Complete Remission of Mouse Melanoma after Temporally Fractionated Microbeam Radiotherapy.

Abstract

Simple SummarySynchrotron Microbeam Radiation Therapy (MRT) provides excellent tumour control in preclinical cancer models. Most of the results obtained in the field employ average peak doses between 300 and 600 Gy. However, despite its proven efficacy, one of the biggest challenges in translating MRT to the clinic is that these high doses can be delivered only at synchrotron facilities, and there are only a few in the world. To solve this problem, we delivered three sessions of lower peak doses of 133 Gy, which approach clinical capabilities. The results showed complete tumour remission for 18 months. In fact, it ablated 50% of the primary melanomas with no metastasis. We believe that this study is of value because (i) it increased the therapeutic index of MRT, and (ii) it demonstrates that MRT can be less dependent on synchrotron sources, which opens the path for future clinical application.Background: Synchrotron Microbeam Radiotherapy (MRT) significantly improves local tumour control with minimal normal tissue toxicity. MRT delivers orthovoltage X-rays at an ultra-high “FLASH” dose rate in spatially fractionated beams, typically only few tens of micrometres wide. One of the biggest challenges in translating MRT to the clinic is its use of high peak doses, of around 300–600 Gy, which can currently only be delivered by synchrotron facilities. Therefore, in an effort to improve the translation of MRT to the clinic, this work studied whether the temporal fractionation of traditional MRT into several sessions with lower, more clinically feasible, peak doses could still maintain local tumour control. Methods: Two groups of twelve C57Bl/6J female mice harbouring B16-F10 melanomas in their ears were treated with microbeams of 50 µm in width spaced by 200 µm from their centres. The treatment modality was either (i) a single MRT session of 401.23 Gy peak dose (7.40 Gy valley dose, i.e., dose between beams), or (ii) three MRT sessions of 133.41 Gy peak dose (2.46 Gy valley dose) delivered over 3 days in different anatomical planes, which intersected at 45 degrees. The mean dose rate was 12,750 Gy/s, with exposure times between 34.2 and 11.4 ms, respectively. Results: Temporally fractionated MRT ablated 50% of B16-F10 mouse melanomas, preventing organ metastases and local tumour recurrence for 18 months. In the rest of the animals, the median survival increased by 2.5-fold in comparison to the single MRT session and by 4.1-fold with respect to untreated mice. Conclusions: Temporally fractionating MRT with lower peak doses not only maintained tumour control, but also increased the efficacy of this technique. These results demonstrate that the solution to making MRT more clinically feasible is to irradiate with several fractions of intersecting arrays with lower peak doses. This provides alternatives to synchrotron sources where future microbeam radiotherapy could be delivered with less intense radiation sources.