Cardiomyopathy in Childhood Cancer Survivors: Lessons from the Past and Challenges for the Future

Abstract

Childhood cancer survivors are at substantial risk for cancer treatment-related cardiomyopathy. Identification of those at highest risk has presented a longstanding challenge for survivorship researchers. To date, risk stratification approaches to screening and subsequent intervention have largely been driven by demographic and treatment-related exposures, possibly missing an opportunity for a more personalized approach. A growing body of literature suggests associations between cardiomyopathy and a number of genetic and acquired risk factors, supporting a need to incorporate these data into existing surveillance and intervention approaches. Efforts to reduce or eliminate modifiable cardiovascular risk factors are needed; however, the impact of these modifications remains to be seen. Moreover, challenges surrounding identification of effective cardiomyopathy treatment strategies in cancer survivors are ongoing. Despite these uncertainties, more accurate identification of those at highest risk and implementation of early and effective interventions for those with disease will lead to improved outcomes for childhood cancer survivors.

This is a preview of subscription content, access via your institution.

Fig. 1

References

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

  1. 1.

    Robison LL, Hudson MM. Survivors of childhood and adolescent cancer: life-long risks and responsibilities. Nat Rev Cancer. 2014;14:61–70.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355:1572–82.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Hudson MM, Ness KK, Gurney JG, et al. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA. 2013;309:2371–81.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol. 2009;27:2328–38.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Yahalom J, Portlock CS. Long-term cardiac and pulmonary complications of cancer therapy. Hematol Oncol Clin N Am. 2008;22:305–18. vii.

    Article  Google Scholar 

  6. 6.

    Moller TR, Garwicz S, Barlow L, et al. Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: a population-based study in the Nordic countries. J Clin Oncol. 2001;19:3173–81.

    CAS  PubMed  Google Scholar 

  7. 7.

    Mertens AC, Yasui Y, Neglia JP, et al. Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol. 2001;19:3163–72.

    CAS  PubMed  Google Scholar 

  8. 8.

    van der Pal HJ, van Dalen EC, Kremer LC, et al. Risk of morbidity and mortality from cardiovascular disease following radiotherapy for childhood cancer: a systematic review. Cancer Treat Rev. 2005;31:173–85.

    Article  PubMed  Google Scholar 

  9. 9.

    Adams MJ, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer. 2005;44:600–6.

    Article  PubMed  Google Scholar 

  10. 10.

    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;332:1738–43.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    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;23:2629–36.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    van Dalen EC, van der Pal HJ, Kok WE, et al. Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer. 2006;42:3191–8.

    Article  PubMed  Google Scholar 

  13. 13.

    Giantris A, Abdurrahman L, Hinkle A, et al. Anthracycline-induced cardiotoxicity in children and young adults. Crit Rev Oncol Hematol. 1998;27:53–68.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Grenier MA, Lipshultz SE. Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol. 1998;25:72–85.

    CAS  PubMed  Google Scholar 

  15. 15.

    Kremer LC, van Dalen EC, Offringa M, Voute PA. Frequency and risk factors of anthracycline-induced clinical heart failure in children: a systematic review. Ann Oncol. 2002;13:503–12.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Mulrooney DA, Armstrong GT, Huang S, et al. Cardiac outcomes in adult survivors of childhood cancer exposed to cardiotoxic therapy: a cross-sectional study. Ann Intern Med. 2016;164:93–101.

    Article  PubMed  Google Scholar 

  17. 17.

    Redfield MM, Jacobsen SJ, Burnett Jr JC, et al. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. 2003;289:194–202.

    Article  PubMed  Google Scholar 

  18. 18.

    Armenian SH, Sun CL, Shannon T, et al. Incidence and predictors of congestive heart failure after autologous hematopoietic cell transplantation. Blood. 2011;118:6023–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000;342:1077–84.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Krischer JP, Epstein S, Cuthbertson DD, et al. Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol. 1997;15:1544–52.

    CAS  PubMed  Google Scholar 

  21. 21.

    Armenian SH, Gelehrter SK, Vase T, et al. Screening for cardiac dysfunction in anthracycline-exposed childhood cancer survivors. Clin Cancer Res. 2014;20:6314–23.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    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;11:950–61.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Children’s Oncology Group: Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. www.survivorshipguidelines.org.

  24. 24.

    Sieswerda E, Postma A, van Dalen EC, et al. The Dutch Childhood Oncology Group guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors. Ann Oncol. 2012;23:2191–8.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Wallace WH, Thompson L, Anderson RA, Guideline DG. Long term follow-up of survivors of childhood cancer: summary of updated SIGN guidance. BMJ. 2013;346:f1190.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    United Kingdom Children’s Cancer Study Group Late Effects Group. Therapy based long term follow up: practice statement. 2005. http://www.cclg.org.uk (accessed November 2, 2015).

  27. 27.••

    Armenian SH, Hudson MM, Mulder RL, et al. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 2015;16:e123–36. Discordant practices exist between leading survivorship organizations. Collaborative efforts to harmonize these practices are ongoing. Future investigations are needed to optimize clinical care for cancer survivors.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.••

    Chow EJ, Chen Y, Kremer LC, et al. Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol. 2015;33:394–402. Newly developed models can reasonably predict cardiomyopathy risk in cancer survivors. These models should be utilized when developing future surveillance strategies.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Armenian SH, Bhatia S. Chronic health conditions in childhood cancer survivors: is it all treatment-related—or do genetics play a role? J Gen Intern Med. 2009;24 Suppl 2:S395–400.

    Article  PubMed  Google Scholar 

  30. 30.

    Blanco JG, Leisenring WM, Gonzalez-Covarrubias VM, et al. Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer. Cancer. 2008;112:2789–95.

    Article  PubMed  Google Scholar 

  31. 31.

    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;30:1415–21.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Wang X, Liu W, Sun CL, et al. Hyaluronan synthase 3 variant and anthracycline-related cardiomyopathy: a report from the Children’s Oncology Group. J Clin Oncol. 2014;32:647–53.

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.••

    Wong FL, Bhatia S, Landier W, et al. Cost-effectiveness of the Children’s Oncology Group long-term follow-up screening guidelines for childhood cancer survivors at risk for treatment-related heart failure. Ann Intern Med. 2014;160:672–83. Cardiomyopathy simulation models suggest that safe and efficacious screening reductions are possible for select groups of cancer survivors.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.••

    Yeh JM, Nohria A, Diller L. Routine echocardiography screening for asymptomatic left ventricular dysfunction in childhood cancer survivors: a model-based estimation of the clinical and economic effects. Ann Intern Med. 2014;160:661–71. Cardiomyopathy simulation models suggest that safe and efficacious screening reductions are possible for select groups of cancer survivors.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Ramjaun A, AlDuhaiby E, Ahmed S, et al. Echocardiographic detection of cardiac dysfunction in childhood cancer survivors: how long is screening required? Pediatr Blood Cancer. 2015;62:2197–203.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    American College of Cardiology Foundation Task Force on Expert Consensus D, Hundley WG, Bluemke DA, et al. ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus document on cardiovascular magnetic resonance: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. J Am Coll Cardiol. 2010;55:2614–62.

    Article  Google Scholar 

  37. 37.

    Armstrong GT, Plana JC, Zhang N, et al. Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging. J Clin Oncol. 2012;30:2876–84.

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Plana JC, Galderisi M, Barac A, et al. 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. J Am Soc Echocardiogr. 2014;27:911–39.

    Article  PubMed  Google Scholar 

  39. 39.

    Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1–90.

    Article  PubMed  Google Scholar 

  40. 40.

    Hunt SA, American College of C, American Heart Association Task Force on Practice G. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2005;46:e1–82.

    Article  PubMed  Google Scholar 

  41. 41.

    van Dalen EC, van der Pal HJ, Reitsma JB, et al. Management of asymptomatic anthracycline-induced cardiac damage after treatment for childhood cancer: a postal survey among Dutch adult and pediatric cardiologists. J Pediatr Hematol Oncol. 2005;27:319–22.

    Article  PubMed  Google Scholar 

  42. 42.

    Goldberg LR, Jessup M. Stage B heart failure: management of asymptomatic left ventricular systolic dysfunction. Circulation. 2006;113:2851–60.

    Article  PubMed  Google Scholar 

  43. 43.

    Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006;114:2474–81.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    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;20:4517–22.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Connuck DM, Sleeper LA, Colan SD, et al. Characteristics and outcomes of cardiomyopathy in children with Duchenne or Becker muscular dystrophy: a comparative study from the Pediatric Cardiomyopathy Registry. Am Heart J. 2008;155:998–1005.

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Raman SV, Hor KN, Mazur W, et al. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015;14:153–61.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Duboc D, Meune C, Pierre B, et al. Perindopril preventive treatment on mortality in Duchenne muscular dystrophy: 10 years’ follow-up. Am Heart J. 2007;154:596–602.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    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;22:820–8.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Bosch X, Rovira M, Sitges M, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol. 2013;61:2355–62.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2010;122:e584–636.

    Article  PubMed  Google Scholar 

  51. 51.

    Smith Jr SC, Collins A, Ferrari R, et al. Our time: a call to save preventable death from cardiovascular disease (heart disease and stroke). J Am Coll Cardiol. 2012;60:2343–8.

    Article  PubMed  Google Scholar 

  52. 52.

    Meacham LR, Chow EJ, Ness KK, et al. Cardiovascular risk factors in adult survivors of pediatric cancer—a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev. 2010;19:170–81.

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Oeffinger KC, Adams-Huet B, Victor RG, et al. Insulin resistance and risk factors for cardiovascular disease in young adult survivors of childhood acute lymphoblastic leukemia. J Clin Oncol. 2009;27:3698–704.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Herman EH, el-Hage AN, Ferrans VJ, Ardalan B. Comparison of the severity of the chronic cardiotoxicity produced by doxorubicin in normotensive and hypertensive rats. Toxicol Appl Pharmacol. 1985;78:202–14.

    CAS  Article  PubMed  Google Scholar 

  55. 55.••

    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;31:3673–80. Modifiable cardiovascular risk factors potentiate the risk for cardiomyopathy in at risk cancer survivors. The impact of detection of and early intervention for these acquired risk factors should be the focus of future investigations.

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Circulation. 2007;116:1081–93.

    Article  PubMed  Google Scholar 

  57. 57.

    Thompson PD, Franklin BA, Balady GJ, et al. Exercise and acute cardiovascular events placing the risks into perspective: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism and the Council on Clinical Cardiology. Circulation. 2007;115:2358–68.

    Article  PubMed  Google Scholar 

  58. 58.

    De Caro E, Smeraldi A, Trocchio G, et al. Subclinical cardiac dysfunction and exercise performance in childhood cancer survivors. Pediatr Blood Cancer. 2011;56:122–6.

    Article  PubMed  Google Scholar 

  59. 59.

    Hoffman MC, Mulrooney DA, Steinberger J, et al. Deficits in physical function among young childhood cancer survivors. J Clin Oncol. 2013;31:2799–805.

    Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Huang TT, Ness KK. Exercise interventions in children with cancer: a review. Int J Pediatr. 2011;2011:461512.

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Rock CL, Doyle C, Demark-Wahnefried W, et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin. 2012;62:243–74.

    Article  PubMed  Google Scholar 

  62. 62.

    Jones LW, Liang Y, Pituskin EN, et al. Effect of exercise training on peak oxygen consumption in patients with cancer: a meta-analysis. Oncologist. 2011;16:112–20.

    Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Kirkham AA, Davis MK. Exercise prevention of cardiovascular disease in breast cancer survivors. J Oncol. 2015;2015:917606.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Saro H. Armenian.

Ethics declarations

Conflict of Interest

Matthew J. Ehrhardt, Joy M. Fulbright, and Saro H. Armenian declare that they have no conflict of interest.

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

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

Matthew J. Ehrhardt and Joy M. Fulbright contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ehrhardt, M.J., Fulbright, J.M. & Armenian, S.H. Cardiomyopathy in Childhood Cancer Survivors: Lessons from the Past and Challenges for the Future. Curr Oncol Rep 18, 22 (2016). https://doi.org/10.1007/s11912-016-0510-4

Download citation

Keywords

  • Childhood cancer survivors
  • Cardiomyopathy
  • Anthracyclines
  • Mediastinal radiation
  • Treatment
  • Prevention
  • Risk stratification
  • Screening