Correlation of serum urokinase plasminogen activator (uPA) to progression of recurrent malignant glioma during bevacizumab treatment: A marker of invasive phenotype and a candidate to monitor therapy

Abstract

2059 Background: Identification of circulating markers that predict tumor response or reflect progression is of crucial importance when using antiangiogenic agents. However, to date, no such parameters have been identified particularly for bevacizumab, for which, recently, increasing data have supported a role in patient with recurrent malignant glioma. Methods: Serial serum levels of VEGF, VEGFR2, FGF, SDFα, urokinase plasminogen activator (uPA), plasminogen activator inhibitor type I (PAI-1), and metalloprotesase type 9 (MMP9) were determined in a cohort of 32 patients treated with bevacizumab and irinotecan for recurrent malignant glioma. Samples were collected at the start of treatment and then at 4 weeks intervals until progression. Serum levels were measured using an enzyme-linked immunosorbent assay. Progression was defined by MacDonald's criteria, modified by integrating increase of infiltration as measured on MRI by Flair sequence. All subjects were followed for PFS and OS. Cox model analysis is used for correlation between markers and clinical outcome. Results: This preliminary analysis is restricted to pre-treatment (D0; n = 32), day 30 (D30; n = 27), and at progression time (DP; n = 15). None of the pretreatment serum level (n = 32) significantly affect PFS or OS although uPA and MMP9 tend to influence OS. Decrease of median level of all serum markers except PAI1 and VEGFR2 is observed from D0 to D30 under bevacizumab therapy, but only uPA and FGF variations tend to impact clinical outcome. From D30 to DP, increase of uPA is correlated to PFS (p = 0.028) while the observed increased of FGF and SDFα fail to reach significant correlation to PFS and OS. Conclusions: Increase of uPA serum level appear to be correlated to disease progression for patients with recurrent malignant glioma treated with bevacizumab and may reflect the invasive phenotype of glioma progression. Serum uPA may help in assessing treatment response under bevacizumab and warrant further studies. No significant financial relationships to disclose.

Bevacizumab for the Treatment of Recurrent Glioblastoma

“…Proposed research methods for evaluating response to bevacizumab include assaying for angiogenic factors (eg, serum or urinary VEGF, basic fibroblast growth factor, matrix metalloproteinase, or urokinase plasminogen activator) or ex vivo markers (eg, circulating endothelial cells); biopsy analysis (to determine tumor density and drug–target interactions); and radiographic assessment (calculating fuoro-L-thymidine-PET response, changes in the apparent diffusion coefficient, or the ratio of fluid-attenuated inversion-recovery [FLAIR] volume to contrast-enhancing tumor volume). 67,69–73…”

“…Proposed research methods for evaluating response to bevacizumab include assaying for angiogenic factors (eg, serum or urinary VEGF, basic fibroblast growth factor, matrix metalloproteinase, or urokinase plasminogen activator) or ex vivo markers (eg, circulating endothelial cells); biopsy analysis (to determine tumor density and drugtarget interactions); and radiographic assessment (calculating fluoro-L-thymidine-PET response, changes in the apparent diffusion coefficient, or the ratio of fluid-attenuated inversion-recovery [FLAIR] volume to contrast-enhancing tumor volume). 67,[69][70][71][72][73] As a secondary benefit, bevacizumab has been shown to decrease both tumoral and peritumoral edema in patients with GBM, thereby reducing the requirement for chronic corticosteroid use. Several studies have reported that corticosteroid reductions were feasible in 33% to 59% of patients with recurrent GBM following bevacizumab treatment, 32,34,36,46,49,74 and 2 trials have reported average corticosteroid dose reductions of 72% and 59%, 36,74 respectively.…”

Bevacizumab: Review of Development, Pharmacology, and Application to Brain Tumors

“…Another study has evaluated circulating serum levels of markers that may predict tumor response or progression during treatment with bevacizumab and irinotecan. 120 In a series of 32 patients with recurrent malignant gliomas, serial serum levels of VEGF, VEGFR-2, FGF, urokinase plasminogen activator (uPA), plasminogen activator inhibitor type I (PAI-1), and MMP-9 were drawn pre-treatment and at four week intervals until progression. None of the pre-treatment serum levels significantly affected PFS or overall survival.…”