Fine-tuning the beam: Biomarker-guided radiation strategies in the evolving management of isocitrate dehydrogenase (IDH)-mutant glioma

Sequential chemoradiotherapy remains a standard treatment option for patients with isocitrate dehydrogenase (IDH)-mutant gliomas. The results of the phase III INDIGO trial have led to the recent regulatory approval of vorasidenib, a brain-penetrant IDH1 and IDH2 inhibitor, indicated for patients with IDH1- or IDH2-mutant WHO grade 2 astrocytoma or oligodendroglioma after biopsy or resection. While IDH inhibitors represent a significant advancement for patients with IDH-mutant glioma, there is substantial controversy regarding which patients are most likely to derive benefit from IDH inhibition and how this strategy can be optimally integrated into clinical practice. Specifically, whether IDH inhibitors should be used prior to, in conjunction with or potentially in lieu of radiation-based treatment strategies are fundamental questions for the neuro-oncology community. Additionally, whether IDH inhibitors can be extrapolated to higher-grade disease settings or utilized in higher-risk patient populations remains unknown. These open questions provide an opportunity for the field of radiation oncology to develop pragmatic biomarker-based approaches to guide patient selection, to monitor treatment response and to identify optimal treatment strategy and timing/sequencing of treatment. Several candidate biomarkers have emerged for IDH-mutant glioma with unique potential to be rationally integrated into radiation oncology workflows to personalize care.