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Breast Cancer Research and Treatment

, Volume 156, Issue 3, pp 501–506 | Cite as

Late cardiac effects of chemotherapy in breast cancer survivors treated with adjuvant doxorubicin: 10-year follow-up

  • G. Murtagh
  • T. Lyons
  • E. O’Connell
  • J. Ballot
  • L. Geraghty
  • D. Fennelly
  • G. Gullo
  • M. Ledwidge
  • J. Crown
  • J. Gallagher
  • C. Watson
  • K. M. McDonald
  • J. M. Walshe
Clinical trial

Abstract

Doxorubicin (Dox), a mainstay of adjuvant breast cancer treatment, is associated with cardiac toxicity in the form of left ventricular dysfunction (LVD), LV diastolic dysfunction, or LV systolic dysfunction. Study objectives were to evaluate the prevalence of LVD in long-term breast cancer survivors treated with Dox and determine if brain-type natriuretic peptide (BNP) may help identify patients at risk for LVD. Patients who participated in prospective clinical trials of adjuvant Dox-based chemotherapy for breast cancer with a baseline left ventricular (LV) ejection fraction evaluation from 1999 to 2006 were retrospectively identified from the St Vincent’s University Hospital database. Patients were invited to undergo transthoracic echocardiography, BNP analysis, and cardiovascular (CV) risk factor assessment. LVDD was defined as left atrial volume index >34 mL/m2 and/or lateral wall E prime <10 m/s, and LVSD as LVEF <50 %. Of 212 patients identified, 154 participated, 19 patients had died (no cardiac deaths), and 39 declined. Mean age was 60.7 [55:67] years. A majority of the patients (128, 83 %) had low CV risk (0/1 risk factors), 21 (13.6 %) had 2 RFs, and 5 (3.2 %) ≥3 RFs. BMI was 27.2 ± 4.9 kg/m2. Median Dox dose was 240 mg/m2 [225–298]; 92 patients (59.7 %) received ≤240 mg/m2 and 62 (40.3 %) > 240 mg/m2. Baseline LVEF was 68.2 ± 8 %. At follow-up of 10.8 ± 2.2 years, LVEF was 64.4 ± 6 %. Three (1.9 %) subjects had LVEF <50 % and one (0.7 %) had LVDD. Dox >240 mg/m2 was associated with any LVEF drop. BNP levels at follow-up were 20.3 pg/ml [9.9–36.5] and 21.1 pg/ml [9.8–37.7] in those without LVD and 61.5 pg/ml [50–68.4] in those with LVD (p = 0.04). Long-term prospective data describing the impact of Dox on cardiotoxicity are sparse. At over 10 years of follow-up, decreases in LVEF are common, and dose related, but LVD as defined is infrequent (2.6 %). Monitoring with BNP for subclinical LVD needs further evaluation.

Keywords

Anthracyclines Cardiotoxicity Doxorubicin Systolic dysfunction 

Notes

Acknowledgements

We wish to thank the patients who participated in the study, as well as the support staff of the STOP-HF project and Oncology departments for their help in completing this study.

Compliance with ethical standards

Conflict of interest

Gillian Murtagh has been an employee of Abbott Diagnostics since 7/6/15, but was not an employee at the time of the study. Abbott played no role in study design, conduct, or funding. John Crown has received Honoraria and a Speakers Bureau from Eisai and Genomic Health; Research Funding from Roche and GSK; and Travel, Accommodation and Expenses from BMS and Roche. All the remaining authors have disclosed no conflict of interest.

References

  1. 1.
    Chen MH, Colan SD, Diller L (2011) Cardiovascular disease: cause of morbidity and mortality in adult survivors of childhood cancers. Circ Res 108(5):619–628CrossRefPubMedGoogle Scholar
  2. 2.
    Von Hoff DD, Layard MW et al (1979) Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91(5):710–717CrossRefGoogle Scholar
  3. 3.
    Ho E, Brown A, Barrett P et al (2010) Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study. Heart 96(9):701–707CrossRefPubMedGoogle Scholar
  4. 4.
    Smith LA, Cornelius VR, Plummer CJ et al (2010) Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer 10:337CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Nagueh SF, Middleton KJ, Kopelen HA et al (1997) Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 30(6):1527–1533CrossRefPubMedGoogle Scholar
  6. 6.
    Ewer MS, Lippman SM (2005) Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol 23(13):2900CrossRefPubMedGoogle Scholar
  7. 7.
    Russell SD, Blackwell KL, Lawrence J et al (2010) Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: a combined review of cardiac data from the National Surgical Adjuvant breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. J Clin Oncol 28(21):3416CrossRefPubMedGoogle Scholar
  8. 8.
    Felker GM, Thompson RE, Hare JM et al (2000) Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 342(15):1077–1084CrossRefPubMedGoogle Scholar
  9. 9.
    Adderley SR, Fitzgerald DJ (1999) Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2. J Biol Chem 274(8):5038CrossRefPubMedGoogle Scholar
  10. 10.
    Lyu YL, Kerrigan JE, Lin CP et al (2007) Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res 67(18):8839–8846CrossRefPubMedGoogle Scholar
  11. 11.
    Carver JR, Shapiro CL, Ng A et al (2007) American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol 25(25):3991CrossRefPubMedGoogle Scholar
  12. 12.
    Swain SM, Whaley FS, Ewer MS (2003) Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97(11):2869CrossRefPubMedGoogle Scholar
  13. 13.
    Bristow MR, Mason JW, Billingham ME et al (1981) Dose-effect and structure-function relationships in doxorubicin cardiomyopathy. Am Heart J 102(4):709CrossRefPubMedGoogle Scholar
  14. 14.
    Lipshultz SE, Lipsitz SR, Sallan SE et al (2005) Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 23(12):2629–2636CrossRefPubMedGoogle Scholar
  15. 15.
    Mulrooney DA, Yeazel MW, Kawashima T et al (2009) Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 8(339):b4606CrossRefGoogle Scholar
  16. 16.
    Bird BR, Swain SM (2008) Cardiac toxicity in breast cancer survivors: review of potential cardiac problems. Clin Cancer Res 14(1):14–24CrossRefPubMedGoogle Scholar
  17. 17.
    Bontenbal M, Andersson M, Wildiers J et al (1998) Doxorubicin vs epirubicin, report of a second-line randomized phase II/III study in advanced breast cancer. EORTC Breast Cancer Cooperative Group. Br J Cancer 77(12):2257–2263CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Schwartz RG, McKenzie WB, Alexander J et al (1987) Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy: a seven year experience using serial radionuclide angiocardiography. Am J Med 82:1109–1118CrossRefPubMedGoogle Scholar
  19. 19.
    Jeyakumar A, DiPenta J, Snow S et al (2012) Routine cardiac evaluation in patients with early-stage breast cancer before adjuvant chemotherapy. Clin Breast Cancer 12(1):4–9CrossRefPubMedGoogle Scholar
  20. 20.
    Von Hoff DD, Rozencweig M, Layard M et al (1977) Daunomycin-induced cardiotoxicity in children and adults. A review of 110 cases. Am J Med 62(2):200CrossRefGoogle Scholar
  21. 21.
    Romond EH, Jeong JH, Rastogi P et al (2012) Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. JCO 30(31):3792–3799CrossRefGoogle Scholar
  22. 22.
    Shapiro CL, Hardenbergh PH, Gelman R et al (1998) Cardiac effects of adjuvant doxorubicin and radiation therapy in breast cancer patients. J Clin Oncol 16(11):3493PubMedGoogle Scholar
  23. 23.
    Plana JC, Galderisi M, Barac A et al (2014) Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 15(10):1063–1093CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ganame J, Claus P, Uyttebroeck A et al (2007) Myocardial dysfunction late after low-dose anthracycline treatment in asymptomatic pediatric patients. J Am Soc Echocardiogr 20:1351–1358CrossRefPubMedGoogle Scholar
  25. 25.
    Tsai HR, Gjesdal O, Wethal T et al (2011) Left ventricular function assessed by two-dimensional speckle tracking echocardiography in long-term survivors of Hodgkin’s lymphoma treated by mediastinal radiotherapy with or without anthracycline therapy. Am J Cardiol 107:472–477CrossRefPubMedGoogle Scholar
  26. 26.
    Thavendiranathan P, Poulin F, Lim KD et al (2014) Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 63(25 Pt A):2751–2768CrossRefPubMedGoogle Scholar
  27. 27.
    Armstrong GT, Plana JC, Zhang N et al (2012) Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging. J Clin Oncol 30:2876CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Thavendiranathan P, Grant AD, Negishi T et al (2013) Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy. J Am Coll Cardiol 61(1):77–84CrossRefPubMedGoogle Scholar
  29. 29.
    Ammon M, Arenja N, Leibundgut G et al (2013) Cardiovascular management of cancer patients with chemotherapy-associated left ventricular systolic dysfunction in real-world clinical practice. J Card Fail 19(9):629–634CrossRefPubMedGoogle Scholar
  30. 30.
    Yoon GJ, Telli ML, Kao DP et al (2010) Left ventricular dysfunction in patients receiving cardiotoxic cancer therapies: are clinicians responding optimally? J Am Coll Cardiol 56(20):1644–1650CrossRefPubMedGoogle Scholar
  31. 31.
    Cardinale D, Sandri MT, Colombo A et al (2004) Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 109(22):2749–2754CrossRefPubMedGoogle Scholar
  32. 32.
    Sawaya H, Sebag IA, Plana JC et al (2012) Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging 5(5):596–603CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Okumura H, Iuchi K, Yoshida T et al (2000) Brain natriuretic peptide is a predictor of anthracycline-induced cardiotoxicity. Acta Haematol 104(4):158–163CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • G. Murtagh
    • 1
  • T. Lyons
    • 2
  • E. O’Connell
    • 1
  • J. Ballot
    • 2
  • L. Geraghty
    • 1
  • D. Fennelly
    • 2
  • G. Gullo
    • 2
  • M. Ledwidge
    • 1
  • J. Crown
    • 2
  • J. Gallagher
    • 1
  • C. Watson
    • 1
  • K. M. McDonald
    • 1
  • J. M. Walshe
    • 2
  1. 1.The STOP-HF Service, Department of CardiologySt Vincent’s University HospitalDublin 4Ireland
  2. 2.Department of Medical OncologySt Vincent’s University HospitalDublin 4Ireland

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