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Background: Very high‐energy electrons (VHEE) radiotherapy, in the energy range of 100–200 MeV is currently considered a promising technique for the future of radiation therapy and could benefit from the promises of ultra‐high dose rate FLASH therapy. However, to our knowledge, no analytical calculation models have been tested for this type of application and the approximations proposed for multiple scattering with electron beams have not been extensively evaluated at these high energies. Purpose: In this work, we discuss the derivation of a simple and fast algorithm based on the Fermi‐Eyges theory of multiple Coulomb scattering for fast dose calculation for VHEE beams (up to 200 MeV). Similar to the Gaussian pencil beam models used for electron or proton beams, this pencil beam kernel is separated into a central and an off‐axis term. Monte Carlo simulations are performed to compare the analytical calculations with simulations and to determine the parametrizations used in the model at the highest electron energies. Methods: The normalized electron planar fluence distribution is described in water according to the Fermi‐Eyges theory of multiple Coulomb scattering and a double Gaussian distribution model. The main quantities used in the model and their calculation (mass angular scattering power, mean energy, range straggling) are discussed and tested for electron energies up to 200 MeV. The TOPAS/Geant4 Monte Carlo (MC) toolkit is used to compare analytical calculations with MC simulations for a theoretical pencil beam irradiation and to find the best parameters describing the range straggling. The model is then tested on a realistic simulation of a pencil beam scanning beamline with treatment field dimensions up to 15 × 15 cm2 and for deep‐seated targets. Results: Radial dose distributions of a pencil beam in water were calculated with the model and compared with the results of a complete Monte Carlo simulation. A good agreement (within 2%/2 mm gamma passing rate superior to 90%, and a mean deviation between calculated and simulated pencil beam radial spread smaller than 0.6 mm) was observed between analytical dose distributions and simulations for energies up to 200 MeV and field sizes up to 15 × 15 cm2. Conclusions: A parameterization of an electron source and an analytical pencil beam model were proposed in this work, thereby allowing a suitable reproduction of the lateral fluence of a VHEE beam and good agreement between calculations and simulated data. Further improvement of the method would require the consideration of a model describing the large‐angle scattering of the electrons. The results of this work could support future research into VHEE radiotherapy and might be of interest for use together with VHEE broad beams produced by scanned narrow pencil beams. [ABSTRACT FROM AUTHOR]

Background: Electrons with kinetic energy up to a few hundred MeV, also called very high energy electrons (VHEE), are currently considered a promising technique for the future of radiation therapy (RT) and in particular ultra‐high dose rate (UHDR) therapy. However, the feasibility of a clinical application is still being debated and VHEE therapy remains an active area of research for which the optimal conformal technique is also yet to be determined. Purpose: In this work, we will apply two existing formalisms based on analytical Gaussian multiple‐Coulomb scattering theory and Monte Carlo (MC) simulations to study and compare the electron and bremsstrahlung photon dose distributions arising from two beam delivery systems (passive scattering with or without a collimator or active scanning). Methods: We therefore tested the application of analytical and MC models to VHEE beams and assessed their performance and parameterization in the energy range of 6–200 MeV. The optimized electron beam fluence, the bremsstrahlung, an estimation of central‐axis and off‐axis x‐ray dose at the practical range and neutron contributions to the total dose, along with an extended parameterization for the photon dose model were developed, together with a comparison between double scattering (DS) and pencil beam scanning (PBS) techniques. MC simulations were performed with the TOPAS/Geant4 toolkit to verify the dose distributions predicted by the analytical calculations. Results: The results for the clinical energy range (between 6 and 20 MeV) as well as for higher energies (VHEE range between 20 and 200 MeV) and for two treatment field sizes (5 × 5 and 10 × 10 cm2) are reported, showing a reasonable agreement with MC simulations with mean differences below 2.1%. The relative contributions of photons generated in the medium or by the scattering system along the central‐axis (up to 50% of the total dose) are also illustrated, along with their relative variations with electron energy. Conclusions: The fast analytical models parametrized in this study allow an estimation of the amount of photons produced behind the practical range by a DS system with an accuracy lower than 3%, providing important information for the eventual design of a VHEE system. The results of this work could support future research on VHEE radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy approach that has shown a significant increase in the therapeutic window in glioma-bearing rats compared to conventional proton therapy. Such preclinical results encourage the preparation of clinical trials. Purpose: In this study, the potential of pMBRT for treating clinical indications candidates for the first clinical trials (i.e., brain, lung, and liver metastases) was evaluated. Methods: Four clinical cases, initially treated with stereotactic radiotherapy (SRT),were selected for this study.pMBRT,SRT,and conventional proton therapy (PT) dose distributions were compared by using three main criteria: (i) the tumor coverage, (ii) the mean dose to organs-at-risk, and (iii) the possible adverse effects in normal tissues by considering valley doses as the responsible for tissue sparing. pMBRT plans consisted of one fraction and one–two fields. Dose calculations were computed by means of Monte Carlo simulations. Results: pMBRT treatments provide a similar or superior target coverage than SRT, even using fewer fields. pMBRT also significantly reduces the biologically effective dose (BED) to organs-at-risk. In addition, valley and mean doses to normal tissues remain below tolerance limits when treatments are delivered in a single fraction, contrary to PT treatments. Conclusions: This work provides a first insight into the possibility of treating metastases with pMBRT. More favorable dose distributions and treatment delivery regimes may be expected from this new approach than SRT.The advantages of pMBRT would need to be confirmed by means of Phase I clinical trials. [ABSTRACT FROM AUTHOR]

Background: Empirical data in proton therapy indicate that relative biological effectiveness (RBE) is not constant, and it is directly related to the linear energy transfer (LET). The experimental assessment of LET with high resolution would be a powerful tool for minimizing the LET hot spots in intensity‐modulated proton therapy, RBE‐ or LET‐guided evaluation and optimization to achieve biologically optimized proton plans, verifying the theoretical predictions of variable proton RBE models, and so on. This could impact clinical outcomes by reducing toxicities in organs at risk. Purpose: The present work shows the first 2D LET maps obtained at a proton therapy facility using the double scattering delivery mode in clinical conditions by means of new silicon 3D‐cylindrical microdetectors. Methods: The device consists of a matrix of 121 independent silicon‐based detectors that have 3D‐cylindrical electrodes of 25‐µm diameter and 20‐µm depth, resulting each one of them in a well‐defined micrometric radiation sensitive volume etched inside the silicon. They have been specifically designed for a hadron therapy, improving the performance of current silicon‐based microdosimeters. Microdosimetry spectra were obtained at different positions of the Bragg curve by using a water‐equivalent phantom along an 89‐MeV pristine proton beam generated in the Y1 proton passive scattering beamline of the Orsay Proton Therapy Centre (Institut Curie, France). Results: Microdosimetry 2D‐maps showing the variation of the lineal energy with depth in the three dimensions were obtained in situ during irradiation at clinical fluence rates (∼108 s−1 cm−2) for the first time with a spatial resolution of 200 µm, the highest achieved in the transverse plane so far. The experimental results were cross‐checked with Monte Carlo simulations and a good agreement between the spectra shapes was found. The experimental frequency‐mean lineal energy values in silicon were 1.858 ± 0.019 keV µm−1 at the entrance, 2.61 ± 0.03 keV µm−1 at the proximal distance, 4.97 ± 0.05 keV µm−1 close to the Bragg peak, and 8.6 ± 0.1 keV µm−1 at the distal edge. They are in good agreement with the expected trends in the literature in clinical proton beams. Conclusions: We present the first 2D microdosimetry maps obtained in situ during irradiation at clinical fluence rates in proton therapy. Our results show that the arrays of 3D‐cylindrical microdetectors are a reliable microdosimeter to evaluate LET maps not only in the longitudinal axis of the beam, but also in the transverse plane allowing for LET characterization in three dimensions. This work is a proof of principle showing the capacity of our system to deliver LET 2D maps. This kind of experimental data is needed to validate variable proton RBE models and to optimize LET‐guided plans. [ABSTRACT FROM AUTHOR]

Purpose: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy approach that has shown a significant increase in the therapeutic window in glioma‐bearing rats compared to conventional proton therapy. The dosimetry of pMBRT is challenging and error prone due to the submillimetric beamlet sizes used. The aim of this study was to perform a robustness analysis on the setup parameters utilized in current preclinical trials and provide guidelines for reproducible dosimetry. The results of this work are intended to guide upcoming implementations of pMBRT worldwide, as well as pave the way for future clinical implementations. Methods: Monte Carlo simulations and experimental data were used to evaluate the impact of variations in setup parameters and uncertainties in collimator specifications on lateral pMBRT dose distributions. The value of each parameter was modified individually to evaluate their effect on dose distributions. Experimental dosimetry was performed by means of high‐resolution detectors, that is, radiochromic films, the IBA Razor and the Microdiamond detector. New guidelines were proposed to optimize the experimental setup in pMBRT studies and perform reproducible dosimetry. Results: The sensitivity of dose distributions to uncertainties and variations in setup parameters was quantified. Quantities that define pMBRT lateral profiles (i.e., the peak‐to‐valley dose ratio [PVDR], peak and valley doses, and peak width) are significantly influenced by small‐scale fluctuations in several of those parameters. The setup implemented at the Orsay proton therapy center for pMBRT irradiation was optimized to increase PVDRs and peak symmetry. In addition, we proposed guidelines to perform accurate and reproducible dosimetry in preclinical studies. Conclusions: This study revealed the importance of adopting guidelines and protocols tailored to the distinct dose delivery method and dose distributions in pMBRT. This new methodology leads to reproducible dosimetry, which is imperative in preclinical trials. The results and guidelines presented in this manuscript can ease the initiation of pMBRT investigations in other centers. [ABSTRACT FROM AUTHOR]

Purpose: Proton minibeam radiation therapy (pMBRT) is an innovative approach that combines the advantages of minibeam radiation therapy with the more precise ballistics of protons to further reduce the side effects of radiation. One of the main challenges of this approach is the generation of very narrow proton pencil beams with an adequate dose‐rate to treat patients within a reasonable treatment time (several minutes) in existing clinical facilities. The aim of this study was to demonstrate the feasibility of implementing pMBRT by combining the pencil beam scanning (PBS) technique with the use of multislit collimators. This proof of concept study of pMBRT with a clinical system is intended to guide upcoming biological experiments. Methods: Monte Carlo simulations (TOPAS v3.1.p2) were used to design a suitable multislit collimator to implement planar pMBRT for conventional pencil beam scanning settings. Dose distributions (depth‐dose curves, lateral profiles, Peak‐to‐Valley Dose Ratio (PVDR) and dose‐rates) for different proton beam energies were assessed by means of Monte Carlo simulations and experimental measurements in a water tank using commercial ionization chambers and a new p‐type silicon diode, the IBA RAZOR. An analytical intensity‐modulated dose calculation algorithm designed to optimize the weight of individual Bragg peaks composing the field was also developed and validated. Results: Proton minibeams were then obtained using a brass multislit collimator with five slits measuring 2 cm × 400 μm in width with a center‐to‐center distance of 4 mm. The measured and calculated dose distributions (depth‐dose curves and lateral profiles) showed a good agreement. Spread‐out Bragg peaks (SOBP) and homogeneous dose distributions around the target were obtained by means of intensity modulation of Bragg peaks, while maintaining spatial fractionation at shallow depths. Mean dose‐rates of 0.12 and 0.09 Gy/s were obtained for one iso‐energy layer and a SOBP conditions in the presence of multislit collimator. Conclusions: This study demonstrates the feasibility of implementing pMBRT on a PBS system. It also confirms the reliability of RAZOR detector for pMBRT dosimetry. This newly developed experimental methodology will support the design of future preclinical research with pMBRT. [ABSTRACT FROM AUTHOR]

Hadron therapy is an innovative mode of radiotherapy (RT) for cancer treatment which enables tumor cells to be more effectively destroyed than conventional RT using photons. The precise knowledge of the lineal energy of particles is used in the field of microdosimetry (MKM model) as a fundamental parameter in the prediction of the relative biological efficiency (RBE) of clinical beams. Based on single‐crystal CVD (scCVD) super‐thin diamond membranes obtained using deep Ar/O2 plasma etching, prototypes of solid‐state microdosimeters for lineal energy measurements are produced at the Diamond Sensors Laboratory of CEA‐LIST. The response of a diamond membrane microdosimeter to single projectiles is investigated in ion microbeams. The microdosimeter is irradiated using a raster scanning method and the charge transport properties of the device are determined with sub‐micron precision by measuring the charge collection efficiency (CCE), the μSVs 3D spatial definition and the pulse‐height spectra. A prototype of this novel microdosimeter is then tested in a 100 MeV therapeutic proton beam at the Institute Curie − Proton Therapy Centre in Orsay. All results effectively demonstrate the great potential for this device to be used for studies of the RBE in clinical applications. Active micro‐sensitive volumes (μSVs) of the tested scCVD diamond membrane based microdosimeter. The colored pixels represent detected ion hits (interactions/pixel) during the ion beam induced charge − IBIC − collection study at AIFIRA facility in CENBG, Bordeaux in France. [ABSTRACT FROM AUTHOR]