Fluoropyrimidine-induced cardiotoxicity: a review of diagnosis and management_West China Medical Journal

Authors：

CHEN Ye ,  QIU Meng

Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

QIU Meng, Email: qiumeng33@hotmail.com

Keywords：

Fluoropyrimidine; Chemotherapy; Cardiotoxicity

DOI：

10.7507/1002-0179.201804057

Video：

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Fluoropyrimidines have been the standard care as ajuvant or palliative treatment for malignant gastrointestinal carcinoma over several decades. Their common adverse effects include gastrointestinal effects, myelosuppression, and hand-foot syndrome. Besides, fluoropyrimidines are the second cause of chemotherapy-induced cardiotoxicity and have the different manifestation and machanisms from anthracyclines. With the development of onco-cardiology, increasing concern is raised on fluoropyrimidine-induced cardiotoxicity. This review addresses the epidemiology, clinical manifestation, and proposed mechanisms; and also highlights the diagnosis, monitoring and management of fluoropyrimidine-induced cardiotoxicity.

Citation： CHEN Ye, QIU Meng. Fluoropyrimidine-induced cardiotoxicity: a review of diagnosis and management. West China Medical Journal, 2018, 33(4): 463-467. doi: 10.7507/1002-0179.201804057 Copy

1.	Anand AJ. Fluorouracil cardiotoxicity. Ann Pharmacother, 1994, 28(3): 374-378.
2.	Akhtar SS, Salim KP, Bano ZA. Symptomatic cardiotoxicity with high-dose 5-fluorouracil infusion: a prospective study. Oncology, 1993, 50(6): 441-444.
3.	Kosmas C, Kallistratos MS, Kopterides P, et al. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol, 2008, 134(1): 75-82.
4.	Ng M, Cunningham D, Norman AR. The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer (CRC). Eur J Cancer, 2005, 41(11): 1542-1546.
5.	Labianca R, Beretta G, Clerici M, et al. Cardiac toxicity of 5-fluorouracil: a study on 1083 patients. Tumori, 1982, 68(6): 505-510.
6.	Meydan N, Kundak I, Yavuzsen T, et al. Cardiotoxicity of de gramont’s regimen: incidence, clinical characteristics and long-term follow-up. Jpn J Clin Oncol, 2005, 35(5): 265-270.
7.	Jensen SA, Hasbak P, Mortensen J, et al. Fluorouracil induces myocardial ischemia with increases of plasma brain natriuretic peptide and lactic acid but without dysfunction of left ventricle. J Clin Oncol, 2010, 28(36): 5280-5286.
8.	Van Cutsem E, Hoff PM, Blum JL, et al. Incidence of cardiotoxicity with the oral fluoropyrimidine capecitabine is typical of that reported with 5-fluorouracil. Ann Oncol, 2002, 13(3): 484-485.
9.	Saif MW, Tomita M, Ledbetter L, et al. Capecitabine-related cardiotoxicity: recognition and management. J Support Oncol, 2008, 6(1): 41-48.
10.	Polk A, Vaage-Nilsen M, Vistisen K, et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev, 2013, 39(8): 974-984.
11.	Jensen SA, Sørensen JB. 5-Fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity. Cancer Chemother Pharmacol, 2012, 69(1): 57-64.
12.	Jensen SA, Sørensen JB. Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother Pharmacol, 2006, 58(4): 487-493.
13.	Becker K, Erckenbrecht JF, Häussinger D, et al. Cardiotoxicity of the antiproliferative compound fluorouracil. Drugs, 1999, 57(4): 475-484.
14.	Rezkalla S, Kloner RA, Ensley J, et al. Continuous ambulatory ECG monitoring during fluorouracil therapy: a prospective study. J Clin Oncol, 1989, 7(4): 509-514.
15.	Shoemaker LK, Arora U, Rocha Lima CM. 5-Fluorouracil-induced coronary vasospasm. Cancer Control, 2004, 11(1): 46-49.
16.	Südhoff T, Enderle MD, Pahlke M, et al. 5-Fluorouracil induces arterial vasocontractions. Ann Oncol, 2004, 15(4): 661-664.
17.	Mosseri M, Fingert HJ, Varticovski L, et al. In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle. Cancer Res, 1993, 53(13): 3028-3033.
18.	Kinhult S, Albertsson M, Eskilsson J, et al. Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: a scanning microscopy evaluation. Scanning, 2001, 23(1): 1-8.
19.	Lemaire L, Malet-Martino MC, De Forni M, et al. Cardiotoxicity of commercial 5-fluorouracil vials stems from the alkaline hydrolysis of this drug. Br J Cancer, 1992, 66(1): 119-127.
20.	Muneoka K, Shirai Y, Yokoyama N, et al. 5-Fluorouracil cardiotoxicity induced by alpha-fluoro-beta-alanine. Int J Clin Oncol, 2005, 10(6): 441-443.
21.	De Forni M, Malet-Martino MC, Jaillais P, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol, 1992, 10(11): 1795-1801.
22.	Tsibiribi P, Bui-Xuan C, Bui-Xuan B, et al. Cardiac lesions induced by 5-fluorouracil in the rabbit. Hum Exp Toxicol, 2006, 25(6): 305-309.
23.	Meyer CC, Calis KA, Burke LB, et al. Symptomatic cardiotoxicity associated with 5-fluorouracil. Pharmacotherapy, 1997, 17(4): 729-736.
24.	Schöber C, Papageorgiou E, Harstrick A, et al. Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer. Cancer, 1993, 72(7): 2242-2247.
25.	Jeremic B, Jevremovic S, Djuric L, et al. Cardiotoxicity during chemotherapy treatment with 5-fluorouracil and cisplatin. J Chemother, 1990, 2(4): 264-267.
26.	Kuzel T, Esparaz B, Green D, et al. Thrombogenicity of intravenous 5-fluorouracil alone or in combination with cisplatin. Cancer, 1990, 65(4): 885-889.
27.	Lestuzzi C, Vaccher E, Talamini R, et al. Effort myocardial ischemia during chemotherapy with 5-fluorouracil: an underestimated risk. Ann Oncol, 2014, 25(5): 1059-1064.
28.	Khan MA, Masood N, Husain N, et al. A retrospective study of cardiotoxicities induced by 5-fluouracil (5-FU) and 5-FU based chemotherapy regimens in Pakistani adult cancer patients at Shaukat Khanum Memorial Cancer Hospital & Research Center. J Pak Med Assoc, 2012, 62(5): 430-434.
29.	Koca D, Salman T, Unek IT, et al. Clinical and electrocardiography changes in patients treated with capecitabine. Chemotherapy, 2011, 57(5): 381-387.
30.	Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol, 2012, 23(Suppl 7):vii155-vii166.
31.	Cardinale D, Colombo A, Colombo N. Acute coronary syndrome induced by oral capecitabine. Can J Cardiol, 2006, 22(3): 251-253.
32.	Holubec L, Topolcan O, Finek J, et al. Dynamic monitoring of cardio-specific markers and markers of thyroid gland function in cancer patients——a pilot study. Anticancer Res, 2007, 27(4A): 1883-1886.
33.	Eskilsson J, Albertsson M. Failure of preventing 5-fluorouracil cardiotoxicity by prophylactic treatment with verapamil. Acta Oncol, 1990, 29(8): 1001-1003.
34.	Cianci G, Morelli MF, Cannita K, et al. Prophylactic options in patients with 5-fluorouracil-associated cardiotoxicity. Br J Cancer, 2003, 88(10): 1507-1509.
35.	Minotti G. Pharmacology at work for cardio-oncology: ranolazine to treat early cardiotoxicity induced by antitumor drugs. J Pharmacol Exp Ther, 2013, 346(3): 343-349.
36.	Ransom D, Wilson K, Fournier M, et al. Final results of Australasian Gastrointestinal Trials Group Arctic study: an audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines. Ann Oncol, 2014, 25(1): 117-121.
37.	Cerny J, Hassan A, Smith C, et al. Coronary vasospasm with myocardial stunning in a patient with colon cancer receiving adjuvant chemotherapy with FOLFOX regimen. Clin Colorectal Cancer, 2009, 8(1): 55-58.
38.	Yamamoto J, Haruno A, Yoshimura Y, et al. Effect of coadministration of uracil on the toxicity of tegafur. J Pharm Sci, 1984, 73(2): 212-214.
39.	Marsh JC, Catalano P, Huang J, et al. Eastern cooperative oncology group phase Ⅱ trial (E4296) of oral 5-fluorouracil and eniluracil as a 28-day regimen in metastatic colorectal cancer. Clin Colorectal Cancer, 2002, 2(1): 43-50.
40.	Yamada Y, Hamaguchi T, Goto M, et al. Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil. Br J Cancer, 2003, 89(5): 816-820.
41.	Reigner B, Verweij J, Dirix L, et al. Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients. Clin Cancer Res, 1998, 4(4): 941-948.
42.	Oguchi KSK, Kazuno H, Ueno H, et al. TAS-102 treatment results in high trifluridine incorporation into DNA with pyrimidine metabolic pathway markedly up-regulated in cancer. Eur J Cancer, 2014, 50(Suppl 6): 27.
43.	Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med, 2015, 372(20): 1909-1919.

1. Anand AJ. Fluorouracil cardiotoxicity. Ann Pharmacother, 1994, 28(3): 374-378.
2. Akhtar SS, Salim KP, Bano ZA. Symptomatic cardiotoxicity with high-dose 5-fluorouracil infusion: a prospective study. Oncology, 1993, 50(6): 441-444.
3. Kosmas C, Kallistratos MS, Kopterides P, et al. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol, 2008, 134(1): 75-82.
4. Ng M, Cunningham D, Norman AR. The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer (CRC). Eur J Cancer, 2005, 41(11): 1542-1546.
5. Labianca R, Beretta G, Clerici M, et al. Cardiac toxicity of 5-fluorouracil: a study on 1083 patients. Tumori, 1982, 68(6): 505-510.
6. Meydan N, Kundak I, Yavuzsen T, et al. Cardiotoxicity of de gramont’s regimen: incidence, clinical characteristics and long-term follow-up. Jpn J Clin Oncol, 2005, 35(5): 265-270.
7. Jensen SA, Hasbak P, Mortensen J, et al. Fluorouracil induces myocardial ischemia with increases of plasma brain natriuretic peptide and lactic acid but without dysfunction of left ventricle. J Clin Oncol, 2010, 28(36): 5280-5286.
8. Van Cutsem E, Hoff PM, Blum JL, et al. Incidence of cardiotoxicity with the oral fluoropyrimidine capecitabine is typical of that reported with 5-fluorouracil. Ann Oncol, 2002, 13(3): 484-485.
9. Saif MW, Tomita M, Ledbetter L, et al. Capecitabine-related cardiotoxicity: recognition and management. J Support Oncol, 2008, 6(1): 41-48.
10. Polk A, Vaage-Nilsen M, Vistisen K, et al. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev, 2013, 39(8): 974-984.
11. Jensen SA, Sørensen JB. 5-Fluorouracil-based therapy induces endovascular injury having potential significance to development of clinically overt cardiotoxicity. Cancer Chemother Pharmacol, 2012, 69(1): 57-64.
12. Jensen SA, Sørensen JB. Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother Pharmacol, 2006, 58(4): 487-493.
13. Becker K, Erckenbrecht JF, Häussinger D, et al. Cardiotoxicity of the antiproliferative compound fluorouracil. Drugs, 1999, 57(4): 475-484.
14. Rezkalla S, Kloner RA, Ensley J, et al. Continuous ambulatory ECG monitoring during fluorouracil therapy: a prospective study. J Clin Oncol, 1989, 7(4): 509-514.
15. Shoemaker LK, Arora U, Rocha Lima CM. 5-Fluorouracil-induced coronary vasospasm. Cancer Control, 2004, 11(1): 46-49.
16. Südhoff T, Enderle MD, Pahlke M, et al. 5-Fluorouracil induces arterial vasocontractions. Ann Oncol, 2004, 15(4): 661-664.
17. Mosseri M, Fingert HJ, Varticovski L, et al. In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle. Cancer Res, 1993, 53(13): 3028-3033.
18. Kinhult S, Albertsson M, Eskilsson J, et al. Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: a scanning microscopy evaluation. Scanning, 2001, 23(1): 1-8.
19. Lemaire L, Malet-Martino MC, De Forni M, et al. Cardiotoxicity of commercial 5-fluorouracil vials stems from the alkaline hydrolysis of this drug. Br J Cancer, 1992, 66(1): 119-127.
20. Muneoka K, Shirai Y, Yokoyama N, et al. 5-Fluorouracil cardiotoxicity induced by alpha-fluoro-beta-alanine. Int J Clin Oncol, 2005, 10(6): 441-443.
21. De Forni M, Malet-Martino MC, Jaillais P, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol, 1992, 10(11): 1795-1801.
22. Tsibiribi P, Bui-Xuan C, Bui-Xuan B, et al. Cardiac lesions induced by 5-fluorouracil in the rabbit. Hum Exp Toxicol, 2006, 25(6): 305-309.
23. Meyer CC, Calis KA, Burke LB, et al. Symptomatic cardiotoxicity associated with 5-fluorouracil. Pharmacotherapy, 1997, 17(4): 729-736.
24. Schöber C, Papageorgiou E, Harstrick A, et al. Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer. Cancer, 1993, 72(7): 2242-2247.
25. Jeremic B, Jevremovic S, Djuric L, et al. Cardiotoxicity during chemotherapy treatment with 5-fluorouracil and cisplatin. J Chemother, 1990, 2(4): 264-267.
26. Kuzel T, Esparaz B, Green D, et al. Thrombogenicity of intravenous 5-fluorouracil alone or in combination with cisplatin. Cancer, 1990, 65(4): 885-889.
27. Lestuzzi C, Vaccher E, Talamini R, et al. Effort myocardial ischemia during chemotherapy with 5-fluorouracil: an underestimated risk. Ann Oncol, 2014, 25(5): 1059-1064.
28. Khan MA, Masood N, Husain N, et al. A retrospective study of cardiotoxicities induced by 5-fluouracil (5-FU) and 5-FU based chemotherapy regimens in Pakistani adult cancer patients at Shaukat Khanum Memorial Cancer Hospital & Research Center. J Pak Med Assoc, 2012, 62(5): 430-434.
29. Koca D, Salman T, Unek IT, et al. Clinical and electrocardiography changes in patients treated with capecitabine. Chemotherapy, 2011, 57(5): 381-387.
30. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol, 2012, 23(Suppl 7):vii155-vii166.
31. Cardinale D, Colombo A, Colombo N. Acute coronary syndrome induced by oral capecitabine. Can J Cardiol, 2006, 22(3): 251-253.
32. Holubec L, Topolcan O, Finek J, et al. Dynamic monitoring of cardio-specific markers and markers of thyroid gland function in cancer patients——a pilot study. Anticancer Res, 2007, 27(4A): 1883-1886.
33. Eskilsson J, Albertsson M. Failure of preventing 5-fluorouracil cardiotoxicity by prophylactic treatment with verapamil. Acta Oncol, 1990, 29(8): 1001-1003.
34. Cianci G, Morelli MF, Cannita K, et al. Prophylactic options in patients with 5-fluorouracil-associated cardiotoxicity. Br J Cancer, 2003, 88(10): 1507-1509.
35. Minotti G. Pharmacology at work for cardio-oncology: ranolazine to treat early cardiotoxicity induced by antitumor drugs. J Pharmacol Exp Ther, 2013, 346(3): 343-349.
36. Ransom D, Wilson K, Fournier M, et al. Final results of Australasian Gastrointestinal Trials Group Arctic study: an audit of raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines. Ann Oncol, 2014, 25(1): 117-121.
37. Cerny J, Hassan A, Smith C, et al. Coronary vasospasm with myocardial stunning in a patient with colon cancer receiving adjuvant chemotherapy with FOLFOX regimen. Clin Colorectal Cancer, 2009, 8(1): 55-58.
38. Yamamoto J, Haruno A, Yoshimura Y, et al. Effect of coadministration of uracil on the toxicity of tegafur. J Pharm Sci, 1984, 73(2): 212-214.
39. Marsh JC, Catalano P, Huang J, et al. Eastern cooperative oncology group phase Ⅱ trial (E4296) of oral 5-fluorouracil and eniluracil as a 28-day regimen in metastatic colorectal cancer. Clin Colorectal Cancer, 2002, 2(1): 43-50.
40. Yamada Y, Hamaguchi T, Goto M, et al. Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil. Br J Cancer, 2003, 89(5): 816-820.
41. Reigner B, Verweij J, Dirix L, et al. Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients. Clin Cancer Res, 1998, 4(4): 941-948.
42. Oguchi KSK, Kazuno H, Ueno H, et al. TAS-102 treatment results in high trifluridine incorporation into DNA with pyrimidine metabolic pathway markedly up-regulated in cancer. Eur J Cancer, 2014, 50(Suppl 6): 27.
43. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med, 2015, 372(20): 1909-1919.

West China Medical Journal

Fluoropyrimidine-induced cardiotoxicity: a review of diagnosis and management

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