Anaplastic Oligodendroglioma

Anaplastic oligodendroglioma is an IDH-mutant and 1p/19q co-deleted diffuse glioma of grade 3, with increased mitotic activity and often microvascular proliferation. It is the most chemosensitive diffuse glioma, and median survival is about 10 to 15 years with radiotherapy and chemotherapy.

It forms about 1% to 2% of primary brain tumours. Median age at diagnosis is the 40s to 50s, with a slight male predominance. Tumours lie mainly in the frontal lobes, then temporal and parietal lobes, and cortical and subcortical calcification is typical.

No environmental risk factor is established. Familial cases are very rare.

Pathophysiology. The defining changes are IDH1 or IDH2 mutation with whole arm co-deletion of 1p and 19q. TERT promoter mutation is almost universal, and CIC and FUBP1 mutations are common. Homozygous CDKN2A/B deletion and high mitotic count identify tumours with worse outcome.

Prognostic factors. Age over 50, poor performance status, CDKN2A/B deletion, extensive necrosis and residual tumour worsen survival. Complete resection, 1p/19q co-deletion and MGMT promoter methylation improve it.

• Seizures in 50% to 70%, often for years before diagnosis.
• Headache, cognitive or personality change, and focal deficits by site (hemiparesis, aphasia).
• Signs of raised intracranial pressure in larger tumours.

Red flags.

• Status epilepticus or rapid decline in consciousness.
• New focal deficit or signs of herniation.
• Intratumoural haemorrhage, which is more frequent than in astrocytoma.

• MRI brain with gadolinium, diffusion and perfusion: cortical and subcortical lesion with variable enhancement, mixed signal, cysts and calcification (CT shows calcification best).
• Tissue by resection or biopsy. Integrated diagnosis: IDH1 R132H immunohistochemistry and sequencing, 1p/19q co-deletion (FISH or array), TERT promoter, CDKN2A/B, ATRX retained, mitotic count, necrosis, microvascular proliferation and MGMT promoter methylation.
• Baseline neuropsychological testing, FBC, liver tests and creatinine.

Differential diagnosis.

• Diffuse astrocytoma and IDH-mutant astrocytoma (ATRX loss, no 1p/19q co-deletion)
• Glioblastoma, IDH-wildtype
• Dysembryoplastic neuroepithelial tumour, ganglioglioma and clear cell ependymoma
• Cavernous malformation and cortical dysplasia

Treatment is maximal safe resection, then radiotherapy with chemotherapy.

Surgery. Maximal safe resection with awake mapping where needed.

Radiotherapy. 59.4 Gy in 33 fractions (1.8 Gy each), starting 3 to 6 weeks after surgery. Proton therapy is an option in young patients.

Chemotherapy.

• Procarbazine, lomustine and vincristine, starting after radiotherapy: 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

Recurrence. Re-resection, re-irradiation in selected cases, and a second line of chemotherapy not used before (temozolomide after PCV, or PCV after temozolomide).

• 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

Monitoring. MRI 4 weeks after radiotherapy, then every 3 months for 2 years and every 6 months to year 5, then yearly. Neurocognitive and endocrine assessment, with monitoring of blood counts and lung function during PCV.

Referral and escalation.

• Neuro oncology multidisciplinary referral at diagnosis.
• Urgent admission for status epilepticus, haemorrhage or herniation signs.

Special groups.

• Pregnancy: surgery in the second trimester, with radiotherapy and chemotherapy deferred. Levetiracetam is preferred over valproate.
• Women of childbearing age and young men: fertility counselling before PCV and temozolomide, and contraception during treatment.
• Older adults: shorter radiotherapy courses or temozolomide alone.