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Abstract

This review article aims to synthesize existing data on radiation-induced heart diseases in patients undergoing chest radiation therapy and also explores cardiac-sparing techniques to mitigate cardiotoxic effects. We conducted a comprehensive database search to review and consolidate data regarding chest radiotherapy and effects on the heart as well as techniques to minimize exposure to the heart. The research findings demonstrate associations between radiation exposure to cardiac substructures and subsequent cardiotoxicity. This review also stresses the importance of identifying patients at high-risk for cardiotoxicity as well as advocates for the adoption of stringent cardiac dose constraints in these patients. Advanced cardiac-sparing techniques, notably respiratory motion management, have emerged as pivotal strategies to minimize the likelihood of cardiac events. This narrative review emphasizes the critical role of these innovations in optimizing cardiac health during radiation treatment.

Keywords

cardiac sparing radiotherapy radiation-induced heart diseases heart LAD

Introduction

Radiation-induced heart disease is a known potential toxicity in patients undergoing chest radiotherapy and thus there is a need to understand the associated risks and find methods to minimize them.^1–4 It is widely known that radiation-induced heart disease can be attributed to both radiation- and patient-specific risk factors.⁵ Known radiation factors include radiation technique, volume of heart exposed, and the mean heart dose (MHD). Whereas patient-specific factors include patient age, cardiac comorbidities, pre-existing cardiovascular risk factors, genetic predisposition, and the use of concurrent cardiotoxic chemotherapy.⁵ Thus, it is of utmost importance for radiation oncologists to identify high-risk patients and modify radiation treatments accordingly to minimize the risk of radiation-induced heart disease. Through searches conducted with keywords “cardiac sparing, radiotherapy, radiation-induced heart diseases” in literature databases, such as PubMed/ScienceDirect, this review compiles comprehensive information on chest radiation therapy concerning the heart, along with techniques aimed at minimizing heart exposure. Therefore, the article encompasses a broad spectrum of site-specific reviews, providing readers with valuable insights into cardiac-sparing techniques.

Breast Radiotherapy

Breast radiotherapy is standard of care treatment after breast conservation surgery for patients with breast cancer. During breast radiotherapy, particularly for left-sided breast cancer, the heart is exposed to radiation and thus is susceptible to cardiotoxic effects. It is known that the risk of these effects is closely linked to the specific dosage received by various cardiac substructures.^6,7 A study by Beaton et al.⁸ investigated the risk factors associated with cardiac death following breast radiotherapy. They found that none of the patients who experienced cardiovascular disease-related deaths after undergoing left-sided radiation treatment had violated the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines for critical structures.⁹ According to the findings of the study, based on 5249 eligible patients from 2002 to 2006, there seems to be an exceptionally low risk (approximately 1.4%) of radiation-induced cardiac death after a 10-year period if the average dose to the heart remains below 3.3 Gy and the maximum dose to the left anterior descending artery (LAD) is maintained below 45.4 Gy. Accordingly, the researchers recommend further evaluating heart and LAD constraints.⁸ The results of another study by Drost et al on heart dosimetry patterns in radiation treatments worldwide between 2014 and 2017 revealed a consistent reduction in the MHD over time, with an average decrease from 4.6 Gy in 2014 to 2.6 Gy in 2017 contributed by advances in treatment techniques.¹⁰ As expected, treatments incorporating breath-control (BH) demonstrated a significantly lower MHD of 1.7 Gy compared with those without BH, which averaged 4.5 Gy.

The delineation guidelines for cardiac structures, such as LAD, on radiotherapy CT planning images were collaboratively developed by the cardiology and radiation oncology departments across multiple institutions.^11,12 Chen et al conducted an extensive analysis into deep learning for cardiac image segmentation.¹³ The study focused on the intricate delineation of major cardiac structures using advanced imaging techniques such as MRI, CT, and ultrasound.

Multiple techniques exist to minimize radiation exposure to the heart during radiation therapy, including deep inspiration BH (DIBH).¹⁴ as well as prone positioning for patients with pendulous breasts.¹⁵ Other more complex treatment planning techniques include the use of volumetric modulated arc therapy (VMAT) or intensity-modulated radiation therapy (IMRT), both with and without DIBH.^16,17 Additionally, proton therapy can serve as an alternative technique for cardiac-sparing purposes.^18–20 and the reirradiation of high-risk recurrent breast cancer.²¹ In proton beam therapy, a spread-out Bragg peak is used to establish a uniform dose distribution within the target volume by modulating the proton beams. This leads to elimination of the exit dose to critical organs, such as the heart, thereby reducing low-dose exposure and facilitating precise high-dose targeting. Moreover, robust optimization in proton treatment plans enables the selection of a plan considering dose uncertainty and range uncertainty.²² If available, the 4D CT technique can further help account for motion uncertainty during the treatment planning process.^23,24.

The results of a study conducted by Kim et al that examined the association between infield heart volume, sternal displacement, and dose sparing of the heart and LAD. This study revealed a robust correlation between delta heart volume in field and delta sternal excursion and cardiac dose.²⁵ The delta represents the difference in heart volume between DIBH and free breathing. The researchers concluded that utilizing the DIBH technique significantly reduces radiation dose exposure to the LAD and heart.

In a correlation study by Das et al.²⁶, a direct relationship was established between treatment parameters and the lung and heart volumes receiving 5, 10, and 20 Gy (ie, V5, V10, and V20). Key parameters include central lung distance, chest wall separation, and maximum heart distance were found to influence this relationship.²⁶ In a study by KnÖchelmann et al assessed the dose reduction to the heart and LAD with and without DIBH. A total of 357 patients with left-sided breast cancer were treated using three-dimensional treatment plans; 159 of those patients underwent DIBH. The study revealed that DIBH significantly reduced the MHD from 2.64 Gy to 1.39 Gy and the LAD dose from 5.68 Gy to 3.88 Gy. However, it should be noted that the DIBH group exhibited higher mean doses and volumes (V5, V10, and V15) to the ipsilateral lung. Despite this finding, the researchers concluded that DIBH effectively reduces the dose to the heart during left-sided breast irradiation, potentially minimizing the risk of cardiac complications.²⁷.

Jimenez et al has presented a challenge to the conventional notion that the MHD serves as the primary predictor of cardiac events. Instead, they propose that the LAD may have a more robust association with radiation-induced cardiac disease. Despite the implementation of cardiac avoidance techniques, as previously described, radiation delivered through tangential treatment fields can still affect the LAD given its anatomical location (see Figure 1. This becomes particularly relevant in the context of VMAT, where we can reduce the dose to the LAD but the MHD could increase.²⁸ To mitigate the risk of heart disease-related deaths following breast radiotherapy, the researchers recommend delineating the LAD in cases involving left-sided treatments with regional nodal irradiation and constraining to meet the LAD mean dose of 3 Gy.

Figure 1.

Proton (left), volumetric modulated arc therapy (VMAT) (middle), and three-dimensional conformal radiation therapy (3DCRT) (right) dosimetry for left-sided regional nodal irradiation. Compared with 3DCRT, VMAT decreases left anterior descending artery (LAD) (dark blue) but increases low dose to the heart (pink), resulting in a higher mean heart dose. Proton therapy is often able to minimize both LAD and mean heart dose (red = 50 Gy; yellow = 40 Gy; green = 20 Gy; blue = 5 Gy). Reprinted from ²⁸ with added labels.

Researchers from our institution have developed a machine learning tool to predict optimal positioning strategies for organ sparing during radiation therapy. By analyzing ten patient-specific features and utilizing nine machine-learning models, we accurately predicted the suitability of supine DIBH versus prone positioning (accuracy: 0.93) aligning with the radiation oncologist's preference for patient positioning. Key features such as breast volume and distance between heart and breast were vital in classifying heart toxicity risk.²⁹.

Thoracic Cancer Radiotherapy

Lung Cancer

Kearney et al conducted a comprehensive review assessing heart dose and strategies to minimize radiation exposure in lung cancer radiotherapy during the period from 2013 to 2020.³⁰ The findings indicated that for stereotactic body radiation therapy (SBRT), heart doses were comparable between left- and right-sided tumors. However, Owen and Sio.³¹ found that the outcomes and side effect profiles of SBRT are significantly influenced by tumor location. Specifically, tumor located centrally (within 2 cm of the heart and major vessels) or ultracentrally (touching or within 1 cm of these structures) present greater challenges. For ultracentally located tumors, it is advisable to use techniques such as IMRT or proton therapy to minimize the mean heart dose and reduce potential toxicities.³¹ When comparing IMRT and three-dimensional conformal radiation therapy photon therapy, similar doses were observed whereas proton and carbon ion therapy demonstrated significantly lower heart doses.^32–34 In the case of IMRT, employing stringent optimization objectives has the potential to reduce heart doses effectively. Moreover, the study.³⁰ showed that the implementation of active respiratory motion management techniques or the utilization of particle therapy may be beneficial in further reducing dose to the heart. The study concluded that establishing a consensus regarding contouring, planning objectives, and dose-volume constraints for the heart and its substructures may lead to reducing heart doses.

Regarding consensus, Herr et al undertook a statewide analysis to investigate the effects of education and standardization of cardiac dose constraints.³⁵ Following the implementation of uniform cardiac dose constraints in 2017, the researchers observed a significant decrease in several key metrics. This included reductions in the average MHD, heart V30 Gy, and the proportion of patients receiving MHD exceeding 20 Gy. Importantly, this reduction in cardiac doses was achieved without compromising coverage of the treatment target.³⁵ These findings stress the importance of incorporating well-defined cardiac constraints into radiotherapy planning through careful consideration of cardiac dose management.

Atkins et al investigated the impact of radiation dose exposure on the LAD and its association with major cardiac events and all-cause mortality in a cohort study of over 700 patients with non-small cell lung cancer.³⁶ For those patients without coronary heart disease, a LAD V15 Gy of ≥ 10% emerged as a predictor of major cardiac events. Conversely, among patients with pre-existing coronary heart disease, a left ventricle V15 Gy of ≥ 1% increased the risk of major cardiac events. These findings emphasize the need to implement more stringent cardiac radiotherapy planning parameters, with separate consideration for LAD dose limits based on the presence of underlying coronary heart disease.³⁶ The same group further examined the interplay between MHD, LAD V15, and major adverse cardiac events.³⁷ The study categorized patients into four groups based on their MHD (≥ 10 Gy vs < 10 Gy) and LAD V15 (≥ 10% vs < 10%). The analysis found that a low LAD V15 was associated with a reduced risk of major cardiac events, and the association was independent of mean heart dose. These results demonstrate that relying solely on MHD is insufficient to predict major cardiac events. Yegya-Raman et al.³⁸ reported that the two-year cumulative incidence of major adverse cardiac events was 9.5% for radiotherapy patients with locally advanced non-small cell lung cancer, increasing to 14.3% for those with pre-existing heart disease. Although there was no direct correlation between cardiac radiation dose and these events, the dose was associated with higher lung cancer mortality rather than mortality from other causes.

Many radiation oncologists also use the “great vessels” dose constraints outlined in RTOG 0915.³⁹ and RTOG 0813.⁴⁰ when trying to spare the heart during treatment planning. As per RTOG protocols, contouring of the great vessels (aorta and vena cava) should commence at a minimum of 10 cm above the superior extent of the planning target volume (PTV) and extend on each CT slice to at least 10 cm below the inferior extent of the PTV. Specifically, for right sided tumors, the vena cava is contoured, and for left sided tumors, the aorta is contoured.

Evidence suggests that higher radiation doses to the heart are associated with lower survival rates in stage III non-small cell lung cancer patients.^41–43 To address the concern of higher radiation doses to the heart in lung cancer treatment, Harms et al have created a knowledge-based planning model using RapidPlan tools for VMAT plans.⁴⁴ This tool incorporates two models: one utilizing clinical plans and another utilizing cardiac-optimized plans. Both models generate treatment plans that meet the required clinical criteria. The cardiac-sparing RapidPlan demonstrated notable improvements in the treatment plans, reducing mean and maximum heart doses as well as minimizing the volumes of the heart receiving specific dose levels. As further research and validation are conducted, this tool holds great promise for improving lung cancer treatment strategies and minimizing the potential negative impact on the heart.

In the context of SBRT for lung treatment, the utilization of DIBH has become a common practice. DIBH is employed to achieve two main objectives: to minimize radiation exposure to the heart and lungs and to reduce the margins of the planning target volume. However, it is important to acknowledge that not all patients can maintain a steady breath hold. In such cases, an alternative approach is to utilize an internal target volume based on four-dimensional computed tomography (4DCT) images or respiratory gating, as needed. To ensure accurate treatment delivery, fluoroscopy can be employed to verify that shifts and target motion align appropriately with simulation and is followed by cone-beam computed tomography registration before the delivery. Overall, by employing these strategies, radiation oncologists can enhance treatment precision, minimize radiation-related side effects, and improve patient outcomes.

Esophageal Cancer

Burke et al investigated the early effects of radiation on cardiac structure and function following chemoradiation for distal esophageal cancer.⁴⁵ The group utilized cardiac magnetic resonance imaging to evaluate the baseline and post-treatment conditions, employing quantitative measures and analyzing serum biomarkers associated with cardiac damage. The study included ten patients, among whom 3 (30%) exhibited new findings of radiation-related structural and functional heart damage as early as 3 months after completing chemoradiation. By utilizing advanced imaging techniques and assessing relevant biomarkers, healthcare providers can monitor the potential impact of radiation on the heart. Early detection of cardiac damage is crucial to implement appropriate interventions and enhance the care and well-being of patients. Vošmik et al conducted a study investigating the cardiotoxicity associated with esophageal radiotherapy.⁴⁶ Motion during treatment can be particularly significant, especially for tumors located in the inferior portion of the esophagus. To address this, 4DCT imaging helps visualize target volumes and heart in different respiratory phases. Respiratory control techniques, such as DIBH or respiratory gating with fluoroscopy to match fiducials (ie, surgical clips, stents, etc), can be employed when necessary to ensure treatment accuracy. To protect the heart during esophageal radiotherapy, advanced techniques, such as IMRT or VMAT in combination with image-guided radiation therapy, which minimize treatment margins, are recommended. These modern techniques can significantly improve the distribution of radiation doses, thereby sparing the heart from unnecessary exposure. However, it is important to note that even with the implementation of these advanced techniques, maintaining awareness of the potential cardiotoxicity in patients undergoing esophageal radiotherapy is equally crucial. Regular monitoring, close follow-up, and proactive management of potential cardiac side effects are essential components of comprehensive patient care.

Mediastinal Lymphoma

Hahn et al explored dosimetric parameters beyond the MHD for predicting late cardiotoxicity after Hodgkin lymphoma radiation therapy.⁴⁷ Analyzing data from 125 patients, the researchers compiled cardiac dose-volume information including the whole heart and three major coronary arteries from the radiotherapy plans and generated multivariable competing risk regression models. They found that the whole heart model (age, sex, MHD, and dose homogeneity) outperformed in overall cardiotoxicity evaluation, whereas the coronary artery-based model (age, LAD V5, and left circumflex V20) excelled in predicting ischemic cardiotoxicity.⁴⁷.

Hoppe et al investigated the correlation between MHD and doses to specific cardiac substructures, such as the right and left ventricles, atria, tricuspid, mitral, and aortic valves, as well as LAD, in 40 mediastinal lymphoma patients treated with diverse radiotherapy techniques.⁴⁸ They observed that the adoption of highly conformal treatment techniques could lead to more heterogeneous dose distributions across the heart, resulting in weaker associations between the MHD and the mean doses to cardiac substructures. Consequently, the traditional MHD-based models for assessing cardiac toxicity risk following radiation therapy can be misleading when using modern treatment techniques. Therefore, it becomes crucial to delineate cardiac substructures and assess their individual doses when employing contemporary radiotherapy.⁴⁸.

Patient-Specific Planning

In clinical practice, physicians may have varying priorities when it comes to establishing dose constraints for normal tissues, depending on patient-specific factors. These considerations often involve balancing the radiation dose delivered to different organs at risk. For instance, physicians may prioritize minimizing the Lung V20, followed by the Heart V30, and then Lung V10. In situations where a physician emphasizes achieving a low Lung V5, the planner may choose static gantry angles of IMRT over VMAT. Static gantry angles in IMRT allow for greater control over the radiation beams’ direction and shape, enabling more precise dose sparing in specific regions of the lung. Personalized treatment planning requires effective communication between the physician and the planner regarding whether to prioritize the heart or the lung-sparing based on the patient's unique characteristics, such as pre-existing conditions, tumor location, and treatment goals. Considering patient-specific factors in the decision-making process contributes to delivering personalized and effective radiation therapy.

Childhood Cancer Survivors

The American Cancer Society estimates that 9910 children under the age of 15 in the United States will be diagnosed with cancer. Currently, the overall survival rate for children with cancer, spanning 5 years or more, is approximately 85%.⁴⁹ Radiation therapy continues to be a crucial component in the comprehensive management of various types of childhood cancer. Because survival rates have significantly improved, the focus extends beyond primary tumor control to addressing potential complications, including cardiotoxicity and radiation-induced cancers. Cardiac toxicity stands out as a significant concern during radiation therapy. All instances of heart toxicity are intricately linked to the dose to the heart.⁵⁰ When the MHD is > 10 Gy, and with parameters such as V20 ≥ 0.1% and V5 ≥ 50%, there is a notable escalation in the rates of cardiac diseases and heart failure. Moreover, the average radiation dose delivered to the heart shows a direct linear correlation with the risk of cardiac mortality. Specifically, for every 1 Gy increase to the mediastinum, the risk of cardiac mortality increases by 60%.⁵¹ Also, for every 10 Gy increase in the MHD, the estimated hazard ratios for various cardiac conditions are strikingly high. These ratios indicate a substantial risk, with values of 2.01, 1.87, 1.87, and 1.88 for coronary artery disease, heart failure, valvular disease, and any cardiac disease, respectively.⁵² Therefore, the primary objective in radiation therapy planning is to minimize the MHD, ideally aiming for ≤ 5 Gy, and employing the principle of ALARA (as low as reasonably achievable) when designing treatment plans. To achieve this goal, modern techniques such as proton therapy and 4DCT prove invaluable. If available, these advanced methods can be employed to significantly assist in further reducing the heart dose while effectively treating the primary disease site.

Cardiac Radioablation

The goal of cardiac radioablation is to precisely treat the target area of the heart while sparing the normal heart tissues and ensuring the maintenance of normal sinus rhythm.⁵³ Several critical factors contributed to the success of this procedure. One essential factor involves accurate image registration and aligning electrophysiology information with anatomical scar imaging. Additionally, effective motion control and motion management techniques play a pivotal role, alongside precise target localization and positioning during treatment sessions. A typical treatment prescription is a single fraction of 25 Gy. Simultaneously, it is crucial to adhere to specific dose constraints: the heart V20 ≤ 15% and the MHD ≤ 2 Gy. Another vital criterion involves limiting the heart receiving 16 Gy to less than 15 cc.⁵⁴ Meeting these planning goals presents a technical challenge but it is achievable. To further mitigate the risk of heart toxicity, the ALARA principle should be diligently applied. When dealing with patients having implantable cardioverter defibrillators (ICD), it is crucial to limit the radiation dose to under 2 Gy.⁵⁵ Whenever feasible, it is recommended to strive for a lower threshold, ideally below 0.5 Gy.⁵⁶ Establishing rigorous quality control protocols, benchmarking them prior to clinical implementation, and ensuring the technology used for treatment is state-of-the-art, with multiple imaging applications and active participation from core team members, are imperative steps in maintaining treatment efficacy. Importantly, fine segmentation of intricate heart substructures should be performed, recognizing that each part of the heart may tolerate radiation doses differently. Careful consideration of the planning margin for the planning tumor volume is vital, tailored to the specific technology accuracy of the radiation clinic. Studies show that radiation can affect all parts of the heart.⁵⁴; however, the aforementioned dose and dose-volume criteria remain within safe tolerance levels for managing heart diseases. Of course, a stringent quality assurance program and a commitment to the ALARA principle are indispensable in ensuring the success and safety of these complex procedures. Table 1 summarizes the cardiac structures dose constraints proposed by researchers and associated parameters.

Table 1.

Thoracic region radiotherapy and their heart substructures dose constraints, motion management techniques, and reported radiation-induced heart diseases.

Disease Site	Heart Metrics^c		LAD Metrics^c	Motion Management	Radiation-induced Heart Diseases Reported	References
Breast	MHD < 3.3 Gy MHD < 1 Gy/2 Gy (PBI-left) MHD < 0.5 Gy/1 Gy (PBI-right) V25 < 0.5%/3% (right/left) V20/V30 ≤ 5% (left) V20/V30 ≤ 2% (right) (Ideal/Acceptable)		D_max< 45.4 Gy D_mean< 3 Gy D_max< 25 Gy/35 Gy (Ideal/Acceptable)	DIBH	Radiation-induced cardiac death after 10-year period, Radiation-induced heart diseases	6–28
Thoracic	MHD < 10 Gy V40 < 10% V30 < 20% D_max: 22 Gy/1fx^a, 30 Gy/3fx^a 34 Gy/4fx^a 50 Gy/5fx^a	(8-15fx) (25-28fx) D_15cc 16 Gy/1fx^a 24 Gy/3fx^a 28 Gy/4fx^a 32 Gy/5fx^a	V15 < 10% V15 < 1% (high-risk patient) D_max: 37 Gy/1fx^b D_10cc 31 Gy/1fx^b	4DCT DIBH EBH Gating Fluoroscopy Compression	Major cardiac events, All-cause mortality Coronary heart disease, Heart attack, Heart failure, Heart structural damage, Heart functional damage, Asymptomatic pericardial effusion	30–48
Childhood Cancer	MHD < 5 Gy/10 Gy (Ideal/Acceptable) V20 < 0.1% V5 < 50%		NA	4DCT	Cardiac mortality Coronary artery disease, Heart failure, Valvular disease, Arrhythmia, Pericardial disease	49–52
Cardiac Radioablation	Whole heart minus PTV: D_50%≤ 5 Gy ALARA: V 20 ≤ 15%, MHD ≤ 2Gy D16 < 15cc		D_max≤ 14 Gy D_median= 10.1 Gy Left atrium: D_max≤ 4.4 Gy Superior vena cava: D_50%≤ 0.6 Gy ICD < 0.5 Gy	DIBH EBH Real-time tracking 4DCT Gating Fluoroscopy Compression	Potential side effects, Potential development of cardiac toxicity	53–56

Abbreviations: MHD – Mean heart dose; DIBH – Deep inspiration breath hold; EBH – Expiration breath hold.

RTOG0915 and RTOG0813 pericarditis endpoints.

RTOG0915 and RTOG0813 aneurysm endpoints.

Dose constraints can vary with prescriptions, dose fractionations, and laterality.

Impact of Chemotherapy on Heart

Various chemotherapeutic agents have also been shown to increase the risk of cardiotoxicity. The mechanism by which chemotherapy drugs affect the heart is not well known.⁵⁷ Factors that increase patient susceptibility to drug induced cardiotoxicity is also not clear.⁵⁸ We do know, however, that drug effects on the heart are frequency subclinical and can appear early (during therapy), late (during first year after therapy), or very late (more than one year after finishing therapy).⁵⁹.

There are many studies that have demonstrated specific classes of chemotherapeutic agents and their associated cardiotoxicity. Congestive heart failure (CHF) and left ventricular dysfunction (LVD) are associated with the use of anthracyclines which are often used in the management of breast cancer and lymphomas.⁶⁰ Furthermore, the administration of trastuzumab (Herceptin), a monoclonal antibody for HER2 protein, increases the risk of cardiotoxicity if administered with anthracyclines.⁶¹ And with the sequential and/or concomitant use of trastuzumab with radiotherapy for HER2 positive breast, the risk for cardiotoxicity increases further. Another commonly used drug, 5-fluorouracil, is known to induce myocardial ischemia.⁶² Antimicrotubule molecules such as vincalkaloids or taxanes have been shown to produce cardiac heart failure, rhythm disturbances, as well as ischemia.

Checkpoint-inhibitor immunotherapies are the newest agents being used in the management of various malignancies including bladder cancer, melanoma, and lung cancer.⁶³ Examples of these drugs include pembrolizumab, durvalumab, nivolumab all of which target PD-L1 and ipilimumab which targets the anti-cytotoxic T lymphocyte antigen (CTLA-4).⁶⁴ Common side effects of these medications include colitis, dermatitis, endocrinopathies, hepatitis, pneumonitis. Patients have also been found to develop cardiotoxicities such as myocarditis, pericarditis, cardiomyopathy, as well as conduction disorders.⁶⁵.

Motion Management Techniques

In recent years, the integration of respiratory motion management into routine clinical care has increased. This surge can be attributed to various factors, such as the formulation of practice guidelines and the outcomes of clinical trials.^66–69 Moreover, concerns about potential late radiation toxicity have driven recommendations to minimize cardiac doses, for instance with the use of BH techniques.¹⁷ The European Society for Therapeutic Radiology and Oncology Advisory Committee for Radiation Oncology Practice (ESTRO-ACROP) has delineated recommendations for optimal utilization of BH techniques in radiotherapy.⁷⁰ These guidelines present particular challenges, including aspects such as staff training, patient coaching, accuracy, and reproducibility. Although the widely adopted DIBH technique remains prevalent, the utilization of expiration BH has proven advantageous, particularly in cases involving upper abdominal tumors.⁷¹ In the context of breast cancer treatment, patients with regional nodal irradiation, involving internal mammary nodes or those with left-side breast cancer, are given preference for DIBH. In the case of thoracic/abdominal tumors, DIBH is favored for patients with mediastinal targets because it facilitates a reduction in radiation dose to the heart and lungs. Additionally, for patients with highly mobile tumors (> 5 mm), BH or other motion management approaches such as abdominal compression, expiration BH, or gating are considered advantages for minimizing the irradiated volume compared with free breathing approaches.

A survey conducted by AAPM TG 324 in 2020 involving 527 respondents quantified the clinical practice of respiratory motion management in radiation oncology.⁷¹ The findings revealed that 84% of the respondents employed DIBH for left-sided breast cancer, and 95% utilized motion management techniques for thoracic and abdominal cancers. Among them, 60% utilized the internal target volume method for treating thoracic and abdominal cancer whereas 25% opted for BH or abdominal compression, and 13% employed gating or tracking methods. This shift in motion management practices is influenced by evolving treatment guidelines, such as the specified use of SBRT, and a heightened emphasis on mitigating late radiation-induced toxicities, notably cardiac damage.⁷¹ Figure 2 illustrates the intricate motion management workflow process, highlighting its complexity and potential associated components.

Figure 2.

Motion management workflow and its associated components in radiotherapy. At least one component from each category is selected in the process.

Conclusions

This paper summarizes literature on cardiac radiation exposure and techniques to minimize it during radiotherapy for various malignancies. We have reviewed cardiac constraints used for each during treatment planning. We discuss emerging cardiac-sparing strategies including the impact of managing respiratory motion during radiation treatment. In addition, the review emphasizes the need to identify patients at elevated risk for radiation-induced heart disease and advocates for the implementation of stringent cardiac dose constraints for these individuals.

Future research should explore the impact of newer radiation therapy modalities, such as proton therapy, on cardiac dose and effects. Proton therapy can spare the heart and other vital organs while still delivering high radiation doses to tumors, potentially making it a superior option for treating breast and lung malignancies. Ongoing studies with longer follow-ups are needed to further elucidate its cardiac sparing advantage. Additionally, we need to investigate the effects of concurrent radiotherapy and immunotherapy on the heart, as existing research indicates that immunotherapy can lead to cardiac issues such as myocarditis, arrythmias, and heart failure. The combination of these therapies may exacerbate these negative effects, so they should be used cautiously. Lastly, we need to further study how patient specific factors, such as pre-existing coronary artery disease or reduced ejection fraction, can help tailor radiation therapy more effectively.

Footnotes

Author Contribution Statement

Maria Chan wrote the first draft of the manuscript. Chengyu Shi conducted most of the database searches and also contributed in writing the manuscript. Dhwani Parikh reviewed and edited the manuscript.

**The materials were presented in the Therapy Educational Course at the 65th AAPM Annual Meeting in Houston, TX, USA, in July 2023.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was partially funded through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748.

ORCID iD

Maria F. Chan

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Narrative Review: Cardiotoxicities and Cardiac-Sparing Techniques in Radiotherapy

Abstract

Keywords

Introduction

Breast Radiotherapy

Thoracic Cancer Radiotherapy

Lung Cancer

Esophageal Cancer

Mediastinal Lymphoma

Patient-Specific Planning

Childhood Cancer Survivors

Cardiac Radioablation

Impact of Chemotherapy on Heart

Motion Management Techniques

Conclusions

Footnotes

Author Contribution Statement

Declaration of Conflicting Interests

Funding

ORCID iD

References