Bridging the treatment gap in infant medulloblastoma: molecularly informed outcomes of a globally feasible regimen

Abstract

Background: Infant medulloblastoma represents an enormous challenge in neuro-oncology, due to their simultaneous high-risk of recurrence and high risk of severe neurodevelopmental sequelae with craniospinal irradiation. Currently infant medulloblastoma are treated with intensified protocols, either comprising intraventricular methotrexate or autologous transplant, both of which carry significant morbidity and are not feasible in the majority of the world. We sought to evaluate the molecular predictors of outcome in a cohort of infants homogeneously treated with induction chemotherapy, focal radiation and maintenance chemotherapy.

Methods: In a retrospective analysis, 29 young children treated with a craniospinal irradiation sparing strategy from Hospital Garrahan in Buenos Aires were profiled using Illumina HumanMethylationEPIC arrays, and correlated with survival.

Results: Twenty-nine children (range, 0.3-4.6 y) were identified, comprising 17 sonic hedgehog (SHH), 10 Group 3/4, and 2 non-medulloblastomas. Progression-free survival (PFS) across the entire cohort was 0.704 (95% CI: 0.551-0.899). Analysis by t-distributed stochastic neighbor embedding revealed 3 predominant groups, SHHβ, SHHγ, and Group 3. Survival by subtype was highly prognostic with SHHγ having an excellent 5-year PFS of 100% (95% CI: 0.633-1) and SHHβ having a PFS of 0.56 (95% CI: 0.42-1). Group 3 had a PFS of 0.50 (95% CI: 0.25-1). Assessment of neurocognitive outcome was performed in 11 patients; the majority of survivors fell within the low average to mild intellectual disability, with a median IQ of 73.5.

Conclusions: We report a globally feasible and effective strategy avoiding craniospinal radiation in the treatment of infant medulloblastoma, including a robust molecular correlation along with neurocognitive outcomes.

Keywords: SHH; brain tumor; infant; medulloblastoma; radiation.

Fig. 1

Molecular and clinical characterization of the Buenos Aires (BA) infant medulloblastoma cohort. (A) tSNE visualization of genome-wide methylation profiling from 29 infants treated in BA in comparison with Robinson et al cohort from St Jude’s. (B) Plot by tSNE of SHH samples only. Samples are colored according to their respective consensus cluster affiliation. Kaplan‒Meier survival curve of (C) PFS and (D) OS for 27 BA-infant medulloblastoma. Shaded areas around curve represent 95% CIs. Kaplan‒Meier estimates of (E) PFS and (F) OS for 27 BA-infant medulloblastoma stratified by molecular subgroup and subtype. P-values are determined using the log-rank method.

Fig. 2

Declines in neurocognitive status over time in patients with infant medulloblastoma treated with posterior fossa radiotherapy. Estimated declines in (A) the Full-Scale Intelligence Quotient (FSIQ) over time (years) since diagnosis. (B) Processing Speed Index (PSI), (C) Perceptual Reasoning/Organization Index (PRI), (D) Working Memory index (WMI), and (E) Verbal Comprehension Index (VCI) in linear term model. Lines represent patients who were seen for longitudinal intellectual assessments; each dot represents a patient who was seen once. The dark gray line at 80 represents the delineation between borderline and low average.