Minibeam Radiation Therapy Valley Dose Determines Tolerance to Acute and Late Effects in the Mouse Oral Cavity

Purpose: Minibeam radiation therapy (MBRT) is an innovative strategy to improve normal tissue sparing by delivering alternating, submillimeter-wide regions of high “peak” and low “valley” doses. The purpose of this study was to characterize both acute and late MBRT-induced normal tissue toxicities and determine the dosimetric parameters that dictate toxicity. Methods and Materials: Mice were stratified by weight and randomized to receive a single dose of conventional radiation therapy (uniform open field) or MBRT (0.5 mm-wide minibeams spaced 1.1 mm center to center) to the oral cavity. The conventional RT groups (n = 4 per group) received 16 or 20 Gy, whereas the MBRT groups (n = 5 per group) received peak:valley doses of 48:8, 72:12, 96:8, 96:16, or 152:8 Gy. Acute toxicity (≤3 weeks) was evaluated using changes in weight and mucosal histology. Late effects on bone and dentition were evaluated using microscopic computed tomography (microCT). Results: Animals irradiated with 16 Gy (n = 1), 20 Gy (n = 4), and 96:16 Gy (n = 5) reached acute toxicity endpoint (≥20% weight loss) between 9 and 11 days postradiation and exhibited histologic changes indicative of mucositis. No animals in the other MBRT groups reached acute toxicity endpoint. Although 96:8 Gy induced marked mucosal damage in peak regions, the spared tissue in the valley regions enabled restoration of mucosal integrity within 2 weeks post-MBRT. MicroCT of surviving mice 12 months postradiation revealed an alternating pattern of decreased bone volume consistent with the MBRT pattern. The upper incisors of most animals were shortened or completely missing. The mice receiving 16 Gy and 48:8 Gy exhibited the most and least dental damage, respectively. Conclusions: This preliminary study emphasizes that normal tissue sparing by MBRT, as determined by the valley dose, significantly ameliorates dose-limiting toxicities and enables escalation to MBRT peak doses up to an order of magnitude greater than conventional RT doses.