Glioblastoma

IDH-wildtype glioblastoma is the commonest and most aggressive primary malignant brain tumour in adults, a grade 4 astrocytic glioma that has no IDH mutation. With surgery, radiotherapy and temozolomide, median survival is about 14 to 16 months, and 5-year survival is about 5%.

Incidence is about 3 to 4 cases in 100,000 people each year, with a median age at diagnosis of about 64 and a male to female ratio of about 1.6 to 1. It forms about half of malignant brain tumours in adults.

Risk factors are previous therapeutic cranial radiotherapy and rare germline syndromes (Li-Fraumeni syndrome, neurofibromatosis type 1, Lynch syndrome and Turcot syndrome). Mobile phone use and other environmental factors are not proven causes.

Pathophysiology. Typical changes are gain of chromosome 7 with loss of chromosome 10, TERT promoter mutation, EGFR amplification or the EGFRvIII variant, CDKN2A/B deletion, PTEN loss and TP53 alteration. Tumour cells infiltrate along white matter tracts, so resection never removes all disease.

Diagnostic definition. An IDH-wildtype astrocytic glioma is classed as glioblastoma when it shows microvascular proliferation or necrosis, or TERT promoter mutation, EGFR amplification or the combined +7/-10 change, even without these histological features.

Prognostic factors. MGMT promoter methylation (about 40% of tumours) predicts benefit from temozolomide and longer survival. Younger age, good performance status and extent of resection also improve outcome.

• Headache (often worse in the morning), nausea and vomiting, and papilloedema from raised intracranial pressure.
• Seizures in 30% to 50%, focal weakness, aphasia, visual field defects, memory and personality change.
• Rapid progression over weeks.
• Venous thromboembolism in 20% to 30% during the illness.

Red flags.

• Falling consciousness, anisocoria or Cushing response (herniation).
• Status epilepticus.
• New unilateral weakness or speech loss in a known patient (progression or haemorrhage).

• MRI brain with gadolinium: irregular ring enhancing mass with central necrosis, extensive T2/FLAIR change and mass effect, and raised perfusion. Diffusion and spectroscopy help. CT is used only in emergencies.
• Tissue by maximal safe resection or stereotactic biopsy, with IDH1/2 (negative), ATRX retained, p53, TERT promoter, EGFR amplification, chromosome 7 and 10 copy number, CDKN2A/B and MGMT promoter methylation.
• Postoperative MRI within 24 to 72 hours to define residual tumour.
• Baseline FBC, liver tests, creatinine, HbA1c and glucose (corticosteroids), and neurocognitive assessment.

Differential diagnosis.

• Cerebral metastasis and brain abscess
• Primary CNS lymphoma
• Anaplastic astrocytoma and IDH-mutant astrocytoma (grade 4)
• Diffuse hemispheric glioma, H3 G34-mutant
• Tumefactive demyelination
• Radiation necrosis and pseudoprogression
• Subacute infarction and cavernous malformation haemorrhage

Treatment is surgery, radiotherapy with temozolomide, and supportive care. Treatment is chosen by age, performance status and MGMT status.

Surgery. Maximal safe resection, with awake mapping near eloquent cortex.

• Fluorescence assisted resection:
  • Aminolevulinic acid 20 mg/kg orally once as a solution, 2 to 4 hours before induction of anaesthesia, so that tumour tissue fluoresces during surgery.
  • Maximum 20 mg/kg as a single dose (one dose each operation).
  • Monitoring: avoid strong light and sunlight for 24 hours, blood pressure after induction, liver tests.
  • Adjustment: avoid in acute or chronic severe hepatic impairment, porphyria and pregnancy; avoid phototoxic drugs for 24 hours.

Radiotherapy with temozolomide (age under 65 to 70, good performance status). Radiotherapy 60 Gy in 30 fractions, beginning 3 to 6 weeks after surgery.

• Temozolomide:
  • During radiotherapy: temozolomide 75 mg/m2 orally once daily at the same time each day on an empty stomach for 42 to 49 days.
  • After a 4-week break: 150 mg/m2 orally once daily on days 1 to 5 of a 28-day cycle for cycle 1, increased to 200 mg/m2 on days 1 to 5 from cycle 2 when neutrophils and platelets allow, for 6 cycles.
  • Maximum 75 mg/m2 daily during radiotherapy and 200 mg/m2 daily in adjuvant cycles.
  • Monitoring: FBC weekly during radiotherapy and on day 22 of each adjuvant cycle, liver tests, antiemetic cover.
  • Adjustment during radiotherapy: hold for neutrophils under 1.5 x 10^9/L or platelets under 100 x 10^9/L, and stop for neutrophils under 0.5 x 10^9/L or platelets under 10 x 10^9/L.
  • Adjustment in adjuvant cycles: reduce by 50 mg/m2 for neutrophils under 1.0 x 10^9/L or platelets under 50 x 10^9/L, and stop if 100 mg/m2 is not tolerated.
  • No change when creatinine clearance is 36 mL/min or more and caution when it is lower; caution in severe hepatic impairment.
• Pneumocystis prophylaxis:
  • Co-trimoxazole 960 mg orally three times weekly (for example Monday, Wednesday and Friday) throughout concurrent temozolomide and radiotherapy, continued while corticosteroids are used and until lymphocytes recover above 0.5 x 10^9/L.
  • Maximum 960 mg daily.
  • Monitoring: FBC, potassium, creatinine, rash.
  • Adjustment: halve the dose when creatinine clearance is 15 to 30 mL/min and avoid under 15 mL/min; stop for rash or severe cytopenia and use a non-sulfonamide agent.
• Alternating electric fields (a device worn on the scalp for at least 18 hours each day at 200 kHz) can be added to adjuvant temozolomide to prolong survival, with skin care to the scalp.

Older adults (age 65 or over) or frail patients. Hypofractionated radiotherapy 40 Gy in 15 fractions with concurrent temozolomide 75 mg/m2 daily, or 25 Gy in 5 fractions for poor performance status. Temozolomide alone (150 to 200 mg/m2 on days 1 to 5 of a 28-day cycle) is an option for MGMT-methylated tumours.

Seizure, oedema and thrombosis.

• Antiseizure therapy:
  • Levetiracetam 500 mg orally twice daily, increased by 500 mg twice daily every 1 to 2 weeks to a usual 1000 to 1500 mg twice daily after a seizure (it is not continued as prophylaxis in seizure free patients after the early postoperative period).
  • Maximum 3000 mg daily.
  • Monitoring: mood, irritability, somnolence, renal function.
  • Adjustment: creatinine clearance 50 to 79 mL/min 500 to 1000 mg twice daily, 30 to 49 mL/min 250 to 750 mg twice daily, under 30 mL/min 250 to 500 mg twice daily.
  • Avoid enzyme inducing antiseizure drugs because they lower temozolomide and lomustine exposure.
• Corticosteroid for symptomatic oedema:
  • Dexamethasone 4 mg orally or IV once or twice daily for mild symptoms and up to 4 mg four times daily for marked oedema or raised intracranial pressure, for the shortest period, tapered over 1 to 2 weeks once symptoms settle.
  • Maximum 16 mg daily.
  • Monitoring: glucose, blood pressure, mood and sleep, gastric symptoms (gastric protection when combined with other risk factors), opportunistic infection, myopathy.
  • Adjustment: use the lowest effective dose, avoid prolonged courses because of myopathy, osteoporosis and infection, use lower doses in hepatic impairment.
• Venous thromboembolism:
  • Enoxaparin 1 mg/kg subcutaneously twice daily (or 1.5 mg/kg once daily) while the thrombotic risk persists, for at least 6 months and as long as active disease remains.
  • Maximum 1.5 mg/kg daily.
  • Monitoring: platelet count at baseline and every 2 to 4 weeks for the first month, creatinine, signs of intracranial haemorrhage, anti-Xa level in obesity or renal impairment.
  • Adjustment: 1 mg/kg once daily when creatinine clearance is under 30 mL/min.
  • Hold for intracranial haemorrhage or platelets under 50 x 10^9/L; avoid in brain metastasis with recent bleeding.

Recurrence. Re-resection for focal recurrence with good performance status, re-irradiation in selected patients (about 35 Gy in 10 fractions), and drug therapy.

• Lomustine:
  • Lomustine 110 mg/m2 orally as a single dose on day 1 of a 6-week cycle, on an empty stomach at bedtime with an antiemetic, for up to 6 cycles.
  • Maximum 110 mg/m2 each cycle and cumulative 1000 mg/m2.
  • Monitoring: FBC before each cycle and weekly for 6 weeks after each dose, liver tests, lung function (pulmonary fibrosis rises with cumulative dose).
  • Adjustment: reduce to 90 mg/m2 then 70 mg/m2 for neutrophil nadir under 1.0 x 10^9/L or platelets under 50 x 10^9/L.
  • Delay until neutrophils reach 1.5 x 10^9/L and platelets 100 x 10^9/L.
  • Avoid when creatinine clearance is under 30 mL/min; caution in hepatic impairment.
  • Prescribe one dose each cycle only to avoid overdose.
• Bevacizumab (symptom control and steroid sparing):
  • Bevacizumab 10 mg/kg IV every 2 weeks (first infusion over 90 minutes, then 60 minutes, then 30 minutes if tolerated) until progression or toxicity.
  • Maximum 10 mg/kg each dose.
  • Monitoring: blood pressure at each visit, urine protein before each dose, FBC, bleeding, thromboembolism, wound healing.
  • Adjustment: omit for 28 days before and after major surgery; hold for urine protein over 2 g in 24 hours until it falls under 2 g.
  • Stop for gastrointestinal perforation, severe haemorrhage, hypertensive crisis, arterial thromboembolism or posterior reversible encephalopathy.

Monitoring. MRI 4 weeks after radiotherapy and every 2 to 3 months for 2 years, then every 3 to 6 months. Distinguish pseudoprogression (within 12 weeks of radiotherapy) from true progression by perfusion imaging and follow up. Neurocognitive, endocrine and mood review.

Referral and escalation.

• Neuro oncology multidisciplinary referral at diagnosis.
• Emergency admission for herniation signs, status epilepticus or rapid neurological decline.
• Early palliative care, with advance care planning and driving counselling.

Special groups.

• Older adults: shorter radiotherapy schedules and fewer chemotherapy cycles.
• Pregnancy: surgery in the second trimester, with radiotherapy and temozolomide deferred where possible.
• Patients on warfarin or anticoagulants: avoid when recent intracranial bleeding, and use low molecular weight heparin.
• Caregivers: carer support, respite and bereavement care.