Out-of-field doses for scanning proton radiotherapy of shallowly located paediatric tumours-a comparison of range shifter and 3D printed compensator.

The lowest possible energy of proton scanning beam in cyclotron proton therapy facilities is typically between 60 and 100 MeV. Treatment of superficial lesions requires a pre-absorber to deliver doses to shallower volumes. In most of the cases a range shifter (RS) is used, but as an alternative solution, a patient-specific 3D printed proton beam compensator (BC) can be applied. A BC enables further reduction of the air gap and consequently reduction of beam scattering. Such pre-absorbers are additional sources of secondary radiation. The aim of this work was the comparison of RS and BC with respect to out-of-field doses for a simulated treatment of superficial paediatric brain tumours. EURADOS WG9 performed comparative measurements of scattered radiation in the Proteus C-235 IBA facility (Cyclotron Centre Bronowice at the Institute of Nuclear Physics, CCB IFJ PAN, Kraków, Poland) using two anthropomorphic phantoms-5 and 10 yr old-for a superficial target in the brain. Both active detectors located inside the therapy room, and passive detectors placed inside the phantoms were used. Measurements were supplemented by Monte Carlo simulation of the radiation transport. For the applied 3D printed pre-absorbers, out-of-field doses from both secondary photons and neutrons were lower than for RS. Measurements with active environmental dosimeters at five positions inside the therapy room indicated that the RS/BC ratio of the out-of-field dose was also higher than one, with a maximum of 1.7. Photon dose inside phantoms leads to higher out-of-field doses for RS than BC to almost all organs with the highest RS/BC ratio 12.5 and 13.2 for breasts for 5 and 10 yr old phantoms, respectively. For organs closest to the isocentre such as the thyroid, neutron doses were lower for BC than RS due to neutrons moderation in the target volume, but for more distant organs like bladder-conversely-lower doses for RS than BC were observed. The use of 3D printed BC as the pre-absorber placed in the near vicinity of patient in the treatment of superficial tumours does not result in the increase of secondary radiation compared to the treatment with RS, placed far from the patient.

Study of the intracellular nanoparticle-based radiosensitization mechanisms in F98 glioma cells treated with charged particle therapy through synchrotron-based infrared microspectroscopy.

The use of nanoparticles (NP) as dose enhancers in radiotherapy (RT) is a growing research field. Recently, the use of NP has been extended to charged particle therapy in order to improve the performance in radioresistant tumors. However, the biological mechanisms underlying the synergistic effects involved in NP-RT approaches are not clearly understood. Here, we used the capabilities of synchrotron-based Fourier Transform Infrared Microspectroscopy (SR-FTIRM) as a bio-analytical tool to elucidate the NP-induced cellular damage at the molecular level and at a single-cell scale. F98 glioma cells doped with AuNP and GdNP were irradiated using several types of medical ion beams (proton, helium, carbon and oxygen). Differences in cell composition were analyzed in the nucleic acids, protein and lipid spectral regions using multivariate methods (Principal Component Analysis, PCA). Several NP-induced cellular modifications were detected, such as conformational changes in secondary protein structures, intensity variations in the lipid CHx stretching bands, as well as complex DNA rearrangements following charged particle therapy irradiations. These spectral features seem to be correlated with the already shown enhancement both in the DNA damage response and in the reactive oxygen species (ROS) production by the NP, which causes cell damage in the form of protein, lipid, and/or DNA oxidations. Vibrational features were NP-dependent due to the NP heterogeneous radiosensitization capability. Our results provided new insights into the molecular changes in response to NP-based RT treatments using ion beams, and highlighted the relevance of SR-FTIRM as a useful and precise technique for assessing cell response to innovative radiotherapy approaches.

A synchrotron-based infrared microspectroscopy study on the cellular response induced by gold nanoparticles combined with X-ray irradiations on F98 and U87-MG glioma cell lines.

The inclusion of nanoparticles (NP) in radiotherapy has been shown to increase the damaging effect on tumor cells. However, the mechanisms of action of NP combined with radiotherapy, and the influence of NP parameters and cell type on their radiosensitization capability at molecular and cellular levels still remain unclear. Gold NP (AuNP) have become particularly popular due to their multiple advantages. Within this context, our research work aimed to study the biochemical radiosensitization capacity of F98 and U87-MG glioma cell lines to 1.9 nm AuNP combined with X-ray irradiation. For this purpose, synchrotron-based infrared microspectroscopy (SR-FTIRM) was used as a powerful tool for biochemical composition and treatment response assessment of cells at a single-cell level. SR-FTIRM data, supported by multivariate analysis, revealed clear AuNP-induced changes in the DNA, protein and lipid spectral regions. The AuNP-related biochemical alterations appear prior to the irradiation, which gave us a first indication on the AuNP radiosensitization action. Biochemical modifications induced by the AuNP in the presence of radiotherapy irradiations include enhanced conformational changes in the protein secondary structures, variations in the intensity and position in the phosphodiester bands, and changes in the CH2 and CH3 stretching modes. These changes are better manifested at 24 hours post-irradiation time. SR-FTIRM results showed a clear heterogeneity in the biochemical cell response, probably due to the distinct cell-NP interactions and thus, to different DNA damage and cell death processes.

COMPARISON OF RESPONSE OF PASSIVE DOSIMETRY SYSTEMS IN SCANNING PROTON RADIOTHERAPY-A STUDY USING PAEDIATRIC ANTHROPOMORPHIC PHANTOMS.

Proton beam therapy has advantages in comparison to conventional photon radiotherapy due to the physical properties of proton beams (e.g. sharp distal fall off, adjustable range and modulation). In proton therapy, there is the possibility of sparing healthy tissue close to the target volume. This is especially important when tumours are located next to critical organs and while treating cancer in paediatric patients. On the other hand, the interactions of protons with matter result in the production of secondary radiation, mostly neutrons and gamma radiation, which deposit their energy at a distance from the target. The aim of this study was to compare the response of different passive dosimetry systems in mixed radiation field induced by proton pencil beam inside anthropomorphic phantoms representing 5 and 10 years old children. Doses were measured in different organs with thermoluminescent (MTS-7, MTS-6 and MCP-N), radiophotoluminescent (GD-352 M and GD-302M), bubble and poly-allyl-diglycol carbonate (PADC) track detectors. Results show that RPL detectors are the less sensitive for neutrons than LiF TLDs and can be applied for in-phantom dosimetry of gamma component. Neutron doses determined using track detectors, bubble detectors and pairs of MTS-7/MTS-6 are consistent within the uncertainty range. This is the first study dealing with measurements on child anthropomorphic phantoms irradiated by a pencil scanning beam technique.

Proton minibeam radiation therapy: Experimental dosimetry evaluation.

PURPOSE: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy (RT) approach that allies the inherent physical advantages of protons with the normal tissue preservation observed when irradiated with submillimetric spatially fractionated beams. This dosimetry work aims at demonstrating the feasibility of the technical implementation of pMBRT. This has been performed at the Institut Curie - Proton Therapy Center in Orsay. METHODS: Proton minibeams (400 and 700 µm-width) were generated by means of a brass multislit collimator. Center-to-center distances between consecutive beams of 3200 and 3500 µm, respectively, were employed. The (passive scattered) beam energy was 100 MeV corresponding to a range of 7.7 cm water equivalent. Absolute dosimetry was performed with a thimble ionization chamber (IBA CC13) in a water tank. Relative dosimetry was carried out irradiating radiochromic films interspersed in a IBA RW3 slab phantom. Depth dose curves and lateral profiles at different depths were evaluated. Peak-to-valley dose ratios (PVDR), beam widths, and output factors were also assessed as a function of depth. RESULTS: A pattern of peaks and valleys was maintained in the transverse direction with PVDR values decreasing as a function of depth until 6.7 cm. From that depth, the transverse dose profiles became homogeneous due to multiple Coulomb scattering. Peak-to-valley dose ratio values extended from 8.2 ± 0.5 at the phantom surface to 1.08 ± 0.06 at the Bragg peak. This was the first time that dosimetry in such small proton field sizes was performed. Despite the challenge, a complete set of dosimetric data needed to guide the first biological experiments was achieved. CONCLUSIONS: pMBRT is a novel strategy in order to reduce the side effects of RT. This works provides the experimental proof of concept of this new RT method: clinical proton beams might allow depositing a (high) uniform dose in a brain tumor located in the center of the brain (7.5 cm depth, the worst scenario), while a spatial fractionation of the dose is retained in the normal tissues in the beam path, potentially leading to a gain in tissue sparing. This is the first complete experimental implementation of this promising technique. Biological experiments are needed in order to confirm the clinical potential of pMBRT.

Evaluation of the local dose enhancement in the combination of proton therapy and nanoparticles.

PURPOSE: The outcome of radiotherapy can be further improved by combining irradiation with dose enhancers such as high-Z nanoparticles. Since 2004, spectacular results have been obtained when low-energy x-ray irradiations have been combined with nanoparticles. Recently, the same combination has been explored in hadron therapy. In vitro studies have shown a significant amplification of the biological damage in tumor cells charged with nanoparticles and irradiated with fast ions. This has been attributed to the increase in the ionizations and electron emissions induced by the incident ions or the electrons in the secondary tracks on the high-Z atoms, resulting in a local energy deposition enhancement. However, this subject is still a matter of controversy. Within this context, the main goal of the authors' work was to provide new insights into the dose enhancement effects of nanoparticles in proton therapy. METHODS: For this purpose, Monte Carlo calculations (gate/geant4 code) were performed. In particular, the geant4-DNA toolkit, which allows the modeling of early biological damages induced by ionizing radiation at the DNA scale, was used. The nanometric radial energy distributions around the nanoparticle were studied, and the processes (such as Auger deexcitation or dissociative electron attachment) participating in the dose deposition of proton therapy treatments in the presence of nanoparticles were evaluated. It has been reported that the architecture of Monte Carlo calculations plays a crucial role in the assessment of nanoparticle dose enhancement and that it may introduce a bias in the results or amplify the possible final dose enhancement. Thus, a dosimetric study of different cases was performed, considering Au and Gd nanoparticles, several nanoparticle sizes (from 4 to 50 nm), and several beam configurations (source-nanoparticle distances and source sizes). RESULTS: This Monte Carlo study shows the influence of the simulations' parameters on the local dose enhancement and how more realistic configurations lead to a negligible increase of local energy deposition. The obtained dose enhancement factor was up to 1.7 when the source was located at the nanoparticle surface. This dose enhancement was reduced when the source was located at further distances (i.e., in more realistic situations). Additionally, no significant increase in the dissociative electron attachment processes was observed. CONCLUSIONS: The authors' results indicate that physical effects play a minor role in the amplification of damage, as a very low dose enhancement or increase of dissociative electron attachment processes is observed when the authors get closer to more realistic simulations. Thus, other effects, such as biological or chemical processes, may be mainly responsible for the enhanced radiosensibilization observed in biological studies. However, more biological studies are needed to verify this hypothesis.

Spatial fractionation of the dose using neon and heavier ions: A Monte Carlo study.

PURPOSE: This work explores a new radiation therapy approach which might trigger a renewed use of neon and heavier ions to treat cancers. These ions were shown to be extremely efficient in radioresistant tumor killing. Unfortunately, the efficient region also extends into the normal tissue in front of the tumor. The strategy the authors propose is to profit from the well-established sparing effect of thin spatially fractionated beams, so that the impact on normal tissues might be minimized while a high tumor control is achieved. The main goal of this work is to provide a proof of concept of this new approach. With that aim, a dosimetric study was carried out as a first step to evaluate the interest of further explorations of this avenue. METHODS: The gate/geant4 v.6.1 Monte Carlo simulation platform was employed to simulate arrays of rectangular minibeams (700 µm × 2 cm) of four ions (Ne, Si, Ar, and Fe). The irradiations were performed with a 2 cm-long spread-out Bragg peak centered at 7 cm-depth. Dose distributions in a water phantom were scored considering two minibeams center-to-center distances: 1400 and 3500 µm. Peak and valley doses, peak-to-valley dose ratios (PVDRs), beam penumbras, and relative contribution of nuclear fragments and electromagnetic processes were assessed as figures of merit. In addition, the type and proportion of the secondary nuclear fragments were evaluated in both peak and valley regions. RESULTS: Extremely high PVDR values (>100) and low valley doses were obtained. The higher the atomic number (Z) of the primary ion is, the lower the valleys and the narrower the penumbras. Although the yield of secondary nuclear products increases with Z, the actual dose being deposited by the secondary nuclear fragments in the valleys starts to be the dominant contribution at deeper points, helping in the sparing of proximal normal tissues. Additionally, a wider center-to-center distance leads to a minimized contribution of heavier secondary fragments in valleys. CONCLUSIONS: The computed dose distributions suggest that a spatial fractionation of the dose combined to the use of submillimetric field sizes might allow profiting from the high efficiency of neon and heavier ions for the treatment of radioresistant tumors, while preserving normal tissues. The authors' results support the further exploration of this avenue. Next steps include the realization of biological experiment to confirm the shifting of normal tissue complication probability curves.

Technical note: Implementation of biological washout processes within GATE/GEANT4--a Monte Carlo study in the case of carbon therapy treatments.

PURPOSE: The imaging of positron emitting isotopes produced during patient irradiation is the only in vivo method used for hadrontherapy dose monitoring in clinics nowadays. However, the accuracy of this method is limited by the loss of signal due to the metabolic decay processes (biological washout). In this work, a generic modeling of washout was incorporated into the GATE simulation platform. Additionally, the influence of the washout on the ß(+) activity distributions in terms of absolute quantification and spatial distribution was studied. METHODS: First, the irradiation of a human head phantom with a (12)C beam, so that a homogeneous dose distribution was achieved in the tumor, was simulated. The generated (11)C and (15)O distribution maps were used as ß(+) sources in a second simulation, where the PET scanner was modeled following a detailed Monte Carlo approach. The activity distributions obtained in the presence and absence of washout processes for several clinical situations were compared. RESULTS: Results show that activity values are highly reduced (by a factor of 2) in the presence of washout. These processes have a significant influence on the shape of the PET distributions. Differences in the distal activity falloff position of 4 mm are observed for a tumor dose deposition of 1 Gy (Tini = 0 min). However, in the case of high doses (3 Gy), the washout processes do not have a large effect on the position of the distal activity falloff (differences lower than 1 mm). The important role of the tumor washout parameters on the activity quantification was also evaluated. CONCLUSIONS: With this implementation, GATE/GEANT4 is the only open-source code able to simulate the full chain from the hadrontherapy irradiation to the PET dose monitoring including biological effects. Results show the strong impact of the washout processes, indicating that the development of better models and measurement of biological washout data are essential.

Dosimetric evaluation of new approaches in GRID therapy using nonconventional radiation sources.

PURPOSE: Spatial fractionation of the dose has proven to be a promising approach to increase the tolerance of healthy tissue, which is the main limitation of radiotherapy. A good example of that is GRID therapy, which has been successfully used in the management of large tumors with low toxicity. The aim of this work is to explore new avenues using nonconventional sources: GRID therapy by using kilovoltage (synchrotron) x-rays, the use of very high-energy electrons, and proton GRID therapy. They share in common the use of the smallest possible grid sizes in order to exploit the dose-volume effects. METHODS: Monte Carlo simulations (penelope/peneasy and geant4/GATE codes) were used as a method to study dose distributions resulting from irradiations in different configurations of the three proposed techniques. As figure of merit, percentage (peak and valley) depth dose curves, penumbras, and central peak-to-valley dose ratios (PVDR) were evaluated. As shown in previous biological experiments, high PVDR values are requested for healthy tissue sparing. A superior tumor control may benefit from a lower PVDR. RESULTS: High PVDR values were obtained in the healthy tissue for the three cases studied. When low energy photons are used, the treatment of deep-seated tumors can still be performed with submillimetric grid sizes. Superior PVDR values were reached with the other two approaches in the first centimeters along the beam path. The use of protons has the advantage of delivering a uniform dose distribution in the tumor, while healthy tissue benefits from the spatial fractionation of the dose. In the three evaluated techniques, there is a net reduction in penumbra with respect to radiosurgery. CONCLUSIONS: The high PVDR values in the healthy tissue and the use of small grid sizes in the three presented approaches might constitute a promising alternative to treat tumors with such spatially fractionated radiotherapy techniques. The dosimetric results presented here support the interest of performing radiobiology experiments in order to evaluate these new avenues.

Minibeam radiation therapy for the management of osteosarcomas: a Monte Carlo study.

PURPOSE: Minibeam radiation therapy (MBRT) exploits the well-established tissue-sparing effect provided by the combination of submillimetric field sizes and a spatial fractionation of the dose. The aim of this work is to evaluate the feasibility and potential therapeutic gain of MBRT, in comparison with conventional radiotherapy, for osteosarcoma treatments. METHODS: Monte Carlo simulations (PENELOPE/penEasy code) were used as a method to study the dose distributions resulting from MBRT irradiations of a rat femur and a realistic human femur phantoms. As a figure of merit, peak and valley doses and peak-to-valley dose ratios (PVDR) were assessed. Conversion of absorbed dose to normalized total dose (NTD) was performed in the human case. Several field sizes and irradiation geometries were evaluated. RESULTS: It is feasible to deliver a uniform dose distribution in the target while the healthy tissue benefits from a spatial fractionation of the dose. Very high PVDR values (⩾20) were achieved in the entrance beam path in the rat case. PVDR values ranged from 2 to 9 in the human phantom. NTD(2.0) of 87 Gy might be reached in the tumor in the human femur while the healthy tissues might receive valley NTD(2.0) lower than 20 Gy. The doses in the tumor and healthy tissues might be significantly higher and lower than the ones commonly delivered used in conventional radiotherapy. CONCLUSIONS: The obtained dose distributions indicate that a gain in normal tissue sparing might be expected. This would allow the use of higher (and potentially curative) doses in the tumor. Biological experiments are warranted.

Monte Carlo-based dose calculation engine for minibeam radiation therapy.

Minibeam radiation therapy (MBRT) is an innovative radiotherapy approach based on the well-established tissue sparing effect of arrays of quasi-parallel micrometre-sized beams. In order to guide the preclinical trials in progress at the European Synchrotron Radiation Facility (ESRF), a Monte Carlo-based dose calculation engine has been developed and successfully benchmarked with experimental data in anthropomorphic phantoms. Additionally, a realistic example of treatment plan is presented. Despite the micron scale of the voxels used to tally dose distributions in MBRT, the combination of several efficiency optimisation methods allowed to achieve acceptable computation times for clinical settings (approximately 2 h). The calculation engine can be easily adapted with little or no programming effort to other synchrotron sources or for dose calculations in presence of contrast agents.

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.

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.

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.

Monte Carlo dose enhancement studies in microbeam radiation therapy.

PURPOSE: A radical radiation therapy treatment for gliomas requires extremely high absorbed doses resulting in subsequent deleterious side effects in healthy tissue. Microbeam radiation therapy (MRT) is an innovative technique based on the fact that normal tissue can withstand high radiation doses in small volumes without any significant damage. The synchrotron-generated x-ray beam is collimated and delivered to 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) confirmed that MRT yields a higher therapeutic index than nonsegmented beams of the same characteristics. This index can be greatly improved by loading the tumor with high atomic number (Z) contrast agents. The aim of this work is to find the high-Z element that provides optimum dose enhancement. METHODS: Monte Carlo simulations (PENELOPE/penEasy) were performed to assess the peak and valley doses as well as their ratio (PVDR) in healthy tissue and in the tumor, loaded with different contrast agents. The optimization criteria used were maximization of the ratio between the PVDR values in healthy tissue respect to the PVDR in the tumor and minimization of bone and brain valley doses. RESULTS: Dose enhancement factors, PVDR, and valley doses were calculated for different high-Z elements. A significant decrease of PVDR values in the tumor, accompanied by a gain in the valley doses, was found in the presence of high-Z elements. This enables the deposited dose in the healthy tissue to be reduced. The optimum high-Z element depends on the irradiation configuration. As a general trend, the best outcome is provided by the highest Z contrast agents considered, i.e., gold and thallium. However, lanthanides (especially Lu) and hafnium also offer a satisfactory performance. CONCLUSIONS: The remarkable therapeutic index in microbeam radiation therapy can be further improved by loading the tumor with a high-Z element. This study reports quantitative data on several dosimetric magnitudes in order to find the optimum contrast agent. Although the final choice of the element will also depend on possible cytotoxicity, three elements were found to be worthy of mention: gold, thallium, and lutetium.

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.

Monte Carlo dosimetry for forthcoming clinical trials in x-ray microbeam radiation therapy.

The purpose of this work is to define safe irradiation protocols in microbeam radiation therapy. The intense synchrotron-generated x-ray beam used for the treatment is collimated and delivered in an array of 50 microm-sized rectangular fields with a centre-to-centre distance between microplanes of 400 microm. The absorbed doses received by the tumour and the healthy tissues in a human head phantom have been assessed by means of Monte Carlo simulations. The identification of safe dose limits is carried out by evaluating the maximum peak and valley doses achievable in the tumour while keeping the valley doses in the healthy tissues under tolerances. As the skull receives a significant fraction of the dose, the dose limits are referred to this tissue. Dose distributions with high spatial resolution are presented for various tumour positions, skull thicknesses and interbeam separations. Considering a unidirectional irradiation (field size of 2 x 2 cm(2)) and a centrally located tumour, the largest peak and valley doses achievable in the tumour are 55 Gy and 2.6 Gy, respectively. The corresponding maximum valley doses received by the skin, bone and healthy brain are 4 Gy, 14 Gy and 7 Gy (doses in one fraction), respectively, i.e. within tolerances (5% probability of complication within 5 years).