BOSTON – For children with average-risk medulloblastoma, it is safe to limit the radiation boost to the posterior fossa, but reducing doses to the craniospinal axis results in worse outcomes among younger children, and is not advisable, according to results from the largest trial conducted in this population.
There were no significant differences in either 5-year event-free survival (EFS) or overall survival (OS) between children who received an involved field radiation therapy boost (boost to the tumor bed only) or a standard volume boost (to the whole posterior fossa) in a phase III randomized trial, reported lead author Jeff M. Michalski, MD, MBA, FASTRO, professor of radiation oncology at Washington University, St. Louis.
“We conclude that the survival rates and event-free survival rates following reduced boost volumes were comparable to standard radiation treatment volumes for the primary tumor site. This is the first trial to state definitively that there is no survival difference between these two approaches,” he said at a briefing following his presentation of the data in an oral abstract session at the annual meeting of the American Society for Radiation Oncology.
Dr. Jeff M. Michalski
“However, the reduced craniospinal axis irradiation was associated with a higher event rate and worse survival. We believe that physicians can adopt smaller boost volumes to the posterior fossa in children with average-risk medulloblastoma, average risk being no evidence of spread at the time of diagnosis and near-complete or complete resection. But for all children, the standard of 23.4 Gy remains necessary to retain high-level tumor control,” he added.
Aggressive malignancy
Medulloblastoma, an aggressive tumor with the propensity to spread from the lower brain to the upper brain and spine, is the most common brain malignancy in children. The current standard of care for children with average-risk disease is surgical resection followed by systemic chemotherapy followed by irradiation to both the posterior fossa and to the craniospinal axis.
“Unfortunately, this strategy has significant negative consequences for the patients’ neurocognitive abilities, endocrine function, and hearing,” Dr. Michalski said.
The Children’s Oncology Group ACNS0331 trial was designed to determine whether reducing the volume of the boost from the whole posterior to the tumor bed only would compromise EFS and OS, and whether reducing the dose to the craniospinal axis from the current 23.4 Gy to 18 Gy in children aged 3-7 years would compromise survival measures.
The trial had two randomizations, both at the time of study enrollment. In the first, children from the ages of 3 to 7 years were randomly assigned to either low-dose craniospinal irradiation (18 Gy, 116 children) or to the standard dose (23.4 Gy, 110 children). All children aged 8 and older were assigned to receive the standard dose.
For the second randomization, all children were randomly allocated to either involved field RT boost or to standard volume boost to the whole posterior fossa.
Following radiation, all children were assigned to nine cycles of maintenance chemotherapy.
At a median follow-up of 6.6 years, 5-year EFS estimates for the primary site irradiation endpoint were 82.2% for 227 patients who received the involved-field radiation, compared with 80.8% for 237 patients who received whole posterior fossa irradiation.
Respective 5-year OS estimates were 84.1% and 85.2%. The upper limit of the hazard ratio confidence interval (CI) for the involved field therapy was lower than the prespecified limit, indicating that involved-field radiation was noninferior.
For the endpoint of low- vs. standard-dose craniospinal irradiation, the 5-year EFS estimates were 72.1% and 82.6%, respectively. The upper limit of the hazard ratio CI exceeded the prespecified limit, indicating that EFS was worse with the low-dose strategy.
Similarly, respective 5-year OS estimates were 78.1% and 85.9%, with the upper limit of the CI also higher than the prespecified upper limit.
When the investigators looked at the patterns of failure among the children in the two randomizations, they saw that there was no significant difference in the rate of isolated local failure between the involved-field or whole posterior fossa groups, or between the low-dose or high-dose craniospinal irradiation groups.
The finding that radiation volume to the primary site can be reduced is likely to be practice changing, said Geraldine Jacobson, MD, MPH, professor and chair of radiation oncology at West Virginia University, Morgantown. Dr. Jacobson moderated the briefing.
However, the worse survival with the low-dose craniospinal radiation “leaves the COG investigators with the challenge to explore other avenues for reducing toxicity of craniospinal irradiation,” she said.