What is the recommended treatment for an adult patient with a history of cancer presenting with leptomeningeal metastases?

Treatment of Leptomeningeal Metastases

For adult patients with leptomeningeal metastases from solid tumors, treatment should prioritize systemic therapy with CNS-penetrating agents as the foundation, complemented by focal radiotherapy for symptomatic lesions, and intrathecal chemotherapy reserved for selected patients with thin linear deposits and unobstructed CSF flow. 1

Initial Treatment Framework

The therapeutic approach depends critically on three factors: performance status (KPS ≥70 versus <70), presence of brain parenchymal metastases, and status of extracranial disease. 2

Systemic Therapy (First-Line for All Appropriate Candidates)

Systemic therapy with CNS bioactivity forms the fundamental pillar of treatment and should be prioritized in all patients with reasonable performance status. 1 The specific agent depends on primary tumor molecular characteristics:

• HER2-positive breast cancer: Trastuzumab deruxtecan or tucatinib-based combinations 1
• EGFR-mutated lung cancer: Third-generation TKIs (osimertinib or almonertinib) 1
• BRAF-mutated melanoma: BRAF/MEK inhibitors with CNS penetration 1

This approach addresses both leptomeningeal disease and prevents reseeding after local therapies. 1

Intrathecal Chemotherapy (Selected Patients Only)

Intrathecal chemotherapy is most effective in patients with thin linear leptomeningeal deposits, floating tumor cells in CSF, and unobstructed CSF flow. 2, 1

Dosing Protocol for Methotrexate (Preservative-Free)

The dosing should be age-based rather than body surface area-based to avoid neurotoxicity in adults and underdosing in children: 3

• Age <1 year: 6 mg
• Age 1 year: 8 mg
• Age 2 years: 10 mg
• Age ≥3 years: 12 mg
• Adults: 15 mg (maximum dose)

Intensive regimen: Twice weekly for 4 weeks (8 doses), then weekly for 4 weeks (4 doses), then monthly until progression. 1, 3, 4

Route of Administration

Ventricular administration via Ommaya reservoir is strongly preferred over lumbar route when feasible, as it is associated with better survival and more uniform CSF distribution. 1 Lumbar administration may be used initially for diagnosis but should transition to Ommaya if continuing therapy. 5

Radiation Therapy

For symptomatic leptomeningeal metastases, whole-brain radiotherapy (WBRT) with memantine may be recommended. 2 The updated 2022 ASCO guidelines specifically recommend WBRT plus memantine for symptomatic brain leptomeningeal metastases. 2

Focal radiotherapy is recommended for circumscribed symptomatic lesions (cranial neuropathies, spinal cord compression, nodular disease). 2, 1 Standard palliative dose: 30-36 Gy in 10-12 fractions. 1, 6 Radiation provides faster symptom relief than chemotherapy. 1

Treatment Algorithm by Clinical Scenario

Favorable Prognosis (KPS >70, Controlled Extracranial Disease)

Type IA (Floating cells, no nodular disease, no active brain metastases, stable extracranial disease):

• Intrathecal therapy + modification of systemic therapy 2
• WBRT optional 2

Type IB (Nodular disease only, no active brain metastases):

• Intrathecal therapy + modification of systemic therapy 2
• Focal radiotherapy to nodular sites 2

Type IC (Linear + nodular disease):

• Intrathecal therapy + modification of systemic therapy 2
• Focal radiotherapy + WBRT (optional) 2

Poor Prognosis (KPS <70 or Life Expectancy <1 Month)

Best supportive care and palliative measures should be prioritized over disease-directed therapy. 2, 6 WBRT may be offered only if symptomatic benefit clearly outweighs treatment toxicities (fatigue, neurocognitive decline). 2, 6

Critical Pitfalls to Avoid

Do not administer intrathecal chemotherapy in the presence of CSF flow obstruction without prior radiotherapy to restore flow—this causes severe neurotoxicity and treatment failure. 1, 6

Do not combine craniospinal radiation with intrathecal or systemic methotrexate due to markedly increased risk of leukoencephalopathy. 1, 6

Do not use preserved formulations of methotrexate for intrathecal administration—only preservative-free formulations are safe, as benzyl alcohol causes severe neurotoxicity. 3

Avoid intrathecal therapy in patients with symptomatic hydrocephalus requiring ventriculoperitoneal shunt or ventricular devices without on/off valves, as this risks systemic dissemination of chemotherapy and peritoneal carcinomatosis. 1, 6

Do not rely on single negative CSF cytology—sensitivity is only 50-60% on first lumbar puncture; perform second LP with optimal collection (≥5-10 mL) if clinical suspicion remains high. 1

Avoid aggressive multimodality therapy in patients with brain parenchymal metastases, as this confers significantly worse prognosis (6-month OS 25% versus 50% without parenchymal disease). 7

Expected Outcomes

Without treatment, median survival is 6-8 weeks; with directed treatment, survival extends to 2-6 months overall, with breast cancer patients achieving 6-7 months in some series. 1, 6 Symptomatic improvement occurs in 70% of patients receiving intrathecal therapy. 7 Complete cytological clearance is achieved in 24-33% of patients. 8, 4

Important prognostic factors include: functional status at diagnosis, primary tumor type, absence of brain parenchymal metastases, CSF protein levels, and administration of combined modality treatment. 1, 7