# An integrated analysis of three medulloblastoma clinical trials refines risk-stratification approaches for reducing toxicity and improving survival

## TL;DR

This study combines data from three medulloblastoma trials to refine treatment risk groups, aiming to reduce toxicity while improving patient outcomes.

## Contribution

The study introduces a novel risk-stratification schema based on integrated clinical and molecular data from multiple trials.

## Key findings

- Adding carboplatin to high-dose craniospinal irradiation improved progression-free survival in specific G3/G4 subgroups.
- Nine actionable risk-stratified groups were identified across WNT, SHH, and G3/G4 molecular subgroups.
- A uniform treatment backbone is proposed to reduce unnecessary toxicity and guide future dose adjustments.

## Abstract

The identification of clinical and molecular heterogeneity in medulloblastoma has produced risk-stratified therapy, but establishing the most effective yet least toxic regimens has remained elusive owing to numerous treatment options. To improve risk-stratification, we performed an integrated analysis from three clinical trials.

Medulloblastoma patients from ACNS0331/NCT00085735, ACNS0332/NCT00392327, and SJMB03/NCT00085202 were included if they had methylation profiling. Molecular groups [WNT, SHH, Group 3 (G3), and Group 4 (G4)], subgroups, and copy number variations were procured from methylation profiles and mutations from next-generation sequencing. Data was assembled into an interactive portal to capture patient characteristics. Cross-trial comparisons, univariable, and multivariable analyses were conducted and used to derive a risk-stratification schema.

Eight hundred ninety-eight patients (WNT = 131, SHH = 151, G3 = 220, G4 = 396) were included. Progression-free-survival (PFS) distributions among analogous cross-trial cohorts were not different, demonstrating no survival advantage of any one therapy over another. The addition of carboplatin to high-dose craniospinal irradiation (HDCSI) containing regimen was selectively superior in PFS in G3/G4 subgroup 3 (P = 0.048) and G3/G4 subgroup 2 (P = 0.035) to HDCSI regimens without carboplatin. Nine actionable risk-stratified groups were identified consisting of 2 WNT groups (low, high-risk), 3 SHH groups (low-, average-, very-high-risk), and 4 G3/G4 groups (low-, average-, high-, and very-high-risk).

Our integrated cross-trial analysis suggests toxicity can be reduced by eliminating disproportionate differences in therapy in favor of a more uniform treatment backbone. Moreover, we propose and model a risk-classification system that identifies the most appropriate cohorts on which to trial significant dose reductions in craniospinal irradiation or select treatment intensifications.