# Glioma & glioblastoma

Source: https://nuclide.cc/indications/glioblastoma/  
Nuclide record `glioblastoma` (Indication). Data CC BY-NC 4.0, attribute "Data from Nuclide (nuclide.cc)"; commercial use needs a licence.

## TL;DR

Gliomas are now diagnosed by molecular class, and three classes got their first targeted drugs in 2024-25 (vorasidenib for IDH-mutant glioma, tovorafenib for BRAF-altered paediatric glioma, dordaviprone for H3 K27M). Glioblastoma itself is the hardest to treat and has kept the same standard since 2005; CAR-T delivered into the brain and focused-ultrasound drug delivery are the live directions.

## Summary

Gliomas are classified by the WHO 2021 system on molecular grounds: IDH-wild-type glioblastoma (grade 4, ~50% of gliomas, median age 65, median survival ~15 months with maximal therapy), IDH-mutant astrocytoma (grades 2-4) and 1p/19q-codeleted oligodendroglioma (better prognosis, decades of survival possible), and paediatric-type tumours including H3 K27M-mutant diffuse midline glioma (median survival ~11 months) and BRAF-altered low-grade glioma (the commonest childhood brain tumour, rarely life-threatening but chronically disabling). The two shared barriers are the blood-brain barrier, which excludes most drugs, and diffuse infiltration, which makes complete resection impossible.

Glioblastoma treatment has been static since 2005: maximal safe resection (improved by 5-ALA fluorescence, intraoperative MRI, and awake mapping; the extent of resection is itself prognostic and is now graded by the RANO resect classes), radiotherapy with concurrent and adjuvant temozolomide (Stupp), and tumour treating fields (EF-14). MGMT promoter methylation predicts temozolomide benefit; unmethylated tumours gain less, though not nothing, and how much remains debated (in the elderly trials NOA-08 and Nordic, unmethylated tumours did better with radiotherapy than with temozolomide alone). Every major systemic trial since has failed: bevacizumab (PFS only), rindopepimut (ACT IV), nivolumab (CheckMate 143, 498, 548), depatuxizumab mafodotin (INTELLANCE-1), and many more. At recurrence, lomustine, re-resection, re-irradiation, LITT, and bevacizumab for oedema are the options, with median survival under a year. DCVax-L's externally controlled phase 3 remains contested.

Progress has come at the edges. Vorasidenib (INDIGO, approved 2024) is the first targeted therapy for grade 2 IDH-mutant glioma, delaying radiation and chemotherapy by years. Dabrafenib with trametinib (2023) was the first targeted therapy approved for BRAF V600E paediatric low-grade glioma; tovorafenib (2024) followed for relapsed or refractory BRAF-altered tumours, including BRAF fusions. Dordaviprone (August 2025) is the first drug approved for H3 K27M diffuse midline glioma. Methylation-based classification and intraoperative nanopore sequencing have transformed diagnosis. For glioblastoma itself the most promising directions are locoregional CAR-T (IL13Rα2, GD2, multi-target), focused-ultrasound and LITT-based barrier opening to deliver ADCs, radioconjugates, and chemotherapy, neoadjuvant immunotherapy with window designs, personalised neoantigen vaccines (NeoVax), and combinations built on the unmethylated-MGMT population where temozolomide adds nothing.

## Fields

- Kind: Indication
- Last checked: 2026-09-17
- Tags: cns; spike
- Group: central nervous system
- Burden: About 300,000 CNS tumours occur per year, most of them not glioblastoma; IDH-mutant and paediatric low-grade gliomas can be lived with for decades and now have targeted drugs. Median survival for glioblastoma with maximal therapy is about 15 months.
- Subtypes: Glioblastoma, IDH-wild-type (WHO grade 4; TERT promoter, EGFR amplification, +7/−10); Astrocytoma, IDH-mutant (grades 2-4; CDKN2A/B deletion defines grade 4); Oligodendroglioma, IDH-mutant and 1p/19q-codeleted (grades 2-3); Diffuse midline glioma, H3 K27M-altered (including DIPG); Paediatric low-grade glioma (BRAF fusion or V600E, NF1); Diffuse hemispheric glioma H3 G34-mutant; infant-type hemispheric glioma (NTRK/ALK/ROS1 fusions)
- Biomarkers: IDH1/2; 1p/19q codeletion; MGMT methylation; H3K27M; EGFR amplification; Methylation class; IDH1/2 mutation (vorasidenib eligibility); MGMT promoter methylation (temozolomide benefit); H3 K27M (dordaviprone eligibility); BRAF fusion / V600E (tovorafenib, dabrafenib-trametinib); TERT promoter, EGFR amplification, +7/−10 (molecular glioblastoma); CDKN2A/B homozygous deletion (grade 4 astrocytoma); DNA methylation class (Heidelberg classifier); NTRK/ALK/ROS1 fusions (infant gliomas); TMB / mismatch repair (rare hypermutant, IO-responsive)

## Standard of care

- Glioblastoma: Resection → RT + temozolomide → TTFields; lomustine/bevacizumab at relapse.
- IDH-mutant grade 2: Resection → vorasidenib or observation; RT/PCV for high-risk.
- Diagnosis: MRI with contrast; maximal safe resection with 5-ALA and intraoperative mapping, with early postoperative MRI to measure the extent of resection; integrated histo-molecular diagnosis with methylation classification where available.
- Glioblastoma, newly diagnosed: Radiotherapy 60 Gy in 30 fractions with concurrent and 6 cycles adjuvant temozolomide; from age 65, short-course radiotherapy (40 Gy in 15 fractions) with temozolomide (CCTG CE.6); for older patients unfit for combined treatment, temozolomide alone or hypofractionated radiotherapy alone, chosen by MGMT status (Nordic, NOA-08); TTFields with maintenance temozolomide; trials for MGMT-unmethylated patients. ([Temozolomide](https://nuclide.cc/drugs/temozolomide/))
- Glioblastoma, recurrent: Re-resection or LITT if feasible; lomustine; bevacizumab for oedema/steroid sparing; re-irradiation; clinical trial (CAR-T, FUS-BBB, vaccines) strongly preferred.
- IDH-mutant grade 2 glioma: Maximal resection; vorasidenib for residual/recurrent disease (INDIGO); radiotherapy plus PCV or temozolomide for high-risk or progressive disease.
- Oligodendroglioma grade 3 / astrocytoma grade 3: Radiotherapy plus PCV (RTOG 9402, EORTC 26951) or temozolomide (CATNON). ([Temozolomide](https://nuclide.cc/drugs/temozolomide/))
- H3 K27M diffuse midline glioma: Radiotherapy; dordaviprone at progression (2025); GD2 CAR-T and ONC201 first-line trials.
- Paediatric low-grade glioma: Resection where safe; chemotherapy (carboplatin/vincristine) or tovorafenib / dabrafenib-trametinib for BRAF-altered relapsed disease; avoid radiation in young children.

## State of the art

- Vorasidenib in low-grade glioma.
- Methylation-based diagnosis.
- TTFields.
- Three first-in-class targeted approvals for glioma subtypes in 2024-25: vorasidenib (IDH-mutant), tovorafenib (BRAF paediatric), dordaviprone (H3 K27M).
- Molecular classification (WHO 2021, methylation classifier, intraoperative nanopore) now defines diagnosis.
- Locoregional CAR-T produces objective responses in recurrent glioblastoma and DIPG, though transient.
- Focused ultrasound opens the blood-brain barrier in humans with 4-6x higher drug delivery; efficacy trials underway.

## Open problems

- Blood-brain barrier.
- Immunologically cold, heterogeneous, infiltrative.
- Glioblastoma: no systemic drug has beaten the 2005 standard; getting drugs across the blood-brain barrier is the crux.
- Glioblastoma's standard has not changed since 2005: every phase 3 systemic agent since temozolomide has failed, so median survival has not moved in 20 years.
- MGMT-unmethylated glioblastoma (~60%) gains almost nothing from chemotherapy and has no approved alternative.
- Blood-brain barrier and diffuse infiltration limit delivery and resection; imaging cannot distinguish progression from pseudoprogression reliably.
- Immunotherapy failure: low TMB, T-cell exclusion, dexamethasone, and treatment-induced lymphopenia; neoadjuvant approaches are the only signal.
- Antigen heterogeneity and loss (EGFRvIII, IL13Rα2) undermine single-target vaccines, ADCs, and CAR-T.
- Paediatric tumours (DIPG) have one approved drug with 22% response; durable control remains out of reach.
- Trial design: single-arm and external-control comparisons (DCVax-L, historical vaccine data) have repeatedly misled the field.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Glioblastoma
- Wikipedia: https://en.wikipedia.org/wiki/Glioblastoma

## Connected records

- indications: [Meningioma](https://nuclide.cc/indications/meningioma/)
- targets: [B7-H3](https://nuclide.cc/targets/b7h3/), [Bradykinin B1 receptor (B1R)](https://nuclide.cc/targets/bradykinin-b1-receptor/)
- companies: [Bristol Myers Squibb](https://nuclide.cc/companies/bms/)
- institutions: [Abramson Cancer Center, University of Pennsylvania](https://nuclide.cc/institutions/penn-abramson/), [Erasmus MC Cancer Institute](https://nuclide.cc/institutions/erasmus-mc/), [Heidelberg University Hospital / NCT / DKFZ](https://nuclide.cc/institutions/heidelberg-nct/), [Inselspital, Bern University Hospital / University Cancer Center Inselspital](https://nuclide.cc/institutions/inselspital-bern/), [University Hospital Zurich / Comprehensive Cancer Center Zurich](https://nuclide.cc/institutions/usz-zurich/), [Uppsala University Hospital / Uppsala University](https://nuclide.cc/institutions/uppsala-akademiska/)
- drugs: [Floretyrosine F-18 (FET)](https://nuclide.cc/drugs/f-18-fet/), [Fluciclovine F-18](https://nuclide.cc/drugs/fluciclovine-f18/), [Fluorodopa F-18](https://nuclide.cc/drugs/f-18-fdopa/), [Fluorothymidine F-18 (FLT)](https://nuclide.cc/drugs/f-18-fluorothymidine/), [Temozolomide](https://nuclide.cc/drugs/temozolomide/)
- terms: [Radiation necrosis (brain)](https://nuclide.cc/terms/radiation-necrosis/)
- fronts: [Neuro-imaging](https://nuclide.cc/fronts/f-neuro-imaging/)
- roadmaps: [Neuro-oncology imaging roadmap: FDG PET → amino acid PET → SSTR2 theranostics in meningioma](https://nuclide.cc/roadmaps/neuro-imaging-roadmap/)

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