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Cardiac Toxicity of Thoracic Radiotherapy: Existing Evidence and Future Directions

  • Kathryn Banfill
    Correspondence
    Corresponding author. Address for correspondence: Kathryn Banfill, MBChB, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M20 4BX, United Kingdom.
    Affiliations
    Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom

    The Christie NHS Foundation Trust, Manchester, United Kingdom
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  • Meredith Giuliani
    Affiliations
    Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

    Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
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  • Marianne Aznar
    Affiliations
    Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
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  • Kevin Franks
    Affiliations
    Leeds Cancer Centre, St James’s University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom

    Radiotherapy Research Group, Leeds Institute of Medical Research at St James’s, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
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  • Alan McWilliam
    Affiliations
    Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom

    The Christie NHS Foundation Trust, Manchester, United Kingdom
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  • Matthias Schmitt
    Affiliations
    Cardiovascular Division, Manchester University Foundation Trust, North West Heart Centre, Wythenshawe Campus, Manchester, United Kingdom
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  • Fei Sun
    Affiliations
    Leeds Cancer Centre, St James’s University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom

    Radiotherapy Research Group, Leeds Institute of Medical Research at St James’s, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
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  • Marie Catherine Vozenin
    Affiliations
    Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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  • Corinne Faivre Finn
    Affiliations
    Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom

    The Christie NHS Foundation Trust, Manchester, United Kingdom
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  • on behalf of theIASLC Advanced Radiation Technology committee
Open AccessPublished:December 02, 2020DOI:https://doi.org/10.1016/j.jtho.2020.11.002

      Abstract

      The impact of radiotherapy on the heart has become an area of interest in recent years. Many different cardiac dose-volume constraints have been associated with cardiac toxicity and survival; however, no consistent constraint has been found. Many patients undergoing treatment for lung cancer have risk factors for cardiovascular disease or known cardiac comorbidities; however, there is little evidence on the effects of radiotherapy on the heart in these patients. We aim to provide a summary of the existing literature on cardiac toxicity of lung cancer radiotherapy, propose strategies to avoid and manage cardiac toxicity, and suggest avenues for future research.

      Keywords

      Introduction

      Lung cancer and heart disease are the two major causes of death owing to noncommunicable diseases worldwide.
      World Health Organization
      Global status report on noncommunicable diseases 2014.
      These conditions share common etiologies in terms of cigarette smoking, increasing age, and socioeconomic deprivation, and approximately a quarter of people diagnosed with having lung cancer have known concomitant cardiac disease.
      • Grose D.
      • Morrison D.S.
      • Devereux G.
      • et al.
      The impact of comorbidity upon determinants of outcome in patients with lung cancer.
      • Janssen-Heijnen M.L.
      • Schipper R.M.
      • Razenberg P.P.
      • Crommelin M.A.
      • Coebergh J.-W.W.
      Prevalence of co-morbidity in lung cancer patients and its relationship with treatment: a population-based study.
      • Islam K.M.
      • Jiang X.
      • Anggondowati T.
      • Lin G.
      • Ganti A.K.
      Comorbidity and survival in lung cancer patients.
      The prognosis of patients with lung cancer is poor compared with patients with other cancers. The 5-year survival rate for all patients with lung cancer worldwide is 10% to 20%
      • Bray F.
      • Ferlay J.
      • Soerjomataram I.
      • Siegel R.L.
      • Torre L.A.
      • Jemal A.
      Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [published correction appears in CA Cancer J Clin. 2020;70:313].
      ; therefore, the priority has been disease control rather than reducing late effects. A seminal phase 3 trial of radiotherapy dose-escalation in stage III lung cancer (RTOG 0617) reported that the median survival for patients in the higher dose arm (74 Gy) was worse than that in the standard dose arm (60 Gy) (20.3 mo versus 28.7 mo, respectively).
      • Bradley J.D.
      • Paulus R.
      • Komaki R.
      • et al.
      Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.
      The dose delivered to the heart has emerged as one contributing factor to the surprising result of RTOG 0617 as higher heart dose was associated with increased risk of death on multivariable analysis.
      • Bradley J.D.
      • Paulus R.
      • Komaki R.
      • et al.
      Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.
      Thoracic radiotherapy in patients with breast cancer or lymphoma is known to cause radiation-induced heart disease (RIHD) many years later. Patients with lung cancer are older at diagnosis than patients with breast cancer (71 y versus 62 y
      National Institutes of HealthNational Cancer Institute
      Surveillance, Epidemiology and End Results Program. SEER∗Stat Database.
      ) and most have multiple comorbidities. Furthermore, the dose to the heart in curative-intent lung radiotherapy is often larger than that for breast cancer or lymphoma, especially in patients treated for stage III disease. Recent targeted lung cancer screening programs have revealed lung cancer incidence rates between 1% and 1.5%
      • de Koning H.J.
      • van der Aalst C.M.
      • de Jong P.A.
      • et al.
      Reduced lung-cancer mortality with volume CT screening in a randomized trial.
      ,
      • Crosbie P.A.
      • Balata H.
      • Evison M.
      • et al.
      Second round results from the Manchester “Lung Health Check” community-based targeted lung cancer screening pilot.
      ; most of whom are diagnosed with having early stage disease and proceed to curative-intent surgery. Nevertheless, in one lung cancer screening program, 31% of patients received curative radiotherapy.
      • Crosbie P.A.
      • Balata H.
      • Evison M.
      • et al.
      Second round results from the Manchester “Lung Health Check” community-based targeted lung cancer screening pilot.
      It is therefore time to consider the evidence around cardiac toxicity of lung cancer radiotherapy separately from previous evidence from other cancer sites.
      This review has been written by a multidisciplinary team comprising of scientists, cardiologists, physicists, and radiation oncologists. We summarize the existing literature on the biology, pathophysiology, management, and prevention of RIHD. We review existing cardiac dose constraints derived from other patient populations with cancer and how these apply to patients with lung cancer treated with radiotherapy. Finally, we discuss the limitations of the literature on RIHD, propose strategies to reduce the effects of radiotherapy on the heart, and suggest future research directions.

      Pathophysiology of RIHD

      In the past four decades, research has enhanced our understanding of the pathophysiological, cellular, and molecular processes governing RIHD. These processes are complex and involve crosstalk between the various cellular types, alteration of wound healing, and proinflammatory signaling pathways.
      • Boerma M.
      • Sridharan V.
      • Mao X.W.
      • et al.
      Effects of ionizing radiation on the heart.
      ,
      • Liu L.K.
      • Ouyang W.
      • Zhao X.
      • et al.
      Pathogenesis and prevention of radiation-induced myocardial fibrosis.
      The classical hallmarks of RIHD include the following: fibrosis and calcification of the aortic root and the aortomitral curtain that can lead to progressive stenosis of the aortic and mitral valves; ostial coronary stenosis; myocardial atrophy and widespread pericardial adhesions and thickening ultimately leading to intractable and inoperable pericardial constriction.
      The hallmarks of RIHD are a result of radiation-induced activation of acute inflammatory pathways (Fig. 1) causing a chronic pathogenic cascade. The process starts with the disruption of the endothelial barrier integrity and albumin leakage leading to up-regulation of inflammatory signals and platelet aggregation. In parallel, radiation-induced decrease of the microvascular density causes tissue ischemia and oxidative stress inside cardiomyocytes causing their death. Reactive oxygen species lead to the up-regulation of NF-ƙB. This protein complex is involved in the regulation of DNA transcription, and its activation increases the expression of cellular adhesion molecules and cytokine secretion.
      • Taunk N.K.
      • Haffty B.G.
      • Kostis J.B.
      • Goyal S.
      Radiation-induced heart disease: pathologic abnormalities and putative mechanisms.
      Oxidative stress and chronic inflammation in coronary arteries cause accelerated atherosclerosis.
      • Stewart F.A.
      • Heeneman S.
      • Te Poele J.
      • et al.
      Ionizing radiation accelerates the development of atherosclerotic lesions in ApoE−/− mice and predisposes to an inflammatory plaque phenotype prone to hemorrhage.
      Damaged and dying cells are removed by macrophages and replaced by amyloid and fibrin, contributing to scar formation. This transmural infiltration of extracellular matrix, associated with pathologic accumulation of immune cells (macrophages, mastocytes) and the alteration of calcium flux in the cardiomyocytes, causes systolic and diastolic dysfunction and affects cardiac conduction systems.
      • Boerma M.
      • Sridharan V.
      • Mao X.W.
      • et al.
      Effects of ionizing radiation on the heart.
      Figure thumbnail gr1
      Figure 1Cardiac endothelial damage caused by radiation resulting in fibrosis. bFGF, basic fibroblast growth factor; IGF, insulin-like growth factor; IL, interleukin; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor.

      Preclinical Models of Cardiac Toxicity

      Radiation-induced congestive heart failure, myocardial infarction (MI), and valvular pathology have been reproduced in rodents.
      • Falk V.
      • Garbade J.
      • Walther T.
      Experimental models of heart failure.
      Until recently, the protocols of irradiation used in rodents were mainly high-dose single fractions, which does not reflect standard clinical radiotherapy regimens delivered in a number of weeks. The implementation of image-guided radiotherapy for small animals has allowed clinically relevant treatment planning to be applied to mice, rats, and rabbits in combination with various chemotherapeutic drugs and biotherapies. The zebrafish is an exotic animal model that is emerging for use in cardiovascular and RIHD research. These preclinical models allowed full characterization of the pathophysiology of acute, subacute, and delayed RIHD, leading to the identification of potential therapeutic targets at the cellular and molecular levels.

      Treating the Patient With Complex Lung Cancer With Radiotherapy

      Animal models provide biological information on the effect of radiotherapy on the heart; however, their use is limited as these animals do not adequately model the comorbidities affecting the patient population with lung cancer. The prevalence of cardiac comorbidities in patients with lung cancer is approximately 25% to 30% and is often associated with smoking.
      • Janssen-Heijnen M.L.
      • Schipper R.M.
      • Razenberg P.P.
      • Crommelin M.A.
      • Coebergh J.-W.W.
      Prevalence of co-morbidity in lung cancer patients and its relationship with treatment: a population-based study.
      ,
      • Islam K.M.
      • Jiang X.
      • Anggondowati T.
      • Lin G.
      • Ganti A.K.
      Comorbidity and survival in lung cancer patients.
      The commonest cardiac comorbidities are ischemic heart disease (IHD) and cardiac arrhythmia.
      • Kravchenko J.
      • Berry M.
      • Arbeev K.
      • Lyerly H.K.
      • Yashin A.
      • Akushevich I.
      Cardiovascular comorbidities and survival of lung cancer patients: Medicare data based analysis.
      Preexisting cardiac comorbidities have been associated with increased incidence of cardiac events and mortality in patients after chemoradiotherapy.
      • Kravchenko J.
      • Berry M.
      • Arbeev K.
      • Lyerly H.K.
      • Yashin A.
      • Akushevich I.
      Cardiovascular comorbidities and survival of lung cancer patients: Medicare data based analysis.
      • Lin S.H.
      • Merrell K.W.
      • Shen J.
      • et al.
      Multi-institutional analysis of radiation modality use and postoperative outcomes of neoadjuvant chemoradiation for esophageal cancer.
      • Ferris M.J.
      • Jiang R.
      • Behera M.
      • Ramalingam S.S.
      • Curran W.J.
      • Higgins K.A.
      Radiation therapy is associated with an increased incidence of cardiac events in patients with small cell lung cancer.
      A retrospective analysis of 748 patients with locally advanced NSCLC who received radiotherapy found that patients with underlying cardiovascular disease (CVD) had a 2-year cumulative incidence estimate of major adverse cardiac events (MACEs) of 11.7%.
      • Atkins K.M.
      • Rawal B.
      • Chaunzwa T.L.
      • et al.
      Cardiac radiation dose, cardiac disease, and mortality in patients with lung cancer.
      The mean heart dose (MHD) did not affect MACE rate in patients with a history of underlying CVD; however, in those with no history of CVD, a MHD ≥ 10 Gy substantially increased the MACE rate (2-y cumulative incidence estimate 3.5% versus 1.1%).
      • Atkins K.M.
      • Rawal B.
      • Chaunzwa T.L.
      • et al.
      Cardiac radiation dose, cardiac disease, and mortality in patients with lung cancer.
      These results indicate that preexisting CVD is a risk factor for future MACE independent of cardiac dose. Cardiac dose may be more relevant in younger patients without CVD as radiation exerts its negative effects in a time-dependent manner.
      At least a quarter of patients treated for lung cancer have CVD; others have known risk factors for CVD such as hyperlipidemia (40%), hypertension (12%–60%), and diabetes mellitus (7%–11%).
      • Grose D.
      • Morrison D.S.
      • Devereux G.
      • et al.
      The impact of comorbidity upon determinants of outcome in patients with lung cancer.
      ,
      • Janssen-Heijnen M.L.
      • Schipper R.M.
      • Razenberg P.P.
      • Crommelin M.A.
      • Coebergh J.-W.W.
      Prevalence of co-morbidity in lung cancer patients and its relationship with treatment: a population-based study.
      ,
      • Kravchenko J.
      • Berry M.
      • Arbeev K.
      • Lyerly H.K.
      • Yashin A.
      • Akushevich I.
      Cardiovascular comorbidities and survival of lung cancer patients: Medicare data based analysis.
      The WHO/International Society of Hypertension (ISH) risk score predicts the 10-year risk of MI or stroke.
      WHO
      WHO/ISH cardiovascular risk prediction charts.
      Wang et al.
      • Wang K.
      • Eblan M.J.
      • Deal A.M.
      • et al.
      Cardiac toxicity after radiotherapy for stage III non-small-cell lung cancer: pooled analysis of dose-escalation trials delivering 70 to 90 Gy.
      paired WHO/ISH risk score with dose parameters and found that, on multivariable analysis, patients with a high WHO/ISH risk score and higher MHD had a significantly higher incidence of cardiac events after radiotherapy for lung cancer (HR, 1.04, p = 0.001). WHO/ISH risk score and other cardiovascular risk predictors such as Q-risk
      • Hippisley-Cox J.
      • Coupland C.
      • Brindle P.
      Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study.
      are not validated for use in patients with a history of cardiovascular events and tend to overestimate the risk of CVD.
      • Dyakova M.
      • Shantikumar S.
      • Colquitt J.L.
      • et al.
      Systematic versus opportunistic risk assessment for the primary prevention of cardiovascular disease.
      Cardiac imaging, especially cross-sectional imaging in the form of cardiac computed tomography, and cardiac magnetic resonance imaging (CMR) are highly sensitive and specific respectively for the identification of IHD in general and oncology patients. CMR offers a multiparametric approach that allows the assessment of cardiac anatomy, function, and perfusion. CMR can simultaneously perform detailed tissue characterization and assessment of specific myocardial injury types including edema and fibrosis.
      • Jordan J.H.
      • Todd R.M.
      • Vasu S.
      • Hundley W.G.
      Cardiovascular magnetic resonance in the oncology patient.
      Cardiac computed tomography can be used to identify coronary artery stenosis and calculate coronary artery calcification scores (CACSs) and soft plaque burden; high CACS is associated with increased rates of MACE and death.
      • Polonsky T.S.
      • McClelland R.L.
      • Jorgensen N.W.
      • et al.
      Coronary artery calcium score and risk classification for coronary heart disease prediction.
      ,
      • Rennenberg R.J.
      • Kessels A.G.
      • Schurgers L.J.
      • van Engelshoven J.M.
      • de Leeuw P.W.
      • Kroon A.A.
      Vascular calcifications as a marker of increased cardiovascular risk: a meta-analysis.
      A high CACS, calculated on radiotherapy planning scan before adjuvant breast radiotherapy, has been associated with subsequent cardiac events.
      • Roos C.T.G.
      • van den Bogaard V.A.B.
      • Greuter M.J.W.
      • et al.
      Is the coronary artery calcium score associated with acute coronary events in breast cancer patients treated with radiotherapy?.
      A small study of CACS in patients who received thoracic radiotherapy found that diabetes and radiation dose to coronary arteries were associated with higher CACS after radiotherapy.
      • Milgrom S.A.
      • Varghese B.
      • Gladish G.W.
      • et al.
      Coronary artery dose-volume parameters predict risk of calcification after radiation therapy.
      A larger study of cardiac calcifications in patients having curative radiotherapy for lung cancer found a relationship between survival and increased dose to calcifications; however, this study did not use CACS.
      • Osorio E.V.
      • Brewster F.
      • Cobben D.
      • et al.
      [OA129] Calcifications in lung cancer patients: can they be used as surrogate for overall survival predictions?.
      Both Q-risk score
      • Hippisley-Cox J.
      • Coupland C.
      • Brindle P.
      Development and validation of QRISK3 risk prediction algorithms to estimate future risk of cardiovascular disease: prospective cohort study.
      and CACS have been found to be raised in a cohort of patients undergoing lung cancer screening compared with the general population,
      • Balata H.
      • Blandin Knight S.
      • Barber P.
      • et al.
      Targeted lung cancer screening selects individuals at high risk of cardiovascular disease.
      revealing the increased risk of cardiac events in this population which could be further increased by cardiac irradiation.

      Limiting Heart Dose: Lessons From Other Cancers

      Existing cardiac dose constraints are based on the Qualitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC)
      • Gagliardi G.
      • Constine L.S.
      • Moiseenko V.
      • et al.
      Radiation dose–volume effects in the heart.
      and are mainly derived from studies of radiotherapy in patients with esophageal cancer and lymphoma. QUANTEC recommended that the volume of heart receiving greater than or equal to 30 Gy (V30) should be kept below 46% and MHD less than 15 Gy. It should be noted that the QUANTEC recommendations for cardiac dose did not include any studies of radiotherapy in patients with lung cancer. Furthermore, challenges in contouring heart substructures, competing patient and treatment risk factors, lack of quantitative dose and volume dependence for cardiac toxicity were acknowledged.
      In contrast to the QUANTEC recommendation suggesting that MHD less than 15 Gy is safe, Darby et al.
      • Darby S.C.
      • Ewertz M.
      • McGale P.
      • et al.
      Risk of ischemic heart disease in women after radiotherapy for breast cancer.
      reported for the first time that the risk of MACE (defined as MI, coronary revascularization, or death from IHD) in breast cancer survivors increases in a linear relationship to cardiac radiation dose, even at low-dose levels. The rate of MACE increased by 7.4% per one gray increase in MHD in this cohort of patients. Radiation dose to the heart was also associated with heart failure
      • van Nimwegen F.A.
      • Schaapveld M.
      • Cutter D.J.
      • et al.
      Radiation dose–response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma.
      and valvular heart disease
      • Cutter D.J.
      • Schaapveld M.
      • Darby S.C.
      • et al.
      Risk for valvular heart disease after treatment for Hodgkin lymphoma.
      in Hodgkin’s lymphoma (HL) survivors. In these patient groups, RIHD can occur up to several decades after treatment.
      • van Nimwegen F.A.
      • Schaapveld M.
      • Janus C.P.
      • et al.
      Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk.
      Patients with breast cancer and HL tend to have a low initial comorbidity burden, and, until recently, RIHD was considered a “late effect” affecting only long-term survivors. Nevertheless, these studies revealed that the risk of cardiac events after chest radiotherapy is even higher in patients with preexisting IHD and in those with other cardiac risk factors such as smoking, hypertension, diabetes mellitus, and obesity.
      • Darby S.C.
      • Ewertz M.
      • McGale P.
      • et al.
      Risk of ischemic heart disease in women after radiotherapy for breast cancer.
      ,
      • van Nimwegen F.A.
      • Schaapveld M.
      • Cutter D.J.
      • et al.
      Radiation dose–response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma.
      ,
      • van Nimwegen F.A.
      • Schaapveld M.
      • Janus C.P.
      • et al.
      Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk.
      Although there are important learning points from the breast and lymphoma literature, a number of limitations of these studies should be considered when applied to patients having radiotherapy for lung cancer. First, outdated radiotherapy techniques, delivering a higher dose to larger volumes of the heart compared with modern radiotherapy techniques, were used in these studies.
      • Taylor C.
      • Correa C.
      • Duane F.K.
      • et al.
      Estimating the risks of breast cancer radiotherapy: evidence from modern radiation doses to the lungs and heart and from previous randomized trials.
      ,
      • Maraldo M.V.
      • Giusti F.
      • Vogelius I.R.
      • et al.
      Cardiovascular disease after treatment for Hodgkin’s lymphoma: an analysis of nine collaborative EORTC-LYSA trials.
      Second, the cardiovascular risk from systemic agents (e.g., anthracyclines) was not always included. Third, these dose-response relationships are based on rough estimates of the average radiation dose received by the whole heart. More recent studies suggest that the dose to the left ventricle or coronary arteries might be more relevant
      • Taylor C.
      • McGale P.
      • Brønnum D.
      • et al.
      Cardiac structure injury after radiotherapy for breast cancer: cross-sectional study with individual patient data.
      ,
      • Van Den Bogaard V.A.
      • Ta B.D.
      • van der Schaaf A.
      • et al.
      Validation and modification of a prediction model for acute cardiac events in patients with breast cancer treated with radiotherapy based on three-dimensional dose distributions to cardiac substructures [published correction appears in J Clin Oncol. 2017;35:3736].
      for patients with breast cancer. Finally, the effect of dose to the heart in lung cancer may occur earlier than in patients with breast cancer or lymphoma.

      Limiting Heart Dose: Applications to Lung Cancer

      RTOG 0617 was the first study that highlighted the issue of cardiac dose in lung cancer radiotherapy. The original article revealed that the volume of heart receiving greater than or equal to 5 Gy (V5) or greater than or equal to 30 Gy (V30) was associated with worse overall survival.
      • Bradley J.D.
      • Paulus R.
      • Komaki R.
      • et al.
      Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.
      A secondary analysis of RTOG 0617 published 2 years later reported that heart volume of heart receiving greater than or equal to 40 Gy was the dose parameter most strongly associated with survival.
      • Chun S.G.
      • Hu C.
      • Choy H.
      • et al.
      Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial.
      Table 1 reveals the results of post hoc analysis of prospective studies that evaluate cardiac toxicity of lung radiotherapy.
      Table 1Cardiac Outcomes of Post hoc Analysis of Prospective Studies of Lung Cancer RT Trials
      TrialData SourceEnd PointNo. of Patients and StageMedian Follow-UpMedian Age, yRT Dose and TechniqueMedian Tumor Volume, cm3CEsConclusions

      Dose Constraints
      Wang et al.2017
      • Wang K.
      • Eblan M.J.
      • Deal A.M.
      • et al.
      Cardiac toxicity after radiotherapy for stage III non-small-cell lung cancer: pooled analysis of dose-escalation trials delivering 70 to 90 Gy.
      6 Phase 1 and 2 radiotherapy dose-escalation trialsSymptomatic CE112 Stage III8.8 y for surviving patients5874 Gy in 37 fractions

      3D conformal
      GTV = 46.629 Events in 26 patients (23%)

      7 Ischemia

      1 CHF

      9 Pericardial

      12 Arrythmia
      MHD, V5, V30, LV V5 sig associated with CEs in patients with IHD or high WHO/ISH risk scores.

      MHD ≥ 20 Gy higher rate of CE

      No association between OS and heart dose
      Dess et al.2017
      • Dess R.T.
      • Sun Y.
      • Matuszak M.M.
      • et al.
      Cardiac events after radiation therapy: combined analysis of prospective multicenter trials for locally advanced non-small-cell lung cancer.
      Radiotherapy Dose-escalation trialsCE ≥ grade 3

      CE ≥ grade 2

      OS
      16 stage II

      109 stage III
      23 mo66Median EQD2 dose 70 Gy

      121 3D-CRT

      4 IMRT
      Not stated28 Grades 1–2 (22%)

      13 ≥Grade 3 (10%)
      Preexisting cardiac disease and higher MHDassociated with higher CE on MVA
      Vivekanandan et al.2017
      • Vivekanandan S.
      • Landau D.B.
      • Counsell N.
      • et al.
      The impact of cardiac radiation dosimetry on survival after radiation therapy for non-small cell lung cancer.
      IDEAL-RT

      Phase 1 trial of dose escalated, accelerated radiotherapy
      OS6 Stage II

      72 Stage III
      Not stated66Isotoxic 63–73 Gy

      Median 67.6 Gy

      3D-CRT and VMAT
      PTV = 40020/53 (38%) had ECG changesHigher death rate in patients with ECG changes at 6 mo and left atrium dose > 64 Gy
      Guberina et al.2017
      • Guberina M.
      • Eberhardt W.
      • Stuschke M.
      • et al.
      Heart dose exposure as prognostic marker after radiotherapy for resectable stage IIIA/B non-small-cell lung cancer: secondary analysis of a randomized trial.
      ESPATUE

      Phase 3 trial of surgery vs. chemoradiotherapy
      OS in patients in155 Stage III72 mo5845 Gy in 30 fractions over 3 wk. Inoperable patients had further 20–26 Gy in 2 Gy per fraction

      3D-CRT
      PTV = 784Not statedHeart V5 is not associated with OS
      Ning et al.2017
      • Ning M.S.
      • Tang L.
      • Gomez D.R.
      • et al.
      Incidence and predictors of pericardial effusion after chemoradiation therapy for locally advanced non-small cell lung cancer.
      Phase 2 trial of IMRT vs. protonsGrade ≥ 2 PCE15 Stage I/II

      174 Stage III/IV
      24 moNot stated74 Gy in 37 fractions

      126 IMRT

      75 Protons
      Not stated81 (43%) Grade 2 PCE

      5 (3%) Grade 3 PCE
      Heart V35 > 10%, adjuvant chemotherapy and preexisting cardiac disease associated with ≥ grade 2 PCE
      Chun et al.2017
      • Chun S.G.
      • Hu C.
      • Choy H.
      • et al.
      Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial.
      RTOG 0617 Phase 3 radiotherapy dose-escalation trial2 y OS

      Toxicity ≥ grade 3
      482 Stage III21.3 mo6460 Gy in 30 fractions

      74 Gy in 37 fractions

      IMRT and 3D-CRT
      PTV = 426.7 for 3D-CRT

      PTV = 486.2 for IMRT
      32 grade ≥ 3 cardiac toxicityLower heart doses with IMRT

      Heart V40 associated with OS
      Xue et al.2019
      • Xue J.
      • Han C.
      • Jackson A.
      • et al.
      Doses of radiation to the pericardium, instead of heart, are significant for survival in patients with non-small cell lung cancer.
      Prospective imaging and phase 1/2 dose-escalation trialsGrade ≥ 2 PCE

      OS
      11 Stage I

      7 Stage II

      76 Stage III
      58 mo for surviving patients6660–85.5 Gy in 2–3.8 Gy fractions

      3D-CRT
      GTV = 129.638 (40%) grade ≥ 2 PCEPrescription dose, hypertension, MHD, cardiac V5 and V55, pericardial mean, V5, V30, and V55 associated with PCE

      Pericardial V30 > 29% and pericardial V50 > 21% associated with worse OS
      Thor et al.2020
      • Thor M.
      • Deasy J.O.
      • Hu C.
      • et al.
      Modeling the impact of cardio-pulmonary irradiation on overall survival in NRG Oncology trial RTOG 0617.
      RTOG 0617 Phase 3 radiotherapy dose-escalation trialOS437 Stage III24 mo6460 Gy in 30 fractions

      74 Gy in 37 fractions

      3D-CRT and VMAT
      GTV = 93Not statedA model combining atria D45%, mean lung dose, minimum dose to hottest 55% of pericardium, and minimum dose to the hottest 5% of both ventricles predicted OS
      3D, three dimensional; CE, cardiac event; CHF, congestive heart failure; CRT, conformal radiotherapy; D45%, dose to 45% of the volume; ECG, electrocardiogram; EQD2, equivalent dose in 2 Gy fractions; GTV, gross tumor volume; IHD, ischemic heart disease; IMRT, intensity modulated radiotherapy; ISH, International Society of Hypertension; LV, left ventricular; MHD, mean heart dose; MVA, mitral valve area; OS, overall survival; PCE, pericardial effusion; PTV, planning target volume; RT, radiotherapy; sig, significantly; VMAT, volumetric-modulated arc therapy; VxGy, volume of organ (%) receiving greater than or equal to XGy.
      After the initial results of RTOG 0617, a number of studies have been published investigating the relationship between cardiac dose, cardiac events, and mortality in patients with lung cancer. Zhang et al.
      • Zhang T.W.
      • Snir J.
      • Boldt R.G.
      • et al.
      Is the importance of heart dose overstated in the treatment of non-small cell lung cancer? A systematic review of the literature.
      performed a systematic review of studies published before January 2018. They included 18 studies of patients with NSCLC treated with concurrent chemoradiotherapy and four studies of patients with early stage disease treated with stereotactic ablative body radiotherapy. Most of the studies evaluated were retrospective, from single institutions, and had different test populations and differing end point definitions. A total of 96 different cardiac dose parameters were examined; 20 dose parameters were found to be significantly associated with either overall survival or cardiac events on multivariable analysis. The most often studied parameters were MHD, heart V5, and V30. Most cardiac dose parameters were only significant in one study. Heart V30 was associated with decreased overall survival in two studies and MHD was associated with postradiotherapy cardiac events in two studies.
      • Wang K.
      • Eblan M.J.
      • Deal A.M.
      • et al.
      Cardiac toxicity after radiotherapy for stage III non-small-cell lung cancer: pooled analysis of dose-escalation trials delivering 70 to 90 Gy.
      ,
      • Dess R.T.
      • Sun Y.
      • Matuszak M.M.
      • et al.
      Cardiac events after radiation therapy: combined analysis of prospective multicenter trials for locally advanced non-small-cell lung cancer.
      These results reveal how testing multiple dose parameters can lead to overfitting the statistical model thus increasing the likelihood of a type 1 error. The analysis could not derive reliable dose constraints for the heart.
      Zhang et al.
      • Zhang T.W.
      • Snir J.
      • Boldt R.G.
      • et al.
      Is the importance of heart dose overstated in the treatment of non-small cell lung cancer? A systematic review of the literature.
      excluded articles that did not report cardiac dose parameters, and therefore, a large retrospective study of residual set-up error in 780 patients with NSCLC treated with radical radiotherapy was not included. This study reported that patients with a small, uncorrected set-up error in the direction of the mediastinum (and therefore the heart) had significantly poorer survival (hazard ratio = 1.1).
      • Johnson-Hart C.N.
      • Price G.J.
      • Faivre-Finn C.
      • Aznar M.C.
      • van Herk M.
      Residual setup errors towards the heart after image guidance linked with poorer survival in lung cancer patients: do we need stricter IGRT protocols?.
      A similar, retrospective study in 136 patients who had stereotactic ablative body radiotherapy to lung lesions outside the “no fly zone” found that the hazard ratio for death was 1.262 per 1 mm shift toward the heart.
      • Johnson-Hart C.
      • Price G.
      • Vasquez Osorio E.
      • Faivre-Finn C.
      • van Herk M.
      The impact of baseline shifts towards the heart after image guidance on survival in lung SABR patients.
      These results suggest a very steep dose-response curve for cardiac dose.
      Since the publication of this systematic review, Thor et al.
      • Thor M.
      • Deasy J.O.
      • Hu C.
      • et al.
      Modeling the impact of cardio-pulmonary irradiation on overall survival in NRG Oncology trial RTOG 0617.
      published a modeling study on the basis of the RTOG0617 data set revealing that the primary drivers for differential mortality were dose-volume loads on multiple cardiopulmonary structures. This suggests a potential negative effect of the irradiation of blood-carrying structures on the immune system, which needs to be elucidated in further studies.
      • Contreras J.A.
      • Lin A.J.
      • Weiner A.
      • et al.
      Cardiac dose is associated with immunosuppression and poor survival in locally advanced non-small cell lung cancer.

      Limiting Dose to Cardiac Substructures

      The lack of a definite dose constraint for the whole heart and effect on survival of small residual set-up errors toward the heart could indicate that dose to cardiac substructures is more important than whole heart dose. Moreover, studies of HL survivors have highlighted that different heart diseases exhibit dose-response relationship with varied shapes and slopes, for example, linear for IHD
      • van Nimwegen F.A.
      • Schaapveld M.
      • Cutter D.J.
      • et al.
      Radiation dose–response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma.
      and nonlinear for valvular heart disease.
      • Cutter D.J.
      • Schaapveld M.
      • Darby S.C.
      • et al.
      Risk for valvular heart disease after treatment for Hodgkin lymphoma.
      The heart is comprised substructures with unique physiological functions. Figure 2 reveals the different cardiac substructures that have been found to be significantly associated with cardiac events or mortality in patients having radical radiotherapy for lung cancer.
      • Wang K.
      • Eblan M.J.
      • Deal A.M.
      • et al.
      Cardiac toxicity after radiotherapy for stage III non-small-cell lung cancer: pooled analysis of dose-escalation trials delivering 70 to 90 Gy.
      ,
      • McWilliam A.
      • Kennedy J.
      • Hodgson C.
      • Vasquez Osorio E.
      • Faivre-Finn C.
      • van Herk M.
      Radiation dose to heart base linked with poorer survival in lung cancer patients.
      • McWilliam A.
      • Khalifa J.
      • Vasquez Osorio E.
      • et al.
      Novel methodology to investigate the effect of radiation dose to heart substructures on overall survival.
      • Ma J.T.
      • Sun L.
      • Sun X.
      • et al.
      Is pulmonary artery a dose-limiting organ at risk in non-small cell lung cancer patients treated with definitive radiotherapy?.
      • Stam B.
      • Peulen H.
      • Guckenberger M.
      • et al.
      Dose to heart substructures is associated with non-cancer death after SBRT in stage I-II NSCLC patients.
      • Wong O.Y.
      • Yau V.
      • Kang J.
      • et al.
      Survival impact of cardiac dose following lung stereotactic body radiotherapy.
      • Yegya-Raman N.
      • Wang K.
      • Kim S.
      • et al.
      Dosimetric predictors of symptomatic cardiac events after conventional-dose chemoradiation therapy for inoperable NSCLC.
      • Hotca A.
      • Thor M.
      • Deasy J.O.
      • Rimner A.
      Dose to the cardio-pulmonary system and treatment-induced electrocardiogram abnormalities in locally advanced non-small cell lung cancer.
      • Vivekanandan S.
      • Landau D.B.
      • Counsell N.
      • et al.
      The impact of cardiac radiation dosimetry on survival after radiation therapy for non-small cell lung cancer.
      • Xue J.
      • Han C.
      • Jackson A.
      • et al.
      Doses of radiation to the pericardium, instead of heart, are significant for survival in patients with non-small cell lung cancer.
      A number of studies point to dose received by cardiac substructures at the base of the heart as being associated with reduced survival or cardiac events. The base of the heart is defined anatomically as posterior to the sternum, at the level of the third costal cartilage. Posteriorly, it is formed by the left atrium and connecting upper pulmonary veins, and anteriorly, it includes the right ventricular outflow tract, aortic root, and origin of the coronary arteries. The base of the heart also includes the junction of the superior vena cava and right atrium, which is the location of the sino-atrial node, the origin of the electrical impulse that stimulates cardiac contraction.
      • Martini F.H.
      • Ober W.C.
      • Garrison C.W.
      • Welch K.
      • Hutchings R.T.
      The heart.
      Figure thumbnail gr2
      Figure 2Cardiac substructures found to be significantly associated with cardiac events or overall survival in prospective and retrospectives studies. Labels in black reveal studies using standard fractionation, those in red reveal studies using hypofractionated radiotherapy, and those in blue reveal studies using SABR. AV, aortic valve; CE, cardiac events; ECG, electrocardiogram; IHD, ischemic heart disease; LA, left atrium; LAD, left anterior descending coronary artery; LV, left ventricle; OS, overall survival; PA, pulmonary artery; RA, right atrium; RCA, right coronary artery; RV, right ventricle; SABR, stereotactic ablative body radiotherapy; SVC, superior vena cava; V30, volume of heart receiving greater than or equal to 30 Gy; V40, volume of heart receiving greater than or equal to 40 Gy; V5, volume of heart receiving greater than or equal to 5 Gy.
      One hypothesis for increased cardiac events after lung radiotherapy is that the conduction system may be damaged directly by radiation or indirectly through inflammation, fibrosis, or ischemia. Dose to both the superior vena cava and left atrium has been associated with electrocardiogram changes.
      • Hotca A.
      • Thor M.
      • Deasy J.O.
      • Rimner A.
      Dose to the cardio-pulmonary system and treatment-induced electrocardiogram abnormalities in locally advanced non-small cell lung cancer.
      ,
      • Vivekanandan S.
      • Landau D.B.
      • Counsell N.
      • et al.
      The impact of cardiac radiation dosimetry on survival after radiation therapy for non-small cell lung cancer.
      Novel applications of stereotactic radiation therapy to treat refractory cardiac arrhythmias reveal that the cardiac conduction system can be considered a serial structure. Although the biological mechanisms underlying the use of radiotherapy in the treatment of refractory ventricular tachycardia are unknown, proof-of-concept and clinical studies have revealed some benefit in reducing the number of episodes.
      • Cuculich P.S.
      • Schill M.R.
      • Kashani R.
      • et al.
      Noninvasive cardiac radiation for ablation of ventricular tachycardia.
      ,
      • Robinson C.G.
      • Samson P.P.
      • Moore K.M.S.
      • et al.
      Phase I/II trial of electrophysiology-guided noninvasive cardiac radioablation for ventricular tachycardia.

      Cardiac Contouring

      The heart is now a recognized organ at risk in lung cancer radiotherapy and is routinely contoured. Current guidelines recommend limiting dose to the whole heart or pericardium
      • Nestle U.
      • De Ruysscher D.
      • Ricardi U.
      • et al.
      ESTRO ACROP guidelines for target volume definition in the treatment of locally advanced non-small cell lung cancer.
      ; however, it is still not known whether we should limit the radiation dose to the whole heart or to the substructures. Several heart contouring atlases have been developed
      • Duane F.
      • Aznar M.C.
      • Bartlett F.
      • et al.
      A cardiac contouring atlas for radiotherapy.
      • Feng M.
      • Moran J.M.
      • Koelling T.
      • et al.
      Development and validation of a heart atlas to study cardiac exposure to radiation following treatment for breast cancer.
      • Kong F.M.
      • Ritter T.
      • Quint D.J.
      • et al.
      Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus.
      with the aim of consistent dose reporting in clinical practice and clinical trials. Key differences exist between atlases with different substructures being highlighted. Two atlases were developed in patients undergoing breast cancer radiotherapy. The atlas by Duane et al.
      • Duane F.
      • Aznar M.C.
      • Bartlett F.
      • et al.
      A cardiac contouring atlas for radiotherapy.
      subdivides the left ventricle into five sections and describes the anatomy of 10 coronary artery segments and is meant only for research use, not for clinical practice. The atlas by Feng et al.
      • Feng M.
      • Moran J.M.
      • Koelling T.
      • et al.
      Development and validation of a heart atlas to study cardiac exposure to radiation following treatment for breast cancer.
      includes the four cardiac chambers, in addition to heart valves and the atrioventricular node. In contrast, the atlas by Kong et al.
      • Kong F.M.
      • Ritter T.
      • Quint D.J.
      • et al.
      Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus.
      was developed in the context of lung radiotherapy and only includes the four cardiac chambers. Most studies of cardiac dosimetry use either the Feng or Kong atlases. The effect of contouring differences on dose parameters (MHD or volumetric parameters) should not be underestimated, and comparison between patients and between institutions depends on clinicians after strictly standardized guidelines. When interpreting the literature on radiotherapy-induced cardiac toxicity, it is important to understand the important differences between contouring atlases because these will affect dose reporting and comparison of outcomes.
      The limitations described in delineating cardiac substructures can be overcome by employing analysis techniques that do not require any cardiac delineation. Studies by Stam et al.
      • Stam B.
      • Peulen H.
      • Guckenberger M.
      • et al.
      Dose to heart substructures is associated with non-cancer death after SBRT in stage I-II NSCLC patients.
      and McWilliam et al.
      • McWilliam A.
      • Kennedy J.
      • Hodgson C.
      • Vasquez Osorio E.
      • Faivre-Finn C.
      • van Herk M.
      Radiation dose to heart base linked with poorer survival in lung cancer patients.
      used a reference anatomy and nonrigidly registered each patient. Stam et al.
      • Stam B.
      • Peulen H.
      • Guckenberger M.
      • et al.
      Dose to heart substructures is associated with non-cancer death after SBRT in stage I-II NSCLC patients.
      evaluated the dose to individual cardiac substructures contoured on the reference anatomy, whereas McWilliam et al.
      • McWilliam A.
      • Kennedy J.
      • Hodgson C.
      • Vasquez Osorio E.
      • Faivre-Finn C.
      • van Herk M.
      Radiation dose to heart base linked with poorer survival in lung cancer patients.
      used a voxel-based approach to find a region associated with worse patient outcomes. The later technique does not use any segmentations removing any need for previous assumptions on the important anatomy.

      Identification and Management of Cardiac Toxicity

      Radiation results in a variety of toxicity depending on the affected substructure. Table 2 reveals the diseases that can occur after thoracic radiotherapy and the possible treatment options for these conditions. The treatment of RIHD is similar to the treatment of heart failure, pericardial, valve, and IHD in the general cardiac setting; however, patients previously exposed to radiotherapy may have worse outcomes. A case-control study of cardiac revascularization in patients who had previous thoracic radiotherapy found that they were at significantly increased risk of death up to 5 years after coronary artery stenting (hazard ratio = 4.2, 95% confidence interval: 1.8–9.5).
      • Dubois C.L.
      • Pappas C.
      • Belmans A.
      • et al.
      Clinical outcome of coronary stenting after thoracic radiotherapy: a case-control study.
      The pathophysiology of RIHD is different to that of standard heart disease, and therefore, further research is required to improve its management.
      Table 2Manifestations of RIHD and Potential Treatments
      DiseaseSymptoms and SignsInvestigationManagement
      Pericardium
       Acute pericarditisFever, chest pain, pericardial rubEcho, CMRSymptomatic pain relief with anti-inflammatory medications (e.g., NSAIDs or aspirin)

      Colchicine
       Pericardial effusionDyspnea, cardiac tamponade, quiet heart soundsSerial echoPericardiocentesis if patient acutely unwell secondary to cardiac constriction/tamponade
       Constrictive pericarditisDyspnea, edema, fatigue, pericardial rubEcho, CMR, CCT to identify calcificationDiuretics if heart failure present

      Surgery in intractable cases
      Myocardium
       Cardiomyopathy and heart failureDyspnea, edema, fatigue, coughBlood NT-proBNP

      Echo

      CMR
      Diuretics, B-blockers, ACE inhibitors, angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors
      Coronary arteries
       IHDChest painBlood troponin levels

      ECG

      Echo

      CCT

      Angiography
      Cardiac risk factor optimization and secondary prevention with statins and aspirin

      B-blockers, Ca-channel blockers

      Antianginals, for example, nitroglycerine, ivadrabine, ranolazine, nicorandil

      Revascularization if high symptom burden or significant stenosis of left main stem/proximal left anterior descending
      Valves
       Regurgitation and stenosisDyspnea, edema, fatigue, cough, chest pain, cardiac murmurEcho

      CMR

      CCT
      Diuretics, anticoagulation, blood pressure control

      Valve replacement with surgery or TAVI
      Conduction system
       ArrythmiaPalpitations, dizziness, dyspnea, chest painECG (ambulatory)

      Echo

      CMR
      Antiarrhythmics

      Pacemaker

      Cardiac resynchronization
      ACE, angiotensin-converting enzyme; Ca, calcium; CCT, cardiac computed tomography; CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram; Echo, echocardiogram; IHD, ischemic heart disease; NSAID, nonsteroidal anti-inflammatory drug; NT-proBNP, N-terminal fragment B-type natriuretic peptide; RIHD, radiation-induced heart disease; TAVI, transcatheter aortic valve implantation.
      Preclinical research on signal transduction pathways has helped to identify potential therapeutic targets for RIHD, some of which have been transferred into the clinic in small studies. Antioxidant drugs such as amifostine and vitamins C and E reduce reactive oxygen species and delay myocardial fibrosis.
      • Kruse J.J.
      • Strootman E.G.
      • Wondergem J.
      Effects of amifostine on radiation-induced cardiac damage.
      Statins target the activation of the Rho/ROCK pathway whereas angiotensin-converting enzyme inhibitors prevent adverse cardiac remodeling to preserve and improve left ventricular function.
      • Montay-Gruel P.
      • Meziani L.
      • Yakkala C.
      • Vozenin M.C.
      Expanding the therapeutic index of radiation therapy by normal tissue protection.
      If patients are suspected of having cardiac complications after radiotherapy, assessment should include current symptoms, risk factors for cardiac disease, and treatment history (including radiotherapy treatment information and previous/current systemic therapy). Cisplatin is often used concurrently with radiotherapy in stage III lung cancer, in the adjuvant setting after surgery, and to treat metastatic disease. The drug is not directly cardiotoxic; however, it can cause endothelial dysfunction and platelet activation leading to ischemia and thrombosis.
      • Cameron A.C.
      • Touyz R.M.
      • Lang N.N.
      Vascular complications of cancer chemotherapy.
      Checkpoint inhibitors are used both after concurrent chemoradiotherapy in stage III NSCLC and in patients with metastatic disease. These drugs can cause myocarditis and cardiac arrhythmias; however, the incidence of these events is low.
      • Du S.
      • Zhou L.
      • Alexander G.S.
      • et al.
      PD-1 modulates radiation-induced cardiac toxicity through cytotoxic T lymphocytes.
      Patients with cardiotoxicity from cancer treatment should be referred to a cardiologist, ideally one with experience of the cardiac complications of cancer treatment.

      Preventing Cardiac Toxicity

      As previous CVD predicts cardiac events after lung radiotherapy, risk factor modification has an important role in these patients before and after thoracic radiotherapy. Risk factor modification includes smoking cessation, blood sugar control, and lowering blood pressure and cholesterol.
      Radiation dose to the heart is another potentially modifiable risk factor. As discussed previously, there is emerging evidence that dose-volume statistics for the whole heart are suboptimal; therefore, clinical benefit could be found with defined heart avoidance regions and tolerance doses combined with improved image-guided radiotherapy. A daily on-treatment imaging strategy with smaller action threshold levels has been found to improve patient survival.
      • Johnson-Hart C.N.
      • Price G.J.
      • Faivre-Finn C.
      • Aznar M.C.
      • van Herk M.
      Residual setup errors towards the heart after image guidance linked with poorer survival in lung cancer patients: do we need stricter IGRT protocols?.
      A number of advanced radiotherapy technologies can be considered to further reduce the radiation dose to the heart. For example, deep inspiratory breath hold can increase lung capacity and reduce tumor motion. This technique has been reported to be tolerable
      • Persson G.F.
      • Aznar M.C.
      • Rydhög J.S.
      • et al.
      Deep inspiration breath hold compliance in radiation therapy for locally advanced lung cancer.
      and to reduce MHD and hospitalizations at 3 months in cohorts of patients with lung cancer.
      • Giraud P.
      • Morvan E.
      • Claude L.
      • et al.
      Respiratory gating techniques for optimization of lung cancer radiotherapy.
      MR-guided radiotherapy strategies may allow reduced planning target volume margins and reduced heart dose.
      • Merna C.
      • Rwigema J.C.
      • Cao M.
      • et al.
      A treatment planning comparison between modulated tri-cobalt-60 teletherapy and linear accelerator–based stereotactic body radiotherapy for central early-stage non−small cell lung cancer.
      In the setting of locally advanced lung cancer, proton beam therapy (PBT) can reduce MHD and spare more heart volume at all dose levels compared with intensity modulated radiotherapy, particularly at low-dose levels.
      • Liao Z.
      • Lee J.J.
      • Komaki R.
      • et al.
      Bayesian adaptive randomization trial of passive scattering proton therapy and intensity-modulated photon radiotherapy for locally advanced non-small-cell lung cancer [published correction appears in J Clin Oncol. 2018;36:2570].
      Another advantage of PBT is that it may decrease the integral dose and reduce the risk of lymphopenia, which can cause severe opportunistic infection and excess mortality.
      • Abravan A.
      • Faivre-Finn C.
      • Kennedy J.
      • McWilliam A.
      • van Herk M.
      Radiotherapy-related lymphopenia affects overall survival in patients with lung cancer.
      Despite promising results, there is to date little evidence that the use of protons reduces cardiac toxicity or mortality so studies are ongoing or in set-up worldwide (Clinicaltrials.gov NCT 01993810). Furthermore, PBT is extremely sensitive to uncertainties related to tumor motion and lung tissue density, which may limit its use as a heart-sparing strategy in patients with lung cancer.

      Conclusions and Future Directions

      Thoracic radiotherapy is known to cause a variety of cardiac damage through the inflammatory pathways. Patients with lung cancer, who typically have multiple comorbidities, are at higher risk of cardiac events and early mortality after thoracic radiotherapy. To make progress in our understanding of radiation-induced cardiac toxicity, a number of issues should be addressed.
      First, prospective and sufficiently powered studies in patients with lung cancer using an agreed cardiac atlas and robust quality assurance are required. A key limitation of the existing literature on cardiac toxicity is that most published work consists of small, retrospective, mostly single-centre studies with varying end points. Furthermore, large variations in preexisting cardiac disease, comorbidities, radiotherapy technique, and use of chemotherapy in test populations contribute to different outcomes. In addition, data pooling between centers would allow the creation of applicable models with improved power to identify heart dose constraints and factors that predict for cardiac toxicity.
      • Marks L.B.
      • Bentzen S.M.
      • Deasy J.O.
      • et al.
      Radiation dose–volume effects in the lung.
      Second, there is a need to develop a better understanding of the impact of radiation dose on cardiac substructures. Such effects are challenging to evaluate as echocardiography, electrophysiological, or cardiac perfusion studies are currently not part of the routine assessment of patients with lung cancer. There is therefore a requirement to perform prospective studies in collaboration with cardiologists, to prospectively investigate and correlate blood and cardiac imaging biomarkers with outcome. Prospective studies are ongoing (NCT04305613, NCT03978377, and NCT03645317).
      Finally, there is a need for high-quality prospective research to investigate advanced radiotherapy technologies such as MR-guided radiotherapy and PBT. Such studies should include cardiac end points and biomarkers to understand the effect of the cardiac-sparing strategy on the outcome of patients with lung cancer treated with thoracic radiotherapy.

      Acknowledgments

      This work was supported by Cancer Research UK RadNet Manchester ( C1994/A28701 ) and by Yorkshire Cancer Research ( MT401 ). The authors are grateful to Dr. Kate Wicks for her assistance with designing the figures for this manuscript.

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