Early Assessment of Tumor Response to Radiation Therapy Using High-Resolution Quantitative Microvascular Ultrasound Imaging

Abstract

Tumor volume imaging several months after radiation therapy is currently used as an indicator for treatment response. For patients who did not respond well to the treatment, precious time may have been wasted as timely modification of the treatment approach may lead to better clinical outcomes. We propose to use tumor microvasculature as a biomarker for early assessment of long-term tumor response to radiation therapy. Acoustic Angiography is a novel contrast ultrasound imaging technique that enables high-resolution microvascular imaging. We aim to demonstrate that AA is capable of early prediction of long-term radiation therapy response by monitoring longitudinal changes in tumor microvasculature. Three cohorts of rats implanted with rat fibrosarcoma tumors were treated with a single dose at three dose levels. The rats were split into four different dose cohorts and received either 0 Gy (treatment control, n = 9), 15 Gy (n = 8), 20 Gy (n = 5), or 25 Gy (n = 8) radiation dose. A non-toxic FDA approved microbubble contrast agent is administrated before each ultrasound imaging by tail vein injection. Contrast enhanced ultrasound (CEUS) is a low-cost and safe imaging modality that can visualize and measure vascularity and perfusion in tissue with high contrast sensitivity compared to CT and MRI. A high-resolution microvascular imaging is performed using Acoustic Angiography, a super-harmonic CEUS imaging technique. A special ultrasound probe capable of both b-mode and Acoustic Angiography mode imaging is used and the longitudinal study lasts until 30 days post radiation. Tumor microvascular density is measured within the tumor volume defined by 3D b-mode ultrasound imaging. All tumors in each dose group responded initially (days 3-15) to treatment as indicated by decreased tumor growth accompanied with decreased vascular density. Tumors that displayed long-term control (complete response) continued to decrease in size and in vascular density. Tumors that regrew after the initial response (partial response) exhibited an increase in tumor volumetric vascular density before an increase in tumor volume. The change in tumor volumetric vascular density can be used to distinguish which animals eventually have complete control or partial control 10.25 ± 1.5 days, 9 ± 4.2 days, and 4 ± 1.4 days earlier than from the observable tumor volume change in the 15, 20, and 25 Gy dose groups, respectively. We have demonstrated the ability of a novel ultrasound tumor vascular imaging for early detection of treatment response in a preclinical study. In clinical practice, tumors often do not significantly change in size until months after treatment. Our study indicates that for some tumors we may detect non-responsive tumors 50% earlier than using the conventional RECIST method alone. By decreasing the wait time to determine treatment response doctors can make more timely modifications to treatment strategy to improve treatment outcome for individual patients.