Systemic high-dose intravenous methotrexate in patients with central nervous system metastatic breast cancer

Twenty-two consecutive patients with CNS metastases of breast cancer were treated by high dose IV MTX at the university hospital of Besancon (Franche – Comte, France) between April 2004 and October 2009. This study was approved by the Institutional Review Board of the Regional Cancer Institute in March 2004. The cut off for data capture was May 31, 2011. Patients, disease and treatment characteristics, were included in the database. Metastases of the CNS included intra-cranial (cerebral and cerebellar), intramedullary and leptomeningeal metastases. CNS metastases were diagnosed by MRI and/or cerebrospinal fluid cytology. Patients were treated by IV MTX 3 g/m2 during 3 h infusion with concomitant hyperalkaline hydration. A rescue by IV folinic acid (40 mg every 6 h) was started 24 h after the completion of MTX until the blood concentration of MTX decreased below 0.05 μmol/l. MTX was administered every two or 3 weeks until the patient progressed clinically or radiographically. A pharmacokinetic assessment was performed to achieve a PK-PD study. Response rate, time to progression (TTP), overall survival (OS), and safety were assessed.

Responses

CNS metastases and non-CNS metastases was assessed using Evaluation Criteria in Solid Tumors (RECIST 1.1) based on appropriate imaging every 12 weeks [10]. Taking into account that all patients were specifically assessed by neurologic exam and by brain MRI every 6 weeks. Leptomeningeal response was evaluated by cytologic examination every 6 weeks. For patients with both, parenchymal metastases and carcinomatous meningitis, progression in either site was assessed as progression of the disease. Patients with worsening neurological symptoms, regardless of the results of radiological controls or cytologic examinations, had a progressive disease. An objective response rate of 20% was determined as reasonable objectives for treatment with meaningful effect.

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Pharmacokinetics

Serum MTX concentrations were determined using a fluorescence polarization immunoassay (TDxFLx system; Abbott) following the manufacturer instructions at 24, 48 and 72 h after the end of the MTX infusion and later until the concentration was below 0.05 μmol/l.

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The patients’ results were split in two groups with respect to their response assessment. The evaluation of the PK/PD relationship was performed using the concentration measured 48 h after the end of the MTX administration. An amount of 57 samples were analyzed. In each group the median number of concentrations assessed for each patient was 2 (range 1-4).

Statistical analysis

OS is defined by the interval between the date of first treatment and date of death or last follow-up, using the Kaplan-Meier method. TTP is defined by the interval between time of first treatment and date of progressive disease or death, using the Kaplan-Meier method. Search for relationship between toxicities, efficacy criteria and pharmacokinetics parameters were performed by univariate and multivariate logistic regression. All statistical computations were performed by using software (SAS System for Windows, version 9.0, 2002; SAS Institute, Cary, NC), and results were declared significant at the two-sided 5% comparison wise significance level (P < .05).

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