Rational administration schedule for high-dose methotrexate in patients with primary central nervous system lymphoma

Abstract

Methotrexate (MTX) at a dose of ≥1 g/m(2) remains the most efficient treatment against primary central nervous system lymphoma (PCNSL), and is the most widely used drug in prospective clinical trials. MTX is a folate analog that inhibits dihydrofolate reductase, thereby blocking de novo purine synthesis. MTX as well as 7-hydroxy-MTX, its main metabolite in serum, are both eliminated by the kidneys. The elimination of MTX is prolonged in patients with renal impairment and third-space fluid collections, and in patients receiving concurrent non-steroidal antirheumatic drugs, benzimidazoles and sulfonamides, among others. Main adverse events with high-dose MTX include severe myelosuppression, renal dysfunction and stomatitis. Supportive measures such as rigorous hydration, urine alkalinization and careful drug monitoring with supplemental leucovorin rescue are crucial to avoid significant toxicity. Strategies to optimize clinical efficacy of high-dose MTX in patients with PCNSL include administration of 3 h instead of longer infusions, potentially supplemented with an additional intravenous MTX bolus, and maintaining MTX dose intensity over the course of four treatment cycles. Some pharmacological studies suggest that achieving an MTX area under the plasma concentration-time curve (AUC(MTX)) of between 1000 and 1100 μmol.h/L may improve clinical outcome, but clinical data are not conclusive at present. In this review, we analyze the impact of patient, lymphoma and pharmacokinetic variables on the antitumor activity of high-dose MTX in patients with PCNSL, summarize recommendations for daily clinical practice and give some suggestions for future trials.

Primary CNS Lymphoma

“…There is general consensus that MTX should be administered as a rapid infusion (2–4 hours) at a dose of at least 3 mg/m 2 to maximise therapeutic CSF concentrations, at an interval of 14–21 days [34]. Higher absolute MTX exposure (area under the plasma concentration-time curve, AUC MTX , >980–1,100 μmol · h/l) correlated with superior outcomes in two post-hoc and retrospective studies [35, 36], but these findings have not been reproduced in all studies [37].…”

High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis

“…High-dose methotrexate (HDMTX) regimens, defined by MTX doses ≥ 1g/m2, and subsequent use of leucovorin to reduce toxicity, are used to treat a wide range of malignancies including lymphoma, breast carcinoma, sarcoma, and others [1-3]. Despite its broad application, the use of HDMTX is complicated by the risk of renal toxicity [4].…”

High-Dose Methotrexate and Cytarabine-Based Multi-Agent Chemotherapy (Modified Bonn Protocol) for Systemic Lymphoma with CNS Involvement

“…Based on the results of pharmacological and clinical studies, high-dose MTX for the treatment of CNS lymphoma is recommended, as a dose of at least 3 g/m 2 , over no longer than 3 h [15]. In this study, the dose of MTX was scheduled to be reduced from 5 to 3 g/m 2 , and it was further reduced in approximately 40% of patients due to advanced age, renal/hepatic dysfunction, or poor PS.…”