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AAP Grand Rounds 18:62-63 (2007)
© 2007 American Academy of Pediatrics
Anthracyclines such as daunorubicin and idarubicin are antineoplastic drugs effective in acute myelogenous leukemia (AML). However, their use is limited by cardiomyopathy. Investigators from the University Children’s Hospital, Muenster, and Medical School, Hannover, both in Germany, evaluated short-term (less than one year) and long-term (more than one year) anthracycline-associated cardiomyopathy in pediatric AML patients. Study subjects were treated between 1993 and 2003 in the two large German clinical oncology trials (AML-BFM93 and AML-BFM98) that used anthracyclines in conjunction with cytarabine and etoposide for induction chemotherapy. Cumulative anthracycline doses were calculated. Clinical cardiotoxicity was defined as clinical signs and symptoms of cardiomyopathy not attributable to other known causes such as sepsis or renal failure.
A total of 1,207 patients were evaluated. Of these, 1,010 patients had de novo AML, 121 had AML associated with Down syndrome (DS-AML), and 76 had secondary AML (AML that occurs following treatment for another malignancy). Median follow-up of the patients was 5.3 years (range 0.8–11.5 years).
The patients received anthracyclines at cumulative doses ranging from 300–450 mg/m2. Data on early cardiotoxicity were available for 885 (73%) patients, on late cardiotoxicity for 547 (45%) patients, and on both early and late cardiotoxicity for 467 (39%) patients. Thirty-eight (4.3%) patients, including three with DS-AML and one with secondary AML, developed early cardiomyopathy. Late cardiomyopathy developed in 16 patients (cumulative incidence after 11 years: 5% ± 1%). Nine (2.5% ± 1%) of these patients showed clinical symptoms, and five of them had a persistent abnormal shortening fraction. Late subclinical cardiomyopathy occurred temporarily in seven patients. The risk of developing late clinical cardiotoxicity was highest in patients with early cardiotoxicity and in patients with secondary malignancy.
The investigators concluded that the frequency of anthracycline-associated cardiomyopathy was low in patients treated on the AML-BFM protocols.
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Commentary by
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| Pediatric Hematology/Oncology, Case Western Reserve University, Rainbow Babies & Children’s Hospital, Cleveland, OH |
Anthracyclines are an essential component of the treatment for AML in children. In adults cardiomyopathy has been shown to occur at cumulative doses of 550 mg/m2 or greater.1 Children appear to be more sensitive with several studies demonstrating the development of cardiac dysfunction when cumulative doses reach 300 mg/m2.2,3
Early cardiotoxicity may occur during the treatment and up to one year later, is often transient, and is manifest by tachycardias, dysrhythmias, or nonspecific ECG changes. Late cardiotoxicity, with onset more than one year after completion of therapy, correlates with the cumulative dose of anthracyclines and is manifest by congestive heart failure.
This study adds to a growing body of literature regarding therapy-induced late effects in survivors of childhood cancer. Although anthracycline-induced cardiotoxicity is well described, data from prospective clinical trials with pediatric AML patients is limited. In one report, investigators from St. Jude reported cardiac abnormalities in 8% of survivors of AML, similar to the rates reported by Creutzig et al.4 By focusing on this specific sub-population of patients who were treated in a uniform manner, both investigators reduced the impact of potential confounding variables. Unfortunately, though, these results are not likely generalizable to patients with AML or other malignancies who receive anthracyclines at different doses, infusion times, or with different combinations of chemotherapeutic agents.
While the low rate of cardiac complications is encouraging, these results should be interpreted cautiously. Only 45% of the original 1,207 patients had data available to examine late cardiotoxicity. Some of these patients may have died; however, the investigators do not address why the compliance with follow-up was so poor. This jeopardizes the validity of the study because of the potential for selection bias. Additionally, the mean follow-up of the cohort was relatively short at 5.3 years; previously reported data suggest that the risk of late cardiotoxicity increases with duration of follow-up time.5–6 Continued follow-up in this large cohort of patients will be important.
Strategies to lessen the risk of cardiac toxicity include: 1) administering the anthracycline as a continuous infusion over 24–48 hours; 2) administering cardioprotectant agents such as dexrazoxane immediately prior to the anthracycline; and 3) switching to less cardiotoxic anthracyclines such as liposomal doxorubicin. Although these strategies have been adopted into some treatment protocols, well-designed clinical trials examining these interventions are needed.
Monitoring for the development of cardiomyopathy has only recently been standardized by guidelines produced by the Children’s Oncology Group.7 These guidelines recommend serial evaluations with echocardiograms for patients who have received chemotherapy, and serial echocardiograms as well as evaluations by a cardiologist for patients who have received chest radiation. General pediatricians will need to become familiar with these guidelines as increasing numbers of survivors of childhood cancer complete their therapy and return to their primary care providers.
| Editors’ Note |
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| References |
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