Microbeam Radiation Therapy – physical and biological aspects of a new cancer therapy and development of a treatment planning system

Die Mikrostrahltherapie (MRT) ist ein neuer Ansatz in der Krebstherapie. Hoch brillante Synchrotronstrahlung wird zu parallelen, wenige Mikrometer breiten, ebenen Strahlenbündeln kollimiert und mit hohen Dosisraten auf das Tumorgewebe gerichtet. Dabei sind die applizierten Peakdosen wesentlich höher als in der konventionellen Strahlentherapie. Die Niedrigdosisbereiche zwischen den Strahlen bleiben jedoch unterhalb der gewohnten Gewebetoleranz. Die bisherige Forschung hat gezeigt, dass derartige Strahlgeometrien das gesunde Gewebe schonen, während Tumore erfolgreich zurückgedrängt werden. In der vorliegenden Arbeit werden physikalische und biologische Aspekte der Therapie untersucht. Es wird ein Therapieplanungssystem für die ersten klinischen Behandlungen an der Europäischen Synchrotronstrahlenquelle in Grenoble (Frankreich) entwickelt und ein Dosimetrieverfahren auf der Basis radiochromer Filme erarbeitet, um geplante Dosen im Mikrometerbereich experimentell zu validieren. Schließlich werden Experimente auf zellulärer Ebene durchgeführt, um physikalisch geplante Dosen und biologische Schäden zu korrelieren. Die Unterschiede zwischen Monte-Carlo-Dosis und Messung sind geringer als 10% im Niedrigund 5% im Peakdosisbereich. Alternativ entwickelte schnellere Dosisberechnungsverfahren weichen von den rechenintensiven Monte-Carlo-Simulationen um weniger als 15% ab und bestimmen die Dosis innerhalb weniger Minuten. In den zellbiologischen Experimenten zeigt sich, dass interzelluläre Signale maßgeblich über das Zellüberleben an Strahlengrenzen entscheiden. Diese Beobachtung ist nicht nur für MRT sondern auch für die konventionelle Strahlentherapie von Bedeutung

Differential tissue sparing of FLASH ultra high dose rates: an {\it in-silico} study

Purpose: To propose a theory for the differential tissue sparing of FLASH ultra high dose rates (UHDR) through inter-track reaction-diffusion mechanism. Methods: We calculate the time-evolution of particle track-structures using a system of coupled reaction-diffusion equations on a random network designed for molecular transport in porous and disordered media. The network is representative of the intra- and inter-cellular diffusion channels in tissues. Spatial cellular heterogeneities over the scale of track spacing have been constructed by incorporating random fluctuations in the connectivity among network sites. Results: We demonstrate the occurrence of phase separation among the tracks as the complexity in intra- and inter-cellular structural increases. At the weak limit of disorder, such as in water and normal tissue, neighboring tracks melt into each other and form a percolated network of nonreactive species. In contrast, at the strong limit of disorder, tracks evolve individually like isolated islands with negligible inter-track overlap. Thus, the spatio-temporal correlation among the chemical domains decreases as the inter-cellular complexity of the tissue increases (e.g. from normal tissue to fractal-type malignant tissue). Conclusions: The differential sparing of FLASH UHDR in normal and tumor tissue may be explained by differences in inter- and intra-cellular structural complexities between the tissue types. The structural complexities of cancerous cells prevent clustering and chemical interaction of tracks, whereas this interaction prevails and thus leads to sparing in normal tissue

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

Synchrotron-generated microbeams induce hippocampal transections in rats

Synchrotron-generated microplanar beams (microbeams) provide the most stereo-selective irradiation modality known today. This novel irradiation modality has been shown to control seizures originating from eloquent cortex causing no neurological deficit in experimental animals. To test the hypothesis that application of microbeams in the hippocampus, the most common source of refractory seizures, is safe and does not induce severe side effects, we used microbeams to induce transections to the hippocampus of healthy rats. An array of parallel microbeams carrying an incident dose of 600 Gy was delivered to the rat hippocampus. Immunohistochemistry of phosphorylated gamma-H2AX showed cell death along the microbeam irradiation paths in rats 48 hours after irradiation. No evident behavioral or neurological deficits were observed during the 3-month period of observation. MR imaging showed no signs of radio-induced edema or radionecrosis 3 months after irradiation. Histological analysis showed a very well preserved hippocampal cytoarchitecture and confirmed the presence of clear-cut microscopic transections across the hippocampus. These data support the use of synchrotron-generated microbeams as a novel tool to slice the hippocampus of living rats in a minimally invasive way, providing (i) a novel experimental model to study hippocampal function and (ii) a new treatment tool for patients affected by refractory epilepsy induced by mesial temporal sclerosis

Evaluation of a pixelated large format CMOS sensor for x-ray microbeam radiotherapy

PURPOSE: Current techniques and procedures for dosimetry in microbeams typically rely on radiochromic film or small volume ionization chambers for validation and quality assurance in 2D and 1D, respectively. Whilst well characterized for clinical and preclinical radiotherapy, these methods are noninstantaneous and do not provide real time profile information. The objective of this work is to determine the suitability of the newly developed vM1212 detector, a pixelated CMOS (complementary metal-oxide-semiconductor) imaging sensor, for in situ and in vivo verification of x-ray microbeams.METHODS: Experiments were carried out on the vM1212 detector using a 220 kVp small animal radiation research platform (SARRP) at the Helmholtz Centre Munich. A 3 x 3 cm2 square piece of EBT3 film was placed on top of a marked nonfibrous card overlaying the sensitive silicon of the sensor. One centimeter of water equivalent bolus material was placed on top of the film for build-up. The response of the detector was compared to an Epson Expression 10000XL flatbed scanner using FilmQA Pro with triple channel dosimetry. This was also compared to a separate exposure using 450 µm of silicon as a surrogate for the detector and a Zeiss Axio Imager 2 microscope using an optical microscopy method of dosimetry. Microbeam collimator slits with range of nominal widths of 25, 50, 75, and 100 µm were used to compare beam profiles and determine sensitivity of the detector and both film measurements to different microbeams.RESULTS: The detector was able to measure peak and valley profiles in real-time, a significant reduction from the 24 hr self-development required by the EBT3 film. Observed full width at half maximum (FWHM) values were larger than the nominal slit widths, ranging from 130 to 190 µm due to divergence. Agreement between the methods was found for peak-to-valley dose ratio (PVDR), peak to peak separation and FWHM, but a difference in relative intensity of the microbeams was observed between the detectors.CONCLUSIONS: The investigation demonstrated that pixelated CMOS sensors could be applied to microbeam radiotherapy for real-time dosimetry in the future, however the relatively large pixel pitch of the vM1212 detector limit the immediate application of the results.</p