Synchrotron microbeam radiation therapy

2017-01-10T04:21:31Z (GMT) by Crosbie, Jeffrey
This thesis presents interdisciplinary, collaborative research in the field of synchrotron microbeam radiation therapy (MRT). Synchrotron MRT is an experimental radiotherapy technique under consideration for clinical use, following demonstration of efficacy in tumour-bearing rodent models with remarkable sparing of normal tissue. A high flux, X-ray beam from a synchrotron is segmented into micro-planar arrays of narrow beams, typically 25 μm wide and with peak-to-peak separations of 200 μm. The radiobiological effect of MRT and the underlying cellular mechanisms are poorly understood. The ratio between dose in the ‘peaks’of the microbeams to the dose in the ‘valleys’, between the microbeams, has strong biological significance. However, there are difficulties in accurately measuring the dose distribution for MRT. The aim of this thesis is to address elements of both the dosimetric and radiobiological gaps that exist in the field of synchrotron MRT. A method of film dosimetry and microdensitometry was adapted in order to measure the peak-to-valley dose ratios for synchrotron MRT. Two types of radiochromic film were irradiated in a phantom and also flush against a microbeam collimator on beamline BL28B2 at the SPring-8 synchrotron. The HD-810 and EBT varieties of radiochromic film were used to record peak dose and valley dose respectively. In other experiments, a dose build-up effect was investigated and the half value layer of the beam with and without the microbeam collimator was measured to investigate the effect of the collimator on the beam quality. The valley dose obtained for films placed flush against the collimator was approximately 0.25% of the peak dose. Within the water phantom, the valley dose had increased to between 0.7–1.8% of the peak dose, depending on the depth in the phantom. We also demonstrated, experimentally and by Monte Carlo simulation, that the dose is not maximal on the surface and that there is a dose build-up effect. The microbeam collimator did not make an appreciable difference to the beam quality. The measured values of peak-to-valley dose ratio were higher than those predicted by previously published Monte Carlo simulation papers. For the radiobiological studies, planar (560 Gy) or cross-planar (2 x 280 Gy or 2 x 560 Gy) irradiations were delivered to mice inoculated with mammary tumours in their leg, on beamline BL28B2 at the SPring-8 synchrotron. Immunohistochemical staining for DNA double strand breaks, proliferation and apoptosis was performed on irradiated tissue sections. The MRT response was compared to conventional radiotherapy at 11, 22 or 44 Gy. The results of the study provides the first evidence for a differential tissue response at a cellular level between normal and tumour tissues following synchrotron MRT. Within 24 hours of MRT to tumour, obvious cell migration had occurred into and out of irradiated zones. MRT-irradiated tumours showed significantly less proliferative capacity by 24 hours post-irradiation (P = 0.002). Median survival times for EMT-6.5 and 67NR tumour-bearing mice following MRT (2 x 560 Gy) and conventional radiotherapy (22 Gy) increased significantly compared to unirradiated controls (P < 0.0005). However, there was markedly less normal tissue damage from MRT than from conventional radiotherapy. MRT-treated normal skin mounts a more coordinated repair response than tumours. Cell-cell communication of death signals from directly irradiated, migrating cells, may explain why tumours are less resistant to high dose MRT than normal tissue.