Area under the curve of methotrexate and creatinine clearance are outcome-determining factors in primary CNS lymphomas

• Published in: British journal of cancer 2004-01, Vol.90 (2), p.353-358
• Main Authors: Ferreri, A J M, Guerra, E, Regazzi, M, Pasini, F, Ambrosetti, A, Pivnik, A, Gubkin, A, Calderoni, A, Spina, M, Brandes, A, Ferrarese, F, Rognone, A, Govi, S, Dell'Oro, S, Locatelli, M, Villa, E, Reni, M
• Format: Article
• Language: English
• Subjects: Adult; Age Factors; Aged; Anticonvulsants - therapeutic use; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - pharmacokinetics; Area Under Curve; Biomedical and Life Sciences; Biomedicine; Cancer Research; Central Nervous System Neoplasms - drug therapy; Central Nervous System Neoplasms - pathology; Clinical; Creatinine - metabolism; Dose-Response Relationship, Drug; Drug Resistance; Epidemiology; Female; Humans; Infusions, Intravenous; Lymphoma - drug therapy; Lymphoma - pathology; Male; Methotrexate - administration & dosage; Methotrexate - pharmacokinetics; Middle Aged; Molecular Medicine; Oncology; Retrospective Studies
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6601472

Although high-dose methotrexate (HD-MTX) is the most effective drug against primary CNS lymphomas (PCNSL), outcome-determining variables related to its administration schedule have not been defined. The impact on toxicity and outcome of the area under the curve (AUC MTX ), dose intensity (DI MTX ) and infusion rate (IR MTX ) of MTX and plasmatic creatinine clearance (CL crea ) was investigated in a retrospective series of 45 PCNSL patients treated with three different HD-MTX-based combinations. Anticonvulsants were administered in 31 pts (69%). Age >60 years, anticonvulsant therapy, slow IR MTX (⩽800 mgm −2 h −1 ), and reduced DI MTX (⩽1000 mgm −2 wk −1 ) were significantly correlated with low AUC MTX values. Seven patients (16%) experienced severe toxicity, which was independently associated with slow CL crea . A total of 18 (40%) patients achieved complete remission after chemotherapy, which was independently associated with slow CL crea . In all, 22 patients were alive at a median follow-up of 31 months, with a 3-year OS of 40±9%; slow CL crea and AUC MTX >1100  μ mol hl −1 were independently associated with a better survival. Slow CL crea and high AUC MTX are favourable outcome-determining factors in PCNSL, while slow CL crea is significantly related to higher toxicity. AUC MTX significantly correlates with age, anticonvulsant therapy, IR MTX , and DI MTX . These findings, which seem to support the choice of an MTX dose ⩾3 gm −2 in a 4–6-h infusion, every 3–4 weeks, deserve to be assessed prospectively in future trials. MTX dose adjustments in patients with fast CL crea should be investigated.