Comparing Acute Oral Mucosa Toxicity Associated with Minibeam and Conventional Radiotherapy

Abstract

Acute oral mucosa toxicity is associated with ulceration, severe pain, and nutritional deficiencies that may lead to treatment interruptions and a decreased quality of life for head and neck cancer patients. Minibeam radiotherapy (MRT) is a type of spatially fractionated radiotherapy that delivers an alternating pattern of sub-millimeter wide peaks of high dose immediately adjacent to much lower valley doses. By delivering a non-uniform dose distribution, MRT allows for elevated peak doses while maintaining extraordinary normal tissue tolerance. In this study, we used an acute oral mucosa toxicity mouse model to test the hypothesis that MRT provides superior tissue sparing compared to conventional radiotherapy (CRT). A total of 33 female C57BLJ6 mice were randomized by body weight (BW) across two CRT groups (n = 4/group) receiving open field radiation of 16 and 20 Gy and five MRT groups (n = 5/group) receiving peak:valley doses of 48:8, 72:12, 96:16, 96:8, and 152:8 Gy. All radiation was given in one fraction. The CRT groups were irradiated with a 10 mm circular field using a 225 kVp PA x-ray beam encompassing the oral cavity and oropharynx. The MRT groups were irradiated with the same arrangement, but the beam was collimated into 0.5 mm wide minibeams spaced 1.1 mm center-to-center using tungsten collimators of 0.5, 1, and 2.5 mm thickness to deliver peak-to-valley ratios (PVRs) of 6:1, 12:1, and 19:1. Acute effects in the oral mucosa were studied using changes in BW as a surrogate for clinically significant oral mucositis. BWs were measured daily starting on the day of treatment, and BW changes were computed relative to the day of treatment. The toxicity endpoint was defined such that mice losing >20% BW were humanely euthanized. Doses of 20 Gy CRT and 96:16 Gy MRT were highly toxic, with all animals in these groups reaching the toxicity endpoint between 9-11 days post-RT, compared to only one animal in the 16 Gy CRT group, and no animals in the other MRT groups. The BWs of all surviving animals returned to baseline within 15 days post-RT. The groups 48:8, 96:8, and 152:8 Gy showed similar BW loss and full recovery patterns. Additionally, the groups 48:8, 72:12, and 96:16 Gy showed that, for the same PVR, increasing the valley dose resulted in increased BW loss. Lastly, animals did not tolerate 96:16 Gy, but those in the 96:8 Gy group fully recovered. Despite the extreme toxicity caused by 20 Gy CRT, animals in the MRT groups tolerated peak doses up to 152 Gy when the valley dose was 8 Gy. These results confirm the superior normal tissue sparing capacity of MRT compared to CRT in an oral mucosa mouse model. We delivered tolerable MRT peak doses an order of magnitude larger than toxic CRT doses. Importantly, our results suggest that valley dose is the most useful parameter to assess acute toxicity when using MRT. Our data may prove useful for eventual clinical applications of MRT in head and neck cancers.