Pediatric Drugs

, Volume 7, Issue 2, pp 67–76

Anthracycline-Induced Cardiotoxicity in Children with Cancer

Strategies for Prevention and Management
  • Diana Iarussi
  • Paolo Indolfi
  • Fiorina Casale
  • Vincenzo Martino
  • Maria Teresa Di Tullio
  • Raffaele Calabrò
Leading Article

Abstract

The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure (CHF) and dilated cardiomyopathy in adults and in children. The prevention of anthracycline-induced cardiotoxicity is particularly important in children who can be expected to survive for decades after being cured of their malignancy. Attempts to reduce anthracycline cardiotoxicity have been directed towards: (i) decreasing myocardial concentrations of anthracyclines and their metabolites by dose limitation and schedule modification; (ii) developing less cardiotoxic analogs; and (iii) concurrently administering cardioprotective agents to attenuate the effects of anthracyclines on the heart. As regards schedule modification, avoidance of anthracycline peak levels may reduce the pathologic and clinical cardiotoxicity, although this has not always been observed. The analogs of doxorubicin, such as idarubicin and epirubicin, have similar cardiotoxicity to that of doxorubicin when given in amounts of equivalent myelotoxicity. Liposomal anthracyclines are a new class of agents that may permit more specific organ targeting, thereby producing less systemic and cardiac toxicity, but more studies are required to assess the advantages, if any, of these preparations over classical anthracyclines. The cardioprotective agent, dexrazoxane, an iron chelator, is highly effective and provides short-term cardioprotection to most patients receiving even the most intensive doxorubicin-containing regimens. Its long-term benefits remain to be determined. In addition, data remain insufficient to make specific recommendations regarding current use of dexrazoxane in children.

It is thought that subtle abnormalities, related to anthracycline treatment in childhood, can develop into more permanent myocardial disease resulting in cardiomyopathy, which may progress to CHF. As regards the therapy of patients with anthracycline cardiotoxicity, two different situations have, therefore, to be considered: (i) if the patient presents with cardiac abnormalities, such as a reduction in fractional shortening at echocardiogram, without cardiac symptoms; and (ii) if the patient has CHF.

In the presence of CHF, recovery with digitalis-diuretic therapy alone seldom occurs, and in patients who have refractory hemodynamic decompensation, heart transplantation is indicated. In patients with CHF, therapy with ACE inhibitors induces improvement in left ventricular structure and function, but this improvement is transient. Randomized clinical trials are, therefore, necessary to determine the effects of ACE inhibitors in mild-to-moderate left ventricular dysfunction.

The beneficial effects of β-adrenoceptor antagonists (β-blockers) on cardiac function in heart failure due to anthracyclines seem comparable with those observed in other forms of heart failure with systolic dysfunction. Many drugs are available to treat children with CHF due to anthracycline treatment, but they are only palliative.

References

  1. 1.
    Young RC, Ozols RF, Myers CE. The anthracycline antineoplastic drug. N Engl J Med 1981; 305: 139–53PubMedCrossRefGoogle Scholar
  2. 2.
    Bu’Lock FA, Mott MG, Oakhill A, et al. Early identification of anthracycline cardiomyopathy: possibilities and implications. Arch Dis Child 1996; 75: 416–22PubMedCrossRefGoogle Scholar
  3. 3.
    Tan CT, Tasaka H, Yu KP, et al. Daunomycin, an antitumor antibiotic in the treatment of neoplastic disease. Cancer 1967; 20: 333–53PubMedCrossRefGoogle Scholar
  4. 4.
    Von Hoff DD, Layard M, Bacerzach SP, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91: 710–7Google Scholar
  5. 5.
    Lipshultz SE, Sallan SE. Cardiovascular abnormalities in long-term survivors of childhood malignancy. J Clin Oncol 1993; 11: 1199–203PubMedGoogle Scholar
  6. 6.
    Bleyer WA. The impact of childhood cancer on the United States and the world. CA Cancer J Clin 1990; 40: 355–67PubMedCrossRefGoogle Scholar
  7. 7.
    Hausdorf G, Morf G, Beron G, et al. Long term doxorubicin cardiotoxicity in childhood: non invasive evaluation of contractile state and diastolic filling. Br Heart J 1988; 60: 309–15PubMedCrossRefGoogle Scholar
  8. 8.
    Goorin AM, Chauvenet AR, Perez-Atayade, et al. Initial congestive heart failure, six to ten years after doxorubicin chemotherapy for childhood cancer. J Pediatr 1990; 116: 144–7PubMedCrossRefGoogle Scholar
  9. 9.
    Steinherz LJ, Steinherz PG, Tan CTC, et al. Cardiac toxicity 4–20 years after completing anthracycline therapy. JAMA 1991; 266: 1672–7PubMedCrossRefGoogle Scholar
  10. 10.
    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: 808–15PubMedCrossRefGoogle Scholar
  11. 11.
    Bu’Lock FA, Mott MG, Oakhill A, et al. Left ventricular diastolic function after anthracycline-chemotherapy in childhood: relation with systolic function, symptoms, and pathophysiology. Br Heart J 1995; 73: 340–3PubMedCrossRefGoogle Scholar
  12. 12.
    Kakadekar AP, Sandor GGS, Fryer C. Differences in dose scheduling as a factor in the etiology of anthracycline-induced cardiotoxicity in Ewing sarcoma patients. Med Pediatr Oncol 1997; 28: 22–6PubMedCrossRefGoogle Scholar
  13. 13.
    Steinhertz LJ, Graham T, Hurwitz R, et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Children’s Cancer Study Group. Pediatrics 1992; 89: 942–9Google Scholar
  14. 14.
    Weiss AJ, Manthel RW. Experience with the use of adriamycin in combination with other agents using a weekly schedule, with particular reference to lack of cardiac toxicity. Cancer 1977; 40: 2046–52PubMedCrossRefGoogle Scholar
  15. 15.
    Casper E, Gaynor JJ, Haidu SI. A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high grade extremity soft tissue sarcoma and an analysis of prognostic factors. Cancer 1991; 68: 1221–9PubMedCrossRefGoogle Scholar
  16. 16.
    Shapira J, Gotfried M, Lishner M, et al. Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen. Cancer 1990; 65: 870–3PubMedCrossRefGoogle Scholar
  17. 17.
    Lipshultz SE, Sallan SE, Giantris AL, et al. 48 hour continuous doxorubicin infusion is not cardioprotective in children assessed 18 months later: the DFCI 91001 ALL protocol. J Clin Oncol 1998; 17: 528–32Google Scholar
  18. 18.
    Goebel M. Oral idarubicin: an anthracycline derivate with unique properties. Ann Hematol 1993; 66: 33–43PubMedCrossRefGoogle Scholar
  19. 19.
    Robert J. Clinical pharmacokinetics of idarubicin. Clin Pharmokinet 1993; 24: 275–88CrossRefGoogle Scholar
  20. 20.
    Tan TC, Hancock C, Steinherz P, et al. Phase I and clinical pharmacological study of 4-demethoxydaunorubicin (idarubicin) in children with advanced cancer. Cancer Res 1987; 47: 2990–5PubMedGoogle Scholar
  21. 21.
    Cersosimo RJ, Hong WK. Epirubicin: a review of the pharmacology, clinical activity and adverse effects of an adriamycin analogue. J Clin Oncol 1986; 4: 425–39PubMedGoogle Scholar
  22. 22.
    Weiss R. The anthracyclines: will we ever find a better doxorubicin? Semin Oncol 1992; 19: 670–86PubMedGoogle Scholar
  23. 23.
    Jain KK, Camper ES, Geller NL, et al. A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J Clin Oncol 1985; 3: 818–26PubMedGoogle Scholar
  24. 24.
    van Dalen EC, van der Pal HJH, Bakker PJM, et al. Cumulative incidence and risk factors of mitoxantrone-induced cardiotoxicity in children: a systematic review. Eur J Cancer 2004; 40: 643–52PubMedCrossRefGoogle Scholar
  25. 25.
    Forssen EA, Coulter DM, Profitt RT. Clinical pharmacokinetics (PK) of liposomal daunorubicin (VS103). Cancer Res 1992; 52: 3255–61PubMedGoogle Scholar
  26. 26.
    Cohen P, Cill PS, Wernz J, et al. Absence of cardiac toxicity in patients who received 600 mg/mq of liposomal encapsulated daunorubicin (daunoxome) [abstract]. 33rd ASCO; 1997 May 17–20; DenverGoogle Scholar
  27. 27.
    Baruchel A, Auvrignon A, Perel Y, et al. Liposomal daunorubicin for childhood acute lymphoblastic leukemia: a phased I–II study [abstract]. 40th annual meeting of ASH; 1998 Dec 4–8; Miami BeachGoogle Scholar
  28. 28.
    Iarussi D, Auricchio U, Agretto A, et al. Protective effect of coenzyme Q10 on anthracyclines cardiotoxicity: control study in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma. Mol Aspects Med 1994; 15: 207–12CrossRefGoogle Scholar
  29. 29.
    Husken BC, de Jong J, Beekman B, et al. Modulation of the in vitro cardiotoxicity of doxorubicin by flavonoids. Cancer Chemother Pharmacol 1995; 17: 55–62CrossRefGoogle Scholar
  30. 30.
    Siveski-Iliskovic N, Hill M, Chow DA, et al. Probucol protect against adriamycin cardiomyopathy without interfering with its antitumor effect. Circulation 1995; 91: 10–5PubMedCrossRefGoogle Scholar
  31. 31.
    Speyer JL, Green MD, Zeleniuch-Jacquotte A, et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol 1992; 10: 117–27PubMedGoogle Scholar
  32. 32.
    Swain SM, Whaley FS, Gerber MC, et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 1997; 15: 1318–22PubMedGoogle Scholar
  33. 33.
    Hellmann K. Anthracycline cardiotoxicity prevention by dexrazoxane: breakthrough of a barrier sharpens antitumor profile and therapeutic index. J Clin Oncol 1996; 14: 332–3PubMedGoogle Scholar
  34. 34.
    Hellmann K. Dexrazoxane and the ASCO guidelines for the use of chemotherapy and radiotherapy protectans: a critique. J Clin Oncol 2000; 18: 2004–6PubMedGoogle Scholar
  35. 35.
    Bu’Lock FA, Gabriel HM, Oakhill A, et al. Cardioprotection by ICRF-187 against high dose anthracycline toxicity in children with malignant disease. Br Heart J 1993; 70: 185–8PubMedCrossRefGoogle Scholar
  36. 36.
    Rubio ME, Wegman A, Naeff MSJ, et al. ICRF-187 (Cardioxane®) protection against doxorubicin induced cardiomyopathy in paediatric osteosarcoma patients. 31st ASCO; 1995 May 20–23; Los AngelesGoogle Scholar
  37. 37.
    Wexler LH, Andrich MP, Venzon D, et al. Randomized trial of the cardioprotective agent ICRF-187 in paediatric sarcoma patients treated with doxorubicin. J Clin Oncol 1996; 14: 362–72PubMedGoogle Scholar
  38. 38.
    Wexler LH. Ameliorating anthracycline cardiotoxicity in children with cancer: clinical trials with dexrazoxane. Semin Oncol 1998; 25Suppl. 10: 86–92PubMedGoogle Scholar
  39. 39.
    Schucther LM, Hensley ML, Meropol NJ, et al. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2002; 20: 2885–903Google Scholar
  40. 40.
    Lopez M, Vici P, Di Lauro K, et al. Randomized prospective clinical trial of high-dose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas. J Clin Oncol 1998; 16: 86–92PubMedGoogle Scholar
  41. 41.
    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: 145–53PubMedCrossRefGoogle Scholar
  42. 42.
    Steinberg JS, Cohen AJ, Wasserman AG, et al. Acute arrhythmogenicity of doxorubicin administration. Cancer 1987; 60: 1213–8PubMedCrossRefGoogle Scholar
  43. 43.
    Bristow MR, Thompson PD, Martin RP, et al. Early anthracyclines cardiotoxicity. Am J Med 1978; 65: 823–32PubMedCrossRefGoogle Scholar
  44. 44.
    Lipshultz SE, Lipsitz SR, Mone SM, et al. Female sex and higher dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 1995; 332: 1738–43PubMedCrossRefGoogle Scholar
  45. 45.
    Iarussi D, Galderisi M, Ratti G, et al. Left ventricular systolic and diastolic function after anthracycline chemotherapy in childhood. Clin Cardiol 2001; 24: 663–9PubMedCrossRefGoogle Scholar
  46. 46.
    Iarussi D, Indolfi P, Pisacane C, et al. Comparison of left ventricular function by echocardiogram in patients with Wilms’ tumor treated with anthracyclines vs those not so treated. Am J Cardiol 2003; 92: 359–61PubMedCrossRefGoogle Scholar
  47. 47.
    Davis LE, Brown CEL. Peripartum heart failure in a patient treated previously with doxorubicin. Obstet Gynecol 1988; 71: 506–8PubMedGoogle Scholar
  48. 48.
    Lefrak EA, Pitha J, Rosenheim S, et al. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 1973; 32: 302–14PubMedCrossRefGoogle Scholar
  49. 49.
    Saini J, Rich MW, Lyss AP. Reversibility of severe left ventricular dysfunction due to doxorubicin cardiomyopathy: report of three cases. Ann Intern Med 1987; 106: 814–6PubMedGoogle Scholar
  50. 50.
    Aricò M, Nespoli L, Pedroni E, et al. Heart transplantation in a child with doxorubicin-induced cardiomyopathy [letter]. N Engl J Med 1988; 319: 1353PubMedGoogle Scholar
  51. 51.
    SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991; 325: 293–302CrossRefGoogle Scholar
  52. 52.
    Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angioten-sin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145–53CrossRefGoogle Scholar
  53. 53.
    Colan SD, Borow KM, Neumann A. Left ventricular end-systolic wall stress-velocity of fiber shortening relation: a load-independent index of myocardial contractility. J Am Coll Cardiol 1984; 4: 715–24PubMedCrossRefGoogle Scholar
  54. 54.
    Borow KM, Colan SD, Neumann A. Altered left ventricular mechanics in patients with valvular aortic stenosis and coarctation of the left aorta: effects on systolic performance and late outcome. Circulation 1985; 72: 512–22CrossRefGoogle Scholar
  55. 55.
    Francis GS, Goldsmith SR, Levine TB, et al. The neurohumoral axis in congestive heart failure. Ann Intern Med 1984; 101: 370–7PubMedGoogle Scholar
  56. 56.
    Jensen BV, Nielsen SL, Skovsgaard T. Treatment with angiotensin-converting-enzyme inhibitor for epirubicin-induced dilated cardiomyopathy. Lancet 1996: 347: 297–9PubMedCrossRefGoogle Scholar
  57. 57.
    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: 4517–22PubMedCrossRefGoogle Scholar
  58. 58.
    Iarussi D, Martino V, Iacono C, et al. Heart failure after pulmonary thromboembolism in subject treated with anthracycline in childhood. Ital Heart J 2004; 5: 294–7Google Scholar
  59. 59.
    Silber JH, Cnaan A, Clark BJ, et al. Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. Clin Oncol 2004; 22: 820–8CrossRefGoogle Scholar
  60. 60.
    Foody JM, Farrel MH, Krumholtz HM. Beta-blocker therapy in heart failure: scientific review. JAMA 2002; 287: 883–9PubMedCrossRefGoogle Scholar
  61. 61.
    Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee to revise the 1995 guidelines for the evaluation and management of heart failure). J Am Coll Cardiol 2001; 38: 2101–13PubMedCrossRefGoogle Scholar
  62. 62.
    Auslender M, Artman M. Overview of the management of pediatric heart failure. Prog Pediatr Cardiol 2000; 11: 231–41PubMedCrossRefGoogle Scholar
  63. 63.
    Lewis AB, Chabot M. The effect of treatment with angiotensin-converting enzyme inhibitors on survival of pediatric patients with dilated cardiomyopathy. Pediatr Cardiol 1993; 14: 9–12PubMedGoogle Scholar
  64. 64.
    Bruns LA, Canter CE. Should beta-blockers be used for the treatment of pediatric patients with chronic heart failure. Pediatrie Drugs 2002; 4: 771–8Google Scholar
  65. 65.
    Bruns LA, Chrisant MK, Lamour JM, et al. Carvedilol as therapy in pediatric heart failure: an initial multicenter experience. J Pediatr 2001; 138: 505–11PubMedCrossRefGoogle Scholar
  66. 66.
    Azeka E, Franchini Ramires JA, Valler C, et al. Delisting of infants and children from the heart transplantation waiting list after carvedilol treatment. J Am Coll Cardiol 2002; 40: 2034–8PubMedCrossRefGoogle Scholar
  67. 67.
    Shaddy RE, Olsen SL, Bristow MR, et al. Efficacy and safety of metoprolol in the treatment of doxorubicin-induced cardiomyopathy in pediatric patients. Am Heart J 1995; 129: 197–9PubMedCrossRefGoogle Scholar
  68. 68.
    Noori A, Lindenfeld J, Wolfel E, et al. Beta-blockade in adriamycin-induced cardiomyopathy. J Card Fail 2000; 6: 115–9PubMedGoogle Scholar
  69. 69.
    Eichhorn EJ, Bristol MR. Practical guidelines for initiation of beta-adrenergic blockade in patients with chronic heart failure. Am J Cardiol 1997; 79: 794–8PubMedCrossRefGoogle Scholar
  70. 70.
    Shaddy RE, Curtin EL, Sower B, et al. The pediatric randomized carvedilol trial in children with heart failure: rationale and design. Am Heart J 2002; 144: 383–9PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Diana Iarussi
    • 1
  • Paolo Indolfi
    • 2
  • Fiorina Casale
    • 2
  • Vincenzo Martino
    • 1
  • Maria Teresa Di Tullio
    • 2
  • Raffaele Calabrò
    • 1
  1. 1.Cattedra di Cardiologia, Dipartimento di Scienze Cardiotoraciche e RespiratorieSeconda Università di NapoliNaplesItaly
  2. 2.Servizio di Oncologia Pediatrica, Dipartimento di PediatriaSeconda Università di NapoliNaplesItaly

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