title: Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts.
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.
authors.affiliation: Department of Medical Oncology, Georges Francois Leclerc Cancer Center, 1 rue du professeur Marion, Dijon 21000, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Lorgis
authors.forename: Geric
authors.initials: G
authors.lastname: Maura
authors.forename: Guillaume
authors.initials: G
authors.lastname: Coppa
authors.forename: Kahina
authors.initials: K
authors.lastname: Hassani
authors.forename: Luc
authors.initials: L
authors.lastname: Taillandier
authors.forename: Bruno
authors.initials: B
authors.lastname: Chauffert
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladoire
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality*; D015331:Cohort Studies; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab
references.citation: J Clin Oncol. 2010 May 1;28(13):2144-50
references.pmid: 20368553
references.citation: Neuro Oncol. 2007 Jan;9(1):29-38
references.pmid: 17108063
references.citation: Neuro Oncol. 2008 Apr;10(2):162-70
references.pmid: 18356283
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2002-7
references.pmid: 8700875
references.citation: Nat Med. 1995 Jan;1(1):27-31
references.pmid: 7584949
references.citation: Neuro Oncol. 2010 Mar;12(3):233-42
references.pmid: 20167811
references.citation: J Clin Oncol. 2008 Jan 10;26(2):271-8
references.pmid: 18182667
references.citation: N Engl J Med. 2005 Mar 10;352(10):987-96
references.pmid: 15758009
references.citation: Clin Cancer Res. 2007 Feb 15;13(4):1253-9
references.pmid: 17317837
references.citation: J Clin Oncol. 1999 Aug;17(8):2572-8
references.pmid: 10561324
references.citation: Neuro Oncol. 2003 Jan;5(1):1-7
references.pmid: 12626127
references.citation: J Clin Oncol. 2009 Oct 1;27(28):4733-40
references.pmid: 19720927
references.citation: N Engl J Med. 2006 Dec 14;355(24):2542-50
references.pmid: 17167137
references.citation: N Engl J Med. 2004 Jun 3;350(23):2335-42
references.pmid: 15175435
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3749-54
references.pmid: 21321221
references.citation: Clin Cancer Res. 2011 Oct 1;17(19):6109-11
references.pmid: 21852387
references.citation: N Engl J Med. 2007 Dec 27;357(26):2666-76
references.pmid: 18160686
references.citation: BMC Cancer. 2010 Jun 02;10:252
references.pmid: 20525214
references.citation: J Neurooncol. 2009 Apr;92(2):149-55
references.pmid: 19043778
references.citation: Nature. 1994 Feb 10;367(6463):576-9
references.pmid: 8107827
references.citation: FASEB J. 2004 Jul;18(10):1111-3
references.pmid: 15132990
references.citation: Nat Rev Neurosci. 2007 Aug;8(8):610-22
references.pmid: 17643088
references.citation: Clin Cancer Res. 2009 Jul 15;15(14):4589-99
references.pmid: 19567589
references.citation: J Clin Oncol. 2003 Jan 1;21(1):60-5
references.pmid: 12506171
references.citation: J Clin Oncol. 2010 Apr 10;28(11):1963-72
references.pmid: 20231676
references.citation: Oncol Rep. 2004 Apr;11(4):863-9
references.pmid: 15010886
references.citation: Adv Cancer Res. 1985;43:175-203
references.pmid: 2581424
references.citation: Anal Quant Cytol Histol. 2004 Aug;26(4):223-9
references.pmid: 15457675
references.citation: Br J Cancer. 2000 Sep;83(5):588-93
references.pmid: 10944597