Drug Protects Heart in Children Receiving Common Chemotherapy
Adapted from the NCI Cancer Bulletin.
The drug dexrazoxane, which can protect heart tissue from the oxidative damage caused by doxorubicin and other anthracycline drugs, reduced the occurrence of long-term heart damage in children undergoing treatment for high-risk acute lymphoblastic leukemia (ALL).
Importantly, however, dexrazoxane did not reduce the effectiveness of anthracycline chemotherapy—children in the study had the same risks of long-term recurrence and development of a second cancer regardless of whether they received the protective drug. The results from the study, which was supported in part by a grant from NCI’s Office of Cancer Survivorship, were published online September 15, 2010, in Lancet Oncology.
“Our goal has been to change the paradigm of what defines a successful treatment for childhood cancer,” said the study’s lead investigator, Steven Lipshultz, M.D., of the University of Miami Leonard M. Miller School of Medicine. “We need to have a balance between oncologic efficacy on one side, which we want to maximize, and the toxicities and late effects, which we want to minimize.”
More than half of children in the United States who have undergone treatment for any type of cancer received chemotherapy with an anthracycline. “What we’ve learned from the first generation of survivors of childhood cancer is that these children are at risk for late effects of treatment, and one of the most common late effects is damage to the heart, which is progressive over time,” explained Dr. Lipshultz. Children treated with an anthracycline have more than a threefold increased risk of cardiac death 30 years after treatment compared with their untreated peers.
To test whether dexrazoxane could help minimize late cardiac effects, Dr. Lipshultz and his colleagues with the Dana-Farber Cancer Institute Childhood ALL Consortium, which is directed by Stephen Sallan, M.D., enrolled 205 children with high-risk ALL into a randomized trial between 1996 and 2000. The children, who were recruited from nine hospitals in the United States, Canada, and Puerto Rico, received either 10 doses of high-dose doxorubicin (300 mg per square meter of body surface) alone or doxorubicin preceded by an infusion of dexrazoxane.
After treatment, the researchers followed the children with echocardiographic measurements of the heart’s structure and functioning, which they compared with age-appropriate predicted measurements according to data from 285 healthy children at the same hospitals. The physicians recording the outcomes remained blinded to the patients’ treatment assignment throughout follow-up—as long as 15 years at the time of the study’s publication.
Sixty-six children who received doxorubicin alone and 68 children who received doxorubicin and dexrazoxane had at least one echocardiogram after treatment. After 5 years of follow-up, the children who received doxorubicin alone had a statistically significant deficit in several measures of heart functioning compared with their healthy peers, while no statistically significant differences were observed for the children given dexrazoxane.
When parsed by gender, this protective effect was only observed in girls. However, Chief of NCI’s Pediatric Oncology Branch Crystal Mackall, M.D., explained, “this was not a large study and hence was not powered to detect potentially smaller differences in protective effects. Since the damage in boys was not as high to begin with, a protective effect of dexrazoxane could have been missed in this study.” Previous studies have suggested that the female heart may be more vulnerable to anthracycline-related damage.
Since this was a small study in a single disease using only one treatment protocol, said Dr. Lipshultz, the researchers encourage further exploration of the subject in cooperative group trials, which have a built-in capability for long-term monitoring of outcomes.
Longer follow-up of the children in the current study will also be needed to determine whether the prevention of non-symptomatic damage to the heart’s structure will result in the prevention of clinical cardiac dysfunction, said Malcolm Smith, M.D., Ph.D., a pediatric cancer specialist in NCI’s Cancer Therapy Evaluation Program.
For now, Dr. Mackall is encouraged by this study. “We knew dexrazoxane could protect the heart in the short term and have been using it here at NCI for the last 20 years, but until now there hasn’t been a randomized study that showed that it was able to protect the heart in the long term,” she said. “There have also been other concerns in the cancer community about dexrazoxane, such as potentially reduced treatment efficacy or second malignancies, which were not born out in this study,” she continued. “This is another piece of evidence that protecting the heart doesn’t protect the tumor.”