Skip to main content

Advertisement

SpringerLink
Log in

Fluoropyrimidine Cardiotoxicity: Incidence, Outcomes, and Safety of Rechallenge

  • Cardio-oncology (JN Upshaw, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Fluoropyrimidine (FDP) chemotherapy regimens used in the treatment of solid tumors such as breast, gastrointestinal, and hepatobiliary malignancies have led to significant survival benefits. However, FDP cardiotoxicity can lead to premature termination of FDP-based chemotherapy treatments. Resuming these crucial therapies after initial FDP cardiotoxicity can be challenging for patients and healthcare providers.

Recent Findings

Symptomatic cardiotoxicity occurs in up to 35% of patients treated with FDP-based chemotherapy. The most common symptom is chest pain, but palpitations, dyspnea, myocardial infarction, cardiogenic shock, and cardiac arrest can also occur. Several large studies have attempted to discern clinical and genetic risk factors in those who develop FDP cardiotoxicity. With cardiac risk factor optimization and aggressive pre-treatment with anti-anginal agents, rechallenging with FDP is possible and allows patients to resume optimal cancer-directed treatment.

Summary

FDP cardiotoxicity remains a poorly understood identity. We highlight several recent publications attempting to define the risk factors associated with developing FDP cardiotoxicity. The management of FDP cardiotoxicity and consideration of rechallenge of FDP-based regimens highlights the importance of a multidisciplinary partnership between oncologists and cardiologists/cardio-oncologists.

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.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. FLUOROURACIL injection [package insert] [Internet]. Spectrum Pharmaceuticals, Inc. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012209s040lbl.pdf.

  2. Capecitabine Food and Drug Administration Label [Internet]. [cited 09/01/2021]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020896s016lbl.pdf.

  3. Upshaw JN, O’Neill A, Carver JR, Dimond EP, Denlinger CS, Kircher SM, et al. Fluoropyrimidine cardiotoxicity: time for a contemporaneous appraisal. Clin Colorectal Cancer. 2019;18(1):44–51.

    Article  PubMed  Google Scholar 

  4. •• Zafar A, Drobni ZD, Mosarla R, Alvi RM, Lei M, Lou UY, et al. The incidence, risk factors, and outcomes with 5-fluorouracil–associated coronary vasospasm. JACC: CardioOncology. 2021;3(1):101–9. A contemporary large single-center retrospective study that sought to address gaps in the incidence and risk factors in those who developed 5-FU vasospasm.

  5. Clasen SC, Ky B, O’Quinn R, Giantonio B, Teitelbaum U, Carver JR. Fluoropyrimidine-induced cardiac toxicity: challenging the current paradigm. J Gastrointest Oncol. 2017;8(6):970–9.

    Article  PubMed  Google Scholar 

  6. •• Padegimas A, Carver JR. How to diagnose and manage patients with fluoropyrimidine-induced chest pain: a single center approach. JACC: CardioOncology. 2020;2(4):650–4. An important clinical approach to address challenges faced in to select and rechallenge patients who experienced FDP coronary vasospasm.

  7. Cheeseman SL, Joel SP, Chester JD, Wilson G, Dent JT, Richards FJ, et al. A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002;87(4):393–9.

    Article  CAS  PubMed  Google Scholar 

  8. Andre T, Louvet C, Maindrault-Goebel F, Couteau C, Mabro M, Lotz JP, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer GERCOR. Eur J Cancer. 1999;35(9):1343–7.

    Article  CAS  PubMed  Google Scholar 

  9. Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nor. J Clin Oncol. 2007;25(13):1670–6.

    Article  CAS  PubMed  Google Scholar 

  10. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.

    Article  CAS  PubMed  Google Scholar 

  11. • Khorana AA, Mckernin SE, Berlin J, Hong TS, Maitra A, Moravek C, et al. Potentially curable pancreatic adenocarcinoma: ASCO clinical practice guideline update. J Clin Oncol. 2019;37(23):2082–8. A recent update on clinical guideline for the treatment of pancreatic cancer using FDP chemotherapy.

  12. Alberts SR, Al-Khatib H, Mahoney MR, Burgart L, Cera PJ, Flynn PJ, et al. Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma. Cancer. 2005;103(1):111–8.

    Article  CAS  PubMed  Google Scholar 

  13. Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019;393(10184):1948–57.

    Article  PubMed  Google Scholar 

  14. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27–40.

    Article  CAS  PubMed  Google Scholar 

  15. Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008;26(7):1086–92.

    Article  CAS  PubMed  Google Scholar 

  16. Lee HS, Choi Y, Hur WJ, Kim HJ, Kwon HC, Kim SH, et al. Pilot study of postoperative adjuvant chemoradiation for advanced gastric cancer: adjuvant 5-FU/cisplatin and chemoradiation with capecitabine. World J Gastroenterol. 2006;12(4):603–7.

    Article  CAS  PubMed  Google Scholar 

  17. Ajani JA. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal. JAMA. 2008;299(16):1914.

    Article  CAS  PubMed  Google Scholar 

  18. Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol. 1996;14(9):2527–39.

    Article  CAS  PubMed  Google Scholar 

  19. Javle MM, Yang G, Nwogu CE, Wilding GE, O’Malley L, Vinjamaram S, et al. Capecitabine, oxaliplatin and radiotherapy: a phase IB neoadjuvant study for esophageal cancer with gene expression analysis. Cancer Invest. 2009;27(2):193–200.

    Article  CAS  PubMed  Google Scholar 

  20. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97.

    Article  CAS  PubMed  Google Scholar 

  21. Cremolini C, Loupakis F, Antoniotti C, Lupi C, Sensi E, Lonardi S, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. Lancet Oncol. 2015;16(13):1306–15.

    Article  CAS  PubMed  Google Scholar 

  22. Venook AP, Niedzwiecki D, Lenz H-J, Innocenti F, Fruth B, Meyerhardt JA, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer. JAMA. 2017;317(23):2392.

    Article  CAS  PubMed  Google Scholar 

  23. Douillard J-Y, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697–705.

    Article  CAS  PubMed  Google Scholar 

  24. Kato KSJ, et al. ESMO Annual Meeting; September 19–21, 2020 Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study [abstract]. Ann Oncol. 2020;31(suppl_4):S1142–215. https://doi.org/10.1016/annonc/annonc325.

    Article  Google Scholar 

  25. Chung HC, Bang Y-J, Fuchs S, Charles, Qin S-K, Satoh T, Shitara K, et al. First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Future Oncol. 2021;17(5):491-501

  26. Moehler MSK, Garrido M, et al. Nivolumab plus chemotherapy versus chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: first results of the CheckMate 649 study. [abstract]. ESMO 2020 Annual Meeting 2020. Ann Oncol. 2020;31(suppl_4):S1142–215. https://doi.org/10.1016/annonc/annonc325.

    Article  Google Scholar 

  27. Masuda N, Lee S-J, Ohtani S, Im Y-H, Lee E-S, Yokota I, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147–59.

    Article  CAS  PubMed  Google Scholar 

  28. Bartsch R, Wenzel C, Altorjai G, Pluschnig U, Rudas M, Mader RM, et al. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol. 2007;25(25):3853–8.

    Article  CAS  PubMed  Google Scholar 

  29. Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1998;16(8):2651–8.

    Article  CAS  PubMed  Google Scholar 

  30. Goldhirsch A, Colleoni M, Coates AS, Castiglione-Gertsch M, Gelber RD. Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike? The International Breast Cancer Study Group (IBCSG). Ann Oncol. 1998;9(5):489–93.

    Article  CAS  PubMed  Google Scholar 

  31. Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, et al. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma. Cancer. 2003;97(11):2716–23.

    Article  CAS  PubMed  Google Scholar 

  32. Kosmas C, Kallistratos MS, Kopterides P, Syrios J, Skopelitis H, Mylonakis N, et al. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol. 2008;134(1):75–82.

    Article  CAS  PubMed  Google Scholar 

  33. Polk A, Vaage-Nilsen M, Vistisen K, Nielsen DL. 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):974–84.

    Article  CAS  PubMed  Google Scholar 

  34. Sara JD, Kaur J, Khodadadi R, Rehman M, Lobo R, Chakrabarti S, et al. 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol. 2018;10:175883591878014.

    Article  Google Scholar 

  35. • More LA, Lane S, Asnani A. 5-FU cardiotoxicity: vasospasm, myocarditis, and sudden death. Curr Cardiol Rep. 2021;23(3). An key work which describes mechanistic hypothesis behind FDP cardiotoxicity.

  36. de Forni M, Malet-Martino MC, Jaillais P, Shubinski RE, Bachaud JM, Lemaire L, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol. 1992;10(11):1795–801.

    Article  PubMed  Google Scholar 

  37. Dyhl‐Polk A, Schou M, Vistisen KK, Sillesen AS, Serup‐Hansen E, Faber J, et al. Myocardial ischemia induced by 5‐fluorouracil : a prospective electrocardiographic and cardiac biomarker study. Oncologist. 2021;26(3).

  38. Jensen SA, Hasbak P, Mortensen J, Sorensen JB. 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):5280–6.

    Article  CAS  PubMed  Google Scholar 

  39. Raber I, Warack S, Kanduri J, Pribish A, Godishala A, Abovich A, et al. Fluoropyrimidine‐associated cardiotoxicity: a retrospective case‐control study. Oncologist. 2020;25(3):theoncologist.2.

  40. • Dyhl-Polk A, Vaage-Nilsen M, Schou M, Vistisen KK, Lund CM, Kümler T, et al. Incidence and risk markers of 5-fluorouracil and capecitabine cardiotoxicity in patients with colorectal cancer. Acta Oncol. 2020;59(4):475–83. A large retrospective study looking at FDP toxicity in CRC patients at a single center.

  41. Freeman NJ, Costanza ME. 5-Fluorouracil-associated cardiotoxicity. Cancer. 1988;61(1):36–45.

    Article  CAS  PubMed  Google Scholar 

  42. Henry PD, Yokoyama M. Supersensitivity of atherosclerotic rabbit Aorta to ergonovine. J Clin Investig. 1980;66(2):306–13.

    Article  CAS  PubMed  Google Scholar 

  43. Kim S-M, Kwak C-H, Lee B, Kim SB, Sir J-J, Cho W-H, et al. A case of severe coronary spasm associated with 5-fluorouracil chemotherapy. Korean J Intern Med. 2012;27(3):342.

    Article  PubMed  Google Scholar 

  44. Tajik R, Saadat H, Taherkhani M, Movahed MR. Angina induced by 5-fluorouracil infusion in a patient with normal coronaries. Am Heart Hosp J. 2010;8(2):E111–2.

    Article  PubMed  Google Scholar 

  45. Camaro C, Danse PW, Bosker HA. Acute chest pain in a patient treated with capecitabine. Neth Hear J. 2009;17(7):288–91.

    Article  CAS  Google Scholar 

  46. Siddiqui NS, Purvey S, Hamal R, Zhang L, Diasio RB, Saif WM. Dihydropyrimidine dehydrogenase gene (DPYD) polymorphism among pts with 5-FU/capecitabine (CAP)-related adverse events (AEs): experience of 2 decades. J Clin Oncol. 2018;36(15):2576.

    Article  Google Scholar 

  47. • Innocenti F, Mills SC, Sanoff H, Ciccolini J, Lenz H-J, Milano G. All you need to know about DPYD genetic testing for patients treated with fluorouracil and capecitabine: a practitioner-friendly guide. JCO Oncol Pract. 2020;16(12):793–8. A clinically oriented approach to the use of DPYD testing in patients getting FDP chemotherapy.

  48. King DA, Diasio RB, Saif MW. Association of pharmacogenetics with adverse events of fluorouracil/capecitabine in patients with cancer. JCO Oncol Pract. 2021;17(7):453–4.

    Article  PubMed  Google Scholar 

  49. Di Paolo A, Cremolini C, Bocci G. Universal pretreatment DPYD genotyping in fluoropyrimidine candidates: still controversial but with clear instructions for practitioners, at last! JCO Oncol Pract. 2020;16(12):801–2.

    Article  PubMed  Google Scholar 

  50. Saif MW, Smith M, Maloney A. The first case of severe Takotsubo cardiomyopathy associated with 5-fluorouracil in a patient with abnormalities of both dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS) genes. Cureus. 2016.

  51. Ambrosy AP, Kunz PL, Fisher GA, Witteles RM. Capecitabine-induced chest pain relieved by diltiazem. Am J Cardiol. 2012;110(11):1623–6.

    Article  CAS  PubMed  Google Scholar 

  52. Chakrabarti S, Sara J, Lobo R, Eiring R, Finnes H, Mitchell J, et al. Bolus 5-fluorouracil (5-FU) in combination with oxaliplatin is safe and well tolerated in patients who experienced coronary vasospasm with infusional 5-FU or capecitabine. Clin Colorectal Cancer. 2019;18(1):52–7.

    Article  PubMed  Google Scholar 

Download references

Funding

Dr. Clasen is supported via the National Cancer Institute Loan Repayment Grant OYFC2282.

Author information

Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Laura B. Vater & Anita Turk

  2. Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Bénédicte Lefebvre

  3. Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indiana University, 1800 N. Capitol Ave, E308, Indianapolis, IN, 46202, USA

    Suparna C. Clasen

Authors
  1. Laura B. Vater
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bénédicte Lefebvre
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anita Turk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Suparna C. Clasen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suparna C. Clasen.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical collection on Cardio-oncology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vater, L.B., Lefebvre, B., Turk, A. et al. Fluoropyrimidine Cardiotoxicity: Incidence, Outcomes, and Safety of Rechallenge. Curr Oncol Rep 24, 943–950 (2022). https://doi.org/10.1007/s11912-022-01256-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-022-01256-6

Keywords

Search

Navigation