But a study led by Miller School researchers and published online today in the journal Pediatrics found that the slow, continuous infusion of doxorubicin, a drug that has dramatically improved the leukemia survival rate, does not provide youngsters with acute lymphoblastic leukemia (ALL) any more cardioprotection than rapid infusion.
Both infusion methods, the multicenter study found, are equally toxic to young hearts.
Spearheaded by Steven E. Lipshultz, M.D., professor of pediatrics, the longest and largest randomized, blinded study comparing the long-term cardiac effects of the two delivery methods recommends discontinuing the slow administration of doxorubicin to children with high-risk acute ALL. The study, which will appear in the December issue of the official journal of the American Academy of Pediatrics with a related commentary, also underscores the depth of what a recent Institute of Medicine report called “a special worry” over the lack of studies on the long-term efficacy and late effects of drugs prescribed for children.
“There is a reason why there is such a paucity of drug studies in children: They are very difficult and expensive to do,” said Lipshultz, the George Batchelor Endowed Chair in Pediatric Cardiology, who first reported in 1991 that significant numbers of childhood cancer survivors suffer from heart failure or die from cardiac disease as adults.
“But this research shows not only why such studies are critical to enhance and prolong the lives of children who survive cancer, but why such studies are, ultimately, very cost-effective. As it turns out, we had hospitalized 4-year-olds for an extra month of their lives at great expense for no benefit and with increased risks.”
Supported by the National Cancer Institute’s Office of Cancer Survivorship, the study, “Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes,” enrolled 204 children who were newly diagnosed with ALL and successfully treated with doxorubicin at 10 collaborating centers in the U.S., Canada and Puerto Rico between 1991 and 1995.
Half of the children were randomly assigned to the group that received doxorubicin via a quick – less than an hour – intravenous bolus infusion in an out-patient setting once every three weeks for nine months; the other half received the slow, intravenous infusion administered in the hospital over a 48-hour period once every three weeks for nine months. All of the youngsters, whose average age at diagnosis was 4, underwent baseline echocardiograms before treatment and then follow-up echocardiograms at various intervals, with the longest follow-up a median of eight years.
Unfortunately, Lipshultz said, he and the research team from the Dana Farber Childhood ALL Consortium, led by Stephen E. Sallan, M.D., the Chief of Staff of the Dana Farber Cancer Institute, found “significant cardiotoxicity” in both groups, indicated by depressed heart function, heart dilation, reduced heart wall thickness and reduced heart mass. The researchers also found no difference in the ten-year, ALL cancer event-free survival rate between the two groups.
But they did note other worrisome health concerns associated with the prolonged therapy. Children treated with the “kinder and gentler” approach had significantly more blood clots and incidents of mucositis, or skin irritations, than the group who underwent the quick treatments.
“There is no evidence of cardioprotection from continuous infusion, yet today, in 2012, continuous infusion is being written into protocols around the world because it was intuitively assumed to be permanently better,” Lipshultz said. “While our study only applies to one subset of children, it sheds light on a larger issue. We give many really strong medications to young children, but if you look at the package insert, it usually says, ‘Not tested in children.’ We need to change that.”
In the accompanying commentary, Smita Bhatia, M.D., M.P.H., professor of population sciences at the City of Hope, a comprehensive cancer center in Duarte, California, said the Lipshultz study “reinforces the need to develop risk-reduction strategies in childhood cancer survivors.”
Her commentary, “Long-term Complications of Therapeutic Exposures in Childhood: Lessons Learned from Childhood Cancer Survivors,” provided an overview of “the clear and unambiguous” relationship between therapeutic exposure and specific adverse events experienced by children who survive cancer, which most do today. As she noted, with improved therapeutics, the overall five-year survival rate for children diagnosed with cancer is now approaching 80 percent.
When the class of anthracycline drugs that include doxorubicin was introduced around 1970, nearly 90 percent of children with ALL died. Today, about 90 percent survive well into adulthood.
Lipshultz’s study co-authors included the Miller School’s Tracie L. Miller, M.D., professor of pediatrics and director of pediatric clinical research, and researchers from Harvard University, who led the consortium; the University of Rochester School of Medicine and Dentistry; San Jorge Children’s Hospital in Santurce, Puerto Rico; McMaster University in Hamilton, Ontario; Centre Hospitalier Universitaire de Québec in Quebec City; Centre Hospitalaire Sainte-Justine in Montreal; Inova Fairfax Hospital for Children in Falls Church, Virginia; Maine Children’s Cancer Program in Portland; and the University of Massachusetts Medical Center in Worcester.
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