Cardiotoxicity is a well-recognised late effect of therapy for childhood and adolescent malignancies and is a serious problem for long-term survivors. Cardiotoxicity may be caused by chemotherapy, radiation therapy or the combined use of both modalities. A survey of paediatric cardiology centres in North America found that more than 12% of all patients with cardiomyopathy had been treated for cancer during childhood or adolescence. 1 In a large cohort of American patients who had survived at least five years from a diagnosis of paediatric cancer, the standardised mortality ratio (SMR) for overall mortality was 10.8 and the SMR for cardiac mortality was 8.2. 2 A study from the Nordic countries produced similar findings (overall SMR, 10.8; cardiac and circulatory system death SMR, 5.8). 3 The SMR for sudden or ill-defined deaths was 3.9; some of these deaths were probably attributable to cardiac causes.
Mortality from anthracycline-induced cardiac failure is substantial, with some large studies reporting rates higher than 20%. 4,5 A study of 474 15-year survivors of childhood cancer found overall SMRs of 3.78 for men and 4.84 for women, with a cardiac SMR for men of 7.91.9├é┬á6 Exposure to doxorubicin was associated with higher risk of death from cardiac disease.
Cardiotoxicity can present as acute, early onset or late onset. It may be subclinical and asymptomatic or progressive with the development of clinical symptoms. Clinical presentation and relationship to known risk factors for chemotherapy-induced cardiotoxicity differ, particularly between acute cardiotoxicity and other categories. 7 Acute cardiotoxicity may occur with or without subsequent development of other forms of cardiotoxicity. Early-onset cardiotoxicity occurs during therapy or within the first year after treatment, and is defined as congestive heart failure not attributable to other known causes or changes in cardiac function that prompted permanent discontinuation of anthracycline therapy. 8 Late toxicity occurs at least one year after the completion of therapy and is defined by an abnormal end systolic wall stress (afterload) or contractility. 9 Of a cohort of 6,493 childhood cancer patients treated with anthracycline, 1.6% were reported to have developed early clinical cardiotoxicity. 8 Late-onset cardiotoxicity is also described in more than half of a cohort of 115 children treated for acute lymphoblastic leukaemia (ALL) with doxorubicin from one to 15 years earlier. 9/>/>
Table 1: Drugs Associated with Cardiotoxicity
- S E Lipshultz, ├óÔé¼┼øVentricular Dysfunction Clinical Research in Infants, Children and Adolescents├óÔé¼┼Ñ, Progress in Pediatric Cardiology, (2000), pp. 121├óÔé¼ÔÇ£128.
- A C Mertens, Y Yasui, J P Neglia, et al., ├óÔé¼┼øLate Mortality Experience in Five-year Survivors of Childhood and Adolescent Cancer: The Childhood Cancer Survivor Study├óÔé¼┼Ñ, Journal of Clinical Oncology, 19 (2001) 13, pp. 3,163├óÔé¼ÔÇ£3,172.
- T R Moller, S Garwicz, L Barlow, et al., ├óÔé¼┼øDecreasing Late Mortality Among Five-year Survivors of Cancer in Childhood and Adolescence: A Population-based Study in the Nordic Countries├óÔé¼┼Ñ, ibid., pp. 3,173├óÔé¼ÔÇ£3,181.
- D D Von Hoff, M W Layard, P Basa, et al., ├óÔé¼┼øRisk Factors for Doxorubicin-induced Congestive Heart Failure├óÔé¼┼Ñ, Annals of Internal Medicine, (1979), pp. 97,710├óÔé¼ÔÇ£97,717.
- C Praga, G Beretta, P L Vigo, et al., ├óÔé¼┼øAdriamycin Cardiotoxicity ├óÔé¼ÔÇ£ Survey of 1273 Patients├óÔé¼┼Ñ, Cancer Treatment Reports, 63 (1979) 5, pp. 827├óÔé¼ÔÇ£834.
- D M Green, A Hyland, C S Chung, et al., ├óÔé¼┼øCancer and Cardiac Mortality Among 15-year Survivors of Cancer Diagnosed During Childhood or Adolescence├óÔé¼┼Ñ, Journal of Clinical Oncology, 17 (1999) 10, pp. 3,207├óÔé¼ÔÇ£3,215.
- A Giantris, L Abdurrahman, A Hinkle, et al., ├óÔé¼┼øAnthracycline-induced Cardiotoxicity in Children and Young Adults├óÔé¼┼Ñ, Critical Reviews in Oncology/Hematology, 27 (1998) 1, pp. 53├óÔé¼ÔÇ£68.
- J P Krischer, S Epstein, D D Cuthbertson, et al., ├óÔé¼┼øClinical Cardiotoxicity Following Anthracycline Treatment for Childhood Cancer: The Pediatric Oncology Group Experience├óÔé¼┼Ñ, Journal of Clinical Oncology, 15 (1997) 4, pp. 1,544├óÔé¼ÔÇ£1,552.
- S E Lipshultz, S D Colan, R D Gelber, et al., ├óÔé¼┼øLate Cardiac Effects of Doxorubicin Therapy for Acute Lymphoblastic- Leukemia in Childhood├óÔé¼┼Ñ, New England Journal of Medicine, 324 (1991) 12, pp. 808├óÔé¼ÔÇ£815.
- L J Steinherz and L H Wexler, ├óÔé¼┼øThe Prevention of Anthracycline Cardiomyopathy├óÔé¼┼Ñ, Progress in Pediatric Cardiology, 8 (1998) 3, pp. 97├óÔé¼ÔÇ£108.
- A Jemal, A Thomas, T Murray, et al., ├óÔé¼┼øCancer Statistics 2002├óÔé¼┼Ñ, Cancer, 52 (2002) 1, pp. 23├óÔé¼ÔÇ£47.
- V C Simbre, M J Adams, S S Deshpande, et al., ├óÔé¼┼øCardiomyopathy Caused by Antineoplastic Therapies├óÔé¼┼Ñ, Current Treatment Options in Cardiovascular Medicine, (2001), pp. 3,493├óÔé¼ÔÇ£3,505.
- V B Pai and M C Nahata, ├óÔé¼┼øCardiotoxicity of Chemotherapeutic Agents├óÔé¼┼Ñ, Drug Safety, 22 (2000) 4, pp. 263├óÔé¼ÔÇ£302.
- S E Lipshultz, A L Giantris, S R Lipsitz, et al., ├óÔé¼┼øDoxorubicin Administration by Continuous Infusion is Not Cardioprotective: The Dana-Farber 91-01 Acute Lymphoblastic Leukemia Protocol├óÔé¼┼Ñ, Journal of Clinical Oncology, 20 (2002) 6, pp. 1,677├óÔé¼ÔÇ£1,682.
- S E Lipshultz, S D Colan, L B Silverman, et al., ├óÔé¼┼øDexrazoxane Reduces Incidence of Doxorubicin-associated Acute Myocardiocyte Injury in Patients with Acute Lymphoblastic Leukemia (ALL)├óÔé¼┼Ñ, Proc. ASCO, (2002), p. 21,390a.
- S E Lipshultz, S R Lipsitz, S M Mone, et al., ├óÔé¼┼øFemale Sex and Higher Drug Dose as Risk-Factors for Late Cardiotoxic Effects of Doxorubicin Therapy for Childhood-Cancer├óÔé¼┼Ñ, New England Journal of Medicine, 332 (1995) 26, pp. 1,738├óÔé¼ÔÇ£1,743.
- M A Grenier and S E Lipshultz, ├óÔé¼┼øEpidemiology of Anthracycline Cardiotoxicity in Children and Adults├óÔé¼┼Ñ, Seminars in Oncology, 25 (1998) 4, pp. 72├óÔé¼ÔÇ£85.
- S E Lipshultz, S P Sanders, A M Goorin, et al., ├óÔé¼┼øMonitoring for Anthracycline Cardiotoxicity├óÔé¼┼Ñ, Pediatrics, 93 (1994) 3, pp. 433├óÔé¼ÔÇ£437.
- S E Lipshultz, S E Sallan, V Dalton, et al., ├óÔé¼┼øElevated Serum Cardiac Troponin-T as a Marker for Active Cardiac Injury During Therapy for Childhood Acute Lymphoblastic Leukemia (ALL)├óÔé¼┼Ñ, Proc. ASCO, (1999), p. 18,568a.
- F Hayakawa, Y Komada, M Hirayama, et al., ├óÔé¼┼øPlasma Levels of Natriuretic Peptides in Relation to Doxorubicin-induced Cardiotoxicity and Cardiac Function in Children with Cancer├óÔé¼┼Ñ, Medical and Pediatric Oncology, 37 (2001) 1, pp. 4├óÔé¼ÔÇ£9.
- L J Steinherz, T Graham, R Hurwitz, et al., ├óÔé¼┼øGuidelines for Cardiac Monitoring of Children During and After Anthracycline Therapy ├óÔé¼ÔÇ£ Report of the Cardiology Committee of the Childrens-Cancer-Study-Group├óÔé¼┼Ñ, Pediatrics, 89 (1992) 5, pp. 942├óÔé¼ÔÇ£949.
- L C M Kremer, E C van Dalen, M Offringa, et al., ├óÔé¼┼øAnthracycline-induced Clinical Heart Failure in a Cohort of 607 Children: Long-term Follow-up Study├óÔé¼┼Ñ, Journal of Clinical Oncology, 19 (2001) 1, pp. 191├óÔé¼ÔÇ£196.
- T Nousiainen, E Vanninen, E Jantunen, et al., ├óÔé¼┼øAnthracycline-induced Cardiomyopathy: Long-term Effects on Myocardial Cell Integrity, Cardiac Adrenergic Innervation and Fatty Acid Uptake├óÔé¼┼Ñ, Clinical Physiology, 21 (2001) 1, pp. 123-128.
- T J Jeon, J D Lee, J W Ha, et al., ├óÔé¼┼øEvaluation of Cardiac Adrenergic Neuronal Damage in Rats with Doxorubicininduced Cardiomyopathy Using Iodine-131 MIBG Autoradiography and PGP 9.5 Immunohistochemistry├óÔé¼┼Ñ, European Journal of Nuclear Medicine, 27 (2000) 6, pp. 686├óÔé¼ÔÇ£693.
- P Nony, J P Guastalla, P Rebattu, et al., ├óÔé¼┼øIn Vivo Measurement of Myocardial Oxidative Metabolism and Blood Flow does not Show Changes in Cancer Patients Undergoing Doxorubicin Therapy├óÔé¼┼Ñ, Cancer Chemotherapy and Pharmacology, 45 (2000) 5, pp. 375├óÔé¼ÔÇ£380.
- S Schaefer, ├óÔé¼┼øMagnetic Resonance Spectroscopy in Human Cardiomyopathies├óÔé¼┼Ñ, Journal of Cardiovascular Magnetic Resonance, 2 (2000) 2, pp. 151├óÔé¼ÔÇ£157.
- K Nysom, K Holm, S R Lipsitz, et al., ├óÔé¼┼øRelationship Between Cumulative Anthracycline Dose and Late Cardiotoxicity in Childhood Acute Lymphoblastic Leukemia├óÔé¼┼Ñ, Journal of Clinical Oncology, 16 (1998) 2, pp. 545├óÔé¼ÔÇ£550.
- S E Lipshultz, ├óÔé¼┼øDexrazoxane for Protection Against Cardiotoxic Effects of Anthracyclines in Children├óÔé¼┼Ñ, Journal of Clinical Oncology, 14 (1996) 2, pp. 328├óÔé¼ÔÇ£331.
- M A Pfeffer, E Braunwald, L A Moye, et al., ├óÔé¼┼øEffect of Captopril on Mortality and Morbidity in Patients with Leftventricular Dysfunction After Myocardial Infarction ├óÔé¼ÔÇ£ Results of the Survival and Ventricular Enlargement Trial├óÔé¼┼Ñ, New England Journal of Medicine, 327 (1992) 10, pp. 669├óÔé¼ÔÇ£677.