title: High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary?
abstract: OBJECTIVE
  Standard treatments for neoplastic meningitis are only modestly effective and are associated with significant morbidity. Isolated reports suggest that concurrent systemic and intrathecal (i.t.) therapy may be more effective than i.t. therapy alone. We present our experience, which includes CSF and serum pharmacokinetic data, on the use of high-dose (HD) intravenous (i.v.) methotrexate (MTX) as the sole treatment for neoplastic meningitis.
  
  
  METHODS
  Sixteen patients with solid-tumor neoplastic meningitis received one to four courses (mean, 2.3 courses) of HD (8 g/m2 over 4 hours) i.v. MTX and leucovorin rescue. Serum and CSF MTX concentrations were measured daily. Toxicity, response, and survival were retrospectively compared with a reference group of 15 patients treated with standard i.t. MTX during the same time interval.
  
  
  RESULTS
  Peak methotrexate concentrations ranged from 3.7 to 55 micromol/L (mean, 17.1 micromol/L) in CSF and 178 to 1,700 micromol/L (mean, 779 micromol/L) in serum. Cytotoxic CSF and serum MTX concentrations were maintained much longer than with i.t. dosing. Toxicity was minimal. Cytologic clearing was seen in 81% of patients compared with 60% of patients treated intrathecally (P = .3). Median survival in the HD i.v. MTX group was 13.8 months versus 2.3 months in the i.t. MTX group (P = .003).
  
  
  CONCLUSIONS
  HD i.v. MTX is easily administered and well tolerated. This regimen achieves prolonged cytotoxic serum MTX concentrations and CSF concentrations at least comparable to those achieved with standard i.t. therapy. Cytologic clearing and survival may be superior in patients treated with HD i.v. MTX. Prospective studies and a reconsideration of the use of i.t. chemotherapy for patients with neoplastic meningitis are warranted.
authors.affiliation: Department of Medicine, Brown University School of Medicine, Providence, RI, USA. mjg@brownvm.brown.edu
authors.forename: M J
authors.initials: MJ
authors.lastname: Glantz
authors.forename: B F
authors.initials: BF
authors.lastname: Cole
authors.forename: L
authors.initials: L
authors.lastname: Recht
authors.forename: W
authors.initials: W
authors.lastname: Akerley
authors.forename: P
authors.initials: P
authors.lastname: Mills
authors.forename: S
authors.initials: S
authors.lastname: Saris
authors.forename: F
authors.initials: F
authors.lastname: Hochberg
authors.forename: P
authors.initials: P
authors.lastname: Calabresi
authors.forename: M J
authors.initials: MJ
authors.lastname: Egorin
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D016080:Arachnoid Cysts / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007278:Injections, Spinal; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate