Developing a Translational Platform for Therapeutic Delivery of Image-Guided Ultra-Hypofractionated Prostate-Directed Radiotherapy in Orthotopic Prostate Cancer Models

Abstract

<h3>Purpose/Objective(s)</h3> Prostate stereotactic body radiation therapy (SBRT) is rapidly evolving as a standard-of-care option for definitive management of localized prostate cancer. To our knowledge, there are currently no preclinical models that deliver SBRT-like treatment to orthotopic prostate tumors that reflect the precision and accuracy of clinical treatment. The objective of this study is to develop and credential a small animal radiation research platform (SAARP)-based therapeutic model of image-guided ultra-hypofractionated prostate-directed radiotherapy (RT) that is dosimetrically accurate with clinically relevant radiation doses. <h3>Materials/Methods</h3> Orthotopic prostate tumors are established following intraprostatic injection of 2 × 10⁵ PC3 tumor cells (stably expressing luciferase following lentiviral transduction) into the dorsal aspect of the prostate gland of nude mice. Serial orthotopic tumor growth is monitored with weekly bioluminescence (BLI) and Q2week MRI. Reverse-contrast cone-beam CT imaging (CBCT) is performed with intraperitoneal injection of 2mL of 60% omnipaque immediately prior to CBCT. Pre-treatment MRI is fused to CBCT to facilitate delineation of organs-at-risk (rectum, bladder, bowel bag) and target (prostate) for contouring. Individual plans (generally 4 or 5-field coplanar beam arrangement) were generated to target the prostate (SV not intentionally targeted) and avoid OAR. The SARRP was used to deliver 36.25Gy in 5 fractions of prostate-directed RT [day 30] and weekly serial BLI + MRI used to assess treatment response. <h3>Results</h3> Reverse contrast CBCT imaging +/- MR fusion was sufficient for OAR and target delineation and facilitated daily image-guidance whereas CBCT alone was insufficient. Radiation dosimetry noted a positive association between pH2AX mean fluorescence intensity (MFI) with escalating radiation doses of 0Gy, 2Gy, 8Gy and 20Gy. Preliminary DVH analysis of therapeutically irradiated orthotopic prostate tumors and adjacent OARs noted CTV prostate coverage>90%, rectumD50%<4Gy and bladderD50<4Gy in 3 of 5 serial fractions delivered. Surgically implanted intraprostatic TLD were harvested post-RT to confirm and quantify intraprostatic radiation dose received. Therapeutic response was observed with significantly lower luminescence counts in irradiated (n=13) vs non-irradiated controls (n=11) [p=0.049] and no treatment-related deaths were observed in irradiated mice. <h3>Conclusion</h3> We have developed a preclinical workflow for image-guided delivery of ultra-hypofractioned radiotherapy of orthotopic prostate tumors with ongoing optimization goals to achieve clinically relevant dose constraints and target coverage of NRG GU-005. Ongoing translational work involves DNA damage response assessment in irradiated prostate and adjacent organs-at-risks. This platform is now being explored in immunocompetent settings to better understand intraprostatic immune responses induced by prostate-directed RT.