Generic placeholder image

Current Reviews in Clinical and Experimental Pharmacology


ISSN (Print): 2772-4328
ISSN (Online): 2772-4336


Efficacy of Anti-VEGF Drugs Based Combination Therapies in Recurrent Glioblastoma: Systematic Review and Meta-Analysis

Author(s): Vinod Solipuram, Ramin Soltani, BP Venkatesulu, Saketh Annam, Firoozeh Alavian and Sorayya Ghasemi*

Volume 19, Issue 2, 2024

Published on: 26 August, 2022

Page: [173 - 183] Pages: 11

DOI: 10.2174/2772432817666220517163609

Price: $65


Background: Recurrent glioblastoma multiforme (rGBM) has a grim prognosis, with current therapies offering no survival benefit. Several combination therapies involving anti-VEGF agents have been studied with mixed results.

Methods: A systematic search was performed using five electronic databases: PubMed, Scopus, ISI, Embase, and the Cochrane Library, without language limitations. The primary outcome of interest was progression-free survival (PFS). Secondary outcomes were overall survival (OS), objective response ratio (ORR), and grade ≥ 3 adverse events. Estimates for PFS and OS were calculated as random effects hazard ratio (HR) with 95% confidence intervals (CIs) using the generic inverse variance method. Estimates for ORR and grade ≥ 3 adverse events were calculated using a random-effects risk ratio (RR) with 95% confidence intervals (CIs) using the Mantel-Haenszel method.

Results: Thirteen studies met the inclusion criteria and a total of 1994 patients were included in the analysis. There was no statistically significant improvement in PFS (HR 0.84; 95% CI (0.68, 1.03); I2=81%), OS (HR 0.99; 95% CI (0.88, 1.12); I2=0%), and ORR (RR 1.36; 95% CI (0.96, 1.92); I2=61%) in the combination therapy group when compared to the control group. Significantly higher grade ≥ 3 adverse events (RR 1.30; 95% CI (1.14, 1.48); I2=47%) were seen in the combination therapy when compared to the control group.

Conclusion: Our analysis showed that the use of combination therapy with anti-VEGF agents did not offer any benefit in PFS, OS, or ORR. In contrast, it had significantly higher grade 3-5 adverse events. Further studies are needed to identify effective therapies in rGBM that can improve survival.

Keywords: GBM, vascular endothelial growth factors, anti-angiogenic therapy, bevacizumab, angiogenesis, rGBM.

Graphical Abstract
Bähr O, Herrlinger U, Weller M, Steinbach JP. Very late relapses in glioblastoma long-term survivors. J Neurol 2009; 256(10): 1756-8.
[] [PMID: 19434438]
Khan I, Mahfooz S, Elbasan EB, Karacam B, Oztanir MN, Hatiboglu MA. Targeting glioblastoma: The current state of different therapeutic approaches. Curr Neuropharmacol 2021; 19(10): 1701-15.
[] [PMID: 33441071]
Jiang H, Yu K, Li M, et al. Classification of progression patterns in glioblastoma: Analysis of predictive factors and clinical implications. Front Oncol 2020; 10: 590648.
[] [PMID: 33251147]
Bredlau AL, Dixit S, Chen C, Broome A-M. Nanotechnology applications for diffuse intrinsic pontine glioma. Curr Neuropharmacol 2017; 15(1): 104-15.
[] [PMID: 26903150]
Johung TB, Monje M. Diffuse intrinsic pontine glioma: New pathophysiological insights and emerging therapeutic targets. Curr Neuropharmacol 2017; 15(1): 88-97.
[] [PMID: 27157264]
Ahir BK, Engelhard HH, Lakka SS. Tumor development and angiogenesis in adult brain tumor: Glioblastoma. Mol Neurobiol 2020; 57(5): 2461-78.
[] [PMID: 32152825]
Shibuya M. VEGF-VEGFR system as a target for suppressing inflammation and other diseases. Endocr, Metab Immune Disord Drug Targets 2015; 15(2): 135-44.
Jászai J, Schmidt MHH. Trends and challenges in tumor anti-angiogenic therapies. Cells 2019; 8(9): 1102.
[] [PMID: 31540455]
Cloughesy TF, Brenner A, de Groot JF, et al. A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE). Neuro-oncol 2020; 22(5): 705-17.
[] [PMID: 31844890]
Russell SM, Elliott R, Forshaw D, Golfinos JG, Nelson PK, Kelly PJ. Glioma vascularity correlates with reduced patient survival and increased malignancy. Surg Neurol 2009; 72(3): 242-6.
[] [PMID: 19329156]
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009; 27(28): 4733-40.
[] [PMID: 19720927]
Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009; 27(5): 740-5.
[] [PMID: 19114704]
Ruan WC, Che YP, Ding L, Li HF. Efficacy and toxicity of addition of bevacizumab to chemotherapy in patients with metastatic colorectal cancer. Comb Chem High Throughput Screen 2018; 21(10): 718-24.
[] [PMID: 30663563]
Snyder M, Bottiglieri S, Almhanna K. Impact of primary tumor location on first-line bevacizumab or cetuximab in metastatic colorectal cancer. Rev Recent Clin Trials 2018; 13(2): 139-49.
[] [PMID: 29595113]
Ghiaseddin A, Peters KB. Use of bevacizumab in recurrent glioblastoma. CNS Oncol 2015; 4(3): 157-69.
[] [PMID: 25906439]
Li Y, Hou M, Lu G, Ciccone N, Wang X, Zhang H. The prognosis of anti-angiogenesis treatments combined with standard therapy for newly diagnosed glioblastoma: A meta-analysis of randomized controlled trials. PLoS One 2016; 11(12): e0168264.
[] [PMID: 28005980]
Martens T, Schmidt NO, Eckerich C, et al. A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res 2006; 12(20 Pt 1): 6144-52.
[] [PMID: 17062691]
Lu KV, Bergers G. Mechanisms of evasive resistance to anti-VEGF therapy in glioblastoma. CNS Oncol 2013; 2(1): 49-65.
[] [PMID: 23750318]
Huang J, Soffer SZ, Kim ES, et al. Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis. Mol Cancer Res 2004; 2(1): 36-42.
[PMID: 14757844]
Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane collaboration’s tool for assessing risk of bias in randomised trials BMJ 2011; 343(oct18 2): d5928.
[] [PMID: 22008217]
Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: Elaboration and explanation. BMJ 2015; 354: i 4086.
[] [PMID: 25555855]
Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials 1996; 17(1): 1-12.
[] [PMID: 8721797]
Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007; 8(1): 16.
[] [PMID: 17555582]
JPT Higgins, Green S, Eds. . Obtaining standard deviations from standard errors. In: Cochrane Handbook for Systematic Reviews of Interventions Version 510. 2011.
Batchelor TT, Mulholland P, Neyns B, et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 2013; 31(26): 3212-8.
[] [PMID: 23940216]
Brandes AA, Gil-Gil M, Saran F, et al. A randomized phase II Trial (TAMIGA) evaluating the efficacy and safety of continuous bevacizumab through multiple lines of treatment for recurrent glioblastoma. Oncologist 2019; 24(4): 521-8.
[] [PMID: 30266892]
Cloughesy T, Finocchiaro G, Belda-Iniesta C, et al. Randomized, double-blind, placebo-controlled, multicenter phase II study of onartuzumab plus bevacizumab versus placebo plus bevacizumab in patients with recurrent glioblastoma: Efficacy, safety, and hepatocyte growth factor and O (6)-methylguanine-DNA methyltransferase biomarker analyses. J Clin Oncol 2017; 35(3): 343-51.
[] [PMID: 27918718]
Field KM, Simes J, Nowak AK, et al. Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma. Neurooncol 2015; 17(11): 1504-13.
[] [PMID: 26130744]
Galanis E, Anderson SK, Twohy EL, et al. A phase 1 and randomized, placebo-controlled phase 2 trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma: Alliance/North Central Cancer Treatment Group N0872. Cancer 2019; 125(21): 3790-800.
[] [PMID: 31290996]
Lee EQ, Zhang P, Wen PY, et al. NRG/RTOG 1122: A phase 2, double-blinded, placebo-controlled study of bevacizumab with and without trebananib in patients with recurrent glioblastoma or gliosarcoma. Cancer 2020; 126(12): 2821-8.
[] [PMID: 32154928]
Nayak L, Molinaro AM, Peters K, et al. Randomized phase II and biomarker study of pembrolizumab plus bevacizumab versus pembrolizumab alone for patients with recurrent glioblastoma. Clin Cancer Res 2021; 27(4): 1048-57.
[] [PMID: 33199490]
Puduvalli VK, Wu J, Yuan Y, et al. A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma. Neuro-oncol 2020; 22(10): 1505-15.
[] [PMID: 32166308]
Taal W, Oosterkamp HM, Walenkamp AM, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): A randomised controlled phase 2 trial. Lancet Oncol 2014; 15(9): 943-53.
[] [PMID: 25035291]
Weathers SP, Han X, Liu DD, et al. A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma. J Neurooncol 2016; 129(3): 487-94.
[] [PMID: 27406589]
Wick W, Gorlia T, Bendszus M, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med 2017; 377(20): 1954-63.
[] [PMID: 29141164]
Huang Y, Yuan J, Righi E, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci USA 2012; 109(43): 17561-6.
[] [PMID: 23045683]
Wang B, Tian KW, Zhang F, Jiang H, Han S. Angiopoietin-1 and C16 peptide attenuate vascular and inflammatory responses in experimental allergic encephalomyelitis. CNS & Neurol Disord Drug Targets 2016; 15(4): 496-513.
Lu X. Structure and function of angiopoietin-like protein 3 (ANGPTL3) in atherosclerosis. Curr Med Chem 2020; 27(31): 5159-74.
[] [PMID: 31223079]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy