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

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.

Deciphering Time-Dependent DNA Damage Complexity, Repair, and Oxygen Tension: A Mechanistic Model for FLASH-Dose-Rate Radiation Therapy.

PURPOSE: Irradiation with ultrahigh dose rates (FLASH) has reemerged as a promising radiation therapy approach to effectively lower potential damage burden on normal tissue without sacrificing tumor control. However, the large number of recent FLASH studies have been conducted under vastly different experimental conditions and circumstances (ie, investigated biological endpoint, radiation quality, and environmental oxygen level), with unverified biological mechanisms of action and unexplored interplay effect of the main dependencies. To facilitate radiobiological investigation of FLASH phenomena and assessment of clinical applicability, we present an extension of the mechanistic radiobiological model "UNified and VERSatile bio response Engine" (UNIVERSE). METHODS AND MATERIALS: The dynamic (time-dependent) extension of UNIVERSE was developed incorporating fundamental temporal mechanisms necessary for dose-rate effect prediction, ie, DNA damage repair kinetics [DDRK], oxygen depletion and reoxygenation during irradiation. Model performance in various experimental conditions is validated based on a large panel of in vitro and in vivo data from the literature. The effect of dose, dose rate, oxygen tension, tissue-type, beam quality and DDRK is analyzed. RESULTS: UNIVERSE adequately reproduces dose-, dose-rate- and oxygen tension-dependent influence on cell killing. For the studied systems, results indicate that the extent of cell/tissue sparing effect, if present at all, strongly depends on DDRK and beam quality used for reference conventional irradiation. A validated mechanistic framework for predicting clinically relevant endpoints comparing conventional and FLASH high-dose-rate effect has been successfully established, relying on time-dependent processing of radiation-induced damage classes taking variable oxygen tension into account. CONCLUSIONS: Highlighted by UNIVERSE itself, the multidimensional nature of this relative sparing effect using high-dose-rate radiation compared with conventional means underlines the importance of robust quantification of biophysical characteristics and consistent, well-documented experimental conditions both in vitro and in vivo before clinical translation. To further elucidate underlying mechanisms and appraise clinical viability, UNIVERSE can provide reliable prediction for biophysical investigations of radiation therapy using ultrahigh dose rate.

O2 Economizer for Inhibiting Cell Respiration To Combat the Hypoxia Obstacle in Tumor Treatments.

Hypoxia, a ubiquitously aberrant phenomenon implicated in tumor growth, causes severe tumor resistance to therapeutic interventions. Instead of the currently prevalent solution through intratumoral oxygen supply, we put forward an "O2-economizer" concept by inhibiting the O2 consumption of cell respiration to spare endogenous O2 and overcome the hypoxia barrier. A nitric oxide (NO) donor responsible for respiration inhibition and a photosensitizer for photodynamic therapy (PDT) are co-loaded into poly(d,l-lactide- co-glycolide) nanovesicles to provide a PDT-specific O2 economizer. Once accumulating in tumors and subsequently responding to the locally reductive environment, the carried NO donor undergoes breakdown to produce NO for inhibiting cellular respiration, allowing more O2 in tumor cells to support the profound enhancement of PDT. Depending on the biochemical reallocation of cellular oxygen resource, this O2-economizer concept offers a way to address the important issue of hypoxia-induced tumor resistance to therapeutic interventions, including but not limited to PDT.

ACRIN 6684: Multicenter, phase II assessment of tumor hypoxia in newly diagnosed glioblastoma using magnetic resonance spectroscopy.

A multi-center imaging trial by the American College of Radiology Imaging Network (ACRIN) "A Multicenter, phase II assessment of tumor hypoxia in glioblastoma using 18F Fluoromisonidazole (FMISO) with PET and MRI (ACRIN 6684)", was conducted to assess hypoxia in patients with glioblastoma (GBM). The aims of this study were to support the role of proton magnetic resonance spectroscopic imaging (1H MRSI) as a prognostic marker for brain tumor patients in multi-center clinical trials. Seventeen participants from four sites had analyzable 3D MRSI datasets acquired on Philips, GE or Siemens scanners at either 1.5T or 3T. MRSI data were analyzed using LCModel to quantify metabolites N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and lactate (Lac). Receiver operating characteristic curves for NAA/Cho, Cho/Cr, lactate/Cr, and lactate/NAA were constructed for overall survival at 1-year (OS-1) and 6-month progression free survival (PFS-6). The OS-1 for the 17 evaluable patients was 59% (10/17). Receiver operating characteristic analyses found the NAA/Cho in tumor (AUC = 0.83, 95% CI: 0.61 to 1.00) and in peritumoral regions (AUC = 0.95, 95% CI 0.85 to 1.00) were predictive for survival at 1 year. PFS-6 was 65% (11/17). Neither NAA/Cho nor Cho/Cr was effective in predicting 6-month progression free survival. Lac/Cr in tumor was a significant negative predictor of PFS-6, indicating that higher lactate/Cr levels are associated with poorer outcome. (AUC = 0.79, 95% CI: 0.54 to 1.00). In conclusion, despite the small sample size in the setting of a multi-center trial comprising different vendors, field strengths, and varying levels of expertise at data acquisition, MRS markers NAA/Cho, Lac/Cr and Lac/NAA predicted overall survival at 1 year and 6-month progression free survival. This study validates that MRSI may be useful in evaluating the prognosis in glioblastoma and should be considered for incorporating into multi-center clinical trials.

ACRIN 6684: Assessment of Tumor Hypoxia in Newly Diagnosed Glioblastoma Using 18F-FMISO PET and MRI.

PURPOSE: Structural and functional alterations in tumor vasculature are thought to contribute to tumor hypoxia which is a primary driver of malignancy through its negative impact on the efficacy of radiation, immune surveillance, apoptosis, genomic stability, and accelerated angiogenesis. We performed a prospective, multicenter study to test the hypothesis that abnormal tumor vasculature and hypoxia, as measured with MRI and PET, will negatively impact survival in patients with newly diagnosed glioblastoma. EXPERIMENTAL DESIGN: Prior to the start of chemoradiation, patients with glioblastoma underwent MRI scans that included dynamic contrast enhanced and dynamic susceptibility contrast perfusion sequences to quantitate tumor cerebral blood volume/flow (CBV/CBF) and vascular permeability (ktrans) as well as 18F-Fluoromisonidazole (18F-FMISO) PET to quantitate tumor hypoxia. ROC analysis and Cox regression models were used to determine the association of imaging variables with progression-free and overall survival. RESULTS: Fifty patients were enrolled of which 42 had evaluable imaging data. Higher pretreatment 18F-FMISO SUVpeak (P = 0.048), mean ktrans (P = 0.024), and median ktrans (P = 0.045) were significantly associated with shorter overall survival. Higher pretreatment median ktrans (P = 0.021), normalized RCBV (P = 0.0096), and nCBF (P = 0.038) were significantly associated with shorter progression-free survival. SUVpeak [AUC = 0.75; 95% confidence interval (CI), 0.59-0.91], nRCBV (AUC = 0.72; 95% CI, 0.56-0.89), and nCBF (AUC = 0.72; 95% CI, 0.56-0.89) were predictive of survival at 1 year. CONCLUSIONS: Increased tumor perfusion, vascular volume, vascular permeability, and hypoxia are negative prognostic markers in newly diagnosed patients with gioblastoma, and these important physiologic markers can be measured safely and reliably using MRI and 18F-FMISO PET. Clin Cancer Res; 22(20); 5079-86. ©2016 AACR.