Primary Central Nervous System Lymphoma: Treatment with High-Dose Methotrexate

Methotrexate at doses ≥1 g/m2remains the most efficient anticancer drug against primary central nervous system lymphoma, and is the most widely used drug in prospective cli­nical trials. Methotrexate is a folate analogue that inhibits dihydrofolate reductase, thereby blocking de novo purine synthesis. After intracellular uptake by the reduced folate carrier and the folate receptor-α, methotrexate undergoes intracellular polyglutamation by folypolyglutamate synthase on the γ-position of the parent glutamate moiety, resulting in the active polyglutamate moieties. Methotrexate as well as 7-hydroxy-methotrexate, its main metabolite in serum, are both eliminated by the kidneys. Accordingly, the elimination of methotrexate is prolonged in patients with renal impairment or third space fluid collections, due to a slow redistribution of methotrexate from this extravascular compartment. Main unwanted adverse events with high-dose methotrexate include severe myelosuppression, renal dysfunction and mucositis with diarrhea or stomatitis. Therefore, supportive measures such as rigorous hydration, urine alkalinization and careful drug monitoring with supplemental leucovorin rescue are used to avoid significant drug-related adverse events. A recent randomized clinical study has established a new treatment standard by showing an improved clinical outcome with the addition of high-dose cytarabine 2 g/m2twice daily on days 2 and 3 to high-dose methotrexate 3.5 g/m2on day 1, repeated every 3 weeks, and followed by consolidating radiotherapy if necessary.