Anaplastic Astrocytoma

Anaplastic astrocytoma, in its current definition, is an IDH-mutant diffuse astrocytic glioma of grade 3, with increased mitotic activity and nuclear atypia but without the necrosis and microvascular proliferation of grade 4 disease. It affects adults in their 30s to 50s and has a median survival of about 8 to 10 years with treatment.

It accounts for about 2% of primary brain tumours, with a median age of 40 and a slight male excess. Tumours arise de novo or by progression from grade 2 diffuse astrocytoma.

Risk factors are previous cranial radiotherapy and germline syndromes (Li-Fraumeni syndrome, constitutional mismatch repair deficiency, neurofibromatosis type 1). Most cases are sporadic.

Pathophysiology. IDH1 or IDH2 mutation, TP53 mutation and ATRX loss are characteristic, with no 1p/19q co-deletion. Accumulation of 2-hydroxyglutarate causes DNA hypermethylation. Homozygous deletion of CDKN2A/B upgrades the tumour to grade 4 regardless of histology.

Prognosis. Median survival is about 8 to 10 years in IDH-mutant disease, compared with about 2 years for IDH-wildtype anaplastic gliomas, which behave as glioblastoma. Older age, poor performance status, residual tumour, CDKN2A/B deletion and absence of MGMT methylation worsen outcome.

• Seizures in about half, headache, cognitive or personality change and focal deficits (weakness, aphasia, visual field loss).
• Signs of raised intracranial pressure: morning headache, vomiting, papilloedema and drowsiness.
• Symptoms evolve over weeks to months, faster than in grade 2 disease.

Red flags.

• Rapid decline in consciousness, new focal deficit, or seizures not responding to treatment.
• Signs of raised intracranial pressure or herniation.

• MRI brain with gadolinium: infiltrating T2/FLAIR lesion with patchy or no enhancement and mass effect, and no central necrosis. Perfusion MRI and MR spectroscopy help grading. Spinal MRI is not routine.
• Tissue by maximal safe resection or biopsy, with integrated diagnosis: IDH1/2, ATRX, p53, 1p/19q status, CDKN2A/B deletion, TERT promoter, MGMT promoter methylation, mitotic count and Ki-67.
• Baseline neuropsychological assessment, visual fields, FBC, liver tests and creatinine.

Differential diagnosis.

• Anaplastic oligodendroglioma, IDH-mutant and 1p/19q co-deleted
• Glioblastoma, IDH-wildtype
• Diffuse astrocytoma (grade 2) and IDH-mutant astrocytoma, grade 4
• Pleomorphic xanthoastrocytoma and anaplastic ganglioglioma
• Primary CNS lymphoma
• Brain abscess, tumefactive demyelination and cerebral metastasis

Treatment is surgery followed by radiotherapy and chemotherapy.

Surgery. Maximal safe resection, with awake mapping near eloquent areas. Biopsy is used when resection is unsafe.

Radiotherapy. 59.4 Gy in 33 fractions (1.8 Gy each), starting 3 to 6 weeks after surgery, delivered by conformal or intensity modulated technique. Proton therapy is an option for young patients to spare normal brain.

Chemotherapy after radiotherapy.

• Temozolomide: 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
• Procarbazine, lomustine and vincristine (alternative in selected patients): 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
• Pneumocystis prophylaxis during concurrent temozolomide and while corticosteroids continue: 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

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 when feasible, re-irradiation in selected patients, and lomustine or temozolomide re-challenge.

• 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 and then every 2 to 3 months for 2 years, every 3 to 6 months for years 3 to 5, then yearly. Late neurocognitive, endocrine and vascular effects of radiotherapy.

Referral and escalation.

• Neuro oncology multidisciplinary referral at diagnosis.
• Urgent admission for neurological deterioration, status epilepticus or herniation signs.
• Palliative care when disease progresses.

Special groups.

• Older adults: shorter radiotherapy schedules and temozolomide alone in selected patients.
• Pregnancy: delay radiotherapy and chemotherapy after the first trimester where possible, and use levetiracetam.
• Women of childbearing age: contraception during chemotherapy and for 6 months after, and discussion of fertility.
• Patients with neurofibromatosis type 1: avoid radiotherapy when possible.