When radiation therapy causes heart disease

It has been known for almost a century that thoracic radiotherapy can cause damage to the heart.[2] However, the first study suggesting that this damage may play an important role in patient outcomes was not published until the late 1960s.[3] Until then, research focused primarily on the beneficial effects of radiotherapy in cancer treatment. However, long-term follow-up of breast cancer and Hodgkin lymphoma patients treated with thoracic radiotherapy has indicated an increased risk of cardiovascular disease (CVD).[4][5]


What is radiation-induced heart disease?

Radiation-induced heart disease (RIHD) encompasses a number of deleterious effects on the heart as a consequence of radiation to the chest. It may not become apparent until several years after radiotherapy treatment. One study found an interval of seven years between radiotherapy and coronary artery disease in breast cancer patients.[6] Another study found that 10.4% of Hodgkin lymphoma patients developed coronary artery disease at a median of nine years after radiation therapy.[5]

In addition, there is evidence that past radiotherapy affects not only the frequency but also the outcomes of heart disease. Patients who have previously received radiotherapy for breast cancer have an increased risk of dying on the day of myocardial infarction.[1]

As the prognosis and survival after radiotherapy have improved in the past years, it is becoming increasingly important to understand the risks of RIHD and how they can be prevented and/or managed.[7]

In the video below, Gabe Sonke, MD, PhD, from the Netherlands Cancer Institute, Amsterdam, Netherlands, discusses how exposure to thoracic radiotherapy increases a patient’s risk of cardiovascular disease.



What are the risk factors of radiation-induced heart disease?

Studies of atomic bomb survivors give clues on the risk factors which may increase the incidence of cardiovascular events. These studies have demonstrated that exposure to radiation increases the risk of cardiovascular disease.[8] This effect is dose-dependent; the risk of major coronary events in women treated with radiotherapy for breast cancer increases by 7.4% with each 1 Gy* increase in the radiation dose they absorb.[9][10]

A lot has changed since radiotherapy was first used to treat cancer at the end of the 19th century. This is a result of increased awareness of the damaging effects of radiation exposure.[10]  However, breast cancer patients treated with radiotherapy in the last 25 years continue to have an increased risk of heart disease.[11]


How is RIHD managed?

The pathology seen in RIHD is similar to that seen in heart disease unrelated to radiation.[7] Therapeutic options are the same as those for non-irradiated patients with heart disease.[12] However, prevention remains the best way to manage radiation-induced cardiotoxicity.[7]

Current approaches to limit cardiac radiation exposure include intraoperative radiotherapy, as recently evaluated in the ELIOT (NCT01849133) and TARGIT-A (NCT00983684) trials. Delivering radiotherapy intraoperatively to the intact tumor bed reduced cardiovascular-related deaths in the TARGIT-A trial.[13] Results of the effect of intraoperative radiotherapy on cardiovascular risk in the ELIOT trial are yet to be published.

In Hodgkin lymphoma, new techniques allow more accurate targeting of radiation, such as involved-site and involved-node radiotherapy. Intensity-modulated radiotherapy and proton beam therapy can also reduce the extent of cardiac exposure to radiation.[14][15]

Simple approaches can also significantly reduce the amount of radiation that the heart is exposed to, such as respiratory motion management, namely deep inspiration breath-hold (DIBH) during radiotherapy. DIBH reduces movement caused by breathing, and therefore, allows the radiation to be delivered more precisely.[16][17]New imaging techniques, such as tagged MRI (tMRI), can generate 4D cardiac motion models, which can be used to evaluate damage to the heart caused by radiation. Cardiac motion models can also help improve dose calculation by determining cumulative myocardial dose while taking into consideration the movement of the heart.[18]


Future perspectives

Ultrasound tissue characterization, Doppler-based strain imaging and speckle tracking echocardiography are emerging techniques that may be applied to detect early radiotherapy-induced myocardial alterations.[19][20] Potential biomarkers to detect and monitor radiation-induced cardiovascular disease include NT-proBNP, high sensitivity troponin T (hscTnT) pro-inflammatory cytokines and circulating micro RNAs.[21][22][23][24][25]

The BACCARAT trial (NCT02605512) will study patients before and after adjuvant 3D conformal radiotherapy (3D CRT) for breast cancer. It will assess biomarkers and carry out 2D-speckle-tracking echocardiography to determine changes in cardiac strain. Subclinical cardiac lesions will also be analyzed. This should shed more light on the dose-dependent radiotherapy effects on cardiovascular disease development.[26]


Implications for patients and healthcare professionals

As Dr Sonke argues, the cardiovascular risk associated with radiotherapy should be taken into account when discussing risks with patients: “…not just the risk of breast cancer recurrence, but also the risk of […] cardiac disease in general”. This will help patients make an informed decision on whether to receive radiotherapy treatment. He also highlights that “other healthcare professionals, not just oncologists, [should] be aware of the fact that once patients [have] had this radiotherapy, it may also pose a risk to other organs, such as the heart. So risk factor management may be very important for these patients.”

New technologies may allow the cardiac radiation exposure to be more accurately managed or reduced in the treatment of thoracic cancers with radiotherapy. However, they are not yet able to eliminate it. No minimum threshold of radiation exposure has been identified below which there is no increase in radiation-induced heart disease risk.[27] Therefore, monitoring patients who have received radiotherapy in the past is paramount for early identification and appropriate management of cardiovascular disease.

*Gy is a unit of absorbed ionizing radiation dose



Boekel NB, Boekel LY, Jacobse JN, Schaapveld M, Hooning MJ, Seynaeve CM, et al. Effect of radiotherapy for breast cancer on the prognosis of a subsequent myocardial infarction [Internet]. European Journal of Cancer2017;72:S29. Available from: http://dx.doi.org/10.1016/S0959-8049(17)30174-0 [Source]
Davis KS. Intrathoracic Changes Following X-ray Treatment: A Clinical and Experimental Study [Internet]. Radiology1924;3(4):301–22. Available from: http://dx.doi.org/10.1148/3.4.301
Cohn K, Stewart J, Fajardo L, Hancock E. Heart disease following radiation. Medicine (Baltimore) 1967;46(3):281–98. [PubMed]
Høst H, Brennhovd IO, Loeb M. Postoperative radiotherapy in breast cancer—long-term results from the Oslo study [Internet]. International Journal of Radiation Oncology*Biology*Physics1986;12(5):727–32. Available from: http://dx.doi.org/10.1016/0360-3016(86)90029-5 [Source]
Hull M, Morris C, Pepine C, Mendenhall N. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of hodgkin lymphoma treated with radiation therapy. JAMA 2003;290(21):2831–7. [PubMed]
Veinot J, Edwards W. Pathology of radiation-induced heart disease: a surgical and autopsy study of 27 cases. Hum Pathol 1996;27(8):766–73. [PubMed]
Adams M, Hardenbergh P, Constine L, Lipshultz S. Radiation-associated cardiovascular disease. Crit Rev Oncol Hematol 2003;45(1):55–75. [PubMed]
Shimizu Y, Pierce D, Preston D, Mabuchi K. Studies of the mortality of atomic bomb survivors. Report 12, part II. Noncancer mortality: 1950-1990. Radiat Res 1999;152(4):374–89. [PubMed]
Carr ZA, Land CE, Kleinerman RA, Weinstock RW, Stovall M, Griem ML, et al. Coronary heart disease after radiotherapy for peptic ulcer disease [Internet]. International Journal of Radiation Oncology*Biology*Physics2005;61(3):842–50. Available from: http://dx.doi.org/10.1016/j.ijrobp.2004.07.708
Darby S, Ewertz M, McGale P, Bennet A, Blom-Goldman U, Brønnum D, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013;368(11):987–98. [PubMed]
Boekel NB, Schaapveld M, Gietema JA, Russell NS, Poortmans P, Theuws JCM, et al. Cardiovascular Disease Risk in a Large, Population-Based Cohort of Breast Cancer Survivors [Internet]. International Journal of Radiation Oncology*Biology*Physics2016;94(5):1061–72. Available from: http://dx.doi.org/10.1016/j.ijrobp.2015.11.040
Madan R, Benson R, Sharma D, Julka P, Rath G. Radiation induced heart disease: Pathogenesis, management and review literature. J Egypt Natl Canc Inst 2015;27(4):187–93. [PubMed]
Vaidya JS, Wenz F, Bulsara M, Tobias JS, Joseph DJ, Keshtgar M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial [Internet]. The Lancet2014;383(9917):603–13. Available from: http://dx.doi.org/10.1016/S0140-6736(13)61950-9 [Source]
Hoppe BS, Flampouri S, Su Z, Morris CG, Latif N, Dang NH, et al. Consolidative Involved-Node Proton Therapy for Stage IA-IIIB Mediastinal Hodgkin Lymphoma: Preliminary Dosimetric Outcomes From a Phase II Study [Internet]. International Journal of Radiation Oncology*Biology*Physics2012;83(1):260–7. Available from: http://dx.doi.org/10.1016/j.ijrobp.2011.06.1959
Maraldo MV, Specht L. A Decade of Comparative Dose Planning Studies for Early-Stage Hodgkin Lymphoma: What Can We Learn? [Internet]. International Journal of Radiation Oncology*Biology*Physics2014;90(5):1126–35. Available from: http://dx.doi.org/10.1016/j.ijrobp.2014.06.069
Aznar MC, Maraldo MV, Schut DA, Lundemann M, Brodin NP, Vogelius IR, et al. Minimizing Late Effects for Patients With Mediastinal Hodgkin Lymphoma: Deep Inspiration Breath-Hold, IMRT, or Both? [Internet]. International Journal of Radiation Oncology*Biology*Physics2015;92(1):169–74. Available from: http://dx.doi.org/10.1016/j.ijrobp.2015.01.013
Petersen P, Aznar M, Berthelsen A, Loft A, Schut D, Maraldo M, et al. Prospective phase II trial of image-guided radiotherapy in Hodgkin lymphoma: benefit of deep inspiration breath-hold. Acta Oncol 2015;54(1):60–6. [PubMed]
Chen T, Reyhan M, Yue N, Metaxas D, Haffty B, Goyal S. Tagged MRI based cardiac motion modeling and toxicity evaluation in breast cancer radiotherapy. Front Oncol 2015;5:9. [PubMed]
Tuohinen S, Skyttä T, Huhtala H, Virtanen V, Virtanen M, Kellokumpu-Lehtinen P, et al. Detection of early radiotherapy-induced changes in intrinsic myocardial contractility by ultrasound tissue characterization in patients with early-stage breast cancer. Echocardiography 2017;34(2):191–8. [PubMed]
Thavendiranathan P, Poulin F, Lim K, Plana J, Woo A, Marwick T. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 2014;63(25 Pt A):2751–68. [PubMed]
Skyttä T, Tuohinen S, Boman E, Virtanen V, Raatikainen P, Kellokumpu-Lehtinen P. Troponin T-release associates with cardiac radiation doses during adjuvant left-sided breast cancer radiotherapy. Radiat Oncol 2015;10:141. [PubMed]
D’Errico MP, Grimaldi L, Petruzzelli MF, Gianicolo EAL, Tramacere F, Monetti A, et al. N-Terminal Pro-B–Type Natriuretic Peptide Plasma Levels as a Potential Biomarker for Cardiac Damage After Radiotherapy in Patients With Left-Sided Breast Cancer [Internet]. International Journal of Radiation Oncology*Biology*Physics2012;82(2):e239–46. Available from: http://dx.doi.org/10.1016/j.ijrobp.2011.03.058
Creemers EE, Tijsen AJ, Pinto YM. Circulating MicroRNAs: Novel Biomarkers and Extracellular Communicators in Cardiovascular Disease? [Internet]. Circulation Research2012;110(3):483–95. Available from: http://dx.doi.org/10.1161/CIRCRESAHA.111.247452 [Source]
Ito T, Ikeda U. Inflammatory Cytokines and Cardiovascular Disease [Internet]. CDTIA2003;2(3):257–65. Available from: http://dx.doi.org/10.2174/1568010033484106
Tian S, Hirshfield KM, Jabbour SK, Toppmeyer D, Haffty BG, Khan AJ, et al. Serum Biomarkers for the Detection of Cardiac Toxicity after Chemotherapy and Radiation Therapy in Breast Cancer Patients [Internet]. Front. Oncol.2014;4. Available from: http://dx.doi.org/10.3389/fonc.2014.00277
Jacob S, Pathak A, Franck D, Latorzeff I, Jimenez G, Fondard O, et al. Early detection and prediction of cardiotoxicity after radiation therapy for breast cancer: the BACCARAT prospective cohort study [Internet]. Radiat Oncol2016;11(1). Available from: http://dx.doi.org/10.1186/s13014-016-0627-5
Picano E. Informed consent and communication of risk from radiological and nuclear medicine examinations: how to escape from a communication inferno. BMJ 2004;329(7470):849–51. [PubMed]