Assessment of tumor hypoxia and perfusion in recurrent glioblastoma following bevacizumab failure using MRI and 18F-FMISO PET

Abstract

Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and 18F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and 18F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (rs = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (rs = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.

Hijacking Sexual Immuno-Privilege in GBM—An Immuno-Evasion Strategy

“…They found long-term survivors of GBM (>36 months) tend to have slow-growing diffuse tumors with high T1-contrast and high FLAIR signal, whereas short-term survivors (<19 months) tend to have fast-growing focal tumors with little FLAIR signal [5,6]. Huang and colleagues recently demonstrated small hypoxic tumors display little FLAIR signal and correlate with poor outcome, confirming Swanson's work [5][6][7]. The switch from aerobic to anaerobic respiration in cancers results from elevation of active hypoxia-inducible factor 1α (HiF) levels [8].…”

Tumor Vessels Fuel the Fire in Glioblastoma

“…Subsequently, tumor vasculature is functionally abnormal with markedly increased interstitial fluid pressure, aggravating hypoxia and acidosis [ 173 ]. Under such conditions, radiations are less effective because of the hypoxic environment, while drug delivery is dramatically impeded [ 20 , 174 , 175 , 176 ]. This has given birth to the concept of vessel normalization, a strategy aiming to reduce hypoxia, improve drug distribution, and restore immune cell infiltration ( Figure 3 ) [ 177 ].…”

Perfusion and diffusion-weighted imaging parameters: Comparison between pre- and postbiopsy MRI for high-grade glioma

“…Studies have demonstrated the important role of advanced MRI sequences, including DSC-MRI and DWI, in tumor grading, treatment effect prediction, and evaluation of disease progression in patients with glioma. [1][2][3][4][5][6][7][8][21][22][23][24] The protocol employed by these studies included pretreatment MRI alone, posttreatment MRI alone, and both pre-and posttreatment MRI. Studies that analyzed pretreatment MRI did not often specify whether MRI acquisition was performed before biopsy.…”