Ho-ho-ho! Gather around, my little elves, for a tale not of the North Pole, but of a quest to conquer a formidable foe known as high-grade gliomas (HGG) in children. In a land far from the snowy peaks and twinkling lights, a group of wise scientists embarked on a multicenter phase II trial, a sleigh ride of sorts, through the treacherous terrain of pediatric cancer treatment. Their sleigh was laden with gifts not of toys, but of hope in the form of treatments: vorinostat, bevacizumab, and the trusty steed known as temozolomide, all racing alongside focal radiotherapy (RT) to see which could best improve the 1-year event-free survival (EFS) for the young warriors battling newly diagnosed HGG.

In this tale, our sleigh team was comprised of patients aged 3 to <22 years, each facing their own snowy mountain to climb. They were randomized to receive RT with a dose of 54-59.4Gy, accompanied by either vorinostat, temozolomide, or bevacizumab, followed by 12 cycles of maintenance therapy with bevacizumab and temozolomide to keep the icy relapse at bay.

As the journey unfolded, 90 brave souls were randomized, and the results were as mixed as a Christmas cookie platter. The 1-year EFS for those guided by the bevacizumab reindeer was 43.8% (±8.8%), for the vorinostat sled, it was 41.4% (±9.2%), and leading the pack was temozolomide with a jolly 59.3% (±9.5%). Yet, in a twist as surprising as finding out Santa is real, there was no significant difference among these treatment paths.

As the years passed, the 3- and 5-year EFS for the entire cohort was a sobering 14.8% and 13.4%, respectively, with no significant difference among the chemoradiotherapy arms. But, like finding a hidden present under the tree, certain genetic markers such as IDH mutations brought more favorable EFS, while the naughty list included H3.3 K27M mutations and alterations in PIK3CA or PTEN, associated with worse outcomes.

A glimmer of hope shone bright for patients with telomerase- and alternative lengthening of telomeres (ALT)-negative tumors, who had an EFS of 100%, a Christmas miracle suggesting that the mechanism of telomere maintenance might be a guiding star for future studies.

In the end, my dear elves, this tale teaches us that the journey to conquer HGG in children is fraught with challenges, but also with lessons and hope. The quest for the most effective treatment continues, with the spirit of discovery lighting the way like Rudolph’s red nose on a foggy Christmas Eve. And so, we close this chapter, but not the book, on our quest to bring health and joy to all. Merry research and a hopeful New Year to all, and to all a good night!