Brain Tumor Glioblastoma: Current Approaches from Molecular Diagnosis to Personalized Treatment
In this article
What Are Brain Tumors and Glioblastoma?
The brain is the most complex organ in the human body, and tumors that develop in this delicate tissue are among the most challenging areas in oncology. Brain tumors are abnormal masses caused by uncontrolled cell proliferation in brain tissue and fall into two main groups: primary tumors (arising from the brain's own cells — glial or neuronal) and metastatic (secondary) tumors (caused by cancer elsewhere in the body spreading to the brain, and seen more often in clinical practice than primary tumors). In this guide, we focus on gliomas, the most common and most aggressive group of primary brain tumors, and particularly on glioblastoma (GBM).
Gliomas are the most common group of primary brain tumors originating from glial cells, the brain's supporting cells, and are graded according to the rate of cell proliferation and microscopic features (from Grade 1 to 4). The most aggressive form of glioma, classified by the World Health Organization (WHO) as Grade 4 , is glioblastoma (GBM)— its clinical course is rapid, its tendency to recur (reappear) is high, and it is managed with a multidisciplinary approach involving neurosurgery, radiation oncology, and medical oncology.
Two tumors with the same microscopic appearance may behave very differently at the molecular level. Modern neuro-oncology therefore requires a "molecular fingerprint" for diagnosis: the tumor's genetic/epigenetic signature is crucial in predicting prognosis and treatment response. This guide aims to present this paradigm shift, the current molecular classification, and new targeted treatments approved during 2024-2026 in a clear and comprehensive way.
Epidemiology and Disease Burden
According to the statistical report published by CBTRUS (Central Brain Tumor Registry of the United States) in October 2025, based on diagnoses during 2018-2022, primary brain and central nervous system (CNS) tumors (benign and malignant combined) occur annually in approximately 26,05/100.000 people in the United States; approximately 26% are malignant and 74% benign. The overall 5-year relative survival for malignant primary brain/CNS tumors is %34,8. According to a separate Glioblastoma Fact Sheet, also published by CBTRUS in 2025 but based on diagnoses during 2017-2021, specifically for glioblastoma (GBM) : the annual incidence is 3,27 per 100.000, the median age at diagnosis is 66, and GBM accounts for 51,5% of all malignant brain tumors, remaining the most common malignant primary brain tumor.
According to the Türkiye country fact sheet updated by IARC in July 2026 and its GLOBOCAN 2024 estimates , approximately 5.237 new cases of brain/CNS cancer are reported annually (2,2% of all cancers, the 13th most common cancer type); the age-standardized incidence rate is 5,1 per 100.000. The annual number of deaths due to this disease is approximately 4.385 (3,9% of all cancer deaths), and the 5-year point prevalence (the number of people currently living with the disease) is approximately 20.509. Our sources did not provide an incidence figure specific to Türkiye that distinguishes glioblastoma alone; the figures above cover all brain/CNS tumors (benign and malignant).
The population-based survival figures reported for GBM in the CBTRUS Glioblastoma Fact Sheet mentioned above, based on 2017-2021 data (median ~8-9 months, 5-year survival 7,1%), are lower than the figures in the clinical trials discussed later (for example, the Stupp protocol). Population registries include all patients, including those who cannot tolerate treatment, are older, or have a low performance status; clinical trials generally enroll younger patients in better overall health. This distinction matters for interpreting the statistics correctly.
Symptoms: When Should a Brain Tumor Be Suspected?
Brain tumor symptoms vary depending on the tumor's location in the brain, size, and growth rate. Assessment is needed if one or more of the following symptoms occur, particularly if they are new or rapidly worsening:
- Headache (particularly worsening in the morning, newly occurring, or changing in character)
- New-onset epileptic seizure
- Weakness in an arm or leg (hemiparesis)
- Language impairment (aphasia)
- Visual field loss
- Impaired balance and coordination (ataxia)
- Personality and behavioral changes
- Impaired concentration and executive function
- Nausea and vomiting (particularly in the morning, due to increased intracranial pressure)
- Papilledema (a sign of increased intracranial pressure detected on examination of the back of the eye)
A first epileptic seizure in an adult or rapidly progressing neurological symptoms (worsening over days to weeks) require urgent assessment with contrast-enhanced brain MRI.
The Diagnostic Journey
- Imaging: Contrast-enhanced brain MRI is the first choice. CT is valuable in emergencies; advanced imaging methods, such as perfusion MRI, MR spectroscopy, and PET, are used in selected situations to support differential diagnosis (tumor, infection, or ischemia).
- Neurosurgical assessment: The aim is to achieve the greatest possible safe resection (maximal safe resection). When the tumor is adjacent to functional areas (areas controlling critical functions such as speech and movement), awake craniotomy, intraoperative mapping, and neuronavigation are used. If resection is unsuitable, a tissue diagnosis is obtained by stereotactic biopsy .
- Pathology and molecular analysis: In addition to conventional histological examination, markers such as IDH1/2, ATRX, TP53, the TERT promoter, EGFR amplification, and 1p/19q codeletion are assessed, together with H3 K27M testing where age and location warrant it. The results establish the definitive diagnosis according to the current WHO classification detailed below.
You can learn more about the general principles of genetic testing in cancer in our article What Is a Mutation? How Does It Cause Cancer? .
Molecular Classification: WHO 2021 and Updates
The history of brain tumor classification began in 1926 with Bailey and Cushing's histological approach (based on microscopic appearance). From the 2000s onward, however, advances in molecular neuro-oncology clearly demonstrated that two tumors with the same microscopic appearance can behave completely differently biologically (one may progress rapidly while the other grows slowly; one may resist treatment while the other is sensitive).
This major change was reflected in the 5th edition classification published by WHO in 2021: diagnosis now relies on a multilayered approach integrating molecular biomarkers rather than microscopic appearance alone. One of the most important steps was to treat pediatric-type and adult-type diffuse gliomas as separate groups because of their clinical and biological differences. WHO 2021 simplified adult-type diffuse gliomas into three categories: astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and glioblastoma, IDH-wildtype.
As of 2026, the WHO 2021 (5th edition) classification remains in effect; an official 6th edition has not yet been published, although WHO/IARC is actively working toward it. In the interim, the cIMPACT-NOW consortium publishes interpretive reports that effectively serve as additional updates. The latest, updating diagnostic criteria for IDH- and H3-wildtype high-grade diffuse gliomas and posterior fossa ependymomas, is cIMPACT-NOW Update 11. The three main categories summarized above (astrocytoma/oligodendroglioma/glioblastoma) remain valid; the updates primarily clarify additional molecular criteria used in borderline cases.
The classification also defines two special categories for situations in which molecular testing required for diagnosis cannot be performed: NOS (Not Otherwise Specified — when molecular testing has not been performed) and NEC (Not Elsewhere Classified — when the molecular characteristics do not fit the defined groups).
Key Molecular Biomarkers
By examining the genetic makeup of tumor tissue, molecular tests help us understand how the tumor is likely to behave (prognostic value) and which treatments it may respond to (predictive value).
IDH Mutation
Mutations in the IDH1 and IDH2 genes occur in approximately 20% of gliomas, particularly in younger patients and low-grade gliomas. These mutations cause an oncometabolite called D-2-hydroxyglutarate (2-HG) to accumulate, disrupting cell differentiation. Clinical significance: IDH-mutant gliomas grow more slowly than IDH-wildtype tumors and are associated with significantly longer survival; this mutation is also a prerequisite for the vorasidenib treatment described below.
1p/19q Codeletion
This is the simultaneous loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q). When present together with an IDH mutation, it establishes the diagnosis of oligodendroglioma. Tumors with this genetic signature respond better to temozolomide/PCV chemotherapy and radiotherapy and are associated with a more favorable prognosis.
MGMT Promoter Methylation
The MGMT (O6-methylguanine-DNA methyltransferase) protein normally acts like a "repair technician," removing damaged methyl groups from DNA. When the promoter region of the MGMT gene is methylated, the gene is silenced and the tumor cell cannot repair the methyl groups added to DNA by temozolomide (TMZ), leaving it vulnerable to the drug. Clinical significance: Patients with GBM whose MGMT promoter is methylated respond better to TMZ treatment and have longer survival. This relationship is not absolute, however — some unmethylated tumors may also respond, so MGMT status is assessed alongside other clinical/molecular information rather than on its own.
Other Important Markers
- BRAF V600E mutation: Seen particularly in pediatric low-grade astrocytomas and pleomorphic xanthoastrocytomas; it determines eligibility for targeted treatment (see below).
- NTRK fusions: Rare; they predict response to TRK inhibitors (larotrectinib, entrectinib).
- H3 K27M mutation: Common in diffuse midline gliomas (DMG) and associated with an aggressive course; it is a prerequisite for dordaviprone treatment approved in 2025 (see below).
Standard Treatment: Surgery, Radiotherapy, Chemotherapy
Surgical Resection
The aim is to remove as much of the tumor as possible (maximal safe resection), both to reduce symptoms and to increase the effectiveness of subsequent treatments. Complete (gross-total) resection may not be possible in many cases; the tissue obtained is then used for molecular analysis. The central dilemma in brain surgery is that removing more tumor improves survival, but excessively aggressive resection can permanently impair functions such as speech, movement, or vision. Over the past twenty years, techniques developed to achieve this balance have been the most important area of progress in brain tumor surgery:
Given orally a few hours before surgery, 5-aminolevulinic acid (5-ALA)accumulates selectively in tumor cells and produces a pink-red fluorescent glow under special violet light; this enables the surgeon to see the boundary between normal brain tissue and tumor even where it cannot be distinguished with the naked eye. The groundbreaking randomized trial by Stummer and colleagues (Lancet Oncology, 2006; n=270) showed that it increased the rate of complete removal of contrast-enhancing tumor from 36% to 65% and increased 6-month progression-free survival from 21,1% to 41,0% — without an increase in additional side effects. Although 5-ALA has been used in Europe since 2007, it received FDA approval only on June 6, 2017 (under the name Gleolan, as an optical imaging agent).
If the tumor is adjacent to "eloquent" brain regions controlling critical functions such as speech, movement, or sensation, the patient is awakened during part of the operation. While mapping the tissue point by point with electrical stimulation, the surgeon asks the patient to speak, count, or move their fingers. If stimulation produces a temporary speech arrest or weakness, that site is preserved. This allows the surgeon to define the boundary according to that patient's own functional map rather than an "anatomical estimate" — the location of functional areas can vary between people and even over time in the same person because of reorganization caused by the tumor.
LITT destroys tumor tissue by heating it with a thin laser probe inserted through a small hole in the skull, with real-time temperature monitoring under MRI guidance. It offers an option for deep-seated tumors, tumors unsuitable for open surgery, and radiation necrosis. However, there is an important regulatory distinction: LITT devices (Visualase, NeuroBlate) entered the market through FDA 510(k) equivalence clearance rather than full approval (PMA) — as tools for intracranial soft tissue ablation/coagulation, rather than on the basis of efficacy data for a specific brain tumor indication.
Carmustine-impregnated wafers (Gliadel) are dissolvable discs placed in the cavity left after tumor removal during surgery, releasing chemotherapy directly at the site. They received FDA approval for recurrent GBM on September 23, 1996 and for newly diagnosed high-grade glioma on February 25, 2003 . They are now used in selected cases because their survival benefit is modest and they carry risks of wound-healing problems/brain edema.
Radiotherapy + Temozolomide: The Stupp Protocol
In the current standard "Stupp protocol," concomitant temozolomide (TMZ) is added to radiotherapy after surgery, followed by maintenance TMZ for 6 months. In the original randomized trial, this combination increased median overall survival from 12,1 months to 14,6 months and increased the 2-year survival rate from 10% to 26% . Long-term follow-up data published in 2009 showed that the 5-year survival rate also increased from 1,8% to 9,8% — these results have made the Stupp protocol the unchanged standard of care for GBM for nearly 20 years.
The standard regimen, starting 3-6 weeks after surgery, includes 60 Gy of radiotherapy (30 fractions over 6 weeks) with low-dose temozolomide taken daily at the same time. Beginning 4 weeks after radiotherapy finishes, treatment continues with higher-dose temozolomide given during the first 5 days of 28-day cycles, for 6 cycles of maintenance temozolomide .
Shortened (hypofractionated) regimens have been developed for older patients or those in poor general health who cannot tolerate standard 6-week radiotherapy. The trial by Perry and colleagues (NEJM, 2017) showed that adding temozolomide to short-course radiotherapy over 3 weeks (40,05 Gy, 15 fractions) in patients older than 65 increased overall survival from 7,6 months to 9,3 months (HR 0,67). The benefit was particularly pronounced in the MGMT-methylated subgroup (13,5 versus 7,7 months; HR 0,53), and more limited in patients without methylation (10,0 versus 7,9 months). For even frailer patients, the IAEA trial by Roa and colleagues (J Clin Oncol, 2015) showed that an ultra-short regimen of just 5 sessions (25 Gy) produced equivalent outcomes to a 15-session regimen — a valuable quality-of-life option that reduces weeks in hospital to days.
The German CeTeG/NOA-09 trial (Herrlinger U, et al., Lancet, 2019) reported that adding lomustine to standard temozolomide in newly diagnosed GBM patients with MGMT promoter methylation increased overall survival from 31,4 months to 48,1 months (HR 0,60). Despite this striking figure, the finding has not gained broad acceptance and has not replaced the Stupp protocol. The reasons are that statistical significance was borderline (p=0,0492), the trial was smaller than planned (129 patients), and prognostic factors were unevenly distributed between arms. A difference in overall survival without a difference in progression-free survival raised a methodological concern, and the proportion completing treatment was significantly lower in the combination arm (39% versus 60%). This regimen should therefore be presented as an option for selected, very fit patients with MGMT methylation that may be considered according to the center's experience rather than as a "new standard."
Treatment by Glioma Grade: Gliomas Other Than GBM
Most of this guide focuses on glioblastoma (Grade 4). Treatment of IDH-mutant Grade 2 and Grade 3 gliomas, however, is completely different in both approach and expected survival — for these patients, survival is measured not in months but in years, or even decades . Long-term treatment side effects, particularly the cognitive effects of radiotherapy, therefore matter much more.
Grade 2 (Low-Grade) IDH-Mutant Glioma
In high-risk Grade 2 glioma patients (older than 40 or with incomplete resection), the addition of PCV chemotherapy (procarbazine, lomustine, vincristine) to radiotherapy was tested in RTOG 9802 (Buckner JC, et al., NEJM, 2016), increasing median overall survival from 7,8 years to 13,3 years (HR 0,59; p=0,003); progression-free survival increased from 4,0 years to 10,4 years. The 10-year survival rate rose from 40% to 60%. This is the key evidence establishing the role of chemotherapy in low-grade glioma.
Treatment decisions in Grade 2 glioma are personalized according to molecular subtype and the patient's risk profile: close follow-up (observation) is an option for low-risk, completely resected tumors, while radiotherapy + PCV is the standard approach for high-risk patients. Since August 2024, postoperative vorasidenib (discussed in detail below) has been added to this algorithm as a third option — attracting considerable interest for young patients, particularly because of its potential to delay radiotherapy.
Grade 3 (Anaplastic) Glioma
CATNON/EORTC 26053 trial's final analysis (van den Bent MJ, et al., Lancet Oncology, 2026) definitively answered when temozolomide should be given in anaplastic (Grade 3) astrocytoma without 1p/19q codeletion. The findings have two aspects with direct practical implications: adjuvant temozolomide after radiotherapy provides a clear benefit (HR 0,65; in IDH-mutant patients, median overall survival increases from 6,0 years to 12,5 years ); in contrast, temozolomide given concomitantly with radiotherapy provides no additional benefit (HR 0,91, not significant). Giving concomitant temozolomide as in GBM therefore adds unnecessary toxicity in this patient group. The current approach is: radiotherapy followed by 12 cycles of adjuvant temozolomide — without a concomitant phase.
In anaplastic oligodendroglioma with 1p/19q codeletion, these two parallel trials tested the addition of PCV chemotherapy to radiotherapy. Their joint final report, published with 18-19 years of follow-up (J Clin Oncol, 2022), demonstrated one of oncology's most impressive long-term outcomes. In the codeleted subgroup, median overall survival increased in RTOG 9402 from 7,3 years to 13,2 years and in EORTC 26951 from 9,3 years to 14,2 years (an approximately 40% reduction in the risk of death in both trials). Even more striking was the 20-year survival rate: from 14,9% to 37% in RTOG 9402 and from 13,6% to 37,1% in EORTC 26951 — a third of these patients were still alive twenty years after diagnosis thanks to the addition of chemotherapy.
In codeleted patients, the trial testing whether radiotherapy could be omitted entirely and temozolomide given alone to avoid long-term cognitive side effects was CODEL . Its temozolomide-only arm was closed early: median progression-free survival in that arm was 2,9 years while the median had not been reached in the radiotherapy-containing arms (HR 3,12; p<0,01). Omitting radiotherapy is therefore clearly harmful in this patient group. The trial is continuing with a revised design (radiotherapy + PCV versus radiotherapy + temozolomide); the question of PCV versus temozolomide has not yet been answered.
TTFields (Tumor Treating Fields)
TTFields (the Optune device)is a nondrug treatment that physically disrupts tumor cell division (mitosis) by applying low-intensity alternating electric fields through electrodes placed on the scalp. The patient must wear the device for most of the day (generally at least 75% of the time).
In newly diagnosed GBM, the final analysis of the trial adding TTFields to maintenance TMZ, EF-14 , showed median overall survival of 20,9 versus 16,0 months (HR 0,63; p<0,001) and median progression-free survival of 6,7 versus 4,0 months. The 2-year survival rate was 43% versus 31%; the 5-year survival rate was more than doubled, at 13% versus 5% . These results have made TTFields, added to maintenance TMZ, a standard part of the first-line treatment algorithm in newly diagnosed GBM.
The most common TTFields side effect is skin irritation where the electrodes make contact; this can usually be managed with topical care. Daily device use (head shaving, electrode changes, a portable battery unit) is a practical issue that can affect quality of life and adherence and should be discussed with the patient when deciding on treatment.
Treatment Options for Recurrent Glioblastoma
Despite standard treatment, GBM has a high recurrence (reappearance) rate. Treatment of recurrence is individualized, and available options are less effective than initial treatment.
MRI may show tumor growth early after treatment; this is often not true recurrence but treatment-related inflammatory changes (pseudoprogression). Advanced imaging, such as perfusion MRI or PET, helps distinguish the two; misinterpretation can lead to premature, unnecessary discontinuation of an effective treatment.
Bevacizumab
Bevacizumab, a VEGF inhibitor, first received accelerated approval for recurrent GBM in 2009, based on response rates in single-arm trials (25,9% and 19,6%). Full approval followed on December 5, 2017, based on EORTC 26101 (bevacizumab+lomustine versus lomustine alone), which demonstrated a significant increase in progression-free survival (4,2 versus 1,5 months, a 48% reduction in progression risk); however, there was no significant difference in overall survival. This distinction matters: bevacizumab can rapidly relieve symptoms (particularly those related to brain edema) and delay progression, but evidence that it extends life is limited.
Lomustine (CCNU)
Lomustine is an oral chemotherapy agent given every 6 weeks and has long been used as a standard comparator/combination agent in recurrent GBM; its most common side effect is bone marrow suppression. No new pivotal evidence has replaced lomustine in recent years — its standard status reflects the lack of a proven superior alternative rather than new evidence of superiority.
Temozolomide Rechallenge
For patients who previously benefited from TMZ, particularly those with MGMT promoter methylation, trying TMZ again with a different dosing schedule (rechallenge) may be an option at recurrence.
TTFields (in Recurrent Disease)
TTFields is also FDA-approved in recurrent GBM (April 8, 2011); early studies showed an increase in median survival from 6,6 months to 9,6 months .
Repeat Surgery and Reirradiation
In selected patients — those in good general health, with a limited, accessible recurrence and a sufficient interval since the first operation — repeat surgical resection can reduce mass effect and relieve symptoms while providing a new tissue sample to assess whether the molecular profile has changed (for example, whether a new targetable mutation has emerged). Similarly, patients with a small recurrence and a sufficient interval since initial radiotherapy may be considered for stereotactic reirradiation . Randomized evidence is limited for both approaches; decisions are made by a multidisciplinary tumor board, weighing the expected benefit against the risk of cumulative injury to brain tissue.
The Italian REGOMA phase 2 trial (Lancet Oncology, 2019) reported that regorafenib increased overall survival compared with lomustine in recurrent GBM, from 5,6 months to 7,4 months (HR 0,50), and the agent appeared in guidelines for a time as a promising option. However, the results of the regorafenib arm of the confirmatory GBM AGILE platform trial (J Clin Oncol, 2026) were negative : in recurrent disease, survival was 8,0 months with regorafenib versus 9,2 months in the lomustine control arm; in newly diagnosed, MGMT-unmethylated disease, it was 12,0 months versus 13,7 months in the temozolomide arm. In both settings, regorafenib produced numerically worse outcomes and greater toxicity. On the basis of these data, regorafenib has been removed from recommendations for recurrent GBM. This is an instructive example of why promising results from small phase 2 studies need confirmation in large trials.
Because approved treatments have limited effectiveness in recurrent GBM, current guidelines recommend participation in a suitable clinical trial as equivalent to standard options, or even preferable in some circumstances at this stage. This does not mean a "last resort when no other options remain" — given the pace of progress in the field, access to investigational treatments for recurrent GBM is a real window of opportunity and should be considered early in treatment planning.
Targeted Treatments
The clearest clinical consequence of molecular classification is that approved drugs now exist for specific genetic subgroups. This shows that the era of "treatment according to the molecular fingerprint" has effectively begun in glial tumors as well.
Vorasidenib — IDH-Mutant Low-Grade Glioma
Vorasidenib (Voranigo)is an oral drug that inhibits the mutant IDH1/IDH2 enzyme, stopping production of the oncometabolite 2-HG. INDIGO phase 3 trial showed a substantial reduction in the risk of progression or death versus placebo in postoperative Grade 2 IDH-mutant astrocytoma/oligodendroglioma (HR 0,39 for PFS; HR 0,26 for time to the next treatment). On the basis of these results, vorasidenib received FDA approval on August 6, 2024 — the first targeted drug approved for Grade 2 IDH-mutant glioma after surgery. Approval in Europe (EMA) followed on September 22, 2025 .
Dordaviprone — H3 K27M-Mutant Diffuse Midline Glioma
Dordaviprone (Modeyso), on August 6, 2025, for previously treated, recurrent H3 K27M-mutant diffuse midline glioma (DMG) in patients aged 1 and older, received FDA accelerated approval — this is not full/regular approval, an important distinction. Approval is based on a pooled analysis of 50 patients from 5 separate single-arm (uncontrolled) studies: the objective response rate was %22, and median response duration was 10,3 months. Conversion from accelerated to full approval depends on confirmatory results from the ongoing ACTION phase 3 trial (dordaviprone after radiotherapy in newly diagnosed H3K27M-mutant diffuse glioma). Patients and families need to understand that this drug was approved on preliminary data before a "definitive" benefit in overall or progression-free survival had been demonstrated.
Dabrafenib + Trametinib — BRAF V600E-Mutant Glioma
The BRAF V600E mutation keeps intracellular growth signals continuously active. In gliomas with this mutation, dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) suppress tumor growth in combination. This combination has two separate approval pathways in brain tumors:
Dabrafenib+trametinib received accelerated approval in patients aged 6 and older for all solid tumors with a BRAF V600E mutation (excluding colorectal cancer) that progressed despite prior treatment and had no other satisfactory option. The importance of this approval for brain tumors is that the efficacy population directly included glioma cohorts: in adults, the objective response rate in high-grade glioma was %33 and in low-grade glioma was %50; in the combined pediatric low- and high-grade glioma group, it was reported as 25%.
In the randomized phase 2 trial (CDRB436G2201), dabrafenib+trametinib increased the objective response rate compared with standard chemotherapy in patients aged 1 and older with BRAF V600E-mutant pediatric low-grade glioma requiring systemic treatment, from 10,8% to 46,6% and increased median progression-free survival from 7,4 months to 20,1 months (HR 0,31; p<0,001). Median response duration was 23,7 months in the chemotherapy arm and had not been reached in the combination arm. This is the first systemic treatment approved as first-line therapy in this patient group — an important milestone in which a targeted drug replaced chemotherapy in children.
Tovorafenib — BRAF-Altered Pediatric Low-Grade Glioma
The alteration seen in the great majority of pediatric low-grade gliomas is not the V600E point mutation but a BRAF fusion (most commonly KIAA1549-BRAF). These fusions do not respond to conventional BRAF inhibitors such as dabrafenib, which can even paradoxically accelerate tumor growth. Tovorafenib (Ojemda)is a "type II" BRAF inhibitor designed to overcome this problem and can target both fusions/rearrangements and V600 mutations . FIREFLY-1 provided the basis for accelerated FDA approval in patients aged 6 months and older with relapsed or refractory BRAF-altered pediatric low-grade glioma, on April 23, 2024 . According to the RAPNO-LGG criteria used in the approval assessment, the objective response rate was %51 and median response duration was 13,8 months. Once-weekly dosing also provides a practical advantage for children and their families.
NTRK Fusion: Tumor-Agnostic Approvals
Larotrectinib (November 26, 2018) and entrectinib (August 15, 2019) received tumor-agnostic approval for all solid tumors carrying an NTRK gene fusion; larotrectinib's approval was converted on April 9, 2025 from accelerated to full approval. An important distinction applies to brain tumors: for both drugs, primary brain tumors were absent from the efficacy population underpinning the initial approval — entrectinib's central nervous system data came not from primary brain tumors but from brain metastases . Because the indication states "solid tumors," these drugs may legally be used for a glioma with an NTRK fusion, but their approvals are not based on primary brain tumor data. Subsequent pooled analyses have included primary central nervous system tumors and reported responses.
Belzutifan — CNS Hemangioblastoma Associated with VHL Disease
Von Hippel-Lindau (VHL) disease is an inherited syndrome causing recurrent hemangioblastomas in the central nervous system (particularly the cerebellum and spinal cord); repeated brain operations are themselves a considerable disease burden in these patients. Belzutifan (Welireg)is an oral drug blocking the HIF-2α protein downstream of the VHL pathway, which received FDA approval on August 13, 2021 . In VHL-associated CNS hemangioblastoma not requiring immediate surgery, the reported objective response rate was %63 . This is one of the rare examples of a brain tumor being reduced with an oral drug instead of surgery.
Everolimus — SEGA Associated with Tuberous Sclerosis
In patients with tuberous sclerosis complex (TSC), subependymal giant cell astrocytoma (SEGA)is a tumor that can obstruct cerebrospinal fluid circulation, causing hydrocephalus, and is difficult to operate on. The mTOR inhibitor everolimus (Afinitor), on October 29, 2010 received accelerated approval for SEGA unsuitable for surgery; with confirmatory data from EXIST-1, this was converted on January 29, 2016 to full approval. A dispersible tablet formulation (Afinitor Disperz) was approved on August 29, 2012, to make administration easier in children.
| Molecular Subgroup / Condition | Approved Drug | Pivotal Study | Approval Date | Key Effectiveness Data |
|---|---|---|---|---|
| IDH-mutant Grade 2 glioma (after surgery) | Vorasidenib | INDIGO | August 6, 2024 (full approval) | PFS HR 0,39; time to subsequent treatment HR 0,26 |
| Recurrent H3 K27M-mutant diffuse midline glioma | Dordaviprone | Pool of 5 studies (n=50) | August 6, 2025 (accelerated) | ORR 22%, response duration 10,3 months |
| BRAF V600E-mutant solid tumors (including glioma) | Dabrafenib+trametinib | ROAR/NCI-MATCH basket | June 22, 2022 (accelerated) | High-grade glioma ORR 33%; low-grade 50% |
| BRAF V600E-mutant pediatric low-grade glioma (1st line) | Dabrafenib+trametinib | CDRB436G2201 (randomized phase 2) | March 16, 2023 (full approval) | ORR 46,6% vs 10,8%; PFS 20,1 vs 7,4 months (HR 0,31) |
| Recurrent pediatric low-grade glioma with BRAF fusion/rearrangement or V600 mutation | Tovorafenib | FIREFLY-1 | April 23, 2024 (accelerated) | ORR 51% (RAPNO-LGG), response duration 13,8 months |
| NTRK fusion-positive solid tumors (tumor-agnostic) | Larotrectinib, entrectinib | Pooled basket trials | November 26, 2018 / August 15, 2019 | Primary brain tumors were not included in the initial approval population |
| CNS hemangioblastoma associated with VHL disease | Belzutifan | Study 004 (LITESPARK-004) | August 13, 2021 | ORR 63% in CNS hemangioblastoma |
| SEGA associated with tuberous sclerosis | Everolimus | EXIST-1 | October 29, 2010 (accelerated); January 29, 2016 (full) | Significant reduction in tumor volume |
Immunotherapy and Experimental Approaches
Immunotherapy has had much less success in gliomas than in other tumor types, such as lung cancer or melanoma, because of the blood-brain barrier, the low tumor mutation burden (and therefore low immunogenicity), and the immunosuppressive tumor microenvironment.
Two large phase 3 trials testing PD-1 inhibitors such as nivolumab had negative results in newly diagnosed GBM: CheckMate 498 (nivolumab+RT versus standard TMZ+RT in patients without MGMT methylation) and CheckMate 548 (adding nivolumab to TMZ+RT in MGMT-methylated patients) both failed to meet their primary overall survival endpoint. Unlike in lung cancer or melanoma, checkpoint inhibitors are therefore currently not part of standard treatment for newly diagnosed GBM.
Oncolytic Virus Therapies (Investigational)
Oncolytic viruses selectively replicate inside cancer cells, destroying them from within while stimulating the immune system against the tumor. PVSRIPO (based on poliovirus) produced a median overall survival in a phase 1 trial (n=61) of 12,5 months with both 2- and 3-year survival rates of %21 (historical controls: 14% at 2 years and 4% at 3 years). The plateau of long-term survivors is noteworthy. However, these remain phase 1 data; randomized phase 2/3 results have not yet been published, and PVSRIPO remains investigational.
CAR-T Cell Therapy (Early Research Stage)
CAR-T therapy genetically modifies the patient's own T cells to target tumor antigens (such as IL13Rα2 and EGFR). Although it has transformed the treatment of hematological cancers, it remains at an early (phase 1) research stage in gliomas. Early studies of "bivalent" CAR-T cells targeting both IL13Rα2 and EGFR, delivered into the brain (intracerebroventricularly), have reported partial responses. These are small, uncontrolled, early-phase findings, however, and should not be regarded as standard treatment.
Brain Tumors Other Than Gliomas
Although this guide focuses on gliomas and glioblastoma, most diseases grouped under "brain tumors" are not actually gliomas. The other most common types are summarized below, together with their treatment principles and regulatory status.
Brain Metastases: Actually the Most Common Brain Tumors
Most tumors found in the brain in clinical practice originate not from the brain's own cells but from cancer elsewhere in the body spreading to it (most commonly lung cancer, breast cancer, and melanoma). The treatment principles are also entirely different: the primary target is not the brain tissue but the biology of the originating cancer. If there are a limited number of lesions (usually 1-4, or more in some centers), stereotactic radiosurgery is preferred — it has significantly fewer cognitive side effects than whole-brain radiotherapy. In recent years, targeted drugs able to cross the blood-brain barrier (for example, osimertinib and lorlatinib in lung cancer, tucatinib in breast cancer, and BRAF inhibitors and immunotherapy in melanoma) have also controlled brain metastases in some patients without radiotherapy. For more information, see What Is Brain Metastasis? Symptoms and Treatment for further details.
Meningioma: The Most Common Primary Brain Tumor
Meningiomas develop from the membranes surrounding the brain (the meninges), account for approximately a third of primary brain/CNS tumors, and are predominantly benign (Grade 1) . They occur approximately twice as often in women as in men and are frequently discovered incidentally during imaging for another reason.
The treatment approach is limited to three options: observation (periodic MRI follow-up is entirely reasonable for small, asymptomatic tumors — not every meningioma requires surgery), surgery (for symptomatic or growing tumors), and radiotherapy/radiosurgery (for incompletely resected, high-grade, or recurrent tumors).
This is one of the most important unmet needs in the field: there is no FDA-approved systemic (drug) treatment for meningioma of any grade. All agents used for patients with high-grade (Grade 2-3) meningioma progressing despite surgery and radiotherapy are off-label, with limited evidence. Referral to clinical trials is particularly important for this patient group.
Primary Central Nervous System Lymphoma (PCNSL)
PCNSL is an aggressive B-cell lymphoma arising directly in the brain, spinal cord, or eye without systemic lymphoma. Its key difference from gliomas is that surgical resection has no role in treatment — a biopsy is sufficient for diagnosis, and treatment is systemic from the outset. The standard approach is combination chemotherapy based on high-dose methotrexate at levels sufficient to cross the blood-brain barrier; eligible patients may then receive consolidation with autologous stem cell transplantation.
PCNSL presents a notable regulatory situation: none of the drugs used, including high-dose methotrexate, has formal FDA approval for this indication — all are established but off-label uses. The first change came on February 6, 2026 when the FDA approved, for the CD19-targeted CAR-T therapy axicabtagene ciloleucel (Yescarta) the removal of the label's "limitation of use" excluding PCNSL patients. Technically, this is removal of a restriction rather than approval of a new indication. In practice, however, it makes Yescarta the only CD19 CAR-T therapy whose label explicitly supports use in relapsed/refractory PCNSL. The basis is a small Dana-Farber-led phase 1 trial (n=18): objective response rate %89, complete response rate %67, median progression-free survival 14,3 months. The small sample size and rates of cytokine release syndrome (89%, all mild-moderate) and neurotoxicity (44%, with 28% severe) should be considered.
Medulloblastoma and Ependymoma
Medulloblastoma is the most common malignant brain tumor in childhood and arises in the cerebellum. It has four molecular subgroups (WNT, SHH, Group 3, Group 4), which have markedly different prognoses — survival exceeds 90% in the WNT subgroup, whereas Group 3 has a much worse course. Treatment combines surgery, craniospinal radiotherapy, and chemotherapy.
Ependymoma arises from ependymal cells lining the brain ventricles and spinal canal. Treatment centers on the most complete surgical resection possible, followed by radiotherapy.
For both tumors, no modern targeted or immunotherapy agent is approved; chemotherapy regimens are evidence-based but largely off-label in terms of formal indications. The sole exception is a technical detail: the label of the older drug approved in 1977, carmustine (BiCNU)explicitly lists medulloblastoma and ependymoma — saying "there is no approval at all" would therefore be inaccurate. However, this is labeling dating from the 1970s and does not reflect current standards of care. The lack of a standard systemic treatment, particularly in recurrent ependymoma, makes clinical trials a priority option for these patients.
Supportive Care and Symptom Management
Successful brain tumor treatment is measured not only by tumor shrinkage but also by the patient's ability to maintain daily life. Supportive care is therefore an integral part of treatment, rather than an additional service.
Seizure (Epilepsy) Management
A substantial proportion of brain tumor patients have seizures, directly affecting both quality of life and daily activities such as driving. The current approach has two key principles: (1) Starting "preventive" (prophylactic) antiseizure medication in patients who have never had a seizure is not recommended — no benefit has been demonstrated, whereas the burden of side effects is real. (2) For patients who have had seizures, agents that do not stimulate liver enzymes (non-enzyme-inducing agents), particularly levetiracetam are preferred. Older-generation antiseizure drugs (phenytoin, carbamazepine) can lower blood concentrations of chemotherapy drugs, reducing their effectiveness. Most patients are unaware of this critical interaction, which can directly affect treatment success.
Balancing Corticosteroid Use
Dexamethasone reduces swelling around the tumor, often markedly improving headache and neurological symptoms within days. Prolonged use, however, can cause muscle wasting (particularly in the thighs, to the point of difficulty climbing stairs), high blood glucose, sleep disturbance, weight gain, mood swings, and susceptibility to infection. The current approach is therefore to use the lowest effective dose and gradually reduce it as soon as symptoms improve. In patients taking high-dose steroids for a prolonged period, protective antibiotics against Pneumocystis pneumonia should be considered.
Blood Clot (Venous Thromboembolism) Risk
Among people with cancer, patients with high-grade glioma are one of the groups at greatest risk of blood clots — the risk of clots in leg veins (deep vein thrombosis) or pulmonary embolism is significantly increased. Contributing factors include the tumor's own procoagulant effects, limited mobility, and steroid use. One-sided leg swelling/pain or sudden breathlessness requires prompt assessment. The older belief that anticoagulants are contraindicated in brain tumor patients because of bleeding risk is outdated; anticoagulation can generally be used in patients with a confirmed clot after individual bleeding-risk assessment.
Cognitive Function, Fatigue, and Rehabilitation
Both the tumor itself and radiotherapy can impair memory, attention, and executive function; fatigue is among patients' most common and distressing symptoms. Physical therapy, occupational therapy, speech therapy, and neuropsychological support provide measurable benefits in preserving function. Personality and behavioral changes are often more difficult for family members than the disease itself; support for caregivers should be an explicitly discussed part of the treatment plan.
Global Approval and Evidence Timeline
Progress in brain tumor treatment has been significantly slower than in other areas of oncology: no lasting advance was achieved during the thirty years from the nitrosourea chemotherapies of the 1970s to the Stupp protocol in 2005. The real breakthrough came only in the past five years with drugs targeting molecular subtypes. The timeline below summarizes this slow journey and its recent acceleration.
Approved as an oral nitrosourea able to cross the blood-brain barrier for primary and metastatic brain tumors — fifty years later, it remains in use for recurrent glioblastoma.
Its label explicitly listed glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and brain metastases — still the only formal FDA labeling covering medulloblastoma and ependymoma.
Dissolvable carmustine-impregnated discs were approved as an adjunct to surgery for recurrent glioblastoma; February 25, 2003 the indication was expanded to include newly diagnosed high-grade glioma.
Received accelerated approval for refractory anaplastic astrocytoma — this well-tolerated oral drug, able to cross the blood-brain barrier, would shape the next twenty years in the field.
Temozolomide was approved for newly diagnosed glioblastoma, concomitantly with radiotherapy and then as maintenance. It increased median survival from 12,1 to 14,6 months and 5-year survival from 1,8% to 9,8%, becoming the standard that has remained unchanged for twenty years.
Approved on the basis of response rates in single-arm trials (25,9% and 19,6%); on December 5, 2017 this was converted to full approval — although the underlying EORTC 26101 trial had not met its overall survival endpoint.
Received accelerated approval for SEGA unsuitable for surgery; on the basis of EXIST-1 data, on January 29, 2016 this was converted to full approval — one of the first examples of a brain tumor being reduced with medication.
Received device approval (PMA) for recurrent glioblastoma; based on the EF-14 results, on October 5, 2015 this was expanded to newly diagnosed glioblastoma (median survival from 16,0 to 20,9 months).
Approved as an optical imaging agent for fluorescence-guided surgery — eleven years after the pivotal trial was published and ten years after use began in Europe.
Approved for all solid tumors with an NTRK fusion (entrectinib followed on August 15, 2019); although primary brain tumors were absent from the initial approval population, they were included by the indication wording. Larotrectinib's approval was on April 9, 2025 converted to full approval.
Approved for VHL-associated CNS hemangioblastoma with a 63% response rate — providing an oral alternative to repeated brain operations.
Approved for BRAF V600E-mutant solid tumors; the efficacy population directly included glioma cohorts (high-grade glioma ORR 33%, low-grade 50%).
Dabrafenib+trametinib received first-line approval in BRAF V600E-mutant pediatric low-grade glioma: response rate increased from 10,8% to 46,6%, and PFS from 7,4 to 20,1 months.
Under the FDA's "Project Renewal" program, adjuvant use in newly diagnosed anaplastic astrocytoma was added as a formal indication — updating an older drug's label according to current evidence.
Approved for relapsed/refractory BRAF-altered pediatric low-grade glioma (ORR 51%); its ability to target fusion-type alterations, where conventional BRAF inhibitors are ineffective, filled an important gap.
Based on INDIGO, it received full approval for postoperative Grade 2 IDH-mutant astrocytoma/oligodendroglioma (PFS HR 0,39) — the first systemic treatment approved for this patient group. European approval followed on September 22, 2025.
Received accelerated approval in recurrent H3 K27M-mutant DMG (ORR 22%, response duration 10,3 months) — the first drug approval for a disease mainly affecting children and young adults that previously had no approved systemic treatment. The confirmatory ACTION phase 3 trial is ongoing.
The limitation of use excluding primary CNS lymphoma patients was removed from the axicabtagene ciloleucel label — making it the only CD19 CAR-T therapy whose label explicitly supports use in relapsed/refractory PCNSL.
Two points stand out in this list. First, not a single new drug was approved for brain tumors during the twenty-two years between 1977 and 1999 — a concrete illustration of the challenge the blood-brain barrier poses to drug development. Second, almost all approvals in the past five years (vorasidenib, dordaviprone, tovorafenib, dabrafenib+trametinib) target subgroups carrying a specific molecular alteration . Progress is therefore coming not from finding "a drug that works for all brain tumors" but from separating the disease into subtypes and targeting each individually. This shows why the molecular classification explained at the start of this guide is directly a matter of treatment access rather than an academic detail.
Prognosis and Survival
Prognosis in GBM varies widely according to the tumor's molecular characteristics, the patient's age and general performance status, and the scope of treatment that can be delivered.
| Data Source / Group | Median Overall Survival | 5-Year Survival |
|---|---|---|
| Population registry (CBTRUS, all GBM patients) | ~8-9 months | %7,1 |
| Stupp protocol (RT+TMZ), clinical trial population | 14,6 months | %9,8 |
| Stupp protocol + TTFields (EF-14) | 20,9 months | %13 |
- IDH mutation status: IDH-mutant tumors have a significantly better prognosis than IDH-wildtype (GBM) tumors.
- MGMT promoter methylation: Patients with methylation have better TMZ responses and survival.
- Age and performance status: Younger age and good general performance status (a high Karnofsky/ECOG score) are associated with better survival. These two factors also determine whether the patient can tolerate treatment, particularly aggressive surgery and chemoradiotherapy.
- Extent of resection: More extensive surgical resection, approaching gross-total removal, is generally associated with better survival.
- 1p/19q codeletion (in oligodendrogliomas): Tumors with this genetic signature are more sensitive to chemotherapy and radiotherapy.
Treatment Side Effects and Their Management
Radiotherapy and Temozolomide (the Stupp Protocol)
Radiotherapy-related fatigue, hair loss in the treated area, and skin reactions are common. The most common temozolomide side effects are nausea (managed with preventive antiemetics) and bone marrow suppression (requiring regular blood counts). To address the rare but important risk of Pneumocystis jirovecii pneumonia prophylactic antibiotics are considered, particularly during maintenance.
Corticosteroids (Dexamethasone)
Dexamethasone, frequently used to reduce brain swelling around the tumor, can rapidly relieve symptoms in the short term. Prolonged use, however, can cause weight gain, high blood glucose, muscle wasting, sleep disturbance, mood changes, and susceptibility to infection; the aim is therefore to use the lowest effective dose for the shortest possible duration.
Bevacizumab
It carries risks of high blood pressure, urinary protein loss (proteinuria), delayed wound healing, and rare but serious bleeding or intestinal perforation. Avoiding it for a specified period before/after surgery is therefore recommended.
TTFields
The most common side effect is skin irritation/dermatitis where the electrodes make contact; it is managed through regular skin care and periodic changes in electrode position.
Vorasidenib
Elevated liver enzymes are the most common laboratory abnormality and require regular liver function monitoring; fatigue and headache have also been reported.
For general information on managing side effects, see How Can Chemotherapy Side Effects Be Reduced? provides further information.
Diagnosis, Authorization, and Reimbursement in Türkiye
Temozolomide is a standard treatment that has long been licensed in Türkiye, is widely available, and is reimbursed by SGK. Lomustine is similarly considered accessible as an older, generic drug. Bevacizumab (such as Altuzan) is licensed by TİTCK. However, some Turkish legal sources indicate that SGK reimbursement objections/disputes may arise for certain indications or treatment lines. Our sources did not provide clear confirmation specifically for recurrent GBM; confirming the current situation with your treating center is recommended.
TTFields (Optune) has no record of TİTCK approval or SGK reimbursement in Türkiye in our sources. Vorasidenib was approved in Europe (EMA) only in September 2025 and is therefore unlikely to be licensed in Türkiye yet. Dordaviprone has not yet been approved outside the United States (including by EMA) and is not available in Türkiye. Similarly, tovorafenib is approved only in the United States. Be sure to confirm the current status of these treatments with your treating oncology/neurosurgery center.
Frequently Asked Questions
- What is the most important difference between glioblastoma and other glioma types?
- Glioblastoma (GBM) is classified by WHO as Grade 4, is IDH-wildtype (without a mutation), and is the most aggressive glioma type. IDH-mutant astrocytomas and oligodendrogliomas generally grow more slowly and have a better prognosis.
- What happens if molecular testing is not performed?
- When molecular testing cannot be performed, the diagnosis is classified as "NOS" (Not Otherwise Specified); prognosis and certain targeted treatment options (for example, vorasidenib, dordaviprone) cannot then be assessed. Current guidelines therefore recommend molecular testing whenever possible.
- Is the TTFields device painful?
- No, TTFields use is not painful; the most common problem is skin irritation where the electrodes make contact.
- Why is immunotherapy in glioblastoma not as effective as chemotherapy/immunotherapy?
- Gliomas generally have a low tumor mutation burden (producing fewer "foreign" signals for the immune system to recognize), while the blood-brain barrier and tumor microenvironment suppress the immune response. Checkpoint inhibitors that work in other cancers have therefore so far failed in newly diagnosed GBM.
- A meningioma was found on MRI. Do I definitely need surgery?
- No. Most meningiomas are benign, and many are found incidentally on imaging performed for another reason. For a small, asymptomatic meningioma that is not growing, observation with periodic MRI is a fully valid and frequently preferred approach. Surgery is considered for tumors causing symptoms, growing, or compressing critical structures.
- I have not had a seizure. Should antiseizure medication still be started preventively?
- For brain tumor patients who have never had a seizure, current guidelines do not recommend starting preventive antiseizure medication — there is insufficient evidence that these drugs prevent seizures, while their side effects are real. Patients who have had seizures are treated preferentially with agents that do not interact with chemotherapy, particularly levetiracetam.
- I was diagnosed with Grade 2 glioma. Do the survival figures I read about glioblastoma apply to me?
- No — this distinction is very important. Survival figures measured in months for glioblastoma (Grade 4, IDH-wildtype) do not apply to IDH-mutant Grade 2 gliomas. For example, in RTOG 9802, high-risk Grade 2 glioma patients receiving radiotherapy and PCV chemotherapy had a median overall survival of 13,3 years . Always check which tumor type information you read online refers to.
- When should I consider joining a clinical trial?
- Because approved treatments have limited effectiveness in brain tumors, particularly recurrent glioblastoma, high-grade meningioma, and recurrent ependymoma, current guidelines recommend clinical trials as equivalent to standard options, or sometimes even preferable rather than as a "last resort." Asking your physician early during treatment planning is therefore appropriate.
Glossary
- Glioma
- A general term for tumors originating from glial cells, the brain's supporting cells.
- Glioblastoma (GBM)
- The most common and most aggressive primary brain tumor in adults; defined in the WHO classification as Grade 4, IDH-wildtype.
- Astrocytoma
- A type of glioma developing from star-shaped glial cells called astrocytes; it may be low- or high-grade.
- Oligodendroglioma
- A glioma originating from oligodendrocytes, generally associated with 1p/19q codeletion and an IDH mutation, and responding better to treatment.
- IDH mutation
- A mutation in the IDH1/IDH2 genes, generally associated with better survival.
- 1p/19q codeletion
- Simultaneous loss of certain regions of chromosomes 1 and 19; a key biomarker for diagnosing oligodendroglioma.
- MGMT promoter methylation
- An epigenetic change predicting sensitivity to temozolomide chemotherapy.
- Temozolomide (TMZ)
- The standard oral chemotherapy drug for glioblastoma, killing cancer cells by damaging DNA.
- Pseudoprogression
- A temporary condition in which the tumor appears to grow on MRI after treatment, but the findings actually reflect treatment-related inflammatory changes.
- TTFields (Tumor Treating Fields)
- A nondrug treatment using low-intensity electric fields to disrupt tumor cell division.
- CAR-T cell therapy
- An immunotherapy approach genetically modifying the patient's own T cells to target tumor cells.
- Meningioma
- The most common primary brain/CNS tumor, developing from the membranes surrounding the brain (meninges) and usually benign.
- Hemangioblastoma
- A usually benign tumor of vascular origin; it may recur in the cerebellum and spinal cord in von Hippel-Lindau disease.
- Primary CNS lymphoma (PCNSL)
- An aggressive B-cell lymphoma arising directly in the brain, spinal cord, or eye without lymphoma elsewhere in the body; surgical resection has no role in treatment.
- PCV chemotherapy
- A combination of procarbazine, lomustine (CCNU), and vincristine; significantly increases survival when added to radiotherapy in low-grade and anaplastic oligodendroglial tumors.
- 5-ALA (5-aminolevulinic acid)
- An imaging agent given orally before surgery, accumulating in tumor cells and fluorescing under violet light to help the surgeon see the tumor boundary.
- Awake craniotomy
- A technique in which the patient is awakened during part of the operation to test functions in real time when a tumor is adjacent to areas controlling critical functions such as speech or movement.
- LITT (laser interstitial thermal therapy)
- A minimally invasive technique that destroys tissue by delivering heat through a thin laser probe inserted into the tumor under MRI guidance.
- H3 K27M mutation
- A histone mutation seen in diffuse midline gliomas and associated with an aggressive course; a prerequisite for dordaviprone treatment.
- Hypofractionated radiotherapy
- Delivering the total dose in fewer, higher-dose sessions; reduces treatment time from weeks to days in older or frail patients.
- Ostrom QT, et al. CBTRUS Statistical Report: Primary Brain and Other CNS Tumors, 2025 (2018-2022 data). Neuro-Oncology, 2025. cbtrus.org
- CBTRUS Glioblastoma Fact Sheet, 2025 (2017-2021 data). cbtrus.org
- IARC Global Cancer Observatory (GLOBOCAN) — Türkiye Country Fact Sheet, brain/CNS cancers. gco.iarc.who.int
- Louis DN, et al. "The 2021 WHO Classification of Tumors of the Central Nervous System: a summary." Neuro-Oncology, 2021.
- Wesseling P, et al. cIMPACT-NOW Update 11: Diagnostic criteria for IDH- and H3-wildtype high-grade diffuse gliomas. Brain Pathology, 2025-2026.
- Stupp R, et al. "Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma." NEJM, 2005. Stupp R, et al. 5-year follow-up data, Lancet Oncology, 2009.
- Stupp R, et al. "Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Glioblastoma" (EF-14), final analysis. JAMA/updated review, The Oncologist, 2025.
- FDA. Vorasidenib (Voranigo) approval announcement, August 6, 2024; Mellinghoff IK, et al. "Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma" (INDIGO). NEJM, 2023.
- European Commission / Servier. Vorasidenib (Voranigo) EU approval announcement, September 22, 2025.
- FDA. Dordaviprone (Modeyso) accelerated approval announcement, August 6, 2025; ACTION phase 3 trial (NCT05580562), ongoing.
- FDA. Dabrafenib+trametinib approval for BRAF V600E-mutant pediatric low-grade glioma, 2023.
- Wick W, et al. "Lomustine and Bevacizumab in Progressive Glioblastoma" (EORTC 26101). NEJM, 2017. FDA full approval announcement, December 5, 2017.
- Bristol Myers Squibb. CheckMate 498 and CheckMate 548 trial results announcements, 2019-2020.
- Desjardins A, et al. "Recurrent Glioblastoma Treated with Recombinant Poliovirus" (PVSRIPO). NEJM, 2018.
- Bagley SJ, et al. and Choi BD, et al. Intraventricular bivalent (IL13Rα2/EGFR) CAR-T studies. Nature Medicine, 2024-2025.
- Buckner JC, et al. "Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma" (RTOG 9802). NEJM, 2016;374:1344-1355.
- Joint final report of RTOG 9402 and EORTC 26951 (18-19 years of follow-up). J Clin Oncol, 2022 (JCO.21.02543).
- van den Bent MJ, et al. CATNON/EORTC 26053-22054 final analysis. Lancet Oncology, 2026;27:45-56.
- CODEL trial, results of early closure of the temozolomide-only arm. Neuro-Oncology, 2021;23:347 and 23:457.
- Perry JR, et al. "Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma." NEJM, 2017. Roa W, et al. IAEA hypofractionated radiotherapy trial, J Clin Oncol, 2015 (and Roa W, et al. J Clin Oncol, 2004).
- Herrlinger U, et al. "Lomustine-temozolomide combination therapy versus standard temozolomide therapy in newly diagnosed MGMT-methylated glioblastoma" (CeTeG/NOA-09). Lancet, 2019;393:678-688.
- Stummer W, et al. "Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma." Lancet Oncology, 2006;7:392-401. FDA Gleolan approval, June 6, 2017.
- Lombardi G, et al. "Regorafenib compared with lomustine in patients with relapsed glioblastoma" (REGOMA). Lancet Oncology, 2019;20:110-119. GBM AGILE regorafenib arm results, J Clin Oncol, 2026 (JCO-25-01137).
- Kilburn LB, et al. "Tovorafenib in pediatric low-grade glioma" (FIREFLY-1). Nature Medicine, 2024;30:207-217. FDA approval, April 23, 2024.
- FDA. Dabrafenib+trametinib tumor-agnostic BRAF V600E approval, June 22, 2022; pediatric low-grade glioma approval, March 16, 2023 (CDRB436G2201).
- FDA. Belzutifan (Welireg) approval for VHL disease, August 13, 2021 (LITESPARK-004/Study 004).
- FDA. Everolimus (Afinitor) accelerated approval for SEGA, October 29, 2010; full approval, January 29, 2016 (EXIST-1).
- FDA. Temozolomide (Temodar) approvals: August 11, 1999 (anaplastic astrocytoma), March 15, 2005 (newly diagnosed glioblastoma), September 14, 2023 (Project Renewal label update). Gliadel wafer approvals: September 23, 1996 and February 25, 2003. Lomustine: August 4, 1976; carmustine (BiCNU): March 7, 1977.
- FDA. Optune/NovoTTF-100A device approvals (PMA P100034): April 8, 2011 (recurrent GBM) and October 5, 2015 (newly diagnosed GBM).
- Gilead/Kite. Axicabtagene ciloleucel (Yescarta) label update — removal of the limitation of use in primary CNS lymphoma, February 6, 2026; Dana-Farber phase 1 trial (n=18).
- Republic of Türkiye Ministry of Health, General Directorate of Public Health. Türkiye Cancer Statistics Report.
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