested an increased rate of cardiac events within a few years of RT [16].
●Studies looking at imaging-based measures of cardiac toxicity in these patients note events as early as 6 to 24 months post-RT [48,49].
●Studies in patients irradiated for esophageal cancer, lung cancer, and Hodgkin lymphoma suggest a shorter latency period for RT-associated heart disease [50,51]. (See 'Esophageal cancer' below and 'Hodgkin lymphoma and pediatric malignancies' below and 'Lung cancer' below.)
Reasons for these discrepant observations include the likelihood that differences in subclinical endpoints (eg, imaging changes) and non-lethal clinical events may arise sooner than survival endpoints, as well as improvements in RT technique over time [18,47,52]. A contemporary case control study found a rise in the rate of cardiac events relatively faster than is typically ascribed to RT [16]. (See 'Cardiovascular toxicity with modified RT techniques' above.)
Other risk factors for cardiovascular disease (hypertension, hyperlipidemia, smoking, obesity) and preexisting cardiovascular disease may increase the risk of earlier cardiotoxicity following RT [16,34].
Particular caution is indicated when RT is used in patients who have or will receive known cardiotoxic agents, such as an anthracycline or trastuzumab [53]. The safety of combining RT with agents remains uncertain, and long-term follow-up is required to assess the frequency of late side effects. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)
LUNG CANCER —
RT may be used alone or with chemotherapy/immunotherapy as definitive treatment of stage I to III lung cancer. Historically, cardiotoxicity was considered a late side effect and thus not always pertinent to patients with poor lung cancer-specific survival. Radiation planning practices specifically allowed higher heart doses in order to prioritize lung sparing and prevention of pneumonitis.
Contemporary data have now established the relevance of cardiotoxicity with lung cancer treatment, which is even more pertinent in the era of improved disease-free survival with immunotherapy. Patients with lung cancer often have a history of smoking, a shared risk factor for baseline heart disease. Compared with breast cancer, these patients develop earlier and more heterogeneous cardiac events.
There is likely some contribution of systemic therapy (eg, chemotherapy and/or immunotherapy) to cardiac events in patients with lung cancer, though this has not been as well studied. For instance, one SEER analysis of over 34,000 patients ≥65 years of age reported a relative risk of cardiac dysfunction of 1.5 in patients receiving RT alone, and 2.4 for those managed with chemoradiotherapy, compared with those not receiving RT [54]. The majority of these cardiac events occurred within the first year after treatment.
Impact of dose to whole heart — Dosimetric studies in lung cancer have focused on both endpoints of survival and specific cardiac events. Initial studies examined mean dose to the entire heart, but recent studies have also examined the impact of cardiac substructure dose.
●The Radiation Therapy Oncology Group (RTOG) examined the role of RT dose-escalation in stage III non-small cell lung cancer (NSCLC) patients receiving concurrent chemotherapy, randomizing patients to receive 60 or 74 Gy (RTOG 0617) [55]. Overall survival was worse in the high-dose arm. On multivariate analysis, the volume of heart receiving ≥5 Gy and ≥30 Gy were independent predictors for overall survival, thus implicating RT-related heart disease as a potential cause for the worsened survival rates seen in the high-dose arm. These data suggest that to the degree that the poorer survival in the high-dose arm was due to cardiac disease, RT-associated cardiac injury can occur relatively soon after RT.
●In a series of 112 patients with stage III NSCLC treated on several radiation dose-escalation trials, there was an association between the rate of subsequent cardiac events (including acute coronary syndrome, arrhythmia, symptomatic effusions, and pericarditis) and both heart dose and baseline coronary artery disease (CAD) [56]. The two-year rate of symptomatic cardiac events after adjustment for the competing risk of death was 21 percent with mean heart doses ≥20 Gy versus only 7 and 4 percent with mean heart doses 10 to 20 Gy and <10 Gy, respectively. The median time to event was 26 months (range 1 to 84). These findings are consistent with the findings of RTOG 0617, and support the contention that RT-associated cardiac injury can occur relatively soon following RT for lung cancer and that this might be clinically meaningful. Similarly, other reports in patients with lung cancer noted a correlation between increasing cardiac doses, and increased rates of cardiac toxicity and reduced rates of overall survival [56-60].
Impact of dose to cardiac substructures — The heart is a heterogeneous organ composed of various components, each of which could have a different pathophysiology and clinical manifestation of cardiotoxicity. Though mean heart dose continues to be used as the main parameter in most situations, efforts are underway to refine our understanding of dose to various cardiac substructures. For breast cancer, the left anterior descending (LAD) and left ventricle (LV) are likely the principal drivers of toxicity. In lung cancer, the distribution of dose to various cardiac substructures is dependent on tumor location and thus highly variable. Overall, there appears to be rationale for the specific delineation and minimization of LV/LAD dose, but data must be interpreted with caution given the heterogeneity of baseline comorbidities in patients with lung cancer and the competing priorities of minimizing esophageal and lung doses.
●In the series of 112 patients treated on dose-escalation trials, a subsequent analysis categorized cardiac events as pericardial, ischemic, and arrhythmic. LV dose was correlated only with ischemic events, whereas whole heart and atrial doses were correlated with pericardial events. Arrhythmic events showed the weakest dosimetric correlations [61].
●In a large retrospective cohort of 701 patients with NSCLC that examined major adverse cardiac events (MACE), LAD V15Gy ≥10 percent showed the greatest association with toxicity, along with LV dose [5]. A subsequent dosimetric analysis concluded that mean heart dose was an inadequate surrogate for LAD dose (eg, even when mean dose was high, minimization of LAD V15Gy mitigated risk of MACE) [62].
●An updated analysis of RTOG 0617 examining LAD doses suggested that LAD dose (V15Gy ≥10 percent) was associated with all-cause mortality and performed better than mean heart dose as a dosimetric variable [63], potentially validating the findings from the above study. However, a major confounder for this and prior analyses of RTOG 0617 is the high esophageal doses (and subsequent esophagitis) in the dose-escalated arm, with both esophageal dose and high-grade esophagitis strongly associated with overall survival.
Impact of baseline cardiac risk — Analyses of cardiotoxicity after RT for lung cancer must consider shared risk factors (eg, smoking) for cancer and baseline heart disease. The higher rate of naturally occurring cardiac events (in the absence of cancer and its treatment) in this patient population may confound efforts to distinguish the specific contribution of radiation. Studies support independent contributions from heart dose and baseline heart disease to post-treatment cardiac toxicity. Thus, accurate ascertainment of baseline cardiac disease is an important tenet of cardio-oncology. (See 'Prevention of cardiotoxicity' below.)
●In the retrospective cohort of 701 patients reporting on the significant association of LAD dose with cardiac events, baseline coronary heart disease (CHD) was present in 252 patients (36 percent). The association between LAD dose and cardiac events could only be detected in patients without CHD, due to the higher rate of events in patients with CHD that led to weaker associations with heart doses [5].
●In the series of 112 patients treated on dose-escalation trials, baseline heart disease was quantified both by documented CAD and through delineation of coronary calcifications on simulation and diagnostic CTs. Heart dose, CAD, and calcification burden were all predictive of cardiac events. Calcifications (present to some extent in 59 percent of patients) appeared to be a more sensitive measure of baseline heart disease than CAD (documented in only 15 percent) [64].
●In another retrospective study of 233 patients, adverse cardiac events were associated with doses received by left-sided coronary vasculature and coronary artery calcification score [6].
ESOPHAGEAL CANCER —
Management of patients with nonmetastatic esophageal cancer generally includes RT or chemoradiotherapy. (See "Neoadjuvant and adjuvant therapy for locally advanced resectable thoracic esophageal cancer" and "Management of locally advanced unresectable or inoperable esophageal cancer".)
Because of the proximity of the esophagus to the heart, cardiac exposure is unavoidable and can result in high doses of radiation being administered to the heart and pericardium. Cardiotoxicity from RT or chemoradiotherapy can cause benign pericardial effusions [65-68] and may have an adverse effect on the left ventricular ejection fraction [69,70].
The potential for pericardial toxicity was illustrated by a series of 167 patients with adequate follow-up who were treated with chemoradiotherapy at a single institution between 2001 and 2010 [68]. The overall incidence of pericardial effusion was 36 percent, occurring at a median of six months after treatment; symptomatic effusions occurred in 14 cases (8.4 percent). The incidence of symptomatic effusions was higher in those treated with two-dimensions versus three-dimensional conformal techniques (11 of 70 [16 percent] versus 3 of 97 cases [3 percent]). Increasing doses of radiation to the pericardium was the strongest risk factor for toxicity.
The pathophysiology of cardiac injury after esophageal RT was illustrated in a cross-sectional analysis of 33 survivors of esophageal cancer (17 who had received neoadjuvant chemoradiation at mean 68 months post-treatment, versus 16 controls who received esophagectomy alone at mean 122 months post-treatment). Cardiac magnetic resonance imaging was performed to quantify late myocardial fibrosis (using extracellular volume as a surrogate for collagen burden) and fused to radiation plans. Patients who had received RT had greater myocardial fibrosis, and there was a linear dose-effect relation between greater LV segment fibrosis and RT dose received by that segment [71]. There were no differences in LV ejection fraction, but like breast cancer these imaging findings could serve as a surrogate endpoint for myocardial injury. (See 'Breast cancer' above and 'Surrogate endpoints of myocardial injury' above.)
Timing from therapy to onset of radiation induced heart disease appears faster in patients irradiated for esophageal cancer (versus breast cancer), likely due to much higher cardiac doses/volumes [72]. Additionally, esophageal cancer patients (similarly to lung cancer, though the link to smoking is weaker with esophageal cancer) more often have cardiopulmonary comorbidities at baseline, which likely impacts the incidence of, and time frame for, RT-associated heart disease. A review from 2015 found that the crude incidence of symptomatic cardiac disease (most frequently pericardial effusion, ischemic heart disease, and heart failure) was 10 percent, with a majority of events occurring within two years [73].
Esophageal cancer is also a key disease site for the investigation of the benefits of proton therapy to decrease treatment-related morbidity. Due to the position of the esophagus behind the left atrium, proton therapy with posterior beam arrangements lower heart and lung doses compared with intensity-modulated RT (IMRT). A randomized phase IIB study with 107 evaluable patients (61 IMRT, 46 protons) demonstrated equivalent survival and improved toxicity burden in patients receiving protons [74]. Mean dose to the heart was lower with protons (11.3 versus 19.8 Gy). This translated to a lower number of patients experiencing any grade cardiac toxicity with protons (3 of 46 patients, 7 percent) versus IMRT (12 of 61 patients, 20 percent). Patients receiving protons also had lower rates of pleural effusion and pneumonitis. A subsequent meta-analysis of 45 studies concluded that proton therapy was associated with a dramatically lower rate of grade 2 or higher pericardial effusion (objective response [OR] 0.2) [75].
HODGKIN LYMPHOMA AND PEDIATRIC MALIGNANCIES —
The RT-induced cardiotoxicity associated with the treatment of Hodgkin lymphoma and pediatric malignancies is discussed separately. (See "Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies".)
PREVENTION OF CARDIOTOXICITY —
Until there are long-term data on the cardiac toxicity associated with modern treatment approaches, we advocate a strategy of minimizing the chance of harm based upon modifying both treatment- and patient-related risk factors whenever possible. The key components of this approach include the following:
●All patients – Individualized RT planning and treatment delivery methods that reduce both the volume and dose of incidental cardiac irradiation should be employed whenever possible (balanced with the need to provide adequate target coverage and risks to other organs; eg, involved-site RT, deep inspiration breath holding [DIBH], protons) [74,76-79].
●In breast cancer – In patients receiving RT for left-sided breast cancer, reducing (and hopefully eliminating) the heart from the primary radiation beams is the optimal/preferred strategy. DIBH is a particularly useful approach in this setting as well. Systematic cardiac blocking without DIBH often results in underdosage of portions of the breast/chest wall/internal mammary nodes (IMN) and thus may not be prudent, depending on the clinical setting. With DIBH, the heart is displaced inferior, medial, and posterior (ie, away from the left breast), and thus when the beams are shaped to exclude the heart, the amount of potential targets (ie, breast/chest-wall/IMN) that are underdosed is reduced. Thus, DIBH can improve the therapeutic ratio of RT, and enable cardiac sparing with lesser impacts on target coverage.
•In two prospective trials, patients receiving RT with DIBH and conformal heart blocking were found to be without post-RT single-photon emission computed tomography (SPECT) cardiac perfusion abnormalities [80,81]. Conversely, in a prospective randomized trial comparing DIBH with no DIBH, but where the heart was not systematically excluded from the RT field, post-RT SPECT cardiac perfusion defects were noted in both groups [82].
•Gating the RT to be delivered only during the deep inspiratory phases of respiration should yield similar results to DIBH. Other strategies to reduce cardiac exposure include:
-The purposeful treatment to lesser volumes of the breast (eg, accelerated partial-breast RT)
-Intensity-modulated RT (though the volume of heart, lung, and contralateral breast receiving a low dose of RT may increase with this approach)
-Protons
-Prone positioning (though with this approach the heart is displaced anteriorly [83], so the deep field border needs to be at/near the chest wall to block the heart, and thus this approach is likely only appropriate when the target does not include the deep aspects of the breast or chest-wall/IMN).
However, differences in breast cancer control and cardiac outcomes have not been definitively demonstrated.
•Studies demonstrate that the negative cardiac effects from RT in the setting of breast cancer treatment have declined in magnitude over time with such changes in radiotherapy technique. For example, a population-based Danish Breast Cancer Group analysis demonstrated that in patients treated for early breast cancer, among those treated using older (but modified/relatively modern) techniques (eg, without computed tomography [CT]-based planning, 1999-2007, but limited fraction size), the 10-year cardiac event risk in left- versus right-sided breast cancer was 1.4 (95% CI 1.1–1.9, thus demonstrating RT-associated risks); versus a 10-year event risk ratio in left- versus right-sided treatment of 0.90 (95% CI 0.7–1.2) in the most-modern era (eg, with CT-based planning, 2008-2016) [12]. Similar findings have been reported by others.
Interestingly in this study, the 10-year cumulative cardiac event rate for such patients increased from 1.7 percent in the non-CT based planning to 2.1 percent with CT planning [12]. We surmise that this is most likely due to increasing use of cardiotoxic chemotherapy agents in such patients such as anthracyclines, CAR-T and targeted antibodies, and possibly different patient mix in the two different treatment eras.
●When RT is appropriate in addition to systemic chemotherapy, the minimum necessary total dose of anthracycline should be administered. For patients whose treatment requires an increased number of cycles of anthracycline-based chemotherapy, a lower dose of RT will probably decrease the risk of myocardial infarction, but the higher doses of anthracycline will increase the risk of congestive heart failure and valvular abnormalities. (See "Risk and prevention of anthracycline cardiotoxicity".)
●Because classical coronary heart disease risk factors, such as smoking, elevated lipid levels, obesity, and hypertension, appear to increase the risk of RT-induced heart disease, efforts should be made to screen for and reduce or eliminate these risk factors in patients who have received cardiac irradiation. (See "Overview of established risk factors for cardiovascular disease".)
One method of baseline screening involves the use of diagnostic and/or radiotherapy planning CT to quantify coronary artery calcifications (see 'Lung cancer' above and 'Impact of baseline cardiac risk' above). In cardiology, coronary CT scans have rapidly become a standard and sensitive method of primary disease prevention. Calcifications are readily identifiable on radiation planning CT scans, have been shown to correlate with cardiac events in both breast and lung cancer settings, and could be used as a cost-effective screening method prior to thoracic radiotherapy [6,64,84].
●While no guidelines exist specifically for those who received chest irradiation, consideration should be given to echocardiography, cardiac perfusion imaging, stress testing, and/or coronary calcium scoring by CT if the coronary arteries received >35 Gy of irradiation exposure beginning five years after therapy or after age 30 to 35 years, whichever is last. Screening with one of these modalities is especially encouraged for survivors at high risk based upon other coronary artery disease risk factors [85-87]. (See "Overview of stress radionuclide myocardial perfusion imaging" and "Coronary artery calcium (CAC) scoring: Overview and clinical utilization".)
Strain imaging is promising, but is only beginning to be studied specifically in this population. Although several studies have shown dose-related abnormalities uncovered in the acute phase after RT, the prognostic value of these findings remains unknown [88,89]. Only two studies have demonstrated persistent decreased strain at 12 [90] and 36 months [91], respectively, but without significant change in left ventricular ejection nor definitive association with radiation dose. Therefore, we do not suggest strain imaging for routine clinical use, based on limited available data. Further discussion of cardiac strain in patients treated with anthracyclines is found elsewhere. (See "Risk and prevention of anthracycline cardiotoxicity", section on 'Left ventricular function assessment'.)
●In those survivors who received >300 mg/m2 of doxorubicin as part of their treatment, noninvasive screening with nuclear imaging and/or echocardiography should also be encouraged to evaluate cardiac function and valvular status. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)
SUMMARY
●Introduction – Older radiation therapy (RT) techniques used to treat patients with malignancies involving the thorax clearly caused an increase in cardiovascular morbidity and mortality. Such treatment involved exposure of large volumes of the heart to high doses of radiation. Newer treatment techniques reduce both the dose of radiation and the volume of heart within the RT field, and appear to reduce the risk of late complications. (See 'Introduction' above.)
●Considerations in specific cancers
•Breast cancer
-There does not appear to be any minimum radiation dose that is entirely safe, and the effects of radiation on the heart increase with increasing doses of radiation and volume of heart exposed. The increased risk can be seen within the first five years and remains elevated for at least 20 years. Females with significant cardiac risk factors may be at a particularly increased risk. (See 'Effect of radiation dose to the heart' above.)
-Any associations of RT with cardiotoxicity are not dependent on the presence or absence of a breast, but on the radiation volume. Thus, cardiotoxicities associated with RT should be very similar in the postlumpectomy and postmastectomy settings, if the irradiated volumes are similar.
•Lung cancer
-Patients with lung cancer often have a history of smoking, a shared risk factor for baseline heart disease. Compared with breast cancer, these patients develop earlier and more heterogeneous cardiac events. (See 'Lung cancer' above.)
-In lung cancer, the distribution of dose to various cardiac substructures is dependent on tumor location and thus highly variable. There appears to be rationale for the specific delineation and minimization of dose to the left ventricle/left anterior descending artery. (See 'Impact of dose to cardiac substructures' above.)
•Esophageal cancer
-Because of the proximity of the esophagus to the heart, cardiac exposure is unavoidable and can result in high doses of radiation being administered to the heart and pericardium. Cardiotoxicity from RT or chemoradiotherapy can cause benign pericardial effusions and may have an adverse effect on the left ventricular ejection fraction. (See 'Esophageal cancer' above.)
●Prevention – When treating a patient with thoracic RT, careful attention should be paid to contemporary techniques that minimize the dose of radiation to the heart, and to other factors that may contribute to subsequent cardiotoxicity. (See 'Prevention of cardiotoxicity' above.)
ACKNOWLEDGMENT —
We are saddened by the death of M Jacob Adams, MD, MPH, who passed away in April 2024. UpToDate acknowledges Dr. Adams' past work as an author for this topic.
