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 (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 mg m ^-2h^-1), and reduced DI_MTX (≤ 1000 mg m ^-2wk^-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 μmol h l^-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 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 CL_crea should be investigated.