Abstract B110: Early radiographic and physiologic changes in patients with recurrent low-grade gliomas treated with everolimus under a phase II clinical trial.
Authors: Wahl Michael , Williams Christopher Kazu , Lupo Janine M. , Haas-Kogan Daphne , Nelson Sarah J. 
Published: June 2012

Abstract
Low-grade gliomas (LGG) are slow-growing, primary brain tumors that frequently recur after primary surgical treatment. Recent work has established the activation of the PI3K/mTOR pathway in most LGG, raising the possibility that mTOR inhibitors such as everolimus (RAD001) may benefit patients with LGG. Early imaging markers of treatment response and disease progression are needed to assess patients undergoing experimental therapy.
In this phase II clinical trial, 17 patients with recurrent low-grade gliomas were treated with everolimus. Serial multimodal magnetic resonance imaging was obtained every two months for up to 12 months while patients were undergoing treatment. At each time point, the volume of hyperintensity on T2-weighted imaging (T2ALL) and the contrast-enhancing lesion on T1-weighted imaging (CEL), if present, were manually defined. Maps of imaging parameters were generated, including the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) from diffusion-weighted imaging, the fractional blood volume (fBV) and vascular permeability (Kps) from dynamic contrast enhanced perfusion-weighted imaging, and MR spectroscopic imaging derived parameters (peak heights of choline, lipid and lactate, and the choline to N-acetylaspartate index, CNI). Each parameter was normalized to its median value in normal-appearing white matter, and the median, 10th percentile and 90th percentile values were computed within the T2ALL and CEL volumes.
At the time of analysis, four patients had experienced disease progression (range 3.2 to 15.8 months), 11 had stable disease (median follow-up 13.6 months) and two dropped out of the study due to adverse side effects. Baseline imaging characteristics at the beginning of treatment was similar for progressors and non-progressors. However, at 3–4 months and 5–6 months after starting treatment, the non-progressors demonstrated a significant decrease in FBV within the T2ALL volume, with a decrease in the median FBV of 31% at 3–4 months and of 39% at 5–6 months (p=0.001 and p=0.012, respectively, by the Wilcoxon signed-rank test) and a decrease in the 90th percentile FBV of 32% at 3–4 months (p=0.002) and 42% at 5–6 months (p=0.008). Other spectroscopic, diffusion and perfusion parameters did not change significantly for these subjects during the first 6 months of treatment.
The finding of reduced fractional blood volume in non-progressors corresponds to a decreased capillary density within the tumor volume, and may represent decreased angiogenesis associated with treatment effect. Since no changes in tumor volume were observed, these findings may represent early markers of response to treatment that cannot be assessed by anatomic imaging alone. More patients and longer follow-up are needed to determine whether diffusion and spectroscopic data may aid in the early detection of treatment response or progression in these patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B110.