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

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 (Dl(MTX)) and infusion rate (IRMTX) of MTX and plasmatic creatinine clearance (CLcrea) 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 lR(MTX) (less than or equal to 800 mg m(-2) h(-1)), and reduced DIMTX (less than or equal to1000 mg m(-2) wk(-1)) were significantly correlated with low AUC(MTX) values. Seven patients (16%) experienced severe toxicity, which was independently associated with slow CLcrea. A total of 18 (40%) patients achieved complete remission after chemotherapy, which was independently associated with slow CLcrea. In all, 22 patients were alive at a median follow-up of 31 months, with a 3-year OS of 40 +/- 9%; slow CLcrea and AUC(MTX) > 1100 mumol h l(-1) were independently associated with a better survival. Slow CLcrea and high AUC(MTX) are favourable outcome-determining factors in PCNSL, while slow CLcrea is significantly related to higher toxicity. AUC(MTX) significantly correlates with age, anticonvulsant therapy, IRMTX, and DIMTX. These findings, which seem to support the choice of an MTX dose greater than or equal to 3 g m(-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 CLcrea should be investigated.