Blood Biomarkers of Glioma in Response Assessment Including Pseudoprogression and Other Treatment Effects: A Systematic Review

Imaging-based monitoring of disease burden in glioma patients is frequently confounded by treatment effects. Circulating biomarkers could theoretically augment imaging-based response monitoring. This systematic review aimed to present and evaluate evidence for differential expression and diagnostic accuracy of circulating biomarkers with respect to outcomes of tumor response, progression, stable disease, and treatment effects (pseudoprogression, radionecrosis, pseudoresponse, and pseudolesions) in patients undergoing treatment for World Health Organization grades II-IV diffuse astrocytic and oligodendroglial tumors. MEDLINE, EMBASE, Web Of Science, and SCOPUS databases were searched until August 18, 2019, for observational or diagnostic studies on multiple circulating biomarker types: extracellular vesicles, circulating nucleic acids, circulating tumor cells, circulating proteins, and metabolites, angiogenesis related cells, immune cells, and other cell lines. Methodological quality of included studies was assessed using an adapted Quality Assessment of Diagnostic Accuracy Studies-2 tool, and level of evidence (IA-IVD) for individual biomarkers was evaluated using an adapted framework from the National Comprehensive Cancer Network guidelines on evaluating tumor marker utility. Of 13,202 unique records, 58 studies met the inclusion criteria. One hundred thirty-three distinct biomarkers were identified in a total of 1,853 patients across various treatment modalities. Fifteen markers for response, progression, or stable disease and five markers for pseudoprogression or radionecrosis reached level IB. No biomarkers reached level IA. Only five studies contained data for diagnostic accuracy measures. Overall methodological quality of included studies was low. While extensive data on biomarker dysregulation in varying response categories were reported, no biomarkers ready for clinical application were identified. Further assay refinement and evaluation in larger cohorts with diagnostic accuracy study designs are required. PROSPERO Registration: CRD42018110658.