| Summary: | Simple Summary: Oligodendroglioma is an uncommon brain tumor that often affects younger and middle-aged adults and can progress slowly over many years. The current treatment approach relies on surgery followed by radiation and a three-drug chemotherapy regimen known to improve long-term survival, although many patients struggle with significant treatment-related side effects. Recently, new medicines have been developed that directly target the genetic changes that drive these tumors. These targeted treatments are generally easier to tolerate and may postpone the need for radiation or chemotherapy, but they have not yet been compared directly with the long-established regimen. In this review, we gathered and evaluated all available studies on both approaches to clarify what is known about their benefits, their risks, and the strength of evidence supporting each option. We found that the traditional regimen remains the only therapy with proven survival advantages measured over many years, while the targeted medicines offer early signs of disease control with fewer severe side effects. These findings highlight the need for future studies that directly compare the two strategies. They also provide patients and clinicians with a clearer foundation for thoughtful, individualized treatment decisions. The abstract has been submitted for presentation to the AANS 2026 meeting being held in San Antonio, TX, USA. Introduction: Oligodendrogliomas are an uncommon subset of gliomas that are molecularly defined by 1p/19q codeletion in the setting of an isocitrate dehydrogenase (IDH) 1/2 mutation. Standard-of-care management involves maximal safe resection followed by adjuvant chemoradiation with procarbazine, lomustine, and vincristine (PCV). Although PCV confers a durable survival advantage, treatment-limiting toxicity is common and often necessitates discontinuation. IDH inhibitors such as vorasidenib have demonstrated promising efficacy and more favorable tolerability profiles, but a paucity of comparative data across therapeutic classes limits optimal treatment decision-making. Methods: A systematic search was conducted through to 7 March 2025 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Eligible studies included adult patients (≥18 years) with IDH-mutant, 1p/19q-codeleted oligodendrogliomas treated with PCV chemotherapy or IDH inhibitors and with a minimum follow-up of 12 months. Outcomes of interest included overall survival (OS), progression-free survival (PFS), and grade ≥ 3 adverse events (AEs) that led to treatment discontinuation. Results: Twenty-eight studies met the inclusion criteria, with a total of 406 patients. All 406 patients carried a confirmed diagnosis of oligodendroglioma. For mixed-histology cohorts, only oligodendroglioma-specific data were extracted and analyzed. Among PCV cohorts, median PFS ranged from 24.3 months to 8.4 years and median OS was reported up to 14.7 years in long-term follow-up from RTOG 9402 and EORTC 26951. Grade ≥ 3 AEs resulted in treatment discontinuation in 65–70% of patients, primarily due to hematologic or neurologic events. In comparison, vorasidenib achieved a median PFS of 27.7 months in the phase III INDIGO trial (HR 0.39; 95% CI 0.27–0.56; p < 0.001), with median OS not yet reached at 14.2 months of follow-up. Grade ≥ 3 AEs occurred in 22.8% of patients and led to treatment discontinuation in only 1–3%, primarily due to asymptomatic transaminitis. Early real-world data from expanded-access programs similarly support these tolerability findings. Conclusions: While PCV chemotherapy remains the standard-of-care systemic therapy for oligodendroglioma supported by mature survival data, IDH inhibitors represent a mechanistically targeted alternative with encouraging early-phase outcomes and a significantly improved safety profile. Direct comparison across these regimens is constrained by differences in study design and limited long-term OS data for IDH inhibitors. Prospective head-to-head trials are essential for defining the optimal therapeutic sequence in this evolving treatment landscape. In the interim, we provide a recommend approach for current use.
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