Optimize treatment approaches in isocitrate dehydrogenase (IDH) mutant gliomas: open issues

The 2021 update of the World Health Organization (WHO) Classification of Central Nervous System Tumors1 has reinforced the integration of molecular data with conventional histological features for both diagnosis and treatment of diffuse gliomas. Mutations in isocitrate dehydrogenase (IDH) genes, IDH1 and IDH2, that represent an early event in gliomagenesis, are strong determinant of an improved overall survival in association with 1p/19q codeletion. Thus, the WHO 2021 Classification recognizes WHO grade 2 and 3 IDH-mutant astrocytomas and IDH-mutant, 1p/19q codeleted oligodendrogliomas. Moreover, as CDKN2A/B homozygous deletion has been associated with shorter survival, its presence in an IDH-mutant astrocytoma will qualify the tumor as a WHO grade 4 regardless of a lower grade histological appearance. In this issue of Neuro-Oncology Miller, Gonzalez Castro, and co-authors2 have exhaustively and critically reviewed the state of art and future directions of diagnosis and management of IDH-mutant gliomas. Overall, the WHO Classification 2021 has raised the issue of how to optimize and personalize standard and novel treatments in IDH-mutant gliomas. Supramaximal resection has been suggested to improve progression-free and overall survival in lower grade diffuse gliomas3; however, there is need to examine larger cohort of patients to see whether this is true for either IDH-mutant astrocytomas or IDH-mutant, 1p/19q codeleted oligodendrogliomas or both. The same question applies to reoperation, which is increasingly pursued: based on the more indolent natural course, one could hypothesize a higher relevance in IDH-mutant, 1p/19q codeleted oligodendrogliomas versus IDH-mutant astrocytomas in order to delay the need for radiotherapy and the risk of cognitive deficit in very long surviving patients. The role of adjuvant radiotherapy and chemotherapy for the new category of IDH-mutant astrocytomas with CDKN2A/B homozygous deletion, that represents a poorer prognostic group, needs to be defined: radiotherapy and adjuvant temozolomide, as demonstrated in the CATNON trial on anaplastic gliomas without 1p/19q codeletion, or radiotherapy with concomitant and adjuvant temozolomide, as in grade 4 IDH-wild type glioblastomas?