Skip to main content

Advertisement

SpringerLink
Log in

Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts

  • Clinical Study - Patient Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Bevacizumab is one of the rare drugs that could improve high-grade glioma outcome after failure of chemoradiotherapy. However, to date, there is no biomarker predictive for efficacy of bevacizumab therapy in terms of survival improvement for patients with high-grade glioma. We performed a retrospective analysis of clinical factors associated with patient survival using a training cohort of 110 consecutive patients treated with bevacizumab for recurrent high-grade glioma and an independent validation cohort of 109 patients. In the training cohort, 110 consecutive patients received bevacizumab-based therapy. The number of chemotherapy cycles delivered was 1,411. Median follow-up was 12 months. Thirty-four patients (31%) had objective partial response and 24% had stable disease on magnetic resonance imaging evaluation. Median progression-free survival (PFS) and overall survival (OS) were 4.3 and 9.2 months, respectively. On univariate analysis, among classical prognosis factors, only Karnofsky status ≥70% was associated with improved outcome. Surprisingly, patients with low bevacizumab dose intensity (<5 mg/kg/week) had better PFS (12 vs. 2 months, P < 0.0001) and OS (16 vs. 6 months, P = 0.0002). On multivariate analysis, low bevacizumab dose intensity was the most significant independent prognostic factor of survival. Analysis of the validation cohort yielded similar results, externally validating this observation. This large retrospective study using two independent cohorts of high-grade glioma suggests that the currently recommended dosage of bevacizumab (5 mg/kg/week) is not optimal. Further prospective randomized trials using lower dosages are warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  PubMed  CAS  Google Scholar 

  2. Wong ET, Hess KR, Gleason MJ et al (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578

    PubMed  CAS  Google Scholar 

  3. Lamborn KR, Yung WK, Chang SM et al (2008) Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol 10:162–170

    Article  PubMed  Google Scholar 

  4. Ballman KV, Buckner JC, Brown PD et al (2007) The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme. Neuro Oncol 9:29–38

    Article  PubMed  CAS  Google Scholar 

  5. Yung WK, Albright RE, Olson J et al (2000) A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83:588–593

    Article  PubMed  CAS  Google Scholar 

  6. Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT (2007) Angiogenesis in brain tumours. Nat Rev Neurosci 8:610–622

    Article  PubMed  CAS  Google Scholar 

  7. Gupta K, Radotra BD, Banerjee AK, Nijhawan R (2004) Quantitation of angiogenesis and its correlation with vascular endothelial growth factor expression in astrocytic tumors. Anal Quant Cytol Histol 26:223–229

    PubMed  Google Scholar 

  8. Hong YK, Lange-Asschenfeldt B, Velasco P et al (2004) VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. Faseb J 18:1111–1113

    PubMed  CAS  Google Scholar 

  9. Nam DH, Park K, Suh YL, Kim JH (2004) Expression of VEGF and brain specific angiogenesis inhibitor-1 in glioblastoma: prognostic significance. Oncol Rep 11:863–869

    PubMed  CAS  Google Scholar 

  10. Takano S, Tsuboi K, Matsumura A, Nose T (2003) Anti-vascular endothelial growth factor antibody and nimustine as combined therapy: effects on tumour growth and angiogenesis in human glioblastoma xenografts. Neuro Oncol 5:1–7

    PubMed  CAS  Google Scholar 

  11. Sathornsumetee S, Cao Y, Marcello JE et al (2008) Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol 26:271–278

    Article  PubMed  CAS  Google Scholar 

  12. Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  PubMed  CAS  Google Scholar 

  13. Sandler A, Gray R, Perry MC et al (2006) Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550

    Article  PubMed  CAS  Google Scholar 

  14. Miller K, Wang M, Gralow J et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676

    Article  PubMed  CAS  Google Scholar 

  15. Escudier B, Bellmunt J, Negrier S et al (2010) Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 28:2144–2150

    Article  PubMed  CAS  Google Scholar 

  16. Friedman HS, Prados MD, Wen PY et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740

    Article  PubMed  CAS  Google Scholar 

  17. Wen PY, Macdonald DR, Reardon DA et al (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972

    Article  PubMed  Google Scholar 

  18. Millauer B, Shawver LK, Plate KH, Risau W, Ullrich A (1994) Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367:576–579

    Article  PubMed  CAS  Google Scholar 

  19. Folkman J (1985) Tumor angiogenesis. Adv Cancer Res 43:175–203

    Article  PubMed  CAS  Google Scholar 

  20. Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–31

    Article  PubMed  CAS  Google Scholar 

  21. Parangi S, O’Reilly M, Christofori G et al (1996) Antiangiogenic therapy of transgenic mice impairs de novo tumor growth. Proc Natl Acad Sci USA 93:2002–2007

    Article  PubMed  CAS  Google Scholar 

  22. Vredenburgh JJ, Desjardins A, Herndon JE II et al (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13:1253–1259

    Article  PubMed  CAS  Google Scholar 

  23. Norden AD, Drappatz J, Muzikansky A et al (2009) An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma. J Neurooncol 92:149–155

    Article  PubMed  CAS  Google Scholar 

  24. Xu T, Chen J, Lu Y, Wolff JE (2010) Effects of bevacizumab plus irinotecan on response and survival in patients with recurrent malignant glioma: a systematic review and survival-gain analysis. BMC Cancer 10:252

    Article  PubMed  Google Scholar 

  25. de Groot JF, Fuller G, Kumar AJ et al (2010) Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol 12:233–242

    Article  PubMed  Google Scholar 

  26. Keunen O, Johansson M, Oudin A et al (2011) Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA

  27. Lucio-Eterovic AK, Piao Y, de Groot JF (2009) Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy. Clin Cancer Res 15:4589–4599

    Article  PubMed  CAS  Google Scholar 

  28. de Groot JF (2011) High-dose antiangiogenic therapy for glioblastoma: less may be more? Clin Cancer Res

  29. Kabbinavar F, Hurwitz HI, Fehrenbacher L et al (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60–65

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Georges Francois Leclerc Cancer Center, 1 rue du professeur Marion, Dijon, 21000, France

    Veronique Lorgis, Geric Maura, Sylvain Ladoire & François Ghiringhelli

  2. Neuro-Oncology Unit, Department of Neurology, University Hospital Nancy, Nancy, France

    Guillaume Coppa, Kahina Hassani & Luc Taillandier

  3. Department of Medical Oncology, University Hospital Amiens, Amiens, France

    Bruno Chauffert

  4. University of Burgundy, Faculty of Medicine, Dijon, France

    Lionel Apetoh, Sylvain Ladoire & François Ghiringhelli

  5. INSERM AVENIR Team UMR866, Faculty of Medicine, Dijon, France

    Lionel Apetoh, Sylvain Ladoire & François Ghiringhelli

  6. Department of Pharmacy, University Hospital, Nancy, France

    Guillaume Coppa & Kahina Hassani

Authors
  1. Veronique Lorgis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Geric Maura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guillaume Coppa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kahina Hassani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luc Taillandier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bruno Chauffert
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lionel Apetoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sylvain Ladoire
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. François Ghiringhelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sylvain Ladoire or François Ghiringhelli.

Additional information

V. Lorgis, G. Maura, S. Ladoire, and F. Ghiringhelli share coauthorship.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lorgis, V., Maura, G., Coppa, G. et al. Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts. J Neurooncol 107, 351–358 (2012). https://doi.org/10.1007/s11060-011-0748-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-011-0748-5

Keywords

Search

Navigation