Leptomeningeal Carcinomatosis

Leptomeningeal carcinomatosis (leptomeningeal metastasis) is infiltration of the pia mater, arachnoid and subarachnoid space (cerebrospinal fluid) by solid tumour cells. It causes multifocal neurological deficits, raised intracranial pressure and hydrocephalus, and usually carries a poor prognosis, though targeted therapy and immunotherapy have improved outcomes in selected tumours.

It occurs in 5% to 8% of patients with solid tumours, most often breast cancer (lobular and triple negative), lung adenocarcinoma (especially EGFR and ALK driven) and melanoma. Frequency has risen with longer survival and better imaging. Median age follows the underlying cancer.

Risk factors are a posterior fossa metastasis resected piecemeal, previous brain metastases, advanced and aggressive primary tumours, and driver mutant lung cancer.

Pathophysiology. Cells reach the subarachnoid space by haematogenous spread, direct extension from brain or bone metastases, perineural spread, or at surgery. Tumour cells block CSF flow, invade nerve roots and cranial nerves, and compete for glucose in the CSF.

Prognosis. Median survival is 4 to 8 weeks untreated and about 3 to 10 months with treatment, longer (over 1 year) in some EGFR-mutant, HER2-positive and BRAF-mutant tumours treated with targeted drugs.

• Cerebral: headache, nausea and vomiting, confusion, seizures, hydrocephalus.
• Cranial nerves: diplopia, facial weakness, hearing loss, visual loss.
• Spinal and root: radicular pain, limb weakness, sensory loss, cauda equina syndrome (bladder and bowel dysfunction).
• Signs are multifocal and often asymmetric, with neck stiffness or absent reflexes.

Red flags.

• Headache with vomiting and reduced consciousness (hydrocephalus).
• Rapidly progressive weakness or sphincter dysfunction.
• Seizures.

• MRI of the brain and whole spine with gadolinium (linear or nodular leptomeningeal enhancement, hydrocephalus; negative in a minority). Spine imaging before lumbar puncture.
• CSF analysis: opening pressure, cell count, protein (raised), glucose (low), and cytology. A single sample is positive in about 50% to 60% and three samples in 80% to 90%. CSF tumour DNA and circulating tumour cells increase sensitivity.
• Radionuclide CSF flow study before intrathecal therapy (blocked flow in up to 30%).
• Systemic staging for the primary tumour, and molecular profiling of the primary (EGFR, ALK, HER2, BRAF).

Differential diagnosis.

• Infectious meningitis (tuberculous, fungal), carcinomatous versus chemical meningitis
• Paraneoplastic neurological syndromes and radiation or drug neurotoxicity
• Brain metastases, spinal epidural metastasis and primary CNS lymphoma
• Sarcoidosis and other inflammatory meningitides

Management is individualised in line with performance status, extent of systemic disease and tumour molecular profile. Treatment aims at symptom control and neurological function.

Symptom control.

• Corticosteroids for raised pressure or 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.
• 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.
• Seizures: 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; maximum 3000 mg daily.
• Levetiracetam is not continued as prophylaxis in seizure free patients after the early postoperative period.
• 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.
• Hydrocephalus: ventriculoperitoneal shunt or ventricular reservoir for symptomatic raised pressure with a reasonable prognosis. Lumbar puncture for temporary relief only if no mass lesion.
• Neuropathic pain: gabapentin 300 mg orally at night on day 1, 300 mg twice daily on day 2 and 300 mg three times daily on day 3.
• Then titrate every 3 to 7 days to 900 to 1800 mg daily in 3 divided doses; maximum 3600 mg daily.
• Monitoring: sedation, dizziness, oedema, mood, falls, respiratory depression with opioids.
• Adjustment: creatinine clearance 30 to 59 mL/min 400 to 1400 mg daily in 2 divided doses, 15 to 29 mL/min 200 to 700 mg once daily, under 15 mL/min 100 to 300 mg once daily, taper over at least 1 week when stopping.

Radiotherapy. Involved field radiotherapy to bulky disease, symptomatic sites and areas of CSF flow block (about 30 Gy in 10 fractions). Craniospinal proton radiotherapy is used in selected patients with a good performance status.

Intrathecal chemotherapy. For tumours without effective systemic options, with normal CSF flow.

Methotrexate 12 mg (preservative free) intrathecally by lumbar puncture or through an intraventricular reservoir twice weekly for 4 weeks, then once weekly for 4 weeks, then once monthly. Give leucovorin 10 mg orally every 6 hours for 8 doses starting 24 hours after each dose. Maximum 15 mg in one dose.

Monitoring: FBC, creatinine, CSF cytology and symptoms, chemical arachnoiditis, leukoencephalopathy, reservoir function and infection.

Adjustment:

• reduce the dose or stop for grade 3 neurotoxicity
• give involved field radiotherapy first when CSF flow is blocked (hydrocephalus or bulky disease)
• avoid with concurrent high dose systemic methotrexate or when creatinine clearance is under 30 mL/min

Systemic therapy by tumour type.

• EGFR-mutant lung cancer: osimertinib 80 mg orally once daily (160 mg once daily is used in leptomeningeal disease at specialist centres) until progression or unacceptable toxicity, for EGFR mutation positive lung cancer; maximum 160 mg daily.
• Monitoring: QTc and electrolytes, left ventricular ejection fraction at baseline and when symptomatic, FBC, creatinine, symptoms of interstitial lung disease, skin and nail toxicity.
• 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.
• Trastuzumab deruxtecan (HER2-positive breast cancer): 5.4 mg/kg IV every 3 weeks until progression; maximum 5.4 mg/kg each dose.
• Monitoring: antiemetics for high emetogenic risk, FBC, LVEF every 12 weeks, symptoms and imaging for interstitial lung disease.
• 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.
• Melanoma: 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.
• Monitoring: thyroid function, liver tests, creatinine, glucose and morning cortisol before each dose, symptoms of colitis, pneumonitis and hypophysitis.
• 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.

Monitoring. Neurological examination at each visit, MRI of the brain and spine every 2 to 3 months, and CSF cytology or tumour DNA after each induction course.

Referral and escalation.

• Referral to a neuro oncology team on suspicion.
• Emergency assessment for raised intracranial pressure, seizures or cauda equina syndrome.

Special groups.

• Poor performance status: best supportive care, with palliative care input.
• Driver mutant tumours: continue targeted therapy and consider dose escalation (osimertinib) in specialist centres.
• Pregnancy: individualised planning with neuro oncology and obstetrics.