The γH2AX DSB marker may not be a suitable biodosimeter to measure the biological MRT valley dose.

PURPOSE: γH2AX biodosimetry has been proposed as an alternative dosimetry method for microbeam radiation therapy (MRT) because conventional dosimeters, such as ionization chambers, lack the spatial resolution required to accurately measure the MRT valley dose. Here we investigated whether γH2AX biodosimetry should be used to measure the biological valley dose of MRT-irradiated mammalian cells. MATERIALS AND METHODS: We irradiated human skin fibroblasts and mouse skin flaps with synchrotron MRT and broad beam (BB) radiation. BB doses of 1-5 Gy were used to generate a calibration curve in order to estimate the biological MRT valley dose using the γH2AX assay. RESULTS: Our key finding was that MRT induced a non-linear dose response compared to BB, where doses 2-3 times greater showed the same level of DNA DSB damage in the valley in cell and tissue studies. This indicates that γH2AX may not be an appropriate biodosimeter to estimate the biological valley doses of MRT-irradiated samples. We also established foci yields of 5.9 ± 0.04 and 27.4 ± 2.5  foci/cell/Gy in mouse skin tissue and human fibroblasts respectively, induced by BB. Using Monte Carlo simulations, a linear dose response was seen in cell and tissue studies and produced predicted peak-to-valley dose ratios (PVDRs) of ∼30 and ∼107 for human fibroblasts and mouse skin tissue respectively. CONCLUSIONS: Our report highlights novel MRT radiobiology, attempts to explain why γH2AX may not be an appropriate biodosimeter and suggests further studies aimed at revealing the biological and cellular communication mechanisms that drive the normal tissue sparing effect, which is characteristic of MRT.

Identifying optimal clinical scenarios for synchrotron microbeam radiation therapy: A treatment planning study.

PURPOSE: Synchrotron Microbeam Radiation Therapy (MRT) is a pre-clinical modality characterised by spatial dose fractionation on a microscopic scale. Treatment planning studies using clinical datasets have not yet been conducted. Our aim was to investigate MRT dose-distributions in scenarios refractory to conventional treatment and to identify optimal settings for a future Phase I trial. METHODS: MRT plans were generated for seven scenarios where re-irradiation was performed clinically. A hybrid algorithm, combining Monte Carlo and convolution-based methods, was used for dose-calculation. The valley dose to organs at risk had to respect the single fraction tolerance doses achieved in the corresponding re-irradiation plans. The resultant peak dose and the peak-to-valley dose ratio (PVDR) at the tumour target volume were assessed. RESULTS: Peak doses greater than 80 Gy in a single fraction, and PVDRs greater than 10, could be achieved for plans with small (<35 cm3) or shallow volumes, particularly recurrent glioblastoma, head and neck tumours, and select loco-regionally recurrent breast cancer sites. Treatment volume was a more important factor than treatment depth in determining the PVDR. The mean PVDR correlated strongly with the size of the target volume (rs = -0.70, p = 0.01). The PVDRs achieved in these clinical scenarios are considerably lower than those reported in previous pre-clinical studies. CONCLUSION: Our findings suggest that head and neck sites will be optimal scenarios for MRT.

Comparative toxicity of synchrotron and conventional radiation therapy based on total and partial body irradiation in a murine model.

Synchrotron radiation can facilitate novel radiation therapy modalities such as microbeam radiation therapy (MRT) and high dose-rate synchrotron broad-beam radiation therapy (SBBR). Both of these modalities have unique physical properties that could be exploited for an improved therapeutic effect. While pre-clinical studies report promising normal tissue sparing phenomena, systematic toxicity data are still required. Our objective was to characterise the toxicity of SBBR and MRT and to calculate equivalent doses of conventional radiation therapy (CRT). A dose-escalation study was performed on C57BLJ/6 mice using total body and partial body irradiations. Dose-response curves and TD50 values were subsequently calculated using PROBIT analysis. For SBBR at dose-rates of 37 to 41 Gy/s, we found no evidence of a normal tissue sparing effect relative to CRT. Our findings also show that the MRT valley dose, rather than the peak dose, best correlates with CRT doses for acute toxicity. Importantly, longer-term weight tracking of irradiated animals revealed more pronounced growth impairment following MRT compared to both SBBR and CRT. Overall, this study provides the first in vivo dose-equivalence data between MRT, SBBR and CRT and presents systematic toxicity data for a range of organs that can be used as a reference point for future pre-clinical work.