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Introduction: Charged Particle Therapy plays a key role in the treatment of deep-seated tumours, because of the advantageous energy deposition culminating in the Bragg peak. However, knowledge of the dose delivered in the entrance channel is limited by the lack of data on the beam and fragmentation of the target.Methods: The FOOT experiment has been designed to measure the cross sections of the nuclear fragmentation of projectile and target with two different detectors: an electronic setup for the identification of Z ≥ 3 fragments and a nuclear emulsion spectrometer for Z ≤ 3 fragments. In this paper, we analyze the data taken by exposing four nuclear emulsion spectrometers, with C and C2H4 targets, to 200 MeV/n and 400 MeV/n oxygen beams at GSI Helmholtzzentrum für Schwerionenforschung (Darmstadt, Germany), and we report the charge identification of produced fragments based on the controlled fading induced on nuclear emulsion films.Results: The goal of identifying fragments as heavy as lithium has been achieved.Discussion: The results will contribute to a better understanding of the nuclear fragmentation process in charged particle therapy and have implications for refining treatment planning in the presence of deep-seated tumors.

The study of nuclear fragmentation plays a central role in many important applications: from the study of Particle Therapy (PT) up to radiation protection for space (RPS) missions and the design of shielding for nuclear reactors. The FragmentatiOn Of Target (FOOT) collaboration aims to study the nuclear reactions that describe the interactions with matter of different light ions (like H1, He4, C12, O16) of interest for such applications, performing double differential fragmentation cross section measurements in the energy range of interest for PT and RPS. In this manuscript, we present the analysis of the data collected in the interactions of an oxygen ion beam of 400 MeV/u with a graphite target using a partial FOOT setup, at the GSI Helmholtz Center for Heavy Ion Research facility in Darmstadt. During the data taking the magnets, the silicon trackers and the calorimeter foreseen in the final FOOT setup were not yet available, and hence precise measurements of the fragments kinetic energy, momentum and mass were not possible. However, using the FOOT scintillator detectors for the time of flight (TOF) and energy loss (ΔE) measurements together with a drift chamber, used as beam monitor, it was possible to measure the elemental fragmentation cross sections. The reduced detector set-up and the limited available statistics allowed anyway to obtain relevant results, providing statistically significant measurements of cross sections eagerly needed for PT and RPS applications. Whenever possible the obtained results have been compared with existing measurements helping in discriminating between conflicting results in the literature and demonstrating at the same time the proper functioning of the FOOT ΔE-TOF system. Finally, the obtained fragmentation cross sections are compared to the Monte Carlo predictions obtained with the FLUKA software.

In microdosimetry, lineal energies y are calculated from energy depositions ϵ inside the microdosimeter divided by the mean chord length, whose value is based on geometrical assumptions on both the detector and the radiation field. This work presents an innovative two-stages hybrid detector (HDM: hybrid detector for microdosimetry) composed by a tissue equivalent proportional counter and a silicon tracker made of 4 low gain avalanche diode. This design provides a direct measurement of energy deposition in tissue as well as particles tracking with a submillimeter lateral spatial resolution. The data collected by the detector allow to obtain the real track length traversed by each particle in the tissue equivalent proportional counter and thus estimates microdosimetry spectra without the mean chord length approximation. Using Geant4 toolkit, we investigated HDM performances in terms of detection and tracking efficiencies when placed in water and exposed to protons and carbon ions in the therapeutic energy range. The results indicate that the mean chord length approximation underestimate particles with short track, which often are characterized by a high energy deposition and thus can be biologically relevant. Tracking efficiency depends on the low gain avalanche diode configurations: 34 strips sensors have a higher detection efficiency but lower spatial resolution than 71 strips sensors. Further studies will be performed both with Geant4 and experimentally to optimize the detector design on the bases of the radiation field of interest.The main purpose of HDM is to improve the assessment of the radiation biological effectiveness via microdosimetric measurements, exploiting a new definition of the lineal energy (yT), defined as the energy deposition ϵ inside the microdosimeter divided by the real track length of the particle.

Different qualities of radiation are known to cause different biological effects at the same absorbed dose. Enhancements of the biological effectiveness are a direct consequence of the energy deposition clustering at the scales of DNA molecule and cell nucleus whilst absorbed dose is a macroscopic averaged quantity which does not take into account heterogeneities at the nanometer and micrometer scales. Microdosimetry aims to measure radiation quality at cellular or sub-cellular levels trying to increase the understanding of radiation damage mechanisms and effects. Existing microdosimeters rely on the well-established gas-based detectors or the more recent solid-state devices. They provide specific energy z spectra and other derived quantities as lineal energy (y) spectra assessed at the micrometer level. The interpretation of the radio-biological experimental data in the framework of different models has raised interest and various investigations have been performed to link in vitro and in vivo radiobiological outcomes with the observed microdosimetric data. A review of the major models based on experimental microdosimetry, with a particular focus on ion beam therapy applications and an emphasis on the microdosimetric kinetic model (MKM), will be presented in this work, enlightening the advantages of each one in terms of accuracy, initial assumptions, and agreement with experimental data. The MKM has been used to predict different kinds of radiobiological quantities such as the relative biological effects for cell inactivation or the oxygen enhancement ratio. Recent developments of the MKM will be also presented, including new non-Poissonian correction approaches for high linear energy transfer radiation, the inclusion of partial repair effects for fractionation studies, and the extension of the model to account for non-targeted effects. We will also explore developments for improving the models by including track structure and the spatial damage correlation information, by using the full fluence spectrum and by better accounting for the energy-deposition fluctuations at the intra- and inter-cellular level.

High-Z material nanoparticles are being studied as localized dose enhancers in radiotherapeutic applications. Here, the nano-scale physical dose enhancement of proton, carbon and oxygen ion beam radiation by gold nanoparticles was studied by means of Monte Carlo track structure simulation with the TRAX code. We present 2D distributions and radial profiles of the additional dose and the dose enhancement factor for two geometries which consider an isolated and a water-embedded nanoparticle, respectively. Different nanoparticle sizes (radius of 1.2–22 nm) were found to yield qualitatively different absolute and relative dose enhancement distributions and different maximum dose enhancement factors (up to 20). Whereas the smallest nanoparticles produced the highest local dose enhancement factor close to the metal, larger ones led to lower, more diffuse dose enhancement factors that contributed more at larger distances. Differential absorption effects inside the metal were found to be responsible for those characteristics. For the energy range 15–204 MeVu−1, also a mild trend with ion E/A, regardless of the ion species, was found for embedded nanoparticles. In analogy to the width of the ion track itself, slower ions increased the enhancement at the nanoparticle surface. In contrast, no dependence on linear energy transfer was encountered. For slower ions (3–10 MeVu−1), the enhancement effect began to break down over all distances. Finally, the significance of any indirect physical effect was excluded, giving important hints especially in view of the low probabilities (at realistic concentrations and fluences) of direct ion-NP-hits. The very localized nature of the physical dose enhancement found suggests a strong action upon targets closeby, but no relevant effect at cellular distances. When pondering different possible damage enhancement mechanisms of gold nanoparticles in the context of published in vitro and in vivo experimental results, biological pathways are likely to play the key role. [ABSTRACT FROM AUTHOR]

This work aims at measuring experimentally proton induced secondary electron energy spectra after interaction with gold nano particles (GNPs) and polymer-coated GNPs. Backscattered electron energy spectra were collected over a 0 to 1000 eV energy range using a retarding field analyzer (RFA). This paper presents the spectra obtained for proton beam energies of 0.5 and 2 MeV and diameter 2.5 and 3.8 nm GNPs. The spectra were also measured for 3.8 nm GNPs after 5 and 10 MeV proton irradiations. GNPs were deposited on a 100 nm carbon film. Each experimental spectrum was compared with dedicated simulations based on existing numerical models used in the TRAX and Geant4 Monte Carlo codes. For 100 nm carbon target, good agreement between experimental, TRAX and Geant4 simulation results can be observed. For 3.8 nm GNPs, the TRAX simulations reproduce with good agreement the electron energy spectra produced after 0.5, 2, 5 and 10 MeV proton irradiations, while Geant4 spectra display a lower secondary electron yield at low energy (<600 eV) for all the studied energies. This underestimation can mostly be explained by the 790 eV threshold applied in the condensed history model used by Geant4 which impacts the secondary electron energy distribution. Results obtained for carbon and gold targets highlight the impact of the secondary electron production threshold for proton ionization process considered in condensed history models. The experimental results demonstrate that the single interaction approach used in TRAX is adapted to reproduce secondary electron emission from GNPs. On the other hand, the standard electron generation threshold implement in G4BetheBlochModel and G4BraggModel condensed-history models used in Geant4 is not adapted to reproduce low energy electron emission in gold targets. Finally, the results highlight that the GNP coating leads to a decrease of the electron yield and mostly affects low energy electrons (<500 eV) emitted from GNPs. [ABSTRACT FROM AUTHOR]

In protontherapy, it has been suggested that nanoparticles of high-Z material like gold (GNP) could be used as radiosensitizers. The origin of this enhancement phenomenon for proton radiation is not yet well understood and additional mechanistic insights are required. Previous works have highlighted the good capabilities of TRAX to reproduce secondary electron emission from gold material. Therefore, TRAX cross sections obtained with the binary encounter approximation (BEA) model for proton ionization were implemented within Geant4 for gold material. Based on the TRAX cross sections, improved Geant4 simulations have been developed to investigate the energy deposition and radical species production around a spherical gold nanoparticle (5 and 10 nm in diameter) placed in a water volume during proton irradiation. Simulations were performed for incident 2 MeV proton. The dose enhancement factor and the radiolysis enhancement factor were quantified. Results obtained with the BEA model were compared with results obtained with condensed-history models. Experimental irradiation of 200 nm gold films were performed to validate the secondary electron emission reproduction capabilities of physical models used in Monte Carlo (MC) simulations. TRAX simulations reproduced the experimental backscattered electron energy spectrum from gold film with better agreement than Geant4. Results on gold film obtained with the BEA model enabled to estimate the electron emission from GNPs. Results obtained in our study tend to support that the use of the BEA discrete model leads to a significant increase of the dose in the near vicinity of GNPs (<20 nm), while condensed history models used in Geant4 seem to overestimate the dose and the number of chemical species for increasing distances from the GNP. Based on discrete BEA model results, no enhancement effect due to secondary electron emitted from the GNP is expected if the GNP is not in close proximity to key cellular functional elements (DNA, mitochondria…). [ABSTRACT FROM AUTHOR]

We report on a novel method for simultaneous biological optimization of treatment plans for hypoxic tumors using multiple ion species. Our previously introduced kill painting approach, where the overall cell killing is optimized on biologically heterogeneous targets, was expanded with the capability of handling different ion beams simultaneously. The current version (MIBO) of the research treatment planning system TRiP98 has now been augmented to handle 3D (voxel-by-voxel) target oxygenation data. We present a case of idealized geometries where this method can identify optimal combinations leading to an improved peak-to-entrance effective dose ratio. This is achieved by the redistribution of particle fluences, when the heavier ions are preferentially forwarded to hypoxic target areas, while the lighter ions deliver the remaining dose to its normoxic regions. Finally, we present an in silico skull base chordoma patient case study with a combination of 4He and 16O beams, demonstrating specific indications for its potential clinical application. In this particular case, the mean dose, received by the brainstem, was reduced by 3%–5% and by 10%–12% as compared to the pure 4He and 16O plans, respectively. The new method allows a full biological optimization of different ion beams, exploiting the capabilities of actively scanned ion beams of modern particle therapy centers. The possible experimental verification of the present approach at ion beam facilities disposing of fast ion switch is presented and discussed. [ABSTRACT FROM AUTHOR]

Nowadays there is a rising interest towards exploiting new therapeutical beams beyond carbon ions and protons. In particular, O ions are being widely discussed due to their increased LET distribution. In this contribution, we report on the first experimental verification of biologically optimized treatment plans, accounting for different biological effects, generated with the TRiP98 planning system with O beams, performed at HIT and GSI. This implies the measurements of 3D profiles of absorbed dose as well as several biological measurements. The latter includes the measurements of relative biological effectiveness along the range of linear energy transfer values from  ≈20 up to  ≈750 keV μ , oxygen enhancement ratio values and the verification of the kill-painting approach, to overcome hypoxia, with a phantom imitating an unevenly oxygenated target. With the present implementation, our treatment planning system is able to perform a comparative analysis of different ions, according to any given condition of the target. For the particular cases of low target oxygenation, O ions demonstrate a higher peak-to-entrance dose ratio for the same cell killing in the target region compared to C ions. Based on this phenomenon, we performed a short computational analysis to reveal the potential range of treatment plans, where O can benefit over lighter modalities. It emerges that for more hypoxic target regions (partial oxygen pressure of  ≈0.15% or lower) and relatively low doses (≈4 Gy or lower) the choice of O over C or He may be justified. [ABSTRACT FROM AUTHOR]