Skip to main content

Advertisement

SpringerLink
Log in

Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Aim: 5-Fluorouracil (5-FU) and its prodrug capecitabine are cardiotoxic. This retrospective study aimed to identify risk factors and to give practical measures to make such chemotherapy feasible if cardiotoxicity occur. Method: Review of cardiotoxicity among 668 patients treated with 5-FU or capecitabine for gastrointestinal cancers. Results: Cardiotoxicity occurred in 29 cases (4.3%). The number of cases according to cardiotoxicity CTC grades 2–4 for patients with and without pre-existing cardiovascular disease were none, 10, and 2 cases, and 3, 14, and no cases, respectively (P=0.16). In three patients intercurrent decrease of renal clearances to <30, 48 and 71 ml min-1 led to markedly increased cardiotoxicity. Chemotherapy dose reduction to 70 or 50%, either alone or in addition to antiangina medication prevented cardiotoxicity during subsequent chemotherapy in nine (60%) and three (20%) cases out of 15 assessable patients (P=0.001), respectively. To abolish symptoms of cardiotoxicity, sublingual nitroglycerine was efficient for 15 patients and inefficient for two (P=0.001). Conclusion: Cardiac and renal co-morbidity are risk factors for 5-FU induced cardiotoxicity. In this situation, rechallenge with modified 5-FU-based chemotherapy regimen supported by symptomatic medical treatment is feasible.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Wacker A, Lersch C, Scherpinski U, Reindl L, Seyfarth M (2003) High incidence of angina pectoris in patients treated with 5-fluorouracil. A planned surveillance study with 102 patients. Oncology 65:108–112

    Article  PubMed  CAS  Google Scholar 

  2. Tsavaris N, Kosmas C, Vadiaka M, Efremidis M, Zinelis A, Beldecos D, Sakelariou D, Koufos C, Stamatelos G (2002) Cardiotoxicity following different doses and schedules of 5-fluorouracil administration for malignancy—a survey of 427 patients. Med Sci Monit 8:I51–I57

    Google Scholar 

  3. Keefe DL, Roistacher N, Pierri MK (1993) Clinical cardiotoxicity of 5-fluorouracil. J Clin Pharmacol 33:1060–1070

    PubMed  CAS  Google Scholar 

  4. Schober C, Papageorgiou E, Harstrick A, Bokemeyer C, Mugge A, Stahl M, Wilke H, Poliwoda H, Hiddemann W, Kohne-Wompner CH (1993) Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer. Cancer 72:2242–2247

    Article  PubMed  CAS  Google Scholar 

  5. Labianca R, Beretta G, Clerici M, Fraschini P, Luporini G (1982) Cardiac toxicity of 5-fluorouracil: a study on 1083 patients. Tumor 68:505–510

    CAS  Google Scholar 

  6. Robben NC, Pippas AW, Moore JO (1993) The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy. Cancer 71:493–509

    Article  PubMed  CAS  Google Scholar 

  7. De Forni M, Malet-Martino MC, Jaillais P, Shubinski RE, Bachaud JM, Lemaire L, Canal P, Chevreau C, Carrie D, Soulie P (1992) Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol 10:1795–1801

    PubMed  Google Scholar 

  8. Jeremic B, Jevremovic S, Djuric L, Mijatovic L (1990) Cardiotoxicity during chemotherapy treatment with 5-fluorouracil and cisplatin. J Chemother 2:264–267

    PubMed  CAS  Google Scholar 

  9. Akhtar SS, Salim KP, Bano ZA (1993) Symptomatic cardiotoxicity with high-dose 5-fluorouracil infusion: a prospective study. Oncology 50:441–444

    Article  PubMed  CAS  Google Scholar 

  10. Mosseri M, Fingert HJ, Varticovski L, Chokshi S, Isner JM (1993) 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 53:3028–3033

    PubMed  CAS  Google Scholar 

  11. Porta C, Moroni M, Ferrari S, Nastasi G (1998) Endothelin-1 and 5-fluorouracil-induced cardiotoxicity. Neoplasma 45:81–82

    PubMed  CAS  Google Scholar 

  12. Kohne CH, Thuss-Patience P, Friedrich M, Daniel PT, Kretzschmar A, Benter T, Bauer B, Dietz R, Dorken B (1998) Raltitrexed (Tomudex): an alternative drug for patients with colorectal cancer and 5-fluorouracil associated cardiotoxicity. Br J Cancer 77:973–977

    PubMed  CAS  Google Scholar 

  13. Kuzel T, Esparaz B, Green D, Kies M (1990) Thrombogenicity of intravenous 5-fluorouracil alone or in combination with cisplatin. Cancer 65:885–889

    Article  PubMed  CAS  Google Scholar 

  14. Matsubara I, Kamiya J, Imai S (1980) Cardiotoxic effects of 5-fluorouracil in the guinea pig. Jpn J Pharmacol 30:871–879

    Article  PubMed  CAS  Google Scholar 

  15. Lemaire L, Malet-Martino MC, Longo S, Martino R, De Forni M, Carton M (1991) Fluoroacetaldehyde as cardiotoxic impurity in fluorouracil (Roche). Lancet 337:560

    Article  PubMed  CAS  Google Scholar 

  16. Burger AJ, Mannino S (1987) 5-Fluorouracil-induced coronary vasospasm. Am Heart J 114:433–436

    Article  PubMed  CAS  Google Scholar 

  17. Mizuno Y, Hokamura Y, Kimura T, Kimura Y, Kaikita K, Yasue H (1995) A case of 5-fluorouracil cardiotoxicity simulating acute myocardial infarction. Jpn Circ J 59:303–307

    PubMed  CAS  Google Scholar 

  18. Eskilsson J, Albertsson M (1990) Failure of preventing 5-fluorouracil cardiotoxicity by prophylactic treatment with verapamil. Acta Oncol 29:1001–1003

    Article  PubMed  CAS  Google Scholar 

  19. Diasio RB, Harris BE (1989) Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 16:215–237

    Article  PubMed  CAS  Google Scholar 

  20. Eskilsson J, Albertsson M, Mercke C (1988) Adverse cardiac effects during induction chemotherapy treatment with cis-platin and 5-fluorouracil. Radiother Oncol 13:41–46

    Article  PubMed  CAS  Google Scholar 

  21. Rezkalla S, Kloner RA, Ensley J, al Sarraf M, Revels S, Olivenstein A, Bhasin S, Kerpel-Fronious S, Turi ZG (1989) Continuous ambulatory ECG monitoring during fluorouracil therapy: a prospective study. J Clin Oncol 7:509–514

    PubMed  CAS  Google Scholar 

  22. Lestuzzi C, Viel E, Picano E, Meneguzzo N (2001) Coronary vasospasm as a cause of effort-related myocardial ischemia during low-dose chronic continuous infusion of 5-fluorouracil. Am J Med 111:316–318

    Article  PubMed  CAS  Google Scholar 

  23. McDermott BJ, van den Berg HW, Murphy RF (1982) Nonlinear pharmacokinetics for the elimination of 5-fluorouracil after intravenous administration in cancer patients. Cancer Chemother Pharmacol 9:173–178

    Article  PubMed  CAS  Google Scholar 

  24. Lee JS, Dhingra HM, Chiuten DF, Holoye PY, Jeffries D, Murphy WK, Umsawasdi T, Neidhart JA (1987) Phase II pilot study with cisplatin, etoposide, and continuous-infusion 5-fluorouracil in metastatic non-small cell lung cancer. Am J Clin Oncol 10:512–514

    Article  PubMed  CAS  Google Scholar 

  25. Martin M, Diaz-Rubio E, Furio V, Blazquez J, Almenarez J, Farina J (1989) Lethal cardiac toxicity after cisplatin and 5-fluorouracil chemotherapy. Report of a case with necropsy study. Am J Clin Oncol 12:229–234

    Article  PubMed  CAS  Google Scholar 

  26. Prevost A, Merol JC, Aime P, Moutel K, Roger-Liautaud F, Nasca S, Legros M, Coninx P (2005) A randomized trial between two neoadjuvant chemotherapy protocols: CDDP + 5-FU versus CDDP + VP16 in advanced cancer of the head and neck. Oncol Rep 14:771–776

    PubMed  CAS  Google Scholar 

  27. Yip D, Karapetis C, Strickland AH, Steer C, Holford C, Knight S, Harper P (2003) A dose-escalating study of oral eniluracil/5-fluorouracil plus oxaliplatin in patients with advanced gastrointestinal malignancies. Ann Oncol 14:864–866

    Article  PubMed  CAS  Google Scholar 

  28. Guo XD, Harold N, Saif MW, Schuler B, Szabo E, Hamilton JM, Monahan BP, Quinn MG, Cliatt J, Nguyen D, Grollman F, Thomas RR, McQuigan EA, Wilson R, Takimoto CH, Grem JL (2003) Pharmacokinetic and pharmacodynamic effects of oral eniluracil, fluorouracil and leucovorin given on a weekly schedule. Cancer Chemother Pharmacol 52:79–85

    Article  PubMed  CAS  Google Scholar 

  29. Marsh JC, Catalano P, Huang J, Graham DL, Cornfeld MJ, O’Dwyer PJ, Benson AB III (2002) 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 2:43–50

    Article  PubMed  CAS  Google Scholar 

  30. van Kuilenburg AB, Meinsma R, Zoetekouw L, van Gennip AH (2002) Increased risk of grade IV neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: high prevalence of the IVS14+1g>a mutation. Int J Cancer 101:253–258

    Article  PubMed  CAS  Google Scholar 

  31. Celik I, Kars A, Guc D, Tekuzman G, Ruacan S (2002) Dihydropyrimidine dehydrogenase enzyme deficiency: clinical and genetic assessment of prevalence in Turkish cancer patients. Cancer Invest 20:333–339

    Article  PubMed  CAS  Google Scholar 

  32. Di Paolo A, Danesi R, Falcone A, Cionini L, Vannozzi F, Masi G, Allegrini G, Mini E, Bocci G, Conte PF, Del Tacca M (2001) Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients. Ann Oncol 12:1301–1306

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Lisa og Gudmund Jørgensens Foundation, P.A.Messerschmidt og hustrus Foundation, fabrikant Einar Willumsens Mindelegat and Dagmar Marshalls Foundation, have supported this study.

Author information

Authors and Affiliations

  1. Department of Oncology 5073, National University Hospital, 9 Blegdamsvej, 2100, Copenhagen, Denmark

    Søren Astrup Jensen & Jens Benn Sørensen

Authors
  1. Søren Astrup Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jens Benn Sørensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Søren Astrup Jensen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jensen, S.A., Sørensen, J.B. Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother Pharmacol 58, 487–493 (2006). https://doi.org/10.1007/s00280-005-0178-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-005-0178-1

Keywords

Search

Navigation