Continuing Education Activity

Cardiac toxicity is a known side effect of radiation therapy delivered to the thoracic region. Therapeutic radiation plays a role in the treatment of many malignant and a few benign conditions. As overall survival for cancer patients improves with the development of new therapies and detection of disease at earlier stages, long-term toxicities of treatment become more relevant. This activity describes the pathophysiology of radiation-induced cardiac toxicity, cardiac toxicity mitigation techniques, and the need for team-based monitoring and identification of undesired cardiac toxicity to improve long-term patient outcomes.

Objectives:

• Describe the pathophysiology of radiation therapy-induced cardiac toxicity.
• Identify risk factors for patients at increased risk for suffering major adverse cardiac events resulting from therapeutic radiation.
• Describe the symptomatic presentation associated with a patient with radiation therapy-induced cardiac toxicity.
• Describe how interprofessional team measures can help reduce radiation dose to prevent radiation therapy-induced cardiac toxicity.

Introduction

Radiation therapy is an important component in the treatment of cancer. It may play a role as an adjuvant, neoadjuvant, palliative, or definitive therapy, with or without concurrent chemotherapy. Radiation is most commonly delivered as a local/regional treatment by an external beam consisting of photons, electrons, protons, or heavy particles but may also be delivered via brachytherapy (where a sealed radiation source is placed adjacent to the target) or systemically via unsealed sources. The side effects of radiation therapy are a function of the tissues included in the radiation field. Treatment of diseases within the thoracic region, such as Hodgkin lymphoma, lung, and breast cancer, carries the risk of radiation-induced cardiovascular toxicity (RICT).[1] 

Side effects of therapeutic radiation to the heart and coronary vessels include pericarditis, coronary artery disease (CAD), arrhythmias, cardiomyopathy, valvular dysfunction, and heart failure. Pericarditis and pericardial effusions are potential short-term toxicities that may occur during or within the weeks following treatment. Long-term side effects may present in the months to years after radiation therapy, possibly as late as 20 years or more post-treatment. Late toxicities include CAD, valvular heart disease, and heart failure.[1][2] 

Major risk factors that increase the likelihood of RICT include higher radiation doses, adjuvant treatment with cardiotoxic chemotherapy, irradiation of the left side of the thorax, and the presence of pre-existing cardiovascular disease.[3][4] Studies have correlated the mean dose of radiation received by various heart sub-structures to the incidence of major adverse cardiac events (MACE), such as hospitalization for heart failure, myocardial infarction, and even cardiac death.[5] Given the importance of radiation therapy in treating cancer and the high prevalence of cardiovascular disease in Western populations, numerous preventive measures have been suggested and used in clinical practice, such as dose limitation, proton and particle therapy, conformal radiation therapy, and deep-inspiration breath-hold technique.[3][6]

Issues of Concern

When any tissue is irradiated, the cells comprising the tissue are damaged primarily by the generation of free radicals, predominantly by the hydroxyl radical. In addition to inducing pro-inflammatory cytokines, free radicals react with DNA to cause strand disruption, preventing proper replication and protein synthesis. Cardiomyocytes are stable cells and are therefore relatively resistant to radiation. However, modern therapeutic doses of radiation are sufficient to cause damage to the microvasculature of the myocardium.[7][8] Damage to the microvasculature results in structural changes of the heart through pericardial inflammation, fibrosis of the myocardium, valvular dysfunction, fibrosis of the electrical conduction system, and endothelial damage in the coronary vessels.

The pericardium may become acutely inflamed, leading to pericarditis or pericardial effusion. The pericardium can also develop chronic fibrosis, resulting in constrictive pericarditis. In the myocardium, the diffuse development of infiltrative fibrosis impairs the ability of the ventricles to relax, resulting in diastolic failure. These fibrotic changes can also affect the conduction system in the heart and result in the development of arrhythmias later in life. In the years following radiation therapy, the valvular endothelium can break down or become fibrotic, leading to regurgitation or stenosis.[9] The pro-inflammatory effect of radiation on the coronary vasculature mimics atherosclerosis in that endothelial damage promotes fibrin deposition and intimal proliferation, thereby hastening the progression of coronary artery disease.[7]

Clinical Significance

Specific radiation doses are communicated in Gray (Gy), a measure of absorbed radiation that is the predominant unit used in clinical practice, and the Sievert (Sv), which considers the relative biological effectiveness of the specific type of radiation within the tissue. Both units measure one joule of energy absorbed per kilogram. RICT is both a short and long-term concern, with the median time to diagnosis estimated to be 19 years.[1] The heart is affected by radiation in a dose-dependent manner with higher radiation doses, particularly >40 Gy, associated with significantly increased post-radiation-induced mortality.[1] However, damaging effects can also be seen after doses as low as 2 Gy, and there is no apparent "safe" dose of radiation that the heart may receive.[10][11] Further risk factors associated with radiation-induced heart disease include earlier age at treatment, irradiation of left-sided cancers, concurrent treatment with trastuzumab or anthracyclines, pre-existing cardiovascular disease, and the presence of general cardiovascular risk factors (such as diabetes and hypertension).[11][12][13] RICT may affect any sub-system of the heart and therefore has a varied presentation. In the acute setting, pericarditis and pericardial effusions may manifest during or within the initial weeks following irradiation and may be treated similarly to acute pericarditis or effusion unrelated to radiation. Delayed pericarditis, characterized by thickening and fibrosis of the pericardium, can result in restrictive pericarditis and subsequent diastolic heart dysfunction. Diseases of the pericardium are more common at doses >40 Gy.[14][15]

Valvular disease is a late complication. Fibrosis, calcification, and thickening of the valves can occur asymptomatically for over 15 years before becoming clinically apparent. Prominent damage is more common in the left-sided valves and can manifest as stenosis, regurgitation, or a proclivity towards endocarditis. Valvular effects can occur at doses >30 Gy.[13][15][16] The myocardium itself is affected by the progressive loss of capillary beds due to oxidative stress, DNA damage, and microvasculature inflammation.[17] This damage results in diffuse fibrosis of the myocardium, leading to stiffening, impaired ventricular filling, and potentially leading to restrictive cardiomyopathy (i.e., diastolic heart failure), and eventually systolic heart failure. Severe cardiomyopathy is more prevalent when radiation therapy is combined with anthracyclines, such as daunorubicin and doxorubicin, and the monoclonal antibody trastuzumab - though this effect appears to be additive as opposed to synergistic.[11] Cardiomyocyte toxicity and cardiomyopathy are most common in radiation doses >30 Gy.[14][15]

Arrhythmias are another late effect of radiation therapy due to toxicity to the sinoatrial (SA) and atrioventricular (AV) nodes and the conduction system of the heart. Transient and asymptomatic arrhythmia may occur within a year of therapy, but permanent damage to the cardiac nodes and bundle branch blocks may manifest ten or more years after treatment completion. The association between the development of arrhythmias and the dose received has not been thoroughly studied; therefore, the absorbed dose associated with arrhythmias is not well described.[13][15]

Atherosclerosis is worsened by radiation therapy, as the inflammatory effects of radiation accelerate the damage to the vascular endothelium. Therefore, premature or worsened coronary artery disease (CAD) is another potential complication of radiation therapy to the heart and increases the risk of unstable angina, myocardial infarction, and cardiac mortality.[10][17] An independent association has been shown between the dose received by the left anterior descending artery (LAD) and MACE, including myocardial infarction (MI) and hospitalization for heart failure.[5] Additionally, pre-existing CAD and atherosclerosis affect the dose that the left ventricle may receive. Patients with traditional CAD risk factors such as diabetes mellitus, smoking, hypertension, hyperlipidemia, and male gender are more likely to experience MACE after thoracic radiation therapy.[12][15][5] Atherosclerotic heart disease can be exacerbated by radiation doses as low as 6 Gy.[14] A linear association has been shown between mean cardiac dose and RICT, with a 7.4% relative increase in rates of coronary events with each additional Gray, without an observed threshold.[11]

Given the potentially serious consequences of cardiac damage during radiation therapy, techniques for mitigating collateral cardiac irradiation have been developed. One option is using proton or heavy particle (e.g., carbon ion) therapy due to the theoretical advantage offered by reducing the exit dose characteristic to such particles. Treatment in the prone position is an option for breast cancer that allows the breast to displace through an aperture in the treatment table away from the body that has shown to reduce heart and lung dose received over traditional supine treatment.[18] 

A promising option for the reduction of heart dose in patients with left-sided breast cancer is the deep inspiration breath-hold (DIBH) technique, in which a patient is asked to hold a moderately deep breath while lying supine to increase lung filling, thus moving the chest wall target further from the heart [see attached image]. Surface imaging is used to measure chest rise at the time of simulation and treatment, and treatment is only delivered while the lungs are expanded into the appropriate position, allowing for reproducibility during each fraction and assurance of treatment delivery as planned. Multiple studies have shown up to a 40-50% relative reduction in dose received by the heart as a result of this technique, with mean LAD doses of 2-3Gy.[10][14][19]

In treating lung and esophageal cancer and Hodgkin lymphoma, or when DIBH is not available for left breast cancer, highly conformal therapies such as intensity-modulated radiation therapy (IMRT) may be used to minimize radiation dose to the heart as compared with older 3D planning techniques.[14][20][21] This is done by utilizing multiple non-uniform energy fields in such a way that the high dose region conforms tightly to the target but decreases quickly in the surrounding normal tissues. IMRT has been shown by a prospective NRG Oncology study focusing on lung cancer to aid in reducing the heart V40 from 11.4% to 6.8%, as compared with conventional 3D planning.[20][21] IMRT has also been shown to significantly reduce the dose received by the heart in whole lung irradiation, with 99% of the dose received by the heart when using a 3D plan vs. only 33% of the dose when an IMRT plan is utilized.[22]

It is important to identify pre-existing risk factors for heart disease in cancer patients before administering thoracic radiation therapy, with relevant intervention including smoking cessation counseling, as well as ensuring adequate treatment of hypertension, hyperlipidemia, and diabetes. Additionally, a full cardiac evaluation including EKG and echocardiogram should be performed prior to radiation therapy when planned to be combined with anthracyclines or trastuzumab.[23] When radiation therapy is indicated, patients with impaired cardiac function at baseline may be considered for the omission of systemic therapy in a risk vs. benefit analysis on a case-to-case basis, acknowledging that omitting any therapy places the patient at increased risk for sub-optimal oncologic outcomes.

There are currently no official screening guidelines for radiation-induced cardiac toxicity. However, given the known interplay of radiation with pre-existing cardiovascular risk factors, it is reasonable to suggest that identifying these at-risk patients and close follow-up for all could facilitate earlier diagnosis and treatment of any radiation-induced cardiac toxicities. When evaluating potential heart disease, imaging including cardiac MRI, CT, echocardiography, and myocardial perfusion studies are high-yield diagnostic tests that may guide further intervention.[16][17] However, cardiac MRI is considered the best investigatory option for evaluating radiation-induced heart disease, given that it aids in understanding the pathology and severity of the specific radiation-induced heart toxicity.[12][15]

Enhancing Healthcare Team Outcomes

Generally, the exact detail and pathophysiology of radiation-induced cardiac toxicity are beyond the scope of this portion of the discussion. There are no official published screening or prevention guidelines. Therefore, no precise recommendations are possible. However, there are risks associated with worsened cardiac outcomes following radiation therapy. These include younger age at treatment, radiation doses above 30 Gy (although there is no truly safe dose of radiation), irradiation of left-sided breast cancers or intrathoracic lesions, pre-existing heart disease, and the presence of risk factors for coronary artery disease: diabetes, hypertension, smoking, and hyperlipidemia. The interprofessional team must identify these patients before receiving radiation therapy to optimize lifestyle and pharmacologic interventions and coordinate proper follow-up and care. Nursing and other medical support staff play a critical role in identifying these patients and ensuring that the providing physician is aware of these risk factors to discuss extended cardiac follow-up with the patient. Additionally, nurses involved in the patient intake should remain vigilant for any patient with a remote history of thoracic radiation therapy showing signs or symptoms suggestive of cardiovascular disease. Appropriate identification of risk factors, adequate patient follow-up, and anticipation of cardiac complications are key factors to significantly improve the morbidity and mortality in post-radiation cancer patients.[10][15] [Level 5]