Current and Future Frontiers of Molecularly Defined Oligodendrogliomas

Abstract

Oligodendrogliomas are a subtype of adult diffuse glioma characterized by their better responsiveness to systemic chemotherapy than other high-grade glial tumors. The World Health Organization (WHO) 2021 brain tumor classification highlighted defining molecular markers, including 1p19q codeletion and IDH mutations which have become key in diagnosing and treating oligodendrogliomas. The management for patients with oligodendrogliomas includes observation or surgical resection potentially followed by radiation and chemotherapy with PCV (Procarbazine, Lomustine, and Vincristine) or Temozolomide. However, most of the available research about oligodendrogliomas includes a mix of histologically and molecularly diagnosed tumors. Even data driving our current management guidelines are based on post-hoc subgroup analyses of the 1p19q codeleted population in landmark prospective trials. Therefore, the optimal treatment paradigm for molecularly defined oligodendrogliomas is incompletely understood. Many questions remain open, such as the optimal timing of radiation and chemotherapy, the response to different chemotherapeutic agents, or what genetic factors influence responsiveness to these agents. Ultimately, oligodendrogliomas are still incurable and new therapies, such as targeting IDH mutations, are necessary. In this opinion piece, we present relevant literature in the field, discuss current challenges, and propose some studies that we think are necessary to answer these critical questions.

Long-term follow up of patients with WHO grade 2 oligodendroglioma

“…The advent of molecular definitions in tumor classification has allowed clear demarcations between subtypes and elucidated important differences in anatomical preferential locations, clinical course, treatment responses and prognosis. For oligodendrogliomas, predictors for an unfavorable clinical course are particularly at risk for being concealed in merged analyses due to dominant effects from tumor subtypes with shorter time to event, such as astrocytomas and IDH -wildtype ( IDH -wt) LGG, all being part of older LGG cohorts [ 2 ]. Another shortcoming, common to most publications with molecular data, is that the follow-up time of patients with oligodendrogliomas is too short to adequately assess survival [ 2 , 3 ].…”

“…For oligodendrogliomas, predictors for an unfavorable clinical course are particularly at risk for being concealed in merged analyses due to dominant effects from tumor subtypes with shorter time to event, such as astrocytomas and IDH -wildtype ( IDH -wt) LGG, all being part of older LGG cohorts [ 2 ]. Another shortcoming, common to most publications with molecular data, is that the follow-up time of patients with oligodendrogliomas is too short to adequately assess survival [ 2 , 3 ]. Surrogate markers for survival such as "progression free survival" (PFS) have been used to circumvent this problem, but the correlation between PFS and actual survival may be very weak [ 4 – 8 ].…”