Dr Andrea S Hinkle , Cindy B Proukou , Sampada S Deshpande , Sarah A Duffy , Amy M Kozlowski , Carol A French , Dr Steven E Lipshultz Division of Pediatric Cardiology, Golisano Children’s Hospital at Strong and University of Rochester Medical Center; Department of Pediatrics, University of Rochester School of Medicine and Dentistry; and Division of Hematology/Oncology, Golisano Children’s Hospital at Strong and University of Rochester Medical Center, Rochester, New York

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 ⁶ 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

Anthracyclines are the most common class of chemotherapeutic agents associated with adverse effects on the heart. Anthracyclines were introduced as chemotherapeutic agents in the late 1960s (daunorubicin) and early 1970s (doxorubicin). ¹⁰ They are highly effective against a wide range of malignancies, and survival from paediatric cancers has increased from 45% to 77% since their introduction, although some of the improvement can be attributed to other agents and improvements in supportive care. ¹¹ Thus, the benefits of anthracyclines currently outweigh their cardio-toxicity. The most commonly used drugs in this class are doxorubicin (Adriamycin), daunorubicin (Cerubidine) and idarubicin (Idamycin). ⁷ Other chemotherapeutic agents that may cause cardiac abnormalities include alkylating agents, antimetabolites and antimicrotubule agents (see Table 1). ^12,13