Aim Conduct a systematic review of the effectiveness of systemic therapies for adult recurrent glioblastoma (rGBM). Methods We electronically searched for randomized controlled trials from three major databases and four conferences from 2009-Dec 2020. Two independent reviewers conducted screening, data extraction, and quality assessment. Results 48 randomized trials were identified. Outcome reporting was inconsistent: overall survival (OS) in 46 studies, progression free survival in 37 studies, 6-month PFS in 30 studies, objective response rate in 28 studies, and 6-month OS in 7 studies. Network meta-analysis was not feasible due to heterogeneity in outcome reporting and single-study linkages. Most studies compared lomustine (8 studies), bevacizumab (18), or temozolomide (8) with other treatments. The median OS across all studies ranged from 3-17.6 months. Conclusions Based on level one evidence, there is no superior systemic regimen for rGBM. rGBM is a heterogeneous population with no single regimen demonstrating OS benefit. Registration number: CRD42020148512
