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. 2025 Jul 19;167(1):196.
doi: 10.1007/s00701-025-06612-6.

A scoping review of proton radiation therapy and mutant-isocitrate dehydrogenase-inhibitors in IDH mutated lower-grade gliomas: pushing beyond surrogate end-points

Dima Harba  1 , Alba Corell  1   2 , Alireza Mansouri  3 , Petter Brandal  4   5 , Malin Blomstrand  6   7 , Asgeir Store Jakola  8   9
Affiliations

A scoping review of proton radiation therapy and mutant-isocitrate dehydrogenase-inhibitors in IDH mutated lower-grade gliomas: pushing beyond surrogate end-points

Dima Harba et al. Acta Neurochir (Wien). .

Abstract

Background: Proton radiation therapy (PRT) and mutant isocitrate dehydrogenase inhibitors (mIDH-inhibitors) are emerging therapies for mIDH lower grade gliomas (LGGs). Despite their substantial theoretical benefits, comparisons with current standards - particularly pertaining to patient-centred outcomes - are limited.

Methods: Through PubMed and Scopus, a search strategy based on keywords focusing on PRT and mIDH-inhibitors was applied on December 3, 2024. Studies in English on at least 20 adult patients (≥ 18 years) with mIDH-LGG grade 2 or 3 and published between January 1, 2011 and August 31, 2024 were included. Review articles were excluded.

Results: Of 6383 identified articles, seven per treatment strategy were included. Overall survival was not reported for mIDH-inhibitors. The lack of high-quality studies comparing PRT to photon radiation therapy precludes conclusions regarding efficacy, effectiveness or even post-PRT radiological manifestations. For the mIDH-inhibitor Vorasidenib (AG-881), the radiological objective response rate was 10.0-42.9%, although lower for contrast-enhancing tumors. Vorasidenib significantly delayed tumor progression (27.7 versus 11.1 months, p < 0.001) and time to next intervention (not reached versus 17.8 months, p < 0.001) when compared to placebo. Adverse events were mostly mild, including elevated liver enzymes (15.6-44.2%) and headache (26.9-46.2%). Only 1/14 studies included assessments related to quality of life (QoL)-domains with inconclusive research on cognitive outcomes.

Conclusion: Studies reporting on patient-centred data including survival, cognition and QoL remain scarce. Larger, comparative prospective studies, preferably randomized controlled trials, with such outcomes are needed to inform clinicians whether the theoretical and radiological benefits can be translated to improved outcomes that matter to patients, i.e. living better and/or longer.

Keywords: Glioma; IDH inhibitor; Proton; Quality of life; Survival; Vorasidenib.

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Conflict of interest statement

Declarations. Ethical approval: No ethical approval from an ethics committee or institutional review board was required as no access to sensitive patient information nor any direct involvement of human/animal participants was included in this review. Consent to participate: Not applicable. Consent to publish: Not applicable. Competing interests: Author P.B. declares honoraria for lectures, consultation or advisory board participation from Servier, Ekspertpanelet and Moloklinikken. The remaining authors have no conflicts of interest to declare that are relevant to the content of this article.

Figures

Fig. 1
Fig. 1
PRISMA flow diagram showing inclusion of studies, IDH = Isocitrate dehydrogenase
See this image and copyright information in PMC

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