Dosimetric feasibility study ("proof of concept") of refractory ventricular tachycardia radioablation using proton minibeams.

PURPOSE: Preclinical data demonstrated that the use of proton minibeam radiotherapy reduces the risk of toxicity in healthy tissue. Ventricular tachycardia radioablation is an area under clinical investigation in proton beam therapy. We sought to simulate a ventricular tachycardia radioablation with proton minibeams and to demonstrate that it was possible to obtain a homogeneous coverage of an arrhythmogenic cardiac zone with this technique. MATERIAL AND METHODS: An arrhythmogenic target volume was defined on the simulation CT scan of a patient, localized in the lateral wall of the left ventricle. A dose of 25Gy was planned to be delivered by proton minibeam radiotherapy, simulated using a Monte Carlo code (TOPAS v.3.7) with a collimator of 19 0.4 mm-wide slits spaced 3mm apart. The main objective of the study was to obtain a plan ensuring at least 93% of the prescription dose in 93% of the planning target volume without exceeding 110% of the prescribed dose in the planning target volume. RESULTS: The average dose in the planning treatment volume in proton minibeam radiotherapy was 25.12Gy. The percentage of the planning target volume receiving 93% (V93%), 110% (V110%), and 95% (V95%) of the prescribed dose was 94.25%, 0%, and 92.6% respectively. The lateral penumbra was 6.6mm. The mean value of the peak-to-valley-dose ratio in the planning target volume was 1.06. The mean heart dose was 2.54Gy versus 5.95Gy with stereotactic photon beam irradiation. CONCLUSION: This proof-of-concept study shows that proton minibeam radiotherapy can achieve a homogeneous coverage of an arrhythmogenic cardiac zone, reducing the dose at the normal tissues. This technique, ensuring could theoretically reduce the risk of late pulmonary and breast fibrosis, as well as cardiac toxicity as seen in previous biological studies in proton minibeam radiotherapy.

RadioTransNet, Radiotherapy Translational and Preclinical Research Network: Results from the dedicated French cancer institute (INCa) call for projects.

PURPOSE: The RadioTransNet project is a French initiative structuring preclinical and translational research in radiation therapy for cancer at national level. The network's activities are organized around four chosen priorities, which are: target definition, normal tissue, combined treatments and dose modelling. The subtargets linked to these four major priorities are unlimited. They include all aspects associated with fundamental radiobiology, preclinical studies, imaging, medical physics research and transversal components clearly related to these scientific areas, such as medical oncology, radio-diagnostics, nuclear medicine and cost-effectiveness considerations. METHOD: During its first phase of activity, four workshops following the consensus conference model and based on scientific and medical state of the art in radiotherapy and radiobiology were organized on the four above-mentioned objectives to identify key points. Then a road map has been defined and served as the basis for the opening in 2022 of a dedicated call, SEQ-RTH22, proposed by the French cancer national institute (INCa). RESULTS: Four research projects submitted by RadioTransNet partners have been selected to be supported by INCa: the first by Professor Anne Laprie from Oncopole Claudius-Regaud and Inserm ToNic in Toulouse on neurocognition and health after pediatric irradiation, the second submitted by Fabien Milliat from IRSN aims to study decryption and targeting of endothelial cell-immune cells interactions to limit radiation-induced intestinal toxicity, the third project, submitted by Yolanda Prezado from institut Curie-CNRS on proton minibeam radiotherapy as a new approach to reduce toxicity, and the latest project proposed by R. de Crevoisier from centre Eugène-Marquis in Rennes on predictive multiscale models of head and neck radiotoxicity induced for optimized personalized radiation therapy. Topics of each of these projects are presented here. CONCLUSION: RadioTransNet project has been launched in 2018, supported by INCa, in order to structure and promote preclinical research in oncology radiotherapy and to favor collaboration between the actors of this research. INCa relied on RadioTransNet initiatives and activities, resulting in the opening of dedicated call for projects. Beyond its first main goals, RadioTransNet network is able to help to fund the human and technical resources necessary to conduct optimal translational and preclinical research in radiation oncology.

Novel unconventional radiotherapy techniques: Current status and future perspectives - Report from the 2nd international radiation oncology online seminar.

•Improvement of therapeutic ratio by novel unconventional radiotherapy approaches.•Immunomodulation using high-dose spatially fractionated radiotherapy.•Boosting radiation anti-tumor effects by adding an immune-mediated cell killing.

Scatter factors assessment in microbeam radiation therapy.

PURPOSE: The success of the preclinical studies in Microbeam Radiation Therapy (MRT) paved the way to the clinical trials under preparation at the Biomedical Beamline of the European Synchrotron Radiation Facility. Within this framework, an accurate determination of the deposited dose is crucial. With that aim, the scatter factors, which translate the absolute dose measured in reference conditions (2 × 2 cm(2) field size at 2 cm-depth in water) to peak doses, were assessed. METHODS: Monte Carlo (MC) simulations were performed with two different widely used codes, PENELOPE and GEANT4, for the sake of safety. The scatter factors were obtained as the ratio of the doses that are deposited by a microbeam and by a field of reference size, at the reference depth. The calculated values were compared with the experimental data obtained by radiochromic (ISP HD-810) films and a PTW 34070 large area chamber. RESULTS: The scatter factors for different microbeam field sizes assessed by the two MC codes were in agreement and reproduced the experimental data within uncertainty bars. Those correction factors were shown to be non-negligible for the future MRT clinical settings: an average 30% lower dose was deposited by a 50 µm microbeam with respect to the reference conditions. CONCLUSIONS: For the first time, the scatter factors in MRT were systematically studied. They constitute an essential key to deposit accurate doses in the forthcoming clinical trials in MRT. The good agreement between the different calculations and the experimental data confirms the reliability of this challenging micrometric dose estimation.

Development and commissioning of a Monte Carlo photon beam model for the forthcoming clinical trials in microbeam radiation therapy.

PURPOSE: A new radiotherapy technique, named microbeam radiation therapy (MRT), is under development at the ID17 Biomedical Beamline of the European Synchrotron Radiation Facility (ESRF). This innovative method is based on the fact that normal tissue can withstand high radiation doses in small volumes without any significant damage. The promising results obtained in the preclinical studies have paved the way to forthcoming clinical trials, which are currently in preparation. Highly accurate dose calculations at the treatment planning stage are required in this context. The aims of this study are the development and experimental benchmarking of a photon beam source model, which will be the core of the future MRT treatment planning system (TPS). METHODS: The ID17 x-ray source was modeled by the synchrotron ray tracing code SHADOW. The Monte Carlo (MC) simulation code PENELOPE/PENEASY was employed to transport the photon beam from the source to the patient position through all the beamline components. The phase-space state variables of the particles reaching the patient position were used as an input to generate a photon beam model. Computed dose distributions in a homogeneous media were experimentally verified by using Gafchromic(®) films in a solid-water phantom. Benchmarking was split into two phases. First, the lateral dose profiles and the percentage depth-dose (PDD) curves in the broad beam configuration were considered. The acceptability criteria for radiotherapy dose computations recommended by international protocols such as the Technical Reports Series 430 (TRS 430) of the International Atomic Energy Agency (IAEA) were used. Second, the analogous dosimetric magnitudes in MRT irradiations, i.e., PDD of the central microbeam and the corresponding peak-to-valley dose ratios (PVDR) were evaluated and compared with MC calculations. RESULTS: A full characterization of the ID17 Biomedical Beamline (ESRF) synchrotron x-ray source and the development of an accurate photon beam model were achieved in this work. Calculated and experimental dose distributions agreed to within the recommended acceptability criteria described in international codes of practice (TRS 430) for broad beam irradiations. The overall deviation in low gradient areas amounted to 2%-3%. The maximum distance-to-agreement in high gradient regions was lower than 0.7 mm. MC calculations also reproduced MRT experimental results within uncertainty bars. These results validate the photon beam model for its use in MRT radiation therapy calculations. CONCLUSIONS: The first MC synchrotron photon beam model for MRT irradiations that reproduces experimental dose distributions in homogeneous media has been developed. This beam model will constitute an essential component of the TPS calculation engine for patient dose computation in forthcoming MRT clinical trials.

Monte Carlo-based treatment planning system calculation engine for microbeam radiation therapy.

PURPOSE: Microbeam radiation therapy (MRT) is a synchrotron radiotherapy technique that explores the limits of the dose-volume effect. Preclinical studies have shown that MRT irradiations (arrays of 25-75-µm-wide microbeams spaced by 200-400 µm) are able to eradicate highly aggressive animal tumor models while healthy tissue is preserved. These promising results have provided the basis for the forthcoming clinical trials at the ID17 Biomedical Beamline of the European Synchrotron Radiation Facility (ESRF). The first step includes irradiation of pets (cats and dogs) as a milestone before treatment of human patients. Within this context, accurate dose calculations are required. The distinct features of both beam generation and irradiation geometry in MRT with respect to conventional techniques require the development of a specific MRT treatment planning system (TPS). In particular, a Monte Carlo (MC)-based calculation engine for the MRT TPS has been developed in this work. Experimental verification in heterogeneous phantoms and optimization of the computation time have also been performed. METHODS: The penelope/penEasy MC code was used to compute dose distributions from a realistic beam source model. Experimental verification was carried out by means of radiochromic films placed within heterogeneous slab-phantoms. Once validation was completed, dose computations in a virtual model of a patient, reconstructed from computed tomography (CT) images, were performed. To this end, decoupling of the CT image voxel grid (a few cubic millimeter volume) to the dose bin grid, which has micrometer dimensions in the transversal direction of the microbeams, was performed. Optimization of the simulation parameters, the use of variance-reduction (VR) techniques, and other methods, such as the parallelization of the simulations, were applied in order to speed up the dose computation. RESULTS: Good agreement between MC simulations and experimental results was achieved, even at the interfaces between two different media. Optimization of the simulation parameters and the use of VR techniques saved a significant amount of computation time. Finally, parallelization of the simulations improved even further the calculation time, which reached 1 day for a typical irradiation case envisaged in the forthcoming clinical trials in MRT. An example of MRT treatment in a dog's head is presented, showing the performance of the calculation engine. CONCLUSIONS: The development of the first MC-based calculation engine for the future TPS devoted to MRT has been accomplished. This will constitute an essential tool for the future clinical trials on pets at the ESRF. The MC engine is able to calculate dose distributions in micrometer-sized bins in complex voxelized CT structures in a reasonable amount of time. Minimization of the computation time by using several approaches has led to timings that are adequate for pet radiotherapy at synchrotron facilities. The next step will consist in its integration into a user-friendly graphical front-end.

Dosimetry protocol for the preclinical trials in white-beam minibeam radiation therapy.

PURPOSE: In the quest of a curative radiotherapy treatment for gliomas, new delivery modes are being explored. At the Biomedical Beamline of the European Synchrotron Radiation Facility, a new spatially fractionated technique, called minibeam radiation therapy (MBRT), is under development. The aims of this work were to assess different dosimetric aspects and to establish a dosimetry protocol to be applied in the forthcoming animal (rat) studies in order to evaluate the therapeutic index of this new radiotherapy approach. METHODS: Absolute dosimetry was performed with a thimble ionization chamber (PTW semiflex 31010) whose center was positioned at 2 g cm(-2) depth. To translate the dose measured in broad beam configuration to the dose deposited with a minibeam, the scatter factors were used. Those were assessed by using the Monte Carlo simulations and verified experimentally with Gafchromic films and a Bragg Peak chamber. The comparison of the theoretical and experimental data were used to benchmark the calculations. Finally, the dose distributions in a rat phantom were evaluated by using the validated Monte Carlo calculations. RESULTS: The absolute dosimetry in broad beam configuration was measured in reference conditions. The dose rate was in the range between 168 and 224 Gy∕min, depending on the storage ring current. A scatter factor of 0.80 ± 0.04 was obtained. Percentage depth dose and lateral profiles were evaluated both in homogenous and heterogeneous slab phantoms. The general good agreement between Monte Carlo simulations and experimental data permitted the benchmark of the calculations. Finally, the peak doses in the rat head phantom were assessed from the measurements in reference conditions. In addition, the peak-to-valley dose ratio values as a function of depth in the rat head were evaluated. CONCLUSIONS: A new promising radiotherapy approach is being explored at the ESRF: Minibeam Radiation Therapy. To assess the therapeutic index of this new modality, in vivo experiments are being planned, for which an accurate knowledge of the dosimetry is essential. For that purpose, a complete set of measurements and Monte Carlo simulations was performed. The first dosimetry protocol for preclinical trials in minibeam radiation therapy was established. This protocol allows to have reproducibility in terms of dose for the different biological studies.

Dosimetry protocol for the forthcoming clinical trials in synchrotron stereotactic radiation therapy (SSRT).

PURPOSE: An adequate dosimetry protocol for synchrotron radiation and the specific features of the ID17 Biomedical Beamline at the European Synchrotron Radiation Facility are essential for the preparation of the forthcoming clinical trials in the synchrotron stereotactic radiation therapy (SSRT). The main aim of this work is the definition of a suitable protocol based on standards of dose absorbed to water. It must allow measuring the absolute dose with an uncertainty within the recommended limits for patient treatment of 2%-5%. METHODS: Absolute dosimetry is performed with a thimble ionization chamber (PTW semiflex 31002) whose center is positioned at 2 g cm(-2) equivalent depth in water. Since the available synchrotron beam at the ESRF Biomedical Beamline has a maximum height of 3 mm, a scanning method was employed to mimic a uniform exposition of the ionization chamber. The scanning method has been shown to be equivalent to a broad beam irradiation. Different correction factors have been assessed by using Monte Carlo simulations. RESULTS: The absolute dose absorbed to water at 80 keV was measured in reference conditions with a 2% global uncertainty, within the recommended limits. The dose rate was determined to be in the range between 14 and 18 Gy/min, that is to say, a factor two to three times higher than the 6 Gy/min achievable in RapidArc or VMAT machines. The dose absorbed to water was also measured in a RW3 solid water phantom. This phantom is suitable for quality assurance purposes since less than 2% average difference with respect to the water phantom measurements was found. In addition, output factors were assessed for different field sizes. CONCLUSIONS: A dosimetry protocol adequate for the specific features of the SSRT technique has been developed. This protocol allows measuring the absolute dose absorbed to water with an accuracy of 2%. It is therefore satisfactory for patient treatment.

Secondary neutron dose contribution from pencil beam scanning, scattered and spatially fractionated proton therapy.

The Orsay Proton therapy Center (ICPO) has a long history of intracranial radiotherapy using both double scattering (DS) and pencil beam scanning (PBS) techniques, and is actively investigating a promising modality of spatially fractionated radiotherapy using proton minibeams (pMBRT). This work provides a comprehensive comparison of the organ-specific secondary neutron dose due to each of these treatment modalities, assessed using Monte Carlo (MC) algorithms and measurements. A MC model of a universal nozzle was benchmarked by comparing the neutron ambient dose equivalent,H*(10), in the gantry room with measurements obtained using a WENDI-II counter. The secondary neutron dose was evaluated for clinically relevant intracranial treatments of patients of different ages, in which secondary neutron doses were scored in anthropomorphic phantoms merged with the patients' images. The MC calculatedH*(10) values showed a reasonable agreement with the measurements and followed the expected tendency, in which PBS yields the lowest dose, followed by pMBRT and DS. Our results for intracranial treatments show that pMBRT yielded a higher secondary neutron dose for organs closer to the target volume, while organs situated furthest from the target volume received a greater quantity of neutrons from the passive scattering beam line. To the best of our knowledge, this is the first study to compare MC secondary neutron dose estimates in clinical treatments between these various proton therapy modalities and to realistically quantify the secondary neutron dose contribution of clinical pMBRT treatments. The method established in this study will enable epidemiological studies of the long-term effects of intracranial treatments at ICPO, notably radiation-induced second malignancies.

Treatment plans optimization for contrast-enhanced synchrotron stereotactic radiotherapy.

PURPOSE: Synchrotron stereotactic radiotherapy (SSRT) is a treatment that involves the targeting of high-Z elements into tumors followed by stereotactic irradiation with monochromatic x-rays from a synchrotron source, tuned at an optimal energy. The irradiation geometry, as well as the secondary particles generated at a higher yield by the medium energy x-rays on the high-Z atoms (characteristic x-rays, photoelectrons, and Auger electrons), produces a localized dose enhancement in the tumor. Iodine-enhanced SSRT with systemic injections of iodinated contrast agents has been successfully developed in the past six years in the team, and is currently being transferred to clinical trials. The purpose of this work is to study the impact on the SSRT treatment of the contrast agent type, the beam quality, the irradiation geometry, and the beam weighting for defining an optimized SSRT treatment plan. METHODS: Theoretical dosimetry was performed using the MCNPX particle transport code. The simulated geometry was an idealized phantom representing a human head. A virtual target was positioned in the central part of the phantom or off-centered by 4 cm. The authors investigated the dosimetric characteristics of SSRT for various contrast agents: Iodine, gadolinium, and gold; and for different beam qualities: Monochromatic x-ray beams from a synchrotron source (30-120 keV), polychromatic x-ray beams from an x-ray tube (80, 120, and 180 kVp), and a 6 MV x-ray beam from a linear accelerator. Three irradiation geometries were studied: One arc or three noncoplanar arcs dynamic arc therapy, and an irradiation with a finite number of beams. The resulting dose enhancements, beam profiles, and histograms dose volumes were compared for iodine-enhanced SSRT. An attempt to optimize the irradiation scheme by weighing the finite x-ray beams was performed. Finally, the optimization was studied on patient specific 3D CT data after contrast agent infusion. RESULTS: It was demonstrated in this study that an 80 keV beam energy was a good compromise for treating human brain tumors with iodine-enhanced SSRT, resulting in a still high dose enhancement factor (about 2) and a superior bone sparing in comparison with lower energy x-rays. This beam could easily be produced at the European Synchrotron Radiation Facility medical beamline. Moreover, there was a significant diminution of dose delivered to the bone when using monochromatic x-rays rather than polychromatic x-rays from a conventional tube. The data showed that iodine SSRT exhibits a superior sparing of brain healthy tissue in comparison to high energy treatment. The beam weighting optimization significantly improved the treatment plans for off-centered tumors, when compared to nonweighted irradiations. CONCLUSIONS: This study demonstrated the feasibility of realistic clinical plans for low energy monochromatic x-rays contrast-enhanced radiotherapy, suitable for the first clinical trials on brain metastasis with a homogeneous iodine uptake.

Effects of pulsed, spatially fractionated, microscopic synchrotron X-ray beams on normal and tumoral brain tissue.

Microbeam radiation therapy (MRT) uses highly collimated, quasi-parallel arrays of X-ray microbeams of 50-600keV, produced by third generation synchrotron sources, such as the European Synchrotron Radiation Facility (ESRF), in France. The main advantages of highly brilliant synchrotron sources are an extremely high dose rate and very small beam divergence. High dose rates are necessary to deliver therapeutic doses in microscopic volumes, to avoid spreading of the microbeams by cardiosynchronous movement of the tissues. The minimal beam divergence results in the advantage of steeper dose gradients delivered to a tumor target, thus achieving a higher dose deposition in the target volume in fractions of seconds, with a sharper penumbra than that produced in conventional radiotherapy. MRT research over the past 20 years has yielded many results from preclinical trials based on different animal models, including mice, rats, piglets and rabbits. Typically, MRT uses arrays of narrow ( approximately 25-100 microm wide) microplanar beams separated by wider (100-400 microm centre-to-centre) microplanar spaces. The height of these microbeams typically varies from 1 to 100 mm, depending on the target and the desired preselected field size to be irradiated. Peak entrance doses of several hundreds of Gy are surprisingly well tolerated by normal tissues, up to approximately 2 yr after irradiation, and at the same time show a preferential damage of malignant tumor tissues; these effects of MRT have now been extensively studied over nearly two decades. More recently, some biological in vivo effects of synchrotron X-ray beams in the millimeter range (0.68-0.95 mm, centre-to-centre distances 1.2-4 mm), which may differ to some extent from those of microscopic beams, have been followed up to approximately 7 months after irradiation. Comparisons between broad-beam irradiation and MRT indicate a higher tumor control for the same sparing of normal tissue in the latter, even if a substantial fraction of tumor cells are not receiving a radiotoxic level of radiation. The hypothesis of a selective radiovulnerability of the tumor vasculature versus normal blood vessels by MRT, and of the cellular and molecular mechanisms involved remains under investigation. The paper highlights the history of MRT including salient biological findings after microbeam irradiation with emphasis on the vascular components and the tolerance of the central nervous system. Details on experimental and theoretical dosimetry of microbeams, core issues and possible therapeutic applications of MRT are presented.

Minibeam radiation therapy: A micro- and nano-dosimetry Monte Carlo study.

PURPOSE: Minibeam radiation therapy (MBRT) is an innovative strategy based on a distinct dose delivery method that is administered using a series of narrow (submillimetric) parallel beams. To shed light on the biological effects of MBRT irradiation, we explored the micro- and nanodosimetric characteristics of three promising MBRT modalities (photon, electron, and proton) using Monte Carlo (MC) calculations. METHODS: Irradiation with proton (100 MeV), electron (300 MeV), and photon (effective energy of 69 keV) minibeams were simulated using Geant4 MC code and the Geant4-DNA extension, which allows the simulation of energy transfer points with nanometric accuracy. As the target of the simulations, cells containing spherical nuclei with or without a detailed description of the DNA (deoxyribonucleic acid) geometry were placed at different depths in peak and valley regions in a water phantom. The energy deposition and number of events in the cell nuclei were recorded in the microdosimetry study, and the number of DNA breaks and their complexity were determined in the nanodosimetric study, where a multi-scale simulation approach was used for the latter. For DNA damage assessment, an adapted DBSCAN clustering algorithm was used. To compare the photon MBRT (xMBRT), electron MBRT (eMBRT), and proton MBRT (pMBRT) approaches, we considered the treatment of a brain tumor located at a depth of 75 mm. RESULTS: Both mean energy deposition at micrometric scale and DNA damage in the "valley" cell nuclei were very low as compared with these parameters in the peak region at all depths for xMBRT and at depths of 0 to 30 mm and 0 to 50 mm for eMBRT and pMBRT, respectively. Only the charged minibeams were favorable for tumor control by producing similar effects in peak and valley cells after 70 mm. At the micrometer scale, the energy deposited per event pointed to a potential advantage of proton beams for tumor control, as more aggressive events could be expected at the end of their tracks. At the nanometer scale, all three MBRT modalities produced direct clustered DNA breaks, although the majority of damage (>93%) was composed of isolated single strand breaks. The pMBRT led to a significant increase in the proportion of clustered single strand breaks and double-strand breaks at the end of its range as compared to the entrance (7% at 75 mm vs 3% at 10 mm) in contrast to eMBRT and xMBRT. In the latter cases, the proportions of complex breaks remained constant, irrespective of the depth and region (peak or valley). CONCLUSIONS: Enhanced normal tissue sparing can be expected with these three MBRT techniques. Among the three modalities, pMBRT offers an additional gain for radioresistant tumors, as it resulted in a higher number of complex DNA damage clusters in the tumor region. These results can aid understanding of the biological mechanisms of MBRT.

First proton minibeam radiation therapy treatment plan evaluation.

Proton minibeam radiation therapy (pMBRT) is a novel dose delivery method based on spatial dose fractionation. pMBRT has been shown to be promising in terms of reduced side effects and superior tumour control in high-grade glioma-bearing rats compared to standard irradiation. These findings, together with the recent optimized implementation of pMBRT in a clinical pencil beam scanning system, have triggered reflection on the possible application to patient treatments. In this context, the present study was designed to conduct a first theoretical investigation of the clinical potential of this technique. For this purpose, a dedicated dose engine was developed and used to evaluate two clinically relevant patient treatment plans (high-grade glioma and meningioma). Treatment plans were compared with standard proton therapy plans assessed by means of a commercial treatment planning system (ECLIPSE-Varian Medical systems) and Monte Carlo simulations. A multislit brass collimator consisting of 0.4 mm wide slits separated by a centre-to-centre distance of 4 or 6 mm was placed between the nozzle and the patient to shape the planar minibeams. For each plan, spread-out Bragg peaks and homogeneous dose distributions (±7% dose variations) can be obtained in target volumes. The Peak-to-Valley Dose Ratios (PVDR) were evaluated between 9.2 and 12.8 at a depth of 20 mm for meningioma and glioma, respectively. Dose volume histograms (DVHs) for target volumes and organs at risk were quantitatively compared, resulting in a slightly better target homogeneity with standard PT than with pMBRT plans, but similar DVHs for deep-seated organs-at-risk and lower average dose for shallow organs. The proposed delivery method evaluated in this work opens the way to an effective treatment for radioresistant tumours and will support the design of future clinical research.

Minibeam radiation therapy at a conventional irradiator: Dose-calculation engine and first tumor-bearing animals irradiation.

PURPOSE: Minibeam radiation therapy (MBRT) is a novel therapeutic strategy, whose exploration was hindered due to its restriction to large synchrotrons. Our recent implementation of MBRT in a wide-spread small animal irradiator offers the possibility of performing systematic radiobiological studies. The aim of this research was to develop a set of dosimetric tools to reliably guide biological experiments in the irradiator. METHODS: A Monte Carlo (Geant4)-based dose calculation engine was developed. It was then benchmarked against a series of dosimetric measurements performed with gafchromic films. Two voxelized rat phantoms (ROBY, computer tomography) were used to evaluate the treatment plan of F98 tumor-bearing rats. The response of a group of 7 animals receiving a unilateral irradiation of 58 Gy was compared to a group of non-irradiated controls. RESULTS: The good agreement between calculations and the experimental data allowed the validation of the dose-calculation engine. The latter was first used to compare the dose distributions in computer tomography images of a rat's head and in a digital model of a rat's head (ROBY), obtaining a good general agreement. Finally, with respect to the in vivo experiment, the increase of mean survival time of the treated group with respect to the controls was modest but statistically significant. CONCLUSIONS: The developed dosimetric tools were used to reliably guide the first MBRT treatments of intracranial glioma-bearing rats outside synchrotrons. The significant tumor response obtained with respect to the non-irradiated controls, despite the heterogenous dose coverage of the target, might indicate the participation of non-targeted effects.

X-ray energy optimization in minibeam radiation therapy.

PURPOSE: The purpose of this work is to assess which energy in minibeam radiation therapy provides the best compromise between the deposited dose in the tumor and the sparing of the healthy tissues. METHODS: Monte Carlo simulations (PENELOPE 2006) have been used as a method to calculate the ratio of the peak-to-valley doses (PVDR) in the healthy tissues and in the tumor for different beam energies. The maximization of the ratio of PVDR in the healthy tissues and in the tumor has been used as a criterion. RESULTS: The main result of this work is that, for the parameters being used in preclinical trials (minibeam sizes of 600 microm and 1200 microm center-to-center separation), the optimum beam energy is 375 keV. CONCLUSIONS: The conclusion is that this is the energy of minibeams that should be used in the preclinical studies.

Gadolinium dose enhancement studies in microbeam radiation therapy.

Microbeam radiation therapy (MRT) is an innovative technique to treat brain tumors. The synchrotron generated x-ray beam, used for the treatment, is collimated and delivered in an array of narrow micrometer-sized planar rectangular fields. Several preclinical experiments performed at the Brookhaven National Laboratory (BNL) and at the European Synchrotron Radiation Facility (ESRF) have shown the sparing effect of the healthy tissue and the ablation of tumors in several animal models. It has also been determined that MRT yields a higher therapeutic index than nonsegmented beams of the same energy. This therapeutic index could be greatly improved by loading the tumor with high atomic number (Z) contrast agents. In this work, the dose enhancement factors and the peak to valley dose ratios (PVDRs) are assessed for different gadolinium (Z = 64) concentrations in the tumor and different microbeam energies by using Monte Carlo simulations (PENELOPE 2006 code). A significant decrease in the PVDR values in the tumor, and therefore a relevant increase in the dose deposition, is found in the presence of gadolinium. The optimum energy for the dose deposition in the tumor while keeping a high PVDR in the healthy tissues, which guaranties their sparing, has been investigated.

Biological equivalent dose studies for dose escalation in the stereotactic synchrotron radiation therapy clinical trials.

Synchrotron radiation is an innovative tool for the treatment of brain tumors. In the stereotactic synchrotron radiation therapy (SSRT) technique a radiation dose enhancement specific to the tumor is obtained. The tumor is loaded with a high atomic number (Z) element and it is irradiated in stereotactic conditions from several entrance angles. The aim of this work was to assess dosimetric properties of the SSRT for preparing clinical trials at the European Synchrotron Radiation Facility (ESRF). To estimate the possible risks, the doses received by the tumor and healthy tissues in the future clinical conditions have been calculated by using Monte Carlo simulations (PENELOPE code). The dose enhancement factors have been determined for different iodine concentrations in the tumor, several tumor positions, tumor sizes, and different beam sizes. A scheme for the dose escalation in the various phases of the clinical trials has been proposed. The biological equivalent doses and the normalized total doses received by the skull have been calculated in order to assure that the tolerance values are not reached.

Spatial fractionation of the dose in proton therapy: Proton minibeam radiation therapy.

In radiation therapy, a renewed interest is emerging for the study of spatially fractionated irradiation. In this article, a few applications using spatial fractionation of the dose will be discussed with a focus on proton minibeam radiation therapy. Examples of calculated dose (1D profiles and 2D dose distributions) and biological evidence obtained so far will be presented for various spatially fractionated techniques GRID, micro- and minibeam radiation therapy. Recent results demonstrating that proton minibeam radiation therapy leads to an increase in normal tissues sparing will be discussed, which opens the door to a dose escalation in the tumour and a possibly efficient treatment of very radioresistant tumours.

Spatial fractionation of the dose in heavy ions therapy: An optimization study.

PURPOSE: The alliance of charged particle therapy and the spatial fractionation of the dose, as in minibeam or Grid therapy, is an innovative strategy to improve the therapeutic index in the treatment of radioresistant tumors. The aim of this work was to assess the optimum irradiation configuration in heavy ion spatially fractionated radiotherapy (SFRT) in terms of ion species, beam width, center-to-center distances, and linear energy transfer (LET), information that could be used to guide the design of the future biological experiments. The nuclear fragmentation leading to peak and valley regions composed of different secondary particles, creates the need for a more complete dosimetric description that the classical one in SFRT. METHODS: Monte Carlo simulations (GATE 6.2) were performed to evaluate the dose distributions for different ions, beam widths, and spacings. We have also assessed the 3D-maps of dose-averaged LET and proposed a new parameter, the peak-to-valley-LET ratio, to offer a more thorough physical evaluation of the technique. RESULTS: Our results show that beam widths larger than 400 µm are needed in order to keep a ratio between the dose in the entrance and the dose in the target of the same order as in conventional irradiations. A large ctc distance (3500 µm) would favor tissue sparing since it provides higher PVDR, it leads to a reduced contribution of the heavier nuclear fragments and a LET value in the valleys a factor 2 lower than the LET in the ctc leading to homogeneous distributions in the target. CONCLUSIONS: Heavy ions MBRT provide advantageous dose distributions. Thanks to the reduced lateral scattering, the use of submillimetric beams still allows to keep a ratio between the dose in the entrance and the dose in the target of the same order as in conventional irradiations. Large ctc distances (3500 µm) should be preferred since they lead to valley doses composed of lighter nuclear fragments resulting in a much reduced dose-averaged LET values in normal tissue, favoring its preservation. Among the different ions species evaluated, Ne stands out as the one leading to the best balance between high PVDR and PVLR in normal tissues and high LET values (close to 100 keV/µm) and a favorable oxygen enhancement ratio in the target region.

Transfer of Minibeam Radiation Therapy into a cost-effective equipment for radiobiological studies: a proof of concept.

Minibeam radiation therapy (MBRT) is an innovative synchrotron radiotherapy technique able to shift the normal tissue complication probability curves to significantly higher doses. However, its exploration was hindered due to the limited and expensive beamtime at synchrotrons. The aim of this work was to develop a cost-effective equipment to perform systematic radiobiological studies in view of MBRT. Tumor control for various tumor entities will be addressable as well as studies to unravel the distinct biological mechanisms involved in normal and tumor tissues responses when applying MBRT. With that aim, a series of modifications of a small animal irradiator were performed to make it suitable for MBRT experiments. In addition, the brains of two groups of rats were irradiated. Half of the animals received a standard irradiation, the other half, MBRT. The animals were followed-up for 6.5 months. Substantial brain damage was observed in the group receiving standard RT, in contrast to the MBRT group, where no significant lesions were observed. This work proves the feasibility of the transfer of MBRT outside synchrotron sources towards a small animal irradiator.