Skip to main content

Advertisement

SpringerLink
Log in

Incidence of and risk factors for cardiotoxicity after fluorouracil-based chemotherapy in locally advanced or metastatic gastric cancer patients

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

Abstract

Objectives

Cardiotoxicity is an important side effect in patients receiving chemotherapy and the application of anthracycline drugs for gastric cancer treatment is uncommon. The purpose of this study was to determine the incidence rate of and risk factors for cardiotoxicity in gastric cancer patients treated with fluorouracil-based chemotherapy.

Materials and methods

We retrospectively enrolled patients with locally advanced or metastatic gastric cancer from 2011 to 2016. Patients were treated with multiple cycles of fluorouracil-based chemotherapy at Peking University First Hospital. The incidence of cardiotoxicity and patients’ clinical data were obtained from hospital clinical databases and manually reviewed.

Results

A total of 129 patients were eligible for and were enrolled in this study. A median of 6 chemotherapy cycles were administered (range 1–18 cycles). Cardiotoxicity was observed in 38 of 129 patients (29.5%). Twelve patients (9.3%) exhibited toxicity greater than grade 2, and 2 (1.6%) patients died of cardiac toxicity. The only independent risk factor for serious cardiotoxicity identified by multivariable analysis was a history of cardiac disease (OR 4.108, 95% CI 2.778–6.074, P < 0.001).

Conclusions

Chemotherapy-related cardiotoxicity may be underestimated in Chinese gastric cancer patients. Close monitoring for cardiotoxicity and enhanced cardiac management are recommended for patients who receive fluorouracil-based chemotherapy, especially for patients with high-risk factors for serious cardiotoxicity. New strategies, such as identifying the administration schedule of fluorouracil with minimal cardiotoxicity, and cardio-oncology, are necessary to prevent and treat chemotherapy-induced cardiotoxicity.

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

Similar content being viewed by others

References

  1. GLOBOCAN2018: Estimated cancer incidence, mortality and prevalence worldwide in 2018. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed 2019

  2. Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, Yang YH, Sano T, Yang HK, Zhang X, Park SR, Fujii M, Kang YK, Chen LT (2013) Management of gastric cancer in Asia: resource-stratified guidelines. Lancet Oncol 14(12):e535–e547. https://doi.org/10.1016/S1470-2045(13)70436-4

    Article  PubMed  Google Scholar 

  3. Glimelius B, Hoffman K, Haglund U, Nyren O, Sjoden PO (1994) Initial or delayed chemotherapy with best supportive care in advanced gastric cancer. Ann Oncol 5(2):189–190

    Article  CAS  PubMed  Google Scholar 

  4. Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M (1995) Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71(3):587–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brana I, Tabernero J (2010) Cardiotoxicity. Ann Oncol 21(Suppl 7):vii173–vii179. https://doi.org/10.1093/annonc/mdq295

    Article  PubMed  Google Scholar 

  6. Yeh ET (2006) Cardiotoxicity induced by chemotherapy and antibody therapy. Annu Rev Med 57:485–498. https://doi.org/10.1146/annurev.med.57.121304.131240

    Article  CAS  PubMed  Google Scholar 

  7. Volkova M, Russell R 3rd (2011) Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev 7(4):214–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Perik PJ, de Korte MA, van Veldhuisen DJ, Gietema JA, Sleijfer DT, de Vries EG (2007) Cardiotoxicity associated with the use of trastuzumab in breast cancer patients. Expert Rev Anticancer Ther 7(12):1763–1771. https://doi.org/10.1586/14737140.7.12.1763

    Article  CAS  PubMed  Google Scholar 

  9. Saif MW, Shah MM, Shah AR (2009) Fluoropyrimidine-associated cardiotoxicity: revisited. Expert Opin Drug Saf 8(2):191–202. https://doi.org/10.1517/14740330902733961

    Article  CAS  PubMed  Google Scholar 

  10. Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L, Woulfe K, Pravda E, Cassiola F, Desai J, George S, Morgan JA, Harris DM, Ismail NS, Chen JH, Schoen FJ, Van den Abbeele AD, Demetri GD, Force T, Chen MH (2007) Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370(9604):2011–2019. https://doi.org/10.1016/S0140-6736(07)61865-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Saito K, Takeda K, Imanaka-Yoshida K, Imai H, Sekine T, Kamikura Y (2003) Assessment of fatty acid metabolism in taxan-induced myocardial damage with iodine-123 BMIPP SPECT: comparative study with myocardial perfusion, left ventricular function, and histopathological findings. Ann Nucl Med 17(6):481–488

    Article  CAS  PubMed  Google Scholar 

  12. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL, Becker JR, Slosky DA, Phillips EJ, Pilkinton MA, Craig-Owens L, Kola N, Plautz G, Reshef DS, Deutsch JS, Deering RP, Olenchock BA, Lichtman AH, Roden DM, Seidman CE, Koralnik IJ, Seidman JG, Hoffman RD, Taube JM, Diaz LA Jr, Anders RA, Sosman JA, Moslehi JJ (2016) Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 375(18):1749–1755. https://doi.org/10.1056/NEJMoa1609214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Common Terminology Criteria for Adverse Events. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0. Accessed 2019

  14. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Thygesen K, Alpert JS, White HD, Jaffe AS, Katus HA, Apple FS, Lindahl B, Morrow DA, Chaitman BA, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F, Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasche P, Ravkilde J, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S (2012) Third universal definition of myocardial infarction. Eur Heart J 33(20):2551–2567. https://doi.org/10.1093/eurheartj/ehs184

    Article  PubMed  Google Scholar 

  15. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 18(8):891–975. https://doi.org/10.1002/ejhf.592

    Article  PubMed  Google Scholar 

  16. Curigliano G, Cardinale D, Dent S, Criscitiello C, Aseyev O, Lenihan D, Cipolla CM (2016) Cardiotoxicity of anticancer treatments: epidemiology, detection, and management. CA Cancer J Clin 66(4):309–325. https://doi.org/10.3322/caac.21341

    Article  PubMed  Google Scholar 

  17. Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jager E (2008) Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol 26(9):1435–1442. https://doi.org/10.1200/jco.2007.13.9378

    Article  CAS  PubMed  Google Scholar 

  18. Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V, Park JO, Sawaki A, Celik I, Gotte H, Melezinkova H, Moehler M (2013) Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol 14(6):490–499. https://doi.org/10.1016/s1470-2045(13)70102-5

    Article  CAS  PubMed  Google Scholar 

  19. Kwakman JJ, Simkens LH, Mol L, Kok WE, Koopman M, Punt CJ (2017) Incidence of capecitabine-related cardiotoxicity in different treatment schedules of metastatic colorectal cancer: a retrospective analysis of the CAIRO studies of the Dutch Colorectal Cancer Group. Eur J Cancer (Oxf Engl 1990) 76:93–99. https://doi.org/10.1016/j.ejca.2017.02.009

    Article  CAS  Google Scholar 

  20. Osman M, Elkady M (2017) A prospective study to evaluate the effect of paclitaxel on cardiac ejection fraction. Breast Care 12(4):255–259. https://doi.org/10.1159/000471759

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chen G, Peng J, Dong C, Qiu M, Wang C, Li Hw YuH, Zhang M, Zhao Q, Zhu B, Zhang J, Li W, Wang F, Wu Q, Yuan Y, Zhou W-H (2017) Cardiotoxicity in Chinese cancer patients treated with 5-fluorouracil or capecitabine: a multicenter prospective observational study. J Clin Oncol 35(4_suppl):553. https://doi.org/10.1200/jco.2017.35.4_suppl.553

    Article  CAS  Google Scholar 

  22. Polk A, Vaage-Nilsen M, Vistisen K, Nielsen DL (2013) Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: a systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev 39(8):974–984. https://doi.org/10.1016/j.ctrv.2013.03.005

    Article  CAS  PubMed  Google Scholar 

  23. Kosmas C, Kallistratos MS, Kopterides P, Syrios J, Skopelitis H, Mylonakis N, Karabelis A, Tsavaris N (2008) Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study. J Cancer Res Clin Oncol 134(1):75–82. https://doi.org/10.1007/s00432-007-0250-9

    Article  CAS  PubMed  Google Scholar 

  24. Jensen SA, Sorensen JB (2006) Risk factors and prevention of cardiotoxicity induced by 5-fluorouracil or capecitabine. Cancer Chemother Pharmacol 58(4):487–493. https://doi.org/10.1007/s00280-005-0178-1

    Article  CAS  PubMed  Google Scholar 

  25. Khan MA, Masood N, Husain N, Ahmad B, Aziz T, Naeem A (2012) 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. JPMA J Pak Med Assoc 62(5):430–434

    PubMed  Google Scholar 

  26. Van Cutsem E, Hoff PM, Blum JL, Abt M, Osterwalder B (2002) Incidence of cardiotoxicity with the oral fluoropyrimidine capecitabine is typical of that reported with 5-fluorouracil. Ann Oncol 13(3):484–485

    Article  PubMed  Google Scholar 

  27. Arellano M, Malet-Martino M, Martino R, Gires P (1998) The anti-cancer drug 5-fluorouracil is metabolized by the isolated perfused rat liver and in rats into highly toxic fluoroacetate. Br J Cancer 77(1):79–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yamada Y, Hamaguchi T, Goto M, Muro K, Matsumura Y, Shimada Y, Shirao K, Nagayama S (2003) 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 89(5):816–820. https://doi.org/10.1038/sj.bjc.6601224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Serrano C, Cortes J, De Mattos-Arruda L, Bellet M, Gomez P, Saura C, Perez J, Vidal M, Munoz-Couselo E, Carreras MJ, Sanchez-Olle G, Tabernero J, Baselga J, Di Cosimo S (2012) Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors. Ann Oncol 23(4):897–902. https://doi.org/10.1093/annonc/mdr348

    Article  CAS  PubMed  Google Scholar 

  30. Gavila J, Segui MA, Calvo L, Lopez T, Alonso JJ, Farto M, Sanchez-de la Rosa R (2017) Evaluation and management of chemotherapy-induced cardiotoxicity in breast cancer: a Delphi study. Clin Transl Oncol 19(1):91–104. https://doi.org/10.1007/s12094-016-1508-y

    Article  CAS  PubMed  Google Scholar 

  31. Guenancia C, Lefebvre A, Cardinale D, Yu AF, Ladoire S, Ghiringhelli F, Zeller M, Rochette L, Cottin Y, Vergely C (2016) Obesity as a risk factor for anthracyclines and trastuzumab cardiotoxicity in breast cancer: a systematic review and meta-analysis. J Clin Oncol 34(26):3157–3165. https://doi.org/10.1200/JCO.2016.67.4846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jeong SH, Kim YW, Yu W, Lee SH, Park YK, Park SH, Jeong IH, Lee SE, Park Y, Lee YJ (2015) High morbidity in myocardial infarction and heart failure patients after gastric cancer surgery. World J Gastroenterol 21(21):6631–6638. https://doi.org/10.3748/wjg.v21.i21.6631

    Article  PubMed  PubMed Central  Google Scholar 

  33. Mantarro S, Rossi M, Bonifazi M, D’Amico R, Blandizzi C, La Vecchia C, Negri E, Moja L (2016) Risk of severe cardiotoxicity following treatment with trastuzumab: a meta-analysis of randomized and cohort studies of 29,000 women with breast cancer. Intern Emerg Med 11(1):123–140. https://doi.org/10.1007/s11739-015-1362-x

    Article  PubMed  Google Scholar 

  34. Lee AY (2005) Deep vein thrombosis and cancer: survival, recurrence, and anticoagulant choices. Dis Month DM 51(2–3):150–157. https://doi.org/10.1016/j.disamonth.2005.03.010

    Article  Google Scholar 

  35. Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG, Buller HR (2000) Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 18(17):3078–3083. https://doi.org/10.1200/JCO.2000.18.17.3078

    Article  CAS  PubMed  Google Scholar 

  36. Suter TM, Ewer MS (2013) Cancer drugs and the heart: importance and management. Eur Heart J 34(15):1102–1111. https://doi.org/10.1093/eurheartj/ehs181

    Article  CAS  PubMed  Google Scholar 

  37. Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM (2010) Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst 102(1):14–25. https://doi.org/10.1093/jnci/djp440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sulpher J, Mathur S, Graham N, Crawley F, Turek M, Johnson C, Stadnick E, Law A, Wentzell J, Dent S (2015) Clinical experience of patients referred to a multidisciplinary cardiac oncology clinic: an observational study. J Oncol 2015:671232. https://doi.org/10.1155/2015/671232

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to Lijian Yu from the Dana-Farber Cancer Institute for helpful discussions, and we are grateful to Xiaoping Kang from Peking University who provided help with the statistical analysis. We also thank the patients and their families for supporting the study.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Peking University First Hospital, Beijing, 100034, China

    Xuan Jin, Yu Bai & Shikai Wu

  2. Department of Cardiology, Peking University First Hospital, Beijing, 100034, China

    Lan Gao

Authors
  1. Xuan Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lan Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shikai Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu Bai.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest regarding this study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institution and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jin, X., Bai, Y., Gao, L. et al. Incidence of and risk factors for cardiotoxicity after fluorouracil-based chemotherapy in locally advanced or metastatic gastric cancer patients. Cancer Chemother Pharmacol 84, 599–607 (2019). https://doi.org/10.1007/s00280-019-03888-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-019-03888-1

Keywords

Search

Navigation