We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Radiation-induced coronary artery disease during immune checkpoint inhibitor therapy: a case report

    Xiajing Qian

    Department of Radiation Oncology, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, 315040, China

    ,
    Kequan Ding

    Department of Cardiology, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, 315040, China

    &
    Yi Lu

    *Author for correspondence:

    E-mail Address: 37263205@qq.com

    Department of Radiation Oncology, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, 315040, China

    Published Online:https://doi.org/10.2217/imt-2023-0084

    Radiation-induced coronary artery disease (RICAD) poses a serious concern for cancer patients post radiotherapy, typically emerging after over a decade. Immune checkpoint inhibitors (ICIs), known for cardiotoxicity, are increasingly recognized for causing cardiovascular complications. Here we report the case of a 63-year-old man with metastatic lung cancer who developed coronary artery disease during his third-line therapy with an ICI (nivolumab) and an antiangiogenic agent (bevacizumab), 3 years post chest radiotherapy. Angiography revealed relatively isolated stenosis in the left main coronary artery ostium, consistent with the radiotherapy site, with no other risk factors, suggesting RICAD. The potential for ICIs to accelerate RICAD development should be considered and necessitates careful surveillance in patients receiving both radiotherapy and ICIs.

    Plain language summary

    Sometimes cancer patients receive a type of treatment called radiotherapy, which uses high-energy beams to target the cancer. This treatment is very helpful, but when applied to the chest, it can cause problems in the blood vessels of the heart many years later, a condition called radiation-induced heart disease. This report is about a 63-year-old man who developed this heart problem much sooner than usual, just 3 years after receiving radiation treatment for lung cancer. Alongside radiotherapy, he also received two advanced kinds of cancer treatments. One helped his immune system to better identify and fight the cancer, and the other worked to stop the cancer from getting the blood supply it needs to grow. Our report suggests that these new treatments may interact with radiotherapy in a way that causes heart problems more quickly. This is especially important to consider in patients without previous heart problems. Our findings remind doctors to closely monitor the heart health of patients receiving these treatments and point to the need for more research into how these treatments may affect the heart when used together.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Ravenholt RT. California chiropractors. An epidemiological study of causes of death among them and other characteristics. Calif. Med. 101(5), 341–347 (1964).
    • 2. Donnellan E, Phelan D, McCarthy CP, Collier P, Desai M, Griffin B. Radiation-induced heart disease: a practical guide to diagnosis and management. Cleve. Clin. J. Med. 83(12), 914–922 (2016).
    • 3. Fajardo LF, Stewart JR. Experimental radiation-induced heart disease. I. Light microscopic studies. Am. J. Pathol. 59(2), 299–316 (1970).
    • 4. Pedersen LN, Schiffer W, Mitchell JD, Bergom C. Radiation-induced cardiac dysfunction: practical implications. Kardiol. Pol. 80(3), 256–265 (2022).
    • 5. Garg A, Kumar P. Dosimetric comparison of the heart and left anterior descending artery in patients with left breast cancer treated with three-dimensional conformal and intensity-modulated radiotherapy. Cureus 14(1), e21108 (2022).
    • 6. Pezner RD. Coronary artery disease and breast radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 86(5), 816–818 (2013).
    • 7. Darby SC, Ewertz M, Mcgale P et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N. Engl. J. Med. 368(11), 987–998 (2013). •• These publications furnish a detailed perspective for cardio-oncology and cardiology professionals, framing the management challenges and strategies against the backdrop of a modern understanding of radiation therapy’s impact on cardiac health. They underscore the need to navigate patient care with a nuanced appreciation of the potential or actual cardiac complications arising from such treatments.
    • 8. Lancellotti P, Nkomo VT, Badano LP et al. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J. Am. Soc. Echocardiogr. 26(9), 1013–1032 (2013).
    • 9. Atkins KM, Bitterman DS, Chaunzwa TL et al. Mean heart dose is an inadequate surrogate for left anterior descending coronary artery dose and the risk of major adverse cardiac events in lung cancer radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 110(5), 1473–1479 (2021). •• These publications presented the correlation of left anterior descending coronary artery dose and the risk of major adverse cardiac events, serving as the landmarks in cardio-oncology for lung cancer radiation therapy.
    • 10. Atkins KM, Rawal B, Chaunzwa TL et al. Cardiac radiation dose, cardiac disease, and mortality in patients with lung cancer. J. Am. Coll. Cardiol. 73(23), 2976–2987 (2019).
    • 11. van Nimwegen FA, Schaapveld M, Cutter DJ et al. Radiation Dose-Response Relationship for Risk of Coronary Heart Disease in Survivors of Hodgkin Lymphoma. J. Clin. Oncol. 34(3), 235–43 (2016).
    • 12. Van Nimwegen FA, Schaapveld M, Janus CP et al. Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk. JAMA Intern. Med. 175(6), 1007–1017 (2015).
    • 13. Al-Kindi SG, Oliveira GH. Prevalence of preexisting cardiovascular disease in patients with different types of cancer: the unmet need for onco-cardiology. Mayo Clin. Proc. 91(1), 81–83 (2016).
    • 14. Atkins KM, Chaunzwa TL, Lamba N et al. Association of left anterior descending coronary artery radiation dose with major adverse cardiac events and mortality in patients with non-small cell lung cancer. JAMA Oncol. 7(2), 206–219 (2021). •• These publications presented the correlation of left anterior descending coronary artery dose and the risk of major adverse cardiac events, serving as the landmarks in cardio-oncology for lung cancer radiation therapy.
    • 15. Zhang Z, Liu X, Chen D, Yu J. Radiotherapy combined with immunotherapy: the dawn of cancer treatment. Signal Transduct. Target. Ther. 7(1), 258 (2022).
    • 16. Du S, Zhou L, Alexander GS et al. PD-1 modulates radiation-induced cardiac toxicity through cytotoxic T lymphocytes. J. Thorac. Oncol. 13(4), 510–520 (2018).
    • 17. Yegya-Raman N, Lee SH, Friedes C et al. Cardiac radiation dose is associated with inferior survival but not cardiac events in patients with locally advanced non-small cell lung cancer in the era of immune checkpoint inhibitor consolidation. Radiother. Oncol. 190, 110005 (2024).
    • 18. Lyon AR, López-Fernández T, Couch LS et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur. Heart J. Cardiovasc. Imaging 23(10), e333–e465 (2022).
    • 19. Saro H, Armenian et al. Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. JCO 35, 893–911 (2017).
    • 20. Lyon AR, Yousaf N, Battisti NML, Moslehi J, Larkin J. Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol. 19(9), e447–e458 (2018).
    • 21. Chang HM, Moudgil R, Scarabelli T, Okwuosa TM, Yeh ETH. Cardiovascular complications of cancer therapy: best practices in diagnosis, prevention, and management: part 1. J. Am. Coll. Cardiol. 70(20), 2536–2551 (2017).
    • 22. Virmani R, Farb A, Carter AJ, Jones RM. Comparative pathology: radiation-induced coronary artery disease in man and animals. Semin. Interv. Cardiol. 3(3–4), 163–172 (1998).
    • 23. Jaworski C, Mariani JA, Wheeler G, Kaye DM. Cardiac complications of thoracic irradiation. J. Am. Coll. Cardiol. 61(23), 2319–2328 (2013).
    • 24. Balanescu DV, Donisan T, Dayah T et al. Refractory radiation-induced coronary artery disease: mapping the path and guiding treatment with optical coherence tomography. Int. J. Cardiovasc. Imaging 35(5), 759–760 (2019).
    • 25. Hussey P, Wu I, Johnston T. 2018 ACC/HRS/NASCI/SCAI/SCCT expert consensus document on optimal use of ionizing radiation in cardiovascular imaging: best practices for safety and effectiveness – a review for the cardiac anesthesiologist. J. Cardiothorac. Vasc. Anesth. 33(11), 2902–2908 (2019).
    • 26. Venkatesulu BP, Mahadevan LS, Aliru ML et al. Radiation-induced endothelial vascular injury: a review of possible mechanisms. JACC Basic Transl. Sci. 3(4), 563–572 (2018).
    • 27. Cuomo JR, Javaheri SP, Sharma GK, Kapoor D, Berman AE, Weintraub NL. How to prevent and manage radiation-induced coronary artery disease. Heart 104(20), 1647–1653 (2018).
    • 28. Orzan F, Brusca A, Conte MR, Presbitero P, Figliomeni MC. Severe coronary artery disease after radiation therapy of the chest and mediastinum: clinical presentation and treatment. Br. Heart J. 69(6), 496–500 (1993).
    • 29. Om A, Vetrovec GW. Coronary angioplasty of radiation-induced stenosis. Am. Heart J. 125(4), 1164–1166 (1993).
    • 30. McEniery PT, Dorosti K, Schiavone WA, Pedrick TJ, Sheldon WC. Clinical and angiographic features of coronary artery disease after chest irradiation. Am. J. Cardiol. 60(13), 1020–1024 (1987).
    • 31. Ruiz CR, Mesa-Pabón M, Soto K, Román JH, López-Candales A. Radiation-induced coronary artery disease in young patients. Heart Views 19(1), 23–26 (2018).
    • 32. Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI Guideline for percutaneous coronary intervention: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc. Interv. 79(3), 453–495 (2012).
    • 33. Gaya AM, Ashford RF. Cardiac complications of radiation therapy. Clin. Oncol. (R. Coll. Radiol.) 17(3), 153–159 (2005).
    • 34. Dezorzi C. Radiation-induced coronary artery disease and its treatment: a quick review of current evidence. Cardiol. Res. Pract. 2018, 8367268 (2018). •• These publications furnish a detailed perspective for cardio-oncology and cardiology professionals, framing the management challenges and strategies against the backdrop of a modern understanding of radiation therapy’s impact on cardiac health. They underscore the need to navigate patient care with a nuanced appreciation of the potential or actual cardiac complications arising from such treatments.
    • 35. Darby SC, Cutter DJ, Boerma M et al. Radiation-related heart disease: current knowledge and future prospects. Int. J. Radiat. Oncol. Biol. Phys. 76(3), 656–665 (2010).
    • 36. Bradley JD, Hu C, Komaki RR et al. Long-term results of NRG oncology RTOG 0617: standard-versus high-dose chemoradiotherapy with or without cetuximab for unresectable stage III non-small-cell lung cancer. J. Clin. Oncol. 38(7), 706 (2020).
    • 37. Lee SH, Geng H, Arnold J et al. Interpretable Machine Learning for Choosing Radiation Dose-volume Constraints on Cardio-pulmonary Substructures Associated with Overall Survival in NRG Oncology RTOG 0617. Int. J. Radiat. Oncol. Biol. Phys. 117(5), 1270–1286 (2023).
    • 38. Demirci S, Nam J, Hubbs JL, Nguyen T, Marks LB. Radiation-induced cardiac toxicity after therapy for breast cancer: interaction between treatment era and follow-up duration. Int. J. Radiat. Oncol. Biol. Phys. 73(4), 980–987 (2009).
    • 39. Rehammar JC, Jensen MB, McGale P et al. Risk of heart disease in relation to radiotherapy and chemotherapy with anthracyclines among 19,464 breast cancer patients in Denmark, 1977–2005. Radiother. Oncol. 123(2), 299–305 (2017).
    • 40. Yeboa DN, Evans SB. Contemporary breast radiotherapy and cardiac toxicity. Semin. Radiat. Oncol. 26(1), 71–78 (2016).
    • 41. Marks LB, Yorke ED, Jackson A et al. Use of normal tissue complication probability models in the clinic. Int. J. Radiat. Oncol. Biol. Phys. 76(Suppl. 3), S10–S19 (2010).
    • 42. Brown KN, Hussain K, Richards JR. Radiation induced coronary artery disease. In: StatPearls. StatPearls Publishing, FL, USA (2022).
    • 43. Task Force Members, Montalescot G, Sechtem U et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur. Heart J. 34(38), 2949–3003 (2013).
    • 44. Visseren FLJ, Mach F, Smulders YM et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur. Heart J. 42(34), 3227–3337 (2021).
    • 45. Wei J, Xu H, Liu Y, Li B, Zhou F. Effect of captopril on radiation-induced TGF-β1 secretion in EA.Hy926 human umbilical vein endothelial cells. Oncotarget 8(13), 20842–20850 (2017).
    • 46. Wilkinson EL, Sidaway JE, Cross MJ. Statin regulated ERK5 stimulates tight junction formation and reduces permeability in human cardiac endothelial cells. J. Cell. Physiol. 233(1), 186–200 (2018).
    • 47. O’Herron T, Lafferty J. Prophylactic use of colchicine in preventing radiation induced coronary artery disease. Med. Hypotheses 111, 58–60 (2018).
    • 48. Annest LS, Anderson RP, Li W, Hafermann MD. Coronary artery disease following mediastinal radiation therapy. J. Thorac. Cardiovasc. Surg. 85(2), 257–263 (1983).
    • 49. Veeragandham RS, Goldin MD. Surgical management of radiation-induced heart disease. Ann. Thorac. Surg. 65(4), 1014–1019 (1998).
    • 50. Schömig K, Ndrepepa G, Mehilli J, Pache J, Kastrati A, Schömig A. Thoracic radiotherapy in patients with lymphoma and restenosis after coronary stent placement. Catheter Cardiovasc. Interv. 70(3), 359–365 (2007).
    • 51. Caio G. Myocarditis with immune checkpoint blockade. N. Engl. J. Med. 376(3), 291–292 (2017).
    • 52. Johnson DB, Balko JM, Compton ML et al. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 375(18), 1749–1755 (2016).
    • 53. Grabie N, Lichtman AH, Padera R. T cell checkpoint regulators in the heart. Cardiovasc. Res. 115(5), 869–877 (2019).
    • 54. Wang WX, Song ZZ, Zhang YP. Cardiovascular toxicities associated with immune checkpoint inhibitors. Zhonghua Zhong Liu Za Zhi 42(7), 609–613 (2020).
    • 55. Grabie N, Gotsman I, Dacosta R et al. Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell mediated injury in the heart. Circulation 116(18), 2062–2071 (2007).
    • 56. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 473(7347), 317–325 (2011).
    • 57. Zhao TX, Mallat Z. Targeting the immune system in atherosclerosis: JACC state-of-the-art review. J. Am. Coll. Cardiol. 73(13), 1691–1706 (2019).
    • 58. Bu DX, Tarrio M, Maganto-Garcia E et al. Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation. Arterioscler. Thromb. Vasc. Biol. 31(5), 1100–1107 (2011).
    • 59. Foks AC, Kuiper J. Immune checkpoint proteins: exploring their therapeutic potential to regulate atherosclerosis. Br. J. Pharmacol. 174(22), 3940–3955 (2017).
    • 60. Gelsomino F, Fiorentino M, Zompatori M et al. Programmed death-1 inhibition and atherosclerosis: can nivolumab vanish complicated atheromatous plaques? Ann. Oncol. 29(1), 284–286 (2018). •• These studies highlight the risk of acute coronary syndrome associated with the use of nivolumab, prompting a valid concern that prior or concurrent use of nivolumab following thoracic radiotherapy may precipitate the early onset of radiation-induced coronary artery disease. Hence, as cancer therapies evolve, it is imperative that our comprehension of their potential cardiovascular impacts advances accordingly.
    • 61. Cautela J, Rouby F, Salem JE et al. Acute coronary syndrome with immune checkpoint inhibitors: a proof-of-concept case and pharmacovigilance analysis of a life-threatening adverse event. Can. J. Cardiol. 36(4), 476–481 (2020). •• These studies highlight the risk of acute coronary syndrome associated with the use of nivolumab, prompting a valid concern that prior or concurrent use of nivolumab following thoracic radiotherapy may precipitate the early onset of radiation-induced coronary artery disease. Hence, as cancer therapies evolve, it is imperative that our comprehension of their potential cardiovascular impacts advances accordingly.
    • 62. Son C, Moey MYY, Walker PR, Naqash AR, Peach MS, Ju AW. Cardiac toxicity in patients with lung cancer receiving thoracic radiotherapy and immunotherapy. Front. Oncol. 12, 1025455 (2022).
    • 63. Calabretta R, Hoeller C, Pichler V et al. Immune checkpoint inhibitor therapy induces inflammatory activity in large arteries. Circulation 142(24), 2396–2398 (2020).
    • 64. Newman JL, Stone JR. Immune checkpoint inhibition alters the inflammatory cell composition of human coronary artery atherosclerosis. Cardiovasc. Pathol. 43, 107148 (2019).
    • 65. Drobni ZD, Alvi RM, Taron J et al. Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque. Circulation 142(24), 2299–2311 (2020).
    • 66. Cheng Y, Nie L, Ma W, Zheng B. Early onset acute coronary artery occlusion after pembrolizumab in advanced non-small cell lung cancer: a case report. Cardiovasc. Toxicol. 21(8), 683–686 (2021).
    • 67. Antonia SJ, Villegas A, Daniel D et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 377(20), 1919–1929 (2017).
    • 68. Jabbour SK, Lee KH, Frost N et al. Pembrolizumab plus concurrent chemoradiation therapy in patients with unresectable, locally advanced, stage III non-small cell lung cancer: the phase 2 KEYNOTE-799 nonrandomized trial. JAMA Oncol. 7(9), 1–9 (2021).