Patterns of Failure in Patients With Recurrent High-Grade Glioma Treated With Hypofractionated Stereotactic Re-Irradiation, Pembrolizumab, and Bevacizumab

Abstract

Patients with high-grade gliomas (HGG) progress despite multimodality therapy. Hypofractionated stereotactic re-irradiation therapy (HFSRT) has been used with promising efficacy as a salvage treatment in the setting of recurrent HGG (rHGG). We recently completed a phase I study combining HFSRT with concurrent pembrolizumab and bevacizumab (Bev) for patients with rHGG (NCT02313272). The main objective of this study is to identify patterns of failure in the above regimen.Data from 32 patients enrolled in the phase I trial from June 2015 to January 2018 were reviewed. Patient characteristics, time to progression, and treatment outcomes were evaluated. Brain MRIs were taken at baseline, and every 6 to 8 weeks until progression. T1 post-contrast and T2- FLAIR images at baseline and at progression were imported into commercial software and the extent of hyperintensity was contoured by a single physician and reviewed by a second physician. An automated algorithm was used to compare the volumetric similarities between the pre- and post-treatment structures. This algorithm used Dice similarity coefficient (DSC), a statistical validating index for evaluating reproducibility and spatial overlap accuracy in the MRI image segmentation. A DSC value of 0.3 or greater indicated significant spatial overlap accuracy. Pearson's single and two-tailed tests were used to identify correlation between time to progression and volumetric parameters.The median age of patients at re-irradiation was 56 years (22-68).24 patients had Bev naïve tumor. The median radiation dose was 35 Gy in 5 fractions (25-40). The median progression free survival was 7.92 months (95% CI:6.31-12.45). A total of 22 (68%) patients with radiological progression were included for this analysis. Considerable similarities were observed (11/22) between the pretreatment T2- FLAIR and the post-treatment T1 contrast: with a median DSC of 0.31(range 0.05-0.6) and pre-treatment T2-FLAIR and post-treatment T2-FLAIR; DSC 0.66 (range 0.15-0.7). The median DSC value comparing pre- and post-treatment T1 contrast volumes were 0.24 (range 0-0.5). These findings suggest that recurrence or progression occurred in the pretreatment T2-FLAIR region outside the pre-treatment post-contrast T1 region. A positive correlation between time to progression with maximum dose received by pre-treatment (P = 0.02) and post-treatment T2-FLAIR (P = 0.02) volumes was observed.Our analysis of a prospective trial of HSFRT with concurrent pembrolizumab and bevacizumab showed recurrences occurred outside the radiation field (i.e., region of T1post contrast abnormality). Recurrences predominantly occurred in the pre-treatment T2-FLAIR region. Including T2-FLAIR region in the pre-treatment GTV contours may be needed in achieving optimal local control.R. Padmanabhan: None. G.G. Zhang: None. D.E. Oliver: None. J. Graham: None. D. Grass: None. S. Sahebjam: Research Grant; Merck, Bristol Myers Squibb and Brooklyn Immuno Therapeutics. Advisory Board; Merck, Boehringer Ingelheim. Travel Expenses; Eli Lilly. H.M. Yu: Honoraria; UpToDate. Speaker's Bureau; BrainLab. Advisory Board; Novocure, AbbVie.