title: Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial.
abstract: BACKGROUND
  Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma.
  
  
  METHODS
  In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated.
  
  
  RESULTS
  The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log₁₀CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log₁₀CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS.
  
  
  CONCLUSIONS
  CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam and Cancer Genomics Netherlands, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Beije
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam and Cancer Genomics Netherlands, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Kraan
authors.affiliation: Department of Neuro-oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Taal
authors.affiliation: Erasmus MC Cancer Institute, University Medical Center Rotterdam, Clinical Trial Center, s-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: van der Holt
authors.affiliation: Department of Medical Oncology, Medical Center Haaglanden, Lijnbaan 32, 2512 VA The Hague, The Netherlands.
authors.forename: H M
authors.initials: HM
authors.lastname: Oosterkamp
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Walenkamp
authors.affiliation: Department of Oncology, St Elisabeth Hospital, Hilvarenbeeksweg 60, 5022 GC Tilburg, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Beerepoot
authors.affiliation: Department of Neurology, Catharina Hospital, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Hanse
authors.affiliation: Department of Oncology, VU University Medical Center, De Boelelaan 117, 1081 HV Amsterdam, The Netherlands.
authors.forename: M E
authors.initials: ME
authors.lastname: van Linde
authors.affiliation: Department of Neurology, Isala Klinieken, Dokter van Heesweg 2, 8025 AB Zwolle, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Otten
authors.affiliation: Erasmus MC Cancer Institute, University Medical Center Rotterdam, Clinical Trial Center, s-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: R M
authors.initials: RM
authors.lastname: Vernhout
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: F Y F
authors.initials: FY
authors.lastname: de Vos
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam and Cancer Genomics Netherlands, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: J W
authors.initials: JW
authors.lastname: Gratama
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam and Cancer Genomics Netherlands, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Sleijfer
authors.affiliation: Department of Neuro-oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: van den Bent
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D015703:Antigens, CD / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002465:Cell Movement; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D058851:GPI-Linked Proteins / Q000032:analysis; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007700:Kinetics; D008130:Lomustine / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; C120523:CD109 protein, human; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; D000068258:Bevacizumab; D008130:Lomustine