Abstract 2428: Echo-contrast monitoring of sorafenib early efficacy: animal model for Ewing's sarcoma tumors

Abstract

Abstract Background: Anti-angiogenic drugs are a pillar of the therapeutic approach against cancer. Contrast ultrasound (CUS) can detect perfusion modifications during anti-angiogenic therapy preceding tumor size regression. However, contrast imaging would benefit from better standardization of the technique. This work compares discrimination of tumors in Sorafenib-treated and placebo mice using CUS evaluation of relative blood volume (rBV), mean transit time (mTT) and wash in rate (WiR). Methods: Ewing's sarcoma tumors were grafted orthotopically by sub-capsular injection of 100 µL of SK-NEP-1 cells (5 x 106cells/mL) in the left kidney of nude fifteen mice (Elevage Janvier, Le Genest-St-Isle, France). Contrast enhanced ultrasonography was performed using a clinical ultrasound system Acuson Sequoia 512 with a 14 MHz probe (Siemens Medical Solutions, Mountain View). The tumor area (A) was calculated according to A = (≥ x L x w)/2. CUS (Sonovue, Bracco SA, Milan, Italy) with destruction-reperfusion was performed using cadence pulse-sequence (CPS). Data were acquired from each mouse at 14 days after tumor-cell injection. The treatment was started at day 14 just after the CUS baseline. At day 14 (day of start therapy) the 12 mice were randomized into two groups. One group received (6 mice) the anti-angiogenic treatment Sorafenib daily (10mg/kg/jr) per os and the other group (6 mice) received corresponding doses of placebo by the same route for 8 days. Image sequences were recorded in DICOM format and analyzed with prototype software from Bracco Suisse SA (Geneva, Switzerland) allowing selection of regions of interest, approximate linearization of the data and fitting of flow models to time-intensity data to estimate functional parameters within the tumor. All parameters were normalized with respect to normal cortex perfusion. Statistical analysis was performed using Wilcoxon Signed-Rank tests. Results: Ultrasound estimates of the tumor size increased with time for both groups, but tumor size was never significantly different between the two groups. Before the normalization with the adjacent renal cortex perfusion, the functional parameters did not present a significant difference between the two groups. Therefore after normalization: the rBV shows a significant difference Sorafenib vs placebo (p=0.008) at 8 days, the mTT also becomes significant after 8 days of treatment (p=0.02). The WiR shows a significant difference between groups at 8 days (p=0.005), but also at 6 days (p=0.04). Conclusions: functional CUS was an effective technique for monitoring the early response of anti-angiogenic treatment. The parameters obtained by fitting flow models of destruction-reperfusion demonstrated the capacity to standardize this angiogenesis analysis. Also the normalization with respect to adjacent normal tissue appears to reduce estimate variability and improve functional contrast assessment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2428. doi:1538-7445.AM2012-2428