title: Metronomic vinorelbine (oral) in combination with sorafenib in advanced non-small cell lung cancer.
abstract: BACKGROUND
  To date, biomarkers to predict benefit from anti-angiogenic therapy are still lacking. Sorafenib and metronomic oral vinorelbine combination was studied and changes in blood and DCE-MRI parameters were investigated as biomarkers for benefit.
  
  
  METHODS
  Patients with advanced NSCLC were recruited to 3 successive cohorts. Each cohort was given a fixed metronomic (3 times a week) dose of oral vinorelbine at 60 mg/week, 90 mg/week, or 120 mg/week respectively. Within each cohort, patients received a starting dose of sorafenib at 200mg bid for 4 weeks. In the absence of dose-limiting toxicities, each patient's dose of sorafenib was escalated to 400mg bid for 4 weeks, 600 mg bid for 4 weeks and finally 800 mg bid. Biomarkers measured include DCE-MRI parameters, circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and plasma thrombospondin (TSP-1).
  
  
  RESULTS
  48 evaluable patients were analyzed. There were 4 (8.9%) patients with partial response (PR) and 7 (15.2%) with cavitary response (CaR). Two subpopulations of CECs (CEC(hi), CEC(lo)) were identified that trended in opposite directions during treatment, with CEC(hi) demonstrating an upward trend in contrast to CEC(lo). Higher baseline CEC(hi) and lower baseline blood flow (F) and fractional intravascular blood volume (V1) predicted for response. Multivariate analysis revealed a lower baseline V1, and dynamic changes of CEC during treatment (CEC increase, sum of CEC(hi) and CEC(lo)) predicted for improved survival.
  
  
  CONCLUSIONS
  Sorafenib and metronomic oral vinorelbine is active in advanced NSCLC. Baseline levels and changes in DCE parameters and CEC may be useful predictive biomarkers.
authors.affiliation: Department of Medical Oncology, National Cancer Centre, Singapore. Electronic address: dmoteh@nccs.com.sg.
authors.forename: Eng Huat
authors.initials: EH
authors.lastname: Tan
authors.affiliation: Department of Medical Oncology, National Cancer Centre, Singapore. Electronic address: Daniel.Tan.S.W@nccs.com.sg.
authors.forename: Daniel Shao Weng
authors.initials: DS
authors.lastname: Tan
authors.affiliation: Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore. Electronic address: wenyun_li@139.com.
authors.forename: Wen Yun
authors.initials: WY
authors.lastname: Li
authors.affiliation: Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore; H Milton Stewart School of Industrial & Systems Engineering, Georgia Institute of Technology, United States. Electronic address: ben.haaland@isye.gatech.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haaland
authors.affiliation: Department of Medical Oncology, National Cancer Centre, Singapore. Electronic address: Ang.Mei.Kim@nccs.com.sg.
authors.forename: Mei Kim
authors.initials: MK
authors.lastname: Ang
authors.affiliation: Department of Medical Oncology, National Cancer Centre, Singapore. Electronic address: nmchau@doctors.org.uk.
authors.forename: Noan Min
authors.initials: NM
authors.lastname: Chau
authors.affiliation: Department of Medical Oncology, National Cancer Centre, Singapore. Electronic address: Toh.Chee.Keong@nccs.com.sg.
authors.forename: Chee Keong
authors.initials: CK
authors.lastname: Toh
authors.affiliation: Department of Medical Oncology, National Cancer Centre, Singapore. Electronic address: Iain.Tan.B.H@nccs.com.sg.
authors.forename: Iain Bee Huat
authors.initials: IB
authors.lastname: Tan
authors.affiliation: Department of Oncologic Imaging, National Cancer Centre, Singapore. Electronic address: Koh.T.S@nccs.com.sg.
authors.forename: Tong San
authors.initials: TS
authors.lastname: Koh
authors.affiliation: Department of Oncologic Imaging, National Cancer Centre, Singapore. Electronic address: dditch@nccs.com.sg.
authors.forename: Choon Hua
authors.initials: CH
authors.lastname: Thng
authors.affiliation: Division of Medical Sciences, National Cancer Centre, Singapore. Electronic address: ctebal@nccs.com.sg.
authors.forename: Balram
authors.initials: B
authors.lastname: Chowbay
authors.affiliation: Division of Cellular and Molecular Research, National Cancer Centre, Singapore. Electronic address: cmrhkm@nccs.com.sg.
authors.forename: Kam Man
authors.initials: KM
authors.lastname: Hui
authors.affiliation: Department of Medical Oncology, National Cancer Centre, Singapore; Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore. Electronic address: dmolwt@nccs.com.sg.
authors.forename: Wan Teck
authors.initials: WT
authors.lastname: Lim
authors.affiliation: Department of Medical Oncology, National Cancer Centre, Singapore. Electronic address: Ng.Q.S@nccs.com.sg.
authors.forename: Quan Sing
authors.initials: QS
authors.lastname: Ng
mesh_terms: D059250:Administration, Metronomic; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D000077157:Sorafenib; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D015415:Biomarkers; D010671:Phenylurea Compounds; D009536:Niacinamide; D014747:Vinblastine; D000077157:Sorafenib; D000077235:Vinorelbine
keywords: Anti-angiogenesis; Biomarkers; Metronomic; NSCLC; Sorafenib; Vinorelbine