Korean J Radiol.  2020 Apr;21(4):471-482. 10.3348/kjr.2019.0839.

Optimized Image-Based Surrogate Endpoints in Targeted Therapies for Glioblastoma: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Affiliations
  • 1Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea. radhskim@gmail.com

Abstract


OBJECTIVE
We aimed to determine the optimized image-based surrogate endpoints (IBSEs) in targeted therapies for glioblastoma through a systematic review and meta-analysis of phase III randomized controlled trials (RCTs).
MATERIALS AND METHODS
A systematic search of OVID-MEDLINE and EMBASE for phase III RCTs on glioblastoma was performed in December 2017. Data on overall survival (OS) and IBSEs, including progression-free survival (PFS), 6-month PFS (6moPFS), 12-month PFS (12moPFS), median PFS, and objective response rate (ORR) were extracted. Weighted linear regression analysis for the hazard ratio for OS and the hazard ratios or odds ratios for IBSEs was performed. The associations between IBSEs and OS were evaluated. Subgroup analyses according to disease stage (newly diagnosed glioblastoma versus recurrent glioblastoma), types of test treatment, and types of response assessment criteria were performed.
RESULTS
Twenty-three phase III RCTs published between 2000 and 2017, including 8387 patients, met the inclusion criteria. OS showed strong correlations with PFS (standardized β coefficient [R] = 0.719), 6moPFS (R = 0.647), and 12moPFS (R = 0.638). OS showed no correlations with median PFS and ORR. In subgroup analysis according to types of therapies, PFS showed the highest correlations with OS in targeted therapies for cell cycle pathways (R = 0.913) and growth factor receptors and their downstream pathways (R = 0.962). 12moPFS showed the highest correlation with OS in antiangiogenic therapy (R = 0.821). The response assessment in neuro-oncology criteria provided higher correlation coefficients between OS and IBSEs than the Macdonald criteria.
CONCLUSION
Overall, PFS is an optimized IBSE in targeted therapies for glioblastoma; however, 12moPFS is optimal in antiangiogenic therapy.

Keyword

Glioblastoma; Randomized controlled trial; Biomarkers; Molecular targeted therapy

MeSH Terms

Biomarkers*
Cell Cycle
Disease-Free Survival
Glioblastoma*
Humans
Linear Models
Molecular Targeted Therapy
Odds Ratio
Receptors, Growth Factor
Biomarkers
Receptors, Growth Factor

Figure

  • Fig. 1 Study flow diagram.

  • Fig. 2 Correlation of PFS with OS according to disease entity and types of targeted treatment.A. Bar charts show correlation coefficients according to disease entity and types of targeted treatment. B. Plots show correlation of HR for PFS with HR for OS and that of OR for 12moPFS and HR for OS according to disease entity and types of targeted treatment. GBM = glioblastoma, HR = hazard ratio, IBSEs = image-based surrogate endpoints, OR = odds ratio, OS = overall survival, PFS = progression-free survival, 6moPFS = 6-month PFS, 12moPFS = 12-month PFS

  • Fig. 3 Correlation of PFS with OS according to disease entity and response assessment criteriaA. Bar chart shows correlation coefficients according to response assessment criteria. B. Plots show correlation of HR for PFS with HR for OS and that of OR for 12moPFS and HR for OS according to disease entity and response assessment criteria. RANO = response assessment in neuro-oncology


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