Journal of Neuro-Oncology

, Volume 138, Issue 3, pp 527–535 | Cite as

A predictive value of von Willebrand factor for early response to Bevacizumab therapy in recurrent glioma

  • Andrea Pace
  • Chiara Mandoj
  • Anna Antenucci
  • Veronica Villani
  • Isabella Sperduti
  • Beatrice Casini
  • Mariantonia Carosi
  • Alessandra Fabi
  • Antonello Vidiri
  • Tatiana Koudriavtseva
  • Laura Conti
Clinical Study


Bevacizumab (BV), a neutralizing monoclonal antibody against the vascular endothelial growth factor ligand, is recognized as a potent anti-angiogenic agent with antitumor activity. The aim of this single-center, retrospective, longitudinal study was to investigate the possible predictive value of baseline demographic, clinical and laboratory parameters for early 3-month response to BV therapy in patients with recurrent glioma. Forty-nine patients with recurrent glioma received BV at 10 mg/kg intravenously every 3 weeks alone or in association with chemotherapy were included in this study. Blood samples were collected from all patients before the first (baseline), the second and the third administration of BV. After 3 months of BV therapy, patients with partial response were defined as responders whereas patients with stable or progressive disease were defined as non-responders. The median overall follow-up was 8 months (range 1–73), the median overall survival (OS) was 8 months (95% CI 6–10) and the median progression free survival (PFS) was 4 months (95% CI 3–5). Thirty-five % of patients were responders and showed significantly lower von Willebrand factor (VWF) levels than non-responders at all sample times (p < .02 for all). Also, on multivariate analysis the baseline VWF value was the only predictor for an early response to BV therapy. Furthermore, D-dimer and prothrombin fragment 1+2 were predictive factors for OS while Karnofsky performance status resulted predictive for PFS. VWF antigen value is a possible predictive biomarker for an early 3-month response to BV therapy in recurrent glioma.


Brain neoplasia Recurrent glioma Bevacizumab therapy Coagulation Von Willebrand factor 



Associazione Italiana Tumori Cerebrali (AITC) supported this research.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Schwartzbaum JA, Fisher JL, Aldape KD, Wrensch M (2006) Epidemiology and molecular pathology of glioma. Nat Clin Pract Neurol 2(9):494–503CrossRefPubMedGoogle Scholar
  2. 2.
    Kargiotis O, Rao JS, Kyritsis AP (2006) Mechanisms of angiogenesis in gliomas. J Neurooncol 78(3):281–293CrossRefPubMedGoogle Scholar
  3. 3.
    Jain RK (2002) Tumor angiogenesis and accessibility: role of vascular endothelial growth factor. Semin Oncol 29(6 Suppl 16):3–9CrossRefPubMedGoogle Scholar
  4. 4.
    Yi Li S, Ali J, Clarke, Cha S (2017) Bevacizumab in recurrent glioma: patterns of treatment failure and implications. Brain Tumor Res Treat 5(1):1–9CrossRefPubMedGoogle Scholar
  5. 5.
    Diaz RJ, Ali S, Qadir MG, De La Fuente MI, Ivan ME, Komotar RJ (2017) The role of bevacizumab in the treatment of glioblastoma. J Neurooncol 133(3):455–467CrossRefPubMedGoogle Scholar
  6. 6.
    Khasraw M, Ameratunga MS, Grant R, Wheeler H, Pavlakis N (2014) Antiangiogenic therapy for high-grade glioma. Cochrane Database Syst Rev 22(9):CD008218. CrossRefGoogle Scholar
  7. 7.
    Colavolpe C, Chinot O, Metellus P, Mancini J, Barrie M, Bequet-Boucard C, Tabouret E, Mundler O, Figarella-Branger D, Guedj E (2012) FDG-PET predicts survival in recurrent high-grade gliomas treated with bevacizumab and irinotecan. Neuro Oncology 14(5):649–657. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Harris RJ, Cloughesy TF, Pope WB, Nghiemphu PL, Lai A, Zaw T, Czernin J, Phelps ME, Chen W, Ellingson BM (2012) 18F-FDOPA and 18F-FLT positron emission tomography parametric response maps predict response in recurrent malignant gliomas treated with bevacizumab. Neuro Oncology 14(8):1079–1089. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kickingereder P, Wiestler B, Burth S, Wick A, Nowosielski M, Heiland S, Schlemmer HP, Wick W, Bendszus M, Radbruch A (2015) Relative cerebral blood volume is a potential predictive imaging biomarker of bevacizumab efficacy in recurrent glioblastoma. Neuro Oncology 17(8):1139–1147. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Choi SH, Jung SC, Kim KW, Lee JY, Choi Y, Park SH, Kim HS (2016) Perfusion MRI as the predictive/prognostic and pharmacodynamic biomarkers in recurrent malignant glioma treated with bevacizumab: a systematic review and a time-to-event meta-analysis. J Neurooncol 128(2):185–194. CrossRefPubMedGoogle Scholar
  11. 11.
    Chen C, Huang R, MacLean A, Muzikansky A, Mukundan S, Wen PY, Norden AD (2013) Recurrent high-grade glioma treated with bevacizumab: prognostic value of MGMT methylation, EGFR status and pretreatment MRI in determining response and survival. J Neurooncol 115(2):267–276. CrossRefPubMedGoogle Scholar
  12. 12.
    Toft A, Urup T, Christensen IJ, Michaelsen SR, Lukram B, Grunnet K, Kosteljanetz M, Larsen VA, Lassen U, Broholm H, Poulsen HS (2018) Biomarkers in recurrent grade III glioma patients treated with bevacizumab and irinotecan. Cancer Invest 2:1–10. CrossRefGoogle Scholar
  13. 13.
    Jubb AM, Harris AL (2010) Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol 11:1172–1183. CrossRefPubMedGoogle Scholar
  14. 14.
    Rodríguez Garzotto A, Díaz-García CV, Agudo-López A, Prieto García E, Ponce S, López-Martín JA, Paz-Ares L, Iglesias L, Agulló-Ortuño MT (2016) Blood-based biomarkers for monitoring antiangiogenic therapy in non-small cell lung cancer. Med Oncol 33(10):105. CrossRefPubMedGoogle Scholar
  15. 15.
    Brandes AA, Bartolotti M, Tosoni A, Poggi R, Franceschi E (2015) Practical management of bevacizumab-related toxicities in glioblastoma. Oncologist 20(2):166–175CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Rickles FR, Falanga A (2001) Molecular basis for the relationship between thrombosis and cancer. Thromb Res 102:V215-224CrossRefGoogle Scholar
  17. 17.
    Magnus N, D’Asti E, Garnier D, Meehan B, Rak J (2013) Brain neoplasms and coagulation. Semin Thromb Hemost 39(8):881–895CrossRefPubMedGoogle Scholar
  18. 18.
    Belting M, Dorrell MI, Sandgren S, Aguilar E, Ahamed J, Dorfleutner A, Carmeliet P, Mueller BM, Friedlander M, Ruf W (2004) Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med 10(5):502–509CrossRefPubMedGoogle Scholar
  19. 19.
    Franchini M, Frattini F, Crestani S, Bonfanti C, Lippi G (2013) von Willebrand factor and cancer: a renewed interest. Thromb Res 131(4):290–292CrossRefPubMedGoogle Scholar
  20. 20.
    Thompson WD, Smith EB, Stirk CM, Marshall FI, Stout AJ, Kocchar A (1992) Angiogenic activity of fibrin degradation products is located in fibrin fragment E. J Pathol 168(1):47–53CrossRefPubMedGoogle Scholar
  21. 21.
    Schag CC, Heinrich RL, Ganz PA (1984) Karnofsky performance status revisited: reliability, validity, and guidelines. J Clin Oncology 2(3):187–193CrossRefGoogle Scholar
  22. 22.
    Wen PY, Macdonald DR, Reardon DA et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neurooncology working group. J Clin Oncol 28:1963–1972CrossRefPubMedGoogle Scholar
  23. 23.
    Horton TLB (2003) On the exact distribution of maximally selected rank statistics. Comput Statist Data Anal 43:121–137CrossRefGoogle Scholar
  24. 24.
    Jilma B, Cvitko T, Winter-Fabry A, Petroczi K, Quehenberger P, Blann AD (2005) High dose dexamethasone increases circulating P-selectin and von Willebrand factor levels in healthy men. Thromb Haemost 94(4):797–801PubMedGoogle Scholar
  25. 25.
    Lubberts S, Boer H, Altena R, Meijer C, van Roon AM, Zwart N, Oosting SF, Kamphuisen PW, Nuver J, Smit AJ, Mulder AB, Lefrandt JD, Gietema JA (2016) Vascular fingerprint and vascular damage markers associated with vascular events in testicular cancer patients during and after chemotherapy. Eur J Cancer 63:180–188. CrossRefPubMedGoogle Scholar
  26. 26.
    Nishigori N, Matsumoto M, Koyama F, Hayakawa M, Hatakeyayama K, Ko S, Fujimura Y, Nakajima Y (2015) von Willebrand factor-rich platelet thrombi in the liver cause sinusoidal obstruction syndrome following oxaliplatin-based chemotherapy. PLoS ONE 10(11):e0143136. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Terraube V, O’Donnell JS, Jenkins PV (2010) Factor VIII and von Willebrand factor interaction: biological, clinical and therapeutic importance. Haemophilia 16(1):3–13CrossRefPubMedGoogle Scholar
  28. 28.
    Lenting PJ, Casari C, Christophe OD, Denis CV (2012) von Willebrand factor: the old, the new and the unknown. J Thromb Haemost 10(12):2428–2437CrossRefPubMedGoogle Scholar
  29. 29.
    Starke RD, Ferraro F, Paschalaki KE, Dryden NH, McKinnon TA, Sutton RE, Payne EM, Haskard DO, Hughes AD, Cutler DF, Laffan MA, Randi AM (2011) Endothelial von Willebrand factor regulates angiogenesis. Blood 117(3):1071–1080CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Gritti G, Cortelezzi A, Bucciarelli P, Rezzonico F, Lonati S, LaMarca S et al (2011) Circulating and progenitor endothelial cells are abnormal in patients with different types of von Willebrand disease and correlate with markers of angiogenesis. Am J Hematol 86(3):650–656CrossRefPubMedGoogle Scholar
  31. 31.
    Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370(8):699–708CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ay C, Dunkler D, Pirker R, Thaler J, Quehenberger P, Wagner O, Zielinski C, Pabinger I (2012) HighD-dimer levels are associated with poor prognosis in cancer patients. Haematologica 97(8):1158–1164CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Reitter EM, Kaider A, Ay C, Quehenberger P, Marosi C, Zielinski C, Pabinger I (2016) Longitudinal analysis of hemostasis biomarkers in cancer patients during antitumor treatment. J Thromb Haemost 14(2):294–305CrossRefPubMedGoogle Scholar
  34. 34.
    Falanga A, Panova-Noeva M, Russo L (2009) Procoagulant mechanisms in tumour cells. Best Pract Res Clin Haematol 22:49–60CrossRefPubMedGoogle Scholar
  35. 35.
    Lyman GH, Khorana AA (2009) Cancer, clots and consensus: new understanding of an old problem. J Clin Oncol 27(29):4821–4826CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Andrea Pace
    • 1
  • Chiara Mandoj
    • 2
  • Anna Antenucci
    • 2
  • Veronica Villani
    • 1
  • Isabella Sperduti
    • 3
  • Beatrice Casini
    • 4
  • Mariantonia Carosi
    • 4
  • Alessandra Fabi
    • 5
  • Antonello Vidiri
    • 6
  • Tatiana Koudriavtseva
    • 1
  • Laura Conti
    • 2
  1. 1.Neuroncology, Department of Clinical Experimental OncologyRegina Elena National Cancer Institute, IFORomeItaly
  2. 2.Clinical Pathology, Department of Clinical Experimental OncologyRegina Elena National Cancer Institute, IFORomeItaly
  3. 3.Biostatistics, Scientific DirectionRegina Elena National Cancer Institute, IFORomeItaly
  4. 4.Division of Pathology“Regina Elena” National Cancer InstituteRomeItaly
  5. 5.Division of Medical Oncology“Regina Elena” National Cancer InstituteRomeItaly
  6. 6.Service of Neuroradiology“Regina Elena” National Cancer InstituteRomeItaly

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