Early post-bevacizumab progression on contrast-enhanced MRI as a prognostic marker for overall survival in recurrent glioblastoma: results from the ACRIN 6677/RTOG 0625 Central Reader Study

Abstract

Background: RTOG 0625/ACRIN 6677 is a multicenter, randomized, phase II trial of bevacizumab with irinotecan or temozolomide in recurrent glioblastoma (GBM). This study investigated whether early posttreatment progression on FLAIR or postcontrast MRI assessed by central reading predicts overall survival (OS).

Methods: Of 123 enrolled patients, 107 had baseline and at least 1 posttreatment MRI. Two central neuroradiologists serially measured bidimensional (2D) and volumetric (3D) enhancement on postcontrast T1-weighted images and volume of FLAIR hyperintensity. Progression status on all posttreatment MRIs was determined using Macdonald and RANO imaging threshold criteria, with a third neuroradiologist adjudicating discrepancies of both progression occurrence and timing. For each MRI pulse sequence, Kaplan-Meier survival estimates and log-rank test were used to compare OS between cases with or without radiologic progression.

Results: Radiologic progression occurred after 2 chemotherapy cycles (8 weeks) in 9 of 97 (9%), 9 of 73 (12%), and 11 of 98 (11%) 2D-T1, 3D-T1, and FLAIR cases, respectively, and 34 of 80 (43%), 21 of 58 (36%), and 37 of 79 (47%) corresponding cases after 4 cycles (16 weeks). Median OS among patients progressing at 8 or 16 weeks was significantly less than that among nonprogressors, as determined on 2D-T1 (114 vs 278 days and 214 vs 426 days, respectively; P < .0001 for both) and 3D-T1 (117 vs 306 days [P < .0001] and 223 vs 448 days [P = .0003], respectively) but not on FLAIR (201 vs 276 days [P = .38] and 303 vs 321 days [P = .13], respectively).

Conclusion: Early progression on 2D-T1 and 3D-T1, but not FLAIR MRI, after 8 and 16 weeks of anti-vascular endothelial growth factor therapy has highly significant prognostic value for OS in recurrent GBM.

Keywords: bevacizumab and irinotecan; imaging biomarker; overall survival; progression; recurrent glioblastoma.

Fig. 1.

Kaplan-Meier survival curves stratified by radiologic progression status on 2D-T1 (top row), 3D-T1 (middle row), and FLAIR (bottom row) imaging at 8 weeks (left column) and 16 weeks (right column) after initiation of anti-VEGF therapy, with associated P values. At both 8 and 16 weeks, there was statistically significant difference between the survival curves for progressors (dashed curves) and nonprogressors (solid curves) on 2D-T1 and 3D-T1, but not FLAIR.

Fig. 2.

Kaplan-Meier survival curves stratified by radiologic progression status on 2D-T1 (top row) and 3D-T1 (bottom row) imaging at 8 weeks (left column) and 16 weeks (right column) after initiation of anti-VEGF therapy, with substratification of patients who had not progressed (nonprogressors) into those showing partial or complete response (responders) and those without response (nonresponder, nonprogressors [NR-NPs]). Listed P values are between responders and NR-NPs. At both 8 and 16 weeks, there was no statistically significant difference between the survival curves for responders (dot-dash curves) and NR-NPs (solid curves) on 2D-T1 or 3D-T1. Although not statistically significant, there is better visual separation of Kaplan-Meier curves between the responders and NR-NPs for 3D-T1 than for 2D-T1.

Fig. 3.

Kaplan-Meier survival curves stratified into patients not progressing on T1 or FLAIR (nonprogressors) and progressing on FLAIR but not T1 (isolated FLAIR progressors) for 2D-T1 (top row) and 3D-T1 (bottom row) at 8 weeks (left column) and 16 weeks (right column) after initiation of anti-VEGF therapy. Isolated FLAIR progressors (dashed curves) had no statistically significant reduction in survival time, compared with the nonprogressors (solid curves).