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Brain Tumours

High-Grade Gliomas

An aggressive primary brain tumour — modern treatment combines surgery, radiotherapy and chemotherapy.

In brief

An aggressive, cancerous tumour arising from the brain’s support cells
Corresponds to WHO grade 3 and grade 4 tumours
Molecular markers now guide diagnosis and treatment
Diagnosed on MRI and confirmed by surgery or biopsy
Treated with maximal safe surgery, radiotherapy and chemotherapy

What is a High-Grade Glioma?

A high-grade glioma is an aggressive, cancerous brain tumour. It is a primary brain tumour, meaning it begins in the brain’s own cells rather than spreading to the brain from a cancer elsewhere in the body. Gliomas arise from glial cells — the supporting cells that surround and insulate the brain’s nerve cells. The word “high-grade” refers to tumours that grow quickly and invade the surrounding brain; these correspond to grade 3 and grade 4 tumours in the World Health Organization (WHO) grading system, in contrast to the slower-growing low-grade (grade 1–2) gliomas, which are described in a separate Victoria Neurosurgery information sheet. By far the most common high-grade glioma is glioblastoma (WHO grade 4). Glioblastoma is the most common malignant primary brain tumour in adults, making up just over half of all malignant brain tumours.¹ It is usually diagnosed in older adults, with the average age at diagnosis around 65 and the risk rising further into the seventies, although it can occur at any age.¹ The other high-grade gliomas are grade 3 tumours (previously called “anaplastic”), which are less common and, as a group, less aggressive than glioblastoma. It is important to be honest from the outset: these are serious tumours. Because a high-grade glioma infiltrates normal brain tissue, it cannot be completely removed by surgery and is generally not curable. Treatment can, however, control the tumour, relieve symptoms and prolong life — sometimes considerably — and the outlook varies widely depending on the tumour’s precise molecular type, the patient’s age and general health, and how the tumour responds to treatment (see Prognosis, below).

How are High-Grade Gliomas Classified?

The classification of brain tumours changed fundamentally with the 2021 WHO Classification of Tumours of the Central Nervous System — the current international standard — which defines gliomas primarily by their molecular (genetic) features rather than by their appearance under the microscope alone.² This has improved the accuracy of diagnosis and the ability to predict how a tumour will behave and respond to treatment.

Three molecular features are central to classifying adult high-grade gliomas:²

IDH status — whether the tumour carries a mutation in the isocitrate dehydrogenase (IDH) gene. IDH-mutant tumours generally carry a better prognosis than tumours without the mutation (IDH-wildtype).
1p/19q co-deletion — the combined loss of segments of chromosomes 1 and 19. Together with an IDH mutation, it defines an oligodendroglioma, the glioma subtype with the most favourable outlook.
Additional markers — such as CDKN2A/B deletion and others, which help assign the correct grade.

Under this system, the principal high-grade gliomas in adults are:²

Glioblastoma, IDH-wildtype (WHO grade 4) — the most common and most aggressive. The term “glioblastoma” is now reserved for IDH-wildtype tumours (previously, some IDH-mutant grade 4 tumours were also called glioblastoma; these are now classified as IDH-mutant astrocytomas). Such a tumour may be diagnosed on molecular grounds — for example, a TERT promoter mutation, EGFR gene amplification, or a particular combination of chromosome gains and losses (+7/−10) — even when not all of the classic microscopic features are present.
Astrocytoma, IDH-mutant (WHO grade 3 or 4) — carries an IDH mutation and is not 1p/19q co-deleted. A grade 4 IDH-mutant astrocytoma generally carries a better prognosis than IDH-wildtype glioblastoma, but remains a serious tumour.
Oligodendroglioma, IDH-mutant and 1p/19q co-deleted (WHO grade 3) — the least aggressive of the high-grade gliomas, with the best response to treatment and the longest survival.

Why Do Molecular Markers Matter?

The molecular profile is now the single most important guide to prognosis and treatment. In addition to IDH status and 1p/19q co-deletion (above), one further marker is particularly important in glioblastoma:

MGMT promoter methylation — a chemical “switching-off” of the MGMT gene, found in roughly 40–45% of glioblastomas. When present, the tumour responds considerably better to temozolomide chemotherapy and patients tend to live longer. In the trial that established this marker, adding temozolomide to radiotherapy extended median survival to 21.7 months (compared with 15.3 months for radiotherapy alone) among patients whose tumours were MGMT-methylated, and methylation was itself an independent favourable prognostic factor.³

Knowing these markers allows treatment to be tailored to the individual tumour, and is the reason a full molecular analysis of the tumour tissue is now essential.

What are the Symptoms?

Because high-grade gliomas grow quickly, symptoms usually develop over a short period — often only weeks to a few months. They result from the tumour and its surrounding swelling (oedema) pressing on or damaging brain tissue, and depend on the tumour’s size and location. Common presentations include:⁴

Headache — often worse in the morning, or with lying flat, coughing or straining; caused by raised pressure within the head
Seizures (fits) — a frequent first symptom; a first-ever seizure in an adult should always prompt brain imaging
Focal neurological deficits — such as weakness or numbness down one side, difficulty with speech, or loss of part of the field of vision, depending on the region of brain affected
Cognitive or personality change — difficulties with memory, concentration or thinking speed, or a change in behaviour, particularly with frontal-lobe tumours
Symptoms of raised pressure — nausea, vomiting, drowsiness or increasing confusion, which can signal a need for urgent assessment
Driving — a brain tumour that has caused a seizure, or that affects vision or concentration, usually means you must stop driving and notify the licensing authority; your treating team will advise you in line with national fitness-to-drive guidelines

How are High-Grade Gliomas Diagnosed?

Magnetic Resonance Imaging (MRI)

MRI with contrast (a gadolinium dye) is the key imaging test. High-grade gliomas typically appear as irregular masses that take up contrast, often with a central area where the tumour has outgrown its blood supply (necrosis) and surrounding oedema. Specialised sequences — such as perfusion imaging and MR spectroscopy — can help distinguish a high-grade glioma from other conditions and guide the safest biopsy site. MRI also shows the tumour’s relationship to critical brain regions and guides surgical planning.

Tissue Diagnosis — Biopsy or Resection

Imaging alone cannot give a definitive diagnosis. Tumour tissue must be obtained — either by removing the tumour (resection) or, where it cannot be safely removed, by a stereotactic (image-guided) needle biopsy — so that the diagnosis can be confirmed and the molecular profile determined. Modern diagnosis combines the tumour’s microscopic appearance with molecular testing (including IDH, 1p/19q and MGMT) to reach a precise WHO-2021 diagnosis that directs treatment.²

Functional MRI and Tractography

For tumours close to areas controlling movement, speech or vision, functional MRI (fMRI) and diffusion tensor imaging (DTI, or “tractography”) can map these critical pathways before surgery, helping to plan the safest possible removal.

How are High-Grade Gliomas Treated?

Care is planned and delivered by a multidisciplinary neuro-oncology team — neurosurgeon, radiation oncologist, medical (neuro-)oncologist, neuropathologist and neuroradiologist — working together for each patient.⁵ Treatment usually combines surgery, radiotherapy and chemotherapy.

Surgery — Maximal Safe Resection

Surgery is usually the first step, and has several goals:

To obtain tissue for the combined microscopic and molecular diagnosis that directs all further treatment
To remove as much tumour as can safely be removed (debulking), relieving pressure and improving the effect of subsequent radiotherapy and chemotherapy
To relieve symptoms caused by the tumour and its swelling
Cure is not achievable, because the tumour extends into normal brain beyond the visible mass

The guiding principle is maximal safe resection — removing as much tumour as possible while preserving neurological function. A greater extent of removal is consistently associated with longer survival, so the surgeon aims to maximise this without causing new deficits.⁵ Several techniques help achieve it safely:

Fluorescence-guided resection (5-ALA) — a dye (5-aminolevulinic acid) taken before surgery that makes high-grade tumour tissue glow pink-red under a special blue light, which can help the surgeon tell tumour from normal brain. It is not widely used in Australia; it may assist the completeness of removal but has not been shown to improve overall survival.
Intra-operative brain mapping — for tumours in or near areas that control movement or speech (“eloquent” brain), the surgeon can map and monitor these functions during the operation using direct electrical stimulation, to identify and protect critical areas and maximise safe removal. Much of this — including motor mapping — is now done under general anaesthesia with modern stimulation and monitoring techniques; an awake craniotomy, where the patient is woken for part of the operation, is now used occasionally and mainly to test language.
Intra-operative adjuncts — neuronavigation (a GPS-like guidance system), intra-operative ultrasound or MRI, and monitoring of nerve pathways further improve the safety and completeness of surgery.

Where a tumour cannot be safely removed — for instance, if it is deep or diffusely involves critical brain — a biopsy alone may be the appropriate operation to secure the diagnosis.

Radiotherapy

Radiotherapy — precisely targeted high-energy X-rays — is given to almost all patients after surgery. For glioblastoma, the standard course is 60 Gray delivered in 30 daily treatments (fractions) over about six weeks.⁶ For older or frailer patients, a shorter course — for example, 40 Gray in 15 fractions — gives comparable benefit with less burden and is often preferred.⁷

Chemotherapy — Temozolomide and the “Stupp Protocol”

The standard chemotherapy for glioblastoma is temozolomide, taken as a capsule. Treatment given in addition to the surgery — both the radiotherapy and the chemotherapy — is known as “adjuvant” therapy. The landmark regimen — widely known as the “Stupp protocol” — gives temozolomide together with the radiotherapy (concurrently), followed by six further monthly cycles of temozolomide.⁶ Temozolomide is usually well tolerated but can cause fatigue, nausea and a temporary fall in the blood counts, which is monitored with regular blood tests. In the trial that established it, adding temozolomide to radiotherapy increased median survival from 12.1 to 14.6 months and more than doubled two-year survival (from 10.4% to 26.5%).⁶ The benefit is greatest in tumours with MGMT methylation.³ This combined chemoradiotherapy remains the international standard of care for glioblastoma.⁵

Treatment of Grade 3 Gliomas

Grade 3 gliomas are treated with surgery followed by radiotherapy and chemotherapy, with the chemotherapy matched to the molecular type:

Grade 3 IDH-mutant astrocytoma — radiotherapy followed by temozolomide improves survival, as shown in the CATNON trial.⁸
Grade 3 oligodendroglioma (IDH-mutant, 1p/19q co-deleted) — radiotherapy combined with PCV chemotherapy (procarbazine, CCNU/lomustine and vincristine) gives the best results (temozolomide is sometimes substituted for PCV where it is better tolerated); in long-term trial follow-up, median survival among co-deleted tumours was 14.7 years with radiotherapy plus PCV, compared with 7.3 years with radiotherapy alone.⁹

Clinical Trials

Because the results of standard treatment — particularly for glioblastoma — remain limited, taking part in a clinical trial of a new therapy is actively encouraged where a suitable trial is available, both at diagnosis and at recurrence.⁵ Other approaches, such as Tumour Treating Fields — low-intensity electrical fields applied to the scalp — remain under investigation and are not in routine use in Australia.

What Happens Afterwards — Surveillance and Recurrence

After treatment, regular MRI scans are used to watch for regrowth, usually every two to three months at first.⁵ Nearly all high-grade gliomas eventually recur. When this happens, options may include repeat surgery, further radiotherapy, further chemotherapy, or a clinical trial; the best choice depends on the tumour and its molecular type, the previous treatment, and the patient’s condition and wishes.⁵ The drug (chemotherapy) options at recurrence are chosen for the individual, as no single second-line treatment is agreed as best; the choice depends on general fitness, the tumour’s molecular features (including MGMT status) and the treatment already given.⁵ They include lomustine (CCNU), an oral drug that is the most commonly used second-line agent and the standard comparator in clinical trials,¹⁰ and a further course of temozolomide, which is a reasonable option for tumours with MGMT methylation.¹¹ Bevacizumab — an antibody that reduces a tumour’s blood supply — can delay progression for a time and help control swelling and the need for steroids,⁵ but it has not been shown to lengthen overall survival, and adding it to lomustine did not improve survival in a large randomised trial.¹⁰ Because no second-line treatment has been proven to reliably prolong life, entering a clinical trial is particularly worth considering at recurrence.⁵ Throughout, supportive care is important — corticosteroids (such as dexamethasone) to reduce brain swelling, medication to control seizures, and allied-health support — and specialist palliative care is introduced when appropriate to maintain the best possible quality of life.

Prognosis

It is natural to want to know what the future holds. Honest information matters — but so does understanding that survival figures are averages drawn from large groups and cannot predict any individual’s outcome.

Glioblastoma (IDH-wildtype, grade 4) — with the full standard treatment described above, median survival is of the order of 14–15 months; roughly one in four patients are alive at two years and fewer than one in ten at five years.^6,12 Outcomes are better in patients whose tumours are MGMT-methylated,³ who are younger, who are in good general health, and in whom most of the tumour can be removed.
IDH-mutant grade 4 astrocytoma — generally carries a better outlook than IDH-wildtype glioblastoma, though it remains a serious grade 4 tumour.²
Grade 3 gliomas — carry a substantially better prognosis, with survival often measured in many years; IDH-mutant, 1p/19q co-deleted oligodendrogliomas do best of all, with median survival beyond a decade.^8,9

Because prognosis depends so heavily on the precise molecular diagnosis, age, general health and response to treatment, your neurosurgeon or neuro-oncologist will discuss what your diagnosis means for you individually at your consultation.

References

Helpful links

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High-Grade Gliomas — patient information sheet PDF · prepared by Mr Jeremy Russell

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Content on this page is for education and information only and is not a substitute for advice from your doctor. Medically reviewed by Mr Jeremy Russell.