Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study

Abstract

Background: Breast cancer brain metastases (BCBM) are challenging complications that respond poorly to systemic therapy. The role of the blood-tumor barrier in limiting BCBM drug delivery and efficacy has been debated. Herein, we determined tissue and serum levels of capecitabine, its prodrug metabolites, and lapatinib in women with BCBM resected via medically indicated craniotomy.

Methods: Study patients with BCBM requiring surgical resection received either single-dose capecitabine (1250 mg/m(2)) 2-3 h before surgery or 2-5 doses of lapatinib (1250 mg) daily, the last dose 2-3 h before surgery. Serum samples were collected serially on the day of surgery. Drug concentrations were determined in serum and BCBM using liquid chromatography tandem mass spectrometry.

Results: Twelve patients were enrolled: 8 for capecitabine and 4 for lapatinib. Measurable drug levels of capecitabine and metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil, were detected in all BCBM. The ratio of BCBM to serum was higher for 5-fluorouracil than for capecitabine. As for lapatinib, the median BCBM concentrations ranged from 1.0 to 6.5 µM. A high variability (0.19-9.8) was noted for lapatinib BCBM-to-serum ratio.

Conclusions: This is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system. Trial registration ID: NCT00795678.

Keywords: blood–tumor barrier; brain metastases; breast cancer; capecitabine; lapatinib.

© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Fig. 1.

Time course of serum capecitabine and metabolite concentrations. Example time course of capecitabine and metabolite serum concentrations (patient C7). Six serum draws are plotted against time (h). BCBM was identified at the 4th serum draw

Fig. 2.

Interpatient variability in capecitabine and metabolite concentrations. Mean concentrations of capecitabine, 5′-DFCR, 5′-DFUR, and 5-FU in all patients. Each patient is color coded.

Fig. 3.

Serum, intratumor, and interpatient BCBM lapatinib concentration variability. (A) Time course of serum lapatinib concentration for all 4 patients. (B) Lapatinib concentrations in all patient BCBM, showing range, median, and quartile of concentration.