What is the recommended treatment approach for intracranial lymphoma?

Treatment for Intracranial Lymphoma

The standard treatment for primary CNS lymphoma is high-dose methotrexate-based chemotherapy (at least 3 g/m²), with the MATRix regimen (methotrexate, cytarabine, thiotepa, and rituximab) showing superior outcomes and representing the current gold standard for eligible patients, followed by consolidation therapy with either autologous stem cell transplantation or whole-brain radiotherapy. 1, 2

Initial Diagnostic Approach

Critical caveat: If lymphoma is suspected, corticosteroid therapy should be avoided prior to obtaining histological confirmation, except for patients whose neurological status requires this therapy. 3 This is essential because corticosteroids can cause lymphoma cells to rapidly disappear, making histological diagnosis impossible and potentially delaying definitive treatment.

• Stereotactic or open skull biopsy should be performed to obtain histological confirmation, as neuroimaging alone is not sufficiently specific 3, 1
• Patients should be managed by a multidisciplinary team at specialized centers with experience in primary CNS lymphoma 1

First-Line Treatment Strategy

For Eligible Patients (Age ≤70 years, Good Performance Status)

The MATRix regimen has demonstrated the best outcomes with a complete remission rate of 49% and 7-year overall survival of 56%. 1, 2

The MATRix regimen consists of:

• Methotrexate 3.5 g/m² on day 1
• Cytarabine 2 g/m² twice daily on days 2 and 3
• Thiotepa 30 mg/m² on day 4
• Rituximab 375 mg/m² on days -5 and 0
• Repeated every 3 weeks for 4 courses 2

This regimen significantly outperformed methotrexate-cytarabine alone (complete remission 23%) and methotrexate-cytarabine plus rituximab (complete remission 30%). 2

Alternative Regimens

For patients who cannot tolerate MATRix, high-dose methotrexate (at least 3 g/m²) remains the cornerstone of treatment and should be administered over 2-4 hours 1. Alternative combinations include:

• Methotrexate, rituximab, and temozolomide followed by hyperfractionated whole-brain radiotherapy achieved 2-year overall survival of 80.8% and progression-free survival of 63.6% 4
• High-dose methotrexate and rituximab with deferred radiotherapy showed 70% complete response rate with median progression-free survival of 21 months 5

Consolidation Therapy

After successful induction chemotherapy, consolidation therapy is essential to improve long-term outcomes, with two main strategies showing similar efficacy: high-dose chemotherapy with autologous stem cell transplantation or whole-brain radiotherapy. 1

• Both approaches achieve 7-year overall survival of approximately 70% after MATRix induction 1
• Autologous stem cell transplantation is preferred in younger patients to minimize neurotoxicity risk 1
• Whole-brain radiotherapy can be used but carries increased neurotoxicity risk, particularly in patients >60 years 1

Sequential Approach Alternative

High-dose methotrexate (5 cycles of 3 g/m² every 2 weeks) followed by consolidation whole-brain radiotherapy and cytarabine (2 cycles of 3 g/m²/day for 2 days every 3 weeks) demonstrated:

• Overall response rate of 85.4%
• Complete response rate of 60.9%
• Median progression-free survival of 35.2 months
• Low toxicity profile with only 4.8% grade ≥3 hematologic toxicity 6

Management of Relapsed/Refractory Disease

Patients with relapsed/refractory primary CNS lymphoma should be enrolled in clinical trials when possible. 1

For fit patients with relapsed disease:

• High-dose ifosfamide or high-dose cytarabine-based regimens followed by autologous stem cell transplantation 1
• Alternatively, whole-brain radiotherapy if not previously administered 1
• Treatment approach depends on timing of relapse and patient fitness 1

Supportive Care Management

Cerebral Edema Management

• Patients with clinical or radiological evidence of brain edema should be treated with corticosteroids 3, 7
• Methylprednisolone or prednisolone should be prescribed as single daily doses in the morning 3, 7
• The minimal effective dose should be determined and regularly re-evaluated 3, 7

Gastrointestinal Prophylaxis

• H2-receptor blockers or proton pump inhibitors should be used to prevent gastrointestinal complications in patients receiving high doses of corticosteroids and/or those with risk factors for ulcers 3

Seizure Management

• Peri-operative anticonvulsant treatment should be prescribed routinely for patients who have had seizures 3
• In patients without prior seizures, peri-operative anticonvulsant treatment is optional 3
• First-line treatment should be single-drug therapy, considering any inducing or potentiating effects on chemotherapy toxicity 3

Monitoring and Response Assessment

• Response assessment should follow International PCNSL Collaborative Group criteria with MRI every two cycles during induction and 2 months after consolidation 1
• Clinical and imaging follow-up every 2-3 months is recommended 7
• MRI is preferable to CT scanning for follow-up 7

Common Pitfalls and Toxicity Considerations

Grade 4 hematological toxicity is more frequent with the MATRix regimen, but infective complications remain similar across treatment groups. 2 The most common grade 3-4 adverse events include neutropenia, thrombocytopenia, anemia, and febrile neutropenia or infections 2.

Neurotoxicity risk increases significantly with combined chemoradiotherapy, particularly in patients >60 years, making autologous stem cell transplantation the preferred consolidation approach in this population. 1

Treatment-related mortality occurs in approximately 6% of patients receiving intensive chemotherapy regimens 2.