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

Abstract

Measuring changes in tumor volume using anatomical imaging weeks to months post radiation therapy (RT) is currently the clinical standard for indicating treatment response to RT. For patients whose tumors do not respond successfully to treatment, this approach is suboptimal 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 tumor response to RT. Acoustic angiography is a novel contrast ultrasound imaging technique that enables high-resolution microvascular imaging and has been shown to detect changes in microvascular structure due to cancer growth. Data suggest that acoustic angiography can detect longitudinal changes in the tumor microvascular environment that correlate with RT response.Methods: Three cohorts of Fisher 344 rats were implanted with rat fibrosarcoma tumors and were treated with a single fraction of RT at three dose levels (15 Gy, 20 Gy, and 25 Gy) at a dose rate of 300 MU/min. A simple treatment condition was chosen for testing the feasibility of our imaging technique. All tumors were longitudinally imaged immediately prior to and after treatment and then every 3 days after treatment for a total of 30 days. Both acoustic angiography (using in-house produced microbubble contrast agents) and standard b-mode imaging was performed at each imaging time point using a pre-clinical Vevo770 scanner and a custom modified dual-frequency transducer.Results: Results show that all treated tumors in each dose group initially responded to treatment between days 3-15 as indicated by decreased tumor growth accompanied with decreased vascular density. Untreated tumors continued to increase in both volume and vascular density until they reached the maximum allowable size of 2 cm in diameter. Tumors that displayed complete control (no tumor recurrence) continued to decrease in size and vascular density, while tumors that progressed after the initial response presented an increase in tumor volume and volumetric vascular density. The increase in tumor volumetric vascular density in recurring tumors can be detected 10.25 ± 1.5 days, 6 ± 0 days, and 4 ± 1.4 days earlier than the measurable increase in tumor volume in the 15, 20, and 25 Gy dose groups, respectively. A dose-dependent growth rate for tumor recurrence was also observed.Conclusions: In this feasibility study we have demonstrated the ability of acoustic angiography to detect longitudinal changes in vascular density, which was shown to be a potential biomarker for tumor response to RT.

Conventional dose rate spatially-fractionated radiation therapy (SFRT) treatment response and its association with dosimetric parameters – A preclinical study in a Fisher 344 rat model

“…Forty-two eight-week-old female Fischer 344 rats from Charles River Labs and rat fibrosarcoma tumor allografts were used ( 23 ). The rat fibrosarcoma (FSA) allograft model has been well characterized in several radiotherapy response studies by our and collaborator labs ( 23–25 ). Rat FSA is characterized as a local, non-metastasizing tumor that is highly vascular and oxygen dependent ( 34,35 ).…”

“…In preclinical studies the pre-treatment tumor volume is known to be strongly correlated with treatment tumor control ( 23 ). We minimize this unwanted effect by controlling the pre-treatment tumor volume in a randomized, matched group study design.…”

“…Three-dimensional B-mode ultrasound imaging of the tumors was performed using a Vevo 770 preclinical ultrasound scanner (Vevo 770, VisualSonics, Toronto, ON, Canada) and the resulting images used to calculate tumor volume, as described in a previous publication ( 23 ). Imaging was performed on the day before treatment as well as every third day post-treatment for approximately 30 days, or when maximal tumor burden was met, at which point the animals were humanely sacrificed per IACUC-approved animal protocol.…”

“…Figure (A) is an illustration of the 3D ultrasound imaging setup with anesthetized animal (23). Two-dimensional transverse image slices (B) are acquired along the elevational direction and are then reconstructed into 3D images (29) (C).…”

Quantification of Morphological Features in Non-Contrast-Enhanced Ultrasound Microvasculature Imaging

“…Several preclinical and clinical studies are available to derive quantitative information from microvasculature images obtained by contrast agent ultrasound for diagnostic purposes [9][10][11][12][13]. Additional examples include perfusion imaging [14,15] and molecular imaging [16,17].…”