Microbeam Irradiation as a Simultaneously Integrated Boost in a Conventional Whole-Brain Radiotherapy Protocol

Abstract

Microbeam radiotherapy (MRT), an experimental high-dose rate concept with spatial fractionation at the micrometre range, has shown a high therapeutic potential as well as good preservation of normal tissue function in pre-clinical studies. We investigated the suitability of MRT as a simultaneously integrated boost (SIB) in conventional whole-brain irradiation (WBRT). A 174 Gy MRT SIB was administered with an array of quasi-parallel, 50 µm wide microbeams spaced at a centre-to-centre distance of 400 µm either on the first or last day of a 5 × 4 Gy radiotherapy schedule in healthy adult C57 BL/6J mice and in F98 glioma cell cultures. The animals were observed for signs of intracranial pressure and focal neurologic signs. Colony counts were conducted in F98 glioma cell cultures. No signs of acute adverse effects were observed in any of the irradiated animals within 3 days after the last irradiation fraction. The tumoricidal effect on F98 cell in vitro was higher when the MRT boost was delivered on the first day of the irradiation course, as opposed to the last day. Therefore, the MRT SIB should be integrated into a clinical radiotherapy schedule as early as possible.

Keywords: F98 glioma cells; brain tissue tolerance; microbeam radiotherapy (MRT); simultaneously integrated boost (SIB).

Figure 1

Weight development within 8 days after the first irradiation fraction. The most pronounced weight loss was seen in the animals receiving the MRT SIB at the end of a broad beam irradiation schedule. BB: broad beam radiotherapy, MRT: microbeam radiotherapy.

Figure 2

Section through the cerebellum of an adult rat after MRT SIB with a microbeam peak dose of 174 Gy, followed by four fractions of 4 Gy broad beam radiotherapy (BB) on four subsequent days, at 24 h after the last irradiation fraction. Nissl stain with reduced number of cells in the microbeam paths (arrows; vertical scale bar approximates 400 µm) (a) and immunostaining with DAPI counterstain (blue) and gamma H2AX antibody (green), highlighting DNA double strand breaks (b). DNA double strand breaks are especially numerous in the paths of the microbeams. The bright linear paths of the microbeams can be well-visualised in the cerebellum because of the local density of cell bodies.

Figure 3

Colony counts of F98 glioma cells submitted to the same irradiation schedules used for the in vivo study. The number of colonies grown as a percentage is shown, compared to the number of cells originally seeded in each flask. MRT: Microbeam radiotherapy, BB: broad beam generated with the X-ray generator.

Figure 4

Results from the Monte Carlo simulation for irradiation with an MRT peak dose of 174 Gy at 1 mm depth in water (cell layer of in vitro exposures).