Hostname: page-component-586b7cd67f-rcrh6 Total loading time: 0 Render date: 2024-11-22T23:53:52.895Z Has data issue: false hasContentIssue false
  • English
  • Français

Cardiac complications in childhood cancer survivors treated with anthracyclines*

Published online by Cambridge University Press:  17 September 2015

Vivian I. Franco  and
Steven E. Lipshultz
Vivian I. Franco
Affiliation:
Department of Pediatrics, Wayne State University School of Medicine, Children’s Hospital of Michigan, Detroit, Michigan, United States of America
Steven E. Lipshultz*
Affiliation:
Department of Pediatrics, Wayne State University School of Medicine, Children’s Hospital of Michigan, Detroit, Michigan, United States of America
*
Correspondence to: S. E. Lipshultz, MD, Department of Pediatrics, Wayne State University School of Medicine, Children’s Hospital of Michigan, 3901 Beaubien Boulevard, Suite 1K40, Detroit, MI 48201, United States of America. Tel: +313 745 5870; Fax: +313 993 0390; E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Cardiovascular complications are among the leading causes of morbidity and mortality among survivors of childhood cancer, after cancer relapse and secondary malignancies. Although advances in cancer treatment have improved the 5-year survival rates, the same treatments, such as anthracyclines, that cure cancer also increase the risk for adverse cardiovascular effects. Anthracycline-related cardiotoxicity in survivors of childhood cancer is progressive and can take years to develop, initially presenting as sub-clinical cardiac abnormalities that, if left undetected or untreated, can lead to heart failure, myocardial infarction, or other clinical cardiac dysfunction. A higher cumulative dose of anthracycline is associated with cardiotoxicity in children; however, sub-clinical cardiac abnormalities are evident at lower doses with longer follow-up, suggesting that there is no “safe” dose of anthracycline. Other risk factors include female sex, younger age at diagnosis, black race, trisomy 21, longer time since treatment, and the presence of pre-existing cardiovascular disease and co-morbidities. Cardioprotective strategies during treatment are limited in children. Enalapril provides only temporary cardioprotection, whereas continuous anthracycline infusion extends none. On the other hand, dexrazoxane successfully prevents or reduces anthracycline-related cardiotoxicity in children with cancer, without increased risks for recurrence of primary or second malignancies or reductions in anti-tumour efficacy. With more childhood cancer survivors now reaching adulthood, it is vital to understand the adverse effects of cancer treatment on the cardiovascular system and their long-term consequences to identify and establish optimal prevention and management strategies that balance oncologic efficacy with long-term safety.

Keywords

Anthracyclinescardiotoxicitychildhood cancer survivorsdexrazoxane
Type
Original Articles
Information
Cardiology in the Young , Volume 25 , Supplement S2: Special Supplement of Cardiology in the Young: Proceedings of the 2015 International Paediatric Heart Failure Summit of Johns Hopkins All Children's Heart Institute , August 2015 , pp. 107 - 116
Copyright
© Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

*

Presented at Johns Hopkins All Children’s Heart Institute, International Pediatric Heart Failure Summit, Saint Petersburg, Florida, United States of America, 4–5 February, 2015.

References

1. Tukenova, M, Guibout, C, Oberlin, O, et al. Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol 2010; 28: 1308–1315.Google Scholar
2. Mertens, AC, Liu, Q, Neglia, JP, et al. Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 2008; 100: 1368–1379.Google Scholar
3. Ward, E, DeSantis, C, Robbins, A, et al. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 2014; 64: 83–103.Google Scholar
4. Oeffinger, KC, Mertens, AC, Sklar, CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006; 355: 1572–1582.Google Scholar
5. Armstrong, GT, Oeffinger, KC, Chen, Y, et al. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 2013; 31: 3673–3680.Google Scholar
6. Mulrooney, DA, Yeazel, MW, Kawashima, T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 2009; 339: b4606.CrossRefGoogle Scholar
7. Armstrong, GT, Kawashima, T, Leisenring, W, et al. Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J Clin Oncol 2014; 32: 1218–1227.Google Scholar
8. Lipshultz, SE, Colan, SD, Gelber, RD, et al. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991; 324: 808–815.Google Scholar
9. Diamond, MB, Franco, VI, Miller, TL, et al. Preventing and treating anthracycline-related cardiotoxicity in survivors of childhood cancer. Curr Cancer Ther Rev 2012; 8: 141–151.CrossRefGoogle Scholar
10. Sawyer, DB, Peng, X, Chen, B, et al. Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection? Prog Cardiovasc Dis 2010; 53: 105–113.Google Scholar
11. Zhang, S, Liu, X, Bawa-Khalfe, T, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012; 18: 1639–1642.Google Scholar
12. Lipshultz, SE, Lipsitz, SR, Sallan, SE, et al. Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 2005; 23: 2629–2636.Google Scholar
13. Minow, R, Benjamin, R, Gottlieb, J. Adriamycin (NSC-123127) cardiomyopathy-overview with determination of risk-factors. Cancer Chemother Rep 1975; 6: 195–201.Google Scholar
14. Lipshultz, SE, Scully, RE, Stevenson, KE, et al. Hearts too small for body size after doxorubicin for childhood ALL: Grinch syndrome. J Clin Oncol 2014; 32: 10021, (abstract).Google Scholar
15. Lipshultz, SE. Ventricular dysfunction clinical research in infants, children and adolescents. Prog Pediatr Cardiol 2000; 12: 1–28.Google Scholar
16. Lipshultz, SE, Alvarez, JA, Scully, RE. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 2008; 94: 525–533.Google Scholar
17. van der Pal, HJ, van Dalen, EC, van Delden, E, et al. High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol 2012; 30: 1429–1437.Google Scholar
18. Kremer, LC, van Dalen, EC, Offringa, M, et al. Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol 2001; 19: 191–196.Google Scholar
19. Orgel, E, Zung, L, Ji, L, et al. Early cardiac outcomes following contemporary treatment for childhood acute myeloid leukemia: a North American perspective. Pediatr Blood Cancer 2013; 60: 1528–1533.Google Scholar
20. Leger, K, Slone, T, Lemler, M, et al. Subclinical cardiotoxicity in childhood cancer survivors exposed to very low dose anthracycline therapy. Pediatr Blood Cancer 2015; 62: 123–127.Google Scholar
21. Bansal, N, Franco, VI, Lipshultz, SE. Anthracycline cardiotoxicity in survivors of childhood cancer: clinical course, protection, and treatment. Progr Pediatr Cardiol 2014; 36: 11–18.Google Scholar
22. Lipshultz, SE, Lipsitz, SR, Mone, SM, et al. Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 1995; 332: 1738–1743.Google Scholar
23. Landy, DC, Miller, TL, Lipsitz, SR, et al. Cranial irradiation as an additional risk factor for anthracycline cardiotoxicity in childhood cancer survivors: an analysis from the cardiac risk factors in childhood cancer survivors study. Pediatr Cardiol 2013; 34: 826–834.Google Scholar
24. Armenian, SH, Sun, CL, Vase, T, et al. Cardiovascular risk factors in hematopoietic cell transplantation survivors: role in development of subsequent cardiovascular disease. Blood 2012; 120: 4505–4512.CrossRefGoogle ScholarPubMed
25. Lipshultz, SE, Landy, DC, Lopez-Mitnik, G, et al. Cardiovascular status of childhood cancer survivors exposed and unexposed to cardiotoxic therapy. J Clin Oncol 2012; 30: 1050–1057.Google Scholar
26. Sterba, M, Popelova, O, Vavrova, A, et al. Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxid Redox Signal 2013; 18: 899–8929.Google Scholar
27. Simunek, T, Sterba, M, Popelova, O, et al. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Rep 2009; 61: 154–171.Google Scholar
28. Hasinoff, BB, Kuschak, TI, Yalowich, JC, et al. A QSAR study comparing the cytotoxicity and DNA topoisomerase II inhibitory effects of bisdioxopiperazine analogs of ICRF-187 (dexrazoxane). Biochem Pharmacol 1995; 50: 953–958.Google Scholar
29. Herman, EH, Hasinoff, BB, Steiner, R, et al. A review of the preclinical development of dexrazoxane. Progr Pediatr Cardiol 2014; 36: 33–38.Google Scholar
30. Doroshow, JH. Dexrazoxane for the prevention of cardiac toxicity and treatment of extravasation injury from the anthracycline antibiotics. Curr Pharm Biotechnol 2012; 13: 1949–1956.CrossRefGoogle ScholarPubMed
31. Lipshultz, SE, Rifai, N, Dalton, VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 2004; 351: 145–153.CrossRefGoogle ScholarPubMed
32. Lipshultz, SE, Scully, RE, Lipsitz, SR, et al. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 2010; 11: 950–961.Google Scholar
33. Tebbi, CK, London, WB, Friedman, D, et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin’s disease. J Clin Oncol 2007; 25: 493–500.Google Scholar
34. Lipshultz, SE, Franco, VI, Sallan, SE, et al. Dexrazoxane for reducing anthracycline-related cardiotoxicity in children with cancer: an update of the evidence. Progr Pediatr Cardiol 2014; 36: 39–49.Google Scholar
35. Silber, JH, Cnaan, A, Clark, BJ, et al. Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol 2004; 22: 820–828.CrossRefGoogle ScholarPubMed
36. Lipshultz, SE, Lipsitz, SR, Sallan, SE, et al. Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood cancer. J Clin Oncol 2002; 20: 4517–4522.Google Scholar
37. Levitt, GA, Dorup, I, Sorensen, K, et al. Does anthracycline administration by infusion in children affect late cardiotoxicity? Br J Haematol 2004; 124: 463–468.Google Scholar
38. Legha, SS, Benjamin, RS, Mackay, B, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 1982; 96: 133–139.Google Scholar
39. Lipshultz, SE, Miller, TL, Lipsitz, SR, et al. Continuous versus bolus infusion of doxorubicin in children with ALL: long-term cardiac outcomes. Pediatrics 2012; 130: 1003–1011.Google Scholar
40. Gupta, M, Steinherz, PG, Cheung, NK, et al. Late cardiotoxicity after bolus versus infusion anthracycline therapy for childhood cancers. Med Pediatr Oncol 2003; 40: 343–347.Google Scholar
41. Lipshultz, SE, Giantris, AL, Lipsitz, SR, et al. Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol. J Clin Oncol 2002; 20: 1677–1682.Google Scholar
42. Colan, SD, Lipshultz, SE, Sallan, SE. Balancing the oncologic effectiveness versus the cardiotoxicity of anthracycline chemotherapy in childhood cancer. Progr Pediatr Cardiol 2014; 36: 7–10.Google Scholar
43. Lipshultz, SE, Rifai, N, Sallan, SE, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 1997; 96: 2641–2648.CrossRefGoogle ScholarPubMed
44. Lipshultz, SE, Miller, TL, Scully, RE, et al. Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes. J Clin Oncol 2012; 30: 1042–1049.Google Scholar
45. Blanco, JG, Sun, CL, Landier, W, et al. Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes–a report from the Children’s Oncology Group. J Clin Oncol 2012; 30: 1415–1421.Google Scholar
46. Lipshultz, SE, Lipsitz, SR, Kutok, JL, et al. Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia. Cancer 2013; 119: 3555–3562.Google Scholar
47. Lipshultz, SE, Franco, VI, Miller, TL, et al. Cardiovascular disease in adult survivors of childhood cancer. Annu Rev Med 2015; 66: 161–176.Google Scholar
48. Wexler, LH, Andrich, MP, Venzon, D, et al. Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin. J Clin Oncol 1996; 14: 362–372.Google Scholar
49. Paiva, MG, Petrilli, AS, Moises, VA, et al. Cardioprotective effect of dexrazoxane during treatment with doxorubicin: a study using low-dose dobutamine stress echocardiography. Pediatr Blood Cancer 2005; 45: 902–908.Google Scholar
50. de Matos Neto, RP, Petrilli, AS, Silva, CM, et al. Left ventricular systolic function assessed by echocardiography in children and adolescents with osteosarcoma treated with doxorubicin alone or in combination with dexrazoxane. Arq Bras Cardiol 2006; 87: 763–771.Google Scholar
51. Choi, HS, Park, ES, Kang, HJ, et al. Dexrazoxane for preventing anthracycline cardiotoxicity in children with solid tumors. J Korean Med Sci 2010; 25: 1336–1342.CrossRefGoogle ScholarPubMed
52. Kang, M, Kim, KI, Song, YC, et al. Cardioprotective effect of early dexrazoxane use in anthracycline treated pediatric patients. J Chemother 2012; 24: 292–296.CrossRefGoogle ScholarPubMed
53. Asselin, BL, Devidas, M, Zhou, T, et al. Cardioprotection and safety of dexrazoxane (DRZ) in children treated for newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or advanced stage lymphoblastic leukemia (T-LL). J Clin Oncol 2012; 30: 9504, (abstract).Google Scholar
54. Kopp, LM, Bernstein, ML, Schwartz, CL, et al. The effects of dexrazoxane on cardiac status and second malignant neoplasms (SMN) in doxorubicin-treated patients with osteosarcoma (OS). J Clin Oncol 2012; 30: 94877, (abstract).Google Scholar
55. Shaikh, F, Alexander, S, Dupuis, L, et al. Cardiotoxicity and second malignant neoplasms associated with dexrazoxane in children and adolescents: a systematic review of randomized trials and nonrandomized studies. J Clin Oncol 2014; 32: 10093, (abstract).Google Scholar
56. Barry, EV, Vrooman, LM, Dahlberg, SE, et al. Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. J Clin Oncol 2008; 26: 1106–1111.CrossRefGoogle ScholarPubMed
57. Schwartz, CL, Constine, LS, Villaluna, D, et al. A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 2009; 114: 2051–2059.CrossRefGoogle ScholarPubMed
58. Salzer, WL, Devidas, M, Carroll, WL, et al. Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children’s oncology group. Leukemia 2010; 24: 355–370.Google Scholar
59. Vrooman, LM, Neuberg, DS, Stevenson, KE, et al. The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: a report from the Dana-Farber Cancer Institute ALL Consortium. Eur J Cancer 2011; 47: 1373–1379.CrossRefGoogle ScholarPubMed
60. Tebbi, CK, Mendenhall, NP, London, WB, et al. Response-dependent and reduced treatment in lower risk Hodgkin lymphoma in children and adolescents, results of P9426: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2012; 59: 1259–1265.CrossRefGoogle ScholarPubMed
61. Seif, AE, Walker, DM, Li, Y, et al. Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric oncology patients. Pediatr Blood Cancer 2015; 62: 704–709.Google Scholar
62. Chow, EJ, Asselin, B, Schwartz, CL, et al. Late mortality and relapse after dexrazoxane (DRZ) treatment: an update from the Children’s Oncology Group (COG). J Clin Oncol 2014; 32: 10024 (abstract).Google Scholar