Distribution of Bevacizumab into the Cerebrospinal Fluid of Children and Adolescents with Recurrent Brain Tumors.

BACKGROUND: To date, evidence has been lacking regarding bevacizumab pharmacokinetics in the cerebrospinal fluid (CSF). OBJECTIVE: This study assessed the penetration of bevacizumab, as part of a metronomic antiangiogenic treatment regimen, into the CSF of children, adolescents, and young adults with recurrent brain tumors. PATIENTS AND METHODS: Serum and CSF concentrations, malignant cells, and vascular endothelial growth factor A (VEGF-A) were analyzed in 12 patients (5-27 years) following 10 mg/kg bevacizumab intravenous biweekly administration (EudraCT number 2009-013024-23). A population pharmacokinetic model including body weight, albumin, and tumor type as influential factors was extended to quantify the CSF penetration of bevacizumab. RESULTS: Apart from in serum (minimum concentration/maximum concentration [Cmin/Cmax] 77.0-305/267-612 mg/L, median 144/417 mg/L), bevacizumab could be quantified in the CSF (0.01-2.26 mg/L, median 0.35 mg/L). The CSF/serum ratio was 0.16 and highly variable between patients. Malignant cells could be detected in CSF before initiation of treatment in five of 12 patients; after treatment, the CSF was cleared in all patients. VEGF-A was detected in three patients before treatment (mean ± SD: 20 ± 11 pg/mL), and was still measurable in one of these patients despite treatment (16 pg/mL). CONCLUSIONS: This pharmacokinetic pilot study indicated penetration of bevacizumab into the CSF in a population of children, adolescents, and young adults with recurrent brain tumors.

A pilot study of bevacizumab combined with etoposide and cisplatin in breast cancer patients with leptomeningeal carcinomatosis.

BACKGROUND: Elevated vascular endothelial growth factor (VEGF) was associated with poor prognosis in leptomeningeal carcinomatosis and anti-angiogenic therapy was found to prolong the survival of mice in preclinical studies. This prospective pilot study investigated the efficacy of anti-VEGF therapy plus chemotherapy in patients with leptomeningeal carcinomatosis originating from breast cancer. METHODS: Eligible patients were scheduled to receive bevacizumab combined with etoposide and cisplatin (BEEP) every 3 weeks for a maximum of 6 cycles or until unacceptable toxicity. The primary objective was the central nervous system (CNS)-specific response rate, which was defined as disappearance of cancer cells in the cerebrospinal fluid (CSF) and an improved or stabilized neurologic status. The impact of VEGF inhibition on etoposide penetration into the CSF was analyzed. RESULTS: Eight patients were enrolled. The CNS-specific response rate was 60% in 5 evaluable patients. According to intent-to-treat analysis, the median overall survival of the eight patients was 4.7 months (95% confidence interval, CI, 0.3-9.0) and the neurologic progression-free survival was 4.7 months (95% CI 0-10.5). The most common grade 3/4 adverse events were neutropenia (23.1%), leukopenia (23.1%), and hyponatremia (23.1%). The etoposide concentrations in the CSF were much lower than those in plasma, and bevacizumab did not increase etoposide delivery to the CSF. CONCLUSIONS: BEEP exhibited promising efficacy in breast cancer patients with leptomeningeal carcinomatosis. Additional studies are warranted to verify its efficacy and clarify the role of anti-angiogenic therapy in this disease. TRIAL REGISTRATION: ClinicalTrials.gov identifying number NCT01281696 .