Diffusion MRI quality control and functional diffusion map results in ACRIN 6677/RTOG 0625: A multicenter, randomized, phase II trial of bevacizumab and chemotherapy in recurrent glioblastoma

Abstract

Functional diffusion mapping (fDM) is a cancer imaging technique that quantifies voxelwise changes in apparent diffusion coefficient (ADC). Previous studies have shown value of fDMs in bevacizumab therapy for recurrent glioblastoma multiforme (GBM). The aim of the present study was to implement explicit criteria for diffusion MRI quality control and independently evaluate fDM performance in a multicenter clinical trial (RTOG 0625/ACRIN 6677). A total of 123 patients were enrolled in the current multicenter trial and signed institutional review board-approved informed consent at their respective institutions. MRI was acquired prior to and 8 weeks following therapy. A 5-point QC scoring system was used to evaluate DWI quality. fDM performance was evaluated according to the correlation of these metrics with PFS and OS at the first follow-up time-point. Results showed ADC variability of 7.3% in NAWM and 10.5% in CSF. A total of 68% of patients had usable DWI data and 47% of patients had high quality DWI data when also excluding patients that progressed before the first follow-up. fDM performance was improved by using only the highest quality DWI. High pre-treatment contrast enhancing tumor volume was associated with shorter PFS and OS. A high volume fraction of increasing ADC after therapy was associated with shorter PFS, while a high volume fraction of decreasing ADC was associated with shorter OS. In summary, DWI in multicenter trials are currently of limited value due to image quality. Improvements in consistency of image quality in multicenter trials are necessary for further advancement of DWI biomarkers.

Progressing Bevacizumab-Induced Diffusion Restriction Is Associated with Coagulative Necrosis Surrounded by Viable Tumor and Decreased Overall Survival in Patients with Recurrent Glioblastoma

“…Diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps measure the free diffusion of water in tissue. ADC has been shown to inversely correlate with tumor cellularity in glioma 14,15 , and ADC difference maps, or functional diffusion maps, are predictive of response to chemotherapy 16,17 , radiotherapy 18 , and bevacizumab 19,20 .…”

Restriction spectrum imaging predicts response to bevacizumab in patients with high-grade glioma

“…18 -21 Collectively, these methods demonstrate initial promise in the prediction and evaluation of response to bevacizumab; however, results have occasionally been conflicting, with some studies reporting that a lower ADC is associated with shorter PFS and OS 10,15,16,22 and others reporting that a higher ADC is associated with shorter PFS and OS. 20,23 Although the reason for opposing findings is not entirely clear, a more direct marker of tumor cellularity within the voxel itself (eg, restricted diffusion within cells) that is not influenced by edema and other pathologies in the extracellular matrix would greatly simplify the interpretation of DWI changes and could improve the evaluation of treatment response.…”

MR Imaging Biomarkers in Oncology Clinical Trials

“…The standard image acquisition techniques used to acquire DWIs are susceptible to image artifacts (58). In the ACRIN 6677/RTOG 0625 trial (65), only 47% of the 123 patients had high quality diffusion data free of image distortion and only 68% were considered usable. The complex physiological factors that affect ADC measurements are also a limitation.…”

“…It is generally assumed that the measured ADC primarily reflects tumor cellularity; however, there are several biological processes (e.g., edema and perfusion) that can affect ADC values. Ellingson et al (65) hypothesized that the increase in ADC they measured in patients who sown early disease progression was an indicator that the drug was not effectively reducing vascular edema rather than a change in tumor cellularity. Data analysis methods must be validated as well.…”