Young Children with Medulloblastoma May Be Able to Avoid Post-Surgery Radiotherapy
Children younger than three with a kind of brain cancer called medulloblastoma may be effectively treated with chemotherapy alone after surgery, according to a randomized clinical trial. The study provides the strongest evidence yet supporting doctors’ inclination to avoid post-surgical radiation for this group of very young patients because of the greater risk of significant physical and neurocognitive damage.
New England Journal of Medicine, early online publication, March 10, 2005 (see the journal abstract).
Brain tumors in children are rare. Medulloblastoma is the most common type of childhood brain tumor and often spreads to the spine. Current guidelines call for surgery to remove as much of the tumor as possible, followed by radiation of the brain and spinal cord, and finally treatment with chemotherapy.
Radiotherapy is effective at killing any cancer cells remaining after surgery, but doctors are reluctant to use it on very young children because radiation more seriously affects brain development at that age. Previous studies have shown that post-surgery chemotherapy could delay radiotherapy in this very young group of patients. The current, larger trial sought to determine whether intensive chemotherapy was effective enough to rule out the need for subsequent radiation.
Researchers at 31 sites in Germany registered 43 patients (28 boys and 15 girls) under three years of age who were diagnosed with medulloblastoma. After surgery to remove as much tumor as possible, the children were treated with a complex regimen of five chemotherapy drugs, including a drug called methotrexate delivered directly to the brain.
Doses of some of the drugs were adjusted according to the age of the patient. The chemotherapy regimen was given to all the children in three two-month cycles. Children whose cancer hadn’t progressed after three cycles were able to stop treatment. Children whose cancer did progress after the three cycles of chemotherapy received second surgery, radiotherapy, or experimental chemotherapy as deemed appropriate by their doctors.
The study’s lead author is Stefan Rutkowski from Children’s Hospital, University of Wűrzburg, Wűrzburg, Germany.
Five years after treatment, 58 percent of the 43 children were progression-free and 66 percent were alive. (The researchers defined “disease progression” as a tumor whose size increased by 25 percent or more.) Fourteen of the children around that time also took a battery of intelligence tests. While they scored lower than healthy children in a control group, they scored higher than children in the earlier pilot study who had received radiotherapy as part of their post-surgical treatment.
During their analysis, the researchers noted differences depending on which of three subgroups the children fell into. In the subgroup where children’s tumors had been completely removed by surgery, 82 percent were progression-free after five years and 93 percent were alive. In the second subgroup where most of the children’s tumor had been removed and cancer did not visibly spread after surgery, 50 percent were progression-free and 56 percent were alive. In the third subgroup where cancer had visibly spread after surgery, 33 percent were progression-free and 38 percent were alive.
Radiotherapy was successfully avoided in 20 of the 31 children whose cancer had not visibly spread.
“Our study shows that young children with medulloblastoma can enjoy a lengthy remission after treatment with intensive postoperative chemotherapy alone,” write the authors. They emphasize their results are “especially promising” for patients who had no visible spread of their cancer after initial surgery.
“The surprising thing to come out of this study are the numbers” concerning the rate of disease-free survival, says Howard A. Fine, M.D., chief of the Neuro-Oncology Branch at the National Cancer Institute’s Center for Cancer Research. Earlier studies of children with medulloblastoma had found that disease-free survival rates following treatment with surgery and chemotherapy alone were as low as 15 percent and rarely higher than 45 percent, he says.
Because of the rarity of this disease, it is difficult to enroll enough patients in a clinical trial to get statistically significant results. However, Lisa M. DeAngelis, M.D., of Memorial Sloan-Kettering Cancer Center in New York writes in an accompanying editorial that this study “is the largest that has been conducted in children younger than three years of age…[and] resulted in an excellent outcome.” The results, she says, validate the approach of attempting to avoid radiotherapy in the treatment of this very young group of patients.
Fine thinks that more studies are needed before this finding can be considered definitive. He also notes that it is unclear whether the specific chemotherapy drugs used in the study’s three-cycle regimen were responsible for the improved clinical outcome compared to other clinical trials that used different chemotherapeutic agents.
“Because this disease is relatively rare in this young population, it is difficult to recruit enough patients into clinical trials to produce really statistically meaningful comparisons between several different phase II trials,” he says. Relative to the loss of cognitive function following treatment, Fine says “we know that children who get brain tumors don’t generally emerge with as high a cognitive status as healthy children, either because of the chemotherapy and/or because of the tumor. We do know, however, that when radiation is used the neurocognitive outcomes are much worse.”