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Medulloblastoma is a rare but devastating childhood brain cancer. It can spread through the spinal fluid and be deposited elsewhere in the brain or spine. Radiation therapy to the whole brain and spine followed by an extra radiation dose to the back of the brain prevents this spread and has been the standard of care. However, the radiation used to treat such tumors takes a toll on the brain, damaging cognitive function, especially in younger patients.

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A national study suggests that children with average-risk medulloblastoma can receive a radiation boost to a smaller volume of the brain at the end of a 6-week course of radiation treatment and still maintain the same disease control as those receiving radiation to a larger area.


But the researchers also found that the dose of the preventive radiation treatments given to the whole brain and spine over the 6-week regimen cannot be reduced without reducing survival. Further, the researchers showed that patients' cancers responded differently to therapy depending on the biology of the tumors, setting the stage for future clinical trials of more targeted treatments.


Children with average-risk medulloblastoma have 5-year survival rates of 75-90 percent. In contrast, children with high-risk medulloblastoma have 5-year survival rates of 50-75 percent. Other factors-such as a child's age and tumor spread-help determine the risk category. For this study, the researchers focused on patients with average-risk medulloblastoma. The findings appeared online in the Journal of Clinical Oncology (2021; doi: 10.1200/JCO.20.02730).


"Medulloblastoma is a devastating disease," said Jeff M. Michalski, MD, the Carlos A. Perez Distinguished Professor of Radiation Oncology at Washington University. "It is a malignant brain tumor that develops in the cerebellum, the back lower part of the brain that is important for coordinating movement, speech, and balance. The radiation treatment for this tumor also can be challenging, especially in younger children whose brains are actively developing in these areas. There's a balance between effectively treating the tumor without damaging children's abilities to move, think, and learn."


Children with average-risk medulloblastoma typically undergo surgery to remove as much of the tumor as possible. They also receive chemotherapy and radiation therapy to prevent the spread of the tumor to other parts of the brain and spine.


"We wanted to investigate whether we could safely reduce the amount of radiation these patients receive-sparing normal parts of the brain and lessening the side effects for children with this type of brain cancer-while also maintaining effective treatment," said Michalski. "We found that reducing the dose of radiation received over the 6-week course of treatment had a negative impact on survival. But we also found that we could safely reduce the size of the volume of the brain that receives a radiation boost at the end of the treatment regimen. We hope such measures can help reduce the side effects of this treatment, especially in younger patients."


Study Details

Collaborating with children's hospitals across the U.S. and internationally, the researchers evaluated 464 patients treated for average risk medulloblastoma that was diagnosed between ages 3 and 21. Younger patients, ages 3-7-a key time for brain development-were randomly assigned to receive either standard dose (23.4 gray) or low dose (18 gray) radiation to the head and spine region in each of 30 treatments given over 6 weeks. Older patients all received the standard dose, since their brain development is less vulnerable to radiation.


In addition, all patients were randomly assigned to receive two different sizes of a radiation "boost" at the end of the 6 weeks of therapy. For the boost, all patients received a cumulative radiation dose of 54 gray to either the entire region of the brain called the posterior fossa, which includes the cerebellum, or to a smaller region of the brain that includes the original outline of the tumor plus an additional margin of up to about 2 centimeters beyond the original tumor boundary.


"The patients who received the smaller boost did just as well as those who received the whole posterior fossa boost," said Michalski. "Many doctors have already adopted this smaller boost volume, but now we have high-quality evidence that this is indeed safe and effective."


For patients receiving the smaller boost volume, 82.5 percent survived 5 years with no worsening of the cancer. For those receiving the larger boost volume to the entire posterior fossa, 80.5 percent survived 5 years with no worsening of the disease. These numbers were not statistically different. In a subset of tumors with mutations in the SHH gene, patients showed improved survival with the smaller boost volume.


But for the younger children, the lower dose of radiation over 6 weeks did not result in similar survival numbers. Of those receiving the standard dose of craniospinal radiation, about 83 percent survived 5 years with no worsening of the cancer. Of those receiving the lower dose, about 71 percent survived 5 years with no worsening of the cancer. That difference in survival was statistically significant.


"We saw higher rates of recurrence and tumor spreading in the younger patients receiving the lower dose of craniospinal radiation," Michalski said. "In general, it's not safe to lower the dose of radiation in children with medulloblastoma even if we know the lower dose might spare their cognitive function. However, a specific subgroup of patients-those with mutations in a gene called WNT-did well on the lower dose, so we're now doing studies just with these specific patients to see if we can safely lower the radiation dose for them."


The tumors were categorized into four molecular subgroups based on their gene expression and predicted biology. The first group's tumors have mutations in WNT signaling pathways; the second have mutations in the SHH gene; and the third and fourth groups' tumors each have different and more complex patterns of gene mutations. The researchers found differences in tumors' responses to treatment based on tumor biology that can guide the design of future clinical trials.


"We've made great strides over the last 15 years in appreciating the molecular diversity of medulloblastoma," said senior author Paul Northcott, PhD, of St. Jude Children's Research Hospital. "We performed whole-exome sequencing and DNA methylation profiling to assign patients to molecular subgroups. This was a critical step in contextualizing this trial based on the latest biology and showed us some important differences in how children respond to therapy that would otherwise not have been clear. Results from this study will play a vital role in designing the next generation of clinical trials for children with medulloblastoma."