Measurement of methotrexate in human cerebrospinal fluid using a chemiluminescence immunoassay intended for serum and plasma matrices.

BACKGROUND: The concentration of MTX in blood is often measured quickly and easily by immunoassays. Thus, immunoassays may facilitate the easy determination of the concentration of MTX in the cerebrospinal fluid (CSF). In this study, we measured methotrexate (MTX) concentrations in the CSF using a high-performance liquid chromatography (HPLC) method intended for analyzing CSF matrices and a chemiluminescence immunoassay (CLIA) method intended for assessing serum and plasma matrices and verified the differences in the results of the two methods. METHODS: HPLC analysis for MTX in the CSF was performed using a Prominence UFLC system with a C18 column. The HPLC method was validated in accordance with the 2018 FDA guideline. The CLIA method was performed using an ARCHITECT i1000SR system intended for serum and plasma matrices. A total of 47 CSF samples (14 clinical and 33 spiked specimens) were analyzed using the two methods. RESULTS: The HPLC method passed the validation criteria. The concentration of MTX in the same sample, determined using the HPLC and CLIA methods, differed proportionally; the percent difference in the concentrations averaged -23.0% (95% confidence interval: -36.9% to -9.1%) as revealed by the Bland-Altman plot. The relationship between the measured values, evaluated using the Passing-Bablok regression, was as follows: HPLC = 1.205 × CLIA - 0.024. CONCLUSION: The equation deduced in this study can be used to correct the concentration of MTX measured using the CLIA method.

Genetic polymorphism in MDR1 C3435T is a determinant of methotrexate cerebrospinal fluid concentrations in Chinese children with acute lymphoblastic leukemia
.

AIM: This study aimed to investigate the influence of single-nucleotide polymorphism in exon 26 (C3435T) of multidrug resistance 1 (MDR1) transporter gene on the concentration of methotrexate (MTX) in Chinese childhood patients with acute lymphoblastic leukemia (ALL) receiving intravenous (IV) and intrathecal (IT) high-dose methotrexate (HDMTX) chemotherapy. MATERIALS AND METHODS: MDR1 C3435T polymorphism was investigated in 60 patients with Chinese childhood ALL. The study also compared the MDR1; polymorphism between the patients with Chinese childhood ALL and the published data on Americans, Mexicans, Caucasians, and Thais. The C3435T polymorphism was identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequence analysis. Cerebrospinal fluid (CSF) and plasma concentrations of MTX were measured using high-performance liquid chromatography (HPLC). MTX concentrations were compared according to MDR1 C3435T genotypes. RESULTS: The frequencies of MDR1 C3435T genotype in male and female patients with Chinese childhood ALL were significantly different (p = 0.001). For the frequencies of MDR1 C3435T genotype in Hui and Han patients with Chinese childhood ALL there was no difference (p = 0.188). The distribution of allele frequencies in patients with Chinese childhood ALL was similar to the published data on Americans, Mexican, Caucasians, and Thais (p > 0.05). The CSF concentrations of MTX were found to be significantly different between the C allele (CC + CT) carriers and TT homozygous group (p = 0.04). The plasma concentrations of MTX had no significant difference between the C allele (CC + CT) carriers and TT homozygous group (p > 0.1). CONCLUSION: This study showed that the polymorphism of MDR1 C3435T influenced the CSF concentration of MTX in patients with Chinese childhood ALL receiving IV and IT HDMTX treatment.

Factors Affecting the Upper Limit of the Methotrexate (MTX) CSF Levels Achievable in Children With Brain Tumors Treated With High-dose Intravenous MTX.

BACKGROUND: Little has been published in the medical literature on serum and cerebrospinal fluid (CSF) methotrexate (MTX) levels in children with brain tumors. METHODS: Matched 24-hour serum and CSF MTX levels were studied after 113 treatments in 35 brain tumors patients. RESULTS: A correlation between the 24-hour serum levels of MTX and MTX dosage was observed after 113 treatments in all 35 patients (r=0.39, P<0.001) but no statistical difference was found between CSF MTX levels in the irradiated and nonirradiated groups (P=0.12). Nonirradiated children received a lower dose of MTX (12.3±4.8 cf 14.8±3.7) (P=0.002). The 24-hour MTX CSF levels of these 2 groups were also found to be different (the nonirradiated group 7.6±9.8 cf 12.5±0.15.3). Using the Levene test for variances we found that these variances were not equal and therefore we used the Welch test which resulted in a P-value of 0.04. However, when an analysis of covariance was performed looking at evidence of CSF disease and MTX dose the radiation difference was no longer significant (P=0.15). The 24-hour CSF MTX levels in children without evidence of active CSF disease were consistently lower than those with active disease using a mixed-model analysis (P=0.002). Although a 24-hour CSF MTX level of at least 1 µM was observed after infusions of >5 g/m MTX in previously irradiated children and after infusion of ≥10 g/m in nonirradiated children this difference did not reach statistical significance. CSF MTX levels plateau at doses of MTX 15 g/m putting in doubt the value of administering even higher doses of MTX. CONCLUSIONS: The 24-hour MTX CSF levels are higher in patients with active CSF disease. Doses of <10 gm/m in children with brain tumors may not achieve a guaranteed 24-hour MTX CSF level of 1 µM. There may be little value in a given dose of >15 g/m MTX as CSF levels plateau at this dose.

PBPK model of methotrexate in cerebrospinal fluid ventricles using a combined microdialysis and MRI acquisition.

The objective of the study was to evaluate the distribution of methotrexate (MTX) in cerebrospinal fluid (CSF) lateral ventricles and in cisterna magna after 3rd intraventricular CSF administration in a rabbit model. MTX or gadolinium chelate (Gd-DOTA) was administered in the 3rd ventricle with a local microdialysis to study the pharmacokinetics at the site of administration and with a simultaneous magnetic resonance imaging (MRI) acquisition in the 3rd ventricle, the lateral ventricles and in the cisterna magna. A specific CSF Physiologically Based Pharmacokinetic (PBPK) model was then extrapolated for MTX from Gd-DOTA data. The relative contribution of elimination and distribution processes to the overall disposition of MTX and Gd-DOTA in the 3rd ventricle was similar (i.e., around 60% for CLE and 40% for CLI) suggesting that Gd-DOTA was a suitable surrogate marker for MTX disposition in ventricular CSF. The PBPK predictions for MTX both in CSF of the 3rd ventricle and in plasma were in accordance with the in vivo results. The present study showed that the combination of local CSF microdialysis with MRI acquisition of the brain ventricles and a PBPK model could be a useful methodology to estimate the drug diffusion within CSF ventricles after direct brain CSF administration. Such a methodology would be of interest to clinicians for a rationale determination and optimization of drug dosing parameters in the treatment of leptomeningeal metastases.

Evaluation of Biomarkers of Oxidative Stress and Apoptosis in Patients With Severe Methotrexate Neurotoxicity: A Case Series.

Central nervous system (CNS) treatment is an essential part of acute lymphocytic leukemia (ALL) therapy, and the most common CNS treatment is intrathecal (IT) and high-dose intravenous (IV) methotrexate (MTX). Treatment with MTX may cause neurotoxicity, which is often accompanied by neurologic changes, delays in treatment, and prolonged hospital stays. This article reports clinical presentations of 3 patients with severe MTX toxicity as well as levels of oxidative stress and apoptosis biomarkers in cerebrospinal fluid (CSF). Oxidative stress was measured by oxidized phosphatidylcholine (PC), oxidized phosphatidylinositol (PI), and F2 isoprostanes; apoptosis was measured by caspase 3/7 activity. Most consistent biomarker changes in all 3 cases were increases in caspase 3/7 and F2 isoprostanes prior to acute toxicity while increases in oxidized phospholipids occurred slightly later. Progressive increases in F2 isoprostanes and caspase 3/7 activity prior to and/or during acute toxicity suggests MTX induces oxidative stress and an associated increase in apoptosis. These findings support the role of oxidative stress in MTX-related neurotoxicity.

Prediction of methotrexate CNS distribution in different species - influence of disease conditions.

Children and adults with malignant diseases have a high risk of prevalence of the tumor in the central nervous system (CNS). As prophylaxis treatment methotrexate is often given. In order to monitor methotrexate exposure in the CNS, cerebrospinal fluid (CSF) concentrations are often measured. However, the question is in how far we can rely on CSF concentrations of methotrexate as appropriate surrogate for brain target site concentrations, especially under disease conditions. In this study, we have investigated the spatial distribution of unbound methotrexate in healthy rat brain by parallel microdialysis, with or without inhibition of Mrp/Oat/Oatp-mediated active transport processes by a co-administration of probenecid. Specifically, we have focused on the relationship between brain extracellular fluid (brainECF) and CSF concentrations. The data were used to develop a systems-based pharmacokinetic (SBPK) brain distribution model for methotrexate. This model was subsequently applied on literature data on methotrexate brain distribution in other healthy and diseased rats (brainECF), healthy dogs (CSF) and diseased children (CSF) and adults (brainECF and CSF). Important differences between brainECF and CSF kinetics were found, but we have found that inhibition of Mrp/Oat/Oatp-mediated active transport processes does not significantly influence the relationship between brainECF and CSF fluid methotrexate concentrations. It is concluded that in parallel obtained data on unbound brainECF, CSF and plasma concentrations, under dynamic conditions, combined with advanced mathematical modeling is a most valid approach to develop SBPK models that allow for revealing the mechanisms underlying the relationship between brainECF and CSF concentrations in health and disease.

Comparison of pharmacokinetics and toxicity after high-dose methotrexate treatments in children with acute lymphoblastic leukemia.

We carried out a detailed comparative study of the pharmacokinetics and toxicity of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX) after high-dose intravenous methotrexate (HD-MTX) in children with acute lymphoblastic leukemia (ALL). Overall, 65 children were treated with 5 g/m2/24 h MTX and 88 children were treated with 2 g/m2/24 h MTX according to ALL-BFM 95 and ALL IC-BFM 2002 protocols (mean age: 6.4 years, range 1.0-17.9 years). A total of 583 HD-MTX courses were analyzed. Serum MTX and 7-OH-MTX levels were measured at 24, 36, and 48 h, and cerebrospinal fluid (CSF) MTX levels were determined 24 h after the initiation of the infusion. The area under the concentration-time curve was calculated. Hepatotoxicity, nephrotoxicity, and bone marrow toxicity were estimated by routine laboratory tests. We investigated pharmacokinetics and toxicity in distinct age groups (< 6 and > 14 years). 5 g/m2/24 h treatments resulted in higher serum and CSF MTX and 7-OH-MTX levels (P < 0.05). The CSF penetration rate of MTX was independent of the MTX dose [2.3% (95% confidence interval: 1.7-2.5%) vs. 2.8% (95% confidence interval: 2.4-3%)]. The CSF MTX concentration was correlated with the 24 h MTX serum level (r = 0.38, P < 0.0001). Repeated treatments did not alter MTX or 7-OH-MTX levels. 7-OH-MTX levels were correlated with nephrotoxicity (r = 0.36, P < 0.0001). Higher MTX levels and toxicity occurred more frequently in children aged older than 14 years (P < 0.05). Therapeutic serum and CSF MTX concentrations can be achieved more reliably with 5 g/m2/24 h treatments. To predict the development of toxicity, monitoring of the level of the 7-OH-MTX is useful. Monitoring of pharmacokinetics is essential to prevent the development of severe adverse events in adolescents.

Analysis of methotrexate and its eight metabolites in cerebrospinal fluid by solid-phase extraction and triple-stacking capillary electrophoresis.

We establish a triple-stacking capillary electrophoresis (CE) separation method to monitor methotrexate (MTX) and its eight metabolites in cerebrospinal fluid (CSF). Three stacking methods with different mechanisms were combined and incorporated into CE separation. Complete stacking and sharp peaks were achieved. Firstly, the optimized buffer (60 mM phosphate containing 15% THF and 100 mM SDS) was filled into the capillary, which was followed by the higher conductivity buffer (100 mM phosphate, 2 psi for 45 s). The analytes extracted from CSF were injected at 2 psi for 99.9 s, which provided long sample zones and pH junction for focusing. Finally, the stacking step was performed by sweeping, and separation was achieved by micellar electrokinetic chromatography. The results of the linear regression equations indicated high linearity (r ≥ 0.9981) over the range of 0.5-7 µM. In intra- and inter-batch results, all data of RSD and RE were below 11%, indicating good precision and accuracy of this method. The LODs (S/N = 3) were 0.1 µM for MTX, 7-hydroxymethotrexate (7-OHMTX) and MTX-polyglutamates (MTX-(Glu)(n, n = 2-5)), 0.2 µM for MTX-(Glu)(6), and 0.3 µM for 2,4-diamino-N(10)-methylpteroic acid (DAMPA) and MTX-(Glu)(7). Our method was implemented for analysis of MTX and its metabolites in the CSF, and could be used for evaluation of its curative effects of acute lymphoblastic leukemia patients. The data were also confirmed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The results showed good coincidence.

Transnasal delivery of methotrexate to brain tumors in rats: a new strategy for brain tumor chemotherapy.

Brain tumors are one of the most lethal and difficult to treat. Their treatment is limited by the inadequate delivery of antitumor drugs to the tumor. In order to overcome this limitation, the possibility of the nose-brain direct transport pathway was evaluated using methotrexate (MTX) as a model antitumor agent. The direct transport of nasal MTX to the cerebrospinal fluid (CSF) was examined by comparing the concentration of MTX in the plasma and the CSF after intraperitoneal (IP) and intranasal (IN) administrations. The brain uptake of MTX was evaluated based on a multiple-time/graphical analysis by measuring the concentration of MTX in the plasma and in the brain. The feasibility of nasal chemotherapy was examined by three nasal dosings of MTX to tumor-bearing rats in vivo at two day intervals with peritoneal application as a positive control. MTX showed a significant inhibitory effect on the in vitro growth of 9L glioma cells with 50% growth inhibitory concentration at 7.99 ng/mL. The pharmacokinetic studies clarified the significant direct transport of MTX from nasal cavity both to the CSF and to the brain. Nasal chemotherapy with MTX significantly reduced the tumor weight as compared to nontreatment control and IP group. The strategy to utilize the nose-brain direct transport can be applicable to a new therapeutic system not only for brain tumors but also for other central nervous system disorders such as neurodegenerative diseases.

Therapeutic drug monitoring of methotrexate in cerebrospinal fluid after systemic high-dose infusion in children: can the burden of intrathecal methotrexate be reduced?

The use of intrathecal (IT) methotrexate (MTX) in combination with systemic high-dose (HD) MTX is an established procedure for central nervous system prophylaxis in patients with acute lymphoblastic leukemia, but the evidence for the necessity of this combination is not convincing. The MTX concentration in the cerebrospinal fluid (CSF) was evaluated in 138 samples from children with acute lymphoblastic leukemia and non-Hodgkin lymphoma. CSF samples were obtained by lumbar puncture 12-24 hours after starting the HD MTX infusion (5 g/m2 over 24 hours) and immediately before the IT administration of MTX. Serum MTX concentrations at the end of infusion were assessed by routine therapeutic drug monitoring. Cytotoxic MTX concentrations of 1 microM or greater were detected in 81.2% of CSF samples. CSF MTX concentrations were significantly lower in samples from patients younger than 7 years. The correlation between MTX concentrations in the serum and the CSF was moderate (r = 0.451) and became stronger with increasing age. The median CSF MTX concentrations per cycle were comparable (1.40, 1.25, 1.39, 1.38 microM for cycles 1-4, respectively). The predictive value and the accuracy of the CSF MTX concentration measured during the first cycle of HD MTX in respect to concentrations in the following cycles were high (94.4% and 85.7%, respectively) suggesting that the CSF MTX concentration during the first HD MTX infusion is a useful predictor for sufficient CSF MTX concentrations in the following HD MTX cycles. Our results confirm previously published data on MTX accumulation in the CSF after 5 g/m2 MTX over 24 hours in an independent cohort monitored in a real-life setting. Based on the common opinion that 1 microM represents the minimal antileukemic MTX concentration, current data warrant reevaluation of the necessity of routine IT MTX following HD MTX. Our findings offer a perspective on reducing the burden of IT MTX in children on consolidation therapy by CSF MTX drug monitoring.

Safety and pharmacokinetic analysis of methotrexate administered directly into the fourth ventricle in a piglet model.

We have developed a piglet model to assess chemotherapy administration directly into the fourth ventricle as a potential treatment for medulloblastoma and other malignant posterior fossa tumors. The objective of this study was to assess safety and pharmacokinetics after methotrexate infusions into the fourth ventricle. Catheters were inserted into the fourth ventricle and lumbar cistern in five piglets. Two milligrams of Methotrexate (MTX) was infused into the fourth ventricle on five consecutive days. Safety was assessed by neurological examination, 4.7 T MRI, and post-mortem pathological analysis. MTX levels in serum and cerebrospinal fluid (CSF) were measured, and area under the concentration-time curve (AUC) was calculated for CSF samples. No neurological deficits were caused by MTX infusions. One piglet died from complications of anesthesia induction for MRI scanning. MRI scans showed accurate catheter placement without signal changes in the brainstem or cerebellum. One piglet had asymptomatic ventriculomegaly. Pathological analysis demonstrated meningitis and choroid plexitis consisting predominantly of CD-3 positive T-lymphocytes in all piglets and a small focal area of subependymal necrosis in one. In all piglets, mean peak MTX level in fourth ventricular CSF exceeded that in lumbar CSF by greater than five-fold. Serum MTX levels were undetectable or negligible. Statistically significant differences between fourth ventricle and lumbar AUC were detected at peaks (P = 0.01) and at all collection time points (P = 0.01) but not at troughs (P = 0.36). MTX can be infused into the fourth ventricle without clinical or radiographic evidence of damage. An inflammatory response without clinical correlate is observed. Significantly higher peak MTX levels are observed in the fourth ventricle than in the lumbar cistern.

Delayed recognition of intrathecal methotrexate overdose.

A 10-year-old girl who presented to our hospital was diagnosed as having B-precursor cell acute lymphoblastic leukemia. St Jude's Total XIII protocol was started. In the second block of the consolidation phase, 10 hours after triple intrathecal treatment, we realized that instead of 12 mg, 120 mg of methotrexate had accidentally been given. Although the patient had no symptoms 10 hours after intrathecal treatment, to prevent the possible neurotoxic effects of methotrexate, a cerebrospinal fluid exchange was performed. Simultaneously, systemic dexamethasone and calcium folinic acid were given. At the time of this writing (2 y), the patient has had no symptoms and has continued on the chemotherapy protocol as planned. Administration of high-dose intrathecal methotrexate may not lead to symptoms, as was the case in our patient. This may be related to individual variations in cerebrospinal fluid dynamics and drug metabolism.

[Effects of infusion duration of high-dose methotrexate on cerebrospinal fluid drug levels in lymphoma patients].

BACKGROUND & OBJECTIVE: Methotrexate (MTX) Concentration of higher than minimal therapeutic level in cerebrospinal fluid (CSF) is essential for the therapeutic effects on central nervous system(CNS) lymphoma. The effect of infusion schedules on MTX penetrating into CSF is undear. This study was to evaluate the effect of duration of venous infusion of high-dose MTX (HD-MTX) on drug levels in CSF, and to define the optimal schedule of HD-MTX infusion with high efficiency and low toxicity in CNS lymphomas. METHODS: Thirty-four non-Hodgkin' lymphoma (NHL) patients received 6-hour or 24-hour continuous venous infusion of MTX (1-3 g/m2). CSF samples were obtained right after the end of HD-MTX infusion, and serum samples were obtained at 0 h, 24 h, and 48 h after the end of HD-MTX infusion. MTX concentration was measured by high-pressure liquid chromatography. RESULTS: The serum concentration of MTX at the end of infusion was higher in 6-hour group than in 24-hour group. The CSF concentration of MTX was significantly higher in 6-hour group than in 24-hour group (0.70 micromol/L vs. 0.49 micromol/L, P = 0.044). A weak positive correlation between CSF and serum levels of MTX was observed (r = 0.295, P = 0.002). CSF levels of MTX were much higher in the patients with CNS involvement than in those without CNS involvement. The occurrence rates of grade II-IV mucositis were 15.4% in 6-hour group and 37.8% in 24-hour group; those of grade III-IV myelosuppression were 46.2% in 6-hour group and 67.6% in 24-hour group. CONCLUSION: The shorter duration (6 h) of MTX administration is thought to be more beneficial on the aspects of reducing toxicity and enhancing CNS pharmacokinetics.

Methotrexate concentrations in cerebrospinal fluid and serum, and the risk of central nervous system relapse in children with acute lymphoblastic leukaemia.

The aim of the study was to characterize the relationship between the pharmacokinetics of methotrexate in serum and concentrations in the cerebrospinal fluid, and to analyse the association to risk of a central nervous system relapse in children with acute lymphoblastic leukaemia. In this retrospective study, 353 children with acute lymphoblastic leukaemia treated with high-dose methotrexate according to the Nordic Society of Pediatric Haematology and Oncology-92 acute lymphoblastic leukaemia protocol were studied. Data from 18 patients with a subsequent central nervous system relapse and 335 event-free patients were available. In 34 patients the methotrexate concentrations were monitored repeatedly during each 24-h methotrexate intravenous infusion and a cerebrospinal fluid sample was taken at the end of the infusion. Using statistics separating interindividual and intraindividual variability, methotrexate concentration in cerebrospinal fluid was found to be significantly dependent upon both serum concentrations at the end of infusion and the area under the concentration curve in serum (P<0.0017 and <0.002, respectively). The logistic regression analysis revealed that high patient median serum methotrexate concentrations at the end of infusion were significantly associated with decreased risk for a central nervous system relapse in the standard risk group (P=0.02) and the number of courses with a calculated cerebrospinal fluid concentration of more than 1 mumol/l (P=0.048) with a decreased risk of a central nervous system relapse in the combined (standard risk and intermediate) risk group. In conclusion, methotrexate concentrations in cerebrospinal fluid are dependent on methotrexate concentrations in serum and serum area under the concentration curve. Multivariate analysis indicates that an increased exposure to methotrexate is related to decreased risk for central nervous system relapse.

Influence of particle size on transport of methotrexate across blood brain barrier by polysorbate 80-coated polybutylcyanoacrylate nanoparticles.

Transports of methotrexate-loaded polybutylcyanoacrylate nanoparticles with different sizes across blood brain barrier were investigated in this experiment. The drug-loaded nanoparticles were prepared by emulsion polymerization method. After coating with polysorbate 80, nanoparticles with the size 70, 170, 220, 345 nm were, respectively, i.v. injected into rats at the dose of 3.2 mg/kg. Uncoated nanoparticles and methotrexate solution were also i.v. injected at the same dosage as controls. 0.5, 1, 1.5, 2, 3, 4 h after injection, cerebrospinal fluids and brain tissues were collected for tests. Drug level in all biological samples was determined by HPLC. It was found out that nanoparticles overcoated by polysorbate 80 could significantly improve the drug level in both brain tissues and cerebrospinal fluids compared with uncoated ones and simple solution. Seventy-nanometer nanoparticles could deliver more drugs into brain while no significant difference was observed among the other three size ranges. In conclusion, polysorbate 80-coated polybutylcyanoacrylate nanoparticles could be used to overcome blood brain barrier especially those whose diameter was below 100 nm.

Pharmacodynamic properties of methotrexate and Aminotrexate during weekly therapy.

4-Amino-pteroyl-glutamic acid (Aminotrexate; AMT) has several advantages over the related antifolate methotrexate (MTX), including greater potency, complete oral bioavailability, and greater accumulation by leukemic blasts in vitro. We compared the pharmacodynamic properties of AMT (given orally at 4 mg/m2 in two divided doses per week) and MTX (100 mg/m2 in four divided doses per week) among children with acute lymphoblastic leukemia. We find AMT and MTX to have equivalent penetration into the bone marrow compartment of these patients, as indicated by the steady-state concentrations within mature red blood cells (RBCs). However, MTX concentrations in the cerebrospinal fluid after oral dosage are significantly greater than AMT. To confirm these clinical observations, mice were treated four weekly injections of AMT or MTX, at a 1:20 dosage ratio, and tissue antifolate content was then determined over the subsequent 22 days. We confirm the selective exclusion of AMT from the CNS compartment, while showing equivalent accumulation of AMT and MTX in the RBCs, liver, spleen, kidneys and testes. Finally, we demonstrate that AMT, MTX, and their predominant polyglutamate species are equipotent inhibitors of their target intracellular enzyme dihydrofolate reductase, emphasizing the critical nature of steady-state tissue accumulation in determining the relative cytotoxic potency of these two antifolates.

Management of leptomeningeal malignancy.

Leptomeningeal carcinomatosis is defined as malignant infiltration of the pia matter and arachnoid membrane. Leukaemias and lymphomas, lung, breast cancer and melanoma are the primary tumours commonly associated with leptomeningeal carcinomatosis. Diagnosis is based on compatible symptoms and signs, cytological evidence of malignancy in the cerebrospinal fluid, and neuroimaging studies. Treatment is largely palliative (median survival 2-4 months). Patients with lympomatous or leukaemic meningitis, chemosensitive tumours such as breast cancer, low tumour burden, minimal neurological deficits, good performance status and controllable systemic disease survive longer with occasional long-term responses. Available treatment options include focal radiation therapy to CNS sites of bulky, symptomatic or obstructive meningeal deposits, intrathecal cytotoxic therapy and systemic chemotherapy. No evidence of superiority of intrathecal treatment compared with best palliative care (including radiation therapy and systemic treatment) is available from clinical trials. Novel treatment approaches include intrathecal liposomal Ara-C, the development of new cytotoxic compounds, signal transduction inhibitors and monoclonal antibodies for intrathecal or systemic use. Until data from multi-centre randomised trials are available, rationalisation of therapy should be done by stratifying patients to prognostic groups. High-risk patients will only survive for a few weeks and are better managed with supportive measures, whereas low-risk patients justify vigorous cerebrospinal fluid-directed treatment combined with radiation therapy and systemic chemotherapy.

Intrathecal chemotherapy for patients with meningeal carcinomatosis.

BACKGROUND: Meningeal carcinomatosis (MC) is increasing, and these patients have a poor prognosis. We analyzed the effects of intrathecal (IT) chemotherapy for these patients. METHODS: Patients received both methotrexate (MTX) (15 mg/m(2)) and prednisolone (10 mg/m(2)) 6 times in 2 weeks by Ommaya reservoir, along with cytosine arabinoside (10 mg/m(2)) for 4 doses of MTX. A cycle consisted of a 2-week period during which patients received these drugs and then 2 weeks off. Treatments were repeated 3 to 6 cycles depending on the clinical status. Cerebrospinal fluid (CSF) samples were also analyzed for cytology and a few markers. RESULTS: Of the 58 patients treated the most common tumor was lymphoma (30 patients), followed by lung and breast. Elevated soluble IL-2 receptor levels were observed in 23 of 30 patients with lymphomatous meningitis. Median survival of MC patients with malignant lymphoma, lung cancer, and breast cancer was 32.8 +/- 9.8, 13.0 +/- 4.1, and 18.4 +/- 7.4 months, respectively. Thus, the patients with lymphoma responded best, both by clearing the CSF and clinically. CONCLUSIONS: Our treatment regimen can improve the neurologic status of patients with MC. In particular, early IT chemotherapy can be effective for patients with lymphoma.

Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2.

The bacterial enzyme carboxypeptidase G2 (CPDG2) rapidly hydrolyzes methotrexate to inactive metabolites. We administered recombinant CPDG2 (2000 U) intrathecally to seven cancer patients 3 to 9 hours after they had received an accidental overdose of intrathecal methotrexate (median dose = 364 mg; range = 155-600 mg). Four of the seven patients had cerebrospinal fluid (CSF) exchange to remove methotrexate before CPDG2 administration. Immediate symptoms of the methotrexate overdoses included seizures (n = 5), coma (n = 2), and cardiopulmonary compromise (n = 2). Before CPDG2 administration, the median concentrations of methotrexate in CSF were 264 microM (range = 97-510 microM) among patients who had CSF exchange and 8050 microM (range = 2439-16 500 microM) among patients who did not. After intrathecal CPDG2 administration, methotrexate concentrations in CSF declined by more than 98%. All patients recovered completely from the intrathecal methotrexate overdose except for two patients who had memory impairments. Antibodies to CPDG2 were not detected in plasma after treatment with intrathecal CPDG2. Intrathecal CPDG2 is well tolerated, rapidly decreases CSF methotrexate concentrations, and appears to be efficacious for treating accidental intrathecal methotrexate overdoses.