COMPLEX SYSTEMS AND BIOMEDICAL SCIENCES

68 ESRF

Since 1994, the ID17 biomedical beamline has worked on developing MRT. MRT is based on the spatial fractionation of the incident beam into parallel microbeams, allowing the deposition of several hundred grays in the microbeam paths (called peak ), while the areas of tissue between the microbeams (called valley ) only receive 5% to 10% of the peak dose. The alternating of very high peak dose separated by low valley dose showed beneficial effect in both normal tissue and tumours [2].

This study aims to improve the radiotherapy of GBM by using MRT as a boost after multiple fractions of conventional broad beam (BB) irradiation. Rats bearing intracranial F98 high- grade glioma were either irradiated by five fractions in BB mode (3 x 6 Gy BB + 2 x 8 Gy BB) or by three fractions in BB mode followed by two fractions in MRT mode (3 x 6 Gy BB + 2 x 8 Gy MRT (valley dose)) spread over 10 days (Figure 53a). The tumour growth follow-up by magnetic resonance imaging (MRI) showed that

the MRT boost (BB/MRT) induced a complete arrest of tumour growth (Figures 53b and 53c), associated with an increased median survival time compared to the non-irradiated (CTRL) or the BB/BB group animals (Figure 53d). The MRT boost induces a better tumour control by reducing the number of proliferative cells, due to an arrest of the cell cycle (Figure 54). Indeed, five days after the last irradiation, a significantly higher percentage of cells were arrested in phase G1 and a lower percentage in G2/M phases after the MRT boost compared to the BB/BB group. Surprisingly, the MRT boost did not strongly modify the tumour vascular network compared to the BB/BB irradiation mode.

This study shows, for the first time, the beneficial effect of using MRT as a complementary treatment, increasing the radiotherapeutic effect following temporally fractionated conventional radiotherapy. MRT is now being considered for translation from the preclinical stage to a phase 1 human clinical trial.

Fig. 53: Effect of MRT boost on glioblastoma.

a) Experimental design and timeline, b) MRI follow-up,

c) tumour volume (****: p < 0.0001), and

d) median survival time of non-irradiated GBM (CTRL),

3 x 6 Gy BB + 2 x 8 Gy BB (BB/BB) and 3 x 6 Gy BB +

2 x 8 Gy MRT (BB/MRT).