Dr. Jeff M. Michalski
Results from this analysis were reported at the American Society for Radiation Oncology Annual Meeting 2020.
“Today, molecular diagnostics play a critical role in the classification of tumors, particularly medulloblastoma,” noted lead investigator Jeff M. Michalski, MD, of Washington University St. Louis, Mo.
“It is now recognized that medulloblastoma can be subgrouped into four distinct entities with unique demographics and tumor behaviors,” he said.
Those four groups are the SHH subgroup, the WNT subgroup, group 3, and group 4.
Study rationale and details
The benefits of current multimodality therapy in controlling and curing medulloblastoma come at the cost of toxicity, especially for younger patients, in terms of neurocognitive deficits, secondary cancers, and growth and neuro-endocrine abnormalities.
With this in mind, Dr. Michalski and colleagues conducted a phase 3 trial to test two strategies for reducing radiation in average-risk medulloblastoma without compromising outcomes.
After craniospinal irradiation (CSI), all patients were randomized to a radiation boost to the whole posterior fossa (PFRT) or an involved field volume (IFRT). Patients aged 8-21 years received CSI at the standard dose (23.4 Gy). Patients aged 3-7 years were randomized to standard-dose CSI or low-dose CSI (18 Gy).
There were 464 patients in whom PFRT to IFRT could be compared and 226 patients in whom standard and low-dose CSI could be compared.
Only 362 patients had sufficient tumor tissue to allow for classification into molecular subgroups. Among these patients, 43.1% fell into the group 4 subgroup, 21.0% into the group 3 subgroup, 18.2% into the SHH subgroup, and 17.7% into the WNT subgroup.
Survival results
The trial’s primary outcomes were event-free and overall survival. Events were defined as progression, recurrence, death, or second malignancy.
For the whole cohort, boost volume did not significantly affect outcomes. IFRT and PFRT yielded similar 5-year event-free survival (82.5% vs. 80.5%; P = .44) and overall survival (84.6% vs. 85.2%; P = .44). However, CSI dose did affect outcomes, with the low dose inferior to the standard dose on both 5-year event-free survival (71.4% vs. 82.9%; P = .028) and overall survival (77.5% vs. 85.6%; P = .049).
In analyses stratified by molecular subgroup, event-free survival did not differ significantly by boost volume within subgroups, except for the SHH subgroup, within which PFRT yielded worse outcomes (P = .018). Similarly, event-free survival did not differ significantly by CSI dose within subgroups, except for group 4, within which the low dose yielded a worse outcome (P = .047).
When specific genomic alterations were also considered, patients in the SHH group had worse outcomes if they had chromosome 14q loss, chromosome 10q loss, or p53 mutation. Patients in group 3 had worse outcomes if they had MYC amplification, iso-chromosome 17q, or both of these abnormalities.
No significant correlations were seen for group 4 patients, and there were too few patients in the WNT subgroup to assess correlations.
“Survival rates following reduced radiation boost volumes were comparable to standard treatment volumes for the primary tumor site. Interestingly, the SHH subgroup had worse event-free survival with whole posterior fossa radiation therapy,” Dr. Michalski commented. “Reduced dose of craniospinal axis irradiation was associated with higher event rates and worse survival, and group 4 was the primary subgroup that drove these inferior outcomes.”
“Specific genomic abnormalities are associated with worse outcomes, and future trials should consider subgroup and these genomic abnormalities in their study design,” he recommended.