Brain Metastases

Brain metastases are secondary tumours in the brain parenchyma, the commonest intracranial tumours in adults. They cause headache, focal deficits, seizures and cognitive decline, and management combines local treatment (surgery and radiosurgery or radiotherapy), systemic therapy that penetrates the brain, and symptom control.

They occur in 20% to 40% of patients with cancer, with an incidence of about 10 to 30 cases in 100,000 people each year, rising as systemic control improves. The commonest primaries are lung (40% to 50%), breast (15% to 20%), melanoma (5% to 10%), renal cell carcinoma, and colorectal cancer. About 50% of patients have a single lesion on imaging at diagnosis.

Risk factors include driver mutant lung cancer (EGFR, ALK), HER2-positive and triple negative breast cancer, BRAF-mutant melanoma, and extracranial disease burden.

Pathophysiology. Haematogenous spread to the grey white junction and arterial watershed zones, with 80% in the cerebral hemispheres, 15% in the cerebellum and 5% in the brainstem. Disruption of the blood brain barrier raises vasogenic oedema and intracranial pressure.

Prognosis. Median survival is about 1 month untreated, 2 months with steroids, 3 to 6 months with whole brain radiotherapy, and 1 to 2 years or longer with radiosurgery and effective targeted therapy in selected patients (for example ALK-positive lung cancer). Prognosis is estimated using age, performance status, number of lesions, extracranial disease and tumour subtype.

• Headache (40% to 50%), worse in the morning, with nausea and vomiting.
• Focal deficits (30% to 40%): hemiparesis, aphasia, visual field loss, ataxia.
• Seizures (10% to 20%), and cognitive or personality change (up to 30%).
• Papilloedema, and haemorrhage into a metastasis (melanoma, renal cell carcinoma, choriocarcinoma, thyroid) causing sudden deterioration.

Red flags.

• Reduced consciousness, severe headache with vomiting, or a dilated pupil (herniation).
• Status epilepticus or sudden deterioration (haemorrhage).

• MRI of the brain with gadolinium (thin slices, 3 mm or less) shows the number, size and location of lesions. CT if MRI is unavailable.
• Staging of extracranial disease (CT of the chest, abdomen and pelvis, or PET-CT) and biopsy when the primary is unknown or a solitary lesion could be another disease.
• Molecular profiling of the primary or brain tumour (EGFR, ALK, ROS1, BRAF, HER2, PD-L1).
• Differentiation of radiation necrosis from recurrence after radiosurgery (perfusion MRI, amino acid PET, biopsy).

Differential diagnosis.

• Primary brain tumours (glioblastoma, lymphoma, meningioma)
• Cerebral abscess, toxoplasmosis and tuberculoma
• Demyelination, stroke and radiation necrosis
• Leptomeningeal disease

Management is decided by a neuro oncology team on lesion number and size, symptoms, primary tumour, systemic disease control and performance status.

Symptom control.

• Corticosteroids 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. Use for the shortest period, tapered over 1 to 2 weeks once symptoms settle. Maximum 16 mg daily.
• Dexamethasone monitoring: glucose, blood pressure, mood and sleep, gastric symptoms (gastric protection when combined with other risk factors), opportunistic infection, myopathy.
• Dexamethasone adjustment: use the lowest effective dose. Avoid prolonged courses because of myopathy, osteoporosis and infection. Use lower doses in hepatic impairment.
• Seizures (not as prophylaxis in patients without seizures): levetiracetam 500 mg orally twice daily after a seizure, increased by 500 mg twice daily every 1 to 2 weeks to a usual 1000 to 1500 mg twice daily. It is not continued as prophylaxis in seizure free patients after the early postoperative period. Maximum 3000 mg daily.
• Levetiracetam monitoring: mood, irritability, somnolence, renal function.
• Levetiracetam 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.
• Thromboprophylaxis in immobile patients: enoxaparin 40 mg subcutaneously once daily during active disease and for 4 weeks after surgery. Use therapeutic dosing of 1 mg/kg twice daily if thrombosis is established. Maximum 40 mg daily for prophylaxis.
• Enoxaparin monitoring: platelet count at baseline and every 2 to 4 weeks, creatinine, signs of bleeding, anti-Xa level in obesity or renal impairment.
• Enoxaparin adjustment: 20 mg daily when creatinine clearance is under 30 mL/min. Hold for platelets under 50 x 10^9/L or active bleeding. Time the dose at least 12 hours before and 4 hours after a neuraxial procedure.

Surgery. Resection of a single, accessible lesion over 3 cm, or one causing mass effect, hydrocephalus or needing a tissue diagnosis, followed by radiosurgery to the cavity within 3 to 6 weeks (reduces local recurrence from 50% to 15% or less).

Stereotactic radiosurgery. First choice for patients with up to 4 (and in some centres up to 10) lesions, each up to 3 to 4 cm. Single fraction doses are 24 Gy for lesions under 2 cm, 18 Gy for 2 to 3 cm, and 15 Gy for 3 to 4 cm. Fractionated radiosurgery of 27 Gy in 3 fractions is an option for larger lesions and cavities.

Whole brain radiotherapy. For multiple lesions (over 10) or poor options: 30 Gy in 10 fractions or 20 Gy in 5 fractions, with hippocampal avoidance when possible. Neurocognitive protection:

• Memantine: memantine 5 mg orally once daily, increased by 5 mg each week to 10 mg twice daily (20 mg daily). Start within 3 days of whole brain radiotherapy and continue for 24 weeks. Maximum 20 mg daily.
• Memantine monitoring: cognition, confusion, dizziness, blood pressure, seizures.
• Memantine adjustment: reduce the target to 5 mg twice daily when creatinine clearance is under 30 mL/min. Use caution in epilepsy. Avoid with amantadine or ketamine.

Brain penetrant systemic therapy (often with or without radiotherapy).

• EGFR-mutant lung cancer: osimertinib 80 mg orally once daily until progression or unacceptable toxicity, for EGFR mutation positive lung cancer. 160 mg once daily is used in leptomeningeal disease at specialist centres. Maximum 160 mg daily.
• Osimertinib monitoring: QTc and electrolytes, left ventricular ejection fraction at baseline and when symptomatic, FBC, creatinine, symptoms of interstitial lung disease, skin and nail toxicity.
• Osimertinib adjustment: hold for grade 3 toxicity and resume at 40 mg. Stop for interstitial lung disease or symptomatic cardiac failure. Avoid strong CYP3A4 inducers (use 160 mg daily if unavoidable). No renal adjustment for mild to moderate impairment.
• ALK-positive lung cancer: alectinib 600 mg orally twice daily with food until progression or unacceptable toxicity, for ALK-positive lung cancer including brain metastases. Maximum 1200 mg daily.
• Alectinib monitoring: liver tests every 2 weeks for 3 months and then monthly, creatine kinase, heart rate, FBC, creatinine, photosensitivity.
• Alectinib adjustment: reduce to 450 mg then 300 mg twice daily for toxicity. Hold for ALT or AST over 5 times the upper limit. Use 450 mg twice daily in severe hepatic impairment. Stop for interstitial lung disease. Advise sun protection.
• BRAF V600E-mutant melanoma: dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily until progression or unacceptable toxicity, for BRAF V600E tumours in adults and in adolescents weighing 51 kg or more. Below 51 kg, weight banded doses are set by a paediatric oncology pharmacist. Maximum dabrafenib 300 mg daily and trametinib 2 mg daily.
• Dabrafenib and trametinib monitoring: left ventricular ejection fraction at baseline, 1 month and then every 2 to 3 months, skin and eye examination, blood pressure, liver tests, glucose, temperature.
• Dabrafenib and trametinib adjustment: reduce dabrafenib stepwise to 100 mg then 75 mg twice daily and trametinib to 1.5 mg then 1 mg daily. Hold both for fever of 38.5 C or more. Stop for a fall in ejection fraction of over 10 points to under the lower limit of normal.
• Dabrafenib and trametinib interactions: avoid strong CYP3A4 or CYP2C8 inducers and inhibitors. No renal adjustment for mild to moderate impairment.
• Melanoma without a BRAF mutation: nivolumab 360 mg IV every 3 weeks with ipilimumab 1 mg/kg IV every 6 weeks, for up to 24 months or until progression or unacceptable toxicity. Maximum nivolumab 360 mg each 3-week dose and ipilimumab 1 mg/kg each 6-week dose.
• Nivolumab and ipilimumab monitoring: thyroid function, liver tests, creatinine, glucose and morning cortisol before each dose, symptoms of colitis, pneumonitis and hypophysitis.
• Nivolumab and ipilimumab adjustment: no renal or mild hepatic dose adjustment. Withhold for grade 2 immune toxicity and give prednisolone 0.5 to 1 mg/kg daily. Stop permanently for grade 3 to 4 toxicity and give prednisolone 1 to 2 mg/kg daily tapered over at least 4 to 6 weeks.
• HER2-positive breast cancer: 5.4 mg/kg IV every 3 weeks until progression. Maximum 5.4 mg/kg each dose.
• Breast cancer regimen monitoring: antiemetics for high emetogenic risk, FBC, LVEF every 12 weeks, symptoms and imaging for interstitial lung disease.
• Breast cancer regimen adjustment: reduce to 4.4 then 3.2 mg/kg for toxicity. Interstitial lung disease of grade 1 needs a hold and prednisolone about 0.5 mg/kg daily. Grade 2 or worse needs permanent discontinuation and prednisolone 1 mg/kg daily.

Monitoring. MRI every 2 to 3 months for the first year after treatment, then every 3 to 6 months. Steroid related toxicity and cognitive assessment.

Referral and escalation.

• Urgent neurosurgery and oncology referral on diagnosis.
• Emergency admission for reduced consciousness, uncontrolled seizures, or haemorrhage.

Special groups.

• Poor functional state: best supportive care with corticosteroids and palliative input.
• Pregnancy: MRI without gadolinium, with decisions made by a multidisciplinary team.
• Anticoagulated patients: continue treatment unless there is intracranial haemorrhage, with close monitoring.