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

Abstract

Although high-dose methotrexate (HD-MTX) is the most effective drug against primary CNS lymphomas (PCNSL), outcomedetermining 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 460 years, anticonvulsant therapy, slow IR MTX (p800 mg m À2 h À1 ), and reduced DI MTX (p1000 mg m À2 wk À1 ) 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 4079%; slow CL crea and AUC MTX 41100 mmol h l À1 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 X3 g m À2 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. (Reni et al, 1997;Ferreri et al, 2002b). Any chemotherapy regimen without HD-MTX is associated with outcomes no better than those obtained with radiotherapy (RT) alone in these malignancies (Schultz et al, 1996;O'Neill et al, 1999;Mead et al, 2000), while the survival benefit of the addition of other drugs to HD-MTX remains a matter of debate (Reni et al, 2001;Ferreri et al, 2002b). In spite of its central role in PCNSL treatment, the optimal dose, administration schedule, and dose timing of MTX have not been clearly defined. Moreover, contrary to what is observed in other malignancies in which MTX plays a crucial role, such as acute leukaemia (Evans et al, 1986) and osteosarcoma (Graf et al, 1994;Delepine et al, 1995;Bacci et al, 1998), where a significant association between MTX parameters and outcome has been reported, the impact on toxicity and outcome of MTX administration schedule has not been investigated in PCNSL.The analysis of some MTX parameters, such as the area under the curve (AUC MTX ), dose, dose intensity (DI MTX ), and infusion rate (IR MTX ), as well as the plasmatic creatinine clearance (CL crea ) could allow us to identify subgroups of patients with increased risk of severe toxicity or disappointing outcome, as well as to define the optimal MTX administration schedule against PCNSL. This paper reports the analysis of the impact on toxicity and outcome of the above-mentioned variables in a retro...

High-dose methotrexate in patients with primary central nervous system lymphoma: does drug exposure really matter?

“…More recently, Blasco and colleagues showed that patients with PCNSL who were early non-responders to chemotherapy (n ¼ 12) had a poorer progression-free survival and OS compared to patients who received three cycles of MBVP (HDMTX, methylprednisolone, etoposide, BCNU) combined with radiotherapy as planned (n ¼ 25) [1]. The mean AUC-MTX in the latter study was 1076 mmol*h/L per 3-week cycle, higher than that found in previous studies (731 mmol*h/L [2] and 931 mmol*h/ L [3]). Although these patients had a fairly good drug exposure on average, some of them were nonresponders, suggesting an unfavorable tumor biology in the latter.…”

“…Methotrexate at doses of roughly 3 g/m 2 (high-dose methotrexate; HDMTX) is the most active and widely used drug against PCNSL. HDMTX is also the single anticancer drug in adult oncology whereby therapeutic drug monitoring (TDM) is routinely performed, primarily to guide leucovorin rescue.…”

“…The availability of MTX plasma concentrations has triggered some research to understand the relationship between MTX drug intensity (area under the curve [AUC]-MTX) and clinical outcome [1][2][3][4]. In 2004, Ferreri and colleagues found AUC-MTX 41100 mmol *h/L to be independently associated with an improved overall survival (OS) in 45 patients with PCNSL receiving three different HDMTX-based combination regimens [2]. Similar results were found in a subanalysis of the International Extranodal Lymphoma Study Group (IELSG) study no.…”

Treatment of Primary CNS Lymphoma

“…Doses less than 3 g/m 2 are probably too low to reach sufficient concentrations in the CSF to kill lymphoma cells [28,29]. A dose of 8 g/m 2 MTX was frequently associated with the need for a dose reduction during the course of the treatment, mostly due to renal toxicity [30,31].…”

Primary central nervous system lymphoma: what a neurologist/neurosurgeon should know?

“…MTX inhibits dyhidrofolate reductase, an enzyme that participates in the tetrahydrofolate synthesis. Drug levels over 1 g/m 2 safely penetrates the brain parenchyma, and levels over 3 g/m 2 lead to adequate concentration in the CSF [17][18][19] . For this reason, it has been proposed that in patients receiving 3 g/m 2 or more, intrathecal chemotherapy could be used more cautiously 20 .…”