A potent chemotherapy that is highly effective in treating the most common form of childhood leukemia can significantly harm the heart, but findings from a multi-center study led by Dana-Farber Cancer Institute researchers suggest that adding an experimental drug to the therapy can reduce or prevent the damage.
If longer-term studies confirm the results, it would be the first strategy proven to reduce the heart problems that some acute lymphoblastic leukemia (ALL) survivors develop years after being treated with doxorubicin (Adriamycin). The study will be published in the July 8 issue of the New England Journal of Medicine.
“These findings demonstrate that it is possible to decrease some of the chemotherapy’s toxic effects on the heart,” explains Stephen R. Sallan, MD, senior author of the paper and chief of staff at Dana-Farber.
The use of doxorubicin in children with ALL makes it a highly curable disease, but because the chemotherapy kills heart muscle cells as a side effect, survivors can experience an improperly beating left ventricle, congestive heart failure, or arrhythmias that can cause sudden death. One study estimated that, even 25 years after they were treated, their risk of dying from heart disease is more than eight times normal.
More than 200 children under 18 who had newly diagnosed ALL that was considered high-risk – more life threatening than average – between 1996 and 2000 were invited to participate in the multi-center study.
One group (101 participants) was treated with doxorubicin alone – the standard therapy. The other (105 participants) received doxorubicin and dexrazoxane (Zinecard), an experimental drug manufactured by Pfizer, Inc. that has shown to be cardioprotective in adults receiving chemotherapy.
Studies have shown that doxorubicin injures the heart muscle when it is metabolized. As the body breaks down the drug, “free radicals” – chemicals that are toxic to heart cells – are produced. Dexrazoxane, conversely, is “free radical scavenger” that mops up the harmful substances and reduces the muscle damage.
For a preliminary assessment, the scientists compared blood levels of troponin T, a protein that is elevated when the heart had been injured. This test can detect heart damage before it can be seen with echocardiograms.
Fifty percent of the children in the doxorubicin-alone group had elevated troponin T, compared with 21 percent of those who also received dexrazoxane. Extremely elevated troponin levels – indicating more severe heart muscle injury – occurred in 32 percent of the doxorubicin-only patients, but in just 10 percent of those who received the protective drug.
Importantly, the study also found that adding the dexrazoxane did not reduce the doxorubicin’s ability to cure the children.
“This isn’t a perfect solution but it is promising,” cautioned Sallan, who is also a pediatric oncologist at Dana-Farber and a professor of pediatrics at Harvard Medical School. “We reduced the incidence of heart damage from 50 percent to about 25 percent with dexrazoxane, but there is some damage.”
Lead author of the report is Steven E. Lipshultz, M.D., Chairman of the Department of Pediatrics, University of Miami School of Medicine and Chief of Staff of the Holtz Children's Hospital.
The research was supported in part by the National Institutes of Health, Pharmacia-Upjohn, and Roche Diagnostics.
Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.