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Pediatric Medulloblastoma Subgroups May Benefit from Lower-Dose Radiation Therapy

NEW YORK – Researchers hoping to validate that treatment with a lower dose of craniospinal irradiation (CSI) is effective for children with medulloblastoma found that patients with certain genetic alterations responded better to the lower dose, according to a study published in the Journal of Clinical Oncology on Thursday.

The Phase III trial evaluated 464 patients from age 3 to 21 with average-risk medulloblastoma. All patients were randomly assigned to receive either the standard posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. For younger patients, age 3 to 7, the researchers also randomly assigned them to either a standard dose or lower dose of CSI.

The study was led by Jeff Michalski, vice chair and director of clinical programs at Washington University School of Medicine in St. Louis, and involved researchers from WashU and St. Jude Children’s Research Hospital.

The goal of the study was to determine if lower doses or volume of CSI could be used to treat medulloblastoma, particularly in young children. Younger patients, since their brains are still developing rapidly, are more likely to experience declines in IQ after radiation treatment compared to adult patients.

The reduced boost volume in patients receiving IFRT was found to be as effective as the standard PFRT, with five-year event-free survival rates of 82.5 percent and 80.5 percent, respectively. However, the five-year event-free survival rate was significantly lower among the young patients receiving low-dose CSI compared to those receiving the standard dose, 71.4 percent versus 82.9 percent.

The lower rates of event-free survival seen with low-dose CSI was driven by one molecular subgroup of medulloblastoma patients, dubbed group 4, the researchers reported. Patients in this group treated with low-dose CSI had a five-year event-free survival rate of 77.2 percent, compared to 97 percent for patients in this group who received the standard dose.

The World Health Organization has classified medulloblastoma into four subgroups based on molecular and pathological features of the tumors: WNT, SHH, group 3, and group 4. The WNT subgroup has excellent prognosis and the majority of patients have a CTNNB1 mutation. Most patients in the SHH subgroup have germline or somatic mutations or copy number alterations in the SHH signaling pathway. Patients in groups 3 and 4 don't have common molecular features.

In this trial, researchers used Illumina Infinium Methylation EPIC BeadChip arrays to analyze patients and determine their subgroup status. They looked at additional biomarkers and found that patients who had TP53 alterations had a significantly worse event-free survival rate compared to those without these alterations, 14.3 percent versus 84.7 percent. Additionally, group 4 patients who received low-dose CSI and exhibited balanced chromosomes 11 and 17 saw the worst outcomes.

However, there was no significant difference in event-free survival for low-dose or standard-dose CSI in the other subgroups, WNT, SHH, or group 3. The lower event-free survival rates for low-dose CSI group 4 patients suggests that patients may need to be molecularly selected to receive the lower dose CSI, the researchers wrote.

"Inferior outcomes in the [low-dose CSI] group were driven primarily by group 4 patients, the predominant subgroup in this age group," they wrote. "The number of patients in the favorable WNT group is small, but there is no suggestion that exploring a de-intensification strategy in this population is unwarranted."

The authors also evaluated event-free survival rates with PFRT and IFRT across the subgroups. Patients in the SHH subgroup who received PFRT saw worse event-free survival rates compared to those on IFRT, 74.9 percent versus 90.7 percent, respectively.

The researchers determined that the lower blast volume of IFRT was acceptable in most cases of medulloblastoma, but the lower dose of CSI had an "unacceptable rate of failure" in the younger patient group. Yet, in the analysis of the cognitive effects, the patients who received low-dose CSI saw less decline in IQ. There was no cognitive difference between patients receiving IFRT or PFRT.

"This represents a significant departure from most prior outcomes associated with craniospinal therapy and suggests that modern radiotherapy techniques may be associated with substantial reduction in global cognitive morbidity for older children," the authors concluded. "Future investigations will select patients for treatment de-escalation driven by molecular subgroups that will minimize late cognitive effects while maintaining high event-free survival."

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