ABSTRACT 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 (AUCMTX), dose intensity (DIMTX) 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 IRMTX (⩽800 mgm−2h−1), and reduced DIMTX (⩽1000 mgm−2wk−1) were significantly correlated with low AUCMTX values. Seven patients (16%) experienced severe

survival. Slow CLcrea and high AUCMTX are favourable outcome-determining factors in PCNSL, while slow CLcrea is significantly related to higher toxicity. AUCMTX significantly correlates with

age, anticonvulsant therapy, IRMTX, and DIMTX. 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 CLcrea should be investigated. MAIN High-dose methotrexate (HD-MTX) is the most effective drug against primary

central nervous system lymphomas (PCNSL) (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 (AUCMTX), dose, dose intensity (DIMTX), and infusion rate (IRMTX), as well

as the plasmatic creatinine clearance (CLcrea) 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 retrospective multicentre

series of 45 immunocompetent patients with PCNSL treated with HD-MTX-based primary chemotherapy. PATIENTS AND METHODS STUDY POPULATION A questionnaire requesting epidemiological, clinical,

histopathological, therapeutic, and survival data of immunocompetent patients with PCNSL treated with primary chemotherapy containing HD-MTX (⩾1 gm−2), followed or not followed by RT, was

sent to the seven participating centres. In particular, the questionnaire included body weight and body surface area, creatinine clearance, theoretical and really administrated dose of MTX,

duration of infusion, timing dose, and MTX serum levels at 0, 24, 48, and 72 h. The use of anticonvulsants, type and dose, was also analysed considering the capacity of some of these drugs

to interfere with MTX metabolism (Jacobs et al, 1976). This study conformed to the tenets of the Declaration of Helsinki and all the patients accessioned provided signed informed consent to

the treatment. This consent extended to the use of biological, histopathological, radiological, biochemical, and clinical data for scientific purposes. MTX VARIABLES CLcrea value, determined

before the start of chemotherapy, was obtained by the formula of Cockcroft and Gault (1976): CLcrea value in females was considered as 85% of the value for males. The MTX variables

investigated were AUCMTX, dose, DIMTX, and IRMTX. The individual AUCMTX (_μ_mol hl−1) related to the first course of chemotherapy was determined according to a one-compartment model by using

the statistical population pharmacokinetic program P-PHARM-Version 3 (InnaPhase, 77420 Champs-sur-Marne, France), considering MTX dosage and serum levels at 0, 24, 48, and 72 h after drug

infusion for calculation. DIMTX, expressed as mgm−2wk−1, was calculated by the Hryniuk method (Hryniuk and Goodyear, 1990). This was a ratio between the total dose of MTX administered

(mgm−2) and the treatment duration expressed in days divided by 7. Treatment duration was calculated from the first day of the first course to the 22nd or 29th day of the last course

(respectively for regimens administered every 3 or 4 weeks) (Hryniuk and Goodyear, 1990). The IRMTX, expressed as mgm−2h−1, was defined as the MTX dose (mgm−2) administered per hour during

the first chemotherapy course. STATISTICAL CONSIDERATIONS Correlations between AUCMTX and the other variables were analysed by the Spearman test. The impact of studied variables on severe

toxicity and complete response rate was analysed by logistic regression. Severe toxicity was defined by the onset of one of two major events: toxic death or interruption of chemotherapy due

to toxicity. Complete response was defined as the disappearance of all evidence of lymphoma. CLcrea, AUCMTX, DIMTX, and IRMTX were firstly analysed as continuous variables; then, quartiles

values were applied as cutoff to differentiate the risk groups (categorical variables): lower quartile for CLcrea (85 ml min−1) and upper quartile for DIMTX (1000 mg m−2 wk−1), for AUCMTX

(1100 _μ_mol h l−1), and for IRMTX (800 mg m−2 h−1). Survival curves were generated by the Kaplan–Meier method. The overall survival (OS) was calculated from diagnosis to the date of death

or the last date of follow-up. Impact on survival of clinical and therapeutic variables was evaluated through the log-rank test. The independent prognostic value of variables was analysed

using Cox proportional hazard model. All the probability values were two-sided. All the analyses were carried out using the Statistica 4.0 statistical package for Windows (Statsoft Inc,

1993, Tulsa, OK 74104, USA). RESULTS STUDY GROUP The study group consisted of 45 patients treated between 1995 and 2001 (Calderoni and Aebi 2002; Pasini et al. 2002; Ferreri et al. 2002a).

Patients’ characteristics and extent of disease at diagnosis are summarised in Table 1. Chemotherapy regimens and MTX administration schedules are reported in Table 2. All patients were

treated with adequate pre-MTX hydration, urinary alkalinisation, and escalated leucovorin dosages according to MTX serum levels. Dehydration, aciduria, renal or cardiac dysfunction, pleural

effusion, or gastrointestinal tract obstruction were excluded before commencing treatment in all cases. Post-chemotherapy RT, which consisted of whole-brain irradiation, followed or not

followed by a tumour-bed boost, was planned in all cases, but it was in fact performed as part of the first-line therapy in 31 patients, with median brain and tumour-bed doses of 36±5 and

42±9 Gy, and as part of salvage therapy in six cases. Anticonvulsants were administered in 31 patients (69%), and consisted of phenobarbital (100–150 mg d−1) in 27 cases, hydantoin (100–300 

mg d−1) in two cases and carbamazepine (400–800 mg d−1) in two cases. MTX PARAMETERS The mean value±s.d. of CLcrea was 119±57 ml min−1. The mean value±s.d. of AUCMTX was 731±525 _μ_mol h 

l−1. Patients ⩽60 years old displayed a faster CLcrea (mean±s.d.: 118±38 _vs_ 94±28 ml min−1; _P_=0.01), and a higher AUCMTX (846±562 _vs_ 502±359 _μ_mol h l−1; _P_=0.02) with respect to

patients >60. According to the PS, patients with an ECOG score of 3–4 displayed a similar CLcrea (100±28 _vs_ 112±35 ml min−1; _P_=0.17) and a similar AUCMTX (1397±1208 _vs_ 1238±836 

_μ_mol h l−1; _P_=0.53) with respect to patients with a PS of 0–2. The mean value±s.d. of DIMTX was 992±1140 mg m−2 week−1. Seven patients (16%) received only one course of chemotherapy

(severe toxicity in five, no response in two), 16 (36%) received two, 14 (31%) received three, and eight (18%) received more than three courses. No difference in the used MTX dose according

to age or PS was observed; the proportion of patients ⩽60 years old and >60 treated with a dose >3 g m−2 was similar (47 _vs_ 47%, _P_=0.99); 53% of patients with PS 0–2 and 31% of

patients with PS 3–4 received an MTX dose >3 gm−2 (_P_=0.19). No cases of reduction of more than 25% of the MTX dose in further courses with respect to the planned dose were observed. The

MTX dose of the further courses was increased by more than 25% with respect to the MTX dose of the first course in three (7%) cases. The mean value±s.d. of IRMTX during the first

chemotherapy course was 475±423 mg m−2 h. This parameter remained unmodified during further courses in all cases. AUCMTX-DETERMINING VARIABLES Variables significantly correlated with the

AUCMTX are reported in Table 3. Anticonvulsant use and age correlated inversely with AUCMTX, while a direct correlation between AUCMTX and IRMTX and DIMTX was observed. No correlation with

sex, performance status (PS), and CLcrea was observed. Patients treated with MATILde chemotherapy regimen achieved significantly higher AUCMTX values. SEVERE TOXICITY The predictive value of

MTX variables on severe toxicity was analysed considering toxic death (_n_=2) and interruption of chemotherapy due to toxicity (_n_=5) as events. Severe toxicity consisted of pulmonary

thromboembolism in two cases (lethal in both), sepsis in two, acute renal failure in one, and persistent grade IV thrombocytopenia in two. These events were observed during the first two

courses of chemotherapy. As reported in Table 4, CLcrea was independently associated with severe toxicity; a significantly higher toxicity rate was observed in patients with a CLcrea ⩽85 ml 

min−1. Importantly, a DIMTX >1000 mg m−2/week, and an AUCMTX >1100 _μ_mol h l−1 were not related to a higher toxicity. OBJECTIVE RESPONSE After primary chemotherapy, 18 patients (40%)

achieved a complete remission and 16 (36%) a partial response (overall response rate= 76%); four patients (9%) had stable disease, five (11%) experienced progressive disease, and two (4%)

died of toxicity. As reported in Table 4, a slow CLcrea (⩽85 ml min−1) was significantly and independently associated with a higher complete remission rate. OVERALL SURVIVAL A total of 26

patients experienced failure: early progression of the disease in nine cases, relapse after initial response (complete and partial) in 15 and toxic death in two cases, with a 2-year

failure-free survival of 50±8%. In all, 22 patients are alive (19 NED) at a median follow-up of 31 months (range 4–72 months), with a 3-year OS of 40±9%. The cause of death was lymphoma in

20 cases, acute toxicity in two, and unrelated disorder in one. Univariate analyses showed that patients with a slow CLcrea (⩽85 ml min−1) survived longer than patients with a fast CLcrea

(>85 ml min−1), with 3-year OS values of 88±13 and 25±9% (_P_=0.0005), respectively (Figure 1). Patients treated with an AUCMTX >1100 _μ_mol h l−1 survived significantly longer than

patients treated with lower levels (3-year OS: 78±12 _vs_ 32±9%; _P_=0.05) (Figure 2). The use of anticonvulsants and IRMTX was not associated with survival, and no significant difference in

the efficacy of the used chemotherapy regimens was observed. Multivariate analysis (Table 5) confirmed the independent prognostic value of CLcrea and AUCMTX. DISCUSSION The present study

focused on the impact on toxicity and outcomes of CLcrea, AUCMTX, DIMTX, and IRMTX in a multicentre retrospective series of 45 immunocompetent patients with PCNSL. This series is

representative of PCNSL patients currently treated with HD-MTX-based chemotherapy, since it displays similar median age, PS distribution, histotypes, and ocular and meningeal infiltration

rates with respect to more comprehensive unselected retrospective series (Ferreri et al, 2002b), and to the largest published prospective trials (O’Brien et al, 2000; Deangelis et al, 2002).

A clear relationship between the studied variables and therapeutic outcome is difficult to establish, considering the multitude of other factors, such as protein binding, membrane

transport, dihydrofolate reductase levels, tissue distribution, or concurrent drugs, which may also influence the efficacy of MTX. Nevertheless, as has been reported for other malignancies

(Evans et al, 1986; Graf et al, 1994; Delepine et al, 1995; Bacci et al, 1998), the characterisation of the MTX variables investigated could be useful to identify different risk groups and

to define the optimal administration schedule of this drug in PCNSL patients. HD-MTX is the most effective drug against PCNSL; any regimen without this drug is associated with outcomes which

are no better than with RT alone (Schultz et al, 1996; O’Neill et al, 1999; Mead et al, 2000). When used as primary treatment, alone or combined with other drugs, followed or not followed

by RT, HD-MTX produces a response rate of 70–80%, with a 2-year OS of 60–70% (Ferreri et al, 2000). The survival benefit of the addition of other drugs to HD-MTX is matter of debate,

considering that not only do randomised trials comparing mono-chemotherapy with HD-MTX and poly-chemotherapy not exist, but also that the activity of these drugs has not been assessed as a

single drug in prospective trials. Thus, HD-MTX remains a crucial drug against PCNSL, being an irreplaceable component of primary chemotherapy. Nevertheless, the prognostic role of the

AUCMTX and DIMTX as well as the optimal MTX dose, IR and dose timing of this drug have not been clearly defined in PCNSL. A single study comparing some MTX parameters in PCNSL patients

treated with blood–brain barrier disruption or with systemic chemotherapy has been reported (Zylber-Katz et al, 2000), but their impact on outcome has not been analysed. Conversely, the

prognostic role of MTX pharmacokinetics has been reported in other malignancies in which this drug plays a critical role, such as acute leukaemia (Evans et al, 1986) and osteosarcoma (Graf

et al, 1994; Delepine et al, 1995; Bacci et al, 1998). Patients with acute leukaemia have been grouped according to a slow, medium or fast CLMTX, obtaining an inverse association with

outcome (Evans et al, 1986). A significant correlation between a faster CLMTX and lower serum and cerebrospinal fluid (CSF) MTX concentrations has also been documented, suggesting an

insufficient treatment both of the brain and meninges, and a greater risk of CNS relapse in this subgroup of leukaemia patients (Evans et al, 1983). Likewise, a significant survival effect

of serum peak concentration of MTX has been reported in osteosarcoma (Graf et al, 1994). Our study suggests that CLcrea and AUCMTX are independent predictors of MTX efficacy in PCNSL

patients also. A CLcrea ⩽85 ml min−1 was associated with a higher complete remission rate and better survival, which was independent of age, PS, DIMTX, IRMTX, and other therapeutic

variables. Patients treated with an AUCMTX >1100 _μ_mol h l−1 showed a significantly better survival with respect to those treated with lower AUCMTX levels. CLMTX is defined based upon

CLcrea; decreased CLcrea represents decreased CLMTX, which for a given dose would produce an increased AUCMTX. However, in the present series, CLcrea and AUCMTX are two independent

variables, which is explained by the heterogeneity in MTX dose, DIMTX, and IRMTX, as well as by differences in the MTX metabolism, according to the drug infusion duration (see below). A

strongly inverse correlation between CLcrea and AUCMTX could be observed, for example, in a prospective trial, where the used MTX dose and schedule is the same for the entire series.

Considering that AUCMTX is significantly correlated, among others, with DIMTX, IRMTX, and anticonvulsant therapy, changes in these parameters could lead to significant changes in AUCMTX and

efficacy. Importantly, as reported in Table 4, a higher AUCMTX was not associated with a higher incidence of severe toxicity (9 _vs_ 17%, _P_=0.45). The single case of severe toxicity in the

group of patients treated with an AUCMTX >1100 _μ_mol h l−1 consisted of nonlethal persistent thrombocytopenia, without bleeding complications in a patient with a CLcrea of 186 ml min−1.

On the other hand, four of the five cases of severe renal and haematological toxicity were observed in patients with slow CLcrea. A close follow-up with haematologic profile and renal

function assessment appears advisable in this subgroup of patients. Pretreatment CLcrea assessment could also be useful to identify groups of PCNSL patients with different MTX efficacy, and

the use of higher doses in patients with a fast CLcrea should be critically considered. The choice of the MTX dose is a relevant issue in PCNSL, especially because of the high interpatient

and intrapatient variability of MTX pharmacokinetics. For example, in a recently published trial (Batchelor et al, 2003), the MTX dose (8 g m−2) was adjusted based on the pre-chemotherapy

CLcrea. The dose was reduced by the percentage decrease of this variable below 100 ml min−1. The schedule employed was well tolerated; however, a detailed analysis of the impact on activity

and toxicity of this strategy was not provided. Our data suggest that changes in MTX dose according to the pretreatment CLcrea could lead to more suitable AUCMTX levels, with a consequent

efficacy improvement. This interesting hypothesis will be studied in a prospective series treated with a homogeneous MTX schedule. DI is a debated outcome-conditioning factor in aggressive

systemic lymphomas, while its role has not been investigated in PCNSL patients treated with conventional strategies. In the present series, DIMTX was not associated with survival or

toxicity. However, the significant association between a DIMTX >1000 mg m−2 week−1 and higher AUCMTX levels seems to suggest that, when administered every 3–4 weeks, a MTX dose ⩾3000 mg 

m−2 could produce better results than lower doses. This also seems to be supported by the MSKCC and RTOG experience (Deangelis et al, 1992, 2002). In a previous trial (Deangelis et al,

1992), MTX administered at a dose of 1 g m−2 produced an overall response rate of 64% and a 5-year OS of 28%, while, in a recently reported trial (Deangelis et al, 2002), the use of a 3.5-g 

m−2 MTX dose produced an overall response rate of 90% and a 5-year OS of 50%. Analysed together, these data suggest that a higher amount of MTX administered in a single dose increases drug

exposure and activity. Moreover, as previously reported (Pitman and Frei, 1977; Evans et al, 1983), this strategy seems to lead to a higher diffusion of the drug across the blood–brain

barrier and increased drug concentrations in the CSF, with a potential positive impact on efficacy against PCNSL. From the present analysis, no significant association between IRMTX and

survival was observed. This could be due to the strong correlation observed between this parameter and AUCMTX. The identification of the best IRMTX in PCNSL needs further studies. In the

meantime, an IRMTX of >800 mg m−2 h−1 appears advisable, since it is associated with higher AUCMTX and does not display significantly higher toxicity in comparison to slower rates.

Anticonvulsants are commonly used in PCNSL patients presenting seizures. These drugs interact with hepatic aldehyde oxidase, which constitutes a major mechanism for MTX degradation (Jacobs

et al, 1976). Anticonvulsant therapy increases the systemic CLMTX, as well as the level of other cytostatics, and is associated with lower efficacy of chemotherapy in children treated for

acute lymphoblastic leukaemia (Relling et al, 2000). This effect seems to be more intense in patients treated with HD-MTX by a 24-h infusion, in whom about 40% of the drug is metabolised in

the liver, whereas, when HD-MTX is administered as a short intravenous infusion (4–6 h), most of the drug is cleared by the kidneys (Evans et al, 1983). In the present analysis, no

association between anticonvulsant use and toxicity and outcome was observed, and the impact of these drugs in patients treated with a 24-h infusion cannot be analysed, considering that all

these patients received anticonvulsant therapy. The hypothesis that MTX dose adjustments are needed when anticonvulsants are contemporarily used should be better explored. To identify new

active drugs and combinations remains the most important strategy to improve therapeutic results in PCNSL patients, and any effort to define the best administration schedule for HD-MTX

should be encouraged. With certain limitations due to their retrospective nature, our data seem to suggest that slow CLcrea and high AUCMTX are independently associated with better outcome

in PCNSL patients. Comprehensively, these interesting findings deserve to be assessed in prospective trials. In the meantime, a MTX dose ⩾3000 mg m−2 administered in a 4- or 6-h infusion,

every 3–4 weeks, appears an advisable schedule to adopt in clinical practice. The need to increase the MTX dose to ensure adequate exposure, such as higher AUCMTX values, in patients with a

fast CLcrea, should be critically considered. CHANGE HISTORY * _ 16 NOVEMBER 2011 This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as

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AFFILIATIONS * Department of Radiochemotherapy, San Raffaele H Scientific Institute, Via Olgettina 60, Milan, 20132, Italy A J M Ferreri, A Rognone, S Govi, S Dell'Oro, E Villa & M

Reni * Laboratorio di Standardizzazione per la Chimica Clinica, San Raffaele H Scientific Institute, Milan, Italy E Guerra & M Locatelli * Department of Pharmacology, I.R.C.C.S.

Policlinico San Matteo, University of Pavia, Italy M Regazzi * Divisione Clinicizzata di Oncologia Medica, Ospedale Civile Maggiore, Verona, Italy F Pasini * Divisione di Ematologia,

Policlinico G. B. Rossi, Verona, Italy A Ambrosetti * Hematology and Intensive Care Department, Hematological Center of Russian Academy of Medical Sciences, Moscow, Russia A Pivnik & A

Gubkin * Institut für Medizinische Onkologie Inselspital, Bern, Switzerland A Calderoni * Divisione di Oncologia Medica ‘A’, Centro di Riferimento Oncologico, Istituto Nazionale Tumori,

Aviano, Italy M Spina * Department of Medical Oncology, Azienda Ospedale-Università, Padova, Italy A Brandes * Divisione di Radioterapia, Ospedale Regionale di Treviso, Treviso, Italy F

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AUTHOR Correspondence to A J M Ferreri. RIGHTS AND PERMISSIONS From twelve months after its original publication, this work is licensed under the Creative Commons

Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/ Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Ferreri, A., Guerra, E., Regazzi, M. _et al._ Area under the curve of methotrexate and creatinine clearance are outcome-determining factors in primary CNS

lymphomas. _Br J Cancer_ 90, 353–358 (2004). https://doi.org/10.1038/sj.bjc.6601472 Download citation * Revised: 01 October 2003 * Accepted: 13 October 2003 * Published: 20 January 2004 *

Issue Date: 26 January 2004 * DOI: https://doi.org/10.1038/sj.bjc.6601472 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link

Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * primary central nervous

system lymphoma * methotrexate * plasmatic clearance * dose intensity * area under the curve * chemotherapy