Evaluating the Reproducibility of Mouse Anatomy under Rotation in a Custom Immobilization Device for Conformal FLASH Radiotherapy

Abstract

The observation of an enhanced therapeutic index for FLASH radiotherapy in mice has created interest in practical laboratory-based FLASH irradiators. To date, systems capable of 3D conformal FLASH irradiation in mice have been lacking. We are developing such a system, incorporating a high-current linear accelerator to produce a collimated X-ray beam in a stationary beamline design, rotating the mouse about a longitudinal axis to achieve conformal irradiation from multiple beam directions. The purpose of this work was to evaluate the reproducibility of mouse anatomy under rotation at speeds compatible with conformal FLASH delivery. Three short-hair mice and two hairless mice were immobilized under anesthesia in body weight-specific contoured plastic molds, and subjected to three rotational (up to 3 revolutions/s) and two non-rotational movement interventions. MicroCT images were acquired before and after each intervention. The displacements of 11 anatomic landmarks were measured on the image pairs. The displacement of the anatomical landmarks with any of the interventions was 0.5 mm or less for 92.4% of measurements, with a single measurement out of 275 (11 landmarks 3 5 interventions 3 5 mice) reaching 1 mm. There was no significant difference in the displacements associated with rotation compared to those associated with moving the immobilized mouse in and out of a scanner or with leaving the mouse in place for 5 min with no motion. There were no significant differences in displacements between mice with or without hair, although the analysis is limited by small numbers, or between different anatomic landmarks. These results show that anatomic reproducibility under rotation speed corresponding to FLASH irradiation times appears to be compatible with conformal/stereotactic irradiation in mice.

Ultra‐high dose rate electron beams and the FLASH effect: From preclinical evidence to a new radiotherapy paradigm

“…The FLASH effect, as noted above, is defined by the preservation of normal tissues simultaneous with antitumor efficacy equivalent to that of CONV RT at the same dose level 1,12,13,15,22,23,35–39 . To date, the FLASH effect has been characterized in several in vivo models, primarily wild‐type mice, and in several organ systems, as summarized in Table 2.…”

“…1,12,13,15,22,23,[35][36][37][38][39] To date, the FLASH effect has been characterized in several in vivo models, primarily wild-type mice, and in several organ systems, as summarized in Table 2. These organs include either the so-called acute-responding organs (gut, hematopoietic system) 36,40 as well as late-responding organs (brain, lung, skin), 1,12,13,15,22,23,35,37,38,41,42 thereby suggesting that FLASH RT modifies a common initial event that can control the development of both acute and delayed toxicity. The fundamental physicochemical mechanisms underlying the FLASH effect are currently under investigation; one hypothesis implicating transient local oxygen depletion was first proposed nearly 40 years ago.…”

“…The FLASH effect, as noted above, is defined by the preservation of normal tissues simultaneous with antitumor efficacy equivalent to that of CONV RT at the same dose level. 1,12,13,15,22,23,[35][36][37][38][39] To date, the FLASH effect has been characterized in several in vivo models, primarily wild-type mice, and in several organ systems, as summarized in Table 2. These organs include either the so-called acute-responding organs (gut, hematopoietic system) 36,40 as well as late-responding organs (brain, lung, skin), 1,12,13,15,22,23,35,37,38,41,42 thereby suggesting that FLASH RT modifies a common initial event that can control the development of both acute and delayed toxicity.…”

Monte Carlo simulation of shielding designs for a cabinet form factor preclinical MV‐energy photon FLASH radiotherapy system

“…12 As a first implementation, a single highcurrent, high-energy electron linac is being incorporated as the radiation source to produce MV-energy bremsstrahlung x-rays in a FLASH experimental xray small animal conformal therapy (FLASH-EXACT) system. 13 Advantages of this design include using MV photons of the same energy used for clinical radiation therapy, and that can be shaped with high precision by collimators to deliver highly conformal dose distributions to replicate clinically relevant treatments in preclinical studies. Compared to kV photons, the greater efficiency of bremsstrahlung conversion at MV energies enables a higher dose rate FLASH irradiation.…”

FLASH radiotherapy: A promising new method for radiotherapy (Review)

“…To date, the FLASH effect has been demonstrated in several in vivo models, mostly in wild-type mice, and in several organ systems. These organs comprise the so-called acute reaction organs, such as the gut and hematopoietic system, (81,82), and delayed reaction organs such as the brain, lung and skin (76,(83)(84)(85)(86)(87). In 2019, researchers from Stanford University, the SLAC National Accelerator Laboratory, and Indiana University solved the problem of FLASH-RT device architecture (88).…”