Good Timing Matters: The Spatially Fractionated High Dose Rate Boost Should Come First.

Monoplanar microbeam irradiation (MBI) and pencilbeam irradiation (PBI) are two new concepts of high dose rate radiotherapy, combined with spatial dose fractionation at the micrometre range. In a small animal model, we have explored the concept of integrating MBI or PBI as a simultaneously integrated boost (SIB), either at the beginning or at the end of a conventional, low-dose rate schedule of 5x4 Gy broad beam (BB) whole brain radiotherapy (WBRT). MBI was administered as array of 50 µm wide, quasi-parallel microbeams. For PBI, the target was covered with an array of 50 µm × 50 µm pencilbeams. In both techniques, the centre-to-centre distance was 400 µm. To assure that the entire brain received a dose of at least 4 Gy in all irradiated animals, the peak doses were calculated based on the daily BB fraction to approximate the valley dose. The results of our study have shown that the sequence of the BB irradiation fractions and the microbeam SIB is important to limit the risk of acute adverse effects, including epileptic seizures and death. The microbeam SIB should be integrated early rather than late in the irradiation schedule

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

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

TRANSMISSION OF SIGNALS FROM RATS RECEIVING HIGH DOSES OF MICROBEAM RADIATION TO CAGE MATES: AN INTER-MAMMAL BYSTANDER EFFECT

Inter-animal signaling from irradiated to non-irradiated organisms has been demonstrated for whole body irradiated mice and also for fish. The aim of the current study was to look at radiotherapy style limited exposure to part of the body using doses relevant in preclinical therapy. High dose homogenous field irradiation and the use of irradiation in the microbeam radiation therapy mode at the European Synchrotron Radiation Facility (ESRF) at Grenoble was tested by giving high doses to the right brain hemisphere of the rat. The right and left cerebral hemispheres and the urinary bladder were later removed to determine whether abscopal effects could be produced in the animals and also whether effects occurred in cage mates housed with them. The results show strong bystander signal production in the contra-lateral brain hemisphere and weaker effects in the distant bladder of the irradiated rats. Signal strength was similar or greater in each tissue in the cage mates housed for 48hrs with the irradiated rats. Our results support the hypothesis that proximity to an irradiated animal induces signalling changes in an unirradiated partner. If similar signaling occurs between humans, the results could have implications for caregivers and hospital staff treating radiotherapy patients

Microbeam evolution: From single cell irradiation to preclinical studies

PURPOSE This review follows the development of microbeam technology from the early days of single cell irradiations, to investigations of specific cellular mechanisms and to the development of new treatment modalities in vivo. A number of microbeam applications are discussed with a focus on pre-clinical modalities and translation towards clinical application. CONCLUSIONS The development of radiation microbeams has been a valuable tool for the exploration of fundamental radiobiological response mechanisms. The strength of micro-irradiation techniques lies in their ability to deliver precise doses of radiation to selected individual cells in vitro or even to target subcellular organelles. These abilities have led to the development of a range of microbeam facilities around the world allowing the delivery of precisely defined beams of charged particles, X-rays, or electrons. In addition, microbeams have acted as mechanistic probes to dissect the underlying molecular events of the DNA damage response following highly localized dose deposition. Further advances in very precise beam delivery have also enabled the transition towards new and exciting therapeutic modalities developed at synchrotrons to deliver radiotherapy using plane parallel microbeams, in Microbeam Radiotherapy (MRT)

High-Precision Radiosurgical Dose Delivery by Interlaced Microbeam Arrays of High-Flux Low-Energy Synchrotron X-Rays

Microbeam Radiation Therapy (MRT) is a preclinical form of radiosurgery dedicated to brain tumor treatment. It uses micrometer-wide synchrotron-generated X-ray beams on the basis of spatial beam fractionation. Due to the radioresistance of normal brain vasculature to MRT, a continuous blood supply can be maintained which would in part explain the surprising tolerance of normal tissues to very high radiation doses (hundreds of Gy). Based on this well described normal tissue sparing effect of microplanar beams, we developed a new irradiation geometry which allows the delivery of a high uniform dose deposition at a given brain target whereas surrounding normal tissues are irradiated by well tolerated parallel microbeams only. Normal rat brains were exposed to 4 focally interlaced arrays of 10 microplanar beams (52 µm wide, spaced 200 µm on-center, 50 to 350 keV in energy range), targeted from 4 different ports, with a peak entrance dose of 200Gy each, to deliver an homogenous dose to a target volume of 7 mm3 in the caudate nucleus. Magnetic resonance imaging follow-up of rats showed a highly localized increase in blood vessel permeability, starting 1 week after irradiation. Contrast agent diffusion was confined to the target volume and was still observed 1 month after irradiation, along with histopathological changes, including damaged blood vessels. No changes in vessel permeability were detected in the normal brain tissue surrounding the target. The interlacing radiation-induced reduction of spontaneous seizures of epileptic rats illustrated the potential pre-clinical applications of this new irradiation geometry. Finally, Monte Carlo simulations performed on a human-sized head phantom suggested that synchrotron photons can be used for human radiosurgical applications. Our data show that interlaced microbeam irradiation allows a high homogeneous dose deposition in a brain target and leads to a confined tissue necrosis while sparing surrounding tissues. The use of synchrotron-generated X-rays enables delivery of high doses for destruction of small focal regions in human brains, with sharper dose fall-offs than those described in any other conventional radiation therapy

Faster and safer? FLASH ultra-high dose rate in radiotherapy

Recent results from the Franco-Swiss team of Institute Curie and Centre Hospitalier Universitaire Vaudois demonstrate a remarkable sparing of normal tissue after irradiation at ultra-high dose rate (>40 Gy/s). The “FLASH” radiotherapy maintains tumor control level, suggesting that ultra-high dose rate can substantially enhance the therapeutic window in radiotherapy. The results have been obtained so far only with 4-6 MeV electrons in lung and brain mouse model. Nevertheless, they have attracted a great attention for the potential clinical applications. Oxygen depletion had been discussed many years ago as a possible mechanism for reduction of the damage after exposure to ultra-high dose-rate. However, the mechanism underlying the effect observed in the FLASH radiotherapy remains to be elucidated

Influence of polarization and a source model for dose calculation in MRT

Purpose: Microbeam Radiation Therapy (MRT), an alternative preclinical treatment strategy using spatially modulated synchrotron radiation on a micrometer scale, has the great potential to cure malignant tumors (e.g., brain tumors) while having low side effects on normal tissue. Dose measurement and calculation in MRT is challenging because of the spatial accuracy required and the arising high dose differences. Dose calculation with Monte Carlo simulations is time consuming and their accuracy is still a matter of debate. In particular, the influence of photon polarization has been discussed in the literature. Moreover, it is controversial whether a complete knowledge of phase space trajectories, i.e., the simulation of the machine from the wiggler to the collimator, is necessary in order to accurately calculate the dose. Methods: With Monte Carlo simulations in the Geant4 toolkit, the authors investigate the influence of polarization on the dose distribution and the therapeutically important peak to valley dose ratios (PVDRs). Furthermore, the authors analyze in detail phase space information provided byMartínez-Rovira et al. [ Development and commissioning of a Monte Carlo photon model for the forthcoming clinical trials in microbeam radiation therapy, Med. Phys.39(1), 119-131 (2012)] and examine its influence on peak and valley doses. A simple source model is developed using parallel beams and its applicability is shown in a semiadjoint Monte Carlo simulation. Results are compared to measurements and previously published data. Results: Polarization has a significant influence on the scattered dose outside the microbeam field. In the radiation field, however, dose and PVDRs deduced from calculations without polarization and with polarization differ by less than 3%. The authors show that the key consequences from the phase space information for dose calculations are inhomogeneous primary photon flux, partial absorption due to inclined beam incidence outside the field center, increased beam width and center to center distance due to the beam propagation from the collimator to the phantom surface and imperfect absorption in the absorber material of the Multislit Collimator. These corrections have an effect of approximately 10% on the valley dose and suffice to describe doses in MRT within the measurement uncertainties of currently available dosimetry techniques. Conclusions: The source for the first clinical pet trials in MRT is characterized with respect to its phase space and the photon polarization. The results suggest the use of a presented simplified phase space model in dose calculations and hence pave the way for alternative and fast dose calculation algorithms. They also show that the polarization is of minor importance for the clinical important peak and valley doses inside the microbeam field