Abstract

Undifferentiated carcinoma of the esophagus is a rare, aggressive tumor with no specific treatment guidelines and a poor prognosis. 5-Fluorouracil (5-FU), a key drug in the treatment of gastrointestinal cancer, is known for its rare but serious cardiotoxic effects. Here, we report a case of sudden cardiac death of a 47-yearold male with metastatic undifferentiated esophageal carcinoma following his second cycle of chemotherapy (FOLFOX). The patient developed chest pain and breathlessness after being discharged and was later declared dead on arrival at the hospital. Autopsy revealed myocardial infarction, and histopathology confirmed acute ischemic injury without an underlying coronary artery disease. Immunohistochemistry reaffirmed the undifferentiated carcinoma of the esophagus. This case highlights the fatal cardiotoxic effects of 5-FU, emphasizing the need for cardiac monitoring and considering alternate treatment protocols in high-risk individuals. It also underscores the importance of chemotherapy-induced cardiotoxicity as a differential diagnosis while doing postmortem evaluation of sudden deaths following cancer treatment.

• 1.   Abbas, G., & Krasna, M. (2017). Overview of esophageal cancer. Annals of Cardiothoracic Surgery, 6(2), 131–136. https://doi. org/10.21037/acs.2017.03.03
• 2.   Shiga T, Hiraide M. Cardiotoxicities of 5-Fluorouracil and Other Fluoropyrimidines. Current Treatment Options in Oncology. 2020 Mar 19; 21(4) https://doi.org/10.1007/s11864- 020-0719-1
• 3.   Arnold M, Soerjomataram I, Ferlay J, Forman D. Global incidence of oesophageal cancer by histological subtype in 2012. Gut. 2014 Oct 15; 64(3): 381–7. https://doi.org/10.1136/ gutjnl-2014-308124
• 4.   Abnet, C.C., Arnold, M., & Wei, W.Q. (2018). Epidemiology of Esophageal Squamous Cell Carcinoma. Gastroenterology, 154(2), 360–373. https://doi.org/10.1053/j.gastro.2017.08.023
• 5.   Islami F, Farin Kamangar, Karim Aghcheli, Saman Fahimi, Semnani SH, Taghavi N, et al. Epidemiologic features of upper gastrointestinal tract cancers in Northeastern Iran. 2004 Mar 30; 90(7): 1402–6. https://doi. org/10.1038/sj.bjc.6601737
• 6.   Cook MB, Chow W-H, Devesa SS. Oesophageal cancer incidence in the United States by race, sex, and histologic type, 1977–2005. British Journal of Cancer. 2009 Aug 11; 101(5): 855–9. https://doi.org/10.1038/sj.bjc.6605246
• 7.   Saif M.W., Shah M.M., Shah A.R. Fluoropyrimidine-associated cardiotoxicity: revisited. Expert Opinion on Drug Safety. 2009 Mar; 8(2): 191–202 https://doi. org/10.1517/14740330902733961
• 8.   Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines. (2024). https:// www.uptodate.com/contents/cardiotoxicityof-cancer-chemotherapy-agents-other-thananthracyclines-her2-targeted-agent
• 9.   Kanduri J., More L.A., Godishala A, Asnani A. Fluoropyrimidine-Associated Cardiotoxicity. Cardiology Clinics. 2019 Nov; 37(4): 399–405 https://doi.org/10.1016/j.ccl.2019.07.004
• 10.   Rice T.W., Patil D.T., Blackstone E.H. 8th edition AJCC/UICC staging of cancers of the esophagus and esophagogastric junction: application to clinical practice. Annals of Cardiothoracic Surgery. 2017 Mar; 6(2):119–30. https://doi.org/10.21037/acs.2017.03.14
• 11.   Polk, A., Vaage-Nilsen, M., Vistisen, K., & Nielsen, D.L. (2013). Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. In Cancer Treatment Reviews (Vol. 39, Issue 8, pp. 974–984). https://doi.org/10.1016/j. ctrv.2013.03.005
• 12.   Jain, D., Ahmad, T., Cairo, M., & Aronow, W. (2017). Cardiotoxicity of cancer chemotherapy: Identification, prevention and treatment. Annals of Translational Medicine, 5(17). https://doi.org/10.21037/atm.2017.06.35
• 13.   Shaikh, A.Y., & Shih, J.A. (2012). Chemotherapyinduced cardiotoxicity. Current Heart Failure Reports, 9(2), 117–127. https://doi. org/10.1007/s11897-012-0083-y
• 14.   Singhi, A. D., Seethala, R. R., Nason, K., Foxwell, T. J., Roche, R.L., McGrath, K. M., Levy, R. M., Luketich, J. D., & Davison, J. M. (2015). Undifferentiated carcinoma of the esophagus: A clinicopathological study of 16 cases. Human Pathology, 46(3), 366–375. https://doi. org/10.1016/j.humpath.2014.11.021
• 15.   Kalbakis, K., Kouroussis, C., Kakolyris, S., Mavroudis, D., Souglakos, J., Agelaki, S., Vamvakas, L., Christodoulakis, M., Stylianou, K., & Georgoulias, V. (2001). Salvage chemotherapy with high-dose leucovorin (LV) and 48-hour continuous infusion (CI) of 5-fluorouracil (5-FU) in combination with conventional doses of cyclophosphamide (CPM) in patients with metastatic breast cancer (MBC) pretreated with anthracycline and taxanes. British Journal of Cancer, 85(6), 798– 802. https://doi.org/10.1054/bjoc.2001.2001
• 16.   Sara, J. D., Kaur, J., Khodadadi, R., Rehman, M., Lobo, R., Chakrabarti, S., Herrmann, J., Lerman, A., & Grothey, A. (2018). 5-fluorouracil and cardiotoxicity: a review. In Therapeutic Advances in Medical Oncology (Vol. 10). SAGE Publications Inc. https://doi. org/10.1177/1758835918780140
• 17.   Muneoka, K., Shirai, Y., Yokoyama, N., Wakai, T., & Hatakeyama, K. (2005). 5-Fluorouracil cardiotoxicity induced by alpha-fluoro-betaalanine. International Journal of Clinical Oncology, 10(6), 441–443. https://doi. org/10.1007/s10147-005-0516-7
• 18.   Li, C., Ngorsuraches, S., Chou, C., Chen, L., & Qian, J. (2021). Risk Factors of Fluoropyrimidine Induced Cardiotoxicity among Cancer Patients: A Systematic Review and Meta-analysis. In Critical Reviews in Oncology/Hematology (Vol. 162). Elsevier Ireland Ltd. https://doi. org/10.1016/j.critrevonc.2021.103346

Data Sharing Statement

Funding