A systematic review and meta-analysis of topoisomerase inhibition in pre-clinical glioma models

Abstract

Malignant glioma is a devastating disease affecting both adults and children with limited treatment strategies. Pre-clinical animal studies are critical to the development and planning of novel treatment designs for human clinical trials. Topoisomerases has been a target of interest in the treatment of high grade gliomas, such as glioblastoma, in the past years. Here we assess pre-clinical glioma literature with the aim to identify predictive variables that favour treatment outcomes from topoisomerase inhibition. Data was extracted from 90 experimental comparisons, this was divided based on available survival (n = 61) and tumor volume (n = 29) data. The meta-analysis revealed that the overall effect of topoisomerase inhibition prolonged survival by a factor of 1.33 (95% CI: 1.23-1.43) and reduced tumor growth by a factor of 3.21 (95% CI: 1.99-5.88), with considerable between-study heterogeneity. Multivariable meta-regression identified glioma model, type of control, route of drug administration and drug of choice to be predictive of improved survival outcome. Publication bias assessment by contour-enhanced funnel plots, Egger's regression test and trim and fill analysis showed evidence of publication bias in all studies. This study identified multiple study design factors that should be taken into consideration to improve the translation of pre-clinical investigation of topoisomerase inhibition into clinical use.