Intratumoral pharmacokinetics determined with microdialysis in a patient with glioblastoma multiforme following systemic administration of high dose methotrexate

Abstract

1569 Background: The delivery of therapeutic concentrations of chemotherapeutic agents to brain tumors remains a major concern in the design and interpretation of clinical brain tumor trials. Methods: This study was approved by the National Cancer Institute and IRB at each participating site. Patients with recurrent and refractory glioblastoma multiforme (GBM) where biopsy or partial resection followed by high dose methotrexate (MTX) were planned were eligible. At surgery a microdialysis catheter was placed within residual contrast enhancing tumor. Modified Ringer’s solution was delivered to the catheter at 1 μl/min. On the following day, 12 grams/m2 of intravenous MTX (adjusted for renal function) were administered over 4 hours. Plasma and microdialysate were collected at 30 minute intervals. MTX was assayed using high performance liquid chromatography with mass spectrometric detection (0.5 ng/ml lower limit of quantitation). Results: The first patient evaluated was a 51 year old who had a biopsy to confirm tumor progression after prior surgery, radiation, Gliadel, and temozolomide. The plasma pharmacokinetics of MTX behaved as expected. Renal function remained unchanged and the leukovorin rescue was administered as per protocol. MTX concentrations in extracellular fluid within the GBM rose rapidly to a maximum of 57 μM and subsequently decayed in a monoexponential manner with a half-life of 12.3 h. MTX concentrations in the dialysate exceeded plasma levels 16 hours after the MTX infusion ended. The patient subsequently developed urosepsis with neutropenia, but no mucositis or diarrhea, and died 3 weeks later after care was withdrawn. Detailed review by NABTT, CTEP, and the study site found no association with the microdialysis catheter and an uncertain relationship to MTX. Conclusions: This is the first reported use of microdialysis in a human to monitor local concentrations of a systemically administered anticancer drug within a brain tumor. This approach could significantly impact the selection of drugs, dosing schedules, and routes of administration for future brain tumor trials. No significant financial relationships to disclose.