Prospective international phase-III study to improve neurocognitive outcomes in young children with low-risk medulloblastoma (YCMB-LR)

Cancer is the second most frequent cause of death in children under 15 years of age, and primary central nervous system (CNS) tumors are the most frequent cause of cancer-related childhood deaths. Medulloblastoma (MB) is the most frequent malignant childhood brain tumor (incidence of 5.5/million/year). About 40% of cases occur in children <5 years old, which can be sub-divided by biological markers into two groups: low-risk group, biologically defined by either Wingless/Integrated (WNT) or Sonic Hedgehog (SHH) activation TP53-wt, while the high-risk group is defined by non-WNT/non-SHH biology. As WNT-activated MB is extremely rare in early childhood, only young patients (<5 years of age) with low-risk (SHH-activated) MB are eligible and have an excellent prognosis if treated with either of the two randomized arms in this research study. Craniospinal irradiation (CSI) is an integral component in the treatment of MB; however, because of the devastating impact upon the central nervous system (CNS) and neurocognitive outcomes, it must be avoided whenever possible given the significant interference with educational and vocational attainment. Consequently, maintaining or improving neurocognitive and QoL functioning is an essential opportunity for early childhood survivors who can now be cured with treatment that does not include CSI. The Prospective International SIOPE/CONNECT phase-III study to improve neurocognitive outcomes in young children with low-risk medulloblastoma (YCMB-LR) is the first ever randomized study directly comparing two highly effective irradiation-sparing treatment regimens, Head Start 4 and HIT-SKK, which will take place at pediatric oncology centers across Europe and North America and is the first to include neuropsychological and QoL outcome as the primary objective. Aim 1) Compare the overall intelligence and IQ subdomains as measured by the Wechsler Preschool and Primary Scale of Intelligence administered 2.5 years after diagnosis between patients with newly diagnosed, non-metastatic, SHH-activated, TP53-wt MB randomized to the interventional arms A (Head Start 4) or B (HITSKK). Aim 2) Compare the trajectory between the two randomized groups at baseline and again at 2.5 years post diagnosis for: a) overall intelligence and IQ subdomains, b) behavioral development and c) QoL, along with analyses at 2.5 years post diagnosis for: d) fine motor dexterity and processing speed, e) visual-motor integration, f) executive functioning, and g) social-emotional functioning. Aim 3) Several quantitative imaging metrics with regard to brain volumes and white matter injury will serve as ancillary noninvasive biomarkers for comparison of the two interventional arms in Aim 1, and will be statistically correlated with the neurocognitive, QoL and behavioral outcomes in Aim 2. Impact: Our work will define the new “gold standard” of treatment in early childhood low-risk MB that is associated with better neurocognitive outcomes with less severe late-effects and ultimately yield a better QoL in survivorship, while simultaneously improving and harmonizing international diagnostic and therapeutic standards not only for MB, but also for other pediatric CNS tumors.