Apparent diffusion coefficient histogram analysis stratifies progression-free and overall survival in patients with recurrent GBM treated with bevacizumab: a multi-center study

Abstract

We have tested the predictive value of apparent diffusion coefficient (ADC) histogram analysis in stratifying progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients with recurrent glioblastoma multiforme (GBM) from the multi-center BRAIN study. Available MRI’s from patients enrolled in the BRAIN study (n = 97) were examined by generating ADC histograms from areas of enhancing tumor on T1 weighted post-contrast images fitted to a two normal distribution mixture curve. ADC classifiers including the mean ADC from the lower curve (ADC-L) and the mean lower curve proportion (LCP) were tested for their ability to stratify PFS and OS by using Cox proportional hazard ratios and the Kaplan–Meier method with log-rank test. Mean ADC-L was 1,209 × 10−6mm2/s ± 224 (SD), and mean LCP was 0.71 ± 0.23 (SD). Low ADC-L was associated with worse outcome. The hazard ratios for 6-month PFS, overall PFS, and OS in patients with less versus greater than mean ADC-L were 3.1 (95 % confidence interval: 1.6, 6.1; P = 0.001), 2.3 (95 % CI: 1.3, 4.0; P = 0.002), and 2.4 (95 % CI: 1.4, 4.2; P = 0.002), respectively. In patients with ADC-L<1,209 and LCP>0.71 versus ADC-L>1,209 and LCP <0.71, there was a 2.28-fold reduction in the median time to progression, and a 1.42-fold decrease in the median OS. The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multi-center (BRAIN) study.

Pretreatment ADC Histogram Analysis Is a Predictive Imaging Biomarker for Bevacizumab Treatment but Not Chemotherapy in Recurrent Glioblastoma

“…Conversely, patients with ADCL Յ 1.2 m 2 /ms do not appear to benefit from bevacizumab therapy at recurrence, and it may, in fact, perform slightly worse than standard therapies (Fig 3C). These current results, along with results from previous studies, 9,19 support the use of ADC histogram analysis in recurrent GBM to guide the use of bevacizumab in second-line therapy. The precise mechanism and biologic correlates for survival differences based on ADC histogram analysis remain controversial.…”

“…Although previous studies have demonstrated the ability of pretreatment ADC histogram analysis to predict recurrent GBM response to bevacizumab in both single- 9 and multicenter clinical trials, 19 a significant question remained as to whether this type of analysis is a predictive biomarker, specific to bevacizumab therapy, or whether it is a prognostic biomarker independent of the type of treatment. A previous study 9 did suggest that pretreatment ADC histogram analysis could predict response to recurrent GBM treated with bevacizumab, but not in matched patients with recurrent GBM treated with a non-VEGF-targeted investigative antiangiogenic agent.…”

“…High-risk patients were identified by ADCL Յ 1.2 m 2 / ms, whereas low-risk patients were identified by ADCL Ͼ 1.2 m 2 /ms, based on empiric thresholds identified in previous studies. 9,10,19,20 …”

“…Previous results have shown that pretreatment ADC histogram analysis performed within the contrast-enhancing tumor regions can stratify patients with recurrent GBM into high-and low-risk groups. When using a double Gaussian mixed model to represent the ADC histogram, previous studies have shown that a lower mean value of the Gaussian curve (ADC L ) results in a significantly shorter progression-free survival (PFS) and overall survival (OS) in both single-institution 9 and multicenter clinical trial data 19 when evaluating bevacizumab in malignant gliomas. An important question remains as to whether ADC histogram analysis is a predictive biomarker specific to antiangiogenic therapy in recurrent GBM or whether it is a predictive biomarker independent of the particular treatment administered.…”

A Prognostic Model Based on Preoperative MRI Predicts Overall Survival in Patients with Diffuse Gliomas

“…26 These results support the findings, in a group of 39 highgrade gliomas, previously published by Hamstra et al, 27 who reported that tumor assessment based on functional diffusion maps provides an early biomarker for response, time to progression, and overall survival in patients in malignant gliomas. Recently, Pope et al 28,29 demon- Note:--indicates that at the end of follow-up, patients had not reached median overall survival. strated the relevance of ADC values in the management of gliomas.…”