In childhood leukemia study, aggressive chemotherapy cuts deaths by 37%

More than a third of children who die from a particularly deadly form of leukemia would be saved if doctors used three existing drugs more aggressively – administering them at much higher doses and over a longer period of time. That is one of several important conclusions drawn from a long-term study, published in the October issue of the Journal of Clinical Oncology, that tested a high-dose drug regimen in 125 young leukemia patients and tracked their outcomes for an average of nine years.

The study, conducted by researchers at nine universities and research hospitals, was led by Barbara L. Asselin, M.D., associate professor of Pediatrics and Oncology at the James P. Wilmot Cancer Center at the University of Rochester. It focused on children with T-cell acute lymphoblastic leukemia, or T-ALL, which accounts for 15 percent of all childhood leukemia cases and is fatal in nearly four in 10 children. While dozens of drugs are routinely used to treat children with the disease, the study sheds new light on the fundamental questions about their use: Which combination of those drugs is most effective? And, what are the highest doses that can be given without subjecting children to additional risks – such as kidney damage and neurological problems – that might be caused by the powerful drugs themselves?

To find out, the researchers drew on earlier studies that had pointed to the effectiveness of three cancer-killing drugs – methotrexate, asparaginase, and doxorubicin. The researchers devised an experimental regimen in which all three would be administered at whopping doses – up to five times higher than usual – and for durations of several months instead of weeks. Between 1981 and 2000, 125 children with T-ALL received the experimental treatment. Afterward, each patient’s progress was followed by the researchers for an average of nine years. More than 25 percent of the patients were followed into their 20s, and some into their early 30s. The researchers were interested not only in whether the children survived the cancer, but also whether the high-dose chemotherapy produced any debilitating long-term effects.

Of the 125 children studied, 93 of them were cured, yielding a survival rate of 75 percent compared to survival rates of between 60 and 65 percent for treatment regimens that used much lower drug doses. Years after treatment, despite the more aggressive chemotherapy, the patients did not experience medical problems beyond those reported in those who had received lower doses of the drugs, with one exception. Patients who had received higher doses of doxorubicin experienced slightly higher rates of cardiomyopathy, a weakening of the heart muscle that can usually be controlled with medication.

“This study tells us, without question, that we should be using these drugs much more aggressively,” said Asselin. “Giving these drugs at much higher dosages dramatically improves a child’s chances for survival, and does not pose a significantly greater risk for long-term negative effects. The evidence is so compelling that we are recommending that this new approach become the standard treatment for all children diagnosed with this form of leukemia.”

In addition to high-dose chemotherapy, children in the study received low-dose radiation therapy to the brain, where cancerous cells are most likely to survive chemotherapy and cause a relapse of leukemia in the future. Asselin and her colleagues credit the combination of chemotherapy and radiation with preventing relapse among the majority of children in the study, thereby minimizing the greatest threat to their long-term survival. Equally important, the use of low-dose radiation to the brain did not result in a decline in cognitive abilities that had been reported in earlier studies in which children had received higher does of radiation.

“Our goal in this study, and in our careers as researchers, is to find the right balance of treatment for these children,” said Asselin. “We want to deliver treatment that is powerful enough to kill their cancer, yet not so toxic that the treatment itself robs them of a normal life afterward. We want them to be healthy – to grow up to play and have fun and do well in school and have a normal quality of life.”

The study was funded by the National Institutes of Health and conducted by the Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium. Co-authors of the paper were John M. Goldberg, Lewis B. Silverman, Donna E. Levy, Virginia Kimball Dalton, Richard D. Gelber, Leslie Lehmann, Harvey J. Cohen, and Stephen E. Sallan.