Survivors of childhood cancers are at significantly increased risk of cardiotoxicity if treated with anthracyclines, according to a new review of the literature. That toxicity, though, can be substantially ameliorated if dexrazoxane is administered before each anthracycline dose.
“Survival rates of childhood cancers have substantially improved over the past several decades as a result of new and improved treatments,” wrote review authors led by Steven Lipshultz, MD, of Wayne State University School of Medicine in Detroit, Michigan. “As a result of increased survival, however, these patients are at an increased risk of adverse treatment-related effects.” The review was published online in the British Journal of Clinical Pharmacology.
Anthracyclines such as doxorubicin, daunorubicin, and epirubicin are among the more commonly used chemotherapy agents for pediatric cancers. Studies have shown that anthracyclines can reduce left ventricular (LV) wall thickness and mass, and result in LV fractional shortening. The risk for heart failure, valvular disease, and pericardial disease in children treated with these agents is up to five times higher than their healthy siblings. As many as half of all childhood cancer survivors treated with anthracyclines will have some form of cardiac dysfunction within 20 years.
“A high cumulative dose of anthracyclines is the most important risk factor for cardiotoxicity among survivors,” the authors wrote. At doses greater than 300 mg/m2, the risk of any cardiotoxicity is 11 times that of people who received doses below that threshold. Studies have also shown that concomitant mediastinal or cranial radiation can raise the cardiotoxicity risk.
There may be non-modifiable risk factors associated with cardiac dysfunction. For example, several studies have found that there may be a genetic component predisposing survivors to this complication; a variant of the ABCC5 gene appeared to increase the risk, while another variant of the NOS3 gene was linked to an increase in LV ejection fraction, suggesting a protective effect. Survivors treated with these agents should also work to address modifiable risk factors related to cardiac function such as physical inactivity and obesity.
The review also found strong support for the protective effects of dexrazoxane. The drug is believed to chelate iron, thereby interfering with iron-mediated free radical generation, which can decrease tissue damage caused by the anthracyclines.
Multiple studies have now shown that dexrazoxane can offer cardioprotection without negative effects on the anthracycline therapy. For example, a study of children with acute lymphoblastic leukemia treated with doxorubicin either with or without dexrazoxane showed no differences in event-free survival after 8.7 years of follow-up, and found the additional drug to be cardioprotective. Other studies have also shown no increased risk of second malignant neoplasms with dexrazoxane.
In a press release, the authors stressed that dexrazoxane should be considered a critical part of therapy for young patients treated with anthracyclines. “If implemented, more children with cancer who are treated with anthracyclines may be cured of their malignancy and with less chemotherapy-associated toxicity and late effects,” Lipshultz said.