The study is a five-year follow-up to a 2004 landmark study published in The New England Journal of Medicine that showed it was possible to reduce and even prevent heart damage, a known side effect in children receiving doxorubicin (Adriamycin®), from occurring during cancer therapy. Doxorubicin is a very effective form of chemotherapy for acute lymphoblastic leukemia (ALL).
Although about 80 percent of children with ALL achieve a cancer cure, they face delayed toxic effects from ALL and its therapies years later. Cardiac toxicity is particularly a problem for survivors of childhood cancer, producing increased rates of heart failure and cardiac death 20 to 30 years after treatment. Children treated with doxorubicin have more than a three-fold increased risk of dying of heart disease than those who did not receive doxorubicin. Therefore, the prevention of this late cardiotoxicity in long-term survivors of childhood ALL was the primary end-point of this study and what Steven Lipshultz, M.D., professor and chair of pediatrics at the Miller School and the study’s principal investigator, and his colleague report in Lancet Oncology.
More than 200 children newly diagnosed with high-risk ALL, the most common malignancy in children, were enrolled in this multicenter, randomized, controlled trial, conducted as part of the Dana-Farber Cancer Institute Childhood ALL Consortium platform in Boston under principal investigator Stephen Sallan, M.D. Half of the children were treated using the standard multi-agent protocol for ALL, which includes doxorubicin. The other half were treated with an infusion of dexrazoxane 30 minutes before receiving doxorubicin. Dexrazoxane had not been known to provide long-term protection of the heart in either children or adults receiving the same type of chemotherapy.
“When we were recently unblinded to the results of this study, we found that girls treated with dexrazoxane five years earlier had normal heart function and did not have any pathologic remodeling of the heart, in contrast to girls who did not receive dexrazoxane, where both heart function and remodeling showed progressive deterioration,” said Lipshultz. “For boys, dexrazoxane was not cardioprotective. We previously reported that young girls being treated with doxorubicin for childhood cancer at the same doses as boys were significantly more likely to have damaged hearts as long-term survivors, so the fact dexrazoxane can protect their hearts is very encouraging.”
“The findings of the present trial suggest that dexrazoxane use does not adversely affect oncological efficacy in children with high-risk ALL, and reduces cardiotoxicity in long-term survivors,” adds Lipshultz. “We encourage pediatric oncology protocols for children with high-risk ALL containing doxorubicin to use dexrazoxane before doxorubicin dosing, and to do so in the setting of clinical trials in which dexrazoxane’s use can be monitored.”
The implications in the years to come are enormous, considering the statistics. There are an estimated 300,000 survivors of childhood cancer currently alive in the United States. One study estimates that the childhood cancer survivors are eight times more likely to suffer cardiac death than the normal population, even 25 years after therapy, and this is significantly higher in childhood cancer survivors treated with doxorubicin. As such, having a new treatment that has been validated in a randomized clinical trial to protect the heart from the toxicity of doxorubicin chemotherapy may ultimately reduce the increased risk of heart failure and cardiac death these children face.
“This new paradigm for successfully treating childhood cancer is the balance over a child’s life of oncologic efficacy with toxicities and late effects, and how that balance is in terms of the patient’s quality of life over their lifetime,’‘ Lipshultz says. “Hopefully, use of dexrazoxane may improve this overall balance for girls and may lead to other ways to protect the hearts of boys.”