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.


BACKGROUND
ClinicalTrials.gov identifying number NCT01281696 .
National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei City, 10002, Taiwan. peifangwu@ntu.edu.tw.
Pei-Fang
PF
Wu
Department of Oncology, National Taiwan University Hospital, Taipei City, 10002, Taiwan. chinghlin@ntu.edu.tw.
Ching-Hung
CH
Lin
School of Pharmacy, College of Medicine, National Taiwan University, Taipei City, 10002, Taiwan. kuoch@ntu.edu.tw.
Ching-Hua
CH
Kuo
Department of Oncology, National Taiwan University Hospital, Taipei City, 10002, Taiwan. saxotomy@gmail.com.
Wei-Wu
WW
Chen
Department of Surgery, Taichung Veterans General Hospital, Taichung, 40705, Taiwan. dcyeh@vghtc.gov.tw.
Dah-Cherng
DC
Yeh
School of Pharmacy, College of Medicine, National Taiwan University, Taipei City, 10002, Taiwan. mysticfox29@hotmail.com.
Hsiao-Wei
HW
Liao
Department of Oncology, National Taiwan University Hospital, Taipei City, 10002, Taiwan. smhuang77@gmail.com.
Shu-Min
SM
Huang
Department of Oncology, National Taiwan University Hospital, Taipei City, 10002, Taiwan. alcheng@ntu.edu.tw.|Department of Internal Medicine, National Taiwan University Hospital, Taipei City, 10002, Taiwan. alcheng@ntu.edu.tw.|Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei City, 10002, Taiwan. alcheng@ntu.edu.tw.
Ann-Lii
AL
Cheng
Department of Oncology, National Taiwan University Hospital, Taipei City, 10002, Taiwan. yslu@ntu.edu.tw.|Department of Internal Medicine, National Taiwan University Hospital, Taipei City, 10002, Taiwan. yslu@ntu.edu.tw.
Yen-Shen
YS
Lu
D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000134:cerebrospinal fluid; D001943:Breast Neoplasms / Q000134:cerebrospinal fluid / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage* / Q000134:cerebrospinal fluid; D005047:Etoposide / Q000008:administration & dosage* / Q000134:cerebrospinal fluid; D005260:Female; D006801:Humans; D055756:Meningeal Carcinomatosis / Q000134:cerebrospinal fluid / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging
D000068258:Bevacizumab; D005047:Etoposide; D002945:Cisplatin