Abstract
BackgroundAntiangiogenic treatment of glioblastomas with Bevacizumab lacks predictive markers. Myoinositol (MI) is an organic osmolyte, with intracellular concentration changes depending on the extracellular osmolality. Since Bevacizumab markedly reduces tumor edema and influences the tumor microenvironment, we investigated whether the MI concentration in the tumor changes during therapy.MethodsWe used 1H-magnetic resonance spectroscopy to measure the MI concentrations in the tumor and contralateral control tissue of 39 prospectively recruited patients with recurrent glioblastomas before and 8–12 weeks after starting therapy. 30 patients received Bevacizumab and 9 patients were treated with CCNU/VM26 as control. We performed a survival analysis to evaluate MI as a predictive biomarker for Bevacizumab therapy.ResultsMI concentrations increased significantly during Bevacizumab therapy in tumor (p < .001) and control tissue (p = .001), but not during CCNU/VM26 treatment. For the Bevacizumab cohort, higher MI concentrations in the control tissue at baseline (p = .021) and higher differences between control and tumor tissue (delta MI, p = .011) were associated with longer survival. A Kaplan-Meier analysis showed a median OS of 164 days for patients with a deltaMI < 1,817 mmol/l and 275 days for patients with a deltaMI > 1,817 mmol/l. No differences were observed for the relative changes or the post treatment concentrations. Additionally calculated creatine concentrations showed no differences in between subgroups or between pre and post treatment measurements.ConclusionOur data suggest that recurrent glioblastoma shows a strong metabolic reaction to Bevacizumab. Further, our results support the hypothesis that MI might be a marker for early tumor cell invasion. Pre-therapeutic MI concentrations are predictive of overall survival in patients with recurrent glioblastoma treated with Bevacizumab.
Highlights
The use of the monoclonal VEGF blocking antibody Bevacizumab (BVZ) has a strong biological rationale in glioblastoma [1,2]
We used 1H-magnetic resonance spectroscopy to measure the MI concentrations in the tumor and contralateral control tissue of 39 prospectively recruited patients with recurrent glioblastomas before and 8–12 weeks after starting therapy. 30 patients received Bevacizumab and 9 patients were treated with CCNU/VM26 as control
Our data suggest that recurrent glioblastoma shows a strong metabolic reaction to Bevacizumab
Summary
The use of the monoclonal VEGF blocking antibody Bevacizumab (BVZ) has a strong biological rationale in glioblastoma [1,2]. In first-line therapy, the RTOG 0825 study and the AVAglio study failed to demonstrate a benefit regarding overall survival [5,6]. Bevacizumab in combination with lomustine did not result in an overall survival benefit compared to lomustine alone in glioblastoma at first recurrence. The use of bevacizumab in first line therapy or at first recurrence is not justified. There are biomarkers that can identify patients that benefit from bevacizumab. None of these biomarkers is applicable and/or validated. Since Bevacizumab markedly reduces tumor edema and influences the tumor microenvironment, we investigated whether the MI concentration in the tumor changes during therapy
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