title: Bevacizumab preconditioning followed by Etoposide and Cisplatin is highly effective in treating brain metastases of breast cancer progressing from whole-brain radiotherapy.
abstract: OBJECTIVE
  We hypothesized that a window period between bevacizumab and cytotoxic agents may enhance drug delivery into tumor tissue through bevacizumab-induced vascular normalization in patients with brain metastases of breast cancer (BMBC).
  
  
  METHODS
  A single-arm phase II study was conducted in which BMBC patients refractory to whole-brain radiotherapy (WBRT) were enrolled. In a 21-day cycle, patients received bevacizumab (15 mg/kg) on day 1, which, with a 1-day window period, was followed by etoposide (70 mg/m(2)/day; days 2-4) and cisplatin (70 mg/m(2); day 2; BEEP regimen). The BEEP regimen was administered for a maximum of 6 cycles. The primary endpoint was the central nervous system (CNS)-objective response rate according to volumetric response criteria.
  
  
  RESULTS
  A total of 35 patients were enrolled between January 2011 and January 2013. The median age was 54.3 years (range, 33-75); 19 patients (54.3%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. Twenty-seven patients [77.1%; 95% confidence interval (CI), 59.9-89.6] achieved a CNS-objective response, including 13 patients (37.1%) with a ≥80% volumetric reduction of CNS lesions. With a median follow-up of 16.1 months, the median CNS progression-free survival and overall survival times were 7.3 months (95% CI, 6.5-8.1) and 10.5 months (95% CI, 7.8-13.2), respectively. Common grade 3 or 4 toxicities included neutropenia (30.8%) and infection (21.3%).
  
  
  CONCLUSIONS
  By administering bevacizumab 1 day before etoposide and cisplatin, the BEEP regimen appeared highly effective in BMBC refractory to WBRT. Further study of vascular normalization window concept is warranted.
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yen-Shen
authors.initials: YS
authors.lastname: Lu
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Tom Wei-Wu
authors.initials: TW
authors.lastname: Chen
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ching-Hung
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Dah-Cherng
authors.initials: DC
authors.lastname: Yeh
authors.affiliation: Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Pei-Fang
authors.initials: PF
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Kun-Ming
authors.initials: KM
authors.lastname: Rau
authors.affiliation: Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Bang-Bin
authors.initials: BB
authors.lastname: Chen
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ta-Chung
authors.initials: TC
authors.lastname: Chao
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Shu-Min
authors.initials: SM
authors.lastname: Huang
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chiun-Sheng
authors.initials: CS
authors.lastname: Huang
authors.affiliation: Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Tiffany Ting-Fang
authors.initials: TT
authors.lastname: Shih
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. alcheng@ntu.edu.tw.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000401:mortality / Q000556:secondary* / Q000628:therapy*; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008875:Middle Aged; D011878:Radiotherapy; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D000068258:Bevacizumab; D005047:Etoposide; D002945:Cisplatin