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

Pei-Fang Wu, Ching-Hung Lin, Ching-Hua Kuo, Wei-Wu Chen, Dah-Cherng Yeh, Hsiao-Wei Liao, Shu-Min Huang, Ann-Lii Cheng, Yen-Shen Lu, Pei-Fang Wu, Ching-Hung Lin, Ching-Hua Kuo, Wei-Wu Chen, Dah-Cherng Yeh, Hsiao-Wei Liao, Shu-Min Huang, Ann-Lii Cheng, Yen-Shen Lu

Abstract

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 .

Figures

Figure 1
Figure 1
Efficacy results: Overall Survival (OS) and neurologic progression free survival (PFS).
Figure 2
Figure 2
The effects of bevacizumab administration on the temporal changes of CSF to plasma ratio of etoposide concentration. (A) Individual CSF/ Plasma ratio of etoposide concentration versus time plot. (B) Overall CSF/Plasma ratio of etoposide concentration versus time plot.

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