The risk of cardiovascular toxicity caused by cancer radiotherapy—a narrative review

Introduction

Radiotherapy (RT), also known as radiation therapy, is an important component of anticancer treatment currently administered to about half of the patients with cancer worldwide (1). The modality has led to a significant improvement in the chances of surviving a diagnosis of cancer. On the other hand, during the course of therapeutic radiation, noncancerous normal tissues might be affected either by direct radiation exposure or by radiation-induced bystander effect, resulting in radiation-induced toxicity which sometimes become clinically evident years or decades after completion of therapy (2,3).

It has long been known that high doses of radiation like those given during mediastinal RT may damage cardiovascular health (4,5). A potential short- or long-term complication of cancer RT involving the heart and circulation is so-called radiation-induced cardiovascular toxicity. A range of cardiovascular complications have been recognized as cardiovascular toxicity caused by cancer RT, including pericarditis, valvular disease, arrhythmias, ischemic heart disease, coronary artery diseases, cardiomyopathy and heart failure (6-8). In fact, complications can be seen with any dose. The number of cancer survivors who diagnosed with premature heart disease is increasing despite the patients with no preexisting cardiovascular disease or presence of other cardiac risk factors such as hypertension, dyslipidemia, and diabetes mellitus (9).

Nowadays, despite an awareness of the potential cardiotoxicity of irradiation, leading to the application of improved RT techniques and modalities that reduce the volume of normal tissue to be exposed to high doses of radiation compared with conventional therapies, the risk of subsequent heart disease remains an issue among cancer survivors (10-12). Because the biological mechanisms of harm are very complex and only partially understood, radiation oncologists face the challenge of treating patients with the best strategies without adversely impacting cardiovascular health. This review summarizes the current literature regarding the basic pathogenic mechanisms, development and prevention of radiation-induced cardiovascular toxicity. We present the following article in accordance with the Narrative Review reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-21-34/rc).

Methods

We performed a literature search on PubMed to find reported histological observations and studies on acute and late cardiovascular toxicity in cancer patients treated with RT (Table 1). A systematized review of articles on the present topic published between May 1967 and April 2021 was carried out.

We included literature data on case studies of cardiovascular toxicity after cancer RT, mainly from survivors of breast cancer and Hodgkin’s lymphoma, risk factors, pathogenesis, development of cardiovascular toxicity after RT, and modern RT techniques utilized to reduce cardiac radiation dose. Included studies were limited to publish in English or German languages.

The search strategy used on PubMed included the following terms: ‘radiation’, ‘cancer’, ‘cardiac’, ‘heart’, ‘cardiovascular toxicity’, ‘heart disease’, ‘breast cancer’, ‘lung cancer’, ‘Hodgkin’s lymphoma’, ‘radiotherapy’, ‘modern radiotherapy technique’, ‘cardiac toxicity’, ‘echocardiography’, ‘radiation therapy’, ‘cardiotoxicity’.

Risk factors

Risk factors of radiation induced cardiovascular toxicity have been investigated. A major risk factor for subsequent development of cardiovascular toxicity is the total dose of mediastinal radiation received (13). The dose of radiation per fraction, the volume of heart irradiated, and the extent to which the coronary arteries are exposed in the radiation field are also critical risk factors for development of cardiovascular toxicity (9,14,15). Generally, radiation doses are fractionated into smaller daily doses of <2 Gy because it has been suggested that fractions of >3 Gy are implicated in a greater risk of developing cardiotoxicity, particularly pericardial effusions (15). In addition, concomitant use of cardiotoxic chemotherapy agents, typically 5-fluorouracil, trastuzumab, and anthracyclines further increase the risk of heart disease (16). Other risk factors include younger age at the time of radiation treatment, preexisting cardiovascular disease, presence of cardiac risk factors (hypertension, dyslipidemia, diabetes, smoking and obesity) and genetic susceptibility (6).

Radiation associated cardiotoxicity appears to be delayed—usually 10 to 40 years following treatment, but acute cardiac inflammation can occur at the time of RT or shortly afterwards, resulting in myocarditis or pericarditis (17). Establishment of models for early risk stratification may help to identify high-risk patients. Modification of RT and administration of preventive treatment will be needed for high-risk patients to reduce the risk of cardiovascular toxicity caused by cancer RT.

Case studies of cardiovascular toxicity after cancer RT

In 1967, the first comprehensive series of heart disease following radiation was reported by Cohn et al. (18). Since then cardiac involvement after mediastinal radiation therapy has been increasingly described. Table 2 listed a summary of the selected histological observations and studies of cancer RT reported in the first century. The literature on the late cardiovascular toxicity of RT comes mainly from survivors of breast cancer and Hodgkin’s lymphoma, diseases in which RT is a common modality of the initial management and in which survival is often prolonged. Similar cardiovascular toxic effects may be present in patients with lung cancer, head and neck cancer and esophageal cancer who receive thoracic RT while data are more limited (24-26).

Studying the risk of the radiation-induced cardiovascular toxicity after RT for lung cancer are more complex than others for several reasons. First, patients with lung cancer are old at diagnosis (average 71-year-old) and most have multiple comorbidities including cardiovascular diseases, chronic obstructive pulmonary diseases, diabetes and other malignancies (27-29). Second, the prognosis of patients with lung cancer is poor. The 5-year survival rate for all patients with lung cancer worldwide is 10% to 20% (30). Third, patients with lung cancer have shown a high prevalence of concomitant cardiac disease (approximately 25% to 30%) (27). Preexisting cardiovascular comorbidities have been involved in increased incidence of cardiovascular events and mortality. Sometimes a proportion of lung cancer patients can be treated curatively due to advances in RT, but the dose to the heart in curative-intent lung RT is usually larger than that for lymphoma or breast cancer; some patients received high-dose conformal RT with concurrent chemotherapy (31). Despite a non-negligible risk of complications- the relatively higher heart dose exposure for lung cancer leading to the earlier onset of cardiovascular toxicity, the benefits of application of radiation outweigh its risks in selected cases. Therefore, much work remains to further refine the strategies of cancer RT, and it is suggested that future research with the evidence around cardiovascular toxicity of lung cancer RT can be separated from previous evidence from other cancer sites (27).

Recent thirty years a number of research groups conducted prospective cohort studies to assess the risk of cardiovascular toxicity caused by cancer RT, with a large study population that make it possible to estimate relative and absolute risk of radiation-related heart disease. Selected key studies are described as followed.

Breast cancer

Early studies with RT in breast cancer patients uncovered the correlation of incidental radiation to the heart with an increase in the frequency of cardiovascular disease. Darby SC and colleagues conducted a population-based case-control study of major coronary events in 2,168 women in Sweden and Denmark who underwent RT for breast cancer between 1958 and 2001. They found that incidental exposure of the heart to radiation treatment for breast cancer elevated the rate of major coronary events (i.e., coronary revascularization, myocardial infarction, or death from ischemic heart disease) by 7.4% for each increase of 1 Gy in the mean radiation dose delivered to the heart (13). Moreover, in the study, women with and women without preexisting cardiac risk factors have a similar proportional increase in the rate of major coronary events per gray (13).

The potential damage to the heart is correlated to the heart-absorbed dose and differs between left- and right-breast radiation therapies. The mean cardiac dose from irradiation of a left-sided breast cancer can be 2 or 3 times that for a right-sided breast cancer (32). As a consequence, long-term mortality from heart disease is increased among women with left-sided breast tumors compared with women with right-sided breast tumors. A prospective cohort study reported by Darby et al. have shown that, in women recorded in the US Surveillance Epidemiology and End Results (SEER) cancer registries as having been diagnosed with breast cancer during 1973–1982 and received radiation, the cardiac mortality ratio, left versus right tumor laterality, was during the periods 10–14 years (1.42) and 15 years or more (1.58) after diagnosis, significantly greater than 1.00 (33).

As described above, accumulated studies and clinical evidence indicated that cardiac mortality and morbidity of breast cancer survivors treated with conventional RT was increased, and thus, for chronic cardiac events in breast cancer patients treated until the 1990s, RT was referred as a risk factor (34). However, improved modern techniques minimize heart doses and reduce radiation exposure of the heart. Merzenich and colleagues investigated cardiac mortality and morbidity of breast cancer survivors treated with contemporary RT in Germany (34). A total of 11,982 breast cancer patients treated between 1998 and 2008 were included in the retrospective cohort study. They found that, after a median follow-up time of 11.1 years, there was no significant correlation between tumor laterality and cardiac mortality in irradiated patients and tumor laterality was not a strong risk factor for cardiac morbidity. However, longer follow-up is needed for assessment of clinically manifest late cardiac effects of cancer RT (34).

Hodgkin’s lymphoma (HL)

HL survivors are at relative high risk of cardiovascular diseases and serve as a model for radiation-induced heart diseases because higher radiation doses to the mediastinum are utilized for HL treatment compared to other cancers (7). A retrospective study of 2,232 patients with HL who received mediastinal irradiation from 1960 through 1991 reported that, in comparison with a matched general population, total doses of >30 Gy led to a 3.5-fold higher risk for cardiac death (35). The study further assessed the risk factors of death from heart disease after Hodgkin’s disease therapy by comparing treated patients with a matched general population. The results indicated that high mediastinal doses, young age at irradiation, lack of protective cardiac blocking, and the increased length of follow-up time were the risk factors of subsequent death from heart disease (35).

In 2015, van Nimwegen FA and colleagues conducted a retrospective cohort study to examine relative and absolute excess risk up to 40 years since HL treatment compared with cardiovascular disease incidence in the general population (36). The study included 2,524 Dutch patients who received treatment for HL, including prescribed mediastinal RT dose and anthracycline dose, at younger than 51 years from 1965 through 1995. They found that after 35 years or more, patients still had a 4- to 6-fold increased standardized incidence ratio of coronary heart disease (CHD) or congestive heart failure (HF) compared with the general population. Moreover, patients who received mediastinal RT had a 40-year cumulative incidence of any cardiovascular disease of 54.6% compared with 24.7% in patients not treated with mediastinal RT or anthracyclines (36).

Pathogenesis

RT is the use of ionizing radiation (IR) to eradicate a tumor. Principally, high-energy radiation is deposited on the tumor site to damage the genome of cancer cell and destroy their ability to divide and grow. When living cells are exposed to IR, a burst of excess reactive oxygen species (ROS) is immediately produced and targets molecules such as DNA, proteins, and lipids. This can induce DNA damage and thereafter cell death (37). Ideally, doses are delivered only to the targeted cancer cells, but the physical nature of radiation beams as well as current techniques make this impossible. Therefore, normal tissues are usually exposed or affected by RT, followed by induction of DNA damage, inflammatory responses and oxidative stress, leading to toxicity. This accounts for acute and long-term adverse effects seen with radiation treatment (4,38,39).

The absorption of IR by normal tissue can disrupt DNA structures and produce DNA breaks that activates DNA repair protein ATM. Meanwhile, a sharp increase in ROS through radiolysis of water results in oxidative stress and initiation of a series of molecular and biological signaling events that may repair the damage or injury as well as culminate in permanent physiological changes or cell death (40). Both of activation of ATM and oxidative stress trigger the nuclear factor-kappa B (NF-κB) signaling pathway and inflammatory responses (41,42). Many genes related to the NF-κB signaling pathway were found to be dysregulated even years after radiation (43). NF-κB activation led to sustained inflammation in irradiated human arteries that can explain cardiovascular disease years after radiation exposure (43).

The persistent increase of inflammation markers ICAM-1 and VCAM-1 was observed when comparing time kinetics of radiation-induced changes of inflammatory markers (PECAM-1, ICAM-1, ICAM-2, VCAM-1) in heart microvascular endothelial cells (ECs) (44). When mice received local thorax irradiation with a single dose of 8 Gy, ICAM-1 and VCAM-1 remained up-regulated 20 weeks after irradiation in heart ECs. The late inflammatory responses in heart ECs implied the predisposition for the development of atherosclerotic plaques in heart ECs at later time points (44).

Numerous processes occur, including activation of DNA repair and signaling mechanism, expression of radiation response genes, increased proliferation, and initiation and perpetuation of inflammation, in response to DNA damage to recover the damaged cell, tissue, or organism after radiation exposure. However, these pathways may also play a role in the development of toxicity. The progeny of the irradiated cells may express a high frequency of gene mutations, chromosomal aberrations and cell death. These effects are collectively known as radiation-induced genomic instability (45). Another effect which is proved to be existed outside of radiation field, in non-irradiated cells, is called radiation-induced bystander effect (3). After radiation exposure, free radicals, immune system molecules, expression changes of some genes involved in inflammation and epigenetic factors are produced in irradiated area and may affect nearby non-irradiated cells. Subsequently, process of gene expression, translation, cell proliferation, apoptosis and cells death in nearby non-irradiated cells may be changed. These changes are demonstrated by results of some in vivo studies (46-48). The induction of bystander effects and instabilities may cause a non-specific inflammatory-type response and injury and be implicated in various pathological consequences of radiation exposures (45).

Development of cardiovascular toxicity after RT

The symptoms of radiation-induced cardiovascular toxicity usually require a long incubation period to manifest (18,20,22,23,42,49-53) (Figure 1). It is believed that endothelial cell senescence results from DNA damage and oxidative stress caused by radiation is an initial key pathophysiologic step for development of radiation-induced cardiovascular toxicity (6). After exposure to IR, the damaged cells with double-stranded DNA breaks (DSBs) may continue to divide a limited number of times before undergoing mitotic or apoptotic cell death. Remarkably, malignant transformation and subsequent malignancies may occur years or decades after RT due to some DSBs-affected tumor suppressor genes and cell cycle signaling pathways (2,54).

Figure 1 Sequence of events and cardiovascular structures being affected after RT. Radiation-induced damaging effects on the heart tissue occur within seconds to decades after ionizing radiation (IR), causing acute or chronic cardiac diseases (18,28,30,31,42,49-53). A selection of the damaging effects and diagnosed cardiovascular toxicity are presented to the bottom of the timeline. CAD, coronary artery disease.

In addition, in response to cellular stress, insulin-like growth factor 1 receptor (IGF-1R) signaling cascade is activated and promotes accelerated senescence in irradiated endothelial cells (55). A decrease in nitric oxide bioavailability, premature senescence and mitochondrial dysfunction in endothelial cells resulted from oxidative stress lead to endothelial dysfunction and inflammatory changes in the radiation field (10).

Senescent endothelial cells with chromosomal aberrations and rearrangements release proteins and proinflammatory cytokines (49,55,56). Elevated levels of IL-1, IL-6, IL-8, and TNF-α as well as ROS (superoxide and peroxynitrite) have all been involved as mediators of the subsequent processes, explaining the latency of acute side effects (2,42,57). Senescent endothelial cells with altered morphology do not proliferate but they stay metabolically active such as oxidative metabolism. This may linked to prolonged oxidative stress (58). Importantly, oxidative changes may continue to arise for days and months after the initial exposure not only in the irradiated cells but also in their progeny (58).

Accumulated evidence suggests that radiation-induced cardiovascular toxicity is a result of various mechanisms interacting with each other through multiple complex signaling pathways (4,38,39). Radiobiology research reveals that normal tissue injury is a dynamic and progressive process (59). As a consequence, chronic inflammation occurs and subsequent fibrosis develops that contribute to structural changes of the heart, such as pericardial inflammation (pericarditis), fibrosis of conduction system, chronic development of fibrosis in the myocardium, endothelial damage in the coronary vessels, and valvular heart diseases (5,51,60,61). A short-term complication of RT, acute pericarditis, is rare but may occur during or days to weeks after irradiation while chronic pericardial effusion or constrictive pericarditis may develop months or years later (62,63). Radiation-related myocardial fibrosis can occur asymptomatically for over 10 years before becoming clinically apparent. The diagnosis of radiation-induced coronary artery disease (CAD) often extends to decades, between radiation exposure and development of obstructive coronary disease (20,23). The majority of patients present with angina, dyspnea with exertion, or heart failure which are traditional symptoms of coronary obstruction. Fibrosis of conduction system is one of the main reasons for developing arrhythmias in later life. Valvular disease is a late complication. Fibrosis, calcification, and thickening of the valves is often asymptomatic but can be diagnosed late, at least 15 years after the original treatment (6). Intimal thickening, lipid deposition, and adventitial fibrosis were observed within the vascular system after irradiation in patients as well as animal studies (64). These changes also follow external irradiation to other parts of the body. All these changes, seen in atherosclerosis and with the normal aging process, accelerate the damage to the vascular endothelium. Atherosclerosis is also worsened by IR (64).

The microvasculature of the myocardium are damaged by presently-used doses of radiation (65). The main cause is inflammatory changes in the microvasculature in response to radiation damage to the myocardium, leading to microthrombi and occlusion of vessels, reduced vascular density, perfusion defects and focal ischemia (53). Subsequently, progressive myocardial cell death and fibrosis can occur. Moreover, capillary network damage is appeared to be irreversible, though endothelial cells can regenerate (38). Biologically, cardiac capillary endothelial cells exposure to radiation can result in their proliferation, swelling and degeneration, injury, and dramatically reduce the number of capillaries (66). This may lead to reduction of the blood supply of myocardium. In addition, the myocardium is particularly vulnerable to oxidative activity of free radicals produced by IR due to the low antioxidant capacity (5).

The primary and fundamental cause of myocardial injury is thought to be radiation-induced endothelial cell injury (38). The thresholds for injury are not fully elucidated. The extent of structural damage to a tissue depends on cell radiosensitivity. Mammalian cardiomyocytes are thought to be relatively resistant to radiation because most of them lose the capacity to undergo cell division shortly after birth (67). However, because of, at least partly, the quite limited proliferative capacity, once tissues in cardiomyocyte are damaged, loss is hardly reconstituted and is irreversible. This frequently results in diminished cardiac function and severe heart failure (67). In addition, cardiomyocyte membrane is rich in phospholipids which are particularly sensitive to oxidative stress. Lipid peroxidation in cardiomyocyte membrane can also lead to functional and structural injury (5).

As mentioned above, radiation-induced cardiovascular toxicity can lead to long-term adverse outcomes, with the median time to diagnosis of radiation-related heart disease being approximately 19 years (65). Besides, damage mechanisms in heart irradiation are affected in a dose-dependent manner. Post-radiation-induced mortality is significantly increase with higher radiation doses, particularly dose >40 Gy. In addition, damaging effects can also be observed even after applying doses as low as 2 Gy (65).

Detection of cardiac toxicity

Echocardiography is a type of ultrasound scan wildly used in the evaluation of cardiac toxicity during and after RT (68-70). It is a noninvasive method of examining the structure and function of the heart and nearby blood vessels (71). Left ventricular ejection fraction (LV-EF) obtained using 2D echocardiography or 3D echocardiography and global longitudinal strain (GLS) measurement based on 2D speckle-tracking echocardiography have been used to evaluate radiation-induced cardiac toxicity (69,71-73). Reduction in LVEF and/or GLS reduction >10% have been considered clinically relevant and referred to subclinical LV dysfunction (69,73,74). Doppler echocardiography is also widely used to monitor cardiotoxicity and identify the main forms of cardiac complications, such as left ventricular (systolic and diastolic) dysfunction, pericarditis and pericardial effusion, valve heart disease, carotid artery lesions, of cancer therapy (70). Use of myocardial strain imaging by echocardiography is critical for the early detection of cardiovascular toxicity in patients during and after cancer RT. Another common noninvasive method chosen for evaluation and management in patients with known or suspected cardiac complications, especially coronary artery disease, is nuclear myocardial perfusion imaging (MPI) with single-photon emission tomography (SPECT) or positron emission tomography (PET) (61,75,76). A controlled clinical head-to-head comparative study showed that PET exhibited higher accuracy and higher sensitivity for diagnosis of myocardial ischemia compared with that of SPECT, whereas SPECT revealed better specificity than PET (75).

Protection against radiation-induced cardiovascular toxicity

Patients with thoracic cancers receiving radiation treatment often involve some incidental exposure of the heart to IR, leading to a late cardiovascular toxic effect which negatively affects quality of life. Unfortunately, prospective studies in the modern era hardly determine their long-term impact on cardiovascular health and therefore no precise program is available for effective eradication of the onset and subsequent development of radiation-induced cardiovascular toxicity. Currently, reducing heart exposed range and minimizing the radiation dose given have become a recognized primary strategy. Improvements in RT planning have reduced the volume of the heart and major coronary vessels to be exposed to high doses. Advanced RT delivery modalities include prior computed tomography (CT)-guided field planning, three-dimensional conformal radiotherapy (3D-CRT) intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), proton therapy, and respiratory-gated radiotherapy in deep-inspiration breath-hold (DIBH) (77-79). In order to minimize heart doses over a course of RT, DIBH were developed for a more favorable position of the heart during inspiration (80). The patient is either instructed to hold his or her breath at certain points in the breathing cycle, or use devices named as active breathing control (ABC) to hold their breath to maintain the volume. DIBH serving a tool for cardiac sparing during irradiation can produce a significantly lower mean heart dose (80-82). A number of studies have investigated the effects of modern RT techniques (Table 3). The studies suggest that tangential intensity-modulated radiotherapy (t-IMRT) and proton therapy (PT)-DIBH plans showed a significant reduction in mean cardiac dose than VMAT-DIBH whereas as VMAT-DIBH found to benefit a select group of patients (82-87).

Attention to reducing the risk of cardiovascular disease should be a priority for the long-term care of patients, especially children, adolescents, and young adults, following the diagnosis and treatment of thoracic cancer.

Conclusions

RT has been used to treat carcinomas for over a century. Cancer survivors who receive thoracic RT in the initial treatment carry a higher risk of developing cardiovascular toxicity (6). Reduction of total heart dose (mean/median) is critical as it is importantly correlated with late cardiac toxicity. Mean heart dose (MHD) over 10 Gy can significantly increase the risk of cardiovascular toxicity after radiation therapy (88). Thus, RT delivery modalities have advanced and additional heart shielding techniques are used. Several different clinical conditions such as pericarditis, cardiomyopathy, coronary syndrome, conduction abnormalities, heart failure, and valvular disease can result from radiation-induced cardiovascular toxicity. None of these conditions is restricted to radiation exposure, but it seems that the pathogenesis of these symptoms is accelerated significantly by irradiation. The exact detail and pathophysiology of radiation-induced cardiovascular toxicity are largely unknown. However, modern irradiation techniques in combination with cardio‐oncology have to develop to reduce the risk of cardiac toxicities and optimize the care of patients with cancer.

Acknowledgments

Funding: This study was supported by the Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation (TCRD109-31-HHC; TCRD109-23-HHC).

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Pei-Wei Shueng, Yen-Wen Wu and Long-Sheng Lu) for the series “Cardio-Oncology” published in Therapeutic Radiology and Oncology. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-21-34/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-21-34/coif). The series “Cardio-Oncology” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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