Preclinical Intraoperative FLASH Radiotherapy

Abstract

Intraoperative radiation therapy (IORT) is a method of delivering high radiation doses to an internal target with low dose to adjacent organs. Most organs at risk can often be moved out of the radiation field, so dose is usually limited by in-field vascular and/or nerve structures. It is known that ultra-high (FLASH) dose rate (>40 Gy/s) radiation reduces normal tissue toxicity compared to conventional, while preserving tumor control. We hypothesize that FLASH radiation can increase the dose tolerance of vascular and nerve structures, thus permitting for dose escalation in IORT. Here, we present a novel platform using orthovoltage x-rays to study FLASH effects in preclinical IORT. The experimental setup and dosimetry of the system have been established for FLASH irradiation of the abdominal aorta in rats to investigate dose tolerance. A 150 kVp rotating anode x-ray source with a 75-kW generator was used to deliver FLASH and conventional irradiation. A 3D printed immobilization platform was designed to reproducibly place a surgically exposed rat abdominal aorta at 55mm SSD. A 3-mm thick lead collimator with a 10mm x 10mm aperture was placed into a flange adapter, which docks into the immobilization platform. Phantom and in vivo dosimetry were performed using both calibrated radiographic film and thermoluminescent dosimeters (TLD). Anesthetized 2-month-old Wistar rats underwent laparotomy to expose the abdomen for irradiation. A 10x12x1 mm3 tungsten plate was placed under the aorta to reduce spinal cord dose. Animals were then docked into the irradiator using the immobilization platform. Radiation dose in the range of 20 - 50 Gy were delivered to the abdominal aorta at FLASH and conventional dose-rates. Following treatment, animals undergo MR angiography every two months for 6 months, at which a histological evaluation of aorta wall will be performed. The FLASH dose rate measured at the aorta wall in a rat carcass was 49.7 ± 1.2 Gy/s distal to the collimator. Dose measurements between the films and TLDs showed an agreement within ±3%. Positional uncertainty mainly depends on the visual localization of the aorta on the collimator window, which is verified before irradiation. Vertical uncertainty is less than 1 mm, which is important given the rapid dose fall off of the system. Eight animals went successfully through the procedure, are healthy and currently being follow up with MR angiography. More animals are being treated for meaningful statistical results. MR angiography and IORT are performed on different days to avoid longer times under anesthesia, which initially resulted on mortality. Results of the MR angiography and histological analysis will be presented. The proposed platform has been successfully utilized for precision setup for FLASH IORT in a preclinical laboratory setting. Evaluation of FLASH effects in IORT setup will be an important step in the potential translation of FLASH IORT, where only one high-dose fraction can be delivered.