Diffuse Astrocytoma

Diffuse astrocytoma, in its current definition, is an IDH-mutant diffuse astrocytic glioma of grade 2 that infiltrates the brain slowly and eventually progresses to a higher grade. It mainly affects young adults, usually presents with seizures, and has a median survival of about 10 years.

Lower grade gliomas form about 15% to 20% of gliomas. Median age at diagnosis is 35 to 40, with a slight male predominance. Tumours lie mainly in the frontal and insular regions.

Established risk factors are ionising radiation to the head and rare germline syndromes (Li-Fraumeni syndrome, constitutional mismatch repair deficiency). Most cases are sporadic.

Pathophysiology. The defining change is a mutation in IDH1 (R132H in about 90%) or IDH2, which produces 2-hydroxyglutarate, drives DNA hypermethylation and blocks differentiation. TP53 mutation and loss of ATRX expression accompany it. There is no 1p/19q co-deletion, which distinguishes astrocytoma from oligodendroglioma.

Imaging and molecular markers. The T2-FLAIR mismatch sign on MRI is highly specific for IDH-mutant astrocytoma. MGMT promoter methylation is common. 2-hydroxyglutarate can be detected by MR spectroscopy.

Natural history. Progression to grade 3 or 4 occurs in most cases over 5 to 10 years, with new contrast enhancement as the first sign. Older age, residual tumour, large size and CDKN2A/B deletion shorten survival.

• Seizures (focal or generalised) are the presenting feature in 70% to 80%.
• Headache, subtle cognitive or personality change, and slowly progressive focal deficits.
• Many tumours are found incidentally on imaging for another reason.
• Raised intracranial pressure is uncommon at diagnosis.

• MRI brain with and without gadolinium, including FLAIR, diffusion and perfusion: ill defined non-enhancing T2/FLAIR hyperintense lesion with mass effect. Functional MRI and tractography plan surgery near eloquent cortex.
• Tissue diagnosis by maximal safe resection or stereotactic biopsy, with integrated pathological and molecular testing: IDH1/2 mutation (R132H immunohistochemistry then sequencing when negative), ATRX, p53, 1p/19q status, CDKN2A/B, MGMT promoter methylation and Ki-67.
• EEG and neuropsychological assessment before and after treatment. Visual fields for posterior lesions.
• Baseline FBC, liver tests and creatinine.

Differential diagnosis.

• Oligodendroglioma, IDH-mutant and 1p/19q co-deleted
• Anaplastic astrocytoma and IDH-wildtype glioma
• Ganglioglioma, dysembryoplastic neuroepithelial tumour and pleomorphic xanthoastrocytoma
• Cortical dysplasia and low grade epilepsy associated tumours
• Cerebral infarct and demyelination
• Encephalitis (limbic or herpes)

Management combines surgery, observation, radiotherapy and chemotherapy or targeted therapy, chosen by the extent of resection, age and molecular profile.

Surgery. Maximal safe resection with awake mapping when near language or motor areas. Extent of resection improves seizure control and survival.

Observation. After gross total resection in patients under 40 with no residual disease, MRI every 3 to 6 months for 5 years and then every 6 to 12 months, with treatment held until progression.

Targeted therapy after surgery (residual or recurrent non-enhancing grade 2 disease without prior radiotherapy or chemotherapy).

• Vorasidenib: vorasidenib 40 mg orally once daily at the same time each day, at least 2 hours after or 1 hour before food (20 mg once daily when body weight is under 40 kg), until progression or unacceptable toxicity; maximum 40 mg daily; monitoring: ALT, AST and bilirubin before starting, every 2 weeks for the first 2 months, monthly for the first 2 years, then as indicated; adjustment: reduce stepwise to 20 mg then 10 mg for toxicity, withhold for ALT or AST over 3 times the upper limit and resume at the next lower dose when 3 times or less, stop permanently for recurrence at 10 mg or for ALT or AST over 3 times the upper limit with bilirubin over 2 times, avoid strong and moderate CYP1A2 inhibitors and avoid smoking, use non-hormonal contraception because hormonal methods may fail, avoid in pregnancy

Adjuvant therapy for higher risk disease (age 40 or over, or subtotal resection, or progression). Radiotherapy 54 Gy in 30 fractions, followed by chemotherapy.

• Procarbazine, lomustine and vincristine: procarbazine 60 mg/m2 orally daily on days 8 to 21, lomustine 110 mg/m2 orally on day 1 and vincristine 1.4 mg/m2 IV on days 8 and 29, every 6 to 8 weeks for up to 6 cycles; maximum procarbazine 100 mg daily, lomustine 200 mg each cycle and vincristine 2 mg each dose; monitoring: FBC on day 1 and at the nadir, liver tests, neuropathy and constipation, lung function, avoidance of alcohol and tyramine rich foods during procarbazine; adjustment: reduce procarbazine and lomustine by 25% for grade 3 to 4 haematological toxicity, reduce vincristine by 50% when bilirubin is 26 to 51 micromol/L and avoid it over 51 micromol/L, avoid strong CYP3A inhibitors, avoid lomustine when creatinine clearance is under 30 mL/min
• Temozolomide (alternative when PCV is not tolerated): temozolomide 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 12 cycles starting 4 weeks after radiotherapy (some centres add 75 mg/m2 daily during radiotherapy); maximum 200 mg/m2 daily; monitoring: FBC on day 22 of each cycle, liver tests, antiemetic cover; adjustment: 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

Seizure and oedema control.

• 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

Monitoring. MRI every 3 months after treatment for the first year, then every 3 to 6 months. Seizure review, cognitive assessment, and endocrine and visual review after radiotherapy.

Referral and escalation.

• Neuro oncology multidisciplinary referral at diagnosis.
• Urgent admission for status epilepticus, rapid neurological decline or signs of raised intracranial pressure.
• New contrast enhancement on MRI suggests progression to a higher grade and needs repeat biopsy or resection.

Special groups.

• Pregnancy: surgery is possible in the second trimester, and radiotherapy and chemotherapy are deferred. Avoid valproate; levetiracetam is preferred.
• Driving: counselling on seizure restrictions.
• Women of childbearing age: vorasidenib may weaken hormonal contraception, so use non-hormonal methods.
• Older adults: lower intensity treatment with shorter courses of radiotherapy.