Low-frequency ultrasound radiosensitization and therapy response monitoring of tumors: An in vivo study

A new framework has been introduced in this paper for tumor radiosensitization and therapy response monitoring using low-frequency ultrasound. Human fibrosarcoma xenografts grown in severe combined immunodeficiency (SCID) mice (n = 108) were treated using ultrasound-stimulated microbubbles at various concentration and exposed to different doses of radiation. Low-frequency ultrasound radiofrequency (RF) data were acquired from tumors prior to and at different times after treatment. Quantitative ultrasound (QUS) techniques were applied to generate spectral parametric maps of tumors. Textural analysis were performed to quantify spatial heterogeneities within QUS parametric maps. A hybrid model was developed using multiple regression analysis to predict extent of histological tumor cell death non-invasively based on QUS spectral and textural biomarkers. Results of immunohistochemistry on excised tumor sections demonstrated increases in cell death with higher concentration of microbubbles and radiation dose. Quantitative ultrasound results indicated changes that paralleled increases in histological cell death. Specifically, the hybrid QUS biomarker demonstrated a good correlation with extent of tumor cell death observed from immunohistochemistry. A linear discriminant analysis applied in conjunction with the receiver operating characteristic (ROC) curve analysis indicated that the hybrid QUS biomarker can classify tumor cell death fractions with an area under the curve of 91.2. The results obtained in this research suggest that low-frequency ultrasound can concurrently be used to enhance radiation therapy and evaluate tumor response to treatment.