Radiation Necrosis

Radiation necrosis is focal tissue death in previously irradiated brain from delayed vascular and glial injury. It appears months to years after radiotherapy or radiosurgery, causes oedema and mass effect, and mimics tumour recurrence.

Epidemiology. After stereotactic radiosurgery for brain metastases, symptomatic necrosis occurs in about 5 to 10% and radiographic change in up to 25%. Risk rises with treated volume, dose, repeat irradiation and concurrent immunotherapy or targeted agents.

Timing. Usually 6 to 24 months after treatment, and occasionally many years later.

Scope. Necrosis of bone and soft tissue after radiotherapy is a related late effect, and this article deals with brain.

Outcome. Many lesions stabilise or resolve. Some progress and cause severe oedema, seizures and neurological deficit.

Pathophysiology.

Endothelial injury causes vessel wall thickening, fibrinoid necrosis, ischaemia and hypoxia. Hypoxic cells release HIF-1 alpha and VEGF, which cause leaky capillaries and vasogenic oedema.

Glial and neuronal loss with an inflammatory reaction follows. Excess VEGF is the rationale for treatment with bevacizumab.

• Headache, seizures, focal deficit, cognitive decline and signs of raised intracranial pressure.
• Many lesions are asymptomatic and found on follow up imaging.

Red flags.

• Falling consciousness, rapidly worsening deficit or signs of herniation.
• Status epilepticus.

• Treatment history with dose maps, volume and timing.
• MRI with contrast: ring or feathery enhancement ("soap bubble" or "Swiss cheese" pattern) with surrounding oedema.
• Perfusion MRI (low relative cerebral blood volume favours necrosis), MR spectroscopy and amino acid PET to separate necrosis from recurrence. FDG PET is less accurate.
• Serial imaging at short intervals. Biopsy or resection when imaging remains uncertain and the result will change management; mixed disease is common.

Differential diagnosis. Tumour recurrence or progression, pseudoprogression after immunotherapy, abscess, demyelination, stroke, radiation induced vasculopathy.

• Asymptomatic lesions: observation with repeat imaging.
• Symptomatic oedema: dexamethasone 4 mg orally twice daily, increased to 4 mg four times daily if needed, for 2 to 4 weeks then slow taper to the lowest effective dose. Maximum 16 mg daily. Give a proton pump inhibitor. Monitor glucose, blood pressure, mood and infection, and consider Pneumocystis prophylaxis if therapy continues beyond 4 weeks. Caution in diabetes and peptic ulcer; no renal adjustment.
• Steroid dependent or refractory necrosis: bevacizumab 7.5 mg/kg intravenously every 3 weeks for 2 to 4 cycles. Maximum 7.5 mg/kg each dose. Monitor blood pressure, urine protein, thrombosis, bleeding and wound healing. Avoid within 4 weeks of major surgery, with uncontrolled hypertension, recent haemorrhage or gastrointestinal perforation, and in pregnancy; no renal adjustment but stop for nephrotic range proteinuria. Evidence comes from a small randomised study and case series.
• Seizures: levetiracetam orally 500 mg twice daily, increased by 500 mg twice daily every 2 weeks to a maximum of 1500 mg twice daily. Monitor mood and irritability. If creatinine clearance is 50 to 80 mL/min, give 500 to 1000 mg every 12 hours; 30 to 50 mL/min, 250 to 750 mg every 12 hours; under 30 mL/min, 250 to 500 mg every 12 hours. Not needed for prevention in patients without seizures.
• Surgery (resection) or laser interstitial thermal therapy for refractory mass effect.
• Hyperbaric oxygen, pentoxifylline and vitamin E have limited and inconsistent evidence.

Monitoring. MRI every 4 to 8 weeks during active management, then every 3 months; neurological and cognitive review at each visit.

Referral and escalation. Neuro oncology and radiation oncology review at diagnosis; neurosurgery for mass effect; urgent admission for falling consciousness or status epilepticus.