Rational administration schedule for high-dose methotrexate in patients with primary central nervous system lymphoma
Markus Joerger, A D R Huitema, G Illerhaus & A J M Ferreri
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abstract
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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.
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citation
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Joerger M, Huitema A D R, Illerhaus G, Ferreri A J M. Rational
administration schedule for high-dose methotrexate in patients with
primary central nervous system lymphoma. Leuk Lymphoma 2012;
53:1867-75.
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type
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journal paper/review (English)
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date of publishing
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21-05-2012
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journal title
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Leuk Lymphoma (53/10)
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ISSN electronic
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1029-2403
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pages
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1867-75
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PubMed
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22530664
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DOI
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10.3109/10428194.2012.676177
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