Key Facts

GBM is the most aggressive brain tumour with a dismal prognosis despite treatment. Maximal safe resection followed by chemoradiotherapy (Stupp protocol) is the standard of care. MGMT methylation is the strongest molecular prognostic marker.

Epidemiology

Incidence ~5 per 100,000/year. ~50% of all gliomas. Peak age 55-65 years. M:F 1.6:1. More common in Caucasians. Incidence increasing (possibly due to better diagnosis in elderly).

Aetiology

• No clear modifiable risk factors in most cases
• Only established risk factor: prior ionising radiation to the head
• Genetic syndromes (rare): Li-Fraumeni (TP53), Lynch syndrome, NF1
• NOT associated with mobile phone use (large cohort studies show no association)

Pathophysiology

Characterised by: rapid proliferation, microvascular proliferation (neoangiogenesis), pseudopallisading necrosis, diffuse infiltration into surrounding brain parenchyma. IDH-wildtype tumours arise de novo (primary GBM) without a precursor low-grade lesion. Key molecular alterations: TERT promoter mutations (>80%), EGFR amplification (~40%), PTEN loss, chromosome +7/-10. MGMT gene promoter methylation silences the DNA repair enzyme → increased sensitivity to temozolomide alkylation.

Typical Presentation

• Rapidly progressive symptoms over weeks-months
• Headache (raised ICP pattern), seizures, focal deficit, cognitive/personality change
• Presentation depends on tumour location (see Brain Tumours)
• May present acutely with intratumoral haemorrhage mimicking stroke

Imaging Characteristics

• Ring-enhancing mass with central necrosis
• Irregular thick enhancing rim
• Significant surrounding vasogenic oedema
• Mass effect and midline shift
• May cross corpus callosum ('butterfly' appearance)
• Multifocal in ~5%

Red Flags

• Rapid clinical deterioration → haemorrhage, herniation
• New-onset seizures in adult → urgent MRI
• Progressive focal deficit over weeks

Imaging

• MRI brain with gadolinium: characteristic ring enhancement, necrosis, oedema
• MR perfusion: elevated rCBV (hypervascular tumour)
• MR spectroscopy: elevated choline/creatine ratio, reduced NAA, lipid/lactate peak
• CT head: may show mass, oedema, haemorrhage (often first investigation)

Tissue Diagnosis

• Surgical resection or stereotactic biopsy: essential for definitive diagnosis
• Histopathology: microvascular proliferation, pseudopallisading necrosis
• Molecular testing (WHO 2021): IDH1/2 mutation status (wildtype in GBM), MGMT promoter methylation, TERT promoter, EGFR amplification, +7/-10

Bloods

• Pre-operative baseline: FBC, U&Es, LFTs, coagulation, group and save

Surgical

• Maximal safe resection: extent of resection correlates with survival; fluorescence-guided surgery (5-ALA) improves completeness; awake craniotomy for tumours near eloquent cortex
• Stereotactic biopsy: if tumour is deep/unresectable; provides tissue diagnosis

Chemoradiotherapy (Stupp Protocol)

• Concurrent phase: radiotherapy 60 Gy in 30 fractions (6 weeks) + daily temozolomide 75mg/m² (throughout RT + 1 month)
• Adjuvant phase: temozolomide 150-200mg/m² days 1-5 of 28-day cycle × 6 cycles
• PCP prophylaxis: co-trimoxazole during concurrent phase (lymphopenia risk)
• Antiemetics: ondansetron PRN during temozolomide

Elderly/Frail Patients

• Hypofractionated RT (40 Gy in 15 fractions) + temozolomide
• Temozolomide alone if MGMT methylated and unable to tolerate RT
• RT alone (25 Gy in 5 fractions) if poor performance status

Recurrence

• Bevacizumab (anti-VEGF): used in some centres for recurrent GBM; improves PFS but not OS
• Lomustine (CCNU): alkylating agent for recurrence
• Re-resection: selected cases
• TTFields (tumour treating fields — Optune): alternating electric fields; modest survival benefit when added to temozolomide; NICE not yet routinely recommended
• Clinical trials: encouraged at all stages

Supportive

• Dexamethasone: 4-16mg/day for oedema; taper to lowest effective dose
• Anticonvulsants: levetiracetam if seizures (no prophylaxis)
• VTE prophylaxis: high thrombotic risk in GBM
• Palliative care: early integration; prognosis counselling
• DVLA notification: mandatory; cannot drive

Referral Criteria

• Neuro-oncology MDT: all suspected GBM
• Palliative care: early involvement

Median overall survival ~15 months with Stupp protocol. MGMT methylated: ~21 months. MGMT unmethylated: ~14 months. 5-year survival ~5%. Elderly (>70): shorter survival but still benefit from treatment. KPS <70: significantly worse prognosis. Without treatment: median survival ~3-4 months. Recurrence is almost universal — median time to recurrence ~7 months. GBM is almost invariably fatal.

GBM Prognostic Factors

Key GBM Trials