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Noninvasive Assessment of Tumor Vasculature Response to Radiation-Mediated, Vasculature-Targeted Therapy Using Quantified Power Doppler Sonography

Implications for Improvement of Therapy Schedules

Vanderbilt University School of Medicine, Nashville, Tennessee USA (D.E.H.); Departments of Radiation Oncology (D.W.N.K., J.H., K.J.N., L.G., L.L.L., S.T., D.E.H.), Radiology (R.A.B., C.C.J., T.E.Y., A.C.F.), and Cancer Biology (D.E.H.), Vanderbilt University Medical Center, Nashville, Tennessee USA; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee USA (D.E.H.); and Department of Biomedical Engineering (H.L., D.E.H.) and Institute of Imaging Science (R.A.B., T.E.Y.), Vanderbilt University, Nashville, Tennessee USA.

Address correspondence to Dennis E. Hallahan, MD, Department of Radiation Oncology, Vanderbilt University Medical Center, 1301 22nd Ave S, B-902, Nashville, TN 37232. E-mail: dennis.hallahan{at}vanderbilt.edu

Objective. Stereotactic radiotherapy (ablative radiation) is a modality that holds considerable promise for effective treatment of intracranial and extracranial malignancies. Although tumor vasculature is relatively resistant to small fractionated doses of ionizing radiation, large ablative doses of ionizing radiation lead to effective demise of the tumor vasculature. The purpose of this study was (1) to noninvasively monitor and compare tumor physiologic parameters in response to ablative radiation treatments and (2) to use these noninvasive parameters to optimize the schedule of administration of radiation therapy. Methods. Lewis lung carcinoma tumors were implanted into C57BL/6 mice and treated with ablative radiation. The kinetics of change in physiologic parameters of a response to single-dose 20-Gy treatments was measured. Parameters studied included tumor blood flow, apoptosis, and proliferation rates. Serial tumor sections were stained to correlate noninvasive Doppler assessment of tumor blood flow with microvasculature histologic findings. Results. A single administration of 20 Gy led to an incomplete tumor vascular response, with subsequent recovery of tumor blood flow within 4 days after treatment. Sustained reduction of tumor blood flow by administering the successive ablative radiation treatment before tumor blood flow recovery led to a 3-fold tumor growth delay. The difference in tumor volumes at each measurement time point (every 2 days) was statistically significant (P = .016). Conclusions. This study suggests a rational design of schedule optimization for radiation-mediated, vasculature-directed treatments guided by noninvasive assessment of tumor blood flow levels to ultimately improve the tumor response.

Key Words: radiation therapy • sonography • stereotactic radiation therapy • tumor vasculature

Abbreviations: CDP, color density of pixels • HPF, high-power field • IHC, immunohistochemistry • IR, ionizing radiation • LLC, Lewis lung carcinoma • TUNEL, terminal deoxynucleotidyl transferase–mediated biotin–deoxyuridine triphosphate nick end labeling • VLD, vascular length density • vWF, von Willebrand factor

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